WO2024108179A2 - 2-ethylamine substituted benzofuran and benzothiophene compositions for mental disorders or enhancement - Google Patents

2-ethylamine substituted benzofuran and benzothiophene compositions for mental disorders or enhancement Download PDF

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WO2024108179A2
WO2024108179A2 PCT/US2023/080391 US2023080391W WO2024108179A2 WO 2024108179 A2 WO2024108179 A2 WO 2024108179A2 US 2023080391 W US2023080391 W US 2023080391W WO 2024108179 A2 WO2024108179 A2 WO 2024108179A2
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compound
enantiomerically enriched
disorder
disease
pure enantiomer
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WO2024108179A3 (en
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Matthew J. BAGGOTT
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Tactogen Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms

Definitions

  • the present invention also includes more generally 2-ethylamine substituted benzofuran and benzothiophene compounds, compositions, and methods for modulating central nervous system activity and treating central nervous system disorders.
  • CNS Central nervous system
  • TBI traumatic brain injury
  • dementias dementias
  • headache disorders such as migraine, which affects about 15% of the general population or 47 million people.
  • TBI traumatic brain injury
  • dementias dementias
  • headache disorders such as migraine, which affects about 15% of the general population or 47 million people.
  • CNS disorders Many patients fail to benefit adequately from available treatments.
  • many available pharmacological treatments must be taken for weeks or months before the individual experiences therapeutic benefits. A number of potential new experimental treatments are under investigation.
  • Serotonin is incompletely understood but appears to adjust the stability of the individual's response to changing environmental conditions. As such, serotonin has been linked to mood, anxiety, and appetite.
  • Experimental treatment compounds include serotonin receptor agonists. Serotonin receptors have seven families. Many serotonin receptors are able to stimulate multiple signaling pathways within a cell, which can make it complicated to predict therapeutic effects.
  • Serotonin receptor types that have received recent attention for their therapeutic potential include 5-HT 2A , 5- HT2C, 5-HT1A, and 5-HT1B receptors.
  • 5-HT2A receptor agonists are being investigated as tools to potentially produce rapid therapeutic improvement in CNS disorders including depression, anxiety, and substance use disorders.
  • Compounds such as psilocybin and 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT), produce dramatic psychedelic effects resembling mystical experiences that may contribute to these therapeutic effects.
  • These compounds also produced labile mood and often invoke acute anxiety, which makes close monitoring of patients necessary. There is accordingly a need for 5-HT2A agonists that produce either minimal mood changes or reliably positive ones.
  • 5-HT 2A agonists such as 6-methoxy-N,N-dimethyltryptamine (6-MeO-DMT) and 7-fluoro-N,N-dimethyltryptamine (7-F-DMT) appear to produce therapeutic changes in animal models of depression without producing psychedelic effects (Dunlap et al.2020. Journal of medicinal chemistry, 63(3), pp.1142-1155). Both psychedelic and non-psychedelic 5- HT2A agonists may be useful in migraine, cluster headaches, and other headache disorders. The therapeutic mechanisms of 5-HT2A agonists are incompletely understood but may involve increased neuroplasticity (Ly et al.2018.
  • 5-HT 2A agonists Another potential therapeutic mechanism of 5-HT 2A agonists involves decreases in inflammation (e g., Flanagan, et al.2019. Life sci., 236, 116790).
  • Conditions that may benefit from improved anti-inflammatory treatment include rheumatoid and other forms of arthritis (such as enthesitis-related juvenile idiopathic arthritis, blau syndrome, and juvenile idiopathic arthritis), psoriasis, Crohn’s disease, inflammatory bowel syndrome, ulcerative colitis, and ankylosing spondylitis.
  • 5-HT 2C receptors are closely related to 5-HT 2A receptors, but have a different distribution in the brain and body. Compounds that stimulate 5-HT2C receptors have been proposed as treatments for psychiatric disorders as well as other disorders such as sexual dysfunction, obesity, and urinary incontinence.
  • Lorcaserin (Belviq) is a high affinity 5-HT 2C agonist that, until recently, was FDA-approved for use in conjunction with weight loss programs. The withdrawal of this medicine from the market because of increased risk of cancer highlights the need for safer serotonergic therapeutics that can stimulate 5-HT 2C receptors or otherwise aid weight loss.
  • 5-HT 1A receptor agonists modulate the functioning of dopamine and norepinephrine and decrease blood pressure and heart rate via a central mechanism.
  • Drugs that are 5-HT1A agonists have value for treating anxiety and depression.
  • buspirone (Buspar, Namanspin) is approved for anxiety disorders and may also be useful for treating hypoactive sexual desire disorder (HSDD).
  • HSDD hypoactive sexual desire disorder
  • Studies in rats indicate that 5-HT1A stimulation induces oxytocin release, which contributes to the social effects of 3,4-methylenedioxymethamphetamine (MDMA) (Thompson et al. 2007. Neuroscience, 146(2), pp.509-514).
  • MDMA 3,4-methylenedioxymethamphetamine
  • Compounds (or compound combinations) that include 5-HT 1A stimulation in their pharmacological profile are therefore expected to have therapeutic benefits in comparison to those that do not.
  • Compounds that stimulate 5-HT 1B receptors alter the release of neurotransmitters such as dopamine, serotonin, GABA, acetylcholine, and glutamate and can modulate stress sensitivity, mood, anxiety, and aggression.
  • 5-HT1B agonists such as sumatriptan (Imitrex) and zolmitriptan (Zomig) have been approved for treatment of headache disorders.
  • Studies in mice suggest 5-HT 1B stimulation on dopamine-containing neurons in the central striatum contributes to social effects of MDMA (Heifets et al. 2019. Science translational medicine, 11(522)).
  • 5-HT 1B agonists may have antidepressant effects. More broadly, there is evidence that stimulating 5-HT1B receptors can provide benefits to stress response, affect, and addiction (e.g., Fontaine et al.2021. Neuropsychopharmacology, pp.1-11). As with 5-HT1A receptors, compounds (or compound combinations) that include 5-HT 1B stimulation in their pharmacological profile are therefore expected to have therapeutic benefits in comparison to those that do not.
  • Another group of experimental compounds interact with brain monoamine transporters to increase extracellular concentrations of the three monoamine neurotransmitters. Some compounds increase extracellular concentrations of these molecules by inhibiting reuptake of neurotransmitters, while others induce release of neurotransmitters.
  • Patents and patent applications describing entactogenic compounds include WO 2021/252538, WO 2022/010937, WO 2022/032147, WO 2022/061242, WO 2023/081306, WO 2023/107653, WO 2023/107715, WO 2023/183613, and U.S. Pat. No.11,767,305, which are assigned to Tactogen Inc. Additional patent applications describing entactogenic compounds and methods of using entactogenic compounds include but are not limited to U.S. Pat.
  • a compound of the present invention can be used for mental enhancement or to treat a mental disorder comprising administering an effective amount of the compound to a host, typically a human, in need thereof.
  • the compound of the present invention or compositions described herein can interact with a neurotransmitter and can exhibit entactogenic properties when administered in an effective amount to a host, typically a human, in need thereof.
  • a compound described herein can be used as a fast acting and effective agent for modulating CNS activity and treating a CNS disorder described herein.
  • the embodiments of the invention are presented to meet the goal of assisting persons with mental disorders, who desire mental enhancement or suffer from other CNS disorders by providing milder therapeutics that are fast acting and that reduce the properties that decrease the patient experience, are counterproductive to the therapy, or are undesirably toxic.
  • One goal of the invention is to provide therapeutic compositions that increase empathy, sympathy, openness and acceptance of oneself and others, which can be taken, if necessary, as part of therapeutic counseling sessions, or when necessary, episodically, or even consistently, as prescribed by a healthcare provider.
  • a method of treating a patient with a mental disorder or providing mental enhancement comprising administering an effective amount of a 2-ethylamine substituted benzofuran or benzothiophene compound, pure enantiomer, or enantiomerically enriched mixture of Formula I or Formula II: II);
  • R B1 is selected from ;
  • R 1 , R 2 , and R 3 are in g of hydrogen, halogen, alkyl, aryl, cycloalkyl, haloalkyl, -OP(O)(OR 9 ) 2 , -SR 9 , -NR 9 R 10 , and -OR 9 ;
  • R 4 is selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, -CH 2 OR 11 , and -CH2CH2OR 11 ; in certain embodiments R 4 is selected from hydrogen, -CH 3 , -CH 2 X, -CHX 2 , -CX 3 ,
  • a method of treating a patient with primary or secondary headaches comprising administering an effective amount of a 2-ethylamine substituted benzofuran or benzothiophene compound, pure enantiomer, or enantiomerically enriched mixture of Formula I or Formula II.
  • an enantiomerically enriched mixture of Formula I or Formula II is provided: II); wherein the var
  • an enantiomerically or diasteromerically pure compound of Formula I or Formula II is provided.
  • Non-limiting examples of compounds of Formula I include enantiomerically enriched mixtures of R-Bk-2-MAPB or S-Bk-2-MAPB or a pharmaceutically acceptable salt or salt mixture thereof.
  • Additional examples of compounds of Formula I include enantiomerically enriched mixtures or pure enantiomers of R-Bk-2-EAPB or S-Bk-2-EAPB or a pharmaceutically acceptable salt or salt mixture thereof. riched mixtures of R-Bk-2-MAPBT or S-Bk-2-MAPBT or a pharmaceutically acceptable salt or salt mixture thereof. Additional exam de enantiomerically enriched mixtures of R-Bk-2-EAPBT or S-Bk-2-EAPBT or a pharmaceutically acceptable salt or salt mixture thereof. In certain embod is selected from: nd .
  • isolated enantiomers of the compounds of the present invention show improved binding at the desired receptors and transporters relevant to the goal of treatment of a mental disorder or for mental enhancement.
  • a tuned enantiomerically enriched mixture containing both R- and S-enantiomers in unequal amounts shows improved properties relevant to the goal of treatment of a mental disorder or for mental enhancement.
  • tuned enantiomerically enriched mixtures have fewer side effects than the corresponding pure enantiomers or racemate.
  • Non-limiting examples of unwanted effects that may be minimized by carefully selecting the balance of enantiomers in an enantiomerically enriched mixture include hallucinogenic effects, psychoactive effects (such as excess stimulation or sedation), physiological effects (such as transient hypertension or appetite suppression), toxic effects (such as to the brain or liver), effects contributing to abuse liability (such as euphoria or dopamine release), and/or other side effects.3
  • a 2-ethylamine substituted benzofuran or benzothiophene compound, pure enantiomer, or enantiomerically enriched mixture of Formula III-VIII or Formula IIIA-VIIIA is provided: V) I) II) A) or a pharm wherein: R 1A is selected from -H and -OH; R 1B is selected from -X, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -
  • the present invention thus includes at least the following aspects: (i) A method of treating a CNS disorder or providing mental enhancement comprising administering a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, pharmaceutical composition, isotopic derivative, or prodrug thereof; (ii) An enantiomerically enriched mixture of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof; (iii) A compound, enantiomerically enriched mixture, or pure enantiomer of Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, Formula IIIA, Formula IVA, Formula VA, Formula VIA, Formula VIIA, or Formula VIIIA or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof; (iv) A pharmaceutical composition comprising an effective patient-treating amount of a compound of (ii) or (iii) in a pharmaceutically acceptable carrier or diluent for any of the uses described herein; (v
  • the present invention includes an enantiomerically enriched compound of Formula I or Formula II, and compounds of Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, Formula IIIA, Formula IVA, Formula VA, Formula VIA, Formula VIIA, or Formula VIIIA or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug or pharmaceutically acceptable composition thereof, as well as methods for modulation of CNS activity, and for treatment of CNS disorders, including but not limited to post-traumatic stress, depression, adjustment disorders, addiction, anxiety and other mental disorders as described herein to a host such as a human in need thereof.
  • a compound of the present invention has advantageous pharmacological properties that are desirable as therapeutics for the treatment of mental disorders, particularly as psychotherapeutics and neurotherapeutics.
  • Non-limiting examples of 2-aminoethyl substituted benzofuran and benzothiophene compounds of the present invention include enantiomerically enriched mixtures of R-Bk-2-MAPB or S-Bk-2-MAPB or a pharmaceutically acceptable salt or salt mixture thereof.
  • 2-aminoethyl substituted benzofuran and benzothiophene compounds of the present invention include enantiomerically enriched mixtures or pure enantiomers of R-Bk-2-EAPB, S- Bk-2-EAPB, R-Bk-thio-2-MAPB, S-Bk-thio-2-MAPB, R-Bk-thio-2-EAPB, or S-Bk-thio-2- EAPB, or a pharmaceutically acceptable salt or salt mixture thereof.
  • drug EMCDDA-Europol 2014 Annual Report on the Implementation of Council Decision 2005/387/JHA.
  • racemic 2-MAPB The effect of racemic 2-MAPB on extracellular serotonin in living mouse striatum was studied by Fuwa et al., where it was shown to increase extracellular dopamine, serotonin, and norepinephrine (Fuwa et al. The Journal of Toxicological Sciences, 2016, 41(3), 329-337).
  • the related compound racemic 2-EAPB is also known as a recreational drug and was studied in rats by Sayson et al. to examine potential rewarding and reinforcing effects (Sayson et al. European Journal of Pharmacology 2020, 885, 173527). Sayson et al.
  • racemic 2-EAPB elicited addictive behavior, but at a higher dose than was necessary for the regioisomer 5-EAPB or methamphetamine. Brandt and colleagues reviewed certain properties of racemic (2 ⁇ aminopropyl) benzothiophene (Brandt et al., Drug testing and analysis, 2020 12(8):1109-25). Brandt et al. synthesized racemic 2-APBT, along with the five other positional isomers, and reported their physicochemical characteristics such as IR spectra or tandem mass spectrometry features, without biological data.
  • the embodiments of the invention are presented to meet the goal of assisting persons with mental disorders, who desire mental enhancement, or who suffer from other CNS disorders by providing milder therapeutics that are fast acting and that reduce the properties that decrease the patient experience, are counterproductive to the therapy, or are undesirably toxic.
  • One goal of the invention is to provide therapeutic compositions that increase empathy, sympathy, openness and acceptance of oneself and others, which can be taken, if necessary, as part of therapeutic counseling sessions, when necessary, episodically or even consistently, as prescribed by a healthcare provider.
  • DEFINITIONS When introducing elements of the present invention or the typical embodiments thereof, the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements.
  • the compounds of the invention may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
  • the compounds of the invention may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Unless otherwise indicated, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. Further, it should be understood when partial structures of the compounds of the invention are illustrated, that brackets or dashes indicate the point of attachment of the partial structure to the rest of the molecule. “Composition of the invention” refers to at least one compound of the invention and a pharmaceutically acceptable vehicle with which the compound is administered to a patient. When administered to a patient, the compounds of the invention are administered in isolated form, which means separated from a synthetic organic reaction mixture. In certain embodiments, an enantiomerically enriched compound is an enantiomerically enriched mixture or a pure enantiomer.
  • An enantiomerically enriched mixture is a mixture that contains one enantiomer in a greater amount than the other.
  • An enantiomerically enriched mixture of an S-enantiomer contains at least 55% of the S-enantiomer, and, typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more of the S-enantiomer and not more than 98%.
  • An enantiomerically enriched mixture of an R-enantiomer contains at least 55% of the R-enantiomer, and typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the R-enantiomer and not more than 98%.
  • the specific ratio of S or R enantiomer can be selected for the need of the patient according to the health care specialist to balance the desired effect.
  • the term enantiomerically enriched does not include a pure enantiomer.
  • the term enantiomerically enriched mixture as used in this application does not include a racemic mixture and does not include a pure isomer. Notwithstanding, it should be understood that any compound described herein in enantiomerically enriched form can be used as a pure isomer if it achieves the goal of any of the specifically itemized methods of treatment described herein, including but not limited to pure enantiomer or enantiomerically enriched mixture of Formula I, II, III, IV, V, VI, VII, or VIII.
  • enantiomerically pure refers to a compound with about 98% to 100% stereochemical purity.
  • CNS disorder refers to either a neurological condition (one that is typically treated by a neurologist) or a psychiatric condition (one that is typically treated by a psychiatrist).
  • Neurological disorders are typically those affecting the structure, biochemistry or normal electrical functioning of the brain, spinal cord or other nerves.
  • Psychiatric conditions are more typically thought of as mental disorders, which are primarily abnormalities of thought, feeling or behavior that cause significant distress or impairment of personal functioning.
  • the disclosed compounds can be used in an effective amount to improve neurological or psychiatric functioning in a patient in need thereof.
  • Neurological indications include, but are not limited to improved neuroplasticity, including treatment of stroke, brain trauma, dementia, and neurodegenerative diseases.
  • Compounds of the current invention can be considered psychoplastogens, that is, small molecules that are able to induce rapid neuroplasticity.
  • the disclosed compounds and compositions can be used to improve stuttering and other dyspraxias or to treat Parkinson’s disease or schizophrenia.
  • neurode or disorder includes Alzheimer’s disease, mild cognitive impairment (MCI), Parkinson’s disease, Parkinson’s disease dementia, multiple sclerosis, adrenoleukodystrophy, AIDS dementia complex, Alexander disease, Alper’s disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy, Canavan disease, cerebral amyloid angiopathy, cerebellar ataxia, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, diffuse myelinoclastic sclerosis, fatal familial insomnia, Fazio-Londe disease, Friedreich’s ataxia, frontotemporal dementia or lobar degeneration, hereditary spastic paraplegia, Huntington disease, Kennedy’s disease, Krabbe disease, Lewy body dementia, Lyme disease, Machado-Joseph disease, motor neuron disease, Multiple systems atrophy, neuroa
  • MCI mild
  • the term "improving psychiatric function" is intended to include mental health and life conditions that are not traditionally treated by neurologists but sometimes treated by psychiatrists and can also be treated by psychotherapists, life coaches, personal fitness trainers, meditation teachers, counselors, and the like.
  • the disclosed compounds will allow individuals to effectively contemplate actual or possible experiences that would normally be upsetting or even overwhelming. This includes individuals with fatal illness planning their last days and the disposition of their estate. This also includes couples discussing difficulties in their relationship and how to address them. This also includes individuals who wish to more effectively plan their career.
  • the term “inadequate functioning of neurotransmission” is used synonymously with a CNS disorder that adversely affects normal healthy neurotransmission.
  • the present invention also includes compounds, including enantiomerically enriched mixtures and their use, with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., isotopically enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 17 O, 18 O, 18 F, 36 Cl, and respectively.
  • isotopically labelled compounds can be used in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures that achieves the desired result.
  • isotopes of carbon e.g., 13 C and 14 C
  • isotopes of carbon e.g., 13 C and 14 C
  • Isotopic substitutions for example deuterium substitutions
  • Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
  • the isotope is at least 60, 70, 80, 90, 95 or 99% or more enriched in an isotope at any location of interest.
  • deuterium is 80, 90, 95 or 99% enriched at a desired location.
  • the deuterium is at least 80% at the selected location. Deuteration can occur at any replaceable hydrogen that provides the desired results.
  • the substitution of a hydrogen atom for a deuterium atom can be provided in a compounds or compositions described herein. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within a group selected from any of R B1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , and R 11 .
  • the alkyl residue may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc.).
  • the compounds of the invention also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature.
  • isotopes examples include 2 H, 3 H, 13 C, 14 C, 13 N, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • the methyl group on the nitrogen of a compound of Formula I or Formula II can be prepared with deuterium replacing some or all of the three hydrogens on the N-methyl group. This creates a higher activation energy for bond cleavage and a slower formation of the methyl metabolites.
  • the two hydrogens on the furan ring may be replaced with one or two deuteriums to decrease metabolic opening of the furan ring and formation of hydroxyl- substituted metabolites.
  • isotopically-labeled refers to an analog that is a "deuterated analog", a " 13 C-labeled analog,” or a “deuterated/ 13 C-labeled analog.”
  • deuterated analog means a compound described herein, whereby a H-isotope, i.e., hydrogen/protium ( 1 H), is substituted by a H-isotope, e.g., deuterium ( 2 H).
  • Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium.
  • the isotope is at least 60, 70, 8090, 95 or 99% or more enriched in an isotope at any location of interest. In some embodiments it is deuterium that is 90, 95 or 99% enriched at a desired location. Unless indicated to the contrary, the deuteration is at least 80% at the selected location. Deuteration of the nucleoside can occur at any replaceable hydrogen that provides the desired results.
  • Alkyl is a branched, straight chain, or cyclic saturated aliphatic hydrocarbon group including from 1 to about 8 carbon atoms, from 1 to about 6 carbon atoms, from 1 to about 4 carbon atoms, from 1 to 3 carbon atoms.
  • the alkyl is C1-C2, C1-C3, C1-C4, C 1 -C 5 or C 1 -C 6 .
  • the specified ranges as used herein indicate an alkyl group which is considered to explicitly disclose as individual species each member of the range described as a unique species.
  • the term C1-C6 alkyl as used herein indicates a straight or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and also a carbocyclic alkyl group of 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species.
  • C1-C4alkyl indicates a straight or branched alkyl group having 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2- methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, and hexyl.
  • Haloalkyl indicates both branched and straight-chain alkyl groups substituted with one or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2- fluoroethyl, and penta-fluoroethyl.
  • Halogen or “halo” means fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • halogens such as —CHX2 or —CX3, and for example “where X is halogen,” it will be understood that each X independently will be selected from the group of halogens.
  • Hydrox means the radical —OH.
  • Oxo means the divalent radical ⁇ O.
  • Stepoisomers includes enantiomers, diastereomers, the components of racemic mixtures, and combinations thereof. Stereoisomers can be prepared or separated as described herein or by using other methods. “Isomers” includes stereo and geometric isomers, as well as diastereomers. Examples of geometric isomers include cis isomers or trans isomers across a double bond.
  • “Agonism” refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.
  • “Agonist” refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response.
  • “5HT 1B agonist” can be used to refer to a compound that exhibits an EC50 with respect to 5HT1B activity of no more than about 10, 25 or even 50 ⁇ .
  • “agonist” includes full agonists or partial agonists.
  • “Full agonist” refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor.
  • “Partial agonist” refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist.
  • “Antagonism” refers to the inactivation of a receptor or enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and does not allow activity to occur.
  • “Antagonist” or “neutral antagonist” refers to a modulator that binds to a receptor or enzyme and blocks a biological response.
  • DAT to SERT ratio refers to the tendency of a substance (e.g., a compound or a drug) to increase extracellular dopamine versus increasing extracellular 5-HT concentrations. Higher numbers of this ratio indicate a greater increase of dopamine than serotonin, while lower number indicate an increasing 5-HT more than dopamine. The exact numbers depend on the assay used. The ratio is calculated herein as (DAT EC50) -1 /(SERT EC50) -1 .
  • IC50 refers to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process.
  • IC50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay.
  • EC50 refers to the concentration of a substance that provokes a response halfway between the baseline activity and maximum response. In some instances, an IC50 or EC50 is determined in an in vitro assay system.
  • IC 50 refers to the concentration of a modulator that is required for 50% inhibition (or excitation) of a receptor, for example, 5HT1B.
  • ‘‘Modulate” or “modulating” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule.
  • agonists, partial agonists, antagonists, and allosteric modulators e.g., positive allosteric modulator
  • a G protein-coupled receptor e.g., 5-HT1B
  • Neuroplasticity refers to the ability of the brain to change its structure and/or function throughout a subject’s life. Examples of the changes to the brain include, but are not limited to, the ability to adapt or respond to internal and/or external stimuli, such as due to an injury, and the ability to produce new neurites, dendritic spines, and synapses. “Treating” or “treatment” of a disease, as used in context, includes (i) inhibiting the disease, i.e., arresting or reducing the development or progression of the disease or its clinical symptoms; or (ii) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. Inhibiting the disease, for example, would include prophylaxis.
  • a therapeutic amount necessary to effect treatment for purposes of this invention will, for example, be an amount that provides for objective indicia of improvement in patients having clinically diagnosable symptoms.
  • Other such measurements, benefits, and surrogate or clinical endpoints, whether alone or in combination, would be understood to those of ordinary skill.
  • “Therapeutic effect” means the responses(s) in a mammal after treatment that are judged to be desirable and beneficial. Hence, depending on the CNS disorder to be treated, or improvement in CNS functioning sought, those responses shall differ, but would be readily understood by those of ordinary skill.
  • hallucinations or “hallucinogenic effects” includes but is not limited to perceptual distortions, delusions, depersonalization, derealization and/or labile mood. These effects can include dysphoria of intensities ranging from controllable anxiety to uncontrollable panic.
  • Non-limiting embodiments of the present invention the invention provides the enantiomerically enriched mixtures of R-Bk- 2-MAPB or S-Bk-2-MAPB.
  • the invention provides enantiomerically enriched mixtures or pure enantiomers of R-Bk-2-EAPB or S-Bk-2-EAPB or a pharmaceutically acceptable salt or salt mixture thereof.
  • a pharmaceutical composition comprising Bk-2-MAPB or Bk-2-EAPB or a pure R- or S-enantiomer or enantiomerically enriched mixture thereof: .
  • the invention provides a benzothiophene compound for example an enantiomerically enriched mixtures or pure enantiomers of or a pharmaceutically acce Additional examples of benzothiophene compounds include enantiomerically enriched mixtures or pure enantiomers of or a pharmaceutically a
  • isolated enantiomers of the compounds of the present invention show improved binding at the desired receptors and transporters relevant to the goal of treatment for the mental disorder or for mental enhancement.
  • An enantiomerically enriched mixture is a mixture that contains one enantiomer in a greater amount than the other.
  • An enantiomerically enriched mixture of an S-enantiomer contains at least 55% of the S-enantiomer, and, typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more of the S-enantiomer and not more than 98%.
  • An enantiomerically enriched mixture of an R-enantiomer contains at least 55% of the R-enantiomer, and typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the R-enantiomer and not more than 98%.
  • the specific ratio of S or R enantiomer can be selected for the need of the patient according to the health care specialist to balance the desired effect.
  • the term enantiomerically enriched mixture as used in this application does not include a racemic mixture and does not include a pure isomer. Notwithstanding, it should be understood that any compound described herein in enantiomerically enriched form can be used as a pure isomer (or a racemic form) if it achieves the goal of any of the specifically itemized methods of treatment described herein. It has been discovered that it is useful to have an S- or R-enantiomerically enriched mixture of these entactogenic compounds that is not a racemic mixture.
  • one aspect of the present invention is a balanced mixture of S-Bk-2-MAPB and R-Bk- 2-MAPB or a balanced mixture of S-Bk-2-EAPB and R-Bk-2-EAPB that achieves a predetermined combination of serotonin-receptor-dependent therapeutic effects and nicotinic-receptor-dependent or dopaminergic therapeutic effects.
  • the effect can be modulated as desired for optimal therapeutic effect.
  • unwanted effects that can be minimized by carefully selecting the balance of enantiomers include hallucinogenic effects (for example, perceptual distortions, delusions, depersonalization, derealization, and labile mood), psychoactive effects (including excess stimulation or sedation), physiological effects (including transient hypertension or appetite suppression), toxic effects (including to the brain or liver), effects contributing to abuse liability (including euphoria or dopamine release), and/or other side effects.
  • an enantiomerically enriched mixture of the S- enantiomer or pure enantiomer of S-Bk-2-MAPB or S-Bk-2-EAPB or an enantiomerically enriched mixture of the S-enantiomer or pure enantiomer of S-Bk-2-MAPB or S-Bk-2-EAPB balances therapeutic effects (such as emotional openness and perceptible mood effects) while having less effects associated with abuse liability (such as perceptible ‘good drug effects’ or desire for more drug, which can lead to abuse; Pool et al.2016.
  • the enantiomerically enriched mixture or pure enantiomer achieves a predetermined combination of emotional therapeutic effects and perceptible mood effects.
  • the effect can be modulated as desired for optimal therapeutic effect.
  • an enantiomerically enriched mixture of the R-enantiomer or pure enantiomer of R-Bk-2-MAPB or R-Bk-2-EAPB or an enantiomerically enriched mixture of the R- enantiomer or pure enantiomer of R-Bk-2-MAPB or R-Bk-2-EAPB balances therapeutic effects (such as emotional openness and perceptible mood effects) while having less effects associated with abuse liability (such as perceptible ‘good drug effects’ or desire for more drug, which can lead to abuse; Pool et al. 2016. Neuroscience & Biobehavioral Reviews, 63, pp.124-142) when administered to a host in need thereof, for example a mammal, including a human.
  • a compound of the present invention has favorable pharmacokinetic properties for administration to a mammal, for example a human. These properties can include having more reproducible and less variable pharmacokinetic properties than MDMA.
  • a compound of the present invention has a less variable maximum plasma concentration (Cmax) than MDMA.
  • a compound of the present invention has a less variable area-under-the-concentration-versus-time-curve (AUC) than MDMA.
  • An additional potential beneficial property of a compound of the present invention is reduced inhibition of CYP enzymes compared to MDMA. Inhibition of such enzymes can cause unwanted toxic drug-drug interactions.
  • a compound of the present invention does not inhibit or shows minimal inhibition of cytochrome p450 isozyme 2D6 (CYP2D6).
  • a compound of the present invention shows less potent inhibition of CYP2D6 than MDMA.
  • R 1A is selected from -H and -OH
  • R 1B is selected from -X, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl
  • R 2B is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C
  • an enantiomerically enriched mixture of the present invention is selected from: or a p y p . In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a parmaceutca y accepta e sat or sat mxture tereo.
  • an enantiomerically enriched mixture of the present invention is selected from: or a In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a parmaceu ca y accepa e sa or sa mxure ereo.
  • an enantiomerically enriched mixture of the present invention is selected from: or In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a pharmaceutica In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a p In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a pharmaceutica In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a ph In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a pharmaceutic Embodiments of “alkyl” In certain embodiments “alkyl” is a C1-C6alkyl, C1-C5alkyl, C1-C4alkyl, C1-C3alky
  • alkyl has one carbon. In certain embodiments “alkyl” has two carbons. In certain embodiments “alkyl” has three carbons. In certain embodiments “alkyl” has four carbons. In certain embodiments “alkyl” has five carbons. In certain embodiments “alkyl” has six carbons.
  • Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl. Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl.
  • alkyl examples include: sec-butyl, sec-pentyl, and sec-hexyl. Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl. Additional non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl. In certain embodiments when a term is used that includes “alk” it should be understood that “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context.
  • alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenloxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context.
  • haloalkyl is a C1-C6haloalkyl, C1-C5haloalkyl, C1-C4haloalkyl, C1-C3haloalkyl, and C1-C2haloalkyl.
  • haloalkyl has one carbon.
  • haloalkyl has one carbon and one halogen.
  • haloalkyl has one carbon and two halogens. In certain embodiments “haloalkyl” has one carbon and three halogens. In certain embodiments “haloalkyl” has two carbons. In certain embodiments “haloalkyl” has three carbons. In certain embodiments “haloalkyl” has four carbons. In certain embodiments “haloalkyl” has five carbons. In certain embodiments “haloalkyl” has six carbons.
  • Non-limiting examples of “haloalkyl” include . Additional non-limiting examples of “haloalk , Additional non-limiting examples of “haloalkyl” includ , and . Additional non-limiting examples of “haloalkyl” include: .
  • R 1 is hydrogen. In certain embodiments R 1 group is hydrogen. In certain embodiments R 1 is halogen. In certain embodiments R 1 is -F. In certain embodiments R 1 is -Cl. In certain embodiments R 1 is -Br. In certain embodiments R 1 is -I. In certain embodiments R 1 is alkyl. In certain embodiments R 1 is methyl. In certain embodiments R 1 is ethyl. In certain embodiments R 1 is n-propyl. In certain embodiments R 1 is isopropyl. In certain embodiments R 1 is haloalkyl. In certain embodiments R 1 is -CF 3 . In certain embodiments R 1 is -OP(O)(OR 9 )2.
  • R 1 is -OP(O)(OH)2. In certain embodiments R 1 is -SR 9 . In certain embodiments R 1 is -SH. In certain embodiments R 1 is -SCF3. In certain embodiments R 1 is -SMe. In certain embodiments R 1 is -NR 9 R 10 . In certain embodiments R 1 is -NHR 10 . In certain embodiments R 1 is -NH 2 . In certain embodiments R 1 is -NHMe. In certain embodiments R 1 is -N(Me)2. In certain embodiments R 1 is -OR 9 . In certain embodiments R 1 is -OH. In certain embodiments R 1 is -OCF3. In certain embodiments R 1 is -OCH3.
  • R 1 is selected from hydrogen, F, CH 3 , and -OMe.
  • R 2 is hydrogen.
  • R 2 group is hydrogen.
  • R 2 is halogen.
  • R 2 is -F.
  • R 2 is -Cl.
  • R 2 is -Br.
  • R 2 is -I.
  • R 2 is alkyl.
  • R 2 is methyl.
  • R 2 is ethyl.
  • R 2 is n-propyl.
  • R 2 is isopropyl.
  • R 2 is haloalkyl.
  • R 2 is -CF3.
  • R 2 is -OP(O)(OR 9 )2. In certain embodiments R 2 is -OP(O)(OH) 2 . In certain embodiments R 2 is -SR 9 . In certain embodiments R 2 is -SH. In certain embodiments R 2 is -SCF 3 . In certain embodiments R 2 is -SMe. In certain embodiments R 2 is -NR 9 R 10 . In certain embodiments R 2 is -NHR 10 . In certain embodiments R 2 is -NH 2 . In certain embodiments R 2 is -NHMe. In certain embodiments R 2 is -N(Me)2. In certain embodiments R 2 is -OR 9 . In certain embodiments R 2 is -OH.
  • R 2 is -OCF3. In certain embodiments R 2 is -OCH3. In certain embodiments R 2 is selected from hydrogen, F, CH 3 , and -OMe.
  • Embodiments of R 3 In certain embodiments R 3 is hydrogen. In certain embodiments R 3 group is hydrogen. In certain embodiments R 3 is halogen. In certain embodiments R 3 is -F. In certain embodiments R 3 is -Cl. In certain embodiments R 3 is -Br. In certain embodiments R 3 is -I. In certain embodiments R 3 is alkyl. In certain embodiments R 3 is methyl. In certain embodiments R 3 is ethyl. In certain embodiments R 3 is n-propyl. In certain embodiments R 3 is isopropyl.
  • R 3 is haloalkyl. In certain embodiments R 3 is -CF 3 . In certain embodiments R 3 is -OP(O)(OR 9 ) 2 . In certain embodiments R 3 is -OP(O)(OH)2. In certain embodiments R 3 is -SR 9 . In certain embodiments R 3 is -SH. In certain embodiments R 3 is -SCF3. In certain embodiments R 3 is -SMe. In certain embodiments R 3 is -NR 9 R 10 . In certain embodiments R 3 is -NHR 10 . In certain embodiments R 3 is -NH2. In certain embodiments R 3 is -NHMe. In certain embodiments R 3 is -N(Me) 2 .
  • R 3 is -OR 9 . In certain embodiments R 3 is -OH. In certain embodiments R 3 is -OCF 3 . In certain embodiments R 3 is -OCH3. In certain embodiments R 3 is selected from hydrogen, F, CH3, and -OMe.
  • Embodiments of R 4 In certain embodiments R 4 is hydrogen. In certain embodiments R 4 is alkyl. In certain embodiments R 4 is methyl. In certain embodiments R 4 is ethyl. In certain embodiments R 4 is n-propyl. In certain embodiments R 4 is isopropyl. In certain embodiments R 4 is haloalkyl. In certain embodiments R 4 is -CF3. In certain embodiments R 4 is cycloalkyl.
  • R 4 is CH2OH.
  • R 5 is hydrogen. In certain embodiments R 5 is C1-C3 alkyl. In certain embodiments R 5 is methyl. In certain embodiments R 5 is ethyl. In certain embodiments R 5 is n-propyl. In certain embodiments R 5 is isopropyl. In certain embodiments R 5 is haloalkyl. In certain embodiments R 5 is -CF3. In certain embodiments R 5 is CH2CH2OH. In certain embodiments R 5 is OH.
  • R 6 is hydrogen. In certain embodiments R 6 is C1-C3 alkyl. In certain embodiments R 6 is methyl.
  • R 6 is ethyl. In certain embodiments R 6 is n-propyl. In certain embodiments R 6 is isopropyl. In certain embodiments R 6 is haloalkyl. In certain embodiments R 6 is -CF3. In certain embodiments R 6 is CH 2 CH 2 OH. Additional Embodiments 1.
  • R 1A is selected from -H and -OH
  • R 1B is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl
  • R 1C is selected from -H, -OH, -X, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl
  • R 1D is selected from -OH, -X, -CH 2 OH, -CH 2 X, -CH 2 X, -
  • R 1A is selected from -H and -OH
  • R 2B is selected from -X, -CH 2 OH, -CH 2 X, -CHX 2 , -CX 3 , -CH 2 CH 2 OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 2 -C 4 alkyl
  • R 1C is selected from -H, -OH, -X, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH 2 CH 2 X, -CH 2 CHX 2 , -CH 2 CX 3 , C 3 -C 4 cycloalkyl, and C 1 -C 4 alkyl
  • R 2C is selected from -X, -CH 2 OH, -CH 2 X,
  • R 1 , R 2 , and R 3 are i g of hydrogen, halogen, alkyl, aryl, cycloalkyl, haloalkyl, -OP(O)(OR 9 ) 2 , -SR 9 , -NR 9 R 10 , and -OR 9 ;
  • R 4 is selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, -CH2OR 11 , and -CH2CH2OR 11 ; in certain embodiments R 4 is selected from hydrogen, -CH 3 , -CH 2 X, -CHX 2 , -CX 3 , - CH2CH3, -CH2CH2X, -CH2CHX2, -CH2CX3, -CH2OH, and -CH2CH2OH; in certain embodiments R 4 is selected from hydrogen, -CH 3 , -CH 2 X, -CHX 2 , -CX 3 , - CH2
  • the compound or enantiomerically enriched compound of any one of embodiments 1-61 that shows the therapeutic effect of emotional openness.
  • 72. The compound or enantiomerically enriched compound of any one of embodiments 1-61 wherein the pharmaceutically acceptable salt(s) is selected from HCl, sulfate, aspartate, saccharate, fumarate, succinate, phosphate, oxalate, acetate, amino acid anion, gluconate, maleate, malate, citrate, mesylate, nitrate or tartrate, or a mixture thereof.
  • 73. The compound or enantiomerically enriched compound of embodiment 71 that is also a serotonin reuptake inhibitor.
  • 79. The compound of any one of embodiments 1-35, wherein the compound is an enantiomerically enriched mixture or pure enantiomer or a pharmaceutically acceptable salt or salt mixture thereof.
  • 80. The enantiomerically enriched compound of any one of embodiments 45-61, wherein the compound is an enantiomerically enriched mixture or pure enantiomer or a pharmaceutically acceptable salt or salt mixture thereof.
  • 81. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, wherein the compound has entactogenic properties. 82.
  • the enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80 wherein the compound has serotonin-receptor-dependent properties.
  • 83. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, with decreased hallucinogenic effects relative to MDMA.
  • 84. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, with decreased unwanted psychoactive effects relative to MDMA.
  • 85. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, with decreased physiological effects relative to MDMA.
  • 86. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, with decreased abuse potential relative to MDMA. 87.
  • the enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80 with decreased hallucinogenic effects relative to a clinically used 5-HT2A agonist.
  • the enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80 with decreased unwanted psychoactive effects relative to a clinically used 5-HT2A agonist.
  • the enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80 with decreased physiological effects relative to a clinically used 5-HT 2A agonist.
  • the enantiomerically enriched mixture or pure enantiomer any one of embodiments 78-88 that shows the therapeutic effect of emotional openness. 91.
  • 98. The enantiomerically enriched mixture or pure enantiomer of any one of embodiments 78-97 wherein the enantiomerically enriched mixture or pure enantiomer is an enantiomerically enriched mixture.
  • 99. A method for treating a central nervous system disorder comprising administering an effective amount of a compound, pure enantiomer, or enantiomerically enriched mixture of any one of embodiments 1-98 to a host in need thereof. 100.
  • the central nervous system disorder is selected from: post-traumatic stress disorder, depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic, adjustment disorder, feeding and eating disorders, binge behaviors, body dysmorphic syndromes, addiction, drug abuse or dependence disorders, substance use disorders, disruptive behavior disorders, impulse control disorders, gaming disorders, gambling disorders, memory loss, dementia of aging, attention deficit hyperactivity disorder, personality disorders, attachment disorders, autism, dissociative disorders and headache disorders.
  • the host is a human.
  • the central nervous system disorder is post-traumatic stress disorder.
  • the central nervous system disorder is adjustment disorder.
  • the method of any one of embodiments 99-101 wherein the central nervous system disorder is generalized anxiety. 105. The method of any one of embodiments 99-101 wherein the central nervous system disorder is social anxiety. 106. The method of any one of embodiments 99-101 wherein the central nervous system disorder is depression. 107. The method of any one of embodiments 99-101 wherein the central nervous system disorder is a substance use disorder. 108. The method of any one of embodiments 99-101 wherein the central nervous system disorder is an attachment disorder. 109. The method of any one of embodiments 99-101 wherein the central nervous system disorder is schizophrenia. 110. The method of any one of embodiments 99-101 wherein the central nervous system disorder is a headache disorder. 111.
  • the method of any one of embodiments 99-101 wherein the central nervous system disorder is an eating disorder. 112. The method of embodiment 111 wherein the eating disorder is bulimia. 113. The method of embodiment 111 wherein the eating disorder is binge eating. 114. The method of embodiment 111 wherein the eating disorder is anorexia. 115. The method of any one of embodiments 99-101 wherein the central nervous system disorder is a neurological disorder. 116. The method of embodiment 115 wherein the neurological disorder is stroke. 117. The method of embodiment 115 wherein the neurological disorder is brain trauma. 118. The method of embodiment 115 wherein the neurological disorder is dementia. 119. The method of embodiment 115 wherein the neurological disorder is a neurodegenerative disease or disorder. 120.
  • the neurodegenerative disease or disorder is selected from: Alzheimer’s disease, mild cognitive impairment (MCI), Parkinson’s disease, Parkinson's disease dementia, multiple sclerosis, adrenoleukodystrophy, AIDS dementia complex, Alexander disease, Alper's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy, Canavan disease, cerebral amyloid angiopathy, cerebellar ataxia, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, diffuse myelinoclastic sclerosis, fatal familial insomnia, Fazio- Londe disease, Friedreich's ataxia, frontotemporal dementia or lobar degeneration, hereditary spastic paraplegia, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Lyme disease, Machado-Joseph disease, motor neuron disease
  • MCI mild cognitive impairment
  • a pharmaceutical composition comprising an effective patient-treating amount of a compound, pure enantiomer, or enantiomerically enriched mixture of any one of embodiments 1-98 and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising an effective patient-treating amount of a pure enantiomer, or enantiomerically enriched mixture of ; and a Preparation of Enantiomeric Compounds
  • Various methods are known in the art for preparing optically active forms and determining activity. Such methods include standard processes described herein and other similar assays which are well known in the art.
  • Examples of methods that can be used to obtain optical isomers of the compounds according to the present disclosure include but are not limited to the following: a) physical separation of crystals whereby macroscopic crystals of the individual enantiomers are manually separated. This technique may particularly be used if crystals of the separate enantiomers exist (i.e., the material is a conglomerate), and the crystals are visually distinct; b) simultaneous crystallization whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; c) enzymatic resolutions whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; d) enzymatic asymmetric synthesis, a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; e) chemical asymmetric synthesis whereby
  • the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; g) first- and second-order asymmetric transformations whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
  • the desired enantiomer is then released from the diastereomers; h) kinetic resolutions comprising partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, enantiomerically enriched reagent or catalyst under kinetic conditions; i) enantiospecific synthesis from enantiomerically enriched precursors whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; j) chiral liquid chromatography whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
  • the stationary phase can be made of chiral material, or the mobile phase can contain an additional chiral material to provoke the differing interactions; k) chiral gas chromatography whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed enantiomerically enriched chiral adsorbent phase; l) extraction with chiral solvents whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; and m) transport across chiral membranes whereby a racemate is placed in contact with a thin membrane barrier.
  • Chiral compounds of the invention may be prepared by chiral chromatography from the racemic or enantiomerically enriched free amine.
  • Pharmaceutically acceptable salts of chiral compounds may be prepared from fractional crystallization of salts from a racemic or an enantiomerically enriched free amine and a chiral acid.
  • the free amine may be reacted with a chiral auxiliary and the enantiomers separated by chromatography followed by removal of the chiral auxiliary to regenerate the free amine.
  • separation of enantiomers may be performed at any convenient point in the synthesis of the compounds of the invention.
  • the compounds of the invention may also be prepared using a chiral synthesis.
  • An enantiomerically enriched mixture is a mixture that contains one enantiomer in a greater amount than the other.
  • An enantiomerically enriched mixture of an S-enantiomer contains at least 55% of the S-enantiomer, and more typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and typically not more than 98% of the S-enantiomer.
  • An enantiomerically enriched mixture of an R-enantiomer contains at least 55% of the R-enantiomer, more typically at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and typically not more than 98% of the R-enantiomer.
  • enantiomerically enriched mixtures are created that have a greater amount of the nicotinic-receptor-dependent therapeutic effects.
  • enantiomerically enriched mixtures are created that have a greater amount of the serotonin- receptor-dependent therapeutic effects. In certain embodiments, enantiomerically enriched mixtures are created that have a greater amount of the dopaminergic effects. In certain embodiments, enantiomerically enriched mixtures are created that have a greater amount of the serotonin-receptor-dependent therapeutic effects.
  • unwanted effects include psychoactive effects (such as excess stimulation or sedation), physiological effects (such as transient hypertension or appetite suppression), toxic effects (such as to the brain or liver), effects contributing to abuse liability (such as euphoria or dopamine release), and other side effects.
  • One aspect of the present invention is a balanced mixture of S-Bk-2-MAPB and R-Bk-2- MAPB (not the racemate) that achieves a predetermined combination of serotonin-receptor- dependent therapeutic effects and nicotinic-receptor-dependent therapeutic effects.
  • One aspect of the present invention is a balanced mixture of S-Bk-2-EAPB and R-Bk-2- EAPB (not the racemate) that achieves a predetermined combination of serotonin-receptor- dependent therapeutic effects and nicotinic-receptor-dependent therapeutic effects.
  • One aspect of the present invention is a balanced mixture of S-Bk-2-MAPB and R-Bk-2- MAPB (not the racemate) that achieves a predetermined combination of serotonin-receptor- dependent therapeutic effects and dopaminergic effects.
  • One aspect of the present invention is a balanced mixture of S-Bk-2-EAPB and R-Bk-2- EAPB (not the racemate) that achieves a predetermined combination of serotonin-receptor- dependent therapeutic effects and dopaminergic effects.
  • pharmaceutical compositions of enantiomerically enriched preparations of Bk-2-MAPB or Bk-2-MAPB are provided.
  • the pharmaceutical composition is enriched with S-Bk-2-MAPB.
  • the pharmaceutical composition is enriched with R-Bk-2-MAPB. In certain embodiments, the pharmaceutical composition is enriched with S-Bk-2-MAPB. In certain embodiments, the pharmaceutical composition is enriched with R-Bk-2-MAPB. In certain embodiments, pharmaceutical compositions of enantiomerically enriched preparations of Bk-2-EAPB or Bk-2-EAPB are provided. In certain embodiments, the pharmaceutical composition is enriched with S-Bk-2-EAPB. In certain embodiments, the pharmaceutical composition is enriched with R-Bk-2-EAPB. In certain embodiments, the pharmaceutical composition is enriched with S-Bk-2-EAPB. In certain embodiments, the pharmaceutical composition is enriched with R-Bk-2-EAPB. In certain embodiments, the pharmaceutical composition is enriched with R-Bk-2-EAPB. In certain embodiments, the pharmaceutical composition is enriched with R-Bk-2-EAPB.
  • a salt mixture may be useful to increase solubility of the active substances, to alter pharmacokinetics, or for controlled release or other objective.
  • a salt mixture may comprise 2, 3, 4, 5, 6, or more pharmaceutically acceptable salts together to form a single composition.
  • the compounds of the present invention are amines and thus basic, and therefore, react with inorganic and organic acids to form pharmaceutically acceptable acid addition salts.
  • the compounds of the present invention as free amines are oily and have decreased stability at room temperature. In this case it may be beneficial to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration because in some embodiments, the pharmaceutically acceptable salt is solid at room temperature.
  • Certain embodiments of the present invention are compounds which can exist in the form of zwitterionic salts of phosphate and ammonium ions. Certain embodiments of the present invention include compounds containing a phosphate anion or dianion and one or more metal counterions such as Na + , K + , and Li + .
  • Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
  • the compounds of the present invention are administered as oxalate salts.
  • the compounds are administered as phosphate salts.
  • Exemplary salts include, but are not limited to, 2-hydroxyethanesulfonate, 2- naphthalenesulfonate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, acetate, adipate, alginate, amsonate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, citrate, clavulariate, cyclopentanepropionate, digluconate, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, finnarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hem
  • exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dode
  • compositions of the present invention are administered as prodrugs.
  • Prodrugs are compounds that are metabolized or otherwise transformed inside the body to the active pharmacologic agent(s) of interest. Examples include N-alpha-acyloxyalkoxycarbonyl derivatives or addition of amino acids to the amine, which can be removed within the body by esterases or similar enzymes, and reactions at the keto-group to form enol ethers, enol esters, and imines.
  • Prodrugs are frequently (though not necessarily) pharmacologically less active or inactive until converted to the parent drug. This is done in the body by a chemical or biological reaction. In some cases, the moiety or chemicals formed from it may also have beneficial effects, including increasing therapeutic effects, decreasing undesirable side effects, or otherwise altering the pharmacokinetics or pharmacodynamics of the active drug. When the chemical formed from the prodrug moiety has beneficial effects that contribute to the overall beneficial effects of administering the prodrug, then the formed chemical is considered a “codrug.”
  • Types of prodrugs contemplated to be within the scope of the invention include compounds that are transformed in various organs or locations in the body (e.g., liver, kidney, G.I., lung, tissue) to release the active compound.
  • liver prodrugs will include active compounds conjugated with a polymer or chemical moiety that is not released until acted upon by liver cytochrome enzymes and CYP metabolism includes dealkylation, dehydrogenation, reduction, hydrolysis, oxidation, and the breakdown of aromatic rings.
  • Kidney prodrugs will include active compounds conjugated to L-gamma-glutamyl or N-acetyl-L-gamma glutamic moieties so that they are metabolized by gamma-glutamyl transpeptidase before they are bioactive.
  • the compounds may be conjugated to alkylglucoside moieties to create glycosylation-based prodrugs. Digestive or G.I.
  • prodrugs will include those where an active compound is, e.g., formulated into microspheres or nanospheres that do not degrade until the spheres are subjected to an acidic pH; formulated with an amide that will resist biochemical degradation until colonic pH is achieved; or, conjugated with a linear polysaccharide such as pectin that will delay activation until the combination reaches the bacteria in the colon.
  • an active compound e.g., formulated into microspheres or nanospheres that do not degrade until the spheres are subjected to an acidic pH; formulated with an amide that will resist biochemical degradation until colonic pH is achieved; or, conjugated with a linear polysaccharide such as pectin that will delay activation until the combination reaches the bacteria in the colon.
  • a linear polysaccharide such as pectin
  • physiologically functional derivatives refers to physiologically tolerated chemical derivatives of the compound having the same physiological function thereof, for example, by being convertible in the body thereto, and which on administration to a mammal such as a human is able to form (directly or indirectly) the compound or an active metabolite thereof (acting therefore, like a prodrug), or by otherwise having the same physiological function, despite one or more structural differences.
  • physiologically functional derivatives include esters, amides, carbamates, ureas, and heterocycles.
  • the present invention includes but is not limited to the methods and uses for the treatment of CNS disorders, including, but not limited to, mental disorders as described herein, including post-traumatic stress and adjustment disorders, and other disorders described in the Background, Summary or Description herein, comprising administering the compound of the present invention or composition or a pharmaceutically acceptable salt or salt mixture thereof as described herein. It may be that these compounds display many pharmacological properties that are beneficial to their use as therapeutics and represent an improvement over existing therapeutics.
  • the present invention includes but is not limited to, for example, methods for the treatment of disorders, including, but not limited to depression, dysthymia, anxiety and phobia disorders (including generalized anxiety, social anxiety, panic, post-traumatic stress and adjustment disorders), feeding and eating disorders (including binge eating, bulimia, and anorexia nervosa), other binge behaviors, body dysmorphic syndromes, alcoholism, tobacco abuse, drug abuse or dependence disorders, disruptive behavior disorders, impulse control disorders, gaming disorders, gambling disorders, memory loss, dementia of aging, attention deficit hyperactivity disorder, personality disorders (including antisocial, avoidant, borderline, histrionic, narcissistic, obsessive compulsive, paranoid, schizoid and schizotypal personality disorders), attachment disorders, autism, and dissociative disorders.
  • disorders including, but not limited to depression, dysthymia, anxiety and phobia disorders (including generalized anxiety, social anxiety, panic, post-traumatic stress and adjustment disorders), feeding and eating disorders (including binge eating,
  • a compound or composition of the present invention is provided in an effective amount to treat a host, typically a human, with a CNS disorder that can be either a neurological condition (one that is typically treated by a neurologist) or a psychiatric condition (one that is typically treated by a psychiatrist).
  • a CNS disorder that can be either a neurological condition (one that is typically treated by a neurologist) or a psychiatric condition (one that is typically treated by a psychiatrist).
  • Neurological disorders are typically those affecting the structure, biochemistry or cause electrical abnormalities of the brain, spinal cord or other nerves.
  • Psychiatric conditions are more typically thought of as mental disorders, which are primarily abnormalities of thought, feeling or behavior that cause significant distress or impairment of personal functioning.
  • the disclosed compounds can be used in an effective amount to improve neurological or psychiatric functioning in a patient in need thereof.
  • Neurological indications include, but are not limited to improved neuroplasticity, including treatment of stroke, brain trauma, dementia, and neurodegenerative diseases.
  • MDMA has been reported to have an EC50 of 7.41 nM for promoting neuritogenesis and an E max approximately twice that of ketamine, which has fast acting psychiatric benefits that are thought to be mediated by its ability to promote neuroplasticity, including the growth of dendritic spines, increased synthesis of synaptic proteins, and strengthening synaptic responses ( Figure S3. in Ly et al. Cell reports 23, no.11 (2016): 3170-3182).
  • the compounds of the current invention can similarly be considered psychoplastogens, that is, small molecules that are able to induce rapid neuroplasticity (Olson, 2018, Journal of experimental neuroscience, 12, 1179069518800508).
  • the disclosed compounds and compositions can be used to improve stuttering and other dyspraxias or to treat Parkinson’s disease or schizophrenia.
  • the term "improving psychiatric function" is intended to include mental health and life conditions that are not traditionally treated by neurologists but sometimes treated by psychiatrists and can also be treated by psychotherapists, life coaches, personal fitness trainers, meditation teachers, counselors, and the like.
  • the disclosed compounds will allow individuals to effectively contemplate actual or possible experiences that would normally be upsetting or even overwhelming. This includes individuals with fatal illnesses planning their last days and the disposition of their estate. This also includes couples discussing difficulties in their relationship and how to address them. This also includes individuals who wish to more effectively plan their career.
  • the 2-ethylamine substituted benzofuran compounds and compositions of the present invention may be used in an effective amount to treat a host, typically a human, to modulate an immune or inflammatory response.
  • the compounds disclosed herein alter extracellular serotonin, which is known to alter immune functioning.
  • MDMA produces acute time-dependent increases and decreases in immune response.
  • a host for example a human, is treated with an effective amount of a 2-ethylamine substituted benzofuran compound of Formula I or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof.
  • a host for example a human, is treated with an effective amount of a 2-ethylamine substituted benzothiophene compound of Formula II or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 95 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 90 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 85 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 70 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 65 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 60 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 55 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 55 or 60 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 95 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 90 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 85 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 80 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 75 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 70 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 65 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 60 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 55 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 55 or 60 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 95 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 90 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 85 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 80 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 75 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 70 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 65 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 60 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 55 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 55 or 60 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 95 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 90 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 85 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 80 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 75 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 70 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 65 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 60 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 55 percent.
  • a host for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 55 or 60 percent.
  • the present invention also includes but is not limited to methods for modulating the CNS in a mammal in need thereof, including a human, by administering a pharmaceutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or salt mixture thereof.
  • a method is provided to treat diseases or disorders linked to inadequate functioning of neurotransmission in the CNS comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof in a host in need thereof.
  • This invention also includes but is not limited to the use of compounds of Formula I or Formula II for the manufacture of a medicament for the treatment of maladaptive response to perceived psychological threats.
  • this invention provides a pharmaceutical formulation adapted for the treatment of maladaptive response to perceived psychological threats containing a compound of Formula I or Formula II.
  • this invention includes a method for the treatment of maladaptive response to perceived psychological threats that comprises administering an effective amount of a compound of Formula I or Formula II, given either in the context of psychotherapy or as a stand-alone treatment.
  • a method of treating a patient with primary or secondary headaches comprising administering an effective amount of a compound, pure enantiomer, or enantiomerically enriched mixture of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.
  • a method of treating a patient with primary or secondary headaches comprising administering an effective amount of a compound, pure enantiomer, or enantiomerically enriched mixture of Formula III-VIII, or a pharmaceutically acceptable salt thereof.
  • a method of treating a patient with primary or secondary headaches comprising administering an effective amount of a compound, pure enantiomer, or enantiomerically enriched mixture of Bk-2-MAPB, Bk-2-MAPBT, Bk-2-EAPB, or BK-2-EAPBT, or a pharmaceutically acceptable salt thereof.
  • primary headaches include, but are not limited to migraine, migraine signs and symptoms without cephalgia, tension-type headaches, cluster headaches and other trigeminal autonomic cephalalgias, new daily persistent headache, hypnic headaches, stabbing headaches, and other primary headache disorders.
  • Secondary headaches referred to herein can refer to those due to trauma or injury, cranial or cervical vascular disorder, non-vascular intracranial disorder, headaches due to substance use or substance withdrawal, and other secondary headaches.
  • Non-limiting examples of pharmacotherapeutic counseling use Psychotherapy, cognitive enhancement, or life coaching conducted with the compounds or pharmaceutically acceptable salts as described herein employed as an adjunct (hereafter, “pharmacotherapy” or “pharmacotherapy counseling”) is typically conducted in widely spaced sessions with one, two, or rarely three or more administrations of an entactogen per session. These sessions can be as frequent as weekly but are more often approximately monthly or even less frequently.
  • the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of enantiomerically enriched S-Bk-2-MAPB, R-Bk-2-MAPB, S-Bk-2-EAPB, R-Bk-2-EAPB, S- Bk-2-MAPBT, R-Bk-2-MAPBT, S-Bk-2-EAPBT, or R-Bk-2-EAPBT, or a pharmaceutically acceptable salt thereof.
  • the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of enantiomerically pure S-Bk-2-EAPB, R-Bk-2- EAPB, S-Bk-2-MAPBT, R-Bk-2-MAPBT, S-Bk-2-EAPBT, or R-Bk-2-EAPBT, or a pharmaceutically acceptable salt thereof.
  • the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of enantiomerically enriched mixture of Formula I or Formula II or a pharmaceutically acceptable salt thereof.
  • patient should be understood to mean one or more individuals.
  • Use of a compound or composition of the present invention in conjunction with conventional psychotherapy or coaching the use of a described 2-ethylamine substituted benzofuran compound or composition of the present invention as pharmacotherapy is integrated into the patient’s ongoing psychotherapy or coaching (hereafter abbreviated as “psychotherapy”).
  • a patient in need of the pharmacotherapy counseling is not in ongoing psychotherapy, then psychotherapy may be initiated and the pharmacotherapy counseling added later, after the prescribing physician and treating psychotherapist, physician, coach, member of the clergy, or other similar professional or someone acting under the supervision of such a professional (hereafter, “therapist”) agree that the pharmacotherapy counseling is indicated and that there have been sufficient meetings between the patient and therapist to establish an effective therapeutic alliance.
  • therapist a conversation typically occurs in which the therapist or other members of the therapy team addresses the patient’s questions and concerns about the medicine and familiarizes the patient with the logistics of pharmacotherapy- assisted session.
  • the therapist describes the kinds of experience that can be expected during the pharmacotherapy counseling session.
  • parts of this conversation employ written, recorded, or interactive digital explanations, as might be used in the informed consent process in a clinical trial.
  • the therapist may additionally make commitments to support the participant’s healthcare and wellness process.
  • the patient may be asked to make commitments of their own (such as not to hurt themselves or others and to abstain from contraindicated medicines or drugs for an adequate period before and after the pharmacotherapy counseling).
  • the compounds and compositions of the invention (or alternately herein for convenience, the “medicine”) is administered shortly before or during a scheduled psychotherapy session, with timing optionally selected so that therapeutic effects begin by the time the psychotherapy session begins.
  • references to administering the medicine “during” a psychotherapeutic or other session are intended to refer to timing the administration of the medicine such that the therapeutic effects of the medicine at least partly temporally overlap with the therapeutic effects of the session.
  • the therapist may provide some reminder of their mutual commitments and expected events during the session.
  • the psychotherapy session is carried out by the therapist, who, optionally, may be remote and in communication with the patient using a communication means suitable for telehealth or telemedicine, such as a phone, video, or other remote two-way communication method.
  • video or other monitoring of the patient's response or behavior is used to document or measure the session.
  • the therapist uses their clinical judgment and available data to adjust the session to the needs of the patient. Many therapists view their responsibility as being to facilitate rather than direct the patient’s experience. This may sometimes involve silent empathic listening, while other times it may include more active support to help the patient arrive at new perspectives on their life. It is anticipated that the therapeutic effects of the medicine will allow the patient to make more rapid therapeutic progress than would normally be possible. These effects include decreased neurottim and increased feelings of authenticity. Patients are often able to calmly contemplate actual or possible experiences that would normally be upsetting or even overwhelming. This can facilitate decision making and creativity in addition to mental wellness.
  • the prescribing physician may allow a second or even third administration of the medicine or another psychotherapeutic agent in order to extend the therapeutic effects.
  • a pharmaceutical preparation with modified release is employed to make this unnecessary.
  • the therapist may suggest to the patient activities to support further psychotherapeutic progress after the psychotherapy session has ended. Alternatively, the therapist may continue to work with the patient until the therapeutic effects of the medicine have become clinically minimal.
  • the therapist and patient will typically discuss the patient’s experiences from the pharmacotherapy counseling session and the therapist will often aid the patient in recalling the therapeutic effects and help them to incorporate the experiences into their everyday lives.
  • Pharmacotherapy counseling sessions may be repeated as needed, based on the judgment of the treating physician and therapy team regarding the needs of the patient.
  • a compound or composition of the present invention is administered outside of a conventional psychotherapy.
  • This example method is a broader, more flexible approach to pharmacotherapy that is not centered on supervision by a therapist.
  • These pharmacotherapy counseling sessions can take place in many different quiet and safe settings, including the patient’s home.
  • the setting is typically chosen to offer a quiet setting, with minimal disruptions, where the patient feels psychologically safe and emotionally relaxed.
  • the setting may be the patient’s home but may alternatively be a clinic, retreat center, or hotel room.
  • the medicine is taken by the patient regularly to maintain therapeutic concentrations of the active compound in the blood.
  • the medicine is taken, as needed, for defined psychotherapy sessions.
  • a checklist may be followed to prepare the immediate environment to minimize distractions and maximize therapeutic or decision-making benefits.
  • This checklist can include items such as silencing phones and other communications devices, cleaning and tidying the environment, preparing light refreshments, preparing playlists of appropriate music, and pre- arranging end-of-session transportation if the patient is not undergoing pharmacotherapy counseling at home.
  • the therapeutic or other life-related goals for example, decision-making, increasing creativity, or simply appreciation of life
  • These goals can optionally be determined in advance with support from a therapist.
  • the therapist may help the patient select stimuli, such as photographs, videos, augmented or virtual reality scenes, or small objects such as personal possessions, that will help focus the patient’s attention on the goals of the session or on the patient's broader life journey.
  • these stimuli can include photographs of the patient from when they were young, which can increase self-compassion, or can include stimuli relating to traumatic events or phobias experienced by the patient, which can help the patient reevaluate and change their response to such stimuli.
  • the patient selects these stimuli without assistance (e.g., without the involvement of the therapist) or does not employ any stimuli.
  • stimuli are selected in real time by the therapist, or an algorithm based on the events of the session with the goal of maximizing benefits to the patient.
  • a conversation occurs in which the therapist addresses the patient’s questions and concerns about the medicine and familiarizes the patient with the logistics of a pharmacotherapy-assisted counseling session.
  • the therapist describes the kinds of experience that can be expected during the pharmacotherapy-assisted counseling session.
  • parts of this conversation employ written, recorded, or interactive digital explanations, as might be used in the informed consent process in a clinical trial.
  • the therapist may additionally make commitments to support the participant’s healthcare and wellness process.
  • the patient may be asked to make commitments of their own (such as not to hurt themselves or others and to abstain from contraindicated medicines or drugs for an adequate period before and after the pharmacotherapy counseling).
  • Selected session goals and any commitments or other agreements regarding conduct between the patient and therapy team are reviewed immediately before administration of the medicine.
  • the therapeutic effects of the medicine usually begin within one hour. Typical therapeutic effects include decreased neurottim and increased feelings of authenticity. Patients are often able to calmly contemplate experiences or possible experiences that would normally be upsetting or even overwhelming. This can facilitate decision making and creativity in addition to mental wellness.
  • sleep shades and earphones with music or soothing noise may be used to reduce distractions from the environment.
  • a virtual reality or immersive reality system may be used to provide stimuli that support the therapeutic process.
  • these stimuli are preselected; optionally, they are selected in real time by a person, or an algorithm based on events in the session with the goal of maximizing benefits to the patient.
  • a therapist or other person well-known to the patient is present or available nearby or via phone, video, or other communication method in case the patient wishes to talk, however the patient may optionally undergo a session without the assistance of a therapist.
  • the patient may write or create artwork relevant to the selected session goals.
  • the patient may practice stretches or other beneficial body movements, such as yoga (“movement activity”).
  • the patient may practice movement activity that includes more vigorous body movements, such as dance or other aerobic activity. Movement activity also may make use of exercise equipment such as a treadmill or bicycle.
  • the patient may be presented with music, video, auditory messages, or other perceptual stimuli. Optionally, these stimuli may be adjusted based on the movements or other measurable aspects of the patient.
  • Such adjustment may be done by the therapist with or without the aid of a computer, or by a computer alone in response to said patient aspects, including by an algorithm or artificial intelligence, and “computer” broadly meaning any electronic tool suitable for such purposes, whether worn or attached to a patient (e.g., watches, fitness trackers, “wearables,” and other personal devices; biosensors or medical sensors; medical devices), whether directly coupled or wired to a patient or wirelessly connected (and including desktop, laptop, and notebook computers; tablets, smartphones, and other mobile devices; and the like), and whether within the therapy room or remote (e.g., cloud-based systems).
  • a patient e.g., watches, fitness trackers, “wearables,” and other personal devices; biosensors or medical sensors; medical devices), whether directly coupled or wired to a patient or wirelessly connected (and including desktop, laptop, and notebook computers; tablets, smartphones, and other mobile devices; and the like), and whether within the therapy room or remote (e.g., cloud-based systems).
  • measurable aspects of a patient e.g., facial expression, eye movements, respiration rate, pulse rate, skin color change, patient voice quality or content, patient responses to questions
  • measurable aspects of a patient may be individually transformed into scores on standardized scales by subtracting a typical value and then multiplying by a constant and these scores may be further multiplied by constants and added together to create an overall score that can optionally be transformed by multiplication with a link function, such as the logit function, to create an overall score.
  • a link function such as the logit function
  • This score may be used to select or adjust stimuli such as selecting music with higher or lower beats-per-minute or with faster or slower notes, selecting images, audio, or videos with different emotionality or autobiographical meaning, or selecting activities for the patient to engage in (such as specific movements, journaling prompts, or meditation mantras).
  • stimuli such as selecting music with higher or lower beats-per-minute or with faster or slower notes, selecting images, audio, or videos with different emotionality or autobiographical meaning, or selecting activities for the patient to engage in (such as specific movements, journaling prompts, or meditation mantras).
  • a patient can participate in numerous therapeutically beneficial activities, where such participation follows or is in conjunction with the administration of a compound or composition of the invention, including writing about a preselected topic, engaging in yoga or other movement activity, meditating, creating art, viewing of photographs or videos or emotionally evocative objects, using a virtual reality or augmented reality system, talking with a person, and thinking about a preselected problem or topic, and it should be understood that such participation can occur with or without the participation or guidance of a therapist.
  • the prescribing physician may allow a second or even third administration of the medicine or another psychotherapeutic agent in order to extend the therapeutic effects.
  • a pharmaceutical preparation with modified release is employed to make this unnecessary.
  • the patient typically remains in the immediate environment until the acute therapeutic effects of the medicine are clinically minimal, usually within eight hours. After this point, the session is considered finished.
  • the treatment plan will often include a follow-up session with a therapist. This follow-up session occurs after the pharmacotherapy counseling session has ended, often the next day but sometimes several days later. In this session, the patient discusses their experiences from the pharmacotherapy counseling session with the therapist, who can aid them in recalling the therapeutic effects and help them to incorporate the experiences into their everyday lives. Pharmacotherapy counseling sessions may be repeated as needed, based on the judgment of the treating physician and therapy team regarding the needs of the patient.
  • compositions disclosed herein may be administered orally, topically, systemically, parenterally, by inhalation, insufflation, or spray, mucosally (e.g., buccal, sublingual), sublingually, transdermally, rectally, intravenous, intra-aortal, intracranial, subdermal, intraperitoneal, intramuscularly, inhaled, intranasal, subcutaneous, transnasal, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
  • Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, an injection or infusion solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, a suppository, a buccal or sublingual formulation, a parenteral formulation, an ophthalmic solution, or in a medical device.
  • any pharmaceutically useful form e.g., as an aerosol, a cream, a gel, a pill, an injection or infusion solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, a suppository, a buccal or sublingual formulation, a parenteral formulation, an ophthalmic solution, or in a medical device.
  • compositions thus refers to at least one compound (which may be a mixture of enantiomers or diastereomers, as fully described herein) of the invention and a pharmaceutically acceptable vehicle, excipient, diluent or other carrier in an effective amount to treat a host, typically a human, who may be a patient.
  • the pharmaceutical composition is a dosage form that contains from about 0.1 mg to about 1500 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 1500 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form.
  • Examples are dosage forms with at least 0.1, 1, 5, 10, 20, 25, 40, 50, 100, 125, 150, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt or salt mixture.
  • compositions described herein can be formulated into any suitable dosage form, including tablets, capsules, gelcaps, aqueous oral dispersions, aqueous oral suspensions, solid dosage forms including oral solid dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, self-emulsifying dispersions, solid solutions, liposomal dispersions, lyophilized formulations, pills, powders, delayed-release formulations, immediate-release formulations, modified release formulations, extended-release formulations, pulsatile release formulations, multi particulate formulations, and mixed immediate release and controlled release formulations.
  • the composition should be administered in an effective amount to administer an amount of the active agents of the present invention achieves a plasma level commensurate with the concentrations found to be effective in vivo for a period of time effective to elicit a desired therapeutic effect without abuse liability.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the active ingredient.
  • compositions can be in the form of tablets (including orally disintegrating, swallowable, sublingual, buccal, and chewable tablets), pills, powders, lozenges, troches, oral films, thin strips, sachets, cachets, elixirs, suspensions, emulsions, solutions, slurries, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, dry powders for inhalation, liquid preparations for vaporization and inhalation, topical preparations, transdermal patches, sterile injectable solutions, and sterile packaged powders.
  • compositions may be formulated as immediate release, controlled release, sustained (extended) release or modified release formulations.
  • the compositions of the present invention can be administered by multiple routes, which may differ in different patients according to their preference, co-morbidities, side effect profile, and other factors (IV, PO, transdermal, etc.).
  • the pharmaceutical composition includes the presence of other substances with the active drugs, known to those skilled in the art, such as fillers, carriers, gels, skin patches, lozenges, or other modifications in the preparation to facilitate absorption through various routes (such as, but not limited to, gastrointestinal, transdermal, etc.) and/or to extend the effect of the drugs, and/or to attain higher or more stable serum levels or to enhance the therapeutic effect of the active drugs in the combination.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
  • suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include, but are not limited to, lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents preserving agents such as methyl- and propylhydroxybenzoates
  • sweetening agents and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the compositions are in certain embodiments formulated in a unit dosage form, each dosage containing from at least about 0.05 to about 350 mg or less, more typically at least about 5.0 to about 180 mg or less, of the active ingredients.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
  • the active compounds are effective over a wide dosage range. For example, as-needed dosages normally fall within the range of at least about 0.01 to about 4 mg/kg or less. In the treatment of adult humans, the range of at least about 0.2 to about 3 mg/kg or less, in single dose may be useful.
  • the amount of the compound actually administered will be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient’s symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided for instance that such larger doses may be first divided into several smaller doses for administration.
  • the pharmaceutical compositions of the invention may be administered and dosed in accordance with good medical practice, taking into account the method and scheduling of administration, prior and concomitant medications and medical supplements, the clinical condition of the individual patient and the severity of the underlying disease, the patient’s age, sex, body weight, and other such factors relevant to medical practitioners, and knowledge of the particular compound(s) used. Starting and maintenance dosage levels thus may differ from patient to patient, for individual patients across time, and for different pharmaceutical compositions, but shall be able to be determined with ordinary skill.
  • a powder comprising the active agents of the present invention described herein may be formulated to comprise one or more pharmaceutical excipients and flavors.
  • Such a powder may be prepared, for example, by mixing the active agents of the present invention and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also comprise a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi-dosage packaging units. The term “uniform” means the homogeneity of the bulk blend is substantially maintained during the packaging process.
  • Oral Formulations In certain embodiments, any selected compound of the present invention is formulated in an effective amount in a pharmaceutically acceptable oral dosage form. In certain embodiments, the compound is enantiomerically pure or enriched Bk-2-MAPB or the Bk-2-MAPBT analog thereof or a pharmaceutically acceptable salt thereof.
  • compound is enantiomerically pure or enriched Bk-2-EAPB or Bk-2-EAPBT analog thereof or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula I or Formula II or a pharmaceutically acceptable salt thereof.
  • Oral dosage forms may include, but are not limited to, oral solid dosage forms and oral liquid dosage forms.
  • Oral solid dosage forms may include but are not limited to, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres and/or any combinations thereof.
  • the oral solid dosage forms may be formulated as immediate release, controlled release, sustained (extended) release or modified release formulations.
  • the oral solid dosage forms of the present invention may also contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof.
  • pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof.
  • the solid dosage forms of the present invention may be in the form of a tablet (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol.
  • a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet
  • a pill including a sterile packaged powder
  • the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including a fast- melt tablet. Additionally, pharmaceutical formulations of the present invention may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.
  • the pharmaceutical solid dosage forms described herein can comprise the active agent of the present invention compositions described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, complexing agent, ionic dispersion modulator, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
  • a compatible carrier binder, complexing agent, ionic dispersion modulator, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
  • the pharmaceutical solid dosage forms described herein can comprise the active agent or agents of the present invention (i.e., the “active agent(s)”; but for convenience herein, both “active agent” and “active agents” shall mean “active agent(s)” unless context clearly indicates that what is intended or would be suitable is only one agent or only two or more agents) and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, complexing agent, ionic dispersion modulator, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti- foaming agent, antioxidant, preservative, or one or more combination thereof.
  • a compatible carrier binder, complexing agent, ionic dispersion modulator, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant,
  • a film coating is provided around the active agent of the present invention formulation.
  • some or all of the active agent of the present invention particles are coated.
  • some or all of the active agent of the present invention particles are microencapsulated.
  • some or all of the active agent of the present invention is amorphous material coated and/or microencapsulated with inert excipients.
  • the active agent of the present invention particles are not microencapsulated and are uncoated.
  • Suitable carriers for use in the solid dosage forms described herein include acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.
  • Suitable filling agents for use in the solid dosage forms described herein include lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose (e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, etc.), cellulose powder, dextrose, dextrates, dextrose, dextran, starches, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • microcrystalline cellulose e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, etc.
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxy
  • suitable disintegrants for use in the solid dosage forms described herein include natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or a sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, microcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, Ac-Di- Sol, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crosspovidone, a cross-linked polyvinyl
  • Binders impart cohesiveness to solid oral dosage form formulations: for powder-filled capsule formulation, they aid in plug formation that can be filled into soft- or hard-shell capsules and in tablet formulation, binders ensure that the tablet remains intact after compression and help assure blend uniformity prior to a compression or fill step.
  • Materials suitable for use as binders in the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g., Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crosspovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasse
  • binder levels of 20-70% are typically used in powder-filled gelatin capsule formulations.
  • Binder usage level in tablet formulations is a function of whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binders are used.
  • Formulators skilled in the art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common.
  • Suitable lubricants or glidants for use in the solid dosage forms described herein include stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as CarbowaxTM, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.
  • alkali-metal and alkaline earth metal salts such as aluminum, calcium, magnesium,
  • Suitable diluents for use in the solid dosage forms described herein include sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.
  • Non-water-soluble diluents are compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and micro cellulose (e.g., having a density of about 0.45 g/cm3, e.g. Avicel®, powdered cellulose), and talc.
  • Suitable wetting agents for use in the solid dosage forms described herein include oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.
  • Wetting agents include surfactants.
  • Suitable surfactants for use in the solid dosage forms described herein include docusate and its pharmaceutically acceptable salts, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), and the like.
  • docusate and its pharmaceutically acceptable salts sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), and the like.
  • Suitable suspending agents for use in the solid dosage forms described here include polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 18000, vinylpyrrolidone/vinyl acetate copolymer (S630), sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosic, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80
  • Suitable antioxidants for use in the solid dosage forms described herein include, e.g., butylated hydroxytoluene (BHT), butyl hydroxyanisole (BHA), sodium ascorbate, Vitamin E TPGS, ascorbic acid, sorbic acid and tocopherol.
  • Immediate-release formulations may be prepared by combining superdisintegrants such as Croscarmellose sodium and different grades of microcrystalline cellulose in different ratios. To aid disintegration, sodium starch glycolate will be added.
  • BHT butylated hydroxytoluene
  • BHA butyl hydroxyanisole
  • Immediate-release formulations may be prepared by combining superdisintegrants such as Croscarmellose sodium and different grades of microcrystalline cellulose in different ratios. To aid disintegration, sodium starch glycolate will be added.
  • the above-listed additives should be taken as merely examples and not limiting, of the types of additives that can be included in solid dosage forms of the present invention. The amounts
  • Oral liquid dosage forms include solutions, emulsions, suspensions, and syrups. These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill in the art for the preparation of liquid dosage forms. For example, water, glycerin, simple syrup, alcohol, and combinations thereof. Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water.
  • compositions and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as but not limited to, an oil, water, an alcohol, and combinations of these pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.
  • Suspensions may include oils. Such oils include peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil.
  • Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides.
  • Suspension formulations may include alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol, and propylene glycol.
  • Ethers such as poly(ethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in suspension formulations.
  • formulations are provided comprising particles of Bk-2-MAPB, Bk- 2-EAPB, Bk-2-MAPBT, or Bk-2-EAPBT and at least one dispersing agent or suspending agent for oral administration to a subject in need thereof.
  • formulations are provided comprising particles of compounds of Formula I or Formula II and at least one dispersing agent or suspending agent for oral administration to a subject in need thereof.
  • the formulation may be a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.
  • the aqueous dispersion can comprise amorphous and non-amorphous particles consisting of multiple effective particle sizes such that the drug is absorbed in a controlled manner over time.
  • the aqueous dispersion or suspension is an immediate-release formulation.
  • an aqueous dispersion comprising amorphous particles is formulated such that a portion of the particles of the present invention are absorbed within, e.g., about 0.75 hours after administration and the remaining particles are absorbed 2 to 4 hours after absorption of the earlier particles.
  • addition of a complexing agent to the aqueous dispersion results in a larger span of the particles to extend the drug absorption phase of the active agent such that 50- 80% of the particles are absorbed in the first hour and about 90% are absorbed by about 4 hours.
  • Dosage forms for oral administration can be aqueous suspensions selected from the group including pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, for example, Singh et al., Encyclopedia of Pharm. Tech., 2nd Ed., 754-757 (2002).
  • the liquid dosage forms may comprise additives, such as (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative; (e) viscosity enhancing agents; (f) at least one sweetening agent; and (g) at least one flavoring agent.
  • additives such as (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative; (e) viscosity enhancing agents; (f) at least one sweetening agent; and (g) at least one flavoring agent.
  • the dispersing agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and the carbohydrate-based dispersing agents such as, for example, hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers (e.g.
  • HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone®, e.g., S-630), 4-(1,1,3,3- tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copoly
  • the dispersing agent is selected from a group not comprising one of the following agents: hydrophilic polymers; electrolytes; Tween ® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropyl cellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g.
  • HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium; methylcellulose; hydroxyethylcellulose; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate stearate; non- crystalline cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); 4- (1,1,3,3- tetramethyl butyl)-phenol polymer with ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); or poloxamines (e.g., Tetronic 908® or Poloxamine 908®).
  • Pluronics F68®, F88®, and F108® which are block copolymers of ethylene oxide and propylene oxide
  • poloxamines e.g
  • wetting agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include acetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens® such as e.g., Tween 20® and Tween 80® (ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowaxs 3350® and 1450®, and Carpool 934® (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphat
  • Suitable preservatives for the aqueous suspensions or dispersions described herein include potassium sorbate, parabens (e.g., methylparaben and propylparaben) and their salts, benzoic acid and its salts, other esters of para hydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.
  • Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.
  • the aqueous liquid dispersion can comprise methylparaben and propylparaben in a concentration ranging from at least about 0.01% to about 0.3% or less methylparaben by weight to the weight of the aqueous dispersion and at least about 0.005% to about 0.03% or less propylparaben by weight to the total aqueous dispersion weight.
  • the aqueous liquid dispersion can comprise methylparaben from at least about 0.05 to about 0.1 or less weight % and propylparaben from at least about 0.01 to about 0.02 or less weight % of the aqueous dispersion.
  • Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include methyl cellulose, xanthan gum, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Plasdone® S-630, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.
  • concentration of the viscosity-enhancing agent will depend upon the agent selected and the viscosity desired.
  • the liquid formulations of the present invention can also comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, emulsifiers, and/or sweeteners.
  • the formulation for oral delivery is an effervescent powder containing Bk-2-MAPB, Bk-2-EAPB, Bk-2-MAPB, or Bk-2-EAPB, or a pharmaceutically acceptable salt thereof.
  • the formulation for oral delivery is an effervescent powder containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II or a pharmaceutically acceptable salt thereof.
  • the formulation for oral delivery is an effervescent powder containing a 2-ethylamine substituted benzofuran compound of Formula III-VIII or a pharmaceutically acceptable salt thereof. Effervescent salts have been used to disperse medicines in water for oral administration.
  • the formulation for oral delivery is an effervescent powder containing a 2- ethylamine substituted benzofuran or benzothiophene compound of Formula I-VIII, or a pharmaceutically acceptable salt thereof.
  • Effervescent salts have been used to disperse medicines in water for oral administration.
  • Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid.
  • effervescent salts include sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher. Tablets of the invention described here can be prepared by methods well known in the art.
  • solid dosage forms e.g., tablets, effervescent tablets, and capsules
  • solid dosage forms are prepared by mixing the active agents of the present invention particles with one or more pharmaceutical excipients to form a bulk blend composition.
  • these bulk blend compositions as homogeneous, it is meant that the active agents of the present invention particles are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.
  • the individual unit dosages may also comprise film coatings, which disintegrate upon oral ingestion or upon contact with diluents.
  • These the active agents of the present invention formulations can be manufactured by conventional pharmaceutical techniques.
  • Conventional pharmaceutical techniques for preparation of solid dosage forms include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., Theory and Practice of Industrial Pharmacy (1986). Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tableting, extruding and the like.
  • Compressed tablets are solid dosage forms prepared by compacting the bulk blend the active agents of the present invention formulations described above.
  • compressed tablets which are designed to dissolve in the mouth will comprise one or more flavoring agents.
  • the compressed tablets will comprise a film surrounding a final compressed tablet.
  • the film coating can provide a delayed release of the active agents of the present invention formulation.
  • the film coating aids in patient compliance (e.g., Opadry® coatings or sugar coating). Film coatings comprising Opadry® typically range from about 1% to about 3% of the tablet weight. Film coatings for delayed-release usually comprise 2-6% of a tablet weight or 7-15% of a spray- layered bead weight.
  • the compressed tablets comprise one or more excipients.
  • a capsule may be prepared, e.g., by placing the bulk blend of the active agents of the present invention formulation, described above, inside of a capsule.
  • the formulations of the present invention non-aqueous suspensions and solutions
  • the formulations of the present invention are placed in a soft gelatin capsule.
  • the formulations of the present invention are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC.
  • the formulations of the present invention are placed in a sprinkle capsule, wherein the capsule may be swallowed whole, or the capsule may be opened, and the contents sprinkled on food prior to eating.
  • the therapeutic dose is split into multiple (e.g., two, three, or four) capsules.
  • the entire dose of the active agents of the present invention is delivered in a capsule form.
  • ingredients (including or not including the active agent) of the invention are wet granulated.
  • the individual steps in the wet granulation process of tablet preparation include milling and sieving of the ingredients, dry powder mixing, wet massing, granulation, drying, and final grinding.
  • the active agents of the present invention composition are added to the other excipients of the pharmaceutical formulation after they have been wet granulated.
  • the ingredients may be subjected to dry granulation, e.g., via compressing a powder mixture into a rough tablet or “slug” on a heavy-duty rotary tablet press.
  • the slugs are then broken up into granular particles by a grinding operation, usually by passage through an oscillation granulator.
  • the individual steps include mixing of the powders, compressing (slugging) and grinding (slug reduction or granulation). No wet binder or moisture is involved in any of the steps.
  • the active agents of the present invention formulation are dry granulated with other excipients in the pharmaceutical formulation.
  • the active agents of the present invention formulation are added to other excipients of the pharmaceutical formulation after they have been dry granulated.
  • the formulation of the present invention formulations described herein is a solid dispersion. Methods of producing such solid dispersions are known in the art and include U.S. Pat.
  • the solid dispersions of the invention comprise both amorphous and non-amorphous active agents of the present invention and can have enhanced bioavailability as compared to conventional active agents of the present invention formulations.
  • the active agents of the present invention formulations described herein are solid solutions. Solid solutions incorporate a substance together with the active agent and other excipients such that heating the mixture results in the dissolution of the drug and the resulting composition is then cooled to provide a solid blend that can be further formulated or directly added to a capsule or compressed into a tablet.
  • Non-limiting examples of formulations for oral delivery The examples below provide non-limiting embodiments of formulations for oral delivery, which can be used to deliver any of the compounds described herein in enantiomerically enriched form, pure form or even a racemic mixture.
  • Ingredient Quantity (mg/capsule) Ingredient Quantity (mg/capsule)
  • Ingredient Quantity (mg/capsule) Ingredient Quantity (mg/tablet)
  • the examples below provide non-limiting embodiments of formulations for oral delivery, which can be used to deliver any of the compounds described herein in enantiomerically enriched form, pure form or even a racemic mixture. Therefore, while the compounds below are specified, any desired purity form or compound can be used if it achieves the desired goal of treatment.
  • hard gelatin capsules comprising the following ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities. In one non-limiting embodiment, hard gelatin capsules comprising the following ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities. Ingredient Quantity (mg/capsule) n one non- mtng emo ment, ar geatn capsues comprsng te o owng ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities. Ingredient Quantity (mg/capsule) In one non-limiting embodiment, hard gelatin capsules comprising the following ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities.
  • Ingredient Quantity (mg/capsule) g , g p p g ng ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities.
  • Ingredient Quantity (mg/capsule) In one non-limiting embodiment, hard gelatin capsules comprising the following ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities.
  • Ingredient Quantity (mg/capsule) In one non-limiting embodiment, hard gelatin capsules comprising the following ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities.
  • Ingredient Quantity (mg/capsule) n one non- mtng embodment, ard geatn capsues comprsng te o owng ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities.
  • Ingredient Quantity (mg/capsule) In one non-limiting embodiment, a tablet formulation is prepared comprising the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg. Ingredient Quantity (mg/tablet) g , p p p g the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg.
  • Ingredient Quantity (mg/capsule) In one non-limiting embodiment, a tablet formulation is prepared comprising the ingredients below.
  • a tablet formulation is prepared comprising the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg.
  • Ingredient Quantity (mg/tablet) In one non-limiting embodiment, a tablet formulation is prepared comprising the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg.
  • Ingredient Quantity (mg/tablet) In one non-limiting embodiment, a tablet formulation is prepared comprising the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg Ingredient Quantity (mg/tablet)
  • a tablet formulation is prepared comprising the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg. Ingredient Quantity (mg/tablet) n one non- m t ng embod ment, a tab et ormu at on s prepared compr s ng the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg. Ingredient Quantity (mg/tablet) In one non-limiting embodiment, a tablet formulation is prepared comprising the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg.
  • Ingredient Quantity (mg/tablet) oe o - g e o e , a a e o ua o s pepae co p s g the ingredients below.
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • Ingredient Quantity (mg/tablet) The examples below provide non-limiting embodiments, wherein a tablet formulation is prepared comprising the ingredients below.
  • a tablet comprising the components below, including R- -Bk-2-MAPB, is prepared.
  • the active ingredients, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Ingredient Quantity (mg/tablet) Polyvinylpyrrolidone (as 10% solution in 4.0 g , , p g p , g R- -Bk-2-EAPB, is prepared.
  • the active ingredients, starch and cellulose are passed through a No.20 mesh U.S. sieve and mixed thoroughly.
  • a tablet comprising the components below, including R- Bk-2-MAPB, is prepared.
  • the active ingredients, starch and cellulose are passed through a No.20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No.30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • a tablet comprising the components below, including R-Bk-2- EAPB, is prepared.
  • the active ingredients, starch and cellulose are passed through a No.20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No.30 mesh U.S.
  • a tablet comprising the components below, including an R-enantiomer of a 2-ethylamine substituted benzofuran compound of Formula I and a racemic compound of Formula I is prepared.
  • the active ingredients, starch and cellulose are passed through a No.20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60° C and passed through a 16 mesh U.S.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No.30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Ingredient Quantity (mg/tablet) Sodium carboxymethyl starch 4.5 , , , R- Bk-2-MAPB, is prepared.
  • the active ingredients, starch and cellulose are passed through a No.20 mesh U.S.
  • a tablet comprising the components below, including R- Bk-2-EAPB, is prepared.
  • the active ingredients, starch and cellulose are passed through a No.20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No.30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • a tablet formulation comprising the ingredients below.
  • Ingredient Quantity (mg/capsule) Ingredient Quantity (mg/capsule)
  • Ingredient Quantity (mg/capsule) Ingredient Quantity (mg/capsule)
  • a capsule comprising the components below, including Bk-2-MAPB, is prepared.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Ingredient Quantity (mg/capsule) Magnesium stearate 1.0 , , , ing Bk-2-EAPB, is prepared.
  • a capsule, comprising the components below, including Bk-2-MAPB is prepared.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Ingredient Quantity (mg/capsule) In one non-limiting embodiment, a capsule, comprising the components below, including Bk-2-MAPB, is prepared.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Ingredient Quantity (mg/capsule) In one non-limiting embodiment, a capsule, comprising the components below, including Bk-2-EAPB, is prepared.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Ingredient Quantity (mg/capsule) g , p , p g p , ing a racemic compound of Formula I and an R-enantiomer of a 2-ethylamine substituted benzofuran compound of Formula I, is prepared.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • a capsule comprising the components below, including a racemic compound of Formula II and an R-enantiomer of a 2-ethylamine substituted benzothiophene compound of Formula II, is prepared.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S.
  • Ingredient Quantity (mg/capsule) ing Bk-2-EAPB is prepared.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Ingredient Quantity (mg/capsule) Magnesium stearate 1.0 is prepared using the ingredients below. The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
  • a capsule comprising 15 mg of S-Bk-2-EAPB, is prepared using the ingredients below.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
  • Ingredient Amount (mg/capsule) In one non-limiting embodiment, a capsule, comprising 100 mg of R-Bk-2-MAPB, is prepared using the ingredients below.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 510 mg quantities.
  • Ingredient Amount (mg/capsule) o e o - g e o e , a capsu e, co p s g g o - - - , is prepared using the ingredients below.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 510 mg quantities.
  • Ingredient Amount (mg/capsule) In one non-limiting embodiment, a capsule, comprising 100 mg of an R-enantiomer of a 2-ethylamine substituted benzofuran compound of Formula I, is prepared using the ingredients below.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 510 mg quantities.
  • Ingredient Amount (mg/capsule)
  • a capsule comprising 100 mg of an R-enantiomer of a 2-ethylamine substituted benzothiophene compound of Formula II, is prepared using the ingredients below.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 510 mg quantities.
  • Ingredient Amount (mg/capsule) n one non- m t ng embod ment, a capsu e, comprs ng 00 mg o - - - , is prepared using the ingredients below.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 510 mg quantities.
  • Ingredient Amount (mg/capsule) In one non-limiting embodiment, a capsule, comprising 100 mg of R-Bk-2-EAPB, is prepared using the ingredients below.
  • the pharmaceutical formulation for example, an oral solid dosage form, may contain a suitable amount of controlled-release agents, extended- release agents, and/or modified-release agents (e.g., delayed-release agents).
  • the pharmaceutical solid oral dosage forms comprising the active agents of the present invention described herein can be further formulated to provide a modified or controlled release of the active agents of the present invention.
  • the solid dosage forms described herein can be formulated as a delayed release dosage form such as an enteric-coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which uses an enteric coating to affect release in the small intestine of the gastrointestinal tract.
  • the enteric-coated dosage form may be a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated.
  • the enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated. Enteric coatings may also be used to prepare other controlled release dosage forms including extended-release and pulsatile release dosage forms.
  • the active agents of the formulations described herein are delivered using a pulsatile dosage form. Pulsatile dosage forms comprising the active agents of the present invention described herein may be administered using a variety of formulations known in the art. For example, such formulations include those described in U.S. Pat. Nos. 5,011,692; 5,017,381; 5,229,135; and 5,840,329.
  • the controlled release dosage form is pulsatile release solid oral dosage form comprising at least two groups of particles, each containing active agents of the present invention as described herein.
  • the first group of particles provides a substantially immediate dose of the active agents of the present invention upon ingestion by a subject.
  • the first group of particles can be either uncoated or comprise a coating and/or sealant.
  • the second group of particles comprises coated particles, which may comprise from at least about 2% to about 75% or less, typically from at least about 2.5% to about 70% or less, or from at least about 40% to about 70% or less, by weight of the total dose of the active agents of the present invention in said formulation, in admixture with one or more binders.
  • a coating for providing a controlled, delayed, or extended-release is applied to Bk-2-MAPB or to a core containing Bk-2-MAPB.
  • a coating for providing a controlled, delayed, or extended-release is applied to Bk-2-EAPB or to a core containing Bk-2-EAPB.
  • a coating for providing a controlled, delayed, or extended-release is applied to a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II or to a core containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II.
  • a coating for providing a controlled, delayed, or extended-release is applied to a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I-VIII or to a core containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I-VIII.
  • a coating for providing a controlled, delayed, or extended-release is applied to a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I-VIII, or to a core containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I-VIII.
  • the coating may comprise a pharmaceutically acceptable ingredient in an amount sufficient, e.g., to provide an extended release from e.g., about 1 hours to about 7 hours following ingestion before release of the active agent.
  • Suitable coatings include one or more differentially degradable coatings such as, by way of example only, pH-sensitive coatings (enteric coatings) such as acrylic resins (e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, and Eudragit® NE30D, Eudragit® NE 40D® ) either alone or blended with cellulose derivatives, e.g., ethylcellulose, or non-enteric coatings having variable thickness to provide differential release of the active agents of the present invention formulation.
  • enteric coatings such as acrylic resins (e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S
  • lipids including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like.
  • polymer-based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone, cellulose derivatives (e.g., ethylcellulose), porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like.
  • the controlled release systems may comprise the controlled/delayed/extended-release material incorporated with the drug(s) into a matrix, whereas in other formulations, the controlled release material may be applied to a core containing the drug(s).
  • one drug may be incorporated into the core while the other drug is incorporated into the coating.
  • materials include shellac, acrylic polymers, cellulosic derivatives, polyvinyl acetate phthalate, and mixtures thereof.
  • materials include Eudragit® series E, L, RL, RS, NE, L, L300, S, 100-55, cellulose acetate phthalate, Aquateric, cellulose acetate trimellitate, ethyl cellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, and Cotteric.
  • the controlled/delayed/extended-release systems may use a hydrophilic polymer, including a water-swellable polymer (e.g., a natural or synthetic gum).
  • the hydrophilic polymer may be any pharmaceutically acceptable polymer which swells and expands in the presence of water to slowly release the active agents of the present invention.
  • acrylic polymers include polyethylene oxide, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and the like.
  • the performance of acrylic polymers can vary based on the degree and type of substitution.
  • suitable acrylic polymers which may be used in matrix formulations or coatings include methacrylic acid copolymers and ammonia methacrylate copolymers.
  • the Eudragit series E, L, S, RL, RS and NE are available as solubilized in an organic solvent, aqueous dispersion, or dry powders.
  • the Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting.
  • the Eudragit series E dissolve in the stomach.
  • the Eudragit series L, L-30D and S are insoluble in the stomach and dissolve in the intestine; Opadry Enteric is also insoluble in the stomach and dissolves in the intestine.
  • suitable cellulose derivatives for use in matrix formulations or coatings include ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution.
  • Cellulose acetate phthalate (CAP) dissolves in pH >6.
  • Aquateric (FMC) is an aqueous-based system and is a spray-dried CAP psuedolatex with particles ⁇ 1 ⁇ m.
  • Aquateric can include pluronic, Tweens, and acetylated monoglycerides.
  • suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethylcellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)).
  • HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable.
  • the performance can vary based on the degree and type of substitution.
  • suitable grades of hydroxypropylmethylcellulose acetate succinate include AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.
  • AS-LG LF
  • AS-MG MF
  • AS-HG HF
  • suitable cellulose derivatives include hydroxypropylmethylcellulose.
  • the coating may contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well known in the art.
  • Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate.
  • anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin.
  • Multilayer tablet delivery (e.g., such as that used in the GeoMatrixTM technology) comprises a hydrophilic matrix core containing the active ingredient and one or two impermeable or semi-permeable polymeric coatings. This technology uses films or compressed polymeric barrier coatings on one or both sides of the core. The presence of polymeric coatings (e.g., such as that used in the GeoMatrixTM technology) modifies the hydration/swelling rates of the core and reduces the surface area available for drug release.
  • partial coatings provide modulation of the drug dissolution profile: they reduce the release rate from the device and shift the typical time- dependent release rate toward constant release.
  • This technology enables customized levels of controlled release of specific active agents and/or simultaneous release of two different active agents at different rates that can be achieved from a single tablet.
  • the combination of layers, each with different rates of swelling, gelling and erosion, is used for the rate of drug release in the body. Exposure of the multilayer tablet as a result of the partial coating may affect the release and erosion rates, therefore, transformation of a multilayered tablet with exposure on all sides to the gastrointestinal fluids upon detachment of the barrier layer will be considered.
  • Multi-layered tablets containing combinations of immediate release and modified/extended release of two different active agents or dual release rate of the same drug in a single dosage form may be prepared by using hydrophilic and hydrophobic polymer matrices. Dual release repeat action multi-layered tablets may be prepared with an outer compression layer with an initial dose of rapidly disintegrating matrix in the stomach and a core inner layer tablet formulated with components that are insoluble in the gastric media but release efficiently in the intestinal environment.
  • the dosage form is a solid oral dosage form which is an immediate release dosage form whereby >80% of the active agents of the present invention are released within 2 hours after administration.
  • the invention provides an (e.g., solid oral) dosage form that is a controlled release or pulsatile release dosage form.
  • the release may be, e.g., 30 to 60% of the active agents of the present invention particles by weight are released from the dosage form within about 2 hours after administration and about 90% by weight of the active agents of the present invention released from the dosage form, e.g., within about 4 hours after administration.
  • the dosage form includes at least one active agent in an immediate-release form and at least one active agent in the delayed-release form or sustained-release form.
  • the dosage form includes at least two active agents that are released at different rates as determined by in-vitro dissolution testing or via oral administration.
  • the various release dosage formulations discussed above, and others known to those skilled in the art can be characterized by their disintegration profile. A profile is characterized by the test conditions selected.
  • the disintegration profile can be generated at a pre-selected apparatus type, shaft speed, temperature, volume, and pH of the dispersion media.
  • Several disintegration profiles can be obtained. For example, a first disintegration profile can be measured at a pH level approximating that of the stomach (about pH 1.2); a second disintegration profile can be measured at a pH level approximating that of one point in the intestine or several pH levels approximating multiple points in the intestine (about 6.0 to about 7.5, more specifically, about 6.5 to 7.0).
  • Another disintegration profile can be measured using distilled water.
  • the release of formulations may also be characterized by their pharmacokinetic parameters, for example, C max , T max , and AUC (0- ⁇ ).
  • the controlled, delayed or extended-release of one or more of the active agents of the fixed-dose combinations of the invention may be in the form of a capsule having a shell comprising the material of the rate-limiting membrane, including any of the coating materials previously discussed, and filled with the active agents of the present invention particles.
  • the capsule may be prepared independently of the active agent of the present invention particles; thus, process conditions that would adversely affect the drug can be used to prepare the capsule.
  • the formulation may comprise a capsule having a shell made of a porous or a pH-sensitive polymer made by a thermal forming process.
  • a capsule shell in the form of an asymmetric membrane i.e., a membrane that has a thin skin on one surface and most of whose thickness is constituted of a highly permeable porous material.
  • the asymmetric membrane capsules may be prepared by a solvent exchange phase inversion, wherein a solution of polymer, coated on a capsule-shaped mold, is induced to phase separate by exchanging the solvent with a miscible non-solvent.
  • spray layered active agents of the present invention particles are filled in a capsule.
  • An exemplary process for manufacturing the spray layered the active agents of the present invention is the fluidized bed spraying process.
  • the active agents of the present invention suspensions or the active agents of the present invention complex suspensions described above may be sprayed onto sugar or microcrystalline cellulose (MCC) beads (20-35 mesh) with Wurster column insert at an inlet temperature of 50°C to 60°C and air temp of 30°C to 50°C.
  • MCC microcrystalline cellulose
  • the resulting spray layered the active agents of the present invention particles, or the active agents of the present invention complex particles comprise about 30 to 70 wt% of the active agents of the present invention based on the total weight of the particles.
  • the capsule is a size 0 soft gelatin capsule.
  • the capsule is a swelling plug device.
  • the swelling plug device is further coated with cellulose acetate phthalate or copolymers of methacrylic acid and methylmethacrylate.
  • the capsule includes at least 40 mg (or at least 100 mg or at least 200 mg) of the active agents of the present invention and has a total weight of less than 800 mg (or less than 700 mg).
  • the capsule may contain a plurality of the active agents of the present invention- containing beads, for example, spray layered beads.
  • the beads are 12-25% the active agents of the present invention by weight.
  • some or all of the active agents of the present invention containing beads are coated with a coating comprising 6 to 15% (or 8 to 12%) of the total bead weight. Optimization work typically involves lower loading levels, and the beads constitute 30 to 60% of the finished bead weight.
  • the capsule may contain a granulated composition, wherein the granulated composition comprises the active agents of the present invention.
  • the capsule may provide pulsatile release of the active agents of the present invention oral dosage form.
  • the formulations comprise: (a) a first dosage unit comprising Bk-2-MAPB that is released substantially immediately following oral administration of the dosage form to a patient; (b) a second dosage unit comprising Bk-2-MAPB that is released approximately 2 to 6 hours following administration of the dosage form to a patient.
  • the formulations comprise: (a) a first dosage unit comprising Bk-2-EAPB and/or Bk-2-MAPB that is released substantially immediately following oral administration of the dosage form to a patient; (b) a second dosage unit comprising Bk-2-MAPB and/or Bk-2-EAPB that is released approximately 2 to 6 hours following administration of the dosage form to a patient.
  • the formulation comprises: (a) a first dosage unit comprising compounds of Formula I and/or Formula II that is released substantially immediately following oral administration of the dosage form to a patient; (b) a second dosage unit comprising compounds of Formula I and/or Formula II that is released approximately 2 to 6 hours following administration of the dosage form to a patient.
  • the formulation comprises: (a) a first dosage unit comprising a 2- ethylamine substituted benzothiophene compound of Formula II that is released substantially immediately following oral administration of the dosage form to a patient; (b) a second dosage unit comprising a 2-ethylamine substituted benzothiophene compound of Formula II that is released approximately 2 to 6 hours following administration of the dosage form to a patient.
  • the formulation comprises: (a) a first dosage unit comprising a 2- ethylamine substituted benzofuran compound of Formula III-VIII, or a pharmaceutically acceptable salt thereof that is released substantially immediately following oral administration of the dosage form to a patient; (b) a second dosage unit comprising a 2-ethylamine substituted benzofuran compound of Formula III-VIII, or a pharmaceutically acceptable salt thereof that is released approximately 2 to 6 hours following administration of the dosage form to a patient.
  • the beads can be coated with a coating comprising 6 to 15% (or 8 to 12%) of the total bead weight.
  • the coating is a coating that is insoluble at pH 1 to 2 and soluble at pH greater than 5.5.
  • the pulsatile release capsule contains a plurality of beads formulated for modified release and the at least one agent of the present invention is, for example, spray granulated for immediate release.
  • the release of the active agents of the present invention particles can be modified with a modified release coating, such as an enteric coating using cellulose acetate phthalate or a sustained release coating comprising copolymers of methacrylic acid and methylmethacrylate.
  • the enteric coating may be present in an amount of about 0.5 to about 15 wt%, more specifically, about 8 to about 12 wt%, based on the weight of, e.g., the spray layered particles.
  • the spray layered particles coated with the delayed and/or sustained release coatings can be filled in a modified release capsule in which both enteric-coated particles and immediate release particles of the present invention beads are filled into a soft gelatin capsule. Additional suitable excipients may also be filled with the coated particles in the capsule. The uncoated particles release the active agent of the present invention immediately upon administration while the coated particles do not release the active agent of the present invention until these particles reach the intestine.
  • the ratios between the uncoated and the coated particles are e.g., 20/80, or 30/70, or 40/60, or 50/50, w/w to obtain desirable release.
  • spray layered active agents of the present invention can be compressed into tablets with commonly used pharmaceutical excipients. Any appropriate apparatus for forming the coating can be used to make the enteric coated tablets, e.g., fluidized bed coating using a Wurster column, powder layering in coating pans or rotary coaters; dry coating by double compression technique; tablet coating by film coating technique, and the like. See, e.g., U.S. Pat.
  • the spray layered active agents of the present invention described above and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the active agents of the present invention formulation into the gastrointestinal fluid.
  • a pulsatile release of the active agent of the present invention formulation comprises a first dosage unit comprising a formulation made from the active agent of the present invention containing granules made from a spray drying or spray granulated procedure or a formulation made from the active agent of the present invention complex containing granules made from a spray drying or spray granulated procedure without enteric or sustained-release coatings and a second dosage unit comprising spray layered the active agent of the present invention particles or spray layered the active agent of the present invention complex particles with enteric or sustained-release coatings.
  • the active agent is wet or dry blended and compressed into a mass to make a pulsatile release tablet.
  • binding, lubricating and disintegrating agents are blended (wet or dry) to the spray layered active agent of the present invention to make a compressible blend.
  • the dosage unit containing Bk-2-MAPB and/or Bk-2-EAPB and the dosage unit containing the other pharmacological agent are compressed separately and then compressed together to form a bilayer tablet.
  • the dosage unit containing the other pharmacological agent is in the form of an overcoat and completely covers the second dosage unit containing Bk-2-MAPB and/or Bk-2-EAPB.
  • the dosage unit containing Bk-2-MAPB and/or Bk-2-EAPB is in the form of an overcoat and completely covers the second dosage unit containing the other pharmacological agent.
  • the dosage unit containing Bk-2-MAPB and/or Bk-2-EAPB and the dosage unit containing the other pharmacological agent are compressed separately and then compressed together to form a bilayer tablet.
  • the dosage unit containing the other pharmacological agent is in the form of an overcoat and completely covers the second dosage unit containing Bk-2-MAPB and/or Bk-2-EAPB.
  • the dosage unit containing Bk-2-MAPB and/or Bk-2-EAPB is in the form of an overcoat and completely covers the second dosage unit containing the other pharmacological agent.
  • the dosage unit containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II and the dosage unit containing the other pharmacological agent are compressed separately and then compressed together to form a bilayer tablet.
  • the dosage unit containing the other pharmacological agent is in the form of an overcoat and completely covers the second dosage unit containing a 2- ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II.
  • the dosage unit containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II is in the form of an overcoat and completely covers the second dosage unit containing the other pharmacological agent.
  • the dosage unit containing a 2-ethylamine substituted benzofuran compound of Formula III-VIII and the dosage unit containing the other pharmacological agent are compressed separately and then compressed together to form a bilayer tablet.
  • the dosage unit containing the other pharmacological agent is in the form of an overcoat and completely covers the second dosage unit containing a 2-ethylamine substituted benzofuran compound of Formula III-VIII.
  • the dosage unit containing a 2-ethylamine substituted benzofuran compound of Formula III-VIII is in the form of an overcoat and completely covers the second dosage unit containing the other pharmacological agent.
  • Systemic Formulations The formulations of the present invention can include any selected compound of the present invention for any of the disclosed indications in a form suitable for intramuscular, subcutaneous, or intravenous injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (propylene glycol, polyethylene- glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • the active agents of the present invention can be dissolved at concentrations of greater than about 1 mg/ml using water-soluble beta cyclodextrins (e.g., beta-sulfobutyl-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin.
  • Proper fluidity can be maintained, for example, by the use of a coating such as a lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • the formulations of the present invention suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, benzoic acid, benzyl alcohol, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like.
  • Prolonged drug absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
  • agents delaying absorption such as aluminum monostearate and gelatin.
  • the formulations of the present invention designed for extended-release via subcutaneous or intramuscular injection can avoid first-pass metabolism and lower dosages of the active agents of the present invention will be necessary to maintain plasma levels of about 50 ng/ml.
  • the particle size of the active agents of the present invention and the range of the particle sizes of the active agents of the present invention particles can be used to control the release of the drug by controlling the rate of dissolution in fat or muscle.
  • a pharmaceutical composition containing Bk-2-MAPB and/or Bk- 2-EAPB or a pharmaceutically acceptable salt thereof is formulated into a dosage form suitable for parenteral use.
  • pharmaceutical compositions containing compounds of Formula I and/or Formula II or a pharmaceutically acceptable salt thereof is formulated into a dosage form suitable for parenteral use.
  • pharmaceutical compositions containing compounds of Formula III-VIII or a pharmaceutically acceptable salt thereof is formulated into a dosage form suitable for parenteral use.
  • the dosage form may be selected from, but not limited to, a lyophilized powder, a solution, or a suspension (e.g., a depot suspension).
  • a pharmaceutical composition containing Bk-2-MAPB and/or Bk- 2-EAPB or a pharmaceutically acceptable salt thereof is formulated into a topical dosage form.
  • a pharmaceutical composition containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II or a pharmaceutically acceptable salt thereof is formulated into a topical dosage form.
  • a pharmaceutical composition containing a 2-ethylamine substituted benzofuran compound of Formula III-VIII or a pharmaceutically acceptable salt thereof is formulated into a topical dosage form.
  • the topical dosage form is selected from, but not limited to, a patch, a gel, a paste, a cream, an emulsion, a liniment, a balm, a lotion, and an ointment.
  • Another formulation employed in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly.
  • Direct techniques usually involve placement of a drug delivery catheter into the host’s ventricular system to bypass the blood-brain barrier.
  • Indirect techniques which are generally useful, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood- brain barrier.
  • Non-limiting examples of formulations for systemic delivery The examples below provide non-limiting embodiments of formulations, which can be used to deliver any of the compounds described herein in enantiomerically enriched form, pure form or even a racemic mixture.
  • Ingredient Quantity (mg) Ingredient Quantity (mg)
  • Ingredient Quantity (mg) Ingredient Quantity (mg)
  • the examples below provide non-limiting embodiments of formulations, which can be used to deliver any of the compounds described herein in enantiomerically enriched form, pure form or even a racemic mixture. Therefore, while the compounds below are specified, any desired purity form or compound can be used if it achieves the desired goal of treatment.
  • a suppository comprising 25 mg of S-Bk-2-MAPB, is prepared.
  • the active ingredient is passed through a No.60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary.
  • the mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
  • Ingredient Quantity (mg) n one non- m t ng em o ment, a suppos tory, compr s ng mg o - - - , is prepared.
  • the active ingredient is passed through a No.60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary.
  • a suppository comprising 25 mg of a 2-ethylamine substituted benzofuran compound of Formula I.
  • the active ingredient is passed through a No.60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary.
  • the mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
  • Ingredient Quantity (mg) In one non-limiting embodiment, a suppository, comprising 25 mg of a 2-ethylamine substituted benzothiophene compound of Formula II, is prepared.
  • the active ingredient is passed through a No.60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary.
  • the mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
  • Ingredient Quantity (mg) n one non- m ng em o men, a suppos ory, compr s ng mg o - - - , is prepared.
  • the active ingredient is passed through a No.60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary.
  • the mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
  • a suspension comprising 50 mg of S-Bk-2-EAPB per 5.0 ml dose is prepared using the ingredients below.
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • Sodium carboxymethyl cellulose (11%) 50.0 mg n one non- m ng em o men, a suspens on comprs ng mg o - - - per 5.0 ml dose is prepared using the ingredients below.
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • a suspension comprising 50 mg of an R-enantiomer of a 2-ethylamine substituted benzofuran compound of Formula I per 5.0 ml dose is prepared using the ingredients below.
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No.10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • a suspension comprising 50 mg of an R-enantiomer of a 2-ethylamine substituted benzothiophene compound of Formula II per 5.0 ml dose is prepared using the ingredients below.
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • a suspension comprising 50 mg of R-Bk-2-MAPB per 5.0 ml dose is prepared using the ingredients below.
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No.10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • an intravenous formulation is prepared using the following ingredients: Ingredient Amount In one non-limiting embodiment, an intravenous formulation is prepared using the following ingredients: Ingredient Amount In one non-limiting embodiment, an intravenous formulation is prepared using the following ingredients: Ingredient Amount g , g the following ingredients: Ingredient Amount The example below provides a non-limiting embodiment, wherein a topical formulation is prepared comprising the ingredients below. Ingredient Amount (g) In one non-limiting embodiment, a topical formulation is prepared using the ingredients below. The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • a sublingual or buccal tablet comprising 10 mg of S-Bk-2-EAPB, is prepared using the following ingredients.
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90° C.
  • the solution is cooled to about 50-55° C. and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm.
  • This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • Ingredient Amount (mg/tablet) Sodium Citrate 4.5 , , PB is prepared using the following ingredients. The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90° C. When the polymers have gone into solution, the solution is cooled to about 50-55° C. and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • a sublingual or buccal tablet comprising 20 mg of an R- enantiomer of a 2-ethylamine substituted benzofuran compound of Formula I, is prepared using the following ingredients.
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90° C.
  • the solution is cooled to about 50-55° C. and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm.
  • a sublingual or buccal tablet comprising 20 mg of an R- enantiomer of a 2-ethylamine substituted benzothiophene compound of Formula II, is prepared using the following ingredients.
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90° C.
  • the solution is cooled to about 50-55° C. and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • Ingredient Amount (mg/tablet) Polyvinylpyrrolidone 15.5 B, is prepared using the following ingredients. The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90° C. When the polymers have gone into solution, the solution is cooled to about 50-55° C. and the medicament is slowly admixed.
  • a liquid formulation for vaporization is prepared using the following ingredients.
  • Ingredient Quantity (units)
  • a liquid formulation for vaporization comprising R-Bk- 2-EAPB, is prepared using the ingredients below. The active mixture is mixed and added to a liquid vaporization appliance.
  • Ingredient Quantity (units) oe o- g e o e , a qu o ua o o vapo a o co p s g a 2- ethylamine substituted benzofuran compound of Formula I, is prepared using the ingredients below. The active mixture is mixed and added to a liquid vaporization appliance.
  • Ingredient Quantity (units) In one non-limiting embodiment, a liquid formulation for vaporization comprising a 2- ethylamine substituted benzothiophene compound of Formula II, is prepared using the ingredients below. The active mixture is mixed and added to a liquid vaporization appliance.
  • a liquid formulation for vaporization comprising R-Bk- 2-EAPB, is prepared using the ingredients below.
  • the active mixture is mixed and added to a liquid vaporization appliance.
  • Ingredient Quantity (units) a o- g e o e , a o ua o o y powe o su a o s pepared comprising the components below:
  • Ingredient Weight % In one non-limiting embodiment, a formulation of dry powder for insufflation is prepared comprising the components below.
  • the active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Ingredient Weight % Ingredient Weight %
  • a formulation of dry powder for insufflation comprising the components below.
  • the active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Ingredient Weight % - g , y p p p red comprising the components below.
  • the active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Ingredient Weight % In one non-limiting embodiment, a formulation of dry powder for insufflation is prepared comprising the components below. The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance. Ingredient Weight %
  • a formulation of dry powder for insufflation comprising the components below.
  • the active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Ingredient Weight % y p The compounds described herein, including enantiomerically enriched mixtures, can be administered if desired as a pharmaceutically acceptable salt or a salt mixture.
  • a salt mixture may be useful to increase solubility of the active substances, to alter pharmacokinetics, or for controlled release or other objective.
  • a salt mixture may comprise 2, 3, 4, 5, 6, or more pharmaceutically acceptable salts together to form a single composition.
  • the compounds of the present invention are amines and thus basic, and therefore, react with inorganic and organic acids to form pharmaceutically acceptable acid addition salts.
  • the compounds of the present invention as free amines are oily and have decreased stability at room temperature. In this case it may be beneficial to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration because in some embodiments, the pharmaceutically acceptable salt is solid at room temperature.
  • Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
  • the compounds of the present invention are administered as oxalate salts.
  • the compounds are administered as phosphate salts.
  • Exemplary salts include, but are not limited to, 2-hydroxyethanesulfonate, 2- naphthalenesulfonate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, acetate, adipate, alginate, amsonate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, citrate, clavulariate, cyclopentanepropionate, digluconate, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, finnarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hem
  • exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dode
  • compositions include those employing a hydrochloride anion. While salts of Bk-2-MAPB or Bk-2-EAPB are illustrated, any of the compounds described herein can be substituted, including but not limited to compounds of Formula I-VIII. The compounds can be used as salts or salt mixtures in enantiomerically enriched form, or in pure enantiomeric form.
  • Prodrugs are compounds that are metabolized or otherwise transformed inside the body to the active pharmacologic agent(s) of interest.
  • prodrug will contain the “active” component (for example, Bk-2-MAPB, Bk-2-EAPB, or a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I-VIII, and a prodrug moiety).
  • Examples include N-alpha- acyloxyalkoxycarbonyl derivatives or addition of amino acids to the amine, which can be removed within the body by esterases or similar enzymes, and reactions at the keto-group to form enol ethers, enol esters, and imines.
  • Prodrugs are frequently (though not necessarily) pharmacologically less active or inactive until converted to the parent drug. This is done in the body by a chemical or biological reaction. In some cases, the moiety or chemicals formed from it may also have beneficial effects, including increasing therapeutic effects, decreasing undesirable side effects, or otherwise altering the pharmacokinetics or pharmacodynamics of the active drug.
  • prodrug When the chemical formed from the prodrug moiety has beneficial effects that contribute to the overall beneficial effects of administering the prodrug, then the formed chemical is considered a “codrug.”
  • Types of prodrugs contemplated to be within the scope of the invention include compounds that are transformed in various organs or locations in the body (e.g., liver, kidney, G.I., lung, tissue) to release the active compound.
  • liver prodrugs will include active compounds conjugated with a polymer or chemical moiety that is not released until acted upon by liver cytochrome enzymes and CYP metabolism includes dealkylation, dehydrogenation, reduction, hydrolysis, oxidation, and the breakdown of aromatic rings.
  • Kidney prodrugs will include active compounds conjugated to L-gamma-glutamyl or N-acetyl-L-gamma glutamic moieties so that they are metabolized by gamma-glutamyl transpeptidase before they are bioactive.
  • the compounds may be conjugated to alkylglucoside moieties to create glycosylation-based prodrugs. Digestive or G.I.
  • prodrugs will include those where an active compound is, e.g., formulated into microspheres or nanospheres that do not degrade until the spheres are subjected to an acidic pH; formulated with an amide that will resist biochemical degradation until colonic pH is achieved; or, conjugated with a linear polysaccharide such as pectin that will delay activation until the combination reaches the bacteria in the colon.
  • an active compound e.g., formulated into microspheres or nanospheres that do not degrade until the spheres are subjected to an acidic pH; formulated with an amide that will resist biochemical degradation until colonic pH is achieved; or, conjugated with a linear polysaccharide such as pectin that will delay activation until the combination reaches the bacteria in the colon.
  • a linear polysaccharide such as pectin
  • physiologically functional derivatives refers to physiologically tolerated chemical derivatives of the compound having the same physiological function thereof, for example, by being convertible in the body thereto, and which on administration to a mammal such as a human is able to form (directly or indirectly) the compound or an active metabolite thereof (acting therefore, like a prodrug), or by otherwise having the same physiological function, despite one or more structural differences.
  • physiologically functional derivatives include esters, amides, carbamates, ureas, and heterocycles.
  • compositions of the invention are not limited to combinations of a single compound, and a single carrier, diluent, or excipient alone, but also include combinations of multiple such compounds, and/or multiple carriers, diluents, and excipients.
  • a pharmaceutical composition can be provided to the host, for example a human who can be a patient, with an effective amount of one or more other compounds either of the present invention or other active compounds, in combination, together with one or more other active compounds, and one or more pharmaceutically acceptable carriers, diluents, and/or excipients.
  • a 2-ethylamine substituted benzofuran or benzothiophene compound of the present invention is formulated in a pharmaceutical preparation with other active compounds to increase therapeutic efficacy, decrease unwanted effects, increase stability/shelf-life, and/or alter pharmacokinetics.
  • Such other active compounds include, but are not limited to antioxidants (such alpha-lipoate in acid or salt form, ascorbate in acid or salt form, selenium, or N- acetylcysteine); H2-receptor agonists or antagonists (such as famotidine); stimulants (such as dextroamphetamine, amphetamine, lisdexamphetamine, methylphenidate, or methamphetamine); entactogens (such as MDMA); anti-inflammatories (such as ibuprofen or ketoprofen); matrix metalloproteinase inhibitors (such as doxycycline); NOS inhibitors (such as S-methyl-L- thiocitrulline); proton pump inhibitors (such as omeprazole); phosphodiesterase 5 inhibitors (such as sildenafil); drugs with cardiovascular effects (beta antagonists such as propranolol, mixed alpha and beta antagonists such as carvedilol
  • the ingredients may be in ion, freebase, or salt form and may be isomers or prodrugs.
  • the pharmacological agents that make up the combination therapy disclosed herein may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration.
  • the pharmacological agents that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration.
  • the two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents.
  • the time period between the multiple administration steps may range from, a few minutes to several hours, depending upon the properties of each pharmacological agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmacological agent.
  • Circadian variation of the target molecule concentration may also determine the optimal dose interval.
  • a 2-ethylamine substituted benzofuran or benzothiophene compound of the present invention may be administered while the other pharmacological agent is being administered (concurrent administration) or may be administered before or after other pharmacological agent is administered (sequential administration).
  • the two (or more) drugs are included in the fixed-dose combinations of the present invention are incompatible, cross-contamination can be avoided, e.g., by incorporation of the drugs in different drug layers in the oral dosage form with the inclusion of a barrier layer(s) between the different drug layers, wherein the barrier layer(s) comprise one or more inert/non- functional materials.
  • the formulations of the present invention are fixed-dose combinations of a 2-ethylamine substituted benzofuran or benzothiophene compound of the present invention or a pharmaceutically acceptable salt thereof and at least one other pharmacological agent.
  • Fixed-dose combination formulations may contain, but are not limited to, the following combinations in the form of single-layer monolithic tablet or multi-layered monolithic tablet or in the form of a core tablet-in-tablet or multi-layered multi-disk tablet or beads inside a capsule or tablets inside a capsule.
  • the fixed-dose combination is a therapeutically efficacious fixed- dose combination of immediate-release formulations of Bk-2-MAPB and/or Bk-2-EAPB and other pharmacological agents.
  • the fixed-dose combination is a therapeutically efficacious fixed- dose combinations of extended-release formulations of Bk-2-MAPB and/or Bk-2-EAPB and delayed and/or extended-release other pharmacological agents contained in a single dosage form.
  • the fixed-dose combination is a therapeutically efficacious fixed- dose combinations of immediate-release formulations of compounds of Formula I and/or Formula II and other pharmacological agents.
  • the fixed-dose combination is a therapeutically efficacious fixed- dose combinations of extended-release formulations of compounds of Formula I and/or Formula II and delayed and/or extended-release other pharmacological agents contained in a single dosage form.
  • the fixed-dose combination is a therapeutically efficacious fixed- dose combinations of immediate-release formulations of compounds of Formula III-VIII and other pharmacological agents. In certain embodiments, the fixed-dose combination is a therapeutically efficacious fixed- dose combinations of extended-release formulations of compounds of Formula III-VIII and delayed and/or extended-release other pharmacological agents contained in a single dosage form.
  • the invention includes pharmaceutically acceptable complex derivatives of the compound or composition, including solvates, salts, esters, enantiomers, isomers (stereoisomers and/or constitutional, including ones based on substituting deuterium for hydrogen), derivatives or prodrugs of Bk-2-MAPB and/or Bk-2-EAPB.
  • the invention includes pharmaceutically acceptable complex derivatives of the compound or composition, including solvates, salts, esters, enantiomers, isomers (stereoisomers and/or constitutional, including ones based on substituting deuterium for hydrogen), derivatives or prodrugs of compounds of Formula I and/or Formula II.
  • the invention includes pharmaceutically acceptable complex derivatives of the compound or composition, including solvates, salts, esters, enantiomers, isomers ⁇ stereoisomers and/or constitutional, including ones based on substituting deuterium for hydrogen), derivatives or prodrugs of compounds of Formula III-VIII.
  • extended-release multi-layered matrix tablets are prepared using fixed-dose combinations of Bk-2-MAPB and/or Bk-2-EAPB with another pharmacological agent. In certain embodiments, extended-release multi-layered matrix tablets are prepared using fixed- dose combinations of Bk-2-MAPB and/or Bk-2-EAPB with another pharmacological agent. In certain embodiments, extended-release multi-layered matrix tablets are prepared using fixed-dose combinations of compounds of Formula I and/or Formula II with another pharmacological agent. In certain embodiments, extended-release multi-layered matrix tablets are prepared using fixed- dose combinations of compounds of Formula III-VIII with another pharmacological agent. Such formulations may comprise one or more of the active agents within a hydrophilic or hydrophobic polymer matrix.
  • extended-release multi-layered matrix tablets are prepared using fixed-dose combinations of compounds of Formulas I-VIII or a pharmaceutically acceptable salt thereof, with another pharmacological agent.
  • a hydrophilic polymer may comprise guar gum, hydroxypropylmethylcellulose, and xanthan gum as matrix formers.
  • Lubricated formulations may be compressed by a wet granulation method.
  • Another embodiment of the invention includes multiple variations in the pharmaceutical dosages of each drug in the combination as further outlined below.
  • Another embodiment of the invention includes various forms of preparations including using solids, liquids, immediate or delayed or extended-release forms. Many types of variations are possible as known to those skilled in the art.
  • Bk-2-MAPB and/or Bk-2-EAPB either an enantiomer or a mixture of enantiomers, with zero to five or zero to seven hydrogens replaced with deuterium, is formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of dextroamphetamine in the amount of 2 mg, 4 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, or 25 mg.
  • the required amount of dextroamphetamine will vary depending on the needs of the patient.
  • a 2-ethylamine substituted benzofuran or benzothiophene compound of Bk-2-MAPB and/or Bk-2-EAPB, with zero to five or zero to seven hydrogens replaced with deuterium is formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of dextroamphetamine with dextroamphetamine in a ratio by weight of 1:2, 1:3, 1:4, or 1:5 to a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II.
  • the required amount of dextroamphetamine will vary depending on the needs of the patient.
  • a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II, with zero to five or zero to seven hydrogens replaced with deuterium is formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of dextroamphetamine in the amount of 2 mg, 4 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, or 25 mg.
  • the required amount of dextroamphetamine will vary depending on the needs of the patient.
  • a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II, with zero to five or zero to seven hydrogens replaced with deuterium is formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of dextroamphetamine with dextroamphetamine in a ratio by weight of 1:2, 1:3, 1:4, or 1:5 to a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II.
  • the required amount of dextroamphetamine will vary depending on the needs of the patient.
  • a 2-ethylamine substituted benzofuran compound of Formula III- VIII, with zero to five or zero to seven hydrogens replaced with deuterium is formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of dextroamphetamine in the amount of 2 mg, 4 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, or 25 mg.
  • the required amount of dextroamphetamine will vary depending on the needs of the patient.
  • a 2-ethylamine substituted benzofuran compound of Formula III- VIII is formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of dextroamphetamine with dextroamphetamine in a ratio by weight of 1:2, 1:3, 1:4, or 1:5 to a 2- ethylamine substituted benzofuran compound of Formula III-VIII.
  • the required amount of dextroamphetamine will vary depending on the needs of the patient.
  • Bk-2-MAPB and/or Bk-2-EAPB or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition that also contains dextroamphetamine or a pharmaceutically acceptable salt thereof in the amount of at least about 2 mg, 4 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, or 25 mg.
  • the required amount of dextroamphetamine will vary depending on the needs of the patient.
  • the compound of Bk-2- MAPB and/or Bk-2-EAPB can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S-enantiomers.
  • the compound of Bk-2-MAPB and/or Bk-2-EAPB is deuterated wherein one to five hydrogens have been replaced with deuterium.
  • the ratio of dextroamphetamine (with or without salt) to Bk-2- MAPB and/or Bk-2-EAPB (with or without salt) is about 1:2, about 1:3, about 1:4, or about 1:5 by weight.
  • a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition that also contains dextroamphetamine or a pharmaceutically acceptable salt thereof in the amount of at least about 2 mg, 4 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, or 25 mg.
  • the required amount of dextroamphetamine will vary depending on the needs of the patient.
  • the compound of Formula I and/or Formula II can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S- enantiomers.
  • the compound of Formula I and/or Formula II is deuterated wherein one to five hydrogens have been replaced with deuterium.
  • the ratio of dextroamphetamine (with or without salt) to the compound of Formula I and/or Formula II (with or without salt) is about 1:2, about 1:3, about 1:4, or about 1:5 by weight.
  • a 2-ethylamine substituted benzofuran compound of Formula III- VIII or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition that also contains dextroamphetamine or a pharmaceutically acceptable salt of in the amount of at least about 2 mg, 4 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, or 25 mg.
  • the required amount of dextroamphetamine will vary depending on the needs of the patient.
  • the compound of Formula III-VIII can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S-enantiomers.
  • the compound of Formula III-VIII is deuterated wherein one to five hydrogens have been replaced with deuterium.
  • the ratio of dextroamphetamine (with or without salt) to the compound of Formula III-VIII (with or without salt) is about 1:2, about 1:3, about 1:4, about 1:5 by weight.
  • Bk-2-MAPB and/or Bk-2-EAPB is formulated in a pharmaceutical composition that contains MDMA or a pharmaceutically acceptable salt thereof.
  • the composition comprises between about at least 5 and about 180 mg or less of MDMA or a pharmaceutically acceptable salt thereof.
  • the composition comprises between about 15-60 mg of MDMA or a pharmaceutically acceptable salt thereof.
  • the required amount of MDMA will vary depending on the needs of the patient.
  • the compound of 5-Bk-2-MAPB and/or Bk-2-EAPB can be a racemic compound, an R- or S- enantiomer, or an enantiomerically enriched mixture of R- or S-enantiomers.
  • the compound of Bk-2-MAPB and/or Bk-2-EAPB is deuterated wherein one to five hydrogens have been replaced with deuterium.
  • the ratio of MDMA (with or without salt) to Bk-2-MAPB and/or Bk-2-EAPB (with or without salt) is at least about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, or about 1:5 by weight.
  • a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II is formulated in a pharmaceutical composition that contains MDMA or a pharmaceutically acceptable salt thereof.
  • the composition comprises between about at least 5 and about 180 mg or less of MDMA or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition comprises between about 15-60 mg of MDMA or a pharmaceutically acceptable salt thereof.
  • the compound of Formula I and/or Formula II can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S-enantiomers. In certain embodiments, the compound of Formula I and/or Formula II is deuterated wherein one to five hydrogens have been replaced with deuterium.
  • the ratio of MDMA (with or without salt) to the compound of Formula I and/or Formula II (with or without salt) is at least about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, or about 1:5 by weight.
  • a 2-ethylamine substituted benzofuran compound of Formula III- VIII is formulated in a pharmaceutical composition that contains MDMA or a pharmaceutically acceptable salt thereof.
  • the composition comprises between about at least 5 and about 180 mg or less of MDMA or a pharmaceutically acceptable salt thereof.
  • the composition comprises between about 15-60 mg of MDMA or a pharmaceutically acceptable salt thereof.
  • the compound of Formula III-VIII can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S- enantiomers.
  • the compound of Formula III-VIII is deuterated wherein one to five hydrogens have been replaced with deuterium.
  • the ratio of MDMA (with or without salt) to the compound of Formula III-VIII (with or without salt) is at least about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, or about 1:5 by weight.
  • Bk-2-MAPB and/or Bk-2-EAPB are formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of MDMA, in an amount between 5 and 180 mg, typically 15-60 mg.
  • a pharmaceutically acceptable salt of MDMA in an amount between 5 and 180 mg, typically 15-60 mg. The required amount of MDMA will vary depending on the needs of the patient.
  • Bk-2-MAPB and/or Bk-2-EAPB are formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of MDMA with MDMA in a ratio by weight of 1:2, 1:3, 1:4, or 1:5 to Bk-2-MAPB and/or Bk-2- EAPB.
  • the required amount of MDMA will vary depending on the needs of the patient.
  • a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II, as a mixture of enantiomers, with zero to five or zero to seven hydrogens replaced with deuterium are formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of MDMA, in an amount between 5 and 180 mg, typically 15-60 mg.
  • a pharmaceutically acceptable salt of MDMA in an amount between 5 and 180 mg, typically 15-60 mg.
  • the required amount of MDMA will vary depending on the needs of the patient.
  • a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II as a mixture of enantiomers, with zero to five or zero to seven hydrogens replaced with deuterium, are formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of MDMA with MDMA in a ratio by weight of 1:2, 1:3, 1:4, or 1:5 to a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II.
  • the required amount of MDMA will vary depending on the needs of the patient.
  • a 2-ethylamine substituted benzofuran compound of Formula III-VIII as a mixture of enantiomers, with zero to five or zero to seven hydrogens replaced with deuterium, are formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of MDMA, in an amount between 5 and 180 mg, typically 15-60 mg.
  • a pharmaceutically acceptable salt of MDMA in an amount between 5 and 180 mg, typically 15-60 mg. The required amount of MDMA will vary depending on the needs of the patient.
  • a 2-ethylamine substituted benzofuran compound of Formula III-VIII as a mixture of enantiomers, with zero to five or zero to seven hydrogens replaced with deuterium, are formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of MDMA with MDMA in a ratio by weight of 1:2, 1:3, 1:4, or 1:5 to a 2-ethylamine substituted benzofuran compound of Formula III-VIII.
  • the required amount of MDMA will vary depending on the needs of the patient.
  • Bk-2-MAPB and/or Bk-2-EAPB or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition that also contains psilocybin or a pharmaceutically acceptable salt thereof in the amount of at least about 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg.
  • the required amount of psilocybin will vary depending on the needs of the patient.
  • the compound of Bk-2-MAPB and/or Bk-2-EAPB can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S-enantiomers.
  • the compound of Bk-2-MAPB and/or Bk-2-EAPB is deuterated wherein one to five hydrogens have been replaced with deuterium.
  • a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition that also contains psilocybin or a pharmaceutically acceptable salt thereof in the amount of at least about 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg.
  • the required amount of psilocybin will vary depending on the needs of the patient.
  • the compound of Formula I and/or Formula II can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S- enantiomers.
  • the compound of Formula I and/or Formula II is deuterated wherein one to five hydrogens have been replaced with deuterium.
  • a 2-ethylamine substituted benzofuran compound of Formula III- VIII or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition that also contains psilocybin or a pharmaceutically acceptable salt thereof in the amount of at least about 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg.
  • the required amount of psilocybin will vary depending on the needs of the patient.
  • the compound of Formula III-VIII can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S-enantiomers.
  • the compound of Formula III-VIII is deuterated wherein one to five hydrogens have been replaced with deuterium.
  • Non-limiting examples of combination formulations The examples below provide non-limiting embodiments of combination formulations, which can be used to deliver any of the compounds described herein in enantiomerically enriched form, pure form or even a racemic mixture. Therefore, while the compounds below are specified, any desired purity form or compound can be used if it achieves the desired goal of treatment.
  • a capsule comprising one or more compounds of the present invention, and amphetamine sulfate is prepared using the ingredients below.
  • Ingredient Quantity (mg/capsule) Wetting agent or lubricant 1-20 ngre ent Quantty (mgcapsue)
  • Ingredient Quantity (mg/capsule) Ingredient Quantity (mg/tablet)
  • Carrier or binder 10-100 g , p p g , PB, and amphetamine sulfate is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • a capsule comprising deuterated R-Bk-2-EAPB, R-Bk- 2-MAPB, and amphetamine sulfate is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • Ingredient Quantity (mg/capsule) n one non- m ng em o men , a capsu e, compr s ng a eu era e compoun o ormula I, a deuterated compound of Formula II, and amphetamine sulfate is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • Ingredient Quantity (mg/capsule) 2- ethylamine substituted benzofuran compound of Formula I, a deuterated R-enantiomer of a 2- ethylamine substituted benzothiophene compound of Formula II, and amphetamine sulfate is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • Ingredient Quantity (mg/capsule) In one non-limiting embodiment, a capsule, comprising deuterated R-EAPB, deuterated R- MAPB, and amphetamine sulfate is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • Ingredient Quantity (mg/capsule) nd amphetamine sulfate, is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • Ingredient Quantity (mg/capsule) n ceran non- m ng emo mens, a capsue comprsng one or more compouns o the present invention, and psilocybin hydrochloride is prepared using the ingredients below.
  • Ingredient Quantity (mg/capsule) Ingredient Quantity (mg/capsule)
  • Ingredient Quantity (mg/capsule) Ingredient Quantity (mg/tablet)
  • a capsule, comprising R-Bk-2-EAPB, S-Bk-2-EAPB, and psilocybin hydrochloride is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S.
  • a capsule comprising enantiomerically enriched Bk-2- MAPB, enantiomerically enriched Bk-2-EAPB, and psilocybin hydrochloride, is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • a capsule comprising a non-racemic compound of Formula I, a non-racemic compound of Formula II, and psilocybin hydrochloride, is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • Ingredient Quantity (mg/capsule) In one non-limiting embodiment, a capsule, comprising an enantiomerically enriched mixture of Formula I, an enantiomerically enriched mixture of Formula II, and psilocybin hydrochloride, is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • Ingredient Quantity (mg/capsule) Magnesium stearate 1.0 k- 2-MAPB, and psilocybin hydrochloride, is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • Ingredient Quantity (mg/capsule) It should be readily appreciated that the above formulation examples are illustrative only.
  • any of the other active compounds e.g., amphetamine sulfate or psilocybin hydrochloride as described above
  • substitution of the compound by its prodrug, free base, salt, or hydrochloride salt shall be understood to provide merely an alternative embodiment still within the scope of the invention.
  • compositions within the scope of the invention should be understood to be open-ended and may include additional active or inactive compounds and ingredients.
  • the type of formulation employed for the administration of the compounds employed in the methods of the present invention generally may be dictated by the compound(s) employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s), and the state of the patient.
  • the compounds of the present invention exist as diastereomers.
  • an enantiomerically enriched mixture of Formula I can have two stereogenic centers and thus exist as a mixture of 4 possible stereoisomers.
  • any of the aforementioned formulations involving mixtures of enantiomers could be analogously modified to include mixtures of more than 2 stereoisomers.
  • 2-amino-1-(benzofuran-2-yl)propan-1-ol which exists as four possible stereoisomers.
  • a capsule comprising a mixture of stereoisomers of 2- amino-1-(benzofuran-2-yl)propan-1-ol, and psilocybin hydrochloride, is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • a capsule comprising a mixture of stereoisomers of 2- amino-1-(benzofuran-2-yl)propan-1-ol, and psilocybin hydrochloride, is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • the compounds of the present invention are formulated as a mixture of isomers of Formula III, Formula IV, Formula V, or Formula VI and psilocybin hydrochloride, is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • a capsule, comprising a mixture of stereoisomers of Formula III, Formula IV, Formula V, or Formula VI, and psilocybin hydrochloride is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • Ingredient Quantity (mg/capsule) Psilocybin hydrochloride 2.0 , , of Formula III, Formula IV, Formula V, or Formula VI, and psilocybin hydrochloride, is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • a capsule comprising a mixture of stereoisomers of Formula III, Formula IV, Formula V, or Formula VI, and psilocybin hydrochloride, is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • Ingredient Quantity (mg/capsule) In certain embodiments, the compounds of the present invention are formulated as a mixture of isomers of Formula I or Formula II and psilocybin hydrochloride, is prepared using the ingredients below.
  • a capsule comprising a mixture of stereoisomers of Formula I or Formula II, and psilocybin hydrochloride, is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • Ingredient Quantity (mg/capsule) Alpha lipoic acid 40.0 , , of Formula I or Formula II, and psilocybin hydrochloride, is prepared using the ingredients below.
  • a capsule comprising a mixture of stereoisomers of Formula I or Formula II, and psilocybin hydrochloride, is prepared using the ingredients below.
  • the active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities.
  • compositions as described herein can be administered to the host in any amount, and with any frequency, that achieves the goals of the invention as used by the healthcare provider, or otherwise by the host in need thereof, typically a human, as necessary or desired.
  • the composition as described herein is provided only in a controlled counseling session, and administered only once, or perhaps 2, 3, 4, or 5 or more times in repeated counseling sessions to address a mental disorder as described herein.
  • the composition as described herein is provided outside of a controlled counseling session, and perhaps self-administered, as needed to perhaps 2, 3, 4, or 5 or more times in to address a mental disorder as described herein.
  • the composition of the present invention may be administered on a routine basis for mental wellbeing or for entactogenic treatment.
  • the compounds of the current invention can be administered in a variety of doses, routes of administration, and dosing regimens, based on the indication and needs of the patient.
  • Non- limiting examples of therapeutic use include discrete psychotherapeutic sessions, ad libitum use for treatment of episodic disorders, and ongoing use for treatment of subchronic and chronic disorders.
  • Psychotherapeutic sessions For some indications, the medicine is taken in discrete psychotherapy or other beneficial sessions. It is anticipated that these sessions will typically be separated by more than 5 half-lives of the medicine and, for most patients, will typically occur only 1 to 5 times each year.
  • Non-exhaustive examples of oral doses of medicine that produce clearly perceptible entactogenic effects for exemplary purposes for any of the compounds described herein include (using compounds for illustrative purposes only): about 40 to about 120 mg of non-racemic Bk-2-EAPB, about 40 to about 120 mg of non-racemic Bk-2- EAPB, about 50 to about 300 mg of Bk-2-EAPB, about 50 to about 300 mg of Bk-2-EAPB, about 75 to about 500 mg of Bk-2-EAPB, about 75 to about 500 mg of Bk-2-EAPB, about 75 to about 800 mg of Bk-2-EAPB, about 75 to about 800 mg of Bk-2-EAPB, about 40 to about 120 mg of non-racemic Bk-2-MAPB, about 40 to about 120 mg of non-racemic Bk-2-MAPB, about 50 to about 300 mg of Bk-2-MAPB, about
  • Non-limiting, non-exhaustive examples of indications that may benefit from psychotherapeutic sessions include post-traumatic stress disorder, depression, dysthymia, anxiety and phobia disorders, feeding, eating, and binge disorders, body dysmorphic syndromes, alcoholism, tobacco abuse, drug abuse or dependence disorders, disruptive behavior disorders, impulse control disorders, gaming disorders, gambling disorders, personality disorders, attachment disorders, autism, and dissociative disorders. Also included as exemplary situations where an individual would benefit from a psychotherapeutic session are situations from a reduction of neuroticism or psychological defensiveness, an increase in openness to experience, an increase in creativity, or an increase in decision-making ability.
  • Ad libitum use for treatment of episodic disorders For some indications, such as social anxiety, where the patient has need for relief from episodic occurrence of a disorder, it is anticipated that the medicine would be taken as needed but that uses should be separated by more than 5 half-lives of the medicine to avoid bioaccumulation and formation of tolerance. For treating episodic disorders, clearly perceptible entactogenic effects are often not desirable, as they can impair some aspects of functioning.
  • Non-exhaustive examples of oral doses of medicine for any of the compounds described herein include (using compounds for illustrative purposes only) that produce subtle, barely perceptible therapeutic effects include: about 10 to about 60 mg of non-racemic about 40 to about 120 mg of non-racemic Bk-2-EAPB, about 40 to about 120 mg of non-racemic Bk-2-EAPB, about 50 to about 300 mg of Bk-2-EAPB, about 50 to about 300 mg of Bk-2-EAPB, about 75 to about 500 mg of Bk-2-EAPB, about 75 to about 500 mg of Bk-2-EAPB, about 75 to about 800 mg of Bk-2-EAPB, about 75 to about 800 mg of Bk-2-EAPB., about 10 to about 60 mg of non-racemic Bk-2-MAPB, about 10 to about 100 mg of Bk-2-MAPB, about 10 to about 100 mg of Bk-2-MAPB, about 20 to about 150 mg of Bk-2-MAPB, about 20 to about 150 mg of Bk
  • Non-limiting, non-exhaustive examples of indications that may benefit from episodic treatment include post-traumatic stress disorder, depression, dysthymia, anxiety and phobia disorders, feeding, eating, and binge disorders, body dysmorphic syndromes, alcoholism, tobacco abuse, drug abuse or dependence disorders, disruptive behavior disorders, impulse control disorders, gaming disorders, gambling disorders, personality disorders, attachment disorders, autism, and dissociative disorders, provided that clinically significant signs and symptoms worsen episodically or in predictable contexts.
  • subchronic disorders such as substance use disorders, inflammatory conditions, and neurological indications, including treatment of stroke, brain trauma, dementia, and neurodegenerative diseases, where the patient has need for ongoing treatment, it is anticipated that the medicine would be taken daily, twice daily, or three times per day.
  • subchronic disorders such as treatment of stroke or traumatic brain injury
  • treatment duration will be time-limited and dosing will be tapered when the patient has recovered.
  • An example dose taper regimen is a reduction in dose of 10% of the original dose per week for nine weeks.
  • chronic disorders such as dementia, it is anticipated that treatment will be continued as long as the patient continues to receive clinically significant benefits.
  • Non-exhaustive examples of oral doses of medicine for any of the compounds described herein include (using compounds for illustrative purposes only) that produce subtle, barely perceptible therapeutic effects with ongoing dosing include: about 5 to about 60 mg of non- racemic Bk-2-MAPB, about 5 to about 60 mg of non-racemicBk-2-EAPB, about 5 to about 100 mg of Bk-2-MAPB about 5 to about 100 mg of Bk-2-EAPB, about 10 to about 150 mg of Bk-2- MAPB, about 10 to about 150 mg of Bk-2-EAPB, about 10 to about 200 mg of Bk-2-MAPB, and about 10 to about 200 mg of Bk-2-EAPB.
  • Non-limiting, non-exhaustive examples of subchronic and chronic disorders that may benefit from regular treatment include migraine, headaches (e.g., cluster headache), neurodegenerative disorders, Alzheimer’s disease, Parkinson’s disease, schizophrenia, stroke, traumatic brain injury, phantom limb syndrome, and other conditions where increasing neuronal plasticity is desirable.
  • Example 1 Exemplary Synthetic Methods and Chiral Separations Preparation of Pure Enantiomers or Enantiomerically Enriched Mixtures of the Present Invention from Racemates
  • the enantiomerically enriched mixtures of 2-EAPB and 2-MAPB of the present invention can be synthesized according to the following schemes: Separation of the enantiomers of the racemate mixtures generate ed out by chiral supercritical fluid chromatography (SFC).
  • SFC supercritical fluid chromatography
  • a sepa a o o e e a o e s o a co pou o e p ese ve on can be carried out by prior protection of the amine group with a suitable reagent to aid in resolution of the enantiomers by SFC.
  • the amine can be resolved by SFC as a Fmoc protected amine as follows:
  • Synthesis 1 Preparation of 1-(benzo[b]thiophen-2-yl)-2-(methylamino)propan-1-one (Bk-2- MAPBT):
  • Synthesis 2 Preparation of 1-(benzofuran-2-yl)-2-(methylamino)propan-1-one (Bk-2- MAPB):
  • the reaction sequence shown above can be applied to the synthesis of enantiomerically enriched mixtures by using an appropriate chiral auxiliary reagent.
  • Synthesis 3 Preparation of (R)-1-(benzofuran-2-yl)-2-(methylamino)propan-1-one (R-Bk-2- MAPB):
  • Synthesis 5 Preparation of 1-(benzofuran-2-yl)-2-(methylamino)ethan-1-one:
  • Synthesis 6 Preparation of 1-(benzo[b]thiophen-2-yl)-2-(methylamino)ethan-1-one:
  • Synthesis 7 Preparation of 1-(5-methoxybenzofuran-2-yl)-2-(methylamino)ethan-1-ol:
  • Synthesis 8 Preparation of 1-(benzofuran-2-yl)-2-(methylamino)ethan-1-ol: q pp y omerically enriched mixtures by substituting an appropriate chiral reagent in the reduction step.
  • Synthesis 9 Preparation of (S)-1-(benzofuran-2-yl)-2-(methylamino)ethan-1-ol:
  • Synthesis 10 Preparation of 1-(benzofuran-2-yl)-2-(methylamino)propan-1-ol: y enriched mixtures of the present invention with the modification to incorporate a chiral reduction catalyst.
  • Synthesis 11 Preparation of (2R)-1-(benzofuran-2-yl)-2-(methylamino)propan-1-ol:
  • Alternative embodiments of the present invention can be synthesized according to the following scheme.
  • Synthesis 13 Preparation of (1R,2S)-2-amino-1-(4-amino-5-methoxybenzofuran-2- yl)propan-1-ol: Further examples of general synthetic routes to compounds of the present invention include: Synthesis 14: Preparation of 1-(benzofuran-2-yl)-N-ethylpropan-2-amine (2-EAPB): Synthesis 15: Preparation of 1-(benzo[b]thiophen-2-yl)-N-ethylpropan-2-amine (2-EAPBT): Alternatively, the syntheses of 2-EAPB and 2-EAPBT shown above can be performed with a chiral catalyst in the reduction step to provide the enantiomerically enriched products: Synthesis 16: Preparation of (R)-1-(benzofuran-2-yl)-N-ethylpropan-2-amine (R-2-EAPB): Synthesis 17: Preparation of
  • N, O-dimethylhydroxylamine hydrochloride (9.0 g, 92.513 mmol, 3.0 equiv.) was added to the resulting reaction mixture and was allowed to stir at room temperature for 16h. Upon completion, monitored by TLC (50% ethyl acetate in hexane), the reaction mixture was diluted with dichloromethane (500 mL) and washed with water followed by a brine solution. The combined organic layer was dried over anhydrous sodium sulphate.
  • Step 3 To a stirred solution of 1-(benzofuran-2-yl) propan-1-one (3) (1.8 g, 10.333 mmol, 1 equiv.) in dry tetrahydrofuran (30 mL) was added hydrobromic acid (48% in Water) (26.0 mL, 165.331 mmol, 16.0 equiv.) and bromine (0.63 mL, 12.4 mmol, 1.2 equiv.) dropwise at 0°C and the reaction mixture was allowed to stir at room temperature for 16h.
  • hydrobromic acid 48% in Water
  • bromine (0.63 mL, 12.4 mmol, 1.2 equiv.
  • Step 4 To a stirred solution of 1-(benzofuran-2-yl)-2-bromopropan-1-one (4) (2.1 g, 8.297 mmol, 1 equiv.) in dry DMF (25 mL) was added potassium carbonate (1.71 g, 12.446 mmol, 1.5 equiv.) and methyl amine 2(M) in tetrahydrofuran (12.5 mL, 24.89 mmol, 3.0 equiv.) in a sealed RB and the resulting reaction mixture was allowed to stir at room temperature for 16h.
  • Step 6 To a stirred solution of tert-butyl (1-(benzofuran-2-yl)-1-oxopropan-2-yl) (methyl)carbamate (6) (350 mg, 1.15 mmol, 1 equiv.) in dry dichloromethane (5.0 mL) was added 4(M) HCl in 1,4 dioxane (2.75 mL) at 0 °C and the resulting reaction mixture was allowed to stir at room temperature for 2h.
  • N, O-dimethylhydroxylamine hydrochloride (9.0 g, 92.513 mmol, 3.0 equiv.) was added to the resulting reaction mixture and was allowed to stir at room temperature for sixteen hours. Upon completion, monitored by TLC (50% ethyl acetate in Hexane), the reaction mixture was diluted with dichloromethane (500 mL) and washed with water followed by a brine solution. The combined organic layer was dried over anhydrous sodium sulphate.
  • Step 3 To a stirred solution of 1-(benzofuran-2-yl) propan-1-one (3) (1.8 g, 10.333 mmol, 1 equiv.) in dry tetrahydrofuran (30 mL) was added hydrobromic acid (48% in water) (26.0 mL, 165.331 mmol, 16.0 equiv.) and bromine (0.63 mL, 12.4 mmol, 1.2 equiv.) dropwise at 0 °C and the reaction mixture was allowed to stir at room temperature for sixteen hours.
  • hydrobromic acid 48% in water
  • bromine (0.63 mL, 12.4 mmol, 1.2 equiv.
  • Step 4 To a stirred solution of 1-(benzofuran-2-yl)-2-bromopropan-1-one (4) (2.1 g, 8.297 mmol, 1 equiv.) in dry DMF (25 mL) was added potassium carbonate (1.71 g, 12.446 mmol, 1.5 equiv.) and ethyl amine 2(M) in tetrahydrofuran (16.6 ml, 33.19 mmol, 4.0 equiv.) in a sealed RB and the resulting reaction mixture was allowed to stir at room temperature for 16h.
  • Step 5 To a stirred solution of 1-(benzofuran-2-yl)-2-(ethyl amino) propan-1-one (5) (1.8 g, 8.285 mmol, 1 equiv.) in dry dichloromethane (20 mL) was added triethylamine (2.32 mL, 16.57 mmol, 2 equiv.) and Boc anhydride (3.8 mL, 16.57 mmol, 2 eq.) and the resulting reaction mixture was allowed to stir at room temperature for 4h.
  • Step 6 To a stirred solution of tert-butyl (1-(benzofuran-2-yl)-1-oxopropan-2-yl) (ethyl)carbamate (6) (350 mg, 1.103 mmol, 1 equiv.) in dry dichloromethane (5.0 mL) was added 4(M) HCl in 1,4 dioxane (2.75 mL) at 0 °C and the resulting reaction mixture was allowed to stir at room temperature for two hours.
  • Step 7 To a stirred solution of tert-butyl (R)-(1-(benzofuran-2-yl)-1-oxopropan-2-yl) (ethyl)carbamate (7B) (750 mg, 2.363 mmol, 1 equiv.) in dry dichloromethane (8.0 mL) was added 4(M) HCl in 1,4 dioxane (12.0 mL) at 0 °C and the resulting reaction mixture was allowed to stir at room temperature for two hours.
  • N, O-dimethylhydroxylamine hydrochloride (9.0 g, 92.513 mmol, 3.0 equiv.) was added to the resulting reaction mixture and was allowed to stir at room temperature for 16h. Upon completion, monitored by TLC (50% ethyl acetate in hexane), the reaction mixture was diluted with dichloromethane (500 mL) and washed with water followed by a brine solution. The combined organic layer was dried over anhydrous sodium sulphate.
  • Step 3 To a stirred solution of 1-(benzofuran-2-yl) butan-1-one (3) (500 mg, 2.656 mmol, 1 equiv.) in dry tetrahydrofuran (10 mL) was added hydrobromic acid (48% in Water) (5.0 mL, 42.503 mmol, 16.0 equiv.) and bromine (0.16 mL, 3.188 mmol, 1.2 equiv.) dropwise at 0°C and the reaction mixture was allowed to stir at room temperature for sixteen hours.
  • hydrobromic acid 48% in Water
  • bromine (0.16 mL, 3.188 mmol, 1.2 equiv.
  • Step 4 To a stirred solution of 1-(benzofuran-2-yl)-2-bromobutan-1-one (4) (645 mg, 2.415 mmol, 1 equiv.) in dry DMF (10.0 mL) was added potassium carbonate (500 mg, 3.622 mmol, 1.5 equiv.) and methyl amine (2M) in tetrahydrofuran (7.24 mL, 14.488 mmol, 6.0 equiv.) in a sealed round bottom flask and the resulting reaction mixture was allowed to stir at room temperature for sixteen hours.
  • potassium carbonate 500 mg, 3.622 mmol, 1.5 equiv.
  • methyl amine (2M) methyl amine
  • Step 5 To a stirred solution of 1-(benzofuran-2-yl)-2-(methylamino) butan-1-one (5) (500 mg, 2.301 mmol, 1 equiv.) in dry dichloromethane (10 mL) was added triethylamine (0.64 mL, 4.603 mmol, 2 equiv.) and Boc anhydride (1.05 mL, 4.603 mmol, 2 eq.) and the resulting reaction mixture was allowed to stir at room temperature for four hours.
  • Step 6 To a stirred solution of tert-butyl (1-(benzofuran-2-yl)-1-oxobutan-2-yl) (methyl)carbamate (6) (370 mg, 1.166 mmol, 1 equiv.) in dry dichloromethane (5.0 mL) was added 4(M) HCl in 1,4 dioxane (2.0 mL) at 0°C and the resulting reaction mixture was allowed to stir at room temperature for two hours.
  • DAT/SERT IC 50 ratios >1 are thought to predict psychostimulant effects and compounds with this profile have potential value in treating attention deficit hyperactivity disorder (ADHD) and stimulant use disorders.
  • Example compounds with this profile include dextroamphetamine and methylphenidate (Ritalin, Concerta).
  • serotonin release and a DAT/SERT IC 50 ratio of 0.01–0.1 is said to result in a psychoactive drug profile similar to that of MDMA, which includes feelings of emotional openness, authenticity, and decreased neuroticism.
  • MDMA is an experimental adjunct to psychotherapy that shows great potential for treating PTSD and substance use disorders. It may also be able to generally accelerate progress in psychotherapy and aid emotional decision making.
  • MDMA has a reported DAT/SERT IC50 ratio of 0.08 (Simmler and Liechti, New Psychoactive Substances, pp.143-164).
  • Compounds with intermediate DAT/SERT IC 50 ratios appear to sometimes have antidepressant-like or nootropic (cognitive enhancement) qualities and have been proposed as antidepressants, cognitive enhancers, or treatments for substance use disorders.
  • 4-bromomethcathinone (4-BMC, Brephedrone; IUPAC: 1-(4-bromophenyl)-2- (methylamino)propan-1-one) does not have typical psychostimulant effects and has been proposed as a potential antidepressant (Foley and Cozzi.2003.
  • Liechti's classification system One caveat to Liechti's classification system is that compounds that release neurotransmitter may be misclassified if their relative abilities to release dopamine and serotonin are substantially different from their relative abilities to inhibit uptake of dopamine and serotonin.
  • Compounds that appear misclassified in this manner include 3,4,- methylenedioxyethylamphetamine (MDEA; IUPAC [1-(2H-1,3-benzodioxol-5-yl)propan-2- yl](ethyl)amine), which has a reported DAT/SERT IC 50 ratio of 3.2 (Simmler et al.2013.
  • intermediate compounds may prove useful for treating ADHD, substance use disorders, and other conditions in individuals who experience significant anxiety from approved psychostimulant pharmacotherapies such as d-amphetamine. Similar to the IC 50 system, compounds with higher DAT/SERT EC50 ratios are potential treatments for ADHD and psychostimulant use disorders. Although MDMA has significant therapeutic potential, it has a number of features that limit its clinical use and may make it contraindicated for some patients.
  • CYP2D6 increasing risk of drug-drug interactions
  • oxidative stress likely related to its extensive, though variable, metabolism and formation of reactive metabolites
  • SERT density after high doses
  • diminishing therapeutic benefits with repeated use and a hangover-like after-effects including poor mood and lowered energy.
  • d-methamphetamine has a reported DAT/NET EC50 ratio of 0.5, while d-amphetamine has a ratio of 0.9 (Rothman et al. 2001. Synapse, 39(1), pp.32-41), indicating both are more potent at increasing norepinephrine than dopamine.
  • Differences in the relative balance of dopamine and norepinephrine increases can yield compounds with valuable therapeutic profiles. Norepinephrine increases contribute to cognitive improvements in ADHD but, in excess, can also lead to cardiovascular changes.
  • Dopamine similarly modulates impulsive action but, in excess, can produce compounds with high abuse liability. Nonetheless, individuals with histories of substance abuse who have desensitized dopamine receptors can benefit from compounds that adequately stimulate these receptors. Thus, there is a need for novel treatment compounds that differently balance therapeutic benefits against cardiovascular and abuse liability side effects.
  • increases in extracellular serotonin and direct stimulation of serotonin receptors present ways for compounds (or compound combinations) to decrease off-target effects and increase select therapeutic effects.
  • compounds that release dopamine and/or norepinephrine and also stimulate 5-HT1A or 5-HT1B receptors can provide fast acting therapeutic effects on mood and attention while decreasing social anxiety.
  • EXAMPLE 3 nAChR ⁇ 4 ⁇ 2 Receptor Agonism
  • An IonFluxTM automated patch-clamp system can be used to measure activity of S-Bk-2- MAPB, R-Bk-2-MAPB, S-Bk-2-EAPB, and R-Bk-2-EAPB at nAChR ⁇ 4 ⁇ 2 receptors (Eurofins, cat. No. CYL3106) expressed in HEK-293 cells as described in Yehia & Wei, 2020, Current Protocols in Pharmacology, 88(1).
  • Acetylcholine is used as a positive control.
  • EXAMPLE 4 Serum Serotonin Concentrations to Index Drug Interactions with the Serotonin Transporter (SERT, SLC6A4) Serum serotonin is measured using High Performance Liquid Chromatography and Fluorescence Detection. Venipuncture is used to collect at least 1 mL of sample, which is spun with serum frozen to below -20° C within 2 hours of collection.
  • SERT, SLC6A4 Serum Serotonin Concentrations to Index Drug Interactions with the Serotonin Transporter
  • Venipuncture is used to collect at least 1 mL of sample, which is spun with serum frozen to below -20° C within 2 hours of collection.
  • EXAMPLE 5 Marble Burying Measure of Decreased Anxiety and Neuroticism The marble burying test is a model of neophobia, anxiety, and obsessive-compulsive behavior that has been proposed to have predictive validity for the screening of novel antidepressants
  • Marble Burying Experimental Methods Marble burying experiments are conducted by trained and authorized personnel and are in compliance with applicable guidelines for experiments with laboratory animals. Manipulation of animals is conducted carefully to reduce stress to a minimum. Animal Care Test animals are Swiss CD1 mice, 5-6 weeks old, that have not been subjected to prior experiments. Housing conditions Housing Group housing (8-9 mice/cage): 1290D Eurostandard Type III m d er Hygrometry 50 ⁇ 30% (measured but not controlled) Air renewal Fresh air 12-25 vol/h g g , 42 cm W, 40 cm H) filled with 5 cm sawdust.
  • Test compounds or placebo vehicle are administered intraperitoneally 30 minutes before animals were individually placed in an experimental apparatus for a 30-min session.
  • the number of marbles at least 2/3 buried is counted at the end of the session as the primary outcome measure.
  • Results are generally displayed with scores inverted (proportion of marble left unburied) and expressed as magnitude difference-from-placebo with error bars indicating 95% confidence intervals.
  • EXAMPLE 6 In Vitro Binding Site Studies Select compounds of the present invention can be tested for agonist and antagonist activity against 5-HT1B and 5-HT2A. Select compounds can also be tested for adrenergic ⁇ 2 receptor antagonist activity, MAO-A inhibition, and the ability to inhibit nicotinic acetylcholine ⁇ 4/ ⁇ 2 receptors.
  • Adrenergic ⁇ 2 Receptor cAMP Secondary Messenger Antagonist Assay Methods This assay uses a panel of CHO-K1 cell lines stably expressing non-tagged GPCRs that endogenously signal through cAMP.
  • Hit Hunter® cAMP assays monitor the activation of a GPCR via Gi and Gs secondary messenger signaling in a homogenous, non-imaging assay format using DiscoverX Enzyme Fragment Complementation (EFC) with ⁇ -galactosidase as the functional endpoint.
  • EFC DiscoverX Enzyme Fragment Complementation
  • ED Enzyme Donor
  • EA Enzyme Acceptor
  • ED-cAMP Enzyme Donor
  • Active ⁇ - galactosidase is formed by complementation of exogenous EA to any unbound ED-cAMP.
  • Active enzyme could then convert a chemiluminescent substrate, generating an output signal detectable on a standard microplate reader.
  • Cell lines are expanded from freezer stocks according to standard procedures. Cells are seeded in a total volume of 20 ⁇ L into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing.
  • cAMP modulation is determined using the DiscoverX HitHunter cAMP XS+ assay. Test compounds are assayed at 10 concentrations with the highest concentration either 30 or 10 ⁇ M and subsequent concentrations using a 0.33 dilution factor. For agonist determination, cells are incubated with sample (in the presence of EC80 forskolin to induce response if measuring Gi secondary messenger signaling).
  • Media is aspirated from cells and replaced with 15 ⁇ L 2:1 HBSS/10mM Hepes: cAMP XS+ Ab reagent.
  • Intermediate dilution of sample stocks is performed to generate 4X sample in assay buffer (optionally containing 4X EC80 forskolin).
  • 5 ⁇ L of 4X sample is added to cells and incubated at 37°C or room temperature for 30 or 60 minutes, as appropriate.
  • Final assay vehicle concentration was 1%.
  • cells are pre-incubated with sample followed by agonist challenge at the EC80 concentration.
  • Media is aspirated from cells and replaced with 10 ⁇ L 1:1 HBSS/Hepes: cAMP XS+ Ab reagent.
  • DiscoveRx Calcium NWPLUS Assay can be used for detection of changes in intracellular calcium as signaled by an increase of dye fluorescence in cells expressing 5-HT 2A receptors. Signal is measured on a fluorescent plate reader equipped with fluidic handling capable of detecting rapid changes in fluorescence upon compound stimulation. To conduct the assay, cell lines are expanded from freezer stocks according to standard procedures.
  • cells are pre-incubated with sample followed by agonist challenge at the EC 80 concentration. After dye loading, cells are removed from the incubator and 25 ⁇ L 2X sample is added. Cells are incubated for 30 minutes at room temperature in the dark to equilibrate plate temperature. After incubation, antagonist determination is initiated with addition of 25 ⁇ L 1X compound with 3X EC80 agonist using FLIPR. Compound agonist activity is measured on a FLIPR Tetra. Calcium mobilization is monitored for 2 minutes with a 5 second baseline read. FLIPR read-Area under the curve is calculated for the two minute read. Compound activity is analyzed using CBIS data analysis suite (ChemInnovation, CA).
  • Percentage activity is calculated as 100% x (mean RFU of test sample - mean RFU of vehicle control) / (mean MAX RFU control ligand - mean RFU of vehicle control).
  • percentage inhibition is calculated as 100% x (1 - (mean RFU of test sample - mean RFU of vehicle control) / (mean RFU of EC80 control - mean RFU of vehicle control)).
  • MAO-A Inhibition Assay MAO-A and test compounds are preincubated at 37°C for 15 minutes before substrate addition. Test compounds are assayed at 10 concentrations with the highest concentration either 30 or 10 ⁇ M and subsequent concentrations using a 0.33 dilution factor.
  • the reaction is initiated by addition of kynuramine and incubated at 37°C for 30 minutes. The reaction is terminated by addition of NaOH. The amount of 4-hydroquioline formed is determined through spectrofluorimetric readout with the emission detection at 380 nm and excitation wavelength 310 nm. Clorgyline (IC500.00438 ⁇ M) is used as a positive control. Nicotinic acetylcholine receptor ⁇ 4 ⁇ 2 (nAchRa4/b2) Ion Channel Blocking Assay Cell lines are expanded from freezer stocks according to standard procedures.
  • Cells are seeded in a total volume of 20 ⁇ L into black-walled, clear-bottom, Poly-D-lysine coated 384-well microplates and incubated at 37 ⁇ C for the appropriate time prior to testing. Assays are performed in 1X Dye Loading Buffer consisting of 1X Dye, and 2.5 mM freshly-prepared Probenecid when applicable. Test compounds are assayed at 10 concentrations with the highest concentration either 30 or 10 ⁇ M and subsequent concentrations using a 0.33 dilution factor. Prior to testing, cells are loaded with dye then incubated for 30-60 minutes at 37°C. For antagonist determination, cells are pre-incubated with sample. Dihydro- ⁇ -erythroidine is used as a positive control.
  • hSERT release measurement methods Chinese hamster ovary cells expressing human SERT are seeded in CytostarTM (PerkinElmer) plate with standard culture medium the day before the experiment at a single density (5000 cells / assay). Cells are incubated overnight with 5% CO 2 at 37°C. The day of experiment, the medium is replaced by incubation buffer (140mMNaCl, 4.8mM KCl, 1.2mM MgSO4, 0.1 mM KH2PO4, 10 mM HEPES, pH 7.4) with a single concentration of [ 3 H] Serotonin at 150nM.
  • CytostarTM PerkinElmer
  • radioligand-containing buffer only to verify the control level of release
  • buffer with 1% DMSO solvent used to solubilize the test compounds
  • 100 uM amphetamine in 1% DMSO
  • Cells are incubated at room temperature at different incubation times and radioactivity counted.
  • Example 29 Evaluation of Entactogenic Effect of Decreased Neuroticism The entactogenic effect of decreased neuroticism can be measured as a decrease in social anxiety using the Brief Fear of Negative Evaluation–revised (BFNE) (Carleton et al., 2006, Depression and Anxiety, 23(5), 297-303; Leary, 1983, Personality and Social Psychology bulletin, 9(3), 371-375).
  • BFNE Brief Fear of Negative Evaluation–revised
  • This 12-item Likert scale questionnaire measures apprehension and distress due to concerns about being judged disparagingly or with hostility by others. Ratings use a five-point Likert scale with the lowest, middle, and highest values labeled with “much less than normal,” “normal,” and “much more than normal.”
  • the BFNE can be administered before and repeatedly during therapeutic drug effects.
  • Example 30 Evaluation of Entactogenic Effect of Authenticity The entactogenic effect of authenticity can be measured using the Authenticity Inventory (Kernis & Goldman.2006. Advances in experimental social psychology, 38, 283-357) as modified by Baggott et al (Journal of Psychopharmacology 2016, 30.4: 378-87). Administration and scoring of the instrument is almost identical to that of the BFNE.
  • the Authenticity Inventory consists of the following items, which are each rated on a 1-5 scale, with select items reverse scored as specified by Kernis & Goldman: ⁇ I am confused about my feelings.

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Abstract

Pharmaceutically active 2-ethylamine substituted benzofuran and benzothiophene compositions are provided for the treatment of mental disorders or for mental enhancement, including for entactogenic therapy. The present invention also includes 2-ethylamine substituted benzofuran and benzothiophene compounds, compositions, and methods for generally modulating central nervous system activity and treating central nervous system disorders.

Description

2-ETHYLAMINE SUBSTITUTED BENZOFURAN AND BENZOTHIOPHENE COMPOSITIONS FOR MENTAL DISORDERS OR ENHANCEMENT CROSS-REFERENCE TO RELATED APPLICATIONS The application claims the benefit of the U.S. Provisional Application No. 63/426,634, filed November 18, 2022. The entirety of that application is hereby incorporated by reference herein for all purposes. FIELD OF THE INVENTION The present invention is in the area of pharmaceutically active 2-ethylamine substituted benzofuran and benzothiophene compounds and compositions for the treatment of mental disorders or for mental enhancement, including for entactogenic therapy. The present invention also includes more generally 2-ethylamine substituted benzofuran and benzothiophene compounds, compositions, and methods for modulating central nervous system activity and treating central nervous system disorders. BACKGROUND Central nervous system (CNS) related health problems are a common challenge in society. An estimated 21% of U.S. adults (52.9 million people) experienced mental illness in 2020. This includes major depression (8.4% or 21 million people), anxiety disorders (19.1% or 48 million people), and posttraumatic stress disorder (PTSD) (3.6% or 9 million people). In addition to mental health challenges, there are other CNS disorders that cause substantial suffering and decreased quality of life. These include traumatic brain injury (TBI) (an estimated 12% of adults or 30 million people), dementias, and headache disorders (such as migraine, which affects about 15% of the general population or 47 million people). As the global population ages, many age-related CNS disorders are projected to become more common. For example, 6.2 million people aged 65 and older in the U.S. have Alzheimer's dementia and this population is expected to grow to 12.7 million by 2050. There is a need for improved treatment of CNS disorders. Many patients fail to benefit adequately from available treatments. In addition, many available pharmacological treatments must be taken for weeks or months before the individual experiences therapeutic benefits. A number of potential new experimental treatments are under investigation. These include compounds that modulate the functioning of the monoamine neurotransmitters, dopamine, norepinephrine, and serotonin. Dopamine is involved in learning, incentives, and the initiation of motor movements. Norepinephrine is important for attention and cardiovascular functioning. Serotonin is incompletely understood but appears to adjust the stability of the individual's response to changing environmental conditions. As such, serotonin has been linked to mood, anxiety, and appetite. Experimental treatment compounds include serotonin receptor agonists. Serotonin receptors have seven families. Many serotonin receptors are able to stimulate multiple signaling pathways within a cell, which can make it complicated to predict therapeutic effects. Serotonin receptor types that have received recent attention for their therapeutic potential include 5-HT2A, 5- HT2C, 5-HT1A, and 5-HT1B receptors. One group of experimental therapeutic compounds are 5-HT2A receptor agonists. These are being investigated as tools to potentially produce rapid therapeutic improvement in CNS disorders including depression, anxiety, and substance use disorders. Compounds such as psilocybin and 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT), produce dramatic psychedelic effects resembling mystical experiences that may contribute to these therapeutic effects. These compounds also produced labile mood and often invoke acute anxiety, which makes close monitoring of patients necessary. There is accordingly a need for 5-HT2A agonists that produce either minimal mood changes or reliably positive ones. Another group of putative 5-HT2A agonists, such as 6-methoxy-N,N-dimethyltryptamine (6-MeO-DMT) and 7-fluoro-N,N-dimethyltryptamine (7-F-DMT) appear to produce therapeutic changes in animal models of depression without producing psychedelic effects (Dunlap et al.2020. Journal of medicinal chemistry, 63(3), pp.1142-1155). Both psychedelic and non-psychedelic 5- HT2A agonists may be useful in migraine, cluster headaches, and other headache disorders. The therapeutic mechanisms of 5-HT2A agonists are incompletely understood but may involve increased neuroplasticity (Ly et al.2018. Cell reports, 23(11), pp.3170-3182), suggesting potential benefits in TBI, neurological disorders, and conditions where behavior change or learning is desired. Another potential therapeutic mechanism of 5-HT2A agonists involves decreases in inflammation (e g., Flanagan, et al.2019. Life sci., 236, 116790). Conditions that may benefit from improved anti-inflammatory treatment include rheumatoid and other forms of arthritis (such as enthesitis-related juvenile idiopathic arthritis, blau syndrome, and juvenile idiopathic arthritis), psoriasis, Crohn’s disease, inflammatory bowel syndrome, ulcerative colitis, and ankylosing spondylitis. Inflammation has long been recognized to induce symptoms of depression (Lee & Giuliani. 2019. Frontiers in immunology, 10, 1696). Inflammatory processes have also been implicated in psychotic disorders (Borovcanin et al.2012. J. Psych. Res., 46(11), 1421-1426) and bipolar disorders (Hamdani, Tamouza, & Leboyer.2012. Front. Biosci. (Elite Ed.), 4, 2170-2182). 5-HT2A agonists are also often 5-HT2B agonists. This is undesirable because chronic stimulation of 5-HT2B receptors causes cardiac valvulopathy (Rothman et al. 2000. Circulation, 102(23), pp.2836-2841). There is therefore a need for serotonin agonists that have decreased ability to stimulate 5-HT2B receptors. 5-HT2C receptors are closely related to 5-HT2A receptors, but have a different distribution in the brain and body. Compounds that stimulate 5-HT2C receptors have been proposed as treatments for psychiatric disorders as well as other disorders such as sexual dysfunction, obesity, and urinary incontinence. Lorcaserin (Belviq) is a high affinity 5-HT2C agonist that, until recently, was FDA-approved for use in conjunction with weight loss programs. The withdrawal of this medicine from the market because of increased risk of cancer highlights the need for safer serotonergic therapeutics that can stimulate 5-HT2C receptors or otherwise aid weight loss. 5-HT1A receptor agonists modulate the functioning of dopamine and norepinephrine and decrease blood pressure and heart rate via a central mechanism. Drugs that are 5-HT1A agonists have value for treating anxiety and depression. For example, buspirone (Buspar, Namanspin) is approved for anxiety disorders and may also be useful for treating hypoactive sexual desire disorder (HSDD). Studies in rats indicate that 5-HT1A stimulation induces oxytocin release, which contributes to the social effects of 3,4-methylenedioxymethamphetamine (MDMA) (Thompson et al. 2007. Neuroscience, 146(2), pp.509-514). Compounds (or compound combinations) that include 5-HT1A stimulation in their pharmacological profile are therefore expected to have therapeutic benefits in comparison to those that do not. Compounds that stimulate 5-HT1B receptors alter the release of neurotransmitters such as dopamine, serotonin, GABA, acetylcholine, and glutamate and can modulate stress sensitivity, mood, anxiety, and aggression. 5-HT1B agonists such as sumatriptan (Imitrex) and zolmitriptan (Zomig) have been approved for treatment of headache disorders. Studies in mice suggest 5-HT1B stimulation on dopamine-containing neurons in the central striatum contributes to social effects of MDMA (Heifets et al. 2019. Science translational medicine, 11(522)). Preclinical studies also suggest 5-HT1B agonists may have antidepressant effects. More broadly, there is evidence that stimulating 5-HT1B receptors can provide benefits to stress response, affect, and addiction (e.g., Fontaine et al.2021. Neuropsychopharmacology, pp.1-11). As with 5-HT1A receptors, compounds (or compound combinations) that include 5-HT1B stimulation in their pharmacological profile are therefore expected to have therapeutic benefits in comparison to those that do not. Another group of experimental compounds interact with brain monoamine transporters to increase extracellular concentrations of the three monoamine neurotransmitters. Some compounds increase extracellular concentrations of these molecules by inhibiting reuptake of neurotransmitters, while others induce release of neurotransmitters. Patents and patent applications describing entactogenic compounds include WO 2021/252538, WO 2022/010937, WO 2022/032147, WO 2022/061242, WO 2023/081306, WO 2023/107653, WO 2023/107715, WO 2023/183613, and U.S. Pat. No.11,767,305, which are assigned to Tactogen Inc. Additional patent applications describing entactogenic compounds and methods of using entactogenic compounds include but are not limited to U.S. Pat. No.7,045,545, WO 2005/058865, WO 2020/169850, WO 2020/169851, WO 2021/257169, WO 2021/225796, WO 2022/214889, WO 2022/120181, WO 2022/072808, and WO 2022/038171. Despite the ongoing research on potential new drugs to treat mental disorders, CNS disorders, and related gastrointestinal and inflammatory disorders, the enormous burden of disease caused by these disorders remains a global serious and systemic problem. New drugs and treatments are required to improve personal well-being, mental health, and physical health that are dependent on the alteration of neurotransmitter levels and performance. It is therefore an object of the present invention to provide advantageous compositions and their use and manufacture for the treatment of mental disorders and enhancement for hosts, typically humans, in need thereof. Additional objects are to provide drugs with an efficient onset to be used in a clinical setting such as counseling or a home setting, which open the patient to empathy, sympathy and acceptance. A further object is to provide effective treatments for a range of CNS disorders. SUMMARY OF THE INVENTION The present invention provides advantageous 2-ethylamine substituted benzofuran and benzothiophene compounds and their pharmaceutically acceptable salts and salt mixtures thereof, pharmaceutical compositions, and methods to treat mental disorders and more generally central nervous disorders. A compound of the present invention can be used for mental enhancement or to treat a mental disorder comprising administering an effective amount of the compound to a host, typically a human, in need thereof. The compound of the present invention or compositions described herein can interact with a neurotransmitter and can exhibit entactogenic properties when administered in an effective amount to a host, typically a human, in need thereof. Thus, in certain embodiments a compound described herein can be used as a fast acting and effective agent for modulating CNS activity and treating a CNS disorder described herein. The embodiments of the invention are presented to meet the goal of assisting persons with mental disorders, who desire mental enhancement or suffer from other CNS disorders by providing milder therapeutics that are fast acting and that reduce the properties that decrease the patient experience, are counterproductive to the therapy, or are undesirably toxic. One goal of the invention is to provide therapeutic compositions that increase empathy, sympathy, openness and acceptance of oneself and others, which can be taken, if necessary, as part of therapeutic counseling sessions, or when necessary, episodically, or even consistently, as prescribed by a healthcare provider. In certain aspects a method of treating a patient with a mental disorder or providing mental enhancement is provided comprising administering an effective amount of a 2-ethylamine substituted benzofuran or benzothiophene compound, pure enantiomer, or enantiomerically enriched mixture of Formula I or Formula II: II);
Figure imgf000006_0001
RB1 is selected from ; R1, R2, and R3 are in g of hydrogen, halogen,
Figure imgf000007_0001
alkyl, aryl, cycloalkyl, haloalkyl, -OP(O)(OR9)2, -SR9, -NR9R10, and -OR9; R4 is selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, -CH2OR11, and -CH2CH2OR11; in certain embodiments R4 is selected from hydrogen, -CH3, -CH2X, -CHX2, -CX3, - CH2CH3, -CH2CH2X, -CH2CHX2, -CH2CX3, -CH2OH, and -CH2CH2OH; in certain embodiments R4 is selected from hydrogen, -CH2X, -CHX2, -CX3, -CH2CH3, -CH2CH2X, -CH2CHX2, -CH2CX3, -CH2OH, and -CH2CH2OH; R5 is selected from hydrogen, C1-C3 alkyl, haloalkyl, -CH2CH2OH, and hydroxyl; R6 is selected from hydrogen, C1-C3 alkyl, haloalkyl, and -CH2CH2OH; each R9, R10, and R11 is independently selected from: hydrogen, alkyl, and haloalkyl. In some aspects, a method of treating a patient with primary or secondary headaches is provided, comprising administering an effective amount of a 2-ethylamine substituted benzofuran or benzothiophene compound, pure enantiomer, or enantiomerically enriched mixture of Formula I or Formula II. In other aspects an enantiomerically enriched mixture of Formula I or Formula II is provided: II); wherein the var
Figure imgf000007_0002
In alternative aspects an enantiomerically or diasteromerically pure compound of Formula I or Formula II is provided. Non-limiting examples of compounds of Formula I include enantiomerically enriched mixtures of R-Bk-2-MAPB or S-Bk-2-MAPB or a pharmaceutically acceptable salt or salt mixture thereof. Additional examples of compounds of Formula I include enantiomerically enriched mixtures or pure enantiomers of R-Bk-2-EAPB or S-Bk-2-EAPB or a pharmaceutically acceptable salt or salt mixture thereof. riched
Figure imgf000008_0001
mixtures of R-Bk-2-MAPBT or S-Bk-2-MAPBT or a pharmaceutically acceptable salt or salt mixture thereof. Additional exam
Figure imgf000008_0002
de enantiomerically enriched mixtures of R-Bk-2-EAPBT or S-Bk-2-EAPBT or a pharmaceutically acceptable salt or salt mixture thereof. In certain embod
Figure imgf000008_0003
is selected from: nd
Figure imgf000008_0004
. In certain embodiments, isolated enantiomers of the compounds of the present invention show improved binding at the desired receptors and transporters relevant to the goal of treatment of a mental disorder or for mental enhancement. In certain embodiments, a tuned enantiomerically enriched mixture containing both R- and S-enantiomers in unequal amounts shows improved properties relevant to the goal of treatment of a mental disorder or for mental enhancement. In certain embodiments tuned enantiomerically enriched mixtures have fewer side effects than the corresponding pure enantiomers or racemate. Non-limiting examples of unwanted effects that may be minimized by carefully selecting the balance of enantiomers in an enantiomerically enriched mixture include hallucinogenic effects, psychoactive effects (such as excess stimulation or sedation), physiological effects (such as transient hypertension or appetite suppression), toxic effects (such as to the brain or liver), effects contributing to abuse liability (such as euphoria or dopamine release), and/or other side effects.3 In other aspects a 2-ethylamine substituted benzofuran or benzothiophene compound, pure enantiomer, or enantiomerically enriched mixture of Formula III-VIII or Formula IIIA-VIIIA is provided: V) I) II)
Figure imgf000009_0001
A) or a pharm
Figure imgf000010_0001
wherein: R1A is selected from -H and -OH; R1B is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R2B is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C2-C4 alkyl; R1C is selected from -H, -OH, -X, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R1D is selected from -OH, -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R2C is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, - CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R2D is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3A is selected from -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C4 alkyl; R3B is selected from -H, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3C and R4C are independently selected from -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3D and R4D are independently selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl, wherein if R1D is -OH and R2D is CH3, at least one of R3D and R4D is not -H; R3E is selected from -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C2-C4 alkyl; R3F and R4F are independently selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R4E is selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R5A is selected from -H and CH3; R5B is selected from -H and CH3, and at least one of R1B, R3B, and R5B is not CH3; R5C is selected from -H and CH3, wherein if R5C is -H and R1C is -H, OH, or -F, at least one of R3C, and R4C is not CH3; R5D is selected from -H and CH3; R5E is selected from -H and CH3, wherein if R3E is ethyl and R4E is -H, R5E cannot be -H; R5F is selected from -H and CH3, wherein at least one of R3F, R4F, and R5F is not -H; and X is independently selected from -F, -Cl, and -Br. The present invention thus includes at least the following aspects: (i) A method of treating a CNS disorder or providing mental enhancement comprising administering a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, pharmaceutical composition, isotopic derivative, or prodrug thereof; (ii) An enantiomerically enriched mixture of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof; (iii) A compound, enantiomerically enriched mixture, or pure enantiomer of Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, Formula IIIA, Formula IVA, Formula VA, Formula VIA, Formula VIIA, or Formula VIIIA or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof; (iv) A pharmaceutical composition comprising an effective patient-treating amount of a compound of (ii) or (iii) in a pharmaceutically acceptable carrier or diluent for any of the uses described herein; (v) The pharmaceutically acceptable composition of (iv) in a solid or liquid, systemic, oral, topical, or parenteral dosage form; (vi) A method for treating a patient with a neurological or psychological CNS disorder as described herein that includes administering an effective amount of a compound of (ii) or (iii) to a patient such as a human in need thereof, (vii) A method for treating a neurological or psychological CNS disorder comprising administering an effective amount of a compound of (ii) or (iii) or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, as described herein, to a patient, typically a human, in need thereof; (viii) A compound of (ii) or (iii) or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, for use to treat any disorder as described herein in an effective amount as further described herein; (ix) A compound of (ii) or (iii) for use in the manufacture of a medicament for the treatment of any of the disorders described herein; and (x) Use of a compound of (ii) or (iii) or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, to treat any disorder as described herein in an effective amount as further described herein; (xi) Processes for the preparation of therapeutic products that contain an effective amount of a compound of (ii) or (iii) or a pharmaceutically acceptable salt or salt mixtures, isotopic derivatives, or prodrugs or compositions thereof, as described herein. DETAILED DESCRIPTION OF THE INVENTION The present invention includes an enantiomerically enriched compound of Formula I or Formula II, and compounds of Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, Formula IIIA, Formula IVA, Formula VA, Formula VIA, Formula VIIA, or Formula VIIIA or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug or pharmaceutically acceptable composition thereof, as well as methods for modulation of CNS activity, and for treatment of CNS disorders, including but not limited to post-traumatic stress, depression, adjustment disorders, addiction, anxiety and other mental disorders as described herein to a host such as a human in need thereof. A compound of the present invention has advantageous pharmacological properties that are desirable as therapeutics for the treatment of mental disorders, particularly as psychotherapeutics and neurotherapeutics. Non-limiting examples of 2-aminoethyl substituted benzofuran and benzothiophene compounds of the present invention include enantiomerically enriched mixtures of R-Bk-2-MAPB or S-Bk-2-MAPB or a pharmaceutically acceptable salt or salt mixture thereof. Additional examples of 2-aminoethyl substituted benzofuran and benzothiophene compounds of the present invention include enantiomerically enriched mixtures or pure enantiomers of R-Bk-2-EAPB, S- Bk-2-EAPB, R-Bk-thio-2-MAPB, S-Bk-thio-2-MAPB, R-Bk-thio-2-EAPB, or S-Bk-thio-2- EAPB, or a pharmaceutically acceptable salt or salt mixture thereof.
Figure imgf000013_0001
drug (EMCDDA-Europol 2014 Annual Report on the Implementation of Council Decision 2005/387/JHA). The effect of racemic 2-MAPB on extracellular serotonin in living mouse striatum was studied by Fuwa et al., where it was shown to increase extracellular dopamine, serotonin, and norepinephrine (Fuwa et al. The Journal of Toxicological Sciences, 2016, 41(3), 329-337). The related compound racemic 2-EAPB is also known as a recreational drug and was studied in rats by Sayson et al. to examine potential rewarding and reinforcing effects (Sayson et al. European Journal of Pharmacology 2020, 885, 173527). Sayson et al. found that racemic 2-EAPB elicited addictive behavior, but at a higher dose than was necessary for the regioisomer 5-EAPB or methamphetamine. Brandt and colleagues reviewed certain properties of racemic (2‐aminopropyl) benzothiophene (Brandt et al., Drug testing and analysis, 2020 12(8):1109-25). Brandt et al. synthesized racemic 2-APBT, along with the five other positional isomers, and reported their physicochemical characteristics such as IR spectra or tandem mass spectrometry features, without biological data. As of the filing date, enantiomers of R-Bk-2-MAPB or S-Bk-2-MAPB have been assigned the CAS registry numbers 2290766-37-7 and 2111574-19-5, respectively, but their entries contain no references to their synthesis or use. Similarly, racemic Bk-2-EAPB has been assigned CAS registry number 2140942-24-9, but the entry does not contain any references to its synthesis or use. To the inventor’s knowledge, the benzofurans and benzothiophenes disclosed herein have not been proposed as entactogens and most have not been previously synthesized or evaluated. The embodiments of the invention are presented to meet the goal of assisting persons with mental disorders, who desire mental enhancement, or who suffer from other CNS disorders by providing milder therapeutics that are fast acting and that reduce the properties that decrease the patient experience, are counterproductive to the therapy, or are undesirably toxic. One goal of the invention is to provide therapeutic compositions that increase empathy, sympathy, openness and acceptance of oneself and others, which can be taken, if necessary, as part of therapeutic counseling sessions, when necessary, episodically or even consistently, as prescribed by a healthcare provider. DEFINITIONS When introducing elements of the present invention or the typical embodiments thereof, the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and not exclusive (i.e., there may be other elements in addition to the recited elements). Thus, the terms “including,” “may include,” and “include,” as used herein mean, and are used interchangeably with, the phrase “including but not limited to.” Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments. Unless defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. Further definitions that may assist the reader to understand the disclosed embodiments are as follows, and such definitions may be used to interpret the defined terms, when those terms are used herein. However, the examples given in the definitions are generally non-exhaustive and must not be construed as limiting the invention. It also will be understood that a substituent should comply with chemical bonding rules and steric compatibility constraints in relation to the particular molecule to which it is attached. “Compounds” refers to compounds encompassed by structural formulas disclosed herein and includes any specific compounds within these formulas whose structure is disclosed herein. Although sometimes referred to using different terms, and sometimes used interchangeably with “structures,” compounds will be understood to include the conjugates, codrugs, and prodrugs of the invention. The compounds of the invention may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The compounds of the invention may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Unless otherwise indicated, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. Further, it should be understood when partial structures of the compounds of the invention are illustrated, that brackets or dashes indicate the point of attachment of the partial structure to the rest of the molecule. “Composition of the invention” refers to at least one compound of the invention and a pharmaceutically acceptable vehicle with which the compound is administered to a patient. When administered to a patient, the compounds of the invention are administered in isolated form, which means separated from a synthetic organic reaction mixture. In certain embodiments, an enantiomerically enriched compound is an enantiomerically enriched mixture or a pure enantiomer. An enantiomerically enriched mixture is a mixture that contains one enantiomer in a greater amount than the other. An enantiomerically enriched mixture of an S-enantiomer contains at least 55% of the S-enantiomer, and, typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more of the S-enantiomer and not more than 98%. An enantiomerically enriched mixture of an R-enantiomer contains at least 55% of the R-enantiomer, and typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the R-enantiomer and not more than 98%. The specific ratio of S or R enantiomer can be selected for the need of the patient according to the health care specialist to balance the desired effect. In certain aspects, the term enantiomerically enriched does not include a pure enantiomer. The term enantiomerically enriched mixture as used in this application does not include a racemic mixture and does not include a pure isomer. Notwithstanding, it should be understood that any compound described herein in enantiomerically enriched form can be used as a pure isomer if it achieves the goal of any of the specifically itemized methods of treatment described herein, including but not limited to pure enantiomer or enantiomerically enriched mixture of Formula I, II, III, IV, V, VI, VII, or VIII. The term enantiomerically pure as used herein refers to a compound with about 98% to 100% stereochemical purity. The term “CNS disorder” as used herein refers to either a neurological condition (one that is typically treated by a neurologist) or a psychiatric condition (one that is typically treated by a psychiatrist). Neurological disorders are typically those affecting the structure, biochemistry or normal electrical functioning of the brain, spinal cord or other nerves. Psychiatric conditions are more typically thought of as mental disorders, which are primarily abnormalities of thought, feeling or behavior that cause significant distress or impairment of personal functioning. Thus, the disclosed compounds can be used in an effective amount to improve neurological or psychiatric functioning in a patient in need thereof. Neurological indications include, but are not limited to improved neuroplasticity, including treatment of stroke, brain trauma, dementia, and neurodegenerative diseases. Compounds of the current invention can be considered psychoplastogens, that is, small molecules that are able to induce rapid neuroplasticity. For example, in certain embodiments, the disclosed compounds and compositions can be used to improve stuttering and other dyspraxias or to treat Parkinson’s disease or schizophrenia. The term “neurological disease or disorder” includes Alzheimer’s disease, mild cognitive impairment (MCI), Parkinson’s disease, Parkinson’s disease dementia, multiple sclerosis, adrenoleukodystrophy, AIDS dementia complex, Alexander disease, Alper’s disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy, Canavan disease, cerebral amyloid angiopathy, cerebellar ataxia, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, diffuse myelinoclastic sclerosis, fatal familial insomnia, Fazio-Londe disease, Friedreich’s ataxia, frontotemporal dementia or lobar degeneration, hereditary spastic paraplegia, Huntington disease, Kennedy’s disease, Krabbe disease, Lewy body dementia, Lyme disease, Machado-Joseph disease, motor neuron disease, Multiple systems atrophy, neuroacanthocytosis, Niemann-Pick disease, Pelizaeus-Merzbacher Disease, Pick’s disease, primary lateral sclerosis including its juvenile form, progressive bulbar palsy, progressive supranuclear palsy, Refsum’s disease including its infantile form, Sandhoff disease, Schilder’s disease, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson- Olszewski disease, subacute combined degeneration of the spinal cord, survival motor neuron spinal muscular atrophy, Tabes dorsalis, Tay-Sachs disease, toxic encephalopathy, transmissible spongiform encephalopathy, Vascular dementia, X-linked spinal muscular atrophy, synucleinopathy, progranulinopathy, tauopathy, amyloid disease, prion disease, protein aggregation disease, and movement disorder. The term "improving psychiatric function" is intended to include mental health and life conditions that are not traditionally treated by neurologists but sometimes treated by psychiatrists and can also be treated by psychotherapists, life coaches, personal fitness trainers, meditation teachers, counselors, and the like. For example, it is contemplated that the disclosed compounds will allow individuals to effectively contemplate actual or possible experiences that would normally be upsetting or even overwhelming. This includes individuals with fatal illness planning their last days and the disposition of their estate. This also includes couples discussing difficulties in their relationship and how to address them. This also includes individuals who wish to more effectively plan their career. The term “inadequate functioning of neurotransmission” is used synonymously with a CNS disorder that adversely affects normal healthy neurotransmission. The present invention also includes compounds, including enantiomerically enriched mixtures and their use, with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., isotopically enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 17O, 18O, 18F, 36Cl, and respectively. In one non-limiting embodiment, isotopically labelled compounds can be used in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H) may be used anywhere in described structures that achieves the desired result. Alternatively, or in addition, isotopes of carbon, e.g., 13C and 14C, may be used. Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is at least 60, 70, 80, 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 80, 90, 95 or 99% enriched at a desired location. Unless indicated otherwise, the deuterium is at least 80% at the selected location. Deuteration can occur at any replaceable hydrogen that provides the desired results. The substitution of a hydrogen atom for a deuterium atom can be provided in a compounds or compositions described herein. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within a group selected from any of RB1, R1, R2, R3, R4, R5, R6, R9, R10, and R11. For example, when any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc.). The compounds of the invention also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include 2H, 3H, 13C, 14C, 13N, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl. For example, the methyl group on the nitrogen of a compound of Formula I or Formula II can be prepared with deuterium replacing some or all of the three hydrogens on the N-methyl group. This creates a higher activation energy for bond cleavage and a slower formation of the methyl metabolites. Analogously, the two hydrogens on the furan ring may be replaced with one or two deuteriums to decrease metabolic opening of the furan ring and formation of hydroxyl- substituted metabolites. The term "isotopically-labeled" analog refers to an analog that is a "deuterated analog", a "13C-labeled analog," or a "deuterated/13C-labeled analog." The term "deuterated analog" means a compound described herein, whereby a H-isotope, i.e., hydrogen/protium (1H), is substituted by a H-isotope, e.g., deuterium (2H). Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium. In certain embodiments, the isotope is at least 60, 70, 8090, 95 or 99% or more enriched in an isotope at any location of interest. In some embodiments it is deuterium that is 90, 95 or 99% enriched at a desired location. Unless indicated to the contrary, the deuteration is at least 80% at the selected location. Deuteration of the nucleoside can occur at any replaceable hydrogen that provides the desired results. “Alkyl” is a branched, straight chain, or cyclic saturated aliphatic hydrocarbon group including from 1 to about 8 carbon atoms, from 1 to about 6 carbon atoms, from 1 to about 4 carbon atoms, from 1 to 3 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5 or C1-C6. The specified ranges as used herein indicate an alkyl group which is considered to explicitly disclose as individual species each member of the range described as a unique species. For example, the term C1-C6 alkyl as used herein indicates a straight or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and also a carbocyclic alkyl group of 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C1-C4alkyl as used herein indicates a straight or branched alkyl group having 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2- methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, and hexyl. “Haloalkyl” indicates both branched and straight-chain alkyl groups substituted with one or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2- fluoroethyl, and penta-fluoroethyl. “Halogen” or “halo” means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). For groups containing two or more halogens, such as —CHX2 or —CX3, and for example “where X is halogen,” it will be understood that each X independently will be selected from the group of halogens. “Hydroxy” means the radical —OH. “Oxo” means the divalent radical ═O. “Stereoisomers” includes enantiomers, diastereomers, the components of racemic mixtures, and combinations thereof. Stereoisomers can be prepared or separated as described herein or by using other methods. “Isomers” includes stereo and geometric isomers, as well as diastereomers. Examples of geometric isomers include cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present disclosure. The isomers may be used either in pure form or in admixture with other isomers of the compounds described herein. “Agonism” refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response. “Agonist” refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. As a nonlimiting example, “5HT1B agonist” can be used to refer to a compound that exhibits an EC50 with respect to 5HT1B activity of no more than about 10, 25 or even 50 μΜ. In some embodiments, “agonist” includes full agonists or partial agonists. “Full agonist” refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor. “Partial agonist” refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist. “Antagonism” refers to the inactivation of a receptor or enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and does not allow activity to occur. “Antagonist” or “neutral antagonist” refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response. “DAT to SERT ratio” refers to the tendency of a substance (e.g., a compound or a drug) to increase extracellular dopamine versus increasing extracellular 5-HT concentrations. Higher numbers of this ratio indicate a greater increase of dopamine than serotonin, while lower number indicate an increasing 5-HT more than dopamine. The exact numbers depend on the assay used. The ratio is calculated herein as (DAT EC50)-1/(SERT EC50)-1. Some publications use IC50s for inhibiting uptake instead of EC50s for causing release to calculate this ratio, which will often yield very different results for substances that are monoamine releasers. Thus, it is important to review the numbers in view of the assay and measurement used. “IC50” refers to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process. For example, IC50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay. Similarly, EC50 refers to the concentration of a substance that provokes a response halfway between the baseline activity and maximum response. In some instances, an IC50 or EC50 is determined in an in vitro assay system. In some embodiments as used herein, IC50 (or EC50) refers to the concentration of a modulator that is required for 50% inhibition (or excitation) of a receptor, for example, 5HT1B. ‘‘Modulate” or “modulating” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, agonists, partial agonists, antagonists, and allosteric modulators (e.g., positive allosteric modulator) of a G protein-coupled receptor (e.g., 5-HT1B) are modulators of the receptor. ‘‘Neuroplasticity” refers to the ability of the brain to change its structure and/or function throughout a subject’s life. Examples of the changes to the brain include, but are not limited to, the ability to adapt or respond to internal and/or external stimuli, such as due to an injury, and the ability to produce new neurites, dendritic spines, and synapses. “Treating” or “treatment” of a disease, as used in context, includes (i) inhibiting the disease, i.e., arresting or reducing the development or progression of the disease or its clinical symptoms; or (ii) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. Inhibiting the disease, for example, would include prophylaxis. Hence, one of skill in the art will understand that a therapeutic amount necessary to effect treatment for purposes of this invention will, for example, be an amount that provides for objective indicia of improvement in patients having clinically diagnosable symptoms. Other such measurements, benefits, and surrogate or clinical endpoints, whether alone or in combination, would be understood to those of ordinary skill. “Therapeutic effect” means the responses(s) in a mammal after treatment that are judged to be desirable and beneficial. Hence, depending on the CNS disorder to be treated, or improvement in CNS functioning sought, those responses shall differ, but would be readily understood by those of ordinary skill. The term “hallucinations” or “hallucinogenic effects” includes but is not limited to perceptual distortions, delusions, depersonalization, derealization and/or labile mood. These effects can include dysphoria of intensities ranging from controllable anxiety to uncontrollable panic. Non-limiting embodiments of the present invention In certain aspects, the invention provides the enantiomerically enriched mixtures of R-Bk- 2-MAPB or S-Bk-2-MAPB. In other aspects, the invention provides enantiomerically enriched mixtures or pure enantiomers of R-Bk-2-EAPB or S-Bk-2-EAPB or a pharmaceutically acceptable salt or salt mixture thereof. In certain aspects, a pharmaceutical composition is provided that comprises Bk-2-MAPB or Bk-2-EAPB or a pure R- or S-enantiomer or enantiomerically enriched mixture thereof: .
Figure imgf000022_0001
In other aspects the invention provides a benzothiophene compound for example an enantiomerically enriched mixtures or pure enantiomers of or a pharmaceutically acce
Figure imgf000023_0001
Additional examples of benzothiophene compounds include enantiomerically enriched mixtures or pure enantiomers of or a pharmaceutically a
Figure imgf000023_0002
In certain embodiments, isolated enantiomers of the compounds of the present invention show improved binding at the desired receptors and transporters relevant to the goal of treatment for the mental disorder or for mental enhancement. An enantiomerically enriched mixture is a mixture that contains one enantiomer in a greater amount than the other. An enantiomerically enriched mixture of an S-enantiomer contains at least 55% of the S-enantiomer, and, typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or more of the S-enantiomer and not more than 98%. An enantiomerically enriched mixture of an R-enantiomer contains at least 55% of the R-enantiomer, and typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the R-enantiomer and not more than 98%. The specific ratio of S or R enantiomer can be selected for the need of the patient according to the health care specialist to balance the desired effect. The term enantiomerically enriched mixture as used in this application does not include a racemic mixture and does not include a pure isomer. Notwithstanding, it should be understood that any compound described herein in enantiomerically enriched form can be used as a pure isomer (or a racemic form) if it achieves the goal of any of the specifically itemized methods of treatment described herein. It has been discovered that it is useful to have an S- or R-enantiomerically enriched mixture of these entactogenic compounds that is not a racemic mixture. Enantiomerically enriched mixtures that have a greater amount of the one enantiomer of Bk-2-MAPB or Bk-2-EAPB potentially maximize serotonin-receptor-dependent therapeutic effects, whereas the enantiomerically enriched opposite enantiomer of Bk-2-MAPB or Bk-2-EAPB potentially increases nicotinic-receptor-dependent therapeutic effects relative to the racemic mixture Therefore, one aspect of the present invention is a balanced mixture of S-Bk-2-MAPB and R-Bk- 2-MAPB or a balanced mixture of S-Bk-2-EAPB and R-Bk-2-EAPB that achieves a predetermined combination of serotonin-receptor-dependent therapeutic effects and nicotinic-receptor-dependent or dopaminergic therapeutic effects. The effect can be modulated as desired for optimal therapeutic effect. Non-limiting examples of unwanted effects that can be minimized by carefully selecting the balance of enantiomers include hallucinogenic effects (for example, perceptual distortions, delusions, depersonalization, derealization, and labile mood), psychoactive effects (including excess stimulation or sedation), physiological effects (including transient hypertension or appetite suppression), toxic effects (including to the brain or liver), effects contributing to abuse liability (including euphoria or dopamine release), and/or other side effects. Accordingly, in certain embodiments, an enantiomerically enriched mixture of the S- enantiomer or pure enantiomer of S-Bk-2-MAPB or S-Bk-2-EAPB or an enantiomerically enriched mixture of the S-enantiomer or pure enantiomer of S-Bk-2-MAPB or S-Bk-2-EAPB balances therapeutic effects (such as emotional openness and perceptible mood effects) while having less effects associated with abuse liability (such as perceptible ‘good drug effects’ or desire for more drug, which can lead to abuse; Pool et al.2016. Neuroscience & Biobehavioral Reviews, 63, pp.124-142) when administered to a host in need thereof, for example a mammal, including a human. The enantiomerically enriched mixture or pure enantiomer achieves a predetermined combination of emotional therapeutic effects and perceptible mood effects. The effect can be modulated as desired for optimal therapeutic effect. In another embodiment, an enantiomerically enriched mixture of the R-enantiomer or pure enantiomer of R-Bk-2-MAPB or R-Bk-2-EAPB or an enantiomerically enriched mixture of the R- enantiomer or pure enantiomer of R-Bk-2-MAPB or R-Bk-2-EAPB balances therapeutic effects (such as emotional openness and perceptible mood effects) while having less effects associated with abuse liability (such as perceptible ‘good drug effects’ or desire for more drug, which can lead to abuse; Pool et al. 2016. Neuroscience & Biobehavioral Reviews, 63, pp.124-142) when administered to a host in need thereof, for example a mammal, including a human. The enantiomerically enriched mixture or pure enantiomer achieves a predetermined combination of emotional therapeutic effects and perceptible mood effects. The effect can be modulated as desired for optimal therapeutic effect. In some embodiments, a compound of the present invention has favorable pharmacokinetic properties for administration to a mammal, for example a human. These properties can include having more reproducible and less variable pharmacokinetic properties than MDMA. In certain embodiments, a compound of the present invention has a less variable maximum plasma concentration (Cmax) than MDMA. In certain embodiments, a compound of the present invention has a less variable area-under-the-concentration-versus-time-curve (AUC) than MDMA. An additional potential beneficial property of a compound of the present invention is reduced inhibition of CYP enzymes compared to MDMA. Inhibition of such enzymes can cause unwanted toxic drug-drug interactions. In certain embodiments, a compound of the present invention does not inhibit or shows minimal inhibition of cytochrome p450 isozyme 2D6 (CYP2D6). In certain embodiments, a compound of the present invention shows less potent inhibition of CYP2D6 than MDMA. Compounds of the present invention In some aspects a compound, pure enantiomer, or enantiomerically enriched mixture of Formula III-VIII or Formula IIIA-VIIIA is provided: V) I) II)
Figure imgf000025_0001
A) or a pharm
Figure imgf000026_0001
wherein: R1A is selected from -H and -OH; R1B is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R2B is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C2-C4 alkyl; R1C is selected from -H, -OH, -X, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R1D is selected from -OH, -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R2C is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, - CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R2D is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3A is selected from -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C4 alkyl; R3B is selected from -H, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3C and R4C are independently selected from -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3D and R4D are independently selected from -H, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl, wherein if R1D is -OH and R2D is CH3, at least one of R3D and R4D is not -H; R3E is selected from -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C2-C4 alkyl; R3F and R4F are independently selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R4E is selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R5A is selected from -H and CH3; R5B is selected from -H and CH3, and at least one of R1B, R3B, and R5B is not CH3; R5C is selected from -H and CH3, wherein if R5C is -H and R1C is -H, OH, or -F, at least one of R3C, and R4C is not CH3; R5D is selected from -H and CH3; R5E is selected from -H and CH3, wherein if R3E is ethyl and R4E is -H, R5E cannot be -H; R5F is selected from -H and CH3, wherein at least one of R3F, R4F, and R5F is not -H; and X is independently selected from -F, -Cl, and -Br. In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a
Figure imgf000027_0001
p y p . In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a
Figure imgf000028_0001
In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or
Figure imgf000028_0002
In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a
Figure imgf000028_0003
parmaceutca y accepta e sat or sat mxture tereo. In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a
Figure imgf000029_0001
In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a
Figure imgf000029_0002
In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a
Figure imgf000029_0003
parmaceu ca y accepa e sa or sa mxure ereo. In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or
Figure imgf000030_0001
In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a
Figure imgf000030_0002
In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from:
Figure imgf000030_0003
or a pharmaceutica
Figure imgf000031_0001
In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a p
Figure imgf000031_0002
In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from:
Figure imgf000031_0003
or a pharmaceutica
Figure imgf000032_0001
In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from: or a ph
Figure imgf000032_0002
In certain embodiments, an enantiomerically enriched mixture of the present invention is selected from:
Figure imgf000032_0003
or a pharmaceutic
Figure imgf000033_0001
Embodiments of “alkyl” In certain embodiments “alkyl” is a C1-C6alkyl, C1-C5alkyl, C1-C4alkyl, C1-C3alkyl, or C1- C2alkyl. In certain embodiments “alkyl” has one carbon. In certain embodiments “alkyl” has two carbons. In certain embodiments “alkyl” has three carbons. In certain embodiments “alkyl” has four carbons. In certain embodiments “alkyl” has five carbons. In certain embodiments “alkyl” has six carbons. Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl. Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl. Additional non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl. Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl. Additional non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl. In certain embodiments when a term is used that includes “alk” it should be understood that “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example, and without limitation, the terms alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenloxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context. Embodiments of “haloalkyl” In certain embodiments “haloalkyl” is a C1-C6haloalkyl, C1-C5haloalkyl, C1-C4haloalkyl, C1-C3haloalkyl, and C1-C2haloalkyl. In certain embodiments “haloalkyl” has one carbon. In certain embodiments “haloalkyl” has one carbon and one halogen. In certain embodiments “haloalkyl” has one carbon and two halogens. In certain embodiments “haloalkyl” has one carbon and three halogens. In certain embodiments “haloalkyl” has two carbons. In certain embodiments “haloalkyl” has three carbons. In certain embodiments “haloalkyl” has four carbons. In certain embodiments “haloalkyl” has five carbons. In certain embodiments “haloalkyl” has six carbons. Non-limiting examples of “haloalkyl” include . Additional non-limiting examples of “haloalk
Figure imgf000034_0001
,
Figure imgf000034_0002
Additional non-limiting examples of “haloalkyl” includ , and .
Figure imgf000034_0003
Additional non-limiting examples of “haloalkyl” include: .
Figure imgf000034_0004
Embodiments of R1 In certain embodiments R1 is hydrogen. In certain embodiments R1 group is hydrogen. In certain embodiments R1 is halogen. In certain embodiments R1 is -F. In certain embodiments R1 is -Cl. In certain embodiments R1 is -Br. In certain embodiments R1 is -I. In certain embodiments R1 is alkyl. In certain embodiments R1 is methyl. In certain embodiments R1 is ethyl. In certain embodiments R1 is n-propyl. In certain embodiments R1 is isopropyl. In certain embodiments R1 is haloalkyl. In certain embodiments R1 is -CF3. In certain embodiments R1 is -OP(O)(OR9)2. In certain embodiments R1 is -OP(O)(OH)2. In certain embodiments R1 is -SR9. In certain embodiments R1 is -SH. In certain embodiments R1 is -SCF3. In certain embodiments R1 is -SMe. In certain embodiments R1 is -NR9R10. In certain embodiments R1 is -NHR10. In certain embodiments R1 is -NH2. In certain embodiments R1 is -NHMe. In certain embodiments R1 is -N(Me)2. In certain embodiments R1 is -OR9. In certain embodiments R1 is -OH. In certain embodiments R1 is -OCF3. In certain embodiments R1 is -OCH3. In certain embodiments R1 is selected from hydrogen, F, CH3, and -OMe. Embodiments of R2 In certain embodiments R2 is hydrogen. In certain embodiments R2 group is hydrogen. In certain embodiments R2 is halogen. In certain embodiments R2 is -F. In certain embodiments R2 is -Cl. In certain embodiments R2 is -Br. In certain embodiments R2 is -I. In certain embodiments R2 is alkyl. In certain embodiments R2 is methyl. In certain embodiments R2 is ethyl. In certain embodiments R2 is n-propyl. In certain embodiments R2 is isopropyl. In certain embodiments R2 is haloalkyl. In certain embodiments R2 is -CF3. In certain embodiments R2 is -OP(O)(OR9)2. In certain embodiments R2 is -OP(O)(OH)2. In certain embodiments R2 is -SR9. In certain embodiments R2 is -SH. In certain embodiments R2 is -SCF3. In certain embodiments R2 is -SMe. In certain embodiments R2 is -NR9R10. In certain embodiments R2 is -NHR10. In certain embodiments R2 is -NH2. In certain embodiments R2 is -NHMe. In certain embodiments R2 is -N(Me)2. In certain embodiments R2 is -OR9. In certain embodiments R2 is -OH. In certain embodiments R2 is -OCF3. In certain embodiments R2 is -OCH3. In certain embodiments R2 is selected from hydrogen, F, CH3, and -OMe. Embodiments of R3 In certain embodiments R3 is hydrogen. In certain embodiments R3 group is hydrogen. In certain embodiments R3 is halogen. In certain embodiments R3 is -F. In certain embodiments R3 is -Cl. In certain embodiments R3 is -Br. In certain embodiments R3 is -I. In certain embodiments R3 is alkyl. In certain embodiments R3 is methyl. In certain embodiments R3 is ethyl. In certain embodiments R3 is n-propyl. In certain embodiments R3 is isopropyl. In certain embodiments R3 is haloalkyl. In certain embodiments R3 is -CF3. In certain embodiments R3 is -OP(O)(OR9)2. In certain embodiments R3 is -OP(O)(OH)2. In certain embodiments R3 is -SR9. In certain embodiments R3 is -SH. In certain embodiments R3 is -SCF3. In certain embodiments R3 is -SMe. In certain embodiments R3 is -NR9R10. In certain embodiments R3 is -NHR10. In certain embodiments R3 is -NH2. In certain embodiments R3 is -NHMe. In certain embodiments R3 is -N(Me)2. In certain embodiments R3 is -OR9. In certain embodiments R3 is -OH. In certain embodiments R3 is -OCF3. In certain embodiments R3 is -OCH3. In certain embodiments R3 is selected from hydrogen, F, CH3, and -OMe. Embodiments of R4 In certain embodiments R4 is hydrogen. In certain embodiments R4 is alkyl. In certain embodiments R4 is methyl. In certain embodiments R4 is ethyl. In certain embodiments R4 is n-propyl. In certain embodiments R4 is isopropyl. In certain embodiments R4 is haloalkyl. In certain embodiments R4 is -CF3. In certain embodiments R4 is cycloalkyl. In certain embodiments R4 is CH2OH. Embodiments of R5 In certain embodiments R5 is hydrogen. In certain embodiments R5 is C1-C3 alkyl. In certain embodiments R5 is methyl. In certain embodiments R5 is ethyl. In certain embodiments R5 is n-propyl. In certain embodiments R5 is isopropyl. In certain embodiments R5 is haloalkyl. In certain embodiments R5 is -CF3. In certain embodiments R5 is CH2CH2OH. In certain embodiments R5 is OH. Embodiments of R6 In certain embodiments R6 is hydrogen. In certain embodiments R6 is C1-C3 alkyl. In certain embodiments R6 is methyl. In certain embodiments R6 is ethyl. In certain embodiments R6 is n-propyl. In certain embodiments R6 is isopropyl. In certain embodiments R6 is haloalkyl. In certain embodiments R6 is -CF3. In certain embodiments R6 is CH2CH2OH. Additional Embodiments 1. A compound of formula: V) I) II) or a pharm
Figure imgf000039_0001
wherein: R1A is selected from -H and -OH; R1B is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R1C is selected from -H, -OH, -X, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R1D is selected from -OH, -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R2D is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3A is selected from -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C4 alkyl; R3B is selected from -H, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3C and R4C are independently selected from -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3D and R4D are independently selected from -H, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl, wherein if R1D is -OH and R2D is CH3, at least one of R3D and R4D is not -H; R3E is selected from -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C2-C4 alkyl; R3F and R4F are independently selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R4E is selected from -H, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R5A is selected from -H and CH3; R5B is selected from -H and CH3, and at least one of R1B, R3B, and R5B is not CH3; R5C is selected from -H and CH3, wherein if R5C is -H and R1C is -H, OH, or -F, at least one of R3C, and R4C is not CH3; R5D is selected from -H and CH3; R5E is selected from -H and CH3, wherein if R3E is ethyl and R4E is -H, R5E cannot be -H; R5F is selected from -H and CH3, wherein at least one of R3F, R4F, and R5F is not -H; and X is independently selected from -F, -Cl, and -Br. 2. The compound of embodiment 1 wherein the compound is of formula: II) or a pharmaceutically accept of.
Figure imgf000041_0001
3. The compound of embodiment 1 wherein the compound is of formula: V) or a pharmaceutically accept of.
Figure imgf000041_0002
4. The compound of embodiment 1 wherein the compound is of formula: V) or a pharmaceutically acc
Figure imgf000041_0003
hereof. 5. The compound of embodiment 1 wherein the compound is of formula: I) or a pharmaceutically accepta
Figure imgf000041_0004
of. 6. The compound of embodiment 1 wherein the compound is of formula: II) or a pharmaceutically accepta
Figure imgf000041_0005
of. 7. The compound of embodiment 1 wherein the compound is of formula: II) or a pharmaceutically acceptab .
Figure imgf000042_0001
8. The compound of embodiment 1 or embodiment 2, wherein R1A is -H. 9. The compound of embodiment 1 or embodiment 2, wherein R1A is -OH. 10. The compound of any one of embodiments 1, 2, and 8-9, wherein R3A is -CH2OH. 11. The compound of any one of embodiments 1, 2, and 8-9, wherein R3A is -CH2X, -CHX2, or - CX3. 12. The compound of any one of embodiments 1, 2, and 8-11, wherein R5A is -H. 13. The compound of any one of embodiments 1, 2, and 8-11, wherein R5A is -CH3. 14. The compound of embodiment 1 or embodiment 3, wherein R1B is -X. 15. The compound of embodiment 1 or embodiment 3, wherein R1B is -CH2OH. 16. The compound of any one of embodiments 1, 3, and 14-15, wherein R3B is H. 17. The compound of any one of embodiments 1, 3, and 14-15, wherein R3B is -CH2OH, -CH2X, - CHX2, or -CX3. 18. The compound of any one of embodiments 1, 3, and 14-17, wherein R5B is -H. 19. The compound of any one of embodiments 1, 3, and 14-17, wherein R5B is -CH3. 20. The compound of embodiment 1 or embodiment 4, wherein R1C is -H. 21. The compound of embodiment 1 or embodiment 4, wherein R1C is -OH. 22. The compound of any one of embodiments 1, 4, and 20-21, wherein R5C is -H. 23. The compound of any one of embodiments 1, 4, and 20-21, wherein R5C is -CH3. 24. The compound of embodiment 1 or embodiment 5, wherein R1D is -X. 25. The compound of embodiment 1 or embodiment 5, wherein R1D is -OH. 26. The compound of any one of embodiments 1, 5, and 24-25, wherein R5D is -H. 27. The compound of any one of embodiments 1, 5, and 24-25, wherein R5D is -CH3. 28. The compound of embodiment 1 or embodiment 6, wherein R3E is -CH2OH. 29. The compound of embodiment 1 or embodiment 6, wherein R4E is -H. 30. The compound of any one of embodiments 1, 6, and 28-29, wherein R5E is -H. 31. The compound of any one of embodiments 1, 6, and 28-29, wherein R5E is -CH3. 32. The compound of embodiment 1 or embodiment 7, wherein R3F is -CH2OH. 33. The compound of embodiment 1 or embodiment 7, wherein R4F is -H. 34. The compound of any one of embodiments 1, 7, and 32-33, wherein R5F is -H. 35. The compound of any one of embodiments 1, 7, and 32-33, wherein R5F is -CH3. 36. The compound of any one of embodiments 1-35, wherein the compound has entactogenic properties. 37. The compound of any one of embodiments 1-35, wherein the compound has serotonin- receptor-dependent properties. 38. The compound of any one of embodiments 1-35, with decreased hallucinogenic effects relative to MDMA. 39. The compound of any one of embodiments 1-35, with decreased unwanted psychoactive effects relative to MDMA. 40. The compound of any one of embodiments 1-35, with decreased physiological effects relative to MDMA. 41. The compound of any one of embodiments 1-35, with decreased abuse potential relative to MDMA. 42. The compound of any one of embodiments 1-35, with decreased hallucinogenic effects relative to a clinically used 5-HT2A agonist. 43. The compound of any one of embodiments 1-35, with decreased unwanted psychoactive effects relative to a clinically used 5-HT2A agonist. 44. A compound of formula: A)
Figure imgf000043_0001
A) or a pharm
Figure imgf000044_0001
wherein: R1A is selected from -H and -OH; R2B is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C2-C4 alkyl; R1C is selected from -H, -OH, -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R2C is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, - CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R2D is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3A is selected from -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C4 alkyl; R3B is selected from -H, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3C and R4C are independently selected from -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3D and R4D are independently selected from -H, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3E is selected from -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C2-C4 alkyl; R3F and R4F are independently selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R4E is selected from -H, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R5A is selected from -H and CH3; R5B is selected from -H and CH3; R5C is selected from -H and CH3, wherein if R5C is -H and R1C is -H, OH, or -F, at least one of R3C, and R4C is not CH3; R5D is selected from -H and CH3; R5E is selected from -H and CH3, wherein if R3E is ethyl and R4E is -H, R5E cannot be -H; R5F is selected from -H and CH3, wherein at least one of R3F, R4F, and R5F is not -H; and X is independently selected from -F, -Cl, and -Br. 45. An enantiomerically enriched mixture of Formula: II); or a pharmaceutic
Figure imgf000045_0001
RB1 is selected from ; R1, R2, and R3 are i
Figure imgf000045_0002
g of hydrogen, halogen, alkyl, aryl, cycloalkyl, haloalkyl, -OP(O)(OR9)2, -SR9, -NR9R10, and -OR9; R4 is selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, -CH2OR11, and -CH2CH2OR11; in certain embodiments R4 is selected from hydrogen, -CH3, -CH2X, -CHX2, -CX3, - CH2CH3, -CH2CH2X, -CH2CHX2, -CH2CX3, -CH2OH, and -CH2CH2OH; in certain embodiments R4 is selected from hydrogen, -CH2X, -CHX2, -CX3, -CH2CH3, -CH2CH2X, -CH2CHX2, -CH2CX3, -CH2OH, and -CH2CH2OH; R5 is selected from hydrogen, C1-C3 alkyl, haloalkyl, -CH2CH2OH, and hydroxyl; R6 is selected from hydrogen, C1-C3 alkyl, haloalkyl, and -CH2CH2OH; each R9, R10, and R11 is independently selected from: hydrogen, alkyl, and haloalkyl; and X is independently selected from -F, -Cl, and -Br. 46. The enantiomerically enriched compound of embodiment 45 of Formula: I); or a pharmaceutically acceptable s .
Figure imgf000046_0001
47. The enantiomerically enriched compound of embodiment 45 of Formula: I); or a pharmaceutically accepta eof.
Figure imgf000046_0002
48. The enantiomerically enriched compound of any one of embodiments 45-47, wherein R1 is H or F. 49. The enantiomerically enriched compound of any one of embodiments 45-48, wherein R2 is H or F. 50. The enantiomerically enriched compound of any one of embodiments 45-49, wherein R3 is H or F. 51. The enantiomerically enriched compound of any one of embodiments 45-50, wherein RB1 is . 52.
Figure imgf000046_0003
nantiomerically enriched compound of any one of embodiments 45-51, wherein RB1 is . 53.
Figure imgf000046_0004
e enantiomerically enriched compound of embodiment 45 of Formula: ; or a pharmaceutical
Figure imgf000046_0005
y . 54. The enantiomerically enriched compound of embodiment 45 of Formula: ; or a pharmaceutically
Figure imgf000047_0001
55. The enantiomerically enriched compound of embodiment 45 of Formula: ; or a pharmaceutically
Figure imgf000047_0002
56. The enantiomerically enriched compound of embodiment 45 of Formula: ; or a pharmaceutically a
Figure imgf000047_0003
57. The enantiomerically enriched compound of embodiment 45 of Formula:
Figure imgf000047_0004
Figure imgf000048_0001
or a p
Figure imgf000049_0001
59. The enantiomerically enriched compound of embodiment 57 of Formula:
Figure imgf000049_0002
or a
Figure imgf000050_0001
60. The enantiomerically enriched compound of embodiment 58 of Formula: or or a
Figure imgf000050_0002
61. An enantiomerically enriched compound of formula:
Figure imgf000050_0003
; or a p
Figure imgf000051_0001
62. The enantiomerically enriched compound of any one of embodiments 45-61, wherein the compound has entactogenic properties. 63. The enantiomerically enriched compound of any one of embodiments 45-61, wherein the compound has serotonin-receptor-dependent properties. 64. The enantiomerically enriched compound of any one of embodiments 45-61, with decreased hallucinogenic effects relative to MDMA. 65. The enantiomerically enriched compound of any one of embodiments 45-61, with decreased unwanted psychoactive effects relative to MDMA. 66. The enantiomerically enriched compound of any one of embodiments 45-61, with decreased physiological effects relative to MDMA. 67. The enantiomerically enriched compound of any one of embodiments 45-61, with decreased abuse potential relative to MDMA. 68. The enantiomerically enriched compound of any one of embodiments 45-61, with decreased hallucinogenic effects relative to a clinically used 5-HT2A agonist. 69. The enantiomerically enriched compound of any one of embodiments 45-61, with decreased unwanted psychoactive effects relative to a clinically used 5-HT2A agonist. 70. The enantiomerically enriched compound of any one of embodiments 45-61, with decreased physiological effects relative to a clinically used 5-HT2A agonist. 71. The compound or enantiomerically enriched compound of any one of embodiments 1-61 that shows the therapeutic effect of emotional openness. 72. The compound or enantiomerically enriched compound of any one of embodiments 1-61 wherein the pharmaceutically acceptable salt(s) is selected from HCl, sulfate, aspartate, saccharate, fumarate, succinate, phosphate, oxalate, acetate, amino acid anion, gluconate, maleate, malate, citrate, mesylate, nitrate or tartrate, or a mixture thereof. 73. The compound or enantiomerically enriched compound of embodiment 71 that is also a serotonin reuptake inhibitor. 74. The compound or enantiomerically enriched compound of any one of embodiments 1-35 or 45-61 that has minimal or no direct agonism of 5-HT2A. 75. The compound or enantiomerically enriched compound of any one of embodiments 1-35 or 45-61 that is a direct 5-HT2A agonist. 76. The compound or enantiomerically enriched compound of any one of embodiments 1-35 or 45-61 that is a serotonin releaser. 77. The compound or enantiomerically enriched compound of any one of embodiments 1-35 or 45-61 that is both a direct 5-HT2A agonist and a serotonin releaser. 78. The compound or enantiomerically enriched compound of any one of embodiments 1-35 or 45-61 that is a psychoplastogen. 79. The compound of any one of embodiments 1-35, wherein the compound is an enantiomerically enriched mixture or pure enantiomer or a pharmaceutically acceptable salt or salt mixture thereof. 80. The enantiomerically enriched compound of any one of embodiments 45-61, wherein the compound is an enantiomerically enriched mixture or pure enantiomer or a pharmaceutically acceptable salt or salt mixture thereof. 81. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, wherein the compound has entactogenic properties. 82. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, wherein the compound has serotonin-receptor-dependent properties. 83. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, with decreased hallucinogenic effects relative to MDMA. 84. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, with decreased unwanted psychoactive effects relative to MDMA. 85. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, with decreased physiological effects relative to MDMA. 86. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, with decreased abuse potential relative to MDMA. 87. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, with decreased hallucinogenic effects relative to a clinically used 5-HT2A agonist. 88. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, with decreased unwanted psychoactive effects relative to a clinically used 5-HT2A agonist. 89. The enantiomerically enriched mixture or pure enantiomer of embodiment 79 or 80, with decreased physiological effects relative to a clinically used 5-HT2A agonist. 90. The enantiomerically enriched mixture or pure enantiomer any one of embodiments 78-88 that shows the therapeutic effect of emotional openness. 91. The enantiomerically enriched mixture or pure enantiomer any one of embodiments 78-90 wherein the pharmaceutically acceptable salt(s) is selected from HCl, sulfate, aspartate, saccharate, fumarate, succinate, phosphate, oxalate, acetate, amino acid anion, gluconate, maleate, malate, citrate, mesylate, nitrate or tartrate, or a mixture thereof. 92. The enantiomerically enriched mixture or pure enantiomer of any one of embodiments 78-91 that is also a serotonin reuptake inhibitor. 93. The enantiomerically enriched mixture or pure enantiomer of any one of embodiments 78-91 that has minimal or no direct agonism of 5-HT2A. 94. The enantiomerically enriched mixture or pure enantiomer of any one of embodiments 78-91 that is a direct 5-HT2A agonist. 95. The enantiomerically enriched mixture or pure enantiomer of any one of embodiments 78-91 that is a serotonin releaser. 96. The enantiomerically enriched mixture or pure enantiomer of any one of embodiments 78-91 that is both a direct 5-HT2A agonist and a serotonin releaser. 97. The enantiomerically enriched mixture or pure enantiomer of any one of embodiments 78-91 that is a psychoplastogen. 98. The enantiomerically enriched mixture or pure enantiomer of any one of embodiments 78-97 wherein the enantiomerically enriched mixture or pure enantiomer is an enantiomerically enriched mixture. 99. A method for treating a central nervous system disorder comprising administering an effective amount of a compound, pure enantiomer, or enantiomerically enriched mixture of any one of embodiments 1-98 to a host in need thereof. 100. The method of embodiment 99 wherein the central nervous system disorder is selected from: post-traumatic stress disorder, depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic, adjustment disorder, feeding and eating disorders, binge behaviors, body dysmorphic syndromes, addiction, drug abuse or dependence disorders, substance use disorders, disruptive behavior disorders, impulse control disorders, gaming disorders, gambling disorders, memory loss, dementia of aging, attention deficit hyperactivity disorder, personality disorders, attachment disorders, autism, dissociative disorders and headache disorders. 101. The method of embodiment 99 or 100 wherein the host is a human. 102. The method of any one of embodiments 99-101 wherein the central nervous system disorder is post-traumatic stress disorder. 103. The method of any one of embodiments 99-101 wherein the central nervous system disorder is adjustment disorder. 104. The method of any one of embodiments 99-101 wherein the central nervous system disorder is generalized anxiety. 105. The method of any one of embodiments 99-101 wherein the central nervous system disorder is social anxiety. 106. The method of any one of embodiments 99-101 wherein the central nervous system disorder is depression. 107. The method of any one of embodiments 99-101 wherein the central nervous system disorder is a substance use disorder. 108. The method of any one of embodiments 99-101 wherein the central nervous system disorder is an attachment disorder. 109. The method of any one of embodiments 99-101 wherein the central nervous system disorder is schizophrenia. 110. The method of any one of embodiments 99-101 wherein the central nervous system disorder is a headache disorder. 111. The method of any one of embodiments 99-101 wherein the central nervous system disorder is an eating disorder. 112. The method of embodiment 111 wherein the eating disorder is bulimia. 113. The method of embodiment 111 wherein the eating disorder is binge eating. 114. The method of embodiment 111 wherein the eating disorder is anorexia. 115. The method of any one of embodiments 99-101 wherein the central nervous system disorder is a neurological disorder. 116. The method of embodiment 115 wherein the neurological disorder is stroke. 117. The method of embodiment 115 wherein the neurological disorder is brain trauma. 118. The method of embodiment 115 wherein the neurological disorder is dementia. 119. The method of embodiment 115 wherein the neurological disorder is a neurodegenerative disease or disorder. 120. The method of embodiment 119 wherein the neurodegenerative disease or disorder is selected from: Alzheimer’s disease, mild cognitive impairment (MCI), Parkinson’s disease, Parkinson's disease dementia, multiple sclerosis, adrenoleukodystrophy, AIDS dementia complex, Alexander disease, Alper's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy, Canavan disease, cerebral amyloid angiopathy, cerebellar ataxia, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, diffuse myelinoclastic sclerosis, fatal familial insomnia, Fazio- Londe disease, Friedreich's ataxia, frontotemporal dementia or lobar degeneration, hereditary spastic paraplegia, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Lyme disease, Machado-Joseph disease, motor neuron disease, Multiple systems atrophy, neuroacanthocytosis, Niemann-Pick disease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateral sclerosis including its juvenile form, progressive bulbar palsy, progressive supranuclear palsy, Refsum's disease including its infantile form, Sandhoff disease, Schilder's disease, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson- Olszewski disease, subacute combined degeneration of the spinal cord, survival motor neuron spinal muscular atrophy, Tabes dorsalis, Tay-Sachs disease, toxic encephalopathy, transmissible spongiform encephalopathy, Vascular dementia, X-linked spinal muscular atrophy, synucleinopathy, progranulinopathy, tauopathy, amyloid disease, prion disease, protein aggregation disease, and movement disorder. 121. The method of any one of embodiments 99-120 wherein the compound, pure enantiomer, or enantiomerically enriched mixture is administered in a clinical setting. 122. The method of any one of embodiments 99-120 wherein the compound, pure enantiomer, or enantiomerically enriched mixture is administered in an at-home setting. 123. The method of any one of embodiments 99-120 wherein the compound, pure enantiomer, or enantiomerically enriched mixture is administered during a psychotherapy session. 124. The method of any one of embodiments 99-120 wherein the compound, pure enantiomer, or enantiomerically enriched mixture is administered during a counseling session. 125. A pharmaceutical composition comprising an effective patient-treating amount of a compound, pure enantiomer, or enantiomerically enriched mixture of any one of embodiments 1-98 and a pharmaceutically acceptable carrier or excipient. 126. A pharmaceutical composition comprising an effective patient-treating amount of a pure enantiomer, or enantiomerically enriched mixture of ; and a
Figure imgf000056_0001
Preparation of Enantiomeric Compounds Various methods are known in the art for preparing optically active forms and determining activity. Such methods include standard processes described herein and other similar assays which are well known in the art. Examples of methods that can be used to obtain optical isomers of the compounds according to the present disclosure include but are not limited to the following: a) physical separation of crystals whereby macroscopic crystals of the individual enantiomers are manually separated. This technique may particularly be used if crystals of the separate enantiomers exist (i.e., the material is a conglomerate), and the crystals are visually distinct; b) simultaneous crystallization whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; c) enzymatic resolutions whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; d) enzymatic asymmetric synthesis, a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; e) chemical asymmetric synthesis whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; f) diastereomer separations whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; g) first- and second-order asymmetric transformations whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomers; h) kinetic resolutions comprising partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, enantiomerically enriched reagent or catalyst under kinetic conditions; i) enantiospecific synthesis from enantiomerically enriched precursors whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; j) chiral liquid chromatography whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase. The stationary phase can be made of chiral material, or the mobile phase can contain an additional chiral material to provoke the differing interactions; k) chiral gas chromatography whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed enantiomerically enriched chiral adsorbent phase; l) extraction with chiral solvents whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; and m) transport across chiral membranes whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the enantiomerically enriched chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through. Enantiomerically Enriched Pharmaceutical Compositions Chiral compounds of the invention may be prepared by chiral chromatography from the racemic or enantiomerically enriched free amine. Pharmaceutically acceptable salts of chiral compounds may be prepared from fractional crystallization of salts from a racemic or an enantiomerically enriched free amine and a chiral acid. Alternatively, the free amine may be reacted with a chiral auxiliary and the enantiomers separated by chromatography followed by removal of the chiral auxiliary to regenerate the free amine. Furthermore, separation of enantiomers may be performed at any convenient point in the synthesis of the compounds of the invention. The compounds of the invention may also be prepared using a chiral synthesis. An enantiomerically enriched mixture is a mixture that contains one enantiomer in a greater amount than the other. An enantiomerically enriched mixture of an S-enantiomer contains at least 55% of the S-enantiomer, and more typically at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and typically not more than 98% of the S-enantiomer. An enantiomerically enriched mixture of an R-enantiomer contains at least 55% of the R-enantiomer, more typically at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and typically not more than 98% of the R-enantiomer. In certain embodiments, enantiomerically enriched mixtures are created that have a greater amount of the nicotinic-receptor-dependent therapeutic effects. In certain embodiments, enantiomerically enriched mixtures are created that have a greater amount of the serotonin- receptor-dependent therapeutic effects. In certain embodiments, enantiomerically enriched mixtures are created that have a greater amount of the dopaminergic effects. In certain embodiments, enantiomerically enriched mixtures are created that have a greater amount of the serotonin-receptor-dependent therapeutic effects. Non-limiting examples of unwanted effects that can be minimized include psychoactive effects (such as excess stimulation or sedation), physiological effects (such as transient hypertension or appetite suppression), toxic effects (such as to the brain or liver), effects contributing to abuse liability (such as euphoria or dopamine release), and other side effects. One aspect of the present invention is a balanced mixture of S-Bk-2-MAPB and R-Bk-2- MAPB (not the racemate) that achieves a predetermined combination of serotonin-receptor- dependent therapeutic effects and nicotinic-receptor-dependent therapeutic effects. One aspect of the present invention is a balanced mixture of S-Bk-2-EAPB and R-Bk-2- EAPB (not the racemate) that achieves a predetermined combination of serotonin-receptor- dependent therapeutic effects and nicotinic-receptor-dependent therapeutic effects. One aspect of the present invention is a balanced mixture of S-Bk-2-MAPB and R-Bk-2- MAPB (not the racemate) that achieves a predetermined combination of serotonin-receptor- dependent therapeutic effects and dopaminergic effects. One aspect of the present invention is a balanced mixture of S-Bk-2-EAPB and R-Bk-2- EAPB (not the racemate) that achieves a predetermined combination of serotonin-receptor- dependent therapeutic effects and dopaminergic effects. In certain embodiments, pharmaceutical compositions of enantiomerically enriched preparations of Bk-2-MAPB or Bk-2-MAPB are provided. In certain embodiments, the pharmaceutical composition is enriched with S-Bk-2-MAPB. In certain embodiments, the pharmaceutical composition is enriched with R-Bk-2-MAPB. In certain embodiments, the pharmaceutical composition is enriched with S-Bk-2-MAPB. In certain embodiments, the pharmaceutical composition is enriched with R-Bk-2-MAPB. In certain embodiments, pharmaceutical compositions of enantiomerically enriched preparations of Bk-2-EAPB or Bk-2-EAPB are provided. In certain embodiments, the pharmaceutical composition is enriched with S-Bk-2-EAPB. In certain embodiments, the pharmaceutical composition is enriched with R-Bk-2-EAPB. In certain embodiments, the pharmaceutical composition is enriched with S-Bk-2-EAPB. In certain embodiments, the pharmaceutical composition is enriched with R-Bk-2-EAPB. It will be understood that the above embodiments and classes of embodiments can be combined to form additional embodiments. Particular embodiments for pharmaceutical compositions, including enantiomerically enriched pharmaceutical compositions, of the present invention include: a) S-Bk-2-MAPB; b) R-Bk-2-MAPB; c) Embodiments (a)-(b) wherein the compound is a free base; d) Embodiments (a)-(b) wherein the compound is a salt; e) A mixture of S-Bk-2-MAPB, R-Bk-2-MAPB and there is more S-enantiomer than R-enantiomer; f) A mixture of S-Bk-2-MAPB, R-Bk-2-MAPB and there is less S-enantiomer than R-enantiomer; g) A mixture of S-Bk-2-MAPB, R-Bk-2-MAPB and there is more S-enantiomer than R-enantiomer; h) A mixture of S-Bk-2-MAPB, R-Bk-2-MAPB and there is less S-enantiomer than R-enantiomer; i) A mixture of S-Bk-2-MAPB, R-Bk-2-MAPB and at least about 65% is the S- enantiomer while no more than 35% is the R-enantiomer; j) A mixture of S-Bk-2-MAPB, R-Bk-2-MAPB and greater than 65% is the S- enantiomer while less than 35% is the R-enantiomer; k) A mixture of S-Bk-2-MAPB, R-Bk-2-MAPB and greater than 90% is the S- enantiomer while less than 10% is the R-enantiomer; l) A mixture of S-Bk-2-MAPB, R-Bk-2-MAPB and at least about 35% is the S- enantiomer while not more than 65% is the R-enantiomer; m) A mixture of S-Bk-2-MAPB, R-Bk-2-MAPB and less than 35% is the S- enantiomer while greater than 65% is the R-enantiomer; n) A mixture of S-Bk-2-MAPB, R-Bk-2-MAPB and less than 10% is the S- enantiomer while greater than 90% is the R-enantiomer; o) S-Bk-2-EAPB; p) R-Bk-2-EAPB; q) Embodiments (o)-(p) wherein the compound is a free base; r) Embodiments (o)-(p) wherein the compound is a salt; s) A mixture of S-Bk-2-EAPB, R-Bk-2-EAPB and there is more S-enantiomer than R-enantiomer; t) A mixture of S-Bk-2-EAPB , R-Bk-2-EAPB and there is less S-enantiomer than R-enantiomer; u) A mixture of S-Bk-2-EAPB , R-Bk-2-EAPB and there is more S-enantiomer than R-enantiomer; v) A mixture of S-Bk-2-EAPB , R-Bk-2-EAPB and there is less S-enantiomer than R-enantiomer; w) A mixture of S-Bk-2-EAPB , R-Bk-2-EAPB and at least about 65% is the S- enantiomer while no more than 35% is the R-enantiomer; x) A mixture of S-Bk-2-EAPB , R-Bk-2-EAPB and greater than 65% is the S- enantiomer while less than 35% is the R-enantiomer; y) A mixture of S-Bk-2-EAPB , R-Bk-2-EAPB and greater than 90% is the S- enantiomer while less than 10% is the R-enantiomer; z) A mixture of S-Bk-2-EAPB , R-Bk-2-EAPB and at least about 35% is the S- enantiomer while not more than 65% is the R-enantiomer; aa) A mixture of S-Bk-2-EAPB , R-Bk-2-EAPB and less than 35% is the S- enantiomer while greater than 65% is the R-enantiomer; bb) A mixture of S-Bk-2-EAPB , R-Bk-2-EAPB and less than 10% is the S- enantiomer while greater than 90% is the R-enantiomer; cc) Any of the mixtures described above wherein the compound or mixture is Bk-2-MAPBT or Bk-2-EAPBT. Particular embodiments for pharmaceutical compositions, including enantiomerically enriched pharmaceutical compositions, of the present invention include: a) A compound of the present invention; b) Embodiment (a) wherein the compound is a free base; c) Embodiment (a) wherein the compound is a salt; d) A mixture of an S- and R-enantiomer of the present invention wherein there is more S-enantiomer than R-enantiomer; e) A mixture of an S- and R-enantiomer of the present invention wherein there is less S-enantiomer than R-enantiomer; f) A mixture of an S- and R-enantiomer of the present invention wherein there is more S-enantiomer than R-enantiomer; g) A mixture of an S- and R-enantiomer of the present invention wherein there is less S-enantiomer than R-enantiomer; h) A mixture of an S- and R-enantiomer of the present invention wherein at least about 65% is the S-enantiomer while no more than 35% is the R-enantiomer; i) A mixture of an S- and R-enantiomer of the present invention wherein greater than 65% is the S-enantiomer while less than 35% is the R-enantiomer; j) A mixture of an S- and R-enantiomer of the present invention wherein greater than 90% is the S-enantiomer while less than 10% is the R-enantiomer; k) A mixture of an S- and R-enantiomer of the present invention wherein at least about 35% is the S-enantiomer while not more than 65% is the R-enantiomer; l) A mixture of an S- and R-enantiomer of the present invention wherein less than 35% is the S-enantiomer while greater than 65% is the R-enantiomer; m) A mixture of an S- and R-enantiomer of the present invention wherein less than 10% is the S-enantiomer while greater than 90% is the R-enantiomer; Pharmaceutically Acceptable Salts The compounds described herein, including enantiomerically enriched mixtures, can be administered if desired as a pharmaceutically acceptable salt or a salt mixture. A salt mixture may be useful to increase solubility of the active substances, to alter pharmacokinetics, or for controlled release or other objective. A salt mixture may comprise 2, 3, 4, 5, 6, or more pharmaceutically acceptable salts together to form a single composition. The compounds of the present invention are amines and thus basic, and therefore, react with inorganic and organic acids to form pharmaceutically acceptable acid addition salts. In some embodiments, the compounds of the present invention as free amines are oily and have decreased stability at room temperature. In this case it may be beneficial to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration because in some embodiments, the pharmaceutically acceptable salt is solid at room temperature. Certain embodiments of the present invention are compounds which can exist in the form of zwitterionic salts of phosphate and ammonium ions. Certain embodiments of the present invention include compounds containing a phosphate anion or dianion and one or more metal counterions such as Na+, K+, and Li+. Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. In certain embodiments, the compounds of the present invention are administered as oxalate salts. In certain embodiments of the present invention, the compounds are administered as phosphate salts. Exemplary salts include, but are not limited to, 2-hydroxyethanesulfonate, 2- naphthalenesulfonate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, acetate, adipate, alginate, amsonate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, citrate, clavulariate, cyclopentanepropionate, digluconate, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, finnarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, iodide, sethionate, lactate, lactobionate, laurate, laurylsulphonate, malate, maleate, mandelate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthylate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate, pantothenate, pectinate, persulfate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, propionate, p-toluenesulfonate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, undecanoate, and valerate salts, and the like. Alternatively, exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, finnarate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycollylarsanilate, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, sethiona, hybenzate, hydrabamine, hydrobromide, hydrobromide/bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, sethionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulphonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc and the like. (See Berge et al. (1977) “Pharmaceutical Salts,” J. Pharm. Sci. 66:1-19.) Pharmaceutically acceptable salts include those employing a hydrochloride anion. Prodrugs In certain aspects, the compounds of the present invention are administered as prodrugs. Prodrugs are compounds that are metabolized or otherwise transformed inside the body to the active pharmacologic agent(s) of interest. Examples include N-alpha-acyloxyalkoxycarbonyl derivatives or addition of amino acids to the amine, which can be removed within the body by esterases or similar enzymes, and reactions at the keto-group to form enol ethers, enol esters, and imines. Prodrugs are frequently (though not necessarily) pharmacologically less active or inactive until converted to the parent drug. This is done in the body by a chemical or biological reaction. In some cases, the moiety or chemicals formed from it may also have beneficial effects, including increasing therapeutic effects, decreasing undesirable side effects, or otherwise altering the pharmacokinetics or pharmacodynamics of the active drug. When the chemical formed from the prodrug moiety has beneficial effects that contribute to the overall beneficial effects of administering the prodrug, then the formed chemical is considered a “codrug.” Types of prodrugs contemplated to be within the scope of the invention include compounds that are transformed in various organs or locations in the body (e.g., liver, kidney, G.I., lung, tissue) to release the active compound. For example, liver prodrugs will include active compounds conjugated with a polymer or chemical moiety that is not released until acted upon by liver cytochrome enzymes and CYP metabolism includes dealkylation, dehydrogenation, reduction, hydrolysis, oxidation, and the breakdown of aromatic rings. Kidney prodrugs will include active compounds conjugated to L-gamma-glutamyl or N-acetyl-L-gamma glutamic moieties so that they are metabolized by gamma-glutamyl transpeptidase before they are bioactive. Alternatively, the compounds may be conjugated to alkylglucoside moieties to create glycosylation-based prodrugs. Digestive or G.I. prodrugs will include those where an active compound is, e.g., formulated into microspheres or nanospheres that do not degrade until the spheres are subjected to an acidic pH; formulated with an amide that will resist biochemical degradation until colonic pH is achieved; or, conjugated with a linear polysaccharide such as pectin that will delay activation until the combination reaches the bacteria in the colon. Besides these exemplary prodrug forms, many others will be known to those of ordinary skill. Among derivatives of a compound are included its “physiologically functional derivatives,” which refers to physiologically tolerated chemical derivatives of the compound having the same physiological function thereof, for example, by being convertible in the body thereto, and which on administration to a mammal such as a human is able to form (directly or indirectly) the compound or an active metabolite thereof (acting therefore, like a prodrug), or by otherwise having the same physiological function, despite one or more structural differences. According to the present invention, examples of physiologically functional derivatives include esters, amides, carbamates, ureas, and heterocycles. Methods to treat CNS disorders including mental disorders and for mental enhancement The present invention includes but is not limited to the methods and uses for the treatment of CNS disorders, including, but not limited to, mental disorders as described herein, including post-traumatic stress and adjustment disorders, and other disorders described in the Background, Summary or Description herein, comprising administering the compound of the present invention or composition or a pharmaceutically acceptable salt or salt mixture thereof as described herein. It may be that these compounds display many pharmacological properties that are beneficial to their use as therapeutics and represent an improvement over existing therapeutics. The present invention includes but is not limited to, for example, methods for the treatment of disorders, including, but not limited to depression, dysthymia, anxiety and phobia disorders (including generalized anxiety, social anxiety, panic, post-traumatic stress and adjustment disorders), feeding and eating disorders (including binge eating, bulimia, and anorexia nervosa), other binge behaviors, body dysmorphic syndromes, alcoholism, tobacco abuse, drug abuse or dependence disorders, disruptive behavior disorders, impulse control disorders, gaming disorders, gambling disorders, memory loss, dementia of aging, attention deficit hyperactivity disorder, personality disorders (including antisocial, avoidant, borderline, histrionic, narcissistic, obsessive compulsive, paranoid, schizoid and schizotypal personality disorders), attachment disorders, autism, and dissociative disorders. In addition to treating various diseases and disorders, the employed methods of modulating activity of the serotonergic system in particular can be used to improve CNS functioning in non- disease states, such as reducing neuroticism and psychological defensiveness, increasing openness to experience, increasing creativity, and aiding decision-making. In other embodiments, a compound or composition of the present invention is provided in an effective amount to treat a host, typically a human, with a CNS disorder that can be either a neurological condition (one that is typically treated by a neurologist) or a psychiatric condition (one that is typically treated by a psychiatrist). Neurological disorders are typically those affecting the structure, biochemistry or cause electrical abnormalities of the brain, spinal cord or other nerves. Psychiatric conditions are more typically thought of as mental disorders, which are primarily abnormalities of thought, feeling or behavior that cause significant distress or impairment of personal functioning. Thus, the disclosed compounds can be used in an effective amount to improve neurological or psychiatric functioning in a patient in need thereof. Neurological indications include, but are not limited to improved neuroplasticity, including treatment of stroke, brain trauma, dementia, and neurodegenerative diseases. MDMA has been reported to have an EC50 of 7.41 nM for promoting neuritogenesis and an Emax approximately twice that of ketamine, which has fast acting psychiatric benefits that are thought to be mediated by its ability to promote neuroplasticity, including the growth of dendritic spines, increased synthesis of synaptic proteins, and strengthening synaptic responses (Figure S3. in Ly et al. Cell reports 23, no.11 (2018): 3170-3182). The compounds of the current invention can similarly be considered psychoplastogens, that is, small molecules that are able to induce rapid neuroplasticity (Olson, 2018, Journal of experimental neuroscience, 12, 1179069518800508). For example, in certain embodiments, the disclosed compounds and compositions can be used to improve stuttering and other dyspraxias or to treat Parkinson’s disease or schizophrenia. The term "improving psychiatric function" is intended to include mental health and life conditions that are not traditionally treated by neurologists but sometimes treated by psychiatrists and can also be treated by psychotherapists, life coaches, personal fitness trainers, meditation teachers, counselors, and the like. For example, it is contemplated that the disclosed compounds will allow individuals to effectively contemplate actual or possible experiences that would normally be upsetting or even overwhelming. This includes individuals with fatal illnesses planning their last days and the disposition of their estate. This also includes couples discussing difficulties in their relationship and how to address them. This also includes individuals who wish to more effectively plan their career. In other embodiments, the 2-ethylamine substituted benzofuran compounds and compositions of the present invention may be used in an effective amount to treat a host, typically a human, to modulate an immune or inflammatory response. The compounds disclosed herein alter extracellular serotonin, which is known to alter immune functioning. For example, MDMA produces acute time-dependent increases and decreases in immune response. The following nonlimiting examples are relevant to any of the disorders, indications, methods of use or dosing regimes described herein. In certain embodiments, a host, for example a human, is treated with an effective amount of a 2-ethylamine substituted benzofuran compound of Formula I or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof. In certain embodiments, a host, for example a human, is treated with an effective amount of a 2-ethylamine substituted benzothiophene compound of Formula II or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 95 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 90 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 85 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 80 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 75 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 70 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 65 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 60 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 55 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 55 or 60 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 95 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 90 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 85 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 80 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt or salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 75 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 70 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 65 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 60 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 55 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 55 or 60 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 95 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 90 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 85 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 80 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 75 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 70 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 65 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 60 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 55 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of R enantiomer is greater than about 55 or 60 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 95 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 90 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 85 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 80 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 75 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 70 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 65 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 60 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 55 percent. In certain embodiments, a host, for example a human, is treated with an effective amount of an enantiomerically enriched mixture of enantiomers of Bk-2-MAPB or Bk-2-EAPB or the benzothiophene analog thereof, or a pharmaceutically acceptable salt, salt mixture, isotopic derivative, or prodrug thereof, wherein the percent of S enantiomer is greater than about 55 or 60 percent. The present invention also includes but is not limited to methods for modulating the CNS in a mammal in need thereof, including a human, by administering a pharmaceutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or salt mixture thereof. In certain embodiments, a method is provided to treat diseases or disorders linked to inadequate functioning of neurotransmission in the CNS comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof in a host in need thereof. This invention also includes but is not limited to the use of compounds of Formula I or Formula II for the manufacture of a medicament for the treatment of maladaptive response to perceived psychological threats. Additionally, this invention provides a pharmaceutical formulation adapted for the treatment of maladaptive response to perceived psychological threats containing a compound of Formula I or Formula II. Furthermore, this invention includes a method for the treatment of maladaptive response to perceived psychological threats that comprises administering an effective amount of a compound of Formula I or Formula II, given either in the context of psychotherapy or as a stand-alone treatment. Methods to treat physiological disorders In certain embodiments, a method of treating a patient with primary or secondary headaches is provided, comprising administering an effective amount of a compound, pure enantiomer, or enantiomerically enriched mixture of Formula I or Formula II, or a pharmaceutically acceptable salt thereof. In other embodiments, a method of treating a patient with primary or secondary headaches is provided, comprising administering an effective amount of a compound, pure enantiomer, or enantiomerically enriched mixture of Formula III-VIII, or a pharmaceutically acceptable salt thereof. In further embodiments, a method of treating a patient with primary or secondary headaches is provided, comprising administering an effective amount of a compound, pure enantiomer, or enantiomerically enriched mixture of Bk-2-MAPB, Bk-2-MAPBT, Bk-2-EAPB, or BK-2-EAPBT, or a pharmaceutically acceptable salt thereof. As used herein, primary headaches include, but are not limited to migraine, migraine signs and symptoms without cephalgia, tension-type headaches, cluster headaches and other trigeminal autonomic cephalalgias, new daily persistent headache, hypnic headaches, stabbing headaches, and other primary headache disorders. Secondary headaches referred to herein can refer to those due to trauma or injury, cranial or cervical vascular disorder, non-vascular intracranial disorder, headaches due to substance use or substance withdrawal, and other secondary headaches. Non-limiting examples of pharmacotherapeutic counseling use Psychotherapy, cognitive enhancement, or life coaching conducted with the compounds or pharmaceutically acceptable salts as described herein employed as an adjunct (hereafter, “pharmacotherapy” or “pharmacotherapy counseling”) is typically conducted in widely spaced sessions with one, two, or rarely three or more administrations of an entactogen per session. These sessions can be as frequent as weekly but are more often approximately monthly or even less frequently. In most cases, a small number of pharmacotherapy counseling sessions, on the order of one to three, is needed for the patient to experience significant clinical progress, as indicated, for example, by a reduction in signs and symptoms of mental distress, by improvement in functioning in some domain of life, by arrival at a satisfactory solution to some problem, or by increased feelings of closeness to and understanding of some other person. In some embodiments, the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of enantiomerically enriched S-Bk-2-MAPB, R-Bk-2-MAPB, S-Bk-2-EAPB, R-Bk-2-EAPB, S- Bk-2-MAPBT, R-Bk-2-MAPBT, S-Bk-2-EAPBT, or R-Bk-2-EAPBT, or a pharmaceutically acceptable salt thereof. In some embodiments, the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of enantiomerically pure S-Bk-2-EAPB, R-Bk-2- EAPB, S-Bk-2-MAPBT, R-Bk-2-MAPBT, S-Bk-2-EAPBT, or R-Bk-2-EAPBT, or a pharmaceutically acceptable salt thereof. In certain embodiments, the psychotherapy, cognitive enhancement, or life coaching is conducted with an effective amount of enantiomerically enriched mixture of Formula I or Formula II or a pharmaceutically acceptable salt thereof. The following sections provide detailed examples of pharmacotherapy counseling. While common procedures are described, these are intended as illustrative, non-limiting examples. It is anticipated that the prescribing physician and therapy team may wish to specify different procedures than those described here based on their clinical judgment concerning the needs of the patient. The example methods of treatment can also be modified with very minor changes to treat multiple patients at once, including couples or families. Hence, “patient” should be understood to mean one or more individuals. Use of a compound or composition of the present invention in conjunction with conventional psychotherapy or coaching In certain embodiments, the use of a described 2-ethylamine substituted benzofuran compound or composition of the present invention as pharmacotherapy is integrated into the patient’s ongoing psychotherapy or coaching (hereafter abbreviated as “psychotherapy”). If a patient in need of the pharmacotherapy counseling is not in ongoing psychotherapy, then psychotherapy may be initiated and the pharmacotherapy counseling added later, after the prescribing physician and treating psychotherapist, physician, coach, member of the clergy, or other similar professional or someone acting under the supervision of such a professional (hereafter, “therapist”) agree that the pharmacotherapy counseling is indicated and that there have been sufficient meetings between the patient and therapist to establish an effective therapeutic alliance. If the patient is not experienced with the pharmacotherapy, a conversation typically occurs in which the therapist or other members of the therapy team addresses the patient’s questions and concerns about the medicine and familiarizes the patient with the logistics of pharmacotherapy- assisted session. The therapist describes the kinds of experience that can be expected during the pharmacotherapy counseling session. Optionally, parts of this conversation employ written, recorded, or interactive digital explanations, as might be used in the informed consent process in a clinical trial. The therapist may additionally make commitments to support the participant’s healthcare and wellness process. In turn, the patient may be asked to make commitments of their own (such as not to hurt themselves or others and to abstain from contraindicated medicines or drugs for an adequate period before and after the pharmacotherapy counseling). The compounds and compositions of the invention (or alternately herein for convenience, the “medicine”) is administered shortly before or during a scheduled psychotherapy session, with timing optionally selected so that therapeutic effects begin by the time the psychotherapy session begins. It is to be understood that references to administering the medicine “during” a psychotherapeutic or other session are intended to refer to timing the administration of the medicine such that the therapeutic effects of the medicine at least partly temporally overlap with the therapeutic effects of the session. Either shortly before or after administration of the medicine, it is common for the therapist to provide some reminder of their mutual commitments and expected events during the session. The psychotherapy session is carried out by the therapist, who, optionally, may be remote and in communication with the patient using a communication means suitable for telehealth or telemedicine, such as a phone, video, or other remote two-way communication method. Optionally, video or other monitoring of the patient's response or behavior is used to document or measure the session. The therapist uses their clinical judgment and available data to adjust the session to the needs of the patient. Many therapists view their responsibility as being to facilitate rather than direct the patient’s experience. This may sometimes involve silent empathic listening, while other times it may include more active support to help the patient arrive at new perspectives on their life. It is anticipated that the therapeutic effects of the medicine will allow the patient to make more rapid therapeutic progress than would normally be possible. These effects include decreased neuroticism and increased feelings of authenticity. Patients are often able to calmly contemplate actual or possible experiences that would normally be upsetting or even overwhelming. This can facilitate decision making and creativity in addition to mental wellness. Optionally, the prescribing physician may allow a second or even third administration of the medicine or another psychotherapeutic agent in order to extend the therapeutic effects. Optionally, a pharmaceutical preparation with modified release is employed to make this unnecessary. Because the duration of the scheduled psychotherapy session may be shorter than the therapeutic effects of the medicine, the therapist may suggest to the patient activities to support further psychotherapeutic progress after the psychotherapy session has ended. Alternatively, the therapist may continue to work with the patient until the therapeutic effects of the medicine have become clinically minimal. In a subsequent non-pharmacological psychotherapy session, the therapist and patient will typically discuss the patient’s experiences from the pharmacotherapy counseling session and the therapist will often aid the patient in recalling the therapeutic effects and help them to incorporate the experiences into their everyday lives. Pharmacotherapy counseling sessions may be repeated as needed, based on the judgment of the treating physician and therapy team regarding the needs of the patient. Use of a compound or composition of the present invention outside of conventional psychotherapy In certain embodiments, a compound or composition of the present invention is administered outside of a conventional psychotherapy. This example method is a broader, more flexible approach to pharmacotherapy that is not centered on supervision by a therapist. These pharmacotherapy counseling sessions can take place in many different quiet and safe settings, including the patient’s home. The setting is typically chosen to offer a quiet setting, with minimal disruptions, where the patient feels psychologically safe and emotionally relaxed. The setting may be the patient’s home but may alternatively be a clinic, retreat center, or hotel room. In one alternative embodiment, the medicine is taken by the patient regularly to maintain therapeutic concentrations of the active compound in the blood. In another alternative embodiment, the medicine is taken, as needed, for defined psychotherapy sessions. Optionally, a checklist may be followed to prepare the immediate environment to minimize distractions and maximize therapeutic or decision-making benefits. This checklist can include items such as silencing phones and other communications devices, cleaning and tidying the environment, preparing light refreshments, preparing playlists of appropriate music, and pre- arranging end-of-session transportation if the patient is not undergoing pharmacotherapy counseling at home. Before the pharmacotherapy counseling session, there may be an initial determination of the therapeutic or other life-related goals (for example, decision-making, increasing creativity, or simply appreciation of life) that will be a focus of the session. These goals can optionally be determined in advance with support from a therapist. Optionally, the therapist may help the patient select stimuli, such as photographs, videos, augmented or virtual reality scenes, or small objects such as personal possessions, that will help focus the patient’s attention on the goals of the session or on the patient's broader life journey. As examples that are intended to be illustrative and not restrictive, these stimuli can include photographs of the patient from when they were young, which can increase self-compassion, or can include stimuli relating to traumatic events or phobias experienced by the patient, which can help the patient reevaluate and change their response to such stimuli. Optionally, the patient selects these stimuli without assistance (e.g., without the involvement of the therapist) or does not employ any stimuli. Optionally, stimuli are selected in real time by the therapist, or an algorithm based on the events of the session with the goal of maximizing benefits to the patient. If the patient is not experienced with the pharmacotherapy, a conversation occurs in which the therapist addresses the patient’s questions and concerns about the medicine and familiarizes the patient with the logistics of a pharmacotherapy-assisted counseling session. The therapist describes the kinds of experience that can be expected during the pharmacotherapy-assisted counseling session. Optionally, parts of this conversation employ written, recorded, or interactive digital explanations, as might be used in the informed consent process in a clinical trial. The therapist may additionally make commitments to support the participant’s healthcare and wellness process. In turn, the patient may be asked to make commitments of their own (such as not to hurt themselves or others and to abstain from contraindicated medicines or drugs for an adequate period before and after the pharmacotherapy counseling). Selected session goals and any commitments or other agreements regarding conduct between the patient and therapy team are reviewed immediately before administration of the medicine. Depending on the pharmaceutical preparation and route of administration, the therapeutic effects of the medicine usually begin within one hour. Typical therapeutic effects include decreased neuroticism and increased feelings of authenticity. Patients are often able to calmly contemplate experiences or possible experiences that would normally be upsetting or even overwhelming. This can facilitate decision making and creativity in addition to mental wellness. Optionally, sleep shades and earphones with music or soothing noise may be used to reduce distractions from the environment. Optionally, a virtual reality or immersive reality system may be used to provide stimuli that support the therapeutic process. Optionally, these stimuli are preselected; optionally, they are selected in real time by a person, or an algorithm based on events in the session with the goal of maximizing benefits to the patient. Optionally, a therapist or other person well-known to the patient is present or available nearby or via phone, video, or other communication method in case the patient wishes to talk, however the patient may optionally undergo a session without the assistance of a therapist. Optionally, the patient may write or create artwork relevant to the selected session goals. Optionally, the patient may practice stretches or other beneficial body movements, such as yoga (“movement activity”). Optionally, in other embodiments the patient may practice movement activity that includes more vigorous body movements, such as dance or other aerobic activity. Movement activity also may make use of exercise equipment such as a treadmill or bicycle. In some additional embodiments, the patient may be presented with music, video, auditory messages, or other perceptual stimuli. Optionally, these stimuli may be adjusted based on the movements or other measurable aspects of the patient. Such adjustment may be done by the therapist with or without the aid of a computer, or by a computer alone in response to said patient aspects, including by an algorithm or artificial intelligence, and “computer” broadly meaning any electronic tool suitable for such purposes, whether worn or attached to a patient (e.g., watches, fitness trackers, “wearables,” and other personal devices; biosensors or medical sensors; medical devices), whether directly coupled or wired to a patient or wirelessly connected (and including desktop, laptop, and notebook computers; tablets, smartphones, and other mobile devices; and the like), and whether within the therapy room or remote (e.g., cloud-based systems). For example, measurable aspects of a patient (e.g., facial expression, eye movements, respiration rate, pulse rate, skin color change, patient voice quality or content, patient responses to questions) from these tools may be individually transformed into scores on standardized scales by subtracting a typical value and then multiplying by a constant and these scores may be further multiplied by constants and added together to create an overall score that can optionally be transformed by multiplication with a link function, such as the logit function, to create an overall score. This score may be used to select or adjust stimuli such as selecting music with higher or lower beats-per-minute or with faster or slower notes, selecting images, audio, or videos with different emotionality or autobiographical meaning, or selecting activities for the patient to engage in (such as specific movements, journaling prompts, or meditation mantras). It should be readily appreciated that a patient can participate in numerous therapeutically beneficial activities, where such participation follows or is in conjunction with the administration of a compound or composition of the invention, including writing about a preselected topic, engaging in yoga or other movement activity, meditating, creating art, viewing of photographs or videos or emotionally evocative objects, using a virtual reality or augmented reality system, talking with a person, and thinking about a preselected problem or topic, and it should be understood that such participation can occur with or without the participation or guidance of a therapist. Optionally, the prescribing physician may allow a second or even third administration of the medicine or another psychotherapeutic agent in order to extend the therapeutic effects. Optionally, a pharmaceutical preparation with modified release is employed to make this unnecessary. The patient typically remains in the immediate environment until the acute therapeutic effects of the medicine are clinically minimal, usually within eight hours. After this point, the session is considered finished. The treatment plan will often include a follow-up session with a therapist. This follow-up session occurs after the pharmacotherapy counseling session has ended, often the next day but sometimes several days later. In this session, the patient discusses their experiences from the pharmacotherapy counseling session with the therapist, who can aid them in recalling the therapeutic effects and help them to incorporate the experiences into their everyday lives. Pharmacotherapy counseling sessions may be repeated as needed, based on the judgment of the treating physician and therapy team regarding the needs of the patient. PHARMACEUTICAL COMPOSITIONS AND SALTS The described 2-ethylamine substituted benzofuran and benzothiophene compounds and compositions described herein can be administered in an effective amount as the neat chemical but are more typically administered as a pharmaceutical composition to a host, typically a human, in need of such treatment in an effective amount for any of the disorders described herein. The compounds or compositions disclosed herein may be administered orally, topically, systemically, parenterally, by inhalation, insufflation, or spray, mucosally (e.g., buccal, sublingual), sublingually, transdermally, rectally, intravenous, intra-aortal, intracranial, subdermal, intraperitoneal, intramuscularly, inhaled, intranasal, subcutaneous, transnasal, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. (See, for example, Remington, 2005, Remington: The science and practice of pharmacy, 21st ed., Lippincott Williams & Wilkins.) The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, an injection or infusion solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, a suppository, a buccal or sublingual formulation, a parenteral formulation, an ophthalmic solution, or in a medical device. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. A “pharmaceutically acceptable composition” thus refers to at least one compound (which may be a mixture of enantiomers or diastereomers, as fully described herein) of the invention and a pharmaceutically acceptable vehicle, excipient, diluent or other carrier in an effective amount to treat a host, typically a human, who may be a patient. In certain nonlimiting embodiments the pharmaceutical composition is a dosage form that contains from about 0.1 mg to about 1500 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 1500 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms with at least 0.1, 1, 5, 10, 20, 25, 40, 50, 100, 125, 150, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt or salt mixture. The pharmaceutical compositions described herein can be formulated into any suitable dosage form, including tablets, capsules, gelcaps, aqueous oral dispersions, aqueous oral suspensions, solid dosage forms including oral solid dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, self-emulsifying dispersions, solid solutions, liposomal dispersions, lyophilized formulations, pills, powders, delayed-release formulations, immediate-release formulations, modified release formulations, extended-release formulations, pulsatile release formulations, multi particulate formulations, and mixed immediate release and controlled release formulations. Generally speaking, the composition should be administered in an effective amount to administer an amount of the active agents of the present invention achieves a plasma level commensurate with the concentrations found to be effective in vivo for a period of time effective to elicit a desired therapeutic effect without abuse liability. In making the compositions employed in the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets (including orally disintegrating, swallowable, sublingual, buccal, and chewable tablets), pills, powders, lozenges, troches, oral films, thin strips, sachets, cachets, elixirs, suspensions, emulsions, solutions, slurries, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, dry powders for inhalation, liquid preparations for vaporization and inhalation, topical preparations, transdermal patches, sterile injectable solutions, and sterile packaged powders. Compositions may be formulated as immediate release, controlled release, sustained (extended) release or modified release formulations. The compositions of the present invention can be administered by multiple routes, which may differ in different patients according to their preference, co-morbidities, side effect profile, and other factors (IV, PO, transdermal, etc.). In certain embodiments, the pharmaceutical composition includes the presence of other substances with the active drugs, known to those skilled in the art, such as fillers, carriers, gels, skin patches, lozenges, or other modifications in the preparation to facilitate absorption through various routes (such as, but not limited to, gastrointestinal, transdermal, etc.) and/or to extend the effect of the drugs, and/or to attain higher or more stable serum levels or to enhance the therapeutic effect of the active drugs in the combination. In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include, but are not limited to, lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions are in certain embodiments formulated in a unit dosage form, each dosage containing from at least about 0.05 to about 350 mg or less, more typically at least about 5.0 to about 180 mg or less, of the active ingredients. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient. The active compounds are effective over a wide dosage range. For example, as-needed dosages normally fall within the range of at least about 0.01 to about 4 mg/kg or less. In the treatment of adult humans, the range of at least about 0.2 to about 3 mg/kg or less, in single dose may be useful. It will be understood that the amount of the compound actually administered will be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient’s symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided for instance that such larger doses may be first divided into several smaller doses for administration. Generally, the pharmaceutical compositions of the invention may be administered and dosed in accordance with good medical practice, taking into account the method and scheduling of administration, prior and concomitant medications and medical supplements, the clinical condition of the individual patient and the severity of the underlying disease, the patient’s age, sex, body weight, and other such factors relevant to medical practitioners, and knowledge of the particular compound(s) used. Starting and maintenance dosage levels thus may differ from patient to patient, for individual patients across time, and for different pharmaceutical compositions, but shall be able to be determined with ordinary skill. In certain embodiments, a powder comprising the active agents of the present invention described herein may be formulated to comprise one or more pharmaceutical excipients and flavors. Such a powder may be prepared, for example, by mixing the active agents of the present invention and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also comprise a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi-dosage packaging units. The term “uniform” means the homogeneity of the bulk blend is substantially maintained during the packaging process. Oral Formulations In certain embodiments, any selected compound of the present invention is formulated in an effective amount in a pharmaceutically acceptable oral dosage form. In certain embodiments, the compound is enantiomerically pure or enriched Bk-2-MAPB or the Bk-2-MAPBT analog thereof or a pharmaceutically acceptable salt thereof. In certain embodiments, compound is enantiomerically pure or enriched Bk-2-EAPB or Bk-2-EAPBT analog thereof or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is of Formula I or Formula II or a pharmaceutically acceptable salt thereof. Oral dosage forms may include, but are not limited to, oral solid dosage forms and oral liquid dosage forms. Oral solid dosage forms may include but are not limited to, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres and/or any combinations thereof. The oral solid dosage forms may be formulated as immediate release, controlled release, sustained (extended) release or modified release formulations. The oral solid dosage forms of the present invention may also contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof. In some embodiments, the solid dosage forms of the present invention may be in the form of a tablet (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including a fast- melt tablet. Additionally, pharmaceutical formulations of the present invention may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets. The pharmaceutical solid dosage forms described herein can comprise the active agent of the present invention compositions described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, complexing agent, ionic dispersion modulator, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. Alternatively, the pharmaceutical solid dosage forms described herein can comprise the active agent or agents of the present invention (i.e., the “active agent(s)”; but for convenience herein, both “active agent” and “active agents” shall mean “active agent(s)” unless context clearly indicates that what is intended or would be suitable is only one agent or only two or more agents) and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, complexing agent, ionic dispersion modulator, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti- foaming agent, antioxidant, preservative, or one or more combination thereof. In still other aspects, using standard coating procedures, such as those described in Remington’s Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the active agent of the present invention formulation. In certain embodiments, some or all of the active agent of the present invention particles are coated. In another embodiment, some or all of the active agent of the present invention particles are microencapsulated. In yet another embodiment, some or all of the active agent of the present invention is amorphous material coated and/or microencapsulated with inert excipients. In still another embodiment, the active agent of the present invention particles are not microencapsulated and are uncoated. Suitable carriers for use in the solid dosage forms described herein include acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like. Suitable filling agents for use in the solid dosage forms described herein include lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose (e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, etc.), cellulose powder, dextrose, dextrates, dextrose, dextran, starches, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like. If needed, suitable disintegrants for use in the solid dosage forms described herein include natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or a sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, microcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, Ac-Di- Sol, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crosspovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like. Binders impart cohesiveness to solid oral dosage form formulations: for powder-filled capsule formulation, they aid in plug formation that can be filled into soft- or hard-shell capsules and in tablet formulation, binders ensure that the tablet remains intact after compression and help assure blend uniformity prior to a compression or fill step. Materials suitable for use as binders in the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g., Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crosspovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like. In general, binder levels of 20-70% are typically used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations is a function of whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binders are used. Formulators skilled in the art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common. Suitable lubricants or glidants for use in the solid dosage forms described herein include stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like. Suitable diluents for use in the solid dosage forms described herein include sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like. Non-water-soluble diluents are compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and micro cellulose (e.g., having a density of about 0.45 g/cm3, e.g. Avicel®, powdered cellulose), and talc. Suitable wetting agents for use in the solid dosage forms described herein include oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like. Wetting agents include surfactants. Suitable surfactants for use in the solid dosage forms described herein include docusate and its pharmaceutically acceptable salts, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Suitable suspending agents for use in the solid dosage forms described here include polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 18000, vinylpyrrolidone/vinyl acetate copolymer (S630), sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosic, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like. Suitable antioxidants for use in the solid dosage forms described herein include, e.g., butylated hydroxytoluene (BHT), butyl hydroxyanisole (BHA), sodium ascorbate, Vitamin E TPGS, ascorbic acid, sorbic acid and tocopherol. Immediate-release formulations may be prepared by combining superdisintegrants such as Croscarmellose sodium and different grades of microcrystalline cellulose in different ratios. To aid disintegration, sodium starch glycolate will be added. The above-listed additives should be taken as merely examples and not limiting, of the types of additives that can be included in solid dosage forms of the present invention. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired. Oral liquid dosage forms include solutions, emulsions, suspensions, and syrups. These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill in the art for the preparation of liquid dosage forms. For example, water, glycerin, simple syrup, alcohol, and combinations thereof. Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as but not limited to, an oil, water, an alcohol, and combinations of these pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration. Suspensions may include oils. Such oils include peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol, and propylene glycol. Ethers, such as poly(ethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in suspension formulations. In some embodiments, formulations are provided comprising particles of Bk-2-MAPB, Bk- 2-EAPB, Bk-2-MAPBT, or Bk-2-EAPBT and at least one dispersing agent or suspending agent for oral administration to a subject in need thereof. In some embodiments, formulations are provided comprising particles of compounds of Formula I or Formula II and at least one dispersing agent or suspending agent for oral administration to a subject in need thereof. The formulation may be a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained. As described herein, the aqueous dispersion can comprise amorphous and non-amorphous particles consisting of multiple effective particle sizes such that the drug is absorbed in a controlled manner over time. In certain embodiments, the aqueous dispersion or suspension is an immediate-release formulation. In another embodiment, an aqueous dispersion comprising amorphous particles is formulated such that a portion of the particles of the present invention are absorbed within, e.g., about 0.75 hours after administration and the remaining particles are absorbed 2 to 4 hours after absorption of the earlier particles. In other embodiments, addition of a complexing agent to the aqueous dispersion results in a larger span of the particles to extend the drug absorption phase of the active agent such that 50- 80% of the particles are absorbed in the first hour and about 90% are absorbed by about 4 hours. Dosage forms for oral administration can be aqueous suspensions selected from the group including pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, for example, Singh et al., Encyclopedia of Pharm. Tech., 2nd Ed., 754-757 (2002). In addition to the active agents of the present invention particles, the liquid dosage forms may comprise additives, such as (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative; (e) viscosity enhancing agents; (f) at least one sweetening agent; and (g) at least one flavoring agent. Examples of disintegrating agents for use in the aqueous suspensions and dispersions include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®; a cellulose such as a wood product, microcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka- Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-linked polymer such as crosspovidone; a cross-linked polyvinylpyrrolidone; alginate such as alginic acid or a salt of alginic acid such as sodium alginate; a clay such as Veegum® HV (magnesium aluminum silicate); a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin such as a cation-exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination starch; and the like. In some embodiments, the dispersing agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and the carbohydrate-based dispersing agents such as, for example, hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone®, e.g., S-630), 4-(1,1,3,3- tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corp., Parsippany, N.J.)). In other embodiments, the dispersing agent is selected from a group not comprising one of the following agents: hydrophilic polymers; electrolytes; Tween ® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropyl cellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium; methylcellulose; hydroxyethylcellulose; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate stearate; non- crystalline cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); 4- (1,1,3,3- tetramethyl butyl)-phenol polymer with ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); or poloxamines (e.g., Tetronic 908® or Poloxamine 908®). Wetting agents (including surfactants) suitable for the aqueous suspensions and dispersions described herein are known in the art and include acetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens® such as e.g., Tween 20® and Tween 80® (ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowaxs 3350® and 1450®, and Carpool 934® (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphatidylcholine and the like. Suitable preservatives for the aqueous suspensions or dispersions described herein include potassium sorbate, parabens (e.g., methylparaben and propylparaben) and their salts, benzoic acid and its salts, other esters of para hydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth. In certain embodiments, the aqueous liquid dispersion can comprise methylparaben and propylparaben in a concentration ranging from at least about 0.01% to about 0.3% or less methylparaben by weight to the weight of the aqueous dispersion and at least about 0.005% to about 0.03% or less propylparaben by weight to the total aqueous dispersion weight. In yet another embodiment, the aqueous liquid dispersion can comprise methylparaben from at least about 0.05 to about 0.1 or less weight % and propylparaben from at least about 0.01 to about 0.02 or less weight % of the aqueous dispersion. Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include methyl cellulose, xanthan gum, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Plasdone® S-630, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof. The concentration of the viscosity-enhancing agent will depend upon the agent selected and the viscosity desired. In addition to the additives listed above, the liquid formulations of the present invention can also comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, emulsifiers, and/or sweeteners. In certain embodiments, the formulation for oral delivery is an effervescent powder containing Bk-2-MAPB, Bk-2-EAPB, Bk-2-MAPB, or Bk-2-EAPB, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation for oral delivery is an effervescent powder containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation for oral delivery is an effervescent powder containing a 2-ethylamine substituted benzofuran compound of Formula III-VIII or a pharmaceutically acceptable salt thereof. Effervescent salts have been used to disperse medicines in water for oral administration. In certain embodiments, the formulation for oral delivery is an effervescent powder containing a 2- ethylamine substituted benzofuran or benzothiophene compound of Formula I-VIII, or a pharmaceutically acceptable salt thereof. Effervescent salts have been used to disperse medicines in water for oral administration. Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid. When salts of the present invention are added to water, the acids and the base react to liberate carbon dioxide gas, thereby causing “effervescence.” Examples of effervescent salts include sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher. Tablets of the invention described here can be prepared by methods well known in the art. Various methods for the preparation of the immediate release, modified release, controlled release, and extended-release dosage forms (e.g., as matrix tablets, tablets having one or more modified, controlled, or extended-release layers, etc.) and the vehicles therein are well known in the art. Generally recognized compendia of methods include: Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro, Editor, 20th Edition, Lippincott Williams & Wilkins, Philadelphia, PA; and Sheth et al. (1980), Compressed tablets, in Pharmaceutical dosage forms, Vol.1, edited by Lieberman and Lachtman, Dekker, NY. In certain embodiments, solid dosage forms, e.g., tablets, effervescent tablets, and capsules, are prepared by mixing the active agents of the present invention particles with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as homogeneous, it is meant that the active agents of the present invention particles are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The individual unit dosages may also comprise film coatings, which disintegrate upon oral ingestion or upon contact with diluents. These the active agents of the present invention formulations can be manufactured by conventional pharmaceutical techniques. Conventional pharmaceutical techniques for preparation of solid dosage forms include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., Theory and Practice of Industrial Pharmacy (1986). Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tableting, extruding and the like. Compressed tablets are solid dosage forms prepared by compacting the bulk blend the active agents of the present invention formulations described above. In various embodiments, compressed tablets which are designed to dissolve in the mouth will comprise one or more flavoring agents. In other embodiments, the compressed tablets will comprise a film surrounding a final compressed tablet. In some embodiments, the film coating can provide a delayed release of the active agents of the present invention formulation. In other embodiments, the film coating aids in patient compliance (e.g., Opadry® coatings or sugar coating). Film coatings comprising Opadry® typically range from about 1% to about 3% of the tablet weight. Film coatings for delayed-release usually comprise 2-6% of a tablet weight or 7-15% of a spray- layered bead weight. In other embodiments, the compressed tablets comprise one or more excipients. A capsule may be prepared, e.g., by placing the bulk blend of the active agents of the present invention formulation, described above, inside of a capsule. In some embodiments, the formulations of the present invention (non-aqueous suspensions and solutions) are placed in a soft gelatin capsule. In other embodiments, the formulations of the present invention are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC. In other embodiments, the formulations of the present invention are placed in a sprinkle capsule, wherein the capsule may be swallowed whole, or the capsule may be opened, and the contents sprinkled on food prior to eating. In some embodiments of the present invention, the therapeutic dose is split into multiple (e.g., two, three, or four) capsules. In some embodiments, the entire dose of the active agents of the present invention is delivered in a capsule form. In certain embodiments, ingredients (including or not including the active agent) of the invention are wet granulated. The individual steps in the wet granulation process of tablet preparation include milling and sieving of the ingredients, dry powder mixing, wet massing, granulation, drying, and final grinding. In various embodiments, the active agents of the present invention composition are added to the other excipients of the pharmaceutical formulation after they have been wet granulated. Alternatively, the ingredients may be subjected to dry granulation, e.g., via compressing a powder mixture into a rough tablet or “slug” on a heavy-duty rotary tablet press. The slugs are then broken up into granular particles by a grinding operation, usually by passage through an oscillation granulator. The individual steps include mixing of the powders, compressing (slugging) and grinding (slug reduction or granulation). No wet binder or moisture is involved in any of the steps. In some embodiments, the active agents of the present invention formulation are dry granulated with other excipients in the pharmaceutical formulation. In other embodiments, the active agents of the present invention formulation are added to other excipients of the pharmaceutical formulation after they have been dry granulated. In other embodiments, the formulation of the present invention formulations described herein is a solid dispersion. Methods of producing such solid dispersions are known in the art and include U.S. Pat. Nos.4,343,789; 5,340,591; 5,456,923; 5,700,485; 5,723,269; and U.S. Pub. No. 2004/0013734. In some embodiments, the solid dispersions of the invention comprise both amorphous and non-amorphous active agents of the present invention and can have enhanced bioavailability as compared to conventional active agents of the present invention formulations. In still other embodiments, the active agents of the present invention formulations described herein are solid solutions. Solid solutions incorporate a substance together with the active agent and other excipients such that heating the mixture results in the dissolution of the drug and the resulting composition is then cooled to provide a solid blend that can be further formulated or directly added to a capsule or compressed into a tablet. Non-limiting examples of formulations for oral delivery The examples below provide non-limiting embodiments of formulations for oral delivery, which can be used to deliver any of the compounds described herein in enantiomerically enriched form, pure form or even a racemic mixture. Ingredient Quantity (mg/capsule)
Figure imgf000097_0001
Ingredient Quantity (mg/capsule)
Figure imgf000097_0002
Ingredient Quantity (mg/capsule)
Figure imgf000098_0001
Ingredient Quantity (mg/capsule)
Figure imgf000098_0002
Ingredient Quantity (mg/tablet)
Figure imgf000098_0003
The examples below provide non-limiting embodiments of formulations for oral delivery, which can be used to deliver any of the compounds described herein in enantiomerically enriched form, pure form or even a racemic mixture. Therefore, while the compounds below are specified, any desired purity form or compound can be used if it achieves the desired goal of treatment. In one non-limiting embodiment, hard gelatin capsules comprising the following ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities. In one non-limiting embodiment, hard gelatin capsules comprising the following ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000099_0001
n one non- mtng emo ment, ar geatn capsues comprsng te o owng ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000099_0002
In one non-limiting embodiment, hard gelatin capsules comprising the following ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities.
Ingredient Quantity (mg/capsule)
Figure imgf000100_0001
g , g p p g ng ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000100_0002
In one non-limiting embodiment, hard gelatin capsules comprising the following ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000100_0003
In one non-limiting embodiment, hard gelatin capsules comprising the following ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000101_0001
n one non- mtng embodment, ard geatn capsues comprsng te o owng ingredients are prepared by mixing the ingredients and filling into hard gelatin capsules in 340 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000101_0002
In one non-limiting embodiment, a tablet formulation is prepared comprising the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg. Ingredient Quantity (mg/tablet)
Figure imgf000102_0001
g , p p p g the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg. Ingredient Quantity (mg/capsule)
Figure imgf000102_0002
In one non-limiting embodiment, a tablet formulation is prepared comprising the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg. Ingredient Quantity (mg/tablet)
Figure imgf000102_0003
In one non-limiting embodiment, a tablet formulation is prepared comprising the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg. Ingredient Quantity (mg/tablet)
Figure imgf000103_0001
In one non-limiting embodiment, a tablet formulation is prepared comprising the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg Ingredient Quantity (mg/tablet)
Figure imgf000103_0002
In one non-limiting embodiment, a tablet formulation is prepared comprising the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg. Ingredient Quantity (mg/tablet)
Figure imgf000104_0001
n one non- m t ng embod ment, a tab et ormu at on s prepared compr s ng the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg. Ingredient Quantity (mg/tablet)
Figure imgf000104_0002
In one non-limiting embodiment, a tablet formulation is prepared comprising the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg. Ingredient Quantity (mg/tablet)
Figure imgf000105_0001
oe o - g e o e , a a e o ua o s pepae co p s g the ingredients below. The components are blended and compressed to form tablets, each weighing 240 mg. Ingredient Quantity (mg/tablet)
Figure imgf000105_0002
The examples below provide non-limiting embodiments, wherein a tablet formulation is prepared comprising the ingredients below.
Ingredient Quantity (mg/tablet)
Figure imgf000106_0001
Ingredient Quantity (mg/tablet)
Figure imgf000106_0002
Ingredient Quantity (mg/tablet)
Figure imgf000107_0001
Ingredient Quantity (mg/tablet)
Figure imgf000107_0002
Ingredient Quantity (mg/tablet)
Figure imgf000108_0001
Ingredient Quantity (mg/tablet)
Figure imgf000108_0002
Ingredient Quantity (mg/tablet)
Figure imgf000109_0001
In one non-limiting embodiment, a tablet, comprising the components below, including R- -Bk-2-MAPB, is prepared. The active ingredients, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. Ingredient Quantity (mg/tablet)
Figure imgf000109_0002
Polyvinylpyrrolidone (as 10% solution in 4.0
Figure imgf000110_0001
g , , p g p , g R- -Bk-2-EAPB, is prepared. The active ingredients, starch and cellulose are passed through a No.20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No.30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. Ingredient Quantity (mg/tablet)
Figure imgf000110_0002
In one non-limiting embodiment, a tablet, comprising the components below, including R- Bk-2-MAPB, is prepared. The active ingredients, starch and cellulose are passed through a No.20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No.30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. Ingredient Quantity (mg/tablet)
Figure imgf000111_0001
In one non-limiting embodiment, a tablet, comprising the components below, including R-Bk-2- EAPB, is prepared. The active ingredients, starch and cellulose are passed through a No.20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No.30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. Ingredient Quantity (mg/tablet)
Figure imgf000112_0001
In one non-limiting embodiment, a tablet, comprising the components below, including an R-enantiomer of a 2-ethylamine substituted benzofuran compound of Formula I and a racemic compound of Formula I is prepared. The active ingredients, starch and cellulose are passed through a No.20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. Ingredient Quantity (mg/tablet)
Figure imgf000112_0002
Starch 45.0
Figure imgf000113_0001
n one non- m ng emo men, a a e, comprsng e componens eow,ncu ng an R-enantiomer of a 2-ethylamine substituted benzothiophene compound of Formula II and a racemic compound of Formula III, is prepared. The active ingredients, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No.30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. Ingredient Quantity (mg/tablet)
Figure imgf000113_0002
Sodium carboxymethyl starch 4.5
Figure imgf000114_0001
, , , R- Bk-2-MAPB, is prepared. The active ingredients, starch and cellulose are passed through a No.20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No.30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. Ingredient Quantity (mg/tablet)
Figure imgf000114_0002
In one non-limiting embodiment, a tablet, comprising the components below, including R- Bk-2-EAPB, is prepared. The active ingredients, starch and cellulose are passed through a No.20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60° C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No.30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. Ingredient Quantity (mg/tablet)
Figure imgf000115_0001
The examples below provide non-limiting embodiments, wherein a tablet formulation is prepared comprising the ingredients below. Ingredient Quantity (mg/capsule)
Figure imgf000115_0002
Ingredient Quantity (mg/capsule)
Figure imgf000116_0001
Ingredient Quantity (mg/capsule)
Figure imgf000116_0002
Ingredient Quantity (mg/capsule)
Figure imgf000116_0003
In one non-limiting embodiment, a capsule, comprising the components below, including Bk-2-MAPB, is prepared. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000116_0004
Magnesium stearate 1.0
Figure imgf000117_0003
, , , ing Bk-2-EAPB, is prepared. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000117_0001
In one non-limiting embodiment, a capsule, comprising the components below, including Bk-2-MAPB, is prepared. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000117_0002
In one non-limiting embodiment, a capsule, comprising the components below, including Bk-2-EAPB, is prepared. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000118_0001
g , p , p g p , ing a racemic compound of Formula I and an R-enantiomer of a 2-ethylamine substituted benzofuran compound of Formula I, is prepared. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000118_0002
In one non-limiting embodiment, a capsule, comprising the components below, including a racemic compound of Formula II and an R-enantiomer of a 2-ethylamine substituted benzothiophene compound of Formula II, is prepared. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000119_0001
g , p , p g p , ing Bk-2-MAPB, is prepared. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities. Ingredient Quantity (mg/capsule) ing
Figure imgf000119_0002
Bk-2-EAPB, is prepared. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000119_0003
Magnesium stearate 1.0
Figure imgf000120_0001
, is prepared using the ingredients below. The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities. Ingredient Amount (mg/capsule)
Figure imgf000120_0002
In one non-limiting embodiment, a capsule, comprising 15 mg of S-Bk-2-EAPB, is prepared using the ingredients below. The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities. Ingredient Amount (mg/capsule)
Figure imgf000120_0003
In one non-limiting embodiment, a capsule, comprising 100 mg of R-Bk-2-MAPB, is prepared using the ingredients below. The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 510 mg quantities. Ingredient Amount (mg/capsule)
Figure imgf000121_0001
o e o - g e o e , a capsu e, co p s g g o - - - , is prepared using the ingredients below. The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 510 mg quantities. Ingredient Amount (mg/capsule)
Figure imgf000121_0002
In one non-limiting embodiment, a capsule, comprising 100 mg of an R-enantiomer of a 2-ethylamine substituted benzofuran compound of Formula I, is prepared using the ingredients below. The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 510 mg quantities. Ingredient Amount (mg/capsule)
Figure imgf000121_0003
In one non-limiting embodiment, a capsule, comprising 100 mg of an R-enantiomer of a 2-ethylamine substituted benzothiophene compound of Formula II, is prepared using the ingredients below. The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 510 mg quantities. Ingredient Amount (mg/capsule)
Figure imgf000122_0001
n one non- m t ng embod ment, a capsu e, comprs ng 00 mg o - - - , is prepared using the ingredients below. The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 510 mg quantities. Ingredient Amount (mg/capsule)
Figure imgf000122_0002
In one non-limiting embodiment, a capsule, comprising 100 mg of R-Bk-2-EAPB, is prepared using the ingredients below. The active ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 510 mg quantities. Ingredient Amount (mg/capsule)
Figure imgf000123_0001
x en e - e ease o mu a ons Depending on the desired release profile, the pharmaceutical formulation, for example, an oral solid dosage form, may contain a suitable amount of controlled-release agents, extended- release agents, and/or modified-release agents (e.g., delayed-release agents). The pharmaceutical solid oral dosage forms comprising the active agents of the present invention described herein can be further formulated to provide a modified or controlled release of the active agents of the present invention. In some embodiments, the solid dosage forms described herein can be formulated as a delayed release dosage form such as an enteric-coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which uses an enteric coating to affect release in the small intestine of the gastrointestinal tract. The enteric-coated dosage form may be a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated. The enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated. Enteric coatings may also be used to prepare other controlled release dosage forms including extended-release and pulsatile release dosage forms. In other embodiments, the active agents of the formulations described herein are delivered using a pulsatile dosage form. Pulsatile dosage forms comprising the active agents of the present invention described herein may be administered using a variety of formulations known in the art. For example, such formulations include those described in U.S. Pat. Nos. 5,011,692; 5,017,381; 5,229,135; and 5,840,329. Other dosage forms suitable for use with the active agents of the present invention are described in, for example, U.S. Pat. Nos. 4,871,549; 5,260,068; 5,260,069; 5,508,040; 5,567,441; and 5,837,284. In certain embodiments, the controlled release dosage form is pulsatile release solid oral dosage form comprising at least two groups of particles, each containing active agents of the present invention as described herein. The first group of particles provides a substantially immediate dose of the active agents of the present invention upon ingestion by a subject. The first group of particles can be either uncoated or comprise a coating and/or sealant. The second group of particles comprises coated particles, which may comprise from at least about 2% to about 75% or less, typically from at least about 2.5% to about 70% or less, or from at least about 40% to about 70% or less, by weight of the total dose of the active agents of the present invention in said formulation, in admixture with one or more binders. In certain embodiments, a coating for providing a controlled, delayed, or extended-release is applied to Bk-2-MAPB or to a core containing Bk-2-MAPB. In certain embodiments, a coating for providing a controlled, delayed, or extended-release is applied to Bk-2-EAPB or to a core containing Bk-2-EAPB. In certain embodiments, a coating for providing a controlled, delayed, or extended-release is applied to a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II or to a core containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II. In certain embodiments, a coating for providing a controlled, delayed, or extended-release is applied to a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I-VIII or to a core containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I-VIII. In certain embodiments, a coating for providing a controlled, delayed, or extended-release is applied to a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I-VIII, or to a core containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I-VIII. The coating may comprise a pharmaceutically acceptable ingredient in an amount sufficient, e.g., to provide an extended release from e.g., about 1 hours to about 7 hours following ingestion before release of the active agent. Suitable coatings include one or more differentially degradable coatings such as, by way of example only, pH-sensitive coatings (enteric coatings) such as acrylic resins (e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, and Eudragit® NE30D, Eudragit® NE 40D® ) either alone or blended with cellulose derivatives, e.g., ethylcellulose, or non-enteric coatings having variable thickness to provide differential release of the active agents of the present invention formulation. Many other types of controlled/delayed/extended-release systems known to those of ordinary skill in the art and are suitable for use with the active agents of the present invention formulations described herein. Examples of such delivery systems include polymer-based systems, such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone, cellulose derivatives (e.g., ethylcellulose), porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725; 4,624,848; 4,968,509; 5,461,140; 5,456,923, 5,516,527; 5,622,721, 5,686,105; 5,700,410; 5,977,175; 6,465,014 and 6,932,983. In certain embodiments, the controlled release systems may comprise the controlled/delayed/extended-release material incorporated with the drug(s) into a matrix, whereas in other formulations, the controlled release material may be applied to a core containing the drug(s). In certain embodiments, one drug may be incorporated into the core while the other drug is incorporated into the coating. In some embodiments, materials include shellac, acrylic polymers, cellulosic derivatives, polyvinyl acetate phthalate, and mixtures thereof. In other embodiments, materials include Eudragit® series E, L, RL, RS, NE, L, L300, S, 100-55, cellulose acetate phthalate, Aquateric, cellulose acetate trimellitate, ethyl cellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, and Cotteric. The controlled/delayed/extended-release systems may use a hydrophilic polymer, including a water-swellable polymer (e.g., a natural or synthetic gum). The hydrophilic polymer may be any pharmaceutically acceptable polymer which swells and expands in the presence of water to slowly release the active agents of the present invention. These polymers include polyethylene oxide, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and the like. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers which may be used in matrix formulations or coatings include methacrylic acid copolymers and ammonia methacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available as solubilized in an organic solvent, aqueous dispersion, or dry powders. The Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting. The Eudragit series E dissolve in the stomach. The Eudragit series L, L-30D and S are insoluble in the stomach and dissolve in the intestine; Opadry Enteric is also insoluble in the stomach and dissolves in the intestine. Examples of suitable cellulose derivatives for use in matrix formulations or coatings include ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves in pH >6. Aquateric (FMC) is an aqueous-based system and is a spray-dried CAP psuedolatex with particles <1 µm. Other components in Aquateric can include pluronic, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethylcellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). The performance can vary based on the degree and type of substitution. For example, HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable. The performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are offered as granules or as fine powders for aqueous dispersions. Other suitable cellulose derivatives include hydroxypropylmethylcellulose. In some embodiments, the coating may contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques such as spray or pan coating are employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached. Multilayer tablet delivery (e.g., such as that used in the GeoMatrix™ technology) comprises a hydrophilic matrix core containing the active ingredient and one or two impermeable or semi-permeable polymeric coatings. This technology uses films or compressed polymeric barrier coatings on one or both sides of the core. The presence of polymeric coatings (e.g., such as that used in the GeoMatrix™ technology) modifies the hydration/swelling rates of the core and reduces the surface area available for drug release. These partial coatings provide modulation of the drug dissolution profile: they reduce the release rate from the device and shift the typical time- dependent release rate toward constant release. This technology enables customized levels of controlled release of specific active agents and/or simultaneous release of two different active agents at different rates that can be achieved from a single tablet. The combination of layers, each with different rates of swelling, gelling and erosion, is used for the rate of drug release in the body. Exposure of the multilayer tablet as a result of the partial coating may affect the release and erosion rates, therefore, transformation of a multilayered tablet with exposure on all sides to the gastrointestinal fluids upon detachment of the barrier layer will be considered. Multi-layered tablets containing combinations of immediate release and modified/extended release of two different active agents or dual release rate of the same drug in a single dosage form may be prepared by using hydrophilic and hydrophobic polymer matrices. Dual release repeat action multi-layered tablets may be prepared with an outer compression layer with an initial dose of rapidly disintegrating matrix in the stomach and a core inner layer tablet formulated with components that are insoluble in the gastric media but release efficiently in the intestinal environment. In certain embodiments, the dosage form is a solid oral dosage form which is an immediate release dosage form whereby >80% of the active agents of the present invention are released within 2 hours after administration. In other embodiments, the invention provides an (e.g., solid oral) dosage form that is a controlled release or pulsatile release dosage form. In such instances, the release may be, e.g., 30 to 60% of the active agents of the present invention particles by weight are released from the dosage form within about 2 hours after administration and about 90% by weight of the active agents of the present invention released from the dosage form, e.g., within about 4 hours after administration. In yet other embodiments, the dosage form includes at least one active agent in an immediate-release form and at least one active agent in the delayed-release form or sustained-release form. In yet other embodiments, the dosage form includes at least two active agents that are released at different rates as determined by in-vitro dissolution testing or via oral administration. The various release dosage formulations discussed above, and others known to those skilled in the art can be characterized by their disintegration profile. A profile is characterized by the test conditions selected. Thus, the disintegration profile can be generated at a pre-selected apparatus type, shaft speed, temperature, volume, and pH of the dispersion media. Several disintegration profiles can be obtained. For example, a first disintegration profile can be measured at a pH level approximating that of the stomach (about pH 1.2); a second disintegration profile can be measured at a pH level approximating that of one point in the intestine or several pH levels approximating multiple points in the intestine (about 6.0 to about 7.5, more specifically, about 6.5 to 7.0). Another disintegration profile can be measured using distilled water. The release of formulations may also be characterized by their pharmacokinetic parameters, for example, Cmax, Tmax, and AUC (0-τ). In certain embodiments, the controlled, delayed or extended-release of one or more of the active agents of the fixed-dose combinations of the invention may be in the form of a capsule having a shell comprising the material of the rate-limiting membrane, including any of the coating materials previously discussed, and filled with the active agents of the present invention particles. A particular advantage of this configuration is that the capsule may be prepared independently of the active agent of the present invention particles; thus, process conditions that would adversely affect the drug can be used to prepare the capsule. Alternatively, the formulation may comprise a capsule having a shell made of a porous or a pH-sensitive polymer made by a thermal forming process. Another alternative is a capsule shell in the form of an asymmetric membrane, i.e., a membrane that has a thin skin on one surface and most of whose thickness is constituted of a highly permeable porous material. The asymmetric membrane capsules may be prepared by a solvent exchange phase inversion, wherein a solution of polymer, coated on a capsule-shaped mold, is induced to phase separate by exchanging the solvent with a miscible non-solvent. In another embodiment, spray layered active agents of the present invention particles are filled in a capsule. An exemplary process for manufacturing the spray layered the active agents of the present invention is the fluidized bed spraying process. The active agents of the present invention suspensions or the active agents of the present invention complex suspensions described above may be sprayed onto sugar or microcrystalline cellulose (MCC) beads (20-35 mesh) with Wurster column insert at an inlet temperature of 50°C to 60°C and air temp of 30°C to 50°C. A 15 to 20 wt% total solids content suspension containing 45 to 80 wt% the active agents of the present invention, 10 to 25 wt% hydroxymethylpropylcellulose, 0.25 to 2 wt% of SLS, 10 to 18 wt% of sucrose, 0.01 to 0.3 wt% simethicone emulsion (30% emulsion) and 0.3 to10% NaCl, based on the total weight of the solid content of the suspension, are sprayed (bottom spray) onto the beads through 1.2 mm nozzles at 10 mL/min and 1.5 bar of pressure until a layering of 400 to 700% wt% is achieved as compared to initial beads weight. The resulting spray layered the active agents of the present invention particles, or the active agents of the present invention complex particles comprise about 30 to 70 wt% of the active agents of the present invention based on the total weight of the particles. In certain embodiments the capsule is a size 0 soft gelatin capsule. In certain embodiments, the capsule is a swelling plug device. In another embodiment, the swelling plug device is further coated with cellulose acetate phthalate or copolymers of methacrylic acid and methylmethacrylate. In some embodiments, the capsule includes at least 40 mg (or at least 100 mg or at least 200 mg) of the active agents of the present invention and has a total weight of less than 800 mg (or less than 700 mg). The capsule may contain a plurality of the active agents of the present invention- containing beads, for example, spray layered beads. In some embodiments, the beads are 12-25% the active agents of the present invention by weight. In some embodiments, some or all of the active agents of the present invention containing beads are coated with a coating comprising 6 to 15% (or 8 to 12%) of the total bead weight. Optimization work typically involves lower loading levels, and the beads constitute 30 to 60% of the finished bead weight. The capsule may contain a granulated composition, wherein the granulated composition comprises the active agents of the present invention. The capsule may provide pulsatile release of the active agents of the present invention oral dosage form. In certain embodiments, the formulations comprise: (a) a first dosage unit comprising Bk-2-MAPB that is released substantially immediately following oral administration of the dosage form to a patient; (b) a second dosage unit comprising Bk-2-MAPB that is released approximately 2 to 6 hours following administration of the dosage form to a patient. In certain embodiments, the formulations comprise: (a) a first dosage unit comprising Bk-2-EAPB and/or Bk-2-MAPB that is released substantially immediately following oral administration of the dosage form to a patient; (b) a second dosage unit comprising Bk-2-MAPB and/or Bk-2-EAPB that is released approximately 2 to 6 hours following administration of the dosage form to a patient. In certain embodiments, the formulation comprises: (a) a first dosage unit comprising compounds of Formula I and/or Formula II that is released substantially immediately following oral administration of the dosage form to a patient; (b) a second dosage unit comprising compounds of Formula I and/or Formula II that is released approximately 2 to 6 hours following administration of the dosage form to a patient. In certain embodiments, the formulation comprises: (a) a first dosage unit comprising a 2- ethylamine substituted benzothiophene compound of Formula II that is released substantially immediately following oral administration of the dosage form to a patient; (b) a second dosage unit comprising a 2-ethylamine substituted benzothiophene compound of Formula II that is released approximately 2 to 6 hours following administration of the dosage form to a patient. In certain embodiments, the formulation comprises: (a) a first dosage unit comprising a 2- ethylamine substituted benzofuran compound of Formula III-VIII, or a pharmaceutically acceptable salt thereof that is released substantially immediately following oral administration of the dosage form to a patient; (b) a second dosage unit comprising a 2-ethylamine substituted benzofuran compound of Formula III-VIII, or a pharmaceutically acceptable salt thereof that is released approximately 2 to 6 hours following administration of the dosage form to a patient. For pulsatile release capsules containing beads, the beads can be coated with a coating comprising 6 to 15% (or 8 to 12%) of the total bead weight. In some embodiments, the coating is a coating that is insoluble at pH 1 to 2 and soluble at pH greater than 5.5. In other embodiments, the pulsatile release capsule contains a plurality of beads formulated for modified release and the at least one agent of the present invention is, for example, spray granulated for immediate release. In some embodiments, the release of the active agents of the present invention particles can be modified with a modified release coating, such as an enteric coating using cellulose acetate phthalate or a sustained release coating comprising copolymers of methacrylic acid and methylmethacrylate. In certain embodiments, the enteric coating may be present in an amount of about 0.5 to about 15 wt%, more specifically, about 8 to about 12 wt%, based on the weight of, e.g., the spray layered particles. In certain embodiments, the spray layered particles coated with the delayed and/or sustained release coatings can be filled in a modified release capsule in which both enteric-coated particles and immediate release particles of the present invention beads are filled into a soft gelatin capsule. Additional suitable excipients may also be filled with the coated particles in the capsule. The uncoated particles release the active agent of the present invention immediately upon administration while the coated particles do not release the active agent of the present invention until these particles reach the intestine. By controlling the ratios of the coated and uncoated particles, desirable pulsatile release profiles also may be obtained. In some embodiments, the ratios between the uncoated and the coated particles are e.g., 20/80, or 30/70, or 40/60, or 50/50, w/w to obtain desirable release. In certain embodiments, spray layered active agents of the present invention can be compressed into tablets with commonly used pharmaceutical excipients. Any appropriate apparatus for forming the coating can be used to make the enteric coated tablets, e.g., fluidized bed coating using a Wurster column, powder layering in coating pans or rotary coaters; dry coating by double compression technique; tablet coating by film coating technique, and the like. See, e.g., U.S. Pat. No.5,322,655; Remington’s Pharmaceutical Sciences Handbook: Chapter 90 “Coating of Pharmaceutical Dosage Forms,” 1990. In certain embodiments, the spray layered active agents of the present invention described above and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the active agents of the present invention formulation into the gastrointestinal fluid. In other embodiments, the spray layered active agents of the present invention particles or spray layered active agents complex particles with enteric coatings described above and one or more excipients are dry blended and compressed into a mass, such as a tablet. In certain embodiments, a pulsatile release of the active agent of the present invention formulation comprises a first dosage unit comprising a formulation made from the active agent of the present invention containing granules made from a spray drying or spray granulated procedure or a formulation made from the active agent of the present invention complex containing granules made from a spray drying or spray granulated procedure without enteric or sustained-release coatings and a second dosage unit comprising spray layered the active agent of the present invention particles or spray layered the active agent of the present invention complex particles with enteric or sustained-release coatings. In certain embodiments, the active agent is wet or dry blended and compressed into a mass to make a pulsatile release tablet. In certain embodiments, binding, lubricating and disintegrating agents are blended (wet or dry) to the spray layered active agent of the present invention to make a compressible blend. In certain embodiments, the dosage unit containing Bk-2-MAPB and/or Bk-2-EAPB and the dosage unit containing the other pharmacological agent are compressed separately and then compressed together to form a bilayer tablet. In yet another embodiment, the dosage unit containing the other pharmacological agent is in the form of an overcoat and completely covers the second dosage unit containing Bk-2-MAPB and/or Bk-2-EAPB. In yet another embodiment, the dosage unit containing Bk-2-MAPB and/or Bk-2-EAPB is in the form of an overcoat and completely covers the second dosage unit containing the other pharmacological agent. In certain embodiments, the dosage unit containing Bk-2-MAPB and/or Bk-2-EAPB and the dosage unit containing the other pharmacological agent are compressed separately and then compressed together to form a bilayer tablet. In yet another embodiment, the dosage unit containing the other pharmacological agent is in the form of an overcoat and completely covers the second dosage unit containing Bk-2-MAPB and/or Bk-2-EAPB. In yet another embodiment, the dosage unit containing Bk-2-MAPB and/or Bk-2-EAPB is in the form of an overcoat and completely covers the second dosage unit containing the other pharmacological agent. In certain embodiments, the dosage unit containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II and the dosage unit containing the other pharmacological agent are compressed separately and then compressed together to form a bilayer tablet. In yet another embodiment, the dosage unit containing the other pharmacological agent is in the form of an overcoat and completely covers the second dosage unit containing a 2- ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II. In yet another embodiment, the dosage unit containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II is in the form of an overcoat and completely covers the second dosage unit containing the other pharmacological agent. In certain embodiments, the dosage unit containing a 2-ethylamine substituted benzofuran compound of Formula III-VIII and the dosage unit containing the other pharmacological agent are compressed separately and then compressed together to form a bilayer tablet. In yet another embodiment, the dosage unit containing the other pharmacological agent is in the form of an overcoat and completely covers the second dosage unit containing a 2-ethylamine substituted benzofuran compound of Formula III-VIII. In yet another embodiment, the dosage unit containing a 2-ethylamine substituted benzofuran compound of Formula III-VIII is in the form of an overcoat and completely covers the second dosage unit containing the other pharmacological agent. Systemic Formulations The formulations of the present invention can include any selected compound of the present invention for any of the disclosed indications in a form suitable for intramuscular, subcutaneous, or intravenous injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propylene glycol, polyethylene- glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Additionally, the active agents of the present invention can be dissolved at concentrations of greater than about 1 mg/ml using water-soluble beta cyclodextrins (e.g., beta-sulfobutyl-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin. Proper fluidity can be maintained, for example, by the use of a coating such as a lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. The formulations of the present invention suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, benzoic acid, benzyl alcohol, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged drug absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin. The formulations of the present invention designed for extended-release via subcutaneous or intramuscular injection can avoid first-pass metabolism and lower dosages of the active agents of the present invention will be necessary to maintain plasma levels of about 50 ng/ml. In such formulations, the particle size of the active agents of the present invention and the range of the particle sizes of the active agents of the present invention particles can be used to control the release of the drug by controlling the rate of dissolution in fat or muscle. In certain embodiments, a pharmaceutical composition containing Bk-2-MAPB and/or Bk- 2-EAPB or a pharmaceutically acceptable salt thereof is formulated into a dosage form suitable for parenteral use. In certain embodiments, pharmaceutical compositions containing compounds of Formula I and/or Formula II or a pharmaceutically acceptable salt thereof is formulated into a dosage form suitable for parenteral use. In certain embodiments, pharmaceutical compositions containing compounds of Formula III-VIII or a pharmaceutically acceptable salt thereof is formulated into a dosage form suitable for parenteral use. The dosage form may be selected from, but not limited to, a lyophilized powder, a solution, or a suspension (e.g., a depot suspension). In certain embodiments, a pharmaceutical composition containing Bk-2-MAPB and/or Bk- 2-EAPB or a pharmaceutically acceptable salt thereof is formulated into a topical dosage form. In certain embodiments, a pharmaceutical composition containing a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II or a pharmaceutically acceptable salt thereof is formulated into a topical dosage form. In certain embodiments, a pharmaceutical composition containing a 2-ethylamine substituted benzofuran compound of Formula III-VIII or a pharmaceutically acceptable salt thereof is formulated into a topical dosage form. The topical dosage form is selected from, but not limited to, a patch, a gel, a paste, a cream, an emulsion, a liniment, a balm, a lotion, and an ointment. Another formulation employed in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host’s ventricular system to bypass the blood-brain barrier. Indirect techniques, which are generally useful, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood- brain barrier. Non-limiting examples of formulations for systemic delivery The examples below provide non-limiting embodiments of formulations, which can be used to deliver any of the compounds described herein in enantiomerically enriched form, pure form or even a racemic mixture. Ingredient Quantity (mg)
Figure imgf000135_0001
Ingredient Quantity (mg)
Figure imgf000136_0001
Ingredient Quantity (mg)
Figure imgf000136_0002
Ingredient Quantity (mg)
Figure imgf000137_0001
Ingredient Quantity (mg)
Figure imgf000137_0002
The examples below provide non-limiting embodiments of formulations, which can be used to deliver any of the compounds described herein in enantiomerically enriched form, pure form or even a racemic mixture. Therefore, while the compounds below are specified, any desired purity form or compound can be used if it achieves the desired goal of treatment. In one non-limiting embodiment, a suppository, comprising 25 mg of S-Bk-2-MAPB, is prepared. The active ingredient is passed through a No.60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. Ingredient Quantity (mg)
Figure imgf000138_0001
n one non- m t ng em o ment, a suppos tory, compr s ng mg o - - - , is prepared. The active ingredient is passed through a No.60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. Ingredient Quantity (mg)
Figure imgf000138_0002
In one non-limiting embodiment, a suppository, comprising 25 mg of a 2-ethylamine substituted benzofuran compound of Formula I, is prepared. The active ingredient is passed through a No.60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. Ingredient Quantity (mg)
Figure imgf000138_0003
In one non-limiting embodiment, a suppository, comprising 25 mg of a 2-ethylamine substituted benzothiophene compound of Formula II, is prepared. The active ingredient is passed through a No.60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. Ingredient Quantity (mg)
Figure imgf000139_0001
n one non- m ng em o men, a suppos ory, compr s ng mg o - - - , is prepared. The active ingredient is passed through a No.60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. Ingredient Quantity (mg)
Figure imgf000139_0002
In one non-limiting embodiment, a suspension comprising 50 mg of S-Bk-2-EAPB per 5.0 ml dose is prepared using the ingredients below. The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. Ingredient Amount
Figure imgf000139_0003
Sodium carboxymethyl cellulose (11%) 50.0 mg
Figure imgf000140_0001
n one non- m ng em o men, a suspens on comprs ng mg o - - - per 5.0 ml dose is prepared using the ingredients below. The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. Ingredient Amount
Figure imgf000140_0002
In one non-limiting embodiment, a suspension comprising 50 mg of an R-enantiomer of a 2-ethylamine substituted benzofuran compound of Formula I per 5.0 ml dose is prepared using the ingredients below. The active ingredient, sucrose and xanthan gum are blended, passed through a No.10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. Ingredient Amount
Figure imgf000141_0001
In one non-limiting embodiment, a suspension comprising 50 mg of an R-enantiomer of a 2-ethylamine substituted benzothiophene compound of Formula II per 5.0 ml dose is prepared using the ingredients below. The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate,
flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. Ingredient Amount
Figure imgf000142_0001
In one non-limiting embodiment, a suspension comprising 50 mg of R-Bk-2-MAPB per 5.0 ml dose is prepared using the ingredients below. The active ingredient, sucrose and xanthan gum are blended, passed through a No.10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. Ingredient Amount
Figure imgf000142_0002
Sucrose 1.75 g
Figure imgf000143_0001
g , g the following ingredients: Ingredient Amount
Figure imgf000143_0002
In one non-limiting embodiment, an intravenous formulation is prepared using the following ingredients: Ingredient Amount
Figure imgf000143_0003
In one non-limiting embodiment, an intravenous formulation is prepared using the following ingredients: Ingredient Amount
Figure imgf000143_0004
In one non-limiting embodiment, an intravenous formulation is prepared using the following ingredients: Ingredient Amount
Figure imgf000144_0001
g , g the following ingredients: Ingredient Amount
Figure imgf000144_0002
The example below provides a non-limiting embodiment, wherein a topical formulation is prepared comprising the ingredients below. Ingredient Amount (g)
Figure imgf000144_0003
In one non-limiting embodiment, a topical formulation is prepared using the ingredients below. The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid. Ingredient Amount (g)
Figure imgf000145_0001
n one non- m ng em o men , a op ca ormu a on s prepare us ng e ngre ents below. The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid. Ingredient Amount (g)
Figure imgf000145_0002
In one non-limiting embodiment, a topical formulation is prepared using the ingredients below. The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid. Ingredient Amount (g)
Figure imgf000146_0001
g , p p p g g nts below. The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid. Ingredient Amount (g)
Figure imgf000146_0002
In one non-limiting embodiment, a topical formulation is prepared using the ingredients below. The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid. Ingredient Amount (g)
Figure imgf000146_0003
White Soft Paraffin To 100
Figure imgf000147_0001
nts below: Ingredient Amount (mg/tablet)
Figure imgf000147_0002
In certain embodiments, a sublingual or buccal tablet, comprising 10 mg of S-Bk-2-EAPB, is prepared using the following ingredients. The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90° C. When the polymers have gone into solution, the solution is cooled to about 50-55° C. and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size. Ingredient Amount (mg/tablet)
Figure imgf000147_0003
Sodium Citrate 4.5
Figure imgf000148_0001
, , PB, is prepared using the following ingredients. The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90° C. When the polymers have gone into solution, the solution is cooled to about 50-55° C. and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size. Ingredient Amount (mg/tablet)
Figure imgf000148_0002
In certain embodiments, a sublingual or buccal tablet, comprising 20 mg of an R- enantiomer of a 2-ethylamine substituted benzofuran compound of Formula I, is prepared using the following ingredients. The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90° C. When the polymers have gone into solution, the solution is cooled to about 50-55° C. and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size. Ingredient Amount (mg/tablet)
Figure imgf000149_0001
In certain embodiments, a sublingual or buccal tablet, comprising 20 mg of an R- enantiomer of a 2-ethylamine substituted benzothiophene compound of Formula II, is prepared using the following ingredients. The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90° C. When the polymers have gone into solution, the solution is cooled to about 50-55° C. and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size. Ingredient Amount (mg/tablet)
Figure imgf000149_0002
Polyvinylpyrrolidone 15.5
Figure imgf000150_0001
B, is prepared using the following ingredients. The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90° C. When the polymers have gone into solution, the solution is cooled to about 50-55° C. and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size. Ingredient Amount (mg/tablet)
Figure imgf000150_0002
In a non-limiting embodiment, a liquid formulation for vaporization is prepared using the following ingredients. Ingredient Quantity (units)
Figure imgf000150_0003
In one non-limiting embodiment, a liquid formulation for vaporization comprising R-Bk- 2-EAPB, is prepared using the ingredients below. The active mixture is mixed and added to a liquid vaporization appliance. Ingredient Quantity (units)
Figure imgf000151_0001
oe o- g e o e , a qu o ua o o vapo a o co p s g a 2- ethylamine substituted benzofuran compound of Formula I, is prepared using the ingredients below. The active mixture is mixed and added to a liquid vaporization appliance. Ingredient Quantity (units)
Figure imgf000151_0002
In one non-limiting embodiment, a liquid formulation for vaporization comprising a 2- ethylamine substituted benzothiophene compound of Formula II, is prepared using the ingredients below. The active mixture is mixed and added to a liquid vaporization appliance. Ingredient Quantity (units)
Figure imgf000151_0003
In one non-limiting embodiment, a liquid formulation for vaporization comprising R-Bk- 2-EAPB, is prepared using the ingredients below. The active mixture is mixed and added to a liquid vaporization appliance. Ingredient Quantity (units)
Figure imgf000152_0001
a o- g e o e , a o ua o o y powe o su a o s pepared comprising the components below: Ingredient Weight %
Figure imgf000152_0002
In one non-limiting embodiment, a formulation of dry powder for insufflation is prepared comprising the components below. The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance. Ingredient Weight %
Figure imgf000152_0003
In one non-limiting embodiment, a formulation of dry powder for insufflation is prepared comprising the components below. The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance. Ingredient Weight %
Figure imgf000153_0001
- g , y p p p red comprising the components below. The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance. Ingredient Weight %
Figure imgf000153_0002
In one non-limiting embodiment, a formulation of dry powder for insufflation is prepared comprising the components below. The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance. Ingredient Weight %
Figure imgf000153_0003
In one non-limiting embodiment, a formulation of dry powder for insufflation is prepared comprising the components below. The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance. Ingredient Weight %
Figure imgf000154_0001
y p The compounds described herein, including enantiomerically enriched mixtures, can be administered if desired as a pharmaceutically acceptable salt or a salt mixture. A salt mixture may be useful to increase solubility of the active substances, to alter pharmacokinetics, or for controlled release or other objective. A salt mixture may comprise 2, 3, 4, 5, 6, or more pharmaceutically acceptable salts together to form a single composition. The compounds of the present invention are amines and thus basic, and therefore, react with inorganic and organic acids to form pharmaceutically acceptable acid addition salts. In some embodiments, the compounds of the present invention as free amines are oily and have decreased stability at room temperature. In this case it may be beneficial to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration because in some embodiments, the pharmaceutically acceptable salt is solid at room temperature. Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. In certain embodiments, the compounds of the present invention are administered as oxalate salts. In certain embodiments of the present invention, the compounds are administered as phosphate salts. Exemplary salts include, but are not limited to, 2-hydroxyethanesulfonate, 2- naphthalenesulfonate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, acetate, adipate, alginate, amsonate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, citrate, clavulariate, cyclopentanepropionate, digluconate, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, finnarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, iodide, sethionate, lactate, lactobionate, laurate, laurylsulphonate, malate, maleate, mandelate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthylate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate, pantothenate, pectinate, persulfate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, propionate, p-toluenesulfonate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, undecanoate, and valerate salts, and the like. Alternatively, exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, finnarate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycollylarsanilate, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, sethiona, hybenzate, hydrabamine, hydrobromide, hydrobromide/bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, sethionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulphonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc and the like. (See Berge et al. (1977) “Pharmaceutical Salts,” J. Pharm. Sci. 66:1-19.) Pharmaceutically acceptable salts include those employing a hydrochloride anion. While salts of Bk-2-MAPB or Bk-2-EAPB are illustrated, any of the compounds described herein can be substituted, including but not limited to compounds of Formula I-VIII. The compounds can be used as salts or salt mixtures in enantiomerically enriched form, or in pure enantiomeric form. Nonlimiting examples are the oxalate and phosphate salts (and wherein Bk-2- MAPB and Bk-2-EAPB are used solely for exemplary purposes for ease of drafting, but can be substituted for any of the other compounds herein):
Figure imgf000156_0001
Prodrugs In certain aspects, the compounds of the present invention are administered as prodrugs. Prodrugs are compounds that are metabolized or otherwise transformed inside the body to the active pharmacologic agent(s) of interest. Thus, prodrug will contain the “active” component (for example, Bk-2-MAPB, Bk-2-EAPB, or a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I-VIII, and a prodrug moiety). Examples include N-alpha- acyloxyalkoxycarbonyl derivatives or addition of amino acids to the amine, which can be removed within the body by esterases or similar enzymes, and reactions at the keto-group to form enol ethers, enol esters, and imines. Prodrugs are frequently (though not necessarily) pharmacologically less active or inactive until converted to the parent drug. This is done in the body by a chemical or biological reaction. In some cases, the moiety or chemicals formed from it may also have beneficial effects, including increasing therapeutic effects, decreasing undesirable side effects, or otherwise altering the pharmacokinetics or pharmacodynamics of the active drug. When the chemical formed from the prodrug moiety has beneficial effects that contribute to the overall beneficial effects of administering the prodrug, then the formed chemical is considered a “codrug.” Types of prodrugs contemplated to be within the scope of the invention include compounds that are transformed in various organs or locations in the body (e.g., liver, kidney, G.I., lung, tissue) to release the active compound. For example, liver prodrugs will include active compounds conjugated with a polymer or chemical moiety that is not released until acted upon by liver cytochrome enzymes and CYP metabolism includes dealkylation, dehydrogenation, reduction, hydrolysis, oxidation, and the breakdown of aromatic rings. Kidney prodrugs will include active compounds conjugated to L-gamma-glutamyl or N-acetyl-L-gamma glutamic moieties so that they are metabolized by gamma-glutamyl transpeptidase before they are bioactive. Alternatively, the compounds may be conjugated to alkylglucoside moieties to create glycosylation-based prodrugs. Digestive or G.I. prodrugs will include those where an active compound is, e.g., formulated into microspheres or nanospheres that do not degrade until the spheres are subjected to an acidic pH; formulated with an amide that will resist biochemical degradation until colonic pH is achieved; or, conjugated with a linear polysaccharide such as pectin that will delay activation until the combination reaches the bacteria in the colon. Besides these exemplary prodrug forms, many others will be known to those of ordinary skill. Among derivatives of a 2-ethylamine substituted benzofuran or benzothiophene compound are included its “physiologically functional derivatives,” which refers to physiologically tolerated chemical derivatives of the compound having the same physiological function thereof, for example, by being convertible in the body thereto, and which on administration to a mammal such as a human is able to form (directly or indirectly) the compound or an active metabolite thereof (acting therefore, like a prodrug), or by otherwise having the same physiological function, despite one or more structural differences. According to the present invention, examples of physiologically functional derivatives include esters, amides, carbamates, ureas, and heterocycles. COMBINATION THERAPY In certain embodiments the compositions of the invention are not limited to combinations of a single compound, and a single carrier, diluent, or excipient alone, but also include combinations of multiple such compounds, and/or multiple carriers, diluents, and excipients. In certain embodiments, a pharmaceutical composition can be provided to the host, for example a human who can be a patient, with an effective amount of one or more other compounds either of the present invention or other active compounds, in combination, together with one or more other active compounds, and one or more pharmaceutically acceptable carriers, diluents, and/or excipients. In some aspects, a 2-ethylamine substituted benzofuran or benzothiophene compound of the present invention is formulated in a pharmaceutical preparation with other active compounds to increase therapeutic efficacy, decrease unwanted effects, increase stability/shelf-life, and/or alter pharmacokinetics. Such other active compounds include, but are not limited to antioxidants (such alpha-lipoate in acid or salt form, ascorbate in acid or salt form, selenium, or N- acetylcysteine); H2-receptor agonists or antagonists (such as famotidine); stimulants (such as dextroamphetamine, amphetamine, lisdexamphetamine, methylphenidate, or methamphetamine); entactogens (such as MDMA); anti-inflammatories (such as ibuprofen or ketoprofen); matrix metalloproteinase inhibitors (such as doxycycline); NOS inhibitors (such as S-methyl-L- thiocitrulline); proton pump inhibitors (such as omeprazole); phosphodiesterase 5 inhibitors (such as sildenafil); drugs with cardiovascular effects (beta antagonists such as propranolol, mixed alpha and beta antagonists such as carvedilol, alpha antagonists such as prazosin, imidazoline receptor agonists such as rilmenidine or moxonidine; serotonin antagonists such as ketanserin or lisuride); norepinephrine transporter blockers (such as reboxetine); acetylcholine nicotinic receptor modulators (such as bupropion, hydroxybupropion, methyllycaconitine, memantine, or mecamylamine); gastrointestinal acidifying agents (such as ascorbic acid or glutamic acid hydrochloride); alkalinizing agents (such as sodium bicarbonate), NMDA receptor antagonists (such as ketamine); TrkB agonists (such as 7,8-dihydroxyflavone, 7,8,3'-trihydroxyflavone, or N- acetylserotonin), or serotonin receptor agonists (such as 5-methoxy-N-methyl-N- isopropyltryptamine, N,N-Dimethyl-2-(2-methyl-1H-indol-1-yl)ethan-1-amine, psilocin, or psilocybin). The ingredients may be in ion, freebase, or salt form and may be isomers or prodrugs. The pharmacological agents that make up the combination therapy disclosed herein may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmacological agents that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration. The two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents. The time period between the multiple administration steps may range from, a few minutes to several hours, depending upon the properties of each pharmacological agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmacological agent. Circadian variation of the target molecule concentration may also determine the optimal dose interval. For example, a 2-ethylamine substituted benzofuran or benzothiophene compound of the present invention may be administered while the other pharmacological agent is being administered (concurrent administration) or may be administered before or after other pharmacological agent is administered (sequential administration). In cases where the two (or more) drugs are included in the fixed-dose combinations of the present invention are incompatible, cross-contamination can be avoided, e.g., by incorporation of the drugs in different drug layers in the oral dosage form with the inclusion of a barrier layer(s) between the different drug layers, wherein the barrier layer(s) comprise one or more inert/non- functional materials. In certain embodiments, the formulations of the present invention are fixed-dose combinations of a 2-ethylamine substituted benzofuran or benzothiophene compound of the present invention or a pharmaceutically acceptable salt thereof and at least one other pharmacological agent. Fixed-dose combination formulations may contain, but are not limited to, the following combinations in the form of single-layer monolithic tablet or multi-layered monolithic tablet or in the form of a core tablet-in-tablet or multi-layered multi-disk tablet or beads inside a capsule or tablets inside a capsule. In certain embodiments, the fixed-dose combination is a therapeutically efficacious fixed- dose combination of immediate-release formulations of Bk-2-MAPB and/or Bk-2-EAPB and other pharmacological agents. In certain embodiments, the fixed-dose combination is a therapeutically efficacious fixed- dose combinations of extended-release formulations of Bk-2-MAPB and/or Bk-2-EAPB and delayed and/or extended-release other pharmacological agents contained in a single dosage form. In certain embodiments, the fixed-dose combination is a therapeutically efficacious fixed- dose combinations of immediate-release formulations of compounds of Formula I and/or Formula II and other pharmacological agents. In certain embodiments, the fixed-dose combination is a therapeutically efficacious fixed- dose combinations of extended-release formulations of compounds of Formula I and/or Formula II and delayed and/or extended-release other pharmacological agents contained in a single dosage form. In certain embodiments, the fixed-dose combination is a therapeutically efficacious fixed- dose combinations of immediate-release formulations of compounds of Formula III-VIII and other pharmacological agents. In certain embodiments, the fixed-dose combination is a therapeutically efficacious fixed- dose combinations of extended-release formulations of compounds of Formula III-VIII and delayed and/or extended-release other pharmacological agents contained in a single dosage form. In certain embodiments, the invention includes pharmaceutically acceptable complex derivatives of the compound or composition, including solvates, salts, esters, enantiomers, isomers (stereoisomers and/or constitutional, including ones based on substituting deuterium for hydrogen), derivatives or prodrugs of Bk-2-MAPB and/or Bk-2-EAPB. In certain embodiments, the invention includes pharmaceutically acceptable complex derivatives of the compound or composition, including solvates, salts, esters, enantiomers, isomers (stereoisomers and/or constitutional, including ones based on substituting deuterium for hydrogen), derivatives or prodrugs of compounds of Formula I and/or Formula II. In certain embodiments, the invention includes pharmaceutically acceptable complex derivatives of the compound or composition, including solvates, salts, esters, enantiomers, isomers Ĩstereoisomers and/or constitutional, including ones based on substituting deuterium for hydrogen), derivatives or prodrugs of compounds of Formula III-VIII. In certain embodiments, extended-release multi-layered matrix tablets are prepared using fixed-dose combinations of Bk-2-MAPB and/or Bk-2-EAPB with another pharmacological agent. In certain embodiments, extended-release multi-layered matrix tablets are prepared using fixed- dose combinations of Bk-2-MAPB and/or Bk-2-EAPB with another pharmacological agent. In certain embodiments, extended-release multi-layered matrix tablets are prepared using fixed-dose combinations of compounds of Formula I and/or Formula II with another pharmacological agent. In certain embodiments, extended-release multi-layered matrix tablets are prepared using fixed- dose combinations of compounds of Formula III-VIII with another pharmacological agent. Such formulations may comprise one or more of the active agents within a hydrophilic or hydrophobic polymer matrix. In certain embodiments, extended-release multi-layered matrix tablets are prepared using fixed-dose combinations of compounds of Formulas I-VIII or a pharmaceutically acceptable salt thereof, with another pharmacological agent. For example, a hydrophilic polymer may comprise guar gum, hydroxypropylmethylcellulose, and xanthan gum as matrix formers. Lubricated formulations may be compressed by a wet granulation method. Another embodiment of the invention includes multiple variations in the pharmaceutical dosages of each drug in the combination as further outlined below. Another embodiment of the invention includes various forms of preparations including using solids, liquids, immediate or delayed or extended-release forms. Many types of variations are possible as known to those skilled in the art. Pharmaceutical combinations with dextroamphetamine In certain embodiments, Bk-2-MAPB and/or Bk-2-EAPB, either an enantiomer or a mixture of enantiomers, with zero to five or zero to seven hydrogens replaced with deuterium, is formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of dextroamphetamine in the amount of 2 mg, 4 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, or 25 mg. The required amount of dextroamphetamine will vary depending on the needs of the patient. In other embodiments, a 2-ethylamine substituted benzofuran or benzothiophene compound of Bk-2-MAPB and/or Bk-2-EAPB, with zero to five or zero to seven hydrogens replaced with deuterium, is formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of dextroamphetamine with dextroamphetamine in a ratio by weight of 1:2, 1:3, 1:4, or 1:5 to a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II. The required amount of dextroamphetamine will vary depending on the needs of the patient. In certain embodiments, a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II, with zero to five or zero to seven hydrogens replaced with deuterium, is formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of dextroamphetamine in the amount of 2 mg, 4 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, or 25 mg. The required amount of dextroamphetamine will vary depending on the needs of the patient. In another embodiments, a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II, with zero to five or zero to seven hydrogens replaced with deuterium, is formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of dextroamphetamine with dextroamphetamine in a ratio by weight of 1:2, 1:3, 1:4, or 1:5 to a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II. The required amount of dextroamphetamine will vary depending on the needs of the patient. In certain embodiments, a 2-ethylamine substituted benzofuran compound of Formula III- VIII, with zero to five or zero to seven hydrogens replaced with deuterium, is formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of dextroamphetamine in the amount of 2 mg, 4 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, or 25 mg. The required amount of dextroamphetamine will vary depending on the needs of the patient. In certain embodiments, a 2-ethylamine substituted benzofuran compound of Formula III- VIII, with zero to five or zero to seven hydrogens replaced with deuterium, is formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of dextroamphetamine with dextroamphetamine in a ratio by weight of 1:2, 1:3, 1:4, or 1:5 to a 2- ethylamine substituted benzofuran compound of Formula III-VIII. The required amount of dextroamphetamine will vary depending on the needs of the patient. In certain other embodiments, Bk-2-MAPB and/or Bk-2-EAPB or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition that also contains dextroamphetamine or a pharmaceutically acceptable salt thereof in the amount of at least about 2 mg, 4 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, or 25 mg. The required amount of dextroamphetamine will vary depending on the needs of the patient. The compound of Bk-2- MAPB and/or Bk-2-EAPB can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S-enantiomers. In certain embodiments, the compound of Bk-2-MAPB and/or Bk-2-EAPB is deuterated wherein one to five hydrogens have been replaced with deuterium. In certain embodiments, the ratio of dextroamphetamine (with or without salt) to Bk-2- MAPB and/or Bk-2-EAPB (with or without salt) is about 1:2, about 1:3, about 1:4, or about 1:5 by weight. In certain embodiments, a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition that also contains dextroamphetamine or a pharmaceutically acceptable salt thereof in the amount of at least about 2 mg, 4 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, or 25 mg. The required amount of dextroamphetamine will vary depending on the needs of the patient. The compound of Formula I and/or Formula II can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S- enantiomers. In certain embodiments, the compound of Formula I and/or Formula II is deuterated wherein one to five hydrogens have been replaced with deuterium. In certain embodiments, the ratio of dextroamphetamine (with or without salt) to the compound of Formula I and/or Formula II (with or without salt) is about 1:2, about 1:3, about 1:4, or about 1:5 by weight. In certain embodiments, a 2-ethylamine substituted benzofuran compound of Formula III- VIII or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition that also contains dextroamphetamine or a pharmaceutically acceptable salt of in the amount of at least about 2 mg, 4 mg, 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, or 25 mg. The required amount of dextroamphetamine will vary depending on the needs of the patient. The compound of Formula III-VIII can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S-enantiomers. In certain embodiments, the compound of Formula III-VIII is deuterated wherein one to five hydrogens have been replaced with deuterium. In certain embodiments, the ratio of dextroamphetamine (with or without salt) to the compound of Formula III-VIII (with or without salt) is about 1:2, about 1:3, about 1:4, about 1:5 by weight. Pharmaceutical combinations with MDMA In certain embodiments, Bk-2-MAPB and/or Bk-2-EAPB is formulated in a pharmaceutical composition that contains MDMA or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition comprises between about at least 5 and about 180 mg or less of MDMA or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition comprises between about 15-60 mg of MDMA or a pharmaceutically acceptable salt thereof. The required amount of MDMA will vary depending on the needs of the patient. The compound of 5-Bk-2-MAPB and/or Bk-2-EAPB can be a racemic compound, an R- or S- enantiomer, or an enantiomerically enriched mixture of R- or S-enantiomers. In certain embodiments, the compound of Bk-2-MAPB and/or Bk-2-EAPB is deuterated wherein one to five hydrogens have been replaced with deuterium. In certain embodiments, the ratio of MDMA (with or without salt) to Bk-2-MAPB and/or Bk-2-EAPB (with or without salt) is at least about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, or about 1:5 by weight. In certain embodiments, a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II is formulated in a pharmaceutical composition that contains MDMA or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition comprises between about at least 5 and about 180 mg or less of MDMA or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition comprises between about 15-60 mg of MDMA or a pharmaceutically acceptable salt thereof. The compound of Formula I and/or Formula II can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S-enantiomers. In certain embodiments, the compound of Formula I and/or Formula II is deuterated wherein one to five hydrogens have been replaced with deuterium. In certain embodiments, the ratio of MDMA (with or without salt) to the compound of Formula I and/or Formula II (with or without salt) is at least about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, or about 1:5 by weight. In certain embodiments, a 2-ethylamine substituted benzofuran compound of Formula III- VIII is formulated in a pharmaceutical composition that contains MDMA or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition comprises between about at least 5 and about 180 mg or less of MDMA or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition comprises between about 15-60 mg of MDMA or a pharmaceutically acceptable salt thereof. The compound of Formula III-VIII can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S- enantiomers. In certain embodiments, the compound of Formula III-VIII is deuterated wherein one to five hydrogens have been replaced with deuterium. In certain embodiments, the ratio of MDMA (with or without salt) to the compound of Formula III-VIII (with or without salt) is at least about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, or about 1:5 by weight. In other embodimentsBk-2-MAPB and/or Bk-2-EAPB, either as an enantiomer or a mixture of enantiomers, and with zero to five or zero to seven hydrogens replaced with deuterium, are formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of MDMA, in an amount between 5 and 180 mg, typically 15-60 mg. The required amount of MDMA will vary depending on the needs of the patient. In yet another embodiment, Bk-2-MAPB and/or Bk-2-EAPB, either as an enantiomer or a mixture of enantiomers, and with zero to five or zero to seven hydrogens replaced with deuterium, are formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of MDMA with MDMA in a ratio by weight of 1:2, 1:3, 1:4, or 1:5 to Bk-2-MAPB and/or Bk-2- EAPB. The required amount of MDMA will vary depending on the needs of the patient. In still another embodiment, a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II, as a mixture of enantiomers, with zero to five or zero to seven hydrogens replaced with deuterium, are formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of MDMA, in an amount between 5 and 180 mg, typically 15-60 mg. The required amount of MDMA will vary depending on the needs of the patient. In some embodiments, a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II, as a mixture of enantiomers, with zero to five or zero to seven hydrogens replaced with deuterium, are formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of MDMA with MDMA in a ratio by weight of 1:2, 1:3, 1:4, or 1:5 to a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I or Formula II. The required amount of MDMA will vary depending on the needs of the patient. In yet other embodiments, a 2-ethylamine substituted benzofuran compound of Formula III-VIII, as a mixture of enantiomers, with zero to five or zero to seven hydrogens replaced with deuterium, are formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of MDMA, in an amount between 5 and 180 mg, typically 15-60 mg. The required amount of MDMA will vary depending on the needs of the patient. In certain other embodiments, a 2-ethylamine substituted benzofuran compound of Formula III-VIII, as a mixture of enantiomers, with zero to five or zero to seven hydrogens replaced with deuterium, are formulated in a pharmaceutical composition that contains a pharmaceutically acceptable salt of MDMA with MDMA in a ratio by weight of 1:2, 1:3, 1:4, or 1:5 to a 2-ethylamine substituted benzofuran compound of Formula III-VIII. The required amount of MDMA will vary depending on the needs of the patient. Pharmaceutical combinations with psilocybin In certain embodiments, Bk-2-MAPB and/or Bk-2-EAPB or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition that also contains psilocybin or a pharmaceutically acceptable salt thereof in the amount of at least about 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg. The required amount of psilocybin will vary depending on the needs of the patient. The compound of Bk-2-MAPB and/or Bk-2-EAPB can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S-enantiomers. In certain embodiments, the compound of Bk-2-MAPB and/or Bk-2-EAPB is deuterated wherein one to five hydrogens have been replaced with deuterium. In certain embodiments, a 2-ethylamine substituted benzofuran or benzothiophene compound of Formula I and/or Formula II or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition that also contains psilocybin or a pharmaceutically acceptable salt thereof in the amount of at least about 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg. The required amount of psilocybin will vary depending on the needs of the patient. The compound of Formula I and/or Formula II can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S- enantiomers. In certain embodiments, the compound of Formula I and/or Formula II is deuterated wherein one to five hydrogens have been replaced with deuterium. In certain embodiments, a 2-ethylamine substituted benzofuran compound of Formula III- VIII or a pharmaceutically acceptable salt thereof is formulated in a pharmaceutical composition that also contains psilocybin or a pharmaceutically acceptable salt thereof in the amount of at least about 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg. The required amount of psilocybin will vary depending on the needs of the patient. The compound of Formula III-VIII can be a racemic compound, an R- or S-enantiomer, or an enantiomerically enriched mixture of R- or S-enantiomers. In certain embodiments, the compound of Formula III-VIII is deuterated wherein one to five hydrogens have been replaced with deuterium. Non-limiting examples of combination formulations The examples below provide non-limiting embodiments of combination formulations, which can be used to deliver any of the compounds described herein in enantiomerically enriched form, pure form or even a racemic mixture. Therefore, while the compounds below are specified, any desired purity form or compound can be used if it achieves the desired goal of treatment. In certain non-limiting embodiments, a capsule comprising one or more compounds of the present invention, and amphetamine sulfate is prepared using the ingredients below. Ingredient Quantity (mg/capsule)
Figure imgf000167_0001
Wetting agent or lubricant 1-20
Figure imgf000168_0001
ngre ent Quantty (mgcapsue)
Figure imgf000168_0002
Ingredient Quantity (mg/capsule)
Figure imgf000168_0003
Ingredient Quantity (mg/tablet)
Figure imgf000168_0004
Carrier or binder 10-100
Figure imgf000169_0001
g , p p g , PB, and amphetamine sulfate is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000169_0002
In one non-limiting embodiment, a capsule comprising deuterated R-Bk-2-EAPB, R-Bk- 2-MAPB, and amphetamine sulfate is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000170_0001
n one non- m ng em o men , a capsu e, compr s ng a eu era e compoun o ormula I, a deuterated compound of Formula II, and amphetamine sulfate is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule) 2-
Figure imgf000170_0002
ethylamine substituted benzofuran compound of Formula I, a deuterated R-enantiomer of a 2- ethylamine substituted benzothiophene compound of Formula II, and amphetamine sulfate is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000171_0001
In one non-limiting embodiment, a capsule, comprising deuterated R-EAPB, deuterated R- MAPB, and amphetamine sulfate is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000171_0002
nd amphetamine sulfate, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000172_0001
n ceran non- m ng emo mens, a capsue comprsng one or more compouns o the present invention, and psilocybin hydrochloride is prepared using the ingredients below. Ingredient Quantity (mg/capsule)
Figure imgf000172_0002
Ingredient Quantity (mg/capsule)
Figure imgf000172_0003
Ingredient Quantity (mg/capsule)
Figure imgf000173_0001
Ingredient Quantity (mg/tablet)
Figure imgf000173_0002
In one non-limiting embodiment, a capsule, comprising R-Bk-2-EAPB, S-Bk-2-EAPB, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000174_0001
In one non-limiting embodiment, a capsule, comprising enantiomerically enriched Bk-2- MAPB, enantiomerically enriched Bk-2-EAPB, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000174_0002
In one non-limiting embodiment, a capsule, comprising a non-racemic compound of Formula I, a non-racemic compound of Formula II, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000175_0001
In one non-limiting embodiment, a capsule, comprising an enantiomerically enriched mixture of Formula I, an enantiomerically enriched mixture of Formula II, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000175_0002
Magnesium stearate 1.0
Figure imgf000176_0001
k- 2-MAPB, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000176_0002
It should be readily appreciated that the above formulation examples are illustrative only. Accordingly, it should be understood that the reference to particular compound(s) is likewise illustrative, and the compounds(s) in any of the non-limiting examples of combination formulations may be substituted by other compounds(s) of the invention. Likewise, any of the other active compounds (e.g., amphetamine sulfate or psilocybin hydrochloride as described above) may be substituted by a different other active compound, as may the inactive compounds. Moreover, for any of S-Bk-2-EAPB, S-Bk-2-MAPB, R-Bk-2-EAPB, R-Bk-2-MAPB, and Formula I-VIII, or for any other active compounds of the invention, substitution of the compound by its prodrug, free base, salt, or hydrochloride salt shall be understood to provide merely an alternative embodiment still within the scope of the invention. Further, compositions within the scope of the invention should be understood to be open-ended and may include additional active or inactive compounds and ingredients. The type of formulation employed for the administration of the compounds employed in the methods of the present invention generally may be dictated by the compound(s) employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s), and the state of the patient. In certain embodiments of the present invention, the compounds of the present invention exist as diastereomers. For example, an enantiomerically enriched mixture of Formula I can have two stereogenic centers and thus exist as a mixture of 4 possible stereoisomers. One skilled in the art would recognize that any of the aforementioned formulations involving mixtures of enantiomers could be analogously modified to include mixtures of more than 2 stereoisomers. For illustrative example only, consider the structure of 2-amino-1-(benzofuran-2-yl)propan-1-ol, which exists as four possible stereoisomers.
Figure imgf000177_0001
Figure imgf000177_0002
In one non-limiting embodiment, a capsule, comprising a mixture of stereoisomers of 2- amino-1-(benzofuran-2-yl)propan-1-ol, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000177_0003
Isomer C 10.0
Figure imgf000178_0001
g , p , p g 2- amino-1-(benzofuran-2-yl)propan-1-ol, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000178_0002
In one non-limiting embodiment, a capsule, comprising a mixture of stereoisomers of 2- amino-1-(benzofuran-2-yl)propan-1-ol, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000179_0001
In certain embodiments, the compounds of the present invention are formulated as a mixture of isomers of Formula III, Formula IV, Formula V, or Formula VI and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. In one non-limiting embodiment, a capsule, comprising a mixture of stereoisomers of Formula III, Formula IV, Formula V, or Formula VI, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000179_0002
Psilocybin hydrochloride 2.0
Figure imgf000180_0001
, , of Formula III, Formula IV, Formula V, or Formula VI, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000180_0002
In one non-limiting embodiment, a capsule, comprising a mixture of stereoisomers of Formula III, Formula IV, Formula V, or Formula VI, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000181_0001
In certain embodiments, the compounds of the present invention are formulated as a mixture of isomers of Formula I or Formula II and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. In one non-limiting embodiment, a capsule, comprising a mixture of stereoisomers of Formula I or Formula II, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000181_0002
Alpha lipoic acid 40.0
Figure imgf000182_0001
, , of Formula I or Formula II, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000182_0002
In one non-limiting embodiment, a capsule, comprising a mixture of stereoisomers of Formula I or Formula II, and psilocybin hydrochloride, is prepared using the ingredients below. The active ingredients, cellulose, starch, and magnesium stearate are blended, passed through a No.20 mesh U.S. sieve, and filled into hard gelatin capsules in 155 mg quantities. Ingredient Quantity (mg/capsule)
Figure imgf000182_0003
Isomer D 15.0
Figure imgf000183_0001
The compounds or pharmaceutically acceptable formulations of the present invention can be administered to the host in any amount, and with any frequency, that achieves the goals of the invention as used by the healthcare provider, or otherwise by the host in need thereof, typically a human, as necessary or desired. In certain embodiments, the composition as described herein is provided only in a controlled counseling session, and administered only once, or perhaps 2, 3, 4, or 5 or more times in repeated counseling sessions to address a mental disorder as described herein. In other embodiments, the composition as described herein is provided outside of a controlled counseling session, and perhaps self-administered, as needed to perhaps 2, 3, 4, or 5 or more times in to address a mental disorder as described herein. In other embodiments, the composition of the present invention may be administered on a routine basis for mental wellbeing or for entactogenic treatment. The compounds of the current invention can be administered in a variety of doses, routes of administration, and dosing regimens, based on the indication and needs of the patient. Non- limiting examples of therapeutic use include discrete psychotherapeutic sessions, ad libitum use for treatment of episodic disorders, and ongoing use for treatment of subchronic and chronic disorders. Psychotherapeutic sessions For some indications, the medicine is taken in discrete psychotherapy or other beneficial sessions. It is anticipated that these sessions will typically be separated by more than 5 half-lives of the medicine and, for most patients, will typically occur only 1 to 5 times each year. For these sessions, it will typically be desirable to induce clearly perceptible entactogenic effects that will facilitate fast therapeutic progress. Non-exhaustive examples of oral doses of medicine that produce clearly perceptible entactogenic effects for exemplary purposes for any of the compounds described herein include (using compounds for illustrative purposes only): about 40 to about 120 mg of non-racemic Bk-2-EAPB, about 40 to about 120 mg of non-racemic Bk-2- EAPB, about 50 to about 300 mg of Bk-2-EAPB, about 50 to about 300 mg of Bk-2-EAPB, about 75 to about 500 mg of Bk-2-EAPB, about 75 to about 500 mg of Bk-2-EAPB, about 75 to about 800 mg of Bk-2-EAPB, about 75 to about 800 mg of Bk-2-EAPB, about 40 to about 120 mg of non-racemic Bk-2-MAPB, about 40 to about 120 mg of non-racemic Bk-2-MAPB, about 50 to about 300 mg of Bk-2-MAPB, about 50 to about 300 mg of Bk-2-MAPB, about 75 to about 500 mg of Bk-2-MAPB, about 75 to about 500 mg of Bk-2-MAPB, about 75 to about 800 mg of Bk- 2-MAPB, about 75 to about 800 mg of Bk-2-MAPB.. It is anticipated that the medicine would be taken once or, more rarely, two or three times in a single therapeutic session. In these cases, it is common for each subsequent dose to be half of the previous dose or lower. Multiple doses within a session typically occur because either the patient’s sensitivity to the medicine was unknown and too low of an initial dose was employed or because the patient is experiencing a productive session and it is desirable to extend the duration of therapeutic effects. Controlled release preparations may be used to lengthen the duration of therapeutic effects from a single administration of the medicine. In cases where multiple administrations are used in a session, it is anticipated that individual doses will be lower so that plasma concentrations remain within a desired therapeutic range. Non-limiting, non-exhaustive examples of indications that may benefit from psychotherapeutic sessions include post-traumatic stress disorder, depression, dysthymia, anxiety and phobia disorders, feeding, eating, and binge disorders, body dysmorphic syndromes, alcoholism, tobacco abuse, drug abuse or dependence disorders, disruptive behavior disorders, impulse control disorders, gaming disorders, gambling disorders, personality disorders, attachment disorders, autism, and dissociative disorders. Also included as exemplary situations where an individual would benefit from a psychotherapeutic session are situations from a reduction of neuroticism or psychological defensiveness, an increase in openness to experience, an increase in creativity, or an increase in decision-making ability. Ad libitum use for treatment of episodic disorders For some indications, such as social anxiety, where the patient has need for relief from episodic occurrence of a disorder, it is anticipated that the medicine would be taken as needed but that uses should be separated by more than 5 half-lives of the medicine to avoid bioaccumulation and formation of tolerance. For treating episodic disorders, clearly perceptible entactogenic effects are often not desirable, as they can impair some aspects of functioning. Non-exhaustive examples of oral doses of medicine for any of the compounds described herein include (using compounds for illustrative purposes only) that produce subtle, barely perceptible therapeutic effects include: about 10 to about 60 mg of non-racemic about 40 to about 120 mg of non-racemic Bk-2-EAPB, about 40 to about 120 mg of non-racemic Bk-2-EAPB, about 50 to about 300 mg of Bk-2-EAPB, about 50 to about 300 mg of Bk-2-EAPB, about 75 to about 500 mg of Bk-2-EAPB, about 75 to about 500 mg of Bk-2-EAPB, about 75 to about 800 mg of Bk-2-EAPB, about 75 to about 800 mg of Bk-2-EAPB., about 10 to about 60 mg of non-racemic Bk-2-MAPB, about 10 to about 100 mg of Bk-2-MAPB, about 10 to about 100 mg of Bk-2-MAPB, about 20 to about 150 mg of Bk-2-MAPB, about 20 to about 150 mg of Bk-2-MAPB, about 20 to about 200 mg of Bk-2-MAPB, and about 20 to about 200 mg of Bk-2-MAPB. Non-limiting, non-exhaustive examples of indications that may benefit from episodic treatment include post-traumatic stress disorder, depression, dysthymia, anxiety and phobia disorders, feeding, eating, and binge disorders, body dysmorphic syndromes, alcoholism, tobacco abuse, drug abuse or dependence disorders, disruptive behavior disorders, impulse control disorders, gaming disorders, gambling disorders, personality disorders, attachment disorders, autism, and dissociative disorders, provided that clinically significant signs and symptoms worsen episodically or in predictable contexts. Ongoing use for treatment of subchronic and chronic disorders For some indications, such as substance use disorders, inflammatory conditions, and neurological indications, including treatment of stroke, brain trauma, dementia, and neurodegenerative diseases, where the patient has need for ongoing treatment, it is anticipated that the medicine would be taken daily, twice daily, or three times per day. With some indications (subchronic disorders), such as treatment of stroke or traumatic brain injury, it is anticipated that treatment duration will be time-limited and dosing will be tapered when the patient has recovered. An example dose taper regimen is a reduction in dose of 10% of the original dose per week for nine weeks. With other, chronic disorders, such as dementia, it is anticipated that treatment will be continued as long as the patient continues to receive clinically significant benefits. For treating subchronic and chronic disorders, clearly perceptible entactogenic effects are often not desirable. Non-exhaustive examples of oral doses of medicine for any of the compounds described herein include (using compounds for illustrative purposes only) that produce subtle, barely perceptible therapeutic effects with ongoing dosing include: about 5 to about 60 mg of non- racemic Bk-2-MAPB, about 5 to about 60 mg of non-racemicBk-2-EAPB, about 5 to about 100 mg of Bk-2-MAPB about 5 to about 100 mg of Bk-2-EAPB, about 10 to about 150 mg of Bk-2- MAPB, about 10 to about 150 mg of Bk-2-EAPB, about 10 to about 200 mg of Bk-2-MAPB, and about 10 to about 200 mg of Bk-2-EAPB. Non-limiting, non-exhaustive examples of subchronic and chronic disorders that may benefit from regular treatment include migraine, headaches (e.g., cluster headache), neurodegenerative disorders, Alzheimer’s disease, Parkinson’s disease, schizophrenia, stroke, traumatic brain injury, phantom limb syndrome, and other conditions where increasing neuronal plasticity is desirable.
EXAMPLES Example 1: Exemplary Synthetic Methods and Chiral Separations Preparation of Pure Enantiomers or Enantiomerically Enriched Mixtures of the Present Invention from Racemates The enantiomerically enriched mixtures of 2-EAPB and 2-MAPB of the present invention can be synthesized according to the following schemes:
Figure imgf000187_0001
Figure imgf000187_0002
Figure imgf000187_0003
Separation of the enantiomers of the racemate mixtures generate
Figure imgf000187_0004
ed out by chiral supercritical fluid chromatography (SFC). For example,
Figure imgf000187_0005
a sepa a o o e e a o e s o a co pou o e p ese ve on can be carried out by prior protection of the amine group with a suitable reagent to aid in resolution of the enantiomers by SFC. For example the amine can be resolved by SFC as a Fmoc protected amine as follows:
T
Figure imgf000188_0001
a secondary or primary amine group. Synthetic Methods to Prepare Compounds of the Present Invention Compounds of the present invention can be synthesized via a variety of synthetic routes. Methods for synthesis of the compounds described herein and/or starting materials are either described in the art or will be readily apparent to the skilled artisan in view of general references well-known in the art (see, e.g., Green et al., “Protective Groups in Organic Chemistry,” (Wiley, 2nd ed. 1991); Harrison et al., “Compendium of Synthetic Organic Methods,” Vols. 1-8 (John Wiley and Sons, 1971-1996); “Beilstein Handbook of Organic Chemistry,” Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al, “Reagents for Organic Synthesis,” Volumes 1-17, Wiley Interscience; Trost et al., “Comprehensive Organic Synthesis,” Pergamon Press, 1991; “Theilheimer’s Synthetic Methods of Organic Chemistry,” Volumes 1-45, Karger, 1991; March, “Advanced Organic Chemistry,” Wiley Interscience, 1991; Larock “Comprehensive Organic Transformations,” VCH Publishers, 1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” John Wiley & Sons, 1995) and may be used to synthesize the compounds of the invention. Additional references include: Taniguchi et al.2010. Journal of mass spectrometry, 45(12), 1473-1476; Shulgin & Shulgin.1992. PiHKAL. A chemical love story, Transform Press, Berkeley CA; Glennon et al. 1986. J. Med. Chem., 29(2), 194-199; Nichols et al. 1991. J. Med. Chem., 34(1), 276-281; Kedrowski et al. 2007. Organic Letters, 9(17), 3205-3207; Heravi & Zadsirjan. 2016. Current Organic Synthesis, 13(6), 780-833; Keri et al.2017. European J. Med. Chem., 138, 1002-1033; Pérez-Silanes et al. 2001. J. Heterocyclic Chem, 38(5), 1025-1030; and references therein. Certain embodiments of the present invention can be synthesized according to the following general schemes: Synthesis 1: Preparation of 1-(benzo[b]thiophen-2-yl)-2-(methylamino)propan-1-one (Bk-2- MAPBT):
Figure imgf000189_0001
Synthesis 2: Preparation of 1-(benzofuran-2-yl)-2-(methylamino)propan-1-one (Bk-2- MAPB):
Figure imgf000190_0001
The reaction sequence shown above can be applied to the synthesis of enantiomerically enriched mixtures by using an appropriate chiral auxiliary reagent. For example: Synthesis 3: Preparation of (R)-1-(benzofuran-2-yl)-2-(methylamino)propan-1-one (R-Bk-2- MAPB):
Figure imgf000190_0002
Synthesis 4: Preparation of (R)-1-(benzo[b]thiophen-2-yl)-2-(methylamino)propan-1-one (R-Bk-2-MAPBT):
Figure imgf000191_0001
In the two chiral syntheses of R-Bk-2-MAPB and R-Bk-2-MAPBT above, the S- enantiomer of the product can be obtained by using the opposite enantiomer of the hydrazine chiral auxiliary. Synthesis 5: Preparation of 1-(benzofuran-2-yl)-2-(methylamino)ethan-1-one:
Figure imgf000191_0002
Synthesis 6: Preparation of 1-(benzo[b]thiophen-2-yl)-2-(methylamino)ethan-1-one:
Figure imgf000192_0001
Synthesis 7: Preparation of 1-(5-methoxybenzofuran-2-yl)-2-(methylamino)ethan-1-ol:
Figure imgf000192_0002
Synthesis 8: Preparation of 1-(benzofuran-2-yl)-2-(methylamino)ethan-1-ol:
Figure imgf000192_0003
q pp y omerically enriched mixtures by substituting an appropriate chiral reagent in the reduction step. For example: Synthesis 9: Preparation of (S)-1-(benzofuran-2-yl)-2-(methylamino)ethan-1-ol:
Figure imgf000193_0001
Further examples of general synthetic routes to compounds of the present invention include: Synthesis 10: Preparation of 1-(benzofuran-2-yl)-2-(methylamino)propan-1-ol:
Figure imgf000193_0002
y enriched mixtures of the present invention with the modification to incorporate a chiral reduction catalyst. For example: Synthesis 11: Preparation of (2R)-1-(benzofuran-2-yl)-2-(methylamino)propan-1-ol:
Figure imgf000193_0003
Figure imgf000194_0002
Alternative embodiments of the present invention can be synthesized according to the following scheme. Induction of stereoselectivity is possible at various points in the synthesis of the compounds of the present invention: Synthesis 12: Preparation of (1R,2S)-2-amino-1-(benzofuran-2-yl)propan-1-ol:
Figure imgf000194_0001
In an alternative embodiment, the commercially available benzofuran starting material (CAS # 1781698-57-4) can be used to synthesize compounds of the type indicated by employing standard transition-metal catalyzed alkenylation of a benzofuran followed by enantioselective epoxidation (Jacobsen et. Al. Highly enantioselective epoxidation catalysts derived from 1,2- diaminocyclohexane J. Am. Chem. Soc., 1991, 113, 7063-7064). Synthesis 13: Preparation of (1R,2S)-2-amino-1-(4-amino-5-methoxybenzofuran-2- yl)propan-1-ol:
Figure imgf000195_0001
Further examples of general synthetic routes to compounds of the present invention include: Synthesis 14: Preparation of 1-(benzofuran-2-yl)-N-ethylpropan-2-amine (2-EAPB):
Figure imgf000195_0002
Synthesis 15: Preparation of 1-(benzo[b]thiophen-2-yl)-N-ethylpropan-2-amine (2-EAPBT):
Figure imgf000195_0003
Alternatively, the syntheses of 2-EAPB and 2-EAPBT shown above can be performed with a chiral catalyst in the reduction step to provide the enantiomerically enriched products: Synthesis 16: Preparation of (R)-1-(benzofuran-2-yl)-N-ethylpropan-2-amine (R-2-EAPB):
Figure imgf000196_0001
Synthesis 17: Preparation of (R)-1-(benzo[b]thiophen-2-yl)-N-ethylpropan-2-amine (R-2- EAPBT):
Figure imgf000196_0002
Synthesis 18: Preparation of 1-(benzofuran-2-yl)-2-(methylamino)propan-1-one (Compound 1), (S)-1-(benzofuran-2-yl)-2-(methylamino)propan-1-one (Compound 2), and (R)- 1- (benzofuran-2-yl)-2-(methylamino)propan-1-one (Compound 3)
Figure imgf000197_0001
Step 1 To a stirred solution of benzofuran-2-carboxylic acid (1) (5.0 g, 30.838 mmol, 1 equiv.) in dry dichloromethane (50 mL) were added N,N-diisopropylethylamine (DIPEA) (27.0 mL, 154.188 mmol, 3 equiv.) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) (8.9 g, 46.256 mmol, 1.5 equiv.) and HOBt (6.3 g, 46.256 mmol, 1.5 equiv.) under nitrogen atmosphere at room temperature and the reaction mixture was continued to stir for fifteen minutes. Then N, O-dimethylhydroxylamine hydrochloride (9.0 g, 92.513 mmol, 3.0 equiv.) was added to the resulting reaction mixture and was allowed to stir at room temperature for 16h. Upon completion, monitored by TLC (50% ethyl acetate in hexane), the reaction mixture was diluted with dichloromethane (500 mL) and washed with water followed by a brine solution. The combined organic layer was dried over anhydrous sodium sulphate. The solvent was removed under vacuum and purified by silica gel column chromatography using ethyl acetate/hexane (20:80 v/v) as eluent to afford N-methoxy-N-methylbenzofuran-2-carboxamide (2) as a light-yellow sticky liquid (5.4 g, 85.33%).1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.44-7.39 (m, 1H), 7.30-7.26 (t, J = 7.8 Hz, 7.36 Hz, 1H), 3.82 (s, 3H), 3.41 (s, 3H). LCMS: Rt 1.68 minutes. MS (ES) C11H11NO3 requires 205, found 206 [M + H]+. Step 2 To a stirred solution of N-methoxy-N-methylbenzofuran-2-carboxamide (2) (5.0 g, 24.365 mmol, 1 equiv.) was added dry Diethyl ether (100 mL) at 0°C and was added 3(M) solution of EtMgBr in Diethyl ether (16.24 mL, 48.731 mmol, 2 equiv.) to the reaction mixture and allowed to stir at room temperature for 4h. Upon completion, (monitored by TLC, 20% ethyl acetate in hexane) the reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate, twice (2 x 150 mL), then washed with water followed by brine solution. The combined organic layer was dried over anhydrous sodium sulphate, solvent was evaporated under reduced pressure to get the crude which was purified by silica gel column chromatography using 1% ethyl acetate/hexane as eluent to afford 1-(benzofuran-2-yl) propan-1-one (3) as white solid (3.6 g, 84.82%).1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.84 Hz, 1H), 7.58 (dd, J = 0.72 Hz, 8.44 Hz, 1H), 7.49-7.44 (m, 2H), 7.32-7.28 (m, 1H), 3.02-2.96 (m, 2H), 1.27-1.22 (m, 3H). LCMS: Rt 1.89 minutes. MS (ES) C11H10O2 requires 174, found 175 [M + H]+. Step 3 To a stirred solution of 1-(benzofuran-2-yl) propan-1-one (3) (1.8 g, 10.333 mmol, 1 equiv.) in dry tetrahydrofuran (30 mL) was added hydrobromic acid (48% in Water) (26.0 mL, 165.331 mmol, 16.0 equiv.) and bromine (0.63 mL, 12.4 mmol, 1.2 equiv.) dropwise at 0°C and the reaction mixture was allowed to stir at room temperature for 16h. Upon completion, (monitored by TLC, 5% ethyl acetate in hexane), the reaction mixture was quenched with saturated sodium carbonate solution and extracted with ethyl acetate (2 x 100 mL), washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulphate, then the solvent was evaporated under reduced pressure and purified by silica gel column chromatography using 1% ethyl acetate/hexane as eluent to get the compound 1-(benzofuran-2-yl)-2-bromopropan-1-one (4) as yellow sticky liquid (2.1 g, 80.3%). 1H NMR (400 MHz, DMSO) δ 8.11 (d, J = 0.72 Hz, 1H), 7.88 (d, J = 7.76 Hz, 1H), 7.76 (dd, J = 0.6, 8.4 Hz, 1H), 7.60-7.56 (m, 1H), 7.40 (t, J = 7.2 Hz 1H), 5.69-5.64 (m, 1H), 1.85-1.79 (m, 3H). LCMS: Rt 1.98 minutes. MS (ES) C11H9BrO2 requires 253, found 255 [M + 2]+. Step 4 To a stirred solution of 1-(benzofuran-2-yl)-2-bromopropan-1-one (4) (2.1 g, 8.297 mmol, 1 equiv.) in dry DMF (25 mL) was added potassium carbonate (1.71 g, 12.446 mmol, 1.5 equiv.) and methyl amine 2(M) in tetrahydrofuran (12.5 mL, 24.89 mmol, 3.0 equiv.) in a sealed RB and the resulting reaction mixture was allowed to stir at room temperature for 16h. Upon completion of the reaction (monitored by TLC, 10% ethyl acetate in hexane), volatiles were evaporated, and the crude was diluted with ethyl acetate (100 mL) and washed with water (3 x 50 mL) followed by brine solution. The combined organic layer was dried over anhydrous sodium sulphate. Then the solvent was evaporated under reduced pressure to afford the crude 1-(benzofuran-2-yl)-2- (methylamino)propan-1-one (5) as a yellow sticky liquid (1.7 g) which was proceeded for the next step without further purification. LCMS: Rt 1.46 minutes. MS (ES) C12H13NO2 requires 203, found 204 [M + H]+. Step 5 To a stirred solution of 1-(benzofuran-2-yl)-2-(methylamino)propan-1-one (5) (1.7 g, 8.36 mmol, 1 equiv.) in dry dichloromethane (20 mL) was added triethylamine (2.3 mL, 16.73 mmol, 2 equiv.) and Boc anhydride (3.8 mL, 16.73 mmol, 2 eq.) and the resulting reaction mixture was allowed to stir at room temperature for 4h. Upon completion, (monitored by TLC, 10% ethyl acetate in hexane), the reaction mixture was evaporated under reduced pressure, diluted with dichloromethane (100 mL), and washed with water followed by brine solution. The combined organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated under vacuum and purified by silica gel column chromatography using 10% ethyl acetate/hexane as an eluent to get tert-butyl (1-(benzofuran-2-yl)-1-oxopropan-2-yl)(methyl)carbamate (6) as a light- yellow sticky liquid (1.0 g).1HNMR (400 MHz, DMSO) δ 7.86-7.78 (m, 2H), 7.71 (bs, 1H), 7.56 (t, J = 7.48 Hz, 7.96 Hz, 1H), 7.38 (t, J = 7.60 Hz, 7.36 Hz, 1H), 5.27-4.92 (m, 1H), 2.95-2.81 (m, 3H), 1.35 (s, 9H), 1.18 (s, 3H). LCMS: Rt 2.09 minutes. MS (ES) C17H21NO4 requires 303, found 304 [M + H]+. Step 6 To a stirred solution of tert-butyl (1-(benzofuran-2-yl)-1-oxopropan-2-yl) (methyl)carbamate (6) (350 mg, 1.15 mmol, 1 equiv.) in dry dichloromethane (5.0 mL) was added 4(M) HCl in 1,4 dioxane (2.75 mL) at 0 ℃ and the resulting reaction mixture was allowed to stir at room temperature for 2h. Upon completion of the reaction (monitored by TLC, 10% ethyl acetate in hexane, until starting material was consumed), the solvent was evaporated, and the crude was washed twice with diethyl ether (2 x 30 mL) and dried under vacuum to afford 1-(benzofuran- 2-yl)-2-(methyl amino) propan-1-one hydrochloride (Compound 1) (230 mg, 82%) as an off white solid.1HNMR (400 MHz, DMSO) δ 9.26 (s, 2H), 8.21 (s, 1H), 7.92 (d, J = 7.92 Hz, 1H), 7.79 (d, J = 8.40 Hz, 1H), 7.65 (t, J=7.56 Hz, 8.00 Hz, 1H), 7.45 (t, J = 7.52 Hz, 7.44 Hz, 1H), 4.99-4.94 (m, 1H), 2.61 (s, 3H), 1.57 (d, J = 7.08 Hz, 3H). LCMS: Rt 1.98 minutes. MS (ES) C12H14ClNO22 requires 203, found 204 [M + H]+. HPLC: Rt 5.874 minutes. Purity (λ 220 nm): 99.73%. Preparation of (S)-1-(benzofuran-2-yl)-2-(methylamino)propan-1-one (Compound 2), and (R)- 1-(benzofuran-2-yl)-2-(methylamino)propan-1-one (Compound 3)
Figure imgf000200_0001
Synthesis 19: Preparation of 1-(benzofuran-2-yl)-2-(methylamino)propan-1-one (Compound 4), (S)-1-(benzofuran-2-yl)-2-(ethylamino)propan-1-one (Compound 5), and (R)-1- (benzofuran-2-yl)-2-(ethylamino)propan-1-one (Compound 6)
Figure imgf000201_0001
Step 1 To a stirred solution of benzofuran-2-carboxylic acid (1) (5.0 g, 30.838 mmol, 1 equiv.) in dry dichloromethane (50 mL) were added N,N-diisopropylethylamine (DIPEA) (27.0 mL, 154.188 mmol, 3 equiv.) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) (8.9 g, 46.256 mmol, 1.5 equiv.) and HOBt (6.3 g, 46.256 mmol, 1.5 equiv.) under Nitrogen atmosphere at room temperature and the reaction mixture was continued to stir for fifteen minutes. Then N, O-dimethylhydroxylamine hydrochloride (9.0 g, 92.513 mmol, 3.0 equiv.) was added to the resulting reaction mixture and was allowed to stir at room temperature for sixteen hours. Upon completion, monitored by TLC (50% ethyl acetate in Hexane), the reaction mixture was diluted with dichloromethane (500 mL) and washed with water followed by a brine solution. The combined organic layer was dried over anhydrous sodium sulphate. The solvent was removed under vacuum and purified by silica gel column chromatography using ethyl acetate/hexane (20:80 v/v) as eluent to afford N-methoxy-N-methylbenzofuran-2-carboxamide (2) as a light-yellow sticky liquid (5.4 g, 85.33%).1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.44-7.39 (m, 1H), 7.30-7.26 (t, J = 7.8 Hz, 7.36 Hz, 1H), 3.82 (s, 3H), 3.41 (s, 3H). LCMS: Rt 1.68 minutes. MS (ES) C11H11NO3 requires 205, found 206 [M + H]+. Step 2 To a stirred solution of N-methoxy-N-methylbenzofuran-2-carboxamide (2) (5.0 g, 24.365 mmol, 1 equiv.) was added dry Diethyl ether (100 mL) at 0°C and was added 3(M) solution of EtMgBr in Diethyl ether (16.24 mL, 48.731 mmol, 2 equiv.) to the reaction mixture and allowed to stir at room temperature for four hours. Upon completion, (monitored by TLC, 20% ethyl acetate in Hexane) the reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate, twice (2 x 150 mL), then washed with water followed by brine solution. The combined organic layer was dried over anhydrous sodium sulphate, solvent was evaporated under reduced pressure to get the crude which was purified by silica gel column chromatography using 1% ethyl acetate/hexane as eluent to afford 1-(benzofuran-2-yl) propan-1-one (3) as white solid (3.6 g, 84.82%).1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.84 Hz, 1H), 7.58 (dd, J = 0.72 Hz, 8.44 Hz, 1H), 7.49-7.44 (m, 2H), 7.32-7.28 (m, 1H), 3.02-2.96 (m, 2H), 1.27-1.22 (m, 3H). LCMS: Rt 1.89 minutes. MS (ES) C11H10O2 requires 174, found 175 [M + H]+. Step 3 To a stirred solution of 1-(benzofuran-2-yl) propan-1-one (3) (1.8 g, 10.333 mmol, 1 equiv.) in dry tetrahydrofuran (30 mL) was added hydrobromic acid (48% in water) (26.0 mL, 165.331 mmol, 16.0 equiv.) and bromine (0.63 mL, 12.4 mmol, 1.2 equiv.) dropwise at 0 ℃ and the reaction mixture was allowed to stir at room temperature for sixteen hours. Upon completion, (monitored by TLC, 5% ethyl acetate in Hexane), the reaction mixture was quenched with saturated sodium carbonate solution and extracted with ethyl acetate (2 x 100 mL), washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulphate, then the solvent was evaporated under reduced pressure and purified by silica gel column chromatography using 1% ethyl acetate/hexane as eluent to get the compound 1-(benzofuran-2- yl)-2-bromopropan-1-one (4) as yellow sticky liquid (2.1 g, 80.3%).1H NMR (400 MHz, DMSO) δ 8.11 (d, J = 0.72 Hz, 1H), 7.88 (d, J = 7.76 Hz, 1H), 7.76 (dd, J = 0.6, 8.4 Hz, 1H), 7.60-7.56 (m, 1H), 7.40 (t, J = 7.2 Hz 1H), 5.69-5.64 (m, 1H), 1.85-1.79 (m, 3H). LCMS: Rt 1.98 minutes. MS (ES) C11H9BrO2 requires 253, found 255 [M + 2]+. Step 4 To a stirred solution of 1-(benzofuran-2-yl)-2-bromopropan-1-one (4) (2.1 g, 8.297 mmol, 1 equiv.) in dry DMF (25 mL) was added potassium carbonate (1.71 g, 12.446 mmol, 1.5 equiv.) and ethyl amine 2(M) in tetrahydrofuran (16.6 ml, 33.19 mmol, 4.0 equiv.) in a sealed RB and the resulting reaction mixture was allowed to stir at room temperature for 16h. Upon completion of the reaction (monitored by TLC, 10% ethylacetate in Hexane), volatiles were evaporated, and the crude was diluted with ethyl acetate (100 ml) and washed with water (3 x 50 mL) followed by brine solution. The combined organic solvent was dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to afford crude 1-(benzofuran-2-yl)-2-(ethyl amino) propan-1-one (5) as a yellow sticky liquid (1.8 g) which proceeded to the next step without further purification. LCMS: Rt 1.54 minutes. MS (ES) C11H9BrO2 requires 217, found 218 [M + H]+. Step 5 To a stirred solution of 1-(benzofuran-2-yl)-2-(ethyl amino) propan-1-one (5) (1.8 g, 8.285 mmol, 1 equiv.) in dry dichloromethane (20 mL) was added triethylamine (2.32 mL, 16.57 mmol, 2 equiv.) and Boc anhydride (3.8 mL, 16.57 mmol, 2 eq.) and the resulting reaction mixture was allowed to stir at room temperature for 4h. Upon completion, (monitored by TLC, 10% ethyl acetate in hexane), the reaction mixture was evaporated under reduced pressure, diluted with dichloromethane (100 mL) and washed with water followed by brine solution. The combined organic solvent was dried over anhydrous sodium sulphate. The solvent was evaporated under vacuum and purified by silica gel column chromatography using 10% ethyl acetate/hexane as an eluent to get tert-butyl (1-(benzofuran-2-yl)-1-oxopropan-2-yl) (ethyl)carbamate (6) as light- yellow sticky liquid (1.0 g).1H NMR (400 MHz, DMSO) δ 7.83 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 8.4 Hz, 1H), 5.06-5.05 (m, 1H), 3.36- 3.34 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H), 1.32 (s, 9H), 1.16 (t, J = 6.8 Hz, 3H). Rotamer observed. LCMS: Rt 2.15 minutes. MS (ES) C18H23NO4 requires 317, found 318 [M + H]+. Step 6 To a stirred solution of tert-butyl (1-(benzofuran-2-yl)-1-oxopropan-2-yl) (ethyl)carbamate (6) (350 mg, 1.103 mmol, 1 equiv.) in dry dichloromethane (5.0 mL) was added 4(M) HCl in 1,4 dioxane (2.75 mL) at 0 ℃ and the resulting reaction mixture was allowed to stir at room temperature for two hours. Upon completion of the reaction (monitored by TLC, 10% ethyl acetate in hexane, until starting material was consumed), the solvent was evaporated, and the crude was washed twice with diethyl ether (2 x 30 mL) and dried under vacuum to afford 1- (benzofuran-2-yl)-2-(ethyl amino) propan-1-one hydrochloride (Compound 4) (230 mg, 82%) as a white solid.1HNMR (400 MHz, DMSO) δ 9.50 (s, 1H), 9.14 (s, 1H), 8.26 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.65-7.61 (m, 1H), 7.45 (t, J = 7.52 Hz, 7.48 Hz, 1H), 5.04- 4.99 (m, 1H), 3.09-2.92 (m, 2H), 1.58 (d, J = 7.08 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H). LCMS: Rt 2.18 minutes. MS (ES) C13H16ClNO2 requires 217, found 218 [M + H]+. HPLC: Rt 6.42 minutes. Purity (λ 220 nm): 98.34%. Preparation of (S)-1-(benzofuran-2-yl)-2-(ethylamino)propan-1-one (Compound 5), and (R)- 1-(benzofuran-2-yl)-2-(ethylamino)propan-1-one (Compound 6)
Figure imgf000204_0001
Chiral resolution (NP): Chiral resolution was done on an Agilent 1200 series instrument. Column name: Chiralpak IG (250 x 21 mm) 5µ. The column was operated at ambient temperature and flow rate was 21.0 mL/min. The mobile phase was a mixture of 90% Hexane and 10% ethanol, held this isocratic mixture run up to fourteen minutes with a wavelength of 298 nm. Chiral resolution done by 2.5 g of Int-6, ~ 1.0 g of peak-1 and ~700 mg of peak-2 were obtained at 5.404 minutes and 5.950 minutes respectively. Stereochemistry was assigned arbitrarily. Peak-1: 1HNMR (400 MHz, DMSO) δ 7.85-7.68 (m, 3H), 7.55 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.52 Hz, 1H), 5.20-4.83 (m, 1H), 3.50-3.24 (m, 2H), 1.34 (bs, 9H), 1.15 (m, 6H). LCMS: Rt 3.86 minutes. MS (ES) C13H16ClNO2 requires 317, found 318 [M + H]+. HPLC: Rt 5.46 minutes. Purity (λ 298 nm): 100%. Peak-2: 1HNMR (400 MHz, DMSO) δ 7.85-7.68 (m, 3H), 7.55 (t, J = 7.44 Hz, 7.96 Hz, 1H), 7.37 (t, J = 7.48 Hz, 7.52 Hz, 1H), 5.21-4.48 (m, 1H), 3.50-3.24 (m, 2H), 1.34 (s, 9H), 1.15 (m, 6H). LCMS: Rt 2.16 minutes. MS (ES) C13H16ClNO2 requires 317, found 318 [M + H]+. HPLC: Rt 5.96 minutes. Purity (λ 298 nm): 99.73%. Step 6 To a stirred solution of tert-butyl (S)-(1-(benzofuran-2-yl)-1-oxopropan-2-yl) (ethyl)carbamate (7A) (1.0 g, 3.151 mmol, 1 equiv.) in dry dichloromethane (10.0 mL) was added 4(M) HCl in 1,4 dioxane (15.0 mL) at 0 ℃ and the resulting reaction mixture was allowed to stir at room temperature for two hours. Upon completion of reaction (monitored by TLC, 10% ethyl acetate in Hexane), the solvent was evaporated, and the crude was washed twice with diethyl ether (2 x 30 mL) and dried under vacuum to afford (S)-1-(benzofuran-2-yl)-2-(ethyl amino) propan-1- one hydrochloride (Compound 5) (700 mg, 80%) as a white solid.1HNMR (400 MHz, DMSO) δ 9.74 (s, 1H), 9.28 (s, 1H), 8.27 (s, 1H), 7.92 (d, J = 7.84 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 7.52 Hz, 8 Hz, 1H), 7.45 (t, J = 7.48 Hz, 1H) 5.03-5.01 (m, 1H), 3.05-2.94 (m, 2H), 1.59 (d, J = 6.92 Hz, 3H), 1.28 (t, J = 7.08 Hz, 3H). LCMS: Rt 2.15 minutes. MS (ES) C13H16ClNO2 requires 217, found 218 [M + H]+. HPLC: Rt 6.04 minutes. Purity (λ 220 nm): 99.81%. Chiral purity: Rt: 8.614 minutes, (λ 254 nm): 99.898%. Step 7 To a stirred solution of tert-butyl (R)-(1-(benzofuran-2-yl)-1-oxopropan-2-yl) (ethyl)carbamate (7B) (750 mg, 2.363 mmol, 1 equiv.) in dry dichloromethane (8.0 mL) was added 4(M) HCl in 1,4 dioxane (12.0 mL) at 0 ℃ and the resulting reaction mixture was allowed to stir at room temperature for two hours. Upon completion of reaction (monitored by TLC, 10% ethyl acetate in hexane, until starting material was consumed), the solvent was evaporated, and the crude was washed twice with diethyl ether (2 x 25 mL) and dried under vacuum to afford (R)-1- (benzofuran-2-yl)-2-(ethyl amino) propan-1-one hydrochloride (Compound 6) (500 mg, 83.39%) as a white solid.1HNMR (400 MHz, DMSO) δ 9.75 (s, 1H), 9.28 (s, 1H), 8.27 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 7.52 Hz, 1H), 7.45 (t, J = 7.48 Hz, 1H), 5.03- 5.01 (m, 1H), 3.05-2.49 (m, 2H), 1.59 (d, J = 6.92 Hz, 3H), 1.28 (t, J = 7.08 Hz, 3H). LCMS: Rt 2.15 minutes. MS (ES) C13H16ClNO2 requires 217, found 218 [M + H]+. HPLC: Rt 6.04 min. Purity (λ 220 nm): 99.30%. Chiral purity: Rt: 6.759 minutes, (λ 254 nm): 99.721%. Synthesis 20: Preparation of 1-(benzofuran-2-yl)-2-(methylamino)butan-1-one (Compound 7), (S)- 1-(benzofuran-2-yl)-2-(methylamino)butan-1-one (Compound 8), and (R)- 1- (benzofuran-2-yl)-2-(methylamino)butan-1-one (Compound 9)
Figure imgf000206_0001
Figure imgf000206_0002
Figure imgf000206_0003
Figure imgf000206_0004
Step 1 To a stirred solution of benzofuran-2-carboxylic acid (1) (5.0 g, 30.838 mmol, 1 equiv.) in dry dichloromethane (50 mL) were added N,N-diisopropylethylamine (DIPEA) (27.0 mL, 154.188 mmol, 3 equiv.) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) (8.9 g, 46.256 mmol, 1.5 equiv.) and HOBt (6.3 g, 46.256 mmol, 1.5 equiv.) under Nitrogen atmosphere at room temperature and the reaction mixture was continued to stir for fifteen minutes. Then N, O-dimethylhydroxylamine hydrochloride (9.0 g, 92.513 mmol, 3.0 equiv.) was added to the resulting reaction mixture and was allowed to stir at room temperature for 16h. Upon completion, monitored by TLC (50% ethyl acetate in hexane), the reaction mixture was diluted with dichloromethane (500 mL) and washed with water followed by a brine solution. The combined organic layer was dried over anhydrous sodium sulphate. The solvent was removed under vacuum and purified by silica gel column chromatography using ethyl acetate/hexane (20:80 v/v) as eluent to afford N-methoxy-N-methylbenzofuran-2-carboxamide (2) as a light-yellow sticky liquid (5.4 g, 85.33%).1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.44-7.39 (m, 1H), 7.30-7.26 (t, J = 7.8 Hz, 7.36 Hz, 1H), 3.82 (s, 3H), 3.41 (s, 3H). LCMS: Rt 1.68 minutes. MS (ES) C11H11NO3 requires 205, found 206 [M + H]+. Step 2 To a stirred solution of N-methoxy-N-methylbenzofuran-2-carboxamide (2) (3.0 g, 14.619 mmol, 1 equiv.) was added dry tetrahydrofuran (60 mL) at 0°C and was added 2(M) solution of propyl-MgBr in tetrahydrofuran (14.61 mL, 29.238 mmol, 2 equiv.) to the reaction mixture and allowed to stir at room temperature for four hours. Upon completion, (monitored by TLC, 20% ethyl acetate in hexane) the reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate, twice (2 x 150 mL), then washed with water followed by brine solution. The combined organic layer was dried over anhydrous sodium sulphate, solvent was evaporated under a vacuum to get the crude which was purified by silica gel column chromatography using 1% ethyl acetate/hexane as eluent to afford 1-(benzofuran-2-yl)butan-1-one (3) as a white solid (2.2 g, 79.95%).1H NMR (400 MHz, DMSO) δ 7.91 (s, 1H), 7.84 (d, J = 7.84 Hz, 1H), 7.72 (d, J = 8.36 Hz, 1H), 7.55 (t, J = 7.48 Hz, 7.8 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 2.97 (t, J = 7.12 Hz, 7.2 Hz, 2H), 1.71-1.62 (m, 2H), 0.96 (t, J = 7.36 Hz, 7.40 Hz, 3H). LCMS: Rt 1.97 minutes. MS (ES) C12H12O2 requires 188, found 189 [M + H]+. Step 3 To a stirred solution of 1-(benzofuran-2-yl) butan-1-one (3) (500 mg, 2.656 mmol, 1 equiv.) in dry tetrahydrofuran (10 mL) was added hydrobromic acid (48% in Water) (5.0 mL, 42.503 mmol, 16.0 equiv.) and bromine (0.16 mL, 3.188 mmol, 1.2 equiv.) dropwise at 0°C and the reaction mixture was allowed to stir at room temperature for sixteen hours. Upon completion, (monitored by TLC, 5% ethyl acetate in hexane), the reaction mixture was quenched with saturated sodium carbonate solution and extracted with ethyl acetate (2 x 50 mL), washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulphate, solvent was evaporated under reduced pressure and purified by silica gel column chromatography using 1% ethyl acetate/hexane as an eluent to get the compound 1-(benzofuran-2-yl)-2-bromobutan-1- one (4) as light- yellow sticky liquid (645 mg, 90.89%). 1H NMR (400 MHz, DMSO) δ 8.16 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.76-7.74 (m, 1H), 7.61-7.56 (m, 1H), 7.42-7.38 (m, 1H), 5.52-5.49 (m, 1H), 2.20-2.10 (m, 1H), 2.05-1.95 (m, 1H), 1.04 (t, J = 7.24 Hz, 7.28 Hz, 3H). LCMS: Rt 3.68 minutes. MS (ES) C12H11BrO2 requires 267, found 269 [M + 2]+. Step 4 To a stirred solution of 1-(benzofuran-2-yl)-2-bromobutan-1-one (4) (645 mg, 2.415 mmol, 1 equiv.) in dry DMF (10.0 mL) was added potassium carbonate (500 mg, 3.622 mmol, 1.5 equiv.) and methyl amine (2M) in tetrahydrofuran (7.24 mL, 14.488 mmol, 6.0 equiv.) in a sealed round bottom flask and the resulting reaction mixture was allowed to stir at room temperature for sixteen hours. Upon completion of the reaction (monitored by TLC, 10% ethyl acetate in hexane), volatiles were evaporated, and the crude was diluted with ethyl acetate (100 mL) and washed with water (3 X 100 mL) followed by brine solution. The combined organic solvent was dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to afford crude 1- (benzofuran-2-yl)-2-(methylamino) butan-1-one (5) as light-yellow sticky liquid (500 mg) which was proceeded for the next step without further purification. LCMS: Rt 2.78 minutes. MS (ES) C13H15NO2 requires 217, found 218 [M + H]+. Step 5 To a stirred solution of 1-(benzofuran-2-yl)-2-(methylamino) butan-1-one (5) (500 mg, 2.301 mmol, 1 equiv.) in dry dichloromethane (10 mL) was added triethylamine (0.64 mL, 4.603 mmol, 2 equiv.) and Boc anhydride (1.05 mL, 4.603 mmol, 2 eq.) and the resulting reaction mixture was allowed to stir at room temperature for four hours. Upon completion, (monitored by TLC, 10% ethyl acetate in hexane), the reaction mixture was evaporated under reduced pressure, diluted with dichloromethane (100 mL) and washed with water followed by brine solution. The combined organic solvent was dried over anhydrous sodium sulphate. Then the solvent was evaporated under vacuum and purified by silica gel column chromatography using 10% ethyl acetate/hexane as eluent to get tert-butyl (1-(benzofuran-2-yl)-1-oxobutan-2-yl) (methyl)carbamate (6) as a light-yellow sticky liquid (375 mg). 1HNMR (400 MHz, DMSO) δ 7.89-7.79 (m, 2H), 7.71-7.69 (d, J = 7.64 Hz, 1H), 7.57 (t, J = 7.68 Hz, 7.88 Hz, 1H), 7.39 (t, J = 7.44 Hz, 7.48 Hz, 1H), 5.24-4.96 (m, 1H), 2.85-2.73 (m, 3H), 1.88-1.75 (m, 2H), 1.39-1.30 (m, 9H), 0.94-0.87 (m, 3H). Rotamer observed. LCMS: Rt 3.79 minutes. MS (ES) C18H23NO4 requires 317, found 318 [M + H]+. Step 6 To a stirred solution of tert-butyl (1-(benzofuran-2-yl)-1-oxobutan-2-yl) (methyl)carbamate (6) (370 mg, 1.166 mmol, 1 equiv.) in dry dichloromethane (5.0 mL) was added 4(M) HCl in 1,4 dioxane (2.0 mL) at 0°C and the resulting reaction mixture was allowed to stir at room temperature for two hours. Upon completion of the reaction (monitored by TLC, 10% ethyl acetate in hexane), the solvent was evaporated, and the crude was washed twice with diethyl ether (2 X 30 mL) and dried under vacuum to afford 1-(benzofuran-2-yl)-2-(methylamino) butan- 1-one hydrochloride (230 mg, 94.75%) as a white solid. 1HNMR (400 MHz, DMSO) δ 9.63 (s, 1H), 9.34 (s, 1H), 8.27 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.44 Hz, 1H), 7.65-7.61 (m, 1H), 7.45 (t, J = 7.28 Hz, 7.80 Hz, 1H), 5.02 (t, J = 5.48 Hz, 5.36 Hz, 1H), 2.57 (s, 3H), 2.11-2.04 (m, 2H), 0.89 (t, J = 7.52 Hz, 7.56 Hz, 3H). LCMS: Rt 2.27 min. MS (ES) C13H16ClNO2 requires 217, found 218 [M + H]+. HPLC: Rt 5.387 minutes. Purity (λ 260 nm): 99.80%. Preparation of (S)- 1-(benzofuran-2-yl)-2-(methylamino)butan-1-one (Compound 8), and (R)- 1-(benzofuran-2-yl)-2-(methylamino)butan-1-one (Compound 9)
Figure imgf000209_0001
EXAMPLE 2: Evaluation of Therapeutic Properties The clinical and therapeutic effects of compounds that increase extracellular monoamine neurotransmitters are thought to be correlated with their relative tendencies to increase serotonin and dopamine. Liechti and colleagues have proposed that new psychoactive drugs can be classified based on their DAT/SERT inhibition ratios, defined as 1/IC50 at DAT divided by 1/IC50 at SERT (e.g., Luethi and Liechti.2020. Archives of toxicology, 94(4), pp.1085-1133). These authors use IC50 measuring uptake inhibition rather than EC50 measuring neurotransmitter release, presumably because drugs that release neurotransmitter also have measurable effects in uptake inhibition assays, producing a metric that can accommodate both reuptake inhibitors and releasers. In the classification system of Liechti and colleagues, DAT/SERT IC50 ratios >1 are thought to predict psychostimulant effects and compounds with this profile have potential value in treating attention deficit hyperactivity disorder (ADHD) and stimulant use disorders. Example compounds with this profile include dextroamphetamine and methylphenidate (Ritalin, Concerta). In contrast, serotonin release and a DAT/SERT IC50 ratio of 0.01–0.1 is said to result in a psychoactive drug profile similar to that of MDMA, which includes feelings of emotional openness, authenticity, and decreased neuroticism. MDMA is an experimental adjunct to psychotherapy that shows great potential for treating PTSD and substance use disorders. It may also be able to generally accelerate progress in psychotherapy and aid emotional decision making. MDMA has a reported DAT/SERT IC50 ratio of 0.08 (Simmler and Liechti, New Psychoactive Substances, pp.143-164). Compounds with intermediate DAT/SERT IC50 ratios (between 0.1 and 1) appear to sometimes have antidepressant-like or nootropic (cognitive enhancement) qualities and have been proposed as antidepressants, cognitive enhancers, or treatments for substance use disorders. For example, 4-bromomethcathinone (4-BMC, Brephedrone; IUPAC: 1-(4-bromophenyl)-2- (methylamino)propan-1-one) does not have typical psychostimulant effects and has been proposed as a potential antidepressant (Foley and Cozzi.2003. Drug development research, 60(4), pp.252- 260). The different therapeutic profiles of these intermediate compounds are believed to be at least partially the result of serotonin inhibiting and modifying the stimulating effects of dopamine (Kimmel et al.2009. Pharmacology Biochemistry and Behavior, 94(2), pp.278-284; Suyama et al. 2019. Psychopharmacology, 236(3), pp.1057-1066; Wee et al.2005. Journal of Pharmacology and Experimental Therapeutics, 313(2), pp.848-854). One caveat to Liechti's classification system is that compounds that release neurotransmitter may be misclassified if their relative abilities to release dopamine and serotonin are substantially different from their relative abilities to inhibit uptake of dopamine and serotonin. Compounds that appear misclassified in this manner include 3,4,- methylenedioxyethylamphetamine (MDEA; IUPAC [1-(2H-1,3-benzodioxol-5-yl)propan-2- yl](ethyl)amine), which has a reported DAT/SERT IC50 ratio of 3.2 (Simmler et al.2013. British journal of pharmacology, 168(2), pp.458-470) but is also reported to have MDMA-like effects in humans (e.g., Hermle et al.1993. Neuropsychopharmacology, 8(2), pp.171-176). Such releasing compounds may be alternatively classified according to their DAT/SERT EC50 ratios, where MDEA has been reported as 0.76 (Rothman et al. 2012. Journal of Pharmacology and Experimental Therapeutics, 341(1), pp.251-262). In this release-based system, MDMA-like therapeutic effects appear present at ratios below 2, with compounds having DAT/SERT EC50 ratios between 2 and 5 having diminished but often still noticeable MDMA-like effects. These intermediate compounds may prove useful for treating ADHD, substance use disorders, and other conditions in individuals who experience significant anxiety from approved psychostimulant pharmacotherapies such as d-amphetamine. Similar to the IC50 system, compounds with higher DAT/SERT EC50 ratios are potential treatments for ADHD and psychostimulant use disorders. Although MDMA has significant therapeutic potential, it has a number of features that limit its clinical use and may make it contraindicated for some patients. This includes its moderate abuse liability (likely related to its ability to increase extracellular dopamine), acute hypertensive effects (likely related to its norepinephrine release), variable inter-individual metabolism that includes inhibition of the liver enzyme CYP2D6 (increasing risk of drug-drug interactions), potential to induce hyponatremia in women, oxidative stress (likely related to its extensive, though variable, metabolism and formation of reactive metabolites), ability to produce decreases in SERT density after high doses, diminishing therapeutic benefits with repeated use; and a hangover-like after-effects including poor mood and lowered energy. There is therefore a need for additional pharmacologic agents that have similar therapeutic properties while having different pharmacological profiles compared to MDMA. Compounds that increase extracellular dopamine also often increase extracellular norepinephrine to a similar or greater extent. For example, d-methamphetamine has a reported DAT/NET EC50 ratio of 0.5, while d-amphetamine has a ratio of 0.9 (Rothman et al. 2001. Synapse, 39(1), pp.32-41), indicating both are more potent at increasing norepinephrine than dopamine. Differences in the relative balance of dopamine and norepinephrine increases can yield compounds with valuable therapeutic profiles. Norepinephrine increases contribute to cognitive improvements in ADHD but, in excess, can also lead to cardiovascular changes. Dopamine similarly modulates impulsive action but, in excess, can produce compounds with high abuse liability. Nonetheless, individuals with histories of substance abuse who have desensitized dopamine receptors can benefit from compounds that adequately stimulate these receptors. Thus, there is a need for novel treatment compounds that differently balance therapeutic benefits against cardiovascular and abuse liability side effects. As previously noted, increases in extracellular serotonin and direct stimulation of serotonin receptors present ways for compounds (or compound combinations) to decrease off-target effects and increase select therapeutic effects. For example, compounds that release dopamine and/or norepinephrine and also stimulate 5-HT1A or 5-HT1B receptors can provide fast acting therapeutic effects on mood and attention while decreasing social anxiety. Similarly, compounds that stimulate 5-HT2A receptors while increasing extracellular neurotransmitter can provide the therapeutic benefits of 5-HT2A agonists while having predictable positive effects on mood that decrease the need for clinical monitoring. EXAMPLE 3: nAChR α4β2 Receptor Agonism An IonFlux™ automated patch-clamp system can be used to measure activity of S-Bk-2- MAPB, R-Bk-2-MAPB, S-Bk-2-EAPB, and R-Bk-2-EAPB at nAChR α4β2 receptors (Eurofins, cat. No. CYL3106) expressed in HEK-293 cells as described in Yehia & Wei, 2020, Current Protocols in Pharmacology, 88(1). Acetylcholine is used as a positive control. EXAMPLE 4: Serum Serotonin Concentrations to Index Drug Interactions with the Serotonin Transporter (SERT, SLC6A4) Serum serotonin is measured using High Performance Liquid Chromatography and Fluorescence Detection. Venipuncture is used to collect at least 1 mL of sample, which is spun with serum frozen to below -20° C within 2 hours of collection. EXAMPLE 5: Marble Burying Measure of Decreased Anxiety and Neuroticism The marble burying test is a model of neophobia, anxiety, and obsessive-compulsive behavior that has been proposed to have predictive validity for the screening of novel antidepressants and anxiolytics. It is well established to be sensitive to the effects of SSRIs as well as serotonin releasers such as fenfluramine and MDMA (De Brouwer et al., Cognitive, Affective, and Behavioral Neuroscience, 2019, 19(1), 1-39). The test involves the placement of a standardized number of marbles gently onto the surface of a layer of bedding material within a testing arena. Mice are then introduced into the arena for a standardized amount of time and allowed to explore the environment. The outcome measure of the test is the number of marbles covered as scored by automatic scoring software or blinded observers. General locomotor activity, often operationalized as total distance traveled, is used as a control measure. Compounds that attenuate anxiety, neuroticism, or obsessive- compulsive behavior decrease marble burying. Marble Burying Experimental Methods Marble burying experiments are conducted by trained and authorized personnel and are in compliance with applicable guidelines for experiments with laboratory animals. Manipulation of animals is conducted carefully to reduce stress to a minimum. Animal Care Test animals are Swiss CD1 mice, 5-6 weeks old, that have not been subjected to prior experiments. Housing conditions Housing Group housing (8-9 mice/cage): 1290D Eurostandard Type III m d er
Figure imgf000213_0001
Hygrometry 50 ± 30% (measured but not controlled) Air renewal Fresh air 12-25 vol/h
Figure imgf000214_0001
g g , 42 cm W, 40 cm H) filled with 5 cm sawdust. Twenty-five clean glass marbles (15 mm diameter) are evenly spaced 5 cm apart on sawdust. Testing Procedure Testing is carried out during the dark phase, in standardized conditions (T°= 22.0 ± 1.5°C), with artificial light (20 Lux at the level of the apparatus) and low ambient noise (mostly coming from the ventilation system and the experimental apparatus). Test compounds or placebo vehicle are administered intraperitoneally 30 minutes before animals were individually placed in an experimental apparatus for a 30-min session. The number of marbles at least 2/3 buried is counted at the end of the session as the primary outcome measure. Results are generally displayed with scores inverted (proportion of marble left unburied) and expressed as magnitude difference-from-placebo with error bars indicating 95% confidence intervals. EXAMPLE 6: In Vitro Binding Site Studies Select compounds of the present invention can be tested for agonist and antagonist activity against 5-HT1B and 5-HT2A. Select compounds can also be tested for adrenergic β2 receptor antagonist activity, MAO-A inhibition, and the ability to inhibit nicotinic acetylcholine α4/β2 receptors. Adrenergic β2 Receptor cAMP Secondary Messenger Antagonist Assay Methods This assay uses a panel of CHO-K1 cell lines stably expressing non-tagged GPCRs that endogenously signal through cAMP. Hit Hunter® cAMP assays monitor the activation of a GPCR via Gi and Gs secondary messenger signaling in a homogenous, non-imaging assay format using DiscoverX Enzyme Fragment Complementation (EFC) with β-galactosidase as the functional endpoint. The enzyme is split into two complementary portions: Enzyme Acceptor (EA) and Enzyme Donor (ED). In the assay, exogenously introduced ED fused to cAMP (ED-cAMP) competed with endogenously generated cAMP for binding to an anti-cAMP-specific antibody. Active β- galactosidase is formed by complementation of exogenous EA to any unbound ED-cAMP. Active enzyme could then convert a chemiluminescent substrate, generating an output signal detectable on a standard microplate reader. Cell lines are expanded from freezer stocks according to standard procedures. Cells are seeded in a total volume of 20 µL into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing. cAMP modulation is determined using the DiscoverX HitHunter cAMP XS+ assay. Test compounds are assayed at 10 concentrations with the highest concentration either 30 or 10 µM and subsequent concentrations using a 0.33 dilution factor. For agonist determination, cells are incubated with sample (in the presence of EC80 forskolin to induce response if measuring Gi secondary messenger signaling). Media is aspirated from cells and replaced with 15 µL 2:1 HBSS/10mM Hepes: cAMP XS+ Ab reagent. Intermediate dilution of sample stocks is performed to generate 4X sample in assay buffer (optionally containing 4X EC80 forskolin). 5 µL of 4X sample is added to cells and incubated at 37°C or room temperature for 30 or 60 minutes, as appropriate. Final assay vehicle concentration was 1%. For antagonist determination, cells are pre-incubated with sample followed by agonist challenge at the EC80 concentration. Media is aspirated from cells and replaced with 10μL 1:1 HBSS/Hepes: cAMP XS+ Ab reagent. 5 μL of 4X compound is added to the cells and incubated at 37°C or room temperature for 30 minutes. 5 μL of 4X EC80 agonist is added to cells and incubated at 37◦C or room temperature for 30 or 60 minutes. For Gi coupled GPCRs, EC80 forskolin was included. After appropriate compound incubation, assay signal is generated through incubation with 20 μL cAMP XS+ ED/CL lysis cocktail for one hour followed by incubation with 20 μL cAMP XS+ EA reagent for three hours at room temperature. Microplates are read following signal generation with a PerkinElmer EnvisionTM instrument for chemiluminescent signal detection. Compound activity is analyzed using CBIS data analysis suite (ChemInnovation, CA). For Gs antagonist mode assays, percentage inhibition is calculated as 100% x (1 - (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of EC80 control - mean RLU of vehicle control)). 5-HT2A and 5-HT2B Agonist and Antagonist Assays The DiscoveRx Calcium NWPLUS Assay can be used for detection of changes in intracellular calcium as signaled by an increase of dye fluorescence in cells expressing 5-HT2A receptors. Signal is measured on a fluorescent plate reader equipped with fluidic handling capable of detecting rapid changes in fluorescence upon compound stimulation. To conduct the assay, cell lines are expanded from freezer stocks according to standard procedures. Cells (10,000cells/well) are seeded in a total volume of 50μL (200 cells/μL) into black- walled, clear-bottom, Poly-D-lysine coated 384-well microplates and incubated at 37◦C for the appropriate time prior to testing. DMSO concentration for all readouts was ≤ 0.2%. Assays are performed in 1X DyeLoading Buffer consisting of 1X Dye (DiscoverX, Calcium No WashPLUS kit, Catalog No. 90-0091), 1X Additive A and 2.5 mM Probenecid in HBSS / 20 mM Hepes. Probenecid is prepared fresh. Cells are loaded with dye prior to testing. Media is aspirated from cells and replaced with 25 μL Dye Loading Buffer. Test compounds are assayed at 10 concentrations with the highest concentration either 30 or 10 µM and subsequent concentrations using a 0.33 dilution factor. Cells with testing sample are incubated for 45 minutes at 37◦C and then 20 minutes at room temperature. After dye loading, cells are removed from the incubator and 25 μL of 2X compound in HBSS / 20 mM Hepes is added using a FLIPR Tetra (MDS). For 5-HT2A assays, serotonin and altanserin are used as agonist and antagonist reference controls. For 5-HT2B assays, these are serotonin and LY272015. For antagonist determination, cells are pre-incubated with sample followed by agonist challenge at the EC80 concentration. After dye loading, cells are removed from the incubator and 25 μL 2X sample is added. Cells are incubated for 30 minutes at room temperature in the dark to equilibrate plate temperature. After incubation, antagonist determination is initiated with addition of 25 μL 1X compound with 3X EC80 agonist using FLIPR. Compound agonist activity is measured on a FLIPR Tetra. Calcium mobilization is monitored for 2 minutes with a 5 second baseline read. FLIPR read-Area under the curve is calculated for the two minute read. Compound activity is analyzed using CBIS data analysis suite (ChemInnovation, CA). Percentage activity is calculated as 100% x (mean RFU of test sample - mean RFU of vehicle control) / (mean MAX RFU control ligand - mean RFU of vehicle control). For antagonist mode assays, percentage inhibition is calculated as 100% x (1 - (mean RFU of test sample - mean RFU of vehicle control) / (mean RFU of EC80 control - mean RFU of vehicle control)). MAO-A Inhibition Assay MAO-A and test compounds are preincubated at 37°C for 15 minutes before substrate addition. Test compounds are assayed at 10 concentrations with the highest concentration either 30 or 10 µM and subsequent concentrations using a 0.33 dilution factor. The reaction is initiated by addition of kynuramine and incubated at 37°C for 30 minutes. The reaction is terminated by addition of NaOH. The amount of 4-hydroquioline formed is determined through spectrofluorimetric readout with the emission detection at 380 nm and excitation wavelength 310 nm. Clorgyline (IC500.00438 µM) is used as a positive control. Nicotinic acetylcholine receptor α4β2 (nAchRa4/b2) Ion Channel Blocking Assay Cell lines are expanded from freezer stocks according to standard procedures. Cells are seeded in a total volume of 20μL into black-walled, clear-bottom, Poly-D-lysine coated 384-well microplates and incubated at 37◦C for the appropriate time prior to testing. Assays are performed in 1X Dye Loading Buffer consisting of 1X Dye, and 2.5 mM freshly-prepared Probenecid when applicable. Test compounds are assayed at 10 concentrations with the highest concentration either 30 or 10 µM and subsequent concentrations using a 0.33 dilution factor. Prior to testing, cells are loaded with dye then incubated for 30-60 minutes at 37°C. For antagonist determination, cells are pre-incubated with sample. Dihydro-β-erythroidine is used as a positive control. Intermediate dilution of sample stocks was performed to generate 2 - 5X sample in assay buffer. After dye loading, cells are moved from the incubator and 10 - 25 μL 2 - 5X sample is added to cells in the presence of EC80 agonist when appropriate. Cells are incubated for 30 minutes at room temperature in the dark to equilibrate plate temperature. Vehicle concentration was 1%. Compound activity is measured on a FLIPRTetra(MDS) and analyzed using CBIS data analysis suite (ChemInnovation, CA). Percentage inhibition is calculated using the following formula: % Inhibition = 100% x (1 - (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of EC80 control - mean RLU of vehicle control)). hSERT release measurement methods Chinese hamster ovary cells expressing human SERT are seeded in Cytostar™ (PerkinElmer) plate with standard culture medium the day before the experiment at a single density (5000 cells / assay). Cells are incubated overnight with 5% CO2 at 37°C. The day of experiment, the medium is replaced by incubation buffer (140mMNaCl, 4.8mM KCl, 1.2mM MgSO4, 0.1 mM KH2PO4, 10 mM HEPES, pH 7.4) with a single concentration of [3H] Serotonin at 150nM. Experiments comparing release in radioligand-free incubation buffer versus incubation buffer containing [3H] Serotonin determine if the latter provides better signal stability. This can be used for experiments. In control wells, the specificity of hSERT uptake is verified by adding the reference control imipramine (100µM). Two control conditions are used: (1) buffer only (with 1% DMSO concentration to match that in the test compound condition) to verify the background level of release; and (2) one reference SERT substrate compound, norfenfluramine, at 100µM, to make it possible to calculate a relative Emax. Pilot studies varying DMSO concentration from 0.1 to 3% can indicate that signal decreases at higher DMSO concentrations but that 1% DMSO retaines good properties. Cells are incubated at room temperature at different incubation times and radioactivity counted. Test compounds are measured at concentrations of 1e-10, 1e-09, 1e-08,1e-07,1e-06, 1e- 05, and 1e-04 M. Each experiment is performed in duplicate (n=2) and results calculated at two inhibition times (60 and 90). hDAT release measurement methods Chinese hamster ovary cells expressing human DAT are seeded in Cytostar™ plate with standard culture medium the day before experiment at one single density (2500 cells / assay). Cells are incubated overnight with 5% CO2 at 37°C. The day of experiment, the medium is replaced by incubation buffer (TrisHCl 5mM, 120mM NaCl, 5.4mM KCl, 1.2mM MgSO4,1.2 mM CaCl2, Glucose 5mM, 7.5 mM HEPES, pH 7.4) with a single concentration of [3H]dopamine at 300nM. Experiments comparing release in radioligand-free incubation buffer versus incubation buffer containing [3H]dopamine can determine if the latter provides better signal stability. This can be used for experiments. In control wells, the specificity of DAT uptake is verified by adding the reference control GBR 12909 (10µM). For all assays, three reference conditions are employed: (1) radioligand-containing buffer only, to verify the control level of release, (2) buffer with 1% DMSO (solvent used to solubilize the test compounds), (3) 100 uM amphetamine (in 1% DMSO) to make it possible to calculate a relative Emax. Cells are incubated at room temperature at different incubation times and radioactivity counted. Test compounds are measured at concentrations of 1e-10, 1e-09, 1e-08,1e-07,1e-06, 1e- 05, and 1e-04 M. Each experiment is performed in duplicate (n=2) and results calculated at two inhibition times (60 and 90). Statistical analysis EC/IC50s are calculated using the R packages drm (to fit the regression model) and LL.4 (to define the structure of the log-logistic regression model). Values are fit to the following function: f(x) = c + (d - c) / (1 + exp(b (log(x) - log(e))) where b = the Hill coefficient, c = minimum value, d = maximum value, and e = EC50/IC50. Values are calculated for both experimental repetitions at both stable inhibition times (60 and 90 minutes), resulting in four estimates for each compound and transporter. These four values are averaged to produce a final estimate for each compound and transporter. Standard errors of the mean are also calculated based on the four values. Example 29 Evaluation of Entactogenic Effect of Decreased Neuroticism The entactogenic effect of decreased neuroticism can be measured as a decrease in social anxiety using the Brief Fear of Negative Evaluation–revised (BFNE) (Carleton et al., 2006, Depression and Anxiety, 23(5), 297-303; Leary, 1983, Personality and Social Psychology bulletin, 9(3), 371-375). This 12-item Likert scale questionnaire measures apprehension and distress due to concerns about being judged disparagingly or with hostility by others. Ratings use a five-point Likert scale with the lowest, middle, and highest values labeled with “much less than normal,” “normal,” and “much more than normal.” The BFNE can be administered before and repeatedly during therapeutic drug effects. Participants are instructed to answer how they have been feeling for the past hour, or otherwise during the effect of the drug. Baseline-subtracted responses are typically used in statistical models. Example 30 Evaluation of Entactogenic Effect of Authenticity The entactogenic effect of authenticity can be measured using the Authenticity Inventory (Kernis & Goldman.2006. Advances in experimental social psychology, 38, 283-357) as modified by Baggott et al (Journal of Psychopharmacology 2016, 30.4: 378-87). Administration and scoring of the instrument is almost identical to that of the BFNE. The Authenticity Inventory consists of the following items, which are each rated on a 1-5 scale, with select items reverse scored as specified by Kernis & Goldman: ● I am confused about my feelings. ● I feel that I would pretend to enjoy something when in actuality I really didn't. ● For better or worse, I am aware of who I truly am. ● I understand why I believe the things I do about myself ● I want the people with whom I am close to understand my strengths. ● I actively understand which of my self-aspects fit together to form my core or true self. ● I am very uncomfortable objectively considering my limitations and shortcomings. ● I feel that I would use my silence or head-nodding to convey agreement with someone else's statement or position even though I really disagreed. ● I have a very good understanding of why I do the things I do. ● I am willing to change myself for others if the reward is desirable enough. ● I would find it easy to pretend to be something other than my true self. ● I want people with whom I am close to understand my weaknesses. ● I find it difficult to critically assess myself. (unchanged) ● I am not in touch with my deepest thoughts and feelings. ● I feel that I would make it a point to express to those I am close with how much I truly care for them. ● I have difficulty accepting my personal faults, so I try to cast them in a more positive way. ● I feel that I idealize the people close to me rather than objectively see them as they truly are. ● If asked, people I am close to could accurately describe what kind of person I am. ● I prefer to ignore my darkest thoughts and feelings ● I am aware of times when I am not being my true self. ● I am able to distinguish the self-aspects that are important to my core or true self from those that are unimportant. ● People close to me would be shocked or surprised if they discovered what I am keeping inside me. ● It is important for me to understand the needs and desires of those with whom I am close. ● I want people close to me to understand the real me, rather than just my public persona or "image". ● I could act in a manner that is consistent with my personally held values, even if others criticized me or rejected me for doing so. ● If a close other and I were in disagreement, I would rather ignore the issue than constructively work it out. ● I feel that I would do things that I don't want to do merely to avoid disappointing people. ● My behavior expresses my values. ● I actively attempt to understand myself as well as possible. ● I feel that I'd rather feel good about myself than objectively assess my personal limitations and shortcomings. ● My behavior expresses my personal needs and desires. ● I have on a "false face" for others to see. ● I feel that I would spend a lot of energy pursuing goals that are very important to other people even though they are unimportant to me. ● I am not in touch with what is important to me. ● I try to block out any unpleasant feelings I have about myself. ● I question whether I really know what I want to accomplish in my lifetime. ● I am overly critical about myself. ● I am in touch with my motives and desires. ● I feel that I would deny the validity of any compliments that I receive. ● I place a good deal of importance on people close to me understanding who I truly am. ● I find it difficult to embrace and feel good about the things I have accomplished. ● If someone pointed out or focused on one of my shortcomings, I would quickly try to block it out of my mind and forget it. ● The people close to me could count on me being who I am, regardless of what setting we were in. ● My openness and honesty in close relationships are extremely important to me. ● I am willing to endure negative consequences by expressing my true beliefs about things. While the present invention is described in terms of particular embodiments and applications, it is not intended that these descriptions in any way limit its scope to any such embodiments and applications, and it will be understood that many modifications, substitutions, changes, and variations in the described embodiments, applications, and details of the invention illustrated herein can be made by those skilled in the art without departing from the spirit of the invention, or the scope of the invention as described in the appended claims.

Claims

xyyyMS I Claim: 1. A compound of formula: V) I) II) or a pharm
Figure imgf000223_0001
wherein: R1A is selected from -H and -OH; R1B is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R1C is selected from -H, -OH, -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R1D is selected from -OH, -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R2D is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3A is selected from -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C4 alkyl; R3B is selected from -H, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3C and R4C are independently selected from -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3D and R4D are independently selected from -H, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl, wherein if R1D is -OH and R2D is CH3, at least one of R3D and R4D is not -H; R3E is selected from -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C2-C4 alkyl; R3F and R4F are independently selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R4E is selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R5A is selected from -H and CH3; R5B is selected from -H and CH3, and at least one of R1B, R3B, and R5B is not CH3; R5C is selected from -H and CH3, wherein if R5C is -H and R1C is -H, OH, or -F, at least one of R3C, and R4C is not CH3; R5D is selected from -H and CH3; R5E is selected from -H and CH3, wherein if R3E is ethyl and R4E is -H, R5E cannot be -H; R5F is selected from -H and CH3, wherein at least one of R3F, R4F, and R5F is not -H; and X is independently selected from -F, -Cl, and -Br.
2. The compound of claim 1 wherein the compound is of formula: II) or a pharmaceutically accept
Figure imgf000224_0001
of.
3. The compound of claim 1 wherein the compound is of formula: V) or a pharmaceutically accepta
Figure imgf000224_0002
of.
4. The compound of claim 1 wherein the compound is of formula: V) or a pharmaceutically acc hereof.
Figure imgf000225_0001
5. The compound of claim 1 wherein the compound is of formula: I) or a pharmaceutically accepta of.
Figure imgf000225_0002
6. The compound of claim 1 wherein the compound is of formula: II) or a pharmaceutically accept
Figure imgf000225_0003
of.
7. The compound of claim 1 wherein the compound is of formula: II) or a pharmaceutically acceptab
Figure imgf000225_0004
.
8. The compound of claim 1 or claim 2, wherein R1A is -H.
9. The compound of claim 1 or claim 2, wherein R1A is -OH.
10. The compound of any one of claims 1, 2, and 8-9, wherein R3A is -CH2OH.
11. The compound of any one of claims 1, 2, and 8-9, wherein R3A is -CH2X, -CHX2, or -CX3.
12. The compound of any one of claims 1, 2, and 8-11, wherein R5A is -H.
13. The compound of any one of claims 1, 2, and 8-11, wherein R5A is -CH3.
14. The compound of claim 1 or claim 3, wherein R1B is -X.
15. The compound of claim 1 or claim 3, wherein R1B is -CH2OH.
16. The compound of any one of claims 1, 3, and 14-15, wherein R3B is H.
17. The compound of any one of claims 1, 3, and 14-15, wherein R3B is -CH2OH, -CH2X, -CHX2, or -CX3.
18. The compound of any one of claims 1, 3, and 14-17, wherein R5B is -H.
19. The compound of any one of claims 1, 3, and 14-17, wherein R5B is -CH3.
20. The compound of claim 1 or claim 4, wherein R1C is -H.
21. The compound of claim 1 or claim 4, wherein R1C is -OH.
22. The compound of any one of claims 1, 4, and 20-21, wherein R5C is -H.
23. The compound of any one of claims 1, 4, and 20-21, wherein R5C is -CH3.
24. The compound of claim 1 or claim 5, wherein R1D is -X.
25. The compound of claim 1 or claim 5, wherein R1D is -OH.
26. The compound of any one of claims 1, 5, and 24-25, wherein R5D is -H.
27. The compound of any one of claims 1, 5, and 24-25, wherein R5D is -CH3.
28. The compound of claim 1 or claim 6, wherein R3E is -CH2OH.
29. The compound of claim 1 or claim 6, wherein R4E is -H.
30. The compound of any one of claims 1, 6, and 28-29, wherein R5E is -H.
31. The compound of any one of claims 1, 6, and 28-29, wherein R5E is -CH3.
32. The compound of claim 1 or claim 7, wherein R3F is -CH2OH.
33. The compound of claim 1 or claim 7, wherein R4F is -H.
34. The compound of any one of claims 1, 7, and 32-33, wherein R5F is -H.
35. The compound of any one of claims 1, 7, and 32-33, wherein R5F is -CH3.
36. The compound of any one of claims 1-35, wherein the compound has entactogenic properties.
37. The compound of any one of claims 1-35, wherein the compound has serotonin-receptor- dependent properties.
38. The compound of any one of claims 1-35, with decreased hallucinogenic effects relative to MDMA.
39. The compound of any one of claims 1-35, with decreased unwanted psychoactive effects relative to MDMA.
40. The compound of any one of claims 1-35, with decreased physiological effects relative to MDMA.
41. The compound of any one of claims 1-35, with decreased abuse potential relative to MDMA.
42. The compound of any one of claims 1-35, with decreased hallucinogenic effects relative to a clinically used 5-HT2A agonist.
43. The compound of any one of claims 1-35, with decreased unwanted psychoactive effects relative to a clinically used 5-HT2A agonist.
44. A compound of formula: A) A) or a pharm
Figure imgf000227_0001
aceut ca y acceptab e sa t or sa t m xture t ereo ; wherein: R1A is selected from -H and -OH; R2B is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C2-C4 alkyl; R1C is selected from -H, -OH, -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R2C is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, - CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R2D is selected from -X, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3A is selected from -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C4 alkyl; R3B is selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3C and R4C are independently selected from -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3D and R4D are independently selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R3E is selected from -CH2OH, -CH2X, -CHX2, -CX3 , -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C2-C4 alkyl; R3F and R4F are independently selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R4E is selected from -H, -CH2OH, -CH2X, -CHX2, -CX3, -CH2CH2OH, -CH2CH2X, -CH2CHX2, -CH2CX3, C3-C4 cycloalkyl, and C1-C4 alkyl; R5A is selected from -H and CH3; R5B is selected from -H and CH3; R5C is selected from -H and CH3, wherein if R5C is -H and R1C is -H, OH, or -F, at least one of R3C, and R4C is not CH3; R5D is selected from -H and CH3; R5E is selected from -H and CH3, wherein if R3E is ethyl and R4E is -H, R5E cannot be -H; R5F is selected from -H and CH3, wherein at least one of R3F, R4F, and R5F is not -H; and X is independently selected from -F, -Cl, and -Br.
45. An enantiomerically enriched mixture of Formula: II); or a pharmaceutic
Figure imgf000228_0001
RB1 is selected from ; R1, R2, and R3 are in g of hydrogen, halogen,
Figure imgf000229_0001
alkyl, aryl, cycloalkyl, haloalkyl, -OP(O)(OR9)2, -SR9, -NR9R10, and -OR9; R4 is selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, -CH2OR11, and -CH2CH2OR11; in certain embodiments R4 is selected from hydrogen, -CH3, -CH2X, -CHX2, -CX3, - CH2CH3, -CH2CH2X, -CH2CHX2, -CH2CX3, -CH2OH, and -CH2CH2OH; in certain embodiments R4 is selected from hydrogen, -CH2X, -CHX2, -CX3, -CH2CH3, -CH2CH2X, -CH2CHX2, -CH2CX3, -CH2OH, and -CH2CH2OH; R5 is selected from hydrogen, C1-C3 alkyl, haloalkyl, -CH2CH2OH, and hydroxyl; R6 is selected from hydrogen, C1-C3 alkyl, haloalkyl, and -CH2CH2OH; each R9, R10, and R11 is independently selected from: hydrogen, alkyl, and haloalkyl; and X is independently selected from -F, -Cl, and -Br.
46. The enantiomerically enriched compound of claim 45 of Formula: I); or a pharmaceutically acceptable s
Figure imgf000229_0002
.
47. The enantiomerically enriched compound of claim 45 of Formula: I); or a pharmaceutically acceptable
Figure imgf000229_0003
48. The enantiomerically enriched compound of any one of claims 45-47, wherein R1 is H or F.
49. The enantiomerically enriched compound of any one of claims 45-48, wherein R2 is H or F.
50. The enantiomerically enriched compound of any one of claims 45-49, wherein R3 is H or F.
51. The enantiomerically enriched compound of any one of claims 45-50, wherein RB1 .
Figure imgf000230_0001
52. The enantiomerically enriched compound of any one of claims 45-50, wherein RB1 is .
53. The enantiomerically enriched compound of claim 45 of Formula:
Figure imgf000230_0002
; or a pharmaceutically a
Figure imgf000230_0003
54. The enantiomerically enriched compound of claim 45 of Formula: ; or a pharmaceutically
Figure imgf000230_0004
55. The enantiomerically enriched compound of claim 45 of Formula: ; or a pharmaceutically
Figure imgf000230_0005
56. The enantiomerically enriched compound of claim 45 of Formula: ; or a pharmaceutically a
Figure imgf000230_0006
57. The enantiomerically enriched compound of claim 45 of Formula:
Figure imgf000230_0007
Figure imgf000231_0001
or a pharmaceutically acceptable salt or salt mixture thereof.
58. The enantiomerically enriched compound of claim 45 of Formula: or a p
Figure imgf000232_0001
59. The enantiomerically enriched compound of claim 57 of Formula:
Figure imgf000232_0002
or a
Figure imgf000233_0001
60. The enantiomerically enriched compound of claim 58 of Formula: or or a
Figure imgf000233_0002
.
61. An enantiomerically enriched compound of formula: ; or a p
Figure imgf000234_0001
62. The enantiomerically enriched compound of any one of claims 45-61, wherein the compound has entactogenic properties.
63. The enantiomerically enriched compound of any one of claims 45-61, wherein the compound has serotonin-receptor-dependent properties.
64. The enantiomerically enriched compound of any one of claims 45-61, with decreased hallucinogenic effects relative to MDMA.
65. The enantiomerically enriched compound of any one of claims 45-61, with decreased unwanted psychoactive effects relative to MDMA.
66. The enantiomerically enriched compound of any one of claims 45-61, with decreased physiological effects relative to MDMA.
67. The enantiomerically enriched compound of any one of claims 45-61, with decreased abuse potential relative to MDMA.
68. The enantiomerically enriched compound of any one of claims 45-61, with decreased hallucinogenic effects relative to a clinically used 5-HT2A agonist.
69. The enantiomerically enriched compound of any one of claims 45-61, with decreased unwanted psychoactive effects relative to a clinically used 5-HT2A agonist.
70. The enantiomerically enriched compound of any one of claims 45-61, with decreased physiological effects relative to a clinically used 5-HT2A agonist.
71. The compound or enantiomerically enriched compound of any one of claims 1-61 that shows the therapeutic effect of emotional openness.
72. The compound or enantiomerically enriched compound of any one of claims 1-61 wherein the pharmaceutically acceptable salt(s) is selected from HCl, sulfate, aspartate, saccharate, fumarate, succinate, phosphate, oxalate, acetate, amino acid anion, gluconate, maleate, malate, citrate, mesylate, nitrate or tartrate, or a mixture thereof.
73. The compound or enantiomerically enriched compound of claim 71 that is also a serotonin reuptake inhibitor.
74. The compound or enantiomerically enriched compound of any one of claims 1-35 or 45-61 that has minimal or no direct agonism of 5-HT2A.
75. The compound or enantiomerically enriched compound of any one of claims 1-35 or 45-61 that is a direct 5-HT2A agonist.
76. The compound or enantiomerically enriched compound of any one of claims 1-35 or 45-61 that is a serotonin releaser.
77. The compound or enantiomerically enriched compound of any one of claims 1-35 or 45-61 that is both a direct 5-HT2A agonist and a serotonin releaser.
78. The compound or enantiomerically enriched compound of any one of claims 1-35 or 45-61 that is a psychoplastogen.
79. The compound of any one of claims 1-35, wherein the compound is an enantiomerically enriched mixture or pure enantiomer or a pharmaceutically acceptable salt or salt mixture thereof.
80. The enantiomerically enriched compound of any one of claims 45-61, wherein the compound is an enantiomerically enriched mixture or pure enantiomer or a pharmaceutically acceptable salt or salt mixture thereof.
81. The enantiomerically enriched mixture or pure enantiomer of claim 79 or 80, wherein the compound has entactogenic properties.
82. The enantiomerically enriched mixture or pure enantiomer of claim 79 or 80, wherein the compound has serotonin-receptor-dependent properties.
83. The enantiomerically enriched mixture or pure enantiomer of claim 79 or 80, with decreased hallucinogenic effects relative to MDMA.
84. The enantiomerically enriched mixture or pure enantiomer of claim 79 or 80, with decreased unwanted psychoactive effects relative to MDMA.
85. The enantiomerically enriched mixture or pure enantiomer of claim 79 or 80, with decreased physiological effects relative to MDMA.
86. The enantiomerically enriched mixture or pure enantiomer of claim 79 or 80, with decreased abuse potential relative to MDMA.
87. The enantiomerically enriched mixture or pure enantiomer of claim 79 or 80, with decreased hallucinogenic effects relative to a clinically used 5-HT2A agonist.
88. The enantiomerically enriched mixture or pure enantiomer of claim 79 or 80, with decreased unwanted psychoactive effects relative to a clinically used 5-HT2A agonist.
89. The enantiomerically enriched mixture or pure enantiomer of claim 79 or 80, with decreased physiological effects relative to a clinically used 5-HT2A agonist.
90. The enantiomerically enriched mixture or pure enantiomer any one of claims 78-88 that shows the therapeutic effect of emotional openness.
91. The enantiomerically enriched mixture or pure enantiomer any one of claims 78-90 wherein the pharmaceutically acceptable salt(s) is selected from HCl, sulfate, aspartate, saccharate, fumarate, succinate, phosphate, oxalate, acetate, amino acid anion, gluconate, maleate, malate, citrate, mesylate, nitrate or tartrate, or a mixture thereof.
92. The enantiomerically enriched mixture or pure enantiomer of any one of claims 78-91 that is also a serotonin reuptake inhibitor.
93. The enantiomerically enriched mixture or pure enantiomer of any one of claims 78-91 that has minimal or no direct agonism of 5-HT2A.
94. The enantiomerically enriched mixture or pure enantiomer of any one of claims 78-91 that is a direct 5-HT2A agonist.
95. The enantiomerically enriched mixture or pure enantiomer of any one of claims 78-91 that is a serotonin releaser.
96. The enantiomerically enriched mixture or pure enantiomer of any one of claims 78-91 that is both a direct 5-HT2A agonist and a serotonin releaser.
97. The enantiomerically enriched mixture or pure enantiomer of any one of claims 78-91 that is a psychoplastogen.
98. The enantiomerically enriched mixture or pure enantiomer of any one of claims 78-97 wherein the enantiomerically enriched mixture or pure enantiomer is an enantiomerically enriched mixture.
99. A method for treating a central nervous system disorder comprising administering an effective amount of a compound, pure enantiomer, or enantiomerically enriched mixture of any one of claims 1-98 to a host in need thereof.
100. The method of claim 99 wherein the central nervous system disorder is selected from: post- traumatic stress disorder, depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic, adjustment disorder, feeding and eating disorders, binge behaviors, body dysmorphic syndromes, addiction, drug abuse or dependence disorders, substance use disorders, disruptive behavior disorders, impulse control disorders, gaming disorders, gambling disorders, memory loss, dementia of aging, attention deficit hyperactivity disorder, personality disorders, attachment disorders, autism, dissociative disorders and headache disorders.
101. The method of claim 99 or 100 wherein the host is a human.
102. The method of any one of claims 99-101 wherein the central nervous system disorder is post-traumatic stress disorder.
103. The method of any one of claims 99-101 wherein the central nervous system disorder is adjustment disorder.
104. The method of any one of claims 99-101 wherein the central nervous system disorder is generalized anxiety.
105. The method of any one of claims 99-101 wherein the central nervous system disorder is social anxiety.
106. The method of any one of claims 99-101 wherein the central nervous system disorder is depression.
107. The method of any one of claims 99-101 wherein the central nervous system disorder is a substance use disorder.
108. The method of any one of claims 99-101 wherein the central nervous system disorder is an attachment disorder.
109. The method of any one of claims 99-101 wherein the central nervous system disorder is schizophrenia.
110. The method of any one of claims 99-101 wherein the central nervous system disorder is a headache disorder.
111. The method of any one of claims 99-101 wherein the central nervous system disorder is an eating disorder.
112. The method of claim 111 wherein the eating disorder is bulimia.
113. The method of claim 111 wherein the eating disorder is binge eating.
114. The method of claim 111 wherein the eating disorder is anorexia.
115. The method of any one of claims 99-101 wherein the central nervous system disorder is a neurological disorder.
116. The method of claim 115 wherein the neurological disorder is stroke.
117. The method of claim 115 wherein the neurological disorder is brain trauma.
118. The method of claim 115 wherein the neurological disorder is dementia.
119. The method of claim 115 wherein the neurological disorder is a neurodegenerative disease or disorder.
120. The method of claim 119 wherein the neurodegenerative disease or disorder is selected from: Alzheimer’s disease, mild cognitive impairment (MCI), Parkinson’s disease, Parkinson's disease dementia, multiple sclerosis, adrenoleukodystrophy, AIDS dementia complex, Alexander disease, Alper's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy, Canavan disease, cerebral amyloid angiopathy, cerebellar ataxia, Cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, diffuse myelinoclastic sclerosis, fatal familial insomnia, Fazio-Londe disease, Friedreich's ataxia, frontotemporal dementia or lobar degeneration, hereditary spastic paraplegia, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Lyme disease, Machado-Joseph disease, motor neuron disease, Multiple systems atrophy, neuroacanthocytosis, Niemann-Pick disease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateral sclerosis including its juvenile form, progressive bulbar palsy, progressive supranuclear palsy, Refsum's disease including its infantile form, Sandhoff disease, Schilder's disease, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski disease, subacute combined degeneration of the spinal cord, survival motor neuron spinal muscular atrophy, Tabes dorsalis, Tay-Sachs disease, toxic encephalopathy, transmissible spongiform encephalopathy, Vascular dementia, X-linked spinal muscular atrophy, synucleinopathy, progranulinopathy, tauopathy, amyloid disease, prion disease, protein aggregation disease, and movement disorder.
121. The method of any one of claims 99-120 wherein the compound, pure enantiomer, or enantiomerically enriched mixture is administered in a clinical setting.
122. The method of any one of claims 99-120 wherein the compound, pure enantiomer, or enantiomerically enriched mixture is administered in an at-home setting.
123. The method of any one of claims 99-120 wherein the compound, pure enantiomer, or enantiomerically enriched mixture is administered during a psychotherapy session.
124. The method of any one of claims 99-120 wherein the compound, pure enantiomer, or enantiomerically enriched mixture is administered during a counseling session.
125. A pharmaceutical composition comprising an effective patient-treating amount of a compound, pure enantiomer, or enantiomerically enriched mixture of any one of claims 1-98 and a pharmaceutically acceptable carrier or excipient.
126. A pharmaceutical composition comprising an effective patient-treating amount of a pure enantiomer, or enantiomerically enriched mixture of ; and a
Figure imgf000239_0001
127. The pharmaceutical composition of claim 125 or 126 wherein the composition is administered systemically.
128. The pharmaceutical composition of claim 125 or 126 wherein the composition is administered orally.
129. The pharmaceutical composition of claim 125 or 126 wherein the composition is administered to mucosal tissue.
130. The pharmaceutical composition of claim 125 or 126 wherein the composition is administered rectally.
131. The pharmaceutical composition of claim 125 or 126 wherein the composition is administered topically.
132. The pharmaceutical composition of claim 125 or 126 wherein the composition is administered subcutaneously.
133. The pharmaceutical composition of claim 125 or 126 wherein the composition is administered intravenously.
134. The pharmaceutical composition of claim 125 or 126 wherein the composition is administered intramuscularly.
135. The pharmaceutical composition of claim 125 or 126 wherein the composition is administered via inhalation.
136. The pharmaceutical composition of claim 128 wherein the composition is administered as a tablet.
137. The pharmaceutical composition of claim 128 wherein the composition is administered as a gelcap.
138. The pharmaceutical composition of claim 128 wherein the composition is administered as a capsule.
139. The pharmaceutical composition of claim 128 wherein the composition is administered as an aqueous emulsion.
140. The pharmaceutical composition of claim 128 wherein the composition is administered as an aqueous solution.
141. The pharmaceutical composition of claim 128 wherein the composition is administered as a pill.
142. The pharmaceutical composition of claim 129 wherein the composition is administered as a buccal tablet.
143. The pharmaceutical composition of claim 129 wherein the composition is administered as a sublingual tablet.
144. The pharmaceutical composition of claim 129 wherein the composition is administered as a sublingual strip.
145. The pharmaceutical composition of claim 129 wherein the composition is administered as a sublingual liquid.
146. The pharmaceutical composition of claim 129 wherein the composition is administered as a sublingual spray.
147. The pharmaceutical composition of claim 129 wherein the composition is administered as a sublingual gel.
148. The pharmaceutical composition of claim 131 wherein the composition is administered as a cream.
149. The pharmaceutical composition of claim 131 wherein the composition is administered as a topical solution.
150. The pharmaceutical composition of claim 133 wherein the composition is administered as an aqueous solution.
151. The pharmaceutical composition of claim 135 wherein the composition is administered as a powder.
152. The pharmaceutical composition of claim 135 wherein the composition is administered as an aerosol.
153. A compound, pure enantiomer, or enantiomerically enriched mixture or pharmaceutical composition thereof according to any one of claims 1-98 and 125-152 for use in the treatment of a central nervous system disorder in a host.
154. The compound, pure enantiomer, enantiomerically enriched mixture, pharmaceutically acceptable salt, or pharmaceutical composition of claim 153 for use in the treatment of a central nervous system disorder selected from: post-traumatic stress disorder, depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic, adjustment disorder, feeding and eating disorders, binge behaviors, body dysmorphic syndromes, addiction, drug abuse or dependence disorders, substance use disorders, disruptive behavior disorders, impulse control disorders, gaming disorders, gambling disorders, memory loss, dementia of aging, attention deficit hyperactivity disorder, personality disorders, attachment disorders, autism, a dissociative disorder, and a headache disorder in a host in need thereof.
155. The compound, pure enantiomer, or enantiomerically enriched mixture for use of either of claims 153 or 154 wherein the host is a human.
156. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-155 wherein the central nervous system disorder is an anxiety disorder.
157. The compound, pure enantiomer, or enantiomerically enriched mixture for use of claim 156 wherein the anxiety disorder is generalized anxiety.
158. The compound, pure enantiomer, or enantiomerically enriched mixture for use of claim 156 wherein the anxiety disorder is social anxiety.
159. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-155 wherein the central nervous system disorder is depression.
160. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-155 wherein the central nervous system disorder is post-traumatic stress disorder.
161. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-155 wherein the central nervous system disorder is adjustment disorder.
162. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-155 wherein the central nervous system disorder is a substance use disorder.
163. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-155 wherein the central nervous system disorder is an attachment disorder.
164. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-155 wherein the central nervous system disorder is schizophrenia.
165. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-155 wherein the central nervous system disorder is an anxiety disorder.
166. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-155 wherein the central nervous system disorder is an eating disorder.
167. The compound, pure enantiomer, or enantiomerically enriched mixture for use of claim 166 wherein the eating disorder is bulimia.
168. The compound, pure enantiomer, or enantiomerically enriched mixture for use of claim 166 wherein the eating disorder is binge eating.
169. The compound, pure enantiomer, or enantiomerically enriched mixture for use of claim 166 wherein the eating disorder is anorexia.
170. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-155 wherein the central nervous system disorder is a neurological disorder.
171. The compound, pure enantiomer, or enantiomerically enriched mixture for use of claim 170 wherein the neurological disorder is stroke.
172. The compound, pure enantiomer, or enantiomerically enriched mixture for use of claim 170 wherein the neurological disorder is brain trauma.
173. The compound, pure enantiomer, or enantiomerically enriched mixture for use of claim 170 wherein the neurological disorder is dementia.
174. The compound, pure enantiomer, or enantiomerically enriched mixture for use of claim 170 wherein the neurological disorder is a neurodegenerative disease or disorder.
175. The compound, pure enantiomer, or enantiomerically enriched mixture for use of claim 174 wherein the neurodegenerative disease or disorder is selected from: Alzheimer’s disease, mild cognitive impairment (MCI), Parkinson’s disease, Parkinson's disease dementia, multiple sclerosis, adrenoleukodystrophy, AIDS dementia complex, Alexander disease, Alper's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy, Canavan disease, cerebral amyloid angiopathy, cerebellar ataxia, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, diffuse myelinoclastic sclerosis, fatal familial insomnia, Fazio-Londe disease, Friedreich's ataxia, frontotemporal dementia or lobar degeneration, hereditary spastic paraplegia, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Lyme disease, Machado-Joseph disease, motor neuron disease, Multiple systems atrophy, neuroacanthocytosis, Niemann-Pick disease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateral sclerosis including its juvenile form, progressive bulbar palsy, progressive supranuclear palsy, Refsum's disease including its infantile form, Sandhoff disease, Schilder's disease, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski disease, subacute combined degeneration of the spinal cord, survival motor neuron spinal muscular atrophy, Tabes dorsalis, Tay-Sachs disease, toxic encephalopathy, transmissible spongiform encephalopathy, Vascular dementia, X-linked spinal muscular atrophy, synucleinopathy, progranulinopathy, tauopathy, amyloid disease, prion disease, protein aggregation disease, and movement disorder.
176. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-175 wherein the compound or enantiomerically enriched mixture is administered in a clinical setting.
177. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-175 wherein the compound or enantiomerically enriched mixture is administered in an at-home setting.
178. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-175 wherein the compound or enantiomerically enriched mixture is administered during a psychotherapy session.
179. The compound, pure enantiomer, or enantiomerically enriched mixture for use of any one of claims 153-175 wherein the compound or enantiomerically enriched mixture is administered during a counseling session.
180. Use of a compound, pure enantiomer, or enantiomerically enriched mixture or pharmaceutical composition thereof according to any one of claims 1-98 and 125-152 in the treatment of a central nervous system disorder in a host.
181. The use of claim 180 wherein the central nervous system disorder is selected from: post- traumatic stress disorder, depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic, adjustment disorder, feeding and eating disorders, binge behaviors, body dysmorphic syndromes, addiction, drug abuse or dependence disorders, substance use disorders, disruptive behavior disorders impulse control disorders, gaming disorders, gambling disorders, memory loss, dementia of aging, attention deficit hyperactivity disorder, personality disorders, attachment disorders, autism, a dissociative disorder, and a headache disorder.
182. Use of a compound, pure enantiomer, or enantiomerically enriched mixture or pharmaceutical composition thereof according to any one of claims 1-98 and 125-152 in the manufacture of a medicament for the treatment of a central nervous system disorder in a host.
183. The use of any one of claims 180-182 wherein the central nervous system disorder is selected from: post-traumatic stress disorder, depression, dysthymia, anxiety, generalized anxiety, social anxiety, panic, adjustment disorder, feeding and eating disorders, binge behaviors, body dysmorphic syndromes, addiction, drug abuse or dependence disorders, substance use disorders, disruptive behavior disorders, impulse control disorders, gaming disorders, gambling disorders, memory loss, dementia of aging, attention deficit hyperactivity disorder, personality disorders, attachment disorders, autism, a dissociative disorder, and a headache disorder.
184. The use of any one of claims 180-183 wherein the host is a human.
185. The use of any one of claims 180-184 wherein the central nervous system disorder is an anxiety disorder.
186. The use of claim 185 wherein the anxiety disorder is generalized anxiety.
187. The use of claim 185 wherein the anxiety disorder is social anxiety.
188. The use of any one of claims 180-184 wherein the central nervous system disorder is depression.
189. The use of any one of claims 180-184 wherein the central nervous system disorder is post- traumatic stress disorder.
190. The use of any one of claims 180-184 wherein the central nervous system disorder is adjustment disorder.
191. The use of any one of claims 180-184 wherein the central nervous system disorder is a substance use disorder.
192. The use of any one of claims 180-184 wherein the central nervous system disorder is a headache disorder.
193. The use of any one of claims 180-184 wherein the central nervous system disorder is an eating disorder.
194. The use of claim 193 wherein the eating disorder is bulimia.
195. The use of claim 193 wherein the eating disorder is binge eating.
196. The use of claim 193 wherein the eating disorder is anorexia.
197. The use of any one of claims 180-184 wherein the central nervous system disorder is a neurological disorder.
198. The use of claim 197 wherein the neurological disorder is stroke.
199. The use of claim 197 wherein the neurological disorder is brain trauma.
200. The use of claim 197 wherein the neurological disorder is dementia.
201. The use of claim 197 wherein the neurological disorder is a neurodegenerative disease or disorder.
202. The use of claim 201 wherein the neurodegenerative disease or disorder is selected from: Alzheimer’s disease, mild cognitive impairment (MCI), Parkinson’s disease, Parkinson's disease dementia, multiple sclerosis, adrenoleukodystrophy, AIDS dementia complex, Alexander disease, Alper's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy, Canavan disease, cerebral amyloid angiopathy, cerebellar ataxia, Cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, diffuse myelinoclastic sclerosis, fatal familial insomnia, Fazio-Londe disease, Friedreich's ataxia, frontotemporal dementia or lobar degeneration, hereditary spastic paraplegia, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Lyme disease, Machado-Joseph disease, motor neuron disease, Multiple systems atrophy, neuroacanthocytosis, Niemann-Pick disease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateral sclerosis including its juvenile form, progressive bulbar palsy, progressive supranuclear palsy, Refsum's disease including its infantile form, Sandhoff disease, Schilder's disease, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski disease, subacute combined degeneration of the spinal cord, survival motor neuron spinal muscular atrophy, Tabes dorsalis, Tay-Sachs disease, toxic encephalopathy, transmissible spongiform encephalopathy, Vascular dementia, X-linked spinal muscular atrophy, synucleinopathy, progranulinopathy, tauopathy, amyloid disease, prion disease, protein aggregation disease, and movement disorder.
203. The compound, pure enantiomer, or enantiomerically enriched mixture of any one of claims 1-98 wherein the compound has both serotonin-receptor dependent and dopamine- receptor-dependent activity.
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