JP6466792B2 - Treatment of Attention Deficit / Hyperactivity Disorder (ADHD) - Google Patents

Description

  The present invention relates to a method of treating attention deficit / hyperactivity disorder (ADHD). More particularly, the invention relates to methods of using carbamate compounds alone or in combination with other pharmaceuticals for the treatment of ADHD.

  ADHD is a chronic developmental disorder and is characterized by attention, suppression of irrelevant stimuli, and / or problems associated with excessive concentration of specific stimuli to the extent that interferes with work or school productivity. The Such disorders were present in 3-10% of children and 1-6% of adults, and 50-66% of children were confirmed to be affected by ADHD (Spencer et al., 2002; Daley, 2004). Children with ADHD are at high risk associated with smoking and drug abuse. Children growing up with ADHD may face academic disabilities, social disabilities and low self-esteem.

  The Diagnostic and Statistical Manual (DMS) Version IV defines five subtypes: patients exhibit more than 6 hyperactivity / impulsive symptoms and less than 6 inattentive symptoms Hyperactivity / impulse predominance; inattention predominance with 6 or more inattentive symptoms and less than 6 hyperactivity / impulsive symptoms; ADHD combined with more than 6 hyperactivity / impulsion and inattention symptoms; Partial remissions that met the criteria but currently present only some disability symptoms; and unless specified, currently all criteria are not met and it is unclear whether the criteria have been met in the past ( Murphy & Adler, 2004). In particular, the reason for the complexity of diagnosing adults is that there is no diagnostic test for ADHD, and other complex conditions, clinical subjective judgments to investigate interference in at least two areas of life, are necessary. This includes the fact that it is not possible to determine the onset of the disease. Symptoms similar to or associated with ADHD include behavioral disorder, rebellious behavioral disorder, major depressive disorder, anxiety disorder, bipolar disorder, learning disorder and drug abuse (Spencer et al., 2002; Daley, 2004).

  There is no well-defined single etiology of ADHD. The pathophysiology of ADHD can be affected by inheritance, prenatal and prenatal risk factors, and neurobiological defects. Tobacco and alcohol exposure increases risk with a 75% genetic component (Spencer et al., 2002). Areas of attentional brain, including prefrontal cortex dominated by dopamine and norepinephrine receptors, are recorded as smaller and less active for ADHD patients compared to catecholamine, dopamine and norepinephrine related controls (Spencer et al., 2002; Grand et al., 2006; Rader et al., 2009).

Treatment of ADHD has been performed primarily with stimulants including a mixture of methylphenidate, dextroamphetamine and stimulants as the primary treatment (Rader et al., 2009). Stimulants do not necessarily last 24 hours just because they are sustained release formulations. Therefore, stimulants must be taken 2-3 times daily, which leads to compliance issues (Daughton & Kratochville, 2009). However, while compliance issues are improved with sustained release formulations by reducing the problem of having to take medicines at school, side effects tend to last until late on the day and are expensive. Stimulants can be abused and may not be ideal for comorbidities including tic disorders (Spencer et al., 2002). Furthermore, in the case of children, it is necessary to observe the children for the effects of stimulants on growth (Daley, 2004) and changes in blood pressure and heart rate (Daughton & Kratochvir, 2009). Other side effects include appetite suppression, weight loss, abdominal pain, headache, irritation, cardiovascular effects, insomnia, skin irritation and rash (Rader et al., 2009).

  Non-stimulation treatment is also effective because it has the advantages of long-term use, low abuse potential, and treatment of comorbidities compared to stimulants (Daley, 2004). Atomoxetine, recognized as a second-line treatment, shows high selectivity for presynaptic norepinephrine transporters, ensuring long-lasting therapeutic effects and low abuse potential for children and adults with ADHD (Rader et al., 2009; Daughton & Kratochville, 2009). However, the effect achieved by atomoxetine did not reach the level of stimulants. In addition, the onset of efficacy is mild and there is a risk of potential interaction with suicidal ideation, jaundice and CYP2D6 substrates.

Tertiary treatment includes tricyclic antidepressants, bupropion, and alpha ₂ agonists (Rader et al., 2009). Tricyclic antidepressants that reabsorb catecholamines have been formulated in ADHD, but TCA action is not selective and has side effects including dry mouth, changes in blood pressure, weight gain, delayed cardiac conduction, and constipation. Bupropion, an antidepressant with dopamine and norepinephrine agonist effects, appears to be effective against ADHD, but despite the high dose, history of seizures and eating disorders, the high risk of drug-induced seizures (Daley, 2004). The side effects of the alpha 2 agonists clonidine and guanfacine are sleepiness, dizziness, dry mouth and orthostatic hypotension, but these drugs are useful for patients with behavioral disorders and prevent insomnia and appetite suppression caused by stimulants. Help weaken (Rader et al., 2009). Although selective serotonin reuptake inhibitors for ADHD have been studied, proof of efficacy has not been promising (Spencer et al., 2002).

  Therefore, there is a need for a treatment for ADHD that can improve efficacy in treating hyperactivity / impulse and inattention symptoms with a lower side effect profile, including greater compliance and potential for abuse.

（式中、
Ｒは、水素原子、炭素原子数１乃至８の低級アルキル基、Ｆ、Ｃｌ、Ｂｒ及びＩから選択されたハロゲン原子原子、炭素原子数１乃至３のアルコキシ基、ニトロ基、ヒドロキシ基、トリフルオロメチル基、及び炭素原子数１乃至３のチオアルコキシ基からなる群から選択され；
ｘは、１乃至３の整数であり、但し、ｘが２又は３の場合、Ｒは同じであっても異なっても良く；
Ｒ₁及びＲ₂は互いに同じであっても異なっても良く、かつ独立して、水素原子、炭素原子数１乃至８の低級アルキル基、アリール基、アリールアルキル基、及び炭素原子数３乃至７のシクロアルキル基からなる群から選択され；
Ｒ₁及びＲ₂は、結合して、水素原子、アルキル基、及びアリール基からなる群から選択
された置換基で置換された５乃至７−員ヘテロ環を形成することができ、上記ヘテロ環化合物は１乃至２個の窒素原子並びに０乃至１個の酸素原子を含み、上記窒素原子はお互いに直接結合してもおらず又は酸素原子とも連結されていない。）で表される化合物又はその薬学的に許容される塩の治療的有効量の投与を含むＡＤＨＤ治療方法に関する。 The present invention provides a mammal in need of treatment with structural formula (1):

(Where
R is a hydrogen atom, a lower alkyl group having 1 to 8 carbon atoms, a halogen atom atom selected from F, Cl, Br and I, an alkoxy group having 1 to 3 carbon atoms, a nitro group, a hydroxy group, trifluoro Selected from the group consisting of a methyl group and a thioalkoxy group having 1 to 3 carbon atoms;
x is an integer from 1 to 3, provided that when x is 2 or 3, R may be the same or different;
R ₁ and R ₂ may be the same or different from each other, and are independently a hydrogen atom, a lower alkyl group having 1 to 8 carbon atoms, an aryl group, an arylalkyl group, and 3 to 7 carbon atoms. Selected from the group consisting of:
R ₁ and R ₂ can combine to form a 5- to 7-membered heterocycle substituted with a substituent selected from the group consisting of a hydrogen atom, an alkyl group, and an aryl group, The compound contains 1 to 2 nitrogen atoms and 0 to 1 oxygen atoms, and the nitrogen atoms are not directly bonded to each other or linked to oxygen atoms. ) Or a pharmaceutically acceptable salt thereof, and a method for treating ADHD.

  In another embodiment, the present invention provides a method for ameliorating symptoms associated with ADHD in a subject, and for a patient in need of this treatment, a compound represented by structural formula (1) or a pharmaceutically acceptable salt thereof Administering a therapeutically effective amount of the salt.

  In yet another embodiment, the present invention provides a method for ameliorating or eliminating the effects of ADHD in a subject, and provides a subject in need of treatment to a compound of formula (1) or a pharmaceutically acceptable salt thereof Administration of a therapeutically effective amount of

  In yet another embodiment, the present invention relates to a pharmaceutical composition for the treatment of ADHD comprising a therapeutically effective amount of a compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

  In another embodiment, the present invention provides a pharmaceutical composition for amelioration of symptoms associated with ADHD in a subject, and therapeutic treatment of a compound represented by formula (1) or a pharmaceutically acceptable salt thereof Contains an effective amount.

  In yet another embodiment, the present invention provides a pharmaceutical composition for ameliorating or eliminating ADHD symptoms in a subject, wherein the compound of formula (1) or a pharmaceutically acceptable salt thereof is therapeutic. Contains an effective amount.

  The compound represented by the structural formula (1) is an enantiomer mixture in which another enantiomer is substantially absent or one of the compounds represented by the structural formula (1) is dominant. One enantiomer predominates to the extent of about 90% or more, preferably to the extent of about 98% or more.

で表される（Ｓ）又は（Ｌ）鏡像体であるか、又は構造式（１ｂ）：

で表される（Ｒ）又は（Ｄ）鏡像体である。 The enantiomer has the structural formula (1a):

(S) or (L) enantiomer represented by the structural formula (1b):

(R) or (D) is an enantiomer.

（式中、Ｒ_x、Ｒ₁及びＲ₂は全て水素原子から選択され、ｘは１である。）で表される。 Preferably, the following formula:

(Wherein R _x , R ₁ and R ₂ are all selected from hydrogen atoms and x is 1).

  Embodiments of the present invention include compounds of Formula 1 that do not exist in other enantiomers, i.e., an enantiomer represented by Formula 1b or an enantiomeric mixture predominately represented by Formula 1b. Including the method of using. (Note: The following amino group attached to the beta carbon in the structural formula of Formula 1b protrudes into the plane of the paper. This is a dextrorotatory (D) enantiomer of absolute configuration (R).)

  The present invention is based in part on the discovery that the phenylalkylaminocarbamate represented by Formula 1 described above has novel and unique pharmacological properties. Such compounds have been shown to have efficacy in treating animal variants associated with ADHD and ADHD for some animal models.

  Although the exact mechanism of action is not well understood, such compounds are known not to act by the same mechanism as many other known therapies for ADHD. For this reason, the compounds of formula 1 are particularly suitable for use as single or additional treatments for ADHD and the symptom variants associated with ADHD.

FIG. 4 shows the effect of test compounds on percent accuracy during phase II conversion training of visual discrimination. FIG. 2 shows the effect of test compounds on the number of sessions required to reach the criteria in phase II conversion training of visual discrimination. It shows the effect of test compound and amphetamine on locomotor activity. Figure 2 shows the effect of test compound or vehicle administration on extracellular dopamine levels in the rat striatum. Figure 2 shows the effect of test compound or vehicle administration on extracellular norepinephrine levels in the prefrontal cortex of rats.

  These and other objects of the invention will be more fully understood from the following detailed description, the drawings and the claims appended hereto.

（式中、
Ｒは、水素原子、炭素原子数１乃至８の低級アルキル基、Ｆ、Ｃｌ、Ｂｒ及びＩから選択されたハロゲン原子、炭素原子数１乃至３のアルコキシ基、ニトロ基、ヒドロキシ基、トリフルオロメチル基、及び炭素原子数１乃至３のチオアルコキシ基からなる群から選択され；
ｘは、１乃至３の整数であり、但し、ｘが２又は３の場合、Ｒは同じであっても異なっても良く；
Ｒ₁及びＲ₂は互いに同じであっても異なっても良く、かつ独立して、水素原子、炭素原子数１乃至８の低級アルキル基、アリール基、アリールアルキル基、及び炭素原子数３乃至７のシクロアルキル基からなる群から選択され；
Ｒ₁及びＲ₂は、結合して、水素原子、アルキル基、及びアリール基からなる群から選択された置換基で置換された５乃至７−員ヘテロ環を形成することができ、上記ヘテロ環化合物は１乃至２個の窒素原子及び０乃至１個の酸素原子を含み、上記窒素原子はお互いに直接連結もしておらず又酸素原子とも連結されていない。）で表される化合物又はそれらの鏡像体、ジアステレオマー、ラセミ体又はその混合物、又は水和物、溶媒和物及び薬学的に許容される塩及びアミドの治療的有効量の治療を必要とする哺乳類への投与を含むＡＤＨＤの治療方法に関する。 The present invention relates to structural formula (1):

(Where
R represents a hydrogen atom, a lower alkyl group having 1 to 8 carbon atoms, a halogen atom selected from F, Cl, Br and I, an alkoxy group having 1 to 3 carbon atoms, a nitro group, a hydroxy group, or trifluoromethyl. Selected from the group consisting of a group and a thioalkoxy group having 1 to 3 carbon atoms;
x is an integer from 1 to 3, provided that when x is 2 or 3, R may be the same or different;
R ₁ and R ₂ may be the same or different from each other, and are independently a hydrogen atom, a lower alkyl group having 1 to 8 carbon atoms, an aryl group, an arylalkyl group, and 3 to 7 carbon atoms. Selected from the group consisting of:
R ₁ and R ₂ can combine to form a 5- to 7-membered heterocycle substituted with a substituent selected from the group consisting of a hydrogen atom, an alkyl group, and an aryl group, The compound contains 1 to 2 nitrogen atoms and 0 to 1 oxygen atoms, and the nitrogen atoms are not directly linked to each other nor to oxygen atoms. Or the enantiomers, diastereomers, racemates or mixtures thereof, or hydrates, solvates and pharmaceutically acceptable salts and amides of the compounds represented by The present invention relates to a method for treating ADHD comprising administration to a mammal.

又は１ｂ：

、又はその鏡像体、ジアステレオマー、ラセミ体又はその混合物、又は水和物、溶媒和物及び薬学的に許容される塩及びアミドからなる群から選択された化合物の使用を含む。 The method can also be represented by the formula 1a:

Or 1b:

Or the use of a compound selected from the group consisting of enantiomers, diastereomers, racemates or mixtures thereof, or hydrates, solvates and pharmaceutically acceptable salts and amides.

In the above formula, R _x , R ₁ and R ₂ are the same as defined above.

  The method also preferably includes the use of D (or dextrorotatory) enantiomers (of absolute configuration R) selected from the group consisting of Formula 1 or enantiomeric mixtures thereof. In the structural formula of Formula 1b, the amino group attached to the beta carbon protrudes into the plane of the paper. This is a dextrorotatory (D) enantiomer of absolute configuration (R).

で表されるように、構造式１においてＲ_x、Ｒ₁及びＲ₂は水素でありｘは１である。 Preferably, the following structural formula:

In the structural formula 1, R _x , R ₁ and R ₂ are hydrogen and x is 1.

  The compound is O-carbamoyl- (D) -phenylalaninol, named (R)-(beta-amino-benzenepropyl) carbamate monohydrochloride. For the enantiomeric mixture, O-carbamoyl- (D) -phenylalaninol preferably predominates to the extent of about 90% or more, more preferably to the extent of about 98% or more. .

  The compound represented by Formula 1 can be synthesized by methods well known to those skilled in the art. Several reaction schemes for the synthesis of compounds of formula (1) have been described in the literature; US Pat. No. 5,705,640, US Pat. No. 5,756,817, US Pat. No. 5,955,499, and US Pat. No. 6,140,532. Representative examples for the preparation of specific compounds and details of the above reaction scheme are described in the following references: US Pat. No. 5,705,640, US Pat. No. 5,756,817, US Pat. No. 5,955,499, and US Pat. No. 6,140,532, All are incorporated herein by reference.

  A salt of the compound of formula (1) can be prepared by treating the compound with an acid (HX) in a suitable solvent or by means well known to those skilled in the art.

  From structure 1, it is clear that some of the compounds of the invention have at least one and more asymmetric carbon atoms. The present invention is intended to include within its scope not only stereochemically pure isomeric forms of the compounds, but also their racemates. Stereochemically pure isomeric forms can be obtained by applying principles known in the art. Diastereoisomers can be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers can be obtained by selective crystallization of diastereomeric salts using optically active acids or bases or by chiral chromatography. Can be separated from each other. Pure stereoisomers can also be synthesized from suitable stereochemically pure starting materials or can be prepared using stereoselective reactions.

During any of the steps for the preparation of the compounds of the invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is described in Protective Groups in Organic Chemistry, ed. J. et al. F. W. McOmie, Plenum Press, 1973; W. Green & P. G. M.M. Wuts, Protective Groups in Org
It can be achieved using conventional protecting groups similar to those described in anic Synthesis, 3rd edition, John Wiley & Sons, 1999. The protecting group can be removed at an appropriate subsequent stage using methods known in the art.

  The present invention is based in part on the discovery that the phenylalkylaminocarbamate represented by Formula 1 described above has novel and unique pharmacological properties. Such compounds have been shown to have the ability to treat ADHD and ADHD-related symptom variants for some animal models.

  Although the exact mechanism of action is not well understood, it is known that such compounds do not act on ADHD by the same mechanism as many other known therapies. For this reason, the compounds of formula 1 are particularly suitable for use as single or additional treatments for ADHD and the symptom variants associated with ADHD.

  Therefore, such compounds are safe to provide enhanced effects alone or in combination with other useful pharmaceuticals and to reduce side effects, which is possible because of the small dose of each drug used. Can be used.

  In one aspect, the present invention relates to a method for treating a subject suffering from ADHD; said method comprising the therapeutically effective amount of one or more carbamate compounds of the present invention or a pharmaceutically acceptable salt thereof. And providing a pharmaceutically acceptable carrier, diluent or excipient.

  In another aspect, the present invention also provides a method for reducing, suppressing or eliminating ADHD symptoms, including hyperactivity / impulse and inattention symptoms in a subject suffering from ADHD, said method Administration to a subject of an effective amount of a carbamate compound of the invention to reduce, inhibit or eliminate.

For convenience of definition, terms used in the detailed description, examples, and appended claims are collected here.

  It is to be understood that the present invention is not limited to the particular methodologies, protocols, animal species or genera, and reagents described, and can be varied. Also, the terms used herein are for the purpose of describing particular embodiments and are not intended to limit the scope of the invention which is limited only by the scope of the appended claims. I want you to understand again.

  As used herein, the term “subject” means an animal, preferably a mammal, and most preferably both men and women, who are the subject of treatment, observation or experimentation.

  As used herein, the term “therapeutically effective amount” refers to a tissue system, animal, or animal that is sought by a researcher, veterinarian, physician or other clinician, including alleviation of one or more signals or symptoms of the disease or disorder being treated. Or the amount of an active compound or drug that elicits a biological or pharmaceutical response in humans.

  The term “prophylactically effective amount” is a pharmaceutical agent that prevents or reduces the risk of the occurrence of a biological or medical event seeking prevention in a tissue, system, animal or human being sought by a researcher, veterinarian, physician or other clinician. Is meant to mean the amount of.

The term “pharmaceutically acceptable salts” refers to non-toxic salts of the compounds used in the present invention and are generally prepared by reacting the free acid with a suitable organic or inorganic base. Examples of such salts are acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, calcium edetate, d-camphorsulfonate , Carbonate, chloride, clavulanate, citrate, dichloride, edetate, edicylate, estratate, esylate, fumarate, glucoceptate, gluconate, glutamate, glycolyl Arsanylate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleic acid Salt, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucinate, napsylate, nitrate, oleate, oxalic acid , Pamoate, palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, basic acetate, succinate, tannate , Tartrate, teolate, tosylate, triethiodide and valerate.

  Thus, as used herein, the term “patient in need of treatment” refers to any mood disorder that can be treated with an antidepressant, or the patient's current clinical condition or prognosis is one or more of formula (1). As described above, including other disorders that may benefit from administration of the represented compound alone or in combination with other therapeutic interventions, including but not limited to other drugs By a subject or patient who currently has or is likely to develop either a symptom or disorder.

  As used herein, the term “treat or treat” refers to reducing; remission; reducing symptoms or allowing a patient to withstand a damage, medical condition, or condition; the rate of degeneration or weakness or worsening of the disease. ADHD damage, medical condition or condition, including certain objective or subjective parameters such as delaying; less exhaustion in the final stages of deterioration; or improving the physical or mental health of a subject; And a sign of successful prevention or amelioration of a variant of ADHD symptoms. The treatment or amelioration of symptoms can be based on objective or subjective parameters including physical examination, neurological examination, and / or psychological results. Thus, the term “treatment” includes administration of a compound or agent of the invention for some form of ADHD treatment for both men and women. In some cases, treatment with the compounds of the present invention can prevent, inhibit, or prevent ADHD progression in combination with other compounds.

  As used herein, the term “therapeutic effect” means effective amelioration or reduction of ADHD symptoms. The term “therapeutically effective amount” as used herein, as described above, is an amount sufficient for one or more compounds of the invention to exhibit a therapeutic effect for a subject or patient in need of ADHD treatment. means.

  The terms “subject” or “patient” are used interchangeably herein, and the term includes mammals, including but not limited to human patients or humans, to whom the compositions of the invention can be administered. Means. The term “mammal” includes not only laboratory animals such as rabbits, rats, and mice, and other animals, but also human patients including both men and women and non-human primates.

  Methods for determining therapeutically and prophylactically effective amounts for immediate pharmaceutical compositions are well known in the art. For example, the compound can be used at an average adult dose in a daily dosage range of about 0.1 mg to 400 mg, usually on a regimen of 1 to 2 times per day. However, the effective amount may vary depending on the specific compound used, the method of administration, the strength of the formulation, the method of administration, and the development of the disease state. In addition, factors associated with the particular patient being treated, including patient age, weight, dietary habits, and time of administration, will result in the need for dosage adjustments.

  The compounds can be administered to a subject by any conventional route of administration including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral. Depending on the route of administration, the compound of formula (1) can be configured in any form. For example, forms suitable for oral administration include solid forms such as pills, gelcaps, tablets, caplets, capsules (including immediate release, timed release and sustained release formulations, respectively), granules, and powders. Forms suitable for oral administration also include liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. In addition, forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

  In order to produce the pharmaceutical composition of the present invention, at least one compound represented by formula (1) or a salt thereof as an active ingredient is intimately mixed with a pharmaceutical carrier by a conventional pharmaceutical compounding technique. Carriers are essential and inert pharmaceutical excipients include, but are not limited to, binders, suspending agents, lubricants, fragrances, sweeteners, preservatives, dyes and coating agents. Any of the common pharmaceutical carriers can be used in preparing compositions for oral dosage form. For example, suitable carriers and additives for liquid oral formulations include water, glycols, oils, alcohols, fragrances, preservatives, colorants, etc .; suitable carriers and additives for solid oral formulations include starch, sugar , Diluents, granulating agents, lubricants, binders, disintegrants and the like. For parenteral use, the carrier will generally contain sterile water, although it may contain other ingredients for purposes such as, for example, solubility aids or for storage. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents and the like can be employed.

  Because of their ease of administration, tablets and capsules represent the most useful oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets can be sugar coated or enteric coated by standard techniques. Suppositories can be made, in which case cocoa butter can be used as a carrier. The tablets or pills can be coated or otherwise formulated to provide a dosage form that provides sustained action benefits. For example, the tablet or pill can comprise an internal dosage and an external dosage component, the latter being in the form of a skin covering the former. The two components can be separated by an enteric layer that prevents degradation in the stomach and allows the internal components to pass through the duodenum without damage or delay release. Various types of materials can be used as such enteric layers or coating agents, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

  The active agent can also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

  Active agents can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are bound. The active agent can also be coupled together with the soluble polymer as a targetable drug carrier. Such polymers may include polyvinyl-pyrrolidone, pyran copolymers, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. it can. In addition, the active agent can be combined with a group of biodegradable polymers useful for achieving controlled release of the drug, for example, polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid co-polymerization A cross-linked or amphiphilic block copolymer of a polymer, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoester, polyacetal, polydihydropyran, polycyanoacrylate and hydrogel.

  Preferably, such compositions are tablets, pills, capsules, powders, granules, sterile parenteral solutions for oral, parenteral, intranasal, sublingual or rectal administration or for administration by inhalation or insufflation. Or a unit dosage form such as a suspension, metered dose aerosol or liquid spray, drop, ampoule, auto-injector or suppository.

  Alternatively, the composition can be made up in a dosage form suitable for once-weekly or monthly administration; for example, an insoluble salt of an active compound such as decanoate can provide a devo formulation for intramuscular injection. Can be applied.

  In the present specification, the pharmaceutical composition contains a large amount of an active ingredient necessary for delivery of an effective amount as described above per dosage unit such as a tablet, capsule, powder, injection, teaspoon full, suppository and the like. be able to. For example, the pharmaceutical compositions herein can contain from about 25 to about 400 mg of active ingredient per dosage unit. Preferably, the range is from about 50 to about 200 mg of active ingredient.

  In some embodiments of the present invention, carbamate compounds suitable for use in the practice of the present invention can be administered alone or concurrently with at least one or more other compounds or therapeutic agents. In this embodiment, the present invention provides a method for treating a patient with ADHD and a variant of symptoms associated with ADHD. The method includes administering to a patient in need of treatment one effective amount of the carbamate compound disclosed herein together with an effective amount of one or more other compounds or therapeutic agents.

  The substituents and substitution patterns on the compounds of the present invention are not limited to the methods disclosed herein, in order to provide compounds that are readily synthesized and chemically stable by techniques known in the art. Can be selected by one skilled in the art.

  The present invention involves the use of an isolated enantiomer of formula 1. In a preferred embodiment, a pharmaceutical composition comprising an isolated S-enantiomer of formula 1 is used to provide an ADHD therapeutic effect to a subject. In another preferred embodiment, a pharmaceutical composition comprising an isolated R-enantiomer of formula 1 is used to provide an ADHD therapeutic effect to a subject.

  The present invention also includes the use of the enantiomeric mixture represented by Formula 1. In one embodiment of the present invention, a type of enantiomer can predominate. One type of enantiomer that predominates in the mixture is one that is present in the mixture in an amount greater than any other enantiomer present in the mixture, for example, greater than 50%. In one embodiment, a type of enantiomer is on the order of 90% or on the order of 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% or more. Can prevail until. In a preferred embodiment, the predominant enantiomer in a composition comprising a compound represented by Formula 1 is an S-enantiomer represented by Formula 1.

  The present invention provides a method using an enantiomer and a mixture of enantiomers of the compound represented by Formula 1. The carbamate enantiomer of formula 1 contains a chiral center on the second aliphatic carbon adjacent to the phenyl ring.

An isolated enantiomer is one in which the corresponding enantiomer is substantially absent. Thus, an isolated enantiomer refers to a compound that has been separated by separation techniques or has been prepared such that there is no corresponding enantiomer. As used herein, the term “substantially absent” means that the compound is composed of a very large proportion of a single enantiomer. In a preferred embodiment, the compound comprises at least about 90% by weight of a preferred type of enantiomer. In another embodiment of the invention, the compound comprises at least about 99% by weight of a preferred enantiomer. Preferred enantiomers are isolated from racemic mixtures by methods known to those skilled in the art, including high performance liquid chromatography (HPLC) and chiral salt formation and crystallization, or disclosed herein. Can be manufactured by different methods.

Carbamate compounds as drugs:
The present invention provides racemic mixtures, enantiomeric mixtures and isolated enantiomers of formula 1 as drugs. The carbamate compound is formulated as a drug to provide an anti-ADHD action to a subject.

  In general, the carbamate compounds of the invention include oral, buccal, topical, systemic (eg, by transdermal, nasal, or suppository), or parenteral (eg, intramuscular, subcutaneous, or intravenous injection). It can be administered as a pharmaceutical composition by certain methods known in the art for administration of therapeutic agents. The method of directly administering the above compound to the nervous system can be carried out by intracranial or intervertebral needle or catheter delivery with or without a pump device, for example, intracerebral, intraventricular, intraventricular, subarachnoid, intracapsular, Administration of the intraspinal or perispinal route can be included.

The composition may be in the form of a tablet, pill, capsule, semi-solid, powder, sustained release formulation, solution, suspension, emulsion, syrup, elixir, aerosol or other suitable composition and of the present invention At least one of the compounds comprises a combination with at least one pharmaceutically acceptable excipient. Suitable excipients are well known to those skilled in the art, and methods of combining them with compositions are described in Alfonso AR: Remington's Pharmaceutical Sciences , 17th ed. , Mack Publishing Company, Easton PA, 1985, the entire contents and purpose of which are incorporated herein by reference. Suitable liquid carriers, particularly for injectable solutions, include water, aqueous brine, aqueous dextrose solution and glycol.

  The carbamate compound can be provided as an aqueous suspension. The aqueous suspension of the present invention may comprise a carbamate compound with excipients suitable for the manufacture of the aqueous suspension. Such excipients include, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum and natural phospholipids (eg lecithin), alkylene oxides and fatty acids (For example, polyoxyethylene stearate), a condensate of ethylene oxide with a long-chain aliphatic alcohol (for example, heptadecaethyleneoxycetanol), a condensate of ethylene oxide with a fatty acid and a partial ester derived from hexitol (for example, Polyoxyethylene sorbitol mono-oleate) or a condensate of ethylene oxide with a partial ester derived from fatty acid and hexitol anhydride (for example, polyoxyethylene sorbitan mono- Reeto) may contain dispersing or wetting agents such as.

  The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, at least one colorant, one or more fragrances, and sucrose, aspartame or saccharin. At least one sweetener may be included. The osmotic concentration of the formulation can be adjusted.

The oil suspension for use in the method of the present invention is obtained by suspending the carbamate compound in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Can be blended. The oil suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as glycerol, sorbitol or sucrose may be added to provide a palatable oral preparation. Such formulations may be preserved by adding an antioxidant such as ascorbic acid.
Examples of injectable oil vehicles include Minto, J. et al. Pharmacol. Exp. Ther. 281: 93-102, 1997 can be referred to. The pharmaceutical formulation of the present invention may be in the form of an oil-in-water emulsion. The oil phase may be the above-mentioned dietary oil or mineral oil, or a mixture thereof.

  Suitable emulsifying agents include natural gums such as gum acacia and gum tragacanth, natural phospholipids such as soy lecithin, esters or partial esters derived from hexitol anhydrides such as fatty acids and sorbitan mono-oleate, and Includes condensation products of partial esters and ethylene oxide such as polyoxyethylene sorbitan mono-oleate. The emulsion may also contain sweetening and flavoring agents, such as blends of syrups and elixirs. The formulation may contain a relaxation agent, preservative or coloring agent.

  The selected compounds may be made alone or in combination with other suitable ingredients into aerosol formulations to be administered by inhalation (ie, they may be nebulized to be administered by inhalation). The aerosol formulation can be contained within a pressurized acceptable propellant such as dichlorodifluoromethane, propane, nitrogen and the like.

  For example, formulations of the present invention suitable for parenteral administration such as intra-articular, intravenous, intramuscular, intraepidermal, intraperitoneal, and subcutaneous routes include antioxidants, buffers, bacterial growth inhibitors, and Water-soluble and water-insoluble isotonic sterile injection solutions that can contain solutes that render the formulation isotonic with the recipient's blood, suspending agents, solubilizers, thickeners, Water-soluble or water-insoluble isotonic sterile suspensions which may contain stabilizers and preservatives. Among the acceptable vehicles and solvents that may be employed are water and Ringer's solution, an isotonic saline solution. In addition, sterile fixed oils can usually be used as a solvent or suspending medium. For this purpose, mixed fixed oils containing synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid may be used to produce an injectable material. Such solutions are sterilized and generally free of undesirable materials.

  If the above compounds are sufficiently soluble, they can be dissolved directly in physiological saline with or without the use of a suitable organic solvent such as propylene glycol or polyethylene glycol. Finely dispersed dispersants of the compound can be made of a suitable oil such as aqueous starch or sodium carboxymethylcellulose solution, or peanut oil. Such formulations can be sterilized by conventional, well-known sterilization techniques. In order to approximate the physiological condition, the above-mentioned formulation may be used as necessary, for example, pH adjusting agents and buffers such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. Such pharmaceutically acceptable auxiliary substances may be included.

  The concentration of the carbamate compound in such formulations may vary widely and may be selected based primarily on flow rate, viscosity, weight, etc., depending on the particular method of administration selected and patient requirements. For IV administration, the formulation may be a sterile injectable, such as a sterile injectable aqueous or oleaginous suspension. The suspension can be formulated by known techniques using these suitable dispersing or wetting agents and suspending agents. The sterile injection may also be a sterile injection solution or suspension in a non-toxic parenterally acceptable diluent or solvent such as a solution of 1,3-butanediol. Recommended formulations may be presented in single-dose or multi-dose sealed containers such as ampoules and vials. Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

Carbamate compounds suitable for use in the practice of the present invention are preferably administered orally. The amount of the compound of the invention in the composition can vary depending on the form of the composition, the size of the unit dosage, the type of excipient, and other factors well known to those skilled in the art. . Generally, the final composition comprises, for example, 0.000001% by weight (% w) to 50% w, preferably 0.00001% w to 25% w carbamate compound as an excipient or excipient. May be included with some residue.

  Pharmaceutical formulations for oral administration may be formulated with pharmaceutically acceptable carriers well known in the art at dosages suitable for oral administration. The carrier is formulated into a unit dosage form suitable for ingestion by the patient, such as a tablet, pill, powder, dragee, capsule, liquid, troche, gel, syrup, slurry, suspension, etc. It is possible to

  Formulations suitable for oral administration are (a) a liquid solution such as an effective amount of a pharmaceutical formulation suspended in a diluent such as water, saline or polyethylene glycol (PEG) 400; (b) predetermined. Capsules, sachets or tablets each containing a quantity of active ingredient as a liquid, solid, granule or gelatin; (c) a suspension in a suitable liquid; and (d) a suitable emulsion.

  Oral pharmaceutical preparations are prepared by mixing the compound of the invention with a solid excipient, optionally grinding the resulting mixture, and optionally adding a suitable additional compound to obtain a tablet or dragee core. Once added, it can be obtained by processing the mixture of granules. Suitable solid excipients are carbohydrates or protein fillers and sugars including lactose, sucrose, mannitol or sorbitol; starch derived from corn, wheat, rice, potato or other plants; methylcellulose, hydroxymethylcellulose, hydroxypropylmethyl -Cellulose, such as cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; and proteins such as but not limited to gelatin and collagen.

  If desired, disintegrating or solubilizing agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof such as sodium alginate. Tablet forms include one or more lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other Excipients, colorants, fillers, binders, diluents, buffers, wetting agents, preservatives, fragrances, dyes, disintegrants, and pharmaceutically compatible carriers may be included. A lozenge form can contain the active ingredient in a flavoring preparation such as sucrose, and the like and gelatin and glycerin or sucrose and acacia emulsions, gels and the like that contain carriers in addition to the active ingredient A pastille containing the active ingredient in an inert base may be included.

  The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. Such formulations are solid at normal temperature but liquid at rectal temperature, so they are manufactured by mixing the drug with a suitable non-irritating excipient that melts in the rectum to release the drug. good. Such materials are cocoa butter and polyethylene glycol.

  The compounds of the present invention may be administered by intranasal, intraocular, intravaginal and rectal routes including suppositories, inhalations, powders and aerosol formulations (as examples of steroid inhalers, Rohatagi, J. Clin. Pharmacol). 35: 1187-1193, 1995; see Tjwa, Ann. Allergy Asthma Immunol. 75: 107-111, 1995).

  The compounds of the present invention may be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols and delivered transdermally via a topical route. it can.

  Encapsulating materials can be used with the compounds of the present invention, and the term “composition” can include as a formulation an active ingredient associated with the encapsulating material, with or without other carriers. For example, the compounds of the present invention can be delivered as microspheres for slow release in the body. In one embodiment, the microspheres may be administered by intradermal injection of a microsphere-containing drug (eg, mifepristone), wherein the microspheres are administered subcutaneously as biodegradable and injectable gel formulations (eg, Gao, Pharm). Res.12: 857-863, 1995) or as microspheres for oral administration (see, eg, Eyles, J. Pharm. Pharmacol. 49: 669-674, 1997) (Rao, J. Biomatter Sci.Polym.Ed.7: 623-645, 1995 reference). Both transdermal and intradermal routes can be delivered continuously for weeks or months. Cashew can be used to carry the compounds of the invention.

  In other forms, the compounds of the invention may be fused to cell membranes or by using liposomes that are endocytosed, i.e., bound to cell surface membrane protein receptors to result in endocytosis. It can be transported by using an attached ligand. By using liposomes, it is possible to focus on the delivery of carbamate compounds to target cells in vivo, especially when the liposome surface transports specific ligands to target cells or selectively goes to specific organs ( Al-Muhammed, J. Microencapsul.13: 293-306, 1996; Chon, Curr.Opin.Biotechnol.6: 698-708, 1995; Ostro, Am.J.Hosp.Pharm.46: 1576-1587, 1989 Reference ).

  The pharmaceutical composition of the present invention may be provided as a salt and may be formed with acids including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid and the like. Salts tend to be more soluble in aqueous or other protic solvents that are in the form of the corresponding free base. In other cases, preferred formulations are, for example, lyophilized powders that may contain some or all of the following: histidine 1 mM to 50 mM, sucrose 0.1% to 2%, mannitol 2% to At 7%, pH range 4.5 to 5.5, these are combined with a buffer before use.

  Pharmaceutically acceptable salts are salts that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include salts that can be formed when acidic protons present in the compound can react with inorganic or organic bases. Suitable inorganic salts include, for example, those formed with alkali metals of sodium and potassium, magnesium, calcium and aluminum. Suitable organic salts include, for example, those formed from organic bases such as amine bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. Also, pharmaceutically acceptable salts include amine moieties within the parent compound and inorganic acids (eg, hydrochloride and hydrobromic acid) and organic acids (eg, acetic acid, citric acid, maleic acid, and Acid addition salts formed by the reaction of methanesulfonic acid with alkane- and arene-sulfonic acids such as benzenesulfonic acid) may be included. Where there are two acidic groups, the pharmaceutically acceptable salt may be a mono-acid-mono-salt or di-salt; and similarly, if there are two or more acidic groups, Some or all of these groups may be salified.

  The compounds shown in this invention can be in the unsalted or salified form, and the name of such compound is both the original (non-salted) compound and its pharmaceutically acceptable salt. Intended to include. The present invention includes a pharmaceutically acceptable salt form represented by the chemical formula (1). There can be more than one crystalline form of the enantiomer represented by Formula 1, which is also included in the present invention.

  The pharmaceutical composition of the present invention can optionally further comprise at least one other therapeutic agent useful for the treatment of ADHD in the carbamate compound. For example, carbamate compounds represented by Formula 1 can be physically combined with other ADHD therapeutic agents in a fixed dose combination to facilitate their administration.

Methods for formulating pharmaceutical compositions are described in Pharmaceutical Dosage Forms: Tables. Edited by Lieberman et al. Second Edition. Revised and Expanded. Volumes 1-3, and Pharmaceutical Dosage Forms edited by Avis et al .: Parental Medicines. Volumes 1-2 and Pharmaceutical Dosage Forms : Disperse Systems edited by Lieberman et al. Volumes 1-2. Published in Marquel Deker, Inc., all of which are hereby incorporated by reference.

  In general, the pharmaceutical compositions are sterile, substantially isotonic and formulated in full compliance with the rules of the Good Food Manufacturing Practice (GMP) of the US Food and Drug Administration.

Dosage Plan The present invention provides a method utilizing carbamate compounds to provide anti-ADHD action in mammals. The amount of carbamate compound required to reduce or treat ADHD is defined as a therapeutically or pharmaceutically effective amount. The dosage schedule and the amount effective for the application, i.e., administration or dosage regimen, will depend on various factors including the stage of the disease, the physical condition of the patient, age and the like. The dosage form is also taken into account when calculating the dosage regimen for the patient.

  One skilled in the art can determine the pharmaceutically effective amount of a particular substituted carbamate compound for practicing the present invention without undue experimentation in light of the technology and specification (eg, Lieberman, Pharmaceutical Dosage Forms (see Vols. 1-3, 1992)); Lloyd, 1999, The art, Science and Technology of Pharmaceutical Compounding; and Pickar, 1999, Dosage C). A therapeutically effective amount is one that has a therapeutically beneficial effect that exceeds the toxic or adverse side effects of the active ingredient from a clinical point of view. Furthermore, each specific patient, specific dosage regimen should be gradually evaluated and adjusted according to individual requirements and the professional diagnosis of the person administering or supervising the compound.

  For therapeutic purposes, the compositions or compounds disclosed herein may be administered in a single bolus delivery over a long period of continuous delivery, or repeated administration protocols (eg, repeated every hour, daily or weekly). Protocol). The pharmaceutical formulation of the present invention may be administered, for example, once or more daily, three times a week, or once a week. In one aspect of the invention, the pharmaceutical formulation of the invention is administered orally once or twice daily.

In this context, a therapeutically effective amount of a carbamate compound can include medication that is repeated within a long-term treatment regimen that provides clinically noticeable results for ADHD treatment. Dose determination in this context is generally based on animal model studies involving human clinical trials and effective doses and administration protocols that significantly reduce the onset or severity of targeted signs or symptoms in a subject. Led by measuring. In this regard, suitable models include, for example, murine animals, rats, pigs, cats, non-human primates, and other acceptable animal model patients known in the art. Effective dosages can also be determined using in vitro models (eg, immunological and histopathological assays). Using such a model, the usual calculations and adjustments are made at the appropriate concentration and dose for administering a therapeutically effective amount of the biologically active agent (eg, the nasal cavity to induce the desired response). It is generally required to determine an internal effective amount, an intradermal effective amount, an intravenous effective amount or an intramuscular effective amount.

  In an exemplary embodiment of the invention, a single dosage form of the compound is prepared for a standard dosage regimen. In this manner, the composition can be easily subdivided into smaller doses as directed by a physician. For example, unit dosages may be made up in packaged powders, vials or ampoules, preferably in capsules or tablets.

  The active compound that is such a unit dosage form of the composition may be in an amount of about 10 mg to about 1 g or more for single or multiple daily dosages, eg, depending on the particular needs of the patient. By initiating a treatment regimen with a minimum daily dose of about 1 g, the blood concentration of the carbamate compound can be determined to be lower or higher.

  An effective amount of the carbamate compound of the present invention can be administered, for example, orally or parenterally from about 0.01 mg / kg / dose to about 150 mg / kg / dose. Administration is preferably from about 0.1 mg / kg / dose to about 25 mg / kg / dose, more preferably from about 0.2 mg / kg / dose to about 18 mg / kg / dose. Accordingly, the therapeutically effective amount of the active ingredients contained per dosage unit described herein can be, for example, from about 1 mg / day to about 7000 mg / day for a patient having an average body weight of 70 kg. .

  The methods of the invention also provide kits that are used to provide ADHD treatment. After formulating a pharmaceutical composition comprising one or more other compounds beneficial to and useful for treatment and one or more carbamates of the invention in a suitable carrier, it is placed in a suitable container to treat ADHD May be labeled. In addition, other medications, including at least one other therapeutic agent useful for ADHD treatment, can be placed in the container and labeled for treatment of the indicated disease. Such labels can include, for example, instructions regarding the amount, frequency, and method of administration of each drug.

  The foregoing invention has been described in detail by way of example for purposes of clarity of understanding, and those skilled in the art will recognize that certain variations and modifications can be understood by the present disclosure and not excessively within the scope of the appended claims. It is clear that this can be done without experimentation, indicating that this is for purposes of illustration and not limitation. The following examples are intended to provide an illustration of specific embodiments of the invention and are not limited thereby.

Example 1
A test experiment (O-carbamoyl- (D) -phenylalaninol) was administered at 3, 10 or 30 mg / kg IP to conduct behavioral experiments designed to assess behavioral performance against reversal of visual discrimination. Animals treated with 3.0 or 30.0 mg / kg test compound or amphetamine require fewer attempts to reach a specific baseline level of performance compared to rats treated with vehicle, with superior accuracy I got a score. Thus, the test compound at a specific dose has been shown to improve behavioral performance in the same way as it was obtained with d-amphetamine sulfate.

(Method)
At the start of training, approximately 250 g of 40 adult male Long Evans rats (Charles River Laboratories, Wilmington, Mass.) Were used as subjects in this study. Each transport of rats was sequestered for 5 days prior to introduction into the general population. Prior to the start of operant training, rats were allowed a minimum of an additional week of acclimatization.

  Test compounds 3.0, 10.0 and 30.0 mg / mL were dissolved in sterilized 0.9% saline. D-amphetamine as a comparative compound was prepared by dissolving 1.0 mg / mL of amphetamine salt in 0.9% sterilized physiological saline.

  After operant training began, rats were kept individually in the shed. The opportunity to obtain food was limited to 12-20 g per day to maintain the animals at 85-90% free food weight (compared to unrestricted rats). Rats were continuously supplied with water and continued to gain weight during the experiment.

  After the animals reached training criteria for Phase I of the study (Phase I), they were designated as one of the treatment groups; the group was adapted to performance in Phase I (days to baseline performance). This study was designed to be mixed (dose level x repeated training period). The five dose levels are 1.0, 3 and 10 mg / kg test compound, 0.9 percent saline (vehicle) and 1.0 mg / kg d-amphetamine sulfate (control compound), 1.0 mL. / Kg was all delivered intraperitoneally (IP).

  The animals were trained in a set of 10 operant test chambers (Med Associates) with two retractable reaction levers on the front wall. There were two stimulating lights in the chamber, placed on each lever. The food magazine was placed between the two reaction levers on the front wall, and the food transmission was signaled by the magazine light. The collection of food pellets was detected by a light sensor in the food magazine. The dim lighting of the chamber was provided by a house light on the center of the front wall.

  Initially, animals were adapted to push the lever to eat food. During this phase, both levers extended into the chamber and the animals were rewarded with 45 mg pellets by pushing the levers. Once the opposite lever is pressed more than five times, the use of side bias is suppressed by retracting the lever. After pushing the lever 100 times for 3 consecutive days, the subject was moved to Phase I of the study. In this phase, the animals had to be trained to push the lever under the illumination signal light. During each attempt, one of the signal lights (selected randomly) was irradiated for 1.0 second prior to the presentation of the lever (30.0 second time limit). Pushing the proximal lever after the lever extends into the chamber results in the delivery of food pellets. Pushing the distal lever is signaled by the houselight extinguishing for 5.0 seconds causing a timeout. After a correct or incorrect push or a false push, the lever was retracted during a variable intertrial interval (ITI; 5 seconds +/- 2 seconds). After a stable response in this phase (more than 80% correct for 2 consecutive days), the animals began training in the drug administration portion of the experiment (Phase II).

In Phase II, the animals were divided into 5 groups that were adapted with percent accuracy and number of attempts against criteria. Animals within each group received one of three doses of test compound (3.0, 10.0 or 30.0 mg / kg, IP), amphetamine (1.0 mg) one hour prior to behavioral training. / Kg, IP), or vehicle (saline). The distinction in phase II, contrary to the distinction in phase I, was rewarded by pushing the lever distal to the indicator light. Animals were dosed daily approximately 60 minutes before training. Training continued until all animals achieved 80% correctness for the new distinction for two consecutive days.

  Data was analyzed using SPSS 12.0 for Windows (SPSS, Chicago, Illinois). Mixed group repeated measures ANOVA (mixed group groups repeated measures ANOVA) was performed on the reaction accuracy data. A simple one-way ANOVA was performed in response to an attempt to reference data from Phase II.

(result)
Reaction accuracy. The test compounds resulted in significantly improved performance results for visual discrimination conversion measured with percent accuracy. Mixed design ANOVA showed significant main effects of session (F _19,665 = 365.60, p <0.001) and group (F _4,35 = 3.08, p = 0.028), but more important There was a significant group (F _76,665 = 1.78, p = _0.199 ) due to session interaction. Visual inspection of the graph (see Figure 1) showed that vehicle and test compound 10.0 mg / kg doses were lower than test compound 3.0 and 30.0 doses and d-amphetamine 1.0 mg / kg dose. It shows that.

Session against criteria in Phase II. The test compounds resulted in significantly improved performance results for visual discrimination conversion as measured by the number of sessions required to reach the baseline (see FIG. 2). One-way ANOVA showed the effect of the session (F _4,35 = 4.33, p = 0.006). Paired comparisons (p <0.05) compared to the number of sessions required for animals administered daily doses of test compounds 3.0 and 30.0 or d-amphetamine 1.0 mg / kg, It was confirmed that the vehicle group would require additional attempts to reach the performance level (Note: see star in Figure 2). The group administered 10.0 mg / kg test compound is not different from the vehicle group, but is different from the group administered 30 mg / kg dose of test compound and d-amphetamine. In FIG. 2, “*” indicates p <0.05 compared to vehicle control using LSD pair comparison.

Example 2
Test compounds administered subcutaneously (SC) at 10, 30, and 100 mg / kg have an effect on locomotor activity in wild-type and homozygous mutant dopamine transporter knockout (KO) mice somewhat similar to patients diagnosed with ADHD Evaluated to determine. The test compound selectively reduced KO mouse motility in a dose-dependent manner, indicating that the test compound is highly effective in reducing hyperactivity in dopamine transporter KO mice.

(Method)
Male and female wild-type and homozygous mutant dopamine transporter KO mice (n-10 mice / genotype / reagent) were tested for locomotor activity in the open field after a single injection of vehicle or compound. Mice were placed in the open field for 30 minutes and vehicle (sterile water), amphetamine 2 mg / kg, or three concentrations of test compound (10, 30, 100 mg / kg) were administered to the SC. All drugs were provided in a volume of 5 mL / kg. The animals were returned to the open field for an additional 90 minutes. Spontaneous movements were evaluated with an automated Omnitech Digiscan device (Accumscan Instruments, Columbus, Ohio). Exercise was coordinated at 5 minute intervals for 2 hours during which the test was performed. Horizontal motion and spontaneous motion are measured in terms of cm and the total occupied distance, vertical motion or rising motion is measured in terms of the total number of vertical beam interruptions, and stereotypical motion is measured for a given beam with an interval of less than 1 second. Or, it was quantified under the condition of repeated interruption given to the beams. For analysis, 10WT and 10KO mice were tested in each treatment group with approximately the same number of males and females assigned to each group. Data was analyzed with the Statistical Package for Social Science program (Windows version 11.0; SPSS Science, Chicago, Ill.). Results for each dependent variable were analyzed by repeated variance analysis (RMANOVA) for within-subject comparison effects (group differences over time) and between-subject comparison effects (main effects and interaction test). A Bonferroni corrected pairwise comparison was used as a post-mortem experiment. p <0.05 was considered important.

(result)
Reference value: KO mice showed higher levels of spontaneous, standing up and stereotypic movement compared to WT mice.

  Drug treatment: SC amphetamine 2 mg / kg increased spontaneous, standing up and stereotypic movement in WT mice and decreased them in KO animals compared to each vehicle control group. The test compound reduced exercise in a dose-dependent manner, and the 100 mg / kg dose suppressed exercise more effectively than amphetamine. Referring to FIG. 3, representative, locomotor activity (distance traveled, in centimeters) for amphetamine (AMPH) and the test compound decreased after a 90 minute post-injection period. Standing up and stereotypic behavior showed similar results.

Example 3
Test compounds were tested for binding to dopamine, norepinephrine and serotonin transporters and for effects on dopamine, norepinephrine and serotonin reabsorption. The test compound showed weaker binding to dopamine and norepinephrine transporter and weaker effect on dopamine and norepinephrine reabsorption compared to cocaine.

(Method)
Unknown weights were weighed and dissolved in DMSO to produce 10 or 100 mM stock solutions. Initial dilutions were made to 50 or 500 μM with assay buffer for binding, or 1 or 10 mM with assay buffer for reabsorption. Subsequent dilutions were made with assay buffer supplemented with DMSO to maintain a final concentration of 0.1% DMSO. Pipetting was performed using a Biomek 2000 robot workstation.

Test compound concentration tested Assay concentration range Binding:
hDAT 21.6nM-100μM
hSERT 21.6nM-100μM
hNET 21.6nM-10μM
absorption:
hDAT 31.6nM-10μM
hSERT 31.6nM-100μM
hNET 31.6nM-100μM

Inhibition of [ ¹²⁵ I] RTI-55 radioligand binding to hDAT, hSERT or hNET in clonal cells:

Cell production: HEK293 cells expressing hDAT, hSERT or hNET inserts were cultured on a 150 mm diameter tissue culture dish to 80% confluence and provided as a tissue source. Cell membranes were prepared as follows. The medium was removed from the plate and the plate was washed with 10 mL calcium- and magnesium-free phosphate-buffered saline. Lysis buffer (10 mL; 2 mM HEPES and 1 mM EDTA) was added. After 10 minutes, the cells were scraped from the plate, poured into a centrifuge tube, and centrifuged at 30,000 × g for 20 minutes. The supernatant was removed and the pellet was resuspended with 12-32 mL of 0.32 M sucrose using a polytron at setting 7 for 10 seconds. The resuspension volume was determined by the density of binding sites within the cell line and was selected to reflect less than 10% of total radioactivity.

Analytical conditions: Each analytical tube is 50 μL of membrane preparation (about 10-15 μg protein), 25 μL unknown, compounds used to define non-specific binding, or buffer (Krebs-HEPES, pH 7. 4: Buffered with 25 mM HEPES, NaCl 122 mM, CaCl ₂ 2.5 mM, MgSO ₄ 1.2 mM, Pergillin 10 μM, Tropolone 100 μM, Glucose 0.2% and Ascorbic Acid 0.02%), 25 μL [ ¹²⁵ ] RTI-55 (40-80 pM final concentration) and a sufficient amount of additional buffer to make the final volume 150 μL. Pre-incubate membranes with unknowns for 10 minutes prior to addition of [ ¹²⁵ ] RTI-55. The analysis tube was incubated at 25 ° C. for 90 minutes. Binding is determined by filtration through a GF / C filter using a Tomtec 96-well cell harvester. The filter was washed with ice-cold saline for 6 seconds. Scintillation fluid was added to each square and the radioactivity remaining on the filter was determined using a Wallac μ- or beta-plate reader. Specific binding is defined as the difference in binding observed with or without 5 μM mazindol (HEK-hDAT and HEK-hNET) or 5 μM imipramine (HEK-hSERT). Two or three independent competition experiments were performed in duplicate. GraphPAD Prism was used for data analysis and IC ₅₀ values were converted to K _i values using the Cheng-Prusoff equation (K _i = IC ₅₀ / (1 + ([RTI−55] / K _d RTI− 55))).

Filtration analysis for inhibition of [ ³ H] neurotransmitter absorption in HEK293 cells expressing recombinant biogenic amine transporters:

  Cell production: Cells were cultured to confluence as described above. The medium was removed and the cells were washed twice with phosphate buffered saline (PBS) at room temperature. Following the addition of 3 mL of Krebs-HEPES buffer, the plate was warmed with a greedy at 25 ° C. for 5 minutes. The cells were gently scraped and then powdered using a pipette. Cells from multiple plates were combined. One plate provides sufficient cells for the 48 wells required for the production of data for two complete curves for unknowns.

Absorption inhibition analysis conditions: The above analysis was performed on 96 1-mL vials. Krebs-HEPES (350 μL) and the compound used to define the unknown, nonspecific absorption, or buffer (50 μL) were added to the vial and placed in a 25 ° C. water bath. Specific absorption is defined as the difference in absorption observed with or without 5 μM mazindol (HEK-hDAT and HEK-hNET) or 5 μM imipramine (HEK-hSERT). Cells (50 μL) were added and pre-incubated for 10 minutes for unknown. The analysis began with the addition of [ ³ H] dopamine, [ ³ H] serotonin, or [ ³ H] norepinephrine (50 μL, 20 nM final concentration). Whatman presoaked in 0.05% polyethyleneimine
Absorption was terminated after 10 minutes using filtration with a GF / C filter. IC ₅₀ was calculated by applying the GraphPAD Prism program to a triple curve consisting of each of the six drug concentrations. Two or three independent measurements were made for each curve.

(result)
Effect on radioligand ([ ¹²⁵ I] RTI-55) binding and [ ³ H] dopamine absorption by HEK cells (HEK-hDAT cells) expressing eDNA against human dopamine transporter, HEK expressing eDNA against human serotonin transporter Effect on radioligand ([ ¹²⁵ I] RTI-55) binding and [ ³ H] serotonin absorption by cells (HEK-hSERT cells) and radioactivity by HEK cells (HEK-hNET cells) expressing eDNA for human norepinephrine transporter Test compounds were tested for effects on ligand ([ ¹²⁵ I] RTI-55) binding and [ ³ H] norepinephrine absorption.

In HEK-hDAT cells, the affinity of the compound for the binding site was lower than the affinity of the reference compound cocaine for the same site. The K _i value for the displacement of [ ¹²⁵ I] RTI-55 by the test compound was 14,200 nM, and the K _i value for the cocaine displacement of [ ¹²⁵ I] RTI-55 binding was 236 nM. In the absorption assay, the test compound had an IC ₅₀ value of 2900 nM and was less effective in inhibiting [ ³ H] dopamine absorption compared to the efficacy of cocaine (IC ₅₀ = 385 nM). The Hill coefficient showed a complex interaction with the binding or absorption site (Table 1).

In HEK-hSERT cells, the affinity of the compound for the binding site was lower than the affinity of the reference compound cocaine for the same site. The K _i value for the displacement of [ ¹²⁵ I] RTI-55 by the test compound was 81,500 nM, and the K _i value for the cocaine displacement of the [ ¹²⁵ I] RTI-55 bond was 361 nM. In the absorption analysis, 31,827 had an IC ₅₀ value of more than 100 μM and had a weaker inhibitory effect on [ ³ H] serotonin absorption compared to the efficacy of cocaine (IC ₅₀ = 355 nM) (Table 2). .

In HEK-hNET cells, the affinity of the compound for the binding site was lower than the affinity of the reference compound cocaine for the same position. The K _i value for the displacement of [ ¹²⁵ I] RTI-55 by the test compound was 3700 nM, and the K _i value for the cocaine displacement of the [ ¹²⁵ I] RTI-55 bond was 505 nM. In the absorption analysis, the test compound had an IC ₅₀ value of 4400 nM and was less effective in inhibiting [ ³ H] norepinephrine absorption compared to the efficacy of cocaine (IC ₅₀ = 194 nM) (Table 3).

The above numbers represent mean SEM from at least 3 independent experiments, each performed in duplicate (for binding analysis) or triplicate (for absorption analysis) repeated measurements. If the K _i or IC ₅₀ for the test compound is greater than 10 μM, only two experiments are performed and no standard error is reported.

Example 4
Test compounds were tested against extracellular monoaminergic neurotransmitter levels sampled by in vivo brain microdialysis in the prefrontal cortex and striatal brain region of freely moving awake rats. Administration of the test compound 30 mg / kg resulted in increased striatal dopamine and prefrontal cortex norepinephrine.

(Method)
Cerebral dialysate was collected from male Sprague-Dawley rats with chronically implanted cortical and striatal microdialysis guide cannulas and probes. The effects of different doses of test compound (10 and 30 mg / kg, subcutaneous injection) or vehicle (saline, 0.9% NaCl) are 3 50-minute reference samples and 8 consecutive 50-minute post-administration samples. It was evaluated with. The levels of dopamine, norepinephrine and serotonin for two different brain regions were analyzed using HPLC / ECD analysis to determine the effect of the compound.

(result)
The test compound does not show a consistent effect on extracellular neurotransmitter levels anywhere in the brain area tested at a dose of 10 mg / kg. The test compound increases striate dopamine and prefrontal cortex norepinephrine somewhat variably only at a dose of 30 mg / kg and does not show any significant effect on the other neurotransmitters investigated.

  FIG. 4 shows test compounds (10 and 30 mg / kg sc) or vehicle (0.9%) against extracellular dopamine concentrations in the striatum of rats out of 3 reference samples and 8 consecutive post-administration samples. FIG. 5 shows the effect of administration of (NaCl) on test compounds (10 and 30 mg / kg) against extracellular norepinephrine concentrations in the prefrontal cortex of rats out of 3 reference samples and 8 consecutive post-administration samples. s.c.) or vehicle (0.9% NaCl).

  In FIGS. 4 and 5, the results are shown as the average percent change compared to the average reference value for the individual. The arrow indicates the time when the test compound was administered. Mean values (and corresponding SEM) are shown for each group during each 50 minute sample period of n = 12 rats (NB: individual data points are incidental loss of dialysate sample May be based on a small number of samples).

Cited References All references cited herein are incorporated by reference in their entirety for each purpose, each and every patent or patent or patent application, characteristically and individually. Are incorporated herein by reference for their full contents and for the entire purpose.

  In this specification, references to references are made merely to summarize the author's claims and are not an admission that any reference constitutes prior art. Applicants have the right to submit objections to the accuracy and appropriateness of the cited references.

  The present invention is not limited by the conditions of the specific embodiments described herein, which is intended as an example for each embodiment of the invention. Various modifications and alterations of the present invention can be made without departing from the technical idea and viewpoint thereof, which will be apparent to those skilled in the art. In addition to those listed herein, methods and apparatus that are functionally equivalent within the scope of the invention will be apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications and changes are included in the scope of the appended claims. The invention is limited only by the following claims and the equivalent aspects of such claims.

Guide to Classification and Diagnosis of Mental Disorders, IV

Claims (12)

Structural formula (1):

(Where
R represents a hydrogen atom, a lower alkyl group having 1 or 2 carbon atoms, a halogen atom selected from F, Cl, Br and I, an alkoxy group having 1 to 3 carbon atoms, a nitro group, a hydroxy group, trifluoromethyl. Selected from the group consisting of a group and a thioalkoxy group having 1 to 3 carbon atoms;
x is an integer from 1 to 3, provided that when x is 2 or 3, R may be the same or different;
R ₁ and R ₂ may be the same or different from each other, and are independently a hydrogen atom, a lower alkyl group having 1 to 8 carbon atoms, a phenyl group , or a cycloalkyl group having 3 to 7 carbon atoms. Selected from the group consisting of:
R ₁ and R ₂ may form a 5- to 7-membered heterocyclic ring bonded to an unsubstituted, wherein the heterocyclic compound comprises 1 to 2 nitrogen atoms, and 0 to 1 oxygen atoms The nitrogen atoms are not directly connected to each other nor to oxygen atoms. A pharmaceutical composition for the treatment of ADHD, which comprises a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.   The pharmaceutical composition for the treatment of ADHD according to claim 1, wherein R represents a hydrogen atom and x = 1. The pharmaceutical composition for the treatment of ADHD according to claim 1, wherein R ₁ and R ₂ represent a hydrogen atom and x = 1.   The compound represented by the structural formula (1) is an enantiomer in which no other enantiomer is substantially present or an enantiomeric mixture in which one enantiomer of the compound represented by the structural formula (1) predominates. The pharmaceutical composition for the treatment of ADHD according to claim 1.   5. The pharmaceutical composition for the treatment of ADHD according to claim 4, wherein said one enantiomer predominates to the extent of about 90% or more.   6. The pharmaceutical composition for the treatment of ADHD according to claim 5, wherein said one enantiomer predominates to the extent of about 98% or more. The mirror image has the structural formula (1a):

The treatment of ADHD according to claim 4, wherein (S) or (L) is an enantiomer represented by (wherein R, x, R ₁ and R ₂ are the same as defined above). Pharmaceutical composition.   8. The pharmaceutical composition for the treatment of ADHD according to claim 7, wherein said one enantiomer predominates to the extent of about 90% or more.   9. The pharmaceutical composition for the treatment of ADHD according to claim 8, wherein said one enantiomer predominates to the extent of about 98% or more. The mirror image has the structural formula (1b):

The treatment of ADHD according to claim 4, wherein (R) or (D) is an enantiomer represented by (wherein R, x, R ₁ and R ₂ are the same as defined above). Pharmaceutical composition.   11. The pharmaceutical composition for the treatment of ADHD according to claim 10, wherein said one enantiomer predominates to the extent of about 90% or more. 12. The pharmaceutical composition for the treatment of ADHD according to claim 11, wherein said one enantiomer predominates to the extent of about 98% or more.

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