JP2012516845A - Bicyclic amide derivatives for enhancing glutamatergic synaptic responses - Google Patents

Abstract

  The present invention relates to compounds, pharmaceutical compositions, and methods for use in the prevention and treatment of brain failure, including enhancement of receptor function at synapses in brain networks involved in basic and higher order behavior. These brain networks are involved in the cognitive abilities associated with memory impairment, which is observed in various dementias, neuronal activity imbalances between different brain regions, Parkinson's disease, schizophrenia, sleeplessness Disorders such as breathing, attention deficit hyperactivity disorder, and emotional or mood disorders, as well as disorders involving deficiency of neurotrophic factors, as well as central sleep apnea due to stroke, obstructive sleep apnea, congenital hypoxia Ventilation Syndrome, Obesity Hypoventilation Syndrome, Sudden Infant Death Syndrome, Rett Syndrome, Spinal Cord Injury, Traumatic Brain Injury, Cheney-Stokes Breathing, Ondine Curse (Congenital Central Hypoventilation Syndrome), Prader-Willi Syndrome, and Drowning It is shown in such medical conditions. In certain embodiments, the present invention relates to bicyclic amide compounds useful for the treatment of such conditions, and methods of using these compounds for such treatment.

Description

  The present invention relates to compounds, pharmaceutical compositions, and methods for use in the prevention and treatment of brain failure, including enhancement of receptor function at synapses in brain networks involved in various behaviors. Neuronal activity imbalances between different brain regions often include mental and neurological disorders such as memory impairment, Parkinson's disease, schizophrenia, attention deficit and emotional or mood disorders, and disorders involving deficiency of neurotrophic factors May cause disability. In certain aspects, the present invention relates to compounds useful for the treatment of such conditions, and methods of using these compounds for such treatment.

  The release of glutamate at synapses in many parts of the mammalian forebrain stimulates two types of postsynaptic ion channel glutamate receptors. These types are commonly referred to as AMPA receptors and N-methyl-D-aspartate (NMDA) receptors. AMPA receptors mediate voltage-independent fast excitatory post-synaptic currents (fast EPSC), while NMDA receptors generate voltage-dependent slow excitatory currents. Studies conducted on hippocampal or cerebral cortex slices have shown that AMPA receptor-mediated fast EPSC is generally the predominant component of most glutamatergic synapses, and activation of AMPA receptors is usually NMDA receptor This is a prerequisite for activation.

  AMPA receptors are expressed throughout the central nervous system. These receptors are found in high concentrations in the surface layer of the cerebral neocortex, each major synaptic area of the hippocampus, and the striatum complex, as reported in Non-Patent Document 1. Studies in animals and humans suggest that these structures organize complex sensory-motor processes and provide a basis for higher-order behavior. Thus, AMPA receptors mediate transmission in those brain networks that are involved in numerous cognitive activities.

  For the above reasons, agents that modulate and enhance the function of AMPA receptors can have a significant effect on intellectual ability, and such agents should also facilitate memory encoding. Experimental studies as reported in Non-Patent Document 2 suggest that increasing the magnitude of AMPA receptor-mediated synaptic response (s) enhances induction of long-term potentiation (LTP). LTP is a steady increase in the strength of synaptic junctions following a type of repetitive physiological activity known to occur in the brain during learning.

  Compounds that enhance the function of the AMPA subtype of the glutamate receptor facilitate LTP induction and learning task acquisition, as measured in numerous examples. For example, see Non-Patent Documents 3 to 15 and Patent Document 1. There is considerable evidence that LTP is the basis of memory. For example, as reported in Non-Patent Document 16, compounds that block LTP interfere with memory formation in animals, and certain drugs that disrupt learning in humans counteract LTP stabilization. Learning a simple task is to induce LTP by high-frequency stimulation in the hippocampus that blocks the generated LTP (Non-Patent Document 17), and the action of maintaining LTP maintains spatial memory (Non-Patent Document 18). Very important in the field of learning is the discovery that biotherapy with positive AMPA-type glutamate receptor modulators restores the stability of basal dendritic LTP in middle-aged animals (19). .

  Excitatory synaptic transmission provides a major pathway through which neurotrophic factors increase within specific brain regions. Thus, it has been found that the enhancing action of AMPA receptor function by a modulator increases the level of neurotrophic factor, particularly brain-derived neurotrophic factor, ie, BDNF. For example, see Non-Patent Documents 20 to 22 and Patent Document 2. Other studies have linked BDNF levels to a number of neurological disorders such as Parkinson's disease, attention deficit hyperactivity disorder (ADHD), autism, fragile X syndrome, and Rett syndrome (RTT). For example, refer nonpatent literature 23-26. Thus, AMPA receptor potentiators would be useful in the treatment of these and other nervous system diseases that are the result of glutamatergic imbalance or neurotrophic factor deficiency.

  Non-patent document 27 describes a prototype of a compound that selectively promotes the AMPA receptor. These authors confirmed that the nootropic drug aniracetam (N-anisoyl-2-pyrrolidinone) did not affect the response by γ-aminobutyric acid (GABA), kainic acid (KA), or NMDA receptors, and It was found to increase current mediated by brain AMPA receptors expressed in mother cells. Injection of aniracetam into hippocampal slices has also been shown to substantially increase the magnitude of the fast synaptic potential without changing the resting membrane properties. Subsequently, it was confirmed that aniracetam enhances the synaptic response at several sites in the hippocampus and that it does not affect the mediated potential of the NMDA receptor (Non-patent Documents 28 and 29).

  Aniracetam has been found to have very rapid onset and efflux. And it can be used repeatedly without any obvious persistent effects. These are desirable characteristics for behavior-related drugs. However, aniracetam exhibits several drawbacks. Peripheral administration of aniracetam may not easily affect brain receptors. The drug is effective only at a high concentration (approximately 1000 μM), and about 80% of the drug is changed to anisoyl-GABA after peripheral administration in humans (Non-patent Document 30). The metabolite anisoyl-GABA has been found to be less active than aniracetam. In addition to these problems, since aniracetam is presumed to affect many other neurotransmitters and target enzymes in the brain, it uncertains the therapeutic effect of any claimed drug . For example, refer nonpatent literature 31-36.

  A class of AMPA receptor potentiating compounds has been described that do not exhibit the low potency and inherent instability characteristic of aniracetam (Patent Document 1). These compounds, referred to as “Ampkin” ®, are substituted benzamides, for example 6- (piperidin-1-ylcarbonyl) quinoxaline (CX516; Ampalex®). Usually they are more chemically stable than aniracetam and show improved bioavailability. CX516 is effective in animal studies used to find drugs that are effective in treating memory impairment, schizophrenia, and depression. In three separate clinical trials, CX516 has shown evidence for its effectiveness in improving various states of human memory (Non-Patent Documents 11-13).

  Another type of ampakine, benzoxazine, has been found to have very high activity in in vitro and in vivo models that assess the potential for causing cognitive enhancement (Patent Document 3). Substituted benzoxazines are rigid structure benzamide analogs and have different receptor modulating properties than CX516, a flexible structure benzamide.

US Pat. No. 5,747,492: Lynch and Rogers US Pat. No. 6,030,968; Gall et al. US Pat. No. 5,736,543: Rogers and Lynch

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Some substituted [2,1,3] benzooxadiazole compounds have been obtained from compounds previously disclosed in U.S. Patent Application Publication No. 2002/0055508 and U.S. Patent Application Publication No. 2002/099050. It has been found to be markedly and surprisingly effective in attention deficit hyperactivity disorder (ADHD), schizophrenia and cognitive model animals. This new class of bicyclic amides (structure A), described in detail herein, exhibits significant activity in enhancing AMPA-mediated glutamatergic synaptic responses.

  Accordingly, the present invention, in one aspect, includes compounds shown in Structure A and other structures and described in Section II of the Detailed Description below. Administration of this type of compound has been found to enhance AMPA-mediated glutamatergic synaptic responses and significantly improve rodent behavior in d-amphetamine-stimulated gait analysis. This behavioral test has proven useful in assessing the effectiveness of neuroleptics for treating schizophrenia and attention deficit hyperactivity disorder (ADHD). These compounds are significantly and surprisingly more potent than the previously described compounds in enhancing glutamatergic synaptic responses in vivo. This activity leads to corresponding methods of use, including pharmaceutical compounds and therapeutic methods that utilize the present compounds at significantly lower concentrations than prior art compositions. Furthermore, the compounds of the invention show improved pharmacokinetic properties compared to the compounds described above and have good bioavailability by oral administration.

  Because of the ability of the compounds of the invention to increase AMPA receptor mediated responses, the compounds are useful in a variety of applications. These include facilitating learning of glutamate receptor-dependent behavior, treating conditions with a reduced number or ability of AMPA receptors or synapses that utilize these receptors, and disability between brain subregions. Increasing excitatory synaptic activity to restore balance or increase levels of neurotrophic factors is included.

  In another aspect, the invention relates to a mammal suffering from a hypoglutamate condition, or a lack of excitatory synapses or strength or a lack of AMPA receptors, and impaired memory or other cognitive function A method of treating a subject. These conditions also cause cortical / striatum imbalance and may result in schizophrenia or schizophrenia-like behavior.

  In accordance with these methods, such a subject is administered in an effective amount in a pharmaceutically acceptable carrier, as shown in Structure A, and as described in Section II of the Detailed Description below. Treat with the compound. These and other objects and features of the invention will become more fully apparent when the following “DETAILED DESCRIPTION” is read in conjunction with the accompanying drawings.

I. Definitions The following terms have the following meanings unless otherwise indicated. Other terms used to describe the present invention have the same definitions as those terms are commonly used by those skilled in the art.

  As used herein, the term “compound” is used to refer to any particular chemical entity disclosed herein. Within the context of its use in the context, this term usually refers to a single stable compound, but in some cases stereoisomers and / or optical isomers (enantiopure compounds, enantiomers) of the disclosed compounds. Also concentrated compounds, and racemic mixtures).

  The term “effective amount” is selected to be used within its intended use to produce the intended result, eg, to enhance a glutamatergic synaptic response by increasing AMPA receptor activity. The amount of the compound of formula A. The exact amount used will vary depending on the particular compound selected and its intended use, the age and weight of the subject, the route of administration, etc., but will be readily determined by routine experimentation. For the treatment of a condition or condition, an effective amount is the amount used to effectively treat the particular condition or condition.

  The term “pharmaceutically acceptable carrier” refers to a carrier or excipient that is not unacceptably toxic to the subject to which it is administered. Pharmaceutically acceptable excipients include E.I. W. It is described in detail in “Remington's Pharmaceutical Sciences” by E.W. Martin.

  “Pharmaceutically acceptable salts” of amine compounds contemplated in the present invention include inorganic anions or acetates such as chloride, bromide, iodide, sulfate, sulfite, nitrate, nitrite, phosphate, It is an ammonium salt having an organic anion such as malonate, pyruvate, propionate, fumarate, cinnamate and tosylate as a counter ion.

  The term “patient” or “subject” is used throughout this specification to describe an animal, usually a mammal, including a human, against which treatment with a compound or composition according to the present invention or use thereof is provided. The For the treatment or use of those conditions or medical conditions that are unique to a particular animal, such as a human subject or patient, the term patient or subject refers to that particular animal.

  The term “sensory motor problem” refers to a problem in a patient or subject that results from the inability to integrate external information obtained from the known five senses to guide appropriate physical responses including movement and behavior. used.

  The terms “cognitive work” or “cognitive function” are used to describe an attempt or process involving thought or recognition by a patient or subject. The diverse functions of the associated cortex of the parietal, temporal and frontal lobes, which account for approximately 75% of all human brain tissue, are responsible for much of the information processing performed between sensory input and motor output. The diverse functions of the associated cortex are often called cognition, which literally means the process by which we get to know the outside world. Selective attention to specific stimuli, perceiving and identifying associated stimulus features, and planning and experiencing responses are processes or human brain-mediated processes related to cognition or Part of ability.

  The term “brain network” is used to describe different anatomical regions of the brain that communicate with each other through synaptic activity of nerve cells.

  The term “AMPA receptor” refers to a collection of proteins found in some membranes, which is not NMDA but glutamate or AMPA (DL-α-amino-3-hydroxy-5-methyl-4- In response to the binding of (isoxazolepropionic acid), it allows positive ions to cross the membrane.

The term “excitatory synapse” is used to describe a cell-cell junction in which the release of a chemical transmitter by one cell causes depolarization of the outer membrane of another cell. Excitatory synapses represent post-synaptic neurons that have a reversal potential that is more positive than the threshold potential, so that at these synapses, neurotransmitters increase the likelihood that an excitatory post-synaptic potential will occur (neurons Will ignite and produce an action potential). The reversal potential and threshold potential determine post-synaptic excitation and suppression. If the reversal potential at the post-synaptic potential (“PSP”) is more positive than the action potential threshold, the transmitter effect is excitatory and the excitatory post-synaptic potential (“EPSP”) and the action potential of the neuron are Causes ignition. If the reversal potential at the post-synaptic potential is more negative than the action potential threshold, the transmitter is inhibitory and can produce an inhibitory post-synaptic potential (IPSP), so that the synapse fires the action potential. The possibility that it will be reduced. The general rule for post-synaptic action is that excitement occurs if the reversal potential is more positive than the threshold, and suppression occurs if the reversal potential is more negative than the threshold. See, for example, Dale Pabesu (Dale Purves) editing, neuroscience (NEUROSCIENCE), Chapter 7, Shinaua Associates, Inc. (Sinauer Associates Inc.), Massachusetts, Sunderland (Sunderland), 1997.

  The term “exercise task” is used to describe an attempt related to exercise or behavior made by a patient or subject.

  The term “perceptual task” is used to describe the act of directing attention to sensory input by a patient or subject.

  The term “synaptic response” is used to describe a biophysical response in one cell as a result of the release of a chemical messenger by another closely related cell.

  The term “low glutamatergic condition” is used to describe a situation or condition in which transmission mediated by glutamate (or related excitatory amino acids) is reduced below normal levels. Transmission consists of glutamate release, binding to post-synaptic receptors, and opening of channels essential for those receptors. Ultimately, the hypoglutamate state reduces excitatory post-synaptic currents. It can be attributed to any of the above three transmission stages. Conditions or medical conditions that can be treated using compounds, compositions and methods according to the present invention that are considered hypoglutamate conditions include, for example, memory loss, dementia, depression, attention deficit, sexual dysfunction, Parkinson's disease Movement disorders, including schizophrenia or schizophrenia-like behavior, memory and learning disorders, and sleep apnea, including disorders due to aging, trauma, stroke and neurodegenerative disorders, and neurodegenerative disorders Such as those associated with drug-induced conditions, neurotoxins, Alzheimer's disease and aging. These conditions are easily recognized and diagnosed by those skilled in the art.

  The term “cortical-striatal imbalance” is used to describe a condition in which the balance of neuronal activity in the interconnected cortex and underlying striatal complex deviates from what is normally seen. . “Activity” can be assessed by electrical recording techniques or molecular biological techniques. Imbalance can be defined by applying these measurements to the two tissues or by functional (behavioral or physiological) criteria.

  The term “emotional disorder” or “mood disorder” refers to a condition in which sadness or uplifting is excessively intense, which lasts beyond the expected impact of stressful life events, or that occurs intrinsically. Show. In the present specification, the term “emotional disorder” refers to all kinds of psychiatric disorders, for example, Diagnostic and Statistical Manual of Mental disorder, 4th edition (DSM IV), pages 317-391. Includes mood disorders.

  The term “schizophrenia” is characterized by obstacles in the thinking process such as delusions and hallucinations, as well as a great reversal of individual interest from other people and the outside world, and its blockade within itself. Used to represent general types of psychotic conditions. Schizophrenia is now considered as a group of mental disorders rather than alone, and is distinguished between reactive schizophrenia and process schizophrenia. As used herein, the term “schizophrenia” or “schizophrenia-like” refers to outpatient schizophrenia, tension-type schizophrenia, destructive schizophrenia, latent schizophrenia, process schizophrenia, pseudonervous. All types, including symptomatic schizophrenia, reactive schizophrenia, simple schizophrenia, and related psychotic disorders that are similar to schizophrenia but do not necessarily diagnose themselves as schizophrenia Comprehensive schizophrenia. Schizophrenia and other psychotic disorders are described, for example, in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV) Sections 293.81, 293.82, 295.10, 295. 20, 295.30, 295.40, 295.60, 295.70, 295.90, 297.1, 297.3, 298.8 are diagnosed.

  The term “brain function” is used to describe the combined task of perception, integration, selection and reaction of external stimuli and internal motivational processes.

  The term “impaired” is used to describe a function that works to a lesser degree. Impaired functions can be significantly affected, such that they are rarely performed, are virtually nonexistent, or are working significantly worse than normal. Impaired functionality can also be suboptimal. Functional impairment will vary in severity from patient to patient and from condition to condition.

  In this specification, the term “sleep apnea” refers to respiratory-related sleep disorder, and there are two types, central and obstructive. Central sleep apnea is usually defined as a neurological condition that causes the cessation of all respiratory effort during sleep, accompanied by a decrease in blood oxygen saturation, and when the brainstem center that controls breathing is deactivated, respiratory effort And no breathing. A person may wake up from sleep by an automatic breathing reflex and eventually have very little sleep. Obstructive sleep apnea is characterized by repeated interruptions in breathing during sleep due to obstruction and / or collapse of the upper airway, and then wakes up to breathe. Respiratory effort continues during an apnea attack.

  As used herein, the term “prodrug” is pharmacologically inactive in its original form, but is metabolically inactive, rapidly metabolized in human or animal plasma to a pharmacologically active form. Refers to a stable derivative. Examples of prodrugs used herein include, but are not limited to, ester derivatives of hydroxyl-containing moieties. Such esters include, but are not limited to, those formed from substituted or unsubstituted natural or unnatural amino acids.

II. Compounds of the Invention The present invention is directed to compounds having properties that enhance the function of AMPA receptors. They include compounds having the following structure A, or pharmacologically acceptable salts, solvates, or polymorphs thereof.

式中、ＸはＯ又は（ＣＨ₂）_nであり、
ｎは０又は１である。

Where X is O or (CH ₂ ) _n ;
n is 0 or 1.

  Preferred forms include a compound of formula B below, or a pharmaceutically acceptable salt, solvate or polymorph thereof.

  Further preferred forms include a compound of formula C below, or a pharmaceutically acceptable salt, solvate or polymorph thereof.

式中、ＸはＯ又はＣＨ₂である。

In the formula, X is O or CH ₂ .

In a further aspect, the present invention provides a compound of formula A selected from
[2,1,3] -benzooxadiazol-5-yl (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) methanone,
[2,1,3] -benzooxadiazol-5-yl (3-oxa-9-azabicyclo [3.3.1] non-9-yl) methanone, and
[2,1,3] -Benzoxadiazol-5-yl (3,7-dioxa-9-azabicyclo [3.3.1] non-9-yl) methanone.

III. Synthesis The synthesis of the compounds of the present invention is preferably carried out according to the following scheme. Alternative syntheses that are inferred by procedures existing in the art can also be used. Each compound is produced using the described chemical synthesis, following the chemical reaction scheme presented herein, or by making minor modifications to its synthetic chemistry relying on well-known methods available in the art. Can be done. The method of synthesis is relatively easy and can be easily modified within the scope of the teachings herein.

To synthesize the acid chloride (4), starting from 4-amino-3-nitrobenzoic acid (1), it is first oxidized with a bleach to give intermediate (2), then Reduction with triethyl phosphite (P (OEt) ₃ ) gives benzofurazan carboxylic acid (3). Carboxylic acid (3) was converted to the acid chloride (4) by refluxing with thionyl chloride and a catalytic amount of DMF in toluene. Carboxylic acid (3) can be prepared by reaction with a suitable amino group-containing bicyclic compound (aminobicycles) using standard coupling conditions such as CDI, EDCI, HBTU in a suitable solvent. Can be converted to (A). Alternatively, the acid chloride (4) can be prepared under standard coupling conditions using a bicyclic amine in the presence of a base such as triethylamine or aqueous sodium hydroxide in a suitable solvent such as dichloromethane. Can be converted to the bicyclic amide (A).

scheme

IV. Methods of Treatment In accordance with one aspect of the present invention, there is provided a method of treating a mammalian subject suffering from a hypoglutamate condition, or a lack of excitatory synapse number or strength or AMPA receptor number. In these subjects, memory or other cognitive functions may be impaired, or cortical / striatal imbalances may occur, which include memory loss, dementia, depression, attention deficit, gender Results in dysfunction, movement disorders, schizophrenia or schizophrenia-like behavior. Memory and learning disorders that can be treated according to the present invention include disorders resulting from aging, trauma, stroke and neurodegenerative disorders. Examples of neurodegenerative disorders include, but are not limited to, those associated with drug-induced conditions, neurotoxins, Alzheimer's disease, and aging. These conditions are readily recognized and diagnosed by those skilled in the art and are treated by administering to the patient an effective amount of one or more compounds of the invention.

  In a further aspect, the present invention relates to a respiratory related sleep disorder in a subject having sleep apnea, comprising administering to the subject an amount of a compound of the present invention sufficient to reduce or inhibit the respiratory related sleep disorder. Alternatively, a method for reducing or suppressing sleep apnea is provided.

  In the present invention, a therapeutic method comprises treating an effective amount of a compound having the following chemical formula A, or a pharmaceutically acceptable salt, solvate, or polymorph thereof in a pharmaceutically acceptable carrier. Administration to a subject in need.

式中、ＸはＯ又は（ＣＨ₂）_nであり、
ｎは０又は１である。

Where X is O or (CH ₂ ) _n ;
n is 0 or 1.

  The compounds of the invention in most cases exhibit enhanced bioavailability due at least in part to the enhanced metabolic stability by the compounds. Thus, the present compounds can be formulated into pharmaceutical compositions, preferably in various dosage forms, particularly oral dosage forms.

  As mentioned above, treatment of a subject according to the methods of the invention is useful for enhancing AMPA receptor activity, thus facilitating learning of AMPA receptor dependent behavior, as well as AMPA receptors or these It can be used to treat conditions such as memory impairment that reduce the number or ability of synapses to utilize receptors. This method is also useful for enhancing excitatory synaptic activity to restore imbalances between subregions of the brain that appear in schizophrenia or schizophrenia-like behavior or other behaviors described above. Compounds administered according to this method have been found to be more effective than the aforementioned compounds in enhancing AMPA receptor activity, as shown in the in vivo tests below.

V. Biological activity
Enhancement of AMPA receptor function in vivo AMPA receptor- mediated synaptic responses are augmented by the methods of the invention using the compounds described herein.

  The electrophysiological effects of the compounds of the invention were tested in vivo in anesthetized animals according to the following procedure. The animals are maintained under anesthesia with phenobarbital administered using a Hamilton syringe pump. Stimulation electrodes and recording electrodes are inserted into the penetrating fibers and dentate gyrus of the hippocampus, respectively. Once the electrode is implanted, a uniform monophasic pulse (pulse width 100 μsec) delivered three times per minute to the stimulating electrode is used to derive a stable reference value for the evoked response. Field EPSP is monitored until a stable baseline is obtained (approximately 20-30 minutes), after which a solution of test compound is injected intraperitoneally and the evoked field potential is recorded. Evoked potentials are recorded approximately 2 hours after drug administration or until field EPSP amplitudes return to baseline. In the latter case, it is common to administer intravenously using an appropriate dose of the same test compound. The compounds of the present invention were tested in the in vivo electrophysiology test described above. Data for representative test compounds is shown in the table. The compound of the present invention has an activity to increase the field EPSP amplitude in the rat dentate gyrus after intraperitoneal administration. CX516 (1- (quinoxaline- 6-ylcarbonyl) piperidine; U.S. Pat. No. 5,773,434, U.S. Patent Application Publication No. 2002/0055508).

１．１０ｍｐｋ腹腔内投与でのラット歯状回におけるフィールドＥＰＳＰの振幅の増加率（％）
ＮＴ：未測定

1. Percent increase in amplitude of field EPSP in rat dentate gyrus after intraperitoneal administration of 10 mpk
NT: not measured

VI. Administration, Dosages, and Dosage Forms As noted above, the compounds and methods of the present invention increase the AMPA receptor-mediated glutamatergic synaptic response and are useful in the treatment of hypoglutamatergic conditions. They are also useful for the treatment of conditions such as memory or other cognitive impairments caused by lack of excitatory synapses or strength or AMPA receptors. They can also be used in the treatment of schizophrenia or schizophrenia-like behavior resulting from cortical / striatal imbalance and in promoting learning of AMPA receptor dependent behavior.

  In subjects treated with the present compounds, pharmaceutical compositions and methods, memory or other effects that result in memory loss, dementia, depression, attention deficit, sexual dysfunction, movement disorders, schizophrenia or schizophrenia-like behavior Cognitive function may be impaired or cortical / striatal imbalance may have occurred. Memory and learning disorders treatable according to the present invention include disorders resulting from aging, trauma, stroke and neurodegenerative disorders. Examples of neurodegenerative disorders include, but are not limited to, drug-induced conditions, neurotoxins, Alzheimer's disease, and those associated with aging. These conditions are readily recognized and diagnosed by those skilled in the art and are treated by administering to the patient an effective amount of one or more compounds of the invention.

  In general, the dosage and route of administration of a compound will be determined according to the size and condition of the subject, according to standard pharmaceutical practice. The dosage level used can vary widely, but can be readily determined by one skilled in the art. Usually, milligram quantities up to gram quantities are employed. Compositions include, for example, oral, rectal, transdermal administration, for example, orally, transdermally, peripherally or parenterally, i.e. by intravenous, subcutaneous, intraperitoneal or intramuscular injection. May be administered to a subject by various routes. Subjects considered for treatment of the method of the present invention are humans, pets, laboratory animals and the like.

  Formulations containing the compounds of the invention can take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms such as tablets, capsules, powders, sustained release formulations, solutions, suspensions. , Emulsions, suppositories, creams, ointments, lotions, aerosols, patches and the like, preferably unit dosage forms suitable for simple administration of the correct dosage.

  The pharmaceutical composition of the present invention contains an effective amount of one or more compounds of the present invention, usually containing conventional pharmaceutical carriers or excipients, and further containing other drugs, carriers, adjuvants, additives and the like. it can. Preferably, the composition is about 0.5-75% by weight or more of one or more compounds of the invention, the remainder consisting essentially of suitable pharmaceutical excipients. Such excipients for oral administration include pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. If desired, the composition may contain minor amounts of non-toxic auxiliary substances such as wetting, emulsifying, or buffering agents.

  The liquid composition dissolves or disperses the compound (from about 0.5 wt% to about 20 wt% or more) and any adjuncts in a carrier such as, for example, an aqueous saline solution, aqueous dextrose, glycerol or ethanol. And can be prepared by forming a solution or suspension. For use in oral liquid formulations, the compositions can be prepared as solutions, suspensions, emulsions or syrups, in liquid or dry form suitable for hydration with water or saline. Supplied.

  When the composition is used in the form of a solid formulation for oral administration, the formulation can be a tablet, granule, powder, capsule or the like. In tablet dosage form, the composition is usually formulated with additives. Additives are, for example, excipients such as sugars or cellulose preparations, binders such as starch paste or methylcellulose, bulking agents, disintegrants, and other additives commonly used in the manufacture of pharmaceutical preparations. is there.

  Injectable compositions for parenteral administration usually contain the compound in a suitable intravenous solution, such as sterile saline. The composition may also be formulated as a suspension in a lipid or phospholipid, in a liposomal suspension, or in an aqueous emulsion.

Methods for preparing such dosage forms are known or will be apparent to those skilled in the art. See, for example, Remington 's Pharmaceutical science (17th edition, Mack Pub. Co., 1985). The composition to be administered contains an amount of the selected compound in a pharmaceutically effective amount that results in an increase in AMPA receptor current in the subject.

Examples are given in the following examples, which are in no way intended to limit the invention. Unless otherwise specified, all temperatures are given in degrees Celsius. Unless otherwise stated, all NMR spectra are ¹ H NMR spectra and are obtained in deuterated chloroform or deuterated DMSO as solvent using tetramethylsilane as an internal standard. All names of example compounds follow IUPAC nomenclature, as provided in the computer software by ChemSketch by ACD Labs.

I. Chemical method
Intermediate 1
[2,1,3] -Benzoxadiazole-5-carboxylic acid

In a 3 L reactor equipped with mechanical stirring, reflux condenser, thermometer and nitrogen inlet, potassium hydroxide (72.46 g) was dissolved in ethanol (250 ml) and water (250 ml). 4-Amino-3-nitrobenzoic acid (100 g) was added and the orange suspension was heated to 65-70 ° C. within 30 minutes. The resulting suspension was stirred at the same temperature for 45 minutes and cooled to 0 ° C. ± 5 ° C. within 30 minutes. A commercially available solution of sodium hypochlorite (448.93 g) (13 wt%) was added dropwise within 1.5 hours at 0 ° C. ± 5 ° C. The reaction mixture was stirred at the same temperature for 2 hours and managed by thin layer chromatography (CHCl ₃ 100 / acetone 2 / acetic acid 1). Water (350 ml) was added within 15 minutes at 0 ° C. ± 5 ° C. to give a yellow fine suspension. The reaction mixture was then acidified with 6N hydrochloric acid solution (239 ml) until 0.5 <pH <1. Sodium chloride (58.44 g) was added and the resulting suspension was stirred at 0 ° C. ± 5 ° C. for 1.5 hours under nitrogen. The solid was collected by filtration, washed 3 times with 400 ml of water, dried (40 ° C., 30 mbar, 12 hours), and 83.6 g of [2,1,3] -benzooxadiazole-5-carboxyl. The acid N-oxide was obtained (yield 88.8%).

In a 2 L reactor equipped with mechanical stirring, thermometer, dropping funnel, reflux condenser and nitrogen inlet, [2,1,3] -benzooxadiazole-5-carboxylic acid N-oxide (80 g) was added. Dissolved in absolute ethanol (800 ml). To this solution was added triethyl phosphite (114.05 g) at 70 ° C. ± 2 ° C. within 10 minutes. The resulting mixture was heated to reflux (76-78 ° C.) and maintained for 2 hours. Monitoring by thin layer chromatography (CHCl ₃ 100 / acetone 2 / acetic acid 1) confirmed the completion of the reaction. The solvent was removed under vacuum (30 mbar, 40 ° C.) to give a black oil (180 g). Water (400 ml) was added and the mixture was extracted with ethyl acetate (400 and 160 ml). The organic phase was extracted with 850 ml of water containing sodium hydroxide (9.5 <pH <10). The aqueous phase was separated and extracted three times with ethyl acetate (240 ml). When the aqueous phase was acidified at 5 ° ± 2 ° C. to 1 <pH <2 (78 ml of 6N hydrochloric acid), the yellow product crystallized. The crystals were filtered and dried (40 ° C., 30 mbar, 12 hours) to obtain 65.56 g (90% yield) of [2,1,3] -benzooxadiazole-5-carboxylic acid: melting point = 160-161 ° C., ¹ H NMR (300 MHz, DMSO) δ 13.8 (s, 1H); 8.57 (s, 1H); 8.56 (d, 1H, J = 0.6 Hz); 7.87 ppm (D, 1H, J = 0.6 Hz).

Intermediate 2
[2,1,3] -Benzoxadiazole-5-carbonyl chloride

  In a 500 ml reactor equipped with mechanical stirring, thermometer, dropping funnel, reflux condenser and nitrogen inlet, [2,1,3] -benzooxadiazole-5-carboxylic acid (28 g) was toluene (245 ml). ). To this suspension was added thionyl chloride (39.4 g) and DMF (0.35 ml). The resulting mixture was heated to reflux and maintained for 3 hours. A short path column was attached and the toluene was distilled (atmospheric pressure, 124 ml) to remove excess reagent. After cooling, the remaining toluene was distilled off to obtain a thick oily substance. The oil was distilled (90 ° C., 2 mmHg) to remove impurities and the product was allowed to crystallize (yield 79.8%). Melting point: 55-58 ° C.

Example 1
[2,1,3] -Benzoxadiazol-5-yl (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) methanone

Cis-1-benzyl-2,5- (dihydroxymethyl) pyrrolidine hydrochloride (3.0 g, 13.5 mmol, see US Pat. No. 7,011,074) was dissolved in concentrated sulfuric acid (10 ml) and stirred at 120 ° C. for 9 hours. Heated. The cooled solution was basified with 10N sodium hydroxide (until pH 10) and extracted twice with ethyl acetate (100 ml). The organic phase was dried over sodium sulfate and concentrated under vacuum to give 1.5 g of a colorless oil. The product was dissolved in dichloromethane (50 ml) and methanol (50 ml) and 10% Pd / C (0.5 g) was added. The mixture was hydrogenated at 60 psi overnight. The solid was filtered, dioxane solution (2 ml, 4N) containing hydrochloric acid was added and the solvent was evaporated. The residue was dissolved in dichloromethane (100 ml) and triethylamine (3 ml), and a solution of [2,1,3] -benzooxadiazole-5-carbonyl chloride (1.27 g, 7 mmol) in dichloromethane (10 ml) was added. It was. After stirring the mixture for 0.3 hours, water (100 ml) and hydrochloric acid (until pH 2) were added and the organic phase was washed with sodium bicarbonate solution (100 ml), dried over magnesium sulfate and concentrated in vacuo. This material was purified by silica gel chromatography eluting with hexane / THF (60/40) to give 847 mg of the title compound as a white solid after crystallization with dichloromethane / MTBE: mp = 139-140 ° C., LC -MS, MH ⁺ = 260.2; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96-7.92 (m, 2H); 7.56-7.52 (m, 1H); 4.82-4 .69 (s, 1H); 4.06-3.60 (m, 5H); 2.18-1.95 ppm (m, 4H).

Example 2
[2,1,3] -Benzoxadiazol-5-yl (3-oxa-9-azabicyclo [3.3.1] non-9-yl) methanone

9-Benzyl-3-oxa-9-azabicyclo- (3.3.1) nonane (3.0 g, 13.8 mmol, see WO 03/004503 pamphlet) was dissolved in ethanol (100 ml) and 10% Pd / C (0.56 g) was added. The mixture was hydrogenated at 100 psi overnight. The solid was filtered, a dioxane solution (4 ml, 4N) containing hydrochloric acid was added and the solvent was evaporated. Dissolve the residue in dichloromethane (100 ml) and triethylamine (8 ml) and a solution of [2,1,3] -benzooxadiazole-5-carbonyl chloride (3.5 g, 19.2 mmol) in dichloromethane (10 ml) Was added. After stirring the mixture for 20 minutes, water (100 ml) and sulfuric acid (up to pH 2) were added, the organic phase was washed with sodium bicarbonate solution (100 ml), and the aqueous phase was re-extracted with dichloromethane (100 ml) and mixed. The organic phase was dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with hexane / THF (70/30). Upon slow evaporation of the solvent, the product crystallized to give the title compound as a white solid (3.13 g): mp = 128-130 ° C., LC-MS, MH ⁺ = 274.2; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94 (dd, 2H, J = 9.0 and 1.2 Hz); 7.89 (t, 1H, J = 1.2 Hz); 7.47 (dd, 1H, J = 9.0 and 1.2 Hz); 4.62 (s, 1H); 4.05 (d, 1H, J = 11.7 Hz); 3.95-3.89 (m, 2H); 3.79 ( d, 1H, J = 11.7 Hz); 3.66 (s, 1H); 2.71-2.54 (m, 1H); 2.14-1.69 ppm (m, 5H).

Example 3
[2,1,3] -Benzoxadiazol-5-yl (3,7-dioxa-9-azabicyclo [3.3.1] non-9-yl) methanone

9-Benzyl-3,7-dioxa-9-azabicyclo- (3.3.1) nonane (650 mg, 2.96 mmol, “The Journal of Organic Chemistry”, 2006 71, No. 1, p. 413-415) was dissolved in methanol (20 ml) and formic acid (4 ml). 10% Pd / C (0.3 g) was added and the mixture was hydrogenated overnight. The solid was filtered and the solvent was evaporated. The residue was dissolved in methanol (20 ml), a dioxane solution containing hydrochloric acid (2 ml, 4N) was added, and the solvent was evaporated. The residue was dissolved in dichloromethane (80 ml), THF (20 ml) and triethylamine (3 ml) and dichloromethane containing [2,1,3] -benzooxadiazole-5-carbonyl chloride (1.0 g, 5.5 mmol). (10 ml) solution was added. After stirring the mixture for 0.5 h, water (100 ml) and sulfuric acid (up to pH 2) were added, the organic phase was extracted with sodium bicarbonate solution (100 ml), the aqueous phase was re-extracted with dichloromethane (50 ml), The combined organic phases were dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with hexane / THF (50/50). The product was crystallized from dichloromethane / ethanol to give the title compound as an off-white solid (590 mg): mp = 197-199 ° C., LC-MS, MH ⁺ = 276.2; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (dd, 2H, J = 9.0 and 1.2 Hz); 7.94 (t, 1H, J = 1.2 Hz); 7.50 (dd, 1H, J = 9.0 and 1. 4.52 (s, 2H); 4.21 (d, 2H, J = 11.4 Hz); 4.09-4.02 (m, 4H); 3.90 (dd, 2H, J = 10.8 and 2.4 Hz); 3.61 ppm (s, 2H).

II. Biological techniques
In vivo electrophysiology The electrophysiological effects of the compounds of the present invention were tested in vivo in anesthetized animals according to the following procedure.

  Animals are maintained under anesthesia with phenobarbital administered using a Hamilton syringe pump. Stimulation electrodes and recording electrodes are inserted into the penetrating fibers and dentate gyrus of the hippocampus, respectively. Once the electrode is implanted, a uniform monophasic pulse (pulse width 100 μsec) delivered three times per minute to the stimulating electrode is used to derive a stable reference value for the evoked response. Field EPSP is monitored until a stable baseline is obtained (approximately 20-30 minutes), after which time a solution of the test compound is injected into the peritoneum and the evoked field potential is recorded. Evoked potentials are recorded approximately 2 hours after drug administration or until field EPSP amplitudes return to baseline. In the latter case, it is common to administer intravenously using an appropriate dose of the same test compound.

  Although the present invention has been described with respect to particular methods and embodiments, it will be appreciated that various changes may be made without departing from the invention.

Claims (30)

A compound of formula A comprising:

Where X is O or (CH ₂ ) _n ;
n is 0 or 1;
A compound, or a pharmacologically acceptable salt, solvate or polymorph thereof. The compound according to claim 1, which is the chemical formula B, or a pharmacologically acceptable salt, solvate or polymorph thereof.

A compound of formula C,

Where X is O or CH ₂ .
The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or polymorph thereof. 2,1,3-benzooxadiazol-5-yl (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) methanone,
2,1,3-benzooxadiazol-5-yl (3-oxa-9-azabicyclo [3.3.1] non-9-yl) methanone, or 2,1,3-benzooxadiazole-5 -Yl (3,7-dioxa-9-azabicyclo [3.3.1] non-9-yl) methanone,
The compound of claim 1, wherein   A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 4 in combination with a pharmaceutically acceptable carrier, additive or excipient.   The compound is about 0.5% to about 75% by weight of the pharmaceutical composition and the carrier, additive or excipient is about 25% to about 95.5% of the pharmaceutical composition. The pharmaceutical composition according to claim 5.   A method of treating a mammalian subject, wherein the mammalian subject suffers from a hypoglutamate state or a deficiency in the number or intensity of excitatory synapses or the number of AMPA receptors and memory or other cognitive functions are impaired A method of treating a mammalian subject, the method comprising administering to the mammalian subject an effective amount of a compound according to claims 1-4 in a pharmaceutically acceptable carrier.   A method for treating a mammalian subject, wherein the mammalian subject suffers from a schizophrenia or schizophrenia-like behavior suffering from a hypoglutamate state or a deficiency in the number or intensity of excitatory synapses or the number of AMPA receptors Cortical / striatal imbalance has occurred, and the method of treatment comprises administering to the mammalian subject an effective amount of a compound according to claims 1-4 in a pharmaceutically acceptable carrier. A method for treating a mammalian subject.   The treatment method according to claim 7, wherein the symptom is schizophrenia.   The treatment method according to claim 8, wherein the symptom is Parkinson's disease.   A method of treating ADHD in a patient in need of treatment, said method comprising administering to said patient an effective amount of a compound according to any of claims 1-4.   A method of treating Rett syndrome in a patient in need of treatment, wherein the method of treatment comprises administering to the patient an effective amount of a compound according to claims 1-4.   A method of treating fragile X syndrome in a patient in need of treatment, wherein the method of treatment comprises administering to the patient an effective amount of the compound of claims 1-4.   A method of treating respiratory-related sleep disorder or sleep apnea in a patient in need of treatment, the method comprising administering to the patient an effective amount of a compound according to claims 1-4. .   A method of treating Alzheimer's disease in a patient in need of treatment, said method comprising administering to said patient an effective amount of a compound according to claims 1-4.   A method of treating Alzheimer's disease in a patient in need of treatment, said method comprising administering to said patient an effective amount of a compound according to claims 1-4 in combination with at least one acetylcholinesterase inhibitor. A method of treatment comprising:   A method of treating depression in a patient in need of treatment, wherein said method of treatment comprises administering to said patient an effective amount of a compound according to claims 1-4.   A method of treating bipolar disorder in a patient in need of treatment, wherein the method of treatment comprises administering to the patient an effective amount of a compound according to claims 1-4.   Claims in the manufacture of a medicament for use in the treatment of a mammalian subject suffering from a hypoglutamate condition or a deficiency in the number or intensity of excitatory synapses or the number of AMPA receptors and impaired memory or other cognitive function Use of the compound of claim | item 1-4.   A mammalian subject suffering from a hypoglutamate condition, or a deficiency in the number or intensity of excitatory synapses or the number of AMPA receptors, resulting in cortical / striatal imbalance resulting in schizophrenia or schizophrenia-like behavior Use of a compound according to claims 1 to 4 in the manufacture of a medicament for use in the treatment of.   Use of a compound according to claims 1-4 in the manufacture of a medicament for the treatment of schizophrenia.   Use of a compound according to claims 1-4 in the manufacture of a medicament for the treatment of Parkinson's disease.   Use of a compound according to claims 1-4 in the manufacture of a medicament for the treatment of ADHD.   Use of a compound according to claims 1-4 in the manufacture of a medicament for the treatment of Rett syndrome.   Use of a compound according to any of claims 1 to 4 in the manufacture of a medicament for the treatment of cognitive impairment.   Use of a compound according to any of claims 1 to 4 in the manufacture of a medicament for the treatment of respiratory related sleep disorders or sleep apnea.   Use of a compound according to any of claims 1 to 4 in the manufacture of a medicament for the treatment of fragile X syndrome.   Use of a compound according to any of claims 1 to 4 in the manufacture of a medicament for the treatment of Alzheimer's disease.   Use of a compound according to any of claims 1 to 4 in the manufacture of a medicament for the treatment of depression.   Use of a compound according to any of claims 1 to 4 in the manufacture of a medicament for the treatment of bipolar disorder.