WO2014078377A1 - Méthodes et compositions pour le traitement de la schizophrénie - Google Patents

Méthodes et compositions pour le traitement de la schizophrénie Download PDF

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Publication number
WO2014078377A1
WO2014078377A1 PCT/US2013/069836 US2013069836W WO2014078377A1 WO 2014078377 A1 WO2014078377 A1 WO 2014078377A1 US 2013069836 W US2013069836 W US 2013069836W WO 2014078377 A1 WO2014078377 A1 WO 2014078377A1
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antipsychotic
pharmaceutically acceptable
polymorphs
hydrates
aliphatic
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PCT/US2013/069836
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English (en)
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Michela Gallagher
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Agenebio, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings

Definitions

  • the invention relates to methods and compositions for treating
  • schizophrenia or bipolar disorder in particular, mania
  • it relates to the use of a combination of a a5 -containing GABAA receptor agonist and an antipsychotic in treating a subject having or at risk for schizophrenia or bipolar disorder (in particular, mania).
  • Schizophrenia is a chronic psychiatric disorder, characterized by a wide spectrum of psychopathology, including positive symptoms such as aberrant or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by diminution of motivation and adaptive goal-directed action (e.g., anhedonia, affective flattening, avolition), and cognitive impairment. While abnormalities in the brain are proposed to underlie the full spectrum of psychopathology in schizophrenia, currently available antipsychotics are largely ineffective in treating cognitive impairments in schizophrenia patients.
  • Cognitive impairments in schizophrenia involve both frontal and temporal lobe functions that include memory, attention, processing speed, and executive control.
  • Recent observations, drawn from preclinical animal models and human neuroimaging studies, indicate that altered brain activity/excitability in the medial temporal lobe memory system may contribute to cognitive impairment and may also play a role in augmenting psychotic symptoms due to disinhibition of dopaminergic neurons.
  • Cognitive deficits are increasingly recognized as a key clinical feature that can be detected in a prodromal phase and in remission, as well as during full expression of the illness but are not effectively treated by available antipsychotics. Because untreated features of schizophrenia, especially impaired cognition, predict long-term disability in patients (Green et al, Schizophr. Res. 2004, 72, 41-45), it is critical to develop effective therapies for the spectrum of this illness.
  • a method for treating a subject suffering from schizophrenia or bipolar disorder (in particular, mania), or at risk thereof comprising the step of administering to said subject a therapeutically effective amount of a a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof in combination with a therapeutically effective amount of an antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • the methods of the present invention treat one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia.
  • the methods of the present invention treat one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania). In some embodiments of this invention, the methods of this invention prevent or slow the progression of cognitive impairment of schizophrenia or bipolar disorder (in particular, mania) in said subject.
  • the antipsychotic is administered at a dose that is subtherapeutic as compared to the dose at which it is
  • the a5 -containing GABAA receptor agonist useful in this invention may be any a5 -containing GABAA receptor agonist.
  • the a5 -containing GABAA receptor agonist is selected from the compounds disclosed in, e.g., U.S. Patent Application 61/413,971 and PCT publication WO2012068161, which are incorporated herein by reference.
  • the a5 -containing GABAA receptor agonist useful in the present invention is a compound of Formula I:
  • R' is -COOH, -C(0)NR 1 R 2 , or a 5-membered heterocyclic or heteroaryl ring having 1-3 heteroatoms selected from N, NH, O, SO, and S0 2 ; wherein the 5- membered heterocyclic or heteroaryl ring has 0-3 substituents selected
  • R 1 and R 2 are independently selected from:
  • R 1 and R 2 may be taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered aromatic or non-aromatic ring having 0- 3 substituents independently selected from J, and having 0-3 additional heteroatoms independently selected from N, O, S, SO, or S0 2 ;
  • R 1 and R 2 are independently substituted at each substitutable position with 0-3 substituents independently selected from J;
  • R is H, halogen or (Cl-C12)-aliphatic-, wherein said (Cl-C12)-aliphatic group is substituted with 0-3 substituents independently selected from J;
  • a and B are each independently selected from:
  • each J is independently selected from:
  • each R 3 is independently selected from:
  • R 3 groups bound to the same atom may be taken together with the atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 1-3 heteroatoms independently selected from N, O, S, SO, and S0 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5- C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl.
  • the compound of formula I is not:
  • the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof that is useful in the methods and compositions of this invention include both typical and atypical antipsychotics.
  • the antipsychotics suitable for use in the present invention are selected from atypical antipsychotics, including, but not limited to, those disclosed in, for example, U.S.
  • atypical antipsychotics suitable for use in the present invention include, but are not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone and ziprasidone, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • the antipsychotic of this invention is selected from aripiprazole (Bristol-Myers Squibb), olanzapine (Lilly) and ziprasidone (Pfizer), and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • the antipsychotics suitable for use in the present invention are typical antipsychotics, including, but not limited to, acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine, chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine, droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levosulpiride, loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, pipotiazine, prochlorperazine, promazine, promethazine
  • the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be selected from compounds that are dopaminergic agents (such as dopamine Dl receptor antagonists or agonists, dopamine D 2 receptor antagonists or partial agonists, dopamine D3 receptor antagonists or partial agonists, dopamine D4 receptor antagonists), glutamatergic agents, N-methyl-D-aspartate (NMD A) receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), Ml muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), hist
  • dopaminergic agents such as dopamine
  • AMPA kainate receptor antagonists
  • ampakines CX-516
  • glutathione prodrugs noradrenergic agents (such as alpha-2 adrenergic receptor agonists or antagonists and catechol-O-methyl transferase (COMT) inhibitors)
  • serotonin receptor modulators such as 5-HT 2 A receptor antagonists, 5-HT I A receptor partial agonists, 5-HT 2 c agonists, and 5-HT6 antagonists
  • cholinergic agents such as alpha-7 nicotinic receptor agonists, alpha4-beta2 nicotinic receptor agonists, allosteric modulators of nicotinic receptors and acetylcholinesterase inhibitors, muscarinic receptor agonists and antagonists
  • cannabinoid CB 1 antagonists neurokinin 3 antagonists, neurotensin agonists, monoamine oxidase (MAO) B inhibitors, PDE10 inhibitors, neuronal nitric oxide syntha
  • the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof that is useful in the methods and compositions of this invention include compounds that may be used to treat at least one sign or symptom of schizophrenia or bipolar disorder (in particular, mania).
  • the a5 -containing GABAA receptor agonist and the antipsychotic, or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs are administered simultaneously, or sequentially, or in a single formulation, or in separate formulations packaged together.
  • the a5-containing GABAA receptor agonist and the antipsychotic, or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs are administered via different routes.
  • “combination” includes administration by any of these formulations or routes of administration.
  • the combined treatment has a longer or improved therapeutic effect in the subject than is attained by
  • the combined treatment has a longer or improved therapeutic effect in the subject than is attained by
  • a5-containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in the absence of the antipsychotic or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof by at least about 1.5x, or 2.
  • a method of increasing the therapeutic index of an antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in a method of treating schizophrenia or bipolar disorder (in particular, mania) in a subject in need or at risk thereof comprising administering a a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in combination with the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof to said subject.
  • the increase in the therapeutic index of the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is greater than the therapeutic index of the antipsychotic or a
  • a pharmaceutical composition for treating a subject suffering from schizophrenia or bipolar disorder (in particular, mania), or at risk thereof comprising a a5-containing GABAA receptor agonist and an antipsychotic or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof.
  • the composition of this invention is for treating one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia.
  • the composition of this invention is for treating one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania).
  • the composition is in a liquid form.
  • the composition is in an aqueous solution.
  • the composition is in a suspension form. In some embodiments, the composition is in a sustained release form, or a controlled release form, or a delayed release form, or an extended release form. In some embodiments, the composition is in a unit dosage form. In other embodiments, the two components of the compositions are in separate delivery forms packaged together.
  • Figures 1(A)-(D) are graphs showing functional selectivity data, as demonstrated by the potentiation of GAB A EC50 concentration in Xenopus oocytes containing GABAA 5 receptors ( ⁇ 5 ⁇ 3 ⁇ 2) vs. l receptors ( 1 ⁇ 2 ⁇ 2), in the presence of test compounds.
  • Figure 1(A) shows the functional selectivity data for compound 4;
  • Figure 1(B) shows the functional selectivity data for compound 27;
  • Figure 1(C) shows the functional selectivity data for compound 26;
  • Figure 1(D) shows the functional selectivity data for compound 29.
  • Figure 2 is a graph depicting the effects of administering methyl 3,5- diphenylpyridazine-4-carboxylate on the spatial memory retention of ten aged- impaired (Al) rats in an eight-arm Radial Arm Maze (RAM) test.
  • the black bars refer to rats treated with vehicle alone; open bars refer to rats treated with methyl 3,5-diphenylpyridazine-4-carboxylate at different doses; hatched bar refers to rats treated with the combination of TB21007 and methyl 3,5-diphenylpyridazine-4- carboxylate.
  • Figure 3 is a graph showing the effect of methyl 3,5-diphenylpyridazine- 4-carboxylate (administered intravenously) on the binding of Ro 154513 in the hippocampus and cerebellum.
  • Methyl 3,5-diphenylpyridazine-4-carboxylate blocked the binding of Ro 154513 in the hippocampus but did not affect binding of Ro 15413 in the cerebellum.
  • Figure 4 is a graph showing dose-dependent GABAA a5 receptor occupancy by methyl 3,5-diphenylpyridazine-4-carboxylate administered intravenously, with receptor occupancy determined either by the ratio between hippocampus (a region of high GABAA(X5 receptor density) exposure of RO 15- 4513 and cerebellum (a region with low GABAA(X5 receptor density) exposure of RO 15-4513, or by using the GABA A a5 selective compound L-655,708 (10 mg/kg, i.v.) to define full occupancy.
  • Figure 5 is a graph showing exposure occupancy relationships for methyl 3,5-diphenylpyridazine-4-carboxylate in hippocampus. Methyl 3,5- diphenylpyridazine-4-carboxylate occupies about 32% of GABAA 5 receptors at exposures which are behaviorally active in aged-impaired rats.
  • Figure 6 is a graph depicting the effect of ethyl 3-methoxy-7-methyl-9H- benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepine-10-carboxylate on the spatial memory retention of ten aged-impaired (AI) rats in an eight-arm Radial Arm Maze (RAM) test.
  • Figure 6 shows the effect of ethyl 3-methoxy-7-methyl- 9H-benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepine-10-carboxylate on the spatial memory retention of ten aged-impaired (AI) rats in the RAM test, where the vehicle control was tested 3 times, and the different doses of ethyl 3-methoxy- 7-methyl-9H-benzo[fJimidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepine-10- carboxylate were tested twice.
  • black bars refer to rats treated with vehicle alone and open bars refer to rats treated with ethyl 3-methoxy-7-methyl- 9H-benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepine-10-carboxylate at different doses.
  • Figure 7 is a graph showing the effect of ethyl 3-methoxy-7-methyl-9H- benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepine-10-carboxylate (administered intravenously) on the binding of Ro 154513 in the hippocampus and cerebellum.
  • Figure 8 is a graph showing dose-dependent GABAA 5 receptor occupancy by ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[l,5- a][l,2,4]triazolo[4,3-d][l,4]diazepine-10-carboxylate administered intravenously, as calculated by the ratio between hippocampus (a region of high GABAA(X5 receptor density) exposure of RO 15-4513 and cerebellum (a region with low GABA A a5 receptor density) exposure of RO 15-4513 to define full occupancy. .
  • Figure 9(A)-(C) are graphs showing the effect of 6,6 dimethyl-3-(3- hydroxypropyl)thio- 1 -(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one, as compared to vehicle dimethyl sulfoxide (DMSO), in aged-impaired rats using a
  • Figure 9(A) shows the escape latency (i.e., the average time in seconds rats took to find the hidden platform in the water pool) during training in rats received 6,6 dimethyl-3-(3-hydroxypropyl)thio-l-(thiazol-2- yl)-6,7-dihydro-2-benzothiophen-4(5H)-one and rats received vehicle DMSO;
  • Figure 9(B) shows the amount of time spent in target annulus and opposite annulus by rats received 6,6 dimethyl-3-(3-hydroxypropyl)thio-l-(thiazol-2-yl)-6,7- dihydro-2-benzothiophen-4(5H)-one and rats received vehicle DMSO;
  • Figure 9(C) shows number of crossing in target annulus and opposite annulus by rats received 6,6 dimethyl-3-(3-hydroxypropyl)thio- 1 -(thiazol-2-yl)-6,7-dihydro-2- benzothiophen-4(5H)-one and
  • agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
  • Agents include, for example, agents which are known with respect to structure, and those which are not known with respect to structure.
  • a "patient”, “subject”, or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
  • Cognitive function or “cognitive status” refers to any higher order intellectual brain process or brain state, respectively, involved in learning and/or memory including, but not limited to, attention, information acquisition, information processing, working memory, short-term memory, long-term memory, anterograde memory, retrograde memory, memory retrieval, discrimination learning, decision-making, inhibitory response control, attentional set-shifting, delayed reinforcement learning, reversal learning, the temporal integration of voluntary behavior, expressing an interest in one's surroundings and self-care, speed of processing, reasoning and problem solving and social cognition.
  • cognitive function may be measured, for example and without limitation, by the clinical global impression of change scale (CIBIC-plus scale); the Mini Mental State Exam (MMSE); the Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale (CDR); the Cambridge Neuropsychological Test Automated Battery (CANTAB); the Sandoz Clinical Assessment-Geriatric (SC AG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974); the Verbal Paired Associates subtest; the Logical Memory subtest; the Visual
  • cognitive function may be measured in various conventional ways known in the art, including using a Morris Water Maze
  • MLM Microsoft Access to Browse Ratio
  • Barnes circular maze a nursing woman
  • elevated radial arm maze a nursing woman
  • T maze a nursing woman
  • cognitive function can be assessed by reversal learning, extradimensional set shifting, conditional discrimination learning and assessments of reward expectancy.
  • Other tests known in the art may also be used to assess cognitive function, such as novel object recognition and odor recognition tasks.
  • Cognitive function may also be measured using imaging techniques such as Positron Emission Tomography (PET), functional magnetic resonance imaging (fMRI), Single Photon Emission Computed Tomography (SPECT), or any other imaging technique that allows one to measure brain function.
  • imaging techniques such as Positron Emission Tomography (PET), functional magnetic resonance imaging (fMRI), Single Photon Emission Computed Tomography (SPECT), or any other imaging technique that allows one to measure brain function.
  • cognitive function may also be measured with electrophysiological techniques.
  • “Promoting” cognitive function refers to affecting impaired cognitive function so that it more closely resembles the function of a normal, unimpaired subject. Cognitive function may be promoted to any detectable degree, but in humans preferably is promoted sufficiently to allow an impaired subject to carry out daily activities of normal life at the same level of proficiency as a normal, unimpaired subject. [0044] "Preserving" cognitive function refers to affecting normal or impaired cognitive function such that it does not decline or does not fall below that observed in the subject upon first presentation or diagnosis, or delays such decline.
  • “Improving” cognitive function includes promoting cognitive function and/or preserving cognitive function in a subject.
  • “Cognitive impairment” refers to cognitive function in subjects that is not as robust as that expected in a normal, unimpaired subject. In some cases, cognitive function is reduced by about 5%, about 10%, about 30%, or more, compared to cognitive function expected in a normal, unimpaired subject. In other cases, “cognitive impairment” in subjects affected by schizophrenia or bipolar disorder (in particular, mania) refers to cognitive function in subjects that is not as robust as that expected in normal, unimpaired subject.
  • Schirhrenia refers to a chronic debilitating disorder, characterized by a spectrum of psychopathology, including positive symptoms such as aberrant or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by diminution of motivation and adaptive goal-directed action (e.g., anhedonia, affective flattening, avolition), and cognitive impairment. While abnormalities in the brain are proposed to underlie the full spectrum of psychopathology in schizophrenia, currently available antipsychotics are largely ineffective in treating cognitive impairments in patients.
  • BP Bipolar disorder
  • manic depressive disorder or “manic depressive illness” refers to a chronic psychological/mood disorder which can be characterized by significant mood changes including periods of depression and euphoric manic periods.
  • BP may be diagnosed by a skilled physician based on personal and medical history , interview consultation and physical examinations.
  • mania or “manic periods” or other variants refers to periods where an individual exhibits some or all of the following characteristics: racing thoughts, rapid speech, elevated levels of activity and agitation as well as an inflated sense of self-esteem, euphoria, poor judgment, insomnia, impaired concentration and aggression.
  • Treating" a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, preventing or slowing the progression of the disease or disorder, or alleviation, amelioration, or slowing the progression, of one or more symptoms associated with CNS disorders with cognitive impairment, such as schizophrenia or bipolar disorder (in particular, mania).
  • Treating cognitive impairment refers to taking steps to improve cognitive function in a subject with cognitive impairment so that the subject's performance in one or more cognitive tests is improved to any detectable degree, or is prevented from further decline.
  • that subject's cognitive function after treatment of cognitive impairment, more closely resembles the function of a normal, unimpaired subject.
  • Treatment of cognitive impairment in humans may improve cognitive function to any detectable degree, but is preferably improved sufficiently to allow the impaired subject to carry out daily activities of normal life at the same level of proficiency as a normal, unimpaired subject.
  • treating cognitive impairment refers to taking steps to improve cognitive function in a subject with cognitive impairment so that the subject's performance in one or more cognitive tests is improved to any detectable degree, or is prevented from further decline.
  • that subject's cognitive function, after treatment of cognitive impairment more closely resembles the function of a normal, unimpaired subject.
  • “treating cognitive impairment” in a subject affecting by schizophrenia or bipolar disorder (in particular, mania) refers to takings steps to improve cognitive function in the subject so that the subject's cognitive function, after treatment of cognitive impairment, more closely resembles the function of normal, unimpaired subject.
  • administering or "administration of a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitonealy, intravenously, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow, or controlled release of the compound or agent.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • the administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug, or to have the drug administered by another and/or who provides a patient with a prescription for a drug is
  • a compound or an agent is administered orally, e.g., to a subject by ingestion, or intravenously, e.g., to a subject by injection.
  • the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
  • a "a5-containing GABAA receptor agonist”, "a5- containing GABAA R agonist” or a “GABAA 5 receptor agonist” and other variations as used herein refer to a compound that up-regulates the function of a5- containing GABAA receptor (GABAA R), i.e., a compound that increase GABA- gated CI " currents.
  • GABAA R GABAA receptor
  • a5 -containing GABAA R agonist as used herein refers to a positive allosteric modulator, which potentiates the activity of GAB A.
  • antipsychotic compound refers to (1) a typical or an atypical antipsychotic; (2) an agent that is selected from dopaminergic agents, glutamatergic agents, NMDA receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), Ml muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, AMPA/kainate receptor antagonists, ampakines (CX-516), glutathione prodrugs, noradrenergic agents, serotonin receptor modulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin 3 antagonists, neurotensin, neuro
  • Typical antipsychotics refer to conventional antipsychotics, which produce antipsychotic effects as well as movement related adverse effects related to disturbances in the mgrostriatal dopamine system.
  • EPS extrapyramidal side effects
  • dyskinesia and dystonia See Baldessarini and Tarazi in Goodman & Oilman's The Pharmacological Basis of Therapeutics 10 Edition, 2001, pp. 485-520.
  • Antipsychotics refer to antipsychotic drugs that produce antipsychotic effects with little or no EPS and include, but are not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone,
  • Atypical antipsychotics differ from conventional antipsychotics in their pharmacological profiles. While conve tional antipsychotics are characterized principally by D 2 dopamine receptor blockade, atypical antipsychotics show antagonist effects on multiple receptors including the 5HT a and 5HT C serotonin receptors and varying degrees of receptor affinities. Atypical antipsychotic drugs are commonly referred to as
  • atypical antipsychotics often display side effects, including, but not limited to, weight gain, diabetes (e.g., type ⁇ diabetes mellitus), hyperlipidemia, QTc interval prolongation, myocarditis, sexual side effects, extrapyramidal side effects and cataract.
  • side effects including, but not limited to, weight gain, diabetes (e.g., type ⁇ diabetes mellitus), hyperlipidemia, QTc interval prolongation, myocarditis, sexual side effects, extrapyramidal side effects and cataract.
  • atypical antipsychotics do not represent a homogeneous class, given their differences in the context of both alleviation of clinical symptoms and their potential for inducing side effects such as the ones listed above.
  • the common side effects of the atypical antipsychotics as described above often limit the antipsychotic doses that can be used for these agents.
  • a5- containing GABAA receptor agonist and the antipsychotic, or their pharmaceutically acceptable salts, hydrates, solvates, or polymorphs are administered with a time separation of no more than about 15 minutes, and in some embodiments no more than about 10 minutes.
  • the a5 -containing GABAA receptor agonist and the antipsychotic, or their salts, hydrates, solvates, or polymorphs may be contained in the same dosage (e.g., a unit dosage form comprising both the a5-containing GABAA receptor agonist and the antipsychotic) or in discrete dosages (e.g., the a5-containing GABAA receptor agonist or its salt, hydrate, solvate, or polymorph is contained in one dosage form and the antipsychotic or its salt, hydrate, solvate, or polymorph is contained in another dosage form).
  • a5-containing GABAA receptor agonist or the antipsychotic may be administered first.
  • the a5 -containing GABAA receptor agonist and the antipsychotic, or their salts, hydrates, solvents, or polymorphs, for sequential administration may be contained in discrete dosage forms, optionally contained in the same container or package.
  • a "therapeutically effective amount" of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended
  • therapeutic effect e.g. improving cognitive function in a subject suffering from a disease or disorder (e.g., schizophrenia or bipolar disorder (in particular, mania)), preventing or slowing the progression of a disease or disorder (e.g., schizophrenia or bipolar disorder (in particular, mania)), and/or alleviating, ameliorating, or slowing the progression of one or more symptoms associated with the disease or disorder (e.g., schizophrenia).
  • a disease or disorder e.g., schizophrenia or bipolar disorder (in particular, mania)
  • preventing or slowing the progression of a disease or disorder e.g., schizophrenia or bipolar disorder (in particular, mania)
  • alleviating, ameliorating, or slowing the progression of one or more symptoms associated with the disease or disorder e.g., schizophrenia.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations.
  • the precise effective amount needed for a subject will depend upon, for example, the subject's size, health and age, the nature and extent of the cognitive impairment, and the therapeutics or combination of therapeutics selected for administration, and the mode of administration. The skilled worker can readily determine the effective amount for a given situation by routine
  • Subject therapeutic amount refers to an amount administered of an agent or compound of the invention that is less than the therapeutic amount, that is, less than the amount normally used when said agent or compound is administered alone (i.e., individually and in the absence of other therapeutic agents or compounds) to treat disorders, such as schizophrenia or bipolar disorder (in particular, mania).
  • Analog is used herein to refer to a compound which functionally resembles another chemical entity, but does not share the identical chemical structure.
  • an analog is sufficiently similar to a base or parent compound such that it can substitute for the base compound in therapeutic applications, despite minor structural differences.
  • “Derivative” is used herein to refer to the chemical modification of a compound. Chemical modifications of a compound can include, for example, replacement of hydrogen by an alkyl, acyl, or amino group. Many other
  • prodrug is art-recognized and is intended to encompass compounds or agents which, under physiological conditions, are converted into a a5-containing GABAA receptor agonist or an antipsychotic.
  • a common method for making a prodrug is to select moieties which are hydrolyzed or metabolized under physiological conditions to provide the desired compound or agent.
  • the prodrug is converted by, for example, an enzymatic activity of the host animal to a a5 -containing GABAA receptor agonist or an antipsychotic.
  • aliphatic as used herein means a straight chained or branched alkyl, alkenyl or alkynyl. It is understood that alkenyl or alkynyl embodiments need at least two carbon atoms in the aliphatic chain. Aliphatic groups typically contains from 1 (or 2) to 12 carbons, such as from 1 (or 2) to 4 carbons.
  • aryl as used herein means a monocyclic or bicyclic
  • aryl as used herein can be a C5- CIO monocyclic or C8-C12 bicyclic carbocyclic aromatic ring system.
  • Phenyl is an example of a monocyclic aromatic ring system.
  • Bicyclic aromatic ring systems include systems wherein both rings are aromatic, e.g., naphthyl, and systems wherein only one of the two rings is aromatic, e.g., tetralin.
  • heterocyclic as used herein means a monocyclic or bicyclic non-aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH, S, SO, or S0 2 in a chemically stable arrangement.
  • heterocyclic as used herein can be a C5-C10 monocyclic or C8-C12 bicyclic non-aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH, S, SO, or S0 2 in a chemically stable arrangement.
  • heterocyclyl one or both rings may contain said heteroatom or heteroatom groups.
  • one of the two rings may be aromatic.
  • a non-aromatic heterocyclic ring may optionally be fused to an aromatic carbocycle.
  • heterocyclic rings examples include 3-lH-benzimidazol-2-one, 3-(l- alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4- morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1- pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2- tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl
  • heteroaryl as used herein means a monocyclic or bicyclic aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH or S in a chemically stable arrangement.
  • heteroaryl as used herein can be a C5-C10 monocyclic or C8-C12 bicyclic aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH or S in a chemically stable arrangement.
  • - both rings are aromatic
  • heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazo
  • cycloalkyl or cycloalkenyl refers to a monocyclic or fused or bridged bicyclic carbocyclic ring system that is not aromatic.
  • cycloalkyl or cycloalkenyl as used herein can be a C5-C10 monocyclic or fused or bridged C8-C12 bicyclic carbocyclic ring system that is not aromatic.
  • Cycloalkenyl rings have one or more units of unsaturation.
  • Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl and decalinyl.
  • the carbon atom designations may have the indicated integer and any intervening integer.
  • the number of carbon atoms in a (Cl-C4)-alkyl group is 1, 2, 3, or 4. It should be understood that these designation refer to the total number of atoms in the appropriate group.
  • the total number of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9, or 10.
  • “Pharmaceutically acceptable salt” is used herein to refer to an agent or a compound according to the invention that is a therapeutically active, non-toxic base and acid salt form of the compounds.
  • the acid addition salt form of a compound that occurs in its free form as a base can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p- aminosalicylic, pamoic and the like. See, e.g., WO 01
  • Compounds containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt form, e. g. metal or amine salts, by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e. g., lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e. g. N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
  • solvates include for example hydrates, alcoholates and the like. See, e.g., WO 01/062726.
  • hydrate refers to a combination of water with a compound wherein the water retains its molecular state as water and is either absorbed, adsorbed or contained within a crystal lattice of the substrate compound.
  • polymorph refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo- polymorphs, such as hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.
  • pseudo- polymorphs such as hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.
  • pseudo- polymorphs such as hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.
  • Different crystalline polymorphs have different crystal structures due to a different packing of the molecules in the lattice. This results in a different crystal symmetry and/or unit cell parameters which directly influences its physical properties such the X-ray diffraction characteristics of crystals or powders.
  • a different polymorph for example, will in general diffract at a different
  • Crystalline polymorphic forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the polymorphic form is not held constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selected polymorphic form in high purity when the compound is used in clinical studies or commercial products since Impurities present may produce undesired toxicological effects. Certain polymorphic forms may exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain
  • polymorphs may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, and enhanced rates of dissolution due to different lattice energies.
  • stereogenic center in their structure.
  • This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45,11-30.
  • the invention also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726.
  • certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (ent ought) isomers. In each instance, the invention includes both mixture and separate individual isomers.
  • the methods of this invention comprise administration of a a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt thereof in combination with administration of an antipsychotic or a pharmaceutically acceptable salt thereof.
  • the agents or compounds of the a5 -containing GABAA receptor agonist or the antipsychotic and their pharmaceutically acceptable salts also include hydrates, solvates, polymorphs, and prodrugs of those agents, compounds, and salts.
  • Animal models serve as an important resource for developing and evaluating treatments for CNS disorders with cognitive impairment.
  • Features that characterize cognitive impairment in animal models typically extend to cognitive impairment in humans. Efficacy in such animal models is, thus, expected to be predictive of efficacy in humans.
  • the extent of cognitive impairment in an animal model for a CNS disorder, and the efficacy of a method of treatment for said CNS disorder may be tested and confirmed with the use of a variety of cognitive tests.
  • a Radial Arm Maze (RAM) behavioral task is one example of a cognitive test, specifically testing spacial memory (Chappell et al. Neuropharmacology 37: 481-487, 1998).
  • the RAM apparatus consists of, e.g., eight equidistantly spaced arms. A maze arm projects from each facet of a center platform. A food well is located at the distal end of each arm. Food is used as a reward. Blocks can be positioned to prevent entry to any arm. Numerous extra maze cues surrounding the apparatus may also be provided. After habituation and training phases, spatial memory of the subjects may be tested in the RAM under control or test compound- treated conditions.
  • subjects are pretreated before trials with a vehicle control or one of a range of dosages of the test compound.
  • a subset of the arms of the eight-arm maze is blocked.
  • Subjects are allowed to obtain food on the unblocked arms to which access is permitted during this initial "information phase" of the trial.
  • Subjects are then removed from the maze for a delay period, e.g., a 60 second delay, a 15 minute delay, a one-hour delay, a two-hour delay, a six hour delay, a 24 hour delay, or longer) between the information phase and the subsequent "retention test," during which the barriers on the maze are removed, thus allowing access to all eight arms.
  • Another cognitive test that may be used to assess the effects of a test compound on the cognitive impairment of a CNS disorder model animal is the Morris water maze.
  • a water maze is a pool surrounded with a novel set of patterns relative to the maze.
  • the training protocol for the water maze may be based on a modified water maze task that has been shown to be hippocampal-dependent (de Hoz et al, Eur. J. Neurosci., 22:745-54, 2005; Steele and Morris, Hippocampus 9: 118-36, 1999).
  • the subject is trained to locate a submerged escape platform hidden underneath the surface of the pool.
  • a subject is released in the maze (pool) from random starting positions around the perimeter of the pool.
  • the starting position varies from trial to trial. If the subject does not locate the escape platform within a set time, the experimenter guides and places the subject on the platform to "teach" the location of the platform. After a delay period following the last training trial, a retention test in the absence of the escape platform is given to assess spatial memory.
  • the subject's level of preference for the location of the (now absent) escape platform as measured by, e.g., the time spent in that location or the number of crossings of that location made by the mouse, indicates better spatial memory, i.e., treatment of cognitive impairment.
  • the preference for the location of the escape platform under different treatment conditions can then be compared for efficacy of the test compound in treating CNS disorders with cognitive impairment.
  • NPI Neuropsychiatric Inventory
  • CDR Clinical Dementia Rating Scale
  • CANTAB Cambridge Neuropsychological Test Automated Battery
  • SCAG Sandoz Clinical Assessment-Geriatric
  • WMS-R Wechsler Memory Scale- Revised
  • MATRICS Benton Visual Retention Test
  • This invention provides methods and compositions for treating
  • treatment comprises preventing or slowing the
  • Schizophrenia is characterized by a wide spectrum of psychopathology, including positive symptoms such as aberrant or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by diminution of motivation and adaptive goal-directed action (e.g., anhedonia, affective flattening, avolition), and cognitive impairment.
  • treatment comprises alleviation, amelioration or slowing the progression, of one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia.
  • psychiatric diseases such as schizotypical and schizoaffective disorder, other acute- and chronic psychoses and bipolar disorder (in particular, mania), which have an overlapping
  • treatment comprises alleviation, amelioration or slowing the progression of one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania).
  • bipolar disorder in particular, mania
  • the methods and compositions may be used for human patients in clinical applications in treating schizophrenia or bipolar disorder (in particular, mania).
  • the dose of the composition and dosage interval for the method is, as described herein, one that is safe and efficacious in those applications.
  • Cognitive impairments are associated with schizophrenia. They precede the onset of psychosis and are present in non-affected relatives. The cognitive impairments associated with schizophrenia constitute a good predictor for functional outcome and are a core feature of the disorder. Cognitive features in schizophrenia reflect dysfunction in frontal cortical and hippocampal circuits.
  • Animal models serve as an important resource for developing and evaluating treatments for schizophrenia.
  • Features that characterize schizophrenia in animal models typically extend to schizophrenia in humans.
  • efficacy in such animal models is expected to be predictive of efficacy in humans.
  • Various animal models of schizophrenia are known in the art.
  • One animal model of schizophrenia is protracted treatment with methionine.
  • Methionine-treated mice exhibit deficient expression of GAD67 in frontal cortex and hippocampus, similar to those reported in the brain of postmortem schizophrenia patients. They also exhibit prepulse inhibition of startle and social interaction deficits (Tremonlizzo et al, PNAS, 99: 17095-17100, 2002).
  • Another animal model of schizophrenia is methylaoxymethanol acetate (MAM)-treatment in rats. Pregnant female rats are administered MAM (20 mg/kg, intraperitoneal) on gestational day 17. MAM -treatment recapitulate a
  • MAM-treated rats display a decreased density of parvalbumin-positive GABAergic interneurons in portions of the prefrontal cortex and hippocampus.
  • MAM-treated rats display reduced latent inhibition.
  • Latent inhibition is a behavioral phenomenon where there is reduced learning about a stimulus to which there has been prior exposure with any consequence. This tendency to disregard previously benign stimuli, and reduce the formation of association with such stimuli is believed to prevent sensory overload. Low latent inhibition is indicative of psychosis.
  • Latent inhibition may be tested in rats in the following manner. Rats are divided into two groups. One group is pre- exposed to a tone over multiple trials.
  • the other group has no tone presentation. Both groups are then exposed to an auditory fear conditioning procedure, in which the same tone is presented concurrently with a noxious stimulus, e.g. an electric shock to the foot. Subsequently, both groups are presented with the tone, and the rats' change in locomotor activity during tone presentation is monitored. After the fear conditioning the rats respond to the tone presentation by strongly reducing locomotor activity. However, the group that has been exposed to the tone before the conditioning period displays robust latent inhibition: the suppression of locomotor activity in response to tone presentation is reduced. MAM-treated rats, by contrast show impaired latent inhibition. That is, exposure to the tone previous to the fear conditioning procedure has no significant effect in suppressing the fear conditioning, ⁇ see Lodge et ah, J. Neurosci., 29:2344-2354, 2009) Such animal models of schizophrenia may be used to assay the effectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania).
  • a noxious stimulus e.g. an electric shock
  • MAM-treated rats display a significantly enhanced locomotor response (or aberrant locomotor activity) to low dose D-amphetamine administration.
  • the MAM-treated rats also display a significantly greater number of spontaneously firing ventral tegmental dopamine (DA) neurons.
  • DA ventral tegmental dopamine
  • the above results are believed to be a consequence of excessive hippocampal activity because in MAM-treated rats, the ventral hippocampus (vHipp) inactivation (e.g., by intra vHipp administration of a sodium channel blocker, tetrodotoxin (TTX) to MAM rats) completely reversed the elevated DA neuron population activity and also normalized the augmented amphetamine-induced locomotor behavior.
  • vHipp ventral hippocampus
  • TTX tetrodotoxin
  • the methods and compositions of this invention maybe evaluated, using MAM-treated animals, for their effects on the central hippocampus (vHipp) regulation, on the elevated DA neuron population activity and on the hyperactive locomotor response to amphetamine in the MAM- treated animals.
  • vHipp central hippocampus
  • HPC hippocampal
  • a benzodiazepine-positive allosteric modulator (PAM) selective for the a5 subunit of the GABAA receptor, SH-053-2'F-R-CH 3 is tested for its effects on the output of the hippocampal (HPC).
  • the effect of SH-053-2 - Pv-CH 3 on the hyperactive locomotor response to amphetamine in MAM-treated animals is also examined.
  • the a5GABAAR PAM reduces the number of spontaneously active DA neurons in the ventral tegmental area (VTA) of MAM rats to levels observed in saline treated rats (control group), both when
  • MAM-treated rats in the above study may be suitable for use in the present invention to assay the effectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania).
  • the methods and compositions of this invention maybe evaluated, using MAM-treated animals, for their effects on the output of the hippocampal (HPC) and on the hyperactive locomotor response to amphetamine in the MAM-treated animals.
  • Such animal models of schizophrenia may be used to assay the effectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania).
  • Apomorphine-induced climbing (AIC) and stereotype (AIS) in mice is another animal model useful in this invention.
  • Agents are administered to mice at a desired dose level (e.g., via intraperitoneal administration).
  • a desired dose level e.g., via intraperitoneal administration.
  • experimental mice are challenges with apomorphine (e.g., with 1 mg/kg sc).
  • the sniffing-licking-gnawing syndrome stereotyped behavior
  • climbing behavior induced by apomorphine are scored and recorded for each animal. Readings can be repeated every 5 min during a 30- min test session. Scores for each animal are totaled over the 30-min test session for each syndrome (stereotyped behavior and climbing).
  • the a5 -containing GABAA receptor agonist useful in the present invention may be any a5 -containing GABAA receptor agonist. In some
  • the a5-containing GABAA receptor agonist suitable for use in the methods and compositions of the present invention is selected from the compounds disclosed in, e.g., U.S. Patent Application 61/413,971 and PCT publication WO2012068161, which are incorporated herein by reference.
  • the a5-containing GABAA receptor agonist useful in the present invention is a compound of Formula I:
  • R' is -COOH, -C(0)NR 1 R 2 , or a 5-membered heterocyclic or heteroaryl ring having 1-3 heteroatoms selected from N, NH, O, SO, and S0 2 ; wherein the 5- membered heterocyclic or heteroaryl ring has 0-3 substituents selected
  • R 1 and R 2 are independently selected from:
  • R 1 and R 2 may be taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered aromatic or non-aromatic ring having 0-
  • R 1 and R 2 are independently substituted at each substitutable position with 0-3 substituents independently selected from J;
  • R is H, halogen or (Cl-C12)-aliphatic-, wherein said (CI -CI 2)- aliphatic is substituted with 0-3 substituents independently selected from J;
  • a and B are independently selected from:
  • a and B are independently substituted with 0-5 substituents independently selected from J;
  • each J is independently selected from:
  • each R 3 is independently selected from:
  • (C5-C 10)-heteroaryl-(C 1 -C 12)-aliphatic-; or two R 3 groups bound to the same atom may be taken together with the atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 1-3 heteroatoms independently selected from N, O, S, SO, and S0 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5- C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl.
  • the a5 -containing GABAA receptor agonist of present invention is a compound of Formula I:
  • R is -C(0)NR 1 R 2 wherein
  • R 1 and R 2 are independently selected from:
  • R 1 and R 2 may be taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered aromatic or non-aromatic ring having 0- 3 additional heteroatoms independently selected from N, O, S, SO, and S0 2 ; wherein each of R 1 and R 2 is independently substituted at each substitutable position with 0-3 substituents independently selected from J;
  • R is a 5-membered heteroaryl ring having 1-3 heteroatoms selected from N, NH, O, SO, and S0 2 ; wherein the 5-membered heteroaryl ring has 0-2 substituents selected independently from J;
  • R is H, halogen or (Cl-C12)-aliphatic-, wherein said CI -CI 2 aliphatic group is substituted with 0-3 substituents independently selected from J;
  • a and B are independently selected from:
  • each J is independently selected from:
  • each R 3 is independently selected from:
  • R 3 groups bound to the same atom may be taken together with the atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 1- 3 heteroatoms independently selected from N, O, S, SO, and S0 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-
  • C10)heteroaryl (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl.
  • the compound of Formula I is not:
  • the a5 -containing GABAA receptor agonist useful in the present invention is a com ound that has the Formula I-A:
  • R 1 and R 2 are hydrogen.
  • R 1 and R 2 are each independently hydrogen.
  • at least one of R 1 and R 2 is (Cl-C12)-aliphatic- substituted at each substitutable position with 0-3 substituents independently selected from J.
  • R 1 and R 2 are each independently (Cl-C12)-aliphatic- substituted at each substitutable position with 0- 3 substituents independently selected from J.
  • R 1 and R 2 are each independently unsubstituted (Cl-C4)-aliphatic groups, such as methyl, ethyl or allyl.
  • R 1 and R 2 are each independently (Cl-C4)-alkyl, and wherein at least one of R 1 and R 2 is substituted with at least one (C6-C10)- aryl, such as phenyl.
  • R 1 and R 2 are each independently (Cl-C4)-alkyl, and R 1 and R 2 are each independently substituted with at least one (C6-C10)-aryl, such as phenyl.
  • R 1 is H- and R 2 is (Cl-C12)-aliphatic- substituted at each substitutable position with 0-3 substituents independently selected from J.
  • R 1 is H- and R 2 is unsubstituted (Cl- C4)-alkyl, such as methyl or isopropyl.
  • R 1 is H- and R 2 is (Cl-C12)-aliphatic- that is substituted with at least one (C6-C10)-aryl group, such as where R 2 is a phenyl-(Cl-C4)-alkyl- group.
  • R 1 and R 2 taken together with the atom to which they are attached form a C5-C10 aromatic or non- aromatic ring.
  • these rings include a 5-membered aromatic or non- aromatic ring.
  • R 1 and R 2 taken together with the atom to which they are attached form a pyrrolidine ring.
  • the a5 -containing GABAA receptor agonist useful in the present invention is a compound that has the Formula I-B:
  • R 4 and R 5 are each independently selected from:
  • X is-O-.
  • Y is -CR 4 - and R 4 is H or (Cl-C12)-aliphatic.
  • Y is -CR 4 - and R 4 is H.
  • Y is -CR 4 - and R 4 is (Cl-C4)-alkyl.
  • R 5 is (Cl-C12)-aliphatic- or -C(0)OR 3 .
  • R 5 is (Cl-C4)-alkyl, such as methyl or ethyl.
  • R 5 is -C(0)OR 3 , wherein R 3 is (Cl-C12)aliphatic, such as (C1-C4)- alkyl-.
  • R 5 is -C(0)OMe.
  • X is -0-
  • R 5 is (Cl- C12)-aliphatic- or -C(0)OR 3 .
  • the a5 -containing GABAA receptor agonist useful in the present invention is a compound that has the Formula I-C:
  • the a5 -containing GABAA receptor agonist useful in the present invention is a compound that has the Formula I-D:
  • X, Y and Z are each independently selected from -C(R 4 ) 2 -, N(R 4 ), N, O, and S; and each of R 4 and R 5 are independently selected from:
  • X is-O-.
  • Y is -C(R 4 ) 2 .
  • Y is -C(R 4 ) 2 and at least one R 4 is H or (Cl-C12)-aliphatic.
  • Y is -C(R 4 ) 2 and each R 4 is independently H.
  • Y is -C(R 4 ) 2 , where at least one R 4 is (Cl-C4)-alkyl-.
  • R 5 is (Cl-C12)-aliphatic- or -C(0)OR 3 .
  • R 5 is (Cl-C4)-alkyl, such as methyl or ethyl.
  • R 5 is -C(0)OR 3 , where R 3 is (Cl-C12)aliphatic, such as (C1-C4)- alkyl-.
  • R 5 is -C(0)OMe.
  • X is -0-
  • Y is -C(R 4 ) 2
  • R 5 is (CI -CI 2)- aliphatic- or -C(0)OR 3 .
  • the a5-containing GABAA receptor agonist of the present invention is a compound, wherein A is (C6-C10)-aryl- or (C5-C10)-heteroaryl-, each of said aryl or heteroaryl being independently substituted with 0-5
  • A is phenyl, substituted with 0-5 substituents independently selected from J.
  • A can be phenyl that is unsubstituted or substituted with at least one halogen or - OR 3 .
  • A is phenyl that is substituted with at least one F, CI, or -OCH 3 .
  • A is a 5-membered or 6-membered heteroaryl substituted with 0-5 substituents independently selected from J, such as where A is pyrazolyl or pyridyl. Examples of these 5-membered or 6-membered heteroaryl groups are ones that are unsubstituted or substituted with at least one (CI -CI 2)- aliphatic, such as -CH 3 .
  • the a5 -containing GABAA receptor agonist of the present invention is a compound, wherein B is (C6-C10)-aryl- or (C5-C10)- heteroaryl-, each of said aryl or heteroaryl being independently substituted with 0- 5 substituents independently selected from J.
  • B is phenyl substituted with 0-5 substituents independently selected from J.
  • the invention also includes combinations of A and B as described above.
  • B is phenyl substituted with 0-5 substituents independently selected from J
  • A is phenyl, pyrazolyl or pyridyl, substituted with 0- 3 substituents independently selected from J.
  • the a5 -containing GABAA receptor agonist of the present invention is a compound of formula I, wherein B is phenyl; A is phenyl, pyrazolyl or pyridyl, substituted with 0-2 substituents independently selected from -OR 3 where R 3 is (Cl-C4)alkyl- (such as -OMe), halogen (such as - CI and -F), and (Cl-C4)alkyl- (such as -Me); R is hydrogen; R' is selected from the group consisting of:
  • R 1 and R 2 are each independently (Cl-C4)-aliphatic- (such as methyl, ethyl and allyl),
  • R 1 and R 2 are each independently (Cl-C4)-alkyl (such as methyl), wherein at least one of R 1 and R 2 is substituted with at least one phenyl,
  • R 1 is H
  • R 2 is (Cl-C4)-alkyl (such as methyl and isopropyl), or R 1 and R 2 taken together with the nitrogen atom to which they are bound form a 5-membered non-aromatic ring (such as a pyrrolidine ring); and (3) a 5-membered heterocyclic or heteroaryl ring having one nitrogen atom and one oxygen atom (such as oxazole or dihydrooxazole); wherein the 5-membered heterocyclic or heteroaryl ring has 0-2 substituents selected independently from (Cl-C4)-alkyl- (such as methyl, ethyl and isopropyl) and -C(0)OR 3 where R 3 is (C 1 -C4)alkyl- (such as -COOMe).
  • the a5-containing GABAA receptor agonist of the present invention is a compound of formula I, wherein B is phenyl; A is phenyl substituted with 0 or 1 substituent selected from
  • R 3 is (Cl-C4)alkyl- (such as -OMe) and halogen (such as -CI); R is hydrogen; R' is selected from the group consisting of:
  • R 1 and R 2 are each independently (Cl-C4)-alkyl- (such as methyl),
  • R 1 and R 2 are each independently (Cl-C4)-alkyl (such as methyl), wherein at least one of R 1 and R 2 is substituted with one phenyl,
  • R 1 is H, and R 2 is (Cl-C4)-alkyl (such as methyl and isopropyl); and
  • a 5-membered heterocyclic or heteroaryl ring having one nitrogen atom and one oxygen atom such as oxazole or dihydrooxazole
  • the 5-membered heterocyclic or heteroaryl ring has 1 substituent selected from (Cl-C4)-alkyl- (such as methyl and ethyl) and -C(0)OR 3 where R 3 (C 1 -C4)alkyl- (such as -COOMe).
  • Examples of particular a5-containing GABAA receptor agonist useful in the present invention include:
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, U C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 C1, 125 I, respectively.
  • the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 13 C, and 14 C, are present.
  • Such isotopically labeled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly preferred for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. [0122] Any of the individual embodiments recited above, including those embodiments defining compounds 1-37, may define Formula I individually or be combined to produce a preferred embodiment of this invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formulas I, I- A, I-B, I-C or I-D or pharmaceutically acceptable salt form thereof and an antipsychotic or pharmaceutically acceptable salt form thereof.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
  • a5-containing GABAA receptor agonists of this invention may be prepared in general by methods known to those skilled in the art.
  • Schemes 1-9 below illustrate synthetic routes to the compounds of the present invention.
  • Other equivalent schemes, which will be readily apparent to the ordinary skilled organic chemist, may alternatively be used to synthesize various portions of the molecules as illustrated by the general schemes below.
  • Scheme 2 above provides a synthetic route for the preparation of compounds of Formula I-A.
  • compounds of Formula I with A, B, R and R other than those depicted above may be prepared by varying chemical reagents or the synthetic route.
  • compounds of Formula I-A wherein R is other than -C(0)NHMe may be prepared by reacting compound 40 with a compound of Formula R X R 2 NH under appropriate basic conditions, as shown in Scheme 3.
  • Scheme 3
  • compounds of Formula I-A wherein A is other than phenyl and R' is other than -C(0)NHMe may be prepared by reacting compound 38 with a boron reagent of formula A-B(Y) n , wherein Y n is -(OH) 2 , -(0-alkyl) 2 ,
  • Scheme 5 provides a general synthetic route for the preparation of compounds of Formula I-B and compounds of Formula I-D.
  • compounds of Formula I-B or Formula I-D with X, Y and Z, other than those depicted in Scheme 5, may be prepared by varying chemical reagents or the synthetic route.
  • Y is -CH 2 - and R 5 is Me-
  • Formula I-Bl (e.g., compounds of Formula I-B, wherein R is H, X is -0-, Z is
  • compounds of Formula I-B with X, Y, Z and R 5 other than those depicted above in Schemes 7-9 may be prepared by varying chemical reagents or the synthetic route.
  • the antipsychotics suitable for use in the present invention may be any antipsychotic drugs or agents or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof.
  • antipsychotics or pharmaceutically acceptable salts, hydrates, solvates, polymorphs and prodrugs thereof that are useful in the methods and compositions of this invention are atypical and typical antipsychotics.
  • the antipsychotic is an atypical antipsychotic or pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof.
  • Atypical antipsychotics offer several clinical benefits including, for example, superior side effect profiles, particularly with regard to extrapyramidal side effects (EPS).
  • mAtypical antipsychotics typically differ from typical antipsychotics in their "limbic-specific" dopamine type 2 (D2)-receptor binding.
  • D2 dopamine type 2
  • Atypical antipsychotics also display a high ratio of serotonin type 2 (5-HT2)- receptor binding to D2 binding.
  • Atypical antipsychotics have high affinity for the 5 -HT2 -receptor and function as antagonists of serotonin for the 5 -HT2 -receptor.
  • atypical antipsychotics include, but are not limited to:
  • Aripiprazole 7-[4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy]-3,4-di- hydrocarbostyril (commercially available from Bristol-Meyers Squibb Co.,
  • Clozapine 8-chloro- 11 -(4-methyl-l-piperaziny l)-5H-dibenzo[b,e] [ 1 ,4]-diazepine (commercially available from Mylan Pharmaceuticals, Morgantown, WV under the trade name Mylan®) is disclosed in U.S. Patent No. 3,539,573, which is herein incorporated by reference. Clinical efficacy of Clozapine in the treatment of schizophrenia has previously been disclosed. Hanes, et al, Psychopharmacol. Bull, 24, 62 (1988).
  • Iloperidone l-[4-[3-[4-(6-Fluoro-l,2-benzisoxazol-3-y[)-l-piperidmyl]propoxy]-3- methoxypheiiyljethanone (under trade name Fanapt®) is disclosed in EP Patent EP402644, which is incorporated herein by reference.
  • the use of iloperidone in treating psychotic symptom and exemplary dosages of iloperidone suitable for such treatment are disclosed in U.S. Patent USRE39198, which is incorporated herein by reference.
  • olanzapine in treating schizophrenia and exemplary dosages of olanzapine for such use are disclosed in U.S. Patents 5,625897, 5627178, 5,817655, 5,919485 and 6960577.
  • Olanzapine polymorphs are disclosed in U.S. Patent 5,736,541, incorporated herein by reference.
  • Olanzapine hydrate forms are disclosed in U.S. Patent 6,251,895, incorporated herein by reference.
  • Paliperidone 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9- tetrahydro-9-hydroxy-2-methyl-4Hpyrido [l,2-a]pyrimidin-4-one (developed by Janssen Pharmaceutica under the trade name Invega® or Invega sustenna®), is disclosed in EP Patent 368388.
  • the use of paliperidone in treating phychosis and exemplary formulations for such use are disclosed in U.S. Patents 5,158,952, 5,254,556, 5,352459, 6,077,843 and 6,555,544, all of which are incorporated herein by reference.
  • Quetiapine 5-[2-(4-dibenzo[b,fJ [1,4] thiazepin-l l-yl-l-piperazinyl)- eth-oxy]ethanol (commercially available from Astra Zeneca, Wilmington, DE under the tradename Seroquel®) its activity in assays which demonstrate utility in the treatment of schizophrenia are disclosed in U.S. Patent No. 4,879,288, which is herein incorporated by reference.
  • Exemplary formulations of quetiapine for use in treating schizophrenia and bipolar disorder are disclosed in U.S. Patent 5,948,437, incorporated herein by reference.
  • Risperidone 3-[2-[4-(6-fluoro- 1 ,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl- 6,7,8,9-tetrahydro-4H-pyrido-[ 1 ,2-a]pyrimidin-4-one (commercially available from Janssen under the trade name Risperdal®) and its use in the treatment of psychotic diseases are disclosed in U.S. Patent No. 4,804,663, which is herein incorporated by reference.
  • Sertindole l-[2-[4-[5-chloro-l-(4-fiuorophenyl)-lH-indol-3-yl]- 1- piperidinyl]ethyl]imidazolidin-2-one, is described in U.S. Patent No. 4,710,500.
  • the antipsychotic for the methods and compositions of this invention is selected from aripiprazole, olanzapine and ziprasidone, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof.
  • the antipsychotic is a typical antipsychotic.
  • typical antipsychotics include, but are not limited to, acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine, chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine, droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levosulpiride, loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, pipotiazine, prochlorperazine, promazine, promazine, pro
  • Suitable antipsychotics or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof for the present invention may be selected from compounds/agents that are dopaminergic agents, glutamatergic agents, NMD A receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), Ml muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, AMPA/kainate receptor antagonists, ampakines (CX-516), glutathione prodrugs, noradrenergic agents, serotonin receptor modulators, cholinergic agents, cannabinoid CB1
  • the antipsychotic is a dopaminergic agent selected from dopamine Dl receptor antagonists or agonists (for example, dihydrexidine, A77636 and SKF81297), dopamine D 2 receptor antagonists or partial agonists (e.g., some typical and atypical antipsychotics), dopamine D3 receptor antagonists or agonists (for example, S33084, SB-277011-A, AVE5997 and ( ⁇ )-PD 128907), dopamine D4 receptor antagonists (for examples, clozapine and sonepiprazole (U- 101387 or PNU-101387G)).
  • dopamine Dl receptor antagonists or agonists for example, dihydrexidine, A77636 and SKF81297
  • dopamine D 2 receptor antagonists or partial agonists e.g., some typical and atypical antipsychotics
  • dopamine D3 receptor antagonists or agonists for example, S33084, SB-277011-A, AVE5997
  • the antipsychotic is a glutamatergic agent selected from NMDA receptor positive allosteric modulators (e.g., glycine, D-cycloserine and D-serine), glycine reuptake inhibitors (e.g., N-(3-(4'-fluorophenyl)-3-(4'- phenylphenoxy)propyl) sarcosine and glycyldodecylamide) , glutamate reuptake inhibitor (e.g., excitatory amino-acid transporters EAAT3 antagonists), metabotropic glutamate receptors agonists (e.g., LY-354740), AMPA/kainate receptor antagonists (e.g., LY-293558, GYKI52466 and LY-326325), ampakines (CX-516), and glutathione prodrugs.
  • NMDA receptor positive allosteric modulators e.g., glycine, D
  • the antipsychotic is a noradrenergic agent selected from alpha-2 adrenergic receptor agonists or antagonists (e.g., guanfacine, clozapine and risperidone) and COMT inhibitors (e.g., tolcapone).
  • alpha-2 adrenergic receptor agonists or antagonists e.g., guanfacine, clozapine and risperidone
  • COMT inhibitors e.g., tolcapone
  • the antipsychotic is a serotonin receptor modulator selected from 5-HT 2 A receptor antagonists, 5-HT I A receptor partial agonists, 5- HT 2 c agonists, and 5-HT6 antagonists (e.g., some atypical antipsychotics).
  • the antipsychotic is a cholinergic agent selected from alpha-7 nicotinic receptor agonists (e.g., 3-2,4-dimethoxybenzylidene anabaseine (DMXB-A or GTS-21)), alpha4-beta2 nicotinic receptor agonists (e.g., SIB- 1553 A), allosteric modulators of nicotinic receptors and acetylcholinesterase inhibitors, muscarinic receptor agonists and antagonists (e.g., N- desmethylclozapine, xanomeline, PTAC, and BuTAC).
  • alpha-7 nicotinic receptor agonists e.g., 3-2,4-dimethoxybenzylidene anabaseine (DMXB-A or GTS-21)
  • alpha4-beta2 nicotinic receptor agonists e.g., SIB- 1553 A
  • the antipsychotic is selected from cannabinoid CB1 antagonists (e.g., SR141716) , neurokinin 3 antagonists (e.g., osanetant (SR- 142801) and talnetant), neurotensin agonists (e.g., SR-48692), MAO B inhibitors (e.g., Selegiline (deprenyl) and rasagiline), PDE10 inhibitors (e.g., Papaverine), NNOS inhibits (e.g., methylene blue, LNOARG, L-NAME, and 7-nitroindazole), neurosteroids (e.g., dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S), pregnenolone (PREG) and pregnenolone sulfate (PREGS)), and neurotrophic factors (e.g., nerve growth factor (NGF), brain-derived neurotrophic factor (NGF), brain-derived
  • the antipsychotics or pharmaceutically acceptable salts, hydrates, solvates, polymorphs and prodrugs thereof that are useful in the methods and compositions of this invention include those that are useful in treating one or more signs or symptoms of schizophrenia or bipolar disorder (in particular, mania).
  • Schizophrenia is characterized by psychological symptoms such as perception (hallucinations), ideation, reality testing (delusions), thought processes (loose associations), feeling (flatness, inappropriate effect) , behavior (catatonia, disorganization), attention, concentration, motivation (avolition, impaired intentions and planning) and judgment (see for example Diagnostic and Statistical Manual of Mental Disorders IV, American Psychiatric Association).
  • the symptoms of schizophrenia are divided into positive and negative symptoms with hallucinations and delusions being positive features, and features such as flatness, poverty of speech and impaired executive functions representing negative symptoms.
  • Clinical rating scales such as Positive and Negative Syndrome Scale and Scale for the Assessment of Negative Symptoms provide criteria to
  • cognition differentiates between, and rate, positive and negative symptoms.
  • cognitive deficits schizophrenic and schizotypical patients suffer from. These include impairment in attention, verbal fluency, executive functions such as planning, working memory and visual and verbal learning and memory.
  • cognitive dysfunction can be measured with a variety of tests, such as Visual Search, Verbal Fluency, Wisconsin Card Sorting, Trail Making - Part B, Symbol Digit, Hopkins Verbal Learning, Digit Span, Stroop-Color-Word and Attentional Capacity.
  • MATRICS consensus neuropsychological test battery which includes tests of working memory, speed of processing, attention, verbal learning, visual learning, reasoning and problem solving and social cognition.
  • cognitive measures predict work function and overall outcome as assessed by the Global Assessment Scale and Quality of Life Scale.
  • neuropsychological functions reflecting several negative and cognitive symptoms of the disease, may be more impaired in male schizophrenic patients when compared to female patients.
  • psychiatric diseases such as schizotypical and schizoaffective disorder, other acute- and chronic psychoses and bipolar disorder which have an overlapping
  • antipsychotics or pharmaceutically acceptable salts, hydrates, solvates, polymorphs and prodrugs thereof that are useful in the methods and compositions of this invention are those disclosed, for example, in U.S. Patents
  • the antipsychotics useful in this invention include those compounds/agents disclosed, for example, in U.S. Patents or Patent Publications US20020052401A1; US20020091118A1; US20020091119A1;
  • EP1070058B1 EP1082960A2; EP1088819B1; EP1099446B1; EP1104420B1;
  • EP1250336B1 EP1254662A2; EP1254668A2; EP1257526B1; EP1260221A2;
  • WO2004085439A1 WO2004096773A1; WO2004100954A1; WO2004100956A1; WO2004100957A1; WO2004100992A2; WO2005002578A1; WO2005013961A1;
  • WO2007105053 A2 WO2007129183A2; WO2007138431A2; WO2008001182A1; WO2008010073A1; WO2008015516A1; WO2008020302A2; WO2008020306A2;
  • the invention provides methods and compositions for treating a subject suffering from schizophrenia or bipolar disorder (in particular, mania), or the risk thereof by administering a a5-containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in combination with an antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.
  • the methods of this invention treat one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia.
  • the methods of this invention treat one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania).
  • the a5 -containing GABAA receptor agonist and the antipsychotic suitable for the method of this invention may be selected from any of those as described above.
  • the a5-containing GABAA receptor agonist is selected from any of the compounds of Formulas I, I-A, I-B, I-C and I-D, as described above, and in U.S. Patent Application 61/413,971 and PCT publication WO2012068161, including, for example, compounds of any of the embodiments of Formulas I, I-A, I-B, I-C and I-D and the specific compounds described herein and in U.S.
  • the antipsychotic is selected from (1) atypical and typical antipsychotics (such as those described above); (2) agents that are dopaminergic agents (such as dopamine Dl receptor antagonists or agonists, dopamine D 2 receptor antagonists or partial agonists, dopamine D3 receptor antagonists or partial agonists, dopamine D4 receptor antagonists), glutamatergic agents, NMDA receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), Ml muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonist
  • the antipsychotic for the methods of this invention is an atyptical antipsychotic selected from, e.g., aripiprazole, olanzapine and ziprasidone, and pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof.
  • the subject that suffers schizophrenia or bipolar disorder is a human patient.
  • the subject may be a human or other mammal such as a non-human primate, or rodent (e.g., rat).
  • rodent e.g., rat
  • the subject is a human patient.
  • pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof in combination with antipsychotics and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs may reduce the amount of antipsychotics necessary for the treatment of schizophrenia or bipolar disorder (in particular, mania).
  • schizophrenia or bipolar disorder in particular, mania
  • the subject that suffers schizophrenia or bipolar disorder in particular, mania
  • the use of the a5- containing GABA A receptor agonists reduce the side effects caused by
  • the efficacy of a combination of the a5 -containing GABAA receptor agonists and antipsychotics and pharmaceutically acceptable salts, solvates, hydrates, and polymorphs thereof exceeds the efficacy of either drug administered alone at its optimal dose and thus, is an improved treatment for schizophrenia or bipolar disorder (in particular, mania).
  • compositions and methods of this invention preferably should readily penetrate the blood-brain barrier when peripherally administered.
  • Compounds which cannot penetrate the blood-brain barrier can still be effectively administered directly into the central nervous system, e.g., by an intraventricular or other neuro-compatible routes.
  • administration of a5 -containing GABAA receptor agonist and an antipsychotic or pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof "in combination" includes simultaneous administration and/or administration at different times, such as sequential administration.
  • Simultaneous administration of the a5 -containing GABAA receptor agonist and the antipsychotic or their pharmaceutically acceptable salts, hydrates, solvates and polymorphs can optionally be combined with supplemental doses of the a5 -containing GABAA receptor agonist and/or the antipsychotic and their salts, hydrates, solvates and polymorphs.
  • Simultaneous administration of drugs encompasses administration as co-formulation or, alternatively, as separate compositions.
  • the a5 -containing GABAA receptor agonist and the psychotic, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs thereof can be administered to a subject via any suitable route or routes.
  • the drugs are administered orally; however, administration intravenously, subcutaneously, intra-arterially, intramuscularly, intraspinally, rectally, intrathoracically, intraperitoneally, intracentricularly, or transdermally, topically, or by inhalation is also contemplated.
  • the agents can be administered orally, for example, in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, or the like, prepared by art recognized procedures.
  • the a5-containing GABAA receptor agonist and the antipsychotic, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs thereof can be administered to a subject via different routes.
  • the a5-containing GABAA receptor agonist or its salt, solvate, hydrate, or polymorph is administered intravenously and the antipsychotic or its salt, solvate, hydrate, or polymorph is administered orally.
  • the administration is a slow or extended release.
  • extended release is widely recognized in the art of pharmaceutical sciences and is used herein to refer to a controlled release of an active compound or agent from a dosage form to an environment over (throughout or during) an extended period of time, e.g. greater than or equal to one hour.
  • An extended release dosage form will release drug at substantially constant rate over an extended period of time or a substantially constant amount of drug will be released incrementally over an extended period of time.
  • extended release used herein includes the terms “controlled release,” “prolonged release,” “sustained release,” “delayed release,” or “slow release” as these terms are used in the pharmaceutical sciences.
  • the extended release dosage is administered in the form of a patch or a pump.
  • the preparation may be in a tablet, placed in a hard gelatin capsule in powder or pellet form, or it may be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the forms of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • Dosage schedules of the agents and compositions according to the methods of the invention will vary according to the particular compound or compositions selected, the route of administration, the nature of the condition being treated, the age, and condition of the patient, the course, or stage of treatment, and will ultimately be at the discretion of the attending physician. It will be understood that the amount of the a5- containing GABAA receptor agonist and the antipsychotic and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof administered will be amounts effective to produce a desired biological effect, such as beneficial results, including clinical results. It will be understood that an effective amount can be administered in more than one dose and over a course of treatment.
  • Desired duration of administration of the a5 -containing GABAA receptor agonist and the antipsychotic and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof can be determined by routine experimentation by one skilled in the art.
  • the a5 -containing GABAA receptor agonist and the antipsychotic and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof may be administered for a period of 1-4 weeks, 1-3 months, 3-6 months, 6-12 months, 1-2 years, or more, up to the lifetime of the patient.
  • HED equivalent dose for this dosage
  • HED animal dose X (Km animal / Km human) where the Km factor is body weight divided by body surface area (Km rat has been determined as 6, and Km human is 37; see Reagan-Saw, Nihal, Ahmad, 2007).
  • the dose in mg/kg is multiplied by a typical adult weight of 70 kg.
  • the dose of the a5 -containing GABAA R agonist is between 0.0001 and 100 mg/kg/day (which, given a typical human subject of 70 kg, is between 0.007 and 7000 mg/day).
  • the antipsychotic useful in the present invention is an atypical antipsychotic.
  • the amount of an atypical antipsychotic administered to a patient is an amount sufficient to have a therapeutic effect.
  • the amount of an atypical antipsychotic administered to a patient is an amount sufficient to treat at least one symptom or sign of
  • schizophrenia or bipolar disorder in particular, mania
  • the one sign or symptom may include, but are not limited to, any of those described above, including, for example, delusions, hallucinations, disorganized speech (e.g., frequent derailment or incoherence), grossly disorganized or catatonic behavior and negative symptoms (e.g., affective flattening, alogia, avolition).
  • disorganized speech e.g., frequent derailment or incoherence
  • grossly disorganized or catatonic behavior e.g., affective flattening, alogia, avolition.
  • negative symptoms e.g., affective flattening, alogia, avolition.
  • atypical antipsychotic will vary with many factors including the potency of the atypical antipsychotic, the age and weight of the patient, and the severity of the condition or disorder to be treated.
  • the dosages of the drugs used in the present invention can, in the final analysis, be set by the physician in charge of the case, using knowledge of the drugs, the properties of the drugs in combination as detemlined in clinical trials, and the characteristics of the patient, including diseases other than that for which the physician is treating the patient.
  • Non-limiting daily dosage amounts for several atypical antipsychotics are provided herein: Aripiprazole, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in some embodiments, up to about 30 mg/day or about 10-15 mg/day; Asenapine, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in some
  • embodiments about 10 mg/day;
  • Clozapine about 0.1-1000 mg/day, about 1-900 mg/day, about 5-900 mg/day, about 10-900 mg/day, about 100-900 mg/day, about 100-800 mg/day or about 100- 750 mg/day, and in some embodiments, about 150-450 mg/day or about 300-450 mg/day;
  • Iloperidone about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in some embodiments, about 12-24 mg/day;
  • Olanzapine about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in some embodiments, about 10-15 mg/day;
  • Lurasidone about 0.1-500 mg/day, about 1-500 mg/day, about 1-250 mg/day, about 10-250 mg/day, about 10-100 mg/day, or about 20-100 mg/day, and in some embodiments, about 40-80 mg/day;
  • Paliperidone about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in some embodiments, about 6 mg/day; Quetiapine, about 0.1-1000 mg/day, about 1-900 mg/day, about 1-800 mg/day, about 50-800, about 100-800, or about 200-800 mg/day, and in some
  • Risperidone about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in some embodiments, about 4-8 mg/day or 1-6 mg/day; Ziprasidone, about 0.1-250 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 20-100, or about 20-80 mg/day, and in some embodiments, up to about 40 mg/day, or up to about 80 mg/day or about 40-80 mg/day.
  • the antipsychotic or a salt, hydrate, solvate or polymorph thereof may be administered at dosage levels distinct from conventional levels (e.g., at subtherapeutic doses) when provided in combination with a5 -containing GABAA receptor agonist, due to a a5-containing GABAA receptor agonist-dependent increase in the antipsychotic's therapeutic index.
  • the increase in the antipsychotic's therapeutic index due to the combination with a5 -containing GABAA receptor agonist is greater than the therapeutic index of the antipsychotic administered in the absence of a a5-containing GABAA receptor agonist by at least about 1.5x or 2.
  • combination of an antipsychotic with the a5 -containing GABAA receptor agonist reduces the dosage of the antipsychotic required for its therapeutic effect.
  • the antipsychotic is an atypical antipsychotic. When used in combination with a5- containing GABAA receptor agonist, such atypical antipsychotic is administered at a dose lower than required for its therapeutic effect when administered in the absence of a5 -containing GABAA receptor agonist.
  • the frequency of administration of the composition of this invention may be adjusted over the course of the treatment, based on the judgment of the administering physician. It will be clear that the a5 -containing GABAA receptor agonist and the antipsychotic and their salts, hydrates, solvates and polymorphs can be administered at different dosing frequencies or intervals. For example, a5-containing GABAA receptor agonist can be administered daily (including multiple doses per day) or less frequently. An antipsychotic can be administered daily (including multiple doses per day) or less frequently. In some embodiments, sustained continuous release formulations of a a5- containing GABAA receptor agonist and an antipsychotic may be desired. Various formulations and devices for achieving sustained release are known in the art.
  • the combined administration of a5- containing GABAA receptor agonist or a salt, hydrate, solvate and polymorph thereof and an antipsychotic or a salt, hydrate, solvate and polymorph thereof can attain a longer or improved therapeutic effect in the subject than that attained by administering only the a5-containing GABAA receptor agonist or only the antipsychotic, by at least about 1.5x, or 2. Ox, or 2.5x, or 3. Ox, or 3.5x, or 4. Ox, or 4.5x, or 5. Ox, or 5.5x, or 6. Ox, or 6.5x, or 7. Ox, or 7.5x, or 8. Ox, or 8.5x, or 9. Ox, or 9.5x, or lOx, or greater than about lOx.
  • the invention provides compositions comprising a a5- containing GABAA receptor agonist and at least one antipsychotic and their salts, hydrates, solvates and polymorphs.
  • the a5-containing GABAA receptor agonist and the antipsychotic may be present in a single dosage unit (e.g., combined together in one capsule, tablet, powder, or liquid, etc.).
  • the a5 -containing GABAA receptor agonist and the antipsychotic suitable for the compositions of this invention may be selected from any of those as described above.
  • the a5-containing GABAA receptor agonist is selected from any of the compounds of Formulas I, I- A, I-B, I-C and I-D, as described above, and in U.S. Patent Application 61/413,971 and PCT publication WO2012068161, including, for example, compounds of any of the embodiments of Formulas I, I- A, I-B, I-C and I-D and the specific compounds described herein and in U.S. Patent
  • antipsychotic is selected from (1) atypical and typical antipsychotics (such as those described above);
  • agents that are dopaminergic agents such as dopamine Dl receptor antagonists or agonists, dopamine D 2 receptor antagonists or partial agonists, dopamine D3 receptor antagonists or partial agonists, dopamine D4 receptor antagonists), glutamatergic agents, NMDA receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), Ml muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, AMPA/kainate receptor antagonists, ampakines (CX-516), glutathione prodrugs, noradrenergic agents (such as alpha-2 adrene
  • the antipsychotic for the methods of this invention is an atyptical antipsychotic selected from, e.g., aripiprazole, olanzapine and ziprasidone, and pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof
  • composition described herein can contain more than one a5 -containing GABAA receptor agonist and/or more than one antipsychotic.
  • the a5 -containing GABAA receptor agonist and the antipsychotic are in a single dosage form, in a unit dosage form, in separate dosage forms, or in separate dosage forms packaged together.
  • compositions described herein can further contain pharmaceutically acceptable excipient(s) and may contain other agents that serve to enhance and/or complement the effectiveness of the a5-containing GABAA receptor agonist and/or the antipsychotic.
  • compositions may also contain additional agents known to be useful for treating cognitive function disorder.
  • composition in the present invention may be in solid dosage forms such as capsules, tablets, dragrees, pills, lozenges, powders and granule. Where appropriate, they may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled releases of one or more active ingredient such as sustained or prolonged release according to methods well known in the art.
  • coatings such as enteric coatings or they may be formulated so as to provide controlled releases of one or more active ingredient such as sustained or prolonged release according to methods well known in the art.
  • the composition is in form of a slow, controlled, or extended release.
  • extended release is widely recognized in the art of pharmaceutical sciences and is used herein to refer to a controlled release of an active compound or agent from a dosage form to an environment over (throughout or during) an extended period of time, e.g. greater than or equal to one hour.
  • An extended release dosage form will release drug at substantially constant rate over an extended period of time or a substantially constant amount of drug will be released incrementally over an extended period of time.
  • extended release used herein includes the terms “controlled release”, “prolonged release”, “sustained release”, or “slow release”, as these terms are used in the pharmaceutical sciences.
  • the extended release dosage is administered in the form of a patch or a pump.
  • the composition may also be in liquid dosage forms including solutions, emulsions, suspensions, syrups, and elixirs.
  • compositions may be specifically formulated for administration by any suitable route as described herein and known in the art.
  • Compositions for parental administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • Compositions for intraoral and oral delivery include but are not limited to bioadhesive polymers, tablets, patches, liquids and semisolids (see e.g., Smart et al).
  • compositions for respiratory delivery include but are not limited to a variety of pressurized metered dose inhalers, dry powder inhalers, nebulizers, aqueous mist inhalers, drops, solutions, suspensions, sprays, powders, gels, ointments, and specialized systems such as liposomes and microspheres (see e.g. Owens et al, "Alternative Routes of Insulin Delivery” and Martini et al).
  • Compositions for transdermal delivery include but are not limited to colloids, patches, and microemulsions.
  • compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.
  • Therapeutic formulations can be prepared by methods well known in the art of pharmacy, see, e.g., Goodman et al, 2001; Ansel, et al, 2004; Stoklosa et al, 2001; and Bustamante, et al., 1993.
  • compositions and methods described herein may be adapted and modified as is appropriate for the application being addressed and that the compositions and methods described herein may be employed in other suitable applications, and that such other additions and modifications will not depart from the scope hereof.
  • the reaction mixture was cooled and solvent was evaporated under reduced pressure.
  • the residue was dissolved in 25 mL of water and pH was adjusted to 5 using 6N HC1 (25 mL).
  • the precipitated solid was isolated by filtration.
  • the crude product was purified by column chromatography (100-200 mesh silica gel, 5%
  • Example 5 Synthesis of compound 23 [0206] Compound 23 was prepared according to synthetic Scheme 9. The syntheses of the intermediates and the final product are detailed as follows.
  • Step 1 Establish clones of GABAAR subunits(a5, ⁇ 3, ⁇ 2, al, a2 and a3) and prepare the corresponding cRNAs: Human clones of GABAA-R 5, ⁇ 3, ⁇ 2, al, a2 and a3 subunits are obtained from commercial resources ⁇ e.g., OriGene, http://www.origene.com and Genescript, http://www.genescript.com). These clones are engineered into pRC, pCDM, pcDNA, and pBluescript KSM vector (for oocyte expression) or other equivalent expression vectors. Conventional transfection agents ⁇ e.g., FuGene, Lipofectamine 2000, or others) are used to transiently trans feet host cells.
  • Conventional transfection agents ⁇ e.g., FuGene, Lipofectamine 2000, or others) are used to transiently trans feet host cells.
  • benzodiazepine, and diazepam are used as reference compounds to validate the system.
  • the GABA-gated CI- current from oocytes are measured in the TEVC setup in the presence of the test compounds.
  • the agonist activity of each the test compounds is tested in a 5 -point dose-response assay.
  • the test compounds include some reference compounds (literature EC50 values for the ⁇ 5 ⁇ 3 ⁇ 2subtype are in the range of 3-10 ⁇ ). EC50s in the ⁇ 5 ⁇ 3 ⁇ 2subtype are obtained for each compound.
  • the EC50 in ⁇ 5 ⁇ 3 ⁇ 2 is ⁇ 5 ⁇
  • the EC50 of the other three subtypes is further determined individually in order to test for selectivity of the compounds in the ⁇ 5 ⁇ 3 ⁇ 2subtype over other subtypes.
  • the second batch of test compounds are tested using the same strategy, but with a lower EC50 cutoff (0.5 ⁇ ). Again, the EC50s of the ⁇ 5 ⁇ 3 ⁇ 2 subtype for each of the compounds is determined.
  • the l to a3 coupled ⁇ 3 ⁇ 2 subtypes are tested only if the EC 50 for the a5 -containing receptor is ⁇ 0.5 ⁇ .
  • Example 7 Evaluating Compounds for Agonist Activity on the GABA A a5 Receptors
  • the agonist activity of the compounds of this invention was determined by measuring their effect on GABA-gated CI- current from Xenopus oocytes expressing GABAA ⁇ 5 ⁇ 3 ⁇ 2 subtype receptor in a two-electrode voltage clamp (TEVC) setup.
  • TEVC two-electrode voltage clamp
  • GABA stocks were prepared in the extracellular solution, i.e., Modified Barth's Saline (MBS) containing NaCl (88 mM), KC1 (2 mM), MgS0 4 (0.82 mM), Ca(N0 3 ) 2 (0.33 mM), CaCl 2 (0.41 mM), NaHC0 3 (2.4 mM) and HEPES (10 mM).
  • MBS Modified Barth's Saline
  • Flumazenil and compounds of the present invention were prepared in dimethyl sulfoxide (DMSO) and then diluted to an appropriate concentration with the extracellular solution just before use. To avoid adverse effects from DMSO exposure, the final concentration of DMSO was not higher than 0.3% (v/v).
  • DMSO dimethyl sulfoxide
  • Xenopus oocytes were isolated according to previously published procedures (see, e.g., Goldin et al. Methods Enzymol. 207:266-279 (1992)). The isolated Xenopus oocytes were injected with GABAAR CDNAS (1 : 1 : 1 ratio for a total volume of 1 ng of ⁇ 1 ⁇ 2 ⁇ 2 or ⁇ 5 ⁇ 3 ⁇ 2) cloned into mammalian expression vectors. In particular, al, ⁇ 2, ⁇ 2 were cloned into pcDNA3.1. and a5 and ⁇ 3 were cloned into pcDNA3.1 myc-His. Vectors were verified by partial sequencing (DNA Core Facility, University of Southern California, USA).
  • oocytes were stored in incubation medium (Modified Barth's Saline (MBS) supplemented with 2 mM sodium pyruvate, 0.5 mM theophylline and 50 mg/L gentamycin), in petri dishes (VWR, San Dimas, CA). All solutions were sterilized by passage through 0.22 ⁇ filters.
  • Oocytes stored at 18°C, usually expressed GABAARS (e.g., ⁇ 5 ⁇ 3 ⁇ 2 or ⁇ 1 ⁇ 2 ⁇ 2 subtype), 1-2 days after injections. Oocytes were used in experiments for up to 5 days after injection.
  • GABAARS e.g., ⁇ 5 ⁇ 3 ⁇ 2 or ⁇ 1 ⁇ 2 ⁇ 2 subtype
  • TEVC high-throughput two-electrode voltage clamp
  • GABA A Rs or 0.3 ⁇ - 1 mM for a5-containing GABA A Rs) were applied once for 30 sec, with 5-15 min washes between the applications. Longer wash periods were allowed after the applications of higher GAB A concentrations.
  • a GABA dose-response experiment was conducted to determine an approximate GABA EC50 concentration for the batch of oocytes. EC50 ranged from
  • Diazepam and Flumazenil were used as reference compounds.
  • the GABA-gated CI current from oocytes expressing ⁇ 5 ⁇ 3 ⁇ 2 GABA A R was measured in the TEVC setup in the presence of Diazepam and Flumazenil.
  • GABA EC20 was applied for 30 sec 4-5 times to establish a stable response. 1 ⁇
  • Diazepam was pre-applied for 60 sec, followed by co-application of 1 ⁇
  • Diazepam and EC 2 o GABA was repeated to establish the recovery.
  • Diazepam was analyzed from the peak amplitude of Diazepam-(plus EC 2 o GABA)-induced current (test 1) with the peak amplitude of GABA-induced current before the Diazepam application (reference).
  • the effect of Flumazenil was determined from the peak amplitude of Diazepam-plus- Flumazenil-(plus EC 2 o GABA)-induced current (test 2) normalized on the peak amplitude of Diazepam-induced current (control).
  • Other compounds may also be used in this study as reference compounds. For example, methyl-6,7-dimethoxy-4- ethyl-beta-carboline-3-carboxylate (DMCM) and L655708 were tested at 1 ⁇ , using the same protocol.
  • DMCM methyl-6,7-dimethoxy-4- ethyl-beta-carboline-3-carboxylate
  • L655708 were tested at 1 ⁇ , using the same protocol.
  • test compounds (1 ⁇ ) were pre-applied for 60 sec, followed by coadministration of the test compounds (1 ⁇ ) and GABA at EC 50 concentration for 30 sec. After a 15-20 min wash, EC 50 GABA was tested once again. Upon conclusion of compound testing and successful washout, a 1.0 ⁇ Diazepam was tested and used for comparative activity on the two GABA A R subtypes. [0224] The effect of each test compound was determined from the peak amplitude of Diazepam-plus-compound-(plus EC50 GABA)-induced current normalized on the peak amplitude of Diazepam-(plus EC50 GABA)-induced current (control). Other concentrations of the test compound may also be tested following the same protocol.
  • a compound which demonstrates greater than 5% potentiation of the GABA EC50 is indicative that the compound has a positive allosteric modulatory effect on the GABAA 5 receptor. Such compound will enhance the effects of GABA at the GABAA 5 receptor.
  • Exemplary compounds that demonstrated greater than 5% potentiation of the GABA EC50 are shown in Table 3 below.
  • Table 3 Exemplary compounds with >5% Potentiation of GABA EC50 Concentration in Oocytes containing GABAA receptors ( ⁇ 5 ⁇ 3 ⁇ 2)
  • Methyl 3,5-diphenylpyridazine-4-carboxylate corresponding to compound number 6 in van Niel et al. J. Med. Chem. 48:6004-6011 (2005), is a selective a5 -containing GABAA R agonist. It has an a5 in vitro efficacy of +27 (EC 20 ).
  • the effect of methyl 3,5-diphenylpyridazine-4-carboxylate in aged- impaired rats was studied using a RAM task.
  • receptor occupancy by methyl 3,5-diphenylpyridazine-4-carboxylate in a5-containing GABAA receptor was also studied.
  • An elevated maze arm (7 cm width x 75 cm length) projected from each facet of an octagonal center platform (30 cm diameter, 51.5 cm height). Clear side walls on the arms were 10 cm high and were angled at 65° to form a trough. A food well (4 cm diameter, 2 cm deep) was located at the distal end of each arm. Froot LoopsTM (Kellogg Company) were used as rewards. Blocks constructed of PlexiglasTM (30 cm height x 12 cm width) could be positioned to prevent entry to any arm.
  • the AI rats were initially subjected to a pre-training test (Chappell et al. Neuropharmacology 37: 481-487, 1998).
  • the pre-training test consisted of a habituation phase (4 days), a training phase on the standard win-shift task (18 days) and another training phase (14 days) in which a brief delay was imposed between presentation of a subset of arms designated by the experimenter (e.g. , 5 arms available and 3 arms blocked) and completion of the eight-arm win-shift task (i.e., with all eight arms available).
  • Rats were allowed to obtain food on the five arms to which access was permitted during this initial "information phase” of the trial. Rats were then removed from the maze for 60 seconds, during which time the barriers on the maze were removed, thus allowing access to all eight arms. Rats were then placed back onto the center platform and allowed to obtain the remaining food rewards during this "retention test” phase of the trial. The identity and configuration of the blocked arms varied across trials. [0233] The number of "errors" the AI rats made during the retention test phase was tracked. An error occurred in the trial if the rats entered an arm from which food had already been retrieved in the pre-delay component of the trial, or if the rat re-visited an arm in the post-delay session that it had already visited.
  • rats were subjected to trials with more extended delay intervals, i.e., a two-hour delay, between the information phase (presentation with some blocked arms) and the retention test (presentation of all arms). During the delay interval, rats remained off to the side of the maze in the testing room, on carts in their individual home cages.
  • AI rats were pretreated 30 - 40 minutes before daily trials with a one-time shot of the following five conditions: 1) vehicle control - 5% dimethyl sulfoxide, 25% polyethylene glycol 300 and 70% distilled water; 2) methyl 3,5-diphenylpyridazine-4-carboxylate at 0.1 mg/kg; 3) methyl 3,5-diphenylpyridazine-4-carboxylate at 0.3 mg/kg; 4) methyl 3,5- diphenylpyridazine-4-carboxylate at 1 mg/kg); and 5) methyl 3,5- diphenylpyridazine-4-carboxylate at 3 mg/kg; through intraperitoneal (i.p.) injection.
  • vehicle control - 5% dimethyl sulfoxide, 25% polyethylene glycol 300 and 70% distilled water
  • the therapeutic dose of 3 mg/kg became ineffective when the AI rats were concurrently treated with 0.3 mg/kg of TB21007, a a5-containing GABAA R inverse agonist.
  • Ro 15-4513 was used as a receptor occupancy (RO) tracer for GABAA(X5 receptor sites in the hippocampus and cerebellum.
  • Ro 15-4513 was chosen as the tracer based on its selectivity for GABAA(X5 receptors relative to other alpha subunit containing GABA A receptors and because it has been successfully used for GABA A a5 RO studies in animals and humans (see, e.g., Lingford-Hughes et al, J. Cereb. Blood Flow Metab. 22:878-89 (2002); Pym et al, Br. J. Pharmacol. 146:
  • the rats were sacrificed by cervical dislocation 20' post tracer injection. The whole brain was rapidly removed, and lightly rinsed with sterile water. Trunk blood was collected in EDTA coated eppendorf tubes and stored on wet ice until study completion. Hippocampus and cerebellum were dissected and stored in 1.5 ml eppendorf tubes, and placed on wet ice until tissue extraction. In a drug naive rat, six cortical brain tissues samples were collected for use in generating blank and standard curve samples.
  • Acetonitrile containing 0.1% formic acid was added to each sample at a volume of four times the weight of the tissue sample.
  • a calculated volume of standard reduced the volume of acetonitrile.
  • the sample was homogenized (FastPrep-24, Lysing Matrix D; 5.5 m/s, for 60 seconds or 7-8 watts power using sonic probe dismembrator; Fisher
  • Receptor occupancy was determined by the ratio method which compared occupancy in the hippocampus (a region of high GABAA(X5 receptor density) with occupancy in the cerebellum (a region with low GABA A a5 receptor density) and additionally by a high dose of the GABAA(X5 negative allosteric modulator L- 655,708 (10 mg/kg, i.v.) to define full occupancy.
  • Methyl 3,5-diphenylpyridazine-4-carboxylate exposure was below the quantification limits (BQL) at 0.01 mg/kg, i.v., in both plasma and hippocampus and but was detectable at low levels in hippocampus at 0.1 mg/kg, i.v. (see Table 4).
  • Hippocampal exposure was linear as a 10-fold increase in dose from 0.1 to 1 mg/kg, i.v., resulted in a 12-fold increase in exposure.
  • Increasing the dose from 1 to 10 mg/kg, i.v. only increased the exposure by ⁇ 5-fold.
  • Plasma exposure increased 12-fold as the dose increased from 1 to 10 mg/kg, i.v.
  • Table 4 % GABAA 5 Receptor Occupancy by methyl 3,5-diphenylpyridazine-4- carboxylate (0.01-10 mg/kg, i.v.). Hippocampus and Plasma Exposure of methyl 3,5-diphenylpyridazine-4-carboxylate by Treatment Group in young Long Evans rats.
  • Table 5 Hippocampus and Plasma Exposure of methyl 3,5-diphenylpyridazine-4- carboxylate in Young Long Evans Rats by Treatment Group
  • Example 10 Effect of 6,6 dimethyl-3-(3-hydroxypropyl)thio-l-(thiazol-2-yl)- 6,7-dihydro-2-benzothiophen-4(5H)-one in Aged-Impaired Rats Using a Morris Water Maze Behavioral Task
  • intracerebroventricular (ICV) infusion was given during pre -training.
  • rats received ICV infusion of either 100 ⁇ g 6,6 dimethyl-3-(3-hydroxypropyl)thio- 1 -(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-
  • rats treated with 6,6 dimethyl-3-(3- hydroxypropyl)thio- 1 -(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one were able to find the platform more proficiently (i.e., quicker) at the end of training (block 4) than those treated with vehicle alone.
  • rats treated with 6,6 dimethyl-3-(3-hydroxypropyl)thio-l-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen- 4(5H)-one spent about 9.6 seconds to find the escape platform, while rats treated with vehicle spent about 19.69 seconds.
  • target annulus is a designated area 1.5 times the size of the escape platform around the area where the platform was located during pre-trial training.
  • Optosite annulus is a control area of the same size as the size of the target annulus, which is located opposite to the target annulus in the pool.
  • Rats had good long term memory, they would tend to search in the area surrounding the location where the platform was during the pre-trial training (i.e., the "target” annulus; and not the “opposite” annulus).
  • “Time in annulus” is the amount of time in seconds that the rat spent in the target or opposite annulus area.
  • Numberer (#) of crossings” in annulus is the number of times the rat swam across the target or opposite annulus area.
  • compounds of the present invention should produce cognitive enhancing effects in aged-impaired animals (such as rats), similar to the effects produced by other GABA A 5 receptor selective agonists, such as methyl 3,5- diphenylpyridazine-4-carboxylate, ethyl 3-methoxy-7-methyl-9H- benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepine- 10-carboxylate, and 6,6 dimethyl-3-(3-hydroxypropyl)thio-l-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen- 4(5H)-one ⁇ See, e.g., Examples 8-10).
  • GABA A 5 receptor selective agonists such as methyl 3,5- diphenylpyridazine-4-carboxylate, ethyl 3-methoxy-7-methyl-9H- benzo[f]imidazo[l,5-

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Abstract

L'invention concerne des méthodes et des compositions pour le traitement de la schizophrénie ou d'un trouble bipolaire (en particulier une manie), par l'utilisation d'une combinaison d'un agoniste du récepteur de GABAA contenant a5 et un antipsychotique, ou leurs sels, hydrates, solvates, polymorphes pharmaceutiquement acceptables associés. Dans certains modes de réalisation, les méthodes et les compositions sont destinées au traitement d'un ou plusieurs symptômes positifs et/ou négatifs, ainsi qu'un déficit cognitif, associés à la schizophrénie.
PCT/US2013/069836 2012-11-14 2013-11-13 Méthodes et compositions pour le traitement de la schizophrénie WO2014078377A1 (fr)

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US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
JP2018520135A (ja) * 2015-07-14 2018-07-26 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ ２−フェニル−６−イミダゾリル−ピリジン−４−カルボキサミド誘導体及びそのｅａａｔ３阻害剤としての使用
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
CN112704678A (zh) * 2020-12-02 2021-04-27 江苏恩华药业股份有限公司 一种丙酰胺衍生物在制备治疗精神分裂症药物中应用
CN112704678B (zh) * 2020-12-02 2024-02-23 江苏恩华药业股份有限公司 一种丙酰胺衍生物在制备治疗精神分裂症药物中应用

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