WO2014153180A1 - Procédés et compositions pour améliorer la fonction cognitive - Google Patents

Procédés et compositions pour améliorer la fonction cognitive Download PDF

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Publication number
WO2014153180A1
WO2014153180A1 PCT/US2014/029439 US2014029439W WO2014153180A1 WO 2014153180 A1 WO2014153180 A1 WO 2014153180A1 US 2014029439 W US2014029439 W US 2014029439W WO 2014153180 A1 WO2014153180 A1 WO 2014153180A1
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Prior art keywords
memantine
receptor agonist
analog
derivative
pharmaceutically acceptable
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PCT/US2014/029439
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English (en)
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Michela Gallagher
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Michela Gallagher
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Publication of WO2014153180A1 publication Critical patent/WO2014153180A1/fr

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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

Definitions

  • the invention relates to methods and compositions for improving cognitive function by using a combination of a a5 -containing GABAA receptor agonist and memantine or a derivative or an analog thereof.
  • it relates to the use of a combination of a a5-containing GABAA receptor agonist and memantine or a derivative or an analog thereof in treating cognitive impairment associated with central nervous system (CNS) disorders in a subject in need or at risk thereof, including, without limitation, subjects having or at risk for age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI,
  • CNS central nervous system
  • Age- Associated Memory Impairment AAMI
  • Age Related Cognitive Decline ARCD
  • AD Age Related Cognitive Decline
  • PTSD post traumatic stress disorder
  • schizophrenia or bipolar disorder amyotrophic lateral sclerosis (ALS), cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism, compulsive behavior, and substance addiction.
  • ALS amyotrophic lateral sclerosis
  • Cognitive ability may decline as a normal consequence of aging or as a consequence of a central nervous disorder.
  • MCI Mild Cognitive Impairment
  • AAMI Age- Associated Memory Impairment
  • ARCD Age-Related Cognitive Decline
  • MCI there are more than 16 million people with AAMI in the U.S. alone (Barker et al, 1995), and MCI is estimated to affect 5.5 - 7 million in the U.S. over the age of 65 (Plassman et al., 2008).
  • Cognitive impairment is also associated with other central nervous system (CNS) disorders, such as dementia, Alzheimer's Disease(AD), prodromal AD, post traumatic stress disorder (PTSD), schizophrenia or bipolar disorder (in particular, mania), amyotrophic lateral sclerosis (ALS), cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism, compulsive behavior, and substance addiction.
  • CNS central nervous system
  • CNS central nervous system
  • MCI central nervous system
  • AAMI amnestic MCI
  • ARCD ARCD
  • dementia AD
  • prodromal AD PTSD
  • schizophrenia or bipolar disorder in particular, mania
  • amyotrophic lateral sclerosis ALS
  • cancer-therapy-related cognitive impairment mental retardation
  • Parkinson's disease PD
  • autism compulsive behavior
  • substance addiction substance addiction
  • CNS central nervous system
  • GABAA receptors are pentameric assemblies from a pool of different subunits (al-6, ⁇ 1-3, ⁇ 1-3, ⁇ , ⁇ , ⁇ , ⁇ ) that forms a CI- permeable channel that is gated by the neurotransmitter ⁇ -aminobutyric acid (GAB A).
  • GABAA R GABAA receptors
  • GABAA R Various pharmacological effects, including anxiety disorders, epilepsy, insomnia, preanesthetic sedation, and muscle relaxation, are mediated by different GABAA subtypes.
  • a method for treating or improving cognitive function, delaying or slowing the progression of cognitive impairment, or reducing the rate of decline of cognitive function, in a subject suffering from a cognitive impairment associated with central nervous system (CNS) disorder, 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, polymorph, isomer or prodrug thereof in combination with a
  • the methods improve or treat cognitive function in said subject.
  • the methods delay or slow the progression of cognitive impairment in said subject.
  • the methods reduce the rate of decline of cognitive function in said subject.
  • the methods prevent or slow the progression of said cognitive impairment associated with said CNS disorder in said subject.
  • the methods alleviate, ameliorate, or slow the progression, of one or more symptoms associated with said cognitive impairment aspects of said CNS disorder in said subject.
  • the a5 -containing GABAA receptor agonist and/or memantine or a derivative or an analog thereof are administered at doses that are subtherapeutic as compared to the doses at which they are therapeutically effective when administered in the absence of the other.
  • the cognitive impairment associated with said CNS disorder is age-related cognitive impairment, such as Mild Cognitive Impairment (MCI), Age- Associated Memory Impairment (AAMI), Age Related Cognitive Decline (ARCD).
  • MCI Mild Cognitive Impairment
  • AAMI Age- Associated Memory Impairment
  • ARCD Age Related Cognitive Decline
  • the MCI is amnestic MCI.
  • the CNS disorder is dementia, Alzheimer's Disease (AD), prodromal AD, post traumatic stress disorder (PTSD), schizophrenia or bipolar disorder (in particular, mania), amyotrophic lateral sclerosis (ALS), cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism, compulsive behavior, and substance addiction.
  • the subject that suffers such CNS disorder or such cognitive impairment is a human patient.
  • 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 GABA A 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:
  • a and B are each independently substituted with 0-5 substituents independently selected from J;
  • 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.
  • Memantine chemically also known as 3,5-dimethyladamantan-l-amine or 3,5-dimethyltricyclo[3.3.1.1 3 ' 7 ]decan-l-amine, is an uncompetitive N-methyl- D-aspartate (NMD A) receptor antagonist with moderate affinity.
  • NMD A N-methyl- D-aspartate receptor antagonist
  • the proprietary names for memantine include: Axura® and Akatinol® (Merz), Namenda® (Forest Laboratories), Ebixa® and Abixa® (Lundbeck), and Memox® (Unipharm).
  • Memantine is currently available in the U.S. and in over 42 countries worldwide. It is approved for the treatment of moderate to severe Alzheimer's disease (AD) in the United States at a dose of up to 28 mg/day.
  • AD Alzheimer's disease
  • Memantine and some of its derivatives and analogs that are useful in the present invention are disclosed in U.S. Patents Nos. 3,391,142; 4,122,193; 4,273,774; and 5,061,703, all of which are hereby incorporated by reference.
  • Other memantine derivatives or analogs that are useful in the present invention include, but are not limited to, those compounds disclosed in U.S. Patent Application Publication US20040087658,
  • Memantine includes memantine and its derivatives and analogs, as well as hydrates, polymorphs, prodrugs, salts, isomers, and solvates thereof.
  • Memantine also includes a composition comprising memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof, wherein the composition optionally further comprises at least one additional therapeutic agent (such as a therapeutic agent useful for treating a CNS disorder or cognitive impairments associated thereof).
  • the memantine composition suitable for use in the present invention comprises memantine and a second therapeutic agent that is donepezil (under the trade name Aricept).
  • memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof is administered every 12 or 24 hours at a daily dose of about 0.01 to 100 mg.
  • memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof is administered every 12 or 24 hours at a daily dose selected from 0.1-100 mg/day, 1-100 mg/day, 1-80 mg/day, 5-50 mg/day, 5-30 mg/day or 5-20 mg/day.
  • memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof is administered at a dose up to 30 mg/day. In some
  • a subtherapeutic amount (as compared to the therapeutic dose of memantine when administered alone) of memantine or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof is administered.
  • the subtherapeutic amount of memantine administered is a daily dose of less than about 100 mg, less than about 80 mg, less than about 50 mg, less than about 30 mg, less than about 28 mg, less than about 20 mg, less than about 10 mg, less than about 5 mg, less than about 2 mg, less than about 1 mg, less than about 0.5 mg, or less than about 0.1 mg.
  • the a5 -containing GABAA receptor agonist and memantine or the memantine derivative/analog
  • their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or prodrugs are administered simultaneously, or sequentially, or in a single formulation or in separate formulations packaged together.
  • the a5 -containing GABAA receptor agonist and memantine or the memantine derivative/analog
  • their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or prodrugs are administered via different routes.
  • “combination" includes administration by any of these formulations or routes of administration.
  • the a5 -containing GABAA receptor agonist is administered in an extended release form.
  • the a5-containing GABAA receptor agonist in an extended release form is administered together with memantine. In some embodiments, the a5- containing GABAA receptor agonist in an extended release form and memantine are administered separately. In some of the above embodiments where the a5- containing GABAA receptor agonist is in an extended release form, memantine is also in an extended release form. In some of the above embodiments where the a5 -containing GABAA receptor agonist is in an extended release form, memantine is not in an extended release form. In some embodiments of the invention, memantine is administered in an extended release form. In some embodiments, memantine in an extended release form is administered together with the a5- containing GABAA receptor agonist.
  • memantine in an extended release form and the a5 -containing GABAA receptor agonist are administered separately.
  • the a5 -containing GABAA receptor agonist is also in an extended release form.
  • the a5 -containing GABAA receptor agonist is not in an extended release form.
  • 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, polymorph, isomer or prodrug thereof in the absence of memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof by at least about 1.5x, or 2.
  • a method of increasing the therapeutic index of memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof in a method of treating a cognitive impairment associated with central nervous system (CNS) disorder in a subject in need or at risk thereof comprising administering a a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof to said subject.
  • CNS central nervous system
  • the increase in the therapeutic index of memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof is greater than the therapeutic index of memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof when administered in the absence of the a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof 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.
  • a method of increasing the therapeutic index of a a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof in a method of treating a cognitive impairment associated with central nervous system (CNS) disorder in a subject in need or at risk thereof comprising administering a a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof in combination with memantine or a derivative or an analog or a
  • CNS central nervous system
  • the increase in the therapeutic index of the a5- containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof is greater than the therapeutic index of the a5-containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof when administered in the absence of memantine or a derivative or an analog or a pharmaceutically
  • a pharmaceutical composition for treating or improving cognitive function, delaying or slowing the progression of cognitive impairment, or reducing the rate of decline of cognitive function, in a subject suffering from a cognitive impairment associated with central nervous system (CNS) disorder, or at risk thereof comprising a a5-containing GABAA receptor agonist and memantine or a memantine derivative/analog, or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or prodrugs.
  • CNS central nervous system
  • composition is in a solid form. In some embodiments, the composition is in a liquid form. In some embodiments, the composition is in an aqueous solution. In some embodiments, the composition is in a suspension form. In some
  • the composition is in a sustained release form, or a controlled release form, or a delayed release form, or an extended release form.
  • the a5 -containing composition of the present invention the a5 -containing composition of the present invention
  • the GABAA receptor agonist is in an extended release form.
  • the a5 -containing GABAA receptor agonist in an extended release form is formulated together with memantine in a single formulation.
  • the a5-containing GABAA receptor agonist in an extended release form and memantine are formulated in separate formulations, which may be packaged together.
  • memantine is also in an extended release form.
  • memantine is not in an extended release form.
  • memantine is in an extended release form.
  • memantine in an extended release form is formulated together with the a5-containing GABAA receptor agonist in a single formulation.
  • memantine in an extended release form and the a5-containing GABAA receptor agonist are formulated in separate formulations, which may be packaged together.
  • the a5 -containing GABAA receptor agonist is also in an extended release form.
  • the a5 -containing GABAA receptor agonist is not in an extended release form.
  • the composition is in a unit dosage form.
  • memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof is present in an amount of 0.01 mg to 100 mg. In some embodiments, memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof is present in an amount of less than 100 mg, less than 80 mg, less than 50 mg, less than 30 mg, less than 20 mg, less than 10 mg, less than 5 mg, less than 2 mg, less than 1 mg, less than 0.5 mg, or less than 0.1 mg.
  • Figures 1(A)-(D) are graphs showing functional selectivity data, as demonstrated by the potentiation of GAB A EC50 concentration in Xenopus oocytes containing GABA A 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 Rol5413 in the cerebellum.
  • Figure 4 is a graph showing dose-dependent GABA A 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 GABA A a5 receptor density) exposure of RO 15-4513, or by using the GABAA 5 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[f]imidazo[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[ 1 ,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 GABA A a5 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 Morris water maze behavioral task.
  • DMSO vehicle dimethyl sulfoxide
  • 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 rats received
  • 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 (SCAG), 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 a level of proficiency as close as possible to a normal, unimpaired subject or an age-matched normal, unimpaired subject.
  • "promoting" cognitive function in a subject affected by age-related cognitive refers to affecting impaired cognitive function so that it more closely resembles the function of an aged-matched normal, unimpaired subject, or the function of a young adult subject.
  • Cognitive function of that subject 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 a level of proficiency close as possible to a normal, unimpaired subject or a young adult subject or an age-matched normal unimpaired subject.
  • "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 some cases, “cognitive impairment” in subjects affected by aged-related cognitive impairment refers to cognitive function in subjects that is not as robust as that expected in an aged-matched normal, unimpaired subject, or the function of a young adult subject (i.e. subjects with mean scores for a given age in a cognitive test).
  • Age-related cognitive impairment refers to cognitive impairment in aged subjects, wherein their cognitive function is not as robust as that expected in an age-matched normal subject or as that expected in young adult subjects. In some cases, cognitive function is reduced by about 5%, about 10%>, about 30%>, or more, compared to cognitive function expected in an age-matched normal subject. In some cases, cognitive function is as expected in an age-matched normal subject, but reduced by about 5%, about 10%>, about 30%>, about 50%> or more, compared to cognitive function expected in a young adult subject.
  • Age-related impaired cognitive function may be associated with Mild Cognitive Impairment (MCI) (including amnestic MCI and non-amnestic MCI), Age-Associated Memory Impairment (AAMI), and Age-related Cognitive Decline (ARCD).
  • MCI Mild Cognitive Impairment
  • AAMI Age-Associated Memory Impairment
  • ARCD Age-related Cognitive Decline
  • Cognitive impairment associated with AD or related to AD or in AD refers to cognitive function in subjects that is not as robust as that expected in subjects who have not been diagnosed AD using conventional methodologies and standards.
  • Mild Cognitive Impairment or “MCI” refers to a condition
  • MCI memory complaint
  • ADLs normal activities of daily living
  • normal global cognitive function normal global cognitive function
  • abnormal memory for age defined as scoring more than 1.5 standard deviations below the mean for a given age
  • absence of indicators of dementia as defined by DSM-IV guidelines.
  • the cognitive deficit in subjects with MCI may involve any cognition area or mental process including memory, language, association, attention, perception, problem solving, executive function and visuospatial skills. See, e.g., Winbaldet al, J. Intern. Med. 256:240-240, 2004; Meguro, Acta. Neurol. Taiwan. 15:55-57, 2008; Ellison et al, CNS Spectr. 13:66-72, 2008, Petersen, Semin. Neurol. 27:22-31, 2007.
  • MCI is further subdivided into amnestic MCI (aMCI) and non-amnestic MCI, characterized by the impairment (or lack thereof) of memory in particular.
  • MCI is defined as aMCI if memory is found to be impaired given the age and education level of the subject. If, on the other hand, the memory of the subject is found to be intact for age and education, but other non- memory cognitive domains are impaired, such as language, executive function, or visuospatial skills, MCI is defined as non-amnestic MCI.
  • aMCI and non-amnestic MCI can both be further subdivided into single or multiple domain MCI.
  • aMCI- single domain refers to a condition where memory, but not other cognitive areas are impaired.
  • aMCI-multiple domain refers to a condition where memory and at least one other cognitive area are impaired.
  • Non-amnestic MCI is single domain or multiple domain dependent on whether or not more than one non-memory cognitive area is impaired. See, e.g., Peterson and Negash, CNS Spectr. 13:45-53, 2008. [0055] Diagnosis of MCI usually entails an objective assessment of cognitive impairment, which can be garnered through the use of well-established
  • MMSE Mini Mental State Examination
  • CANTAB Cambridge Neuropsychological Test Automated Battery
  • AVLT Rey Auditory Verbal Learning Test
  • WMS-R Logical Memory Subtest of the revised Wechsler Memory Scale
  • NYU New York University
  • AAMI Align-Associate Memory Impairment
  • a patient may be considered to have AAMI if he or she is at least 50 years old and meets all of the following criteria: a) The patient has noticed a decline in memory performance, b) The patient performs worse on a standard test of memory compared to young adults, c) All other obvious causes of memory decline, except normal aging, have been ruled out (in other words, the memory decline cannot be attributed to other causes such as a recent heart attack or head injury, depression, adverse reactions to medication, Alzheimer's disease, etc.).
  • Age-Related Cognitive Decline refers to declines in memory and cognitive abilities that are a normal consequence of aging in humans (e.g., Craik & Salthouse, 1992). This is also true in virtually all mammalian species.
  • Age- Associated Memory Impairment refers to older persons with objective memory declines relative to their younger years, but cognitive functioning that is normal relative to their age peers (Crook et al., 1986).
  • Age-Consistent Memory Decline is a less pejorative label which emphasizes that these are normal developmental changes (Crook, 1993; Larrabee, 1996), are not pathophysiological (Smith et al, 1991), and rarely progress to overt dementia (Youngjohn & Crook, 1993).
  • the DSM-IV (1994) has codified the diagnostic classification of ARCD.
  • “Dementia” refers to a condition characterized by severe cognitive deficit that interferes in normal activities of daily living. Subjects with dementia also display other symptoms such as impaired judgment, changes in personality, disorientation, confusion, behavior changes, trouble speaking, and motor deficits. There are different types of dementias, such as Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies, and frontotemporal dementia.
  • AD Alzheimer's disease
  • vascular dementia dementia with Lewy bodies
  • frontotemporal dementia There are different types of dementias, such as Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies, and frontotemporal dementia.
  • AD Alzheimer's disease
  • vascular dementia dementia with Lewy bodies
  • frontotemporal dementia There are different types of dementias, such as Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies, and frontotemporal dementia.
  • AD Alzheimer's disease
  • vascular dementia dementia with Lew
  • Dementia with Lewy bodies is characterized by abnormal deposits of alpha-synuclein that form inside neurons in the brain.
  • Cognitive impairment may be similar to AD, including impairments in memory and judgment and behavior changes.
  • Frontotemporal dementia is characterized by gliosis, neuronal loss, superficial spongiform degeneration in the frontal cortex and/or anterior temporal lobes, and Picks' bodies. Symptoms include changes in personality and behavior, including a decline in social skills and language expression/comprehension.
  • Post traumatic stress disorder refers to an anxiety disorder characterized by an immediate or delayed response to a catastrophic event, characterized by re-experiencing the trauma, psychic numbing or avoidance of stimuli associated with the trauma, and increased arousal. Re-experiencing phenomena include intrusive memories, flashbacks, nightmares, and psychological or physiological distress in response to trauma reminders.
  • Schiria 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 persona] 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.
  • ALS Amyotrophic lateral sclerosis
  • ALS refers to a progressive, fatal, neurodegenerative disease characterized by a degeneration of motor neurons, the nerve cells in the central nervous system that control voluntary muscle movement.
  • ALS is also characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory deficits, and neuronal
  • Cancer-therapy-related cognitive impairment refers to cognitive impairment that develops in subjects that are treated with cancer therapies such as chemotherapy and radiation. Cytotoxicity and other adverse side-effects on the brain of cancer therapies result in cognitive impairment in such functions as memory, learning and attention.
  • Parkinson's disease is a neurological disorder characterized by a decrease of voluntary movements.
  • the afflicted patient has reduction of motor activity and slower voluntary movements compared to the normal individual.
  • the patient has characteristic "mask” face, a tendency to hurry while walking, bent over posture and generalized weakness of the muscles.
  • Another important feature of the disease is the tremor of the extremities occurring at rest and decreasing during movements.
  • “Autism Spectrum Disorder” refers to a group of developmental disabilities that includes: autism; Asperger syndrome; pervasive developmental disorder not otherwise specified (PDD-NOS or atypical autism); Rett syndrome; and childhood
  • Mental retardation is a generalized disorder characterized by significantly impaired cognitive function and deficits in adaptive behaviors. Mental retardation is often defined as an Intelligence Quotient (IQ) score of less than 70. Inborn causes are among many underlying causes for mental retardation. The dysfunction in neuronal communication is also considered one of the underlying causes for mental retardation (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214).
  • IQ Intelligence Quotient
  • mental retardation includes, but are not limited to, Down syndrome, velocariofacial syndrome, fetal alcohol syndrome, Fragile X syndrome, Klinefelter' s syndrome, neurofibromatosis, congenital hypothyroidism, Williams syndrome, phenylketonuria (PKU), Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermid syndrome, Mowat- Wilson syndrome, ciliopathy, Lowe syndrome and siderium type X-linked mental retardation.
  • Down syndrome is a disorder that includes a combination of birth defects, including some degree of mental retardation, characteristic facial features and, often, heart defects, increased infections, problems with vision and hearing, and other health problems.
  • Fragile X syndrome is a prevalent form of inherited mental retardation, occurring with a frequency of 1 in 4,000 males and 1 in 8,000 females. The syndrome is also characterized by developmental delay, hyperactivity, attention deficit disorder, and autistic-like behavior. There is no effective treatment for fragile X syndrome.
  • Obsessive compulsive disorder is a mental condition that is most commonly characterized by intrusive, repetitive unwanted thoughts
  • OCD OCD is the fourth most common mental disorder in the United States. Some studies suggest the prevalence of OCD is between one and three percent, although the prevalence of clinically recognized OCD is much lower, suggesting that many individuals with the disorder may not be diagnosed. Patients with OCD are often diagnosed by a psychologist, psychiatrist, or psychoanalyst according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition text revision (DSM-IV-TR) (2000) diagnostic criteria that include characteristics of obsessions and compulsions.
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, 4th edition text revision
  • the addiction is not triggered instantaneously upon exposure to substance of abuse. Rather, it involves multiple, complex neural adaptations that develop with different time courses ranging from hours to days to months (Kauer J. A. Nat. Rev. Neurosci. 2007, 8, 844-858).
  • the path to addiction generally begins with the voluntary use of one or more controlled substances, such as narcotics, barbiturates, methamphetamines, alcohol, nicotine, and any of a variety of other such controlled substances. Over time, with extended use of the controlled substance(s), the voluntary ability to abstain from the controlled substance(s) is compromised due to the effects of prolonged use on brain function, and thus on behavior.
  • substance addiction generally is characterized by compulsive substance craving, seeking and use that persist even in the face of negative consequences.
  • the cravings may represent changes in the underlying neurobiology of the patient which likely must be addressed in a meaningful way if recovery is to be obtained.
  • Substance addiction is also characterized in many cases by withdrawal symptoms, which for some substances are life threatening (e.g., alcohol, barbiturates) and in others can result in substantial morbidity (which may include nausea, vomiting, fever, dizziness, and profuse sweating), distress, and decreased ability to obtain recovery.
  • alcoholism also known as alcohol dependence
  • Alcoholism is primarily characterized by four symptoms, which include cravings, loss of control, physical dependence and tolerance. These symptoms also may characterize addictions to other controlled substances.
  • the craving for alcohol, as well as other controlled substances often is as strong as the need for food or water. Thus, an alcoholic may continue to drink despite serious family, health and/or legal ramifications.
  • 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 of cognitive impairment associated with CNS disorders, such as age- related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI (aMCI), Age- Associated Memory Impairment (AAMI), Age Related Cognitive Decline (ARCD), dementia, Alzheimer's Disease (AD), prodromal AD, PTSD, schizophrenia or bipolar disorder (in particular, mania), amyotrophic lateral sclerosis (ALS), cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism, compulsive behavior, or substance addiction.
  • MCI Mild Cognitive Impairment
  • aMCI amnestic MCI
  • AAMI Age- Associated Memory Impairment
  • ARCD Age Related Cognitive Decline
  • AD Alzheimer's
  • treatment comprises preventing or slowing the progression, of a CNS disorder (such as one as described herein).
  • treatment comprises alleviation, amelioration, or slowing the progression of one or more symptoms associated with that CNS disorder.
  • the symptom to be treated is cognitive impairment or cognitive deficit. Treating age- related cognitive impairment further comprises slowing the conversion of age- related cognitive impairment (including, but not limited to MCI, ARCD and AAMI) into dementia (e.g., AD).
  • 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 age-related cognitive impairment 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 an age- matched normal, unimpaired subject, or the function of a young adult 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 GABA.
  • a5-containing GABA A receptor agonists suitable for use in the present invention, include the a5 -containing GABAA receptor agonists of all formulas and specific a5-containing GABAA receptor agonists described herein, and their hydrates, solvates, polymorphs, salts (e.g., pharmaceutically acceptable salts), isomers (e.g., stereoisomers, E/Z isomers, and tautomers), prodrugs, and combinations thereof.
  • Memantine is chemically known as 3,5-dimethyladamantan-l-amine or 3,5-dimethyltricyclo[3.3.1.1 3 ' 7 ]decan-l-amine, which is an uncompetitive N- methyl-D-aspartate (NMD A) receptor antagonist with moderate affinity.
  • NMD A N- methyl-D-aspartate
  • the proprietary names for memantine include: Axura® and Akatinol® (Merz), Namenda® (Forest Laboratories), Ebixa® and Abixa® (Lundbeck), and Memox® (Unipharm).
  • Memantine is approved for the treatment of moderate to severe Alzheimer's disease (AD) in the United States at a dose of up to 28 mg/day.
  • AD Alzheimer's disease
  • Derivatives or analogs of memantine which include compounds that structurally or chemically resemble memantine, are also useful in the present invention.
  • Such derivatives or analogs of memantine include, but are not limited to those compounds disclosed in U.S. Patents Nos. 3,391,142; 4,122,193; 4,273,774; and 5,061,703; U.S. Patent Application Publication US20040087658, US20050113458, US20060205822, US20090081259, US20090124659, and US20100227852; EP
  • Memantine includes memantine and its derivatives and analogs, as well as hydrates, polymorphs, isomers, prodrugs, salts, and solvates thereof. Memantine, as used herein, also includes a composition comprising memantine or a derivative or an analog or a pharmaceutically
  • composition optionally further comprises at least one additional therapeutic agent (such as a therapeutic agent useful for treating a CNS disorder or cognitive impairments associated thereof).
  • additional therapeutic agent such as a therapeutic agent useful for treating a CNS disorder or cognitive impairments associated thereof.
  • composition suitable for use in the present invention comprises memantine and a second therapeutic agent that is donepezil (under the trade name Aricept).
  • administration of a a5-containing GABAA receptor agonist and memantine or a memantine derivative/analog, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or prodrugs thereof "in combination” or “together” includes simultaneous administration and/or
  • administration at different times such as sequential administration. It also includes administration in a single formulation or in separate formulation packaged
  • the a5-containing GABAA receptor agonist may be formulated/administered in an extended release form, which may be administered together or separately with memantine, wherein memantine may or may not be in an extended release form itself.
  • memantine may be formulated/administered in an extended release form, which may be administered together or separately with a a5 -containing GABAA receptor agonist, wherein the a5 -containing GABAA receptor agonist may or may not be in an extended release form itself.
  • Extended release dosage form or “extended release form”, as used herein, refers to a dosage form that contains one or more active ingredients, where the release of at least one of the active ingredients, when placed in water or other biological fluids or solvents, may occur over an extended period, e.g. greater than or equal to one hour. In some embodiments, the release is extended for a period of at least about 1 hour, at least about 1 day, at least 5 days, at least about 10 days, at least about 20 days, at least about 30 days, at least about 60 days, at least about 90 days, or at least about 150 days.
  • 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.
  • only one of the a5 -containing GABAA receptor agonist and memantine is in an extended release dosage form.
  • the a5 -containing GABAA receptor agonist and memantine are each in an extended release dosage form (together in one formulation or separately in different formulations).
  • spontaneous administration means that the a5- containing GABAA receptor agonist and memantine (or the memantine
  • the a5 -containing GABAA receptor agonist and memantine or the memantine derivative/analog, or their salts, hydrates, solvates, polymorphs, isomers or prodrugs may be contained in the same dosage (e.g., a unit dosage form comprising both the a5 -containing GABAA receptor agonist and memantine or a memantine derivative/analog) or in discrete dosages (e.g., the a5- containing GABAA receptor agonist or its salt, hydrate, solvate, polymorph, isomer or prodrug is contained in one dosage form and memantine or the memantine
  • a5 -containing GABAA receptor agonist or memantine or the memantine derivative/analog may be administered first.
  • the a5 -containing GABAA receptor agonist and memantine or the memantine derivative/analog, or their salts, hydrates, solvates, polymorphs, isomers or prodrugs 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, e.g., a patient having cognitive impairment associated with a CNS disorder.
  • 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 or other
  • CNS disorder such as age-related cognitive impairment, Mild Cognitive Impairment (MCI), dementia, Alzheimer's Disease(AD), prodromal AD, post traumatic stress disorder (PTSD), schizophrenia , bipolar, ALS, cancer- therapy-related cognitive impairment, mental retardation, Parkinson's disease
  • PD neurodegenerative disease
  • autism autism
  • compulsive behavior and substance addiction
  • substance addiction 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 experimentation.
  • 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 involving cognitive dysfunction.
  • 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 memantine.
  • 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 an enzymatic activity of the host animal to a a5-containing GABAA receptor agonist or memantine (or a memantine derivative/ analog) .
  • 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- C10 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 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.
  • 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; and - one or both rings may contain said heteroatom or heteroatom groups.
  • heteroaryl rings examples 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-triazolyl and 5-triazolyl), 2-thienyl
  • 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.
  • an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like
  • an organic acid such as, for example, acetic
  • 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.
  • This application contemplates all the isomers of the compounds (e.g., the a5 -containing GABAA receptor agonists, and memantine and its derivatives and analogues) as disclosed herein.
  • “Isomer” as used herein includes optical isomers (such as stereoisomers, e.g., enantiomers and diastereoisomers), Z (zusammen) or E (entussi) isomers, and tautomers.
  • Many of the compounds useful in the methods and compositions of this invention have at least one 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.
  • 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.
  • the invention includes both mixture and separate individual isomers. Multiple substituents on a piperidinyl or the azepanyl ring can also stand in either cis or trans relationship to each other with respect to the plane of the piperidinyl or the azepanyl ring. Some of the compounds may also exist in tautomeric forms.
  • 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 memantine or a derivative or an analog or a pharmaceutically acceptable salt thereof.
  • Animal models serve as an important resource for developing and evaluating treatments for cognitive impairment associated with CNS disorders.
  • 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 cognitive impairment associated with CNS disorders.
  • the progression of age- related cognitive impairment and dementia may be monitored by assessing surrogate changes in the brain of the subject.
  • Surrogate changes include, without limitation, changes in regional brain volumes, perforant path degradation, and changes seen in brain function through resting state fMRI (R-fMRI) and fluorodeoxyglucose positron emission tomography (FDG-PET).
  • R-fMRI resting state fMRI
  • FDG-PET fluorodeoxyglucose positron emission tomography
  • regional brain volumes useful in monitoring the progression of age-related cognitive impairment and dementia include reduction of hippocampal volume and reduction in volume or thickness of entorhinal cortex. These volumes may be measured in a subject by, for example, MRI. Aisen et al, Alzheimer's &
  • Perforant path degradation has been shown to be linked to age, as well as reduced cognitive function. For example, older adults with more perforant path degradation tend to perform worse in hippocampus- dependent memory tests. Perforant path degradation may be monitored in subjects through ultrahigh-resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107: 12687-12691 (2010). Resting-state fMRI (R-fMRI) involves imaging the brain during rest, and recording large-amplitude spontaneous low- frequency ( ⁇ 0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related areas.
  • DTI ultrahigh-resolution diffusion tensor imaging
  • Seed-based functional connectivity, independent component analyses, and/or frequency-domain analyses of the signals are used to reveal functional connectivity between brain areas, particularly those areas whose connectivity increase or decrease with age, as well as the extent of cognitive impairment and/or dementia.
  • FDG-PET uses the uptake of FDG as a measure of regional metabolic activity in the brain. Decline of FDG uptake in regions such as the posterior cingulated cortex, temporoparietal cortex, and prefrontal association cortex has been shown to relate to the extent of cognitive decline and dementia. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al,
  • This invention provides methods and compositions for treating age-related cognitive impairment or the risk thereof using a a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or prodrug thereof in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • treatment comprises preventing or slowing the progression, of age-related cognitive impairment.
  • treatment comprises alleviation, amelioration or slowing the progression, of one or more symptoms associated with age-related cognitive impairment.
  • treatment of age-related cognitive impairment comprises slowing the conversion of age-related cognitive impairment (including, but not limited to MCI, ARCD and AAMI) into dementia (e.g., AD).
  • age-related cognitive impairment including, but not limited to MCI, ARCD and AAMI
  • the methods and compositions may be used for human patients in clinical applications in the treating age-related cognitive impairment in conditions such as MCI, ARCD and AAMI or for the risk thereof.
  • the dose of the composition and dosage interval for the method is, as described herein, one that is safe and efficacious in those applications.
  • a method of preserving or improving cognitive function in a subject with age-related cognitive impairment comprising the step of administering to said subject a therapeutically effective amount of a a5-containing GABAA receptor agonist of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • a subject to be treated by the methods and compositions of this invention exhibits age-related cognitive impairment or is at risk of such impairment.
  • the age-related cognitive impairment includes, without limitation, Age-Associated Memory Impairment (AAMI), Mild Cognitive Impairment (MCI) and Age-related Cognitive Decline (ARCD).
  • AAMI Age-Associated Memory Impairment
  • MCI Mild Cognitive Impairment
  • ARCD Age-related Cognitive Decline
  • Animal models serve as an important resource for developing and evaluating treatments for such age-related cognitive impairments. Features that characterize age-related cognitive impairment in animal models typically extend to age-related cognitive impairment in humans. Efficacy in such animal models is, thus, expected to be predictive of efficacy in humans.
  • Aged rats in the study population have no difficulty swimming to a visible platform, but an age-dependent impairment is detected when the platform is camouflaged, requiring the use of spatial information. Performance for individual aged rats in the outbred Long- Evans strain varies greatly. For example, a proportion of those rats perform on a par with young adults. However, approximately 40-50% fall outside the range of young performance. This variability among aged rats reflects reliable individual differences. Thus, within the aged population some animals are cognitively impaired and designated aged-impaired (Al) and other animals are not impaired and are designated aged-unimpaired (AU). See, e.g., Colombo et al., Proc. Natl. Acad. Sci.
  • compositions this invention in treating age-related cognitive impairment.
  • the efficacy of the methods and compositions of this invention in treating age-related cognitive impairment may be assessed using a variety of cognitive tests, including the Morris water maze and the radial arm maze, as discussed above. Dementia
  • This invention also provides methods and compositions for treating dementia using a a5-containing GABAA receptor agonist, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • treatment comprises preventing or slowing the progression, of dementia.
  • treatment comprises alleviation, amelioration, or slowing the progression of one or more symptoms associated with dementia.
  • the symptom to be treated is cognitive impairment.
  • a method of preserving or improving cognitive function in a subject with dementia comprising the step of administering to said subject a therapeutically effective amount of a a5- containing GABAA receptor agonist of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • the dementia is Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies, or frontotemporal dementia.
  • the methods and compositions may be used for human patients in clinical applications in treating dementia.
  • the dose of the composition and dosage interval for the method is, as described herein, one that is safe and efficacious in those applications.
  • Animal models serve as an important resource for developing and evaluating treatments for dementia.
  • Features that characterize dementia in animal models typically extend to dementia in humans.
  • efficacy in such animal models is expected to be predictive of efficacy in humans.
  • Various animal models of dementia are known in the art, such as the PDAPP, Tg2576, APP23, TgCR D8, J20, hPS2 Tg, and APP + PS1 transgenic mice.
  • Sankaranarayanan Curr. Top. Medicinal Chem. 6: 609-627, 2006; Kobayashi et al. Genes Brain Behav. 4: 173- 196. 2005; Ashe and Zahns, Neuron. 66: 631-45, 2010.
  • Such animal models of dementia may be used to assay the effectiveness of the methods and compositions of this invention of the invention in treating dementia.
  • This invention also provides methods and compositions for treating post traumatic stress disorder (PTSD) using a a5 -containing GABA A receptor agonist, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • treatment comprises preventing or slowing the progression, of PTSD.
  • treatment comprises alleviation, amelioration, or slowing the progression of one or more symptoms associated with PTSD.
  • the symptom to be treated is cognitive
  • a method of preserving or improving cognitive function in a subject with PTSD comprising the step of administering to said subject a therapeutically effective amount of a a5 -containing GABAA receptor agonist of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • the methods and compositions may be used for human patients in clinical applications in treating PTSD.
  • the dose of the composition and dosage interval for the method is, as described herein, one that is safe and efficacious in those applications.
  • PTSD is also associated with impaired cognitive performance. Older individuals with PTSD have greater declines in cognitive performance relative to control patients (Yehuda et al., Bio. Psych. 60: 714-721, 2006) and have a greater likelihood of developing dementia (Yaffe et al., Arch. Gen. Psych. 678: 608-613, 2010).
  • Animal models serve as an important resource for developing and evaluating treatments for PTSD.
  • Features that characterize PTSD in animal models typically extend to PTSD in humans.
  • efficacy in such animal models is expected to be predictive of efficacy in humans.
  • Various animal models of PTSD are known in the art.
  • TDS Time-dependent sensitization
  • Rats are placed in a restrainer, then placed in a swim tank and made to swim for a period of time, e.g., 20 min. Following this, each rat is then immediately exposed to a gaseous anesthetic until loss of consciousness, and finally dried. The animals are left undisturbed for a number of days, e.g., one week.
  • the rats are then exposed to a "restress" session consisting of an initial stressor, e.g., a swimming session in the swim tank (Liberzon et al, Psychoneuroendocrinology 22: 443-453, 1997; Harvery et al, Psychopharmacology 175:494-502, 2004).
  • TDS results in an enhancement of the acoustic startle response (ASR) in the rat, which is comparable to the exaggerated acoustic startle that is a prominent symptom of PTSD (Khan and Liberzon, Psychopharmacology 172: 225-229, 2004).
  • ASR acoustic startle response
  • Such animal models of PTSD may be used to assay the effectiveness of the methods and compositions of this invention of the invention in treating PTSD.
  • This invention additionally provides methods and compositions for treating schizophrenia or bipolar disorder (in particular, mania) using a a5- containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • treatment comprises preventing or slowing the progression of schizophrenia or bipolar disorder (in particular, mania).
  • 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 symptomatology with schizophrenia.
  • 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
  • schizophrenia or bipolar disorder comprising the step of administering to said subject a therapeutically effective amount of a a5 -containing GABAA receptor agonist of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • 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. [0123] Cognitive impairments are associated with schizophrenia.
  • 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. Patients with schizophrenia also present hippocampal pathologies such as reductions in hippocampal volume, reductions in neuronal size and dysfunctional hyperactivity. An imbalance in excitation and inhibition in these brain regions has also been documented in schizophrenic patients suggesting that drugs targeting inhibitory mechanisms could be therapeutic. See, e.g., Guidotti et al,
  • 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 pathodevelopmental process to schizophrenia-like phenotypes in the offspring, including anatomical changes, behavioral deficits and altered neuronal information processing. More specifically, MAM-treated rats display a decreased density of parvalbumin-positive GABAergic interneurons in portions of the prefrontal cortex and hippocampus. In behavioral tests, 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.
  • a noxious stimulus e.g. an electric shock to the foot.
  • both groups are presented with the tone, and the rats' change in locomotor activity during tone presentation is monitored.
  • the rats respond to the tone presentation by strongly reducing locomotor activity.
  • 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.
  • 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).
  • 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
  • MAM-treated rats in the above study may be suitable for use to assay the effectiveness of the methods and compositions of the present 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 central
  • hippocampus (vHipp) regulation on the elevated DA neuron population activity and on the hyperactive locomotor response to amphetamine in the MAM-treated animals.
  • HPC hippocampal
  • a benzodiazepine-positive allosteric modulator (PAM) selective for the a5 subunit of the GABA A receptor, SH-053-2'F-R-CH 3i is tested for its effects on the output of the hippocampal (HPC).
  • the effect of SH-053-2 - R-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.
  • 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).
  • 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 efficacy of the methods and compositions of this invention in treating schizophrenia may also be assessed in animal models of schizophrenia or bipolar disorder (in particular, mania), as well as human subjects with schizophrenia, using a variety of cognitive tests known in the art, as discussed above.
  • schizophrenia or bipolar disorder in particular, mania
  • human subjects with schizophrenia using a variety of cognitive tests known in the art, as discussed above.
  • ALS Amyotrophic Lateral Sclerosis
  • This invention additionally provides methods and compositions for treating ALS using a a5-containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • treatment comprises preventing or slowing the progression, of ALS.
  • treatment comprises alleviation, amelioration or slowing the progression, of one or more symptoms associated with ALS.
  • the symptom to be treated is cognitive impairment.
  • a method of preserving or improving cognitive function in a subject with ALS comprising the step of administering to said subject a therapeutically effective amount of a a5- containing GABAA receptor agonist of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • the methods and compositions may be used for human patients in clinical applications in treating ALS.
  • the dose of the composition and dosage interval for the method is, as described herein, one that is safe and efficacious in those applications.
  • ALS In addition to the degeneration of motor neurons, ALS is characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory deficits, and neuronal hyperexcitability in different brain areas such as the cortex.
  • treatment comprises preventing or slowing the progression, of cancer therapy-related cognitive impairment. In certain embodiments, treatment comprises alleviation, amelioration or slowing the progression, of one or more symptoms associated with cancer therapy-related cognitive impairment.
  • a method of preserving or improving cognitive function in a subject with cancer therapy-related cognitive impairment comprising the step of administering to said subject a therapeutically effective amount of a a5 -containing GABAA receptor agonist of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or prodrug thereof in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • the methods and compositions may be used for human patients in clinical applications in treating cancer therapy-related cognitive impairment.
  • 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 impairment following cancer therapies reflects dysfunction in frontal cortical and hippocampal circuits that are essential for normal cognition.
  • exposure to either chemotherapy or radiation adversely affects performance on tests of cognition specifically dependent on these brain systems, especially the hippocampus (Kim et al, J. Radiat. Res. 49:517-526, 2008; Yang et al., Neurobiol. Learning and Mem. 93:487-494, 2010).
  • drugs targeting these cortical and hippocampal systems could be neuroprotective in patients receiving cancer therapies and efficacious in treating symptoms of cognitive impairment that may last beyond the interventions used as cancer therapies.
  • Animal models serve as an important resource for developing and evaluating treatments for cancer therapy-related cognitive impairment.
  • Features that characterize cancer therapy-related cognitive impairment in animal models typically extend to cancer therapy-related cognitive impairment in humans.
  • efficacy in such animal models is expected to be predictive of efficacy in humans.
  • Various animal models of cancer therapy-related cognitive impairment are known in the art.
  • Examples of animal models of cancer therapy-related cognitive impairment include treating animals with anti-neoplastic agents such as cyclophosphamide (CYP) or with radiation, e.g., 60 Co gamma-rays.
  • anti-neoplastic agents such as cyclophosphamide (CYP)
  • radiation e.g., 60 Co gamma-rays.
  • the cognitive function of animal models of cancer therapy-related cognitive impairment may then be tested with cognitive tests to assay the effectiveness of the methods and compositions of the invention in treating cancer therapy-related cognitive impairment.
  • compositions of this invention in treating cancer therapy-related cognitive impairment, as well as human subjects with cancer therapy-related cognitive impairment, using a variety of cognitive tests known in the art, as discussed above.
  • Parkinson's disease is a neurological disorder characterized by a decrease of voluntary movements.
  • the afflicted patient has reduction of motor activity and slower voluntary movements compared to the normal individual.
  • the patient has characteristic "mask” face, a tendency to hurry while walking, bent over posture and generalized weakness of the muscles.
  • Another important feature of the disease is the tremor of the extremities occurring at rest and decreasing during movements.
  • Parkinson's disease belongs to a group of the most common movement disorders named parkinsonism, which affects approximately one person per one thousand.
  • parkinsonism which affects approximately one person per one thousand.
  • These other disorders grouped under the name of parkinsonism may result from viral infection, syphilis, arteriosclerosis and trauma and exposure to toxic chemicals and narcotics. Nonetheless, it is believed that the inappropriate loss of synaptic stability may lead to the disruption of neuronal circuits and to brain diseases.
  • PD Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214.
  • the main pathologic feature is degeneration of dopaminergic cells in basal ganglia, especially in substantia nigra. Due to premature death of the dopamine containing neurons in substantia nigra, the largest structure of the basal ganglia, the striatum, will have reduced input from substantia nigra resulting in decreased dopamine release.
  • the understanding of the underlying pathology led to the introduction of the first successful treatment which can alleviate Parkinson's disease.
  • Virtually all approaches to the therapy of the disease are based on dopamine replacement. Drugs currently used in the treatment can be converted into dopamine after crossing the blood brain barrier, or they can boost the synthesis of dopamine and reduce its breakdown.
  • the main pathologic event, degeneration of the cells in substantia nigra is not helped. The disease continues to progress and frequently after a certain length of time, dopamine replacement treatment will lose its effectiveness.
  • the invention provides methods and compositions for treating PD using a a5 -containing GABAA receptor agonist, such as one selected from the compounds or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or prodrugs thereof as described herein, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • a a5 -containing GABAA receptor agonist such as one selected from the compounds or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or prodrugs thereof as described herein, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • treatment comprises preventing or slowing the progression of PD.
  • treatment comprises alleviation, amelioration, or slowing the progression of one or more symptoms associated with PD.
  • the symptom to be treated is cognitive
  • methods and compositions of the disclosure can be used to improve the motor/cognitive impairments symptomatic of Parkinson's disease.
  • methods and compositions of the disclosure may be useful for treating the memory impairment symptomatic of Parkinson's disease.
  • a method of preserving or improving cognitive function in a subject with PD comprising the step of administering to said subject a therapeutically effective amount of a a5 -containing GABAA receptor agonist of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • animal models for PD include the reserpine model, the methamphetamine model, the 6- hydroxydopamine (6-OHDA) model, the l-methyl-4-phenyl-l,2,3,6- tetrahydropyridine (MPTP) model, the paraquat (PQ)-Maneb model, the rotenone model, the 3-nitrotyrosine model and genetic models using transgenic mice.
  • Transgenic models include mice that over express a-synuclein, express human mutant forms of a -synuclein, or mice that express LR K2 mutations. See review of these models by Ranjita B. et al. (Ranjita B. et al. BioEssays 2002, 24, 308-318). Additional information regarding these animal models is readily available from Jackson Laboratories (see also http://research.jax.org/grs/parkinsons.html), as well as in numerous publications disclosing the use of these validated models.
  • Autism is a neurodevelopmental disorder characterized by dysfunction in three core behavioral dimensions: repetitive behaviors, social deficits, and cognitive deficits.
  • the repetitive behavior domain involves compulsive behaviors, unusual attachments to objects, rigid adherence to routines or rituals, and repetitive motor mannerisms such as stereotypies and self- stimulatory behaviors.
  • the social deficit dimension involves deficits in reciprocal social interactions, lack of eye contact, diminished ability to carry on conversation, and impaired daily interaction skills.
  • the cognitive deficits can include language abnormalities.
  • Autism is a disabling neurological disorder that affects thousands of Americans and encompasses a number of subtypes, with various putative causes and few documented ameliorative treatments.
  • the disorders of the autistic spectrum may be present at birth, or may have later onset, for example, at ages two or three.
  • the invention also provides methods and compositions for treating autism using a a5 -containing GABA A receptor agonist, such as one selected from the compounds or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or prodrugs thereof as described herein, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • a a5 -containing GABA A receptor agonist such as one selected from the compounds or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or prodrugs thereof as described herein, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • treatment comprises preventing or slowing the progression of autism.
  • a a5 -containing GABA A receptor agonist such as one selected from the compounds or pharmaceutically acceptable salts, hydrates, solvates
  • treatment comprises alleviation, amelioration, or slowing the progression of one or more symptoms associated with autism.
  • the symptom to be treated is cognitive impairment or cognitive deficit.
  • methods and compositions of the disclosure can be used to improve the motor/cognitive deficits symptomatic of autism.
  • a method of preserving or improving cognitive function in a subject with autism comprising the step of administering to said subject a therapeutically effective amount of a a5- containing GABAA receptor agonist of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • VP A valproic acid
  • mental retardation includes, but are not limited to, Down syndrome, velocariofacial syndrome, fetal alcohol syndrome, Fragile X syndrome, Klinefelter' s syndrome, neurofibromatosis, congenital hypothyroidism, Williams syndrome, phenylketonuria (PKU), Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermid syndrome, Mowat- Wilson syndrome, ciliopathy, Lowe syndrome and siderium type X-linked mental retardation.
  • Down syndrome is a disorder that includes a combination of birth defects, including some degree of mental retardation, characteristic facial features and, often, heart defects, increased infections, problems with vision and hearing, and other health problems.
  • Fragile X syndrome is a prevalent form of inherited mental retardation, occurring with a frequency of 1 in 4,000 males and 1 in 8,000 females. The syndrome is also characterized by developmental delay, hyperactivity, attention deficit disorder, and autistic-like behavior. There is no effective treatment for fragile X syndrome.
  • the present invention contemplates the treatment of mild mental retardation, moderate mental retardation, severe mental retardation, profound mental retardation, and mental retardation severity unspecified.
  • mental retardation may be, but is not required to be, associated with chromosomal changes, (for example Down Syndrome due to trisomy 21), heredity, pregnancy and perinatal problems, and other severe mental disorders.
  • This invention provides methods and compositions for treating mental retardation using a a5 -containing GABAA receptor agonist, such as one selected from the compounds or
  • treatment comprises preventing or slowing the progression of mental retardation.
  • treatment comprises alleviation, amelioration, or slowing the progression of one or more symptoms associated with mental retardation.
  • the symptom to be treated is cognitive deficit/impairment.
  • methods and compositions of the disclosure can be used to improve the motor/cognitive impairments symptomatic of mental retardation.
  • a method of preserving or improving cognitive function in a subject with mental retardation comprising the step of administering to said subject a therapeutically effective amount of a a5 -containing GABAA receptor agonist of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or prodrug thereof, in combination with memantine or a derivative or an analog or a
  • Fragile X syndrome is a common form of mental retardation caused by the absence of the FMR1 protein, FMRP.
  • FMRP Two homologs of FMRP have been identified, FXRIP and FXR2P.
  • FXR2P shows high expression in brain and testis, like FMRP.
  • Fxr2 and Fmrl knockout mice, and Fmrl/Fxr2 double knockout mice are believed to be useful models for mental retardation such as Fragile X syndrome. See, Bontekoe C. J. M. et al. Hum. Mol. Genet. 2002, 11 (5): 487-498.
  • the efficacy of the methods and compositions of this invention in treating mental retardation, or cognitive deficit/impairment associated with mental retardation may be assessed in the these mouse models and other animal models developed for mental retardation, as well as human subjects with mental retardation, using a variety of cognitive tests known in the art, as discussed herein.
  • Obsessive compulsive disorder is a mental condition that is most commonly characterized by intrusive, repetitive unwanted thoughts
  • OCD OCD is the fourth most common mental disorder in the United States. Some studies suggest the prevalence of OCD is between one and three percent, although the prevalence of clinically recognized OCD is much lower, suggesting that many individuals with the disorder may not be diagnosed. Patients with OCD are often diagnosed by a psychologist, psychiatrist, or psychoanalyst according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition text revision (DSM-IV-TR) (2000) diagnostic criteria that include characteristics of obsessions and compulsions.
  • Characteristics of obsession include: (1) recurrent and persistent thoughts, impulses, or images that are experienced as intrusive and that cause marked anxiety or distress; (2) the thoughts, impulses, or images are not simply excessive worries about real-life problems; and (3) the person attempts to ignore or suppress such thoughts, impulses, or images, or to neutralize them with some other thought or action.
  • the person recognizes that the obsessional thoughts, impulses, or images are a product of his or her own mind, and are not based in reality.
  • Characteristics of compulsion include: (1) repetitive behaviors or mental acts that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly; (2) the behaviors or mental acts are aimed at preventing or reducing distress or preventing some dreaded event or situation; however, these behaviors or mental acts are not actually connected to the issue, or they are excessive.
  • the dysfunction in neuronal communication is considered one of the underlying causes for obsession disorder (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214).
  • OCD may be related to abnormal levels of a neurotransmitter called serotonin.
  • the first- line treatment of OCD consists of behavioral therapy, cognitive therapy, and medications.
  • Medications for treatment include serotonin reuptake inhibitors (SRIs) such as paroxetine (SeroxatTM, Paxil®, XetanorTM, ParoMerckTM,
  • RexetinTM sertraline
  • Zoloft® StimulotonTM
  • fluoxetine Prozac®, BioxetinTM
  • escitalopram Livox®
  • fluvoxamine Livox®
  • clomipramine clomipramine
  • Benzodiazepines are also used in treatment. As much as 40 to 60% of the patients, however, fail to adequately respond to the SRI therapy and an even greater proportion of patients fail to experience complete remission of their symptoms.
  • the invention provides methods and compositions for treating OCD using a a5 -containing GABAA receptor agonist, such as one selected from the compounds or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or prodrugs thereof as described herein, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • treatment comprises preventing or slowing the progression of OCD.
  • treatment comprises alleviation, amelioration, or slowing the progression of one or more symptoms associated with OCD.
  • the symptom to be treated is cognitive deficit.
  • methods and compositions of the disclosure can be used to treat the cognitive deficits in OCD, and/or to improve cognitive function in patients with OCD.
  • a method of preserving or improving cognitive function in a subject with OCD comprising the step of administering to said subject a therapeutically effective amount of a a5 -containing GABAA receptor agonist of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • a quinpirole-sensitized rat model has been developed for OCD.
  • the compulsive checking behavior of the quinpirole-sensitized rats is subject to interruption, which is an attribute characteristic of OCD compulsions.
  • the efficacy of the methods and compositions of this invention in treating OCD, or cognitive deficits associated with OCD may be assessed in this rat model and other animal models developed for OCD, as well as human subjects with OCD, using a variety of cognitive tests known in the art, as discussed herein.
  • Substance addiction e.g., drug substance addiction, alcohol substance addiction
  • substance addiction is not triggered instantaneously upon exposure to substance of abuse. Rather, it involves multiple, complex neural adaptations that develop with different time courses ranging from hours to days to months (Kauer J. A. Nat. Rev. Neurosci. 2007, 8, 844-858).
  • the path to substance addiction generally begins with the voluntary use of one or more controlled substances, such as narcotics, barbiturates, methamphetamines, alcohol, nicotine, and any of a variety of other such controlled substances.
  • substance addiction generally is characterized by compulsive substance craving, seeking and use that persist even in the face of negative consequences.
  • the cravings may represent changes in the underlying neurobiology of the patient which likely must be addressed in a meaningful way if recovery is to be obtained.
  • Substance addiction is also characterized in many cases by withdrawal symptoms, which for some substances are life threatening (e.g., alcohol, barbiturates) and in others can result in substantial morbidity (which may include nausea, vomiting, fever, dizziness, and profuse sweating), distress, and decreased ability to obtain recovery.
  • Alcoholism also known as alcohol dependence
  • Alcoholism is one such substance addiction.
  • Alcoholism is primarily characterized by four symptoms, which include cravings, loss of control, physical dependence and tolerance. These symptoms also may characterize substance addictions to other controlled substances. The craving for alcohol, as well as other controlled substances, often is as strong as the need for food or water. Thus, an alcoholic may continue to drink despite serious family, health and/or legal ramifications.
  • CNS central nervous system
  • the invention provides methods and compositions for treating substance addiction using a a5-containing GABAA receptor agonist, such as one selected from the compounds or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or prodrugs thereof as described herein, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • a a5-containing GABAA receptor agonist such as one selected from the compounds or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or prodrugs thereof as described herein, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • treatment comprises preventing or slowing the progression of substance addiction.
  • treatment comprises alleviation, amelioration, or slowing the progression of one or more symptoms associated with substance addiction.
  • the symptom to be treated is cognitive impairment.
  • compositions of the disclosure can be used to treat the cognitive impairment and/or to improve cognitive function in patients with substance addiction.
  • a method of preserving or improving cognitive function in a subject with substance addiction comprising the step of administering to said subject a therapeutically effective amount of a a5 -containing GABAA receptor agonist of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or prodrug thereof, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • msP Marchigian Sardinian alcohol-preferring
  • the invention further provides methods and compositions for treating impairment in neurological disorders and neuropsychiatric conditions using a a5- containing GABAA R agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or prodrug thereof as described herein, in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • treatment comprises alleviation, amelioration or slowing the progression, of one or more symptoms associated with such impairment.
  • RDoC Research Domain Criteria
  • the a5-containing GABAA receptor agonist useful in the present invention may be any a5 -containing GABAA receptor agonist.
  • 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 GABA A 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 (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 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; or 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:
  • At least one of R 1 and R 2 is 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:
  • I-B or pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof; wherein X, Y and Z are each independently selected from -CR 4 -, -N(R 4 )-, -N , -O- and -S-,
  • R 4 and R 5 are each independently selected from:
  • 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 GABA A 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 substituents independently selected from J.
  • 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
  • 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 (Cl-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
  • 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), or 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
  • R 2 is (Cl-C4)-alkyl (such as methyl and isopropyl); 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 1 substituent selected from (Cl-C4)-alkyl- (such as methyl and ethyl) and -C(0)OR 3 where R 3 (Cl-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.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula 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
  • polyethylene-polyoxypropylene-block polymers polyethylene glycol and wool fat.
  • 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.
  • Memantine and memantine derivatives and analogs which functionally o structurally resemble memantine, and their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomer or prodrugs are useful in the present invention.
  • Memantine chemically known as 3,5-dimethyladamantan-l -amine or 3 dimethyltricyclo[3.3.1.1 3 ' 7 ]decan-l-amine, has the following structure:
  • Memantine is an uncompetitive N-methyl-D-aspartate (NMD A) receptor antagonist with moderate affinity. Memantine was discovered in 1968 and patented by Eli Lilly. Merz later developed it in collaboration with NMD A receptor antagonist with moderate affinity. Memantine was discovered in 1968 and patented by Eli Lilly. Merz later developed it in collaboration with NMD A receptor antagonist with moderate affinity. Memantine was discovered in 1968 and patented by Eli Lilly. Merz later developed it in collaboration with NMD A receptor antagonist with moderate affinity. Memantine was discovered in 1968 and patented by Eli Lilly. Merz later developed it in collaboration with NMD A receptor antagonist with moderate affinity. Memantine was discovered in 1968 and patented by Eli Lilly. Merz later developed it in collaboration with NMD A receptor antagonist with moderate affinity. Memantine was discovered in 1968 and patented by Eli Lilly. Merz later developed it in collaboration with NMD A receptor antagonist with moderate affinity. Memantine was discovered in 1968 and patented by Eli Lilly. Merz later developed it in collaboration with NMD A receptor antagonist with moderate affinity.
  • Memantine was then licensed to Forest laboratories for development in the United States as well as Lundbeck for other international markets.
  • the proprietary names for memantine include: Axura® and Akatinol® (Merz), Namenda® (Forest Laboratories), Ebixa® and Abixa®
  • Memantine is currently available in the U.S. and in over 42 countries worldwide. It is approved for the treatment of moderate to severe Alzheimer's disease (AD) in the United States at a dose of up to 28 mg/day.
  • AD Alzheimer's disease
  • Memantine and some of its derivatives and analogs are disclosed in U.S. Patents Nos. 3,391,142; 4,122,193; 4,273,774; and 5,061,703, all of which are hereby incorporated by reference.
  • Other memantine derivatives or analogs that are useful in the present invention include, but are not limited to, those compounds disclosed in U.S. Patent Application Publication US20040087658,
  • memantine derivatives or analogs suitable for the present invention are adamantyl amines described in U.S. Patent 3,391,142. In some embodiments, such memantine derivatives or analogs have the following formula:
  • Ad is 1-adamantyl, 3-methyl-l -adamantyl, 3.5 -dimethyl- 1 -adamantyl, or 3,5,7- trimethyl-l-adamantyl;
  • R 5 when taken alone, is hydrogen
  • R 6 when taken alone, is Ad, phenyl, or — ⁇ — ⁇ (— ⁇
  • R 5 and R 6 when taken together with the nitrogen atom to which they are attached, form a heterocyclic ring of the class consisting of piperazine and 4-(substituted) piperazine, the substituents on said piperazine ring being Ci-C 5 alkyl, hydroxy- substituted C 1 -C 5 alkyl, phenyl, or substituted phenyl, the substituents on said substituted phenyl being C 1 -C 5 alkyl or halo; and
  • Z is C 2 -C8 alkylene
  • memantine derivatives or analogs suitable for the present invention are described in U.S. Patent 4,122,193, which derivatives or analogs have the formula: wherein:
  • Ri and R 2 radicals represent lower straight-chain or branched alkyl groups; the R 3 radical represents hydrogen, a lower straight-chain, branched, or cyclic alkyl group; and the
  • R4 radical represents hydrogen, or a methyl group, or a salt of the compound.
  • memantine derivatives or analogs suitable for the present invention are adamantyl amines described in U.S. Patent 5,061,703, which derivatives or analogs have the formula:
  • Ri and R 2 are identical or different, representing hydrogen or a straight or branched alkyl group of 1 to 6 C atoms or, in conjunction with N, a heterocyclic group with 5 or 6 ring C atoms;
  • R 3 and R 4 are identical or different, being selected from hydrogen, a straight or branched alkyl group of 1 to 6 C atoms, a cycloalkyl group with 5 or 6 C atoms, and phenyl;
  • R 5 is hydrogen or a straight or branched Ci-C 6 alkyl group
  • memantine derivatives or analogs suitable for the present invention are described in EP2260839A2, which derivatives or analogs are 1-aminocyclohexane derivatives having the formula (I):
  • R* is -(A) n -(CR 1 R 2 ) m -NR 3 R 4 ,
  • n+m 0, 1, or 2
  • A is selected from the group consisting of linear or branched lower alkyl (Ci-
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, linear or branched lower alkyl (Ci-C 6 ), linear or branched lower alkenyl (C 2 -C 6 ), linear or branched lower alkynyl (C 2 -C 6 ) aryl, substituted aryl and arylalkyl,
  • R 5 is independently selected from the group consisting of hydrogen, linear or branched lower alkyl (Ci-C 6 ), linear or branched lower alkenyl (C 2 -C 6 ), and linear or branched lower alkynyl (C 2 -C 6 ), or R 5 combines with the carbon to which it is attached and the next adjacent ring carbon to form a double bond,
  • R p , R q , R r , and R s are independently selected from the group consisting of hydrogen, linear or branched lower alkyl (Ci-C 6 ), linear or branched lower alkenyl (C 2 -C 6 ), linear or branched lower alkynyl (C 2 -C 6 ), cycloalkyl (C 3 -C 6 ) and aryl, substituted aryl and arylaklyl or R p , R q , R r , and R s independently may form a double bond with U or with Y or to which it is attached, or R p , R q , R r , and R s may combine together to represent a lower alkylene -(CH 2 ) X - or a lower alkenylene bridge wherein x is 2-5, inclusive, which alkylene bridge may, in turn, combine with R 5 to form an additional lower alkylene -(CH 2 ) y - or
  • R p , R q , R r , R s and R 5 are as defined above for formula (I)
  • R 6 is hydrogen, linear or branched lower alkyl (Ci-C 6 ), linear or branched lower alkenyl (C 2 -C 6 ), linear or branched lower alkynyl (C 2 -C 6 ), aryl, substituted aryl or arylalkyl
  • the memantine or derivatives/analogs useful in the present invention include, but are not limited to:
  • N-alkyl e.g., N-methyl, N-ethyl, and N-propyl
  • ⁇ , ⁇ -dialkyl e.g., ⁇ , ⁇ -dimethyl
  • Memantine as used in the present invention, includes memantine and its derivatives and analogs, as well as hydrates, polymorphs,isomers prodrugs, salts, and solvates thereof.
  • Memantine as used herein, also includes a composition comprising memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof, wherein the composition optionally further comprises at least one additional therapeutic agent (such as a therapeutic agent useful for treating a CNS disorder or cognitive impairments associated thereof).
  • the memantine includes memantine and its derivatives and analogs, as well as hydrates, polymorphs,isomers prodrugs, salts, and solvates thereof.
  • Memantine as used herein, also includes a composition comprising memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof, wherein the composition optionally further comprises at least one additional therapeutic agent (such
  • composition suitable for use in the present invention comprises memantine and a second therapeutic agent that is donepezil (under the trade name Aricept).
  • a second therapeutic agent that is donepezil (under the trade name Aricept).
  • the invention provides methods and compositions for treating or improving cognitive function, delaying or slowing the progression of cognitive impairment, or reducing the rate of decline of cognitive function, in a subject suffering from a cognitive impairment associated with central nervous system (CNS) disorder (e.g., age-related cognitive impairment, MCI, amnestic MCI, dementia, AD, prodromal AD, PTSD, schizophrenia or bipolar disorder, ALS, cancer therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism, compulsive behavior, and substance addiction.), or at risk thereof in a subject in need thereof by administering a a5-containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof in combination with memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof.
  • CNS central nervous system
  • the a5-containing GABAA receptor agonist and memantine or memantine derivative/analog 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 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 Application 61/413,971 and PCT publication WO2012068161.
  • memantine or a pharmaceutically acceptable salt or a solvate, or a hydrate, or a polymorph, or an isomer, or a prodrug thereof is administered in combination with the a5 -containing GABAA receptor agonist.
  • the a5 -containing GABAA receptor agonist which is selected from 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 Application 61/413,971 and PCT publication WO2012068161 or derivatives or analogs or pharmaceutically acceptable salts, or solvates, or hydrates, or polymorphs, or isomers, or prodrugs thereof, is administered in combination with memantine or a pharmaceutically acceptable salt, or a solvate, or a hydrate, or a polymorph, or an isomer, or a prodrug thereof.
  • the CNS disorder with cognitive impairment is age-related cognitive impairment, such as Mild Cognitive Impairment (MCI), MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI, MCI), MCI
  • the MCI is amnestic MCI.
  • the CNS disorder with cognitive impairment is dementia, post traumatic stress disorder (PTSD), schizophrenia or bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism, compulsive behavior, or substance addiction.
  • the subject that suffers such cognitive impairment is a human patient.
  • the subject may be a human or other mammal such as a non-human primate, or rodent (e.g., rat).
  • the subject is a human patient.
  • the use of the a5-containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof in combination with memantine or a memantine derivative/analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or prodrug thereof may reduce the amount of memantine or the memantine derivative/analog necessary for the treatment of CNS disorders involving cognitive dysfunction and other affective disorders, including MCI, amnestic MCI, AAMI, ARCE, dementia, AD, PTSD, schizophrenia or bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer- therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism, compulsive behavior, or substance addiction.
  • MCI amnestic MCI
  • AAMI Alzheimer's disease
  • ARCE Alzheimer's disease
  • PD Parkinson's disease
  • autism compulsive behavior, or substance addiction.
  • the subject that suffers such cognitive impairment is a human patient, and thus reduce the side effects caused by memantine or the memantine derivative/analog without diminishing efficacy.
  • the efficacy of a combination of the a5 -containing GABAA receptor agonist and memantine (or a memantine derivative/analog) and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, isomers, and prodrugs thereof exceeds the efficacy of either drug administered alone at its optimal dose and thus is an improved treatment for cognitive impairment associated with CNS disorders.
  • 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 route.
  • administration of a a5-containing GABAA receptor agonist and memantine (or a memantine derivative/analog) or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers and prodrugs 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 memantine (or the memantine derivative/analog) or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers and prodrugs can optionally be combined with supplemental doses of the a5 -containing GABAA receptor agonist and/or memantine (or the memantine derivative/analog) and their salts, hydrates, solvates, polymorphs, isomers and prodrugs.
  • Simultaneous administration of drugs encompasses administration as co-formulation or, alternatively, as separate compositions.
  • the a5 -containing GABAA receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug may be administered at a subtherapeutic dosage level (as compared to the therapeutic dose of the a5 -containing GABAA receptor agonist when administered alone) when provided in combination with memantine or its analog, derivative or pharmaceutically acceptable salt.
  • the a5 -containing GABAA receptor agonist and memantine (or the memantine derivative/analog), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, isomers or prodrugs 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 memantine can be administered to a subject via different routes.
  • the a5-containing GABAA receptor agonist or its salt, solvate, hydrate, polymorph, isomer or prodrug is administered intravenously and memantine (or the memantine derivative/analog) or its salt, solvate, hydrate, polymorph, isomer or prodrug 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 a5 -containing GABAA receptor agonist is administered in an extended release form.
  • the a5- containing GABAA receptor agonist in an extended release form is administered together with memantine.
  • the a5-containing GABAA receptor agonist in an extended release form and memantine are administered separately.
  • memantine is also in an extended release form.
  • memantine is not in an extended release form.
  • memantine is administered in an extended release form.
  • memantine in an extended release form is administered together with the a5-containing GABAA receptor agonist. In some embodiments, memantine in an extended release form and the a5-containing GABAA receptor agonist are administered separately. In some of the above embodiments where memantine is in an extended release form, the a5 -containing GABAA receptor agonist is also in an extended release form. In some of the above embodiments where memantine is in an extended release form, the a5 -containing GABAA receptor agonist is not in an extended release form. [0222] When a solid carrier is used for administration, 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.
  • 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 memantine (or the memantine)
  • an effective amount can be administered in more than one dose and over a course of treatment.
  • the a5 -containing GABAA receptor agonist and memantine (or the memantine derivative/analog) and their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers and prodrugs 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
  • 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 a5 -containing GABAA receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer and prodrug may be administered at a subtherapeutic dosage levels when provided in combination with memantine or its derivative, analog, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer and prodrug, due to memantine-dependent increase in the therapeutic index of the a5-containing GABAA receptor agonist.
  • combination with memantine is greater than the therapeutic index of the a5 -containing GABAA receptor agonist administered in the absence of memantine (or the memantine derivative/analog) by at least about 1.5x or 2.
  • combinations of a a5-containing GABAA receptor agonist with memantine reduce the dosage of the a5 -containing GABAA receptor agonist required for its therapeutic effect.
  • the amount of the a5-containing GABAA receptor agonist administered in combination with memantine is a subtherapeutic amount.
  • Memantine or its derivative or analog or pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer and prodrug may be administered at a dosage level up to conventional dosage levels. Suitable dosage levels will depend upon memantine or its derivative/analog that is chosen. Memantine may be administered on a regimen of 2 times per day, 1 time per day, or it may be administered less often. In other embodiments of the invention, memantine or a derivative or an analog or a
  • memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof is administered every 12 or 24 hours at a daily dose of about 0.01 to 100 mg.
  • memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof is administered every 12 or 24 hours at a daily dose selected from 0.1-100 mg/day, 1-100 mg/day, 1-80 mg/day, 5-50 mg/day, 5-30 mg/day or 5-20 mg/day.
  • memantine or a derivative or an analog or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or prodrug thereof is administered at a dose up to 30 mg/day.
  • the memantine or a salt, hydrate, solvate, polymorph, isomer or prodrug thereof may be administered at dosage levels distinct from conventional levels (e.g., at a subtherapeutic level) when provided in combination with a a5 -containing GABAA receptor agonist, due to a a5 -containing GABAA receptor agonist-dependent increase in memantine's therapeutic index.
  • the increase in memantine's therapeutic index due to the combination with a a5 -containing GABAA receptor agonist thereof is greater than the therapeutic index of memantine administered in the absence of a a5-containing GABAA receptor agonist by at least about 1.5x or 2. Ox or 2.5x or 3. Ox or 3.5x or 4.
  • combination of memantine (or the memantine derivative/analog) with the a5 -containing GABAA receptor agonist reduces the dosage of memantine (or the memantine derivative/analog) required for its therapeutic effect. In some embodiments, the amount of memantine (or the memantine derivative/analog) administered in
  • combination with the a5 -containing GABAA receptor agonist thereof is about 0.1 to 30 mg.
  • the amount of memantine administered in combination with the a5-containing GABAA receptor agonist is a subtherapeutic amount.
  • the amount of memantine administered in combination with the a5- containing GABAA receptor agonist is less than 100 mg, less than 80 mg, less than 50 mg, less than 30 mg, less than 20 mg daily, less than 10 mg daily, less than 5 mg daily, less than 1 mg daily, less than 0.5 mg daily, or less that 0.1 mg daily.
  • 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 memantine (or the memantine derivative/analog) and their salts, hydrates, solvates, polymorphs, isomers and prodrugs can be administered at different dosing frequencies or intervals.
  • a5-containing GABAA receptor agonist can be administered daily (including multiple doses per day) or less frequently.
  • Memantine or a derivative or and analog thereof can be administered daily (including multiple doses per day) or less frequently.
  • the use of a combination of a a5-containing GABAA receptor agonist and memantine may reduce the amount of memantine (or the memantine derivative/analog) necessary for treatment of cognitive impairment associated with CNS disorders, and may thus reduce the side effects caused by memantine (or the memantine derivative/analog).
  • the combination of a a5 -containing GABAA receptor agonist with a reduced amount of memantine (or a memantine derivative/analog) may reduce the side effects without negatively impacting efficacy of memantine (or the memantine derivative/analog. Accordingly, in some embodiments, a subtherapeutic amount of memantine is administered.
  • a suitable amount of the a5-containing GABAA receptor agonist is administered so as to reduce the dose of memantine or a
  • derivative/analog thereof e.g., a dose required to effect a degree of cognitive function improvement or treat age-associated cognitive impairment
  • a dose required to effect a degree of cognitive function improvement or treat age-associated cognitive impairment by at least about 20%, at least about 30%, at least about 40%>, or at least about 50%>, at least about 60%>, at least about 70%
  • the reduction may be reflected in terms of amount administered at a given administration and/or amount administered over a given period of time (reduced frequency).
  • the combined administration of an a5-containing GABAA receptor agonist or a salt, hydrate, solvate, polymorph, isomer and prodrug thereof and memantine or a derivative or an analog or a salt, hydrate, solvate, polymorph, isomer and prodrug thereof can attain a longer or improved therapeutic effect in the subject than that attained by administering only memantine (or the memantine derivative/analog) or only the a5 -containing GABAA receptor agonist, 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 memantine or a memantine derivative/analog and their salts, hydrates, solvates, polymorphs, isomers and prodrugs.
  • the a5-containing GABAA receptor agonist and memantine 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 memantine or memantine derivative/analog suitable for the composition of this invention may be selected from any of those as described above.
  • the a5-containing GABAA receptor agonist is selected from 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 Application 61/413,971 and PCT publication WO2012068161.
  • the composition comprises memantine or a pharmaceutically acceptable salt or a solvate, or a hydrate, or a polymorph, or an isomer, or a prodrug thereof in combination with the a5 -containing GABAA receptor agonist.
  • the composition comprises a a5-containing GABAA receptor agonist, which is selected from 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 Application
  • composition described herein can contain more than one a5-containing GABAA receptor agonist and/or more than one memantine (or memantine
  • 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 memantine (or the memantine derivative/analog).
  • the 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.
  • the a5- containing GABAA receptor agonist is in an extended release form.
  • the a5 -containing GABAA receptor agonist in an extended release form is formulated together with memantine in a single formulation.
  • the a5 -containing GABAA receptor agonist in an extended release form and memantine are formulated in separate formulations, which may be packaged together.
  • memantine is also in an extended release form.
  • memantine is not in an extended release form. In some embodiments of the composition of the present invention, memantine is in an extended release form. In some embodiments, memantine in an extended release form is formulated together with the a5 -containing GABAA receptor agonist in a single formulation. In some embodiments, memantine in an extended release form and the a5-containing GABAA receptor agonist are formulated in separate formulations, which may be packaged together. In some of the above composition embodiments where memantine is in an extended release form, the a5 -containing GABAA receptor agonist is also in an extended release form.
  • 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 including sublingual and buccal administration, e.g.
  • Danckwerts et al, and oral 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.
  • suitable administration forms for the above and other include depot injectable formulations, suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
  • 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.
  • 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
  • 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%
  • reaction mixture was cooled to rt and filtered through a celite pad to remove the solid impurities.
  • the filtrate was diluted with ethyl acetate (40 mL), washed with aq NaHC0 (5 mL x 1), brine solution (5 mL x 1) and dried over anhydrous Na 2 S0 4 .
  • the organic extracts were evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (100-200 mesh silica gel, 5 % EtOAc in hexane) to furnish methyl 3, 5-diphenylpyridazine-4-carboxylate (300 mg, 82 %) as a white solid.
  • Example 5 Synthesis of compound 23 [0273] 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 a5p3y2subtype are in the range of 3-10 ⁇ ). EC50s in the a5p3y2subtype are obtained for each compound. If the EC50 in ⁇ 5 ⁇ 3 ⁇ 2 is ⁇ 5 ⁇ , then the EC50 of the other three subtypes ( ⁇ 1 ⁇ 2 ⁇ 2, ⁇ 2 ⁇ 3 ⁇ 2 and ⁇ 3 ⁇ 3 ⁇ 2) is further determined individually in order to test for selectivity of the compounds in the c ⁇ 3y2subtype 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. Compounds demonstrating greater than 5% potentiation of the
  • GABA EC50 were indicative of compounds with positive allosteric modulation of the GABAA 5 receptor. That is, these compounds would enhance the effects of GABA at the GABA A a5 receptor.
  • 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).
  • 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.
  • GABA dose-response in Xenopus Oocyte expressing al and a5 GABAA RS [0285] A high-throughput two-electrode voltage clamp (TEVC) system
  • GABAARS or 0.3 ⁇ - 1 mM for a5-containing GABAARS
  • GABAARS or 0.3 ⁇ - 1 mM for a5-containing GABAARS
  • 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 100-200 ⁇ for al-containing GABAARS, and 10-20 ⁇ a5-containing
  • Diazepam and Flumazenil were used as reference compounds.
  • the GABA-gated CI current from oocytes expressing ⁇ 5 ⁇ 3 ⁇ 2 GABAAR 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 EC20 GABA was repeated to establish the recovery. [0289] The effect of Diazepam was analyzed from the peak amplitude of
  • Diazepam-(plus EC20 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 EC20 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 GABAAR subtypes.
  • test compound The effect of each test compound was determined from the peak amplitude of Diazepam-plus-compound-(plus EC 50 GABA)-induced current normalized on the peak amplitude of Diazepam-(plus EC 50 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 EC 50 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 EC 50 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)
  • Compound 26 demonstrated positive allosteric modulation of GABA at the GABAA a5 receptor with no evidence of activity at the GABAA al receptor, indicating that this compound is a GABAA a5 receptor specific agonist, consistent with specificity of this compound for the GABAA a5 receptor relative to the GABAA al receptor.
  • 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.
  • the RAM apparatus used consisted of eight equidistantly-spaced arms.
  • 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.
  • 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
  • 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 GABAA receptors and because it has been successfully used for GABAA(X5 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: 817-825 (2005); and Maeda et al, Synapse 47: 200-208 (2003)).
  • RO receptor occupancy
  • 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 na ' ive 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 Scientific) and centrifuged for 16-minutes at 14,000 rpm.
  • the (100 ⁇ ) supernatant solution was diluted by 300 ⁇ of sterile water (pH 6.5). This solution was then mixed thoroughly and analyzed via LC/MS/MS for Ro 15-4513 (tracer) and methyl 3 ,5 -diphenylpyridazine-4-carboxylate .
  • 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 GABAA(X5 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 % GABA A 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
  • Cognitive ly impaired aged rats were implanted unilaterally with a cannula into the lateral ventricle.
  • Stereotaxic coordinates were 1.0 mm posterior to bregma, 1.5 mm lateral to midline, and 3.5 mm ventral to the skull surface.
  • the rats were pre-trained in a water maze for 2 days (6 trials per day) to locate a submerged escape platform hidden underneath the surface of the pool, in which the escape platform location varied from day to day.
  • intracerebroventricular (ICV) infusion was given during pre -training.
  • 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 compositions pour le traitement d'un déficit cognitif associé à des troubles du système nerveux central (SNC). En particulier, l'invention concerne l'utilisation d'un agoniste du récepteur GABAA contenant a5 en combinaison avec la mémantine ou un dérivé ou un analogue de celle-ci, dans le traitement d'un déficit cognitif associé à des troubles du système nerveux central (SNC) chez un sujet en ayant besoin ou présentant un risque d'en avoir, comprenant, sans y être limité, des sujets ayant ou présentant un risque pour un déficit cognitif lié à l'âge, un trouble léger cognitif (MCI), un MCI amnésique (aMCI), des troubles de la mémoire associés à l'âge (AAMI), un déclin cognitif associé à l'âge (ARCD), une démence, la maladie d'Alzheimer (AD), l'AD prodromale, un état de stress post-traumatique (PTSD), la schizophrénie ou un trouble bipolaire, la sclérose latérale amyotrophique, un déficit cognitif associé à une thérapie anticancéreuse, un retard mental, la maladie de Parkinson (PD), l'autisme, un comportement compulsif et la toxicomanie.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060167032A1 (en) * 2002-01-16 2006-07-27 Galer Bradley S Pharmaceutical composition and method for treating disorders of the central nervous system
US20070112017A1 (en) * 2005-10-31 2007-05-17 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
US20100081723A1 (en) * 2004-09-23 2010-04-01 Forest Laboratories Holdings Limited Memantine For The Treatment Of Childhood Behavioral Disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060167032A1 (en) * 2002-01-16 2006-07-27 Galer Bradley S Pharmaceutical composition and method for treating disorders of the central nervous system
US20100081723A1 (en) * 2004-09-23 2010-04-01 Forest Laboratories Holdings Limited Memantine For The Treatment Of Childhood Behavioral Disorders
US20070112017A1 (en) * 2005-10-31 2007-05-17 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis

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