CA2409720A1 - A pharmaceutical composition and method of treatment of diseases of cognitive dysfunction in a mammal - Google Patents

A pharmaceutical composition and method of treatment of diseases of cognitive dysfunction in a mammal Download PDF

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Publication number
CA2409720A1
CA2409720A1 CA002409720A CA2409720A CA2409720A1 CA 2409720 A1 CA2409720 A1 CA 2409720A1 CA 002409720 A CA002409720 A CA 002409720A CA 2409720 A CA2409720 A CA 2409720A CA 2409720 A1 CA2409720 A1 CA 2409720A1
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Canada
Prior art keywords
triene
methano
hexahydro
pyrido
diazocin
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Abandoned
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CA002409720A
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French (fr)
Inventor
Jotham Wadsworth Coe
Edmund Patrick Harrigan
Brian Thomas O'neill
Steven Bradley Sands
Eric Jacob Watsky
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Pfizer Products Inc
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Individual
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Abstract

A pharmaceutical composition and method of treatment of diseases of cognitive dysfunction in a mammal comprising administration of a nicotine receptor partial agonist or a pharmaceutically acceptable salt thereof; and an acetylcholinesterase inhibitor, butylcholinesterase inhibitor, an estrogenic agent, selective estrogen receptor modulator or muscarinic agonist or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The nicotine receptor partial agonist and acetylcholinesterase inhibitor, butylcholinesterase inhibitor, estrogen, selective estrogen receptor modulator or muscarinic agonist are present in amounts that render the composition effective enhancing cognition or in the treatment of diseases of cognitive dysfunction including but not limited to Alzheimer's Disease, mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinson's disease dementia, Huntington's Disease, Stroke, TBI, AIDS
associated dementia and schizophrenia. The method of using these compositions is also disclosed.

Description

A Pharmaceutical Composition and Method of Treatment of Diseases of Cognitive Dysfunction in a Mammal.
Background of the Invention The present invention relates to pharmaceutical compositions for the prevention and/or treatment of diseases of cognitive dysfunction in a mammal comprising nicotine receptor partial agonists (NRPA) in combination with acetylcholinesterase inhibitors, butylcholinesterase inhibitors, estrogen, selective estrogen receptor modulators (SERMS) or muscarinic agonists and a pharmaceutically acceptable carrier. The pharmaceutical compositions are useful in enhancing memory in patients suffering from diseases of~ cognitive dysfunction such as, but not limited to, Alzheimer's Disease (AD), mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinson's disease dementia, Huntington's disease, stroke, traumatic brain injury (TBI), AIDS associated dementia and schizophrenia.
Cognitive and/or degenerative brain disorders are characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. In an example of such disorders, AD is a common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. Such disorders have been observed in varied races and ethnic groups worldwide and presents a major present and future public health problem. These diseases are currently estimated to affect about two to three million individuals in the United States alone. These diseases are incurable and will increase worldwide as the human lifespan increases.
Alzheimer's Disease is associated with degeneration of cholinergic neurons in the basal forebrain that play a fundamental rote in cognitive functions, including memory [Becker et al., Drug Development Research, 12, 163-195 (1988)]. As a result of such degeneration, patients suffering from the disease exhibit a marked reduction in acetylcholinesterase activity and choline uptake.
The term NRPA refers to all chemical compounds which bind at neuronal nicotinic acetylcholine specific receptor sites in mammalian tissue and elicit a partial agonist response.
A partial agonist response is defined here to mean a partial, or incomplete functional effect in a given functional assay. Additionally, a partial agonist will also exhibit some degree of antagonist activity by its ability to block the action of a full agonist (Feldman, R.S., Meyer, J.S.
& Quenzer, L.F. Principles of Neuropsychopharmacology, 1997; Sinauer Assoc.
Inc.).
NRPAs are expected to improve cognitive function in the above mentioned conditions.
Referenced herein are well-documented findings that cholinergic mechanisms are important for normal cognitive functioning and that cholinergic hypofunction accompanies the cognitive deficits associated with Alzheimer's Disease (AD). It has been shown previously that nicotine administration improves some aspects of cognitive performance in both animal models of cognitive function and in patients with AD [Wilson et al., Pharmacology Biochemistry and Behavior, 51,509-514 (1995); Arneric et al., Alzheimer Disease and Associated Disorders, 9(suppl 2), 50-61 (1995); Buccafusco et al., Behavioural Pharmacology, 10, 681-690 (1999)].
The present invention also relates to the combination use of acetylcholinesterase and butylcholinesterase inhibitors and NRPAs which result in cognition enhancement. It is known that acetylcholinesterase and butylcholinesterase inhibitors are effective in enhancing cholinergic activity and useful in improving the memory of Alzheimer's patients. By inhibiting the acetylcholinesterase or butylcholinesterase enzyme, these compounds increase the level of the neurotransmitter acetylcholine in the brain and thus enhance memory.
Becker et al., (Drug Development Research, 12, 163-195 (1988)], report that behavioral changes following cholinesterase inhibition appear to coincide with predicted peak levels of acetylcholine in the brain. They discuss the efficacy of three known acetylcholinesterase inhibitors physostigmine (Synapton), metrifonate, and tetrahydroaminoacridine. The development of specific acetylcholinesterase inhibitors has greatly improved the treatment options available for patients suffering from degenerative neurological disorders (eg. Aricept).
The present invention also relates to the combination use of estrogen and/or selective estrogen receptor modulators (SERMs) and NRPAs which result in cognition enhancement.
Estrogen has been shown to have protective effects in both in vivo model systems of cognitive dysfunction as well as human clinical studies. Singh et al. [Brain Research, 644, 305-312 (1994)] demonstrates a decline of cognitive function in the ovarectomized rat which can be prevented by administration of estrogen. Fifteen clinical studies examining the role of estrogen replacement therapy in cognition demonstrate statistically significant improvements in cognitive function [Haskell et al., Journal of Clinical Epidemiology, 50(11 ), 1249-1264 (1997)].
Such combinations are useful in the treatment of disorders associated with cognition impairment including, but not limited to, Alzheimer's Disease (AD), mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinson's disease dementia, Huntington's disease, stroke, traumatic brain injury (TBI) AIDS associated dementia and schizophrenia.
The present invention also relates to the combination use of NRPAs and muscarinic agonists which result in cognition enhancement. Muscarinic and nicotinic agonists have been reported to enhance cognitive tasks in animal models and in humans. Schwarz et al., Journal of Pharmacology & Experimental Therapeutics 291: 812-22 (1999); Veroff et al., Alzheimer Disease & Associated Disorders 12, 304-12 (1998); Bodick et al., Alzheimer Disease &
Associated Disorders 11 Suppl 4, S16-22 (1997).
it is expected that combinations of NRPAs with these other agents would be useful in the treatment of disorders associated with cognition impairment including, but not limited to, Alzheimer's Disease (AD), mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinson's disease dementia, Huntington's disease, stroke, traumatic brain injury (TBI) AIDS associated dementia and schizophrenia.
Summary of the Invention The present invention relates to a pharmaceutical composition for the enhancement of cognition or the treatment of disorders involving cognitive dysfunction in a mammal comprising (a) a nicotine receptor partial agonist (NRPA) or a pharmaceutical acceptable salt thereof; (b) an acetylcholinesterase inhibitor, a butylcholinesterase inhibitor, estrogenic agent, a selective estrogen receptor modulator (SERM) or a muscarinic agonist or a pharmaceutically acceptable salt thereof; and (c), a pharmaceutically acceptable carrier;
wherein the active ingredients (a) and (b) above are present in amounts that render the composition effective in the enhancement of cognition or the treatment of disorders of cognitive dysfunction.
The nicotine receptor partial agonists are selected from:
9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-vinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-bromo-3-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-one;
3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-one;
3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-one;
9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-ethynyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-propenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-propyl)- 1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
one;
9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2aj[1,5]diazocin-8-one;
9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
one;
one;
one;
one;
9-(4-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-9-(3-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-9-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-9-(2,4-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-9-(2,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyridoj1,2a][1,5]diazocin-8-one;
6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.OZ''°.p4,e]pentadeca-2(10),3,8-triene;
5-oxo-6,13-diazatetracyclo[9.3.1.OZ''°.04~g]pentadeca-2(10),3,8-triene;
6-oxo-5,7,13-triazatetracyclo[9.3.1.Oz~'°.04'8]pentadeca-2(10),3,8-triene;
4,5-difluoro-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
triene;
5-fluoro-10-aza-tricyclo[6.3.1.Oz~']dodecc-2(7),3,5-triene-4-carbonitrile;
4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.OZ'']dodecc-2(7),3,5-triene;
5-ethynyl-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene-4-carbonitrile;
6-methyl-5-this-5-dioxa-6,13-diazatetracyclo[9.3.1.Oz''°.04,8]pentadeca-2(10),3,8-10-aza-tricyclo[6.3.1.Oz'']dodecc-2(7),3,5-triene;
4-fluoro-10-aza-tricyclo[6.3.1.OZ'']dodecc-2(7),3,5-triene;
4-methyl-10-aza-tricyclo[6.3.1.OZ'']dodecc-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.1.0~~']dodecc-2(7),3,5-trieve;
4-vitro-10-azatricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
7-methyl-5,7,13-triazatetracyclo[9.3.1.OZ~'°.04'e]pentadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,13-triazatetracyclo[9.3.1.O2''°.04'8]pentadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.OZ''°.04'e]pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.O2''°.048]pentadeca-2(10),3,5,8-tetraene;

6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0~~".049]hexadeca-2(11 ),3,5,7,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.02'".0''9]hexadeca-2(11 ),3,5,7,9-pentaene;
14-methyl-5,8,14-triazatetracyclo[10.3.1.02'".04'9]hexadeca-2(11 ),3,5,7,9-pentaene;
5-oxa-7,13-diazatetracyclo[9.3.1.02~'°.04'e]pentadeca-2(10),3,6,8-tetraene;
6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.OZ''°.04'e]pentadeca-2(10),3,6,8-tetraene;
4-chloro-10-azatricyclo[6.3.1.OZ~']dodecc-2(7),3,5-triene;
10-azatricyclo[6.3.1.02'']dodecc-2(7),3,5-trien-4-yl cyanide;
1-( 10-azatricyclo[6.3.1.Oz'']dodecc-2(7),3,5-trien-4-yl)-1-ethanone;
10-azatricyclo[6.3.1.OZ'']dodecc-2(7),3,5-trien-4-ol;
7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.OZ''°.0a,a]pentadeca-2,4(8),6,9-tetraene;
~ 4,5-dichloro-10-azatricyclo[6.3.1.0z~']dodecc-2(7),3,5-triene;
11-azatricyclo[7.3.1.Oz~']trideca-2(7),3,5-triene-5-carbonitrile;
1-[11-azatricyclo[7.3.1.Oz~']trid eca-2(7),3,5-trien-5-yl]-1-ethanone;
1-[11-azatricyclo[7.3.1.OZ'']trideca-2(7),3, 5-trien-5-yl]-1-propanone;
4-fluoro-11-azatricyclo[7.3.1.OZ'']trideca-2(7),3,5-triene-5-carbonitrile;
5-fluoro-11-azatricyclo[7.3.1.0"']trideca-2(7),3,5-triene-4-carbonitrile;
6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.OZ''°.04'a]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,14-triazatetracyclo[10.3.1.OZ~'°.04'8]hexadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.Oz''°.0a,a]hexadeca-2(10),3,5,8-tetraene;
5,7,14-triazatetracyclo[10.3.1.0~~'°.04'8]hexadeca-2(10),3,5,8-tetraene;
5,6-dimethyl-5,7,14-triazatetracyclo[10.3.1.02''°.04'a]hexadeca-2(10),3,6,8-tetraene;
5-methyl-5,7,14-triazatetracyclo[10.3.1.OZ''°.04'a]hexadeca-2(10),3,6,8-tetraene;
6-(trifluoromethyl)-7-this-5,14-diazatetracyclo[10.3.1.OZ''°.04'8]hexadeca-2(10),3,5,8-tetraene;
5,8,15-triazatetracyclo[11.3.1.02'".04'9]heptadeca-2(11 ),3,5,7,9-pentaene;
7-methyl-5,8,15-triazatetracyclo[11.3.1.02~".0''9]heptadeca-2(11),3,5,7,9-pentaene;
6-methyl-5,8,15-triazatetracyclo[11.3.1.02".049]heptadeca-2(11 ),3,5,7,9-pentaene;
6,7-dimethyl-5,8,15-triazatetracyclo[11.3.1.02'".04'9]heptadeca-2(11 ),3,5,7,9-pentaene;
7-oxa-5,14-diazatetracyclo[10.3.1.0~~'°.04'a]hexadeca-2(10),3,5,8-tetraene;
6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.02''°.04~g]hexadeca-2(10),3,5,8-tetraene;
5-methyl-7-oxa-6,14-diazatetracyclo[10.3.1.0~~'°.0~~8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.OZ''°.048]hexadeca-2(10),3,6,8-tetraene;
7-methyl-5-oxa-6,14-diazatetracyclo[10.3.1.02''°.04'a]hexadeca-2(10),3,6,8-tetraene;
4,5-difluoro-11-azatricyclo[7.3.1.OZ'']trideca-2(7),3,5-triene;
4-chloro-5-fluoro-11-azatricyclo[7.3.1.Oz'']trideca-2(7),3,5-triene;

5-chloro-4-fluoro-11-azatricyclo[7.3.1.02'']trideca-2(7),3,5-trieve;
4-( 1-ethynyl)-5-fluoro-11-azatricycio[7.3.1.Oz~']trideca-2(7),3, 5-triene;
5-(1-ethynyl)-4-fluoro-11-azatricyclo[7.3.1.Oz'']trideca-2(7),3,5-triene;
5,6-difluoro-11-aza-tricyclo[7.3.1.02'']trideca-2,4,6-triene;
6-trifluo~omethyl-11-aza-tricyclo[7.3.1.0~~']trideca-2,4,6-triene;
6-methoxy-11-aza-tricyclo[7.3.1.0~~'Jtrideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.Oz'']trideca-2(7),3,5-trien-6-ol;
6-fluoro-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.0~~']trideca-2(7),3,5-trien-5-ol;
4-vitro-11-aza-tricyclo[7.3.1.Oz~']trideca-2(7),3,5-triene;
5-vitro-11-aza-tricyclo[7.3.1.02~'Jtrideca-2(7),3,5-triene;
5-fluoro-11-aza-tricyclo[7.3.1.02']trideca-2(7),3,5-triene; and 6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene and their pharmaceutically acceptable salts and their optical isomers.
Preferably, the nicotine receptor partial agonist is selected from:
9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-chioro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-aJ[1,5]diazocin-8-one;
9-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,SJdiazocin-one;
9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]di.azocin-8-one;
9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.Oz~'°.04~8]pentadeca-2(10),3,8-triene;
4-fluoro-10-aza-tricyclo[6.3.1.OZ'']dodecc-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.1.OZ'']dodecc-2(7),3,5-trieve;
4-vitro-10-azatricyclo[6.3.1.02~']dodeca-2(7),3,5-triene;
6-methyl-5,7,13-triazatetracyclo[9.3.1.OZ''°.04'e]pentadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.02'".04'9]hexadeca-2(11),3,5,7,9-pentaene;

-7_ 5,8,14-triazatetracycloj10.3.1.Oz~".04'9]hexadeca-2(11),3,5,7,9-pentaene;
5-oxa-7,13-diazatetracyclo[9.3.1.OZ~'°.04'8]pentadeca-2(10),3,6,8-tetraene;
6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.Oz''°.0''e]pentadeca-2(10),3,6,8-tetraene;
10-azatricycloj6.3.1.02~']dodeca-2(7),3,5-trien-4-yl cyanide;
1-(10-azatricyclo[6.3.1.Oz'']dodecc-2(7),3,5-trien-4-yl)-1-ethanone;
11-azatricyclo[7.3.1.Oz'']trideca-2(7),3,5-triene-5-carbonitrile;
1-[11-azatricyclo[7.3.1.02'']trideca-2(7), 3,5-trien-5-yl]-1-ethanone;
1-[11-azatricycloj7.3.1.02~']trideca-2(7),3,5-trien-5-yl)-1-propanone;
4-fluoro-11-azatricyclo[7.3.1.Oz'']trideca-2(7),3,5-triene-5-carbonitrile;
5-fluoro-11-azatricyclo[7.3.1.OZ'']trideca-2(7),3,5-triene-4-carbonitrile;
6-methyl-7-thia-5,14-diazatetracyclo(10.3.1.Oz''°.04'a]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,14-triazatetracyclo[10.3.1.OZ''°.048]hexadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.Oz~'°.04,a]hexadeca-2(10),3,5,8-tetraene;
6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.O2''°.p4,a]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0~~'°.04~g]hexadeca-2(10),3,6,8-tetraene;
5,6-difluoro-11-aza-tricyclo[7.3.1.02']trideca-2,4,6-triene;
6-trifluoromethyl-11-aza-tricyclo[7.3.1.02'']trideca-2,4,6-triene;
6-methoxy-11-aza-tricyclo[7.3.1.OZ'']trideca-2(7),3,5-triene;
6-fluoro-11-aza-tricyclo[7.3.1.Oz~']trideca-2(7),3,5-triene; and 11-aza-tricyclo[7.3.1.OZ'']trideca-2(7),3,5-trien-5-of and their pharmaceutically acceptable salts and their optical isomers.
The acetylcholinesterase or butylcholinesterase inhibitor are selected from donepizil (AriceptTM), tacrine (CognexT"'), rivastigmine (ExelonT""), physostigmine (Synapton), galanthamine (Reminyl), metrifonate (Promem), quilostigmine, tolserine, thiatolserine, cymserine, thiacymserine, neostigmine, eseroline, zifrosilone, mestinon, huperzine A and icopezil. U.S.
Patent Application Ser. No. 07/639,614 filed Jan 10, 1991; U.S. Patent Application Ser. No.
07/676,918 filed March 28, 1991; U.S. Patent No. 5,750,542; and U.S. Patent No. 5,574,046 all of which are assigned in common with the present application, and refer to heteroaryl amine acetylcholinesterase inhibitors and are incorporated by reference.
The estrogenic agent is estradiol or a pharmaceutically acceptable form of estradiol.
The estrogen receptor modulators are selected from estrogen, lasofoxifene, droloxifene, tamoxifen and raloxifene (Evista).
The muscarinic agonists are selected from milameline, xanomeline, sabcomeline, arecoline, oxotremorine and pilocarpine.
The pharmaceutical compositions are useful in the enhancement of cognition or the treatment of disorders involving cognitive dysfunction including but not limited to Alzheimer's _8_ Disease, mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinson's disease, dementia, Huntington's disease, stroke, traumatic brain injury (TBI), AIDS
associated dementia and schizophrenia.
Another aspect of this invention is a method of enhancing cognition or the treatment of a disorder involving cognitive dysfunction in a mammal comprising administering to the mammal, an amount of (a) a nicotine receptor partial agonist or a pharmaceutically acceptable salt thereof;
and (b) an acetylcholinesterase inhibitor, a butylcholinesterase inhibitor, estrogenic agent, a selective estrogen receptor modulator (SERM) or a muscarinic agonist or a pharmaceutically acceptable salt thereof; wherein the active ingredients (a) and (b) are administered in amounts that render the combination of the two ingredients effective in cognition or the enhancement of a disorder involving treatment of disorders cognitive dysfunction.
The nicotine receptor partial agonists is selected from 9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-chioro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-flouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5Jdiazocin-8-one;
9-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-vinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-bromo-3-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-one;
3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a](1,SJdiazocin-one;
3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-one;
9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-ethynyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-propenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-propyl)- 1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;

-g_ 9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2aj[1,5]diazocin-8-one;
one;
one;
9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-9-(4-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2aJ[1,5]diazocin-9-(3-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
one;
one;
one;
9-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[,1,2a][1,5]diazocin-8-9-(2,4-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,SJdiazocin-8-9-(2,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.OZ''°.04'8]pentadeca-2(10),3,8-triene;
5-oxo-6,13-diazatetracyclo[9.3.1.0~~'°.04'8]pentadeca-2(10),3,8-triene;
6-oxo-5,7,13-triazatetracyclo[9.3.1.02''°.04'8]pentadeca-2(10),3,8-triene;
4,5-difluoro-10-aza-tricyclo[6.3.1.02~'Jdodeca-2(7),3,5-triene;
5-fluoro-10-aza-tricyclo[6.3.1.Oz'']dodecc-2(7),3,5-triene-4-carbonitrile;
4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.Oz'']dodecc-2(7),3,5-triene;
5-ethynyl-10-aza-tricyclo[6.3.1.Oz'']dodecc-2(7),3,5-triene-4-carbonitrile;
6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.02''°.04'8]pentadeca-2(10),3,8-triene;
10-aza-tricyclo[6.3.1.Oz'']dodecc-2(7),3,5-triene;
4-fluoro-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
4-methyl-10-aza-tricyclo[6.3.1.OZ'']dodecc-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.~1.OZ~']dodecc-2(7),3,5-triene;
4-vitro-10-azatricyclo[6.3.1.Oz'']dodecc-2(7),3,5-triene;
7-methyl-5,7,13-triazatetracyclo[9.3.1.Oz''°.04'8]pentadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,13-triazatetracyclo[9.3.1.Oz''°.04'e]pentadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.02~'°.04'$]pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.02''°.04~8]pentadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0~~".049]hexadeca-2(11 ),3,5,7,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.02".049]hexadeca-2(11 ),3,5,7,9-pentaene;
14-methyl-5,8,14-triazatetracyclo[10.3.1.0~~".049]hexadeca-2(11 ),3,5,7,9-pentaene;
5-oxa-7,13-diazatetracycio[9.3.1.02''°.04'8]pentadeca-2(10),3,6,8-tetraene;

6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.02~'°.04'e]pentadeca-2(10),3;6,8-tetraene;
4-chloro-10-azatricyclo[6.3.1.Oz'']dodecc-2(7),3,5-triene;
10-azatricyclo[6.3.1.02'']dodecc-2(7),3,5-trien-4-yl cyanide;
1-(10-azatricyclo[6.3.1.OZ'']dodecc-2(7),3,5-trien-4-yl)-1-ethanone;
10-azatricyclo[6.3.1.Oz'']dodecc-2(7),3,5-trien-4-ol;
7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.02''°.04'a]pentadeca-2,4(8),6,9-tetraene;
4,5-dichloro-10-azatricyclo[6.3.1.Oz'']dodecc-2(7),3,5-triene;
11-azatricyclo[7.3.1.02~']trideca-2(7),3,5-triene-5-carbonitrile;
1-[11-azatricyclo[7.3.1.OZ'']trideca-2(7),3,5-trien-5-yl]-1-ethanone;
1-[11-azatricyclo[7.3.1.OZ~']trideca-2(7),3, 5-trien-5-yl]-1-propanone;
4-fluoro-11-azatricyclo[7.3.1.0z~']trideca-2(7),3,5-triene-5-carbonitrile;
5-fluoro-11-azatricyclo[7.3.1.Oz'']trideca-2(7),3,5-triene-4-carbonitrile;
6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.02''°.048]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,14-triazatetracyclo[10.3.1.Oz''°.048]hexadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.OZ''°.04'a]hexadeca-2(10),3,5,8-tetraene;
5,7,14-triazatetracyclo[10.3.1.02~'°.048]hexadeca-2(10),3,5,8-tetraene;
5,6-dimethyl-5,7,14-triazatetracycio[10.3.1.OZ''°.04'a]hexadeca-2(10),3,6,8-tetraene;
5-methyl-5,7,14-triazatetracyclo[10.3.1.02''°,pa,e]hexadeca-2( 10),3,6,8-tetraene;
6-(trifluoromethyl)-7-thia-5,14-diazatetracyclo[10.3.1.OZ''°.04'8]hexadeca-2(10),3,5,8-tetraene;
5,8,15-triazatetracyclo[11.3.1.OZ'".04'9]heptadeca-2(11),3,5,7,9-pentaene;
7-methyl-5,8,15-triazatetracyclo[11.3.1.Oz~".04'9]heptadeca-2(11 ),3,5,7,9-pentaene;
6-methyl-5,8,15-triazatetracyclo[11.3.1.OZ~".049]heptadeca-2(11 ),3,5,7,9-pentaene;
6,7-dimethyl-5,8,15-triazatetracyclo[11.3.1.02'".04'9]heptadeca-2(11 ),3,5,7,9-pentaene;
7-oxa-5,14-diazatetracyclo[10.3.1.Ozv'°.04'a]hexadeca-2(10),3,5,8-tetraene;
6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.Oz''°.04'8]hexadeca-2(10),3,5,8-tetraene;
5-methyl-7-oxa-6,14-diazatetracyclo[10.3.1.02''°.0ø~8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.Oz~'°.04'a]hexadeca-2(10),3,6,8-tetraene;
7-methyl-5-oxa-6,14-diazatetracyclo[10.3.1.02''°.04'8] hexadeca-2( 10),3,6,8-tetraene;
4,5-difluoro-11-azatricyclo[7.3.1.0z~']trideca-2(7),3,5-triene;
4-chloro-5-fluoro-11-azatricyclo[7.3.1.02']trideca-2(7),3,5-triene;
5-chloro-4-fluoro-11-azatricyclo[7.3.1.OZ'']trideca-2(7),3,5-triene;
4-(1-ethynyl)-5-fluoro-11-azatricyclo[7.3.1.Oz'']trideca-2(7),3,5-triene;
5-(1-ethynyl)-4-fluoro-11-azatricyclo[7.3.1.02']trideca-2(7),3,5-triene;
5,6-difluoro-11-aza-tricyclo[7.3.1.Oz~']trideca-2,4,6-triene;

6-trifluoromethyl-11-aza-tricyclo[7.3.1.0~~']trideca-2,4,6-triene;
6-methoxy-11-aza-tricyclo[7.3.1.OZ'']trideca-2(7),3,5-triene;
11-aza-tricycloj7.3.1.Oz'']trideca-2(7),3,5-trien-6-ol;
6-fluoro-11-aza-tricyclo[7.3.1.02.']trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.Oz'']trideca-2{7),3,5-trien-5-ol;
4-vitro-11-aza-tricyclo[7.3.1.Oz~']trideca-2(7),3,5-triene;
5-vitro-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
5-fluoro-11-aza-tricyclo[7.3.1.Oz.']trideca-2(7),3,5-triene; and 6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene and their pharmaceutically acceptable salts and their optical isomers.
Preferably, the nicotine receptor partial agonist is selected from:
9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-cyan0-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.O2.,o.0a.e]pentadeca-2(10),3,8-triene;
4-fluoro-10-aza-tricyclo[6.3.1.O2'']dodecc-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.1.02.']dodecc-2(7),3,5-trieve;
4-vitro-10-azatricyclo[6.3.1.Oz.']dodecc-2(7),3,5-triene;
6-methyl-5,7,13-triazatetracyclo[9.3.1.0z''°.04'e]pentadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.02'".04'9]hexadeca-2(11 ),3,5,7,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.02.".04.9]hexadeca-2(11 ),3,5,7,9-pentaene;
5-oxa-7,13-diazatetracyclo[9.3.1.02.'°.04.8]pentadeca-2(10),3,6,8-tetraene;
6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.OZ''°.04.e]pentadeca-2(10),3,6,8-tetraene;
10-azatricyclo[6.3.1.02.']dodecc-2(7),3,5-trien-4-yl cyanide;
1-( 10-azatricyclo[6.3.1.Oz'']dodecc-2(7),3,5-trien-4-yl)-1-ethanone;
11-azatricyclo[7.3.1.0~~']trideca-2(7),3,5-triene-5-carbonitrile;
1-[11-azatricyclo[7.3.1.02'']trideca-2(7),3, 5-trien-5-yl]-1-ethanone;
1-[11-azatricyclo[7.3.1.02']trideca-2(7),3, 5-trien-5-yl]-1-propanone;
4-fluoro-11-azatricyclo[7.3.1.OZ'']trideca-2(7),3,5-triene-5-carbonitrile;
5-fluoro-11-azatricyclo[7.3.1.02~']trideca-2(7),3,5-triene-4-carbonitrile;
6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.O2''°.04'a]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,14-triazatetracyclo[10.3.1.OZ''°.04'8]hexadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0~~'°.04~e]hexadeca-2(10),3,5,8-tetraene;
6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0z~'°.OA,a]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.02''°.04'a)hexadeca-2(10),3,6,8-tetraene;
5,6-difluoro-11-aza-tricyclo[7.3.1.Oz~')trideca-2,4,6-triene;
6-trifluoromethyl-11-aza-tricyclo[7.3.1.02~')trideca-2,4,6-triene;
6-methoxy-11-aza-tricyclo[7.3.1.OZ'']trideca-2(7),3,5-triene;
6-fluoro-11-aza-tricyclo[7.3.1.0~~']trideca-2(7),3,5-triene; and 11-aza-tricyclo[7.3.1.Oz'']trideca-2(7),3,5-trien-5-of and their pharmaceutically acceptable salts and their optical isomers.
A preferred aspect of this method is wherein the NRPA is in combination with an acetylcholinesterase or butylcholinesterase inhibitor selected from donepizil (AriceptT"'), tacrine (CognexT"') rivastigmine (ExelonT~"), physostigmine (Synapton), galanthamine (Reminyl), metrifonate (Promem) quilostigmine, tolserine, thiatolserine, cymserine, thiacymserine, neostigmine, eseroline, zifrosilone, mestinon, huperzine A and icopezil or a pharmaceutically acceptable salt of one of the foregoing compounds.
Another preferred aspect of this method is wherein the NRPA is in combination with an estrogenic agent or a pharmaceutically acceptable form of estrogen.
Another preferred aspect of this method is wherein the NRPA is in combination with a SERM selected from lasofoxifene, droloxifene, tamoxifen and raloxifene (Evista) or a pharmaceutically acceptable salt of one of the foregoing compounds. , Another preferred aspect of this method is wherein the NRPA is in combination with a muscarinic agonist selected from milameline, xanomeline, sabcomeline, arecoline, oxotremorine and pilocarpine or a pharmaceutically acceptable salt of one of the foregoing compounds.
Another preferred aspect of this method is wherein the NRPA is administered substantially simultaneously with the acetylcholinesterase inhibitor, the butylcholinesterase inhibitor, an estrogenic agent, SERM, or the muscarinic agent.
The pharmaceutical composition is used for enhancing cognition or treating a disorder involving cognitive dysfunction, including but not limited to, Alzheimer's Disease, mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinson's disease dementia, Huntington's disease, Stroke, TBI, AIDS associated dementia and Schzophrenia in a mammal, including a human. The method comprises administering to said mammal a cognitive dysfunction attenuating effective amount of the above pharmaceutical composition comprising (a) a nicotine receptor partial agonist or a pharmaceutically acceptable salt thereof; (b) an acetyl cholinesterase inhibitor, a butylcholinesterase inhibitor, an estrogenic agent, a SERM or a muscarinic agonist or a pharmaceutically acceptable carrier. In the pharmaceutical composition (a) and (b) are present in amounts that render the composition effective in treating such disorders.
A method of treating a disorder or condition selected from the group consisting of Alzheimer Disease, mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinson's disease dementia, Huntington's Disease, Stroke, TBI, AIDS
associated dementia and Schizophrenia comprises administering to a mammal (a) a nicotine receptor partial agonist or a pharmaceutically acceptable salt thereof; (b) an acetylcholinesterase inhibitor, a butylcholinesterase inhibitor, an estrogenic agent, a SERM or a muscarinic agonist or a pharmaceutically acceptable salt thereof; where in the active agents (a) and (b) above are administered in amounts that render the combination of the two ingerdients effective in treating Alzheimer's Disease, mild Cognitive impairment, age-related cognitive decline, Vascular dementia, Huntington's Disease, Strole, TBI, AIDS associated dementia and Schizophrenia.
The term "treating", "treat" or "treatment" as used herein includes preventive (e.g., prophylactic) and palliative treatment.
The chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. Hydrates of the compounds of this invention are also included.
The chemist of ordinary skill will recognize that certain combinations of heteroatom-containing substituents listed in this invention define compounds which will be less stable under physiological conditions (e.g. those containing acetal or animal linkages).
Accordingly, such compounds are less preferred.
Detailed Description Of The invention A mammalian nicotine receptor partial agonist (NRPA), ifs optical isomers or a pharmaceutically acceptable salt of the forgoing compounds may be used in this invention. The term NRPA refers to chemical compounds that bind to neuronal nicotine receptor sites and elicit a partial agonist response.
An acetylcholinesterase or a butylcholinesterase inhibitor or a pharmaceutically acceptable salt of the foregoing compounds such as donepizil (AriceptT"'), tacrine (CognexT"~) rivastigmine (ExelonT""), physostigmine (Synapton),galanthamine (Reminyl), metrifonate (Promem) quilostigmine, tolserine, thiatolserine, cymserine, thiacymserine, neostigmine, eseroline, zifrosilone, mestinon, huperzine A and icopezil may be used in this invention.
An estrogenic agent or a pharmaceutically acceptable form of estrogen may be used in this invention.
An estrogen receptor modulator agent or a SERM or a pharmaceutically acceptable salt of the foregoing compounds such as estrogen, lasofoxifene, droloxifene, tamoxifen, raloxifene (Evista) may be used in this invention.
A muscarinic agonist agent or a pharmaceutically acceptable salt of the foregoing compounds such as milameline, xanomeline, sabcomeline, arecoline, oxotremorine, or pilocarpine may be used in this invention.
In general, the compounds of this invention can be made by processes which include processes known in the chemical arts, particularly in light of the description contained herein.
Some of the preparation methods useful for making the compounds of this invention may require protection of remote functionality (i.e., primary amine, secondary amine, carboxyl).
The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991. The starting materials and reagents for the compounds of this invention are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein are related to, or are derived from compounds found in nature, in which there is a large scientific interest and commercial need, and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.
Some of the compounds of this invention are ionizable at physiological conditions.
Thus, for example some of the compounds of this invention are acidic and they form a salt with a pharmaceutically acceptable cation. All such salts are within the scope of this invention and they can be prepared by conventional methods. For example, they can be prepared simply by contacting the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate.
In addition, some of the compounds of this invention are basic, and they form a salt with a pharmaceutically acceptable anion. All such salts are within the scope of this invention and they can be prepared by conventional methods. For example, they can be prepared simply by contacting the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate.
In addition, when the compounds of this invention form hydrates or solvates they are also within the scope of the invention.
The utility of the compounds of the present invention as medical agents in the treatment of conditions which present with low cognitive function (such as Alzheimer's Disease, mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinson's disease dementia, Huntington's disease, stroke, traumatic brain injury (TBI), AIDS
associated dementia and schizophrenia) in mammals (e.g. humans) is demonstrated by the activity of the compounds of this invention in conventional assays and the in vitro assays described below: nicotine receptor binding assay, dopamine turnover, acetylcholinesterase inhibitor protocol, in vitro estrogen receptor binding assay and muscarinic receptor binding. Cognitive function of the agents themselves or of the combination agents in mammals is measured in the radial arm maze in rodents or delayed matching to sample tests in primates. Such assays also provide a means whereby the activities of the compounds of this invention can be compared between themselves and with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
Biological Assays Procedures Nicotine receptor binding assay. The efFectiveness of the active compounds in suppressing nicotine binding to specific receptor sites is determined by the following procedure which is a modification of the methods of Lippiello, P. M. and Fernandes, K.
G. (in The Binding of L-[3H]Nicotine To A Single Class of High-Affinity Sites in Rat Brain Membranes , Molecular Pharm., 29, 448-54, (1986)) and Anderson, D. J. and Arneric, S. P. (in Nicotinic Receptor Binding of 3H-Cystisine, 3H-Nicotine and 3H-Methylcarmbamylcholine In Rat Brain, European J.
Pharm., 253, 261-67 (1994)). Male Sprague-Dawley rats (200-300 g) from Charles River were housed in groups in hanging stainless steel wire cages and were maintained on a 12 hour light/dark cycle (7 a.m.-7 p.m. light period). They received standard Purina Rat Chow and water ad libitum. The rats were killed by decapitation. Brains were removed immediately following decapitation. Membranes were prepared from brain tissue according to the methods of Lippiello and Fernandez (Molec Pharmacol, 29, 448-454, (1986) with some modifications.
Whole brains were removed, rinsed with ice-cold buffer, and homogenized at 0° in 10 volumes of buffer (w/v) using a Brinkmann PolytronT"', setting 6, for 30 seconds. The buffer consisted of 50 mM Tris HCI
at a pH of 7.5 at room temperature. The homogenate was sedimented by centrifugation (10 minutes; 50,000 x g; 0° to 4°C). The supernatant was poured off and the membranes were gently resuspended with the Polytron and centrifuged again (10 minutes; 50,000 x g; 0 to 4°C.
After the second centrifugation, the membranes were resuspended in assay buffer at a concentration of 1.Og/100mL. The composition of the standard assay buffer was 50 mM Tris HCI, 120 mM NaCI, 5 mM KCI, 2 mM MgCl2, 2 mM CaCl2 and has a pH of 7.4 at room temperature.
Routine assays were performed in borosilicate glass test tubes. The assay mixture typically consisted of 0.9 mg of membrane protein in a final incubation volume of 1.0 mL. Three sets of tubes were prepared wherein the tubes in each set contained 50NL of vehicle, blank, or test compound solution, respectively. To each tube was added 200pL of j3H]-nicotine in assay buffer followed by 750pL of the membrane suspension. The final concentration of nicotine in each tube was 0.9 nM. The final concentration of cytisine in the blank was 1 NM. The vehicle consisted of deionized water containing 30NL of 1 N acetic acid per 50 mL of water. The test compounds and cytisine were dissolved in vehicle. Assays were initiated by vortexing after addition of the membrane suspension to the tube. The samples were incubated at 0° to 4° C in an iced shaking water bath. Incubations were terminated by rapid filtration under vacuum through Whatman GF/BTM glass fiber filters using a BrandelT"" mufti-manifold tissue harvester.
Following the initial filtration of the assay mixture, filters were washed two times with ice-cold assay buffer (5 m each). The filters were then placed in counting vials and mixed vigorously with 20 ml of Ready SafeTM (Beckman) before quantification of radioactivity.
Samples were counted in a LKB Wallach RackbetaT"~ liquid scintillation counter at 40-50%
efficiency. All determinations were in triplicate.
Calculations: Specific binding (C) to the membrane is the difference between total binding in the samples containing vehicle only and membrane (A) and non-specific binding in the samples containing the membrane and cytisine (B), i.e., Specific binding = (C) _ (A) - (B).
Specific binding in the presence of the test compound (E) is the difference between the total binding in the presence of the test compound (D) and non-specific binding (B), i.e. , (E) _ (D) - (B).
% inhibition = (1-((E)/(C)) times 100.
The compounds of the invention that were tested in the above assay exhibited ICso values of less than 10pM.
Dopamine Turnover: Rats were injected s.c. or p.o. (gavage) and then decapitated either 1 or 2 hours later. Nucleus accumbens was rapidly dissected (2 mm slices, 4°C, in 0.32 M sucrose), placed in 0.1 N perchloric acid, and then homogenized. After centrifugation lOuL of the supernatant was assayed by HPLC-ECD. Turnover/ utilization of dopamine (DA) was calculated as the ratio of tissue concentrations of metabolites ([DOPAC]+[HVA]) to DA
and expressed as percent of control.
Acetylcholinesterase inhibitor Protocol Inhibition of Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE).
The method of Ellman, GL.; Courtney, K.D.; Andres, V., Jr.; Featherstone, R.M. A
New and Rapid Colorimetric Determination of Acetylcholinesterase Activity. Biochem.
Pharmacol. 1961, 7, 88-95 was followed. The assay solution consists of a 0.1 M sodium phosphate buffer, pH 8.0, with the addition of 100 yM tetraisopropypyrophosphoramide (iso-OMPA), 100 yM
5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), 0.02 unitsimL AChE (Sigma Chemical Col, from human erythrocytes) and 200 yM acetylthiocholine iodide. The final assay volume was 0.25 mL.
Test compounds were added to the assay solution prior to enzyme addition, whereupon a 20-min preincubation period with enzyme was followed by addition of substrate.
Changes in absorbance at 412 nM were recorded for 5 min. The reaction rates were compared, and the percent inhibition due to the presence of test compounds was calculated.
Inhibition of butyrylcholinesterase was measured as described above for AChE
by omitting addition of iso-OMPA and substitution 0.02 units/mL of BuChE (Sigma Chemical Co., from horse serum) and 200 yM butyrylthiocholine for enzyme and substrate, respectively.
In vivo Microdialysis. Male Sprague-Dawley rats were implanted in the corpus striatum with guide cannulae and dialysis probes (Bioanalytical Systems, West Lafayette, IN) and superfused at a rate 3 mLlminute. The dialysis fluid was a Ringer's buffer (pH 7.2) containing 500 nM physostigmine to reduce degradation of Ach by AChE.
Fractions (60 ELI) were collected every 20 minutes for 2 hours before drug administration and for 3 hours following oral administration of drug. Samples (50 Etl) were used directly for HPLC analysis of Ach content as described above. Basal Ach release was defined as the average Ach content in the three fractions just prior to drug administration. Ach content in all fractions was converted to a percentage of these basal control values.
Estrogen receptor binding assay cDNA cloning of human ERa. and ER(3: The coding region of human ERa was cloned by RT-PCR from human breast cancer cell mRNA using ExpandTM High Fidelity PCR
System according to manufacturer's instructions (Boehringer-Mannheim, Indianapolis, IN). The coding region of human ERA was cloned by RT-PCR from human testes and pituitary mRNA
using ExpandT"~ High Fidelity PCR System according to manufacturer's instructions (Boehringer-Mannheim, Indianapolis, IN). PCR products were cloned into pCR2.1 TA Cloning Kit (Invitrogen, Carlsbad, CA) and sequenced. Each receptor coding region was subcloned into the mammalian expression vector pcDNA3 ((Invitrogen, Carlsbad, CA).
Mammalian cell expression. Receptor proteins were overexpressed in 293T cells.
These cells, derived from HEK293 cells (ATCC, Mantissas, VA), have been engineered to stably express large T antigen and can therefore replicate plasmids containing a SV40 origin of replication to high copy numbers. 293T cells were transfected with either hERa-pcDNA3 or hER[i-pcDNA3 using lipofectamine as described by the manufacturer (Gibco/BRL, Bethesda, MD). Cells were harvested in phosphate buffered saline (PBS) with 0.5 mM EDTA
at 48 h post-transfection. Cell pellets were washed once with PBS/EDTA. Whole cell lysates were prepared by homogenization in TEG buffer (50 mM Tris pH 7.4, 1.5 mM EDTA, 50 mM NaCI, 10% glycerol, 5 mM DTT, 5 pg/ml aprotinin, 10 yg/ml leupeptin, 0.1 mg/ml Pefabloc) using a dounce homogenizor. Extracts were centrifuged at 100,000 x g for 2 h at 4C and supernatants were collected. Total protein concentrations were determined using BioRad reagent (BioRad, Hercules, CA).
Competition binding assay. The ability of various compounds to inhibit [3H]-estradiol binding was measured by a competition binding assay using dextran-coated charcoal as has been described (Leake RE, Habib F 1987 Steroid hormone receptors: assay and characterization. In: B. Green and R.E. Leake (eds). Steroid Hormones a Practical Approach.
IRL Press Ltd, Oxford. 67-92.) 293T cell extracts expressing either hERa or hERp were incubated in the presence of increasing concentrations of competitor and a fixed concentration of [3H]-estradiol (141 Ci/mmol, New England Nuclear, Boston, MA) in 50 mM
TrisHCl pH 7.4, 1.5 mM EDTA, 50 mM NaCI, 10% glycerol, 5 mM DTT, 0.5 mg/mL ~-lactoglobulin in a final volume of 0.2 mL. All competitors were dissolved in dimethylsulfoxide.
The final concentration of receptor was 50 pM with 0.5 nM [3H]-estradiol.
After 16 h at 4C, dextran-coated charcoal (20 yL) was added. After 15 min at room temperature the charcoal was removed by centrifugation and the radioactive ligand present in the supernatant was measured by scintillation counting. All reagents were obtained from Sigma (St.
Louis, MO) unless otherwise indicated.
Muscarinic The activity of muscarinic receptors can be determined according to the following protocol. Chinese hamster ovary cells (CHO-K1 ) stably transformed to express human ml -m5 receptors can be obtained from Dr. Tom Bonner (Laboratory of Cell Biology, National Institute of Mental Health, Building 36, Rm 3A-17, National Institute of Health, Bethesda, MD
20892). Celis are maintained in Dulbecco's Modified Eagle Medium containing 10% fetal calf serum and harvested at confluence by brief incubation in Ca++/Mg++ free phosphate-buffered saline containing 4 mM EDTA.
For ligand binding studies, cells are homogenized by sonication in distilled water and membranes are collected by centrifugation (10 minutes at 15,000 X g).
Membranes are incubated 45 minutes at 20-22°C with 3H-N-methylsco (NMS; 0.5-1.0 nM) in 0.25 ml 20 mM
HEPES (N-2-hydroxyethylpiperazine-N'-2-ethane sulfonic acid), 2 mM MgCl2, pH
7.4. Bound ligand is collected by rapid filtration and quantified by liquid scintillation spectroscopy. Non-specific binding is defined in the presence of 10 uM unlabeled NMS. Apparent Ki for competing ligands is calculated as described by Cheng and Prusoff, Biochem.
Pharm., 22, 3099-3108 (1973).
Functional responses at m2 and m4 receptors can be determined by measuring inhibition of forskolin-stimulated cAMP accumulation. Harvested cells are preincubated (15 minutes at 20-22°C) with 3-isobutyl-I-methyl-xanthine (IBAs MX; 0.2 mM) and then incubated (10 minutes at 20-22°C) in a HEPES-buffered Krebs solution with test compounds in the presence of 5 uM forskolin. The reaction is stopped by the addition of 10 N
acetic acid and the CAMP content of dried supernatants is determined using a scintillation proximity assay (Amersham). Carbachol is used as the standard agonist, typically providing 60-80% inhibition of the forskolin-stimulated CAMP levels.
Functional responses at ml, m3 and m5 receptors can be determined by measuring increases in phosphotidylinositol hydrolysis. Harvested cells are preincubated (60 minutes at 37°C) in HEPES-buffered Krebs with 3H-myoinositol (ARC Inc.; 7.3 uCi/ml). Labelled cells are added to test compounds and incubated 1 hour at 37°C in the presence of 10 mM LiCI. Cells are extracted with chloroform:methanol (1 :2) and the aqueous phase is loaded onto columns of DOWEX AG1-X8 ion exchange resin. Inositol phosphates (mainly IP3) are eluted with 0.1 M formic acid/1 M ammonium formate and counted.
All of the compounds of this invention, which were tested in the above functional assays, have EC50 in the m2 and m4 receptor assay of about 0.1 nM to about 10 uM or less.
Ali of the compounds of this invention, which were tested, have EC50 in the m1, m3 and m5 receptor assay of about 0.1 nM to about 100 nM or less.
Assays for cognitive dysfunction Radial Arm Maze Animals were food restricted to approximately 85% of their normal free-feeding weight and maintained at this level for 3 days prior to the first day of exposure to the maze.
Habituation: Reinforcement (Peanut Butter Chips) was placed near the entrance and at the mid-point of each arm, the animal was placed on the maze and allow to explore and consume the chips for a period of ten minutes, or until all chips were consumed. On the second day of habituation, the chips were placed at the mid-point and in a food cup at the end of each arm. Again, the animal was allowed ten minutes to explore or until all chips were consumed.
Training: Reinforcement is placed only in the food cup at the end of each arm.
The animal is placed on the maze oriented away from the experimenter, and facing the same arm at the start of each trial. The timer is started and each entry is recorded in sequence. An entry is defined as all four paws entering the arm. The animal is allowed to choose until all eight arms are entered and the chip is consumed, or until 5 minutes has elapsed. Entry into an arm previously chosen is counted as an error. If an animal fails to choose all eight arms in 5 minutes, arms not chosen are also counted as errors. Animals are trained once a day. The criterion for learning is < 1 error per day on at least two consecutive days.
Dependent measures are number of errors, time to complete the maze, and number of days to reach criterion.
Drug Administration: Compounds to test for improvement of cognition are administered prior to each training session, or immediately following the training session.
Data analysis: Number of errors, and time to complete the maze are analyzed using repeated measures ANOVA Statview (SAS Institute) and post hoc testing using Dunnett's test.
Delayed matching to sample Animals are tested in their home cages using a computer-automated training and testing system which measures and categorizes, in addition to percent correct at each delay, the latency of response at each step of each matching problem, and percent correct for every possible combination of matching stimuli (position and color). Stimuli on the test panels (attached to the home cages) are 2.54 cm diameter colored disks (red, yellow, or green) presented by light-emitting diodes located behind clear plastic push-keys. A
trial is initiated with the illumination of the sample key by one of the colored disks. The sample light remains lit until the sample key is depressed by the subject, initiating one of four pre-programmed delay intervals, during which no disks are illuminated. Following the delay interval, two choice lights located below the sample key are illuminated. One of the choice lights matches the color of the sample light. These disks remain illuminated until the subject presses one of the two lited keys. Key-presses of choice stimuli that match the color of the sample stimulus are rewarded by dispensing a 300 mg fruit-flavored food pellet. Non-matching choices are neither rewarded nor punished. Matching configurations are fully counterbalanced for side, delay, and color. A 5 sec inter-trial interval is used. Monkeys complete 96 trials on each day of testing. In standard DMTS sessions, four possible delay intervals between a subject's response to the sample light and the presentation of the two choice lights are employed: a Zero delay, and a Short, Medium, and Long delay. Short, Medium, and Long delay intervals are individually adjusted to produce stable performance levels approximating the following levels of accuracy: Zero delay (85-100% correct) Short (75-85% correct);
Medium (65-75%
correct); and Long (55-65% correct).
Variables relating to the monkey's performance are tabulated in a matrix for each daily session. It is possible to separate two main components of the DMTS
task, a test of memory recall and a cognitive component which tests the abstract conceptualization of "matching". Baseline runs are generally performed on Mondays, with drug administered on Tuesdays and Thursdays. Wednesdays and Fridays the animals are tested, but no drug or vehicle will be administered. The animals are not run on weekends. We have not found any effect of day of testing on animal performance of the DMTS task. However, baseline performance is continuously monitored and redefined should the animal's performance change during the study. In such cases it would be necessary to determine if the baseline change is temporary (e.g., drug related) or permanent. In either case drug testing is discontinued to allow the adjustment(if necessary) of delay intervals until a typical and stable level of baseline performance is once again attained [Paule et al., Neurotoxicology and Teratology, 20, 493-502 (1998); Buccafusco et al., Behavioral Pharmacology, 10, 681-690 (1999)].
The utility of the NRPA compounds employed in the present invention as medicinal agents include neuronal nicotinic receptor binding, dopamine turnover, and animal models of cognitive impairment. Such assays also provide a means whereby the activities of the compounds of this invention can be compared between themselves and with the activities of other known compounds.
The combination of a NRPA and acetylcholinesterase or butylcholinesterase inhibitor will result in increased efficacy in comparison to the efficacy displayed by either agent alone.
In addition, such a combination may allow lower, subefficacious doses of each agent to be administered, resulting in efficacy similar to the one observed with higher doses of either agent alone and fewer side effects (or higher therapeutic index).
The combination of a NRPA and estrogen andlor SERM will result in increased efficacy in comparison to the efficacy displayed by either agent alone. In addition, such a combination may allow lower, subefficacious doses of each agent to be administered, resulting in efficacy similar to the one observed with higher doses of either agent alone and fewer side effects (or higher therapeutic index).
The combination of a NRPA and muscarinic receptor agonist will result in increased efficacy in comparison to the efficacy displayed by either agent alone. In addition, such a combination may allow lower, subefficacious doses of each agent to be administered, resulting in efficacy similar to the one observed with higher doses of either agent alone and fewer side effects (or higher therapeutic index).
The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
Administration of the compositions of this invention can be via any method which delivers a compound of this invention systemically andlor locally. These methods include oral routes and transdermal routes, etc. Generally, the compounds of this invention are administered orally, but parenteral administration may be utilized (e.g., intravenous, intramuscular, subcutaneous or intrameduliary). The two different compounds of this invention can be co-administered simultaneously or sequentially in any order, or a single pharmaceutical composition comprising a NRPA as described above and an anti-depressant or anxiolytic as described above in a pharmaceutically acceptable carrier can be administered.
The amount and timing of compounds administered will, of course, be based on the judgement of the prescribing physician. Thus, because of patient to patient variability, the dosages given below are a guideline and the physician may titrate doses of the agent to achieve the activity that the physician considers appropriate for the individual patient. In considering the degree of activity desired, the physician must balance a variety of factors such as cognitive function, age of the patient, presence of preexisting disease, as well as presence of other diseases (e.g., cardiovascular). The following paragraphs provide preferred dosage ranges for the various components of this invention (based on average human weight of 70 kg).
In general, an effective dosage for the NRPA in the range of 0.001 to 200 mg/kg/day, preferably 0.01 to 10.0 mg/kglday.
in general an effective dosage for the acetylcholinesterase or butylcholinesterase inhibitor is 0.01 to 10 mg/kg/day. More spectic dosages are as follows:
The specific dosages for the cholinesteraselbutylcholinesterase inhibitors are as follows:
For donepezil (AriceptT"~) the range is 0.01 to 0.15 mg/kg/day For tacrine (CognexT"~) the range is 0.1 to 2.3 mg/kg/day For rivastigmine (ExelonT"") the range is 0.1 to 0.1 mg/kg/day For physostigmine (Synapton) the range is 0.01 to 0.4 mg/kg/day For galanthamine (Reminyl) the range is 0.05 to 0.5 mg/kg/day For metrifonate (Promem) the range is 0.1 to 5.0 mglkg/day For quilostigmine the range is 0.1 to 2.0 mg/kg/day For tolserine the range is 0.1 to 10.0 mg/kg/day For thiatolserine the range is 0.1 to 10.0 mg/kg/day For cymserine the range is 0.1 to 10.0 mg/kg/day For thiacymserine the range is 0.1 to 10.0 mg/kg/day For neostigmine (Prostigmin) the range is 0.1 to 5.0 mg/kglday For eseroline the range is 0.1 to 10.0 mg/kglday For zifrosilone the range is 0.1 to 10.0 mg/kg/day For pyridostigmine (Mestinon) the range is 0.5 to 9.0 mglkg/day For huperzine A the range is 0.01 to 1.0 mg/kg/day For icopezil the range is 0.001 to 0.01 mg/kg/day The specific dosages for the estrogens or Serms are as follows:
For estradiol the range is 0.005 to 0.03 mglkg/day For lasofoxifene the range is 0.0001 to 0.01 mg/kg/day For droloxifine the range is 0.1 to 1.5 mglkg/day For tamoxifen the range is 0.05 to 0.5 mg/kg/day For raloxifene (Evista) the range is 0.1 to 1.7 mg/kg/day The specific dosages for the muscarinics are as follows:
For milameline the range is 0.005 to 0.1 mg/kg/day For xanomeline the range is 0.1 to 4.0 mglkglday For sabcomeline the range is 0.1 to 2.5 Eig/kg/day (a) Equivalently, in mgs: the range is 1.0 x 10~ to 2.5 x 10'3 mg/kg/day For arecoline the range is .01 to 0.1 mg/kg/day For oxotremorine the range is 0.001 to 0.03 mg/kg/day For pilocarpine (Salagen) the range is 0.05 to 0.4 mg/kg/day The compositions of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable vehicle or diluent. Thus, the compounds of this invention can be administered individually or together in any conventional oral, parenteral or transdermal dosage form.
For oral administration a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diiuent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
For purposes of transdermal (e.g.,topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1 % to 5% concentration), otherwise similar to the above parenteral solutions, are prepared.
Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).
Pharmaceutical compositions according to the invention may contain 0.1 %-95%
of the compounds) of this invention, preferably 1 %-70%. In any event, the composition or formulation to be administered will contain a quantity of a compounds) according to the invention in an amount effective to treat the disease/condition of the subject being treated.

Claims (22)

1. A pharmaceutical composition for the enhancement of cognition or the treatment of disorders involving cognitive dysfunction in a mammal comprising:
(a) a nicotine receptor partial agonist or a pharmaceutically acceptable salt thereof;
(b) an acetylcholinesterase inhibitor, a butylcholinesterase inhibitor, an estrogenic agent, a selective estrogen receptor modulator or a muscarinic agonist or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier;
wherein the active ingredient (a) and (b) above are present in amounts that render the composition effective in the enhancement of cognition or the treatment of disorders involving cognitive dysfunction.
2. A pharmaceutical composition as recited in claim 1 wherein the nicotine receptor partial agonist.is selected from:
9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-flouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-vinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-bromo-3-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-one;
3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-one;
3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-one;
9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-ethynyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-propenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-propyl)- 1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;

9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1;5]diazocin-one;~
9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
9-(4-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
9-(3-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
9-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2,4-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,8-triene;
5-oxo-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,8-triene;
6-oxo-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,8-triene;
4,5-difluoro-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
5-fluoro-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene-4-carbonitrile;
4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
5-ethynyl-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene-4-carbonitrile;
6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.02~'o.0a,a]pentadeca-2(10),3,8-triene;
10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
4-fluoro-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
4-methyl-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
4-nitro-10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
7-methyl-5,7,13-triazatetracyclo[9.3.1.0 2.10 .0 4,8]pentadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4.8]pentadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,5,8-tetraene;

6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9]hexadeca-2(11),3,5,7,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9]hexadeca-2(11),3,5,7,9-pentaene;
14-methyl-5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9]hexadeca-2(11),3,5,7,9-pentaene;
5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,6,8-tetraene;
6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,6,8-tetraene;
4-chloro-10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-trien-4-yl cyanide;
1-(10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;
10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-trien-4-ol;
7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2,4(8),6,9-tetraene;
4,5-dichloro-10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-5-carbonitrile;
1-[11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-yl]-1-ethanone;
1-[11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-men-5-yl]-1-propanone;
4-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-5-carbonitrile;
5-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-4-carbonitrile;
6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0 2,10 ,0 4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
5,6-dimethyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,6,8-tetraene;
5-methyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,6,8-tetraene;
6-(trifluoromethyl)-7-thia-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
5,8,15-triazatetracyclo[11.3.1.02,11 .0 4,9]heptadeca-2(11),3,5,7,9-pentaene;
7-methyl-5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9]heptadeca-2(11),3,5,7,9-pentaene;
6-methyl-5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9]heptadeca-2(11),3,5,7,9-pentaene;
6,7-dimethyl-5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9]heptadeca-2(11),3,5,7,9-pentaene;
7-oxa-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
5-methyl-7-oxa-6,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,6,8-tetraene;
7-methyl-5-oxa-6,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,6,8-tetraene;
4,5-difluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
4-chloro-5-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;

5-chloro-4-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
4-(1-ethynyl)-5-fluoro-11-azatricyclo[7.3.1.0 2.7]trideca-2(7),3,5-triene;
5-(1-ethynyl)-4-fluoro-11-azatricyclo]7.3.1.0 2,7]trideca-2(7),3,5-triene;
5,6-difluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2,4,6-triene;
6-trifluoromethyl-11-aza-tricyclo[7.3.1.0 2,7]trideca-2,4,6-triene;
6-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-aza-tricyclo(7.3.1.0 2,7]trideca-2(7),3,5-trien-6-ol;
6-fluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-ol;
4-nitro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5-nitro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5-fluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene; and 6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene and their pharmaceutically acceptable salts and their optical isomers.
3. A pharmaceutical composition as recited in claim 2 wherein the nicotine receptor partial agonists is selected from:

9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-flouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-fluorophenyi)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
6-methyl-5-this-5-dioxa-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,8-triene;
4-fluoro-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
4-nitro-10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
6-methyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,5,8-tetraene;

6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9]hexadeca-2(11),3,5,7,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9]hexadeca-2(11),3,5,7,9-pentaene;
5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,9]pentadeca-2(10),3,6,8-tetraene;
6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,6,8-tetraene;
10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-trien-4-yl cyanide;
1-(10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;
11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-5-carbonitrile;
1-[11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-yl]-1-ethanone;
1-[11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-yl]-1-propanone;
4-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-5-carbonitrile;
5-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-4-carbonitrile;
6-methyl-7-this-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,14-triazatetracyclo[10.3.1.0 2m10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,6,8-tetraene;
5,6-difluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2,4,6-triene;
6-trifluoromethyl-11-aza-tricyclo[7.3.1.0 2,7]trideca-2,4,6-triene;
6-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
6-fluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene; and 11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-of and their pharmaceutically acceptable salts and their optical isomers.
4. A pharmaceutical composition according to claim 1 wherein the acetylcholinesterase inhibitor or the butylcholinesterase inhibitor is selected from donepizil (Aricept.TM.), tacrine (Cognex.TM.) rivastigmine (Exelon.TM.), physostigmine (Synapton),galanthamine (Reminyl), metrifonate (Promem) quilostigmine, tolserine, thiatolserine, cymserine, thiacymserine, neostigmine, eseroline, zifrosilone, mestinon, huperzine A and icopezil or a pharmaceutically acceptable salt of one of the foregoing compounds.
5. A pharmaceutical composition according to Claim 1 wherein the estrogenic agent is estradiol or a pharmaceutically acceptable form of estradiol.
6. A pharmaceutical composition according to Claim 1 wherein the selective estrogen receptor modulator (SERM) is selected from lasofoxifene, droloxifene, tamoxifen and raloxifene (Evista) or a pharmaceutically acceptable salt of one of the foregoing compounds.
7. A pharmaceutical composition according to Claim 1 wherein the muscarinic agonist is selected from milameline, xanomeline, sabcomeline, arecoline, oxotremorine, and pilocarpine or a pharmaceutically acceptable salt of one of the foregoing compounds.
8. A pharmaceutical composition according to Claim 1 wherein diseases of cognitive dysfunction are selected from, but are not limited to, Alzheimer's Disease, mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinson's disease dementia, Huntington's disease, stroke, traumatic brain injury (TBI), AIDS
associated dementia and schizophrenia.
9. A method of enhancing cognition or treating a disorder involving cognitive dysfunction in a mammal comprising administering to said mammal, an amount of a a nicotine receptor partial agonist or a pharmaceutically acceptable salt thereof; and b. an acetylcholinesterase inhibitor, a butylcholinesterase inhibitor, an estrogenic agent, selective estrogen receptor modulator or muscarinic agonist or a pharmaceutically acceptable salt thereof;
wherein the active ingredients (a) and (b) are administered in amounts that render the combination of the two ingredients effective in the treatment of diseases of cognitive dysfunction.
10. A method as recited in claim 9 wherein the nicotine receptor partial agonist is selected from 9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-flouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-vinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-bromo-3-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-one;
3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-one;
3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-one;
9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-ethynyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;

9-(2-propenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-propyl)- 1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1.5]diazocin-8-one;
9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
9-(4-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-9-(3-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
9-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2,4-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,8-triene;
5-oxo-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,8-triene;
6-oxo-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,8-triene;
4,5-difluoro-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
5-fluoro-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene-4-carbonitrile;
4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
5-ethynyl-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene-4-carbonitrile;
6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,8-triene;
10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
4-fluoro-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
4-methyl-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
4-nitro-10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
7-methyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4.8]pentadeca-2(10),3,5,8-tetraene;

6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3;5,8-tetraene;
6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9]hexadeca-2(11),3,5,7,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9]hexadeca-2(11),3,5,7,9-pentaene;
14-methyl-5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9]hexadeca-2(11),3,5,7,9-pentaene;
5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,6,8-tetraene;
6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,6,8-tetraene;
4-chloro-10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-trien-4-yl cyanide;
1-(10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;
10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-trien-4-ol;
7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2,4(8),6,9-tetraene;
4,5-dichloro-10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-5-carbonitrile;
1-[11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3, 5-trien-5-yl]-1-ethanone;
1-[11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-yl]-1-propanone;
4-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-5-carbonitrile;
5-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-4-carbonitrile;
6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
5,6-dimethyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,6,8-tetraene;
5-methyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,6,8-tetraene;
6-(trifluoromethyl)-7-thia-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9]heptadeca-2(11),3,5,7,9-pentaene;
7-methyl-5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9]heptadeca-2(11),3,5,7,9-pentaene;
6-methyl-5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9]heptadeca-2(11),3,5,7,9-pentaene;
6,7-dimethyl-5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9]heptadeca-2(11),3,5,7,9-pentaene;
7-oxa-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
5-methyl-7-oxa-6,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,6,8-tetraene;

7-methyl-5-oxa-6,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,6,8-tetraene;
4,5-difluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
4-chloro-5-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5-chloro-4-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
4-(1-ethynyl)-5-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5-(1-ethynyl)-4-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5,6-difluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2,4,6-triene;
6-trifluoromethyl-11-aza-tricyclo[7.3.1.0 2.7]trideca-2,4,6-triene;
6-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-6-ol;
6-fluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-ol;
4-nitro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5-nitro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5-fluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene; and 6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene and their pharmaceutically acceptable salts and their optical isomers.
11. The method of claim 10 wherein the nicotine partial agonist is selected from:
9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-flouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-one;
6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,8-triene;
4-fluoro-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;

4-nitro-10-azatricycio[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
6-methyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .04,8]pentadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9]hexadeca-2(11),3,5,7,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.0 2,11 .04,9]hexadeca-2(11),3,5,7,9-pentaene;
5-oxa-7,13-diazatetracycio[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,6,8-tetraene;
6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]pentadeca-2(10),3,6,8-tetraene;
10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-trien-4-yl cyanide;
1-(10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;
11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-5-carbonitrile;
1-[11-azafricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-yl]-1-ethanone;
1-[11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-yl]-1-propanone;
4-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-5-carbonitrile;
5-fluoro-11-azatricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-4-carbonitrile;
6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0 2,10.0 4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0 2,10 ,0 4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,6,8-tetraene;
5,6-difluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2,4,6-triene;
6-trifluoromethyl-11-aza-tricyclo[7.3.1.0 2,7]trideca-2,4,6-triene;
6-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
6-fluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene; and 11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-ol and their pharmaceutically acceptable salts and their optical isomers.
12. A method according to claim 9 wherein the acetylcholinesterase inhibitor or butylcholinesterase inhibitor is selected from donepizil (Aricept.TM.), tacrine (Cognex.TM.) rivastigmine (Exelon.TM.), physostigmine (Synapton), galanthamine (Reminyl), metrifonate (Promem) quilostigmine, tolserine, thiatolserine, cymserine, thiacymserine, neostigmine, eseroline, zifrosilone, mestinon, huperzine A and icopezil or a pharmaceutically acceptable salt of one of the foregoing compounds.
13. A method according to Claim 9 wherein the estrogenic agent is estradiol or a pharmaceutically acceptable form of estradiol.
14. A method according to claim 9 wherein the selective estrogen receptor modulator (SERM) is selected from lasofoxifen, droloxifene, tamoxifen and raloxifene (Evista) or a pharmaceutically acceptable salt of one of the foregoing compounds.
15. A method according to claim 9 wherein the muscarinic agonist is selected from milameline, xanomeline, sabcomeline, arecoline, oxotremorine, and pilocarpine or a pharmaceutically acceptable salt of one of the foregoing compounds.
16. A method according to Claim 9 wherein the disorders of cognitive dysfunction are selected from, but not limited to, Alzheimer's Disease, mild cognitive impairment, age-related cognitive decline vascular dementia, Parkinson's disease dementia, Huntington's disease, stroke traumatic brain injury (TBI), AIDS associated dementia and schizophrenia.
17. A method according to claim 9 wherein the nicotine receptor partial agonist and the acetylcholinesterase inhibitor or butylcholinesterase are administered substantially simultaneously.
18. A method according to claim 9 wherein the nicotine receptor partial agonist and estradiol are administered substantially simultaneously.
19. A method according to Claim 9 wherein the nicotine receptor partial agonist and the selective estrogen receptor modulator are administered substantially simultaneously.
20. A method as recited in claim 9 wherein the nicotine receptor partial agonist and the muscarinic agonist are administered substantially simultaneously.
21. A pharmaceutical composition for enhancing cognition or treating a disorder involving cognitive dysfunction, including but not limited to, Alzheimer's Disease, mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinson's disease dementia, Huntington's Disease, Stroke, TBI, AIDS associated dementia and schizophrenia in a mammal, including a human, the method comprises administering to said mammal a cognitive dysfunction attenuating effective amount of a pharmaceutical composition comprising (a) a nicotine receptor partial agonist or a pharmaceutically acceptable salt thereof;
(b) an acetylcholinesterase inhibitor, a butylcholinesterase inhibitor, an estrogenic agent, a SERM, or a muscamic agonist or a pharmaceutially acceptable salt thereof;
(c) a pharmaceutically acceptable carrier, wherein (a) and (b) are present in amounts that render the composition effective in treating such disorders.
22. A method of treating a disorder or conditon selected from the group consisting of Alzheimer's Disease, mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinson's disease dementia, Huntington's Disease, Stroke, TBI, AIDS
associated dementia and schizophrenia comprising adminstering to said mammal;
(a) a nicotine receptor partial agonist or a pharmaceuitcally acceptable salt thereof;

(b) an acetylcholinesterase inhibitor, a butylcholinesterase inhibitor, an estrogenic agent, a SERM, or a muscarnic agonist or a pharmaceutically acceptable salt thereof; and wherein the active agents (a) and (b) above are administered in amounts that render the combination of the two ingredients effective in treating Alzheimer's Disease, mild cognitive impairment, age-related cognitive decline, vascular dementia, Parkinson's disease dementia, Huntington's Disease, Stroke, TBI, AIDS associated dementia and schizophrenia.
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