Pharmaceutical compositions and their methods of use

• US 20080167286A1
• Filed: 12/10/2007
• Published: 07/10/2008
• Est. Priority Date: 12/12/2006
• Status: Abandoned Application

• Current Assignee: Abbott Laboratories
• Original Assignee: Abbott Laboratories
• Inventors: Lee, Chih-Hung, Sippy, Kevin B., Li, Tao, Anderson, David J., Schrimpf, Michael R., Ji, Jianguo, Gopalakrishnan, Murali, Honore, Marie P., Malysz, John
• Application Number:
  US11/953,625
• Publication Number:
  US 20080167286A1
• Time in Patent Office: Days
• US Class Current: 514/210.16
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/443 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 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
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: G01N 2333/70571 : for neuromediators, e.g. serotonin receptor, dopamine receptor
• CPC Class Codes: G01N 33/944 : Acetylcholine

Abstract

The invention relates to a composition comprising a neuronal nicotinic receptor ligand and an α4β2 positive allosteric modulator, a method of using the same, and a related article of manufacture.

Claims

1. A composition, comprising:

(i) a nicotinic acetylcholine receptor ligand and

(ii) a nicotinic acetylcholine receptor subtype α

4β

2 positive allosteric modulator in admixture with at least one pharmaceutically acceptable excipient.

2. The composition of claim 1, wherein the nicotinic acetylcholine receptor ligand is a nicotinic acetylcholine receptor subtype α

4β

2 ligand demonstrating a K_i value that as measured by [³H]-cytisine binding assay (K_i Cyt) of about 0.001 nanomolar to about 100 micromolar.

3. The composition of claim 1, wherein the nicotinic acetylcholine receptor ligand is a nicotinic acetylcholine receptor subtype α

4β

2 agonist or partial agonist.

4. The composition of claim 1, wherein the nicotinic acetylcholine receptor ligand is a heterocyclic ether derivative, a N-substituted diazabicyclic derivative, or a heterocyclic substituted amino azacycle compound.

5. The composition of claim 1, wherein the nicotinic acetylcholine receptor ligand is a compound selected from:

5-[(2R)-azetidin-2-yl methoxy]-2-chloropyridine,

(3R)-1-pyridin-3-ylpyrrolidin-3-amine, and

2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

3-(5,6-dichloro-pyridin-3-yl)-1(S),5(S)-3,6-diazabicyclo[3.2.0]heptane; and

(R,R)-1-(pyridin-3-yl)octahydro-pyrrolo[3,4-b]pyrrole;

or is a pharmaceutically acceptable salt thereof.

6. The composition of claim 1, wherein the nicotinic acetylcholine receptor ligand is selected from aryl-fused azapolycyclic compounds, aryl-substituted olefinic amine compounds, pyridopyranoazepine derivatives, benzylidene- and cinnamylidene-anabaseines, and 3-pyridoxylalkyl heterocyclic ether compounds.

7. The compound of claim 6, wherein the nicotinic acetylcholine receptor ligand is selected from the group consisting of:

5-[(2R)-azetidin-2-yl methoxy]-2-chloropyridine;

(3R)-1-pyridin-3-ylpyrrolidin-3-amine;

2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine;

3-(5,6-dichloro-pyridin-3-yl)-1S,5S-3,6-diazabicyclo[3.2.0]heptane;

(R,R)-1-(pyridin-3-yl)octahydro-pyrrolo[3,4-b]pyrrole;

6,10-methano-6H-pyrazino[2,3-h][3]benzazepine;

7,8,9,10-tetrahydro-(2S,4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine;

(2S,4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine;

(2S,4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine;

(2S,4E)-N-methyl-3-pyrimidine-4-penten-2-amine;

(5aS,8S,10aR)-5a,6,9,10-tetrahydro-7H,11H-8,10a-methanopyrido[2′

,3′

;

5,6]pyrano[2,3-d]azepine;

3-[1-(2,4-dimethoxy-phenyl)-meth-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3′

]bipyridinyl; and

3-[1-(2-methoxy-4-hydroxyphenyl)-meth-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3′

]bipyridinyl;

or is a pharmaceutically acceptable salt thereof.

8. The composition of claim 1, wherein the nicotinic acetylcholine receptor subtype α

4β

2 positive allosteric modulator has a formula;

9. The composition of claim 1, wherein the nicotinic subtype α

4β

2 positive allosteric modulator has the formula;

10. The composition of claim 1, wherein the nicotinic subtype α

4β

2 positive allosteric modulator is a compound of formula;

11. The composition of claim 10, wherein Ar² is cyanophenyl and Ar³ is pyridin-3-yl.

12. The composition of claim 1, wherein the nicotinic subtype α

4β

2 positive allosteric modulator is selected from;

3,5-diphenylisoxazole;

3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;

3,5-di(pyridin-3-yl)-1,2,4-oxadiazole;

3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile;

3-(5-(6-fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile;

5-(5-bromopyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

3-(pyridin-3-yl)-5-(3-(trifluoromethylsulfonyl)phenyl)-1,2,4-oxadiazole;

3-(3-(6-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;

5-(5-(pyrrol-1-yl)pyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyridin-3-ol;

5-(3,4-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(2,3-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(pyrazin-2-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(3,5-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(2,3,5-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(2,4,5-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(2,5-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(4-chloro-2,5-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(5-methylpyrazin-2-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;

2,3,6-trifluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol;

2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol;

2-fluoro-4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol;

5-(3-chloro-4-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(3,4-dichlorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

2-nitro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol;

5-(2,3,6-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

2,2,2-trifluoro-1-(4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)ethanone;

5-(3-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(4-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(2-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

3-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;

3-(2,3-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;

3-(3,4-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(2,6-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide;

5-(2,4-difluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(2,3,4-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(3,4,5-trifluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(4-chloro-3-fluorophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(3-nitrophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(3-(methylsulfonyl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

3-(2-chloropyridin-4-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;

3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzamide;

4-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-one;

tert-butyl 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzoate;

2-amino-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenol;

N,N-dimethyl-4-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;

3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzoic acid;

5-(3-(1H-tetrazol-5-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

N,N-diethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide;

2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;

3-(3-(1H-tetrazol-5-yl)phenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;

3-(6-chloropyridin-3-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(6-chloropyridin-3-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-one;

5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyridin-2(1H)-one;

N-methyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide;

3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)aniline;

(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine;

5-(2-chloropyridin-4-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

4-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyridin-2(1H)-one;

tert-butyl 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzylcarbamate;

5-(3-bromophenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidin-2-one;

tert-butyl 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenylcarbamate;

N,N-dimethyl-1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine;

5-(3-(piperazin-1-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)ethanone;

3-(6-chloropyridin-3-yl)-5-(2,3-difluorophenyl)-1,2,4-oxadiazole;

3-(6-chloropyridin-3-yl)-5-(3,4-difluorophenyl)-1,2,4-oxadiazole;

(R)-3-(pyridin-3-yl)-5-(3-(pyrrolidin-2-yl)phenyl)-1,2,4-oxadiazole;

5-(3-(1H-pyrazol-3-yl)phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;

1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)phenyl)ethanol;

3-(3-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;

3-(4-fluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;

3-(5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile;

3-(5-(2-fluoropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile;

3-fluoro-5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile;

2,5-di(pyridin-3-yl)-1,3,4-oxadiazole;

2-(5-bromopyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(pyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazole;

2-(pyridin-3-yl)-5-o-tolyl-1,3,4-oxadiazole;

2-(pyridin-3-yl)-5-m-tolyl-1,3,4-oxadiazole;

2-(pyridin-3-yl)-5-p-tolyl-1,3,4-oxadiazole;

2-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol;

3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol;

4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol;

2-(3-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(4-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-fluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3-fluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(4-fluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(4-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-bromophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3-bromophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(4-bromophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)benzonitrile;

4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)benzonitrile;

N,N-dimethyl-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)aniline;

N,N-dimethyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)aniline;

2-(pyridin-3-yl)-5-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazole;

2-(pyridin-3-yl)-5-(3-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole;

2-(4-phenoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(4-(benzyloxy)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3,4-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,4-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3,4-dimethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,3-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,4-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,5-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,4-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3,5-dimethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(pyridin-3-yl)-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazole;

2-(3,4-dichlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,4-dichlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,5-dichlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3,4-dichlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

5-methyl-2-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol;

2-methyl-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol;

2-(3-fluoro-2-methyl phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(5-fluoro-2-methyl phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3-fluoro-4-methyl phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,3-difluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,4-difluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,5-difluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3,5-difluorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

1-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)ethanone;

2-(4-isopropylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3-methoxy-4-methyl phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(4-ethoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(4-(methylthio)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3-fluoro-4-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(naphthalen-1-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(naphthalen-2-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

4-chloro-2-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol;

2-(4-tert-butylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

N-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)acetamide;

2-(4-propoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(4-isopropoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(5-chloro-2-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(4-fluoronaphthalen-1-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

N,N-diethyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)aniline;

2-(4-butoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-methoxy-4-(methylthio)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(4-(methylsulfonyl)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-chloro-5-(methylthio)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-fluoro-5-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-chloro-5-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-phenethylphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-bromo-5-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(5-bromo-2-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-iodophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(3-iodophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(4-iodophenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(pyridin-3-yl)-5-(pyrimidin-5-yl)-1,3,4-oxadiazole;

2-(5-methylpyrazin-2-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-chloro-6-methylpyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-(ethylthio)pyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,6-dimethoxypyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-(methylthio)pyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

5-chloro-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-ol;

2-(2,6-dichloro-5-fluoropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,5-dichloropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(6-chloropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2,6-dichloropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole;

2-(2-chloropyridin-3-yl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; and

2-(pyridin-3-yl)-5-(quinolin-3-yl)-1,3,4-oxadiazole;

or is a pharmaceutically acceptable salt thereof.

13. The composition of claim 1, wherein the nicotinic subtype α

4β

2 positive allosteric modulator is a 2,5-disubstituted-1,3,4-oxadiazole derivative;

a 3,5-disubstituted-1,2,4-oxadiazole derivative, or 3,5-diphenylisoxazole.

14. A method for use in treating or preventing pain in a patient, comprising:

(i) administering an amount of nicotinic subtype α

4β

2 positive allosteric modulator to the patient; and

(ii) administering a pain medication comprising a compound selected from an opioid, gabapentin, pregabalin, duloxetine, a cannabinoid ligand, a vaniolloid receptor antagonist, calcium channel blocker and a sodium channel blocker wherein a descending modulatory pathway that is shared or commonly activated via the α

4β

2 nicotinic receptor mechanism is activated.

15. A method for use in treating or preventing pain, including neuropathic pain and cognitive disorders in a patient, comprising:

(i) administering an amount of nicotinic acetylcholine receptor ligand to the patient; and

(ii) administering an amount of nicotinic acetylcholine receptor subtype α

4β

2 positive allosteric modulator to the patient;

wherein the amounts of (i) and (ii) together are more effective in treating pain or cognitive disorders.

16. A method for use in treating or preventing a condition or disorder selected from attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer'"'"'s disease (AD), substance abuse including alcohol abuse, bipolar disorder, mild cognitive impairment, age-associated memory impairment (AAMI), senile dementia, AIDS dementia, Pick'"'"'s Disease, dementia associated with Lewy bodies, dementia associated with Down'"'"'s syndrome, schizophrenia, schizoaffective disorder, smoking cessation, amyotrophic lateral sclerosis, Huntington'"'"'s disease, diminished CNS function associated with traumatic brain injury, infertility, lack of circulation, need for new blood vessel growth associated with wound healing, ischemia, sepsis, inflammation and inflammatory disorders comprising:

(i) administering an amount of nicotinic acetylcholine receptor ligand to the patient; and

(ii) administering an amount of nicotinic acetylcholine receptor subtype α

4β

2 positive allosteric modulator to the patient;

wherein the amounts of (i) and (ii) together are more effective in treating disorders.

17. A method for use of treating or preventing a condition or disorder characterized by attention or cognitive dysfunction comprising administering a therapeutically effective amount of a nicotinic acetylcholine receptor subtype α

4β

2 positive allosteric modulator to a subject in need thereof in combination with a nicotinic acetylcholine receptor ligand or an acetylcholinesterase inhibitor.

21. The compound of claim 17, wherein Ar² is cyanophenyl and Ar³ is pyridin-3-yl.

18. A method of treating or preventing a condition or disorder characterized by neuropsychological dysfunction comprising administering a therapeutically effective amount of a nicotinic acetylcholine receptor subtype α

4β

2 positive allosteric modulator to a subject in need thereof in combination with an antipsychotic agent.

19. An article of manufacture, comprising:

(i) a first pharmaceutical dosage form comprising at least one nicotinic acetylcholine receptor ligand; and

(ii) a second pharmaceutical dosage form comprising at least nicotinic acetylcholine receptor subtype α

4β

2 positive allosteric modulator;

wherein the article contains first and second pharmaceutical dosage forms.

20. A compound of formula:

22. A compound of formula:

23. A compound that is [³H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile.

24. Use of a radiolabelled form of a compound of formula (II*) for determining the binding affinity of nicotinic acetylcholine receptor subtype α

4β

2 positive allosteric modulators.