# US 5,346,911 A · Azabicyclo and azacyclo oxime and amine cholinergic agents and methods of treatment

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- Number: US 5,346,911 A
- Document ID: US5346911A
- Status: Granted
- Kind: A
- Application number: 08/110,904
- Filed: 1993-08-24
- Granted: 1994-09-13
- Earliest claimed: 1990-03-06
- Assignees: Warner-Lambert Company
- Inventors: Corinne E. Augelli-Szafran; Stephen D. Barrett; Bradley W. Caprathe; Adam A. Galan; Juan C. Jaen; David J. Lauffer; Walter H. Moos; Michael R. Pavia; Kathryn B. Sanders; Haile Tecle; Anthony J. Thomas
- Web page: https://patentgrep.com/patent/US5346911A

## CPC

- C07D 211/72: with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D 451/04: with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D 453/02: containing not further condensed quinuclidine ring systems
- C07D 487/08: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Pharmaceutically useful nitrogen containing cyclic oxime and amine substituted compounds which are azabicyclo[2.2.1]oximes, azabicyclo[2.2.2]oximes, azabicyclo[2.2.1]amines, azabicyclo[2.2.2]amines, azabicyclo[3.2.1]oximes, and amine containing heterocyclic oximes wherein the heterocyclic ring contains from 3 to 7 carbon atoms are disclosed.

## Claims

### Claim 1

A compound of the formula
wherein R is selected from the group ##STR84## wherein Ar is an aromatic group selected from phenoxy, phenyl, 2-or 3-thienyl, 2-or 3-furanyl,
2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, wherein the aromatic group is unsubstituted or substituted with 1 or 2 substituents selected from straight or branched alkyl having from 1 to 4 carbon atoms, straight or branched alkoxy having from 1 to 4 carbon atoms, chlorine, fluorine, bromine, trifluoromethyl, nitro, hydroxy, trifluoromethoxy, amino, amino substituted with 1 or 2 straight or branched lower alkyl groups having from 1 to 4 carbon atoms;
R.sub.11 is an alkyl group of 1 to 4 carbon atoms;
R.sub.12 is hydrogen or Ar as defined above; or an individual geometric and optically active isomer, or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound of claim 1 wherein Ar is phenyl or phenyl substituted with one substituent selected from straight alkyl from 1 to 4 carbons, straight alkoxy having from 1 to 4 carbon atoms, chlorine fluorine, bromine, trifluoromethyl, or trifluoromethoxy.

### Claim 3 (depends on 1)

A compound of claim 1 wherein R.sub.12 is hydrogen, phenyl or phenyl substituted with one substituent selected from straight alkyl from 1 to 4 carbons, straight alkoxy having from 1 to 4 carbon atoms, chlorine, fluorine, bromine, trifluoromethyl, or trifluoromethoxy.

### Claim 4 (depends on 1)

A compound of claim 1 wherein R.sub.11 is a methyl group.

### Claim 5 (depends on 2)

A compound of claim 2 which is selected from
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(2'-methoxyphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(2'-methoxyphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methoxylphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methoxyphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-methoxyphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-methoxyphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(2'-chlorophenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(2'-chlorophenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-chlorophenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-chlorophenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-chlorophenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-chlorophenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(2'-fluorophenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(2 '-fluorophenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3 '-fluorophenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-fluorophenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-fluorophenyl)-2-propynyl)oxime; and
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-fluorophenyl)-2-propynyl)oxime.

### Claim 6 (depends on 3)

A compound according to claim 3, which is selected from
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one O-(Z-3-methyl-5-phenyl-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(Z-3-methyl-5-phenyl-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-phenyl-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-phenyl-2-penten-4-ynyl)oxime;
E-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(Z-3-methyl-5-phenyl-2-penten-4-ynyl)oxime
E-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(Z-3-methyl-5-phenyl-2-penten-4-ynyl)oxime;
E-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-phenyl-2-penten-4-ynyl)oxime;
E -(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-phenyl-2-penten-4-ynyl)oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(Z-3-methyl-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(Z-3-methyl-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(Z-3-methyl-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl -2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-2-penten-4-ynyl)oxime;
E-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(Z-3-methyl-2-penten-4-ynyl)oxime;
E-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(Z-3-methyl-2-penten-4-ynyl)oxime;
E-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(Z-3-methyl-2-penten-4-ynyl)oxime;
E -(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-2-penten-4-ynyl)oxime;
E-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-2-penten-4-ynyl)oxime; and
E-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-2-penten-4-ynyl)oxime.

### Claim 7 (depends on 1)

A compound according to claim 1, which is selected from
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',4'-dimethoxyphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',4'-dimethoxyphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',4'-dimethoxyphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-methylphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-methylphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-methylphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methylphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methylphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methylphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(2'-methylphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(2'-methylphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(2'-methylphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-trifluoromethylphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-trifluoromethylphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-trifluoromethylphenyl)-2-propynyl)oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-trifluoromethylphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-trifluoromethylphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-trifluoromethylphenyl)-2-propynyl)oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(2'-trifluoromethylphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(2'-trifluoromethylphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(2'-trifluoromethylphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-phenyl-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-phenyl-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(3',4'-dichlorophenyl-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(3',4'-dichlorophenyl-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(3',4'-dichlorophenyl-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan -3-one, O-2-propynyl oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-2-propynyl oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(2,5-hexadiynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(2,5-hexadiynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(2,5-hexadiynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(2,5,8-nonatriynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(2,5,8 -nonatriynyl)oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-ethoxyphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-ethoxyphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-ethoxyphenyl)-2-propynyl)oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-ethoxyphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan -3-one, O-(3-(3'-ethoxyphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-ethoxyphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',4'-methylenedioxyphenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',4'-methylenedioxyphenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',4'-methylenedioxyphenyl)-2-propynyl)oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',4'-dichlorophenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',4'-dichlorophenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',4'-dichlorophenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',5'-dichlorophenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',5'-dichlorophenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',5'-dichlorophenyl)-2-propynyl)oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',5'-bis(trifluoromethyl)phenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',5'-bis(trifluoromethyl)phenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3',5'-bis(trifluoromethyl)phenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-nitrophenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-nitrophenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(4'-nitrophenyl)-2-propynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-nitrophenyl)-2-propynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-nitrophenyl)-2-propynyl)oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(4'-methoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(4'-methoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(4'-methoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(3'-methoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(3'-methoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(3'-methoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(2'-methoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(2'-methoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(2'-methoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(3',4'-dimethoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(3',4'-dimethoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(3',4'-dimethoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(3',4',5-trimethoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(3',4',5-trimethoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(3',4',5-trimethoxyphenyl)-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(4'-methylphenyl)-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(4'-methylphenyl)-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(4'-methylphenyl)-2-penten-4-ynyl)oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(4'-chlorophenyl)-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(4'-chlorophenyl)-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(4'-chlorophenyl)-2-penten-4-ynyl)oxime;
Z-(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(4'-fluorophenyl)-2-penten-4-ynyl)oxime;
Z-(+)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(4'-fluorophenyl)-2-penten-4-ynyl)oxime;
Z-(-)-1-Azabicyclo[2.2.1]heptan-3-one, O-(E-3-methyl-5-(4'-fluorophenyl)-2-penten-4-ynyl)oxime.

### Claim 8 (depends on 1)

A pharmaceutically acceptable salt of a compound of claim 1 wherein the salt is a hydrochloride or an oxalate.

### Claim 9 (depends on 1)

A pharmaceutical composition useful for alleviating pain in a mammal comprising an analgesically effective amount of a compound of claim 1 as the sole active ingredient together with a pharmaceutically acceptable carrier.

### Claim 10 (depends on 1)

A pharmaceutical composition useful for treating the symptoms of cognitive decline comprising a compound of claim 1 as the sole active ingredient together with a pharmaceutically acceptable carrier.

### Claim 11 (depends on 9)

A method of alleviating pain in a mammal which comprises administering to a mammal in need of such treatment a composition of claim 9.

### Claim 12 (depends on 10)

A method of treating the symptoms of cognitive decline in a patient in need thereof which comprises administering to said patient an effective amount of a composition of claim 10.