Geminal substituted aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors
The present invention relates to novel geminal substituted aminobenzisoxazole compounds, and pharmaceutical compositions of the same, that are suitable as agonists or partial agonists of α7-nAChR, and methods of preparing these compounds and compositions, and the use of these compounds and compositions in methods of maintaining, treating and/or improving cognitive function. In particular, methods of administering the compound or composition to a patient in need thereof, for example a patient with a cognitive deficiency and/or a desire to enhance cognitive function, that may derive a benefit therefrom.
1. A compound represented by Formula (Ia) or Formula (Ib):
wherein:
R 1 and R 2 independently represent an unbranched C 1 -C 4 -alkyl radical or a branched C 3 -C 4 -alkyl radical; or the C(R 1 )(R 2 ) moiety forms a (3-4 membered)-carbocycle, wherein R 1 and R 2 taken together represent a C 2 -C 3 -alkyl di-radical; wherein the unbranched C 1 -C 4 -alkyl radical, the branched C 3 -C 4 -alkyl radical, and the C 2 -C 3 -alkyl di-radical may be independently substituted with up to 4 radical substituents selected from the group consisting of: -D, —F, —Cl, —CN, —CH 3 , —CH 2 CH 3 , ═O, and —OR 3 ;
R 3 independently represents —H; an unbranched C 1 -C 4 -alkyl radical; a branched C 3 -C 4 -alkyl radical; or a C 3 -C 4 -cycloalkyl radical; wherein the unbranched C 1 -C 4 -alkyl radical, the branched C 3 -C 4 -alkyl radical, and the C 3 -C 4 -cycloalkyl radical may be independently substituted with up to 4 radical substituents selected from the group consisting of: -D, —F, —Cl, —CN, ═O, —OH, —OC 1 -C 4 -alkyl, and —OCF 3 ,
R 4 and R 5 independently represent —H, -D, or halogen radical;
R 6 independently represents —F, —Cl, —Br, —CN, —CH 3 , —CH 2 CH 3 , cyclopropyl radical, —CHF 2 , —CH 2 F, —CF 3 , —CH 2 CF 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —O-cyclopropyl, or —OCF 3 ; and
R 7 independently represents —H, -D, —F, —Cl, —CN, —CH 3 , —CH(CH 3 ) 2 , cyclopropyl radical, cyclobutyl radical, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —OCH 3 , —OH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —O-cyclopropyl, —OCF 3 , or —OCH 2 CF 3 ;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 6 independently represents —F, —C, —CH 3 , or —OCH 3 .
3. The compound of claim 1 , wherein R 7 independently represents —H, -D, —F, —C, —CH 3 , or —OCH 3 .
4. The compound of claim 1 , wherein R 4 and R 5 independently represent —H or -D.
5. The compound of claim 1 , wherein R 6 independently represents —Cl.
6. The compound of claim 5 , wherein R 7 independently represents —H or -D.
7. The compound of claim 5 , wherein R 7 independently represents —H, -D, or —F.
8. The compound of claim 1 , wherein the compound is represented by Formula (Ia).
9. The compound of claim 8 , wherein R 1 and R 2 independently represent an unbranched C 1 -alkyl radical and said compound is represented by Formula (IIa):
10. The compound of claim 1 , wherein the compound is selected from the group consisting of:
6-chloro-N-(2,2-dimethylquinuclidin-3-yl)benzo[d]isoxazol-3-amine;
6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-fluorobenzo[d]isoxazol-3-amine;
N-(2,2-dimethylquinuclidin-3-yl)-6-methoxybenzo[d]isoxazol-3-amine;
6,7-dichloro-N-(2,2-dimethylquinuclidin-3-yl)benzo[d]isoxazol-3-amine;
6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-methoxybenzo[d]isoxazol-3-amine;
N-(2,2-dimethylquinuclidin-3-yl)-6-methylbenzo[d]isoxazol-3-amine;
N-(2,2-dimethylquinuclidin-3-yl)-7-fluoro-6-methylbenzo[d]isoxazol-3-amine;
7-chloro-N-(2,2-dimethylquinuclidin-3-yl)-6-fluorobenzo[d]isoxazol-3-amine;
N-(2,2-dimethylquinuclidin-3-yl)-5-fluoro-6-methylbenzo[d]isoxazol-3-amine;
6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-methylbenzo[d]isoxazol-3-amine;
6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-5-fluorobenzo[d]isoxazol-3-amine;
6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-ethoxybenzo[d]isoxazol-3-amine;
7-chloro-N-(2,2-dimethylquinuclidin-3-yl)-6-methylbenzo[d]isoxazol-3-amine;
6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-(trifluoromethyl)benzo[d]isoxazol-3-amine;
6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-isopropoxybenzo[d]isoxazol-3-amine;
6-chloro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol 3-amine;
6-chloro-7-fluoro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
6-methoxy-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
6,7-dichloro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo [d]isoxazol-3-amine;
6-chloro-7-methoxy-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2] octan]-3′-yl)benzo[d]isoxazol-3-amine;
6-methyl-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
7-fluoro-6-methyl-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
7-chloro-6-fluoro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
5-fluoro-6-methyl-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
6-chloro-7-methyl-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
6-chloro-5-fluoro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
6-chloro-7-ethoxy-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
7-chloro-6-methyl-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
6-chloro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)-7-(trifluoromethyl)benzo[d]isoxazol-3-amine; and
6-chloro-7-isopropoxy-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
and single enantiomers and pharmaceutically acceptable salts thereof.
11. The compound of claim 1 , wherein the compound is selected from the group consisting of:
6-chloro-7-(difluoromethyl)-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
6-chloro-7-(difluoromethyl)-N-(2,2-dimethylquinuclidin-3-yl)benzo[d]isoxazol-3-amine;
6-chloro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)-7-(trifluoromethoxy)benzo[d]isoxazol-3-amine;
6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-(trifluoromethoxy)benzo[d]isoxazol-3-amine;
6-chloro-7-cyclopropoxy-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
6-chloro-7-cyclopropoxy-N-(2,2-dimethylquinuclidin-3-yl)benzo[d]isoxazol-3-amine;
6-chloro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)-7-(2,2,2-trifluoroethyl)benzo[d]isoxazol-3-amine;
6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-(2,2,2-trifluoroethyl)benzo[d]isoxazol-3-amine;
6-chloro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)-7-(2,2,2-trifluoroethoxy)benzo[d]isoxazol-3-amine;
6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-(2,2,2-trifluoroethoxy)benzo[d]isoxazol-3-amine;
6-chloro-7-isopropyl-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine; and
6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-isopropylbenzo[d]isoxazol-3-amine;
and single enantiomers and pharmaceutically acceptable salts thereof.
12. The compound of claim 1 , wherein the compound is selected from the group consisting of:
(R)-6-chloro-N-(2,2-dimethylquinuclidin-3-yl)benzo[d]isoxazol-3-amine;
(R)-6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-fluorobenzo[d]isoxazol-3-amine;
(R)-6,7-dichloro-N-(2,2-dimethylquinuclidin-3-yl)benzo[d]isoxazol-3-amine;
(R)-6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-methoxybenzo[d]isoxazol-3-amine;
(R)—N-(2,2-dimethylquinuclidin-3-yl)-6-methylbenzo[d]isoxazol-3-amine;
(R)-7-chloro-N-(2,2-dimethylquinuclidin-3-yl)-6-fluorobenzo[d]isoxazol-3-amine;
(R)-6-chloro-N-(2,2-dimethylquinuclidin-3-yl)-7-methylbenzo[d]isoxazol-3-amine;
(R)-6-chloro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
(R)-6-methoxy-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine; and
(R)-7-fluoro-6-methyl-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[d]isoxazol-3-amine;
and pharmaceutically acceptable salts thereof.
13. A pharmaceutical composition, comprising:
i) the compound, or pharmaceutically acceptable salt thereof, of claim 1 ; and
ii) at least one pharmaceutically acceptable carrier, excipient or diluent.