8-aza-bicyclo (3.2.1) octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
This invention relates to novel 8-aza-bicyclop[3.2.1]octane derivatives useful as monoamine neurotransmitter re-up-take inhibitors. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.
1. A chemical compound which is an 8-aza-bicyclo[3.2.1]octane derivative of the Formula I:
or any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof,
wherein
R represents hydrogen or alkyl;
R 2 represents —CH 2 —X—R a ; wherein X represents —O— or —S—; R a represents phenyl or naphthyl, which phenyl or naphthyl is optionally substituted with one or more substituents selected from the group consisting of: halo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, and alkynyl;
R 3 represents heteroaryl; which heteroaryl is optionally substituted with one or more substituents selected from the group consisting of: halo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, and alkynyl.
2. The chemical compound of claim 1 , wherein R represents hydrogen or methyl.
3. The chemical compound of claim 1 , wherein R a represents phenyl optionally substituted with one or more halo or one or more alkoxy.
4. The chemical compound of claim 1 , wherein R a represents naphthyl.
5. The chemical compounds claim 1 , wherein R 3 represents thienyl optionally substituted with one or more halo or alkoxy.
6. The chemical compounds of claim 1 , wherein R 3 represents furyl optionally substituted with one or more halo.
7. The chemical compound of claim 1 , wherein R represents hydrogen or methyl; X represents —O—; R a represents 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethoxyphenyl or naphthyl; and R 3 represents thienyl or furyl, optionally substituted with one or more halo or alkoxy.
8. The chemical compound of claim 1 , which is
(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(3-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(1-Naphthyloxymethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(1-Naphthyloxymethyl)-8-methyl-3-(3-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(5-chloro-thien-2-yl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(1-naphthyl)-8-methyl-3-(5-chloro-thien-2-yl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Difluorophenoxymethyl)-8-methyl-3-(5-chloro-furan-2-yl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Difluorophenoxymethyl)-8-methyl-3-(5-methoxy-thien-2-yl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Dimethoxyphenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(5-methoxy-thien-2-yl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2-naphthyl)-8-methyl-3-(5-chloro-thien-2-yl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Difluorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-furanyl)-8-aza-bicyclo[3.2.1]octane
(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(3-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(1-Naphthyloxymethyl)-8-H-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(1-Naphthyloxymethyl)-8-H-3-(2-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-furanyl)-8-aza-bicyclo[3.2.1]octane;
(2S,3R)-2-(1-Naphthyloxymethyl)-8-H-3-(3-furanyl)-8-aza-bicyclo[3.2.1]octane;
or any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of claim 1 , or any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient or diluent.