8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

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

wherein R b and R c are independently selected from the group consisting of:

halo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, and alkynyl;

or R a represents naphthyl;

which naphthyl is optionally with 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; and

R 3 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;

or R 3 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, or alkynyl;

which alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, or alkynyl is optionally substituted with one or more substituents 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

wherein R b is halo and R c is halo.

4. The chemical compound of claim 1 , wherein

R a represents

wherein R b is alkoxy and R c alkoxy.

5. The chemical compound of claim 1 , wherein R a represents naphthyl.

6. The chemical compound of claim 1 , wherein

R 3 represents phenyl optionally substituted with one or more halo.

7. The chemical compound of claim 1 , wherein

R 3 represents hydrogen, alkyl or cycloalkyl.

8. The chemical compound of claim 1 , wherein

R represents hydrogen or methyl;

R a represents 2,3-dihalophenyl, 2,3-dimethoxyphenyl or naphthyl; and

R 3 represents hydrogen, alkyl, cycloalkyl or phenyl optionally substituted with one or more halo.

9. The chemical compound of claim 1 , which is

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(1-Naphthaleneoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Chlorophenylthiomethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(2,3-Dichloro-phenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(1-Naphthaleneoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(2,3-Chlorophenylthiomethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenylthiomethyl)-8-methyl-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dimethoxyphenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-8-aza-bicyclo[3.2.1]octane;

(2R)-2-(1-Naphthyloxymethyl)-8-methyl-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-fluorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Difluorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2-chloro-3-fluorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-ethyl-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-cyclopropyl-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-isopropyl-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Chlorophenylthiomethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]-octane;

(2S,3R)-2-(2,3-Dichloro-phenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(1-Naphthyloxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(2,3-Chlorophenylthiomethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenylthiomethyl)-8-H-3-(n-butyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dimethoxyphenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-fluorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Difluorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2-Chloro-3-fluorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-ethyl-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-cyclopropyl-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-isopropyl-8-aza-bicyclo[3.2.1]octane;

or any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of claim 1 , or any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient or diluent.