Benzimidazole derivatives and their use for modulating the GABA

1. A compound of the general formula (I):

or an N-oxide thereof, any of its stereoisomers or any mixture of its stereoisomers,

or a pharmaceutically acceptable salt thereof,

wherein

R a represents halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, R c , R c O—, R c O-alkyl-, R c —O—N═(CR d )—, R c —(C═O)—, R c —(C═O)-alkyl-, R c —(C═O)—(NR d )—, R c —(C═O)—(NR d )-alkyl-, or R c —O—(C═O)—;

wherein R c is hydrogen, alkyl, cycloalkyl, cycloalkylakyl, alkenyl, or alkynyl; which alkyl, cycloalkyl, cycloalkylakyl, alkenyl, and alkynyl is optionally substituted with one or more azido or R′R″N—;

wherein R′ and R″ independent of each other are hydrogen or alkyl or R′ and R″ together with the together with the nitrogen to which they are attached form a pyrrolidine or piperidine ring;

R d is hydrogen or alkyl;

R b represents an aryl or a heteroaryl group;

which aryl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:

halo, hydroxy, R′″R″″N—, R′″R″″N-alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, and alkynyl;

wherein R′″ and R″″ independent of each other are hydrogen or alkyl; and

X represents —O—, NR e ;

wherein R e represents hydrogen or alkyl.

2. The compound of claim 1 , or an N-oxide thereof, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R a represents trifluoromethyl.

3. The compound of claim 1 , or an N-oxide thereof, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R a represents R c or R c O-alkyl-, wherein R c represents hydrogen or alkyl.

4. The compound of claim 1 , or an N-oxide thereof, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R a represents alkyl substituted with azido or R′R″N-alkyl-.

5. The compound of claim 1 , or an N-oxide thereof, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R a represents R c —O—N═(CR d )—, wherein R c represents hydrogen or alkyl and R d represents hydrogen or alkyl.

6. The compound of claim 1 , or an N-oxide thereof, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R a represents R c —(C═O)— or R c —O—(C═O)—, wherein R c represents hydrogen or alkyl.

7. The compound of claim 1 , or an N-oxide thereof, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R a represents R c —(C═O)—(NR d )— or R c —(C═O)—(NR d )-alkyl-, wherein R c represents hydrogen or alkyl and R d represents hydrogen.

8. The compound of claim 1 , or an N-oxide thereof, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein X represents —O—.

9. The compound of claim 1 , or an N-oxide thereof, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein X represents NR e ; wherein R e represents hydrogen or alkyl.

10. The compound of claim 1 , or an N-oxide thereof, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R b represents an optionally substituted phenyl.

11. The compound of claim 1 , or an N-oxide thereof, any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R b ) represents a heteroaryl group selected from the group of triazolyl, pyridyl, imidazolyl, pyrazolyl, pyrimidyl and thiazolyl; and which heteroaryl group is optionally substituted with one or more substituents.

12. The compound of claim 1 , which is

1-[3-(Pyridin-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid ethyl ester;

1-[3-(1-Methyl-1H-imidazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid ethyl ester;

1-[3-(2-Methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid ethyl ester;

1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid ethyl ester;

1-[3-(1,3-Thiazol-2-ylmethoxymethyl)phenyl]-1H-benzoimidazole-5-carboxylic acid ethyl ester;

1-[3-(Pyridin-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid ethyl ester;

1-[3-(Pyrimidin-4-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid ethyl ester;

{1-[3-(Pyridin-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-methanol;

{1-[3-(1-Methyl-1H-imidazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-methanol;

{1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-methanol;

{1-[3-(1,3-Thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-methanol;

{1-[3-(2-Methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-methanol;

{1-[3-(Pyridin-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-methanol;

{1-[3-(2-Methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-methanol;

{1-[3-(Pyrimidin-4-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5}-methanol;

5-Methoxymethyl-1-[3-(pyridin-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole;

5-Methoxymethyl-1-[3-(1-methyl-1H-imidazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole;

5-Methoxymethyl-1-[3-(2-methyl-2H-[1,2,4]-triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole;

5-Methoxymethyl-1-[3-(2-methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole;

5-Methoxymethyl-1-[3-(1,3-thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole;

5-Methoxymethyl-1-[3-(pyridin-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole;

5-Methoxymethyl-1-[3-(pyrimidin-4-ylmethoxymethyl)-phenyl]-1H-benzoimidazole;

1-[3-(Pyridin-2-ylmethoxymethyl)-phenyl]-5-pyrrolidin-1-ylmethyl-1H-benzoimidazole;

1-[3-(1-Methyl-1H-imidazol-2-ylmethoxymethyl)-phenyl]-5-pyrrolidin-1-ylmethyl-1H-benzoimidazole;

1-[3-(Pyridin-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime;

1-[3-(1-Methyl-1H-imidazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime;

1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime;

O-Methyl 1-[3-(2-methyl-2H-[1,2,4]-triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime;

1-[3-(2-Methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime;

O-Methyl 1-[3-(2-methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime;

1-[3-(1,3-Thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime;

O-Methyl 1-[3-(1,3-thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime;

1-[3-(Pyridin-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime;

1-[3-(Pyrimidin-4-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime;

C-{1-[3-(1-Methyl-1H-imidazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-methylamine;

C-{1-[3-(Pyridin-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-methylamine;

N-{1-[3-(1-Methyl-1H-imidazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-ylmethyl}-acetamide;

N-{1-[3-(Pyridin-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-ylmethyl}-acetamide;

N-{1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-ylmethyl}-acetamide;

N-{1-[3-(2-Methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-ylmethyl}-acetamide;

N-{1-[3-(1,3-Thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-ylmethyl}-acetamide;

1-[3-(2-Methyl-2H-[1,2,4]-triazol-3-ylmethoxymethyl)-phenyl]-5-trifluoromethyl-1H-benzoimidazole;

1-[3-(2-Ethyl-2H-[1,2,4]-triazol-3-ylmethoxymethyl)-phenyl]-5-trifluoromethyl-1H-benzoimidazole;

5-Methyl-1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole;

1-{1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-ethanone;

1-{1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-ethanone oxime;

1-{1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-ethanone O-ethyl-oxime;

1-{1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-ethanone O-methyl-oxime;

1-{1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-ethanol;

5-(1-Methoxy-ethyl)-1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole;

5-(1-Ethoxy-ethyl)-1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole;

5-Azidomethyl-1-[3-(thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole;

5-Azidomethyl-1-{3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl}-1H-benzoimidazole;

5-Azidomethyl-1-[3-(2-methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole;

C-{1-[3-(1,3-Thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-yl}-methylamine;

C-{1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-methylamine;

C-{1-[3-(2-Methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-yl}-methylamine;

1-{3-[(3,4-Difluoro-benzylamino)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid ethyl ester;

1-(3-{[(Pyridin-2-ylmethyl)-amino]-methyl}-phenyl)-1H-benzoimidazole-5-carboxylic acid ethyl ester;

1-(3-{[(Pyridin-4-ylmethyl)-amino]-methyl}-phenyl)-1H-benzoimidazole-5-carboxylic acid ethyl ester;

1-(3-{[(Pyridin-3-ylmethyl)-amino]-methyl}-phenyl)-1H-benzoimidazole-5-carboxylic acid ethyl ester;

1-{3-[(3,4-Dichloro-benzylamino)-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid ethyl ester;

(1-{3-[(3,4-Difluoro-benzylamino)-methyl]-phenyl}-1H-benzoimidazol-5-yl)-methanol;

(3,4-Difluoro-benzyl)-[3-(5-methoxymethyl-benzoimidazol-1-yl)-benzyl]-methyl-amine;

1-{3-[(3,4-Difluoro-benzylamino)-methyl]-phenyl}-1H-benzoimidazole-5-carbaldehyde;

1-{3-[(3,4-Difluoro-benzylamino)-methyl]-phenyl}-1H-benzoimidazole-5-carbaldehyde oxime;

or an N-oxide thereof, any of its isomers or any mixture of its isomers,

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of claim 1 , or an N-oxide thereof, 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.

14. The compound of claim 12 , wherein said compound is 5-(1-Ethoxy-ethyl)-1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole or a pharmaceutically acceptable salt thereof.

15. The composition according to claim 13 , wherein said compound is 5-(1-Ethoxy-ethyl)-1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole or a pharmaceutically acceptable salt thereof.