Benzimidazoles that are useful in treating male sexual dysfunction

1. A method of treating male erectile dysfunction in a male mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of a compound of formula (I)

a pharmaceutically acceptable salt, ester, or amide thereof, wherein

A is a selected from the group consisting of

X is selected from the group consisting of NH, O and S;

L is selected from the group consisting of CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 and CH 2 CH 2 CH 2 CH 2 ;

R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, —NZ 1 Z 2 , (NZ 1 Z 2 )carbonyl and (NZ 1 Z 2 )sulfonyl wherein Z 1 and Z 2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl and formyl;

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, —NZ 1 Z 2 and (NZ 1 Z 2 )carbonyl;

R E is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl and (NZ 1 Z 2 )carbonyl;

R F is selected from the group consisting of hydrogen and alkyl;

Z is selected from the group consisting of N, C and CH; and

--- is a bond when Z is C and --- is absent when Z is N or CH.

2. The method according to claim 1 wherein

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

Z is N;

--- is absent; and

A is

3. The method according to claim 1 wherein

L is CH 2 ;

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

R F is hydrogen;

Z is N;

--- is absent;

A is

 and

R 2 , R 3 and R 4 are each hydrogen.

4. The method according to claim 3 wherein said compound of formula (I) is selected from the group consisting of

2-[(4-phenylpiperazin-1-yl)methyl]-1H-benzimidazole;

2-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]benzonitrile;

2-{[4-(2-chlorophenyl)piperazin-1-yl]methyl}-1H-benzimidazole;

2-{[4-(2-fluorophenyl)piperazin-1-yl]methyl}-1H-benzimidazole;

2-{[4-(2-nitrophenyl)piperazin-1-yl]methyl}-1H-benzimidazole;

2-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-1H-benzimidazole;

2-({4-[2-(methylthio)phenyl]piperazin-1-yl}methyl)-1H-benzimidazole;

2-{[4-(2-ethoxyphenyl)piperazin-1-yl]methyl}-1H-benzimidazole; and

2-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]phenol.

5. The method according to claim 1 wherein

L is CH 2 ;

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

R F is hydrogen;

Z is N;

--- is absent;

A is

 and

R 1 , R 2 , R 4 and R 5 are each hydrogen.

6. The method according to claim 5 wherein said compound of formula (I) is 4-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]phenol.

7. The method according to claim 1 wherein

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

Z is N;

--- is absent; and

A is

8. The method according to claim 1 wherein

L is CH 2 ;

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

R F is hydrogen;

Z is N;

--- is absent,

A is

R 2 , R 3 and R 4 are each hydrogen.

9. The method according to claim 8 wherein said compound of formula (I) is selected from the group consisting of

2-{[4-(3-methylpyridin-2-yl)piperazin-1-yl]methyl}-1H-benzimidazole;

2-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]nicotinonitrile;

5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole;

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole;

2-{[4-(6-methylpyridin-2-yl)piperazin-1-yl]methyl}-1H-benzimidazole;

N-{2-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]pyridin-3-yl}methanesulfonamide; and

2-{[4-(3-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-benzimidazole.

10. The method according to claim 8 wherein said compound of formula (I) is 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole.

11. The method according to claim 1 wherein

L is CH 2 ;

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

R F is alkyl;

Z is N;

--- is absent;

A is

R 2 , R 3 and R 4 are each hydrogen.

12. The method according to claim 11 wherein said compound of formula (I) is selected from the group consisting of

2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole;

2-{[(2S)-2-methyl-4-pyridin-2-ylpiperazin-1-yl]methyl}-1H-benzimidazole; and

2-{[(2R)-2-methyl-4-pyridin-2-ylpiperazin-1-yl]methyl}-1H-benzimidazole.

13. The method according to claim 1 wherein

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

Z is N;

--- is absent;

A is

R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen and hydroxy.

14. The method according to claim 1 wherein

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

R F is hydrogen;

L is CH 2 ;

Z is N;

--- is absent;

A is

R 1 , R 2 and R 4 are each hydrogen; and

R 3 is hydroxy.

15. The method according to claim 14 wherein said compound of formula (I) is 6-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]pyridin-3-ol.

16. The method according to claim 1 wherein

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

Z is N;

--- is absent; and

A is

17. The method according to claim 1 wherein

L is CH 2 ;

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

R F is hydrogen;

Z i s N;

--- is absent;

A is

R 2 , R 3 and R 4 are each hydrogen.

18. The method according to claim 17 wherein said compound of formula (I) is 2-[(4-pyrimidin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole.

19. The method according to claim 1 wherein

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

Z is N;

--- is absent; and

A is

20. The method according to claim 1 wherein

L is CH 2 ;

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

R F is hydrogen;

Z is N;

--- is absent;

A is

R 2 and R 3 are each hydrogen; and

X is S.

21. The method according to claim 20 wherein said compound of formula (I) is 2-{[4-(1,3-thiazol-2-yl)piperazin-1-yl]methyl}-1H-benzimidazole.

22. The method according to claim 1 wherein

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is selected from the group consisting of alkoxycarbonyl, alkylcarbonyl, alkyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl and (NZ 1 Z 2 )carbonyl;

Z is N;

--- is absent; and

A is

23. The method according to claim 1 wherein

L is CH 2 ;

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is selected from the group consisting of alkoxycarbonyl, alkylcarbonyl, (NZ 1 Z 2 )carbonyl and heterocyclecarbonyl wherein the heterocycle portion of said heterocyclecarbonyl is pyrrolidinyl;

R F is hydrogen;

Z is N;

--- is absent;

A is

R 2 , R 3 and R 4 are each hydrogen.

24. The method according to claim 23 wherein said compound of formula (I) is selected from the group consisting of

isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole-1-carboxylate;

2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1-(pyrrolidin-1-ylcarbonyl)-1H-benzimidazole; and

N,N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole-1-carboxamide.

25. The method according to claim 1 wherein

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

Z is CH;

--- is absent; and

A is

26. The method according to claim 1 wherein

L is CH 2 ;

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

R F is hydrogen;

Z is CH;

--- is absent;

A is

R 2 , R 3 and R 4 are each hydrogen.

27. The method according to claim 26 wherein said compound of formula (I) is 2-{[4-(2-methoxyphenyl)piperidin-1-yl]methyl}-1H-benzimidazole.

28. The method according to claim 1 wherein

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

Z is CH;

--- is absent; and

A is

29. The method according to claim 1 wherein

L is CH 2 ;

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

R F is hydrogen;

Z is CH;

--- is absent;

A is

R 2 , R 3 and R 4 are each hydrogen.

30. The method according to claim 29 wherein said compound of formula (I) is 2-[(4-pyridin-2-ylpiperidin-1-yl)methyl]-1H-benzimidazole.

31. The method according to claim 1 wherein

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

Z is C;

--- is a bond; and

A is

32. The method according to claim 1 wherein

L is CH 2 ;

R A , R B , R C and R D are each independently selected from the group consisting of hydrogen and halogen;

R E is hydrogen;

R F is hydrogen;

Z is C;

--- is a bond;

A is

R 2 , R 3 and R 4 are each hydrogen.

33. The method according to claim 32 wherein said compound of formula (I) is 2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)methyl]-1H-benzimidazole.

34. A method of treating male erectile dysfunction in a male mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, or amide thereof according claim 1 , in combination with a pharmaceutically acceptable carrier.

35. The method according to claim 34 wherein said compound of formula (I) is selected from the group consisting of

2-{[4-(3-methylpyridin-2-yl)piperazin-1-yl]methyl}-1H-benzimidazole;

2-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]nicotinonitrile;

5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole;

5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole;

2-{[4-(1,3-thiazol-2-yl)piperazin-1-yl]methyl}-1H-benzimidazole;

isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole-1-carboxylate;

2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1-(pyrrolidin-1-ylcarbonyl)-1H-benzimidazole;

N,N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole-1-carboxamide;

2-[(4-phenylpiperazin-1-yl)methyl]-1H-benzimidazole;

2-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]benzonitrile;

2-{[4-(2-chlorophenyl)piperazin-1-yl]methyl}-1H-benzimidazole;

2-{[4-(2-fluorophenyl)piperazin-1-yl]methyl}-1H-benzimidazole;

2-{[4-(2-nitrophenyl)piperazin-1-yl]methyl}-1H-benzimidazole;

2-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-1H-benzimidazole;

4-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]phenol;

2-({4-[2-(methylthio)phenyl]piperazin-1-yl}methyl)-1H-benzimidazole;

2-{[4-(2-ethoxyphenyl)piperazin-1-yl]methyl}-1H-benzimidazole;

2-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]phenol;

2-{[4-(2-methoxyphenyl)piperidin-1-yl]methyl}-1H-benzimidazole;

2-[(4-pyridin-2-ylpiperidin-1-yl)methyl]-1H-benzimidazole;

2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)methyl]-1H-benzimidazole;

2-{[4-(6-methylpyridin-2-yl)piperazin-1-yl]methyl}-1H-benzimidazole;

2-[(2-methyl-4-pyridin-2-yl piperazin-1-yl)methyl]-1H-benzimidazole;

2-{[(2S)-2-methyl-4-pyridin-2-ylpiperazin-1-yl]methyl}-1H-benzimidazole;

2-{[(2R)-2-methyl-4-pyridin-2-ylpiperazin-1-yl]methyl}-1H-benzimidazole;

N-{2-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]pyridin-3-yl}methanesulfonamide; and

2-{[4-(3-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-benzimidazole.

36. The method according to claim 34 wherein said compound of formula (I) is 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole.

37. The method according to claim 34 wherein said compound of formula (I) is 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole bis((L)tartrate).

38. The method according to claim 34 wherein said compound of formula (I) is 2-[(4-pyrimidin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole.

39. The method according to claim 34 wherein said compound of formula (I) is 6-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]pyridin-3-ol.