N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H;

R 2 is H;

R 3 is halo, methylsulfonyl or perfluoromethyl;

R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from H, halo, perfluoromethyl and alkylsulfonyl, provided that:

(1) one of R 3 and R 7 is other than H;

(2) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than halo; and

(3) when one of R 3 or R 7 is halo and the R 3 or R 7 that is not halo is H and one of R 4 or R 6 is halo and the R 4 or R 6 that is not halo is H, R 5 is other than halo or H.

2. The compound of claim 1 , wherein R 3 is halo.

3. The compound of claim 1 , wherein:

R 3 is alkylsulfonyl methylsulfonyl.

4. The compound of claim 1 , wherein at least three of R 4 , R 5 , R 6 and R 7 are H.

5. The compound of claim 1 , wherein R 3 is halo, methylsulfonyl or perfluoromethyl.

6. The compound of claim 1 , wherein:

R 3 is halo, methylsulfonyl or perfluoromethyl; and

at least three of R 4 , R 5 , R 6 and R 7 are H.

7. The compound of claim 1 , wherein:

R 3 is halo, methylsulfonyl or perfluoromethyl; and

R 4 , R 5 , R 6 and R 7 are H.

8. The A compound of claim 1 , wherein the compound is selected from:

2,6-Dichloro-N-hydroxy benzene sulfonamide;

2-Bromo-4-fluoro-N-hydroxy benzene sulfonamide;

2,5-Di-trifluoromethyl-N-hydroxy benzene sulfonamide;

2-Chloro-4-fluoro-N-hydroxy benzene sulfonamide;

2,3-Dichloro-N-hydroxy benzene sulfonamide;

2-Chloro-4-bromo-N-hydroxy benzene sulfonamide;

2-Iodo-N-hydroxy benzene sulfonamide;

N-Hydroxy-2-methanesulfonyl benzene sulfonamide N-Hydroxy-2-methylsulfonyl benzene sulfonamide;

2,4-Di-bromo-N-hydroxy benzene sulfonamide;

2-Chloro-4-trifluoromethyl-N-hydroxy benzene sulfonamide;

2,4-Di-fluoro-N-hydroxy benzene sulfonamide;

2-Fluoro-N-hydroxy benzene sulfonamide;

2-Bromo-N-hydroxy benzene sulfonamide;

2-(Trifluoromethyl)-N-hydroxy benzenesulfonamide 2-(Trifluoromethyl)-N-hydroxy benzene sulfonamide;

and pharmaceutically acceptable salts thereof.

9. The compound of claim 1 , wherein the compound is 2-Iodo-N-hydroxy benzene sulfonamide.

10. The compound of claim 1 , wherein the compound is N-Hydroxy-2-methanesulfonyl benzene sulfonamide N-Hydroxy-2-methylsulfonyl benzene sulfonamide.

11. The compound of claim 1 , wherein the compound is 2-Fluoro-N-hydroxybenzenesulfonamide 2-Fluoro-N-hydroxy benzene sulfonamide.

12. The compound of claim 1 , wherein the compound is 2-Chloro-N-hydroxybenzenesulfonamide 2-Chloro-N-hydroxy benzene sulfonamide.

13. The compound of claim 1 , wherein the compound is 2-Bromo-N-hydroxybenzenesulfonamide 2-Bromo-N-hydroxy benzene sulfonamide.

14. The compound of claim 1 , wherein the compound is 2-(Trifluoromethyl)-N-hydroxybenzenesulfonamide 2-(Trifluoromethyl)-N-hydroxy benzene sulfonamide.

15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

16. The A pharmaceutical composition of claim 15 comprising a compound and a pharmaceutically acceptable carrier, wherein the compound is selected from:

2,6-Dichloro-N-hydroxy benzene sulfonamide;

2-Bromo-4-fluoro-N-hydroxy benzene sulfonamide;

2,5-Di-trifluoromethyl-N-hydroxy benzene sulfonamide;

2-Chloro-4-fluoro-N-hydroxy benzene sulfonamide;

2,3-Dichloro-N-hydroxy benzene sulfonamide;

2-Chloro-4-bromo-N-hydroxy benzene sulfonamide;

2-Iodo-N-hydroxy benzene sulfonamide;

N-Hydroxy-2-methanesulfonyl benzene sulfonamide N-Hydroxy-2-methylsulfonyl benzene sulfonamide;

2,4-Di-bromo-N-hydroxy benzene sulfonamide;

2-Chloro-4-trifluoromethyl-N-hydroxy benzene sulfonamide;

2,4-Di-fluoro-N-hydroxy benzene sulfonamide;

2-Fluoro-N-hydroxy benzene sulfonamide;

2-Bromo-N-hydroxy benzene sulfonamide;

2-(Trifluoromethyl)-N-hydroxy benzenesulfonamide 2-(Trifluoromethyl)-N-hydroxy benzene sulfonamide;

and pharmaceutically acceptable salts thereof.

17. The pharmaceutical composition of claim 15 , wherein the compound is 2-Iodo-N-hydroxy benzene sulfonamide.

18. The pharmaceutical composition of claim 15 , wherein the compound is N-Hydroxy-2-methanesulfonyl benzene sulfonamide N-Hydroxy-2-methylsulfonyl benzene sulfonamide.

19. The pharmaceutical composition of claim 15 , wherein the compound is 2-Fluoro-N-hydroxybenzenesulfonamide 2-Fluoro-N-hydroxy benzene sulfonamide.

20. The pharmaceutical composition of claim 15 , wherein the compound is 2-Chloro-N-hydroxybenzenesulfonamide 2-Chloro-N-hydroxy benzene sulfonamide.

21. The pharmaceutical composition of claim 15 , wherein the compound is 2-Bromo-N-hydroxybenzenesulfonamide 2-Bromo-N-hydroxy benzene sulfonamide.

22. The pharmaceutical composition of claim 15 , wherein the compound is 2-(Trifluoromethyl)-N-hydroxybenzenesulfonamide 2-(Trifluoromethyl)-N-hydroxy benzene sulfonamide.

23. The compound of claim 1 , wherein R 3 is perfluoromethyl.

24. A compound of formula (Va)-(Vj):

or a pharmaceutically acceptable salt thereof, wherein:

the R 2 group is H, aralkyl, or heterocyclyl;

the R 8 group is halo, nitro, alkyl, or cyano; and

halo is F, Cl, Br, or I.

25. The compound of claim 24, wherein the R 2 group is H, benzyl, or tetrahydropyran-2-yl.

26. The compound of claim 24, wherein the R 2 group is H.

27. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein the R 8 alkyl group is methyl.

28. The compound of claim 25, wherein the R 8 alkyl group is methyl.

29. The compound of claim 26, wherein the R 8 alkyl group is methyl.

30. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein the R 8 group is Cl, Br, nitro, methyl, or cyano.

31. The compound of claim 25, wherein the R 8 group is Cl, Br, nitro, methyl, or cyano.

32. The compound of claim 26, wherein the R 8 group is Cl, Br, nitro, methyl, or cyano.

33. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Vf):

34. The compound of claim 31, wherein the compound is a compound of formula (Vf):

35. The compound of claim 32, which is:

36. The compound of claim 32, which is:

37. A compound of formula (Vf):

wherein:

the R 2 group is H; and

the R 8 group is Cl, Br, nitro, methyl, or cyano.

38. A pharmaceutical composition comprising:

the compound of claim 24 or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable carrier.

39. A pharmaceutical composition comprising:

the compound of claim 32; and

a pharmaceutically acceptable carier.

40. A pharmaceutical composition comprising:

the compound of claim 37; and

a pharmaceutically acceptable carrier.

41. A method for treating, preventing, delaying the onset of, or delaying the development of heart failure, comprising administering to an individual in need thereof an effective amount of a compound of formula (Va)-(Vj):

or a pharmaceutically acceptable salt thereof, wherein:

the R 2 group is H, aralkyl, or heterocyclyl;

the R 8 group is halo, nitro, alkyl, or cyano; and

halo is F, Cl, Br, or I.

42. The method of claim 41, wherein the heart failure is acute decompensated heart failure.

43. A method for treating, preventing, delaying the onset of, or delaying the development of heart failure, comprising administering to an individual in need thereof an effective amount of the compound of claim 32.

44. The method of claim 43, wherein the heart failure is acute decompensated heart failure.

45. A method for treating, preventing, delaying the onset of, or delaying the development of heart failure, comprising administering to an individual in need thereof an effective amount of a compound of formula (Vf):

wherein:

the R 2 group is H; and

the R 8 group is Cl, Br, nitro, methyl, or cyano.

46. The method of claim 45, wherein the heart failure is acute decompensated heart failure.