N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors
View Patent ↗The invention relates to N-hydroxysulfonamide derivatives that donate nitroxyl (HNO) under physiological conditions and are useful in treating and/or preventing the onset and/or development of diseases or conditions that are responsive to nitroxyl therapy, including heart failure and ischemia/reperfusion injury. Novel N-hydroxysulfonamide derivatives release NHO at a controlled rate under physiological conditions, and the rate of HNO release is modulated by varying the nature and location of functional groups on the N-hydroxysulfonamide derivatives.
1. A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H;
R 2 is H;
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.
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 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;
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;
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.
11. The compound of claim 1 , wherein the compound is 2-Fluoro-N-hydroxybenzenesulfonamide.
12. The compound of claim 1 , wherein the compound is 2-Chloro-N-hydroxybenzenesulfonamide.
13. The compound of claim 1 , wherein the compound is 2-Bromo-N-hydroxybenzenesulfonamide.
14. The compound of claim 1 , wherein the compound is 2-(Trifluoromethyl)-N-hydroxybenzenesulfonamide.
15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
16. The pharmaceutical composition of claim 15 , 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;
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;
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.
19. The pharmaceutical composition of claim 15 , wherein the compound is 2-Fluoro-N-hydroxybenzenesulfonamide.
20. The pharmaceutical composition of claim 15 , wherein the compound is 2-Chloro-N-hydroxybenzenesulfonamide.
21. The pharmaceutical composition of claim 15 , wherein the compound is 2-Bromo-N-hydroxybenzenesulfonamide.
22. The pharmaceutical composition of claim 15 , wherein the compound is 2-(Trifluoromethyl)-N-hydroxybenzenesulfonamide.
23. The compound of claim 1 , wherein R 3 is perfluoromethyl.