N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors

Abstract

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.

The invention claimed is: 
     
       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 sulfonamideN-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 benzenesulfonamide2-(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 sulfonamideN-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 benzenesulfonamide2-(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.