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.

1 . A compound of the formula (I), (II), (III) or (IV): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H; 
 R 2  is H, aralkyl or heterocyclyl; 
 m and n are independently an integer from 0 to 2; 
 x and b are independently an integer from 0 to 4; 
 y is an integer from 0 to 3; 
 T is an alkyl or substituted alkyl; 
 Z is an electron withdrawing group; 
 R 3 , R 4 , R 5 , R 6  and R 7  are independently selected from the group consisting of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl and arylsulfinyl, provided that:
 (1) at least one of R 3 , R 4 , R 5 , R 6  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; 
 (3) when R 3 , R 4 , R 6  and R 7  are H, R 5  is other than halo, nitro, cyano, alkyl or alkoxy; 
 (4) 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; 
 (5) when R 3 , R 7  and R 5  are H and one of R 4  and R 6  is H, the R 4  or R 6  that is not H is other than N-hydroxysulfonamidyl, perhaloalkyl or nitro; 
 (6) when R 4 , R 5  and R 6  are H and one of R 3  and R 7  is H, the R 3  or R 7  that is not H is other than nitro or alkyl; 
 (7) when R 3  and R 7  are H, R 5  is nitro and one of R 4  and R 6  is H, the R 4  or R 6  that is not H is other than halo; 
 (8) when R 4  and R 6  are nitro and R 3  and R 7  are H, R 5  is other than dialkylamino; 
 (9) when R 4  and R 6  are H and R 3  and R 7  are alkyl, R 5  is other than alkyl; and 
 (10) when R 3  and R 7  are H and R 4  and R 6  are nitro, R 5  is other than dialkylamino; 
 
 each R 8  and R 9  is independently selected from the group consisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, NH 2 , OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH 2 , NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH 2 , OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH 2 , cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, and arylsulfinyl; 
 A is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 1 , Q 2 , Q 3  and Q 4 , which are taken together with V and W to form ring A; 
 B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 5 , Q 6 , Q 7  and Q 8 , which are taken together with the V and W to form ring B; 
 V and W are independently C, CH, N or NR 10 ; 
 Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7  and Q 8  are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S, provided that either (1) when rings A and B form naphthalene, x is an integer from 1 to 3 or y is an integer from 2 to 4 or R 8  is other than Cl or (2) at least one of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7  and Q 8  is N, NR 10 , O or S; 
 C is a heteroaromatic ring containing ring moieties Q 9 , Q 10 , Q 11 , Q 12 , Q 13  and Q 14  that are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S, provided that at least one of Q 9 , Q 10 , Q 11 , Q 12 , Q 13  and Q 14  is N, NR 10 , O or S; 
 R 10  is H, alkyl, acyl or sulfonyl, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein R 2  is H. 
     
     
         3 . The compound of  claim 1 , wherein each R 8  and R 9  is independently selected from the group consisting of Cl, F, I, Br, SO 2 CH 3 , SO 2 NHOH, CF 3 , CH 3 , NO 2 , phenyl, CN, OCH 3 , OCF 3 , t-Bu, O-iPr, 4-nitrophenyloxy (OPh4-NO 2 ), propane-2-thiyl (SCH(CH 3 ) 2 ), propane-2-sulfinyl (S(O)CH(CH 3 ) 2 ), morpholino, N-methyl-piperazino, dimethylamino, piperidino, cyclohexyloxy, cyclopentylsulfanyl, phenylsulfanyl and phenylsulfinyl. 
     
     
         4 . The compound of  claim 1 , wherein the compound is of the formula (I). 
     
     
         5 . The compound of  claim 4  wherein the compound is of the formula (I) and at least one of R 3  and R 7  is other than H. 
     
     
         6 . The compound of  claim 4 , wherein the compound is of the formula (I) and at least one of R 3  and R 7  is an electron withdrawing group. 
     
     
         7 . The compound of  claim 4 , wherein the compound is of the formula (I) and R 3 , R 4 , R 5 , R 6  and R 7  are independently selected from the group consisting of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, and arylsulfinyl, provided that (1) at least one of R 3 , R 4 , R 5 , R 6  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 F; (3) when R 3 , R 4 , R 6  and R 7  are H, R 5  is other than F, Cl, Br, I, NO 2 , CN, CH 3  or OCH 3 ; (4) when one of R 3  or R 7  is Cl and the R 3  or R 7  that is not Cl is H and one of R 4  or R 6  is Cl and the R 4  or R 6  that is not Cl is H, R 5  is other than Cl; (5) when R 3 , R 7  and R 5  are H and one of R 4  and R 6  is H, the R 4  or R 6  that is not H is other than SO 2 NHOH, CF 3  or NO 2 ; (6) when R 4 , R 5  and R 6  are H and one of R 3  and R 7  is H, the R 3  or R 7  that is not H is other than NO 2  or CH 3 ; (7) when R 3  and R 7  are H, R 5  is NO 2  and one of R 4  and R 6  is H, the R 4  or R 6  that is not H is other than Cl; (8) when R 4  and R 6  are nitro and R 3  and R 7  are H, R 5  is other than a C 1 -C 5  dialkylamino; (9) when R 4  and R 6  are H and R 3  and R 7  are alkyl, R 5  is other than CH 3 ; and (10) when R 3  and R 7  are H and R 4  and R 6  are nitro, R 5  is other than a C 1 -C 5  dialkylamino. 
     
     
         8 . The compound of  claim 1 , wherein the compound is of the formula (II). 
     
     
         9 . The compound of  claim 1 , wherein the compound is of the formula (III). 
     
     
         10 . The compound of  claim 1 , wherein the compound is of the formula (IV). 
     
     
         11 . A method of modulating the in vivo nitroxyl levels in an individual in need thereof, the method comprising administering to the individual an N-hydroxysulfonamide that donates nitroxyl under physiological conditions or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A method of treating, preventing or delaying the onset or development of a disease or condition that is responsive to nitroxyl therapy, comprising administering to an individual in need thereof an N-hydroxysulfonamide that donates nitroxyl under physiological conditions or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 12  wherein the method comprises administering to the individual a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H; 
 R 2  is H; 
 m and n are independently an integer from 0 to 2; 
 x and b are independently an integer from 0 to 4; 
 y is an integer from 0 to 3; 
 T is an alkyl or substituted alkyl; 
 Z is an electron withdrawing group;
 R 3 , R 4 , R 5 , R 6  and R 7  are independently selected from the group consisting of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl and arylsulfinyl, provided that at least one of R 3 , R 4 , R 5 , R 6  and R 7  is other than H; 
 
 each R 8  and R 9  is independently a substituent; 
 A is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 1 , Q 2 , Q 3  and Q 4 , which are taken together with V and W to form ring A; 
 B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 5 , Q 6 , Q 7  and Q 8 , which are taken together with the V and W to form ring B; 
 V and W are independently C, CH, N or NR 10 ; 
 Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7  and Q 8  are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S, provided that either (1) when rings A and B form naphthalene, x is an integer from 1 to 3 or y is an integer from 2 to 4 or R 8  is other than Cl or (2) at least one of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7  and Q 8  is N, NR 10 , O or S; 
 C is a heteroaromatic ring containing ring moieties Q 9 , Q 10 , Q 11 , Q 12 , Q 13  and Q 14  that are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S, provided that at least one of Q 9 , Q 10 , Q 11 , Q 12 , Q 13  and Q 14  is N, NR 10 , O or S; 
 R 10  is H, alkyl, acyl or sulfonyl, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         14 . The method of  claim 13 , wherein each R 8  and R 9  is independently selected from the group consisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, NH 2 , OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH 2 , NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH 2 , OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH 2 , cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, and arylsulfinyl. 
     
     
         15 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         16 . The method of  claim 13 , wherein the disease or condition is a cardiovascular disease or condition. 
     
     
         17 . The method of  claim 16 , wherein the disease or condition is acute heart failure. 
     
     
         18 . The method of  claim 13 , wherein the disease or condition implicates ischemia/reperfusion injury. 
     
     
         19 . A kit comprising a compound of the  claim 1  and instructions for use in the treatment of a disease or condition that is responsive to nitroxyl therapy. 
     
     
         20 . A method of treating heart failure comprising administering to an individual in need thereof a compound selected from the group consisting of: 2-fluoro-N-hydroxybenzenesulfonamide; 2-chloro-N-hydroxybenzenesulfonamide; 2-bromo-N-hydroxybenzenesulfonamide; 2-(trifluoromethyl)-N-hydroxybenzenesulfonamide; 5-chlorathiophene-2-sulfohydroxainic acid; 2,5-dichlorothiophene-3-sulfohydroxamic acid; 4-fluoro-N-hydroxybenzenesulfonamide; 4-(trifluoromethyl)-N-hydroxybenzenesulfonamide; 4-cyano-N-hydroxybenzenesulfonamide; and 4-nitro-N-hydroxybenzenesulfonamide, or a pharmaceutically acceptable salt thereof.