N-HYDROXYLSULFONAMIDE DERIVATIVES AS NEW PHYSIOLOGICALLY USEFUL NITROXYL DONORS

摘要

The invention relates to N-hydroxylsulfonamide 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-hydroxylsulfonamide 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-hydroxylsulfonamide derivatives.

主权项

1. A compound of the formula (I), (II) or (III):wherein:
R1 is H; R2 is H, aralkyl or heterocyclyl; m and n are independently an integer from 0 to 2; x is an integer from 0 to 4 and y is an integer from 0 to 3, provided that at least one of x and y is greater than 0; b is an integer from 1-4; R3, R4, R5, R6 and R7 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, arylsulfinyl, carboxyl, carboxyl ester, acylamino and sulfonylamino, provided that at least one of R3, R4, R5, R6 and R7 is carboxyl, carboxyl ester, acylamino or sulfonylamino; each R8 and R9 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, NH2, OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH2, NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH2, OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH2, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, arylsulfinyl, carbonylamino and sulfonylamino, provided that: (1) at least one R8 is carbonylamino or sulfonylamino when the compound is of the formula (III) and (2) at least one of R8 and R9 is carbonylamino or sulfonylamino when the compound is of the formula (II); A is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q1, Q2, Q3 and Q4, which are taken together with V and W to form ring A; B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q5, Q6, Q7 and Q8, which are taken together with the V and W to form ring B; V and W are independently C, CH, N or NR10; Q1, Q2, Q3, Q4, Q5, Q6, Q7 and Q8 are independently selected from the group consisting of C, CH2, CH, N, NR10, O and S; C is a heteroaromatic ring containing ring moieties Q9, Q10, Q11, Q12, Q13 and Q14 that are independently selected from the group consisting of C, CH2, CH, N, NR10, O and S, provided that at least one of Q9, Q10, Q11, Q12, Q13 and Q14 is N, NR10, O or S, and R10 is H, alkyl, acyl or sulfonyl or a pharmaceutically acceptable salt thereof.