N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors
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 HNO 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 method of preparing a compound of formula C2:
the method comprising (a) combining a compound of formula C1 with a compound of formula A1,
wherein:
the compound of formula C1 is:
and
the compound of formula A1 is:
and
wherein R is
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. The method of claim 1 , wherein R 3 , R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of H, Cl, F, I, Br, SO 2 CH 3 , SO 2 NHOH, CF 3 , NO 2 , phenyl, CN, OCH 3 , OCF 3 , t-Bu, O-iPr, 4-nitrophenyloxy, propane-2-thiyl, propane-2-sulfinyl, morpholino, N-methyl-piperazino, dimethylamino, piperidino, cyclohexyloxy, cyclopentylsulfanyl, phenylsulfanyl and phenylsulfinyl.
3. The method of claim 1 , wherein one of R 3 , R 4 , R 5 , R 6 , and R 7 is halo.
4. The method of claim 3 , wherein one of R 3 , R 4 , R 5 , R 6 , and R 7 is bromo.
5. The method of claim 1 , wherein step (a) comprises the substep of combining a base with the compound of formula C1.
6. The method of claim 5 , wherein the base is potassium carbonate.
7. The method of claim 1 , wherein the compound of formula C2 is:
8. A method of preparing a compound of formula A2:
the method comprising:
(a) deprotecting the compound of formula C2 to form the compound of formula A2;
wherein:
the compound of formula C2 is:
and
and wherein, in the compounds of formulae A2 and C2:
R is:
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.
9. The method of claim 8 , wherein R 3 , R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of H, Cl, F, I, Br, SO 2 CH 3 , SO 2 NHOH, CF 3 , NO 2 , phenyl, CN, OCH 3 , OCF 3 , t-Bu, O-iPr, 4-nitrophenyloxy, propane-2-thiyl, propane-2-sulfinyl, morpholino, N-methyl-piperazino, dimethylamino, piperidino, cyclohexyloxy, cyclopentylsulfanyl, phenylsulfanyl and phenylsulfinyl.
10. The method of claim 8 , wherein one of R 3 , R 4 , R 5 , R 6 , and R 7 is halo.
11. The method of claim 10 , wherein one of R 3 , R 4 , R 5 , R 6 , and R 7 is bromo.
12. A method of preparing a compound of the formula A2:
the method comprising:
(a) combining a compound of formula C1 with a compound of formula A1 to form a compound of formula C2; and
(b) deprotecting the compound of formula C2 to form the compound of formula A2;
wherein:
the compound of formula C1 is:
the compound of formula A1 is:
the compound of formula C2 is:
and
and wherein, in the compounds of formulae A1, A2 and C2:
R is:
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′ is other than H.
13. The method of claim 12 , wherein R 3 , R 4 , R 5 , R 6 , and Ware independently selected from the group consisting of H, Cl, F, I, Br, SO 2 CH 3 , SO 2 NHOH, CF 3 , NO 2 , phenyl, CN, OCH 3 , OCF 3 , t-Bu, O-iPr, 4-nitrophenyloxy, propane-2-thiyl, propane-2-sulfinyl, morpholino, N-methyl-piperazino, dimethylamino, piperidino, cyclohexyloxy, cyclopentylsulfanyl, phenylsulfanyl and phenylsulfinyl.
14. The method of claim 12 , wherein one of R 3 , R 4 , R 5 , R 6 , and R 7 is halo.
15. The method of claim 14 , wherein one of R 3 , R 4 , R 5 , R 6 , and R 7 is bromo.