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 B2:
comprising (a) combining a compound of formula B1 with a compound of formula A1 in the presence of potassium carbonate, wherein the compound of formula B1 is
and the compound of formula A1 is
and wherein
R is phenyl substituted by R 3 , R 4 , R 5 , R 6 , and R 7 ; 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 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.
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 , OCF3, t-Bu, O-iPr, 4-nitrophenyloxy, propane-2-thiyl, propane-2-sulfinyl, morpholino, N-methyl-peperazino, dimethylamino, peiperidino, 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 , further comprising (b) combining the product of step (a) with a boronic acid and a palladium catalyst, wherein, in the product of step (a), one of R 3 , R 4 , R 5 , R 6 , and R 7 is halo.
6. The method of claim 5 , wherein the boronic acid is an aryl boronic acid.
7. The method of claim 6 , wherein the aryl boronic acid is benzene boronic acid.
8. The method of claim 5 , wherein the palladium catalyst is [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).