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 the formula (III)
or a pharmaceutically acceptable salt thereof, wherein
R 1 is H;
R 2 is H;
n is 0;
b is an integer from 1 to 4;
each R 8 is independently selected from halo, CF 3 , NO 2 , CN, phenyl, (C 1 -C 8 )alkyl, SO 2 NHOH, SO 2 CH 3 , SO 2 phenyl, C(O)O(C 1 -C 4 )alkyl, and C(O)morpholino; and
Q 9 , Q 11 , Q 12 , Q 13 and Q 14 are defined such that ring C is furan or thiophene;
the method comprising reacting a compound of formula A1 with hydroxylamine hydrochloride, wherein the compound of formula A1 has the structure:
and R is furan or thiophene and is substituted with 1 to 4 R 8 .
2. The method of claim 1 , wherein, in the compound of formula (III), each R 8 is independently selected from F, Br, Cl, CF 3 , phenyl, methyl, SO 2 NHOH, and C(O)O(C 1 -C 4 )alkyl.
3. The method of claim 2 , wherein, in the compound of formula (III), R 8 is methyl and ring C is furan.
4. A method of preparing a compound of the formula (III)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H;
R 2 is H;
n is 0;
b is 1;
R 8 is Cl, Br, nitro, methyl or cyano; and
Q 9 , Q 11 , Q 12 , Q 13 and Q 14 are defined such that ring C is furan or thiophene;
the method comprising reacting a compound of formula A1 with hydroxylamine hydrochloride, wherein the compound of formula A1 has the structure:
and R is furan or thiophene and is substituted with 1 R 8 .
5. The method of claim 4 , wherein, in the compound of formula (III), R 8 is methyl and ring C is furan.
6. A method of preparing a compound which is:
or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound of formula A1 with hydroxylamine hydrochloride, wherein the compound of formula A1 has the structure:
and is 3,5-dimethylisoxazole-4-sulfonyl chloride.
7. A method of preparing a compound which is:
or a pharmaceutically acceptable salt thereof,
the method comprising reacting a compound of formula A1 with hydroxylamine hydrochloride, wherein the compound of formula A1 has the structure:
and is 1-methyl-1H-pyrazole-3-sulfonyl chloride.
8. A method of preparing a compound which is
or a pharmaceutically acceptable salt thereof,
the method comprising reacting a compound of formula A1 with hydroxylamine hydrochloride, wherein the compound of formula A1 has the structure:
and is 4-bromothiophene-3-sulfonyl chloride, 3-bromothiophene-2-sulfonyl chloride, 4-bromo-2,5-dichlorothiophene-3-sulfonyl chloride or 4-phenyl-5-(trifluoromethyl)thiophene-3-sulfonyl chloride.