N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors

Patent metadata

Field	Value
Publication number	US-10829445-B2
Application number	US-201916685534-A
Country	US
Kind code	B2
Filing date	Nov 15, 2019
Priority date	Mar 17, 2006
Publication date	Nov 10, 2020
Grant date	Nov 10, 2020

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 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.

First claim

What is claimed:

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.

Assignees

• Cardioxyl Pharmaceuticals Inc
• Univ Johns Hopkins

Inventors

• Toscano John P
• Brookfield Frederick Arthur
• Cohen Andrew D
• Courtney Stephen Martin
• Frost Lisa Marie
• Kalish Vincent Jacob

Classifications

• C07D263/58

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2 · CPC title

• C07D317/14

  with substituted hydrocarbon radicals attached to ring carbon atoms · CPC title

• C07C311/48 Primary

  having nitrogen atoms of sulfonamide groups further bound to another hetero atom · CPC title

• C07D309/12

  only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers · CPC title

• C07D333/62

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring · CPC title