N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors

Patent metadata

Field	Value
Publication number	US-9969684-B2
Application number	US-201715640342-A
Country	US
Kind code	B2
Filing date	Jun 30, 2017
Priority date	Mar 17, 2006
Publication date	May 15, 2018
Grant date	May 15, 2018

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 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-hydroxysulfonamide derivatives.

First claim

What is claimed:

1. A method for modulating in vivo nitroxyl levels, treating a cardiovascular disease or condition, or treating heart failure, comprising administering to an individual in need thereof
(a) an effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H;
R 2 is H;
R 3 is halo, methylsulfonyl or perfluoromethyl;
R 4 , R 5 , R 6 and R 7 are H; and
halo is F, Cl, Br or I; and
(b) an effective amount of at least one other positive inotropic agent.

2. The method of claim 1 , wherein the other positive inotropic agent is selected from a beta-adrenergic receptor agonist, an inhibitor of phosphodiesterase activity, a calcium-sensitizer, and any combination thereof and the heart failure is acute decompensated heart failure.

3. The method of claim 1 , wherein R 3 is Cl, Br or I.

4. The method of claim 3 , wherein the other positive inotropic agent is selected from a beta-adrenergic receptor agonist, an inhibitor of phosphodiesterase activity, a calcium-sensitizer, and any combination thereof and the heart failure is acute decompensated heart failure.

5. The method of claim 1 , wherein R 3 is methylsulfonyl.

6. The method of claim 5 , wherein the other positive inotropic agent is selected from a beta-adrenergic receptor agonist, an inhibitor of phosphodiesterase activity, a calcium-sensitizer, and any combination thereof and the heart failure is acute decompensated heart failure.

7. The method of claim 1 , wherein R 3 is perfluoromethyl.

8. The method of claim 7 , wherein the other positive inotropic agent is selected from a beta-adrenergic receptor agonist, an inhibitor of phosphodiesterase activity, a calcium-sensitizer, and any combination thereof and the heart failure is acute decompensated heart failure.

9. A method for treating, preventing, delaying the onset of, or delaying the development of heart failure, comprising administering to an individual in need thereof
(a) an effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H;
R 2 is H;
R 3 is halo, methylsulfonyl or perfluoromethyl;
R 4 , R 5 , R 6 and R 7 are H; and
halo is F, Cl, Br or I; and
(b) an effective amount of at least one other positive inotropic agent.

10. The method of claim 9 , wherein the other positive inotropic agent is selected from a beta-adrenergic receptor agonist, an inhibitor of phosphodiesterase activity, a calcium-sensitizer, and any combination thereof and the heart failure is acute decompensated heart failure.

11. The method of claim 9 , wherein R 3 is Cl, Br or I.

12. The method of claim 11 , wherein the other positive inotropic agent is selected from a beta-adrenergic receptor agonist, an inhibitor of phosphodiesterase activity, a calcium-sensitizer, and any combination thereof and the heart failure is acute decompensated heart failure.

13. The method of claim 9 , wherein R 3 is methylsulfonyl.

14. The method of claim 13 , wherein the other positive inotropic agent is selected from a beta-adrenergic receptor agonist, an inhibitor of phosphodiesterase activity, a calcium-sensitizer, and any combination thereof and the heart failure is acute decompensated heart failure.

15. The method of claim 9 , wherein R 3 is perfluoromethyl.

16. The method of claim 15 , wherein the other positive inotropic agent is selected from a beta-adrenergic receptor agonist, an inhibitor of phosphodiesterase activity, a calcium-sensitizer, and any combination thereof and the heart failure is acute decompensated heart failure.

17. The method of claim 1 , wherein the other positive inotropic agent is selected from dopamine, dopexamine, dobutamine, terbutaline, isoproterenol, and any combination thereof.

18. The method of claim 9 , wherein the other positive inotropic agent is selected from dopamine, dopexamine, dobutamine, terbutaline, isoproterenol, and any combination thereof.

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title