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 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.
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.