Patent
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 compound of the formula (IV):
wherein:
R 1 is H;
R 2 is H, aralkyl or heterocyclyl;
T is alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; and
Z is an electron withdrawing group;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is H.
3. A method of treating, preventing, delaying the onset of, or delaying the development of a disease or condition that is responsive to nitroxyl therapy, comprising administering to an individual in need thereof a compound of the formula (IV):
wherein:
R 1 is H;
R 2 is H;
T is alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; and
Z is an electron withdrawing group;
or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
5. The method of claim 3 , wherein the disease or condition is a cardiovascular disease or condition.
6. The method of claim 5 , wherein the disease or condition is acute heart failure.
7. The method of claim 3 , wherein the disease or condition implicates ischemia/reperfusion injury.
8. The method of claim 5 , wherein the disease or condition is acute decompensated heart failure.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is H, benzyl or tetrahydropyran-2-yl.
10. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein T is alkyl having from 1 to 8 carbon atoms, alkyl having from 1 to 8 carbon atoms and substituted by from 1 to 5 substituents, cycloalkyl having from 3 to 8 carbon atoms, or cycloalkyl having from 3 to 8 carbon atoms and substituted by from 1 to 5 substituents.
11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein each substituent is independently selected from halo, nitro, cyano, oxo, alkoxy having from 1 to 8 carbon atoms, acyl having from 1 to 8 carbon atoms, acylamino having from 1 to 8 carbon atoms, amino, hydroxyl, carboxyl, carboxylalkyl having from 1 to 8 carbon atoms, thiol, thioalkyl having from 1 to 8 carbon atoms, and —OS(O) 2 -alkyl having from 1 to 8 carbon atoms.
12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein Z is —F, —Cl, —Br, —I, —CN, —CF 3 , —NO 2 , —SH, —C(O)H, —C(O)alkyl having from 1 to 8 carbon atoms, —C(O)Oalkyl having from 1 to 8 carbon atoms, —C(O)OH, —C(O)Cl, —S(O) 2 OH, —S(O) 2 NHOH, or —NH 3 .
13. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein T is a branched alkyl having from 3 to 6 carbon atoms.
14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein Z is —F, —Cl, —Br, —I, —CN, —CF 3 , —NO 2 , —SH, —C(O)H, —C(O)alkyl having from 1 to 8 carbon atoms, —C(O)Oalkyl having from 1 to 8 carbon atoms, —C(O)OH, —C(O)Cl, —S(O) 2 OH, —S(O) 2 NHOH, or —NH 3 .
15. The compound of claim 13 or a pharmaceutically acceptable salt thereof; wherein T is isopropyl, t-butyl or sec-butyl.
16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein Z is —F, —Cl, —Br, —I, —CN, —CF 3 , —NO 2 , —SH, —C(O)H, —C(O)alkyl having from 1 to 8 carbon atoms, —C(O)Oalkyl having from 1 to 8 carbon atoms, —C(O)OH, —C(O)Cl, —S(O) 2 OH, —S(O) 2 N 2 NHOH, or —NH 3 .
17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is —F, —Cl, —Br, —I, —CN, —CF 3 , —NO 2 , —SH, —C(O)H, —C(O)alkyl having from 1 to 8 carbon atoms, —C(O)Oalkyl having from 1 to 8 carbon atoms, —C(O)OH, —C(O)Cl, —S(O) 2 OH, —S(O) 2 NHOH, or —NH 3 .
18. The compound of claim 17 which is:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 3 , wherein for the compound of the formula (IV) or a pharmaceutically acceptable salt thereof T is a branched alkyl having from 3 to 6 carbon atoms.
20. The method of claim 19 , wherein for the compound of the formula (IV) or a pharmaceutically acceptable salt thereof Z is —F, —Cl, —Br, —I, —CN, —CF 3 , —NO 2 , —SH, —C(O)H, —C(O)alkyl having from 1 to 8 carbon atoms, —C(O)Oalkyl having from 1 to 8 carbon atoms, —C(O)OH, —C(O)Cl, —S(O) 2 OH, —S(O) 2 NHOH, or —NH 3 .