N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors

Patent metadata

Field	Value
Publication number	US-9487498-B2
Application number	US-201514857308-A
Country	US
Kind code	B2
Filing date	Sep 17, 2015
Priority date	Mar 17, 2006
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

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

The invention claimed is:

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 .

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

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title