N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors

Patent metadata

Field	Value
Publication number	US-9617208-B2
Application number	US-201514815917-A
Country	US
Kind code	B2
Filing date	Jul 31, 2015
Priority date	Sep 26, 2007
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

The invention relates to N-hydroxylsulfonamide 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-hydroxylsulfonamide 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-hydroxylsulfonamide derivatives.

First claim

The invention claimed is:

1. A compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein
R 1 is H;
R 2 is H;
n is 0;
Q 9 , Q 10 , Q 11 , Q 12 , Q 13 and Q 14 are defined such that ring C is thiophene or furan;
b is 1;
R 8 is a carbonylamino having the formula —CONR-alkyl, wherein R is hydrogen or alkyl, or —CONR 2 , wherein each R is taken together with the nitrogen to which they are attached to form a 6-membered heterocyclic or substituted heterocyclic ring.

2. The compound of claim 1 , wherein ring C is thiophene.

3. The compound of claim 1 , wherein ring C is furan.

4. The compound of claim 1 , wherein R 8 is a carbonylamino having the formula —CONR 2 .

5. The compound of claim 1 , wherein each R is taken together with the nitrogen to which they are attached to form a 6-membered heterocyclic ring.

6. The compound of claim 1 , wherein the 6-membered heterocyclic ring is a morpholine ring.

7. The compound of claim 1 , wherein R 8 is a carbonylamino having the formula —CONR-alkyl.

8. The compound of claim 7 , wherein the alkyl is a lower alkyl.

9. The compound of claim 7 or 8 , wherein R is hydrogen.

10. The compound of claim 7 or 8 , wherein R is alkyl.

11. The compound of claim 10 , wherein R is a lower alkyl.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I):

wherein:
R 1 is H;
R 2 is H;
R 3 is H or sulfonylamino;
R 4 is H or sulfonylamino;
R 5 is H;
R 6 is H; and
R 7 is H, provided that one of R 3 or R 4 is sulfonylamino.

13. The compound of claim 12 , wherein R 3 is sulfonylamino.

14. The compound of claim 12 , wherein R 4 is sulfonylamino.

15. The compound of claim 12 , wherein R 3 is —SO 2 NR 2 , where the two R groups are taken together and with the nitrogen atom to which they are attached form a heterocyclic or substituted heterocyclic ring.

16. The compound of claim 15 , wherein the heterocyclic ring is a morpholino ring.

17. The compound of claim 12 , wherein R 4 is —SO 2 NR-alkyl, where R is hydrogen or alkyl.

18. The compound of claim 17 , wherein R is hydrogen.

19. The compound of claim 17 , wherein R is alkyl.

20. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I):

wherein:
R 1 is H;
R 2 is H;
R 3 is halo;
R 4 is H;
R 5 is H;
R 6 is carboxyl or carbonylamino; and
R 7 is H.

21. The compound of claim 20 , wherein R 6 is carboxyl.

22. The compound of claim 20 , wherein R 3 is chloro.

23. The compound of claim 21 , wherein R 3 is bromo.

24. A compound of formula II:

wherein:
R 1 is H;
R 2 is H, aralkyl or heterocyclyl;
m and n are independently an integer from 0 to 2;
x is an integer from 0 to 4 and y is an integer from 0 to 3, provided that at least one of x and y is greater than 0;
b is an integer from 1-4;
each R 8 and R 9 is independently selected from the group consisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, NH 2 , OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH 2 , NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH 2 , OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH 2 , cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, arylsulfinyl, carbonylamino and sulfonylamino, provided that: at least one of R 8 and R 9 is carbonylamino or sulfonylamino;
A is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 1 , Q 2 , Q 3 and Q 4 , which are taken together with V and W to form ring A;
B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 5 , Q 6 , Q 7 and Q 8 , which are taken together with the V and W to form ring B;
V and W are independently C, CH, N or NR 10 ;
Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 and Q 8 are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S; and
R 10 is H, alkyl, acyl or sulfonyl.

25. The compound of claim 24 , wherein R 2 is H.

26. The compound of claim 24 , wherein x and y are both 1.

27. The compound of claim 12 , wherein the compound is

28. A pharmaceutical composition comprising a compound of claim 12 and a pharmaceutically acceptable carrier.

29. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

30. A pharmaceutical composition comprising a compound of claim 20 and a pharmaceutically acceptable carrier.

31. A pharmaceutical composition comprising a compound of claim 24 and a pharmaceutically acceptable carrier.

Assignees

• Univ Johns Hopkins
• Cardioxyl Pharmaceuticals Inc

Inventors

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

Classifications

• A61P43/00

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

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title