Pyrazolone derivatives as nitroxyl donors

Patent metadata

Field	Value
Publication number	US-9682938-B2
Application number	US-201514722141-A
Country	US
Kind code	B2
Filing date	May 26, 2015
Priority date	May 27, 2014
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

The disclosed subject matter provides pyrazolone derivative compounds, pharmaceutical compositions comprising such compounds, kits comprising such compounds, and methods of using such compounds or pharmaceutical compositions. In particular, the disclosed subject matter provides methods of using such compounds or pharmaceutical compositions for treating heart failure.

First claim

What is claimed is:

1. A compound of formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is (C 1 -C 6 )alkyl or unsubstituted phenyl;
R 2 is phenyl wherein said phenyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituent(s) independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )perhaloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 4 )haloalkoxy, (C 1 -C 4 )perhaloalkoxy, (C 1 -C 6 )alkylsulfanyl, (C 1 -C 4 )haloalkylsulfanyl, (C 1 -C 4 )perhaloalkylsulfanyl, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 3 -C 6 )cycloalkylsulfonyl, (C 1 -C 4 )haloalkylsulfinyl, (C 1 -C 4 )haloalkylsulfonyl, (C 1 -C 4 )perhaloalkylsulfinyl, (C 1 -C 4 )perhaloalkylsulfonyl, —S(O) 2 —NH 2 , N—(C 1 -C 6 )alkylaminosulfonyl, and N,N-di(C 1 -C 6 )alkylaminosulfonyl; and
R 3 is (C 1 -C 6 )alkyl or —C(═NOR 9 )R 10 wherein R 9 and R 10 are independently selected from (C 1 -C 6 )alkyl.

2. The compound of claim 1 , wherein R 1 is (C 1 -C 6 )alkyl unsubstituted or substituted with C(═O)OH.

3. The compound of claim 1 , wherein R 1 is unsubstituted phenyl.

4. The compound of claim 1 , wherein R 2 is phenyl substituted with 1, 2, or 3 substituent(s) independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 4 )perhaloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 4 )haloalkoxy, (C 1 -C 4 )perhaloalkoxy, (C 1 -C 6 )alkylsulfanyl, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 4 )haloalkylsulfinyl, (C 1 -C 4 )haloalkylsulfonyl, (C 1 -C 4 )perhaloalkylsulfinyl, (C 1 -C 4 )perhaloalkylsulfonyl, —S(O) 2 —NH 2 , or N,N-di(C 1 -C 6 )alkylaminosulfonyl.

5. The compound of claim 1 , wherein R 2 is unsubstituted phenyl.

6. The compound of claim 1 , wherein R 3 is (C 1 -C 6 )alkyl.

7. The compound of claim 1 , wherein R 3 is —C(═NOR 9 )R 10 .

8. The compound of claim 1 , wherein, R 3 is —C(═NOR 9 )R 10 wherein each of R 9 and R 10 is methyl.

9. A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable excipient.

10. The pharmaceutical composition of claim 9 , wherein the pharmaceutical composition is suitable for oral administration.

11. The pharmaceutical composition of claim 9 , wherein the pharmaceutical composition is formulated for administration in solid form.

12. The pharmaceutical composition of claim 9 , wherein the at least one pharmaceutically acceptable excipient is selected from lactose, microcrystalline cellulose, croscarmellose, or any mixture thereof.

13. A method of treating a cardiovascular disease, comprising administering an effective amount of the compound of claim 1 or a pharmaceutical composition of claim 9 to a patient in need thereof.

14. The method of claim 13 , wherein the cardiovascular disease is heart failure.

15. The method of claim 13 , wherein the cardiovascular disease is acute decompensated heart failure.

16. The method of claim 13 , wherein the compound or the pharmaceutical composition is administered orally.

17. A compound of formula (Ib)

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is (C 1 -C 6 )alkyl or unsubstituted phenyl;
R 2 is (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, or (C 1 -C 4 )perhaloalkyl;
R 3 is (5- or 6-membered)heteroaryl or phenyl wherein said heteroaryl and phenyl are unsubstituted or substituted with 1, 2, 3, 4, or 5 substituent(s) independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, phenyl, —C(═O)NR 4 R 5 , (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, and N,N-di(C 1 -C 6 )alkylaminosulfonyl; and
R 4 and R 5 are independently H or (C 1 -C 6 )alkyl.

18. The compound of claim 17 , wherein R 1 is (C 1 -C 6 )alkyl.

19. The compound of claim 17 , wherein R 2 is methyl.

20. The compound of claim 17 , wherein R 3 is phenyl substituted with halo or (C 1 -C 6 )alkylsulfonyl.

21. The compound of claim 17 , wherein:
R 1 is (C 1 -C 6 )alkyl or unsubstituted phenyl;
R 2 is (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, or (C 1 -C 4 )perhaloalkyl; and
R 3 is phenyl wherein said phenyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituent(s) independently selected from halo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylsulfinyl and (C 1 -C 6 )alkylsulfonyl.

22. The compound of claim 17 , wherein R 1 is unsubstituted phenyl.

23. The compound of claim 17 , wherein R 3 is unsubstituted phenyl.

24. A pharmaceutical composition comprising the compound of claim 17 and at least one pharmaceutically acceptable excipient.

25. A compound of formula (Ic)

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is (C 1 -C 6 )alkyl or phenyl, wherein said phenyl is unsubstituted or substituted with 1, 2, or 3 substituent(s) independently selected from halo;
R 2 is (C 1 -C 6 )alkoxy, phenylsulfanyl, phenylsulfonyl, phenylsulfinyl or (C 3 -C 6 )cycloalkyl; and
R 3 is (C 1 -C 6 )alkyl or —C(═NOR 9 )R 10 wherein R 9 and R 10 are independently selected from (C 1 -C 6 )alkyl.

26. The compound of claim 25 , wherein R 1 is (C 1 -C 6 )alkyl.

27. The compound of claim 25 , wherein R 1 is unsubstituted phenyl.

28. The compound of claim 25 , wherein R 2 is cyclopropyl.

29. The compound of claim 25 , wherein R 3 is —C(═NOR 9 )R 10 wherein each of R 9 and R 10 is methyl.

30. The compound of claim 25 , wherein:
R 1 is (C 1 -C 6 )alkyl or phenyl, wherein said phenyl is unsubstituted or substituted with 1, 2, or 3 substituent(s) independently selected from halo;
R 2 is (C 3 -C 6 )cycloalkyl; and
R 3 is —C(═NOR 9 )R 10 wherein R 9 and R 10 are independently selected from (C 1 -C 6 )alkyl.

31. The compound of claim 25 , wherein R 1 is phenyl substituted with 1, 2, or 3 substituent(s) independently selected from halo.

32. A pharmaceutical composition comprising the compound of claim 25 and at least one pharmaceutically acceptable excipient.

33. A compound selected from:
5-(4-chlorophenyl)-4-(hydroxyamino)-2,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one,
5-(2-chlorophenyl)-4-(hydroxyamino)-2,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one,
5-(2-fluorophenyl)-4-(hydroxyamino)-2,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one,
4-(hydroxyamino)-2,4-dimethyl-5-(4-(trifluoromethyl)phenyl)-2,4-dihydro-3H-pyrazol-3-one,
5-(4-fluorophenyl)-4-(hydroxyamino)-2,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one,
4-(hydroxyamino)-2,5-dimethyl-4-phenyl-2,4-dihydro-3H-pyrazol-3-one,
5-(3,5-dimethylphenyl)-4-(hydroxyamino)-2,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one,
5-(2-chlorophenyl)-4-(hydroxyamino)-2-iso-propyl-4-methyl-2,4-dihydro-3H-pyrazol-3-one,
5-(3,5-dichlorophenyl)-4-(hydroxyamino)-2,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one,
4-(hydroxyamino)-2,4-dimethyl-5-(4-(methylsulfinyl)phenyl)-2,4-dihydro-3H-pyrazol-3-one,
5-(2-chloro-4-fluorophenyl)-4-(hydroxyamino)-2,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one,
4-(hydroxyamino)-2,4-dimethyl-5-(4-(methylsulfonyl)phenyl)-2,4-dihydro-3H-pyrazol-3-one,
4-(hydroxyamino)-2,4-dimethyl-5-phenyl-2,4-dihydro-3H-pyrazol-3-one,
2-(4-br

Assignees

• Cardioxyl Pharmaceuticals Inc
• Univ Johns Hopkins

Inventors

• Kalish Vincent Jacob
• Brookfield Frederick Arthur
• Courtney Stephen Martin
• Frost Lisa Marie
• Toscano John P
• Guthrie Daryl A
• North Carl Leslie

Classifications

• A61P9/04

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title