O-substituted hydroxamic acids

Patent metadata

Field	Value
Publication number	US-10913728-B2
Application number	US-201716321378-A
Country	US
Kind code	B2
Filing date	Jul 27, 2017
Priority date	Jul 28, 2016
Publication date	Feb 9, 2021
Grant date	Feb 9, 2021

Abstract

O-substituted hydroxamic acids with carbon-based leaving groups as HNO donors are disclosed. Pharmaceutical compositions and kits comprising such compounds, and methods of using such compounds or pharmaceutical compositions also are disclosed.

First claim

The invention claimed is:

1. A compound of formula (I), formula (II) or formula (III):

or a pharmaceutically acceptable salt thereof, wherein:
R and R 1 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )perhaloalkyl, (C 6 -C 10 )aryl, (C 1 -C 6 )heteroalkyl, (C 5 -C 7 )heterocycloalkyl, (5- or 6-membered)heteroaryl, phenylsulfanyl, phenylsulfonyl, phenylsulfinyl and (C 3 -C 6 )cycloalkyl;
R 2 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, —C(═O)R 4 , —C(═S)R 4 , C(═NR 4 )R 5 , —C(═NOR 4 )R 5 , (5- or 6-membered)heteroaryl and (C 6 -C 10 )aryl;
R 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, —NR 6 R 7 , and —OR 8 ; and
R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, phenyl and benzyl;
wherein said alkyl, aryl, phenyl, benzyl, heteroalkyl, heterocycloalkyl and heteroaryl are unsubstituted or substituted with 1, 2, 3, 4 or 5 substituent(s) 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(═O)OH, —C(═O)O(C 1 -C 6 )alkyl, —C(═O)NR 4 R 5 , —C(═O)—(C 5 -C 7 )heterocycloalkyl, (C 5 -C 7 )heterocycloalkyl, (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 , —S(O) 2 —NR 6 R 7 , —S(O) 2 -phenyl, —S(O) 2 —(C 5 -C 7 )heterocycloalkyl, —S(═O)(═NR 8 )(C 1 -C 6 )alkyl, —NR 4 R 5 , N—(C 1 -C 6 )alkylaminosulfonyl, and N,N-di(C 1 -C 6 )alkylaminosulfonyl.

2. The compound of claim 1 , wherein R is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl and (5- or 6-membered)heteroaryl, wherein said alkyl, heteroaryl and aryl are unsubstituted or substituted with 1, 2 or 3 substituent(s).

3. The compound of claim 1 , wherein R 1 is selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 4 )perhaloalkyl, (C 1 -C 6 )alkoxy, (C 6 -C 10 )aryl, (5- or 6-membered)heteroaryl, phenylsulfanyl, phenylsulfonyl, phenylsulfinyl and (C 3 -C 6 )cycloalkyl, wherein said alkyl, perhaloalkyl, alkoxy, aryl, heteroaryl, phenylsulfanyl, phenylsulfonyl, phenylsulfinyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituent(s).

4. The compound of claim 1 , wherein R 2 is selected from the group consisting of (C 1 -C 6 )alkyl, —C(═O)R 4 , —C(═S)R 4 , C(═NR 4 )R 5 , —C(═NOR 4 )R 5 , (5- or 6-membered)heteroaryl and (C 6 -C 10 )aryl, wherein said aryl is unsubstituted or substituted with 1, 2 or 3 substituent(s).

5. The compound of claim 1 , wherein R 3 is selected from the group consisting of (C 1 -C 6 )alkyl, phenyl, —NR 6 R 7 , and (C 1 -C 6 )alkoxy, wherein R 6 and R 7 are independently selected from hydrogen and (C 1 -C 6 )alkyl.

6. The compound of claim 1 , wherein the compound of formula (I) is:

7. The compound of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:

8. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.

9. A method of treating a cardiovascular disease responsive to nitroxyl therapy, the method comprising administering an effective amount of the compound of claim 1 to a patient in need thereof.

10. A kit for treating a disease or condition responsive to nitroxyl therapy comprising a compound of claim 1 ; and instructions for use of the kit.

11. The compound of claim 1 , wherein R is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (5- or 6-membered)heteroaryl or phenyl, wherein said alkyl, heteroaryl and phenyl are unsubstituted or substituted with 1, 2 or 3 substituent(s).

12. The compound of claim 1 , wherein R is selected from the group consisting of hydrogen, methyl and phenyl.

13. The compound of claim 1 , wherein R is methyl or phenyl.

14. The compound of claim 1 , wherein R 1 is selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 4 )perhaloalkyl, (C 1 -C 6 )alkoxy, phenyl, (5- or 6-membered)heteroaryl, phenylsulfanyl, phenylsulfonyl, phenylsulfinyl and (C 3 -C 6 )cycloalkyl, wherein said alkyl, perhaloalkyl, alkoxy, phenyl, heteroaryl, phenylsulfanyl, phenylsulfonyl, phenylsulfinyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituent(s).

15. The compound of claim 1 , wherein R 1 is methyl or phenyl, wherein said phenyl is unsubstituted or substituted with 1, 2 or 3 substituent(s).

16. The compound of claim 1 , wherein R 2 is selected from the group consisting of (C 1 -C 6 )alkyl, —C(═NOR 4 )R 5 , (5- or 6-membered)heteroaryl and phenyl, wherein said alkyl, heteroaryl and phenyl are unsubstituted or substituted with 1, 2 or 3 substituent(s).

17. The compound of claim 1 , wherein R 2 is methyl, —C(═NOR 4 )R 5 , or phenyl; and R 4 and R 5 are independently selected from (C 1 -C 6 )alkyl.

18. The compound of claim 1 , wherein R 2 is methyl or —C(═NOR 4 )R 5 ; and R 4 and R 5 are each methyl.

19. The compound of claim 1 , wherein R 3 is (C 1 -C 6 )alkyl, —NR 6 R 7 or (C 1 -C 6 )alkoxy.

20. The compound of claim 1 , wherein the compound of formula (I) is:

Assignees

• Univ Johns Hopkins
• Toscano John P
• Nourian Saghar
• Guthrie Daryl A

Inventors

• Toscano John P
• Nourian Saghar
• Guthrie Daryl A

Classifications

• C07D239/62

  Barbituric acids · CPC title

• C07D231/28 Primary

  Two oxygen or sulfur atoms · CPC title

• A61K31/37

  Coumarins, e.g. psoralen · CPC title

• A61P9/04

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

• A61K31/515

  Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital · CPC title