N-substituted hydroxylamine derivatives with carbon-based leaving groups

Patent metadata

Field	Value
Publication number	US-2016115148-A1
Application number	US-201514927039-A
Country	US
Kind code	A1
Filing date	Oct 29, 2015
Priority date	Oct 17, 2011
Publication date	Apr 28, 2016
Grant date	—

Abstract

The disclosed subject matter provides certain N-substituted hydroxylamine derivative compounds, pharmaceutical compositions and 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, preventing, or delaying the onset and/or development of a disease or condition. In some embodiments, the disease or condition is selected from cardiovascular diseases, ischemia, reperfusion injury, cancerous disease, pulmonary hypertension and conditions responsive to nitroxyl therapy.

First claim

1 . A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
X and Z are independently selected from —O—, —NR—, —S—, —CR 3 —, and —CR 3 R 4 —;
Y is selected from —C(═O)—, —C(═S)—, —C(═NR 5 )—, and —CR 5 R 6 —;
R is selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkoxy, C 5 -C 10 aryl, —C(═O)R 7 , —C(═S)R 7 , —C(═NR 7 )R 8 , and —C(═NOR′)R 8 , wherein the alkyl, alkenyl, alkynyl, alkoxy and aryl are unsubstituted or substituted with one or more substituents;
and
R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from —H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 5 -C 10 aryl, C 5 -C 10 heterocycloalkyl, C 5 -C 10 heterocycloalkenyl, and C 5 -C 10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl and heteroaryl are unsubstituted or substituted with one or more substituents.

2 .- 3 . (canceled)

4 . The compound of claim 1 , wherein R is C 1 -C 8 alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents.

5 . The compound of claim 1 , wherein R is C 1 -C 4 alkyl.

6 . The compound of claim 1 , wherein R is —C(═NOR 5 )R 6 .

7 . The compound of claim 1 , wherein R is —C(═NOR 5 )R 6 ; and R 5 and R 6 are independently C 1 -C 4 alkyl.

8 . The compound of any one of claims 1 , and 4 to 7 , wherein X and Z are each —O—.

9 . The compound of any one of claims 1 , and 4 to 7 , wherein X and Z are each —NR 2 —.

10 . The compound of any one of claims 1 , and 4 to 7 , wherein X and Z are each —NR 2 —; and R 2 is C 1 -C 4 alkyl.

11 . The compound of any one of claims 1 , and 4 to 7 , wherein Y is —CR 3 R 4 —.

12 . The compound of any one of claims 1 , and 4 to 7 , wherein Y is —C(═O)—.

13 .- 19 . (canceled)

20 . The compound of claim 1 , wherein the compound is selected from:

21 . A pharmaceutical composition comprising:
a compound of claim 1 ; and a pharmaceutically acceptable excipient.

22 . A method of treating a disease or condition selected from cardiovascular diseases, ischemia, reperfusion injury, cancerous disease, pulmonary hypertension and conditions responsive to nitroxyl therapy, comprising administering a compound of claim 1 to a subject in need thereof.

23 . A method of modulating in vivo nitroxyl levels, comprising administering a compound of claim 1 to a subject in need thereof.

24 . A kit comprising:
a compound of claim 1 ; and instructions for treating a condition that is responsive to nitroxyl therapy.

25 . The compound of any one of claims 1 and 4 to 7 , wherein X and Z are each —O—; and Y is —CR 3 R 4 —.

26 . The compound of any one of claims 1 and 4 to 7 , wherein X and Z are each —NR 2 —; and Y is —CR 3 R 4 —.

27 . The compound of any one of claims 1 and 4 to 7 , wherein X and Z are each —NR 2 —; R 2 is C 1 -C 4 alkyl; and Y is —CR 3 R 4 —.

28 . The compound of any one of claims 1 and 4 to 7 , wherein X and Z are each —O—; and Y is —C(═O)—.

29 . The compound of any one of claims 1 and 4 to 7 , wherein X and Z are each —NR 2 —; and Y is —C(═O)—.

30 . The compound of any one of claims 1 and 4 to 7 , wherein X and Z are each —NR 2 —; R 2 is C 1 -C 4 alkyl; and Y is —C(═O)—.

Assignees

• Univ Johns Hopkins

Inventors

• Toscano John P
• Guthrie Daryl A

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/04

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

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/12

  Antihypertensives · CPC title