O-substituted hydroxamic acids
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.
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: