Meldrum's acid, barbituric acid and pyrazolone derivatives substituted with hydroxylamine as HNO donors
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.
1. A compound of formula (II)
or a pharmaceutically acceptable salt thereof, wherein:
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 7 )R 8 , wherein the alkyl, alkenyl, alkynyl, alkoxy and aryl are unsubstituted or substituted with one or more substituents;
R 1 is 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; and
R 2 , 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. 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.
3. 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.
4. The compound of claim 1 , wherein R 1 is —H.
5. The compound of claim 3 , wherein R 1 is C 1 -C 8 alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents.
6. The compound of claim 1 , wherein R 1 is C 1 -C 4 alkyl.
7. The compound of claim 2 , wherein R 1 is C 5 -C 10 aryl or C 5 -C 10 heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted with one or more substituents.
8. The compound of claim 2 , wherein R 1 is phenyl, wherein the phenyl is unsubstituted or substituted with halo.
9. The compound of claim 7 , wherein R 2 is C 1 -C 8 alkyl wherein the alkyl is unsubstituted or substituted with one or more substituents.
10. The compound of claim 8 , wherein R 2 is C 1 -C 4 alkyl.
11. The compound of claim 1 , wherein the compound is selected from:
12. A pharmaceutical composition comprising:
a compound of claim 1 ; and
a pharmaceutically acceptable excipient.
13. A method of treating a disease or condition selected from cardiovascular diseases, ischemia, reperfusion injury, pulmonary hypertension and conditions responsive to nitroxyl therapy, comprising administering a compound of claim 1 to a subject in need thereof.
14. A method of modulating in vivo nitroxyl levels, comprising administering a compound of claim 1 to a subject in need thereof.
15. The compound of claim 2 , wherein R is methyl.
16. The compound of claim 6 , wherein R 1 is methyl.
17. The compound of claim 1 , wherein R 2 is C 5 -C 10 aryl and wherein said aryl is unsubstituted or substituted with one or more substituents.
18. The compound of claim 17 , wherein R 2 is phenyl and wherein said phenyl is unsubstituted or substituted with one or more substituents.
19. The compound of claim 17 , wherein said aryl is substituted with one or more substituents selected from —F, —Cl, —Br, —I, —OH, —NH 2 , —CN, —NO 2 , —SH, ═O, ═S, ═N-alkyl, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, —C(═O)H, —C(═O)NH 2 , —C(═O)OH, —NH—C(═O)—NH 2 , —NH—C(═S)—NH 2 , —S—CN, —SO 2 NH 2 , —COR′, —C(O)OR′, —C(O)NHR′, —C(O)NR′R″, —NHR′, —NR′R″, —SR′, —SOR′, —SO 2 R′, and —OR′, wherein R′ and R″ are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl are unsubstituted.
20. The compound of claim 18 , wherein said phenyl is substituted with one or more substituents selected from —F, —Cl, —Br, —I, —OH, —NH 2 , —CN, —NO 2 , —SH, ═O, ═S, ═N-alkyl, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, —C(═O)H, —C(═O)NH 2 , —C(═O)OH, —NH—C(═O)—NH 2 , —NH—C(═S)—NH 2 , —S—CN, —SO 2 NH 2 , —COR′, —C(O)OR′, —C(O)NHR′, —C(O)NR′R″, —NHR′, —NR′R″, —SR′, —SOR′, —SO 2 R′, and —OR′, wherein R′ and R″ are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl are unsubstituted.
21. The compound of claim 2 , wherein R 1 is C 1 -C 4 alkyl.
22. The compound of claim 21 , wherein R and R 1 are each methyl.