Nitroxyl donors with improved therapeutic index
The disclosed subject matter provides 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 heart failure.
1. A compound of formula (3):
wherein
R is hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, —(C 5 -C 7 )heterocycloalkyl, benzyloxy, —O—(C 1 -C 6 )alkyl, —NH 2 , —NH—(C 1 -C 4 )alkyl, or —N((C 1 -C 4 )alkyl) 2 ,
wherein said —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, —(C 5 -C 7 )heterocycloalkyl, benzyloxy, —O—(C 1 -C 6 )alkyl, —NH—(C 1 -C 4 )alkyl, or —N((C 1 -C 4 )alkyl) 2 can be unsubstituted or substituted with one or more substituents selected from halo, —(C 1 -C 6 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 3 )alkynyl, -(5- or 6-membered)heteroaryl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —NO 2 , —NH 2 , —NH—(C 1 -C 4 )alkyl, —N(—(C 1 -C 4 )alkyl) 2 , —C(═O)(C 1 -C 4 )alkyl, —C(═O)O(C 1 -C 4 )alkyl, —OC(═O)(C 1 -C 4 )alkyl, —OC(═O)NH 2 , —S(═O)(C 1 -C 4 )alkyl, or —S(═O) 2 (C 1 -C 4 )alkyl.
2. The compound of claim 1 , wherein R is methyl or ethyl.
3. The compound of claim 1 , wherein R is methyl.
4. The compound of claim 1 , wherein R is ethyl.
5. The compound of claim 1 , wherein R is benzyl or phenyl.
6. The compound of claim 1 , wherein R is phenyl.
7. The compound of claim 1 , wherein R is benzyl.
8. The compound of claim 1 , wherein R is —NH 2 .
9. The compound of claim 1 , wherein R is unsubstituted.
10. The compound of claim 1 , wherein R is substituted with a substituent selected from -halo, —NH 2 , —NHCH 3 , —CF 3 , or —OCH 3 .
11. A method of treating a cardiovascular disease, comprising administering an effective amount of the compound of claim 1 to a patient in need thereof.
12. The method of claim 11 , wherein the compound is administered intravenously.
13. The method of claim 11 , wherein the cardiovascular disease is heart failure.
14. The method of claim 13 , wherein the compound is administered intravenously.
15. The method of claim 11 , wherein the cardiovascular disease is acute decompensated heart failure.
16. The method of claim 15 , wherein the compound is administered intravenously.
17. A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable excipient.
18. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition is suitable for intravenous administration.
19. The pharmaceutical composition of claim 17 , wherein the at least one pharmaceutically acceptable excipient is at least one species of cyclodextrin.
20. The pharmaceutical composition of claim 19 , wherein the pharmaceutical composition is suitable for intravenous administration.
21. A method of treating a cardiovascular disease, comprising administering an effective amount of the pharmaceutical composition of claim 17 a patient in need thereof.
22. The method of claim 21 , wherein the pharmaceutical composition is administered intravenously.
23. The method of claim 21 , wherein the cardiovascular disease is heart failure.
24. The method of claim 23 , wherein the pharmaceutical composition is administered intravenously.
25. The method of claim 21 , wherein the cardiovascular disease is acute decompensated heart failure.
26. The method of claim 25 , wherein the pharmaceutical composition is administered intravenously.