Bis-acylated hydroxylamine derivatives
The invention provides certain bis-acylated hydroxylamine derivative compounds, pharmaceutical compositions and kits comprising such compounds, and methods of using such compounds or pharmaceutical compositions. In particular, the invention provides methods of using such compounds or pharmaceutical compositions for treating, preventing, or delaying the onset and/or develop 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:
W is halo, —OH, —CN, —NO 2 , —CONR 3 R 4 , —CH(C(O)R 3 ) 2 , or —COX, wherein X is halo, and R 3 , R 4 and R 5 are independently (C 1 -C 8 )alkyl or (C 5 -C 6 )aryl, or R 3 and R 4 are taken together to form a (C 3 -C 8 )heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with from one to five substituents independently selected from the group consisting of halo, nitro, cyano, oxo, (C 5 -C 6 )aryl, (C 1 -C 8 )alkoxy, (C 1 -C 8 )acyl, acylamino, amino, hydroxyl, carboxyl, (C 1 -C 8 )carboxyalkyl, thiol, (C 1 -C 8 )thioalkyl, (C 3 -C 8 )heterocyclyl and —OS(O) 2 —(C 1 -C 8 )alkyl;
R 1 is hydrogen, (C 1 -C 8 )alkyl, (C 5 -C 6 )aryl, benzyl, (C 1 -C 8 )alkoxy, (C 5 -C 6 )aryloxy, benzyloxy or —NR 6 R 7 , wherein said alkyl, aryl, benzyl, alkoxy, aryloxy and benzyloxy are unsubstituted or substituted with from one to three substituents independently selected from the group consisting of halo, alkyl, nitro, alkylsulfonyl and trihalomethyl;
R 2 is hydrogen, (C 1 -C 8 )alkyl, (C 5 -C 6 )aryl, benzyl, (C 5 -C 6 )aryloxy, benzyloxy or —NR 6 R 7 , wherein said alkyl, aryl, benzyl, aryloxy and benzyloxy are unsubstituted or substituted with from one to three substituents independently selected from the group consisting of halo, alkyl, nitro, alkylsulfonyl and trihalomethyl;
R 6 and R 7 are independently (C 1 -C 8 )alkyl or (C 5 -C 6 )aryl;
provided that when R 1 and R 2 are each phenyl, then W is not —CN; and
provided that when R 1 is phenylethyl and R 2 is methyl, then W is not chloro.
2. A pharmaceutical composition comprising:
a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable excipient.
3. 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 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
4. The method of claim 3 , wherein the disease or condition is a cardmvascular disease.
5. The method of claim 4 , wherein the cardiovascular disease is heart failure.
6. The method of claim 5 , wherein the heart failure is congestive heart failure.
7. The method of claim 5 , wherein the heart failure is acute conuestive heart failure.
8. The method of claim 5 , wherein the heart failure is acute decompensated heart failure.
9. The method of claim 3 , wherein the disease or condition is ischemia or reperfusion injury.
10. The method of claim 3 , wherein the disease or condition is a cancerous disease.
11. The method of claim 3 , wherein the disease or condition is breast cancer, pancreatic cancer, prostate cancer or colorectal cancer.
12. A method of modulating in vivo nitroxyl levels, comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
13. A kit comprising:
a compound of claim 1 or a pharmaceutically acceptable salt thereof; and
instructions for treating a condition that is responsive to nitroxyl therapy.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is chloro.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is bromo.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy or phenyl, wherein said alkyl and phenyl are unsubstituted or substituted with from one to three substituents independently selected from the group consisting of halo, nitro, alkylsulfonyl and trihalomethyl; and R 2 is (C 1 -C 8 )alkyl or phenyl, wherein said alkyl and phenyl are unsubstituted or substituted with from one to three substituents independently selected from the group consisting of halo, nitro, alkylsulfonyl and trihalomethyl.
17. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
N-chloro-N-benzoyloxy-benzamide;
N-chloro-N-(4-chlorobenzoyloxy)-4-chlorobenzamide;
N-chloro-N-(4-nitrobenzoyl)-4-nitrobenzamide;
N-chloro-N-(4-nitrobenzoyl)-benzamide;
N-chloro-N-(2,6-difluorobenzoyl)-benzamide;
N-chloro-N-acetoxy-benzamide;
N-chloro-N-diehloroacetyloxy-benzamide;
N-chloro-N-(2,2,2-trifluoroacetoxy)benzamide;
N-chlora-N-acetyloxy-acetamide;
N-chloro-N-acetyloxy-tert-butyl-carbamate;
N-chloro-N-ethyl-carbonoxy-ethyl-carbamate;
N-chloro-N-(trimethylacetyloxy)-trimethylacetamide;
N-chloro-N-(4-nitrobenzoyloxy)-tert-butyl-carbamate;
N-chloro-N-(acetyloxy)-trimethylacetamide; and
N-bromo-N-acetyloxy-acetamide.
18. The compound of claim 17 , wherein the compound is N-chloro-N-acetyloxy-tert-butyl-carbamate.