Nitroso compounds as nitroxyl donors and methods of use thereof
The invention relates to nitroso derivatives including carboxylic acid and phosphoric acid esters of hydroxy nitroso compounds that donate nitroxyl (HNO) under physiological conditions. The compounds and compositions of the invention are useful in treating and/or preventing the onset and/or development of diseases or conditions that are responsive to nitroxyl therapy, including heart failure, ischemia/reperfusion injury and cancer.
1. A compound of the formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
each R 1 and R 2 is independently a moiety of the formula C 1 -C 4 alkyl-O—C 1 -C 4 alkyl- or acyl-O—C 1 -C 4 alkyl;
D is selected from the group consisting of alkyl-C(O)—, substituted alkyl-C(O)—, perhaloalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, and heterocyclyl-C(O)—.
2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein D is selected from the group consisting of alkyl-C(O)—, substituted alkyl-C(O)—, perhaloalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, and heterocyclyl-C(O)—.
3. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each of the formula CH 3 CH 2 —O—CH 2 — or CH 3 C(O )—O—CH 2 —.
4. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein D is C 1 -C 8 alkyl-C(O)—.
5. A compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein D is CH 3 —C(O)—.
6. A pharmaceutical composition comprising (i) a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 6 wherein the composition is amenable to parenteral administration.
8. A method of treating a condition selected from the group consisting of coronary obstructions, coronary artery disease (CAD), angina, heart attack, myocardial infarction, high blood pressure, ischemic cardiomyopathy and infarction, diastolic heart failure, pulmonary congestion, pulmonary edema, cardiac fibrosis, valvular heart disease, pericardial disease, circulatory congestive states, peripheral edema, ascites, Chagas' disease, ventricular hypertrophy, heart valve disease, heart failure, congestive heart failure, acute congestive heart failure, acute decompensated heart failure, pulmonary hypertension and cardiac hypertrophy comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
9. The method of claim 8 wherein the condition is heart failure.
10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is
11. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is