NOVEL NITROSO COMPOUNDS AS NITROXYL DONORS AND METHODS OF USE THEREOF

• US 20160052862A1
• Filed: 10/30/2015
• Published: 02/25/2016
• Est. Priority Date: 05/07/2008
• Status: Active Grant

• Current Assignee: Cardioxyl Pharmaceuticals, Inc. (Bristol-Myers Squibb Company)
• Original Assignee: Cardioxyl Pharmaceuticals, Inc. (Bristol-Myers Squibb Company)
• Inventors: Frost, Lisa Marie, Courtney, Stephen Martin, Brookfield, Frederick Arthur, Kalish, Vincent Jacob
• Granted Patent: US 9,725,402 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 207/00 Compounds containing nitroso groups bound to a carbon skeleton
• CPC Class Codes: C07C 207/04 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 255/19 containing cyano groups and carboxyl groups, other than cyano groups, bound to the same saturated acyclic carbon skeleton
• CPC Class Codes: C07D 211/44 attached in position 4
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 309/10 Oxygen atoms
• CPC Class Codes: C07D 309/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/42 with nitro or nitroso radicals directly attached to ring carbon atoms
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 407/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/10 : acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
• CPC Class Codes: C07F 9/117 : with cycloaliphatic alcohols
• CPC Class Codes: C07F 9/58 : Pyridine rings
• CPC Class Codes: C07F 9/59 : Hydrogenated pyridine rings
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

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.

Claims

1. A compound of the formula I:

2. A compound of claim 1 having the formula II:

3. The compound of claim 2 wherein X is O, NR⁴, S, S(O) or S(O)₂.

4. The compound of claim 3 wherein X is O.

5. The compound of claim 3 wherein X is NR⁴.

6. The compound of claim 3 wherein X is S.

7. A compound of claim 1 having the formula III:

8. A compound of claim 7 wherein X is O, NR⁴, S, S(O) or S(O)₂.

9. A compound of claim 7 wherein X is O.

10. A compound of claim 7 wherein X is NR⁴.

11. A compound of claim 1 having the formula IV:

12. A compound of claim 11 wherein X is S.

13. A compound of claim 7 having the formula V:

14. A compound of claim 13, wherein each R⁵, R⁶, R^11a, R^11b, R^12a, R^12b, R^13a, R^13b, R^14a and R^14b is H.

15. A compound of claim 1 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)—

, heterocyclyl-C(O)—

.

16. A compound of claim 1 wherein D is P(O)(O C₁-C₈alkyl)₂.

17. A compound of claim 13 wherein D is a moiety of the formula:

18. A compound of claim 1 wherein R¹ and R² are independently a substituted C₁-C₈alkyl.

19. A compound of claim 1 wherein R¹ and R² are independently a moiety of the formula C₁-C₄alkyl-O—

C₁-C₄alkyl- or acyl-O—

C₁-C₄alkyl-.

20. A compound of claim 1 wherein R¹ and R² are each of the formula CH₃CH₂—

O—

CH₂—

or CH₃C(O)—

O—

CH₂—

.

21. A compound of claim 18 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)—

, heterocyclic-C(O)—

.

22. A compound of claim 21 wherein D is C₁-C₈alkyl-C(O)—

.

23. A compound of claim 22 wherein D is CH₃—

C(O)—

.

24. A pharmaceutical composition comprising (i) a compound according to claim 1 and (ii) a pharmaceutically acceptable carrier.

25. The pharmaceutical composition of claim 24 wherein the composition is amenable to parenteral administration.

26. A method of treating a condition that is responsive to nitroxyl therapy 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.

27. The method of claim 26 wherein the condition is a cardiovascular disease.

28. The method of claim 26 wherein the condition is heart failure.

29. The method of claim 26 wherein the condition is 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.

30. The method of claim 26 wherein the condition is ischemia/reperfusion injury.

31. The method of claim 26 wherein the condition is a cancerous disease.

32. A method of claim 30 wherein the cancerous disease is breast cancer, pancreatic cancer, prostate cancer or colorectal cancer.