Novel sterol/stanol phosphorylnitroderivatives and use thereof in treating or preventing cardiovascular disease, its underlying conditions and other disorders

• US 20070232688A1
• Filed: 04/03/2006
• Published: 10/04/2007
• Est. Priority Date: 04/03/2006
• Status: Active Grant

• Current Assignee: Avoca Incorporated (Bank of Montreal)
• Original Assignee: Forbes Medi-Tech (Research), Inc. (FMI Holdings Ltd.)
• Inventors: Orchansky, Patricia, Kutney, James
• Granted Patent: US 7,645,748 B2
• Time in Patent Office: Days
• US Class Current: 514/461
• CPC Class Codes: C07D 307/32 Oxygen atoms

Abstract

Sterol and stanol phosphorylnitro derivatives and their use in treating or preventing cardiovascular disease, its underlying conditions and other disorders are disclosed. The disclosed compounds include a phosphate linker, at least one moiety that releases nitric oxide (NO), and a sterol or stanol moiety. Some compounds additionally include an ascorbyl moiety to make the compound more readily soluble in aqueous and non-aqueous media.

Claims

1. Sterol and/or stanol nitroderivatives, including pharmaceutically acceptable salts and stereoisomers thereof, represented by the general formulae:

6. The nitroderivatives of claim 1 wherein the sterol and stanol are selected from the group consisting of sitosterol, campesterol, stigmasterol, brassicasterol, desmosterol, chalinosterol, poriferasterol, clionasterol, sitostanol, campestanol, stigmastanol, brassicastanol, desmostanol, chalinostanol, poriferastanol, and clionastanol.

7. Pharmaceutical compositions comprising the sterol and/or stanol nitroderivatives of claim 1 and one or more suitable carriers, excipients or adjuvants.

8. The sterol/stanol nitroderivatives of claim 1 wherein the sterol and stanol are in either a natural or synthesized form.

9. The sterol/stanol nitroderivatives of claim 1 wherein the sterol and stanol are in any one of their isomeric forms.

10. The sterol/stanol nitroderivatives of claim 1 wherein the sterol/stanol is selected from the group consisting of sitostanol, sitosterol, campestnaol and campesterol.

11. The sterol/stanol nitroderivatives of claim 1 additionally comprising at least one agent which reduces cholesterol synthesis in humans.

12. The sterol/stanol nitroderivatives of claim 11 wherein the agent is a 3-hydroxy-3-methyl glutaryl coenzyme-A (HMG-CoA) reductase inhibitor.

13. The sterol/stanol nitroderivatives of claim 1 additionally comprising one or more of the following:

ACE inhibitors, angiotensin II receptor antagonists, beta-andrenergic blockers, calcium channel blockers, anti-thrombotics such as aspririn, nitrosated ACE inhibitors, nitrosated angiotensin II receptor antagonists, nitrosated beta-andrenergic blockers and nitrosated aspirin.

14. Use of the sterol/stanol nitroderivatives of claims 1 in the manufacture of a medication to lower serum cholesterol in humans.

15. Use of the sterol/stanol nitroderivatives of claim 1 in the manufacture of a medication to prevent and/or reduce atherosclerotic plaque formation in humans.

16. Use of the sterol/stanol nitroderivatives of claims 1 in the manufacture of a medication to reduce hypertension in humans.

17. Use of the sterol/stanol nitroderivatives of claim 1 in the manufacture of a medication to treat and/or prevent one ore more of the following:

cardiovascular disease and its underlying conditions such as hypercholesterolemia, hyperlipidemia, arteriosclerosis, hypertension, and thrombosis in humans.

18. Use of the sterol/stanol nitroderivatives of claim 1 in the manufacture of a medication to treat and/or prevent Type II diabetes in humans.

19. Use of the sterol/stanol nitroderivatives of claim 1 in the manufacture of a medication to treat and/or prevent diseases that include oxidative damage as part of the underlying disease process such as dementia, Alzheimer'"'"'s disease, aging, and cancer in humans.

2. Sterol and/or stanol nitroderivatives, including pharmaceutically acceptable salts and stereoisomers thereof, represented by the general formulae:

3. Sterol and/or stanol nitroderivatives, including pharmaceutically acceptable salts and stereoisomers thereof, represented by the general formulae:

4. Sterol and/or stanol nitroderivatives, including pharmaceutically acceptable salts and stereoisomers thereof, represented by the general formulae:

5. Sterol and/or stanol nitroderivatives, including pharmaceutically acceptable salts and stereoisomers thereof, represented by the general formulae: