Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof

• US 7,378,518 B2
• Filed: 02/20/2007
• Issued: 05/27/2008
• Est. Priority Date: 03/07/2003
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Clader, John W., Burnett, Duane A.
• Primary Examiner(s): Berch; Mark L
• Application Number:
  US11/708,449
• Publication Number:
  US 20070155676A1
• Time in Patent Office: 462 Days
• Field of Search: 536/29.11
• US Class Current: 536/29.11
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: 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: Y10S 930/28 Bound to a nonpeptide drug, nonpeptide label, nonpeptide carrier, or a nonpeptide resin

Abstract

The present invention provides compounds represented by the structural formula (I):

or pharmaceutically acceptable isomers, salts, solvates or esters of the compound of Formula (I), wherein each of the substituents is as specified herein, formulations including the above compounds, processes for preparing the same and methods for treating vascular conditions, such as atherosclerosis or hypercholesterolemia, diabetes, obesity, stroke, demyelination and lowering plasma levels of sterols and/or stanols.

Claims

1. A compound represented by the structural formula (I):

2. The compound according to claim 1, wherein m, n and r are each zero, q is 1, p is 2, and Z is —

CH₂—

.

3. The compound according to claim 1, wherein m, n and r are each zero, q is 1, p is 2, and Z is —

CH₂—

, Q¹ is —

OR⁶, wherein R⁶ is hydrogen and Q⁵ is fluorine.

4. The compound according to claim 1, wherein R² and R³ are each hydrogen.

5. The compound according to claim 1, wherein Q¹ and Q² are each independently selected from the group consisting of —

OR⁶, —

O(CO)R⁶, —

O(CO)OR⁹ and —

O(CO)NR⁶R⁷.

6. The compound according to claim 1, wherein Q⁴ is halo or —

OR⁶.

7. The compound according to claim 1, wherein Q¹ is —

OR⁶ wherein R⁶ is H.

8. The compound according to claim 1, wherein Q¹, Q², Q³, Q⁴ or Q⁵ is -L-M.

9. The compound according to claim 1, wherein Q¹, Q², Q³, Q⁴ or Q⁵ is -G or —

(C₁-C₃₀ alkylene)-G.

10. The compound according to claim 1, wherein G is selected from the group consisting of:

11. The compound according to claim 10, wherein G is selected from:

12. The compound according to claim 1, wherein optionally one or more carbon atoms of the —

(C₁-C₃₀ alkylene)- radical of Q¹, Q², Q³, Q⁴ and Q⁵ is independently replaced by —

O—

.

13. The compound according to claim 1, wherein L is

14. The compound according to claim 1, wherein L is

15. The compound according to claim 1, wherein M is

16. The compound according to claim 1, wherein M is

17. The compound according to claim 1, wherein M is

18. The compound according to claim 1, wherein M is

19. The compound according to claim 1, wherein M is

20. A pharmaceutical composition for the treatment of atherosclerosis, hypercholesterolemia, sitosterolemia, lowering a concentration of cholesterol, phytosterol or 5α

-stanol in plasma of a mammal, treating demyelination or treating Alzheimer'"'"'s disease and/or regulating levels of amyloid β

peptides in a subject comprising a therapeutically effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

21. A pharmaceutical composition comprising a cholesterol-lowering effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

22. A method of treating atherosclerosis, hypercholesterolemia, sitosterolemia, lowering a concentration of cholesterol, phytosterol or 5α

-stanol in plasma of a mammal, treating demyelination or treating Alzheimer'"'"'s disease or regulating a level of an amyloid β

peptide in a subject comprising the step of administering to a subject in need of such treatment an effective amount of a compound of claim 1.

23. A method of lowering cholesterol level in plasma of a mammal in need of such treatment comprising administering a pharmaceutically effective amount of the compound of claim 1.