Substituted 2-azetidinones useful as hypocholesterolemic agents

• US 20030105028A1
• Filed: 06/11/2002
• Published: 06/05/2003
• Est. Priority Date: 12/20/2000
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Patrick, James E., Chowdhury, Swapan K., Ghosal, Anima, Alton, Kevin B., Feng, Wenqing, Zbaida, Shmuel, Iannucci, Robert M., Davis, Harry R.
• Granted Patent: US 6,982,251 B2
• Time in Patent Office: Days
• US Class Current: 514/23
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07H 15/26 Acyclic or carbocyclic radicals, substituted by hetero rings

Abstract

Hypocholesterolemic substituted 2-azetidinone compounds of the formula:

are disclosed, as well as a methods of lowering cholesterol by administering said compounds, pharmaceutical compositions containing them, and the combination of a substituted 2-azetidinone cholesterol-lowering agent and a cholesterol biosynthesis inhibitor for the treatment and prevention of atherosclerosis.

Claims

1. A compound represented by the Formula (IA):

2. The compound according to claim 1, wherein R¹ is G.

3. The compound according to claim 2, wherein G is selected from the group consisting of

4. The compound according to claim 3, wherein G is selected from the group consisting of

5. The compound according to claim 4, wherein G is selected from the group consisting of:

6. The compound according to claim 5, wherein G is:

7. The compound according to claim 3, wherein G is:

8. The compound according to claim 7, wherein G is:

9. The compound according to claim 8, wherein R³⁰ is 2-fluorophenyl, 2,4-difluorophenyl, 2-methylphenyl, 2-thienylmethyl, 2-methoxycarbonyl-ethyl, thiazol-2-yl-methyl, 2-methoxycarbonylbutyl or phenyl, or W is —

O—

C(O)— and

R³⁰ is (C₁-C₆)alkyl, T, or T substituted by one or two halo or (C₁-C₆)alkyl groups.

10. The compound according to claim 1, wherein R¹ is G¹ which is represented by the structure:

11. The compound according to claim 1, wherein Ar¹ is phenyl or R¹⁰-substituted phenyl and Ar² is phenyl or R¹¹-substituted phenyl.

12. The compound according to claim 11, wherein R¹⁰ is halo and R¹¹ is lower alkoxy or halo.

13. The compound according to claim 1, wherein:

Ar¹ is phenyl or R¹⁰-substituted phenyl;

Ar² is phenyl or R¹¹-phenyl;

R¹⁰ is halo;

R¹¹ is lower alkoxy or halo;

Q is —

(CH₂)_q—

, wherein q is 2-6;

or Q, with the 3-position ring carbon of the azetidinone, forms the group

wherein R¹³ and R¹⁴ are each ethylene and a and b are each 1, and wherein R¹² is

R¹ is selected from the group consisting of

wherein R², R³, R⁴, R⁵, R⁶ and R⁷ are each independently selected from the group consisting of H, (C₁-C₆)alkyl, benzyl and acetyl;

or R¹ is

wherein R³, R^3a, R⁴ and R^4a are each independently selected from the group consisting of H, (C₁-C₆)alkyl, benzyl and acetyl; and

R, R^a and R^b are each independently selected from the group consisting of H, —

OH, halo, —

NH₂, azido, (C₁-C₆)alkoxy(C₁-C₆)alkoxy and —

W—

R³⁰, wherein W is —

O—

C(O)—

or —

O—

C(O)—

NR³¹—

, R³¹ is H and R³⁰ is (C₁-C₆)alkyl, —

C(O)—

(C₁-C₄)alkoxy-(C₁-C₆)alkyl, T, T—

(C₁-C₆)alkyl, or T or T—

(C₁-C₆)alkyl wherein T is substituted by one or two halo or (C₁-C₆)alkyl groups.

17. A method of treating or preventing a vascular condition, diabetes, obesity or lowering concentration of a sterol in plasma of a mammal, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1.

18. A method of treating or preventing a vascular condition or lowering concentration of a sterol in plasma of a mammal, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1.

19. A pharmaceutical composition for the treatment of a vascular condition, diabetes, obesity or lowering concentration of a sterol in plasma of a mammal, comprising an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

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

21. A pharmaceutical composition for the treatment or prevention of a vascular condition, diabetes, obesity or lowering concentration of a sterol in plasma of a mammal, comprising an effective amount of a combination of a compound of claim 1, a cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier.

22. The pharmaceutical composition according to claim 21, wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, L-659,699, squalestatin 1, NB-598, pitavastatin and ZD4522.

23. The pharmaceutical composition according to claim 22, wherein the cholesterol biosynthesis inhibitor is simvastatin.

24. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat or prevent a vascular condition, diabetes, obesity or lowering concentration of a sterol in plasma of a mammal which comprises in one container an effective amount of a cholesterol biosynthesis inhibitor in a pharmaceutically acceptable carrier, and in a second container, an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

25. A method of treating or preventing a vascular condition, diabetes, obesity or lowering concentration of a sterol in plasma of a mammal comprising simultaneously or sequentially administering to a mammal in need of such treatment an effective amount of a combination of a cholesterol biosynthesis inhibitor and a compound of claim 1.

26. The method according to claim 25, wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, L-659,699, squalestatin 1, NB-598, pitavastatin and ZD4522.

27. The method according to claim 26, wherein the cholesterol biosynthesis inhibitor is simvastatin.

14. A compound represented by the Formula II:

15. A compound represented by the Formula III:

28. A method of lowering cholesterol levels in a mammal in need of such treatment comprising administering an effective amount of the compound of claim 15.

29. A pharmaceutical composition comprising a cholesterol-lowering effective amount of the compound of claim 15 and a pharmaceutically acceptable carrier.

30. A pharmaceutical composition for the treatment or prevention of atherosclerosis, or for the reduction of cholesterol levels, comprising an effective amount of a combination of the compound of claim 15, a cholesterol biosynthesis inhibitor and a pharmaceutically acceptable carrier.

31. The pharmaceutical composition according to claim 30, wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, L-659,699, squalestatin 1, NB-598, pitavastatin and ZD4522.

32. The pharmaceutical composition according to claim 31, wherein the cholesterol biosynthesis inhibitor is simvastatin.

33. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat or prevent atherosclerosis or to reduce cholesterol levels which comprises in one container an effective amount of a cholesterol biosynthesis inhibitor in a pharmaceutically acceptable carrier, and in a second container, an effective amount of the compound of claim 15 in a pharmaceutically acceptable carrier.

34. A method of treating or preventing atherosclerosis or reducing cholesterol levels comprising simultaneously or sequentially administering to a mammal in need of such treatment an effective amount of a combination of a cholesterol biosynthesis inhibitor and the compound of claim 15.

35. The method according to claim 34, wherein the cholesterol biosynthesis inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, L-659,699, squalestatin 1, NB-598, pitavastatin and ZD4522.

36. The method according to claim 35, wherein the cholesterol biosynthesis inhibitor is simvastatin.

16. A compound represented by the structural formula I