Use of substituted azetidinone compounds for the treatment of sitosterolemia

• US 7,417,039 B2
• Filed: 01/25/2002
• Issued: 08/26/2008
• Est. Priority Date: 01/26/2001
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Davis, Harry R.
• Primary Examiner(s): HUI, SAN MING R
• Application Number:
  US10/057,629
• Publication Number:
  US 20020169134A1
• Time in Patent Office: 2,405 Days
• Field of Search: 514/183, 514/461, 514/451
• US Class Current: 514/183
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/7042 Compounds having saccharide radicals and heterocyclic rings
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 31/06 for tuberculosis
• 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 9/04 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

Abstract

The present invention is directed to the use of sterol absorption inhibiting compounds, pharmaceutical compositions thereof, therapeutic combinations and their use in combination with other lipid lowering agents to treat or prevent sitosterolemia and/or to lower the concentration of sterol(s) other than cholesterol in plasma or tissue of a mammal. Methods of treating or preventing vascular disease and coronary events also are provided.

Claims

1. A method of treating sitosterolemia, comprising administering to a mammal in need of such treatment an effective amount of at least one sterol absorption inhibitor, or pharmaceutically acceptable salt or solvate of the least one sterol absorption inhibitor, or prodrug of the at least one sterol absorption inhibitor or pharmaceutically acceptable salt or solvate of the least one sterol absorption inhibitor, or mixture thereof.

2. The method of claim 1, wherein the at least one sterol absorption inhibitor is represented by Formula (I):

3. The method of claim 1, wherein the at least one sterol absorption inhibitor is represented by Formula (II):

4. The method of claim 1, wherein the at least one sterol absorption inhibitor is represented by Formula (III):

5. The method of claim 1, wherein the at least one sterol absorption inhibitor is represented by Formula (IV):

6. The method of claim 1, wherein the at least one sterol absorption inhibitor is represented by Formula (VA) or Formula (VB):

7. The method of claim 1, wherein the at least one sterol absorption inhibitor is represented by Formula (VI):

8. The method of claim 1, wherein the at least one sterol absorption inhibitor is represented by Formula (VII):

9. The method of claim 1, wherein the at least one sterol absorption inhibitor is represented by Formula (VIII):

10. The method of claim 1, wherein the at least one sterol absorption inhibitor is represented by Formula (IX):

11. The method of claim 10, wherein the at least one sterol absorption inhibitor is represented by Formula (X):

12. The method of claim 10, wherein the at least one sterol absorption inhibitor is represented by Formula (XI):

13. The method according to claim 1, wherein the sterol absorption inhibitor is administered to the mammal in an amount ranging from about 0.1 to about 30 milligrams of sterol absorption inhibitor per kilogram of mammal body weight per day.

14. The method according to claim 13, wherein the sterol absorption inhibitor is administered to the mammal in an amount ranging from about 0.1 to about 15 milligrams of sterol absorption inhibitor per kilogram of mammal body weight per day.

15. The method of claim 1, further comprising administering to the mammal in need of such treatment an effective amount of at least one lipid lowering agent in combination with the at least one sterol absorption inhibitor.

16. The method of claim 15, wherein the lipid lowering agent is a HMG-CoA reductase inhibitor.

17. The method of claim 16, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, itavastatin and mixtures thereof.

18. The method of claim 17, wherein the HMG-CoA reductase inhibitor is simvastatin or atorvastatin.

19. The method of claim 15, wherein the sterol absorption inhibitor is administered to the mammal in an amount ranging from about 0.1 to about 30 milligrams of sterol absorption inhibitor per kilogram of mammal body weight per day.

20. The method of claim 15, wherein the lipid lowering agent is administered to the mammal in an amount ranging from about 0.1 to about 80 milligrams of lipid lowering agent per kilogram of mammal body weight per day.

21. The method of claim 15, wherein the sterol absorption inhibitor and lipid lowering agent are present in separate treatment compositions.

22. The method of claim 15, comprising:

a) a sterol absorption inhibitor represented by Formula (VIII);

23. The method of claim 22, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, rosuvastatin, itavastatin and mixtures thereof.

25. A pharmaceutical composition for the treatment or prevention of sitosterolemia, comprising an effective amount of the sterol absorption inhibitor used in the method of claim 1 in a pharmaceutically acceptable carrier.

26. A pharmaceutical composition for the treatment or prevention of sitosterolemia, comprising an effective amount of the sterol absorption inhibitor used in the method of claim 8 in a pharmaceutically acceptable carrier.

24. A method of treating sitosterolemia comprising administering to a mammal in need of such treatment:

(a) an effective amount of a sterol absorption inhibitor represented by Formula (VIII);

27. A pharmaceutical composition for the treatment or prevention of sitosterolemia, comprising an effective amount of the compound of Formula (VIII)

28. A pharmaceutical composition for the treatment or prevention of sitosterolemia, comprising:

a) an effective amount of the compound of Formula (VIII)

29. The composition of claim 28, wherein the lipid lowering agent is a HMG-CoA reductase inhibitor.

30. The composition of claim 29, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, rosuvastatin, itavastatin and mixtures thereof.

31. The composition of claim 30, wherein the HMG-CoA reductase inhibitor is simvastatin or atorvastatin.

32. A method of treating sitosterolemia, comprising administering to a mammal in need of such treatment:

(1) an effective amount of at least one sterol absorption inhibitor, or pharmaceutically acceptable salt or solvate of the least one sterol absorption inhibitor, or prodrug of the least one sterol absorption inhibitor or pharmaceutically acceptable salt or solvate of the least one sterol absorption, or mixture thereof; and

(2) an effective amount of at least one bile acid sequestrant or other lipid lowering agent.

33. A method of treating sitosterolemia comprising administering to a mammal in need of such treatment:

(1) an effective amount of at least one sterol absorption inhibitor, or pharmaceutically acceptable salt or solvate of the least one sterol absorption inhibitor, or prod rug of the least one sterol absorption or pharmaceutically acceptable salt or solvate of the least one sterol absorption inhibitor, or mixture thereof; and

(2) at least one sterol biosynthesis inhibitor.

34. A method of reducing plasma or tissue concentration of at least one non-cholesterol sterol, 5α

-stanol, or mixture thereof, comprising administering to a mammal in need of such treatment an effective amount of at least one treatment composition comprising an effective amount of at least one sterol absorption inhibitor or at least one stanol absorption inhibitor, or pharmaceutically acceptable salt or solvate of the least one sterol absorption inhibitor or the at least one stanol absorption inhibitor, or prodrug of the least one sterol absorption inhibitor or the at least one stanol absorption inhibitor or pharmaceutically acceptable salt or solvate of the least one sterol absorption inhibitor or the at least one stanol absorption inhibitor, or mixture thereof.

35. The method according to claim 34, wherein the non-cholesterol sterol is at least one phytosterol.

36. The method according to claim 35, wherein the phytosterol is selected from the group consisting of sitosterol, campesterol, stigmasterol, avenosterol, and mixtures thereof.

37. The method according to claim 36, wherein the phytosterol is selected from the group consisting of sitosterol and campesterol.

38. The method according to claim 34, wherein the 5α

-stanol is selected from the group consisting of cholestanol, 5α

-campestanol, 5α

-sitostanol and mixtures thereof.

39. A method of reducing plasma or tissue concentration of at least one non-cholesterol sterol, 5α

-stanol, or mixture thereof, comprising administering to a sitosterolemic mammal in need of such treatment an effective amount of at least one treatment composition comprising an effective amount of at least one sterol absorption inhibitor or at least one stanol absorption inhibitor, or pharmaceutically acceptable salt or solvate of the least one sterol absorption inhibitor or the at least one stanol absorption inhibitor, or prodrug of the least one sterol absorption inhibitor or the at least one stanol absorption inhibitor or pharmaceutically acceptable salt or solvate of the least one sterol absorption inhibitor or the at least one stanol absorption inhibitor, or mixture thereof.

43. The method of claim 39, further comprising administering to the mammal in need of such treatment an effective amount of at least one bile acid sequestrant in combination with at least one of the sterol absorption inhibitors.

44. The method of claim 39, wherein the sterol absorption inhibitor is represented by Formula (VIII)

45. The method of claim 44, wherein the bile acid sequestrant is selected from the group consisting of cholestyramine, colesevelam hydrochloride, and colestipol.

40. The method of 39, wherein the sterol absorption inhibitor is represented by Formula (VIII)

41. The method of claim 40, wherein the treatment composition further comprises at least one lipid lowering agent which is an HMG-CoA reductase inhibitor.

42. The method of claim 41, wherein the HMG-CoA reductase inhibitor is simvastatin or atorvastatin.

46. A pharmaceutical composition for the treatment or prevention of sitosterolemia, comprising:

a) an effective amount of the compound of Formula (VIII)

47. The composition of claim 46, wherein the bile acid sequestrant is selected from the group consisting of cholestyramine, colesevelam hydrochloride, and colestipol.

48. A method of reducing plasma or tissue concentration of at least one compound selected from the group consisting of phytosterols, 5α

-stanols and mixtures thereof, comprising administering to a sitosterolemic mammal in need of such treatment an effective amount of at least one sterol absorption inhibitor or a prodrug or a pharmaceutically acceptable salt thereof.

49. A method of reducing plasma or tissue concentration of at least one compound selected from the group consisting of phytosterols, 5α

-stanols and mixtures thereof, comprising administering to a mammal in need of such treatment an effective amount of at least one sterol absorption inhibitor or a prodrug or a pharmaceutically acceptable salt thereof and at least one lipid lowering agent.

50. A method of reducing plasma or tissue concentration of at least one compound selected from the group consisting of phytosterols, 5α

-stanols and mixtures thereof, comprising administering to a sitosterolemic mammal in need of such treatment an effective amount of at least one sterol absorption inhibitor or a prodrug or a pharmaceutically acceptable salt thereof and at least one lipid lowering agent.

51. A method of reducing plasma or tissue concentration of at least one compound selected from the group consisting of phytosterols, 5α

-stanols and mixtures thereof, comprising administering to a mammal in need of such treatment an effective amount of at least one sterol absorption inhibitor or a prodrug or a pharmaceutically acceptable salt thereof and at least one bile acid sequestrant.

52. A therapeutic combination comprising:

a) a first amount of the compound of Formula (VIII)

53. A therapeutic combination comprising:

a) a first amount of the compound of Formula (VIII)