Combinations for cardiovascular indications

• US 20040058908A1
• Filed: 10/09/2002
• Published: 03/25/2004
• Est. Priority Date: 12/23/1998
• Status: Abandoned Application

• Current Assignee: GD Searle LLC (Pfizer Inc.)
• Original Assignee: GD Searle LLC (Pfizer Inc.)
• Inventors: Lappe, Rodney W., Sikorski, James A., Keller, Bradley T., Reitz, David B., Tremont, Samuel J., Schuh, Joseph R.
• Application Number:
  US10/266,743
• Publication Number:
  US 20040058908A1
• Time in Patent Office: Days
• US Class Current: 514/211.09
• 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 31/38 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• 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: A61P 9/12 Antihypertensives

Abstract

The present invention provides combinations of cardiovascular therapeutic compounds for the prophylaxis or treatment of cardiovascular disease including hypercholesterolemia and atherosclerosis. Combinations disclosed include an ileal bile acid transport inhibitor combined with a cholesteryl ester transport protein (CETP) inhibitor, a fibric acid derivative, a nicotinic acid derivative, a microsomal triglyceride transfer protein inhibitor, a cholesterol abosrption antagonist, a phytosterol, a stanol, an antihypertensive agent, or others. Further combinations include a CETP inhibitor with a fibric acid derivative, a nicotinic acid derivative, a bile acid sequestrant, a microsomal triglyceride transfer protein inhibitor, a cholesterol abosrption antagonist, or others.

Claims

1. A therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of a microsomal triglyceride transfer protein inhibiting compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.

2. The therapeutic combination of claim 1 wherein the ileal bile acid transport inhibitor is a compound having the structure of formula B-2:

3. The therapeutic combination of claim 1 wherein the ileal bile acid transport inhibiting compound has the structure of formula B-12:

4. The therapeutic combination of claim 1 wherein the ileal bile acid transport inhibiting compound has the structure:

5. The therapeutic combination of claim 1 wherein the ileal bile acid transport inhibiting compound has the structure of formula B-7:

6. A therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of a cholesterol absorption antagonist compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.

7. The combination of claim 6 wherein the cholesterol absorption antagonist compound comprises an azetidinone compound.

8. The combination of claim 7 wherein the cholesterol absorption antagonist compound comprises [3R-[3α

(S*),4β

]]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone.

9. A therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of an antiobesity compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.

10. The combination of claim 9 wherein the antiobesity compound comprises orlistat.

11. A therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of an antihypertensive compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, an anti-hypercholesterolemic condition effective amount, or an antihypertensive condition effective amount of the compounds.

12. The combination of claim 11 wherein the ileal bile acid transport inhibiting compound comprises a benzothiazepine ileal bile acid transport inhibiting compound.

13. The combination of claim 12 wherein the benzothiazepine ileal bile acid transport inhibiting compound has the structure:

14. The combination of claim 12 wherein the benzothiazepine ileal bile acid transport inhibiting compound has the structure:

15. The combination of claim 11 wherein the antihypertensive compound comprises eplerenone.

16. The combination of claim 11 wherein the antihypertensive compound comprises spironolactone.

17. The combination of claim 11 wherein the antihypertensive compound comprises losartan or a salt thereof.

18. The combination of claim 11 wherein the ileal bile acid transport inhibiting compound comprises a benzothiepine ileal bile acid transport inhibiting compound.

19. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

20. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

21. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

22. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

23. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

24. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

25. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

26. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

27. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

28. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

29. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

30. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

31. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

32. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

33. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

34. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

35. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

36. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

37. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

38. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

39. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

40. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

41. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

42. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

43. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

44. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

45. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

46. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

47. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

48. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

49. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

50. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

51. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

52. The combination of claim 18 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

53. A therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of a phytosterol compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.

63. The combination of claim 53 wherein the ileal bile acid transport inhibitor compound comprises a benzothiazepine ileal bile acid transport inhibitor compound.

64. The combination of claim 63 wherein the ileal bile acid transport inhibitor compound has the structure:

65. The combination of claim 63 wherein the benzothiazepine ileal bile acid transport inhibiting compound has the structure:

66. The combination of claim 53 wherein the ileal bile acid transport inhibiting compound comprises a benzothiepine ileal bile acid transport inhibiting compound.

67. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

68. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

69. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

70. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

71. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

72. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

73. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

74. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

75. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

76. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

77. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

78. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

79. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

80. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

81. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

82. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

83. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

84. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

85. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

86. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

87. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

88. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

89. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

90. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

91. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

92. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

93. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

94. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

95. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

96. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

97. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

98. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

99. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

100. The combination of claim 66 wherein the benzothiepine ileal bile acid transport inhibiting compound has the structure:

101. The combination of claim 53 wherein the ileal bile acid transport inhibiting compound comprises a naphthalene ileal bile acid transport inhibiting compound.

54. The combination of claim 54 wherein the phytosterol comprises a stanol.

55. The combination of claim 54 wherein the stanol is campestanol.

56. The combination of claim 54 wherein the stanol is cholestanol.

57. The combination of claim 54 wherein the stanol is clionastanol.

58. The combination of claim 54 wherein the stanol is coprostanol.

59. The combination of claim 54 wherein the stanol is 22,23-dihydrobrassicastanol.

60. The combination of claim 54 wherein the stanol is epicholestanol.

61. The combination of claim 54 wherein the stanol is fucostanol.

62. The combination of claim 54 wherein the stanol is stigmastanol.

102. A therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of probucol wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.

103. The combination of claim 102 wherein the ileal bile acid transport inhibiting compound is a benzothiepine ileal bile acid transport inhibiting compound.

104. The combination of claim 102 wherein the ileal bile acid transport inhibiting compound is a benzothiazepine ileal bile acid transport inhibiting compound.

105. The combination of claim 102 wherein the ileal bile acid transport inhibiting compound is a naphthalene ileal bile acid transport inhibiting compound.

106. A method for the prophylaxis or treatment of a hyperlipidemic condition or disorder in a mammal which comprises administering a first amount of an ileal bile acid transport inhibitor compound and a second amount of a microsomal triglyceride transfer protein inhibiting compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.

107. A method for the prophylaxis or treatment of a hyperlipidemic condition or disorder in a mammal which comprises administering a first amount of an ileal bile acid transport inhibitor compound and a second amount of a cholesterol absorption antagonist compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.

108. A method for the prophylaxis or treatment of a hyperlipidemic condition or disorder in a mammal which comprises administering a therapeutic combination comprising a first amount of an ileal bile acid transport inhibiting compound and a second amount of an antihypertensive compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount of the compounds.

109. A method for the prophylaxis or treatment of a hyperlipidemic condition or disorder in a mammal which comprises administering a first amount of an ileal bile acid transport inhibitor compound and a second amount of a phytosterol compound wherein the first amount and the second amount together comprise an anti-hyperlipidemic condition effective amount, an anti-atherosclerotic condition effective amount, or an anti-hypercholesterolemic condition effective amount of the compounds.

110. The method of claim 110 wherein the phytosterol compound comprises a stanol.

111. A kit for achieving a therapeutic effect in a mammal comprising an amount of an ileal bile acid transport inhibiting compound in a first unit dosage form;

an amount of a microsomal triglyceride transfer protein inhibiting compound in a second unit dosage form; and

container means for containing said first and second unit dosage forms.

112. A kit for achieving a therapeutic effect in a mammal comprising an amount of an ileal bile acid transport inhibiting compound in a first unit dosage form;

an amount of a cholesterol absorption antagonist compound in a second unit dosage form; and

container means for containing said first and second unit dosage forms.

113. A kit for achieving a therapeutic effect in a mammal comprising an amount of an ileal bile acid transport inhibiting compound in a first unit dosage form;

an amount of an antihypertensive compound in a second unit dosage form; and

container means for containing said first and second unit dosage forms.

114. A kit for achieving a therapeutic effect in a mammal comprising an amount of an ileal bile acid transport inhibiting compound in a first unit dosage form;

an amount of a phytosterol compound in a second unit dosage form; and

container means for containing said first and second unit dosage forms.

115. The kit of claim 114 wherein the phytosterol compound comprises a stanol.