Compounds useful for treating hypertriglyceridemia

• US 20040019026A1
• Filed: 04/07/2003
• Published: 01/29/2004
• Est. Priority Date: 10/06/2000
• Status: Abandoned Application

• Current Assignee: BioVie Inc.
• Original Assignee: BioVie Inc.
• Inventors: Schwartz, Arthur G.
• Application Number:
  US10/408,466
• Publication Number:
  US 20040019026A1
• Time in Patent Office: Days
• US Class Current: 514/177
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/5685 having an oxo group in position 17, e.g. androsterone
• 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 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
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention is directed to a method for treating a patient having hypertriglyceridemia comprising administering thereto a compound of the formula:

Claims

1. A method for treating a patient having hypertriglyceridemia comprising administering thereto a therapeutically effective amount of a compound of the formula:

2. The method according to claim 1 wherein R₁₆ and R₁₇ are independently hydrogen, lower alkyl, hydroxy, loweralkoxy or halogen.

3. The method according to claim 2 wherein R₁₇ is hydrogen and R₁₆ is lower alkyl, hydroxy, lower alkoxy or halogen.

4. The method according to claim 2 wherein R₁₆ and R₁₇ are independently hydrogen, fluoro or chloro.

5. The method according to claim 2 wherein R₁₆ is fluoro and R₁₇ is hydrogen.

6. The method according to claim 1 wherein R₅ and R₆ are hydrogen.

7. The method according to claim 2 wherein R₅ and R₆ are hydrogen.

8. The method according to claim 3 wherein R₅ and R₆ are hydrogen.

9. The method according to claim 8 wherein R₁₆ is fluoro.

10. The method according to claim 1 wherein R₁, R₂, R₃, R₄, R₇, R₈, R₁₃, R₁₄ and R₁₅ are hydrogen, R₉ is hydrogen, lower alkyl, or halogen and R₁₁ and R₁₂ are independently hydrogen, hydroxy, lower alkoxy, halogen or lower alkyl and R₁₆ and R₁₇ are independently hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy and R₅ and R₆ are independently hydrogen or lower alkyl.

11. The method according to claim 10 wherein R₁₆ is fluoro, chloro, methyl, methoxy, R₁₇ is hydrogen, R₉ is hydrogen, methyl or fluoro or chloro and R₁₁ and R₁₂ are independently hydrogen, hydroxy, methoxy or methyl, fluoro or chloro.

12. The method according to claim 11 wherein R₁₆ is fluoro.

13. The method according to claim 10 wherein one of R₉, R₁₁ and R₁₂ is other than hydrogen.

14. The method according to claim 10 wherein R₅ and R₆ are hydrogen.

15. The method according to claim 14 wherein R₁₇ is hydrogen or halogen;

R₁₁ and R₁₂ are independently hydrogen, hydroxy, lower alkyl, R₉ is hydrogen.

16. The method according to claim 14 wherein R₁₇ is hydrogen;

R₉ is hydrogen;

R₁₁ and R₁₂ are independently hydrogen or hydroxy and R₁₆ is fluoro, chloro or methyl.

17. The method according to claim 10 wherein R₁₆ is chloro or fluoro.

18. The method according to claim 1 wherein the compound is 16α

-fluoro-5-androsten-17-one or 16α

-fluoro-7β

-hydroxy-5-androsten-17-one.

19. The method according to claim 1 or 10 wherein the patient has in addition at least one of the following characteristics:

(a) is insulin resistant

(b) is obese

(c) has a HDL level less than about 40 mg/dl if male and less than about 45 mg/dl if female.

20. The method according to claim 19 wherein the patient has a BMI greater than about 30 Kg/m².

64. The method according to any one of claims 1, 42 or 53 wherein the compound is 16α

-fluoro-5-androsten-17-one, 7α

-hydroxy-16α

-fluoro-5-androsten-17-one or 7β

-hydroxy-16α

-fluoro-5-androsten-17-one.

66. The method according to any one of claims 1, 21, 42, 48, 53 or 58 wherein the compound is administered buccally.

67. The method according to claim 64, where the compound is administered buccally.

107. The method according to any one of claims 1, 18, 21, 39, 42, 48, 53, 58, 69, 75, 78, 84, 87, 91, 92, 93, 97, 101, 102 or 106 wherein a statin is additionally present.

21. A method for treating a patient having hypertriglyceridemia comprising administering thereto a therapeutically effective amount of a compound of the formula:

22. The method according to claim 21 wherein R₅ or R₆ is other than hydroxy.

23. The method according to claim 21 wherein R₁₆ and R₁₇ are independently hydrogen, lower alkyl, hydroxy, loweralkoxy or halogen.

24. The method according to claim 23 wherein R₁₇ is hydrogen and R₁₆ is lower alkyl, hydroxy, lower alkoxy or halogen.

25. The method according to claim 23 wherein R₁₆ and R₁₇ are independently hydrogen, fluoro or chloro.

26. The method according to claim 25 wherein R₁₆ is fluoro and R₁₇ is hydrogen.

27. The method according to claim 21 wherein R₅ and R₆ are hydrogen.

28. The method according to claim 23 wherein R₅ and R₆ are hydrogen.

29. The method according to claim 24 wherein R₅ and R₆ are hydrogen.

30. The method according to claim 29 wherein R₁₆ is fluoro.

31. The method according to claim 21 wherein R₁, R₂, R₃, R₄, R₇, R₈, R₁₃, R₁₄ and R₁₅ are hydrogen, R₉ is hydrogen, lower alkyl, or halogen and R₁₁ and R₁₂ are independently hydrogen, hydroxy, lower alkoxy, halogen or lower alkyl, R₁₆ and R₁₇ are independently hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy and R₅ and R₆ are independently hydrogen or lower alkyl.

32. The method according to claim 31 wherein R₁₆ is fluoro or chloro, methyl, methoxy, R₁₇ is hydrogen, R₉ is hydrogen, methyl or fluoro or chloro and R₁₁ and R₁₂ are independently hydrogen, hydroxy, methoxy or methyl, fluoro or chloro, and R₅ and R₆ are hydrogen.

33. The method according to claim 31 wherein R₁₆ is fluoro.

34. The method according to claim 21 wherein one of R₉, R₁₁ and R₁₂ is other than hydrogen, R₁₇ is hydrogen and R₁₆ is chloro or fluoro.

35. The method according to claim 21 wherein R₅ and R₆ are hydrogen.

36. The method according to claim 35 wherein R₁₇ is hydrogen or fluoro;

R₁₁ and R₁₂ are independently hydrogen, hydroxy, lower alkyl or halogen;

R₉ is hydrogen, and R₁₆ is fluoro or chloro.

37. The method according to claim 35 wherein R₁₇ is hydrogen;

R₉ is hydrogen and R₁₁ and R₁₂ are independently hydrogen or hydroxy and R₁₆ is fluoro, chloro or methyl.

38. The method according to claim 37 wherein R₁₆ is chloro or fluoro.

39. The method according to claim 21 wherein the compound is 16α

-fluoro-5α

-androstan-17-one or 16α

-fluoro-7β

-hydroxy-5α

-androsten-17-one.

40. The method according to claim 21 or 31 wherein the patient additionally has at least one of the following characteristics:

(a) is insulin resistant

(b) is obese

(c) has a HDL level less than about 40 mg/dl if male and less than about 45 mg/dl if female.

41. The method according to claim 40 wherein the patient has a BMI greater than about 30 Kg/m².

65. The method according to any one of claims 21, 48 or 58 wherein the compound is 16α

-fluoro-5α

-androstan-17-one, 7α

-hydroxy-16α

-fluoro-5α

-androstan-17-one or 16α

-fluoro-7β

-hydroxy-5α

-androstan-17-one.

68. The method according to claim 65 wherein the compound is administered buccally.

42. A method of preventing atherosclerosis, coronary heart disease or stroke comprising administering to a patient a therapeutically effective amount of a compound of the formula:

43. The method according to claim 42 wherein R₅ and R₆ are hydrogen and R₁₆ is lower alkyl, hydroxy, lower alkoxy, or halogen and R₁₇ is hydrogen, lower alkyl, hydroxy, lower alkoxy or halogen.

44. The method according to claim 43 wherein R₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₃, R₁₄ and R₁₅ are hydrogen, R₁₁ is hydrogen and R₁₂ is hydrogen or hydroxy.

45. The method according to claim 43 wherein halogen is fluoro or chloro.

46. The method according to claim 43 wherein R₁₆ is fluoro and R₁₇ is hydrogen.

47. The method according to claim 44 wherein R₁₆ is fluoro and R₁₇ is hydrogen.

48. A method of preventing atherosclerosis, coronary heart disease or stroke comprising administering to a patient a therapeutically effective amount of a compound of the formula:

49. The method according to claim 48 wherein R₅ and R₆ are hydrogen and R₁₆ is lower alkyl, hydroxy, lower alkoxy, or halogen and R₁₇ is hydrogen, lower alkyl, hydroxy, lower alkoxy or halogen.

50. The method according to claim 49 wherein R₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₃, R₁₄ and R₁₅ are hydrogen, R₁₁ is hydrogen and R₁₂ is hydrogen or hydroxy.

51. The method according to claim 49 wherein halogen is fluoro or chloro.

52. The method according to claim 50 wherein R₁₆ is fluoro and R₁₇ is hydrogen.

53. A method of treating Syndrome X which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the Formula:

54. The method according to claim 53 wherein R₅ and R₆ are hydrogen and R₁₆ is lower alkyl, hydroxy, lower alkoxy, or halogen and R₁₇ is hydrogen, lower alkyl, hydroxy, lower alkoxy or halogen.

55. The method according to claim 54 wherein R₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₃, R₁₄ and R₁₅ are hydrogen, R₁₁ is hydrogen and R₁₂ is hydrogen or hydroxy.

56. The method according to claim 54 wherein halogen is fluoro or chloro.

57. The method according to claim 55 wherein R₁₆ is fluoro and R₁₇ is hydrogen.

58. A method of treating Syndrome X which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula:

59. The method according to claim 58 wherein R₅ and R₆ are hydrogen and R₁₆ is lower alkyl, hydroxy, lower alkoxy, or halogen and R₁₇ is hydrogen, lower alkyl, hydroxy, lower alkoxy or halogen.

60. The method according to claim 59 wherein R₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₃, R₁₄ and R₁₅ are hydrogen, R₁₁ is hydrogen and R₁₂ is hydrogen or hydroxy.

61. The method according to claim 59 wherein halogen is fluoro or chloro.

62. The method according to claim 59 wherein R₁₆ is fluoro and R₁₇ is hydrogen.

63. The method according to claim 60 wherein R₁₆ is fluoro and R₁₇ is hydrogen.

69. A method of lowering the concentration of excess glucocorticoid in a mammal which comprises administering to said mammal, an anti-glucocorticoid effective amount of a compound of the formula:

70. The method according to claim 69 wherein R₅ and R₆ are hydrogen and R₁₆ is lower alkyl, hydroxy, lower alkoxy, or halogen and R₁₇ is hydrogen, lower alkyl, hydroxy, lower alkoxy or halogen.

71. The method according to claim 70 wherein R₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₃, R₁₄ and R₁₅ are hydrogen, R₁₁ is hydrogen and R₁₂ is hydrogen or hydroxy.

72. The method according to claim 70 wherein halogen is fluoro or chloro.

73. The method according to claim 70 wherein R₁₆ is fluoro and R₁₇ is hydrogen.

74. The method according to claim 71 wherein R₁₆ is fluoro and R₁₇ is hydrogen.

75. The method according to claim 69 wherein the compound is 16α

-fluoro-5-androsten-17-one, 7α

-hydroxy-16α

-fluoro-5-androsten-17-one or 7β

-hydroxy-16α

-fluoro-5-androsten-17-one.

76. The method according to claim 69 wherein the compound is administered buccally.

77. The method according to claim 75 wherein the compound is administered buccally.

84. The method according to claim 77 wherein the compound is 16α

-fluoro-5α

-androstan-17-one, 7α

-hydroxy-16α

-fluoro-5α

-androstan-17-one or 7β

-hydroxy-16α

-fluoro-5α

-androstan-17-one.

85. The method according to claim 77 wherein the compound is administered buccally.

86. The method according to claim 84 wherein the compound is administered buccally.

78. The method of lowering the concentration of excess glucocorticoid in a mammal which comprises administering to said mammal an anti-glucocorticoid effective amount of a compound of the formula:

79. The method according to claim 78 wherein R₅ and R₆ are hydrogen and R₁₆ is lower alkyl, hydroxy, lower alkoxy, or halogen and R₁₇ is hydrogen, lower alkyl, hydroxy, lower alkoxy or halogen.

80. The method according to claim 79 wherein R₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₃, R₁₄ and R₁₅ are hydrogen, R₁₁ is hydrogen and R₁₂ is hydrogen or hydroxy.

81. The method according to claim 79 wherein halogen is fluoro or chloro.

82. The method according to claim 79 wherein R₁₆ is fluoro and R₁₇ is hydrogen.

83. The method according to claim 80 wherein R₁₆ is fluoro and R₁₇ is hydrogen.

87. A method of minimizing the androgenicity of a steroid when administered to a patient, the steroid having the formula:

88. The method according to claim 87 wherein R₅ and R₆ are hydrogen and R₁₆ is halo.

89. The method according to claim 88 wherein R₁₆ is chloro or fluoro.

90. The method according to claim 89 wherein R₁₆ is fluoro.

91. The method according to claim 87 wherein the compound is 16α

-fluoro-5-androsten-17-one or 16α

-fluoro-7β

-hydroxy-5-androsten-17-one.

92. A method of minimizing the androgenicity of a steroid when administered to a patient, the steroid having the formula:

93. The method according to claim 92 wherein the steroid is 16α

-fluoro-5α

-androstan-17-one or 16α

-fluoro-7β

-hydroxy-5α

-androsten-17-one.

94. The method according to claim 92 wherein R₅ and R₆ are hydrogen and R₁₆ is halo.

95. The method according to claim 94 wherein R₁₆ is chloro or fluoro.

96. The method according to claim 95 wherein R₁₆ is fluoro.

97. A method for treating or preventing a condition selected from the group consisting of hippocampal damage and immunosescence in a patient which comprises administering to said patient a therapeutically effective amount of a compound of the formula:

98. The method according to claim 97 wherein R₅ and R₆ are hydrogen and R₁₆ is halo.

99. The method according to claim 98 wherein R₁₆ is chloro or fluoro.

100. The method according to claim 99 wherein R₁₆ is fluoro.

101. The method according to claim 97 wherein the compound is 16α

-fluoro-5-androsten-17-one or 16α

-fluoro-7β

-hydroxy-5-androsten-17-one.

102. A method for treating or preventing a condition selected from the group consisting of hippocampal damage and immunosescence in a patient which comprises administering to said patient a therapeutically effective amount of a compound of the formula:

103. The method according to claim 102 wherein R₅ and R₆ are hydrogen and R₁₆ is halo.

104. The method according to claim 103 wherein R₁₆ is chloro or fluoro.

105. The method according to claim 104 wherein R₁₆ is fluoro.

106. The method according to claim 102 wherein the steroid is 16α

-fluoro-5α

-androstan-17-one or 16α

-fluoro-7β

-hydroxy-5α

-androstan-17-one.