2α-methyl and 2β-methyl analogs of 19,26,27-trinor-(20S)-1α-hydroxyvitamin D 3 and their uses

• US 8,440,647 B2
• Filed: 07/09/2007
• Issued: 05/14/2013
• Est. Priority Date: 11/22/2004
• Status: Expired due to Fees

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: DeLuca, Hector F., Plum, Lori A., Grzywacz, Pawel K., Clagett-Dame, Margaret
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US11/775,042
• Publication Number:
  US 20070270391A1
• Time in Patent Office: 2,136 Days
• Field of Search: 514/167, 552/653
• US Class Current: 514/167
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 401/00 Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

This invention discloses 2α-methyl and 2β-methyl analogs of 19,26,27-trinor-(20S)-1α-hydroxyvitamin D₃ and pharmaceutical uses therefor. These compounds exhibit pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anti-cancer agent and for the treatment of skin diseases such as psoriasis as well as skin conditions such as wrinkles, slack skin, dry skin and insufficient sebum secretion. These compounds also have little, if any, calcemic activity and therefore may be used to treat autoimmune disorders or inflammatory diseases in humans as well as renal osteodystrophy. These compounds may also be used for the treatment or prevention of obesity.

Claims

1. A compound having the formula:

2. A pharmaceutical composition containing an effective amount of at least one compound as claimed in claim 1 together with a pharmaceutically acceptable excipient.

3. The pharmaceutical composition of claim 2 wherein said effective amount comprises from about 0.01 μ

g to about 1000 μ

g per gram of composition.

4. The pharmaceutical composition of claim 2 wherein said effective amount comprises from about 0.1 μ

g to about 500 μ

g per gram of composition.

5. A method of treating psoriasis comprising administering to a subject with psoriasis art effective amount of a compound having the formula:

6. The method of claim 5 wherein the compound is administered orally.

7. The method of claim 5 wherein the compound is administered parenterally.

8. The method of claim 5 wherein the compound is administered transdermally.

9. The method of claim 5 wherein the compound is administered topically.

10. The method of claim 5 wherein the compound is administered rectally.

11. The method of claim 5 wherein the compound is administered nasally.

12. The method of claim 5 wherein the compound is administered sublingually.

13. The method of claim 5 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

14. A method of treating a disease selected from the group consisting of leukemia, colon cancer, breast cancer, skin cancer or prostate cancer comprising administering to a subject with said disease an effective amount of a compound having the formula:

15. The method of claim 14 wherein the compound is administered orally.

16. The method of claim 14 wherein the compound is administered parenterally.

17. The method of claim 14 wherein the compound is administered transdermally.

18. The method of claim 14 wherein the compound is administered rectally.

19. The method of claim 14 wherein the compound is administered nasally.

20. The method of claim 14 wherein the compound is administered sublingually.

21. The method of claim 14 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

22. A method of treating an autoimmune disease selected from the group consisting of multiple sclerosis, lupus, diabetes mellitus, host versus graft rejection, and rejection of organ transplants, comprising administering to a subject with said disease an effective amount of a compound having the formula:

23. The method of claim 22 wherein the compound is administered orally.

24. The method of claim 22 wherein the compound is administered parenterally.

25. The method of claim 22 wherein the compound is administered transdermally.

26. The method of claim 22 wherein the compound is administered rectally.

27. The method of claim 22 wherein the compound administered nasally.

28. The method of claim 22 wherein the compound is administered sublingually.

29. The method of claim 22 wherein the compound is administered in a dosage of from about 1 μ

g/day to about 1000 μ

g/day.

30. A method of treating an inflammatory disease selected from the group consisting of rheumatoid arthritis, asthma, and inflammatory bowel diseases, comprising administering to a subject with said disease an effective amount of a compound having the formula:

31. The method of claim 30 wherein the compound is administered orally.

32. The method of claim 30 wherein the compound is administered parenterally.

33. The method of claim 30 wherein the compound administered transdermally.

34. The method of claim 30 wherein the compound is administered rectally.

35. The method of claim 30 wherein the compound is administered nasally.

36. The method of claim 30 wherein the compound is administered sublingually.

37. The method of claim 30 wherein the compound is administered in a dosage of from about 0.0 μ

g/day to about 1000 μ

g/day.

38. A method of treating a skin condition selected from the group consisting of wrinkles, lack of adequate skin firmness, lack of adequate dermal hydration and insufficient sebum secretion which comprises administering to a subject with said skin condition an effective amount of a compound having the formula:

39. The method of claim 38 wherein the compound is administered orally.

40. The method of claim 38 wherein the compound is administered parenterally.

41. The method of claim 38 wherein the compound is administered transdermally.

42. The method of claim 38 wherein the compound is administered topically.

43. The method of claim 38 wherein the compound is administered rectally.

44. The method of claim 38 wherein the compound is administered nasally.

45. The method of claim 38 wherein the compound is administered sublingually.

46. The method of claim 38 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

47. A method of treating renal osteodystrophy comprising administering to a subject with renal osteodystrophy an effective amount of a compound having the formula:

48. The method of claim 47 wherein the compound is administered orally.

49. The method of claim 47 wherein the compound is administered parenterally.

50. The method of claim 47 wherein the compound is administered transdermally.

51. The method of claim 47 wherein the compound is administered rectally.

52. The method of claim 47 wherein the compound is administered nasally.

53. The method of claim 47 wherein the compound is administered sublingually.

54. The method of claim 47 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

55. A method of treating psoriasis comprising administering to a subject with psoriasis an effective amount of a compound having the formula:

56. The method of claim 55 wherein the compound is administered orally.

57. The method of claim 55 wherein the compound is administered parenterally.

58. The method of claim 55 wherein the compound is administered transdermally.

59. The method of claim 55 wherein the compound is administered topically.

60. The method of claim 55 wherein the compound is administered rectally.

61. The method of claim 55 wherein the compound is administered nasally.

62. The method of claim 55 wherein the compound is administered sublingually.

63. The method of claim 55 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

64. A method of treating a disease selected from the group consisting of leukemia, colon cancer, breast cancer, skin cancer or prostate cancer comprising administering to a subject with said disease an effective amount of a compound having the formula:

65. The method of claim 64 wherein the compound is administered orally.

66. The method of claim 64 wherein the compound is administered parenterally.

67. The method of claim 64 wherein the compound is administered transdermally.

68. The method of claim 64 wherein the compound is administered rectally.

69. The method of claim 64 wherein the compound is administered nasally.

70. The method of claim 64 wherein the compound is administered sublingually.

71. The method of claim 64 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

72. A method of treating an autoimmune disease selected from the group consisting of multiple sclerosis, lupus, diabetes mellitus, host versus graft rejection, and rejection of organ transplants, comprising administering to a subject with said disease an effective amount of a compound having the formula:

73. The method of claim 72 wherein the compound is administered orally.

74. The method of claim 72 wherein the compound is administered parenterally.

75. The method of claim 72 wherein the compound is administered transdermally.

76. The method of claim 72 wherein the compound is administered rectally.

77. The method of claim 72 wherein the compound is administered nasally.

78. The method of claim 72 wherein the compound is administered sublingually.

79. The method of claim 72 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

80. A method of treating an inflammatory disease selected from the group consisting of rheumatoid arthritis, asthma, and inflammatory bowel diseases, comprising administering to a subject with said disease an effective amount of a compound having the formula:

81. The method of claim 80 wherein the compound is administered orally.

82. The method of claim 80 wherein the compound is administered parenterally.

83. The method of claim 80 wherein the compound is administered transdermally.

84. The method of claim 80 wherein the compound is administered rectally.

85. The method of claim 80 wherein the compound is administered nasally.

86. The method of claim 80 wherein the compound is administered sublingually.

87. The method of claim 80 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

88. A method of treating a skin condition selected from the group consisting of wrinkles, lack of adequate skin firmness, lack of adequate dermal hydration and insufficient sebum secretion which comprises administering to a subject with said skin condition an effective amount of a compound having the formula:

89. The method of claim 88 wherein the compound is administered orally.

90. The method of claim 88 wherein the compound is administered parenterally.

91. The method of claim 88 wherein the compound is administered transdermally.

92. The method of claim 88 wherein the compound is administered topically.

93. The method of claim 88 wherein the compound is administered rectally.

94. The method of claim 88 wherein the compound is administered nasally.

95. The method of claim 88 wherein the compound is administered sublingually.

96. The method of claim 88 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

97. A method of treating renal osteodystrophy comprising administering to a subject with renal osteodystrophy an effective amount of a compound having the formula:

98. The method of claim 97 wherein the compound is administered orally.

99. The method of claim 97 wherein the compound is administered parenterally.

100. The method of claim 97 wherein the compound is administered transdermally.

101. The method of claim 97 wherein the compound is administered rectally.

102. The method of claim 97 wherein the compound is administered nasally.

103. The method of claim 97 wherein the compound is administered sublingually.

104. The method of claim 97 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.