17,20(E)-dehydro vitamin D analogs and their uses

• US 20070249568A1
• Filed: 07/09/2007
• Published: 10/25/2007
• Est. Priority Date: 11/22/2004
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Plum, Lori, Clagett-Dame, Margaret, DeLuca, Hector, Tadi, Bulli
• Granted Patent: US 7,741,313 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• 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 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 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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: Y02P 20/55 : Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

This invention discloses 17,20(E)-dehydro vitamin D analogs, and specifically 17(E)-1α,25 -dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ and pharmaceutical uses therefor. This compound exhibits 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. This compound also has little, if any, calcemic activity and therefore may be used to treat autoimmune disorders and inflammatory diseases in humans as well as renal osteodystrophy and obesity.

Claims

1. A compound having the formula:

2. The compound of claim 1 wherein Y₂ is hydrogen.

3. The compound of claim 1 wherein Y₁ is hydrogen.

4. The compound of claim 1 wherein Y₁, Y₂ and R⁵ are hydrogen.

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

6. The pharmaceutical composition of claim 5 wherein said effective amount comprises from about 0.01 μ

g to about 1000 μ

g per gram of composition.

7. The pharmaceutical composition of claim 5 wherein said effective amount comprises from about 0.1 μ

g to about 500 μ

g per gram of composition.

8. A compound having the formula:

9. The compound of claim 8 wherein Y₂ is hydrogen.

10. The compound of claim 8 wherein Y₁ is hydrogen.

11. The compound of claim 8 wherein Y₁ and Y₂ are both t-butyldimethylsilyl.

12. A pharmaceutical composition containing an effective amount of at least one compound as claimed in claim 8 together with a pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12 wherein said effective amount comprises from about 0.01 μ

g to about 1000 μ

g per gram of composition.

14. The pharmaceutical composition of claim 12 wherein said effective amount comprise from about 0.1 μ

g to about 500 μ

g per gram of composition.

15. 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ having the formula;

17. The pharmaceutical composition of claim 15 wherein said effective amount comprises from about 0.01 μ

g to about l 000 μ

g per gram of composition.

18. The pharmaceutical composition of claim 15 wherein said effective amount comprises from about 0.1 μ

g to about 500 μ

g per gram of composition.

16. A pharmaceutical composition containing an effective amount of 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ together with a pharmaceutically acceptable excipient.

19. A method of treating psoriasis comprising administering to a subject with psoriasis an effective amount of a 17(20)-dehydro vitamin D analog having the formula:

20. The method of claim 19 wherein the vitamin D analog is administered orally.

21. The method of claim 19 wherein the vitamin D analog is administered parenterally.

22. The method of claim 19 wherein the vitamin D analog is administered transdermally.

23. The method of claim 19 wherein the vitamin D analog is administered topically.

24. The method of claim 19 wherein the vitamin D analog is administered in a dosage of from about 0.01 g/day to about 1000 kg/day.

25. A method of treating psoriasis comprising administering to a subject with psoriasis an effective amount of 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ having the formula;

26. The method of claim 25 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered orally.

27. The method of claim 25 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered parenterally.

28. The method of claim 25 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered transdermally.

29. The method of claim 25 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered topically.

30. The method of claim 25 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

31. 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 17(20)-dehydro vitamin D analog having the formula:

32. The method of claim 31 wherein the vitamin D analog is administered orally.

33. The method of claim 31 wherein the vitamin D analog is administered parenterally.

34. The method of claim 31 wherein the vitamin D analog is administered transdermally.

35. The method of claim 31 wherein the vitamin D analog is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

36. 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 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ having the formula;

37. The method of claim 36 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered orally.

38. The method of claim 36 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered parenterally.

39. The method of claim 36 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered transdermally.

40. The method of claim 36 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

/day to about 1000 μ

g/day.

41. A method of treating an autoimmune disease selected from the group consisting of multiple sclerosis, lupus, diabetes mellitus, hot versus graft rejection, and rejection of organ transplants, comprising administering to a subject with said disease an effective amount of a 17(20)-dehydro vitamin D analog having the formula:

42. The method of claim 41 wherein the vitamin D analog is administered orally.

43. The method of claim 41 wherein the vitamin D analog is administered parenterally.

44. The method of claim 41 wherein the vitamin D analog is administered transdermally.

45. The method of claim 41 wherein the vitamin D analog is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

46. 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 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ having the formula;

47. The method of claim 46 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered orally.

48. The method of claim 46 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered parenterally.

49. The method of claim 46 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered transdermally.

50. The method of claim 46 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

51. 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 17(20)-dehydro vitamin D analog having the formula:

52. The method of claim 51 wherein the vitamin D analog is administered orally.

53. The method of claim 51 wherein the vitamin D analog is administered parenterally.

54. The method of claim 51 wherein the vitamin D analog is administered transdermally.

55. The method of claim 51 wherein the vitamin D analog is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

56. 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 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ having the formula;

57. The method of claim 56 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered orally.

58. The method of claim 56 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered parenterally.

59. The method of claim 56 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered transdermally.

60. The method of claim 56 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

/day to about 1000 μ

g/day.

61. 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 17(20)-dehydro vitamin D analog having the formula:

62. The method of claim 61 wherein the vitamin D analog is administered orally.

63. The method of claim 61 wherein the vitamin D analog is administered parenterally.

64. The method of claim 61 wherein the vitamin D analog is administered transdermally.

65. The method of claim 61 wherein the vitamin D analog is administered topically.

66. The method of claim 61 wherein the vitamin D analog is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

67. 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 administered to a subject with said skin condition an effective amount of 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ having the formula;

68. The method of claim 67 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered orally.

69. The method of claim 67 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered parenterally.

70. The method of claim 67 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered transdermally.

71. The method of claim 67 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered topically.

72. The method of claim 67 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered in a dosage of from about 0.0 μ

g/day to about 1000 μ

g/day.

73. A method of treating renal osteodystrophy comprising administering to a subject with renal osteodystrophy an effective amount of a 17(20)-dehydro vitamin D analog having the formula:

74. The method of claim 73 wherein the vitamin D analog is administered orally.

75. The method of claim 73 wherein the vitamin D analog is administered parenterally.

76. The method of claim 73 wherein the vitamin D analog is administered transdermally.

77. The method of claim 73 wherein the vitamin D analog is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

78. A method of treating renal osteodystrophy comprising administering to a subject with renal osteodystrophy an effective amount of 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ having the formula;

79. The method of claim 78 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered orally.

80. The method of claim 78 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered parenterally.

81. The method of claim 78 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered transdermally.

82. The method of claim 78 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

83. A method of treating or preventing obesity of an animal, inhibiting adipoctye differentiation, inhibiting SCD-1 gene transcription, and/or reducing body fat in an animal comprising administering to an animal in need thereof an effective amount of a 17(20)-dehydro vitamin D analog having the formula:

84. The method of claim 83 wherein the vitamin D analog is administered orally.

85. The method of claim 83 wherein the vitamin D analog is administered parenterally.

86. The method of claim 83 wherein the vitamin D analog is administered transdermally.

87. The method of claim 83 wherein the vitamin D analog is administered in a dosage of from about 0.01 μ

g/date to about 1000 μ

g/day.

88. The method of claim 83 wherein the animal is a human.

89. The method of claim 83 wherein the animal is a domestic animal.

90. The method of claim 83 wherein the animal is an agricultural animal.

91. A method of treating or preventing obesity of an animal, inhibiting adipoctye differentiation, inhibiting SCD-1 gene transcription, and/or reducing body fat in an animal comprising administering to an animal in need thereof an effective amount of 17(E)-1α

,25 -dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ having the formula;

92. The method of claim 91 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered orally.

93. The method of claim 91 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered parenterally.

94. The method of claim 91 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered transdermally.

95. The method of claim 91 wherein 17(E)-1α

,25-dihydroxy-17(20)-dehydro-2-methylene-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

96. The method of claim 91 wherein the animal is a human.

97. The method of claim 91 wherein the animal is a domestic animal.

98. The method of claim 91 wherein the animal is an agricultural animal.