(20S) 1alpha-hydroxy-2alpha-methyl and 2beta-methyl-19-nor-vitamin D3 and their uses

• US 20030203882A1
• Filed: 04/22/2002
• Published: 10/30/2003
• Est. Priority Date: 04/22/2002
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: DeLuca, Hector F., Sicinski, Rafal R., Grzywacz, Pawel K.
• Granted Patent: US 6,846,811 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• 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 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• 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 3/10 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07C 49/433 the condensed ring system containing seven carbon atoms
• CPC Class Codes: C07C 49/443 the condensed ring system containing eight or nine carbon atoms

Abstract

This invention discloses (20S)-1α-hydroxy-2α-methyl-19-nor-vitamin D₃ and (20S)-1α-hydroxy-2β-methyl-19-nor-vitamin 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 very significant calcemic activity and therefore may be used to treat immune disorders in humans as well as metabolic bone diseases such as osteoporosis.

Claims

1. A method of treating psoriasis comprising administering to a patient with psoriasis an effective amount of (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ having the formula;

2. The method of claim 1 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin is administered orally.

3. The method of claim 1 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin is administered parenterally.

4. The method of claim 1 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin is administered transdermally.

5. The method of claim 1 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin is administered topically.

6. The method of claim 1 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

7. A method of treating a disease selected from the group consisting of leukemia, colon cancer, breast cancer or prostate cancer comprising administering to a patient with said disease an effective amount of (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin having the formula;

8. The method of claim 7 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered orally.

9. The method of claim 7 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered parenterally.

10. The method of claim 7 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered transdermally.

11. The method of claim 7 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

12. A method of treating an autoimmune disease selected from the group consisting of multiple sclerosis, lupis, diabetes, mellitus, host versus graft reaction, and rejection of organ transplants, comprising administering to a patient with said disease an effective amount of (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ having the formula;

13. The method of claim 12 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered orally.

14. The method of claim 12 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered parenterally.

15. The method of claim 12 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered transdermally.

16. The method of claim 12 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

17. A method of treating an inflammatory disease selected from the group consisting of rheumatoid arthritis, asthma, and inflammatory bowel diseases, comprising administering to a patient with said disease an effective amount of (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ having the formula;

18. The method of claim 17 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered orally.

19. The method of claim 17 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered parenterally.

20. The method of claim 17 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered transdermally.

21. The method of claim 17 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

22. (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ having the formula;

23. 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 patient with said skin condition an effective amount of (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ having the formula;

24. The method of claim 23 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered orally.

25. The method of claim 23 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered parenterally.

26. The method of claim 23 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered transdermally.

27. The method of claim 23 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered topically.

28. The method of claim 23 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

29. A method of treating a metabolic bone disease where it is desired to maintain or increase bone mass comprising administering to a patient with said disease an effective amount of (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ having the formula;

30. The method of claim 29 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered orally.

31. The method of claim 29 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered parenterally.

32. The method of claim 29 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered transdermally.

33. The method of claim 29 wherein (20S)-1α

-hydroxy-2α

-methyl-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

34. The method of claim 29 wherein the disease is senile osteoporosis.

35. The method of claim 29 wherein the disease is postmenopausal osteoporosis.

36. The method of claim 29 wherein the disease is steroid-induced osteoporosis.

37. The method of claim 29 wherein the disease is low bone turnover osteoporosis.

38. The method of claim 29 wherein the disease is osteomalacia.

39. A method of treating psoriasis comprising administering to a patient with psoriasis an effective amount of (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ having the formula;

40. The method of claim 39 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered orally.

41. The method of claim 39 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered parenterally.

42. The method of claim 39 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃is administered transdermally.

43. The method of claim 39 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered topically.

44. The method of claim 39 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

45. A method of treating a disease selected from the group consisting of leukemia, colon cancer, breast cancer or prostate cancer comprising administering to a patient with said disease an effective amount of (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ having the formula;

46. The method of claim 45 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered orally.

47. The method of claim 45 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered parenterally.

48. The method of claim 45 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered transdermally.

49. The method of claim 45 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

50. A method of treating an autoimmune disease selected from the group consisting of multiple sclerosis, lupis, diabetes, mellitus, host versus graft reaction, and rejection of organ transplants, comprising administering to a patient with said disease an effective amount of (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ having the formula;

51. The method of claim 50 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered orally.

52. The method of claim 50 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered parenterally.

53. The method of claim 50 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered transdermally.

54. The method of claim 50 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

55. A method of treating an inflammatory disease selected from the group consisting of rheumatoid arthritis, asthma, and inflammatory bowel diseases, comprising administering to a patient with said disease an effective amount of (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ having the formula;

56. The method of claim 55 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered orally.

57. The method of claim 55 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered parenterally.

58. The method of claim 55 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered transdermally.

59. The method of claim 55 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

60. (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ having the formula;

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 patient with said skin condition an effective amount of (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ having the formula;

62. The method of claim 61 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered orally.

63. The method of claim 61 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered parenterally.

64. The method of claim 61 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered transdermally.

65. The method of claim 61 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered topically.

66. The method of claim 61 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

67. A method of treating a metabolic bone disease where it is desired to maintain or increase bone mass comprising administering to a patient with said disease an effective amount of (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ having the formula;

68. The method of claim 67 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered orally.

69. The method of claim 67 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered parenterally.

70. The method of claim 67 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered transdermally.

71. The method of claim 67 wherein (20S)-1α

-hydroxy-2β

-methyl-19-nor-vitamin D₃ is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

72. The method of claim 67 wherein the disease is senile osteoporosis.

73. The method of claim 67 wherein the disease is postmenopausal osteoporosis.

74. The method of claim 67 wherein the disease is steroid-induced osteoporosis.

75. The method of claim 67 wherein the disease is low bone turnover osteoporosis.

76. The method of claim 67 wherein the disease is osteomalacia.

77. A compound having the formula: