2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-vitamin D analogs

• US 7,713,953 B2
• Filed: 07/10/2008
• Issued: 05/11/2010
• Est. Priority Date: 07/10/2008
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Barycki, Rafal, Plum, Lori A., DeLuca, Hector F., Clagett-Dame, Margaret
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US12/171,094
• Publication Number:
  US 20100009943A1
• Time in Patent Office: 670 Days
• Field of Search: 514/167, 552/653
• US Class Current: 514/167
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• 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

Abstract

This invention discloses 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-vitamin D analogs, and specifically 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-1α,24(R)-dihydroxyvitamin D₃, and pharmaceutical uses therefor. This compound exhibits relatively high transcription activity as well as 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 shows lower activity in vivo on bone calcium mobilization and intestinal calcium transport activity compared to the native hormone 1α,25-dihydroxyvitamin D₃, and therefore may be used to treat autoimmune disorders or inflammatory diseases in humans as well as renal osteodystrophy. This compound may also be used for the treatment or prevention of obesity.

Claims

1. A compound having the formula:

2. The compound of claim 1 wherein X₃ is hydrogen.

3. The compound of claim 1 wherein X₁ is hydrogen.

4. The compound of claim 1 wherein X₁, X₂ and X₃ are all t-butyldimethylsilyl.

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. 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-1α

,24(R)-dihydroxyvitamin D₃ having the formula;

9. A pharmaceutical composition containing an effective amount of 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-1α

,24(R)-dihydroxyvitamin D₃ together with a pharmaceutically acceptable excipient.

10. The pharmaceutical composition of claim 9 wherein said effective amount comprises from about 0.01 μ

g to about 1000 μ

g per gram of composition.

11. The pharmaceutical composition of claim 9 wherein said effective amount comprises from about 0.1 μ

g to about 500 μ

g per gram of composition.

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

13. The method of claim 12 wherein the compound is administered orally.

14. The method of claim 12 wherein the compound is administered parenterally.

15. The method of claim 12 wherein the compound is administered transdermally.

16. The method of claim 12 wherein the compound is administered topically.

17. The method of claim 12 wherein the compound is administered rectally.

18. The method of claim 12 wherein the compound is administered nasally.

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

20. The method of claim 12 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

21. The method of claim 12 wherein the compound is 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-1α

,24(R)-dihydroxyvitamin D₃ having the formula;

22. 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:

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 is 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 0.01 μ

g/day to about 1000 μ

g/day.

30. The method of claim 22 wherein the compound is 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-1α

,24(R)-dihydroxyvitamin D₃ having the formula;

31. 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:

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

33. The method of claim 31 wherein the compound is administered parenterally.

34. The method of claim 31 wherein the compound is administered transdermally.

35. The method of claim 31 wherein the compound is administered rectally.

36. The method of claim 31 wherein the compound is administered nasally.

37. The method of claim 31 wherein the compound is administered sublingually.

38. The method of claim 31 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

39. The method of claim 31 wherein the compound is 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-1α

,24(R)-dihydroxyvitamin D₃ having the formula;

40. 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:

41. The method of claim 40 wherein the compound is administered orally.

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

43. The method of claim 40 wherein the compound is administered transdermally.

44. The method of claim 40 wherein the compound is administered rectally.

45. The method of claim 40 wherein the compound is administered nasally.

46. The method of claim 40 wherein the compound is administered sublingually.

47. The method of claim 40 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

48. The method of claim 40 wherein the compound is 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-1α

,24(R)-dihydroxyvitamin D₃ having the formula;

49. 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:

50. The method of claim 49 wherein the compound is administered orally.

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

52. The method of claim 49 wherein the compound is administered transdermally.

53. The method of claim 49 wherein the compound is administered topically.

54. The method of claim 49 wherein the compound is administered rectally.

55. The method of claim 49 wherein the compound is administered nasally.

56. The method of claim 49 wherein the compound is administered sublingually.

57. The method of claim 49 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

58. The method of claim 49 wherein the compound is 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-1α

,24(R)-dihydroxyvitamin D₃ having the formula;

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

60. The method of claim 59 wherein the compound is administered orally.

61. The method of claim 59 wherein the compound is administered parenterally.

62. The method of claim 59 wherein the compound is administered transdermally.

63. The method of claim 59 wherein the compound is administered rectally.

64. The method of claim 59 wherein the compound is administered nasally.

65. The method of claim 59 wherein the compound is administered sublingually.

66. The method of claim 59 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

67. The method of claim 59 wherein the compound is 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-1α

,24(R)-dihydroxyvitamin D₃ having the formula;

68. A method of treating obesity of an animal, inhibiting adipocyte 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 compound having the formula:

69. The method of claim 68 wherein the compound is administered orally.

70. The method of claim 68 wherein the compound is administered parenterally.

71. The method of claim 68 wherein the compound is administered transdermally.

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

73. The method of claim 68 wherein the compound is administered nasally.

74. The method of claim 68 wherein the compound is administered sublingually.

75. The method of claim 68 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

76. The method of claim 68 wherein the compound is 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-1α

,24(R)-dihydroxyvitamin D₃ having the formula;

77. The method of claim 68 wherein the animal is a human.

78. The method of claim 68 wherein the animal is a domestic animal.

79. The method of claim 68 wherein the animal is an agricultural animal.