1α-hydroxy-2-(3′-hydroxypropylidene)-19-nor-vitamin D compounds with a 1,1-dimethylpropyl side chain

• US 7,763,598 B2
• Filed: 04/06/2007
• Issued: 07/27/2010
• Est. Priority Date: 04/10/2006
• 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: Plum, Lori A., DeLuca, Hector F., Clagett-Dame, Margaret, Sicinski, Rafal R., Glebocka, Agnieszka
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US11/697,430
• Publication Number:
  US 20070238703A1
• Time in Patent Office: 1,208 Days
• Field of Search: 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 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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 1α-hydroxy-2-(3′-hydroxypropylidene)-19-nor-vitamin D compounds with a 1,1-dimethylpropyl side chain, 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. The compound of claim 1 wherein Y₁ is hydrogen.

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

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

5. The compound of claim 1 wherein X is hydrogen.

6. The compound of claim 1 wherein each of Y₁ and X is hydrogen.

7. The compound of claim 1 wherein each of Y₂ and X is hydrogen.

8. The compound of claim 1 wherein each of Y₁, Y₂ and X is t-butydimethylsilyl.

9. A pharmaceutical composition containing an effective amount of at least one compound as claimed in claim 1 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 10 mg per gram of composition.

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

g to about 1 mg per gram of composition.

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

g to about 10 mg per gram of composition.

15. The pharmaceutical composition of claim 10 wherein said effective amount comprises from about 0.1 μ

g to about 1 mg per gram of composition.

12. 1α

-hydroxy-2-[3′

-hydroxypropylidene]-20-methyl-19, 24, 25, 26, 27-pentanorvitamin D₃ (E-isomer) having the formula;

13. A pharmaceutical composition containing an effective amount of 1α

-hydroxy -2-[3′

-hydroxypropylidene]-20-methyl-19, 24, 25, 26, 27-pentanorvitamin D₃ (E-isomer) together with a pharmaceutically acceptable excipient.

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

17. The method of claim 16 wherein the compound is administered orally.

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

19. The method of claim 16 wherein the compound is administered transdermally.

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

21. The method of claim 16 wherein the compound is administered rectally.

22. The method of claim 16 wherein the compound is administered nasally.

23. The method of claim 16 wherein the compound is administered sublingually.

24. The method of claim 16 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 10 mg/day.

25. The method of claim 16 wherein the compound is 1α

-hydroxy-2-[3′

-hydroxypropylidene]-20-methyl-19, 24, 25, 26, 27-pentanorvitamin D₃ (E-isomer) having the formula;

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

27. The method of claim 26 wherein the compound is administered orally.

28. The method of claim 26 wherein the compound is administered parenterally.

29. The method of claim 26 wherein the compound is administered transdermally.

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

31. The method of claim 26 wherein the compound is administered nasally.

32. The method of claim 26 wherein the compound is administered sublingually.

33. The method of claim 26 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 10 mg/day.

34. The method of claim 26 wherein the compound is 1α

-hydroxy-2-[3′

-hydroxypropylidene]-20-methyl-19, 24, 25, 26, 27-pentanorvitamin D₃ (E-isomer) having the formula;

35. 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:

36. The method of claim 35 wherein the compound is administered orally.

37. The method of claim 35 wherein the compound is administered parenterally.

38. The method of claim 35 wherein the compound is administered transdermally.

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

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

41. The method of claim 35 wherein the compound is administered sublingually.

42. The method of claim 35 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 10 mg/day.

43. The method of claim 35 wherein the compound is 1α

-hydroxy-2-[3′

-hydroxypropylidene]-20-methyl-19, 24, 25, 26, 27-pentanorvitamin D₃ (E-isomer) having the formula;

44. 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:

45. The method of claim 44 wherein the compound is administered orally.

46. The method of claim 44 wherein the compound is administered parenterally.

47. The method of claim 44 wherein the compound is administered transdermally.

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

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

50. The method of claim 44 wherein the compound is administered sublingually.

51. The method of claim 44 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 10 mg/day.

52. The method of claim 44 wherein the inflammatory bowel disease is celiac disease.

53. The method of claim 44 wherein the inflammatory bowel disease is ulcerative colitis.

54. The method of claim 44 wherein the inflammatory bowel disease is Crohn'"'"'s disease.

55. The method of claim 44 wherein the compound is 1α

-hydroxy-2-[3′

-hydroxypropylidene]-20-methyl-19, 24, 25, 26, 27-pentanorvitamin D₃ (E-isomer) having the formula;

56. 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:

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

58. The method of claim 56 wherein the compound is administered parenterally.

59. The method of claim 56 wherein the compound is administered transdermally.

60. The method of claim 56 wherein the compound is administered topically.

61. The method of claim 56 wherein the compound is administered rectally.

62. The method of claim 56 wherein the compound is administered nasally.

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

64. The method of claim 56 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 10 mg/day.

65. The method of claim 56 wherein the compound is 1α

-hydroxy-2-[3′

-hydroxypropylidene]-20-methyl-19, 24, 25, 26, 27-pentanorvitamin D₃ (E-isomer) having the formula;

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

67. The method of claim 66 wherein the compound is administered orally.

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

69. The method of claim 66 wherein the compound is administered transdermally.

70. The method of claim 66 wherein the compound is administered rectally.

71. The method of claim 66 wherein the compound is administered nasally.

72. The method of claim 66 wherein the compound is administered sublingually.

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

g/day to about 10 mg/day.

74. The method of claim 66 wherein the compound is 1α

-hydroxy-2-[3′

-hydroxypropylidene]-20-methyl-19, 24, 25, 26, 27-pentanorvitamin D₃ (E-isomer) having the formula;

75. 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:

76. The method of claim 75 wherein the compound is administered orally.

77. The method of claim 75 wherein the compound is administered parenterally.

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

79. The method of claim 75 wherein the compound is administered rectally.

80. The method of claim 75 wherein the compound is administered nasally.

81. The method of claim 75 wherein the compound is administered sublingually.

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

g/day to about 10 mg/day.

83. The method of claim 75 wherein the compound is 1α

-hydroxy-2-[3′

-hydroxypropylidene]-20-methyl-19, 24, 25, 26, 27-pentanorvitamin D₃ (E-isomer) having the formula;

84. The method of claim 75 wherein the animal is a human.

85. The method of claim 75 wherein the animal is a domestic animal.

86. The method of claim 75 wherein the animal is an agricultural animal.