2-propylidene-19-nor-vitamin D compounds

• US 7,241,747 B2
• Filed: 04/09/2004
• Issued: 07/10/2007
• Est. Priority Date: 04/10/2003
• 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 A., DeLuca, Hector F., Sicinski, Rafal R., Glebocka, Agnieszka
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US10/821,479
• Publication Number:
  US 20040229851A1
• Time in Patent Office: 1,187 Days
• Field of Search: 552/653, 514/167
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/08 of the prostate
• 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 17/14 for baldness or alopecia
• 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 3/10 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 9/12 Antihypertensives
• 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
• CPC Class Codes: Y02P 20/55 : Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

2-propylidene-19-nor-vitamin D compounds are disclosed as well as pharmaceutical uses for these compounds and methods of synthesizing these compounds. These compounds are characterized by high bone calcium mobilization activity and high intestinal calcium transport activity. This results in novel therapeutic agents for the treatment and prophylaxis of diseases where bone formation is desired, particularly osteoporosis, as well as autoimmune diseases such as multiple sclerosis, diabetes mellitus and lupus. These compounds also 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. These compounds also increase both breaking strength and crushing strength of bones evidencing use in conjunction with bone replacement surgery such as hip and knee replacements.

Claims

1. A compound having the formula:

2. The compound of claim 1 where R is a side chain of the formula

3. The compound of claim 1 where R is a side chain of the formula

4. The compound of claim 1 where R is a side chain of the formula

5. The compound of claim 1 where R is a side chain of the formula

6. The compound of claim 1 where R is a side chain of the formula

7. The compound of claim 1 where R is a side chain of the formula

8. The compound of claim 1 where R is a side chain of the formula

9. The compound of claim 1 where R is a side chain of the formula

10. The compound of claim 1 where R is a side chain of the formula

11. The compound of claim 1 where R is a side chain of the formula

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

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

g to about 100 μ

g per gram of composition.

19. The pharmaceutical composition of claim 17 wherein said effective amount comprises from about 0.1 μ

g to about 50 μ

g per gram of composition.

22. The pharmaceutical composition of claim 17 containing 2-(3′

-hydroxypropylidene)-19-nor-1α

,25-(OH)₂D₃ (E-isomer) in an amount from about 0.01 μ

g to about 100 μ

g.

23. The pharmaceutical composition of claim 17 containing 2-(3′

-hydroxypropylidene)-19-nor-1α

,25-(OH)₂D₃ (E-isomer) in an amount from about 0.1 μ

g to about 50 μ

g.

24. The pharmaceutical composition of claim 17 containing 2-(3′

-hydroxypropylidene)-19-nor-1α

,25-(OH)₂D₃ (Z-isomer) in an amount from about 0.01 μ

g to about 100 μ

g.

25. The pharmaceutical composition of claim 17 containing 2-(3′

-hydroxypropylidene)-19-nor-1α

,25-(OH)₂D₃ (Z-isomer) in an amount from about 0.1 μ

g to about 50 μ

g.

26. The pharmaceutical composition of claim 17 containing 2-(3′

-hydroxypropylidene)-19-nor-(20S)-1α

,25-(OH)₂D₃ (E-isomer) in an amount from about 0.01 μ

g to about 100 μ

g.

27. The pharmaceutical composition of claim 17 containing 2-(3′

-hydroxypropylidene)-19-nor-(20S)-1α

,25-(OH)₂D₃ (E-isomer) in an amount from about 0.1 μ

g to about 50 μ

g.

28. The pharmaceutical composition of claim 17 containing 2-(3′

-hydroxypropylidene)-19-nor-(20S)-1α

,25-(OH)₂D₃ (Z-isomer) in an amount from about 0.01 μ

g to about 100 g.

29. The pharmaceutical composition of claim 17 containing 2-(3′

-hydroxypropylidene)-19-nor-(20S)-1α

,25-(OH)₂D₃ (Z-isomer) in an amount from about 0.1 μ

g to about 50 μ

g.

12. 2-[(3′

-methoxymethoxy)propylidene]-19-nor-1α

,25-(OH)₂D₃ having the formula;

13. 2-(3′

-hydroxypropylidene)-19-nor-1α

,25-(OH)₂D₃ (E-isomer) having the formula;

14. 2-(3′

-hydroxypropylidene)-19-nor-1α

,25-(OH)₂D₃ (Z-isomer) having the formula;

15. 2-(3′

-hydroxypropylidene)-19-nor-(20S)-1α

,25-(OH)₂D₃ (E-isomer) having the formula;

16. 2-(3′

-hydroxypropylidene)-19-nor-(20S)-1α

,25-(OH)₂D₃ (Z-isomer) having the formula;

20. The pharmaceutical composition containing 2-[(3′

-methoxymethoxy)propylidene]-19-nor-1α

,25-(OH)₂D₃ in an amount from about 0.01 μ

g to about 100 μ

g per gram of composition.

21. The pharmaceutical composition of claim 20 containing 2-[(3′

-methoxymethoxy)propylidene]-19-nor-1α

,25-(OH)₂D₃ in an amount from about 0.1 μ

g to about 50 μ

g per gram compositon.

30. A method of treating 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 a compound having the formula:

31. The method of claim 30 where the disease is senile osteoporosis.

32. The method of claim 30 where the disease is postmenopausal osteoporosis.

33. The method of claim 30 where the disease is steroid-induced osteoporosis.

34. The method of claim 30 where the disease is low bone turnover osteoporosis.

35. The method of claim 30 where the disease is osteomalacia.

36. The method of claim 30 where the disease is renal osteodystrophy.

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

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

39. The method of claim 30 wherein the compound is administered transdermally.

40. The method of claim 30 wherein the compound is administered in a dosage of from 0.01 μ

g to 100 μ

g per day.

41. The method of claim 30 wherein the compound is 2-(3′

-methoxymethoxy)propylidene)-19-nor-1α

,25-(OH)₂D₃.

42. The method of claim 30 wherein the compound is 2-(3′

-hydroxypropylidene)-19-nor-1α

,25-(OH)₂D₃ (E-isomer).

43. The method of claim 30 wherein the compound is 2-(3′

-hydroxypropylidene)-19-nor-1α

,25-(OH)₂D₃ (Z-isomer).

44. The method of claim 30 wherein the compound is 2-(3′

-hydroxypropylidene)-19-nor-(20S)-1α

,25-(OH)₂D₃ (E-isomer).

45. The method of claim 30 wherein the compound is 2-(3′

-hydroxypropylidene)-19-nor-(20S)-1α

,25-(OH)₂D₃ (Z-isomer).

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

47. The method of claim 46 wherein the compound is administered orally.

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

49. The method of claim 46 wherein the compound is administered transdermally.

50. The method of claim 46 wherein the compound is administered topically.

51. The method of claim 46 wherein said effective amount comprises about 0.01 μ

g/day to about 100 μ

g/day of said compound.

52. The method of claim 46 wherein the compound is 2-[3′

-methoxymethoxy)propylidene]-19-nor-1α

,25-(OH)₂D₃.

53. The method of claim 46 wherein the compound is 2-(3′

-hydroxypropylidene)-19-nor-1α

,25-(OH)₂D₃ (E-isomer).

54. The method of claim 46 wherein the compound is 2-(3′

-hydroxypropylidene)-19-nor-1α

,25-(OH)₂D₃ (Z-isomer).

55. The method of claim 46 wherein the compound is 2-(3′

-hydroxypropylidene)-19-nor-(20S)-1α

,25-(OH)₂D₃ (E-isomer).

56. The method of claim 46 wherein the compound is 2-(3′

-hydroxypropylidene)-19-nor-(20S)-1α

,25-(OH)₂D₃ (Z-isomer).

57. A method of treating leukemia, colon cancer, breast cancer, skin cancer or prostate cancer comprising administering to a patient an effective amount of a compound having the formula:

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

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

60. The method of claim 57 wherein the compound is administered transdermally.

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

g/day to about 100 μ

g/day.

62. The method of claim 57 wherein the compound is 2-[(3′

-methoxymethoxy)propylidene]-19-nor-1α

,25-(OH)₂D₃.

63. The method of claim 57 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-1α

,25-(OH)₂D₃ (E-isomer).

64. The method of claim 57 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-1α

,25-(OH)₂D₃ (Z-isomer).

65. The method of claim 57 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-(20S)-1α

,25-(OH)₂D₃ (E-isomer).

66. The method of claim 57 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-(20S)-1α

,25-(OH)₂D₃ (Z-isomer).

67. A method of increasing the strength of a bone comprising administering to a patient in need of such treatment an effective amount of a compound having the formula:

68. The method of claim 67 wherein the bone strength is cortical strength.

69. The method of claim 67 wherein the bone strength is trabecular strength.

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

71. The method of claim 67 wherein the compound is administered parenterally.

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

73. The method of claim 67 wherein the compound is administered in a dosage of from 0.01 μ

g to 100 μ

g per day.

74. The method of claim 67 wherein the compound is 2-[(3′

-methoxymethoxy)propylidene]-19-nor-1α

,25-(OH)₂D₃.

75. The method of claim 67 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-1α

,25-(OH)₂D₃ (E-isomer).

76. The method of claim 67 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-1α

,25-(OH)₂D₃ (Z-isomer).

77. The method of claim 67 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-(20S)-1α

,25-(OH)₂D₃ (E-isomer).

78. The method of claim 67 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-(20S)-1α

,25-(OH)₂D₃ (Z-isomer).

79. A method of treating an autoimmune disease comprising administering to a patient with said disease an effective amount of a compound having the formula

80. The method of claim 79 where the disease is multiple sclerosis.

81. The method of claim 79 where the disease is diabetes mellitus.

82. The method of claim 79 where the disease is lupus.

83. The method of claim 79 wherein the compound is administered orally.

84. The method of claim 79 wherein the compound is administered parenterally.

85. The method of claim 79 wherein the compound is administered transdermally.

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

g/day to about 100 μ

g/day.

87. The method of claim 79 wherein the compound is 2-[(3′

-methoxymethoxy)propylidene]-19-nor-1α

,25-(OH)₂D₃.

88. The method of claim 79 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-1α

,25-(OH)₂D₃ (E-isomer).

89. The method of claim 79 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-1α

,25-(OH)₂D₃ (Z-isomer).

90. The method of claim 79 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-(20S)-1α

,25-(OH)₂D₃ (E-isomer).

91. The method of claim 79 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-(20S)-1α

,25-(OH)₂D₃ (Z-isomer).

92. A method of treating an inflammatory bowel disease comprising administering to a patient with said disease an effective amount of a compound having the formula

93. The method of claim 92 wherein the disease is Crohn'"'"'s disease.

94. The method of claim 92 wherein the disease is ulcerative colitis.

95. The method of claim 92 wherein the compound is administered orally.

96. The method of claim 92 wherein the compound is administered parenterally.

97. The method of claim 92 wherein the compound is administered transdermally.

98. The method of claim 92 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

99. The method of claim 92 wherein the compound is 2-[(3′

-methoxymethoxy)propylidene]-19-nor-1α

,25-(OH)₂D₃.

100. The method of claim 92 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-1α

,25-(OH)₂D₃ (E-isomer).

101. The method of claim 92 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-1α

,25-(OH)₂D₃ (Z-isomer).

102. The method of claim 92 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-(20S)-1α

,25-(OH)₂D₃ (E-isomer).

103. The method of claim 92 wherein the compound is 2-[(3′

-hydroxypropylidene]-19-nor-(20S)-1α

,25-(OH)₂D₃ (Z-isomer).