19-Nor-Vitamin D Analogs with 1,2 or 3,2 Heterocyclic Ring

• US 20070238712A1
• Filed: 04/06/2007
• Published: 10/11/2007
• Est. Priority Date: 04/06/2006
• 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., Clagett-Dame, Margaret, Sicinski, Rafal R., Glebocka, Agnieszka
• Granted Patent: US 7,538,098 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 311/74 Benzo[b]pyrans, hydrogenated in the carbocyclic ring

Abstract

19-nor-vitamin D analogs having an additional heterocyclic ring connecting the 3β-oxygen and carbon-2 or the 1α-oxygen and carbon-2 of the A-ring of the analog, and pharmaceutical uses therefore, are described. These compounds exhibit significant activity in mobilization of bone, making them therapeutic agents for the treatment or prophylaxis of osteoporosis, osteomalacia, osteopenia, renal osteodystrophy and hypoparathyroidism.

Claims

1. A compound having the formula:

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

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

4. The pharmaceutical composition of claim 3 wherein said effective amount comprises from about 0.01 μ

g to about 10 mg per gram of composition.

5. The pharmaceutical composition of claim 3 wherein said effective amount comprises from about 0.1 μ

g to about 1 mg per gram of composition.

6. A method of treating a metabolic bone disease comprising administering to a subject with said disease an effective amount of a compound having the formula:

7. The method of claim 6 where the disease is senile osteoporosis.

8. The method of claim 6 where the disease is postmenopausal osteoporosis.

9. The method of claim 6 where the disease is steroid-induced osteoporosis.

10. The method of claim 6 where the disease is low bone turnover osteoporosis.

11. The method of claim 6 where the disease is osteomalacia.

12. The method of claim 6 wherein the compound is administered orally.

13. The method of claim 6 wherein the compound is administered parenterally.

14. The method of claim 6 wherein the compound is administered transdermally.

15. The method of claim 6 wherein the compound is administered rectally.

16. The method of claim 6 wherein the compound is administered nasally.

17. The method of claim 6 wherein the compound is administered sublingually.

18. The method of claim 6 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 10 mg/day.

19. The method of claim 6 wherein the compound is a 1α

,25-dihydroxy-19-norvitamin D₃ analog having the formula;

28. The method of claim 6 wherein the compound is a 1α

,25-dihydroxy-19-norvitamin D₃ analog having the formula;

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

21. The method of claim 20 wherein the compound is administered orally.

22. The method of claim 20 wherein the compound is administered parenterally.

23. The method of claim 20 wherein the compound is administered transdermally.

24. The method of claim 20 wherein the compound is administered rectally.

25. The method of claim 20 wherein the compound is administered nasally.

26. The method of claim 20 wherein the compound is administered sublingually.

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

g/day to about 10 mg/day.

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

30. The method of claim 29 wherein the compound is administered orally.

31. The method of claim 29 wherein the compound is administered parenterally.

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

33. The method of claim 29 wherein the compound is administered rectally.

34. The method of claim 29 wherein the compound is administered nasally.

35. The method of claim 29 wherein the compound is administered sublingually.

36. The method of claim 29 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 10 mg/day.

37. The method of claim 29 wherein the compound is a 11,25-dihydroxy-19-norvitamin D₃ analog having the formula:

38. The method of treating or preventing 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:

39. The method of claim 38 wherein the compound is administered orally.

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

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

42. The method of claim 38 wherein the compound is administered rectally.

43. The method of claim 38 wherein the compound is administered nasally.

44. The method of claim 38 wherein the compound is administered sublingually.

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

g/day to about 10 mg/day.

46. The method of claim 38 wherein the compound is a 1α

,25-dihydroxy-19-norvitamin D₃ analog having the formula;

47. The method of claim 38 wherein the animal is a human.

48. The method of claim 38 wherein the animal is a domestic animal.

49. The method of claim 38 wherein the animal is an agricultural animal.

50. A compound having the formula:

51. The compound of claim 50 wherein Y is hydrogen.

52. A pharmaceutical composition containing an effective amount of at least one compound as claimed in claim 50 together with a pharmaceutically acceptable excipient.

53. The pharmaceutical composition of claim 52 wherein said effective amount comprises from about 0.01 μ

g to about 10 mg per gram of composition.

54. The pharmaceutical composition of claim 52 wherein said effective amount comprises from about 0.1 μ

g to about 1 mg per gram of composition.

55. A method of treating a metabolic bone disease comprising administering to a subject with said disease an effective amount of a compound having the formula:

56. The method of claim 55 where the disease is senile osteoporosis.

57. The method of claim 55 where the disease is postmenopausal osteoporosis.

58. The method of claim 55 where the disease is steroid-induced osteoporosis.

59. The method of claim 55 where the disease is low bone turnover osteoporosis.

60. The method of claim 55 wherein the disease is osteomalacia.

61. The method of claim 55 wherein the compound is administered orally.

62. The method of claim 55 wherein the compound is administered parenterally.

63. The method of claim 55 wherein the compound is administered transdermally.

64. The method of claim 55 wherein the compound is administered rectally.

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

66. The method of claim 55 wherein the compound is administered sublingually.

67. The method of claim 55 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 10 mg/day.

68. The method of claim 55 wherein the compound is a 3β

,25-dihydroxy-19-norvitamin D₃ analog having the formula;

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

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

71. The method of claim 69 wherein the compound is administered parenterally.

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

73. The method of claim 69 wherein the compound is administered rectally.

74. The method of claim 69 wherein the compound is administered nasally.

75. The method of claim 69 wherein the compound is administered sublingually.

76. The method of claim 69 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 10 mg/day.

77. The method of claim 69 wherein the compound is a 3β

,25-dihydroxy-19-norvitamin D₃ analog having the formula;

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

79. The method of claim 78 wherein the compound is administered orally.

80. The method of claim 78 wherein the compound is administered parenterally.

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

82. The method of claim 78 wherein the compound is administered rectally.

83. The method of claim 78 wherein the compound is administered nasally.

84. The method of claim 78 wherein the compound is administered sublingually.

85. The method of claim 78 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 10 mg/day.

86. The method of claim 78 wherein the compound is a 3β

,25-dihydroxy-19-norvitamin D₃ analog having the formula;

87. A method of treating or prevention 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:

88. The method of claim 87 wherein the compound is administered orally.

89. The method of claim 87 wherein the compound is administered parenterally.

90. The method of claim 87 wherein the compound is administered transdermally.

91. The method of claim 87 wherein the compound is administered rectally.

92. The method of claim 87 wherein the compound is administered nasally.

93. The method of claim 87 wherein the compound is administered sublingually.

94. The method of claim 87 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 10 mg/day.

95. The method of claim 87 wherein the compound is a 3β

,25-dihydroxy-19-norvitamin D₃ analog having the formula;

96. The method of claim 87 wherein the animal is a human.

97. The method of claim 87 wherein the animal is a domestic animal.

98. The method of claim 87 wherein the animal is an agricultural animal.

99. A compound having the formula:

100. The compound of claim 99 wherein Y₁ is an acyl group.

101. A compound having the formula:

102. The compound of claim 101 wherein Y₃ is hydrogen.

103. The compound of claim 101 wherein Y₃ is t-butyldimethylsilyl.

104. A compound having the formula:

105. The compound of claim 104 wherein Y₁, Y₂, and Y₃ are each hydrogen.