2Alpha-Methyl and 2Beta-Methyl Analogs of 19,26,27-Trinor-(20S)-1Alpha-Hydroxyvitamin D3 and Their Uses

• US 20070270391A1
• Filed: 07/09/2007
• Published: 11/22/2007
• Est. Priority Date: 11/22/2004
• 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, Clagett-Dame, Margaret, Grzywacz, Pawel, DeLuca, Hector
• Granted Patent: US 8,440,647 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• 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 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 3/04 Anorexiants; Antiobesity agents
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 2α-methyl and 2β-methyl analogs of 19,26,27-trinor-(20S)-1α-hydroxyvitamin 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 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:

where the methyl group attached to carbon 2 may have an R or S configuration, and where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

2. The compound of claim 1 wherein X₂ is hydrogen.

3. The compound of claim 1 wherein X₁ and X₂ are both hydrogen.

4. The compound of claim 1 wherein X₁ and X₂ are both 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. 2α

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin D₃ having the formula;

9. A pharmaceutical composition containing an effective amount of 2α

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin 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:

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

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 2α

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin 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:

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

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 2α

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin 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:

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

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 2α

-methyl-19,26,27-trinor-(20S)-1-hydroxyvitamin 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:

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

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 0.0 μ

g/day to about 1000 μ

g/day.

48. The method of claim 40 wherein the compound is 2α

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin 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:

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

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 2α

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin D₃ having the formula;

83. The pharmaceutical composition of claim 53 wherein said effective amount comprises from about 0.1 μ

g to about 500 μ

g per gram of composition.

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

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

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 2α

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin D₃ having the formula;

68. A method of treating or preventing obesity of an animal comprising administering to an animal in need thereof an effective amount of a compound having the formula:

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

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 1000μ

g/day.

76. The method of claim 68 wherein the compound is 2α

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin 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.

80. 2β

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin D₃ having the formula;

81. A pharmaceutical composition containing an effective amount of 2β

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin D₃ together with a pharmaceutically acceptable excipient.

82. The pharmaceutical composition of claim 81 wherein said effective amount comprises from about 0.01 μ

g to about 1000 μ

g per gram of composition.

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

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

85. The method of claim 84 wherein the compound is administered orally.

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

87. The method of claim 84 wherein the compound is administered transdermally.

88. The method of claim 84 wherein the compound is administered topically.

89. The method of claim 84 wherein the compound is administered rectally.

90. The method of claim 84 wherein the compound is administered nasally.

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

92. The method of claim 84 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

93. The method of claim 84 wherein the compound is 2β

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin D₃ having the formula;

94. 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:

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

95. The method of claim 94 wherein the compound is administered orally.

96. The method of claim 94 wherein the compound is administered parenterally.

97. The method of claim 94 wherein the compound is administered transdermally.

98. The method of claim 94 wherein the compound is administered rectally.

99. The method of claim 94 wherein the compound is administered nasally.

100. The method of claim 94 wherein the compound is administered sublingually.

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

g/day to about 1000 μ

g/day.

102. The method of claim 94 wherein the compound is 2β

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin D₃ having the formula;

103. 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:

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

104. The method of claim 103 wherein the compound is administered orally.

105. The method of claim 103 wherein the compound is administered parenterally.

106. The method of claim 103 wherein the compound is administered transdermally.

107. The method of claim 103 wherein the compound is administered rectally.

108. The method of claim 103 wherein the compound is administered nasally.

109. The method of claim 103 wherein the compound is administered sublingually.

110. The method of claim 103 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

111. The method of claim 103 wherein the compound is 2β

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin D₃ having the formula;

112. 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:

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

113. The method of claim 112 wherein the compound is administered orally.

114. The method of claim 112 wherein the compound is administered parenterally.

115. The method of claim 112 wherein the compound is administered transdermally.

116. The method of claim 112 wherein the compound is administered rectally.

117. The method of claim 112 wherein the compound is administered nasally.

118. The method of claim 112 wherein the compound is administered sublingually.

119. The method of claim 112 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

120. The method of claim 112 wherein the compound is 2β

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin D₃ having the formula;

121. 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:

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

122. The method of claim 121 wherein the compound is administered orally.

123. The method of claim 121 wherein the compound is administered parenterally.

124. The method of claim 121 wherein the compound is administered transdermally.

125. The method of claim 121 wherein the compound is administered topically.

126. The method of claim 121 wherein the compound is administered rectally.

127. The method of claim 121 wherein the compound is administered nasally.

128. The method of claim 121 wherein the compound is administered sublingually.

129. The method of claim 121 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

130. The method of claim 121 wherein the compound is 2β

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin D₃ having the formula;

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

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

132. The method of claim 131 wherein the compound is administered orally.

133. The method of claim 131 wherein the compound is administered parenterally.

134. The method of claim 131 wherein the compound is administered transdermally.

135. The method of claim 131 wherein the compound is administered rectally.

136. The method of claim 131 wherein the compound is administered nasally.

137. The method of claim 131 wherein the compound is administered sublingually.

138. The method of claim 131 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

139. The method of claim 131 wherein the compound is 2β

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin D₃ having the formula;

140. A method of treating or preventing obesity of an animal, inhibiting adipoctye 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:

where X₁ and X₂, which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.

141. The method of claim 140 wherein the compound is administered orally.

142. The method of claim 140 wherein the compound is administered parenterally.

143. The method of claim 140 wherein the compound is administered transdermally.

144. The method of claim 140 wherein the compound is administered rectally.

145. The method of claim 140 wherein the compound is administered nasally.

146. The method of claim 140 wherein the compound is administered sublingually.

147. The method of claim 140 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

148. The method of claim 140 wherein the compound is 2α

-methyl-19,26,27-trinor-(20S)-1α

-hydroxyvitamin D₃ having the formula;

149. The method of claim 140 wherein the animal is a human.

150. The method of claim 140 wherein the animal is a domestic animal.

151. The method of claim 140 wherein the animal is an agricultural animal.