26,27-Homologated-20-EPI-2-alkyl-19-nor-vitamin D compounds

• US 20040082802A1
• Filed: 10/10/2003
• Published: 04/29/2004
• Est. Priority Date: 03/17/1997
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: DeLuca, Hector F., Sicinski, Rafal R.
• Granted Patent: US 7,112,579 B2
• Time in Patent Office: Days
• US Class Current: 552/653
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

This invention provides a novel class of vitamin D related compounds, namely, the 2-alkyl-19-nor-vitamin D derivatives, as well as a general method for their chemical synthesis. The compounds have the formula:

where Y₁ and Y₂, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R₆ is selected from the group consisting of alkyl, hydroxyalkyl and fluoroalkyl, and where the group R represents any of the typical side chains known for vitamin D type compounds. These 2-substituted compounds, especially the 2α-methyl and the 2α-methyl-20S derivatives, are characterized by relatively high intestinal calcium transport activity and relatively high bone calcium mobilization activity resulting in novel therapeutic agents for the treatment of diseases where bone formation is desired, particularly low bone turnover osteoporosis. These compounds also exhibit pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as anti-cancer agents and for the treatment of diseases such as psoriasis.

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

8. A pharmaceutical composition containing at least one compound as claimed in claim 1 together with a pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 8 containing 19-nor-26,27-dihomo-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃ in an amount from about 0.1 μ

g to about 50 μ

g.

10. The pharmaceutical composition of claim 8 containing 19-nor-26,27-dihomo-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃ in an amount from about 0.1 μ

g to about 50 μ

g.

11. The pharmaceutical composition of claim 8 containing 19-nor-26,27-dimethylene-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃ in an amount from about 0.1 μ

g to about 50 μ

g.

12. The pharmaceutical composition of claim 8 containing 19-nor-26,27-dimethylene-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃ in an amount from about 0.1 μ

g to about 50 μ

g.

4. 19-nor-26,27-dihomo-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃.

5. 19-nor-26,27-dihomo-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃.

6. 19-nor-26,27-dimethylene-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃.

7. 19-nor-26,27-dimethylene-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃.

13. 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:

14. The method of claim 13 where the disease is senile osteoporosis.

15. The method of claim 13 where the disease is postmenopausal osteoporosis.

16. The method of claim 13 where the disease is steroid-induced osteoporosis.

17. The method of claim 13 where the disease is low bone turnover osteoporosis.

18. The method of claim 13 where the disease is osteomalacia.

19. The method of claim 13 where the disease is renal osteodystrophy.

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

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

22. The method of claim 13 wherein the compound is administered transdermally.

23. The method of claim 13 wherein the compound is administered in a dosage of from 0.1 μ

g to 50 μ

g per day.

24. The method of claim 13 wherein the compound is 19-nor-26,27-dihomo-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃.

25. The method of claim 13 wherein the compound is 19-nor-26,27-dihomo-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃.

26. The method of claim 13 wherein the compound is 19-nor-26,27-dimethylene-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃.

27. The method of claim 13 wherein the compound is 19-nor-26,27-dimethylene-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃.

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

29. The method of claim 28 wherein the compound is 19-nor-26,27-dihomo-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃.

30. The method of claim 28 wherein the compound is 19-nor-26,27-dihomo-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃.

31. The method of claim 28 wherein the compound is 19-nor-26,27-dimethylene-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃.

32. The method of claim 28 wherein the compound is 19-nor-26,27-dimethylene-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃.

33. The method of claim 28 wherein said effective amount comprises about 0.01 μ

g/day to about 100 μ

g/day of said compound.

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

35. The method of claim 34 where the disease is leukemia.

36. The method of claim 34 where the disease is colon cancer.

37. The method of claim 34 where the disease is breast cancer.

38. The method of claim 34 where the disease is prostate cancer.

39. The method of claim 34 wherein the compound is administered orally.

40. The method of claim 34 wherein the compound is administered parenterally.

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

42. The method of claim 34 wherein the compound is administered in a dosage of from 0.1 μ

g to 50 μ

g per day.

43. The method of claim 34 wherein the compound is 19-nor-26,27-dihomo-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃.

44. The method of claim 34 wherein the compound is 19-nor-26,27-dihomo-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃.

45. The method of claim 34 wherein the compound is 19-nor-26,27-dimethylene-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃.

46. The method of claim 34 wherein the compound is 19-nor-26,27-dimethylene-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃.