3-desoxy-2-methylene-19-nor-vitamin D analogs and their uses

• US 8,993,547 B2
• Filed: 06/13/2012
• Issued: 03/31/2015
• Est. Priority Date: 06/14/2011
• 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., Plum, Lori A., Sicinski, Rafal R., Sibilska, Izabela, Clagett-Dame, Margaret
• Primary Examiner(s): Badio, Barbara P
• Application Number:
  US13/495,548
• Publication Number:
  US 20120322775A1
• Time in Patent Office: 1,021 Days
• Field of Search: 552/653, 514/167, 568/8
• US Class Current: 514/167
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• 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 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/24 the ring system containing nine carbon atoms, e.g. perhydroindane
• 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 9/53 Organo-phosphine oxides; Organo-phosphine thioxides
• CPC Class Codes: C07F 9/5325 Aromatic phosphine oxides or thioxides (P-C aromatic linkage)

Abstract

This invention discloses 3-desoxy-2-methylene-19-nor-vitamin D analogs, and specifically (20S)-3-desoxy-2-methylene-1α,25-dihydroxy-19-nor-vitamin D₃ and (20R)-3-desoxy-2-methylene-1α,25-dihydroxy-19-nor-vitamin D₃ as well as pharmaceutical uses therefor. These compounds exhibit relatively high binding activity and pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to monocytes thus evidencing use as anti-cancer agents especially for the treatment or prevention of osteosarcoma, leukemia, colon cancer, breast cancer, skin cancer or prostate cancer. These compounds also exhibit relatively high calcemic activity evidencing use in the treatment of bone diseases.

Claims

1. A compound of the formula:

2. The compound of claim 1 wherein X is hydogen.

3. The compound of claim 1 wherein R is selected from:

4. The compound of claim 3 wherein X is hydrogen.

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. A compound of the formula:

9. The compound of claim 8 wherein X₂ is hydrogen.

10. The compound of claim 8 wherein X₁ is hydrogen.

11. The compound of claim 8 wherein X₁ and X₂ are both t-butyldimethylsilyl.

12. A pharmaceutical composition containing an effective amount of at least one compound as claimed in claim 8 together with a pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12 wherein said effective amount comprises from about 0.01 μ

g to about 1000 μ

g per gram or composition.

14. The pharmaceutical composition of claim 12 wherein said effective amount comprise from about 0.1 μ

g to about 500 μ

g per gram of composition.

15. A compound of the formula:

16. A pharmaceutical composition containing an effective amount of (20S)-3-desoxy-2-methylene-1α

,25-dihydroxy-19-nor-vitamin D₃ together with a pharmaceutically acceptable excipient.

17. The pharmaceutical composition of claim 16 wherein said effective amount comprises from about 0.01 μ

g to about 1000 μ

g per gram of composition.

18. The pharmaceutical composition of claim 16 wherein said effective amount comprises from about 0.1 μ

g to about 500 μ

g per gram of composition.

19. A method of treating a disease selected from the group consisting of osteosarcoma, leukemia, colon cancer, breast cancer, skin cancer or prostate cancer comprising administering to a subject with said disease an effective amount of a 3-desoxy-2-methylene-19-nor-vitamin D analog having of the formula:

20. The method of claim 19 wherein the vitamin D analog is administered orally, parenterally, transdermally, rectally, nasally, or sublingually.

21. The method of claim 19 wherein the vitamin D analog is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

22. The method of claim 19 wherein the vitamin D analog is of the formula:

23. The method of claim 19 wherein the vitamin D analog is of the formula:

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

25. The method of claim 24 where the disease is senile osteoporosis, postmenopausal osteoporosis, steroid-induced osteoporosis, low bone turnover osteoporosis, osteomalacia, or renal osteodystrophy.

26. The method of claim 24 wherein the compound is administered orally, parenterally, transdermally, rectally, nasally or sublingually.

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

g/day to about 1000 μ

g/day.

28. The method of claim 24 wherein the compound is of the formula

29. The method of claim 24 wherein the compound is of the formula

30. A compound of the formula:

31. The compound of claim 30 wherein X₂ is hydrogen.

32. The compound of claim 30 wherein X₁ is hydrogen.

33. The compound of claim 30 wherein X₁ and X₂ are both t-butyldimethylsilyl.

34. A pharmaceutical composition containing an effective amount of at least one compound as claimed in claim 30 together with as pharmaceutically acceptable excipient.

35. The pharmaceutical composition of claim 34 wherein said effective amount comprises from about 0.01 μ

g to about 1000 μ

g per gram of composition.

36. The pharmaceutical composition of claim 34 wherein said effective amount comprise from about 0.1 μ

g to about 500 μ

g per gram of composition.

37. A compound of the formula:

38. A Pharmaceutical composition containing an effective amount of (20R)-3-desoxy-2-methylene-1α

,25-dihydroxy-19-nor-vitamin D₃ together with a pharmaceutically acceptable excipient.

39. The pharmaceutical composition of claim 38 wherein said effective amount comprises from about 0.01 μ

g to about 1000 μ

g per gram of composition.

40. The pharmaceutical composition of claim 38 wherein said effective amount comprises from about 0.1 μ

g to about 500 μ

g per gram of composition.

41. A compound of the formula:

42. The compound of claim 41 wherein X is hydrogen.

43. The compound of claim 41 wherein X is t-butyldimethylsilyl.