A-ring modified 19-nor-vitamin D analogs and their uses

• US 8,785,422 B2
• Filed: 03/14/2013
• Issued: 07/22/2014
• Est. Priority Date: 06/06/2012
• 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., Clagett-Dame, Margaret, Plum, Lori A., Glebocka, Agnieszka
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US13/828,168
• Publication Number:
  US 20130331459A1
• Time in Patent Office: 495 Days
• Field of Search: 514/167, 552/653
• US Class Current: 514/167
• 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

Abstract

Disclosed are 19-nor-vitamin D compounds, and specifically seco-A-2,19-dinor-1,25-dihydroxyvitamin D₃ as well as pharmaceutical uses therefor. These compounds exhibit relatively high activity in vivo, specifically in intestinal tissues, but relatively low VDR binding activity, cell differentiation activity and gene transcription activity. There is thus potential for these compounds to have strong cell selectivity for use as therapeutic agents against some cancers, such as colon cancer or polyps, as well as hyperplastic intestinal disorders, such as Crohn'"'"'s disease, ulcerative colitis and celiac disease. These compounds also have relatively high intestinal calcium transport activity evidencing potential in the treatment of bone diseases.

Claims

1. A compound having the formula:

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

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 composes 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 having the formula:

9. A pharmaceutical composition containing an effective amount of seco-A-2,19-dinor-1,25-dihydroxyvitamin 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 a disease selected from the group consisting of colon cancer, Crohn'"'"'s disease, ulcerative colitis, and celiac disease comprising administering to a subject with said disease an effective amount of a 19-nor-vitamin D having the formula:

13. The method of claim 12 wherein the vitamin D is administered orally.

14. The method of claim 12 wherein the vitamin D is administered parenterally.

15. The method of claim 12 wherein the vitamin D is administered transdermally.

16. The method of claim 12 wherein the vitamin D is administered rectally.

17. The method of claim 12 wherein the vitamin D is administered nasally.

18. The method of claim 12 wherein the vitamin D is administered sublingually.

19. The method of claim 12 wherein the vitamin D is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

20. The method of claim 12 wherein the vitamin D has the formula:

21. 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:

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

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

24. The method of claim 21 wherein the compound is administered transdermally.

25. The method of claim 21 wherein the compound is administered rectally.

26. The method of claim 21 wherein the compound is administered nasally.

27. The method of claim 21 wherein the compound is administered sublingually.

28. The method of claim 21 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

29. The method of claim 21 where the disease is senile osteoporosis.

30. The method of claim 21 where the disease is postmenopausal osteoporosis.

31. The method of claim 21 where the disease is steroid-induced osteoporosis.

32. The method of claim 21 where the disease is low bone turnover osteoporosis.

33. The method of claim 21 where the disease is osteomalacia.

34. The method of claim 21 where the disease is renal osteodystrophy.

35. The method of claim 21 wherein the compound has the formula: