Vitamin D receptor antagonists and their use in treating asthma

• US 20050182033A1
• Filed: 02/16/2005
• Published: 08/18/2005
• Est. Priority Date: 02/17/2004
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Rivera-Bermudez, Moises A., Barycki, Rafal, Plum, Lori A., DeLuca, Hector F., Clagett-Dame, Margaret
• Granted Patent: US 7,915,242 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• 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

Various compounds such as those having the formula I and XIV where the variables have the values described herein antagonize the vitamin D receptor and are useful in treating conditions such as asthma and in preparing medicaments for use in antagonizing the vitamin D receptor or treating conditions such as asthma

Claims

1. A compound of formula I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer

2. The compound of claim 1, wherein R⁶ is OH and R⁷ is H;

or R⁶ and R⁷ together represent a ═

O group.

3. The compound of claim 2, wherein R⁴ is a methyl group and R⁵ is a H.

4. The compound of claim 2, wherein R⁴ and R⁵ together represent a ═

CH₂ group.

5. The compound of claim 2, wherein R² and R³ are either both methyl groups, or R² and R³ join together to form a cyclopropyl ring that includes the carbon to which they are both attached.

6. The compound of claim 2, wherein X is an R¹ group.

7. The compound of claim 2, wherein X is an —

OR¹ group.

8. The compound of claim 2, wherein R⁶ is OH and R⁷ is H.

9. The compound of claim 2, wherein R⁶ and R⁷ together represent a ═

O group.

10. The compound of claim 2, wherein the compound has the formula IA

11. The compound of claim 2, wherein the compound has the formula IB

12. The compound of claim 2, wherein the compound is a compound of formula II, formula III, formula IV, or formula V

13. The compound of claim 2, wherein the compound is a compound of formula VI, formula VII, formula VIII, or formula IX

14. The compound of claim 2, wherein the compound is a compound of formula X, formula XI, formula XII, or formula XIII

15. A pharmaceutical composition, comprising:

the compound of claim 1, and a pharmaceutically acceptable carrier.

16. A method of antagonizing the vitamin D receptor, comprising administering an effective amount of the compound of claim 1 or a pharmaceutical composition comprising an effective amount of the compound of claim 1 to an animal subject, wherein the compound administered to the subject antagonizes the vitamin D receptor.

17. A method of treating asthma or eczema in an animal subject suffering from asthma or eczema, comprising administering an effective amount of the compound of claim 1 or a pharmaceutical composition comprising an effective amount of the compound of claim 1 to the animal subject.

18. The method of claim 17, wherein the compound is administered orally, parenterally, rectally, transdermally, or topically.

21. A method of treating hypercalcemia, hyperparathyroidism, sarcoidosis, or vitamin D intoxication in an animal subject suffering from hypercalcemia, hyperparathyroidism, sarcoidosis, or vitamin D intoxication, comprising administering an effective amount of the compound of claim 1 or a pharmaceutical formulation comprising an effective amount of the compound of claim 1 to the animal subject.

19. The method of claim 19, wherein the compound is administered by delivering the compound or pharmaceutical formulation in an aerosol.

20. The method of claim 19, wherein the aerosol is administered using an inhaler or a nebulizer.

22. A compound of formula XIV, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer

23. The compound of claim 22, wherein R⁴ is a methyl group.

24. The compound of claim 22, wherein R² and R³ are either both methyl groups, or R² and R³ join together to form a cyclopropyl ring that includes the carbon to which they are both attached.

25. The compound of claim 22, wherein R¹ is an ethyl, propyl, butyl, hexyl, or heptyl group.

26. The compound of claim 22, wherein R⁶ is OH and R⁷ is H.

27. The compound of claim 22, wherein R⁶ and R⁷ together represent a ═

O group.

28. The compound of claim 22, wherein the compound has the formula XIVA

29. The compound of claim 22, wherein the compound has the formula XIVB

30. The compound of claim 22, wherein the compound is a compound of formula XV, formula XVI, formula XVII, or formula XVIII

31. A pharmaceutical composition, comprising:

the compound of claim 22, and a pharmaceutically acceptable carrier.

32. A method of antagonizing the vitamin D receptor, comprising administering an effective amount of the compound of claim 22 or a pharmaceutical composition comprising an effective amount of the compound of claim 22 to an animal subject, wherein the compound administered to the subject antagonizes the vitamin D receptor.

33. A method of treating asthma or eczema in an animal subject suffering from asthma or eczema, comprising administering an effective amount of the compound of claim 22 or a pharmaceutical composition comprising an effective amount of the compound of claim 22 to the animal subject.

34. The method of claim 33, wherein the compound is administered orally, parenterally, rectally, transdermally, or topically.

35. The method of claim 33, wherein the compound is administered by delivering the compound or pharmaceutical formulation in an aerosol.

36. A method of treating hypercalcemia, hyperparathyroidism, sarcoidosis, or vitamin D intoxication in an animal subject suffering from hypercalcemia, hyperparathyroidism, sarcoidosis, or vitamin D intoxication, comprising administering an effective amount of the compound of claim 22 or a pharmaceutical formulation comprising an effective amount of the compound of claim 22 to the animal subject.

45. The method of claim 32, wherein the compound is administered orally, rectally, parenterally, transdermally, or topically.

37. A compound of formula XIX or formula XX

38. The compound of claim 37, wherein R¹ is an ethyl, propyl, butyl, pentyl, or hexyl group.

39. A pharmaceutical composition, comprising:

the compound of claim 37, and a pharmaceutically acceptable carrier.

40. A method of antagonizing the vitamin D receptor, comprising administering an effective amount of the compound of claim 37 or a pharmaceutical composition comprising an effective amount of the compound of claim 37 to an animal subject, wherein the compound administered to the subject antagonizes the vitamin D receptor.

41. A method of treating asthma or eczema in an animal subject suffering from asthma or eczema, comprising administering an effective amount of the compound of claim 37 or a pharmaceutical composition comprising an effective amount of the compound of claim 37 to the animal subject.

42. A method of treating hypercalcemia, hyperparathyroidism, sarcoidosis, or vitamin D intoxication in an animal subject suffering from hypercalcemia, hyperparathyroidism, sarcoidosis, or vitamin D intoxication, comprising administering an effective amount of the compound of claim 37 or a pharmaceutical formulation comprising an effective amount of the compound of claim 37 to the animal subject.

43. A method of antagonizing the vitamin D receptor, comprising administering an effective amount of a compound of formula XXI or XXII to an animal subject, wherein the compound administered to the subject antagonizes the vitamin D receptor

44. The method of claim 43, wherein the animal subject suffers from asthma or eczema and administration of the compound of formula XXI or XXII results in a reduction of symptoms associated with asthma or eczema in the subject.