Itraconazole Analogs and Use Thereof

• US 20140221393A1
• Filed: 09/07/2012
• Published: 08/07/2014
• Est. Priority Date: 09/07/2011
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Liu, Jun O., Shi, Wei, Pasunooti, Kalyan Kumar
• Granted Patent: US 9,346,791 B2
• Time in Patent Office: Days
• US Class Current: 514/254.07
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

Provided herein are Itraconazole analogs. Also provided herein are methods of inhibition of Hedgehog pathway, vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, angiogenesis and treatment of disease with Itraconazole analogs.

Claims

1. A compound of structural Formula (I):

2. The compound of claim 1, wherein:

X and Z are N;

Y is CH;

A is CR⁶;

B is CR⁷;

W is CR⁸;

V is CR⁹;

D is

3. The compound of claim 2, wherein the compound is of structural Formula (II):

4. The compound of claim 3, wherein Q is CH₂.

5. The compound of claim 4, wherein T is hydrogen.

6. The compound of claim 4, wherein:

T is OR¹¹; and

R¹¹ is hydrogen.

7. The compound of claim 3, wherein Q is O.

8. The compound of claim 7, wherein T is hydrogen.

9. The compound of claim 7, wherein:

T is OR11; and

R11 is hydrogen.

10. The compound of claim 2, wherein the compound is of structural Formula (III):

11. The compound of claim 1, wherein the compound is of structural Formula (IV):

12. The compound of claim 11, wherein:

m is 2; and

each R² is independently chlorine.

13. The compound of claim 12, wherein R¹⁴ is

14. The compound of claim 13, wherein:

W is CR8; and

V is CR9.

15. The compound of claim 14, wherein p is 0.

16. The compound of claim 15, wherein:

each R⁴ is independently alkyl; and

q is 0, 1, or 2.

17. The compound of claim 16, wherein:

each R⁵ is independently halogen; and

t is 0, 1, or 2.

18. The compound of claim 17, wherein A is CR⁶.

19. The compound of claim 18, wherein B is CR⁷.

20. The compound of claim 18, wherein B is N.

21. The compound of claim 17, wherein A is N.

22. The compound of claim 21, wherein B is CR⁷.

23. The compound of claim 13, wherein:

A is CR6;

and B is CR7.

24. The compound of claim 23, wherein t is 0.

25. The compound of claim 24, wherein:

each R⁴ is independently alkyl; and

q is 0, 1, or 2.

26. The compound of claim 25, wherein:

each R³ is independently halogen; and

p is 0, 1, or 2.

27. The compound of claim 26, wherein W is CR⁸.

28. The compound of claim 27, wherein V is CR⁹.

29. The compound of claim 27, wherein V is N.

30. The compound of claim 26, wherein W is N.

31. The compound of claim 30, wherein V is CR⁹.

32. The compound of claim 1, wherein the compound is of structural Formula (V):

33. The compound of claim 32, wherein:

m is 2; and

each R² is independently chlorine.

34. The compound of claim 33, wherein R¹⁴ is

35. The compound of claim 34, wherein X is CH.

36. The compound of claim 35, wherein:

Y is CH; and

Z is CR10.

37. The compound of claim 35, wherein:

Y is CH; and

Z is N.

38. The compound of claim 35, wherein:

Y is N; and

Z is CR¹⁰.

39. The compound of claim 35, wherein Y and Z are each independently N.

40. The compound of claim 34, wherein X is N.

41. The compound of claim 40, wherein:

Y is CH; and

Z is CR¹⁰.

42. The compound of claim 40, wherein Y and Z are each independently N.

43. The compound of claim 40, wherein:

Y is N; and

Z is CR¹⁰.

44. The compound of claim 1, wherein the compound is of structural Formula (VI):

45. The compound of claim 44, wherein:

m is 2;

each R² is independently chlorine; and

D is

46. The compound of claim 1, wherein the compound is of structural Formula (VII):

47. The compound of claim 46, wherein R¹⁴ is

48. The compound of claim 47, wherein m is 2.

50. A pharmaceutical composition comprising the compound of claim 1 together with a pharmaceutically acceptable carrier.

51. A method of inhibiting Hedgehog (Hh) pathway, comprising contacting a cell with a compound of claim 1, thereby inhibiting Hh pathway.

52. A method of treating a Hh pathway-mediated disease, comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.

53. A method of inhibiting angiogenesis, comprising contacting a cell with a compound of claim 1, thereby inhibiting angiogenesis.

54. A method of treating a disease or disorder associated with angiogenesis, comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.

55. A method of inhibiting vascular endothelial growth factor receptor 2 (VEGFR2), comprising contacting VEGFR2 with a compound of claim 1.

56. The method of claim 55, wherein VEGFR² glycosylation is inhibited.

57. A method of treating a VEGFR2-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

58. A method of treating fungal infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

59. The method of claim 58, wherein the administration is topical.

60. The method of claim 58, wherein the administration is systemic.

49. The compound of 48, wherein each R² is independently chosen from the group consisting of hydrogen, halogen, and perhaloalkyl.