AZIRIDINE BISPHENOL ETHERS AND RELATED COMPOUNDS AND METHODS FOR THEIR USE

• US 20130336962A1
• Filed: 04/16/2013
• Published: 12/19/2013
• Est. Priority Date: 04/16/2012
• Status: Active Grant

• Current Assignee: British Columbia Cancer Agency Branch (Province of British Columbia), University of British Columbia
• Original Assignee: British Columbia Cancer Agency Branch (Province of British Columbia), The University of British Columbia
• Inventors: Andersen, Raymond John, Sadar, Marianne Dorothy
• Granted Patent: US 9,365,510 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/396 having three-membered rings, e.g. aziridine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 203/10 Radicals substituted by singly bound oxygen atoms

Abstract

Compounds having a structure of Formula I:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R, R¹, R², R³, R⁴, M¹, M², X, L¹, L², J¹, J², a¹, a², b¹ and b² are as defined herein, and wherein at least one of M² or L² is a moiety comprising an aziridine, acrylamide or sulfonate functional group, are provided. Uses of such compounds for treatment of various indications, including prostate cancer as well as methods of treatment involving such compounds are also provided.

Claims

1. A compound having a structure of Formula I:

2. The compound of claim 1, wherein the compound has the following structure (Ia):

3. The compound of claim 1, wherein R⁸ and R⁹ are each independently H or C₁-C₁₀ alkyl.

4. The compound of claim 1, wherein R⁸ and R⁹ are each C₁-C₁₀ alkyl.

5. The compound of claim 1, wherein R⁸ and R⁹ join to form a mono-, bi- or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms.

6. The compound of claim 1, wherein X is —

[(CR⁵R⁶)-aryl-(CR⁵R⁶)]—

.

7. The compound of claim 1, wherein X is —

CH₂—

, —

C(CH₃)₂—

, —

S—

, —

(C═

O)—

,

8. The compound of claim 7, wherein X is —

C(CH₃)₂—

.

9. The compound of claim 1, wherein at least one of R¹, R², R³ or R⁴ is H.

10. The compound of claim 1, wherein each of R¹, R², R³ and R⁴ is H.

11. The compound of claim 1, wherein at least one of R¹, R², R³ or R⁴ is C₁-C₁₀ alkyl.

12. The compound of claim 1, wherein at least one of R¹, R², R³ or R⁴ is halogen.

13. The compound of claim 1, wherein at least one of J¹ or J² is —

O—

.

14. The compound of claim 1, wherein each of J¹ and J² is —

O—

.

15. The compound of claim 1, wherein a¹ is 0 or 1.

16. The compound of claim 1, wherein a² is 1.

17. The compound of claim 1, wherein b¹ is 0.

18. The compound of claim 1, wherein b² is 0.

19. The compound of claim 1, wherein each R is independently H or fluoro.

20. The compound of claim 1, wherein at least one R is fluoro.

21. The compound of claim 1, wherein each R is H.

22. The compound of claim 1, wherein L¹ is —

OH.

23. The compound of claim 1, wherein L² is —

OH.

24. The compound of claim 1, wherein L¹ is H.

25. The compound of claim 1, wherein L² is H.

26. The compound of claim 1, wherein L¹ is —

OY.

27. The compound of claim 1, wherein L² is —

OY.

28. The compound of claim 26, wherein Y is

29. The compound of claim 1, wherein M¹ is halogen.

30. The compound of claim 29, wherein M¹ is fluoro.

31. The compound of claim 1, wherein M¹ is —

OH.

32. The compound of claim 1, wherein M¹ is —

OR⁵.

33. The compound of claim 32, wherein R⁵ is an unsaturated alkyl.

34. The compound of claim 32, wherein R⁵ is a saturated alkyl.

35. The compound of claim 33, wherein one or more carbon atoms of the C₁-C₂₀ alkyl are replaced with an oxygen atom.

36. The compound of claim 33, wherein the alkyl is substituted with one or more —

OH groups.

37. The compound of claim 1, wherein M¹ has one of the following structures:

38. The compound of claim 1, wherein M² is Z.

39. The compound of claim 1, wherein L² is Z.

40. The compound of claim 1, wherein the compound has one of the following structures:

41. The compound of claim 1, wherein Z has one of the following structures:

42. The compound of claim 1, wherein Z has the following structure:

43. The compound of claim 42, wherein Z has the following structure:

44. The compound of claim 1, wherein Z has the following structure:

45. The compound of claim 44, wherein R¹⁰ is methyl or 4-methylphenyl.

53. A method of modulating androgen receptor (AR) activity, the method comprising administering a compound, or pharmaceutically acceptable salt thereof, of claim 1 to a subject in need thereof.

54. The method of claim 53, wherein modulating androgen receptor (AR) activity is for the treatment of one or more of the following:

prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration.

55. The method of claim 54, wherein the method is for treatment of prostate cancer.

56. The method of claim 55, wherein the prostate cancer is castration resistant prostate cancer.

57. The method of claim 55, wherein the prostate cancer is androgen-dependent prostate cancer.

58. The method of claim 54, wherein the spinal and bulbar muscular atrophy is Kennedy'"'"'s disease.

59. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

60. The pharmaceutical composition of claim 59, further comprising an additional therapeutic agent.

61. The pharmaceutical composition of claim 60, wherein the additional therapeutic agent is for treating prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy or age-related macular degeneration.

62. The pharmaceutical composition of claim 60, wherein the additional therapeutic agent is MDV3100, TOK 001, TOK 001;

ARN-509;

abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, VN/124-1, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111 or a related compound thereof.

46-52. -52. (canceled)

63-75. -75. (canceled)