Androgen receptor modulators and methods for their use

Patent metadata

Field	Value
Publication number	US-9682933-B2
Application number	US-201514726129-A
Country	US
Kind code	B2
Filing date	May 29, 2015
Priority date	May 30, 2014
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

Compounds having a structure of Structure I:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 6 , Y 1 and Y 2 are as defined herein, and wherein at least one of R 3 or R 4 is a straight-chain C 1 -C 6 haloalkyl, 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.

First claim

We claim:

1. A compound having the following structure (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
Y 1 and Y 2 are each independently O or S;
R 1 is H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
R 2 is H, —C(═O)R 7 or —S(O) n R 8 ;
R 3 and R 4 are straight-chain C 1 -C 6 haloalkyl;
R 5 and R 6 are each independently H, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy;
R 7 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy;
R 8 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
is a carbon-carbon double bond or a carbon-carbon single bond, such that all valences are satisfied; and
n is 0, 1 or 2.

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

3. The compound of claim 1 , wherein Y 1 is O.

4. The compound of claim 1 , wherein Y 2 is O.

5. The compound of claim 1 , wherein R 1 is H.

6. The compound of claim 1 , wherein R 2 is H.

7. The compound of claim 1 , wherein R 2 is —C(═O)R 7 .

8. The compound of claim 7 , wherein R 7 is C 1 -C 6 alkyl.

9. The compound of claim 8 , wherein R 7 is ethyl, t-butyl or

10. The compound of claim 7 , wherein R 7 is C 1 -C 6 alkoxy.

11. The compound of claim 10 , wherein R 7 is t-butoxy.

12. The compound of any one of claims 1 - 5 , wherein R 2 is —S(O) n R 8 .

13. The compound of claim 12 , wherein R 8 is C 1 -C 6 alkyl.

14. The compound of claim 13 , wherein R 8 is ethyl.

15. The compound of claim 12 , wherein n is 2.

16. The compound of claim 1 , wherein R 5 is C 1 -C 6 alkoxy.

17. The compound of claim 16 , wherein C 1 -C 6 alkoxy is methoxy.

18. The compound of claim 1 , wherein R 6 is H.

19. The compound of claim 1 , wherein at least one of R 3 or R 4 is a straight-chain C 1 -C 6 chloroalkyl.

20. The compound of claim 19 , wherein C 1 -C 6 chloroalkyl comprises a perchloro-substituted carbon.

21. The compound of claim 1 , wherein R 3 or R 4 , or both, is 3,3,3-trichloropropyl.

22. The compound of claim 1 , wherein is a carbon-carbon double bond.

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

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

25. A pharmaceutical composition comprising a compound of claim 1 , an additional therapeutic agent and a pharmaceutically acceptable carrier.

26. A method for modulating androgen receptor (AR) activity, the method comprising administering the pharmaceutical composition of claim 24 to a subject in need thereof.

27. A method for modulating androgen receptor (AR) activity, the method comprising administering the compound of claim 1 and an additional therapeutic agent to a subject in need thereof.

28. The compound of claim 1 , wherein the compound has the following structure (Ib):

29. The compound of claim 1 , wherein the compound has the following structure (Ic):

30. The compound of claim 1 , wherein the compound has the following structure (Id):

Assignees

• British Columbia Cancer Agency Branch
• Univ British Columbia

Inventors

• Yan Luping
• Andersen Raymond J
• Sadar Marianne Dorothy
• Mawji Nasrin R
• Banuelos Carmen Adriana

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P17/10

  Anti-acne agents · CPC title

• A61P17/14

  for baldness or alopecia · CPC title