Androgen receptor modulators and methods for their use

Patent metadata

Field	Value
Publication number	US-10071962-B2
Application number	US-201715626526-A
Country	US
Kind code	B2
Filing date	Jun 19, 2017
Priority date	May 30, 2014
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

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 pharmaceutical composition comprising a compound of structure (I), an additional therapeutic agent and a pharmaceutically acceptable carrier; wherein the compound of structure (I) has the following formula:

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 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; and
wherein the additional therapeutic agent is for treating prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, kidney cancer, liver 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.

2. The pharmaceutical composition of claim 1 , wherein the additional therapeutic agent is enzalutamide, Galeterone, ARN-509, ODM-201, abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN (humanized form of LM609), sunitinib (N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide), ZD-4054, Cabazitaxel (XRP-6 258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, Radium 233 or prednisone.

3. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for topical administrations.

4. A method for modulating androgen receptor (AR) activity, the method comprising administering the pharmaceutical composition of 1 to a subject in need thereof, 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, bladder cancer, pancreatic cancer, hepatocellular cancer, kidney cancer, liver cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, ovary disease, precocious puberty, spinal and bulbar muscular atrophy, polycystic or age-related macular degeneration.

5. The method of claim 4 , wherein the method is for treatment of prostate cancer.

6. The method of claim 5 , wherein the prostate cancer is castration resistant prostate cancer.

7. The method of claim 5 , wherein the prostate cancer is androgen-dependent prostate cancer.

8. The method of claim 4 , wherein the administration is topical.

9. The method of claim 4 , wherein the administration is intravenous.

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

11. The pharmaceutical composition of claim 10 , wherein at least one of Y 1 and Y 2 is 0.

12. The pharmaceutical composition of claim 10 , wherein at least one of R 1 and R 2 is H.

13. The pharmaceutical composition of claim 10 , wherein R 2 is —C(═O)R 7 or —S(O) n R 8 .

14. The method pharmaceutical composition of claim 13 , wherein R 7 is ethyl, t-butyl

or t-butoxy; or R 8 is ethyl.

15. The pharmaceutical composition of claim 13 , wherein n is 2.

16. The pharmaceutical composition of claim 10 , wherein R 5 is C 1 -C 6 alkoxy or R 6 is H.

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

18. The pharmaceutical composition of claim 10 , wherein at least one of R 3 or R 4 is a straight-chain C 1 -C 6 chloroalkyl.

19. The pharmaceutical composition of claim 18 , wherein C 1 -C 6 chloroalkyl comprises a perchloro-substituted carbon.

20. The pharmaceutical composition of claim 10 , wherein R 3 or R 4 , or both, is 3,3,3-trichloropropyl.

21. The pharmaceutical composition of claim 10 , wherein is a carbon-carbon double bond.

22. The pharmaceutical composition of claim 1 , wherein the compound has one of the following structures:

23. The pharmaceutical composition of claim 1 , wherein the compound has the following structure (Ib), structure (Ic), or 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

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title