Ester derivatives of androgen receptor modulators and methods for their use
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 5 , J 1 , J 2 , X, Z, n 1 and n 2 are as defined herein, and wherein at least one of R 1 , R 2 or R 3 is an alkyl, alkenyl, aryl or aralkyl ester, 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.
1. A compound having the following structure (Ic):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
R 1 is hydroxyl or —OC(═O)R 13 ;
R 2 is hydroxyl or —OC(═O)R 13 ;
R 3 is hydroxyl, halo, or —OC(═O)R 13 ;
wherein, halo is selected from the group consisting of F, Br, and I;
R 8 is methyl;
R 9 is methyl;
R 11a , R 11b , R 11c and R 11d are each independently H;
R 13 is C 1 -C 6 alkyl;
n 1 and n 2 are each independently 1; and
wherein at least one of R 1 , R 2 , or R 3 is —OC(═O)R 13 ;
wherein R 3 is not —OC(═O)CH 3 when R 1 and R 2 are both hydroxyl;
wherein R 1 and R 2 are not both —OC(═O)CH═CH 2 ; and
wherein R 1 and R 2 are not both —OC(═O)C(CH 1 )═CH 2 .
2. The compound of claim 1 , wherein R 3 is halo.
3. The compound of claim 1 , wherein R 3 is fluoro.
4. The compound of claim 1 , wherein each R 13 is independently methyl, ethyl or propyl.
5. The compound of claim 1 , wherein each R 13 is methyl.
6. The compound of claim 1 selected from one or more of:
7. The compound of claim 1 selected from one or more of:
8. A pharmaceutical composition, comprising: a compound according to claim 1 ; and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition, comprising: a compound according to claim 1 ; a pharmaceutically acceptable carrier; and an additional therapeutic agent selected from the group consisting of enzalutamide, galeterone, ARN-509 (4-(7-(6-cyano-5-(trifluoromethyl)pylidin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3,4]octan-5-yl)-2-fluoro-N-methylbenzamide), abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, bevacizumab, OSU-HDAC42 ((S)-(+)-N-Hydroxy-4-(3-methyl-2-phenyl-butyrylamino)benzamide, monoclonal antibody against the vascular integrin αvβ3, sunitumib, ZD-4054 (zibotentan), cabazitaxel (XRP-6258), MDX-010 (ipilimumab), OGX 427 (apatorsen), OGX 011 (custirsen), finasteride, dutasteride, turosteride, bextosteride, izonsteride, PCE 28260 ((1S,3aS,3bS,5aR,9aR,9bS,11aS)-9a,11a-dimethyl-7-oxo-N-(1,1,1-trifluoro-2-phenylpropan-2-yl)-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindeno[5,4-f]-quinoline-1-carboxamide), SKF105,111 (17β-(Di-isopropyl-aminocarbonyl)androsta-3,5-diene-3-carboxylic acid), radium 233, and related compounds thereof.
10. The pharmaceutical composition of claim 9 , 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.
11. A method for modulating androgen receptor activity, comprising: administering a compound according to claim 1 to a patient in need thereof.
12. A method for treating a condition or disease that is responsive to modulation of androgen receptor activity, comprising: administering a compound according to claim 1 to a patient in need thereof,
wherein said condition or disease is selected from the group consisting of: 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.
13. The method of claim 12 , wherein the condition or disease is prostate cancer.
14. The method of claim 12 , wherein the condition or disease is castration resistant prostate cancer.
15. The method of claim 12 , wherein the condition or disease is androgen-dependent prostate cancer.
16. A pharmaceutical composition, comprising: a compound having the following structure:
or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
17. The pharmaceutical composition according to claim 16 , further comprising: an additional therapeutic agent selected from the group consisting of enzalutamide, galeterone, ARN-509 (4-(7-(6-cyano-5-(trifluoromethyl)pylidin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3,4]octan-5-yl)-2-fluoro-N-methylbenzamide), abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, bevacizumab, OSU-HDAC42 ((S)-(+)-N-Hydroxy-4-(3-methyl-2-phenyl-butyrylamino)benzamide, monoclonal antibody against the vascular integrin αvβ3, sunitumib, ZD-4054 (zibotentan), cabazitaxel (XRP-6258), MDX-010 (ipilimumab), OGX 427 (apatorsen), OGX 011 (custirsen), finasteride, dutasteride, turosteride, bextosteride, izonsteride, PCE 28260 ((1S,3aS,3bS,5aR,9aR,9bS,11aS)-9a,11a-dimethyl-7-oxo-N-(1,1,1-trifluoro-2-phenylpropan-2-yl)-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindeno[5,4-f]-quinoline-1-carboxamide), SKF105,111 (17β-(Di-isopropyl-aminocarbonyl)androsta-3,5-diene-3-carboxylic acid), radium 233, and related compounds thereof.
18. The pharmaceutical composition of claim 17 , 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.
19. A method for modulating androgen receptor activity, comprising: administering a pharmaceutical composition according to claim 16 to a patient in need thereof.
20. A method for treating a condition or disease that is responsive to modulation of androgen receptor activity, comprising: administering a pharmaceutical composition according to claim 16 to a patient in need thereof,
wherein said condition or disease is selected from the group consisting of: 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.
21. The method of claim 20 , wherein the condition or disease is prostate cancer.
22. The method of claim 20 , wherein the condition or disease is castration resistant prostate cancer.
23. The method of claim 20 , wherein the condition or disease is androgen-dependent prostate cancer.
24. A method for treating a condition or disease selected from the group consisting of: 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, comprising:
a) administering to a patient in need thereof a compound having the following structure:
or a pharmaceutically acceptable salt of said compound.
25. The method of claim 24 , wherein the condition or disease is prostate cancer.
26. The method of claim 24 , wherein the condition or disease is castration resistant prostate cancer or androgen-dependent prostate cancer.
27. The compound of claim 1 selected from one or more of:
28. The compound of claim 1 , wherein the compound has the following structure:
29. A compound selected from one of the following: