Claims for Patent: 7,419,983

Summary for Patent: 7,419,983

Title:	Gonadotropin-releasing hormone receptor antagonists and methods related thereto
Abstract:	GnRH receptor antagonists are disclosed that have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: ##STR00001## wherein R.sub.1a, R.sub.1b, R.sub.1c, R.sub.2a, R.sub.2b, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and X are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.
Inventor(s):	Guo; Zhiqiang (San Diego, CA), Chen; Yongsheng (San Diego, CA), Wu; Dongpei (San Diego, CA), Chen; Chen (San Diego, CA), Wade; Warren (San Diego, CA), Dwight; Wesley J. (San Diego, CA), Huang; Charles Q. (San Diego, CA), Tucci; Fabio C. (San Diego, CA)
Assignee:	Neurocrine Biosciences, Inc. (San Diego, CA)
Application Number:	11/627,204
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,419,983
Patent Claims:	1. A compound having the following structure (I): ##STR00047## or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R.sub.1a is halogen; R.sub.1b is alkoxy; R.sub.1c is hydrogen; R.sub.2a is halogen; R.sub.2b is trifluoromethyl; R.sub.3 is methyl; R.sub.4 is phenyl; R.sub.5 is hydrogen; R.sub.6 is --COOH; and X is C.sub.1-6alkanediyl. 2. The compound according to claim 1, wherein R.sub.1a is at the 2-position of the phenyl ring and R.sub.1b is at the 3-position of the phenyl ring. 3. The compound according to claim 2, wherein R.sub.1a is fluoro or chloro and R.sub.1b is methoxy. 4. The compound according to claim 1, wherein R.sub.2a is at the 2-position of the phenyl ring and R.sub.2b is at the 6-position of the phenyl ring. 5. The compound according to claim 4, wherein R.sub.2a is fluoro. 6. The compound according to claim 1, wherein R.sub.1a is fluoro or chloro. 7. The compound according to claim 6, wherein R.sub.1b is methoxy. 8. The compound according to claim 7, wherein R.sub.2a is fluoro. 9. The compound according to claim 8, wherein X is --CH.sub.2CH.sub.2CH.sub.2--. 10. The compound according to claim 9, wherein R.sub.1a is fluoro. 11. The compound according to claim 9, wherein R.sub.1a is chloro. 12. The compound according to claim 1, wherein the compound is 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-- 2,4(1H,3H)-dione,3-[2(R)-{hydroxylcarbonylpropyl-amino}-2-phenylethyl]-5-(- 2-chloro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylp- yrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt thereof. 13. The compound according to claim 12, wherein the compound is 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione or a pharmaceutically acceptable salt thereof. 14. The compound according to claim 13, wherein the compound is the sodium salt or calcium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 15. The compound according to claim 14, wherein the compound is the sodium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 16. The compound according to claim 14, wherein the compound is the calcium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 17. The compound according to claim 12, wherein the compound is 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione or a pharmaceutically acceptable salt thereof. 18. The compound according to claim 17, wherein the compound is the sodium salt or calcium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 19. The compound according to claim 18, wherein the compound is the sodium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 20. The compound according to claim 18, wherein the compound is the calcium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound having the following structure (I): ##STR00048## or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R.sub.1a is halogen; R.sub.1b is alkoxy; R.sub.1c is hydrogen; R.sub.2a is halogen; R.sub.2b is trifluoromethyl; R.sub.3 is methyl; R.sub.4 is phenyl; R.sub.5 is hydrogen; R.sub.6 is --COOH; and X is C.sub.1-6alkanediyl. 22. The pharmaceutical composition according to claim 21, wherein the compound is 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione, 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chlor- o-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidi- ne-2,4(1H,3H)-dione or a pharmaceutically acceptable salt thereof. 23. The pharmaceutical composition according to claim 22, wherein the compound is 3-[2(R)-{hydroxycarbonylpropyl-amino}-2phenylethyl]-5-(2-fluoro-3-methoxy- phenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3- H)-dione or a pharmaceutically acceptable salt thereof. 24. The pharmaceutical composition according to claim 23, wherein the compound is the sodium or calcium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 25. The pharmaceutical composition according to claim 24, wherein the compound is the sodium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino }-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromet- hyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-dione. 26. The pharmaceutical composition according to claim 24, wherein the compound is the calcium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 27. The pharmaceutical composition according to claim 22, wherein the compound is 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione or a pharmaceutically acceptable salt thereof. 28. The pharmaceutical composition according to claim 27, wherein the compound is the sodium salt or calcium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 29. The pharmaceutical composition according to claim 28, wherein the compound is the sodium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 30. The pharmaceutical composition according to claim 28, wherein the compound is the calcium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 31. A method for treating a condition selected from the group of prostate cancer, benign prostatic hypertrophy, breast cancer or endometriosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound having the following structure (I): ##STR00049## or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R.sub.1a is halogen; R.sub.1b is alkoxy; R.sub.1c is hydrogen; R.sub.2a is halogen; R.sub.2b is trifluoromethyl; R.sub.3 is methyl; R.sub.4 is phenyl; R.sub.5 is hydrogen; R.sub.6 is --COOH; and X is C.sub.1-6 alkanediyl. 32. The method according to claim 31, wherein the compound is 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione,3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro- -3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidin- e-2,4(1H,3H)-dione or a pharmaceutically acceptable salt thereof. 33. The method according to claim 32, wherein the compound is 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione or a pharmaceutically acceptable salt thereof. 34. The method according to claim 33, wherein the compound is the sodium or calcium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 35. The method according to claim 34, wherein the compound is the sodium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-- 3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine- -2,4(1H,3H)-dione. 36. The method according to claim 34, wherein the compound is the calcium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-- 3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine- -2,4(1H,3H)-dione. 37. The method according to claim 32, wherein the compound is 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione or a pharmaceutically acceptable salt thereof. 38. The method according to claim 37, wherein the compound is the sodium salt or calcium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,- 3H)-dione. 39. The method according to claim 38, wherein the compound is the sodium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-- 3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine- -2,4(1H,3H)-dione. 40. The method according to claim 38, wherein the compound is the calcium salt of 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-- 3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine- -2,4(1H,3H)-dione.