Claims for Patent: 7,056,927

Summary for Patent: 7,056,927

Title:	Gonadotropin-releasing hormone receptor antagonists and methods relating 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: wherein R1a, R1b, R1c, R2a, R2b, R3, R4, R5, R6 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):	Zhiqiang Guo, Yongsheng Chen, Dongpei Wu, Chen Chen, Warren Wade, Wesley J. Dwight, Charles Q. Huang, Fabio C. Tucci
Assignee:	Neurocrine Biosciences Inc
Application Number:	US10/885,491
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,056,927
Patent Claims:	1. A compound having the following structure: or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R1a, R1b and R1c are the same or different and independently hydrogen, halogen, C1-4alkyl, hydroxy or alkoxy, or R1a and R1b taken together form —OCH2O— or —OCH2CH2—; R2a and R2b are the same or different and independently hydrogen, halogen, trifluoromethyl, cyano or —SO2CH3; R3 is hydrogen or methyl; R4 is phenyl or C3-7alkyl; R5 is hydrogen or C1-4alkyl; R6 is —COOH or an acid isostere; and X is C1-6alkanediyl optionally substituted with from 1 to 3 C1-6alkyl groups. 2. The compound of claim 1 wherein R1a is halogen. 3. The compound of claim 1 wherein R1b is alkoxy. 4. The compound of claim 3 wherein R1b is methoxy. 5. The compound of claim 1 wherein R1c is halogen. 6. The compound of claim 5 wherein R1c is fluoro or chloro. 7. The compound of claim 1 wherein R2a is halogen. 8. The compound of claim 1 wherein R2b is hydrogen, halogen or —SO2CH3. 9. The compound of claim 1 wherein R3 is hydrogen. 10. The compound of claim 1 wherein R3 is methyl. 11. The compound of claim 1 wherein R4 is phenyl. 12. The compound of claim 1 wherein R4 is C3-7alkyl. 13. The compound of claim 12 wherein C3-7alkyl is cyclopentyl or cyclohexyl. 14. The compound of claim 1 wherein R5 is H or methyl. 15. The compound of claim 1 wherein R6 is —COOH. 16. The compound of claim 1 wherein R6 is an acid isostere. 17. The compound of claim 16 wherein the acid isostere is tetrazol-5-yl. 18. The compound of claim 1 wherein X is a straight chain C1-6alkanediyl. 19. The compound of claim 18 wherein the straight chain C1-6alkanediyl is —CH2CH2CH2—. 20. The compound of claim 19 wherein R4 is phenyl. 21. The compound of claim 20 wherein R1a and R2a are halogen. 22. The compound of claim 21 wherein R3 is methyl. 23. The compound of claim 21 wherein R3 is hydrogen. 24. The compound of claim 1 wherein X is a branched C1-6alkanediyl. 25. The compound of 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-methyl-pyrimidine-2,4(1H,3H)-dione, 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(3-isopropylphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione, 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-(cyclohexyl)ethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione, or 3-[2(R)-{2-[1-(5-tetrazoyl)propyl]-amino}-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-methylsulfonylbenzyl]-6-methylpyrimidine-2,4(1H,3H)-dione. 26. The compound of claim 1 wherein the compound is 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chlorophenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-pyrimidine-2,4(1H,3H)-dione, 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-pyrimidine-2,4(1H,3H)-dione, 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methylphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-pyrimidine-2,4(1H,3H)-dione, 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chlorophenyl)-1-[2-fluoro-6-(methylsulfonyl)benzyl]-pyrimidine-2,4(1H,3H)-dione, 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-pyrimidine-2,4(1H,3H)-dione, or 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-(isobutyl)ethyl]-5-(2-chloro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-pyrimidine-2,4(1H,3H)-dione. 27. The compound of claim 15, wherein R1a is halogen and R1b is alkoxy. 28. The compound of claim 27, wherein R2a is halogen and R2b is halogen or trifluoromethyl. 29. The compound of claim 28, wherein R3 is methyl. 30. The compound of claim 15, wherein X is a straight chain C1-6alkanediyl. 31. The compound of claim 30, wherein R4 is phenyl, cyclohexyl or cyclopentyl. 32. The compound of claim 31, wherein R5 is hydrogen or methyl. 33. The compound of claim 15, wherein: R1a is halogen; R1b is alkoxy; R2a is halogen; R2b is halogen or trifluoromethyl; R3 is methyl; and X is a straight chain C1-6 alkanediyl. 34. The compound of claim 33, wherein R4 is phenyl, cyclohexyl or cyclopentyl, and R5 is hydrogen or methyl. 35. The compound of claim 34, wherein R1a is fluoro and R1b is methoxy. 36. The compound of claim 35, wherein R2a is fluoro and R2b is trifluoromethyl. 37. The compound of claim 36, wherein X is —(CH2CH2CH2)—. 38. The compound of claim 37, wherein R4 is phenyl. 39. The compound of claim 38, wherein R5 is hydrogen. 40. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent. 41. A pharmaceutical composition comprising a compound of claim 15 and a pharmaceutically acceptable carrier or diluent. 42. A pharmaceutical composition comprising a compound of claim 25 and a pharmaceutically acceptable carrier or diluent. 43. A pharmaceutical composition comprising a compound of claim 33 and a pharmaceutically acceptable carrier or diluent. 44. A pharmaceutical composition comprising a compound of claim 37 and a pharmaceutically acceptable carrier or diluent. 45. A pharmaceutical composition comprising a compound of claim 39 and a pharmaceutically acceptable carrier or diluent.