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Last Updated: September 21, 2021

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Claims for Patent: 7,056,927


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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: ##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:10/885,491
Patent Claims: 1. A compound having the following structure: ##STR00047## or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R.sub.1a, R.sub.1b and R.sub.1c are the same or different and independently hydrogen, halogen, C.sub.1-4alkyl, hydroxy or alkoxy, or R.sub.1a and R.sub.1b taken together form --OCH.sub.2O-- or --OCH.sub.2CH.sub.2--; R.sub.2a and R.sub.2b are the same or different and independently hydrogen, halogen, trifluoromethyl, cyano or --SO.sub.2CH.sub.3; R.sub.3 is hydrogen or methyl; R.sub.4 is phenyl or C.sub.3-7alkyl; R.sub.5 is hydrogen or C.sub.1-4alkyl; R.sub.6 is --COOH or an acid isostere; and X is C.sub.1-6alkanediyl optionally substituted with from 1 to 3 C.sub.1-6alkyl groups.

2. The compound of claim 1 wherein R.sub.1a is halogen.

3. The compound of claim 1 wherein R.sub.1b is alkoxy.

4. The compound of claim 3 wherein R.sub.1b is methoxy.

5. The compound of claim 1 wherein R.sub.1c is halogen.

6. The compound of claim 5 wherein R.sub.1c is fluoro or chloro.

7. The compound of claim 1 wherein R.sub.2a is halogen.

8. The compound of claim 1 wherein R.sub.2b is hydrogen, halogen or --SO.sub.2CH.sub.3.

9. The compound of claim 1 wherein R.sub.3 is hydrogen.

10. The compound of claim 1 wherein R.sub.3 is methyl.

11. The compound of claim 1 wherein R.sub.4 is phenyl.

12. The compound of claim 1 wherein R.sub.4 is C.sub.3-7alkyl.

13. The compound of claim 12 wherein C.sub.3-7alkyl is cyclopentyl or cyclohexyl.

14. The compound of claim 1 wherein R.sub.5 is H or methyl.

15. The compound of claim 1 wherein R.sub.6 is --COOH.

16. The compound of claim 1 wherein R.sub.6 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 C.sub.1-6alkanediyl.

19. The compound of claim 18 wherein the straight chain C.sub.1-6alkanediyl is --CH.sub.2CH.sub.2CH.sub.2--.

20. The compound of claim 19 wherein R.sub.4 is phenyl.

21. The compound of claim 20 wherein R.sub.1a and R.sub.2a are halogen.

22. The compound of claim 21 wherein R.sub.3 is methyl.

23. The compound of claim 21 wherein R.sub.3 is hydrogen.

24. The compound of claim 1 wherein X is a branched C.sub.1-6alkanediyl.

25. The compound of claim 1 wherein the compound is 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-fluoro-3-methox- yphenyl)-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)-di- one, 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-(cyclohexyl)ethyl]-5-(2-fluor- o-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimid- ine-2,4(1H,3H)-dione, or 3-[2(R)-{2-[1-(5-tetrazoyl)propyl]-amino}-2-phenylethyl]-5-(2-fluoro-3-me- thoxyphenyl)-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-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-pyrimidine-2,4(1H,3H)-dion- e, 3-[2(R)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-meth- ylphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-pyrimidine-2,4(1H,3H)-dio- ne, 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-methox- yphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-pyrimidine-2,4(1H,3H)-dion- e, 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 R.sub.1a is halogen and R.sub.1b is alkoxy.

28. The compound of claim 27, wherein R.sub.2a is halogen and R.sub.2b is halogen or trifluoromethyl.

29. The compound of claim 28, wherein R.sub.3 is methyl.

30. The compound of claim 15, wherein X is a straight chain C.sub.1-6alkanediyl.

31. The compound of claim 30, wherein R.sub.4 is phenyl, cyclohexyl or cyclopentyl.

32. The compound of claim 31, wherein R.sub.5 is hydrogen or methyl.

33. The compound of claim 15, wherein: R.sub.1a is halogen; R.sub.1b is alkoxy; R.sub.2a is halogen; R.sub.2b is halogen or trifluoromethyl; R.sub.3 is methyl; and X is a straight chain C.sub.1-6 alkanediyl.

34. The compound of claim 33, wherein R.sub.4 is phenyl, cyclohexyl or cyclopentyl, and R.sub.5 is hydrogen or methyl.

35. The compound of claim 34, wherein R.sub.1a is fluoro and R.sub.1b is methoxy.

36. The compound of claim 35, wherein R.sub.2a is fluoro and R.sub.2b is trifluoromethyl.

37. The compound of claim 36, wherein X is --(CH.sub.2CH.sub.2CH.sub.2)--.

38. The compound of claim 37, wherein R.sub.4 is phenyl.

39. The compound of claim 38, wherein R.sub.5 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.

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