Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
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 R 1a , R 1b , R 1c , R 2a , R 2b , R 3 , R 4 , R 5 , R 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.
1. A compound having the following structure:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
R 1a , R 1b and R 1c are the same or different and independently hydrogen, halogen, C 1-4 alkyl, hydroxy or alkoxy, or R 1a and R 1b taken together form —OCH 2 O— or —OCH 2 CH 2 —;
R 2a and R 2b are the same or different and independently hydrogen, halogen, trifluoromethyl, cyano or —SO 2 CH 3 ;
R 3 is hydrogen or methyl;
R 4 is phenyl or C 3-7 alkyl;
R 5 is hydrogen or C 1-4 alkyl;
R 6 is —COOH or an acid isostere; and
X is C 1-6 alkanediyl optionally substituted with from 1 to 3 C 1-6 alkyl groups.
2. The compound of claim 1 wherein R 1a is halogen.
3. The compound of claim 1 wherein R 1b is alkoxy.
4. The compound of claim 3 wherein R 1b is methoxy.
5. The compound of claim 1 wherein R 1c is halogen.
6. The compound of claim 5 wherein R 1c is fluoro or chloro.
7. The compound of claim 1 wherein R 2a is halogen.
8. The compound of claim 1 wherein R 2b is hydrogen, halogen or —SO 2 CH 3 .
9. The compound of claim 1 wherein R 3 is hydrogen.
10. The compound of claim 1 wherein R 3 is methyl.
11. The compound of claim 1 wherein R 4 is phenyl.
12. The compound of claim 1 wherein R 4 is C 3-7 alkyl.
13. The compound of claim 12 wherein C 3-7 alkyl is cyclopentyl or cyclohexyl.
14. The compound of claim 1 wherein R 5 is H or methyl.
15. The compound of claim 1 wherein R 6 is —COOH.
16. The compound of claim 1 wherein R 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 1-6 alkanediyl.
19. The compound of claim 18 wherein the straight chain C 1-6 alkanediyl is —CH 2 CH 2 CH 2 —.
20. The compound of claim 19 wherein R 4 is phenyl.
21. The compound of claim 20 wherein R 1a and R 2a are halogen.
22. The compound of claim 21 wherein R 3 is methyl.
23. The compound of claim 21 wherein R 3 is hydrogen.
24. The compound of claim 1 wherein X is a branched C 1-6 alkanediyl.
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 R 1a is halogen and R 1b is alkoxy.
28. The compound of claim 27 , wherein R 2a is halogen and R 2b is halogen or trifluoromethyl.
29. The compound of claim 28 , wherein R 3 is methyl.
30. The compound of claim 15 , wherein X is a straight chain C 1-6 alkanediyl.
31. The compound of claim 30 , wherein R 4 is phenyl, cyclohexyl or cyclopentyl.
32. The compound of claim 31 , wherein R 5 is hydrogen or methyl.
33. The compound of claim 15 , wherein:
R 1a is halogen;
R 1b is alkoxy;
R 2a is halogen;
R 2b is halogen or trifluoromethyl;
R 3 is methyl; and
X is a straight chain C 1-6 alkanediyl.
34. The compound of claim 33 , wherein R 4 is phenyl, cyclohexyl or cyclopentyl, and R 5 is hydrogen or methyl.
35. The compound of claim 34 , wherein R 1a is fluoro and R 1b is methoxy.
36. The compound of claim 35 , wherein R 2a is fluoro and R 2b is trifluoromethyl.
37. The compound of claim 36 , wherein X is —(CH 2 CH 2 CH 2 )—.
38. The compound of claim 37 , wherein R 4 is phenyl.
39. The compound of claim 38 , wherein R 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.