Gonadotropin-releasing hormone receptor antagonists and methods related 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 (I):
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
R 1a is halogen;
R 1b is alkoxy;
R 1c is hydrogen;
R 2a is halogen;
R 2b is trifluoromethyl;
R 3 is methyl;
R 4 is phenyl;
R 5 is hydrogen;
R 6 is —COOH; and
X is C 1-6 alkanediyl.
2. The compound according to claim 1 , wherein R 1a is at the 2-position of the phenyl ring and R 1b is at the 3-position of the phenyl ring.
3. The compound according to claim 2 , wherein R 1a is fluoro or chloro and R 1b is methoxy.
4. The compound according to claim 1 , wherein R 2a is at the 2-position of the phenyl ring and R 2b is at the 6-position of the phenyl ring.
5. The compound according to claim 4 , wherein R 2a is fluoro.
6. The compound according to claim 1 , wherein R 1a is fluoro or chloro.
7. The compound according to claim 6 , wherein R 1b is methoxy.
8. The compound according to claim 7 , wherein R 2a is fluoro.
9. The compound according to claim 8 , wherein X is —CH 2 CH 2 CH 2 —.
10. The compound according to claim 9 , wherein R 1a is fluoro.
11. The compound according to claim 9 , wherein R 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-methylpyrimidine-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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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):
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
R 1a is halogen;
R 1b is alkoxy;
R 1c is hydrogen;
R 2a is halogen;
R 2b is trifluoromethyl;
R 3 is methyl;
R 4 is phenyl;
R 5 is hydrogen;
R 6 is —COOH; and
X is C 1-6 alkanediyl.
22. The pharmaceutical composition according to claim 21 , 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)-{hydroxycarbonylpropyl-amino}-2-phenylethyl]-5-(2-chloro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-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-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-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-methoxyphenyl)-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-(trifluoromethyl)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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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):
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
R 1a is halogen;
R 1b is alkoxy;
R 1c is hydrogen;
R 2a is halogen;
R 2b is trifluoromethyl;
R 3 is methyl;
R 4 is phenyl;
R 5 is hydrogen;
R 6 is —COOH; and
X is C 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-methoxyphenyl)-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-methylpyrimidine-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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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.