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 method for treating a condition selected from the group of prostate cancer, benign prostatic hypertrophy, breast cancer and endometriosis in a subject in need thereof comprising administering to the subject a pharmaceutically effective amount of a compound represented by 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. A method according to claim 1 , wherein X is a straight chain C 1-6 alkanediyl.
3. A method according to claim 2 , wherein R 6 is —COOH.
4. A method according to claim 3 , wherein R 4 is phenyl.
5. A method according to claim 4 , wherein R 1a is halogen and R 1b is alkoxy.
6. A method according to claim 4 , wherein R 3 is methyl.
7. A method according to claim 4 , wherein the condition is endometriosis.
8. A method according to claim 4 , wherein the condition is benign prostatic hypertrophy.
9. A method according to claim 4 , wherein the condition is prostate cancer.
10. A method according to claim 4 , wherein the condition is breast cancer.
11. A method 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-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.
12. A method according to claim 11 , wherein the condition is endometriosis.
13. A method according to claim 11 , wherein the condition is benign prostatic hypertrophy.
14. A method according to claim 11 , wherein the condition is prostate cancer.
15. A method according to claim 11 , wherein the condition is breast cancer.
16. A method according to 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.
17. A method according to claim 16 , wherein the condition is endometriosis.
18. A method according to claim 16 , wherein the condition is benign prostatic hypertrophy.
19. A method according to claim 16 , wherein the condition is prostate cancer.
20. A method according to claim 16 , wherein the condition is breast cancer.