Trisubstituted thiophenes as progesterone receptor modulators
The present invention is directed to novel trisubstituted thiophene derivatives, pharmaceutical compositions containing them and their use in the treatment or prevention of disorders and diseases mediated by agonists and antagonists of the progesterone receptor. The clinical usage of these compounds are related to hormonal contraception, the treatment and/or prevention of secondary dysmenorrhea, amenorrhea, dysfunctional uterine bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon or prostate. Additional uses of the invention include stimulation of food intake.
1. A compound of formula (I):
wherein
R 1 and R 2 are connected together with the carbon atom to which they are bound via a—O(CH 2 ) 2 O— linker to form a ring, R 1 and R 2 are connected together with the carbon atom to which they are bound to form C(O);
R 3 is aryl or pyridinyl, optionally substituted by up to three of R 5 ;
R 4 is selected from the group consisting of CH 3 CH 2 —, CH 3 CH(CH 3 ), CH 3 CH 2 CH 2 —, aryl and pyridinyl, wherein the aryl or pyridinyl is optionally substituted by up to three of R 5 ;
wherein R 5 is selected from the group consisting of halogen, CF 3 , MeO, NO 2 and CN;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 selected from the group consisting of
[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(3-methoxy-phenyl)-methanone;
(3-Bromo-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanone;
1-[5-(4-Fluoro-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one;
1-[5-(3,5-Bis-trifluoromethyl-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one; and
1-[5-(3,5-Bis-trifluoromethyl-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-4-one.
3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 .