Trisubstituted Thiophenes as Progesterone Receptor Modulators

Abstract

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 method of treating or preventing a disorder mediated by a progesterone receptor, wherein the disorder is selected from the group consisting of: secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon or prostate, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of 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, or 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 and pyridinyl are optionally substituted with up to three R 5 ; 
       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 method of  claim 1  wherein said compound is 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 . The method of  claim 1  wherein said therapeutically effective amount of said compound is from about 0.1 to about 500 mg/day. 
   
   
       4 . The method of  claim 2  wherein said therapeutically effective amount of said compound is from about 0.1 to about 500 mg/day.