Pyridine Imidazoles and Aza-indoles as Progesterone Receptor Modulators

Abstract

The present invention is directed to novel heteroatom containing tetracyclic derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders mediated by one or more estrogen receptors. The compounds of the invention are useful in the treatment of disorders associated with the depletion of estrogen such as hot flashes, vaginal dryness, osteopenia and osteoporosis; hormone sensitive cancers and hyperplasia of the breast, endometrium, cervix and prostate; endometriosis, uterine fibroids, osteoarthritis and as contraceptive agents, alone or in combination with a progestogen or progestogen antagonist.

1 . A method of contraception; and of treating a disorder mediated by a progesterone receptor, wherein said disorder is selected from the group consisting of: the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, or mitigation of side effects of cyclic menstrual bleeding, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of formula (I): 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 2  are the same unsubstituted alkyl group, or R 1  and R 2  are connected by —(CH 2 ) 4 — to form a 5-membered spiro ring or R 1 , R 2  are connected by —(CH 2 ) 5 — to form a 6-membered spiro ring; 
       R 3  is phenyl substituted with one or two substituents selected from the group consisting of: halogen, nitro, cyano, trifluoromethyl, and methoxy; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       2 . The method of  claim 1  that is contraception. 
   
   
       3 . A method of contraception comprising co-therapy with a therapeutically effective amount of a compound of  claim 1  and estrogen or an estrogen agonist. 
   
   
       4 . The method of  claim 1  wherein said compound is selected from the group consisting of:
 6-(3-nitro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one,   6-(3-trifluoromethyl -phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one,   6-(3-cyano-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one,   6-(3,5-Difluoro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one,   6-(3,5-Dichloro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one, and   6-(2,4-Difluoro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one.   
   
   
       5 . The method of  claim 4  that is contraception. 
   
   
       6 . A method of contraception comprising co-therapy with a therapeutically effective amount of a compound of  claim 4  and estrogen or an estrogen agonist.