ER-beta-selective ligands

Abstract

Compounds of the formula (I) for use as an estrogen receptor -β-selective ligand are described wherein: X is O or S; and R 1 , R 3 -R 6 are as described in the specification. The use of these compounds in treating Alzheimer's disease, anxiety disorders, depressive disorders, osteoporosis, cardiovascular disease, rheumatoid arthritis and prostate cancer is described; as are processes for making them.

1 . A compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein: 
 X is O or S;  
 R 1  is a 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms each independently selected from O, N and S and additionally having 0 or 1 oxo groups and 0 or 1 fused benzo rings, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents selected from —R a , —OR a , —SR a , —NR a R a , —CO 2 R a , —OC(═O)R a , —C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano, nitro and C 1-3 haloalkyl;  
 R 3  is —R a , —OR a , —SR a , —NR a R a , —CO 2 R a , —OC(═O)R a , —C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano, nitro or C 1-3 haloalkyl; or R 3  is C 1-3 alkyl containing 1 or 2 substituents selected from —OR a , —SR a , NR a R a , —CO 2 R a , OC(═O)R a , —C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , NR a S(═O) 2 R a , C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano and nitro;  
 R 4  is R a , —OR a , —SR a  —NR a R a , —CO 2 R a , —OC(═O)R a , —C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano, nitro or C 1-3 haloalkyl;  
 R 5  is R a , —OR a , —SR a , —NR a R a , —CO 2 R a , —OC(═O)R a , —C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano, nitro or C 1-3 haloalkyl;  
 R 6  is —R a , —OR a , —SR a , —NR a R a , —CO 2 R a , —OC(═O)R a , —C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano, nitro or C 1-3 haloalkyl; or R 6  is  
 C 1-3 alkyl containing 1 or 2 substituents selected from —OR a , —SR a , —NR a R a , —CO 2 R a , —OC(═O)R a , —C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano and nitro; and  
 R 1  is H, C 1-6 alkyl, C 1-3 haloalkyl, phenyl or benzyl.  
 
     
     
         2 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 1  wherein X is S.  
     
     
         3 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 1  wherein X is O.  
     
     
         4 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 2  or  3  wherein R 3  is halo, cyano, carbamoyl or C 1-6 alkyl.  
     
     
         5 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 2  or  3  wherein R 3  is hydrogen.  
     
     
         6 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 2  or  3  wherein R 4  is halo, hydroxy or C 1-6 alkoxy.  
     
     
         7 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 2  or  3  wherein R 4  is hydrogen.  
     
     
         8 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 2  or  3  wherein R 5  is halo, hydroxy or C 1-6 alkoxy.  
     
     
         9 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 2  or  3  wherein R 5  is hydrogen.  
     
     
         10 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 2  or  3  wherein R 6  is halo, C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, carboxy, C 1-4 alkoxycarbonyl, cyano, halomethyl, cyanoC 1-4 alkyl, carbamoyl, methylcarbamoyl or dimethylcarbamoyl.  
     
     
         11 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 2  or  3  wherein R 6  is hydrogen.  
     
     
         12 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 3  wherein R 3  is chloro or bromo; R 5  is hydroxy; and R 4  and R 6  are both hydrogen.  
     
     
         13 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 2  wherein R 6  is cyano or carboxy; R 4  is hydroxy; and R 3  and R 5  are both hydrogen.  
     
     
         14 . A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof as defined in  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         15 . A method for achieving selective targeting of the β-estrogen receptor, which comprises administering an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 1 .  
     
     
         16 . A method for treating Alzheimer's disease, anxiety disorders, depressive disorders, osteoporosis, cardiovascular disease, rheumatoid arthritis or prostate cancer, which comprises administering an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 1  to a patient in need of such treatment.  
     
     
         17 . A process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in  claim 1  which comprises: 
 a) cyclizing a compound of the formula:                          wherein X, R 1 , and R 3 -R 6  are as defined in  claim 1  and L is hydrogen or a leaving group; or    b) cyclizing a compound of the formula:                          wherein R 1  and R 3 -R 6  are as defined in  claim 1  or:    c) cyclizing a compound of the formula:                          wherein R 1 , R 3 -R 6  and X are as defined in  claim 1  and L is hydrogen or a leaving group; or    d) cyclizing a compound of the formula:                          wherein R 1  and R 3 -R 6  are as defined in  claim 1;     and thereafter, if desired, 
 forming a pharmaceutically acceptable salt.  
   
     
     
         18 . A method for treating a condition for which ERT has a beneficial effect, which comprises administering an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 1  to a patient in need of such treatment.