Estrogen receptor modulators

Abstract

Estrogen receptor-modulating pyrazole compounds are described in addition to methods and compositions for treating or preventing estrogen receptor-mediated disorders. The compounds described have been found to have unexpected and surprising activity in modulating estrogen receptor activity. Thus, the compounds of the present invention have utility in preventing or treating estrogen receptor-mediated disorders such as osteoporosis, breast and endometrial cancers, atherosclerosis, and Alzheimer's disease.

1. A compound having a formula selected from the group consisting of: 
                 
 
       and their  its pharmaceutically acceptable salts, wherein:
 R 1    is optionally substituted para - hydroxyphenyl;   
 R 1  and  R 3  areis selected independently  from the group consisting of optionally substituted hydroxyaryls and alkoxyaryls;  
 R 2  is selected from the group consisting of hydrogen and  optionally substituted loweralkyls; and  
 R 4  is selected from the group consisting of optionally substituted cycloalkyls.  
 
     
     
       2. The compound of  claim 1 , wherein R 1  iand  R 3  are  is selected independently  from the group consisting of optionally substituted hydroxyaryls. 
     
     
       3. The compound of  claim 1 , wherein R 1  and  R 3  are  is selected independently  from the group consisting of optionally substituted  substituted alkoxyaryls. 
     
     
       4. The compound of  claim 1 , wherein at least one of R 1  and R 3  is substituted with at least one hydroxy or alkyloxy group. 
     
     
       5. The compound of  claim 1 , wherein  A compound having a formula selected from the group consisting of:
                 
 
       
         and its pharmaceutically acceptable salts, wherein:  
           R   1    is optionally substituted para - hydroxyphenyl;   
         at least one of R 1  and  R 3  is selected independently  from the group consisting of optionally substituted phenyloxyloweralkyls;  
         
           R 
           2  
           is selected from the group consisting of optionally substituted loweralkyls; and  
         
         
           R 
           4  
           is selected from the group consisting of optionally substituted cycloalkyls.  
         
       
     
     
       6. The compound of  claim 5 , wherein at least one of R 1  and R 3  is substituted with a substituent selected from the group consisting of halogen, nitro, cyano, loweralkyl, halolowerlalky  halolowerlalkyl, loweralkyloxy, haloloweralkyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl) oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl) oxycarbonyl, loweralkylsulfinyl, loweralkylsulfonyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroarylcarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl) carbonyloxy, alkylsulfonylamino, (heterocycloloweralkyl) carbonyloxy, aminocarbonyl, loweraklylaminocarbolnyl  loweraklylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl, and heteroaralkylalminocarbonyl  heteroaralkylaminocarbonyl. 
     
     
       7. The compound of  claim 6 , wherein at least one of R 1  and R 3  is substituted with a substituent selected from the group consisting of halogen, nitro, cyano, loweralkyl, haloloweralalkyl  haloloweralkyl, loweralkyloxy, halolowerlakyloxy  haloloweralkyloxy, carboxy, loweralkylthio, aminocarbonyl, and loweralkylsulfinyl. 
     
     
       8. The compound of  claim 1 , wherein R2 is hydrogen. 
     
     
       9. The compound of  claim 1 , wherein R2 is optionally substituted loweralkyl. 
     
     
       10. The compound of  claim 1 , wherein at least one of R1 and R3 is substituted with at least one hydroxy or thio group. 
     
     
       11. The compound of  claim 1 , wherein at least one of R 1  and R 3  is substituted with a substituent selected from the group consisting of halogen, loweralkyl, haloloweralalkyl  haloloweralkyl, loweralkyloxy, halolowerlakyloxy  haloloweralkyloxy, carboxy, loweralkyloxycarbonyl, aryloxycarbonyl, (cycloloweralkyl) oxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, (heterocycloloweralkyl) oxycarbonyl, loweralkylsulfinyl, loweralkylsulfinyl, loweralkylthio, arylthio, loweralkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroarylcarbonylloxy  heteroarylcarbonyloxy, heteroaralkylcarbonyloxy, (cycloloweralkyl) carbonyloxy, (heterocycloloweralkyl) carbonyloxy, aminocarbonyl, loweralkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, heteroarylaminocarbonyl, and heteroaralkylaminocarbonyl. 
     
     
       12. A composition for use in treating an estrogen receptor-mediated disorder in a mammal, comprising a therapeutically effective amount of a compound of  claim 1  in a pharmaceutically effective carrier.