Estrogen agonist/antagonist metabolites

Abstract

This invention relates to compounds that are mammalian metabolites of (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol. The compounds of the invention can be used as standards for analytical assays or as intermediates for the further chemical synthesis or biosynthesis of chemical entities. The invention also relates to pharmaceutical compositions for the treatment of disease and methods of treating disease.

1. A metabolite of (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol corresponding to formula I: 
                   
       wherein R 1  is selected from 
                 
 
       or
 NH(CH 2 ) 3 COR 6 ;  
 R 5  is selected from H or CH 3 ;  
 R 2 , R 3 , R 4  and R 7  are the same or different and are selected from H and OR 5 ; and  
 R 6  is selected from —OH, or —NHCH 2 COOH, provided that: 
 (a) if R 1  is 
                 
 
  or —NH(CH 2 ) 3 COOH and  
 (b) R 2  is OH or OCH 3  and R 3  and R 7  are H, or if R 1  is as defined in (a) above and  
 (c) R 2  and R 7  are H and R 3  is OH or OCH 3 , then R 4  is not H; 
 and further provided that when R 2 , R 3 , R 4  and R 7  are H, then R 1  is not 
                 
 
 
 
 
       or an optical, stereo, regio or configurational isomer or geometric isomer thereof or a tautomer, pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug thereof. 
     
     
       2. A metabolite of (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol according to  claim 1   that is selected from the group consisting of: 
                 
                 
                 
 
       and stereoisomers, tautomers, regio and configurational isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof and combinations thereof. 
     
     
       3. A kit comprising a metabolite of (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol corresponding to formula I: 
                   
       wherein R 1  is selected from 
                 
 
       or
 —NH(CH 2 ) 3 COR 6 ;  
 R 5  is selected from H, or CH 3 ;  
 R 2 , R 3 , R 4  and R 7  are the same or different and are selected from H and OR 5 ; and  
 R 6  is selected from —OH, or —NHCH 2 COOH, provided that: 
 (a) if R 1  is 
                 
 
  or —NH(CH 2 ) 3 COOH and  
 (b) R 2  is OH or OCH 3  and R 3  and R 7  are H, or if R 1  is as defined in (a) above and  
 (c) R 2  and R 7  are H and R 3  is OH or OCH 3 , then R 4  is not H; 
 and further provided that when R 2 , R 3 , R 4  and R 7  are H, then R 1  is not 
                 
 
 
 
 
       or an optical, stereo, regio or configurational isomer or geometric isomer thereof or a tautomer, pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug thereof. 
     
     
       4. A kit according to  claim 3  wherein said metabolite of (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol is selected from the group consisting of: 
                                     
       and stereoisomers, tautomers, regio and configurational isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof and combinations thereof. 
     
     
       5. A method of treating disease  osteoporosis, breast cancer, or hyperlipidemia, the method comprising administering to a subject in need thereof, an effective amount of a metabolite of (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol corresponding to formula I: 
                 
 
       wherein R 1  is selected from 
                 
 NH(CH 2 ) 3 COR 6 ;  
 R 5  is selected from H, or CH 3 ;  
 R 2 , R 3 , R 4  and R 7  are the same or different and are selected from H and OR 5 ; and  
 R 6  is selected from —OH, or —NHCH 2 COOH, provided that: 
 (a) if R 1  is 
                 
 
  or —NH(CH 2 ) 3 COOH and  
 (b) R 2  is OH or OCH 3  and R 3  and R 7  are H, or if R 1  is as defined in (a) above and  
 (c) R 2  and R 7  are H and R 3  is OH or OCH 3 , then R 4  is not H; 
 and further provided that when R2, R3, R4 and R7 are H, then R1 is not 
                 
 
 
 
 
       or an optical, stereo, regio or configurational isomer or geometric isomer thereof or a tautomer, pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug thereof. 
     
     
       6. A method as claimed in  claim 5  wherein said metabolite of (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol is selected from the group consisting of: 
                 
                 
 
       and stereoisomers, tautomers, regio and configurational isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof and combinations thereof. 
     
     
       7. A method as claimed in  claim 5  wherein said method substantially reduces the concomitant liability of adverse effects associated with estrogen administration. 
     
     
       8. A method as claimed in  claim 6  wherein said method substantially reduces the concomitant liability of adverse effects associated with estrogen administration. 
     
     
       9. A pharmaceutical composition comprising a metabolite of (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol corresponding to formula I: 
                 
 
       wherein R 1  is selected from 
                 
 
       or
 —NH(CH 2 ) 3 COR 6 ;  
 R 5  is selected from H, or CH 3 ;  
 R 2 , R 3 , R 4  and R 7  are the same or different and are selected from H and OR 5 ; and  
 R 6  is selected from —OH, or —NHCH 2 COOH, provided that: 
 (a) if R 1  is 
                 
 
  or —NH(CH 2 ) 3 COOH and  
 (b) R 2  is OH or OCH 3  and R 3  and R 7  are H, or if R 1  is as defined in (a) above and  
 (c) R 2  and R 7  are H and R 3  is OH or OCH 3 , then R 4  is not H; 
 and further provided that when R 2 , R 3 , R 4  and R 7  are H, then R 1  is not 
                 
 
 
 
 
       or an optical, stereo, regio or configurational isomer or geometric isomer thereof or a tautomer, pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug thereof, and 
       a pharmaceutically acceptable carrier, vehicle or diluent. 
     
     
       10. A composition according to  claim 9  wherein said metabolite of (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol is selected from the group consisting of: 
                 
                 
 
       and stereoisomers, tautomers, regio and configurational isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof and combinations thereof. 
     
     
       11. A compound selected from the group consisting of:
 6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2,3-diol;    3-methoxy-7-phenyl-8-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol;    3-methoxy-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol;    6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-1,2-diol;    2-methoxy-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-1-ol;    1-methoxy-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol;    and stereoisomers, tautomers, regio and configurational isomers thereof;    
       and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof and combinations thereof.