Non-steroidal ligands for the estrogen receptor

Abstract

Novel non-steroidal ligands for the estrogen receptor which possess tissue-dependent estrogenic and antiestrogenic activity as well as methods for making the same and their applications in treating a variety of disease states.

We claim:  
     
         1 . A compound of Formula I:  
       
         
           
           
               
               
           
         
         wherein 
 R 1  is —(CH 2 ) n CR 5 ═CR 6 R 7 ; —(CH 2 ) m C(X)NR 8 R 9 ; or  
                     
  R 2  and R 3  are independently H, —CH 3 , —OH, —OCH 3 , —OCH 2 CH 3  or —CH 2 (CH 3 ) 2 ;  
 R 4  is —CN, —NO 2 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 —Y or —Y;  
 R 5  and R 6  are independently H, —C 1-4 alkyl, —C 2-4 alkenyl, -C 2-4 alkynyl, —X—C 1-3 alkyl, —X—C 2-4 alkenyl, —X—C 2-4 alkynyl or —Y;  
 R 7  is —CN, —C 1-4 alkyl-OH, —C(O)O(CH 3 ) 3 , —C(O)NR 10 R 11 , —C(O)NR 12 R 13 , —C 1-4 alkyl-NR 10 R 11 , —C(O)R 12 , —C(O)OR 12 , —C(O)NR 12 OR 13 , —C(O)NHC(O)R 12 , —C(O)NHCH 2 R 12 , —C(NH 2 )(NOR 12 ), —S(O)R 12 , —S(O)(O)(OR 12 ), —S(O)(O)(NHCO 2 R 12 ), PO 3 R 12 , —P(O)(NR 12 R 13 )(NR 12 R 13 ), —P(O)(NR 12 R 13 )(OR 14 ), —CONR 12 (CH 2 ) q OCH 3 , —CONR 12 (CH 2 ) q NR 8 R 9  or oxadizole substituted with methyl;  
 R 8  and R 9  are independently hydrogen, —C 1-7 alkyl, —C 3-7 cycloalkyl, —O—C 1-7 alkyl, —C 1-7 alkyl-Y or phenyl;  
 R 10  and R 11  are independently methyl or ethyl or, taken together form a morpholino group bonded via its nitrogen atom;  
 R 12 , R 13  and R 14  are independently H, —C 1-12 alkyl, —C 2-12 alkenyl, —C 2-12 alkynyl, —O—C 1-12 alkyl, —O—C 2-12 alkenyl, —O—C 2-12 alkynyl, —C 3-7 cycloalkyl, —C 3-7 cycioalkenyl, linear and cyclic heteroalkyl, aryl, heteroaryl or —Y;  
 X is oxygen or sulfur;  
 Y is a halogen;  
 n is an integer selected from 0, 1 or 2;  
 m is the integer 1 or 2;  
 p is an integer selected from 1 to 4; and  
 q is an integer from 1-12.  
 
       
     
     
         2 . A compound according to  claim 1  wherein X is 0.  
     
     
         3 . A compound according to  claim 2  wherein R 1  is R 1  is —(CH 2 ) n CR 5 ═CR 6 R 7 .  
     
     
         4 . A compound according to  claim 1  wherein R 2  and R 3  are independently selected from H, —OH or —OCH 3 .  
     
     
         5 . A compound according to  claim 4  wherein R 2  and R 3  are H.  
     
     
         6 . A compound according to  claim 1  wherein R 4  is either —CH 3 , —CH 2 CH 3  or —CH 2 CH 2 —Cl.  
     
     
         7 . A compound according to  claim 1  wherein R 5  and R 6  are independently H or —C 1-4 alkyl.  
     
     
         8 . A compound according to  claim 1  wherein R 8  and R 9  are independently hydrogen, —C 1-7 alkyl or —C 3-7 cycloalkyl.  
     
     
         9 . A compound according to  claim 3  wherein R 7  is C(O)O(CH 3 ) 3 , —C(O)NR 10 R 11 , —C(O)NR 12 R 13 , —C(O)OR 12 , —C(O)NHC(O)R 12 , —C(NH 2 )(NOR 12 ), —S(O)(O)(NHCO 2 R 12 ), PO 3 R 12 , —P(O)(NR 12 R 13 )(NR 12 R 13 ) or P(O)(NR 12 R 13 )(OR 14 ).  
     
     
         10 . A compound according to  claim 1  wherein R 12 , R 13  and R 14  are independently H, —C 1-12 alkyl, —C 2-12 alkenyl.  
     
     
         11 . A compound according to  claim 1  wherein the compound is selected from one of the following: 
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N,N-diethyl acrylamide;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N,N-diethyl propionamide;  
 2-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]cyclopropanecarboxylic acid diethylamide;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N,N-diethyl-2-methyl-acrylamide;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-but-2-enoic acid diethylamide;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acrylic acid methyl ester;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acrylonitrile;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acrylic acid tert-butyl ester;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-acrylic acid;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-1-morpholin-4-yl-prop-2-en-1-one;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N-(3methoxy-propyl)-acrylamide;  
 N,N-Dicyclohexyl-3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]acrylamide;  
 N-(2-Dimethylamino-ethyl)-3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-N-ethyl acrylamide;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N-methyl-N-octyl acrylamide;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]acrylamide;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N-ethyl acrylamide;  
 1-Amino-3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-prop-2-ene-1-one oxime;  
 3-{2-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-vinyl}-5-methyl-[1,2,4]-oxadiazole;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-prop-2-ene-1-ol;  
 {3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-allyl}-dimethylamine;  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N,N-diethyl thioacrylamide; or  
 3-[4-(1,2-Diphenyl-but-1-enyl)-phenyl]-N-(3-hydroxy-propyl)-acrylamide.  
 
     
     
         12 . A method of treating a mammal for osteoporosis comprising administering to said mammal an effective amount of a compound according to  claim 1 .  
     
     
         13 . A method of treating a mammal for arthritic diseases which comprises administering to said mammal an effective amount of a compound according to  claim 1 .  
     
     
         14 . A method of treating a mammal for breast cancer which comprises administering to said mammal an effective amount of a compound according to  claim 1 .  
     
     
         15 . A method of treating a mammal for cardiovascular disease which comprises administering to said mammal an effective amount of a compound according to  claim 1 .  
     
     
         16 . A method of preventing osteoporosis in a mammal comprising administering to said mammal an effective amount of a compound according to  claim 1 .  
     
     
         17 . A method of preventing arthritic diseases in a mammal which comprises administering to said mammal an effective amount of a compound according to  claim 1 .  
     
     
         18 . A method of preventing breast cancer in a mammal which comprises administering to said mammal an effective amount of a compound according to  claim 1 .  
     
     
         19 . A method of preventing cardiovascular disease in a mammal which comprises administering to said mammal an effective amount of a compound according to  claim 1.