Estrogen agonists/antagonists for preventing breast cancer

Abstract

Compounds of this formula are useful for preventing breast cancer.

What is claimed is:  
     
         1 . A method of preventing breast cancer in a mammal which comprises administering to a mammal in need of such prevention an effective amount of a compound of the formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is selected from CH 2  and NR;  
 B, D and E are independently selected from CH and N;  
 Y is 
 (a) phenyl, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (b) naphthyl, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (c) C 3 -C 8  cycloalkyl, optionally substituted with 1-2 substituents independently selected from R 4 ;  
 (d) C 3 -C 8  cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R 4 ;  
 (e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 —and —S(O) n —, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 — and —S(O) n —optionally substituted with 1-3 substituents independently selected from R 4 ; or  
 (g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 —, NR 2 — and —S(O) n —, optionally substituted with 1-3 substituents independently selected from  
 
 z 1  is 
 (a) —(CH 2 ) p W(CH 2 ) q —;  
 (b) —O(CH 2 ) p CR 5 R 6 —;  
 (c) —O(CH 2 ) p W(CH 2 ) q- ;  
 (d) —OCHR 2 CHR 3 —; or  
 (e) —SCHR 2 CHR 3 —;  
 
 G is 
 (a) —NR 7 R 8 ;  
 (b)  
                     
  wherein n is 0, 1 or 2; m is 1, 2 or 3; Z 2  is —NH—, —O—, —S—, or —CH 2 —; optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R 4 ; or  
 (c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R 4 ;  
 
 Z 1  and G in combination may be  
                     
 W is 
 (a) —CH 2 —;  
 (b) —CH═CH—;  
 (c) —O—;  
 (d) —NR 2 —;  
 (e) —S(O) n —;  
 (f)  
                     
 (g) —CR 2 (OH)—;  
 (h) —CONR 2 —;  
 (i) —NR 2 CO—;  
 (j)  
                     
 (k) —C≡C—;  
 
 R is hydrogen or C 1 -C 6  alkyl;  
 R 2  and R 3  are independently 
 (a) hydrogen; or  
 (b) C 1 -C 4  alkyl;  
 
 R 4  is 
 (a) hydrogen;  
 (b) halogen;  
 (c) C 1 -C 6  alkyl;  
 (d) C 1 -C 4  alkoxy;  
 (e) C 1 -C 4  acyloxy;  
 (f) C 1 -C 4  alkylthio;  
 (g) C 1 -C 4  alkylsulfinyl;  
 (h) C 1 -C 4  alkylsulfonyl;  
 (i) hydroxy (C 1 -C 4 )alkyl;  
 (j) aryl (C 1 -C 4 )alkyl;  
 (k) —CO 2 H;  
 (I) —CN;  
 (m) —CONHOR;  
 (n) —SO 2 NHR;  
 (o) —NH 2 ;  
 (p) C 1 -C 4  alkylamino;  
 (q) C 1 -C 4  dialkylamino;  
 (r) —NHSO 2 R;  
 (s) —NO 2 ;  
 (t) -aryl; or  
 (u) —OH.  
 
 R 5  and R 6  are independently C 1 -C 8  alkyl or together form a C 3 -C 10  carbocyclic ring;  
 R 7  and R 8  are independently 
 (a) phenyl;  
 (b) a C 3 -C 10  carbocyclic ring, saturated or unsaturated;  
 (c) a C 3 -C 10  heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;  
 (d) H;  
 (e) C 1 -C 6  alkyl; or  
 (f) form a 3 to 8 membered nitrogen containing ring with R 5  or R 6 ;  
 
 R 7  and R 8  in either linear or ring form may optionally be substituted with up to three substituents independently selected from C 1 -C 6  alkyl, halogen, alkoxy, hydroxy and carboxy;  
 a ring formed by R 7  and R 8  may be optionally fused to a phenyl ring;  
 e is 0, 1 or 2;  
 m is 1, 2or 3;  
 n is 0, 1 or 2;  
 p is 0, 1,2 or 3;  
 q is 0, 1,2 or 3;  
 and optical and geometric isomers thereof; and nontoxic pharmacologically acceptable acid addition salts, N-oxides, esters, and quaternary ammonium salts thereof.  
 
     
     
         2 . A method of  claim 1  wherein the compound is a compound of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         3 . A method of preventing breast cancer in a mammal which comprises administering to a mammal in need of such prevention an effective amount of (−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol, or a nontoxic pharmacologically acceptable acid addition salt, N-oxide, ester, or quaternary ammonium salt thereof.  
     
     
         4 . A method of preventing breast cancer in a mammal which comprises administering to a mammal in need of such prevention an effective amount of Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol, or an optical or geometric isomer thereof; or a nontoxic pharmacologically acceptable acid addition salt, N-oxide, ester, or quaternary ammonium salt thereof.