5-Substituted-6-cyclic-5,6,7,8-tetrahydronaphthalen 2-ol compounds which are useful for treating osteoporosis

Abstract

Compounds of this formula are useful for treating or preventing, obesity, breast cancer, osteoporosis, endometriosis, cardiovascular disease and prostatic disease.

1. A compound of the formula I: 
                 
 
       wherein:
 A is CH 2 ;  
 B, D and E are CH;  
 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   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-, and -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-, and -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-, and -NR 2 -, NR 2 - and -S(O) n -,  optionally substituted with 1-3 substituents independently selected from R 4 . ; 
 
 Z 1  is 
 (a) -O(CH 2 ) p  CR 5 R 6 -;  
 (b) -O(CH 2 ) p W(CH 2 ) q ; or  
 (c) -OCHR 2 CHR 3 -;  
 
 G is -NR 7 R 8  
                 
 
 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 -; or 
 (i) -NR 2 CO-;  
 (j) 
                   
 
 
       or
   (k) -C═C-;    
 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;  
 (l) -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  in ring form may optionally be substituted with up to three substituents independently selected from C-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 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 
 or an optical or geometric isomer thereof; or a nontoxic pharmacologically acceptable acid addition salt, N- oxide, ester, or quaternary ammonium salt thereof .  
 
     
     
       2. A compound of  claim 1  which is of the formula: 
                 
 
     
     
       3. A compound of  claim 2  wherein G is 
                   
     
     
       4. A compound of claim  3    2  wherein R 4  is H, OH, F or Cl. 
     
     
       5. A compound of  claim 4  wherein:
 B and E are CH  the formula:
                 
 
 
       wherein:
   G is                          R   4    is H, OH, F or Cl;        or an optical or geometric isomer thereof; or a nontoxic pharmacologically acceptable acid addition salt, N - oxide, ester, or quaternary ammonium salt thereof.      
     
     
       6. The compound of  claim 1  which is
 (−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol.  
 
     
     
       7. The compound of  claim 1  which is
 Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol.  
 
     
     
       8. A pharmaceutical composition for treating or preventing osteoporosis comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       9. A method of treating or preventing osteoporosis in a mammal which comprises administering to a mammal in need of such treatment an effective amount of compound of  claim 1 . 
     
     
       10. The compound of  claim 1  which is Cis-(6-(4-fluoro-phenyl)-5-[4-2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen 2-ol  Cis-(   6   -(   4   - fluoro - phenyl )-   5   - [ 4   -   2   - piperidin -   1   - yl - ethoxy )- phenyl] -   5 , 6 , 7 , 8   - tetrahydronaphthalen -   2   - ol.    
     
     
       11. The compound of  claim 1  which is Cis-(6-(4′-hydroxyphenyl)-5-[4-2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen2-ol  Cis-(   6   -(   4 ′ - hydroxyphenyl )-   5   - [ 4   -   2   - piperidin -   1   - yl - ethoxy )- phenyl] -   5 , 6 , 7 , 8   - tetrahydronaphthalen -   2   - ol.    
     
     
       12. A nontoxic pharmacologically acceptable acid addition salt of a compound of  claim 1 . 
     
     
       13. A nontoxic pharmacologically acceptable acid addition salt of (-)- Cis -   6   - phenyl -   5   - [ 4   -(   2   - pyrrolidin -   1   - yl - ethoxy )- phenyl] -   5 , 6 , 7 , 8   - tetrahydronaphthalen -   2   - ol.   
     
     
       14. A nontoxic pharmacologically acceptable acid addition salt of Cis-   6   - phenyl -   5   - [ 4   -(   2   - pyrrolidin -   1   - yl - ethoxy )- phenyl] -   5 , 6 , 7 , 8   - tetrahydronaphthalen -   2   - ol.   
     
     
       15. A method of treating or preventing osteoporosis in a mammal which comprises administering to a mammal in need of such treatment an effective amount of (-)- Cis -   6   - phenyl -   5   - [ 4   -(   2   - pyrrolidin -   1   - yl - ethoxy )- phenyl] -   5 , 6 , 7 , 8   - tetrahydronaphthalen -   2   - ol or a nontoxic pharmacologically acceptable acid addition salt, N - oxide, ester, or quaternary ammonium salt thereof.   
     
     
       16. A pharmaceutical composition for treating or preventing osteoporosis comprising (-)- Cis -   6   - phenyl -   5   - [ 4   -(   2   - pyrrolidin -   1   - yl - ethoxy )- phenyl] -   5 , 6 , 7 , 8   - tetrahydronaphthalen -   2   - ol or a nontoxic pharmacologically acceptable acid addition salt, N - oxide, ester, or quaternary ammonium salt thereof and a pharmaceutically acceptable carrier.