CRF receptor antagonists and methods relating thereto

Abstract

CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, such as stroke. The CRF receptor antagonists of this invention have the following structure: including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 5 , R 6 , X and Y are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same

1 . A compound having the following structure:  
       
         
           
           
               
               
           
         
       
       or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, 
 wherein: 
 X is nitrogen or CR 3 ;  
 Y is nitrogen or CR 4;    
 R 1  is alkyl, substituted alkyl, —NR 7 R 8 , aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 2  is hydrogen, alkyl, alkoxy, thioalkyl or haloalkyl;  
 R 3  is hydrogen, alkyl, halo or haloalkyl;  
 R 4  is hydrogen, halogen, —NR 7 R 8 , alkyl, alkoxy, thioalkyl or haloalkyl;  
 R 5  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 6  is hydrogen, alkyl, substituted alkyl, —NR 7 R 8 , —OR 9 , —SR 9 , aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 7  and R 8  are the same or different and independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; and  
 R 9  is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.  
 
 
     
     
         2 . The compound of  claim 1  wherein X is CR 3 .  
     
     
         3 . The compound of  claim 1  wherein X is nitrogen.  
     
     
         4 . The compound of  claim 1  wherein Y is CR 4 .  
     
     
         5 . The compound of  claim 1  wherein Y is nitrogen.  
     
     
         6 . The compound of  claim 1  wherein R 1  is substituted aryl or substituted heteroaryl.  
     
     
         7 . The compound of  claim 1  wherein R 5  is alkyl, substituted alkyl, aryl or substituted aryl.  
     
     
         8 . The compound of  claim 6  wherein R 5  is alkyl, substituted alkyl, aryl or substituted aryl.  
     
     
         9 . The compound of  claim 7  wherein R 1  is —NR 7 R 8 .  
     
     
         10 . The compound of  claim 1  wherein both X and Y are nitrogen.  
     
     
         11 . The compound of  claim 1  wherein X is CR 3  and Y is nitrogen.  
     
     
         12 . The compound of  claim 1  wherein X is nitrogen and Y is CR 4 .  
     
     
         13 . The compound of  claim 1  wherein X is CR 3  and Y is CR 4 .  
     
     
         14 . A composition comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier or diluent.  
     
     
         15 . A method for treating a disorder manifesting hypersecretion of CRF in a warm-blooded animal, comprising administering to the animal an effective amount of the pharmaceutical composition of  claim 14 .  
     
     
         16 . The method of  claim 15  wherein the disorder is stroke.  
     
     
         17 . The method of  claim 15  wherein the disorder is depression.  
     
     
         18 . The method of  claim 15  wherein the disorder is anxiety.  
     
     
         19 . The method of  claim 15  wherein the disorder is irritable bowel syndrome.