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 m, R, R 1 , R 2 , X, Y, A, B and C 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 O or S(O) 0-2 ;  
 “ - - - ” represents an option double bond;  
 A and C are the same or different and independently nitrogen, carbon or CH;  
 B is nitrogen or CR 4 ;  
 with the provisos that at least one of A, B or C is nitrogen, A, B and C are not all nitrogen, and either A-B or B-C is a double bond;  
 R is an optional substituent which, at each occurrence, is independently alkyl, substituted alkyl, aryl, arylalkyl, alkylidenyl, heterocycle, heterocyclealkyl, alkoxy or —CO(alkoxy), wherein m is 0, 1, 2 or 3 and represents the number of R substituents;  
 R 1  is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 2  is hydrogen, alkyl, alkoxy or thioalkyl or haloalkyl;  
 R 3  is hydrogen, alkyl, halogen or haloalkyl; and  
 R 4  is hydrogen, halogen, alkyl, alkoxy, thioalkyl or haloalkyl.  
 
 
     
     
         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 0.  
     
     
         5  The compound of  claim 1  wherein Y is S(O) 0-2 .  
     
     
         6 . The compound of  claim 5  wherein Y is S.  
     
     
         7 . The compound of  claim 5  wherien Y is SO.  
     
     
         8 . The compound of  claim 5  wherein Y is SO 2 .  
     
     
         9 . The compound of  claim 1  wherein A is nitrogen, B is nitrogen, C is carbon and the double bond is between B and C.  
     
     
         10 . The compound of  claim 1  wherein A is carbon, B is nitrogen, C is nitrogen, and the double bond is between A and B.  
     
     
         11 . The compound of  claim 1  wherein A is carbon, B is CR 4 , C is nitrogen, and the double bond is between A and B.  
     
     
         12 . The compound of  claim 1  wherein A is nitrogen, B is CR 4 , C is carbon, and the double bond is between B and C.  
     
     
         13 . The compound of  claim 1  wherein R 1  is substituted aryl.  
     
     
         14 . The compound of  claim 13  wherein R 1  is substituted phenyl.  
     
     
         15 . The compound of  claim 1  wherein R 2  is hydrogen or alkyl.  
     
     
         16 . The compound of  claim 1  wherein R 3  is hydrogen, halogen, alkyl or haloalkyl.  
     
     
         17 . The compound of  claim 1  wherein R 4  is hydrogen or alkyl.  
     
     
         18 . A composition comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier or diluent.  
     
     
         19 . 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 18 .  
     
     
         20 . The method of  claim 19  wherein the disorder is stroke.  
     
     
         21 . The method of  claim 19  wherein the disorder is depression.  
     
     
         22 . The method of  claim 19  wherein the disorder is anxiety.