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 animal, 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 , A, X, Y and Z 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: 
 the following structure (I):                          or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,    wherein: 
 X is nitrogen or CR 3 ;  
 Z is O, S or NR 4 ;  
 Y is N, NR 5  or O;  
 A is O, S, or NR 6 ;  
 “----” represents an optional double bond;  
 R is an optional substituent which, at each occurrence, is independently alkyl, aryl, heteroaryl, alkylidenyl, arylalkyl or heteroarylalkyl, 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, substituted alkyl, alkoxy or thioalkyl;  
 R 3  is hydrogen, halogen, alkyl or substituted alkyl;  
 R 4  is hydrogen, cyano, nitro, alkyl or substituted alkyl;  
 R 5  is hydrogen, alkyl or substituted alkyl; and  
 R 6  is hydrogen, 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 A is O.  
     
     
         5 . The compound of  claim 1  wherein A is S.  
     
     
         6 . The compound of  claim 1  wherein A is NR 6 .  
     
     
         7 . The compound of  claim 6  wherein R 6  is alkyl.  
     
     
         8 . The compound of  claim 1  wherein Y is N.  
     
     
         9 . The compound of  claim 1  wherein Y is NR 5 .  
     
     
         10 . The compound of  claim 9  wherein R 5  is alkyl.  
     
     
         11 . The compound of  claim 1  wherein Y is O.  
     
     
         12 . The compound of  claim 1  wherein Z is O.  
     
     
         13 . The compound of  claim 1  wherein Z is S.  
     
     
         14 . The compound of  claim 1  wherein Z is NR 4 .  
     
     
         15 . The compound of  claim 1  wherein R 1  is substituted aryl.  
     
     
         16 . The compound of  claim 15  wherein R 1  is substituted phenyl.  
     
     
         17 . The compound of  claim 1  wherein R 2  is alkyl.  
     
     
         18 . The compound of  claim 1  wherein m is  0 .  
     
     
         19 . A composition comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier or diluent.  
     
     
         20 . 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 composition of  claim 19 .  
     
     
         21 . The method of  claim 20  wherein the disorder is stroke.  
     
     
         22 . The method of  claim 20  wherein the disorder is depression.  
     
     
         23 . The method of  claim 20  wherein the disorder is anxiety.