Pyrazolopyrimidines as CRF receptor antagonists

Abstract

This invention concerns compounds of formula including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein R 1 is NR 4 R 5 or OR 5 ; R 2 is C 1-6 alkyl, C 1-6 alkyloxy or C 1-6 alkylthio; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfoxy or C 1-6 alkylthio; R 4 is hydrogen, C 1-6 alkyl, mono- or di(C 3-6 cycloalkyl)methyl, C 3-6 cycloalkyl, C 3-6 alkenyl, hydroxyC 1-6 alkyl, C 1-6 alkylcarbonyloxyC 1-6 alkyl or C 1-6 alkyloxyC 1-6 alkyl; R 5 is C 1-8 alkyl, mono- or di(C 3-6 cycloalkyl)methyl, Ar 1 CH 2 , C 1-6 alkyloxyC 1-6 alkyl, hydroxyC 1-6 alkyl, C 3-6 alkenyl, thienylmethyl, furanylmethyl, C 1-6 alkylthioC 1-6 alkyl, morpholinyl, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, di(C 1-6 alkyl)amino, C 1-6 alkylcarbonylC 1-6 alkyl, C 1-6 alkyl substituted with imidazolyl; or a radical of formula -Alk-O—CO—Ar 1 ; or R 4 and R 5 taken together with the nitrogen atom to which they are attached may form an optionally substituted pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group; having CRF receptor antagonistic properties; pharmaceutical compositions containing such compounds as active ingredients; methods of treating disorders related to hypersecretion of CRF such as depression, anxiety, substance abuse, by administering an effective amount of a compound of formula (I).

1 . A compound of formula  
     
       
         
         
             
             
         
       
     
     or a stereoisomer or pharmaceutically acceptable salt thereof, 
 wherein: 
 R 1  is OR 5 ;  
 R 2  is C 1-6 alkyl;  
 R 3  is hydrogen, C 1-6 alkyl, C 1-6 alkylsulfonyl or C 1-6 alkylthio;  
 R 4  is hydrogen or C 1-6 alkyl  
 R 5  is C 1-8 alkyl, C 1-6 alkyloxyC 1-6 alkyl or hydroxyC 1-6 alkyl; and  
 
 Ar is phenyl; phenyl substituted with 1, 2 or 3 substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkyloxy, amino and mono- and di(C 1-6 alkyl)amino; pyridinyl; pyridinyl substituted with 1, 2 or 3 substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkyloxy, amino, and mono- or di(C 1-6 alkyl)amino; and wherein said substituted phenyl may optionally be further substituted with one or more halogens;  
 with the proviso that 2,5-dimethyl-7-(methylamino)-3-phenyl-pyrazolo[1,5-a]pyrimidine is not included.  
 
   
   
       2 - 11 . (canceled)  
   
   
       12 . A process for preparing a compound as claimed in  claim 1 , comprising 
 a) reacting an intermediate of formula (II) with an intermediate of formula (III) in a reaction-inert solvent, yielding a compound of formula (I),                          or    b) O-alkylating an intermediate of formula (VI) with an intermediate of formula (VII) in a reaction-inert solvent and in the presence of a suitable base, yielding a compound of formula (I-a), defined as a compound of formula (I) wherein R 1  is OR 5 ,                          wherein in the above reaction schemes the radicals R 1 , R 2 , R 3 , R 5  and Ar are as defined in  claim 1  and W is an appropriate leaving group.    
   
   
       13 . A process of preparing a compound as claimed in  claim 1   
     
       
         
         
             
             
         
       
       comprising reacting an intermediate of formula (IV) with a β-keto ester (V) in a reaction-inert solvent, thereby yielding a compound of formula (II′-a)  
       
         
           
           
               
               
           
         
       
       and optionally converting the compound of formula (II′-a) into a compound of formula (II′-b), defined as a compound of formula (II′) wherein W′ is other than hydroxy;  
       wherein in the above reaction schemes the radicals R 2 , R 3  and Ar are as defined in  claim 1 , and W′ is hydroxy, halo, mesyloxy or tosyloxy.  
     
   
   
       14 . A compound according to  claim 1 , wherein R 3  is hydrogen, C 1-6 alkyl or C 1-6 alkylthio.  
   
   
       15 . A compound according to  claim 14 , wherein R 3  is hydrogen, methyl or —SCH 3 .  
   
   
       16 . A compound according to  claim 1 , wherein R 4  is hydrogen or C 2-4 alkyl.  
   
   
       17 . A compound according to  claim 16 , wherein R 4  is hydrogen or n-propyl.  
   
   
       18 . A compound according to  claim 1 , wherein Ar is phenyl substituted with 1, 2 or 3 substituents independently selected from halo and C 1-6 alkyloxy; or Ar is pyridinyl substituted with 1, 2 or 3 substituents independently selected from halo, C 1-6 alkyl and di(C 1-6 alkyl)amino.  
   
   
       19 . A compound according to  claim 18 , wherein Ar is phenyl substituted with 2 or 3 substituents independently selected from halo and methoxy; or Ar is pyridinyl substituted with 2 or 3 substituents independently selected from halo, methyl and dimethylamino.  
   
   
       20 . A compound according to  claim 1 , wherein R 2  is methyl.  
   
   
       21 . A compound according to  claim 1 , wherein R 3  is hydrogen, C 1-6 alkyl or C 1-6 alkylthio; R 4  is hydrogen or C 2-4 alkyl; and Ar is phenyl substituted with 1, 2 or 3 substituents independently selected from halo and C 1-6 alkyloxy, or pyridinyl substituted with 1, 2 or 3 substituents independently selected from halo, C 1-6 alkyl and di(C 1-6 alkyl)amino.  
   
   
       22 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to  claim 1 .  
   
   
       23 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to  claim 15 .  
   
   
       24 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to  claim 17 .  
   
   
       25 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to  claim 19 .  
   
   
       26 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to  claim 21 .  
   
   
       27 . A method for treating depression in a warm-blooded animal comprising administering to said animal in need of treatment a therapeutically effective amount of a compound according to  claim 1 .  
   
   
       28 . A method for treating an anxiety disorder in a warm-blooded animal comprising administering to said animal in need of treatment a therapeutically effective amount of a compound according to  claim 1 .  
   
   
       29 . A method for treating irritable bowel syndrome in a warm-blooded animal comprising administering to said animal in need of treatment a therapeutically effective amount of a compound according to  claim 1.