Neurotrophin antagonist compositions

Abstract

A pharmaceutical composition comprising a compound of Formula I wherein R 1 is selected from, inter alia, alkyl, aryl-loweralkyl, heterocycle-loweralkyl, loweralkyl-carbonate; optionally substituted amino; benzimidaz-2-yl; optionally substituted phenyl; loweralkyl-(R 5 )(R 6 ) wherein one of R 5 and R 6 is selected from H and the other is selected from carboxy, carboxy-loweralkyl and loweralkoxycarbonyl; NHCH 2 CH 2 OX wherein X represents an in vivo hydrolyzable ester; and R 2 and R 3 are independently selected from H, NO 2 , halo, di(loweralkyl)amino, cyano, C(O)OH, phenyl-S—, loweralkyl, and Z(O)OR 7 wherein Z is selected from C and S and R 7 is selected from H, loweralkylamino and arylamino; or pharmaceutically acceptable salts or certain in vivo hydrolyzable esters or amides thereof, in an amount effective to inhibit neurotrophin-mediated activity, and a suitable carrier, is described. The compositions are useful to inhibit undesirable neurotrophin-mediated activity such as the neurite outgrowth that occurs in some neurodegenerative disease states.

1 . A pharmaceutical composition comprising a compound of Formula I, 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is selected from alkyl; aryl-loweralkyl; heterocycle-loweralkyl; loweralkyl-carbonate; amino optionally monosubstituted or disubstituted with a substituent selected from loweralkyl, aryl and hydroxyloweralkyl; benzimidaz-2-yl; 
     
     
       
         
         
             
             
         
       
       wherein R 4  is phenyl optionally monosubstituted or disubstituted with a substituent selected from loweralkyl and halo; phenyl optionally monosubstituted or disubstituted with a substituent selected from amino, loweralkoxy, hydroxy and loweralkyl; 
       NHCH 2 CH 2 OX wherein X represents an in vivo hydrolyzable ester, and loweralkyl-(R 5 )(R 6 ) wherein one of R 5  and R 6  is selected from H and loweralkyl and the other is selected from carboxy, carboxy-loweralkyl and loweralkoxycarbonyl; and 
       R 2  and R 3  are independently selected from H, NO 2 , halo, di(loweralkyl)amino, cyano, C(O)OH, phenyl-S—, loweralkyl, and Z(O)OR 7  wherein Z is selected from C and S and R 7  is selected from H, loweralkylamino and arylamino; 
       and pharmaceutically acceptable salts thereof, in an amount effective to inhibit neurotrophin-mediated activity, and a suitable carrier. 
     
   
   
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