Anxiolytic Agents With Reduced Sedative And Ataxic Effects

Abstract

Orally active benzodiazepine derivatives and their salts are disclosed. These compounds and their salts have anxiolytic and anticonvulsant activity with reduced sedative/hypnotic/muscle relaxant/ataxic effects.

1 . A compound of formula I, or a salt thereof,  
     
       
         
         
             
             
         
       
       wherein:  
       Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7) position with at least the substituent —C≡C—R, where R is H, Si (CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; R 1  is one of H, CH 3 , C 2 H 4 N(C 2 H 5 ) 2 , CH 2 CF 3 , CH 2 CCH, cyclopropyl or methyl cyclopropyl; R 2  is a substituted or unsubstituted at least partially unsaturated 5 membered or 6 membered carbocyclic ring or 5 membered or 6 membered heterocyclic ring having at least one heteroatom selected from N, O and S, wherein if substituted the substituent is at least one of F, Cl, Br, or NO 2  at the 2′-position;  
       R 3  is one of H, OH, OCON(CH 3 ) 2 , COOH, COOCH 3 , COOC 2 H 5 ,  
       
         
           
           
               
               
           
         
       
       n is 0 to 4;  
       Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7)′ position with at least the substituent —C≡C—R′, where R′ is H, Si (CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;  
       R 1  and R 1 ′ are independently one of H, CH 3 , CF 3 , CH 2 CF 3 , CH 2 CH 3 , or cyclopropyl;  
       R 2  and R 2 ′ are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered carbocyclic ring or 5 membered or 6 membered heterocyclic ring having at least one heteroatom selected from N, O and S, wherein if substituted the substituent is at least one of F, Cl, Br, or NO 2  at the 2′-position, or wherein if R 3  is  
       
         
           
           
               
               
           
         
       
       Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7)′ position with at least the substituent —C≡C—R′, where R′ is H, Si (CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;  
       R 1  and R 1 ′ are independently one of H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3  or cyclopropyl;  
       R 2  and R 2 ′ are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered carbocyclic ring or 5 membered or 6 membered heterocyclic ring having at least one heteroatom selected from N, O and S, wherein if substituted the substituent is at least one of F, Cl, Br, or NO 2  at the 2′-position;  
       B is O or NH and wherein —BCH 2 B— is optionally replaced with —N(R 7 )—N(R 7 )—, where R 7  is one of H, branched or straight chain C 1  to C 4  alkyl, cyclopropyl or methyl cyclopropyl;  
       wherein if R 3  is  
       
         
           
           
               
               
           
         
       
       Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7)′ position with at least the substituent —C≡C—R′, where R′ is H, Si (CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;  
       R 1  and R 1 ′ are independently one of H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3  or cyclopropyl;  
       R 2  and R 2 ′ are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered carbocyclic ring or 5 membered or 6 membered heterocyclic ring having at least one heteroatom selected from N, O and S, wherein if substituted the substituent is at least one of F, Cl, Br, or NO 2  at the 2′-position;  
       B is O, NH, or —N(R 7 )—N(R 7 )—, where R 7  is one of H, branched or straight chain C 1  to C 4  alkyl, cyclopropyl or methyl cyclopropyl;  
       wherein R 2  is not phenyl when R 3  is H, R 1  is H or CH 3  and Y and Z taken together form a phenyl ring.  
     
   
   
       2 . The compound of  claim 1  or a salt thereof, wherein the compound is  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       3 . The compound of  claim 1  or a salt thereof, wherein the compound is  
     
       
         
         
             
             
         
       
     
   
   
       4 . The compound of  claim 1  or a salt thereof, wherein the compound is  
     
       
         
         
             
             
         
       
     
   
   
       5 . The compound of  claim 1  or a salt thereof, wherein the compound is  
     
       
         
         
             
             
         
       
     
   
   
       6 . A composition comprising the compound according to any one of claims  1 - 5  and a pharmaceutically acceptable carrier.