Non-sedating barbituric acid derivatives

Abstract

The present invention relates to novel non-sedating barbituric acid derivatives, pharmaceutical compositions containing them and methods of neuroprotection in cases of cerebral ischemia, head trauma and other acute neurologic injuries, and prevention of resulting neuronal damage. The invention also relates to the use of non-sedating barbituric acid derivatives given in a manner and dosage effective to produce blood levels and brain levels of these drugs and/or their active metabolites sufficient to provide a therapeutic effect.

1 - 34 . (canceled)  
   
   
       35 . A method of protecting a mammal from neurological damage, comprising administering to said mammal a dose of the salts of a non-sedative barbiturate, having the structure  
     
       
         
         
             
             
         
       
     
     which is sufficient to provide a neuroprotecfive effect, said non-sedative barbiturate being non-sedative and non-hypotic, at said dose, wherein 
 R 1  and R 2  may be the same or different and are independently hydrogen;  
 lower alkyl, optionally substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, lower alkoxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms;  
 phenyl;  
 CH 2 XR 5 , wherein X is S or O and R 5  is lower alkyl, aryl, alkylaryl, or benzyl;  
 C(O)XR 6 , wherein X is as defined above and R 6  is lower alkyl or aryl;  
 CXR 7 , wherein X is as defined above and R 7  is hydrogen, lower alkyl or aryl; and  
 CH(XR 8 ) 2 , wherein X is as defined above and R 8  is a lower alkyl group, with the proviso that at least one of R 1  and R 2  is not hydrogen; and wherein  
 R 3  and R 4  may be the same or different and are independently hydrogen;  
 aryl optionally containing one or more heteroatoms selected from the group consisting of N, S, and O;  
 lower acyloxy;  
 phenyl;  
 phenyl substituted with a halogen, lower alkyl group, lower acyl group or derivative thereof or acetamide;  
 benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both;  
 cycloalkyl, which optionally contains one or more heteroatoms selected from the group consisting of N, O, and S;  
 lower alkyl; or lower alkyl substituted with an aromatic moiety;  
 provided that at least one of R 3  and R 4  is an aromatic ring or an aromatic ring containing moiety.