Neurotherapeutic composition and method therefor

Abstract

Neurotherapeutically pharmaceutical effective compositions are prepared using carboxypeptidase E inhibitors. One class of carboxypeptidase E inhibitors found to exhibit significant neurotropic activity are β-lactam compounds, particularly penam and cephem β-lactam antibiotics and non-antibiotic derivatives thereof.

1 . A method of manufacturing a pharmaceutical composition useful for treatment of behavioral disorders and enhancing cognitive function in patients in need of such therapy, said method comprising the steps of combining an inhibitor of carboxypeptidase E with a pharmaceutically acceptable carrier and forming a unit dosage form comprising a neurotherapeutically effective amount of the carboxypeptidase E inhibitor.  
     
     
         2 . The method of  claim 1  wherein the carboxypeptidase E inhibitor is a compound comprising a β-lactam ring structure.  
     
     
         3 . The method of  claim 2  wherein the carboxypeptidase E inhibitor is selected from the group consisting of penams, cephems, 1-oxa-1-dethia cephems, clavams, clavems, azetidinones, carbapenams, carbapenems and carbacephems.  
     
     
         4 . The method of  claim 2  wherein the carboxypeptidase E inhibitor is a penam or cephem compound.  
     
     
         5 . The method of  claim 2  wherein the carboxypeptidase E inhibitor is a penicillin or cephalosporin.  
     
     
         6 . The method of  claim 2  wherein the carboxypeptidase E inhibitor is a penam sulfoxide or sulfone.  
     
     
         7 . The method of  claim 2  wherein the carboxypeptidase E inhibitor is a cephem sulfoxide.  
     
     
         8 . The method of  claim 2  wherein the carboxypeptidase E inhibitor is a cephem sulfone.  
     
     
         9 . The method of  claim 2  wherein the carboxypeptidase E inhibitor is a sulfoxide or sulfone derivative of a penicillin or a cephalosporin.  
     
     
         10 . The method of  claim 2  wherein the carboxypeptidase E inhibitor is a 1-dethia-1-oxa-cephem.  
     
     
         11 . The method of  claim 2  wherein the carboxypeptidase E inhibitor is moxalactam or a pharmaceutically acceptable salt or ester thereof.  
     
     
         12 . The method of  claim 1  wherein the carboxypeptidase E inhibitor is a compound of the formula  
       
         
           
           
               
               
           
         
         wherein R is a salt forming group or an active ester forming group; R 1  is hydrogen or C 1 -C 4  alkoxy; X is S, SO, SO 2 , O or C; and T is C 1 -C 4  alkyl, halo, hydroxy, O(C 1 -C 4 ) alkyl, or —CH 2 B wherein B is the residue of a nucleopbile B:H, and Acyl is the residue of an organic acid AcylOH.  
       
     
     
         13 . A neurotherapeutic pharmaceutical composition in unit dosage form comprising a neurotherapeutically effective amount of a carboxypeptidase E inhibitor with the proviso that when the carboxypeptidase E inhibitor is a β-lactam antibiotic, the neurotherapeutically effective amount of the carboxypeptidase E inhibitor in the unit dosage form is less than an antibiotically effective amount of the carboxypeptidase E inhibitor if such β- lactam antibiotic were to be administered in a unit dosage form designed for the same route of administration.  
     
     
         14 . The neurotherapeutic composition of  claim 13  wherein the carboxypeptidase E inhibitor is a compound comprising a β- lactam ring structure.  
     
     
         15 . The neurotherapeutic composition of  claim 13  wherein the carboxypeptidase E inhibitor is a penicillin or cephalosporin.  
     
     
         16 . The neurotherapeutic composition of  claim 13  wherein the carboxypeptidase E inhibitor is a cephem sulfoxide or sulfone.  
     
     
         17 . The neurotherapeutic composition of  claim 13  wherein the carboxypeptidase E inhibitor is a penam sulfoxide or sulfone.  
     
     
         18 . The neurotherapeutic composition of  claim 13  wherein the carboxypeptidase E inhibitor is a 1-dethia-1-oxa-cephem compound.  
     
     
         19 . The neurotherapeutic composition of  claim 13  wherein the carboxypeptidase E inhibitor is moxalactam or a pharmaceutically acceptable salt or ester thereof.  
     
     
         20 . A neurotherapeutic pharmaceutical composition comprising a neurotherapeutically effective amount of a cephem sulfoxide and a pharmaceutically acceptable carrier thereof.  
     
     
         21 . A neurotherapeutic pharmaceutical composition comprising a neurotherapeutically effective amount of a cephem sulfone and a pharmaceutically acceptable carrier thereof.  
     
     
         22 . A neurotherapeutic pharmaceutical composition comprising a neurotherapeutically effective amount of a penam sulfoxide and a pharmaceutically acceptable carrier thereof.  
     
     
         23 . A neurotherapeutic pharmaceutical composition comprising a neurotherapeutically effective amount of a penam sulfone and a pharmaceutically acceptable carrier thereof.