Neurotherapeutic composition and method therefor

Abstract

Neurotherapeutically effective pharmaceutical compositions are described that include 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 neurotherapeutic pharmaceutical composition in unit dosage form comprising a neurotherapeutically effective amount of a carboxypeptidase E inhibitor and a pharmaceutically acceptable carrier thereof, providing that when the carboxypeptidase E inhibitor is a β-lactam antibiotic, the neurotherapeutically effective amount of the carboxypeptidase E inhibitor 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 by the same route of administration.  
     
     
         2 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the neurotherapeutically effective amount is an amount effective for treating behavioral disorders or enhancing cognitive function in patients in need of such therapy.  
     
     
         3 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the carboxypeptidase E inhibitor is a compound comprising a β-lactam ring structure.  
     
     
         4 . The neurotherapeutic pharmaceutical composition of  claim 1  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.  
     
     
         5 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the carboxypeptidase E inhibitor is a penam or cephem compound.  
     
     
         6 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the carboxypeptidase E inhibitor is a cephem sulfoxide or cephem sulfone compound.  
     
     
         7 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the carboxypeptidase E inhibitor is a cephem sulfoxide compound.  
     
     
         8 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the carboxypeptidase E inhibitor is a cephem sulfone compound.  
     
     
         9 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the carboxypeptidase E inhibitor is a penam sulfoxide or penam sulfone compound.  
     
     
         10 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the carboxypeptidase E inhibitor is a penam sulfone compound.  
     
     
         11 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the carboxypeptidase E inhibitor is a penam sulfoxide compound.  
     
     
         12 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the carboxypeptidase E inhibitor is a penicillin or cephalosporin.  
     
     
         13 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the carboxypeptidase E inhibitor is a sulfoxide or sulfone derivative of a penicillin or of a cephalosporin.  
     
     
         14 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the carboxypeptidase E inhibitor is a 1-dethia-1-oxa-cephem compound.  
     
     
         15 . The neurotherapeutic pharmaceutical composition 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 CH 2 ; 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 nucleophile B:H.  
     
     
         16 . The neurotherapeutic pharmaceutical composition of  claim 1  wherein the carboxypeptidase E inhibitor is moxalactam or a pharmaceutically acceptable salt or ester thereof.