Synthesis and anticonvulsant activity of 3-alkoxycarbonylaminomethylcarbonylamino-4-benzoylpyridines .

Abstract

3-Alkoxycarbonylaminomethylcarbonylamino-4-(arylcarbonyl)pyr idines--in which the chlorophenyl ring of dipeptidylaminobenzophenones is replaced by a pyridyl ring--were synthesized and evaluated as anticonvulsants using subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) induced seizure screening tests. The substituent on the aryl ring of the 4-arylcarbonyl moiety was a determinant of activity in both tests, the potency order of substituents being generally 2-F greater than 2-H greater than 2-Cl. Compounds possessing a 3-benzyloxycarbonylaminomethylcarbonylamino substituent exhibited moderate activity in the scPTZ test, whereas all 3-tert-butoxycarbonylaminomethylcarbonylamino derivatives were inactive. The test results in the scPTZ screen suggest that the 3-benzyloxycarbonylaminomethylcarbonyl(N-methyl)amino compounds may undergo biotransformation, at least in part, to pyrido[3,4-e]-1,4-diazepin-2-ones. 3-Alkoxycarbonylaminomethylcarbonyl(N-methyl)amino-substituted compounds were always more potent than analogous 3-alkoxycarbonylaminomethylcarbonylamino-substituted compounds in the scPTZ test, whereas they were equipotent in the MES screen. Following oral administration, 3-benzyloxycarbonylaminomethylcarbonyl(N-methyl)amino-4-(2-chlorob enzoyl) pyridine exhibited a potency greater than that of valproic acid but less than that of clonazepam in the rat scPTZ screening test. 3-Benzyloxycarbonylaminomethylcarbonylamino-4-(2-fluorobenzoyl)pyr idine was the most potent compound in the rat oral MES screening test, exhibiting an activity greater than that of clonazepam but less than that of phenytoin. The 3-alkoxycarbonylaminomethylcarbonylamino-4-(arylcarbonylpyridin es had moderate affinity for the benzodiazepine receptor site(s); the IC50s in displacing 10 nM [3H]flunitazepam were in the 0.37-15.11 microM range (clonazepam = 0.003 microM).