The effect of N-alkyloxycarbonyl group on the anticonvulsant activities ofN-alkyloxycarbonyl-alpha-aminoglutarimides

In connection with the development of new anticonvulsant agents with a broa d spectrum, we reported that N-Cbz-alpha-aminoglutarimides, combining commo n structures of other anticonvulsants such as N-CO-C-N and cyclic imides in a single molecule, showed significant anticonvulsant activities in the MES (maximal electroshock seizure) and PTZ (pentylenetetrazole induced seizure ) tests. In these studies, a series of (R) and (S) N-alkyloxycarbonyl-alpha -aminoglutarimides 7a similar to 7e and 8a similar to 8e, which were substi tuted with various alkyloxycarbonyl group instead of Cbz group, were prepar ed from the corresponding (R) and (S) N-Cbz-glutamic acid 3 and 4, and were evaluated with their anticonvulsant activities against the MES and PTZ tes ts, including neurotoxicity, in order to define the effect of N-alkyloxycar bonyl group on the anticonvulsant activities of N-alkyloxycarbonyl-alpha-am inoglutarimides. Among them, (3) N-4-nitrobenzyloxycarbonyl-alpha-amino-N-m ethylglutarimide 8e was the most active in MES (ED50=35.6 mg/kg, PI=2.7) an d PTZ tests (ED50= 15.6, PI=6.1). Interestingly, (R) and (S) N-4-nitrobenzy loxycarbonyl-alpha-amino-N-methylglutarimide 7e and 8e and (R) N-phenoxycar bonyl-alpha-amino-N-methylglutrimide 7d showed significant anti-convulsant activities in both the MES and PTZ tests and other compounds showed anti-co nvulsant activities in only the PTZ test In addition, it was found that the ir anticonvulsant activities were dependent on their stereochemistries and N-substituted alkyloxycarbonyl groups.