The effect ofN-alkyloxycarbonyl group on the anticonvulsant activities ofN-alkyloxycarbonyl-α-aminoglutarimides.

Abstract

In connection with the development of new anticonvulsant agents with a broad spectrum, we reported thatN-Cbz-α-aminoglutarimides, combining common 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-α-aminoglutarimides7a∼7e and8a∼8e, which were substituted with various alkyloxycarbonyl group instead ofCbz group, were prepared from the corresponding (R) and (S)N-Cbz-glutamic acid3 and4, and were evaluated with their anticonvulsant activities against the MES and PTZ tests, including neurotoxicity, in order to define the effect ofN-alkyloxycarbonyl group on the anticonvulsant activities ofN-alkyloxycarbonyl-α-aminoglutarimides. Among them, (S)N-4-nitrobenzyloxycarbonyl-α-amino-N-methylglutarimide8e was the most active in MES (ED50=35.6 mg/kg, Pl=2.7) and PTZ tests (ED50=15.6, Pl=6.1). Interestingly, (R) and (S)N-4-nitrobenzyloxycarbonyl-α-amino-N-methylglutarimide7e and8e and (R)N-phenoxycarbonyl-α-amino-N-methylglutrimide7d showed significant anticonvulsant activities in both the MES and PTZ tests and other compounds showed anticonvulsant activities in only the PTZ test. In addition, it was found that their anticonvulsant activities were dependent on their stereochemistries andN-substituted alkyloxycarbonyl groups.