Synthesis and anticonvulsant evaluation ofN-Cbz-α-amino-N-alkoxysuccinimides

Abstract

In previous studies for the development of new anticonvulsants, we found thatN-Cbz-α-amino-N-alkylsuccinimides exhibited significant anticonvulsant activities in the Maximal electroshock seizure (MES) and Pentylenetetrazol induced seizure (PTZ) tests, and also their anticonvulsant activities were dependent on theN-alkyl substituents existent in their structures. Based on these estimations,N-Cbz-α-amino-N-hydroxysuccinimide and variousN-Cbz-α-amino-N-alkoxysuccinimides were prepared in order to develop more active anticonvulsants and to examine the effects ofN-hydoxy orN-alkoxy groups on their anticonvulsant activities. The (R)-or (S)-N-Cbz-α-amino-N-hydroxysuccinimide andN-Cbz-α-amino-N-alkoxysuccinimides were prepared from the corresponding (R)- or (S)-N-Cbz-aspartic acid through the known synthetic procedures. Their anticonvulsant activities in the MES and PTZ test were evaluated. All of these compounds except3a showed significant anticonvulsant activities against the PTZ test, but these compounds were not active in the MES test. The most active compound in the PTZ test was (R)-N-Cbz-α-amino-N-benzyloxysuccinimide (ED₅₀=62.5 mg/kg). In addition, the anticonvulsant activities of these compounds were dependent on their N-substited groups. The order of anticonvulsant activity against the PTZ test, as judged from the ED₅₀ values for (R) series wasN-benzyloxy >N-hydroxy >N-isopropoxy >N-methoxy >N-ethoxy; for the (S) seriesN-ethoxy >N-benzyloxy >N-methoxy >N-isopropoxy.