Synthesis and anticonvulsant evaluation of N-Cbz-alpha-amino-N-alkoxysuccinimides.
In previous studies for the development of new anticonvulsants, we found that N-Cbz-alpha-amino-N-alkylsuccinimides exhibited significant anticonvulsant activities in the Maximal electroshock seizure (MES) and Pentylenetetrazole induced seizure (PTZ) tests, and also their anticonvulsant activities were dependent on the N-alkyl substituents existent in their structures. Based on these estimations, N-Cbz-alpha-amino-N-hydroxysuccinimide and various N-Cbz-alpha-amino-N-alkoxysuccinimides were prepared in order to develop more active anticonvulsants and to examine the effects of N-hydoxy or N-alkoxy groups on their anticonvulsant activities. The (R)- or (S)-N-Cbz-alpha-amino-N-hydroxysuccinimide and N-Cbz-alpha-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 except 3a 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-alpha-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 was N-benzyloxy > N-hydroxy > N-isopropoxy > N-methoxy > N-ethoxy; for the (S) series N-ethoxy > N-benzyloxy > N-methoxy > N-isopropoxy.
Byun
Aesun
A
College of Pharmacy, Kyungsung University, 110-1 Daeyeon-Dong, Nam-Gu, Busan, Korea 608-736.
Kim
Minjeong
M
Choi
Jongwon
J
Moon
Kyung Ho
KH
Lee
Chung Kyu
CK
Park
Minsoo
M
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012640:Seizures / Q000188:drug therapy*; D013388:Succinimides / Q000138:chemical synthesis* / Q000627:therapeutic use*
D000927:Anticonvulsants; D013388:Succinimides