Kwon C H, Iqbal M T, Wurpel J N
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York 11439.
J Med Chem. 1991 Jun;34(6):1845-9. doi: 10.1021/jm00110a013.
Iminohydantoins selectively substituted at position C-5 and their 1-carbobenzoxy derivatives have been synthesized, and their anticonvulsant activity was evaluated in mice. In general, the more lipophilic 1-carbobenzoxy iminohydantoins were more potent than the unsubstituted counterparts. Evaluation of the individual enantiomers of the chiral iminohydantoins showed that the anticonvulsant activity resided primarily in the S isomers. In this study, (S)-(+)-1-carbobenzoxy-5-isobutyl-2-iminohydantoin (9a) was the most active member. This compound was not nearly as active as phenytoin against electrically induced convulsions, but was also active against pentylenetetrazole-induced seizures, suggesting a broader clinical potential. The closest analogue of phenytoin, viz., 5,5-diphenyl-2-iminohydantoin (1), failed to show any significant activity. Methylation on N-3 or the imino nitrogen of 1 also did not provide a compound with substantial activity. 2-Thiophenytoin was not active against electroshock seizures and showed only a weak activity against pentylenetetrazole. This study suggested that the structure-activity relationship of 2-iminohydantoins was quite different from that of 2-hydantoins.
已经合成了在C-5位选择性取代的亚氨基乙内酰脲及其1-苄氧羰基衍生物，并在小鼠中评估了它们的抗惊厥活性。一般来说，亲脂性更强的1-苄氧羰基亚氨基乙内酰脲比未取代的对应物更有效。对手性亚氨基乙内酰脲的各个对映体的评估表明，抗惊厥活性主要存在于S异构体中。在本研究中，(S)-(+)-1-苄氧羰基-5-异丁基-2-亚氨基乙内酰脲(9a)是活性最高的成员。该化合物对电诱导惊厥的活性远不如苯妥英，但对戊四氮诱导的癫痫发作也有活性，表明其具有更广泛的临床潜力。苯妥英最接近的类似物，即5,5-二苯基-2-亚氨基乙内酰脲(1)，未显示出任何显著活性。对1的N-3或亚氨基氮进行甲基化也没有得到具有显著活性的化合物。2-硫代苯妥英对电休克惊厥无活性，对戊四氮仅显示微弱活性。这项研究表明，2-亚氨基乙内酰脲的构效关系与2-乙内酰脲的构效关系有很大不同。
