Sun Z Y, Kwon C H, Wurpel N D
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York 11439.
J Med Chem. 1994 Sep 2;37(18):2841-5. doi: 10.1021/jm00044a003.
On the basis of our previous findings, a series of 5-substituted 2-iminohydantoins has been synthesized and tested for anticonvulsant activity to better understand the SAR of 2-iminohydantoins. Among the compounds tested, (S)-(+)-1-carbobenzoxy-2-iminohydantoin analogs with ethyl (6)-, n-propyl (7a)-, isopropyl (8)-, allyl (9)-, and sec-butyl (11)-substituted groups at the C5 of the iminohydantoin ring provided the best activities against the MES test with ED50 values in the range of 52-74 mg/kg. All of the above compounds except 8 also showed activity against the scMET test with ED50 values in the range of 141-223 mg/kg. All significantly active compounds (1, 6, 7a, 8, 9, and 11) possessed aliphatic hydrocarbon side chains of two- to three-carbon lengths at the C5 position. All of the compounds with no or minimal activity had either shorter or longer side chains. The compounds substituted at the C5 position by aryl groups, arylalkyl groups, or alkyl and arylalkyl groups containing heteroatoms also showed no activity against the MES and scMET tests. The results suggested that the C5 side chain with the correct stereochemistry in 2-iminohydantoins provides optimal anticonvulsant activity when the side chains are aliphatic hydrocarbons with the length, ignoring branching, of two to three carbons.
基于我们之前的研究结果，已合成了一系列5-取代的2-亚氨基乙内酰脲，并对其抗惊厥活性进行了测试，以更好地了解2-亚氨基乙内酰脲的构效关系。在所测试的化合物中，在亚氨基乙内酰脲环的C5位带有乙基（6）-、正丙基（7a）-、异丙基（8）-、烯丙基（9）-和仲丁基（11）-取代基的（S）-（+）-1-苄氧羰基-2-亚氨基乙内酰脲类似物对最大电休克（MES）试验表现出最佳活性，ED50值在52-74mg/kg范围内。除8之外的上述所有化合物对皮下注射最大电休克（scMET）试验也表现出活性，ED50值在141-223mg/kg范围内。所有显著有活性的化合物（1、6、7a、8、9和11）在C5位具有两到三个碳长度的脂肪烃侧链。所有无活性或活性极小的化合物具有较短或较长的侧链。在C5位被芳基、芳烷基或含有杂原子的烷基和芳烷基取代的化合物对MES和scMET试验也无活性。结果表明，当2-亚氨基乙内酰脲中C5侧链为脂肪烃且长度（不考虑支链）为两到三个碳时，具有正确立体化学的C5侧链可提供最佳抗惊厥活性。
