新型全氢吡咯并[1,2-a]吡嗪衍生物的合成及其在癫痫动物模型中的评价。

Dawidowski Maciej, Lewandowski Wojciech, Turło Jadwiga

Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland.

Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland.

Molecules. 2014 Oct 7;19(10):15955-81. doi: 10.3390/molecules191015955.

A series of novel stereochemically pure derivatives of the investigative broad-spectrum anticonvulsant ADD408003 was designed and synthesized. Five-center four-component (U-5C-4CR) and four-center three-component (U-4C-3CR) variants of Ugi reaction were used in the key step of the synthetic pathways. The compounds obtained were evaluated for the anticonvulsant activitiy in the maximal electroshock seizure (MES), subcutaneous Metrazole (scMET) and minimal clonic seizure (6 Hz) animal models of epilepsy. The efficacies of most derivatives in the 6 Hz model of pharmacoresistant partial seizures were markedly higher than in the 'classical' MES and scMET models. The most active compounds, (4R,8aR)-3a, and (4S,8aS)-6 displayed median effective doses (ED50) of 47.90 and 126.19 mg/kg, respectively, for the 6 Hz test.

设计并合成了一系列研究性广谱抗惊厥药ADD408003的新型立体化学纯衍生物。在合成途径的关键步骤中使用了乌吉反应的五中心四组分（U-5C-4CR）和四中心三组分（U-4C-3CR）变体。对所得到的化合物在癫痫的最大电休克惊厥（MES）、皮下注射戊四氮（scMET）和最小阵挛性惊厥（6 Hz）动物模型中进行抗惊厥活性评估。大多数衍生物在耐药性部分性癫痫发作的6 Hz模型中的疗效明显高于“经典”的MES和scMET模型。对于6 Hz试验，最具活性的化合物（4R，8aR）-3a和（4S，8aS）-6的半数有效剂量（ED50）分别为47.90和126.19 mg/kg。