Lattmann Eric, Lattmann Pornthip, Boonprakob Yodchai, Airarat Wanchai, Singh Harjit, Offel Michael, Sattayasai Jintana
The School of Pharmacy, Aston University, Aston Triangle, Birmingham B4 7ET, England.
Arzneimittelforschung. 2009;59(2):61-71. doi: 10.1055/s-0031-1296366.
Oxazepam (CAS 604-75-1) 4a served as building block in the synthesis of substituted 3-amino-1,4-benzodiazepines, which were subsequently tested in various CNS animal models. The hydroxy group of oxazepam was either activated as a chloride (Method A) or as a phosphor-oxy derivative (Method B) giving the desired 3-amino-1,4-benzodiapines 6a-6r in high yields with primary and secondary amines in a typical nucleophilic substitution reaction. Eighteen 3-substituted 1,4-benzodiazepines were prepared and served as new chemical entities and for lead structure discovery. The mixed cholecystokinin (CCK) antagonist 6e showed anxiolytic and antidepressant effects from 10 microg/kg in mice in the elevated x-maze test and the forced swimming test. The CCK1 antagonist 6 g has shown antidepressant effects from the same dose, but lacked anxiolytic properties. Both compounds potentiated at a dose of 0.5 mg/kg morphine antinociception with a maximum possible effect (MPE) about 35%. By assessing initially the MPE of antinocipection for the 18 newly synthesised benzodiazepines in the tail-flick test, 4 other benzodiazepines were found active. In further in vive evaluation the cyclohexyl derivative 6 i displayed anxiolytic, antidepressant and antinociceptive properties as single agent at a dose of 5 mg/kg without toxicity. The benzodiazepines 6i and 6p, which initially showed a higher MPE in terms of morphine potentiation (43/44%) showed analgesic effects as single agents, without having anxiolytic or antidepressant properties. The amino-piperidinyl derivative 6p displayed a similar dose-response relationship to morphine, but was 3 times more potent.
奥沙西泮（CAS 604-75-1）4a是合成取代3-氨基-1,4-苯二氮䓬类化合物的起始原料，随后在各种中枢神经系统动物模型中进行了测试。奥沙西泮的羟基要么被活化成氯化物（方法A），要么被活化成磷氧基衍生物（方法B），通过典型的亲核取代反应，与伯胺和仲胺反应以高产率得到所需的3-氨基-1,4-苯二氮䓬类化合物6a - 6r。制备了18种3-取代的1,4-苯二氮䓬类化合物，作为新的化学实体用于先导结构发现。混合胆囊收缩素（CCK）拮抗剂6e在高架十字迷宫试验和强迫游泳试验中，对小鼠显示出10μg/kg起的抗焦虑和抗抑郁作用。CCK1拮抗剂6g在相同剂量下显示出抗抑郁作用，但缺乏抗焦虑特性。两种化合物在0.5mg/kg剂量下均增强了吗啡的镇痛作用，最大可能效应（MPE）约为35%。通过最初在甩尾试验中评估18种新合成的苯二氮䓬类化合物的镇痛MPE，发现另外4种苯二氮䓬类化合物具有活性。在进一步的体内评估中，环己基衍生物6i作为单一药物在5mg/kg剂量下显示出抗焦虑、抗抑郁和镇痛特性且无毒性。苯二氮䓬类化合物6i和6p最初在吗啡增强作用方面显示出较高的MPE（43/44%），作为单一药物显示出镇痛作用，但不具有抗焦虑或抗抑郁特性。氨基哌啶基衍生物6p显示出与吗啡相似的剂量 - 反应关系，但效力强3倍。
