Hara T, Kayama Y, Mori T, Itoh K, Fujimori H, Sunami T, Hashimoto Y, Ishimoto S
J Med Chem. 1978 Mar;21(3):263-8. doi: 10.1021/jm00201a005.
A series of 6-phenyl-4H-pyrrolo[1,2-a][1,4]benzodiazepines (2) has been prepared with 2-phthalimidomethylfurans (12) and 1-phthalimidoalkane-2,5-diones (15) or 2,5-dimethoxy-2-phthalimidomethyltetrahydrofurans (16) as the key intermediates and subsequently evaluated for CNS activity. The structure-activity data generated indicate that, in general, introduction of the methyl and/or ethyl group(s) in the pyrrole ring and a chlorine atom at the ortho position of the 6-phenyl group increases the activity and that substitution of the above chlorine atom for a fluorine atom decreases the activity. 8-Chloro-6-(2-chlorophenyl)-1,3-dimethyl-4H-pyrrolo[,2-a][1,4]benzodiazepine (2p), the most potent among the compounds synthesized, was equipotent in taming and sedative activities to diazepam. The acute LD50 of 2p in mice was larger than 3000 mg/kg po.
已制备了一系列以2-邻苯二甲酰亚胺基甲基呋喃（12）和1-邻苯二甲酰亚胺基烷-2,5-二酮（15）或2,5-二甲氧基-2-邻苯二甲酰亚胺基甲基四氢呋喃（16）为关键中间体的6-苯基-4H-吡咯并[1,2-a][1,4]苯并二氮杂䓬（2），并随后对其进行了中枢神经系统活性评估。所产生的构效关系数据表明，一般而言，在吡咯环中引入甲基和/或乙基以及在6-苯基的邻位引入氯原子会增加活性，而将上述氯原子替换为氟原子会降低活性。8-氯-6-(2-氯苯基)-1,3-二甲基-4H-吡咯并[1,2-a][1,4]苯并二氮杂䓬（2p）是合成化合物中活性最强的，其在驯服和镇静活性方面与地西泮相当。2p在小鼠中的急性半数致死量经口大于3000 mg/kg。
