Lednicer D, VonVoigtlander P F, Emmert D E
J Med Chem. 1980 Apr;23(4):424-30. doi: 10.1021/jm00178a014.
Investigation of central nervous system activity of phenylcyclohexylamines was continued by preparation of "reversed" analogues. Following the unexpected finding of analgesic activity with 1-(dimethylamino)-1-phenylcyclohexylamine, the SAR of the series was investigated. Synthesis starts by double Michael reaction of acrylate on arylacetonitriles. Following cyclization, decarboxylation, ketalization, and saponification, the geminally substituted acid is rearranged to the isocyanate by means of (C6H5O)2PON3. Isocyanates were then converted to the title compounds. Analgesic activity is very sensitive to the nature and position of the substitutent on the aromatic ring. The most potent compounds in this series (p-CH3, p-Br) showed 50% the potency of morphine. Deletion of the ring oxygen abolishes activity.
通过制备“反向”类似物继续对苯基环己胺的中枢神经系统活性进行研究。在意外发现1-(二甲基氨基)-1-苯基环己胺具有镇痛活性后，对该系列的构效关系进行了研究。合成从丙烯酸酯与芳基乙腈的双迈克尔反应开始。经过环化、脱羧、缩酮化和皂化反应后，偕二取代的酸通过(C6H5O)2PON3重排为异氰酸酯。然后将异氰酸酯转化为目标化合物。镇痛活性对芳环上取代基的性质和位置非常敏感。该系列中最有效的化合物（对甲基、对溴）显示出吗啡效力的50%。环上氧原子的缺失会消除活性。
