McKenzie T C, Epstein J W, Fanshawe W J, Dixon J S, Osterberg A C, Wennogle L P, Regan B A, Abel M S, Meyerson L R
J Med Chem. 1984 May;27(5):628-33. doi: 10.1021/jm00371a012.
A series of 5-aryl-3-azabicyclo[3.2.0] heptan -6-one ketals 6 were synthesized by hydride reduction of 1-aryl-4, 4-dimethoxy-1,2- cyclobutanedicarboximides 5. Imides 5 were obtained as the sole, regioselective products of the [2 + 2] photocycloaddition of 1,1- dimethoxyethylene to 2- arylmaleimides . The m-methoxyphenyl-N-methyl analogue 6a was demethylated to phenol 7 with EtSNa -DMF. Both 6a and 7 were similar to morphine in analgesic potency in rats and mice and showed physiological effects that were identical with those of morphine and that were completely reversed by naloxone. Compound 7 was identical with morphine in its ability to displace [3H]naloxone from homogenates of rat brain minus cerebellum. A molecular mechanics analysis of the m-methoxyphenyl analogue 6a showed that the nitrogen atom, the methoxyphenyl group, and the methoxyl oxygen cis to the phenyl group can be superimposed on the corresponding features of the morphine molecule, and perhaps this accounts for the observed opiate-receptor binding properties of 7.
通过1-芳基-4,4-二甲氧基-1,2-环丁烷二甲酰亚胺5的氢化物还原反应合成了一系列5-芳基-3-氮杂双环[3.2.0]庚烷-6-酮缩酮6。酰亚胺5是1,1-二甲氧基乙烯与2-芳基马来酰亚胺[2 + 2]光环加成反应的唯一区域选择性产物。间甲氧基苯基-N-甲基类似物6a用EtSNa - DMF脱甲基生成苯酚7。6a和7在大鼠和小鼠中的镇痛效力与吗啡相似，并且显示出与吗啡相同的生理效应，且能被纳洛酮完全逆转。化合物7在从大鼠脑（不含小脑）匀浆中置换[3H]纳洛酮的能力方面与吗啡相同。对间甲氧基苯基类似物6a的分子力学分析表明，氮原子、间甲氧基苯基以及与苯基顺式的甲氧基氧原子可以与吗啡分子的相应特征重叠，也许这就解释了观察到的7的阿片受体结合特性。
