Griffith R C, Gentile R J, Robichaud R C, Frankenheim J
J Med Chem. 1984 Aug;27(8):995-1003. doi: 10.1021/jm00374a011.
Molecular modelling studies suggested the synthesis of cis-1,3,4,6,7, 11b-hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline (7a) as a rigid analogue of the atypical antidepressant mianserin. Acylation of 2,2-diphenylethylamine with chloroacetyl chloride gives the chloroacetamide (2). Cyclization of 2 with P2O5 in xylene provides 1-(chloromethyl)-3,4-dihydro-4-phenylisoquinoline (3). Amination of 3, followed by reduction, gives the isomeric (aminomethyl)tetrahydroisoquinolines (4a and 5). Treatment of 4a with diethyl oxalate, followed by reduction of the diamide with borane, provides 7a. A variety of N-substituted, aromatic substituted, and optically resolved derivatives were prepared and evaluated for anticholinergic, antihistaminic, and antidepressant activity. In particular, the target cis isomer 7a as predicted from the modelling studies appears to possess excellent atypical antidepressant activity. This activity resides in the (+)-S,S optical isomer 10, which has the same absolute configuration as (+)-mianserin.
分子建模研究表明，合成顺式-1,3,4,6,7,11b-六氢-2-甲基-7-苯基-2H-吡嗪并[2,1-a]异喹啉（7a）作为非典型抗抑郁药米安色林的刚性类似物。2,2-二苯乙胺与氯乙酰氯酰化得到氯乙酰胺（2）。2与五氧化二磷在二甲苯中环化得到1-(氯甲基)-3,4-二氢-4-苯基异喹啉（3）。3进行胺化，然后还原，得到异构体（氨基甲基）四氢异喹啉（4a和5）。4a用草酸二乙酯处理，然后用硼烷还原二酰胺，得到7a。制备了多种N-取代、芳基取代和光学拆分的衍生物，并对其抗胆碱能、抗组胺和抗抑郁活性进行了评估。特别是，建模研究预测的目标顺式异构体7a似乎具有优异的非典型抗抑郁活性。这种活性存在于(+)-S,S光学异构体10中，其绝对构型与(+)-米安色林相同。
