cis-1,3,4,6,7,11b-Hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline: a new atypical antidepressant

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Abstract
Molecular modeling 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 analog 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. The target cis isomer 7a as predicted from the modeling studies appears to posses excellent atypical antidepressant activity. The activity resides in the (+)-S,S opitcal isomer 10, which has the same absolute configuration as (+)-mianserin.