Synthesis of Tetracyclic Pyrido[2,3-b]azepine Derivatives as Analogues of Mirtazapine via N-Acyliminium Ion Cyclization

Abstract

Tetracyclic pyrido[2,3-b]azepine derivatives 4a-d and 4f as analogues of mirtazapine were synthesized via N-acyliminium ion cyclization by using aromatic rings such as benzene and thiophene ring as a <TEX>${\pi}-nucleophile$</TEX>, and evaluated for the binding affinity for <TEX>${\alpha}2-adrenoceptor$</TEX>. Among tested compounds, 2,3,9,13b-tetrahydro-1H-benzo[f]pyrrolo[2,1-a]pyrido[2,3-c]azepine (4a) was the most potent (Ki = 0.26 <TEX>${\mu}M)$</TEX> but showed about 3-fold less binding affinity than mirtazapine (Ki = 0.08 <TEX>${\mu}M)$</TEX> for a2-adrenoceptor.