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 pi-nucleophile., and evaluated for the binding affinity for alpha(2)-adrenoceptor. 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 (K-i = 0.26 muM) but showed about 3-fold less binding affinity than mirtazapine (K-i = 0.08 muM) for alpha(2)-adrenoceptor.