The Synthesis and Preliminary Pharmacological Evaluation of a Series of Substituted 4'-Phenoxypropyl Analogues of the Atypical Antipsychotic Clozapine

Herein we report the synthesis, characterization, and preliminary pharmacological activity of a new series of substituted 4′-phenoxypropyl tricyclic analogues of clozapine as potential antipsychotic agents for the treatment of schizophrenia. The lead compound (3) for this investigation was designed based on a revised model derived from the structural hybridization of the commercial therapeutics clozapine (1) and haloperidol (2). The compounds described in this paper probe the biochemical effects of introducing a variety of electron-withdrawing and electron-donating substituents with the primary focus on the para-position of the introduced distal aromatic ring. The target compounds were readily prepared in three steps using the key intermediate lactam (8-chloro-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-11-one, 9), piperazine and commercially available substituted phenols. The chemistry and structural characterization of this series of substituted 4′-phenoxypropyl analogues of clozapine are described. Preliminary in vitro results on the pharmacological effects of the ring substituents on affinity for dopamine D4 and serotonin 5-HT2A receptors are discussed. Psychosis-related in vivo animal behavioural data for compounds identified with potential from the receptor binding screen are also presented.