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

Ben Capuano; Ian T. Crosby; Fiona M. McRobb; Anna Podloucka; David A. Taylor; Amelia Vom; Elizabeth Yuriev

doi:10.1071/CH09345

RESEARCH ARTICLE

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

Ben Capuano ^A ^B , Ian T. Crosby ^A , Fiona M. McRobb ^A , Anna Podloucka ^A , David A. Taylor ^A , Amelia Vom ^A and Elizabeth Yuriev ^A

+ Author Affiliations

- Author Affiliations

^A Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Vic. 3052, Australia.

^B Corresponding author. Email: ben.capuano@pharm.monash.edu.au

Australian Journal of Chemistry 63(1) 116-124 https://doi.org/10.1071/CH09345
Submitted: 18 June 2009 Accepted: 27 July 2009 Published: 8 January 2010

Abstract

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-HT_2A receptors are discussed. Psychosis-related in vivo animal behavioural data for compounds identified with potential from the receptor binding screen are also presented.

Acknowledgement

The authors gratefully acknowledge the contributions to this paper by Bachelor of Medicinal Chemistry (Monash University) undergraduate students (Theola Louie, Andrew Lin, Tam Nguyen, Victoria Oliver, and Sean Lim) and sincerely thank Dr Simon Egan and Mr Stuart Thomson for NMR and mass spectra of compounds described.

References

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

Abstract

Acknowledgement

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