Synthesis and Preliminary Pharmacological Evaluation of 4´-Arylmethyl Analogues of Clozapine. I. The Effect of Aromatic Substituents

Abstract

As part of a research program to develop compounds with mixed dopamine D4 and serotonin 5-HT2A antagonist activity with potential for the treatment of schizophrenia, we report a family of compounds based on structural modification of the atypical antipsychotic, clozapine (2). The chemical synthesis, structural characterization and pharmacological evaluation of a series 4�-arylmethyl analogues of clozapine are described. Preliminary receptor binding data are presented, examining primarily the electronic and positional effects of substituents on the introduced arylmethyl group, and secondarily the nature of the aryl ring.

New hybrids of clozapine and haloperidol and their isosteric analogues: synthesis, X-ray crystallography, conformational analysis and preliminary pharmacological evaluation

“…Such structural hybrids contain a tricyclic motif attached to piperazine, with an additional p-system anchored to the common distal nitrogen atom (N4 0 ) of the piperazine ring system by a suitable spacer. The resulting 'chain-extended' analogues of clozapine demonstrated excellent receptor affinity for the target receptors of interest, and a select number exhibited clozapine-like in vivo potency in a rodent behavioural model predictive of potential antipsychotic activity [24][25][26][27]. Compound (I) is a derivative of this hybridization process consisting of the tricyclic nucleus of clozapine linked to the butyrophenone portion of haloperidol through the piperazine moiety, and the fluorine of haloperidol has been replaced with a methyl substituent in the hybrid.…”

“…The synthesis component of the drug discovery programme presented here is a continuation of previous work done in our research group [24][25][26][27] and is based on the structural hybridization of two common therapeutic antipsychotics, namely clozapine and haloperidol (Fig. 1).…”

8-Chloro-5-(4-phenethylpiperazin-1-yl)pyrido[2,3-b][1,5]benzoxazepine

“…However, clozapine has been found to induce the blood disorder agranulocytosis that can, in some cases, be fatal. The synthesis component of this drug discovery programme is a continuation of previous work done in our research group (Capuano et al, 2002(Capuano et al, , 2003 and is based on the structural hybridisation of two common antipsychotics, namely clozapine and haloperidol. The resulting structural series contains a tricyclic motif attached to piperazine, with an additional π-system anchored to the distal nitrogen atom of the piperazine ring system by a suitable spacer (Capuano et al, 2003).…”

“…For related literature see: Andreasen et al (1994Andreasen et al ( , 2000; Dupont & Lié geois (2003); Petcher & Weber (1976) ;Capuano et al (1999Capuano et al ( , 2002Capuano et al ( , 2003Capuano et al ( , 2006; Gerlach (1991); Gerson & Meltzer (1992); Lié geois et al (1994,1997,2000); MouithysMickalad et al (2001);Vom (2006).…”

Synthesis of Benzyl 2-(4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)piperazin-1-yl)acetate

“…The starting material, desmethylclozaine, 1 was synthesized in accordance with a previously reported literature procedure [1]. Subsequent treatment of 1 with benzyl 2-bromoacetate (2) afforded the title compound 3 in very good yield.…”