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

Abstract

Schizophrenia is a debilitating mental disorder which affects approximately 1% of the world's population. Clozapine is an atypical antipsychotic showing unmatched effectiveness in the control of treatment-resistant schizophrenia. Unlike typical antipsychotics, clozapine does not induce extrapyramidal side effects (EPS), tardive dyskinesia or elevate prolactin levels. However, clozapine can induce a potentially fatal blood disorder, agranulocytosis, in 1-2% of patients, severely limiting its clinical use. The model for antipsychotic activity under investigation is based on obtaining a clozapine-like profile with preferential dopamine D 4 and serotonin 5-HT 2A receptor affinity. Profiled herein are three unique members of a series of prospective antipsychotic agents. Compound (I) originated from the structural hybridization of the commercial therapeutics, clozapine and haloperidol, whilst compounds (II) and (III) possess an alternative tricyclic nucleus derived from JL13; a clozapine-like atypical antipsychotic developed by Liégeois et al. These compounds have been synthesized and characterized by means of elemental analysis, IR, 1 H and 13 C-NMR spectroscopy, MS and X-ray diffraction. Compound (I) crystallizes in space group P(-1) with a = 10.5032 (1), b = 10.6261(2), c = 12.6214(3) Å , a = 81.432(1)°, b = 83.292(1)°, c = 61.604(1)°, Z = 2, V = 1223.62(4) Å 3 , C 28 H 29 ClN 4 O, M r = 473.00, D c = 1.284 Mg/m 3 , l = 0.185 mm -1 , F(000) = 500, R = 0.0506 and wR = 0.1304. Compound (II) crystallizes in the monoclinic space group P2 1 /c with a = 10.8212(2), b = 9.3592(2), c = 22.9494(5) Å , b = 106.471(1)°, Z = 4, V = 2228.88(8) Å 3 , C 25 H 25 ClN 4 O 2 , M r = 448.94, D c = 1.338 Mg/m 3 , l = 0.202 mm -1 , F(000) = 944, R = 0.0529 and wR = 0.1129. Compound (III) crystallizes in the monoclinic space group P2 1 /c with a = 10.5174(2), b = 9.3112(2), c = 24.2949(5) Å , b = 98.666(1)°, Z = 4, V = 2352.03(8) Å 3 , C 25 H 24 Cl 2 N 4 O 2 , M r = 483.38, D c = 1.365 Mg/m 3 , l = 0.306 mm -1 , F(000) = 1008, R = 0.0478 and wR = 0.1067. The solid state conformations of (I), (II) and (III) exhibit the characteristic V-shaped buckled nature of the respective dibenzodiazepine and pyridobenzoxazepine nuclei with the central seven-membered heterocycle in a boat conformation. The molecules of (I) form a head-to-tail dimeric motif stabilized by hydrogen bonding. The results of a conformational analysis of compounds (I)-(III) investigating the effect of environment (in vacuo and aqueous solution) are presented. These analogues were tested for in vitro affinity for the dopamine D 4 and serotonin 5-HT 2A receptors and their comparative receptor binding profiles to clozapine and JL13 are reported.

Update 1 of: Recent Progress in Development of Dopamine Receptor Subtype-Selective Agents: Potential Therapeutics for Neurological and Psychiatric Disorders

“…A similar profile was observed on analogs such as 517 , bearing various substituted phenyloxypropyl tail groups . Like clozapine, compounds 515 – 517 strongly blocked apomorphine-induced climbing in mice. − Aminimides such as 518 proved to be much less potent at D 4 and 5-HT 2A receptors than clozapine . As analogs of D 1 –D 2 agonist tetrahydroprotoberberines, the homo- C -congeners 519 and 520 showed moderate affinity but substantial selectivity for the D 4 receptor.…”

“…419 A similar profile was observed on analogs such as 517, bearing various substituted phenyloxypropyl tail groups. 420 Like clozapine, compounds 515−517 strongly blocked apomorphine-induced climbing in mice. 419−421 Aminimides such as 518 proved to be much less potent at D 4 and 5-HT 2A receptors than clozapine.…”

“…In addition, Taylor et al also conducted extensive structural modifications on clozapine, with a focus on optimizing the N -methylpiperazine component. − They first modified the linkage of the piperazinyl-4-methyl to arylalkyl moieties with various alkyl chains. The resulting analogs, represented by 514 , were much less potent than clozapine at either D 4 or 5-HT 2A receptors .…”

Synthesis, molecular structure, NMR spectroscopic and computational analysis of a selective adenosine A2A antagonist, ZM 241385

“…12 [bottom]) is likely to be a result of the intermolecular interactions in the crystal lattice (discussed above). We have previously observed similar environment-dependent conformational behavior for other molecules containing rigid hydrophobic elements decorated with polarizable groups, and connected by flexible linkers [20][21][22]. X-ray structure Intensity data for compound 9 was collected on an Oxford Diffraction SuperNova CCD diffractometer using Cu-K radiation, the temperature during data collection was maintained at 130.0(1) using an Oxford Cryostream cooling device.…”

Interplay of thermochemistry and Structural Chemistry, the journal (volume 21, 2010) and the discipline

“…With the purpose to develop compounds with the clozapine-like profile of high dopamine D4 and serotonin 5-HT2A receptor affinity for the treatment of schizophrenia Capuano et al [161] synthesized, characterized, and determined X-ray crystal structures of three new prospective antipsychotic agents, one originating from the structural hybridization of the commercial therapeutics, clozapine, and haloperidol, while the others possess an alternative tricyclic nucleus derived from JL13, a clozapine-like atypical antipsychotic. Clozapine is a dibenzo-1,4-diazepine derivative; haloperidol is a piperidine-4-ol derivative.…”