New Pyridobenzoxazepine Derivatives Derived from 5-(4-Methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13): Chemical Synthesis and Pharmacological Evaluation

Abstract

A series of new pyridobenzoxazepine derivatives with various heterocyclic amine side chains were synthesized to explore two main parameters related to the distal basic nitrogen. These compounds were tested for their affinity for dopamine D(2L) and D(4), serotonin 5-HT(1A) and 5-HT(2A), and adrenergic α(2A) receptors in comparison with 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine, JL13 (1), and other diarylazepine derivatives. In terms of multireceptor target strategy, 2 and 5 present the most promising in vitro binding profile. Bulky, polar, and more flexible side chains are not favorable in this context. Compounds 2 and 5 were tested in adult rats to evaluate their long-term effects on dopamine and serotonin receptors density in different brain areas. Similar to 1 and other second-generation antipsychotic drugs, repeated treatment with 2 significantly increased D(1) and D(4) receptors in nucleus accumbens and caudate putamen and D(2) receptors in medial prefrontal cortex and hippocampus, while 5 significantly increased D(2) and D(4) receptors in nucleus accumbens. In addition, 2 increased 5-HT(1A) and decreased 5-HT(2A) receptors in cerebral cortex. In contrast, 5 did not alter levels of any 5-HT receptor subtype in any brain region examined. These results encourage further development of 2 as a novel second-generation antipsychotic agent.

Synthesis of isoindolo[1,4]benzoxazinone and isoindolo[1,5]benzoxazepine: two new ring systems of pharmaceutical interest

“…Column chromatography was performed with Merck silica gel 230e400 mesh ASTM or with a B€ uchi Sepacor chromatography module (prepacked cartridge system). All melting points were taken on a B€ uchi B 540 melting point apparatus; IR spectra were determined in bromoform with a Shimadzu FT/IR 8400S spectrophotometer; 1 H and 13 C NMR spectra were measured in DMSO-d 6 …”

“…5 Also benzoxazepine derivatives are well-known pharmacophores showing promising properties against various diseases such as antipsychotic, 6 central nervous system, 7 and anti-cancer activities. 8 Variously substituted pyrrolo [1,5]benzoxazepines have shown antiproliferative activity in a wide range of tumor cell lines at micromolar concentrations.…”

Synthesis of Benzoxazepine Derivatives From Pyrazole-Chalcone via a Simple and Convenient Protocol Using Basic Alumina as Solid Support

“…Pyrazoles were found to possess inhibitory activities against XO, cyclooxygenase, and alkaline phosphatases 16,17 . Benzoxazepine derivatives are prevalent designs of biologically active compounds 18,19 . These derivatives are well-known pharmacophores showing capable properties against various diseases such as antipsychotic 20 , central nervous system damage 21 and anticancer activities 22 .…”

“…Benzoxazepine derivatives are prevalent designs of biologically active compounds 18,19 . These derivatives are well-known pharmacophores showing capable properties against various diseases such as antipsychotic 20 , central nervous system damage 21 and anticancer activities 22 . Usually, benzoxazepine derivatives preparation involves multistep synthesis [23][24][25] .…”

Synthesis of Novel 7‐methylene‐6,7‐dihyrobenzo[f]Benzo[4,5]Imidazo[1,2‐d][1,4]Oxazepines via Base‐mediated Regioselective Intramolecular Hydroamination

“…The connection of benzoxazepines with various biological activities such as anticonvulsant and hypnotic , anticancer, and antipsychotic activities is well documented in the literature review section. Most syntheses of 2,3,4,5‐tetrahydro‐1,4‐benzooxazepines can be prepared by different synthetic methods: (i) condensation of 2‐aryloxyethylamines with 2‐formylbenzoic acid to form aminonaphtalides followed by cyclization; (ii) rearrangement of methyl 2‐(8‐methoxy‐2,3‐dihydro‐1,4‐benzooxazepine‐5‐yl) benzoate using Bischler–Napieralski conditions; and (iii) scandium or copper triflate‐catalyzed acylaminoalkylation of α‐methoxy‐isoindolones with the formation of 1,4‐benzoxazepine .…”