Synthesis And Anticonvulsant Activity Studies Of [1,2,4] Triazolo[4,3-a][2] Benzazepin Derivatives

Benzozepines derivatives exhibit a broad spectrum of pharmacological activity. Some of them have been clinically used as antianxiety, hypnotic and eardiovascular drugs. Over the past decade, the studies on their structures, synthesis and biological activities have always been paid much more attention. But, mostly of the commonly used benzozepines are 1,5 and 1,4-benzothiazepine and 1,4-benzodiazepines compounds.Benzoxazepines are a important group of benzozepines, and also have high pharmacological activities, or can be used as intermediates in preparing of biologically active compounds. The present anti-hypertension drugs such as Libezapril and Benazeprilat contain 2-oxo-benazepine basic skeleton, growth hormone secretagogue L-692,429 and L-739,943 also contain the skeleton. Synthesis and modification of their structure is one of the research focus in organic chemistry nowdays. According to literature reports, benzoxazepines compounds with the basic skeleton have the analgesic effect.Triazoles compounds because of their wide range of biological activity have attracted attention, many of them have been developed and applied as fungicides, drugs, and plant growth regulators. The triazole compounds with different structures have different biological activities, such as anti-tumor, anti-inflammatory, antibacterial, anti-thrombotic, anti-platelet and anticonvulsant effects. Rsearch for the development of new types of triazole compounds is still hot. The introduction of triazole ring to some active molecules may significantly improve the biological activity of the parent molecule due to the superposition of biological activity. Currently, the synthesis of heterocyclic compounds tend to combine some active groups to the same molecule in order to obtain derivatives with stronger biological activity.The chemical structures of benzazepines derivatives are similar to the structures of benzodiazepines compounds, so they may have similar or opposite biological activities. The benzodiazepine compounds have good anxiolytic, sedative and hypnotic and anti-epileptic activity. Therefore, this study designed and synthesized a series of tetrahydro-7-alkoxy-1H-2-benzazepin-1-ones,9-alkoxy-6,7-dihydro-5H-benzo[c] [1,2,4]triazolo[4,3-a][2]azepins and 9-alkoxy-6,7-dihydro-2H-benzo[c][1, 2,4] triazolo [4,3-a] azepin-3 (5H)-ones, and their structures confirmed by IR,1H NMR,13C NMR, mass and elemental analysis, their anticonvulsant activities were evaluated by the maximal electroshock test (MES) and the subcutaneous pentylenetetrazole test (sc-PTZ) and the neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). In the clinical, the MES is the most commonly used method of screening antiepileptic drugs. The results revealed that all of the compounds exhibited anticonvulsant activity, among which compound 6e was found to possess the most potential anticonvulsant activity in the anti-MES test, it showed median effective dose (ED50) of 12.3 mg/kg, median toxicity dose (TD50) of 73.5 mg/kg, and the protective index (PI) of 6.0. Its ED50 and PI is better than that of the prototype drug Phenobarbital(ED50=21.8, PI=3.2). The most active compound was 6d with ED50 of 19.8 mg/kg, and had PI of 4.1 in the scMet tests, which is much greater than PI of the prototype drugs carbamazepin(PI<0.22). It was found that the compounds 6d and 6e possess the potent of being explored to be a new anticonvulsant agent. Possible structure-activity relationship was discussed in this paper.The first chapter serves as a brief treatise on benzazepines compounds.The second chapter is about the synthesis of 2,3,4,5-tetrahydro-7-methoxy-1H-2-benzazepin-1-one, and its reaction mechanism was also discussed.The third chapter aims at the synthesis of a series of tetrahydro-7-alkoxy-1H-2-benzazepin-1-ones,9-alkoxy-6,7-dihydro-5H-benzo[c] [1,2,4]triazolo[4,3-a] [2]azepins and 9-alkoxy-6,7-dihydro-2H-benzo [c] [1,2,4] triazolo [4,3-a] azepin-3 (5H)-ones, and their structures confirmed by IR, MS,1H NMR,13C NMR, mass and elemental analysis. Furthemore, the spectra data have also been presented.In chapter four, the anticonvulsant activities of the synthesized compounds were evaluated by the maximal electroshock test (MES) and the subcutaneous pentylenetetrazole test (sc-PTZ) and the neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). In chapter five, the structure-activity relationship methods were described, and the general structure activity relationship of the synthesized compounds were studied.In chapter six, we made a summary of the whole thesis.