1,2,4-三唑-3-硫醇的含吡唑新衍生物的合成与镇痛活性

S. Fedotov, A. S. Hotsulia, Y. Karpenko
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The combination of two different heterocyclic fragments within one molecule makes it possible to use the possibilities of influencing such a molecule on various mechanisms of occurrence and development of various pathological conditions, including those accompanied by pain. Chemical modifications of pyrazole and 1,2,4-triazole structures, involving their incorporation into a single molecule, have the potential, as suggested by in silico predictions, to yield biologically active compounds with analgesic properties. The aim of this work was to determine the optimal conditions for the chemical transformation and properties of 4-amino-5-(3-methylpyrazol-5-yl)-1,2,4-triazole-3-thiol, 4-amino-5-(3-(3-fluorophenyl)pyrazol-5-yl)-1,2,4-triazole-3-thiol and their derivatives for the preparation of bioactive systems with analgesic activity. Materials and methods. The creation of a target series of compounds was implemented by consistently using well-known methods of organic synthesis. 4-Amino-5-(3-methylpyrazole-5-yl)-1,2,4-triazole-3-thiol and 4-amino-5-(3-(3-fluorophenyl)pyrazole-5-yl)-1,2,4-triazole-3-thiol were resynthesized as starting materials using acetone or 1-(3-fluorophenyl)ethane-1-one, diethyloxalate, and sodium methylate using step-by-step hydrazinolysis and carbon disulfide involvement in an alkaline medium. Further targeted functionalization involved the introduction of a 2,6-dichlorophenyl substitute, alkane acid residues, and esters based on them into the structure of the target compounds. The structure of all synthesized substances was determined by IR spectrophotometry, 1H NMR spectroscopy, and elemental analysis. The individuality of the compounds was confirmed by high-performance liquid chromatography-mass spectrometry. The analgesic properties were studied on two models: the “acetic acid-induced writhing test” and a formalin model of pain inflammation. Pharmacokinetic parameters were predictably calculated using the SwissADME online platform. Results. Based on the results of the synthetic part of the work, the structure of 4-amino-5-(3-methylpyrazole-5-yl)-1,2,4-triazole-3-thiol and 4-amino-5-(3-(3-fluorophenyl)pyrazole-5-yl)-1,2,4-triazole-3-thiol, as well as their derivatives, was successfully recreated. The presence of a beneficial effect of 2,6-dichlorophenyl substitute, as well as fragments of saturated carboxylic acids and their esters on the formation of antinociceptive activity has been proven. The quantitative indicators of pharmacokinetic parameters, as determined during ADME analysis, fall within acceptable ranges in nearly all instances. Conclusions. The optimal conditions for the synthesis and structural modification of 4-amino-5-(3-methylpyrazol-5-yl)-1,2,4-triazole-3-thiol, 4-amino-5-(3-(3-fluorophenyl)pyrazol-5-yl)-1,2,4-triazole-3-thiol were established, which allowed the preparation of 2-((4-amino-5-(3-methylpyrazol-5-yl)-1,2,4-triazol-3-yl)thio)alkanoic acids and their esters, as well as [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine systems. 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引用次数: 0

摘要

疼痛是多种疾病和病症的主要症状,影响着全球数百万人。有效的镇痛药物可以减轻或消除疼痛,从而提高患者的生活质量,帮助他们恢复正常的身体和社交活动。然而,现有的几种镇痛药可能会带来不必要的副作用,如溃疡、凝血问题、嗜睡等。新型镇痛药的研发重点是创造出既有效又能减少不良反应的药物。考虑到患有神经病、肿瘤和其他疾病并伴有慢性疼痛的患者人数持续上升,对创新治疗和疼痛管理方法的需求日益增长。在一个分子中结合两种不同的杂环片段,可以利用这种分子对各种病症(包括伴有疼痛的病症)的发生和发展机制产生影响的可能性。对吡唑和 1,2,4-三氮唑结构进行化学修饰,将其纳入一个分子中,正如硅学预测所表明的那样,有可能产生具有镇痛特性的生物活性化合物。这项工作的目的是确定 4-氨基-5-(3-甲基吡唑-5-基)-1,2,4-三唑-3-硫醇、4-氨基-5-(3-(3-氟苯基)吡唑-5-基)-1,2,4-三唑-3-硫醇及其衍生物化学转化和特性的最佳条件,以制备具有镇痛活性的生物活性体系。材料和方法。目标系列化合物的制备一直采用众所周知的有机合成方法。以 4-氨基-5-(3-甲基吡唑-5-基)-1,2,4-三唑-3-硫醇和 4-氨基-5-(3-(3-氟苯基)吡唑-5-基)-1,2,4-三唑-3-硫醇为起始原料,在碱性介质中使用丙酮或 1-(3-氟苯基)乙烷-1-酮、二乙醇胺和甲酸钠,通过逐步肼解和二硫化碳参与重新合成。进一步的定向功能化包括在目标化合物的结构中引入 2,6-二氯苯基替代物、烷酸残基和以它们为基础的酯。所有合成物质的结构都是通过红外分光光度法、1H NMR 光谱法和元素分析确定的。通过高效液相色谱-质谱法确认了化合物的独特性。在 "醋酸诱发的蠕动试验 "和福尔马林疼痛炎症模型中研究了化合物的镇痛特性。药代动力学参数通过 SwissADME 在线平台进行预测计算。结果根据合成部分的研究结果,成功再现了 4-氨基-5-(3-甲基吡唑-5-基)-1,2,4-三唑-3-硫醇和 4-氨基-5-(3-(3-氟苯基)吡唑-5-基)-1,2,4-三唑-3-硫醇及其衍生物的结构。事实证明,2,6-二氯苯基替代物以及饱和羧酸片段及其酯类对形成抗痛觉活性有好处。在 ADME 分析过程中确定的药代动力学参数定量指标几乎都在可接受的范围内。结论建立了 4-氨基-5-(3-甲基吡唑-5-基)-1,2,4-三唑-3-硫醇、4-氨基-5-(3-(3-氟苯基)吡唑-5-基)-1,2,4-三唑-3-硫醇合成和结构修饰的最佳条件、从而制备出 2-((4-氨基-5-(3-甲基吡唑-5-基)-1,2,4-三唑-3-基)硫)烷酸及其酯类,以及 [1,2,4]三唑并[3,4-b][1,3,4]噻二嗪系统。研究表明,1,2,4-三唑-3-硫醇的吡唑衍生物与 2,6-二氯苯基取代基以及饱和羧酸及其酯的片段相结合,为形成具有抗痛觉活性的化合物创造了条件,醋酸诱导的蠕动试验和福尔马林炎症模型的实验数据证实了这一点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Synthesis and analgesic activity of new pyrazole-containing derivatives of 1,2,4-triazole-3-thiol
Pain represents a primary symptom of numerous diseases and conditions, affecting millions of people worldwide. Effective analgesic medications can alleviate or eliminate pain, thereby enhancing patients’ quality of life and assisting them in resuming normal physical and social activities. However, several existing analgesics may carry unwanted side effects, such as ulcers, blood clotting issues, drowsiness, and more. The development of new analgesics is focused on creating drugs that are both effective and associated with fewer adverse effects. Considering the continuous rise in the number of patients dealing with neurological, oncological, and other conditions accompanied by chronic pain, there is a growing demand for innovative methods of treatment and pain management. The combination of two different heterocyclic fragments within one molecule makes it possible to use the possibilities of influencing such a molecule on various mechanisms of occurrence and development of various pathological conditions, including those accompanied by pain. Chemical modifications of pyrazole and 1,2,4-triazole structures, involving their incorporation into a single molecule, have the potential, as suggested by in silico predictions, to yield biologically active compounds with analgesic properties. The aim of this work was to determine the optimal conditions for the chemical transformation and properties of 4-amino-5-(3-methylpyrazol-5-yl)-1,2,4-triazole-3-thiol, 4-amino-5-(3-(3-fluorophenyl)pyrazol-5-yl)-1,2,4-triazole-3-thiol and their derivatives for the preparation of bioactive systems with analgesic activity. Materials and methods. The creation of a target series of compounds was implemented by consistently using well-known methods of organic synthesis. 4-Amino-5-(3-methylpyrazole-5-yl)-1,2,4-triazole-3-thiol and 4-amino-5-(3-(3-fluorophenyl)pyrazole-5-yl)-1,2,4-triazole-3-thiol were resynthesized as starting materials using acetone or 1-(3-fluorophenyl)ethane-1-one, diethyloxalate, and sodium methylate using step-by-step hydrazinolysis and carbon disulfide involvement in an alkaline medium. Further targeted functionalization involved the introduction of a 2,6-dichlorophenyl substitute, alkane acid residues, and esters based on them into the structure of the target compounds. The structure of all synthesized substances was determined by IR spectrophotometry, 1H NMR spectroscopy, and elemental analysis. The individuality of the compounds was confirmed by high-performance liquid chromatography-mass spectrometry. The analgesic properties were studied on two models: the “acetic acid-induced writhing test” and a formalin model of pain inflammation. Pharmacokinetic parameters were predictably calculated using the SwissADME online platform. Results. Based on the results of the synthetic part of the work, the structure of 4-amino-5-(3-methylpyrazole-5-yl)-1,2,4-triazole-3-thiol and 4-amino-5-(3-(3-fluorophenyl)pyrazole-5-yl)-1,2,4-triazole-3-thiol, as well as their derivatives, was successfully recreated. The presence of a beneficial effect of 2,6-dichlorophenyl substitute, as well as fragments of saturated carboxylic acids and their esters on the formation of antinociceptive activity has been proven. The quantitative indicators of pharmacokinetic parameters, as determined during ADME analysis, fall within acceptable ranges in nearly all instances. Conclusions. The optimal conditions for the synthesis and structural modification of 4-amino-5-(3-methylpyrazol-5-yl)-1,2,4-triazole-3-thiol, 4-amino-5-(3-(3-fluorophenyl)pyrazol-5-yl)-1,2,4-triazole-3-thiol were established, which allowed the preparation of 2-((4-amino-5-(3-methylpyrazol-5-yl)-1,2,4-triazol-3-yl)thio)alkanoic acids and their esters, as well as [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine systems. It has been shown that the combination of pyrazole derivatives of 1,2,4-triazol-3-thiol with 2,6-dichlorophenyl substituent and fragments of saturated carboxylic acids and their esters creates conditions for the formation of compounds with antinociceptive activity, which was confirmed in vivo by experimental data acetic acid-induced writhing test and formalin inflammation model.
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