6-(2,6-二氯苯基)-3-(3-甲基- 1h -吡唑-5-基)-6,7-二氢- 5h -[1,2,4]三唑[3,4-b][1,3,4]噻二嗪-7-羧酸及其盐类的合成与性质

S. Fedotov, A. S. Hotsulia
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引用次数: 0

摘要

羧酸及其衍生物是许多生物过程的重要组成部分。例如,它们可以用来制造新药,这些新药可以用于对抗各种疾病。此外,含有噻唑基团的化合物可在实际药学中具有有益的特性。这种杂环结构在分子中的结合可以积极影响一些生物学特性,如抗炎、抗病毒和抗真菌活性。因此,探索结合噻唑片段和羧基的新化合物有望促进新药和诊断工具的发展,这些新药物和诊断工具可以为对抗许多疾病做出重大贡献。本工作的目的是制备一系列6-(2,6-二氯苯基)-3-(3-甲基- 1h -吡唑-5-基)-6,7-二氢- 5h -[1,2,4]三唑[3,4-b][1,3,4]噻二嗪-7-羧酸的有机和无机盐,并研究它们的性质,以及对这些化合物的生物潜力的选择性测定。材料和方法。本研究的合成部分包括使用先前文章中描述的成熟方法顺序合成原始化合物4-氨基-5-(3-甲基- 1h -吡唑-5-基)-1,2,4-三唑-3-硫醇。下一阶段是硫醇与2,3-二氯苯甲醛在冰醋酸介质中的反应。得到的希夫碱随后在四氢呋喃中与2-氯乙酸在等量氢化钠的存在下反应。6-(2,6-二氯苯基)-3-(3-甲基- 1h -吡唑-5-基)-6,7-二氢- 5h -[1,2,4]三唑[3,4-b][1,3,4]噻二嗪-7-羧酸在水-醇介质中与有机碱和无机碱反应生成相应的酸盐。所有合成化合物的结构均通过1H NMR和元素分析确定。此外,采用高效液相色谱-质谱联用技术确定了每种化合物的特性。研究确定了6-(2,6-二氯苯基)-3-(3-甲基- 1h -吡唑-5-基)-6,7-二氢- 5h -[1,2,4]三唑[3,4-b][1,3,4]噻二嗪-7-羧酸有机和无机盐的最佳生成条件。利用ADME分析药代动力学参数和理化性质(吸收、分布、代谢和排泄),可以鉴定有前途的合成化合物,并为进一步研究选择更优的化合物。合成并确认了12个化合物的结构。对ADME参数进行了理化和药代动力学分析,筛选出有前景的化合物进行更深入的研究。
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 properties of 6-(2,6-dichlorophenyl)-3- (3-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazine-7-carboxylic acid and its salts
Carboxylic acids and their derivatives are an important component of many biological processes. For example, they can be used to create new medicines that can be useful in the fight against various diseases. Additionally, compounds containing a thiazole moiety may possess beneficial properties in practical pharmacy. The incorporation of this heterocyclic structure in molecules can positively impact several biological characteristics, such as anti-inflammatory, antiviral, and antifungal activities. Consequently, exploring novel compounds that combine a thiazole fragment with a carboxyl group holds promise for the advancement of new drugs and diagnostic tools that can contribute significantly to the battle against numerous diseases. The aim of the work was to create a number of organic and inorganic salts of 6-(2,6-dichlorophenyl)-3-(3-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-7-carboxylic acid and study of their properties, as well as selective determination of the biological potential of these compounds. Materials and methods. The synthetic part of the study involved the sequential synthesis of the original compound 4-amino-5-(3-methyl-1H-pyrazol-5-yl)-1,2,4-triazole-3-thiol using a well-established method described in previous articles. The next stage involved the reaction of thiol with 2,3-dichlorobenzaldehyde in a medium of glacial acetic acid. The resulting Schiff base was subsequently reacted with 2-chloroethanoic acid in tetrahydrofuran in the presence of an equimolar amount of sodium hydride. Salts of the corresponding acid were formed during the reaction of 6-(2,6-dichlorophenyl)-3-(3-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-7-carboxylic acid with both organic and inorganic bases in an aqueous-alcohol medium. The structures of all synthesized compounds were determined using 1H NMR spectroscopy and elemental analysis. Additionally, the individuality of each compound was confirmed using high-performance liquid chromatography-mass spectrometry. Results. The study determined the optimal conditions for the formation of both organic and inorganic salts of 6-(2,6-dichlorophenyl)-3-(3-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-7-carboxylic acid. The analysis of pharmacokinetic parameters and physicochemical properties using ADME (absorption, distribution, metabolism, and excretion) allowed for the identification of promising synthesized compounds and the selection of more optimal compounds for further investigation. Conclusions. The structure of 12 compounds was synthesized and confirmed. Physical-chemical and pharmacokinetic analysis of ADME parameters was carried out and promising compounds were selected for more in-depth research.
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