Introduction: An analysis of the literature on the painkillers long used in traditional medicine, which are isolated from plant materials, has shown that many of them are alkylamides of various carboxylic acids. This fact served as the basis for the study of a large group of N-alkyl-4- methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides as potential new analgesics. The objects of the study were synthesized in the traditional way involving the initial conversion of 4-methyl- 2,2-dioxo-1H-2λ6,1- benzothiazine-3-carboxylic acid to imidazolide, in which imidazolide was used as an acylating agent. The method is simple to implement and, as a rule, gives high yields of final alkylamides. However, in reaction with sterically hindered tert-butylamine, along with the “normal” product, an unexpected formation of N-tert-butyl-4-methyl-1-(4-methyl-2,2-dioxo-1H-2λ6,1- benzothiazine-3-carbonyl)-2,2-dioxo-2λ6,1-benzothiazine-3-carboxamide was observed, which was characterized by X-ray diffraction analysis as a monosolvate with N,N-dimethylformamide. These synthetic problems can be avoided using a more powerful acylating agent, 4-methyl-2,2-dioxo-1H- 2λ6,1- benzothiazine-3-carbonyl chloride. Background: A large group of new N-alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3- carboxamides was synthesized. Objective: On the basis of molecular docking, some derivatives of N-alkyl-4-methyl-2,2-dioxo-1H- 2λ6,1-benzothiazine-3-carboxamides have been designed. Their preliminary structure-activity relationships (SAR) have been studied. The most rational approaches to the synthesis of lead compounds have been developed. The most active compounds have shown high anti-inflammatory and analgesic activities. Methods: The structure of all compounds prepared has been confirmed by the data of elemental analysis, 1H- and 13C NMR spectroscopy, and electrospray ionization liquid chromato-mass spectrometry. For rational drug design, optimization of further pharmacological screening and prediction of a possible mechanism of pharmacological action, molecular docking has been performed. For the determination of activity, pharmacological studies have been carried out. Results: Pharmacological tests have determined that the transition from N-aryl(heteroaryl) alkylamides to “pure” N-alkylamides we carried out is accompanied by a significant reduction and even complete loss of anti-inflammatory effect with remaining analgesic activity. Conclusion: According to the studies, compounds from N-alkyl-4-methyl-2,2-dioxo-1H-2λ6,1- benzothiazine-3-carboxamides are potential anti-inflammatory and analgesic agents.

中文翻译：

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新型 N-Alkyl-4-Methyl-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxamides 作为有前途的镇痛药的设计、合成和生物学评价

简介：对传统医学中长期使用的止痛药的文献分析表明，这些止痛药是从植物材料中分离出来的，其中许多是各种羧酸的烷基酰胺。这一事实为研究大量 N-alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides 作为潜在的新型镇痛药奠定了基础。研究对象以传统方式合成，涉及将4-甲基-2,2-二氧代-1H-2λ6,1-苯并噻嗪-3-甲酸初步转化为咪唑啉，其中咪唑啉作为酰化剂. 该方法实施简单，通常最终烷基酰胺的产率高。然而，在与位阻叔丁胺以及“正”产物反应时，意外形成了 N-tert-butyl-4-methyl-1-(4-methyl-2, 观察到 2-dioxo-1H-2λ6,1- benzothiazine-3-carbonyl)-2,2-dioxo-2λ6,1-benzothiazine-3-carboxamide，其通过 X 射线衍射分析表征为与 N 的单溶剂化物， N-二甲基甲酰胺。使用更强大的酰化剂 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carbonyl chloride 可以避免这些合成问题。背景：合成了大量新的 N-alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides。目的：在分子对接的基础上，设计了N-alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides的一些衍生物。已经研究了它们的初步构效关系 (SAR)。已经开发出最合理的先导化合物合成方法。最活跃的化合物已显示出高抗炎和镇痛活性。方法：制备的所有化合物的结构均通过元素分析、1H-和13C核磁共振谱、电喷雾电离液相色谱-质谱等数据进行了确证。为了合理的药物设计，优化进一步的药理筛选和预测可能的药理作用机制，进行了分子对接。为了测定活性，进行了药理学研究。结果：药理学试验已经确定，我们进行的从 N-芳基（杂芳基）烷基酰胺到“纯”N-烷基酰胺的转变伴随着抗炎作用的显着降低甚至完全丧失以及剩余的镇痛活性。结论：根据研究，来自 N-alkyl-4-methyl-2,2-dioxo-1H-2λ6 的化合物，