4-Methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic Acid. Peculiarities of Preparation, Structure, and Biological Properties

Abstract

In order to determine the regularities of the structure–analgesic activity relationship, the peculiarities of obtaining, the spatial structure, and biological properties of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid and some of its derivatives have been studied. Using nuclear magnetic resonance (NMR) spectroscopy and X-ray diffraction analysis, it has been proven that varying the reaction conditions using alkaline hydrolysis of methyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate makes it possible to successfully synthesize a monohydrate of the target acid, its sodium salt, or 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine. The derivatographic study of the thermal stability of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid monohydrate has been carried out; based on this study, the optimal conditions completely eliminating the possibility of unwanted decomposition have been proposed for obtaining its anhydrous form. It has been shown that 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine is easily formed during the decarboxylation of not only 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid, but also its sodium salt, which is capable of losing СО2 both in rather soft conditions of boiling in an aqueous solution, and in more rigid conditions of dry heating. The NMR spectra of the compounds synthesized are given; their spatial structure is discussed. To study the biological properties of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid and its sodium salt, the experimental model of inflammation caused by subplantar introduction of the carrageenan solution in one of the hind limbs of white rats was used. The anti-inflammatory activity and analgesic effect were assessed by the degree of edema reduction and the ability to affect the pain response compared to the animals of control groups. According to the results of the tests performed, it has been found that after intraperitoneal injection, the substances synthesized demonstrate a moderate anti-inflammatory action and simultaneously increase the pain threshold of the experimental animals very effectively, exceeding Lornoxicam and Diclofenac in a similar dose by their analgesic activity.

Biological properties of two enantiomorphic forms ofN-(2,6-dimethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, a structural analogue of piroxicam

“…The control group received an equivalent amount of water with Tween-80. A detailed description of the biological experiments and the methods of statistical processing of the results obtained are given in Ukrainets et al (2018a).…”

The Crystal Structure of N-(1-Arylethyl)-4-methyl- 2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides as the Factor Determining Biological Activity Thereof

“…In the synthesis of all N-(1-arylethyl)-4-methyl-2,2-dioxo-1H-2λ 6 ,1-benzothiazine-3-carboxamides, 3-5 described in this article the commercial N,N -carbonyldiimidazole (CDI) and the anhydrous N,N-dimethylformamide (DMF) for peptide synthesis of Aldrich company (St. Louis, MO, USA) were used. The synthesis of the starting anhydrous 4-methyl-2,2-dioxo-1H-2λ 6 ,1-benzothiazine-3-carboxylic acid (1) was carried out by the method described in [14].…”

“…The animals of the control group received an equivalent amount of water with Tween-80. Other details of pharmacological experiments, as well as the statistical processing of the results, were described in detail earlier [14].…”

Molecular Conformations and Biological Activity of N-Hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides

“…The animals of the control group received an equivalent amount of water with Tween-80. Other details of pharmacological experiments, as well as statistical processing of the results were described in detail earlier [18].…”

“…Calcd. was for C 18 The crystals of pyridin-4-ylmethylamide monohydrate 2c (C 16 H 15 N 3 O 3 S · H 2 O) were monoclinic, colorless. At 273 K: a 9.0159(4), b 9.0159(4), c 14.1003(6) Å; β 101.805(3) • ; V 1590.4(1) Å 3 , Z 4, space group P2 1 /c, d calc 1.451 g/cm 3 , µ(MoK α ) 0.230 mm −1 , F(000) 728.…”