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.
Highlights
Even a cursory review of reference works on drugs reveals the fact that in the arsenal of modern non-narcotic products products against againstpain, pain,the theimportant importantrole rolebelongs belongs various carboxylic acids [1,2].to to various carboxylic acids InIn accordance with chemical structure,analgesic analgesicacids acidscan canbe bedivided dividedinto intoseveral several groups. groups
6,1-benzothiazine-3-carboxylates methyl-4-methyl-2,2-dioxo-1H-2λ well as as excellent results obtained during the transition from quinolone esters X, which are similar in terms of their structure, to acids XI [7] (Figure 2)
Another incentive to study the behavior of 4-methyl-substituted benzothiazine esters VIII in alkaline hydrolysis conditions was a simple scientific curiosity: as is results obtained during the transition from quinolone esters X, which are similar in terms of their structure, to acids XI [7] (Figure 2)
Summary
Even a cursory review of reference works on drugs reveals the fact that in the arsenal of modern non-narcotic products products against againstpain, pain,the theimportant importantrole rolebelongs belongs various carboxylic acids [1,2]. In accordance with chemical structure,analgesic analgesicacids acidscan canbe bedivided dividedinto intoseveral several groups. First of accordance with thethe chemical structure, all, it is, undoubtedly, derivatives of long-known salicylic acid I (Figure 1). And popular were created the basis of structurally close acid. Important andanalgesics popular analgesics wereon created on the phenylacetic acid III. The most representative group of analgesics officially permitted basis of phenylacetic acid III. The most representative group of analgesics officially for use is comprised of 2-phenylpropionic acids IV.acids.
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