Methyl 4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxylate and Its Analogs Modified in the Benzene Moiety of the Molecule as New Analgesics

Abstract

In order to identify new regularities of the “structure–analgesic activity” relationship in the series of 2,1-benzothiazine derivatives, the synthesis of methyl 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate and a group of its analogs substituted in the benzene moiety of the molecule, as well as their mono-and diammonium salts, was performed with tris(hydroxymethyl)aminomethane. The algorithm was proposed; it allows for uniquely solving the question of the nature of the substituent and its true position in the benzothiazine core based on the complex use of NMR (1H and 13C) and mass spectrometry data. Using single-crystal X-ray diffraction analysis it was proven that salt formation first passes through the cyclic sulfamide group and only then through the 4-hydroxyl group, and is always accompanied by a significant conformational rearrangement of the molecule. Based on the results of pharmacological tests it was found that modification of the benzene moiety of the molecule can be used as a method for enhancing the analgesic properties of the class of compounds studied. The presence of a substitute in position 7 is particularly effective, regardless of its nature. A comparative analysis of the analgesic activity of the initial esters and their mono- and diammonium salts convincingly showed that the common belief about a direct relationship between the solubility of a substance and the level of its biological effect is not always true. As it turned out, increasing the solubility in water can lead to a variety of consequences: From a significant increase in analgesia to its complete elimination. It was suggested that the analgesic activity of the compounds studied is determined not by solubility, but by the molecular conformations formed during their obtainment.

3,3′-(Phenylmethylene)bis(1-ethyl-3,4-dihydro-1H-2,1-benzothiazine-2,2,4-trione): single-crystal X-ray diffraction study, quantum-chemical calculations and Hirshfeld surface analysis

“…To analyze the possibility of the existence of the similar compounds in different tautomeric forms, a search of the Cambridge Structural Database (CSD Version 5.41, update of June 2022; Groom et al, 2016) for the benzothiazine fragment was performed. Of the 45 hits found, 19 reported the enol form of this fragment [refcodes: AKIJIP, AKIJIP01 (Ukrainets et al, 2016b), CABBEP (Lei et al, 2016), DUCBEL, DUCBEL01 (Shishkina et al, 2020b), IJUJAA (Ukrainets et al, 2015b), LANNUM (Ukrainets et al, 2016a), LOGHEW (Ukrainets et al, 2014a), MINJAW (Shishkina et al, 2013), NODGUK (Ukrainets et al, 2013), NOXJOC (Lei et al, 2019), RACQUL (Shishkina et al, 2020a), TAJXUB, TAJXUB01, TAJXUB02 (Ukrainets et al, 2020a), UWUCIA (Ukrainets et al, 2015a), XEKPUB (Ukrainets et al, 2017), ZUZJIQ, ZUZJOW (Ukrainets et al, 2020b)], while the keto form was detected in 12 hits [refcodes: KANTIE (Shafiq et al, 2011), LIVPUC (Tahir et al, 2008), LIVQAJ (Shafiq et al, 2008a), MOTDOP (Shafiq et al, 2009b), PONWEV (Shafiq et al, 2009d), SEJWAI (Shishkina et al, 2017), SOGDOI (Shafiq et al, 2008b), SOLKOU (Shafiq et al, 2009a), UZAMOZ (Ukrainets et al, 2014b), VACKER (Khan et al, 2010), WACRUP (Shafiq et al, 2010), YOVBER (Shafiq et al, 2009c)]. Both of these two forms are presented in structure NAKZAD (Lega et al, 2016c).…”