Synthesis, Structure, and Analgesic Properties of Halogen-Substituted 4-Hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxanilides

Abstract

As potential new analgesics, the corresponding 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxanilides have been obtained by amidation of ethyl 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate with aniline and its halogenated analogsin boiling dry xylene. The peculiarities of the mass and nuclear magnetic resonance (1Н and 13С) spectra of the synthesized compounds are discussed. Using X-ray diffraction analysis, the ability of the compounds to form stable solvates with N,N-dimethylformamide has been shown on the example of 4-bromo-substituted derivative. It should be further studied to be considered in their crystallization. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick (tail immersion test) among halogen-substituted 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxanilides, substances which are considerably superior to meloxicam and piroxicam by their analgesic activity have been found. They are of interest for further profound studies.

New Synthesis, Structure and Analgesic Properties of Methyl 1-R-4-Methyl-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxylates

“…By the example of allyl [ 31 ], isopropyl ( Figure 3 ) and benzyl ( Figure 4 ) derivatives it has been conclusively proven that actually methyl 4-methyl-2,2-dioxo-1 H -2λ 6 ,1-benzothiazine-3-carboxylate ( 3 ) is alkylated exclusively at the nitrogen atom independently from the structure of alkyl halide. Simultaneously, it has been found that the tendency to form solvates with various organic solvents previously mentioned for 4-hydroxy-2,2-dioxo-1 H -2λ 6 ,1-benzothiazines over and over again [ 17 , 32 ] is also typical for their 4-methyl-substituted analogs. In particular, the ability of methyl 1-benzyl-4-methyl-2,2-dioxo-1 H -2λ 6 ,1-benzothiazine-3-carboxylate ( 5g ) to form a monosolvate easily from methanol already in crystallization has been found ( Figure 4 ).…”

“…In addition, our results can be regarded somewhat broader, for example, as the substantiation for involving not only esters described in the compounds under study, but 1-R-4-methyl-2,2-dioxo-1 H -2λ 6 ,1-benzothiazine-3-carboxylic acids as their basis, as well as various N -R-amides. Moreover, N -R-amides were specified as the most promising analgesics in the series of 4-hydroxy-2,1-benzothiazine analogs previously studied [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…First, because of synthetic difficulties, they still remain chemically and pharmacologically understudied, and it makes them particularly attractive from the point of view of novelty that is important for any innovation project. Secondly, having synthesized and studied only approximately 200 compounds of this chemical class we succeeded in demonstrating convincingly that esters (especially methyl esters) [ 10 , 11 ], arylalkylamides [ 12 , 13 , 14 ], anilides [ 15 , 16 , 17 ] and hetarylamides [ 18 , 19 ] of 1-R-4-hydroxy-2,2-dioxo-1 H -2λ 6 ,1-benzothiazine-3-carboxylic acids have real prospects for developing highly effective analgesics. Finally, another important factor is that derivatives of 4-hydroxy-2,2-dioxo-1 H -2λ 6 ,1-benzothiazine-3-carboxylic acids and, first of all, their esters of the general formula I ( Figure 1 ), possess a wide synthetic potential allowing to make a variety of chemical transformations to the basic molecule virtually unrestrictedly and thereby to change its pharmaceutical and (or) pharmacological properties in the right direction.…”

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).…”