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

Abstract

According to the principles of the methodology of bioisosteric replacements a series of methyl 1-R-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates has been obtained as potential analgesics. In addition, a fundamentally new strategy for the synthesis of compounds of this chemical class involving the introduction of N-alkyl substituent at the final stage in 2,1-benzothiazine nucleus already formed has been proposed. Using nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and X-ray diffraction analysis it has been proven that in the DMSO/K2CO3 system the reaction of methyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate and alkyl halides leads to formation of N-substituted derivatives with good yields regardless of the structure of the alkylating agent. The peculiarities of NMR (1Н and 13С) spectra of the compounds synthesized, their mass spectrometric behavior and the spatial structure are discussed. In N-benzyl derivative the ability to form a monosolvate with methanol has been found. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick it has been determined that replacement of 4-ОН-group in methyl 1-R-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates for the methyl group is actually bioisosteric since all methyl 1-R-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates synthesized demonstrated a statistically significant analgesic effect. The majority of the substances can inhibit the thermal pain response much more effective than piroxicam in the same dose. Under the same conditions as an analgesic the N-methyl-substituted analog exceeds not only piroxicam, but more active meloxicam as well. Therefore, it deserves in-depth biological studies on other experimental models.

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

“…The sample was heated in the inert gas atmosphere (argon, 20 mL/min), and the rate of heating was 5 °C/min. The synthesis of the starting methyl 4-methyl-2,2-dioxo-1 H -2λ 6 ,1-benzothiazine-3-carboxyate ( 1 ) was carried out by the method described in the study [ 6 ].…”

“…Taking into account the above, it is of interest to study the structure and biological properties of 4-methyl-2,2-dioxo-1 H -2λ 6 ,1-benzothiazine-3-carboxylic acids IX . The main prerequisites for this research were the expressed analgesic activity demonstrated by their synthetic precursors — methyl-4-methyl-2,2-dioxo-1 H -2λ 6 ,1-benzothiazine-3-carboxylates VIII [ 6 ] as well 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 known [ 8 ], the corresponding acids cannot be obtained from their 4-hydroxy analogs XII since in the process of their formation, they are immediately decarboxylated to 4-oxo-3,4-dihydro-1 H -2λ 6 ,1-benzothiazin-2,2-diones XIII .…”

Synthesis, Crystal Structure, and Biological Activity of Ethyl 4-Methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate Polymorphic Forms

“… The conventional method for the synthesis of alkyl 1-R-4-methyl-2,2-dioxo-1 H -2λ 6 ,1-benzothiazine-3-carboxylates IX [ 22 , 23 , 24 , 25 ] . …”

“…This is the method that we used to transform 4-methyl-2,2-dioxo-1 H -2λ 6 ,1-benzothiazine-3-carboxylic acid into an ester. Naturally, the lower alkyl esters of this acid are easier to obtain according to the usual linear scheme [ 22 , 23 ] when the required substituent is introduced at the preliminary stage of the synthesis of the corresponding alkyl (chlorosulfonyl) acetate VII ( Scheme 1 ). It must be remembered that the use of bases at the final stage of the hetericyclization provides an opportunity to avoid easy transesterification [ 24 , 25 ].…”

“…However, we deliberately focused on the alkylation of the benzothiazine-3-carboxylic acid salt with the alkyl halide in order to involve the most diverse esters in the alcoholic part of the molecule, in addition to the already studied methyl 4-methyl-2,2-dioxo-1 H -2λ 6 ,1-benzothiazine-3-carboxylates [ 23 ]. It is the alkylation of the salts of the carboxylic acids with the alkyl halides characterized by a very wide synthetic potential (unlike the method presented in Scheme 1 ) that allows for the solution of similar problems.…”