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.
