Bondarenko P. Experimental sudy of pharmacodynamics and pharmacolonetics of 4-R-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carbonic acids crystalline forms

Screening studies in a model of carrageenan edema in rats was found that heterogeneous crystallization from ethanol was revealed to result in a monoclinic polymorphic form of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid, that has the best analgesic and anti-inflammatory effect. In the process of chemical synthesis of N- (4-trifluoromethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, crystals with different habit were detected: sticks (compound A), plates (Compound B) and blocks (compound C). The study of the analgesic properties of compounds A, B and C in different models of pain perception ("acetic-acid-induced writhing" in mice, "hot plate", "tail-flick", tail electric stimulation, and diabetic neuropathy in rats) showed that the fastest and the potent effect of compound B. For the first time, a comparative evaluation of the efficacy and safety of three crystalline modifications of N-(4-trifluoromethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide was performed. According to the therapeutic index and the safety factor, the best was the polymorphic form B that was chosen as the leader compound for further research. Analysis of pharmacokinetic parameters showed that compounds B had a statistically higher degree of absorption, maximum concentration and a faster time to reach it, and greater bioavailability. At the same time, compound B has a faster elimination. Polymorphic compound B is able to eliminate all components of the inflammatory reaction (alteration, exudation and proliferation) and is comparable in efficiency, and sometimes superior to meloxicam. In the adjuvant arthritis model, two weeks of compound B administration lead to reduction in affected limb edema and hematologic signs of inflammation. Compound B also inhibited IL-1β levels and PgH synthase activity, and more markedly reduced meloxicam production of nitrogen monoxide and hydrogen sulfide in the stomach mucosa homogenate.