Synthesis, Spatial Structure and Analgesic Activity of Sodium 3-Benzylaminocarbonyl-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazin-4-olate Solvates

Abstract

In order to obtain and then test pharmocologically any possible conformers of the new feasible analgesic N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, its 4-O-sodium salt was synthesized using two methods. X-ray diffraction study made possible to determine that, depending on the chosen synthesis conditions, the above-mentioned compound forms either monosolvate with methanol or monohydrate, where organic anion exists in the form of three different conformers. Pharmacological testing of the two known pseudo-enantiomeric forms of the original N-benzylamide and of the two solvates of its sodium salt was performed simultaneously under the same conditions and in equimolar doses. Comparison of the results obtained while studying the peculiarities of the synthesized compounds spatial structure and biological properties revealed an important structure-action relationship. In particular, it was shown that the intensity of analgesic effect of different conformational isomers of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide may change considerably: while low active conformers are comparable with piroxicam, highly active conformers are more than twice as effective as meloxicam.

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

“…If we also take into account the fact that one of these substances in the water-insoluble acid form 4f does not have activity, then only methyl 7-chloro-4-hydroxy-2,2-dioxo-1H-2λ 6 ,1-benzothiazine-3carboxylate (4g) can be recommended as the leader structure of all substances studied. The decrease in the analgesic effect of the same substance during the transition from its acid form to the salt form was noted by us earlier [27]. Moreover, it was already experimentally proven that such chemical modifications were accompanied by significant conformational rearrangements and eventually by a decrease in activity.…”

“…Product R The decrease in the analgesic effect of the same substance during the transition from its acid form to the salt form was noted by us earlier [27]. Moreover, it was already experimentally proven that such chemical modifications were accompanied by significant conformational rearrangements and eventually by a decrease in activity.…”

“…As we have shown repeatedly before, the spatial structure o of 4-R-2,2-dioxo-1H-2λ 6 ,1benzothiazine-3-carboxylic acids derivatives can significantly affect their biological properties [22][23][24][25][26]. On the other hand, it is well known that salt formation by 4-ОН group is accompanied by drastic changes of 4-hydroxy-2,2-dioxo-1H-2λ 6 ,1-benzothiazines crystal molecular conformations [18,27]. Hence, it is interesting along with esters 4a-p to include their salts in the range of the objects studied-both mono-and disubstituted ones since the salt formation by each of the acid groups of esters 4a-p must make a specific contribution to changing their structure.…”

Molecular Conformations and Biological Activity of N-Hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides

“…The next important point is the introduction of test samples in the form of an aqueous suspension, which provides their entry into the body of the experimental animal in the initial crystalline state. And finally, the last argument in favor of our research is that in pharmaceutical and medical chemistry it is well known that the molecular and crystal structure of organic compounds has a significant impact on their pharmacological properties, and therefore, often becomes the object of close attention of researchers [34][35][36][37][38][39].…”

“…The thiophene cycle was located in orthogonal position to the carbamide fragment (the C (9) −N (2) −C (10) −C (11) torsion angle was −94.2(2) • ) and was disordered over two positions (A and B) with equal populations due to rotation around the C (10) −C (11) bond (the N (2) −C (10) −C (11) suspension, which provides their entry into the body of the experimental animal in the initial crystalline state. And finally, the last argument in favor of our research is that in pharmaceutical and medical chemistry it is well known that the molecular and crystal structure of organic compounds has a significant impact on their pharmacological properties, and therefore, often becomes the object of close attention of researchers [34][35][36][37][38][39].…”