1-Allyl-4-hydroxy-2,2-dioxo-N-(4-methoxyphenyl)-1H-2λ6,1-benzothiazine-3-carboxamide: polymorphic transition due to grinding with the loss of the biological activity.

A study of two polymorphic forms of 1-allyl-4-hydroxy-2,2-dioxo-N-(4-methoxyphenyl)-1-2λ6,1-benzothiazine-3-carboxamide (a structural analogue of piroxicam) has revealed some regularities in the crystal structure formation due to different evaporation rates from the tested solvents. The monoclinic polymorph crystallized from ethyl acetate is formed due to a large number of very weak C-H...O and C-H...π interactions as well as one strong stacking interaction. The triclinic polymorph crystallized from N,N-dimethylformamide is formed due to a small number of weak specific interactions and a maximal number of strong stacking interactions. The stacked dimer is a complex building unit in both polymorphic structures. Further analysis showed that the monoclinic structure is layered while the triclinic one is columnar. The two polymorphic structures also differ in their biological activity (antidiuretic and analgesic). The monoclinic polymorph possesses very high biological activity while the triclinic polymorph is almost inactive. The polymorphic transition of the biologically active metastable monoclinic structure into the inactive stable triclinic one within four weeks of grinding is caused by orientational factors rather than conformational ones and is accompanied by a change in the redistribution of interaction energies in the crystal from anisotropic to more isotropic. Thus, a slow polymorphic transition after grinding results in a loss of the biological activity.

Biological properties of two enantiomorphic forms of N-(2,6-dimethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, a structural analogue of piroxicam.

The title benzothiazine-3-carboxamide, C17H16N2O4S, crystallized in two enantiomorphic crystal forms with the space groups P32 and P31 despite the absence of a classic stereogenic atom. The molecular structures are mirror images of each other. Only one sulfonyl O atom takes part in intramolecular hydrogen bonding as a proton acceptor and this atom is different in the two enantiomorphic structures. As a result, the S atom becomes a pseudo-stereogenic centre. This fact is worth taking into account due to the different biological activities of the enantiomorphic forms. One form possesses a high analgesic activity, while the other form revealed a high anti-inflammatory activity.

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

Continuing the search for new potential analgesics among the derivatives of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid, the possibility of obtaining its esters by the alkylation of the corresponding sodium salt with iodoethane in dimethyl sulfoxide (DMSO) at room temperature was studied. It was found that under such conditions, together with the oxygen atom of the carboxyl group, a heteroatom of nitrogen is also alkylated. Therefore, the product of the reaction studied is a mixture of ethyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate (major) and its 1-ethyl-substituted analog (minor). A simple but very effective method of preparative separation of these compounds was proposed. Moreover, the heterogeneous crystallization from ethanol was revealed to result in a monoclinic polymorphic form of ethyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate, while the homogeneous crystallization results in its orthorhombic form. The molecular and crystal structures of both forms were confirmed by X-ray diffraction analysis, and the phase purity by powder diffraction study. The pharmacological tests carried out on the model of a carrageenan edema showed that the screening dose of 20 mg/kg of 1-ethyl-substituted ester and the orthorhombic form of its analog unsubstituted in position 1 exhibited weak anti-inflammatory and moderate analgesic effects. At the same time, the monoclinic form of ethyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate appeared to be both a powerful analgesic and an anti-inflammatory agent that exceeded Piroxicam and Meloxicam in the same doses by these indicators. A detailed comparative analysis of the molecular and crystal structures of two polymorphic forms of ethyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate was carried out using quantum chemical calculations of the energies of pairwise interactions between molecules. An explanation of the essential differences of their biological properties based on this was offered.