Racemic and unusual enantiomeric crystal forms of <i>N</i>-cycloalkyl-4-methyl-2,2-dioxo-1<i>H</i>-2λ⁶,1-benzothiazine-3-carboxamides and their biological activity

Abstract The absence of a stereogenic center in N -cycloalkyl-4-methyl-2,2-dioxo-1 H -2λ 6 ,1-benzothiazine-3-carboxamides (cycloalkyl moiety is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl) does not interfere with their ability to be crystallized from the ethanol solution into a centrosymmetric or a non-centrosymmetric space group. The non-centrosymmetric crystals containing opposite conformer of a molecule were obtained using aqueous acetic acid as another solvent. Pairs of enantiomorphic crystals have the same crystal shape and unit cell parameters and can only be recognized by X-ray diffraction study due to anomalous dispersion. The formation of such unusual enantiomers may be caused by the ability of the sulfur atom to become a stereogenic center due to the different participation of the oxygen atoms of the sulfonyl group in hydrogen bonds formation. Similar to classical polymorphic modifications, the enantiomorphic crystals may differ in their biological activity. Analgesic activity does not depend on the type of conformation of 1,2-benzothiazine, while the diuretic effect is much stronger in the case of the crystals containing one type of conformer. This property of 1,2-benzothiazines is to be expected of great importance in future drug developments.