Crystal structure of 7-chloro-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide monohydrate, C10H11CIN2O3S · H2O

Dupont, L.; Boverie, S.; Pirotte, B.; Tullio, P. de

doi:10.1524/ncrs.2005.220.14.595

Cited by 1 publication

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“…In addition, the crystallographic data obtained with 4 , 10c , and 12c indicated that the three compounds adopted the 4 H -tautomeric form in the solid state. Indeed, the bond length between C(3) and N(4) was always greater than the bond length between N(2) and C(3) [C(3)−N(4) for 4 , 10c , and 12c = 1.352 Å, 1.339 Å, and 1.360 Å, respectively; N(2)−C(3) for 4 , 10c , and 12c = 1.330 Å, 1.289 Å, and 1.310 Å, respectively], − assuming that the double bond in the thiadiazine ring is located at N(2)−C(3) rather than at C(3)−N(4). Therefore, the hydrogen atom must be found at the N(4) position (4 H -tautomerism).…”

Section: Resultsmentioning

confidence: 92%

“…All calculations have been performed with the Gaussian03 program. Starting from the crystal structure of 10c , 12c , and 4 , a conformational scan was performed by varying both so-called dihedral angles T1 and T2 from 0 to 360°. In the case of 15c , a QM-minimized structure was first calculated as a starting point, because no crystal structure was available.…”

Section: Methodsmentioning

confidence: 99%

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Impact of the Nature of the Substituent at the 3-Position of 4H-1,2,4-Benzothiadiazine 1,1-Dioxides on Their Opening Activity toward ATP-Sensitive Potassium Channels

et al. 2011

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The synthesis of diversely substituted 3-isopropoxy-, 3-isopropylsulfanyl-, 3-isopropylsulfinyl-, and 3-isobutyl-4H-1,2,4-benzothiadiazine 1,1-dioxides is described. Their activity on pancreatic β-cells (inhibitory effect on the insulin releasing process) and on vascular and uterine smooth muscle tissues (myorelaxant effects) was compared to that of previously reported K(ATP) channel openers belonging to 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides. The present study aimed at evaluating the impact on biological activity of the isosteric replacement of the NH group of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides by a O, S, S(═O), or CH(2) group. By comparing compounds bearing identical substituents, the following rank order of potency on pancreatic β-cells was observed: 3-isopropylamino > 3-isobutyl > 3-isopropoxy > 3-isopropylsulfanyl > 3-isopropylsulfinyl-substituted 4H-1,2,4-benzothiadiazine 1,1-dioxides (NH > CH(2) > O > S > S(═O)). A molecular modeling study revealed that 3-isopropoxy-, 3-isopropylsulfanyl-, and 3-isopropylamino-substituted compounds adopted a similar low-energy conformation (preferred orientation of the isopropyl chain). Moreover, no direct relationship was detected between the conformational freedom of the different classes of benzothiadiazines (from the most to the lowest conformationally constrained compounds: NH > O > S > CH(2)) and their biological activity on insulin-secreting cells. Therefore, the present study confirmed the critical role of the NH group at the 3-position for the establishment of a strong hydrogen bond responsible for optimal activity expressed by 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides on insulin-secreting cells. Radioisotopic and fluorimetric experiments conducted with 7-chloro-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 10c demonstrated that such a compound, bearing a short branched O-alkyl group instead of the NH-alkyl group at the 3-position, also behaved as a specific K(ATP) channel opener. Lastly, the present work further identified 3-(alkyl/aralkyl)sulfanyl-substituted 7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides as a class of promising myorelaxant drugs acting on uterine smooth muscles, at least in part, through the activation of K(ATP) channels.

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