The synthesis and biological properties of hydroxy-(alkoxy)substituted anilides of 4-hydroxy-2,2-dioxo-1h-2λ6,1-benzothiazine-3-carboxylic acids

I. V. Ukrainets, L. A. Petrushova, O. V. Gorokhova, L. V. Sidorenko


Continuing the search for new biologically active substances of 2,1-benzothiazines a series of the corresponding anilides of 1-R-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acids has been synthesized by the reaction of alkyl-1-R-4- hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates and the equimolar quantities of hydroxy- and alkoxy-substituted anilines. Their structure has been confi rmed by the data of elemental analysis, NMR 1H spectroscopy (1H and 13C), as well as mass spectrometry. All compounds obtained were subjected to pharmacological screening to identify their analgesic properties. Testing was carried out in non-pedigree male rats using the standard model of the thermal tail-fl ick (tail immersion test) in parallel and in comparison with the structurally related drugs – Meloxicam and Piroxicam. Among the substances studied the potent analgesics have been found. When administered orally in the dose of 20 mg/kg they several times exceed the reference medicines in their analgesic effect and are of interest for the profound research. The study of the effect of the compounds synthesized on the urinary function of the kidneys has shown that in this case transition from quinoline analogues to 2,1-benzothiazine ones is accompanied by some decrease in diuretic properties although some compounds increase diuresis at the level of hydrochlorothiazide in a much lower dose.


anilides; 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides; synthesis; analgesic activity; diuretic action


Kleemann A., Engel J., Kutscher B., Reichert D. Pharmaceutical Substances: Syntheses, Patents, Applications of the most relevant APIs, 5-th ed. Stuttgart, Thieme, 2008.

Mashkovskii M. D. Drugs. Moscow, “Novaya Volna”: Publisher Umerenkov, 2009, p.160.

Lam F. W., Rumbaut R. E. Blood, 2015, Vol. 126, No.15, pp.1738-1739. doi: 10.1182/blood-2015-07-659516.

Roberto G., Simonetti M., Piccinni C., Lora Aprile P., Cricelli I., Fanelli A., Cricelli C., Lapi F. Toxicology Letters, 2015, Vol. 241, pp.133-142. doi: 10.1016/j.toxlet.2015.11.008.

Chen Y. G., Lin C. L., Dai M. S., Chang P. Y., Chen J. H., Huang T. C., Wu Y. Y., Kao C. H. Medicine (Baltimore), 2015, Vol. 94, No.46, p. e2040. doi: 10.1097/MD.0000000000002040.

Jain S. S., Green S., Rose M. Anaesthesia and Intensive Care, 2015, Vol. 43, No.6, pp.779-781.

Aminoshariae A., Khan A. Journal of Endodontics, 2015, Vol. 41, No.5, pp.588-593. doi: 10.1016/j.joen.2015.01.024.

King J. P., McCarthy D. M., Serper M., Jacobson K. L., Mullen R. J., Parker R. M., Wolf M. S. Journal of Medical Toxicology: Of™icial Journal of the American College of Medical Toxicology, 2015, Vol. 11, No.4, pp.410-414. doi: 10.1007/s13181-015-0464-1.

Star K., Choonara I. Archives of Disease in Childhood, 2015, Vol. 100, No.1, pp.73-74. doi: 10.1136/archdischild-2014-307431.

Kissin I. Anesthesia and Analgesia, 2010, Vol. 110, No.3, pp.780-789. doi: 10.1213/ANE.0b013e3181cde882.

Correll D. J., Vlassakov K. V., Kissin I. Journal of Pain Research, 2014, Vol. 7, pp.199-210. doi: 10.2147/JPR.S60842.

Kissin I. Journal of Pain Research, 2014, Vol. 7, pp.505-514. doi: 10.2147/JPR.S67479.

Joselyn A., Bhalla T., McKee C., Pepper V., Diefenbach K., Michalsky M., Tobias J. D. Saudi Journal of Anaesthesia, 2015, Vol. 9, No.4, pp.442-445. doi: 10.4103/1658-354X.159472.

Ziolkowski K., Kaufman J., Jambunathan J., Berge J., Menet L., Chappy S., Messerschmidt M. AORN Journal, 2015, Vol. 102, No.5, pp.515.e1-515.e10. doi: 10.1016/j.aorn.2015.09.011.

Friedman B. W., Dym A. A., Davitt M., Holden L., Solorzano C., Esses D., Bijur P. E., Gallagher E. J. JAMA, 2015, Vol. 314, No.15, pp.1572-1580. doi: 10.1001/jama.2015.13043.

Chang A. K., Bijur P. E., Holden L., Gallagher E. J. Academic Emergency Medicine: Of™icial Jjournal of the Society for Academic Emergency Medicine, 2015, Vol. 22, No.11, pp.1254-1260. doi: 10.1111/acem.12813.

Berthelot J. M., Darrieutort-La™itte C., Le Goff B., Maugars Y. Joint, Bone, Spine: Revue du Rhumatisme, 2015, Vol. 82, No.6, pp.397-401. doi: 10.1016/j.jbspin.2015.08.003.

Hoban B., Larance B., Gisev N., Nielsen S., Cohen M., Bruno R., Shand F., Lintzeris N., Hall W., Farrell M., Degenhardt L. International Journal of Clinical Practice, 2015, Vol. 69, No.11, pp.1366-1376. doi: 10.1111/ijcp.12716.

Innaurato G., Piguet V., Simonet M. L. Revue Médicale Suisse, 2015, Vol. 11, No.480, pp.1380, 1382-1384.

Campagne D. D., Young M., Wheeler J., Stroh G. The Western Journal of Emergency Medicine, 2015, Vol. 16, No.5, pp.665-670. doi: 10.5811/westjem.2015.6.25618.

Benitez M. E., Roush J. K., McMurphy R., KuKanich B., Legallet C. American Journal of Veterinary Research, 2015, Vol. 76, No.9, pp.755-762. doi: 10.2460/ajvr.76.9.755.

Ukrainets I. V., Petrushova L. A., Dzyubenko S. P., Sim G. Chemistry of Heterocyclic Compounds, 2014, Vol. 50, No.1, pp.103-110. doi: 10.1007/s10593-014-1452-0.

Ukrainets I. V., Petrushova L. A., Dzyubenko S. P., Liu Yangyang. Chemistry of Heterocyclic Compounds, 2014, Vol. 50, No.4, pp.564-572. doi: 10.1007/s10593-014-1508-1.

Vogel H. G. Drug Discovery and Evaluation: Pharmacological Assays. Berlin, Springer; 2008, pp.1011-1013.

Ukrainets I. V., Mospanova E. V., Bereznyakova N. L., Naboka O. I. Chemistry of Heterocyclic Compounds, 2007, Vol. 43, No.12, pp.1532-1539.

Sernov L. N., Gatsura V. V. Elementy eksperimentalnoi farmakologii (Elements of Experimental Pharmacology). Moscow, Nauka, 2000, pp.103-104.

Ukrainets I. V., Petrushova L. A., Dzyubenko S. P. Chemistry of Heterocyclic Compounds, 2013, Vol. 49, No.9, pp.1378-1383.

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