The Effective Synthesis of N-(Arylalkyl)-1-R-4-hydroxy-2,2-dioxo- 1H-2λ(6),1-benzothiazine-3-carboxamides as Promising Analgesics of a New Chemical Class

Igor V Ukrainets; Lidiya A Petrushova; Sergiy P Dzyubenko; Galina Sim; Lina A Grinevich

doi:10.3797/scipharm.1506-04

The Effective Synthesis of N-(Arylalkyl)-1-R-4-hydroxy-2,2-dioxo- 1H-2λ(6),1-benzothiazine-3-carboxamides as Promising Analgesics of a New Chemical Class

Sci Pharm. 2015 Jul 17;83(4):549-66. doi: 10.3797/scipharm.1506-04. Print 2015 Oct-Dec.

Authors

Igor V Ukrainets¹, Lidiya A Petrushova¹, Sergiy P Dzyubenko², Galina Sim³, Lina A Grinevich¹

Affiliations

¹ Department of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska St., 61002, Kharkiv, Ukraine.
² Department of Pharmaceutical Chemistry, N. I. Pirogov Vinnitsa National Medical University, 56 Pirogov St., Vinnitsa, 21018, Ukraine.
³ Department of Pharmaceutical Chemistry, Far Eastern State Medical University, 35 Murav'eva-Amurskogo St., 680000, Khabarovsk, Russia.

Abstract

A new, effective preparative method has been proposed and the synthesis of a series of N-(arylalkyl)-1-R-4-hydroxy-2,2-dioxo-1H-2λ(6),1-benzothiazine-3-car-boxamides has been carried out. It has been shown that amidation of alkyl 1-R-4-hydroxy-2,2-dioxo-1H-2λ(6),1-benzothiazine-3-carboxylates with arylalkyl-amines in boiling xylene proceeds with good yield and purity to the corresponding N-(arylalkyl)-amides. However, the presence of water in the reaction mixture has been shown to cause the formation of specific impurities: N-(arylalkyl)-1-R-2,2-dioxo-1H-2λ(6),1-benzothiazin-4-amines. According to the results of the pharmacological studies, powerful analgesics have been found among the substances synthesized.

Keywords: 2,1-Benzothiazines; 4-Hydroxy-2,2-dioxo-1,2-dihydro-2λ6,1-benzothiazine-3-carboxamides; Amidation; Analgesia; Arylalkylamines; Pain syndrome; Synthesis.