Design, Synthesis and Biological Evaluation of Novel Promising Analgesics.

Introduction: An analysis of the literature on the painkillers long used in traditional medicine, which are isolated from plant materials, has shown that many of them are alkylamides of various carboxylic acids. This fact served as the basis for the study of a large group of N-alkyl-4- methyl-2,2-dioxo-1H-2λ,1-benzothiazine-3-carboxamides as potential new analgesics. The objects of the study were synthesized in the traditional way involving the initial conversion of 4-methyl- 2,2-dioxo-1H-2λ,1- benzothiazine-3-carboxylic acid to imidazolide, in which imidazolide was used as an acylating agent.

1-Allyl-4-hydroxy-2,2-dioxo-N-(4-methoxyphenyl)-1H-2λ,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)-1-2λ,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..

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

The title benzothiazine-3-carboxamide, CHNOS, crystallized in two enantiomorphic crystal forms with the space groups P3 and P3 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.

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

Continuing the search for new potential analgesics among the derivatives of 4-methyl-2,2-dioxo-1-2λ⁶,1-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-1-2λ⁶,1-benzothiazine-3-carboxylate (major) and its 1-ethyl-substituted analog (minor).

N-Aryl-7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido-[3,2,1-ij]quinoline-6-carboxamides. The Synthesis and Effects on Urinary Output.

Continuing a targeted search for new leading structures with diuretic action among tricyclic derivatives of hydroxyquinolines, which are of interest as potential inhibitors of aldosterone synthase, the synthesis of a series of the corresponding pyrido[3,2,1-]quinoline-6-carboxanilides was carried out by amidation of ethyl-7-hydroxy-5-oxo-2,3-dihydro-1,5-pyrido[3,2,1-]quinoline-6-carboxylate with aniline, aminophenols and -alkylsubstituted analogs with high yields and purity. The optimal conditions of this reaction are proposed; they make it possible to prevent partial destruction of the original heterocyclic ester and thereby avoid formation of specific impurities of 7-hydroxy-2,3-dihydro-1,5-pyrido[3,2,1-]quinolin-5-one. To confirm the structure of all substances obtained, elemental analysis, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry were used.

4-Methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic Acid. Peculiarities of Preparation, Structure, and Biological Properties.

In order to determine the regularities of the structure-analgesic activity relationship, the peculiarities of obtaining, the spatial structure, and biological properties of 4-methyl-2,2-dioxo-1-2λ⁶,1-benzothiazine-3-carboxylic acid and some of its derivatives have been studied. Using nuclear magnetic resonance (NMR) spectroscopy and X-ray diffraction analysis, it has been proven that varying the reaction conditions using alkaline hydrolysis of methyl 4-methyl-2,2-dioxo-1-2λ⁶,1-benzothiazine-3-carboxylate makes it possible to successfully synthesize a monohydrate of the target acid, its sodium salt, or 4-methyl-2,2-dioxo-1-2λ⁶,1-benzothiazine. The derivatographic study of the thermal stability of 4-methyl-2,2-dioxo-1-2λ⁶,1-benzothiazine-3-carboxylic acid monohydrate has been carried out; based on this study, the optimal conditions completely eliminating the possibility of unwanted decomposition have been proposed for obtaining its anhydrous form.

The Study of Structure-Analgesic Activity Relationships in a Series of 4-Hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic Acid Toluidides and Xylidides.

In continuing the search for new analgesics among derivatives of 2,1-benzothiazines, a series of corresponding toluidides and xylidides of 4-hydroxy-2,2-dioxo-1-2λ⁶,1-benzothiazine-3-carboxylic acid has been synthesized by the reaction of ethyl 4-hydroxy-2,2-dioxo-1-2λ⁶,1-benzothiazine-3-carboxylate with equimolar amounts of mono- and dimethyl-substituted anilides in boiling dry xylene. Their structure has been confirmed by the data of elemental analysis, nuclear magnetic resonance (NMR) spectroscopy (¹Н and С), as well as mass spectrometry. All compounds obtained were subjected to pharmacological screening to identify their analgesic properties.

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.

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.