Polymorphism and the analgesic activity of N-(3-pyridylmethyl)-4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

Украинец, И. В.; Mospanova, O. V.; Bereznyakova, N. L.; Davydenko, O. O.

doi:10.24959/ophcj.15.832

Cited by 4 publications

(7 citation statements)

References 14 publications

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“…Noteworthy is the fact that meta-isomer 5 is the most potent analgesic and anti-inflammatory agent in the series of unsubstituted pyridylamides 4a, 5 and 6. The presence of 3-substituent of the pyridine nucleus has been repeatedly noted by us earlier as a factor contributing to the enhancement of analgesic properties [3,[42][43][44][45]. However, the modification of N-(pyridin-3-yl)-amide 5 in N,N-dimethylformamide monosolvate 5a causes a considerable decline in the biological activity probably due to a significant conformational rearrangement of the molecule because of solvation.…”

Section: Evaluation Of the Analgesic And Anti-inflammatory Activitymentioning

confidence: 80%

Synthesis and Regularities of the Structure–Activity Relationship in a Series of N-Pyridyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides

et al. 2019

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According to our quantum and chemical calculations 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid imidazolide is theoretically almost as reactive as its 2-carbonyl analog, and it forms the corresponding N-pyridyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides with many aminopyridines. However, in practice, the sulfo group introduces significant changes at times and prevents the acylation of sterically hindered amines. One of these products was 2-amino-6-methylpyridine. Thus, it has been concluded that aminopyridines interact with imidazolide in aromatic form where the target for the initial electrophilic attack is the ring nitrogen. To confirm the structure of all substances synthesized, 1H-NMR spectroscopy and X-ray diffraction analysis were used. From X-ray diffraction data it follows that in the crystalline phase the carbonyl and sulfo group may occupy different positions with respect to the plane of the benzothiazine bicycle: this position may be unilateral, typical for 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides, versatile, and not yet encountered in compounds of this type. A comparison of these data with the results of the pharmacological screening conducted on the standard model of carrageenan inflammation showed that the N-pyridylamides of the first group demonstrated a direct dependence of their analgesic and anti-inflammatory activity on the mutual arrangement of the planes of the benzothiazine and pyridine fragments. The new molecular conformation of the benzothiazine nucleus provides a sufficiently high level of analgesic (but not anti-inflammatory) properties in all N-pyridylamides of the second group with an extremely weak dependence on the spatial arrangement of the pyridine cycle. All substances presented this article proved themselves in varying degrees as analgesics and antiphlogistics. Moreover, two of them—N-(5-methylpyridin-2-yl)- and N-(pyridin-3-yl)-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides—exceeded the most effective drug of oxicam type Lornoxicam by these indicators.

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Section: Evaluation Of the Analgesic And Anti-inflammatory Activitymentioning

confidence: 80%

Synthesis and Regularities of the Structure–Activity Relationship in a Series of N-Pyridyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides

et al. 2019

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“…There is a paradoxical situation-with a very extensive amount of information about the physical and chemical properties and the structure of various crystal modifications of many medicinal substances (see, for example, the Cambridge Crystallographic Data Centre [39]) it is extremely difficult, if not impossible, to find information about their biological activity. In the open press such information gets only in those rare cases when there are legal disputes between developers of different polymorphic forms of commercially successful pharmaceuticals [9], or when a drug that had already entered the market suddenly undergoes spontaneous structural transformation into a new crystal modification-more stable, but much less active and even dangerous [8][9][10]40]. It should be emphasized that we are talking only about real pharmaceuticals that have official permission for medical use.…”

Section: Evaluation Of the Biological Propertiesmentioning

confidence: 99%

Crystal Habits and Biological Properties of N-(4-Trifluoromethylphenyl)-4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxamide

et al. 2019

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In order to study polymorphic modifications of N-(4-trifluoromethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, which is of interest as a promising analgesic, its three colorless crystal forms with different habitus have been obtained: sticks of ethyl acetate, plates of meta-xylene and blocks of ortho-xylene. However, the X-ray diffraction analysis has shown that all the forms studied have the identical molecular and crystal structure in spite of such significant differences in appearance. Moreover, pharmacological tests have revealed significant differences in the analgesic activity in these samples (a total of five experimental models were used: “acetic-acid-induced writhing”, “hot plate”, “thermal irritation of the tail tip” (tail-flick), “tail electric stimulation” and “neuropathic pain”), acute toxicity and the ability to cause gastric damage. As a result, only the plate crystal form of N-(4-trifluoromethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide is recommended for further studies. Thus, it has been proven that the habitus of crystals is an important characteristic of the drug substance and is able to have a noticeable effect on its biological properties. Changes in habitus should be considered as a guide to the mandatory verification of at least the basic pharmacological parameters of the new form regardless of whether the molecular and crystal structure changes.

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“…. C (9) is 2.51 Å compared to the van der Waals radii sum [41] 2.87 Å) caused the rotation of the substituent relatively the thiazine cycle (the C (7) −C (8) −C (9) −O (1) torsion angle was 67.5(2) • ) and elongation of the C (7) −C (8) and C (8) −C (9) bonds (1.349(2) Å and 1.498(2) Å) compared to their mean values [42] 1.326 Å and 1.455 Å, respectively. In addition the repulsion between the methyl group and benzene ring was observed (the shortened intramolecular contacts were: H (15a) .…”

Section: The Molecular and Crystal Structure Studymentioning

confidence: 99%

“…The crystals of thiophen-2-ylmethylamide 2g (C 15 H 14 N 2 O 3 S 2 ) were monoclinic, white with yellowish. At 20 • C: a 12.0760 (7), b 9.3641 (5), c 14.9258(9) Å; β 111.304 (7) • ; V 1572.5(2) Å 3 , Z 4, space group P2 1 /c, d calc 1.413 g/cm 3 , µ(MoK α ) 0.352 mm −1 , F(000) 696. The unit cell parameters and intensities of 6539 reflections (2762 independent reflections, R int = 0.040) were measured on an Xcalibur-3 diffractometer (Oxford Diffraction Limited) using MoK α radiation, a CCD detector, graphite monochromator, and ω-scanning to 2θ max 50 • .…”

Section: Introductionmentioning

confidence: 99%

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Molecular Conformations and Biological Activity of N-Hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides

et al. 2018

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The analysis of our previous studies on the search for synthetic analgesics among N-R-amides of bicyclic hetaryl-3-carboxylic acids has been performed; on its basis N-hetaryl(aryl)-alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides have been selected as new study objects. The “one pot synthesis” of these compounds, which is simple to perform and at the same time highly effective, has been offered. The method consists in the initial reaction of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid and N,N′-carbonyldiimidazole in anhydrous N,N-dimethylformamide with the subsequent amidation of imidazolide formed with hetarylalkyl- or benzylamines in the same solvent. The peculiarities of 1H- and 13C-NMR spectra of the substances obtained, as well as their electrospray ionization liquid chromato-mass spectra are discussed. According to the results of the pharmacological tests carried out on the model of carrageenan inflammation it has been found that all without exception N-hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides demonstrate the statistically significant analgesic and anti-inflammatory properties. Among the substances presented in this article analgesics and antiphlogistics, which increase the pain threshold and suppress the inflammatory response more effectively than Lornoxicam and Diclofenac in the same doses, have been identified. The molecular and crystal structures of a large group of the substances synthesized have been studied by X-ray diffraction analysis. Comparison of these data with the results of biological tests has revealed the fact of excellent correlation between the molecular conformations of N-hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides recorded in the crystal and the potency of their analgesic effect. N-Thiophen-2-ylmethyl- and N-4-methoxybenzyl-amides of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid has shown a high analgesic and anti-inflammatory effect, therefore, they deserve more careful research.

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Polymorphism and the analgesic activity of N-(3-pyridylmethyl)-4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

Cited by 4 publications

References 14 publications

Synthesis and Regularities of the Structure–Activity Relationship in a Series of N-Pyridyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides

Synthesis and Regularities of the Structure–Activity Relationship in a Series of N-Pyridyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides

Crystal Habits and Biological Properties of N-(4-Trifluoromethylphenyl)-4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxamide

Molecular Conformations and Biological Activity of N-Hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides

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