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..

Methyl 5-chloro-4-hy-droxy-2,2-dioxo-1-2λ,1-benzo-thia-zine-3-carboxyl-ate: structure and Hirshfeld surface analysis.

The title compound, CHClNOS, which has potential analgesic activity, crystallizes in space group 2/. The benzo-thia-zine ring system adopts an inter-mediate form between sofa and twist-boat conformations. The coplanarity of the ester substituent to the bicyclic fragment is stabilized by an O-H⋯O intra-molecular hydrogen bond.

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.

Polymorphic modifications of a 1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide possessing strong diuretic properties.

6-Hydroxy-N-(4-methoxyphenyl)-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide, CHNO, possesses strong diuretic properties and can be used as a new hypertension remedy. Two polymorphic modifications of this compound have been found, namely the triclinic polymorph (space group P-1), with one molecule in the asymmetric unit, and the monoclinic polymorph (space group P2/n), with two molecules in asymmetric unit. An analysis of the pairwise interaction energies between the molecules in the crystal phase revealed differences in the crystal packing.

Metabolomics in Vitamin Status Assessment.

The issue of vitamin deficiency persists to be a major health issue worldwide despite the advancements in medicine. At the same time, the effect of marginal vitamin deficiency status on physiological processes is proven. However, general methods such as immune-enzyme and fluorescence analysis, microbiological assays, for example, have limitations in vitamin status assessment and are not able to reliably reflect personal vitamin demand.

The Study of the Structure-Diuretic Activity Relationship in a Series of New -(Arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1-pyrrolo-[3,2,1-]quinoline-5-carboxamides.

In accordance with the principles of "me-too" technique, the preparative method for obtaining has been proposed, and the synthesis of a large series of new -(arylalkyl)-6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1-pyrrolo[3,2,1-]quinoline-5-carboxamides as structurally close analogs of tricyclic pyrrolo- and pyridoquinoline diuretics has been carried out. All target compounds were obtained with high yields and purity by amidation of ethyl ester of the corresponding 2-methyl-pyrroloquinoline-5-carboxylic acid with arylalkylamines in boiling ethanol. Their structure was confirmed by the data of elemental analysis, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and polarimetry.

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.

Synthesis, Structure, and Analgesic Properties of Halogen-Substituted 4-Hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxanilides.

As potential new analgesics, the corresponding 4-hydroxy-2,2-dioxo-1-2λ⁶,1-benzothiazine-3-carboxanilides have been obtained by amidation of ethyl 4-hydroxy-2,2-dioxo-1-2λ⁶,1-benzothiazine-3-carboxylate with aniline and its halogenated analogsin boiling dry xylene. The peculiarities of the mass and nuclear magnetic resonance (¹Н and С) spectra of the synthesized compounds are discussed. Using X-ray diffraction analysis, the ability of the compounds to form stable solvates with ,-dimethylformamide has been shown on the example of 4-bromo-substituted derivative.

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.

New Synthesis, Structure and Analgesic Properties of Methyl 1-R-4-Methyl-2,2-Dioxo-1H-2λ⁶,1-Benzothiazine-3-Carboxylates.

According to the principles of the methodology of bioisosteric replacements a series of methyl 1-R-4-methyl-2,2-dioxo-1-2λ⁶,1-benzothiazine-3-carboxylates has been obtained as potential analgesics. In addition, a fundamentally new strategy for the synthesis of compounds of this chemical class involving the introduction of -alkyl substituent at the final stage in 2,1-benzothiazine nucleus already formed has been proposed. Using nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and X-ray diffraction analysis it has been proven that in the DMSO/K₂CO₃ system the reaction of methyl 4-methyl-2,2-dioxo-1-2λ⁶,1-benzothiazine-3-carboxylate and alkyl halides leads to formation of -substituted derivatives with good yields regardless of the structure of the alkylating agent.

Synthesis, Spatial Structure and Analgesic Activity of Sodium 3-Benzylaminocarbonyl-1-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazin-4-olate Solvates.

In order to obtain and then test pharmocologically any possible conformers of the new feasible analgesic benzyl-4-hydroxy-1-methyl-2,2-dioxo-1-2λ⁶,1-benzothiazine-3-carboxamide, its 4--sodium salt was synthesized using two methods. X-ray diffraction study made possible to determine that, depending on the chosen synthesis conditions, the above-mentioned compound forms either monosolvate with methanol or monohydrate, where organic anion exists in the form of three different conformers. Pharmacological testing of the two known pseudo-enantiomeric forms of the original benzylamide and of the two solvates of its sodium salt was performed simultaneously under the same conditions and in equimolar doses.

Two pseudo-enantiomeric forms of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ(6),1-benzothiazine-3-carboxamide and their analgesic properties.

The fact that molecular crystals exist as different polymorphic modifications and the identification of as many polymorphs as possible are important considerations for the pharmaceutic industry. The molecule of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ(6),1-benzothiazine-3-carboxamide, C17H16N2O4S, does not contain a stereogenic atom, but intramolecular hydrogen-bonding interactions engender enantiomeric chiral conformations as a labile racemic mixture. The title compound crystallized in a solvent-dependent single chiral conformation within one of two conformationally polymorphic P212121 orthorhombic chiral crystals (denoted forms A and B).

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.

(R,S)-2'-Amino-6'-methyl-2,5',5'-trioxo-6'H-spiro-[indoline-3,4'-pyrano[3,2-c][2,1]benzo-thia-zine]-3'-carbo-nitrile di-methyl-formamide monosolvate.

The title solvate, C20H14N4O4S·C3H7NO, comprises a stereogenic centre but the centrosymmetric space group causes the presence of the racemate in the crystal. The spiro-joined fragments are almost orthogonal, with a dihedral angle of 86.8 (2)° between the mean planes of the pyrane ring and the dihydroindolone ring system.

Methyl 1-allyl-4-hy-droxy-2,2-dioxo-1H-2λ(6),1-benzo-thia-zine-3-carboxyl-ate.

There are two independent mol-ecules in the asymmetric unit of the title compound, C13H13NO5S, in both of which the ester substituent is nearly coplanar [C-C-C-O torsion angles = 2.7 (7) and -0.8 (7)°] with the planar fragment of the bicycle due to the formation of a strong O-H⋯O intra-molecular hydrogen bond.

6-Hy-droxy-1,2-dihydro-4H-pyrrolo-[3,2,1-ij]quinolin-4-one.

The mol-ecule of the title compound, C11H9NO2, is essentially planar [r.m.s.

6-Eth-oxy-carbonyl-5,7-dihy-droxy-2,3-dihydro-1H-pyrido[3,2,1-ij]quinolinium tribromide.

In the title salt, C15H16NO4(+.)Br3(-), classical intra-molecular O-H⋯O hydrogen bonds are found, which results in the co-planarity of the ester substituents with the quinolinium residue [C-C-C-O torsion angle = 1.0 (10)°].

(RS)-2-Oxo-4-(1-phenyl-ethyl-amino)-1,2-dihydro-quinoline-3-carb-oxy-lic acid.

The mol-ecular structure of the title compound, C(18)H(16)N(2)O(3), does not differ in the crystals of the racemic mixture, (I), and the pure enantiomer, (II). In their crystal structures, inversion dimers occur in (I) via N-H⋯O hydrogen bonds and infinite chains in (II) also via N-H⋯O hydrogen bonds.

Methyl 2-(4-hy-droxy-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl)acetate.

In the title compound, C(13)H(13)NO(4), the bicyclic quinolone fragment and the ester group are approximately orthogonal, making a dihedral angle of 83.3 (2)° and an intramolecular C-H⋯O interaction occurs. In the crystal, inter-molecular O-H⋯O hydrogen bonding generates a zigzag chain along the c axis.

Ethyl 2-(4-hydr-oxy-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl)acetate.

In the title compound, C(14)H(15)NO(4), the bicyclic fragment and the ester group form a dihedral angle of 86.7 (2)°. Inter-molecular O-H⋯O and C-H⋯O hydrogen bonding connects mol-ecules into a helix along the crystallographic b axis.

Ethyl 5-[(1H-benzoimidazol-2-yl)amino-carbon-yl]-4-hydr-oxy-2-methyl-6-oxo-1-propyl-1,6-dihydro-pyridine-3-carboxyl-ate-ethanol-methanol (4/2/1).

The asymmetric unit of the title compound, 4C(20)H(22)N(4)O(5)·2C(2)H(6)O·CH(4)O, contains two pyridine-3-carboxyl-ate mol-ecules, one ethanol mol-ecule and one methanol mol-ecule disordered about in a centre of symmetry. The pyridinone ring, the carbamide group and the bicyclic fragment in both independent mol-ecules are planar within 0.03 Å due to the formation of intra-molecular O-H⋯O and N-H⋯O hydrogen bonds.

2-Bromo-methyl-N-isopropyl-7,8-dimeth-oxy-1,2-dihydro-1,3-oxazolo[3,2-a]quinoline-4-carboxamide.

In the title compound, C(18)H(21)BrN(2)O(5), conjugation between the π-donating N-C-O fragment and the π-withdrawing carbonyl group results in considerable redistribution of the electron density within the dihydropyridinol ring. This effect is also promoted by the formation of an intra-molecular N-H⋯O hydrogen bond. The five-membered heterocycle is disordered over two envelope conformations in a 0.