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A series of close analogs of 4-hydroxy-6,7-dimethoxy-2-oxo-N-(pyridin-3-ylmethyl)-1,2-dihydroquinoline-3-carboxamide modified in the benzene moiety of the quinolone nucleus were synthesized to identify the structural fragments determining their analgesic effect. Results of pharmacological tests found that these chemical changes had a relatively weak influence on the analgesic activity of the tested compounds, leading to the conclusion that the modified fragment interacted insignificantly with the biological targets.

With the aim of establishing a structure-analgesic activity relationship, a series of picolylamides of 2-hydroxy-4-oxo-4H-pyrido[1,2-a]-pyrimidine-3-carboxylic acids were synthesized. The characteristics of the spatial structure of this group of substances were assessed. The results of pharmacological studies identified compounds in the study series with marked analgesic properties. However, it was noted that the transition from 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides to the structurally similar pyrido[1,2-a]pyrimidine derivatives was generally accompanied by some decrease in analgesic activity.

Objectives Treatment of diseaes of the biliary system is one of the urgent problems of modern medicine. Materials and methods An original pharmaceutical drug "Lavaflam" in the form of combined tablets, which includes a composition of herbal components flamin (0.05 g) and lavender oil (0.02 g), was proposed for the complex treatment of diseases of the biliary system. Flamin is phytomedicine from the immortelle flowers [Helichrysum arenarium (L.) Moench, Asteraceae], which contains a complex of active substances from the flavonoids group (salipurposide, isosalipurposide, kaempferol, luteolin). It is applied as a choleretic and an anti-inflammatory agent in cholecystitis, cholangitis, and biliary dyskinesia. Tablets were prepared by pressing for separate granulation technology. Results The lavender oil granulate was prepared using the solid phase method, and β-cyclodextrin was used as an excipient substance. The flamin granulate was prepared by mixing with the spherical-shaped filler mannitol PARTECK M 200. On the basis of previous studies, the excipients of the designed composition tablet "Lavaflam" were β-cyclodextrin (0.27 g), mannitol PARTECK M 200 (0.20 g), croscarmellose sodium (0.03 g), potato starch (0.022 g), PEG 6000 (0.002 g), and magnesium stearate (0.006 g). The assay of the main components of lavender oil with the references linalol and linalyl acetate was performed using gas chromatography. The assay of the total flavonoids of flamin was performed using spectrophotometry with isosalipurposide as the reference. Conclusion The new phytomedicine tablets "Lavaflam" meet European Pharmacopoeia requirements on the following parameters: appearance, geometric size, average weight, disintegration, friability, resistance of tablets to crushing, and quantification.

Hepatobiliary system diseases are medical and social problem at the present time. Important issue is the development of a new complex of herbal medicine and its pharmacoeconomic study. The purpose of the work was an experimental substantiation of the hepatoprotective properties of the drug Lavaflam. Methods of research: pharmacological, morphological, histological, methods of mathematical statistics. Materials of research . Experimental pharmacological studies were performed on the white rats weighing 180–220 g. The study was carried out in the Central Research Laboratory (CRL) of the National University of Pharmacy,Kharkіv,Ukraine (Certificate № 023/13 of 05.03.2013) according to the methodological recommendations of theStateExpertCenter of the Ministry of Health ofUkraine. The rats were divided into four experimental groups: the first group – intact control; the second group – positive pathology – the animals were injected TChM; the third group – animals, received TChM and Lavaflam; the fourth group – animals, received TChM and reference drug Сarsil. Results. It has been found that the test drug Lavaflam showed hepatoprotective properties in experimental model of the subchronic hepatitis (diffuse inflammatory liver disease) in rats. Conclusions. Lavaflam, in comparison with Carsil contributed to the elimination and reduction in a number of pathological changes, increased adaptive capacity of hepatocytes, and Lavaflam promoted the physiological regeneration of cells. Relating to the effect of a positive influence on the hepatic parenchyma condition with induced subchronic hepatitis by TChM, the drug Lavaflam was not inferior to the comparison drug Carsil (by the effect on necrotic manifestations), or was superior to the comparison drug Carsil (by the zones of destruction spread, dystrophic changes in hepatocytes).

An x-ray crystal structure analysis found that the bromination of methyl 1-allyl-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate by Br2 in glacial HOAc involved not heterocyclization but classical addition of Br2 to the unsaturated allyl bond, in contrast with structurally similar alkyl 1-allyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates. Pharmacological tests showed that removal of the double bond from the 1-N-alkyl moiety in the esters was associated with a decrease of analgesic activity.

Розширене вивчення аналгетичної активності N-(3-піридилметил)-4-гідрокси-2-оксо-1,2,5,6,7,8-гексагідрохінолін-3-карбоксаміду, відібраного за результатами первинного фармакологічного скринінгу як структури-лідера, виявило суттєву зміну знеболюючих властивостей у різних зразків цієї сполуки. Оскільки досліджувана речовина нерозчинна у воді і піддослідним тваринам вводилась перорально у вигляді тонкої водної суспензії, то найбільш ймовірною причиною виявленого ефекту визнали зміни кристалічної будови N-(3-піридилметил)-4-гідрокси-2-оксо-1,2,5,6,7,8-гексагідрохінолін-3-карбоксаміду, які відбуваються у ньому під впливом зовнішніх факторів. Це припущення повністю підтвердилось ретельним мікроскопічним дослідженням високо- та низькоактивного зразків, а також більш об’єктивними даними, одержаними методами порошкового і монокристалічного рентгеноструктурного аналізу. Так, зокрема, встановлено, що при всьому розмаїтті кристалічних та аморфних форм, що входять у досліджувані зразки, їх якісний склад виявився доволі схожим. В той же час кількісний вміст деяких фаз сильно розрізняється, що, очевидно, й послужило визначальним фактором для величини аналгетичного ефекту., The advanced study of the analgesic activity of N-(3-pyridylmethyl)-4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide selected by the results of the primary pharmacological screening as the leading structure has revealed a significant change in anesthetic properties in different samples of this compound. Since the substance under study was not soluble in water, and animals received it orally as a thin aqueous suspension, the most likely cause of the effect observed was thought to be the changes in the crystalline structure of N-(3-pyridylmethyl)-4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide occurring in it under the influence of external factors. This assumption has been fully confirmed by the thorough microscopic investigation of righ – and low-active samples, as well as more objective data, the methods of powder and single crystal X-ray diffraction analysis. Thus, in particular, it has been found that with all the variety of crystalline and amorphous forms included in the samples studied their qualitative composition appeared to be quite similar. At the same time the quantitative content of some of the phases varies greatly, and obviously, it was the factor determining the size of the analgesic effect., Расширенное изучение анальгетической активности N-(3-пиридилметил)-4-гидрокси-2-оксо-1,2,5,6,7,8-гексагидрохинолин-3-карбоксамида, отобранного по результатам первичного фармакологического скрининга в качестве структуры-лидера, выявило существенное изменение обезболивающих свойств у разных образцов этого соединения. Поскольку испытуемое вещество не растворимо в воде и подопытным животным вводилось перорально в виде тонкой водной суспензии, то наиболее вероятной причиной обнаруженного эффекта посчитали изменения кристаллического строения N-(3-пиридилметил)-4-гидрокси-2-оксо-1,2,5,6,7,8-гексагидрохинолин-3-карбоксамида, происходящие в нем под воздействием внешних факторов. Это предположение полностью подтвердилось тщательным микроскопическим исследованием высоко- и низкоактивного образцов, а также более объективными данными, полученными методами порошкового и монокристаллического рентгеноструктурного анализа. Так, в частности, установлено, что при всем многообразии кристаллических и аморфных форм, входящих в изучаемые образцы, их качественный состав оказался довольно схожим. В то же время количественное содержание некоторых фаз сильно различается, что, очевидно, и послужило определяющим для величины анальгетического эффекта фактором.

The reaction of alkyl 1-R-4-hydroxy-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carboxylates with 1H-1,2,4-triazol-5-amine in refluxing xylene produced not only 1-R-4-hydroxy-2,2-dioxo-N-(1H-1,2,4-triazol-5-yl)-1H-2λ6,1-benzothiazine-3-carboxamides, but also 6,6-dioxides of 7-R-3H-[1,2,4]triazolo[5',1':2,3]pyrimido[5,4-c][2,1]benzothiazin-5(7H)-ones.

According to the principles of the methodology of bioisosteric replacements a series of methyl 1-R-4-methyl-2,2-dioxo-1H-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 N-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-1H-2λ6,1-benzothiazine-3-carboxylate and alkyl halides leads to formation of N-substituted derivatives with good yields regardless of the structure of the alkylating agent. The peculiarities of NMR (1Н and 13С) spectra of the compounds synthesized, their mass spectrometric behavior and the spatial structure are discussed. In N-benzyl derivative the ability to form a monosolvate with methanol has been found. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick it has been determined that replacement of 4-ОН-group in methyl 1-R-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates for the methyl group is actually bioisosteric since all methyl 1-R-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates synthesized demonstrated a statistically significant analgesic effect. The majority of the substances can inhibit the thermal pain response much more effective than piroxicam in the same dose. Under the same conditions as an analgesic the N-methyl-substituted analog exceeds not only piroxicam, but more active meloxicam as well. Therefore, it deserves in-depth biological studies on other experimental models.

2,2-Dioxides of 1-R-1H-2,1-benzothiazin-4(3H)-ones easily undergo a three-component condensation with N-substituted isatins and malononitrile in the presence of triethylamine giving 6'-R-1-R1-2'-amino-2-oxo-1,2-dihydro-6'H-spiro[indole-3,4'-pyrano[3,2-c][2,1]benzothiazine]-3'-carbonitrile 5',5'-dioxides in good yields. The reaction with 1-unsubstituted 1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide follows an analogous route, but the products are triethylammonium salts of the corresponding spiro compounds.

With the aim of deducing a structure-biological dependence we have carried out the synthesis of quinoline-3-carboxylic acid N-R-amides with a p-methoxyphenyl substituent in the amide part of the molecule. The effects of the compounds prepared on the excretory function of the kidney are discussed. Using a system of simplex descriptors and the method of tree type classification a QSAR model has been constructed which is suitable for prediction of the diuretic activity of novel quinolinecarboxylic acid N-R-amides.

NMR spectroscopy showed that treatment of 1-allyl-3-[(arylamino)methylene]quinoline-2,4-(1H,3H)-diones with an equivalent amount of dry bromine in anhydrous acetic acid leads to the formation of 4-aryliminomethyl-2-bromomethyl-5-oxo-1,2-dihydro-5H-oxazolo[3,2-a]quinolinium bromides.

Bromination of 1-allyl-substituted 3-(arylaminomethylene)quinoline-2,4-(1H,3H)-diones with one equivalent of molecular bromine in glacial acetic acid and subsequent dilution of the reaction mixture with water is accompanied by halocyclization and hydrolysis to form 2-bromomethyl-5-oxo-1,2 dihydro-5H-oxazolo[3,2-a]quinoline-4-carbaldehyde.

Prolonged treatment of ethyl 1-alkyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates with refluxing phosphorus oxychloride gives not only the target 4-chloro derivatives but is also accompanied by a marked loss of the 1-N-alkyl groups to form the side product 2,4-dichloro-3-ethoxycarbonylquinoline.

4-Methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid hetarylamides can be prepared by two fundamentally different routes with allowance made for the thermal stability of the starting hetarylamines.

A simple and efficient method for preparing 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid alkyl amides is proposed. The results of a study of the diuretic activity of the compounds synthesized are reported.

In the presence of aqueous solutions of alkali, 2-bromomethyl-3,9-dihydro-2H-furo[2,3-b]quinolin-4-one is subjected to dehydrobromination and converted to 2-methyl-9H-furo[2,3-b]quinolin-4-one which exists in acid solution in the 4-oxo-and in base in the 4-hydroxy tautomeric forms.

By analogy with the 4-hydroxy derivatives, the bromination of N-allyl-4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid leads to the closure of a five membered oxazole ring but, in contrast, it forms the 2-bromomethyl-4-carboxy-5-methyl-1,2-dihydrooxazolo[3,2-a]quinolinium bromide salt.

Bromination of N-allyl-4-hydroxy-2-oxo-1,2-dihydroquinoline and N-allyl-5-ethoxycarbonyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine is accompanied not only by closing of a five membered oxazole ring but also by a second bromination of the 2-bromomethyl-5-oxo-1,2-dihydro-5H-oxazolo[3,2-a]-derivatives formed at position 4.

Treatment of ethyl 1-R-4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylates with sodium nitrite in DMSO is a convenient method for their conversion to the corresponding 4-hydroxy derivatives.

The hydrogenation of the benzene part of the molecule in N-allyl-substituted 4-hydroxy-2-quinolinones does not affect the nature of their bromination by molecular bromine and gives 2-bromomethyl-5-oxo-1,2,6,7,8,9-hexahydro-5H-oxazolo[3,2-a]quinolines.

A simple method is proposed for preparing 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]-quinoline-2-carboxylic acid alkylamides. For the case of the secondary butylamide features of the steric structure of the synthesized compounds is discussed. The results of a study of their anti-inflammatory and diuretic activities are presented.

In acid medium ethyl 1-R-4-dicyanomethyl-2-oxo-1,2-dihydroquinoline-3-carboxylates are hydrated in the ketenimine tautomer form exclusively to the corresponding quinolylcyanoacetamides.

Hydration of ethyl 1-R-4-dicyanomethyl-2-oxo-1,2-dihydroquinoline-3-carboxylate gives the corresponding substituted cyanoacetamides which are readily and quantitatively cyclized to 6-R-5-hydroxy-2,4-dioxo-2,3,4,6-tetrahydrobenzo[c][2,7]naphthyridine-1-carbonitriles in the presence of aqueous base.

A preparative method of obtaining 1-substituted 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acids is proposed. Features of their spatial structure have been studied.

The alkylation of the ethyl esters of 4-methyl, 4-chloro-, and 4-amino substituted 2-oxo-1,2-dihydroquinoline-3-carboxylic acid by ethyl iodide in the system DMF/K2CO3 has been studied. Features of the structure of the starting compounds and their effect on the ratio of the N-and O-alkyl products formed are discussed.

The first stage of the reaction of triethyl methanetricarboxylate with indoline is the formation of the diethyl ester of 2-(indoline-1-carbonyl)malonic acid, which then, depending on the conditions selected, may be converted into the ethyl ester of 2-(indoline-1-carbonyl)-3-(indolin-1-yl)-3-oxopropionic acid, methanetri-N-(indolin-1-yl)carboxamide, or the ethyl ester or (indolin-1-yl)amide of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid.

Предложен улучшенный способ получения этилового эфира 2-гидрокси-8-метил-4-оксо-4Н-пиридо[1,2-а] пиримидин-3-карбоновой кислоты, представляющего интерес как основа для синтеза противовирусных лекарственных средств. Метод заключается в постепенном прибавлении в предварительно нагретый до 150°С избыток триэтил-метантрикарбоксилата раствора 2-амино-4-метилпиридина в триэтил-метантри-карбоксилате, используемом в качестве ацилирующего и конденсирующего агента, а также высококипящего теплоносителя одновременно. Такая модификация позволяет не только значительно упростить регенерацию взятого в избытке триэтилметантри-карбоксилата, но и практически полностью избежать нежелательного образования побочного 2-гидрокси-8-метил-4-оксо-N-(4-метилпиридин-2-ил)-4Н-пиридо[1,2-а]пиримидин-3-карбоксамида. С помощью рентгеноструктурного анализа установлено, что в кристалле синтезированный этиловый эфир 2-гидрокси-8-метил-4-оксо-4Н-пиридо[1,2-а]пиримидин-3-карбоновой кислоты существует в цвиттер-ионной форме с локализацией положительного заряда на протонированном атоме азота и отрицательного заряда на атоме углерода в положении 3 пиридопиримидинового ядра. На основании изучения спектров ЯМР 1Н и 13С высказано предположение, что исследуемое соединение и в растворе существует в виде равновесной смеси двух таутомерных форм., The improved method for obtaining ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate being of interest as a base for synthesis of antiviral medicines has been suggested. The method involves a gradual addition of the solution of 2-amino-4-methylpyridine in triethylmethanetricarboxylate used as an acylating and condensing agent, as well as a high boiling heating agent simultaneously in the excess of triethylmethanetricarboxylate preheated to 150°C. This modification allows not only to reduce considerably regeneration of triethylmethanetricarboxylate taken in excess, but practically to avoid completely the undesirable formation of by-product – 2-hydroxy-8-methyl-N-(4-methypyridin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide. It has been found by X-ray diffraction analysis that in the crystal the ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate synthesized exists in the zwitterionic form with localization of the positive charge at the protonated nitrogen atom and the negative charge at the carbon atom in position 3 of the pyridopyrimidine ring. Based on the study of NMR 1H and 13C spectra the assumption that the test compound exits as an equilibrium mixture of two tautomeric forms in solution has been expressed., Запропоновано покращений спосіб одержання етилового естеру 2-гідрокси-8-метил-4-оксо-4Н-піридо [1,2-а]піримідин-3-карбонової кислоти, який представляє інтерес як основа для синтезу противірусних лікарських засобів. Метод полягає у поступовому додаванні в попередньо нагрітий до 150°С надлишок триетилметантрикарбоксилату розчину 2-аміно-4-метилпіридину в триетилметантрикарбоксилаті, що використовується як ацилуючий та конденсуючий агент, а також як висококиплячий теплоносій одночасно. Така модифікація дозволяє не тільки значно спростити регенерацію взятого у надлишку триетилметантрикарбоксилату, але й практично повністю уникнути небажаного утворення побічного 2-гідрокси-8-метил-4-оксо-N-(4-метилпіридин-2-іл)-4Н-піридо[1,2-а]піримідин-3-карбоксаміду. За допомогою рентгеноструктурного аналізу встановлено, що в кристалі синтезований етиловий естер 2-гідрокси-8-метил-4-оксо-4Н-піридо[1,2-а]піримідин-3-карбонової кислоти існує у цвіттер-іонній формі з локалізацією позитивного заряду на протонованому атомі нітрогену і негативного заряду на атомі карбону у положенні 3 піридопіримідинового ядра. На основі вивчення спектрів ЯМР 1Н та 13С зроблено припущення, що досліджувана сполука і в розчині існує у вигляді рівноважної суміші двох таутомерних форм.

Dialkylaminoalkylamides of 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acids have been obtained as potential antiviral agents. The special features of the spatial structure of one example of the synthesized compounds have been studied. Results are given of the investigation of cytotoxicity and antiviral activity in relation to type 1 herpes virus and coronavirus.

The mean planes of the propyl chain and carboxyl­ate group of the ethoxy­carbonyl substituent are almost orthogonal to the virtually planar dihydro­quinoline bicyclic framework of the title compound, C18H19N3O4 [dihedral angles 89.6 (2) and 79.5 (1)°, respectively]. The nitrile group bond vector forms an angle of 59.4 (1)° with the dihydro­quinoline plane. Both H atoms of the amide group participate in inter­molecular hydrogen bonds which link mol­ecules into infinite chains running along the a axis of the crystal structure.