Introduction. The use of drugs derived from benzodiazepine for the treatment of various diseases continues to be relevant. Benzodiazepines are approved by most regulatory authorities around the world. Despite the large number of side effects and non-medical use, they are becoming more promising in emergency care for prolonged seizures and epileptic status. Aim. To analyze the existing medicines on the market of the Russian Federation based on benzodiazepine derivatives and assess the prospects for development in this direction. Materials and methods. The study was conducted on the basis of regulatory legal acts in the field of healthcare and the circulation of medicines, publications of Russian and foreign authors, the results of scientific research using situational, comparative, structural-logical and content analysis methods. The information base of the study was the online database "State Register of Medicines" (grls.minzdrav.gov.ru), databases of peer-reviewed publications: PubMed and Scopus. Results and discussion. Data were obtained on the range of medicines derived from benzodiazepines according to the following indicators: international nonproprietary names, trade names, medicines, manufacturing countries and enterprises, dosage forms. The problem of "medicinal sovereignty" is discussed. Promising niches have been found for the development of innovative drugs derived from benzodiazepines. Conclusion. It has been established that mainly domestic benzodiazepine-type drugs are represented on the Russian pharmaceutical market, while there is a certain shortage of pharmaceutical substances. In Russia, such dosage forms as films, transdermal plasters and preparations for the inhalation use of benzodiazepine derivatives are not registered. It is important to create innovative dosage forms capable of providing a fast, non-invasive and socially acceptable method of use and a high rate of adherence to treatment by patients.

The data obtained on the synthesis and search for biological activity among metal complexes based on 4-aryl-2-hydroxy-4-oxo-2-butenoic acid (hetero)arylamides were integrated. The data on the antimicrobial, anti-inflammatory, analgesic, hypoglycemic, antihypoxic, and immunotropic activities of the synthesized compounds were analyzed. The relationship between the chemical structure and biological activity of chelate complexes was discussed and some regular features were identified. Promising compounds for further research and development of new domestic pharmaceutical substances were found.

Introduction. The use of anticoagulants is relevant in therapeutic, cardiological, neurological practice, geriatrics, obstetrics and gynecology, as well as in complications associated with COVID-19 infection and vaccination. In-depth studies of additional pleiotropic effects of existing anticoagulants are being conducted. The anti-inflammatory effect of heparins and direct oral anticoagulants was found. Special emphasis is placed on the existing close relationship between coagulation and inflammatory processes. The interaction of anticoagulants with nonsteroidal anti-inflammatory drugs when taken together is actively discussed. The combination of anticoagulant and anti-inflammatory action in one chemical molecule can solve the problem of polypragmasia.Aim. To study the anti-inflammatory activity of promising 2-hydroxy-4-oxo-4-R-2-butenoates of heterylammonium, which have an effect on the blood clotting system.Materials and methods. For further study of anti-inflammatory activity, 2-hydroxy-4-oxo-4-R-2-butenoates of heterylammonium, which have an effect on the blood clotting system, were selected. The anti-inflammatory effect was studied on a model of acute inflammatory edema in mongrel rats of both sexes weighing 180–250 g. The studied compounds were administered intragastrically. Diclofenac sodium and nimesulide substances administered similarly were used as comparison drugs. Acute toxicity of substances that showed activity was studied on white nonlinear mice of both sexes weighing 18–22 g with the definition of LD50.Results and discussion. All the studied 2-hydroxy-4-oxo-4-R-2-butenoates of heterylammonium have anti-inflammatory effects of varying severity. Data on the study of acute toxicity during intragastric administration, allow us to attribute the studied compounds to the 4.5 class of the hazard classification of chemical products.Conclusion. The anti-inflammatory activity of 14 2-hydroxy-4-oxo-4-R2-butenoates of heterylammonium has been studied. Five butanoate have an effect lower than comparison drugs, eight compounds are comparable to the effect of reference drugs, one compound is superior to nimesulide. The studied compounds can be assigned to class 4,5 of the hazard classification of chemical products. Medicinal candidates have been selected for further pharmacological, toxicological and technological study.

Introduction. The hemostasis system is a set of functional, morphological and biochemical mechanisms of a living organism that ensure the preservation of the liquid state of the blood, the prevention and stopping of bleeding, as well as the integrity of blood vessels. Anticoagulants and hemostatic agents can significantly change the mechanism of hemostasis. Interest in the synthesis and search for compounds that affect the blood coagulation system remains high. Substances exhibiting anticoagulant and hemostatic effects have been found. The search for compounds among the products of organic synthesis that affect the hemostasis system seems relevant.Aim. To study the effect of new water-soluble 2-amino heteryl-3-ium 4-(get)aryl-2-hydroxy-4-oxobut-2-enoates on the hemostasis system using an in vitro model.Materials and methods. Direct interaction 4-(het)aryl-2-hydroxy-4-oxobut-2-enoic acids with heterocyclic amines have been obtained new water soluble 2-aminoheteryl-3-ium 4-(het)aryl-2-hydroxy-4-oxobut-2-enoates. The study of the effect of substances on the hemostasis system was carried out using the coagulometer "APK 4-02-P". Ethamsylate and sodium heparin were used as comparison drugs for hemostatic and anticoagulant activity, respectively. Acute toxicity of the compounds was determined by intravenous administration of aqueous solutions of the compounds to non-linear white mice of both sexes with the definition of LD50.Results and discussion. 10 New 2-aminoheteryl-3-ium 4-(het)aryl-2-hydroxy-4-oxobut-2-enoates have been synthesized. In vitro screening of the effect of compounds on the hemostasis system found that 3 substances have a pronounced anticoagulant effect, and 4 compounds showed hemostatic activity. Some patterns of the "structure-pharmacological action" relationship have been found. The studied butenoates can be classified as moderately toxic compounds according to the classification of chemical toxicity.Conclusion. Pharmacological screening in vitro of the effect of compounds on the hemostasis system was carried out. It was found that all the studied compounds have an effect on the blood coagulation system of varying degrees of severity. The combination of a pronounced pharmacological effect, low acute toxicity and water solubility of butenoates may become a prerequisite for further search and possible development of new domestic medicines that have an effect on the hemostasis system.

Introduction. Vascular pathologies associated with thromboembolism are common complications and the leading cause of morbidity and mortality among patients of various nosological groups. Previously, we obtained water-soluble 2-hydroxy-4-oxo-4-R-2-butenoates of hetarylammonium, which exhibit a significant pharmacological effect on the blood coagulation system». A compound with a pronounced anticoagulant effect was found in various routes of administration. It was of interest to study various methods of confirming the authenticity of a potential anticoagulant.Aim. Development of methods for identification of a potential anticoagulant 2-hydroxy-4-oxo-(4-chlorophenyl)-2-butenoate of thiazolinammonium.Materials and methods. The studies were carried out on three series of the substance 2-hydroxy-4-oxo-(4-chlorophenyl)-2-butenoate of thiazolinammonium obtained in laboratory conditions. The melting point of BAS was measured by the capillary method according to GF XV OFS.1.2.1.0011 "Melting point". The solubility of the substance was determined in accordance with GF XV of the OFS.1.2.1.0005 "Solubility". The absorption spectra in the IR region were taken in accordance with GF XV of the OFS.1.2.1.1.0002 "Spectrophotometry in the middle infrared region". Absorption spectra in the UV region were taken in accordance with GF XV of the OFS.1.2.1.1.0003 "Spectrophotometry in the ultraviolet and visible regions". In carrying out qualitative reactions, reagents prepared in accordance with GF XV of the OFS were used.1.3.0001 "Reagents. Indicators".Results and discussion. A description of the substance has been carried out. The melting point and solubility of the compound were determined. Spectra in the IR and UV regions of the spectrum were taken. Methods were selected, and qualitative reactions of authenticity of a potential anticoagulant were carried out.Conclusion. The studied characteristics of the new BAS can be used in the standardization of the substance according to the indicators "Description", "Solubility", "Identification", "Melting point". These indicators characterize the physico-chemical properties of 2-hydroxy-4-oxo-(4-chlorophenyl)-2-butenoate of thiazolinammonium, and will be included in the draft regulatory documentation for the substance in the future.

Introduction. COVID-19 is recognized as the most significant pandemic of the modern era. Studies have shown the potential benefits of taking ascorbic acid in the complex treatment of this disease, especially in people with vitamin C deficiency. One of the most popular and affordable sources of ascorbic acid in the diet are rosehip fruits. The quality of water extracts from plant raw materials depends on a number of technological factors. The study of the influence of the technological regime of the production of water extraction from rosehip fruits on the release of ascorbic acid in the obtained dosage forms is relevant.Aim. To obtain water extracts from rosehip fruits by various production modes and to study the effect of technological parameters on the content of ascorbic acid.Materials and methods. The object of the study was rosehip fruits in bundles and water extracts based on them, obtained in the 6 different ways. Pharmacopoeial techniques, manufacturers' recommendations, as well as thermos infusion with and without preheating of the thermos flask were used. For quantitative determination of the ascorbic acid in the obtained aqueous extracts, we used the pharmacopoeia method (titration with 2,6-dichlorophenolindophenolate sodium).Results and discussion. The lowest content of ascorbic acid was noted in the decoction according to the pharmacopoeia method. High levels of ascorbic acid content were noted in the variants of thermos infusion of rosehip fruits.Conclusion. We have obtained extemporal water extracts of rosehip fruits by the 6 different extraction modes. According to the content of ascorbic acid, the most effective method of obtaining extemporal water extraction of rosehip fruits is a six-hour thermos infusion with preheating of the thermos flask. The largest amount of ascorbic acid is released during a six-hour thermos infusion. In the twelve-hour thermos infusions, a decrease in the amount of ascorbic acid was found. It was found that preheating the thermos flask leads to an increase in the yield of ascorbic acid in aqueous extraction by 25 %.

Introduction. Recently, there has been a significant increase in fungal infections. The most common is vulvovaginal candidiasis, affecting millions of women worldwide. Resistance is formed to existing antifungal drugs, and they are not devoid of side effects. Previously, we have shown high antimicrobial activity of derivatives of 4-R-2-hydroxy-4-oxo-2-butenic acids. The creation of soft dosage forms based on them and the study of antifungal action is promising.Aim. To develop experimental soft dosage forms based on one of the most active derivatives of 4-R-2-hydroxy-4-oxo-2-butenic acids and to evaluate the effect of the ointment composition of the ointment composition on the severity of antifungal action.Materials and methods. As a pharmacologically active component, a hydrazone derivative of 4-phenyl-2-hydroxy-4-oxo-2-butenoic acid synthesized by us was used, which has pronounced antifungal activity. 8 experimental soft dosage forms based on hydrophobic and hydrophilic character have been developed. The active substance in a concentration of 1 % was introduced by standard technological methods according to the rules for the manufacture of dermatological ointments. To determine the antifungal activity of the ointments obtained, a three-nesting variant of the agar diffusion method was used. Comparison preparations are 2 % cream "Pimafucin" and 1 % cream "Clotrimazole".Results and discussion. All the studied experimental soft dosage forms showed antifungal effects of varying degrees of severity. The greatest pharmacological effect was found in ointment compositions based on hydrophilic components of sodium-carboxymethylcellulose and polyethylene oxides. Their antifungal effect is comparable or exceeds the effect of comparison drugs.Conclusion. 8 experimental soft dosage forms based on a derivative of 4-phenyl-2-hydroxy-4-oxo-2-butenic acid have been developed. Their antifungal activity has been studied. Two most active samples of experimental ointments were selected for further in-depth study.

Hetarylammonium 2-hydroxy-4-oxo-4-(thien-2-yl)but-2-enoates and 2-hydroxy-4-oxo-4-(thien-2-yl)but-2-enoic acid hetarylamides were obtained. Their biological activity was studied. Marginally toxic compounds with activities comparable to and exceeding those of reference compounds were discovered. Results of biological tests indicated the expediency of seeking hemostatic and anthelminthic agents in the series of hetarylammonium 2-hydroxy-4-oxo-4-(thien-2-yl)but-2-enoates. 2-Hydroxy-4-oxo-4-(thien-2-yl)but-2-enoic acid hetarylamides are promising candidates for developing new drugs possessing anti-inflammatory activity

The reactions of 4-aryl- N -hetaryl-2-hydroxy-4-oxobut-2-enamides (hetaryl is 2-pyridyl, 2-azolyls, benzo[ d ]thiazol-2-yl) with hydroxylamine yielded 4-aryl- N -hetaryl-2-hydroxyimino-4-oxobutanamides and 5-aryl- N -hetarylisoxazole-3-carboxamides. The products were searched for representatives with high antimicrobial and anti-inflammatory activities and low acute toxicity. A structure—pharmacological activity relationship of the prepared compounds was established.

Получены амиды 4-арил-2-[(2-оксо-1,2-дифенилэтилиден)гидразинил]-4-оксобут-2-еновых кислот дециклизацией 3-[(2-оксо-1,2-дифенилэтилиден)гидразоно]-5-арилфуран-2(3Н)-онов соответствующими аминами, а также взаимодействием гетариламидов 4-арил-2-гидрокси-4-оксобут-2-еновых кислот с 2-гидразоно-1,2-дифенилэтаноном. Изучена их анальгетическая и антибактериальная активность. Обнаружены вещества, сопоставимые и превышающие по активности препараты сравнения с низкой токсичностью.

The interaction of 5-arylfuran-2,3-diones with 5,6-R-benzo[ d ]thiazole-2-amines has resulted in 4-aryl- N -(5,6-R-benzo[ d ]thiazol-2-yl)-2-hydroxy-4-oxobut-2-enamides. The products structure has been confirmed by means of IR, NMR, and 1 H NMR spectroscopy as well as mass spectrometry. Analgesic and antimicrobial activities of the prepared compounds have been studied; acute toxicity of the most active compounds has been determined. The relationship between the structure and biological activity of the obtained compounds has been elucidated. The compounds acting comparably or better than the reference drugs have been found.

4-Aryl-2-[(2-oxo-1,2-diphenylethylidene)hydrazinyl]-4-oxobut-2-enoic-acid amides were produced via decyclization of 3-[(2-oxo-1,2-diphenylethylidene)hydrazono]-5-arylfuran-2(3H)-ones by the corresponding amines and via reaction of 4-aryl-2-hydroxy-4-oxobut-2-enoic-acid hetarylamides with 2-hydrazono-1,2-diphenylethanone. Their analgesic and antibacterial activities were studied. Compounds with low toxicities and activities comparable to and exceeding those of reference drugs were discovered.

The influence of newly synthesized compound--thiazoline ammonium 4-chlorophenyl-2-hydroxy-4-oxo-2-butenoate (FS-169), which has a direct anticoagulant--on the indices of coagulation activity has been studied in rabbit blood plasma with the aid of an APG4-02-P coagulometer. It is established that FS-169 reliably extends the partial thromboplastin time by 122.2% (p < 0.001) and the prothrombin time by 49.1% (p = 0.001), increases the prothrombin index by 30.9% (p = 0.001), and decreases the prothrombin ratio and international normalized ratio by 40.0% (p = 0.001). At the same time FS-169 does not influence the thrombin time FS-169.

We have carried out a selection of optimal conditions for chromatographic control of four classes of potentially biologically active derivants of 4-(get)aril-2-hydroxy-4-oxo-2-butenic acids.

4-Aryl-2-arylamino-4-oxo-2-butenoic acid hetarylamides were synthesized by the reaction of 4-aryl-2-hydroxy-4-oxo-2-butenoic acid hetarylamides with aromatic amines and also by ring opening of 5-aryl-3-arylamino-3H-furan-2-ones by heterocyclic amines. Their analgesic activity was studied. Compounds with activity comparable to and exceeding that of the reference drugs and with low toxicity were found.

2-Benzothiazolylamides of 4-aryl-2-hydroxy-4-oxo-2-butenoic and 4-aryl-3-bromo-2,4-dioxobutanoic acids in addition to complexes with manganese, cobalt, and copper were synthesized. Their hypoglycemic and antimicrobial activity was studied. Compounds with low toxicity and activity comparable to or exceeding that of reference drugs were discovered.

Взаимодействием гетариламидов 4-арил-2-гидрокси-4-оксо-2-бутеновых кислот с ароматическими аминами, а также дециклизацией 5-арил-3-арилимино-3Н-фуран-2-онов гетероциклическими аминами получены гетариламиды 4-арил-2-ариламино-4-оксо-2-бутеновых кислот. Изучена их анальгетическая активность. Обнаружены вещества, сопоставимые и превышающие активность препаратов сравнения, с низкой токсичностью.