A modified method for the synthesis of a promising non-narcotic analgesic agent of the hexaazaisowurtzitane class with pronounced anti-inflammatory activity is described. Methods for reducing the cost of the target substance are considered. The physicochemical characteristics are described. The efficacy and safety of the synthesized agent are shown in several animal models.

The compact, nitrogen‐rich structure of 2,4,6,8,10,12‐hexaazaisowurtzitanes calls attention among researchers worldwide. These compounds have found the greatest utility as substrates for nitration to obtain the caged polynitramine, 2,4,6,8,10,12‐hexanitro‐2,4,6,8,10,12‐hexaazaisowurtzitane, which possesses a high‐energy performance. All new derivatives of hexaazaisowurtzitane are nitratable. The present study examined the nitration process of 2,6,8,12‐tetraacetyl‐2,4,6,8,10,12‐hexaazaisowurtzitane derivatives obtained through the condensation reaction with aldehydes under various conditions to yield CL‐20. The yield of CL‐20, a well‐known nitration product of hexaazaisowurtzitane compounds, was found to depend on the substrate structure and the nitrating mixture composition. The revealed dependence of the synthesis of various nitrated compounds on the holding time enables the synthesis of products with different physicochemical properties in a single process.

При лечении различных заболеваний почек широкое применение находят диуретические препараты. Диуретики занимают важное место в терапевтическом лечении больных, поскольку данные заболевания сочетаются с задержкой натрия, влияющей на формирование отёчного синдрома, и артериальной гипертензией. Однако, ряд побочных эффектов толкает исследователей на поиски новых лекарственных веществ, оказывающих направленное фармакологическое действие на мочеполовую систему человека, а также максимально возможно не проявляющих побочных нежелательных эффектов. На основании проведенного авторами виртуального скрининга с использованием программного пакета PASS Online были получены данные о вероятной активности производных теофиллина в качестве диуретических препаратов, кроме того, среди расчётных активностей также стоит отметить спазмолитическую, вазодилатирующую и антидиабетическую активности. Ранее теофиллин использовали в качестве мочегонного средства, но в настоящее время его применяют лишь для усиления действия других диуретических препаратов. Диуретическое действие теофиллина основано на повышении почечного кровообращения и ускорения процесса клубочковой фильтрации, а также благодаря уменьшению обратного всасывания натрия в проксимальных канальцах почек. В данной работе рассмотрен метод синтеза производного теофиллина – этамифиллина, а также впервые показан его диуретический эффект в эксперименте in vivo. Этамифиллин был получен путем алкилирования теофиллина гидрохлоридом 2-хлор-N,N-диэтилэтанамина в солевой форме, что существенно повышает растворимость препарата и существенно облегчает введение экспериментальным животным. По итогам проведенных экспериментальных исследований установлено, что при 10-ти дневном пероральном введении этамифиллина развивается диуретический эффект с увеличением почечной экскреции натрия и калия. In the treatment of various kidney diseases, diuretic drugs are widely used. Diuretics play an important role in the therapeutic treatment of patients, since these diseases are combined with sodium retention, which affects the formation of edema syndrome, and arterial hypertension. However, a number of side effects push researchers to search for new drugs that have a targeted pharmacological effect on the human genitourinary system, and also do not exhibit side effects as much as possible. Based on the virtual screening conducted by the authors using the PASS Online software package, data were obtained on the theoretical activity of theophylline derivatives as diuretics, in addition, among the calculated activities, it is also worth noting the antispasmodic, vasodilating and antidiabetic activity. Previously, theophylline was used as a diuretic, but currently it is used only to enhance the effect of other diuretics. The diuretic effect of theophylline is based on an increase in renal blood flow and glomerular filtration rate, as well as a decrease in sodium reabsorption in the proximal tubules of the kidneys. In this paper, a method for synthesizing a theophylline derivative, etamiphylline, is considered, and its diuretic effect is demonstrated for the first time in an in vivo experiment. Etamiphylline was obtained by alkylating theophylline with 2-chloro-N,N-diethylethanamine hydrochloride in salt form, which significantly increases the solubility of the drug and significantly facilitates its administration to experimental animals. Based on the results of the experimental studies, it was found that with 10-day oral administration of etamiphylline, a diuretic effect develops with an increase in renal excretion of sodium and potassium.

A study on the Pd-catalyzed hydrodebromination of 2,3,4,5-tetrabromothiophene (1) to 3,4-dibromothiophene (2) is reported. The effect of the solvent nature, main agent, temperature and concentration of 1 on the yield of 2 was studied. Optimal conditions of the process were found: a 5 % Pd/Sibunit catalyst constituting 10 % of the substrate weight, a temperature of 80 °С, a pressure of 0.7 MPa, dimethyl formamide with the addition of triethylamine as the main agent in the amount of 2.2 equiv per 1 equiv of the initial substance 1, and the yield of 2 constituting up to 97.5 %. It was shown that the catalyst could be reused with the preservation of the high yield of 2. In comparison with the conventional method of chemical reduction of 1 under the action of zinc in acetic acid, the novel method ensures high output and low wastes.

Biologically active compounds of natural or synthetic origin have a complex structure and generally contain various structural groups among which polycyclic cage amines are found. Hexaazaisowurtzitanes are representatives of these amines and studies on their biological activity began less than two decades ago, starting with research on the environmental impact of CL-20. This research helped to evaluate the risks of potential pollution in the habitat environments of living organisms and determine whether the chemical compounds in question could be utilized in pesticides, herbicides, fungicides, or medicinal drugs. The nomenclature of hexaazaisowurtzitane compounds has recently been expanded significantly, and some of them have demonstrated promise in the design of medicinal drugs. This paper review studies the pharmacological activity of the acyl derivatives of hexaazaisowurtzitane. Most of the compounds have been found to possess a high analgesic activity, providing a solution to the pressing issue of pain management in current pharmacology. Analgesic drugs currently used in the clinical practice do not meet all of the efficacy and safety requirements (gastro-, nephro-, hepato-, haematotoxicity, etc.). The material presented in the seven sections of this paper highlights information about hexaazaisowurtzitane derivatives. Furthermore, they have been observed to exhibit anti-inflammatory, anticonvulsant, antihypoxic, and antimetastatic activities, which render them highly promising for evaluation in various fields of medicinal practice.

A method for production of a promising non-narcotic analgesic of the hexaazaisowurtzitane class is developed. Data on the physicochemical characteristics and conditions for obtaining the target substance are presented. The effectiveness of the resulting agent is shown in several animal models. A pronounced analgesic effect of the newly synthesized compound 4-(3,4-dibromothiophenecarbonyl)-2,6,8,10,12-pentaacetyl-2,4,6,8,10,12-hexaazaisowurtzitane comparable or even superior to that of tramadol was revealed.

In this work, we studied the pharmacological activity of a newly-synthesized compound 4-(3,4- dibromothiophenylcarbonyl)-10-(2-ethoxyacetyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11,05,9]dodecane (M3) using somatogenic pain models of various genesis (thermal and visceral pain, mechanical compression of a paw). The compound showed a high antinociceptive efficacy, comparable to or exceeding that of tramadol. It was shown that the new molecule from the class of hexaazaisowurtzitane effectively blocks nociceptive reactions at the supraspinal and peripheral levels of pain sensitivity organization. The results obtained confirm the possibility of creating new pharmacologically active molecules based on the high-energy substance of hexaazaisowurtzitane, which is a priority in domestic pharmaceutical production.

Analysis of specific pharmacological activity evaluated high antinociceptive efficacy of the first synthesized compound 10-di(ethoxyacetyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,0(3,11),0(5,9)]dodecane (ethowurtzine) in models of somatogenic pain of different genesis (thermal, visceral pain, mechanical compression of paw).The new molecule from the class of hexaazaisowurtzitane effectively blocks nociceptive reactions at the supraspinal and peripheral levels of pain sensitivity organization. The effect of ethowurtzine was comparable or exceeded the effect of tramadol. The obtained results prove the possibility of creating new pharmacologically active molecules based on the high-energy substance hexaazaisowurtzitane.

В настоящее время полиазациклические соединения (азотсодержащие гетероциклические структуры) рассматриваются в качестве перспективных биологически активных веществ. Цель работы заключалась в исследовании возможности получения салициловых производных инновационного анальгетика 4-(3,4-дибромтиофенкарбонил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазаизовюрцитана по реакции ацилирования. В ходе работы, на примере ацилирования хлорангидридами салициловых кислот, было установлено, что возможно введение дополнительных объёмных заместителей в молекулу тиовюрцина. На основании проведения виртуального скрининга при помощи программного пакета PASS Onlineбыли получены данные о теоретической анальгетической активности полученных продуктов на уровне исходного соединения, однако, введение дополнительных фармакофоров с противовоспалительным и жаропонижающим действием, не оказывает влияния на терапевтическую широту. Currently, polyazacyclic compounds (nitrogen-containing heterocyclic structures) are considered as promising biologically active substances. The aim of the work was to study the possibility of obtaining salicylic derivatives of the innovative analgesic 4-(3,4-dibromothiophenecarbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane by the acylation reaction. In the course of the work, using the example of acylation with salicylic acid chlorides, it was found that it is possible to introduce additional bulky substituents into the thiowurtzine molecule. Based on the virtual screening using the PASS Online software package, data were obtained on the theoretical analgesic activity of the obtained products at the level of the parent compound, however, the introduction of additional pharmacophores with anti-inflammatory and antipyretic effects does not affect the therapeutic breadth.

Разработка обезболивающих средств является важной задачей фармацевтической химии. Производные 2,4,6,8,10,12-гексаазаизовюрцитана обладают широким спектром биологической активности. Представлены результаты ацилирования 2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазаизовюрцитана хлорангидридом этоксиуксусной кислоты. Исследовано влияние природы растворителя на выход 4,10-ди(этоксиацетил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло [5,5,0,03,11,05,9]додекана, обладающего анальгетической активностью. The development of painkillers is an important task of pharmaceutical chemistry. Derivatives of 2,4,6,8,10,12-hexaazaisovurcitan have a wide range of biological activity. The results of acylation of 2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazaisovurcitan with ethoxyacetic acid chlorohydride are presented. The effect of the solvent nature on the yield of 4,10-di(ethoxyacetyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo [5,5,0,03,11,05,9]dodecane with analgesic activity was investigated.

The efficiency of mathematical modeling of the operational frequency spectra of composite materials caused by the processes of elastic electronic polarization is examined. The second part of the paper presents the results of modeling the electronic properties of pure oxides.

The number of candidate molecules for new non-narcotic analgesics is extremely limited. Here, we report the identification of thiowurtzine, a new potent analgesic molecule with promising application in chronic pain treatment. We describe the chemical synthesis of this unique compound derived from the hexaazaisowurtzitane (CL-20) explosive molecule. Then, we use animal experiments to assess its analgesic activity in vivo upon chemical, thermal, and mechanical exposures, compared to the effect of several reference drugs. Finally, we investigate the potential receptors of thiowurtzine in order to better understand its complex mechanism of action. We use docking, molecular modeling, and molecular dynamics simulations to identify and characterize the potential targets of the drug and confirm the results of the animal experiments. Our findings finally indicate that thiowurtzine may have a complex mechanism of action by essentially targeting the mu opioid receptor, the TRPA1 ion channel, and the Cav voltage-gated calcium channel.

The cybernetic equation for the permittivity of a condensed sample is examined. The results of modeling the long-wavelength optical spectra of pure crystalline oxides as well as the resulting spectral dependences of the electronic properties of the experimental sample are presented.

The methodology of efficient macroscopic calculation of parameters of the cubic crystal lattice based on the use of the coefficient of structured packing of its elementary cell is considered. The possibility of precision theoretical determination of the numerical values of interatomic distances in crystals of the type under consideration is shown.

The methodology of effective macroscopic calculation of numerical values of internuclear distances in binary crystals of a cubic crystal system is based on the use of coefficients of the structural packing density of the crystal lattice. The possibility of combining the reference data on the main physicochemical parameters of the substance is implemented by synthesis of the corresponding mathematical models.

An efficient mathematical model of the elastic polarization of a material in the condensed state is examined. The results of computer modeling of the optical spectra of four raw-material crystalline oxides as well as the spectral properties based on them are presented for three different samples of refractory glasses.