The reaction of aryl(dichloro)phosphines with (2-chloroethoxy)trimethylsilane in the presence of haloacetic acid esters was studied with the goal of developing a new method for the synthesis of ethyl [(2-chloroethoxy)(4-dimethylaminophenyl)phosphoryl]acetate. The effect of various factors, such as substituent in the para position of the aromatic ring in the initial aryl(dichloro)phosphine, halogen nature in haloacetic acid ester, and chloro(trimethyl)silane, on the reaction course was analyzed.

The structures of the molecular complexes based on calix[4]resorcinol bearing a p -tolyl moiety at the lower rim with phosenazid (2-(diphenylphosphoryl)acetohydrazide) and CAPAH (2-{[4-(dimethylamino)phenyl](2-chloroethoxy)phosphoryl}acetohydrazide) were studied by NMR, IR, and UV spectroscopy and X-ray powder diffraction. The results of the screening of neurotrophic activities of the molecular complexes are presented.

С целью оптимизации скрининга новых психотропных соединений с использованием компьютерной программы PASS был осуществлен прогноз психотропной активности 47 новых соединений, относящихся к ряду арил(гидразинокарбонилметил)фосфиновых кислот, из которых были выделены 16 наиболее перспективных. Психотропная активность этих веществ была изучена на лабораторных животных с использованием поведенческих моделей. Для этих соединений была прогнозирована мнемотропная активность (Pa = 0,742 – 0,840), антидепрессивная активность (Pa = 0,543 – 0,663) и анксиолитическая активность (Pa = 0,330 – 0,642). Результаты экспериментального изучения психотропной активности производных арил(гидразинокарбонилметил)фосфиновых кислот показали, что соединения оказывают мнемотропное, антидепрессивное и анксиолитическое действие в дозах, составляющих 1/100 и 1/1000 от ДЛ50. Результаты экспериментального изучения мнемотропной, антидепрессивной и анксиолитической активности в целом совпадают с данными компьютерного прогноза по программе PASS.

В настоящей работе представлены разработанные методики определения доброкачественности нового биологически активного вещества (БАВ) натриевой соли ацетилгидразино-4-хлорфенилфосфиновой кислоты (Na-CPAH), обладающего нейротропной активностью: «прозрачность раствора», «цветность раствора», «рН», «посторонние примеси», «потеря в массе при высушивании», «хлориды», «сульфаты», «сульфатная зола и тяжелые металлы». Представленные методики являются необходимыми для фармацевтического анализа и обязательными в анализе доброкачественности соединения при определении содержания посторонних примесей в лекарственных препаратах. Предложена методика идентификации посторонних примесей методом тонкослойной хроматографии в системе растворителей – этанол:хлороформ:аммиака раствор концентрированный 25 % (80:20:5) восходящим методом. Результаты испытания считаются достоверными, если на хроматограмме в УФ-свете при 254 нм четко видно одно пятно с Rf = 0,58 и возможно наличие пятна по размеру и интенсивности поглощения, не превышающее пятно СОВС. Подобранные оптимальные условия хроматографирования БАВ Na-CPAH способствуют высокочувствительному определению посторонних примесей в субстанции.

A new compound, (2-chloroethoxy-4’-dimethylaminophenyl)phosphorylacetic acid N -acetohydrazide (II) has been synthesized. Compound II is proposed to be a metabolite of 2-(chloroethoxy-4’-dimethylaminophenyl)phosphoryl acetohydrazide (CAPAH, I) – a phosphorylacetic acid derivative possessing nootropic activity. Psychotropic and antiarrhythmic properties of II were studied in comparison to those of I. It is established that II does not possess nootropic and antidepressant activities, but its antiarrhythmic properties are more pronounced. It is suggested that C(O)CH 3 fragment, being a substitute of hydrazide in the structure of II, decreases penetration of this compound through blood-brain barrier, which can explain the absence of psychotropic activity.

We were studied some pharmaceutical effects of new derivatives of with various cation enzymes’ nature. Compounds are possessed of ancsiolytic activity and exert positive influence upon memory and educational processes. Was also studied the dependence of compound’s activity on its chemical structure. We was conducted a detailed pharmaceutical analysis of one of the most active compounds — IX, which have a strongly pronounced mnemothropic effect and low toxicity. The compound is a norefedrinic salt of 4-fluorinephenylhydroxyphosphorylacetic acid’s hydraside. The compound’s structure is proved by elemental analysis findings, by infrared and ultraviolet spectroscopy methods. Conducted pharmaceutical ananlysis includes the designing of identificaion methodology, quality control and estimation of quantitative concentration.

The new compound (2-chloroethoxy-4′-dimethylaminophenyl)phosphorylacetic acid N-acetylhydrazide (II) was synthesized. Compound II was proposed as a metabolite of (2-chloroethoxy-4′-dimethylaminophenyl)phosphorylacetic acid hydrazide (CAPAH, I), a drug possessing nootropic activity. The psychotropic and antiarrhythmic properties of II were compared with those of I. It was established that II did not possess nootropic and antidepressant activities although its antiarrhythmic properties were more pronounced. It was suggested that the C(O)CH3 fragment, being a substituent on the hydrazide in II, decreased penetration of the compound through the blood―brain barrier, which could explain the absence of psychotropic activity.

Application of computer modeling to a series of phosphorylated carboxylic acid derivatives revealed new compounds possessing high psychotropic activity, i.e., hydrazinium salts of phosphorylacetohydrazides. It was proved experimentally that these compounds contributed to the improvement of memory and learning processes, possessed antihypoxic properties, and exhibited antidepressant activity. The pharmacologically relevant pharmacophores in this group were the methyl and fluorine atom in the phosphoryl aryl radical. The obtained results confirmed the expediency of using a complex analysis of computer modeling of the structure–activity relationship and an experimental search for pharmacophores for scientifically justified prognosis and design of new drugs.

A number of the pharmacological effects of new phosphorylacetohydrazides with different types of cationic fragments were studied. These compounds had anxiolytic activity, along with positive influences on memory and learning. The relationship between the activities of these compounds and their chemical structures was studied. Adetailed pharmacological analysis of one of the most active compounds – compound IX, which had marked mnemotropic actions and low toxicity – is presented. This compound is the norephedrine salt of 4-fluorophenylhydroxyphosphorylacetic acid hydrazide. The structure of this compound was confirmed by elemental analysis and IR and UV spectroscopy. Pharmaceutical analysis included development of an identification method, quality monitoring, and assay.

Цель настоящей работы – провести анализ «химическая структура - нейротропная активность» среди производных фосфорилированных карбоновых кислот, экспериментально выявить фармакофоры и наиболее перспективные соединения. Проведен синтез, фармакологическое изучение и установление зависимости в ряду новых производных гидразидов фосфорилуксусной кислоты для определения направлений синтеза и изучения наиболее перспективных соединений. Анализ зависимости структура-нейротропная активность среди незамещенных фосфорилацетогидразидов выявил фармакофоры, синтезированы новые ряды соединений: соли арил,гидроксифосфорилацетогидразидов с общей формулой: 4-XPhP(O)(O-)CH2C(O)NHNH2•[Z+] с различной природой катионного и анионного фрагментов. На поведенческих моделях экспериментально изучена мнемотропная и антидепрессивная активность данных соединений, установлены функциональные группы, отвечающие за эти виды активностей. Среди изученных фосфорилацетогидразидов выявлены перспективные для дальнейшего изучения соединения – производные 4-хлорфенилфосфорилуксусной кислоты, даны рекомендации для направленного синтеза новых эффективных соединений.

We have studied the main physicochemical properties of a new bioactive substances Na-CPAH, which belongs to a class of phosphorylacetohydrazides, with neurotropic activity. Based on these properties, we have developed methods of determining the qualitative and quantitative content. Oxidation-reduction reactions of Na-CPAH with known oxidants were suggested by high-sensitivity reaction with potassium permanganate. Furthermore, there was shown the necessity to use a complex of chemical and physicochemical methods to verify the authenticity of Na-CPAH: qualitative reaction on functional groups, parameters of IR and UV-absorption spectra. We studied its’ UV and IR absorption spectra, highlighted the characteristic bands of the major functional groups; and suggested the methodology of determining the authenticity of Na-CPAH by the IR absorption spectrum. The optimal conditions for spectrometric determination of Na-CPAH in substance were found. The method was developed for the quantitative analysis of the substance Na-CPAH of UV-spectrometry; The optimal conditions for the quantitative determination were suggested and it was found that concentration can be calculated by the index of absorption, as well as sucrose standard sample or calibration curve. The relative error in determination is not more than ± 0,72%.