SYNTHESIS AND PROPERTIES OF N-[ 2-( BENZOYLAMINO ) ( 2-OXOINDOLIN-3-YLIDENE ) ACETYL ] AMINO ACIDS ETHYL ESTERS

Analysis of scientific and patent literature testifies that search of biologically active compounds among derivatives of 2-oxoindoline is prospective. They include well-known amino acids (tryptophane), neurohormone serotonine, a number of natural alkaloids and synthetic drugs (indomethacin, dimecarbin). For many years at the Analytical chemistry department of the National University of Pharmacy the extensive studies have been conducted in the field of development of synthetic methods and the study of physicochemical and biological characteristics of hetarylcarboxylic acids, in particular, 2-oxaindolineacetic acids and products of their transformation in order to search active and harmless medicines. The pharmacological research of (2-oxoindolin-3-ylidene)-2-oxoacetic acid derivatives allow making a conclusion that the highest nootropic activity is shown by substances containing amino acid esters moieties. Extending directions of the target-based search for biologically active compounds and basing on the previous studies it has been decided to include the fragments of amino acids into the core structure – 2-(benzoylamino)(2-oxoindolin-3-ylidene)-2-oxoacetic acid and to carry out the synthesis of N-[2-(benzoylamino)(1-R-2-oxoindolin-3-ylidene)acetyl]amino acids ethyl esters. The structure of the compounds synthesized has been confirmed by the data of elemental analysis, IRand 1H NMRspectroscopy. In 1H NMR spectrum of N-[2-(benzoylamino)(1-R-2-oxoindolin-3-ylidene)acetyl]glycine the signal of the methylene group of the amino acid residue is observed as a duplet at δ 4.0 ppm. The signal of the carboxyl group proton in the spectrum of the acid is not observed as a result of deuterium exchange. The signal of СН2-group is shifted downfield (4.08 ppm) for the ester. The signals of the ethoxy group are recognized as a quartet at 4.20 ppm (2Н, СН2) and a triplet at 1.21 ppm (3Н, СН3).


Analysis of scientific and patent literature testifies that search of biologically active compounds among derivatives of 2-oxoindoline is prospective. They include well-known amino acids (tryptophane), neurohormone serotonine, a number of natural alkaloids and synthetic drugs (indomethacin, dimecarbin). For many years at the Analytical chemistry department of the National University of Pharmacy the extensive studies have been conducted in the field of development of synthetic methods and the study of physicochemical and biological characteristics of hetarylcarboxylic acids, in particular, 2-oxaindolineacetic acids and products of their transformation in order to search active and harmless medicines. The pharmacological research of (2-oxoindolin-3-ylidene)-2-oxoacetic acid derivatives allow making a conclusion that the highest nootropic activity is shown by substances containing amino acid esters moieties. Extending directions of the target-based search for biologically active compounds and basing on the previous studies it has been decided to include the fragments of amino acids into the core structure -2-(benzoylamino)(2-oxoindolin-3-ylidene)-2-oxoacetic acid and to carry out the synthesis of N-[2-(benzoylamino)(1-R-2-oxoindolin-3-ylidene)acetyl]amino acids ethyl esters. The structure of the compounds synthesized has been confirmed by the data of elemental analysis, IR-and 1 H NMRspectroscopy. In 1 H NMR spectrum of N-[2-(benzoylamino)(1-R-2-oxoindolin-3-ylidene)acetyl]glycine
the signal of the methylene group of the amino acid residue is observed as a duplet at δ 4.0 ppm.The signal of the carboxyl group proton in the spectrum of the acid is not observed as a result of deuterium exchange.The signal of СН 2 -group is shifted downfield (4.08 ppm) for the ester.The signals of the ethoxy group are recognized as a quartet at 4.20 ppm (2Н, СН 2 ) and a triplet at 1.21 ppm (3Н, СН 3 ).
In Ukraine, as well as in the most countries all over the world, a cerebral stroke is one of the most frequent causes of disability and death rate.According to the research data there are 600 patients with the consequences of stroke per each 100 thousand of the population; 60% of them remain invalids.At the same time an active rehabilitation allows to decrease the degree of disability for patients that overcome the cerebral stroke and to turn them back to work.
Due to the fact that the native nootropic drugs nomenclature is significantly less than the nomenclature of this group of drugs available at foreign markets, and which is very often insufficient for necessities of medical practice satisfaction, the search of new nootropic drugs is an urgent task.Taking into consideration the reference sources the interest for chemistry of 2-oxoindolinacetic acids is conditioned by a significant biological activity of their derivatives [12,[14][15][16].
Lately the attempts of modification of different compounds by amino acids, which have a wide spectrum of the pharmacological activity and provide harmless and easily digestible form to other substances, are performed.In many cases they have the potentiating effect [17][18][19][20].In addition, amino acids participate in the processes of nervous, vascular and other types of regulation of the body's functions.
IR-spectra of the compounds synthesized, except the stretching bands n N-H 3332 and 3291 cm -1 (2-4) and 3297 cm -1 (5-5.5),have an increased intensity of stretching bands n С-H in the range of 3150-2928 cm -1 , and it indicates the presence of aliphatic substituents.The stretching band n С=O at 1733 (2-4) and 1737 cm -1 (5-5.5)testifies the presence of the carbonyl group in the structure bonded to the alkyl radical [1,4].
In 1 H NMR spectrum of N-[2-(benzoylamino)(1-R-2-oxoindolin-3-ylidene)acetyl]glycine (2) the signal of the methylene group of amino acid is recognized as a duplet at δ 4.0 ppm.The signal of the carboxyl group proton in the spectrum of the acid is not observed as a result of the deuterium exchange.The signal of the СН 2 -group is shifted downfield (4.08 ppm) for the ester (5).The signals of the ethoxy-group are observed as a quartet at 4.20 ppm (2Н, СН 2 ) and a triplet at 1.21 ppm (3Н, СН 3 ) [13].
Experimental Part When studying the objects under research in order to confirm the structure and purity of the substances synthesized the physical and chemical methods described in the State Pharmacopeia of Ukraine were used [2].
Melting points were determined by the capillary method on a "PTM (М)" apparatus.The elemental analysis of Nitrogen was carried out on an automatic analyser "CNH", model ЕА 1108 "Carlo Erba".
ІR-spectra were registered on a "Tensor 27" apparatus in KBr tablets, the concentration of the substance − 1%.The data of elemental analysis correspond to the calculated one.
2. The structure of the compounds synthesized has been proven by the data of elemental analysis, IR-and

1 Н
NMR spectra of the compounds synthesized were recorded on a Varian Mercury VX-200 spectrophotometer (200 MHz).The solvent was DMSO-D 6 , the internal standard was tеtramethylsilane (ТМS).Chemical shifts are given at the ppm scale.