Detection of diuretic properties of 4-R-2-oxo-1,2-dihydroquinoline-3-carboxamides and determination as leader structures of 6-hydroxy-N-(4-methoxyphenyl)-4-oxo-1,2-dihydro-4H-pyrrolo-[3,2,1-ij]quinoline-5-carboxamide under the conditional name " Himopiron " and 6-hydroxy-N-(4-methoxybenzyl)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide, which were developed by scientists at the National University of Pharmacy, became the basis for the modification of these structures in order to further in-depth study of quinoline derivatives as bases for compounds capable of enhancing diuretic activity and thus protecting intellectual property of these leading structures. To modify the leader structures into a simpler bicyclic chemical structure, 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbon and 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acids derivatives were synthesized. The peculiarities of the application of N,N'-dicyclohexylcarbodiimide in the synthesis of ethyl esters of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids were analyzed. Elemental analysis and spectroscopy NMR 1Н were used to prove the chemical structure of all synthesized of compounds, which made it possible to easily identify proton-containing functional groups. High diuretic activity, low toxicity, no side effects and, most interestingly, the ability to inhibit aldosterone production, have been found in joint leaders. As a result of the above and using the principles of "me-too" technology, methylated analogues of the above pyrroloquinolines were included in the scope of research to find new diuretics. For the first time, a series of new 6-hydroxy-2-methyl-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamides was obtained. The chemical structure of the synthesized substances was confirmed by elemental analysis, 1H and 13C NMR spectroscopy data, mass and chromato-mass spectrometry, UV and IR spectroscopy, and in some cases by X-ray diffraction analysis. Modern physicochemical methods for quality control of promising substances are substantiated. Comparative analysis of biological studies allows us to conclude that the transition from tricyclic pyrrolo- and pyridoquinolines to bicyclic quinolones is accompanied by a decline in diuretic properties. Our structure-action (SAR) analysis showed that pyrroloquinolines are a more promising group for further study. In this group, a larger number of promising substances and higher activity rates compared with pyridoquinolines. We also found pharmacophore fragments that steadily increase diuresis. Summing up the comprehensive studies of the most promising leader compound - N-benzyl-6-hydroxy-2-methyl-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide, a study on the standardization of this substance, namely, proposed methods of identification, substantiated the presence of concomitant impurities and developed methods for their determination, developed a method of quantitative determination using acid-base titration in non-aqueous solvents with potentiometric fixation of the end-point of titration, validation procedure The developed methods are included in the MCQ project.
