Synthesis and biological properties of 3-(3-cycloalkylcarbamoyl-4-hydroxy-2-oxo- 1,2-dihydroquinolin-1-yl)propanoic acids and their nitriles

I. V. Ukrainets, O. V. Gorokhova, X. V. Andreeva


Based on the generally recognized in modern medical chemistry methodology of the chemical modification of substances, which are promising in the pharmacological respect, the preparative methods for their obtaining have been suggested and the synthesis of a series of new 3-(3-cycloalkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl)propanoic acids and their nitriles has been carried out. At the same time the alternatives of the synthesis of both intermediate cycloalkylamides of 4-hydroxy-2-oxo-1-(2-cyanoethyl)-1,2-dihydroquinoline-3-carboxylic acid and final quinolinylpropanoic acids are considered. It has been demonstrated that in the first case the choice of one or another method is determined by the physical characteristics of amine. So, it is expedient to perform amidation of ethyl 1-(2-cyanoethyl)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate with low boiling cycloalkylamines by the excess of amine in boiling alcohol, whereas with high boiling or crystalline amines thermolysis of equimolar amounts of reagents is more preferable. Transformation of quinolinylpropionitriles obtained into the corresponding quinolinylpropanoic acids without destruction of cycloalkylamide moieties can be performed by long-term heating in the mixture of hydrochloric and acetic acids with the low content of water. However, as the experiments carried out show, alkaline hydrolysis being more available and simple in its performance is suitable for the given trasformation. Thus, undesirable destruction of cycloalkylamide groupings occurs to only a small extent, and it can be neglected. The peculiarities of NMR 1H spectra of the compounds synthesized allowing to control easily the course of both side and planned reactions are discussed. Using standard screening models the analgesic and diuretic properties of all substances obtained have been studied. It has been found that transfer from 3-(3-R-carbamoyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl)propanoic acids and nitriles with alkyl substituents in the amide moieties to their cyclic analogues with the same number of carbon atoms does not lead to increase in the biological activity, and therefore, it is unpractical.


amides; 4-hydroxy-2-oxo-1,2-dihydroquinolines; hetarylpropanoic acids; hydrolysis; synthesis; analgesic activity; diuretic action


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