4-Hydroxy-2-quinolones 142. 4-Methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid anilides as potential diuretics

Abstract

A large series of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid anilides has been prepared as potential diuretic agents. The effect of all of the synthesized compounds on the urinary function of the kidney has been investigated. The appearance of a "structure -diuretic activity" relationship is discussed.In recent years along with the well known efficient use of diuretics in the treatment of kidney deficiency [2], glaucoma [3], epilepsy [4], and insipid diabetes [5, 6] the attention of pharmacologists and doctors has been increasingly paid to currently uncommon areas of use of the extrarenal effects of diuretic medicines in the treatment of bronchial obstruction syndrome, mucoviscidose [7], oncological [8,9], and a series of other illnesses. There is particular interest in the medicinal uses of diuretics which show both their diuretic properties together with anti-inflammatory [10,11], antioxidant [12, 13], antimicrobial [14, 15], cholagogue [16], hepatoprotective [17], hypolipidemic [18], and other useful activity. Even a cursory glance at the literature shows a marked and steadily increasing tendency to broaden the catalog of indications for diuretic agents in clinical practice. At the same time, over the last 30 years not a single class of novel diuretic has appeared in the world pharmaceutical market although the need for such preparations is obvious.It is interesting that quinoline type compounds have not been considered up to recent times as possible diuretic agents because such a type of pharmacological activity is considered atypical. None the less, in the process of carrying out systematic investigations, potential diuretics have been discovered by us amongst 4-hydroxyquinol-2-ones. It was possible to discover an interesting relationship, particularly fully and clearly identified in the case of amide derivatives of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acids. As a result it was convincingly shown that the level of the diuretic effect of the quinolone compounds depends significantly on the structure of the amide fragment and increases in the sequence: alkylamides < cycloalkylamides < 3-arylpropylamides < 2-arylethylamides < benzylamides << anilides [19,20].

4-Hydroxy-2-quinolones. 177*. Study of a structure-diuretic activity relationship in a series of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-R-amides

“…In later extended screening studies a similar type of biological activity was revealed in the closely structurally related amide derivatives of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-and also 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acids ( [3][4][5] and [6][7] respectively). In this way it was possible to show several important structure-biological activity relationships.…”

“…It is of interest that, of all of the 4-methoxyanilides in this series, the highest diuretic activity is shown only by the product with a free carboxyl group in the 1-N-alkyl fragment, i.e. the acid 20 [7]. The presence of such a substituent in the anilide part of the molecule is generally known [7] to bring about a totally opposite effect independently of its position in the aromatic ring.…”

“…the acid 20 [7]. The presence of such a substituent in the anilide part of the molecule is generally known [7] to bring about a totally opposite effect independently of its position in the aromatic ring. HCl, AcOH p-anisidine (compounds 2, 10a-d, 14a-d, 19, 20, 22) or ethanol (compounds 3-5, 8, 13, 15, 16).…”

“…In this way all of the compounds considered were separated into two approximately equal groups (see Table 1). In addition, within the class of active substances there were added those studied before which had clear diuretic properties and served as the basis for our investigation of the p-methoxyanilides of the 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-and 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acids [5] and [7] respectively.…”

4-Hydroxy-2-quinolones 150*. Efficient synthesis, structure, and biological activities of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid alkyl amides

“…In turn, thanks to the intermolecular hydrogen bonds N (2a) -H (2Na) ···O (2b) (H···O 2.09 Å, N-H···O 158º) and N (2b) -H (2Nb) ···O (2a') (1+x, y, z, H···O 2.11 Å, N-H···O 160º) these dimers are grouped in infinite chains along the crystallographic (1 0 0) direction. In addition, formation of the intermolecular hydrogen bonds likely leads to lengthening of the O (1) -C(9) bond to 1.244(4) in molecule A and to 1.268(4) Å in molecule B and the O (2) -C(10) bond to 1.245(3) in A and to 1.227(3) Å in B when compared with their mean value of 1.210 Å[7].…”