4-hydroxy-2-quinolones. 176*. 4-R-2-oxo-1,2-dihydroquinoline-3-carboxylic acids. synthesis, physicochemical and biological properties

Abstract

Keywords: 4-R-2-oxo-1,2-dihydroquinoline-3-carboxylic acids, pKa, analgesic activity, hydrolysis.Even a brief glance at the scientific literature and patent documentation for 4-hydroxy-2-quinolones shows a very broad range of biological properties typifying them. In the series of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids the overwhelming number of publications relate to N-R-amides and the products of their subsequent chemical transformations. Esters have been studied much less frequently and the acids themselves hardly at all. Such a situation becomes fully understandable if one actually takes into account the diverse and well tested arsenal of highly efficient methods for synthesizing the amide derivatives [2][3][4][5][6][7][8]. Not least is the unlimited choice and availability of intermediate derivatives available from chemical industry in such syntheses in the form of primary or secondary alkyl-, aryl-, and hetarylamines. Thanks to this there is a real opportunity for a targeted change of properties of the N-R-amides obtained within very broad limits and so for achieving optimum properties. This is of particular value when carrying out work to create novel biologically active materials. Quite a number of fundamentally different methods of preparing 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids esters are well known [2][3][4][5][6][9][10][11][12]. However, all of these are only effective in relation to the lowest alkyl esters. In the reminder of the examples it is necessary to turn to special methods (e.g., high temperature transesterification [9]) but these are unfortunately characterized by low yields.

4-hydroxy-2-quinolones. 179*. Synthesis, structure, and anti-inflammatory activity of 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-ylacetic acid and its derivatives

“…It was proposed that the reason for this unusual effect lies in the impossibility of the reaction centers of the quinolineacetic acid forming strong intramolecular hydrogen bonds, thanks to which its acidic properties are markedly increased [9]. A similar relationship is seen in the N-methyl-substituted derivative pair 5 and 6.…”

4-Hydroxy-2-quinolones. 180*. Synthesis, chemical reactions, and analgesic activity of 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid alkylamides

“…In the first publication connected to this problem the 4-R-2-oxo-1,2-dihydroquinoline-3-carboxylic acids [3] were studied. The next step is to their amidated derivatives, and specifically in this report to 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid alkylamides 1a-x.…”

“…All of the alkylamide compounds obtained 1a-x are colorless, odorless, and tasteless, crystalline materials which are insoluble in water (Table 1). Their structure was confirmed by their 1 H NMR spectra, the assignment of whose signals did not cause difficulty ( 1 a R = Me, b R = Et, c R = All, d R = Pr, e R = i-Pr, f R = Bu, g R = i-Bu, h R = s-Bu, i R = C 5 H 11 , j R = i-C 5 H 11 , k R = C 6 H 13 , l R = C 7 H 15 , m R = C 8 H 17 , n R = C 9 H 19 , o R = C 10 H 21 , p R = C 12 H 25 , q R = -(CH 2 ) 2 OH, r R = -(CH 2 ) 3 OH, s R = -(CH 2 ) 3 OMe, t R = -(CH 2 ) 3 OPr-i, u R = cyclo-C 3 H 5 , v R = cyclo-C 5 H 9 , w R = cyclo-C 6 H 11 , x R = cyclo-C 7 H 13 The presence of an N(1)-allyl substituent in the 4-hydroxy-2-oxoquinoline nucleus of amides 1a-x infers the possible synthesis from them of the corresponding derivatives of 2-bromomethyl-7,8-dimethoxy-5-oxo-1,2-dihydro-5H-oxazolo [3,2-a]quinoline-4-carboxylic acid. As shown by us previously in the case of the isopropylamide 1e, reaction with an equimolar amount of molecular bromine can very readily cause halocyclization to the oxazolo [3,2-a]quinoline 3 [5].…”

“…The experiment was carried out by us with the same isopropylamide 1e. It was found that addition of a fivefold excess of bromine to its solution in glacial acetic acid immediately gave an orange, crystalline product which clearly differed in properties from those of the colorless 2-bromomethyl-7,8-dimethoxy-5-oxo-1,2-dihydro-5H-oxazolo[3,2-a]quinoline-4-carboxylic acid isopropylamide (3). At the same time, however, the 1 H NMR spectra of both samples proved remarkably similar.…”

“…The 5-methyl-substi-tuted oxazoloquinolinium bromides 9 (R = Me) are unable to undergo a similar transformation and remain unchanged after addition of water [9]. The analgesic properties of the 1-allyl-4-hydroxy-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid alkylamides 1a-x were studied in non-pedigree, white male rats using the method reported in detail by us before [3] for the standard electric current model of rectal mucosa stimulation [10]. Analysis of the screening results are given in Table 1 and conclusively confirm the correctness of our selection of this set.…”