Synthesis and antibacterial activity of 1-(substituted-benzyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acids and their 6,8-difluoro analogs

Alkylation of 6,7-difluoro-4-hydroxyquinoline-3-carboxylic acid ethyl ester with substituted-benzyl chlorides gave 1-(substituted-benzyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl esters. Their treatment with piperazine or N-methylpiperazine in pyridine yielded 1-(substituted-benzyl)-6-fluoro-1,4-dihydro-4-oxo-7-(l-piperazinyl)quinoline-3-carboxylic acid ethyl esters which were hydrolyzed with aqueous sodium hydroxide and then acidified with hydrochloric acid afforded the desired 1-(substituted-benzyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-iperazinyl)quinoline-3-carboxylic acids. The 6,8-difluoro analogs were prepared similarly using 6,7,8-trifluoro-4-hydroxyquinoline-3-carboxylic acid ethyl ester as a starting material. Some of these quinolones demonstrated fairly good antibacterial activities. Among them, 6-fluoro-1-(4-fluorophenylmethyl)-1,4-dihydro-7-(1-iperazinyl)-4-oxoquinoline-3-carboxylic acid ( 7d ) and 6,8-difluoro-1-(3-fluorophenylmethyl)-1,4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-3-carboxylic acid ( 8c ) are two of the best.     

New 7-substituted quinolone antibacterial agents. The synthesis of 1-ethyl-1,4-dihydro-4-oxo-7-(2-thiazolyl and 4-thiazolyl)-3-quinolinecarboxylic acids

A series of 1-ethyl-1,4-dihydro-4-oxo-7-(4-thiazolyl)-3-quinolinecarboxylic acids and 1-ethyl-1,4-dihydro-4-oxo-7-(2-thiazolyl)-3-quinolinecarboxylic acids were prepared. Also prepared was 10-[2-(aminomethyl)-4-thiazolyl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. Analogs with basic amine substituents on the thiazole moiety were found to have antibacterial activity.     

Synthesis and Crystal Structure of Ethyl 2-(6-(1,3-Dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl) Butanoate

The title compound ethyl 2-(6-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl) butanoate 3 was synthesized by the reaction of ethyl 2-(6-amino-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl) butanoate with 4,5,6,7-tetraydrophthalic anhydride,and its structure was determined by X-ray single-crystal diffraction.The crystal belongs to the monoclinic system,space group P21/n with a = 9.3469(2),b = 16.7715(5),c = 13.7153(4) ,β = 104.9680(10)°,μ = 0.107 mm-1,Mr = 430.42,V = 2077.08(10) 3,Z = 4,Dc = 1.376 g/cm3,F(000) = 904,T = 296(2) K,R = 0.0508 and wR = 0.1478.     

Synthesis of New Fluorinated Derivatives of Quinolinecarboxylic Acids

Ethyl esters of 1-(7-Z-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbamoyl)-5-X-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acids (X = H, F; Z = pyrrolidino-, piperidino-, hexamethylenimino-, morpholino-, thiomorpholino-) have been synthesized by the interaction of quinolone-3-carboxylic acid hydrazides with ethyl esters of 3-ethoxy-2-(polyfluorobenzoyl)acrylic acid . It was shown possible to cyclize intramolecularly the esters obtained with the formation of 1,3,4-oxadiazino[6,5,4-i,j]quinoline derivatives.     

Synthesis of fluorinated pyridines by the balz-schiemann reaction. An alternative route to enoxacin,a new antibacterial pyridonecarboxylic acid

Fluorination of the 2,6-disubstituted 3-aminopyridines 5 and 12 by the Balz-Schiemann reaction is described. 2,6-Dichloro-3-pyridinediazonium tetrafluoroborate ( 6 ) and 2-substituted 6-acetylamino-3-pyridinediazonium tetrafluoroborates 13 were heated with or without a solvent to give the corresponding fluorinated pyridines 7 and 14 , respectively, in good yields. 2-Substituted 6-acetylamino-3-fluoropyridines ( 14 ) were converted by a known method into a series of 7-substituted 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids 21 including enoxacin [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid [( 2 )], a new potential antibacterial agent.     

氨基清除树脂辅助合成2-(7-氟-3-氧-3,4-2H-苯并[b][1,4]噁嗪-6-基)异吲哚1,3-二酮

采用氨基清除树脂辅助合成方法,由6-氨基-7-氟-4-取代基-3(4H)-酮与取代邻苯二甲酸酐在冰醋酸中加热反应制备了2-(7-氟-3-氧-3,4-2H-苯并[b][1,4]噁嗪-6-基)异吲哚-1,3-二酮类化合物,纯度86％～95％．其结构经^1H NMR,IR和MS表征。     

Synthetic antibacterials. VIII. 7-(1′-alkylhydrazino)-1,8-naphthyridines and related compounds

Synthesis and in vitro antibacterial activity of 7-(1′-alkylhydrazino)-1,8-naphthyridines related to nalidixic acid were investigated. Namely, treatment of 7-alkylamino-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids 1a-d with sodium nitrite in the presence of hydrochloric acid gave the 1-ethyl-1,4-dihydro-7-(N-nitrosoalkylamino)-4-oxo-1,8-naphthyridine-3-carboxylic acids 2a-d , which upon reacting with zinc dust in acetic acid gave the 7-(1′-alkylhydrazino)-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacids 3a-d. The compound 3a was alternately obtained by the reaction of 7-chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphth-yridine-3-carboxylic acid ( 4 ) with methylhydrazine. The reaction of 7-chloro-4-hydroxy-1,8-naphthyridine-3-carboxylic acid ( 5 ) with methylhydrazine gave the 4-hydroxy-7-(1′-methylhydrazino)-4-oxo-1,8-naphthyridine-3-carboxylic acid ( 6 ), which upon treatment with alkyl halides afforded the 1-alkyl-1,4-dihydro-7-(1′-methyl-hydrazino)-4-oxo-1,8-naphthyridines 3a and 3e-g. The reaction of the appropriate 3 with ketones gave the corresponding 7-(1′-methylalkylidenehydrazino)-1,8-naphthyridines 7a-c and 8a-b. Among the compounds prepared, certain 3 and 7 exhibited good activity against Gram-negative bacteria.     

An efficient synthesis of 6-fluoronalidixic acid and its conversion to enoxacin

1-Ethyl-6-fluoro-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid ( 8 ) has been prepared in large quantities by a highly efficient process. It has in turn been degraded to give 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ( 11 ). This intermediate has been reacted with piperazine to give the known antibacterial agent, enoxacin ( 12 ).     

A novel approach to Finafloxacin hydrochloride (BAY35-3377)

Finafloxacin hydrochloride, an important clinical compound was synthesized by a novel synthetic approach. An active intermediate ethyl 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate 19 was prepared by a new route. The chiral (S,S′)-N-Boc 10 was derived from protected pyrrolidine and the absolute stereochemistry was established by X-ray analysis.     

Electrochemical, quantum chemical and SEM investigation of the inhibiting effect and mechanism of ciprofloxacin, norfloxacin and ofloxacin on the corrosion for mild steel in hydrochloric acid

The inhibiting effect and mechanism of 1-cyclopropyl-6-fluoro-1,4-dihydro -4-oxo-7-(1-piperazinyl) -3- quinoline carboxylicacid(ciprofloxacin), 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid (norfloxacin) and (?)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7- oxo-7 H-pyrido(1,2,3-de)-1,4- benzoxazine-6 carboxylic acid (ofloxacin) on the corrosion of mild steel in 1 mol/L HCl have been studied using electrochemical method, quantum chemical method and SEM at 303 K. The potentiodynamic results showed that these compounds suppressed both cathodic and an-odic processes of mild steel corrosion in 1 mol/L HCl. The impedance spectroscopy showed that Rp values increased, and Cdl values decreased with the rising of the working concentration. Quantum chemical calculation showed that there was a positive correlation between some inhibitors structure properties and the inhibitory efficiency. The inhibitors function through adsorption followed Langmuir isotherm, and chemisorption made more contribution to the adsorption of the inhibitors on the steel surface compared with physical adsorption. SEM analysis suggested that the metal had been protected from aggressive corrosion because of the addition of the inhibitors.     

Absorption Spectra of the 4f Electron Transitions of the Nd, Ho and and Er Complexes with 1-Cyclopyropyl-6-fluoro-1,4-dihydro-7- (4-ethyl-1-piperazinyl)-4-oxo-3-quinoline Carboxylic Acid Hydrochloride in the Presence of TX-100

The tripositive rare earth metal ions show comparatively little tendencies to form complexes with a variety of normally powerful coordinating agents due to their peculiar electronic configurations. However, certain chelating groups, notably the β-diketones1,2 and 8-quinolinols3,4, are capable of overcoming this difficulty through the formation of inner complex compounds. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7-(4-ethyl-1-piperazinyl)-4-oxo-3-quinoline carboxylic acid hydrochloride (NN…     

Synthesis ofN-substituted 2-(5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinolin-3-yl)glyoxylic acids

Methods for the synthesis of the earlier unknownN-substituted 2-(5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinolin-3-yl)glycoxylic acids their esters from copper chelate of ethyl pentafluorobenzoylpyruvate were developed. The structure of intermediate ethyl 4-(R-amino)-2-oxo-3-pentafluorobenzoylbut-3-enoates is discussed. Published inIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1234–1239, July, 2000.     

An intramolecular cyclization of 7-substituted 6-fluoro- 1,8-naphthyridine and -quinoline derivatives

A synthesis of 1,4-oxazine and pyrazine ring systems by an intramolecular cyclization of 7-substituted 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine and -quinoline derivatives having a nitrogen or oxygen nucleophilic site in the C-7 appendage was studied. The in vitro antibacterial activities of compounds prepared by this method were tested.     

The interaction of 2-(4-acetylphenylamino)-3-piperidino-1,4-naphthoquinone with hydroxylamine and hydrazines

With acid catalysts 2-(4-acetylphenylamino)-3-piperidino-1,4-naphthoquinone reacts with hydroxylamine and aryl hydrazines exclusively at the carbonyl group of its side chain. The products corresponding to the condensation at the naphthoquinone C=O group could not be detected.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1086–1088, June, 1994.     

New hexaarylbenzene-containing di- and tetrafluoroarenes

New hexaarylbenzene-containing di- and tetrafluoroarenes were prepared by the Diels—Alder reactions of 1,4-bis(1-oxo-2,4,5-triphenylcyclopentadien-3-yl)benzene with 4-fluoro-4′-(phenylethynyl)- and 4-fluoro-4′-(4-fluorophenylethynyl)benzophenone, respectively. __________ Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1881–1883, August, 2005.     

Heterocycles [h]-fused to 4-oxoquinoline-3-carboxylic acid. Part VII: synthesis of some 6-oxoimidazo[4,5-h]quinoline-7-carboxylic acids and esters

Abstract  

A series of ethyl 2-(substituted)-9-cyclopropyl-4-fluoro-6-oxo-1H-imidazo[4,5-h]quinoline-7-carboxylates has been prepared from ethyl 7,8-diamino-1,4-dihydroquinoline-3-carboxylate via thermally induced reactions with model alkanoic acids or via microwave-assisted cyclocondensation with some arene carboxaldehydes. Acid-catalysed hydrolysis of the resulting ester derivatives furnished the corresponding imidazoquinoline-7-carboxylic acids. The structures of these new acid and ester derivatives are based on microanalytical and spectral (IR, MS, and NMR) data.     

Synthesis and antibacterial activity of new 5-substituted 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids

The 5-hydroxymethyl and the 5-formyl-1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids have been prepared via a 5-trimethylsilyl group and were tested in vitro as potential antibacterials.     

Synthesis and calcium channel antagonist activity of new symmetrical and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-dihydropyridines

New symmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-di-hydropyridines were synthesized in moderate to good yields via the modified Hantzsch reaction of β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the presence of an excess amount of NH₄OAc. Also, the reaction of β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the presence of enamino esters and ketones was performed, and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-dihydropyridines were obtained in moderate to good yields at room temperature. The calcium channel blocking activity of these compounds was assessed. They demonstrated moderate to weak effects, although one compound had a comparable effect (IC₅₀ =1.40×10⁻⁷ M) with respect to the reference drug Nifedipine.     

Synthesis and antibacterial activities of novel dihydrooxazine and dihydrothiazine ring-fused tricyclic quinolonecarboxylic acids: 9-Fluoro-3-methylene-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7h-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and its 1-thia congener

A new synthetic method was developed to obtain two novel tricyclic quinolonecarboxylic acids, 9-fluoro-3-methylene-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ( 2 ) and its 1-thia congener 3 . The method involves the key intermediate of an oxetane derivative and its cleavage with acids. Evaluation of the antibacterial activities showed that 2 and 3 are excellent against both Gram-positive and Gram-negative organisms in vitro, being comparable to or only slightly less effective than Ofloxacin. In experimental systemic infections in mice, compound 2 showed distinctly higher activity than Ofloxacin, especially against infection caused by Escherichia coli.     

A regiospecific synthesis of 1-methylamino-6-fluoro-7-(4-methylpiperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

An efficient and regiospecific synthesis of 1-methylamino-6-fluoro-7-(4-methylpiperizin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ( 3 ) via an intramolecular nucleophilic displacement cyclization reaction is reported.