1-Ethyl-1,4-dihydro-4-oxo-7-(pyridinyl)-3-quinolinecarboxylic acids. I. Synthesis of 3- and 4-(3-aminophenyl)pyridine intermediates

A series of substituted 3- and 4-(3-aminophenyl)pyridines has been prepared as intermediates for the synthesis of some 1-alkyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acids. The Hantzsch, Hauser and other pyridine syntheses were used. 4-(3-Aminophenyl)pyridine was prepared via 3-(4-pyridinyl)-2-cyclohexen-1-one using the Semmler-Wolff reaction.     

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.     

New 7-substituted quinolone antibacterial agents. II. The synthesis of 1-ethyl-1,4-dihydro-4-oxo-7-(pyrazolyl,isoxazolyl, and pyrimidinyl)-1,8-naphthyridine and quinolone-3-carboxylic acids

Synthetic methods for the construction of certain aromatic heterocyclic side chains for the quinolone anti-bacterials have been provided. In particular a series of 7-(pyrazol-3 or 4-yl, 4- or 5-isoxazolyl and 4- or 5-pyrimidinyl)-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine and quinoline-3-carboxylic acids have been prepared. All of the heterocycles were prepared from masked 1,3-dicarbonyl derivatives of nalidixic acid ( 9,17 ) or 7-acetyl-1-ethyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acids ( 8 ). These masked 1,3-dicarbonyl derivatives were prepared by the use of t-butoxy-bis-dimethylaminomethane on the activated methyls of 9,19 and 8 . The pyrimidinyl analogs, substituted with a 2-amino or a 2-aminomethyl moiety, were the only derivatives with substantial antibacterial activity.     

Quinolone antibacterials. 1. 7-(2-substituted-4-thiazolyl and thiazolidinyl)quinolones

A series of 7-(2-substituted-4-thiazolyl and thiazolidinyl)-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids and their 6-fluoro analogues were synthesized. The Hantzsch method was used for the preparation of the thiazolylquinolones. The thiazolidinylquinolones were synthesized by quaternization of the corresponding thiazolyl analogues, followed by reduction of the obtained thiazolium salts with sodium borohydride in aqueous solution. Antibacterial activity was tested in vitro. Most of the compounds were inactive against Gram-negative bacteria but some of them showed however good activity against Gram-positive bacteria and mycobacteria. This activity pattern is rarely found among the quinolone antibacterials.     

Synthesis and isomeric conversions of several 2-substituted 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives

Ethyl ester derivatives of 6- and 8-substituted 2-methyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids have been synthesized by treatment of the diethyl ester of acetylmalonic acid with 2- or 4-substituted anilines. Condensation of these newly synthesized quinolinecarboxylic acid derivatives with 4-nitrobenzaldehyde resulted in the formation of 6- and 8-substituted 2-[2-(4-nitrophenyl)-vinyl]-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acids and ethyl esters of 6- and 8-substituted 2-[2-(4-nitrophenyl)vinyl]-4-acetoxy-3-quinolinecarboxylic acids. The tautomeric and conformational transformations of these newly synthesized compounds have also been investigated, using IR, NMR, and UV spectroscopy.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 931–938, July, 1988.     

Studies on quinoline derivatives and related compounds. VI. A novel displacement reaction of 1-ethylquinolinium iodides with nucleophiles

The reaction of 4-amino- ( 3a ) and 4-anilino-3-carbethoxy-1-ethyl-6,7-methylenedioxy-quinolinium iodide ( 3b ) with nucleophilic reagents produced 7-substituted 4-amino-3-carboxy-1-ethyl-6-hydroxyquinolinium betaines ( 5b-d ) and 7-substituted 1-ethyl-1,4-dihydro-6-hydroxy-4-phenylimino-3-quinolinecarboxylic acid ( 6b-d ), respectively, which led to 7-substituted 1-ethyl-1,4-dihydro-6-hydroxy-4-oxo-3-quinolinecarboxylic acids ( 1b-d ) by alkaline hydrolysis. With a variety of 1-ethyl-1,4-dihydroquinoline carboxylates ( 16a-e ) these novel displacement reactions were attempted.     

Studies on quinoline derivatives and related compounds. II. Synthesis of 5-substituted 1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

The cyclization of m-substituted anilinomethylenemalonates ( 1 ) in the presence of polyphosphate ester and some other cyclizing agents gave mixtures of the isomeric ethyl 5- ( 2 ) and 7-substituted 4-hydroxy-3-quinolinecarboxylates ( 3 ), which led to mixtures of the corresponding quinolinecarboxylic acids ( 4 and 5 ) by hydrolysis. The proportions of 4 and 5 in the mixtures were determined on the basis of their nmr spectra. Novel 5-chloro- ( 8a ), 5-methyl- ( 8b ) and 5-nitro-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids were prepared and evaluated for antimicrobial activities. No significant activity, however, was noted.     

Studies on quinoline derivatives and related compounds. 1. A new synthesis of 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids

A novel preparative method for 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids was developed. The key process is the cyclization of N-alkylanilinomethylenemalonales, which was effected successfully in the presence of polyphosphoric acid, polyphosphate ester, boron tri-fluoride or a mixture of acetic anhydride and sulfuric acid. With phosphorus oxychloride, N-alkylanilinomethylenemalonates yielded 1-alkyl-4-chloro-3-carbethoxyquinolinium salts which were hydrolyzed readily to ethyl 1-alkyl-1,4-dihydro-4-oxo-3-quinolineearboxylates or their acids. By means of this novel method several new 1-alkyl-1,4-dihydro-4-oxo-3-quinolineearboxylic acids were prepared.     

Synthesis of a novel analog of nalidixic acid: 1-Ethyl-1,4-dihydro-4-oxo-7-(trifluororaethyl)-1,8-naphthyridine- 3-carboxylic acid

Reaction of nalidixic acid ( 1 ) with thionyl chloride and subsequent treatment with ethanol gave a mixture of ethyl 1-ethyl-1,4-dihydro-4-oxo-7-(trichloromethyl)-1,8-naphthyridine-3-carboxylate ( 3 ) and diethyl 1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3,7-dicarboxylate ( 4 ). Ethyl1-ethyl-1,4-dihydro-4-oxo-7-(trichloromethyl)-1,8-naphthyridine-3-carboxylate ( 3 ) was reacted with antimony pentafluoride to afford 1-ethyl-1,4-dihydro-4-oxo-7-(trifluoromethyl)-l,8-naphthyridine-3-carboxylic acid ( 5 ).     

Synthesis of 5,8-dihydro-5-oxo-2-(3- or 4-pyridinyl)-pyrido[2,3-d]pyrimidine-6-carboxylic acids and the reinvestigation of the thermal cyclization of diethyl (2-hydroxy-4-pyrimidinyl)amino-methylenemalonate

Diethyl [2-(3- or 4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonates 5 prepared by the reaction between 2-(3- or 4-pyridinyl)-4-pyrimidinamines 3 and diethyl ethoxymethylenemalonate ( 4 ) were thermally cyclized to afford ethyl 5,8-dihydro-5-oxo-2-(3- or 4-pyridinyl)pyrido[2,3-d]pyrimidine-6-carboxylates 6 . The later were alkylated with ethyl iodide and then saponified to give 5,8-dihydro-8-ethyl-5-oxo-2-(3- or 4-pyridinyl)pyrido-[2,3-d]pyrimidine-6-carboxylic acids 2 . Thermal cyclization of diethyl (2-hydroxy-4-pyrimidinyl)amino-methylenemalonate ( 8 ) gave ethyl 1,6-dihydro-4,6-dioxo-4H-pyrimido[1,6-a]pyrimidine-3-carboxylate ( 10 ) instead of ethyl 5,8-dihydro-2-hydroxy-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate ( 9 ) as previously claimed.     

Quinolone antibacterials. 2. 6-Substituted-7-(2-thiazolyl and thiazolidinyl)quinolones

A series of 6-substituted-1-ethyl-1,4-dihydro-4-oxo-7-(2-thiazolyl- and thiazolidinyl)quinoline-3-carboxylic acids were synthesized. Substitution at the 6-position was H, F or Cl. The Hantzsch method was used for the preparation of the thiazolylquinolones. The thiazolidinylquinolones were synthesized by quaternization of the corresponding thiazolyl analogues, followed by reduction of the obtained thiazolium salts with sodium borohydride in aqueous solution. Antibacterial activity was tested in vitro. The compounds were inactive against Gram-negative bacteria but some of them showed good activity against Gram-positive bacteria and mycobacteria. This activity pattern is rarely found among the quinolone antibacterials.     

Synthesis of some novel 7-substituted quinolonecarboxylic acids via nitroso and nitrone cycloadditions

1-Ethyl-6-fluoro-7-hydroxylamino-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7 can be either oxidized to the corresponding nitroso intermediate 8 or converted to the methylene nitrone 9. Both intermediates form cycloaddition products with selected dienes and olefins respectively. Also, the preparation of 1-ethyl-6-fluoro-7-(hexahydro-2-methyl-5H-pyrrolo[3,4-d]isoxazol-5-yl)-3-quinolinecarboxylic acid 5 via a nitrone cycloaddition is presented.     

Synthesis and chromatographic enantioresolution of anti-HIV quinolone derivatives

The successful enantioseparation of five 6-desfluoroquinolones with three polysaccharide-based stationary phases (namely, the cellulose-based Chiralpak IB and the two amylose-based Chiralpak AD-H and Lux Amylose-2) is herein described. The investigated species differ for the nature of substituents and/or the position of the stereogenic centre on the quinolone scaffold.The effect on the enantioseparation performance exerted by the different morphology of the cellulose-based and amylose-based polymers, was systematically evaluated for all compounds. In this frame, the impact of alternative alcoholic (ethanol, 2-ethoxyethanol, methanol, 2-propanol) and acidic (acetic, methanesulfonic and trifluoroacetic acid) modifiers as well as of a “non-standard” solvent (chloroform), was investigated in normal phase conditions along with the stereo-electronic peculiarities of the selected polymers. While 7-[4-(1,3-benzothiazol-2-yl)-2-methyl-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (1) was enantioresolved with conventional normal-phase conditions by means of the largely employed amylose-based Chiralpak AD-H column, the recruitment of a bulky alcohol (2-ethoxyethanol) succeeded in the enantioresolution of 6-amino-1-methyl-7-[2-methyl-4-(2-pyridinyl)-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (2) and 6-amino-1-[1-(hydroxymethyl)propyl]-4-oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (3) with the same column. The use of the amylose-based Lux Amylose-2 column, carrying both an electro-withdrawing (chlorine) and an electro-donating (methyl) group on the carbamate residue, allowed to get 6-amino-1-methyl-4-oxo-7-[3-(2-pyridinyl)-1-pyrrolidinyl]-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride (4) enanantioresolved, and 6-amino-1-methyl-4-oxo-7-(3-pyridin-2-ylpiperidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (5) enantioseparated.     

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.     

An Efficient Synthesis of N-Alkyl-1,4-Dihydro-4-Oxo-3-Quinolinecarboxylic Acid via 2-(2',2',2'-Tri-Chloro)Ethylidene-3-Oxo-3-(2'-Chlorophenyl)Propionate

A clay catalyzed synthesis of 2-(2',2',2'-trichloro)ethylidene-3-oxo-3-(2''-chlorophenyl)propionate (2) and its application for the preparation of various N-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids (5a-e) has been described.     

Synthesis and antibacterial activity of some 7-substituted 1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acids: Ethers,secondary amines and sulfides as c-7 substituents

A series of 7-substituted 1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acids were prepared from 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8 . Those derivatives reported contain acyclic and heterocyclic substituents linked to the quinolone C-7 position via O, NH or S. The in vitro antibacterial data of some of these derivatives against 4 Gram positive and 4 Gram negative organisms are reported.     

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.     

Design, synthesis, and biological evaluation of a library of 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides

A library of 422 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides was prepared in five steps using solution-phase chemistry. The first step in the synthesis was the reaction of ethyl 2-ethoxymethylene-3-oxo-4,4,4-trifluorobutanoate with thiosemicarbazide, which is reported in the literature to afford a 1:1 mixture of ethyl 1-thiocarbamoyl-5-(trifluoromethyl)pyrazole-4-carboxylate and ethyl 1-thiocarbamoyl-3-(trifluoromethyl)pyrazole-4-carboxylate. We reassigned the structure of the product to be a single compound, ethyl 5-hydroxy-1-thiocarbamoyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-carboxylate. This common intermediate was diversified by reaction with 17 alpha-bromoketones affording, in two steps, 17 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxylic acids. Scavenger resins were used to facilitate formation and purification of up to 27 amides from each of these acids in the last step. In addition, the Curtius reaction was applied to 12 of the acids followed by quenching with alcohols to afford a 108-member carbamate library. Certain compounds in the two libraries were toxic to C. elegans.     

Synthesis and In vitro biological activity of some 7-(5-aminomethyl-2-isoxazolidinyl)quinolone-3-carboxylic acids

The synthesis of the title compounds via nitrone cycloaddition is described. The in vitro antibacterial activity of these compounds is compared against 1-ethyl-6,8-difluoro-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (CI-934).     

Condensed pyridazines. Part III. Rearrangement and ring cyclization during the thermolysis of (z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate

The thermolysis of (Z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate ( II ) provides a new synthetic route to pyrrolo[2,3-c-]pyridazines, specifically, methyl 3-chloro-1,6-dimethyl-4-oxo-1,4-dihydro-7H-pyrrolo[2,3-c]pyridazine-5-carboxylate ( III ) in 91% yield. Treatment of III with ozone provides an entry into the novel pyridazino[3,4-d][1,3]oxazine ring system, specifically, 3-chloro-1,7-dimethylpyridazino[3,4-d][1,3]oxazine-4,5-dione ( IV ) in 73% yield. Compound IV is smoothly hydrolyzed into 6-acetylamino-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( V ) which is readily recyclized into IV by dehydration with acetic anhydride. Furthermore, IV undergoes a facile reductive ring opening reaction with sodium borohydride to give 3-chloro-6-ethylamino-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( VI ) in 95% yield.