8- Fluoro- l,2-dihydro

Treatment of 8-fluoro-l,2-dihydro-4 7,67/-[l,4]oxazino[4,3-a]quinoline-4,6-dione with 6N aqueous NaOH and PhCH2Br under reflux overnight and with NaOMe in DMF at ambient temperature yielded l-(2-benzyloxyethyl)- and l-vinyl-6-fluoro-l, 4-dihydroquinoline-2-carboxylic acids, respectively (01SL833). 

Reaction of ethyl 7-bromo-8-fluoro-l-(2-bromo-l-methylethyl)-4-oxo-l,4-dihydroquinoline-3-carboxylate with MeNH2 yielded 10-bromo-A, 1, 3-trimethyl-7-oxo-2,3-dihydro-7//-pyrido[l,2,3-<7e]quinoxaline-3-carboxamide (OOMIPIO). 

CN (la,5a,6a)-7-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)-l-(2,4-difluorophenyl)-6-fluoro-l,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid... 

A suspension of the diazonium salt in toluene was gradually heated and kept at 120°C (bath temp.) for 30 minutes with stirring. After evaporation of the solvent under reduced pressure, the residue was made alkaline with 10% sodium carbonate and then extracted with chloroform. The chloroform extract was dried over anhydrous potassium carbonate. After evaporation of the solvent, the crystalline residue was recrystallized from ethyl acetate to give 6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoropyridine (mp 132°-133°C). The 3-fluoro derivative was hydrolyzed with a mixture of 15% hydrochloric acid and methanol (1 2 v/v) to give 6-amino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoropyridine. This compound was treated with diethyl ethoxymethylenemalonate at 130°-140°C to give N-[2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate (mp 144°-145°C) and then the product was cyclized by heating at 255°C to give ethyl 7-(4-ethoxycarbonyl-l-piperazinyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (mp 279°-281°C). 

Ethyl 7-(4-ethoxycarbonyl-l-piperazinyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate was suspended in dimethylformamide (10 ml) and to the suspension was added potassium carbonate (0.53 g). After the mixture was kept at 60°C for 10 minutes with stirring, ethyl iodide (1.2 g) was added to the solution. The mixture was stirred for 2 hours at 60°-70°C. The reaction mixture was concentrated to dryness under reduced pressure, and water was added to the residue. After extraction with chloroform, the chloroform extract was dried over anhydrous potassium carbonate. After removal of the chloroform by distillation, the resulting precipitate was recrystallized from a mixture of dichloromethane and n-hexane to give 0.89 g of ethyl l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(4-ethoxycarbonyl-l-piperazinyl)-l,8-naphthyridine-3-carboxylate (mp 171°-173°C). A mixture of the above ethyl ester (0.8 g), 10% sodium hydroxide (6 ml) and ethanol (2 ml) was refluxed by heating for 3 hours. After cooling, the solution was adjusted to pH 7.0-7.5 with 10% acetic acid. The precipitate was collected by filtration, washed with ethanol and recrystallized from a mixture of dimethylformamide and ethanol to give 0.57 g of l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-l,8-naphthyridine-3-carboxylic acid. Melting point 220°-224°C. 

Syntesis of l-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hydrochloride (moxifloxacin hydrochloride) ... 

The slurry was filtered, and the compound was isolated as a white solid (75.5% yield based on (la,5a,6a)-3-N-benzyl-6-nitro-2,4-dioxo-3-azabicyclo[3.1.0]hexane 96.6% based on ethyl 7-chloro-l-(2,4-difluorophenyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid). The ethyl (la,5a,6a)-7-(6-benzylidenylamino-3-azabicyclo[3.1.0]hex-3yl)-l-(2,4-difluorophenyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate was recrystallized from acetonitrile, melting point 148°-155°C decomp. 

Ethyl 7-ethylsulfonyl-6-fluoro- l-(2-fluoroethy 1)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate 176-178 418... 

In addition to BAY X 8843 36, its 8-chlorine analogue 8-chloro-l-cyclopropyl-7-(S,S-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarbo-xylic acid hydrochloride BAY Y 3118 45 was also an important developmental candidate. Due to its broad activity spectrum, which included anaerobic bacteria [129-136], it had the potential for becoming a problem-solver . Unfortunately, during the Phase I trials photo toxic side effects occurred [137] which were due to the chlorine substituent in the 8-position, and these led to an abandonment of the development of this compound. 

The systematic names are as follows (2) l-Cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinolinecarboxylic acid (7) l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-l,8-naphthyridine-3-carboxylic acid (8) l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinolinecarbox5dic acid (6a)... 

Ethyl 8-amino- (26, R = NH2) underwent diazotization in fluoroboric acid to give ethyl 8-fluoro-l-hydroxymethyl-5,7-dimethyl-4-oxo-3,4-dihydro-6-phthalazinecarboxylate (26, R = F) [substrate, HBF4, H2O, 0°C, NaN02 in H20, 30 min solid. A, A, gasf 7%, after separation from the product of spontaneous cyclization, ethyl 4,6-dimethyl-3-oxo-2,3-dihydro-8//-furo[4,3,2-rie]phthalazine-5-carboxylate (26a) (31%)]." ... 

Rather high antineoplastic activity of ciprofloxacin derivatives, containing a substituent in position 4 of the piperazine fragment has been shown [302], Elucidation of the structure-activity relationships for l-(2-thiazolyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxylic acids has shown that several compounds of this series exhibit activity, comparable with the well-known drug etoposide [316-318], Also the data on activity of amides of 7-substituted l-(2-thia-zolyl)- and l-(2-benzothiazolyl)-l,8-naphthyridin-4-on-3-carboxylic acids have been reported [319], Ethyl l-(4-cyano-2,3,5,6-tetrafluorophenyl)-6,7,8-trifluoro-4-oxo-l,4-dihydroquinolin-3-carboxylate proved to inhibit the phosphorylation process of transcription STAT3 activator that plays an important role for cancer therapy [320],... 

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