NL9100648A - ANTIBACTERIAL PREPARATION, AND ONE IN PLACE 1 SUBSTITUTED 7- (CYCLIC AMINO) -6-FLUORO-4-OXO-1,4-DIHYDRO-1,8-NAFTYRIDINE-3-CARBONIC ACID DERIVATIVE. - Google Patents

Description

Extract

A 6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivative of the formula below, wherein R 1 is a hydrogen atom or a carboxyl protecting group, R 2 is an optionally substituted aryl group, and R 3 is a 1-pyrrolidi group is substituted with at least one hydroxyl or alkyl amino group or a pharmaceutically acceptable salt thereof, as well as an antibacterial composition containing such pyrrolidino-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivative.

Short designation: Antibacterial preparation, as well as a 7- (cyclic amino) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid derivative substituted in position 1.

The invention relates to an antibacterial preparation containing a 1-substituted 7- (cyclic amino) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid derivative as active substance .

Such a preparation is known from European patent application 0.027.752, which concerns the use of the 7- (3-aminopyrrolidino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydro-1,4 as active substance. 8-naphthyridine-3-carboxylic acid or a pharmaceutically acceptable salt thereof. As a pharmaceutically acceptable salt, a salt with hydrogen chloride or with methanesulfonic acid is preferably used. The preparation shows strong antibacterial activity against both Gram positive and Gram negative bacteria, including Pseudomonas aeruoinosa.

Such a preparation is also known from French patent application 2,500,833, in which reference is made in place 1 with a vinyl or 2-fluoroethyl group substituted 7- (3-aminopyrrolidino) -6-fluoro-4-oxo-1,4 dihydro-1,8-naphthyridine-3-carboxylic acid or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt can be an acid addition salt, but also a salt with a base. The preparation exhibits a strong antibacterial action, especially against Gram-negative bacteria, including Pseudomona strains. The degree of activity against Gram-negative bacteria is stronger than that of a preparation containing the active substance 7- (3-aminopyrrolidino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydro-1,8 -naphthyridine-3-carboxylic acid.

It has now been found that new position 1 substituted compounds of the formula 1 hereinafter described wherein R2 is a hydrogen atom or a carboxyl protecting group, R2 is an optionally substituted aryl group and R2 is a piperazino group, which may be substituted with at least one hydroxyl or alkylamino group have a strong antibacterial activity. against Gram-positive and Gram-negative bacteria, in particular against bacteria, which have become resistant to antibiotics.

The invention therefore relates to the antibacterial preparation described in the opening paragraph, characterized in that the active substance is a compound of the formula 1, wherein R 2 is a hydrogen atom or a carboxyl protecting group, R 2 is an optionally substituted aryl group and R 3 is a piperazine group, which may be substituted with at least one hydroxyl or alkylamino group, or a pharmaceutically acceptable salt thereof.

The salt formation with the compounds of formula 1 can occur both on basic groups, such as amino groups, and on the acidic carboxyl group. For the former, salts with inorganic and organic acids are suitable, such as hydrogen chloride, sulfuric acid, oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid. For example, salts with the carboxyl group are suitable for sodium, potassium, calcium, magnesium and ammonium salts, as well as salts with organic nitrogen bases such as procaine, dibenzylamine, N-benzyl / 3-phenethylamine, 1-ephenamine, N, N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, Ν, Ν-dimethylaniline, N-methyl-piperidine, N-methylmorpholine, diethylamine and dicyclohexylamine.

The optical antipodes of the compounds of the formula I as well as all crystal forms and hydrates of those compounds are within the scope of this invention.

It should also be noted that in a publication by J. Matsumoto et. al. in J. Medicinal Chem 27, 292-301 (March 1984), the results of an investigation of the antibacterial activity of various 1,6,7-trisubstituted 4-oxo-1,4-dihydro-1,8- are described. naphthyridine-3-carboxylic acid derivatives. As substituents at position 1 are mentioned deethyl, 2-fluoroethyl, difluoromethyl and vinyl group. This publication does not indicate to a person skilled in the art that together substituted in position 1 - (3-substituted pyrrolidino) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid derivative replacing an ethyl, 2-fluoroethylvinyl group as substituents in position 1 with an optionally substituted aryl group results in compounds - the compounds of the present formula 1 - which exhibit a strong antibacterial activity both against Gram-positive and against Gram-negative bacteria.

It should also be noted that in the unpublished European patent application 0,153,580; in which the Netherlands is one of the designated States and for which a priority right has been claimed as of January 26, 1984; it refers to the antibacterial activity of 1,7-disubstituted 6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridi -ne-3-carboxylic acid derivatives, to be represented by the present formula 1, wherein R 2 represents an unsubstituted or substituted phenyl group or an aromatic hetocyclic group, R 3 represents an unsubstituted or substituted amino group or an aliphatic heterocyclic group. However, the compounds of formula I herein have been cited as such in the earlier grade of this European patent application.

Listed below are the antibacterial actions of some representative compounds of the invention, which were determined as follows: 1. In vitro activity

According to the standard method of the Japanese Chemotherapy Association [Chemotherapy 29 (1), 76-79 (1981)], a plate of cardiac infusion agar containing the test substance was inoculated with a bacterial suspension obtained by cultivation at 37 ° for 20 hours. C in a heart infusion broth (from the firm Oak Kagaku). After 20 hours incubate the inoculated plate

Oak Kagaku). After incubation of the inoculated plate at 37 ° C for 20 hours, it was checked whether bacteria were growing on it. The minimum concentration of the test substance which inhibited the growth of bacteria was determined; this is the MIC value (inμg / ml). The seed was 104 cells per plate (106 cells / ml). MIC values found are shown in Table A. In this table, penicillmase-forming bacteria are indicated by * 1 and cell alosporinase-forming bacteria by * 2.

2. Acute toxicity

The test compound was dissolved in 1st equivalent 0.1N NaOH in water, and per ml mouse 10 ml of this solution was slowly injected into the tail vein of male mice of the ICR strain (of 20 ± 2 g; 5 mice per group).

The LD50 values of the compound 2 in Table A is greater than 200 mg / kg.

Table A.

The invention further relates to a 1-substituted 7- (substituted pyrrolidino) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid derivative) of the formula 1 as above defined or a pharmaceutically acceptable salt thereof, suitable for use as active substance in the antibacterial composition described in the opening paragraph.

The compounds of the invention are prepared in analogous manner for analogous compounds. In particular, this can be done according to the reaction scheme given herein, in which R 1, R 2 and R 3 meet the definitions given earlier, R 1a represents the same protecting group as in R 1 and R 3a is a halogen atom, such as fluorine, chlorine and bromine. As appropriate, the corresponding salts can also be recovered from the given compounds.

Compounds of the general formula 3 or 6 or a salt thereof can be obtained by reacting an appropriate acetal such as Ν, Ν-diethylformamide dimethyl acetal or N, N-dimethylformamide diethyl acetal etc. with a compound according to formula 2 or formula 5 and then with an amine with the formula R2 -nh2.

The solvent to be used in these reactions can be any solvent which is inert under the reaction conditions, such as benzene, toluene, xylene, dioxane, tetrahydrofuran, anisole, dimethoxyethane, methylene chloride, chloroform, dichloromethane, Ν, Ν-dimethylformamide N, N-dimethylacetamide, and dimethyl sulfoxide; these solvents can be used alone or in combination. The amount of acetal used is preferably 1 mole or more, in particular 1.0-1.3 moles per mole of compound of formula 2 or a salt thereof is generally carried out at a temperature between 0 ° and 100 ° C, preferably between 50 ° and 80 ° C, and generally requires between 20 minutes and 50 hours, usually between 1 and 3 hours. 1 mole or more of the amine per mole compound of formula 2 or 5 or a salt thereof is used. The reaction proceeds between 0 ° and 100 ° C, preferably between 10 ° and 60 ° C, and requires between 20 minutes and 30 hours, usually between 1 and 5 hours.

Alternatively, it is also possible to react a compound of general formula 2 or of formula 5 or a salt thereof in the presence of acetic anhydride with methyl chloroformate or methyl orthoformate, and then with an amine of formula R2-NH2 or a salt thereof. Then, too, a compound of formula 3 or 6 or a salt thereof is obtained.

The compound of general formula 4 or 1 or a salt thereof is obtained by causing a base closure in a compound according to formula 3 or formula 6 (preferably under heating).

The solvent to be used in this cyclization reaction can be any solvent that is in the reaction inert, such as Ν, Ν-dimethylformamide, N, N-dimethoxyethane and dimethyl sulfoxide. These solvents can be used alone or in combination. The base can be, for example, NaHCO3, K2CO3, potassium tertiary butoxide or NaH. The amount of base used is between 0.5 and 5 moles of permole compound according to formula 3 or 6. The reaction generally takes place between 20 ° and 160 ° C, preferably between 100 ° and 150 ° C, and generally requires between 5 minutes and 30 hours, usually between 5 minutes and 1 hour.

A compound of the general formula 5, 6 or a salt thereof can be obtained by reacting a compound of the general formula 2, 3 or 4 or a salt thereof with a piperazine according to the general formula R3-H or a salt thereof.

The solvent to be used in that reaction may be any inert liquid in the reaction, such as benzene, toluene and xylene, dioxane, dimethoxyethane, methylene chloride, chloroform, dichloroethane, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and dimethyl sulfoxide; these solvents can be used alone or in combination. The piperazine compound used is preferably an excess, most preferably between 2 and 5 moles per mole compound of formula 2, 3 or 4 or a salt thereof.

It is also possible to suffice with 1 to 1.3 mol if the permole compound of the formula 2, 3 or 4 or a salt thereof contains 1 mol of an acid binding agent. Deacid-binding agents include organic and inorganic bases such as triethylamine, 1,8-diazabicyclo [5,4,0] -7-undecene, potassium tertiary butoxide K2CO3, Na2CO3 and NaH.

The cyclic amine of the formula R3-H can also be j

used as salt. The reaction generally becomes I.

conducted between 0 ° and 150 ° C, preferably between 50 ° and 100 ° C, and generally lasts between 5 minutes and 30 hours, usually between 30 minutes and 3 hours.

A compound of the general formula 1, 3, 4 or 6 in which 1 represents a carboxyl protecting group, and the salts thereof may be converted, if desired, into the corresponding free acids by hydrolyzing them conventionally with acid or base, generally between 0 ° and 100 ° C, preferably between 20 ° and 100 ° C. This hydrolysis takes between 5 minutes and 50 hours, usually between 5 minutes and 4 hours. Furthermore, a compound of formula 1, 3, 4 or 6 can be converted into a salt or an ester in a known manner. When the compound of formula 3, 4, 5 or 6 or a salt thereof contains a protecting group, the protecting group is removed in the usual manner.

The compounds obtained can be isolated and purified by conventional means, using methods such as column chromatography, recrystallization, extraction, etc.

When the compound according to the invention is used as a medicament, it is suitably combined with carriers used in pharmaceutical preparations. The compositions may be in the form of tablets, capsules, powdered syrups, granules, suppositories, ointments, injection fluids and the like. The mode of administration, the doses used and the number of doses can be varied as needed depending on the symptoms of the patients; usually they will be administered orally or parenterally (for example, by injection, drip or through the rectum) at a dose between 0.1 and 100 mg / kg per day, optionally in multiple portions.

The invention is now further illustrated by the following examples.

Example 1.

a) A solution of 21 g of 2,6-dichloro-5-fluoro-nicotinic acid, 23.8 g of thionyl chloride and 0.1 g of dimethylformamide in 210 ml of chloroform was reacted for 2 hours at 70 ° C. Solvent and excess thionyl chloride distillation under reduced pressure was then removed and the residue (2,6-dichloro-5-fluoro-nicotinoyl chloride) was taken up in 21 ml of tetrahydrofuran.

A solution of 25.1 g of diethylethoxymagnesium melonate in 110 ml of tetrahydrofuran was cooled to between -40 ° and -30 ° C, and the above-mentioned solution of 2,6-dichloro-5-fluoro-nicotinoyl chloride was added dropwise for 30 minutes at the same temperature. This mixture was stirred at the same temperature for an additional 1 hour and then the mixture was allowed to warm gradually to room temperature. The solvent was removed by distillation under reduced pressure and 200 ml of chloroform and 100 ml of water were added to the residue. The pH value was adjusted to 1 with hydrochloric acid. The organic layer was separated and washed successively with 50 ml of water, 50 ml of 5% NaHCO 3 solution and 50 ml of saturated NaCl solution, and finally dried over MgSO 4. The solvent was then distilled off under reduced pressure and 50 ml of water, 0.15 g of p-toluenesulfonic acid was added to the residual oily liquid, and the mixture was reacted with stirring at 100 ° C for 2 hours. The reaction mixture was then extracted with 100 ml of chloroform. know. The organic layer was washed with 50 ml of saturated NaCl solution and dried over MgSO 4, then the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography with toluene on Wako Silica Gel C-200, adding 23.5 g of ethyl (2,6-dichloro-5-fluoro-nicotinoyl) acetate with mp. 64-65 ° C. IR (in KBr): maxima at 1650, 1630, 1620 cm-1NMR (CDC13) maxima at 5 values (in ppm) 1.25 (1.29H, t, J = 7Hz), 1.33 (1.71H , t, J = 7Hz), 4.07 (1.14H, S), 4.28 (2H, q, J = 7Hz), 5.82 (0.43H, s), 7.80 (1H, d J = 7Hz), 12.62 (0.43H, s).

b) A solution of 8.8 g of ethyl (2,6-dichloro-5-fluoro-nicotinoyl) acetate and 4.5 g of N, N-dimethylformamide dimethyl acetal in 40 ml of benzene was allowed to creave at 70 ° for 1 hour. Then 4.1 g of 2,4-difluoroaniline was added and the mixture was allowed to stand at room temperature for 4 hours. The solvent was then removed by distillation under reduced pressure. The residue obtained was purified by column chromatography with chloroform (Wakosilicagel C-200), yielding 9.0 g of ethyl 2- (2,6-dichloro-5-fluoro-nicotinoyl) -3- (2,4-difluorophenylamino) acrylate with mp . 138-139 ° C.

IR (in KBr) maxima at 1690 cm -1 NMR (CDCl3) maxima at 5 values (in ppm) 1.08 (3H, t, J = 7HZ), 4.10 (2H, q, J = 7Hz), 6.77-7.40 (4H, m), 8.50 (1H, d, J = 13Hz), 12.70 (1H, d, J = 13Hz).

o) To a solution of 9.0 g of ethyl 2- (2,6-dichloro-5-fluornicinoyl) -3- (2,4-difluorophenylamino) acrylate in 90 ml of dimethylformamide, 3.6 g of NaHCO3 were added and the mixture was stirred for 20 minutes kept at 120 ° C. The solvent was then distilled off under reduced pressure and the residue was taken up in 50 ml of chloroform. This solution was washed successively with 30 ml of water and 30 ml of saturated NaCl solution and then dried over MgSO 4. The solvent was distilled off under reduced pressure and the crystalline residue was washed with 30 ml of diethyl ether to give 7.0 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4- dihydro-1,8-naphthyridine-3-carboxylate mp 220-222 ° C.

IR (in KBr) maxima at 1730, 1690 cm-1 NMR (CDCI3) maxima at 5 values (in ppm) 1.36 (3H, t, J = 7Hz), 4.30 (2H, q, J = 7Hz ), 6.80-7.60 (3H, m), 8.27 (1H, d, J = 7Hz), 8.42 (1H, s).

d) A solution of 3.5 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate, 1, 5 g of N-acetylpiperazine and 1.6 g of triethylamine in 35 ml of chloroform were kept at 60 ° C for one hour and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (with 3% ethanol in chloroform on Wako silica gel C-200) some 3,5-ethyl 7- (4-acetylpiperazino) -6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate mp 207-209 ° C.

IR (in KBr) maxima at 1730, 1695 cm -1 NMR (CDCl3) maxima at <S-values (in ppm) 1.38 (3H, t, J = 7Hz), 2.05 (3H, s), 3 .53 (8H, bs), 4.30 (2H, q, J = Hz), 6.80-7.75 (3H, m), 8.00 (1H, d, J = 13Hz), 8.30 (1H, s).

e) A solution of 2.5 g of ethyl 7- (4-acetylpiperazino) -6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine- 3-carboxylate in 25 ml of 6N hydrochloric acid was refluxed for 2 hours. After cooling to room temperature, the pH was adjusted to 12 with N NaOH solution, then 6.5 with acetic acid. The separating crystals were collected by filtration, washed with 30 ml of water and then dried to give 1.8 g of 6-fluoro-1- (2,4-difluoro-phenyl) -7-piperazino-4-oxo-1,4-dihydro -1,8-naphthyridine-3-carboxylic acid.

NMRiTFA-dL) maxima at 3.30-4.50 (8H, m), 7.00-7.85 (3H, m), 8.33 (1H, d, J = 13HZ), 9.21 (1H , s).

Table B.

Compounds of formula 1 Rx = H.

{"IR spectrum measured in nujol.

Example 2.

a) A solution of 5.5 g of ethyl [2,6-dichloro-5-fluoro-nicotinoyl) acetate (prepared as indicated in Example 1a), 2.37 g of N-methylpiperazine and 2.37 g of triethylamine in 55 ml of chloroform was left for 2 hours react at 60-65 ° C. The reaction mixture was now washed with 30 ml of water, dried over MgSO 4 and evaporated to dryness under reduced pressure. The residue obtained was purified by column chromatography (metchloroform on Wako silica gel C-200) to yield 5.4 ethyl- [2-chloro-5-fluoro-6- (4-methylpiperazino) nicotinoyl] acetate in the form of an oily liquid .

IR maxima at 1750, 1695 cm -1 NMR (CDCI3) maxima at £ values (in ppm) 1.25 (3H, t, J = 7Hz), 2.32 (3H, s), 2.12-2, 70 (4H, H1), 3.55-3.96 (4H, m), 4.03 (2H, s), 4.20 (2H, q, J = 7Hz), 7.78 (1H, d, J = 13Hz).

b) To a solution of 4.5 g of ethyl [2-chloro-5-fluoro-6- (4-methylpiperazino) nicotinoyl] acetate in 22.5 ml of benzene was added 1.87 g of N, N-dimethylformamide dimethyl acetal, and that mixture was allowed to stand at 70 ° C for 2 hours. 1.8 g of 4-methoxy-2-methylaniline was added to the reaction mixture, and that mixture was allowed to stand at room temperature for 4 hours. The solvent was then removed by distillation under reduced pressure and the residue was purified by column chromatography (with 1% ethanol in chloroformover Wako silica gel C-200). There was thus obtained a crystalline substance which was washed with 10 ml of diethyl ether to give 5.0ethyl 2- [2-chloro-5-fluoro-6- (4-methylpiperazino) nicotinoyl] 3- (4-methoxy-2-methylphenylamino) acrylic with mp. 141-142 ° C.

IR (in KBr) sch. at 1710 cm-1, maximum at 1695 cm-1NMR (CDCI3) maxima at 6 values 1.08 (3H, t, J = 7Hz), 2.32 (3H, s), 2.40 (3H, s) , 2.23-2.68 (4H, m), 3.47-3.83 (4H, m), 3.75 (3H, s), 4.07 (2H, q, J = 7 Hz), 5.65-7.25 (3H, m), 7.20 (1H, d, J = 13Hz), 8.48 (1H, d, J = 13Hz), 12.82 (1H, d, J = 13Hz) ).

c) To a solution of 5.0 g of ethyl 2- [2-chloro-5-fluoro-6- (4-methylpiperazino) nicotinoyl] -3- (4-methoxy-2-methylphenylamino) acrylate in 50 ml N, N Dimethylformamide was added 1.03 g of NaHCO3 and the mixture was reacted at 120 ° C for 3 hours. The solvent was then distilled off under reduced pressure. The residue was dissolved in 50 ml of chloroform. This solution was washed successively with 30 ml water and 30 ml saturated NaCl solution and dried over MgSO 4. The solvent was removed under reduced pressure and the resulting crystalline substance was washed with 30 ml of diethyl ether to add 2.38 g of ethyl 6-fluoro-1- (4-methoxy-2-methylphenyl) -7- (4-methyl-piperazino) -4- oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate mp 144-145 ° C.

IR (in KBr) maxima at 1730, 1690 cm -1 NMR (in CDCl3) maxima at 6 values (in ppm) 1.33 (3H, t, J = 7Hz), 1.95 (3H, s), 2 .20 (3H, s), 2.05-2.62 (4H, m), 3.32-3.63 (4H, m), 3.82 (3H, s), 4.32 (2H, q , J = 7Hz), 6.60-7.15 (3H, m), 8.02 (1H, d, J = 13Hz), 8.23 (1H, s).

In the same manner, the compounds indicated in Table C were obtained.

Table C.

Compounds of formula 1, Rx = ethyl.

(Continued from Table C).

Example 3.

a) A suspension of 0.50 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (see Example 1c), in 15 ml of 6N hydrochloric acid, was refluxed for 3 hours. The reaction mixture was then diluted with 50 ml of water and extracted with 3 x 50 ml of chloroform. The extracts were washed together with 100 ml of saturated NaCl solution and dried over MgSO 4. The solvent was distilled off under reduced pressure, the crystalline substance thus obtained was washed with 15 ml of diethyl ether to give 0.40 g of 7-chloro-6-fluoro-1- ( 2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, m.p. 244-248 ° C.

IR (in KBr) maximum at 1720 cm-1 NMR (in d6-DMS0) maxima at δ values (in ppm) 7.26-8.56 (3H, m), 8.86 (1H, d, J = 7Hz) and 9.18 (1H, s).

b) To a suspension of 0.30 g of 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid in 3 ml dimethyl sulfoxide, 0.25 g of N-methyl-piperazine was added and the suspension was allowed to react at 60 ° C for 30 minutes. The solvent was then distilled off under reduced pressure and 30 ml of water was added to the residue. The pH of the mixture was adjusted to 12 with 10% NaOH solution, then to 7 with acetic acid. The crystalline precipitate was collected by filtration and washed with 5 ml of water to give 0.24 g of 6-fluoro-1- (2, 4-difluorophenyl) -7- (4-methylpiperazino) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, m.p. 208-209 ° C.

IR (in KBr) maximum at 1730 cm-1 NMR (in TFA-d · ^ maxima at δ values (in ppm) 3.30 (3H, s), 3.45-5.25 (8H, m), 7.12-8.10 (3H, H1), 8.49 (1H, d, J = 13Hz) and 9.38 (1H, s).

Example 4 a) In the manner of Example 1b, ethyl (2,6-dichloro-5-fluoro-nicotinoyl) acetate with 4-fluoroaniline was converted into ethyl 2- (2,6-dichloro-5-fluoro-nicotinoyl-3- (4-fluorophenylamino)) acrylic, melting point 110-114 ° C.

IR (KBr) maxima at 1710, 1680 cm-1.

b) The acrylate prepared under a) was converted to ethyl 7-chloro-6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine in the manner of Example 1c. 3-carboxylate with melting point 231-232 ° C.

IR (KBr) maxima at 1730, 1765 cm-1.

c) The carboxylate prepared under b) was reacted in the manner of Example 1d with 4-methylpiperazine into ethyl 7- (4-methylpiperazino) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo 1,8-naphthyridine-3-carboxylate.

d) In a mixture of 2 ml 1N aqueous NaOH and 2 mlethanol, 100 mg of ethyl 7- (4-methylpiperazino) -6-fluoro-1- (4-fluorophenyl) -4-oxo-1,4-dihydro-1,4 8-Naphthyridine-3-carboxylate dissolved and that solution was kept at 40-50 ° C for 10 minutes. Then the pH of the mixture was adjusted to 6.5 with acetic acid. Then it was extracted with 2 x 5 ml of chloroform. The combined extracts were washed successively with 5 ml water and 5 ml saturated NaCl solution and dried over MgSO 4. The solvent was removed by distillation under reduced pressure and the crystalline substance thus obtained was washed with 2 ml of diethyl ether to give 80 mg of 7- (4-methylpiperazino) -6-fluoro-1- (4-fluorophenyl) -4-oxo-1,4 dihydro-1,8-naphthyridine-3-carboxylic acid with m.p. 282-290 ° C gave IR (in KBr) maxima at 1725 cm -1 sc. at 1700 cm-1NMR (in d6-DMS0) maxima at δ-values (in ppm) 2.05 (3H, s), 3.57 (8H, bs), 7.13-7.80 (4H, m) , 8.13 (1H, d, J = 13Hz), 8.70 (1H, s).

Likewise, the ones shown in Table D

indicated compounds.

Table D

Compounds of formula 1 (Rx = H).

(Continued from Table D).

Example 5

A solution of 2.0 g of ethyl 6-fluoro-1- (4-methoxy-2-methylphenyl) -7- (4-methylpiperazino) -4-oxo-1,4-dihydro-1,8-naphthyridine- 3-carboxylate (see example 2c) in 5 ml of 47% hydrobromic acid was kept at 120 ° -125 ° C for 2 hours. Then the pH was adjusted to 13 with 10% NaOH and then to 6.5 with acetic acid. The crystals which precipitate out were collected by filtration and washed with 10 ml of water to give 1.8 g of 6-fluoro-1- (4-hydroxy-2-methyl-phenyl) -7- (4-methyl-piperazino) -4-oxo-1 4-dihydro-1,8-naphthyridine-3-carboxylic acid with m.p. > 280 ° C.

IR (in KBr) sch. at 1725, 1700 cm -1 NMR (in TFA-d, .max. at $ values (in ppm) 2.08 (3H, s), 3.12 (3H, s), 2.88-5.12 (8H, m), 6.93-7.62 (3H, m), 9.25 (1H, s), 9.43 (1H, d, J = 13Hz).

In the same manner, the compounds indicated in Table E were obtained.

Table E

Compounds of formula 1, R-1 = H

(Continued from Table E).

Example 6

To a solution of 250 mg of 6-fluoro-1- (4-hydroxy-2-methylphenyl) -4-oxo-7-piperazino-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (see table E) In 2.5 ml concentrated hydrochloric acid, 20 ml ethanol was added and that mixture was stirred at room temperature for 15 minutes. The crystals which precipitate out were collected by filtration and washed with 5 ml of ethanol to give 200 mg of hydrochloride of 6-fluoro-1- (4-hydroxy-2-methylphenyl) -4-oxo-7-piperazino-1,4-dihydro- 1,8-naphthyridine-3-carboxylic acid with m.p. > 280 ° C. In the IR spectrum (in KBr) gave signals at 1725 (sch) and 1705cm-1.

Likewise, the compounds listed in Table 2 were also obtained.

Table F

Hydrochlorides of acids according to formula 1, (R1 = H)

Example 7 a) A solution of 0.5 ethyl 2- (2,6-dichloro-5-fluoro-nicotinoyl) -3- (2,4-difluorophenylamino) -acrylate, (see example lb) 0.143 g N-methylpiperazine and 0.145 g trie Thylamine in 2.5 ml of chloroform was refluxed for 3 hours. The reaction mixture was then washed successively with 3 ml water and 3 ml saturated NaCl solution and dried over MgSO 4. The solvent was removed by distillation under reduced pressure and the residue thus obtained was purified by column chromatography (with 2% ethanol in chloroform over Wako silica gel C-200). This gave 0.294 g of ethyl 2- [2-chloro-5-fluoro-6- (4-methylpiperazino) -nicotinoyl] -3- (2,4-difluorophenylamino) acrylate as an oily liquid.

IR (as oil) maxima at 1735, 1700 cm-1 NMR (in CDCI3) maxima at δ values (in ppm) 1.13 (3H, t, J = 7Hz), 2.36 (3H, s), 2 .55 (4H, t, J = 5Hz), 3.70 (4H, t, J - 5Hz), 4.15 (2H, q, J - 7Hz), 6.77-7.90 (4H, m) 8.51 (1H, d, J = 13Hz), 12.50 (1H, d, J = 13Hz).

b) By 200 mg of ethyl 2- [chloro-5-fluoro-6- (4-methylpiperazino) nicotinoyl] -3- (2,4-difluorophenyl-amino) -acrylate successively in the same manner as in examples 2c and 5, 120 mg of 6-fluoro-1- (2,4-difluorophenyl) -7- (4-methylpiperazino) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with mp. 208-209 ° C.

Example 8

A mixture of 300 mg of ethyl 7- (4-ethoxycarbonyl-2-methylpiperazino) -6-fluoro-1- (2,4-difluorophenyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3- carboxylate (mp 202-204 ° C; prepared in the manner of Example 1d using 4-ethoxy-carbonyl-2-methylpiperazine instead of N-acetyl-piperazine), 5 ml N aqueous NaOH solution and 5 ml ethanol Kept at 90 ° C for 2 hours. Then acetic acid was added to the mixture to a pH of 6.5. The resulting crystals were filtered off, washed with water and dried, yielding 200 mg of 6-fluoro-1- (2,4-difluorophenyl) -7- (2-methylpiperazino) -4-oxo-1,4-dihydro-1,8- naphthyridine-3-carboxylic acid with mp. 230-239 ° C.

IR (in KBr) maximum at 1730 cm -1 NMR (in TFA-d1) maximum at 5 values (in ppm) 1.50 (3H, s), 3.20-5.15 (7H, m), 7 0.00-7.90 (3H, m), 8.35 (1H, d, J = 13Hz) and 9.20 (1H, s).

Example 9

From a mixture of 50 g of 6-fluoro-1- (2,4-difluorophenyl) -4-oxo-7-piperazino-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (see Table F) 1000 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate were punched 1000 flat tablets.

Example 10

With a mixture of 100 g of 6-fluoro-1- (2,4-difluorophenyl) -4-oxo-7-piperazino-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with 50 g of corn starch 1000 capsules were filled.

Claims (2)

1. In position 1-substituted 7- (cyclic amino) -6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivative characterized in that the derivative is a compound of the formula wherein Rx is a hydrogen atom or a carboxyl protecting group, R 2 represents an optionally substituted aryl group and R 3 represents an optionally containing at least one alkyl or alkenyl group-substituted piperazine group or is a pharmaceutically acceptable salt thereof. Antibacterial preparation containing a 1-substituted 7- (cyclic amino) -6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivative in the position characterized in that the active substance comprises a compound according to claim 1.