SE463102B - 1,4-DIHYDRO-4-OXONAFTYRIDINE DERIVATIVES AND SALTS THEREOF, PROCEDURES FOR THE PREPARATION OF THESE ANTIBACTERIAL AGENTS INCLUDING THESE - Google Patents

Description

463 192 gram-positive bacteria.

Under these circumstances, as a result of extensive research, the applicant has found that the above-mentioned novel 1,4-dihydro-4-oxonaphthyridine derivatives or a salt thereof can solve the above-mentioned problems.

An object of the present invention is to provide a novel 1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof having excellent properties, e.g. strong antibacterial activities against gram-positive and gram-negative bacteria, especially against antibiotic-resistant bacteria, and which give high concentrations in the blood during oral or parenteral administration and show high safety.

Another object of the present invention is to provide a process for the preparation of the nva 1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof.

A further object of the present invention is to provide an antibacterial agent useful for the treatment of infections caused by bacteria or the like and which comprises the novel 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof.

According to the present invention there is provided the 1,4-dihydrogen-4-xonaphthyridine derivative represented by the general formula: COOR (I) min 65 102 wherein R 1 represents a hydrogen atom or a C 1-4 alkyl group, R 2 represents a 2,4- difluorophenyl group and R represents a 3-amino- or 3-acylamino-1-pyrrolidinyl group.

There is further provided according to the invention a process for the preparation of the 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula (I) or a salt thereof together with an antibacterial agent comprising the 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula ( I) or a salt thereof.

The present invention is explained in detail below.

The salt of the compound represented by the general formula (I) includes customary salts at basic groups such as an amino group and the like and at acidic groups such as a carboxyl group and the like. The salts in the basic group include e.g. salts with mineral acids such as hydrochloric acid, sulfuric acid and the like; salts with organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like; salts with sulfonic acids, such as methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like. The salts of the acidic groups include, for example, salts with alkali metals, such as sodium, potassium and the like; salts with alkaline earth metals such as calcium, magnesium and the like; ammonium salts and salts with nitrogen-containing organic bases such as procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-phenenamine, N, N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N, N-dimethylaniline , N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine and the like.

If the compound represented by the general formula (I) and a salt thereof has isomers (eg, optical isomers, geometric isomers, tautomers and the like), the present invention includes all of these isomers, crystal forms and hydrates thereof.

Antibacterial activities and acute toxicities are illustrated with reference to common compounds of the present invention. Antibacterial activity Test method According to the standard method of the Japan Society of Chemotherapy / CHEMOTHERAPY, 29 (l), 76-79 (l98l) /, a bacterial solution obtained by culturing Heart Infusion broth (manufactured by Eiken Kagaku) was inoculated at 37 °. C for 20 hours on "Heart Infusion" agar containing a drug and cultured at 37 ° C for 20 hours, after which the growth of the bacteria was observed in order to determine the minimum concentration at which the bacterial growth was inhibited as MIC (ng / ml). was 104 cells / plate (106 cells / ml).

The MIC values for the following test compounds are shown in Table 1.

The compound of the present invention can be prepared, for example, according to the following methods of preparation: 0 CO 1 a F COOR a F ---- e> _ N Cl N cl a R3a R3b [n] [IV] or a salt thereof in O $ O la la CQQR COOR FF iii-_; 2 N 2 N cl NH-R R3a Cl NH-R R3 [III] or a salt thereof [V1 or a Salt ÖäräV lol O 1, CQOR1 COOR FFNN b NN 113 | 2 3a IR R2 R i [Ia] or a salt thereof [Ib] or a Salt of which R 1a represents the same group as R 1; R a represents the same fluorine atom as R 3; R 3b represents the same pyrrolidinyl group as R 1 and R 2 and R 2 have the meaning given above.

The salts of the compounds represented by the general formulas (Ia), (Ib), (III), (IV) and (V) include the same salts as those of the compounds denoted by the general formula (I). (i) The compound represented by the general formula (III) or a salt thereof or the compound represented by the general formula (V) or a salt thereof is obtained by reacting the compound represented by the general formula (II) resp. the compound represented by the general formula (IV) or a salt thereof with an acetal such as N, N-diethylformamidido dimethylacetal, NN, dimethylformamidodiethyl acetal or the like and then with an amine represented by the general formula R2-NH2 (R2 has the meaning given above ).

The solvent to be used in the above reactions may be any solvent inert to the reactions and includes, but is not limited to, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amines such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like, etc. and these solvents may be used alone or in a mixture of two or more. The amount of acetal used is preferably 1 mole or more, especially about 1.0 to 1.3 moles, per mole of compound represented by the general formula (II) or the compound represented by the general formula (IV) or salt thereof. The reactions are usually carried out at 0 ° to 100 ° C, preferably at 50 ° to 50 ° C and usually for 20 minutes to 50 hours, preferably C "F FC; 465 μl to 3 hours. In addition, the amine is used in an amount of 1 mole or more per mole of compound represented by the general formula (II) or the compound represented by the general formula (IV) or salt thereof.The reaction is usually carried out at 0 ° to 100 ° C, preferably 10 ° to 50 ° C and usually for 20 minutes to 30 hours, preferably 1 to 5 hours.

As an alternative method, it is possible to react the compound represented by the general formula (II) or the compound represented by the general formula (IV) or a salt thereof with ethyl orthoformate or methyl orthoformate in the presence of acetic anhydride, and then with an amine represented by the general formula R 2 -NH 2 or a salt thereof to obtain the compound represented by the general formula (III) or a salt thereof resp. the compound denoted by the general formula (V) or a salt thereof. (ii) The compound represented by the general formula (Ia) or a salt thereof or the compound represented by the general formula (Ib) or a salt thereof is obtained by allowing the compound represented by the general formula (III) or a salt thereof resp. the compound represented by the general formula (V) or a salt thereof undergoes cyclization reaction (preferably under heating) in the presence or absence of a base.

The solvent to be used in this reaction may be any solvent inert to the reaction and includes, but is not limited to, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; ethers such as dioxane, anisole, diethylene glycol dimethyl ether and the like; sulfoxides, such as dimethyl sulfoxide and the like, etc. These solvents may be used separately or in a mixture of two or more. The base includes, for example, sodium bicarbonate, potassium carbonate, potassium tert-butoxide, sodium hydride and the like. The amount of base to be used is preferably 0.5 to 5 moles per mole of compound represented by the general formula (III) or (V) or a salt thereof. The reaction is usually carried out at 200 to 160 ° C, preferably at 100 ° to 150 ° C, and usually for 5 minutes to 30 hours, preferably 5 minutes to 1 hour. (iii) The compound represented by the general formula (IV) or a salt thereof, the compound represented by the general formula (V) or a salt thereof or the compound represented by the general formula (Ib) or a salt thereof are obtained resp. by reacting the compound represented by the general formula (II), the compound represented by the general formula (III) or a salt thereof or the compound represented by (Ia) or a salt thereof having 3b_H nad of the general formula a cyclic amine represented by the general formula R or a salt thereof (wherein R 3b is as defined above).

The solvent to be used in the reaction may be any solvent inert to the reaction and includes, but is not limited to, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides, such as dimethyl sulfoxide and the like; alcohols such as methanol, ethanol and the like; nitriles, such as acetonitrile and the like, etc. and these solvents may be used alone or in a mixture of two or more. The amount of cyclic amine or a salt thereof to be used is preferably an excess, more preferably 2 to 5 moles per mole of compound represented by the general formula (II), the compound represented by the general formula (III) or a salt thereof or the compound represented by the general formula Ia) or a salt thereof. If the amount of cyclic amine used is about 1 to 1.3 moles, it is sufficient that an acid-binding agent is used in an amount of 1 moles per mole of compound designated 463 102 of the general formula (II), the compound represented by the) general formula ( III) files a salt thereof or the compound represented by the general formula (Ia) or a salt thereof.

The acid-binding agent includes organic or inorganic bases such as triethylamine, 1,8-diazabicyclo [5.4% / undec-7-ene "BU), potassium tert-butoxide, potassium carbonate, sodium carbate, sodium hydride and the like.

The salt of R3b-H includes the same as the salts of the basic group of the compound represented by the general formula (I).

The reaction is usually carried out at 0 to 150 ° C, preferably at 50 ° to 100 ° C, and usually for 5 minutes to 30 hours, preferably 30 minutes to 3 hours.

The compound represented by the general formula (Ia), (Ib), (III) or (V), wherein R 1 represents an alkyl group or a salt thereof can, if desired, be converted to the corresponding free carboxylic acid by hydrolyzing it. the same in the presence of a conventional acid or alkali, which is used for hydrolysis, usually at 0 ° to 100 ° C, preferably at 200 to 100 ° C for 5 minutes to 50 hours, preferably 5 minutes to 4 hours. Furthermore, the compound represented by the general formula (Ia), (Ib), (III) or (V) or a salt thereof, if desired, may be converted into a salt or an ester of the corresponding compound by subjecting it to a salt-forming reaction. or esterification known per se. If the compound represented by the general formula (Ia), (III), (IV) or (V) or a salt thereof shows an active group (eg hydroxyl group, amino group or the like) at positions other than the reaction sites it is possible to protect the active group beforehand according to a conventional method and remove the protecting group after the reaction has ended.

The compound thus obtained can undergo customary isolation CP.

CN ._ \.

CD F. "and purification steps, such as column chromatography, recrystallization, extraction and the like.

When the compound of the present invention is used as a medicine or medicine, it is suitably combined with carriers used in conventional pharmaceutical preparations and prepared into tablets, capsules, powders, syrups, granules, suppositories, ointments, injections and the like in the usual manner. Method of administration, doses and number of administrations can be suitably varied depending on the patient's symptoms and it is usually administered orally or parenterally (eg as injection, drip, administration to the rectum) to an adult in an amount of 0.1 to 100 mg / kg / day in one to several portions.

The present invention is explained below with reference to Reference Examples, Examples and Preparation Examples.

Symbols used in reference examples and examples have the following meanings: Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group, Ac: acetyl group, ¿9 \, /: allyl group,, ethylene group.

Reference Example 1 In 210 ml of chloroform, 21 g of 2,6-dichloro-5-fluoronicotinic acid were dissolved and 23.8 g of thionyl chloride and 0.1 g of N, N-dimethylformamide were added to the resulting solution. The resulting mixture was reacted at 70 ° C for 2 hours. The solvent and excess thionyl chloride were removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 21 ml of tetrahydrofuran. In 110 ml of tetrahydrofuran was dissolved 25.1 g of diethyl ethoxymagnesium malonate and the solution was cooled to -400 to -30 ° C. Into this solution was dropped a tetrahydrofuran solution of 2,6-dichloro-5-fluoronicotinoyl chloride, previously prepared at the same temperature over 30 minutes. This mixed solution was stirred at the same temperature for 1 hour, after which the temperature of the solution was gradually increased to room temperature.

The solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 200 ml of chloroform and 100 ml of water. The pH was adjusted to 1 with 6 N hydrochloric acid. The organic layer was separated, washed successively with 50 ml of water, 50 ml of 5% aqueous sodium bicarbonate solution and 50 ml of a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the resulting oily product was added 50 ml of water and 0.15 g of p-toluenesulfonic acid, after which the resulting mixture was allowed to react with vigorous stirring at 10 ° C for 2 hours. The reaction mixture was extracted with 100 ml of chloroform. The organic layer was washed with 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The obtained residue was purified by column chromatography (WAKO SILICA GEL C-200, eluent: toluene) to obtain 23.5 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) acetate, m.p. 64 DEG-65 DEG.

IR (KBr) cm -1 = 0 C = 0 1650, 1630, 1620 NMR (CDCl 3) δ values = 1.25 (1.29H, t, J = 7Hz), 1.33 (1.7lH, t, J = 7Hz): 4.07 (1,14H, s), 4.28 (2H, q, J = 7Hz), 5.82 (0.43H, s), 7.80 (ln, a, J = 7Hz ), 12.62 (0.43H, S). Reference Example 2 In 40 ml of benzene was dissolved 8.8 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) acetate and 4.5 g of N, N-dimethylformamidodimethylacetal were added, after which the resulting mixture was allowed to react. at 70 ° C for 1.5 hours. Then, 4.1 g of 2,4-difluoroaniline was added to the reaction mixture, and the resulting mixture was allowed to react at room temperature for 4 hours. The solvent was removed by distillation under reduced pressure.

The obtained residue was purified by column chromatography (WACO SILICA GEL C-200, eluent: chloroform) to obtain 9.0 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (2,4-fluorophenylamino) -acrylate with melting point 138 - 139 ° C.

IR (mar) cnfl: ac = o 1690 NMR (CDCl 3) δ values: 1.08 (3H, t, J = 7Hz), 4.10 (2H, q, J = 7Hz), 6.77-7, (4H, m), 8.50 (1H, d, J = 13Hz), 12.70 (1H, d, J = 13Hz) CD 4453 Example 1 (1) In 5 ml of chloroform was dissolved 0.50 g of ethyl -7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and the resulting solution was added with 0.20 g of 3- acetylaminopyrrolidine and 0.15 g of triethylamine, after which the resulting mixture was allowed to react at 60 ° C for 1 hour. Then the solvent was removed by distillation under reduced pressure and the obtained residue was purified by column chromatography / WAKO SILICA GEL C-200, eluent: chloroform-ethanol = 30: 1 (by volume) / to give 0.5 g of ethyl-7 - (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate with a melting point of 233 - 235 ° C.

IR (KBr) cm -1 = δ C = o 1725, 1700 NMR (CDCl 3) δ values: 1.3 (3H, t, J = 7Hz), 1.77-2.27 (m)} (SH) 2.08 (s) ', 12 * 3.74 (4H, m), 4.02-4.74 (m) f (BH) 4.29 (q, J = 7HZ)' d] 8.24 (1H, S). (2) In 2.5 ml of 6 N hydrochloric acid was dissolved 0.25 g of ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and the resulting solution was heated under reflux for 2 hours. The reaction mixture was then cooled to room temperature and its pH was adjusted to 12 with 1 N aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The crystals thus precipitated were collected by filtration, washed with 2 ml of water and then dried to obtain 0.18 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

NMR (TFA-dl) δ values: 2.25-2.85 (2H, m), 3.37-4.69 (SH, m), 6.93-7.81 (3H, m), δ 22 (1H, d, J = 11Hz), 9.16 (1H, s).

P-J .Pa O \ LN 'f? [R 14 Example 2 l! (1) In 20 ml of chloroform were dissolved 2.0 g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate, 0.96 g of 3-acetylaminopyrrolidine and 0.8 g of triethylamine, and the resulting solution was reacted at 600 to 65 °. C for 2 hours. The reaction mixture was washed with 30 ml of water and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography / WAKO SILICA GEL C-200, eluent: benzenesethyl acetate = 1: 1 (by volume) / to obtain 1.8 g of oily ethyl / 2-chloro. -5-fluoro-6- (3-acetylamino-1-pyrrolidinyl) nicotinoyl / acetate.

IR (neat) cnfl; 0 ° C = O 1740, 1650 NMR (cDc13) δ values: 1.28 (311, t, J = 711z), 1.97 (311, s), 1.90-2.62 (211, m), δ , 02 (211, s), 4.15 (211, q, J = 7Hz), 3.5o-4.70 (511, m), 7.06 (111, d, J = 611z), 7.57 (111, d, J = 1311z) (2) In 10 ml of benzene was dissolved 0.7 g of ethyl 2-chloro-5-fluoro-6- (3-acetylamino-1-pyrrolidinyl) nicotinoyl acetate and to the suspended solution was added 0.235 g of N, N-dimethylformamido-dimethylacetal, after which the resulting mixture was allowed to react at 70 ° C for 2 hours. To the reaction mixture was added 0.243 g of 2,4-difluoroaniline, and the resulting mixture was allowed to react at room temperature for 8 hours. Then the solvent was removed by distillation under reduced pressure and the residue thus obtained was purified by column chromatography / WAKO SILICA GEL C-200, eluent: benzenesethyl acetate = 1: 1 (by volume) / and the oily product thus obtained was decomposed with to give 0.25 g of ethyl 2- [2-chloro-5-fluoro-6- (3-acetylamino-1-pyrrolidinyl) nicotinoyl] -3- (2,4-difluorophenylamino) acrylate with a melting point of 82 85 ° C.

I1 O \ OJ CD PO 15 IR (xßr) cm -1 =, C = 0 1695 (sh), 1660 NMR (CDCl 3) δ values: 1.25 (3H, t, J = 7Hz), 2.07 (3H, s), 1.90-2.30 (2H, m), 4.19 (2H, q, J = 7Hz), 3.60-4.70 (5H, m), 6.49 (1H , d, J = 6Hz), 6.80-7.50 (4H, m), 8.53 (1H, d, J = 13Hz), 12.46 (1H, d, J = 13Hz). (3) In 3 ml of N, N-dimethylformamide was dissolved 0.2 g of ethyl 2- [2-chloro-5-fluoro-6- (3-acetylamino-1-pyrrolidinyl) nicotinoyl] -3- (2,4-difluorophenylamino) acrylate and the resulting solution was added with 0.04 g of sodium bicarbonate, after which the resulting mixture was allowed to react at 120 ° C for 1 hour, then the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 10 ml of chloroform. was taken successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulphate, the solvent was removed by distillation under reduced pressure and the crystalline substance thus obtained was washed with 5 ml of diethyl ether. to give 0.13 g of ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyl ridin-3-carboxyate having a melting point of 233 ° C.

Example 3 In 20 ml of concentrated hydrochloric acid was dissolved 2.0 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1, 8-Naphthyridine-3-carboxylic acid, after which 200 ml of ethanol was added to the resulting solution at room temperature and the resulting solution was stirred for 15 minutes. Thus precipitated crystals were collected by filtration and washed with 40 ml of ethanol to give 1.4 g of the hydrochloric acid salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1, 4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 247 DEG-25 DEG C. (sonic acid).

IR (KBr) cm-1 = dczo 1730 Ms 102 16 Example 4 In 20 ml of ethanol, 1.0 g of disaltic acid salt of 3-aminopyrrolidine was suspended and 2.06 g of triethylamine was added to the resulting suspension to form a solution. Then, 2.0 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was added to the solution at 30 ° C over 15 minutes and the resulting mixture was allowed to react at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was added with 30 ml of water, and the crystals thus precipitated were collected by filtration and washed with 4 ml of water. The crystalline substance thus obtained was suspended in 13 ml of 6 N hydrochloric acid, and the resulting suspension was heated under reflux for 2 hours. Then the reaction mixture was cooled and the crystals thus precipitated were collected by filtration and washed with two 2 ml portions of water to give 1.97 g of hydrochloric acid salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1 - (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

IR (Kßr) cnfl: vc = o 1730 Example 5 In 75 ml of ethanol and 75 ml of water was suspended 10.0 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. To the resulting suspension was added 5.2 g of p-toluenesulfonic acid monohydrate at 40 ° C, and the resulting mixture was stirred at the same temperature for 30 minutes. Then the reaction mixture was cooled to 15 ° C and the crystals thus precipitated were collected by filtration and washed with a mixed solvent of 5 ml of ethanol and 5 ml of water to give 12.8 g of p-toluenesulfonic acid monohydrate salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid with a melting point of 258 260 ° C. dh 17 465 δ2 IR (KBr) em "1 = vC = O 17 5 NMR (DM 50 -do) δ values; 1.82-2.42 (m) 3.12-4.30 (5H, m), (SH), 2.27 (s) 6.92-8.17 (8H, m), 8.79 (1H, s).

In a similar manner the following compound was obtained: The oxalic acid salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine -3- carbovyl acid. melting point (° c) = 250 - 253: R (KBr) cm -1 = 1730 ° C = 0 Example 6 To the solution of 1.6 g of methanesulfonic acid and 25 ml of acetic acid was added 5.00 g of 7- (3-amino-1 -pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, after which the resulting suspension was stirred at 2 ° C for 2 h. to form a solution. The solution was added r 10 ml of ethanol at 40 ° to 45 ° C over 30 minutes. The reaction mixture was then cooled to room temperature and stirred for 30 minutes. The crystals thus precipitated were collected by filtration and washed with three 20 ml portions of ethanol to obtain 12 g of methanesulfonic acid salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) - 1,4-dihydro-4-oxo- [1,5-s-nephrylamine-3-kerbexylic acid with melting point:> 30 ° C.

IR (KBr) cm-1 Q Q = O 1735 In a similar manner the following compound was obtained: The sulfuric acid salt of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid.

~ P () \ (J-J CD PCW 18 melting point (° c) = 220 - 230 IR (Kßr) cm -1 = uczo 1735.

Preparation Example 1 With 50 g of 7- (3-amino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate were mixed and the mixture was compressed into 1000 flat tablets.

Preparation Example 2 With 100 g of 7- (3-amino-1-pyrroliainyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 50 g of corn starch was mixed and 1000 capsules were filled with the resulting mixture to give capsules. f) (1) - 19 Comparative test Antibacterial activity Test method According to the standard method of the Japan Society of Chemotherapy / CHEMOTHERAPY, 29 (l), 76-79 (l98l) / a bacterial solution obtained by culturing in cardiac infusion broth (prepared by Eiken) was inoculated Kagaku) at 37 ° C for 20 hours on a cardiac infusion agar containing a drug and cultured at 37 ° C for 20 hours, after which the growth of the bacterium was observed to determine the minimum concentration at which the growth of the bacterium was inhibited as MIC (pg / ml). The amount of the inoculated bacterium was 104 cells / plate (10 6 cells / ml). The results of the test for the antibacterial activity of the compound of the present invention and representative comparative compounds are shown in the following table.

Symbols used in the table have the following meanings: * 1: penicillinase-producing bacterium, * 2: cephalosporinase-producing bacterium, Me: methyl group, Et: ethyl group Compound A: Enoxacin: O F COOH MeNH // | 0 3, N F / coon N än \ NI _. | 2 5 HN y I C2H5 (Hydrochloride salt) Jb ..

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Claims (9)

CT »(JJ CD [ND 2 / PATENTKRAV 1,1,4-Dihydro-4-oxonaphthyridine derivative illustrated by the formula, or a salt thereof: O 1 F COOR 3 N N R | R 2 wherein R 1 represents a hydrogen atom or a C 1-4 alkyl group, R 2 represents a 2,4-difluorophenyl group and R represents a 3-amino- or 3-acylamino-1-pyrrolidinyl group. 1,4-Dihydro-4-oxonaphthyridine derivative or a salt thereof according to claim 1, characterized in that R1 represents a hydrogen atom. 1,4-Dihydro-4-oxonaphthyridine derivative or a salt thereof according to claim 1 or 2, characterized in that R 3 represents a 3-amino-1-pyrrolidinyl group. A process for the preparation of a 1,4-dihydro-4-oxo-naphthyridine derivative or a salt thereof according to claim 1, characterized in that a compound illustrated by the following formula, or a salt thereof, is subjected to: wherein R 1a represents a carboxyl protecting group and R 2 and R 3 are as defined above, a cyclization reaction and the removal of the carboxyl protecting group thereafter, if desired; A process according to claim 4, wherein the cyclization reaction takes place at a temperature of 20-160 ° C. A process for the preparation of a 1,4-dihydro-oxonaphthyridine derivative or a salt thereof according to claim 1, characterized in that reacting the compound illustrated by the formula, or a salt thereof: 0 lb COOR F \ 3a NNR | 2 R. 3a. lb n wherein R represents a nalogen atom, R represents a hydrogen atom or a carboxyl protecting group and R 2 has the meaning given above, with a compound illustrated by the formula, or a salt thereof: R 3 -H wherein R 3 has the meaning given in claim 1, and then, if desired, removing the carboxyl protecting group. A process according to claim 6, wherein the reaction takes place at a temperature of 0-150 ° C. 'up A process according to claim 6, wherein R 1 represents a hydrogen atom. & 3 An antibacterial agent comprising a 1,4-dihydro-4-oxonaphthyridine derivative of the formula O 1 F COOR 3 N N R | 2 R or a salt thereof according to any one of claims 1-3.