KR0139946B1 - Pyridone carboxylic acid derivatives and method of production thereof - Google Patents

Abstract

The present invention relates to a pyridone carboxylic acid compound represented by the following general formula (I), a salt thereof and an antimicrobial composition containing the same.

In formula (I), R ₁ means methyl, ethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoroisopropyl group,

A means nitrogen atom or C-H,

Z represents a group represented by the following formula.

(Wherein R ₂ , R ₃ means a hydrogen atom or a methyl group, one of which means hydrogen, one of R ₄ , R ₅ means hydroxy, alkoxy, amino group, and the other means hydrogen.)

Description

Novel pyridone carboxylic acid derivatives and preparation method thereof

The present invention relates to a novel pyridone carboxylic acid derivative that can be used as a medicine, animal medicine, fish disease as a new antibacterial substance having excellent antimicrobial activity, a preparation method thereof and a pharmacological preparation thereof.

Many synthetic antimicrobial derivatives known to date have high antimicrobial activity but are difficult to use as medicines due to their high toxicity.

The present inventors have completed the present invention by developing a novel quinolone antibacterial agent having an excellent drug to solve this disadvantage.

The compound of this invention is a pyridone carboxylic acid derivative represented by the following general formula (I), its ester, and its salt.

In general formula (I), R ₁ means methyl, ethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoroisopropyl group,

A means nitrogen atom or C-H,

Z means group represented by the following formula.

(Wherein R ₂ , R ₃ means a hydrogen atom or a methyl group, one of which means hydrogen, one of R ₄ , R ₅ means a hydroxy, alkoxy, amino group, the other means hydrogen. )

Salts of the compounds of the present invention include salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; Salts with organic acids such as acetic acid, lactic acid, oxylic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid and gluconic acid; Salts with acidic amino acids such as aspartic acid and glutamic acid; Or metal salts such as sodium, potassium, calcium, magnesium, zinc and silver of the compound of formula (I); Salts with organic bases such as dimethylamine, triethylamine, dicyclohexylamine and benzylamine; Salts with basic amino acids such as lysine and arginine.

The ester of the compound of general formula (I) is a lower alkyl ester such as methyl ester or ethyl ester of compound (I), or a known ester which is hydrolyzed or easily released in vivo to be compound (I). Aminoethyl esters such as acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonylethyl ester, choline ester, dimethylaminoethyl ester and 1-piperidinylethyl ester, 5-indanyl ester, phthalic Dynyl ester etc. are meant.

The compound of the present invention is also obtained as a hydrate, which of course is included in the compound of the present invention.

In the compound of the present invention, since the substituent at the 7 position has a sub-carbon atom, it can be obtained also as an optically active substance, and such optically active substance is also included in the compound of the present invention.

Hereinafter, the manufacturing method of the compound of this invention is demonstrated.

The compound of the present invention can be produced by reacting a compound represented by the following general formula (II) with a novel compound represented by the following general formula (III) and isolating the product by a conventional method.

(In the general formula (II), Y means a halogen atom, R ₆ means hydrogen or a lower alkyl group, and A and R ₁ are as described above.)

Z-H (Ⅲ)

(In the general formula (III), Z is as described above.)

This reaction is carried out using the raw materials (II) and (III) with alcohols such as ethanol, dioxane, tetrahydrofuran, ethers such as 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile And inert organic solvents such as dimethylformamide, dimethyl sulfoxide, pyridine, and water at a temperature of 0 to 200 ° C. for 10 minutes to 24 hours.

This reaction generally uses the equivalent or excessive amount of the raw material compound (III) relative to the raw material compound (II) in the presence of an acid acceptor, but may also serve as the acid acceptor by using an excessive amount of the raw material compound (III).

As the acid acceptor, hydroxides such as sodium hydroxide or potassium hydroxide, carbonates such as sodium carbonate or potassium carbonate, bicarbonates such as sodium bicarbonate or potassium bicarbonate, triethylamine, dimethylaniline, N, N-diisopropylethylamine, 1,8 Organic bases such as -diazabicyclo [5.4.0] undec-7-ene (DBU); and the like.

The raw material compound (III) used in the above reaction may be used by itself, but may be used in the form of protecting an amine group not involved in the reaction. In this case, after completion of the reaction, remove the protecting group according to a conventional method. do. As a protecting group, what can be removed without destroying the structure of the compound of this invention formed by reaction is a protecting group normally used by a peptide, an amino acid, hexane, or a beta lactam type compound. Preferred protecting groups include, for example, hydrolyzable groups such as acetyl trifluoroacetyl, ethoxycarbonyl groups, or benzyl groups.

Raw material compound (II) is manufactured according to the method described in the following literature, for example as the said compound, or by the method according to it. Med. Chem., 1988, 31, 503; J. Org. Chem., 1981, 46, 846; EP 0132845 (1985); USP 4826987 (1989); EP 0271275 (1987); JP 01-268662; JP 64-16746; J. Heterocyclic Chem., 1990, 27, 1609; J. Heterocyclic Chem., 1991, 28, 541]

Raw material compound (III) is a novel compound synthesized in the present invention, one of which is 6-amino-1-methyl-3-azabicyclo [3.2.0] heptane can be prepared by the following method.

[Wherein R ₇ is hydrogen or methyl group]

In other words, a known compound, Np-toluenesulfonyl-1-methyl-6-oxo-3-azabicyclo [3.2.0] heptane (Heterocycles, 1989, 25, 29), was prepared in the presence of a methoxyamine or hydroxy. Reduction of the methoxyimine or hydroxyimine compound (IV) produced by condensation reaction with the hydrochloride salt of the amine with a reducing agent produces an amino compound (V), and the removal of the protecting group in the presence of the acid results in the desired racemate. [1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane (VI) can be prepared.

On the other hand, in order to optically divide the racemate (VI), the amino compound (V) was condensed with Np-toluenesulfonyl-L-phenylalanine to synthesize amide compounds (VII) and (VII), and then column chromatography or recrystallization. After separating each optically active diastereomer (Diastereomer) through the acid hydrolysis of each to obtain an optical isomer of compound (VI).

When the compound of the present invention obtained by the above method is an ester, the ester moiety is hydrolyzed by a conventional method to change the compound of the general formula (I). On the other hand, if necessary, the compound of the general formula (I) may be esterified by a conventional method to produce an ester of the compound of the general formula (I).

The compound of the present invention prepared as described above is isolated and purified according to a conventional method. In the refining conditions, they are obtained in the form of a salt or in a free form, but these are mutually converted according to the purpose to prepare the compound of the present invention in the desired form.

The compound of the present invention represented by the general formula (I), its ester or salt thereof is a novel compound, and in particular, the compound (I) or salt thereof exhibits a wide range of strong antimicrobial activity as shown in the following table, as well as Gram-positive bacteria. And because it has a strong antimicrobial activity to methicillin-resistant bacteria, its value as an antimicrobial agent is sufficient.

CPFX: Ciprofloxacin, OFLX: Ofloxacin

* 1 The minimum stunt development concentration (MIC: mcg / ml) is described in Chemotheraphy, 29 (1), 76 (1981).

It measured according to the method and the result is shown to the standard | standard.

* 2 A: Staphylococcus aureus smith

B: Streptococcus pyogenes C4003

C: MRSA C2208

D: Escherichia coli A10536

E: Klebsiella pneumoniae A10031

F: Pseudomonas aeruginosa A27853

Compound (I) or a salt thereof can be used not only for human or animal drugs but also as a fish disease drug, pesticide, food preservative, and the like. In addition, the ester of compound (I) is of course valuable as a synthetic raw material of compound (I), but when the compound is easily converted into compound (I) in vivo, it exhibits the same effect as compound (I). Compounds useful as antibacterial agents.

When the compound of the present invention is used as an antimicrobial agent in humans, its dosage varies depending on age, weight, symptoms, route of administration, etc., but 5 mg to 5 g per day may be administered from one to several times and the route is oral, It is possible on both parenteral sides.

Although the compound of this invention may be used as it is, it is normally administered in the form of preparation like a carrier for formulation. Specific examples thereof include tablets, liquids, capsules, granules, fine granules, powders, syrups, injections, ointments, and the like.

As a carrier of the oral preparation, a substance which is commonly used in the preparation of starch, mannitol, crystalline cellulose, CMC Na, water, ethanol and the like, and which does not react with the compound of the present invention is used. Examples of carriers for injection include carriers commonly used in the field of injections such as water, saline, glucose solution, and fluids.

EXAMPLE

In the following, the preparation method of the compound of the present invention will be described in detail.

Reference Example 1

[1α, 5α] -6-methoxyimino-1-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

A mixture of 40.0 g of [1α, 5α] -1-methyl-6-oxo-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane, 14.35 g of methoxylamine hydrochloride and 400 ml of pyridine was prepared at room temperature. Stirred for 2 h.

The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 500 ml of ethyl acetate, washed twice with 200 ml of 5% aqueous hydrochloric acid solution, and once with 200 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

The solid was removed by filtration under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain 43.0 g of a yellowish brown oily title compound (yield 98%).

¹ H NMR (CDCl ₃ ) δ: 7.7 (2H, d, J = 8.28Hz), 7.3 (2H, d, J = 9.6Hz), 3.84 (0.6H, s), 3.81 (0.4H, s), 3.9 ~ 2.3 (7H, m), 2.4 (3H, s), 1.3 (3H, s)

Reference Example 2

[1α, 5α, 6β] -6-amino-1-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

27.0 g of NaBH ₄ were suspended in 150 ml of THF and 55.0 ml of trifluoroacetic acid (TFA) was dissolved in 150 ml of THF and added at room temperature over 2 hours. 43.0 g of the title compound of Reference Example 1 was dissolved in 200 ml of THF, added over 2 hours at room temperature, and the reaction solution was stirred at room temperature for 3 hours, and 50 ml of water and 30 ml of 40% sodium hydroxide aqueous solution were added thereto, and the mixture was heated to reflux for 5 hours. . The reaction solution was concentrated under reduced pressure to remove THF, and extracted three times with 200 ml of dichloromethane. The organic layer was washed with 200 ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure to give 39.0 g of the titled compound as a tan oil (98% yield).

¹ H-NMR (CDCl ₃ ) δ: 7.7 ~ 7.1 (4H, m), 3.4 ~ 2.0 (10H, m), 2.3 (3H, s), 1.3 (3H, S)

Reference Example 3

[1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane

A mixture of 5.0 g of the title compound of Reference Example 2 and 30 ml of an aqueous 48% HBr solution was heated to reflux for 5 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 5 ml of water, 3 ml of 40% aqueous sodium hydroxide solution was added, and then extracted three times with 100 ml of chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove solids, and then concentrated under reduced pressure to obtain 1.8 g of a pale yellow oily title compound (yield 80%).

¹ H-NMR (CDCl ₃ ) δ: 3.5 ~ 2.5 (10H, m), 1.3 ~ 1.1 (1H, m), 1.26 (3H, s)

Reference Example 4

(-)-[1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane and (+)-[1α, 5α, 6β] -6-amino-1-methyl -3-azabicyclo [3.2.0] heptane

(1) [1α, 5α, 6β] -6-amino-1-methyl-3- (p-toluenesulfonyl) -3-azabicyclo [3.2.0] heptane

1.20 g and N- (p-toluenesulfonyl) -L-phenylalanine were dissolved in 30 ml of dimethylformamide, 0.78 ml of diethylcyanophosphonate and 1.20 ml of triethylamine were added and stirred at room temperature for 5 hours. The reaction solution was diluted with 200 ml of ethyl acetate, washed twice with 100 ml of 5% aqueous hydrochloric acid solution, twice with 100 ml of saturated aqueous sodium hydrogen carbonate solution, twice with 100 ml of water, once with 100 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Under reduced pressure filtration, and the filtrate was concentrated under reduced pressure. 20 ml of ethanol was added to the residue, followed by stirring at room temperature for 1 hour, followed by filtration under reduced pressure to obtain 0.67 g of a white solid. The filtrate was concentrated under reduced pressure and column chromatography was performed on silica gel to obtain 1.00 g of a colorless oily substance.

(2) A mixture of 0.67 g of the white solid obtained in (1) and 200 ml of a 48% aqueous HBr solution was heated to reflux for 8 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in 5 ml of water, 2 ml of 40% aqueous sodium hydroxide solution was added, followed by extraction three times with 30 ml of chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, the solid was filtered off under reduced pressure and concentrated under reduced pressure to obtain (-)-[1α as a slightly yellow sulfur substance. 0.13 g of, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was obtained (yield 48%).

[α] _D ²⁰ -15.0 (C = 1.0, MeOH)

¹ H-NMR (CDCl ₃ ) δ: 3.5 ~ 2.5 (10H, m), 1.3 ~ 1.1 (1H, m), 1.26 (3H, s)

(3) A mixture of 1.00 g of the oily substance obtained in (1) and 20 ml of a 48% aqueous solution of 48% HBr was treated in the same manner as in (2) to give (+)-[1,5,6] -6-amino as a pale yellow oily substance. 0.19 g of -1-methyl-3-azabicyclo [3.2.0] heptane was obtained (yield 70%).

[α] _D ²⁰ +15.0 (C = 1.0, MeOH)

¹ H-NMR (CDCl ₃ ) δ: 3.5 ~ 2.5 (10H, m), 1.3 ~ 1.1 (1H, m), 1.26 (3H, s)

Example 1

(-)-7-([1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptan-3-yl) -1-trifluoroethyl-6-fluoro -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

500 mg of 7-chloro-1,4-dihydro-6-fluoro-4-oxo-1-trifluoroethyl-1,8-naphthyridine-3-carboxylic acid is suspended in 6 ml of acetonitrile and 0.84 ml of DBU. 366 mg of (-)-[1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added thereto, followed by stirring at room temperature for 2 hours. 6 ml of water was added to the reaction solution, adjusted to pH 7 with acetic acid, and the resulting solid was filtered, washed with water and ethanol to obtain 450 mg of the target compound (yield 70.6%).

Melting Point: 190 ~ 193 ℃

¹ H-NMR (DMSO-d ₆ + TFA-d) δ: 9.00 (1H, s), 8.04 (1H, d, J = 13Hz), 5.63 ~ 5.40 (2H, m), 4.40 (1H, d, J = 13 Hz). 4.15 (1H, d, J = 11Hz), 4.00 ~ 3.73 (2H, m), 3.30 ~ 3.15 (1H, m), 2.90 ~ 2.80 (1H, m), 2.25 ~ 2.00 (2H, m), 1.40 (3H , s)

Example 2

(-)-7-([1α, 5α, 6β] -1-methyl-6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1-((s) 2-fluoro-1-methyl) ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

200 mg of 1-((s) -2-fluoro-1-methyl) ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are suspended in 10 ml of acetonitrile. After addition, 300 mg of DBU and 166 mg of (−)-[1α, 5α, 6β] -1-methyl-6-amino-3-azabicyclo [3.2.0] heptane dihydrochloride were added and refluxed for 5 hours. After cooling the reaction solution to room temperature, the solid formed was filtered, washed with 10 ml of acetonitrile and dried to obtain 153 mg of the target product (yield 56%).

Melting point: 250 ° C or more (decomposition)

¹ H-NMR (DMSO-d ₆ + TFA-d) δ: 9.01 (1H, s), 8.0 (1H, d, J = 13Hz), 7.8 (1H, d, J = 8Hz) 5.7 (3H, m) , 4.0 (1H, d, J = 13Hz), 3.8 ~ 3.5 (2H, m), 3.3 ~ 3.0 (1H, m), 2.9 ~ 2.7 (1H, m), 2.2 ~ 2.1 (2H, m), 1.8 ( 3H, d, J = 11Hz), 1.6 (3H, s)

Example 3

(-)-7-([1α, 5α, 6β] -1-methyl-6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1-((s) 2-fluoro-1-methyl) ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

1-((s) -2-fluoro-1-methyl) ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 200 mg was suspended in 10 ml of acetonitrile and 290 mg of DBU was added.

150 mg of (-)-[1α, 5α, 6β] -1-methyl-6-amino-3-azabicyclo [3.2.0] heptane dihydrochloride was added and stirred at room temperature for 5 hours, followed by the same method as in Example 2 219 mg were obtained (yield 85%).

Melting point: 240 ° C or more (decomposition)

¹ H-NMR (DMSO-d ₆ + TFA-d) δ: 9.3 (1H, s), 8.2 (1H, d, J = 13Hz), 5.9 (3H, m), 4.0 (1H, d, J = 13Hz ), 3.7 to 3.5 (2H, m), 3.2 to 3.0 (1H, m), 2.8 to 2.6 (1H, m), 2.4 to 2.1 (2H, m), 1.7 (3H, d, J = 10 Hz), 1.6 (3H, s)

Example 4

(-)-7-([1α, 5α, 6β] -1-methyl-6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1-methyl-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

132 mg of 1-methyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was suspended in 3 ml of acetonitrile and 0.3 ml of DBU was added. Was added. 120 mg of (-)-[1α, 5α, 6β] -1-methyl-6-amino-3-azabicyclo [3.2.0] heptane dihydrochloride was added and stirred at room temperature for 2 hours. 160 mg of compound was obtained (yield 90%).

Melting Point: 300 ℃ or higher

¹ H-NMR (DMSO-d ₆ + TFA-d) δ: 8.96 (1H, s), 8.06 (1H, d, J = 13 Hz), 4.23-3.77 (11H, m), 1.61 (3H, s)

Example 5

(-)-7-([1α, 5α, 6β] -1-methyl-6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -6-fluoro-1-ethyl-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

140 mg of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was suspended in 4 ml of acetonitrile, followed by DBU 360 mg and (- 120 mg of)-[1α, 5α, 6β] -1-methyl-6-amino-3-azabicyclo [3.2.0] heptane dihydrochloride was added. After stirring the reaction solution at room temperature for 3 hours, 130 mg of the target compound was obtained in the same manner as in Example 2 (yield 70%).

Melting Point: 215 ~ 217 ℃

¹ H-NMR (DMSO-d ₆ + TFA-d) δ: 8.98 (1H, s), 8.03 (1H, d, J = 13Hz), 4.53 ~ 1.62 (13H, m), 1.50 (3H, s)

Example 6

(-)-7-([1α, 5α, 6β] -1-methyl-6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1- (2-fluoroethyl) -6 -Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

200 mg of 1- (2-fluoroethyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid suspended in 10 ml of acetonitrile Then 0.34 ml of DBU was added at room temperature, and 190 mg of (-)-[1α, 5α, 6β] -1-methyl-6-amino-3-azabicyclo [3.2.0] heptane dihydrochloride was added. After stirring at room temperature for 5 hours, 250 mg of the target compound was obtained in the same manner as in Example 1 (yield 94%).

Melting point: 250 ° C or more (decomposition)

¹ H-NMR (DMSO-d ₆ + TFA-d) δ: 9.01 (1H, s), 8.0 (1H, d, J = 13Hz), 5.8 (3H, m), 4.1 (1H, d, J = 13Hz ), 4.0 ~ 3.5 (2H, m), 3.3 ~ 3.0 (1H, m), 2.9 ~ 2.8 (1H, m), 2.2 ~ 2.0 (2H, m), 1.6 (3H, s)

Example 7

(-)-7-([1α, 5α, 6β] -1-methyl-6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1-trifluoroethyl-6-fluoro -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

470 mg of 6,7-difluoro-1-trifluoroethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was suspended in 5 ml of acetonitrile, followed by (-)-[1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane 360 mg and DUB 830 mg were added, and the reaction solution was refluxed at 50 ° C. for 5 hours to obtain 440 mg of the target compound in the same manner as in Example 1. Obtained (yield 70%).

Melting Point: 270 ℃

¹ H-NMR (DMSO-d ₆ + TFA-d) δ: 9.00 (1H, s). 8.04 (1H, d, J = 13Hz), 7.24 (1H, d, J = 7.4Hz), 5.63 ~ 5.40 (2H, m), 4.40 (1H, d, J = 13Hz), 4.15 (1H, d, J = 11 Hz), 4.00-3.73 (2H, m), 3.30-3.15 (1H, m), 2.90-2.80 (1H, m), 2.25-2.00 (2H, m), 1.40 (3H, s)

Example 8

(-)-7-([1α, 5α, 6β] -1-methyl-6-amino-3-azabicyclo [3.2.0] heptan-3-yl) -1-difluoroethyl6-fluoro -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

470 mg of 7-chloro-1,4-dihydro-6-fluoro-4-oxo-1-difluoroethyl-1,8-naphthyridine-3-carboxylic acid is suspended in 5 ml of acetonitrile and DBU 0.83 366 mg of (-)-[1α, 5α, 6β] -6-amino-1-methyl-3-azabicyclo [3.2.0] heptane was added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was treated in the same manner as in Example 1 to obtain 440 mg of the target compound (yield 73%).

Melting Point: 282 ℃

¹ H-NMR (DMSO-d ₆ + TFA-d) δ: 9.00 (1H, s), 8.04 (1H, d, J = 13Hz), 5.60 ~ 5.31 (2H, m), 4.40 (1H, d, J = 13 Hz), 4.15 (1H, d, J = 11 Hz), 4.00-3.73 (2H, m), 3.43-3.15 (2H, m), 2.90-2.80 (1H, m), 2.25-2.00 (2H, m) , 1.40 (3H, s)

Claims (2)

The pyridone carboxylic acid derivative represented by the following general formula (I), its ester, and its salt. In general formula (I), R ₁ means methyl, ethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoroisopropyl group, A means nitrogen atom or C-H, Z means a group represented by the following formula. (Wherein R ₂ , R ₃ means a hydrogen atom or a methyl group, one of which means hydrogen, one of R ₄ , R ₅ means hydroxy, alkoxy, amino group, and the other means hydrogen.) The compound represented by the following general formula (II) and the compound represented by the following general formula (III) or acid addition salts thereof are condensed in an inert organic solvent, or when R ₆ is lower alkyl, represented by the following general formula (II) A method of preparing a pyridone carboxylic acid derivative represented by the following general formula (I) by condensation reaction of the compound represented by the following general formula (III) and a compound represented by the following general formula (III) or an acid addition salt thereof in an inert organic solvent. Z-H (Ⅲ) R ₁ in the general formulas (I), (II) and (III) means methyl, ethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoroisopropyl groups, A means nitrogen atom or and C-H, R ₆ means hydrogen or lower alkyl group, Y means halogen atom, Z means a group represented by the following formula. (Wherein R ₂ , R ₃ means a hydrogen atom or a methyl group, one of the stones means hydrogen, one of R ₄ , R ₅ means a hydroxy, alkoxy, amino group and the other means hydrogen.)