KR0167486B1 - 6-methyl-5-aminoquinoline carboxylic acid derivative and process for preparing thereof - Google Patents

Abstract

The present invention provides a novel quinoline carboxylic acid derivative of the general formula (I) below, which exhibits excellent antimicrobial activity and broad antimicrobial spectrum by simultaneously introducing a methyl group at position 6 and an amino group at position 5 of the quinolone mother nucleus, a method for preparing the compounds, and an activity thereof. It relates to an antimicrobial composition containing as a component.

In the above formula,

X represents hydrogen, fluorine, chlorine, methyl or methoxy;

A is hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl unsubstituted or substituted by amino, C ₁ -C ₄ alkyl substituted by unsubstituted or C ₁ -C ₂ alkyl amino and methoxy C ₄ -C ₈ cycloamine, piperazine or morpholine unsubstituted or substituted by one or more substituents selected from the group consisting of imino.

Description

6-methyl-5-amino quinoline carboxylic acid derivative and its preparation method

The present invention relates to a novel quinolone compound, particularly represented by the following general formula (I) showing excellent antimicrobial activity and broad antibacterial spectrum by introducing a methyl group at the 6-position and an amino group at the 5-position at the same time Novel quinoline carboxylic acid derivatives, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, solvates and isomers.

Wherein X represents hydrogen, fluorine, chlorine, methyl or methoxy;

A is hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl unsubstituted or substituted by amino, C ₁ -C ₄ alkyl substituted by unsubstituted or C ₁ -C ₂ alkyl amino and methoxy C ₄ -C ₈ cycloamine, piperazine or morpholine unsubstituted or substituted by one or more substituents selected from the group consisting of imino.

The present invention also relates to a method for producing the compound of the general formula (I) and an antimicrobial composition containing the compound as an active ingredient.

Since the emergence of nalidic acid (GY Lesher, et al., J. Med. Chem., 5, 1063-1065 (1962)) as a therapeutic agent for urinary tract infections in 1962, many quinoline carboxylic acid-based antimicrobials, oxolinic acid (Oxolinic acid) acid, Rosoxacin and Pipemidic acid have been developed, and these early antimicrobial agents (Albrecht R., Prog. Drug Res., 221, 9 (1977)) have almost no activity against Gram-positive bacteria. It has been used only as an antimicrobial agent of gram negative bacteria.

Recently, a new generation of quinolones-containing nofloxacin (H. Koga, et al., J. Med. Chem., 23, 1358-1363 (1980)) containing fluorine at position 6 was developed. Research on quinolone antibiotics has been very extensively attempted. However, nofloxacin was used only for the treatment of diseases caused by Gram-negative bacteria due to its weak antimicrobial activity against Gram-positive bacteria and its poor distribution and absorption. Ciprofloxacin (R. Wise, et al., J. Antimicrob. Agents Chemother, 23, 559 (1983)), and ofloxacin (K. Sata, et al., Antimicrob. Agents Chemother, 22, 548 (1982) and the like, and these antimicrobials have a broader antimicrobial activity than earlier antimicrobials, and are widely used in clinical and therapeutic practice today.

The conventionally developed antimicrobial agents are limited to derivatives in which the substituent at position 6 is fixed with a fluorine atom and the other position is changed assuming that the optimal form for the quinolone compound to have antimicrobial activity is fluorine at position 6. It is. However, existing antimicrobial agents substituted with fluorine at position 6 have excellent antimicrobial activity against Gram-negative bacteria, but are relatively weak against Gram-positive and anaerobic bacteria, and some bacteria still exhibit quinolone resistance to these antimicrobial agents. Has its drawbacks.

So far, the role of the fluorine atom at position 6 has not been accurately identified. However, the quinolone compound of the general formula [A] having no fluorine atom at position 6 (Hiroshi Koya, et al., J. Med. Chem. 23, 1358-1363, 1980) has a fluorine atom at position 6 Although it is reported that the antimicrobial activity is somewhat lower than that of the compound having the present invention, a recently published paper (Benoit ledoussal, et al., J. Med. Chem., 35, 198-200, 1992) has the following structural formula [B] In addition to showing good antimicrobial activity in the state that does not have a fluorine atom at position 6, and the structural change of the fluorine atom at position 6 to position 8 has been reported to exhibit similar antimicrobial activity to the compound at position 6 Based on this, it can be inferred that the fluorine atom at position 6 is not a necessary substituent for good antibacterial activity.

Wherein R represents Cl, Br, CH ₃ , SCH ₃ , CN, NO ₂ or COCH ₃ .

Under this analogy, the present inventors continued the study of the preferred substituent at position 6, which can supplement the weaknesses of the previously known quinolone antimicrobial agents. As a result of introducing a methyl group having completely different chemical properties from the fluorine atom, Gram-negative bacteria We have already reported successful development of a new quinolone derivative of the following general formula [C], which shows a wide range of activities from anaerobic bacteria including gram-positive bacteria to Pseudomonas aeruginosa, as well as excellent antibacterial activity against quinolone-resistant bacteria (Korea) Patent application no. 93-11402).

Wherein A represents a 4 to 7 membered cycloamine,

X represents a halogen atom.

The present inventors, however, have further advanced the studies on 6-methyl quinolone compounds already reported as above, which not only show stronger antimicrobial activity, but also have high solubility in water and organic solvents, and thus have an intracellular absorption rate. In order to develop a new quinolone compound with improved features, various groups were introduced at the 5 position of the quinolone nucleus and their pharmacological effects were examined. As a result, the following group was introduced with an amino group at the 5 position of the quinoline nucleus. The discovery of the fact that the compound of general formula (I) meets this purpose has led to the completion of the present invention.

It is therefore an object of the present invention to provide novel quinolone compounds of the general formula (I), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, solvates and isomers thereof.

In the above formula,

X represents hydrogen, fluorine, chlorine, methyl or methoxy;

A is hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl unsubstituted or substituted by amino, C ₁ -C ₄ alkyl substituted by unsubstituted or C ₁ -C ₂ alkyl amino and methoxy C ₄ -C ₈ cycloamine, piperazine or morpholine unsubstituted or substituted by one or more substituents selected from the group consisting of imino.

Among the compounds of the general formula (I), preferred compounds are those in which X represents fluorine; A is a compound representing the A1, A2 or A3 group of the following general formula.

In the above formula,

R represents hydrogen or C ₁ -C ₄ alkyl, R 1 and R 2 are each independently amino, C ₁ -unsubstituted or substituted by hydrogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl C ₁ -C ₂ aminoalkyl or methoxyimino unsubstituted or substituted by C ₄ alkyl, n represents 0 or 1.

On the other hand, as a representative compound according to the present invention, among the preferred compounds, 5-amino-1-cyclopropyl-8-fluoro-6-methyl-7- (1-piperazinyl) -1,4-dihydro-4- Oxoquinoline-3-carboxylic acid; 5-amino-7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-8-fluoro-6-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 5-Amino-7- (3-aminomethyl-1-pyrrolidinyl) -1-cyclopropyl-8-fluoro-6-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid ; 5-amino-1-cyclopropyl-8-fluoro-6-methyl-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 5-amino-1-cyclopropyl-7- (3,5-dimethyl-1-piperazinyl) -8-fluoro-6-methyl-1,4-dihydro-4-oxoquinoline-3-carboxyl mountain; 5-amino-1-cyclopropyl-8-fluoro-6-methyl-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 5-amino-1-cyclopropyl-8-fluoro-6-methyl-7- (4-aminomethyl-3-methoxyimino-1-pyrrolidinyl) -1,4-dihydro-4-oxoquinoline 3-carboxylic acid; 5-amino-1-cyclopropyl-8-fluoro-6-methyl-7- (4-amino-3-methoxyimino-1-pyrrolidinyl) -1,4-dihydro-4-oxoquinoline- Mention may be made of 3-carboxylic acids.

When substituent 7 in the compound of general formula (I) is a cycloamine having one substituent, the compound may be in R or S form or in the form of R, S mixture. In addition, when A is a cycloamine having two or more substituents, it may be a cis or trans isomer or a mixture thereof, and the present invention includes each of these isomers and mixtures thereof.

In addition, modifications obtained by conventional operations in the field of the present invention, such as pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, solvates and isomers of the above general formula (I) compounds, are also within the scope of the present invention. Included in

Pharmaceutically acceptable non-toxic salts of the compounds of general formula (I) according to the invention are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or the like or acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, hydroxyl acid, Organic carboxylic acids such as succinic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, ascorbic acid or dried acid or salts with sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid and quinolone compounds which are known and used in the art Salts with other acids. These acid addition salts can be prepared by conventional conversion processes.

According to the invention there is also provided a process for the preparation of the novel compounds of general formula (I).

The compound of formula (I) can be prepared by reacting a compound of formula (III) with a compound of formula (IV) in the presence of an acid acceptor in an inert solvent according to the method of Scheme 1 below.

Wherein A and X are as defined above.

On the other hand, the compound of the general formula (III) used as a starting material in the above reaction scheme can be prepared by heating the compound of the following general formula (II) by an acid catalyst under hydrolysis.

In the formula, X represents a halogen atom.

The acid catalyst may be an inorganic acid such as hydrochloric acid, acetic acid, sulfuric acid, organic acid such as trimethylsiliodide, or Lewis acid such as aluminum chloride, or a mixture thereof. The mixture is heated and stirred in the temperature range of 10 to 100 ° C.

The compound of formula (III) thus prepared is mixed and stirred for 10 minutes to 24 hours with the compound of formula (IV) at a reaction temperature of 10 to 180 ° C to obtain a compound of formula (I). In this reaction the compounds of formula (IV) can be used in the form of free compounds or in the form of salts with acids such as hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid and the like.

In the scheme 1, any solvent may be used as long as it does not adversely affect the reaction. Preferably, the solvent may be selected from dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, pyridine, and hexamethylphosphoamide. .

The reaction is generally carried out in the presence of an acid acceptor, wherein in order to increase the reaction efficiency of the relatively expensive starting material (III), the reaction material (IV) is added in the same amount or in excess of the starting material (III), for example. It is used in an equimolar amount or 10 mol times. When the reactant (IV) is used in excess, the compound of the general formula (IV) remaining after the reaction can be recovered and reused. The acid acceptors that can be used include sodium hydrogen carbonate as the inorganic base, potassium carbonate or triethylamine as the organic base, diisopropylethylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, 1,8 -Diazabicyclo [5.4.0] undec-7-ene, 1, 4- diazabicyclo [2.2.2] octane, etc. are mentioned.

The compound of formula (I) according to the present invention also protects the compound of formula (II) with an appropriate protecting group in the amine in the compound of formula (IV), as shown in Scheme 2 below. By reacting with a compound of the following general formula (IV ′) to obtain a compound of the following general formula (V), which can also be prepared by a method of reducing and deprotecting.

In the above formula,

A'NH ₂ represents A,

A and X are as defined above,

P represents an aminoprotecting group.

The amino protecting group P usable in the compound of general formula (IV ′) can be removed without decomposing the structure of the target compound obtained as a result of the reaction, so that the amino group in the technical field of peptide, amino sugar, nucleic acid or β-lactam compound As long as it is normally used as a protecting group, it is good. Specific examples of protecting groups that can be used for this purpose include formyl, acetyl, trifluoroacetyl, benzyl, p-methoxybenzyl, methoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, p-meth Oxybenzyloxycarbonyl, trityl, tetrahydropyranyl group and the like.

Reduction reaction of the general formula (V) compound in Scheme 2 may vary slightly depending on the nature of the amine protecting group, but the temperature of 10 to 100 ℃ in the presence of a catalyst such as platinum, palladium, nickel and the like in an inert solvent It is usually carried out by blowing the hydrogen stream at or by treating with metallic sodium or metallic lithium in liquid ammonia at temperatures between -50 and -10 ° C. In addition, after the reduction reaction is completed, the aminoprotecting group and the ester group of the parent nucleus are depending on the nature of the group, solubilization or reduction reaction including hydrolysis, for example, in the presence of an acid or a base in a temperature range of 0 to 130 ° C. in a solvent. Or in the absence of the reaction. In this case, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like may be used, and organic acids such as acetic acid, trifluoroacetic acid, formic acid, toluenesulfonic acid, or Lewis acids such as boron tribromide and aluminum chloride may be used. Examples of the base include hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide and barium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal alkoxides such as sodium methoxide and sodium ethoxide, sodium acetate, and the like. have. As the solvent, a solvent such as ethanol, dioxane, ethylene glycol, dimethyl ether, benzene, acetic acid, or a mixed solvent of these solvents and water may be used depending on the water or the compound, and in some cases, the reaction may be carried out without a solvent.

In addition, when the protecting group is benzyl, trityl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or the like, it can be effectively removed using a reduction reaction. The removal of the protecting group by the reduction reaction may be slightly different depending on the nature of the protecting group, but is carried out by blowing a hydrogen stream at a temperature of 10 to 100 ℃ in the presence of a catalyst such as platinum, palladium, nickel and the like in an inert solvent Or by treatment with metallic sodium or metallic lithium in liquid ammonia at temperatures between -50 and -10 ° C.

The compound of the general formula (I) according to the present invention may also optionally react the compound of the general formula (VI) with the compound of the general formula (IV) according to the method of the following scheme (III) Can be obtained by deprotecting the compound.

Wherein X and A are as defined above.

The reaction conditions of Scheme 3 are the same as those described for Scheme 2, wherein the general formula (VI) compound used as starting material is a hydrofluorobolic compound of general formula (III) at room temperature as shown in Scheme 4 below. It can be easily prepared by treating with lyric acid and activating it.

On the other hand, the compounds of the general formula (II) or (III) used as starting materials in the present invention is the method of the Federal Republic of Germany Patent Publication No. 3,142,824 developed by Bayer researchers, or as reported by Chu et al. DT Chu et al., J. Med. Chem., 28, 1558-1564, 1987), can be prepared according to the method of Scheme 5 below.

The preparation method of Scheme 5 is described in detail.

First, the compound (1) is reacted with sodium nitrite to prepare a diazonium salt, and then the compound (2) is synthesized by reacting with cuprous bromide. The compound is reacted with magnesium to form a green reagent, and dimethyl sulfate is added thereto to synthesize compound (3). When compound (4) is synthesize | combined from compound (3) by Friedel-Crafts reaction, compound (5) can be synthesize | combined according to a haloform reaction. Subsequently, compound (5) was nitrated to prepare compound (6), which was then reacted with thionyl chloride to prepare compound (7), and compound (7) was reacted with monoethylester of malonic acid to give compound (8). ) Is treated with triethylorthoformate and then reacted with cyclopropyl amine to synthesize compound (9). Cyclization of compound (9) with sodium hydride yields compound of formula (II), which is treated with a hydrogen stream in the presence of nickel to reduce the nitro group to an amine and hydrolyze to form compound (III). do.

The synthetic methods mentioned above will be explained in more detail in the preparation examples described below.

According to the present invention, there is also provided an antimicrobial composition containing as an active ingredient the novel compound of formula (I) or a pharmaceutically acceptable salt thereof. Such antimicrobial compositions consist of a therapeutically effective amount of the active ingredient and a pharmaceutically acceptable carrier, excipient or other additive, and the like, and can be formulated by known methods using known pharmaceutical carriers and excipients.

As mentioned above, the compounds according to the present invention show a broad spectrum of antimicrobial spectrum and stronger antimicrobial activity against pathogens including various Gram-positive and Gram-negative bacteria. Or nofloxacin or the like), showing an antimicrobial activity equivalent to or greater than that of a conventional Gram-positive bacterium, and excellent resistance to a quinolone compound.

Furthermore, the compounds according to the present invention have an amino group at position 5 together with the methyl group at position 6, so that their solubility in water and organic solvents is increased, resulting in higher absorption than conventional quinolone compounds and very low toxicity. It has been found that it can be used very effectively for the purpose of preventing and treating diseases caused by bacterial infection in animals including humans.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention is not limited thereto unless the main configuration is changed.

Preparation Example 1 Synthesis of 1-Bromo-2,3,4, -trifluorobenzene

30 g (0.2 mol) of 2,3,4-trifluoroaniline and 62 ml of 48% hydrobromic acid were added to a 100 ml reaction vessel equipped with a thermometer and an addition funnel, cooled to 0 ° C., followed by 14.1 g of sodium nitrite ( 0.204 mol) was dissolved in 26 mL and added little by little. At this time, the temperature of the reactants should not exceed 10 ℃. Meanwhile, 32.18 g (0.112 mol) of cuprous bromide and 17 ml of 48% hydrobromic acid were added to the other 1 L reaction vessel and heated to reflux. The diazonium solution prepared in this mixture was slowly added and heated to reflux for 30 minutes. The reaction mixture was extracted with ethyl ether (50 mL × 3), washed several times with 1N HCl, and the organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue obtained here was distilled under reduced pressure (62 ° C., 43.5 mm Hg) to give 28 g (yield: 67%) of the title compound.

GC / MASS (M ⁺ ): 210

¹ H NMR (CDCl ₃ ): δ 6.9 (m, 1H), 7.27 (m, 1H)

Preparation Example 2 Synthesis of 2,3,4-Trifluoro Toluene

8 g (0.33 mol) of finely chopped magnesium was added to a 1 L reaction vessel, and then dried well, and 50 ml of ethyl ether was added thereto. A mixture of 63 g (0.3 mol) of 1-bromo-2,3,4-trifluorobenzene and 250 ml of ethyl ether was added thereto while maintaining the conditions under which the ethyl ether was heated to reflux, and then heated to reflux for 1 hour. . 85.2 mL (0.9 mole) of dimethylsulfate was slowly added while maintaining the temperature of the reaction mixture below 10 ° C and left for 24 hours. 1N HCl was added thereto, stirred for 30 minutes, the ethyl ether layer was separated, washed with H ₂ O (150 mL × 3), and the ethyl ether layer was removed by simple distillation. At room temperature the residue was added slowly to a sodium ethoxide solution consisting of sodium (24 g) and ethanol (400 mL) and heated to reflux for 30 minutes. 500 ml of ethyl ether and 200 ml of water were added thereto, stirred for 20 minutes, the ethyl ether layer was separated, washed several times with water, dried over anhydrous magnesium sulfate, filtered and distilled (120 DEG C, 1 atm), and the title compound was 28.7 g. (Yield 66%) was obtained.

GC / MASS (M ⁺ ): 146

¹ H NMR (CDCl ₃ ): δ 2.25 (s, 3H), 6.85 (m, 2H)

Preparation Example 3: Synthesis of 2,3,4-trifluoro-5-methylacetophenone

In a 500 ml reaction vessel equipped with a thermometer, a cooler and an addition funnel, 28.7 g (0.197 mole) of the compound obtained in Preparation Example 2 and 104.9 g (0.786 mole) of aluminum chloride were mixed well while the internal temperature did not exceed 50 ° C. 56 mL (0.786 mol) of acetyl chloride was added in portions. The mixture is heated at 90 ° C. for 1 hour 30 minutes and the progress of the reaction is required for G / C [column: ov-1, temperature: 50 ° C. → 270 ° C. (15 ° C./min), 270 ° C. (20 min) starting material Time: 2.41 min, required time for product: 5.93 min]. 1N HCl was carefully added to the reaction, and then 100 ml of dichloromethane was added and stirred for 30 minutes to separate the dichloromethane layer. This was washed successively with saturated sodium hydrogen carbonate and saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate salt, distilled under reduced pressure and purified to give 20 g (yield: 55%) of the title compound.

GC / MASS (M ⁺ ): 188

¹ H NMR (CDCl ₃ ): δ 2.29 (s, 3H), 2.61 (d, J = 5 ′, 3H), 7.54 (t, J = 8 ′, 1H)

Preparation Example 4 2,3,4-trifluoro-5-methylbenzoic acid

5.3 g (0.133 mole) of sodium hydroxide was dissolved in 21 ml of water, cooled to 0 ° C., and 4.22 g (0.027 mole) of bromine was added thereto. At this time, the temperature of the reactant is maintained at 10 ° C or less. Meanwhile, 1.67 g (0.0089 mol) of 2,3,4-trifluoro-5-methylacetophenone, dioxane (33 mL) and water (16.7 mL) were added to a 250 mL reaction vessel, followed by cooling, and then the temperature of the reactant. The NaBr solution made above was slowly added while maintaining at 3 ° C. After stirring for 30 minutes at the same temperature, 1.12 g (0.0089 mol) of Na ₂ SO ₃ was dissolved in 11 ml of water, added, stirred at room temperature for 30 minutes, and the reaction was concentrated to 1/3. 27 ml of water was added, diluted, washed (11 ml x 5), and concentrated hydrochloric acid was added little by little. The precipitated solid was filtered, washed with water and dried to give 0.77 g (yield 45%) of the title compound.

GC / MASS (M ⁺ ): 191

¹ H NMR (CDCl ₃ ): δ 2.31 (s, 3H), 7.65 (t, J = 7 Hz, 1H)

Preparation Example 5 Synthesis of 2,3,4-Trifluoro-5-methyl-1-nitrobenzoic Acid

100 ml of chloroform was mixed with 37.6 g (0.2 mol) of 2,3,4-trifluoro-5-methylbenzoic acid in a 2 L reaction vessel and cooled to 0 ° C. A mixture of 198 ml of 98% sulfuric acid and 98 ml of 94% nitric acid was slowly added thereto and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C., diluted with 300 ml of cold water, and extracted with 400 ml of ethyl acetate. The extracted organic layer was washed with 200 ml of brine and distilled under reduced pressure to obtain 46.5 g of the title compound quantitatively.

GC / MASS (M ⁺ ): 236

¹ H NMR (CDCl ₃ ): δ 2.30 (s, 3H)

Preparation Example 6 Synthesis of 2,3,4-Trifluoro-5-methyl-6-nitrobenzoylchloride]

46.5 g (0.2 mol) of 2,3,4-trifluoro-5-methyl-6-nitrobenzoic acid, 43.3 ml (0.59 mol) of thionyl chloride and 75 ml of dichloromethane were mixed and heated to reflux for 4 hours. The solvent was removed by distillation under reduced pressure and dried in vacuo to yield 50.19 g of the title compound quantitatively.

MASS (FAB): 254

¹ H NMR (CDCL ₃ ): δ 2.40 (s, 3H)

Preparation Example 7 Synthesis of Ethyl-4,5,6, -trifluoro-3-methyl-2-nitrobenzoylacetate

To a solution of 60.2 g (0.46 mol) of monoethylmalonate in 1 L of tetrahydrofuran, 412 ml (1.03 mol) of n-butyllithium was added at -30 ° C, and then gradually heated up to -5 ° C. It was again cooled to −50 ° C., and 50.2 g (0.2 mol) of 2,3,4-trifluoro-5-methyl-6-nitrobenzoyl chloride dissolved in 300 ml of tetrahydrofuran was slowly added thereto. After 30 minutes the reaction mixture was again cooled to −30 ° C. and 460 mol of 1N HCl was added. After 30 minutes the reaction mixture was cooled back to -30 ° C and 460 moles of 1N HCl was added. The organic layer was separated, the aqueous layer was extracted with 500 mL of ethyl ether, combined with the first organic layer, and washed sequentially with saturated sodium dicarbonate (200 mL × 2) and brine (200 mL). The residue obtained by distillation of the organic layer under reduced pressure was purified by column chromatography to give 24.5 g (yield: 40%) of the title compound.

MASS (FAB): 306

¹ H NMR (CDCL ₃ , 2 sets of signals): δ 1.2 (t, J = 7㎐, 3H), 1.31 (t, J = 7㎐, 3H), 2.25 (s, 3H), 2.40 (s, 3H ), 3.95 (d, J = 3 μs, 2H), 4.20 (q, J = 7 μs, 2H), 4.35 (q, J = 7 μs, 2H), 5.50 (s, 1H), 12.35 (s, 1H )

Preparation Example 8 Synthesis of Ethyl 3-cyclopropylamine-2- (4,5,6-trifluoro-3-methyl-2-nitrobenzoyl) propenoate

15 g (0.049 mol) of ethyl-4,5,6-trifluoro-3-methyl-2-nitrobenzoyl acetate, 2.6 g (0.12 mol) of acetic anhydride and 11.2 g (0.08 mol) of triethylorthoformate were mixed After heating to reflux for 1 hour, excess acetic anhydride and triethylorthoformate were removed by distillation under reduced pressure. The residue was cooled to 0 ° C. and 4.2 g (0.07 mol) of cyclopropylamine were added dropwise, followed by stirring for 10 hours. The precipitated solid was filtered and dried to give 13.3 g (yield: 73%) of the title compound.

MASS (FAB): 373

¹ H NMR (CDCL ₃ , major isomer): δ 0.89 (m, 4H), 1.10 (t, J = 7 Hz, 3H), 1.16 (s, 3H), 2.95 (m, 1H), 4.07 (q, J = 7 μs, 2H), 8.26 (d, J = 12 μs, 1H)

Preparation Example 9 Synthesis of Ethyl 1-cyclopropyl-7,8-difluoro-6-methyl-5-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylate]

12.1 g (0.033 mol) of ethyl 3-cyclopropylamine-2- (4,5,6-trifluoro-3-methyl-2-nitrobenzoyl) propenoate and 300 ml of tetrahydrofuran were added to a 1 liter reaction vessel. It was then cooled to 0 ° C. and 1.56 g (0.039 mol) of NaH were added little by little. The temperature of the reaction was raised to room temperature, stirred for 1 hour, and then, 39 mol of 1N HCl was added thereto, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 500 mL of dichloromethane, washed with water (200 mL × 2) and distilled under reduced pressure to give 11 g (yield: 91%) of the title compound.

MASS (FAB): 353

¹ H NMR (CDCL ₃ ): δ 1.15 (m, 1H), 1.27 (m, 2H), 1.30 (t, J = 7 Hz, 3H), 2.28 (s, 3H), 3.92 (s, m), 4.34 (q, J = 7 Hz, 2H), 8.55 (s, 1H)

Preparation Example 10 Synthesis of Ethyl 5-amino-1-cyclopropyl-7,8-difluoro-6-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate]

2.5 g (7.1 mmol) of ethyl 1-cyclopropyl-7,8-difluoro-6-methyl-5-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylate in a 5 L reaction vessel, 2 L of ethanol and excess Ranickel were mixed and then reacted under hydrogen stream (1 atm) for 4 hours, and then the Ranickel was filtered and distilled under reduced pressure to give 2.04 g (yield: 89%) of the title compound.

MASS (FAB): 323

1 H NMR (CDCL3): δ 0.99 (m, 2H), 1.13 (m, 2H), 1.30 (t, J = 7 Hz, 3H), 2.01 (s, 3H), 3.77 (s, 1H), 4.25 (q , J = 7 Hz, 2H), 7.03 (bs, 2H), 8.34 (s, 1H)

Preparation Example 11 Synthesis of 5-amino-1-cyclopropyl-7,8-difluoro-6-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

6 ml of acetic acid was added to 0.5 g (1.5 mmol) of ethyl 5-amino-1-cyclopropyl-7,8-difluoro-6-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate. And heated to 85 ° C. At the same temperature, 3 ml of 3N HCl was added little by little, and further stirred for 2 hours. The resulting solid was filtered, washed with ethyl ether and dried to give 0.32 g (yield: 73%) of the title compound.

MASS (FAB): 295

¹ H NMR (CDCL ₃ ): δ 1.1 (m, 1H), 1.21 (m, 2H), 2.11 (s, 3H), 3.92 (m, 1H), 6.85 (m, 2H), 8.68 (s, 1H)

Preparation Example 12 Ethyl 7- [3- (Nt-butoxycarbonylaminomethyl) -1-pyrrolidinyl] -1-cyclopropyl-8-fluoro-6-methyl-5-nitro-1,4 Synthesis of Dihydro-4-oxoquinoline-3-carboxylate]

200 mg (0.568 mmol) of the compound obtained in Preparation Example 9 and 2 ml of acetonitrile were added to a 10 ml reaction vessel, followed by stirring. To this was added 85 mg (0.568 mmol) of DBU and 228 mg (1.14 mmol) of N-t-butoxycarbonylaminomethylpyrrolidine and heated to reflux for 4 hours. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure and purified by column chromatography to give 250 mg (yield: 85%) of the title compound.

MASS (FAB): 533

¹ H NMR (CDCl ₃ ): δ 1.07 (m, 2H), 1.25 (m, 2H), 1.38 (t, J = 7 Hz, 3H), 1.55 (s, 9H), 1.90 (m, 1H), 2.10 (m, 1H), 2.20 (s, 1H), 2.45 (s, 1H), 3.30 (m, 3H), 3.40 (m, 3H), 4.00 (m, 1H), 4.37 (q, J = 7 Hz, 2H), 4.90 (m, 1H), 8.54 (s, 1H)

Preparation Example 13: Ethyl 5-amino-7- [3- (Nt-butoxycarbonylaminomethyl) -1-pyrrolidinyl] -1-cyclopropyl-8-fluoro-6-methyl-1,4 Synthesis of Dihydro-4-oxoquinoline-3-carboxylate]

250 mg (0.483 mmol) of the compound obtained in Preparation Example 12 and 100 ml of ethanol were added to a 250 ml reaction vessel, followed by stirring. An excess of Ranickel was added thereto and reacted for 24 hours under a hydrogen stream (1 atmosphere). Ranickel was filtered and distilled under reduced pressure to give 70 mg (yield: 30%) of the title compound.

MASS (FAB): 503

¹ H NMR (CDCl ₃ ): δ 1.10 (m, 2H), 1.20 (m, 2H), 1.40 (t, J = 7 Hz, 3H), 1.55 (s, 9H), 1.81 (m, 1H), 2.10 (s, 3H), 2.15 (m, 1H), 3.10 (m, 1H), 3.25 (m, 5H), 3.95 (m, 1H), 4.30 (q, J = 7 Hz, 2H), 4.65 (m, 1H), 6.80 (bs, 2H), 8.39 (s, 1H)

Preparation Example 14 Ethyl 7- (4-t-butoxycarbonyl-3-methyl-1-piperazinyl) -1-cyclopropyl-8-fluoro-6-methyl-5-nitro-1,4 Synthesis of Dihydro-4-oxoquinoline-3-carboxylate]

200 mg (0.568 mmol) of the compound obtained in Preparation Example 9 and 2 ml of acetonitrile were added to a 10 ml reaction vessel, followed by stirring. To this was added 85 mg (0.568 mmol) of DBU and 227 mg (2.27 mmol) of 2-methylpiperazine and heated to reflux for 4 hours. The reaction was cooled and distilled under reduced pressure, then the residue was dissolved in 5 ml of dichloromethane and 124 mg (0.568 mmol) of di-t-butyldicarbonate were added and stirred for 30 minutes. The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography to give 230 mg (yield: 84%) of the title compound.

MASS (FAB): 533

¹ H NMR (CDCl ₃ ): δ 1.16 (m, 2H), 1.26 (m, 2H), 1.36 (t, J = 7 Hz, 3H), 1.45 (d, 3H), 1.49 (s, 9H), 2.32 (s, 3H), 2.80 (m, 2H), 3.10 (m, 2H), 3.25 (m, 1H), 3.95 (m, 2H), 4.25 (m, 1H), 4.30 (q, J = 7 Hz, 2H), 8.53 (s, 1H)

Preparation Example 15 Ethyl 5-amino-7- (4-t-butoxycarbonyl-3-methyl-1-piperazinyl) -1-cyclopropyl-8-fluoro-6-methyl-1,4 Synthesis of Dihydro-4-oxoquinoline-3-carboxylate]

230 mg (0.433 mmol) of the compound obtained in Preparation Example 14 and 100 ml of ethanol were added to a 250 ml reaction vessel, followed by stirring. An excess of Ranickel was added thereto and reacted for 24 hours under a hydrogen stream (1 atmosphere). Ranickel was filtered and distilled under reduced pressure to give 200 mg (yield: 92%) of the title compound.

MASS (FAB): 503

¹ H NMR (CDCl ₃ ): δ 0.95 (m, 2H), 1.23 (m, 2H), 1.35 (t, 3H), 1.40 (d, 3H), 1.51 (s, 9H), 2.19 (s, 3H) , 2.95 (m, 2H), 3.20 (m, 2H), 3.41 (m, 1H), 3.90 (m, 2H), 4.10 (m, 1H), 4.20 (q, 2H), 6.89 (bs, 2H), 8.20 (s, 1 H)

Preparation Example 16: Ethyl 7- (4-t-butoxycarbonyl-3,5-dimethyl-1-piperazinyl) -1-cyclopropyl-8-fluoro-6-methyl-5-nitro-1 Synthesis of, 4-dihydro-4-oxoquinoline-3-carboxylate]

200 mg (0.568 mmol) of the compound obtained in Preparation Example 9 and 2 ml of acetonitrile were added to a 10 ml reaction vessel, followed by stirring. To this was added 87 mg (0.568 mmol) of DBU and 129.7 mg (1.14 mmol) of 2,6-dimethylpiperazine and heated to reflux for 4 hours. The reaction was cooled to room temperature and distilled under reduced pressure, and the residue was dissolved in 5 ml of dichloromethane and 123.8 mg (0.568 mmol) of di-t-butyldicarbonate was added and stirred for 30 minutes. The solvent was removed by distillation under reduced pressure and purified by column chromatography to give 264 mg (yield: 85%) of the title compound.

MASS (FAB): 547

¹ H NMR (CDCl ₃ ): δ 1.10 (m, 2H), 1.23 (m, 2H), 1.36 (t, 3H), 1.40 (d, 6H), 1.49 (s, 9H), 2.31 (s, 3H) , 3.10 (m, 6H), 4.15 (m, 1H), 4.28 (q, 2H), 8.55 (s, 1H)

Preparation Example 17 Ethyl 5-amino-7- (4-t-butoxycarbonyl-3,5-dimethyl-1-piperazinyl) -1-cyclopropyl-8-fluoro-6-methyl-1 Synthesis of, 4-dihydro-4-oxoquinoline-3-carboxylate]

264 mg (0.483 mmol) of the compound obtained in Preparation Example 16 and 110 ml of ethanol were added to a 250 ml reaction vessel, followed by stirring. An excess of Ranickel was added thereto and reacted for 24 hours under a hydrogen stream (1 atmosphere). Raney nickel was filtered and distilled under reduced pressure to obtain 224 mg (yield: 90%) of the title compound.

MASS (FAB): 517

¹ H NMR (CDCl ₃ ): δ 0.90 (m, 2H), 1.10 (m, 2H), 1.36 (t, 3H), 1.35 (d, 6H), 1.45 (s, 9H), 2.30 (s, 3H) , 3.10 (m, 6H), 4.10 (m, 1H), 4.25 (q, 2H), 6.89 (bs, 2H), 8.23 (s, 1H)

Preparation Example 18 Ethyl 1-cyclopropyl-8-fluoro-6-methyl-7- (4-methyl-1-piperazinyl) -5-nitro-1,4-dihydro-4-oxoquinoline- Synthesis of 3-carboxylate]

200 mg (0.588 mmol) of the compound obtained in Preparation Example 9 and 2 ml of acetonitrile were added to the 10 ml reaction vessel, followed by stirring. To this was added 85 mg (0.568 mmol) of DBU and 227 mg (2.27 mmol) of N-methylpiperazine and heated to reflux for 4 hours. The reaction was cooled to room temperature and the resulting solid was filtered and dried to yield 216 mg (yield: 90%) of the title compound.

MASS (FAB): 433

¹ H NMR (CDCl ₃ ): δ 1.19 (m, 2H), 1.23 (m, 2H), 1.36 (t, 3H), 1.48 (s, 9H), 2.31 (s, 3H), 2.76 (s, 3H) , 3.30 (m, 8H), 4.15 (m, 1H), 4.29 (q, 2H), 8.57 (s, 1H)

Preparation Example 19 Ethyl 5-amino-1-cyclopropyl-8-fluoro-6-methyl-7- (4-methyl1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3 Synthesis of Carboxylate]

216 mg (0.511 mmol) of the compound obtained in Preparation Example 18 and 100 ml of ethanol were added to a 250 ml reaction vessel, followed by stirring. An excess of Ranickel was added thereto and reacted for 24 hours under a hydrogen stream (1 atmosphere). Raney nickel was filtered and distilled under reduced pressure to give 175 mg (yield: 85%) of the title compound.

MASS (FAB): 403

¹ H NMR (CDCl ₃ ): δ 1.10 (m, 2H), 1.21 (m, 2H), 1.35 (t, 3H), 1.47 (s, 9H), 2.25 (s, 3H), 2.65 (s, 3H) , 3.30 (m, 8H), 4.09 (m, 1H), 4.20 (q, 2H), 6.85 (bs, 2H), 8.30 (s, 1H)

Preparation Example 20 Synthesis of Borate of 5-Amino-1-cyclopropyl-7,8-difluoro-6-methyl-1,4-dihydro-4-oxoquinolinecarboxylic acid]

In a 10 ml reaction vessel, 100 mg (0.34 mmol) of the compound obtained in Preparation Example 11 and 2.2 ml of 42% hydrofluoroboric acid were mixed and stirred at room temperature for 10 hours. The resulting solid was filtered and dried to yield 105 mg (yield: 90%) of the title compound.

MASS (FAB): 343

¹ H NMR (DMSO-d ₆ ): δ 1.28-1.38 (m, 4H), 2.38 (s, 1H), 4.17 (m, 1H), 7.20 (bs, 2H), 8.75 (s, 1H)

Example 1 5-Amino-1-cyclopropyl-8-fluoro-6-methyl-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid Synthesis of

76 mg (0.269 mmol) of the compound obtained in Preparation Example 11 and 0.8 ml of acetonitrile were added to a 10 ml reaction vessel and heated to reflux. To this was added 40 mg (0.26 mmol) of DBU and 45 mg (0.52 mmol) of piperazine and heated to reflux for 30 hours. The resulting solid was filtered and washed several times with methanol to give 47 mg (yield: 50%) of the title compound.

MASS (FAB): 361

¹ H NMR (DMSO-d ₆ ): δ 1.10 (m, 4H), 2.10 (s, 3H), 2.80 (m, 4H), 3.00 (m, 4H), 4.10 (m, 1H), 7.56 (bs, 2H), 8.55 (s, 1H)

Example 2: 5-amino-7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-8-fluoro-6-methyl-1,4-dihydro-4-oxoquinoline-3 Synthesis of Carboxylic Acids]

50 mg (0.17 mmol) of the compound obtained in Preparation Example 11 and 0.5 ml of acetonitrile were added to a 10 ml reaction vessel and heated to reflux. To this was added 26 mg (0.17 mmol) of DBU and 29.3 mg (0.34 mmol) of aminopyrrolidine and heated to reflux for 38 hours. The solvent was removed by distillation under reduced pressure, followed by Prep. Purification by HPLC gave 25 mg (yield 41%) of the title compound.

MASS (FAB): 361

¹ H NMR (DMSO-d ₆ ): δ 1.15 (m, 2H), 1.25 (m, 2H), 1.70 (m, 1H), 2.30 (m, 2H), 2.51 (s, 3H), 3.10 (m, 1H), 3.56 (m, 2H), 3.80 (m, 4H), 4.00 (m, 2H), 8.41 (s, 1H)

[Example 3: 5-amino-7- (3-aminomethyl-1-pyrrolidinyl) -1-cyclopropyl-8-fluoro-6-methyl-1,4-dihydro-4-oxoquinoline- Synthesis of 3-carboxylic acid]

To 70 mg (0.14 mmol) of the compound obtained in Preparation Example 1 were added 1 ml of ethanol and 1 ml of 1N HCl, and heated to reflux for 4 hours. Purification by HPLC gave 37 mg (yield: 70%) of the title compound.

MASS (FAB): 375

¹ H NMR (DMSO-d ₆ ): δ 0.95 (m, 2H), 1.10 (m, 2H), 1.89 (m, 1H), 2.10 (s, 3H), 2.20 (m, 1H), 2.85 (m, 1H), 3.10 (m, 3H), 3.25 (m, 2H), 3.65 (m, 1H), 3.95 (m, 1H), 8.30 (s, 1H)

Example 4: 5-Amino-1-cyclopropyl-8-fluoro-6-methyl-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3 Synthesis of Carboxylic Acids]

2 ml of ethanol and 2 ml of 1N HCl were added to 200 mg (0.389 mmol) of the compound obtained in Preparation Example 15 in a 10 ml reaction vessel and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and the resulting solid was filtered to yield 80 mg (yield: 55%) of the title compound.

MASS (FAB): 375

¹ H NMR (DMSO-d ₆ ): δ 1.10 (m, 4H), 1.20 (d, 2H), 2.10 (s, 3H), 3.30 (m, 7H), 4.10 (m, 2H), 7.40 (bs, 2H), 8.51 (s, 1H), 9.25 (bs, 1H)

Example 5 5-Amino-1-cyclopropyl-7- (3,5-dimethyl-1-piperazinyl) -8-fluoro-6-methyl-1,4-dihydro-4-oxoquinoline Synthesis of 3-carboxylic Acid]

2 ml of ethanol and 2 ml of 1N HCl were added to 224 mg (0.44 mmol) of the compound obtained in Preparation Example 17 in a 10 ml reaction vessel and heated to reflux for 4 hours. The reaction was cooled to room temperature and the resulting solid was filtered to yield 102 mg (yield: 60%) of the title compound.

MASS (FAB): 389

¹ H NMR (DMSO-d ₆ ): δ 1.11 (s, 3H), 1.15 (s, 3H), 1.17 (m, 2H), 1.35 (m, 2H), 2.20 (s, 3H), 3.30 (m, 6H), 4.00 (m, 1H), 7.29 (bs, 2H), 8.52 (s, 1H), 8.89 (s, 1H)

Example 6: 5-amino-1-cyclopropyl-8-fluoro-6-methyl-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3 Synthesis of Carboxylic Acids]

1 mL of ethanol and 1 mL of 1N HCl were added to 105 mg (0.434 mmol) of the compound obtained in Preparation Example 19 in a 10 mL reaction vessel and heated to reflux for 4 hours. The reaction was cooled to room temperature and the resulting solid was filtered to give 97 mg (yield: 60%) of the title compound.

MASS (FAB): 375

¹ H NMR (DMSO-d ₆ ): δ 1.22 (m, 2H), 1.28 (m, 2H), 2.39 (s, 3H), 2.92 (s, 3H), 3.30 (m, 8H), 4.09 (m, 1H), 6.90 (bs, 2H), 8.50 (s, 1H)

Example 7: 5-Amino-1-cyclopropyl-8-fluoro-6-methyl-7- (4-aminomethyl-3-methoxyimino-1-pyrrolidinyl) -1,4-dihydro [Synthesis of 4-oxoquinoline-3-carboxylic acid]

In a 20 ml reaction vessel, 90 mg (0.27 mmol) of the compound obtained in Production Example 20 and 132 mg (0.61 mmol) of 4-aminomethylpyrrolidin-3-one-O-methyloxime hydrochloride were mixed and stirred. 81 mg (0.80 mmol) of triethylamine and 9 ml of dimethylsulfoxide were added thereto, followed by stirring at room temperature for 24 hours. 10 ml of water was added to the reaction solution, shaken, and the precipitated yellow solid was filtered and dried. The obtained solid was mixed with 140 ml of 80% ethanol and 7 ml of triethylamine and heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and then Prep. Purification by HPLC gave 34 mg (yield: 30%) of the title compound.

MASS (FAB): 418

¹ H NMR (DMSO-d ₆ ): δ 1.10 (m, 2H), 1.20 (m, 2H), 2.30 (s, 3H), 3.0 (m, 2H), 3.3 (m, 1H), 3.6 (m, 1H), 3.9 (m, 1H), 4.0 (s, 3H), 4.4 (m, 1H), 4.7 (m, 2H), 7.30 (bs, 2H), 8.54 (s, 1H)

Example 8: 5-Amino-1-cyclopropyl-8-fluoro-6-methyl-7- (4-amino-3-methoxyimino-1-pyrrolidinyl) -1,4-dihydro- Synthesis of 4-oxoquinoline-3-carboxylic acid]

In a 20 ml reaction vessel, 100 mg (0.29 mmol) of the compound obtained in Production Example 20 and 125 mg (0.58 mmol) of 4-aminomethylpyrrolidin-3-one-O-methyloxime hydrochloride were mixed and stirred. 87 mg (0.86 mmol) of triethylamine and 9 ml of dimethylsulfoxide were added thereto, followed by stirring at room temperature for 24 hours. 10 ml of water was added to the reaction solution, shaken, and the precipitated yellow solid was filtered and dried. The obtained solid was mixed with 150 ml of 80% ethanol and 7 ml of triethylamine and heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and then Prep. Purification by HPLC gave 41 mg (yield 35%) of the title compound.

MASS (FAB): 404

¹ H NMR (DMSO-d ₆ ): δ 1.11 (m, 2H), 1.21 (m, 2H), 2.33 (s, 3H), 3.34 (m, 1H), 3.59 (m, 1H), 3.86 (m, 1H), 4.05 (s, 3H), 4.42 (m, 1H), 4.8 (m, 2H), 7.29 (bs, 2H), 8.55 (s, 1H)

Biological Example 1: In vitro Antimicrobial Activity Assay

The usefulness of the compound according to the present invention is the minimum inhibitory concentration for a standard strain, a clinically isolated strain, and a strain resistant to some antibiotics using a known compound, Ofloxacin, as a control agent. MIC, μg / ml) was obtained and evaluated. The minimum inhibitory concentration was obtained by diluting the test compound by a 2-fold dilution method and dispersing it in Mueller-Hinton atar medium, then inoculating 5 μl of a standard strain having 10 ⁷ CFU / ml and 18 at 37 ° C. Obtained by time incubation, the results are shown in Table 1.

Biological Example 2: Acute Oral Toxicity Test

To investigate the acute oral toxicity of the compound obtained in the examples, a solution containing the compound in various concentrations was orally administered to male mice of the ICR line at a dose of 10 ml per kg. The mortality and symptoms for 7 days after oral administration were observed and the median lethal dose (LD, mg / kg) was calculated according to the Litchfield-Wilcoxon method and the results are shown in Table 2.

Claims (13)

Quinoline carboxylic acid derivatives represented by the following general formula (I), pharmaceutically acceptable salts thereof, physiologically hydrolysable esters, solvates and isomers. Wherein X represents hydrogen, fluorine, chlorine, methyl or methoxy; A is hydroxy-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl substituted by unsubstituted amino, C ₁ -C ₄ alkyl substituted by unsubstituted or C ₁ -C ₂ alkyl amino and methoxy already C ₄ -C ₈ cycloamine, piperazine or morpholine unsubstituted or substituted by one or more substituents selected from the group consisting of no. The compound of claim 1, wherein X represents fluorine; A represents a compound represented by the group A1, A2 or A3 of the following general formula. Wherein R represents hydrogen or C ₁ -C ₄ alkyl and R ₁ and R ₂ are each independently unsubstituted or substituted by hydrogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl , optionally substituted by C ₁ -C ₄ alkyl, or represents an unsubstituted C ₁ -C ₂ alkyl amino or methoxy toksiyi Mino, n represents 0 or 1. The compound of claim 2, wherein 5-amino-1-cyclopropyl-8-fluoro-6-methyl-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxyl mountain; 5-amino-7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-8-fluoro-6-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 5-Amino-7- (3-aminomethyl-1-pyrrolidinyl) -1-cyclopropyl-8-fluoro-6-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid ; 5-amino-1-cyclopropyl-8-fluoro-6-methyl-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 5-amino-1-cyclopropyl-7- (3,5-dimethyl-1-piperazinyl) -8-fluoro-6-methyl-1,4-dihydro-4-oxoquinoline-3-carboxyl mountain; 5-amino-1-cyclopropyl-8-fluoro-6-methyl-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 5-amino-1-cyclopropyl-8-fluoro-6-methyl-7- (4-aminomethyl-3-methoxyimino-1-pyrrolidinyl) -1,4-dihydro-4-oxoquinoline 3-carboxylic acid; 5-amino-1-cyclopropyl-8-fluoro-6-methyl-7- (4-amino-3-methoxyimino-1-pyrrolidinyl) -1,4-dihydro-4-oxoquinoline- 3-carboxylic acid. A process for preparing a compound of formula (I), wherein the compound of formula (III) is reacted with a compound of formula (IV) in the presence of an acid acceptor in an inert solvent. Wherein X and A are as defined in claim 1. The process according to claim 4, wherein the compound of general formula (IV) is used in the form of a salt with hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid. The method according to claim 4, wherein the compound of general formula (IV) is used in an equimolar amount to 10 molar times relative to the compound of general formula (III). The process of claim 4 wherein the solvent is selected from dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine and hexamethylphosphoamide. The acid acceptor according to claim 4, wherein the acid acceptor is sodium hydrogen carbonate, potassium carbonate as an inorganic base or triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaminopyriline, N, N-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,4-diazabicyclo [2.2.2] octane. The process of claim 4 wherein the reaction temperature is 10 to 180 ° C. 6. A compound of formula (II) is reacted with a compound of formula (IV ′) to give a compound of formula (V), which is reduced and deprotected to form a compound of formula (I) Method for preparing the compound. Wherein A'NH ₂ represents A, A and X are as defined in claim 1, and P represents an aminoprotecting group. The aminoprotecting group of claim 10, wherein the aminoprotecting group is formyl, acetyl, trifluoroacetyl, benzyl, para-methoxybenzyl, methoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, para-methoxybenzyloxy Carbonyl, trityl, tetrahydropyranyl, para-toluenesulfonyl, benzyloxyketyl, β, β, β-trichloroethoxycarbonyl, beta-iodoethoxycarbonyl. A compound of formula (I) is prepared by reacting a compound of formula (VI) with a compound of formula (IV) to give a compound of formula (VII), which is deprotected. Way. Wherein X and A are as defined in claim 1. An antimicrobial composition comprising the compound of formula (I) according to claim 1 as an active ingredient.