KR940002955B1 - Quino/one derivatives - Google Patents

Abstract

The quinolone cpd. or its salts of formula (I) are prepd. by heating and reacting the cpd. (II) with the cpd. (III) or (IIIa) in presence of the base. In the formulas, R1 is opt. substd. C1-7 lower alkyl, opt. substd. C3-7 cycloalkyl, opt. substd. lower alkenyl, opt. substd. phenyl; R2 is H, protecting gp. of carboxyl gp. or pharmaceutically usuable metalic or organic cation; R3 is H or C1-4 lower alkyl, C2-4 hydroxy alkyl, C3-7 cycloalkyl or biodegradable N-protecting gp.; X is Cl or Br; Z is methyl; n is 1-3; n is 1 or 2; A is Cl or Br; L is halogen, ethane sulfonyl or paratoluene sulfonyl. The compound is antibacterial.

Description

New Quinolone Compounds

The present invention relates to a novel quinolone compound useful as a synthetic antimicrobial agent and a method for preparing the same, more particularly, having a diazabicycloamine derivative at position 7 and a chlorine atom or bromine atom at position 8, and a Gram-positive bacterium. And a novel compound represented by the following general formula (I) having a strong antibacterial activity against gram-negative bacteria and salts thereof and a method of preparing the same.

In formula (I), R ₁ is a substituted or unsubstituted lower alkyl group having 1 to 7 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms, a substituted or unsubstituted lower alkenyl group, substituted or unsubstituted Phenyl group, R ₂ represents a hydrogen atom, a protecting group of a carboxyl group or a pharmaceutically useful metal cation or organic cation, R ₃ represents a hydrogen atom, a lower alkyl group of 1 to 4 carbon atoms, a hydroxyalkyl group of 2 to 4 carbon atoms, A cycloalkyl group having 3 to 7 carbon atoms or a nitrogen protecting group degradable in vivo, X represents a chlorine atom or a bromine atom, Z represents a hydrogen atom, a halogen atom, an amino group or a methyl group, and m is an integer of 1 to 3 , n is 1 or 2 and includes pharmaceutically useful acid addition salts, base addition salts or hydrates thereof of the general formula (I).

Many compounds with pyridonecarboxylic acid as the backbone have been known as synthetic antimicrobial agents with strong antibacterial activity and broad antimicrobial spectrum. It is widely used for treatment.

A characteristic of these compounds is that they have a quinoline skeleton or a naphthyridine skeleton having a fluorine atom at position 6 and a secondary amine group at position 7 as a substituent. In particular, by introducing a pyreazine ring or a pyrrolidine ring at position 7, the antibacterial activity was greatly increased.

However, these compounds are not completely satisfactory in terms of antimicrobial activity, gastrointestinal absorption, stability to metabolism and side effects.

Therefore, many efforts are being made to prepare new compounds that can satisfy these requirements. As part of this effort, 3,7-diazabicyclo [3,3,0] oct-1 (5) ene or 3,8-diazabicyclo [4,3,0] nona-1 (6) ene is substituted New quinolines have been developed (Korean Patent Application Nos. 89-15202, 89-15203 and 89-15204, European Patent Applications 9012024.4, 90120240.8 and 90120241.6).

In one aspect of the development of these new quinoline compounds, the present invention provides a 3,7-diazabicyclo [3,3,0] oct-1 (5) at position 7 of 8-chloro (or bromo) quinoline carboxylic acid. By introducing ene or 3,8-diazabicyclo [4,3,0] nona-1 (6) ene derivatives, it exhibits strong antimicrobial activity, and in particular, can reduce phototoxicity, have high bioavailability and increase solubility. The purpose of the present invention is to provide a novel quinoline compound and an antimicrobial agent having the same as an active ingredient.

Hereinafter, the present invention will be described in detail.

The present invention relates to a quinolone compound represented by the general formula (I), wherein in the general formula (I), when R ₁ is a lower alkyl group, when the substituent has a straight or branched chain, 1 to 5 carbon atoms is appropriate, In the case where the substituent is a cycloalkyl group, 3 to 7 carbon atoms are appropriate. Examples of the lower alkyl group include methyl group, ethyl group, isopropyl group, t-butyl group and t-pentyl group, and the substituted lower alkyl group includes one, two or more halogen atoms or As a hydroxyl group, suitable examples include 2-fluoroethyl group, 2-hydroxyethyl group and difluoromethyl group; Substituted or unsubstituted alkenyl group includes a vinyl group, isopropenyl group, an aryl group and 2-butenyl group; Examples of the substituted or unsubstituted cycloalkyl group include a cyclopropyl group, a 1-methylcyclopropyl group, a cyclobutyl group and a cyclopentyl group; Substituted or unsubstituted phenyl group means a phenyl group or a phenyl group having one or two or more halogen atoms, a lower alkoxy group, a hydroxy group, an amino group, a lower alkyl or a nitro group, and suitable examples include phenyl group, 2-fluorophenyl group, 4 -Fluorophenyl group, 2,4-difluorophenyl group, 2-hydroxyphenyl group, 4-hydroxyphenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 2-fluoro-4-methoxyphenyl group, 2 -Fluoro-4-hydroxyphenyl group, 4-methylphenyl group, 4-aminophenyl group, 4-nitrophenyl group, and the like.

When R ₂ is a protecting group of carboxyl group, it forms ester type which can easily make free carboxylic acid by hydrolysis or the like, and there are methyl group as lower alkyl group, ethyl group, n-propyl group, t-butyl group and phenyl group as aryl group. In particular, lower alkanoyloxy-lower alkyl groups (acetoxymethyl group, pavaroyloxymethyl group, etc.) which are easily decomposed in vivo, lower alkoxycarbonyloxy-lower alkyl groups (methoxycarbonyloxymethyl group, 1-ethoxycarbonioxy Ethyl group etc.), lower alkoxy methyl group (methoxymethyl group etc.), di (lower alkyl) amino-lower alkyl group (1-dimethylaminoethyl group etc.), 4-methylene-5-methyl-1,3-dioxoene-2- In the case of pharmaceutically useful metal cations, alkali metal cations or alkaline earth cations or ammonium or silver cations are suitable sodium cations, potassium cations, calcium cations and magnesium cations. Ions, ammonium cations or silver cations and suitable as organic cations are tertiary or quaternary alkylammonium ions having 1 to 4 carbon atoms.

When R ₃ is a lower alkyl group, it is preferably a methyl group or an ethyl group, and in the case of a hydroxyalkyl group, a suitable 2-hydroxyethyl group is preferable. In the case of a cycloalkyl group, a suitable cycloalkyl group is a nitrogen protecting group degradable in vivo. Examples are a formyl group, an alkyloxycarboxyl group, an alkyloxycarbonylmethyl group, a 2 or 3-oxoalkyl group, 4-methylene-5-methyl-1, 3-dioxoren-2-one group and the like.

In the case of a halogen atom in Z, it represents a fluorine atom, a chlorine atom and a bromine atom, and a fluorine atom and a chlorine atom are suitable, and the compound of the general formula (I) of the present invention can be made into an acid addition salt or a base addition salt. Methane as a salt of hydrochloric acid, sulfuric acid, phosphoric acid, strong carboxylic acid, formic acid, acetic acid, propionic acid, citric acid, lactic acid, tartaric acid, fumaric acid, maleic acid, malonic acid, ascorbic acid, glutamic acid or succinic acid and salts of sulfonic acid Salts of sulfonic acid, benzenesulfonic acid or paratoluenesulfonic acid.

As base addition salts, salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium and magnesium, ammonium salts and salts of nitrogen-containing organic bases, tertiary or quaternary carbon atoms such as trimethylamine, triethylamine and tributylamine 1 Salts of ˜4 alkylamines.

Such compounds of formula (I) are in the form of anhydrides or hydrates.

Each compound represented by general formula (I) of the present invention as described above can be produced by condensing a compound represented by the following general formula (II) with an amine compound represented by general formula (III) or (IIIa).

In formulas (II), (III) and (IIIa), R ₁ , R ₂ , R ₃ , m, n, Z and X are the same as defined in formula (I), and A is a chlorine atom or It is a bromine atom, L represents a fluorine atom, a chlorine atom, or a bromine atom as a leaving group, or an ethanesulfonyl, benzenesulfonyl, or paratoluenesulfonyl group.

The compound of formula (II) is a compound well known in the field of quinoline antimicrobial agent can be prepared by a known manufacturing process, the amine compound of formula (III) and (IIIa) is Korean Patent Application No. 89-15204, 91-1726, European Patent Application No. 9012024.4.

The condensation reaction is carried out in a solvent which does not affect the reaction. For example, aromatic hydrocarbon-based benzene, toluene or xylene, ether-based diethyl ether, tetrahydrofuran or dioxane, polar solvent dimethylformamide, dimethyl sulfoxide It is carried out in a solvent such as seed, sulfolane, alcohol, acetonitrile and pyridine.

In addition, the reaction is sodium hydride, calcium hydride, sodium or potassium, caustic soda, caustic for the purpose of neutralizing the acid generated during the reaction or converting the compound of the general formula (IIIa) into free amine in the reaction vessel. , Inorganic carbonates such as sodium carbonate, and calcium carbonate, or organic bases such as triethylamine, diisopropylethylamine and 1,8-diazabicyclo [5,4,0] undecene (DBU). The reaction temperature is 10 to 150 ° C, preferably 10 to 110 ° C, and the reaction is terminated within 10 minutes to 24 hours. In this case, the general formula (III) or (IIIa) is used at least in the same molar ratio, and suitably 1 to 5 times the excess of the compound of the general formula (II).

According to the present invention, among the compounds represented by the general formula (I), the following general formula (I b), which is a compound when R ₂ is a protecting group of a carboxyl group, can be prepared by the following reaction formula.

In the general formula, R ₁ , R ₃ , m, n, Z and X are as defined in the general formula (I), respectively, R _2a represents a carboxyl group protecting group, Hal. Represents a halogen atom.

That is, the compound of the general formula (I b) can be obtained by reacting the halogen compound (IV) and the compound of the general formula (I a). Solvents that can be used in this reaction include benzene, toluene, dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, and the like. The reaction temperature is about room temperature to about 100 ° C, preferably triethyl. It is carried out in the presence of a base such as amine, diisopropylamine, dicyclohexylamine, 1,8-diazabicyclo [5,4,0] undecene, sodium carbonate, potassium carbonate, caustic soda or caustic cal.

Furthermore, according to the present invention, the compound of the following general formula (I d) which is a compound when R ₃ is a lower alkyl group, a hydroxyalkyl group or a decomposable nitrogen protecting group in vivo among some compounds of the general formula (I) is represented by the following general formula It can also manufacture from (I c) by the following reaction formula.

In the general formula, R ₁ , R ₂ , m, n, X and Z are the same as defined in the general formula (I), respectively, and R _3a is a lower alkyl group, a hydroxyalkyl group or a nitrogen protecting group degradable in vivo. Indicates.

In addition, in the general formula (I), a compound in which R ₃ is a formyl group is prepared by reacting formic acid and acetic anhydride with the compound of the general formula (I c), and when R ₃ is a methyl group, formalin and formic acid Prepared by working with a compound of formula (I c).

In the case where R ₃ is a lower alkyl group or a hydroxyalkyl group, an inorganic base in a solvent such as dimethylformamide, dimethyl sulfoxide or dichloromethane, which is a non-reactive solvent, may be a compound of R ₃ -halogen and the compound of the general formula (I c). Or by reacting in the presence of an organic base.

In the case where the R _3a donor is an acrylate derivative, the compound of the general formula (I d) is prepared by reacting the general formula (I c) with R _3a and the donor in a solvent such as dimethylformamide.

On the other hand, the acid addition salt and base addition salt of the general formula (I) is dissolved or suspended in a mixed solvent of a haloalkane such as dichloromethane, chloroform, dichloroethane and a lower alcohol such as methanol, ethanol After addition, an addition salt is prepared by adding an aqueous solution or an alcohol solution of an acid or base selected as the addition salt and taking the resulting precipitate or removing the solvent under reduced pressure.

Acids selected are strong acids such as hydrochloric acid, sulfuric acid and phosphoric acid, or organic acids such as lactic acid, acetic acid, propionic acid, methanesulfonic acid, paratoluenesulfonic acid, fumaric acid, formic acid, maleic acid, malonic acid, tartaric acid, citric acid, ascorbic acid, glutamic acid, and the like. Caustic soda, caustic, calcium hydroxide, magnesium hydroxide, silver nitrate, tertiary or quaternary lower alkyl ammonium having 1 to 4 carbon atoms is used as a suitable base, and hydrates of these salts are also included.

Examples of the specific compounds which can be prepared according to the following examples of the compounds of the general formula (I) according to the present invention are summarized in Table 1 below.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by Examples.

TABLE 1

Examples of Representative Compounds of Formula (I) of the Present Invention

Example 1

8-chloro-1-cyclopropyl-6-fluoro-7- {3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1,4-dihydro Preparation of 4-oxoquinoline-3-carboxylic acid (compound 1)

8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 540 mg (1.806 mmol), 3,7-diazabicyclo [ 3,3,0] oct-1 (5) ene dihydrobromide 580 mg (2.132 mmol) and 1 g of 1.8-diazabicyclo [5,4,0] undec-7-ene were added to 7 ml of acetonitrile. It was dissolved and refluxed for 4 hours.

The reaction mixture was stirred for one day at room temperature, and the resulting precipitate was filtered, washed sequentially with acetonitrile, water and acetonitrile and dried under reduced pressure to obtain 530 mg of the target compound (yield 75%).

Melting Point 229 ~ 231 ℃

¹ H NMR (CDCl ₃ + DMSO-d ₆ + CD ₃ OD + CF ₃ COOD, δ ppm): 9.09 (1H, s), 8.07 (1H, d, J = 12.4 Hz), 4.53 (4H, s), 4.50 (1H, m), 4.31 (4H, s), 1.41 (2H, m), 1.05 (2H, m).

Example 2

8-chloro-1-cyclopropyl-6-fluoro-7- {7-methyl-3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1, Preparation of 4-dihydro-4-oxoquinoline-3-carboxylic acid (compound 2)

8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1.80 g (6.02 mmol), 3-methyl-3,7- Acetonitrile is 0.9 g (7.24 mmol) of diazabicyclo [3,3,0] oct-1 (5) and 1.2 g of 1,8-diazabicyclo [5,4,0] undec-7-ene. It was dissolved in 10 ml and refluxed for 6 hours.

The reaction mixture was left at room temperature overnight, and the resulting precipitate was filtered, washed with acetonitrile, water and acetonitrile and dried under reduced pressure to obtain 1.5 g of the target compound (yield 60%).

Melting Point 226 ~ 227 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.91 (1H, s), 8.00 (1H, d, J = 12.2 Hz), 4.41 (4H, s), 4.05 (1H, m), 3.68 (4H, s), 2.85 (3H, s), 1.30 (2H, m), 1.02 (2H, m).

Example 3

8-chloro-1-cyclopropyl-6-fluoro-7- {7-methyl-3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1, Preparation of 4-dihydro-4-oxoquinoline-3-carboxylic acid acetate

8-chloro-1-cyclopropyl-6-fluoro-7- {3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1,4-dihydro 600 mg of 4-oxoquinoline-3-carboxylic acid was suspended in 15 ml of 97% formic acid and 1 ml of 37% formalin and refluxed for 5 hours.

Concentrate to remove excess reagent. 8-Chloro-1-cyclopropyl-6-fluoro-7- {7-methyl-3,7-diazabicyclo [3.3.0] oct-1 (5) ene-3 -Yl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid formate was prepared. This was dissolved in 158 ml of water, the insoluble matter was filtered off, and 4N-caustic soda solution was added to the filtrate, adjusted to pH 8, concentrated to remove water, and soluble in chloroform, chloroform-methanol-acetic acid (6: 4: 1) ) Was purified by silica gel column chromatography with a solvent to obtain 365 mg of the target compound (yield 51%).

Melting Point 216 ~ 217 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.93 (1H, s), 8.04 (1H, d, J = 12.2 Hz), 4.43 (4H, s), 4.35 (1H, m), 3.95 (4H, s), 2.87 (3H, s), 2.03 (3H, s), 1.33 (2H, m), 1.00 (2H, m).

Example 4

8-chloro-1-cyclopropyl-6-fluoro-7- {7-methyl-3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1, Preparation of 4-dihydro-4-oxoquinoline-3-carboxylic acid lactate (Compound 3)

8-chloro-1-cyclopropyl-6-fluoro-7- {7-methyl-3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1, Dissolve 810 mg (2.01 mmol) of 4-dihydro-4-oxoquinoline-3-carboxylic acid in 10 ml of dichloromethane and 2 ml of ethanol, add 210 mg of 85% lactic acid, mix well, and concentrate under reduced pressure at 40 ° C or below. After removing the solvent, ethyl ether was added to form a powder, followed by filtration and drying under reduced pressure to obtain the target compound in quantitative yield.

Melting Point 169 ~ 171 ℃, 183 ~ 185 ℃

¹ H NMR (CDCl ₃ + CD ₃ OD, δ ppm): 8.97 (1H, s), 8.05 (1H, d, J = 12.2 Hz), 4.44 (4H, s), 4.40 (1H, m), 4.13 (1H, q, J = 7 Hz), 4.13 (4H, s), 2.88 (3H, s), 1.41 (3H, d, J = 7 Hz), 1.35 (2H, m), 1.05 (2H, m).

Example 5

8-chloro-1-cyclopropyl-6-fluoro-7- {3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1,4-dihydro Preparation of 4-oxoquinoline-3-carboxylic acid hydrochloride

8-chloro-1-cyclopropyl-6-fluoro-7- {3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl} -1,4-dihydro-4 97 mg of oxoquinoline-3-carboxylic acid was suspended in 5 ml of 3% isopropyl alcohol solution of hydrogen chloride and refluxed for 3 hours.

The reaction mixture was cooled at room temperature, the precipitate was filtered off, washed with ethyl ether and dried under reduced pressure to obtain 90 mg of the target compound (yield 84%).

Melting Point: 217 ~ 220 ℃ (Decomposition)

¹ H NMR (D ₂ O, δ ppm): 8.97 (1H, s), 8.10 (1H, d, J = 12.2 Hz), 4.51 (4H, s), 4.30 (1H, m), 4.20 (4H, s) , 1.35 (2H, m), 1.02 (2H, m).

Example 6

8-chloro-1-cyclopropyl-6-fluoro-7- {7-ethyl-3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1, Preparation of 4-dihydro-4-oxoquinoline-3-carboxylic acid

150 mg (0.501 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-ethyl-3,7- Diacebicyclo [3.3.0] oct-1 (5) ene dihydrobromide 180 mg (0.566 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene 260 mg were acetonitrile It was dissolved in 5 ml and refluxed for 6 hours.

The reaction mixture was concentrated to remove the solvent, dissolved in 10 ml of chloroform and washed with brine (3 ml × 5 times). The residue obtained by concentrating the organic layer was crystallized in ethanol-dichloromethane to obtain 146 mg of the target compound (yield 70). %).

Melting Point 204 ~ 207 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.91 (1H, s), 8.00 (1H, d, J = 12.2 Hz), 4.45 (4H, s), 4.30 (1H, q, J = 7.1 Hz), 4.14 ( 1H, m), 3.70 (4H, s), 1.45 (3H, t, J = 7.1 Hz), 1.30 (2H, m), 1.02 (2H, m).

Example 7

8-Chloro-1-cycloporphyl-6-fluoro-7- {7- (2-hydroxyethyl-3,7-diazabicyclo [3,3,0] oct-1 (5) ene-3 Preparation of -yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 150 mg (0.501 mmol), 3- (2-hydroxyethyl ) -3,7-diazabicyclo [3.3.0] oct-1 (5) ene dihydrobromide 180 mg (0.573 mmol) and 1,8-diazabicyclo [5.4.0] undec-7- En 260 was dissolved in 3 ml of acetonitrile and refluxed for 5 hours.

The reaction mixture was left overnight in a refrigerator, and the resulting precipitate was filtered, washed with cooled acetonitrile, water, acetonitrile and dried under reduced pressure to obtain 113 mg of the target compound (yield 50%).

Melting Point: 217 ~ 220 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.95 (1H, s), 8.05 (1H, d, J = 12.2 Hz), 4.45 (4H, s), 4.30 (1H, m), 3.98 (2H, t, J = 5.3 μs), 3.84 (4H, s), 2.97 (2H, t, J = 5.3 μs), 1.30 (2H, m), 1.03 (2H, m).

Example 8

8-chloro-1-cyclopropyl-6-fluoro-7- {7-cyclopropyl-3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1 Preparation of, 4-dihydro-4-oxoquinoline-3-carboxylic acid

150 mg (0.501 mmol) of 8-chloro-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-cyclopropyl-3,7 90 mg (0.6 mmol) of diazabicyclo [3.3.0] oct-1 (5) and 180 mg of 1,8-diazabicyclo [5.4.0] undec-7-ene in 5 ml of acetonitrile. It was dissolved and refluxed for 5 hours.

The reaction mixture was left overnight in a refrigerator, and the resulting precipitate was filtered, washed with cooled acetonitrile, water and ethanol, and dried under reduced pressure to obtain 124 mg of the target compound (yield 55%).

Melting Point 219 ~ 224 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.94 (1H, s), 8.04 (1H, d, J = 12.2 Hz), 4.44 (4H, s), 4.30 (1H, m), 3.80 (4H, s), 3.10 (1H, m), 1.31-1.20 (6H, m), 0.95 (2H, m).

Example 9

8-chloro-1-cyclopropyl-6-fluoro-7- {7- (4-methylene-5-methyl-1,3-dioxoren-2-one) -3,7-diazabicyclo [3 , 3,0] oct-1 (5) en-3-yl} -1,4-dihydro-oxoquinoline-3-carboxylic acid

8-chloro-1-cyclopropyl-6-fluoro-7- {3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl) -1,4-dihydro-4 -98 mg (0.251 mmol) of oxoquinoline-3-carboxylic acid is suspended in 7 ml of chloroform, 60 mg of 4-bromomethyl-5-methyl-1,3-dioxoren-2-one and potassium carbonate 100 mg was added and stirred at room temperature for 24 hours.

The solid was removed by filtration, the filtrate was washed with water, dehydrated with anhydrous forget-me-not and the obtained residue was crystallized in ethanol-chloroform to obtain 70 mg of the target compound (yield 55%).

Melting Point 157 ~ 160 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.90 (1H, s), 8.01 (1H, d, J = 12.2 Hz), 5.75 (2H, br, s), 4.46 (4H, s), 4.30 (1H, m) ), 3.75 (4H, s), 2.45 (3H, s), 1.30-1.10 (4H, m).

Example 10

8-chloro-1-cyclopropyl-6-fluoro-7- {7- (2-oxopropyl-3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl } -1,4-Dihydro-4-oxoquinoline-3-carboxylic acid

8-chloro-1-cyclopropyl-6-fluoro-7- {3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl) -1,4-dihydro-4 -195 mg (0.501 mmol) of oxoquinoline-3-carboxylic acid was dissolved in 8 ml of dimethylformamide, 100 mg of chloroacetone and 120 mg of potassium carbonate were added, followed by stirring at room temperature for 16 hours.

The solvent was removed under reduced pressure, 10 parts of chloroform was taken up with a soluble part, washed with water, and the residue obtained by concentration of the solvent was crystallized in ethanol-chloroform to give 134 mg of the target compound (yield 60%).

Melting Point: 190 ~ 194 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.93 (1H, s), 8.03 (1H, d, J = 12.2 Hz), 4.60 (4H, s), 4.05 (1H, m), 3.83 (4H, s), 3.51 (2H, s), 2.24 (3H, s), 1.30-1.12 (4H, m).

Example 11

8-chloro-1-cyclopropyl-6-fluoro-7- {7- (ethoxycarbonylmethyl) -3,7-diazabicyclo [3,3,0] oct-1 (5) ene-3 Preparation of -yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

8-chloro-1-cyclopropyl-6-fluoro-7- {3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl) -1,4-dihydro-4 -195 mg (0.501 mmol) of oxoquinoline-3-carboxylic acid was suspended in 10 ml of chloroform, 100 mg of ethyl bromo acetate and 100 mg of potassium carbonate were added, followed by stirring at room temperature for 24 hours.

The solid was filtered off, the filtrate was washed with water, and the residue was crystallized in ethanol to obtain 170 mg of the target compound (yield 75%).

Melting Point: 215 ~ 219 ℃ (Decomposition)

¹ H NMR (CDCl ₃ , δ ppm): 8.90 (1H, s), 8.00 (1H, d, J = 12.2 Hz), 4.47 (4H, s), 4.24 (2H, q, J = 7 Hz), 4.10 ( 1H, m), 3.80 (4H, s), 3.36 (2H, s), 1.35 (3H, t, J = 7 μs), 1.31-1.10 (4H, m).

Example 12

8-chloro-1-cyclopropyl-6-fluoro-7- {7- (3-oxobutyl) -3,7-diazabicyclo [3,3,0] oct-1 (5) ene-3- Preparation of Japanese} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

8-chloro-1-cyclopropyl-6-fluoro-7- {3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl) -1,4-dihydro-4 -195 mg (0.501 mmol) of oxoquinoline-3-carboxylic acid was suspended in 20 ml of chloroform, 200 mg of methyl vinyl ketone was added, and the mixture was stirred at 45 ° C for 70 hours. The insoluble matter was removed by filtration, the filtrate was concentrated and the remaining residue was crystallized in chloroform-ethanol to obtain 120 mg of the target compound (yield 52%).

Melting Point: 200 ~ 205 ℃ (Decomposition)

¹ H NMR (CDCl ₃ , δ ppm): 8.92 (1H, s), 8.04 (1H, d, J = 12.2 Hz), 4.45 (4H, s), 4.13 (1H, m), 3.85 (4H, s), 2.74 (4H, br, s), 2.18 (3H, s), 1.32-1.11 (4H, m).

Example 13

8-chloro-1-ethyl-6-fluoro-7- (3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl) -1,4-dihydro-4- Preparation of oxoquinoline-3-carboxylic acid

144 mg (0.501 mmol) of 8-chloro-6,7-difluoro-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3,7-diazabicyclo [3.3 .0] Oct-1 (5) ene dihydrobromide 156 mg (0.573 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene 270 mg are dissolved in 7 ml of acetonitrile. It was refluxed for time. The reaction mixture was cooled to room temperature, the precipitate was filtered, washed sequentially with acetonitrile, water and ethanol and dried under reduced pressure to obtain 140 mg of the target compound (yield 70%).

Melting Point: 214 ~ 216 ℃ (Decomposition)

¹ H NMR (CDCl ₃ + CF ₃ COOD, δppm): 9.00 (1H, s), 8.05 (1H, d, J = 12.4 Hz), 4.52 (4H, s), 4.43 (1H, m), 4.30 (4H, s), 4.25 (2H, q, J = 7 Hz), 1.45 (3H, t, J = 7 Hz).

Example 14

8-chloro-1-ethyl-6-fluoro-7- (7-methyl-diazabicyclo [3.3.0] oct-1 (5) en-3-yl) -1,4-dihydro-4- Preparation of oxoquinoline-3-carboxylic acid

144 mg (0.501 mmol) of 8-chloro-6,7-difluoro-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-methyl-3,7-dia 75 mg (0.604 mmol) of Xavicyclo [3.3.0] oct-1 (5) and 200 mg of diisopropylethylamine were dissolved in 10 ml of acetonitrile and refluxed for 6 hours. The solvent was concentrated and the residue was dissolved in 20 mL of dichloromethane and washed with brine (5 mL × 5 times). The organic layer was concentrated and the residue was crystallized in ethanol to obtain 124 mg of the target compound (yield 63%).

Melting Point: 221 ~ 223 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.90 (1H, s), 8.00 (1H, d, J = 12.3 Hz), 4.43 (4H, s), 4.22 (2H, q, J = 7 Hz), 4.01 ( 1H, m), 3.69 (4H, s), 2.82 (3H, s), 1.46 (3H, t, J = 7 Hz).

Example 15

8-chloro-1-ethyl-6-fluoro-7- (7- (2-hydroxyethyl) -3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl) Preparation of -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

8-chloro-6,7-difluoro-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 144 mg (0.501 mmol), 3- (2-hydroxyethyl) -3,7-diazabicyclo [3.3.0] oct-1 (5) ene dihydrobromide 192 mg (0.574 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene 270 mg was dissolved in 5 ml of acetonitrile and refluxed for 5 hours.

The reaction mixture was stirred overnight at room temperature, and the resulting precipitate was filtered, washed successively with acetonitrile, water and ethanol, and dried under reduced pressure to obtain 127 mg of the target compound (yield 60%).

Melting Point: 207 ~ 212 ℃ (Decomposition)

¹ H NMR (CDCl ₃ , δ ppm): 8.93 (1H, s), 8.04 (1H, d, J = 12.3 Hz), 4.46 (4H, s), 4.25 (2H, q, J = 7 Hz), 4.07 ( 1H, m), 3.95 (2H, t, J = 5.3 kPa), 3.87 (4H, s), 2.97 (2H, t, J = 5.3 kPa), 1.47 (3H, t, J = 7 kPa).

Example 16

1-t-butyl-8-chloro-6-fluoro-7- {3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl) -1,4-dihydro- Preparation of 4-oxoquinoline-3-carboxylic acid

158 mg (0.501 mmol) of 1-t-butyl-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3,7-diazabicyclo [3.3.0] 162 mg (0.6 mmol) of oct-1 (5) ene dihydrobromide and 280 mg of 1,8-diazabicyclo [5.4.0] undec-7-ene are added to 6 ml of acetonitrile. It was dissolved and refluxed for 4 hours.

The reaction mixture was cooled to room temperature, the precipitate was filtered off, washed with acetonitrile and dried under reduced pressure to obtain 152 mg of the target compound (yield 75%).

Melting Point: 183 ~ 187 ℃

¹ H NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.94 (1H, s), 8.03 (1H, d, J = 12.2 Hz), 4.42 (4H, s), 4.30 (4H, s), 1.93 (9H, s).

Example 17

1-t-butyl-8-chloro-6-fluoro-7- {7-methyl-3,7-difluoro [3.3.0] oct-1 (5) en-3-yl) -1,4 Preparation of -dihydro-4-oxoquinoline-3-carboxylic acid

158 mg (0.501 mmol) of 1-t-butyl-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-methyl-3,7 72 mg (0.58 mmol) of diazabicyclo [3.3.0] oct-1 (5) and 200 μl of disopropylethylamine were added to 5 ml of acetonitrile and refluxed for 7 hours.

After cooling the reaction mixture to room temperature, the resulting precipitate was filtered and crystallized in ethanol and chloroform to obtain 122 mg of the target compound (yield 58%).

Melting Point: 180 ~ 183 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.87 (1H, s), 8.00 (1H, d, J = 12.2 Hz), 4.45 (4H, s), 3.82 (4H, s), 2.70 (3H, s), 1.90 (9 H, s).

Example 18

8-chloro-6-fluoro-1- (4-fluorophenyl) -7- {3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl) -1,4 Preparation of -dihydro-4-oxoquinoline-3-carboxylic acid

177 mg (0.501 mmol) of 8-chloro-6,7-difluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3,7 162 mg (0.6 mmol) of dihydrobromide and 275 mg of 1.8-diazabicyclo [5.4.0] undec-7-ene were treated with acetonitrile 6-diazabicyclo [3.3.0] oct-1 (5) ene. Dissolved in mL and refluxed for 4 hours.

After the reaction mixture was allowed to stand at room temperature overnight, the resulting precipitate was filtered, washed sequentially with acetonitrile, water and ethanol and dried under reduced pressure to obtain 155 mg of the target compound (yield 70%).

Melting Point: 165 ~ 168 ℃

¹ H NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.85 (1H, s), 8.00 (1H, d, J = 12.2 Hz), 7.45 (2H, m), 7.30 (2H, m), 4.54 (4H, s), 4.22 (4 H, s).

Example 19

8-chloro-1- (4-fluorophenyl) -6-fluoro-7- {7-methyl-3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl) Preparation of -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

177 mg (0.501 mmol) of 8-chloro-6,7-difluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-methyl 75 mg (0.604 mmol) of -3,7-diazabicyclo [3.3.0] oct-1 (5) ene and 270 mg of 1.8-diazabicyclo [5.4.0] undec-7-ene were prepared in acetonitrile 5 It was dissolved in ml and refluxed for 7 hours.

The reaction mixture was allowed to stand at room temperature overnight, and the resulting precipitate was filtered and washed sequentially with acetonitrile, water and acetonitrile and dried under reduced pressure to obtain 144 mg of the target compound (yield 63%).

Melting Point: 157 ~ 160 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.86 (1H, s), 8.01 (1H, d, J = 12.2 Hz), 7.48 (2H, m), 7.31 (2H, m), 4.47 (4H, s), 3.78 (4H, s), 2.65 (3H, s).

Example 20

8-chloro-1- (2,4-difluorophenyl) -6-fluoro-7- (7-methyl-3,7-diazabicyclo [3.3.0] oct-1 (5) ene-3 Preparation of -yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

186 mg (0.501 mmol) of 8-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-methyl 75 mg (0.604 mmol) of -3,7-diazabicyclo [3.3.0] oct-1 (5) and 200 µl of disopropylethylamine were added to 10 ml of acetonitrile and refluxed for 7 hours.

The solvent was concentrated, dissolved in 20 mL of dichloromethane, washed with brine (5 mL × 5 times), and the residue was concentrated in ethanol to obtain 131 mg of the target compound (yield 55%).

Melting Point: 157 ~ 160 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.84 (1H, s), 8.02 (1H, d, J = 12.2 Hz), 7.45 (1H, m), 7.18 (2H, m), 4.45 (4H, s), 3.81 (4H, s), 2.64 (3H, s).

Example 21

8-chloro-1-cyclopropyl-6-fluoro-7- {3-methyl-3,8-diazabicyclo [4.3.0] nona-1 (6) en-8-yl} -1,4- Preparation of Dihydro-4-oxoquinoline-3-carboxylic Acid (Compound 4)

8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 148 mg (0.50 mmol), 3-methyl-3,8- Diacebicyclo [4.3.0] nona-1 (6) ene dihydrobromide 100 mg (0.53 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene 230 mg were acetonitrile It was dissolved in 5 ml and refluxed for 5 hours.

The half-silver mixture was cooled to room temperature, the resulting precipitate was filtered, washed with cooled acetonitrile, water and ethyl ether, and dried under reduced pressure to obtain 82 mg of the target compound (yield 40%).

Melting Point: 210 ~ 211 ℃

¹ H NMR (CDCl ₃ , δppm): 8.89 (1H, s), 8.01 (1H, d, J = 12.8 Hz), 4.45 (4H, s), 4.34 (1H, m), 3.03 (2H, s), 2.59 (2H, t, J = 5.7 Hz), 2.49 (3H, s), 2.31 (2H, br, s), 1.31 (2H, m), 0.95 (2H, m).

Example 22

8-chloro-1-ethyl-fluoro-7- {3-methyl-3,8-diazabicyclo [4.3.0] nona-1 (6) en-8-yl} -1,4-dihydro- Preparation of 4-oxoquinoline-3-carboxylic acid

144 mg (0.501 mmol) of 9-chloro-6,8-difluoro-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-methyl-3,8-dia Xavicyclo [4.3.0] nona-1 (6) ene dihydrobromide 180 mg (0.6 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene 270 mg were acetonitrile 5 It was dissolved in ml and refluxed for 7 hours.

The reaction mixture was stirred overnight at room temperature, and the resulting precipitate was filtered, washed sequentially with acetonitrile, water and ethanol, and dried under reduced pressure to obtain 122 mg of the target compound (yield 60%).

Melting Point: 201 ~ 204 ℃

¹ H NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.85 (1H, s), 8.00 (1H, d, J = 12.8 Hz), 4.42 (4H, s), 4.25 (2H, q, J = 7 Hz) , 3.01 (2H, s), 2.60 (2H, t, J = 5.7 μs), 2.50 (3H, s), 2.33 (2H, br, s), 1.46 (3H, t, J = 7 μs), 1.30 ( 2H, m), 0.97 (2H, m).

Example 23

1-t-butyl-8-chloro-6-fluoro-7- {3-methyl-3,8-diazabicyclo [4.3.0] nona-1 (6) en-8-yl} -1,4 Preparation of -dihydro-4-oxoquinoline-3-carboxylic acid

158 mg (0.501 mmol) of 1-t-butyl-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-methyl-3,8 Diacebicyclo [4.3.0] nona-1 (6) ene dihydrobromide 165 mg (0.55 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene 260 mg were aceto It was dissolved in 5 ml of nitrile and refluxed for 6 hours.

The reaction mixture was left at room temperature overnight, and the resulting precipitate was filtered, washed sequentially with acetonitrile, water and acetonitrile and dried under reduced pressure to obtain 135 mg of the target compound (yield 62%).

Melting Point: 195 ~ 198 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.88 (1H, s), 8.00 (1H, d, J = 12.8 Hz), 4.41 (4H, s), 3.04 (2H, s), 2.60 (2H ,, t, J = 5.7 Hz), 2.50 (3H, s), 2.33 (2H, br, s), 1.90 (9H, s).

Example 24

8-chloro-1-cyclopropyl-6-fluoro-7- {8-methyl-3,8-diazabicyclo [4.3.0] nona-1 (6) en-3-yl} -1,4- Preparation of Dihydro-4-oxoquinoline-3-carboxylic Acid

150 mg (0.501 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 8-methyl-3,8- Dissolve 85 mg (0.615 mmol) of diazabicyclo [4.3.0] nona-1 (6) and 270 mg of 1,8-diazabicyclo [5.4.0] undec-7-ene in 3 ml of acetonitrile. It was refluxed for 6 hours.

The reaction mixture was allowed to stand at room temperature overnight, and the resulting precipitate was filtered and washed with cooled acetonitrile, water and acetonitrile in order to obtain 126 mg of the target compound under reduced pressure (yield 60%).

Melting Point: 177 ~ 180 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.81 (1H, s), 7.84 (1H, d, J = 12.2 Hz), 3.87 (7H, br.s), 3.51 (2Hbr.s), 2.80 (3H, s ), 2.33 (2H, br.s), 1.30-1.12 (4H, m).

Example 25

8-bromo-1-cyclopropyl-6-fluoro-7- {8-methyl-3,8-diazabicyclo [4.3.0] nona-1 (6) en-3-yl} -1,4 Preparation of -dihydro-4-oxoquinoline-3-carboxylic acid

172 mg (0.5 mmol) of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 8-methyl-3,8 -80 mg (0.579 mmol) of diazabicyclo [4.3.0] nona-1 (6) ene, 130 μl of 1,8-diazabicyclo [5.4.0] undec-7-ene were added to 4 ml of acetonitrile. It was refluxed for 10 hours.

The reaction mixture was allowed to stand at room temperature overnight, and the resulting precipitate was filtered, washed with cooled acetonitrile, water and ethanol in turn and dried under reduced pressure to obtain 104 mg of the target compound (yield 45%).

Melting Point: 155 ~ 158 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.85 (1H, s), 7.86 (1H, d, J = 12.3 Hz), 3.87 (4H, s), 3.85 (3H, m), 3.50 (2H, br.s ), 2.82 (3H, s), 2.35 (2H, br.s), 1.30-1.15 (4H, m).

Example 26

8-bromo-1-cyclopropyl-6-fluoro-7- {3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl} -1,4-dihydro- Preparation of 4-oxoquinoline-3-carboxylic acid

621 mg (1.806 mmol) of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3,7-diazabicyclo [3.3.0] Oct-1 (5) ene dihydrobromide 580 mg (2.132 mmol) and 1 g of 1,8-diazabicyclo [5.4.0] undec-7-ene are dissolved in 7 ml of acetonitrile. It was refluxed for 4 hours.

The reaction mixture was stirred overnight at room temperature, and the resulting precipitate was filtered, washed sequentially with acetonitrile, water and acetonitrile and dried under reduced pressure to obtain 548 mg of the target compound (yield 70%).

Melting Point: 235 ~ 238 ℃

¹ H NMR (CDCl ₃ + CF ₃ COOD, δ ppm): 9.11 (1H, s), 8.15 (1H, d, J = 12.4 Hz), 4.55 (4H, s), 4.42 (1H, m), 4.25 (4H, s), 1.45 (2H, m), 1.07 (2H, m).

Example 27

8-bromo-1-cyclopropyl-6-fluoro-7- {7-methyl-3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl} -1,4 Preparation of -dihydro-4-oxoquinoline-3-carboxylic acid

2.07 g (6.02 mmol) of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-methyl-3,7 0.9 g (7.24 mmol) of dia-WK bicyclo [3.3.0] oct-1 (5) and 1.2 g of 1,8-diazabicyclo [5.4.0] undec-7-ene are acetonitrile 10 It was dissolved in ml and refluxed for 6 hours.

The reaction mixture was left at room temperature overnight, and the resulting precipitate was filtered, washed with acetonitrile, water and acetonitrile and dried under reduced pressure to obtain 1.56 g of the target compound (yield 58%).

Melting Point: 228 ~ 231 ℃

¹ H NMR (CDCl ₃ , δ ppm): 8.93 (1H, s), 8.05 (1H, d, J = 12.3 Hz), 4.40 (4H, s), 4.09 (1H, m), 3.65 (4H, s), 2.91 (3H, s), 1.28 (2H, m), 1.01 (2H, m).

Some of the compounds of formula (I) prepared according to the above examples were measured by in vitro antibacterial activity by agar medium dilution method to determine the minimum growth inhibitory concentration (MIC: μg / ml) for the selected bacteria. As shown in Table 2, as shown in the following Table 2, the quinolone mixture of the general formula (I) according to the present invention showed much stronger antibacterial activity against gram-positive bacteria than opfloxacin and ciprofloxacin, and almost identical to gram-negative bacteria. Slightly weak antibacterial activity.

TABLE 2

In vitro antibacterial activity of quinolones (lowest growth inhibitory concentration ㎍ / ㎖)

Claims (10)

Quinolone compounds and their salts represented by the following general formula (I). In the general formula, R ₁ is a substituted or unsubstituted lower alkyl group of 1 to 7 carbon atoms, a substituted or unsubstituted cycloalkyl group of 3 to 7 carbon atoms, a lower or alkenyl group which is substituted or unsubstituted, or a substituted or unsubstituted phenyl group R ₂ represents a hydrogen atom, a protecting group of a carboxyl group or a pharmaceutically useful metal cation or organic cation, R ₃ represents a hydrogen atom, a lower alkyl group of 1 to 4 carbon atoms, a hydroxyalkyl group of 2 to 4 carbon atoms, 3 to 7 represents a cycloalkyl group or a nitrogen protecting group degradable in vivo, X represents a chlorine atom or bromine atom, Z represents a methyl group, m is an integer of 1 to 3, n is 1 or 2. The method of claim 1, wherein R ₁ is methyl, ethyl, isopropyl, t-butyl, t-pentyl, 2-fluoroethyl, 2-hydroxyethyl, difluoromethyl, vinyl, isopro Phenyl group, aryl group, 2-butenyl group, cyclopropyl group, 1-methylcyclopropyl group, cyclobutyl group, cyclopentyl group, phenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 2,4-difluoro Phenyl group, 2-hydroxyphenyl group, 4-hydroxyphenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 2-fluoro-4-methoxyphenyl group, 2-fluoro-4-hydroxyphenyl group, 4- Quinolone compound which is a methylphenyl group, 4-aminophenyl group, or 4-nitrophenyl group. The method of claim 1, wherein R ₂ is a hydrogen atom or a methyl group, ethyl group, n-propyl group, t-butyl group, lower alkanoyloxy-lower alkyl group, lower alkoxycarbonyloxy-lower alkyl group, lower alkoxymethyl group, di ( Lower alkyl) amino-lower alkyl groups, 4-methylene-5-methyl-1,3-dioxoren-2-one groups, sodium cations, potassium cations, calcium cations, magnesium cations, ammonium cations or tertiary having 1 to 4 carbon atoms Or a quinolone compound which is a quaternary alkylammonium ion. The method according to claim 1, wherein R ₃ is a hydrogen atom, methyl group, ethyl group, 2-hydroxyethyl group, cyclopropyl group, formyl group, alkyloxycarboxyl group, 2 or 3-oxoalkyl group, 4-methylene-5-methyl-1 Quinolone compound which is a 3-dioxene-2-one group. The salt of the quinolone compound represented by the general formula (I) is hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, propionic acid, methanesulfonic acid, paratoluenesulfonic acid, fumaric acid, formic acid, maleic acid, malonic acid, tartaric acid and citric acid. , Acid addition salts consisting of ascorbic acid or glutamic acid, or hydrates thereof, or base addition salts consisting of caustic soda, caustic, calcium hydroxide, magnesium hydroxide, silver nitrate, or lower alkyl ammonium of 1 to 4 carbon atoms Being a luggage. A method for producing a quinolone compound represented by the following general formula (I) by heating a compound of the following formula (II) and a compound of formula (III) or (IIIa) in the presence of a base. In the formulas (II), (III) and (IIIa), R ₁ , R ₂ , R ₃ , Z, X, m and n are as defined in the general formula (I), and A is a chlorine atom. Or a bromine atom, and L represents a halogen atom, an ethanesulfonyl or paratoluenesulfonyl group as a leaving group. The method of claim 6, wherein the heating reaction is performed for 10 minutes to 24 hours at a temperature of 10 to 150 ℃ in a non-reactive solvent selected from acetonitrile, pyridine, dimethylformamide or dioxane. According to claim 6, The compound of general formula (I) is a haloalkane having 1 to 3 carbon atoms, an aqueous solution of an acid or base selected from a lower alcohol solution, a lower alcohol solution is added to the acid addition salt or base addition of the general formula (I) Method of preparation in the form of a salt. A method of preparing a quinolone compound represented by the following general formula (I b) by reacting the compound of the following general formula (I a) with the compound of the following general formula (IV) in the presence of a base. In the formulas, R ₁ , R ₃ , Z, X, m and n are the same as defined in the general formula (I), R ₂ represents a carboxyl group protecting group, and Hal. Represents a halogen atom. A method of preparing a quinolone compound of the following general formula (I d) by reacting a compound of general formula (I c) with an R ₃ donor. In the formulas, R ₁ , R ₂ , Z, X, m and n are as defined in the general formula (I), respectively, R ₃ is a lower alkyl group of 1 to 4 carbon atoms, hydroxyalkyl group of 2 to 4 carbon atoms Or a nitrogen protecting group degradable in vivo.