KR940002954B1 - Quino/one derivatives - Google Patents

Abstract

The quinolone carboxylic acid derivs. are prepd. by heating and reacting the cpd. (II) with the amine cpd. of formula (III) or (IIIa) in presence of the base in the solvent at 20-200 deg.C. In the formulas, R1=C1-4 alkyl, haloalkyl, hydroxyalkyl, alkenyl, C3-6 cycloalkyl or halogen-substd. phenyl; R2 is H, protecting gp. of carboxyl of pharmacentically usable metallic or organic cation; R3 is H, C1-4 lower alkyl, hydroxyalkyl, cycloalkyl or N-protecting gp. decomposable in human body; n=1,2; m=1,2 or 3; Z is H, halogen, amino or methyl, and contains pharmaceutically usuable acid added salt or its hydrate if R2 is H. (I) has excellent antibiosis to the gram positive (or negative) bacillus.

Description

Quinoline carboxylic acid derivative and preparation method thereof

The present invention relates to a quinoline carboxylic acid derivative and a method for producing the same, and more particularly, an unsaturated diazabicycloamine at position 7 of the quinoline mother nucleus and a methoxy group at position 8, and a Gram-positive bacterium and Gram. It relates to a quinoline carboxylic acid derivative represented by the following general formula (I) having a strong antibacterial activity against negative bacteria, and salts thereof and a method of preparing the same.

In the above formula, R ₁ represents an alkyl group having 1 to 4 carbon atoms, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, a cycloalkyl group having 3 to 6 carbon atoms, a halogen substituted phenyl group, and R ₂ represents a hydrogen atom, a protecting group of a carboxyl group, or A pharmaceutically useful metal cation or an organic cation, R ₃ represents a hydrogen atom, a lower alkyl group of 1 to 4 carbon atoms, a hydroxyalkyl group cycloalkyl group or a nitrogen protecting group decomposable in vivo, Z represents a hydrogen atom, a halogen, an amino group Or a methyl group, n is 1 or 2, m is an integer of 1-3. Pharmaceutically acceptable acid addition salts and their hydrates when R ₂ is H.

In general, it is well known that quinolone antibacterial agents in which a methoxy group is introduced at the parent nucleus 8 position of quinoline show good antimicrobial activity, in particular, lower toxicity and have high bioavailability.

As quinoline compounds exhibiting such characteristics have recently been actively researched, it has been confirmed that the introduction of any introductory group at the position 7 of the quinoline mother nucleus does not show antimicrobial resistance but shows superior antimicrobial characteristics.

The purpose of the present invention is to provide a new quinolone compound exhibiting a strong antimicrobial activity against Gram-negative bacteria and Gram-positive bacteria by introducing a new cycloamine compound at position 7 of the quinoline mother nucleus as part of this study.

Hereinafter, the present invention will be described in detail.

The present invention relates to a quinoline carboxylic acid represented by the general formula (I) and salts thereof.

In the above general formula (I), when R ₁ is an alkyl group having 1 to 4 carbon atoms, it is a methyl group, an ether group, n-propyl group, isobutyl group or tert-butyl group, preferably an ethyl group or tert-butyl In the case of a haloalkyl group, suitable carbon number is 2-4, a suitable halogen atom is fluorine, a suitable substituent is 2-fluoroethyl group, and in the case of a hydroxyalkyl group, 2-4 carbon atoms are appropriate and 2-hydroxyethyl group In the case of a cycloalkyl group having 3 to 6 carbon atoms, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group is preferably a cyclopropyl group, and in the case of a halogen-substituted phenyl, preferably 1 to 2 the substituted phenyl group is a fluorine for example, a phenyl group or a 2,4-difluoro-4-fluorophenyl group, if R ₂ is a pharmaceutically usable metal cation, alkali metal cation of sodium or potassium cation, alkaline Among the metal cations are calcium or magnesium cations, and furthermore, ammonium cations or silver cations, and organic cations represent tertiary or quaternary alkyl ammonium ions having 1 to 4 carbon atoms, and in the case of protecting groups of carboxyl groups, such as by hydrolysis. As making ester type which can make free carboxylic acid, Lower alkyl group, such as methyl group, ethyl group, n-propyl group, t-butyl group, lower alkanoyloxy- lower alkyl group, such as acetoxymethyl group and pivaloyloxymethyl group, Lower alkoxycarbonyloxy-lower alkyl groups such as methoxycarbonyloxymethyl group and 1-ethoxycarbonyloxyethyl group, lower alkoxymethyl groups such as methoxymethyl group and di (lower alkyl) amino-lower groups such as 1-dimethylaminoethyl group group, 4-methylene-dioxo -5-1,3- alkylene refers to warm-2, etc., R ₃ is a methyl group or an ethyl group to, if appropriate having a carbon number of 1 to 4 lower alkyl, hydroxy Even in the case of a cialkyl group, the accumulation is 2-hydroxyethyl group, and in the case of a cycloalkyl group, a cyclopropyl group is also suitable, and in the case of a nitrogen protecting group decomposable in vivo, a formyl group, an alkyloxycarboxyl group and 2-oxoalkyl , 4-methylene-5-methyl-1,3-dioxoren-2-one and the like, and when Z is a halogen atom, fluorine atom is preferable.

According to the present invention, in the above general formula (I), R ₁ is an ethyl group, tert-butyl group, 2-fluoroethyl group, 2-hydroxyethyl group, cyclopropyl group, 4-fluorophenyl group or 2, It is a 4-difluorophenyl group, R <_2> is a hydrogen atom, a C1-C4 lower alkyl group, a lower alkanoyloxy- lower alkyl group, a lower alkoxycarbonyloxy- lower alkyl group, a lower alkoxy methyl group, sodium ion, potassium ion, calcium Ions, magnesium ions, ammonium ions or silver ions or tertiary or quaternary alkyl ammonium ions having 3 to 4 carbon atoms, R ₃ is a hydrogen atom, a methyl group, an ethyl group, 2-hydroxyethyl group, a cyclopropyl group, Wheat group, ethoxycarbonyl group, ethoxycarbonylmethyl group, 2-oxopropyl group, 3-oxobutyl group or 4-methylene-5-methyl-1,3-dioxoren-2-one, Z is a hydrogen atom And a fluorine atom, an amino group or a methyl group.

The present invention includes a method for preparing a compound of Formula (I) as described above and an antimicrobial agent containing the compound as an active ingredient. Looking at the method for preparing Formula (I), the reaction scheme is as follows. The compound represented by the general formula (II) and the amine compound represented by the following general formula (III) or (IIIa) are prepared by heating at a temperature of 20 to 200 ° C. in a solvent in the presence of a base.

In the above formulas, R ₁ , R ₂ , R ₃ and Z, n, m are each as defined above, and X represents a halogen atom, in particular chlorine or bromine.

The compound of the general formula (II) used as a starting material in the present invention is a compound well known in the field of quinoline derivative antibacterial compounds, and can be prepared, for example, by the method described in Japanese Patent Application No. 64-16746.

In addition, the compounds of the general formulas (III) and (IIIa) are novel amine compounds, which are described in Korean Patent Application Nos. 89-15204, 91-1726 and European Patent Application No. 9012024.4 by the present inventors. Can be manufactured and used.

The reaction is carried out in a non-reactive solvent such as water, alcohols, acetonitrile, pyridine or dimethylformamide, or a mixed solvent thereof at 20 to 200 ° C., and the reaction time is from one hour to several hours.

In addition, a base is used to promote the reaction or to convert the compound of the general formula (IIIa) into the compound of the general formula (III) in free amine form in a reaction vessel, wherein the base used is triethylamine, diisopropyl. Organic bases such as ethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene, and carbonates of alkali metals may be used.

In addition, according to the present invention as another method for preparing a compound of formula (I), R ₃ in a solvent after preparing a compound of formula (IV) wherein R ₃ in the compound of formula (I) _It can also be prepared by incorporating _{3 as} a donor of ₃ .

In the above formulas, R ₁ , R ₂ , R ₃ and Z, n, m are as defined above, respectively.

The process for preparing the compound of general formula (I) by the above method is advantageous when R ₃ is an amine protecting group, for example alkylhalide, acyl halide, lower halogen haloalka having 1 to 3 carbon atoms in the presence of a base such as potassium carbonate, The reaction is carried out in a solvent such as dimethylformamide or the acrylate.

Moreover, even when R <_3> is a methyl group, general formula (I) can be manufactured easily by heating the said general formula (IV) in presence of formaldehyde formic acid.

On the other hand, the salt of the acid of the general formula (I) (when R ₂ is H) or the base (R ₂ is a metal cation, an organic cation), the compound of the general formula (I) to a mixed solvent of haloalkane and lower alcohol It is prepared by dissolving and adding the corresponding acid or base with a solvent selected from water, lower alcohol and haloalkanes to take up the resulting precipitate or remove the solvent.

Suitable acids used at this time include lactic acid, maleic acid, ascorbic acid, fumaric acid, tartaric acid, citric acid, acetic acid, propionic acid, paratoluenesulfonic acid, glutamic acid and hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, and the like. , Calcium hydroxide, magnesium hydroxide, and nitric acid are tertiary or quaternary alkylammonium, and the hydrates of these salts are also included. Examples of representative compounds of the general formula (I) which can be prepared by the above-described preparation method of the present invention are shown in Table 1 below.

As described above, the compound of Formula (I) and salts thereof according to the present invention have very strong antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria, and are used as antibacterial agents such as oral or injectable preparations with various excipients that can be used pharmaceutically. Very useful.

In order to determine the antimicrobial activity of the compound of formula (I) in the present invention, in vitro antimicrobial activity of some of the quinolone compounds synthesized by the example was measured by agar medium dilution and is shown in Table 2 below.

As shown in Table 2, the quinolone compound of the present invention showed much stronger antimicrobial activity against Gram-positive bacteria than the existing antibacterial agents ciprofloxacin and oploxacin. In addition, it can be seen that Gram-negative bacteria are almost the same as or slightly inferior to existing quinolone antibacterial agents. However, 8-methoxy quinolone compounds generally show excellent oral absorption and bioavailability, indicating that they are poor in vitro. I expect to be rewarded within.

In addition, it can be seen that the antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA), which is a problem in the clinic, is much superior to the existing antimicrobial agent ciprofloxacin.

Hereinafter, the present invention will be described in 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 Invention

TABLE 2

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

TABLE 3

In vitro Antibacterial Activity of Quinolone Against Methicillin-Resistant Strains (Minimum Growth Inhibition Concentration ㎍ / mL)

Example 1

1-cyclopropyl-6-fluoro-8-methoxy-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)

1.3 g (4.4 mmol) of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3,7-diazabicyclo [3.3.0] 1.4 g (5.14 mmol) of oct-1 (5) ene dihydrobromide and 2.5 g (16.44 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene It was dissolved in 15 ml of acetonitrile and refluxed for 5 hours.

The reaction mixture was left at room temperature for 16 hours, and then the precipitate was filtered, washed with acetonitrile, water, acetonitrile and ethyl ether in that order and dried under reduced pressure to obtain 1.05 g of the target compound (yield 62%).

Melting Point: 189 ~ 191 ℃

¹ H-NMR (CDCl ₃ + CD ₃ COOD + CD ₃ OD, δppm): 8.87 (1H, s), 7.84 (1H, d, J = 13.7Hz), 4.55 (4H, s), 4.24 (4H, s ), 4.09 (1H, m), 3.66 (3H, s), 1.23 (2H, m), 1.03 (2H, m).

Example 2

1-cyclopropyl-6-fluoro-8-methoxy-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 (compound 2)

3.5 g (11.86 mmol) of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-methyl-3,7 1.7 g (13.70 mmol) of diazabicyclo [3.3.0] oct-1 (5) and 2 g of 1,8-diazabicyclo [5.4.0] undec-7-ene in 35 ml of acetonitrile. It was dissolved and refluxed for 7 hours.

The reaction mixture was allowed to stand at room temperature for 16 hours, and the resulting precipitate was filtered, washed with acetonitrile, water and ethyl ether, and dried under reduced pressure to obtain 1.35 g of the target compound (yield 28%).

Melting Point: 209 ~ 211 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.82 (1H, s), 7.81 (1H, d, J = 13.7 Hz), 4.45 (4H, s), 4.01 (1H, m), 3.65 (4H, s) , 3.60 (3H, s), 2.65 (3H, s), 1.21-1.01 (4H, m).

Example 3

1-cyclopropyl-6-fluoro-8-methoxy-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 lactate (Compound 3)

1-cyclopropyl-6-fluoro-8-methoxy-7- [7-methyl-3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl] -1,4 0.91 g (2.28 mmol) of dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in 5 ml of dichloromethane and 2 ml of methanol, 0.2 ml of 85% lactic acid was added, mixed well, and concentrated under reduced pressure at 40 ° C. or lower. . Ethyl ether was added to the powder, filtered and dried under reduced pressure to obtain the target compound in quantitative yield.

Melting Point: 164 ~ 166 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.81 (1H, s), 7.77 (1H, d, J = 13.7 Hz), 4.50 (4H, s), 4.15 (4H, s), 4.05 (1H, m) , 3.65 (3H, s), 3.50 (1H, m), 2.95 (3H, s), 1.42 (3H, d, J = 7 Hz), 1.25-1.02 (4H, m).

Example 4

1-cyclopropyl-6-fluoro-8-methoxy-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

1-cyclopropyl-6-fluoro-8-methoxy-7- [3,7-diazabicyclo [3.3.0] oct-1 (5) en-3-yl] -1 prepared in Example 1 770 mg (2 mmol) of, 4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in 10 ml of 98% formic acid, and 1 ml of 37% formal S aqueous solution was added thereto, and the mixture was refluxed for 5 hours.

After distillation under reduced pressure, the excess reagent was removed, the residue was dissolved in 10 ml of distilled water, the insolubles were filtered off, and the filtrate was adjusted to pH 8 with 4N aqueous sodium hydroxide solution. A soluble part was taken up in dichloromethane in the residue obtained by concentration under reduced pressure, and the solvent was removed, followed by crystallization in ethanol to obtain 580 mg of the target compound (yield 72%).

Melting Point: 208 ~ 211 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.82 (1H, s), 7.81 (1H, d, J = 13.7 Hz), 4.45 (4H, s), 4.01 (1H, m), 3.65 (4H, s) , 3.60 (3H, s), 2.65 (3H, s), 1.21-1.01 (4H, m).

Example 5

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

1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-kiric acid 295 mg (1 mmol), 3-ethyl-3,7- Diazabicyclo [3.3.0] oct-1 (5) ene dihydrobromide 366 mg (1.15 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene 530 mg (3.48 m) Mol) was dissolved in 3 ml of acetonitrile and refluxed for 6 hours.

The reaction mixture was left at room temperature overnight, and the resulting precipitate was filtered, washed with acetonitrile, distilled water and acetonitrile and dried under reduced pressure to obtain 248 mg of the target compound (yield 60%).

Melting Point: 201 ~ 204 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.84 (1H, s), 7.83 (1H, d, J = 14 Hz), 4.47 (4H, s), 4.31 (2H, q, J = 7.1 Hz), 4.04 ( 1H, m), 3.72 (4H, s), 3.65 (3H, s), 1.45 (3H, t, J = 7.1 Hz), 1.25-1.02 (4H, m).

Example 6

1-cyclopropyl-6-fluoro-8-methoxy-7- [7- (2-hydroxyethyl) -3,7-diazabicyclo [3.3.0] oct-1 (5) ene-3- Preparation of Japanese] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 295 mg (1 mmol), 3- (2-hydroxyethyl ) -3,7-diazabicyclo [3.3.0] oct-1 (5) ene dihydrobromide 380 mg (1.19 mmol) and 1,8-diazabicyclo [5.4.0] undec-7 -540 mg (3.55 mmol) of ene was dissolved in 5 ml of acetonitrile and refluxed for 7 hours.

The reaction mixture was left at room temperature overnight, the resulting precipitate was filtered, washed with acetonitrile, water and acetonitrile and dried under reduced pressure to obtain 310 mg of the target compound (yield 72%).

Melting Point: 209 ~ 214 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ , δ ppm): 8.80 (1H, s), 7.1 (1H, d, J = 13.7 Hz), 4.46 (4H, s), 4.05 (1H, m), 3.94 (2H, t, J = 5.3 Hz), 3.80 (4H, s), 3.65 (3H, s), 2.98 (2H, t, J = 5.3 Hz), 1.25-1.05 (4H, m).

Example 7

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

148 mg (0.501 mmol) of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-cyclopropyl-3, 7-diazabicyclo [3,3,0] oct-1 (5) ene dihydrobromide 185 mg (0.592 mmol) and 1,8-diazabicyclo [5,4,0] undec-7- 270 mg of ene was dissolved in 5 ml of acetonitrile and refluxed for 7 hours. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 20 ml of dichloromethane and washed 4 times with 5 ml of water. The organic layer was dehydrated with anhydrous forget-me-not and concentrated. The residue was crystallized in ethanol to obtain 139 mg of the target compound (65% yield).

Melting Point: 221 ~ 113 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.81 (1H, s), 7.82 (1H, d, J = 13.8 Hz), 4.68 (4H, s), 4.00 (1H, m), 3.85 (4H, s) , 3.62 (3H, s), 3.04 (1H, m), 1.34-1.21 (6H, m), 0.96 (2H, m).

Example 8

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

1-cyclopropyl-6-fluoro-8-methoxy-7- {3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1,4-di 293 mg (0.501 mmol) of hydro-4-oxoquinoline-3-carboxylic acid was dissolved in 10 ml of chloroform, and 116 mg of 4-bromomethyl-5-methyl-1,3-dioxoren-2-one and carbonic acid 130 mg potassium was added and stirred at room temperature for 24 hours. The solid was removed by filtration, the filtrate was washed with water and the solvent was removed under reduced pressure, and the residue was crystallized in ethanol to obtain 162 mg of the target compound (65% yield).

Melting Point: 151 ~ 154 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.80 (1H, s), 7.80 (1H, d, J = 13.8Hz), 5.93, 5.70 (each 1H, d, J = 2.4Hz), 4.70 (4H, s ), 4.05 (1H, m), 3.82 (4H, s), 3.65 (3H, s), 2.42 (3H, s), 1.30-1.15 (4H, m).

Example 9

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

1-cyclopropyl-6-fluoro-8-methoxy-7- {3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1,4-di 293 mg of hydro-4-oxoquinoline-3-carboxylic acid was dissolved in 10 ml of dimethylformamide, 150 mg of chloroacetone and 150 mg of potassium carbonate were added, followed by stirring at room temperature for 10 hours. The solvent was removed under reduced pressure, extracted with 10 ml of chloroform, washed with water, the solvent was removed, and the residue was crystallized in ethanol to obtain 133 mg of the target compound (65% yield).

Melting Point: 191 ~ 195 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.78 (1H, s), 7.79 (1H, d, J = 13.8Hz), 4.70 (4H, s), 4.01 (1H, m), 3.82 (4H, s) , 3.65 (3H, s), 3.53 (2H, s), 2.23 (3H, s), 1.30-1.19 (4H, m).

Example 10

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

1-cyclopropyl-6-fluoro-8-methoxy-7- {3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1,4-di 293 mg of hydro-4-oxoquinoline-3-carboxylic acid was dissolved in 10 ml of chloroform, 150 mg of ethyl bromoacetate and 150 mg of potassium carbonate were added, followed by stirring at room temperature for 24 hours. The residue obtained by filtration, washing the filtrate with water and removing the solvent was crystallized in ethanol-cyclohexane to give 148 mg of the target compound (yield 63%).

Melting Point: 225 ~ 229 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.77 (1H, s), 7.80 (1H, d, J = 13.7 Hz), 4.71 (4H, s), 4.23 (2H, q, J = 7 Hz), 4.03 ( 1H, m), 3.88 (4H, s), 3.65 (3H, s), 3.31 (2H, s), 1.36 (3H, t, J = 7 Hz), 1.30-1.21 (4H, m).

Example 11

1-cyclopropyl-6-fluoro-8-methoxy-7- {3,7-diazabicyclo [3,3,0] oct-1- (5) en-3-yl} -1,4- Preparation of Dihydro-4-oxoquinoline-3-carboxylic Acid Hydrochloride

1-cyclopropyl-6-fluoro-8-methoxy-7- {3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} prepared in Example 1 120 mg of -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in 5 ml of dichloromethane and 1 ml of ethanol, saturated with hydrogen chloride gas. Solvent was removed. Ethyl ether was added to the residue to make a powder. The residue was filtered, washed with ethyl ether, and dried under reduced pressure to obtain a pale yellow target compound in quantitative yield.

Melting Point: 175 ~ 178 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.70 (1H, s), 7.74 (1H, d, J = 14Hz), 4.47 (4H, s), 4.20 (4H, s), 4.01 (1H, m), 3.65 (3H, s), 1.25-1.02 (4H, m).

Example 12

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

1-cyclopropyl-6-fluoro-8-methoxy-7- {7-methyl-3,7-diazabicyclo [3,3,0] oct-1- (5) ene, prepared in Example 2 250 mg of -3-yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in 5 ml of dichloromethane and 1 ml of ethanol, and ethanol saturated with hydrogen chloride gas was excess to reduce the solvent at room temperature. The mixture was removed, ethyl ether was added, powdered, filtered, washed with ethyl ether, and dried under reduced pressure to obtain the target compound in quantitative yield.

Melting Point: 187 ~ 191 ℃

¹ H-NMR (CDCl ₃ + CD ₃ OD, δ ppm): 8.80 (1H, s), 7.79 (1H, d, J = 13.8 Hz), 4.54 (4H, s), 4.17 (4H, s), 4.02 ( 1H, m), 3.64 (3H, s), 3.00 (3H, s), 1.30-1.11 (4H, m).

Example 13

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

1-ethyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 142 mg (0.50 mmol), 3.7 (diazabicyclo [3, 2 ml of acetonitrile in 160 mg (0.588 mmol) of 3,0] oct-1 (5) ene dihydrobromide and 270 mg of 1,8-diazabicyclo [5,4,0] undec-7-ene The reaction mixture was left in a refrigerator overnight, filtered, and the resulting precipitate was filtered, washed sequentially with acetonitrile, water and acetonitrile, and dried under reduced pressure to obtain 159 mg of the target compound (yield 85%).

Melting Point: 227 ~ 230 ℃

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.84 (1H, s), 7.82 (1H, d, J = 13.7 Hz), 4.50 (4H, s), 4.26 (4H, s), 4.21 ( 2H, q, J = 7 Hz), 3.65 (3H, s), 1.46 (3H, t, J = 7 Hz).

Example 14

1-ethyl-6-fluoro-8-methoxy-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

142 mg (0.50 mmol) of 1-ethyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 3-methyl-3,7- 136 mg of diazabicyclo [3,3,0] oct-1 (5) ene was dissolved in 2 ml of acetonitrile and refluxed for 7 hours. The solvent was removed under reduced pressure, the residue was dissolved in 10 mL of dichloromethane, washed with brine (2 mL × 5 times), and the organic layer was concentrated and the residue was crystallized in ethanol to obtain 165 mg of the target compound (yield 85%).

Melting Point: 200 ~ 203 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.81 (1H, s), 7.82 (1H, d, J = 13.7 Hz), 4.47 (4H, s), 4.25 (2H, q, J = 7 Hz), 3.70 ( 4H, s), 3.61 (3H, s), 2.97 (3H, s), 1.44 (3H, t, J = 7 Hz).

Example 15

1-ethyl-6-fluoro-8-methoxy-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

1-ethyl-6-fluoro-8-methoxy-7- {7-methyl-3,7-diazabicyclo [3,3,0] oct-1 (5) ene-3 prepared in Example 14 -Il} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (94 mg) was dissolved in 2 ml of dichloromethane and 1 ml of ethanol and mixed well by adding 26 mg of 85% lactic acid, and then the solvent was removed under reduced pressure. To give a pale yellow target compound in quantitative yield.

Melting Point: 177 ~ 180 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.80 (1H, s), 7.80 (1H, d, J = 13.7 Hz), 4.54 (4H, s), 4.24 (2H, q, J = 7 Hz), 3.75 ( 4H, s), 3.64 (3H, s), 3.54 (1H, m), 2.95 (3H, s), 1.46 (3H, d, J = 7 Hz), 1.42 (3H, t, J = 7 Hz).

Example 16

1-tert-butyl-6-fluoro-8-methoxy-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

1-tert-butyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 311 mg (1 mmol), 3-methyl-3,7 140 mg (1.12 mmol) of diazabicyclo [3,3,0] oct-1- (5) ene and 180 mg of 1,8-diazabicyclo [5,4,0] undec-7-ene It was dissolved in 2 ml of acetonitrile and refluxed for 7 hours. The reaction mixture was left in the refrigerator overnight, and the resulting precipitate was filtered, washed with acetonitrile and dried under reduced pressure to obtain 262 mg of the target compound (yield 63%).

Melting Point: 193 ~ 196 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.80 (1H, s), 7.80 (1H, d, J = 13.8Hz), 4.46 (4H, s), 3.71 (4H, s), 3.63 (3H, s) , 2.67 (3H, s), 1.91 (9H, s).

Example 17

1-tert-butyl-6-fluoro-8-methoxy-7- {3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl} -1,4- Preparation of Dihydro-4-oxoquinoline-3-carboxylic Acid

1-tert-butyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 156 mg (0.50 mmol), 3,7-diazabi Cyclo [3,3,0] oct-1- (5) ene dihydrobromide 164 mg (0.6 mmol) and 1,8-diazabicyclo [5,4,0] undec-7-ene 270 mg Was dissolved in 2 ml of acetonitrile and refluxed for 5 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 136 mg of the target compound (yield 75%).

Melting Point: 178 ~ 181 ℃

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.88 (1H, s), 7.85 (1H, d, J = 13.7 Hz), 4.58 (4H, s), 4.27 (4H, s), 3.65 ( 3H, s), 1.92 (9H, s).

Example 18

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

156 mg (0.50 mmol) of 1-tert-butyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-ethyl-3, 7-diazabicyclo [3,3,0] oct-1- (5) ene dihydrobromide 180 mg (0.6 mmol) and 1,8-diazabicyclo [5,4,0] undec-7 280 mg of -ene was dissolved in 2.5 ml of acetonitrile and refluxed for 7 hours. The reaction mixture was concentrated to remove the solvent, the residue was dissolved in 10 ml of chloroform and washed with water (3 ml × 5 times). The organic layer was concentrated and the remaining residue was crystallized in ethanol to obtain 140 mg of the target compound (yield 65%).

Melting Point: 229 ~ 234 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ , δ ppm): 8.83 (1H, s), 7.84 (1H, d, J = 13.7Hz), 4.45 (4H, s), 4.30 (2H, q, J = 7.1Hz), 3.70 (4H, s), 3.62 (3H, s), 1.91 (9H, s), 1.46 (3H, t, J = 7.1 Hz).

Example 19

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

1-tert-butyl-6-fluoro-8-methoxy-7- {3,7-diazabicyclo [3,3,0] oct-1 (5) en-3-yl, prepared in Example 17. } -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 100 mg was dissolved in 5 ml of dimethylformamide, 65 mg of chloroacetone and 150 mg of potassium hydrogencarbonate were added, followed by stirring at 50 ° C for 6 hours. The solvent was removed under reduced pressure, dissolved in 10 ml of dichloromethane, washed with water, and the residue obtained by concentrating the organic layer was crystallized in ethanol to obtain 69 mg of the target compound (yield 60%).

Melting Point: 188 ~ 191 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.81 (1H, s), 7.82 (1H, d, J = 13.7 Hz), 4.47 (4H, s), 3.75 (4H, s), 3.65 (3H, s) , 3.51 (2H, s), 2.22 (3H, s), 1.90 (9H, s).

Example 20

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

117 mg (0.33 mmol) of 6,7-difluoro-1- (4-fluorophenyl) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3, 7-diazabicyclo [3,3,0] oct- (5) ene dihydrobromide 110 mg (0.40 mmol) and 1,8-diazabicyclo [5,4,0] undec-7- 180 mg of yen was dissolved in 2 ml of acetonitrile and refluxed for 5 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 115 mg of the target compound (yield 78%).

Melting Point: 179 ~ 182 ℃

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.80 (1H, s), 7.88 (1H, d, J = 13.7 Hz), 7.48 (2H, m), 7.29 (2H, m), 4.56 ( 4H, s), 4.27 (4H, s), 3.65 (3H, s).

Example 21

6-fluoro-1- (4-fluorophenyl) -8-methoxy-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

6,7-difluoro-1 (4-fluorophenyl) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 88 mg (0.25 mmol), 3-methyl 37 mg (0.298 mmol) and 1,8-diazabicyclo [5,4,0] undec-7-ene in -3,7-diazabicyclo [3,3,0] oct-1 (5) ene 46 mg was dissolved in 1.5 ml of acetonitrile and refluxed for 7 hours. The reaction mixture was left at room temperature overnight, and the resulting precipitate was filtered, washed with acetonitrile and crystallized in ethanol to give 86 g of the target compound (yield 75%).

Melting Point: 181 ~ 185 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.84 (1H, s), 7.82 (1H, d, J = 13.7 Hz), 7.47 (2H, m), 7.30 (2H, m), 4.45 (4H, s) , 3.70 (4H, s), 3.65 (3H, s), 2.65 (3H, s).

Example 22

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

1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 148 mg (0.501 mmol), 3-methyl-3,8 -Diazabicyclo [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 was dissolved in 5 ml of acetonitrile and refluxed for 7 hours. The reaction mixture was left at room temperature overnight, and the resulting precipitate was filtered, washed sequentially with acetonitrile, water and ethanol, and dried under reduced pressure to obtain 120 mg of the target compound (yield 58%).

Melting Point: 207 ~ 210 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.80 (1H, s), 7.80 (1H, d, J = 13.7 Hz), 4.42 (4H, s), 4.00 (1H, m), 3.61 (3H, s) , 3.11 (2H, s), 2.95 (2H, t, J = 5.3 Hz), 2.51 (3H, s), 2.31 (2H, br.s), 1.20-1.02 (4H, m).

Example 23

1-ethyl-6-fluoro-8-methoxy-7- {3-methyl-3,8-diazabicyclo [4,3,0] nona-1 (6) en-8-yl} -1, Preparation of 4-dihydro-4-oxoquinoline-3-carboxylic acid

1-ethyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 142 mg (0.501 mmol), 3-methyl-3,8- Diazabicyclo [4,3,0] nona-1 (6) ene dihydrobromide 180 mg (0.6 mmol) and 1,8-diazabicyclo [5,4,0] undec-7-ene 270 The mg was dissolved in 5 ml of acetonitrile and refluxed for 7 hours. The reaction mixture was left at room temperature overnight, and the resulting precipitate was filtered, washed sequentially with acetonitrile, water and ethanol, and dried under reduced pressure to obtain 151 mg of the target compound (yield 75%).

Melting Point: 177 ~ 180 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.82 (1H, s), 7.83 (1H, d, J = 13.7 Hz), 4.40 (4H, s), 4.26 (2H, q, J = 7 Hz), 3.60 ( 3H, s), 3.09 (2H, s), 2.94 (2H, t, J = 5.3Hz), 2.50 (3H, s), 2.30 (2H, br.s), 1.45 (3H, t, J = 7Hz) .

Example 24

1-tert-butyl-6-fluoro-8-methoxy-7- {3-methyl-3,8-diazabicyclo [4,3,0] nona-1 (6) en-8-yl}- Preparation of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1-tert-butyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 156 mg (0.510 mmol), 3-methyl-3, 8-diazabicyclo [4,3,0] nona-1 (6) ene dihydrobromide 180 mg (0.6 mmol) and 1,8-diazabicyclo [5,4,0] undec-7- 270 mg of ene was dissolved in 4 ml of acetonitrile and refluxed for 7 hours. The solvent was distilled off under reduced pressure, dissolved in 15 ml of dichloromethane, washed 5 times with 3 ml of brine, and the residue obtained by concentrating the organic layer was crystallized in ethanol to obtain 140 mg of the target compound (yield 65%).

Melting Point: 195 ~ 199 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.82 (1H, s), 7.82 (1H, d, J = 13.7 Hz), 4.42 (4H, s), 3.60 (3H, s), 3.10 (2H, s) , 2.91 (2H, t, J = 5.3 Hz), 2.54 (3H, s), 2.31 (2H, br.s), 1.91 (9H, s).

Example 25

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

1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 134 mg (0.501 mmol), 8-methyl-3,8 80 mg (0.579 mmol) of diazabicyclo [4,3,0] nona-1 (6) and 120 μl of 1,8-diazabicyclo [5,4,0] undec-7-ene are obtained in aceto. It was dissolved in 3 ml of nitrile and refluxed for 10 hours. The reaction mixture was left at room temperature overnight, and the resulting precipitate was filtered, washed with cooled acetonitrile, water and diethyl ether, and dried under reduced pressure to obtain 87 mg of the target compound (yield 45%).

Melting Point: 161 ~ 164 ℃

¹ H-NMR (CDCl ₃ , δ ppm): 8.85 (1H, s), 7.85 (1H, d, J = 12.1 Hz), 3.85 (7H, br.s), 3.62 (3H, s), 3.54 (2H, br.s), 2.83 (3H, s), 2.30 (2H, br.s), 1.25-1.10 (4H, m).

Claims (8)

Quinoline carboxylic acid derivatives represented by the following general formula (I) and their salts. In the above formula, R ₁ represents an alkyl group having 1 to 4 carbon atoms, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, a cycloalkyl group having 3 to 6 carbon atoms, a halogen substituted phenyl group, and R ₂ represents a hydrogen atom, a protecting group of a carboxyl group, or a pharmaceutical Useful metal cations or organic cations, R ₃ represents a hydrogen atom, a lower alkyl group of 1 to 4 carbon atoms, a hydroxyalkyl group, a cycloalkyl group or a nitrogen protecting group degradable in vivo, n is an integer of 1 or 2, m represents an integer of 1 to 3, Z represents a hydrogen atom, a halogen, an amino group or a methyl group and includes pharmaceutically useful acid addition salts and their hydrates when R ₂ is H. The quinoline car of claim 1, wherein R ₁ is an ethyl group, tert-butyl group, 2-fluoroethyl group, 2-hydroxyethyl group, cyclopropyl group, 4-fluorophenyl group, or 2,4-difluorophenyl group. Acid derivatives. The method of claim 1, wherein R ₂ is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a lower alkanoyloxy-lower alkyl group, a lower alkoxycarbonyloxy-lower alkyl group, a lower alkoxymethyl group, a di (lower alkyl) amino-lower A derivative of quinoline carboxylic acid which is an alkyl group, sodium ion, potassium ion, calcium ion, magnesium ion, ammonium ion, silver ion or tertiary or quaternary alkyl ammonium ion having 3 to 4 carbon atoms. The method according to claim 1, wherein R ₃ is a hydrogen atom, a methyl group, an ethyl group, 2-hydroxyethyl group, cyclopropyl group, formyl group, ethoxycarbonyl, ethoxycarbonylmethyl group, 2 or 3-oxoalkyl group or 4- Quinoline carboxylic acid derivatives which are methylene-5-methyl-1,3-dioxoren-2-ones. The quinoline carboxylic acid derivative according to claim 1, wherein Z is a hydrogen atom, a fluorine atom, an amino group or a methyl group. The compound represented by the following general formula (II) and the amine compound represented by the following general formula (III) or (IIIa) are heated to a temperature of 20 to 200 ° C. in a solvent in the presence of a base and represented by the following general formula (I). To prepare a quinoline carboxylic acid. In the above formulas, R ₁ , R ₂ , R ₃ and Z, n, m are each as defined above, and X represents a halogen atom selected from chlorine or bromine. The method for producing quinoline carboxylic acid according to claim 6, wherein the solvent is selected from water, alcohol, acetonitrile, pyridine, diphenylformamide or a mixture of one or more thereof. A method for preparing a quinoline carboxylic acid represented by the following general formula (I) by reacting the compound of the following general formula (IV) with a R ₃ donor in a solvent. In the above formulas, R ₁ , R ₂ , R ₃ and Z, n, m are as defined above, respectively.