KR960001721B1 - Novel quinolone carboxylic acid derivatives - Google Patents

Abstract

The quinolone carboxylic acid derivs. of formula (I) are prepared by reacting a quinolone carboxylic acid of formula (II) with an amine of formula (III) in the inert or basic solvent i.e. tetrahydrofuran, pyridine, ethanol, propanol, butanol, chloroform, dimethyl sulfoxide and/or acetonitrile at 50˜190deg. C for 1˜48hr. In the formulas, X is H or amino; Y is H or halogen; R1 is C1-4 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl or phenyl; R2 is C1-6 haloalkyl or H; W is halogen; Z is (a); R3, R4 and R5 are each H or C1-3 alkyl; P is H, -OR6, -SR7, -NR8R9 or C1-3 alkyl; R6 and R7 are each H or C1-3 alkyl; R8 and R9 are each H or C1-3 alkyl. The derivs. (I) have a strong bactericidal activity against gram positive bacteria, and are useful as antibacteria.

Description

Novel Quinolone Carboxylic Acid Derivatives

The present invention relates to a novel quinolone carboxylic acid derivative, and more particularly to a quinolone carboxylic acid derivative and a quinolone carboxylic acid derivative represented by the following structural formula (I) having a strong activity against Gram-positive bacteria It relates to salts.

Wherein X is a hydrogen atom or an amino group, Y is a hydrogen atom or a halogen atom, R ¹ is lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, 1 Or a phenyl group optionally substituted by two fluorine atoms, R ² is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and Z is Wherein R ³ , R ⁴ and R ⁵ are the same as or different from each other as a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and R ³ and R ⁴ are (n may form a ring such as 1 or 2), and P is a hydrogen atom or -OR ⁶ , -SR ⁷ , -NR ⁸ R ⁹ or an alkyl group having 1 to 3 carbon atoms, wherein R ⁶ and R ⁷ are Each is a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and R ⁸ and R ⁹ are the same as or different from each other as a hydrogen atom or a chain or cyclic alkyl group having 1 to 3 carbon atoms, respectively.

The antimicrobial activity of the quinolone carboxylic acid-based antimicrobial substance greatly depends on the kind of substituents introduced at the 7 position. Quinolone carboxylic acid derivatives having amino pyrrolidine or aminomethyl pyrrolidine substituents at their 7 positions are specified in European Patent Publication Nos. 183129, 207497 and 208210, and are known to be excellent in antibacterial activity.

The present inventors conducted a study of introducing an amine derivative having a substituted amidine group or a substituted imidazoline group as a substituent at the 7-position of a conventional quinolone carboxylic acid nucleus as a modification of the quinolone carboxylic acid in use at present. In particular, a novel compound having high antimicrobial activity against Gram-positive bacteria was synthesized, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide a novel quinolone carboxylic acid derivative compound which exhibits antimicrobial activity against various strains, in particular excellent antimicrobial activity against Gram-positive bacteria, and a pharmaceutically acceptable salt thereof.

Hereinafter, the present invention will be described in detail.

The present invention relates to a novel quinolone carboxylic acid derivative represented by the above formula (I), and examples of the Z group in the above formula (I) include the following ones.

3-amidinopyrrolidinyl, 3- (N, N-dimethylamidino) pyrrolidinyl, 3- (2-imidazolinyl) pyrrolidinyl, 3- [2- (N-methylimidazolinyl )] Pyrrolidinyl, 3- [2- (N-ethylimidazolinyl)] pyrrolidinyl, 3-hydroxy-4- (2-imidazolinyl) pyrrolidinyl.

In addition, specific examples of the Y group in the structural formula (I) include hydrogen, fluoro, chloro group, specific examples of the R1 group may be ethyl, fluoroethyl, vinyl, tertiary butyl, cyclopropyl, 4-fluoro A phenyl, a 2, 4- difluoro phenyl group, etc. are mentioned, As a specific example of R <2>, hydrogen, a methyl, an ethyl group, etc. are mentioned.

As such, the compound of formula (I) of the present invention is very useful as an antimicrobial agent as a compound exhibiting strong antimicrobial activity against various strains, especially Gram-positive bacteria.

Specific examples of the novel compound of formula (I) according to the present invention can be enumerated as follows. However, the present invention is not limited to the compounds described below.

1-cyclopropyl-6,8-difluoro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid

1-cyclopropyl-6-fluoro-8-chloro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid

1-cyclopropyl-5-amino-6,8-difluoro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-quinolinecarboxylic acid

1-cyclopropyl-6,8-difluoro-7- [3- (2-imidazolinyl) pyrrolidinyl] -1,4-dihydro-4-oxo-3-quinoline carboxylic acid

1-cyclopropyl-6,8-difluoro-7- {3- [2- (N-ethylimidazolinyl) pyrrolidinyl} -1,4-dihydro-4-oxo-3-quinolinecarr Acid

1- (2,4-difluorophenyl) -6,8-difluoro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid

1-cyclopropyl-6-fluoro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid

1-cyclopropyl-6,8-difluoro-7- [3-hydroxy-4- (2-imidazolinyl) pyrrolidinyl] -1,4-dihydro-4-oxo-3-quinoline Carboxylic acid

Looking at the preparation method of the compound of formula (I) according to the present invention, it can be prepared by reacting the quinolone carboxylic acid of the following formula (III) in an inert solvent or a basic solvent with the amine of the following formula (II). .

In the above formulas, X, Y, R ¹ , R ² and Z are each as defined above, W is a halogen atom, and R ³ , R ⁴ , R ⁵ and P are also as defined above.

Examples of suitable solvents used in the preparation process of the present invention include tetrahydrofuran, pyridine, ethanol, protanol, butanol, chloroform, dimethyl sulfoxide, dimethylformamide, water, acetonitrile, dioxane or mixtures thereof. have.

According to the present invention, when the solvent used in this process is not a basic solvent such as pyridine, it is preferable to add a base to the reaction mixture, and the base reacts with hydrogen fluoride generated in the reaction to promote completion of the reaction. As it is made, organic bases and inorganic bases can be used.

In the dimethylsulfoxide solvent, it is preferable to use 5 to 6 equivalents of the amine to be reacted, and 1,8-diazabicyclo [5, 4, 0] undes-7- is the preferred base in the acetonitrile solvent. N (DBU), triethylamine and mixtures thereof, preferably containing 1 to 3 equivalents of base.

In addition, such a method is usually more preferably prepared under atmospheric pressure at 50 to 190 ° C, the reaction time is prepared by reacting for 1 to 48 hours, and the produced product is separated by a conventional method.

For example, the resulting precipitate is filtered or water is added to the reaction mixture, the pH is adjusted to 7.0-7.4, the resulting precipitate is collected by filtration, washed with water or an organic solvent and the precipitate is dried. Can be separated, or the solvent is concentrated, and the precipitate produced in the alcohol solvent can be separated by filtration.

On the other hand, the compound of the formula (III) used in the preparation of the compound of the formula (I) of the present invention is known methods (European Patent Publication No. 78382, 106489, 113091, 131839, 153580). No. 154780, 202763, 221463, 235762, 350950, 360258).

In addition, the amine compound of the formula (II) is a novel compound useful for the preparation of the quinolone carboxylic acid derivative having an antimicrobial activity according to the present invention 1-benzyl-3-pyrrolidinol (Aldrich reagent), methyl 1-benzyl-2-pyrrolidone-3-carboxylic acid (J. Org. Chem. V. 26, 1519 (1961)), 1-benzyl-3-hydroxy-4-ethoxycarbonyl pyrrolidine (J. Org. Chem. V. 30, 740 (1965)) can be prepared via the following reaction.

In the above scheme, X is an alkylsulfonyloxy, arylsulfonyloxy or halide leaving group, n is 1 or 2, and R ³ , R ⁴ and R ⁵ are hydrogen or lower alkyl groups having 1 to 3 carbon atoms, respectively, or different.

Compound (A) may be obtained by converting a hydroxyl group into a suitable leaving group in the process of preparing the structural formulas (II) -1, (II) -2, and (II) -3. For example, methanesulfonylchloride or P-toluenesulfonylchloride can be reacted in the presence of a base (eg triethylamine, pyridine) or by reaction with thionylchloride or phosphorus halide.

In the reaction process, compound (B) may be obtained by reacting compound (A) with a metal cyanide (eg, KCN, NaCN), and compound (E) may react compound (D) with an appropriate reducing agent (eg borane ( borane)), and the compounds (C), (F) and (H) can be obtained by the reaction of various amines or their hydrochlorides with trialkylaluminum to compounds (B), (E) and (G). You can get it.

And the desired compounds (II) -1, (II) -2, (II) -3 are compounds (C), (F), and (H) that can be removed from the amine by known methods (e.g. palladium / hydrogen gas). Can be obtained by protection.

On the other hand, in the amine compound of the formula (II) when P = -OR ⁶ , -SR ⁷ , -NR ⁸ R ⁹ (where R ⁶ and R ⁷ is a lower alkyl group having 1 to 3 carbon atoms, R ⁸ and R ⁹ Silver may be the same or different as a chain or cyclic alkyl group having 1 to 3 carbon atoms) may be prepared through the following reaction.

Wherein n is 1 or 2, and R ⁵ is hydrogen or a lower alkyl group having 1 to 3 carbon atoms.

Here, compound (I) can be obtained by converting a hydroxyl group into a suitable leaving group, and compound (J) can be prepared by substitution reaction of compound (I) with an alkoxide, thioalkoxide or amine, and the desired compound ( II-4) can also be obtained by deprotecting the amine by a known method.

On the other hand, pharmaceutically acceptable acid addition salts of the novel compounds of formula (I) prepared as described above allow a solution or suspension of the free base of formula (I) to contain about 1 chemical equivalent of pharmaceutically. Prepared by treatment with acid as possible.

Here, conventional concentration and recrystallization methods are used for the separation of salts, and examples of suitable acids include acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzic acid, methanesulfonic acid, Cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc. are mentioned.

In addition, pharmaceutically acceptable cationic salts of the compounds of formula (I) are prepared by conventional methods from the corresponding acids, for example, can be prepared with about 1 equivalent molar base, and examples of cationic salts include Alkali metals (eg sodium or potassium), alkaline metals (eg magnesium or calcium), ammonium or organic amines (eg diethanolamine, N-methylglucaine or arginine) salts.

According to the present invention, the compound of the formula (I) and its pharmaceutically acceptable salts have been shown to be low in toxicity to experimental animals by oral administration, and are antibacterial agents having a wide range of effects useful for the treatment of bacterial infections. It turned out.

In order to elucidate the pharmacological usefulness of the compound of the formula (I) according to the present invention, the antimicrobial activity was performed on the representative compounds of the compound (I) of the present invention.

At this time, the test method of the antimicrobial test was carried out by the standard method of Japanese Chemotherpy Society (refer to Chemotherapy, Vol. 29, 76 ~ 79 (1981)), which is agar plate dilution method.

In addition, the test strain was continuously passaged three times or more (37 ℃, 18 hours) in Mueller-Hinton Agar (Mueller-Hinton Agar) to have the optimum activity, and then again this Mueller-Hinton broth (Mueller-Hinton broth) ) Was incubated for 18 hours at 37 ℃.

Muller-Hinton Hanton medium (100-0.002 µg / day) containing test compounds diluted to about 18 concentrations (CFU) of the culture solution per milliliter of this culture solution, and then diluted twice with the microbial inoculator. Ml) was inoculated at a concentration of 5 microliters.

Thereafter, the medium was incubated at 37 ° C. for 18 hours, and the agar plates inoculated by diluting stepwise two times were arranged in a row, and visually observed to determine the concentration of the antimicrobial material whose growth was inhibited. (10% sheep blood was added during subculture and 10% horse serum was used for incubation).

The 13 test strains used in the present invention were urinary tract infections, Sungheung fever, impetigo, purulent skin disease, intestinal bacterial infections, respiratory infections and pneumonia, and meningitis-inducing bacteria.

Gram-positive bacteria

Streptococcus pyogenes A308

2. Streptococcus pyogenes A77

3. Streptococcus faecium MD86

4. Staphylococcus aureus SG511

5. Staphylococcus aureus 285

6. Staphylococcus aureus 503

Gram-negative bacteria

7. Escherichia coli 055

8. Pseudomonas aeruginosa 1771M

9. Salmonella typhimurium

10.Klebsiella oxytoca 1082E

11.Klebsiella aerogenes 1522E

12. Enterobacter cloacae 99

13. Enterobacter cloacae 1321E

[Antibacterial Activity Test (µg / mL)]

NFLX = Norfloxacin

Typically, the compound of Example 1 was administered once orally to a group of male mice, and LD ₅₀ values were determined by the Litchfield-Wilcoxon method 10 days after administration. The result was LD ₅₀ (mg / kg)> 3000.

Hereinafter, the present invention will be described in detail with reference to Examples.

Reference Example 1

Preparation of 1-benzyl-3-[(methylsulfonyl) -oxy] pyrrolidine

After dissolving 7.1 g (0.04 mol) of 1-benzylpyrrolidine in 100 ml of dichloromethane, 6.2 ml (0.044 mol) of triethylamine were added and cooled to about -5 ° C. 3.4 ml (0.044 mol) of methanesulfonyl chloride are mixed with 20 ml of dichloromethane and added dropwise for 20 minutes. After stirring at room temperature for 10 hours, 100 ml of distilled water was added, extracted with an organic layer, and dried over MgSO ₄ . The solution was filtered, concentrated under reduced pressure, and the target product was separated using column chromatography (ethyl acetate).

Concentration of the separation solution under reduced pressure yields the compound as 9.7 g (yield = 86%) of oil.

¹ H NMR (ppm, CDCl ₃ ): 2.01 to 2.87 (m, 6H), 2.97 (s, 3H), 3.64 (s, 2H), 5.15 to 5.44 (m, 1H), 7.29 (s, 5H)

Reference Example 2

Preparation of 1-benzyl-3-cyanopyrrolidine

To 9.2 g (0.036 mol) of 1-benzyl-3-[(methylsulfonyl) -oxy] pyrrolidine, 5.3 g (0.11 mol) of sodium cyanide and 120 ml of anhydrous dimethylformamide were added, followed by stirring at 80 DEG C for 6 hours. Cool to room temperature. 60 ml of distilled water was added, 50 ml of diethyl ether was extracted three times, and the organic layer was washed three times with 50 ml of water. The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and the target product was separated using column chromatography (ethyl acetate). The separated solution was concentrated under reduced pressure to obtain 5.6 g (yield = 83%) of the compound as an oil.

¹ H-NMR (ppm, CDCl ₃ ): 1.98 to 2.30 (m, 2H), 2.54 to 3.04 (m, 5H), 3.61 (s, 2H), 7.28 (s, 5H)

Reference Example 3

Preparation of 1-benzyl-3-amidinopyrrolidine

To 0.66 g (0.012 mol) of ammonium chloride, 3 ml of anhydrous toluene was added, 6 ml (0.012 mol) of 2M trimethylaluminum toluene solution was added at 0 ° C. with a syringe, and stirred at room temperature for 1 hour.

1.12 g (0.006 mol) of 1-benzyl-3-cyanopyrrolidine is dissolved in 10 ml of toluene and then added to the solution and stirred at 80 ° C. for 10 hours. The reaction solution was cooled to room temperature, added to the silica gel-chloroform mixture, stirred for 10 minutes, filtered, and the filtrate was washed with 150 ml of methanol. Concentration of the filtrate under reduced pressure gave 0.87 g of the compound as a pale yellow solid (yield = 75%).

¹ HNMR (DMSO-d ⁶ / D ₂ O): 2.31 to 2.52 (m, 2H), 3.31 to 3.69 (m, 5H), 4.41 (s, 2H), 7.51 (s, 5H)

Reference Example 4

Preparation of 1-benzyl-3- (N, N-dimethylamidino) pyrrolidine

In the same manner as in Reference Example 3, the compound may be obtained as a pale yellow solid by using dimethylamine hydrochloride instead of ammonium chloride.

Yield = 61%

¹ H NMR (DMSO-d ⁶ / D ₂ O): 2.13 to 2.52 (m, 2H), 3.08 (s, 3H), 3.24 (s, 3H), 3.01 to 3.89 (m, 5H), 4.46 (s, 2H), 7.41 to 7.70 (m, 5H)

Reference Example 5

Preparation of 3-amidinopyrrolidine

0.78 g (0.004 mol) of 1-benzyl-3-amidinopyrrolidine was dissolved in 10 ml of ethanol, 0.1 g of 10% palladium-charcoal was added, the reaction was carried out under hydrogen gas for 16 hours, and the filtrate was concentrated under reduced pressure. 0.36 g (yield = 86%) of the compound is obtained in the form of an oil.

¹ H NMR (ppm, DMSO-d ⁶ / D ₂ O): 2.03 to 2.50 (m, 2H), 2.83 to 3.60 (m, 5H)

Reference Example 6

Preparation of 3- (N, N-dimethylamidino) pyrrolidine

1-benzyl-3- (N, N-dimethylamidino) pyrrolidine is reacted in the same manner as in Reference Example 5 to obtain the compound as a pale yellow solid.

Yield = 88%

¹ H NMR (ppm, D ₂ O): 2.14 to 2.62 (m, 2H), 3.11 (s, 3H), 3.20 (s, 3H), 3.08 to 4.01 (m, 5H)

Reference Example 7

Preparation of Methyl 1-benzylpyrrolidine-3-carboxylic Acid

11.65 g (0.05 mole) of methyl 1-benzyl-2-pyrrolidone-4-carboxylic acid was dissolved in 50 mL of anhydrous tetrahydrofuran, passed through nitrogen, and added to 75 mL (0.075 mole) of 1M borane-tetrahydrofuran complex. After refluxing for 2 hours and cooling, 10 ml of 50% aqueous methanol solution was added thereto, cooled, and extracted twice with 100 ml of diethyl ether. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. After separation using column chromatography (diethyl ether), the concentrate is concentrated under reduced pressure to yield 8.29 g (yield = 75%) of the compound as a pale yellow oil.

¹ H NMR (ppm, CDCl ₃ ): 1.93 to 2.20 (m, 2H), 2.47 to 3.08 (m, 5H), 3.61 (s, 2H), 3.64 (s, 3H), 7.31 (s, 5H)

Reference Example 8

Preparation of 1-benzyl-3- (2-imidazolinyl) pyrrolidine

Dissolve 1.44 g (0.024 mole) of ethylenediamine in 10 mL of anhydrous toluene, and slowly add 12 mL (0.024 mole) of 2M trimetalaluminum toluene solution at -10 DEG C with a syringe and stir at room temperature for 1 hour. 4.38 g (0.02 mol) of methyl 1-benzylpyrrolidine-3-carboxylic acid dissolved in 10 ml of toluene are added to the reaction at room temperature, and then refluxed for 4 hours. The reaction mixture is cooled to room temperature, 2 ml of distilled water is added, stirred for 0.5 hour, methylene chloride and methanol are added and filtered. The filtrate was concentrated under reduced pressure to give 2.65 g (yield = 61%) of the compound as a yellow oil.

¹ H NMR (ppm, DMSO-d ⁶ / D ₂ O): 1.86-2.20 (m, 2H), 2.34-2.98 (m, 5H), 3.61 (s, 2H), 7.35 (s, 5H)

Reference Example 9

Preparation of 1-benzyl-3- [2- (N-ethylimidazolinyl)] pyrrolidine

In the same manner as in Reference Example 8, the compound was obtained as a yellow oil by reaction with N-ethylethylenediamine instead of ethylenediamine.

Yield = 51%

¹ H NMR (ppm, CDCl ₃ ): 1.09 (t, 3H), 1.89 to 2.14 (m, 2H), 2.38 to 3.01 (m, 5H), 3.27 (q, 2H), 3.45 (s, 4H), 3.64 (s, 2H), 7.30 (s, 5H)

Reference Example 10

Preparation of 3- (2-imidazolinyl) pyrrodine

Dissolve 1.52 g (0.007 mol) of 1-benzyl-3- (2-imidazolinyl) pyrrolidine in methanol solution, add 0.3 g of 10% palladium-charcoal, react for 16 hours under hydrogen, and then filter. Then, the filtrate was concentrated under reduced pressure to obtain 0.64 g of the compound as a yield (88%).

¹ H NMR (ppm, CDCl ₃ ): 1.84 to 2.20 (m, 2H), 2.58 to 3.54 (m, 7H), 3.45 (s, 4H)

Reference Example 11

Preparation of 3- [2- (N-ethylimidazolinyl)] pyrrolidine

1-benzyl-3- [2- (N-ethylimidazolinyl)] pyrrolidine is reacted by the method of Reference Example 10 to obtain the compound as a yellow oil.

Yield = 91%

¹ H NMR (ppm, D ₂ O): 1.01 to 1.46 (t, 3H), 2.01 to 2.48 (m, 2H), 2.98 to 3.56 (m, 9H), 3.84 to 4.21 (q, 2H)

Reference Example 12

Preparation of 1-benzyl-3-hydroxy-4- (2-imidazolinyl) pyrrolidine

The compound is obtained as a tan oil using 1-benzyl-3-hydroxy-4-ethoxycarbonylpyrrolidine and ethylenediamine in the same manner as in Reference Example 8.

Yield = 60%

¹ H NMR (ppm, CDCl ₃ / D ₂ O): 2.30 to 3.21 (m, 5H), 3.50 to 3.72 (m, 6H), 4.20 to 4.41 (m, 1H), 7.28 (s, 5H)

Reference Example 13

Preparation of 3-hydroxy-4- (2-imidazolinyl) pyrrolidine

The compound is obtained as a tan oil in the same manner as in Reference Example 10 using 1-benzyl-3-hydroxy-4- (2-imidazolinyl) pyrrolidine.

Yield = 91%

¹ H NMR (ppm, CDCl ₃ / D ₂ O): 2.46 to 3.30 (m, 5H), 3.56 to 4.01 (m, 4H), 4.21 to 4.52 (m, 1H)

Example 1

Preparation of 1-cyclopropyl-6,8-difluoro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid

To 0.2 g (0.7 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 0.4 g of 3-amidinopyrrolidine ( 3.5 mmol) and 5 ml of dimethyl sulfoxide are added, followed by reaction at 110 ° C. for 6 hours. After cooling to room temperature, 10 ml of distilled water is added and adjusted to pH 7.0-7.5 with 30% sulfuric acid.

The precipitated crystals were filtered off and washed with diethyl ether and acetone. The crystals are dried to give 0.16 g (yield = 60%) of the compound as a white solid.

m.p. : 255 to 260 ° C

¹ H NMR (ppm, NaOD / D ₂ O): 0.89 to 1.24 (m, 4H), 1.83 to 2.24 (m, 2H), 2.86 to 3.21 (m, 1H), 3.30 to 3.98 (m, 5H), 7.40 (dd, 1H), 8.40 (s, 1H)

Example 2

Preparation of 1-cyclopropyl-6-fluoro-8-chloro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid

In the same manner as in Example 1 using 1-cyclopropyl-6,7-difluoro-8-chloro1, 4-dihydro-4-oxo-3-quinoline carboxylic acid and 3-amidinopyrrolidine The compound is obtained as an off-white solid.

m.p. : 250 to 255 ° C (decomposition)

¹ H NMR (ppm, NaOD / D ₂ O): 0.90 to 1.21 (m, 4H), 1.82 to 2.20 (m, 2H), 2.80 to 3.24 (m, 1H), 3.30 to 4.01 (m, 5H), 7.41 (dd, 1H), 8.41 (s, 1H)

Example 3

Preparation of 1-cyclopropyl-6-fluoro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid

The compound was prepared in the same manner as in Example 1 using 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and 3-amidinopyrrolidine. Obtained as an off-white solid.

m.p. : 270-274 ° C (decomposition)

¹ H NMR (ppm, NaOD / D ₂ O): 0.90 to 1.21 (m, 4H), 1.82 to 2.26 (m, 2H), 2.83 to 3.21 (m, 1H), 3.30 to 3.96 (m, 5H), 6.98 (d, 1H), 7.40 (d, 1H), 8.41 (s, 1H)

Example 4

1- (2,4-difluorophenyl) -6,8-difluoro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid Manufacture

Using 1- (2,4-difluorophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and 3-amidinopyrrolidine In the same manner as in Example 1, the compound is obtained as an off-white solid.

m.p. : 265 ~ 270 ℃

¹ H NMR (ppm, NaOD / D ₂ O): 1.84 to 2.40 (m, 2H), 2.84 to 3.12 (m, 1H), 3.28 to 4.01 (m, 4H), 6.90 to 7.84 (m, 4H), 8.16 (s, 1H)

Example 5

Preparation of 1-cyclopropyl-6,8-difluoro-7- [3- (2-imidazolinyl) pyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid

3- (2-imidazolinyl) pi in 0.2 g (0.7 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid 0.49 g (3.5 mmol) of lollidine and 5 ml of pyridine were added and then refluxed for 8 hours. After pyridine was concentrated under reduced pressure, 10 ml of ethanol was added thereto, followed by stirring at room temperature for 30 minutes. The precipitated crystals were filtered off, washed with ethanol and diethyl ether and dried to yield 0.17 g (yield = 60%) of the compound as a pale yellow solid.

¹ H NMR (ppm, NaOD / D ₂ O): 0.82 to 1.32 (m, 4H), 1.76 to 2.41 (m, 2H), 2.68 to 4.01 (m, 6H), 3.55 (s, 4H), 7.41 (dd) , 1H), 8.40 (s, 1H)

Example 6

1-cyclopropyl-6,8-difluoro-7- {3- [2- (N-methylimidazolinyl) pyrrolidinyl]}-1,4-dihydro-4-oxo-3-quinoline Preparation of Carboxylic Acids

1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and 3- [2- (N-ethylimidazolinyl)] pyrrolidine To obtain the compound as a pale yellow solid in the same manner as in Example 5.

¹ H NMR (ppm, NaOD / D ₂ O): 0.88-1.32 (m, 7H), 1.84-2.26 (m, 2H), 2.87-2.38 (m, 6H), 3.53 (s, 4H), 4.02 (q , 2H), 7.40 (dd, 1H), 8.41 (s, 1H)

Example 7

Preparation of 1-cyclopropyl-5-amino-6,8-difluoro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid

Example 5 using 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and 3-amidinopyrrolidine In the same manner the compound is obtained as a pale yellow solid.

m.p. : 260 to 264 ° C (decomposition)

¹ H NMR (ppm, NaOD / D ₂ O): 0.91 to 1.24 (m, 4H), 1.84 to 2.24 (m, 2H), 2.81 to 3.30 (m, 1H), 3.30 to 4.10 (m, 5H), 8.22 (s, 1H)

Example 8

1-cyclopropyl-6,8-difluoro-7- [3-hydroxy-4- (2-imidazolinyl) pyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline Preparation of Carboxylic Acids

1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and 3-hydroxy-4- (2-imidazolinyl) pyrrolidine The compound is obtained as an off-white solid in the same manner as in Example 5.

¹ H NMR (ppm, NaOD / D ₂ O): 0.84-1.26 (m, 4H), 2.30-3.24 (m, 5H), 3.30-4.01 (m, 5H), 4.10-4.34 (m, 1H), 7.41 (dd, 1H), 8.41 (s, 1H)

Claims (8)

A novel quinolone carboxylic acid derivative represented by the following structural formula (I) and a pharmaceutically acceptable salt thereof. Wherein X is a hydrogen atom or an amino group, Y is a hydrogen atom or a halogen, R ¹ is lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms, cycloalkyl of 1 to 3 carbon atoms, 1 or A phenyl group optionally substituted by two fluorine atoms, R ² is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and Z is to be. Wherein R ³ , R ⁴ and R ⁵ are hydrogen or a lower alkyl group having 1 to 3 carbon atoms, each being the same or different and R ³ and R ⁴ are may form a ring such as (n = 1,2), P is hydrogen or -OR ⁶ , -SR ⁷ , -NR ⁸ R ⁹ , an alkyl group having 1 to 3 carbon atoms, R ⁶ and R ⁷ are hydrogen or A lower alkyl group having 1 to 3 carbon atoms and R ⁸ and R ⁹ are the same or different as hydrogen or a chain or cyclic alkyl group having 1 to 3 carbon atoms, respectively. The quinolone carboxylic acid derivative according to claim 1, wherein R ² is hydrogen. The quinolone carboxylic acid derivative according to claim 1, wherein R ¹ is cycloflophyll, 2,4-difluorophenyl. The quinolone carboxylic acid derivative according to claim 1, wherein Y is hydrogen, fluoro or chloro. The compound of formula (I) according to claim 1, wherein the compound of formula (I) is 1-cyclopropyl-6,8-difluoro-7- (3-amidino pyrrolidinyl) -1,4-dihydro-4-oxo- 3-quinoline carboxylic acid, 1-cyclopropyl-6-fluoro-8-chloro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid , 1-cyclopropyl-5-amino-6,8-difluoro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 1- Cyclopropyl-6,8-difluoro-7- [3- (2-imidazolinyl) pyrrolidinyl] -1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 1-cyclo Propyl-6,8-difluoro-7- {3- [2- (N-ethylimidazolinyl)] pyrrolidinyl} -1,4-dihydro-4-oxo-3-quinoline carboxylic acid , 1- (2,4-difluorophenyl) -6,8-difluoro-7- (3-amidinopyrrolidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxyl Acid, 1-cyclopropyl-6-fluoro-7- (3-amidinopyrrolidi Nyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 1-cyclopropyl-6,8-difluoro-7- [3-hydroxy-4- (2-imidazoli Nil) pyrrolidinyl] -1,4-dihydro-4-oxo-3-quinoline carboxylic acid and a quinolone carboxylic acid derivative selected from the group consisting of pharmaceutically acceptable salts thereof. A method for producing a novel quinolone carboxylic acid derivative represented by the following structural formula (I) by reacting a quinolone carboxylic acid represented by the following structural formula (III) with an amine represented by the following structural formula (II). Wherein X is a hydrogen atom or an amino group, Y is a hydrogen atom or a halogen, R ¹ is lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms, cycloalkyl of 1 to 3 carbon atoms, 1 or A phenyl group optionally substituted by two fluorine atoms, R ² is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, W is a halogen, and Z is to be. Wherein R ³ , R ⁴ and R ⁵ are hydrogen or a lower alkyl group having 1 to 3 carbon atoms, each being the same or different and R ³ and R ⁴ are and (n = 1, 2) to form a ring, P is hydrogen or -OR ⁶ , -SR ⁷ , -NR ⁸ R ⁹ , an alkyl group having 1 to 3 carbon atoms, R ⁶ and R ⁷ is hydrogen or A lower alkyl group having 1 to 3 carbon atoms and R ⁸ and R ⁹ are the same or different as hydrogen or a chain or cyclic alkyl group having 1 to 3 carbon atoms, respectively. Z in claim 1 Phosphorus quinolone carboxylic acid derivatives, wherein R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen or lower alkyl groups having 1 to 3 carbon atoms, each having the same or different values. An amine compound represented by the following structural formula (II) which is useful for preparing a quinolone carboxylic acid derivative having antibacterial activity. Wherein R ³ , R ⁴ and R ⁵ are the same as or different from each other as hydrogen or a lower alkyl group having 1 to 3 carbon atoms and R ³ and R ⁴ are and may form a ring such as (n = 1, 2), which is —OR ⁶ , —SR ⁷ , —NR ⁸ R ⁹ , an alkyl group having 3 to 3 carbon atoms, and R ⁶ and R ⁷ hydrogen or lower having 1 to 3 carbon atoms It is an alkyl group, R <^8> and R <^9> is hydrogen or a C1-C3 linear or cyclic alkyl group, respectively, same or different.