KR930006162B1 - Novel quinolone compounds - Google Patents

Abstract

Quinolone derivs. of formula (I) and their salts are new. In (I), X=N or C-Y; Y=H,F,Cl, methoxy or methyl; Z=H, halogen or amino; R1=C1-4 alkyl, haloalkyl, hydroxyalkyl or alkenyl, C3-6 cycloalkyl, fluoro-substd. phenyl, X-O (or S) CH2CH(CH3)-N, etc.; R2=H or a cation; R3=H or lower alkyl; R4 and R5 each = H, lower alkyl, cycloalkyl or OH; m = 1 or 2. Also claimed is the prepn. of (I) which comprises a condensation reaction of the cpd. of formula (II) and the cpd. of formula (III) at 20-180 deg.C for 1-12 hr(s). The cpds. (I) have a good antibacterial activity.

Description

Novel Quinolone Compounds

The present invention is in excess of the novel quinolone compounds and salts thereof represented by the following general formula (I) having antibacterial activity.

Wherein X represents a nitrogen atom or CY, wherein Y represents a transport atom, a fluorine, a chlorine atom, a methoxy group or a methyl group, Z represents a hydrogen atom, a halogen atom or an amino group, and R ₁ represents 1 to 4 carbon atoms. An alkyl group, haloalkyl group, hydroxyalkyl group or akenyl group having a dog, a cycloalkyl group or a fluorine-substituted phenyl group having 3 to 6 carbon atoms, or XO (or S) CH which is closed at the X position to form a thiazole or oxazole ring ₂ CH (CH ₃ ) -N, etc., R ₂ represents a hydrogen atom or a cation useful as a drug, R ₃ represents a hydrogen atom or a lower alkyl group, R ₄ and R ₅ are the same as or different from each other hydrogen atom, Lower alkyl group, chloroalkyl group or hydroxyl group, m being an integer of 1 or 2.

Since nalidixic acid was introduced in 1963 as a therapeutic agent for urethritis, much research has been conducted on the invention of quinoline-based antimicrobial agents having superior antibacterial activity and broad antimicrobial spectrum. As a result, norfloxacin and enoxacin Ciprofloxacin and Ofloxacin have been developed and are currently commercially available, and all of these compounds have a structure having a piperazine group.

However, these conventional compounds show excellent antimicrobial spectrum, but not only have a significantly lower antimicrobial activity against Gram-positive bacteria, but also have been reported to express resistance equally in recent years, and thus development of new antimicrobial agents is required.

Accordingly, an object of the present invention is to provide a quinolone compound of a novel structure having a stronger antimicrobial action and a broader antimicrobial spectrum than before.

Hereinafter, the present invention will be described in detail. The present invention relates to novel pyrrolidinyl quinolone compounds represented by the general formula (I) and salts thereof.

According to the present invention, in the general formula (I), when Z is a halogen atom, it is a chlorine or fluorine atom, preferably a fluorine atom, and when R ₁ is an alkyl group having 1 to 4 carbon atoms, it is methyl, ethyl, n- Propyl, isopropyl or tert-butyl, preferably an ethyl or tert-butyl group, and a haloalkyl group having 1 to 4 carbon atoms, preferably a fluoroalkyl group having 2 to 4 carbon atoms, particularly preferably 2- In the case of a fluoroethyl group, a hydroxyalkyl group is preferably a hydroxyalkyl group having 2 to 4 carbon atoms, suitably a 2-hydroxyethyl group and a cycloalkyl group having 3 to 6 carbon atoms, preferably cyclopropyl. , when a fluorine-substituted phenyl, one or two fluorine-substituted paenil are preferred, and refers to, for example phenyl and phenyl or 2,4-difluoro-4-fluoro, R ₂ is useful as a drug If the cation, it represents an alkali metal or is preferably calcium or magnesium, sodium, potassium, an alkaline earth metal cation, for example, a cation of an organic base, a tertiary or quaternary C ₁ ~ C ₄ alkyl ammonium cation, R _{When a trivalent} lower alkyl group is represented, it is a methyl group, an ethyl group, and isopropyl group, Preferably it is a methyl group, and when R <_4> or R <_5> is a lower alkyl group, it represents a methyl group and an ethyl group, and when it is a cyclo alkyl group, a cyclopropyl group is preferable.

The compound of the general formula (I) of the present invention as described above is a salt of the compound represented by the following general formula (II) and the amine compound represented by the following general formula (III) or the amine compound represented by the general formula (IIIa). Prepared by condensation reaction in a non-reactive solvent in the presence of a base.

In the above formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , m, Z, X are as defined in the general formula (I), respectively, L is a halogen group, preferably as a divalent group. Represents a halogen atom selected from fluorine, chlorine and bromine, or an alkylsulfonyl or paratoluene sulfonyl group having 1 to 4 carbon atoms, preferably a tosyl group or ethylsulfonyl group, A represents hydrochloric acid, bromine, sulfuric acid, phosphoric acid, Acid selected from trifluoroacetic acid and methanesulfonic acid.

As the non-reactive solvent used in the condensation reaction in the present invention, acetonitrile, detrahydrofuran, ethanol, chloroform, dimethyl sulfoxide, dimethylformamide, pyridine, picoline or water is used, and among them, acetonitrile is used. desirable.

In addition, an excess of free amine of general formula (III) is used to neutralize the acid generated during the condensation reaction, or alternatively, carbonate of an alkali metal or alkaline earth metal, that is, sodium carbonate (or potassium carbonate), sodium hydrogen carbonate ( Or inorganic bases such as potassium hydrogen carbonate), triethylamine, diisopropylethylamine, pyridine, picoline, especially DBU (1,8-diazabicyclo [5,4,0] undec-7-ene) Organic bases, such as these, are used individually or in mixture.

According to the invention, the condensation reaction can be carried out in a wide temperature range, that is, from room temperature to 180 ℃, preferably at the breaking point of the solvent used, the reaction time is 1 to 10 hours It is suitable.

On the other hand, the general formula (II) compound used as a starting material in the present invention is well known in the field of quinolone antibacterial research, it can be prepared by a known method according to the following references. J. P. Sanchez et al., J. Med. Chem. 31, 983 (1988), J. M. Domacala et al., J. Med. Chem. 31,503 (1988), J. Michumoto et al., J. Heterocycl. Chem. 21,673 (1984).

In addition, the amine compound of general formula (III) or general formula (IIIa) to be used as a starting material is a novel compound, and 1-benzyl-3-pyrrolidinone (or 1-benzyl-3-piperidinone) Witting reaction with ethyl phosphonoacetate or ethyl bromoacetate triphenylphosphine salt to make a compound having an exo double bond, and after changing the benzyl protecting group to an ethoxycarbonyl protecting group, diisobutyl aluminum hydride (Dibal-H) was used to reduce the ester to alcohol, and then the alcohol compound was converted to a methanesulfonyl derivative, then substituted with a suitable amine, and then removed with a nitrogen protecting group by alkali or acid decomposition. III) or a general formula (IIIa) compound can be obtained. The detailed manufacturing method for such a compound of general formula (III) and (IIIa) follows the preparation example described next.

The general formula (II) and the general formula (III) or (IIIa) compound thus obtained are preferably reacted using a 1: 1 equivalent ratio or an excess of the general formula (III) or (IIIa) compound.

Specific examples of the preferred compounds for the compounds of the general formula (I) according to the present invention prepared as described above are as follows.

1-cyclopropyl-6,8-difluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3- Carboxylic acid, 1-cyclopropyl-6,8-difluoro-7- {3- (trans-methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4 Oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7- {3- (cis-methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 6,8-difluoro-1-ethyl-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-tert-butyl-6,8-difluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidine -1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 9-fluoro-3 (S) -methyl-10- {3-cis-methylaminomethylmethylene) -1 -Pyrrolidin-1-yl} -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] -1,4-benzooxazine-6-carboxylic acid, 1 -Cyclopropyl-6-fluoro-7- {3- (meth Tylaminomethylmethylene) -1-pyrrolidin-1-yl} -4-oxo-1,8-naphthyridine-3-carboxylic acid, 1-ethyl-6-fluoro-7- {3- ( Methylaminomethylmethylene) -1-pyrrolidin-1-yl} -4-oxo-1,8-naphthyridine-3-carboxylic acid, 1- (2,4-difluorophenyl) -6- Fluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -4-oxo-1,8-naphthyridine-3-carboxylic acid, 1-ethyl-6- Fluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-tert-butyl- 6-fluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 6,8- Difluoro-1- (4-fluorophenyl) -7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3 -Carboxylic acid, 1-cyclopropyl-6-fluoro-8-methoxy-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro- 4-oxoquinoline-3-carboxylic acid, 5-amino-1- Cyclopropyl-6,8-difluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxyl Acid, 1- (2-fluoroethyl) -6-fluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxo Quinoline-3-carboxylic acid, 1- (2-fluoroethyl) -6-fluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -4-oxo- 1,8-naphthyridine-3-carboxylic acid, 6,8-difluoro-1- (2-fluoroethyl) -7- {3- (methylaminomethylmethylene) -1-pyrrolidine- 1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 8-chloro-6-fluoro-1- (2-fluoroethyl) -7- {3- (methylamino Methylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 8-chloro-1-cyclopropyl-6-fluoro-7- { 3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 8-chloro-1 ethyl-6-fluoro- 7- {3- (methylamino Thylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-tert-butyl-8-chloro-6-fluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 8-chloro-1- (4-fluoro Phenyl) -6-fluoro-7- {3- (methylaminomethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1- Cyclopropyl-6,8-difluoro-7- {3- (methylaminomethylmethylene) -1-piperidin-1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxyl Acid, 1-cyclopropyl-8-chloro-6-fluoro-7- {3- (methylaminomethylmethylene-1-piperidin-1-yl} -1,4-dihydro-4-oxoquinoline- 3-carboxylic acid, 1-cyclopropyl-6-fluoro-8-methoxyl-7- {3- (methylaminomethylmethylene) -1-piperidin-1-yl} -1,4-dihydro 4-oxoquinoline-3-carboxylic acid, 5-amino-6,8-difluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4 -Dihydro-4-jade Quinoline-3-carboxylic acid, and lactic acid, hydrochloric acid, asbestos Colvin acid salt of the compound.

An acid or base salt of formula (I) is produced by dissolving a compound of formula (I) in a haloalkane solvent such as chloroform and methylene chloride and a mixed solvent such as methanol and ethanol and adding the selected acid with a suitable solvent such as alcohol. Precipitation is taken or the solvent is removed to prepare the desired compound. Acids used in the acid addition salt of the target compound include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, methanesulfonic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, citric acid, paratoluenesulfonic acid, ascorbic acid, glutamic acid, etc. This is available.

Hereinafter, the present invention will be described in detail with reference to Examples. Here, the preparation example shows a preparation example of the general formula (III) as a starting material, and the present invention is not limited by this example.

[Production Example 1]

Preparation of 1-benzyl-3- (ethoxycarbonylmethylene) -1-pyrrolidine

4.24 g of sodium hydride (NaH, 55%) was added to 130 ml of tetrahydrofuran, cooled to -20 ° C under nitrogen stream, and 19.8 g (88.39 mmol) of triethylphosphonoacetate was added thereto, followed by stirring at room temperature, to obtain a clear solution. When 14.2 g (81.14 mmol) of N-benzyl-3-pyrrolidone was dissolved in 30 ml of tetrahydrofuran, a solution was added and stirred overnight at room temperature. The reaction mixture was diluted with 250 ml of ethyl acetate, washed with brine (100 ml × 3 times), dehydrated and concentrated with anhydrous forget-me-not and separated and purified by silica gel column to obtain 16.6 g of the target compound (yield 83.5%). .

Solvent; Hexane: ethyl acetate (3: 1)

¹ H-NMR (CDCl ₃ , δ ppm): 7.28 (5H, m), 5.68 (1H, m), 4.07 (2H, q, J = 7.2 Hz), 3.61 (3H, m), 3.17 (1H), 2.91 (1H, t, J = 6.8 Hz), 2.64 (1H, t, J = 6.8 Hz), 2.55 (2H, s), 1.19 (3H, m).

[Production Example 2]

Preparation of 1-ethoxycarbonyl-3- (ethoxycarbonylmethylene) -1-pyrrolidine

16.5 g (67.34 mmol) of 1-benzyl-3- (ethoxycarbonylmethylene) -1-pyrrolidine was dissolved in 40 ml of benzene, and 40 ml of ethyl chloroformate was added and refluxed for 4 hours. The solvent and excess reagent were removed under reduced pressure, and the residue was separated and purified through silica gel column chromatography to obtain 11.9 g of the target compound (yield 77.8%).

Solvent; Hexane: ethyl acetate (3: 1)

¹ H-NMR (CDCl ₃ , δ ppm): 5.77 (1H, m), 4.41 (1H, br.s), 4.11 (5H, m), 3.51 (2H, m), 3.07 (1H, br.s), 2.70 (1H, t, J = 7.1 Hz), 1.21 (6H, m).

[Manufacture example 3]

Preparation of 1-ethoxycarbonyl-3- (hydroxymethylmethylene) -1-pyrrolidine

18.3 g (80.61 mmol) of 1-ethoxycarbonyl-3- (ethoxycarbonylmethylene) -1-pyrrolidine was dissolved in 120 ml of toluene, cooled to -78 ° C under nitrogen stream, and diisobutylaluminum hydride ( 20 mL, 111.26 mmol) was added slowly. After stirring for 3 hours at the same temperature and stirred for 15 hours at -20 ℃, the reaction was stopped with 50 ml of ethyl acetate and water, filtered and the filtrate was concentrated and purified by silica gel column chromatography.

Solvent; Hexane: ethyl acetate (5: 1 → 2: 1 → 1: 1 → 1: 2 → 1: 3)

5 g of a starting material was collected, and a trans body: 1.2 g, a cis body: 0.8 g, and a trans body cis body 1.27 g were obtained (yield 21%).

MS m / z (rel. Int.%): 185 (M ⁺ , 10), 167 (100), 156 (37), 154 (85), 140 (18), 126 (30).

¹ H-NMR (CDCl ₃ , δ ppm): transcis body; 5.58 (1H, m), 4.13 (4H, m), 4.06 (2H, br.s), 3.52 (2H, m), 2.58 (2H, br.s), 1.26 (3H, t, J = 6.8㎐) .

Transbody; 5.58 (1H, m), 4.13 (4H, m), 4.01 (2H, br.s), 3.46 (2H, br.q, J = 7.5 ㎐), 2.67 (2H, br.s), 1.26 (3H, t, J = 7.2 Hz).

Sheath; 5.60 (1H, m), 4.10 (4H, m), 4.00 (2H, br.s), 3.52 (2H, br.q, J = 6.1㎐), 2.59 (2H, br.s), 1.28 (3H, t, J = 7.1 ms).

[Production Example 4]

Preparation of 1-ethoxycarbonyl-3- (methylaminomethylmethylene) -1-pyrrolidine

1.06 g (5.72 mmol) of 1-ethoxycarbonyl-3- (hydroxymethylmethylene) -1-pyrrolidine was dissolved in 25 ml of methylene chloride, 2 ml of triethylamine was added, cooled to -10 ° C, and methanesulfonyl A dilution of 0.97 mL of chloride in 50 mL of methylene chloride was slowly added. After stirring for 2 hours at -5 ℃ or less, 5 ml of methylene chloride was added and washed with water (20 ml x 2). The organic layer was dehydrated with anhydrous forget-me-not and concentrated in 2 ml of methanol, and 5 ml of 40% aqueous methylamine solution was added. It was added and stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and the remaining material was purified by silica gel column chromatography to obtain 600 mg of the target compound (yield 53%).

Column solvent; Chloroform: Methanol: Triethylamine (50: 1: 1.5 → 40: 1: 1.5 → 30: 1: 1.5)

MS m / z (rel. Int.%): 198 (M ⁺ , 3), 167 (100), 153 (10), 139 (18), 122 (8), 108 (35), 94 (30).

¹ H-NMR (CDCl ₃ , δ ppm): 5.55 (1H, m), 4.15 (2H, m), 4.04 (2H, br.s), 3.50 (2H, m), 3.43,3.33 (2H, d, d , J = 6.2 Hz), 2.61 (2H, br.s), 2.50,2.52 (3H, two singlet), 1.25 (3H, m).

Production Example 5

Preparation of 3- (methylaminomethylmethylene) -1-pyrrolidine

550 mg (2.77 mmol) of 1-ethoxycarbonyl-3- (methylaminomethylmethylene) -1-pyrrolidine was dispersed in 10 ml of distilled water, 520 mg (13 mmol) of sodium hydroxide was added thereto, and the mixture was refluxed for 2.5 hours. The reaction mixture was cooled to room temperature and salt was added to make a saturated solution. The mixture was extracted with methylene chloride (20 mL × 6). The organic layer was dehydrated with anhydrous forget-me-not and concentrated at 40 ° C. or lower to obtain 320 mg of the target compound (yield 91%). .

MS m / z (rel. Int.%): 126 (M ⁺ , 3), 95 (100), 82 (25), 68 (20).

¹ H-NMR (CDCl ₃ , δ ppm): 5.42 (1H, m), 3.48 (2H, m), 3.18, 3.15 (2H, d, d, J = 6.0 Hz), 3.02, 2.96 (2H, t, t , J = 6.8 Hz), 2.42,2.41 (3H, s, s), 2.36 (2H, m).

[Manufacture example 6]

Preparation of 1-ethoxycarbonyl-3- (trans-methylaminomethylmethylene) -1-pyrrolidine

555 g (3 mmol) of 1-ethoxycarbonyl-3- (trans-hydroxymethylmethylene) -1-pyrrolidine was dissolved in 10 ml of methylene chloride, cooled to -20 ° C, and 1 ml (7.12 mmol) of triethylamine was added. After diluting 0.51 ml (6.62 mmol) of methanesulfonyl chloride in 3 ml of methylene chloride, the reaction mixture was stirred for 1 hour at ice water temperature. Dilute to 20 ml of saturated brine, extract with methylene chloride, combine (20 ml x 4), dehydrate with anhydrous forget-me-not and dissolve the residue in 2 ml of methanol, cool to ice water, and add 2.5 ml of 40% aqueous methylamine solution. Stirred at room temperature for 16 hours. The residue obtained by concentrating the reaction mixture was purified by silica gel column to obtain 268 mg of the target compound (yield 45%).

¹ H-NMR (CDCl ₃ , δ ppm): 5.47 (1H, m), 4.15 (2H, q, J = 7.1 μs), 3.98 (2H, br.s), 3.55 (2H, br.q, J = 6.1 I), 3.21 (2H, d, J = 6.9 kPa), 2.56 (2H, br.t), 2.42 (3H, s), 1.26 (3H, t, J = 7.1 kPa).

[Manufacture example 7]

Preparation of 3- (trans-methylaminomethylmethylene) -1-pyrrolidine

250 mg (1.26 mmol) of 1-ethoxycarbonyl-3- (trans-methylaminomethylmethylene) -1-pyrrolidine was suspended in 6 ml of distilled water, 300 mg of sodium hydroxide was added thereto, and the mixture was refluxed for 2.5 hours. The reaction mixture was cooled to room temperature, extracted with methylene chloride (20 mL × 5), dehydrated with anhydrous forget-me-not and concentrated at 40 ° C. or lower to obtain 128 mg of the target compound (yield 80%).

¹ H-NMR (CDCl ₃ , δ ppm): 5.40 (1H, m), 3.47 (2H, br.s), 3.14 (2H, d, J = 6 Hz), 3.00 (2H, t, J = 6.9 Hz) , 2.40 (3H, s), 2.36 (2H, m).

[Manufacture example 8]

Preparation of 1-ethoxycarbonyl-3- (cis-methylaminomethylmethylene) -1-pyrrolidine

555 mg (3 mmol) of 1-ethoxycarbonyl-3- (cis-hydroxymethylmethylene) -1-pyrrolidine was dissolved in 10 ml of methylene chloride, cooled to -20 ° C, and 1 ml (7.12 mmol) of triethylamine. After adding 0.51 ml (6.62 mmol) of methanesulfonyl chloride to 5 ml of methylene chloride, the reaction mixture was slowly added, and the reaction mixture was stirred at an ice water temperature for 1 hour. 20 ml of saturated brine was added thereto, extracted with methylene chloride (20 ml × 4), dehydrated with anhydrous forget-me-not, and the resulting liquid was dissolved in 2 ml of methanol, 2.5 ml of 40% aqueous methylamine solution was added thereto, and the mixture was stirred at room temperature for 16 hours. The residue obtained by concentrating the reaction mixture was purified by silica gel column to obtain 291 mg of the target compound (yield 48%).

¹ H-NMR (CDCl ₃ , δ ppm): 5.44 (1H, m), 4.15 (2H, q, J = 7.1 Hz), 3.98 (2H, d, J = 11.6 Hz), 3.50 (2H, m), 3.16 (2H, d, J = 9 μs), 2.57 (2H, br.s), 2.42 (3H, s), 1.27 (3H, t, J = 7.1 μs).

[Manufacture example 9]

Preparation of 3- (sheet-methylaminomethylmethylene) -1-pyrrolidine

270 mg (1.36 mmol) of 1-ethoxycarbonyl-3- (cis-methylaminomethylmethylene) -1-pyrrolidine was suspended in 6 ml of distilled water, and dissolved in 300 mg of sodium hydroxide and refluxed for 2.5 hours. The reaction mixture was cooled, methylene chloride was extracted (20 mL × 5), combined with dehydration with anhydrous forget-me-not and concentrated at 40 ° C. or lower to obtain 128 mg of the target compound (yield 74%).

¹ H-NMR (CDCl ₃ , δ ppm): 5.40 (1H, m), 3.45 (2H, q, J = 1.6 Hz), 3.19 (2H, d, J = 6 Hz), 3.02 (2H, t, J = 6.9 Hz), 2.41 (3H, s), 2.37 (2H, m).

Example 1

1-cyclopropyl-6,8-difluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3- Preparation of Carboxylic Acid (KR-10851)

1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 500 mg (1.76 mmol), 3- (methylaminomethylmethylene) -1- 285 mg (2.26 mmol) of pyrrolidine and 350 mg (2.30 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) were dissolved in 10 ml of acetonitrile and refluxed for 4.5 hours. The reaction mixture was left at room temperature for 16 hours, and the resulting crystalline precipitate was filtered, washed sequentially with acetonitrile, water (10 mL), ethanol + ethyl ether (1: 1), and dried under reduced pressure to obtain 276 mg of the target compound ( Yield 40%).

Melting Point: 200 ° C (Decomposition)

MS m / z (rel. Int.%): 389 (M ⁺ , 10), 358 (100), 345 (10), 314 (50).

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.76 (1 H, s), 7.81 (1 H, d, J = 14.2 Hz), 5.58 (1 H, m), 4.39 (2 H, s), 4.00 ( 1H, m), 3.84 (2H, m), 3.70, 3.63 (2H, d, d, d, J = 7.4 kPa), 2.72 (2H, m), 2.70 (3H, s), 1.27 (4H, m).

Example 2

1-cyclopropyl-6,8-difluoro-7- {3- (trans-methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline- Preparation of 3-carboxylic acid (KR-10868)

1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 270 mg (0.95 mmol), 3- (trans-methylaminomethylmethylene)- 120 mg (0.95 mmol) of 1-pyrrolidine and 150 mg (0.98 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) were dissolved in 7 ml of acetonitrile and refluxed for 4 hours. . The reaction mixture was left at room temperature for 16 hours, and the resulting crystalline precipitate was filtered, washed with acetonitrile, water and ethyl ether, and dried under reduced pressure to obtain 240 mg of the target compound (yield 64%).

Melting Point: 212 ~ 215 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.77 (1 H, s), 7.83 (1 H, d, J = 13.5 Hz), 5.57 (1 H, m), 4.39 (2 H, s), 4.01 ( 1H, m), 3.84 (2H, t), 3.63 (2H, d, J = 6.3 Hz), 2.73 (2H, m), 2.69 (3H, s), 1.30-1.19 (4H, m).

Example 3

1-cyclopropyl-6,8-difluoro-7- {3- (cis-methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline- Preparation of 3-carboxylic acid (KR-10869)

1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 140 mg (0.49 mmol), 3- (cis-methylaminomethylmethylene)- 60 mg (0.47 mmol) of 1-pyrrolidine and 80 mg (0.52 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) were dissolved in 5 ml of acetonitrile and refluxed for 4 hours. . The reaction mixture was left at room temperature for 16 hours, and the resulting crystalline precipitate was filtered, washed with acetonitrile, water and ethyl ether, and dried under reduced pressure to obtain 113 mg of the target compound (yield 64%).

Melting Point: 208 ~ 210 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.79 (1H, s), 7.84 (1H, dd, J = 13.4, 1.5 Hz), 5.59 (1H, m), 4.37 (2H, s), 3.99 (1H, m), 3.89 (2H, br.s), 3.71 (2H, d, J = 6.4㎐), 2.73 (2H, m), 2.70 (3H, s), 1.30 ~ 1.19 (4H, m) .

Example 4

6,8-difluoro-1-ethyl-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3-carr Preparation of Acids

1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 68 mg (0.25 mmol), 3- (methylaminomethylmethylene) -1-pi 38 mg (0.3 mmol) of rollidine and 40 mg of 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) were dissolved in 3 ml of acetonitrile and refluxed for 4 hours. The reaction mixture was left at room temperature overnight, and the precipitate was filtered, washed with acetonitrile, water and ethyl ether in that order and dried under reduced pressure to obtain 65 mg of the target compound (yield 69%).

Melting Point: 216-219 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.77 (1 H, s), 7.83 (1 H, d, J = 14.2 Hz), 5.57 (1 H, m), 4.40 (2 H, s), 4.37 ( 2H, q, J = 7.1 μs, 3.85 (2H, m), 3.71, 3.64 (each 1H, d, J = 6.4 μs), 2.74 (2H, m), 2.70 (3H, s), 1.50 (3H, t, J = 7.1 ms).

Example 5

1-tert-butyl-6,8-difluoro-1-ethyl-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4- Preparation of oxoquinoline-3-carboxylic acid

1-tert-butyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 75 mg (0.25 mmol), 3- (methylaminomethylmethylene) -1 -38 mg (0.30 mmol) of pyrrolidine and 40 mg of 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) were dissolved in 3 ml of acetonitrile and refluxed for 3.5 hours. The reaction mixture was left at room temperature overnight, the precipitate was filtered off, washed with acetonitrile, water and acetonitrile and dried under reduced pressure to obtain 76 mg of the target compound (yield 75%).

Melting Point: 196-200 ° C (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δppm): 8.75 (1H, s), 7.82 (1H, d, J = 14.2 Hz), 5.56 (1H, m), 4.41 (2H, s), 3.84 ( 2H, m), 3.70, 3.64 (each 1H, d, J = 6.4 Hz), 2.73 (2H, m), 2.71 (3H, s), 1.91 (9H, s).

Example 6

9-Fluoro-3 (S) -methyl-10- {3-cis-methylaminomethylmethylene) -1-pyrrolidin-1-yl} -7-oxo-2,3-dihydro-7H-pyri Preparation of [1,2,3-de] -1,4benzoxazine-6-carboxylic acid

9,10-difluoro-3 (S) -methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6- 71 mg (0.25 mmol) of carboxylic acid, 38 mg (0.30 mmol) of 3- (cis-methylaminomethylmethylene) -1-pyrrolidine and 1,8-diazabicyclo [5,4,0] undec- 46 mg of 7-ene (DBU) was dissolved in 2 ml of acetonitrile and refluxed for 4 hours. The reaction mixture was left at room temperature overnight, and the resulting precipitate was filtered, washed with acetonitrile, water and ether, and dried under reduced pressure to obtain 63 mg of the target compound (yield 65%).

Melting Point: 185-189 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δppm): 8.80 (1H, s), 7.67 (1H, d, J = 14.1㎐), 5.58 (1H, m), 4.50 (1H, m), 4.36 ( 2H, s), 4.30 (2H, br, s), 3.88 (2H, br, s), 3.71 (2H, d, J = 6.4 ㎐), 2.72 (2H, m), 2.70 (3H, s), 1.65 (3H, d, J = 6.5 Hz).

Example 7

1-cyclopropyl-6-fluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -4-oxo-1,8-naphthyridine-3-carboxylic acid Manufacture

1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid 71 mg (0.251 mmol), 3- (methyl-aminomethylmethylene) -1- 36 mg (0.285 mmol) of pyrrolidine and 45 mg (0.30 mmol) of 1,8-diazabicyclo [5,4,0] undec-7-ene were dissolved in 2 ml of acetonitrile and refluxed for 30 minutes. The reaction mixture was cooled to room temperature, and the resulting precipitate was filtered, washed sequentially with acetonitrile, water and ethyl ether, and dried under reduced pressure to obtain 79 mg of the target compound (yield 85%).

Melting Point: 207-212 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δppm): 8.81 (1H, s), 8.10 (, d, J = 12.4 Hz), 5.56 (1H, m), 4.42 (2H, s), 4.00 (1H m, 3.86 (2H, m), 3.72, 3.65 (each 1 H, d, J = 6.4 μs), 2.74 (2H, m), 2.70 (3H, s).

Example 8

Of 1-ethyl-6-fluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -4-oxo-1,8-naphthyridine-3-carboxylic acid Produce

7-chloro-1-ethyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid 68 mg (0.251 mmol), 3- (methyl-aminomethylmethylene) -1-pi 36 mg (0.285 mmol) of rollidine and 45 mg of 1,8-diazabicyclo [5,4,0] undec-7-ene were dissolved in 2 ml of acetonitrile and refluxed for one hour. The reaction mixture was left at room temperature overnight, the precipitate was filtered off, washed sequentially with acetonitrile, water and acetonitrile and dried under reduced pressure to obtain 69 mg of the target compound (yield 76%).

Melting Point: 177-181 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.82 (1H, s), 8.10 (1H, d, J = 12.4 Hz), 5.57 (1H, m), 4.41 (2H, s), 4.35 ( 2H, q, J = 7.1 μs, 3.87 (2H, m), 3.72, 3.66 (each 1H, d, J = 6.4 μs), 2.75 (2H, m), 2.70 (3H, s), 1.52 (3H, t, J = 7.1 ms).

Example 9

1- (2,4-difluorophenyl) -6-fluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -4-oxo-1,8-naph Preparation of Tilidine-3-carboxylic Acid

7-chloro-1- (2,4-difluorophenyl) -6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid 80 mg (0.207 mmol), 3- (methyl 30 mg (0.238 mmol) of aminomethylene) -1-pyrrolidine and 40 mg of 1,8-diazabicyclo [5,4,0] undec-7-ene were dissolved in 2 ml of acetonitrile and refluxed for 1.5 hours. . The reaction mixture was cooled to room temperature, and the resulting precipitate was filtered, washed with acetonitrile and water, and dried under reduced pressure to obtain 69 mg of the target compound (yield 70%).

Melting Point: 241-245 ° C (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δppm): 8.75 (1H, s), 7.85 (1H, d, J = 12.4 Hz), 7.47 (1H, m), 7.19 (2H, m), 5.55 ( 1H, m), 4.40 (2H, s), 3.86 (2H, m), 3.72, 3.65 (each 1H, d, J = 6.4 Hz), 2.74 (2H, m), 2.70 (3H, s).

Example 10

Of 1-ethyl-6-fluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxylic acid Produce

1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 64 mg (0.252 mmol), 3- (methyl-aminomethylmethylene) -1-pyrroli 35 mg of Dean (0.277 mmol) and 46 mg of 1,8-diazabicyclo [5,4,0] undec-7-ene were dissolved in 2 ml of acetonitrile and refluxed for 4 hours. The reaction mixture was cooled to room temperature, and the resulting precipitate was filtered, washed sequentially with acetonitrile, water and ethyl ether, and dried under reduced pressure to obtain 65 mg of the target compound (yield 72%).

Melting Point: 195-199 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.52 (1H, s), 7.84 (1H, d, J = 12.4 Hz), 7.19 (1H, d, J = 7.3 Hz), 5.56 (1H, m), 4.45 (2H, s), 4.32 (2H, q, J = 7.1 μs), 3.88 (2H, m), 3.73, 3.66 (each 1H, d, J = 6.4 μs), 2.76 (2H, m) , 2.71 (3H, s), 1.47 (3H, t, J = 7.1 μs).

Example 11

1-tert-butyl-6-fluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3-carboxyl Manufacture of acid

1-tert-butyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 72 mg (0.251 mmol), 3- (methyl-aminomethylmethylene) -1- 36 mg (0.285 mmol) of pyrrolidine and 45 mg of 1,8-diazabicyclo [5,4,0] undec-7-ene were dissolved in 1.5 ml of acetonitrile and refluxed for 4 hours. The reaction mixture was left at room temperature overnight, and the resulting precipitate was filtered, washed sequentially with acetonitrile, water and ethyl ether, and dried under reduced pressure to obtain 66 mg of the target compound (yield 68%).

Melting Point: 225-229 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.54 (1H, s), 7.84 (1H, d, J = 12.3 Hz), 7.21 (1H, d, J = 7.3 Hz), 5.55 (1H, m), 4.40 (2H, s), 3.86 (2H, s), 3.71, 3.65 (each 1H, d, J = 6.4 Hz), 2.73 (2H, m), 2.71 (3H, s), 1.90 (9H, s).

Example 12

6,8-difluoro-1- (4-fluorophenyl) -7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4- Preparation of oxoquinoline-3-carboxylic acid

1- (4-fluorophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 85 mg (0.251 mmol), 3- (methyl-amino 36 mg (0.285 mmol) of methylmethylene) -1-pyrrolidine and 45 mg of 1,8-diazabicyclo [5,4,0] undec-7-ene were dissolved in 2 ml of acetonitrile and refluxed for 4 hours. The reaction mixture was cooled to room temperature, and the resulting precipitate was filtered, washed sequentially with acetonitrile, water and acetonitrile, and dried under reduced pressure to obtain 78 mg of the target compound (yield 70%).

Melting Point: 185-190 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δppm): 8.71 (1H, s), 8.02 (1H, d, J = 14.2 Hz), 7.42 (2H, m), 7.28 (2H, m), 5.56 ( 1H, m), 4.40 (2H, s), 3.85 (2H, m), 3.71, 3.65 (each 1H, d, J = 6.4 Hz), 2.74 (2H, m), 2.71 (3H, s).

Example 13

1-cyclopropyl-6-fluoro-8-methoxyl-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline- Preparation of 3-carboxylic Acid

1-cyclopropyl-6,7-difluoro-8-methoxyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 74 mg (0.25 mmol), 3- (methyl-aminomethylmethylene 35 mg (0.277 mmol) of 1-1-pyrrolidine and 46 mg of 1,8-diazabicyclo [5,4,0] undec-7-ene were dissolved in 1.5 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 60 mg of the target compound (yield 60%).

Melting Point: 199-204 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δppm): 8.87 (1H, s), 7.84 (1H, d, J = 13.6㎐), 5.55 (1H, m), 4.41 (2H, s), 4.09 ( 1H, m), 3.84 (2H, m), 3.71, 3.68 (each 1H, d, J = 6.4 ㎐), 3.65 (3H, s), 2.74 (2H, m), 2.70 (3H, s), 1.23- 1.05 (4 H, m).

Example 14

5-amino-1-cyclopropyl-6,8-difluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxo Preparation of Quinoline-3-carboxylic Acid

5-Amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 74 mg (0.25 mmol), 3- (methyl-aminomethyl 35 mg (0.277 mmol) of methylene) -1-pyrrolidine and 45 mg of 1,8-diazabicyclo [5,4,0] undec-7-ene were dissolved in 2 ml of acetonitrile and refluxed for 5 hours. The reaction mixture was allowed to stand at room temperature overnight, and the resulting precipitate was filtered, washed sequentially with acetonitrile, water and ethanol, and dried under reduced pressure to obtain 70 mg of the target compound (yield 70%).

Melting Point: 220-225 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.77 (1 H, s), 5.55 (1 H, m), 4.40 (2 H, s), 4.01 (1 H, m), 3.85 (2 H, m), 3.71, 3.65 (each 1H, d, J = 6.4 Hz), 2.74 (2H, m), 2.70 (3H, s), 1.31-1.18 (4H, m).

Example 15

1-cyclopropyl-6,8-difluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4-oxoquinoline-3- Preparation of Carboxylic Acid Lactic Acid

1-cyclopropyl-6,8-difluoro-7- {3- (methylaminomethylmethylene) -1-pyrrolidin-1-yl} -1,4-dihydro-4 prepared in Example 1 -Dissolve 97 mg of oxoquinoline-3-carboxylic acid in 1 ml of dichloromethane and 0.5 ml of ethanol, mix well with 26 mg of 85% lactic acid, remove the solvent under reduced pressure, add ethyl ether to make powder, filter and dry under reduced pressure. To obtain the target compound in quantitative yield.

Melting Point: 195-198 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ + CD ₃ OD, δppm): 8.72 (1H, s), 7.78 (1H, d, J = 14.2 Hz), 5.55 (1H, m), 4.34 (2H, s), 4.01 ( 1H, m), 3.80 (2H, m), 3.70, 3.60 (2H, d, d, d, J = 7.4 ㎐), 3.52 (1H, m), 274 (2H, m), 2.68 (3H, s), 1.45 (3H, d, J = 7 Hz), 1.28-1.01 (4H, m).

Some of the quinolone compounds synthesized by the above examples were measured by in vitro antimicrobial activity by agar distillation method and are shown in Table 1 and Table 2 below. Most of these compounds showed superior antimicrobial activity against Gram-positive strains than Ciprofloxacin and Ofloxacin. . It can be seen that these antibacterial effects are not affected by the stereoisomers of the side chains of the amine compounds of the present invention bound to carbon number 7 of the quinolone mother nucleus (see Table 1). In addition, as shown in Table 2, the strains exhibiting resistance to the quinolone antimicrobial agent oploxacin showed strong antimicrobial activity as compared to opfloxacin and siflofloxacin, so that the novel quinolone compound synthesized by the present invention is It can be seen that it does not exhibit cross resistance with conventional quinolone compounds.

TABLE 1

In Vitro Antimicrobial Activity of Quinolone Compounds

TABLE 2

In vitro Antimicrobial Activity against Ofloxacin-Resistant Strains of KR-10851

Claims (12)

The novel quinolone compound represented by the following general formula (I), and its salt.

Wherein X represents a nitrogen atom or CY, wherein Y represents a hydrogen atom, a fluorine, a chlorine atom, a methoxy group or a methyl group, Z represents a hydrogen atom, a halogen atom or an amino group, and R ₁ represents 1 to 4 carbon atoms. An alkyl group, a haloalkyl group, a hydroxyalkyl group or an alkenyl group having a dog, a cycloalkyl group or a fluorine-substituted phenyl group having 3 to 6 carbon atoms, or an XO (or S) CH which is closed at the X position to form a thiazole or oxazole ring ₂ CH (CH ₃ ) -N, etc., R ₂ represents a hydrogen atom or a cation useful as a drug, R ₃ represents a hydrogen atom or a lower alkyl group, R ₄ and R ₅ are the same as or different from each other hydrogen atom, Lower alkyl group, a cycloalkyl group, or a hydroxyl group is represented, m is an integer of 1 or 2. The compound of claim 1, wherein Z is a hydrogen atom, a chlorine atom, a fluorine atom, or an amino group. The method of claim 1, wherein R ₁ is methyl, ethyl, n-propyl, isopropyl, tert-butyl, fluoroalkyl group having 2 to 4 carbon atoms, hydroxyalkyl group having 2 to 4 carbon atoms, cyclopropyl, cyclobutyl, cyclo A pentyl, cyclohexyl, or 1-2 fluorine substituted phenyl group. The compound according to claim 1 or 3, wherein R ₁ is an ethyl, tert-butyl, 2-fluoroethyl, 2-hydroxyethyl, cyclopropyl, 4-fluorophenyl, or 2,4-difluorophenyl group. compound. The compound of claim 1, wherein R ₂ is a hydrogen atom, sodium, potassium, calcium, magnesium or a tertiary or quaternary C ₁ -C ₄ alkylammonium cation. The compound of claim 1, wherein the salt of the quinolone compound of formula (I) when R ₂ is H is a salt of hydrochloric acid, sulfuric acid, methanesulfonic acid, lactic acid or ascolic acid. The compound of claim 1, wherein R ₃ is a hydrogen atom, a methyl group, an ethyl group, or an isopropyl group. The compound of claim 1, wherein R ₄ and R ₅ are the same as or different from each other, and are each a hydrogen atom, a methyl group, an ethyl group, a cyclopropyl group, or a hydroxyl group. New compound represented by the following general formula (I) by condensation reaction of a compound represented by the following general formula (II) with a compound represented by the following general formula (III) or the following general formula (IIIa) in an unreacted solvent in the presence of a base. A method of making a quinolone compound.

In the above formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , Z, X, m are each as defined above, L is a divalent group, halogen atom, alkylsulfonyl having 1 to 4 carbon atoms Or a paratoluenesulfonyl group, and A represents an acid selected from hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid and methanesulfonic acid. The method of claim 9, wherein the non-reactant solvent is water, alcohol, acetonitrile, dimethylformamide or dimethyl sulfoxide. The method of claim 9, wherein the condensation reaction is a method for producing a quinolone compound, characterized in that the reaction for 1 to 12 hours at a temperature of 20 ~ 180 ℃. The method for preparing a quinolone compound according to claim 9, wherein when R ₂ is H, the compound of formula (I) is added to an inorganic acid or an organic acid in a solvent selected from haloalkanes or lower alcohols to form an acid addition salt.