JPS62135458A - Novel quinolone compound and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is halogen; R<2> is lower alkylamino; R<3> is carboxyl or protected carboxyl; R<4>=R<1>; R<5> is H or lower alkyl) and its salt. EXAMPLE:1-(3-Methylamino-4-fluorophenyl)-3-carboxyl-6-fluoro-7-(3-meth ylpipera zin-1-yl)-4-quinolone. USE:A medicinal drug and an antibacterial agent. It has high antibacterial activity and inhibits the growth of various pathogenic microorganisms including Gram- positive and Gram-negative bacterial. It is administered in a dose of 1-6,000mg of the active component per person daily. PREPARATION:The compound of formula I or its salt can be produced by reacting the novel compound of formula II (R<6> is acid residue) or its salt with the compound of formula III or its salt in a solvent such as pyridine, optionally in the presence of a base, at normal temperature or under mild heating or heating, preferably under heating.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel quinolone compounds and salts thereof.

More specifically, the present invention relates to novel quinolone compounds and salts thereof having antibacterial activity, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient.

That is, one object of the present invention is to provide a novel quinolone compound and its salts that are effective against many pathogenic bacteria.

Another object of this invention is to provide a method for producing novel quinolone compounds or salts thereof.

Yet another object of the present invention is to provide a pharmaceutical composition containing the novel quinolone compound or its salt as an active ingredient.

The target quinolone compound is new and has the following general formula (
It can be shown as I).

(In the formula, R1 is a halogen, R2 is a lower alkylamino group, R3 is a carboxy group or a protected carboxy group, R4 is a halogen, and R5 is hydrogen or a lower alkyl group.)
.

According to the present invention, a novel quinolone compound can be produced by the production method shown in the following reaction formula.

or salts thereof CI) or salts thereof (wherein R1, R2, R3, R4 and R5 each have the same meaning as before, and R6 means an acid residue).

The raw material compound (II) of this invention is a new compound and can be produced by the steps shown below.

Process for producing raw material compounds, or salts thereof (VI) or salts thereof, or salts thereof (X) (wherein R, R, R, R and R6 each have the same meaning as before, R2 is N-protected ( (lower) alkylamino group, R7 means an acid residue, and R8 means a lower alkoxy group, respectively.) Suitable salts of the target compound (1) are conventional non-toxic salts, such as sodium salts, potassium salts, etc. Metal salts such as alkali metal salts and alkaline earth metal salts such as calcium salts, magnesium salts, ammonium salts such as trimethylamine salts, triethylamine salts, pyridine salts, pilin salts, dicyclohexylamine salts, N,N'-)pencil Organic base salts such as ethylenediamine salts, such as acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, formic salts, toluenesulfonates, etc., such as hydrochloric acid; Examples include inorganic acid salts such as salts, hydrobromides, hydroiodides, sulfates, and phosphates, and salts with amino acids such as arginine, aspartic acid, and glutamic acid.

In the foregoing and following description of this specification, pertinent examples and explanations of the various definitions falling within the scope of this invention are set forth in detail below.

"Lower" shall mean 1 to 6 carbon atoms unless otherwise specified.

Preferred "lower alkyl groups" and preferred lower alkyl moieties of r-lower alkylamino groups include methyl,
Mention may be made of those having 1 to 6 carbon atoms such as ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. And more preferably (C
, -C4) alkyl group.

Suitable halogens include chlorine, bromine, fluorine and iodine.

Suitable "protected carboxy groups" include esterified carboxy groups, and the ester moieties include, for example, methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, tertiary Alkyl esters such as butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, heptyl ester, octyl ester, nonyl ester, decyl ester, undecyl ester, dodecyl ester, hexadecyl ester; For example, vinyl ester, allyl ester, etc. Lower alkenyl esters; lower alkynyl esters such as ethynyl ester and propynyl ester; mono(or di- or tri)-halo(lower) alkyl esters such as 2-iodoethyl ester and 2.2°2-trichloroethyl ester; e.g. Acetoxymethyl ester, propionyloxymethyl ester, 1-acetoxypropyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-propionyloxyethyl ester, 1-yne Lower alkanoyloxy (lower) alkyl esters such as butyryloxyethyl ester: lower alkanesulfonyl (lower) such as mesylmethyl ester, 2-mesylethyl ester, etc.
Alkyl ester; for example benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3 , 5-ditertiary butyl benzyl ester, etc., such as phenyl (lower) alkyl ester, which may have one or more suitable substituents; e.g. methoxycarbonyloxymethyl ester, ethoxy Lower alkoxycarbonyloxy (lower) alkyl esters optionally substituted with an azide group, such as carbonyloxymethyl ester and ethoxycarbonyloxyethyl ester; preferably benzotetrahydrofuryl esters optionally substituted with an oxo group, more preferably is a heterocyclic ester such as a phthalidyl ester; for example, benzoyloxymethyl ester4. aroyloxy (lower) alkyl esters such as benzoyloxyethyl ester, toluoyloxyethyl ester; one or more suitable esters such as phenyl ester, tolyl ester, tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc. Examples include aryl esters which may have substituents.

Preferred examples of "r protected carboxy group" include f
Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, impropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyl Examples include alkoxycarbonyl groups such as oxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, and more preferably lower alkoxycarbonyl groups.

Suitable "acid residues" include, for example, halogens such as fluorine, chlorine, bromine or iodine, for example mesyloxy,
Examples include sulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy.

Preferred embodiments of the target compound (1) are as follows.

A preferred embodiment of R1 is halogen.

A preferred embodiment of )2 is a lower alkylamino group, preferably a (C,)alkylamino group.

A preferred embodiment of R3 is a carboxy group or a lower alkoxycarbonyl group, more preferably a carboxy group.

A preferred embodiment of R4 is halogen.

A preferred embodiment of R5 is hydrogen or a lower alkyl group,
More preferably hydrogen or a (C1-C4) alkyl group.

The method for producing the object compound of the present invention will be explained in detail below.

1. The desired compound (I) or a salt thereof can be produced by reacting the compound (I[) or a salt thereof with the compound (I[[) or a salt thereof.

For suitable salts of compound (II), the target compound (
Salts such as those exemplified for 1) can be mentioned.

Suitable salts of compound (III) include acid addition salts such as those exemplified for target compound (I).

This reaction may be carried out in the presence of a base.

Suitable bases include, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide, alkali metal hydroxides such as sodium carbonate, potassium carbonate, etc. carbonates, e.g. alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate;
For example, alkali metal acetates such as sodium acetate and potassium acetate, alkaline earth metal phosphates such as magnesium phosphate and calcium phosphate, alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, etc. Examples include inorganic bases such as, for example, trialkylamines such as trimethylamine, triethylamine, etc., organic bases such as bifrin, N-methylmorpholine, etc.

In this reaction, compound (III) can also be used as a base.

This reaction is usually carried out in a solvent.

Suitable solvents include chloroform, methylene chloride, diethyl ether, tetrahydrofuran, pyridine, N,
N-dimethylformamide, dimethylsulfoxide and any other solvents that do not adversely affect the reaction are included.

Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature, with or without heating, preferably with heating.

The method for producing the raw material compound of this invention will be explained in detail below.

Process for producing raw material compound Step (1): Compound (V) or a salt thereof can be produced by subjecting compound (IV) or a salt thereof to a TI-alkylation reaction.

Suitable salts of compounds (V) and (IV) include acid addition salts as exemplified for the target compound (1).

Suitable N-alkylating agents include alkyl halides (
For example, methyl iodide, ethyl bromide, etc.) can be mentioned.

The reaction is usually carried out in a solvent, and suitable solvents include:
Examples include diethyl ether, dioxane, hexamethylphosphoramide, etc., but any solvent can be used as long as it does not adversely affect the reaction.

Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature to elevated temperature.

Step (2): Compound (VI) can be produced by subjecting compound (V) or a salt thereof to an N-protecting group introduction reaction.

Suitable N-protecting groups for the N-protected (lower) alkylamine group of R2 in compound (l) include lower alkanoyl groups (eg, formyl group, acetyl group, etc.).

For the introduction reaction of the N-protecting group, methods commonly used in the art are used, such as a method using a mixture of formic acid and acetic anhydride, a method using formylimidazole, a method using acetic anhydride, and a method using acetyl chloride. etc.

Step (3): Compound (■) or its salt is the compound (VI) with NO3
It can be produced by subjecting it to a reduction reaction of groups.

Suitable salts for compound (■) include acid addition salts such as those exemplified for target compound (I).

Suitable methods for reducing NO□ groups include catalytic reduction using catalysts such as platinum oxide, palladium-carbon, and Raney nickel.

Step (4): Compound ([X) or a salt thereof can be produced by reacting compound (■) or a salt thereof with compound (■).

Examples of the acid residue of R7 in compound (■) are the same as those exemplified above, and examples of the lower alkoxy group of R8 include methoxy, ethoxy, propoxy, tertiary butoxy and the like.

Desirable salts of compound (IX) include target compound (1)
Examples include salts such as those exemplified in .

This reaction may be carried out in the presence of a base such as trimethylamine or triethylamine.

This reaction can be carried out without a solvent, but it can also be carried out using a conventional solvent that does not adversely affect the reaction.

Although the reaction temperature is not particularly limited, it is usually carried out at room temperature to elevated temperature.

Step (5): Compound (X) can be produced by subjecting compound (IX) or a salt thereof to a ring-closing reaction.

This ring-closing reaction can be carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or the like.

This reaction is usually carried out in a solvent such as N,N-dimethylformamide, lysine, dimethyl sulfoxide, etc., but it can be carried out in any solvent as long as it does not adversely affect the reaction.

Although the reaction temperature is not particularly limited, the reaction is usually carried out at or under heating.

Step <6): Compound (I[) or a salt thereof can be produced by subjecting compound (X) to an N-protecting group elimination reaction.

As the elimination reaction of the N-protecting group, hydrolysis using an acid or a base can be mentioned.

Suitable acids include organic or inorganic acids such as formic acid, acetic acid, p-+-luenesulfonic acid, hydrochloric acid, and the like. These acids can be used in combination.

Suitable bases include organic or inorganic bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate, trimethylamine, triethylamine, pilin, and the like.

When carrying out the hydrolysis reaction using a solvent, commonly used organic solvents, water, and mixtures thereof can be used.

Compound (I) and its salts are novel compounds, have high antibacterial activity, inhibit the growth of various pathogenic bacteria including Durum-positive bacteria and Durum-negative bacteria, and are useful as antibacterial agents. For treatment the compounds of this invention are
Use in the form of conventional preparations containing said compounds as active ingredients in admixture with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or topical administration. can do.

The formulation may be in solid form, such as a capsule, tablet, dragee, ointment, or herbal medicine, or in liquid form, such as a solution, suspension, or emulsion. If necessary, auxiliary agents, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives may be included in the above formulation.

Although the dosage of the compound varies depending on the age and condition of the patient, the compound of this invention is administered at a single dose of about 10 mg, 50 mg.
mg, 100mg, 250mg, 500mg, 100
It was found that 0 mg is effective in treating infections caused by pathogenic bacteria. Generally 1 mg/individual ~ about 6000 mg
/individual or more may be administered per day.

In order to demonstrate the usefulness of the target compounds, the antibacterial activity of representative compounds of this invention is shown below.

Minimum inhibitory concentration (A) In vitro antibacterial activity was measured by the following agar plate multiple dilution method.

Each test strain was cultured overnight in trypticase soy broth, and a loopful of it (106 viable bacteria/l11) was transferred to heart infusion agar (l (I agar) containing the test compound at each concentration level. ) for 37 °CCl2O hours. Minimal inhibition, f1 degree (MIC) was expressed as Hg/mQ.

(B) Me M1 needle (1) 1-(3-methylamino-4-fluorophenyl)-3-carboxy-6-fluoro-7-(3-methylpiperazin-1-yl)-4-quinolone (C ) Test result MIC (</relative) This invention will be described in more detail below with reference to Production Examples and Examples.

Production example 1 1-fluoro-2-amino-4-nitrobenzene (2g
) to a solution of hexamethylphosphoramide (10 mQ), sodium bicarbonate (3,2 g) and methyl iodide (2, amB) were added at room temperature, and the mixture was stirred overnight at the same temperature. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue.This residue was extracted with silica gel (60 g). It is subjected to column chromatography using M and eluted with a mixed solution of n-hexane and ethyl acetate (volume ratio, 10:1).First, the fractions containing the eluted compound are collected, and then the solvent is Distill under pressure to 1
-Fluoro-2-dumedelamino-4-nitrobenzene (1,19 g) is obtained as a syrup.

IR): 1625. 1530.
1460-1450. 1415°1350, 123
0 (:TlTl1 -1N (CDCl2.8 >' 2.93 (3H
1s), 2.95 (3H1s).

7.05 (LH, dd, J=9)1z and J=12
Hz), 7.6-7.80 (2H, m) Mass: 184 (M'') Next, both fractions containing the target compound to be eluted were collected and concentrated under reduced pressure to obtain 1-fluoro-2-methylamino-4. -Nitrobenzene (0.99 g) is obtained as crystals.

Fill): 89-90°C IR: 3400. 1635.
1535. 1380. 1290°1190 CI
ClTl -1N (CDCl2.δ): 2.95 (3H,
s), 6.85-7.63 (3H, m) Mass: 170 (M) Production Example 2 1-Fluoro-2-methylamino-4-nitrobenzene was added to a mixture of formic acid (10ml) and acetic anhydride (10IQ). (0.99 g) was added under water cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under pressure to obtain a residue. This residue was dissolved in ethyl acetate (5011111
) dissolves in The solution was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to give 1-fluoro-2-(N-methyl-N-formylamine)-4-nitrobenzene (0.96 g). is obtained as a syrup.

1R (knee): 1690-1670.
1620. 1590. 1525°1500, 1
350-1330.1250 am-'NMR (CDC
l2.8): 3.34 (3H9s), 7.15-
7.60 (11, m), 8.00-8.45 (3L
m) Mass: 198 (M”), 170 (M
"-28) Production Example 3 1-fluoro-2-(N-methyl-N-formylamino)-4-nitrobenzene (0.93 g) in methanol (
101!112) solution to 10% palladium-carbon (1
g) in a hydrogen atmosphere at atmospheric pressure for 4 hours. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to obtain 1-fluoro-2-(N-methyl-N-formylamine)-4-aminobenzene (0.70 g) as a crude solid.

NMR (CD30D, δ): 3.20 (3H, s
), 6.45-7.20 (3H, m), 8.20
(LH, d, J = 2Hz>1 stolen peak 1 2-(2,4-dichloro-5-fluorobenzoyl)-
3-Ethoxyacrylic acid ethyl ester (E,Z mixture) (1,3g) and triethylamine (0,30IQ
) 1-Fluoro-2-(N-methyl-N-formylamino)-4-aminebenzene (0.67 g) is added at room temperature. The mixture is stirred at the same temperature overnight. The reaction mixture was concentrated in reduced EE to give a residue. This residue is dissolved in ethyl acetate (50!1111). The solution was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to give 2-(2,4-dichloro-5-fluorobenzoyl)-3-[3-(N-methyl-N-formylamino). -4-Fluorophenylaminocoacrylic acid ether ester (E,Z mixture) (1,91 g) is obtained as a syrup.

IR(EtOH): 1680-1620.1510
．． 1250 cm-1NMR (CDCl2zo): 0
．． 75-1.30 (3B, m), 3.33 (3H,
s), 3.90-4.30 (2H, m>, 6.9
0-7.50 (5H, m), 8.33 (LH, d,
J=2Hz), 8.53 (IH, d.

J=13Hz) Mass: 458.457.456 Production Example 5 2-(2,4-dichloro-5-fluorobenzoyl)-
3-[3-(N-methyl-N-formylamino)-4-
Fluorophenylaminocoacrylic acid ethyl ester (
A solution of E, zf1 compound) (187 g) and potassium carbonate (13 g) in N,N-dimethylformamide (20 Peng) was stirred at 100 °C for 2 hours. The reaction mixture was poured into ice water (1 oomQ) and the solution was pH 4~ with IN hydrochloric acid
Adjust to 5. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure in the presence of phosphorus pentoxide to give 1-[:3-(N-methyl-N-formylamino)-4-fluorophenyl]-3.
-ethoxycarbonyl-6-fluoro-7-chloro-4
- Obtain the quinolone (1.44 g) as a solid.

mp' 225-228℃ IR (suji meal): 1720. 1665.
1610. 1540. 1510°1260, 12
20 am-' NMR (DMSO-da, 8)' 124 (3H
, t, J=7Hz), 3.25-3.60 (3H,
m), 4.19 (2H, q, J=7Hz), 7.
28 (11, d, J4Hz), 7.50-8.05
(4)1. m), 8.30-8.53 (2H, m
>Mass: 423 (M”+2), 4
21 (M”), 420 (M”-1) Production Example 6 1-[3-(N-methyl-N-formylamino)-4-
A solution of fluorophenyl-3-ethquinecarbonyl-6-fluoro-7-10rho4-4nolone (t, 40 g) in a mixture of acetic acid (1QmQ) and concentrated hydrochloric acid (2,511111) is refluxed for 4 hours.

After cooling, water (somc) is added to the reaction mixture.

The formed precipitate was collected by filtration, washed with water and ethanol,
Drying under reduced pressure in the presence of phosphorus pentoxide gave 1-(3-methylamino-4-fluorophenyl)-3-carboxy-6
-Fluoroleof-chloro-4-quinolone (0.92g
) to obtain a solid.

mp: 269-271℃ IR (strewn carbonate): 1730, 16
15, 1530. 1500. 1260.

1210 am-1 NMR (CF3COOH.8)' 3-51 (
3H. s), 7-68 (IH, d.J=6Hz), 7
．． 70-8.10 (3H.m), 8.53 (IH.m)
d. J=8Hz), 9.46 (LH.s)Mass
: 366, 365. 364 (M”) C 1 1-(3-methylamino-4-fluorophenyl)-3
-carboxy-6-fluoro-7-chloro-4-quinolone (0.36 g) and 2-methylpiperazine (0.4
A warm mixture of 5g) of pyridine (zomQ) is refluxed with stirring for 40 hours. The reaction mixture is concentrated under reduced pressure, and water is added to the residue. Adjust the solution to pH 5.0 with dilute hydrochloric acid while cooling with water. The precipitate was collected by filtration, washed with water, and dried under reduced pressure at 90°C to obtain 1-
(3-Methylamino-4-fluorophenyl)-3-levoxy-6-fluoro-7-(3-methylpiperazin-1-yl)-4-quinolone (0.14 g) is obtained.

mp: 190-192°C IR (streak 3-l): 3350. 17
15. 1635. 1620.

1530 country-1 NMR (CF3COOH, δ): 1.56 (3
H. d. J=4Hz), 3.25-4, 20 (7H
．． m), 3.53 (3H.s), 3.80 (L
H. d.

J: 6Hz>, 7.70-8.50 (4H.m),
9.26 (IH.s) Example 2 1-(3-methylamino-4-fluorophenyl)-3
A solution of -carboxy-6-fluorolof-chloro- (0.41 g) in dimethyl sulfoxide (6 mm) is stirred at 105-110°C for 5 hours. The reaction mixture is concentrated under reduced pressure to obtain a residue. This residue is mixed with water (SO+++
Grind with Q). The resulting precipitate is filtered, washed with water and ethanol, and dried under reduced pressure in the presence of phosphorus pentoxide. The resulting solid was rated at N. The 1-
(3-Methylamino-4-fluorophenyl)-3-carboxy-6-fluoro-7-(piperazin-1-yl)-4-quinolone (0.19 g) is obtained.

mp: 144-146℃ IR (suji meal): 1710. 16
20. 1530. 1300, 1270.

Claims (1)

[Claims] 1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is a halogen, R^2 is a lower alkylamino group, and R^3 is a carboxy group or a protected A quinolone compound represented by a carboxy group, R^4 means a halogen, R^5 means hydrogen or a lower alkyl group, and salts thereof. 2) R^2 is (C_1-C_4) alkylamino group, R
The compound according to claim 1, wherein ^3 is a carboxy group or a lower alkoxycarbonyl group, and R^5 is hydrogen or a (C_1-C_4) alkyl group. 3) R^1 is fluorine, R^2 is methylamino group, R^3
3. The compound according to claim 2, wherein is a carboxy group, R^4 is fluorine, and R^5 is hydrogen or a methyl group. 4) 1-(3-methylamino-4-fluorophenyl)
-3-carboxy-6-fluoro-7-(3-methylpiperazin-1-yl)-4-quinolone, and 1-(3-methylamino-4-fluorophenyl)-3
-carboxy-6-fluoro-7-(piperazine-1-
4. A compound according to claim 3 selected from the group consisting of yl)-4-quinolones. 5) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is halogen, R^2 is lower alkylamino group, R^3 is carboxy group or protected carboxy group, R^4 is halogen, R^6 means an acid residue) or its salts, by the general formula: ▲ mathematical formula,
There are chemical formulas, tables, etc. ▼ (In the formula, R^5 means hydrogen or lower alkyl group) When reacted with the compound shown by or its salts, the general formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( In the formula, R^1, R^2, R^3, R^4 and R^5
(each has the same meaning as above) 6) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is a halogen, R^2 is a lower alkylamino group, R^3 is a carboxyl group or a protected carboxy group, R^4 represents a halogen, and R^6 represents an acid residue, respectively.) Compounds and salts thereof. 7) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is a halogen, R^2 is a lower alkylamino group, R^3 is a carboxyl group or a protected carboxy group, R^4 represents a halogen, R^5 represents hydrogen or a lower alkyl group, respectively) A pharmaceutical composition containing a quinolone compound or a salt thereof as an active ingredient.