JPH01258684A - 3-substituted quinolinium thiomethylcephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> represents H, (substituted)lower alkyl, (substituted)cycloalkyl, (substituted)aryl, etc.; R<2> represents (substituted)lower alkyl, (substituted)cycloalkyl, etc.; R<3>-R<5> represent H, halogen, (substituted)lower alkyl, OH, lower alkoxy, etc.] or salt thereof. EXAMPLE:7beta-[2-(2-Aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamide]-3- [(1-methyl- quinolinium-4-yl)thiomethyl]-3-cephem-4-carboxyl ate. USE:A remedy for microbisms. PREPARATION:A compound expressed by formula II (R<10> represents OH- protecting group, etc.; R<6> represents H or amino-protecting group; R<7> represents H or carboxyl-protecting group; X represents halogen or acetoxy) is reacted with a compound expressed by formula III (R<20> represents H or group of R<2> which functional group is protected; R<30>, R<40> and R<50> represent respectively group of R<3>, R<4> and R<5> which functional groups are protected), followed by N-alkylation of a quinoline ring and deprotection as required.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel cephalosporin derivative useful in the medical field as a therapeutic agent for bacterial infections.

Previously, cephalosporin antibiotics have been widely used to treat diseases caused by infection with pathogenic bacteria in humans and animals, such as infections caused by bacteria resistant to penicillin antibiotics. Cephalosporin antibiotics are particularly useful in the treatment of diseases caused by cephalosporins, and have low toxicity, making them excellent in terms of safety. Against this background, many attempts have been made to create cephalosporin antibiotics that have stronger antibacterial activity and are superior in terms of safety.

Among such attempts, many compounds having a heterocyclic thiomethyl group as a substituent at the 3-position of the cephalosporin nucleus are known. For example, 5-(1-methyl-111-
Those having a (tetrazolyl)thiomethyl group include the generic names cefmenoxime, cefviramide, cefviramide, etc.
Also, 2-(5-methyl-1,3゜4-thiadiazolyl)
The common name cefazolin as having a thiomethyl group is also known as 5-[1-(2-dimethylaminoethyl)-LH
Examples of compounds having a -tetrazolylcothiomethyl group include the common name cefothiam. However, no compound having a substituted quinolinium thiomethyl group at the 3-position is known.

Problem to be Solved by the Invention It is an object of the invention to provide a compound that exhibits excellent antibacterial activity against pathogenic bacteria and has excellent safety properties.

As a result of intensive research to create a cephalosporin derivative with excellent antibacterial activity and excellent safety, the present inventors discovered a substituted compound at the 3-position of the cephalosporin core. The present invention was completed by discovering that a novel cephalosporin derivative having a nolinium thiomethyl group has excellent antibacterial activity.

The present invention is directed to the general group [wherein R' is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group].

an optionally substituted lower alkynyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, R1 is an optionally substituted lower alkyl group,
R3, R4 and R' may be the same or different, and a hydrogen atom, Halogen atom, optionally substituted lower alkyl group, hydroxyl group, lower alkoxy group, lower alkanoyloxy group, amino group, lower alkylamino group, lower alkanoylamino group, carboxyl group, lower alkoxycarbonyl group, even if substituted The present invention relates to a compound represented by a carbamoyl group, a sulfo group, a sulfamoyl group, a lower alkanoyl group, or a nitro group, respectively, or a non-toxic salt thereof, a method for producing the same, and an antibacterial agent containing the compound as an active ingredient.

Next, various terms and appropriate examples thereof mentioned in the description of this specification will be explained below.

A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Examples of the optionally substituted lower alkyl group include a halogen atom, hydroxyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, formyloxy group, and acetoxy group. , fluoroacetoxy group, carbamoyl group, N-methylcarbamoyl group, N,N-dimethylcarbamoyl group, carbamoyloxy group, N-methylcarbamoyloxy group, N,N-dimethylcarbamoyloxy group, amino group, methylamino group, dimethyl Amino group, formamide group, acetamide group, fluoroacetamide group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, sulfo group, sulfamoyl group, cyano group, formyl group, acetyl group, fluoroacetyl group, methylthio group, ethylthio group, fluoro Methylthio group, 1-fluoroethylthio group, 2-fluoroethylthio group, thiazolyl group, 2-aminothiazolyl group, 5-
Amino-1,2,4-thiadiazolyl group, L, 2.3-
Even if it is substituted with one or more substituents selected from the group consisting of thiadiazolyl group, imidazolyl group, thienyl group, furanyl group, pyridyl group, quinolyl group, isoquinolyl group, piperazinyl group, pyrrolidinyl group, morpholinyl group, etc. Good, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group,
Examples include alkyl groups having 1 to 6 carbon atoms such as 5ee-butyl group, tert-butyl group, pentyl group, and hexyl group.

Examples of the optionally substituted cycloalkyl group include one or more groups selected from the group consisting of carboxyl group, carbamoyl group, amino group, methylamino group, dimethylamino group, sulfo group, hydroxyl group, cyano group, etc. For example, a cycloalkyl group having 3 to 6 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group may be substituted with a substituent.

Examples of the optionally substituted lower alkenyl group include one or more substituents selected from the group consisting of a halogen atom, a carboxyl group, an amino group, a sulfo group, a hydroxyl group, a carbamoyl group, a cyano group, etc. 2 to 6 carbon atoms, such as a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 1-pentenyl group, or a 1-hexenyl group. Examples include alkenyl groups.

Examples of the optionally substituted lower alkynyl group include a halogen atom, a hydroxyl group, an amino group, a carboxyl group,
Optionally substituted with one or more substituents selected from the group consisting of carbamoyl group, sulfo group, cyano group, etc., such as ethynyl group, 1-propynyl group, propargyl group, 1-butynyl group, 1- Examples include alkynyl groups having 2 to 6 carbon atoms such as pentynyl group and 1-hexynyl group.

Examples of the optionally substituted aryl group include a halogen atom, methyl group, ethyl group, fluoromethyl group, trifluoromethyl group, aminomethyl group, carboxymethyl group, carbamoylmethyl group, sulfomethyl group, hydroxyl group, methoxy group, Fluoromethoxy group, acetoxy group, amino group, methylamino group, dimethylamino group, acetamido group, carboxyl group, methoxycarbonyl group, carbamoyl group, N-methylcarbamoyl group, NlN-dimethylcarbamoyl group, carbamoyloxy group, sulfo group, Examples include aryl groups having 6 to 10 carbon atoms such as phenyl groups or naphthyl groups, which may be substituted with one or more substituents selected from the group consisting of sulfamoyl groups, cyano groups, nitro groups, etc. It will be done.

As the optionally substituted aralkyl group.

For example, halogen atom, methyl group, ethyl group, fluoromethyl group, trifluoromethyl group, aminomethyl group, carboxymethyl group, carbamoylmethyl group, sulfomethyl group, hydroxyl group, methoxy group, fluoromethoxy group, acetoxy group, amino group, methyl Amino group, dimethylamino group, acetamido group, carboxyl group, methoxycarbonyl group, carbamoyl group, N-methylcarbamoyl group, N
, N-dimethylcarbamoyl group, carbamoyloxy group, sulfo group, sulfamoyl group, cyano group, nitro group, etc., for example, benzyl group, phenethyl group. or an aralkyl group having 7 to 12 carbon atoms such as a naphthylmethyl group.

Examples of the lower alkoxy group include methoxy group.

Ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, r, ert-butoxy group.

Examples of the lower alkanoyloxy group include alkoxy groups having 1 to 6 carbon atoms such as pentyloxy group, isopentyloxy group, and hexyloxy group.9 Examples of lower alkanoyloxy groups include acetoxy group, propionyloxy group, and isovaleryloxy group. Examples include alkanoyloxy groups having 1 to 6 carbon atoms.

Examples of lower alkylamino groups include those having 1 to 6 carbon atoms, such as a methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, diisopropylamino group, butylamino group, pentylamino group, or hexylamino group. A monoalkylamino group or a dialkylamino group substituted with one or two lower alkyl groups may be mentioned.

Examples of the lower alkanoylamino group include alkanoylamino groups having 1 to 6 carbon atoms, such as a formamide group, an acetamido group, a propionylamino group, a butyrylamino group, a pentanoylamino group, or a hexanoylamino group.

Examples of the lower alkoxycarbonyl group include alkoxycarbonyl groups having 2 to 7 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl group, impropoxycarbonyl group, butoxycarbonyl group, pentyloxycarbonyl group, or hexyloxycarbonyl group. .

Examples of the lower alkanoyl group include alkanoyl groups having 1 to 6 carbon atoms such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, and hexanoyl group.

Examples of carbamoyl groups that may be substituted/substituted.

For example, N-methylcarbamoyl group, N-ethylcarbamoyl group, N,N-dimethylcarbamoyl group, N-propylcarbamoyl group, N-isopropylcarbamoyl group,
Examples include carbamoyl groups optionally substituted with one or two lower alkyl groups having 1 to 6 carbon atoms, such as N-butylcarbamoyl, N-pentylcarbamoyl, or N-hexylcarbamoyl.

R in the target compound of the present invention represented by the general group [■
Preferred examples of ' include hydrogen atom, methyl group, ethyl group, carboxymethyl group, 1-carboxy-1-methylethyl group, l-carboxycycloprobyl group, 1-
Carboxydiglobutyl group, 1-carboxycyclopentyl group, 1-carboxyvinyl group, 2-carboxyvinyl group, 2-carboxyethynyl group, fluoromethyl group,
2-fluoroethyl group.

2.2-difluoroethyl group, chloromethyl group, 2-chloroethyl group, bromomethyl group, 2-bromoethyl group,
Examples include vinyl group, ethynyl group, 3,4-dihydroxybenzyl group, α-carboxy-3,4-dihydroxybenzyl group, and benzyl group.

Preferred examples of the substituent at the 3-position of the target compound of the present invention represented by the general group [I] include (1-methylquinolinium-2-yl)thiomethyl group, (1-methylquinolinium-2-yl), (1-methylquinolinium-2-yl), (1-methylquinolinium-2-yl), (1-methylquinolinium-3-yl)thiomethyl group, (1-methylquinolinium-4-yl)thiomethyl group, (1-methylquinolinium-5-yl)thiomethyl group, (1-methylquinolinium-8-yl) )thiomethyl group, (1-carboxymethylquinolinium-4-yl)thiomethyl group, (1-carbamoylmethylquinolinium-4-yl)thiomethyl group, [:1-(2-fluoroethyl)quinolinium-4
-ylkothiomethyl group, [1-(2-fluoroethyl)
Quinolinium-5-ylcothiomethyl group, [1-(2
-dimethylaminoethyl)quinolinium-4-ylcothiomethyl group, (5-amino-1-methylquinolinium-
4-yl)thiomethyl group, (8-chloro-1-methylquinolinium-4-yl)thiomethyl group, (6-hydroxy-1-methylquinolinium-4-yl)thiomethyl group, (6,7- Examples include a cyhydroxy-1-methylquinolinium-4-yl)thiomethyl group and a [6,7-cyhydroxy-1-(2-fluoroethyl)quinolinium-4-ylcothiomethyl group.

Non-toxic salts of the compound of the present invention represented by the general formula [11] include salts with alkali metals such as sodium, potassium or lithium; salts with alkaline earth metals such as calcium or magnesium; '−
Salts with organic amines such as dibenzylethylenediamine, ethanolamine or triethylamine, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid, salts with organic acids such as citric acid or tartaric acid, such as methanesulfonic acid. Alternatively, salts with organic sulfonic acids such as P-toluenesulfonic acid, or salts with amino acids such as aspartic acid, glutamic acid, or lysine can be mentioned.

Furthermore, the compound of the present invention has geometric isomers [E-isomer and 2-isomer] derived from the oximino group in the 7-position side chain, both of which are included in the present invention, but 2-isomer is preferred.

Next, a method for producing the compound of the present invention will be explained.

General group [wherein R'' is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group R1 is an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group. group or optionally substituted lower alkynyl group, R1, R4 and R' may be the same or different, hydrogen atom, halogen atom, optionally substituted lower alkyl group, hydroxyl group, lower alkoxy group , lower alkanoyloxy group, amino group, lower alkylamino group, lower alkanoylamino group, carboxyl group, lower alkoxycarbonyl group, optionally substituted carbamoyl group, sulfo group, sulfamoyl group, lower alkanoyl group or nitro group, respectively. The production of the object compound [11] of the present invention represented by the general formula [wherein R"° is a hydroxyl-protecting group or the above-mentioned R" or a substituent in which the functional group of Ro is protected, Ro represents a hydrogen atom or a protecting group for an amino group, Ro represents a hydrogen atom or a protective group for a carboxyl group, and X represents a halogen atom or an acetoxy group. In the formula, Hll is a hydrogen atom or the above R3, or R
The substituents in which the functional group of 1 is protected are R"°, R"° and R
o0 is each of the above R3, R4 and R', or R
3, R4 and Ro functional groups represent protected substituents]
1. Then, as desired.

(+) Step (if) of N-alkylating the quinoline ring
Step of removing the protecting group (in) Step of converting into a non-toxic salt This can be carried out by performing one or more of the above steps.

The reaction between the compound of the general formula [■] and the compound of [tIl] is performed using the general formula CI! When X is a halogen atom in 1,
For example, it can be carried out in methylene chloride, chloroform, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof, with or without a deoxidizing agent. can. Examples of deoxidizers include metal salts such as sodium carbonate, potassium carbonate, calcium carbonate or magnesium carbonate, or organic amines such as triethylamine, diisopropylethylamine, N-methylmorpholine or N,N-dimethylaniline. For 1 mol of the compound of general formula [0], 1 to 2 mol of the compound of general formula [ml] is used.The reaction temperature and reaction time are not particularly limited, but are usually 0 to 40°C.
It takes 0.5 to 5 hours.

In general formula [II], the reaction between the compound in which X is an acetoxy group and the compound of general formula [I11] can be carried out using, for example, water, phosphate buffer, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, dioxane. , N,N-dimethylformamide.

One reaction that can be carried out in dimethyl sulfoxide or a mixed solvent thereof is preferably carried out near neutrality, and the reaction temperature and reaction time are not particularly limited, but are usually room temperature to 90°C and 1 to 15 hours.

This reaction can also be carried out in the presence of an iodide such as sodium iodide or potassium iodide, a thiocyanate such as sodium thiocyanate or potassium thiocyanate, or a quaternary ammonium salt such as benzyltrimethylammonium bromide. Facilitated by doing. The amount used is 1-20 mol per 11 mol of compound [n.

In the reaction between the compound of general group [111] and [III], when R1 of general group [I [1] is a hydrogen atom (i.e., a quinolinthiol compound), after one reaction, the quinoline ring is toalkylated with an alkylating agent. The alkylating agent used in the reaction is an optionally substituted lower alkyl halide such as methyl iodide, ethyl iodide, 1-bromo-2-fluoroethane, iodoacetic benzhydryl ester, or iodoacetic acid amide. .

Alkenyl halides such as vinyl chloride or furyl iodide; alkynyl halides such as propargyl chloride; cycloalkyl halides such as cyclopropyl iodide, cyclobutyl iodide or cyclopentyl iodide; The nine reactions include alkyl sulfonate esters such as methyl lomethanesulfonate and ethyl trifluoromethanesulfonate. Examples of the nine reactions include water, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, and methylene chloride. .

The reaction can be carried out using 1 to 5 moles of the alkylating agent in chloroform or a mixed solvent thereof.

The reaction temperature and reaction time are not particularly limited, but are usually between -10°C and 50°C and between 1 and 24 hours.

During the above steps, various functional groups may be protected as necessary, and when a - protecting group is present, the compound [+] of the present invention can be obtained by finally removing the protecting group. .

As the protecting groups for the carboxyl group, amino group and hydroxyl group in the general group, protecting groups commonly used in the field of β-lactam synthesis can be appropriately selected and used.

Methods for introducing and removing protecting groups vary depending on the type of protecting group.
Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis) by
oups inOrganic 5 synthesis)
, from Plenum Press 1
Protective Groups in Organic Chemistry, written by J.F. McOmte, published in 1973.
Protective Groups in Orga
This can be carried out by appropriately selecting a method described in NIC Chemis-try) and the like. As a protecting group for carboxyl group, for example, t-butyl group, 2,2.24
Lichloroethyl group, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, l-acetoxyethyl group, l-propionyloxyethyl group, 1
-(Ethoxycarbonyloxy)ethyl group, phthalidyl group, benzyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group, bis(4-methoxyphenyl)methyl group, (
5-Methyl-2-oxo-1,3-dioxo-4-
yl)methyl group, trimethylshinol group, tert-butyldimethylsilyl group, etc., and particularly preferred are benzhydryl group, tert-butyl group, and silyl group.

Examples of protecting groups for amino groups include trityl group, formyl group, chloroacetyl group, trifluoroacetyl group, t
Examples include ert-butoxycarbonyl group, trimethylsilyl group, and tert-butyldimethylsilyl group.

Examples of protecting groups for hydroxyl groups include 2-methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, phenacyl group, isopropyl group, tert-butyl group, benzyl group, 4-nitrobenzyl group, and acetyl group. , 2,2.2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, trimethylsilyl group, tert-butyldimethylsilyl group or, for example, orthoesters such as methoxyethylidene, methoxyethylidene, etc., formed by combining protective groups with each other, benzylidene acetal , cyclic acetals such as methylene acetal and ethylene acetal, cyclic ketals such as isopropylidene ketal, and cyclic carbonate esters.

To explain specifically how to remove the protecting group, trityl group,
Removal of protecting groups such as formyl group, tert-butoxycarbonyl group, benzhydryl group, tert-butyl group or 2-methoxyethoxymethyl group can be carried out using, for example, hydrochloric acid, formic acid,
This can be carried out using an inorganic or organic acid such as trifluoroacetic acid, benzenesulfonic acid or P-toluenesulfonic acid, with trifluoroacetic acid being particularly preferred.

In addition, when trifluoroacetic acid is used as the acid, the reaction is promoted and side reactions are also suppressed by adding anisole, thioanisole or phenol.

In addition, the reaction can be carried out in a solvent that does not participate in the reaction, such as water, methylene chloride, chloroform, ethylene chloride, benzene, or a mixed solvent thereof.The reaction temperature and reaction time are suitable for compound [II] and the present compound [ It is suitably selected depending on the chemical properties of No. 11 and the type of protecting group, and it is particularly preferable to carry out the reaction under conditions of water cooling or heating.

The compound represented by the general formula [11], which is a synthetic intermediate for the compound of the present invention, is a compound represented by the general formula [in the formula, R'' and X have the above-mentioned meanings]. , R'' and R10 have the above-mentioned meanings] or a reactive derivative of its carboxyl group.

The step of producing a compound represented by general group [1] by reacting a compound represented by general group [IV] with a compound represented by general group [Vl or a reactive derivative of its carboxyl group] is as follows: For example, water, acetone, dioxane, ether,
In a solvent that does not adversely affect the reaction, such as tetrahydrofuran, ethyl methyl ketone, chloroform, methylene chloride, dichloroethane, ethyl acetate, ethyl formate, N,N-dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof, under cooling or at a reaction temperature of The reaction can be carried out at room temperature and for a reaction time of 1 to 10 hours. Examples of reactive derivatives of the carboxyl group of the compound represented by the general group [Vl include N, N'-
Active esters formed with dehydrating agents such as dicyclohexylcarbodiimide and, for example, N-hydroxysuccinimide or 1-hydroxybenzotriazole; formed with halogenating agents, such as thionyl chloride, phosphorus pentachloride, or oxalyl chloride. Acid halides; for example, mixed acid anhydrides formed by deoxidizing agents such as triethylamine or N-methylmorpholine and chlorocarbonate esters such as methyl chloroformate or isobutyl chloroformate; Furthermore, depending on the type of the reactive derivative of the carboxylic acid used, it may be preferable to carry out the reaction in the presence of a base to allow the reaction to proceed smoothly.6 Examples of such bases include potassium hydrogen carbonate, sodium carbonate, etc. or an inorganic base such as potassium carbonate or an organic base such as trimethylamine, triethylamine, N,N-dimethylaniline or pyridine. Time is N, N
'-dicyclohexylcarbodiimide or N.

It is preferable to use a condensing agent such as N'-diethylcarbodiimide. Note that compounds represented by the general group [IV'l] are described in the Journal of Antibiotics (J
Antibiotics), Vol. 38, p. 1738 (1985). (
Chew, Pharm, Bull, ), Volume 25, 3
It can be produced according to the method described in p. 115 (1977) and Journal of the Chemical Society of Japan, p. 785 (1981).

The compound of general formula [I11] represents quinolylthiol or quinoliniumthiol, and forms the following tautomeric system depending on the substitution position of the thiol group (for example, the 2- or 4-position).

The compound represented by the general formula [III] is known per se or can be synthesized by a known general reaction. It can be easily obtained by reaction, reaction between chlorine atom and sodium hydrogen sulfide, hydrolysis of 1 inch uronium group or dithiocarbonate, etc.

The compounds of the present invention exhibit excellent antibacterial activity and are novel compounds useful as pharmaceuticals, and are used for the treatment and prevention of bacterial infections, such as respiratory infections, urinary tract infections, purulent diseases, or surgical infections. be able to. The method of administration is intravenous injection.

Parenteral administration via intramuscular injection or suppositories, or tablets;
Oral administration using powders, capsules, syrups, etc. is applicable. Note that these dosage forms can be produced by conventional methods in this field, and may contain commonly used additives such as auxiliaries, wetting agents, emulsifiers, binders, or excipients. The dosage may also depend on age and gender.

It is determined by taking into account body weight, sensitivity difference, administration method, time and interval of administration, degree of medical condition, physical condition, properties of pharmaceutical preparation, type of preparation, type of active ingredient, etc., but usually 1 to 100 mg per day. 100mg/kg, 5-30 mg/day
It is preferable to administer ntg/- in 2 to 4 divided doses.

In order to specifically demonstrate the usefulness of the compounds of the present invention, in vitro antibacterial activity against various bacteria was measured by the agar plate dilution method described below. That is, one loopful of each test strain cultured overnight in Mueller-Hinton broth (inoculum amount:
Mueller-Hinton agar was inoculated with 10'CFU/ill. This medium contained the test drug at a predetermined concentration, and after culturing at 37° C. for 16 hours, the minimum inhibitory concentration (MIC, g/m(+)) was measured. The results are shown in the table.

As is clear from the table, it can be seen that the compounds according to the present invention exhibit a wide range of antibacterial activity against a wide variety of test bacteria.

(The following is a blank space) 341 animals The present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 1 7β-[2-(2-aminothiazol-4-yl)-(
Z)-2-methoxyiminoacetamide]-3-[(1
-methylquinolinium-4-yl)thiomethyl]-3-
Cephemu 4-carboxylate 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamide]-3
-Iodomethyl-3-cephem-4-carboxylic acid benzhydryl ester 466 mg (0.5 ma + ol) was added to N
, dissolved in N-dimethylformamide 6me, at room temperature,
N-methylquinoline-4-thione 87.5 mg (0,5
mmol) and stirred for 1 hour.

After evaporation of the solvent, the residue was triturated with isopropyl ether to give 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamide]-3-[(i- Methylquinolinium-4-
yl)thiomethyl]-3-cephemu 4-carboxylic acid benzhydryl ester iodide 363 mg (yield 6
5.4%). Of these, 352i+g (0,317
mff1ol) was dissolved in 1.8 d of methylene chloride and 0.38 me of anisole, and 2.0 d of trifluoroacetic acid was dissolved under water cooling.
Add 8- and stir at the same temperature for 1 hour. After distilling off the solvent, isopropyl ether is added to the residue to obtain the trifluoroacetate of the title compound as a powder. Dissolve this in water, adjust the pH to 6.5 with an aqueous sodium hydrogen carbonate solution,
Reversed phase column chromatography (Chemco LC-5ORB
, 5P-B-ODS.

The title compound was purified by eluting with a 40-50% aqueous methanol solution and lyophilized to give 51.2 mg of the title compound (yield 28.3%).
).

mp: 155-160°C (decomposition) IR (KBr)-: 3400, 1765, 1670,
1610, 1560, 153 ON MR (DMSO-
d, ) δ: 3.84 (3H, s), 4.46 (3H,
s).

4.70 (2H, bs), 5.03 (IH, d, J=5
Hz), 5.58 (LH, dd.

J=5&7Hz), 6.74(LH,s), 7.25
(2)1. bs), 7.2-9.3 (6H, m), 9.
54 (LH, d, J=7Hz) In the same manner as in Example 1, the following compounds of Examples 2 to 4 were synthesized.

Example 2 7β-[2-(2-aminothiazol-4-yl)-(
Z)-2-methoxyiminoazedoamide co-3-([1
-(2-fluoroethyl)quinolinium-4-ylcothiomethyl)-3-cephem-4-carboxylate m p: 145-150°C (decomposition) I R (KBr
)a(:3400,1770,1670,1600,1
530,1380°1350.1160,1035.7
6ON MR(DMSO-d, )δ:3.42,3
．． 64 (2B, ABq, J=17Hz).

3.82 (3H, s), 4.73 (2H, bs), 4.
98 (28, d, J”46Hz).

5.04 (LH, d, Jl15Hz), 5.34 (2
H, d, J = 27 Hz), 5.59 (IFI, dd, J
=5&8Hz), 6.75 (111,s), 7.24
(2H, bs).

7.97 (IH, d, J = 7) 1z), 8.52 (2t
l, bs), 8.79 (In, d.

J=8Hz), 8.84 (IH, d, J=8Hz), 9
．． 19 (IH, d, J=7Hz).

9.55(II, d, J=8I(Z) Example 3 7β-[2-(2-aminothiazol-4-yl)-(
Z)-2-methoxyiminoacetamide]-3-(1-
Carboxymethylquinolinium-4-yl)thiomethyl-3-cephem-4-carboxylate sodium m
p: 165-175℃ (decomposition) I R (KBr)a
i: 3400, 1770, 1620, 1530, 13
80,1210°1180.1010 4ON (DMSO-d, +D, 0) δ: 3.45,
3.64 (2H, ABq.

JJ8Hz), 3.83 (3H, s), 4.67 (2B
, bs), 5.04 (LH, d.

J"5Hz), 5.22 (2H, bs), 5.61 (L
H, d, J”5Hz), 6.71 (IH, s), 8.0
(lfl, d, J=7Hz), 8.14 (2H, bs)
, 8.37 (IH, d, J=8Hz), 8.47 (1B
, d, J”8Hz) , 8.96 (IH, d.

J=7Hz) Example 4 7β-[2-(2-aminothiazol-4-yl)-(
Z)-2-methoxyiminoazedoamide]-3-(6,
7-hydroxy-1-methylquinolinium-4-yl)thiomethyl-3-cephem-4-carboxylate mp: 170-180°C (decomposition) r R (KBr
) ail: 3400, 1770, 1670, 1620
,1555,1505゜1290.1170,1100
．． 104ON MR (DIIISO-d, +D□O)
δ: 3.36, 3.61 (28, ABq.

J = 18Hz), 3.82 (3H, s), 3.94 (3
H,s), 4.98 (11,d.

J=5Hz), 5.62 (IH, d, J=5Hz), 6
．． 55 (IH, s), 6.75 (IH, s), 7.14
(18, d, J=7H1), 7.95 (IH, S), 8
．． 08 (IH, d, J = 7H2) Example 5 7β-[2-(2-aminothiazol-4-yl)-(
Z)-2-(1-carboxy-1-methylethoxyimino)acetamide]-3-(1-methylquinolinium-
4-yl)thiomethyl-3-cephem-4-carboxylate Sodium 7β-C2-<2-tritylaminothiazol-4-yl)-(Z)-2-(1-diphenylmethoxycarbonyl-1-methylethoxyimino) Acetamitoco-3-
585 mg (0.5 m++ ol) of iodomethyl-3-cephem-4-carboxylic acid benzhydryl ester with N,
Dissolved in N-dimethylformamide 6d and added N- at room temperature.
Methylquinoline-4-thione 87.5 mg (0.5 mm
ol) and stir for 1 hour. After distilling off the solvent,
Trituration of the residue with isopropyl ether gives 7
β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-(1-diphenylmethoxycarbonyl-1-methylethoxyimino)acetamide]-3-[
1 g (yield: 69.9%) of (1-methylquinolinium-4-yl)thiomethyl2-3-cephem-4-carboxylic acid benzhydryl ester iodide 468II is obtained.

Of this, 460 mg (0,343 mmol) was dissolved in 1,9 mQ of methylene chloride and 0.41 m9 of anisole, and 3 parts of trifluoroacetic acid was added under water cooling, followed by stirring at the same temperature for 1 hour. After distilling off the solvent, isopropyl ether is added to the residue to obtain the trifluoroacetate of the title compound as a powder. This was dissolved in water, adjusted to pH 6.5 with an aqueous sodium bicarbonate solution, and subjected to reverse phase column chromatography (Chemco LC-3ORB, 5P-B-ODS,
40-50 & elution with an aqueous methanol solution) and lyophilized to give 128 mg (yield 28.3%) of the title compound.
get.

m p + 150-160℃ (decomposition) I R (KBr
) aW: 3400, 1765, 1660, 1600.
153ON MR(DMSO-d, )δ: 1.37
(311,S), 1.42 (3H,S).

4.49 (3H, s), 4.50, 4.87 (2H, A
Bq, J=13Hz), 5.04(IH, d, J=5H
z), 5.67 (IH, dd, J=5 & 9) 1z), 6
．． 71 (LH, s), 7.20 (IH, bs), 7.3
-7.4 (6H, o+) In the same manner as in Example 5, the following compounds of Examples 6 to 8 were synthesized.

Example 6 7β-[2-(2-aminothiazol-4-yl)-(
Z)-2-(1-carboxy-1-methylethoxyimino)acetamide]~3-f(:1-(2-fluoroethyl)quinolinium-4-ylcothiomethyl)-3-cephem-4-carboxylate sodium mp: 150-160℃ (decomposition) I R (KBr) a (: 3400, 1770, 1600
, 1530, 1400, 1360° 1200.116O NMR (DMSO-d, +D, O) δ: 1.42 (
61 (, S), 3.45° 3.66 (2B, ABq, J
'17Hz), 4.66 (2H, bs), 5.0 (2H
,d.

J'46Hz), 5.08 (IFI, d, J=5Hz)
, 5.28 (2H, d, J=26Hz), 5.72 (
IH, d, J=5Hz), 6.8 (LH, s), 8
．． 05(Iff, d.

J=7)1z), 8.28(2H,d, J=7Hz),
8.46 (IH, d, J=8Hz).

8.56 (IH, d, J=8Hz), 9.05 (IH,
d, J=7Hz) Example 7 7β-[:2-(2-aminothiazol-4-yl)-
(Z)-2-(l-carboxy-1-methylethoxyimino)acetamide]-3-(1-carboxymethylquinolinium-4-yl)thiomethyl-3-cephem-4
-Sodium carboxylate 2-sodium m p: 145-155°C (decomposition) I R (KBr
) aW: 3400, 1770, 1600, 1530
, 1380, 1200° 16O NMR (DMSO-d,) δ: 1.40 (3H, s
), 1.42 (3H, s).

3.42, 3.63 (2H, ABq, J-18!Tz)
, 4.57, 4.77 (2fl.

ABq, J=14Hz), 5.04(IH, d, J=5
Hz), 5.23 (2B, s).

5.69 (LH, d, J = 5Hz), 6.76 (1! (
, s), 7.99 (LH, d, J=8Hz), 8.14
(2■, bs), 8.23 (IH, d, J=7) 1z)
, 8.48 (IH, d, J=8Hz), 8.98 (II
, d, J=71fz) Example 8 7β-[2-(2-aminothiazol-4-yl)-(
Z)-2-(l-carboxy-1-methylethoxyimino)acetamitoco-3-(6,7-cyhydroxy-1
Sodium -methylquinolinium-4-yl)thiomethyl-3-cephem-4-carboxylate: 175-185°C (decomposition) IR (KBr
) Cil: 3400, 1780, 1610, 1520,
1370, 1150° 1100.98O NMR (DMSO-d, +D, O) δ: 1.40 (3H
,s), 1.42(31(.

s), 3.42.3.67 (2H, ABq, J=18H
z), 4.0 (3H, s).

5.04 (IH, d, , I'5Hz), 5.68 (IH
, d, 5tlz), 6.61 (IH, s), 6.81
(IH, s), 7.20 (IH, d, J=7Hz), 8
．． 01(LH,s), 8.14(11(,d, 7Hz
) Example 9 7β-[2-(2-aminothiazol-4-yl)-(
Z)-2-methoxyiminoacetamide]-3-(1-
Methylquinolinium-5-yl)thiomethyl-3-cephem-4-carboxylate 5-benzoylthioquinoline 100II+g (0,37
Dissolve 7 mmol) in 2 volumes of 6N hydrochloric acid and heat under reflux for 1 hour.The reaction mixture is allowed to cool, washed with ether, adjusted to pH 3.0 with 6N sodium hydroxide, and extracted with methylene chloride.

The extract was dried over sodium sulfate, the solvent was distilled off, and 5
- 35 mg of crude mercaptoquinoline (yield 57.
6%). This was used in the next reaction without purification. 7β-[2-(2-tritylaminothiazole-4
-yl)-(Z)-2-methoxyiminoacetamide]
-3-iodomethyl-3-cephem-4-carboxylic acid benzhydryl ester 200 [Ilg (0,21 mmo
l) to Ill, N-dimethylformamide 2mi! The solution dissolved in
and further stirred at the same temperature for 3 hours. After distilling off the solvent, the residue was diluted with 1 mg of methylene chloride and 0.2 mg of anisole.
+njl! 1 mQ of trifluoroacetic acid was added under water cooling, and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent, isopropyl ether is added to the residue to obtain the trifluoroacetate of the title compound as a powder. This was dissolved in water, adjusted to pH 6.5 with an aqueous sodium carbonate solution, and subjected to reverse phase column chromatography (Chemco LC-SORB, 5P-
B-ODS, eluted with 20% methanol aqueous solution) and lyophilized to give the title compound 27a+g (yield 22%)
get.

m p: 130-140°C (decomposition) I R (KBr
)cffl:3400,1765,1670,160
5.153ONMR(DMSO-d,)δ:3.84(
3Ls), 4.25(II(,d.

J=13Hz), 4.60(11(,d, J=13Hz
), 4.62 (3H,s>.

4.95 (LH, d, J=4Hz), 5.45 (IH,
m), 6.76 (11(, s).

7.26 (2H, bs), 8.0-8.4 (4H, m)
, 9.50 (2H, m) Example 10 7β-[2-(2-aminothiazol-4-yl)-(
Z)-2-(1-ruboxy-1-methylethoxyimino)acetamitoco-3-(1-methylquinolinium-
Sodium 5-yl)thiomethyl-3-cephem-4-carboxylate was synthesized in the same manner as in Example 9.

m p: 130-140°C (decomposition) IR (Br)
ai: 3400, 1760, 1600, 1530, 1
400,136ONMR (DMSO-d,) δ: 1.3
8(3)1. s), 1.45 (311, s) 4.22 (
IH, d, JJ2Hz), 4.35 (IH, d, J=1
2Hz), 4.64 (3H, s), 4.92 (1) 1.
d, J=4Hz), 5.62(II(, dd, J=43
8Hz), 6.72 (IH, s), 7.20 (2H, b
s), 8.0-8.4 (4H, m).

9.45 (IH, m), 9.62 (LH, m) Reference example 1 N-methylquinoline-4-thione N-methyl-4-quinolone 6.37 g (40I+1
Dissolve 8.9 mol of pyridine in 8.9 mol of phosphorus trisulfide.
g (40 mmol) and heated under reflux for 1 hour while stirring. After distilling off the solvent, 400 d of ethyl acetate was added to the residue.
400ml of tetrahydrofuran! Add 200 m2 of water, separate the solid layer, and wash with dilute hydrochloric acid and then saturated saline.
After drying over anhydrous magnesium sulfate, the solvent was distilled off and the residue was crystallized from methanol to yield 4.63 g of the title compound.
(yield 66%).

IR(KBr)ci71:1650,1535,15
20,1370.1160UVλ:: 226nm(t
=34,000), 252na+(t =6,800
).

272 nm (t = 7,500), 404 nm (tw
t23,700)NMR(CDC1,)δ:3.9
(3H, s), 7.32 (Ill, t, J = 4Hz) 7
．． 4-7.6 (2H, m), 7.7 (1B, s+), 9
．． 02 (IH, d, J=8Hz) Reference Example 2 N-(2-fluoroethyl)quinoline-4-thione (A
) 4-hydroxyquinoline 2.18 g (15mio
l) in 45+d of N,N-dimethylformamide and 1.08 g of 50% oily sodium hydride (22,
5 mmol) and stirred while heating at 60°C for 15 minutes. After cooling, 1.68 d of 1-bromo-2-fluoroethane (
22.5a+mol) and stirred at room temperature for 1.5 hours. After distilling off the solvent, the residue was subjected to silica gel column chromatography (Wakogel C-300).

eluted with 1-3% methanol-chloroform),
N-(2-fluoroethyl)-4-quinolone 1.27g
(yield 44.3%).

r R(KBr)cffl :3400.1630,1
590,1490,1230.1030UV λ':
: : 236 nm (t = 20,900), 32
2r+m (E = 14,200) 335nlIl (E:
15,800) NMR(CDC1,”)δ:4.44(2H,d5
J=24 & 4 Sat).

4.81 (2H, dt, J=47 & 4m), 6.3
0 (18, d, J=7 ratio).

7.38 (IH, d, J = 7 soil), 7.42 (IH, t
, J=7 ratio), 7.57 (1B, d, J=7Hz), 7
．． 70 (xH, t, J = 7Hz), 8.50 (18, d
.

J=7 ratio) (B) 1.15 g (6 mn+ol) of N-(2-fluoroethyl)-4-quinolone obtained in (A) was dissolved in 10 d of pyridine, and 1.33 g (6 mn+ol) of phosphorus trisulfide was dissolved in 10 d of pyridine.
a+mol) and stirred while heating at 60°C for 1 hour.

The solvent was distilled off, the residue was dissolved in chloroform 150-
Wash with water and then saturated saline.

Dry over anhydrous magnesium sulfate, remove the solvent, and triturate the residue with ethyl acetate to obtain 1.15 g of the title compound.
(yield 92.5%).

I R(KBr)a(:1600,1590,1530
,1440,1370,1160UVλ' : : : 2
27 nm (E = 32,700), 406 nm (ε = 2
3,400) Reference Example 3 N-diphenylmethoxycarbonylmethylquinoline-4
-thione (A) 4-hydroxyquinoline 726 mg (5ml
l) in 10 volumes of N,N-dimethylformamide,
50% oily sodium hydride 360mg (7.5mn
ol) and stirred while heating at 60°C for 15 minutes. After cooling,
Monochloroacetic acid benzhydryl ester 1.96 g
(7.5 mmol) and potassium iodide 1.66 g (
lornrnol') and stirred at 60°C for 1 hour.

After evaporating the solvent, the residue was purified by silica gel column chromatography (Fuco-gel C-300, eluted with 0-5% methanol-chloroform) to obtain 1.55 g of N-diphenylmethoxycarbonylmethyl-4-quinolone (
Yield: 83.9%).

IR(KBr)cffl :1750,1620,1
590,1485,1220.119ON M R(C
DCI, ) δ: 4.87 (2) 1. s), 6.35(
11 (, d, J=8Hz) 6.94 (IH, s), 7.
1-7.6 (15H, !l), 8.49 (IH, d, 8 ratio) (B) Obtained in (A). N-diphenylmethoxycarbonylmethyl-4-quinolone 1.48g (4mmo
l) in 10 parts of pyridine, 0.89 parts of phosphorus trisulfide
g (4 mol) was added, and the mixture was heated and stirred at 60°C for 1 hour. Distill the solvent.

To the residue were added 500 d of ethyl acetate, 10 farts of N,N-dimethylformamide and 50 mff 1 of water, and the organic layer was separated.

The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was triturated with ethyl acetate to give 0.93 g of the title compound (yield: 6
0.3%).

IR(KBr)cffl :1750,1590.1
160UVλ':: 224nm (t = 33,6
00), 408 nc (E = 24,900) N M R
(CDCIs) δ: 4.94<2H,s), 6.94(
1) f, s), 7.2-7.6 (15H, m), 9.0
5 (IH, d, J = 8 Hz) Reference example 4 6.7-dihydroxy-N-methylquinoline-4-thione (A) Journal of the American Chemical Society (J, Am, Chem, Soc,),
6,7-Simethoxy-4-quinolinol 3. synthesized by the method described in Vol. 68, p. 1264 (1964).
Dissolve 08 g (15 mmol) in 60% N,N-dimethylformamide to obtain 1.4IIIQ methyl iodide.
(22,5 mmol) and potassium carbonate 3.1 g
(22.5 mmol) and stirred at 40°C for 4 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Wako Gel C-300, eluted with 0-3% methanol-dichloromethane) to obtain 1.97 g of 6.7-dimethoxy-N-methyl-4-quinolone ( Yield: 59.
9%).

I R(KBr)ai? :3400,1620,15
50,1490.1270UVλ' : : : 249n
m (i = 28,100), 324 nm (F = io, 3
oo) 337 nm (t = 11,200) NMR(DMSO-d,') δ: 3.82 (3H
, S), 3.86 (3H, S).

3.96 (3H, s), 5.96 (18, d, J'8H
z), 7.03 (Ill, s) + 7.55 (1)! ,s
), 7.87 (lH, d, J=8Hz) (B) (A
), 6,7-dimethoxy-N-methyl-4-
1.32 g (6 mmol) of quinolone was dissolved in 47% hydrobromic acid 13- and heated to reflux overnight. The solvent was distilled off, the residue was washed with acetone, and the 6,7-dihydroxy-N
-Methyl-4-quinolone hydrobromide 1.3 g (yield 7
9.6%).

IR(KBr)aW :3400,3150,163
0,1580,1550,1510°30O NMR(DMSO-d, )δ:4.22(38,
s), 6.99 (IH, d, J=7Hz), 7.38 (
LH, s), 7.61 (IH, s), 8.70 (LH,
d, J near ratio) (C) Obtained in (B). 6,7-dihydroxy-N
-Methyl-4-quinolone hydrobromide 1.22 g (
4.5fflfflol) was dissolved in 7d of pyridine, 1 g (4.5 mmol) of phosphorus trisulfide was added, and the mixture was heated and stirred at 60° C. for 1 hour. The solvent was distilled off and the residue was washed with water and then methanol to obtain 0.5 g of the title compound (
Yield: 53.6%).

I R(KBr)a[:3400,1630,1610
,1480,1460,1265UVλ' : : : 2
34nm (i = 19,000), 331na+(E
= 5,800).

402 nm (t 1113,900) NMR (DMSO-d, ) δ: 3.92 (3B,
s), 7.22 (lH, d, J near ratio), 7.43 (I
H, s'), 7.84 (ILd, J near ratio), 8.2
4(II(.

S) Since the compound of the present invention exhibits excellent antibacterial activity, it is useful as a therapeutic agent for bacterial infections in mammals including humans.

Claims (3)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [I] [In the formula, R^1 is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group,
An optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, R^
2 is an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, or an optionally substituted lower alkynyl group, R^3, R^4 and R^5 may be the same or different, and include a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a lower alkylamino group, and a lower alkanoyl group. an amino group, a carboxyl group, a lower alkoxycarbonyl group, an optionally substituted carbamoyl group, a sulfo group, a sulfamoyl group, a lower alkanoyl group, or a nitro group, or a non-toxic salt thereof. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] [In the formula, R^1^0 is a protecting group for the hydroxyl group or a functional group of R^1 or R^1 in the general formula [I] described below. The group is a protected substituent, R^6 is a hydrogen atom or an amino group protecting group, R^
7 represents a hydrogen atom or a protecting group for a carboxyl group, X represents a halogen atom or an acetoxy group, respectively] or its salt is represented by the general formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [III ] [In the formula, R^2^0 is a hydrogen atom or the general formula [ I
] R^2 or a substituent in which the functional group of R^2 is protected, R^3^0, R^4^0 and R^5^0 are respectively R^3 of the general formula [I] below , R^4 and R^5, or the functional groups of R^3, R^4 and R^5 each represent a protected substituent],
Then, if desired, (i) step (ii) of N-alkylating the quinoline ring.
General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [I] [In the formula, R^1 is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group,
An optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, R^
2 is an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, or an optionally substituted lower alkynyl group, R^3, R^4 and R^5 may be the same or different, and include a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a lower alkylamino group, and a lower alkanoyl group. A method for producing a compound represented by an amino group, a carboxyl group, a lower alkoxycarbonyl group, an optionally substituted carbamoyl group, a sulfo group, a sulfamoyl group, a lower alkanoyl group, or a nitro group, or a non-toxic salt thereof. (3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [I] [In the formula, R^1 is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group,
An optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, R^
2 is an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, or an optionally substituted lower alkynyl group, R^3, R^4 and R^5 may be the same or different, and include a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a lower alkylamino group, and a lower alkanoyl group. An active ingredient is a compound represented by an amino group, a carboxyl group, a lower alkoxycarbonyl group, an optionally substituted carbamoyl group, a sulfo group, a sulfamoyl group, a lower alkanoyl group, or a nitro group, or a non-toxic salt thereof. antibacterial agent.