JP2676763B2 - Cephalosporin derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel cephalosporin derivative useful in the medical field, a method for producing the same, and use thereof as an antibacterial agent.

2. Description of the Related Art Conventionally, cephalosporin antibiotics have been widely used for treatment of diseases caused by human and animal pathogenic bacteria, for example, treatment of diseases caused by infection of bacteria having resistance to penicillin antibiotics. Also, cephalosporin antibiotics are excellent in terms of safety because they are particularly useful for treating bacterial infections in penicillin-sensitive patients and have low toxicity. Against this background, there have been numerous attempts to create cephalosporin antibiotics having stronger antibacterial activity and superior safety.

Among such attempts, a derivative in which the 3-position of the cephalosporin skeleton is directly substituted with an oxygen atom is known and disclosed in JP-A-49-
55687, 50-108287, 51-56489, 51-6319
No. 1, No. 53-103493, No. 59-76089, No. 6140292,
61-130293 and 62-19594, etc. However, many of the compounds described therein are merely used as intermediates for production or have a simple lower alkoxy group represented by a methoxy group as a substituent at the 3-position. Therefore, a compound having an alkoxy group substituted with a heterocyclic group which may be substituted at the 3-position of the cephalosporin skeleton as in the present invention is not known.

The object of the present invention is to provide a compound having excellent antibacterial activity against pathogenic bacteria and also having excellent safety properties.

Means for Solving the Problems As a result of earnest studies to create a cephalosporin derivative having excellent antibacterial activity, the present inventors have found that a heterocyclic group which may be substituted at the 3-position of the cephalosporin nucleus is used. It was found that a series of cephalosporin derivatives having a substituted alkoxy group have excellent antibacterial activity,
The present invention has been completed.

The present invention provides a compound represented by the general formula [I]: [In the formula, R ¹ is an amino group substituted with an acyl group selected from the group consisting of an aliphatic acyl group, an aromatic acyl group and a heterocyclic acyl group, R ² is a halogen atom, a methyl group, an ethyl group, Propyl group, hydroxymethyl group, aminomethyl group, sulfomethyl group, carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfur Famoylmethyl group, oxo group, N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group, ethoxy group, fluoromethoxy group,
Difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group, carbamoyloxy group, N- 1 or it selected from the group consisting of methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. The heterocyclic group optionally substituted with the above substituents, R ³ is a hydrogen atom, negative charge or lower alkanoyloxymethyl group, 1- (lower alkoxycarbonyloxy) ethyl group, 5-substituted-2-oxo- 1,3-dioxole An ester residue capable of forming a non-toxic ester hydrolyzable in vivo selected from the group consisting of -ylmethyl group, 1-phthalidyl group and 5-cyano-1-phthalidyl group, and X represents an alkylene group, respectively] The present invention relates to a cephalosporin derivative represented by or a non-toxic salt thereof, a method for producing the same, and an antibacterial agent containing the cephalosporin derivative as an active ingredient.

Next, in the description of the present specification, definitions of various terms included in the scope of the present invention referred to and appropriate examples thereof will be described below.

The aliphatic acyl group is, for example, a lower or higher alkanoyl group having 1 to 20 carbon atoms such as formyl group, acetyl group, succinyl group, hexanoyl group, heptanoyl group or stearoyl group, for example, methoxycarbonyl group, ethoxycarbonyl group, tert. A lower alkoxycarbonyl group having 2 to 8 carbon atoms such as butoxycarbonyl group, tert-pentyloxycarbonyl group or heptyloxycarbonyl group, for example, 1 to 4 carbon atoms such as methanesulfonyl group, ethanesulfonyl group or propanesulfonyl group A lower alkanesulfonyl group of, for example, a vinylthioacetyl group, an allylthioacetyl group, an allylthiopropionyl group or a butenylthioacetyl group, and a lower alkenylthioalkanoyl group having 4 to 8 carbon atoms, such as methylthioacyl group. Lower alkylthioalkanoyl group having 3 to 8 carbon atoms such as cetyl group, ethylthioacetyl group or methylthiopropionyl group, or unsaturated cycloalkenylalkanoyl group having 8 to 10 carbon atoms such as cyclohexenylacetyl group or cyclohexadienylacetyl group Means an aliphatic acyl group such as a group.

The aromatic acyl group is, for example, a benzoyl group, a toluoyl group or a naphthoyl group, and an aroyl group having a carbon number of 7 to 12, such as a phenylacetyl group or a phenylpropionyl group, and an arylalkanoyl group having a carbon number of 8 to 10, for example. Aryloxycarbonyl group having 7 to 12 carbon atoms such as phenoxycarbonyl group or naphthyloxycarbonyl group, for example, arylalkoxycarbonyl group having 8 to 10 carbon atoms such as benzyloxycarbonyl group or phenethyloxycarbonyl group, or for example phenoxyacetyl group Alternatively, it means an acyl group containing an aromatic carbocycle such as an aryloxyalkanoyl group having 8 to 10 carbon atoms such as a phenoxypropionyl group.

The heterocyclic acyl group, for example, a heterocyclic carbonyl group such as a thenoyl group, a furoyl group or a nicotinoyl group,
For example, thienylacetyl group, thiazolylacetyl group, thiadiazolylacetyl group, dithiynylacetyl group, pyridylacetyl group, pyrimidinylacetyl group, triazolylacetyl group, tetrazolylacetyl group, furylacetyl group, oxazolyl. Heterocyclic alkanoyl group such as acetyl group or thiadiazolylpropionyl group or heterocyclic oxyalkanoyl group such as pyridyloxyacetyl group, pyridylthioacetyl group or pyridyloxypropionyl group or heterocyclic thioalkanoyl group Means an acyl group containing

The acyl group may have one or more same or different, suitable substituents, and examples of the substituents include a halogen atom and an optionally substituted alkyl group, Hydroxyl group, methoxy group, ethoxy group,
Fluoromethoxy group, trifluoromethoxy group, difluoromethoxy group, formyloxy group, acetoxy group, fluoroacetoxy group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, carbamoyloxy group, N, N-dimethyl A carbamoyloxy group,
N-methylcarbamoyloxy group, amino group, acetamide group, formamide group, fluoroacetamide group, carboxyl group, sulfo group, sulfamoyl group, cyano group, formula (a ₁ ) = N to OR ⁵ (a ₁ ) (in the formula, R ⁵ is a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a formyloxy group, an acetoxy group, a fluoroacetoxy group, an N-methylcarbamoyl group. A carbamoyl group,
N-methylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, amino group, methylamino group, dimethylamino group, formamide group, acetamido group, fluoroacetamido group, carboxyl group, methoxycarbonyl Group, ethoxycarbonyl group, sulfo group, sulfamoyl group, cyano group, formyl group, acetyl group, fluoroacetyl group, diethylamino group, ethylamino group, methylthio group, ethylthio group, propylthio group, fluoromethylthio group, 2-fluoroethylthio group Group, 1-fluoroethylthio group, tetrazolyl group, 1-methyltetrazolyl group, thiazolyl group,
2-aminothiazolyl group, 5-amino-1,2,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, imidazolyl group, thienyl group, furanyl group, 2-aminooxazoli Group, isothiazolyl group, isoxazolyl group, quinolyl group, isoquinolyl group, pyridyl group, 3,4-dihydroxy-6-pyridyl group, piperazinyl group, pyrrolidinyl group, piperidyl group, pyrrolyl group, morpholinyl group, benzothiazolyl group and benzimidazolyl group A group consisting of a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of, a carbamoyl group, a carboxyl group, an amino group, a methylamino group, a dimethylamino group, a sulfo group, a hydroxyl group and a cyano group. Cycloalkyl optionally substituted with one or more substituents selected from , A halogen atom, a carboxyl group, an amino group, a sulfo group, a hydroxyl group, a lower alkenyl group optionally substituted with one or more substituents selected from the group consisting of a carbamoyl group and a cyano group, a halogen atom, a hydroxyl group, Lower alkynyl group optionally substituted by one or more substituents selected from the group consisting of amino group, carboxyl group, carbamoyl group, sulfo group and cyano group, halogen atom, methyl group,
Hydroxymethyl group, fluoromethyl group, trifluoromethyl group, ethyl group, bromomethyl group, difluoromethyl group, hydroxyl group, aminomethyl group, carboxymethyl group,
Carbamoylmethyl group, sulfomethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, amino group, methylamino group,
Dimethylamino group, ethylamino group, propylamino group, formamide group, acetamide group, propionylamino group, formyloxy group, acetoxy group, propionyloxy group, carboxyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethyl Carbamoyl group,
Aryl group, methyl group, ethyl group, propyl group which may be substituted with one or more substituents selected from the group consisting of methoxycarbamoyl group, ethoxycarbamoyl group, sulfamoyl group, sulfo group, cyano group and nitro group. Group, halogen atom, fluoromethyl group, difluoromethyl group, trifluoromethyl group, carboxymethyl group, aminomethyl group, sulfomethyl group, carbamoylmethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, fluoroethoxy group, Difluoroethoxy group,
Trifluoroethoxy group, hydroxyl group, formyloxy group,
Acetoxy group, trifluoroacetoxy group, amino group,
Methylamino group, ethylamino group, dimethylamino group,
Diethylamino group, formamide group, acetamide group,
One or more substituents selected from the group consisting of carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, sulfo group, cyano group and nitro group. An aralkyl group or a halogen atom which may be substituted with, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, an aminomethyl group, a sulfomethyl group,
Carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group,
N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group,
Ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group , Carbamoyloxy group, N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group,
A group represented by a hydroxyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group or a heterocyclic group which may be substituted with one or more substituents) or a group represented by the formula (a ₂ ) (In the formula, R ⁶ and R ⁷ may be the same or different, a hydrogen atom or a halogen atom or a halogen atom, a hydroxyl group,
Methoxy group, ethoxy group, propoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, formyloxy group, acetoxy group, fluoroacetoxy group, N-methylcarbamoyl group, carbamoyl group,
N-methylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, amino group, methylamino group, dimethylamino group, formamide group, acetamido group, fluoroacetamido group, carboxyl group, methoxycarbonyl Group, ethoxycarbonyl group, sulfo group, sulfamoyl group, cyano group, formyl group, acetyl group, fluoroacetyl group, diethylamino group, ethylamino group, methylthio group, ethylthio group, propylthio group, fluoromethylthio group, 2-fluoroethylthio group Group, 1-fluoroethylthio group, tetrazolyl group, 1-methyltetrazolyl group, thiazolyl group,
2-aminothiazolyl group, 5-amino-1,2,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, imidazolyl group, thienyl group, furanyl group, 2-aminooxazoli Group, isothiazolyl group, isoxazolyl group, quinolyl group, isoquinolyl group, pyridyl group, 3,4-dihydroxy-6-pyridyl group, piperazinyl group, pyrrolidinyl group, piperidyl group, pyrrolyl group, morpholinyl group, benzothiazolyl group and benzimidazolyl group A lower alkyl group optionally substituted by one or more substituents selected from the group consisting of, halogen atom, methyl group, hydroxymethyl group, fluoromethyl group, trifluoromethyl group, ethyl group, bromomethyl group, difluoromethyl group Group, hydroxyl group, aminomethyl group, carboxymethyl group, carbamoy Methyl, sulfomethyl group, N- methylaminomethyl group, a methoxy group, an ethoxy group, a propoxy group, fluoromethoxy group, an amino group,
Methylamino group, dimethylamino group, ethylamino group,
Propylamino group, formamide group, acetamide group,
Propionylamino group, formyloxy group, acetoxy group, propionyloxy group, carboxyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, methoxycarbamoyl group, ethoxycarbamoyl group, sulfamoyl group, sulfo group, cyano Aryl group or methyl group, ethyl group, propyl group, halogen atom, fluoromethyl group, difluoromethyl group, trifluoro group which may be substituted with one or more substituents selected from the group consisting of groups and nitro groups. Methyl group, carboxymethyl group, aminomethyl group, sulfomethyl group, carbamoylmethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, fluoroethoxy group, difluoroethoxy group, trifluoroethoxy group, hydroxyl group, formyloxy group, Setokishi group, trifluoroacetoxy group, an amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, formamide group, acetamide group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, N
A methylcarbamoyl group, an N, N-dimethylcarbamoyl group, a sulfo group, a cyano group and a nitro group, which may be substituted with one or more substituents. Represents a group), etc.

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

The optionally substituted lower alkyl group is, for example, a halogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group, a difluoromethoxy group,
Trifluoromethoxy group, formyloxy group, acetoxy group, fluoroacetoxy group, N-methylcarbamoyl group, carbamoyl group, N-methylcarbamoyloxy group, N, N-dimethylcarbamoyl group, N, N-dimethylcarbamoyloxy group, amino Group, methylamino group, dimethylamino 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, Diethylamino group, ethylamino group methylthio group, ethylthio group, propylthio group, fluoromethylthio group, 2-fluoroethylthio group, 1-fluoroethylthio group, tetrazolyl group, 1-methyltetrazolyl group, thiazolyl group, 2- Minothiazolyl group, 5-amino-1,2,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, imidazolyl group, thienyl group, furanyl group, 2-aminooxazolyl group , Isothiazolyl group, isoxazolyl group, quinolyl group, isoquinolyl group, pyridyl group, 3,4-dihydroxy-6-pyridyl group, piperazinyl group, pyrrolidinyl group, piperidyl group, pyrrolyl group, morpholinyl group, benzothiazolyl group and benzimidazolyl group 1 selected from
Optionally substituted with one or more substituents,
For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-
It means an alkyl group having 1 to 6 carbon atoms such as a butyl group, a pentyl group, an isopentyl group, a hexyl group or an isohexyl group.

The optionally substituted cycloalkyl group is, for example, one or more selected from the group consisting of carbamoyl group, carboxyl group, amino group, methylamino group, dimethylamino group, sulfo group, hydroxyl group and cyano group. It means a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a substituent, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

The optionally substituted lower alkenyl group is, for example, a halogen atom, a carboxyl group, an amino group, a sulfo group,
It may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, a carbamoyl group and a cyano group. For example, alkenyl having 2 to 6 carbon atoms such as vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 1-pentenyl group or 1-hexenyl group. Means a group.

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

The optionally substituted aryl group is, for example, a halogen atom, a methyl group, a hydroxymethyl group, a fluoromethyl group, a trifluoromethyl group, an ethyl group, a bromomethyl group, a difluoromethyl group, a hydroxyl group, an aminomethyl group, a carboxymethyl group. , Carbamoylmethyl group, sulfomethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, amino group,
Methylamino group, dimethylamino group, ethylamino group,
Propylamino group, formamide group, acetamide group,
Propionylamino group, formyloxy group, acetoxy group, propionyloxy group, carboxyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, methoxycarbamoyl group, ethoxycarbamoyl group, sulfamoyl group, sulfo group, cyano Means an aryl group having 6 to 10 carbon atoms, which may be substituted with one or more substituents selected from the group consisting of a group and a nitro group, for example, a phenyl group or a naphthyl group.

The heterocyclic group which may be substituted is, for example, a halogen atom, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, an aminomethyl group, a sulfomethyl group, a carboxymethyl group, a cyanomethyl group, a fluoromethyl group, a chloromethyl group. , Difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group, N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino Group, methoxy group, ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy Group, formyloxy , Carbamoyloxy group, N
1 selected from the group consisting of a methylcarbamoyloxy group, an acetamide group, a formamide group, an acetyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a hydroxyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. Optionally substituted with one or more substituents, for example
1,2,3-thiadiazolyl group, 1,3,4-thiadiazolyl group,
1,2,4-thiadiazolyl group, 1,2,3-triazolyl group, 1,
3,4-Triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, imidazolyl group, pyridyl group, pyrimidinyl group, thienyl group, furanyl group, piperazinyl group, piperidyl group, morpholinyl group, morpholino group, pyrrolidinyl Group, quinolyl group, isoquinolyl group, benzothiazolyl group or benzimidazolyl group, etc., such as monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom. means. In addition, when a positive charge is generated due to the presence of a substituent on the nitrogen atom of the heterocycle, an intramolecular salt or an intermolecular salt is formed.

The optionally substituted aralkyl group includes, for example, methyl group, ethyl group, propyl group, halogen atom, fluoromethyl group, difluoromethyl group, trifluoromethyl group, carboxymethyl group, aminomethyl group, sulfomethyl group, carbamoylmethyl group. Group, N-methylaminomethyl group, methoxy group, ethoxy group, fluoroethoxy group, difluoroethoxy group, trifluoroethoxy group, hydroxyl group, formyloxy group, acetoxy group, trifluoroacetoxy group, amino group, methylamino group, ethyl Amino group, dimethylamino group, diethylamino group, formamide group, acetamide group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, N
-Methylcarbamoyl group, N, N-dimethylcarbamoyl group, sulfo group, cyano group, nitro group and the like, which may be substituted with one or more substituents selected from the group consisting of, for example, benzyl group, phenethyl group Or, it means an aralkyl group having 7 to 12 carbon atoms such as a naphthylmethyl group.

The alkylene group is, for example, a methylene group, an ethylene group,
Ethylidene group, isopropylidene group, propylene group, trimethylene group, tetramethylene group, 1,2-cyclopentylene group, 1,3-cyclopentylene group, 1,2-cyclohexylene group, 1,3-cyclohexylene group Alternatively, it means a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms such as a 1,4-cyclohexylene group.

The carboxyl group-protecting group is, for example, acid hydrolysis or catalytic reduction of tert-butyl group, phenyl group, methoxymethyl group, ethoxymethyl group, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group or benzhydryl group. Means a protective group for a carboxyl group and the like which can be easily removed by such methods.

Amino group-protecting groups include, for example, trityl group, formyl group, chloroacetyl group, trifluoroacetyl group, tert.
-Butoxycarbonyl group, trimethylsilyl group, or te
The rt-butyldimethylsilyl group means a protecting group for an amino group which can be easily removed by a method such as acid hydrolysis or catalytic reduction.

The ester residue capable of forming a non-toxic ester hydrolyzable in vivo is, for example, a lower alkanoyloxymethyl group such as acetoxymethyl group, propionyloxymethyl group or pivaloyloxymethyl group, 1- (methoxycarbonyloxy group. ) Ethyl group, 1- (lower alkoxycarbonyloxy) ethyl group such as 1- (ethoxycarbonyloxy) ethyl group or 1- (tert-butoxycarbonyloxy) ethyl group, 5-methyl-2-oxo-
5-substituted-2-oxo-1,3-dioxol-4-ylmethyl group such as 1,3-dioxol-4-ylmethyl group or 5-phenyl-2-oxo-1,3-dioxol-4-ylmethyl group, It means an ester residue or the like capable of forming an ester that can be easily hydrolyzed in vivo, such as a 1-phthalidyl group or a 5-cyano-1-phthalidyl group.

R ¹ represents an amino group substituted with an acyl group selected from the group consisting of an aliphatic acyl group, an aromatic acyl group and a heterocyclic acyl group.

The aliphatic acyl group, aromatic acyl group and heterocyclic acyl group each have the above meaning. The aromatic acyl group means an acyl group having an aromatic ring in its substituent, and the heterocyclic acyl group means an acyl group having a heterocycle in its substituent.

Generally, R ¹ is of formula (a) [In the formula, R ⁴ is a halogen atom, a methyl group, a hydroxymethyl group, a fluoromethyl group, a trifluoromethyl group, an ethyl group, a bromomethyl group, a difluoromethyl group, a hydroxyl group,
Aminomethyl group, carboxymethyl group, carbamoylmethyl group, sulfomethyl group, N-methylaminomethyl group,
Methoxy, ethoxy, propoxy, fluoromethoxy, amino, methylamino, dimethylamino, ethylamino, propylamino, formamide, acetamide, propionylamino, formyloxy, acetoxy, propionyl Oxy group, carboxyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, methoxycarbamoyl group, ethoxycarbamoyl group, sulfamoyl group,
An aryl group which may be substituted with one or more substituents selected from the group consisting of a sulfo group, a cyano group and a nitro group, or a halogen atom, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, aminomethyl Group, sulfomethyl group, carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group,
Trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfamoylmethyl group,
Oxo group, N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group, ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, Methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group,
Ethynyl group, acetoxy group, formyloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl Base,
A heterocyclic group which may be substituted with one or more substituents selected from the group consisting of a cyclopentyl group and a cyclohexyl group, Y is a formula (a ₁ ) = N to OR ⁵ (a ₁ ) (wherein R ⁵ is a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a formyloxy group, an acetoxy group, a fluoroacetoxy group, an N-methylcarbamoyl group, Carbamoyl group,
N-methylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, amino group, methylamino group, dimethylamino group, formamide group, acetamido group, fluoroacetamido group, carboxyl group, methoxycarbonyl Group, ethoxycarbonyl group, sulfo group, sulfamoyl group, cyano group, formyl group, acetyl group, fluoroacetyl group, diethylamino group, ethylamino group, methylthio group, ethylthio group, propylthio group, fluoromethylthio group, 2-fluoroethylthio group Group, 1-fluoroethylthio group, tetrazolyl group, 1-methyltetrazolyl group, thiazolyl group,
2-aminothiazolyl group, 5-amino-1,2,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, imidazolyl group, thienyl group, furanyl group, 2-aminooxazoli Group, isothiazolyl group, isoxazolyl group, quinolyl group, isoquinolyl group, pyridyl group, 3,4-dihydroxy-6-pyridyl group, piperazinyl group, pyrrolidinyl group, piperidyl group, pyrrolyl group, morpholinyl group, benzothiazolyl group and benzimidazolyl group A group consisting of a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of, a carbamoyl group, a carboxyl group, an amino group, a methylamino group, a dimethylamino group, a sulfo group, a hydroxyl group and a cyano group. Cycloalkyl optionally substituted with one or more substituents selected from , A halogen atom, a carboxyl group, an amino group, a sulfo group, a hydroxyl group, a lower alkenyl group optionally substituted with one or more substituents selected from the group consisting of a carbamoyl group and a cyano group, a halogen atom, a hydroxyl group, Lower alkynyl group optionally substituted by one or more substituents selected from the group consisting of amino group, carboxyl group, carbamoyl group, sulfo group and cyano group, halogen atom, methyl group,
Hydroxymethyl group, fluoromethyl group, trifluoromethyl group, ethyl group, bromomethyl group, difluoromethyl group, hydroxyl group, aminomethyl group, carboxymethyl group,
Carbamoylmethyl group, sulfomethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, amino group, methylamino group,
Dimethylamino group, ethylamino group, propylamino group, formamide group, acetamide group, propionylamino group, formyloxy group, acetoxy group, propionyloxy group, carboxyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethyl Carbamoyl group,
Aryl group, methyl group, ethyl group, propyl group which may be substituted with one or more substituents selected from the group consisting of methoxycarbamoyl group, ethoxycarbamoyl group, sulfamoyl group, sulfo group, cyano group and nitro group. Group, halogen atom, fluoromethyl group, difluoromethyl group, trifluoromethyl group, carboxymethyl group, aminomethyl group, sulfomethyl group, carbamoylmethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, fluoroethoxy group, Difluoroethoxy group,
Trifluoroethoxy group, hydroxyl group, formyloxy group,
Acetoxy group, trifluoroacetoxy group, amino group,
Methylamino group, ethylamino group, dimethylamino group,
Diethylamino group, formamide group, acetamide group,
One or more substituents selected from the group consisting of carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, sulfo group, cyano group and nitro group. An aralkyl group or a halogen atom which may be substituted with, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, an aminomethyl group, a sulfomethyl group,
Carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group,
N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group,
Ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group , Carbamoyloxy group, N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group,
A group represented by a hydroxyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group or a heterocyclic group which may be substituted with one or more substituents) or a group represented by the formula (a ₂ ) (In the formula, R ⁶ and R ⁷ may be the same or different, a hydrogen atom or a halogen atom or a halogen atom, a hydroxyl group,
Methoxy group, ethoxy group, propoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, formyloxy group, acetoxy group, fluoroacetoxy group, N-methylcarbamoyl group, carbamoyl group,
N-methylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, amino group, methylamino group, dimethylamino group, formamide group, acetamido group, fluoroacetamido group, carboxyl group, methoxycarbonyl Group, ethoxycarbonyl group, sulfo group, sulfamoyl group, cyano group, formyl group, acetyl group, fluoroacetyl group, diethylamino group, ethylamino group, methylthio group, ethylthio group, propylthio group, fluoromethylthio group, 2-fluoroethylthio group Group, 1-fluoroethylthio group, tetrazolyl group, 1-methyltetrazolyl group, thiazolyl group,
2-aminothiazolyl group, 5-amino-1,2,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, imidazolyl group, thienyl group, furanyl group, 2-aminooxazoli Group, isothiazolyl group, isoxazolyl group, quinolyl group, isoquinolyl group, pyridyl group, 3,4-dihydroxy-6-pyridyl group, piperazinyl group, pyrrolidinyl group, piperidyl group, pyrrolyl group, morpholinyl group, benzothiazolyl group and benzimidazolyl group A lower alkyl group optionally substituted by one or more substituents selected from the group consisting of, halogen atom, methyl group, hydroxymethyl group, fluoromethyl group, trifluoromethyl group, ethyl group, bromomethyl group, difluoromethyl group Group, hydroxyl group, aminomethyl group, carboxymethyl group, carbamoy Methyl, sulfomethyl group, N- methylaminomethyl group, a methoxy group, an ethoxy group, a propoxy group, fluoromethoxy group, an amino group,
Methylamino group, dimethylamino group, ethylamino group,
Propylamino group, formamide group, acetamide group,
Propionylamino group, formyloxy group, acetoxy group, propionyloxy group, carboxyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, methoxycarbamoyl group, ethoxycarbamoyl group, sulfamoyl group, sulfo group, cyano Aryl group or methyl group, ethyl group, propyl group, halogen atom, fluoromethyl group, difluoromethyl group, trifluoro group which may be substituted with one or more substituents selected from the group consisting of groups and nitro groups. Methyl group, carboxymethyl group, aminomethyl group, sulfomethyl group, carbamoylmethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, fluoroethoxy group, difluoroethoxy group, trifluoroethoxy group, hydroxyl group, formyloxy group, Setokishi group, trifluoroacetoxy group, an amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, formamide group, acetamide group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, N
A methylcarbamoyl group, an N, N-dimethylcarbamoyl group, a sulfo group, a cyano group and a nitro group, which may be substituted with one or more substituents. Or a group represented by the formula (b) [In the formula, R ⁸ is a halogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a formyloxy group, an acetoxy group, a fluoroacetoxy group, and an N-methylcarbamoyl group. , Carbamoyl group, N-methylcarbamoyloxy group, N, N-dimethylcarbamoyl group, N, N-
Dimethylcarbamoyloxy group, amino group, methylamino group, dimethylamino 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, diethylamino group, ethylamino group, methylthio group, ethylthio group, propylthio group, fluoromethylthio group, 1-fluoroethylthio group, tetrazolyl group, 1-methyltetra Zolyl group, thiazolyl group, 2-aminothiazolyl group, 5-amino-1,2,
4-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,
3-thiadiazolyl group, imidazolyl group, thienyl group,
Furanyl group, 2-aminooxazolyl group, isothiazolyl group, isoxazolyl group, quinolyl group, isoquinolyl group, pyridyl group, 3,4-dihydroxy-6-pyridyl group, piperazinyl group, pyrrolidinyl group, piperidyl group,
Lower alkyl group optionally substituted with one or more substituents selected from the group consisting of pyrrolyl group, morpholinyl group, benzothiazolyl group and benzimidazolyl group, halogen atom, carboxyl group, amino group, sulfo group, hydroxyl group, carbamoyl Group and a lower alkenyl group which may be substituted with one or more substituents selected from the group consisting of cyano groups, halogen atoms, methyl groups, hydroxymethyl groups, fluoromethyl groups, trifluoromethyl groups, ethyl groups , Bromomethyl group, difluoromethyl group, hydroxyl group, aminomethyl group, carboxymethyl group, carbamoylmethyl group, sulfomethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, propoxy group,
Fluoromethoxy group, amino group, methylamino group, dimethylamino group, ethylamino group, propylamino group, formamide group, acetamide group, propionylamino group, formyloxy group, acetoxy group, propionyloxy group, carboxyl group, carbamoyl group, Substituted with one or more substituents selected from the group consisting of N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, methoxycarbamoyl group, ethoxycarbamoyl group, sulfamoyl group, sulfo group, cyano group and nitro group. Optionally substituted aryl group or halogen atom, methyl group, ethyl group, propyl group, hydroxymethyl group, aminomethyl group, sulfomethyl group, carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, triflu Romethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group, N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group, ethoxy group , A fluoromethoxy group, a difluoroethoxy group, a trifluoroethoxy group,
Sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, acetamide group, formamide Substituted with one or more substituents selected from the group consisting of group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. R ⁹ is a hydrogen atom, a carboxyl group, an amino group, a sulfo group, a sulfamoyl group, a carbamoyl group, a hydroxyl group, a formyloxy group, a carbamoyloxy group or a formula (b ₁ ) R ¹⁰ -CONH- (b ₁₎ (wherein, R ¹⁰ is a halogen atom, menu Group, an ethyl group, a propyl group, a hydroxymethyl group, aminomethyl group, a sulfomethyl group, a carboxymethyl group, a cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, a carbamoylmethyl group, N
-Methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group, N-methylaminomethyl group, amino group,
Methylamino group, dimethylamino group, ethylamino group,
Methoxy group, ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, Formyloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. A group represented by a heterocyclic group which may be substituted with one or more substituents selected from the group consisting of
Above all, the formula (c) (In the formula, R ¹¹ is a hydrogen atom, a halogen atom, a hydroxyl group,
Methoxy group, ethoxy group, propoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, formyloxy group, acetoxy group, fluoroacetoxy group, N-methylcarbamoyl group, carbamoyl group,
N-methylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, amino group, methylamino group, dimethylamino group, formamide group, acetamido group, fluoroacetamido group, carboxyl group, methoxycarbonyl Group, ethoxycarbonyl group, sulfo group, sulfamoyl group, cyano group, formyl group, acetyl group, fluoroacetyl group, diethylamino group, ethylamino group, methylthio group, ethylthio group, propylthio group, fluoromethylthio group, 2-fluoroethylthio group Group, 1-fluoroethylthio group, tetrazolyl group, 1-methyltetrazolyl group, thiazolyl group,
2-aminothiazolyl group, 5-amino-1,2,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, imidazolyl group, thienyl group, furanyl group, 2-aminooxazoli Group, isothiazolyl group, isoxazolyl group, quinolyl group, isoquinolyl group, pyridyl group, 3,4-dihydroxy-6-pyridyl group, piperazinyl group, pyrrolidinyl group, piperidyl group, pyrrolyl group, morpholinyl group, benzothiazolyl group and benzimidazolyl group A group consisting of a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of, a carbamoyl group, a carboxyl group, an amino group, a methylamino group, a dimethylamino group, a sulfo group, a hydroxyl group and a cyano group. Cycloalkyl optionally substituted with one or more substituents selected from , A halogen atom, a carboxyl group, an amino group, a sulfo group, a hydroxyl group, a lower alkenyl group optionally substituted with one or more substituents selected from the group consisting of a carbamoyl group and a cyano group, a halogen atom, a hydroxyl group, Lower alkynyl group optionally substituted by one or more substituents selected from the group consisting of amino group, carboxyl group, carbamoyl group, sulfo group and cyano group, halogen atom, methyl group,
Hydroxymethyl group, fluoromethyl group, trifluoromethyl group, ethyl group, bromomethyl group, difluoromethyl group, hydroxyl group, aminomethyl group, carboxymethyl group,
Carbamoylmethyl group, sulfomethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, amino group, methylamino group,
Dimethylamino group, ethylamino group, propylamino group, formamide group, acetamide group, propionylamino group, formyloxy group, acetoxy group, propionyloxy group, carboxyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethyl Carbamoyl group,
Aryl group, methyl group, ethyl group, propyl group which may be substituted with one or more substituents selected from the group consisting of methoxycarbamoyl group, ethoxycarbamoyl group, sulfamoyl group, sulfo group, cyano group and nitro group. Group, halogen atom, fluoromethyl group, difluoromethyl group, trifluoromethyl group, carboxymethyl group, aminomethyl group, sulfomethyl group, carbamoylmethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, fluoroethoxy group, Difluoroethoxy group,
Trifluoroethoxy group, hydroxyl group, formyloxy group,
Acetoxy group, trifluoroacetoxy group, amino group,
Methylamino group, ethylamino group, dimethylamino group,
Diethylamino group, formamide group, acetamide group,
One or more substituents selected from the group consisting of carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, sulfo group, cyano group and nitro group. An aralkyl group or a halogen atom which may be substituted with, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, an aminomethyl group, a sulfomethyl group,
Carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group,
N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group,
Ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group , Carbamoyl group, N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group,
A heterocyclic group optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, and Z ² represents a carbon atom or a nitrogen atom, respectively. ) Or a group represented by formula (d) A group represented by the formula (wherein R ¹² represents 1 or 2 substituents selected from the group consisting of a hydrogen atom, a hydroxyl group, an acetoxy group and a halogen atom) is preferable.

Preferable specific examples of R ¹ include, for example, (2-fluoro-
2-carbamoylvinylthio) acetylamino group, difluoromethylthioacetylamino group, phenylacetylamino group, 2-amino-2-phenylacetylamino group, 2-amino-2- (4-hydroxyphenyl) acetylamino group, 2- Carboxy-2-phenylacetylamino group, 2-carboxy-2- (4-hydroxyphenyl) acetylamino group, 2- (4-hydroxyphenyl) -2-[(4-ethyl-2,3-dioxo-1) -Piperazinyl) carbonylamino] acetylamino group, 2-
Phenyl-2-[(4-ethyl-2,3-dioxo-1-
Piperazinyl) carbonylamino] acetylamino group,
2-sulfo-2-phenylacetylamino group, 2-hydroxy-2-phenylacetylamino group, 2- (1,4-
Cyclohexadienyl) acetylamino group, 2-amino-2- (1,4-cyclohexadienyl) acetylamino group, 2- (2-thienyl) acetylamino group, 2- (2
-Furanyl) acetylamino group, 2- (2-aminomethylphenyl) acetylamino group, 2-carboxy-2-
(3-thienyl) acetylamino group, 2-tetrazolylacetylamino group, 2-methoxyimino-2- (2-thienyl) acetylamino group, 2-methoxyimino-2-
(2-furanyl) acetylamino group, 2- (4-pyridylthio) acetylamino group, 2- (4-pyridyloxy) acetylamino group, 2-hydroxyimino-2-phenylacetylamino group, 2-cyanomethylthioacetylamino Group, 2- (2-fluorovinylthio) acetylamino group, 2-trifluoromethylthioacetylamino group, 2- (2-aminothiazol-4-yl) acetylamino group, 2-methoxyimino-2- (2- Aminothiazol-4-yl) acetylamino group, 2-ethoxyimino-2- (2-aminothiazol-4-yl) acetylamino group, 2-propoxyimino-2- (2-aminothiazol-4-yl) acetyl Amino group, 2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetylamino 2- Butokishiimino 2- (2
-Aminothiazol-4-yl) acetylamino group, 2
-Sec-butoxyimino-2- (2-aminothiazol-4-yl) acetylamino group, 2-tert-butoxyimino-2- (2-aminothiazol-4-yl) acetylamino group, 2-pentyloxyimino -2- (2-aminothiazol-4-yl) acetylamino group, 2-hexyloxyimino-2- (2-aminothiazol-4)
-Yl) acetylamino group, 2-hydroxyimino-2
-(2-aminothiazol-4-yl) acetylamino group, 2-cyclopropoxyimino-2- (2-aminothiazol-4-yl) acetylamino group, 2-cyclobutoxyimino-2- (2-aminothiazole) -4-yl) acetylamino group, 2-cyclopentyloxyimino-2- (2-aminothiazol-4-yl) acetylamino group, 2-cyclohexyloxyimino-2- (2
-Aminothiazol-4-yl) acetylamino group, 2
-(1-carboxy-1-cyclopropoxyimino)-
2- (2-aminothiazol-4-yl) acetylamino group, 2- (1-carboxy-1-cyclobutoxyimino) -2- (2-aminothiazol-4-yl) acetylamino group, 2- (1 -Carboxy-1-cyclopentyloxyimino) -2- (2-aminothiazole-4-
Yl) acetylamino group, 2- (1-carboxy-1-)
Cyclohexyloxyimino) -2- (2-aminothiazol-4-yl) acetylamino group, 2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetylamino group, 2- (2-carboxyethoxy) Imino) -2- (2-aminothiazol-4-yl) acetylamino group, 2- (1-carboxyethoxyimino) -2- (2-aminothiazol-4-yl) acetylamino group, 2- (1- Carboxy-1-methylethoxyimino) -2- (2-aminothiazol-4-yl)
Acetylamino group, 2- (1-carboxy-1-ethenyloxyimino) -2- (2-aminothiazole-4-
Yl) acetylamino group, 2- (2-carboxy-1-)
Ethenyloxyimino) -2- (2-aminothiazol-4-yl) acetylamino group, 2-fluoromethoxyimino-2- (2-aminothiazol-4-yl) acetylamino group, 2-bromomethoxyimino- 2- (2-
Aminothiazol-4-yl) acetylamino group, 2-
(2-Fluoroethoxyimino) -2- (2-aminothiazol-4-yl) acetylamino group, 2- (2-chloroethoxyimino) -2- (2-aminothiazol-
4-yl) acetylamino group, 2- (1-fluoro-1)
-Methylethoxyimino) -2- (2-aminothiazol-4-yl) acetylamino group, 2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetylamino group, 2- (3,4 -Dihydroxybenzyloxyimino) -2- (2-aminothiazol-4-yl)
Acetylamino group, 2- (α-carboxy-3,4-dihydroxybenzyloxyimino) -2- (2-aminothiazol-4-yl) acetylamino group, 2- (α-carboxybenzyloxyimino) -2- (2-Aminothiazol-4-yl) acetylamino group, 2- (2-carboxymethylbenzyloxyimino) -2- (2-aminothiazol-4-yl) acetylamino group, 2-
(2-Carboxybenzyloxyimino) -2- (2-
Aminothiazol-4-yl) acetylamino group, 2-
Methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetylamino group, 2-ethoxyimino-2- (5-amino-1,2,4-thiadiazole-3)
-Yl) acetylamino group, 2- (2-fluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetylamino group, 2- (1-carboxy-1-e) Tenyloxyimino) -2- (5-amino-
1,2,4-thiadiazol-3-yl) acetylamino group, 2- (1-carboxy-1-methylethoxyimino) -2- (5-amino-1,2,4-thiadiazole-3
-Yl) acetyl group, 2- (α-carboxy-3,4-dihydroxybenzyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetylamino group, 1- (2 -Aminothiazol-4-yl) -1-propenylcarbonyl group, 2-benzylidene-2- (2-
Aminothiazol-4-yl) acetylamino group, 2-
Chloromethylene-2- (2-aminothiazol-4-yl) acetylamino group or 2-fluoromethylene-2-
Examples thereof include an amino group substituted with an acyl group such as (2-aminothiaol-4-yl) acetylamino group.

R ² is a halogen atom, methyl group, ethyl group, propyl group, hydroxymethyl group, aminomethyl group, sulfomethyl group, carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, Carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group, N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group, ethoxy group, fluoromethoxy Group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group,
Carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl Group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group, which may be substituted with one or more substituents selected from the group consisting of It means a ring group.

The heterocyclic group, 1,2,3-thiadiazolyl group,
1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group,
1,2,3-triazolyl group, 1,3,4-triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, imidazolyl group, pyridyl group, pyrimidinyl group, thienyl group, furanyl group, piperazinyl group A piperidinyl group, a morpholinyl group, a morpholino group, a pyrrolidinyl group, a quinolyl group, an isoquinolyl group, a benzothiazolyl group, a benzimidazolyl group, or the like, which contains 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom, and oxygen atom. Examples include monocyclic or bicyclic heterocyclic groups, among them, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, tetrazolyl group, thiazolyl group, Imidazolyl group, isothiazolyl group, isoxazolyl group, oxazolyl group, pyridyl group, thieni Group, benzothienyl group,
A furanyl group, a pyrimidinyl group, a piperazinyl group, a piperidyl group, a morpholinyl group, a pyrrolidinyl group, a quinolyl group, an isoquinolyl group, a benzothiazolyl group or a benzimidazolyl group is preferable.

R ² represents a compound represented by the formula: —O—, together with an oxygen atom and an alkylene group.
It forms a substituent at the 3-position of the cephem nucleus represented by X—R ² . Preferred examples thereof include thiazol-4-ylmethoxy group, thiazol-2-ylmethoxy group, thiazol-5-ylmethoxy group, 4-methylthiazol-2-ylmethoxy group, 2-methylthiazol-5-ylmethoxy group, 1, 2,3-thiadiazol-4-ylmethoxy group,
1,2,4-thiadiazol-3-ylmethoxy group, 1,3,4-
Thiadiazol-2-ylmethoxy group, 1-methylimidazol-2-ylmethoxy group, 2-pyrrolidone-5-
Ylmethoxy group, 1-methyl-2-pyrrolidone-5-ylmethoxy group, tetrazol-5-ylmethoxy group, 1,
3,4-triazol-2-ylmethoxy group, 2-pyridylmethoxy group, 3-pyridylmethoxy group, 4-pyridylmethoxy group, 1-methyl-2-pyridiniomethoxy group,
1-methyl-3-pyridiniomethoxy group, 1-methyl-
4-pyridiniomethoxy group, 1-ethyl-2-pyridiniomethoxy group, 1-ethyl-4-pyridiniomethoxy group, 1-propyl-4-pyridiniomethoxy group, 1-allyl-2- Pyridiniomethoxy group, 1-allyl-4-pyridiniomethoxy group, 1-carboxymethyl 3-pyridiniomethoxy group, 1-carboxymethyl-4-pyridiniomethoxy group, 1-carbamoylmethyl-2- Pyridiniomethoxy group, 1-carbamoylmethyl-4-pyridiniomethoxy group, 1- (2-pyridyl) ethoxy group, 1-
(3-Pyridyl) ethoxy group, 1- (4-pyridyl) ethoxy group, 1- (1-methyl-4-pyridinio) ethoxy group, 1- (1-methyl-3-pyridinio) ethoxy group, 1- (1 -Methyl-2-pyridinio) ethoxy group,
2- (2-pyridyl) ethoxy group, 2- (3-pyridyl) ethoxy group, 2- (4-pyridyl) ethoxy group, 2
-(1-methyl-2-pyridinio) ethoxy group, 2-
(1-Methyl-3-pyridinio) ethoxy group, 2- (1
-Methyl-4-pyridinio) ethoxy group, 3,4-dihydroxy-1-methyl-6-pyridiniomethoxy group, 3,4
-Dihydroxy-1- (2-fluoroethyl) -6-pyridiniomethoxy group, 2-chloro-1-methyl-4-pyridiniomethoxy group, 1,2-dimethyl-4-pyridiniomethoxy group, 2-carbamoyl-1-methyl-4-pyridiniomethoxy group, 3-carboxy-1-methyl-5-
Pyridiniomethoxy group, 4-hydroxy-1-methyl-
2-pyridiniomethoxy group or 1- (2-methoxy-4
-Pyridyl) ethoxy group and the like.

R ³ is hydrogen atom, negative charge or lower alkanoyloxymethyl group, 1- (lower alkoxycarbonyloxy) ethyl group, 5-substituted-2-oxo-1,3-dioxole-4
-Ylmethyl group, 1-phthalidyl group and 5-cyano-1
-Indicates an ester residue capable of forming a non-toxic ester hydrolyzable in vivo selected from the group consisting of phthalidyl groups.

 X represents an alkylene group.

Next, a suitable compound group of the compound of the general formula [I] is shown. In R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ , the aryl group is a phenyl group or a naphthyl group, or R ⁵ , R ^{In 6} or R ⁷ , the aralkyl group is a benzyl group, a phenethyl group or a naphthylmethyl group, or in R ² , the heterocyclic group is 1,2,3
-Thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4
-Thiadiazolyl group, tetrazolyl group, thiazolyl group,
Imidazolyl group, isothiazolyl group, isoxazolyl group, oxazolyl group, pyridyl group, thienyl group, benzothienyl group, furanyl group, pyrimidinyl group, piperazinyl group, piperidyl group, morpholinyl group, pyrrolidinyl group, quinolyl group, isoquinolyl group, benzothiazolyl group or benz Is an imidazolyl group, or in R ⁴ , the heterocyclic group is a furanyl group, a thienyl group, a thiazolyl group, 1,2,4
-Thiadiazolyl group, pyridyl group, isothiazolyl group,
An oxazolyl group, a pyrimidinyl group or a 1,3,4-triazolyl group, or in R ⁵ , the heterocyclic group is a pyridyl group,
Furanyl group, thienyl group, imidazolyl group, thiazolyl group, isothiazolyl group, isoquinolyl group, quinolyl group,
An oxazolyl group, an isoxazolyl group or a tetrazolyl group, or in R ⁸ , the heterocyclic group is a thiazolyl group, an isothiazolyl group, a 1,2,4-thiadiazolyl group, a furanyl group, a thienyl group, a benzothienyl group, a pyridyl group, a tetrazolyl group. Or an oxazolyl group, or in R ¹⁰ , the heterocyclic group is a pyridyl group, an imidazolyl group, a piperazinyl group, a thiazolyl group or an oxazolyl group,
In R ⁵ , R ⁶ , R ⁷ or R ⁸ , the lower alkyl group has 1 carbon atom.
To R 6 are alkyl groups, R ⁵ is a cycloalkyl group having 3 to 6 carbon atoms, or R ⁵ or R ⁸ is a lower alkenyl group having 2 to 6 carbon atoms. An alkenyl group, a lower alkynyl group for R ⁵ is an alkynyl group having 2 to 6 carbon atoms, or X is a linear, branched, or cyclic alkylene group having 1 to 6 carbon atoms. Compounds are preferable, and among these, in R ¹¹ , the aryl group is a phenyl group or a naphthyl group, the aralkyl group is a benzyl group, a phenethyl group or a naphthylmethyl group, or the heterocyclic group is a pyridyl group or a furanyl group. , Thienyl group, imidazolyl group, thiazolyl group, isothiazolyl group, isoquinolyl group, quinolyl group, oxazolyl group, isoxazolyl group or tetrazolyl group A lower alkyl group is an alkyl group having 1 to 6 carbon atoms, a lower cycloalkyl group is a cycloalkyl group having 3 to 6 carbon atoms, or a lower alkynyl group is an alkynyl group having 2 to 6 carbon atoms Or a compound in which the lower alkenyl group is an alkenyl group having 2 to 6 carbon atoms is preferable.

The non-toxic salt of the object compound of the present invention represented by the general formula [I] is, for example, a salt with an alkali metal such as sodium, potassium or lithium, a salt with an alkaline earth metal such as calcium or magnesium, N, N-dibenzylethylenediamine, salts with organic amines such as ethanolamine or triethylamine, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid, salts with organic acids such as acetic acid, citric acid or tartaric acid, methanesulfone Acid or p-
Examples thereof include salts with organic sulfonic acids such as toluene sulfonic acid and salts with amino acids such as aspartic acid, glutamic acid or lysine.

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

General formula [I] [In the formula, R ¹ is an amino group substituted with an acyl group selected from the group consisting of an aliphatic acyl group, an aromatic acyl group and a heterocyclic acyl group, R ² is a halogen atom, a methyl group, an ethyl group, Propyl group, hydroxymethyl group, aminomethyl group, sulfomethyl group, carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfur Famoylmethyl group, oxo group, N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group, ethoxy group, fluoromethoxy group,
Difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group, carbamoyloxy group, N- 1 or it selected from the group consisting of methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. The heterocyclic group optionally substituted with the above substituents, R ³ is a hydrogen atom, negative charge or lower alkanoyloxymethyl group, 1- (lower alkoxycarbonyloxy) ethyl group, 5-substituted-2-oxo- 1,3-dioxole An ester residue capable of forming a non-toxic ester hydrolyzable in vivo selected from the group consisting of -ylmethyl group, 1-phthalidyl group and 5-cyano-1-phthalidyl group, and X represents an alkylene group, respectively] The target compound of the present invention represented by the general formula [II] In the formula, ^{R 1 'is} the general formula [I], R ¹ or
The functional group of R ¹ is a substituted group, R ^{3 ′} is a hydrogen atom,
Carboxyl protecting group or lower alkanoyloxymethyl group, 1- (lower alkoxycarbonyloxy) ethyl group, 5-substituted-2-oxo-1,3-dioxole-4
-Ylmethyl group, 1-phthalidyl group and 5-cyano-1
-Indicating an ester residue capable of forming a non-toxic ester hydrolyzable in vivo selected from the group consisting of phthalidyl groups] or a salt thereof with a compound represented by the general formula [III] HO-X-R ^{2 ′} [III] [wherein R ^{2 ′} is a halogen atom, a methyl group, an ethyl group,
Propyl group, hydroxymethyl group, aminomethyl group, sulfomethyl group, carboxymethyl group, cyanomethyl group,
Fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N
-Methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group, N-methylaminomethyl group, amino group,
Methylamino group, dimethylamino group, ethylamino group,
Methoxy group, ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, Formyloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. X represents an alkylene group, each of which is a heterocyclic group which may be substituted with one or more substituents selected from the group consisting of groups (wherein the functional group of the substituent in R ^{2 ′} is appropriately protected). It is good.)] The compound of general formula [IV] [Wherein R ^{1 ′} , R ^{2 ′} , R ^{3 ′} and X have the above-mentioned meanings], and, if desired, (i) removing the protecting group Step of converting (iii) Step of converting into a non-toxic ester that can be hydrolyzed in a living body It is produced by carrying out one or more of the above steps.

The step of reacting the compound of the general formula [II] with the compound of the general formula [III] to produce the compound of the general formula [IV] includes, for example, aromatic hydrocarbons such as benzene and toluene,
A solvent that does not adversely affect the reaction of ethers such as diethyl ether, tetrahydrofuran or dioxane, chlorinated hydrocarbons such as methylene chloride or chloroform, or acid amides such as N, N-dimethylformamide or N, N-dimethylacetamide. It can be carried out in the presence of an azodicarboxylate reagent and a trialkylphosphine or a triarylphosphine.

Examples of the azodicarboxylate reagent used in this step include dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc., preferably diethyl azodicarboxylate, and trialkylphosphine. Examples of triarylphosphine include triethylphosphine, tributylphosphine, and triphenylphosphine, with triphenylphosphine being preferred.

As the conditions for carrying out this step, the amount of each raw material and each reagent used can be appropriately selected, but it is preferable to use the compound [I
I], the compound [III], the azodicarboxylate reagent and the phosphine have a molar ratio of about 1: 1: 1: 1, and the reaction temperature should be appropriately selected between -50 ° C and the reflux temperature of the solvent. However, it is preferably −30 ° C. to room temperature,
The reaction time is 5 minutes to 24 hours.

When R ^{2 ′ of the} compound represented by the general formula [IV] thus obtained is a heterocyclic group, the step of introducing a substituent into the heterocyclic ring can be carried out by, for example, methylene chloride, chloroform, tetrahydrofuran, acetone, acetonitrile. ,
It is carried out by reacting an alkylating agent in a non-aqueous solvent such as N, N-dimethylformamide, N, N-dimethylacetamide or a mixture thereof.

Examples of the alkylating agent used at this time include lower alkyl iodides such as methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide or butyl iodide, and iodide such as allyl iodide or 1-butenyl iodide. Alkyl sulfonates that may be substituted with halogen atoms such as alkenyl iodide, methyl dimethylsulfate fluorosulfonate, methyl trifluoromethanesulfonate, ethyl trifluoromethanesulfonate, iodoacetic acid benzhydryl ester, or iodoacetic acid amide Etc.

The reaction conditions in this step are generally -10 ° C to 50 ° C, preferably room temperature, 1 hour to 48 hours, preferably 24 hours.

When a protective group for a functional group is present in the product of the above steps, the removal of the protective group depends on the type of the protective group, and the protective groups in organic synthesis (Protective Groups in Organic Synthes
can be performed by selecting a known method such as 1981. Specifically, removal of the amino-protecting group can be carried out, for example, by
The tert-butoxycarbonyl group or trityl group is treated with an acid, the 2,2,2-trichloroethoxycarbonyl group is treated with zinc and an acid, and the p-nitrobenzyloxycarbonyl group is treated with a catalytic reduction. Further, the removal of the protective group for the hydroxyl group is carried out, for example, by using potassium hydrogen carbonate in water-containing methanol for the formyl group and trifluoroacetyl group, dilute hydrochloric acid for the tetrahydropyranyl group, and zinc and acid for the 2,2,2-trichloroethoxycarbonyl group. Be seen. Removal of the protecting group of the carboxyl group can be carried out, for example, by using a benzhydryl group and p
-Methoxybenzine group and the like with an acid such as trifluoroacetic acid in the presence of anisole, 2-methylsulfonyl group with an alkali, trimethylsilyl group or tert-butyldimethylsilyl group with water or hydrous alcohol,
The 2,2,2-trichloroethyl group is formed by zinc and acid, and the p-nitrobenzyl group is formed by reduction. The product obtained in each of the above steps, for example, column chromatography,
It can be purified by a solvent extraction method, a precipitation method or a recrystallization method. If necessary, it can be converted into a desired salt or ester by a method known per se.

Next, among the raw material compounds used in the method for producing the target compound of the present invention, the compound represented by the general formula [II] is, for example, Helvetica Chimica Acta.
Acta) 57, 1919 (1974) and 7-amino-3-hydroxy-3-cephem-4-carboxylic acid prepared by the method described in Acta). It is produced by reacting a compound, an acid halide, an azide or an active ester. Also,
As the compound represented by the general formula [III], a commercially available product or a compound easily produced by a known method can be used.

The compound of the present invention exhibits excellent antibacterial activity, is useful as a medicine, and can be used for the treatment and prevention of bacterial infections such as respiratory infections, urinary tract infections, purulent diseases, and surgical infections. it can. As the administration method, intravenous injection,
Parenteral administration such as intramuscular injection or suppository, or oral administration such as tablets, powders, capsules and syrups is applied. Formulation can be carried out according to a conventional method in this field, and additives such as auxiliary agents, stabilizers, wetting agents and emulsifiers which are usually used may be contained. The dose is
It is determined by a doctor in consideration of age, sex, weight, sensitivity difference, administration method, administration time and interval, degree of medical condition, physical condition, properties of pharmaceutical preparation, formulation, type, type of active ingredient and the like. Usually, it is used in the range of 1 to 100 mg / kg per day, and is preferably administered in 5 to 30 mg / kg per day in 2 to 4 divided doses.

In order to more specifically show the usefulness of the compound of the present invention,
The in vitro antibacterial activity against various bacteria was measured by the agar plate dilution method described below. One platinum loop of each test strain cultured overnight in Mueller Hinton Broth (inoculum size: 10 ⁶ CFU /
ml) was inoculated into a muller Hinton agar. This medium contained an antibacterial agent at each concentration, and after culturing at 37 ° C. for 16 hours, the minimum inhibitory concentration (MIC: μg / ml) was measured. The results are shown in Table 1 below.

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

Example 1 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (4
-Pyridylmethoxy) -3-cephem-4-carboxylate sodium 7β- [2- (2-tritylaminothiazole-4-
Yl)-(Z) -2-methoxyiminoacetamide]-
2-Hydroxy-3-cephem-4-carboxylic acid p-methoxybenzyl ester 2.29 g (3.01 mmol) and triphenylphosphine 982 mg (3.75 mmol) were dissolved in tetrahydrofuran 48 ml, and 4-pyridinemethanol was added at room temperature under a nitrogen stream. 408 mg (3.74 mmol) of tetrahydrofuran (2
4 ml) solution is added. Then, a solution of 0.58 ml (3.67 mmol) of diethyl azodicarboxylate in tetrahydrofuran (24 ml) was added dropwise to this solution at room temperature, and the mixture was stirred at the same temperature for 2 hours, and then the solvent was distilled off. Dissolve the residue in ethyl acetate,
The extract is washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent is evaporated. The residue was subjected to silica gel column chromatography (Wako gel C-300, eluted with 1% methanol-chloroform).
7β- [2- (2-Tritylaminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -3- (4-pyridylmethoxy) -3-cephem-4-carboxylic acid. p-methoxybenzyl ester
1.46 g (56.9% yield) are obtained as a pale yellow powder. 660 mg (0.774 mmol) of this powder is dissolved in 4.1 ml of dichloromethane and 0.9 ml of anisole, 6.6 ml of trifluoroacetic acid is added dropwise under ice cooling, and the mixture is stirred at the same temperature for 1 hour. After distilling off the solvent, isopropyl ether was added to the residue to obtain the trifluoroacetic acid salt of the title compound as a powder. Dissolve this in water,
The pH was adjusted to 6.5 with an aqueous sodium hydrogen carbonate solution, and reversed phase column chromatography (Chemco LC-SORB, SP-B-ODS, 2
Purify with 0% aqueous methanol) and lyophilize to give 221 mg (55.7% yield) of the title compound.

mp: 175 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1670,1620,1540 NMR (DMSO-d ₆ ) δ: 3.45 (2H, br), 3.86 (3H, s), 5.02
(1H, d, J = 4.5Hz), 5.03 (2H, s), 5.5 (1H, dd, J = 4.5Hz)
& 8Hz), 6.75 (1H, s), 7.22 (2H, br), 7.41 (2H, d, J = 5
Hz), 8.5 (2H, d, J = 5Hz), 9.47 (1H, d, J = 8Hz) In the same manner as in Example 1, the following compounds of Examples 2 to 24 were synthesized.

Example 2 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Ethoxyiminoacetamide] -3- (4
-Pyridylmethoxy) -3-cephem-4-carboxylate sodium mp: 170 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1640,1620,1535 NMR (DMSO-d ₆ ) δ: 1.2 (3H, t , J = 7Hz), 4.08 (2H, q, J
= 7Hz), 5.01 (3H, bs), 5.50 (1H, dd, J = 5 & 7Hz), 6.7
(1H, s), 7.19 (2H, br), 7.39 (2H, d, J = 5Hz), 8.48 (2
H, d, J = 5 Hz), 9.43 (1H, d, J = 7 Hz) Example 3 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Carboxymethoxyiminoacetamide]
-3- (4-Pyridylmethoxy) -3-cephem-4-
Carboxylic acid disodium mp: 170 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1610,1535 NMR (DMSO-d ₆ ) δ: 4.3 (2H, bs), 4.95 to 5.1 (3H, m),
5.51 (1H, dd, J = 4.5 & 8Hz), 6.81 (1H, s), 7.2 (2H, b
r), 7.39 (2H, d, J = 5Hz), 8.49 (2H, d, J = 5Hz), 11.71
(1H, d, J = 8Hz) Example 4 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-carboxy-1-methylethoxyimino)
Acetamide] -3- (4-pyridylmethoxy) -3-
Cephem-4-carboxylic acid disodium mp: 180 ° C. (decomposition) IR (KBr) cm ⁻¹ : 1760,1560 to 1680,1530 NMR (DMSO-d ₆ ) δ: 1.38 (3H, s), 1.45 (3H, s), 5.0 (3
H, s), 5.55 (1H, dd, J = 4.5 & 8Hz), 6.69 (1H, s), 7.17
(2H, bs), 7.38 (2H, d, J = 5Hz), 8.48 (2H, d, J = 5Hz),
11.44 (1H, d, J = 8Hz) Example 5 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2- (1-Carboxyvinyloxyimino) acetamido] -3- (4-pyridylmethoxy) -3-cephem-4-carboxylic acid disodium mp: 175 ° C (decomposition) IR (KBr) cm ^-1 : 1760, 1600, 1535 NMR (DMSO-d ₆ ) δ: 4.86 (1H, bs), 5.01 (3H, bs), 5.16
(1H, bs), 5.53 (1H, m), 6.90 (1H, s), 7.26 (2H, bs),
7.4 (2H, d, J = 5Hz), 8.49 (2H, d, J = 5Hz) Example 6 7β- [2- (5-amino-1,2,4-thiazole-3-
Il)-(Z) -2-ethoxyiminoacetamide]-
Sodium 3- (4-pyridylmethoxy) -3-cephem-4-carboxylic acid mp: 190 ° C. (decomposition) IR (KBr) cm ⁻¹ : 1760,1600,1530,1410 NMR (DMSO-d ₆ ) δ: 1.25 (3H, t, J = 8Hz), 3.4 (2H, b
s), 4.16 (2H, m), 5.0 (3H, bs), 5.55 (2H, dd, J = 5 & 8
Hz), 7.42 (2H, d, J = 5Hz), 8.2 (2H, bs), 8.5 (2H, d, J
= 5Hz), 9.42 (1H, d, J = 8Hz) Example 7 7β- (D-2-amino-2-phenylacetamide)
-3- (4-Pyridylmethoxy) -3-cephem-4-
Carboxylic acid mp: 165 ° C (decomposition) IR (KBr) cm ^-1 : 3430,3050,1755,1670,1600,1410 NMR (DMSO-d ₆ ) δ: 3.45 (2H, bs), 4.52 (2H, bs) , 4.9
(1H, d, J = 5Hz), 4.99 (1H, bs), 5.44 (1H, d, J = 5Hz),
7.44 (7H, m), 8.5 (2H, d, J = 4Hz), 8.76 (1H, br) Example 8 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3- (3
-Pyridylmethoxy) -3-cephem-4-carboxylate sodium mp: 175 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1580 to 1680,1540 NMR (DMSO-d ₆ + D ₂ O) δ: 3.39 ( 2H, bs), 3.86 (3H, s),
5.0 (3H, bs), 5.49 (1H, d, J = 4Hz), 6.77 (1H, s), 7.37
(1H, dd, J = 4.5 & 8Hz), 7.9 (1H, d, J = 8Hz), 8.48 (1H,
d, J = 4.5 Hz), 8.58 (1H, s) Example 9 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3- (2
-Pyridylmethoxy) -3-cephem-4-carboxylate sodium mp: 140 ° C (decomposition) IR (KBr) cm ^-1 : 1760, 1600 to 1680, 1530 NMR (DMSO-d ₆ + D ₂ O) δ: 3.08, 3.4 (2H, ABq, J = 13Hz),
3.88 (3H, s), 5.05 to 5.25 (1H, m), 5.4 to 5.75 (3H, m),
6.77 (1H, s), 7.8 to 8.25 (2H, m), 8.57 (1H, d, J = 6.5H
z), 8.99 (1H, d, J = 6Hz) Example 10 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3- [2
Sodium-(2-pyridyl) ethoxy] -3-cephem-4-carboxylic acid mp: 180 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1580 to 1680,1540 NMR (DMSO-d ₆ + D ₂ O) δ: 3.04 (2H, t, J = 6.5Hz), 3.21
(2H, bs), 3.86 (3H, s), 4.2 (2H, t, J = 6.5Hz), 4.97
(1H, d, J = 5Hz), 5.46 (1H, d, J = 5Hz), 6.77 (1H, s),
7.0 to 7.5 (2H, m), 7.67 (1H, d, J = 8Hz), 8.45 (1H, d, J
= 5 Hz) Example 11 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- [1
Sodium-(4-pyridyl) ethoxy] -3-cephem-4-carboxylate mp: 175-180 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1660,1600,1530 Example 12 7β- [2- (2-Aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamido] -3- (thiazol-4-ylmethoxy) -3-cephem-4-carboxylic acid sodium mp: 150-155 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1620 , 1535,1415,1370 NMR (DMSO-d ₆ ) δ: 3.4 (m), 3.82 (3H, s), 4.95 (1H,
d, J = 5Hz), 5.08 (2H, s), 5.45 (1H, dd, J = 5 & 9Hz),
6.71 (1H, s), 7.18 (2H, br), 7.72 (1H, s), 9.02 (1H,
s), 9.45 (1H, d, J = 9Hz) Example 13 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (4
-Methylthiazol-2-ylmethoxy) -3-cephem-4-carboxylic acid sodium mp: 175-180 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1615,1530,1365 NMR (DMSO-d ₆ ) δ : 2.35 (3H, s), 3.4 (m), 3.85 (3H,
s), 5.0 (1H, d, J = 5Hz), 5.21 (2H, s), 5.5 (1H, m), 6.
72 (1H, s), 7.22 (3H, bs), 9.5 (1H, bd, J = 8Hz) Example 14 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3- (2
-Methylthiazol-5-ylmethoxy) -3-cephem-4-carboxylic acid sodium mp: 170-175 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1615,1535,1360 NMR (DMSO-d ₆ ) δ : 2.62 (3H, s), 3.4 (m), 3.85 (3H,
s), 4.97 (1H, d, J = 5Hz), 5.15 (2H, s), 5.5 (1H, m),
6.72 (1H, s), 7.25 (2H, br), 7.55 (1H, s), 9.5 (1H, b
d, J = 8 Hz) Example 15 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (1,
2,3-thiadiazol-4-yl) -3-cephem-4
-Sodium carboxylate mp: 160-165 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1620,1535,1370 NMR (DMSO-d ₆ ) δ: 3.4 (m), 3.85 (3H, s), 4.98 (1H,
d, J = 5Hz), 5.5 (3H, m), 6.72 (1H, s), 7.2 (2H, br),
9.35 (1H, s), 9.46 (1H, d, J = 9Hz) Example 16 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3- (1
-Methylimidazol-2-ylmethoxy) -3-cephem-4-carboxylic acid sodium mp: 160-165 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1600,1610,1535,1360 NMR (DMSO-d ₆ ) Δ: 3.4 (m), 3.72 (3H, s), 3.86 (3H,
s), 4.95 to 5.05 (3H, m), 5.5 (1H, m), 6.75 (1H, s), 6.
82 (1H, s), 7.12 (1H, s), 7.22 (2H, br), 9.5 (1H, br) Example 17 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3-
[(5S)-(2-Pyrrolidone-5-ylmethoxy)]-
3-Cephem-4-carboxylic acid sodium mp: 190-195 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1670,1530,1365 NMR (DMSO-d ₆ ) δ: 1.9-2.3 (4H, m) , 3.4 (m), 3.6
(3H, m), 3.88 (3H, s), 4.1 (1H, m), 5.04 (1H, dd, J =
5 & 8Hz), 6.75 (1H, s), 7.25 (2H, br), 9.32 (1H, b)
r), 9.5 (1H, d, J = 8Hz) Example 18 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3-
[(5RS)-(2-Pyrrolidone-5-ylmethoxy)]
Sodium -3-cephem-4-carboxylate mp: 185-190 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1670,1530,1365 NMR (DMSO-d ₆ ) δ: 1.9-2.3 (4H, m ), 3.4 (m), 3.5 ~
3.7 (2H, m), 3.85 (3H, s), 4.0 (1H, m), 5.0 (1H, d, J =
5Hz), 5.45 (1H, m), 6.75 (1H, s), 7.2 (2H, br), 8.8 ~
9.6 (2H, m) Example 19 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Carboxymethoxyiminoacetamide]
-3-[(5RS)-(2-Pyrrolidone-5-ylmethoxy)]-3-cephem-4-carboxylic acid disodium mp: 155-160 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1670, 1600,1530,1360 NMR (DMSO-d ₆ ) δ: 1.9 to 2.2 (4H, m), 3.4 (m), 3.5 to
3.7 (2H, m), 3.9 to 4.1 (2H, m), 3.9 to 4.1 (1H, m), 4.3
(2H, s), 5.02 (1H, d, J = 5Hz), 5.5 (1H, m), 6.82 (1H,
s), 7.2 (2H, br), 8.8 to 9.2 (1H, m), 11.6 (1H, br) Example 20 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Carboxymethoxyiminoacetamide]
-3- [Thiazol-4-ylmethoxy)]-3-cephem-4-carboxylic acid disodium mp: 70-80 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1610,1535,1415,1380 NMR ( DMSO-d ₆ ) δ: 3.4 (m), 4.28 (2H, s), 4.96 (1H,
d, J = 5Hz), 5.09 (2H, br), 5.5 (1H, m), 6.82 (1H, s),
7.18 (2H, br), 7.78 (1H, s), 9.06 (1H, s) Example 21 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Carboxymethoxyiminoacetamide]
-3- (4-methylthiazol-2-ylmethoxy)-
3-Cephem-4-carboxylic acid disodium mp: 175-180 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1610,1530,1410,1370 NMR (DMSO-d ₆ ) δ: 2.34 (3H, s ), 3.4 (m), 4.3 (2H, b
s), 5.0 (1H, d, J = 5Hz), 5.2 (2H, bs), 5.5 (1H, m), 6.82 (1H, s), 7.2 (3H, bs) Example 22 7β- [2- ( 2-aminothiazol-4-yl)-
(Z) -2-Carboxymethoxyiminoacetamide]
-3- (2-methylthiazol-5-ylmethoxy)-
3-Cephem-4-carboxylic acid disodium mp: 170-175 ° C. (decomposition) IR (KBr) cm ⁻¹ : 1760,1610,1530,1410 NMR (DMSO-d ₆ ) δ: 2.62 (3H, s), 3.4 (2H, bs), 4.98
(1H, d, J = 5Hz), 5.14 (2H, s), 5.5 (1H, m), 6.82 (1H,
s), 7.25 (2H, br), 7.55 (1H, s) Example 23 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Carboxymethoxyiminoacetamide]
-3- (1,2,3-thiazol-4-ylmethoxy) -3
-Cephem-4-carboxylic acid disodium mp: 160 to 165 ° C (decomposition) IR (KBr) cm ^-1 : 1760, 1600, 1535, 1410, 1370 NMR (DMSO-d ₆ ) δ: 3.4 (m), 4.28 (2H, s), 4.96 (1H,
d, J = 5Hz), 5.45 (3H, m), 6.8 (1H, s), 7.18 (2H, br),
9.31 (1H, s) Example 24 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Carboxymethoxyiminoacetamide]
-3- (1-methylimidazol-2-ylmethoxy)
-3-Cephem-4-carboxylic acid disodium mp: 155-160 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1620,1535,1410,1370 NMR (DMSO-d ₆ ) δ: 3.4 (m) , 3.7 (3H, s), 4.28 (2H,
s), 4.9 to 5.1 (3H, m), 5.4 (1H, m), 6.82 (2H, s), 7.12
(1H, s), 7.16 (2H, br) Example 25 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Carboxymethoxyiminoacetamide]
3-sodium 4- (4-carboxybenzyloxy) -3-cephem-4-carboxylic acid Synthesized by the same method as in Reference Example 3.

mp: 160-165 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1620,1535,1380 NMR (DMSO-d ₆ + D ₂ O) δ: 3.35 (2H, m), 4.48 (2H, br),
4.98 (3H, m), 5.45 (1H, d, J = 5Hz), 6.82 (1H, s), 7.34
(2H, d, J = 9Hz), 7.84 (2H, d, J = 9Hz) Example 26 7β- [2- (2-aminothiazol-4-yl)-
(Z) -Methoxyiminoacetamido] -3- (1-methyl-4-pyridiniomethoxy) -3-cephem-4-
Carboxylate 7β- [2- (2-triethylaminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -3- (4-pyridylmethoxy) -obtained in Example 1.
3-cephem-4-carboxylic acid p-methoxybenzyl ester 492 mg (0.577 mmol) was dissolved in acetone 58 ml,
To this, 2.1 ml (34 mmol) of methyl iodide is added and stirred overnight at room temperature. The solvent was evaporated, the residue was triturated with ether, and 7β- [2- (2-tritylaminothiazole-4 was used.
-Yl)-(Z) -2-methoxyiminoacetamide]
-3- (1-methyl-4-pyridiniomethooxy) -3
-Cephem-4-carboxylic acid p-methoxybenzyl ester iodo salt 541 mg (yield 94.2%) is obtained as a yellow powder. 519 mg (0.522 mmol) of this powder was added to dichloromethane 2.
Dissolve it in 9 ml and 0.92 ml of anisole, add 4.6 ml of trifluoroacetic acid dropwise under ice cooling, and stir at the same temperature for 1 hour. The solvent is evaporated, and isopropyl ether is added to the residue to give the trifluoroacetic acid salt of the title compound as a powder. This was dissolved in water, adjusted to pH 6.5 with an aqueous sodium hydrogen carbonate solution, and subjected to reverse phase column chromatography (Chemco LC-SORB, S
P-B-ODS, eluted with 30% aqueous methanol solution)
Lyophilize to give 88.5 mg of the title compound (yield 33.6%).

mp: 140 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1650,1610,1535 NMR (DMSO-d ₆ ) δ: 3.84 (3H, s), 4.33 (3H, bs), 5.0
(1H, d, J = 5Hz), 5.27 (2H, bs), 5.5 (1H, dd, J = 5 & 8H
z), 6.76 (1H, s), 7.22 (2H, br), 8.16 (2H, d, J = 4H
z), 9.93 (2H, d, J = 4Hz), 9.49 (1H, d, J = 8Hz) In the same manner as in Example 26, the following compounds of Examples 27 to 43 were synthesized.

Example 27 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Ethoxyiminoacetamide] -3- [1
-Methyl-4-pyridiniomethoxy) -3-cephem-
4-Carboxy chelate mp: 150 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1645,1620,1530 NMR (DMSO-d ₆ ) δ: 1,22 (3H, t, J = 7Hz), 4.09 (2H, q, J
= 7Hz), 7.32 (3H, bs), 4.99 (1H, d, J = 4.5Hz), 5.25
(2H, bs), 5.51 (1H, dd, J = 4.5 & 8Hz), 6.71 (1H, s),
7.18 (2H, br), 8.13 (2H, d, J = 5Hz), 8.92 (2H, d, J = 5H
z), 9.42 (1H, d, J = 8Hz) Example 28 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Benzyloxyiminoacetamide] -3
-(1-Methyl-4-pyridiniomethoxy) -3-cephem-4-carboxylate mp: 165 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1660,1645,1610,1530 NMR (DMSO- d ₆ ) δ: 4.3 (3H, bs), 4.98 (1H, d, J = 4.5H
z), 5.13 (2H, bs), 5.23 (2H, bs), 5.5 (1H, dd, J = 4.5
& 8Hz), 6.72 (1H, s), 7.2 (2H, br), 7.33 (5H, bs), 8.
12 (2H, d, J = 6Hz), 8.9 (2H, d, J = 6Hz), 9.55 (1H, d, J
= 8 Hz) Example 29 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Carboxymethoxyiminoacetamide]
-3- (1-methyl-4-pyridiniomethoxy) -3-
Cephem-4-carboxylate Sodium mp: 130 ° C. ^{(decomposition) IR (KBr) cm -1:} 1760,1600,1540 NMR (DMSO-d 6) δ: 3.48,3.78 (2H, ABq, J = 17Hz), 4.58
(3H, s), 5.23 (1H, d, J = 4.5Hz), 5.3 (2H, s), 5.71 (1
H, d, J = 4.5Hz), 7.03 (1H, s), 8.03 (2H, d, J = 5Hz), 8.
71 (2H, d, J = 5Hz) Example 30 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2- (1-Carboxy-1-methylethoxyimino) acetamido] -3- (1-methyl-4-pyridiniomethoxy) -3-cephem-4-carboxylate sodium mp: 155 ° C (decomposition ) IR (KBr) cm ^-1 : 1760,1640,1585,1530 NMR (DMSO-d ₆ + D ₂ O) δ: 4.86 (1H, bs), 5.01 (3H, b
s), 5.16 (1H, bs), 5.53 (1H, m), 6.9 (1H, s), 7.26 (2
H, br), 7.4 (2H, d, J = 5Hz), 8.49 (2H, d, J = 5Hz) Example 31 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2- (1-Carboxyvinyloxyimino) acetamido] -3- (1-methyl-4-pyridiniomethoxy) -3-cephem-4-carboxylate sodium mp: 145 ° C. (decomposition) IR ( KBr) cm ^-1 : 1760,1640,1595,1530 NMR (DMSO-d ₆ + D ₂ O) δ: 3.45 (2H, bs), 4.29 (3H, b
s), 4.9 (1H, bs), 5.01 (1H, d, J = 4.5Hz), 5.16 (1H, b
s), 5.52 (1H, d, J = 4.5Hz), 6.92 (1H, s), 8.1 (2H, d, J
= 6 Hz), 8.8 (2H, d, J = 6 Hz) Example 32 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2- (α-Carboxy-3,4-dihydroxybenzyloxyimino) acetamide] -3- (1-methyl-4-pyridiniomethoxy) -3-cephem-4-carboxylate sodium diastereo Mer A isomer mp: 170 ° C. (decomposition) IR (KBr) cm ⁻¹ : 1760,1570,1530 Example 33 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2- (α-Carboxy-3,4-dihydroxybenzyloxyimino) acetamide] -3- (1-methyl-4-pyridiniomethoxy) -3-cephem-4-carboxylate sodium diastereo Mer B isomer mp: 175 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1570,1530 Example 34 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2- (2-Carboxymethylbenzyloxyimino) acetamido] -3- (1-methyl-4-pyridiniomethoxy) -3-cephem-4-carboxylate sodium mp: 145 ° C (decomposition) IR (KBr) cm ⁻¹ : 1760,1645,1585,1535 NMR (DMSO−d ₆ + D ₂ O) δ: 3.34 (2H, s), 4.27 (3H, s),
4.98 (1H, d, J = 4.5Hz), 5.23 (2H, bs), 5.5 (1H, d, J =
4.5Hz), 6.73 (1H, s), 7.13 (4H, br), 8.1 (2H, bd, J = 5
Hz), 8.79 (2H, bd, J = 5Hz) Example 35 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-ethoxyiminoacetamido] -3- (1-methyl-4-pyridiniomethoxy)-
3-Cephem-4-carboxylate mp: 140 ° C. (decomposition) IR (KBr) cm ⁻¹ : 1760,1670,1640,1610,1520 NMR (DMSO-d ₆ ) δ: 1.25 (3H, t, J = 8Hz ), 3.53 (2H, b
s), 4.16 (2H, m), 4.32 (3H, s), 4.98 (1H, d, J = 5Hz),
5.23 (2H, bs), 5.55 (1H, dd, J = 5 & 8Hz), 8.13 (2H, d,
J = 5Hz), 8.92 (2H, d, J = 5Hz), 9.43 (1H, d, J = 9Hz) Example 36 7β- (D-2-amino-2-phenylacetamide)
-3- (1-methyl-4-pyridiniomethoxy) -3-
Cephem-4-carboxylate mp: 130 ° C (decomposition) IR (KBr) cm ^-1 : 1760, 1665, 1640, 1600 NMR (DMSO-d ₆ + D ₂ O) δ: 3.4 (2H, bs), 4.3 (3H , s), 4.
4 (2H, bs), 4.9 (1H, m), 5.06 (1H, s), 5.4 (1H, s), 7.
32 (5H, m), 8.1 (2H, m), 8.85 (2H, m) Example 37 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3- (1
-Methyl-3-pyridiniomethoxy) -3-cephem-
4-carboxylate mp: 155 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1580 to 1680,1535 NMR (DMSO-d6) δ: 3.82 (3H, s), 4.34 (3H, s), 4.95
(1H, d, J = 4.5Hz), 5.13 (2H, s), 5.45 (1H, dd, J = 4.5)
& 7.5Hz), 6.71 (1H, s), 7.17 (2H, br), 7.9 to 8.2 (1H,
m), 8.57 (1H, d, J = 8Hz), 8.89 (1H, d, J = 5Hz), 9.32
(1H, bs), 9,43 (1H, d, J = 7.5Hz) Example 38 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3- (1
-Methyl-2-pyridiniomethoxy) -3-cephem-
4-carboxylate mp: 0.99 ° C. ^{(decomposition) IR (KBr) cm -1:} 1760,1660,1630,1600 NMR (DMSO-d 6) δ: 3.53 (2H, bs), 3.84 (3H, s), 4.33
(3H, bs), 4.97 (1H, d, J = 4.5Hz), 5.3 to 5.6 (3H, m),
6.74 (1H, s), 7.2 (2H, br), 7.85 to 8.15 (1H, m), 8.15
~ 8.4 (1H, m), 8.4 ~ 8.7 (1H, m), 8.9 ~ 9.2 (1H, m), 9.
47 (1H, bd, J = 8Hz) Example 39 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2- (2-Fluoroethoxyimino) acetamide] -3- (1-methyl-4-pyridiniomethoxy)
-3-cephem-4-carboxylate mp: 148-151 ° C. ^{(decomposition) IR (KBr) cm -1:} 1760,1680~1600,1530 NMR (DMSO-d 6) δ: 4.00~4.93 (7H, m) , 4.98 (1H, d, J
= 5Hz), 5.23 (2H, bs), 5.50 (1H, dd, J = 5 & 8Hz), 6.7
4 (1H, s), 7.20 (2H, br), 8.11 (2H, d, J = 5Hz), 8.90
(2H, d, J = 5Hz), 9.48 (1H, d, J = 8Hz) Example 40 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3- (1
-Propyl-4-pyridiniomethoxy) -3-cephem-4-carboxylate mp: 128-130 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1560-1700,1530 NMR (DMSO-d ₆ ). δ: 0.85 (3H, t, J = 7Hz), 1.6 to 2.2 (2
H, m), 3.83 (3H, s), 4.3 to 4.7 (2H, m), 4.9 (1H, d, J =
4.5Hz), 5.26 (2H, bs), 5.46 (1H, dd, J = 4.5 & 8Hz), 6.
72 (1H, s), 7.2 (2H, bs), 8.16 (2H, d, J = 5Hz), 9.03
(2H, d, J = 5Hz), 9.45 (1H, d, J = 8Hz) Example 41 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3- (1
-Allyl-4-pyridiniomethoxy) -3-cephem-
4-carboxylate mp: 145-150 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1560-1700,1530 NMR (DMSO-d ₆ ) δ: 3.85 (3H, s), 5.0 (1H, d, J = 4.5H
z), 5.1 to 5.6 (7H, m), 5.9 to 6.4 (1H, m), 6.75 (1H,
s), 7.18 (2H, bs), 8.1 to 8.3 (2H, m), 8.8 to 9.1 (2H,
m) Example 42 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- [1
-(1-Methyl-4-pyridinio) ethoxy] -3-cephem-4-carboxylate mp: 120-122 ° C (decomposition) IR (KBr) cm ^-1 : 1755,1640,1610,1530 Example 437β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3- (1
-Carbamoylmethyl-4-pyridiniomethoxy) -3
-Cephem-4-carboxylate mp: 130 to 135 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1720 to 1560,1530 NMR (DMSO-d ₆ + D ₂ O) δ: 3.1 to 3.6 (2H, m ), 5.02 (1H,
d, J = 4.5Hz), 5.35 (2H, bs), 5.53 (1H, d, J = 4.5Hz),
6.78 (1H, s), 8.19 (2H, d, J = 5Hz), 8.83 (2H, d, J = 5H
z) Example 44 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-methoxyiminoacetamide] -3- (1
-Carboxymethyl-4-pyridiniomethoxy) -3-
Cephem-4-carboxylate sodium 7β- [2- (2-triethylaminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -3- (4-pyridylmethoxy) obtained in Example 1. −
800 mg (0.938 mmol) of 3-cephem-4-carboxylic acid p-methoxybenzyl ester was dissolved in 93 ml of acetone,
3.34 g of iodoacetic acid benzhydryl ester (9.49 m
mol) and a few drops of N, N-dimethylformamide and stir overnight at room temperature. The solvent is distilled off and the residue is triturated with ether to give 1.33 g of a powder. 1.3 g of this powder is dissolved in 6 ml of dichloromethane and 1.3 ml of anisole, 9 ml of trifluoroacetic acid is added dropwise under ice-cooling, and the mixture is stirred at the same temperature for 1 hour. The solvent is evaporated, and isopropyl ether is added to the residue to give the trifluoroacetic acid salt of the title compound as a powder. Dissolve this in water, adjust to pH 7.0 with aqueous sodium hydrogen carbonate solution,
Reversed phase column chromatography (Chemco LC-SORB, SP-
B-ODS, eluted with 30% aqueous methanol solution) and lyophilized to give 133 mg (yield 21.8%) of the title compound.

mp: 150 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1640,1535 NMR (DMSO-d ₆ ) δ: 3.83 (3H, s), 4.93 (2H, bs), 5.03
(1H, d, J = 4.5Hz), 5.27 (2H, bs), 5.52 (1H, dd, J = 4.5)
& 8Hz), 6.74 (1H, s), 7.22 (2H, bs), 8.07 (2H, d, J = 6
Hz), 8.78 (2H, d, J = 6Hz), 9.53 (1H, d, J = 8Hz) In the same manner as in Example 44, the compounds of the following Examples 45 and 46 were synthesized.

Example 45 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Ethoxyiminoacetamide] -3- (1
-Carboxymethyl-4-pyridiniomethoxy] -3-
Cephem-4-carboxylate Sodium mp: 0.99 ° C. ^{(decomposition) IR (KBr) cm -1:} 1760,1640,1530 NMR (DMSO-d 6) δ: 1.22 (3H, t, J = 7Hz), 4.08 (2H , q, J
= 7Hz), 4.9 (2H, bs), 5.01 (1H, d, J = 4.5Hz), 5.25 (2
H, bs), 5.52 (1H, dd, J = 4.5 & 7Hz), 6.71 (1H, s), 7.2
(2H, bs), 8.05 (2H, d, J = 5Hz), 8.76 (2H, d, J = 5Hz),
9.46 (1H, d, J = 7Hz) Example 46 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Carboxymethoxyiminoacetamide]
-3- (1-Carboxymethyl-4-pyridiniomethoxy] -3-cephem-4-carboxylate disodium mp: 150 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1700 to 1580,1540 NMR (DMSO-d ₆ ) δ: 3.5,3.8 (2H, ABq, J = 18Hz), 4.95
(2H, s), 5.18 (1H, d, J = 4Hz), 5.21 (2H, s), 5.35 (2
H, s), 5.73 (1H, d, J = 4Hz), 7.06 (1H, s), 8.07 (2H, d,
J = 6Hz), 8.7 (2H, d, J = 6Hz) Example 47 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (3,
4-dihydroxy-1-methyl-6-pyridiniomethoxy) -3-cephem-4-carboxylate 7β- [2- (2-tritylaminothiazole-4-
Yl)-(Z) -2-methoxyiminoacetamide]-
3-hydroxy-3-cephem-4-carboxylic acid p-
340 mg (0.446 mmol) of methoxybenzyl ester and 146MG (0.557 mmol) of triphenylphosphine were dissolved in 7 ml of tetrahydrofuran, and under a nitrogen stream at -20 ° C, 4,5-bis (4-methoxybenzyloxy) -2-hydroxymethyl. A solution of 170 mg (0.446 mmol) pyridine in tetrahydrofuran (3.5 ml) is added. Then, a solution of 0.087 ml (0.55 mmol) of diethyl azodicarboxylate in tetrahydrofuran (3.5 ml) was added dropwise to this solution at -20 ° C, and the mixture was stirred at the same temperature for 1 hour, and ethyl acetate (30 ml) was added. The solution is washed with water, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent is evaporated. The residue was purified by silica gel chromatography (Wakogel C-300, eluted with 1-2% methanol-chloroform) to give 7β- [2- (2-
Triethylaminothiazol-4-yl)-(Z) -2
-Methoxyiminoacetamide] -3- [3,4-bis (4-methoxybenzyloxy) -6-pyridylmethoxy] -3-cephem-4-carboxylic acid p-methoxybenzyl ester 325 mg (yield 64.8%) is obtained. . This powder 3
Dissolve 25 mg (0.289 mmol) in 28 ml of methylene chloride, and under nitrogen stream, at −20 ° C., methyl triflate 0.067 ml (0.592 mm)
ol) in methylene chloride (2 ml), and the mixture is stirred at room temperature for 1 hour. After evaporating the solvent, the residue was triturated with ether to give 7β- [2- (2-triethylaminothiazol-4-yl)-(Z) -2-methoxyiminoacetamide] -3- [3,4- Bis (4-methoxybenzyloxy) -1-methyl-6-pyridiniomethoxy] -3-cephem-4-carboxylic acid p-methoxybenzyl ester trifluoromethanesulfonate 355 m
g (95.2% yield) is obtained as a powder. This powder 355 mg (0.
275 mmol) and 3-methyl-4-methylthiophenol 429
mg (2.79mmol) to methylene chloride 2ml and thioanisole
Dissolve in 0.34 ml (2.5 mmol), add 2 ml of trifluoroacetic acid under ice cooling, and stir at room temperature for 1 hour. The solvent is distilled off, and ether is added to the residue to obtain the trifluoroacetic acid salt of the title compound as a powder. This was dissolved in water and the insoluble material was filtered off, followed by reverse phase column chromatography (Chemco LC
-SORB, SP-B-ODS, eluted with 30% aqueous methanol solution) and lyophilized to give 28.1 mg (yield 19%) of the title compound.

mp: 150-160 ℃ (decomposition) IR (KBr) cm ^-1 : 3350,1760,1670,1630,1560,1535 NMR (DMSO-d ₆ ) δ: 3.68 (3H, s), 3.86 (3H, s) , 5.07
(2H, s), 5.18 (1H, d, J = 5Hz), 5.61 (1H, dd, J = 5 & 8H
z), 6.40 (1H, s), 6.84 (1H, s), 7.26 (2H, br), 7.50
(1H, s), 9.60 (1H, d, J = 8Hz) Example 48 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2- (1-Carboxy-1-methylethoxyimino) acetamide] -3- (3,4-dihydroxy-1)
-Methyl-6-pyridiniomethoxy) -3-cephem-
4-Carboxylate sodium Synthesized in the same manner as in Example 47.

mp: 170-180 ° C (decomposition) IR (KBr) cm ^-1 : 3450,1765,1670,1635,1560 NMR (DMSO-d ₆ ) δ: 1.44 (3H, s), 1.46 (3H, s), 3.68
(3H, s), 5.07 (2H, s), 5.20 (1H, d, J = 4Hz), 5.68 (1
H, dd, J = 4 & 8Hz), 6.41 (1H, s), 6.80 (1H, s), 7.33
(2H, br), 7.51 (1H, s), 9.45 (1H, d, J = 8Hz) Example 49 In the same manner as in Reference Example 4, the compound of the following Example 49 was synthesized.

7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (1,
2,3-thiadiazol-4-ylmethoxy) -3-cephem-4-carboxylic acid pivaloyloxymethyl ester mp: 115-120 ° C (decomposition) IR (KBr) cm ^-1 : 1780,1750,1675,1615, 1535 NMR (DMSO-d ₆ ) δ: 1.10 (9H, s), 3.8-4.0 (5H, m), 5.
22 (1H, d, J = 4Hz), 5.6 ~ 5.9 (5H, m), 6.85 (1H, s), 7.
3 (1H, br), 9.24 (1H, s), 9.62 (1H, d, J = 8Hz) Reference Example The compounds of Reference Example 1 and Reference Example 2 were synthesized in the same manner as in Example 1.

Reference Example 1 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (4
-Cyanobenzyloxy) -3-cephem-4-carboxylic acid sodium mp: 175 to 180 ° C (decomposition) IR (KBr) cm ^-1 : 2230,1760,1610,1530,1360 NMR (DMSO-d ₆ ) δ: 3.4 (m), 3.88 (3H, s), 4.95 ~ 5.1
(3H, m), 5.4 (1H, dd, J = 5 & 8Hz), 6.75 (1H, s), 7.27
(2H, br), 7.62 (2H, d, J = 8Hz), 7.79 (2H, d, J = 8Hz),
9.5 (1H, d, J = 8Hz), Reference Example 2 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Carboxymethoxyiminoacetamide]
-3- (1,2,3-thiadiazol-4-ylmethoxy)
-3-cephem-4-carboxylic acid disodium mp: 160-165 ° C. ^{(decomposition) IR (KBr) cm -1:} 1760,1600,1535,1410,1370 NMR (DMSO-d 6) δ: 3.4 (m) , 4.28 (2H, s), 4.96 (1H,
d, J = 5Hz), 5.45 (3H, m), 6.8 (1H, s), 7.18 (2H, br),
9.31 (1H, s) Reference Example 3 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (4
-Carboxybenzyloxy) -3-cephem-4-carboxylic acid disodium 7β- [2- (2-tritylaminothiazole-4-
Yl)-(Z) -2-methoxyiminoacetamide]-
3-hydroxy-3-cephem-4-carboxylic acid p-
Methoxybenzyl ester 1.14 g (1.5 mmol) and triphenylphosphine 472 mg (1.8 mmol) were dissolved in tetrahydrofuran 20 ml, and p-hydroxymethylbenzoic acid benzhydryl ester 537.1 mg (1.8
tetrahydrofuran solution (10 ml) is added. Then 0.28 ml of diethyl azodicarboxylate in this solution
A solution of (1.8 mmol) in tetrahydrofuran (10 ml) is added at the same temperature, and the mixture is stirred for 20 minutes. Ethyl acetate was added to the reaction solution,
The extract is washed with water, 1N hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent is evaporated. The residue was purified by silica gel chromatography (Wakogel C-300, eluted with dichloromethane-chloroform) to give powdery 7β- [2- (2-tritylaminothiazol-4-yl)-(Z) -2-methoxyimino. Acetamide] -3- (4-diphenylmethoxycarbonylbenzyloxy) -3-cephem-4-
1.28 g (yield 80.5%) of carboxylic acid p-methoxybenzyl ester is obtained. 1.2 g (1.13 mmol) of this powder is dissolved in 12 ml of anisole, 12 ml of trifluoroacetic acid is added dropwise under ice cooling, and the mixture is stirred at the same temperature for 30 minutes. After distilling off the solvent, isopropyl ether was added to the residue to obtain the trifluoroacetic acid salt of the title compound as a powder. This was dissolved in water, adjusted to pH 7.6 with an aqueous sodium hydrogen carbonate solution, and subjected to reverse phase column chromatography (Chemco LC-SORB, SP-B-ODS, 10
% Methanol aqueous solution) and lyophilize to give the title compound 312 mg (yield 53.8%).

mp: 190-195 ° C (decomposition) IR (KBr) cm ^-1 : 1760,1600,1540,1380 NMR (DMSO-d ₆ ) δ: 3.4 (m), 3.82 (3H, s) 4.98 (3H,
m), 5.5 (1H, m) Reference Example 4 7β- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (4
-Cyanobenzyloxy) -3-cephem-4-carboxylic acid pivaloyloxymethyl ester Dissolve 57.4 mg (0.38 mmol) of chloromethyl pivalate in 2 ml of acetone, add 63 mg (0.42 mmol) of sodium iodide, and add 50 ° C. After heating for 30 minutes at room temperature, 4 ml of ether is added, the insoluble matter is filtered off, the solvent is distilled off, and the residue is dissolved in 1 ml of N, N-dimethylformamide. 7β- [2- (2-aminothiazole-4) obtained in the same manner as in Example 1
-Yl)-(Z) -2-methoxyiminoacetamide]
-3- (4-cyanobenzyloxy) -3-cephem-
Sodium 4-carboxylate (Compound of Reference Example 1) 100 m
g (0.217 mmol) is dissolved in 1 ml of N, N-dimethylformamide, the above solution is added under ice cooling, and the mixture is stirred at room temperature for 30 minutes. Water and ethyl acetate are added to the reaction solution, the ethyl acetate layer is separated, washed with saturated aqueous sodium hydrogencarbonate and then with saturated saline, dried over magnesium sulfate, and the solvent is evaporated. Triturate the residue with ether to give the title compound 2
4.8 mg (21.2% yield) are obtained.

mp: 120-123 ° C (decomposition) IR (KBr) cm ^-1 : 1780,1750,1675,1620,1530 NMR (DMSO-d ₆ ) δ: 1.16 (9H, s), 3.78 (2H, s), 3.86
(3H, s), 5.11 (2H, s), 5.23 (1H, d, J = 4Hz), 5.73 (1
H, dd, J = 4 & 8Hz), 5.79,5.89 (2H, ABq, J = 6Hz), 6.81
(1H, s), 7.24 (2H, br), 9.64 (1H, d, J = 8Hz) EFFECTS OF THE INVENTION The compound of the present invention exhibits excellent antibacterial activity. It is useful as a therapeutic agent.

Claims (7)

(57) [Claims] 1. A compound of the general formula [I] [In the formula, R ¹ is an amino group substituted with an acyl group selected from the group consisting of an aliphatic acyl group, an aromatic acyl group and a heterocyclic acyl group, R ² is a halogen atom, a methyl group, an ethyl group, Propyl group, hydroxymethyl group, aminomethyl group, sulfomethyl group, carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfur Famoylmethyl group, oxo group, N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group, ethoxy group, fluoromethoxy group,
Difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group, carbamoyloxy group, N- 1 or it selected from the group consisting of methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. The heterocyclic group optionally substituted with the above substituents, R ³ is a hydrogen atom, negative charge or lower alkanoyloxymethyl group, 1- (lower alkoxycarbonyloxy) ethyl group, 5-substituted-2-oxo- 1,3-dioxole An ester residue capable of forming a non-toxic ester hydrolyzable in vivo selected from the group consisting of -ylmethyl group, 1-phthalidyl group and 5-cyano-1-phthalidyl group, and X represents an alkylene group, respectively] A cephalosporin derivative represented by or a non-toxic salt thereof. 2. R ¹ is the formula (a). [In the formula, R ⁴ is a halogen atom, a methyl group, a hydroxymethyl group, a fluoromethyl group, a trifluoromethyl group, an ethyl group, a bromomethyl group, a difluoromethyl group, a hydroxyl group,
Aminomethyl group, carboxymethyl group, carbamoylmethyl group, sulfomethyl group, N-methylaminomethyl group,
Methoxy, ethoxy, propoxy, fluoromethoxy, amino, methylamino, dimethylamino, ethylamino, propylamino, formamide, acetamide, propionylamino, formyloxy, acetoxy, propionyl Oxy group, carboxyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, methoxycarbamoyl group, ethoxycarbamoyl group, sulfamoyl group,
An aryl group which may be substituted with one or more substituents selected from the group consisting of a sulfo group, a cyano group and a nitro group, or a halogen atom, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, aminomethyl Group, sulfomethyl group, carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group,
Trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfamoylmethyl group,
Oxo group, N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group, ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, Methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group,
Ethynyl group, acetoxy group, formyloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl Base,
A heterocyclic group which may be substituted with one or more substituents selected from the group consisting of a cyclopentyl group and a cyclohexyl group, Y is a formula (a ₁ ) = N to OR ⁵ (a ₁ ) (wherein R ⁵ is a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a formyloxy group, an acetoxy group, a fluoroacetoxy group, an N-methylcarbamoyl group, Carbamoyl group,
N-methylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, amino group, methylamino group, dimethylamino group, formamide group, acetamido group, fluoroacetamido group, carboxyl group, methoxycarbonyl Group, ethoxycarbonyl group, sulfo group, sulfamoyl group, cyano group, formyl group, acetyl group, fluoroacetyl group, diethylamino group, ethylamino group, methylthio group, ethylthio group, propylthio group, fluoromethylthio group, 2-fluoroethylthio group Group, 1-fluoroethylthio group, tetrazolyl group, 1-methyltetrazolyl group, thiazolyl group,
2-aminothiazolyl group, 5-amino-1,2,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, imidazolyl group, thienyl group, furanyl group, 2-aminooxazoli Group, isothiazolyl group, isoxazolyl group, quinolyl group, isoquinolyl group, pyridyl group, 3,4-dihydroxy-6-pyridyl group, piperazinyl group, pyrrolidinyl group, piperidyl group, pyrrolyl group, morpholinyl group, benzothiazolyl group and benzimidazolyl group A group consisting of a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of, a carbamoyl group, a carboxyl group, an amino group, a methylamino group, a dimethylamino group, a sulfo group, a hydroxyl group and a cyano group. Cycloalkyl optionally substituted with one or more substituents selected from , A halogen atom, a carboxyl group, an amino group, a sulfo group, a hydroxyl group, a lower alkenyl group optionally substituted with one or more substituents selected from the group consisting of a carbamoyl group and a cyano group, a halogen atom, a hydroxyl group, Lower alkynyl group optionally substituted by one or more substituents selected from the group consisting of amino group, carboxyl group, carbamoyl group, sulfo group and cyano group, halogen atom, methyl group,
Hydroxymethyl group, fluoromethyl group, trifluoromethyl group, ethyl group, bromomethyl group, difluoromethyl group, hydroxyl group, aminomethyl group, carboxymethyl group,
Carbamoylmethyl group, sulfomethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, amino group, methylamino group,
Dimethylamino group, ethylamino group, propylamino group, formamide group, acetamide group, propionylamino group, formyloxy group, acetoxy group, propionyloxy group, carboxyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethyl Carbamoyl group,
Aryl group, methyl group, ethyl group, propyl group which may be substituted with one or more substituents selected from the group consisting of methoxycarbamoyl group, ethoxycarbamoyl group, sulfamoyl group, sulfo group, cyano group and nitro group. Group, halogen atom, fluoromethyl group, difluoromethyl group, trifluoromethyl group, carboxymethyl group, aminomethyl group, sulfomethyl group, carbamoylmethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, fluoroethoxy group, Difluoroethoxy group,
Trifluoroethoxy group, hydroxyl group, formyloxy group,
Acetoxy group, trifluoroacetoxy group, amino group,
Methylamino group, ethylamino group, dimethylamino group,
Diethylamino group, formamide group, acetamide group,
One or more substituents selected from the group consisting of carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, sulfo group, cyano group and nitro group. An aralkyl group or a halogen atom which may be substituted with, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, an aminomethyl group, a sulfomethyl group,
Carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group,
N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group,
Ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group , Carbamoyloxy group, N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group,
A group represented by a hydroxyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group or a heterocyclic group which may be substituted with one or more substituents) or a group represented by the formula (a ₂ ) (In the formula, R ⁶ and R ⁷ may be the same or different, a hydrogen atom or a halogen atom or a halogen atom, a hydroxyl group,
Methoxy group, ethoxy group, propoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, formyloxy group, acetoxy group, fluoroacetoxy group, N-methylcarbamoyl group, carbamoyl group,
N-methylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, amino group, methylamino group, dimethylamino group, formamide group, acetamido group, fluoroacetamido group, carboxyl group, methoxycarbonyl Group, ethoxycarbonyl group, sulfo group, sulfamoyl group, cyano group, formyl group, acetyl group, fluoroacetyl group, diethylamino group, ethylamino group, methylthio group, ethylthio group, propylthio group, fluoromethylthio group, 2-fluoroethylthio group Group, 1-fluoroethylthio group, tetrazolyl group, 1-methyltetrazolyl group, thiazolyl group,
2-aminothiazolyl group, 5-amino-1,2,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, imidazolyl group, thienyl group, furanyl group, 2-aminooxazoli Group, isothiazolyl group, isoxazolyl group, quinolyl group, isoquinolyl group, pyridyl group, 3,4-dihydroxy-6-pyridyl group, piperazinyl group, pyrrolidinyl group, piperidyl group, pyrrolyl group, morpholinyl group, benzothiazolyl group and benzimidazolyl group A lower alkyl group optionally substituted by one or more substituents selected from the group consisting of, halogen atom, methyl group, hydroxymethyl group, fluoromethyl group, trifluoromethyl group, ethyl group, bromomethyl group, difluoromethyl group Group, hydroxyl group, aminomethyl group, carboxymethyl group, carbamoy Methyl, sulfomethyl group, N- methylaminomethyl group, a methoxy group, an ethoxy group, a propoxy group, fluoromethoxy group, an amino group,
Methylamino group, dimethylamino group, ethylamino group,
Propylamino group, formamide group, acetamide group,
Propionylamino group, formyloxy group, acetoxy group, propionyloxy group, carboxyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, methoxycarbamoyl group, ethoxycarbamoyl group, sulfamoyl group, sulfo group, cyano Aryl group or methyl group, ethyl group, propyl group, halogen atom, fluoromethyl group, difluoromethyl group, trifluoro group which may be substituted with one or more substituents selected from the group consisting of groups and nitro groups. Methyl group, carboxymethyl group, aminomethyl group, sulfomethyl group, carbamoylmethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, fluoroethoxy group, difluoroethoxy group, trifluoroethoxy group, hydroxyl group, formyloxy group, Setokishi group, trifluoroacetoxy group, an amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, formamide group, acetamide group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, N
A methylcarbamoyl group, an N, N-dimethylcarbamoyl group, a sulfo group, a cyano group and a nitro group, which may be substituted with one or more substituents. Or a group represented by the formula (b) [In the formula, R ⁸ is a halogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a formyloxy group, an acetoxy group, a fluoroacetoxy group, and an N-methylcarbamoyl group. , Carbamoyl group, N-methylcarbamoyloxy group, N, N-dimethylcarbamoyl group, N, N-
Dimethylcarbamoyloxy group, amino group, methylamino group, dimethylamino 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, diethylamino group, ethylamino group, methylthio group, ethylthio group, propylthio group, fluoromethylthio group, 2-fluoroethylthio group, 1-fluoroethylthio group, Tetrazolyl group, 1-
Methyltetrazolyl group, thiazolyl group, 2-aminothiazolyl group, 5-amino-1,2,4-thiadiazolyl group, 1,
2,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, imidazolyl group, thienyl group, furanyl group, 2-aminooxazolyl group, isothiazolyl group, isoxazolyl group, quinolyl group, isoquinolyl group, pyridyl group, 3, 4-
A lower alkyl group which may be substituted with one or more substituents selected from the group consisting of a dihydroxy-6-pyridyl group, a piperazinyl group, a pyrrolidinyl group, a piperidyl group, a pyrrolyl group, a morpholinyl group, a benzothiazolyl group and a benzimidazolyl group. , A halogen atom, a carboxyl group, an amino group, a sulfo group, a hydroxyl group, a carbamoyl group and a cyano group, a lower alkenyl group which may be substituted with one or more substituents, a halogen atom, a methyl group , Hydroxymethyl group, fluoromethyl group, trifluoromethyl group, ethyl group, bromomethyl group, difluoromethyl group, hydroxyl group, aminomethyl group, carboxymethyl group, carbamoylmethyl group, sulfomethyl group, N-methylaminomethyl group, methoxy group ,
Ethoxy group, propoxy group, fluoromethoxy group, amino group, methylamino group, dimethylamino group, ethylamino group, propylamino group, formamide group, acetamide group, propionylamino group, formyloxy group, acetoxy group, propionyloxy group, One or more selected from the group consisting of a carboxyl group, a carbamoyl group, an N-methylcarbamoyl group, an N, N-dimethylcarbamoyl group, a methoxycarbamoyl group, an ethoxycarbamoyl group, a sulfamoyl group, a sulfo group, a cyano group and a nitro group. An aryl group or a halogen atom which may be substituted with a substituent, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, an aminomethyl group, a sulfomethyl group, a carboxymethyl group, a cyanomethyl group, a fluoromethyl group,
Chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group, N-
Methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group, ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano Group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group, carbamoyloxy group,
N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group,
A heterocyclic group which may be substituted with one or more substituents selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group is represented by R ⁹
Is a hydrogen atom, a carboxyl group, an amino group, a sulfo group, a sulfamoyl group, a carbamoyl group, a hydroxyl group, a formyloxy group, a carbamoyloxy group or a formula (b ₁ ) R ¹⁰ -CONH- (b ₁ ) (wherein R ¹⁰ is Halogen atom, methyl group, ethyl group, propyl group, hydroxymethyl group, aminomethyl group, sulfomethyl group, carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group , N
-Methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group, N-methylaminomethyl group, amino group,
Methylamino group, dimethylamino group, ethylamino group,
Methoxy group, ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, Formyloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. A heterocyclic group which may be substituted with one or more substituents selected from the group consisting of groups), Z ¹ is an oxygen atom or a sulfur atom, and n is 0 or 1. Which is a group represented by] The compounds of the Motomeko described. 3. In R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ , the aryl group is a phenyl group or a naphthyl group, or R ⁵ , R ⁶ or R ⁷
In, the aralkyl group is a benzyl group, a phenethyl group or a naphthylmethyl group, or in R ² , a heterocyclic group is
1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group,
1,3,4-thiadiazolyl group, tetrazolyl group, thiazolyl group, imidazolyl group, isothiazolyl group, isoxazolyl group, oxazolyl group, pyridyl group, thienyl group,
A benzothienyl group, a furanyl group, a pyrimidinyl group, a piperazinyl group, a piperidyl group, a morpholinyl group, a pyrrolidinyl group, a quinolyl group, an isoquinolyl group, a benzothiazolyl group or a benzimidazolyl group, or in R ⁴ ,
Heterocyclic group is furanyl group, thienyl group, thiazolyl group, 1,
2,4-thiadiazolyl group, pyridyl group, isothiazolyl group, oxazolyl group, pyrimidinyl group or 1,3,4-triazolyl group, or in R ⁵ , the heterocyclic group is pyridyl group, furanyl group, thienyl group, imidazolyl group , A thiazolyl group, an isothiazolyl group, an isoquinolyl group, a quinolyl group, an oxazolyl group, an isoxazolyl group or a tetrazolyl group, or in R ⁸ , the heterocyclic group is a thiazolyl group, an isothiazolyl group, a 1,2,4-thiadiazolyl group, a furanyl group. , A thienyl group, a benzothienyl group, a pyridyl group, a tetrazolyl group or an oxazolyl group, or R ¹⁰
In, the heterocyclic group is a pyridyl group, an imidazolyl group, a piperazinyl group, a thiazolyl group or an oxazolyl group, or in R ⁵ , R ⁶ , R ⁷ or R ⁸ , the lower alkyl group is an alkyl group having 1 to 6 carbon atoms. Or in R ⁵ , the cycloalkyl group is a cycloalkyl group having 3 to 6 carbon atoms, or in R ⁵ or R ⁸ , the lower alkenyl group is an alkenyl group having 2 to 6 carbon atoms, The lower alkynyl group for R ⁵ is an alkynyl group having 2 to 6 carbon atoms, or X is a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. 2. The compound according to claim 3. 4. R ¹ is the formula (c). (In the formula, R ¹¹ is a hydrogen atom, a halogen atom, a hydroxyl group,
Methoxy group, ethoxy group, propoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, formyloxy group, acetoxy group, fluoroacetoxy group, N-methylcarbamoyl group, carbamoyl group,
N-methylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, N, N-dimethylcarbamoyloxy group, amino group, methylamino group, dimethylamino group, formamide group, acetamido group, fluoroacetamido group, carboxyl group, methoxycarbonyl Group, ethoxycarbonyl group, sulfo group, sulfamoyl group, cyano group, formyl group, acetyl group, fluoroacetyl group, diethylamino group, ethylamino group, methylthio group, ethylthio group, propylthio group, fluoromethylthio group, 2-fluoroethylthio group Group, 1-fluoroethylthio group, tetrazolyl group, 1-methyltetrazolyl group, thiazolyl group,
2-aminothiazolyl group, 5-amino-1,2,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, imidazolyl group, thienyl group, furanyl group, 2-aminooxazoli Group, isothiazolyl group, isoxazolyl group, quinolyl group, isoquinolyl group, pyridyl group, 3,4-dihydroxy-6-pyridyl group, piperazinyl group, pyrrolidinyl group, piperidyl group, pyrrolyl group, morpholinyl group, benzothiazolyl group and benzimidazolyl group A group consisting of a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of, a carbamoyl group, a carboxyl group, an amino group, a methylamino group, a dimethylamino group, a sulfo group, a hydroxyl group and a cyano group. Cycloalkyl optionally substituted with one or more substituents selected from , A halogen atom, a carboxyl group, an amino group, a sulfo group, a hydroxyl group, a lower alkenyl group optionally substituted with one or more substituents selected from the group consisting of a carbamoyl group and a cyano group, a halogen atom, a hydroxyl group, Lower alkynyl group optionally substituted by one or more substituents selected from the group consisting of amino group, carboxyl group, carbamoyl group, sulfo group and cyano group, halogen atom, methyl group,
Hydroxymethyl group, fluoromethyl group, trifluoromethyl group, ethyl group, bromomethyl group, difluoromethyl group, hydroxyl group, aminomethyl group, carboxymethyl group,
Carbamoylmethyl group, sulfomethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, amino group, methylamino group,
Dimethylamino group, ethylamino group, propylamino group, formamide group, acetamide group, propionylamino group, formyloxy group, acetoxy group, propionyloxy group, carboxyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethyl Carbamoyl group,
Aryl group, methyl group, ethyl group, propyl group which may be substituted with one or more substituents selected from the group consisting of methoxycarbamoyl group, ethoxycarbamoyl group, sulfamoyl group, sulfo group, cyano group and nitro group. Group, halogen atom, fluoromethyl group, difluoromethyl group, trifluoromethyl group, carboxymethyl group, aminomethyl group, sulfomethyl group, carbamoylmethyl group, N-methylaminomethyl group, methoxy group, ethoxy group, fluoroethoxy group, Difluoroethoxy group,
Trifluoroethoxy group, hydroxyl group, formyloxy group,
Acetoxy group, trifluoroacetoxy group, amino group,
Methylamino group, ethylamino group, dimethylamino group,
Diethylamino group, formamide group, acetamide group,
One or more substituents selected from the group consisting of carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, sulfo group, cyano group and nitro group. An aralkyl group or a halogen atom which may be substituted with, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, an aminomethyl group, a sulfomethyl group,
Carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group,
N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group,
Ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group , Carbamoyl group, N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group,
A heterocyclic group optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, and Z ² represents a carbon atom or a nitrogen atom, respectively. ) Or a group represented by formula (d) (Wherein R ¹² represents 1 or 2 substituents selected from the group consisting of hydrogen atom, hydroxyl group, acetoxy group and halogen atom), R ² is a halogen atom, a methyl group, Ethyl group, propyl group, hydroxymethyl group,
Aminomethyl group, sulfomethyl group, carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group,
Sulfamoylmethyl group, oxo group, N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group, ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, Sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, acetamide group, formamide Substituted with one or more substituents selected from the group consisting of group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. Also a heterocyclic group, R ³ is a hydrogen atom, negative charge, or a lower alkanoyloxymethyl group, 1
-(Lower alkoxycarbonyloxy) ethyl group, 5-
Can form a non-toxic ester hydrolyzable in vivo selected from the group consisting of substituted 2-oxo-1,3-dioxol-4-ylmethyl group, 1-phthalidyl group and 5-cyano-1-phthalidyl group The compound according to claim 1, which is an ester residue and X is an alkylene group. 5. In R ¹¹ , an aryl group is a phenyl group or a naphthyl group, an aralkyl group is a benzyl group, a phenethyl group or a naphthylmethyl group, a heterocyclic group is a pyridyl group, a furanyl group, a thienyl group, An imidazolyl group, a thiazolyl group, an isothiazolyl group, an isoquinolyl group, a quinolyl group, an oxazolyl group, an isoxazolyl group or a tetrazolyl group, a lower alkyl group having 1 to 6 carbon atoms, or a lower cycloalkyl group having a carbon atom 5. A fourth alkyl group which is a cycloalkyl group having 3 to 6 carbon atoms, a lower alkynyl group is an alkynyl group having 2 to 6 carbon atoms, or a lower alkenyl group is an alkenyl group having 2 to 6 carbon atoms. Compound of. 6. A general formula [I] [In the formula, R ¹ is an amino group substituted with an acyl group selected from the group consisting of an aliphatic acyl group, an aromatic acyl group and a heterocyclic acyl group, R ² is a halogen atom, a methyl group, an ethyl group, Propyl group, hydroxymethyl group, aminomethyl group, sulfomethyl group, carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfur Famoylmethyl group, oxo group, N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group, ethoxy group, fluoromethoxy group,
Difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group, carbamoyloxy group, N- 1 or it selected from the group consisting of methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. The heterocyclic group optionally substituted by the above substituents, R ³ is a hydrogen atom, negative charge or an ester residue capable of forming a non-toxic ester hydrolyzable in vivo, and X is an alkylene group. [Indicated by] In producing the derivative or its non-toxic salts of the general formula [II] In the formula, ^{R 1 'is} the general formula [I], R ¹ or
The functional group of R ¹ is a substituted group, R ^{3 ′} is a hydrogen atom,
Carboxyl protecting group or lower alkanoyloxymethyl group, 1- (lower alkoxycarbonyloxy) ethyl group, 5-substituted-2-oxo-1,3-dioxole-4
-Ylmethyl group, 1-phthalidyl group and 5-cyano-1
-Indicating an ester residue capable of forming a non-toxic ester hydrolyzable in vivo selected from the group consisting of phthalidyl groups] or a salt thereof with a compound represented by the general formula [III] HO-X-R ^{2 ′} [III] [wherein R ^{2 ′} is a halogen atom, a methyl group, an ethyl group,
Propyl group, hydroxymethyl group, aminomethyl group, sulfomethyl group, carboxymethyl group, cyanomethyl group,
Fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N
-Methylcarbamoylmethyl group, sulfamoylmethyl group, oxo group, N-methylaminomethyl group, amino group,
Methylamino group, dimethylamino group, ethylamino group,
Methoxy group, ethoxy group, fluoromethoxy group, difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, Formyloxy group, carbamoyloxy group, N-methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. X represents an alkylene group, each of which is a heterocyclic group which may be substituted with one or more substituents selected from the group consisting of groups (wherein the functional group of the substituent in R ^{2 ′} is appropriately protected). It is good.)] The compound of general formula [IV] [Wherein R ^{1 ′} , R ^{2 ′} , R ^{3 ′} and X have the above-mentioned meanings], and, if desired, (i) removing the protecting group Step of converting (iii) Step of converting into a non-toxic ester hydrolyzable in vivo, the cephalosporin derivative represented by the general formula [I] or a salt thereof, which comprises performing one or more of the above steps Manufacturing method. 7. A general formula [I] [In the formula, R ¹ is an amino group substituted with an acyl group selected from the group consisting of an aliphatic acyl group, an aromatic acyl group and a heterocyclic acyl group, R ² is a halogen atom, a methyl group, an ethyl group, Propyl group, hydroxymethyl group, aminomethyl group, sulfomethyl group, carboxymethyl group, cyanomethyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, trifluoromethyl group, carbamoylmethyl group, N-methylcarbamoylmethyl group, sulfur Famoylmethyl group, oxo group, N-methylaminomethyl group, amino group, methylamino group, dimethylamino group, ethylamino group, methoxy group, ethoxy group, fluoromethoxy group,
Difluoroethoxy group, trifluoroethoxy group, sulfamoyl group, carboxyl group, methoxycarbonyl group, cyano group, nitro group, vinyl group, allyl group, propargyl group, ethynyl group, acetoxy group, formyloxy group, carbamoyloxy group, N- 1 or it selected from the group consisting of methylcarbamoyloxy group, acetamide group, formamide group, acetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. The heterocyclic group optionally substituted with the above substituents, R ³ is a hydrogen atom, negative charge or lower alkanoyloxymethyl group, 1- (lower alkoxycarbonyloxy) ethyl group, 5-substituted-2-oxo- 1,3-dioxole An ester residue capable of forming a non-toxic ester hydrolyzable in vivo selected from the group consisting of -ylmethyl group, 1-phthalidyl group and 5-cyano-1-phthalidyl group, and X represents an alkylene group, respectively] An antibacterial agent comprising a cephalosporin derivative represented by or a nontoxic salt thereof as an active ingredient.