JPH0764852B2 - 1-Carboxy-1-vinyloxyimino aminothiazole cephalosporin derivatives and their preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION FIELD OF INDUSTRIAL APPLICATION The present invention relates to a novel cephalosporin derivative, a process for producing the same, and an antibacterial agent containing the compound as an active ingredient.

Prior Art and Problems to be Solved by the Invention Up until now, a great number of compounds have been synthesized that have a 2-substituted oximinoacetamide group at the 7-position side chain of the cephem nucleus. For example, 2-(2-aminothiazol-4-yl)-
Examples of such groups include 2-substituted oximinoacetamide groups, 2-(2-aminooxazol-4-yl)-2-substituted oximinoacetamide groups, 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-substituted oximinoacetamide groups, 2-(furyl-2-yl)-2-substituted oximinoacetamide groups, and 2-substituted phenyl-2-substituted oximinoacetamide groups. Examples of the disclosed techniques that describe these groups include JP-A-50-52083 and JP-A-52-1022.
No. 293, No. 52-116492, No. 53-137988, No. 54-154786
No. 54-157596, No. 55-154980, No. 56-86187, No.
No. 57-59895, No. 57-99592, No. 57-158769, No. 57-1923
No. 94, No. 58-8087, No. 58-174387 and The Chemical Society of Japan, pages 785-805 (198
1 year), which are active against Gram-positive bacteria and Gram-negative bacteria including Pseudomonas aeruginosa, suggesting that they have excellent antibacterial activity and a broad antibacterial spectrum.

In addition to the above-mentioned published art, the prior art relating to the present invention includes, for example, Japanese Patent Application Laid-Open Nos. 54-9296, 58-162592, 59-108792,
Nos. 59-130294, 60-34972, 60-67483 and 60-
The claims of these published art documents list a large number of substituent groups, including alkyl and alkenyl groups, as the substituents of the 2-(2-aminothiazol-4-yl)-2-substituted oxyiminoacetamide group at the 7-position of the cephem nucleus.
Furthermore, the description of alkenyl groups generally refers to optionally substituted alkenyl groups, substituted or unsubstituted _C2 - _C6 alkenyl groups, etc. However, the alkenyl groups suggested by the specific disclosures and examples in the specification are unsubstituted alkenyl groups such as vinyl groups and allyl groups, and the only carboxyl-substituted alkenyl group is a 1-carboxylate allyl group, and the above prior art does not disclose or suggest a 1-carboxy-1-vinyl group at all. Furthermore, with regard to prior art on production intermediates, a great number of 2-substituted oximinoacetic acid derivatives have been synthesized as acyl side chain acids at the 7-position of the cephem nucleus, and examples of such acyl side chain acids include, for example, 2-(2-aminothiazol-4-yl)-2-substituted oximinoacetic acid, 2-(thiazol-4-yl)-2-aminothiazol-4-yl
-substituted oximinoacetic acid, 2-(2-aminooxazol-4-yl)-2-substituted oximinoacetic acid, 2-(5
-amino-1,2,4-thiadiazol-3-yl)-2-
Substituted oximinoacetic acid, 2-(furyl-2-yl)-2
-substituted oximinoacetic acid, 2-(substituted phenyl)-2-
Examples of the disclosed techniques that describe these 2-substituted oximinoacetic acid compounds include the Journal of the Chemical Society of Japan, pp. 785-804 (1981);
Journal of Antibiotics
otics), Vol. 34, pp. 1447-1455 (1981),
Vol. 36, pp. 1205-1210 (1983), Vol. 37, pp. 532-571 (1984), Vol. 39
Vol. 111-127, pp. 404-414 (1986). Examples of the substituent of the substituted oxyimino group include a hydrogen atom, a carboxyl group, a carbamoyl group, a cyano group,
Commonly known groups include lower alkyl groups, lower alkenyl groups, lower alkynyl groups, aralkyl groups, aryl groups, and the like, which may have one or more substituents such as amino groups, halogen atoms, alkyl groups, and aryl groups.

Also, 2-(1-vinyloxyimino)acetic acid derivatives having a vinyl group as a substituent of the substituted oximino group are disclosed in JP-A-54-22392 (German Office, 2,831,332; Chem. Abst.
r.,90-168630n), and its synthesis is as follows:

[wherein X represents a chlorine, bromine or iodine atom; alk represents 1
The disclosure in this publication is that 2-(1-vinyloxyimino)
The compound of the present invention, 2, is limited to acetic acid derivatives only.
There is no suggestion, let alone a synthesis, of 1-(1-carboxy-1-vinyloxyimino)acetic acid derivatives.

β-lactam antibiotics exhibit selective toxicity only to bacteria,
Since it has no effect on animal cells, it is widely used as an antibiotic with few side effects in the treatment of bacterial infections and is a highly useful drug. However, in recent years, the isolation of resistant Gram-positive bacteria and resistant glucose-non-fermenting Gram-negative bacilli as causative bacteria of infectious diseases has tended to increase, and there is a demand for enhanced antibacterial activity against these bacteria.

The object of the present invention is to provide novel cephalosporin derivatives having excellent antibacterial activity. Although various cephalosporin derivatives having a 2-substituted oxyiminoacetamido group at the 7-position of the cephem nucleus have been synthesized, no compounds having a 1-carboxy-1-vinyloxyimino group in the substituted oxyimino group have been synthesized, nor have they been disclosed in patent applications.

Means for Solving the Problems The present inventors have discovered that the compound of the present invention, which has a 2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamide group at the 7-position of the cephem nucleus, is a novel compound not previously described in the literature, and has potent antibacterial activity against sensitive and resistant Gram-negative and Gram-positive bacteria, and is highly stable against β-lactamases, thereby completing the present invention.

The present invention relates to a compound represented by the general formula [I] [wherein R represents a hydrogen atom, a carboxyl protecting group or a negative charge; Q represents a hydrogen atom, a halogen atom, an azide group, an optionally substituted quaternary ammonio group, or two adjacent
the compound represented by the formula (I) represents a heterocyclic thio group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, which may have a substituent, and which is substituted with a phenyl group having one or more hydroxyl groups or lower alkanoyloxy groups; its non-toxic salts or physiologically hydrolyzable non-toxic esters; a process for producing them; and an antibacterial agent containing the compound as an active ingredient.

Next, various symbols and terms used in this specification will be explained.

The lower alkyl group means a straight-chain, branched or cyclic lower alkyl group.

The straight-chain or branched lower alkyl group is a group having 1 to 6 carbon atoms.
Specifically, the alkyl group includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
isobutyl group, sec-butyl group, tert-butyl group, n-
Examples include a pentyl group and an n-hexyl group, and particularly preferred are a methyl group, an ethyl group, an n-propyl group and an isopropyl group.

The cyclic lower alkyl group refers to a cyclic alkyl group having 3 to 6 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, with a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group being particularly preferred.

The lower alkenyl group refers to an alkenyl group having 2 to 6 carbon atoms, and specific examples thereof include a vinyl group, an allyl group, an isopropenyl group, a 1,1-dimethylallyl group, a 2-butenyl group, a 3-
Examples include a butenyl group.

The lower alkynyl group refers to an alkynyl group having 2 to 3 carbon atoms, and specific examples thereof include an ethynyl group and a 2-propynyl group.

The lower alkoxy group refers to an alkoxy group having 1 to 4 carbon atoms, and specific examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy groups, with methoxy and ethoxy groups being particularly preferred.

Examples of the lower alkanoyloxy group include an acetoxy group, a propionyloxy group, and a butyryloxy group, with an acetoxy group being particularly preferred.

The lower alkoxycarbonyl group refers to an alkoxycarbonyl group having 2 to 5 carbon atoms, specifically a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, or an isobutoxycarbonyl group, with a methoxycarbonyl group or an ethoxycarbonyl group being particularly preferred.

The amino group which may have a substituent refers to an amino group, an alkylamino group substituted with an alkyl group having 1 to 4 carbon atoms, such as a methylamino group, an ethylamino group, a dimethylamino group, or an ethylmethylamino group, a formylamino group, or an alkanoylamino group, such as an acetylamino group, a propionylamino group, or a butyrylamino group, with an amino group, a methylamino group, a dimethylamino group, a formylamino group, or an acetylamino group being particularly preferred.

The substituted imino group is a hydroxyimino group, a group having 1 to 4 carbon atoms,
alkoxy-substituted, for example, methoxyimino groups;
It represents an alkoxyimino group such as an ethoxyimino group or a propoxyimino group, or a carboxymethoxyimino group, and in particular
A hydroxyimino group, a methoxyimino group, or a carboxymethoxyimino group is preferred.

The fluoroalkyl group is a group having 1 to 4 carbon atoms, such as a fluoromethyl group, a trifluoromethyl group, or a 2-fluoroethyl group.
In particular, a trifluoromethyl group and a 2-fluoroethyl group are preferred.

The aryl group is a group having 6 carbon atoms, such as a phenyl group or a naphthyl group.
It represents an aryl group having a carbon number of 1 to 12, and a phenyl group is particularly preferred.

Examples of heterocyclic groups having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl,
Examples thereof include a pyridyl group, a pyrazinyl group, a pyridazinyl group, and a triazinyl group, and particularly preferred are an oxazolyl group, a thiazolyl group, an oxadiazolyl group, a thiadiazolyl group, and a tetrazolyl group.

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

The optionally substituted quaternary ammonio group refers to a quaternary ammonio group known as a substituent at the 3-position of a cephem nucleus. More preferably, the quaternary ammonio group is represented by the formula wherein R ^a , R ^b and R ^c may be the same or different;
It represents a lower alkyl group, a lower alkenyl group, or a lower alkynyl group, or two or three of R ^a , R ^b , and R ^c are bonded to each other and, together with the adjacent nitrogen atom, form a monocyclic ring, polycyclic ring group, or bridged polycyclic group which may be saturated or unsaturated and which may contain at least one heteroatom selected from the group consisting of oxygen atoms, nitrogen atoms, and sulfur atoms.

wherein the lower alkyl group, the lower alkenyl group, the lower alkynyl group, the monocyclic ring group, the polycyclic ring group and the bridged polycyclic ring group are each independently selected from the group consisting of a hydroxyl group, a lower alkoxy group, a formyloxy group, a lower alkanoyloxy group,
Carbamoyloxy group, hydroxy lower alkyl group, sulfo lower alkyl group, carboxy lower alkyl group, carbamoyl lower alkyl group, carboxyl group, lower alkoxycarbonyl group, carbamoyl group, cyano group, sulfo group, sulfamoyl group, optionally substituted amino group, halogen atom, aryl group, or 5- or 6-membered aromatic heterocyclic group having at least one heteroatom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, which may have one or more identical or different substituents selected from the group consisting of lower alkyl group, lower alkenyl group, lower alkynyl group,
and optionally having one, or the same or different, substituents selected from the group consisting of a fluoroalkyl group, a lower alkoxy group, a lower alkanoyloxy group, a carbamoyloxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a cyano group, a sulfo group, a sulfamoyl group, an amino group which may have a substituent, a substituted oxyimino group, and a halogen atom.

The monocyclic, polycyclic or bridged polycyclic group in which two or three of R ^a , R ^b and R ^c are bonded to each other and, together with the adjacent nitrogen atom, may be saturated or unsaturated and may contain at least one heteroatom selected from the group consisting of oxygen atoms, nitrogen atoms and sulfur atoms includes, for example, an azetidinio group, a pyrrolidinio group, a piperidinio group, a 3-oxopipeperidinio group, a 4-oxopipeperidinio group, a 1,2,3,6-tetrahydropiperidinio group, a hexamethyleneiminio group, a morpholinio group, a thiomorpholinio group, a 3-oxomorpholinio group, a piperazinio group, a homopiperazinio group, a 3-oxopiperazinio group,
an isoindolinio group, a 1,2,3,4-tetrahydroisoquinolinio group, a 2,3,4,5-tetrahydro-1H-2-benzoazepinio group, a 1,2,4,5-tetrahydro-3H-3-benzoazepinio group, an imidazolinio group, a pyrimidinio group, an oxazolinio group, a pyridazinio group, a thiazolinio group, a pyridinio group, a quinolinio group, an isoquinolinio group, a 1H-imidazo[4,5-b]pyridinio group, a thiazolo[4,5-b]pyridinio group, an oxazo[4,5-b]pyridinio group, a 1H-2-
a methylimidazo[4,5-b]pyridinio group, a 3-methyl-3H-imidazo[4,5-b]pyridinio group, a 1-methyl-1H-imidazo[4,5-c]pyridinio group, a 5-aminoisoquinolinio group, a 5-hydroxyisoquinolinio group,
6-acetoxyisoquinolinio group, 5,6-diacetoxyisoindolinio group, 5,6-dihydroxyisoindolinio group, 4-carboxypyridinio group, 4-sulfopyridinio group, 4-carbamoylpyridinio group, 4-(oxazol-2-yl)pyridinio group, 4-(4,5-dihydrooxazol-2-yl)pyridinio group, 2,3-cyclopentenopyridinio group, 3,4-cyclopentenopyridinio group, 3,4-cyclohexenopyridinio group, 3-aminopyridinio group, 4-(2-carboxyethyl)pyridinio group, 4-sulfomethylpyridinio group, 4-(2-
sulfoethyl)pyridinio group, 3-formamidopyridinio group, 3-acetamidopyridinio group, 2-hydroxymethylpyridinio group, dihydrofuranopyridinio group,
a 3-hydroxymethylpyridinio group, a 4-hydroxymethylpyridinio group, a 4-(2-hydroxyethyl)pyridinio group, a 3-carboxypyridinio group, a 4-carboxypyridinio group, a 3-carboxymethylpyridinio group,
3-(2-carboxyethyl)pyridinio group, 3-carbamoylpyridinio group, 3-carbamoylmethylpyridinio group, 3-(2-carbamoylethyl)pyridinio group, 4-(2-carbamoylethyl)pyridinio group, 3
-fluoropyridinio group, 4-fluoropyridinio group,
3-chloropyridinio group, 4-chloropyridinio group, 3
-bromopyridinio group, 4-bromopyridinio group, 3-
Examples thereof include a trifluoromethylpyridinio group, a 4-trifluoromethylpyridinio group, a 4-(2-fluoroethyl)pyridinio group, a sulfamoylpyridinio group, a 1-azoniabicyclo[2.2.1]pentan-1-yl group, a 1-azoniabicyclo[3.3.1]nonan-1-yl group, a quinuclidinio group, and a 2-dehydroquinuclidinio group. Among these, a pyridinio group, a 3-aminopyridinio group, a 3-carboxypyridinio group, a 3-carbamoylpyridinio group, a 4-amino ...
Preferred are a 4-carboxypyridinio group, a 4-carbamoylpyridinio group, a 4-sulfomethylpyridinio group, a 4-(2-sulfoethyl)pyridinio group, a 3-formamidopyridinio group, a 2,3-cyclopentenopyridinio group, and the like.

Examples of the heterocyclic thio group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, which may have a substituent, include a thienylthio group, a furylthio group, an imidazolylthio group, a pyrazolylthio group, a thiazolylthio group, an isothiazolylthio group, an oxazolylthio group, an isoxazolylthio group, a triazolylthio group, a thiadiazolylthio group, an oxadiazolylthio group, a tetrazolylthio group, a pyridylthio group, a pyrazinylthio group, a pyridazinylthio group, and a triazinylthio group, which may have a substituent. Among these, a thiazolylthio group, an oxazolylthio group, a thiadiazolylthio group, and an oxadiazolylthio group are preferred.

The substituent of the heterocyclic thio group may be, for example, a hydroxyl group, a lower alkanoyl group, a carbamoyloxy group, a carboxyl group, a carbamoyl group, a cyano group, a sulfo group, a sulfamoyl group, an amino group which may have a substituent, a substituted imino group, or a lower alkyl group which may be substituted by a halogen atom, such as a lower alkoxy group, a formyloxy group,
It may have one or two or more, the same or different, substituents selected from the group consisting of lower alkanoyloxy groups, carbamoyloxy groups, fluoroalkyl groups, alkylidene groups represented by -( _CH2 ) _3-5- , carboxyl groups, lower alkoxycarbonyl groups, carbamoyl groups, cyano groups, sulfo groups, sulfamoyl groups, amino groups which may have a substituent, substituted imino groups, halogen atoms, aryl groups, and heterocyclic groups having at least one heteroatom selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. However, the aryl group and the heterocyclic group may have one or two or more, the same or different, substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a fluoroalkyl group, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, a carbamoyloxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a cyano group, a sulfo group, a sulfamoyl group, an amino group which may have a substituent, a substituted oxyimino group, and a halogen atom.

The heterocyclic thio group may be condensed with a benzene nucleus, and examples thereof include a 2-benzoxazolethio group, a 2-benzothiazolethio group, and a 2-benzimidazolethio group.

The benzene nucleus may have a substituent, for example, a lower alkyl group, a hydroxyl group, a fluoroalkyl group, a lower alkoxy group, a formyloxy group, a lower alkanoyloxy group, a carbamoyloxy group, a fluoroalkyl group, -
The aryl group and the heterocyclic group may have one or more substituents, the same or different, selected from the group consisting of alkylidene groups represented by ( _CH2 ) _3-5- , carboxyl groups, lower alkoxycarbonyl groups, carbamoyl groups, cyano groups, sulfo groups, sulfamoyl groups, amino groups which may have a substituent, substituted imino groups, halogen atoms, aryl groups, and heterocyclic groups having at least one heteroatom selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, provided that the aryl group and the heterocyclic group are not selected from the group consisting of lower alkyl groups, lower alkenyl groups, lower alkynyl groups, fluoroalkyl groups, hydroxyl groups, lower alkoxy groups, lower alkanoyloxy groups, carbamoyloxy groups, carboxyl groups, lower alkoxycarbonyl groups, carbamoyl groups, cyano groups, sulfo groups,
The group may have one or more, the same or different, substituents selected from the group consisting of a sulfamoyl group, an amino group which may have a substituent, a substituted oxyimino group, and a halogen atom.

Examples of the heterocyclic thio group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, which is substituted with a phenyl group having two or more adjacent hydroxyl groups or lower alkanoyloxy groups and which may have a substituent, include a [5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio group, a [5-(3,4-diacetoxyphenyl)-1,3,4-oxadiazol-2-yl]thio group, a [5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazole-2-yl]thio group, and a [5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazole-2-yl]thio group.
yl]thio group, [5-(3,4-diacetoxyphenyl)
-1,3,4-thiadiazol-2-yl]thio group, [4-
(3,4-dihydroxyphenyl)-5-carboxymethylthiazol-2-yl]thio group, [4-(3,4-diacetoxyphenyl)-5-carboxymethylthiazol-2-yl]thio group, [4-carboxy-5-(3,4-
[4-carboxy-5-(3,4-diacetoxyphenyl)thiazol-2-yl]thio group, [5-(3,4-dihydroxyphenyl)thiazol-2-yl]thio group,
[5-(3,4-diacetoxyphenyl)oxazol-2-yl]thio group, [4-(3,4-dihydroxyphenyl)-5-carboxymethyloxazol-2-yl]thio group, [4-(3,4-dihydroxyphenyl)-
5-carboxymethylthiazol-2-yl]thio group,
[4-(3,4-diacetoxyphenyl)-5-carboxymethyloxazol-2-yl]thio group, [4-(3,
[5-(3,4-diacetoxyphenyl)-5-carboxymethylthiazol-2-yl]thio group, among others, [5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio group, [5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-2-yl]thio group, and the like.
yl]thio group, [4-carboxy-5-(3,4-dihydroxyphenyl)thiazol-2-yl]thio group, [5
-(3,4-dihydroxyphenyl)oxazole-2-
yl]thio group, [5-(3,4-dihydroxyphenyl)
thiazol-2-yl]thio group, [4-(3,4-diacetoxyphenyl)-5-carboxymethyloxazol-2-yl]thio group, [4-(3,4-diacetoxyphenyl)-5-carboxymethylthiazol-2-yl]
A thio group is preferred.

The partial structure of the oxyimino group in general formula [I] exists as a syn isomer (Z configuration) and an anti isomer (E configuration), and generally, the syn isomer exhibits superior antibacterial activity. All substituted oxyimino groups in this specification are syn isomers. The E/Z nomenclature is based on the Journal of the American Chemical Society (J. Am. Chem. Soc), Vol. 90, pp. 509-510.
This is described on page (1968).

The compound of the general formula [I] can be converted into its non-toxic salt or physiologically hydrolyzable ester by a conventional method.

The non-toxic salts of the compound of the general formula [I] mean conventional pharmaceutically acceptable salts, and include those in which the carboxyl group at the 4-position of the cephem nucleus, the 1-carboxy-1-
Examples include salts of a vinyl group, a 2-aminothiazole group at the 7-position of the cephem nucleus, and a carboxyl group, an acid group such as a sulfo group, or a basic group such as an amino group substituted on Q.

Suitable salts of the general formula [I] include, for example, sodium,
Metal salts with potassium, calcium, magnesium, aluminum, etc., organic amine salts with, for example, N,N'-dibenzylethylenediamine, procaine, etc., inorganic acid salts with, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, etc., acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid,
Examples include organic acid salts with malic acid, tartaric acid, citric acid, etc.; sulfonates with methanesulfonic acid, isethionic acid, p-toluenesulfonic acid, etc.; and amino acid salts with glutamic acid, aspartic acid, lysine, arginine, etc.

The non-toxic ester of the general formula [I] means a pharmaceutically acceptable conventional ester at the carboxyl group at the 4-position of the cephem nucleus, such as an alkanoyloxymethyl group such as an acetoxymethyl group or a pivaloyloxymethyl group;
alkoxycarbonyloxyalkyl groups such as 1-(ethoxycarbonyloxy)ethyl group and 1-(isopropoxycarbonyloxy)ethyl group; phthalidyl group; (5-
methyl-2-oxo-1,3-dioxol-4-yl
and (5-substituted-2-oxo-1,3-dioxol-4-yl)methyl groups such as methyl groups.

The present invention is characterized by the presence of a 1-carboxy-1-vinyloxyimino structure as a partial structure of the side chain at the 7-position of the cephem nucleus.
The heterocyclic thiomethyl group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent, is preferably substituted with a phenyl group having two or more adjacent hydroxyl groups or lower alkanoyloxy groups.

The side chain at the 3-position of the cephem nucleus may be any side chain commonly used in the field of cephalosporin chemistry. Typical examples include a methyl group, a chloromethyl group,
Bromomethyl group, iodomethyl group, azidomethyl group, pyridiniomethyl group, 2,3-cyclopentenopyridiniomethyl group, 3,4-cyclopentenopyridiniomethyl group, 2,3
-cyclohexenopyridiniomethyl group, 3,4-cyclohexenopyridiniomethyl group, 2,3-dihydrofuro[2,3-
b] pyridiniomethyl group, 2,3-dihydrothieno[2,3-
b] pyridiniomethyl group, 3-aminopyridiniomethyl group, 3-formamidopyridiniomethyl group, 3-acetamidopyridiniomethyl group, 2-hydroxymethylpyridiniomethyl group, 3-hydroxymethylpyridiniomethyl group, 4-hydroxymethylpyridiniomethyl group, 3-
(2-hydroxyethyl)pyridiniomethyl group, 4-
(2-hydroxyethyl)pyridiniomethyl group, 3-carboxypyridiniomethyl group, 4-carboxypyridiniomethyl group, 3-carboxymethylpyridiniomethyl group, 3-(2-carboxyethyl)pyridiniomethyl group, 4-(2-carboxyethyl)pyridiniomethyl group, 3-carbamoylpyridiniomethyl group, 4-carbamoylpyridiniomethyl group, 3-carbamoylmethylpyridiniomethyl group, 4-carbamoylmethylpyridiniomethyl group, 3-(2-carbamoylethyl)pyridiniomethyl group, 4-(2-carbamoylethyl)pyridiniomethyl group, 4-sulfomethylpyridiniomethyl group, 4-
(2-sulfoethyl)pyridiniomethyl group, 3-fluoropyridiniomethyl group, 4-fluoropyridiniomethyl group, 3-chloropyridiniomethyl group, 4-chloropyridiniomethyl group, 3-bromopyridiniomethyl group, 4-bromopyridiniomethyl group, 3-trifluoromethylpyridiniomethyl group, 4-trifluoromethylpyridiniomethyl group, 1-methyl-1-hexamethyleneiminiomethyl group, 1,4-dimethyl-1-piperaziniomethyl group, 1
-methyl-1,2,3,6-tetrahydropyridiniomethyl group, 4-acetyl-1-methylpiperaziniomethyl group,
3-(1,2,4-oxadiazol-3-yl)pyridiniomethyl group, 3-(imidazol-2-yl)pyridiniomethyl group, 1-methylpyrrolidiniomethyl group, 2-methylisoindoliniomethyl group, 2-methyl-5,6-dihydroxyisoindoliniomethyl group, 2-methyl-5,
Examples thereof include a 6-diacetoxyisoindoliniomethyl group, a 2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoliniomethyl group, an isoquinolinio group, a quinoliniomethyl group, a 6,7-dihydroxyquinolinio group, and a 6,7-diacetoxyquinolinio group.

Preferable examples of the compound of the general formula [I] provided by the present invention include the following.

1) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)thiazol-2-yl]-3-cephem-4-carboxylic acid (syn isomer) 2) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-(3,4-diacetoxyphenyl)-5-carboxymethylthiazol-2-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 3) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) 4) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(2,3-cyclopenteno-1-pyridinio)methyl-3-cephem-4-carboxylic acid (syn isomer) 5) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-carboxy-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) 6) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) 7) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-carboxy-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) 8) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) 9) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-sulfonatemethyl-1-pyridinio)methyl-3-cephem-4-carboxylic acid (syn isomer) 10) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-(2-sulfonate ethyl)
-1-pyridinio]methyl-3-cephem-4-carboxylic acid (syn isomer) 11) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-amino-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) 12) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-formylamino-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) 13) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazol-2-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 14) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 15) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)oxazol-2-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 16) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-carboxy-5-(3,4-dihydroxyphenyl)thiazol-2-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 17) 7β-[2-(2-aminothiazol-4-yl)
-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-(3,4-diacetoxyphenyl)-5-carboxymethylthiazol-2-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer). Next, a method for producing the compound of the present invention will be described.

General formula [IV] [wherein ^R2 is a hydrogen atom, a carboxyl protecting group or a negative charge; ^Q2 is a hydrogen atom, a halogen atom, an azide group, a quaternary ammonio group which may have a substituent, or a heterocyclic thio group which is substituted by a phenyl group having two or more adjacent hydroxyl groups or lower alkanoyloxy groups and which has at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom and which may have a substituent; Y is S
or SO (provided that ^Q2 and its substituents may be protected)] or a salt thereof, [wherein ^R3 represents a hydrogen atom or an amino-protecting group, and ^R4 and ^R5 are the same or different and represent a hydrogen atom or a carboxyl-protecting group] or a reactive derivative thereof, to obtain a compound represented by the general formula [II-1] wherein R ² , R ³ , R ⁴ , Q ² and Y have the above-mentioned meanings.
or a salt thereof, and optionally reacting a compound of general formula [II-1] in which ^Q2 is a leaving group or a salt thereof with a nucleophilic reagent to obtain a compound of general formula [II-2] wherein R ² , R ³ , R ⁴ and Y have the same meanings as above, and Q ³ represents a halogen atom, an azide group, a fourth group which may have a substituent,
a heterocyclic thio group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent and has a phenyl group substituted by two or more adjacent hydroxyl groups or lower alkanoyloxy groups, or a compound represented by the general formula [II
-1] or a salt thereof of the general formula [II-2], by reducing and/or removing the protecting group, to obtain the compound of the present invention [I]
can be manufactured.

When the compound ^Q2 of the general formula [II-1] is a leaving group, specific examples of the leaving group include a halogen atom such as chlorine, bromine, or iodine, an acetoxy group, a carbamoyloxy group, etc. In particular, a chlorine atom, a bromine atom, an iodine atom,
The acetoxy group is preferred.

Nucleophilic reagents to be reacted with the compound of the general formula [II-1] include all those generally used in cephalosporin chemistry.

Examples of nitrogen nucleophiles include tertiary aliphatic amine derivatives, aromatic amine derivatives, aromatic ring-fused aliphatic amine derivatives, cyclic amine derivatives, as well as pyrimidine derivatives, purine derivatives, pyridazine derivatives, pyrazine derivatives, pyrazole derivatives, imidazole derivatives, triazole derivatives, and azide compounds each having one or more different heteroatoms.

Examples of sulfur nucleophilic reagents include dithiocarbamic acid derivatives, aromatic thioamide derivatives, aliphatic thioamide derivatives, cyclic thioamide derivatives, thiosulfate derivatives, thiol derivatives, thiophenol derivatives, thioacid derivatives, etc. These nucleophilic reagents are usually commercially available and can be easily obtained.

The mercapto derivatives having two adjacent hydroxyl or acetoxy groups which provide the compounds of the present invention are novel compounds not previously described in the literature. These compounds can be prepared by the following method.

2-mercapto-5-(3,4-disubstituted phenyl)-1,3,4
The oxadiazole derivative can be produced by reacting a benzoic acid hydrazide derivative with carbon disulfide in the presence of potassium hydroxide in an ethanol solvent.

2-mercapto-5-(3,4-disubstituted phenyl)-1,3,4
The thiadiazole derivative can be produced by the following method (i) or (ii).

(i) It is produced by reacting 3,4-disubstituted thiobenzamide with hydrogen sulfide in the presence of triethylamine in a pyridine solvent.

(ii) 2-mercapto-4-(3,4-disubstituted phenyl)thiazole derivatives prepared by reacting potassium 3-(3,4-disubstituted benzoyl)dithiocarbazate with concentrated sulfuric acid are described in Chemical Abstracts, 8
It can be produced by reacting 2-chloro-3',4'-dihydroxyacetophenone, which has been synthesized by the method described in J. Chem. Soc., 1976, 4-43639s, with ammonium dithiocarbamate in a methanol solvent.

4-carboxy-5-(3,4-disubstituted phenyl)-2-
Mercaptothiazole derivatives were synthesized by organic synthesis (Org. Synth.), Coll., starting from piperonal.
Vol., II, pp. 11-12, 1-3 and 519-520, to obtain 3-(3,4-disubstituted phenyl)pyruvic acid;
The compound can be produced by brominating it to form 3-bromo-(3,4-disubstituted phenyl)pyruvic acid, and then reacting this compound with ammonium dithiocarbamate.

The 5-carboxymethyl-2-mercaptothiazole derivative can be produced by reacting veratrole with succinic anhydride in the presence of anhydrous aluminum chloride to give 3-(3,4-dimethoxybenzoyl)propionic acid, then demethylating with hydrobromic acid to give 3-(3,4-dihydroxybenzoyl)propionic acid, converting the compound into an enol lacton in the presence of acetic anhydride and sodium acetate, then reacting with N-bromosuccinimide and then diphenyldiazomethane to give 3-(3,4-diacetoxybenzoyl)-3-bromopropionic acid ester, and further reacting the compound with ammonium dithiocarbamate.

2-Mercapto-5-(3,4-disubstituted phenyl)oxazole derivatives were synthesized by Chemical Abstracts.
2-Chloro-3',4'-dihydroxyacetophenone synthesized by the method described in Chem.Abstr., 84-43639s (1976) is reacted with sodium azide to form an azide compound, which is then converted into 2-amino-3',4'-dihydroxyacetophenone by catalytic reduction, and the resulting compound is further reacted with carbon disulfide in the presence of sodium ethoxide in an ethanol solvent according to the method described in Chem.Abstr., 67-43806t (1967).

2-Mercaptobenzimidazole derivatives can be synthesized from veratrole as a starting material as described in Synthesis, p. 1033 (1974) and Org. Syntheses.
h.), Coll. Vol., IV, p. 56 (1963).

2-Mercaptobenzoxazole derivatives are synthesized from veratrol aldehyde as a starting material, as described in J. Chem. Soc. Perkin Trans. 1, p. 1353 (1974); Canadian Journal of Chemistry (Can. J. Ch.
em.), Vol. 44, p. 1879 (1966) and Journal of the Pharmaceutical Society (J.Pharm.Soc.
Jpn., vol. 76, p. 1002 (1956).

2-Mercaptobenzothiazole derivatives are synthesized from veratrole by nitration and catalytic reduction.
This compound is converted into a diazonium salt, which is then reacted with potassium O-ethyldithiocarbonate to give O-ethyl 3,4-dimethoxy-6-nitroaniline.
-nitrophenyl dithiocarbonate, which is then subjected to a reductive ring-closure reaction with stannous chloride in an ethanol solvent.

Next, the method for producing the compound [I] of the present invention will be explained in detail.

The compound of general formula [II-1] can be produced by reacting the compound of general formula [IV] with the carboxylic acid of general formula [III] or its reactive derivative (e.g., acid halide, mixed acid anhydride, activated ester, etc.).
Acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, ethylene chloride,
Benzene, ethyl acetate, N,N-dimethylformamide,
In a solvent such as dimethyl sulfoxide that does not adversely affect the reaction or a mixture thereof, 1 to 1.5 moles of a carboxylic acid of general formula [III] or a reactive derivative thereof are used per mole of a compound of general formula [IV], and the reaction temperature is -40 to 40°C.

When an acid halide is used as the reactive derivative of the general formula [III], the reaction is preferably carried out in the presence of an acid scavenger such as triethylamine, N-methylmorpholine, N,N-dimethylaniline, or pyridine.

The acid halide forming reaction is carried out by using 1 to 10 moles, preferably 1 to 1.5 moles, of a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, or phosgene per mole of carboxylic acid [III].
The reaction temperature is -40 to 100°C, preferably -20 to
At 20°C, the reaction is completed within 10 to 120 minutes.

The mixed acid anhydride formation reaction is carried out by reacting 1 mole of carboxylic acid [III] with triethylamine, N-methylmorpholine, N,
In the presence of 1 to 1.2 moles of a scavenger such as N-dimethylaniline or pyridine, 1 to 1.2 moles of a chloroformate such as methyl chloroformate, ethyl chloroformate, or isobutyl chloroformate is used, and the reaction temperature is −40 to 20° C.
Preferably, the reaction temperature is -20 to 5°C and the reaction time is 10 to 60 minutes.

The active ester forming reaction is carried out using 1 to 1.2 moles of an N-hydroxy compound (e.g., N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc.) or a phenol compound (e.g., 4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol, etc.) and 1 to 1.4 moles of N,N'-dicyclohexylcarbodiimide per mole of carboxylic acid [III] at a reaction temperature of -10
The reaction temperature is 50°C or less and the reaction time is 0.5 to 2 hours.

In addition, when the carboxylic acid of general formula [III] is used in the form of a free acid in the acylation reaction, the compound of general formula [II-1] can also be produced in the presence of a condensing agent such as a carbodiimide such as N,N'-dicyclohexylcarbodiimide, phosphorus oxychloride, or N,N-dimethylformamide-phosphorus oxychloride adduct.

Furthermore, when ^Q2 in the general formula [II-1] is a leaving group, it can be subjected to a substitution reaction with a nucleophilic reagent, if necessary. The substitution reaction can be carried out in, for example, water, methylene chloride, chloroform, ether, ethyl acetate, butyl acetate, tetrahydrofuran,
The reaction can be carried out in an organic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, etc., or a mixed solvent thereof.

The reaction is carried out using 1 to 2 moles of the nucleophilic reagent per mole of the compound of the general formula [II-1], and the reaction temperature and reaction time are set to -20 to
At 40°C, it is 0.5 to 5 hours.

Furthermore, when ^Q2 in general formula [II-1] is an acetoxy group, the reaction with the nucleophilic reagent can be carried out in an organic solvent such as water, phosphate buffer solution, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or a mixture thereof. The reaction is preferably carried out at a near-neutral pH, at a reaction temperature of room temperature to 90°C, for 1 to 15 hours. This reaction is promoted by the presence of an iodide such as sodium iodide or potassium iodide, a thiocyanate such as sodium thiocyanate or potassium thiocyanate, or a quaternary ammonium salt such as trimethylbenzylammonium bromide.

The compounds of the general formula [II-1] or [II-2] in which the group Y is SO are described in Journal of Organic Chemistry, Vol. 35, p. 2430 (1974)
For example, the sulfoxide group can be reduced by the method described in the publications such as [II-1], in which the group Y is SO.
Alternatively, the compound of general formula [II-2] can be reduced with phosphorus trichloride or acetyl chloride-sodium iodide, etc. That is, the compound of general formula [II-1] or general formula [II-2] in which the group Y is SO can be reduced by reacting it with phosphorus trichloride in a solvent such as N,N-dimethylformamide at -40 to 0°C for 1 to 5 hours.
Compound 1 of general formula [II-1] or general formula [II-2], wherein SO
2 to 6 moles of phosphorus trichloride are used per mole of the compound.

Alternatively, the general formula [II-1] or the general formula [II]
The reduction can also be carried out by adding acetyl chloride dropwise to a compound of formula [II-1] in the presence of an iodide such as sodium iodide in an acetone solvent at -40 to 0°C and reacting for 1 to 5 hours.
Alternatively, 3.5 to 10 moles of iodide and 1.2 to 5 moles of acetyl chloride are used per mole of the compound of formula [II-2].
Alternatively, it can be prepared by removing the protecting group from the compound of the general formula [II-2].

In the general formula, the carboxyl group, amino group, or hydroxyl group can be protected and removed by appropriately selecting a protecting group that is commonly used in the field of β-lactam synthesis. The method for introducing and removing a protecting group can be described, for example, in "Protective Groups in Organic Synthesis" by T.W. Greene, published by Wiley in 1981.
This can be carried out in accordance with the method described in, for example, Protective Groups in Organic Synthesis by J.F.W. McComie, published by Plenum Press in 1973, or Protective Groups in Organic Chemistry by J.F.W. McComie.

Examples of the carboxyl protecting group include a tert-butyl group,
2,2,2-trichloroethyl group, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group, 1-propionyloxyethyl group, 1-(ethoxycarbonyloxy)ethyl group, phthalidyl group, benzyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group, bis(4-methoxyphenyl)
Methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, trimethylsilyl group, tert
butyldimethylsilyl group, and the like, and particularly preferred are a benzhydryl group, a tert-butyl group, a silyl group, and the like.

Examples of the amino-protecting group include a trityl group, a formyl group, a chloroacetyl group, a trifluoroacetyl group, a tert
-butoxycarbonyl group, trimethylsilyl group, tert-
butyldimethylsilyl group and the like.

Examples of the hydroxyl-protecting group include a 2-methoxyethoxymethyl group, a methoxymethyl group, a methylthiomethyl group, a tetrahydropyranyl group, a phenacyl group, an isopropyl group, a tert-butyl group, a benzyl group, a 4-nitrobenzyl group, an acetyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, or a cyclic acetal such as methylene acetal, ethylene acetal, or benzylidene acetal, an orthoester such as methoxymethylidene or methoxyethylidene, a cyclic ketal such as isopropylidene ketal, or a cyclic carbonate, which is formed by bonding protective groups to each other.

The method for removing the protecting group can be selected from a conventional method depending on the type of the protecting group. For example, the removal of protecting groups such as trityl group, formyl group, tert-butoxycarbonyl group, benzhydryl group, tert-butyl group, 2-methoxyethoxymethyl group, etc. can be carried out with inorganic or organic acids such as hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., and trifluoroacetic acid is particularly preferred. When trifluoroacetic acid is used as the acid, the reaction can be promoted and side reactions can be suppressed by adding anisole, thioanisole, phenol, etc. The reaction can be carried out in a solvent that does not adversely affect the reaction, such as water, methylene chloride, chloroform, ethylene chloride, benzene, etc.
The reaction temperature and reaction time are appropriately selected depending on the chemical properties of the compound of formula [II-1] or formula [II-2] and the compound [I] of the present invention, and the type of protecting group, and it is particularly preferable to carry out the reaction under mild conditions such as ice-cooling or warming.

The compound of the general formula [IV] or the general formula [II-1] in which the group Y is SO is a compound of the general formula [IV] or the general formula [II-1] in which the group Y is S.
The compound is dissolved in an organic solvent that does not participate in the reaction, such as methylene chloride, ethylene chloride, chloroform, ether, or acetic acid.
It can be produced by oxidation with m-chloroperbenzoic acid, hydrogen peroxide, or metaperiodic acid under ice-cooling or room temperature [J. Org. Chem., Vol. 35, p. 2430 (1970)].

The compound of the general formula [IV] in which the group Y is an iodine atom ^is
is a chlorine atom,
It can be produced by reacting it with an iodide such as sodium iodide in a solvent such as N,N-dimethylformamide at ice-cooling or room temperature [see, for example, JP-B 51-27679, Synth. Commun., Vol. 16, No. 16, 2001].
vol., pp. 1029-1035 (1986)], which may be used in the next reaction either with or without isolation.

The compound of general formula [IV] is described in Cephalosporins and Penicillins by Flynn, published by Academic Press in 1972, pp. 151-171 and 675, and in Journal of Organic Chemistry, Vol. 32, p. 500 (1972).
For example, 7β-amino-3-chloromethyl-3-cephem-4-carboxylic acid derivatives (prepared, for example, by the methods described in JP-A-50-76089 and JP-A-56-86178), 7β-acylamino-3-halomethyl-
3-Cephem-4-carboxylic acid derivatives (e.g., those disclosed in Japanese Patent Application Laid-Open No. 2003-124524)
58-72590, 58-154588, etc.), 7β-aminocephalosporanic acid or a 7β-acylaminocephalosporanic acid derivative is reacted with the above-mentioned nucleophilic reagent to obtain a compound represented by the general formula wherein ^R2 is a hydrogen atom, a carboxyl protecting group or a negative charge,
^R9 is a hydrogen atom or an acyl group; ^Q2 is a hydrogen atom, a halogen atom, an azide group, an optionally substituted quaternary ammonio group, or a phenyl group having two or more adjacent hydroxyl groups or lower alkanoyloxy groups substituted therewith;
a heterocyclic thio group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, which may have a substituent; Y represents S or SO (provided that
^Q2 and its substituents may be protected.], and then deacylated as necessary.

Deacylation reactions are already known in the art, and include, for example, a method comprising iminochlorination with phosphorus pentachloride or the like, followed by iminoetherification with methanol or the like and hydrolysis (e.g., JP-B-49-20319), or a method using acylase (e.g., JP-B-61-291431).

Examples of the acyl group include a phenylacetyl group, a phenoxyacetyl group, and an aminoadipyl group.

The following formula (II) is useful as an intermediate raw material for the compound of the present invention.
The method for producing the compound I will now be described.

The compound of the general formula [III] is represented by the general formula [VI] [wherein ^R6 represents a hydrogen atom or an amino-protecting group, and ^R7 represents a hydrogen atom or a carboxyl-protecting group], [wherein ^R8 represents a hydrogen atom or a carboxyl-protecting group]
and, if necessary, removing the protecting group.

The reaction of the compound of general formula [VI] with the hydroxylamine derivative of general formula [V] is carried out in a suitable solvent that does not adversely affect the reaction, such as water, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, or a mixture of these organic solvents with water, using 1.0 to 1.5 moles of the compound of general formula [V] per mole of the compound of general formula [VI] at a reaction temperature of 5 to 70°C.
The reaction is completed by carrying out the reaction at 0.5 to 5 hours.

After the reaction is completed, if necessary, the protecting group of the compound of the present invention can be removed by appropriately selecting a removal method commonly used in the field of organic synthetic chemistry. The method for removing the protecting group can be, for example, described in "Protective Groups in Organic Synthesis" by T.W. Green, published by Wiley in 1981, or "Protective Groups in Organic Synthesis" by J.F.W. McComy, published by Plenum Press in 1973.
Protective Groups in Organic Chemistry by Omie
The protective group can be easily removed by a conventional method such as acid treatment, hydrolysis, or reduction.

For example, when the amino-protecting group ^R6 is, for example, a formyl group, a benzhydryl group, a trityl group, a tert-butoxycarbonyl group, and/or the carboxyl-protecting groups ^R7 and ^R8 are the same or different and are a tert-butyl group or a benzhydryl group, the protecting group can be removed by treating the compound [III] of the present invention with an inorganic or organic acid such as hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Trifluoroacetic acid is particularly preferred. When trifluoroacetic acid is used as the acid, the reaction is promoted and side reactions are suppressed by adding anisole, thioanisole, or phenol. The reaction can be carried out in a solvent such as water, methylene chloride, chloroform, ethylene chloride,
In a solvent that does not adversely affect the reaction, such as benzene, or a mixture of these solvents, 0.1
The reaction can be carried out using an amount of acid in an amount of 0.5 to 20 times (V/W), preferably _0.5 to 10 times (V/ _W ). The reaction can be carried out under mild conditions such as ice-cooling or warming. For example, when the amino-protecting group _R6 is a trifluoroacetyl group or a trimethylsilyl group and/or the carboxyl-protecting groups R7 and R8 are the same or different and are methyl, ethyl, propyl, isopropyl, tert-butyl, benzyl or benzhydryl groups, the protecting groups can be removed by, for example, alkaline or acid hydrolysis of the compound [III] of the present invention. Examples of alkalis include sodium hydroxide,
Examples of the acid include hydrochloric acid, hydrobromic acid, dilute sulfuric acid, etc. The reaction can be carried out in a solvent such as water, methanol, ethanol, tetrahydrofuran, dioxane, or a mixture thereof, in an amount of 0.5 to 1 equivalent of the compound of the present invention.
5 equivalent moles, preferably 1 to 3 equivalents of base or 0.1 to 2
The reaction temperature is 0 to 80°C.

For example, when the amino-protecting group ^R6 is a benzyloxycarbonyl group and/or the carboxyl-protecting groups ^R7 and ^R8 are the same or different and are benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 4-nitrobenzyl, or benzhydryl, the protecting groups can be removed by catalytic reduction of the compound [III] of the present invention in a hydrogen gas stream in the presence of a catalyst such as palladium black at normal or elevated pressure at 10 to 70° C. The reaction solvent that can be used may be, for example, water, methanol, ethanol, tetrahydrofuran, or a mixture of these organic solvents with water.

After the reaction is completed, the compound of the present invention represented by the general formula [III] or a salt thereof can be isolated and purified from the reaction solution by solvent extraction, recrystallization,
This can be done by a separation means such as chromatography.

The compound [III] of the present invention can be converted into an addition salt with a base or acid, or a solvate with an appropriate solvent, by a conventional method.

Examples of the addition salts of the compound [III] of the present invention with bases include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and amine salts such as ammonium salt, trimethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, pyridine salt, picoline salt, quinoline salt, isoquinoline salt, etc. Examples of the addition salts with acids include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate, etc., organic acid salts such as acetate, propionate, trifluoroacetic acid, etc., sulfonate salts such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, etc., and amino acid salts such as arginine salt, lysine salt, etc.

Examples of solvents that form solvates with compound [III] include water, methanol, ethanol, propanol, glycol, methyl cellosolve, acetone, acetonitrile, tetrahydrofuran, dioxane, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, formamide, N,N-dimethylformamide, acetamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

The starting compound [III] of the present invention can be prepared, for example, according to the method described in the Journal of the Chemical Society of Japan, pp. 785-801 (1981).

The starting compound [V] is a novel compound and can be prepared, for example, according to the following reaction scheme.

[wherein ^R8 represents a hydrogen atom or a carboxyl-protecting group] That is, compound [V] can be obtained by the method described in British Patent Specification No. 1,602,725, using N-(1-carboxy-1-methyl-N ...
The (-vinyloxy)phthalimide derivative [VIII] is reacted in a solvent such as methanol, ethanol, methylene chloride, ethylene chloride, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. at a reaction temperature of -5
The compound [VIII] can be produced by reacting 1.0 to 2.5 moles of hydrazine with 1 mole of compound [VIII] at 40°C or below, and can be used in the next reaction with or without isolation.

Next, in order to demonstrate the usefulness of the compound [I] of the present invention, the in vitro antibacterial activity of the compound of the present invention against various bacteria was measured by the following agar plate dilution method.

Mueller Hinton Bros.
h), one loopful (inoculum size: 10 ⁶ CFU/ml) of each test strain was cultured overnight in Mueller-Hinton agar (MH
The medium contained various concentrations of antibiotics, and after 16 hours of incubation at 37°C, the minimum inhibitory concentration (MIC: μg/ml) was measured. The results are shown in the table below.

In addition, the compounds of the present invention have good pharmacokinetics. As a representative example, the compound of Example 15 was subcutaneously administered to mice, and the blood concentration was measured.

Four-week-old ddY male mice (body weight 19-22 g) were divided into groups of five. The test compound was dissolved in physiological saline to prepare a drug at a concentration of 2 mg/ml. 0.1 ml of the drug was administered subcutaneously per 10 g of mouse body weight. After drug administration, the mice were examined at 7.5 minutes, 15 minutes, 30 minutes, 60 minutes, and 1 minute.
After 20 and 240 minutes, blood samples were taken from the mouse's heart using a heparinized syringe. The blood concentrations at each measurement are shown in the table below.

Ceftazidime was used as a control compound. The antibacterial activity of the sample diluted to an appropriate concentration in plasma was measured using Morganella morganii as a test bacterium.
ganii) Measured by the paper disc method using IFO3843.

As is clear from the results in the table below, the compounds of the present invention rapidly attain high blood concentrations, which are superior to those of ceftazidime.

Furthermore, the acute toxicity of the compound of Example 1 is 6 g/kg or more (intravenous administration to mice), and it is extremely safe.

The compounds of the present invention exhibit strong antibacterial activity against both Gram-positive and Gram-negative bacteria, and particularly exhibit excellent activity against resistant Gram-negative bacteria including Pseudomonas aeruginosa. Therefore, the compounds of formula [I], their non-toxic salts, and their physiologically hydrolyzable non-toxic esters are useful as antibacterial agents.

The compounds of the present invention can be mixed with solid or liquid excipient carriers known in the art and used in the form of pharmaceutical preparations suitable for parenteral, oral or external administration.

Examples of pharmaceutical preparations include liquid preparations such as injections, syrups, and emulsions, solid preparations such as tablets, capsules, and granules, and ointments.
Examples include external preparations such as suppositories.

Furthermore, these preparations may contain, as necessary, commonly used additives such as auxiliary agents, stabilizers, wetting agents, emulsifiers, absorption enhancers, surfactants, etc. Examples of additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup,
Gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate,
Examples include talc.

Additionally, the compounds of the present invention can be used as antibacterial agents to treat bacterial infections in humans.

The dosage varies depending on the patient's age, sex, and other conditions.
Usually, the daily dose is in the range of 1 to 100 mg/kg, and preferably 5 to 30 mg/kg per day in 2 to 4 divided doses.

The present invention will now be further explained with reference to examples and reference examples, but the present invention is not limited to these.

Examples Example 1 7β-[2-(2-aminothiazol-4-yl)-2
(A) 5.06 g (9.76 mmol) of 2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (syn isomer) and benzhydryl 7β-amino-3-chloromethyl-
3-cephem-4-carboxylate 4.05 g (9.76 mmol)
1) was dissolved in 100 ml of methylene chloride, and the solution was added with 5.56 ml (43.9 mmol) of N,N-dimethylaniline and 1.07 ml of phosphorus oxychloride at 0°C.
Add dropwise 0.5 ml (11.5 mmol) of HCl and stir for 1 hour.
The extract was washed with 5N hydrochloric acid and saturated saline in that order, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure.
Benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide]-3-
8.7 g (96.7% yield) of chloromethyl-3-cephem-4-carboxylate (syn-isomer) are obtained.

IR (KBr) cm ^-1 :3400,2960,1790,1720,1520,1150,700 NMR (DMSO-d ₆ ) δ:1.48 (9H,s),3.47 and 3.75 (2H,AB
q, J = 18Hz), 4.45 (2H, br s), 5.19 (1H, br s), 5.27 (1H, d, J = 4.5Hz),
5.35 (1H, br s), 5.77 (1H, dd, J = 4.5 and 7.5 Hz), 6.92 (1H, s), 6.95 (1H,
s),7.30(25H,m),8.86(1H,br s),9.79(1H,d,J=7.
(B) 4 g (4.34 mmol) of the compound obtained in the above reaction (A) was dissolved in 80 ml of acetone and 3.25 g (21.7 mmol) of sodium iodide was added.
(1) was added and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and 80 ml of ethyl acetate was added to the residue. The mixture was washed successively with water, 10% aqueous sodium thiosulfate, and saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was washed with diisopropyl ether to give 3.98 g (90.5% yield) of benzhydryl 7β-[2-(tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (syn-isomer).

(C) 304 mg (0.3 mmol) of the compound obtained in the above reaction (B)
Dissolve in 6 ml of N,N-dimethylformamide and add 0.03 ml of pyridine.
The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel C-300). The eluted fraction (8% methanol/chloroform) was concentrated to give benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-
vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate;
280 mg (85.4% yield) of the iodide (syn isomer) are obtained as a foam.

(D) 280 mg (0.26 mmol) of the compound obtained in the above reaction (C)
Dissolve in 4 ml of methylene chloride and 0.8 ml of anisole, add 8 ml of trifluoroacetic acid under ice cooling, and stir for 1 hour. Remove the solvent under reduced pressure, add ether to the residue, and filter the precipitate. Dissolve this precipitate in 50 ml of 10% aqueous methanol solution and then use ODS column chromatography (LC-Sorb RP-
The mixture was subjected to a column chromatography (18, Checom Co., Ltd.) and eluted with 20% aqueous methanol. The eluted fraction containing the target compound was concentrated and lyophilized to obtain 70 mg of the title compound (yield 50%).

mp: 150℃ (decomposition) IR (KBr) cm ^-1 : 3420, 1780, 1630, 1540, 1395, 1200 NMR (DMSO-d ₆ /D ₂ O) δ: 2.90-3.60 (2H, ABq), 5.06 (1
H,d,J=4.5Hz), 5.20~5.50(4H,m),5.70(2H,d,J=4.5Hz)6.95(1H,
s), 7.95 (2H,m), 8.40 (1H,m), 8.90 (1H,m) Example 2 7β-[2-(2-aminothiazol-4-yl)-2
Structure of benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(2,3-cyclopenteno-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer)
Using 234 mg (0.28 mmol) of iodomethyl-3-cephem-4-carboxylate (syn-isomer) and 0.033 ml (0.28 mmol) of 2,3-cyclopentenopyridine, Example 1
The same procedures as in (C) and (D) were carried out, and the mixture was subjected to ODS column chromatography, eluting with 20% aqueous methanol to obtain 45 mg of the title compound (yield 28.1%).

mp: 150℃ (decomposition) IR (KBr) cm ^-1 :3420,1770,1620,1540,1400,1200 NMR (DMSO-d ₆ /D ₂ O) δ: 2.15 (2H, m), 2.80-3.30, (6
H,m),5.05(2H,d,J=4.5Hz),5.10~5.30(4H,m),5.6
6 (1H, d, J = 4.5Hz), 6.93 (1H, s), 7.60 (1H, m,), 8.15
(1H, d, J = 8 Hz), 8.45 (1H, d, J = 8 Hz) Example 3 7β-[2-(2-aminothiazol-4-yl)-2
Structure of benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(3-carboxy-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer)
Using 305 mg (0.3 mmol) of iodomethyl-3-cephem-4-carboxylate (syn-isomer) and 95.6 mg (0.31 mmol) of benzhydryl nicotinate, the reaction mixture (C) of Example 1 was prepared.
The same procedure as in (D) was carried out and the resulting mixture was subjected to ODS column chromatography, followed by elution with 20% aqueous methanol to obtain 31 mg of the title compound (yield 18.0%).

mp: 130℃ (decomposition) IR (KBr) cm ^-1 : 3400, 1770, 1640, 1620, 1390, 1200 NMR (DMSO-d ₆ /D ₂ O) δ: 3.10-3.80 (2H, ABq), 5.10 (1
H,d,J=4.5Hz), 5.25~5.50(4H,m),5.70(1H,d,J=4.5Hz)6.93(1H,
s),8.00(1H,m),8.70(1H,br s),8.95(1H,br s),
9.25 (1H,s) Example 4 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-carbamoyl-1-pyridinio)
Preparation of methyl 3-cephem-4-carboxylate (syn isomer) Benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-
Iodomethyl-3-cephem-4-carboxylate (syn-isomer) 305 mg (0.3 mmol) and nicotinamide
Using 38.4 mg (0.31 mmol), the same procedures as in (C) and (D) of Example 1 were carried out, and the product was subjected to ODS column chromatography, eluting with 20% aqueous methanol to obtain 55.8 mg (yield 32.4%) of the title compound.

mp: 150℃ (decomposition) IR (KBr) cm ^-1 :3400,1780,1680,1620,1400,1200 NMR (DMSO-d ₆ /D ₂ O) δ: 3.10-3.80 (2H, ABq), 5.20 (1
H,d,J=4.5Hz), 5.40~5.60(4H,m),5.83(1H,d,J=4.5Hz),7.06(1H,
s),8.21(1H,m),8.90(1H,br s),9.20(1H,br s),
9.45 (1H,s) Example 5 7β-[2-(2-aminothiazol-4-yl)-2
Preparation of benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)acetamido]-3-(4-carboxy-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer)
Using 203 mg (0.2 mmol) of iodomethyl-3-cephem-4-carboxylate (syn-isomer) and 203 mg (0.2 mmol) of benzhydryl isonicotinate, the same procedures as in (C) and (D) of Example 1 were carried out, and the mixture was subjected to ODS column chromatography and eluted with 20% aqueous methanol to obtain 36 mg (yield 31.3%) of the title compound.

mp: 150℃ (decomposition) IR (KBr) cm ^-1 :3420,1780,1630,1380,1200 NMR (DMSO-d ₆ /D ₂ O) δ: 3.10-3.75 (2H, ABq), 5.22 (1
H,d,J=4.5Hz), 5.40~5.70(4H,m),5.85(1H,d,J=4.5Hz),7.10(1H,
s), 8.30 (2H, d, J = 6 Hz), 9.05 (2H, d, J = 6 Hz) Example 6 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-carbamoyl-1-pyridinio)
Preparation of methyl 3-cephem-4-carboxylate (syn isomer) Benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-
Using 203 mg (0.2 mmol) of iodomethyl-3-cephem-4-carboxylate (syn-isomer) and 25.6 mg (0.21 mmol) of isonicotinamide, the same procedures as in (C) and (D) of Example 1 were carried out, and the mixture was subjected to ODS column chromatography, eluting with 20% aqueous methanol to obtain 31 mg (yield 27.0%) of the title compound.

mp:160℃ (decomposition) IR (KBr)cm ^-1 :3420,1780,1670,1630,1540,1400,1350,1
200 NMR (DMSO- _d6 / _D2O ) δ:3.10-3.70(2H,ABq),5.10(1
H,d,J=4.5Hz), 5.30~5.55(4H,m),5.75(1H,d,J=4.5Hz),7.00(1H,
s), 8.30 (2H, d, J = 6 Hz), 9.10 (2H, d, J = 6 Hz) Example 7 7β-[2-(2-aminothiazol-4-yl)-2
Preparation of 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)acetamido]-3-(4-sulfonatemethyl-1-pyridinio)methyl-3-cephem-4-carboxylic acid (syn isomer) (A) Benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-
tritylaminothiazol-4-yl)acetamide]
773 mg (0.73 mmol) of 3-iodomethyl-3-cephem-4-carboxylate 1-oxide (syn-isomer)
The mixture was dissolved in 5 ml of N,N-dimethylformamide, and 293 mg (1.5 mmol) of potassium 4-pyridylmethanesulfonate was added. The mixture was then left to stand at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (Wako Gel C-30
0) to give benzhydryl 7β-[2-(1-tert
-butoxycarbonyl-1-vinyloxyimino)-2
-(2-tritylaminothiazol-4-yl)acetamido]-3-(4-sulfonatemethyl-1-pyridinio)methyl-3-cephem-4-carboxylate 1
650 mg (81.7% yield) of the -oxide (syn isomer) are obtained as a foam.

(B) 650 mg (0.60 mmol) of the compound obtained in the above reaction (A)
Dissolve in 4 ml of N,N-dimethylformamide and add 0.13 ml (1.5 mmol) of phosphorus trichloride at -40°C.
After stirring at -40°C for 2 hours, the mixture was poured into ice water and the precipitate was collected by filtration. The precipitate was dissolved in methylene chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure.
Benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide]-3-
(4-sulfonatemethyl-1-pyridinio)methyl-
3-Cephem-4-carboxylate (syn isomer) 51
The product was used in the next reaction without further purification.

(C) 500 mg (0.41 mmol) of the compound obtained in the above reaction (B)
The resulting product was subjected to the same procedure as in Example 1 (D) and eluted with 20% aqueous methanol on an ODS column to obtain 94.2 mg (yield 32.1%) of the title compound.

mp: 130℃ (decomposition) IR (KBr) cm ^-1 :3450,1780,1640,1400,1200,1040 NMR (DMSO-d ₆ /D ₂ O) δ: 3.20-3.60 (2H, ABq), 4.20 (2
H,s),5.20(1H,d,J=4.5Hz),5.30~5.60(4H,m),5.8
6 (1H, d, J = 4.5Hz), 7.00 (1H, s), 8.05 (2H, d, J = 6H
z), 8.90 (2H, d, J = 6 Hz) Example 8 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-(2-sulfonate ethyl)-1
Preparation of 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-
Iodomethyl-3-cephem-4-carboxylate 1
-oxide (syn isomer) 773 mg (0.73 mmol) and 2-
(4-pyridyl)ethanesulfonic acid potassium salt 328mg
(1.5 mmol) was used in the same manner as in Example 7, and O
Elution with 20% aqueous methanol in DS column chromatography gave 76 mg (yield 15.5%) of the title compound.

mp: 130℃ (decomposition) IR (KBr) cm ^-1 : 3450, 1780, 1630, 1520, 1400, 1200 NMR (DMSO-d ₆ /D ₂ O) δ: 3.20-3.16 (2H, ABq), 3.30-
3.70 (4H, m), 5.20 (1H, d, J=4.5Hz), 5.30~5.60 (4H,
m),5.75(1H,d,J=4.5Hz),6.96(1H,s),8.15(2H,d,
J = 6 Hz), 9.10 (2H, d, J = 6 Hz). Example 9 Sodium 7β-[2-(2-aminothiazole-4
-yl)-2-(1-carboxylate-1-vinyloxyimino)acetamide]-3-(3-amino-1-
Preparation of (pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-
Iodomethyl-3-cephem-4-carboxylate 1
-oxide (syn isomer) 773 mg (0.73 mmol) and 3-
Using 276.5 mg (0.83 mmol) of tritylaminopyridine, the same procedures as in (A), (B), and (C) of Example 7 were carried out. The trifluoroacetate salt obtained in step (C) was adjusted to pH 6.5 with aqueous sodium bicarbonate, and then subjected to ODS column chromatography to eluate with 5% aqueous methanol to obtain the title compound 23.
mg (yield 5.4%).

mp: 125℃ (decomposition) IR (KBr) cm ^-1 : 3400, 1770, 1620, 1540, 1400, 1200 NMR (DMSO−d ₆ /D ₂ O) δ: 3.20 ~ 3.60 (2H, ABq), 5.00 ~
5.25 (5H, m), 5.65 (1H, d, J = 4.5Hz), 6.90 (1H, s), 7.
60-8.40 (4H,m) Example 10 Sodium 7β-[2-(2-aminothiazole-4
Preparation of benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(3-formylamino-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer)
Iodomethyl-3-cephem-4-carboxylate 1
-oxide (syn isomer) 773 mg (0.73 mmol) and 3-
Using 101 mg (0.83 mmol) of formylaminopyridine,
The same procedure as in Example 9 was carried out, and the product was subjected to ODS column chromatography, eluting with 5% aqueous methanol to obtain 125 mg of the title compound (yield 28.8%).

mp: 120℃ (decomposition) IR (KBr) cm ^-1 :3400,1770,1660,1600,1540,1500,1400 NMR (DMSO−d ₆ /D ₂ O) δ: 3.20~3.60 (2H, ABq), 4.95~
5.20 (4H, m), 5.05 (1H, d, J = 4.5Hz), 5.70 (1H, d, J =
4.5Hz), 6.85 (1H, s), 7.60~8.40 (4H, m), 9.45 (1H,
s) Example 11 Disodium 7β-[2-(2-aminothiazole-
4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazol-2-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) (A) Preparation of benzhydryl 3-chloromethyl-7β-[2
461 mg (0.48 mmol) of [1-tert-butoxycarbonyl-1-vinyloxyimino]-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn-isomer) was dissolved in 8 ml of N,N-dimethylformamide, and 375 mg (2.
Add 50 mmol of ethanol to the reaction solution and stir at room temperature for 50 minutes.
-(3,4-dihydroxyphenyl)-2-mercapto-
Add 105 mg (0.5 mmol) of 1,3,4-oxadiazole and
The reaction mixture was stirred for 1 hour. 50 ml of ethyl acetate was added to the reaction mixture, washed with water, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and ether was added to the residue to obtain crude benzhydryl.
7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide]-3-[5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazole-2
420 mg of [-yl]thiomethyl-3-cephem-4-carboxylate (syn-isomer) is obtained, which is used in the next reaction without further purification.

(B) 440 mg (0.36 mmol) of the compound obtained in the above reaction (A)
Dissolve in 5 ml of methylene chloride and 1 ml of anisole and cool to 0° C. Add a solution of 5 ml of methylene chloride and 10 ml of trifluoroacetic acid, which has been cooled to 0° C., all at once and stir for 1 hour.
The solvent was removed under reduced pressure, ether was added to the residue, and the precipitate was collected by filtration. The precipitate was suspended in water and the pH was adjusted with saturated sodium bicarbonate water.
After adjusting to 7.1, reverse phase column chromatography (LC-
The mixture was applied to a column (SorbRP-18, Chemco) and eluted with 8% aqueous methanol. The eluted fraction containing the target compound was concentrated and lyophilized to give 114 mg of the title compound (yield 41.4%).

mp: 190℃ (decomposition) IR (KBr) cm ^-1 : 3400, 1760, 1600, 1400 NMR (D ₂ O) δ: 3.45 and 3.78 (2H,ABq,J=17.5Hz), 4.17
(2H,br s),5.17 (1H,d,J=4.5Hz),5.22(1Hd,J=2Hz),5.36(1H,d,J
= 2Hz), 5.82 (1H, d, J = 4.5Hz), 6.84 (1H, br s), 7.
10-7.20 (3H,m) Example 12 Disodium 7β-[2-(2-aminothiazole-
Preparation of]-3-[4-(3,4-dihydroxyphenyl)thiazol-2-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) (A) Benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2
1.17 g (1.12 mmol) of [(tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-4-carboxylate (syn-isomer) and 0.3 g (1.33 mmol) of 4-(3,4-dihydroxyphenyl)-2-mercaptothiazole
Benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[4-
0.96 mg (74.9% yield) of (3,4-dihydroxyphenyl)thiazol-2-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) is obtained.

NMR (DMSO-d ₆ ) δ: 1.42 (9H, s), 3.70 (2H, m), 4.20 (1
H,d,J=14Hz), 4.46(1H,d,J=14Hz),5.15(1H,br s),5.18(1H,d,J
=5Hz),5.32(1H,br s), 5.72(1H,m),6.73(1H,s),6.85(1H,s),6.94(1H,
s), 7.00-7.70 (27H, m) (B) 0.96 g (0.84 mmol) of the compound obtained in the above reaction (A)
The same procedure as in Example 11(B) was repeated to obtain 225 mg of the title compound.
(yield 41.4%).

mp: 110℃ (decomposition) IR (KBr) cm ^-1 : 3400, 1742, 1517 NMR (DMSO-d ₆ ) δ: 3.53 (2H, m), 4.48 (2H, m), 4.88 (1
H,br s),5.01(1H,d,J=4Hz),5.18(1H,br s),5.65
(1H,m),6.78(1H,d,J=9Hz),6.90(1H,s),7.18(1
H, dd, J = 2 and 9 Hz), 7.76 (1H, d, J = 2 Hz), 7.56 (1H,
s) Example 13 Disodium 7β-[2-(2-aminothiazole-
4-yl)-2-(1-carboxylate-1-vinyloxyimino)acetamide]-3-[5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazole-2-
Preparation of Benzhydryl 7β-[2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)-2-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer)
1.0 g (0.96 mmol) of 5-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (syn-isomer) and 5-
(3,4-dihydroxyphenyl)-2-mercapto-1,
Using 0.24 g (1.06 mmol) of 3,4-thiadiazole, benzhydryl 7β
-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazole-
425 mg (41% yield) of [5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-2-yl]-acetamido]-3-[5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) are obtained as a foam.

NMR (DMSO-d ₆ ) δ: 1.47 (9H, s), 3.70 (2H, m), 4.20 (1
H,br d,J=12Hz),4.52(1H,br d,J=12Hz),5.20(1H,
br s), 5.22 (1H, d, J = 5Hz), 5.35 (1H, br s), 5.75 (1
H, m), 6.88 (1H, m), 6.90 (1H, s), 7.00~7.70 (27H,
m), 8.88 (1H,m), 9.78 (1H,m) (B) 451 mg (0.39 mmol) of the compound obtained in the above reaction (A)
The same procedure as in Example 11(B) was carried out to obtain 68 mg of the title compound.
(yield 24%).

mp: 160℃ (decomposition) IR (KBr) cm ^-1 : 3430, 1765, 1600, 1540 NMR (DMSO-d ₆ ) δ: 3.50 (2H, m), 4.50 (2H, m), 4.92 (1
H,br s),5.05(1H,d,J=4Hz),5.22(1H,br s),5.66
(1H,m),6.90(1H,m),6.92(1H,s),7.15(1H,m),7.
30 (1H, br s) Example 14 Disodium 7β-[2-(2-aminothiazole-
Preparation of]-3-[5-(3,4-dihydroxyphenyl)oxazol-2-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) (A) Benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-
tritylaminothiazol-4-yl)acetamide]
1.0 g (1.06 mmol) of 3-chloromethyl-3-cephem-4-carboxylate (syn-isomer), 175 mg (1.17 mmol) of sodium iodide, and 0.26 g (1.21 mmol) of 5-(3,4-dihydroxyphenyl)-2-mercaptooxazole
Benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[5
-(3,4-dihydroxyphenyl)oxazole-2-
0.75 g (63.2% yield) of [[[(2-methyl-2-yl)-2-methyl-1-methyl ...

IR (KBr) cm ^-1 :1790,1720,1660,1530,1370,1150,700 NMR (DMSO- _d6 ) δ:1.40 (9H,s),3.55~3.80 (2H,m),
3.90~4.35 (2H, m), 5.10~5.35 (3H, m), 5.70 (1H,
m), 6.70-7.70 (31H, m), 9.25 (1H, m) (B) 0.72 mg (0.64 mmol) of the compound obtained in the above reaction (A)
The trifluoroacetate obtained by the same procedure as in Example 11(B) was suspended in water, adjusted to pH 6.5 with saturated sodium bicarbonate water, and insoluble matter was removed by filtration. The filtrate was subjected to reverse phase column chromatography (LC-Sorb RP-18, Chemco), and the eluted fractions containing the target compound (eluted with 3% aqueous methanol) were collected, concentrated, and lyophilized to give 110 mg of the title compound (yield 27.2%).
%).

mp: 190℃ (decomposition) IR (KBr) cm ^-1 :1760,1600,1530,1400,1280,1200,1010 NMR (DMSO-d ₆ /D ₂ O) δ: 3.30-3.70 (2H, m), 4.30 (2H,
br s),4.80~5.25(3H,m),5.63(1H,m),6.75~7.15
(4H,m), 7.33 (1H,s) Example 15 Preparation of trisodium 7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxylate-1-vinyloxyimino)acetamide]-3-[4-carboxylate-5-(3,4-dihydroxyphenyl)thiazol-2-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) (A) Benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-
tritylaminothiazol-4-yl)acetamide]
11.43 g (12 mmol) of 1-chloromethyl-3-cephem-4-carboxylate (syn-isomer) was dissolved in 90 ml of N,N-dimethylformamide, and 8.3 g (55
The reaction mixture was stirred at room temperature for 1 hour.
Carboxy-5-(3,4-dihydroxyphenyl)-2
Add 3.23 g (12 mmol) of mercaptothiazole and 1.67 ml (12 mmol) of triethylamine, and stir at the same temperature for 45 minutes. Remove the solvent under reduced pressure, and add 500 ml of ethyl acetate to the residue.
Add 150 ml of water and adjust the pH to 1.5 with 2N hydrochloric acid.
150 ml of % sodium thiosulfate solution and 150 ml of saturated saline solution
The mixture was washed with hexane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wako Gel C-300, eluted with 2% methanol/chloroform) to obtain benzhydryl 7β-[2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide]-3-[4-carboxy-5-(3,
8.33 g (59% yield) of [4-dihydroxyphenyl]thiazol-2-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) are obtained.

IR (KBr) cm ^-1 :1790,1720,1680,1640,1530,1500,1370,1
280,1200,1150 NMR (DMSO- _d6 ) δ:1.46(9H,s),3.75(2H,ABq),4.27
(2H,ABq),5.19(1H,s),5.22(1H,d,J=4.5Hz),5.35
(1H,s), 5.75 (1H,dd,J=4.5 and 9Hz), 6.77 (2H,s),
6.93(2H,s),6.96(1H,s),7.35(25H,s),8.86(1H,b
rs),9.16(1H,br s),9.33(1H,br s),9.77(1H,d,J
= 9 Hz) (B) Dissolve 8.30 g of the compound obtained in the above reaction (A) in 38 ml of methylene chloride and 7.6 ml of anisole, add 38 ml of trifluoroacetic acid dropwise at -10°C over 20 minutes, and stir at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, and add 200 ml of diisopropyl ether to the oily residue. Collect the precipitated insoluble matter by filtration, wash with diisopropyl ether (50 ml x 2), and dry under reduced pressure to obtain 5.53 g (85% yield) of the trifluoroacetate salt of the title compound as a powder.

NMR (DMSO−d ₆ ) δ:3.73 (2H, ABq), 4.35 (2H, ABq), 5.
19 (1H, d, J = 4.5Hz), 5.41 (1H, s), 5.48 (1H, s), 5.83
(1H,dd,J=4.5 and 9Hz), 6.00-7.20 (4H,m), 6.78 (2
H,s),6.91(1H,s),7.03(1H,s),9.83(1H,d,J=9H
z) (C) 5.45 mg (7.26 mmol) of the compound obtained in the above reaction (B)
The suspension was suspended in 80 ml of water, and the pH was adjusted to 7.3 with saturated sodium bicarbonate water under ice cooling.
The insoluble matter was removed by filtration, and the filtrate was subjected to reverse phase column chromatography (LC-Sorb RP-18, Chemco, eluted with water), and the eluted fraction containing the target compound was concentrated and lyophilized to give the title compound 2.51.
mg (44% yield).

mp: 270℃ (decomposition) IR (KBr) cm ^-1 : 1760, 1670, 1595, 1540, 1405 NMR (D ₂ O) δ: 3.57 (2H, ABq), 4.18 (2H, ABq), 5.17 (1
H, d, J = 4.5Hz), 5.19 (1H, s), 5.34 (1H, s), 5.80 (1H,
d,J=4.5Hz),6.88(2H,s),6.98(1H,s),7.17(1H,
s) Example 16 Trisodium 7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxylate-1-vinyloxyimino)acetamide]-3-[4-(3,4-
Diacetoxyphenyl)-5-carboxylate methylthiazol-2-yl]-thiomethyl-3-cephem-
Preparation of 4-carboxylate (syn isomer) (A) 5.0 g (9.01 mmol) of 2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (syn isomer) and benzhydryl 7β-amino-3-chloromethyl-3-
3.73 g (9.0 mmol) of cephem-4-carboxylate was dissolved in 80 ml of methylene chloride, and under ice cooling, 5.11 ml (40.5 mmol) of N,N-dimethylaniline was added, followed by 1.01 ml of phosphorus oxychloride.
(10.8 mmol) was added dropwise. After stirring at room temperature for 1 hour, 0.
The residue was washed with 5N hydrochloric acid and saturated saline, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give benzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-
A foamy residue of 3-cephem-4-carboxylate (syn isomer) is obtained and used in the next reaction without further purification.

(B) The compound obtained in the above reaction (A) is dissolved in 200 ml of acetone, 2.7 g (18 mmol) of sodium iodide is added, and the mixture is stirred at room temperature for 30 minutes. The solvent is removed under reduced pressure, and ethyl acetate is added to the residue. The mixture is washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent is removed by evaporation to give benzhydryl 7β
-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazole-
10.2 g of [4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (syn-isomer) are obtained.

NMR (DMSO-d ₆ ) δ: 1.48 (9H, s), 3.30-3.90 (2H, m),
4.35 (2H, m), 5.18 (1H, br s), 5.22 (1H, d, J = 5.0H
z),5.36(1H,br s),5.75(1H,m),6.90～7.80(27H,
m), 8.88 (1H, br s), 9.80 (1H, br d, J = 8.0 Hz) (C) 1.13 mg (approximately 1.08 mm) of the crude product obtained in the above reaction (B).
ol) was dissolved in 10 ml of N,N-dimethylformamide, and 4-
(3,4-Diacetoxyphenyl)-5-benzhydryloxycarbonylmethyl-2-mercaptothiazole 0.
The mixture is stirred at room temperature for 1 hour, and the solvent is removed by distillation under reduced pressure to give benzhydryl 7β-[2-
(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[4-(3,4-diacetoxyphenyl)-5-benzhydryloxycarbonylmethylthiazol-2-yl]thiomethyl-3-cephem-
The 4-carboxylate (syn isomer) is obtained and used in the next reaction without purification.

(D) The crude product obtained in the above reaction (C) is dissolved in methylene chloride 5.
This was dissolved in 1.0 mL of ethanol and 1.0 mL of anisole, and 5.0 mL of trifluoroacetic acid was added under ice cooling and stirred for 1 hour. The solvent was removed under reduced pressure, and ether was added to the residue. The precipitate was collected by filtration. This precipitate was suspended in water, adjusted to pH 6.5 with saturated sodium bicarbonate water, and then subjected to reverse-phase column chromatography (LC-Sorb RP-18, Chemco) and eluted with 5% aqueous methanol. The eluted fractions containing the target compound were collected, concentrated, and lyophilized to obtain 122 mg of the title compound (13% yield from step (B)).

mp:180~185℃ (decomposition) IR (KBr) cm ^-1 :3400,1760,1590,1535,1370,1210 NMR (DMSO− _d6 ) δ:2.30 (6H,s),4.10~4.80 (2H,m),
4.95(1H,br s),5.03(1H,d,J=5.0Hz),5.22(1H,br
s), 5.62 (1H,m), 6.95 (1H,s), 7.20-7.70 (3H,m) Example 17 7β-[2-(2-aminothiazol-4-yl)-2
Preparation of benzhydryl 7β-[2-(1-carboxy-1-vinyloxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn-isomer)
(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn-isomer) 210 mg (0.23 mmol)
l) is dissolved in 5 ml of methylene chloride and 1 ml of anisole, and 5 ml of trifluoroacetic acid is added under ice cooling, followed by stirring for 1.5 hours.
The solvent was removed under reduced pressure, and the residue was diluted with diisopropyl ether.
The precipitated powder was collected by filtration and dried to give the title compound 11.
5 mg (yield 83.8%) was obtained.

mp: 130℃ (decomposition) IR (KBr) cm ^-1 :3400,1780,1660,1630,1190,1000 NMR (DMSO− _d6 ) δ:3.60 (2H,br s),4.55 (2H,br s),
5.18 (1H, d, J = 5Hz), 5.46 (2H, br s), 5.80 (1H, dd, J
= 5 and 9 Hz), 7.02 (1H, s), 9.82 (1H, d, J = 9 Hz) Reference Example Reference Example 1 2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazole-4-
Preparation of N-(1-tert-butoxycarbonyl-1-vinyloxy) phthalimide (syn-isomer)
After dissolving it in a mixed solution of 1000 ml of hydrazine hydrate and 10 ml of methanol, a solution of 1.88 ml of 80% hydrazine hydrate and 40 ml of methanol was added dropwise.
The mixture was stirred at room temperature for 1.5 hours. After removing the insoluble matter, the filtrate was washed with 8% aqueous ammonia three times and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.
The residue is dissolved in 120 ml of methanol.
After dissolving in 1 ml of water, 7.46 g (18 mmol) of 2-(2-tritylaminothiazol-4-yl)glyoxylic acid was added, and
The mixture was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration to give the title compound.
7.08 g (70.9% yield) is obtained.

mp:110~150℃ (decomposition) IR (KBr) cm ^-1 :3400,2970,1725,1630,1100,700 NMR (DMSO- _d6 ) δ:1.45 (9H,s),5.20 (1H,br s),5.33
(1H,br s),7.05(1H,s),7.10～7.40(15H,m),8.82
(1H, br s) Elemental analysis: Calculated for _C31H29N3O5S (%): C, _67.00 ; H, _5.26 ; N, _7.56 ; S, 5.77 Found (%): C, 67.30; H, 5.58; N, 7.74; S, 5.54 Reference Example 2 2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazole-4-
Preparation of N-(1-tert-butoxycarbonyl-1-vinyloxy) phthalimide (syn-isomer) Dissolve 392 mg (1.3 mmol) of N-(1-tert-butoxycarbonyl-1-vinyloxy) phthalimide in 8 ml of methylene chloride.
After dissolving this in a mixed solution of 0.8 ml of methanol, a solution of 0.165 ml (2.6 mmol) of 80% hydrazine hydrate and 2 ml of methanol was added dropwise and stirred at room temperature for 1 hour. After removing the insoluble matter, the filtrate was washed three times with 8% aqueous ammonia and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the residue of O-(1-tert-butoxycarbonyl-1-vinyl)hydroxylamine. This residue was dissolved in 5 ml of methanol and then added with 414 mg (1.0 mmol) of 2-(2-tritylaminothiazol-4-yl)glyoxylic acid.
Add the above and stir at room temperature for 2 hours. The precipitated crystals are collected by filtration to obtain 400 mg of the title compound (yield 76.1%).
The spectrum is exactly the same as that of Reference Example 1.

Reference Example 3 2-(2-aminothiazol-4-yl)-2-(1-te
Preparation of rt-butoxycarbonyl-1-vinyloxyimino)acetic acid (syn-isomer) Using 172 mg (1.0 mmol) of 2-(2-aminothiazol-4-yl)glyoxylic acid, the same procedure as in Reference Example 1 was carried out to give 207.5 mg (yield 66.2%) of the title compound.

mp:120℃ (decomposition) IR (KBr)cm ^-1 :3400,3150,2990,1720,1640,1380,1320,1
200,1150,980,850,730 NMR (DMSO-d ₆ /CD3OD)) δ:1.48 (9H,s),5.29 (1H,
s), 5.39 (1H,s), 7.10 (1H,s), 7.30 (2H,br s) Reference Example 4 Preparation of 2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) Using 200 mg (1.0 mmol) of 2-(2-formamidothiazol-4-yl)glyoxylic acid, the same procedure as in Reference Example 1 was carried out to obtain 183 mg (yield 53.6%) of the title compound.

mp: 130℃ (decomposition) IR (KBr) cm ^-1 :3400,3150,2980,1720,1690,1630,1560,1
400,1380,1280,1210,1150,980,850,740 NMR (DMSO- _d6 ) δ:1.48 (9H,s),5.18 (1H,s),5.24
(1H,s), 7.49 (1H,s), 8.51 (1H,s) Reference Example 5 2-(2-aminothiazol-4-yl)-2-(1-
Preparation of 2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazole-4-)-carboxy-1-vinyloxyiminoacetic acid trifluoroacetate (syn-isomer)
350 mg (0.63 mmol) of (syn)-(methyl)acetic acid (syn-isomer) was dissolved in a mixture of 4 ml of methylene chloride and 0.8 ml of anisole, and the mixture was heated at 0°C.
After cooling to 0°C, 4 ml of trifluoroacetic acid pre-cooled to 0°C was added.
Add 1 ml of diisopropyl ether to the oily residue, filter the precipitate, and wash with diisopropyl ether to obtain 200 mg of the title compound (yield 85.5%).

mp:110-150℃ (decomposition) IR (KBr) cm ^-1 :3400,3120,1650,1630,1610,1590,1190,1
180,980 NMR (DMSO- _d6 / _D2O ) δ:5.40(1H,s),5.47(1H,s),
7.15 (1H,s) Reference Example 6 Preparation of O-(1-tert-butoxycarbonyl-1-vinyl)hydroxylamine. 602 mg (2.0 mmol) of N-(1-tert-butoxycarbonyl-1-vinyloxy)phthalimide prepared by the method described in British Patent Specification No. 1,602,725 was dissolved in 5 ml of methylene chloride.
After dissolving in a mixture of 0.1 ml of hydrazine hydrate and 0.5 ml of methanol, add dropwise 0.25 ml (5 mmol) of hydrazine hydrate and 0.5 ml of methanol under ice-cooling, and stir at room temperature for 1.5 hours. The solvent is distilled off under reduced pressure, and 20 ml of ethyl acetate is added to the residue. The mixture is washed twice each with 8% aqueous ammonia and saturated brine, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to obtain 260 ml of the title compound.
g (78.5% yield).

IR (KBr) cm ^-1 :3300,2970,1720,1640,1370,1330,1220,1
150 NMR (DMSO-d ₆ ) δ: 1.50 (9H,s), 5.18 (1H,s), 5.25
(1H,s),6.10 (2H,br s) Reference Example 7 Preparation of 2-mercapto-5-[3,4-di(2-methoxyethoxymethoxy)phenyl]-1,3,4-oxadiazole (A) 2.5 g (14.9 mmol) of methyl protocatechuate was suspended in 50 ml of methylene chloride, and 7.84 ml (45 mmol) of ethyldiisopropylamine was added at 0°C to form a homogeneous solution.
After adding 5.8 ml (45 mmol) of methoxyethoxymethyl chloride dropwise and stirring for 30 minutes, the reaction mixture was washed successively with water, 0.5 N aqueous sodium hydroxide, and saturated brine. The aqueous layer was extracted twice more with methylene chloride, and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 5.1 g (99% yield) of methyl 3,4-di(2-methoxyethoxymethoxy)benzoate.

NMR (CDCl ₃ ) δ:3.32(3H,s),3.34(3H,s),3.35(4H,
m),3.83(4H,m),3.86(3H,s),5.32(4H,m),7.18
(1H, d, J = 9 Hz), 7.67 (1H, dd, J = 2 and 9 Hz), 7.79 (1
(H, d, J = 2 Hz) (B) 5.1 g (15 mmol) of the compound obtained in the above reaction (A) was dissolved in 100 ml of methanol, and 40 ml (300 ml) of 80% hydrazine hydrate was added.
After adding 40 ml of 80% hydrazine hydrate and heating under reflux for 1 hour, 40 ml of 80% hydrazine hydrate was added and the mixture was heated under reflux for another 2 hours. After cooling the reaction mixture, it was poured into water and extracted three times with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 4.2 g of crude 3,4-di(2-methoxyethoxymethoxy)benzoic acid hydrazide.

(C) 4.2 g (12 mmol) of the compound obtained in the above reaction (B) and carbon disulfide were added to 42 ml of an ethanol solution containing 1.27 g (18 mmol) of 80% potassium hydroxide (1.0 g of potassium hydroxide and 0.27 ml of water).
Add 3.64 ml (61 mmol) of the solvent and heat under reflux for 1 hour. After distilling off the solvent under reduced pressure, the residue is dissolved in water and adjusted to pH 1.5 with 1N hydrochloric acid.
The resulting mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (Wako Gel C-300, ethyl acetate:hexane = 3:1) to obtain 3.03 g (yield 52.3%) of the title compound.

MP:84℃ IR (KBr) cm ^-1 :1620,1585,1520,1500,1360,1250,1105,1
090,995.

NMR (DMSO-d ₆ ) δ:3.27 (6H,s),3.51 (4H,m),3.80
(4H,m),5.38(2H,s),5.39(2H,s),7.32(1H,d,J=6
Hz), 7.54 (1H, dd, J = 1.8 and 6 Hz), 7.62 (1H, d, J = 1.8
Hz) Elemental analysis: Calculated for _C16H22N2O7S (%): C, _49.73 ; H, _5.74 ; N, _7.25 ; S, 8.30 Found (%): C, 49.66; H, 5.85; N, 7.10; S, 8.24 Reference Example 8 Preparation of 2-mercapto-5-[3,4-di(2-methoxyethoxymethoxy)phenyl]-1,3,4-thiadiazole (A) 15.0 g (50.7 mmol) of 3,4-di(2-methoxyethoxymethoxy)benzonitrile was dissolved in 15.0 ml of pyridine, and 7.5 ml (50 mmol) of triethylamine was added. Hydrogen sulfide gas was introduced into this solution at room temperature and stirred for 6 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 18.8 g (yield 100%) of crude 3,4-di(2-methoxyethoxymethoxy)thiobenzamide, which was used in the next reaction without further purification.

IR (KBr) cm ^-1 : 3320, 3200, 2900, 1635, 1515 (B) 2.0 g (5.8 mmol) of the compound obtained in the above reaction (A) was dissolved in 20.0 ml of ethanol, 0.40 ml of hydrazine hydrate was added, and the mixture was stirred at 70°C for 1 hour.
Add 0.40 g (5.70 mmol) of toluene and 1.38 ml (18 mmol) of carbon disulfide and reflux for 20 minutes. Remove the solvent under reduced pressure, dissolve the residue in water, and wash with ethyl acetate. Adjust the aqueous layer to pH 3.0 with 2N hydrochloric acid.
After adjusting the temperature to 0, extract with ethyl acetate and dry over anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the crystalline residue is washed with ether to give 0.94 g (40% yield) of the title compound.

IR (KBr) cm ^-1 :3160,2500,1600,1585,1510,1455 NMR (DMSO−d ₆ ) δ:3.25 (6H,s),3.50 (4H,m) 3.78 (4
H,m),5.34(4H,br s),7.26(1H,d,J=8Hz),7.33(1
Elemental analysis (%) for C16H22N2O6S2: Calculated: C, _47.75 H, _5.51 N, _6.96 S, _15.93 Found: C, 47.75 H, 5.44 N, 6.94 S, _15.72 Reference Example 9: Preparation of 5-(3,4-dihydroxyphenyl)-2-mercapto-1,3,4-thiadiazole (A) Dissolve 10 g (178 mmol) of potassium hydroxide in 400 ml of ethanol.
1, and add 20 g (119 mmol) of protocatechuic acid hydrazide at 5°C or below while stirring.
Add 28.0 ml of carbon disulfide dropwise over 10 minutes at 0-10°C.
After stirring for 30 minutes, the precipitate was collected by filtration, washed with ethanol, and dried to obtain 25.3 g (yield 75.3%) of potassium 3-protocatechuyldithiocarbazate.

(B) 25.3 g (89.6 mmol) of the compound obtained in the above reaction (A)
Add the mixture little by little to 125 ml of concentrated sulfuric acid at 10°C or below over 20 minutes, then stir at 10°C for 20 minutes. Add the reaction solution little by little to 600 mg of ice and 300 ml of water, stir for another 10 minutes, and filter the precipitate. Dissolve this precipitate in 125 ml of acetone, add 600 ml of ethyl acetate, 20 ml of water, and 1 mg of activated carbon, and mix for 15 minutes.
After filtering off the activated carbon, the filtrate was washed successively with 200 ml of 5% aqueous sodium thiosulfate solution, 150 ml of water, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate.
The solvent is evaporated and the crystalline residue is washed with ether to give 3.6 g (17.8% yield) of the title compound.

IR (KBr) cm ^-1 :3600～2000,1650,1600,1430,1300,1250 NMR (DMSO− _d6 ) δ:6.82 (1H,d,J=9Hz),7.01(1H,dd,
J = 2 and 9 Hz), 7.13 (1H, d, J = 2 Hz), 9.50 (2H, br
s), 14.38 (1H, br s) Reference Example 10 Preparation of 4-(3,4-dihydroxyphenyl)-2-mercaptothiazole 2-chloro-3'4'-dihydroxyacetophenone 1
After dissolving 0.0g (53.6mmol) in 100ml of methanol, add 5.90g (53.6mmol) of ammonium dithiocarbamate and stir at room temperature for 30 minutes. The solvent is removed under reduced pressure, and water is added to the residue, adjusted to pH 2.0, and extracted twice with ethyl acetate. The extract is dried over anhydrous sodium sulfate, concentrated, and the crystalline residue is washed with ether to obtain 8.80g of the title compound.
(72.9% yield)

MP: 236°C (recrystallization solvent: ethyl acetate) IR (KBr) cm ^-1 : 3240, 1615, 1525, 1470 NMR (DMSO-d ₆ ) δ: 6.77 (1H, d, J = 9 Hz), 6.92 (1H,
s), 7.03 (1H, dd, J = 2 and 9 Hz), 7.08 (1H, d, J = 2H
Elemental analysis: Calculated for C9H7NO2S2 (%): C, _47.98 ; H, _3.13 ; N, _6.21 ; S, _28.47 Found (%): C, 48.07; H, 3.02; N, 6.22; S, 28.16 Reference Example 11 4-carboxy-5-(3,4-dihydroxyphenyl)
(A) Preparation of 2-mercaptothiazole using 60.1 g of piperonal as a starting material.
3-12, 519-520, and the same procedure as described on pages 12-12.
(3,4-methylenedioxyphenyl)pyruvic acid 48.3g
(yield 58%).

IR (KBr) cm ^-1 :1670,1500,1490,1450,1250,1040 NMR (DMSO− _d6 ) δ:6.03 (2H,s),6.83 (1H,s),6.87
(1H,d,J=7.5Hz),7.23(1H,d,J=7.5Hz),7.46(1H,
s), 9.00 (2H, s) (B) 10.4 g (0.05 mol) of the compound obtained in the above reaction (A) was suspended in 100 ml of ethyl acetate and 2.56 ml (0.05 m
100 ml) and stir at the same temperature for 30 minutes. 200 ml of ethanol was added to the reaction solution, and 9.92 g (0.09 mol) of ammonium dithiocarbamate was added at -10°C. The mixture was stirred at the same temperature for 20 minutes and then at room temperature for 2 hours. The reaction solution was cooled in an ice bath for 40 minutes, and the insoluble material was removed by filtration and washed with 40 ml of ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. 350 ml of water was added to the residue, and the mixture was heated at 80°C for 18 hours. The gummy insoluble material was removed by hot filtration. The filtrate was adjusted to pH 1.5 with 6N hydrochloric acid under ice-cooling, and the precipitate was collected by filtration, washed with 30 ml of water, and dried to give 7.23 g of the title compound as a yellow powder.

The gummy insoluble matter was then suspended in 20 ml of acetone, filtered, and dried to obtain 1.02 g of secondary crystals. Total yield: 8.25 g
(Yield 66%).

IR (KBr) cm ^-1 :1710,1690,1500,1490,1450,1430,1320,1
260,1060,1040 NMR (DMSO−d ₆ ) δ:6.10 (2H,s),6.97 (2H,s),7.12
(1H, s), 12.0-15.0 (2H, br s) (C) 6.79 g (0.024 mo) of the compound obtained in the above reaction (B)
l) was suspended in a solution of 180 ml of methylene chloride and 13 ml of ethanethiol, and 16.0 g (0.12 mol) of anhydrous aluminum chloride was added at 5°C.
Add 100 ml of 6N hydrochloric acid dropwise under ice cooling, and stir at the same temperature for 4 hours and then at 10°C for 24 hours. After adding 100 ml of 6N hydrochloric acid dropwise, stir at the same temperature for 1.5 hours. Filter the insoluble matter, wash with 50 ml of water twice, and dry to obtain 5.35 g of crude product. Recrystallize from a methanol-water mixture to obtain 3.93 g (61% yield) of the title compound as yellow needles.

MP: 245-247℃ (decomposition) IR (KBr) cm ^-1 :1710,1700,1610,1520,1480,1350,1300,1
250,1210,1190,1120,1070,1010 NMR (DMSO-d ₆ ) δ:5.00-7.50 (2H, br s), 6.79 (2H,
s), 6.90 (1H, s), 8.00~10.0 (2H, br s) UVλmax (MeOH) nm (▲E ^1% _1cm ▼): 309.5 (480), 340.5
(481) Reference Example 12 Preparation of 4-(3,4-diacetoxyphenyl)-5-benzhydryloxycarbonylmethyl-2-mercaptothiazole (A) 70 g (0.7 mol) of succinic anhydride and 96.6 g of veratrole
(0.7 mol) was dissolved in 2000 ml of methylene chloride, and 237 g (1.75 mol) of anhydrous aluminum chloride was added at room temperature.
After leaving the reaction solution to stand for 15 hours, add 1600 ml of 6N hydrochloric acid dropwise while stirring, and stir for another hour. Separate the organic layer, add 300 ml of water, and adjust the pH to 7.5 with saturated sodium bicarbonate water.
The aqueous layer was separated. The pH of the aqueous layer was adjusted to 2.5 with 6N hydrochloric acid, and the mixture was left in a refrigerator for 2 days. The precipitated crystals were then filtered, washed with water, and dried.
-(3,4-dimethoxybenzoyl)propionic acid 106.8g
(64% yield).

IR (KBr) cm ^-1 :3360,1740,1665,1590,1515,1415,1335,1
270,1150,1020,800,770,610 NMR (DMSO− _d6 ) δ:2.56 (2H,t,J=6.0Hz),3.21(2H,
t,J=6.0Hz),3.93(3H,s),3.95(3H,s),7.04(1H,d,
J = 8.7Hz), 7.45 (1H, d, J = 1,5Hz), 7.67 (1H, dd, J = 1.
5 and 4.5 Hz), 11.0-12.5 (1H, br) (B) 48% of the compound obtained in the above reaction was
Add 1070 ml of hydrobromic acid and boil under reflux for 5 hours. Remove the solvent under reduced pressure, and add 1000 ml of water to the residue. After heating and dissolving, treat with activated carbon, and keep the filtrate refrigerated overnight to obtain black-brown crystals. These colored crystals are hot-dissolved in 1000 ml of water, treated with activated carbon twice, and kept refrigerated overnight to obtain 37.2 g (yield 39.8%) of colorless plate-like 3-(3,4-dihydroxybenzoyl)propionic acid.
%).

IR (KBr) cm ^-1 :3460,3370,1740,1660,1590,1405,1380,1
245,1165,1125,885,820,610 NMR (DMSO−d ₆ ) δ:2.53 (2H,t,J=6.2Hz),3.12(2H,
t, J = 6.2Hz), 6.82 (1H, d, J = 8.7Hz), 7.30~7.50 (2H,
m), 9.00-10.50 (2H, br), 11.30-12.80 (1H, br). (C) To 2.0 g (9.52 mmol) of the compound obtained in the above reaction (B), 9.0 ml of acetic anhydride and 0.78 g (9.5 mmol) of sodium acetate are added, and the mixture is heated under reflux for 30 minutes. The solvent is distilled off under reduced pressure, and ethyl acetate is added to the residue. The mixture is washed with 5% aqueous sodium bicarbonate and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and
The residue was purified by silica gel column chromatography (Wakogel
C-300, 2% methanol/methylene chloride) to 4-
(3,4-diacetoxyphenyl)-2(3H)-furanone
1.33 g (50% yield) is obtained.

NMR (DMSO-d ₆ ) δ:2.30 (6H,s),3.58 (2H,m),6.24
(1H,m), 7.30-7.60 (3H,m) (D) 300 mg (1.08 mmol) of the compound obtained in the above reaction (C)
Dissolved in 8 ml of a dioxane/water (3:1) mixed solvent, added 193 mg of N-bromosuccinimide at room temperature, and stirred for 15 minutes. The reaction solution was poured into ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. To the filtrate, 300 mg (1.54 mmol) of diphenyldiazomethane was added and stirred for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-300, ethyl acetate:hexane = 1:3) to obtain 350 mg of benzhydryl 3-(3,4-diacetoxybenzoyl)-3-bromopropionate.
(60% yield).

NMR (DMSO-d ₆ ) δ:2.33 (6H,s),3.20~3.80 (2H,m),
6.00 (1H,t,J=8.0Hz),6.80(1H,s),7.10~7.60(13
H,m) (E) 700 mg (1.30 mmol) of the compound obtained in the above reaction was treated with N,N-
Dissolved in 7.0 ml of dimethylformamide, added 143 mg (1.30 mmol) of ammonium dithiocarbamate under ice cooling, and
The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (Wakogel C-300, ethyl acetate:hexane=1:2) to give 470 mg (yield 68%) of the title compound.

IR (KBr) cm ^-1 :3400,3240,1750,1735,1500,1470,1370,1
260,1200,1160,1050 NMR (DMSO−d ₆ ) δ:2.30 (6H,s),3.00 (2H,m),4.40
(1H,br t,J=7.0Hz),6.78(1H,s),7.10～7.60(13H,
m) Reference Example 13: Preparation of 5-(3,4-dihydroxyphenyl)-2-mercaptooxazole (A) 10 g (53.6 mmol) of 2-chloro-3',4'-dihydroxyacetophenone was dissolved in 50 ml of acetone, and the solution was diluted with 600 mg (4.0 mmol) of sodium iodide and 5.23 mg (4.0 mmol) of sodium azide.
g (80.5 mmol) of acetonitrile was added and the mixture was refluxed for 24 hours. Insoluble matter was removed by filtration and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the reaction mixture, which was then washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the oily residue was dissolved in 100 ml of methanol and 13.6 ml of concentrated hydrochloric acid. 1.5 g of 10% palladium-carbon catalyst was added, and the mixture was heated and stirred at 40°C for 5 hours in a hydrogen gas stream. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Acetone was added to the concentrated residue, and the precipitated crystals were collected by filtration to obtain 5.5 mg of 2-amino-3',4'-dihydroxyacetophenone hydrochloride (yield: 50.4%).

NMR (DMSO- _d6 / _D2O ) δ:4.40(2H,s),6.90(1H,d,J=
9.0 Hz), 7.30-7.50 (2H, m) (B) 1.0 g (4.9 mmol) of the compound obtained in the above reaction (A)
The mixture was suspended in 17 ml of 0.043 N sodium ethoxide ethanol solution, and 2.1 ml (35 mmol) of carbon disulfide was added and stirred at 60°C for 20 hours. The reaction solution was poured into 50 ml of water and adjusted to pH 1.5 with 6 N hydrochloric acid.
The mixture is stirred for 1 hour and then extracted with ethyl acetate.
The organic layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound 75.
0 mg (73% yield).

MP:215~8℃ IR (KBr) cm ^-1 :1640,1600,1520,1500,1300,1180,1120 NMR (DMSO− _d6 / _D2O )δ:6.70~6.95(2H,m),7.00(1
Elemental analysis: Calculated for C9H7NO3S (%): C, 51.12 _; H, _3.12 ; N, _6.43 Found (%): C, 51.67; H, 3.37; N, 6.69 Reference Example 14 Preparation of 2-mercapto-5,6-di(2-methoxyethoxymethoxy)benzimidazole (A) 10 g of 4,5-dimethoxy-1,2-dinitrobenzene (4
The resulting solution was cooled to room temperature, and 500 ml of water was added.
Extract three times with ethyl acetate. Wash the organic layer with 10% sodium bicarbonate water, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure. Wash the crystalline residue with methylene chloride to obtain 7 g of 4,5-dihydroxy-1,2-dinitrobenzene (79% yield).

NMR (DMSO- _d6 ) δ: 7.48 (2H, s), 8.50 (2H, br s) (B) 28 g (0.14 mol) of the compound obtained in the above reaction (A) was suspended in 280 ml of methylene chloride, and 30 ml (0.42 mol) of ethyldiisopropylamine was added at room temperature to dissolve the compound. 30 ml (0.42 mol) of 2-methoxyethoxymethyl chloride was added to the reaction solution at 0°C.
mol) and stirred for 30 minutes. The reaction solution was poured into water, and the organic layer was washed with 1N aqueous sodium hydroxide and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 39 g (74% yield) of 4,5-di(2-methoxyethoxymethoxy)-1,2-dinitrobenzene.

IR (KBr) cm ^-1 :2900,1525,1362 NMR (DMSO-d ₆ ) δ:3.23 (6H,s),3.50 (4H,m),3.78
(4H,m), 5.58 (4H,s), 8.01 (2H,s) (C) 9.5 g (25 mmol) of the compound obtained in the above reaction (B) was dissolved in 180 ml of ethanol, and 1 g of 10% palladium carbon catalyst was added, followed by catalytic hydrogenation at 80°C for 2 hours.
Add 1 g of 100% palladium-carbon solvent and perform catalytic hydrogenation under the same conditions (repeated twice). The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate/hexane = 1:1). The eluted fraction containing the target product is concentrated and purified to give 4,5-di(2-methoxyethoxymethoxy)-2-
5.07 g (57% yield) of nitroaniline was obtained (it was unstable and was used immediately in the next reaction).

(D) 3.5 g (10 mmol) of the compound obtained in the above reaction (C) is dissolved in 70 ml of ethanol, and 0.6 g of a 10% palladium carbon catalyst is added, followed by catalytic hydrogenation at 80°C for 1 hour.
Add 0.6 g of 10% palladium catalyst and perform the reduction reaction under the same conditions (repeat this process twice). After filtering off the catalyst, add 10 g of potassium O-ethyldithiocarbonate to the filtrate.
Add 3 ml of water (6.1 mmol) and boil under reflux for 3 hours. Remove the solvent under reduced pressure, dissolve the residue in water, and adjust the pH to 3.0 with acetic acid.
The mixture was adjusted to 100% and extracted three times with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-300, ethyl acetate/hexane = 3:
1), and the eluted fraction containing the target compound was concentrated and purified by 2-mercapto-5,6-di(2-methoxyethoxymethoxy)
Benzimidazole (61% yield) is obtained.

IR (KBr) cm ^-1 :3280,1622,1475,1332 NMR (DMSO- _d6 ) δ:3.25 (6H,s),3.32 (2H,s),3.48
(4H,m), 3.75 (4H,m), 5.20 (4H,s), 6.94 (2H,s) Reference Example 15 Preparation of 2-mercapto-5,6-di(2-methoxyethoxymethoxy)-1-methylbenzimidazole (A) 1.57 g (4.54 mmol) of 4,5-di(2-methoxyethoxymethoxy)-2-nitroaniline obtained in Reference Example 34(C)
l) in 16 ml of N,N-dimethylformamide, and add silver oxide.
Add 2 g (8.63 mmol) of methyl iodide and 10 ml (160 mmol) of methyl iodide, and stir at room temperature for 1 hour. The solvent is removed under reduced pressure, and the residue is purified by silica gel column chromatography (Wako Gel
C-300, ethyl acetate/hexane = 1:1), and the eluted fraction containing the target compound was concentrated to give crude 4,5-di(2-methoxyethoxymethoxy)-N-methyl-2-nitroaniline.
Obtain 0.85g.

(B) 0.85 g of the crude product obtained in the above reaction (A) was dissolved in 16 ml of ethanol, and 0.4 g of 10% palladium-carbon catalyst was added.
Catalytic hydrogenation is carried out at 80°C for 2 hours. After filtering off the catalyst,
The filtrate was treated with 1 g (6.25
The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water and adjusted to pH 5.0 with acetic acid.
The mixture is then extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The residue is subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate/hexane = 3:1) to obtain 67 mg of the title compound.

NMR (CDCl ₃ ) δ: 3.40 (6H, s), 3.60 (4H, m), 3.68 (3H,
s), 3.88 (4H, m), 5.27 (2H, s), 5.30 (2H, s), 7.02 (1
Reference Example 16: Preparation of 2-mercapto-5,6-di(2-methoxyethoxymethoxy)benzoxazole (A) 5.4 g (17 mmol) of 3,4-di(2-methoxyethoxymethoxy)benzaldehyde was dissolved in 216 ml of methylene chloride, and 4.4 g (20 mmol) of 80% m-chloroperbenzoic acid was added. The mixture was then boiled under reflux for 20 hours. The reaction solution was washed with aqueous sodium bicarbonate and saturated brine, dried, and the solvent was distilled off under reduced pressure to obtain 4.85 g (86% yield) of O-formyl-3,4-di(2-methoxyethoxymethoxy)phenol, which was used in the next reaction without purification.

NMR (CDCl ₃ /DMSO−d ₆ ) δ: 3.36 (6H, s), 3.58 (4H, m),
3.82 (4H, m), 5.28 (4H, br s), 6.73 (1H, dd, J = 2 and
9Hz), 7.02 (1H,d,J=2Hz), 7.29 (1H,d,J=9Hz) (B) 4.85g (14.7mmol) of the compound obtained in the above reaction (A)
Dissolve in 4 ml of methanol and add 7.0 ml of 10% sodium hydroxide.
(17.6 mmol) and stirred at room temperature for 30 minutes. The reaction solution was poured into 1000 ml of water and washed with ethyl acetate. The aqueous layer was adjusted to pH 5.0 with 6N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 8 ml of acetic acid, and 0.70 ml (11 mmol) of concentrated nitric acid was added at 10°C and stirred for 1 hour. The reaction solution was poured into ethyl acetate and
The mixture was washed with water and saturated sodium bicarbonate solution, the organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate/hexane = 1:3).
The eluted fraction containing the target substance was concentrated to give 1.51 g of 4,5-di(2-methoxyethoxymethoxy)-2-nitrophenol.
(yield 29.6%).

NMR (DMSO-d ₆ ) δ:3.25 (6H,s),3.50 (4H,m),3.76
(4H,m), 5.23 (4H,s), 6.87 (1H,s), 7.75 (1H,s) (C) 1.5 g (4.3 mmol) of the compound obtained in the above reaction (B) was dissolved in 30 ml of ethanol and 0.5 g of 10% palladium carbon catalyst was added.
The mixture was then subjected to catalytic hydrogenation at 70°C for 1.5 hours. After filtering off the contact, the filtrate was added with 0.36g (4.73mmol) of carbon disulfide and 80%
0.35g (5.0mmol) potassium hydroxide aqueous solution and 0.78ml water
Add 43 mmol of HCl (43 mmol) and boil under reflux for 1.5 hours. Remove the solvent under reduced pressure, dissolve the residue in water, adjust the pH to 5.0 with 6N hydrochloric acid, and extract with ethyl acetate. Dry and concentrate the organic layer. Apply silica gel column chromatography (Wako Gel C-300, ethyl acetate:hexane = 1:1) to obtain 857 mg of the title compound (yield 55.5%).

NMR (DMSO-d ₆ ) δ:3.22 (6H,s),3.46 (4H,m),3.75
(4H,m), 5.23 (4H,s), 7.00 (1H,s), 7.34 (1H,s) 1. Effect of the Invention According to the present invention, a compound of the general formula [I] useful as an antibacterial agent is provided. [wherein R represents a hydrogen atom, a carboxyl protecting group or a negative charge; Q represents a hydrogen atom, a halogen atom, an azide group, an optionally substituted quaternary ammonio group, or two adjacent
and (iii) a heterocyclic thio group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, which is substituted with a phenyl group having one or more hydroxyl groups or lower alkanoyloxy groups, and which may have a substituent; a non-toxic salt or a physiologically hydrolyzable non-toxic ester thereof; and a process for producing the same.

──────────────────────────────────────────────────── Continued from the front page (31) Priority Number: Patent Application No. 61-309178 (32) Priority Date: December 27, 1986 (33) Priority Country: Japan (JP) (72) Inventor: Yoshiharu Tanaka 14-18 Daimon 3-chome, Okazaki City, Aichi Prefecture (72) Inventor: Moriaki Ishikawa 88-1 Hongo, Hekoshi-cho, Okazaki City, Aichi Prefecture (72) Inventor: Ryosuke Ushijima 14-3 Tozaki Motomachi, Okazaki City, Aichi Prefecture Examiner: Masato Ikeda (56) References: Japanese Patent Application No. 61-254584 (JP, A)

Claims (12)

[Claims] [Claim 1] General formula [I] [wherein R represents a hydrogen atom, a carboxyl protecting group or a negative charge; Q represents a hydrogen atom, a halogen atom, an azide group, an optionally substituted quaternary ammonio group, or two adjacent
a heterocyclic thio group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent, and which is substituted with a phenyl group having one or more hydroxyl groups or lower alkanoyloxy groups, or a non-toxic salt or physiologically hydrolyzable non-toxic ester thereof. [Claim 2] General formula 10. The compound according to claim 1, represented by the formula: wherein ^R1 is a hydrogen atom, a carboxyl-protecting group, or a negative charge; ^Q1 is a hydrogen atom, a quaternary ammonio group which may have a substituent, or a heterocyclic thio group which has at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, and which is substituted with a phenyl group having two or more adjacent hydroxyl groups or lower alkanoyloxy groups (the aromatic heterocycle may be condensed with a benzene ring or a heterocycle). Claim 3: Q ¹ is a group represented by the formula wherein R ^a , R ^b and R ^c may be the same or different;
It represents a lower alkyl group, a lower alkenyl group, or a lower alkynyl group, or two or three of R ^a , R ^b , and R ^c are bonded to each other and, together with the adjacent nitrogen atom, form a monocyclic ring, polycyclic ring group, or bridged polycyclic group which may be saturated or unsaturated and which may contain at least one heteroatom selected from the group consisting of oxygen atoms, nitrogen atoms, and sulfur atoms. Here, the lower alkyl group, the lower alkenyl group, the lower alkynyl group, the monocyclic ring group, the polycyclic ring group and the bridged polycyclic ring group may have one or more identical or different substituents selected from the group consisting of a hydroxyl group, a lower alkoxy group, a formyloxy group, a lower alkanoyloxy group, a carbamoyloxy group, a hydroxy lower alkyl group, a sulfo lower alkyl group, a carboxy lower alkyl group, a carbamoyl lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a cyano group, a sulfo group, a sulfamoyl group, an amino group which may have a substituent, a halogen atom, an aryl group, or a 5- or 6-membered aromatic heterocyclic group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. (However, the aryl group and the aromatic heterocyclic group are not limited to a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a fluoroalkyl group, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, a carbamoyloxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a cyano group, a sulfo group,
3. The compound according to claim 1, wherein the aryl group is a group represented by the formula (III) (which may have one or more identical or different substituents selected from the group consisting of a sulfamoyl group, an optionally substituted amino group, a substituted oximino group, and a halogen atom). [Claim 4] The compound according to claim 2, wherein Q ¹ is a 5- or 6-membered aromatic heterocyclic ammonio group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, which may have a substituent. 5. The compound according to claim 3, wherein Q ¹ is an imidazolio group, a pyrimidio group, a pyridazinio group, a thiazolinio group, an oxazolinio group, a pyridinio group, a quinolinio group, or an isoquinolinio group, each of which may have a substituent. 6. Q ¹ is an azetidinio group, a pyrrolidinio group, a piperidinio group, a 3-oxopiperidinio group, a 4-oxopiperidinio group, a 1,2,3,6-oxo-1,2-dimethyl-2,3-dimethyl-3,3-dimethyl-4,3-dimethyl-2,3-dimethyl-3 ...
A compound according to claim 2, which is a tetrahydropyridinio group or a hexamethyleneiminio group. 7. The compound according to claim 2, wherein Q ¹ is a morpholinio group, a thiomorpholinio group, a 3-oxomorpholinio group, a piperazinio group, a homopiperazinio group, or a 3-oxopiperazinio group, each of which may have a substituent. 8. The compound according to claim 2, wherein Q ¹ is an isoindolinio group, a 1,2,3,4-tetrahydroisoquinolinio group, a 2,3,4,5-tetrahydro-1H-2-benzazepinio group or a 1,2,4,5-tetrahydro-3H-3-benzazepinio group, each of which may have a substituent. 9. The compound according to claim 2, wherein Q ¹ is a 2-benzoxazolethio group, a 2-benzothiazol-2-ylthio group, or a 2-benzimidazol-2-ylthio group, each of which may have a substituent. 10. 7β-[2-(2-aminothiazole-
4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-(2,3-cyclopenteno-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-carboxy-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-carbamoyl-1-pyridinio)
Methyl-3-cephem-4-carboxylate (syn-isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-carboxy-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-carbamoyl-1-pyridinio)
Methyl-3-cephem-4-carboxylate (syn-isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-sulfonatemethyl-1-pyridinio)methyl-3-cephem-4-carboxylic acid (syn isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-(2-sulfonate ethyl)-1
-pyridinio]methyl-3-cephem-4-carboxylic acid (syn isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-amino-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-formylamino-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)
-1,3,4-oxadiazol-2-yl]thiomethyl-
3-Cephem-4-carboxylic acid (syn-isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-(3,4-dihydroxyphenyl)
Thiazol-2-yl]thiomethyl-3-cephem-4
-carboxylic acid (syn isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)
-1,3,4-thiadiazol-2-yl]thiomethyl-3
-Cephem-4-carboxylic acid (syn-isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)
Oxazol-2-yl]thiomethyl-3-cephem-
4-carboxylic acid (syn isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-carboxy-5-(3,4-dihydroxyphenyl)thiazol-2-yl]thiomethyl-
3-Cephem-4-carboxylic acid (syn-isomer), 7β-[2-(2-aminothiazol-4-yl)-2
-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-(3,4-diacetoxyphenyl)
-5-carboxymethylthiazol-2-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) or 7β-[2-(2-aminothiazol-4-yl)-2
2. The compound according to claim 1, which is [-(1-carboxy-1-vinyloxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid (syn-isomer). [Claim 11] General formula [IV] [wherein ^R2 is a hydrogen atom, a carboxyl protecting group or a negative charge; ^Q2 is a hydrogen atom, a halogen atom, an azide group, an optionally substituted quaternary ammonio group, or two adjacent
a heterocyclic thio group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which is substituted with a phenyl group having one or more hydroxyl groups or lower alkanoyloxy groups, and which may have a substituent; and Y represents S or SO (provided that ^Q2 and its substituents may be protected), or a salt thereof, [wherein ^R3 represents a hydrogen atom or an amino-protecting group, and ^R4 and ^R5 are the same or different and represent a hydrogen atom or a carboxyl-protecting group] or a reactive derivative thereof, to obtain a compound represented by the general formula [II-1] wherein R ² , R ³ , R ⁴ , Q ² and Y have the above-mentioned meanings.
or a salt thereof, and optionally reacting a compound of general formula [II-1] in which ^Q2 is a leaving group or a salt thereof with a nucleophilic reagent to obtain a compound of general formula [II-2] wherein R ² , R ³ , R ⁴ and Y have the same meanings as above, and Q ³ represents a halogen atom, an azide group, a fourth group which may have a substituent,
a heterocyclic thio group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which is substituted with a phenyl group having two or more adjacent hydroxyl groups or lower alkanoyloxy groups, and which may have a substituent, or a compound represented by the general formula [II-
1] or general formula [II-2] or a salt thereof, by reducing and/or removing the protecting group, [wherein R represents a hydrogen atom, a carboxyl protecting group or a negative charge; Q represents a hydrogen atom, a halogen atom, an azide group, an optionally substituted quaternary ammonio group, or two adjacent
a heterocyclic thio group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which is substituted with a phenyl group having one or more hydroxyl groups or lower alkanoyloxy groups, and which may have a substituent, or a non-toxic salt or physiologically hydrolyzable non-toxic ester thereof. Claim 12: General formula [I] [wherein R represents a hydrogen atom, a carboxyl protecting group or a negative charge; Q represents a hydrogen atom, a halogen atom, an azide group, an optionally substituted quaternary ammonio group, or two adjacent
and n is an integer of 0 to 10. The antibacterial agent is characterized by comprising, as an active ingredient, a compound represented by the formula (I): wherein R represents a heterocyclic thio group having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, and which is substituted with a phenyl group having one or more hydroxyl groups or lower alkanoyloxy groups, and which may have a substituent; a non-toxic salt or a physiologically hydrolyzable non-toxic ester thereof.