JPH0761987A - Cephem compound, its production and antibacterial composition - Google Patents

Abstract

PURPOSE:To obtain a cephem compound effective for treating infectious diseases and having broad antibacterial spectra against gram-positive and gram-negative bacteria and excellent antibacterial activity by reacting a specific cephem compound with a carboxylic acid. CONSTITUTION:The objective cephem compound of the formula I [R1 is (protected)amino; Q is N or C-R2 (R2 is H or halogen); R3 is H or (substituted) hydrocarbon; A is (substituted)triazolothiadiazolyl or imidazothiadiazolyl], e.g. 7beta-[2-(2-aminothizol-4-yl)-2(Z)-methoxyiminoacetamido]-3-[imidazo[2,1- b][1,3,4]thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylic acid sodium salt, etc., is obtained by reacting a cephem compound of the formula II, its salt or its ester with a carboxylic acid of the formula III, its salt or its reactive derivative.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel cephem compound having an excellent antibacterial action, a process for producing the same and an antibacterial composition.

[0002]

BACKGROUND OF THE INVENTION Cephem antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals. For example, the treatment of diseases caused by bacteria resistant to penicillin antibiotics and penicillin susceptible patients. Is especially useful for the treatment of In that case, it is desirable to use a cephem antibiotic having activity against both Gram-positive bacteria and Gram-negative bacteria, and for this reason, research on Cephem antibiotics having a broad antibacterial spectrum has been actively conducted.
However, their antibacterial activity is not fully satisfactory. There is also a need for a cephem antibiotic that is active against a resistant bacterium that is resistant to a cephalo compound, that is, a so-called cephalosporin-resistant bacterium, as was previously experienced with penicillin. On the other hand, as the cephem compound,
Various compounds having a fused heterocyclic thiomethyl group at the 3-position of the cephem skeleton have been synthesized (JP-A-53-3479).
4, JP-A-53-34795, JP-A-54-9296
Etc.), the fused heterocycle at the 3-position was a 5-6 fused heterocycle in which a 5-membered ring and a 6-membered ring were fused. In the 3-position condensed heterocyclic thiomethyl group, almost no cephem compound having a 5-5 type condensed heterocyclic ring has been synthesized, and 3-thiazolo [2,3-c] which is a condensed heterocyclic ring of a thiazole ring and a triazole ring. Cephem compounds having [1,2,4] triazole and thiazolo [3,2-b] [1,2,4] triazole [Corrian Journal of Medicinal Chemistry, Vol. 1, p. 8 (199)
1)] is only known.

[0003]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention Some Escherichia coli bacteria resistant to known cephalosporins, some Citrobacter genus and Indole-positive Proteus genus, and further Enterobacter genus, Serratia genus or Pseudomonas genus It is desired to develop a novel cephem compound having clinically usable antibacterial activity against pathogenic bacteria classified into the following categories.

[0004]

SUMMARY OF THE INVENTION In view of the above circumstances, the inventors of the present invention have earnestly studied variously about a cephem compound having a 5-5 type condensed heterocycle as a condensed heterocycle of a 3-position condensed heterocycle thiomethyl group. As a result, in the 3-position condensed heterocyclic thiomethyl group of the cephem ring, the compound has a thiadiazole ring and a 5-membered condensed heterocyclic ring such as triazolothiadiazole or imidazothiadiazole ring, and 2- (2-
Aminothiazol-4-yl)-, 2- (2-amino-
5-halogenothiazol-4-yl)-or 2- (5
-Amino-1,2,4-thiadiazol-3-yl)-
A novel cephem compound or a salt or ester thereof having a chemical structure characteristic of having a 2-hydroxy (or substituted hydroxy) iminoacetamide group was synthesized for the first time, and the synthesized novel compound was unexpectedly resistant to cephalo-resistant bacteria. It was found that it has a strong antibacterial action against various bacteria including, and based on these, the present invention was completed.

That is, the present invention has the general formula [I]:

[Chemical 8] [In the formula, R ₁ represents an optionally protected amino group, Q represents a nitrogen atom or a group represented by C—R ₂ (R ₂ represents a hydrogen atom or a halogen atom), and R ₃ represents a hydrogen atom. Or a hydrocarbon group which may be substituted, and A represents an optionally substituted triazolothiadiazolyl or imidazothiadiazolyl group, respectively] or a salt or ester thereof, and production thereof The present invention relates to a method and an antibacterial composition. The cephem compound in the present specification is a group of compounds named based on “cephem” described in “The Journal of the American Chemical Society” Vol. 84, page 3400 (1962). The compound means a compound having a double bond at the 3,4-position among the cephem compounds.

In the above cephem compound [I], the substituent R ₁ represents an optionally protected amino group, that is, an amino group or a protected amino group. In the field of β-lactam and peptide synthesis, amino-protecting groups have been thoroughly studied and their protection methods have already been established, and in the present invention, those known as amino-protecting groups are appropriately adopted. sell. As the amino-protecting group,
For example, C _6-10 aryl-carbonyl group, C _1-5 alkanoyl group, C _3-5 alkenoyl group, C _6-10 arylsulfonyl group, C _1-10 alkylsulfonyl group, substituted oxycarbonyl group, carbamoyl group, thiocarbamoyl group. Base, C
_6-10 aryl-methyl group, C _6-10 aryl-methylene group, C _6-10 arylthio group, substituted silyl group, 2-C _1-8
Examples thereof include an alkoxycarbonyl group and a 1-methyl-1-ethenyl group.

Specific examples of the C _6-10 aryl-acyl group include benzoyl, naphthoyl and phthaloyl, and these aromatic rings have C _1-4 alkyl, C _1-6 alkoxy,
It may be substituted with halogen, nitro and the like. Specific examples of the substituted aryl-carbonyl group include p-toluoyl, p-tert-butylbenzoyl, p-methoxybenzoyl, p-tert-butoxybenzoyl, p-chlorobenzoyl, p-nitrobenzoyl and the like. Specific examples of the C _1-5 alkanoyl group include formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, succinicyl, glutaryl and the like, and these alkanoyl groups further include C _1-6 alkoxy, halogen, C _6-10 Aryl,
C _6-10 aryloxy, optionally substituted, such as with C _6-10 arylthio. Specific examples of the substituted alkanoyl group include monochloroacetyl, dichloroacetyl, trichloroacetyl, monobromoacetyl, monofluoroacetyl, difluoroacetyl, trifluoroacetyl, monoiodoacetyl, acetoacetyl, 3-oxobutyryl,
4-chloro-3-oxobutyryl, phenylacetyl, p
-Chlorophenylacetyl, phenoxyacetyl, p-chlorophenoxyacetyl and the like can be mentioned. Specific examples of the C _3-5 alkenoyl group include acryloyl, crotonoyl, maleoyl and the like, and these alkenoyl groups may be further substituted with C _6-10 aryl or the like. Specific examples of the substituted alkenoyl group include cinnamoyl and the like. Specific examples of the C _6-10 arylsulfonyl group include benzenesulfonyl, naphthalenesulfonyl and the like. Even if these aromatic rings are substituted with C _1-4 alkyl, C _1-6 alkoxy, halogen, nitro and the like. Good. Specific examples of the substituted arylsulfonyl group include p-toluenesulfonyl, p-tert-butylbenzenesulfonyl, p-methoxybenzenesulfonyl, p-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl and the like. Specific examples of the C _1-10 alkylsulfonyl group include methanesulfonyl, ethanesulfonyl, camphorsulfonyl, etc. These alkylsulfonyl groups are substituted with C _6-10 aryl, C _6-10 aryloxy, halogen and the like. May be. Examples of the substituted oxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, ter
C _1-8 alkoxy-carbonyl groups such as t-butoxycarbonyl and isobornyloxycarbonyl, such as C such as phenoxycarbonyl and naphthyloxycarbonyl
_6-10 aryloxy-carbonyl groups such as C _7-12 aralkyloxy-carbonyl groups such as benzyloxycarbonyl and the like. The C _1-8 alkoxy-carbonyl group may be further substituted with C _1-6 alkoxy, C _2-5 alkanoyl, substituted silyl, C _1-4 alkylsulfonyl, halogen, cyano and the like. Examples of the substituted alkoxy-carbonyl group include methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2-cyanoethoxycarbonyl. can give. C _6-10 aryloxy-carbonyl group and C _7-10
The aromatic ring of the aralkyloxy-carbonyl group may be substituted with C _1-4 alkyl, C _1-6 alkoxy, halogen, nitro and the like. Specific examples of the substituted aryloxycarbonyl group include p-methylphenoxycarbonyl, p
-Methoxyphenoxycarbonyl, p-chlorophenoxycarbonyl and the like can be mentioned. Specific examples of the substituted aralkyloxycarbonyl group include p-methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and the like. Also C _7-10
The alkyl group of the aralkyloxy-carbonyl group is C _6-10.
It may be substituted with aryl, halogen or the like, and specific examples thereof include benzhydryloxycarbonyl and the like. The carbamoyl group may be substituted. Specific examples of the substituted carbamoyl group include N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N-phenylcarbamoyl and N- (p-methoxyphenyl) carbamoyl. The thiocarbamoyl group may be similarly substituted. Specific examples of the substituted thiocarbamoyl group include N-methylthiocarbamoyl and the like. Specific examples of the C _6-10 aryl-methyl group include benzyl and naphthylmethyl, and these aromatic rings may be substituted with C _1-4 alkyl, C _1-6 alkoxy, halogen, nitro and the like. Good.
Specific examples of the substituted arylmethyl group include p-methylbenzyl, p-methoxybenzyl, p-chlorobenzyl, p-nitrobenzyl and the like. Further, the methyl group of the arylmethyl group may be substituted with another 1 to 2 C _6-10 aryl groups, specifically, benzhydryl,
Examples include trityl. Specific examples of the C _6-10 aryl-methylene group include benzylidene, and these aromatic rings may be substituted with C _1-4 alkyl, C _1-6 alkoxy, halogen, nitro and the like. Specific examples of the substituted arylmethylene group include p-methylbenzylidene and p-chlorobenzylidene. C
Specific examples of the _6-10 arylthio group include o-nitrophenylthio and the like.

The substituted silyl group is represented by the general formula R ₆ R ₇ R ₈ SiNH, (R ₆ R ₇ R ₈ Si) ₂ N or the amino group to be protected.

[Chemical 9] [Wherein R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₉ ′ and R ₁₀ ′ are each a C _1-4 alkyl group such as methyl, ethyl or tert-butyl or a C such as phenyl. _6-10 aryl groups are shown and may be the same or different.
Z'represents, for example, a C _1-3 alkylene group such as methylene or ethylene], specifically, trimethylsilyl, tert-butyldimethylsilyl, -Si (CH ₃ ) ₂ CH _{2 CH 2 Si (CH 3)} 2 - and the like. 2-C _1-8 alkoxy-carbonyl-1
Examples of the C _1-8 alkoxy group of the —methyl-1-ethenyl group include methoxy, ethoxy, tert-butoxy and the like. In the above cephem compound [I], the symbol Q represents a nitrogen atom or a group represented by C—R ₂ , and the substituent R ₂ represents a hydrogen atom or a halogen atom. Examples of the halogen atom include fluorine, chlorine, bromine and iodine, and chlorine is preferable.

In the above cephem compound [I], the substituent R ₃ represents a hydrogen atom or an optionally substituted hydrocarbon group. Examples of the hydrocarbon group include a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _3-6 cycloalkyl group, etc., and a C _1-3 alkyl group (eg methyl, ethyl, propyl etc.) or a substituted group. Particularly preferred are C _1-3 alkyl groups. Specific examples of the C _1-6 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. Specific examples of the C _2-6 alkenyl group include vinyl, allyl, isopropenyl, methallyl, 1,1-dimethylallyl,
Examples include 2-butenyl and 3-butenyl. Specific examples of the C _3-6 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Substituents for these hydrocarbon groups include, for example, hydroxyl group, C _3-6 cycloalkyl group, C _1-6 alkoxy group, C
_3-6 cycloalkyloxy group, C _6-10 aryloxy group,
C _7-12 aralkyloxy group, mercapto group, C _1-6 alkylthio group, C _3-6 cycloalkylthio group, C _6-10 arylthio group, C _7-12 aralkylthio group, amino group, mono C _1-4 alkyl Amino group, di C _1-4 alkylamino group, C _3-6 cycloalkylamino group, C _6-10 arylamino group, C _7-12 aralkylamino group, cyclic amino group, azido group, nitro group, halogen atom, Cyano group, carboxyl group, C _1-8 alkoxy-
Carbonyl group, C _6-10 aryloxy-carbonyl group, C
_3-6 cycloalkyloxy-carbonyl group, C _7-12 aralkyloxy-carbonyl group, C _6-10 aryl-acyl group,
C _1-5 alkanoyl group, C _3-5 alkenoyl group, C _6-10 aryl-acyloxy group, C _2-5 alkanoyloxy group, C
_3-5 Alkenoyloxy group, carbamoyl group, substituted carbamoyl group, thiocarbamoyl group, substituted thiocarbamoyl group, carbamoyloxy group, substituted carbamoyloxy group,
Phthalimido group, C _2-5 alkanoylamide group, C _6-10 aryl-acylamide group, C _1-4 alkoxy-carbonylamino group, C _6-10 aryloxy-carbonylamino group,
Examples thereof include C _7-12 aralkyloxy-carbonylamino group and heterocyclic group. Specifically, C _3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, C _1-6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert- butoxy and the like, C _{3- 6} cycloalkyloxy groups include cyclopropyloxy, cyclohexyloxy, C _6-10
Aryloxy groups include phenoxy, naphthyloxy, etc.
C _7-12 aralkyloxy group is benzyloxy, 2-phenylethyloxy, etc., C _1-6 alkylthio group is methylthio, ethylthio, propylthio, butylthio, etc.
C _3-6 cycloalkylthio group is cyclopropylthio, cyclohexylthio, etc., C _6-10 arylthio group is phenylthio, etc., C _7-12 aralkylthio group is benzylthio, etc. Mono C _1-4 alkylamino group is methyl Amino, ethylamino, propylamino, butylamino, etc.
_1-4 alkylamino groups include dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino, etc., C _3-6 cycloalkylamino groups include cyclopropylamino, cyclohexylamino, etc., C _6-10 arylamino groups Is anilino, etc., C _7-12 aralkylamino group is benzylamino, 2-phenylethylamino, etc., cyclic amino group is pyrrolidino, piperidino, piperazino, morpholino, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, etc. Halogen atom is fluorine, chlorine, bromine, etc., C _1-8 alkoxy-carbonyl group is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, isobornyloxycarbonyl, etc.
The C _6-10 aryloxy-carbonyl group is phenoxycarbonyl, etc., the C _3-6 cycloalkyloxy-carbonyl group is cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, etc., and the C _7-12 aralkyloxy-carbonyl group is benzyloxycarbonyl. , C
_6-10 aryl-acyl groups include benzoyl, phthaloyl, phenylacetyl, etc., C _1-5 alkanoyl groups include formyl,
Acetyl, propionyl, butyryl, valeryl, pivaloyl, etc., C _3-5 alkenoyl group is acryloyl, crotonoyl, maleoyl, etc., C _6-10 aryl-acyloxy group is benzoyloxy, etc., C _2-5 alkanoyloxy group is acetoxy, Propionyloxy, butyryloxy,
Pivaloyloxy and the like, C _3-5 alkenoyloxy group is acryloyloxy and the like, and substituted carbamoyl group is N
-Methylcarbamoyl, N, N-dimethylcarbamoyl,
N-ethylcarbamoyl, N-phenylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, morpholinocarbonyl, etc., substituted thiocarbamoyl group is N-methylthiocarbamoyl, etc., substituted carbamoyloxy group is N-methylcarbamoyl Oxy, N, N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy and the like, C _2-5 alkanoylamide group such as acetamide and propionamide, C _6-10 arylacylamide group such as benzamide, C _1-4 alkoxy - carbonyl amino group is methoxycarbonylamino, ethoxycarbonylamino, tert- butoxycarbonylamino, etc., C _6-10 aryloxy - carbonylamino group and the like phenoxycarbonylamino, C _7-12 aralkyloxy - carbonyl Amino groups such as benzyloxycarbonylamino, heterocyclic group 2-pyridyl, 3
-Pyridyl, 4-pyridyl, N-oxide-2-pyridyl, N-oxide-3-pyridyl, N-oxide-4-pyridyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, piperazinyl, 2-pyrazinyl, 2 -Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyranyl, 3-pyranyl,
4-pyranyl, 2-thiopyranyl, 3-thiopyranyl, 4
-Thiopyranyl, 3H-indol-2-yl, 3H-indol-3-yl, 1,2,3-thiadiazole-4-
Yl, 1,2,4-thiadiazol-5-yl, 1,2,4-
Thiadiazol-3-yl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1H-tetrazolyl, benzopyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl,
5-isothiazolyl, 2-pyrrolyl, 3-pyrrolyl, 2-
Pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolyl, 4
-Imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4
-A 5- to 8-membered ring containing 1 to several heteroatoms such as pyrazolyl, 5-pyrazolyl and the like (which may be oxidized), oxygen atom, sulfur atom or the like, or a fused ring thereof to a carbon atom. Are represented respectively. Further, the alkyl group constituting the aralkyl group of the above aralkyloxy group, aralkylthio group, aralkylamino group, aralkyloxycarbonyl group and aralkyloxycarbonylamino group may be substituted with another C _6-10 aryl group. Well, specific examples thereof include benzhydryloxy, benzhydrylthio, benzhydrylamino, benzhydryloxycarbonyl, and benzhydryloxycarbonylamino. The number of substituents of the above-mentioned hydrocarbon group is not limited to one and may be the same or different (2 to 4). Also included are those in which two substituents substituted at the α-position of a C _1-6 alkyl group are combined to form a heterocycle. As the substituted hydrocarbon group, a C _1-3 alkyl group substituted with a halogen atom, a hydroxyl group, an amino group, a C _1-6 alkoxy group, a carboxyl group, a C _1-6 alkoxy-carbonyl group, a cyano group or the like is more preferable. preferable. Specific examples of the substituted hydrocarbon group include methoxymethyl, 1-
Methoxyethyl, 1-ethoxyethyl, 2-hydroxyethyl, 2-aminoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, carboxymethyl, cyanomethyl, 1-carboxy-1-methylethyl, 1-carboxycyclopropyl , Methoxycarbonylmethyl, ethoxycarbonylmethyl, 1-methoxycarbonylcyclopropyl, tert-butoxycarbonylmethyl, 1-methoxycarbonyl-1-methylethyl, 1-ethoxycarbonyl-1-methylethyl, 1-tert-butoxycarbonyl-1 -Methylethyl, 1-benzyloxycarbonyl-
1-methylethyl, 1-pivaloyloxycarbonyl-
1-methylethyl, 2- (pyrazolyl) ethyl, 2- (imidazolyl) ethyl, 2- (2-oxopyrrolidin-3-yl) ethyl, 2-amino-4- or 5-thiazolylmethyl, 5-amino-1, 2,4-thiadiadiazole-3-
Examples thereof include ylmethyl, 1-carboxy-1- (2,3,4-trihydroxyphenyl) methyl, 2-oxo-3-pyrrolidyl, and many others. R ₃ is particularly preferably a hydrogen atom or a C _1-6 alkyl group such as methyl or ethyl. Further, in the present specification, all OR ₃ groups are in syn coordination (Z coordination).

In the above-mentioned cephem compound [I], the substituent A represents an optionally substituted triazolothiadiazolyl group or imidazothiadiazolyl group. The triazolothiadiazolyl ring constituting the triazolothiadiazolyl group is specifically

[Chemical 10] Can be given. Specifically, the imidazothiadiazole ring that constitutes the imidazothiadiazolyl group is

[Chemical 11] Can be given. Substituent A is a group having a bond at any carbon atom of the above condensed ring. Further, a hydrogen atom on a carbon atom other than the carbon atom having a bond of the condensed ring group (A) may be substituted with another substituent.

Such substituents include, for example, hydroxyl group, C _1-4 hydroxyalkyl group, C _1-6 alkyl group, C _2-6
Alkenyl group, C _2-6 alkynyl group, C _4-6 alkadienyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkenyl group,
C _3-6 cycloalkyl-C _1-6 alkyl group, C _6-10 aryl group, C _7-12 aralkyl group, heterocyclic group, C _1-6 alkoxy group, C _1-6 alkoxy-C _1-4 alkyl group Group, C _3-6 cycloalkyloxy group, C _6-10 aryloxy group, C _7-12 aralkyloxy group, mercapto group, C _1-4 mercaptoalkyl group, sulfo group, C _1-4 sulfoalkyl group, C _1-6 alkylthio group, C _1-6 alkylthio-C _1-4 alkyl group, C _3-6 cycloalkylthio group, C _6-10 arylthio group, C _7-12 aralkylthio group, C _2-4 cyanoalkylthio group, Amino group, C
_1-4 aminoalkyl group, mono C _1-4 alkylamino group, di C
_1-4 alkylamino group, mono C _1-4 alkylamino-C _1-4
Alkyl group, di-C _1-4 alkylamino-C _1-4 alkyl group,
C _3-6 cycloalkylamino group, C _6-10 arylamino group, C _7-12 aralkylamino group, cyclic amino group, cyclic amino-C _1-4 alkyl group, cyclic amino-C _1-4 alkylamino group, Azido group, nitro group, halogen atom, C _1-4 halogenoalkyl group, cyano group, cyano-C _1-4 alkyl group, carboxyl group, carboxy-C _1-4 alkyl group, C _1-8 alkoxy-carbonyl group, C _1-8 alkoxy-carbonyl-C
_1-4 alkyl group, C _6-10 aryloxy-carbonyl group,
C _3-6 cycloalkyloxy-carbonyl group, C _7-12 aralkyloxy-carbonyl group, C _6-10 aryl-carbonyl group, C _1-5 alkanoyl group, C _2-5 alkanoyl-C
_1-4 alkyl group, C _3-5 alkenoyl group, C _6-10 aryl-
Acyloxy group, C _2-5 alkanoyloxy group, C _2-5 alkanoyloxy-C _1-4 alkyl group, C _3-5 alkenoyloxy group, carbamoyl group, carbamoyl-C _1-4 alkyl group, substituted carbamoyl group, Thiocarbamoyl group, substituted thiocarbamoyl group, carbamoyloxy group, carbamoyloxy-C _1-4 alkyl group, substituted carbamoyloxy group,
Phthalimide group, C _2-5 alkanoylamide group, C _6-10 aryl-acylamide group, sulfonamide group, 2-amino-2-carboxyethyl group, C _1-4 alkoxy-carbonylamino group, C _6-10 aryloxy group _{-Carbonylamino} group, C _7-12 aralkyloxy-carbonylamino group and the like. Specifically, the C _1-4 hydroxyalkyl group is hydroxymethyl, 2-hydroxyethyl, etc., and the C _1-6 alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
Pentyl, hexyl, etc., C _2-6 alkenyl groups are vinyl, allyl, isopropenyl, methallyl, 1,1-dimethylallyl, 1-butenyl, 2-butenyl, 3-butenyl, etc., C _2-6 alkynyl groups are Ethynyl, 1-propynyl, 2
-Propynyl, propargyl, etc., C _4-6 alkadienyl group is 1,3-butadienyl, etc., C _3-6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl etc., C _3-6 cycloalkenyl group is 1
-Cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1,4-cyclohexadienyl, etc. are added to C _3-6 cycloalkyl-C _1-6 Alkyl groups include cyclopentylmethyl, cyclohexylmethyl, C
_6-10 aryl groups include phenyl and naphthyl, C _7-12 aralkyl groups include benzyl and phenethyl, and heterocyclic groups include 2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxide-2-pyridyl, N -Oxide-3-pyridyl, N-oxide-4-pyridyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, piperazinyl, 2-pyrazinyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyranyl,
3-pyranyl, 4-pyranyl, 2-thiopyranyl, 3-thiopyranyl, 4-thiopyranyl, 3H-indole-2-
Yl, 3H-indol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,3, 4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, benzopyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 4-oxazolyl,
5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5
-Thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolyl, 2-imidazolyl 1,4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl and other nitrogen atoms (which may be oxidized), oxygen atoms, sulfur atoms and other heteroatoms A 5- to 8-membered ring containing several rings or a condensed ring thereof having a bond at a carbon atom, a C _1-6 alkoxy group is methoxy,
Ethoxy, propoxy, isopropoxy, butoxy, tert-
Butoxy etc., C _1-6 alkoxy-C _1-4 alkyl groups such as methoxymethyl, ethoxymethyl, 2-methoxyethyl etc. C _3-6 cycloalkyloxy groups such as cyclopropyloxy, cyclohexyloxy etc., C _{6- 10} Aryloxy group is phenoxy, naphthyloxy, etc., C _7-12 aralkyloxy group is benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, etc., C _1-4 mercaptoalkyl group is mercaptomethyl, 2- Mercaptoethyl etc., C _1-4 sulfoalkyl group is sulfomethyl,
2-sulfoethyl, etc., C _1-6 alkylthio group is methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc., C _1-6 alkylthio-C _1-4 alkyl group is methylthiomethyl, 2-methylthioethyl, etc.,
_3-6 cycloalkylthio groups include cyclopropylthio and cyclohexylthio, C _6-10 arylthio groups include phenylthio, C _7-12 aralkylthio groups include benzylthio, and C _1-4 cyanoalkylthio groups include cyanomethylthio,
Cyanoethylthio and the like, C _1-4 aminoalkyl groups such as aminomethyl and 2-aminoethyl, mono C _1-4 alkylamino groups such as methylamino, ethylamino, propylamino and butylamino, and di C _{1- 4} alkylamino groups include dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino, etc., and mono-C _1-4 alkylamino-C _1-4 alkyl groups include methylaminomethyl, ethylaminomethyl, 2- (N -Methylamino) ethyl, 3-
(N-methylamino) propyl and the like, di C _1-4 alkylamino-C _1-4 alkyl group is N, N-dimethylaminomethyl, N, N-diethylaminomethyl, 2- (N, N-dimethylamino) Ethyl, 2- (N, N-diethylamino) ethyl,
3- (N, N-dimethylamino) propyl and the like, C _3-6 cycloalkylamino groups such as cyclopropylamino and cyclohexylamino, C _6-10 arylamino groups such as anilino and N-methylanilino, and C _{7 -12} aralkylamino groups are benzylamino, 1-phenylethylamino, 2
-Phenylethylamino and the like, cyclic amino groups such as pyrrolidino, piperidino, piperazino, morpholino and 1-pyrrolyl, and cyclic amino C _1-4 alkyl groups such as pyrrolidinomethyl, piperidinomethyl, piperazinomethyl, morpholinomethyl,
2- (morpholino) ethyl, 1-imidazolylmethyl, 1-
Imidazolylethyl, etc., cyclic amino C _1-4 alkylamino groups such as pyrrolidinomethylamino, piperidinomethylamino, piperazinomethylamino, morpholinomethylamino, halogen atoms such as fluorine, chlorine, bromine, C
_1-4 halogenoalkyl groups are monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2
-Fluoroethyl, monochloromethyl, dichloromethyl,
Trichloromethyl, 1-chloroethyl, 2-chloroethyl, bromomethyl, iodomethyl, etc. were added to cyano-C _1-4
Alkyl groups include cyanomethyl, 2-cyanoethyl, etc.
Carboxy-C _1-4 alkyl group is carboxymethyl, 1-
Carboxyethyl, 2-carboxyethyl, etc. can be _converted into C _1-8
The alkoxy-carbonyl group is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, isobornyloxycarbonyl, etc., and the C _1-8 alkoxy-carbonyl-C _1-4 alkyl group is methoxy. Carbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, etc., C _6-10 aryloxy-carbonyl group such as phenoxycarbonyl, C _3-6 cycloalkyloxy-carbonyl group such as cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, etc. The C _7-12 aralkyloxy-carbonyl group is benzyloxycarbonyl and the like, the C _6-10 aryl-carbonyl group is benzoyl, phthaloyl, phenylacetyl and the like,
The C _1-5 alkanoyl group is formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, etc., and the C _2-5 alkanoyl-C _1-4 alkyl group is acetylmethyl, 1-acetylethyl, 2-acetylethyl, etc. _3-5 Alkenoyl groups include acryloyl, crotonoyl, maleoyl, etc.
The C _6-10 aryl-acyloxy group is benzoyloxy and the like, the C _2-5 alkanoyloxy group is acetoxy, propionyloxy, butyryloxy, pivaloyloxy and the like, and the C _2-5 alkanoyloxy-C _1-4 alkyl group is acetoxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, etc., a C _3-5 alkenoyloxy group is acryloyloxy, etc., a carbamoyl-C _1-4 alkyl group is carbamoylmethyl, etc., and a substituted carbamoyl group is N-methylcarbamoyl, N. , N-dimethylcarbamoyl, N-ethylcarbamoyl, N, N-diethylcarbamoyl, N-
Phenylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, morpholinocarbonyl, etc., carbamoyloxy-C _1-4 alkyl group is carbamoyloxymethyl, etc., substituted thiocarbamoyl group is N-methylthiocarbamoyl, etc., substituted carbamoyloxy group, etc. Is N-
Methylcarbamoyloxy, N, N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy and the like are used as C _2-5
The alkanoylamide group is acetamide, propionamide, etc., the C _6-10 aryl-acylamide group is benzamide, etc., and the C _1-4 alkoxy-carbonylamino group is methoxycarbonylamino, ethoxycarbonylamino,
tert-butoxycarbonylamino and the like, the C _6-10 aryloxy-carbonylamino group represents phenoxycarbonylamino and the like, and the C _7-12 aralkyloxy-carbonylamino group represents benzyloxycarbonylamino and the like. The above C _7-12 aralkyl group, C _7-12 aralkyloxy group, C _7-12 aralkylthio group, C _7-12 aralkylamino group, C _7-12 aralkyloxy-carbonyl group and C _7-12 aralkyloxy group -The alkyl group constituting the aralkyl group such as a carbonylamino group may be substituted with another C _6-10 aryl group, and specific examples thereof include benzhydryl, benzhydryloxy, benzhydrylthio, and benzhydryl. Amino, benzhydryloxycarbonyl,
Examples include benzhydryloxycarbonylamino.

The above substituents are the same or different and are 1-2.
It may be replaced individually. A is a lower alkyl group (eg, C _1-6 alkyl group such as methyl or ethyl), a lower alkoxycarbonyl group (eg, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, etc.), a carbamoyl group or Carbamoyl-lower alkyl group (eg, carbamoylmethyl etc. carbamoyl-C _1-6
Triazolothiazolyl (especially s-triazolo [3,4-b]) which may be substituted with an alkyl group etc.)
[1,3,4] Thiadiazol-6-yl is preferred)
Alternatively, an imidazothiadiazolyl (in particular, imidazo [2,1-b] [1,3,4] thiadiazol-2-yl) group is preferable.

The cephem compound [I] may be a salt or an ester. Among the salts of the compound [I], a pharmaceutically acceptable salt is a salt used when the compound [I] is used as an antibacterial agent. And other salts are salts that can be used as synthetic intermediates. Examples of the salt of the compound [I] include inorganic base salts, ammonium salts, organic base salts, inorganic acid addition salts, organic acid addition salts, basic amino acid salts and the like. Inorganic bases that can form inorganic base salts include alkali metals (such as sodium and potassium) and alkaline earth metals (such as calcium), and organic bases that can form organic base salts include procaine and 2-phenyl. Ethylbenzylamine, dibenzylethylenediamine,
Ethanolamine, diethanolamine, trishydroxymethylaminomethane, polyhydroxyalkylamine,
N-methylglucosamine, 1,1,1-tris (hydroxymethyl) methylamine and the like are inorganic acids capable of forming an inorganic acid addition salt such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Examples of the organic acid capable of forming an organic acid addition salt include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid, succinic acid, and ethylsuccinic acid, which are basic acids capable of forming a basic amino acid salt. Examples of amino acids include lysine, arginine, ornithine and histidine. Of these salts, base salts (that is, inorganic base salts, ammonium salts, organic base salts, basic amino acid salts) are base salts that can be formed at the 4-position carboxyl group of compound [I] or substitution of compound [I] A base salt that can be formed when an acidic group such as a carboxyl group or a sulfo group is present in the group R ₃ or on the substituent A. An acid addition salt (that is, an inorganic acid addition salt, an organic acid addition salt) is a compound Amino group, monoalkylamino group, dialkylamino group, cycloalkylamino group, arylamino group, aralkylamino group, cyclic amino group, nitrogen-containing heterocyclic group or the like in the substituent R ₃ of [I] or on the substituent A Means an acid addition salt which can be formed when a basic group of is present.

The ester derivative of the compound [I] means an ester which can be produced by esterifying a carboxyl group contained in the molecule, especially a carboxyl group at the 4-position, and an ester which can be used as a synthetic intermediate and a metabolically active ester. An unstable, non-toxic ester. As the ester that can be used as a synthetic intermediate, C _1-4 alkyl ester, C _2-4 alkenyl ester, C _3-6 cycloalkyl ester, C _3-6 cycloalkyl-C _1-4 alkyl ester, C
Examples thereof include _6-10 aryl ester, C _7-12 aralkyl ester, and substituted silyl ester, which may be further substituted. Specific examples of alkyl forming a C _1-4 alkyl ester include methyl, ethyl, propyl, butyl and tert-butyl, and examples of alkenyl forming a C _2-4 alkenyl ester include vinyl, allyl,
Examples of cycloalkyl such as isopropenyl which forms a C _3-6 cycloalkyl ester include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like which form a C _3-6 cycloalkyl-C _1-4 alkyl ester. Specific examples of alkyl include cyclopropylmethyl, cyclohexylmethyl, etc., specific examples of aryl forming a C _6-10 aryl ester include phenyl, and specific examples of aralkyl forming C _7-12 aralkyl ester. Benzyl, phenethyl, etc.
Specific examples of the substituted silyl forming the substituted silyl ester include trimethylsilyl and tert-butyldimethylsilyl. The alkyl constituting the aralkyl ester may be substituted with another 1 to 2 C _6-10 aryl, and specifically, benzhydryl ester,
Examples include trityl ester.

The non-toxic metabolically unstable ester means an orally administrable ester, and such an ester which is already established in the field of penicillin and cephalosporin is conveniently used in the present invention. Can be adopted.
Such metabolically unstable non-toxic esters include, for example, C _1-5 alkanoyloxymethyl ester, C _1-5
Alkanoyloxyethyl ester, C _1-6 alkoxy-
C _1-4 alkyl ester, C _1-6 alkylthio-C _1-4 alkyl ester, 1- (C _1-6 alkoxycarbonyloxy)
_Examples thereof include C _1-6 alkyl ester, and specific examples thereof include acetoxymethyl ester, 1-acetoxyethyl ester, 1-acetoxybutyl ester, 2-acetoxyethyl ester, pivaloyloxymethyl ester, methoxymethyl ester, ethoxymethyl. Ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, methylthiomethyl ester, ethylthiomethyl ester, ethoxycarbonyloxymethyl ester, 1- (ethoxycarbonyloxy) ethyl ester, tert-butoxycarbonyloxymethyl ester Ester, 1- (tert-butoxycarbonyloxy) ethyl ester, 1-{(2-methyl-2-methoxypropionyloxy) carbonyloxy} ethyl ester, 1- (cyclohexyloxycarbonyloxy) ethyl Ester, and the like. The present invention includes, in addition to the above ester derivative, a pharmaceutically acceptable compound which can be converted into the compound [I] in vivo.

The compound [I] of the present invention has broad-spectrum antibacterial activity, and can be used in humans and mammals (eg, mouse,
It can be used for the prevention and treatment of various diseases caused by pathogenic bacteria in rats, rabbits, dogs, cats, cows, pigs, etc., such as respiratory tract infection and urinary tract infection. The features of the antibacterial spectrum of the compound [I] are as follows. (1) High activity against various Gram-negative bacteria. (2) It has high activity against Gram-positive bacteria (eg Staphylococcus aureus, Corynebacterium diphtheriae, etc.). (3) Many β-lactamase-producing Gram-negative bacteria (e.g., Escherichia, Enterobacter, Serratia,
It also has high activity against Proteus and the like).
In addition, the compound [I] of the present invention has characteristics such as excellent stability, high blood concentration, long duration of effect, and remarkable tissue transferability.

The method for producing the cephem compound [I], its salt or ester of the present invention is described in detail below. The compound [I] can be produced, for example, by the following three methods (1) to (3). (1) General formula

[Chemical 12] [Wherein the symbols have the same meanings as defined above] and a cephem compound or a salt or ester thereof and a general formula

[Chemical 13] [Wherein the symbols in the formula have the same meanings as described above] or by reacting with a carboxylic acid or a salt or reactive derivative thereof,

[Chemical 14] [Wherein R ₁₁ represents a hydroxyl group, an acyloxy group, a carbamoyloxy group, a substituted carbamoyloxy group or a halogen atom, and other symbols have the same meanings as those defined above] and a salt or ester thereof and a general formula ASH By reacting with a thiol compound represented by the formula [wherein A has the same meaning as defined above] or a salt thereof, or

(3) General formula

[Chemical 15] [The symbols in the formula have the same meanings as described above] and a cephem compound or a salt or ester thereof and the general formula R ₃ ′ OH [wherein, R ₃ ′ represents an optionally substituted hydrocarbon group] The compound [I] can be produced by reacting with the compound represented by or a reactive derivative thereof and then removing the protecting group if necessary. In addition, the compound [I] in which Q is a C—R ₂ group can also be produced by the following production method (4). (4) General formula

[Chemical 16] [In the formula, X represents a halogen atom or a group represented by R ₆ SO ₂ O (R ₆ represents a lower alkyl group or an optionally substituted phenyl group), and other symbols have the same meanings as above] After reacting the cephem compound represented by or a salt or ester thereof with a compound represented by the general formula R ₁ C (═S) NH ₂ [wherein R ₁ has the same meaning as defined above], if necessary, Compound [I] can be produced by removing the protecting group. Manufacturing method (1) ~ (4),
The protecting group removing method and the compound [I] purification method will be sequentially described.

Manufacturing method (1):

[Chemical 17] In this method, 7-amino compound [II] is converted to carboxylic acid [III]
Alternatively, it is a method of acylating with a reactive derivative thereof. In this method, the carboxylic acid [III] remains free or its salt or reactive derivative is a 7-amino compound [I].
I] used as an acylating agent for the amino group at the 7-position. That is, free acid [III] or an inorganic salt of free acid [III],
Organic salt, acid halide, acid azide, acid anhydride, mixed acid anhydride,
Reactive derivatives such as active amides, active esters, and active thioesters are subjected to acylation reaction. As inorganic salts, alkali metal salts (for example, sodium salt, potassium salt, etc.),
Alkaline earth metal salts (such as calcium salts) are organic salts such as trimethylamine salt, triethylamine salt, tert-butyldimethylamine salt, dibenzylmethylamine salt, benzyldimethylamine salt, N, N.
− Dimethylaniline salt, pyridine salt, quinoline salt, etc.
Examples of the acid halide include acid chloride and acid bromide, and examples of the mixed acid anhydride include mono C _1-4 alkyl carbonic acid mixed acid anhydride (for example, free acid [III] and monomethyl carbonic acid, monoethyl carbonic acid, monoisopropyl carbonic acid, monoisobutyl). Carbonic acid, mono-tert-butyl carbonic acid, monobenzyl carbonic acid, mono (p-nitrobenzyl) carbonic acid, mixed acid anhydride with monoallyl carbonic acid, etc., C _1-6 aliphatic carboxylic acid mixed acid anhydride (eg free acid [III ] And acetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid, acetoacetic acid, etc.), C _7-11 aromatic carvone Acid mixed acid anhydrides (e.g. mixed acid anhydrides of free acid [III] with benzoic acid, p-toluic acid, p-chlorobenzoic acid, etc.), organic sulfonic acid mixed acid anhydrides (e.g. methanesulfonic acid, ethanesulfone) Acid, benzenesulfonic acid, mixed acid anhydride with p-toluenesulfonic acid, etc.) and the like as an active amide with an amide with a nitrogen-containing heterocyclic compound (for example, free acid [III] and pyrazole, imidazole, benzotriazole, etc.). Acid amide of
These nitrogen-containing heterocyclic compounds may be substituted with C _1-4 alkyl, C _1-6 alkoxy, halogen atom, oxo, thioxo, C _1-6 alkylthio, etc.).

As active esters, β-lactams and all those used for this purpose in the field of peptide synthesis are available, for example organic phosphates (eg diethoxyphosphates, diphenoxyphosphates) and p-nitro. Phenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 6-chloro-1-
Examples thereof include hydroxybenzotriazole ester and 1-hydroxy-1H-2-pyridone ester. As the active thioester, an ester with an aromatic heterocyclic thiol compound (for example, 2-pyridylthiol ester, 2
-Benzothiazolyl thiol ester and the like, and these heterocycles may be substituted with C _1-4 alkyl, C _1-6 alkoxy, halogen atom, C _1-6 alkylthio and the like). On the other hand, the 7-amino compound [II] is used as its salt or ester while remaining free. Examples of the salt of the compound [II] include inorganic base salts, ammonium salts, organic base salts, inorganic acid addition salts, organic acid addition salts and the like. Inorganic base salts include alkali metal salts (for example, sodium salt, potassium salt, etc.), alkaline earth metal salts (for example, calcium salt, etc.), and organic base salts include, for example, trimethylamine salt, triethylamine salt, tert-butyldimethylamine salt. , Dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt, pyridine salt, quinoline salt and the like, and inorganic acid addition salts include, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphorus Acid salts,
Examples of organic acid addition salts include formate, acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate and the like. As the ester of the compound [II], the ester already described as the ester derivative of the compound [I] can be directly used here. That is, C _1-4 alkyl ester, C _2-4 alkenyl ester, C _3-6 cycloalkyl ester, C _3-6 cycloalkyl-C _1-4 alkyl ester, C _6-10 aryl ester, C _7-12 aralkyl ester , C _1-5 alkanoyloxymethyl ester, C _1-5 alkanoyloxyethyl ester and these further include hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, cyano group, mercapto group, C _1-6 alkylthio group, Examples include those substituted with an oxo group, a thioxo group, and the like.

The raw material [II] salts and esters thereof, and the raw material [III] and reactive derivatives thereof can be easily produced by known methods or methods analogous thereto. The reactive derivative of the compound [III] can be reacted with the compound [II] as a substance isolated from the reaction mixture or as it is, the reaction mixture containing the reactive derivative of the compound [III] before isolation. Carboxylic acid [III]
When is used as a free acid or salt, a suitable condensing agent is used. Examples of the condensing agent include N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide, azolides such as N, N'-carbonyldiimidazole, such as N-ethoxycarbonyl-2-ethoxy-1, Dehydrating agents such as 2-dihydroquinoline, phosphorus oxychloride, and alkoxyacetylene, such as 2
2-Halogenopyridinium salts such as -chloropyridinium methyl iodide and 2-fluoropyridinium methyl iodide are used. When these condensing agents are used, the reaction is considered to proceed via the reactive derivative of carboxylic acid [III].

The reaction is generally carried out in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, and ethylene glycol dimethyl ether, esters such as ethyl formate, ethyl acetate, butyl acetate, such as dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride, trichlene and 1,2-dichloroethane, such as hydrocarbons such as n-hexane, benzene and toluene, such as formamide,
Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide, sulfolane, Hexamethylphosphoramide, water, etc. are used alone or as a mixed solvent. The amount of the acylating agent [III] used is usually 1 to 5 mol, preferably 1 to 1 mol, relative to 1 mol of the compound [II].
2 mol. The reaction is -80 to 80 ° C, preferably -4
It is carried out in a temperature range of 0 to 50 ° C, most preferably -30 to 30 ° C. The reaction time depends on the kinds of the compounds [II] and [III], the kind of the solvent (the mixing ratio in the case of a mixed solvent), the reaction temperature, etc., and is usually 1 minute to 72 hours, preferably 1 minute.
5 minutes to 3 hours. When an acid halide is used as the acylating agent, the reaction can be carried out in the presence of a deoxidizing agent for the purpose of removing released hydrogen halide from the reaction system.
Examples of such deoxidizing agents include inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine,
Pyridine, lutidine, γ-collidine, N, N-dimethylaniline, N-methylpiperzine, N-methylpyrrolidine, N
And tertiary amines such as methylmorpholine, and alkylene oxides such as propylene oxide and epichlorohydrin.

Manufacturing method (2):

[Chemical 18] This method uses thiol compound A for cephem compound [IV]
In this method, SH is reacted and a cephem compound [I] is synthesized by a nucleophilic substitution reaction. R in compound [IV]
₁₁ represents a hydroxyl group, an acyloxy group, a carbamoyloxy group, a substituted carbamoyloxy group or a halogen atom. Here, the acyloxy group represents an optionally substituted C _2-5 alkanoyloxy group or a C _6-10 aryl-acyloxy group, and the optionally substituted C _2-5 alkanoyloxy group is specifically Acetoxy, chloroacetoxy, propionyloxy, butyryloxy, pivaloyloxy, 3-oxobutyryloxy, 4-chloro-3-
Oxobutyryloxy, 3-carboxypropionyloxy, 4-carboxybutyryloxy, 3-ethoxycarbamoylpropionyloxy and the like are specifically substituted C _6-10 aryl-acyloxy groups, specifically o-carboxy Examples thereof include benzoyloxy, o- (ethoxycarbonylcarbamoyl) benzoyloxy and o- (ethoxycarbonylsulfamoyl) benzoyloxy. Specific examples of the substituted carbamoyloxy group include methylcarbamoyloxy and N, N-dimethylcarbamoyloxy. Chlorine as a halogen atom,
Examples include bromine and iodine. The compound [IV] is used as its salt or ester as it is. As the salt and ester of the compound [IV], those mentioned as the salt and ester of the compound [II] in the production method (1) can be directly applied here. Compound [IV], its salt and ester, and thiol compound ASH or its salt can be easily produced by a method known per se or a method analogous thereto. The thiol compound ASH is also used as a salt. Examples of the salt of the thiol compound ASH include alkali metal salts (eg sodium salt, potassium salt, etc.),
Examples thereof include alkaline earth metal salts (eg calcium salt).

This nucleophilic substitution reaction of compound [IV] with thiol compound ASH or a salt thereof is a reaction which is well known in itself and is usually carried out in a solvent. As the solvent used in this reaction, solvents such as ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles and water used in the production method (1) can be directly applied. However, in addition to these, alcohols such as methanol, ethanol, propanol, isopropanol, ethylene glycol, and 2-methoxyethanol are also used. (2-1): When R ₁₁ is an acyloxy group, a carbamoyloxy group or a substituted carbamoyloxy group A more preferable solvent is water or a mixed solvent of water and an organic solvent which can be mixed with water. Out of
More preferred are acetone, methyl ethyl ketone, acetonitrile and the like. The amount of the thiol compound ASH or a salt thereof used is usually 1 to 5 per 1 mol of the compound [IV].
Mol, preferably 1 to 3 mol. Reaction is 10-10
It is carried out in a temperature range of 0 ° C, preferably 30 to 80 ° C. The reaction time depends on the kind of compound [IV] and compound ASH, kind of solvent (mixing ratio in the case of mixed solvent), reaction temperature, etc., and is usually 10 minutes to 5 days, preferably 15 minutes to 5 hours . The reaction is advantageously carried out at pH 2-8, preferably near neutral, ie pH 5-8.

(2-2): When R ₁₁ is a hydroxyl group It is carried out in the presence of an organic phosphorus compound in the same manner as described in, for example, Japanese Patent Laid-Open Publication No. 58-43979.
Examples of the organic phosphorus compound used here include o-
Phenylene phosphorochloride, o-phenylene phosphorofluoride, methyl o-phenylene phosphate, ethyl o-phenylene phosphate, propyl o-phenylene phosphate, isopropyl o-phenylene phosphate, butyl o-phenylene phosphate, Isobutyl o-phenylene phosphate, scc-butyl o-
Phenylene phosphate, cyclohexyl o-phenylene phosphate, phenyl o-phenylene phosphate, p-chlorophenyl o-phenylene phosphate, p
-Acetylphenyl o-phenylene phosphate, 2-
Chloroethyl o-phenylene phosphate, 2,2,2-
Trichloroethyl o-phenylene phosphate, ethoxycarbonylmethyl o-phenylene phosphate, carbamoylmethyl o-phenylene phosphate, 2-cyanoethyl o-phenylene phosphate, 2-methylsulfonylethyl o-phenylene phosphate, benzyl
o-Phenylene phosphate, 1,1-dimethyl-2-propenyl o-phenylene phosphate, 2-propenyl
o-Phenylene phosphate, 3-methyl-2-butenyl
o-Phenylene phosphate, 2-thienylmethyl o
-Phenylene phosphate, 2-furfurylmethyl o-
Phenylene phosphate, bis-o-phenylene pyrophosphate, 2-phenyl-1,3,2-benzodioxaphosphole-2-oxide, 2- (p-chlorophenyl)-
1,3,2-benzodioxaphosphole-2-oxide,
2-Butyl-1,3,2-benzodioxaphosphole-2
-Oxide, 2-anilino-1,3,2-benzodioxaphosphole-2-oxide, 2-phenylthio-1,3,
2-Benzodioxaphosphole-2-oxide, 2-methoxy-5-methyl-1,3,2-benzodioxaphosphole-2-oxide, 2-chloro-5-ethoxycarbonyl-1,3,2 -Benzodioxaphosphole-2-oxide, 2-methoxy-5-ethoxycarbonyl-1,3,
2-benzodioxaphosphole-2-oxide, 5-ethoxycarbonyl-2-phenyl-1,3,2-benzodioxaphosphole-2-oxide, 2,5-dichloro-
1,3,2-benzodioxaphosphole-2-oxide,
4-chloro-2-methoxy-1,3,2-benzodioxaphosphole-2-oxide, 2-methoxy-4-methyl-1,3,2-benzodioxaphosphole-2-oxide, 2, 3-naphthalene methyl phosphate, 5,6-dimethyl-2-methoxy-1,3,2-benzodioxaphosphole-2-oxide, 2,2-dihydro-4,5,6,7-
Tetrachloro-2,2,2-trimethoxy-1,3,2-benzodioxaphosphole, 2,2-dihydro-4,5,6,
7-tetrachloro-2,2,2-triphenoxy-1,3,
2-benzodioxaphosphole, 2,2-dihydro-2,
2-ethylenedioxy-2-methoxy-1,3,2-benzodioxaphosphole, 2,2-dihydro-2-benzyl-2,2-dimethoxy-1,3,2-benzodioxaphosphole, 2,2-dihydro-4,5-benzo-2,2,2-
Trimethoxy-1,3,2-benzodioxaphosphole,
2,2-dihydro-2,2,2-triphenoxy-1,3,
2-benzodioxaphosphole, 2,2-dihydro-2,
2- (o-phenylenedioxy) -2-phenoxy-1,
3,2-benzodioxaphosphole, 2-chloro-2,2
-Dihydro-2,2- (o-phenylenedioxy) -1,3,
2-benzodioxaphosphole, 2,2-dihydro-2-
Methoxy-2,2- (o-phenylenedioxy) -1,3,2
-Benzodioxaphosphole, 2,2-dihydro-2,2,
2-trichloro-1,3,2-benzodioxaphosphole, 9,10-phenanthrene dioxytrimethoxyphosphorus, o-phenylene phosphorochloridide, o-phenylene phosphorobromidide, o-phenylene phosphoro Fluoride, methyl o-phenylene phosphite, butyl
o-phenylene phosphite, methoxycarbonylmethyl o-phenylene phosphite, phenyl o-phenylene phosphite, p-chloro (or p-nitro) phenyl o-phenylene phosphite, 2-phenyl-1,3,
2-benzodioxaphosphole, bis-o-phenylenepyrophosphite, 2-methoxy-5-methyl-1,3,2
-Benzodioxaphosphole, 5-acetyl-2-phenoxy-1,3,2-benzodioxaphosphole, 9,10
-Phenanthrene phosphorochloridite, 2-chloro-
4-methyl-1,3,2-benzodioxaphosphole, 5
-Ethoxycarbonyl-2-phenyl-1,3,2-benzodioxaphosphole, 2-chloro-2-thioxo-1,
3,2-benzodioxaphosphole, 2-phenoxy-2
-Oxo-1,3,2-benzodiazaphosphole, 2-phenoxy-1,3,2-benzooxaazaphosphole, 2,
3-dihydro-2-oxo-2-methoxy-4,5-dimethyl-1,3,2-dioxaphosphole, 2,2-dihydro-2-oxo-2-chloro-4,5-dimethyl-1 ,
3,2-dioxaphosphole, 2,2-dihydro-2-oxo-2- (1-imidazolyl) -4,5-dimethyl-1,
3,2-dioxaphosphole, 2,2-dihydro-2,2-
Ethylenedioxy-2-methoxy-4,5-dimethyl-
1,3,2-dioxaphosphole, 2,2-dihydro-2,
2-dimethoxy-2-phenoxy-4,5-dimethyl-
1,3,2-dioxaphosphole, 2,2-dihydro-2,
2,2-Trimethoxy-4,5-dimethyl-1,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-triphenoxy-4,5-dimethyl-1,3,2- Dioxaphosphole, 2,2-dihydro-2,2,2-triethoxy-
4,5-diphenyl-1,3,2-dioxaphosphole,
2,2-dihydro-2,2,2-trimethoxy-4,5-diphenyl-1,3,2-dioxaphosphole, 2,2-dihydro-2-oxo-2-methoxy-4,5-diphenyl -1,3,2-dioxaphosphole, 2,2-dihydro-
2,2,2-trimethoxy-1,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-trimethoxy-4-phenyl-1,3,2-dioxaphosphole, 2, 2-dihydro-2,2,2-trimethoxy-4-methyl-1,3,2-
Dioxaphosphole, 2,2-dihydro-2,2,2-trimethoxy-4-methyl-5-phenylcarbamoyl-
1,3,2-dioxaphosphole, 2,2,4,5,6,7-hexahydro-2,2,2-trimethoxy-1,3,2-benzodioxaphosphole, 2,2'- Oxybis (4,5-dimethyl-2,2-dihydro-1,3,2-dioxaphosphole), 2,2'-oxybis (4,5-dimethyl-2,2-
Dihydro-1,3,2-dioxaphosphole-2-oxide) and the like.

The solvent used in the reaction may be any solvent as long as it does not inhibit the reaction, and preferably the above-mentioned ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles or the like alone or Used as a mixed solvent. Especially, for example, dichloromethane, acetonitrile, formamide, a mixed solvent of formamide and acetonitrile, a mixed solvent of dichloromethane and acetonitrile, and the like can be used to obtain a favorable effect. Thiol compound A
The amount of SH or a salt thereof and the organic phosphorus compound used is 1 to 5 mol and 1 to 1 mol, respectively, relative to 1 mol of the compound [IV].
It is 0 mol, more preferably 1 to 3 mol and 1 to 6 mol, respectively. The reaction is -80 to 50 ° C, preferably -40 to 4
It is carried out in the temperature range of 0 ° C. Reaction time is usually 30 minutes
It is 40 hours, preferably 1 to 20 hours. An organic base may be added to the reaction system. Examples of such organic bases include amines such as triethylamine, tributylamine, dibutylamine, diisobutylamine, dicyclohexylamine, and 2,6-lutidine. The addition amount of the base is preferably 1 to 5 mol per 1 mol of the compound [IV].

(2-3): When R ₁₁ is a halogen atom Preferred solvents are the above ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, alcohols and water. And so on. Thiol compound ASH
Alternatively, the amount of the salt used is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound [IV]. Reaction is 0
It is carried out in a temperature range of -80 ° C, preferably 20-60 ° C. The reaction time is usually 30 minutes to 15 hours, preferably 1
~ 5 hours. The reaction can be carried out in the presence of a dehalogenating agent to accelerate the reaction. As such a dehalogenating agent, the deoxidizing agents such as the inorganic bases, tertiary amines and alkylene oxides described in the section of the production method (1) can be mentioned here. The halogen atom represented by R ₁₁ is chlorine, bromine, iodine or the like, preferably iodine. The compound [IV] in which R ₁₁ is iodine is disclosed in, for example, Japanese Patent Laid-Open Publication No.
It can be easily produced by the method described in 58-57390 or a method analogous thereto.

Manufacturing method (3):

[Chemical 19] This method is a method for synthesizing a compound [I] by reacting a compound represented by the general formula R ₃ ′ OH or a reactive derivative thereof with a hydroxyimino compound [V], which is a well-known etherification reaction. is there. R ₃ ′ represents an optionally substituted hydrocarbon group, and as such a hydrocarbon group, those already mentioned as the optionally substituted hydrocarbon group for R ₃ can be directly applied here.
R ₃ ′ OH is used as it is or as a reactive derivative thereof. The reactive derivative of R ₃ ′ OH means a derivative of R ₃ ′ OH having a group capable of leaving together with the hydrogen atom of the compound [V], that is, a compound represented by the general formula R ₃ ′ Y. Here, the group Y which is split off together with the hydrogen atom is a halogen atom, a sulfo group, a mono-substituted sulfonyloxy group or the like. Examples of the halogen atom include chlorine, bromine and iodine. Examples of the mono-substituted sulfonyloxy group include C _1-4 alkylsulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, C _6-10 arylsulfonyloxy groups, and the like. In addition, in the case of producing a C _1-4 alkyl ether form of the compound [V], in addition to the above-mentioned reactive derivative, a C _1-4 diazoalkane such as diazomethane or diazoethane, or a diester such as dimethylsulfate or diethylsulfate. C _1-4 alkyl sulfuric acid and the like are also used.

[0029] (3-1): R ₃ 'when using the OH suitable dehydrating agent is reacted with the compound (V) with the synthesis of the compounds [I]. Examples of the dehydrating agent used for such purpose include phosphorus oxychloride, thionyl chloride, dialkyl azodicarboxylate (usually used in the coexistence with phosphine), N, N'-dicyclohexylcarbodiimide, and the like. Is diethyl azodicarboxylate in the presence of triphenylphosphine. The reaction using diethyl azodicarboxylate in the presence of triphenylphosphine is usually carried out in an anhydrous solvent, and the above ethers, hydrocarbons and the like are used. R ₃ ′ OH, diethyl azodicarboxylate, and triphenylphosphine are all used in an amount of 1 to 1.5 mol with respect to 1 mol of the compound [V].
It takes 1 hour to 4 days in a temperature range of 0 to 50 ° C. (3-2): When R ₃ ′ Y is used The reaction between R ₃ ′ Y and compound [V] is an ordinary etherification reaction and is carried out in a solvent. Manufacturing method as solvent
Ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitriles, which are mentioned in the section (1),
Solvents such as alcohols and water, or mixed solvents are also mentioned here, and a mixed solvent of water-miscible solvent and water (for example, water-containing methanol, water-containing ethanol, water-containing acetone, water-containing dimethyl sulfoxide, etc.) is preferable. This reaction can also be allowed to proceed smoothly in the presence of a suitable base. Examples of such a base include sodium carbonate,
Examples thereof include alkali metal salts such as sodium hydrogen carbonate and potassium carbonate, and inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Further, this reaction may be carried out in a buffer solution having a pH of 7.5 to 8.5.
Starting compound (V) 1 each reagent R ₃ 'number of moles of Y and bases used for the molar 1～5,1～10, preferably each 1～3,1～5. The reaction temperature is -30 to
The temperature is 100 ° C, preferably 0 to 80 ° C. The reaction time is 10 minutes to 15 hours, preferably 30 minutes to 5 hours.

(3-3): When using C _1-4 diazoalkane The reaction is usually carried out in a solvent. As the solvent, the above-mentioned ethers and hydrocarbons are used. After the compound [V] is dissolved in a solvent, a solution of a diazoalkane compound is added, and the reaction proceeds. The reagent is used in an amount of 1-10 mol, preferably 1-5 mol, per 1 mol of compound [V]. The reaction is carried out in the temperature range of -50 to 80 ° C, preferably -30 to 30 ° C. The reaction time is 1 minute to 5 hours, preferably 10 minutes to 1 hour. (3-4): When using di-C _1-4 alkyl sulfuric acid The reaction is usually carried out in water or a mixed solvent of water and a water-miscible solvent. As the mixed solvent, the water-containing solvent mentioned in the item (3-2) can be mentioned here. This reaction is carried out in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. The reagent is 0.5 to 10 mol, preferably 1 to 2 with respect to 1 mol of the compound [V].
Use mol. The reaction temperature is 20 to 100 ° C, preferably 50
The range is up to 100 ° C. The reaction time is 10 minutes to 5 hours, preferably 30 minutes to 3 hours.

Manufacturing method (4):

[Chemical 20] This method uses a cephem compound [VI] and a general formula R ₁ C (= S) NH ₂
And thiourea or thiourea derivatives represented in reacted is a method for synthesizing the desired compound [I] _{(Q = C-R 2)} . The compound [VI] is used as a salt or an ester in a free state. X in the compound [VI] represents a halogen atom or a group represented by R ₆ SO ₂ O. Here, the halogen atom represents, for example, chlorine, bromine, iodine or the like. R ₆ represents a lower alkyl group or an optionally substituted phenyl group. Examples of the lower alkyl group include C _1-4 alkyl groups such as methyl, ethyl and propyl. Examples of the substituted phenyl group include p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, p
-Nitrophenyl and the like. As the salt of [VI], the salt of the compound [II] (inorganic base salt, ammonium salt, organic base salt, inorganic acid addition salt, organic acid addition salt, etc.) mentioned in the production method (1) is also applied here. To be As the ester of [VI], the compound [II] mentioned in the section of the production method (1) is also used.
Ester of (C _1-4 alkyl ester, C _2-4 alkenyl ester, C _3-6 cycloalkyl ester, C _3-6 cycloalkyl-C _1-4 alkyl ester, C _6-10 aryl ester, C _7-12 Aralkyl esters, C _1-5 alkanoyloxymethyl esters, C _1-5 alkanoyloxyethyl esters and their further substitutions) also apply here. The starting compound [VI] has the general formula

[Chemical 21] A compound represented by the formula [wherein the symbols have the same meaning as defined above] or a reactive derivative thereof and the 7-amino compound [II] or a salt or ester thereof are prepared by the process (1)
It can be manufactured using a method similar to the method described in. General formula

[Chemical formula 22] The compound represented by or a reactive derivative thereof can be easily produced by a method known per se or a method analogous thereto. The reaction between compound [VI] and R ₁ C (═S) NH ₂ is usually carried out in a solvent. Examples of the solvent include ethers such as dioxane, tetrahydrofuran and diethyl ether, alcohols such as methanol, ethanol and propanol, and amides such as dimethylformamide and dimethylacetamide. The amount of thiourea or its derivative R ₁ C (═S) NH ₂ used is usually 1 to 5 mol, preferably 1 to 3 mol, based on the compound [VI]. The reaction is carried out in the temperature range of 0 to 100 ° C, preferably 20 to 60 ° C. The reaction time is usually 30 minutes to 15 hours, preferably 1 to 5 hours. Manufacturing method (1) above
In (4), the compound [I] is syn [Z]-, anti [E]
-May be obtained as a mixture of isomers. A method known per se or a method analogous thereto is applied to separate the desired syn isomer from the mixture. Examples of these methods include a fractionation method utilizing a difference in solubility and crystallinity, a separation by chromatography, a separation method utilizing a difference in hydrolysis rate of ester derivatives, and the like.

Protective group removal method: As mentioned above, in the field of β-lactam and peptide synthesis, the protective group of amino group has been thoroughly studied and its protective method has already been established.
Also, a method for removing an amino protecting group is similarly established,
Also in the present invention, the conventional technique can be used as it is for the removal of the protecting group. For example, a monohalogenoacetyl group (chloroacetyl, bromoacetyl, etc.) is thiourea, an alkoxycarbonyl group (methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.) is an acid (hydrochloric acid, etc.), and an aralkyloxycarbonyl group (benzyloxy). Carbonyl, p-methylbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.) can be removed by catalytic reduction, and 2,2,2-trichloroethoxycarbonyl can be removed by zinc and an acid (eg acetic acid, etc.). On the other hand, when the compound [I] is esterified as a synthetic intermediate, the ester residue can be removed by a method known per se or a method analogous thereto. For example, 2-methylsulfonylethyl ester is treated with an alkali to give an aralkyl ester (benzyl ester,
p-methoxybenzyl ester, p-nitrobenzyl ester, etc.) is an acid (eg, trifluoroacetic acid, etc.) or catalytic reduction, and 2,2,2-trichloroethyl ester is a silyl ester with zinc and an acid (eg, acetic acid, etc.).
(Trimethylsilyl ester, tert-butyldimethylsilyl ester, etc.) can be removed only with water.

Purification method of compound [I]: Compound produced in the reaction mixture by various production methods detailed in (1) to (4) and, if necessary, the above protecting group removal method [I] can be isolated and purified by a known treatment means such as an extraction method, a column chromatography, a precipitation method and a recrystallization method. On the other hand, the isolated compound [I] can be converted into a desired pharmaceutically acceptable salt or metabolically unstable nontoxic ester by a known method. The sulfoxide of the cephem compound [I] can be obtained by the oxidation reaction of the compound [I]. Such an oxidation reaction is a well-known reaction. Suitable oxidizing agents for the oxidation of the sulfur atom in the cephem ring include, for example, oxygen, peracid, hydroperoxide, hydrogen peroxide, etc. Peracid should be produced in situ by mixing the acid and peroxide. You can also Peracetic acid, perbenzoic acid, p-chloroperbenzoic acid and the like are frequently used as the peracid. The reaction is usually performed in a solvent. Examples of the solvent used in this reaction include ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, chloroform and chlorobenzene,
For example, organic acids such as formic acid, acetic acid, trifluoroacetic acid,
Examples include amides such as dimethylformamide and dimethylacetamide. The reaction temperature is -20 to
It is carried out in the range of 80 ° C, but at a temperature as low as possible, preferably at -20 to 20 ° C. It is generally known that sulfoxide having S-configuration is mainly produced during the oxidation of the compound of the formula [I]. R- and S-
Sulfoxides are separated by their different solubilities and different migration rates during chromatographic separations. The above oxidation reaction to obtain the sulfoxide is as described above.
It may be performed before the reaction of (1) ~ (4), or (1) ~ (4)
You may carry out after the reaction of.

[0034]

The compound [I] of the present invention can be administered parenterally or orally as injections, capsules, tablets and granules as well as known penicillins and cephalosporins. The dose is 0.5 to 80 mg / kg, preferably 1 to 20 per kg body weight of humans and animals infected with the above-mentioned pathogenic bacteria.
The dose may be divided into 2 to 4 times a day for administration. When used as an injection, for example, distilled water, physiological saline, etc. are used, and when used as capsules, powders, granules, tablets, known pharmaceutically acceptable excipients (for example, Starch, lactose, sucrose, calcium carbonate,
Calcium phosphate, etc. Used as a mixture. A pharmaceutical composition containing compound [I] or a salt / ester thereof can be produced by a known method. The composition is usually produced by mixing at least one compound [I] or a pharmaceutically acceptable salt or ester thereof with the above-mentioned carrier, excipient and the like. The compounding ratio of the compound [I] to the whole composition is usually 5 to 100% by weight, preferably 20 to 100% by weight in solid preparations such as capsules, tablets and granules, and 5 to 100% by weight in liquid preparations such as injections. ~ 30% by weight. The compound [I] or a salt / ester thereof is used for treating urinary tract infection caused by Escherichia coli by administering it as an injection. In this case, the dose is 0.5 to 80 mg / day, more preferably 1 to 20 mg / day, per 1 kg of human and animal body weight, and the dose is divided into 2 to 4 times a day. The injection can be easily produced, for example, by dissolving or suspending the compound [I] or a salt or ester thereof in physiological saline.

[0035]

EXAMPLES The present invention will be further described in detail with reference to the following Reference Examples and Examples. However, these examples are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. You may change it. Elution by column chromatography in Reference Examples and Examples was carried out by TLC (Thin Layer C
hromatography, thin layer chromatography). In the TLC observation, the Kieselgel 60F ₂₅₄ Merck (Merck) manufactured as a TLC plate,
As a developing solvent, a solvent used as an elution solvent in column chromatography was used, and as a detection method, a UV detector was adopted. As the silica gel for the column, Kieselgel 60 (230 to 400 mesh) also manufactured by Merck was used. ″
"Sephadex" is manufactured by Pharmacia Fine Chemicals. Hyporus polymer is DIAION CHP-20P manufactured by Mitsubishi Kasei.
Was used. The NMR spectra are Varian EM-390 using tetramethylsilane as internal or external reference.
Measured with a (200 MHz) type spectrometer, total δ
Values are given in ppm. In the mixed solvent, the value shown in parentheses is the volume mixing ratio of each solvent. In addition,% in the solution represents the number of g in 100 ml of the solution. The symbols in Reference Examples and Examples have the following meanings. s: singlet d: doublet t: triplet q: quartet ABq: AB type quartet dd: double doublet m: matillet br. : Broad J: Coupling constant Hz: Herz mg: Milligram g: Gram ml: Milliliter l: Liter%: Percentage DMSO: dimethylsulfoxide D ₂ O: heavy water CDCl ₃ : heavy chloroform Room temperature: 25 ° C

Test Example 1 Test compound minimum inhibitory concentration (MIC)
cpncentration is agar dilution method
determined by d). That is, 1.0 ml of the diluted test compound aqueous solution was poured into a petri dish,
Next, trypticase soy agar
9.0 ml of agar) was poured and mixed. A suspension of the test bacteria (about 10 ⁶ CFU / ml) was smeared on the mixed agar plate. After overnight incubation at 37 ° C, the minimum concentration of the test compound that completely inhibits the growth of the test strain was determined to be MIC.
And Test bacteria (1) Staphylococcus aureus 308 A-1 (2) Escherichia coli NIHJ JC-2 ( Escherichia coli NIHJ JC-2) (3) Haemophilus influenza NN-400 ( Haemophilus influenzae NN) -400) result

[Table 1] From the above results, it is clear that the cephem compound [I] of the present invention or a salt or ester thereof exhibits a well-balanced and excellent antibacterial action against representative strains of pathogenic bacteria which are clinically important. .

Reference Example 1 Imidazo [2,1-b] [1,3,4] thiadiazole-2-thiol 1) bromoacetaldehyde dimethyl acetal (2
5 ml), 48% hydrobromic acid (15 ml), H ₂ O (15 m)
The mixture of l) was heated at 100 ° C. for 2 hours. After cooling, dimethoxyethane (100 ml) was added and the mixture was neutralized with sodium hydrogen carbonate. The insoluble material was filtered off, and the filtrate was treated with 2-amino-5-methylthio-1,3,4-thiadiazole (12.5 g),
Dimethoxyethane (200 ml) was added and the mixture was heated under reflux for 4 hours. The solvent was evaporated, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated solution of NaCl dried (MgSO _4). The solvent was evaporated, the residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2: 1). Concentrate the relevant fractions to 2
-Methylthioimidazo [2,1-b] [1,3,4] thiadiazole was obtained as crystals (3.2 g, 22.0).
%). Recrystallization from isopropyl ether gave white crystals. mp. 87-88 ° C. NMR (CDCl ₃ ): 2.74 (3H, s), 7.26 (1H, d, J = 1.4Hz),
7.68 (1H, d, J = 1.4Hz). Elemental analysis value: Calculated value as C ₅ H ₅ N ₃ S ₂ (%): C, 35.07; H, 2.94; N, 24.54 Measured value (%): C, 35.02; H, 3.03; N, 24.72 2) 2-methylthioimidazo [2,1-b] [1,
3,4] Thiadiazole (1.37g) in acetic acid (24m
l) Concentrated sulfuric acid (1.6 ml) was added to the solution. Then 30%
Hydrogen peroxide solution (6.0 ml) was added under ice-cooling, and the mixture was allowed to stand at room temperature for 16
Stir for hours. The reaction solution was adjusted to pH 3 with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with dichloromethane. Extract aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate solution, washed and dried with a saturated solution of NaCl (MgSO ₄₎
did. The solvent was distilled off to give 2-methylsulfonylimidazo [2,1-b] [1,3,4] thiadiazole as crystals (1.34 g, 83%). Recrystallization from methanol gave colorless crystals. mp. 133-137 ° C. NMR (CDCl ₃ ): 3.42 (3H, s), 7.50 (1H, s), 7.89 (1H,
s). Elemental analysis value: calculated as C ₅ H ₅ N ₃ O ₂ S ₂ (%): C, 29.55; H, 2.48; N, 20.67 actual value (%): C, 29.52; H, 2.46: N , 20.40 3) Methyl 3-mercaptopropionate (1.1 ml)
28% sodium methylate (3.1 ml of methanol solution) was added to a methanol (40 ml) solution of the above, and then 2-methylsulfonylimidazo [2,1-b] [1,3,4].
Thiadiazole (1.0 g) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was adjusted to pH 4 with 2N HCl and the solvent was evaporated to give the title compound as crystals. It was collected by filtration and washed with H ₂ O and then with isopropyl ether (0.71 g, 91
%). Recrystallization from methanol gave white crystals. m
p. 260 ° C (decomposition). NMR (DMSO-d ₆ ): 7.68 (1H, d, J = 2.2Hz), 8.01 (1H, d, J
= 2.2Hz). Elemental analysis value: Calculated value as C ₄ H ₃ N ₃ S ₂ (%): C, 30.56; H, 1.92; N, 26.73 Measured value (%): C, 30.76; H, 1.90: N ， 26.86

Reference Example 2 6-Methylimidazo [2,1-b] [1,3,4] thiadiazole-2-thiol 1) 2-amino-5-methylthio-1,3,4-thiadiazole (1.73 g) ), Bromoacetone (1.01)
A mixture of (ml) and ethanol (25 ml) was heated under reflux for 5 hours. The solvent was distilled off, saturated aqueous sodium hydrogen carbonate solution was added, and 6-methyl-2-methylthioimidazo [2,1-
b] [1,3,4] thiadiazole was obtained as crystals.
It was collected by filtration and washed with H ₂ O (1.20 g, 55%). Recrystallization from isopropyl ether gave white crystals. mp. 7
2-73 ° C. NMR (CDCl ₃ ): 2.34 (3H, d, J = 1.0Hz), 2.72 (3H, s),
7.41 (1H, d, J = 1.0Hz). Elemental analysis value: Calculated value as C ₆ H ₇ N ₃ S ₂ (%): C, 38.90; H, 3.81; N, 22.68 Measured value (%): C, 39.08; H, 3.74: N, 22.70 2) 6-Methyl-2-methylthioimidazo [2,1-b] [1,3,4] thiadiazole to 6-methyl-2 in the same manner as in Reference Example 1-2). -Methylsulfonylimidazo [2,1-b] [1,3,4] thiadiazole was obtained. Yield 69%, mp. 165-166 ° C (ethyl acetate). NMR (CDCl ₃ ): 2.42 (3H, s), 3.39 (3H, s), 7.62 (1H,
s). Elemental analysis value: calculated as C ₆ H ₇ N ₃ O ₂ S ₂ (%): C, 33.17; H, 3.25; N, 19.34 measured value (%): C, 33.02; H, 3.42: N , 13.13 3) 6-Methyl-2-methylsulfonylimidazo [2,1-b] [1,3,4] in the same manner as in Reference Example 1-3).
Thiadiazole to 6-methylimidazo [2,1-b]
[1,3,4] Thiadiazole-2-thiol was obtained.
Yield 87%, mp. 255 ° C (decomposition, methanol). _{NMR (DMSO-d 6):} 2.31 (3H, s), 7.7
6 (1H, s). Elemental analysis value: Calculated value as C ₅ H ₅ N ₃ S ₂ (%): C, 35.07; H, 2.94; N, 24.54 Actual value (%): C, 35.38; H, 3.20: N, 24.54

Reference Example 3 Ethyl 2-mercaptoimidazo [2,1-b] [1,
3,4] Thiadiazole-6-carboxylate 1) A mixture of 5-amino-2-methylthio-1,3,4-thiadiazole (14.7 g), ethyl bromopyruvate (25 ml) and ethanol (250 ml) for 40 hours. Heated to reflux. The solvent was distilled off, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated solution of NaCl dried (MgSO _4). The solvent was evaporated, the residue was subjected to silica gel column chromatography, and eluted with dichloromethane-methanol (100: 1). The relevant fractions were concentrated to give ethyl 2-methylthioimidazo [2,1-b] [1,3,4] thiadiazole-
6-carboxylate was obtained as crystals. Recrystallization from isopropyl ether gave white crystals (5.3 g, 2
2%). mp. 130 ° C. _{NMR (CDCl 3): 1.42 (} 3H, t, J = 7.2Hz), 2.77 (3H, s),
4.41 (2H, q, J = 7.2Hz), 8.25 (1H, s). Elemental analysis value: Calculated value as C ₈ H ₉ N ₃ O ₂ S ₂ (%): C, 39.49; H, 3.73; N, 17.27 Found (%): C, 39.38; H, 3.74: N, 17.32.

2) In the same manner as in Reference Example 1-2), ethyl 2-methylthioimidazo [2,1-b] [1,3,3]
4] Thiadiazole-6-carboxylate to ethyl 2-methylsulfonylimidazo [2,1-b] [1,
3,4] thiadiazole-6-carboxylate was obtained as white crystals. Yield 82%, mp. 130 ° C (methanol). NMR (CDCl ₃ ): 1.44 (3H, t, J = 7.1H
z), 3.45 (3H, s), 4.45 (2H,
q, J = 7.1 Hz), 8.46 (1H, s). Elemental analysis value: Calculated as C ₈ H ₉ N ₃ O ₄ S ₂ (%): C, 34.90; H, 3.30; N, 15.26 Actual value (%): C, 34.70; H, 3.00: N, 15.35 3 ) Ethyl 2-methylsulfonylimidazo [2,1
-B] [1,3,4] thiadiazole-6-carboxylate (1.44 g), sodium hydrosulfide (70%,
0.72 g), tetramethylammonium chloride (1.0 g), ethanol (35 ml), tetrahydrofuran (35 ml) was heated under reflux for 8 hours, and sodium hydrosulfide (70%, 0.12 g) was added, and further. The mixture was heated under reflux for 15 hours. The reaction mixture was adjusted to pH 3 with 1N HCl and the solvent was evaporated to give the title compound as crystals. It was collected by filtration and washed successively with H ₂ O, ethanol and isopropyl ether (1.07 g, 89%). Recrystallization from methanol gave white crystals. mp. 240 ° C (decomposition). NMR (DMSO-d ₆ ): 1.30 (3H, t, J = 7.0Hz), 4.30 (2H, q, J
= 7.0Hz), 8.47 (1H, s). Elemental analysis value: Calculated value as C ₇ H ₇ N ₃ O ₂ S ₂ (%): C, 36.67; H, 3.08; N, 18.33 Measured value (%): C, 36.71; H, 2.95: N, 18.55.

Reference Example 4 Ammonium 6-carbamoylimidazo [2,1-
b] [1,3,4] thiadiazole-2-thiolate ethyl 2-mercaptoimidazo [2,1-b] [1,
3,4] thiadiazole-6-carboxylate (30
A mixture of 0 mg) and 25% aqueous ammonia (8 ml) was heated in a sealed tube at 60 ° C for 1 hour. The solvent was distilled off to obtain the title compound as crystals. It was collected by filtration, washed with ethanol and then with ether (220 mg, 78%). Recrystallization from methanol gave white crystals. mp. 275 ° C (decomposition). NMR (DMSO-d ₆ ): 7.09 (5H, br), 7.30 (1H, brs), 7.87
(1H, s). Elemental analysis value: calculated as C ₅ H ₄ N ₄ OS ₂ · NH ₃ (%): C, 27.64; H, 3.25; N, 32.23 measured value (%): C, 27.70; H , 3.26: N, 31.9
7

Reference Example 5 2-Mercaptoimidazo [2,1-b] [1,3,4]
Thiadiazole-6-acetamide 1) 5-amino-2-methylthio-1,3,4-thiadiazole (10.3 g), methyl 4-bromoacetoacetate (19.5 g), methanol (100 ml), dimethoxyethane (100 ml) The mixture was heated to reflux for 37 hours. The solvent was evaporated, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated solution of NaCl dried (MgSO _4). The solvent was evaporated, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1). The corresponding fractions were concentrated to give methyl 2-methylthioimidazo [2,1-b] [1,
3,4] thiadiazole-6-acetate was obtained as crystals. Then, it was recrystallized from isopropyl ether to give brown crystals (6.6 g, 39%). mp. 85-88
° C. NMR (CDCl ₃ ): 2.73 (3H, s), 3.74 (5H, s), 7.64 (1H,
s). Elemental analysis value: Calculated value as C ₈ H ₉ N ₃ O ₂ S ₂ (%): C, 39.49; H, 3.73; N, 17.27 Actual value (%): C, 39.55; H, 3.96: N , 17.26 2) Methyl 2-methylthioimidazo [2,1-b]
[1,3,4] thiadiazole-6-acetate (4.
To a solution of 0 g) in dichloromethane (50 ml) was added m-chloroperbenzoic acid (4.18 g) under ice cooling. 1 under ice cooling
Filtered off time agitation insolubles, the filtrate an aqueous solution of sodium thiosulfate and saturated aqueous sodium bicarbonate solution, washed and dried with a saturated solution of NaCl (MgSO _4). The solvent was distilled off, and methyl 2-methylsulfinylimidazo [2,1-
b] [1,3,4] thiadiazole-6-acetate was obtained as crystals (3.97 g, 93%). Ethyl acetate-
Recrystallization from isopropyl ether gave white crystals. m
p. 116-118 ° C. NMR (CDCl ₃ ): 3.10 (3H, s), 3.76 (3H, s), 3.80 (2H,
s), 7.79 (1H, s). Elemental analysis value: Calculated as C ₈ H ₉ N ₃ O ₃ S ₂ (%): C, 37.06; H, 3.50; N, 16.20 Measured value (%): C, 37.11; H, 3.61: N, 16.0
8

3) Methyl 2-methylsulfinylimidazo [2,1-b] in the same manner as in Reference Example 3-3).
[1,3,4] Thiadiazole-6-acetate to methyl 2-mercaptoimidazo [2,1-b] [1,
3,4] thiadiazole-6-acetate was obtained as light brown crystals. Yield 59%, mp. 230 ° C (decomposition). _{NMR (DMSO-d 6):} 3.67 (3H, s), 3.89 (2H, s),
7.88 (1H, s). Elemental analysis value: Calculated value as C ₇ H ₇ N ₃ O ₂ S ₂ (%): C, 36.67; H, 3.08; N, 18.33 Measured value (%): C, 36.33; H , 3.16: N, 18.39 4) Methyl 2-mercaptoimidazo [2,1-b]
[1,3,4] Thiadiazole-6-acetate (57
A mixture of 2 mg) and 25% aqueous ammonia (18 ml) was heated in a sealed tube at 60 ° C for 1.5 hours. The solvent was distilled off, the residue was dissolved in aqueous sodium hydrogen carbonate solution, and the pH was adjusted to 1 NHCl.
It was adjusted to 2 to give the title compound as crystals (494 mg, 9
2%). mp. 240 ° C (decomposition). NMR (DMSO-d ₆ ): 3.58 (2H, s), 7.23 (1H, br), 7.59 (1
H, br), 7.82 (1H, s).

Example 1 7β- [2- (2-aminothiazol-4-yl) -2
(Z) -Methoxyiminoacetamide] -3- [imidazo [2,1-b] [1,3,4] thiadiazole-2-
Il] thiomethyl-3-cephem-4-carboxylic acid sodium salt

[Chemical formula 23] 7β- [2- (2-aminothiazol-4-yl) -2
(Z) -Methoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylic acid sodium salt (435 mg), imidazo [2,1-b] [1,3,4]
Ethyl o-phenylene phosphate (EPPA, 1.0 g) was added dropwise to a solution of thiadiazole-2-thiol (196 mg) in dimethylformamide (20 ml) under ice cooling. After stirring at room temperature for 20 hours, isopropyl ether was added. The supernatant was removed and the same operation was repeated. The residue was dissolved in an aqueous sodium hydrogen carbonate solution and subjected to DIAION CHP-20P column chromatography, and eluted with 20% ethanol. The desired fraction was concentrated and freeze-dried to obtain the title compound (265 mg, 46 mg).
%). IR _max ^KBr cm ⁻¹ : 3425, 1765, 1600. NMR (DMSO-d ₆ ): 3.30 (1H, d, J = 17.6Hz), 3.63 (1H, d,
J = 17.6Hz), 3.84 (3H, s), 4.35 (1H, d, J = 12.8Hz), 4.51 (1
H, d, J = 12.8Hz), 5.02 (1H, d, J = 4.8Hz), 5.59 (1H, dd, J = 8.
0 and 4.8Hz), 6.74 (1H, s), 7.23 (2H, brs), 7.26 (1H, d, J =
1.4Hz), 8.09 (1H, d , J = 1.4Hz), 9.57 (1H, d, J = 8.0Hz) Elemental _{analysis:. C 18 H 15 N 8} O 5 S 4 Na · 2.5H calculated as ₂ O Value (%): C, 34.89; H, 3.25; N, 18.08 Actual value (%): C, 35.29; H, 3.49: N, 17.87

Example 2 In the same manner as in Example 1, 7β- [2- (2-aminothiazol-4-yl) -2 (Z) -methoxyiminoacetamido] -3- [6-methylimidazo [2,1] -B]
[1,3,4] Thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid sodium salt was obtained.

[Chemical formula 24] IR _max ^KBr cm ⁻¹ : 3420, 1760, 1605. NMR (DMSO-d ₆ ): 2.23 (3H, s), 3.34 (1H, d, J = 17.6H
z), 3.61 (1H, d, J = 17.6Hz), 3.83 (3H, s), 4.30 (1H, d, J = 1
2.8Hz), 4.48 (1H, d, J = 12.8Hz), 4.99 (1H, d, J = 4.8Hz),
5.57 (1H, dd, J = 8.0 and 4.8Hz), 6.73 (1H, s), 7.22 (2H, s),
7.80 (1H, s), 9.54 (1H, d, J = 8.0Hz). Elemental analysis value: C ₁₉ H ₁₇ N ₈ O ₅ S ₄ Na ・ 2.0H ₂ O calculated value (%): C, 36.53; H, 3.39; N, 17.94 Found (%): C, 36.85; H, 3.61: N, 17.91

Example 3 7β- [2- (2-Aminothiazol-4-yl) -2 (Z) -methoxyiminoacetamido] -3- [6-carbamoylimidazo [2,1] was prepared in the same manner as in Example 1. −
b] [1,3,4] thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid sodium salt was obtained.

[Chemical 25] IR _max ^KBr cm ⁻¹ : 3430, 1760, 1660. NMR (DMSO-d ₆ ): 3.40 (1H, d, J = 17.2Hz), 3.65 (1H, d,
J = 17.2Hz), 3.84 (3H, s), 4.33 (1H, d, J = 12.8Hz), 4.53 (1
H, d, J = 12.8Hz), 5.03 (1H, d, J = 4.8Hz), 5.62 (1H, dd, J = 8.
0 and 4.8Hz), 6.74 (1H, s), 7.23 (1H, brs), 7.36 (1H, brs),
7.53 (1H, brs), 8.48 (1H, s), 9.57 (1H, d, J = 8.0Hz). Elemental analysis value: Calculated value as C ₁₉ H ₁₆ N ₉ O ₆ S ₄ Na ・ 2.0H ₂ O ( %): C, 34.91; H, 3.08; N, 19.28 Actual value (%): C, 34.96; H, 2.81: N, 19.21

Example 4 7β- [2- (2-aminothiazol-4-yl) -2
(Z) -Hydroxyiminoacetamide] -3- [imidazo [2,1-b] [1,3,4] thiadiazole-2
-Yl] thiomethyl-3-cephem-4-carboxylic acid sodium salt

[Chemical formula 26] 7β- [2- (2-aminothiazol-4-yl) -2
(Z) -Triphenylmethoxyiminoacetamide]-
3-Hydroxymethyl-3-cephem-4-carboxylic acid sodium salt (663 mg), imidazo [2,1-b]
[1,3,4] Thiadiazole-2-thiol (196
E) to dimethylformamide (DMF, 8 ml) solution of
PPA (1.0 g) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 18 hr. Isopropyl ether was added to the reaction mixture, and the mixture was stirred well and the supernatant was removed. The same operation was repeated, 90% formic acid (30 ml) was added to the residue, and the mixture was stirred at room temperature for 1 hr, and the solvent was evaporated. An aqueous solution of sodium hydrogen carbonate was added to the residue, and the insoluble material was filtered off. The filtrate was subjected to Diaion CHP-20P column chromatography 1
It was eluted with 0% ethanol, concentrated and freeze-dried. The resulting powder was dissolved in H ₂ O, after elution with subjected to Sephadex LH-20 column chromatography H ₂ O, to give the title compound freeze-dried (210mg, 38%). IR _max ^KBr cm ⁻¹ : 3430, 1765, 1620. NMR (DMSO-d ₆ ): 3.37 (1H, d, J = 17.2Hz), 3.62 (1H, d,
J = 17.2Hz), 4.33 (1H, d, J = 12.4Hz), 4.53 (1H, d, J = 12.4H
z), 5.01 (1H, d, J = 4.8Hz), 5.61 (1H, dd, J = 8.0 and 4.8Hz),
6.64 (1H, s), 7.14 (2H, brs), 7.25 (1H, d, J = 1.4Hz), 8.09
(1H, d, J = 1.4Hz), 9.45 (1H, d, J = 8.0Hz), 11.41 (1H, s). Elemental analysis: C ₁₇ H ₁₃ N ₈ O ₅ S ₄ Na ・ 2.5H ₂ O Calculated value (%): C, 33.71; H, 3.00; N, 18.50 Measured value (%): C, 33.97; H, 2.94: N, 18.68

Example 5 In the same manner as in Example 4, 7β- [2- (2-aminothiazol-4-yl) -2 (Z) -hydroxyiminoacetamido] -3- [6-ethoxycarbonylimidazo [2,2] 1-b] [1,3,4] thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid sodium salt was obtained.

[Chemical 27] NMR (DMSO-d ₆ ): 1.29 (3H, t, J = 7.0Hz), 3.36 (1H, d, J
= 17.2Hz), 3.61 (1H, d, J = 17.2Hz), 4.27 (2H, q, J = 7.0Hz),
4.34 (1H, d, J = 13.0Hz), 4.55 (1H, d, J = 13.0Hz), 5.01 (1
H, d, J = 5.0Hz), 5.60 (1H, dd, J = 8.2 and 5.0Hz), 6.64 (1H,
s), 7.13 (2H, brs), 8.72 (1H, s), 9.41 (1H, d, J = 8.2Hz),
. 11.33 (IH, s) Elemental _{analysis: C 20 H 17 N 8 O} 7 S 4 Na · 3.0H 2 O Calculated (%): C, 34.98; H, 3.38; N, 16.32 Found (%) : C, 34.86; H, 3.21: N, 16.49

Example 6 7β- [2- (2-Aminothiazol-4-yl) -2 (Z) -hydroxyiminoacetamido] -3- [6-carbamoylimidazo [2,1] was prepared in the same manner as in Example 4. −
b] [1,3,4] thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid sodium salt was obtained.

[Chemical 28] IR _max ^KBr cm ⁻¹ : 3430, 1760, 1610. NMR (DMSO-d ₆ ): 3.36 (1H, d, J = 18.0Hz), 3.61 (1H, d, J = 1)
8.0Hz), 4.34 (1H, d, J = 12.6Hz), 4.54 (1H, d, J = 12.6Hz),
5.01 (1H, d, J = 4.8Hz), 5.61 (1H, dd, J = 8.3 and 4.8Hz), 6.67
(1H, s), 7.14 (2H, brs), 7.36 (1H, brs), 7.54 (1H, brs),
8.48 (1H, s), 8.40-8.90 (1H, brs), 11.37 (1H, br). Elemental analysis: C ₁₈ H ₁₄ N ₉ O ₆ S ₄ Na ・ 4.0H ₂ O Calculated (%): C, 32.00; H, 3.28; N, 18.66 Found (%): C, 31.86; H, 2.93: N, 18.72

Example 7 In the same manner as in Example 4, 7β- [2- (2-aminothiazol-4-yl) -2 (Z) -hydroxyiminoacetamido] -3- [6-carbamoylmethylimidazo [2,2] 1-b] [1,3,4] thiadiazol-2-yl] thiomethyl-3-cephem-4-carboxylic acid sodium salt was obtained.

[Chemical 29] IR _max ^KBr cm ⁻¹ : 3420, 1765, 1665, 1600. NMR (DMSO-d ₆ ): 3.35 (1H, d, J = 17.2Hz), 3.40 (2H,
s), 3.61 (1H, d, J = 17.2Hz), 4.32 (1H, d, J = 14.0Hz), 4.51
(1H, d, J = 14.0Hz), 5.01 (1H, d, J = 4.8Hz), 5.61 (1H, dd, J =
8.2 and 4.8Hz), 6.65 (1H, s), 6.96 (1H, brs), 7.14 (2H, br
s), 7.34 (1H, brs), 7.88 (1H, s), 9.43 (1H, d, J = 8.2Hz),
11.38 (1H, s). Elemental analysis value: Calculated as C ₁₉ H ₁₆ N ₉ O ₆ S ₄ Na.3.0H ₂ O (%): C, 33.98; H, 3.30; N, 18.77 Measured value (%) : C, 34.09; H, 3.11: N, 19.00

Example 8 In the same manner as in Example 1, 7β- [2- (2-aminothiazol-4-yl) -2 (Z) -methoxyiminoacetamido] -3- [3-methyl-s-triazolo [ 3,4-
b] [1,3,4] thiadiazol-6-yl] thiomethyl-3-cephem-4-carboxylic acid sodium salt was obtained.

[Chemical 30] IR _max ^KBr cm ⁻¹ : 3400, 1760, 1665, 1600. NMR (DMSO-d ₆ ): 2.59 (3H, s), 3.35 (1H, d, J = 17.6H
z), 3.63 (1H, d, J = 17.6Hz), 3.84 (3H, s), 4.33 (1H, d, J = 1
2.4Hz), 4.56 (1H, d, J = 12.4Hz), 5.01 (1H, d, J = 4.8Hz),
5.59 (1H, dd, J = 8.0 and 4.8Hz), 6.73 (1H, s), 7.20 (2H, br
. s), 9.54 (1H, d, J = 8.0Hz) Elemental _{analysis: C 18 H 16 N 9 O} 5 SNa · 2.5H 2 O Calculated (%): C, 34.06; H, 3.31; N, 19.86 Found (%): C, 34.39; H, 3.08: N, 19.55

Example 9 In the same manner as in Example 1, 7β- [2- (5-amino-1,
2,4-thiadiazol-3-yl) -2 (Z) -methoxyiminoacetamido] -3- [3-methyl-s-triazolo [3,4-b] [1,3,4] thiadiazol-6-yl ] Sodium thiomethyl-3-cephem-4-carboxylic acid was obtained.

[Chemical 31] IR _max ^KBr cm ⁻¹ : 3400, 1760, 1670, 1600. NMR (DMSO-d ₆ ): 2.60 (3H, s), 3.35 (1H, d, J = 18.2H
z), 3.61 (1H, d, J = 18.2Hz), 3.91 (3H, s), 4.33 (1H, d, J = 1
2.4Hz), 4.55 (1H, d, J = 12.4Hz), 4.98 (1H, d, J = 4.8Hz),
5.60 (1H, dd, J = 8.0 and 4.8Hz), 8.11 (2H, brs), 9.50 (1H, d,
. J = 8.0 Hz) Elemental _{analysis: C 17 H 15 N 10 O} 5 S 4 Na · 4H 2 O Calculated (%): C, 30.81; H, 3.50; N, 21.14 Found (%): C , 30.42; H, 3.55: N, 21.06

Example 10 7β- [2- (2-Aminothiazol-4-yl) -2 (Z) -methoxyiminoacetamido] -3- [s-triazolo [3,4-similar to Example 1 b] [1,
3,4] Thiadiazol-6-yl] thiomethyl-3-
Cefem-4-carboxylic acid sodium salt was obtained.

[Chemical 32] IR _max ^KBr cm ⁻¹ : 3400, 1760, 1660, 1600. NMR (DMSO-d ₆ ): 3.38 (1H, d, J = 18.0Hz), 3.64 (1H, d,
J = 18.0Hz), 4.36 (1H, d, J = 12.8Hz), 4.51 (1H, d, J = 12.8H)
z), 5.02 (1H, d, J = 4.8Hz), 5.60 (1H, dd, J = 8.0 and 4.8Hz),
6.73 (1H, s), 7.20 (2H, bs), 9.42 (1H, s), 9.55 (1H, d, J =
. 8.0 Hz) Elemental _{analysis: C 17 H 14 N 9 O} 5 S 4 Na · 2.5H 2 O Calculated (%): C, 32.90; H, 3.09; N, 20.31 Found (%): C, 32.82; H, 2.75: N, 19.90

Example 11 In the same manner as in Example 4, 7β- [2- (2-aminothiazol-4-yl) -2 (Z) -hydroxyiminoacetamido] -3- [3-methyl-s-triazolo [ 3,4
-B] [1,3,4] thiadiazol-6-yl] thiomethyl-3-cephem-4-carboxylic acid sodium salt was obtained.

[Chemical 33] IR _max ^KBr cm ⁻¹ : 3400, 1765, 1665, 1600. NMR (D ₂ O): 2.69 (3H, s), 3.48 (1H, d, J = 17.6Hz), 3.
88 (1H, d, J = 17.6Hz), 4.05 (1H, d, J = 14.0Hz), 4.69 (1H, d,
J = 14.0Hz), 5.20 (1H, d, J = 2.6Hz), 5.80 (1H, d, J = 2.6Hz),
. 7.00 (IH, s) Elemental _{analysis: C 17 H 14 N 9 O} 5 S 4 Na · 2.5H 2 O Calculated (%): C, 32.90; H, 3.09; N, 20.31 Found (%) : C, 33.11; H, 3.08: N, 20.02

Example 12 7β- [2- (2-Aminothiazol-4-yl) -2 (Z) -hydroxyiminoacetamido] -3- [s-triazolo [3,4-similar to Example 4 b] [1,
3,4] Thiadiazol-6-yl] thiomethyl-3-
Cefem-4-carboxylic acid sodium salt was obtained.

[Chemical 34] IR _max ^KBr cm ⁻¹ : 3400, 1765, 1660, 1600. NMR (DMSO-d ₆ ): 3.38 (1H, d, J = 17.6Hz), 3.62 (1H, d,
J = 17.6Hz), 4.36 (1H, d, J = 12.2Hz), 4.51 (1H, d, J = 12.2H
z), 5.01 (1H, d, J = 4.8Hz), 5.62 (1H, dd, J = 8.2 and 4.8Hz),
6.64 (1H, s), 7.08 (2H, s), 9.37 (1H, d, J = 8.2Hz), 9.41 (1
H, s). Elemental analysis value: calculated as C ₁₆ H ₁₂ N ₉ O ₅ S ₄ Na · 2H ₂ O (%): C, 32.16; H, 2.70; N, 21.09 measured value (%): C, 32.14; H, 2.75: N, 20.78

Example 13 In the same manner as in Example 1, 7β- [2- (5-amino-1,
2,4-thiadiazol-3-yl) -2 (Z) -methoxyiminoacetamido] -3- [6-methyl-s-triazolo [3,4-b] [1,3,4] thiadiazol-3-yl ] Sodium thiomethyl-3-cephem-4-carboxylic acid was obtained.

[Chemical 35] IR _max ^KBr cm ⁻¹ : 3400, 1760, 1670, 1600. NMR (DMSO-d ₆ ): 3.27 (1H, d, J = 17.0Hz), 3.57 (1H, d,
J = 17.0Hz), 4.22 (1H, d, J = 12.0Hz), 4.27 (1H, d, J = 12.0H
z), 4.94 (1H, d, J = 4.8Hz), 5.58 (1H, dd, J = 8.0 and 4.8Hz),
. 8.11 (2H, s), 9.47 (1H, d, J = 8.0Hz) Elemental _{analysis: C 17 H 15 N 10 O} 5 S 4 Na · 3.5H 2 O Calculated (%): C, 31.24; H, 3.39; N, 21.43 measured value (%): C, 31.03; H, 3.33: N, 21.14

Example 14 Pivaloyloxymethyl 7β- [2- (2-aminothiazol-4-yl) -2 (Z) -methoxyiminoacetamido] -3- [3-methyl-s-triazolo [3,3
4-b] [1,3,4] thiadiazol-6-yl] thiomethyl-3-cephem-4-carboxylate

[Chemical 36] 7β- [2- (2-aminothiazol-4-yl) -2
(Z) -Methoxyiminoacetamido] -3- [3-methyl-s-triazolo [3,4-b] [1,3,4] thiadiazol-6-yl] thiomethyl-3-cephem-
DMF of 4-carboxylic acid sodium salt (202 mg)
A solution of pivaloyloxymethyl iodide (97 mg) in DMF (0.3 ml) was added to the solution (1.5 ml) under ice cooling. After stirring for 30 minutes under ice cooling, H ₂ O was added and the precipitated powder was collected by filtration. This powder was added to dichloromethane (20m
l), and the solution was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and H ₂ O and then dried (MgSO ₄ ). The solvent was distilled off to obtain the title compound as a powder. It was collected by filtration and washed with ether (10
0 mg, 44.1%). IR _max ^KBr cm ^-1 : 3425, 3325, 1780, 1740, 1675, 16
25. NMR (CDCl ₃ ): 1.22 (9H, s), 2.69 (3H, s), 3.59 (1H,
d, J = 18.4Hz), 3.74 (1H, d, J = 18.4Hz), 4.06 (3H, s), 4.37
(1H, d, J = 13.6Hz), 4.44 (1H, d, J = 13.6Hz), 5.11 (1H, d, J =
5.2Hz), 5.39 (2H, brs), 5.86 (1H, d, J = 5.6Hz), 5.92 (1H,
d, J = 5.6Hz), 6.06 (1H, dd, J = 8.0 and 5.2Hz), 6.83 (1H, s),
7.70 (1H, brs).

Example 15 Pivaloyloxymethyl 7β was prepared in the same manner as in Example 14.
-[2- (2-aminothiazol-4-yl) -2
(Z) -Hydroxyiminoacetamide] -3- [3-
Methyl-s-triazolo [3,4-b] [1,3,4]
Thiadiazol-6-yl] thiomethyl-3-cephem-4-carboxylate was obtained.

[Chemical 37] IR _max ^KBr cm ^-1 : 3400, 3325, 1780, 1745, 1670, 16
15. NMR (DMSO-d ₆ ): 1.37 (9H, s), 2.59 (3H, s), 3.64 (1
H, d, J = 18.4Hz), 3.81 (1H, d, J = 18.4Hz), 4.25 (1H, d, J = 1
3.8Hz), 4.48 (1H, d, J = 13.8Hz), 5.20 (1H, d, J = 4.8Hz),
5.78-5.91 (3H, m), 6.65 (1H, s), 7.11 (2H, brs), 9.49 (1
H, d, J = 8.4Hz).

Example 16 Pivaloyloxymethyl 7β was prepared in the same manner as in Example 14.
-[2- (2-aminothiazol-4-yl) -2
(Z) -Methoxyiminoacetamide] -3- [imidazo [2,1-b] [1,3,4] thiadiazole-2-
Il] thiomethyl-3-cephem-4-carboxylate

[Chemical 38] IR _max ^KBr cm ⁻¹ : 3420, 3340, 1790, 1745, 1680. NMR (CDCl ₃ ): 1.23 (9H, s), 3.59 (1H, d, J = 18.6Hz),
3.76 (1H, d, J = 18.6Hz), 4.03 (3H, s), 4.19 (1H, d, J = 13.2H
z), 4.47 (1H, d, J = 13.2Hz), 5.10 (1H, d, J = 4.8Hz), 5.31 (2
H, brs), 5.88 (1H, d, J = 5.2Hz), 5.92 (1H, d, J = 5.2Hz), 6.
08 (1H, dd, J = 8.6 and 5.2Hz), 6.87 (1H, s), 7.21 (1H, d, J = 1.
2Hz), 7.64 (1H, d, J = 1.2Hz), 8.60 (1H, d, J = 8.6Hz).

[0060]

The cephem compound [I] or a salt or ester thereof of the present invention has a broad antibacterial spectrum and an excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and is based on these bacteria. An antibacterial agent effective against infectious diseases can be provided.

Claims (6)

[Claims] 1. A general formula: [In the formula, R ₁ represents an optionally protected amino group, Q represents a nitrogen atom or a group represented by C—R ₂ (R ₂ represents a hydrogen atom or a halogen atom), and R ₃ represents a hydrogen atom. Or a hydrocarbon group which may be substituted, and A represents an optionally substituted triazolothiadiazolyl or imidazothiadiazolyl group, respectively] or a salt or ester thereof. 2. The compound according to claim 1, wherein A is a triazolothiadiazolyl or imidazothiadiazolyl group which may be substituted with a lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl group or a carbamoyl-lower alkyl group. . 3. A s-triazolo [3, wherein A may be substituted with a lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl group or a carbamoyl-lower alkyl group.
The compound according to claim 1, which is a 4-b] [1,3,4] thiadiazol-6-yl or imidazo [2,1-b] [1,3,4] thiadiazol-2-yl group. 4. The compound according to claim 1, wherein R ₃ is a hydrogen atom or a lower alkyl group. 5. A general formula: [Wherein A represents an optionally substituted triazolothiadiazolyl or imidazothiadiazolyl group] or a salt or ester thereof and a general formula [In the formula, R ₁ represents an optionally protected amino group, Q represents a nitrogen atom or a group represented by C—R ₂ (R ₂ represents a hydrogen atom or a halogen atom), and R ₃ represents a hydrogen atom or A hydrocarbon group which may be substituted] is reacted with a carboxylic acid or a salt or reactive derivative thereof, or a compound represented by the following general formula: [Wherein R ₁₁ represents a hydroxyl group, an acyloxy group, a carbamoyloxy group, a substituted carbamoyloxy group or a halogen atom, and other symbols have the same meanings as defined above] and a salt or ester thereof and a general formula A- By reacting with a thiol compound represented by SH [wherein A has the same meaning as defined above] or a salt thereof, or a compound represented by the general formula: [Symbols in the formula are as defined above] is an cephem compound or the general formula R ₃ '-OH wherein, R _3' and its salt or ester may also be substituted hydrocarbon group represented by ] Or a reactive derivative thereof, or by reacting a compound represented by the general formula: [In the formula, X is a halogen atom or R ₆ —SO ₂ —O (R ₆
Represents a lower alkyl group or an optionally substituted phenyl group), and other symbols have the same meanings as defined above] and a salt or ester thereof represented by the general formula R ₁ C ( = S) NH ₂ [wherein R
₁ has the same meaning as defined above] or by reacting with a compound represented by the formula or a salt thereof, and then the protecting group is removed if necessary. A method for producing a cephem compound represented by [the symbols in the formula have the same meanings as defined above] or a salt or ester thereof. 6. An antibacterial composition containing the compound according to claim 1.