JPH09100283A - Cephem compound, its production and antimicrobial composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a specific new cephem compound capable of manifesting excellent antimicrobial activities against Gram-positive and Gram-negative bacteria including methicillin-resistant Staphylococcus aureus(MRSA) and useful as an antimicrobial agent, etc., for treatment, etc., of microbisms. SOLUTION: This cephem compound (ester or salt) is represented by formula I [R<1> is a (protected) amino; R<2> is H or a group bonded through C; either of R<3> and R<4> is a (substituted) pyridinium group and the other is H, a (substituted) hydrocarbon group or R<3> and R<4> mutually bonded to represent a (substituted) heterocyclic ring; Q and X are each N or CH; Y is S, O or CH2 ; (n) is 0 or 1]. The cephem compound is useful as an antimicrobial agent, etc., capable of manifesting excellent antimicrobial activities against Gram-positive and Gram-negative bacteria including MRSA for treatment and prevention, etc., of microbisms. The compound is obtained by reacting a 7β- aminocephemcarboxylic acid compound represented by formula II with a heterocyclic compound, represented by formula III and having 2-hydroxyiminoacetic acid group or its salt or a reactive derivative thereof and then, as necessary, removing the protecting group from the resultant compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel cephem compound having an excellent antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria, particularly Staphylococcus and methicillin-resistant Staphylococcus aureus (MRSA), a process for producing the same, and an antibacterial composition thereof. Regarding

[0002]

2. Description of the Related Art A cephem compound having a 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -oxyiminoacetamide group at the 7-position and a thiazolylthio group at the 3-position is a special feature. 2- (2-aminothiazol-4-yl) -2 (Z)-in the 7-position and in Kaihei 5-255345.
A cephem compound having an oximinoacetamido group and a thiazolylthio group at the 3-position is disclosed in JP-A-4-3211691. However, there is no description in these publications that the 3-position may be substituted with a pyridinium thiazolylthio or thiazolopyridiniumthio group.

[0003]

The conventional cephem compounds have a sufficient antibacterial activity against staphylococci and methicillin-resistant staphylococcus aureus (MRSA) among others, in view of the range or strength of antibacterial activity. In particular, MRSA has caused serious infections in recent years, and the emergence of new compounds that overcome this problem has been desired.

[0004]

[Means for Solving the Problems] In view of the above circumstances, the present inventors have made various studies and as a result, have found that the compound at the 3-position of the cephem, oxacephem or carbacephem skeleton is of the formula

Embedded image [In the formula, R ³ and R ^{4 each} represent a pyridinium group which may be substituted, and the other represents a hydrogen atom or a hydrocarbon group which may be substituted, or R ³ and R ⁴ are bonded to each other. Represents an optionally substituted heterocycle containing a quaternized nitrogen atom, X represents a nitrogen atom or CH,
n represents 0 or 1. ] And a formula at the 7-position

Embedded image [In the formula, R ¹ represents an optionally protected amino group, R ² represents a group bonded via a hydrogen atom or a carbon atom, and Q represents a nitrogen atom or CH. ] The compound represented by the chemical structure having a group represented by the following is chemically synthesized for the first time or its ester or salt thereof, and the synthesized compound is based on the above-mentioned unique chemical structure. It was unexpectedly found that it has a broad and excellent antibacterial action against gram-positive bacteria and gram-negative bacteria including Staphylococcus and MRSA, and the present invention was completed based on these.

That is, the present invention is based on the formula (1) [I]

Embedded image [In the formula, Y represents S, O or CH ₂ , and other symbols have the same meanings as described above. However, when n is 0, Y represents S or O. ] The compound or its ester represented by these, or its salt, (2) Formula [I ']

Embedded image [The symbols in the formula are as defined above. ] The compound or its ester represented by these, or its salt, (3) Formula [II]

Embedded image [The symbols in the formula are as defined above. ] The compound or its ester or its salt represented by the formula [III]

Embedded image [The symbols in the formula are as defined above. ] The method for producing a compound according to (1) above, which comprises reacting with a carboxylic acid represented by the following formula or a salt or reactive derivative thereof, and removing the protective group if necessary, (4) Formula [IV ]

Embedded image [Wherein R ³ ′ and R ⁴ ′ each represent an optionally substituted pyridyl group and the other represents a hydrogen atom or an optionally substituted hydrocarbon group, or R ³ ′ and R ⁴ ′
Represents an optionally substituted heterocycle containing a nitrogen atom bonded to each other, and other symbols have the same meanings as described above. ]
An optionally substituted pyridyl group represented by R ³ ′ or R ⁴ ′ in the compound represented by or the salt thereof, or a salt thereof, which contains a nitrogen atom formed by bonding of R ³ ′ and R ⁴ ′ to each other. The method for producing a compound according to (1) above, wherein the nitrogen atom in the optionally substituted heterocycle is quaternized, and the protecting group is removed if necessary, and (5) above (1) ) Pharmaceutical composition etc. containing the compound of description.

In the present specification, the cephem compound is “the
Journal of the American Chemical Society, Vol. 84, p. 3400 (1962). It means a compound having a double bond at the 4-position. The compound of the present invention includes a compound of the formula [I] or an ester thereof or a salt thereof (a salt of the compound [I] or a salt of the ester of the compound [I]) in a free form. In the following description of the present application, except for special cases, a compound of formula [I] or an ester or salt thereof which represents a free form is simply represented by compound [I], antibacterial compound [I] or formula [I]. Only the compound represented is abbreviated. Therefore, the compound [I] in the present specification usually includes not only the free form but also its ester and salts thereof. This applies not only to the compound [I] but also to the compound [I '] and starting compounds such as the following compounds [II], [III] and [IV].

R ¹ represents an optionally protected amino group. In the field of β-lactams and peptides, 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. Examples of the amino-protecting group include optionally substituted C
_1-6 alkanoyl group, optionally substituted C _3-5 alkenoyl group, optionally substituted C _6-10 aryl-carbonyl group, heterocyclic carbonyl group, optionally substituted C _1-10 alkyl Sulfonyl group, optionally substituted C
_6-10 arylsulfonyl group, substituted oxycarbonyl group,
Optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted C
_6-10 aryl-methyl group, _optionally substituted di-C
_6-10 aryl-methyl group, _optionally substituted tri-C
_6-10 aryl-methyl group, _optionally substituted C _6-10
Aryl-methylene group, optionally substituted C _6-10 arylthio group, substituted silyl group, 2-C _1-10 alkoxy-
Carbonyl-1-methyl-1-ethenyl group, formula M'OC
O- [in the formula, M'represents an alkali metal. ] The group etc. which are represented by these are used.

Examples of the "optionally substituted C _1-6 alkanoyl group" include halogen, oxo, C _1-6 alkoxy, C _1-6 alkanoyl, C _6-10 aryl and C.
_A C _1-6 alkanoyl group optionally substituted with 1 to 3 substituents selected from _6-10 aryloxy, C _6-10 arylthio and the like is used. Specifically, for example, formyl, acetyl, Propionyl, butyryl, valeryl, pivaloyl, succinyl, glutaryl, monochloroacetyl, dichloroacetyl, trichloroacetyl, monobromoacetyl, monofluoroacetyl, difluoroacetyl, trifluoroacetyl, monoiodoacetyl, acetoacetyl, 3-oxobutyryl, 4-chloro. -3-Oxobutyryl, phenylacetyl, p-chlorophenylacetyl, phenoxyacetyl, p-chlorophenoxyacetyl and the like are used. "Optionally substituted C
Examples of the “ _3-5 alkenoyl group” include halogen, C
_A C _3-5 alkenoyl group optionally substituted with 1 to 3 substituents selected from _6-10 aryl and the like is used, and specific examples thereof include acryloyl, crotonoyl, maleoyl, cinnamoyl and p-chloro. Cinnamoyl, β-
Phenylcinnamoyl or the like is used. Examples of the “optionally substituted C _6-10 aryl-carbonyl group” include 1 to 3 substituents selected from halogen, nitro, hydroxy, C _1-6 alkyl, C _1-6 alkoxy and the like. An optionally substituted C _6-10 aryl-carbonyl group is used, specifically, for example, benzoyl, naphthoyl, phthaloyl, p-toluoyl, p-tert-butylbenzoyl, p-hydroxybenzoyl, p-methoxybenzoyl. , P-tert-butoxybenzoyl, p-chlorobenzoyl, p-nitrobenzoyl and the like are used.

The "heterocyclic group" in the "heterocyclic carbonyl group" refers to a group formed by removing one hydrogen atom bonded to a carbon atom of the heterocycle, and such a heterocycle is, for example, a nitrogen atom ( 5 to 8 membered ring containing 1 to several, preferably 1 to 4 heteroatoms such as (optionally oxidized), oxygen atom and sulfur atom, or a condensed ring thereof. Specific examples of such a heterocyclic group include 2- or 3-pyrrolyl; 3-, 4- or 5-pyrazolyl; 2-, 4-
Or 5-imidazolyl; 1,2,3- or 1,2,4-
Triazolyl; 1H- or 2H-tetrazolyl; 2-
Or 3-furyl; 2- or 3-thienyl; 2-, 4
-Or 5-oxazolyl; 3-, 4- or 5-isoxazolyl; 1,2,3-oxadiazol-4-yl or 1,2,3-oxadiazol-5-yl; 1,2,4
-Oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl; 1,2,5- or 1,3,4-oxadiazolyl; 2-, 4- or 5-thiazolyl; 3
-, 4- or 5-isothiazolyl; 1,2,3-thiadiazol-4-yl or 1,2,3-thiadiazole-
5-yl; 1,2,4-thiadiazol-3-yl or 1,2,4-thiadiazol-5-yl; 1,2,5- or 1,3,4-thiadiazolyl; 2- or 3-pyrrolidinyl; 2-, 3- or 4-pyridyl; 2-, 3- or 4-pyridyl-N-oxide; 3- or 4-pyridazinyl; 3- or 4-pyridazinyl-N-oxide;
2-, 4- or 5-pyrimidinyl; 2-, 4- or 5-pyrimidinyl-N-oxide; pyrazinyl;
3- or 4-piperidinyl; piperazinyl; 3H-indol-2-yl or 3H-indol-3-yl; 2-, 3- or 4-pyranyl; 2-, 3- or 4-thiopyranyl; benzopyranyl; quinolyl; pyrido [2,3-d] pyrimidyl; 1,5-, 1,6-, 1,7
-, 1,8-, 2,6- or 2,7-naphthyridyl; thieno [2,3-d] pyridyl; pyrimidopyridyl; pyrazinoquinolyl; benzopyranyl and the like are used. The "optionally substituted C _1-10 alkylsulfonyl group" is, for example, substituted with 1 to 3 substituents selected from halogen, C _6-10 aryl, C _6-10 aryloxy and the like. C _1-10 alkylsulfonyl group is also used, and specifically, for example, methanesulfonyl, ethanesulfonyl, camphorsulfonyl and the like are used.

Examples of the " _optionally substituted C _6-10 arylsulfonyl group" include halogen, nitro, C
1-3 selected from _1-6 alkyl, C _1-6 alkoxy, etc.
C _6-10 arylsulfonyl group _optionally substituted with one substituent is used, specifically, for example, benzenesulfonyl, naphthalenesulfonyl, p-toluenesulfonyl, p-tert-butylbenzenesulfonyl, p-methoxy. Benzenesulfonyl, p-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl and the like are used.
Examples of the “substituted oxycarbonyl group” include C _1-10
Alkoxy-carbonyl group, C _3-10 cycloalkyloxy-carbonyl group, C _5-10 bridged cyclic hydrocarbon oxy-carbonyl group, C _2-10 alkenyloxy-carbonyl group,
In addition to a C _6-10 aryloxy-carbonyl group or a C _7-19 aralkyloxy-carbonyl group, they are further C
_1-6 alkoxy, C _1-6 alkanoyl, C _1-10 alkanoyloxy, C _1-10 alkoxy-carbonyloxy, C
_3-10 cycloalkyloxy-carbonyloxy, substituted silyl group (substituted silyl group described later, eg, trimethylsilyl, tert-butyldimethylsilyl, etc.), C _1-6 alkylsulfonyl, halogen, cyano, C _1-6 alkyl, nitro Those having 1 to 3 substituents selected from the above are also included. Specifically, for example, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-cyanoethoxycarbonyl, allyloxycarbonyl, p- Methylphenoxycarbonyl, p-methoxyphenoxycarbonyl, p-chlorophenoxycarbonyl, m-nitrophenoxycarbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, 3,4-dimethoxy-6-
Nitrobenzyloxycarbonyl or the like is used.

"Carbamoyl group which may be substituted"
_Are , for example, C _1-6 alkyl, C _6-10 aryl,
C _1-6 alkanoyl, C _6-10 arylcarbonyl, C _1-6
A carbamoyl group which may be substituted with one or two substituents selected from an alkoxy-phenyl group and the like is used. Specifically, for example, N-methylcarbamoyl,
N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N- (p-methoxyphenyl) carbamoyl and the like are used. As the “optionally substituted thiocarbamoyl group”, for example, a thiocarbamoyl group optionally substituted by 1 or 2 substituents selected from C _1-6 alkyl, C _6-10 aryl and the like is used. For example, thiocarbamoyl, N-methylthiocarbamoyl, N-phenylthiocarbamoyl and the like are used.

“Optionally substituted C _6-10 aryl-
Examples of the “methyl group” include halogen, nitro, C
1-3 selected from _1-6 alkyl, C _1-6 alkoxy, etc.
C _6-10 aryl-methyl group which may be substituted with one substituent is used, specifically, for example, benzyl, naphthylmethyl, p-methylbenzyl, p-methoxybenzyl, p-chlorobenzyl, p -Nitrobenzyl and the like are used. Examples of the “ _optionally substituted di C _6-10 aryl-methyl group” include halogen, nitro, C
1-3 selected from _1-6 alkyl, C _1-6 alkoxy, etc.
_{DiC 6-10} aryl-, which may be substituted with one substituent
A methyl group is used, and specifically, for example, benzhydryl, di (p-tolyl) methyl and the like are used. Examples of the “ _optionally substituted tri-C _6-10 aryl-methyl group” include halogen, nitro, C _1-6 alkyl,
A tri-C _6-10 aryl-methyl group which may be substituted with 1 to 3 substituents selected from C _1-6 alkoxy and the like is used, and specific examples include trityl and tri (p-
Trilyl) methyl and the like are used. Examples of the “ _optionally substituted C _6-10 aryl-methylene group” include:
A C _6-10 aryl-methylene group which may be substituted with 1 to 3 substituents selected from halogen, nitro, C _1-6 alkyl, C _1-6 alkoxy and the like is used. For example, benzylidene, p-methylbenzylidene, p
-Chlorobenzylidene or the like is used. Examples of the “ _optionally substituted C _6-10 arylthio group” include:
A C _6-10 arylthio group which may be substituted with 1 to 3 substituents selected from halogen, nitro, C _1-6 alkyl, C _1-6 alkoxy and the like is used. Specifically, for example, o-Nitrophenylthio and the like are used.

The "substituted silyl group" is combined with the amino group to be protected to represent the formula R ⁶ R ⁷ R ⁸ SiNH-, (R ⁶ R ⁷ R ⁸ Si) ₂ N.
-Or

Embedded image [In the formula, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^9a and R ^10a are each a C _1-6 alkyl group or a C _6-10 aryl group, and Z ^a is a C _1-3 alkylene group. (Representing methylene, ethylene, propylene, etc.)] is formed. Preferable examples of “substituted silyl group” include, for example, trimethylsilyl, tert-butyldimethylsilyl, —Si (CH ₃ ).
_{2 CH 2 CH 2 Si (CH} 3) 2 - and the like. "2-C
Specific examples of the “ _1-10 alkoxy-carbonyl-1-methyl-1-ethenyl group” include 2-methoxycarbonyl-1-methyl-1-ethenyl, 2-ethoxycarbonyl-1-methyl-1-ethenyl, 2 -Tert-butoxycarbonyl-1-methyl-1-ethenyl, etc. are used. As the “alkali metal” represented by M ′, for example, sodium, potassium and the like are preferable, and sodium and the like are particularly preferable. R ¹ is preferably an amino group from the viewpoint of antibacterial activity.

R ² represents a group bonded via a hydrogen atom or a carbon atom. Examples of the “group bonded via a carbon atom” represented by R ² include an optionally substituted hydrocarbon group (eg, an optionally substituted alkyl group,
An optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aralkyl group, an optionally substituted cyclic hydrocarbon group), an acyl group or a substituent having a bond at a carbon atom A non-aromatic heterocyclic group which may be substituted is preferable, and an alkyl group which may be substituted, an alkenyl group which may be substituted, a cyclic hydrocarbon group which may be substituted and the like are particularly preferable. As the "alkyl group" of the "optionally substituted alkyl group", a C _1-6 alkyl group and the like are preferable, and methyl, ethyl, isopropyl and the like are particularly preferable. As the "alkenyl group" in the "optionally substituted alkenyl group", a C _2-6 alkenyl group and the like are preferable. The "alkynyl group" of the "optionally substituted alkynyl group" is preferably a C _2-6 alkynyl group. The “aralkyl group” of the “optionally substituted aralkyl group” is C
_7-19 aralkyl groups are preferred. Examples of the "cyclic hydrocarbon group" of the "optionally substituted cyclic hydrocarbon group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl. , 2-
Cyclohexen-1-yl, 3-cyclohexene-1-
Examples thereof include _{3- to} 7-membered non-aromatic cyclic hydrocarbon groups such as yl, and especially C _3-7 such as cyclobutyl and cyclopentyl.
A cycloalkyl group and the like are preferable. Examples of the “acyl group” include “optionally substituted C _1-6 alkanoyl group” and “optionally substituted” which are exemplified as the protective group in the “optionally protected amino group” represented by R ^1. good C _3-5 alkenoyl group "," optionally substituted C _6-10 aryl - carbonyl group "and the like" heterocyclic group ". Examples of the “non-aromatic heterocyclic group” of the “optionally substituted non-aromatic heterocyclic group having a bond at a carbon atom” include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl. In addition to carbon atoms such as tetrahydropyranyl, morpholinyl and thiomorpholinyl, 3- to 6-membered non-aromatic heterocyclic groups containing 1 or 2 hetero atoms such as nitrogen atom, oxygen atom and sulfur atom are preferable.

The substituent which the above-mentioned "hydrocarbon group" may have is, for example, a heterocyclic group, a hydroxyl group, a C _1-6 alkoxy group, a C _3-10 cycloalkyl group or a C _3-7 cycloalkyloxy group. , C _6-10 aryloxy group, C _7-19 aralkyloxy group, heterocyclic oxy group, mercapto group, C _1-6 alkylthio group, C _3-10 cycloalkylthio group, C _6-10 arylthio group, C _{7- 19} aralkylthio group, heterocyclic thio group, amino group, mono C _1-6 alkylamino group, di C _1-6 alkylamino group, tri C _1-6 alkylammonium group,
C _3-10 cycloalkylamino group, C _6-10 arylamino group, C _7-19 aralkylamino group, heterocyclic amino group, cyclic amino group, azido group, nitro group, halogen atom, cyano group, carboxyl group, C _1-10 alkoxy - carbonyl group, C _6-10 aryloxy - carbonyl group, C _7-19 aralkyloxy - carbonyl group, C _6-10 aryl - carbonyl group, C _1-6 alkanoyl group, C _3-5 alkenoyl group ，
C _6-10 aryl-carbonyloxy group, C _2-6 alkanoyloxy group, C _3-5 alkenoyloxy group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted Good carbamoyloxy group, phthalimido group, C _1-6 alkanoylamino group, C _6-10 aryl-carbonylamino group, C _1-10 alkoxy-carboxamide group, C _6-10 aryloxy-carboxamide group, C _7-19 Aralkyloxy-carboxamide group and the like, and the same or different 1 to 4
Individuals may exist.

Among the specific examples of the substituent of the above "hydrocarbon group", the "optionally substituted carbamoyl group" is, for example, C _1-6 alkyl group, C _6-10 aryl group, C _1-6.
Alkanoyl group, C _6-10 arylcarbonyl group, C _1-6
A carbamoyl group which may be substituted with 1 or 2 substituents selected from an alkoxy-phenyl group, a cyclic aminocarbonyl group and the like are used, and specifically, for example, carbamoyl, N-methylcarbamoyl, N-
Ethylcarbamoyl, N, N-dimethylcarbamoyl,
N, N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N- (p-methoxyphenyl) carbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, morpholinocarbonyl, etc. Used. "A thiocarbamoyl group which may be substituted"
Is, for example, a thiocarbamoyl group which may be substituted with 1 or 2 substituents selected from C _1-6 alkyl group, C _6-10 aryl group and the like.
Thiocarbamoyl, N-methylthiocarbamoyl, N-
Phenylthiocarbamoyl or the like is used. An “optionally substituted carbamoyloxy group” includes, for example, C
1 selected from _1-6 alkyl group, C _6-10 aryl group, etc.
Alternatively, a carbamoyloxy group which may be substituted with two substituents is used, and specifically, for example, carbamoyloxy, N-methylcarbamoyloxy, N, N-
Dimethylcarbamoyloxy, N-ethylcarbamoyloxy, N-phenylcarbamoyloxy and the like are used.

The heterocyclic group such as the heterocyclic group, the heterocyclic oxy group, the heterocyclic thio group and the heterocyclic amino group in the substituent of the "hydrocarbon group" is the same as the heterocyclic group in the above "heterocyclic carbonyl group". Groups are used. "Alkyl group" of "alkyl group which may be substituted", "alkenyl group" of "alkenyl group which may be substituted",
Examples of the substituent which the “cyclic hydrocarbon group” of the “aralkyl group” of the “optionally substituted aralkyl group” and the “optionally substituted cyclic hydrocarbon group” may have are as described above. Optionally substituted hydrocarbon group "
The same as the substituent which the “hydrocarbon group” of may have, etc. are used. Examples of the substituent of the “optionally substituted non-aromatic heterocyclic group having a bond at a carbon atom” include the hydrocarbon group and its substituents exemplified in the above “optionally substituted hydrocarbon group”. And so on.

R ² is preferably an “optionally substituted hydrocarbon group” and the like, for example, a hydroxyl group, a C _3-10 cycloalkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, an amino group. , Halogen atom, carboxyl group, C
_1-10 alkoxycarbonyl group, an optionally substituted carbamoyl group, a cyano group, azido group, a heterocyclic 1 selected from such ring to three optionally substituted with a substituent C _1-6 alkyl group And specifically, cyclopropylmethyl, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-hydroxyethyl, methylthiomethyl, 2-aminoethyl, fluoromethyl, 2-fluoroethyl,
2,2-difluoroethyl, chloromethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl, 2,
2,2-trifluoroethyl, carboxymethyl, 1-
Carboxyethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, cyanomethyl, 1-carboxy-1-methylethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1- Methoxycarbonyl-1-methylethyl, 1-ethoxycarbonyl-1-methylethyl, 1-tert-butoxycarbonyl-1-methylethyl, 1-benzyloxycarbonyl-1-methylethyl, 1-pivaloyloxycarbonyl-1 -Methylethyl, carbamoylmethyl, N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, 2-azidoethyl, 2- (pyrazolyl) ethyl, 2- (imidazolyl) ethyl, 2- (2-oxopyrrolidin-3-yl ) D Le, 1-carboxy-1-
(2,3,4-trihydroxyphenyl) methyl and the like can be mentioned. Most preferred as R ² are, for example, methyl, ethyl, n-propyl, isopropyl, butyl,
Isobutyl, sec-butyl, fluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, carbamoylmethyl, N-methylcarbamoylmethyl, Substituted with 1 to 3 substituents selected from halogen such as N, N-dimethylcarbamoylmethyl, hydroxyl group, C _1-6 alkoxy group, carboxyl group, C _1-10 alkoxycarbonyl group, cyano group and carbamoyl group. Optionally linear or branched C _1-6 alkyl group, C _3-5 cycloalkyl group such as cyclopropyl, cyclobutyl and cyclopentyl, C _3-5 cycloalkyl-C ₁ -such as cyclopropylmethyl ₃ Examples include an alkyl group. Particularly, optionally substituted C _1-6 alkyl group and C _3-5 cycloalkyl group are preferable.

One of R ³ and R ⁴ represents an optionally substituted pyridinium group and the other represents a hydrogen atom or an optionally substituted hydrocarbon group, or R ³ and R ⁴
Represents an optionally substituted heterocycle containing a quaternized nitrogen atom bonded to each other. Examples of the “optionally substituted pyridinium group” include those represented by the formula

Embedded image [In the formula, R ⁵ represents an optionally substituted hydrocarbon group;
_{Represents a} C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxy-carbonyl group, amino, nitro, halogen or carboxy, and p represents an integer of 0 to 4]
A group represented by is used. When R ³ and R ⁴ are bonded to each other to represent an optionally substituted heterocycle containing a quaternized nitrogen atom,

Embedded image A 6-membered unsaturated heterocycle represented by the formula [wherein q is an integer of 0 to 3 and the other symbols have the same meanings as described above] and the like are used. The "optionally substituted hydrocarbon group" represented by R ³ , R ⁴ or R ⁵ is "optionally substituted" exemplified in the "group bonded via a carbon atom" represented by R ^2. The same thing as a "hydrocarbon group" is used. Each of p and q is preferably 0. R ⁵ is preferably a C _1-4 alkyl group such as methyl. R ³
And as the R ^4, good pyridinium group optionally R ³ is substituted, 6-membered containing a nitrogen atom wherein R ⁴ is hydrogen atom, or R ³ and R ⁴ is quaternized bonded to each other not The case where a saturated heterocycle is formed is preferable.

Q and X are each a nitrogen atom or CH.
Is shown. Each of Q and X is preferably a nitrogen atom. Y
Represents S, O or CH ₂ . Y is preferably S. That is, as the compound [I], [I ′]

Embedded image [The symbols in the formula are as defined above. ] The compound or its ester represented by these or its salt is preferable. n represents 0 or 1, but is preferably 1.

[0021]

Embedded image It shows that it forms an inner salt with the above positive charge. On the other hand, compound [I] may form a pharmacologically acceptable ester or salt. As the pharmacologically acceptable salts, inorganic base salts, ammonium salts, organic base salts, inorganic acid addition salts, organic acid addition salts, basic amino acid salts and the like are used. Inorganic bases capable of forming inorganic base salts include alkali metals (eg sodium, potassium etc.), alkaline earth metals (eg calcium etc.), and organic bases capable of forming organic base salts include eg procaine, 2-phenyl. Ethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane,
Polyhydroxyalkylamine, N-methylglucosamine, and the like can form inorganic acid addition salts. Examples of inorganic acids that can form inorganic acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of the acid include p-toluenesulfonic acid, methanesulfonic acid, formic acid,
Trifluoroacetic acid, maleic acid and the like are used as the basic amino acid capable of forming a basic amino acid salt such as lysine, arginine, ornithine and histidine. Of these salts, base salts (ie inorganic base salts,
(Ammonium salt, organic base salt, basic amino acid salt) is an amino group, a monoalkylamino group, a dialkylamino group, a cycloalkylamino group, an arylamino group in the substituents R ¹ , R ² and R ⁵ of the compound [I]. , An aralkylamino group, a cyclic amino group, a nitrogen-containing heterocyclic group and the like, and an acid addition salt that can be formed in the presence of a basic group. Also, as acid addition salts

Embedded image For example, chloride ion, bromide ion, sulfate ion, p-toluenesulfonate ion, methanesulfonate ion, trifluoroacetate ion, etc.] are also included. The ester derivative of the compound [I] means an ester which can be produced by esterifying a carboxyl group contained in a molecule, and is an ester usable as a synthetic intermediate and a non-toxic non-toxic ester metabolically unstable. As the ester that can be used as a synthetic intermediate, an optionally substituted C _1-6 alkyl ester, C _2-6 alkenyl ester, C _3-10 cycloalkyl ester, C _3-10 cycloalkyl C _1-6 alkyl ester, An optionally substituted C _6-10 aryl ester,
Optionally substituted C _7-12 aralkyl ester, di-C
_6-10 aryl-methyl ester, tri-C _6-10 aryl-
Methyl ester, substituted silyl ester, etc. are used.

Examples of the " _optionally substituted C _1-6 alkyl ester" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-
Butyl, tert-butyl, n-pentyl, n-hexyl and the like are used, for example, benzyloxy, C _1-4
Alkylsulfonyl (eg, methylsulfonyl, etc.), trimethylsilyl, halogen (eg, fluorine, chlorine, bromine, etc.), acetyl, nitrobenzoyl, mesylbenzoyl, phthalimide, succinimide, benzenesulfonyl, phenylthio, di-C _1-4 alkylamino (eg. , Dimethylamino, etc.), pyridyl, C _1-4 alkylsulfinyl (eg, methylsulfinyl, etc.), cyano, etc., and 1 to 3 substituents may be used, and specific examples of such a group include benzyloxy. Methyl, 2-methylsulfonylethyl, 2-trimethylsilylethyl, 2,2,2-trichloroethyl, 2-iodoethyl, acetylmethyl,
p-nitrobenzoylmethyl, p-mesylbenzoylmethyl, phthalimidomethyl, succinimidomethyl, benzenesulfonylmethyl, phenylthiomethyl, dimethylaminoethyl, pyridine-1-oxide-2-methyl, methylsulfinylmethyl, 2-cyano-1 , 1-
Dimethylethyl and the like are used. The C _2-6 alkenyl group forming the “C _2-6 alkenyl ester” is vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, methallyl, 1,
1-Dimethylallyl, 3-methyl-3-butenyl and the like are used.

The C _3-10 cycloalkyl group forming the "C _3-10 cycloalkyl ester" is cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl and the like are used. As the C _3-10 cycloalkyl C _1-6 alkyl group forming the “C _3-10 cycloalkyl C _1-6 alkyl ester”, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like are used. Examples of the “C _6-10 aryl group” which forms the “ _optionally substituted C _6-10 aryl ester” include phenyl and α-
Naphthyl, β-naphthyl, biphenylyl and the like are used,
They may be substituted by, for example, 1 to 3 nitro, halogen (eg, fluorine, chlorine, bromine, etc.) and the like, and specific examples of such groups include p-nitrophenyl, p-chlorophenyl and the like. Is used.

Examples of the "C _7-12 aralkyl group" which forms the " _optionally substituted C _7-12 aralkyl ester" include benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, naphthylmethyl and the like. Are used, such as nitro, C _1-4 alkoxy (eg,
1 to 3 substituents such as methoxy), C _1-4 alkyl (eg, methyl, ethyl, etc.) and hydroxy, and specific examples of such a group include p-nitrobenzyl and p-methoxy. Benzyl, 3,5-ditert-butyl-
4-hydroxybenzyl and the like are used. "Ji C _6-10
Examples of the di-C _6-10 aryl-methyl group forming “aryl-methyl ester” include benzhydryl and the like.
_{Examples of} tri-C _6-10 aryl-methyl group forming _6-10 aryl-methyl ester include trityl and the like, and examples of substituted silyl group forming substituted silyl ester include trimethylsilyl, tert-butyldimethylsilyl and -Si (CH ₃ ). ₂ C
_{H 2 CH 2 Si (CH 3} ) 2 - , etc. can be used. The above-mentioned esters include esters at the 4-position. Thus, those in which the 4-position is the above-mentioned ester group are represented by the formula in the 3-position.

Embedded image [The symbols in the formula have the same meanings as described above] to form a salt having a group.

The present invention includes, in addition to the above ester derivative, a pharmacologically acceptable compound which is converted into the compound [I] in vivo. In the case where the compound [I] of the present invention and the starting compound are n = 1, the cis isomer (Z
Isomers), trans isomers (E isomers) and cis, trans mixtures. Compound of the present invention [I]
Is preferably a trans isomer (E-form). Compound [I]
For example, the cis isomer (Z-form) is represented by the formula [XVII]

Embedded image Means one of the geometrical isomers having the partial structure represented by the formula: [XVIII]

Embedded image It means a geometrical isomer having a partial structure represented by.

Specific examples of each substituent unless otherwise specified in the present specification are as follows. Halogen: fluoro, chloro, bromo, iodo, etc .; C _1-4 alkyl group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, etc .; C _1-6 alkyl group: the above C _1-4 alkyl group and Pentyl,
2,2-dimethylpropyl, hexyl, etc .; C _2-6 alkenyl groups: vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3
-Butenyl, methallyl, 1,1-dimethylallyl, etc .; C _2-6 alkynyl group: ethynyl, 1-propynyl, 2-
Propinyl, 2-butynyl, 2-pentynyl, 2-hexynyl, etc .; C _3-5 cycloalkyl group: cyclopropyl, cyclobutyl, cyclopentyl, etc .; C _3-10 cycloalkyl group: the above C _3-5 cycloalkyl group and cyclohexyl, Cycloheptyl, cyclooctyl, cyclodecyl, etc .; C _6-10 aryl group: phenyl, naphthyl, etc .; C _7-20 aralkyl group: benzyl, 1-phenylethyl,
2-phenylethyl, phenylpropyl, naphthylmethyl, benzhydryl, etc .;

C _1-10 alkoxy-carbonyloxy group:
Methoxycarbonyloxy, ethoxycarbonyloxy, tert-butoxycarbonyloxy, etc .; C _1-6 alkoxy groups: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, 2,2-dimethylpropyloxy, Hexyloxy, etc .; C _3-7 cycloalkyloxy groups: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc .; C _6-10 aryloxy groups: phenoxy, naphthyloxy, etc .; C _7-19 aralkyloxy groups: Benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, benzhydryloxy and the like;

C _1-6 alkylthio group: methylthio, ethylthio, propylthio, butylthio, isobutylthio,
t-butylthio, pentylthio, 2,2-dimethylpropylthio, hexylthio, etc .; C _3-10 cycloalkylthio group: cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio, cyclooctylthio, cyclodecylthio. C _6-10 arylthio group: phenylthio, naphthylthio, etc .; C _7-19 aralkylthio group: benzylthio, phenylethylthio, benzhydrylthio, tritylthio, etc .; C _1-4 alkylsulfinyl group: methylsulfinyl,
Ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, t-butylsulfinyl and the like; C _1-6 alkylsulfonyl group: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, t
-Butylsulfonyl, pentylsulfonyl, 2,2-dimethylpropylsulfonyl, hexylsulfonyl and the like;

Mono C _1-6 alkylamino group: methylamino, ethylamino, n-propylamino, n-butylamino, etc .; Di C _1-4 alkylamino group: dimethylamino, diethylamino, methylethylamino, di- ( n-propyl) amino, di- (n-butyl) amino and the like; diC _1-6 alkylamino group: the above diC _1-4 alkylamino group and di (pentyl) amino, di (n-hexyl) amino and the like; Tri C _1-6 alkylammonium group: trimethylammonium, etc .; C _3-10 cycloalkylamino group: cyclopropylamino, cyclopentylamino, cyclohexylamino, etc .; C _6-10 arylamino group: anilino, N-methylanilino, etc .; C _{7 -19} aralkylamino group: benzylamino, 1-phenylethylamino, 2-phenylethyl amino, Lens benzhydryl-amino and the like; cyclic amino group: pyrrolidino, piperidino, piperazino,
Morpholino, 1-pyrrolyl, etc .; C _1-6 alkanoylamino group: acetamide, propionamide, butyroamide, valeroamide, pivaloamide, etc .; C _6-10 aryl-carbonylamino group: benzamide,
Naphthoylamide, phthalimide, etc .;

C _1-6 alkanoyl group: formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl,
Succinyl, glutaryl, etc .; C _2-6 alkanoyloxy groups: acetoxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy, etc .; C _1-10 alkanoyloxy groups: the above C _2-6 alkanoyloxy groups and formyloxy, hexanoyloxy, hepta. Noyloxy and the like; C _3-5 alkenoyl groups: acryloyl, crotonoyl,
Maleoyl, etc .; C _3-5 alkenoyloxy group: acryloyloxy, crotonoyloxy, maleoyloxy, etc .; C _6-10 aryl-carbonyl group: benzoyl, naphthoyl, phthaloyl, phenylacetyl, etc .; C _6-10 aryl-carbonyl Oxy group: benzoyloxy, naphthoyloxy, phenylacetoxy, etc .; C _1-6 alkoxy-phenyl group: methoxyphenyl, ethoxyphenyl, propoxyphenyl, butoxyphenyl, t-butoxyphenyl, etc .;

C _1-10 alkoxy-carbonyl group: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, 2,2-dimethylpropyloxycarbonyl, Hexyloxycarbonyl, heptyloxycarbonyl, decyloxycarbonyl, etc .; C _1-10 alkoxy-carbonyloxy groups: methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy,
Butoxycarbonyloxy, isobutoxycarbonyloxy, t-butoxycarbonyloxy, pentyloxycarbonyloxy, 2,2-dimethylpropyloxycarbonyloxy, hexyloxycarbonyloxy, heptyloxycarbonyloxy, decyloxycarbonyloxy, etc .; C _3-10 Cycloalkyloxy-carbonyl group: cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl,
Cyclooctyloxycarbonyl, cyclodecyloxycarbonyl and the like; C _3-10 cycloalkyloxy-carbonyloxy group: cyclopropyloxycarbonyloxy, cyclobutyloxycarbonyloxy, cyclopentyloxycarbonyloxy, cyclohexyloxycarbonyloxy, cycloheptyloxycarbonyloxy , Cyclooctyloxycarbonyloxy, cyclodecyloxycarbonyloxy and the like;

C _5-10 bridged cyclic hydrocarbon oxy-carbonyl group: norbornyloxycarbonyl, adamantyloxycarbonyl, etc .; C _2-10 alkenyloxy-carbonyl group: allyloxycarbonyl, etc .; C _{6-10 aryloxy-} Carbonyl group: phenoxycarbonyl, naphthyloxycarbonyl, etc. C _7-19 aralkyloxy-carbonyl group: benzyloxycarbonyl, benzhydryloxycarbonyl, etc .; C _1-10 alkoxy-carboxamide group: methoxycarboxamide (CH ₃ OCONH-), ethoxy carboxamide, etc. tert- butoxy-carboxamide; C _6-10 aryloxy - carboxamide group: phenoxy carboxamide (C ₆ H ₅ OCONH-), etc.; C _7-10 aralkyloxy - carboxamide group: benzyloxy-carbonitrile Samido _{(C 6 H 5 CH 2 OCONH-} ),
Such as benzhydryloxycarboxamide;

The production method of the compound [I] of the present invention will be described in detail below. Production method (1): For example, formula [II]

Embedded image [The symbols in the formula are as defined above. ] Represented by 7
-Amino compound or its ester or its salt and formula [III]

Embedded image [The symbols in the formula are as defined above. The compound [I] can be synthesized by reacting with a carboxylic acid represented by the above formula] or a salt thereof or a reactive derivative thereof.

This method is a method of acylating a 7-amino compound [II] with a carboxylic acid [III] or a salt thereof or a reactive derivative thereof. In this method, the carboxylic acid [III] remains free, or its salt or its reactive derivative is used as an acylating agent for the 7-amino group of the 7-amino compound [II]. That is, a free acid [III] or an inorganic base salt, an organic base salt, an acid halide, an acid azide, an acid anhydride, a mixed acid anhydride, an active amide, an active ester, an active thioester or the like of a free acid [III] is used as a reactive derivative. It is subjected to an acylation reaction. Inorganic base salts include alkali metal salts (eg sodium salt, potassium salt, etc.), alkaline earth metal salts (eg 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 salts and the like, acid halides such as acid chlorides and acid bromides, and mixed acid anhydrides such as mono-C _1-6 alkyl carbonic acid mixed acid anhydrides (eg free acid [I
II] 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, monoallyl carbonic acid, etc.), C _{1- 6} Aliphatic carboxylic acid mixed acid anhydride (for example, free acid [III]
And acetic acid, trichloroacetic acid, cyanoacetic acid, propionic acid,
Butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid, acetoacetic acid, and other mixed acid anhydrides), C _7-12 aromatic carboxylic acid mixed acid anhydrides (eg, free acid [ III] and benzoic acid, p-toluic acid, p-chlorobenzoic acid and the like), organic sulfonic acid mixed acid anhydride [eg free acid [III] and methanesulfonic acid, ethanesulfonic acid, benzenesulfone) Acid, a mixed acid anhydride with p-toluenesulfonic acid, etc., is an amide with a nitrogen-containing heterocyclic compound as an active amide (for example, an acid amide with a free acid [III] and pyrazole, imidazole, benzotriazole, etc.). these nitrogen-containing heterocyclic compound is a C _1-6 alkyl group, C _1-6 alkoxy groups, halogen, oxo group, thioxo group, optionally substituted by a C _1-6 alkylthio group There.], And the like. Can all use what is used for this purpose in the field of β- lactam and peptide synthesis as an active ester, for example an organic phosphate ester (e.g. Jietokishirin acid ester, diphenoxyphosphoric cylindrical esters, etc.)
In addition to p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 6-chloro-1
-Hydroxybenzotriazole ester, 1-hydroxy-1H-2-pyridone ester and the like can be mentioned.
The active thioester is an ester with an aromatic heterocyclic thiol compound [eg, 2-pyridylthiol ester, 2-benzothiazolylthiol ester, etc., and these heterocycles are C _1-6 alkyl group, C _1-6 alkoxy group ，
It may be substituted with halogen, a C _1-6 alkylthio group or the like. ] Is mentioned. On the other hand, 7-amino compound [I
I] is used as its salt or ester as it is. Examples of salts of the 7-amino 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 (eg sodium salt, potassium salt, etc.),
Alkaline earth metal salts (eg, calcium salts) and the like are organic base salts such as trimethylamine salt,
Triethylamine salt, tert-butyldimethylamine salt,
Dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt, pyridine salt, quinoline salt and the like are inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphoric acid. Salts such as organic acid addition salts include formate, acetate, trifluoroacetate,
Examples thereof include methane sulfonate and p-toluene sulfonate. As the ester of the 7-amino compound [II], the ester already described as the ester derivative of the compound [I] can be directly used here. That is, C _1-6
Alkyl ester, C _2-6 alkenyl ester, C _3-10
Cycloalkyl ester, C _3-6 Cycloalkyl-C _1-6
Alkyl ester, C _6-10 aryl ester, C _7-12 aralkyl ester, di-C _6-10 arylmethyl ester, tri-C _6-10 arylmethyl ester, C _2-6 alkanoyloxy-C _1-6 alkyl ester And so on. The starting material [III], its salt and its reactive derivative can be prepared by known methods (for example, JP-A-60-231684,
It can be easily produced by a method described in JP-A-62-149682) or a method analogous thereto. Compound [II
The reactive derivative of I] may be reacted with the 7-amino compound [II] as a substance isolated from the reaction mixture, or a reaction mixture containing the reactive derivative of compound [III] before isolation may be used. It is also possible to react with the 7-amino compound [II] as it is. When the carboxylic acid [III] is used in the free acid or salt form, 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 and N, N'-thiocarbonyldiimidazole, and the like. For example, N-ethoxycarbonyl-2-ethoxy-1,2-
Dehydrating agents such as dihydroquinoline, phosphorus oxychloride, and alkoxyacetylene, for example, 2-halogenopyridinium salts such as 2-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 performed 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, ethylene glycol-dimethyl ether, such as ethyl formate, ethyl acetate, acetic acid n.
-Esters such as butyl, eg dichloromethane,
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane, such as n-
Hydrocarbons such as hexane, benzene and toluene, such as formamide, N, N-dimethylformamide, N,
In addition to amides such as 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. Used alone or as a mixed solvent. The amount of the acylating agent [III] used is usually about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of the 7-amino compound [II]. The reaction is about -80 to 80 ° C, preferably about -40 to 5
It is carried out in a temperature range of 0 ° C, most preferably about -30 to 30 ° C. The reaction time depends on the type of 7-amino compound [II] and carboxylic acid [III], the type of solvent (in the case of a mixed solvent, the mixing ratio thereof), the reaction temperature, etc., and is usually about 1 minute to
72 hours, preferably about 15 minutes to 10 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 hydrogencarbonate, such as triethylamine, tri (n-propyl) amine, tri (n-butyl) amine, diisopropylethylamine, cyclohexyldimethyl. Tertiary amines such as amine, pyridine, lutidine, γ-collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine, and alkylene oxides such as propylene oxide and epichlorohydrin. .

Of the 7-amino compound [II] which is the starting material for this reaction, the compound of Y = S or its ester or its salt can be obtained, for example, as follows. First, the formula [VII]

Embedded image [Wherein R ¹¹ is an amino-group protecting group, R ¹² is a carboxyl-group protecting group, L is a halogen atom, a lower acyloxy group,
Alternatively, a sulfonyloxy group and other symbols have the same meanings as described above. ] And a compound represented by the formula [VIII]

Embedded image [The symbols in the formula are as defined above. ] By reacting with a pyridine compound or a salt thereof represented by the formula [IX]

Embedded image [The symbols in the formula are as defined above. ] The compound or its salt represented by these are manufactured, Then, for example, JP-A-55-55
154978 and the like to reduce the S-oxide to give a compound of formula [X]

Embedded image [The symbols in the formula are as defined above. ] The compound or its salt represented by these is manufactured. Then, the compound [X]
A, R ³ 'or R ^4' pyridyl group or optionally substituted represented by R ³ 'and R ^4' are bonded in the heterocyclic ring which may be substituted containing a nitrogen atom which is formed by mutually A compound that quaternizes a nitrogen atom (hereinafter referred to as a quaternary ammonium agent) is reacted to give a compound of the formula [XI]

Embedded image [The symbols in the formula are as defined above. Is obtained. Then, the compound [II] can be produced by optionally removing the protecting group. Examples of the quaternary ammonium-forming agent include compounds represented by R ⁵ -Z (R ⁵ has the same meaning as described above, and Z represents a leaving group).

Examples of the protecting group for the carboxy group represented by R ¹² include the above-mentioned esters. In particular, tri (lower) alkylsilyl group such as trimethylsilyl group, benzhydryl group, p-methoxybenzyl group, tert-butyl group,
P-nitrobenzyl group, phenacyl group and the like, which are commonly used in this field and which can be easily removed, are preferably protective groups for carboxy group.

As a protecting group for the amino group represented by R ¹¹ ,
Examples thereof include the amino-protecting groups described above. Particularly, acyl such as tri (lower) alkylsilyl group such as trimethylsilyl group, formyl group, trifluoroacetyl group, acetyl group, tert-butoxycarbonyl group, methoxyacetyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group and the like. System protecting groups, aralkyl group protecting groups such as benzyl group, benzhydryl group and trityl group are preferred. L is a halogen atom such as chlorine, bromine or iodine,
Acetoxy, propionyloxy, butyryloxy, 3
-Acyloxy groups such as oxobutyryloxy, alkylsulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy, benzenesulfonyloxy, naphthalenesulfonyloxy, p-toluenesulfonyloxy, p-tert-butylbenzenesulfonyloxy, p-
Arylsulfonyloxy groups such as methoxybenzenesulfonyloxy, p-chlorobenzenesulfonyloxy and p-nitrobenzenesulfonyloxy are preferred. Particularly preferred are benzenesulfonyloxy and p-toluenesulfonyloxy groups. Z represents a leaving group, but a halogen atom such as chlorine, bromine or iodine is preferable.

The compound [VIII] is also used as a salt.
Examples of the salt of the compound [VIII] include alkali metal salts such as lithium salt, sodium salt and potassium salt, addition salts with trialkylamine such as triethylamine and diisopropylamine, and the like. The nucleophilic substitution reaction between the compound [VII] and the compound [VIII] is usually carried out by using ketones such as acetone, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, acetonitrile and the like. It is preferably carried out in an inert solvent such as nitriles, alcohols such as methanol, ethanol and n-propanol, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethylsulfoxide. The amount of the nucleophile [VIII] used is usually 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of the compound [VII]. The reaction temperature is -30 ° C to 120 ° C, preferably -20
The temperature is from 80 ° C to 80 ° C. The reaction is carried out for 5 minutes to 24 hours, preferably 15 to 10 hours. This reaction can be accelerated by adding a base or a salt. Examples of these bases and salts include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; and organic amines such as trialkylamines such as triethylamine and diisopropylethylamine. As the salts, quaternary ammonium salts such as tetrabutylammonium salts are used.

Examples of the compound represented by R ⁵ Z which is reacted with the compound [X] include C _1-6 lower alkyl halide, C _2-6 lower alkenyl halide, C _2-6 lower alkynyl halide, hydroxy lower alkyl halide, Carboxy lower alkyl halides, carbamoyl lower alkyl halides, lower alkenoyl lower alkyl halides and the like can be mentioned. Examples of the above various halides include chloride, bromide, iodide and the like. The reaction of the compound [X] with the quaternary ammonium agent is usually dichloromethane,
Halogenated hydrocarbons such as dichloroethane, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, ether solutions such as diethyl ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, methanol, ethanol, n- It is preferably carried out in an inert solvent such as alcohols such as propanol, amides such as dimethylformamide and dimethylacetamide, and sulfoxys such as dimethylsulfoxide. The amount of the quaternary ammonium agent used is 1 to 50 mol, preferably 5 to 20 mol. The reaction temperature is 0 to 120 ° C, preferably 15 to 100 ° C. The reaction is carried out for 0.5 to 48 hours, preferably 1 to 24 hours. Removal of the protecting group from the compound [XI] obtained above can be carried out, for example, by treating with water when the protecting group is a tri (lower) alkylsilyl group. When the protective group is a benzhydryl group, a trityl group, a p-methoxybenzyl group, a tert-butyl group, a tert-butoxycarbonyl group, a formyl group, etc., formic acid, hydrochloric acid, trifluoroacetic acid, acetic acid, phenol, cresol It can be removed by treating with a kind. Due to the deprotection reaction, Y
A 7-amino compound [II] having S is obtained.

The compound [I] in which Y = S is also produced, for example, by the production methods (2) and (3). Production method (2): For example, formula [XII]

Embedded image [In the formula, m is 0 or 1, and other symbols have the same meanings as described above. ] And a compound represented by the formula [VIII]

Embedded image [The symbols in the formula are as defined above. ] By reacting with a compound represented by the formula [XIII]

Embedded image [The symbols in the formula are as defined above. ] The compound of the formula [XIV] is prepared by reacting with a quaternary ammonium agent.

Embedded image The method for producing the compound according to (1) above, wherein the compound represented by the formula has the same meaning as above, and the protecting group is removed.

The nucleophilic substitution reaction of the compound [XII] and the compound [VIII] is carried out by the compound [VII] and the compound [VII] of the production method (1).
It can be carried out under the same reaction conditions as the reaction with I].
Compound [XIII] is converted to quaternary ammonium by the production method (1).
Can be carried out under the same reaction conditions as the reaction of the compound [X] with the quaternary ammonium agent. The protecting group can be removed from the compound [XIV] thus obtained by the method shown in the production method (1) to produce the compound of the present invention of the formula [I].

Production method (3): For example, the formula [XII]

Embedded image [The symbols in the formula are as defined above. ] And a compound represented by the formula [XV]

Embedded image [The symbols in the formula are as defined above. ] Represented by the formula [XIV]

Embedded image [The symbols in the formula are as defined above. ] The manufacturing method of the compound as described in said (1) characterized by manufacturing the compound represented by these, and further removing a protecting group. The reaction between the compound [XII] and the compound [XV] can be carried out under the same reaction conditions as the reaction between the compound [VII] and the compound [VIII] in the production method (1). The protecting group can be removed from the compound [XIV] thus obtained by the method shown in the production method (1) to produce the compound of the present invention of the formula [I].

The compound [XII] used in the present production method has the formula [XII]
VI)

Embedded image [The symbols in the formula are as defined above. ] And a compound represented by the formula [III]

Embedded image [The symbols in the formula are as defined above. ] It is manufactured by reacting the carboxylic acid represented by the above or its salt or its reactive derivative in the same manner as in the manufacturing method (1).
Further, the compound [XV] in the present production method is the compound [VII
It is produced by carrying out I] and a quaternary ammonium-forming agent under the same reaction conditions as in the quaternary ammonium-forming reaction of the compound [X] of the production method (1). The compound [I] in which Y = O or CH ₂ is described, for example, in JP-A-53-21188 and Tetrahedron Letters, Vol. 26, page 3787 (1985).
Year)) or a compound prepared by a method analogous thereto, or a compound prepared by the method described in US 4123528 or Heterocycles, Vol. 7, page 839 (1977) or a method analogous thereto.
X]

Embedded image [The symbols in the formula are as defined above. 3-
Methyloxacephem or formula [XX]

Embedded image [The symbols in the formula are as defined above. 3-
Methylcarbacephem is produced according to the production methods (1) to (3) using a compound produced by the method described in JP-A-55-154978 or a method analogous thereto as a raw material. Among the reactions of the above-mentioned production methods (1) to (3),
If necessary, the target compound [I] of the present invention can be obtained by removing the protecting group and purifying. Hereinafter, the method for removing the protecting group and the method for purification will be described.

Protecting group removal method: As described above, the protecting group of amino group has been well studied in the field of β-lactam and peptide synthesis, and its protecting method and deprotecting method have already been established. In the present invention, the conventional technique can be used for the removal of the protecting group. For example, a monohalogenoacetyl group (eg, chloroacetyl, bromoacetyl, etc.) is treated with thiourea, an alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.) is treated with an acid (eg, hydrochloric acid, etc.), and aralkyloxy. A carbonyl group (eg, benzyloxycarbonyl,
p-methylbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.) can be converted into 2,2,
2-Trichloroethoxycarbonyl can be removed with 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, aralkyl ester (eg, benzyl ester, benzhithryl ester, p-methoxybenzyl ester, p-nitrobenzyl ester, etc.) is treated with an acid (eg, trifluoroacetic acid, etc.) or catalytic reduction. , 2,2,2-Trichloroethyl ester can be removed with zinc and an acid (eg, acetic acid, etc.), and silyl ester (eg, trimethylsilyl ester, tert-butyldimethylsilyl ester, etc.) can be removed with water only. For the reduction of S-oxide, a method established in the field of β-lactam is used, and the conventional technique can be used as it is in the present invention. For example, phosphorus trichloride and phosphorus tribromide are used. Purification method of compound [I]: Compound formed in the reaction mixture by various production methods detailed in Production methods (1) to (3) 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 to a desired physiologically acceptable salt by a known method.

The compound [I] of the present invention has broad-spectrum antibacterial activity, low toxicity, human and mammalian (eg,
It can be safely used for the prevention and treatment of various diseases caused by pathogenic bacteria in mice, rats, rabbits, dogs, cats, cows, pigs, etc., such as respiratory tract infection and urinary tract infection. The antibacterial spectrum of the antibacterial compound [I] has the following features. (1) Very high activity against various Gram-negative bacteria. (2) It has high activity against Gram-positive bacteria (eg Staphylococcus aureus, Corynebacterium diphtheriae, etc.). (3) It has high activity against methicillin-resistant Staphylococcus aureus (MRSA). (4) Many β-lactamase-producing Gram-negative bacteria (e.g., Escherichia, Enterobacter, Serratia,
It also has high activity against Proteus and the like). Further, the antibacterial compound of the present invention (I) has (1) excellent stability, (2) high blood concentration, (3) long duration of effect, (4) remarkable tissue migration. It also has some features.

The compound [I] of the present invention is used in the same manner as known penicillin agents and cephalosporin agents, injections, capsules,
It can be administered parenterally or orally as tablets or granules (particularly preferably injections). The dose is 0.5 to 80 mg / day, more preferably 2 to 4 as compound [I] per 1 kg of body weight of humans and animals infected with the above-mentioned pathogenic bacteria.
The dose may be 0 mg / day divided into 2 to 3 times a day. When used as an injection, the carrier is, for example, distilled water,
When physiological saline is used and used as capsules, powders, granules and tablets, known pharmacologically acceptable excipients (eg starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), Used as a mixture with binders (eg starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose etc.), lubricants (eg magnesium stearate, talc etc.), destroying agents (eg carboxymethyl calcium, talc etc.) To be The pharmaceutical composition and the antibacterial composition used in the present specification may be the compound [I] alone, may include the carrier as described above, and other antibacterial compounds and the like. May be contained in an appropriate amount.

[0047]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further described in detail by the following reference examples, examples and test examples, but these examples are merely illustrative and do not limit the present invention. You may change within the range which does not deviate from the range. Elution by column chromatography in Reference Examples and Examples was carried out under the observation by TLC (Thin Layer Chromatography, thin layer chromatography). In the TLC observation, the 60F ₂₅₄ Merck (Merck) manufactured as a TLC plate, the solvent used as an elution solvent in column chromatography as a developing solvent, employing a UV detector as a detection method. As the silica gel for the column, Kieselgel 60 (70-230 mesh) also manufactured by Merck was used. "Sephadex" is Pharmacia Fine Chemicals (Pharmacia Fine Chemicals)
s). XAD-2 resin is manufactured by Rohm & Haas Co. Diaion HP20 is manufactured by Mitsubishi Kasei. NMR spectra are measured using tetramethylsilane as an internal or external standard.
Measured with an emini 200 type spectrometer and measured all δ values.
Shown in ppm. In the mixed solvents, the numerical values shown in parentheses are the volume mixing ratios of the respective solvents. Further,% 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: multiplet bs : Broad singlet J: Coupling constant

[0048]

【Example】

Reference Example 1 7β-tert-butoxycarbonylamino-3-[(E) -2- (5-methylthiazolo [4,5-c] pyridinium-2-yl) thioethenyl]
-3-cephem-4-carboxylate iodide diphenylmethyl 7β-tert-butoxycarbonylamino
-3-[(E) -2- (tosyloxy) ethenyl] -3-cephem-4-carboxylate 1-oxide (679mg), 2-mercaptothiazolo [4,5-c] pyridine (216mg), dimethylformamide (D
Diisopropylamine (209 μl) was added to the mixture of MF (6 ml), and the mixture was stirred at 60 ° C. for 1 hr. Ethyl acetate (100 ml) was added, the mixture was washed with water and saturated brine, and dried (MgSO ₄ ). The solvent was evaporated, the residue was subjected to silica gel chromatography, and eluted with ethyl acetate to diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(E) -2- (thiazolo [4,5-] pyridine-
2-yl) thioethenyl] -3-cephem-4-carboxylate
The 1-oxide was obtained as an oil (216 mg, 32.0%). NMR
(CDCl ₃ ): 1.48 (9H, s), 3.38 (1H, d, J = 18.2Hz), 4.24
(1H, d, J = 18.2Hz), 4.58 (1H, d, J = 4.8Hz), 5.71-5.89
(2H, m), 7.00 (1H, s), 7.21-7.52 (11H, m), 7.63 (1H,
d, J = 15.8Hz), 7.75 (1H, d, J = 5.6Hz), 8.49 (1H, d, J = 5.
6Hz), 9.20 (1H, s). A DMF (1.5 ml) solution of this oily substance was cooled to −70 ° C., phosphorus trichloride (86.5 μl) was added, and the mixture was stirred for 10 minutes, and then added to aqueous sodium hydrogen carbonate-ethyl acetate (1: 1, 20 ml). The organic layer was separated, washed with water, and dried (MgSO ₄ ). The solvent was evaporated, the residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (1: 1), and diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(E) -2- (thiazolo [4 , 5-] Pyridin-2-yl) thioethenyl] -3-cephem-4-carboxylate was obtained as an oil (182 mg, 83.9%). NMR (CDCl ₃ ): 1.48 (9H,
s), 3.69 (1H, d, J = 17.6Hz), 3.82 (1H, d, J = 17.6Hz),
5.05 (1H, d, J = 4.8Hz), 5.29 (1H, d, J = 9.0Hz), 5.69 (1
H, dd, J = 4.8, 9.0Hz), 7.00 (1H, s), 7.20-7.49 (12H,
m), 7.75 (1H, d, J = 5.6Hz), 8.48 (1H, d, J = 5.6Hz), 9.
20 (1H, s). This oily matter was mixed with acetone (12 ml), tetrahydrofuran (THF,
4 ml), methyl iodide (372 μl) was added, and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated, ether was added to the residue, and diphenylmethyl 7β-tert-butoxycarbonylamino-3- was added.
[(E) -2- (5-Methylthiazolo [4,5-c] pyridinium-2-yl) thioethenyl] -3-cephem-4-carboxylate iodide was obtained as crystals (174 mg, 78.7%). NMR (DMSO-
d ₆ ): 1.43 (9H, s), 3.75 (1H, d, J = 18.0Hz), 4.10 (1H,
d, J = 18.0Hz), 4.44 (3H, s), 5.24 (1H, d, J = 5.0Hz),
5.651H, dd, J = 5.0, 8.2Hz), 7.00 (1H, s), 7.17-7.49
(12H, m), 8.13 (1H, d, J = 8.2Hz), 8.74 (1H, d, J = 7.2H
z), 8.80 (1H, d, J = 7.2Hz), 9.74 (1H, s).

Reference Example 2 Diphenylmethyl 7β-tert-butoxycarbonylamino
-3-[(E) -2- (1-methylpyridinium-4-ylthiazole-2
-Yl) thioethenyl] -3-cephem-4-carboxylate
Iodide diphenylmethyl 7β-tert-butoxycarbonylamino
-3-[(E) -2- (tosyloxy) ethenyl] -3-cephem-4-carboxylate 1-oxide (1.7 g), 4- (4-pyridyl) -2-
Mercaptothiazole (582mg), dimethylformamide
Triethylamine (0.42 ml) was added dropwise to the mixture (15 ml) under ice cooling. After stirring at room temperature for 3 hours, the mixture was added to sodium bicarbonate water and extracted with ethyl acetate. The extract was washed with water and dried (MgSO ₄ ), the solvent was evaporated, and the residue was dissolved in dimethylformamide (10 ml). Then add phosphorus trichloride (0.65 ml) dropwise at -40 ° C for 20 minutes.
The mixture was stirred at -40 ° C and added to sodium bicarbonate water. After extracting with ethyl acetate, washing with water and drying (MgSO ₄ ), the solvent was evaporated and the residue was subjected to silica gel chromatography and eluted with ethyl acetate to obtain diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(E) -2- (Four
-(4-Pyridyl) thiazol-2-yl) thioethenyl] -3-cephem-4-carboxylate was obtained as crystals (807 mg, 4
7%). NMR (CDCl ₃ ): 1.48 (9H, s), 3.68 (1H, d, J = 17.2H
z), 3.72 (1H, d, J = 17.2Hz), 5.04 (1H, d, J = 4.8Hz),
5.27 (1H, d, J = 9.2Hz), 5.68 (1H, dd, J = 4.8, 9.2Hz),
6.99 (1H, s), 7.11 (1H, d, J = 16Hz), 7.30-7.47 (11H,
m), 7.66 (1H, s), 7.76 (2H, d, J = 6.2Hz), 8.69 (2H, d,
J = 6.2Hz). Diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(E) -2- (4- (4-pyridyl) thiazol-2-yl) thioethenyl] -3-cephem-4-carboxylate (137mg), iodinated Methyl (0.25 ml), tetrahydrofuran-acetone
The mixture of (1: 3, 2 ml) was stirred at room temperature for 16 hours. The solvent was evaporated, isopropyl ether was added to the residue, and diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(E)-
2- (4- (1-Methylpyridinium-4-yl) thiazol-2-yl) thioethenyl] -3-cephem-4-carboxylate iodide was quantitatively obtained as a powder. NMR (DMSO-d ₆ ): 1.42
(9H, s), 3.73 (1H, d, J = 17.6Hz), 4.07 (1H, d, J = 17.6H
z), 4.32 (3H, s), 5.21 (1H, d, J = 4.8Hz), 5.61 (1H, d
d, J = 4.8, 9.0Hz), 6.95 (1H, s), 7.11 (1H, d, J = 15.8H
z), 7.24-7.49 (11H, m), 8.11 (1H, d, J = 9.0Hz), 8.57 (2
H, d, J = 7.0Hz), 8.98 (1H, s), 9.00 (2H, d, J = 7.0Hz).

Reference Example 3 7β-Amino-3- [4- (1-methylpyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate 4- (4-pyridyl) -2 -Mercaptothiazole (388 mg) and tetrahydrofuran (10 ml) in a mixture of NaH (60% oil content,
80 mg) was added, and the mixture was stirred at room temperature for 20 minutes. Under cooling to -15 ℃,
p-Methoxybenzyl 7-phenylacetamido-3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylate (1.06 g) was added, and the mixture was stirred at -15 ° C for 30 minutes. Water was added and the obtained crystals were collected by filtration, washed with water and cooled acetone, and p-methoxybenzyl 7-phenylacetamide-3- [4-
(4-Pyridyl) thiazol-2-yl] thio-3-cephem-4-carboxylate was obtained (1.10 g, 87.3%). NMR (DMSO-
d ₆ ): 3.46-3.69 (3H, m), 3.70 (3H, s), 3.94 (1H, d, J =
17.8Hz), 5.23 (2H, s), 5.28 (1H, d), 5.82 (1H, dd, J =
5.0, 8.0Hz), 6.84 (2H, d, J = 8.4Hz), 7.22-7.30 (7H,
m), 7.89 (2H, d, J = 6.0Hz), 8.52 (1H, s), 8.66 (2H, d,
J = 6.0Hz), 9.27 (1H, d, J = 8.4Hz). p-Methoxybenzyl 7-phenylacetamide-3- [4- (4-
Methyl iodide (2.0 ml) was added to a mixture of pyridyl) thiazol-2-yl] thio-3-cephem-4-carboxylate (1.0 g) and dimethylformamide (15 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, ether was added to the residue, and p-methoxybenzyl 7-phenylacetamido-3- [4- (1-methylpyridinium-4-yl) thiazol-2-yl] thio-3-cephem-
4-Carboxylate iodide was obtained as crystals (1.2 g,
95%). Pyridine (0.364 ml) was added dropwise to a mixture of phosphorus pentachloride (936 mg) and dichloromethane (6 ml) under ice cooling, and the mixture was stirred under ice cooling for 1 hour. Then p-methoxybenzyl 7-phenylacetamido-3- [4- (1-methylpyridinium-4-yl) thiazole-2-
Ile] thio-3-cephem-4-carboxylate iodide
(1.16 g) was added, and the mixture was further stirred for 1 hr, cooled to -30 ° C, and methanol (2.0 ml) was added dropwise. After stirring at -10 ° C for 1 hour, ether was added and the supernatant was removed. The residue was dissolved in dichloromethane (6 ml) and anisole (0.5 ml), trifluoroacetic acid (3 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr, and the solvent was evaporated. Ether was added to the residue, and the precipitate was collected by filtration, dissolved in aqueous sodium hydrogen carbonate solution, subjected to diaion HP-20 chromatography, eluted with 20% ethanol, concentrated, freeze-dried, and 7β-amino-3- [4- (1 -Methylpyridinium-4-yl) thiazole-
2-yl] thio-3-cephem-4-carboxylate was obtained as a powder (427 mg, 70%). NMR (D ₂ O): 3.48 (1H, d, J = 17.
6Hz), 3.87 (1H, d, J = 17.6Hz), 4.30 (3H, s), 4.79 (1H,
d, J = 5.2Hz), 5.16 (1H, d, J = 5.2Hz), 8.27 (2H, d, J =
7.0Hz), 8.44 (1H, s), 8.69 (2H, d, J = 7.0Hz).

Reference Example 4 Diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(E) -2- (7-methylthiazolo [5,
4-b] pyridinium-2-yl) thioethenyl] -3-cephem-4
-Produced a carboxylate iodide. NMR (DMSO-
d ₆ ): 1.42 (9H, s), 3.76 (1H, d, J = 17.6Hz), 4.11 (1H,
d, J = 17.6Hz), 4.50 (3H, s), 5.23 (1H, d, J = 5.4Hz), 5.
65 (1H, dd, J = 5.4, 8.4Hz), 6.99 (1H, s), 7.11-7.46 (1
2H, m), 8.08-8.21 (2H, m), 8.96 (1H, d, J = 7.6Hz), 9.
07 (1H, d, J = 5.8Hz).

Reference Example 5 The following compounds were produced in the same manner as in Reference Example 3. 7β-Amino-3- [4- (1- (2-thiazolylmethyl) pyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate hydrochloride NMR (D ₂ O): 3.64 ( 1H, d, J = 17.6Hz), 3.93 (1H, d, J = 17.
6Hz), 5.19 (1H, d, J = 5.0Hz), 5.40 (1H, d, J = 5.0Hz),
6.15 (2H, s), 7.73 (1H, d, J = 3.2Hz), 7.85 (1H, d, J =
3.2Hz), 8.41 (2H, d, J = 7.0Hz), 8.59 (1H, s), 8.93 (2
H, d, J = 7.0 Hz). 7β-Amino-3- (5-methylthiazolo [4,5-c] pyridinium-
2-yl) thio-3-cephem-4-carboxylate NMR (D ₂ O): 3.58 (1H, d, J = 17.6Hz), 4.03 (1H, d, J = 17.
6Hz), 4.58 (3H, s), 4.88 (1H, d, J = 5.2Hz), 5.27 (1H,
d, J = 5.2Hz), 8.49 (2H, m), 9.26 (1H, s). 7β-Amino-3- [4- (1-methylpyridinium-3-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate NMR (D ₂ O): 3.50 (1H, d, J = 17.4Hz), 3.88 (1H, d, J = 17.
4Hz), 4.42 (3H, s), 4.85 (1H, d, J = 5.2Hz), 5.18 (1H,
d, J = 5.2Hz), 8.05 (1H, dd, 6.2, 8.0Hz), 8.15 (1H,
s), 8.71 (1H, d, J = 6.2Hz), 8.81 (1H, d, J = 8.9Hz), 9.
21 (1H, s). 7β-Amino-3- [4- (1-methylpyridinium-2-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate NMR (DMSO-D ₆ ): 3.50 (1H, d, J = 17.6Hz), 3.84 (1H, d, J
= 17.6Hz), 4.40 (3H, s), 4.66 (1H, d, J = 5.4Hz), 4.99
(1H, d, J = 5.4Hz), 8.15 (1H, m), 8.36 (1H, m), 8.51 (1
H, s), 8.62 (1H, m), 9.08 (1H, m). 7β-amino-3- [5-methyl-4- (1-methylpyridinium-4-
Il) thiazol-2-yl] thio-3-cephem-4-carboxylate NMR (D ₂ O): 2.61 (3H, s), 3.43 (1H, d, J = 17.4Hz), 3.80
(1H, d, J = 17.4Hz), 4.30 (3H, s), 4.78 (1H, d, J = 5.2H
z), 5.12 (1H, d, J = 5.2Hz), 8.14 (1H, d, J = 6.4Hz), 8.
69 (1H, d, J = 6.4Hz).

Reference Example 6 3- (4-pyridyl) thiophene 4-pyridineboronic acid (1.23 g), 3-bromothiophene (1.63
g), tetrakis (triphenylphosphine) palladium
(0) (0.58g), 2M sodium carbonate aqueous solution (8ml), toluene
A mixture of (20 ml) and ethanol (5 ml) was heated under reflux for 5 hours under a nitrogen stream. Extract with ethyl acetate, wash the extract with water,
It was dried (MgSO ₄ ). The solvent was evaporated, the residue was subjected to silica gel chromatography, and hexane-ethyl acetate (2:
Elution in 1) gave the title compound (0.8g, 49.7%). NMR (CDCl
₃ ): 7.45 (2H, d, J = 2.2Hz), 7.49 (2H, d, J = 6.2Hz), 7.
66 (1H, t, J = 2.2Hz), 8.62 (2H, d, J = 6.2Hz). Reference Example 7 2- (2,4-dinitrophenylthio) -4- (4-pyridyl) thiophene 3- (4-pyridyl) thiophene (0.8 g), 2,4-dinitrophenylsulfenyl chloride (1.29 g), Nitroethane (15 ml)
Aluminum chloride (1.33 g) was added to the mixture of 2
Stirred for hours. H ₂ O was added, the mixture was neutralized with an aqueous sodium hydrogen carbonate solution, the insoluble material was filtered off, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried (MgSO ₄ ) and the solvent was distilled off. The residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (1: 1) to give the title compound (0.85g, 47.8%).
NMR (CDCl ₃ ): 7.25 (1H, d, J = 9.2Hz), 7.51 (2H, d, J =
6.2Hz), 7.77 (1H, d, J = 1.6Hz), 8.02 (1H, d, J = 1.6H
z), 8.26 (1H, dd, J = 2.6, 9.2Hz), 8.70 (2H, d, J = 6.2H
z), 9.13 (1H, d, J = 2.6Hz).

Reference Example 8 7β-Amino-3- [4- (1-methylpyridinium-4-yl) thiophen-2-yl] thio-3-cephem-4-carboxylate 2- (2,4-dinitrophenyl Thio) -4- (4-pyridyl) thiophene (0.72g), potassium hydroxide (0.16g), methanol (15m
After heating the mixture of (l) to reflux for 30 minutes, the solvent is distilled off,
Potassium 4- (4-pyridyl) thiophene-2-thiolate was obtained as a powder. It was collected by filtration and washed with ether. This product was reacted with p-methoxybenzyl 7-phenylacetamido-3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylate by the method described in Reference Example 3, and treated in the same manner as in Reference Example 3, The title compound was obtained. NMR
(D ₂ O): 3.08 (1H, d, J = 17.2Hz), 3.41 (1H, d, J = 17.2H)
z), 4.25 (1H, s), 4.63 (1H, d, J = 6.0Hz), 4.85 (1H, d,
J = 6.0Hz), 7.59 (1H, s), 7.99 (2H, d, J = 6.4Hz), 8.27
(1H, s), 8.58 (2H, d, J = 6.4Hz). Reference Example 9 7β-Amino-3- [4- (1-methylpyridinium-3-yl) thiophen-2-yl] thio-3-cephem-4-carboxylate By the same method as in Reference Examples 6, 7, and 8. The title compound was obtained. NMR (D ₂ O): 3.29 (1H, d, J = 17.6Hz), 3.53 (1H, d, J
= 17.6Hz), 4.36 (3H, s), 4.65 (1H, d, J = 4.0Hz), 4.98
(1H, d, J = 4.0Hz), 7.61 (1H, d, J = 1.4Hz), 8.00 (1H,
m), 8.02 (1H, d, J = 1.4Hz), 8.58 (2H, m), 9.01 (1H, s).

Reference Example 10 5-Acetyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine 2- (2-thienyl) ethylamine (26.0 g) was added to acetic anhydride (42.0 m
l) was added dropwise at -15 ° C. After stirring at -15 ° C for 30 minutes and further at room temperature for 30 minutes, the solvent was distilled off. Toluene (300
ml), paraformaldehyde (7.36 g) and p-toluenesulfonic acid hydrate (1.94 g) were added, and the mixture was equipped with a Dean-Stark water separator and heated under reflux for 40 minutes. The extract was washed successively with aqueous sodium hydrogen carbonate solution and water, dried (MgSO ₄ ) and the solvent was evaporated. The residue was subjected to silica gel chromatography,
Elution with hexane-acetone (2: 1) gave the title compound.
(24.0g, 65%). _{NMR (CDCl 3): 2.18 (} 1.5H, s), 2.20 (1.5
H, s), 2.52 (3H, s), 2.87-2.99 (2H, m), 3.76 (1H, t,
J = 5.8Hz), 3.92 (1H, t, J = 5.8Hz), 4.55 (1H, s), 4.67 (1
H, s), 7.40 (1H, s). Reference Example 11 5-Acetyl-4,5,6,7-tetrahydro-2- (2,4-dinitrophenylthio) thieno [3,2-c] pyridine 5-Acetyl-4,5,6,7-tetrahydro A mixture of thieno [3,2-c] pyridine (23.8g), 2,4-dinitrophenylsulfenyl chloride (32.3g) and nitroethane (240ml) under ice cooling,
Aluminum chloride (21.0 g) was added slowly. 30 under ice cooling
The mixture was stirred for 1 minute at room temperature for 1 hour, added to ice water and extracted with ethyl acetate. The extract was washed with water and dried (MgSO ₄ ) and the solvent was evaporated to give the title compound as crystals. It was collected by filtration and washed with isopropyl ether (47.0 g, 94%). _{NMR (CDCl 3): 2.21 (} 1.5H,
s), 2.24 (1.5H, s), 2.92-3.00 (2H, m), 3.83 (1H, t, J
= 5.8Hz), 4.60 (1H, s), 4.73 (1H, s), 7.15-7.29 (2H,
m), 8.22-8.29 (1H, m), 9.10 (0.5H, s), 9.11 (0.5H, s).

Reference Example 12 4,5,6,7-Tetrahydro-2- (2,4-dinitrophenylthio)
Thieno [3,2-c] pyridine 5-acetyl-4,5,6,7-tetrahydro-2- (2,4-dinitrophenylthio) thieno [3,2-c] pyridine (12.3g), 6N HCl (50
ml), dimethoxyethane (50 ml) and ethanol (15 ml) were heated under reflux for 7 hours. The solvent was distilled off, and the obtained crystals were collected by filtration and washed with acetone. This crystal was added to an aqueous sodium hydrogen carbonate solution, and ethyl acetate-tetrahydrofuran was added.
Extracted at (1: 1). The extract was dried (MgSO ₄ ) and the solvent was evaporated to give the title compound. _{NMR (CDCl 3): 2.89 (} 2H, t,
J = 5.8Hz), 3.22 (2H, t, J = 5.8Hz), 3.98 (2H, s), 7.08 (1
H, s), 7.27 (1H, d, J = 9.0Hz), 8.23 (1H, dd, J = 2.4,
9.0Hz), 9.10 (1H, d, J = 2.4Hz). Reference Example 13 2- (2,4-dinitrophenylthio) thieno [3,2-c] pyridine 4,5,6,7-tetrahydro-2- (2,4-dinitrophenylthio)
Thieno [3,2-c] pyridine (9.33g), manganese dioxide (50g),
Add a mixture of dimethoxyethane (130 ml) and toluene (130 ml).
The mixture was refluxed for 2 hours. Manganese dioxide was distilled off, the filtrate was concentrated, and the obtained crystals were collected by filtration and washed with ether to obtain the title compound (6.62 g, 65%). _{NMR (CDCl 3): 7.28 (} 1
H, d, J = 9.0 Hz), 7.82-7.86
(1H, m), 7.88 (1H, d, J = 1.
0 Hz), 8.25 (1H, dd, J = 2.6,
9.0 Hz), 8.61 (1H, d, J = 5.8)
Hz), 9.15 (1H, d, J = 2.6H
z), 9.22 (1H, d, J = 1.0 Hz).

Reference Example 14 Potassium thieno [3,2-c] pyridine-2-thiolate A solution of potassium hydroxide (317 mg) in methanol (25 ml) was added with 2-
(2,4-Dinitrophenylthio) thieno [3,2-c] pyridine (1.
33 g) was added and the mixture was heated under reflux for 0.5 hr. The solvent was distilled off, and the obtained crystals were collected by filtration and washed with ether to give the title compound quantitatively. NMR (CD ₃ OD): 6.85 (1H, s), 7.50 (1H, d,
J = 5.0Hz), 7.97 (1H, d, J = 5.0Hz), 8.45 (1H, s). Reference Example 15 2- (2,4-Dinitrophenylthio) thieno [2,3-c] pyridine According to the method described in Reference Examples 10, 11, 12, and 13, the title compound was obtained from 2- (3-thienyl) ethylamine. Manufactured. NMR (C
DCl ₃ ): 7.27 (1H, d, J = 9.0Hz), 7.78 (1H, d, J = 5.6Hz),
7.80 (1H, s), 8.25 (1H, dd, J = 2.2, 9.0Hz), 8.64 (1H,
d, J = 5.6Hz), 9.15 (1H, d, J = 2.6Hz), 9.21 (1H, s).

Reference Example 16 Potassium thieno [2,3-c] pyridine-2-thiolate In the same manner as in Reference Example 14, 2- (2,4-dinitrophenylthio)
The title compound was prepared from thieno [2,3-c] pyridine. NMR
(DMSO-d ₆ ): 6.33 (1H, s), 6.98 (1H, d, J = 5.6Hz), 7.93
(1H, d, J = 5.6Hz), 8.32 (1H, s). Reference Example 17 7β-amino-3- (5-methylthieno [3,2-c] pyridinium-2-
Il) thio-3-cephem-4-carboxylate By using potassium thieno [3,2-c] pyridine-2-thiolate obtained in Reference Example 14 and in the same manner as in Reference Example 3, the title compound was obtained. . NMR (DMSO-d ₆ ): 3.20 (1H, d, J = 17.0H
z), 3.70 (1H, d, J = 17.0Hz), 4.37 (3H, s), 4.65 (1H,
d, J = 5.2Hz), 4.96 (1H, d, J = 5.2Hz), 7.78 (1H, s), 8.
62 (2H, s), 9.41 (1H, s). Reference Example 18 7β-amino-3- (6-methylthieno [2,3-c] pyridinium-2-
Il) thio-3-cephem-4-carboxylate By using potassium thieno [2,3-c] pyridine-2-thiolate obtained in Reference Example 16 and in the same manner as in Reference Example 3, the title compound was obtained. . NMR (DMSO-d ₆ ): 3.25 (1H, d, J = 17.0H
z), 3.81 (1H, d, J = 17.0Hz), 4.31 (3H, s), 4.69 (1H,
d, J = 5.2Hz), 5.02 (1H, d, J = 5.2Hz), 7.59 (1H, s), 8.
11 (2H, d, J = 6.0Hz), 8.57 (1H, d, J = 6.0Hz), 9.52 (1H,
s).

Reference Example 19 7β-Amino-3-[(E) -2- (5-methylthieno [3,2-c] pyridinium-2-yl) thioethenyl] -3-cephem-4-carboxylate ditrifluoroacetate Potassium thieno [3,2-c] pyridine-2-thiolate (1.17g)
Was cooled to 0 ° C and diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(E) -2- (tosyloxy) ethenyl] -3-cephem-4-carboxylate 1-oxide (2.46
g) was added to a solution of dimethylformamide (20 ml) in small portions. After stirring at 0 ° C. for 30 minutes, the mixture was diluted with ethyl acetate, washed with water and dried (MgSO ₄ ), and the solvent was evaporated. The residue was dissolved in dimethylformamide (18 ml), and phosphorus trichloride (0.96 ml) was added dropwise while cooling to -40 ° C. The mixture was stirred at -40 ° C for 15 minutes, added to ice water, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and water, and dried (MgSO ₄ ). The solvent was evaporated, the residue was subjected to silica gel chromatography, and eluted with hexane-ethyl acetate (1: 1), diphenylmethyl 7β-tert-butoxycarbonylamino-3-[(E) -2-
(Thieno [3,2-c] pyridin-2-yl) thioethenyl] -3-cephem-4-carboxylate was obtained (1.27 g). This product was dissolved in dimethylformamide (8 ml), methyl ethoxide (2 ml) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, isopropyl ether was added to the residue, the mixture was stirred well, and isopropyl ether was removed. The residue was dichloromethane (10 ml),
Dissolve in anisole (2 ml) and cool on ice with trifluoroacetic acid.
(10 ml) was added. After stirring at room temperature for 2 hours, the solvent was evaporated, ether was added, and the precipitate was collected by filtration to give the title compound. NM
R (DMSO-d ₆ ): 3.66 (1H, d, J = 18.0H
z), 3.97 (1H, d, J = 18.0H
z), 4.41 (3H, s), 4.93 (1H,
d, J = 5.2 Hz), 5.11 (1H, d,
J = 5.2 Hz), 7.16 (2H, s), 8.
03 (1H, s), 8.71 (2H, s), 9.
47 (1H, s).

Reference Example 20 7β-amino-3- [4- (1-carbamoylmethylpyridinium
-4-yl) Thiazol-2-yl] thio-3-cephem-4-carboxylate To a solution of phosphorus pentachloride (1.25 g) in dichloromethane (10 ml), pyridine (0.45 ml) was added under ice cooling. After stirring for 30 minutes under ice cooling, p-methoxybenzyl 7β-phenylacetamido-3- [4- (4-pyridyl) thiazol-2-yl] obtained in Reference Example 3 was obtained.
Thio-3-cephem-4-carboxylate (1.4g) was added.
The mixture was stirred under ice-cooling for 1 hour, and then methanol (2 ml) was added dropwise under cooling to -30 ° C. Stir for 30 minutes at 0 ° C, then add ether (50m
l) was added and the supernatant was removed. Aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried (MgSO ₄ ), then the solvent was distilled off, and tetrahydrofuran (10 m
It was dissolved in l). Di-tert-butyl dicarbonate (0.83 g) was added,
After stirring at room temperature for 2 hours, add ethyl acetate, wash with water and dry.
After (MgSO ₄ ), the solvent was distilled off. The residue was subjected to silica gel chromatography and eluted with hexane-acetone (1: 1) to isolate p-methoxybenzyl 7β-tert-butoxycarbonylamino-3- [4- (4-pyridyl) thiazol-2-yl] thio. -3
-Cephem-4-carboxylate was obtained. This product is dissolved in dimethylformamide (6 ml) and iodinated acetamide (1.8 ml) is added.
g) was added, the mixture was stirred at room temperature for 45 hours, ether was added, and the precipitate was collected by filtration and p-methoxybenzyl 7β-tert-butoxycarbonylamino-3- [4- (1-carbamoylmethylpyridinium-4-
Yield) thiazol-2-yl] thio-3-cephem-4-carboxylate iodide was obtained (0.6 g). This product was dissolved in dichloromethane (5 ml) and anisole (0.5 ml), trifluoroacetic acid (5 ml) was added under ice cooling, and the mixture was stirred at room temperature for 40 minutes. Ether was added, and the precipitated powder was collected by filtration to give the title compound (0.4
g, 95.2%). NMR (DMSO-d ₆ ): 3.75 (1H, d, J = 16.6Hz),
3.99 (1H, d, J = 16.6Hz), 5.24 (1H, d, J = 6.0Hz), 5.36
(1H, d, J = 6.0Hz), 5.39 (2H, s), 7.73 (1H, s), 8.08 (1
H, s), 8.61 (2H, d, J = 6.0Hz), 8.98 (2H, d, J = 6.0Hz),
9.11 (1H, s).

Example 1 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Methoxyiminoacetamido] -3-[(E) -2- (5-methylthiazolo [4,5-c] pyridinium-2-yl) thioethenyl] -3-
Cephem-4-carboxylate diphenylmethyl 7β-tert-butoxycarbonylamino
-3-[(E) -2- (5-methylthiazolo [4,5-c] pyridinium-2-
Il) thioethenyl] -3-cephem-4-carboxylate
Trifluoroacetic acid (0.7 ml) was added to a mixture of iodide (86 mg), dichloromethane (0.7 ml) and anisole (100 μ),
The mixture was stirred at room temperature for 1 hour. The solvent was evaporated, saturated aqueous sodium hydrogen carbonate (1.0 ml) and THF (1.0 ml) were added to the residue, and the mixture was stirred under ice-cooling,
2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z) -methoxyiminoatyl chloride hydrochloride (55 mg) was added. 1
After 0 minutes, THF was distilled off, and the residue was subjected to diaion HP-20 column chromatography, eluted with 20% ethanol, concentrated and freeze-dried to obtain the title compound (25 mg, 39.6%). IR (KBr) cm ^-1 : 3400, 1770, 1670, 1603. NMR (DMSO-
d ₆ ): 3.54 (1H, d, J = 17.0Hz), 3.68 (1H, d, J = 17.0Hz),
3.93 (3H, s), 4.41 (3H, s), 5.13 (1H, d, J = 5.0Hz),
5.68 (1H, dd, J = 5.0, 8.2Hz), 6.65 (1H, d, J = 15.2Hz),
7.68 (1H, d, J = 15.2Hz), 8.16 (2H, s), 8.71 (1H, d, J
= 6.6Hz), 8.76 (1H, d, J = 6.6Hz), 9.58 (1H, d, J = 8.2H
z), 9.70 (1H, s). Example 2 The following compounds were produced in the same manner as in Example 1. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamide] -3-[(E) -2- (5-
Methylthiazolo [4,5-c] pyridinium-2-yl) thioethenyl] -3-cephem-4-carboxylate IR (KBr) cm ⁻¹ : 3425, 1770, 1670, 1610. NMR (DMSO-
d ₆ ): 3.55 (1H, d, J = 16.8Hz), 3.67 (1H, d, J = 16.8Hz),
4.41 (3H, s), 5.14 (1H, d, J = 5.0Hz), 5.67 (1H, dd, J =
5.0, 7.8Hz), 5.81 (2H, d, J = 54.2Hz), 6.64 (1H, d, J =
15.4Hz), 7.70 (1H, d, J = 15.4Hz), 8.23 (2H, s), 8.70
(1H, d, J = 6.6Hz), 8.76 (1H, d, J = 6.6Hz), 9.68 (1H,
s), 9.76 (1H, d, J = 7.8Hz).

Example 3 The following compounds were produced in the same manner as in Example 1. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Ethoxyiminoacetamido] -3-[(E) -2- (5-methylthiazolo [4,5-c] pyridinium-2-yl) thioethenyl] -3-
Cephem-4-carboxylate IR (KBr) cm ⁻¹ : 3400, 1762, 1670, 1605. NMR (DMSO-
d ₆ ): 1.29 (3H, t, 7.0Hz), 3.58 (1H, d, 16.8Hz), 3.75
(1H, d, J = 16.8Hz), 4.21 (2H, q, J = 7.0Hz), 4.43 (3H,
s), 5.17 (1H, d, J = 5.2Hz), 7.75 (1H, dd, J = 5.2, 8.0H
z), 6.77 (1H, d, J = 15.4Hz), 7.64 (1H, d, J = 15.4Hz),
8.17 (2H, s), 8.721H, d, J = 6.6Hz), 8.78 (1H, d, J = 6.
6Hz), 9.58 (1H, d, J = 8.0Hz), 9.71 (1H, s). Example 4 The following compounds were produced in the same manner as in Example 1. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
- isopropoxycarbonyl alkoximinoalkyl syn-amide] -3 - [(E) -2- (5- methylthiazolo [4,5-c] pyridinium-2-yl) Chioeteniru] -3-cephem-4-carboxylate IR (KBr) cm ^{- 1} : 3400, 1762, 1670, 1602. NMR (DMSO-
d ₆ ): 1.19-1.30 (6H, m), 3.55 (1H, d, J = 16.8Hz), 3.70
(1H, d, J = 16.8Hz), 4.41 (1H, m), 4.42 (3H, s), 5.15 (1
H, d, J = 5.2Hz), 5.70 (1H, dd, J = 5.2, 8.4Hz), 6.69 (1
H, d, J = 15.4Hz), 7.68 (1H, d, J = 15.4Hz), 8.17 (2H,
s), 8.71 (1H, d, 6.8Hz), 8.77 (1H, d, J = 6.8Hz), 9.53
(1H, d, J = 8.4Hz), 9.70 (1H, s).

Example 5 The following compounds were produced in the same manner as in Example 1. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Cyclopentyloxyiminoacetamide] -3-[(E) -2-
(5-Methylthiazolo [4,5-c] pyridinium-2-yl) thioethenyl] -3-cephem-4-carboxylate IR (KBr) cm ⁻¹ : 3400, 1762, 1662, 1602. NMR (DMSO-
d ₆ ): 1.24-1.92 (8H, m), 3.53 (1H, d, J = 16.8Hz), 3.66
(1H, d, J = 16.8Hz), 4.41 (3H, s), 4.74 (1H, m), 5.13 (1
H, d, J = 5.0Hz), 5.64 (1H, dd, J = 6.0, 8.4Hz), 6.95 (1
H, d, J = 15.0), 7.69 (1H, d, J = 15.0Hz), 8.15 (2H, s),
8.70 (1H, d, J = 6.6Hz), 8.76 (1H, d, J = 6.6Hz), 9.52
(1H, d, J = 8.4Hz), 9.68 (1H, s). Example 6 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Methoxyiminoacetamido] -3-[(E) -2- (4- (1-methylpyridinium-4-yl) thiazol-2-yl) thioethenyl
-3-Cephem-4-carboxylate Diphenylmethyl 7β-tert-butoxycarbonylamino
-3-[(E) -2- (4- (1-Methylpyridinium-4-yl) thiazol-2-yl) thioethenyl] -3-cephem-4-carboxylate iodide (130 mg), anisole (0.25 ml) , Dichloromethane (1.5 ml) under ice cooling to a mixture of trifluoroacetic acid (1.5
ml) was added and the mixture was stirred at room temperature for 1 hour. Ether was added, the precipitate was collected by filtration, dissolved in tetrahydrofuran-water (1: 1, 2 ml), and 2- (5-amino-1,2,4-thiadiazol-3-yl) was added while keeping the pH at 9 with sodium bicarbonate solution. -2 (Z) -Methoxyiminoatyl chloride hydrochloride (82 mg) was added. After stirring for 30 minutes, tetrahydrofuran was distilled off, and the residue was subjected to diaion HP-20 chromatography, eluted with 20% ethanol and concentrated,
Lyophilization gave the title compound (9 mg, 9%). IR (KBr): 1765, 1640, 1605. NMR (DMSO-d ₆ ): 3.52 (1H,
d, J = 18.4Hz), 3.62 (1H, d, J = 18.4Hz), 3.93 (3H, s),
4.30 (3H, s), 5.09 (1H, d, J = 5.2Hz), 5.65 (1H, dd, J =
5.2, 8.4Hz), 6.53 (1H, d, J = 15.4Hz), 7.57 (1H, d, J =
15.4Hz), 8.14 (2H, s), 8.56 (2H, d, J = 6.8Hz), 8.92 (1
H, s), 8.97 (2H, d, J = 6.8Hz), 9.56 (1H, d, 8.4Hz).

Example 7 The following compounds were produced in the same manner as in Example 6. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamide] -3-[(E) -2- (4-
(1-Methylpyridinium-4-yl) thiazol-2-yl) thioethenyl-3-cephem-4-carboxylate IR (KBr): 1765, 1640, 1600. NMR (DMSO-d ₆ ): 3.53 (1H,
d, J = 17Hz), 3.63 (1H, d, J = 17.0Hz), 4.31 (3H, s), 5.1
1 (1H, d, J = 4.8Hz), 5.67 (1H, dd, J = 4.8, 8.4Hz), 5.8
0 (2H, d, J = 54.0Hz), 6.53 (1H, d, J = 15.2Hz), 7.57 (1
H, d, J = 15.2Hz), 8.23 (2H, bs), 8.56 (2H, d, J = 6.4H
z), 8.93 (1H, s), 8.98 (2H, d, J = 6.4Hz), 9.76 (1H, d,
J = 8.4Hz). Example 8 The following compounds were produced in the same manner as in Example 6. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Ethoxyiminoacetamido] -3-[(E) -2- (4- (1-methylpyridinium-4-yl) thiazol-2-yl) thioethenyl
-3-Cephem-4-carboxylate IR (KBr): 1765, 1640, 1600. NMR (DMSO-d ₆ ): 1.27 (3H,
t, J = 7.0Hz), 3.53 (1H, d, J = 18.0Hz), 3.64 (1H, d, J =
18.0Hz), 4.19 (2H, q, J = 7.0Hz), 4.31 (3H, s), 5.10 (1
H, d, J = 5.0Hz), 5.66 (1H, dd, J = 5.0, 8.4Hz), 6.53 (1
H, d, J = 15.2Hz), 7.57 (1H, d, J = 15.2Hz), 8.16 (2H, b
s), 8.57 (2H, d, J = 7.0Hz), 8.93 (1H, s), 8.98 (2H, d,
J = 7.0Hz), 9.55 (1H, d, J = 8.4Hz).

Example 9 The following compounds were produced in the same manner as in Example 6. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Isopropoxyiminoacetamide] -3-[(E) -2- (4- (1-
Methylpyridinium-4-yl) thiazol-2-yl) thioethenyl-3-cephem-4-carboxylate IR (KBr): 1760, 1635, 1600. NMR (DMSO-d ₆ ): 1.26 (3H,
d, J = 6.0Hz), 1.28 (3H, d, J = 6.0Hz), 3.52 (1H, d, J = 1
7.2Hz), 3.64 (1H, d, J = 17.2Hz), 4.31 (3H, s), 4.31-
4.48 (1H, m), 5.10 (1H, d, J = 5.0Hz), 5.66 (1H, dd, J =
5.0, 8.4Hz), 6.53 (1H, d, J = 15.4Hz), 7.56 (1H, d, J =
15.4Hz), 8.16 (2H, s), 8.52 (2H, d, J = 6.2Hz), 8.92 (1
H, s), 8.97 (2H, d, J = 6.2Hz), 9.52 (1H, d, J = 8.4Hz). Example 10 The following compounds were produced in the same manner as in Example 6. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Cyclopentyloxyiminoacetamide] -3-[(E) -2-
(4- (1-methylpyridinium-4-yl) thiazol-2-yl)
Thioethenyl-3-cephem-4-carboxylate IR (KBr): 1765, 1635, 1605. NMR (DMSO-d ₆ ): 1.42-2.00
(8H, m), 3.52 (1H, d, J = 17.6Hz), 3.62 (1H, d, J = 17.6H
z), 4.31 (3H, s), 4.70-4.77 (1H, m), 5.10 (1H, d, J =
4.8Hz), 5.64 (1H, dd, J = 4.8, 8.2Hz), 6.53 (1H, d, J =
15.2Hz), 7.57 (1H, d, 15.2Hz), 8.15 (2H, bs), 8.56 (2
H, d, J = 6.6Hz), 8.92 (1H, s), 8.98 (2H, d, J = 6.6Hz),
9.50 (1H, d, J = 8.2Hz).

Example 11 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Isopropoxyiminoacetamido] -3- [4- (1-methylpyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate 7-amino-3- [4- (1- Methylpyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate (81m
A solution of g) in water-tetrahydrofuran (1: 2,3 ml) was adjusted to pH 8 with aqueous sodium hydrogen carbonate, and 2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)-was added. Isopropoxy iminoatyl chloride hydrochloride (86 mg) was added in small portions. After 15 minutes the tetrahydrofuran was distilled off and the residue was subjected to diaion HP-20 chromatography, eluting with 20% and 25% ethanol,
Concentration and freeze-drying gave the title compound (47 mg, 40.5%). IR (KBr): 1775, 1640, 1610. NMR (DMSO-d ₆ ): 1.23 (3H,
d, J = 6.4Hz), 1.27 (3H, d, J = 6.4Hz), 3.32 (1H, d, J = 1
7.2Hz), 3.90 (1H, d, J = 17.2Hz), 4.32 (3H, s), 4.39 (1
H, m), 5.19 (1H, d, J = 5.2Hz), 5.72 (1H, dd, J = 5.2,
8.4Hz), 8.17 (2H, s), 8.46 (2H, d, J = 6.6Hz), 8.89 (1
H, s), 8.97 (2H, d, J = 6.6Hz), 9.61 (1H, d, J = 8.4Hz). Example 12 The following compound was produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamido] -3- [4- (1-methylpyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1775, 1640, 1610. NMR (DMSO-d ₆ ): 3.34 (1H,
d, J = 16.8Hz), 3.89 (1H, d, J = 16.8Hz), 4.30 (3H, s),
5.19 (1H, d, J = 5.0Hz), 5.74'1H, dd, J = 5.0,8.4Hz),
5.79 (2H, d, J = 54.6Hz), 8.22 (2H, d, J = 6.8Hz), 8.49
(2H, d, J = 6.8Hz), 8.88 (1H, s), 8.95 (2H, d, J = 6.8H
z), 9.84 (1H, d, J = 8.4Hz).

Example 13 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Ethoxyiminoacetamido] -3- [4- (1-methylpyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-
Carboxylate IR (KBr): 1775, 1640, 1615. NMR (DMSO-d ₆ ): 1.25 (3H,
t, J = 7.0Hz), 3.34 (1H, d, J = 17.2Hz), 3.89 (1H, d, J =
17.2Hz), 4.18 (2H, q, J = 7.0Hz), 4.30 (3H, s), 5.18 (1
H, d, J = 5.2Hz), 5.73 (1H, dd, J = 5.2, 8.4Hz), 8.13 (2
H, s), 8.49 (2H, d, J = 6.6Hz), 8.88 (1H, s), 8.95 (2H,
d, J = 6.6Hz), 9.62 (1H, d, J = 8.4Hz). Example 14 The following compound was produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Cyclopentyloxyiminoacetamide] -3- [4- (1-
Methylpyridinium-4-yl) thiazol-2-yl] thio-3
-Cephem-4-carboxylate IR (KBr): 1770, 1640, 1615. NMR (DMSO-d ₆ ): 1.42-1.98
(8H, m), 3.33 (1H, d, J = 17.6Hz), 3.90 (1H, d, J = 17.6H
z), 4.30 (3H, s), 4.70-4.78 (1H, m), 5.18 (1H, d, J =
5.2Hz), 5.70 (1H, dd, J = 5.2, 8.2Hz), 8.14 (2H, s),
8.49 (2H, d, J = 6.6Hz), 8.89 (1H, s), 8.95 (2H, d, J =
6.6Hz), 9.75 (1H, d, J = 8.2Hz).

Example 15 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Methoxyiminoacetamido] -3- [4- (1-methylpyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-
Carboxylate IR (KBr): 1770, 1640, 1610. _{NMR (DMSO-d 6):} 3.53 (1H,
d, J = 17.5Hz), 3.91 (1H, d, J = 17.5Hz), 3.92 (3H, s),
4.31 (3H, s), 5.17 (1H, d, J = 5.2Hz), 5.74 (1H, dd, J =
5.2, 8.4Hz), 8.15 (2H, s), 8.47 (2H, d, J = 6.6Hz), 8.
89 (1H, s), 8.97 (2H, d, J = 6.6Hz), 9.66 (1H, d, J = 8.4
Hz). Example 16 The following compounds were produced in the same manner as in Example 1. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Methoxyiminoacetamido] -3-[(E) -2- (7-methylthiazolo [5,4-b] pyridinium-2-yl) thioethenyl] -3-
Cephem-4-carboxylate IR (KBr): 3400, 1770, 1670, 1600. _{NMR (DMSO-d 6):} 3.5
8 (1H, d, J = 17.0Hz), 3.73 (1H, d, J = 17.0Hz), 3.93 (3H,
s), 4.50 (3H, s), 5.13 (1H, d, J = 4.8Hz), 5.69 (1H, d
d, J = 4.8, 8.4Hz), 6.66 (1H, d, J = 15.2Hz), 7.71 (1H,
d, J = 15.2Hz), 8.09-8.17 (4H, m), 8.91 (1H, d, J = 8.2H
z), 9.04 (1H, d, J = 5.8Hz), 9.58 (1H, d, J = 8.4Hz).

Example 17 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Methoxyiminoacetamido] -3- [4- (1- (2-thiazolylmethyl) pyridinium-4-yl) thiazol-2-yl] thio-
3-Cephem-4-carboxylate IR (KBr): 1770, 1670, 1635, 1610. NMR (DMSO-d ₆ ): 3.3
4 (1H, d, J = 16.8Hz), 3.89 (1H, d, J = 16.8Hz), 3.91 (3H,
s), 5.16 (1H, d, J = 5.2Hz), 5.72 (1H, dd, J = 5.2, 8.4
Hz), 6.24 (2H, s), 7.86 (1H, d, J = 3.2Hz), 7.89 (2H,
d, J = 3.2Hz), 8.12 (2H, bs), 8.58 (2H, d, J = 6.8Hz),
8.93 (1H, s), 9.16 (2H, d, J = 6.8Hz), 9.63 (1H, d, J =
8.4Hz). Example 18 The following compound was produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamido] -3- [4- (1- (2-thiazolylmethyl) pyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1770, 1670 , 1635, 1610. NMR (DMSO-d ₆ ):
3.34 (1H, d, J = 17.0 Hz), 3.9
0 (1H, d, J = 17.0 Hz), 4.30
(3H, s), 5.19 (1H, d, J = 5.
2 Hz), 5.74 (1H, dd, J = 5.2,
8.0 Hz), 5.78 (2H, d, J = 5)
5.2 Hz), 6.25 (2H, s), 7.86
(1H, d, J = 3.2Hz), 7.88 (1H,
d, J = 3.2 Hz), 8.20 (2H, b
s), 8.57 (2H, d, J = 6.6 Hz),
8.92 (1H, s), 9.16 (2H, d,
J = 6.6 Hz), 9.84 (1H, d, J =
8.0 Hz).

Example 19 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Methoxyiminoacetamido] -3- (1- (5-methylthiazolo [4,5-c] pyridinium-2-yl) thio-3-cephem-4-carboxylate IR (KBr): 1775, 1645, 1610. NMR (D ₂ O): 3.61 (1H, d, J
= 18.4Hz), 4.07 (1H, d, J = 18.4Hz), 4.08 (3H, s), 4.52
(3H, s), 5.44 (1H, d, J = 4.8Hz), 5.92 (1H, d, J = 4.8H
z), 8.48 (2H, m), 9.26 (1H, s). Example 20 The following compound was produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamido] -3- (1- (5-methylthiazolo [4,5-c] pyridinium-2-yl) thio-3-cephem-4-carboxylate IR (KBr): 1775, 1645, 1610. NMR (D ₂ O): 3.63 (1H, d, J
= 16.8Hz), 4.09 (1H, d, J = 16.8Hz), 4.47 (3H, s), 5.47
(1H, d, J = 4.6Hz), 5.87 (1H, d, J = 53.8Hz), 5.87 (1H,
d, J = 4.6Hz), 8.49 (2H, m), 9.27 (1H, s).

Example 21 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Methoxyiminoacetamido] -3- [4- (1-methylpyridinium-3-yl) thiazol-2-yl] thio-3-cephem-4-
Carboxylate IR (KBr): 1770, 1665, 1610. _{NMR (DMSO-d 6):} 3.31 (1H,
d, J = 16.4Hz), 3.87 (1H, d, J = 16.4Hz), 3.92 (3H, s),
4.42 (3H, s), 5.16 (1H, d, J = 5.2Hz), 5.72 (1H, dd, J =
5.2, 8.6Hz), 8.12-8.18 (3H, m), 8.52 (1H, s), 8.92 (1
H, d, J = 6.2Hz), 8.99 (1H, d, J = 9.2Hz), 9.52 (1H, s),
9.64 (1H, d, J = 8.6Hz). Example 22 The following compound was produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamido] -3- [4- (1-methylpyridinium-3-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1770, 1670, 1620. _{NMR (DMSO-d 6):} 3.31 (1H,
d, J = 16.8Hz), 3.88 (1H, d, J = 16.8Hz), 4.42 (3H, s),
5.18 (1H, d, J = 5.0Hz), 5.74 (1H, dd, J = 5.0, 8.4Hz),
5.79 (2H, d, J = 55.4Hz), 8.16 (1H, dd, J = 5.6, 8.4Hz),
8.22 (2H, s), 8.51 (1H, s), 8.92 (1H, d, J = 5.6Hz),
8.98 (1H, d, J = 8.4Hz), 9.52 (1H, s), 9.85 (1H, d, J =
8.4Hz).

Example 23 The following compound was produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Methoxyiminoacetamido] -3- [4- (1-methylpyridinium-2-yl) thiazol-2-yl] thio-3-cephem-4-
Carboxylate IR (KBr): 1770, 1660, 1610. NMR (DMSO-d ₆ ): 3.28 (1H,
d, J = 16.0Hz), 3.86 (1H, d, J = 16.0Hz), 3.92 (3H, s),
4.40 (3H, s), 5.16 (1H, d, J = 5.0Hz), 5.72 (1H, dd, J =
5.0, 8.2Hz), 8.11 (1H, m), 8.16 (2H, s), 8.53 (1H,
s), 8.64 (1H, m), 9.52 (1H, d, J = 5.2Hz), 9.66 (1H, d,
J = 8.4Hz). Example 24 The following compound was produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamido] -3- [4- (1-methylpyridinium-2-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1775, 1660, 1615. NMR (DMSO-d ₆ ): 3.30 (1H,
d, J = 17.6Hz), 3.86 (1H, d, J = 17.6Hz), 4.40 (3H, s),
5.18 (1H, d, J = 5.0Hz), 5.73 (1H, dd, J = 5.0, 8.4Hz),
8.11 (1H, m), 8.25 (2H, s), 8.34 (1H, d, J = 7.8Hz),
8.63 (1H, m), 9.11 (1H, d, J = 3.8Hz), 9.86 (1H, d, J =
8.4Hz).

Example 25 The following compound was produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Isopropoxyiminoacetamido] -3- [4- (1-methylpyridinium-2-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1770, 1660, 1610. NMR (DMSO-d ₆ ): 1.22 (3H,
d, J = 4.6Hz), 1.27 (3H, d, J = 4.6Hz), 3.27 (1H, d, J = 1
7.2Hz), 3.88 (1H, d, J = 17.2Hz), 4.37 (1H, m), 4.40 (3
H, s), 5.18 (1H, d, J = 5.0Hz), 5.73 (1H, dd, J = 5.0, 9.
0Hz), 8.11 (1H, m), 8.17 (2H, s), 8.54 (1H, s,), 8.
63 (1H, m), 9.11 (1H, d, J = 6.0Hz), 9.61 (1H, d, J = 8.6
Hz). Example 26 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Methoxyiminoacetamido] -3- [4- (1-methylpyridinium-3-yl) thiophen-2-yl] thio-3-cephem-4-
Carboxylate IR (KBr): 1770, 1660, 1610. NMR (DMSO-d ₆ ): 3.19 (1H,
d, J = 18.6Hz), 3.41 (1H, d, J = 18.6Hz), 3.88 (3H, s),
4.39 (3H, s), 4.99 (1H, d, J = 5.0Hz), 5.58 (1H, dd, J =
5.0, 9.0Hz), 7.91 (1H, d, J = 1.4Hz), 8.14 (3H, m),
8.44 (1H, d, J = 1.4Hz), 8.89 (2H, d, J = 6.2Hz), 9.50 (1
H, d, J = 8.6Hz), 9.53 (1H, s).

Example 27 The following compound was prepared in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamido] -3- [4- (1-methylpyridinium-3-yl) thiophen-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1770, 1665, 1610. NMR (DMSO-d ₆ ): 3.1
9 (1H, d, J = 17.0 Hz), 3.40
(1H, d, J = 17.0 Hz), 4.39 (3
H, s), 5.01 (1H, d, J = 4.6H
z), 5.61 (1H, dd, J = 4.6, 8.0)
Hz), 5.75 (2H, d, J = 55.2H
z), 7.91 (1H, d, J = 1.4 Hz),
8.14 (1H, m), 8.23 (2H, m
s), 8.43 (1H, d, J = 1.4 Hz),
8.89 (2H, d, J = 6.2Hz), 9.5
3 (1H, s), 9.70 (1H, d, J = 8.
0 Hz). Example 28 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Isopropoxyiminoacetamido] -3- [4- (1-methylpyridinium-3-yl) thiophen-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1770, 1660, 1615. NMR (DMSO-d ₆ ): 1.19 (3H,
d, J = 3.2Hz), 1.22 (3H, d, J = 3.2Hz), 3.18 (1H, d, J =
17.2Hz), 3.49 (1H, d, J = 17.2Hz), 4.36 (1H, m), 4.39
(3H, s), 5.01 (1H, d, J = 4.8Hz), 5.61 (1H, dd, J = 4.8,
8.6Hz), 7.91 (1H, d, J = 1.4Hz), 8.16 (3H, m), 8.44 (1
H, d, J = 1.4Hz), 8.89 (2H, d, J = 7.0Hz), 9.52 (1H, s).

Example 29 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Isopropoxyiminoacetamido] -3- [4- (1-methylpyridinium-3-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1770, 1670, 1610. NMR (DMSO-d ₆ ): 1.23 (3H,
d, J = 6.0Hz), 1.26 (3H, d, J = 6.0Hz), 3.31 (1H, d, J = 1
6.8Hz), 3.88 (1H, d, J = 16.8Hz), 4.33-4.45 (1H, m),
4.42 (3H, s), 5.18 (1H, d, J = 5.2Hz), 5.73 (1H, dd, J =
5.2, 8.6Hz), 8.13-8.20 (3H, m), 8.52 (1H, s), 8.92 (1
H, d, J = 5.6Hz), 8.98 (1H, d, J = 8.2Hz), 9.52 (1H, s),
9.60 (1H, d, J = 8.6Hz). Example 30 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Ethoxyiminoacetamido] -3- [4- (1-methylpyridinium-3-yl) thiazol-2-yl] thio-3-cephem-4-
Carboxylate IR (KBr): 1770, 1670, 1615. NMR (DMSO-d ₆ ): 1.25 (3H,
t, J = 7.0Hz), 3.31 (1H, d, J = 17.2Hz), 3.87 (1H, d, J =
17.2Hz), 4.18 (2H, q, J = 7.0Hz), 4.42 (3H, s), 5.17 (1
H, d, J = 5.0Hz), 5.73 (1H, dd, J = 5.0, 8.4Hz), 8.12-
8.19 (3H, m), 8.51 (1H, s), 8.91 (1H, d, J = 6.2Hz), 8.
97 (1H, d, J = 8.6Hz), 9.51 (1H, s), 9.63 (1H, d, J = 8.4
Hz).

Example 31 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Methoxyiminoacetamide] -3- (5-methylthieno [3,2
-c] pyridinium-2-yl) thio-3-cephem-4-carboxylate IR (KBr): 1770, 1665, 1610. _{NMR (DMSO-d 6):} 3.23 (1H,
d, J = 17.0Hz), 3.70 (1H, d, J = 17.0Hz), 3.89 (3H, s),
4.48 (3H, s), 5.10 (1H, d, J = 5.2Hz), 5.68 (1H, dd, J =
5.2, 8.2Hz), 7.82 (1H, s), 8.14 (2H, bs), 8.63 (2H,
s), 9.42 (1H, s), 9.60 (1H, d, J = 8.2Hz). Example 32 The following compound was produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamido] -3- (5-methylthieno [3,2-c] pyridinium-2-yl) thio-3-cephem-4-
Carboxylate IR (KBr): 1770, 1670, 1610. NMR (DMSO-d ₆ ): 3.22 (1H,
d, J = 16.6Hz), 3.71 (1H, d, J = 16.6Hz), 4.38 (3H, s),
5.13 (1H, d, J = 5.0Hz), 7068 (1H, dd, J = 5.0,8.2Hz),
5.77 (2H, d, J = 55.2Hz), 7.82 (1H, s), 8.23 (2H, bs),
8.63 (2H, s), 9.43 (1H, s), 9.80 (1H, d, J = 8.2Hz).

Example 33 The following compounds were prepared in the same manner as in Example 1. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamide] -3-[(E) -2- (5-
Methylthieno [3,2-c] pyridinium-2-yl) thioethenyl] -3-cephem-4-carboxylate IR (KBr): 1760, 1670, 1600. NMR (DMSO-d ₆ ): 3.49 (1H,
d, J = 17.2Hz), 3.63 (1H, d, J = 17.2Hz), 4.83 (3H, s),
5.10 (1H, d, J = 5.2Hz), 5.65 (1H, dd, J = 5.2,8.4Hz),
5.80 (2H, d, J = 55.0Hz), 6.51 (1H, d, J = 15.2Hz), 7.50
(1H, d, J = 15.2Hz), 7.81 (1H, s), 8.23 (2H, bs), 8.64
(2H, s), 9.40 (1H, s), 9.75 (1H, d, J = 8.4Hz). Example 34 The following compounds were produced in the same manner as in Example 1. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamide] -3-[(E) -2- (7-
Methylthiazolo [5,4-b] pyridinium-2-yl) thioethenyl] -3-cephem-4-carboxylate IR (KBr): 1760, 1670, 1600. _{NMR (DMSO-d 6):} 3.57 (1H,
d, J = 16.0Hz), 3.70 (1H, d, J = 16.0Hz), 4.51 (3H, s),
5.15 (1H, d, J = 4.8Hz), 5.69 (1H, dd, J = 4.8,8.0Hz),
5.81 (2H, d, J = 55.8Hz), 6.62 (1H, d, J = 14.8Hz), 7.73
(1H, d, J = 14.8Hz), 8.13 (1H, dd, J = 6.0, 8.4Hz), 8.2
4 (2H, s), 8.92 (1H, d, J = 8.4Hz), 9.04 (1H, d, J = 6.0H
z), 9.78 (1H, d, J = 8.0Hz).

Example 35 The following compound was prepared in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Isopropoxyiminoacetamido] -3- (5-methylthieno [3,2-c] pyridinium-2-yl) thio-3-cephem-4-carboxylate IR (KBr): 1770, 1665, 1610. _{NMR (DMSO-d 6):} 1.21 (3H,
d, J = 6.2Hz), 1.23 (3H, d, J = 6.2Hz), 3.23 (1H, d, J = 1
6.8Hz), 3.70 (1H, d, J = 16.8Hz), 4.30-4.44 (1H, m),
4.38 (3H, s), 5.12 (1H, d, J = 4.8Hz), 5.71 (1H, dd, J =
4.8, 8.4Hz), 7.84 (1H, s), 8.16 (2H, bs), 8.64 (2H,
s), 9.42 (1H, s), 9.55 (1H, d, J = 8.4Hz). Example 36 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamido] -3- (6-methylthieno [2,3-c] pyridinium-2-yl) thio-3-cephem-4-
Carboxylate IR (KBr): 1770, 1670, 1615. NMR (DMSO-d ₆ ): 3.29 (1H,
d, J = 17.0Hz), 3.83 (1H, d, J = 17.0Hz), 4.31 (3H, s),
5.19 (1H, d, J = 5.0Hz), 5.74 (1H, dd, J = 5.0,8.4Hz),
5.79 (2H, d, J = 54.6Hz), 7.64 (1H, s), 8.14 (1H, d, J =
6.6Hz), 8.22 (2H, bs), 8.58 (1H, d, J = 6.6Hz), 9.51 (1
H, s), 9.85 (1H, d, J = 8.4Hz).

Example 37 The following compounds were produced in the same manner as in Example 1. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Isopropoxyiminoacetamido] -3-[(E) -2- (5-methylthiazolo [3,2-c] pyridinium-2-yl) thioethenyl] -3-cephem-4-carboxylate IR (KBr): 1760 , 1670, 1600. NMR (DMSO-d ₆ ): 1.26 (3H,
d, J = 6.2Hz), 1.28 (3H, d, J = 6.2Hz), 3.48 (1H, d, J = 1
6.8Hz), 3.64 (1H, d, J = 16.8Hz), 4.34-4.46 (1H, m),
4.39 (3H, s), 5.09 (1H, d, J = 4.8Hz), 5.65 (1H, dd, J =
4.8, 8.4Hz), 6.52 (1H, d, J = 15.2Hz), 7.49 (1H, d, J =
15.2Hz), 7.81 (1H, s), 8.18 (2H, bs), 8.64 (2H, s),
9.41 (1H, s), 9.52 (1H, d, J = 8.4Hz). Example 38 The following compound was prepared in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Isopropoxyiminoacetamido] -3- (6-methylthieno [2,3-c] pyridinium-2-yl) thio-3-cephem-4-carboxylate IR (KBr): 1770, 1660, 1615. NMR (DMSO-d ₆ ): 1.23 (3H,
d, J = 6.2Hz), 1.25 (3H, d, J = 6.2Hz), 3.30 (1H, d, J =
16.8Hz), 3.84 (1H, d, J = 16.8Hz), 4.32 (3H, s), 4.32-
4.45 (1H, m), 5.19 (1H, d, J = 5.0Hz), 5.75 (1H, dd, J =
5.0, 8.4Hz), 7.63 (1H, s), 8.12 (1H, d, J = 6.68z), 8.
16 (2H, bs), 8.58 (1H, d, J = 6.8Hz), 9.61 (1H, d, J = 8.
4Hz).

Example 39 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Ethoxyiminoacetamide] -3- (5-methylthieno [3,2
-c] pyridinium-2-yl) thio-3-cephem-4-carboxylate IR (KBr): 1765, 1660, 1610. NMR (DMSO-d ₆ ): 1.22 (3H,
t, J = 7.0Hz), 3.23 (1H, d, J = 17.2Hz), 3.70 (1H, d, J =
17.2Hz), 4.15 (1H, q, J = 7.0Hz), 4.37 (3H, s), 5.11 (1
H, d, J = 4.8Hz), 5.69 (1H, dd, J = 4.8, 8.4Hz), 7.83 (1
H, s), 8.13 (2H, bs), 8.63 (2H, s), 9.40 (1H, s), 9.5
8 (1H, d, J = 8.4Hz). Example 40 The following compounds were produced in the same manner as in Example 1. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Ethoxyiminoacetamido] -3-[(E) -2- (5-methylthiazolo [3,2-c] pyridinium-2-yl) thioethenyl] -3-
Cephem-4-carboxylate IR (KBr): 1760, 1675, 1600. NMR (DMSO-d ₆ ): 1.27 (3H,
t, J = 7.0Hz), 3.49 (1H, d, J = 17.0Hz), 3.61 (1H, d, J =
17.0Hz), 4.18 (2H, q, J = 7.0Hz), 4.18 (2H, q, J = 7.0H
z), 4.39 (3H, s), 5.08 (1H, d, J = 4.8Hz), 5.65 (1H, d
d, J = 4.8, 8.8Hz), 6.52 (1H, d, J = 15.4Hz), 7.49 (1H,
d, J = 15.4Hz), 7.81 (1H, s), 8.16 (2H, bs), 8.64 (2H,
s), 9.40 (1H, s), 9.54 (1H, d, J = 8.8Hz).

Example 41 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamide] -3- [5-methyl-4
-(1-Methylpyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1770, 1680, 1640, 1610. NMR (DMSO-d ₆ ): 2.7
1 (3H, s), 3.41 (1H, d, J = 16.8Hz), 3.85 (1H, d, J = 16.
8Hz), 4.33 (3H, s), 5.16 (1H, d, J = 5.2Hz), 5.73 (1H, d
d, J = 5.2, 8.2Hz), 5.79 (2H, d, J = 55.2Hz), 8.23 (2H,
s), 8.32 (2H, d, J = 6.8Hz), 8.94 (2H, d, J = 6.8Hz), 9.
84 (1H, d, J = 8.2Hz). Example 42 The following compound was produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Ethoxyiminoacetamido] -3- [5-methyl-4- (1-methylpyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1770, 1665, 1640, 1610. _{NMR (DMSO-d 6):} 1.2
5 (3H, t, J = 7.0Hz), 2.70 (3H, s), 3.42 (1H, d, J = 17.0
Hz), 3.84 (1H, d, J = 17.0Hz), 4.17 (2H, q, J = 7.0Hz),
4.33 (3H, s), 5.15 (1H, d, J = 4.8Hz), 5.72 (1H, dd, J =
4.8, 8.4Hz), 8.15 (2H, s), 8.31 (2H, d, J = 6.6Hz), 8.
94 (2H, d, J = 6.6Hz), 9.62 (1H, d, J = 8.4Hz).

Example 43 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Isopropoxyiminoacetamide] -3- [5-methyl-4-
(1-Methylpyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1770, 1670, 1640, 1610. _{NMR (DMSO-d 6):} 1.2
5 (6H, m), 2.74 (3H, s), 3.43 (1H, d, J = 16.6Hz), 3.85
(1H, d, J = 16.6Hz), 4.39 (1H, m), 5.16 (1H, d, J = 5.2H
z), 5.72 (1H, dd, J = 5.2, 9.2Hz), 8.15 (2H, s), 8.33 (2
H, d, J = 7.2Hz), 8.95 (2H, d, J = 7.2Hz), 9.58 (1H, d,
J = 9.2Hz). Example 44 The following compounds were produced in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamide] -3- [5-methyl-4
-(1-carbamoylmethylpyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1770, 1690, 1640, 1610. _{NMR (DMSO-d 6):} 3.5
3 (1H, d, J = 16.8Hz), 3.91 (1H, d, J = 16.8Hz), 5.21 (1H,
d, J = 5.2Hz), 5.37 (2H, s), 5.77 (1H, dd, J = 5.2, 8.2H
z), 5.81 (2H, d, J = 55.2Hz), 7.72 (1H, s), 8.25 (3H, b
s), 8.48 (2H, d, J = 6.6Hz), 8.91 (2H, s), 8.92 (2H, d,
J = 6.6Hz), 9.88 (1H, d, J = 8.2Hz).

Example 45 In the same manner as in Example 11, the following compound was prepared. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Ethoxyiminoacetamido] -3- [5-methyl-4- (1-carbamoylmethylpyridinium-4-yl) thiazol-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1770, 1690 , 1640. NMR (DMSO-d ₆ ): 1.25 (3H,
t, J = 7.4Hz), 3.40 (1H, d, J = 17.2Hz), 3.90 (1H, d, J =
17.2Hz), 4.17 (2H, q, J = 7.4Hz), 5.19 (1H, d, J = 5.2H
z), 5.36 (2H, s), 5.47 (1H, dd, J = 5.2, 8.8Hz), 7.70 (1
H, s), 8.15 (3H, bs), 8.48 (2H, d, J = 7.0Hz), 8.91 (2H,
s), 8.92 (2H, d, J = 7.0Hz), 9.63 (1H, d, J = 8.8Hz). Example 46 The following compound was prepared in the same manner as in Example 11. 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z)
-Fluoromethoxyiminoacetamido] -3- [4- (1-methylpyridinium-4-yl) thiophen-2-yl] thio-3-cephem-4-carboxylate IR (KBr): 1760, 1670, 1635, 1605 . NMR (DMSO-d ₆ ): 3.
19 (1H, d, J = 16.8Hz), 3.54 (1H, d, J = 16.8Hz), 4.29 (3
H, s), 5.02 (1H, d, J = 4.8Hz), 5.62 (1H, dd, J = 4.8, 8.
4Hz), 5.76 (2H, d, J = 55.8Hz), 8.04 (1H, d, J = 1.2Hz),
8.25 (2H, bs), 8.43 (2H, d, J = 6.6Hz), 8.78 (1H, d, J
= 1.2Hz), 8.95 (2H, d, J = 6.6Hz), 9.74 (1H, d, J = 8.4H
z). The structural formulas of the compounds of Examples are as follows.

[0084]

[Table 1]

[0085]

[Table 2]

[0086]

[Table 3]

[0087]

[Table 4]

[0088]

[Table 5]

[0089]

[Table 6]

Test Example 1 Test compound minimum inhibitory concentration (MIC)
concentration) is the agar dilution method
determined by d). That is, 1.0 ml of an aqueous solution of the test compound diluted in sequence was poured into a petri dish,
Next, trypticase soy agar
9.0 ml of agar) was poured and mixed. A suspension of test bacteria (about 10 ⁶ CFU / ml) was spread on the mixed agar plate. After incubation at 37 ° C. overnight, the lowest concentration of the test compound that completely inhibits the growth of the test strain was defined as MIC. Test bacteria: (1) Staphylococcus aureus N133 (MR
SA) ( Staphylococcus aureus N133) (MRSA) (2) Staphylococcus aureus OFU4 (MR
SA) ( Staphylococcus aureus OFU4) (MRSA) Results:

[0091]

[Table 7] From this result, it is clear that the cephem compound (I) of the present invention or a salt or ester thereof exhibits an excellent antibacterial action against pathogenic bacteria which are clinically regarded as important, particularly MRSA.

[0092]

INDUSTRIAL APPLICABILITY The cephem compound [I] or its ester or salt thereof of the present invention has an excellent antibacterial spectrum over a wide range against Gram-negative bacteria including Pseudomonas bacteria and Gram-positive bacteria including Staphylococcus and MRSA. It also has an antibacterial action and can provide an effective antibacterial agent against infectious diseases based on these bacteria.

Claims (13)

[Claims] (1) Formula (1) [In the formula, R ¹ represents an optionally protected amino group,
R ² represents a hydrogen atom or a group bonded via a carbon atom, R ³ and R ⁴ represent a pyridinium group which may be substituted on one side, and a hydrogen atom or a hydrocarbon group which may be substituted on the other side. Or R ³ and R ⁴ represent an optionally substituted heterocycle containing a quaternized nitrogen atom bonded to each other, Q and X each represent a nitrogen atom or CH, and Y represents S, O or shows a CH _2, n is 0 or 1. However, when n is 0, Y represents S or O. ] The compound represented by these, its ester, or its salt. 2. A compound of the formula [Each symbol in the formula has the same meaning as in claim 1. ] The compound represented by these, its ester, or its salt. 3. The compound according to claim 1, wherein R ² is an optionally substituted C _1-6 alkyl group or C _3-5 cycloalkyl group. 4. The compound according to claim 1, wherein R ³ is an optionally substituted pyridinium group and R ⁴ is a hydrogen atom. 5. embedded image [In the formula, R ⁵ represents an optionally substituted hydrocarbon group. ] The compound of Claim 1 which is a group shown by these. 6. The compound according to claim 1, wherein Q is a nitrogen atom. 7. The compound according to claim 1, wherein X is a nitrogen atom. 8. The compound according to claim 1, wherein n is 1. 9. The formula: [The symbols in the formula are as defined in claim 1. ] The compound or its ester or its salt represented by the following formula and [The symbols in the formula are as defined in claim 1. ] The carboxylic acid represented by these or its salt, or a reactive derivative is made to react, and a protective group is removed as needed, The manufacturing method of the compound of Claim 1 characterized by the above-mentioned. 10. The formula: [Wherein R ³ ′ and R ⁴ ′ each represent an optionally substituted pyridyl group and the other represents a hydrogen atom or an optionally substituted hydrocarbon group, or R ³ ′ and R ⁴ ′
Represents an optionally substituted heterocycle containing a nitrogen atom bonded to each other, and other symbols have the same meanings as in claim 1. ] In the compound represented by the following formula or its ester or its salt, an optionally substituted pyridyl group represented by R ³ ′ or R ⁴ ′ or a nitrogen atom formed by R ³ ′ and R ⁴ ′ bonded to each other is The method for producing a compound according to claim 1, wherein the nitrogen atom in the optionally substituted heterocycle is quaternized, and the protecting group is removed if necessary. 11. A pharmaceutical composition containing the compound according to claim 1. 12. The pharmaceutical composition according to claim 11, which is an antibacterial composition. 13. The pharmaceutical composition according to claim 11, which is an anti-MRSA agent.