JPH07112976B2 - Antibacterial agent - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention relates to an antibacterial agent containing a 2-oxa-isosephem derivative.

DISCLOSURE OF THE INVENTION As a 2-oxa-isocephem derivative having an antibacterial action, for example, compounds described in JP-A-57-192387 are known, but the isocephem derivative contained in the antibacterial agent of the present invention is It is a novel compound not described in the literature and is represented by the following general formula (1).

[In the formula, R ¹ represents an amino group, a lower alkanoylamino group, a halogen-substituted lower alkanoylamino group, or a phenyl group.
~ 3 phenyl lower alkylamino group, phenyl lower alkoxycarbonylamino group or lower alkoxycarbonylamino group; R ² is a lower alkyl group, cycloalkyl group, cyano lower alkyl group, carboxy lower alkyl group or carbamoyl lower alkyl group; R ³ represents a pyridyl group or a pyridinio group, and the pyridinio group is a lower alkyl group, a cycloalkyl lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanoyl lower alkyl group, a benzoyl lower alkyl group, a halogen-substituted lower alkyl group, a halogen-substituted lower group. Lower alkyl group substituted with alkanoyl group, carboxycarbonyl lower alkyl group, lower alkyl group substituted with lower alkoxyimino group or group: (In the formula, A is a lower alkylene group, R ⁵ is a hydrogen atom or a lower alkyl group, R ⁶ is a lower alkyl group or a hydroxy group, and R ⁵ and R ⁶ are an oxygen atom, a nitrogen atom together with a nitrogen atom to be bonded. A 5-membered or 6-membered saturated heterocycle may be formed with or without an atom or a sulfur atom, and the saturated heterocycle may be substituted with a hydroxy group or a lower alkyl group. R ⁴ represents a carboxy group, a carboxylate group or an esterified carboxy group.

However, when R ³ is a pyridinyl group or a pyridinio group substituted with a lower alkyl group, R ² represents a carbamoyl lower alkyl group. The compound represented by the above general formula (1) exhibits excellent antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria, and particularly as a Gram-positive bacterium Staphylococcus
Aureus (Staphylococcus aureus FDA-209-P),
Streptococcus pn
eumoniae) and Corynebacterium diphtheria (Co
ryne-bacterium diphtheriae). In addition, the above-mentioned compounds have the properties of good absorbability in vivo, long duration of drug effect, and low toxicity, and exhibit excellent effects against resistant bacteria and clinical isolates.
Furthermore, the above compounds have high stability and are excellent in absorption and excretion. That is, renal excretion is high and bile transfer is good. Moreover, the distribution to each organ including the lungs is high. There is little difference between the minimum inhibitory concentration and the minimum bactericidal concentration, and there are few side effects such as immunosuppressive action and allergic action.

Therefore, the antibacterial agent containing the above compound is useful as a therapeutic agent for human, animal and fish diseases caused by various pathogenic bacteria, and is also useful as an external germicide or disinfectant for medical instruments and the like.

More specifically, each group shown in the present specification is as follows.

Examples of the lower alkanoylamino group include formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pentanoylamino,
Examples thereof include alkanoylamino groups having 1 to 6 carbon atoms such as hexanoylamino.

Examples of the halogen-substituted lower alkanoylamino group include monochloroacetylamino, monofluoroacetylamino, monobromoacetylamino, monoiodoacetylamino, dichloroacetylamino, trichloroacetylamino, tribromoacetylamino, 3-chloropropionylamino, 2 , 3-dichloropropionylamino,
Halogen such as 3,3,3-trichloropropionylamino, 4-chlorobutyrylamino, 5-chloropentanoylamino, 6-chlorohexanoylamino, 3-fluoropropionylamino, 4-fluorobutyrylamino is 1 to 1
An alkanoylamino group having 2 to 6 carbon atoms, which is substituted by 3, can be exemplified.

Examples of the phenyl lower alkylamino group having 1 to 3 phenyl groups include benzyl groups such as benzylamino, α-phenethylamino, β-phenethylamino, 3-phenylpropylamino, benzhydrylamino and tritylamino. Examples thereof include phenylalkylamino groups having 3 to 3 and having 1 to 6 carbon atoms in the alkyl moiety.

As the phenyl lower alkoxycarbonylamino group,
For example, 1-phenylethoxycarbonylamino, 2-
Phenylalkoxycarbonylamino having 1 to 6 carbon atoms in the alkoxy moiety such as phenylethoxycarbonylamino, 3-phenylpropoxycarbonylamino, 4-phenylbutoxycarbonylamino, 5-phenylpentyloxycarbonylamino, 6-phenylhexyloxycarbonylamino A group can be illustrated.

As the lower alkoxycarbonylamino group, for example,
Alkoxy having 1 to 6 carbon atoms in the alkoxy moiety such as methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, tertiary butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino. A carbonylamino group can be exemplified.

Examples of the lower alkyl group include alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl.

Examples of the cycloalkyl group include cyclopropyl,
Examples thereof include cycloalkyl groups having 3 to 8 carbon atoms such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Examples of the cyano lower alkyl group include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 2-cyano-1-methylethyl, 4-cyanobutyl, 5-cyanopentyl, 6
Examples thereof include a cyano group-containing alkyl group having 1 to 6 carbon atoms such as cyanohexyl.

Examples of the carboxy lower alkyl group include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 2-carboxy-1-methylethyl, 4-carboxybutyl, 5-carboxypentyl. And an alkyl group having 1 to 6 carbon atoms having a carboxy group such as 6-carboxyhexyl.

Examples of the carbamoyl lower alkyl group include carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl, 2-carbamoylpropyl, 3-carbamoylpropyl, 2-carbamoyl-1-methylethyl,
4-carbamoylbutyl, 5-carbamoylpentyl,
Examples thereof include alkyl groups having 1 to 6 carbon atoms having a carbamoyl group such as 6-carbamoylhexyl.

As the cycloalkyl lower alkyl group, for example, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 5
-Cyclohexylpentyl, 6-cyclohexylhexyl, cyclopropylmethyl, 2-cyclobutylethyl,
Examples thereof include cycloalkyl-alkyl groups such as cyclopentylmethyl, 2-cycloheptylethyl, cyclooctylmethyl and the like, in which the cycloalkyl moiety has 3 to 8 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms.

Examples of the lower alkoxy lower alkyl group include methoxymethyl, 3-methoxypropyl, 4-ethoxybutyl, 6-propoxyhexyl, 5-isopropoxypentyl, 1,1-dimethyl-2-ethoxyethyl, and tertiary butoxymethyl. , 2-pentyloxyethyl, 6-hexyloxyhexyl, etc. have 1 to 6 carbon atoms in the alkoxy moiety.
And an alkoxyalkyl group in which the alkyl moiety has 1 to 6 carbon atoms can be exemplified.

Examples of the lower alkanoyl lower alkyl group include formylmethyl, acetonyl, 3-acetylpropyl, 4
-Acetylbutyl, 6-propionylhexyl, 5-isobutyrylpentyl, 1,1-dimethyl-2-pentanoylethyl, hexanoylmethyl, 6-hexanoylhexyl and the like have an alkanoyl moiety having 1 to 6 carbon atoms. And an alkanoylalkyl group in which the alkyl moiety has 1 to 6 carbon atoms.

The benzoyl lower alkyl group includes, for example, carbon of an alkyl moiety such as benzoylmethyl, 2-benzoylethyl, 3-benzoylpropyl, 2-benzoylbutyl, 1-benzoyl-2-methylbutyl, 5-benzoylpentyl and 6-benzoylhexyl. A benzoylalkyl group having a number of 1 to 6 can be exemplified.

Examples of the halogen-substituted lower alkyl group include chloromethyl, bromomethyl, iodomethyl, fluoromethyl, dichloromethyl, dibromomethyl, difluoromethyl, trichloromethyl, tribromomethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-
Fluoroethyl, 1,2-dichloroethyl, 2,2-difluoroethyl, 1-chloro-2-fluoroethyl, 2,2,2-
Trifluoroethyl, 2,2,2-trichloroethyl, 3-
Fluoropropyl, 3,3,3-trichloropropyl, 4-
A halogen-substituted alkyl group having 1 to 3 halogen atoms such as chlorobutyl, 5-chloropentyl, 6-chlorohexyl, 3-chloro-2-methylpropyl, etc., and having an alkyl moiety having 1 to 6 carbon atoms can be exemplified. .

Examples of the halogen-substituted lower alkanoyl group include 2
-Chloroacetyl, 2-bromoacetyl, 2-iodoacetyl, 2-fluoroacetyl, 2,2-dichloroacetyl, 2,2-difluoroacetyl, 2,2,2-trifluoroacetyl, 2,2,2-trichloro Acetyl, 3-chloropropionyl, 3-fluoropropionyl, 3,3,3-trichloropropionyl, 4-chlorobutyryl, 4-bromobutyryl, 5-chloropentanoyl, 6-chlorohexanoyl, 3-chloro-2-methylpropionyl, etc. 1-3
An example is a halogen-substituted alkanoyl group having 2 halogen atoms and an alkanoyl moiety having 2 to 6 carbon atoms. Therefore, examples of the lower alkyl group substituted with these halogen-substituted lower alkanoyl groups include 2-chloroacetylmethyl, 2-bromoacetylmethyl, 2-fluoroacetylmethyl, 2,2-dichloroacetylmethyl and 2,2
-Difluoroacetylmethyl, 2,2,2-trifluoroacetylmethyl, 2,2,2-trichloroacetylmethyl, 3
-Fluoropropionylmethyl, 4-chlorobutyrylmethyl, 5-chloropentanoylmethyl, 6-chlorohexanoylmethyl, 1- (2-chloroacetyl) ethyl,
2- (2-chloroacetyl) ethyl, 1- (2-fluoroacetyl) ethyl, 2- (2-fluoroacetyl) ethyl, 2- (2,2,2-trichloroacetyl) ethyl, 2
-(2-Fluoropropionyl) ethyl, 2- (3-chloro-2-methylpropionyl) ethyl, 2- (6-chlorohexanoyl) ethyl, 3- (2-chloroacetyl) propyl, 2- (2-chloro Acetyl) propyl,
3- (2-fluoroacetyl) propyl, 3- (3-fluoropropionyl) propyl, 3- (6-chlorohexanoyl) propyl, 3- (2-fluoroacetyl) butyl, 4- (2-fluoroacetyl) butyl , 4- (6
-Chlorohexanoyl) butyl, 5- (2-chloroacetyl) pentyl, 5- (2,2,2-trifluoroacetyl) pentyl, 5- (3-fluoropropionyl) pentyl, 5- (6-chlorohexanoyl) ) Pentyl, 6-
(2-fluoroacetyl) hexyl, 6- (5-bromopentanoyl) hexyl, 6- (6-chlorohexanoyl) hexyl and the like having the above halogen-substituted lower alkanoyl group, and having an alkyl moiety having 1 carbon atom. Examples thereof include alkyl groups substituted with a halogen-substituted alkanoyl group of -6.

Examples of the carboxycarbonyl lower alkyl group include carboxycarbonylmethyl, 1-carboxycarbonylethyl, 2-carboxycarbonylethyl, 2-
Carboxycarbonyl-1-methylethyl, 1-carboxycarbonylpropyl, 3-carboxycarbonylpropyl, 3-carboxycarbonyl-2-methylpropyl, 2-carboxycarbonylbutyl, 4-carboxycarbonylbutyl, 5-carboxycarbonylpentyl, 3- Examples thereof include an alkyl group having 1 to 6 carbon atoms having a carboxycarbonyl group such as carboxycarbonylhexyl and 6-carboxycarbonylhexyl.

The lower alkoxyimino group in the lower alkyl group substituted with a lower alkoxyimino group is a methoxyimino, ethoxyimino, propoxyimino, isopropoxyimino, butoxyimino, pentyloxyimino, hexyloxyimino or the like having 1 to 6 carbon atoms. Examples of the lower alkyl group substituted with the lower alkoxyimino group include an alkoxyimino group having an alkoxy group, and examples thereof include methoxyiminomethyl, ethoxyiminomethyl, propoxyiminomethyl, butoxyiminomethyl, and pentyloxyiminomethyl. , Hexyloxyiminomethyl, 1-methoxyiminoethyl, 2-methoxyiminoethyl, 1-ethoxyiminoethyl, 2-ethoxyiminoethyl, 2-propoxyiminoethyl, 2-propoxyiminoethyl , 2-hexyloxyiminoethyl, 1-methoxyiminopropyl, 2-methoxyiminopropyl, 3-methoxyiminopropyl, 3-ethoxyiminopropyl, 1-methoxyiminobutyl, 4-ethoxyiminobutyl, 1-methoxyiminopentyl, 5-
C1-C6 alkyl group having a lower alkoxyimino group such as methoxyiminopentyl, 5-ethoxyiminopentyl, 1-methoxyiminohexyl, 6-methoxyiminohexyl, 6-ethoxyiminohexyl, 6-hexyloxyiminohexyl Can be illustrated.

Examples of the lower alkylene group include methylene, methylmethylene, ethylene, dimethylmethylene, trimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, tetramethylene, pentamethylene and hexamethylene. An alkylene group having 1 to 6 carbon atoms can be exemplified.

Examples of the 5- or 6-membered saturated heterocyclic group formed with or without an oxygen atom, a nitrogen atom or a sulfur atom together with the nitrogen atom to be bonded include 1-piperazinyl, piperidino, 1-pyrrolidinyl, 1- Examples thereof include imidazolidinyl, morpholino, thiomorpholino, 2-isoxazolidinyl and 3-thiazolidinyl.

The ester residue in the esterified carboxy group is a normal ester residue, for example, an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. Group; benzyl, benzhydryl, α-phenethyl, β-phenethyl, α, β-diphenylethyl, 3-
Phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl and other alkyl moieties having 1 to 6 carbon atoms (mono or di) phenyl lower alkyl group; vinyl, allyl, crotyl, 2-pentenyl, 2 −
C2-C6 alkenyl group such as hexenyl; C3-C8 such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
Cycloalkyl group; cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, 4-
Cyclohexyl butyl, 5-cyclohexyl pentyl,
6-cyclohexylhexyl, cyclopropylmethyl,
2-cyclobutylethyl, cyclopentylmethyl, 2-
Examples thereof include cycloalkyl (lower) alkyl groups such as cycloheptylethyl and cyclooctylmethyl, in which the cycloalkyl portion has 3 to 8 carbon atoms and the alkyl portion has 1 to 6 carbon atoms.

The phenyl moiety of the (mono- or di) phenyl lower alkyl group of the above-mentioned ester residue has, as a substituent, a halogen atom such as a chlorine atom, a bromine atom, a fluorine atom or an iodine atom; methyl, ethyl, propyl or isopropyl. , Butyl, isobutyl, tertiary butyl, pentyl,
Lower alkyl group having 1 to 6 carbon atoms such as hexyl; lower alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, hexyloxy; nitro group; carboxy Group; cyano group; lower alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl A hydroxyl group; and a lower alkanoyloxy group having 1 to 6 carbon atoms in the alkanoyl moiety such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, and hexanoyloxy. One to three substituents or methylenedioxy, ethylenedioxy, trimethylenedioxy, may have a lower alkylenedioxy group having 1 to 4 carbon atoms such as tetramethylene dioxy.

Further, the lower alkyl group of the ester residue, as a substituent, for example, 1 to 3 of the above halogen atoms, a hydroxyl group, a mercapto group, the above lower alkoxy group, the above lower alkanoyloxy group, a carboxy group , Cyano group,
Nitro group, amino group, lower alkyl group described above, (mono or di) lower alkylamino group such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, butylamino, lower alkanoylamino group or methylthio, ethylthio , Propylthio,
A lower alkylthio group such as butylthio may be substituted.

In the above compounds, R ³ is a pyridinio group,
For example, a compound in which R ³ is a pyridyl group is substituted with a lower alkyl halide, a cycloalkyl lower alkyl halide, a lower alkoxy lower alkyl halide, a lower alkanoyl lower alkyl halide, a benzoyl lower alkyl halide, a halogen-substituted lower alkyl halide, or a halogen-substituted lower alkanoyl group. Lower alkyl halide, carboxycarbonyl lower alkyl halide, lower alkyl halide or group substituted with a lower alkoxyimino group: (In the formula, A, R ⁵ and R ⁶ are the same as above, and X represents a halogen atom.) And the like can be obtained. Examples of the halide portion of the above various halide compounds include chloride, bromide, iodide and the like.

Next, typical examples of the compounds of the following general formula contained in the antibacterial agent of the present invention are shown in the following table.

The compound contained in the antibacterial agent of the present invention can be produced by various methods. For example, the following reaction process formulas
It can be produced by the method shown in Reaction Process Formula-6.

[Wherein R ¹ , R ² and R ⁴ are the same as above, R represents a pyridyl group or a pyridinio group, and the pyridinio group is a lower alkyl group, a cycloalkyl lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanoyl lower group. An alkyl group,
Benzoyl lower alkyl group, halogen substituted lower alkyl group, halogen substituted lower alkanoyl group substituted lower alkyl group, carboxycarbonyl lower alkyl group, lower alkoxyimino group substituted lower alkyl group or group: (In the formula, A, R ⁵ and R ⁶ are the same as the above). In the above reaction process formula-1, the compound represented by the general formula (1-a) includes an amine compound represented by the general formula (2) and a carboxylic acid compound represented by the general formula (3) or a compound thereof. It can be produced by reacting a compound in which a carboxy group is activated in a usual amide bond forming reaction.

As the amide bond formation reaction, any of the known amide bond formation reaction conditions can be applied. For example, a) a method using a condensing agent: that is, a method in which a carboxylic acid compound represented by the general formula (3) and an amine compound represented by the general formula (2) are reacted in the presence of a condensing agent; b) Mixed acid anhydride method: That is, a carboxylic acid compound represented by the general formula (3) is reacted with an alkylhalocarboxylic acid to prepare a mixed acid anhydride, and this is reacted with an amine compound represented by the general formula (2). C) Active esterification method: That is, a carboxylic acid compound represented by the general formula (3) is converted into p-nitrophenyl ester,
An active ester such as N-hydroxysuccinimide ester or 1-hydroxybenzotriazole ester,
A method of reacting this with an amine compound represented by the general formula (2); d) converting the carboxylic acid compound represented by the general formula (3) into a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, Method of reacting amine compound represented by (2); e) Lower alcohol ester of carboxylic acid compound represented by general formula (3) and amine compound represented by general formula (2) under high temperature and high pressure F) a carboxylic acid compound represented by the general formula (3) as an acid halide, that is, a carboxylic acid halide, and a reaction with an amine compound represented by the general formula (2). it can.

Next, an example of the amide bond formation reaction will be described more specifically.

The compound represented by the general formula (1-a) is obtained by reacting the amine compound represented by the general formula (2) with the carboxylic acid compound represented by the general formula (3) in the presence of a condensing agent without using a solvent or a solvent. Obtained by reacting in the presence of an active solvent.

Examples of the condensing agent used in the reaction include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, such as (chloromethylene) dimethylammonium chloride synthesized by the reaction of dimethylformamide with thionyl chloride, phosphorus oxychloride, phosgene and the like. Bill Smeier (Vi
lsmeier) reagent, dicyclohexylcarbodiimide (DC
Examples of the condensing agent include C) and 2,2'-pyridinyl disulfide-triphenylphosphine.

As the solvent, any solvent can be used as long as it does not adversely affect this reaction, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane,
Halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, amines such as pyridine, piperidine and triethylamine, and aliphatic hydrocarbons such as hexane and heptane. , Methanol, ethanol,
Examples thereof include alcohols such as propanol, aprotic polar solvents such as dimethylformamide (DMF), hexamethylphosphoric triamide (HMPA) and dimethylsulfoxide (DMSO), carbon disulfide and the like.

More preferably, the above reaction is carried out in the presence of a basic compound. Examples of the basic compound include trialkylamines such as triethylamine and tributylamine,
Pyridine, picoline, 1,5-diazabicyclo [4.3.0] nonene-5,1,4-diazabicyclo [2.2.2] octane, 1,
Organic bases such as 8-diazabicyclo [5.4.0] undecene-7, alkali metal hydroxides such as monotrimethylsilylacetamide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate,
Examples thereof include inorganic bases such as alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate.

In the above reaction, the ratio of the carboxylic acid compound represented by the general formula (3) to the amine compound represented by the general formula (2) is 1 to 10 times, preferably 1 to 10 times by mole.
It is preferable to use a 3-fold molar amount. The basic compound is used in an equimolar to 40-fold molar amount, preferably 5 to 20-fold molar amount with respect to the amine compound represented by the general formula (2).

The above reaction is -20 ℃ ~ 100 ℃, preferably -20 ℃ ~ 50
It is carried out for 30 minutes to 24 hours, preferably 30 minutes to 10 hours under the temperature condition of ° C.

Thus, the compound represented by the general formula (1-a) is obtained.

In the reaction of the amine compound represented by the general formula (2) with the carboxylic acid compound represented by the general formula (3), when the group R ⁴ is a carboxy group or a carboxylate group, the general formula ( A compound in which the carboxy group or carboxylate group of the target compound represented by 1-a) and the carboxyl group or carboxylate group of the amine compound represented by the general formula (2) are condensed may be obtained. In this case, it is represented by the general formula (1-a) by hydrolyzing the condensation compound in the presence of an acid catalyst, for example, an inorganic acid or an organic acid such as hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like. Can be obtained.

[In the formula, R ¹ , R ² , R ⁴ and R are the same as defined above, and X represents a halogen atom. In the above reaction scheme, the compound represented by the general formula (5) is obtained by reacting the amine compound represented by the general formula (2) with the carboxylic acid compound represented by the general formula (4). To be In the compound represented by the general formula (4), the halogen atom represented by X is chlorine, bromine,
Examples include iodine and fluorine. This reaction can be carried out in the same manner as the amide bond-forming reaction between the amine compound represented by the general formula (2) and the carboxylic acid compound represented by the general formula (3) in the above reaction process formula-1. it can.

The compound represented by the general formula (5) thus obtained is reacted with the thioacetamide compound represented by the general formula (6) in the presence or absence of an appropriate solvent to give the compound represented by the general formula ( The compound represented by 1-a) can be obtained.

In this reaction, the inert solvent used is not particularly limited, and the solvent used in the above-mentioned reaction process formula-1 can be used.

In the reaction, the thioacetamide compound represented by the general formula (6) is used in a molar ratio of 1 to 10 times, preferably 1 to 5 times the molar amount of the compound represented by the general formula (5). Is good. The reaction is usually carried out at -10 ° C to 100 ° C, preferably -10 ° C to 50 ° C, and is generally completed in 1 to 50 hours, preferably 1 to 10 hours.

[Wherein R ¹ , R ² and R are the same as defined above, R ^4a represents a carboxy group or a carboxylate group, and R ^4b represents an esterified carboxy group. The ester compound represented by the general formula (1-c) can be obtained by subjecting the compound represented by the general formula (1-b) to a usual esterification reaction.

For example, the above-mentioned esterification reaction is carried out in the presence of a catalyst, and the catalyst used is a conventional catalyst for the esterification reaction. Specifically, hydrogen chloride, concentrated sulfuric acid,
Inorganic acids such as phosphoric acid, polyphosphoric acid, boron trifluoride, perchloric acid, trifluoroacetic acid, trichloromethanesulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid,
Examples thereof include organic acids such as benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trichloromethanesulfonic acid anhydride and trifluoromethanesulfonic acid anhydride, thionyl chloride and dimethylacetal. A cation exchange resin (acid type) can also be used.

The above esterification reaction is carried out without solvent or in the presence of a suitable solvent. As the solvent used, any solvent commonly used in esterification reactions can be used, for example, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride. And ethers such as diethyl ether, tetrahydrofuran, dioxane and the like.

The catalyst is used in an equimolar to 100-fold molar amount, preferably 10 to 30-fold molar amount with respect to the compound represented by the general formula (1-b). The reaction temperature is -20 ° C to 200
C., preferably 0 to 150.degree. C.

Further, the compound represented by the general formula (1-c) can also be obtained by the following method. For example, 1) Desalting / condensation method This method is applied to an alkali metal salt (for example, sodium salt, potassium salt, etc.) of the compound represented by the general formula (1-b).
It is for reacting a halide compound corresponding to the ester residue in the esterified carboxy group of R ^4b , and any solvent that does not affect the reaction can be used, for example, dimethyl ether, diethyl ether. , Ethers such as tetrahydrofuran, tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, dimethylformamide (DMF), dimethylsulfoxide (DMS
O), aprotic polar solvents such as hexamethylphosphoric triamide (HMPA), and the like. The use ratio of the halide compound to the alkali metal salt of the compound represented by the general formula (1-b) is at least equimolar amount, preferably 1 to
It is preferable that the molar amount is about 3 times. Also, the reaction is −10 ° C.
~ 100 ℃, preferably 1 ~ 12 under the temperature condition of 0 ℃ ~ room temperature
It only has to be done for about an hour.

2) Diazotization Method In this reaction, a diazo compound corresponding to the ester residue in the esterified carboxy group of R ^4b is added to the compound represented by the general formula (1-b) in the presence of an inert solvent, for example, , Diazomethane, phenyldiazomethane, diphenyldiazomethane, etc., as an inert solvent, for example, dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, etc. Ethers, nitro compounds such as nitromethane and nitrobenzene, alcohols such as methanol and ethanol, acetic acid esters such as methyl acetate and ethyl acetate, aliphatic hydrocarbons such as hexane, heptane and octane, dimethylformamide (DMF), Dimethyl sulfoxy (DMSO), hexamethylphosphoric triamide (HM
Examples thereof include aprotic polar solvents such as PA) and carbon disulfide.

The proportion of the diazo compound used with respect to the compound represented by the general formula (1-b) is at least an equimolar amount, preferably 1 to
It is preferable that the molar amount is about 3 times. Also, the reaction is −10 ° C.
~ Properly proceeds at room temperature, and the reaction is usually completed in about 10 minutes to 6 hours.

[Wherein R ² , R ⁴ , R and X are the same as defined above, R ⁷ is a lower alkanoyl group, a halogen-substituted lower alkanoyl group, a phenyl lower alkyl group having 1 to 3 phenyl groups, a phenyl lower alkoxycarbonyl group or A lower alkoxycarbonyl group is shown. ] The compound represented by the general formula (1-e) has the general formula (1-
It can be obtained by reacting the compound represented by d) with the compound represented by the general formula (7).

This reaction is carried out by reacting the compound represented by the general formula (1-d) with the compound represented by the general formula (7) in the absence of a solvent or an inert solvent in the presence of a basic compound. The reaction can be carried out in substantially the same manner as the amide bond forming reaction of the above reaction process formula-1. Therefore, the reaction method and reaction conditions (for example, basic compound, solvent, reaction temperature,
For the reaction time and the like), the explanation of the above reaction process formula-1 can be referred to.

[Wherein R ⁴ and R are the same as defined above, R ⁸ is a halogen atom,
Lower alkanesulfonyloxy group or lower alkyl group optionally substituted with halogen atom, arylsulfonyloxy group optionally substituted with halogen atom or nitro group, R ⁹ is azido group, amino group, phthalimido group, phenylacetic acid Amido group or group: (In the formula, R ¹ and R ² are the same as above). There are various methods for introducing a thiomethyl group having a pyridine ring into the 3-position of the isosephem skeleton of the compound represented by the general formula (8), and an example of the method is shown in Reaction scheme-5.

That is, the compound of the present invention is obtained by reacting the compound represented by the general formula (8) with the thiol compound represented by the general formula (9) in the presence of a basic compound in a suitable inert solvent. A compound represented by the general formula (10), a part of which is included, is obtained.

In the compound represented by the general formula (8), examples of the halogen atom represented by R ⁸ include chlorine, bromine, iodine, fluorine and the like, and as a lower alkanesulfonyloxy group which may be substituted with a halogen atom. Include methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc., and as the lower alkyl group, an arylsulfonyloxy group which may be substituted with a halogen atom or a nitro group, benzenesulfonyloxy group. , Toluenesulfonyloxy, p-chlorobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy and the like.

Examples of the basic compound used in the above reaction include organic basic compounds such as tertiary amines such as triethylamine and pyridine, and inorganic basic compounds such as sodium carbonate and potassium carbonate.

As the inert solvent, the solvent used in the above reaction process formula-1 can be widely used.

The ratio of the compound represented by the general formula (9) to the compound represented by the general formula (8) should be at least an equimolar amount, preferably 1 to 2 times the molar amount.
The ratio of the basic compound to the compound represented by
At least an equimolar amount, preferably an equimolar to 2-fold molar amount is preferable. The reaction temperature is -10 ° C to 100 ° C, preferably 0 to 50 ° C.

Thus, the compound represented by the general formula (10) is obtained.

In the above compound, at least one of the groups R ¹ and R ⁴ is a lower alkanoylamino group, a halogen-substituted lower alkanoylamino group, a phenyl lower alkylamino group having 1 to 3 phenyl groups, a phenyl lower alkoxycarbonylamino group, or When a lower alkoxycarbonylamino group or an esterified carboxy group is shown, it can be converted into a compound in which one or more protecting groups are eliminated by subjecting it to a deprotecting group reaction represented by the following reaction scheme. You can

Wherein, R ² and R are as defined above, identical to each R ^1a and R ^4c R ¹ and R ^4, provided that at least one of R ^1a and R ^4c are, respectively, a lower alkanoylamino group, a halogen-substituted 1 lower alkanoylamino group and 1 phenyl group
A phenyl lower alkylamino group, a phenyl lower alkoxycarbonylamino group or a lower alkoxycarbonylamino group having 3 to 3, and an esterified carboxy group.

R ^1b and R ^4d are the same as R ¹ and R ⁴ , respectively, where R
^At least one of ^1b and R ^4d shall represent an amino group and a carboxy group or a carboxylate group, respectively. ] In the above reaction process formula, the reaction for obtaining the compound represented by the general formula (1-g) from the compound represented by the general formula (1-f) is carried out in the absence of a solvent or an inert solvent. It is carried out by a method of reacting the compound represented by 1-f) with an acidic compound or a basic compound, a method of subjecting the compound represented by the general formula (1-f) to a catalytic reduction reaction, and the like.

Examples of the inert solvent used in the above reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane and anisole, nitromethane and nitrobenzene. Nitro compounds, alcohols such as methanol and ethanol, acetic acid esters such as ethyl acetate and methyl acetate, aliphatic hydrocarbons such as hexane, heptane and octane, aromatic hydrocarbons such as benzene, toluene and xylene, pyridine, Amine such as piperidine, dimethylformamide (DMF), hexamethylphosphoric triamide (HMP
A), an aprotic polar solvent such as dimethylsulfoxide (DMSO), carbon disulfide, water, or a mixed solvent of water and the above organic solvent can be exemplified.

Examples of the acidic compound used include anhydrous aluminum chloride, stannic chloride, titanium tetrachloride, boron trichloride, boron trifluoride-diethyl ether complex, Lewis acids such as zinc oxide, inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid. , Trichloroacetic acid,
Trifluoroacetic acid, methanesulfonic acid, organic acids such as acetic acid, acids such as acid type ion exchange resins, and basic compounds such as triethylamine, trialkylamine such as tributylamine, pyridine, picoline, 1,5
-Diazabicyclo [4.3.0] nonene-5,1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.
0] Organic bases such as undecene-7, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate Examples include bases such as salts and other inorganic bases.

When the above reaction is carried out by the catalytic reduction method, examples of the catalytic reduction catalyst used include platinum catalysts (for example, platinum oxide, platinum black, platinum wire, platinum plate, sponge platinum, colloidal platinum, etc.), palladium catalysts. (For example, palladium black, palladium chloride, palladium oxide, palladium-
Carbon, palladium-barium sulfate, palladium-barium carbonate, sponge-like palladium), nickel catalyst (for example, reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalyst (for example, reduced cobalt, Raney cobalt, etc.), iron catalyst (for example, , Reduced iron, Raney iron, etc.),
Examples thereof include copper catalysts (for example, reduced copper, Raney copper, etc.).

When an acidic compound or a basic compound is used in the above reaction, the ratio of the acidic compound or the basic compound to the compound represented by the general formula (1-f) is 1 to 10
The molar amount is 0 times, preferably 1 to 20 times. Further, the reaction is -20 ℃ ~ 80 ℃, preferably -10 ℃
It is carried out under a temperature condition of -50 ° C and is completed in 30 minutes to 48 hours, preferably 1 to 24 hours.

When the catalytic reduction method is applied, the general formula (1-
The proportion of the catalytic reduction catalyst used with respect to the compound represented by f) is 0.1 to 10-fold molar amount, preferably 0.1 to 1-fold molar amount. Further, the reaction is 0 to 200 ° C., preferably 0
It is carried out under a temperature condition of -100 ° C and is completed in 30 minutes to 48 hours, preferably in 30 minutes to 6 hours.

The reaction represented by Reaction Scheme-6 will be described in more detail by the following Reaction Scheme-6a to Reaction Scheme-6b.

[In the formula, R ¹ , R ² , R, R ^4a and ^44b are the same as the above] The carboxylic acid derivative represented by the general formula (1-b) is an isocephem represented by the general formula (1-c). It can be produced by subjecting an ester compound at the 4-position of the ring to a deesterification reaction.

The deesterification reaction is carried out without solvent or in a suitable inert solvent in the presence of a hydrolysis catalyst. Examples of the inert solvent and the hydrolysis catalyst used include the inert solvent, the acidic compound and the basic compound, which are exemplified in the above-mentioned Reaction Scheme-6.

The deesterification reaction can also be carried out by the catalytic reduction method when the ester residue of R ^{4b is} an ester residue such as benzyl which is easily eliminated by the catalytic reduction method. Examples of the catalyst used in the catalytic reduction method include the catalysts exemplified in the above Reaction Process Formula-6.

In the above reaction, when an acid or a base is used, the ratio of the acid or the base to the compound represented by the general formula (1-c) is 1 to 100 times mol, preferably 1 to 20 times mol. It is good to use quantity. The reaction is carried out at a temperature of -20 ° C to 80 ° C, preferably -10 ° C to 50 ° C for 30 minutes to 48 hours,
Preferably, it may be carried out for about 1 to 24 hours.

When the catalytic reduction method is applied, the general formula (1-
The use ratio of the catalytic reduction catalyst to the compound represented by c) is 0.1 to 10 times molar amount, preferably 0.1 to 1 times molar amount. The reaction is 0 to 200 ° C, preferably 0 to 100
Under temperature conditions of ℃, 30 minutes to 48 hours, preferably 30 minutes to 6
It only has to be done for about an hour.

[Wherein R ² , R ⁴ , R and R ⁷ are the same as defined above] General formula (1-d) in which the 2-position of the thiazolyl group is an amino group
The compound represented by the following formula is a compound represented by the general formula (1-e) in which the 2-position of the thiazolyl group is a protected amino group, and the reaction formula-6a is substantially the same as the deesterification reaction conditions. Can be obtained by subjecting the compound to a reaction under similar conditions, for example, by reacting with an acidic compound or a basic compound in the absence of a solvent or in the presence of a suitable solvent, or by subjecting it to a catalytic reduction reaction.

The solvent used in the reaction is not particularly limited, and examples thereof include the solvents exemplified in Reaction Scheme-6.

Examples of the above-mentioned acidic compound include the acidic compounds exemplified in the above reaction process formula-6, and preferable examples of the acidic compound include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, and trifluoroacetic acid. Examples thereof include organic acids such as acetic acid and formic acid, and acid type ion exchange resins. Of these acidic compounds, liquid ones can be used also as a solvent.

Further, as the basic compound, trialkylamines such as triethylamine and tributylamine, pyridine, picoline, 1,5-diazabicyclo [4.3.0] nonene-5,1,4
-Diazabicyclo [2.2.2] octane, organic bases such as 1,8-diazabicyclo [5.4.0] undecene-7, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkalis such as sodium carbonate and potassium carbonate Examples thereof include inorganic bases such as metal carbonates, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and urea compounds such as thiourea and urea.

When water is added to the reaction system, the water content is preferably about 10 to 80 V / V% with respect to the acidic compound or the basic compound, and after the reaction is completed, it is preferably added in an amount of 10 to 20 times.

The ratio of the acidic compound or the basic compound used to the compound represented by the general formula (1-e) is preferably equimolar to 100 times the molar amount, and preferably 2 to 10 times the molar amount. Also,
The reaction temperature is -20 ° C to 80 ° C, preferably -10 ° C to 50 ° C. The reaction time is about 1 to 24 hours.

When the reaction of the reaction step formula-6b is carried out by a catalytic reduction reaction, the conditions of the catalytic reduction reaction (eg, catalytic reduction catalyst, catalyst amount, solvent, reaction temperature, reaction time, etc.) are the same as those of the reaction step formula-6a.
The catalytic reduction reaction conditions of can be applied.

Thus, the amine compound represented by the general formula (1-d) is obtained.

In addition, in the compound represented by the general formula (1), the compound in which R ³ is a pyridinio group is the same as the corresponding compound in the presence of an inert solvent, for example, lower alkyl halide, cycloalkyl lower alkyl halide, lower alkoxy. Lower alkyl halide, lower alkanoyl lower alkyl halide, benzoyl lower alkyl halide, halogen-substituted lower alkyl halide, lower alkyl halide substituted with halogen-substituted lower alkanoyl group, carboxycarbonyl lower alkyl halide, lower alkyl substituted with lower alkoxyimino group Halide or compound represented by the following general formula: (In the formula, A, R ⁵ , R ⁶ and X are the same as the above) and the like can be obtained. Examples of the halide portion of the above various halide compounds include chloride, bromide, iodide and the like. Examples of the inert solvent used in the above reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran and dioxane. Ethers such as can be exemplified. The reaction is carried out at room temperature to about 100 ° C, preferably 50 to 8 ° C.
The reaction is completed at about 0 ° C. for about 2 to 8 hours. The above halide compound is preferably used in an amount of about 1 to 1.5 times the molar amount of the corresponding compound.

After the reaction was completed, Diaion HP-20 (Mitsubishi Kasei Kogyo Co., Ltd.)
Halogen ion can be removed by purification by column chromatography using Amberlite XAD-2 (produced by Rohm and Hass) or the like to form an inner salt.

In the above-mentioned reaction process formulas-1 to 6, the compounds represented by the general formulas (2) and (8), which are the starting materials, include novel compounds and can be produced by the following reaction process.

[In the formula, R ⁴ and R are the same as defined above, and R ^9a is an azido group, a phenylacetic acid amide group or a phthalimido group. ] The above-mentioned reaction process formula -7, by subjecting the compound represented by the general formula (11) to a reduction reaction, a hydrolysis reaction or a hydrazine decomposition reaction, depending on the kind of R ^9a which is the substituent, It is a method for producing a compound represented by the general formula (2) including a part of a novel compound.

In the above reaction scheme, when the group R ^9a is an azido group,
The compound represented by the general formula (2) is represented by the general formula (2) by reacting the compound represented by the general formula (11) with a reducing agent in the absence of a solvent or in the presence of a suitable inert solvent. An amine compound is obtained.

As the solvent used in this reaction, for example, dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, benzene, toluene,
Examples thereof include aromatic hydrocarbons such as xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, and amines such as triethylamine and pyridine.

Examples of the reducing agent include hydrogen sulfide and the like. When hydrogen sulfide or the like is used, amines such as triethylamine and pyridine may be added.

The reducing agent is used in an equimolar to 100-fold molar amount, preferably 3 to 50-fold molar amount with respect to the compound represented by the general formula (11), and the reaction is usually -30 ° C to 50 ° C. It is preferably carried out at -10 ° C to 10 ° C and is completed in about 30 minutes to 10 hours.

When the group R ^9a is a phenylacetic acid amide group, it is represented by the general formula (2) by subjecting the compound represented by the general formula (11) to a hydrolysis reaction in the absence of solvent or an inert solvent. An amine compound is obtained.

This reaction can be carried out in substantially the same manner as in the above Reaction scheme-6b, and the reaction method and reaction conditions (for example, hydrolysis catalyst, solvent, reaction temperature, reaction time, etc.) are the same as those in the above Reaction scheme-6b. Can be referred to.

When the group R ^9a is a phthalimido group, the compound represented by the general formula (11) can be subjected to a hydrazine decomposition reaction by reacting the compound represented by the general formula (11) with hydrazine or a hydrazine derivative in the presence of the general formula (2). The amine compound represented is obtained.

Examples of the inert solvent used in this reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, alcohols such as methanol and ethanol. Examples of the hydrazine derivative include lower alkyl-substituted hydrazine such as methylhydrazine and ethylhydrazine, and aryl-substituted hydrazine such as phenylhydrazine.

The use ratio of hydrazine or hydrazine derivative to the compound represented by the general formula (11) is at least an equimolar amount, preferably 1 to 2 times the molar amount, and the reaction is usually 0 to 100 ° C., preferably 0 to 0 ° C. Done at 80 ° C, 1
The reaction is completed in about 40 hours.

In addition, in the compound represented by the general formula (2) obtained by the above reaction, when the group R ⁴ is an esterified carboxy group, the product is substantially subjected to the deesterification reaction of the above reaction process formula-6a. deesterified in the same manner, the group R ⁴ can be be converted into the compound of the carboxy group or carboxylate group, and if group R ⁴ is a carboxy group or carboxylate group, the reaction scheme of the product - Esterification can be conducted by a method substantially similar to the esterification reaction of 3 to give a compound in which the group R ⁴ is an esterified carboxy group.

[In the formula, R ^4b , R ^9a and X are the same as defined above, and R ¹⁰ is a hydrogen atom or a lower alkanoyl group. This reaction is a halogenation reaction in which the alcoholic hydroxyl group or the lower alkanoyloxy group of the compound represented by the general formula (12) is replaced with a halogen atom, and a wide range of ordinary halogenation reaction conditions can be applied.

For example, when R ¹⁰ is a hydrogen atom, by reacting a compound represented by the general formula (12) with a thionyl halide such as thionyl chloride, thionyl bromide or thionyl iodide in the presence or absence of a solvent. A compound represented by the general formula (8-a) can be obtained. Any solvent can be used as long as it does not affect the reaction, and examples thereof include dichloromethane, dichloroethane, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, nitro compounds such as nitromethane and nitrobenzene, acetic ester compounds such as ethyl acetate and methyl acetate, hexane, heptane, octane, etc. Examples thereof include aprotic polar solvents such as aliphatic hydrocarbons, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and hexamethylphosphoric triamide (HMPA), and carbon disulfide. The use ratio of thionyl halide to the general formula (12) is at least an equimolar amount, preferably 1 to 2 times the molar amount, and the reaction is performed at −10 ° C. to room temperature, preferably under ice cooling. It takes about 5 minutes to 1 hour to finish.

In the reaction, it is preferable to add a basic compound such as pyridine, dimethylaniline or triethylamine as a deoxidizing agent to the reaction system.

When R ¹⁰ is a lower alkanoyl group, the compound represented by the general formula (8-) can be obtained by reacting the compound represented by the general formula (12) with tri (lower alkyl) silyl halide in the presence of no solvent or an inert solvent. The compound represented by a) is obtained.

Examples of the inert solvent used in this reaction include the same solvents as described above. Examples of tri (lower alkyl) silyl halides include trimethylsilyl chloride and triethylsilyl chloride.

The tri (lower alkyl) silyl halide is used in at least an equimolar amount, preferably 1 to 2 times the molar amount of the compound represented by the general formula (12). The reaction is
It is carried out at -20 ° C to 50 ° C, preferably room temperature, and is completed in about 30 minutes to 5 hours.

In the compound represented by the general formula (1) contained in the antibacterial agent of the present invention, the compound having an optical activity can be obtained by using the starting material having an optical activity in the method of the above reaction process formulas 1 to 6. The compound can be produced according to the method described above, and the target compound having a three-dimensional structure corresponding to the three-dimensional structure of the starting material is obtained.

An example of a method for producing a starting material having optical activity is shown below, but the present invention is not limited to the three-dimensional structure shown in the following reaction scheme, and, for example, if a cis isomer or a trans isomer is used, the corresponding It is possible to obtain a compound having a three-dimensional structure.

[In the formula, R ^4a and R are the same as defined above. ] In the above reaction process formula, the reaction for producing the compound represented by the general formula (10-b) from the compound represented by the general formula (10-a) is performed by reacting the compound of the general formula (10-a) with phenyl It is carried out by reacting acetic acid or its reactive derivative at the carboxy group. The reaction is carried out according to the above reaction process formula-
Substantially the same as the method of 1, the acylation conditions (eg, reactive derivative, solvent, reaction temperature,
For the reaction time etc.), refer to the explanation of reaction process formula-1.

From the compound represented by the general formula (10-b), the compound represented by the general formula (10-
The reaction for producing the compound represented by c) can be carried out by the general formula (10-
The phenylacetic acid amide group at the 7-position of the compound represented by b) is selectively hydrolyzed using an enzymatic reaction to give a compound represented by the general formula (10
It is a reaction for obtaining the compound represented by -c).

The reaction is carried out in water or an aqueous solvent in the presence of the enzyme. As the enzyme used in this reaction, any enzyme can be used as long as it can selectively hydrolyze an amide group, and examples thereof include penicillin G amidase.

The enzyme is usually used in a proportion of about 0.5 to 2 gram equivalent with respect to the compound represented by the general formula (10-b). In addition, in the reaction, the reaction system becomes acidic due to the acid generated as the reaction proceeds, so the pH of the reaction system should be adjusted to the optimum level of the enzyme.
To maintain the pH, add a basic compound to the reaction system to
Is preferably adjusted. Examples of the basic compound include ammonia water, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium carbonate,
Examples thereof include alkali metal carbonates such as potassium carbonate and sodium hydrogen carbonate, hydrogen carbonates and the like. The reaction temperature of the reaction is preferably an optimum temperature of the enzyme, and the reaction is completed in about 1 to 10 hours, preferably about 1 to 5 hours.

[Wherein R ^4b , R ^9a and X are the same as defined above, R ¹¹ and R ¹²
Is a lower alkyl group optionally substituted with a halogen atom, or a lower alkyl group, an aryl group optionally substituted with a halogen atom or a nitro group, R ¹³ is a lower alkanoyl group, and M is an alkali metal. ] In the above process formula, a reaction (a) for producing a compound represented by the general formula (15) from a compound represented by the general formula (13)
Is a compound of the general formula (1) in the presence or absence of an inert solvent.
It is carried out by reacting the compound represented by 3) with a sulfonic acid compound represented by the general formula (14) or a reactive derivative of the sulfo group thereof.

Examples of the inert solvent include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, ethers such as dimethyl ether and diethyl ether, and aliphatic hydrocarbons such as hexane, heptane and octane. .

Examples of the sulfonic acid compound represented by the general formula (14) include lower alkanesulfonic acids such as methanesulfonic acid, ethanesulfonic acid and propanesulfonic acid, such as trifluoromethanesulfonic acid and 2-trifluoroethanesulfonic acid. Halogen-substituted lower alkane sulfonic acids such as benzene sulfonic acid, toluene sulfonic acid, p-
Examples thereof include lower alkyl groups such as chlorobenzene sulfonic acid and p-nitrobenzene sulfonic acid, and aryl sulfonic acids which may be substituted with a halogen atom or a nitro group. Examples of the reactive derivative of sulfonic acid include sulfonic acid halides such as sulfonic acid chloride and sulfonic acid bromide, and sulfonic acid anhydride.

The ratio of the sulfonic acid compound or the reactive derivative in the sulfo group thereof to the compound represented by the general formula (13) is at least an equimolar amount, preferably 1 to 1.5 times the molar amount. It is carried out at -50 ° C to under ice cooling, and is completed in about 1 to 50 minutes. The reaction can be carried out in the presence of a deoxidizing agent such as pyridine or triethylamine, but it is preferable to add a deoxidizing agent after completion of the above reaction,
The reaction is carried out for about 30 minutes to 3 hours, preferably about 1 hour. The proportion of the deoxidizer used is at least an equimolar amount with respect to the reactive derivative of the sulfonic acid, preferably 1 to 1.
It is recommended to use about 5 times the molar amount.

Reaction (b) for producing a compound represented by the general formula (16) from the compound represented by the general formula (15) obtained in the above reaction
Is a compound of the general formula (1) in the presence or absence of an inert solvent.
5) compound represented by triethylamine, pyridine,
It is for reacting a basic compound such as piperidine.
Examples of the inert solvent used include the solvent used in the above step (a). The use ratio of the basic compound to the compound represented by the general formula (15) is at least an equimolar amount, preferably about 1 to 1.5 times the molar amount, and the reaction is performed under ice-cooling to room temperature. 10 minutes to 2 hours,
It is preferably completed in about 1 hour.

In the reaction (c) for producing the compound represented by the general formula (18) from the compound represented by the general formula (16), the halogen molecule represented by the general formula (17) is added to the compound represented by the general formula (16). It is a reaction of addition. The use ratio of the halogen molecule to the compound represented by the general formula (16) is at least about equimolar amount, preferably 1 to 1.2 times the molar amount, and iodine molecule is preferable as the halogen molecule. The reaction is carried out under ice cooling to room temperature,
The process is completed in about 1 to 5 hours, preferably about 3 hours.

The reaction (d) for producing the compound represented by the general formula (12-a) from the compound represented by the general formula (18) includes the above-mentioned (a).
In a mixed solvent of water and the solvent exemplified in the step, the compound represented by the general formula (18), the sodium formate represented by the general formula (19), potassium formate, sodium acetate, potassium acetate, propionic acid It is for reacting a lower alkanoic acid alkali metal salt such as sodium.

The mixing ratio of water in the solvent is 0.1 to 1 with respect to the solvent.
It is better to add about% (volume). The use ratio of the lower alkanoic acid alkali metal salt represented by the general formula (19) to the compound represented by the general formula (18) is 1 to 6 times the molar amount, preferably 4 to 5 times the molar amount. , The reaction is at room temperature,
It takes about 6 to 24 hours to finish.

From the compound represented by the general formula (12-a), the compound represented by the general formula (12-
The reaction (e) for producing the compound represented by b) is carried out by adding a mineral acid such as hydrochloric acid, nitric acid or sulfuric acid to the compound represented by the general formula (12-a) in the presence or absence of an inert solvent. Is to react. As the inert solvent used in the reaction,
For example, water, ketones such as acetone, diethyl ketone and acetophenone, ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, benzene, toluene and xylene. Aromatic hydrocarbons, amines such as pyridine, piperidine and triethylamine, aliphatic hydrocarbons such as hexane and heptane, alcohols such as methanol, ethanol and propanol, dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexa Methylphosphoric triamide (HM
Examples thereof include aprotic polar solvents such as PA) and carbon disulfide. The ratio of the mineral acid used to the compound represented by the general formula (12-a) is about 3-fold molar amount. The reaction is completed at room temperature in about 1 to 10 hours.

From the compound represented by the general formula (12-b), the compound represented by the general formula (8-
The reaction (f) for producing the compound represented by b) is performed by reacting the compound represented by the general formula (12-b) with the compound represented by the general formula (14) in the presence of a basic compound such as pyridine and triethylamine. The sulfonic acid compound or its reactive derivative at the sulfo group is reacted, and the reaction can be carried out in the same manner as in the above step (a).

If a compound represented by the general formula (13) has (R, R), (R, S) and (S, R) at the 3 and 4 positions of the azetidinone ring, the corresponding three-dimensional structure is obtained. A compound represented by the general formula (8-b) having

The compound represented by the general formula (13) can be obtained by the following reaction formula.

[In the formula, R ^4b , R ¹¹ and X are the same as defined above, and R ^9b is a phthalimido group or a phenylacetic acid amide group. In the above reaction scheme, the reaction (a) for producing the compound represented by the general formula (22) from the compound represented by the general formula (20) is carried out in the presence or absence of a basic compound, It is carried out by reacting the compound represented by the general formula (20) with the compound represented by the general formula (21). As the basic compound used here, sodium hydroxide, an alkali metal hydroxide such as potassium hydroxide, sodium carbonate, potassium carbonate, an inorganic base such as an alkali metal carbonate or hydrogen carbonate such as sodium hydrogen carbonate, Organic bases such as triethylamine, pyridine and N, N-dimethylaniline can be mentioned. The reaction is usually carried out in an organic solvent, and examples of the solvent used include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether and tetrahydrofuran, methylene chloride, dichloroethane and chloroform. , And halogenated hydrocarbons such as carbon tetrachloride. The ratio of the compound represented by the general formula (21) to the compound represented by the general formula (20) is at least an equimolar amount, preferably 1 to 2
It is used in a double molar amount. The reaction is carried out at -50 ° C to room temperature, preferably -30 ° C to 0 ° C, and is completed in 1 to 10 hours, preferably 30 minutes to 6 hours.

The reaction (b) for producing the compound represented by the general formula (23) from the compound represented by the general formula (22) includes reacting the compound represented by the general formula (22) with hydrazine or a hydrazine derivative. Performed by. This reaction can be carried out in substantially the same manner as in the hydrazine decomposition method of the above Reaction Scheme-7, and the reaction conditions (for example, reaction reagent, solvent,
For the reaction temperature, reaction time, etc., refer to the explanation of the reaction process formula-7.

The reaction (c) for producing the compound represented by the general formula (24) from the compound represented by the general formula (23) is a reaction of the compound represented by the general formula (23) with phenylacetic acid or a carboxy group thereof. It is carried out by reacting a sex derivative. This reaction is carried out in substantially the same manner as in the above Reaction scheme-1, and the reaction method (for example, the method using a condensing agent, the mixed acid anhydride method, the active esterification method, etc.) and the reaction conditions (for example, the basicity) For the compound, solvent, reaction temperature, reaction time, etc., refer to the explanation of the above-mentioned reaction process formula-1.

The reaction (d) for producing the compound represented by the general formula (25) from the compound represented by the general formula (24) is represented by the general formula (24) in the presence of a basic compound in an inert solvent. The compound is subjected to a deesterification reaction.

Examples of the activated solvent used in the above reaction include, for example,
Examples thereof include water, alcohols such as methanol, ethanol, propanol and isopropanol, and ethers such as diethyl ether, dioxane and tetrahydrofuran. Further, as the basic compound, sodium hydroxide,
Examples thereof include alkali metal hydroxides such as potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium ethoxide.
The reaction is carried out at 0 ° C to 100 ° C, preferably 0 ° C to room temperature, and the reaction is completed in about 1 to 10 hours.

The method (e) for producing the compounds represented by the general formulas (26) and (27) from the compound represented by the general formula (25) is a compound represented by the general formula (25). It is carried out by allowing the enzyme to act. This reaction is
Substantially the same as the method for producing the compound represented by the general formula (10-c) from the compound represented by the general formula (10-b) in the reaction formula-9, the reaction conditions (for example, For the enzyme, solvent, pH of reaction solution, reaction temperature, reaction time, etc. used), refer to the explanation of the above-mentioned reaction process formula-9. After completion of the reaction, by separating the compound in which the amide bond has been cleaved by the enzymatic reaction and the compound in which the amide bond has not been cleaved from the reaction solution, the compound represented by the general formula (26) and the general formula (27 ) The compound represented by this can be obtained.

The method (f) for producing the compound represented by the general formula (28) from the compound represented by the general formula (26) is carried out by subjecting the compound represented by the general formula (26) to an esterification reaction. . This reaction is carried out in substantially the same manner as in the above Reaction scheme-3, and the reaction conditions (eg, acid catalyst, solvent, reaction temperature, reaction time, etc.) can be referred to the explanation of the above Reaction scheme-3. it can.

The reaction (g) for producing the compound represented by the general formula (29) from the compound represented by the general formula (28) is the reaction of the compound represented by the general formula (28) with phenylacetic acid or its carboxy group. It is carried out by reacting a sex derivative or by reacting phthalic acid or a reactive derivative of phthalic acid.

The reaction of the compound represented by the general formula (28) with phenylacetic acid or its reactive derivative at the carboxy group is carried out in substantially the same manner as the reaction of the above-mentioned reaction process formula-1, and a reaction method (for example, a condensing agent , A mixed acid anhydride method,
For the active esterification method and the like) and the reaction conditions (for example, the basic compound, the solvent, the reaction temperature, the reaction time and the like), the explanation of the above reaction process formula-1 can be referred to.

The reaction between the compound represented by the general formula (28) and phthalic acid or a reactive derivative of phthalic acid is usually carried out in an inert solvent. Examples of the reactive derivative of phthalic acid include N- (esterified carboxy) phthalimide such as phthalic anhydride, N-methoxycarbonylphthalimide, N-ethoxycarbonylphthalimide and N-phenoxycarbonylphthalimide, 2-methoxycarbonylbenzoic acid chloride,
Examples thereof include 2- (esterified carboxy) benzoic acid halides such as 2-ethoxycarbonylbenzoic acid chloride and 2-phenoxycarbonylbenzoic acid chloride.

When phthalic acid is used in this reaction, the reaction can be carried out in substantially the same manner as in the above-mentioned reaction process formula-1, and the reaction method (for example, a method using a condensing agent, a mixed acid anhydride method) can be used. , Active esterification method, etc.) and reaction conditions (eg, solvent, reaction temperature, reaction time, etc.) can be referred to the explanation of the above-mentioned reaction process formula-1.

When phthalic anhydride is used, the reaction is carried out in an inert solvent, and examples of the inert solvent include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, dimethyl ether and diethyl ether. , Ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, and aliphatic hydrocarbons such as hexane, heptane and octane. In this reaction, the general formula (28)
The use ratio of the phthalic anhydride to the compound represented by is at least an equimolar amount, preferably 1-2 times the molar amount, and the reaction temperature is room temperature to 100 ° C, preferably 40 to 80 ° C.
Done in degrees.

When N- (esterified carboxy) phthalimide is used, the reaction is carried out in an inert solvent in the presence of a basic compound.

Examples of the inert solvent used in this reaction include water, alcohols such as methanol, ethanol and propanol, ethers such as dimethyl ether, diethyl ether, dioxane and tetrahydrofuran. As the basic compound, sodium hydroxide, an alkali metal hydroxide such as potassium hydroxide, an inorganic base such as an alkali metal carbonate or a hydrogen carbonate such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, triethylamine,
Examples include organic bases such as pyridine and N, N-dimethylaniline.

The proportion of N- (esterified carboxy) phthalimide used with respect to the compound represented by the general formula (28) is at least an equimolar amount, preferably 1 to 2 times the molar amount, and represented by the general formula (28). The basic compound is used in a molar ratio of 1 to 10 times the compound. The reaction temperature of the reaction is 0 to 50 ° C., preferably room temperature, and the reaction is completed in 1 to 5 hr.

When 2- (esterified carboxy) benzoic acid halide is used, the reaction is carried out in an inert solvent in the presence of a basic compound.

Examples of the inert solvent used in this reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, ethers such as dimethyl ether, diethyl ether, dioxane and tetrahydrofuran, benzene, toluene, xylene and the like. And aromatic hydrocarbons such as hexane, heptane, octane and the like. Examples of the basic compound include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, inorganic bases such as alkali metal carbonates and hydrogen carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, triethylamine and pyridine. , N, N-dimethylaniline and other organic bases.

The use ratio of 2- (esterified carboxy) benzoic acid halide to the compound represented by the general formula (28) is at least an equimolar amount, preferably 1 to 2 times the molar amount.
The reaction is carried out at 0 ° C to room temperature and is completed in 1 to 5 hours.

The reaction order of the reaction (f) and the main reaction (g) may be reversed. That is, the compound represented by the general formula (26) may be subjected to this reaction and then subjected to the esterification reaction to produce the compound represented by the general formula (29).

In the reaction (h) for producing the compound represented by the general formula (30) from the compound represented by the general formula (29), the compound represented by the general formula (29) is treated with ozone in the presence of an inert solvent. It is carried out by subjecting it to an oxidation reaction. Examples of the inert solvent include halogenated hydrocarbons such as methylene chloride, dichloroethane and chloroform, and alcohols such as methanol and ethanol. The proportion of ozone used with respect to the compound represented by the general formula (29) is at least an equimolar amount or more, and is usually used in excess with respect to the compound represented by the general formula (29). The reaction is carried out at -100 ° C to 0 ° C, preferably -50 ° C to -30 ° C. The reaction time varies depending on the amount of ozone supplied, the reaction temperature, etc., but the reaction is usually performed until excess ozone is detected in the reaction system (for example, until blue ozone is detected in the reaction system). After completion of the reaction, it is preferable that after the reaction, if necessary, an inert gas such as nitrogen gas is introduced to remove excess ozone, and then post-treatment with a reducing agent is performed. As the reducing agent, dimethyl sulfide,
Examples thereof include sodium borohydride and sodium sulfite. This post-treatment is usually performed under cooling or at room temperature.

The reaction (i) for producing the compound represented by the general formula (31) from the compound represented by the general formula (30) is to reduce the aldehyde group of the compound represented by the general formula (30) to a hydroxyl group. Any conventional reduction method of reducing an aldehyde group to a hydroxyl group can be used. This reaction is carried out, for example, by reacting the compound represented by the general formula (30) with a reducing agent in the presence of a solvent. Examples of the solvent used in this reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, alcohols such as methanol and ethanol. As the reducing agent used, a borohydride compound (for example, sodium borohydride, lithium borohydride, sodium cyanoborohydride, tetramethylammonium borohydride, diborane, etc.), an aluminum hydride compound (for example, , Lithium aluminum hydride, sodium aluminum hydride, aluminum hydride, lithium trimethoxyaluminum hydride, lithium tri-t-butoxyaluminum hydride and the like). The reaction is −60 ° C.
The reaction is completed at room temperature, preferably -30 ° C to -10 ° C, for 1 to 10 hours, preferably 1 to 5 hours.

In the reaction (j) for producing the compound represented by the general formula (32) from the compound represented by the general formula (31), a sulfonic acid compound or a compound represented by the general formula (31) is added in the presence of a solvent. It is carried out by reacting the reactive derivative at the sulfo group. As the solvent used in this reaction,
For example, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether and tetrahydrofuran,
Examples thereof include halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, aprotic polar solvents such as dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide, and acetonitrile. As the sulfonic acid compound used in this reaction and the reactive derivative at the sulfo group thereof, the above-mentioned reaction process formula-10
Examples thereof include the sulfonic acid compound exemplified in the step (a) and a reactive derivative in the sulfo group. General formula (3
The ratio of the reactive derivative in the sulfonic acid compound or its sulfo group to the compound represented by 1) is
At least an equimolar amount, preferably about 1 to 1.5 times the molar amount is recommended. The reaction is preferably carried out in the presence of base. As the base, an organic or inorganic basic compound as exemplified in the above reaction step (a) is used, and preferably an organic base is used. The reaction is usually performed at -10 ° C to 100 ° C, preferably 0 ° C to room temperature, and is completed in 1 to 20 hours, preferably 1 to 10 hours.

The reaction (k) for producing the compound represented by the general formula (13-a) from the compound represented by the general formula (32) is represented by the general formula (32) in the presence or absence of a solvent. It is carried out by reacting the compound with an acid. The acids used include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, organic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, aluminum chloride, titanium tetrachloride, tin tetrachloride, zinc chloride. Examples thereof include Lewis acids such as, and compounds having a phenolic hydroxyl group such as phenol and cresol. The acid is usually used in an excess amount with respect to the compound represented by the general formula (32). Examples of the solvent used include organic acids such as acetic acid, alcohols such as methanol and ethanol, aprotic polar solvents such as dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide, and acetonitrile. further,
When the above-mentioned acids used are liquid, they can be used also as a solvent. The reaction is carried out at -20 ° C to 80 ° C, preferably 0 ° C to room temperature and is completed in 1 to 10 hours, preferably 1 to 5 hours.

The reaction (1) for producing the compound represented by the general formula (33) from the compound represented by the general formula (27) involves subjecting the compound represented by the general formula (27) to elimination reaction of a phenylacetyl group. It is done by The reaction can be carried out in substantially the same manner as in the method of the reaction scheme-6b, and the reaction method and reaction conditions (for example, acidic compound, solvent, reaction temperature, reaction time, etc.) are the same as those of the reaction scheme-6b. See description.

In the reaction for producing the compound represented by the general formula (13-b) from the compound represented by the general formula (33), the compound represented by the general formula (33) is converted into the above (f) and (g). , (H),
The reaction steps (i), (j) and (k) are sequentially performed, and the reaction method and reaction conditions of each step can be referred to the description of each reaction step.

Among the compounds represented by the general formula (1) contained in the antibacterial agent of the present invention, the compound having a basic group is reacted with a pharmaceutically acceptable acid, and the compound having an acidic group is A salt can be easily formed by reacting a basic compound that is permissible with. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, acetic acid, p-toluenesulfonic acid. , Organic acids such as ethanesulfonic acid can be exemplified, and examples of the basic compound include sodium hydroxide, potassium hydroxide,
Metal hydroxides such as calcium hydroxide, sodium carbonate,
Examples thereof include alkali metal carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, bicarbonates and the like.

Further, the salt of the compound contained in the antibacterial agent of the present invention naturally includes an intramolecular salt and a quaternary ammonium salt.

The compound thus obtained can be easily isolated and purified by a conventional separation means. Examples of the separating means include solvent extraction method, dilution method, recrystallization method, column chromatography,
Preparative thin layer chromatography or the like can be adopted.

The compound represented by the general formula (1) contained in the antibacterial agent of the present invention naturally includes optical isomers as well as syn isomers and anti isomers. These isomers can be separated by a conventional resolution method, for example, a method using an optical resolving agent or a method using an enzyme.

The antibacterial agent of the present invention is usually used in the form of a general pharmaceutical preparation. The preparation is prepared using diluents or excipients such as fillers, fillers, binders, moisturizers, disintegrants, surfactants and lubricants which are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections ( Solutions, suspensions, etc.) and the like. In the case of molding in the form of tablets, as the carrier, those conventionally known in this field can be widely used, for example, lactose, sucrose, sodium chloride, glucose,
Excipients such as urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinyl Binders such as pyrrolidone, dry starch, sodium alginate, agar powder laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agents such as lactose, sucrose, Disintegration inhibitors such as stearin, cocoa butter and hydrogenated oils, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose and kaolin. Bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, such as lubricants such as polyethylene glycol can be exemplified. Further, the tablet may be a tablet which is coated with a usual coating, if necessary, such as a sugar coating, a gelatin-coated tablet, an enteric coated tablet, a film-coated tablet, a double tablet or a multilayer tablet. In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, and gum arabic. At the end
Examples include tragacanth powder, gelatin, binders such as ethanol, disintegrators such as laminaran and agar. In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. . When prepared as an injection, a liquid preparation,
Emulsions and suspensions are preferably sterilized and isotonic with blood, and when molding these solutions, emulsions and suspensions, all of the diluents commonly used in this field are used. It can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be further added. If necessary, coloring agents, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may be included in the therapeutic agent. When forming into a paste, cream or gel, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. can be used as a diluent.

The amount of the compound represented by the general formula (1) or a salt thereof to be contained in the antibacterial agent of the present invention is not particularly limited and may be selected in a wide range, but is usually 1 to 70% by weight in the entire composition. Good to do.

The administration method of the antibacterial agent of the present invention is not particularly limited, and the antibacterial agent may be administered according to various preparation forms, patient's age, sex and other conditions, degree of disease and the like. For example, tablets, pills, liquids,
In the case of suspensions, emulsions, granules, and capsules, it is orally administered. In the case of an injection, it may be administered intravenously alone or in a mixture with a normal replacement fluid such as glucose or amino acid, and if necessary, may be administered intramuscularly, intradermally, subcutaneously or intraperitoneally alone. In the case of suppositories, it will be administered rectally.

The dose of the antibacterial agent of the present invention is appropriately selected depending on the usage, age of the patient, other conditions such as sex, degree of disease, etc., but usually 1 to 100 mg per 1 kg of body weight per day as the active ingredient amount,
Preferably, it should be 5 to 20 mg, and this should be 2 to 1 day.
It can be administered in four divided doses.

<Example> Hereinafter, the present invention will be described in detail based on Reference Examples, Examples, Formulation Examples and pharmacological tests.

Reference Example 1 (3S, 4S) -N- (α-benzyloxycarbonyl-β
-Trifluoromethanesulfonyloxy-α, β-propenyl) -3-azido-4-methanesulfonyloxymethyl-2-azetidinone (3S, 4S) -N- (α-benzyloxycarbonyl-β
-Hydroxy-α, β-propenyl) -3-azido-4
-Methanesulfonyloxymethyl-2-azetidinone 2
6.3 g (64 mmol) are dissolved in 300 ml of dry methylene chloride and the solution is cooled to -30 ° C in a dry ice-acetone bath. To this solution is added 21.7 g (77 mmol) of trifluoromethanesulfonic anhydride. Triethylamine 12.
A solution prepared by dissolving 5 ml (90 mmol) in 110 ml of dry methylene chloride is added dropwise to the above solution over 40 minutes. After completion of dropping, the mixture was stirred at the same temperature for 20 minutes, 10% hydrochloric acid water was added to the reaction solution, washed twice with water, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Compound 31.3g
As a dark red oil.

[Α] _D ²⁰ = -15.9 ° (C = 3.48, chloroform) NMR (CDCl ₃ ) δ: 2.27 (3H, s), 2.86 (3H, s), 4.18 ~
4.64 (3H, m), 4.95 (1H, d, J = 5Hz), 5.27 (2H, s),
7.38 (5H, s) Reference Example 2 Benzyl (6S, 7S) -7- azido-3-hydroxymethyl--Δ ³ -O-2- Isosefemu-4-carboxylate A) (3S, 4S) -N- (α -Benzyloxycarbonyl-β-trifluoromethanesulfonyloxy-α, β
30.3 g (56 mmol) of -propenyl) -3-azido-4-methanesulfonyloxymethyl-2-azetidinone are dissolved in 300 ml of methylene chloride and the solution is cooled to 0 ° C. A solution of 9.37 ml (67 mmol) of triethylamine in 94 ml of methylene chloride is added dropwise to this solution. After the addition is complete, stir at room temperature for 40 minutes. Next, 672 ml (67 mmol) of a 0.1 M methylene chloride solution of iodine is added dropwise to the reaction solution over one and a half hours. After stirring for 1 hour, the reaction solution is washed twice with water and dried over anhydrous magnesium sulfate to remove the solvent.
Thus, 42.0 g of crude (3S, 4S) -N- (α-benzyloxycarbonyl-β, γ-diiodo-α, β-propenyl) -3-azido-4-methanesulfonyloxymethyl-2-azetidinone To get The obtained crude product was directly used in the next reaction without being purified.

B) 42.0 g of the crude iodide obtained in the above reaction was dissolved in 600 ml of dimethylformamide, and 0.6 ml of water was added to this solution. Next, 18.8 g (224 mmol) of potassium formate was added under ice cooling. After stirring for 12 hours at room temperature, the reaction solution is poured into ice water 1 and extracted 5 times with methylene chloride. The extract is washed 4 times with water. After drying over anhydrous magnesium sulfate, the solvent was removed, and 24.7 g of crude benzyl (6S, 7S) -7-azido- ³ -formyloxymethyl-Δ3-O-2-isosephem-4-carboxylate was obtained as a brown oil. Obtained.

C) Crude formate compound 2 obtained as described above
Dissolve 4.7 g in a mixed solution of 200 ml of acetone and 100 ml of water,
To this, 12 ml of 12M hydrochloric acid was added, and the mixture was heated to 28 ° C and stirred at the same temperature for 6 hours. The reaction solution is poured into water, extracted with methylene chloride 5 times, and further washed with water 3 times. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to obtain crude benzyl (6S, 7S) -7-azido-3-hydroxymethyl-Δ ³ -O-2-isocephem-4-carboxylate. This is purified by silica gel column chromatography [eluent; methylene chloride: methyl acetate = 15: 1] to obtain 31.5 g of the title compound as an orange oil.

[Α] _D ²² = -29 ° (C = 0.62, chloroform) NMR (CDCl ₃ ) δ: 3.60 to 3.90 (1H, m), 3.94 (1H, d, J = 1)
0Hz), 4.27 (1H, d, J = 14Hz), 4.51 (1H, d, J = 14H)
z), 4.61 (1H, dd, J = 10Hz, 3Hz), 5.20 (1H, d, J = 5H
z), 5.29 (2H, s ), 7.00~7.73 (5H, m) Reference Example 3 Benzyl (6S, 7S) -7- azido-3-methanesulfonyloxy-methyl - [delta ³ -O-2-Isosefemu 4- after dissolving the carboxylate benzyl (6S, 7S) -7- azido-3-hydroxymethyl--Δ ³ -O-2- Isosefemu-4-carboxylate 3.15 g (9.54 mmol) of methylene chloride 100 ml, ice - methanol bath Cooled and triethylamine 2.13
ml (15.6 mmol), followed by methanesulfonyl chloride 0.96
ml (12.40 mmol) is added dropwise. After stirring for 40 minutes, the reaction solution is washed twice with water and once with saturated saline. After drying over anhydrous sodium sulfate, the solvent is removed to obtain 4.82 g of the title compound.

Reference Example 4 Benzhydryl (6S, 7S) -7- azido-3- (pyridin-4-thiomethyl) -Δ ³ -O-2- Isosefemu-4-carboxylate Benzyl (6S, 7S) -7- azido-3- acetoxymethyl -Δ ³ -O-2- Isosefemu-4-carboxylate 15g of (40.32 mmol) cooled with ice was dissolved in methylene chloride 150 ml. Next, 12.62 ml of trimethyliodosilane (8
8.71 mmol) is added dropwise. After reacting at room temperature for 1 hour, the reaction solution was cooled with an ice-sodium chloride cryogen, and 9.85 g (88.71 mmol) of 4-mercaptopyridine and 18.50 m of triethylamine.
A solution of 1 in 150 ml of methylene chloride is added dropwise at the same temperature. After reacting at room temperature for 2 hours, the reaction solution was concentrated, 80 ml of methanol was added to the residue, and the mixture was stirred and concentrated. The obtained residue was washed with 80 ml of n-hexane and then 80 ml of diethyl ether to be powdered. The obtained powder is dissolved in 100 ml of methanol-tetrahydrofuran (1: 1), 15.65 g (80.65 mmol) of diphenyldiazomethane is added, and the mixture is stirred at room temperature overnight. The reaction solution was concentrated to 1/2, cooled with ice, and the precipitate was collected by filtration.
After washing with methanol and drying, the title compound 10.5
Get 5g.

Light yellow ridges mp: 197-198 ° C Reference Example 5 Benzhydryl (6S, 7S) -7- [2- (2-t-butoxycarbonylaminothiazol-4-yl) -2-methoxyiminoacetamide] -3- (pyridin-4-thiomethyl) -Δ ³ -O-2- Isosefemu-4-carboxylate (syn isomer) benzhydryl (6S, 7S)-7-azido-3- (pyridin-4-thiomethyl) - [delta ³ - O-2-Isosephem-4-carboxylate 13.60 g methylene chloride 150 ml
Dissolve in. Under ice cooling, add 5.67 ml of triethylamine,
Pass hydrogen sulfide gas for 10 minutes. Then return to room temperature and stir for 40 minutes. The reaction mixture is washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and filtered. This filtrate is referred to as solution A.

On the other hand, di-cyclohexylcarbodiimide (DCC) 6.16 was added to a suspension of 2- (2-t-butoxycarbonylaminothiazol-4-yl) -2-methoxyiminoacetic acid (syn isomer) 9 g in methylene chloride (150 ml) under ice cooling. After adding g and stirring for 10 minutes, the above solution A is added and reacted under ice cooling for 1 hour and further at room temperature for 15 hours. After the reaction, the solution is filtered and the filtrate is concentrated. The residue is separated and purified by silica gel column chromatography [eluent; chloroform: n-hexane = 9: 1] to obtain 15.02 g of the title compound.

Light yellow plate mp: 140-142 ° C Reference Example 6 3,4-cis-3-phthalimido-1- (2,2-ethyleneketal-1-ethoxycarbonylpropyl) -4-styryl-azetidin-2-one 1- (3-Phenylarylidene) amino-2,2-ethylene ketal Ethyl butyrate 30.3 g (0.1 mol) was added to methylene chloride.
Dissolve in 200 ml. 21 ml of triethylamine (0.15 mol)
And cool to -30 ° C. Next, 24,6 g (0.11 mol) of 2-phthalimidoacetyl chloride was added to 200 ml of methylene chloride.
The solution dissolved in ml is added dropwise and stirred for 1 hour. After completion of the reaction, 200 ml of 10% hydrochloric acid water is added to wash. 200 ml of organic layer
After being washed twice with, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography [eluent; methylene chloride: ethyl acetate = 10: 1].
Separation and purification with to give 36.8 g of the title compound.

mp: 143-144 ° C Elemental analysis C H N calculated value 66.11 5.34 5.71 Measured value 65.92 5.51 5.74 Reference Example 7 3,4-cis-3-phenylacetamide-1- (2,2-ethyleneketal-1-ethoxycarbonylpropyl) ) −
4-Styryl-azetidin-2-one 3,4-cis-3-phthalimido-1- (2,2-ethylene ketal-1-ethoxycarbonylpropyl) -4-styryl-azetidin-2-one 49 g (0.1 mol) Is suspended in 300 ml of ethanol, 100 ml of 1M hydrazine hydrate ethanol solution is added, and the mixture is heated under reflux for 2 hours. After completion of the reaction, the precipitate is filtered and the filtrate is concentrated under reduced pressure. 300 ml of methylene chloride is added to the residue, and the precipitated crystals are filtered. 16.7 ml (0.12 mol) of triethylamine was added to the filtrate, cooled to 0 ° C., and 15.4 g (0.1 mol) of phenylacetyl chloride was added dropwise. After the dropping is completed, the reaction is carried out at the same temperature for 2 hours. 200 ml of 10% hydrochloric acid water is added for washing, the organic layer is washed with saturated saline and then dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated, and the residue is recrystallized from benzene to obtain 40.5 g of the title compound.

mp: 111-112 ° C Elemental analysis CHN Calculated 67.77 6.32 5.85 Measured 67.92 6.18 5.79 Reference Example 8 3,4-cis-3-phenylacetamide-1- (2,2-ethyleneketal-1-carboxypropyl) -4-styryl-azetidin-2-one 3,4-cis-3-phenylacetamido-1- (2,2-ethylene ketal-1-ethoxycarbonylpropyl)-
4-styryl-azetidin-2-one 47.9 g (0.1 mol)
Is dissolved in 150 ml of tetrahydrofuran and 100 ml of water is added. Then, at room temperature, 110 ml of 1N sodium hydroxide aqueous solution
Is added dropwise and the mixture is reacted at the same temperature for 3 hours. After the reaction,
After adjusting the pH to 2 with concentrated hydrochloric acid, the mixture is extracted twice with 250 ml of ethyl acetate. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and the residue is recrystallized from ethyl acetate to obtain 38.5 g of the title compound.

mp: 165 to 167 ° C Elemental analysis CHN Calculated value 66.66 5.82 6.22 Measured value 66.48 5.92 6.35 Reference Example 9 (3S, 4R) -3-Amino-1- (2,2-ethyleneketal-1-carboxypropyl)- 4-styryl-azetidin-2-one and (3S, 4R) -3-phenylacetamido-1- (2,2-ethyleneketal-1-carboxypropyl) -4-styryl-azetidin-2-one 3,4- Cis-3-Phenylacetamide-1- (2,2-ethylene ketal-1-carboxypropyl) -4-styryl-azetidin-2-one 66.4 g (0.147 mol) was added to water 74
Suspend in 0 ml. To this is added 147 ml of 1N thorium hydroxide. After adjusting the pH to 8 or less, 13.3 g of penicillin G amidase is added. The mixture is stirred at room temperature for 4 hours while adjusting the pH to 8 using a saturated aqueous sodium hydrogen carbonate solution. After completion of the reaction, penicillin G amidase is filtered off, and the pH of the filtrate is adjusted to 2.
The mixture is washed twice with a mixed solvent of ethyl acetate-tetrahydrofuran (1: 1), and the organic layer as a washing solution is extracted three times with 0.1N aqueous hydrochloric acid. The aqueous layers are combined, adjusted to pH 7, concentrated to about 300 ml, and adjusted to pH 3 with 10% hydrochloric acid water. The white crystals formed are filtered off. After washing with ice water three times, it was dried and white crystals of (3S, 4R) -3-amino-1- (2,2-ethyleneketal-1-carboxypropyl) -4-styryl-azetidin-2-one 8.9 get g.

mp: 129-131 ° C [α] _D ²³ = -102.8 ° (C = 0.924, ethanol) Elemental analysis C H N calculated value 61.44 6.07 8.42 Measured value 61.59 5.92 8.56 The ethyl acetate-tetrahydrofuran washing solution was concentrated, By separating and purifying by silica gel column chromatography, (3S, 4R) -3-phenylacetamide-1- (2,2-ethyleneketal-1) of white ridge crystals was obtained.
-Carboxypropyl) -4-styryl-azetidine-
Get a 2-on.

mp: 166-167 ° C. [α] _D ²³ = −2.9 ° (C = 1.05, chloroform-dimethylformamide) Reference Example 10 (3S, 4R) -3-phthalimido-1- (2,2-ethyleneketal-1- Benzyloxycarbonylpropyl) -4
-Styryl-azetidin-2-one (3S, 4R) -3-amino-1- (2,2-ethylene ketal-1-carboxypropyl) -4-styryl-azetidin-2-one 16.6 g (0.05 mol) It is dissolved in a mixed solvent of 100 ml of water and 100 ml of acetone, 55 ml of 1N sodium hydroxide aqueous solution is added, and then cooled to -20 ° C. A solution prepared by dissolving 11 g (0.055 mol) of o-methoxycarbonylbenzoyl chloride in 30 ml of acetone is added dropwise thereto. After completion of dropping, the mixture is stirred at the same temperature for 1 hour and adjusted to pH 1 with 10% hydrochloric acid water. Extract with ethyl acetate (200 ml), wash the extract with saturated brine, and dry over anhydrous magnesium sulfate. After filtration,
The filtrate is concentrated under reduced pressure, 50 ml of dimethylformamide and 19 g (0.06 mol) of cesium carbonate are added to the residue, and then 10.3 g (0.06 mol) of benzyl bromide is added, and the mixture is reacted at room temperature for 3 hours. After the reaction was completed, add 300 ml of water and add 200 ml of ethyl acetate.
Extract twice with. The extract is washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated, and the residue is separated and purified by silica gel column chromatography [eluent: n-hexane: ethyl acetate = 3: 2] to obtain 17.7 g of the title compound as a white powder.

_{mp: 57~61 ℃ [α] D} 23 = -50.0 ° (C = 1.02, chloroform) Elemental analysis C H N calc 69.56 5.11 5.07 Found 69.77 5.39 5.21 Reference Example 11 (3S, 4R) -3- phthalimido - 1- (2,2-ethylene ketal-1-benzyloxycarbonylpropyl) -4
-Formyl-azetidin-2-one (3S, 4R) -3-phthalimido-1- (2,2-ethylene ketal-1-benzyloxycarbonylpropyl) -4
26.56 g (48.1 mmol) of styryl-azetidin-2-one are dissolved in 150 ml of methylene chloride. After cooling to -50 ° C, ozone is introduced. When the color of the reaction liquid changed to light blue, the introduction of ozone was stopped, and nitrogen gas was introduced to sufficiently replace nitrogen. After adding 7.3 ml of dimethyl sulfide, gradually warm it to room temperature over 2.5 hours. 5% of reaction liquid
After washing with 150 ml of an aqueous solution of sodium hydrogencarbonate, it is washed twice with 150 ml of water. It is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The residue is washed twice with n-hexane and then washed again with a mixed solvent of 50 ml of diethyl ether and 50 ml of n-hexane. The residue is sufficiently dried under reduced pressure to obtain 23.28 g of the title compound as a white powder.

mp: 38-42 ° C [α] _D ²³ = -60.2 ° (C = 1.245, chloroform) Elemental analysis CHN Calculated value 55.91 4.69 5.02 Measured value 55.72 4.73 5.29 Reference example 12 (3S, 4R) -1- (1 -Benzyloxycarbonyl-2,2
-Ethylene ketal propyl) -3-phthalimide-4
-Hydroxymethyl-azetidin-2-one (3S, 4R) -1- (1-benzyloxycarbonyl-2,2
-Ethylene ketal propyl) -3-phthalimide-4
Formyl-azetidin-2-one 8.65 g (18 mmol) are dissolved in a mixed solvent of 40 ml of tetrahydrofuran and 10 ml of water. Add sodium cyanoborohydride with stirring at room temperature. The reaction is carried out for 3 hours while adjusting the pH between 3 and 4 using 10% hydrochloric acid water. After adding 40 ml of saturated saline to the reaction solution, the mixture is extracted twice with 40 ml of ethyl acetate. The ethyl acetate layers are combined and washed twice with 80 ml of saturated saline. After anhydrous sodium sulfate was added and dried, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow powder 7.80.
get g.

mp: 37-44 ℃ [α] _D ²³ = + 10.3 ° (C = 1.07, chloroform) Elemental analysis CHN Calculated value 62.50 5.03 5.83 Measured value 62.38 5.24 6.02 Practical example 13 (3S, 4R) -1- (1-benzyloxycarbonyl-2,2
-Ethylene ketal propyl) -3-phthalimide-4
-Mesyloxymethyl-azetidin-2-one (3S, 4S) -1- (1-benzyloxycarbonyl-2,2
-Ethylene ketal propyl) -3-phthalimide-4
-Hydroxymethyl-azetidin-2-one 8.65 g (18
Mmol) in 90 ml of methylene chloride. After cooling to 3 ° C, 3.0 ml of triethylamine and mesyl chloride
Add 1.5 ml and stir for 1 hour. 90m of 5% hydrochloric acid in the reaction solution
After washing with l, wash 3 times with 90 ml of water. After drying over anhydrous sodium sulfate, the mixture is filtered, and the filtrate is concentrated under reduced pressure to give 9.80 g of the title compound as a pale yellow powder.

mp: 43-47 ° C [α] _D ²³ = 18.6 ° (C = 1.02, chloroform) Elemental analysis CHN Calculated value 62.76 4.63 5.85 Measured value 63.03 4.75 6.09 Reference example 14 (3S, 4R) -1- (1- Benzyloxycarbonyl-2
-Hydroxy-1-propenyl) -3-phthalimido-
4-Mesyloxymethyl-azetidin-2-one (3S, 4R) -1- (1-benzyloxycarbonyl-2,2
-Ethylene ketal propyl) -3-phthalimide-4
-Mesyloxymethyl-azetidin-2-one 8.94 g (1
To 6 mmol), 32 ml of 5% trifluoroacetic acid was added and dissolved. After stirring for 30 minutes, concentrate under reduced pressure. After adding 100 ml of water, the mixture is extracted twice with 50 ml of methylene chloride. The methylene chloride layers are combined and washed 4 times with 100 ml of water. After drying over anhydrous sodium sulfate, it is filtered and the filtrate is concentrated under reduced pressure. The residue is separated and purified using silica gel column chromatography [eluent; methylene chloride: ethyl acetate = 20: 1] to obtain 6.41 g of the title compound as a white powder.

mp: 61-65 ° C [α] _D ²³ = -34.10 ° (C = 0.85, chloroform) Elemental analysis CHN calculated 56.03 4.31 5.44 Measured 56.12 4.37 5.17 Reference Example 15 (3S, 4S) -1- (1 -Benzyloxycarbonyl-2
-Trifluoromethanesulfonyloxy-1-propenyl) -3-phthalimido-4-mesyloxymethyl-azetidin-2-one (3S, 4S) -1- (1-benzyloxycarbonyl-2
-Hydroxy-1-propenyl) -3-phthalimido-
4-mesyloxymethyl-azetidin-2-one 5.15 g
(10 mmol) is dissolved in 40 ml of methylene chloride. -30 ° C
Cool to and add trifluoromethanesulfonic anhydride. Next, add 1.9 ml of triethylamine to 20 m of methylene chloride.
The solution dissolved in 1 is added dropwise over 10 minutes. After dropping, 5
Stir for 0 minutes. After adding 10% hydrochloric acid to make it weakly acidic,
Return to room temperature. The reaction mixture is washed 3 times with 100 ml of water. Anhydrous sodium sulfate was added and dried, then filtered, and the filtrate was concentrated under reduced pressure to obtain 6.21 g of the title compound as a white powder.

mp: 51 to 55 ° C [α] _D ²³ = + 40.8 ° (C = 1.03, chloroform) Elemental analysis C H N calculated value 46.44 3.27 4.33 Measured value 46.70 3.09 4.61 Reference example 16 Benzyl (6S, 7S) -7- phthalimido-3-acetoxymethyl -Δ ³ -O-2- Isosefemu-4-carboxylate (3S, 4S) -1- (1- benzyloxycarbonyl -2
1.94 g (3 mmol) of trifluoromethanesulfonyloxy-1-propenyl) -3-phthalimido-4-mesyloxymethyl-azetidin-2-one are dissolved in 15 ml of methylene chloride. Triethylamine 0.42 while cooling with ice
After adding ml, stir at room temperature for 35 minutes. A solution of 0.15 ml of bromine in 15 ml of methylene chloride was added dropwise over 5 minutes,
Stir for 15 minutes after completion of dropping. The reaction solution is washed 3 times with 30 ml of water, and then anhydrous sodium sulfate is added and dried. After filtration, the filtrate is concentrated under reduced pressure. After adding and dissolving 15 ml of dimethylformamide, 1.18 g of potassium acetate and 0.15 ml of water are added and the mixture is stirred for 5 hours. After adding 150 ml of water to the reaction solution, the mixture is extracted 3 times with 50 ml of ethyl acetate. Combine the ethyl acetate layers,
After washing 3 times with 100 ml of water, wash once with 100 ml of saturated saline. Anhydrous sodium sulfate is added, dried and filtered, and the filtrate is concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [eluent; n-hexane: ethyl acetate = 7:
Separation and purification using [4] and 0.92 g of the title compound as a pale yellow powder.
To get

mp: 80-83 ° C [α] _D ²³ = + 11.4 ° (C = 2.016, chloroform) Elemental analysis CHN calculated 63.02 4.23 5.88 Found 63.21 4.34 5.71 Example 1 (6S, 7S) -7- [ 2- (2-aminothiazole-4-
Il) -2-Methoxyiminoacetamide] -3-
[[1- (1-Pyrrolidinylcarbonylmethyl) -4-
Pyridinio] thiomethyl] -Δ ³ -O-2- Isosefemu-4-carboxylate (syn isomer) benzhydryl (6S, 7S) -7- [2- (2-t- butoxycarbonylamino-4-yl) - 2-Methoxyiminoacetamide] -3- (pyridin-4-ylthiomethyl-Δ ³ -O-2-isosephem-4-carboxylate (syn isomer) to 8 g of dimethylformamide
20 ml and N- (2-bromoacetyl) pyrrolidine (9.6 g) are added, and the mixture is reacted at room temperature for 16 hours. After the completion of the reaction, a mixed solution of 150 ml of diethyl ether and 50 ml of n-hexane is added to the reaction solution, the resulting oily substance is isolated by a gradient method, and further treated with 50 ml of diethyl ether to give a powder. The powder is collected by filtration, 300 ml of methylene chloride and 30 ml of nitromethane.
It is dissolved in a mixed solution of and nitromethane solution of 13.3 g of anhydrous aluminum chloride is added dropwise under ice cooling. After reacting at room temperature for 1.5 hours, the mixture was poured into ice water 1 to remove insoluble matter, the filtrate was separated, the aqueous layer was adjusted to pH 4 with saturated sodium hydrogen carbonate, and then the nonionic adsorption resin Diaion HP-20 was added. 200 g was added, and the resin was washed with water (1), eluted with 0 to 30% aqueous isopropanol solution, and lyophilized to give 2.82 g of the title compound.

mp: 163 ° C. (discoloration) In the same manner as in Example 1, using the appropriate starting materials, the compounds of Examples 2 to 23 below are obtained.

Example 2 (6S, 7S) -7- [2- (2-aminothiazole-4-
Il) -2-Methoxyiminoacetamide] -3-
[(1-Benzoylmethyl-4-pyridinio) thiomethyl]-[Delta] ^3- O-2-isocephem-4-carboxylate (syn isomer) NMR (DMSO-d6) [delta]: 3.84 (3H, s), 3.8-4.1 (2H, m),
4.3 to 4.8 (3H, m), 5.1 (2H, br.), 5.2 to 5.65 (1H, d
d), 6.77 (1H, s), 7.0 to 7.8 (5H, m), 7.9 to 8.15 (2
H, dd), 8.4 to 8.65 (2H, dd), 9.0 to 9.16 (1H, d) Example 3 (6S, 7S) -7- [2- (2-aminothiazole-4-
Il) -2-Methoxyiminoacetamide] -3-
[(1-acetonyl-4-pyridinio) thiomethyl]-
[Delta] ^3- O-2-isocephem-4-carboxylate (syn isomer) NMR (DMSO-d6) [delta]: 2.28 (3H, s), 3.83 (3H, s), 3.85.
~ 4.05 (2H, m), 4.40 ~ 4.70 (3H, m), 5.04 (2H, s),
5.45 ~ 5.65 (1H, m), 6.76 (1H, s), 8.2 ~ 8.35 (2H, d
d), 8.37 to 8.52 (2H, dd), 9.0 to 9.15 (1H, d) Example 4 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2-Cyclopentyloxyiminoacetamido] -3-[[1- (1-pyrrolidinylcarbonylmethyl) -4-pyridinio] thiomethyl] -Δ ³ -O-2-
Isocephem-4-carboxylic acid sulfate (syn isomer) mp: 138 ° C (color change) Example 5 (6S, 7S) -7- [2- (2-aminothiazole-4-
2-cyclopentyloxyiminoacetamide] -3-[(1-N, N-dimethylcarbamoylmethyl-4-pyridinio) thiomethyl] -Δ ³ -O-2-isosephem-4-carboxylic acid sulfate (syn isomerism Body) mp: 154 ° C (discoloration) Example 6 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2-carbamoylmethoxyiminoacetamido] -3-[(1-methyl-4-pyridinio) thiomethyl] -Δ ³ -O-2-isocephem-4-carboxylate (syn isomer) mp: 165 ° C (discoloration ) Example 7 (6S, 7S) -7- [2- (2-aminothiazole-4-
Il) -2-Methoxyiminoacetamide] -3-
[(1-N, N-Dimethylcarbamoylmethyl-4-pyridinio) thiomethyl]-[Delta] ^3- O-2-isocephem-
4-Carboxylic acid sulfate (syn isomer) mp: 121 ° C (discoloration) Example 8 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2-Cyclopentyloxyiminoacetamido] -3-[(1-propanoylmethyl-4-pyridinio) thiomethyl] -Δ ³ -O-2-isosephem-4-
Carboxylic acid sulfate (syn isomer) NMR (DMSO-d6) δ: 1.02 (3H, t), 1.36 to 2.0 (8H, b
r.), 3.8 to 4.1 (2H, m), 4.35 to 5.0 (6H, m), 5.45 to
5.83 (3H, m), 6.85 (1H, s), 8.0 to 8.18 (2H, dd), 8.
4-8.58 (2H, dd), 9.05-9.25 (1H, d) Example 9 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2-Cyclopentyloxyiminoacetamido] -3-[[1- (1-piperazinylcarbonylmethyl-4-pyridinio] thiomethyl] -Δ ³ -O-2-isosephem-4-carxylate (syn isomer) mp: 148 ° C. (color change to brown) Example 10 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2-Cyclopentyloxyiminoacetamido] -3-[(1-hydroxyaminocarbonylmethyl-4-pyridinio) thiomethyl] -Δ ³ -O-2-isosephem-4-carboxylate (syn isomer) mp: 156 C (discolored to brown) Example 11 (6S, 7S) -7- [2- (2-aminothiazole-4-
Il) -2-Methoxyiminoacetamide] -3-
[(1-morpholinocarbonyl-4- pyridinio) thiomethyl] -Δ ³ -O-2- Isosefemu 4-
Carboxylate (syn isomer) mp: 153 ° C. (discolored to brown) Example 12 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2-Cyclopentyloxyiminoacetamido] -3-[(1-chloromethyl-4-pyridinio) thiomethyl] -Δ ³ -O-2-isosephem-4-carxylate (syn isomer) NMR (DMSO-d6) δ: 1.4 to 2.0 (8H, m), 3.6 to 3.9 (2H, m
m), 4.2 to 5.2 (6H, m), 5.47 (1H, dd), 6.72 (1H, m)
s), 7.16 (2H, bs), 7.95 (2H, d), 8.31 (2H, d), 9.
07 (1H, d) Light yellow powder mp: Gradually discolored from around 134 ° C. Example 13 Benzhydryl (6S, 7S) -7- [2- (2-tritylaminothiazol-4-yl) -2-cyclopentyloxyimino Acetamide] -3-[(1-chloromethyl-4-pyridinio) thiomethyl] -Δ ³ -O-2-isosephem-4-carboxylate iodide (syn isomer) reddish brown powder mp: 172-175 ° C (decomposition) Example 14 Benzhydryl (6S, 7S) -7- [2- (2-tritylaminothiazol-4-yl) -2-cyclopentyloxyiminoacetamido] -3-[(1-cyclopropylmethyl-4-pyridinio) thiomethyl ] −Δ ³ −O−
2-Isosephem-4-carboxylate Bromide (syn isomer) Light yellow powder mp: 161-164 ° C Example 15 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2-Cyclopentyloxyiminoacetamido] -3-[(1-cyclopropylmethyl-4-pyridinio) thiomethyl] -Δ ³ -O-2-isocephem-4
-Carboxylic acid ditrifluoroacetate (syn isomer) NMR (DMSO-d6) δ: 0.56 to 0.65 (4H, m), 1.3 to 1.9 (9
H, m), 3.8 to 4.8 (12H, m), 5.68 (1H, dd), 6.80 (1H, m)
s), 8.08 (1H, d), 8.85 (2H, d), 9.16 (1H, d) Light yellow powder mp: Gradual discoloration from 145 ° C Browning from 162 ° C Example 16 Benzhydryl (6S, 7S)- 7- [2- (2-tritylaminothiazol-4-yl) -2-cyclopentyloxy syn-amide] -3 - [[1- (2-fluoroethyl) -4-pyridinio] thiomethyl] - [delta ³ -O
2-Isosephem-4-carboxylate methanesulfonate (syn isomer) Yellow powder mp: 117-119 ° C Example 17 (6S, 7S) -7- [2- (2-aminothiazole-4-
Il) -2-cyclopentyloxyiminoacetamido] -3-[[1- (2-fluoroethyl) -4-pyridinio] thiomethyl] -Δ ³ -O-2-isosephem-
4-carboxylate (syn isomer) NMR (DMSO-d6) δ: 1.4-2.0 (8H, m), 3.3-5.2 (10H,
m), 5.52 (1H, dd), 6.72 (1H, s), 7.16 (2H, bs),
8.30 (2H, bs), 8.75 (2H, bs) 9.06 (1H, d) Pale yellow powder mp: Gradual color change from 164 ° C Brown color change from 176 ° C Example 18 (6S, 7S) -7- [2- (2-aminothiazole-4-
Il) -2-cyclopentyloxyiminoacetamido] -3-[[1- (2-fluoroethyl) -4-pyridinio] thiomethyl] -Δ ³ -O-2-isosephem-
4-Carboxylic acid Sulfate (syn isomer) Slightly yellow powder mp: Gradual color change from 161 ° C Brown color change from 174 ° C Example 19 Benzhydryl (6S, 7S) -7- [2- (2-tritylaminothiazole-4] -Yl) -2-methoxyiminoacetamide] -3-[[1- (2-fluoroethyl)-
4-pyridinio] thiomethyl]-[Delta] ^3- O-2-isocephem-4-carboxylate methanesulfonate (syn isomer) pale yellow powder mp: 126-129 [deg.] C Example 20 (6S, 7S) -7- [ 2- (2-aminothiazole-4-
Il) -2-Methoxyiminoacetamide] -3-
[[1- (2-Fluoroethyl) -4-pyridinio] thiomethyl]-[Delta] ^3- O-2-isosephem-4-carboxylate (syn isomer) NMR (DMSO-d6) [delta]: 3.2-5.2 (12H, m), 5.60 (1H, d
d), 6.77 (1H, s), 7.16 (2H, bs), 8.34 (2H, d), 8.
72 (2H, d), 9.14 (1H, d) Light red powder mp: Gradual discoloration from 128 ° C Strong discoloration from 174 ° C, turning brown Example 21 (6S, 7S) -7- [2- (2- Aminothiazole-4-
Il) -2-cyclopentyloxyiminoacetamido] -3-[(1-acetonyl-4-pyridinio) thiomethyl] -Δ ³ -O-2-isosephem-4-carboxylate (syn isomer) Light yellow powder mp: 152 C (discoloration) NMR (DMSO-d6) δ: 1.3-1.9 (8H, m), 2.28 (3H, s),
3.7 ~ 4.0 (2H, m), 4.3 ~ 4.75 (3H, m), 5.08 (1H, m
m), 5.38-5.76 (3H, m), 6.72 (1H, s), 7.16 (2H, b
s), 8.36 (2H, d), 8.56 (2H, d), 9.08 (1H, d) Example 22 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2-Cyclopentyloxyiminoacetamido] -3-[(1-acetonyl-4-pyridinio) thiomethyl] -Δ ³ -O-2-isosephem-4-carboxylic acid sulfate (syn isomer) slightly yellow ridges Crystal mp: 154 ° C (discoloration) Example 23 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2-Cyclopentyloxyiminoacetamido] -3-[(1-acetonyl-4-pyridinio) thiomethyl] -Δ ³ -O-2-isocephem-4-carboxylic acid sulfate (syn isomer) yellow ridge crystals mp: 161 ° C. (discoloration) [α] _D ²⁰ = −70.3 ° C. (C = 1.55, water) Example 24 Benzhydryl (6S, 7S) -7- [2- (2-aminothiazol-4-yl) -2 -Carbamoylmethoxyiminoacetamido] -3-[(pyridin-4-yl) thiomethyl]-[Delta] ^3- O-2-isocephem-4-carboxylate (syn isomer) benzhydryl (6S, 7S) -7- [2- (2-Trimethylaminothiazol-4-yl) -2-carbamoylmethoxyiminoacetamido] -3-[(pyridine-4
-Yl) thiomethyl]-[Delta] ^3- O-2-isocephem-
0.21 g (0.22 mmol) of 4-carboxylate (syn isomer) is dissolved in a mixed solution of 6 ml of acetic acid and 1 ml of water and heated to 40 ° C. After 2 hours the reaction is evaporated to dryness and the residue is dissolved in ethyl acetate. This solution was washed with a 5% aqueous sodium hydrogen carbonate solution and then with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off to obtain 0.09 g of the title compound.

mp: 147 ° C (discoloration) In the same manner as in Reference Example 5, using the appropriate starting materials, the compounds of Examples 25 to 28 were obtained.

Example 25 benzhydryl (6S, 7S) -7- [2- (2- tritylaminothiazol-4-yl) -2-carbamoyl methoxyiminoacetamido] -3 - [(pyridin-4-yl) thiomethyl] - [delta ³ -O-2-isocephem-4-
Carboxylate (syn isomer) NMR (CDCl ₃ ) δ: 3.7 to 4.0 (2H, m), 4.28 (2H, dd, J = 1)
3.5Hz), 4.4 to 4.7 (3H, m), 5.60 (1H, dd, J = 4.5H
z), 6.67 (1H, s), 6.91 (1H, s), 7.05 to 7.50 (30H,
m), 8.23 (2H, d, J = 6Hz), 8.55 (1H, bs) Example 26 Benzhydryl (6S, 7S) -7- [2- (2-t-butoxycarbonylaminothiazol-4-yl)- 2-Methoxyiminoacetamide] -3-[[1- (1-pyrrolidinylcarbonylmethyl) -4-pyridinio] thiomethyl] -Δ ³ -O-2-isosephem-4-carboxylate bromide (syn isomer) mp : 143 ° C (discoloration) Example 27 Benzhydryl (6S, 7S) -7- [2- (2-benzyloxycarbonylaminothiazol-4-yl) -2-
Methoxyiminoacetamido] -3 - [[1- (1-pyrrolidinylcarbonyl) -4-pyridinio] thiomethyl] -Δ ³ -O-2- Isosefemu-4-carboxylate bromide (syn isomer) mp: 156 C. (Discoloration) Example 28 Benzhydryl (6S, 7S) -7- [2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido] -3-[[1- (1-pyrrolidinylcarbonyl Methyl) -4-pyridinio] thiomethyl] -Δ ³ -O
2-Isosephem-4-carboxylate Bromide (syn isomer) mp: 151 ° C (color change) Example 29 (6S, 7S) -7- [2- (2-aminothiazole-4-
Il) -2-cyanomethoxyiminoacetamide] -3
-[(1-acetonyl-4-pyridinio) thiomethyl]
-Δ ³ -O-2- Isosefemu-4-carboxylate (syn isomer) in the same manner as in Example, using the appropriate starting materials, the title compound was obtained.

mp: 115 ° C (color change) NMR (DMSO-d6) δ: 2.28 (3H, s), 3.60 to 3.95 (2H,
m), 4.2 to 4.75 (3H, m), 5.01 (2H, s), 5.30 (1H, d
d), 5.78 (2H, s), 6.70 (1H, s), 7.18 (2H, bs), 8.
56 (4H, dd), 9.08 (1H, d) Example 30 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2- (1-carbamoyl-1-methylethoxyimino) acetamido] -3-[(4-pyridinio) thiomethyl] -Δ ³ -O-2-isosephem-4-carboxylate (syn isomer) Examples The title compound was obtained in a similar manner to 1 using the appropriate starting materials.

Light orange fringe crystals mp: 126 ° C (discoloration) Example 31 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2- (1-carbamoyl-- (1S) - ethoxyimino) acetamido] -3 - [(4-pyridinio) thiomethyl] -Δ ³ -O-2- Isosefemu-4-carboxylate (syn isomer) carried The title compound was obtained in a similar manner to Example 1 using the appropriate starting materials.

Light yellow ridges mp: 134 ° C (discoloration) Example 32 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2- (1-carbamoyl-1-methylethoxyimino) acetamido] -3-[(1-methyl-4-pyridinio) thiomethyl] -Δ ³ -O-2-isosephem-4-carboxylic acid sulfate ( Syn isomer) In the same manner as in Example 1, using the appropriate starting materials, the title compound was obtained.

White ridge crystals mp: 168 ° C (discoloration) Example 33 (6S, 7S) -7- [2- (2-aminothiazole-4-
Yl) -2- (isopropoxyimino) acetamide]
-3 - [(1-acetonyl-4-pyridinio) thiomethyl] -Δ ³ -O-2- Isosefemu-4-carboxylic acid
Sulfate (syn isomer) In the same manner as in Example 1 and using appropriate starting materials, the title compound was obtained.

White ridge crystals mp: 165 ° C (discoloration) Formulation Example 1 (6S, 7S) -7- [2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(1-acetonyl) 4-pyridinio) thiomethyl] - [delta ³ - to O-2-Isosefemu-4-carboxylate (syn isomer) 200 mg glucose 250mg distilled water for injection appropriate amount total amount 5ml distilled water for injection, (6S, 7S) -7 -[2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(1-acetonyl-4-pyridinio) thiomethyl]-[Delta] ^3- O-2-isocephem-4-carboxylate After dissolving the (syn isomer) and glucose, the mixture is poured into a 5 ml ampoule, purged with nitrogen, and sterilized under pressure at 121 ° C. for 15 minutes to give an injection of the above composition.

Formulation Example 2 Benzhydryl (6S, 7S) -7- [2- (2-tritylaminothiazol-4-yl) -2-cyclopentyloxyiminoacetamido] -3-[(1-chloromethyl-4-pyridinio) thiomethyl] -Δ ³ -O-2- isocephem-4-carboxylate iodide (syn isomer) 100 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g corn starch 30 g magnesium stearate 2 g TC-5 (trade name, Shin-Etsu Chemical Co., Ltd. Co., Ltd., Hydroxypropyl methylcellulose) 10 g Polyethylene glycol-6000 3 g Castor oil 40 g Ethanol 40 g Benzhydryl (6S, 7S) -7- [2- (2-Tritylaminothiazol-4-yl) -2-cyclopentyloxyiminoacetamide ] -3 - [(1-chloromethyl-4-pyridinio) thiomethyl] - [delta ³ - 2 Isosefemu-4-carboxylate iodide (syn isomer), Avicel, corn starch and magnesium stearate, after mixing polished to tableting in punch glycocalyx R10mm. The obtained tablets are TC-5, polyethylene glycol-
A film coating agent coating consisting of 6000, castor oil and ethanol is applied to produce a film coated tablet having the above composition.

Formulation Example 3 (6S, 7S) -7- [2- (2-Aminothiazol-4-yl) -2-cyclopentyloxyiminoacetamido] -3-[(1-chloromethyl-4-pyridinio) thiomethyl] -Δ ^3- O-2-Isosephem-4-carboxylate (syn isomer) 2g Purified lanolin 5g White beeswax 5g White petrolatum 88g Total amount 100g White beeswax is heated to form a liquid, and then (6S, 7
S) -7- [2- (2-Aminothiazol-4-yl)
-2-Cyclopentyloxyiminoacetamide] -3
-[(1-Chloromethyl-4-pyridinio) thiomethyl]-[Delta] ^3- O-2-isocephem-4-carboxylate (syn isomer), purified lanolin and white petrolatum were added, and the mixture was heated until it became liquid, Stir until solidification begins to obtain an ointment of the above composition.

[Antibacterial test] In order to investigate the antibacterial activity against various bacteria, the minimum inhibitory concentration (MIC) of the test compound shown below was determined by the agar dilution plate method.

[See CHEMOTHERAPY, 22, 1126-1128 (1974)] The results obtained are shown in Table 1.

In addition, various bacteria are 1 × 10 ⁶ bacteria / ml (OD600mμ, 0.07-0.1
Adjusted to 6).

Test compound No. 1 (6S, 7S) -7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3
-[(1-Benzoylmethyl-4-pyridinio) thiomethyl]-[Delta] ^3- O-2-isocephem-4-carboxylate (syn isomer) No. 2 (6S, 7S) -7- [2- (2- Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3
-[[1- (1-pyrrolidinylcarbonylmethyl) -4
-Pyridinio] thiomethyl]-[Delta] ^3- O-2-isocephem-4-carboxylate (syn isomer) No.3 (6S, 7S) -7- [2- (2-aminothiazol-4-yl) -2 -Cyclopentyloxyiminoacetamido] -3-[[1- (1-pyrrolidinylcarbonylmethyl) -4-pyridinio] thiomethyl]-[Delta] ^3- O-
2-Isosephem-4-carboxylic acid sulfate (syn isomer) No.4 (6S, 7S) -7- [2- (2-aminothiazol-4-yl) -2-cyclopentyloxyiminoacetamide] -3- [(1-N, N- dimethylcarbamoyl-4- pyridinio) thiomethyl] -Δ ³ -O-2-
Isocephem-4-carboxylic acid sulfate (syn isomer) No. 5 (6S, 7S) -7- [2- (2-aminothiazol-4-yl) -2-carbamoylmethoxyiminoacetamide] -3-[( 1-Methyl-4-pyridinio) thiomethyl]-[Delta] ^3- O-2-isosephem-4-carboxylate (syn isomer) No. 6 (6S, 7S) -7- [2- (2-aminothiazole-4] -Yl) -2-methoxyiminoacetamide] -3
-[(1-N, N-Dimethylcarbamoylmethyl-4-pyridinio) thiomethyl]-[Delta] ^3- O-2-isocephem-4-carboxylic acid sulfate (syn isomer) No.7 (6S, 7S) -7 -[2- (2-Aminothiazol-4-yl) -2-cyclopentyloxyiminoacetamide] -3-[(1-propanoylmethyl-4-pyridinio) thiomethyl]-[Delta] ^3- O-2-isocephem-
4-Carboxylic Acid Sulfate (Syn Isomer) No.8 (6S, 7S) -7- [2- (2-Aminothiazol-4-yl) -2-cyclopentyloxyiminoacetamide] -3-[[1- (1-piperazinylcarbonyl) -4-pyridinio] thiomethyl] - [delta ³ -O-
2-Isosephem-4-carboxylate (syn isomer) No. 9 (6S, 7S) -7- [2- (2-aminothiazol-4-yl) -2-cyclopentyloxyiminoacetamide] -3-[( 1-Hydroxyaminocarbonylmethyl-4-pyridinio) thiomethyl] -Δ ³ -O-2-
Isocephem-4-carboxylate (syn isomer) No.10 (6S, 7S) -7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3
-[(1-morpholinocarbonylmethyl-4-pyridinio) thiomethyl]-[Delta] ^3- O-2-isosephem-4-
Carboxylate (syn isomer) No. 11 (6S, 7S) -7- [2- (2-aminothiazol-4-yl) -2-cyclopentyloxyiminoacetamide] -3-[(1-chloromethyl-4 -Pyridinio) thiomethyl]-[Delta] ^3- O-2-isocephem-4-
Carboxylate (syn isomer) No. 12 (6S, 7S) -7- [2- (2-aminothiazol-4-yl) -2-cyclopentyloxyiminoacetamido] -3-[(1-cyclopropylmethyl- 4-pyridinio) thiomethyl] -Δ ³ -O-2- Isosefemu-4-carboxylic acid ditrifluoroacetate (syn isomer) No.13 (6S, 7S) -7- [2- (2- aminothiazol -4 -Yl) -2-cyclopentyloxyiminoacetamido] -3-[[1- (2-fluoroethyl) -4-
Pyridinio] thiomethyl]-[Delta] ^3- O-2-isocephem-4-carboxylate (syn isomer) No.14 (6S, 7S) -7- [2- (2-aminothiazol-4-yl) -2- Methoxyiminoacetamide] -3
-[[1- (2-Fluoroethyl) -4-pyridinio]
Thiomethyl] -Δ ³ -O-2- Isosefemu-4-carboxylate (syn isomer) No.15 (6S, 7S) -7- [2- (-4- 2- aminothiazol-yl) -2- (1 -Carbamoyl-1-methylethoxyimino) acetamido] -3-[(4-pyridinio) thiomethyl]-[Delta] ^3- O-2-isocephem-4-
Carboxylate (syn isomer) No. 16 (6S, 7S) -7- [2- (2-Aminothiazol-4-yl) -2- (1-carbamoyl- (1S) -ethoxyimino) acetamide] -3 -[(4-Pyridinio) thiomethyl]-[Delta] ^3- O-2-isosephem-4-
Carboxylate (syn isomer) No. 17 (6S, 7S) -7- [2- (2-aminothiazol-4-yl) -2- (1-carbamoyl-1-methylethoxyimino) acetamide] -3- [(1-methyl-
4-Pyridinio) thiomethyl]-[Delta] ^3- O-2-isocephem-4-carboxylic acid sulfate (syn isomer) No. 18 (6S, 7S) -7- [2- (2-aminothiazol-4-yl) ) -2- (Isopropoxyimino) acetamide] -3-[(1-acetonitrile-4-pyridinio) thiomethyl]-[Delta] ^3- O-2-isocephem-4-
Carboxylic acid sulfate (syn isomer)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hidetsugu Tsubouchi 2-6, Nomonohama, Otsu City, Shiga Prefecture-608 (72) Inventor, Kimio Sudo 1-1-26-302 Misora Town, Otsu City, Shiga Prefecture (72) ) Inventor Koichi Tsuji 7-30-6 Sakamoto, Otsu City, Shiga Prefecture

Claims (1)

[Claims] 1. A general formula [In the formula, R ¹ represents an amino group, a lower alkanoylamino group, a halogen-substituted lower alkanoylamino group, or a phenyl group.
~ 3 phenyl lower alkylamino group, phenyl lower alkoxycarbonylamino group or lower alkoxycarbonylamino group; R ² is a lower alkyl group, cycloalkyl group, cyano lower alkyl group, carboxy lower alkyl group or carbamoyl lower alkyl group; R ³ represents a pyridyl group or a pyridinio group, and the pyridinio group is a lower alkyl group, a cycloalkyl lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanoyl lower alkyl group, a benzoyl lower alkyl group, a halogen-substituted lower alkyl group, a halogen-substituted lower group. Lower alkyl group substituted with alkanoyl group, carboxycarbonyl lower alkyl group, lower alkyl group substituted with lower alkoxyimino group or group: (In the formula, A is a lower alkylene group, R ⁵ is a hydrogen atom or a lower alkyl group, R ⁶ is a lower alkyl group or a hydroxy group, and R ⁵ and R ⁶ are an oxygen atom, a nitrogen atom together with a nitrogen atom to be bonded. A 5-membered or 6-membered saturated heterocycle may be formed with or without an atom or a sulfur atom, and the saturated heterocycle may be substituted with a hydroxy group or a lower alkyl group. R ⁴ represents a carboxy group, a carboxylate group or an esterified carboxy group. However, when R ³ is a pyridinyl group or a pyridinio group substituted with a lower alkyl group, R ² represents a carbamoyl lower alkyl group. ] The antibacterial agent containing at least 1 sort (s) selected from the group which consists of the 2-oxa- isocephem derivative represented by these, and the pharmaceutically acceptable salt of those compounds as an active ingredient.