JPH0459781A - Cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [X and Y are such that one of them is methylene, the other being S; Z is alkylene; R<1> is heterocyclic thiomethyl having 1-4 heteroatom(s) (N or S) (heterocyclic fragment may have alkyl, carboxyalkyl, carboxy or OH); R<2> is carboxyl or carboxylate] or its salt. EXAMPLE:(6S,7S)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1,5-dihydr oxy-4-pyridon-2- ylmethoxyimino)acetamido]-3-(5-carboxymethyl-4-methylthiazol-2-ylthiom ethyl)- isocephem-4-carboxylic acid. USE:An antifungal agent. PREPARATION:For example, one of compounds of formula IV including the objective compound of the formula I can be obtained by reaction between an amino compound of formula II (R<3> is H or ester residue) and a carboxylic acid compound of formula III (R<4> and R<5> are each R<3>).

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field of the Invention The present invention relates to cephalosporin derivatives having antibacterial activity.

Disclosure of the Invention Cephasporin derivatives having antibacterial activity are disclosed in JP-A-63-201191 and JP-A-62-1523.
Although those described in Publication No. 83 and the like are known, the cephalosporin derivative of the present invention is a new compound that has not been described in any literature, and is represented by the following general formula (1).

(In the formula, one of X and Y represents a methylene group, the other represents a sulfur atom, Z represents a lower alkylene group, and R1 represents 1 to 4 hetero atoms selected from the group consisting of nitrogen atoms and sulfur atoms. The heterocyclic portion of the heterocyclic thiomethyl group may have a lower alkyl group, a carboxy lower alkyl group, a carboxy group or a hydroxy group, and R2 is a carboxy group or a carboxylate group. shows.

) The compound of the present invention represented by the above general formula (1) exhibits excellent antibacterial activity against a wide range of Durum-positive bacteria and Durum-negative bacteria, and particularly against Staphylococcus aureus as Durum-positive bacteria. -coccus
aureus PDA-209-P), Streptococcus pneumoniae (Streptococcus pneumoniae)
pneuionIae) and Corynebacterium diphtheriae (Corynebacterium diphtheriae +Hp
Shows excellent antibacterial activity against Hther4ae). Furthermore, it exhibits excellent antibacterial activity against non-glucose-fermenting bacteria. In addition, the compound of the present invention has good absorption into the living body,
It has the characteristics of long-lasting medicinal efficacy and low toxicity,
It also shows excellent effects against resistant bacteria and clinically isolated bacteria. Furthermore, the compound of the present invention has high stability and excellent absorption and excretion properties.

That is, renal excretion is high and bile transit is also good.

It is also highly distributed in various organs including the lungs. The difference between the minimum inhibitory concentration and the minimum bactericidal concentration is small, and there are few side effects such as immunosuppressive effects and allergic effects.

Therefore, the compounds of the present invention are useful as therapeutic agents for diseases of humans, animals, and fish caused by various pathogenic bacteria, and are also useful as external disinfectants and disinfectants for medical instruments and the like.

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

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.

Carboxy lower alkyl groups include carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4
Examples include carboxyalkyl groups having 1 to 6 carbon atoms in the alkyl group moiety, such as -carboxybutylquinpentyl and 6-carboxyhexyl.

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

The heterocyclic moiety of the heterocyclic thiomethyl group includes an unsaturated heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of nitrogen atoms and sulfur atoms, for example,
1,3.4-thiadiazolyl, 1,2.3-thiadiazolyl, 1,2.4-thiadiazolyl, 1,2.4-triazolyl, 1.2.

To 5- or 6-membered monocyclic rings such as 3-triazolyl, 1.3.4-1-riazolyl, tetrazolyl, pyridyl, 1.2-thiazolyl, 1,3-thiazolyl, imidazolyl, 1,2.4-triazinyl, etc. An example is a terocyclic group.

Examples of the hydroxy lower alkyl group include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,
2-hydroxy-1,1-dimethylethyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1.

Examples include 2-dihydroxyethyl and 2,3-dihydroxypropyl.

Next, typical examples of the compounds of the present invention represented by the general formula (1) are shown in Table 1.

(Hereinafter, blank space) The compound and raw material compound of the present invention can be produced by various methods, and for example, can be produced by the methods shown in Reaction Scheme-1 to Reaction Scheme-6b below.

Reaction scheme-1 (wherein, R1, X, Y and Z are the same as above, R'',
R' and R5 each represent a hydrogen atom or an ester residue. ) In the above reaction scheme-1, the compound represented by the general formula (1-a) containing the compound of the present invention as a part thereof is represented by the general formula (3).
It can be produced by reacting a carboxylic acid compound represented by or a compound whose carboxy group is activated with an amino compound represented by general formula (2) in a normal amide bond forming reaction.

The ester residues represented by R3, RJ and R5 above include common ester residues such as methyl, ethyl,
Alkyl groups having 1 to 6 carbon atoms such as propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl; benzyl, benzhydryl, α-phenethyl, β
- (Mono or di)phenyl lower alkyl group with 1 to 6 carbon atoms in the alkyl moiety such as phenethyl, a, β-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, etc. ;
Alkenyl groups with 2 to 6 carbon atoms such as vinyl, allyl, crotyl, 2-pentenyl, and 2-hexenyl; alkenyl groups with 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy, Cycloalkyl group; cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 5-cyclohexylpentyl, 6
-cyclohexylhexyl, cyclopropylmethyl, 2
- A cycloalkyl (lower) alkyl group in which the cycloalkyl part has 3 to 8 carbon atoms and the alkyl part has 1 to 6 carbon atoms, such as cyclobutylethyl, cyclopentylmethyl, 2-cyclohebutylethyl, cyclooctylmethyl, etc. I can give an example.

The phenyl moiety in the (mono- or di)phenyl lower alkyl group of the ester residue has, as a substituent, a halogen atom such as a fallen tree, a chlorine atom, a bromine atom, a fluorine atom, an iodine atom; methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, tertiary butyl, pentyl,
Lower alkyl groups having 1 to 6 carbon atoms such as hexyl; methoxy, ethoxy, propoxy, isopropoxy, butoxy,
Lower alkoxy groups having 1 to 6 carbon atoms such as tertiary butoxy, pentyloxy, hexyloxy, etc.; nitro group; carboxy group; cyano group; and 1 to 3 substituents selected from the group consisting of hydroxyl group, or methylene It may have a lower alkylenedioxy group having 1 to 4 carbon atoms such as dioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy.

In addition, the lower alkyl group of the ester residue has substituents such as 1 to 3 halogen atoms, hydroxyl group, mercapto group, lower alkoxy group, lower alkanoyloxy group, or carboxy group. , cyano group,
Nitro group, amino group, lower alkyl group mentioned above, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, butylamino, etc. (mono or di)
It may be substituted with a lower alkylamino group, the above-mentioned lower alkanoylamino group, or a lower alkylthio group such as methylthio, ethylthio, propylthio, butylthio.

As the amide bond forming reaction, any known amide bond forming reaction conditions can be applied. For example, a) a method using a condensing agent: that is, a method in which the carboxylic acid compound (3) and the amine compound (2) are reacted in the presence of a condensing agent; b) a mixed acid anhydride method: that is, a method that uses a carboxylic acid compound ( 3
) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and this is reacted with the amine compound (2); C) Active esterification method: That is, a method in which a carboxylic acid compound (
3) into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and reacting this with the amine compound (2); d) carboxylic acid compound (
3) is converted into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and this is reacted with the amine compound C); e) A method in which the lower alcohol ester of the carboxylic acid compound (3) and the amine compound (2) are heated at high temperature, A method of reacting under high pressure; f) converting the carboxylic acid compound (3) into an acid halide, that is, a carboxylic acid halide, and reacting this with the amine compound (2)
An example is a method of reacting.

Next, an example of the amide bond forming reaction will be explained in more detail.

The compound represented by the general formula (1-a) is added to the amine compound represented by the general formula (2) in the presence of a condensing agent to form the compound represented by the general formula (3).
It is obtained by reacting the carboxylic acid compound represented by without a solvent or in the presence of an inert solvent.

Examples of the condensing agent used in the reaction include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, and (chloromethylene)dimethylammonium chloride synthesized by the reaction of dimethylformamide with thionyl chloride, phosphorus oxychloride, phosgene, etc. Vilsmeier (V
ilsmeler reagent, dicyclohexylcarbodiimide (DCC), and 2°2-1 pyridinyl disphide 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, dioxane, etc.
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, alcohols such as propatool, dimethylformamide (
DMF), hexamethyl phosphate triamide (HMPA)
), aprotic polar solvents such as dimethyl sulfoxide (DMSO), and carbon disulfide.

The above reaction is more preferably carried out in the presence of a basic compound. Examples of the basic compound include trialkylamines such as triethylamine and tributylamine;
Pyridine, picoline, 1° trialkylamine, pyridine, picoline, 1° 5-diazabicyclo[4,3,01
Organic bases such as nonene-5,1,4-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,0]undecene-7, monotrimethylsilylacetamide, sodium hydroxide, potassium hydroxide, etc. Examples include inorganic bases such as alkali metal hydroxides, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate.

In addition, 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 (3) is 1 to 10% molar amount, preferably 1 to 3% by molar amount.
It is better to double the molar amount. The ratio of the basic compound to the amine compound represented by the general formula (2) is equimolar -
The amount is preferably 40 times the molar amount, preferably 5 to 20 times the molar amount.

The above reaction is carried out at a temperature of -20'C to 100'C, preferably 0 to 50''C, for about 30 minutes to 24 hours, preferably about 30 minutes to 10 hours.

In addition, in the reaction of the amine compound represented by the above general formula (2) with the carboxylic acid compound represented by the general formula (3), when the groups R3, R4 and/or R5 are carboxy groups, the general formula (1 ) and the carboxy group of the amine compound represented by general formula (2) may be obtained. In this case, an acid catalyst such as hydrochloric acid, odorant By hydrolyzing the condensed compound in the presence of an inorganic or organic acid such as hydrochloric acid or trifluoroacetic acid, a compound represented by general formula (1) containing the compound of the present invention as a part can be obtained. .

(Left below) Reaction scheme-2 (4)' In formula 1, R' s R3, X and Y are the same as above, R
6 represents an azide group, a phenylacetamide group or a phthalimide group. The above reaction scheme-2 is a reaction process in which the compound represented by the general formula (4) is subjected to a reduction reaction, a hydrolysis reaction, or a hydrazine decomposition reaction depending on the type of R6, which is a substituent thereof. This is a method for producing a compound represented by the general formula (2) including a new compound.

In the above reaction scheme, when the group R6 is an azido group,
The compound represented by the general formula (2) can be obtained by reacting the compound represented by the general formula (4) with a reducing agent without a solvent or in the presence of a suitable inert solvent.

Examples of the solvent used in this reaction include dichloromethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, benzene, toluene,
Examples 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. When hydrogen sulfide or the like is used, amines such as triethylamine and pyridine may be added.

The ratio of the reducing agent used to the compound represented by the general formula (4) is preferably an equimolar amount to 100 times the molar amount, preferably 3 to 50 times the molar amount, and the reaction is usually carried out at -30°C to 50°C.
The process is carried out at a temperature of -10°C to 10°C, and is completed in about 30 minutes to 10 hours.

In addition, when the group R6 is a phenylacetamide group, the amine represented by the general formula (2) can be prepared by subjecting the compound represented by the general formula (4) to a hydrolysis reaction without a solvent or in an inert solvent. A compound is obtained.

This reaction can be carried out in substantially the same manner as Reaction Scheme-5a described below, and the reaction method and reaction conditions (e.g.
(hydrolysis catalyst, solvent, reaction temperature, reaction time, etc.), refer to the explanation of Reaction Scheme-5a.

When the group R6 is a phthalimide group, the compound represented by the general formula (2) is subjected to a hydrazinolysis reaction in which the compound represented by the general formula (4) is reacted with hydrazine or a hydrazine derivative without a solvent or in an inert solvent. An amine compound is obtained.

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

The ratio of hydrazine or hydrazine derivative used to the compound represented by general formula (4) is at least an equimolar amount, preferably 1 to 2 times the molar amount (1, and the reaction is usually carried out at 0 to 100°C, preferably The reaction is carried out at 0 to 80°C, and the reaction Ct is completed in about 1 to 40 hours.

In addition, in the compound represented by the general formula (3) obtained by the above reaction, when the group R3 is an ester residue, the product is subjected to a deesterification reaction substantially similar to the deesterification reaction of Reaction Scheme-58 described below. Deesterification can be carried out by a method to lead to a compound in which the group R3 is a hydrogen atom.

(Left below) Reaction scheme-3 R4 (In the formula, R4, R5, R6 and Z are the same as above.) In reaction scheme-3, the compound represented by general formula (5) is combined with its substituents. Depending on the type of R6, a primary amine compound represented by the general formula (6) is produced by subjecting it to a reduction reaction, a hydrolysis reaction, or a hydrazine decomposition reaction, and then the primary amine compound represented by the general formula This is a method for producing a compound represented by general formula (3) by reacting a carbonyl compound represented by q).

In the reduction reaction, hydrolysis reaction and hydrazine decomposition reaction when producing the compound represented by general formula (6),
For each reaction method and reaction conditions, those described in Reaction Scheme-2 above can be applied.

Moreover, the reaction for obtaining the compound represented by general formula (3) can be carried out without a solvent or in the presence of an inert solvent. The inert solvent used in this reaction is not particularly limited, but
For example, the inert solvent shown in Reaction Scheme-1 can be exemplified.

The ratio of the compound represented by the general formula σ) to the compound represented by the general formula (6) may be at least 0.5 times the molar amount, preferably 0.8 to 1.2 times the molar amount.

The reaction temperature is preferably 0 to 50°C, preferably 15 to 25°C.

(Leaving space below) Reaction scheme-4 0OR3 xy group, R8 is an azide group, an amino group, a phthalimide group, a phenylacetamide group or a group: [wherein, R3, X and Y are the same as above, R7 is a halogen atom, A lower alkanesulfonyloxy group which may be substituted with a halogen atom, a lower alkyl group, an arylsulfonyloxy group which may be substituted with a halogen atom or a nitro group (wherein R', R5 and Z are the same as above) R9 represents a heterocyclic moiety which may have a substituent in the above R1. ] There are various methods for introducing a thiomethyl group as a substituent into the cephalosporin skeleton of the compound of the present invention, and one example of the method is shown in Reaction Scheme-4.

That is, the compound of the present invention can be prepared by reacting the compound represented by the general formula [F]) with the thiol compound represented by the general formula (9) in a suitable inert solvent in the presence of a basic compound. A compound having a heterocyclic thiomethyl group represented by the general formula 00) partially including the following is obtained.

In the compound represented by general 2〇, examples of the halogen atom represented by R7 include chlorine, bromine, iodine, fluorine, etc., and examples of the lower alkanesulfonyloxy group which may be substituted with a halogen atom include methane. Examples include sulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, and arylsulfonyloxy groups optionally substituted with a lower alkyl group, halogen atom, or nitro group include benzenesulfonyloxy, toluenesulfonyl oxy, p-chlorobenzenesulfonyloxy,
Examples include p-nitrobenzenesulfonyloxy.

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, a wide variety of solvents used in the above reaction scheme-1 can be used.

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

In this way, a compound having a heterocyclic thiomethyl group represented by the general formula 00) is obtained.

(Left space below) In formula c, R1 is the same as above, R31, R'' and R51 are respectively)j3, R4
and R5 represent an ester residue, and RIO represents an amino group that may have a protecting group. General formula (1-
The carboxylic acid derivative represented by c) has the general formula (1-b)
It can be produced by subjecting the ester compound represented by to a deesterification reaction.

As the protecting group for the amino group in R, common protecting groups such as lower alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, and hexanoyl; monochloroacetyl, monofluoroacetyl, Monobromoacetyl, monoiodoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, 3-chloropropionyl, 2
゜3-dichloropropionyl, 3.3.3-)dichloropropionyl, 4-chlorobutyryl, 5-chloropentanoyl, 6-chlorohexanoyl, 3-fluoropropionyl, 4-fluorobutyryl, etc., where the halogen atom is 1 ~
3-substituted lower alkanoyl group having 2 to 6 carbon atoms; having 1 to 3 phenyl groups such as benzyl, a-phenethyl, β-phenethyl, 3-phenylpropyl, benzhydryl, trityl, and the number of carbon atoms in the alkyl portion is 1 to 6 phenyl (lower) alkyl groups; phenylmethoxycarbonyl, 1-phenylethoxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl,
Phenyl (lower) alkoxycarbonyl groups having 1 to 6 carbon atoms in the alkoxy moiety such as 4-phenylbutoxycarbonyl, 5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, The number of carbon atoms in the alkoxy moiety is 1 to 6, such as isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.
Examples include lower alkoxycarbonyl groups.

The above deesterification reaction is carried out without a solvent or in a suitable inert solvent in the presence of a hydrolysis catalyst. Examples of the inert solvent used include those exemplified in Reaction Scheme-1 above.

Acidic compounds used include anhydrous aluminum chloride, stannic chloride, titanium tetrachloride, boron trichloride, boron trifluoride-ethyl ether complex, Lewis acids such as zinc chloride, and inorganic acids such as hydrochloric acid, nitric acid, and sulfuric acid. , organic acids such as trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, and acetic acid, acids such as acid type ion exchange resins, and basic compounds include trialkylamines such as triethylamine and tributylamine, pyridine, picoline, Organic bases such as 1°5-diazabicyclo[4,3,0] nonene-5,1,4-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,0]undecene-7, Bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and inorganic bases such as alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate are I can give an example.

In the above deesterification reaction, R31, R41 or R51
However, in the case of an ester residue such as a benzyl group that is easily eliminated by a catalytic reduction method, the reaction can also be carried out by a catalytic reduction method. Examples of catalysts used in the catalytic reduction method include platinum catalysts (e.g., platinum oxide, platinum black, platinum wire, platinum plate, sponge platinum, colloidal platinum, etc.), palladium catalysts (e.g., palladium black, palladium chloride, Palladium oxide, palladium-carbon, palladium-barium sulfate, palladium-barium carbonate, spongy palladium, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.) cobalt catalysts (e.g. reduced cobalt, Raney nickel, kurt, etc.) ), iron catalysts (eg, reduced iron, Raney iron, etc.), copper catalysts (eg, reduced iron, Raney iron, etc.), and the like.

When an acid or base is used in the above reaction, the molar ratio of the acid or base to the compound represented by general formula (1-b) is 1 to 100 times, preferably 1 to 20 times the molar amount.
It is better to double the molar amount. Moreover, the reaction is carried out at -20°C to 8°C.
3 at a temperature of 0°C, preferably -10°C to 50°C.
It may be carried out for about 0 minutes to 48 hours, preferably about 1 to 24 hours.

In addition, when applying the catalytic reduction method, the general formula (1-b
) The ratio of the catalytic reduction catalyst to be used is 0.1 to 10 times the molar amount, preferably 0.1 to 1 times the molar amount. The reaction may be carried out at a temperature of 0 to 200°C, preferably 0 to 100°C, for about 30 minutes to 48 hours, preferably about 30 minutes to 6 hours.

(The following is a blank space) [In the formula, R1, R3, RA, R5, X, Y and Z are the same as above, and R's represents a protecting group for an amino group having a protecting group as shown in R1° above. ] The general formula (1-
The compound of the present invention represented by e) is a compound of the present invention represented by the general formula (1-d) in which the 5-position of the thiadiazolyl group is a substituted amino compound, by the deesterification reaction of the above reaction formula-5a. For example, by reacting with an acidic or basic compound in the absence of a solvent or in the presence of a suitable solvent, or by performing a catalytic reduction reaction. It can be obtained by adding

The solvent used in the reaction is not particularly limited,
Examples include the solvents exemplified in Reaction Scheme-1.

Examples of the above-mentioned acidic compounds include the acidic compounds exemplified in the reaction scheme-5a above. Preferred examples of the acidic compounds include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid, and trifluoroacetic acid. , organic acids such as acetic acid and formic acid, and acid type ion exchange resins (examples include).Among these acidic compounds, liquid ones can also be used as solvents.

In addition, basic compounds include trialkylamines such as triethylamine and tributylamine, pyridine, picoline, and 1,5-diazabicyclo[4,3,0]nonene-
5,1,4-diazabicyclo[2,2,23 octane,
1.8-Diazabishifo [5,4,Q]Launsen-
Organic bases such as 7, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and inorganic bases such as alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Examples include bases, thiourea, urea compounds such as urea, and the like.

When adding water to the reaction system, the water is preferably about 10 to 80% v/v based on the acidic compound or basic compound,
Furthermore, after the completion of the reaction, it is preferable to add 10 to 20 times the amount.

The ratio of the acidic compound or basic compound used to the compound of the present invention represented by the general formula (1-d) is equivalent to -10
The amount is preferably 0 times the molar amount, preferably 2 to 10 times the molar amount. Further, the reaction temperature is preferably -20°C to 80°C, preferably -10°C to 50°C. The reaction time is approximately 1 to 24 hours.

When the reaction of reaction scheme-5b is carried out by catalytic reduction reaction,
Conditions for catalytic reduction reaction (e.g. catalytic reduction catalyst, amount of catalyst,
(solvent, reaction temperature, reaction time, etc.) are according to the above reaction scheme -
The catalytic reduction reaction conditions of 5a can be used.

In this way, the general formula (1-c
) is obtained.

(Left below) Reaction scheme - Deesterification of the 5c position and deprotection reaction to remove the protecting group of the amino group represented by R'' are simultaneously carried out to form the general formula (1-
This is a reaction to obtain the compound represented by g), and can be carried out under substantially the same conditions as in Reaction Scheme-58 or 5b,
At this time, it is preferable to use acids as the hydrolysis catalyst, and more preferable examples include Lewis acids such as anhydrous aluminum chloride, zinc chloride, iron chloride, tin chloride, and boron trifluoride, and organic acids such as trifluoroacetic acid.

(The following is a margin) [In the formula, R1, R4, R5, R11, R31, R''R5
1, XSY and Z are the same as above. ] This reaction is
4 Reaction Scheme-6 of Compound Represented by General Formula (1-f)
a [wherein R1, R3, R4, R5, X, Y and 2 are the same as above, A is a halogen atom, and R'2 represents a lower alkyl group or a carboxy lower alkyl group. This reaction scheme-6a is carried out without a solvent or in an inert solvent,
A compound represented by general formula (1-h) is reacted with a compound represented by general formula (11) to obtain a compound represented by general formula (1-j). In the compound represented by general formula (11), the halogen atom represented by A is:
Examples include chlorine, iodine, bromine, and fluorine.

In the reaction, it is preferable to react the compound represented by general formula (1-h) with a silylating agent in advance to protect the carboxy group possessed by the compound represented by general formula (1-h). As such a silylating agent, various lower alkyl silylating agents can be used, but it is particularly preferable to use N,0-bistrimethylsilylacetamide (BSA). As the solvent, any solvent can be used as long as it does not adversely affect this reaction, and examples thereof include those used in Reaction Scheme-1 above.

The silylating agent is used in an amount of 1 to 10 moles, preferably 2 to 3 times the mole of the compound represented by general formula (1-h). The reaction temperature is 0 to 60°C, preferably 15 to 20°C.
The reaction is usually completed in 5 to 20 hours.

The reaction purified product is treated with an anion exchange resin or the like to obtain the compound of the present invention represented by the general formula (1-j).

(Left below) In formula c, R3, R', R5, R'2, X and Y are the same as above. ] In the same manner as the reaction scheme-68, general formula (1-h)
The compound represented by is reacted with the compound represented by general formula (11) to obtain the compound represented by general formula (1-1), which is deesterified using an acidic compound such as trifluoroacetic acid. A compound represented by the general formula (l-j) is obtained by a chemical reaction.

The compound represented by the general formula (1) of the present invention naturally includes optical isomers, syn isomers, and anti isomers. These isomers can be determined using conventional resolution methods, e.g.
Separation can be performed by methods using optical resolution agents, enzymes, etc.

The compound of the present invention is usually used in the form of a pharmaceutical preparation. The formulation is prepared using commonly used diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, gunpowder, powders, liquids, suspensions, emulsions,
Granules, capsules, fully opened, injections (solutions, suspensions, etc.)
7 etc. When forming into a tablet, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, Disintegrants such as laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil; Absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, purified talc, stearate, and boric acid powder. ,
Examples include lubricants such as polyethylene glycol. In addition, tablets may be coated with a normal coating if necessary.
For example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets can be used. When forming an emulsion, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, gum arabic powder, etc. , tragacanth powder, gelatin, binders such as ethanol, laminaran,
Examples include disintegrants such as agar. When molding into a fully expanded form, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and when formed into the form of solutions, emulsions and suspensions, dilution is required. All agents commonly used in this field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose or glycerin to prepare an iso-strength solution may be included in the pharmaceutical preparation, and conventional solubilizing agents, buffers, soothing agents, etc. may also be added. If necessary, the therapeutic agent may contain colorants, preservatives, fragrances, flavors, sweeteners, and other pharmaceutical agents. When forming pastes, creams and gels, diluents such as white petrolatum, paraffin, glycerin, cellulose etc.
-sugar derivatives, polyethylene glycol, silicon, bentonite, etc. can be used.

The amount of the compound represented by the general formula or its salt to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be selected from a wide range, but it is usually 1 to 70% by weight of the total composition. good.

There are no particular restrictions on the method of administering the pharmaceutical preparation of the present invention, and the method can be administered in accordance with various preparation forms, age, sex and other conditions of the patient, degree of disease, and the like. For example, tablets, emulsions, solutions, suspensions, emulsions, granules, and capsules are administered orally.

In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acids, and furthermore, if necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. When fully dilated, one dose is administered rectally.

The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc.
Usually, the amount of the compound of the present invention is 1 to 1 per kg of body weight per day.
005 g, preferably 5 to 20 g, and the preparation can be administered in divided doses 2 to 4 times a day.

(Margin below) <Example> The present invention will be described in more detail below based on reference examples, examples, formulation examples, and pharmacological tests.

Reference Example 1 3.5 g of 2-phthalimidoxymethyl-1,5-dibenzhydryloxy-4-pyridone was dissolved in 351 g of ethanol.
! 0.27xl of hydrazine hydrate was added thereto, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, insoluble matter was filtered off, and the filtrate was concentrated to dryness. Then, the residue was dissolved in chloroform 501! After the insoluble matter was filtered off, the filtrate was concentrated to dryness.

Then, the residue is methanol 501! Dissolved in 2-(5
-amino-1,2,4-thiadiazol-3-yl)-
0.95 g of 2-oxoacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After distilling off the solvent, ether was added to the residue and the resulting white powder was collected by filtration to obtain 3.31 g of the labeled compound.

mp: 145-147℃ NMR (DMSO-d6) 4.88 (2H, s), 6° 6.31 (IH, s), 6° 7.34 (20H, bs), 8.12 (2H, bs ) Reference Example 2 δ (ppm): 01 (IH,s), 35 (IH,s), 7, 53 (IH,s) Boxylate benzhydryl (6S,7S)-7-phthalimide-3
-(5-benzhydryloxycarbonylmethyl-4-
1.18 g of methylthiazol-2-ylthiomethyl)isocephem-4-carboxylate was dissolved in 21 g of dimethylformamide.

Then, it was cooled to -10°C, and a 2M solution of methylhydrazine in tetrahydrofuran was added to 13F! was dripped. After the dropwise addition was completed, the reaction solution was stirred for 40 minutes while being kept at -10°C.

Add 20 yil of ethyl acetate and 201k of water to the above reaction solution.
was added, shaken, and separated. Then, the ethyl acetate was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off, and the benzhydryl (6S, 7S)-7-
Amino-3-(5-benzhydryloxycarbonylmethyl-4-methylthiazol-2-ylthiomethyl)isocephem-4-carboxylate was obtained. Add this to 20ν of dimethylformamide! (Z) under water cooling.
-2(5-amino-1,2,4-thiadiazole-3-
yl)-2-(1,5-dibenzhydryloxy-4-
Pyridon-2-ylmethoxyimino)acetic acid 0.9 g, 1
0.18 g of -hydroxybenzotriazole was added, and further 0.28 g of dicyclohexylcarbodiimide was added, and the mixture was reacted at room temperature for 15 hours. Then, insoluble matters were removed by filtration, and the filtrate was mixed with 200 yl of ethyl acetate and 200 y of water.
Extracted using l. Next, the ethyl acetate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified using silica gel chromatography (elution solvent: chloroform:methanol-m20:1) to obtain 0.9 g of the title compound as a pale yellow powder.

mp: 117-120°C NMR (DMSO-d6) δ (ppm): 2.1 g (
3H,s), 2.66-3.18(2H,m), 3
．． 79~4.11 (IH, m), 4゜01 (2H
,s) ,4.36 (2H,q) ,4゜86 (2
H, s), 5.70 (IH, dd), 6°08
(IH, s), 6.32 (IH, s), 6°35
(IH, s), 6.81 (IH, s), 6°8
4 (IH,s), 6.95-7.70 (41H.

m), 8.16 (2H, bs), 9.37
(IH.

d) Reference Example 3 Benzhydryl(6R,7R)-7-[(Z) Benzhydryl(6R,7R)-7-amino-3-(5-benzhydryloxycarbonylmethyl-4-methylthiazol-2-ylthiomethyl) The slightly yellow title compound was obtained in the same manner as in Reference Example 2, except that -3-cephem-4-carboxylate was used as the starting material.

mp: 112-115°C NMR (CDCl2) δ (ppm): 2.19 (3H, s), 3.61 (2H, q),
3.69 (2H, s) 1.4.22 (2H, q)
, 4.7-5.1 (3H, m), 5.79 (IH
.

dd), 5.82 (2H, bs), 5.95 (
1H,s), 6. 07 (IH,s), 6
．． 48 (IHs), 6. 66 (IH,s
), 6. 88 (IH,s), 7. 24
(40H, s), 7. 51 (I H, s) Reference example 4 NMR (DMSO-d6) δ (ppm): 2
．． 71~3.16 (2H, m), 3.71~4゜15 (IH, m), 4.32 (2H, Q)
, 4°88 (2H,s) , 5.64 (2
H, s), 5°71 (IH, dd), 6.1
1 (IH, s), 6°3-4 (IH, s)
, 6.37 (IH,s) , 6゜83 (IH
, s) , 6.88 (IH, s) , 6°91~
7.68 (41H, m), 8.15 (2H.

bs), 9. 35 (IH, d) Reference Example 5 Boxylate benzhydryl (6S, 7S)-7-phthalimide-3
-(1-benzhydryloxycarbonylmethyl-IH
The title compound as a slightly yellow powder was obtained in the same manner as in Reference Example 2, except that -tetrazol-5-ylthiomethyl)-isocephem-4-carboxylate was used as the starting material.

mp: 11g to 120°C paramethoxybenzyl (6R,7R)-7-amino-3
-(1-dibenzhydryloxycarbonylmethyl-I
The title compound as a slightly yellow powder was obtained in the same manner as in Reference Example 2, except that H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate was used as the starting material.

mp: 121-125°C NMR (DMSO-d6) δ (ppm): 3.37 (
2H, q), 3.75 (3H, s), 4.32 (
2H, q), 4.84 (2H, s), 5.01 (
IH, d), 5.19 (2H, s), 5.65 (
2H, s), 5.78 (IH, dd), 6.30
(IH,s), 6.41 (IH,s), 6.43
(IH,s), 6.88 (IH,s), 6.89
(2H, d), 7.34 (32H, s), 7.88
(IH,s), 8.14 (2H,bs), 9.6
7 (2H,d) Reference Example 6 -acetamide]-3-(4-carboxy-3benzhydryl(65,7S)-7-phthalimide-3-(
4-carboxy-3-hydroxyisothiazole-5-
ylthiomethyl) incephem-4-carboxylate)
1.18g of dimethylformamide 2'I! dissolved in. Then, it was cooled to -10°C and a 2M methylhydrazine solution in tetrahydrofuran was added. was dripped. After the dropwise addition was completed, the reaction solution was stirred for 40 minutes while being kept at -10°C.

Water 501! Add the above reaction solution to the solution, collect the resulting powder by filtration,
After drying, benzhydryl (6S,7S)-7-amino-3-(4-carboxy-3-hydroxyisothiazol-5-ylthiomethyl)isocephem-4-carboxylate was obtained.

Add the above powder to 21% dimethylformamide! Dissolved in N,
O-bistrimethylsilylacetamide 0°851! was added and stirred for 30 minutes while maintaining the temperature at room temperature, and this solution was designated as solution A.

Also, (Z)-,,2-(5-amino-1,2,4-thiadiazol-3-y/I/)-2-(1,5dibenzhydryloxy-4-pyridon-2-yl 1.13 g of methoxyimino)acetic acid was dissolved in 51 g of dimethylformamide, and 1.13 g of 1-hydroxybenzotriazole was dissolved under water cooling.
23 g of dicyclohexylluposiimide and 0.36 g of dicyclohexylluposiimide were added in this order, and the mixture was stirred at room temperature for 1 hour. Then, insoluble matters were removed by filtration, and the above solution A was added to the filtrate, followed by reaction at room temperature for 15 hours.

The above reaction solution was added to 100 liters of water, the resulting powder was collected by filtration, and subjected to silica gel column chromatography (elution solvent: chloroform: methanol: water - 100: 10).
: Purified using 1) to give 0.91 of the slightly yellow title compound.
I got g.

mp: 108°C NMR (DMSO-d6) δ (ppm): 2.60-3
．． 21 (2H, m), 3.72-4.01 (IH, m), 4.31 (2
H,Q), 4.84 (2I(,s), 5.69
(1H, dd), 6. 01 (11(,s)
,6. 36 (IH, s), 6. 41 (I
H,s), 6. 80(11(,s), 6.
89-7. 68 (31H, m)8, 14
(2H, bs), 9. 31 (IH, d) Reference Example 7 Monoparamethoxybenzyl (6R,7R)-7-amino-3
-(4-carboxy-3-hydroxyisothiazole-
The slightly yellow title compound was obtained in the same manner as in Reference Example 6, except that 5-ylthiomethyl)-3-cephem-4-carboxylate was used as the starting material.

mp: 111°C (discoloration) NMR (DMSO-d6) δ (ppm): 3
, 41 (2H,Q) ,3. 81 (3H
,s) ,4, 29 (2H,Q) ,4.
85 (2H, s) , 5, 05 (IH, d
), 5. 16 (2H,s), 5, 7
1 (IH, dd), 6. 29 (IH,s
), 6, 38 (IH,s), 6. 4
3 (IH, m), 6, 91 (2H, d)
,7. 15-7. 68 (23H, m)
, 8. 13 (2H, bs), 9.
66 (IH, d) Example 1 Rubonic acid Benzhydryl (6S, 7S)-7-[ obtained in Reference Example 2
(Z) -2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxyimino)acetamide] - 0.87 g of 3-(5-benzhydryloxycarbonylmethyl-4-methylthiazol-2-ylthiomethyl) incephem-4-carboxylate, 0.5 yl of anisole and 4.511 l of trifluoroacetic acid
was added and stirred at room temperature for 2 hours.

Next, 50 ν! of diethyl ether was added to this reaction solution. was added, and the resulting powdery solid was collected by filtration and suspended in water 201. Then, a dropwise equivalent amount of a 7% aqueous sodium bicarbonate solution was added to adjust the pH to 3, and the powdery solid in the liquid was filtered and washed with water to obtain 0.2 g of the title compound as a pale yellow powder.

mp: 116°C (discoloration) NMR (DMSO-d6) δ (ppm): 2.22 (
3H,s), 2.9-3.3 (2H.

m), 3.73 (2H, s), 3.85-4.1
0 (IH, m), 4.35 (2H, Q), 5.2
3 (2H, s), 5.60 (IH, dd), 6.
69 (IH, s), 7.72 (IH, s), 8,
14 (2H, bs), 9. 38 (I
H, d) Example 2 NMR (DMSO-66) δ (ppm): 2
, 22 (3H,s) , 3. 2-5. 9
(6H.

m), 3. 72 (2H,s), 5.
22 (2H.

s), 6. 72 (IH,s), 7.
74 (IH.

s), 8. 11 (2H, bs), 9.
61 (IH.

d) Example 3 Rubonic acid Benzhydryl (6R,7R)-7-[ obtained in Reference Example 3
(Z) -2-(5-amino-1,2,4=thiadiazol-3-yl)-2-(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxyimino)acetamide]2 Using 3-(5-benzhydryloxycarbonylmethyl-4-methylthiazol-2-ylthiomethyl)-3-cephem-4-carboxylate,
In the same manner as in Example 1, the title compound as a slightly red powder was obtained.

mp: 101°C (discoloration) Benzhydryl (6S, 7S)-7-[
(Z)-2-(5-amino-1,2,4thiadiazol-3-yl)-2-(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxyimino)acetamide] -3 Example 1 Using -(1-benzhydryloxycarbonylmethyl-IH-tetrazol-5-ylthiomethyl)-isocephem-4-carboxylate
The title compound as a slightly yellow powder was obtained in the same manner as above.

mp: 108°C (discoloration) NMR (DMSO-d6) δ (ppm): 3.01-3
．． 21 (2H, m), 3.80~4°12 (IH
,m) ,4.38 (2H,s) ,5゜21 (2
H,s), 5.22 (2H,s), 5゜66 (
IH, dd), 6.71 (IH, s), 7°75
(IH,s) ,8.12 (2I(,bs) ,9
゜40 (IH, d) Example 4 7R) -7-[(Z)-2-(5-amino-1゜2.
4-thiadiazol-3-yl)-2-(1゜5-dibenzhydryloxy-4-pyridon-2-ylmethoxyimino)acetamide] -3-(1-benzhydryloxycarbonylmethyl-IH-tetrazole) The slightly yellow title compound was obtained in the same manner as in Example 1 using -5-ylthiomethyl)-3-cephem-4-carboxylate.

mp: 118°C (discoloration) NMR (DMSO-d6) δ (ppm): 3.48 (
2H, ABq), 4.31 (2H, bs), 5.
09 (IH, d), 5.22 (2H.

s), 5.23 (2H,s), 5.78 (IH
.

dd), 6.80 (IH,s), 7.80 (I
H.

s), 8.12 (2H, bs), 9.63 (I
H.

d) Example 5 Para-methoxybenzyl (6R1-2-(
1,5-Dihydroxy-4-pyridon-2-ylmethoxyimino)acetamitoco-3 - Example 6 Rubonic acid Benzhydryl (6S, 7S) obtained in Reference Example 6 -7-[
(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxyimino)acetamide] - 3-(4-carboxy-3-hydroxyisothiazol-5-ylthiomethyl)isocephem-4-
The title compound as a slightly yellow powder was obtained in the same manner as in Example 1 using carboxylate.

mp: 112°C (discoloration) NMR (DMSO-d6) δ (ppm): 3.05-3
．． 31 (2H, m), 3.35~3゜52 (IH
,m) ,4.39 (2H,s) ,5゜20 (2
H, s), 5.59 (IH, dd), 6°69
(IH, s), 7.72 <IH, s), 8°14
(2H, bs), 9.41 (1B, d) Carboxylic acid Paramethoxybenzyl (6R17R) obtained in Reference Example 7
77 [(Z)-2-(5-amino-1°2.4-thiadiazol-3-yl)-2-(1°5-dibenzhydryloxy-4-pyridon-2-ylmethoxyimino)
The title compound as a slightly yellow powder was obtained in the same manner as in Example 1 using acetamitoco-3-(4-carboxy-3-hydroxyisothiazol-5-ylthiomethyl)-3-cephem-4-carboxylate.

mp: 111'c (discoloration) NMR (DMSO-d6) δ (ppm): 3.41 (
2H, ABq) , 4.29 (2H, bs) , 5
．． 12 (IH, d), 5. 21 (2H
.

s), 5. 72 (IH, dd), 6.
82 (IH.

s), 7. 83 (IH,s), 8. 1
4 (2H.

bs), 9. 66 (IH, d) Example 7 Monotobenzhydryl (65,7S)-7-phthalimide-3
-(pyrid-4-ylthiomethyl)isocephem-4-
Benzhydryl (5S, 7S)-7-[(Z)-2-(5
-amino-1,2,4-thiadiazol-3-yl)-
2-(1,5-dibenzhydryloxy-4-pyridon-2-ylmethoxyimino)acetamide] -3-(
Pyrid-4-ylthiomethyl)isocephem-4-carboxylate was obtained.

1.08g of this compound was mixed with 201! of methylene chloride! tert-butyl bromoacetate (0.39 g) was added thereto, and the mixture was stirred at room temperature for 24 hours. Next, ether 5 was added to this reaction solution.
0 was added to obtain a brown powdery solid. After filtering this powdery solid and washing with ether, anisole 11
1 and trifluoroacetic acid 51 were added, and the mixture was stirred at room temperature for 2 hours. Next, 50 ν! of ether was added to this reaction solution. was added to obtain a powdery solid. This powdery solid was collected by filtration and washed with ether. Then, this was dissolved in a 5% aqueous sodium hydrogen carbonate solution, and a nonionic adsorption resin (HP-
20) 10C1f was added, pn was adjusted to 2 with 10% HCg aqueous solution, and adsorption was carried out. The above nonionic adsorption resin was packed in a column, water 5001 was passed through it, and then eluted with a 5-20% aqueous isopropyl alcohol solution. The desired fraction was concentrated, and the concentrate was freeze-dried to obtain 0.26 g of the title compound as a pale yellow powder.

mp: 128°C (discoloration) NMR (DMSO-66) δ (ppm): 2
, 89-3. 35 (2H, m) 1.3.7
2~4゜01 (11(,m), 4.46
(2H,s), 4°79 (2H,s),
5. 16 (2H,s), 5゜41 (I
H, dd, J=3Hz, J-9Hz), 6
, 83 (IH,s), 7. 68 (I
H,s), 7, 88 (2H,d, J-6
Hz), 8. 11 (2H, bs), 8. 5
1 (2H, d, J=6H2), 9. 4
6 (11(,d, J=9Hz)Example 8 Tobaramethoxybenzyl(6R,7R)-7-amino-3
-(pyrid-4-ylthiomethyl)-3-cephem-4
- Using carboxylate, in the same manner as in Reference Example 5,
paramethoxybenzyl (6R,7R)-7-[(Z)-
2-(5-amino-1,2,4-thiadiazole-3-
yl)-2-(1,5-dibenzhydryloxy-4-
Pyridon-2-ylmethoxyimino)acetamitoco3
-(pyrid-4-ylthiomethyl)-3-cephem-4
-carboxylate was obtained.

This was reacted with tert-butyl bromoacetate in the same manner as in Example 7, treated with trifluoroacetic acid, and then purified to give the title compound as a slightly yellow powder.

mp: 131°C (discoloration) NMR (DMSO-d6) δ (ppm): 3.05
(2H, ABq), 4.62 (2H, bs), 4.
86 (2H, s), 5.04 (IH.

d) , 5.18 (2H,s) , 5.55 (IH
.

dd), 6.78 (IH,s), 7.78 (I
H.

s), 8.01 (2H, d), 8.12 (2H
.

bs), 8.52 (2H,d), 9.43 (I
H.

d) Formulation examples are shown below.

Formulation Example 1 (6S, 7S)-7-[(Z) 2-(5-amino-1,2,4-thiadiazol-3-yl) 2-(1,5-dihydroxy-4-pyridon-2-yl Methoxyimino)acetamitoco3-(5-carboxymethyl-4-methylthiazol-2-ylthiomethyl)-isocephem-4-carboxylic acid 200 ■ Glucose 250 ■ Distilled water for injection Appropriate amount Total amount
51!
(6S,7S)-7-[(Z)-2-(5-amino-1
,2,4-thiadiazol-3-yl)-2-(1,5
-dihydroxy-4-pyridon-2-ylmethoxyimino)acetamitoco-3-(5-carboxymethyl-4
After dissolving the -methylthiazol-2-ylthiomethyl)-isocephem-4-carboxylic acid (Example 1) and glucose, 51! Inject into an ampoule and after replacing with nitrogen, 1
The mixture was autoclaved at 21° C. for 15 minutes to obtain an injection having the above composition.

Formulation Example 2 (6R,7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)2-(1,5-dihydroxy-4-pyridone-2- ylmethoxyimino)acetamide] 3-(5-carboxymethyl-4-methylthiazole-2=ylthiomethyl)-3-cephem-4-carboxylic acid 100 g Avicel (trade name, manufactured by Asahi Kasei ■) 40 g Cornstarch
80g magnesium stearate 2gTC-5 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropyl methyl cellulose) 1
0g polyethylene glycol-1i000 3
g Castor oil 40g
Ethanol 40g total amount 255g (6R, 7R
)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1,5-dihydroxy-4-pyridon-2-ylmethoxyimino)acetamide]- After mixing and polishing 3-(5-carboxymethyl-4-methylthiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (Example 2), Avicel, cornstarch, and magnesium stearate, sugar coating R1 (
Compress the tablets with Jam's kine. The obtained tablets were coated with a film coating agent consisting of TC-5, polyethylene glycol-8000° castor oil, and ethanol to produce film-coated tablets having the above composition.

Formulation Example 3 (6S, 7S)-7-[(Z) 2-(5-amino-1,2,4-thiadiazol-3-yl) 2-(1,5-dihydroxy-4-h:lydon-2 -ylmethoxyimino)acetamide] 3-(1-carboxymethyl-IH-tetrazol-5-ylthiomethyl)-isocephem-4-carboxylic acid 2g purified lanolin 5g salami wax 5g white petrolatum
881r total amount
100g of Sarashimiro was heated to make it liquid, and then (6S, 75)-7-[(Z)-2-(5
-amino-1,2,4-thiadiazol-3-yl)2
-(1,5-dihydroxy-4-pyridon-2-ylmethoxyimino)acetamide]-3-(1-carboxymethyl-IH-tetrazol-5-ylthiomethyl)-
Isosephem-4-carboxylic acid (Example 3), purified lanolin, and white petrolatum were added, heated until it became liquid, and then stirred until it began to solidify, to obtain an ointment with the above composition.

[Antibacterial test] In order to investigate the antibacterial effects of the compounds obtained in Examples 1 to 8 and the comparative example ceftazidime (CAZ, a cephem antibiotic) against various bacteria, the minimum inhibitory concentration ( MIC) was calculated.

[CHEMOTHERAPY, 22.1126-112
8 (1974)] The results obtained are shown in Table 2.

In addition, various bacteria are 1 x 106 bacteria count #7 (0, D.

600rntt, 0.07-0.16).

(Margin below)

Claims (1)

[Claims] 1. General formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, one of X and Y represents a methylene group, and the other represents a sulfur atom. Z is a lower alkylene group R^1 represents a heterocyclic thiomethyl group having 1 to 4 heteroatoms selected from the group consisting of nitrogen atoms and sulfur atoms, and the heterocyclic portion of the heterocyclic thiomethyl group is a lower alkyl group, a carboxy lower A cephalosporin derivative or a pharmaceutically acceptable salt thereof, which may have an alkyl group, a carboxy group, or a hydroxy group (R^2 represents a carboxy group or a carboxylate group).