JPS6236387A - 3,7-disubstituted-3-cephem compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> is (protected) amino; R<2> is (protected) carboxy; R<3> is H or hydroxy-protecting group] and its salt. EXAMPLE:7-[( 2-Amonothiazol-4-yl )-2-hydroxyiminoacetamido]-3-(1,2,4-thidiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer). USE:A preventive and remedy for microbism. PREPARATION:A compound shown by the formula II or a reactive derivative at the amino group or its salt is reacted with a compound shown by the formula III or its reactive derivative at the carboxyl group or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] This invention relates to novel 3,7-disubstituted-3-cephem compounds and salts thereof.

More specifically, this invention discloses novel 3
．． 7-disubstituted-3-cephem compounds and their salts, their production methods, and prevention of bacterial infections using them as active ingredients
Regarding therapeutic agents.

[Object of the Invention] That is, one object of the present invention is to provide a novel 3,7-disubstituted-3-cephem compound and its salts that have strong antibacterial activity against many pathogenic bacteria.

Another object of this invention is the novel 3,7-disubstituted-3
- To provide a method for producing cephem compounds and salts thereof.

Yet another object of the present invention is to provide a prophylactic/therapeutic agent for bacterial infections containing the 3,7-disubstituted-3-cephem compound and its salts as active ingredients.

[Prior Art] As prior art to this invention, for example, the following compounds are known.

(Patent Application Publication No. 11713 of 1985) [Problems to be Solved by the Invention] However, the antibacterial spectrum of such known compounds is limited, and the antibacterial activity against Durham-positive bacteria is not particularly strong.

Under such circumstances, there is a strong desire for an antibacterial agent that has a broad antibacterial spectrum and has particularly strong antibacterial activity against Durham-positive bacteria.

As a result of intensive research, the inventors of this invention succeeded in obtaining an excellent antibacterial agent.

[Means for Solving the Problems] The novel 3,7-disubstituted-3-cephem compound of the present invention can be represented by the following general formula (1).

[In the formula, R1 means an amino or protected amine group, R2 means a carboxy or protected carboxy group, and R3 means hydrogen or a hydroxy protecting group, respectively].

In this specification, the compound (1) having the stereogenic structure represented by the formula: (wherein R3 has the same meaning as before) is referred to as a syn isomer, and the term "syn isomer" refers to a compound having the above stereospecific structure. shall mean.

Suitable salts of the target compound (I>) are customary non-toxic and pharmaceutically acceptable salts, such as salts with inorganic bases, such as alkali metal salts such as sodium salts, potassium salts, cesium salts, e.g. Alkaline earth metal salts such as lesium salts and magnesium salts, ammonium salts; salts with organic bases, such as triethylamine salts,
Pyridine salt, bifrin salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,
Organic amine salts such as N'-dibenzylethylenediamine salt; inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate; for example, formate, acetate, trifluoroacetate, maleic acid; Organic carboxylic acid addition salts or organic sulfonic acid addition salts such as salt, tartrate, methanesulfonate, benzenesulfone acetate, p-toluenesulfonate;
Examples include salts with bases or acid addition salts such as salts with basic or acidic amino acids such as arginine, aspartic acid, and glutamic acid.

The object compound (I) of this invention or its salts can be produced by various methods shown in the following reaction formula.

Production method 1 (III) or a reactive derivative thereof in an amine group or a salt thereof CI) or a salt thereof Production method 2 (Ia) or a salt thereof (Ib) or a salt thereof Group 1 or a salt thereof (I) or a salt thereof Production method 4 (Ib) or its salt or its salt manufacturing method 5 (Id) or its salt (IC) or its salt manufacturing method 6 (If') or its salt (Ig) or its salt 1 unit (Vl) or its salt or its salt [In the formula, R1, R2 and R3 each have the same meaning as before, R1 is a protected amino group, R2 is a protected carboxy group, Rb is an esterified carboxy group, R3 is a hydroxy protecting group, X represents an acid residue, and Y represents a group that can be substituted with the formula: ].

Among the raw material compounds of this invention, compound (IV) and its intermediates are novel, and such novel compounds have the following general formula: [wherein R2 and X each have the same meaning as above, and A is methylene or the formula "/C-N~OR (in the formula, R3
means a hydrogen or hydroxy protecting group) or a salt thereof, and
It can be produced by the production method shown in the reaction formula below or by a conventional method.

or a reactive derivative thereof at an amino group or a salt thereof [wherein R2, A and X each have the same meaning as before].

In the foregoing and following description of this specification, preferred examples and explanations of the various definitions falling within the scope of this invention are set forth in detail below.

"Lower", unless otherwise specified, shall mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

"Higher grade means 7 to 20 carbon atoms, unless otherwise specified.
shall mean an individual.

Suitable 1-protected amino'' groups include the conventional 7-amino protecting groups used in penicillin and cephalosporin compounds, such as the following acyl groups, such as mono-(or di- or an a(lower)alkyl group such as tri)-phenyl(lower)alkyl, e.g. 1-methoxycarbonyl-1-
Examples include amine groups substituted with lower alkoxycarbonyl (lower) alkylidene such as propen-2-yl or its enamine type tautomer, for example di(lower) alkylamino methylene such as dimethylamino methylene.

Suitable "acyl groups" include aliphatic acyl groups, aromatic acyl groups, heterocyclic acyl groups, and aliphatic acyl groups substituted with aromatic or heterocyclic groups.

Examples of aliphatic acyl groups include formyl, acedel,
Lower alkanoyl groups such as propionyl, butyryl, imbutyryl, valeryl, invaleryl, pivaloyl, hexanoyl, lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary Lower alkoxycarbonyl groups such as butoxycarbonyl, lower alkenoyl groups such as acryloyl, methacryloyl, crotonoyl, etc. (03-C
7) Saturated or unsaturated, acyclic or cycloaliphatic acyl groups such as cycloalkanecarbonyl groups, amidino groups, etc. are included.

Examples of the aromatic acyl group include aroyl groups such as benzoyl, toluoyl, and xyloyl, and allenesulfonyl groups such as benzenesulfonyl and tosyl.

Examples of the heterocyclic acyl group include furoyl, thenoyl,
Nicotinoyl, innicotinoyl, thiazolylcarbonyl, thiadiazolyl carbonyl &.

Examples include heterocyclic carbonyl groups such as tetrazolylcarbonyl.

Examples of the aliphatic acyl group substituted with an aromatic group include alkanoyl groups such as phenyl(lower)alkanoyl groups such as phenylacedel, phenylpropionyl, and phenylhexanoyl, such as benzyloxycarbonyl and phenethyloxy. phenyl (lower) such as carbonyl; alkoxycarbonyl (lower);
Alkoxycarbonyl groups, such as phenoxyacetyl,
Examples include phenoxy (lower) alkanoyl groups such as phenoxypropylene.

Examples of the aliphatic acyl group substituted with a heterocyclic group include chenyl acetyl, imidazolylacetyl, furylacetyl,
Examples include tetrazolylacetyl, thiazolyl acetyl, thiadiazolyl acetyl, thenylfuropionyl, thiadiazolylpropionyl and the like.

These acyl groups may further include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, halogens such as chlorine, bromine, iodine, fluorine, methoxy, ethoxy, propoxy,
One or more suitable substitutions such as lower alkoxy groups such as isopropoxy, butquine, pentyloxy, hexyloxy, lower alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, nitro groups, etc. Preferred acyl groups having such substituents include mono(or di-halo)-halo(lower) alkanoyl such as chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc. mono(or di- or tri)-halo(lower)alkoxycarbonyl groups such as chloromethoxycarbonyl, dichloromethoxycarbonyl, 2.2.2-trichloroethoxycarbonyl, etc., such as nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl, methoxy Examples include nitro (or halo or lower alkoxy) phenyl (lower) alkoxycarbonyl groups such as benzyloxycarbonyl.

Suitable 1-protected carboxy groups include esterified carboxy groups commonly used in penyline or cephalosporin compounds.

Examples of "a suitable monoester moiety of an esterified carboxy group" include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary Lower alkyl esters such as pentyl esters and hexyl esters, lower alkenyl esters such as vinyl esters and allyl esters,
(Column, tl; i' Lower alkynyl esters such as ethynyl ester, propynyl ester, etc., e.g. methoxymethyl ester, broboxymethyl ester, lower alkoxy (lower) allyl ester such as 1-methoxyethyl ester, 1-ethoxyethyl ester, etc. Lower alkylthio (lower) alkyl esters such as methylthiomethyl ester, ethylthiomethyl ester, ethylthioether ester, isopropylthiomethyl ester, etc., such as carboxymethyl ester, 2-carboxyethyl ester, 3-
Carboxy-substituted lower allylic esters such as carboxybrobyl ester, lower alkoxycarbonyl-substituted compounds such as tertiary-butoxycarbonylmethyl ester, 2-tertiary butoxycarbonyl ethyl ester, 3-tertiary butoxycarbonylpropyl ester, etc. protected carboxy-substituted (lower) alkyl esters such as 2-iodoethyl esters, 2.2
.

Mono (or di or tri) halo (lower) alkyl esters such as 2-trichloroethyl ester, e.g. acetoxymethyl ester, pro and onyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxy Methyl ester, hexanoyloxymethyl ester, 1 (or 2)-acetoxyethyl ester, 1 (or 2 or 3)-acetoxypropyl ester, 1 (or 2 or 3 or 4)-acetoxybutyl ester, 1 (or 2)-acetoxybutyl ester -propionyloxyethyl ester, 1 (or 2 or 3) -propionyloxypropyl ester, 1 (or 2) -butyryloxyethyl ester, 1 (or 2)
)-isobutyryloxyethyl ester, 1 (or 2
)-pivaloyloxyethyl ester, 1 (or 2)
-Lower alkanoyloxy such as hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymedel ester, 3,3-dimethylbutyryloxymethyl ester, 1 (or 2)-pentanoyloxyethyl ester, etc. (Lower) alkyl esters, such as hebutanoyloxymethyl ester, octanoyloxyethyl ester, nonanoyloxymethylester, decanoyloxymethyl ester, undecanoyloxymethyl ester, lauroyloxymethyl ester, tridecanoyloxymethyl ester, myristoyloxymethyl ester, pentadecanoyloxymethyl ester, toyloxymethyl ester, heptadecanoyloxymethyl ester, stearoyloxymethyl ester, nonadecanoyloxymethyl ester, eicosanoyloxymethyl ester, 1 (or 2)- heptanoyloxyethyl ester, 1 (or 2)-octanoyloxyethyl ester, 1 (or 2)-nonanoyloxyethyl ester, 1 (or 2)-octanoyloxyethyl ester,
)-decanoyloxyethyl ester, 1 (or 2)
-undecanoyloxymethyl ester 1 (or 2) -lauroyloxyethyl ester, 1 (or 2)
)-tridecanoyloxymethyl ester, 1 (or 2)-myristoyloxyethyl ester, 1 (or 2)-pentadecanoyloxyethyl ester, 1 (or 2)-valmitoyloxyethyl ester, 1 (
or 2)-heptadecanoyloxyethyl ester,
1 (or 2)-stearoyloxyethyl ester,
Higher alkanoyloxy (lower) alkyl esters such as 1 (or 2)-nonadecanoyloxyethyl ester (or 2)-eifsanoyloxyethyl ester,
For example, methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, tertiary butoxycarbonyloxymethyl ester, 1(or 2)-methoxycarbonyloxyethyl ester, 1(or 2)-ethoxycarbonyloxyethyl ester, 1(or 2)-ethoxycarbonyloxyethyl ester, 2)-Propoxycarbonyloxyethyl ester, 1 (or 2)-isopropoxycarbonyloxyethyl ester, 1 (or 2)
)-butoxycarbonyloxyethyl ester, 1 (or 2)-isobutoxycarbonyloxyethyl ester, 1 (or 2)-tertiary butoxycarbonyloxyethyl ester, 1 (or 2)-hexyloxycarbonyloxyethyl ester, 1 (or 2 or 3)
-Methoxyloxypropylesterone 1 (
or 2 or 3) -ethoxylponyloxypropyl ester, 1 (or 2 or 3) -isobutoxycarbonyloxyethyl ester, 1 (or 2 or 3) -
or 4)-Ethoxycarbonyloxybutyl ester, 1 (or 2 or 3 or 4)-butoxycarbonyloxybutyl ester, 1 (or 2 or 3 or 4 or 5)-pentyloxycarbonyloxypentyl ester, 1 (or 2 or 3 or 4 or 5)
-neopentyloxycarbonyloxypentyl ester, 1 (or 2 or 3 or 4 or 5 or 6)
-lower alkoxycarbonyloxy (lower) alkyl esters such as ethoxycarbonyloxyhexyl ester, e.g.
Oxo-1.

3-dioxol-4-yl)methyl ester, (5-
Propyl-2-oxo-1,3-dioki7-ru
(5-lower alkyl-2-xo-1,3-dioxo-4-yl)(lower) alkyl esters such as 4-yl)ethyl ester, such as mesylmethyl ester;
lower alkanesulfonyl (lower) alkyl esters such as 2-mesylethyl ester, e.g. benzyl ester,
4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, benzhydryl ester, trityl ester, bis(methoxyphenyl)methyl ester, 3.4-dimethoxybenzyl ester, 4-
Mono(
or di- or tri)phenyl (lower) alkyl ester,
(lower) alkyl esters, such as phenyl esters, tolyl esters, tertiary butyl phenyl esters, xylyl esters, mesityl esters, cumenyl esters, salicyl esters, etc., even if they have one or more suitable fIt, substituents. Good aryl esters include, for example, heterocyclic esters such as phthalidyl esters.

"Suitable monoacid residues" include halogens (e.g., fluorine,
(chlorine, bromine, iodine, etc.), acyloxy groups, etc.
Regarding the acyl moiety of the ``acyloxy group'', reference may be made to those exemplified above.

Regarding the suitable "esterified carboxy group", reference may be made to the above-mentioned examples of the protected carboxy group.

Suitable 1-hydroxy protecting groups include the above acyl group,
Examples include alkyl (lower) alkyl groups such as benzyl and trityl, lower alkoxy (lower) alkyl groups such as 1-methyl-1-methoxyethyl and methoxypropyl, and a tetrahydropyranyl group.

Groups include halogens, eg, single acid residues such as acyloxy such as lower alkanoyloxy (eg, acetoxy, etc.).

Preferred embodiments of R1, R2 and R3 of the target compound (I) are as follows.

R1 is an amine or an al(lower)alkylamino group such as mono(or di- or tri)-phenyl(lower)alkylamino, more preferably an amine or triphenyl(01-C,)alkylamino, most preferably amino or Tritylamino; -R2 is carboxy or lower alkanoyloxy (lower) alkoxycarbonyl and al(lower) alkoxy carbonyl ruboxy optionally substituted by a nitro group, more preferably carboxy, 01-C7 lukanoyloxy cyclocarbonyl; Nitrophenyl(C1-C4)flucoquinecarbonyl or diphenyl(01-C4)alkoxycarbonyl, most preferably carboxy, pivaloyloxymethoxycarliponyl, nitrobenzyloxycarbonyl or benzhydryloxycarbonyl R3 is hydrogen, tetrahydropyrani or lower alkanoyl hydrogen, tetrahydropyran-2-yl or C1-C4
Alkanoyl, most preferably hydrogen, tetrahydrobilan-2-yl or acetyl.

The method for producing the object compound of the present invention will be explained in detail below.

Production method 1 Target compound (I) or a salt thereof is prepared by combining compound (I[) or its reactive derivative in an amine group or a salt thereof,
It can be produced by reacting with compound (I[[) or a reactive derivative thereof or a salt thereof at the carboxy group.

Suitable reactive derivatives of the amine group of compound (I[) include Schiff's base type imino or its enamine type tautomer produced by the reaction of compound (IF) with a carbonyl compound such as an aldehyde, ketone, etc. ; Compound (I[> and bis(trimethylsilyl)acetamide,
Mono(trimethylsilyl)acetamide, N. Examples include silyl derivatives produced by reaction with N-bis(trimethylsilyl)urea and the like; derivatives produced by reaction of compound (II) with trichloride or phosgene, and the like.

Suitable salts of compounds (I[) and (III) include:
For example, organic acid salts such as acetates, maleates, tartarates, benzenesulfonates, toluenesulfonates, etc. or inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates, etc. Examples include acid addition salts; metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts; ammonium salts; organic amine salts such as triethylamine salts and dicyclohexylamine salts;

Suitable reactive derivatives at the carboxy group of compound (III) include acid halides, acid anhydrides, activated amides, activated esters, and the like.

Suitable examples include acid chlorides, acid azides; substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl phosphoric acid, etc. back acid,
For example, pivalic acid, pentanoic acid, impentanoic acid, 2-
Mixed acid anhydrides with acids such as aliphatic carboxylic acids such as ethylbutyric acid or trichloroacetic acid or aromatic carboxylic acids such as benzoic acid; symmetrical acid anhydrides; imidazole, 4-
activated amides with fl-substituted imidazoles, dimethylpyrazoles, triazoles or tetrazoles; or e.g. cyanomethyl esters, methoxymethyl esters, dimethyliminomethyl c(cu3>2i=cu-) vinyl esters, propargyl esters, p-nitrophenyl Esters, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-talesylthioester, carboxymethylthioester, pyranyl ester, pyridyl activated esters such as esters, piperidyl esters, 8-quinolylthioesters, or e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1
1()-pyridone, N-hydroxysuccinimide, N
-Hydroxyphthalimide, 1-hydroxy-IH-benzotriazole, 1-hydroxy-6-chloro-IH
Examples include esters with N-hydroxy compounds such as -benzotriazole. These reactive derivatives can be arbitrarily selected depending on the type of compound (III) to be used.

The reaction is usually carried out in conventional solvents such as water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine. However, the reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. These conventional solvents can also be used in combination with water.

When compound (I[[) is used in the reaction in the form of the free acid or its salt, the reaction is carried out using N,N'-dicyclohexylcarbodiimide-N'-morpholinoethylcarbodiimide F;. N-cyclohexyl-N'-(4-diethylaminocyclohexylcarbodiimide, N,N'-gedelcarbodiimide. N,N'-diisopropylcarbodiimide,
N=ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N. N-carbonylbis-(2-methylimidazole); Pentamethyleneketene-N-cyclohexylimine; Diphenylketene-N-cyclohexylimine; Ethoxyacetylene; 1-Alfoxy 1-
Chloroethylene; 1,1'-(carbonyldioxy)dibenzotriazole, 1,1'-dibenzotriazolyl oxalate: trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); Phosphorus chloride; Thionyl chloride; Oxalyl chloride;
Triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-
sulfophenyl) isoxazolium hydroxide inner salt; 1-(p-chlorobenzenesulfonyloxy)-
6-chloro-IH-benzotriazole; preferably carried out in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by reaction of dimethylformamide with thiodiJL chloride, phosgene, phosphorus oxychloride, etc.

The reaction also includes alkali metal acid hydrogen salts, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N. It may be carried out in the presence of an inorganic or organic base such as N-di(lower)alkylbenzylamine and the like.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling to heating.

It is also included within the scope of this reaction if the hydroxy protecting group of R is removed during the reaction or work-up steps of this process.

Production method 2 Compound (Ib) or a salt thereof can be produced by subjecting compound (Ia> or a salt thereof to an elimination reaction of a carboxy protecting group).

Suitable salts of compounds (Ia) and (Ib) include:
The same compounds as those exemplified for compound (I) can be mentioned.

Suitable methods for this elimination reaction include conventional methods such as hydrolysis and reduction.

(1) Hydrolysis Hydrolysis is preferably carried out in the presence of an acid.

Suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, for example formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfone H1p-
Examples include organic acids such as 1-luenesulfonic acid, acidic ion exchange resins, and the like. When organic acids such as trifluoroacetic acid and p-toluenesulfonic acid are used in this reaction, it is preferred to carry out the reaction in the presence of a cation scavenger, such as, for example, anisole.

Furthermore, in place of the above acids, acids such as boron trifluoride, boron trifluoride-ether addition compounds, aluminum trichloride, antimony pentachloride, ferric chloride, stannic chloride, titanium tetrachloride, zinc chloride, etc. Acids can also be used in this reaction, and when Lewis acid is used, the reaction is preferably carried out in the presence of a cation scavenger, such as, for example, anisole.

Hydrolysis is usually carried out using conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, tertiary butyl alcohol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, and dichloromethane. It is carried out in the presence or absence of a solvent or a mixture thereof; the acids mentioned above can also be used as solvents if they are liquid.

The reaction temperature for this hydrolysis is not particularly limited, but the reaction is usually carried out in a temperature range of from cooling to slightly elevated temperature.

(i) Reduction Reduction is carried out by conventional methods including chemical reduction and catalytic reduction.

Suitable reducing agents that can be used for chemical reduction include, for example, tin,
Metals such as zinc and iron or metal compounds such as chromium chloride and chromium acetate, and formic acid, acetic acid, propionic acid,
It is a combination with an organic or inorganic acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or hydrobromic acid.

Suitable catalysts used for catalytic reduction are platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, e.g. palladium sponges, haladium black, palladium oxide, palladium-carbon, colloidal palladium. ,
Palladium catalysts such as palladium-barium sulfate and palladium-barium carbonate; nickel catalysts such as reduced nickel, nickel oxide and Raney nickel; cobalt catalysts such as reduced cobalt and Raney TI belts; iron catalysts such as reduced iron and Raney iron; For example, the catalyst may be a conventional one such as reduced steel, Raney copper, Ullmann steel, etc. as a copper catalyst.

This reduction is usually carried out in conventional solvents or mixtures thereof that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,N-dimethylformamide. Additionally, if the acids used in the chemical reduction are liquids, they can also be used as solvents.

Still further, suitable solvents for use in catalytic reduction include those mentioned above and other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran, etc., or mixtures thereof.

The reaction temperature for this reduction is not particularly limited, but the reaction is usually carried out under cooling or heating.

In this carboxy-protecting group elimination reaction, there are cases where the protected amine group in R1 changes to a free amine group or the hydroxy-protecting group on R3 is simultaneously eliminated during the reaction or post-treatment step of this production method. Yes, such cases are also included within the scope.

Production method 3 Compound (I) or a salt thereof can be produced by reacting compound (IV) or a salt thereof with compound (V).

Suitable salts of compound (rV) include the same salts as exemplified for compound (I).

This reaction is usually carried out using ethyl acetate, dichloromethane, chloroform, back tetrachloride, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide,
It is carried out in customary solvents that do not adversely affect the reaction, such as dioxane, water, acetic acid, phosphoric acid, etc., or mixtures thereof.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.

Production method 4 Compound (Ic) or a salt thereof can be produced by subjecting compound (Ib) or a salt thereof to an esterification reaction.

For suitable salts of compounds (Ib) and (Ic),
Reference may be made to the examples given for compound (1).

This reaction may be carried out by reacting the compound (Ib> or a salt thereof with an esterifying agent).

A suitable esterifying agent has the formula: (wherein R7 is the ester moiety of the esterified carboxy group, and Z represents a hydroxy group or a reactive derivative thereof)
Examples include compounds represented by:

Suitable reactive derivatives of the hydroxy group of Z include the aforementioned halogens and acid residues such as acyloxy.

This reaction is usually carried out in a solvent such as dimethylformamide, pyridine, hexamethylphosphoric triamide, or dimethyl sulfoxide, but the reaction can be carried out in any other solvent that does not adversely affect the reaction.

When compound (Ib) is used in the form of a free acid, it is preferable to carry out the reaction in the presence of a base or a condensing agent as described in Production Method 1.

Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction under cooling, room temperature, or heating.

Production method 5 Compound (Ie) or a salt thereof can be produced by subjecting compound (Id) or a salt thereof to an elimination reaction of a hydroxy protecting group.

Suitable salts of compounds (Id) and (Ie) include the same salts as exemplified for compound (I).

This elimination reaction of the hydroxy protecting group of compound (Id) can be carried out in the same manner as in Preparation Method 2, and therefore, Preparation Method 2 may be referred to for the reagents used and reaction conditions such as solvent and reaction temperature.

In this elimination reaction, the unprotected amino group in R1 and/or the unprotected carboxy group in R2 are removed during the reaction or post-treatment step of this production method.
It may be changed to a corresponding free amino group and/or free carbonate group, and such cases are also included within the scope.

Production method 6 Compound (Ig) or a salt thereof can be produced by subjecting compound (If) or a salt thereof to an amino-protecting group elimination reaction.

Suitable salts of compounds (If) and (Ig) include:
The same compounds as those exemplified for compound (1) can be mentioned.

This elimination reaction can be carried out in the same manner as in factor 1 above, and therefore, for the reagents to be used and reaction conditions such as solvent and reaction temperature, please refer to the instructions.

In this elimination reaction, during the reaction or post-treatment step of this production method, the protected carboxy group in R may change to a free carboxy group, and the hydroxy protecting group in R3 may be simultaneously eliminated. Such cases are also included within the scope.

1 and Production Method 7 The target compound (1) or a salt thereof can be produced by reacting compound (IX) or a semi-reactive derivative with compound (VI) or a salt thereof.

Suitable salts for compound (VI) include the same salts as exemplified for compound (1).

Suitable reactive derivatives at the mercapto group of compound (IX) include metal salts such as alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as magnesium salts.

This reaction may be carried out in the presence of sodium iodide, sodium thiocyanate, etc.

The reaction is usually carried out in water, acetone, chloroform, nitrobenzene, dichloromethane, ethyl chloride/dimethylformamide, methanol, ethanol, ether, tetrahydrofuran or other solvents that do not adversely affect the reaction. Solvents with strong polarity are preferred. ,
Such solvents may also be used in mixtures with water.

When compound (VI) and/or compound (IX) are used in the free state, the reaction can be carried out using a base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate, a trialkylamine, pyridine, etc. It is preferable to carry out the reaction in the presence of an organic or inorganic base, and it is preferable to carry out the reaction under conditions around neutrality. Although the reaction temperature is not particularly limited, it is usually preferable to carry out the reaction from room temperature to heating.

The method for producing the raw material compound of this invention will be explained in detail below.

Molding compound (■) or a salt thereof is produced by reacting compound (If) or a reactive derivative thereof at an amino group or a salt thereof with compound (■) or a reactive derivative thereof at a carboxy group or a salt thereof be able to.

Suitable reactive derivatives of compound (■) include acid halides such as acid chlorides, acid bromides, etc. which can be produced, for example, by the reaction of diketene with a halogen.

Suitable salts for compound (■) include those similar to the bases exemplified for compound (I),
Suitable salts for compound (■) include the same salts as for compound (1).

The reaction is usually carried out using conventional solvents that do not adversely affect the reaction, such as water, acetone, dioxane, acetonitrile, chloroform, benzene, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, hexamethylsulforamide, etc. solvent or mixtures thereof.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.

1. Compound (IVa) or a salt thereof can be produced by reacting compound (■) or a salt thereof with a nitrosating agent.

Suitable salts of compound (IVa) include compound (1)
The same salts as those exemplified for are mentioned.

Suitable nitrosating agents include nitrous acid and nitrosyl halides such as nitrosyl chloride, nitrosyl bromide, alkali metal nitrites such as sodium nitrite, potassium nitrite, such as butyl nitrite, pentyl nitrite, isoamyl nitrite. Examples include conventional derivatives of nitrous acid such as alkyl nitrites such as nitrites and the like.

When a salt of nitrous acid or an alkali metal salt thereof is used as a nitrosating agent, the reaction is preferably carried out in the presence of an acid such as an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, acetic acid, etc.

This reaction is preferably carried out in the presence of an active methylene compound such as an acyl chloride (eg, acetyl chloride) or acetylacetone, ethyl acetoacetate, and the like.

This reaction is usually carried out in conventional solvents or mixtures thereof that do not adversely affect the reaction, such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran, dichloromethane.

Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction under cooling or heating.

Compounds (IVa) of this reaction include syn-isomers, anti-isomers and mixtures thereof in their hydroxyimino groups; such compounds have the substructural formula: The target compounds (1) and (Ib
), (re), (Ie) and (rg), as well as adult seedlings Φ and compounds (Na) and (■) obtained by production method ■
can be isolated and purified by conventional methods such as extraction, precipitation, fractional crystallization, recrystallization, chromatography, etc.

When the target compound (I) has a free amino group at R1 and a free carboxyl group at R2, it can be converted into a pharmaceutically acceptable salt thereof by a conventional method.

The object compound (1) of this invention and its salts are novel, exhibit high antibacterial activity, and are effective against a wide range of pathogenic bacteria, including Durum-positive bacteria and Durum-negative bacteria, especially Durum-positive bacteria such as Staphylococcus arasius. It is useful as a preventive and therapeutic agent for bacterial infections.

In order to demonstrate the usefulness of the target compounds, the antibacterial activity of representative compounds of this invention is shown below in comparison with known compounds.

The in vitro antibacterial activity of 30 mouthfuls of each sample was measured using the following agar plate dilution method.

Each test strain was cultured overnight in Tryptocase Soy Pross, and one platinum loop (108 viable bacteria/relative) was added to Heart Infusion Agar (containing the test compound at each aJf stage).
After inoculation on HI agar) and incubation for 20 hours at 37°C, the minimum inhibitory concentration (MIC) was expressed as (/l!111).

(B)! & Zosho Kosho 7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-(1,2,4-
thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) [hereinafter referred to as compound (I)].

7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-(3-methyl-
1,2,4-thiadiazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer) [Known compound (a)] [Hereinafter referred to as compound (A)]
.

Cefmetuxime sodium salt [sodium salt of known compound (b)] [hereinafter referred to as compound (
B)].

Cefmetuxime [known compound (c)] [hereinafter referred to as compound (C)]
.

Cefothiam [known compound (d)] [hereinafter referred to as compound (D>)]
.

(C) Test results M, 1. C(x/ml) For therapeutic use of the compounds of this invention, organic or inorganic solid or liquid excipients containing said compounds as active ingredients and suitable for oral, parenteral or external administration. It can be mixed with a pharmaceutically acceptable carrier such as a pharmaceutical agent and used in the form of a conventional pharmaceutical formulation. Pharmaceutical formulations may be in solid form, such as capsules, tablets, dragees, ointments or suppositories, or in liquid form, such as solutions, suspensions or emulsions; if desired, additives may be added to the formulation. agents, stabilizers, wetting agents or emulsifiers, buffers and others Lactose, fumaric acid, citric acid, tartaric acid, stearic acid, maleic acid, succinic acid, malic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin , agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol, etc. may also be included.

Although the dosage of the compound will vary depending on the age and condition of the patient, the compounds of this invention have an average single dose of about 10 mg;
50mg, 100mg, 250mg, 500m
g, 1000q is effective in treating pathogenic bacterial infections. In addition, generally 1mg/solid to about 6000mg/day
Solid or larger doses may be administered.

The present invention will be explained below with reference to production examples and practical examples.

Production example 1 7-amino-3-(1,2,4-thiadiazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (3
,5 g) and N,N'-bis(trimethylsilyl)urea (6,5 g) in tetrahydrofuran (1001nJ1
4-Bromoacetoacetyl bromide obtained from diketene (1,15 g) and bromine (2,15 g) in dichloromethane (7,5 mQ) was added to the solution at -20 °C under cooling, and the mixture was heated at -15 °C. Stir for 30 minutes.

The reaction mixture was mixed with ethyl acetate (100 mQ) and water (150 mQ).
The organic layer is separated, washed with water and brine, and the solvent is evaporated. The residue is triturated in diisopropyl ether (300111'). The resulting precipitate was collected by filtration and dried under vacuum to give 7-(4-bromoacetoacetamide)-3-(1,2,4-thiadiazol-5-yl)thiomesol-3-cephem-4-carboxylic acid (4, 64 g) is obtained.

NMR (DMSO-da, S)' 3.90-4.
00 (4H9m).

4.20 (2H, ABq, J=12Hz), 4.5
0 (2H, s).

5.20 (LH, d, J=5Hz), 5.73 (
IH, d-d.

J=5Hz, 8Hz), 8.70 (IH,
s), 9.10 <IH, d.

J=8Hz) Manufacturing example 2 The following compound was obtained in the same manner as in "Washij Kumito" 2.

7-(4-chloroacetoacetamide)-3-(1,2
, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester.

IR: 1775. 1710
am-'NMR (DMSO-da, 8)' 3.
40-3.93 (4H1m), 4.18 and 4.
63 (2H, ABq, 14Hz), 4.55 (2
H,s), 5.16 (IH,d,,C3Hz),
5.84 (IH.

dd, J-5Hz, 8Hz>, 7.01 (IH
,s), 7.28(IH,s), 7.13-7.6
7 (10H, m), 8.52 (IH, s), 9.
04 (IH, dJ = 8Hz) Mouse 1'' - (1) 2-(2-triple aminothiazol-4-yl)-2-hydroxyiminoacetic acid benzhydryl ester (syn isomer) (2.8 g) in dichloromethane (561
Add pyridine (0,47 all) to the 1Q) solution under water cooling.6 Next, add a solution of acetyl chloride (0,47 mQ) in dichloromethane (5,6 all). After stirring for 20 minutes under water cooling, the reaction mixture is washed with water and dried over magnesium sulfate. The solvent is evaporated and the residue is triturated in a mixture of diethyl ether and n-hexane. The resulting precipitate is collected by filtration to obtain 2-(2-tritylaminodeazol-4-yl)-2-acetoxyiminoacetic acid benzhydryl ester (syn isomer) (3, Og).

IR (suji e-ru): 331G, 1750
．． 1600. 1530 am″″INMR(DM
SO-da, ε): 1.88 (3H, s), 6
．． 75 (IH, s), 7.07-7.57 (26H
, m), 8.87 (IH, 5) (2) 2-(2-1
-ditylaminothiazol-4-yl)-2-acetoxyiminoacetic acid benzhydryl ester (syn isomer) (
Triple oroacetic acid (51) is added to a solution of 3.0 g) of dichloromethane (somQ) and anisole (1.5 mm) under water cooling. The mixture was stirred for 4 hours, and the resulting crystals were collected by filtration and washed with diisopropyl ether and water to give 2-(2-aminothiazol-4-yl).
-2-acetoxyiminoacetic acid (syn isomer) (0.5g
).

NMR (DMSO-ds, l; ): 1.48 (3
H1s), 7.22(1)! , s>, 7.13-7.
47 (2H,m) Production Example 4 7-(4-chloroacetoacetamide)-3-(1,2
,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (72
Isoamyl nitrite (176 g) and acetyl chloride (91.8 g) were added to a solution of 0 g) in dichloromethane (13j).
was added at room temperature and the mixture was stirred at the same temperature for 1 hour.The reaction mixture was poured into a mixture of tetrahydrofuran (3,22) and a saturated aqueous solution of sodium chloride (7,242).The organic layer was separated and brine was added. (7,212) and dry. The solution was evaporated and the residue was triturated in n-hexane (361). The precipitate was filtered off, washed with n-hexane, dried in a pentoxide groove and purified with 7-(4-chloro-2- Hydroxyiminoacetoacetamide)-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid benzhydryl ester (688.6g)
get.

IR (Streak 1-L): 1780. 1710
am-'NMR (DMSO-d6.S): 3
．． 57 and 3.8 (2H, ABq.

J=18Hz), 4.68 and 4.22 (2H,
ABq.

J=14)1z), 4.76 (2)1. s), 5
．． 06 (IH, d.

J=5Hz), 5.86 (IH, dd,, C3H
z, 8Hz), 7.02(LH,s), 7.28
(IH, s), 7.17-7.63 (10H, m)
, 8.31 (LH,s), 9.40 <IH,d
.

J=8Hz>, 11.29 (LH,s) Example 1 7-(4-bromoacetoacetamide)-3-(1,2
,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (4,64 g) in dichloromethane (401119) and acetic acid (2011LQ') was added an aqueous solution of sodium nitrite (0,84 g) (
4.3 mm) was added dropwise at -10°C. After stirring for 1.5 hours, the reaction mixture is poured into a mixture of water (80+1111) and tetrahydrofuran (4oraQ), the organic layer is separated and washed with water and brine. Distill the solvent, 7
-(4-Bromo-2-hydroxyiminoacetoacetamide)-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is obtained.

A solution of thiodine (0.86 g) in dimethylacetamide (13 ml) is added to this product. Mixture at room temperature 2
Stir the reaction mixture for 0 hours in ethyl acetate (50 ffll
1) and water (70 ml+), the mixture is adjusted to pH 6.5 with 2N sodium hydroxide. The aqueous layer was separated, concentrated, and adjusted to pH 4.4 with IN hydrochloric acid. !
do. The acidified aqueous solution is passed through a column of nonionic adsorption resin 1Diaion HP-20 (trademark: manufactured by Mitsubishi Chemical Industries, Ltd.) and eluted with a 20% isopropyl alcohol aqueous solution. The eluate was lyophilized to yield 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem- 4-carboxylic acid (syn isomer) (0.70 g) is obtained.

IR (Sujimeal) '2900. 1770.
1620. 1520 cm-'NMR (DMSO
-ds, l; ) ' 3-63 (2H,
ABq, J=18Hz).

4.42 (2)1. ABq,, c13Hz>, 5.
12 (LH, d.

J:5Hz), 5.77 (IH, dd, J=5H
z, 8Hz), 6.62(LH,s), 8.68
(IH, s), 9.38 (IH, d, J=8Hz
) 叉1”B.

Phosphorous oxychloride (0.38 g) and tetrahydrofuran (1.2 mm) were added to a mixture of dimethylformamide (0.38 g) and tetrahydrofuran (1.2 mm).
8g) at 0°C. After stirring for 30 minutes, add 2-(
27 tritylaminothiazol-4-yl)-2-(2
Add a solution of -tetrahydropyranyloxyimino)acetic acid (syn isomer) (z, o 7 g) in tetrahydrofuran. The mixture is stirred at -3-3°C for 1 hour to obtain an activated acid solution.

7- containing monotrimethylsilylacetamide (4g)
Amino-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (2,0 g) in tetrahydrofuran (4
0ffL11) To the solution, add the activated acid solution obtained above all at once at -20°C, and stir the mixture at -15 to -10°C for 1.5 hours. The aqueous layer is separated and extracted several times with a mixed solvent of ethyl acetate and tetrahydrofuran. The combined organic layers are washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was triturated in diisopropyl ether, filtered off and dried in a pentoxide groove to give 7-[2-(2-tetrahydropyranyloxyimino)-2-(2-tritylaminothiazole). 4,40
g) is obtained.

IR(X-a-L)' 3350. 1770.
1700. 1660 am-'NMR (DMSO
-ds, S): L50-2-00 (m)
, 3-50-4.30 (4H, m>, 5.30 (
IH, d, J=5Hz>, 5.85 (IH, dd.

J:5Hz, J=8Hz>, 6.83 (IH,s
), 7.03 (IH,s).

7.10-7.77 (m>, 8.57 (L
H,s), 9.67 (LH,d.

J=8Hz) Example 3 7-[2-(2-tetrahydropyranyloxyimino)
-2-(2-tritylaminothiazol-4-yl)acetamitoco-3-(1,2,4-thiadiazol-5
-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (4,0 g) and anisole (4-
gn+Q). After stirring for 2 hours at room temperature, the mixture is poured into diisopropyl ether (100+njl).
The formed precipitate is collected by filtration and dissolved in a 5% aqueous sodium hydrogen carbonate solution. The aqueous solution was washed with ethyl acetate, adjusted to pH 4.5 with IN hydrochloric acid, and subjected to column chromatography using a nonionic adsorption resin 1Diaion HP-20. Elute with 15% isopropyl alcohol aqueous solution and collect the eluate containing the desired compound. The eluate was adjusted to pH 2.0 with 10% hydrochloric acid while cooling with water. The formed precipitate is collected by filtration, washed with water, and dried to give 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(1,2,4-thiadiazol-5- yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0,13 g) is obtained.

IR (X Shiroru>: 3200. 1750.
1690. 1650 cm-'NMR (DMSO
-d6. ): 3.52 and 3.78 (2
H, ABq, J=18Hz>, 4.30 and 4.6
2 (2H, ABq, J-13Hz>, 5.13 (L
H, d, J = 5Hz>.

5.78 (IH, dd, J=5Hz, 8Hz),
6.65 (LH,s).

7.07 (2H, br s), 8.70 (IH,
s), 9.42 (IH, d, J=8Hz), 113
6 (LH, br s) Mars ■1 7-(4-chloro-2-hydroxyiminoacetoacetamide)-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid Dimethylacetamide of benzhydryl ester g) (2.7
j2) Add thiourea (160.8 g) to the solution at room temperature, and stir the mixture at the same temperature for 3 hours. The reaction mixture is poured into a mixture of ethyl acetate (9.5jl) and ice water (4.7i).

The organic layer was separated and diluted twice with water C4.71) and brine (
4.7ffi) and dried over magnesium sulfate. The solvent was distilled off, and the residue (1.5i) was dissolved in ethyl acetate (4.5
ffi) and diisopropyl ether ('l). The precipitate was filtered, washed with diisopropyl ether, dried in a pentoxide groove, and ? -C2-C2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(1.2.4-thiadiazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (436.5
g) is obtained.

IR (Suji a-IL): 1780. 1
720, 1665, 1620 CITI-I
NMR (DMSO-9.δ): 3.59 and 3
．． 83 (2H.

ABq. J: 18Hz>, 4.23 and 4.58
(2H.ABq.

J=13Hz>, 5.23<LH, d. J=5Hz
), 5.90 (LH.

dd, J=5Hz. 8) 1z), 6.67 (
LH. s).

7, 00-7.80 (10H.m), 8.55 (
18, s), 9.46 (LH.d.J: 8Hz),
11.40 (IH.s) Example 5 7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide co-3-(1,2,4-
Thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (430g) and anisole (430m+1) in dichloromethane (1,77g) at moderate temperature, trifluoroacetic acid (ssomu) is added dropwise under ice-cooling.
Stir at ~10°C for 2 hours. The reaction mixture is poured into diisopropyl ether (21.5 mm) and triturated. The precipitate is collected by filtration, washed with diisopropyl ether, and dried in a pentoxide groove to obtain a yellow powder.

This powder (400 g) is suspended in water and adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. Insoluble materials were removed by filtration, and the filtrate was adjusted to pH 6.0 with IN hydrochloric acid. This solution was subjected to column chromatography using a nonionic adsorption resin 1Diaion HP-20 and eluted with a 35% aqueous isopropyl alcohol solution. Fractions containing the desired compound are collected and adjusted to p) 12.2 with 10% hydrochloric acid. The formed precipitate was collected by filtration, washed with ice water, dried in a pentoxide groove,
7-[2-(2-aminethiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-(1,2,4-
Thiadiazol-5-yl)thiomethyl-3-cefnimu-4-carboxylic acid (syn isomer) (98.9 g) is obtained.

IR (xa-ru): 3200. 1750.
1690. 1650 cm-'NMR (DMSO
-d6. δ): 3.52 and 3.78 (2H.

ABq, J=18Hz), 4.30 and 4.62
(2H, ABq.

J=13Hz), 5.13 (LH,d, J=5H2
), 5.78 (IH.

dd, J: 5Hz, 8Hz), 6.65 (IH
, s), 7.07 <28°-br s), 8.7
0 (IH, s'), 9.42 (LH, d, JJH
z).

11.36 (LH, br s) 2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetic acid (synisomer) (0.2 g) in tetrahydrofuran (25 ml) was added anhydrous. 1-Hydroxy-IH-benzotriazole (0,135 g) and N,N'-dicyclohexylcarbodiimide (0,1
82g). After stirring the mixture for 1 hour at room temperature, the precipitate is filtered off. The filtrate contains 7-amino-3-(1,2,4-
thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (0.43 g
) at room temperature. The solvent was evaporated and the residue was triturated in diisopropyl ether to give 7-C2-C2-aminothiazol-4-yl)-2-acetoxyiminoacetamidoco-3-(1,2,4-thiadiazol-5- )
Thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (0.7 g) is obtained.

NMR (DMSO-d6.δ): 2.1
8 (3H, s), 3.17-4.67 (4H,
m), 5.17-6.17 (2H, m), 7.0
(IH, s).

7.12 (IH,s), 7.22-7.73 (1
0H, m), 8.57 (IH, s) cold l(M near C2-C2-aminothiazol-4-yl)-2-
Acetoxyiminoacetamidoco-3-(1,2,4-
Thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (0.7 g) in a mixture of dichloromethane (3111) and anisole (0.7 mQ) was added to Add fluoroacetic acid (1.4 mQ) under water cooling. The mixture is stirred at the same temperature for 1 hour. The reaction mixture is poured into diisopropyl ether (70me).

The precipitate is filtered and washed with diisopropyl ether. This powder is poured into water, adjusted to 1) H6 with saturated aqueous sodium bicarbonate solution, and washed with ethyl acetate. Aqueous solution I
Adjust the pH to 3.5 with N hydrochloric acid and extract with ethyl acetate.

# The solvent was distilled off and the residue was triturated in diisopropyl ether to give 7-[2-(2-aminothiazol-4-yl)
-2-acetoxyiminoacetamidoco-3-(1,2
, 4-thiadiazol-5-yl)deomether-3-cephemu 4-carboxylic acid (syn isomer) (0.1 g) is obtained.

IR(X';a-L)" 1760-1770.
1660. 1530. Cm″″INMR(DM
SO-d6. δ): 2.15 (3H,s), 3
．． 67 (2H.

ABq, J:18)1z), 4.28 and 4.59
(2H, ABq.

J=13Hz), 5.15 (IH, d, J=5H
z), 5.78 (IH.

dd, J=5Hz, 8Hz), 7.01
(LH,s), 7.10-7.43(2H,br
s), 8.64 (LH,s), 9.76 (
LH, d.

J:8H2) large m(1 mutual?-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (I
The suspension in water (30ffL11) obtained in g) was adjusted to pH 6.3 with a saturated aqueous solution of sodium bicarbonate. Potassium-1,2,4-thiadiazole-5-thiolate is added to this solution at room temperature while maintaining the pH at 6.0 to 6.5.

The mixture is stirred at 60-65°C for 5 hours. The precipitate in the reaction mixture is filtered off, and the remaining aqueous solution is adjusted to pH 3 with IN salt water. The precipitate was collected by filtration and dried on a pentoxide groove to give 7-[2-
(2-aminethiazol-4-yl)-2-hydroxyiminoacetamide]-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0 , 37 g).

IR (Streak 1-L): 3200. 1750.
1690. 1650 cm-INMR (DMSO
-d6. δ): 3.52 and 3.78 (2H.

ABq, J: 18Hz), 4.30 and 4.62
(2H, ABq.

J=13)1z), 5.13 (IH, d, J=5H
z), 5.78 (1) 1°d-d, J=5Hz,
8Hz), 6.65 (LH,s), 7.07 (
2H.

br s), 8.70 (LH, s), 9.42
(IH, d, J=8Hz).

11.36 (IH, br s) 7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide co-3-(1,2,4-
N of thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1,0 g)
, Cesium carbonate (0.39 g) is added to a solution of N-dimethylformamide (20 mG) at room temperature. The mixture was stirred at the same temperature under reduced pressure for 20 minutes, and pivaloyloxymethyl iodide (0.27 g) was added to the mixture under water cooling. After stirring at the same temperature for 15 minutes, the reaction mixture was mixed with ethyl acetate (200ml
Pour into a mixture of 1) and water (100 ml!), separate the organic layer, wash with water, 5% aqueous sodium bicarbonate solution and brine and dry over magnesium sulfate. The solution was evaporated and the residue was triturated in diisopropyl ether to give 7-[2-(2-aminodeazol-4-yl)
-2-hydroxyiminoacetamide]-3-(1,2
, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer) (0.57 g).

IR (Sujoor): 3250. 1780.
1740. 1680 cm-INMR (DMSO
-da, f; )' 1. ts (9H9s), 3
-54 and 3.83 (2H, ABq, J=18Hz
), 4.20.4.60 (2H.

ABq, J:13)1z), 5.15 (IH,d,
J=5Hz), 5.84(LH, dd, J=5.8
Hz), 5.90 (2H, ABq, J=6Hz>.

6.62 (iH,s), 8.66 (IH,s),
9.35 (IH, d.

J=8Hz> JdnJ seal The following compound is obtained in the same manner as LLLg-.

(1) 7-[2-(2-aminothiazol-4-yl)
-2-hydroxyiminoacetamidoco-3-(1,2
, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR(Xdi+-4): 3200. 1750
．． 1690. 1650 cm-'NMR (DMS
O-d6. l;'): 3.52 and 3.78
(2H.

ABq, J: 18Hz), 4.30 and 4.62
(2H, ABq.

J=13Hz), 5.13 (1)1. d, J=5H
z), 5.78 (IH.

dd, 5Hz, 8Hz), 6.65 (IH,
s), 7.07 (2H.

br s), 8.70 (IH, s), 9.42
(IH, dJ=8Hz).

11.36 (1)1. br 5) (2) 7-[2-(2-aminothiazol-4-yl)
-2-hydroxyiminoacetamide]-3-(1,2
, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

IR (Stripe*-L)' 1780. 1720.
1665. 1620 cm-1NMR (DMSO
-d6.8): 3.59 and 3.83 (2H
.

ABq, J=18)1z), 4.23 and 4.58
(2H, ABq.

J=13Hz), 5.23 (18,d, J:5H
z), 5.90 <1)t.

dd, J=5Hz, 8Hz>, 6.67 (LH,
s), 7.00-7.80 (10H, m), 8.5
5 (LH, s), 9.46 (1B, d.

J=8Hz), 11.40 (LH,5)(3)? −
[2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetamide]-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer).

IR (streak 1-4): 1760-1770.
1660. 1530 cm-1BMR (DMSO-
ds, S)' 2.15 (3H1s), 3.67
(2H1ABq, J: 18Hz>, 4.28 and 4.59 (2H,ABq.

U=13Hz), 5.15 (IH, d, J=5Hz
), 5.78 (LH.

dd, J = 5Hz, 8Hz), 7.01 (I
H, s), 7.10-7.43<2H, br s)
, 8.64 (11(,s), 9.76
(1)1. d.

J=8Hz) (4) 7-[2-(2-aminothiazol-4-yl)
-2-hydroxyiminoacetamidoco-3-(1,2
, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer).

IR: 3250. 1780.
1740. 1680 11-III-INMR(D
MSO-ds, 8)' 1.15 (9H,s),
3-54 and 3.83 (2H, ABq, J=18
)1z), 4.20.4.60 (2H.

ABq, J43Hz), 5.15 (IH, d, J
=5Hz), 5.84(LH, dd, J=5.8H
z), 5.90 (2H, ABq, 6Hz).

6.62 (LH, s), 8.66 (IH, s),
9.35 (LH, d.

J-8Hz) dog boy The following compound is obtained in the same manner as in 1.

7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-(1,2,4-
Thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer).

IR (Sujoor): 3250. 1780.
1740. 1680 cm-'NMR (DMSO
-da, f; ) 2L 15 (9H1s), 3.5
4 and 3.83 (2H, ABq, J=18Hz),
4.20.4.60 (2H.

ABq, J=13Hz>, 5.15 (IH, d,
J=5Hz), 5.84(LH, dd, J=5H
, 8Hz), 5.90 (2H, ABQ.

J-6Hz), 6.62 (IH,s), 8.
66 (IH, s), 9.35 (LH, d, J=8
H2) Example 12 The following compound is obtained in the same manner as in Example 3.

7-[2-(2-aminothiazol-4-yl)-2-
Acetoxyiminoacetamide]-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer).

IR: 1760-1770. 1
660. 1530 Low 1NMR (DMSO-d6
．． δ): 2.15 (3H,s), 3.67 (
2H.

ABq, J=18Hz>, 4.28 and 4.59
(2H, ABq.

J=13Hz), 5.15 (IH, d, J:5Hz
), 5.78 (IH.

dd, J=5Hz, 8Hz), 7.01 (1)
! , s), 7.10-7.43 (2H, br s),
8.64 (LH,s), 9.76 (IH,d.

J=8Hz) 【Leave】Ue l The following compound is obtained in the same manner as in Example 8.

(1) 7-[2-(2-tetrahydropyranyloxyimino)-2-(2-tritylaminethiazol-4-yl)acetamide]-3-(L2.4-thiadiazol-5-yl)thiomethyl-3 -Cephem-4-carboxylic acid benzhydryl ester (syn isomer).

IR(X!; e-L): 3350. 1770
．． 1700. 1660 cm-'NMR (DMS
O-da, S) = 1-50-2.00 (m), 3
．． 50-4-30 (4H, m), 5.30 (1)1
．． d, J=5Hz), 5.85 (1)1. dd.

J=5Hz, J:8Hz), 6.83 (1)t,
s), 7.03(LH,s), 7.10-7.77
(m), 8.57 (IH, s).

9.67 (IH, d, J: 8Hz> (2) 7-[2-(2-aminothiazol-4-yl)
-2-hydroxyiminoacetamide]-3-(1,2
, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

IR (suji a-IL): 1780. 1720
．． 1665. 1620 cm-1NMR (DMS
O-da, δ): 3.59 and 3.83 (2H.

ABq, J=18Hz>, 4.23 and 4.58
(2H, ABq.

J=13Hz), 5.23 (LH, d, J=5)
1z), 5.90 (LH.

d-dJ=5Hz, 8Hz), 6.67 (1
8,s), 7.00-7.80(IOH,m>,
8.55 (IH, s), 9.46 (IH, d
.

J=8Hz), 11.40 (LH,5)(3)7
-[:2-(2-aminothiazol-4-yl)-2-
acetoxyiminoacetamide]-3-(1,2,4-
Thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer).

NMR (DMSO-da-8>' 2.18 (3H
1s), 3.17-4.67 (4H, m), 5.17
-6.17 (2H, m), 7.0 (LH, s).

7.12 (LH,s), 7.22-7.73 (1
0H, m), 8.57 (LH, 5) (4) 7-[2-(2-aminothiazol-4-yl)
-2-acetoxyiminoacetamide]-3-(1,2
, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR: 1760-1770. 1
660. 1530 cm-1HMR (DMSO-d
a, 8)' 2-15 (3)1. s), 3.67
(2H9ABq, J=18Hz), 4.28 and 4.59 (2H,ABq.

J=13Hz), 5.15 <LH, d, J=5H
z), 5.78 (LH.

dd, J: 5Hz, 8Hz), 7.01 (
LH, s), 7.10-7.43 (2H, br s
), 8.64 (LH,s), 9.76 (L
H,d.

J=8H2) (5) 7-[:2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-(1,
2,4-thiadiazol-5-yl)thiomethyl-3-
Cephem-4-carboxylic acid pivaloyloxymethyl ester (Syn A form).

IR (Suji Meal): 3250. 17$0.
1740. 1680 cTII-INMR (DM
SO-ds, S)' 1.15 (9H1s), 3
．． 54 and 3.83 (2H, ABqJ=18Hz)
, 4.20.4.60 (2H.

ABq, J=13Hz>, 5.15 (IH, d, J
=5Hz>, 5.84(LH, dd, J=5.8H
z), 5.90 (2H, ABq, J=6Hz).

6.62 (LH, s), 8.66 (IH, s),
9.35 (LH, d.

J=8H2) 7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-(1,2,4-
Thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (5.0 g) in water (5.0 g)
0111) Sodium hydrogen carbonate (924 m
g) is added under stirring. Add this solution to aluminum oxide (
50 g) (manufactured by Woollum) (gamma Luma, type W2O0) was subjected to column chromatography using water. The eluate was lyophilized to yield 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-(1,2,4-thiadiazol-5-yl).
Sodium thiomethyl-3-cephem-4-carboxylate (syn isomer) (4.2 g) is obtained.

IR (S'; Yor): 3300. 1750
．． 1650. 16001520 aTl-1 Fuo five? -[2-(2-aminothiazol-4-yl)-2-
hydroquiniminoacetamide]-3-(1,2,4-
To a suspension of thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (5.0 g) in methanol (25 mA) was added 5 molar sulfuric acid (2 m
) is added at room temperature while stirring.

The solution was poured into diethyl ether (600 mQ), the precipitate was collected by filtration, washed with diethyl ether, and the 7-[
2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid sulfate (syn isomer) (5.6 g) is obtained.

IR (Sujiuru); 1770. 1640.
1590. 1520 INMR (DMSO-
da, δ) i 3.60 and 3.80 (2H.

ABq, J=18Hz), 4.40 and 4.60
(2H, ABq.

J=14Hz>, 5.20 (IH, d, J=5Hz
), 5.80 <18゜dd, J-5Hz, 8Hz
), 6.87 (IH,s), 8.70 (IH,s
), 9.68 (IH, d, J = 8Hz) Fugoikdan (1) 7-[2-(2-aminothiazol-4-yl)
-2-hydroxyiminoacetamide]-3-(1,2
,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (10,0g
) Concentrated hydrochloric acid (2.0 ml) was added to the middle suspension of methanol (40 mQ) under stirring at room temperature.

The solution was poured into diethyl ether (500ml), the precipitate was collected by filtration, washed with diethyl ether, and the 7-
[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid hydrochloride (syn isomer) (10.6g
).

mp: 160-165°C (decomposition) LR (X di-il): 1780. 1680.
1635. 1530 cm-INMR (DMSO
-ds, l; )' 3.70 (2H1m), 4.
34 and 4.71 (2H, ABq, J: 13Hz)
, 5.21 (1)1. d.

J:5Hz), 5.80 (IH, dd, J=5Hz
, 8Hz), 6.87 (18,s), 8.72
(LH,s), 9.71 (18,d, 8Hz) (
2) 7-[2-(2-aminothiazol-4-yl)-
2-hydroxyiminoacetamide]-3-(1,2,
4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (40
A suspension of 0 mg) in acetonitrile (4 mQ) was heated under stirring at 45°C for 2 hours. After cooling, the precipitate was collected by filtration and washed with acetonitrile and diethyl ether.
7-[2-(2-amitthiazol-4-yl)-2-
Hydroxyiminoacetamide co-3-(1,2,4-
Thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (410 mg
) to obtain crystals. The crystals contain 1 molar equivalent of acetonitrile.

mp: 80-84°C (decomposition) IR (xdim-x)' 3260-3050.
2240. 1770. 1710°1650, 163
0.1540 cTII-1HMR (DMSO-d6.
δ): 2.05 (3H, s), 3.66 (2H
, m), 4.31 and 4.81 (2H, ABq.

J=13)1z), 5.14 (IH, d, J=5H
z), 5.73 (IH.

Claims (1)

[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is amino or a protected amino group, R^2 is carboxy or a protected carboxy group, R^ 3 means a hydrogen or hydroxy protecting group, respectively] A cephem compound and its salts. 2) The compound according to claim 1, wherein R^1 is amino or al(lower) alkylamino, R^2 is carboxy or esterified carboxy, and R^3 is hydrogen, acyl or tetrahydropyranyl. . 3) The compound according to claim 2, wherein R^1 is amino and R^3 is hydrogen. 4) 7-[2-(2-aminothiazol-4-yl)-
2-hydroxyiminoacetamide]-3-(1,2,
4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) or its sodium salt. 5) The compound according to claim 3, wherein R^2 is esterified carboxy. 6) The compound according to claim 5, wherein R^2 is al(lower)alkoxycarbonyl or lower alkanoyloxy(lower)alkoxycarbonyl. 7) 7-[2-(2-aminothiazol-4-yl)-
2-hydroxyiminoacetamide]-3-(1,2,
7. The compound according to claim 6, which is 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer). 8) 7-[2-(2-aminothiazol-4-yl)-
2-hydroxyiminoacetamide]-3-(1,2,
7. The compound according to claim 6, which is 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn isomer). 9) The compound according to claim 2, wherein R^3 is lower alkanoyl or tetrahydropyranyl. 10) 7-[2-(2-aminothiazol-4-yl)
-2-acetoxyiminoacetamide]-3-(1,2
, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), 7-[2-(2-aminothiazol-4-yl)-2-
acetoxyiminoacetamide]-3-(1,2,4-
thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer), and 7-[2-(2-tetrahydropyranyloxyimino)-2-(2-tritylaminothiazole-
4-yl)acetamido]-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-
The compound according to claim 9, selected from the group consisting of carboxylic acid benzhydryl esters (syn isomer). 11) i) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^2 means carboxy or protected carboxy group) A compound represented by the following or its reactive derivative in an amino group or a salt thereof , the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 means amino or a protected amino group, R^3 means hydrogen or a hydroxy protecting group, respectively) or carboxy By reacting with its reactive derivative or its salt in the group, it is expressed by the formula: ▲Mathematical formula, chemical formula, table, etc.▼ (wherein R^1, R^2 and R^3 each have the same meaning as before) ii) Formula: ▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, R^1 and R^3 each have the same meaning as before, and R^2_a is a protected (meaning a carboxy group) or a salt thereof is subjected to an elimination reaction of the carboxy protecting group, and the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^3 are each has the same meaning as before)
iii) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^2 and R^3 each have the same meaning as before, and X is an acid residue ) or its salt is reacted with a compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R^1 has the same meaning as before) to form the formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2 and R^3 each have the same meaning as before) Do you obtain the compound or its salt? iv) Formula: ▲Mathical formula, chemical formula , tables, etc. ▼ (In the formula, R^1 and R^3 each have the same meaning as before)
The compound represented by or its salt is subjected to an esterification reaction to form the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^3 each have the same meaning as before, R^ 2_b means an esterified carboxy group) or its salt; v) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 are each The same meaning as before, R^3_a means a hydroxy protecting group) or its salt is subjected to a hydroxy protecting group elimination reaction to form the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 each have the same meaning as before)
vi) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^2 and R^3 each have the same meaning as before, and R^1_a is protected The compound represented by (representing an amino group) or its salt is subjected to an amino-protecting group elimination reaction to form the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 3 has the same meaning as before)
vii) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2 and R^3 each have the same meaning as before, and Y means a group that can be substituted by a group represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼) A compound or its salt represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ When reacted with a compound or its reactive derivative in the mercapto group, the compound represented by the formula: ▲Mathematical formula, chemical formula, table, etc.▼ (wherein R^1, R^2 and R^3 each have the same meaning as before) A general formula characterized by obtaining a compound or a salt thereof: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1, R^2 and R^3 each have the same meaning as before] A method for producing cephem compounds or their salts. 12) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is amino or a protected amino group, R^2 is carboxy or a protected carboxy group, R^3 is hydrogen or hydroxy A prophylactic/therapeutic agent for bacterial infections containing a cephem compound or a salt thereof as an active ingredient. 13) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^2 is carboxy or protected carboxy group, A is methylene or the formula: >C=N~OR^3 (In the formula, ^3 means a hydrogen or hydroxy protecting group), X means an acid residue] and salts thereof. 14) i) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^2 means carboxy or protected carboxy group) A compound represented by the following or its reactive derivative in an amino group or a salt thereof , a group represented by the formula: means an acid residue] or its reactive derivative in the carboxy group or its salt to form a compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ii) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^2 and The compound shown or a salt thereof is reacted with a nitrosating agent to form a compound shown by the formula: ▲Mathematical formula, chemical formula, table, etc.▼ (wherein R^2 and X each have the same meaning as before) or its salt. General formulas characterized by obtaining salts: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^2, X and A each have the same meanings as before.) A method for producing the compound or its salt.