JPS61243090A - Novel cephem compound and salt thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is (protected) COOH; R<2> is (protected) COOH or COO<->; R<3> is substitutable heterocyclic thiomethyl or pyridiniomethyl; X<1> and X<2> are halogen]. EXAMPLE:7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoace tamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate. USE:An antibacterial agent. PREPARATION:The compound of formula II and the compound of formula IV are used as starting raw materials, and are made to react with each other in a solvent usually THF, etc. When the compound of formula IV is used in the form of free acid (salt), the reaction is preferably carried out in the presence of a condensation agent such as Vilsmeier reagent. The compound of formula IV is a novel compound which can be produced according to the reaction formula by reacting the compound of formula VI with the compound of formula VII.

Description

DETAILED DESCRIPTION OF THE INVENTION "Industrial Application Field" The cephem compound of the present invention represented by the following general formula (I) and its salts have antibacterial activity and are useful as medicines.

"Prior Art" Many cephem compounds are known, but the cephem compound represented by the following general formula (I) of the present invention is not known.

'The problem that the invention seeks to solve.

Although many cephem compounds that have antibacterial effects and are useful as medicines are known, this invention was made with the intention of developing even better medicines.

``Means for solving problems'' This invention relates to novel cephem compounds and salts thereof.

More specifically, this invention relates to novel cephem compounds and salts thereof having antibacterial activity.

The target cephem compound and its salt are novel;
It can be represented by the following general formula (1).

(In the formula, R1 is an amine group or a protected amino group, R2 is a carboxy group, -coo'' or a protected carboxy group, and R3 is a heterocyclic thiomethyl group that may be substituted with an appropriate substituent or an appropriate substituted a pyridiniomethyl group which may be substituted with a group, xl means a halogen, and X2 means a halogen).

According to this invention, the target compound (I) can be produced by the following production method.

1. Reactive derivatives thereof, derivatives thereof, base salts thereof, or salts thereof, in the reaction of amino groups or carboxy groups (wherein R1, R2, R3, xl and Each has the same meaning as before, and R1 means a protected amino group).

Raw material compound (III) is a new compound and can be produced by the following production method.

1 production shame (II/) (V) or its salt or its salt production method B or its salt or its salt production method C or its salt or its salt production method D (wherein R1, x 1 and X2 are Each has the same meaning as before, W means a carboxy group or a protected carboxy group, Y means an acid residue, and Wa means a protected carboxy group).

Compounds (I), (Ia), (Ib>, (III), (I
Regarding I[a), (IIb) and (VI), syn isomers, anti-isomers and mixtures thereof are meant to be included.

For example, regarding the target compound (I), the syn isomer means one geometric isomer having a partial structure represented by the following formula: However, the anti-isomer means another geometric isomer having a partial structure represented by the following formula = (wherein R1, xl and x2 each have the same meanings as before).

Suitable salts of the target compound (1) are conventional non-toxic salts,
For example, alkali metal salts such as sodium salts and potassium salts,
For example, metal salts such as alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts such as trimethylamine salts, triethylamine salts, pyridine salts, pilin salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc. Organic base salts, such as acetates, maleates, tartrates, methanesulfonates, benzenesulfonates, formates, toluenesulfonates, etc.; organic acid salts, such as hydrochlorides, hydrobromides, sulfates; , inorganic acid salts such as phosphates, and salts with amino acids such as arginine, aspartic acid, and glutamic acid.

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

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

Suitable monoprotected amino groups include acylamino groups, or at least one monoprotected amino group, such as benzyl, trityl, etc.
Examples thereof include amino groups substituted with conventional protecting groups such as al(lower) alkyl groups which may have one or more suitable substituents.

Preferred acyl moieties of the acylamino group include aliphatic acyl groups and acyl groups containing aromatic or heterocycles. Preferred examples of these acyl groups include formyl, acetyl, propionyl, butyryl, Lower alkanoyl groups such as inbutyryl, valeryl, invaleryl, oxalyl, succinyl, pivaloyl; e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl , hexyloxycarbonyl; lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl; arenesulfonyl groups such as benzenesulfonyl, tosyl; examples include benzoyl, toluoyl, Aroyl groups such as xyloyl, naphthoyl, phthaloyl, indancarbonyl; Al(lower) alkanoyl groups such as phenylacetyl and phenylpropionyl; Examples include al(lower) alkoxycarbonyl such as benzyloxycarbonyl and phenethyloxycarbonyl. The acyl moiety may have at least one suitable substituent such as halogen such as chlorine, bromine, fluorine and iodine.

Examples of suitable 1-protected carboxy groups include esterified carboxy groups, and preferable examples of the ester portions of these esterified carboxy groups include methyl ester, ethyl ester, propyl ester, etc. , lower alkyl esters which may have at least one suitable substituent, such as isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester; Examples include acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester Lower alkanoyloxy (lower) alkyl esters such as 4. Lower alkanesulfonyl (lower) alkyl esters such as e.g. 2-mesyl nibble ester or e.g.
Mono (or di or tri) halo (lower) such as iodoethyl ester, 2.2.2-IJ dichlorothyl ester, etc.
Alkyl esters; lower alkenyl esters such as vinyl esters and allyl esters; lower alkynyl esters such as ethynyl esters and propynyl esters; such as benzyl esters, 4-methoxybenzyl esters, 4-nitrobenzyl esters, phenethyl esters, trityl esters It has at least one suitable substituent such as benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiary butylbenzyl ester, etc. Al(lower) alkyl esters which may have at least one suitable substituent; for example, phenyl esters, 4-chlorophenyl esters, tolyl esters, tertiary butylphenyl esters, xylyl esters, mesityl esters, cumenyl esters, etc. Examples include aryl esters that may be saturated.

A suitable heterocyclic moiety of "heterocyclic thiomethyl group" refers to a saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one heteroatom such as an oxygen atom, an atom, a nitrogen atom, etc. means. Particularly preferred heterocyclic groups include, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxyto, pyrimidyl,
Pyrazinyl, pyridazinyl, e.g. 4H-1,2,4-
Triazolyl, I H-1゜2.3-1 Riazolyl, 2
Triazolyl such as H-1,2,3-triazolyl, e.g. IH-tetrazolyl, tetrazolyl such as 2H-tetrazolyl, e.g. 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2, Unsaturated 3- to B-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as dihydrotriazinyl such as 4-triazinyl; For example, saturated 3- to B-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc. 3-8
Member heteromonocyclic groups; for example, indolyl, isoindolyl, intridinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetracylopyridyl, tetracylopyridazine such as tetracylo[1,5-bcopyridazinyl] unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms such as
．． an unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxadiazolyl, such as 4-oxadiazolyl, 1.3.4-oxadiazolyl, and 1.2.5-oxadiazolyl; For example, a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl; For example, 1 to 2 oxygen atoms and nitrogen, such as benzoxacylyl, benzoxadiazolyl, etc. Unsaturated fused heterocyclic groups containing 1 to 3 atoms; for example thiazolyl, thiazolidinyl, for example 1.2.
4-thiadiazolyl, 1.3.4-thiadiazolyl, 1
, 2.5-thiadiazolyl, 1,2.3-thiadiazolyl, and other unsaturated 3- to 8-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; For example, thiazolidinyl, etc. a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms;
8-membered heteromonocyclic group; For example, a heterocyclic group such as an unsaturated fused heterocyclic group containing 1 to 2 carbon atoms and 1 to 3 nitrogen atoms such as benzothiazolyl and benzothiadiazolyl can be mentioned. , the heterocyclic group is, for example, a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl;
For example, lower alkylthio groups such as methylthio, ethylthio, propylthio; lower alkenyl groups such as vinyl, allyl, butenyl; lower alkenylthio groups such as vinylthio, allylthio, butenylthio; hydroxy groups;
Aryl groups such as phenyl, tolyl; e.g. chlorine,
halogens such as bromine, iodine or fluorine; amino groups;
For example, dimethylamine methyl, dimethylaminoethyl,
Dimethylaminopropyl group Di(lower)alkylamino(lower)alkyl group such as diethylaminobutyl; Carboxy(lower)alkyl group such as carboxymethylcarboxypropyl: The esterified carboxy moiety is exemplified above. Esterified carboxy(lower)alkyl groups that are esters; amino(lower)alkyl groups such as aminomethyl, aminoethyl, aminopropyl, 1-aminomethylethyl, aminobutyl, aminohexyl; protected amine moieties and a protected amine (lower) alkyl group, in which the lower alkyl moieties are each as exemplified above;
Preferably lower alkoxycarbonylamino (lower) alkyl groups such as methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, tertiary butoxycarbonylaminomethyl, tertiary butoxycarbonylaminoethyl, tertiary butoxycarbonylaminopropyl, etc. or a lower alkanoylamino (lower) alkyl group such as acetylaminomethyl, acetylaminoethyl, acetylaminopropyl, 1-acetylaminomethylethyl; a carboxy group; an oxo group; an esterified carboxy group such as those exemplified above. , preferably lower alkoxycarbonyl groups: lower alkoxy (lower) alkyl groups such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl; hydroxy (lower) alkyl groups such as hydroxymethyl, hydroxyethyl, hydroxyethyl, hydroxybutyl; ) Alkyl group; for example, lower alkylthio (lower) alkyl group such as methylthiomethyl, methylthioethyl, methylthiopropyl, ethylthiomethyl; for example, sulfomethyl, sulfoethyl,
Sulfo(lower)alkyl groups such as sulfopropyl, sulfobutyl; acyl(lower)alkyl groups in which the acyl and lower alkyl moieties are respectively as exemplified above, preferably lower such as mesylmethyl, mesylethyl, ethanesulfonylmethyl; Alkanesulfonyl (lower)alkyl group; acylamino (
lower)alkyl groups, preferably lower alkanesulfonylamino(lower)alkyl groups such as, for example, mesylaminomethyl, mesylaminoethyl, mesylaminopropyl, ethanesulfonylaminemethyl; carboxy(lower)alkylthio, such as carboxymethylthio, carboxyethylthio, etc. groups; e.g. morpholino (lower) alkyl groups such as morpholinomethyl, morpholinoethyl, morpholinopropyl; piperidino (lower) alkyl groups such as piperidinomethyl, piperidinoethyl, piperidinopropyl;
For example, it may be substituted with 1 to 3 suitable substituents such as a piperazinyl (lower) alkyl group which may be substituted with a lower alkyl group such as 4-methyl-1-piperazinylprobyl.

Examples of "preferred r substituent for the pyridiniomethyl group which may be substituted with a suitable substituent" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples include lower alkyl groups such as tertiary butyl, pentyl, tertiary pentyl, and hexyl.

Suitable "halogens" include chlorine, bromine, fluorine and iodine, with fluorine being preferred.

Suitable "acid residues" include, for example, halogens such as fluorine, chlorine, bromine or iodine.

Preferred embodiments of the target compound (I) are as follows.

A preferred embodiment of R1 is an amino group or an al(lower)alkylamino group (more preferably triphenyl(
A preferred embodiment of R is a carboxy group, -cooe or an esterified carboxy group (more preferably an al(lower) alkyl dicarbonyl group, most preferably a benzyl) A preferred embodiment of R3 is a thiadiazolylthiomethyl group (more preferably a 1.3.4-thiadiazolylthiomethyl group, a 1.2.4-thiadiazolylthiomethyl group, or a 1.2.4-thiadiazolylthiomethyl group). .2.3-deadiazolylthiomethyl group); thiadiazolylthiomethyl group substituted with a lower alkyl group (more preferably 1, substituted with a lower alkyl group);
2.4-thiadiazolylthiomethyl group); deadiazolylthiomethyl group substituted with a lower alkenyl group (more preferably a 1,2.4-thiadiazolylthiomethyl group substituted with a lower alkenyl group); A dihydrotriazinylthiomethyl group substituted with an oxo group, a hydroxy group, and a lower alkyl group (more preferably a 4,5-dihydro-1,2,4-triazinyl group substituted with an oxo group, a hydroxy group, and a lower alkyl group) a pyridiniomethyl group; or a pyridiniomethyl group substituted with two lower alkyl groups; a preferred embodiment of Xl is halogen (more preferably fluorine); a preferred embodiment of X2 is halogen (more preferably fluorine); be.

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

1. The target compound (I) or a salt thereof is a compound (I[) or a reactive derivative thereof at the amino group or a salt thereof,
It can be produced by reacting with compound (I[I) or a reactive derivative thereof or a salt thereof at the carboxy group.

Suitable reactive derivatives of the amino group of compound (I) include Schiff's base-type imino group or its enamine-type tautomer formed by the reaction of compound (I) with a carbonyl compound such as an aldehyde, a ketone, etc. ; Silyl derivatives produced by the reaction of compound (I[) with silyl compounds such as N, O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide, etc.; reaction of compound (I[) with phosphorus trichloride or phosgene; Examples include derivatives produced by.

Suitable salts of compounds (IF) and (III) include:
Examples include those exemplified for compound (I).

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, such as methanesulfonic acid. , alkanesulfonic acids such as ethanesulfonic acid, sulfuric acid,
Mixed acid anhydrides with acids such as alkyl carbonates, aliphatic carboxylic acids such as pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid or aromatic carboxylic acids such as benzoic acid; symmetrical acid anhydrides activated amides with imidazoles, 4-substituted imidazoles, dimethylpyrazoles, triazoles or tetrazoles;
or for example cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [:(CH3)2N=C
H-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthio ester,
p-nitrophenylthioester, p-talesylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, activated ester of the 8-quinolylthioester moiety, or e.g. N,N-dimethylhydroxylamine, 1-hydroxy- 2-(IH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-
6-chloro-IH-benzotriazole etc. (7) N-
Examples include esters with hydroxy compounds.

These reactive derivatives are arbitrarily selected from among them depending on the type of compound (III) that can be used.

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

When the compound (II [>) is used in the reaction in the form of the free acid or its salt, the reaction is carried out with N, N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclo hexyl
N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide, N,
N'-diisopropylcarbodiimide; N-ethyl-
N'-(3-dimethylaminopropyl)carbodiimide, N,N-carbonylbis(2-methylimidazolentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloro Ethylene; trialkyl phosphite; polyethyl phosphate: isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); trichloride groove; thionyl chloride; oxalyl chloride; 2-ethyl-5-(m-sulfophenyl) isoxazolium hydroxide inner salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-IH-benzotriazole; Preferably, it is carried out in the presence of a conventional condensing agent, such as the so-called Vilsmeier reagent prepared by the reaction of methylformamide with thionyl chloride, phosgene, phosphorus oxychloride, and the like.

The reaction can also be carried out in the presence of inorganic or organic bases such as alkali metal bicarbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N,N-di(lower)alkylbenzylamines, etc. You may go. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or at room temperature.

The target compound (Ib) or a salt thereof is compound (Ia)
Alternatively, it can be produced by subjecting a salt thereof to an elimination reaction of an amine protecting group.

Suitable salts of compounds (Ia> and (Ib)) include those exemplified for compound (I).

The elimination reaction is hydrolysis; reduction, the compound (Ia) in which the protected amine group of R1 is an acylamino group is treated with an iminohalogenating agent and an iminoetherifying agent, and then the product is hydrolyzed as necessary. It can be carried out by conventional methods such as methods. Examples of hydrolysis include methods using acids, bases, hydrazine, and the like. These methods may be selected depending on the type of protecting group to be removed.

In these methods, hydrolysis using acids can be performed, for example, on tertiary pentyloxycarbonyl groups, lower alkanoyl groups such as formyl, acetyl, cycloalfkydicarbonyl groups, substituted or unsubstituted aralkoxycarbonyl groups. Protecting groups such as substituted or unsubstituted alkoxycarbonyl groups, e.g. aralkyl groups such as trityl, substituted phenylthio groups, substituted aralkylidene groups, substituted alkylidene groups, substituted cycloalkylidene groups, etc. is one of the most common and preferred methods for the desorption of

Suitable acids include organic or inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, etc., but the most suitable acids include, for example, formic acid, trifluoroacetic acid, hydrochloric acid, etc. It is an acid that can be easily recovered from the reaction mixture by conventional methods such as vacuum distillation. The acid can be selected depending on the type of protecting group to be removed. When the elimination reaction is carried out with an acid, the reaction can be carried out in the presence or absence of a solvent.

Suitable solvents include water, methylene chloride, alcohols such as methanol, ethanol, tetrahydrofuran or any other organic solvent or mixtures thereof that do not adversely affect the reaction.

Elimination reactions using trifluoroacetic acid may be carried out in the presence of anisole.

Hydrolysis using hydrazine is commonly applied to remove phthaloyl- and succinyl-type amino protecting groups.

Elimination using a base is used to eliminate acyl groups such as trifluoroacetyl groups.

Suitable bases include inorganic bases and organic bases.

Elimination by reduction generally includes, for example, haloalkoxycarbonyl groups such as trichloroethoxycanosyponyl, substituted or unsubstituted aralkoxycarbonyl groups such as benzyloxycarbonyl, 2-pyridyl, etc. Applicable for removing protective groups such as methoxycarbonyl groups. Suitable reduction methods include, for example, reduction with alkali metal borohydrides, such as sodium borohydride; metals such as tin, zinc, iron, and metal salts thereof, such as chromous chloride, chromous acetate, etc. and combinations with organic or inorganic acids such as acetic acid, propionic acid, hydrochloric acid; and catalytic reduction. Suitable catalysts include conventional catalysts such as Raney nickel, platinum oxide, palladium-carbon, and the like.

Among the protecting groups, the acyl group is generally removed by hydrolysis. In particular, halogen-substituted alkoxycarbonyl groups and 8-quinolyloxycarbonyl groups are usually eliminated by treatment with heavy metals such as copper, zinc, and the like.

The acyl group in the protecting group can also be removed by treatment with an iminohalogenating agent such as oxychloride, followed by an iminoetherifying agent such as a lower alkanol such as methanol or ethanol, and optionally hydrolysis. You can also.

The reaction temperature is not particularly limited and may be appropriately selected depending on the type of amino protecting group and the type of the above-mentioned elimination method, and the reaction is usually carried out under mild conditions such as cooling or a slight increase in temperature.

In this reaction, cases where the protected carboxy group of R2 is converted into a free carboxy group during the course of the above-mentioned elimination reaction or during work-up of the reaction mixture or reaction product are also included within its scope.

The method for producing the raw material compound (III) will be explained in detail below.

Production method A Compound (V) or a salt thereof can be produced by oxidizing compound (IV) or a salt thereof.

For suitable salts of compounds (IV) and (V), reference may be made to those exemplified for compound (I).

This oxidation reaction is carried out by a conventional method applied to the conversion of so-called active methylene groups into carbonyl groups. That is,
This oxidation is carried out by conventional methods such as oxidation using selenium dioxide or the like.

This reaction is usually carried out in conventional solvents that do not adversely affect the reaction.

Although the reaction temperature is not particularly limited, the reaction is usually carried out with or without heating.

Production method B Compound (Vl) or a salt thereof can be produced by reacting compound (V) or a salt thereof with hydroxylamine or a salt thereof.

For suitable salts of compound (W), reference may be made to the salts exemplified for compound (I).

Suitable salts of hydroxylamine include, for example, inorganic acid salts such as hydrochloride and hydrobromide.

This reaction is usually carried out in conventional solvents that do not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction is carried out in a temperature range from cooling to heating.

Production method C Compound (III) or a salt thereof can be produced by reacting compound (VI) or a salt thereof with compound (1).

This reaction is usually carried out in the presence of a base.

Suitable bases include inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide.

The reaction is usually carried out in water, an alcohol such as methanol or ethanol, acetonitrile, or a mixture thereof, but the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction.

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

The manufacturing method Compound (DIb) or its salt is Compound (Illa)
Alternatively, it can be produced by subjecting a salt thereof to an elimination reaction of a carboxy protecting group.

Suitable salts of compound (I[[a) include compound (I>
The acid addition salts exemplified above may be mentioned.

For suitable salts of compound (mb), refer to those exemplified for compound (I).

This reaction can be carried out by conventional methods such as hydrolysis, reduction, etc.

When the protecting group is an ester, it can be removed by hydrolysis. Hydrolysis is preferably carried out in the presence of a base or acid. Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydroxides or reconstituted salts or bicarbonates of these metals, trialkyls such as trimethylamine, triethylamine, etc. amine,
Pirin, 1,5-diazabicyclo[4,3,(lconon-5-ene, 1,4-diazabicyclo[2,2゜2]
Inorganic bases and organic bases such as octane, 1,8-diazabicyclo[5,4,0]undecene-7, and the like may be mentioned. Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, and hydrochloric acid,
Examples include inorganic acids such as hydrobromic acid and sulfuric acid.

The reaction is usually carried out in water, alcohols such as methanol and ethanol, dioxane, and mixtures thereof, but the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction. Liquid bases or acids can also be used as solvents.

The reaction temperature is not particularly limited, and the reaction is carried out in a temperature range from cooling to heating.

NycAt4-nitrobenzyl, 2-iodoethyl, 2
．． 2.2-) Reduction methods applicable to the elimination reaction, which are preferably applied to the elimination of protecting groups such as dichloroethyl, include metals such as zinc, zinc amalgam, etc. or chromium chloride, acetic acid, etc. Reduction using a combination of a chromium compound, such as monochromic acid, and an organic or inorganic acid, such as acetic acid, propionic acid, hydrochloric acid; and catalytic reduction methods in the presence of conventional metal catalysts, such as palladium-on-carbon. An example of this is:

Compound (I) and its salts are novel compounds that exhibit high antibacterial activity and inhibit the growth of a wide range of pathogenic bacteria, including gram-positive and gram-negative bacteria, and are useful as antibacterial agents. The compounds of this invention may be used for treatment:
The compound is used in the form of a pharmaceutical preparation containing the compound as an active ingredient in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic isotropic or liquid excipient suitable for oral, parenteral or topical administration. Ru.

Pharmaceutical preparations include capsules, tablets, dragees, ointments or layers,
The formulations, which may be in the form of solutions, suspensions, emulsions, etc., may optionally contain auxiliaries, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives.

Although the dosage of the compound varies depending on the age and condition of the patient, the compound according to the present invention has an average single dose of about 10 m
g, 50mg, 100mg, 250mg, 50
0mg.

1000n+g is effective in treating pathogenic bacterial infections. Generally, amounts ranging from 1 mg to about 6000 mg per day, or even more, may be administered.

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

[1] Trial test stand Nia-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamide]-3-(1-pyridiniomethyl)-3-cephem- 4-carboxilade (syn isomer) [hereinafter compound (
[2] Test method: In vitro antibacterial activity was measured by the following agar plate multiple dilution method.

The test strain was cultured in tryptocase soypros overnight, and one platinum loop (108 viable bacteria/-) was inoculated onto heart infusion agar (II agar) containing the test compound at each concentration level, and incubated at 37°C. After culturing for 20 hours, the minimum inhibitory concentration (MIC) was expressed as (/-).

[3] Test results: Mxc(x/mQ) The present invention will be explained below according to production examples and examples.

Fengxy Selenium dioxide (14.0g) was added to dioxane (500ml
1) Add methyl 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetate (47,5 g) and stir the mixture at 80-82 °C for 4 hours.0 Filter the reaction mixture. , the residue was extracted with dioxane (50mQ''). The solvent of the extract was distilled off, and the residue was extracted with silver nitrate (42,8
Add to the mixture of g) in ethyl acetate (soomu) and stir the mixture for 14 hours at room temperature.Filter the reaction mixture;
The residue is extracted with ethyl acetate. The extract was washed twice with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate.
The mixture was then evaporated to dryness under reduced pressure to obtain methyl 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)glyoxylate (26.2 g).

IR (Streak 1-L): 3200. 1740.
1700. 1580° 1530 Rho 1 1 Sumire ■ 1 To a solution of methyl 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)glyoxylate (22.0 g) in 80% aqueous tetrahydrofuran solution (250-) , add hydroxylamine hydrochloride (3.56 g).

After stirring for 2.5 hours at room temperature, the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution, dried and the solvent is evaporated to give an oil.

The crude oil is subjected to column chromatography using silica gel, eluting with a mixed solvent of ethyl acetate and n-hexane (1:1). Fractions containing the target compound were collected, the solvent was distilled off, and dried in vacuo to give methyl 2-hydroxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetate (synisomer body) (14,
0 g) as a powder.

IR (Suji meeting): 1735. 1580.
1520 cm-'NMR (CDC13,8)'
3.89 (3H1s), 7.20 (15H1s)
OjIi1 2-hydroxyimino-2-(5-triple amino-1
, 2,4-thiadiazol-3-yl) methyl acetate (syn isomer) (0,50 g) and sodium iodide (0,
A mixture of 5 g) in acetonitrile (6,31111) and ethanol (1,3111) was stirred under cooling to 10"C, and chlorodifluoromethane gas was introduced into the mixture at about 5 g.
Infuse for a minute.

4N aqueous sodium hydroxide solution (3,51Q) was divided into three portions and added to the mixture over 30 minutes, and the mixture was stirred at the same temperature for 30 minutes.The reaction mixture was neutralized with 6N hydrochloric acid,
Extract with ethyl acetate. The extract is washed with brine, dried and the solvent is distilled off under reduced pressure. The residue is subjected to column chromatography on silica gel, eluting with methylene chloride. The solvent of the eluate containing the target compound was distilled off under reduced pressure to obtain methyl 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetate (syn isomer). (120 mg) is obtained as a crude oil.

IR (film): 3400-3150. 1
740. 1590. 1580°1520 an-1 NMR (CDC1a, l; ): 3.93 (3H9
s), 6-73 (IH, t, J=70.5Hz), 7
．． 29 (15H, m) 11 2-(5-)Ritylamino-1.2.4-thiadiazol-3-yl)-2-difluoromethoxyiminomethyl acetate (syn isomer) (4,2 g) in ethanol (42 f
IN sodium hydroxide aqueous solution is added to the mixed solvent solution of f1M) and dioxane (4,2 relative) at room temperature. The mixture was warmed to 35-40°C for 2 hours under stirring, cooled and
Acidify to pH 2 with hydrochloric acid and extract with ethyl acetate.

The extract was washed with a saturated aqueous solution of sodium chloride and dried.
The solvent is evaporated under reduced pressure to obtain a crude oil.

The oil is dissolved in diethyl ether (1001111) and saturated aqueous sodium bicarbonate solution (30 mR) is added to it. The mixture is stirred at room temperature for 30 minutes. The generated precipitate was collected by filtration, washed with diethyl ether, and suspended in a mixed solvent (11) of ethyl acetate and tetrahydrofuran,
Acidify to pH 2 with IN hydrochloric acid and extract with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off under reduced pressure.

The residue was triturated with n-hexane and collected by filtration to give 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetic acid (syn isomer).
(1.5 g) is obtained.

mp: 124-127°C (decomposition) IR: 3400-3200.
1720. 1585°1535 cTll-1 NMR (DMSO-da, l; )'? -20(I
Hlt, J=70Hz).

7.30 (15H, s), 10.10 (IH,
s) Next 11 Add 2-(5
-tritylamino-1,2,4-thiadiazole-3-
yl)-2-difluoromethoxyiminoacetic acid (syn isomer) (0,8 g) is added at 0-3°C. The mixture is stirred at the same temperature for 30 minutes to obtain an activated acid solution. 7-Amino-
A solution of 3-(1-pyridiniomethyl)-3-cephem-4-carboxilade dihydrochloride dihydrochloride (0.67 g) and N-trimethylsilylacetamide (4.4 g) in tetrahydrofuran (l0rnQ) was heated at -20°C. Add the activated acid solution obtained above. After stirring at the same temperature for 30 minutes, the mixture was poured into water and extracted with ethyl acetate.

The extract was washed with water, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with diisopropyl ether to give 7-[2-(5-tritylamino-1,2,4-thiadiazole-3). -yl)-2-difluoromethoxyiminoacetamide]-3-(1-pyridiniomethyl)-
3-cephem-4-carboxilade (syn isomer) (
1.25 g).

IR (Stripe 9-L) j 3250. 1780.
1680. 1630°1530 cyn-1 NMR (DMSO-da, δ): 3.30.3.6
7 (2H, ABq.

J=18)1z), 5.17 (IH, d, 5)1
z), 5.63 (2H.

m), 5.90 (LH, dd, J=5Hz, 8H
z), 6.95 (IH.

t, J=72Hz), 6.90-7.50 (15H
, m>, 8.22 (2H.

d, J=8Hz>, 8.63 (IH, dd, J=6
Hz, 8Hz).

9.07 (2H, d, J-6Hz) Fire phoenix grab The following compound is obtained in the same manner as in Example 1.

(1) 7-[2-(5-tritylamino-1,2゜4-
Thiadiazol-3-yl)-2-difluoromethoxyiminoacetamide]-3-(1,3°4-deadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR(, Suji 9-1>: 3200. 1775
．． 1680. 1!530 cm″″INMR(D
MSO-da, l; ): 3.68 (2H, m),
4.22.4-63 (2H, ABq, J=14Hz)
, 5.15 (IH,d,,T=5Hz).

5.83 (IH, dd, C3Hz, 8Hz),
7.17 (ILt.

J=72Hz), 7.22-7.55 (15H,
m), 7.55 (LH,s), 9.80 (I
H, d, J = 8Hz) (2) 7-[2-(5-amino-
1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamide]-3-(1-pyridiniomethyl)-3-cephem-4-carboxilade (
syn isomer).

IR (Suji Meal): 3250. 1770.
1680. 1600°1520 elT+-1 (3) 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamidoco-3-(1,3,4-thiadiazole -2
-yl)thiomethyl-3-cephem-4-carboxylic acid (
syn isomer).

IR (Via-4): 3300. L770
．． 1680. 1620°1530 cll+-1 (4)7-[2-(5-tritylamino-1,2°4-
thiadiazol-3-yl)-2-difluoromethoxyiminoacetamidoco-3-(3-methyl-1,2,4
-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) IR (stin-3-yl): 3200. 1780.
1690. 1530 am-INMR (DMSO
-ds, S) = 2-53 (3H, s), 3.4
7.3-83 (2H, ABq, J=18Hz>, 4.
22.4.65 (2H, ABq.

J=14Hz), 5.13 (IH, d, J=5Hz
>, 5.77 (IH.

dd, J=5)1z, 8Hz), 7.20 (LH
, t, J=72Hz).

7.20-7.50 (15H, m), 9.82 (
IH, d, J = 8Hz).

10.10 (IH, float 5) (5) 7-[2
-(5-amino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamidoco-
3-(3-methyl-1,2,4-thiadiazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) IR (Sujimil): 3300 (Broad), 1770. 1680. 1620°1520
cm-1 (6)7-[2-(5-tritylamino-1,2゜4-
thiadiazol-3-yl)-2-difluoromethoxyiminoacetamide]-3-(1,2゜3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) IR<sudital)' 3
250. 1780. L690. 1530a
m-'N1(R(DMSO-d6.S): 3.4
2.5.75 (2H, AB (1°J=18Hz>,
4.20 (28, Broad s), 5.10
(LH, d.

J:5Hz), 5.73 (IH, dd, J=5Hz
, 8Hz), 7.13 (IH, J near 2Hz),
7.00-7.53 (15H, m), 8.80 (I
H, s), 9.77 (IH, d, J=8Hz),
10.03 (IH, Broad 5) (7) 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamidoco-3-(1,2, 3-thiadiazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid (
syn isomer) IR (X dimyl): 3280. 1770.
1680. 1620°1525 Cm' (8)7-[2-(5-tritylamino-1,2°4-
Thiadiazol-3-yl)-2-difluoromethoxyiminoacetamidoco-3-(1,2゜4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) IR (*di1 -4) 7 32
50. 17g0. 1690. 1530 cm-
'NMR (DMSO-9,8): 3.50.3.
80 (2H, AB (1°J=18Hz), 4.29
．． 4.63 (2H, ABq, J=14Hz).

5.13 (LH, d, J=5Hz>, 5.77 (
IH, dd, J = 5Hz.

8Hz), 7.17 (LH, t, J=72Hz>,
7.10-7.53 (15H, m), 8.70 (
IH, s), 9.83 (IH, d.

J=8Hz), 10.13 (IH, broad
5) (9) 7-[:2-(5-amino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamide]-3-(1,2,4-thiadiazol-5- yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) IR (sudital)? 3250. 1770.
1680. 1620°1520 cm-' (10)7-[2-(5-tritylamino-1,2°4
-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamidoco-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-
triazin-3-yl)thiomethyl-3-cephem-4
-Benzhydryl carboxylate (syn isomer) IR (sudital): 3250. 1780.
1700. 1580°1520 cm-1 Nl(R(DMSO-d6.δ): 3.23
(2)! , broad s), 3.33(3H,s
), 3.58.3.85 (2H, ABq, J=14
Hz＞.

5.22 (IH, d, J=5Hz>, 5.83 (
LH, dd, J = 5Hz.

8Hz), 6.95 (IH, t, J=72Hz),
7.10-7.70 (15H, m), 9.85 (
IH, d, J = 8 Hz), 10.10 (IH, broad 5) (11) 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamide co-3-(4-methyl-5=oxo-6-
Hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) IR (sujimil): 32
50. 1770. 1700. 1620°1525
cm-' (12)7-42-(5-tritylamino-1,2゜4
-thiadibuzol-3-yl)-2-difluoromethoxyiminoacetamide]-3-(3-vinyl-1,2,
4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) IR (stripe 1-x): 3200. 1780.
1690. 1530 am-'NMR (DMSO
-d6. S): 3.67 (2H, Broad S), 4.27゜4.68 (2H, ABq
, J=14)1z), 5.13 (LH,d.

J=5Hz>, 5.83 (2H, m), 6.32
(LH, dd, J=2Hz.

18Hz), 6.82 (IH, dd, J=10Hz
, 18Hz>.

7.00-7.65 (15H, m), 7゜16 (
IH, t, J = 72Hz>.

9.78 (IH, d, J=8Hz>, 10.0
7 (LH, Broad 5) (13) 7-[2-(5
-amino-1,2,4-thiadiazol-3-yl)-
2-difluoromethoxyiminoacetamide,] -3
-(3-vinyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid isomer) IR (Sujol): 3300. 1
770. 1620. 1520 can″″1 (1
4) 7-[2-(5-tritylamino-1,2゜4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamidoco-3-(2,3-dimethy,ru-1-
(pyridiniomethyl)-3-cephem-4-carboxilade (syn isomer) IRCZdia-JL): 3
300. 1780. 1660. 1520 cm
-INMR(DMSO-ds,l; )' 2.40
(3H1s), 2-60 (3H,s), 3.33
(2H, Broad s), 5.13 (IH
,d.

J=5Hz), 5.53.5.77 (2H, ABq
, J=14Hz>.

5.83 (IH, dd, J=5Hz, 8Hz),
7.47 (IH, t.

J=72Hz), 7.15-7.60 (15H, m
), 7.90 (IH.

dd, J=6Hz, 8Hz), 8.40 (LH,
d, J=8Hz).

8.83 (LH, d, J=6Hz), 9.84 (
LH, d, J = 8Hz).

10.13 (IH, Broad 5) (xs) 7-[
-(s-amino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamidoco-
3-(2,3-dimethyl-1-pyridiniomethyl)-3
-Cephem-4-carboxilade (syn isomer) IR (screwtal): 3350 (broad), 1'760. 1660°1600 am-1 Mars ■1 7-[2-(5-tritylamino-1,2,4-deadiazol-3-yl)-2-difluoromethoxyiminoacetamide]-3-(1-pyridiniomethyl)-3 −
Cephem-4-carboxilade (syn isomer) (
1,25 g), concentrated hydrochloric acid (0,45 g) and formic acid (1
3111) is stirred at 3-5° C. for 3 hours. The mixture is concentrated under reduced pressure and the residue is dissolved in water. 5 aqueous solution
% sodium bicarbonate aqueous solution to pua and o! It is,
The column is subjected to column chromatography using a nonionic adsorption resin R Diaion HP-20 (trademark: manufactured by Mitsubishi Chemical Industries, Ltd.). After washing the column with water, the column is eluted with a 30% methanol aqueous solution. The eluate was concentrated under reduced pressure and lyophilized to give 7-
[2-(5-amino-1,2,4-thiadiazole-3
-yl)-2-difluoromethoxyiminoacetamide]-3-(1-pyridiniomethyl)-3-cephem-4
- Carboxilald (syn isomer) (0.35 g) is obtained.

IR (suji rule): 3250. 1770.
1680. 1600°1520 cm-1 NMR (D20-NaHCO3,S)' 3.16
．． 3.155 (2H1ABq.

J=18Hz), 5.27 (LH,d, J=5Hz
), 5.32.5.56 (2H, ABq, J: 14H
z), 5.86 (IH, d, J=5Hz).

6.94 (IH, t, J near 2Hz), 8.05
(2H, dd, J=6Hz.

8Hz), 8.54 (LH, dd, J=6Hz,
8Hz), 8.92 (zn, a, J=auz) 1 7-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamidoco -3-(1,3,4-thiadiazole-
A mixture of 2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (o, 7g), salt preparation # (0,23g) and formic acid (7ml) (7) was stirred at 3-5°C for 3 hours. do. The mixture is concentrated under reduced pressure and the residue is dissolved in water. The aqueous solution was adjusted to pH 7 with 5% sodium hydrogen suboxide aqueous solution.
After washing with ethyl acetate, adjust the pH to 2 with 10% hydrochloric acid.
,5. The precipitate was collected by filtration, washed with water, and dried to give 7-[
2-(5-amino-1,2,4-thiadiazole-3-
yl)-2-difluoromethoxyiminoacetamide]
-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
(0.24 g) is obtained.

IR: 3300. 1770.
1680. 1620°1530 country-1 NMR (DMSO-d6.8): 3.53.3.
80 (2H, ABq.

J=18Hz), 4.24.4.57 (2H, AB
q, J=14Hz>.

5.14 (IH, d, J=5Hz>, 5.80 (
IH, dd, J = 5Hz.

8Hz), 7.17 (IH, t, J=72Hz),
8.20 (21° broad s), 9.51
(IH, s), 9.82 (IH, d, J=8
Hz) Cover 1 The following compound is obtained in the same manner as in Examples 3 and 4.

(1) 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamidoco-3-(3-methyl-1.2.4-thiadiazol-5- yl)thiomethyl-3-cephem-4-
Carboxylic acid isomer) IR (sudisil):
3300 (Broad), 1770. 168
0. 1620°1520 cm-' NMR (DMSO-d6.ε) + 2.53 (3H
,s), 3.46.3.76(2H, ABq, J=1
8Hz), 4.25.4.62 (2H, ABq.

J=14Hz), 5.13 (IH, d, J=5Hz
), 5.78 (IH.

dd, J=5Hz, 8Hz), 7.16 (IH
, t, J=72Hz>.

8.21 (21, Broad S), 9.80
(IH, d, J=8Hz) (2) 7-(2-(5-amino-1,2,4-thiadiazol-3-yl)-2-
difluoromethoxyiminoacetamide]-3-(1,
2,3-thiadiazol-5-yl)thiomethyl-3-
Cephem-4-carboxylic acid (syn isomer) IR (Nugir)? 3280. 177G,
1680. 1820°15253=NMR (DMSO-d6.S”): 3.48.
3.75 (2H, ABq.

J=18Hz), 4.25 (21, broad
s), 5.16 (IH, d.

J=5Hz>, 5.80 (18,dd, J=5Hz
, 8Hz), 7.17 (LH, t, J=72Hz)
, 8.21 (2H, broad s), 8.
85 (IH, s), 9.83 (11, d, J-8H
z) (3)? -[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-difluoromethoxyiminoacetamide]-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem -4-Carboxylic acid (syn isomer) IR (sudital): 3250. 1770.
1680. 1620°1520 cll-1 NMR (DMSO-d6.δ): 3.50.3.7
8 (20, ABq.

J=18Hz), 4.27.4.60 (2H, AB
q, J=14Hz>.

5.15 (IH, d, J=5Hz), 5.80 (
IH, dd, J = 5Hz.

8Hz>, 7.17 (IH,t,]=72Hz),
8.20 (2H.

Broad s), 8.68 (111, s),
9.83 (IH, d, J=8Hz) (4) 7-[
2-(5-amino-1,2,4-thiadiazole-3-
yl)-2-difluoromethoxyiminoacetamide]
-3-(4-methyl-5-year-old xo-6-hydroxy-4
,5-dihydro-1,2,4-triazin-3-yl)
Thiomesol-3-cephem-4-carboxylic acid (syn isomer) XR (shr) + 3250. 1770
．． "1700. 1620°1525■-1 NMR (DMSO-d6.δ): 3.30 (3H
, s), 3.53.3.77 (2H, ABq, J=1
8Hz>, 3.97. 4.18 (2H, ABq
.

J: 14Hz>, 5.15 (IH, d, J=5H
z), 5.73 (IH.

dd, J=5Hz, 8Hz), 7.20 (IH,
tJ=72Hz).

8.22 (2H, broad s), 9.85
(IH, d, J=8Hz) (5) 7-[2-(5-amino-1,2,4-thiadiazol,-3-yl)-2
-difluoromethoxyiminoacetamide]-3-(3
-vinyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) IR (sudital): 330G, 1770
．． 1620. 1520 Cr11″″INMR(
DMSOds,S)' 3.52.3-83
(2H9ABq.

J=18Hz), 4.32.4.68 (2H, AB
q, J=14Hz).

5.19 (IH, d, J=5Hz), 5.85 (
2H, m), 6.37 (IH, dd, J=2Hz,
18Hz), 6.83 (IH, dd.

J=10.5Hz, 18Hz), 7.22 (1)
r, t, J=72Hz>.

8.25 (2H, broad s), 9.85
(IH, d, J=8Hz) (6) 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-
Difluoromethoxyiminoacetamide co-3-(2,
3-Dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylade (syn isomer) IR (syn 3-l'): 3350 (Broad), 1760. Taso.

1600-1 NMR (D20-NaHCO3, δ): 2.50
(3H, s), 2.71 (3H, s), 3.13.
3.43 (2H, ABq, J=14Hz>.

5.25 (IH, d, J=5Hz), 5.32.5
．． 60 (2H, ABq.

J=14Hz), 5.87 (IH, d, J=5Hz
), 6.97 (IH, t.

Claims (1)

[Claims] 1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is an amino group or a protected amino group, R^2 is a carboxy group, -COO^■ or protected carboxy group, R^3 is a heterocyclic thiomethyl group optionally substituted with an appropriate substituent or a pyridiniomethyl group optionally substituted with an appropriate substituent, X^1 is halogen, X^2 is Novel cefem compounds and salts thereof represented by halogen (respectively meaning halogen). 2) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is an amino group or a protected amino group, W is a carboxy group or a protected carboxy group, X^1 is a halogen, ^2 means halogen) and its salts.