DE2935232A1 - 3,7-DISUBSTITUTED-3-CEPHEM-4-CARBONIC ACID COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THE SAME - Google Patents

Description

The invention relates to new 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and their salts, in particular their pharmaceutically acceptable salts, especially those which have antibacterial activities (efficacies), processes for their preparation, pharmaceutical agents containing them and their therapeutic use for the treatment of infectious diseases in humans and animals.

The invention relates to 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and their salts, in particular their pharmaceutically acceptable salts, which are highly active against a number of pathogenic bacteria.

The invention also relates to processes for the preparation of these 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and their salts, in particular their pharmaceutically acceptable salts.

The invention also relates to pharmaceutical agents which contain as active ingredient (s) at least one of the 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and / or their pharmaceutically acceptable salts.

Finally, the subject matter of the invention is the use of the abovementioned compounds or pharmaceutical agents containing them for the treatment of infectious diseases caused by pathogenic bacteria in humans and animals.

The 3,7-disubstituted-3-cephem-4-carboxylic acid compounds which are an object of the invention are new and they can be represented by the general formula:

(I)

where mean:

R [high] 1 amino or protected amino,

R [high] 2 is an aliphatic hydrocarbon group with one or more suitable substituents,

R [high] 3 carboxy or protected carboxy and

R [high] 4 is hydrogen, acyloxy or a heterocyclic thio group which may have lower alkyl, with the proviso that R [high] 2 is not carboxy (lower) alkyl, protected carboxy (lower) alkyl or benzyl when R [high] ] 4 is acetoxy, and when R [high] 4 is tetrazolylthio with a methyl group, R [high] 2 does not represent benzyl.

The novel compounds of the general formula (I) given above can be prepared by processes 1 to 4 given below.

Procedure 1

(II)

or its reactive derivative at the amino group or a salt thereof

+

(III)

or its reactive derivative on the carboxy group or a salt thereof

(I)

or a salt thereof

Procedure 2

(Ia)

or a salt thereof

(Ib)

or a salt thereof

Procedure 3

(Ic)

or a salt thereof

(Id)

or a salt thereof

Procedure 4

(Ia)

or a salt thereof

+

(XVIII)

or its reactive derivative on the mercapto group

(If)

or a salt thereof

wherein R [high] 1, R [high] 2, R [high] 3 and R [high] 4 each have the meanings given above,

R [high] 1a protected amino,

R [high] 2a protected carboxy (lower) alkyl,

R [high] 2b carboxy (lower) alkyl and

X 'denotes a group which can be substituted by a radical of the formula R [high] 4'-S-, wherein R [high] 4 'represents a heterocyclic group which may have a lower alkyl,

R [high] 4 'has the meaning given above,

R [high] 4a is hydrogen, carbamoyloxy or a heterocyclic thio group which may have lower alkyl,

provided that R [high] 2 is not benzyl when R [high] 4 'is tetrazolyl with a methyl group.

Among the starting compounds, the compounds of the formula (III) are new and they can be prepared by processes which are illustrated by the following reaction scheme:

(1)

(2)

(3) wherein R [high] 1, R [high] 1a and R [high] 2 each have the meanings given above,

Z protected carboxy and

Y signify halogen.

Some of the other starting compounds (II) are also new and they can be prepared by the methods which are explained below:

wherein R [high] 3 has the meanings given above,

Y 'an acid residue,

R [high] 5 lower alkyl,

R [high] 6 is a group represented by a radical of the formula can be substituted, and

X represent an alkali metal.

With regard to the compounds according to the invention of the formulas (I), (Ib), (Id) and (If) and the starting compounds of the formulas (Ia), (Ic), (Ie), (III), (IIIa), (IIIa ') , (IIIb), (VII), (VIIII) and (X) to (XII) it should be noted that these compounds and starting compounds according to the invention also include the tautomeric isomers with regard to their thiazole groups. That is, if the group of the formula

(wherein R [high] 1 has the meanings given above) in the formula for the compounds and starting compounds according to the invention has the form

(wherein R [high] 1 is as defined above), this group of the formula alternatively also through their tautomeric form

(where R [high] 1b is imino or protected imino)

being represented. This means that the two groups (A) and (B) exist as so-called tautomeric forms in the equilibrium state, which can be represented by the following equation:

(wherein R [high] 1 and R [high] 1b each have the meanings given above).

These types of tautomerism between 2-aminothiazole compounds and 2-iminothiazoline compounds, as indicated above, are known per se in the literature and it is readily apparent to the person skilled in the art that both tautomeric isomers are in the equilibrium state and are easily mutually convertible into one another and that accordingly these isomers are also within the scope of the present invention, ie belong to the compound itself. Both tautomeric forms of the compounds according to the invention and of the starting compounds are clearly encompassed by the present invention. If the compounds according to the invention and the starting compounds which contain the group with these tautomeric isomers are represented here using one of the expressions suitable for this, ie in the form

(A)

so only for the sake of convenience.

In addition, with regard to the compounds (I), (Ib), (Id) and (If) according to the invention and the starting compounds (Ia), (Ic), (Ie), (III), (IIIa), (IIIa '), ( IIIb), (IV) to (VII) and (X) to (XII) that these compounds and starting compounds according to the invention also include the respective syn isomers, anti isomers and mixtures thereof. For example, in the compound (I) according to the invention, the syn isomer can be obtained through the partial structure of the formula are represented in their molecule, while the corresponding anti-isomer is represented by the partial structure of the formula can be represented in its molecule and if it is expedient for the explanation of the present invention to express both the syn-isomer and the anti-isomer by a general formula, this is represented by the partial structure of the formula

With regard to the other compounds according to the invention and starting compounds, as mentioned above, the syn isomers and anti isomers can also be based on the same geometric isomers as are shown for the compound (I).

Suitable salts, in particular pharmaceutically acceptable salts of the 3,7-disubstituted-3-cephem-4-carboxylic acid compounds (I) according to the invention are conventional salts, in particular conventional non-toxic salts and these may include an inorganic salt, for example a metal salt, such as an alkali metal salt (e.g. sodium salt, potassium salt and the like) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt and the like), the ammonium salt and the like, an organic salt such as an organic amine salt (e.g. trimethylamine salt, triethylamine salt, ethanolamine salt, diethanolamine salt, pyridine salt, Picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt and the like) and the like, an organic acid salt (e.g. an acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate and the like), an inorganic acid salt (e.g. a hydrochloride, hydrobromide) Sulfate, phosphate, etc.) or a salt with an amino acid (such as arginine, aspartic acid, glutamic acid, etc.) and the like.

The various definitions as used here are explained in more detail below and suitable examples are given.

The term "lower" or "low" as used here, unless otherwise specified, stands for a group having 1 to 6 carbon atoms.

Suitable protected amino may include an acylamino group and an amino group substituted by a conventional protecting group other than the acyl group, such as ar (lower) alkyl (such as benzyl, trityl, and the like) or the like.

Suitable protected imino may include an acylimino group and an imino group substituted by a conventional protecting group other than the acyl group, such as ar (lower) alkyl (such as benzyl, trityl, and the like) and the like.

Suitable acyl radical in the terms "acylamino", "acylimino" and "acyloxy" may include carbamoyl, an aliphatic acyl group and an acyl group containing an aromatic or heterocyclic ring. Suitable examples of the acyl can be lower alkanoyl (such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, hexanoyl and the like), preferably one with 1 to 4 carbon atoms, in particular one with 1 to 2 carbon atoms; lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl and the like);

lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, and the like);

Arenesulfonyl (e.g. benzenesulfonyl, tosyl and the like),

Aroyl (e.g. benzoyl, toluoyl, naphthoyl, phthaloyl, indanecarbonyl, and the like);

Ar (lower) alkanoyl (such as phenylacetyl, phenylpropionyl, and the like);

Ar (lower) alkoxycarbonyl (such as benzyloxycarbonyl, phenethyloxycarbonyl and the like); and the like

The above The acyl radical can have 1 to 3 suitable substituents, such as halogen (such as chlorine, bromine, iodine or fluorine),

Hydroxy, cyano, nitro, lower alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy and the like), lower alkyl (such as methyl, ethyl, propyl, isopropyl, butyl and the like), lower alkenyl (such as vinyl, allyl and the like). ), Aryl (such as phenyl, tolyl, etc.) or the like.

A preferred example of acylamino can be lower alkanoylamino or mono-, di- or trihalo (lower) alkanoylamino and a preferred example of acyloxy can be lower alkanoyloxy or carbamoyloxy.

The aliphatic hydrocarbon group is a straight chain (unbranched), branched or cyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms, and it may include lower alkyl, cyclo (lower) alkyl, lower alkenyl, lower alkynyl and the like to 2 suitable substituents, such as carboxy, protected carboxy, arylthio, lower alkylthio, aryl, acyloxy, lower alkoxy, aryloxy, a heterocyclic group or the like.

Suitable lower alkyl and a lower alkyl radical in the terms "lower alkylthio", "carboxy (lower) alkyl" and "protected carboxy (lower) alkyl" may include those which may be branched, such as methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like, whereby lower alkyl can preferably be one with 1 to 4 carbon atoms, in particular one with 1 to 2 carbon atoms.

Suitable cyclo (lower) alkyl is one having 3 to 6 carbon atoms and it can include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

Suitable lower alkenyl is one having 2 to 6 carbon atoms and it may include, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl, and the like.

Suitable lower alkynyl is one having 2 to 6 carbon atoms and it can include ethynyl, 2-propynyl, 2-butynyl, 3-pentenyl, 3-hexynyl, and the like.

Suitable protected carboxy and a protected carboxy radical in the term "protected carboxy (lower) alkyl" can include esterified carboxy in which the ester radical can be, for example, a lower alkyl ester (such as methyl, ethyl, propyl, isopropyl, butyl , Isobutyl, t-butyl, pentyl, t-pentyl, hexyl, 1-cyclopropylethyl ester and the like.), Wherein the lower alkyl radical can preferably be one with 1 to 4 carbon atoms; a lower alkenyl ester (such as vinyl, allyl and the like); a lower alkynyl ester (such as ethynyl, propynyl, and the like); a mono- or di- or tri-halogen (lower) alkyl ester (such as 2-iodoethyl ester, 2,2,2-trichloroethyl ester and the like.); a lower alkanoyloxy (lower) alkyl ester (such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl, 2-acetoxyethyl, 2-propionyloxyethyl ester and the like); a lower alkanesulfonyl (lower) alkyl ester (such as mesylmethyl, 2-mesylethyl ester and the like.);

an ar (lower) alkyl ester (such as phenyl (lower) alkyl ester), which can have one or more suitable substituents (such as benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, diphenylmethyl, bis (methoxyphenyl) methyl, 3,4-dimethoxybenzyl, 4- Hydroxy-3,5-di-tert-butylbenzyl ester and the like); an aryl ester which may have one or more suitable substituents (such as a phenyl, tolyl, tert-butylphenyl, xylyl, mesityl, cumenyl ester, and the like); and the like.

Preferred examples of protected carboxy can be lower alkoxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, and the like) having 2 to 7 carbon atoms, preferably 2 to 5 carbon atoms.

Suitable aryl and a suitable aryl radical in the terms "arylthio" and "aryloxy" can include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl and the like, where the aryl group can have 1 to 3 suitable substituents, such as halogen (such as chlorine , Bromine, iodine or fluorine), hydroxy, amino (lower) alkyl (such as aminomethyl, aminoethyl, aminopropyl, aminobutyl and the like.), Protected amino (lower) alkyl, in which the protected amino is as defined above, preferably lower alkoxycarbonylamino (lower ) alkyl (such as methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, t-butoxycarbonylaminomethyl and the like) or the like.

Suitable lower alkoxy may include one which may be branched, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy,

Hexyloxy and the like, and it may preferably include one having 1 to 4 carbon atoms, particularly one having 1 to 2 carbon atoms.

A suitable heterocyclic group and a suitable heterocyclic radical in the expression "a heterocyclic thio group which may have lower alkyl" is to be understood as meaning a saturated or unsaturated, monocyclic or polycyclic heterocyclic group which has at least one heteroatom, such as an oxygen or sulfur -, nitrogen atom and the like. Contains. A particularly preferred heterocyclic group may be a heterocyclic group such as an unsaturated 3 to 8-membered (preferably 5- to 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atoms such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (such as 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and the like), tetrazolyl ( such as 1H-tetrazolyl or 2H-tetrazolyl) and the like;

a saturated 3- to 8-membered (preferably 5- to 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atoms such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, and the like;

an unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl and the like;

an unsaturated 3 to 8-membered (preferably 5- to 6-membered) heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl

(such as 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, and the like) and the like;

a saturated 3- to 8-membered (preferably 5- to 6-membered) heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as morpholinyl and the like;

an unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as benzoxazolyl, benzoxadiazolyl and the like;

an unsaturated 3- to 8-membered (preferably 5- to 6-membered) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl (such as 1,2,4-thiadiazolyl, 1,3 , 4-thiadiazolyl, 1,2,5-thiadiazolyl and the like) and the like;

a saturated 3- to 8-membered (preferably 5- to 6-membered) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as thiazolidinyl and the like;

an unsaturated 3 to 8-membered (preferably 5 to 6-membered) heteromonocyclic group containing a sulfur atom such as thienyl and the like;

an unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as benzothiazolyl, benzothiadiazolyl and the like;

wherein the heterocyclic group may have 1 to 2 lower alkyl substituents (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, and the like).

Suitable halogen can include chlorine, bromine, fluorine and iodine.

Suitable acid residue may include the above halogen, lower alkanesulfonyloxy (such as mesyloxy, ethanesulfonyloxy and the like), arenesulfonyloxy (such as benzenesulfonyloxy, p-toluenesulfonyloxy and the like) and the like.

A suitable group represented by a group of the formula may be substituted, may include azido, the above halogen, acyloxy, and the like.

Suitable alkali metal can include sodium, potassium, and the like.

A suitable radical X 'can include azido, the above-mentioned halogen, acyloxy and the like.

Among the suitable examples of each of the groups of the compounds of the invention as illustrated above, preferred examples are the following:

a preferred example of R [high] 1 may be amino or acylamino (especially lower alkanoylamino or halogen (lower) alkanoylamino);

a preferred example of R [high] 2 may be lower alkylthio (lower) alkyl, lower alkoxy (lower) alkyl, ar (lower) alkyl (especially phenyl (lower) alkyl), which may include halogen, hydroxy, amino (lower) alkyl or acylamino (lower) alkyl, ar (lower) alkenyl (especially phenyl (lower) alkenyl), acyloxy (lower) alkyl (especially lower alkanoyloxy (lower) alkyl), carboxy (lower) alkyl, protected carboxy (lower) alkyl ( especially lower alkoxycarbonyl (lower) alkyl) or

Isoxazolyl (lower) alkyl;

a preferred example of R [high] 3 can be carboxy;

and a preferred example of R [high] 4 may be hydrogen, acyloxy (especially carbamoyloxy or lower alkanoyloxy), tetrazolylthio, which may include lower alkyl, thiadiazolylthio, or tetrazolopyridazinylthio, provided that R [high] 2 is not carboxy (lower) is alkyl, protected carboxy (lower) alkyl or benzyl, when R [high] 4 is acetoxy and that R [high] 2 is not benzyl, when R [high] 4 is tetrazolylthio with a methyl group.

The processes for preparing the compounds according to the invention are explained in more detail below.

Procedure 1

The compound (I) of the present invention or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group or a salt thereof.

Suitable reactive derivatives at the amino group of the compound (II) may include the Schiff base type imino isomer or its tautomeric enamine type formed by reacting the compound (II) with a carbonyl compound such as acetoacetic acid or the like, a silyl derivative by reacting the compound (II) with a silyl compound such as trimethylsilylacetamide, bis (trimethylsilyl) acetamide or the like; a derivative formed by reacting the compound (II) with phosphorus trichloride or phosgene, and the like.

Suitable salts of the compounds (II) and (III) may include an acid addition salt such as an organic acid salt (such as an acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, and the like) or an inorganic acid salt (such as a hydrochloride, hydrobromide, sulfate , Phosphate and the like); a metal salt (such as a sodium, potassium, calcium, magnesium salt, and the like); the ammonium salt; an organic amine salt (such as a triethylamine, dicyclohexylamine salt, etc.) and the like.

Suitable reactive derivatives on the carboxy group of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester and the like.

A suitable example may be an acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid and the like), dialkylphosphorous acid, sulphurous acid, thiosulfuric acid, sulfuric acid, alkylcarboxylic acid such as pentanoic acid, an aliphatic acid 2-ethylbutyric acid or trichloroacetic acid and the like) or an aromatic carboxylic acid (such as benzoic acid and the like); a symmetrical acid anhydride, an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g. a cyanomethyl, methoxymethyl, dimethyliminomethyl

Vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, mesylphenyl, phenylazophenyl, phenylthio, p-nitrophenylthio, p-cresylthio, carboxymethylthio, pyranyl, pyridyl -, piperidyl, 8-quinolyl thioester and the like) or an ester with an N-hydroxy compound (such as N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) pyridone,

N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole and the like) and the like. These reactive derivatives can be arbitrarily selected from them depending on the kind of the compound (III) used.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent that does not adversely affect the reaction, carried out. These conventional solvents can also be used in the form of a mixture.

When the compound (III) is used in the form of the free acid or in the form of its salt in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '- (4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide; N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide; N, N-carbonylbis (2-methylimidazole); Pentamethylene ketene-N-cyclohexylimine; Diphenylketene-N-cyclohexylimine; Ethoxyacetylene; 1-alkoxy-1-chloroethylene; Trialkyl phosphite; Ethyl polyphosphate; Isopropyl polyphosphate; Phosphorus oxychloride; Phosphorus trichloride; Thionyl chloride; Oxalyl chloride; Triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide intramolecular salt; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; the so-called Vilsmeier reagent, manufactured by

Reaction of dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride and the like; or the like.

The reaction can also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, a tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine or the like. The reaction temperature is not critical and the reaction is usually carried out with cooling or at ambient temperature.

In the reaction according to the invention, a syn isomer of the compound (I) according to the invention can preferably be obtained if the reaction of the compound (II) with the corresponding syn isomer of the starting compound (III) is carried out, for example in the presence of a Vilsmeier reagent, as mentioned above , and the like. and under approximately neutral conditions.

Procedure 2

The compound (Ib) of the present invention or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to an elimination reaction to remove the amino-protective group.

To suitable salts of the compound
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can include a metal salt, the ammonium salt,
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Amine salt and the like. As stated above.

The elimination reaction of the present invention is carried out using a conventional method such as hydrolysis, reduction, a method by reacting the compound (Ia) in which the protective group is an acyl group with an imino halogenating agent and then reacting with an imino etherifying agent and, if necessary, carrying out hydrolysis with the compound obtained in this way; or the like

The hydrolysis may include a method using an acid or a base or hydrazine and the like. These methods can be selected depending on the kinds of protective groups to be eliminated.

Among these methods, hydrolysis, which is carried out using an acid, is one of the usual and preferred methods for eliminating protecting groups such as substituted or unsubstituted alkoxycarbonyl (such as t-butoxycarbonyl, t-pentyloxycarbonyl and the like), alkanoyl (e.g. formyl , Acetyl and the like), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (such as benzyloxycarbonyl, substituted benzyloxycarbonyl and the like), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene or the like.

Suitable acids may include an inorganic or inorganic acid, e.g., formic acid, trifluoroacetic acid, benzenesulfonic acid, p -toluenesulfonic acid, hydrochloric acid, and the like, and a preferred acid is one based on conventional such as formic acid, trifluoroacetic acid, hydrochloric acid and the like. The acid suitable for the reaction can be selected depending on the kind of the protecting group to be eliminated. When the elimination reaction is carried out with an acid, it can be carried out in the presence or absence of a solvent. Suitable solvents can include an organic solvent, water, or a mixed solvent thereof. When trifluoroacetic acid is used, the elimination reaction can preferably be carried out in the presence of anisole.

The hydrolysis carried out using hydrazine is usually used to eliminate protecting groups such as succinyl or phthaloyl.

The hydrolysis with a base is preferably used for eliminating acyl groups such as haloalkanoyl (such as trifluoroacetyl and the like) and the like. Suitable base may include an inorganic base or an organic base. The hydrolysis, which is carried out using a base, is often carried out in water or in a hydrophilic organic solvent or in a mixed solvent thereof. A preferred base can be an alkali metal acetate.

Among the protecting groups, the acyl group can generally be eliminated by hydrolysis as mentioned above or by using other conventional hydrolysis. If the

If the acyl group is halogen-substituted alkoxycarbonyl or 8-quinolyloxycarbonyl, it can be eliminated by treatment with a heavy metal such as copper, zinc or the like.

The reductive elimination is generally used for eliminating protective groups such as haloalkoxycarbonyl (such as trichloroethoxycarbonyl and the like), substituted or unsubstituted aralkoxycarbonyl (such as benzyloxycarbonyl, substituted benzyloxycarbonyl and the like), 2-pyridylmethoxycarbonyl and the like reduction with an alkali metal borohydride (such as sodium borohydride and the like) and the like.

Among the protecting groups, the acyl group can be eliminated by treatment with an imino halogenating agent (such as phosphorus oxychloride, phosphorus pentachloride and the like) and an imino etherifying agent such as lower alkanol (e.g. methanol, ethanol and the like), if necessary, followed by hydrolysis.

The reaction temperature is not critical and it can be suitably selected depending on the type of amino-protecting group and the elimination method used, as described above, and the reaction of the invention is preferably carried out under mild conditions, for example under cooling, at ambient temperature or at slightly elevated temperature carried out.

The present invention also includes the cases in which protected carboxy in the free carboxy group and protected

Amino (lower) alkyl, which is the substituent on ar (lower) alkyl for R [high] 2, is converted into amino (lower) alkyl, depending on the reaction conditions, in the course of the reaction or in the aftertreatment.

Procedure 3

The compound (Id) of the present invention or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to an elimination reaction to remove the carboxy protective group. Suitable salts of the compound (Ic) include those as exemplified above for the compound (Ia).

The elimination reaction of the present invention is carried out using a conventional method such as hydrolysis or the like. The hydrolysis may include a method using an acid or a base, and the like. These methods can be selected depending on the kinds of protective groups to be eliminated.

The hydrolysis, which is carried out using an acid, is one of the most common and preferred methods for eliminating protecting groups such as phenyl (lower) alkyl, substituted phenyl (lower) alkyl, lower alkyl, substituted lower alkyl or the like. A suitable acid may include an inorganic or organic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like. The reaction of the present invention can be carried out in the presence of anisole. The for the

Acid suitable for the reaction can be selected depending on the protecting group to be eliminated and depending on other factors.

The hydrolysis, which is carried out using an acid, can be carried out in the presence of a solvent such as an organic solvent, water or a mixed solvent thereof.

The reaction temperature is not critical and can be appropriately selected depending on the kind of the protecting group and the elimination method employed, and the reaction of the present invention is preferably carried out under mild conditions such as cooling, ambient temperature or gentle heating.

The present invention also includes the cases in which the protected carboxy group for R [high] 3 is converted into the free carboxy group and the protected amino group is converted into the free amino group during the reaction or post-treatment in the reaction according to the invention.

Procedure 4

The compound (If) of the present invention or a salt thereof can be prepared by reacting the compound (Ie) or a salt thereof with the compound (XVIII) or its reactive derivative at the mercapto group. Suitable salts for the compound (Ie) include those exemplified above for the compound (II). To suitable reactive derivatives on the mercapto group of the compound (XVIII) may include a metal salt such as an alkali metal salt (such as a sodium, potassium salt, and the like) or the like.

The reaction according to the invention can be carried out in a solvent such as water, in a phosphate buffer, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide or in any other organic solvent which does not adversely affect the reaction, preferably in those with strong polarities. Among the solvents, the hydrophilic solvents can be used in admixture with water. The reaction is preferably carried out in an approximately neutral medium. When the compound (Ie) or the compound (XVIII) is used in a free form, the reaction is preferably carried out in the presence of a base such as an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an organic base such as a trialkylamine and the like. The reaction temperature is not critical and the reaction is usually carried out at ambient temperature, with warming or with gentle heating.

The reaction according to the invention also includes the case that protected amino for R [high] 1 is converted into free amino, depending on the type of protective group and / or the reaction conditions used.

The reaction of the compound (VIII) with the compound (IX) is usually carried out in a solvent such as water, alcohol, a mixture thereof or the like. Performed. The reaction temperature is not critical and the reaction is usually carried out with cooling to heating.

The processes for preparing the starting compound (IIa) are explained in more detail below.

1.) The compound (XIII) or its salt can be prepared by reacting hexylamine with carbon disulfide in the presence of a strong base.

Suitable strong base may include an inorganic base or an organic base such as an alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide, and the like), an alkali metal alkoxide (such as sodium methylate, sodium ethylate, potassium methylate, and the like), an alkali metal hydride (such as sodium hydride, and the like). ) or the like.

The reaction of the present invention is usually carried out in a solvent such as water or in any other solvent which does not adversely affect the reaction, and usually it is carried out under cooling or at ambient temperature.

2.) The compound (XV) can be prepared by reacting the compound (XIII) or its salt with the compound (XIV).

The reaction according to the invention is usually carried out in a solvent such as water or in any other solvent which does not adversely affect the reaction it is usually carried out under cooling or at ambient temperature.

3.) 1-Hexyl-1H-tetrazole-5-thiol or a salt thereof can be prepared by reacting the compound (XV) with the compound (XVI).

The reaction of the present invention is usually carried out in a solvent such as an alcohol (e.g. methanol, ethanol and the like), an aqueous alcohol or any other solvent which does not adversely affect the reaction, and preferably it is carried out with warming or heating.

4.) The compound (IIa) or a salt thereof can be prepared by reacting 1-hexyl-1H-tetrazole-5-thiol or a salt thereof with the compound (XVII) or a salt thereof. Suitable salts of the compound (XVII) include those as exemplified above for the compound (Ia). Suitable salt of 1-hexyl-1H-tetrazole-5-thiol may include a metal salt such as an alkali metal salt (such as a sodium, potassium salt, and the like) or the like.

The reaction according to the invention can be carried out in a solvent such as water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide, in a buffer solution or in any other solvent which does not adversely affect the reaction, preferably in those with strong polarities. Among the solvents can the hydrophilic solvents are used in admixture with water. The reaction is preferably carried out under weakly basic or approximately neutral conditions. When the compound (XVII) and / or 1-hexyl-1H-tetrazole-5-thiol is (are) used in free form, the reaction is preferably carried out in the presence of a base, for example an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an organic base such as a trialkylamine, pyridine, and the like. The reaction temperature is not critical and the reaction is usually carried out at ambient temperature or with heating. The reaction product can be isolated from the reaction mixture by conventional methods.

In the above-mentioned reactions and / or in the aftertreatment of the reactions according to the invention, the above-mentioned tautomeric isomers can occasionally be converted into the other tautomeric isomers and such a case also falls within the scope of the present invention.

When the compound (I) of the invention is obtained in the form of the free acid at the 4-position and / or when the compound (I) of the invention has a free amino group, it can be converted into a salt, particularly a pharmaceutically acceptable one, using a conventional method Salt thereof, as indicated above, can be transferred.

The compound (I) according to the invention and its salts, in particular their pharmaceutically acceptable salts are all new compounds which have a high antibacterial activity (effectiveness), inhibit the growth of a wide variety of pathogenic microorganisms, including gram-positive and gram-negative bacteria, and are valuable antibacterial agents.

In order to demonstrate the usefulness of the compound (I) according to the invention with the aid of a few representative compounds according to the invention, some test data relating to the in vitro antibacterial activity are given below.

Test connections

1.) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

2.) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

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

In vitro antibacterial activity

Test procedure

In vitro antibacterial activity was determined using the two-fold agar plate dilution procedure described below.

An eyelet filling of an overnight culture of each test strain in trypticase soy broth (10 [high] 8 viable cells per ml) was streaked on a heart infusion agar (HI agar) containing graduated concentrations of the test compounds and the minimum inhibitory concentration (MIC) was applied. , expressed in µg / ml, determined after incubation at 37 ° C for 20 hours.

Test results

Test bacteria MIC (µg / ml)

Test connections

(1) (2) (3)

Staph.aureus 6 1.56 0.78 0.78

Staph.aureus 32 1.56 0.78 1.56

For therapeutic administration, the compound (I) according to the invention or its pharmaceutically acceptable salts are used in the form of a conventional pharmaceutical preparation which contains this compound as an active ingredient (active ingredient), optionally in admixture with pharmaceutically acceptable carriers, such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration. The pharmaceutical preparations can be in solid form, e.g. in the form of capsules, tablets, coated tablets, salts or suppositories, or in liquid form for injection, e.g. in the form of solutions, suspensions or emulsions. If necessary, auxiliary substances,

Stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives can be incorporated.

The dosage of the compounds may vary and it also depends on the age, the condition of the patient, the type of disease, the type of compound (I) administered and the like, an average single dose of about 10 mg, 50 mg, 100 However, mg, 250 mg, 500 mg and 1000 mg of the compound (I) of the present invention have been found to be effective in treating infectious diseases caused by pathogenic bacteria.

In general, a daily dose between 1 mg and about 6000 mg / body weight or more can be administered to a patient.

The invention is illustrated in more detail by the following production examples and examples, without, however, being restricted thereto.

Production example 1

1.) 500 ml of water was added to 490.0 g of hexylamine and a solution of 193.6 g of sodium hydroxide in 700 ml of water was added with ice-cooling and stirring. 367.8 g of carbon disulfide were added dropwise at 2 to 10 ° C. over a period of 2 hours and 687.3 g of methyl iodide were then added dropwise over a period of 1 hour at 0 to 5 ° C. The resulting mixture was stirred at the same temperature for 30 minutes and at ambient temperature for 2 hours. The reaction mixture was extracted with 1.5 liters of diethyl ether. The extract was washed with 300 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to give 825.5 g of methyl N-hexyldithiocarbamate in the form of an oil.

I.R. (Film): 3225, 2960, 2935, 2860 cm [high] -1

N.M.R. (CDCl [deep] 3, small delta): 0.86 (3H, t, J = 5.0Hz), 1.10 ~ 1.90 (8H, m), 2.58 (3H, s), 3.72 (2H, m)

2.) 155.9 g of sodium azide and 0.8 l of water were added with stirring to a solution of 430 g of methyl N-hexyldithiocarbamate in 1.7 l of ethanol and the resulting mixture was kept at 90 ° C. for 3.5 hours heated to reflux. Ethanol was distilled off from the reaction mixture and the residue was washed with 1 liter of diethyl ether, adjusted to pH 2.0 with concentrated hydrochloric acid and extracted with 1 liter of diethyl ether. The extract was washed with water, dried over magnesium sulfate and concentrated to give 431.3 g of 1-hexyl-1H-tetrazole-5-thiol as an oil.

I.R. (Film): 3110, 2960, 2930, 2860 cm [high] -1

N.M.R. (CDCl [deep] 3, small delta): 0.91 (3H, t, J = 5.0Hz), 1.10-1.65 (6H, m), 1.97 (2H, m), 4.33 (2H, t, J = 7.0Hz)

3.) To 150.0 g of 7-aminocephalosporanic acid, 3 l of a 0.2 M phosphate buffer solution, which had previously been prepared by dissolving 62.1 g of sodium biphosphate dihydrate and 25.5 g of disodium hydrogen phosphate in 3 l of water, was added and the resulting solution The mixture was adjusted to pH 6.5 with an aqueous 2N sodium carbonate solution. 154.6 g of 1-hexyl-1H-tetrazole-5-thiol were added to the mixture, and the mixture obtained was kept at a pH of from 6.0 to 6 for 2 hours at 60 to 65 ° C. while introducing nitrogen gas , 5 stirred. The reaction mixture was adjusted to pH 3.5 with concentrated hydrochloric acid under ice-cooling. The precipitates were collected by filtration and washed with water, and 4 liters of methanol and 400 ml of concentrated hydrochloric acid were added. The mixture was stirred for 2 hours and an insoluble matter was filtered off. The filtrate was treated with activated charcoal and adjusted to pH 3.5 with a 28% strength aqueous ammonia solution. The precipitates were collected by filtration, washed successively with water, acetone and diethyl ether and dried to give 116.38 g of 7-amino-3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid received in the form of a powder.

I.R. (Nujol): 1803, 1620, 1350 cm [high] -1

N.M.R. (d [deep] 6-DMSO, small delta): 0.95 (3H, t, J = 6.5Hz), 1.26 (6H, m), 1.80 (2H, m), 3.65 (2H, AB [deep] q, J = 18Hz), 4.00 ~ 4.50 (4H, m), 4.79 (1H, d, J = 6.0Hz), 4.95 (1H, d, J = 6.0Hz)

Production example 2

1.) 0.84 g of sodium bicarbonate were added to a suspension of 2 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid in 120 ml of water to produce a solution. To the solution was added 4.56 g of ethyl 2-aminooxyacetate hydrochloride and stirred for 3 hours at ambient temperature while the pH was adjusted to 6 with sodium bicarbonate. The resulting solution was adjusted to pH 1.5 with hydrochloric acid, salted out and extracted 3 times with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether and the precipitates were collected by filtration and dried to give 1.44 g of 2-ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer), mp 112 ° C (Decomposition).

I.R. (Nujol): 3150, 1740, 1670, 1550 cm [high] -1

N.M.R. (DMSO-d [low] 6, small delta): 1.23 (3H, t, J = 7Hz), 4.16 (2H, q, J = 7Hz), 4.77 (2H, s), 7.56 (1H, s), 8.54 (1H, s)

2.) A mixture of 7.2 g of 2-ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-Isomeres), 10 ml of concentrated hydrochloric acid, 70 ml of ethanol and 20 ml of tetrahydrofuran was added for 2 hours at ambient temperature touched. After removing the solvent from the reaction mixture in vacuo, water was added and the mixture was washed with an aqueous sodium bicarbonate solution while cooling with ice adjusted to pH 3.3. The precipitates were collected by filtration and dried to obtain 4.6 g of 2-ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer).

I.R. (Nujol): 3170, 1720, 1660, 1620 cm [high] -1

N.M.R. (d [deep] 6-DMSO, small delta): 1.27 (3H, t, J = 7Hz), 4.25 (2H, q, J = 7Hz), 4.77 (2H, s), 6.96 (1H, s)

Production example 3

4.2 g of sodium bicarbonate was added to a suspension of 10 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid in 500 ml of water to prepare a solution. To the solution was added 8.1 g of t-butyl 2-aminooxyacetate hydrochloride and stirred for 3 hours at ambient temperature while the solution was adjusted to pH 6 with sodium bicarbonate. The resulting solution was adjusted to pH 1.5 with hydrochloric acid, salted out and extracted 3 times with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether and the precipitates were collected by filtration and dried to give 11.3 g of 2-t-butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer), m.p. 117 ° C (dec.).

I.R. (Nujol): 3180, 3140, 1750, 1690, 1630 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 1.46 (9H, s), 4.66 (2H, s), 7.56 (1H, s), 8.56 (1H, s), 12.67 (1H, broad s)

Production example 4

1.) 27.5 g of 2-bromoethyl benzoate were added to a stirred mixture of 15.7 g of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer), 20.7 g of potassium carbonate and 25 ml of N, N-dimethylformamide via a Was added dropwise over a period of 10 minutes while cooling with ice and stirred for 4 hours at ambient temperature. The resulting mixture was filtered and washed with acetone. The filtrate and the wash waters were combined with one another and concentrated in vacuo. After adding 100 ml of water to the residue, the solution was extracted 3 times with methylene chloride. The extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo, 28 g of ethyl 2- (2-benzoyloxyethoxyimino) -3-oxobutyrate (syn-isomer) being obtained.

2.) A mixture of 28 g of ethyl 2- (2-benzoyloxyethoxyimino) -3-oxobutyrate (syn-isomer), 13.5 g of sulfuryl chloride and 30 ml of acetic acid was for 10 minutes at 40 ° C and 5.5 hours stirred at room temperature. After adding 200 ml of water to the resulting solution, the mixture was extracted with methylene chloride. The extract was washed successively with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated in vacuo, 29 g of ethyl 2- (2-benzoyloxyethoxyimino) -4-chloro-3-oxobutyrate (syn -Isomeres).

3.) A mixture of 29 g of ethyl 2- (2-benzoyloxyäthoxyimino) -

4-chloro-3-oxobutyrate (syn-isomeres), 7.76 g thiourea, 8.37 g sodium acetate, 75 ml water and 75 ml ethanol were stirred at 40 ° C. for 1 hour. The resulting solution was concentrated in vacuo and the residue was extracted twice with ethyl acetate. The extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. After 200 ml of diethyl ether had been added to the oily residue, the soluble substance was separated off by decantation and the solution was concentrated in vacuo. The residue was crystallized from diisopropyl ether and the precipitates were collected by filtration, whereby 9 g of ethyl 2- (2-benzoyloxyethoxyimino) -2- (2-aminothiazol-4-yl) acetate (syn isomer) were obtained.

N.M.R. (DMSO-d [deep] 6, small delta): 1.28 (3H, t, J = 7Hz), 4.34 (2H, q, J = 7Hz), 4.56 (4H, m), 6.44 (2H, broad s), 6.68 (1H, s); 7.68-7.34 (3H, m), 8.06 (2H, d, d, J = 8Hz, 2Hz)

4.) A mixture of 8.5 g of ethyl 2- (2-benzoyloxyäthoxyimino) -2- (2-aminothiazol-4-yl) acetate (syn-Isomeres), 35 ml of an aqueous 1N sodium hydroxide solution, 40 ml of methanol and 40 ml of tetrahydrofuran was stirred for 9 hours at 35 to 40 ° C and for 12 hours at ambient temperature. After adjusting the resulting solution to pH 6.5 with concentrated hydrochloric acid, the solution was concentrated to about 2/3 of its initial volume. The concentrate was adjusted to pH 3.5 with concentrated hydrochloric acid under ice-cooling, and the precipitates were collected by filtration, washed with water and acetone, and then successively dried over phosphorus pentoxide under reduced pressure, 3.3 g of 2- (2-hydroxyethoxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn isomer) being obtained.

I.R. (Nujol): 3350, 3075, 1680, 1620 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 3.64 (2H, t, J = 5Hz), 4.10 (2H, t, J = 5Hz), 6.84 (1H, s), 7.16 (2H, m)

5.) A solution of 1.6 g of formic acid and 3.6 g of acetic anhydride was stirred at 50 ° C. for 1 hour. After cooling, 1 g of 2- (2-hydroxyethoxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn-isomer) was added to the solution and stirred for 3 hours at ambient temperature. Diisopropyl ether was added to the resulting solution and the precipitates were filtered off. The filtrate was concentrated in vacuo and the residue was pulverized in diisopropyl ether. The precipitates were collected by filtration, whereby 0.7 g of 2- (2-formyloxyethoxyimino) -2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer) was obtained.

I.R. (Nujol): 3200, 1710, 1690 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 4.38 (4H, s), 7.58 (1H, s), 8.26 (1H, s), 8.54 (1H, s)

Production example 5

1.) 126.4 g of ethyl 2-hydroxyimino-2- (2-aminothiazol-4-yl) acetate, 81.3 g of formic acid and 180 g of acetic anhydride were treated in a similar manner to Preparation Example 4- (5), 109.6 g of ethyl 2-hydroxyimino-2- (2-formamidothiazole-

4-yl) acetate (syn isomer) was obtained.

I.R. (Nujol): 3320, 3140, 3050, 1710, 1555 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 1.30 (3H, t, J = 7Hz), 4.33 (2H, q, J = 7Hz), 7.54 (1H, s), 8.34 (1H, s), 11.98 (1H, s), 12.58 (1H, s)

2.) A mixture of 7.97 g of chloromethylthiomethane, 15.1 g of powdered potassium iodide and 79 ml of acetone was stirred for 1 hour at ambient temperature and the resulting mixture was filtered and washed with a small amount of acetone. The wash water and the filtrate were combined with one another and formed into a stirred suspension of 17.5 g of ethyl 2-hydroxyimono-2- (2-formamidothiazol-4-yl) acetate (syn isomer) and 15.5 g of powdered potassium carbonate in 300 ml ml of acetone was added. The mixture was stirred at ambient temperature for 3 hours and washed with acetone. The wash waters and the filtrate were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed twice with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The oily residue was subjected to column chromatography on silica gel and eluted with chloroform to give 2.4 g of ethyl 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetate (syn-isomer), F.

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3.) A mixture of 2.4 g of ethyl 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetate (syn-Isomeres), 23.8 ml of an aqueous 1N sodium hydroxide solution and 19.8 ml of methanol was Stirred for 2.5 hours at 30 ° C. The resulting solution was adjusted to pH 7 with 10% hydrochloric acid, and methanol was distilled off in vacuo. The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid while cooling with ice, and extracted 3 times with ethyl acetate. The extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 1.13 g of 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer), m.p. 157 ° C (dec.).

I.R. (Nujol): 3210, 3160, 3075, 1700, 1555 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 2.24 (3H, s), 5.31 (2H, s), 7.61 (1H, s), 8.57 (1H, s), 12.73 (1H, s)

Production example 6

The following compounds were prepared in a manner similar to Preparation Examples 2 to 5:

(1) 2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn-isomer)

I.R. (Nujol): 3330, 3200, 3100, 1660, 1590 cm [high] -1

(2) 2- (3-isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer) mp 110 ° C (dec.)

I.R. (Nujol): 3270, 3130, 1680, 1540 cm [high] -1

(3) 2- (2-ethoxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer)

I.R. (Nujol): 3350, 3140, 1740, 1700 cm [high] -1

Production example 7

A solution of 17.4 g of 4-bromo-3-hydroxybenzyloxyamine phosphate in 200 ml of water and 200 ml of ethanol was stirred at room temperature and adjusted to pH 7.0 with sodium bicarbonate. 10.0 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid were added to the solution and the resulting suspension was adjusted to pH 4.0 to 4.5. After stirring the solution at room temperature for 2 hours, ethanol was removed from the resulting solution in vacuo. Ethyl acetate was added to the aqueous residue and adjusted to pH 2.5 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate. The solution was concentrated in vacuo to give 14.8 g of 2- (2-formamidothiazol-4-yl) -2- (4-bromo-3-hydroxybenzyloxyimino) acetic acid (syn isomer).

I.R. small Ny [high] Nujol [low] max: 3350, 3150, 1720, 1680, 1570 cm [high] -1

N.M.R. small delta (DMSO-d [deep] 6, ppm): 5.13 (2H, m), 6.8 (1H, dd, J = 8Hz, 2Hz), 7.02 (1H, d, J = 2Hz), 7.5 (1H, d , J = 8Hz), 7.58 (1H, s), 8.58 (1H, s), 10.35 (1H, broad s), 12.7 (1H, broad s).

Production example 8

1.) A mixture of 25 g of 1,4-bis (chloromethyl) benzene, 23.4 g of N-hydroxyphthalimide and 14.5 g of triethylamine in 200 ml of acetonitrile was refluxed for 1.5 hours. The reaction mixture was poured into 1 liter of ice water, and the precipitates were collected by filtration. The precipitates were washed with ethanol and dried to obtain 25.5 g of N- (4-chloromethylbenzyloxy) phthalimide.

I.R. small Ny [high] Nujol [low] max: 1780, 1740 cm [high] -1

N.M.R. small delta (DMSO-d [low] 6, ppm): 4.8 (2H, s), 5.23 (2H, s), 7.22 (4H, s), 7.9 (4H, s).

2.) A mixture of 18.5 g of N- (4-chloromethylbenzyloxy) phthalimide and 15.4 g of potassium phthalimide in 180 ml of N, N-dimethylformamide was stirred at 60 ° C. for 5 hours. The mixture was poured into ice water and the precipitates were collected by filtration. The precipitates were washed successively with water and acetone to obtain 21.0 g of N- (4-phthalimidomethylbenzyloxy) phthalimide.

I.R. small Ny [high] Nujol [low] max: 1780, 1760, 1740, 1720, 1610 cm [high] -1

N.M.R. small delta (DMSO-d [low] 6, ppm): 4.78 (2H, s), 5.13 (2H, s), 7.38 (4H, m), 7.83 (8H, m).

3.) 4.2 g of 100% hydrazine hydrate were added to a suspension of 16.4 g of N- (4-phthalimidomethylbenzyloxy) phthalimide in 160 ml of ethanol at 60 ° C. and the mixture was stirred at the same temperature for 1 hour. To the resulting mixture, 12 ml of concentrated hydrochloric acid and 120 ml of water were added while cooling with ice. After the insoluble matter had been filtered off, the filtrate was concentrated in vacuo. The residue was adjusted to pH 7.0 with a 10% sodium hydroxide solution and washed with ethyl acetate. To the aqueous solution containing 4-aminomethylbenzyloxyamine, 5.3 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid and 150 ml of ethanol were added and the solution was left at pH 4.0 to 4 for 2.5 hours. 5 stirred. The precipitates were collected by filtration and washed with water. The precipitates containing 2- (2-formamidothiazol-4-yl) -2- (4-aminomethylbenzyloxyimino) acetic acid (syn-isomeres) were added to a mixture of 100 ml of water and 100 ml of dioxane and mixed with 10% sodium hydroxide adjusted to pH 8.0. 3.2 g of triethylamine and 4.7 g of 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile were added to the mixture and the mixture was stirred at room temperature for 6 hours. Dioxane was removed in vacuo and the aqueous residue was washed with diethyl ether. Diethyl ether was added to the aqueous solution and adjusted to pH 3.0 with 10% hydrochloric acid. After the removal of diethyl ether from the mixture, the residue was washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo, giving 3.8 g of 2- (2-formamidothiazol-4-yl) -2- (4-tert. -butoxycarbonylaminomethylbenzyloxyimino) acetic acid (syn-isomeres).

I.R. small Ny [high] Nujol [low] max: 3300, 3150, 1710, 1690, 1620, 1560 cm [high] -1

N.M.R. small delta (DMSO-d [deep] 6, ppm): 1.38 (9H, s), 4.15 (2H, d, J = 6Hz), 5.22 (2H, s), 7.6 (1H, s), 7.68 (4H, s), 8.62 (1H, s), 12.8 (1H, broad s).

Production example 9

1.) 40.0 g of ethyl 2-hydroxyimino-3-oxobutyrate (syn-isomer), 43.6 g of 4-fluorobenzyl chloride, 60.0 ml of N, N-dimethylformamide, 52.0 g of potassium carbonate and 60.0 ml Ethyl acetate was treated in the conventional manner to give 64.4 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxobutyrate (syn-isomeres).

I.R. (Film): 3000, 2940, 1730, 1690, 1600 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 1.21 (3H, t, J = 7.0Hz), 2.34 (3H, s), 4.26 (2H, q, J = 7.0Hz), 5.32 (2H, s) , 6.97-7.73 (4H, m).

2.) 64.0 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxobutyrate (syn-isomer) and 35.6 g of sulfuryl chloride and 70.0 ml of acetic acid were obtained in a manner similar to Preparation Example 4- (2) treated, whereby 29.55 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn-isomer) were obtained.

I.R. (Film): 1720, 1600 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 1.20 (3H, t, J = 7.0Hz), 4.28 (2H, q, J = 7.0Hz), 4.87 (2H, s), 5.36 (2H, s) , 7.00-7.75 (4H, m).

3.) 29.0 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn-Isomeres), 8.8 g of thiourea, 7.9 g of sodium acetate, 72.5 ml of water, 60 ml Tetrahydrofuran and 72.5 ml of ethanol were treated in a similar manner to Preparation 4- (3) to obtain 28.0 g of ethyl 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn-isomeres) received.

I.R. (Nujol): 3450, 3150, 3100, 1710, 1620 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 1.23 (3H, t, J = 7.0Hz), 4.30 (2H, q, J = 7Hz), 5.15 (2H, s), 6.90 (1H, s), 6.95-7.60 (4H, m)

4.) 25.5 g of ethyl 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn-Isomeres), 1.3 g of 1-methylimidazole, 118.3 ml of a 1 n Sodium hydroxide solution, 250 ml of methanol and 200 ml of tetrahydrofuran were treated in a similar manner to Production Example 4- (4) to obtain 22.11 g of 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn-isomeres) received.

I.R. (Nujol): 3650, 3450, 3300, 3150, 1630 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 5.16 (2H, s), 6.88 (1H, s), 7.04-7.66 (4H, m)

5.) 23.4 g of 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn-isomeres), 32.2 g of bis (trimethylsilyl) acetamide, 49.9 g of 2.2 , 2-Trifluoroacetic anhydride and 234 ml of dry ethyl acetate were treated in a manner similar to Preparation Example 4- (5) to obtain 18.9 g of 2- (4-fluorobenzyloxyimino) -2- [2- (2,2,2- trifluoroacetamido) thiazol-4-yl] acetic acid (syn isomer), mp 180 to 182 ° C.

I.R. (Nujol): 3200, 3150, 1730 cm [high] -1

N.M.R. (DMSO-d [low] 6, small delta): 5.25 (2H, s), 7.02-7.60 (4H, m), 7.72 (1H, s).

Preparation example 10

1.) The compound given below was prepared by reacting ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) with 3,4-dichlorobenzyl chloride in a conventional manner:

Ethyl 2- (3,4-dichlorobenzyloxyimino) -3-oxobutyrate (syn-isomeres), oil

I.R. (Film): 1730, 1690, 1600, 1470, 1400, 1370, 1310, 1240, 1130, 1080, 1010 cm [high] -1

N.M.R. (CCl [low] 4, small delta): 1.30 (3H, t, J = 6Hz), 2.30 (3H, s), 4.30 (2H, q, J = 6Hz), 4.47 (2H, s), 7.00-7.53 (3H, m)

2.) The following compound was prepared in a manner similar to Preparation Example 4- (2):

Ethyl 2- (3,4-dichlorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn-isomeres), oil

I.R. (Film): 1740, 1710, 1590, 1470, 1400, 1370, 1320, 1260, 1200, 1130, 1010 cm [high] -1

N.M.R. (CCl [low] 4, small delta): 1.37 (3H, t, J = 6Hz), 4.23 (2H, q, J = 6Hz), 4.43 (2H, s), 5.27 (2H, s), 7.10-7.60 (3H, m)

3.) The following compound was prepared in a similar manner to Preparation Example 4- (3):

Ethyl 2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn-isomer)

I.R. (Nujol): 3460, 1720, 1600, 1540, 1460, 1390, 1260, 1180, 1020, 1010, 880, 810 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 1.25 (3H, t, J = 7Hz, 4.30 (2H, q, J = 7Hz), 5.17 (2H, s), 6.93 (1H, s), 7.27- 7.73 (3H, m)

4.) The following compound was prepared in a manner similar to Preparation Example 4- (4):

2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn-isomer)

I.R. (Nujol): 3430, 1660, 1590, 1400, 1010 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 5.23 (2H, s), 6.93 (1H, s), 7.30-7.77 (3H, m)

5.) The following compound was prepared in a similar manner to Preparation Example 4- (5):

2- (3,4-dichlorobenzyloxyimino) -2- [2- (2,2,2-trifluoroacetamido) thiazol-4-yl] acetic acid (syn-isomer)

I.R. (Nujol): 1720, 1580, 1300, 1260, 1200, 1160, 1150 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 5.40 (2H, s), 7.47-7.93 (4H, m)

Preparation example 11

To a suspension of 21.0 g of N- (cinnamyloxy) phthalimide in 200 ml of ethanol, 8.3 g of hydrazine hydrate was added at 60 ° C. and the mixture was stirred for 1.5 hours at the same temperature. To the mixture were added 22 ml of concentrated hydrochloric acid and 220 ml of water, and the resulting mixture was filtered. The filtrate was concentrated to give precipitates which were filtered off. The filtrate was adjusted to pH 7.0, and to the solution containing O-cinnamylhydroxylamine, 300 ml of ethanol and 10.0 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid were added. The mixture was stirred at pH 4.0-4.5 for 2 hours. The reaction mixture was concentrated and, after the addition of ethyl acetate, adjusted to pH 2.0. The organic layer was washed with an aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to give 8.6 g of 2-cinnamyloxyimono-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomeres).

I.R. (Nujol): 3400-3100, 1700, 1550 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 4.85 (2H, d, J = 5Hz), 6.2-6.93 (2H, m), 7.2-7.72 (5H, m), 7.6 (1H, s), 8.57 (1H, s), 12.7 (1H, broad s).

example 1

The Vilsmeier reagent was prepared from 0.139 g dry dimethylformamide, 0.290 g phosphorus oxychloride and 1.0 ml dry tetrahydrofuran by the conventional method. 3.0 ml of dry tetrahydrofuran were added and then were at

-5 to 0 ° C. 0.4 g of 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) was added. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was added at -5 to 0 ° C to a stirred solution of 0.725 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in a mixture of 7 ml of water and 7 ml of acetone, the pH of which was kept at 7.5 to 8.5 by triethylamine, were added dropwise and the mixture was stirred for 30 minutes at the same temperature at pH 7.5 to 8.5. Acetone was removed from the reaction mixture. Ethyl acetate and water were added to the residue, and the mixture was adjusted to pH 2.0 with 10% hydrochloric acid. The insoluble matter was filtered off and the filtrate was extracted twice with ethyl acetate. The combined extracts were washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with diethyl ether, whereby 0.64 g of 7- [2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazole- 2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres).

I.R. (Nujol): 3230, 1780, 1680, 1550 cm [high] -1

N.M.R. (d [deep] 6-DMSO, small delta): 2.22 (3H, s), 3.72 (2H, AB [deep] q, J = 18Hz), 4.44 (2H, AB [deep] q, J = 14Hz), 5.18 (1H, d, J = 5Hz), 5.23 (2H, s), 5.84 (1H, d, d, J = 5 and 9Hz), 7.46 (1H, s), 8.52 (1H, s), 9.54 (1H , s), 9.74 (1H, d, J = 9Hz), 12.64 (1H, broad s)

Example 2

2.3 g of phosphorus oxychloride were added all at once to a suspension of 3.4 g of 2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn-isomer) in 30 ml of dry tetrahydrofuran at -3 ° C and the The mixture was stirred for 20 minutes at the same temperature. 2.4 g of trimethylsilylacetamide and 5 ml of tetrahydrofuran were added dropwise and the resulting mixture was stirred for 20 minutes at the same temperature. 2.3 g of phosphorus oxychloride were added and the mixture was stirred at 0 to 3 ° C. for 30 minutes. 1.1 g of dry dimethylformamide was added all at once at 0 to 3 ° C. and the mixture was stirred at the same temperature for 1 hour to give a clear solution.

On the other hand, 12.7 g of trimethylsilylacetamide was added to a stirred suspension of 4.0 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in 60 ml of dry ethyl acetate was added and the solution was stirred for 1 hour at ambient temperature. To this stirred solution, the tetrahydrofuran solution obtained above was then added all at once at -20 ° C and the resulting mixture was stirred at -5 to -15 ° C for 2 hours. To the reaction mixture, 50 ml of a saturated sodium chloride aqueous solution was added. The organic layer was separated and extracted with a saturated aqueous sodium bicarbonate solution (pH 7.0). The extract was washed with ethyl acetate, treated with activated charcoal and adjusted to pH 4.5 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and drying, whereby 1.03 g of 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem -4-carboxylic acid (syn isomer) obtained in the form of a powder.

I.R. (Nujol): 3320, 3200, 1770, 1670, 1610 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 3.59 (2H, AB [low] q, J = 18.0Hz), 4.47 (2H, AB [low] q, J = 12.0Hz), 5.09 (1H, i , J = 4.0Hz), 5.15 (2H, s), 5.73 (1H, d, d, J = 4.0 and 8.0Hz), 6.74 (1H, s), 7.36 (5H, m), 9.56 (1H, s) , 9.69 (1H; d, J = 8.0Hz)

Example 3

The Vilsmeier reagent was prepared from 0.667 g dry dimethylformamide, 1.40 g phosphorus oxychloride and 4 ml dry ethyl acetate by the conventional method. 16 ml of dry ethyl acetate were added and then 2 g of 2-t-butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer) were added at 0 ° C. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was added to a stirred solution of 3.01 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid and 9.6 at -15 ° C g of trimethylsilylacetamide in 30 ml of dry ethyl acetate were added dropwise and the mixture was stirred at -15 to -5 ° C. for 50 minutes. 50 ml of water was added to the reaction mixture. An insoluble material was filtered off and the filtrate was extracted twice with ethyl acetate, the extracts were washed twice with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diethyl ether, and the powder was collected by filtration and dried to give 2.67 g of 7- [2-t-butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres).

I.R. (Nujol): 3225, 1780, 1725, 1685, 1550 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 1.38 (9H, s), 3.64 (2H, AB [low] q, J = 17Hz), 4.38 (2H, AB [low] q, J = 14Hz), 4.56 (2H, s), 5.12 (1H, d, J = 5Hz), 5.77 (1H, d, d, J = 5 and 9Hz), 7.38 (1H, s), 8.47 (1H, s), 9.49 (1H , s), 9.54 (1H, d, J = 9Hz), 12.57 (1H, broad s)

Example 4

The compounds given below were prepared in a manner similar to that given in Examples 1 to 3:

(1) 7- [2-Methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3250, 1780, 1675, 1550 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 2.22 (3H, s), 3.72 (2H, AB [low] q, J = 19Hz), 3.96 (3H, s), 4.33 (2H, AB [low] q, J = 14Hz), 5.17 (1H, d, J = 5Hz), 5.26 (2H, s), 5.85 (1H, d, d, J = 5 and 8 Hz), 7.48 (1H, s), 8.54 ( 1H, s), 9.78 (1H, d, J = 8Hz), 12.64 (1H, s)

(2) 7- [2- (2-Ethoxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem -4-carboxylic acid (syn isomer)

I.R. (Nujol): 3500, 3200, 1780, 1720, 1680 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 1.13 (3H, t, J = 7Hz), 3.2 ~ 4.0 (6H, m), 4.30 (2H, t, J = 4Hz), 4.50 (2H, AB [ low] q, J = 13Hz), 5.23 (1H, d, J = 5Hz), 5.87 (1H, d, d, J = 5 and 8Hz), 7.48 (1H, s), 8.58 (1H, s), 9.60 (1H, s), 9.70 (1H; d, J = 8Hz)

(3) 7- [2- (2-formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 1770, 1710, 1670 cm [high] -1

N.M.R. (d [deep] 6-DMSO, small delta): 3.50 (2H, m), 4.10 ~ 4.60 (4H, m), 4.79 (2H, m), 5.16 (1H, d, J = 5.0Hz), 5.81 ( 1H, d, d, J = 5.0 and 8.0Hz), 6.58 (2H, broad s), 7.47 (1H, s), 8.28 (1H, s), 8.55 (1H, s)

(4) 7- [2- (2-formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido] -3-methyl-3-cephem-4-carboxylic acid (syn-isomeres)

I.R. (Nujol): 3150, 1765, 1675 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 2.03 (3H, s), 3.45 (2H, AB [low] q, J = 18Hz), 4.36 (4H, m), 5.11 (1H, d, J = 5Hz), 5.75 (1H, d, d, J = 5 and 8Hz), 7.46 (1H, s), 8.24 (1H, s), 8.53 (1H, s), 9.63 (1H, d, J = 8Hz)

(5) 7- [2- (2-Formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem -4-carboxylic acid (syn isomer)

I.R. (Nujol): 3160, 1775, 1710, 1670 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 3.71 (2H, AB [low] q, J = 18.0Hz), 3.96 (3H, s), 4.00 ~ 4.54 (6H, m), 5.16 (1H, i , J = 4.5Hz), 5.84 (1H, d, d, J = 4.5 and 9.0Hz), 7.45 (1H, s), 8.24 (1H, s), 8.53 (1H, s), 9.70 (1H, d, J = 9.0Hz)

(6) 7- [2- (2-Formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem -4-carboxylic acid (syn isomer)

I.R. (Nujol): 3180, 1775, 1673 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 3.75 (2H, m), 4.25 ~ 4.65 (6H, m), 5.22 (1H, d, J = 5.0Hz), 5.88 (1H, d, d, J = 5.0 and 9.0Hz), 7.49 (1H, s), 8.26 (1H, s), 8.57 (1H, s), 9.59 (1H, s), 9.71 (1H, d, J = 9.0Hz)

(7) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid ( syn isomer)

I.R. (Nujol): 3250, 1775, 1720, 1680, 1540 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 1.22 (3H, t, J = 7Hz), 3.74 (2H, s), 4.20 (2H, q, J = 7Hz), 4.77 (2H, s), 5.22 (1H, d, J = 5Hz), 5.88 (1H, d, d, J = 5 and 8Hz), 7.51 (1H, s), 8.58 (1H, s), 9.63 (1H, s), 9.70 (1H, d, J = 8Hz), 12.68 (1H, broad s)

(8) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid ( syn isomer)

I.R. (Nujol): 3250, 1780, 1725, 1680, 1540 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 1.22 (3H, t, J = 7Hz), 3.73 (2H, s), 3.97 (3H, s), 4.18 (2H, q, J = 7Hz), 4.35 (2H, AB [low] q, J = 14Hz), 4.76 (2H, s), 5.18 (1H, d, J = 5Hz), 5.86 (1H, d, d, J = 5 and 9Hz), 7.48 (1H , s), 8.56 (1H, s), 9.67 (1H, d, J = 9Hz), 12.69 (1H, broad s)

(9) 7- [2-t-Butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3180, 1785, 1725, 1690, 1550 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 1.45 (9H, s), 3.72 (2H, AB [low] q, J = 17Hz), 3.96 (3H, s), 4.33 (2H, AB [low] q, J = 14Hz), 4.64 (2H, s), 5.17 (1H, d, J = 5Hz), 5.84 (1H, d, d, J = 5 and 9Hz), 7.46 (1H, s), 8.52 (1H , s), 9.62 (1H, d, J = 9Hz), 12.61 (1H, broad s)

(10) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1633 cm [high] -1

N.M.R. (d [deep] 6-DMSO, small delta): 0.86 (3H, m), 0.97 ~ 1.53 (6H, m), 1.53 ~ 2.10 (2H, m), 3.70 (2H, m), 4.10 ~ 4.77 (4H , m), 5.00 ~ 5.50 (3H, m), 5.85 (1H, d, d, J = 5.0 and 8.0Hz), 6.80 (1H, s), 6.98 ~ 7.63 (7H, m), 9.71 (1H, d , J = 8.0Hz)

(11) 7- [2- (3-Isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer)

I.R. (Nujol): 3200, 1775, 1675, 1540 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 3.72 (2H, s), 4.45 (2H, AB [low] q, J = 13Hz), 5.18 (1H, d, J = 5Hz), 5.30 (2H, s), 5.96 (1H, d, d, J = 5 and 8Hz), 6.67 (1H, d, J = 2Hz), 7.50 (1H, s), 8.55 (1H, s), 8.90 (1H, d, J = 2Hz), 9.58 (1H, s), 9.79 (1H, d, J = 8Hz), 12.69 (1H, s)

(12) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3340, 3200, 1775, 1670 cm [high] -1

(13) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3300, 1770, 1670, 1530 cm [high] -1

(14) 7- [2- (2-ethoxyethoxy) imino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer)

I.R. (Nujol): 3160, 3100, 1780, 1670, 1630 cm [high] -1

(15) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3350, 3220, 1780, 1680, 1630 cm [high] -1

(16) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3350, 3230, 3100, 1780, 1680, 1630 cm [high] -1

(17) 7- [2-t-Butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3300, 1775, 1730, 1675, 1630 cm [high] -1

(18) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3340, 3200, 1775, 1675, 1630 cm [high] -1

(19) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer)

I.R. (Nujol): 3350, 3230, 3110, 1775, 1675 cm [high] -1

(20) 7- [2-Carboxymethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3200, 1780, 1720, 1680, 1545 cm [high] -1

(21) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3360, 3240, 3100, 1780, 1680, 1635 cm [high] -1

(22) 7- [2- (4-t-Butoxycarbonylaminomethylbenzyloxyimino) -2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer)

I.R. (Nujol): 3300-3150, 1790, 1690, 1550 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 1.33 (9H, s), 3.6 (2H, m), 4.08 (2H, d, J = 5Hz), 4.4 (2H, AB [deep] q, J = 14Hz), 5.11 (1H, d, J = 5Hz), 5.13 (2H, m), 5.78 (1H, dd, J = 5 and 8Hz), 7.25 (4H, m), 7.33 (1H, s), 8.47 ( 1H, s), 9.5 (1H, s), 9.68 (1H, d, J = 8Hz), 12.5 (1H, broad s)

(23) 7- [2- (t-Butoxycarbonylmethoxyimino) -2- (2-formamidothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3170, 1770, 1720, 1670 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 1.44 (9H, s), 3.68 (2H, m), 4.33 (2H, AB [deep] q, J = 12.0Hz), 4.63 (2H, s), 5.16 (1H, d, J = 5.0Hz), 5.82 (1H, dd, J = 5.0 and 8.0Hz), 7.43 (1H, s), 8.51 (1H, s), 9.56 (1H, d, J = 8.0Hz )

(24) 7- [2- (4-Fluorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacetamido) thiazol-4-yl} acetamido] -3- (1-methyl-1H-tetrazole-5- yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3370, 3180, 1760, 1710, 1680, 1650 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 3.68 (2H, m), 3.92 (3H, s), 4.32 (2H, m), 5.03-5.35 (3H, m), 5.83 (1H, dd, J = 5 and 8Hz), 6.99-7.70 (4H, m), 7.54 (1H, s), 9.87 (1H, d, J = 8Hz)

(25) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), M.p. 112-125 ° C (dec.).

I.R. (Nujol): 3250, 1770, 1730, 1680 cm [high] -1

N.M.R. (DMSO-d [low] 6, small delta): 1.20 (3H, t, J = 8Hz), 3.71 (2H, m), 4.07 (2H, q, J = 8Hz), 4.36 (2H, m), 4.77 (2H, m), 5.20 (1H, d, J = 5Hz), 5.88 (1H, dd, J = 5 and 8Hz), 7.50 (1H, s), 8.57 (1H, s), 9.67 (1H, d, J = 8Hz), 12.38 (1H, broad s)

(26) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) , M.p. 172-174 ° C (dec.).

I.R. (Nujol): 3250, 3150, 1770, 1620 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 3.67 (2H, m), 4.33 (2H, m), 5.08-5.36 (3H, m), 5.83 (1H, dd, J = 4 and 8Hz), 6.88 (1H, s), 7.39 (5H, s), 9.73 (1H, d, J = 8Hz)

(27) 7- [2- (4-Fluorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacetamido) thiazol-4-yl} acetamido] -3- (1,3,4-thiadiazole-2- yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres)

I.R. (Nujol): 3200, 1770, 1720, 1650 cm [high] -1

N.M.R. (DMSO-d [low] 6, small delta): 3.73 (2H, AB [low] q, J = 18Hz), 4.49 (2H, AB [low] q, J = 14Hz), 5.03-5.46 (3H, m ), 5.88 (1H, dd, J = 4 and 8Hz), 7.03-7.84 (4H, m), 7.59 (1H, s), 9.60 (1H, s), 9.88 (1H, d, J = 8Hz)

(28) 7- [2-Cinnamyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3400-3100, 1780, 1680, 1540 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 3.67 (2H, m), 4.45 (2H, AB [deep] q, J = 14Hz), 4.83 (2H, d, J = 5Hz), 5.18 (1H, d, J = 5Hz), 5.87 (1H, dd, J = 5 and 8Hz), 6.65 (1H, s), 6.12-7.0 (2H, m), 7.1-7.7 (5H, m), 8.53 (1H, s ), 9.57 (1H, s), 9.73 (1H, d, J = 8Hz), 12.6 (1H, broad s)

(29) 7- [2- (4-Fluorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacetamido) thiazol-4-yl} acetamido] -3- (1H-tetrazol-5-yl) thiomethyl- 3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3200, 1780, 1730, 1660 cm [high] -1

(30) 7- [2- (4-fluorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacetamido) thiazol-4-yl} acetamido] -cephalosporanic acid (syn-isomeres)

I.R. (Nujol): 3250, 1780, 1730, 1660, 1630 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 2.07 (3H, s), 3.59 (2H, m), 4.90 (2H, AB [deep] q, J = 14Hz), 5.13-5.46 (3H, m) , 5.90 (1H, dd, J = 5 and 8Hz), 7.30-7.77 (4H, m), 7.58 (1H, s), 9.68 (1H, d, J = 4.0 Hz)

(31) 7- [2- (3,4-dichlorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacetamido) thiazol-4-yl} acetamido] -cephalosporanic acid (syn-isomeres)

I.R. (Nujol): 1780, 1730, 1650 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 2.03 (3H, s), 3.57 (2H, m), 4.87 (2H, AB [deep] q, J = 12Hz), 5.17-5.23 (3H, m) , 5.87 (1H, dd, J = 6 and 8Hz), 7.33-7.73 (4H, m), 9.87 (1H, d, J = 8Hz)

(32) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl- 3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3400-3100, 1780, 1680, 1540 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 3.7 (2H, wide s), 4.45 (2H, AB [deep] q, J = 13Hz), 5.13 (1H, d, J = 5Hz), 5.18 (2H , s), 5.82 (1H, dd, J = 5 and 8Hz), 6.97 (1H, d, J = 2Hz), 7.4 (1H, s), 7.45 (1H, d, J = 8Hz), 8.5 (1H, s), 9.68 (1H, d, J = 8Hz), 12.6 (1H, wide s)

(33) 7- [2- (4-Aminomethylbenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -carboxylic acid dihydrochloride (syn isomer)

I.R. (Nujol): 3400-3100, 1770, 1660, 1620, 1540 cm [high] -1

(34) 7- [2- (t-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3280, 3200, 1770, 1670, 1630 cm [high] -1

(35) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer)

I.R. (Nujol): 3300, 3200, 1770, 1660, 1620, 1600 cm [high] -1

(36) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), M.p. 168 - 185 ° C (decomp.)

I.R. (Nujol): 3250, 1765, 1670, 1625 cm [high] -1

(37) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer), m.p. 145 - 149 ° C (decomp.).

I.R. (Nujol): 3250, 1765, 1650 cm [high] -1

(38) 7- [2-Cinnamyloxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer)

I.R. (Nujol): 3350-3100, 1760, 1650, 1620, 1520 cm [high] -1

(39) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3300, 3200, 1770, 1660, 1630, 1600 cm [high] -1

(40) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -cephalosporanic acid (syn-isomeres), mp 185-192 ° C (dec.).

I.R. (Nujol): 3380, 3250, 1780, 1700, 1650 cm [high] -1

(41) 7- [2- (3,4-Dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] cephalosporanic acid (syn isomer), mp 200-205 ° C (dec.).

I.R. (Nujol): 1730, 1640, 1600, 1230, 1020 cm [high] -1

(42) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3400-3100, 1760, 1660, 1620, 1520 cm [high] -1

(43) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), F. 178 - 180 ° C (decomp.)

I.R. (Nujol): 3300, 3280, 1770, 1670, 1630 cm [high] -1

(44) 7- [2-t -Butoxycarbonylmethoxyimono-2- (2-formamidothiazol-4-yl) acetamido] -3- [tetrazolo [1,5-b] pyridazin-6-yl] thiomethyl-3-cephem-4 -carboxylic acid (syn isomer).

I.R. (Nujol): 3150, 1780, 1720, 1670 cm [high] -1

N.M.R. (DMSO-d [low] 6, small delta): 1.42 (9H, s), 3.73 (2H, m), 4.25-4.85 (4H, m), 5.17 (1H, d, J = 4Hz), 5.84 (1H , dd, J = 4 and 8Hz), 7.43 (1H, s), 7.72 (1H, d, J = 10Hz), 8.50 (1H, s), 8.56 (1H, d, J = 10Hz), 9.56 (1H, d, J = 8Hz)

(45) 7- [2- (t-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- [tetrazolo [1,5-b] pyridazin-6-yl] thiomethyl-3-cephem -4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1770, 1670, 1620 cm [high] -1

(46) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [tetrazolo [1,5-b] pyridazin-6-yl] thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3270, 3170, 1765, 1670, 1620 cm [high] -1

Example 5

A mixture of 0.58 g of 7- [2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 carboxylic acid (syn isomer), 0.405 g of concentrated hydrochloric acid, 8.7 ml of methanol and 5 ml of tetrahydrofuran was stirred for 2 hours and 10 minutes at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a 10% sodium hydroxide aqueous solution (pH 7 to 8.5). An insoluble matter was filtered off, and the filtrate was adjusted to pH 3.4 with 10% hydrochloric acid under ice-cooling and stirred for 30 minutes. The precipitates were collected by filtration, washed with water and dried to give 0.4 g of 7- [2-methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres).

I.R. (Nujol): 3340, 3200, 1775, 1670 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 2.23 (3H, s), 3.74 (2H, s), 4.48 (2H, AB [low] q, J = 13Hz), 5.20 (1H, d, J = 5Hz), 5.24 (2H, s), 5.83 (1H, d, d, J = 5 and 9Hz), 6.83 (1H, s), 7.28 (2H, broad s), 9.62 (1H, s), 9.68 (1H , d, J = 9Hz)

Example 6

A mixture of 2.3 g of 7- [2-t-butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer), 3.74 g of concentrated hydrochloric acid and 35 ml of methanol was stirred for 2 hours and 40 minutes at ambient temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in a 10% sodium hydroxide aqueous solution (pH 7 to 8). The aqueous solution was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirred for 30 minutes. The precipitates were collected by filtration, washed with water and dried to give 1.1 g of 7- [2-t-butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4 -thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres).

I.R. (Nujol): 3300, 1775, 1730, 1675, 1630 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 1.46 (9H, s), 3.67 (2H, s), 4.42 (2H, AB [low] q, J = 14Hz), 4.55 (2H, s), 5.16 (1H, d, J = 5Hz), 5.78 (1H, d, d, J = 5 and 9Hz), 6.77 (1H, s), 7.21 (2H, s), 9.43 (1H, d, J = 9Hz), 9.52 (1H, s)

Example 7

To a stirred solution of 2.7 g of sodium acetate in 46 ml of water, 2.3 g of 7- [2- (4-fluorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacetamido) thiazol-4-yl} acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid was added and the mixture was stirred at ambient temperature for 20.5 hours. The reaction mixture was adjusted to pH 5.0 with 10% hydrochloric acid after the addition of ethyl acetate, and the resulting mixture was shaken. The aqueous layer was separated, washed twice with ethyl acetate and adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 1.82 g of 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3 , 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-Isomeres), mp 145 to 149 ° C (dec.).

I.R. (Nujol): 3250, 1765, 1650 cm [high] -1

N.M.R. (DMSO-d [low] 6, small delta): 3.73 (2H, AB [low] q, J = 18Hz), 4.48 (2H, AB [low] q, J = 14Hz), 5.01-5.39 (3H, m ), 5.85 (1H, dd, J = 4 and 8Hz), 6.83 (1H, s), 7.02-7.75 (4H, m), 9.63 (1H, s), 9.75 (1H, d, J = 8Hz)

Example 8

The following compounds were prepared in a manner similar to that indicated in Examples 5 to 7:

(1) 7- [2-Benzyloxyimono-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3320, 3200, 1770, 1670, 1610 cm [high] -1

(2) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1633 cm [high] -1

(3) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3300, 1770, 1670, 1530 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 2.20 (3H, s), 3.72 (2H, s), 3.97 (3H, s), 4.36 (2H, s), 5.17 (1H, d, J = 5Hz ), 5.22 (2H, s), 5.82 (1H, d, d, J = 5 and 8Hz), 6.82 (1H, s), 7.28 (2H, broad s), 9.60 (1H, d, J = 8Hz)

(4) 7- [2- (2-ethoxyethoxy) imino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer)

I.R. (Nujol): 3160, 3100, 1780, 1670, 1630 cm [high] -1

N.M.R. (d [deep] 6-DMSO, small delta): 1.08 (3H, t, J = 7Hz), 3.45 (2H, q, J = 7Hz), 3.5 ~ 3.90 (4H, m), 4.20 (2H, t, J = 4Hz), 4.47 (2H, AB [low] q, J = 13Hz), 5.17 (1H, d, J = 5Hz), 5.80 (1H, d, d, J = 5 and 8Hz), 6.77 (1H, s), 9.55 (1H, s), 9.55 (1H, d, J = 8Hz)

(5) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3350, 3220, 1780, 1680, 1630 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 1.23 (3H, t, J = 7Hz), 3.70 (2H, s), 3.97 (3H, s), 4.16 (2H, q, J = 7Hz), 4.35 (2H, s), 4.69 (2H, s), 5.15 (1H, d, J = 5Hz), 5.80 (1H, d, d, J = 5 and 9 Hz), 6.81 (1H, s), 7.24 (2H , wide s), 9.54 (1H, d, J = 9Hz)

(6) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid ( syn isomer)

I.R. (Nujol): 3350, 3230, 3100, 1780, 1680, 1630 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 1.21 (3H, t, J = 7Hz), 3.72 (2H, AB [low] q, J = 18Hz), 4.18 (2H, q, J = 7Hz), 4.70 (2H, s), 5.20 (1H, d, J = 5Hz), 5.84 (1H, d, d, J = 5 and 8Hz), 6.84 (1H, s), 7.26 (2H, broad s), 9.56 ( 1H, d, J = 8Hz), 9.60 (1H, s)

(7) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3340, 3200, 1775, 1675, 1630 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 3.68 (2H, s), 3.94 (3H, s), 4.32 (2H, AB [low] q, J = 14Hz), 4.70 (2H, s), 5.14 (1H, d, J = 5Hz), 5.78 (1H, d, d, J = 5 and 9Hz), 6.81 (1H, s), 7.1 (2H, wide s), 9.59 (1H, d, J = 9Hz)

(8) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer)

I.R. (Nujol): 3350, 3230, 3110, 1775, 1675 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 3.71 (2H, AB [low] q, J = 18Hz), 4.46 (2H, AB [low] q, J = 14Hz), 5.17 (1H, d, J = 5Hz), 5.27 (2H, s), 5.82 (1H, d, d, J = 5 and 8Hz), 6.66 (1H, s), 6.83 (1H, s), 7.30 (2H, broad s), 8.87 ( 1H, s), 9.57 (1H, s), 9.75 (1H, d, J = 8Hz)

(9) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3360, 3240, 3100, 1780, 1680, 1635 cm [high] -1

(10) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), 172-174 ° C (dec.).

I.R. (Nujol): 3250, 3150, 1770, 1620 cm [high] -1

(11) 7- [2- (4-aminomethylbenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -carboxylic acid dihydrochloride (syn isomer)

I.R. (Nujol): 3400-3100, 1770, 1660, 1620, 1540 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 3.68 (2H, broad s), 3.97 (2H, d, J = 6Hz), 4.43 (2H, AB [deep] q, J = 13Hz), 5.12 (1H , d, J = 5Hz), 5.12 (2H, s), 5.72 (1H, dd, J = 5 and 7Hz), 6.88 (1H, s), 7.43 (4H, s), 9.5 (1H, s), 9.8 (1H, d, J = 7Hz)

(12) 7- [2- (t-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3280, 3200, 1770, 1670, 1630 cm [high] -1

(13) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer)

I.R. (Nujol): 3300, 3200, 1770, 1660, 1620, 1600 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 3.67 (2H, m), 3.94 (3H, s), 4.32 (2H, m), 4.98-5.36 (3H, m), 5.78 (1H, dd, J = 5 and 8Hz), 6.72 (1H, s),

6.95-7.65 (4H, m), 9.65 (1H, d, J = 8Hz)

(14) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), M.p. 168-185 ° C (dec.).

I.R. (Nujol): 3250, 1765, 1670, 1625 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 1.21 (3H, t, J = 7Hz), 3.70 (2H, broad s), 4.18 (2H, q, J = 7Hz), 4.31 (2H, m), 4.72 (2H, broad s), 5.17 (1H, d, J = 4Hz), 5.82 (1H, dd, J = 4 and 7Hz), 6.83 (1H, s), 7.17 (2H, broad s), 9.57 (1H , d, J = 7Hz)

(15) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer), m.p. 145 - 149 ° C (decomp.).

I.R. (Nujol): 3250, 1765, 1650 cm [high] -1

(16) 7- [2-Cinnamyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3350-3100, 1760, 1650, 1620, 1520 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 3.47-3.97 (2H, m), 4.47 (2H, AB [deep] q, J = 14Hz), 4.8 (2H, d, J = 5Hz), 5.18 ( 1H, d, J = 5Hz), 5.83 (1H, dd, J = 5 and 8Hz), 6.83 (1H, s), 6.1-7.0 (2H, m), 7.08-7.72 (5H, m), 9.6 (1H , s), 9.72 (1H, d, J = 8Hz)

(17) 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazole-

4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres)

I.R. (Nujol): 3300, 3200, 1770, 1660, 1630, 1600 cm [high] -1

N.M.R. (DMSO-d [low] 6, small delta): 3.69 (2H, AB [low] q, J = 18Hz), 4.35 (2H, AB [low] q, J = 15Hz), 4.93-5.43 (3H, m ), 5.81 (1H, dd, J = 5 and 8Hz), 6.80 (1H, s), 6.96-7.70 (4H, m), 9.73 (1H, d, J = 8Hz)

(18) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] cephalosporanic acid (syn-isomer), mp 185-192 ° C (dec.)

I.R. (Nujol): 3380, 3250, 1780, 1700, 1650 cm [high] -1

N.M.R. (DMSO-d [low] 6, small delta): 2.02 (3H, s), 3.53 (2H, m), 4.84 (2H, AB [low] q, J = 13Hz), 5.13 (2H, s), 5.40 (1H, d, J = 4Hz), 5.79 (1H, dd, J = 4 and 8Hz), 6.73 (1H, s), 6.96-7.63 (4H, m), 9.62 (1H, d, J = 8Hz)

(19) 7- [2- (3,4-Dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] cephalosporanic acid (syn isomer), mp 200-205 ° C (dec.).

I.R. (Nujol): 1730, 1640, 1600, 1230, 1020 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 2.00 (3H, s), 3.30 (2H, AB [deep] q, J = 18Hz), 4.68-5.12 (5H, m), 5.60 (1H, dd, J = 6 and 8Hz), 6.72 (1H, s), 7.32-7.64 (3H, m), 9.60 (1H, d, J = 8Hz)

(20) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3400-3100, 1760, 1660, 1620, 1520 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 3.72 (2H, wide s), 4.47 (2H, AB [deep] q, J = 14Hz), 5.1 (1H, d, J = 5Hz), 5.22 (2H , s), 5.83 (1H, dd, J = 5 and 8Hz), 6.85 (1H, s), 6.87 (1H, dd, J = 2 and 8Hz), 7.08 (1H, d, J = 2Hz), 7.52 ( 1H, d, J = 8Hz), 9.67 (1H, s), 9.77 (1H, d, J = 8Hz)

(21) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), M.p. 178-180 ° C (dec.).

I.R. (Nujol): 3300, 3280, 1770, 1670, 1630 cm [high] -1

(22) 7- [2- (t-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- [tetrazolo [1,5-b] pyridazin-6-yl] thiomethyl-3-cephem -4-carboxylic acid (syn isomer)

I.R. (Nujol): 3300, 1770, 1670, 1620 cm [high] -1

N.M.R. (DMSO-d [low] 6, small delta): 1.41 (9H, s), 3.72 (2H, m), 4.42 (2H, AB [low] q, J = 14Hz), 4.55 (2H, s), 5.16 (1H, d, J = 4Hz), 5.80 (1H, dd, J = 4 and 8Hz), 6.79 (1H, s), 7.74 (1H, d, J = 10Hz), 8.57 (1H, d, J = 10Hz ), 9.48 (1H, d, J = 8Hz)

(23) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [tetrazolo [1,5-b] pyridazin-6-yl] thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3270, 3170, 1765, 1670, 1620 cm [high] -1

Example 9

4 ml of trifluoroacetic acid were added with ice cooling to a stirred suspension of 1.0 g of 7- [2-t-butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2 -yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres) in 1 ml of anisole was added and the resulting mixture was stirred for 70 minutes at ambient temperature. The reaction mixture was concentrated under reduced pressure and diethyl ether was added. The precipitates were collected by filtration, washed with diethyl ether, dried, suspended in 10 ml of water and then dissolved in a 10% aqueous sodium hydroxide solution (pH 7 to 7.5). The solution was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring, and then it was stirred for 30 minutes under ice-cooling. The precipitates were collected by filtration, washed with water and dried to give 0.75 g of 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres).

I.R. (Nujol): 3360, 3240, 3100, 1780, 1680, 1635 cm [high] -1

N.M.R. (d [low] 6-DMSO, small delta): 3.68 (2H, s), 4.46 (2H, AB [low] q, J = 15Hz), 4.61 (2H, s), 5.17 (1H, d, J = 5Hz), 5.82 (1H, d, d, J = 5 and 9Hz), 6.83 (1H, s), 7.23 (2H, broad s), 9.50 (1H, d, J = 9Hz), 9.53 (1H, s)

Example 10

The following compounds were prepared in a manner similar to Example 9:

(1) 7- [2-Carboxymethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3200, 1780, 1720, 1680, 1545 cm [high] -1

N.M.R. (d [low] 6, DMSO, small delta): 3.72 (2H, AB [low] q, J = 16Hz), 3.96 (3H, s), 4.33 (2H, AB [low] q, J = 14Hz), 4.67 (2H, s), 5.17 (1H, d, J = 5Hz), 5.86 (1H, d, d, J = 5 and 9Hz), 7.47 (1H, s), 8.52 (1H, s), 9.64 (1H , d, J = 9Hz), 12.64 (1H, broad s)

(2) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3340, 3200, 1775, 1675, 1630 cm [high] -1

(3) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), M.p. 178-180 ° C (dec.).

I.R. (Nujol): 3300, 3280, 1770, 1670, 1630 cm [high] -1

N.M.R. (DMSO-d [deep] 6, small delta): 3.69 (2H, m), 4.32 (2H, AB [deep] q, J = 14Hz), 4.60 (2H, m), 5.14 (1H, d, J = 5Hz), 5.79 (1H, d, d, J = 5 and 8Hz), 6.79 (1H, s), 9.47 (1H, d, J = 8Hz)

(4) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [tetrazolo [1,5-b] pyridazin-6-yl] thiomethyl-3-cephem-4-carboxylic acid (syn isomer)

I.R. (Nujol): 3270, 3170, 1765, 1670, 1620 cm [high] -1

N.M.R. (DMSO-d [low] 6, small delta): 3.77 (2H, AB [low] q, J = 18Hz), 4.45 (2H, AB [low] q, J = 14Hz), 4.63 (2H, s), 5.20 (1H, d, J = 4Hz), 5.86 (1H, d, d, J = 4 and 8Hz), 6.84 (1H, s), 7.78 (1H, d, J = 10Hz), 8.61 (1H, d, J = 10Hz), 9.54 (1H, d, J = 8Hz)

Example 11

1.1 g of 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] cephalosporanic acid (syn-isomeres) and 0.23 g of 1,3,4-thiadiazole-2-thiol were added to a stirred solution of 0.34 g of sodium bicarbonate in 30 ml of pH 6.8 phosphate buffer and the mixture was stirred at 60 to 65 ° C for 3 hours. The reaction mixture was cooled and adjusted to pH 3 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 0.45 g of 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3 , 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-Isomeres), mp 145 to 149 ° C (dec.).

I.R. (Nujol): 3250, 1765, 1650 cm [high] -1

N.M.R. (DMSO-d [low] 6, small delta): 3.73 (2H, AB [low] q, J = 18Hz), 4.48 (2H, AB [low] q, J = 14Hz), 5.01-5.39 (3H, m ), 5.85 (1H, dd, J = 4 and 8Hz), 6.83 (1H, s), 7.02-7.75 (4H, m), 9.63 (1H, s), 9.75 (1H, d, J = 8Hz)

Example 12

The following compounds were prepared in a manner similar to Example 11:

(1) 7- [2-Methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer)

I.R. (Nujol): 3230, 1780, 1680, 1550 cm [high] -1

(2) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3320, 3200, 1770, 1670, 1610 cm [high] -1

(3) 7- [2-t -Butoxycarbonylmethoxyimino-2- (2-formamido-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer).

I.R. (Nujol): 3225, 1780, 1725, 1685, 1550 cm [high] -1

(4) 7- [2-Methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3250, 1780, 1675, 1550 cm [high] -1

(5) 7- [2- (2-Ethoxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem -4-carboxylic acid (syn isomer).

I.R. (Nujol): 3500, 3200, 1780, 1720, 1680 cm [high] -1

(6) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-formamido-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3250, 1775, 1720, 1680, 1540 cm [high] -1

(7) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-formamido-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3250, 1780, 1725, 1680, 1540 cm [high] -1

(8) 7- [2-t-Butoxycarbonylmethoxyimino-2- (2-formamido-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer).

I.R. (Nujol): 3180, 1785, 1725, 1690, 1550 cm [high] -1

(9) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3350, 3250, 1780, 1680, 1633 cm [high] -1

(10) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-formamido-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3- cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3200, 1775, 1675, 1540 cm [high] -1

(11) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3340, 3200, 1775, 1670 cm [high] -1

(12) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3300, 1770, 1670, 1530 cm [high] -1

(13) 7- [2- (2-ethoxyethoxy) imino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer).

I.R. (Nujol): 3160, 3100, 1780, 1670, 1630 cm [high] -1

(14) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3350, 3220, 1780, 1680, 1630 cm [high] -1

(15) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3350, 3230, 3100, 1780, 1680, 1630 cm [high] -1

(16) 7- [2-t-Butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1775, 1730, 1675, 1630 cm [high] -1

(17) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3340, 3200, 1775, 1675, 1630 cm [high] -1

(18) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 3230, 3110, 1775, 1675 cm [high] -1

(19) 7- [2-Carboxymethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3200, 1780, 1720, 1680, 1545 cm [high] -1

(20) 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3- cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3360, 3240, 3100, 1780, 1680, 1635 cm [high] -1

(21) 7- [2- (t-Butoxycarbonylmethoxyimino) -2- (2-formamidothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3170, 1770, 1720, 1670 cm [high] -1

(22) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), M.p. 112-125 ° C (dec.).

I.R. (Nujol): 3250, 1770, 1730, 1680 cm [high] -1

(23) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), 172-174 ° C (dec.).

I.R. (Nujol): 3250, 3150, 1770, 1620 cm [high] -1

(24) 7- [2-Cinnamyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3400-3100, 1780, 1680, 1540 cm [high] -1

(25) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3400-3100, 1780, 1680, 1540 cm [high] -1

(26) 7- [2- (4-aminomethylbenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -carboxylic acid dihydrochloride (syn isomer).

I.R. (Nujol): 3400-3100, 1770, 1660, 1620, 1540 cm [high] -1

(27) 7- [2- (t-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3280, 3200, 1770, 1670, 1630 cm [high] -1

(28) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 3200, 1770, 1660, 1620, 1600 cm [high] -1

(29) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), M.p. 168-185 ° C (dec.).

I.R. (Nujol): 3250, 1765, 1670, 1625 cm [high] -1

(30) 7- [2-Cinnamyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3350-3100, 1760, 1650, 1620, 1520 cm [high] -1

(31) 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazole-

4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres).

I.R. (Nujol): 3300, 3200, 1770, 1660, 1630, 1600 cm [high] -1

(32) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3400-3100, 1760, 1660, 1620, 1520 cm [high] -1

(33) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), M.p. 178-180 ° C (dec.).

I.R. (Nujol): 3300, 3280, 1770, 1670, 1630 cm [high] -1

(34) 7- [2- (t-Butoxycarbonylmethoxyimino) -2- (2-formamidothiazol-4-yl) acetamido] -3- [tetrazolo [1,5-b] pyridazin-6-yl] thiomethyl-3- cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3150, 1780, 1720, 1670 cm [high] -1

(35) 7- [2- (t-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- [tetrazolo [1,5-b] pyridazin-6-yl] thiomethyl-3-cephem -4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1770, 1670, 1620 cm [high] -1

(36) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [tetrazolo [1,5-b] pyridazin-6-yl] thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3270, 3170, 1765, 1670, 1620 cm [high] -1

Claims (42)

1. 3,7-disubstituted-3-cephem-4-carboxylic acid compounds, characterized by the general formula (I) where mean: R [high] 1 amino or protected amino, R [high] 2 is an aliphatic hydrocarbon group with one or more suitable substituents, R [high] 3 carboxy or protected carboxy and R [high] 4 is hydrogen, acyloxy or a heterocyclic thio group which may have lower alkyl, with the proviso that R [high] 2 is not carboxy (lower) alkyl, protected carboxy (lower) alkyl or benzyl when R [high] ] 4 is acetoxy, and that R [high] 2 is not benzyl when R [high] 4 is tetrazolylthio with a methyl group, as well as the salts, especially the pharmaceutically acceptable salts thereof. 2. Syn isomer of a compound according to claim 1, characterized in that the -Group is one of the formula 3. Compound according to claim 1 or 2, characterized in that R [high] 2 lower alkylthio (lower) alkyl, lower alkoxy (lower) alkyl, ar (lower) alkenyl, acyloxy (lower) alkyl, carboxy (lower) alkyl, protected carboxy (lower) alkyl, isoxazolyl (lower) alkyl or ar (lower) alkyl which may include halogen, hydroxy, amino (lower) alkyl or acylamino (lower) alkyl, R [high] 3 carboxy and R [high] 4 Hydrogen, lower alkanoyloxy, carbamoyloxy, thiadiazolylthio, tetrazolopyridazinylthio or tetrazolylthio, which may have a lower alkyl group, with the proviso that R [high] 2 is not carboxy (lower) alkyl, protected carboxy (lower) alkyl or benzyl, if R [high] 4 is acetoxy, and when R [high] 4 is tetrazolylthio with a methyl group, R [high] 2 is not benzyl. 4. A compound according to claim 3, characterized in that R [high] 1 is lower alkanoylamino, R [high] 2 is lower alkanoyloxy (lower) alkyl and R [high] 4 is hydrogen or carbamoyloxy. 5. A compound according to claim 3, characterized in that R [high] 2 is ar (lower) alkyl having 1 to 2 halogen atoms and R [high] 4 is lower alkanoyloxy. 6. A compound according to claim 5, characterized in that R [high] 1 Amino or halogen (lower) alkanoylamino and R [high] 2 signify phenyl (lower) alkyl with 1 to 2 halogen atoms. 7. A compound according to claim 6, characterized in that R [high] 1 is amino or trihalogen (low) alkanoylamino, R [high] 2 is benzyl with 1 to 2 chlorine or fluorine atoms and R [high] 4 is acetoxy. 8. A compound according to claim 7, characterized in that R [high] 1 is amino or 2,2,2-trifluoroacetamido and R [high] 2 is 4-fluorobenzyl or 3,4-dichlorobenzyl. 9. A compound according to claim 3, characterized in that R [high] 1 amino, lower alkanoylamino or halogen (lower) alkanoylamino, R [high] 2 lower alkylthio (lower) alkyl, lower alkoxy (lower) alkyl, Ar (lower) alkenyl, lower alkanoyloxy (lower) alkyl, carboxy (lower) alkyl, lower alkoxycarbonyl (lower) alkyl, isoxazolyl (lower) alkyl or ar (lower) alkyl containing 1 to 2 halogen atoms, hydroxy, amino (lower) alkyl or may have lower alkoxycarbonylamino (lower) alkyl groups, and R [high] 4 is thiadiazolylthio. 10. A compound according to claim 9, characterized in that R [high] 1 amino, lower alkanoylamino or trihalogen (lower) alkanoylamino and R [high] 2 lower alkylthio (lower) alkyl, lower alkoxy (lower) alkyl, phenyl (lower) alkenyl, lower alkanoyloxy (lower) alkyl, carboxy (lower) alkyl, lower alkoxycarbonyl (lower) alkyl, isoxazolyl (lower) alkyl or phenyl (lower) alkyl containing 1 to 2 halogen atoms, hydroxy, amino (lower) alkyl or may have lower alkoxycarbonylamino (lower) alkyl groups. 11. A compound according to claim 10, characterized in that R [high] 1 amino, formamido or 2,2,2-trifluoroacetamido and R [high] 2 methylthiomethyl, ethoxyethyl, cinnamyl, formyloxyethyl, carboxymethyl, ethoxycarbonylmethyl, t-butoxycarbonylmethyl, isoxazolylmethyl or benzyl, which can have 1 to 2 fluorine, bromine, hydroxy, aminomethyl or t-butoxycarbonylaminomethyl groups. 12. A compound according to claim 11, characterized by the formula 7- [2-methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 13. A compound according to claim 11, characterized by the formula 7- [2-cinnamoyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 14. A compound according to claim 11, characterized by the formula 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 15. A compound according to claim 11, characterized by the formula 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2- yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres). 16. A compound according to claim 11, characterized by the formula 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 17. A compound according to claim 11, characterized by the formula 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl ) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 18. A compound according to claim 11, characterized by the formula 7- [2- (3-hydroxy-4-bromobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres). 19. A compound according to claim 11, characterized by the formula 7- [2- (4-aminomethylbenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl ) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) and its dihydrochloride. 20. A compound according to claim 3, characterized in that R [high] 1 is amino or lower alkanoylamino, R [high] 2 is carboxy (lower) alkyl or lower alkoxycarbonyl (lower) alkyl and R [high] 4 is tetrazolopyridazinylthio. 21. A compound according to claim 20, characterized in that R [high] 1 is amino or formamido and R [high] 2 is carboxymethyl or t-butoxycarbonylmethyl. 22. A compound according to claim 21, characterized by the formula 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [tetrazolo [1,5-b] pyridazin-6-yl] - thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 23. A compound according to claim 3, characterized in that R [high] 1 amino, lower alkanoylamino or halogen (lower) alkanoylamino, R [high] 2 lower alkylthio (lower) alkyl, lower alkanoyloxy (lower) alkyl, carboxy (lower) alkyl, lower alkoxycarbonyl (lower) alkyl or phenyl (lower) alkyl which may have a halogen atom and R [high] 4 denotes tetrazolylthio which may have a lower alkyl group, provided that R [high] 2 is not benzyl when R [high] 4 is tetrazolylthio having a methyl group. 24. A compound according to claim 23, characterized in that R [high] 2 is carboxy (lower) alkyl, lower alkoxycarbonyl (lower) alkyl or phenyl (lower) alkyl, which may have a halogen atom, and R [high] 4 is tetrazolylthio, the may have a hexyl group. 25. A compound according to claim 24, characterized in that R [high] 1 is amino, formamido or 2,2,2-trifluoroacetamido, R [high] 2 is carboxymethyl, ethoxycarbonylmethyl, t-butoxycarbonylmethyl or benzyl, which may have a fluorine atom . 26. A compound according to claim 25, characterized by the formula 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 27. A compound according to claim 25, characterized by the formula 7- [2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer). 28. A compound according to claim 25, characterized by the formula 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 29. A compound according to claim 23, characterized in that R [high] 2 lower alkylthio (lower) alkyl, lower alkanoyloxy (lower) alkyl, carboxy (lower) alkyl, lower alkoxycarbonyl (lower) alkyl or phenyl (lower) alkyl with a Halogen atom and R [high] 4 represent tetrazolylthio with a methyl group. 30. A compound according to claim 29, characterized in that R [high] 1 is amino, formamido or 2,2,2-trifluoroacetamido and R [high] 2 is methylthiomethyl, formyloxyethyl, carboxymethyl, ethoxycarbonylmethyl, t-butoxycarbonylmethyl or benzyl with a fluorine atom . 31. A compound according to claim 30, characterized by the formula 7- [2-methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 32. A compound according to claim 30, characterized by the formula 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 33. Compound according to claim 30, characterized by the formula 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl ) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 34. Process for the preparation of 3,7-disubstituted-3-cephem- 4-carboxylic acid compounds of the general formula (I) where mean: R [high] 1 amino or protected amino, R [high] 2 is an aliphatic hydrocarbon group with one or more suitable substituents, R [high] 3 carboxy or protected carboxy and R [high] 4 is hydrogen, acyloxy or a heterocyclic thio group which may have a lower alkyl group, with the proviso that R [high] 2 is not carboxy (lower) alkyl, protected carboxy (lower) alkyl or benzyl when R [ high] 4 is acetoxy, and that R [high] 2 is not benzyl when R [high] 4 is tetrazolylthio with a methyl group, and the salts, in particular the pharmaceutically acceptable salts thereof, characterized in that a compound of the general formula (II) wherein R [high] 3 and R [high] 4 each have the meanings given above, or a reactive derivative at the amino group or a salt thereof with a compound of the general formula (III) wherein R [high] 1 and R [high] 2 each have the meanings given above, or reacts a reactive derivative at the carboxy group or a salt thereof. 35. Process for the preparation of a compound of the general formula (Ib) wherein R [high] 2 is an aliphatic hydrocarbon group having one or more suitable substituents, R [high] 3 is carboxy or protected carboxy, and R [high] 4 is hydrogen, acyloxy or a heterocyclic thio group which lower alkyl may have, with the proviso that R [high] 2 is not carboxy (lower) alkyl, protected carboxy (lower) alkyl, or benzyl when R [high] 4 is acetoxy, and that R [high] 2 is not benzyl when R [high] 4 Means tetrazolylthio with a methyl group, or the salts, in particular the pharmaceutically acceptable salts thereof, characterized in that a compound of the general formula (Ia) wherein R [high] 2, R [high] 3 and R [high] 4 each have the meanings given above and R [high] 1a is protected amino, or a salt thereof is subjected to an elimination reaction to remove the amino protective group. 36. Process for the preparation of a compound of the general formula (Id) wherein R [high] 1 amino or protected amino, R [high] 2b carboxy (lower) alkyl, R [high] 3 carboxy or protected carboxy, and R [high] 4a hydrogen, carbamoyloxy or a heterocyclic thio group which may have lower alkyl , mean, or the salts, in particular the pharmaceutically acceptable salts thereof, characterized in that a compound of the general formula (Ic) wherein R [high] 1, R [high] 3 and R [high] 4a each have the meanings given above, and R [high] 2a denotes protected carboxy (lower) alkyl, or subjects a salt thereof to an elimination reaction to remove the carboxy protective group. 37. Process for the preparation of a compound of the general formula (If) wherein R [high] 1 is amino or protected amino, R [high] 2 is an aliphatic hydrocarbon group having one or more suitable substituents, R [high] 3 is carboxy or protected carboxy, and R [high] 4 'is a heterocyclic group having lower alkyl may, with the proviso that R [high] 2 is not benzyl when R [high] 4 'denotes tetrazolyl with a methyl group, or the salts, in particular the pharmaceutically acceptable salts thereof, characterized in that a compound of the general formula (Ie) wherein R [high] 1, R [high] 2 and R [high] 3 each have the meanings given above and X 'denotes a group which can be substituted by a radical of the formula R [high] 4'-S-, wherein R [high] 4 'has the meanings given above, or a salt thereof with a compound of the general formula R [high] 4'-SH (XVIII) wherein R [high] 4 'has the meanings given above, or converts its reactive derivative at the mercapto group. 38. Compound characterized by the general formula (III) where R [high] 1 is amino or protected amino and R [high] 2 is Ar (lower) alkenyl, as well as their salts. 39. Syn isomer of a compound according to claim 38, characterized in that R [high] 2 is cinnamyl. 40. Process for the preparation of a compound of the general formula (III) wherein R [high] 1 is amino or protected amino and R [high] 2 is Ar (lower) alkenyl, or a salt thereof, characterized in that one is a compound of the general formula (VIII) wherein R [high] 1 has the meanings given above, with a compound of the general formula R [high] 2-ONH [low] 2 (IX) wherein R [high] 2 has the meanings given above, or converts a salt thereof. 41. Antibacterial pharmaceutical agent, characterized in that it contains at least one 3,7-disubstituted-3-cephem-4-carboxylic acid compound according to any one of claims 1 to 33, and / or contains or consists of at least one pharmaceutically acceptable salt thereof, optionally in combination with at least one pharmaceutically acceptable, essentially non-toxic carrier or excipient. 42. Process for the production of an antibacterial pharmaceutical agent, characterized in that at least one 3,7-disubstituted-3-cephem-4-carboxylic acid compound according to one of claims 1 to 33 and / or at least one pharmaceutically acceptable salt thereof is used as the active ingredient (active ingredient) mixed with at least one inert carrier.