RU2081874C1 - Cephem compounds and their pharmaceutically acceptable salts - Google Patents

Abstract

FIELD: organic chemistry, antibiotics. SUBSTANCE: invention proposes new derivatives of cephem of the formula (I)

where: R¹ means amino- or protected amino-group; R² means lower alkyl that can be substituted with 1-3 halogen atoms; R³ means COO^⊖, carboxy- or substituted carboxy-group; R⁴ means hydroxy(lower)alkyl or protected hydroxy(lower)alkyl; R⁵ means amino- or protected amino-group; R⁶ means hydrogen or lower alkyl; X^⊖ means trifluoroacetate; n = 0 when R³ means COO^⊖ at condition that and n = 1 when R³ means carboxy- or protected carboxy-group, and its pharmaceutically acceptable salt. Synthesized compounds show antibacterial activity. EFFECT: improved method of synthesis. 7 cl, 3 tbl

Description

 The present invention relates to a new compound of Cephem and its pharmaceutically acceptable salt.

 More specifically, it relates to a new compound of Cephem and its pharmaceutically acceptable salt, which possess antimicrobial activity.

 Accordingly, an object of the present invention is to provide a Cephem compound and a pharmaceutically acceptable salt thereof that are highly active against a number of pathogenic microorganisms.

 Another objective of the present invention is the provision of a method for producing a cefemic substance or its salt.

в которой R¹ представляет собой амино- или защищенную аминогруппу,
R² низший алкил, который может иметь один или несколько подходящих заместителей,
R³ это COO^⊖ карбокси- или защищенная карбоксигруппа,
R⁴ это гидрокси(низший)алкил или защищенный гидрокси(низший)алкил,
R⁵ амино- или защищенная аминогруппа,
R⁶ атом водорода или низший алкил,
X^⊖ представляет собой анион, и
n это 0 или 1,
при условии, что:
1) Когда R³ это COO^⊖, тогда n равно 0, и
2) когда R³ является карбокси- или защищенной карбоксигруппой, тогда n равно 1.The target compound of Cephem is new and can be represented by the following general formula (I)

in which R ¹ represents an amino or protected amino group,
R ² lower alkyl, which may have one or more suitable substituents,
R ³ is COO ^⊖ carboxy or protected carboxy,
R ⁴ is hydroxy (lower) alkyl or protected hydroxy (lower) alkyl,
R ^{5 is an} amino or protected amino group,
R ^{6 is} a hydrogen atom or lower alkyl,
X ^⊖ is an anion, and
n is 0 or 1,
provided that:
1) When R ³ is COO ^⊖ , then n is 0, and
2) when R ³ is a carboxy or protected carboxy group, then n is 1.

 As for the target substance (1), the following points should be noted.

(в которой R¹ и R² каждый является таким, как указано выше), и анти-изомер означает другой геометрический изомер, имеющий частичную структуру, представленную следующей формулой:

(в которой R¹ и R² каждый является таким, как указано выше), причем все такие геометрические изомеры и их смеси включены в объем этого изобретения.That is, the target substance (1) includes the syn-isomer, anti-isomer and mixtures thereof. Syn-isomer means a geometric isomer having a partial structure represented by the following formula:

(in which R ¹ and R ^{2 are} each as described above), and the anti-isomer means another geometric isomer having a partial structure represented by the following formula:

(in which R ¹ and R ^{2 are} each as described above), all such geometric isomers and mixtures thereof being included within the scope of this invention.

(в которой R¹ и R² каждый является таким, как указано выше).In the present description and claims, the partial structure of these geometric isomers and their mixtures for convenience is represented by the following formula:

(in which R ¹ and R ^{2 are} each as described above).

(в которой R⁴, R⁵ и R⁶ каждый является таким, как указано выше).The next point that should be noted is that the pyrazolio group of the substance (1) can also exist in tautomeric forms, and such a tautomeric equilibrium can be represented by the following scheme:

(in which R ⁴ , R ⁵ and R ^{6 are} each as described above).

 Both of the above tautomeric isomers are included in the scope of the present invention, however, in the present description and claims, the target substance (1) is presented for convenience by one expression of the pyrazolio group of formula (A).

 The cephemic substance (I) of the present invention can be obtained using methods that are illustrated by the following reaction schemes.

R $\genfrac{}{}{0ex}{}{\text{5}}{\text{a}}$ защищенная аминогруппа и
Y это отщепляемая группа.

R $\genfrac{}{}{0ex}{}{\text{5}}{\text{a}}$ protected amino group and
Y is a leaving group.

 The starting compound (II) or its salt is new, and it can be prepared according to the following reaction schemes.

n каждый такой, как обозначено выше,
R⁷ является защищенной аминогруппой и
z отщепляемой группой.

n each as indicated above
R ⁷ is a protected amino group and
z a leaving group.

 Some of the starting materials (Y) or their salts are new, and they can be prepared in accordance with the methods disclosed in the preparative examples described below, or similar methods.

 Suitable pharmaceutically acceptable salts of the target substance (1) are conventional non-toxic mono- or double salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt , magnesium salt, etc.), ammonium salt, organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N-dibenzylethylenediamine salt, etc.), organic acid addition salt (e.g. formate, and cetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.) and an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), an amino acid salt (e.g., arginine salt, aspartic salt acids, glutamic acid salt, etc.), etc.

 In the foregoing and subsequent description of this application, corresponding examples of various definitions are explained in detail as follows.

 The term "lower" means from 1 to 6 carbon atoms, unless otherwise indicated.

 A suitable protecting group in a “protected amino group” may include ar (lower) alkyl, such as mono- or di-, or triphenyl (lower) alkyl (eg, benzyl, phenethyl, 1-phenyl ethyl, benzhydryl, trityl, etc.), acyl, as explained below, and the like.

 Suitable acyl can be aliphatic acyl, aromatic acyl, arylaliphatic acyl and heterocyclic-aliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid, sulfonic acid, and the like.

 A suitable example of an acyl group thus explained may be lower alkanoyl (e.g., formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc.) mono- (or di- or three-) -halo (lower) alkanoyl (e.g., chloroacetyl, trifluoroacetyl etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, hexyl-hydroxycarbonyl, etc.), mono- (or di- or tri-) halo (lower) alkoxycarbonyl (e.g. chloromethoxycarbonyl , dichloroethoxycarbonyl, trichloroethoxycarbonyl, etc.), aroyl (e.g. benzoi , toluoyl, xyloyl, naphthoyl, etc.), ar (lower) alkanoyl, such as phenyl (lower) alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.), aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl, etc.), aryloxy- ( lower) -alkanoyl, such as phenoxy (lower) alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl, etc.), arylglyoxyloyl (e.g. phenylglyoxyoyl, naphthylglyoxyloyl, etc.), ar (lower) alkoxycarbonyl, which may have suitable substituents (s) such as phenyl (lower) alkoxycarbonyl, which may have a nitro or lower alkoxy uppu (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, paranitrobenziloksikarbonil, p-methoxybenzyloxycarbonyl, etc.), thienylacetyl, imidazolilatsetil, furilatsetil, tetrazolilatsetil, triazolilatsetil, tiadiazolilatsetil, tienilpropionil, tiadiazolpropionil, lower alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl), isopropylsulfonyl, pentylsulfonyl, butylsulfonyl and other arylsulfonyl (e.g., phenethylsulfonyl, toliosulfonyl, xylylsulfonyl, naphthylsulfonyl, etc.), ar (lower) alkylsulfonyl, such as enyl (lower) alkylsulfonyl (e.g., benzylsulfonyl, phenylsulfonyl, benzgidrilsulfonil et al.), etc.

 A preferred example of the thus-defined “protected amino group” may be an ar (lower) alkylamino and lower alkanoylamino group, more preferred may be triphenyl (CL-C4) alkylamino and CL-C4-alkanoylamino, and most preferred may be trilylamino, formamido and acetamido groups.

 A suitable “protected carboxy” can be an esterified carboxy group or the like, and specific examples of the ester function in said esterified carboxy group can be such as a lower alkyl ester (for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropyl ethyl ester, etc.) that may be suitable substituents (s), for example, lower alkanoyloxy (lower) alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxymethyl ester, 1-acetoxymethyl ester , pivaloyloxymethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.), lower alkanesulfonyl (lower) -alkyl ester (e.g., 2-mesylate octylphenyl ether, etc.) or mono (or di or tri) halo (lower) alkyl ester (e.g., 2-iodomethyl ester, 2,2,2-trichloroethyl ester, etc.)..; lower alkenyl ester (for example, vinyl ester, allyl ester, etc.); lower alkynyl ester (for example, ethinyl ester, propynyl ester, etc.); ar (lower) -alkyl ester, which may have a suitable substituent (s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis ester (methoxyphenyl) methyl ether, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.); an aryl ester which may have a suitable substituent (s) (e.g., phenyl ester, 4-chlorophenyl ester, tolyl ester, 4-tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.) ; or the like, in which mono- or di- or tri-phenyl (CL-C4) alkyl ester may be preferred, and benzhydryl ester may be most preferred.

 Suitable "lower alkyl" may be straight or branched chain alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, 2-ethylpropyl, hexyl or the like. in which preferred "lower alkyl" may be (CL-C4) alkyl and most preferred may be methyl.

 Suitable examples of "suitable substituent (s)" in "lower alkyl, which may have one or more suitable substituents (s)", may include halogen (e.g. fluorine, chlorine, bromine, iodine) and the like.

 Suitable examples of said lower alkyl having one or more suitable substituents (s) may include lower alkyl having one or more halogen atoms such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloro-2-fluoroethyl, 3- bromo-2-fluoropropyl, 1-chloromethyl-2-iodo-1-bromoethyl, 2-difluoropropyl, 1-dichloromethyl-1-methylethyl, 2-fluoro-4-chloro-5-bromopentyl, 1-difluoro-2-ethylpropyl, 2-fluoro-3-iodhexyl or the like. in which (CL-C4) alkyl having 1 to 3 halogen atoms may be preferred, dihalo (CL-C4) alkyl may be more preferred and difluoromethyl may be most preferred.

 Suitable "hydroxy (lower) alkyl" may include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 1- (hydroxymethyl) ethyl, 1-hydroxybutyl, 1-hydroxymethyl-1-methylethyl, 3-hydroxypentyl, 3-hydroxy -2-ethylpropyl, 6-hydroxyhexyl and the like, in which hydroxy (CL-C4) alkyl may be preferred and 2-hydroxyethyl may be most preferred.

 Suitable "protected hydroxy (lower) alkyl" may include acyloxy (lower) alkyl and the like, in which a suitable "acyl" function may be referred to as indicated by way of example for the "protected amino group" above, with suitable examples of "acyloxy (lower) ) alkyl "may be lower alkanoyloxy (lower) alkyl (e.g., formyloxymethyl, 1-formyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 3-acetoxypropyl, 1- (propionyloxymethyl) ethyl, 1-butyryloxybutyl, 1-hexanoyloxybutyl, 1- pivaloyloxymethyl-1-methylethyl, 8-formyl sipentyl, 3-formyloxy-2-ethylpropyl, 6-acetoxyhexyl and others), carbamoyloxy (lower) alkyl (e.g. carbamoyloxymethyl, 1-carbamoyloxyethyl, 2-carbamoyloxyethyl, 3-carbamoyloxypropyl, 1- (carbamoyloxymethyl-ethyl) , 1-carbamoyloxymethyl-1-methylethyl, 3-carbamoyloxypentyl, 3-carbamoyloxy-2-ethylpropyl, 6-carbamoyloxyhexyl, etc.) or the like, in which (CL-C4) alkanoyloxy (CL-C4) alkanoyloxy ( CL-C4) alkyl or carbamoyloxy (CL-C4) alkyl and 2-formyloxyethyl, 2-acetoxyethyl may be most preferred Is 2-carbamoyloxyethyl.

 A suitable "anion" may be formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, chloride, bromide, iodide, sulfate, phosphate and the like.

 A suitable “leaving group” may be a halogen atom (eg, chlorine, bromine, iodine, etc.), an acyloxy group such as sulfonyloxy (eg, benzenesulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy group (eg, acetyloxy -, propionyloxy, etc.), etc.

 Methods of obtaining the target substance of the present invention are explained in detail below.

 Method 1

 The target substance (1) or its salt can be obtained by reacting compound (II) or its reactive derivative with an amino group, or its salt with compound (III) or its reactive derivative with a carboxy group, or its salt.

 A suitable reactive derivative at the amino group of compound (II) may include an imine-type Schiff base or its amine-type tautomeric isomer formed by reacting compound (II) with a carbonyl compound such as an aldehyde, ketone, and the like. a silyl derivative formed by the reaction of compound (II) with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea or the like. a derivative formed by the interaction of compound (II) with phosphorus trichloride or phosgene, etc.

 Suitable salts of compound (II) and its reactive derivative may be referred to as indicated by way of example for substance (1).

Suitable reactive derivatives at the carboxy group of compound (III) may include acid halide, acid anhydride, activated amide, activated ester, and the like. Suitable examples of reactive derivatives may be an acid chloride; acid azide, mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphoric acid, sulfuric acid, thiosulfuric acid, sulfur acid (e.g., methanesulfonic acid, etc.), aliphatic carboxylic acid (e.g., acetic acid, propionic acid, butyric acid, isobutyric acid, trimethylacetic acid, p entanoic acid, isopentanoic acid, 2-ethylbutyric acid, tetraacetic acid, etc.) or aromatic carboxylic acid (for example, benzoic acid, etc.), symmetric acid anhydride; activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; or an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N = CH-] ester, vinyl ester, propargyl ester, para-nitrophenyl ester, 2,4-dinitrophenyl ester , trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthio ester, para-nitrophenyl-thioester, para-cresyl-thioester, carboxymethyl-thio ester dil ester, piperidyl ester, 8-quinolyl-thioether ester, etc.), or an ester with an N-hydroxy compound (e.g., N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc., etc. These reactive derivatives may not necessarily be selected from those corresponding to the type of compound (III) used.

 Suitable salts of compound (III) and its reactive derivative may be referred to as, for example, for substance (I).

 Typically, the reaction is carried out in a traditional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any another organic solvent that does not adversely affect the reaction. These traditional solvents can also be used in a mixture with water.

 In this reaction, when compound (III) is used as a free acid or as a salt thereof, preferably the reaction is carried out in the presence of a conventional condensing agent such as N, N-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N ' - (4-di-ethylaminocyclohexyl) 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; trialkylphosphite; ethyl polyphosphate; phosphorus oxychloride (phosphoryl chloride), phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate (e.g. ethyl chloroformate, isopropyl chloroformate, etc.); triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolinium salt; the intramolecular salt of 2-ethyl-5- (metasulfophenyl) isoxazolinium hydroxide; 1- (para-chlorobenzenesulfonyloxy) -6-chloro-1H-benzothiazole; the so-called Vilsmeier reagent prepared by reacting N, N-dimethylformamide with thionyl chloride, phosgene, chloroformic acid trichloromethyl ether, phosphorus oxychloride, methanesulfonyl chloride, etc. or the like.

 This reaction can also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate, alkali metal bicarbonate, three (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine or the like. P.

 The reaction temperature is not critical, and usually the reaction is carried out either by cooling or by heating.

 Method 2

The target substance (1b) or its salt can be obtained by involving the substance (1a) or its salt in the elimination reaction of the amino protecting group in R $\genfrac{}{}{0ex}{}{\text{one}}{\text{a}}$ .

 This reaction is carried out in accordance with a conventional method, such as hydrolysis, reduction, or the like.

 Preferably, the hydrolysis is carried out in the presence of a base or acid, including Lewis acid. A suitable base may include an inorganic base and an organic base such as an alkali metal (e.g. sodium, potassium, etc.), an alkaline earth metal (e.g. magnesium, calcium, etc.), a hydroxide, or a carbonate, or bicarbonate of these metals, trialkylamine (e.g. trimethylamine, triethylamine, etc.), picolin, 1,5-diazobicyclo- / 4,3,0 / non-5-ene, 1,4-diazabicyclo / 2,2,2 / octane, 1,8 -diazabicyclo / 5.4.0 / -uned-7-ene or the like

 Suitable acids may include organic acid (e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide and hydrogen chloride. )

 The elimination reaction using a Lewis acid, such as trihaloacetic acid (e.g. trichloroacetic acid, trifluoroacetic acid, etc.) or the like, is preferably carried out in the presence of cation trapping agents (e.g., anisole, phenol, etc.).

 Typically, the reaction is carried out in a solvent such as water, alcohol (for example, methanol, ethanol, etc.), methylene chloride, tetrahydrofuran, mixtures thereof, or in any other solvent that does not adversely affect the reaction. A liquid base or acid may also be used as a solvent. The reaction temperature is not critical, and usually the reaction is carried out under conditions from cooling to heating.

 The interaction method used for the elimination reaction may include chemical reduction and catalytic reduction.

 Suitable reducing agents that can be used in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or a metal compound (e.g. chromium chloride, chromium acetate etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, para-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

 Suitable catalysts that can be used in catalytic reduction are traditional catalysts such as platinum catalysts (e.g., platinum plate, sponge platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., sponge palladium , palladium black, palladium oxide on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g., reduced nickel, nickel oxide, nickel P Renea et al.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced iron, Raney iron, etc.), copper catalysts (e.g., reduced copper, Raney copper, Ulman copper, and etc.), etc.

 Usually, the reduction is carried out in a traditional solvent which does not adversely affect the reaction, such as water, methanol, ethanol, propanol, N, N-dimethylformamide or mixtures thereof.

 In addition, in the case where the aforementioned acid used in the reaction is a liquid, it can also be used as a solvent. Further, a suitable solvent that is used in the catalytic reduction may be the aforementioned solvent, another conventional solvent such as diethyl ether, dioxane, tetrahydrofuran and the like, or mixtures thereof.

 The temperature of the reaction mixture during reduction is not critical, and usually the reaction is carried out under conditions from cooling to heating.

The present invention includes within the scope of protection the case where the protected amino group in R ^{5 is} converted to an amino group, the case when the protected carboxy group in R ^{3 is} converted to a carboxy group, and the case when the protected hydroxy (lower) alkyl in R ^{4 is} converted to hydroxy (lower) alkyl .

 Method 3

 The target substance (I) or its salt can be obtained by reacting compound (IV) or its salt with compound (V) or its salt.

 Suitable salts of compounds (IV) may be salts of organic acids (e.g., acetate formate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), inorganic acid salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.) etc.

 The present reaction can be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzyl, methylene chloride, ethylene chloride, formamide, N, N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide or any other an organic solvent that does not adversely affect the reaction, preferably in solvents with strong polarity. Among solvents, hydrophilic solvents may be used in admixture with water. When compound (V) is a liquid, it can also be used as a solvent. Preferably, the reaction is 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 and the like. The reaction temperature is not critical, and usually the interaction is carried out at room temperature, by heating or by cooling. Preferably, the present reaction is carried out in the presence of an alkali metal halide (e.g., sodium iodide, potassium iodide, etc.), an alkali metal thiocyanate (e.g., sodium thiocyanate, potassium thiocyanate, etc.) or the like.

Anion X ^⊖ may be one of the derivatives of the leaving group Y and may be another one converted by the anion according to the traditional method.

 Method 4

The target compound (1d) or its salt can be obtained by involving the substance (1c) or its salt in the elimination reaction of the carboxy protecting group in R $\genfrac{}{}{0ex}{}{\text{3}}{\text{b}}$ .

 This reaction can be carried out in a similar manner as mentioned in method 2, and therefore, for the type of reaction and reaction conditions (for example, base, acid, catalyst, solvent, reaction temperature, etc.) of this interaction, we will refer to those that are explained in the method 2.

The present invention includes within the scope of protection cases where the protected amino group in R ¹ and / or R ⁵ and / or the protected hydroxy (lower) alkyl in R ^{4 is} converted to the amino group and / or hydroxy (lower) alkyl, respectively, during this reaction.

 Method 5

The target substance (1f) or its salt can be obtained by involving the compound (1e) or its salt in the elimination reaction of the hydroxy protecting group in R $\genfrac{}{}{0ex}{}{\text{4}}{\text{a}}$ ..

 This reaction can be carried out in a manner similar to that mentioned above in method 2, and therefore, for the type of reaction and reaction conditions (for example, base, acid, catalyst, solvent, reaction temperature, etc.) of this interaction, we will refer to those that are explained in the method 2.

The present invention includes, within the scope of protection, the protected amino group in R ¹ and / or R ⁵ and / or the protected carboxy group in R ³ during this reaction is converted to an amino and / or carboxy group, respectively.

 Method 6

The target substance (1h) or its salt can be obtained by involving the compound (1g) or its salt in the elimination reaction of the amino protecting group in R $\genfrac{}{}{0ex}{}{\text{5}}{\text{a}}$
This reaction can be carried out in a similar manner as mentioned above in method 2, and therefore, we will refer to those described in the type of reaction and reaction conditions (e.g., base, acid, catalyst, solvent, reaction temperature, etc.) of this interaction. method 2.

The present invention includes within the scope of protection the case where the protected amino group in R ¹ and / or the protected carboxy group in R ³ and / or the protected hydroxy (lower) alkyl in R ^{4 are} converted to the amino and / or carboxy group and / or hydroxy (lower) alkyl accordingly during this reaction.

 The reactions in methods A to C for the preparation of starting compounds (II) or their salts can be carried out in accordance with methods similar to those described in methods 2 to 6 for the preparation of substance (I) or its salt.

 Now, in order to demonstrate the usefulness of the target substance (I), the MIC data (minimum inhibitory concentration) of the characteristic substance (I) of this invention is given below.

 Test Method 1.

 In vitro antimicrobial activity is determined by double dilution of the agar plate, as described below.

One loop of the night culture of each test strain in trypticase-soy broth (10 ⁸ viable cells per 1 ml) is applied in stripes on cardiac extract agar (H1 agar) containing graduated concentrations of a particular test substance, with the minimum inhibitory concentration (MIC) expressed in units of μg / ml after incubation at 37 ^o C for 20 hours.

 Test substance.

 (1) 7beta- [2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem-4 β-carboxylate (syn isomer) is a substance of Example 4.

 The test result is shown in table. one.

 Comparative test results.

 1) Test method 2.

 The in vitro antibacterial activity was determined by double dilution of the agar plate as described below.

One complete loop of overnight culture of each test line in trypticase soy broth (10 ⁸ viable cells per ml volume) was applied to heart extract agar (H1 agar) containing graduated concentrations of a particular test compound and minimal inhibitory concentration (MIC) was expressed in units of μg / ml after incubation at 37 ^° C. for 20 hours.

 2) Test compound.

 Test compound (1): 7β- [2- (2-Aminothiazol-4-yl) -2- (difluoromethoxyimino) acetamido] -3- [3-amino-2- (2-hydroxyethyl) -1-pyrozolium] - methyl 3-cephem-4-carboxylate (syn isomer) (compound of Example 3).

 Test compound (2): 7β- [2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [4-methyl-3-amino-2- (2-hydroxyethyl) -1-pyrazolium] - methyl 3-cephem-4-carboxylate (syn isomer) (compound of Example 17).

 Test compound (A): 7β- [2- (2- Aminothiazol-4-yl) -2- (difluoromethoxyimino) acetamido] -3- (3-amino-2-methyl-1-pyrozolium) methyl-3- cefem-4-carboxylate (syn isomer) (compound of Example 67 from European Patent N0223246).

 Test compound (B): 7β- [2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (4-methyl-3-amino-2-methyl-1-pyrazolium) methyl-3- cefem-4-carboxylate (syn isomer) (compound of Example 89 from European Patent N0223246).

 3) The test results are given in table. 2.

 Test Method 3.

 Antibacterial activity in vitro was determined using the method of double dilution of the plates with agar medium.

One complete loop of overnight culture of each test line in trypticosoy soy broth (10 ⁸ viable cells per ml volume) was applied to agar with a cardiac extract (H1 agar) containing graduated concentrations of a particular test compound and a minimum inhibitory concentration (MIC) was expressed in units of μl / ml after incubation at 37 ^o C for 20 hours.

 Test compound: 7β- [2- (2-aminothiazol-4-yl) -2 - / (difluoromethoxyimino) acetamido] -3- [3-formamido-2- (2-hydroxyethyl) -1-pyrazolo] methyl-3 cephem-4-carboxylate (syn isomer) (compound of Example 8).

 The test result is shown in table. 3.

 For therapeutic purposes, the target substance (I) and its pharmaceutically acceptable salt of the present invention are used in the form of a traditional pharmaceutical preparation, which contains the specified substance as an active ingredient, in a mixture with pharmaceutically acceptable carriers, such as organic or inorganic solid or liquid medium for the drug, which is suitable for oral, parenteral and external use. These pharmaceutical preparations may be in solid form, such as tablets, granules, powder, capsules, or in liquid form, such as solution, suspensions, syrup, emulsion, lemonade and the like.

 If necessary, the aforementioned preparations may include auxiliary compounds, stabilizing aluents, moisturizing agents and other commonly used additives, such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, white earth, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol, etc.

 The dosage of the substance (I) can vary and, in addition, depend on the age, condition of the patient, the nature of the disease, the type of substance (I) that is used, etc. In general, doses of between 1 mg and approximately 4000 mg or even more. For the treatment of diseases caused by pathogenic microorganisms, average unit doses of approximately 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, 2000 mg of the target substance (I) of the present invention can be used.

 The following data on the testing of the claimed compounds of Cephem for toxicity upon intravenous administration clearly show that they are practically non-toxic.

 Analysis method.

 The test compound (dose: 320 mg / kg per day) was administered intravenously to SD rats (one group: 5 rats) for 4 weeks and observed. During this period of time, no animal died.

 Test compound: 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3-amino-2- (2-hydroxyethyl) -1-pyrazolo] methyl-3-cefem-4- carboxylate (syn isomer) (compound of Example II).

 The following preparative examples and examples are given in order to more fully illustrate the present invention.

 Preparative example 1.

A mixture of acetic anhydride (11, 13 ml) and formic acid (5.93 ml) was stirred at room temperature for 30 minutes. To this solution, 5 g of 5-amino-1- (2-hydroxyethyl) pyrazole was added under ice-cooling, and the mixture was stirred at 30 ^° -40 ^° C. for 1 hour. The reaction mixture was poured into a mixture of water, tetrahydrofuran and ethyl acetate and its pH was adjusted to 6 with an aqueous solution of sodium bicarbonate. The organic layer was separated, and the aqueous layer was extracted with a mixture of tetrahydrofuran and ethyl acetate three times. The organic layers were combined, dried over magnesium sulfate and evaporated in vacuo to give 5.18 g of 6-formamido-1- (2-formyloxyethyl) pyrazole.

IR (in nujol): 3180, 1705, 1660 cm ^-1 .

 NMR spectrum (in perdeuterodimethyl sulfoxide), d: 4.21 4.61 (4H, multiplet), 6.11 and 6.34 (1H, each doublet, J 3 Hz), 7.47 (1H, doublet, J 3 Hz), 8.00 (1H, singlet), 8.33 (1H, singlet).

 Preparative example 2.

 To a mixture of 7-beta-tert-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (20 g) and sodium iodide (5.82 g) in 20 ml of N, N-dimethylformamide was added 21.34 g 5-formamido-1- (2-formyloxyethyl) pyrazole at room temperature. After stirring for 24 hours at the same temperature, the mixture was poured into a mixture of water and ethyl acetate. The organic layer was separated and washed with water, an aqueous solution of sodium chloride, and dried over magnesium sulfate. The solutions were evaporated in vacuo to give 7-beta-tert-butoxycarbonylamino-3- (3-formamido-2- (2-formyloxyethyl) -1-pyrazolo) methyl-3-cephem-4-carboxylic acid benzhydryl ester, iodide (29, 6 g).

IR (in nujol): 17.80, 1720 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 1.49 (9H, singlet), 3.43 (2H, broad singlet), 4.14 4.38 (2H, multiplet), 4.52 4.73 (2H, multiplet ), 5.15 (1H, doublet, J = 5 Hz), 5.40 (2H, wide singlet), 5.67 (1H, doublets, J = 5 Hz and 8 Hz), 6.88 (1H, singlet ), 7.02 (1H, doublet, J = 3 Hz), 7.18 - 7.52 (10H, multiplet), 7.94 (1H, doublet, J = 8 Hz), 7.99 (1H, singlet ), 8.27 (1H, doublet, J = 3 Hz), 8.51 (1H, broad singlet).

 Preparative example 3.

 To a solution of 7-beta-tert-butoxycarbonylamino-3- (3-formamido-2- (2-formyloxyethyl) -1-pyrazolo) methyl-3-cephem-4-carboxylic acid benzhydryl ester, iodide (29.5 g) and 30 ml of anisole in 90 ml of methylene chloride are added dropwise 60 ml of trifluoroacetic acid under ice cooling. After stirring for 1 hour at room temperature, the mixture was poured into a mixture of diisopropyl ether (600 ml) and ethyl acetate (600 ml). The precipitate formed is collected by filtration, obtaining salts of bis (trifluoroacetic acid) 7-beta-amino-3- (3-formamido-2- (2-formyloxyethyl) -1-pyrazolo) methyl-3-cefem-4-carboxylate (22, 7 g).

IR (nujol): 1780, 1715, 1660 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide): s 3.53 (2H, broad singlet), 4.28 4.56 (2H, multiplet), 4.78 4.99 (2H, multiplet), 5.29 (2H, wide singlet) ), 5.53 (2H, broad singlet), 7.14 (1H, doublet, J = 3 Hz), 8.22 (1H, singlet), 8.46 (1H, doublet, J = 3 Hz), 8 , 63 (1H, singlet).

 Preparative example 4.

 Concentrated hydrochloric acid (5.67 ml) was added to a mixture of salts of bis (trifluoroacetic acid) 7-beta-amino-3- (3-formamido-2- (2-formyloxyethyl) -1-pyrazolo) methyl-3-cefem- 4-carboxylate (10 g) in 50 ml of methanol at room temperature. After stirring at this temperature for 3 hours, this mixture was added dropwise to 500 ml of ethyl acetate. The precipitate formed was collected by filtration to obtain 7-beta-amino-3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cephem-4-carboxylate trihydrochloride (6.1 g).

IR (nujol): 3250, 1770, 1700, 1625 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 3.43 (2H, broad singlet), 3.52 3.88 (2H, multiplet), 4.18 4.48 (2H, multiplet), 5.28 (2H, wide singlet), 5.37 (2H, broad singlet), 5.97 (1H, doublet, J = 3 Hz), 8.18 (1H, doublet, J = 3 Hz).

 Example 1

A mixture of N, N-dimethylformamide (0.41 ml) and 0.49 ml of phosphoryl chloride in 2 ml of ethyl acetate was stirred under ice-cooling for 30 minutes to prepare the Vilsmeier reagent. To the above solution, at 0 5 ^° C., 1.02 g of 2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetic acid was added and the mixture was stirred at the indicated temperature for 30 minutes to obtain an activated acid solution. This activated acid solution was added to a solution of 7-beta-amino-3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cephem-4-carboxylate, trihydrochloride (2 g) and 5, 85 g of N- (trimethylsilyl) acetamide in 40 ml of tetrahydrofuran under ice-cooling, and then the mixture was stirred at 10-15 ^° C for 1 hour. The resulting mixture was poured into 500 ml of diethyl ether, and the precipitate formed was collected by filtration to obtain 7-beta- (2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) -3- (3-amino-2- ( 2-hydroxyethyl) -1-pyrazolio) methyl-3-cephem-4-carboxylate, dihydrochloride (syn isomer, 2.55 g).

IR (nujol): 1770, 1660 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 3.30 (2H, multiplet), 3.68 (2H, multiplet), 3.92 (3H, singlet), 4.31 (2H, multiplet), 5.29 (1H doublet, J = 5 Hz), 5.32 (2H, multiplet), 5.88 (1H, doublets, J = 5 Hz and 8 Hz), 5.99 (1H, doublet, J = 3 Hz), 7 48 (1H, singlet), 8.12 (1H, doublet, J = 3 Hz), 8.59 (1H, singlet), 9.81 (1H, doublet, J = 8 Hz).

 The following substances (examples 2 and 3) were obtained by a method similar to that in example 1.

 Example 2

 7-beta- (2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido) -3-3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem-4 β-carboxylate (syn isomer).

IR (nujol): 3300, 1770, 1640 cm ^-1 .

 Example 3

 7-beta- (2- (2-Aminothiazol-4-yl) -2- (difluoromethoxyimino) acetamido) -3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3- cefem-4-carboxylate (syn isomer).

IR (nujol): 3300, 1760, 1660 cm ^-1 .

 Example 4

 To a solution of 7beta- (2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) -3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem-4- carboxylate (syn-isomer, 2.5 g) in methanol (12.5 ml) add 0.88 ml of concentrated hydrochloric acid (0.88 ml) at room temperature. After stirring at the same temperature for 2 hours, the mixture was poured into ethyl acetate (500 ml) and the precipitate formed was collected by filtration. The precipitate was dissolved in water (100 ml) and basified to pH 2 with an aqueous solution (5%) of sodium bicarbonate. This solution was chromatographed on a column with macroporous non-ionic adsorption resin “Daych-PI-20" (Trademark, manufactured by Mitsubishi Chemical Industries). The target material is eluted with 10% diisopropyl alcohol and lyophilized to give 0.43 g of (7-beta- (2- (2-aminothiazole) -4-yl) -2-methoxyiminoacetamido) -3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolio) methyl-3-cephem-4-carboxylate (syn isomer, 0.43 g).

IR (nujol): 3300, 1770, 1640 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 3.00 and 3.30 (2H, AB quartet, J 18 Hz), 3.60 (2H, multiplet), 3.83 (3H, singlet), 4.37 ( 2H, multiplet), 5.06 (1H, doublet, J 5 Hz), 5.18 (2H, broad singlet), 5.65 (1H, doublet, J = 5 Hz and 8 Hz), 5.84 (1H doublet, J3 Hz), 6.71 (1H, singlet), 7.18 (2H, broad singlet), 7.38 (2H, broad singlet), 8.03 (1H, doublet, J 3 Hz), 9 52 (1H, doublet, J = 8 Hz).

 The following substance (example 5) was obtained by a method similar to that in example 4.

 Example 5

 7-beta- (2- (2-Aminothiazol-4-yl) -2- (difluoromethoxyimino) acetamido) -3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem -4-carboxylate (syn isomer).

IR (nujol): 3300, 1760, 1660 cm ^-1 .

 Example 6

 To a suspension of 7-beta- (2-difluoromethoxyimino) -2- (2-tritylaminothiazole) -4-yl) acetamido-3-chloromethyl-3-cefem-4-carboxylic acid benzhydryl ester (syn-isomer, 5 g) and 0.856 g of sodium iodide in 5 ml of N, N-dimethylformamide add 4.18 g of 5-formamido-1- (2-formyloxyethyl) pyrazole at room temperature. After stirring for 24 hours, the mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in tetrahydrofuran and chromatographed on an Amberlite AI-Ay Ey 400 ion exchange resin column (type trifluoroacetate) (Trademark, manufactured by Rome and Haas Co.). The target material is eluted with tetrahydrofuran and evaporated in vacuo to give the 7-beta- (2-difluoromethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido-3- (3-formamido-2- (2) trifluoroacetic acid salt of benzhydryl ester -formyloxyethyl) -1-pyrazolo) methyl-3-cephem-4-carboxylic acid (syn-isomer, 4.80 kg).

IR (nujol): 1780, 1720, 1675 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 3.50 (2H, multiplet), 3.65 (2H, multiplet), 4.35 (2H, multiplet), 5.25 (1H, doublet, J = 5 Hz), 5 50 (2H, broad singlet), 5.88 (1H, doublets, J = 5 Hz & 8 Hz), 6.91 (1H, singlet), 7.03 (1H, singlet), 7.04 7.70 ( 27H, multiplet), 8.08 (1H, singlet), 8.33 (1H, doublet, J 3 Hz), 8.67 (1H, singlet), 9.05 (1H, singlet), 10.05 (1H doublet, J 5 Hz).

 The following substance (example 7) was obtained by a method similar to that in example 6.

 Example 7

 7-beta- (2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl 3-cefem-4-carboxylate (syn isomer).

 To a suspension of 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cefem-4-carboxylic acid (syn isomer) 152); iodotrimethylsilane (6.6 g in N, N-diisopropylethylamine (6.4 g) in methylene chloride (20 ml) is added a mixture of 5-amino (2-hydroxyethyl) pyrazole (4.20 g), chloromethylsilane (7.2 g ) and N, N-diisopropylethylamine (7.5 g) in methylene chloride (10 ml) at room temperature After stirring for 20 hours, the mixture was poured into a mixture of 1N hydrochloric acid and methylene chloride under ice cooling and the pH was adjusted with sodium bicarbonate solution. the aqueous layer and chromatographic on a column with microporous non-ionic absorption resin "Dayion HP-20", the target substance is eluted with 10% - diisopropyl alcohol and lyophilized to give 0.4 g of the title compound.

IR (nujol): 3300, 1770, 1640 cm ^-1 .

 Example 8

 To a solution of the salt of trifluoroacetic acid of benzhydryl ether 7beta- (2- (difluoromethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido) -3- (3-formamido-2- (2-formyloxyethyl) -1-pyrazolo) - methyl 3-cefem-4-carboxylic acid (syn-isomer, 4.7 g) in 15 ml of methylene chloride and 5 ml of anisole add 10 ml of trifluoroacetic acid under ice cooling. After stirring for 1.5 hours, the mixture was poured into diisopropyl ether and the precipitate formed was collected by filtration. This precipitate is dissolved in water, the solution is alkalinized to pH 12 with an aqueous solution of sodium hydroxide under ice-cooling. The mixture is stirred at the same temperature for 10 minutes and acidified to pH 2 with a solution of hydrochloric acid (1 normal). This solution is subjected to column chromatography with a Macro-porous nonionic adsorption resin, “HRP-20.” The target material is eluted with 10% diisopropyl alcohol and lyophilized to obtain 0.80 g of 7beta- (2- (2-aminothiazol-4-yl) -2- (difluoromethoxyimino) acetamido) -3- (3-formamido-2- ( 2-hydroxyethyl) -1-pyrazolo) methyl 3-cephem-4-carboxylate (syn isomer).

IR (nujol): 3250, 1770, 1665 cm ^-1 .

 NMR spectrum (deuterium oxide and perdeuterodimethyl sulfoxide), s 3.11 and 3.50 (2H, AB quartet, J 18 Hz), 3.85 (2H, multiplet), 4.60 (2H, multiplet), 5.22 (1H, doublet, J 5 Hz), 5.36 (2H, broad singlet), 5.81 (1H, doublet, J 5 Hz), 6.91 (1H, triplet, J 71 Hz), 7.05 ( 1H, doublet, J 3 Hz), 7.18 (1H, singlet), 8.24 (doublet, J 3 Hz), 8.44 (1H, singlet).

 Example 9

 To a suspension of 7-beta- (2- (2-aminothiazol-4-yl) -2- (difluoromethoxyimino) acetamido) -3- (3-formamido-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem- 4-carboxylic acid (syn-isomer, 0.7 g) in methanol (3.5 ml) was added 0.42 ml of concentrated hydrochloric acid at room temperature. After stirring at the same temperature for 2 hours, the mixture was poured into ethyl acetate. The precipitate formed is dissolved in water and alkalinized to pH 2 with a 5% aqueous sodium bicarbonate solution. This solution is subjected to column chromatography with a Macro-porous nonionic adsorption resin, “HRP-20.” The target material is eluted with 10% diisopropyl alcohol and lyophilized to obtain 0.41 g of 7 beta (2- (2-aminothiazol-4-yl) -2- (difluoromethoxyimino) acetamido) -3- (3-amino-2- ( 2-hydroxyethyl) -1-pyrazolo) methyl 3-cephem-4-carboxylate (syn isomer).

IR (nujol): 3300, 1760, 1660 cm ^-1 .

 NMR spectrum (in heavy water), s: 3.02 and 3.35 (2H, AB quartet, J 18 Hz), 3.78 (2H, multiplet), 4.28 (2H, multiplet), 4.95 and 5.16 (2H, AB quartet, J 16 Hz), 5.16 (1H, doublet, J 3 Hz), 6.86 (1H, triplet, J 69 Hz), 7.16 (1H, singlet), 7.83 (1H, doublet, J = 3 Hz).

 The following substance (example 10) was obtained by a method similar to that in example 9.

 Example 10

 7-beta- (2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl 3-cefem-4-carboxylate (syn isomer).

IR (nujol): 3300, 1770, 1640 cm ^-1 .

 Example 11

 Into a solution of 6.5 g of 7-beta- (2- (2-aminothiazol-4-yl) -2-methoxy iminoacetamido) -3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3- cefem-4-carboxylate (syn-isomer) in 6.5 ml of water add 6.5 ml of di-normal sulfuric acid at room temperature. The mixture is stirred at this temperature to precipitate a crystalline precipitate. These crystals are collected by filtration and washed with ice water and then acetone to give the sulfuric acid salt of 7-beta- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- (3-amino-2- ( 2-hydroxyethyl) -1-pyrazolo) methyl 3-cephem-4-carboxylate (syn-isomer, 5.92 g).

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 3.13 3.83 (2H, multiplet), 3.40 3.83 (4H, multiplet), 5.15 (1H, doublet, J = 5 Hz), 5.05 and 5.30 (2H, AB quartet, J 13 Hz), 5.79 (1H, doublets, J 5 Hz and 8 Hz), 5.88 (1H, doublet, J 3 Hz), 6.71 (1H, singlet ), 7.28 (2H, broad singlet), 7.95 (1H, doublet, J 3 Hz), 9.57 (1H, doublet, J 8 Hz).

 Preparative example 5.

 7-beta-amino-3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cephem-4-carboxylate, trihydrochloride (66 g) was dissolved in 264 ml of water. The aqueous solution is subjected to chromatography on a column of HRP-20 Dayion using water as an eluent. Fractions containing the target material were combined, and 1.15 L of isopropyl alcohol was added dropwise to this combined solution under ice-cooling. This mixture was stirred for 1.5 hours under ice cooling to precipitate crystals. These crystals are collected by filtration and washed with a mixture of isopropyl alcohol and water (10: 1) under ice cooling and dried over phosphorus pentoxide to obtain 29.95 g of 7 beta-amino-3- (3-amino-2- (2-hydroxyethyl) ) -1-pyrazolo) -methyl-3-cephem-4-carboxylate, dihydrate hydrochloride.

IR (nujol): 3270, 1790, 1560 1635 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 3.43 3.77 (2H, multiplet), 4.47 5.07 (1H, doublet, J 5 Hz), 5.12 and 5.38 (2H, AB quartet, J 16 Hz), 5.92 (1H, doublet, J 3 Hz), 7.56 (2H, broad singlet), 8.11 (1H, doublet, J 3 Hz).

Analysis (%): calculated for C ₁₃ H ₁₇ N ₅ O ₄ S. HCl. 2H ₂ O C-37.90, H-5.38, N-17.00, Cl 8.60
Found: C-37.82, H-5.56, N-16.73, Cl 8.60.

 Preparative example 6.

A mixture of acetic anhydride (44.5 ml) and formic acid (22.3 ml) was stirred at room temperature for 1 hour. To this mixture was added 30 g of 5-amino-1- (2-hydroxyethyl) -pyrazole at 0 ^° -10 ^° C. and the mixture was stirred under ice-cooling for 30 minutes. This mixture was poured into ice-cooled water, made alkaline to pH 10.5 with potassium carbonate solution (40%) and stirred under ice-cooling for 30 minutes. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate 6 times. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give 30.8 g of 5-formamido-1- (2-hydroxyethyl) pyrazole. Melting point 109 112 ^o C.

IR (nujol): 3230, 1695, 1570, 1540 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 3.62 3.95 (2H, multiplet), 3.98 4.32 (2H, multiplet), 6.22 and 6.36 (1H, each doublet, J = 3 Hz ), 7.42 (1H, doublet, J = 3 Hz), 8.32 and 3.36 (1H, each singlet).

 Preparative example 7.

To a suspension of 5-formamido-1- (2-hydroxyethyl) pyrazolo (1 G) in 50 ml of acetonitrile was added dropwise 0.77 ml of chlorosulfonyl isocyanate at a temperature of from -15 ^° C to -20 ^° C.

 This mixture was stirred for 3 hours under ice cooling. 1 ml of water was added to the reaction mixture and allowed to stand overnight. The solution was made alkaline to pH = 7.5 with a 5-normal sodium hydroxide solution and then adjusted to pH 8.5 with a normal sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with tetrahydrofuran. The extract and the indicated organic layer are combined and dried over magnesium sulfate. The solvent was distilled off, and the residue was crystallized from ethyl acetate to give 0.60 g of 5-amino-1- (2-carbamoyloxyethyl) pyrazole.

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 3.83, 4.35 (4H, multiplet), 4.80, 5.18 (2H, broad singlet), 5.32 (1H, doublet, J = 3 Hz), 6, 38.6.87 (2H, broad singlet); 7.08 (1H, doublet, J = 3 Hz).

 Preparative example 8.

 5-Formamido-1- (2-carbamoyloxyethyl) pyrazole (3.69 g) was obtained from 5-amino-1- (2-carbamoyloxyethylpyrazole (3.3 g) by a procedure similar to that in Preparative Example 6.

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 4.22 (4H, singlet), 6.17 - 6.40 (1H, multiplet), 6.40 6.63 (2H, multiplet), 7.30 7.53 ( 1H, multiplet), 8.13 8.47 (1H, multiplet).

 Example 12

 To a solution of benzhydryl 7beta- (2-2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) -3-chloromethyl-3-cephem-4-carboxylate (syn-isomer, 1.52 g) in N, N-dimethylformamide ( 3 ml) sodium iodide (0.36 g) was added under a nitrogen atmosphere. This mixture was stirred at room temperature for 30 minutes.

Then, 1.42 g of 5-formamido-1- (2-carbamoyloxyethyl) pyrazole was added thereto, and the mixture was stirred at the same temperature for 24 hours. A mixture of ethyl acetate (50 ml) and ice water (30 ml) was added to this reaction mixture. The separated organic layer was washed with water and a solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo and the resulting compound was chromatographed on an Amberlit 1RA 400 ion exchange resin column (type CF ₃ OOO ^- ) to give 7beta- (2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) - trifluoroacetate 3- (3-formamido-2- (2-carbamoyloxyethyl) -1-pyrazolo) methyl-3-cephem-4-carboxylate (syn isomer, 1.60 g).

 Example 13

 7beta- (2- (2-Formamidothiazol-4-yl) -2-methoxyiminoacetamido) -3- (3-formamido-2- (2-carbamoyloxyethyl) -1-pyrazolo) methyl-3-cefem-4-carboxylate (syn -isomer, 1.10 g) was obtained from 7beta- (2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) -3- (3-formamido-2- (2-carbamoyloxyethyl) -1 -benzohydryl ether trifluoroacetate - pyrazolo) methyl-3-cephem-4-carboxylic acid (syn-isomer, 1.6 g) according to a procedure similar to that described in example 8.

 Example 14

 7beta- (2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido-3- (3-amino-2- (2-carbamoyloxyethyl) -1-pyrazolo) methyl 3-cefem-4-carboxylate (syn- isomer, 0.10 g) was obtained from 7beta- (2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) -3- (3-formamido-2- (2-carbamoyloxyethyl) -1-pyrazolo) methyl -3-Cephem-4-carboxylate (syn isomer) according to a procedure similar to that described in example 9.

IR (nujol): 3200 3300, 1760, 1710, 1650 cm ^-1 .

 NMR (in perdeuterodimethyl sulfoxide), s: 3.0 3.90 (2H, multiplet), 3.90 4.27 (4H, multiplet), 3.82 (3H, singlet), 4.40 5.47 (5H, multiplet), 5.47 5.77 (1H, multiplet), 5.81 (1H, doublet, J = 3 Hz), 6.71 (1H, singlet), 6.90 7.57 (4H, multiplet), 7.97 (1H, doublet, J = 3 Hz); 9.51 (1H, doublet, J = 8 Hz).

 Preparative example 9.

 5-Formamido-4-methyl-1- (2 formyloxyethyl) pyrazole was prepared according to a procedure similar to that described in Preparative Example 1.

IR (nujol): 3180, 1715, 1660 cm ^-1 .

 NMR spectrum (in perdeuterodimethyl sulfoxide), s: 1.81 and 1.86 (3H, each singlet), 4.01 4.48 (4H, multiplet), 7.25 and 7.40 (1H, each singlet), 8.06 (1H, singlet), 8.22 and 9.13 (1H, each singlet).

 Preparative example 10.

5-amino-1- (2-hydroxyethyl) pyrazole (5 g) was added to 14.7 ml of acetic anhydride with stirring and cooling with ice. 6.3 ml of pyridine are added there. This mixture is stirred for 2 hours at 25 ^o C.

The reaction mixture was added to a mixture of ethyl acetate (50 ml) and an aqueous solution of sodium chloride (50 ml). Then there is added an aqueous sodium bicarbonate solution to bring the pH of the solution to 7.0. The aqueous layer was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract is dried over magnesium sulfate. Magnesium sulfate was filtered off and the filtrate was evaporated under reduced pressure to obtain 5.98 g of 5-acetamido-1- (2-acetoxyethyl) pyrazole. Melting point 83 - 84 ^o C.

IR (nujol): 3270, 1750, 1670, 1565 cm ^-1 .

 NMR spectrum (in perdeuterodimethyl sulfoxide), s: 1.93 (3H, singlet), 2.03 (3H, singlet), 4.22 (4H, broad singlet), 6.13 (1H, doublet, J = 2 Hz) 7.82 (1H, doublet, J = 2 Hz); 9.76 (1H, singlet).

 The following substances (preparative examples 11 to 13) were prepared according to a procedure similar to that described in preparative example 2.

 Preparative example 11.

 7beta-tert-butoxycarbonylamino-3- (4-methyl-3-formamido-2- (2-formyloxyethyl) -1-pyrazolo) methyl-3-cefem-4-carboxylic acid benzhydryl ester, iodide.

IR (nujol): 3250, 1780, 1710, 1680 cm ^-1 .

 NMR spectrum (perdeuterodimethylsulfoxy), s: 1.53 (9H, singlet), 1.97 (3H, singlet), 3.51 (2H, broad singlet), 4.04 4.42 (2H, multiplet), 4 52 4.78 (2H, multiplet), 5.08 (1H, doublet, J 5Hz), 5.39 (2H, broad singlet), 5.61 (1H, doublets, J 5 Hz and 8 Hz), 6 86 (1H, singlet), 7.08 7.52 (10H, multiplet), 7.93 (1H, singlet), 8.18 (1H, singlet), 8.34 (1H, singlet), 9.12 (1H, singlet).

 Preparative example 12.

 7beta-tert-butoxycarbonylamino-3- (3-acetamido-2- (2-acetoxyethyl) -1-pyrazolo) methyl-3-cefem-4-carboxylic acid benzhydrol ester, iodide.

IR (nujol): 1780, 1720, 1230 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 1.41 (9H, singlet), 1.86 (3H, singlet), 2.25 (3H, singlet), 3.40 (2H, broad singlet), 4.0 4 4 (4H, multiplet), 5.12 (1H, doublet, J 5 Hz), 5.37 (2H, singlet), 5.60 (1H, doublet, J 8 Hz and 5 Hz), 6.85 ( 1H, singlet), 7.24 (1H, doublet, J 3 Hz), 7.1 7.6 (10H, multiplet), 7.90 (1H, doublet, J 8 Hz), 8.21 (1H, doublet , J 3 Hz), 11.17 (1H, singlet).

 Preparative example 13.

 7beta-tert-butoxycarbonylamino-3- (3-formamido-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem-4-carboxylic acid benzhydryl ester, iodide

IR (nujol): 3300, 1780, 1710, 1560, 1150 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 1.43 (9H, singlet), 3.53 (2H, broad singlet), 4.02 4.5 (4H, multiplet), 5.15 (1H, doublet, J 5 Hz), 5.40 (2H, singlet), 5.55 (1H, doublets, J 8 Hz and 5 Hz), 6.90 (1H, singlet), 7.01 (1H, doublet, J 3 Hz), 7.1 7.5 (10H, multiplet), 7.97 (1H, doublet, J = 8 Hz), 8.28 (1H, doublet, J = 3 Hz), 8.50 (1H, singlet).

 The following substances (preparative examples 14-16) were obtained by a method similar to that described in preparative example 3.

 Preparative example 14.

 Bis (trifluoroacetic acid salts) of 7-beta-amino-3- (4-methyl-3-formamido-2- (2-formyloxyethyl) -1-pyrazolo) methyl-3-cefem-4-carboxylate.

IR (nujol): 1780, 1710, 1670 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s 1.98 (3H, singlet), 3.49 (2H, broad singlet), 4.22 4.48 (2H, multiplet), 4.61 4.87 (2H, multiplet) 5.18 (2H, broad singlet), 5.46 (2H, broad singlet), 8.05 (1H, singlet), 8.23 (1H, singlet), 8.35 (1H, singlet).

 Preparative example 15.

 Bis (trifluoroacetic acid salts) 7-beta-amino-3- (3-acetamido-2- (2-acetoxyethyl) -1-pyrazolo) methyl-3-cefem-4-carboxylate.

IR (nujol): 1780, 1660, 1990 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 1.95 (3H, singlet), 2.23 (3H, singlet), 3.46 (2H, broad singlet), 4.2 4.4 (4H, multiplet), 5 , 20 (2H, multiplet), 5.46 (2H, singlet), 7.01 (1H, doublet, J 3 Hz), 8.27 (1H, doublet, J 3 Hz), 11.17 (1H, singlet )

 Preparative example 16.

 Bis (trifluoroacetic acid salts) of 7-beta-amino-3- (3-formamino-2- (2-hydroxyethyl) -1-pyrazolo) methyl 3-cefem-4-carboxylate.

IR spectrum (nujol): 3 400, 1 780, 1 680, 1 580, 1200, 1 140 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 3.70 (2H, broad singlet), 4.2 4.7 (4H, multiplet), 5.23 (2H, multiplet), 5.50 (2H, singlet), 7 07 (1H, doublet, J 3 Hz), 8.35 (1H, doublet, J 3 Hz), 8.53 (1H, singlet).

 The following substances (preparative examples 17 and 18) were obtained by a method similar to that described in preparative example 4.

 Preparative example 17.

 7beta-amino-3- (4-methyl-3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem-4-carboxylate, trihydrochloride

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 1.94 (3H, singlet), 3.39 (2H, broad singlet), 3.47 3.78 (2H, multiplet), 4.06 4.42 (2H, multiplet ), 5.21 (4H, broad singlet), 7.87 (1H, singlet).

 Preparative example 18.

 7beta-amino-3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cephem-4-carboxylate, trihydrochloride.

IR (nujol): 3300, 3150, 1780, 1710, 1640, 1580 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 3.60 (2H, broad singlet), 4.1 4.5 (4H, multiplet), 5.23 (2H, multiplet), 5.30 (2H, singlet), 5 92 (1H, doublet, J = 3 Hz), 8.07 (1H, doublet, J = 3 Hz).

 The following substances (examples 15 to 18) were obtained by a method similar to that described in example 1.

 Example 15

 7beta-2 (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido) -3- (4-methyl-3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem-4- carboxylate (syn isomer).

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 1.94 (3H, singlet), 3.32 (2H, broad singlet), 3.52 3.68 (2H, multiplet), 3.88 (3H, singlet), 4 , 12 4.39 (2H, multiplet), 5.14 (2H, broad singlet), 5.19 (1H, doublet, J = 5 Hz), 5.82 (2H, doublets, J = 5 Hz and 8 Hz ), 7.36 (1H, singlet), 7.83 (1H, singlet), 8.47 (1H, singlet), 9.63 (1H, doublet, J = 8 Hz).

 Example 16

 7beta- (2- (2-formamidothiazol-4-yl) -2-methoxyimidoacetamido) -3- (3-acetamido-2- (acetoxyethyl) -1-pyrazolo) methyl-3-cefem-4-carboxylate (syn- isomer).

IR (nujol): 1780, 1660, 1550 cm ^-1 .

 NMR spectrum (perdeuterodimethyl sulfoxide), s: 1.96 (3H, singlet), 2.27 (3H, singlet), 3.2 3.6 (2H, multiplet), 3.87 (3H, singlet), 4, 1 4.5 (4H, multiplet), 5.22 (1H, doublet, J = 5 Hz), 5.43 (2H, singlet), 5.90 (1H, doublets, J = 8 Hz and 5 Hz), 7.00 (1H, doublet, J = 3 Hz), 7.33 (1H, singlet), 8.29 (1H, doublet, J = 3 Hz), 8.43 (1H, singlet), 9.62 ( 1H, doublet, J = 8 Hz).

 Example 17

 7beta- (2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- (4-methyl-3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem-4 - carboxylate (syn isomer).

IR (nujol): 3300, 1765, 1660, 1605 cm ^-1 .

 Example 18

 7beta- (2-2-Aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- (3-acetamido-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem-4-carboxylate ( syn isomer).

IR (nujol): 3200, 1770, 1600 cm ^-1 .

 Example 19

 7beta- (2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- (4-methyl-3-amino-2- (2-hydroxyethyl) -1-pyrazolio) methyl-3-cefem- 4-carboxylate (syn-isomer) was obtained by the method similar to that described in example 4.

IR (nujol): 3300, 1765, 1660, 1605 cm ^-1 .

 NMR spectrum (in heavy water), s: 1.97 (3H, singlet) 3.06 and 3.37 (2H, AB quartet, J = 18 Hz), 3.73 3.93 (2H, multiplet), 3, 98 (3H, singlet), 4.19 - 4.43 (2H, singlet), 5.09 (2H, broad singlet), 5.19 (1H, doublet, J = 5 Hz), 5.89 (1H, doublet, J = 5 Hz), 6.96 (1H, singlet), 7.71 (1H, singlet).

 Example 20

 To a suspension of 7beta- (2- (2-formamidothiazol-4-yl (-2-methoxyiminoacetamido) -3- (3-acetamido-2- (2-acetoxyethyl) -1-pyrazolo) -methyl-3-cefem-4- carboxylate (syn-isomer) (1.46 g) in 7.3 ml of methanol add 0.51 ml of concentrated hydrochloric acid at room temperature. This mixture is stirred for 5 hours at room temperature.

The reaction mixture was added to ethyl acetate with stirring and cooling with ice. The resulting amorphous solid is dried in vacuo and dissolved in 40 ml of water. The aqueous solution was adjusted to pH = 13 with a 1-normal aqueous solution of sodium hydroxide with stirring and a temperature of from -3 ^o to 0 ^o C and stirred for 2 hours at the same temperature. The pH of the aqueous solution was adjusted to 2 with 1-normal hydrochloric acid, and the solution was chromatographed on a Dayion-PI-20 column and eluted with 10% isopropyl alcohol. Fractions containing the target compound are combined and concentrated to remove isopropyl alcohol. Lyophilization yields 159 mg of 7-beta- (2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- (3-acetamido-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem- 4-carboxylate (syn isomer). T. melting point 160 ^o C (decomposition). IR (nujol): 3200, 1770, 1600 cm ^-1 .

 NMR spectrum (in heavy water), s: 2.26 (3H, singlet), 3.10 (1H, doublet, J 18 Hz), 3.47 (1H, doublet, J 18 Hz), 3.8 4 , 1 (4H, multiplet), 3.95 (3H, singlet), 5.20 (1H, doublet, J 5 Hz), 5.32 (2H, singlet), 5.77 (1H, doublet, J5 Hz) 6.93 (1H, doublet, J = 3 Hz); 6.94 (1H, singlet); 8.16 (1H, doublet, J = 3 Hz).

 The following substances (examples 21 and 22 were obtained by a method similar to that described in example 7).

 Example 21

 7beta- (2- (2-Aminothiazole) -4-yl (-2-methoxyiminoacetamido) -3- (4-methyl-3-amino-2- (2-hydroxyethyl) -1-pyrazolo) - methyl-3-cefem -4-carboxylate (syn isomer).

IR (nujol): 3300, 1765, 1660, 1605 cm ^-1 .

 Example 22

 7 beta- (2-2-Aminothiazole) -4-yl) -2-methoxyiminoacetamido) -3- (3-acetamido-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem-4-carbo- silate (syn-isomer).

IR (nujol): 3200, 1770, 1600 cm ^-1 .

 The following substances (examples 23 to 27) were obtained by a method similar to that described in example 8.

 Example 23

 7beta- (2- (2-Aminothiazole) -4-yl) -2-methoxyiminoacetamido) -3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl 3-cefem-4-carboxylate ( syn isomer).

IR (nujol): 3300, 1770, 1640 cm ^-1 .

 Example 24

 7beta- (2- (2-aminothiazol-4-yl) -2- (difluoromethoxyimino-acetamido) -3- (3-amino-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cefem-4- carboxylate (syn isomer).

IR (nujol): 3300, 1760, 1660 cm ^-1 .

 Example 25

 7beta- (2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- (3-amino -2- (2-carbamoyloxyethyl) -1-pyrazolo) methyl 3-cefem-4-carboxylate (syn isomer).

IR (nujol): 3200 3300, 1760, 1710, 1650 cm ^-1 .

 Example 26

 7beta- (2 - (- Aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- (4-methyl-3-amino-2- (2-hydroxyethyl) -1-pyrazolio) methyl-3-cefem-4 carboxylate (syn isomer).

IR (nujol): 3300, 1765, 1660, 1605 cm ^-1 .

 Example 27

 7beta- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- (3-acetamido-2- (2-hydroxyethyl) -1-pyrazolo) methyl-3-cephem-4-carboxylate (syn isomer) .

IR (nujol): 3200, 1770, 1600 cm ^-1 .

Claims (7)

1. The Cepheme compound of General formula I

where R ^{1 is an} amino or protected amino group;
R ² lower alkyl, which may be substituted by 1 to 3 halogen atoms;
R ^{3 is a} carboxylate group, a carboxy or protected carboxy group;
R ⁴ hydroxy (lower) alkyl or protected hydroxy (lower) alkyl;
R ^{5 is an} amino or protected amino group;
R ^{6 is} a hydrogen atom or lower alkyl;

trifluoroacetate;
n 0 provided that R ^{3 is a} carboxylate group, and n 1 provided that R ^{3 is a} carboxy or protected carboxy group,
and their pharmaceutically acceptable salts. 2. The compounds according to claim 1, in which R ^{1 is an} amino group, triphenyl (lower) alkylamino or (lower) alkanoylamino group; R ² alkyl, which may be substituted by 1 to 3 halogen atoms; R ^{3 is a} carboxylate group, a carboxy group or a mono-, di- or tri- (phenyl) - or mono, di- or tri (substituted phenyl) (lower) alkoxycarbonyl group; R ⁴ is hydroxy (lower) alkyl, lower alkanoyloxy (lower) alkyl or carbamoyloxy (lower) alkyl; R ^{5 is an} amino group or a (lower) alkanoylamino group. 3. The compounds of claim 2, wherein R ^{1 is an} amino group; R ³ is a carboxylate group or a carboxy group. 4. The compounds of claim 3, wherein R ^{2 is} lower alkyl or dihalo (lower) alkyl. 5. The compound of claim 4, wherein R ^{2 is} methyl or difluoromethyl; R ⁴ 2-hydroxyethyl, 2-formyloxyethyl, 2-acetoxyethyl or 2-carbamoyloxyethyl; R ^{5 is an} amino group, formamido or acetamido group; R ^{6 is} a hydrogen atom or methyl.  6. The compound of claim 5, which is 7β - [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3-amino-2- (2-hydroxyethyl) -1-pyrazolo] methyl -3-Cephem-4-carboxylate (syn-isomer) or its sulfuric acid salt.  7. The compounds of claim 1 or their pharmaceutically acceptable salts as antimicrobial agents. Priority by signs:
09/14/87 R ¹ , R ² , R ³ , R ⁴ , R ⁵ such as defined in the claims; R ^{6 is} a hydrogen atom;
09/13/88 R ⁶ lower alkyl.

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