JPH093074A - Cephalosporin compound, its use and intermediate compound - Google Patents

Abstract

PURPOSE: To obtain a new cephalosporin compound which is a specific one containing a difluoroalkyl group, capable of manifesting excellent antimicrobial activities, effective for both Gram-positive and Gram-negative bacteria and useful as a preventing and therapeutic agent, etc., for microbism. CONSTITUTION: A new cephalosporin compound (salt) of formula I (A is CH=CH, CH=CH-CH2 ON=CH or CH2 ON=CH; R<1> is H, alanyl or an amino- protecting group; R<2> is H, a lower alkyl or a hydroxy-protecting group; R<3> is carboxyl or an esterified carboxyl; Z is =CH or =N). The compound has excellent antimicrobial activities against both Gram-positive and Gram-negative bacteria and is useful as a preventing and therapeutic agent for microbism used by peroral administration. The compound is obtained by reacting a new 7-aminocephalosporin compound of formula II with a carboxylic acid containing a heterocyclic group of formula III or its reactive derivative.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel cephalosporin compound and a salt thereof useful as a preventive / therapeutic agent for bacterial infections, their use, and an intermediate compound for producing the cephalosporin compound and a salt thereof. Regarding

[0002]

BACKGROUND OF THE INVENTION In recent years, the progress of research on cephalosporin compounds as therapeutic agents for infectious diseases has been remarkable, and various cephalosporin compounds with strong antibacterial activity and broad antibacterial spectrum have been developed. However, the emergence of cephalosporin compounds having characteristic antibacterial properties and antibacterial spectra according to the emergence of resistant bacteria and disease states is further desired. Further, conventional cephalosporin compounds are poorly absorbed from the digestive tract, and there is a demand for cephalosporin compounds suitable for oral administration.

An object of the present invention is to provide a cephalosporin compound having antibacterial properties and absorption properties from the digestive tract that are superior to those of the conventional products.

Another object of the invention is to provide uses of the compounds.

Still another object of the present invention is to provide an intermediate suitable for producing the cephalosporin compound.

[0006]

[Means for Solving the Problems] The inventors of the present invention have conducted various studies in order to achieve the above object, and as a novel cephalosporin compound represented by the following general formula (I) and a medicine thereof, The acceptable salt has excellent antibacterial properties, particularly excellent antibacterial properties against both Gram positive and negative, and the compound has excellent gastrointestinal absorbability and is extremely useful as an oral antibacterial agent. The present invention has been completed by finding usefulness and further finding a novel intermediate compound used for producing the compound. That is, the present invention is, firstly, the general formula (I)

[0007]

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[In the formula, A is -CH = CH-, -CH = C
H-CH_TwoON = CH- or -CH _TwoON = CH-
And R¹Is a hydrogen atom, an alanyl group or an amino protecting group
And R^TwoIs a hydrogen atom, a lower alkyl group or hydroxy
The protecting group is R^ThreeIs a carboxyl group or esterified
Is a carboxyl group, and Z is = CH- or = N-.
You. ] The cephalosporin compound represented by
It is called an arosporin compound (I). ] Or its medicine
And acceptable salts.

Secondly, the present invention is a prophylactic / therapeutic agent for infectious diseases, which comprises a cephalosporin compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient, particularly an oral prophylactic / therapeutic agent for infectious diseases, In particular, in the general formula (I), R ³ is an oral cephalosporin compound (I) having an esterified carboxyl group or a pharmaceutically acceptable salt thereof as an active ingredient for oral prophylaxis and treatment of infectious diseases. .

The third aspect of the present invention is the general formula (II)

[0011]

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[In the formula, A and R ³ have the same meanings as described above. ]
A 7-aminocephalosporin compound represented by
It is called a compound (II). ] Or a salt thereof.

The symbols used in this specification will be described below. The lower alkyl group for R ² preferably has 1 to 6 carbon atoms and may be linear or branched, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-. Butyl, pentyl, hexyl and the like can be mentioned.

With respect to R ³ , the ester in the esterified carboxyl group is a carboxyl group protecting group or an ester that is easily hydrolyzed in vivo (a free carboxyl group that is easily hydrolyzed in vivo is To give).

Examples of the protecting group for the carboxyl group include t-butyl, t-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl and methylthio. Methyl, trityl, 2,
2,2-trichloroethyl, trimethylsilyl, diphenylmethoxybenzenesulfonylmethyl, dimethylaminoethyl and the like can be mentioned.

Examples of the ester which is easily hydrolyzed in vivo include an aryl group which may have a substituent (eg phenyl, tolyl, xylyl, indanyl etc.), a 1-alkanoyloxyalkyl group, 1 -Alkoxycarbonyloxyalkyl group, phthalidyl group, 5-
Methyl-1,3-dioxolen-2-on-4-ylmethyl group and the like can be mentioned.

The carbon number of the alkanoyl moiety in the 1-alkanoyloxyalkyl group is preferably 2 to 10,
It is more preferably 2 to 7, and may be linear, branched, or cyclic, and the alkyl moiety has preferably 1 to 3, more preferably 1 or 2 carbon atoms. Examples of such groups include acetoxymethyl, propionyloxymethyl, n-butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, n-valeryloxymethyl, 2-methylbutyryloxymethyl, isovaleryl. Oxymethyl, n-hexanoyloxymethyl,
3-methylvaleryloxymethyl, neohexanoyloxymethyl, 2-methylhexanoyloxymethyl,
2,2-Dimethylvaleryloxymethyl, neoheptanoyloxymethyl, cyclohexanecarbonyloxymethyl, cyclohexylacetoxymethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-n-butyryloxyethyl, 1-isobutyryl Oxyethyl,
1-n-valeryloxyethyl, 1-pivaloyloxyethyl, 1-isovaleryloxyethyl, 1-n-hexanoyloxyethyl, 1-cyclohexanecarbonyloxyethyl and the like can be mentioned.

The number of carbon atoms of the alkoxy moiety in the 1-alkoxycarbonyloxyalkyl group is preferably 1-10, more preferably 1-7, which may be linear, branched or cyclic. The carbon number of the moiety is preferably 1 to 3, more preferably 1 or 2. Examples of such groups include 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl,
1-n-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-n-butoxycarbonyloxyethyl, 1-sec-butoxycarbonyloxyethyl, 1-t-butoxycarbonyloxyethyl, 1-pentyloxycarbonyloxy ethyl,
1-cyclohexyloxycarbonyloxyethyl etc. are mentioned.

As the amino-protecting group for R ¹ and the hydroxy-protecting group for R ² , those used for this purpose in the field of β-lactam synthesis and peptide synthesis are expediently adopted, and specifically, Are exemplified.

Examples of the amino protecting group include phthaloyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, P-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl and methoxy. Methylcarbonyl, methoxymethyloxycarbonyl, trimethylsilyl, 2,2,2-trichloroethoxycarbonyl,
2-Methylsulfonylethyloxycarbonyl, t-butoxycarbonyl (hereinafter referred to as BOC), trityl and the like can be mentioned.

Examples of the hydroxy protecting group include formyl, acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 2,2,2.
2-trichloroethoxycarbonyl, benzoyl, trityl, trimethylsilyl, tetrahydropyranyl, 1-
Methyl-1-methoxyethyl and the like can be mentioned.

The cephalosporin compound (I) may form a pharmaceutically acceptable salt at its amino group or carboxyl group.

An acid addition salt is formed at the amino group moiety, and the acid for forming such an acid addition salt is particularly preferably any acid that can form a salt with the amino group moiety and is pharmaceutically acceptable. There is no limit. Such acids include hydrochloric acid, sulfuric acid,
Examples thereof include inorganic acids such as phosphoric acid and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid and methanesulfonic acid.

Examples of the salt at the carboxyl group include alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth metal salts (eg calcium salt, magnesium salt etc.), organic base salts (eg triethylamine salt, dicyclohexylamine salt). , Pyridine salt, etc.).

Further, the salts of the compound (II) include the salts as mentioned above. 7-position side chain portion (III) in the cephalosporin compound (I) represented by the following formula

[0026]

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[In the formula, R ¹ and R ² have the same meanings as described above. ], There are syn-isomer and anti-isomer geometric isomers, but the preferred compound is the syn-isomer.

Further, A in the cephalosporin compound (I) and compound (II) is -CH = CH- or -CH.
= CH-CH ₂ ON = CH- case is, geometric isomers about the double bond of the vinyl group (cis and trans forms,
Or Z-form and E-form exist, but both isomers are included in the present invention.

The cephalosporin compound (I) and its pharmaceutically acceptable salt are produced, for example, as follows.

A is -CH = CH- or -CH = CH-
When CH ₂ ON = CH-. (Production method 1) General formula (I
V)

[0031]

[Chemical 6]

[Wherein R ¹ , R ² , R ³ and Z have the same meanings as defined above.] ] Or a salt thereof is reacted with difluoroacetaldehyde, or a compound represented by the formula (V)

[0033]

[Chemical 7]

A compound represented by the formula [hereinafter referred to as compound (V). ] Is reacted and, if necessary, sulfoxidation and reduction of sulfoxide are carried out to produce.

This reaction is carried out in a solvent which does not inhibit the reaction (for example, water, acetone, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, N, N'-dimethylformamide, N, N '). -Dimethylacetamide, dimethylsulfoxide, etc., and mixtures of two or more thereof)
Can be easily progressed in the presence of The time required for the reaction is usually 30 minutes to several dozen hours. The reaction temperature is not particularly limited, but is usually -20 to 80 ° C, preferably -20 to 30 ° C.

(Production method 2) General formula (VI)

[0037]

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[In the formula, R ¹ , R ² , R ³ and Z are the same as defined above. ] The compound or its salt represented by these, and general formula (VII)

[0039]

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[In the formula, B is —CH ₂ — or —CH═N
OCH ₂ CH ₂ — and X represent a halogen atom. ) The compound represented by the formula [hereinafter, referred to as compound (VII). ] Is reacted and, if necessary, sulfoxidation and reduction of sulfoxide are carried out to produce.

This reaction can be carried out under the same conditions as those described in (Production method 1).

[0042] A is _{-CH = CH-CH 2 ON =} CH- or -CH ₂ ON = CH- if it.

(Production Method 3) General Formula (VIII)

[0044]

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[In the formula, R ¹ , R ² , R ³ and Z are the same as defined above. Y is -CH ₂ - or -CH = CH
-CH ₂ - shows the. ] The compound or its salt represented by these, and difluoroacetaldehyde are made to react, and if necessary, sulfoxidation and reduction of sulfoxide are performed, and the manufacturing method.

This reaction is carried out in a solvent which does not inhibit the reaction (for example, water, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, N, N'-dimethylformamide, N, N'-dimethyl. It can be easily proceeded in the presence of acetamide, dimethyl sulfoxide, etc., and a mixture of two or more thereof. The time required for the reaction is usually 30 minutes to several hours. The reaction temperature is not particularly limited, but is usually -20 to 40 ° C, preferably -20 to 0 ° C.
It is.

When Z is --CH--.

(Production Method 4) General Formula (IX)

[0049]

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[In the formula, A, X, R ² and R ³ are the same as defined above. ] The compound or its salt represented by these, and general formula (X)

[0051]

[Chemical 12]

(Wherein R ¹ has the same meaning as defined above) is reacted and, if necessary, sulfoxidation and reduction of sulfoxide are carried out to produce.

This reaction is usually carried out in a solvent such as N, N'-dimethylformamide, N, N'-dimethylacetamide, dioxane, acetonitrile, tetrahydrofuran, alcohol or the like which does not inhibit the reaction or a mixture thereof with water. You can easily proceed with. The time required for the reaction is usually 30 minutes to several dozen hours. The reaction temperature is not particularly limited, but is usually -20 to 80 ° C, preferably 0 to 60 ° C.

(Production Method 5) General Formula (XI)

[0055]

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[In the formula, A, R ¹ , R ³ and Z have the same meanings as defined above. ] The compound or its salt represented by these, and general formula (XII)

[0057]

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[In the formula, R ² has the same meaning as described above. ] The compound represented by these or its salt is made to react, and if necessary, sulfoxidation and reduction of sulfoxide are performed, and the manufacturing method.

This reaction is usually carried out in a solvent such as N, N'-dimethylformamide, N, N'-dimethylacetamide, dioxane, acetonitrile, tetrahydrofuran, alcohol or the like which does not inhibit the reaction or a mixture thereof with water. You can easily proceed with. The time required for the reaction is usually 30 minutes to several dozen hours. The reaction temperature is not particularly limited, but is usually -20 to 80 ° C, preferably 0 to 60 ° C.

(Production Method 6) General Formula (II)

[0061]

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[In the formula, A and R ³ are as defined above. ]
Compound (II) represented by or a salt thereof and general formula (XIII)

[0063]

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[Wherein R ¹ , R ² and Z have the same meanings as defined above.] ] The compound represented by the following [hereinafter, compound (XI
II). ] Or a reactive derivative thereof,
Method of manufacturing.

The compound (XIII) is used in this reaction (acylation reaction) as a free carboxylic acid or as its reactive derivative, and any embodiment is included in this reaction. That is, as a free acid or a salt of sodium, potassium, calcium, triethylamine, pyridine, or the like, or an acid halide thereof (acid chloride, acid bromide, etc.), acid anhydride, mixed acid anhydride [substituted phosphoric acid (dialkylphosphoric acid, etc.) , Alkyl carbonate (monoethyl carbonate etc.)
Etc.], a reactive derivative such as an active amide (amide with imidazole), an ester (cyanomethyl ester, 4-nitrophenyl ester, etc.), etc., and subjected to the acylation reaction.

In this reaction, the compound (XII
When I) is used in the form of a free acid or salt, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of the condensing agent include N, N'-dicyclohexylcarbodiimide and other N, N'-di Substituted carbodiimides; 1-ethyl-
Carbodiimide compounds such as 3- (3′-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N′-morpholinoethylcarbodiimide, N-cyclohexyl-N ′-(4-diethylaminocyclohexyl) carbodiimide; N, N′-carbonyldiimidazole ,
A dehydrating agent such as an azolide compound such as N, N′-thionyldiimidazole is used. When these condensing agents are used, the reaction is thought to proceed via a reactive derivative of the carboxylic acid.

This reaction is usually carried out in an inert solvent.
As the solvent, specifically, water, acetone, dioxane,
Acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
Examples include N, N′-dimethylformamide, pyridine and the like, and mixtures of two or more thereof. This reaction is preferably carried out at -20 to 0 ° C.

Compound (II) and its salt are produced, for example, as follows. A is -CH = CH-,
_{-CH = CH-CH 2 ON =} CH- if it.

(Production Method 7) General Formula (XIV)

[0070]

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[In the formula, R ³ is as defined above, and R ⁴ is a hydrogen atom or an amino-protecting group. ] The compound [Hereafter, it is called a compound (XIV). ] Or a salt thereof and difluoroacetaldehyde are reacted, or a compound (V) is reacted, and if necessary, sulfoxidation and reduction of sulfoxide are carried out to remove the protecting group of R ⁴ .

This reaction can be carried out under the same conditions as described in (Production Method 1).

(Production method 8) General formula (XV)

[0074]

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(In the formula, R ³ and R ⁴ have the same meanings as defined above.) [Hereinafter referred to as compound (XV). ] Or a salt thereof and compound (VII) are reacted, and if necessary, sulfoxidation and reduction of sulfoxide are carried out to remove the protecting group of R ⁴ .

This reaction can be carried out under the same conditions as described in (Production Method 1).

[0077] A is _{-CH = CH-CH 2 ON =} CH- or -CH ₂ ON = CH- if it.

(Production method 9) General formula (XVI)

[0079]

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[In the formula, R ³ , R ⁴ and Y are the same as defined above. ] A compound represented by the following [compound (XV
I). ] Or a salt thereof and difluoroacetaldehyde are reacted, and if necessary, sulfoxidation and reduction of sulfoxide are carried out to remove the protecting group of R ⁴ .

This reaction can be carried out under the same conditions as described in (Production Method 3).

Compounds (XIV), (XV) and (XV
The amino protecting group for R ⁴ in I) is, for example, an amino protecting group existing in itself, for example, phenylacetyl, phenoxyacetyl, 2-thienylacetyl, 2-furylacetyl, D-5-amino-5-carboxyvaleryl, t. -Butoxycarbonyl (BOC), trityl, phthaloyl,
O-hydroxybenzylidene etc. are mentioned.

In this reaction, compounds (XIV), (X
R ^{4 in} V) and (XVI) is preferably an amino protecting group, in which case compounds (XIV), (XV)
The reaction with the general formula (I
A compound in which the 7-position amino group in I) is protected can be obtained, and the protecting group can be eliminated by a means known per se.

Specific examples of means for removing the amino protecting group include the following methods. That is, phenylacetyl, phenoxyacetyl, 2-thienylacetyl,
For elimination of 2-furylacetyl, D-5-amino-5-carboxyvaleryl and the like, for example, a method of decomposing with methanol or the like after iminochlorination with phosphorus pentachloride is used.
For elimination of C, trityl, O-hydroxybenzylidene and the like, for example, a method of treating with acid (for example, hydrochloric acid, formic acid, trifluoroacetic acid and the like) and the like, and for elimination of phthaloyl and the like, use Ing-Manske Law etc. are mentioned.

In the cephalosporin compound (I) or compound (II) obtained by each of the above methods, when R ³ is a carboxyl group or a salt thereof,
If necessary, the reactive derivative (for example, an alkali metal salt such as sodium salt, potassium salt, etc., an alkaline earth metal salt such as calcium salt, triethylamine salt, pyridine salt, etc.) is introduced, and R ³ is converted by a known method. The cephalosporin compound (I) or compound (II), which is a carboxyl group esterified with an ester of a prodrug that is easily hydrolyzed in vivo, can be used.

The cephalosporin compound (I) and its pharmaceutically acceptable salts obtained by the above methods usually have a protecting group.

As means for removing the protective group, depending on the type of the protective group, decomposition with an acid (eg formyl, BO
C, trityl, tetrahydropyranyl and the like are decomposed by acids such as hydrochloric acid and trifluoroacetic acid), and are decomposed by bases (for example, dichloroacetyl, trifluoroacetyl and the like are decomposed by bases such as sodium hydroxide and sodium bicarbonate), Methods such as decomposition with hydrazine (for example, phthaloyl and the like with hydrazine), catalytic reduction (for example, benzyl, benzyloxycarbonyl, and the like with palladium-carbon, etc.) are employed, and these methods are used for β-lactam synthesis and peptide synthesis. The conventional method used can be appropriately selected and performed.

The cephalosporin compound (I) can be converted into its pharmaceutically acceptable salt by a method known per se.

[0089]

The cephalosporin compound (I) and a pharmaceutically acceptable salt thereof, particularly a compound in which R ³ is a carboxyl group, have excellent antibacterial activity, and Staphylococcus aureus,
Staphylococcus, Epidermidis
ccus epidermidis) and other Gram-positive bacteria, such as Escherichia
Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Protius mirabilis
It has extremely excellent antibacterial activity against all Gram-negative bacteria such as eus mirabllis).

That is, the cephalosporin compound (I)
Also, the pharmaceutically acceptable salt thereof is a valuable antibacterial agent in which the antibacterial activity against Gram-negative bacteria is maintained while the antibacterial activity against Gram-positive bacteria is remarkably improved. Moreover, these compounds have extremely low toxicity.

The cephalosporin compound (I) and its pharmaceutically acceptable salts are useful as agents for preventing and / or treating infectious diseases (particularly bacterial infections). Prevention of the infectious disease
The therapeutic agent is, for example, a warm-blooded animal including a human (dog, cat, cow,
It can be used as a prophylactic / therapeutic agent for diseases (for example, purulent diseases, respiratory infections, biliary tract infections, urinary tract infections, etc.) caused by bacteria of horses, rats, mice, etc.

The cephalosporin compound (I) and its pharmaceutically acceptable salts can be administered as an oral preparation (tablets, capsules, etc.) and a parenteral preparation (eg, injections, rectal preparations, etc.).

Particularly, the cephalosporin compound (I) in which R ³ is a carboxyl group and a pharmaceutically acceptable salt thereof are to be administered as a rectal composition (eg, suppository or retention enema) or as an injection. Is preferred.

R ³ is an esterified carboxyl group,
Particularly, the cephalosporin compound (I) which is an esterified carboxyl group which is easily hydrolyzed in vivo and its pharmaceutically acceptable salt are rapidly absorbed into blood by oral administration, A high blood concentration of the cephalosporin compound (I) in which R ³ as a metabolite is a carboxyl group and a pharmaceutically acceptable salt thereof can be obtained, and this high blood concentration is sustained.

The cephalosporin compound (I), in which R ³ is an esterified carboxyl group, has a significantly increased solubility in the gastrointestinal tract by being converted into a pharmaceutically acceptable salt thereof to further improve absorption efficiency. Improved and more absorbable.

Therefore, a prophylactic / therapeutic agent for infectious diseases, which comprises the cephalosporin compound (I) in which R ³ is an esterified carboxyl group and a pharmaceutically acceptable salt thereof, is excellent by oral administration as described above. It has an action and is usually orally administered as an oral preparation.

The prophylactic / therapeutic agent for infectious diseases can be produced by diluting with a pharmaceutical excipient according to a method known per se. For example, as the excipient, specifically, starch, lactose, sugar, calcium carbonate, calcium phosphate and the like are used.

Further, it is preferable to add an organic acid to the infectious disease preventive / therapeutic agent. Thus, the cephalosporin compound (I) in which R ³ is an esterified carboxyl group and its pharmaceutically acceptable salt are more soluble in the gastrointestinal tract, and are more easily absorbed into the blood.

The organic acid is not particularly limited as long as it is pharmaceutically acceptable. For example, maleic acid, fumaric acid, tartaric acid, citric acid, succinic acid, malic acid, oxalic acid, mandelic acid, malonic acid, benzoic acid. Preferred examples include organic carboxylic acids and the like. The amount of such organic acid is R
^The amount is usually 0.01 to 20 mol, preferably 0.02 to 2 mol, per 1 mol of the cephalosporin compound (I) in which ³ is an esterified carboxyl group and a pharmaceutically acceptable salt thereof. .

If desired, the prophylactic / therapeutic agent for infectious diseases may further contain other additives such as a binder (eg, starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.) and a lubricant. Lubricants (eg, magnesium stearate, talc, etc.), disintegrating agents (eg, carboxymethyl cellulose calcium, talc, etc.) and the like can be mentioned as preferable additives. After mixing the components, the mixture is formulated into a dosage form suitable for oral administration, such as capsules, tablets, fine granules, granules, and dry syrup, according to a method known per se, so that an infectious disease for oral administration can be obtained. Prophylactic / therapeutic agents are manufactured.

The dose of the cephalosporin compound (I) and its pharmaceutically acceptable salt depends on the administration subject, symptoms,
For example, when administered to an adult purulent disease, the dose may be, for example, about 1 to 40 mg / k, depending on other factors.
g body weight is administered about 1 to 4 times a day.

Further, the cephalosporin compound (I)
And pharmaceutically acceptable salts thereof are other antibacterial active substances such as antibacterial agents (penicillins, aminoglycosides, cephalosporins, etc.) or therapeutic agents for systemic symptoms due to bacterial infection (antipyretics, analgesics, anti-inflammatory agents). Agent).

Next, in order to clarify the excellent properties of the compound of the present invention, an antibacterial test and an oral absorption test were conducted as follows, and the results are shown in Tables 1 and 2.

[0104]

[Experimental example]

Experimental Example 1 (antibacterial test) The antibacterial activities of the compound of the present invention and the control compound were pre-cultured.
Mueller Hinton broth, Mueller Hinton for sensitivity measurements
Number of bacteria is 10 by agar plate multiple dilution method using medium
^It was measured as the minimum inhibitory concentration (MIC) at ⁶ cells / ml. The results are shown in Table 1.

[0105]

[Table 1]

Experimental Example 2 (Oral Absorption Experiment) Mice (3 mice per group) were orally administered with 20 mg / Kg of the compound of the present invention, and the urinary recovery rate of the hydrolyzed compound from 0 to 24 hours was determined by Escherichia coli. The bioavailability (B.
A.) was sought. Table 2 shows the results.

[0107]

[Table 2]

[0108]

EXAMPLES The physical properties and production method of the compound of the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

Example 1 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylic acid sodium salt (1) p-methoxybenzyl 7β-[(Z) -2-
(2-Tritylaminothiazol-4-yl) -2-trityloxyiminoacetamide] -3-triphenylphosphoniomethyl-3-cephem-4-carboxylate Iodide (8.5 g) was dissolved in methylene chloride (85 ml),
85 ml of water and 1.48 of difluoroacetaldehyde
g was added and the mixture was stirred at room temperature for 3 hours (pH was adjusted to 8.
Maintained at 5-9.0). The two layers were separated, the aqueous layer was extracted with 50 ml of methylene chloride, the methylene chloride layers were combined,
The mixture was washed successively with 10% citric acid water and 100 ml each of saturated saline and dried over anhydrous sodium sulfate. Methylene chloride was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain p-methoxybenzyl 7β-[(Z) -2.
-(2-Tritylaminothiazol-4-yl) -2-
Trityloxyiminoacetamide] -3-[(Z)-
2.2 g of 3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate were obtained.

IR (Nujol, cm ^-1 ): 3300,
1790, 1725, 1685. ¹ H-NMR (DMSO-d ₆ , δppm): 3.58
_{(Brs, 2H, C 2 -H} 2), 3.75 (s, 3H,
_{-OCH 3), 5.11 (s,} 2H, -CO 2 CH
₂₋ ), 5.29 (d, J = 5.0 Hz, 1H, C ₆ −
H), 5.60~6.10 (m, 2H , C 7 -H, = C
H−), 6.50 (d × t, J = 7.5, 55.0H
_{z, 1H, -CHF 2),} 6.58 (s, 1H, thi
azoleC ₅ -H), 6.67 (d, J = 12.0H
z, 1H, C ₃ —CH =), 6.80 to 7.60 (m,
34H, Ph), 8.69 (brs, 1H, thiaz
_{oleC 2 -NH -), 9.87 (} d, J = 8.0H
z, 1H, -CONH-).

(2) 2.1 g of the compound of (1) was suspended in 2.1 ml of anisole, and trifluoroacetic acid 6.3 under ice cooling.
ml was added, and the mixture was stirred at the same temperature for 1.5 hours. 50 ml of n-hexane was added, the oily substance was separated by decantation, and 50 ml of isopropyl ether was added to solidify,
1.35 g of powder was obtained. 80% formic acid was added to the obtained powder.
After adding 4 ml and stirring at room temperature for 1 hour, the mixture was poured into 100 ml of a mixed solution of ethyl ether-isopropyl ether (1: 1). The precipitate was collected by filtration to obtain 0.72 g of powder. Suspend the obtained powder in 70 ml of water and adjust the pH with sodium bicarbonate.
= 7.5 after dissolution, Diaion HP-21 (70 m
l). After washing with water, eluting with 5% acetonitrile water, the target fraction was concentrated under reduced pressure and freeze-dried to obtain 460 mg of the title compound powder.

IR (Nujol, cm ^-1 ): 3180,
1765. ¹ H-NMR (DMSO-d ₆ , δppm): 3.3
3, 3.75 (ABq, J = 16.5 Hz, 2H, C _{2
-H 2), 5.12 (d,} J = 5.0Hz, 1H, C 6
-H), 5.20 to 5.70 (m, 1H, = CH-),
5.71 (d × d, J = 5.0, 8.0 Hz, 1H, C
_7- H), 6.64 (s, 1H, thiazoleC ₅
-H), 6.79 (d * t, J = 7.0, 55.5H)
_{z, 1H, -CHF 2),} 7.01 (d, J = 12.0
_{Hz, 1H, C 3 -CH =} ), 7.10 (brs, 2
_{H, -NH 2), 9.43 (} d, J = 8.0Hz, 1
H, -CONH-), 11.50 to 12.20 (br,
1H, -OH).

Example 2 p-Methoxybenzyl 7β-amino-3-[(Z)-
3,3-Difluoro-1-propenyl] -3-cephem-4-carboxylate hydrochloride (Compound A) and p-
Methoxybenzyl 7β-amino-3-[(E) -3,
3-Difluoro-1-propenyl] -3-cephem-4
-Carboxylate hydrochloride (Compound B) (1) p-methoxybenzyl 7β-phenylacetamido-3- (triphenylphosphoranylidene) methyl-3-cephem-4
-Dissolving 7.8 g of carboxylate in 90 ml of methylene chloride, adding 1.6 g of difluoroacetaldehyde,
The mixture was stirred at room temperature for 4 hours. The extract was washed with 100 ml of saturated saline and dried over anhydrous sodium sulfate, and methylene chloride was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and p-methoxybenzyl 7β-phenylacetamide-3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate (compound C) and p-methoxybenzyl 7β-phenylacetamido-3-[(E) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate (Compound D) in an 8: 2 mixture. 2.89 was obtained. The obtained mixture was recrystallized from ethyl acetate to obtain 1.3 crystals of compound C.
4 g were obtained. Further, the filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.45 g of compound D powder.

Compound C IR (Nujol, cm ^-1 ): 3300,1790,1
725, 1685. ¹ H-NMR (DMSO-d ₆ , δppm): 3.40
_{~3.70 (m, 4H, C 2} -H 2, -CH 2 CO
-), 3.75 (s, 3H , -OCH 3), 5.00,
5.15 (ABq, J = 11.0Hz, 2H, -CO 2
CH ₂ −), 5.18 (d, J = 5.0 Hz, 1H, C
_{6 -H), 5.60~6.00 (m,} 2H, C 7 -H,
= CH-), 6.49 (dxt, J = 7.5, 55.0)
_{Hz, 1H, -CHF 2),} 6.66 (d, J = 12.
_{0Hz, 1H, C 3 -CH =} ), 6.92,7.30
(ABq, J = 8.5 Hz, 4H, Ph), 7.26
(S, 5H, Ph), 9.10 (d, J = 8.0 Hz,
1H, -CONH-). Compound D IR (Nujol, cm ⁻¹ ): 3270, 1775, ¹
720, 1650. ¹ H-NMR (DMSO-d ₆ , δppm): 3.40
_{~3.70 (m, 4H, C 2} -H 2, -CH 2 CO
-), 3.75 (s, 3H , -OCH 3), 5.18
(D, J = 5.0Hz, 1H , C 6 -H), 5.21
_{(Brs, 2H, -CO 2 CH} 2 -), 5.60~6.
_{02 (m, 2H, C 7} -H, = CH -), 6.50 (d
Xt, J = 7.5, 55.0 Hz, 1H, -CH
F ₂ ), 7.07 (d, J = 15.5 Hz, 1H, C ₃
-CH =), 6.92, 7.30 (ABq, J = 8.5)
Hz, 4H, Ph), 7.27 (s, 5H, Ph),
9.14 (d, J = 8.0 Hz, 1H, -CONH
−).

(2) 1.62 g of phosphorus pentachloride was dissolved in 27 ml of methylene chloride, 0.63 ml of pyridine was added at 0 ° C, and the mixture was stirred at 0 to 5 ° C for 1 hour. Compound C of (1)
1.34 g was added, and the mixture was stirred at the same temperature for 1 hr, cooled to -5 ° C, and isobutanol 1.5 ml was added dropwise, then -5 to 0
Stirred at C for 1 hour. After adding 1.5 ml of water and stirring at the same temperature for 20 minutes, the precipitate was collected by filtration to obtain 0.85 g of the title compound A crystals. Similarly, 0.25 g of the crystal of the title compound B was obtained from 0.45 g of the compound D.

Compound A IR (Nujol, cm ^-1 ): 3300,1790,1
725, 1685. ¹ H-NMR (DMSO-d ₆ , δppm): 3.00
^{~7.00 (br, 3H, -N +} H 3), 3.70
_{(S, 2H, C 2 -H} 2), 3.75 (s, 3H, -O
CH ₃ ), 5.05, 5.18 (ABq, J = 11.0
_{Hz, 2H, -CO 2 CH 2} -), 5.20~5.40
_{(M, 2H, C 6,} 7 -H), 5.70~6.00
(M, 1H, = CH-), 6.51 (dxt, J = 7.
_{0,54.5Hz, 1H, -CHF 2),} 6.71
(D, J = 12.0Hz, 1H , C 3 -CH =), 6.
92,7.31 (ABq, J = 8.5 Hz, 4H, P
h). Compound B IR (Nujol, cm ^-1 ): 3300, 1785, ¹
720, 1685. ¹ H-NMR (DMSO-d ₆ , δppm): 2.80
^{~9.00 (br, 3H, -N +} H 3), 3.70
_{(S, 2H, C 2 -H} 2), 3.76 (s, 3H, -O
_{CH 3), 5.18 (brs,} 2H, -CO 2 CH
_2- ), 5.24 (brs, 2H, _C6,7- H), 5.
72 to 6.02 (m, 1H, = CH-), 6.52 (d
× t, J = 7.0, 54.5 Hz, 1H, -CH
F ₂ ), 6.93, 7.31 (ABq, J = 8.5H
z, 4H, Ph), 7.09 (d, J = 15.5Hz,
1H, C ₃ -CH =).

Example 3 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylic acid sodium salt (1) p-methoxybenzyl 7β-amino-3-
[(Z) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylate hydrochloride 0.8 g and (Z) -2- (2-tritylaminothiazole-4-
1.73 g of dicyclohexylamine salt of (yl) -2-trityloxyiminoacetic acid was suspended in 30 ml of methylene chloride and cooled to -10 ° C. Pyridine (0.33 ml) and phosphorus oxychloride (0.25 ml) were sequentially added, and the mixture was stirred at the same temperature for 30 minutes. Ethyl acetate (100 ml) was added, and the mixture was washed successively with 10% citric acid water, saturated sodium hydrogen carbonate solution and saturated saline (100 ml each), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and p-methoxybenzyl 7β-[(Z) -2-
(2-Tritylaminothiazol-4-yl) -2-trityloxyiminoacetamide] -3-[(Z) -3,
3-Difluoro-1-propenyl] -3-cephem-4
-1.88 g of carboxylate was obtained.

IR and ¹ H-NMR were consistent with (1) of Example 1.

(2) 1.88 g of the compound of (1) was suspended in 1.8 ml of anisole, and trifluoroacetic acid was added under ice cooling.
4 ml was added, and the mixture was stirred at the same temperature for 1.5 hours. 100 ml of n-hexane was added, the oily substance was separated by decantation, and n-hexane-isopropyl ether (3:
50 ml of the mixed solution of 1) was added and solidified to obtain 1.16 g of powder. To the resulting powder was added 80% formic acid (4.6 ml), the mixture was stirred at room temperature for 1 hour, poured into 200 ml of a mixed solution of ethyl ether-isopropyl ether (1: 1), and the precipitate was collected by filtration. 0.6 g of powder was obtained. The obtained powder is mixed with water 6
The solution was suspended in 0 ml, adjusted to pH = 7.5 with sodium bicarbonate and dissolved, and then adsorbed on Diaion HP-21 (60 ml). After washing with water, eluting with 5% acetonitrile water, the target fraction was concentrated under reduced pressure, and lyophilized to give 410 mg of the title compound powder.
I got

IR and ¹ H-NMR were consistent with (2) of Example 1.

Example 4 1-Isopropoxycarbonyloxyethyl 7β-amino-3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate hydrochloride (1) p- Methoxybenzyl 7β-phenylacetamide-3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate (3.5 g) was suspended in anisole (3.5 ml) and cooled under ice-cooling. 10.5 ml of trifluoroacetic acid was added, and the mixture was stirred at the same temperature for 1 hour. After pouring into 100 ml of isopropyl ether, the precipitate was collected by filtration, and 7β-phenylacetamide-3-[(Z) -3,
3-Difluoro-1-propenyl] -3-cephem-4
-2.3 g of carboxylic acid was obtained. 2.3 g of the obtained powder
Was dissolved in 46 ml of ethyl acetate, 1.5 ml of dicyclohexylamine was added, the precipitate was collected by filtration, and 7β-phenylacetamide-3-[(Z) -3,3-difluoro-1 was added.
3.2 g of dipropenyl] -3-cephem-4-carboxylic acid dicyclohexylamine salt was obtained.

IR (Nujol, cm ^-1 ): 3320,
1765, 1660. ¹ H-NMR (DMSO-d ₆ , δppm):

[0123]

Embedded image

3.30, 3.73 (ABq, J = 17.
_{0Hz, 2H, C 2 -H 2} ), 3.53 (s, 2H, -
CH ₂ CO-), 5.05 (d, J = 5.0 Hz, 1
_{H, C 6 -H), 5.20~5.70} (m, 2H, C 7
-H, = CH-), 6.77 (dxt, J = 7.5, 5
_{5.0Hz, 1H, -CHF 2),} 6.94 (d, J =
_{12.5Hz, 1H, C 3 -CH =} ), 7.27 (s,
5H, Ph), 9.04 (d, J = 8.0 Hz, 1H,
-CONH-).

(2) 2.65 g of the compound of (1) was added to N, N
-Suspended in 26.5 ml of dimethylacetamide, added with 2.0 g of 1-iodoethyl isopropyl carbonate, and stirred at 20 ° C for 0.5 hours. Ethyl acetate 200
ml was added, and the mixture was washed successively with 10% citric acid water, saturated sodium bicarbonate water, and saturated saline 200 ml each, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and isopropyl ether 1
After pouring into 100 ml, the precipitate was collected by filtration, and 1-isopropoxycarbonyloxyethyl 7β-phenylacetamide-3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem- 4-carboxylate 1.95 g
I got

IR (Nujol, cm ^-1 ): 3270,
1760, 1730, 1665. ¹ H-NMR (DMSO-d ₆ , δppm): 1.23
(D, J = 6.0Hz, 6H , - (CH 3) 2), 1.
45 (d, J = 5.5Hz, 3H, -CH 3), 3.5
_{3 (s, 2H, -CH 2} CO -), 3.60 (brs,
_{2H, C 2 -H 2),} 4.60~5.00 (m, 1H,
-OCO ₂ CH <), 5.20 (d, J = 5.0 Hz,
1H, C ₆ -H), 5.60 to 6.00 (m, 2H, C
_7- H, = CH-), 6.50 (d * t, J = 7.0,
_{55.0Hz, 1H, -CHF 2),} 6.69 (d, J
_{= 12.0Hz, 1H, C 3 -CH} =), 6.60~
_{6.90 (m, 1H, -CO 2} CH <), 7.27
(S, 5H, Ph), 9.09 (d, J = 8.0 Hz,
1H, -CONH-).

(3) 1.73 g of phosphorus pentachloride was dissolved in 28 ml of methylene chloride, 0.67 ml of pyridine was added at 0 ° C, and the mixture was stirred at 0-5 ° C for 1 hour. After adding 1.9 g of the compound of (2) and stirring at the same temperature for 1 hour, it was cooled to -5 ° C and 1.54 ml of isobutanol was added dropwise, then -5 to 0.
Stirred at C for 1 hour. After adding 1.54 ml of water and stirring at the same temperature for 30 minutes, add 50 ml of methylene chloride and add 10
It was washed with 100 ml of a saline solution. The water layer was extracted with 50 ml of methylene chloride, and the methylene chloride layers were combined to give 10%.
After washing with 100 ml of saline, it was dried with anhydrous sodium sulfate.
The solution was concentrated under reduced pressure and 200 ml of isopropyl ether
After pouring into the mixture, the precipitate was collected by filtration to give the title compound as a powder 0.9.
8 g was obtained.

IR (Nujol, cm ^-1 ): 1760,
1725. ¹ H-NMR (DMSO-d ₆ , δppm): 1.23
(D, J = 6.0Hz, 6H , - (CH 3) 2), 1.
46 (d, J = 5.5Hz, 3H, -CH 3), 3.7
_{0 (s, 2H, C 2} -H 2), 4.60~5.00
_{(M, 1H, -OCO 2 CH} <), 5.21,5.31
(D, d, J = 5.0Hz , 1H, C 6, 7 -H),
5.60 to 6.00 (m, 1H, = CH-), 6.00
^{~10.00 (br, 3H, -N +} H 3), 6.52
(D × t, J = 6.5, 54.5 Hz, 1H, -CHF
_{2), 6.60~7.00 (m, 1H} , -CO 2 CH
<), 6.73 (d, J = 12.0 Hz, 1H, C ₃ −
CH =).

Example 5 1-Isopropoxycarbonyloxyethyl 7β-
[(Z) -2- (2-aminothiazol-4-yl)-
2-Hydroxyiminoacetamide] -3-[(Z)-
3,3-Difluoro-1-propenyl] -3-cephem-4-carboxylate hydrochloride (1) 1-isopropoxycarbonyloxyethyl 7
β-amino-3-[(Z) -3,3-difluoro-1-
0.93 g of propenyl] -3-cephem-4-carboxylate hydrochloride and 1.79 g of (Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetic acid dicyclohexylamine salt are added to methylene chloride. It was suspended in 28 ml and cooled to -10 ° C. Pyridine (0.34 ml) and phosphorus oxychloride (0.29 ml) were sequentially added, and the mixture was stirred at the same temperature for 30 minutes. 100 ml of ethyl acetate
Was added, and the mixture was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and 100 ml each of saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and 1-isopropoxycarbonyloxyethyl 7β-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityl was used. Oxyiminoacetamide] -3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate (1.64 g) was obtained.

IR (Nujol, cm ^-1 ): 1790,
1760, 1685. ¹ H-NMR (DMSO-d ₆ , δppm): 1.22
(D, J = 6.0Hz, 6H , - (CH 3) 2), 1.
47, 1.49 (d, d, J = 5.5 Hz, 3H, -C)
H ₃ ), 3.50, 3.72 (ABq, J = 15.0H
_{z, 2H, C 2 -H 2} ), 4.60~5.00 (m, 1
_{H, -OCO 2 CH <),} 5.31 (d, J = 5.0H
z, 1H, C ₆ -H), 5.60 to 6.10 (m, 2
_{H, C 7 -H, = CH} -), 6.52 (d × t, J =
_{6.0,54.5Hz, 1H, -CHF 2),} 6.59
_{(S, 1H, thiazoleC 5 -H} ), 6.70~
_{7.00 (m, 1H, -CO 2} CH <), 6.71
(D, J = 12.5Hz, 1H , C 3 -CH =), 7.
00 to 7.50 (m, 30H, Ph), 8.71 (br
_{s, 1H, thiazoleC 2 -NH -} ), 9.89
(D, J = 8.0 Hz, 1H, -CONH-).

(2) To 1.6 g of the compound of (1) was added 12.8 ml of 80% formic acid, and the mixture was stirred at room temperature for 1 hour. 300 ml of cold water was added, the insoluble matter was filtered, 1.1 g of sodium chloride was added, and the mixture was washed with 30 ml of isopropyl ether. 40 g of sodium chloride was added to the obtained aqueous layer, and the mixture was extracted with 200 ml of ethyl acetate. 300 ml of 5% aqueous sodium hydrogen carbonate,
The extract was washed successively with 100 ml of saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 820 mg of powder. The obtained powder was dissolved in 4.9 ml of methylene chloride, 0.2 ml of a 8.68N hydrogen chloride-2-propanol solution was added at -10 ° C, and immediately poured into 100 ml of isopropyl ether. The precipitate was collected by filtration to give the title compound (800 mg).

IR (Nujol, cm ^-1 ): 1785
1760, 1635. ¹ H-NMR (DMSO-d ₆ , δppm): 1.23
(D, J = 6.0Hz, 6H , - (CH 3) 2), 1.
46 (d, J = 5.5Hz, 3H, -CH 3), 3.0
^{0~8.00 (br, 3H, -N +} H 3), 3.50,
3.75 (ABq, J = 16.0Hz, 2H, C 2 -H
_{2), 4.60~5.00 (m, 1H} , -OCO 2 CH
<), 5.30 (d, J = 5.0 Hz, 1H, C ₆ −
H), 5.60~6.00 (m, 2H , C 7 -H, = C
H−), 6.51 (d × t, J = 6.0, 55.0H
_{z, 1H, -CHF 2),} 6.60~7.00 (m, 1
_{H, -CO 2 CH <),} 6.71 (d, J = 12.0H
_{z, 1H, C 3 -CH =} ), 6.84 (s, 1H, th
_{iazoleC 5 -H), 9.70 (d} , J = 8.0H
z, 1H, -CONH-), 12.36 (brs, 1
H, -OH).

Example 6 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylic acid 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -3,3-difluoro-1-propenyl] -3
-0.5 g of cephem-4-carboxylic acid sodium salt was dissolved in 5 ml of water, adjusted to pH 3.0 with 1N hydrochloric acid, and extracted twice with 10 ml of ethyl acetate. After washing with 5 ml of saturated saline, ethyl acetate was distilled off under reduced pressure to give the title compound (0.1%).
35 g were obtained.

IR (Nujol, cm ^-1 ): 3300,
1775, 1650. ¹ H-NMR (DMSO-d ₆ , δppm): 2.50
_{~5.50 (br, 1H, -CO 2} H), 3.43,
3.70 (ABq, J = 18.5Hz, 2H, C 2 -H
₂ ), 5.23 (d, J = 5.0 Hz, 1H, C ₆ −
H), 5.50~6.02 (m, 2H , C 7 -H, = C
H−), 6.54 (d × t, J = 7.0, 55.5H
_{z, 1H, -CHF 2),} 6.66 (s, 1H, thi
azoleC ₅ -H), 6.72 (d, J = 12.0H
_{z, 1H, C 3 -CH =} ), 6.83~7.50 (br
_{s, 2H, -NH 2),} 9.45 (d, J = 8.0H
z, 1H, -CONH-), 11.32 (brs, 1
H, -OH).

Example 7 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylic acid sodium salt This compound was synthesized according to Example 3.

IR (Nujol, cm ^-1 ): 3200,
1770. ¹ H-NMR (DMSO-d ₆ , δppm): 3.3
4, 3.76 (ABq, J = 16.5 Hz, 2H, C ₂
-H ₂ ), 5.10 (d, J = 5.0 Hz, 1H, C ₆
-H), 5.22 to 5.74 (m, 1H, = CH-),
5.69 (d × d, J = 5.0, 8.0 Hz, 1H, C
_7- H), 6.64 (s, 1H, thiazoleC ₅
-H), 6.80 (d * t, J = 7.0, 55.5H)
_{z, 1H, -CHF 2),} 7.13 (brs, 2H, -
NH ₂ ), 7.31 (d, J = 15.5 Hz, 1H, C
_3- CH =), 9.44 (d, J = 8.0 Hz, 1H,
-CONH-), 11.20 to 12.00 (br, 1
H, -OH).

Example 8 p-Methoxybenzyl 7β-amino-3-[(2,2
-Difluoroethylidene) aminooxy] methyl-3-
Cephem-4-carboxylate hydrochloride (1) p-methoxybenzyl 7β-phenylacetamido-3-aminooxymethyl-3-cephem-4-carboxylate (6.92 g) and tetrahydrofuran (70 m)
2.3 g of difluoroacetaldehyde was added, and the mixture was stirred at room temperature for 1 hour. 200 ml of ethyl acetate was added, and the mixture was washed successively with 5% saline and 300 ml each of saturated saline, dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.3 g of p-methoxybenzyl 7β-phenylacetamide-3-[(2,2-difluoroethylidene) aminooxy] methyl-3-cephem-4-carboxylate. Obtained.

IR (Nujol, cm ^-1 ): 3380,
1785, 1715, 1660. ¹ H-NMR (DMSO-d ₆ , δppm): 3.57
_{(Brs, 4H, -CH 2 CO-} , C 2 -H 2), 3.
_{74 (s, 3H, -OCH 3} ), 4.93 (brs, 2
_{H, C 3 -CH 2 -)} , 5.08,5.28 (ABq,
_{J = 13.5Hz, 2H, -CO 2} CH 2 -), 5.1
1 (d, J = 5.0Hz, 1H, C 6 -H), 5.71
(D × d, J = 5.0, 8.0 Hz, 1H, C ₇ −
H), 6.44 (d × t, J = 5.5, 55.5 Hz,
_{1H, -CHF 2), 6.91,7.33 (} ABq, J
= 8.0 Hz, 4H, Ph), 7.27 (s, 5H, P)
h), 7.80 (q, J = 5.5 Hz, 1H, -N = C
H-), 9.08 (d, J = 8.0 Hz, 1H, -CO
NH-).

(2) 1.15 g of phosphorus pentachloride was dissolved in 20 ml of methylene chloride, 0.44 ml of pyridine was added at 0 ° C, and the mixture was stirred at 0 to 5 ° C for 1 hour. After adding 1.0 g of the compound of (1) and stirring at the same temperature for 1 hour, it was cooled to -5 ° C, 1.0 ml of isobutanol was added dropwise, and then -5 to 0 ° C
It was stirred for 1 hour. Water (1.5 ml) was added, the mixture was stirred at the same temperature for 20 minutes, washed with 10% brine (20 ml), and the aqueous layer was extracted with methylene chloride (20 ml). The methylene chloride layers were combined, washed with 20 ml of 10% saline and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, poured into 100 ml of diethyl ether, and the precipitate was collected by filtration to obtain 0.55 g of the title compound powder.

IR (Nujol, cm ^-1 ): 2600,
1785, 1725, 1640. ¹ H-NMR (DMSO-d ₆ , δppm): 3.63
_{(Brs, 2H, C 2 -H} 2), 3.75 (s, 3H,
_{-OCH 3), 4.97 (brs,} 2H, C 3 -CH 2
-), 5.19 (brs, 4H , C 6, 7 -H, -CO
₂ CH ₂ −), 6.45 (d × t, J = 6.0, 55.
_{0Hz, 1H, -CHF 2),} 6.92,7.34 (A
Bq, J = 8.0 Hz, 4H, Ph), 7.50-1
^{1.50 (br, 3H, -N +} H 3), 7.81 (q,
J = 6.0 Hz, 1H, -N = CH-).

Example 9 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(2,2-Difluoroethylidene) aminooxy] methyl-3-cephem-4-carboxylic acid sodium salt (1) p-methoxybenzyl 7β-amino-3-
[(2,2-Difluoroethylidene) aminooxy] methyl-3-cephem-4-carboxylate hydrochloride 0.
77 g and 1.86 g of (Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetic acid dicyclohexylamine salt were added to 40 m of methylene chloride.
It was suspended in 1 and cooled to -10 ° C. Pyridine 0.32m
1, 0.24 ml of phosphorus oxychloride were sequentially added, and the mixture was stirred at the same temperature for 30 minutes. Add 100 ml of ethyl acetate and add 10
% Citric acid water, saturated sodium bicarbonate water, then saturated saline water 100 each
It was washed successively with ml and dried over anhydrous Glauber's salt. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and p-methoxybenzyl 7β-[(Z)
-2- (2-Tritylaminothiazol-4-yl)-
2-Trityloxyiminoacetamide] -3-[(2,
2-difluoroethylidene) aminooxy] methyl-3
-1.5 g of cephem-4-carboxylate are obtained.

IR (Nujol, cm ^-1 ): 1790,
1725, 1675. ¹ H-NMR (DMSO-d ₆ , δppm): 3.47.
_{(Brs, 2H, C 2 -H} 2), 3.75 (s, 3H,
_{-OCH 3), 4.94 (brs,} 2H, C 3 -CH 2
-), 5.05~5.33 (m, 3H , C 6 -H, -C
O ₂ CH ₂ −), 5.85 (d, J = 5.0, 8.0H
_{z, 1H, C 7 -H)} , 6.45 (d × t, J = 6.
_{0,55.0Hz, 1H, -CHF 2),} 6.59
_{(S, 1H, thiazoleC 5 -H} ), 6.92
(D, J = 8.0 Hz, 2H, Ph), 7.05-7.
60 (m, 32H, Ph), 7.80 (q, J = 6.0)
Hz, 1H, -N = CH-), 8.74 (brs, 1
_{H, thiazoleC 2 -NH -),} 9.85 (d,
J = 8.0 Hz, 1H, -CONH-).

(2) 1.0 g of the compound of (1) was suspended in 1.0 ml of anisole, and trifluoroacetic acid was added to 3.0 ml under ice cooling.
ml was added, and the mixture was stirred at the same temperature for 1.5 hours. After adding 60 ml of n-hexane and separating the oily matter by decantation, n-hexane-isopropyl ether (3: 1)
80 ml of a mixed solution of was added to solidify to obtain 0.6 g of powder.
2.4 ml of 80% formic acid was added to the obtained powder, and the mixture was stirred at room temperature for 1 hour. After pouring into 100 ml of a mixed solution of ethyl ether-isopropyl ether (1: 1), the precipitate was collected by filtration to obtain 0.4 g of powder. 40m of the obtained powder in water
It was suspended in 1 l, adjusted to pH = 7.5 with sodium bicarbonate and dissolved, and then adsorbed on Diaion HP-21 (40 ml). After washing with water
The product was eluted with 5% acetonitrile water, and the target fraction was concentrated under reduced pressure and freeze-dried to obtain 210 mg of the title compound powder.

IR (Nujol, cm ^-1 ): 3350,
1760. ¹ H-NMR (DMSO-d ₆ , δppm): 3.2
9, 3.55 (ABq, J = 17.0 Hz, 2H, C _{2
-H 2), 4.87,5.19 (ABq,} J = 12.0
_{Hz, 2H, C 3 -CH 2} -), 5.00 (d, J =
5.0 Hz, 1H, C ₆ -H), 5.62 (d, J =
_{5.0,8.0Hz, 1H, C 7 -H)} , 6.45 (d
Xt, J = 6.0, 54.0 Hz, 1H, -CH
F ₂ ), 6.64 (s, 1H, thiazoleC ₅ −
H), 6.90~7.30 (br, 2H , -NH 2),
7.75 (q, J = 6.0 Hz, 1H, -N = CH
-), 9.35 (d, J = 8.0 Hz, 1H, -CON
H-), 11.20 to 12.40 (br, 1H, -O
H).

Example 10 p-Methoxybenzyl 7β-amino-3-[(Z)-
3- (2,2-difluoroethylidene) aminooxy-
1-propenyl] -3-cephem-4-carboxylate hydrochloride (1) p-methoxybenzyl 7β-phenylacetamido-3-[(Z) -3-aminooxy-1-propenyl] -3-cephem- 4-carboxylate 2.23 g
Was dissolved in 24 ml of tetrahydrofuran, 0.7 g of difluoroacetaldehyde was added, and the mixture was stirred at room temperature for 1 hour. 150 ml of ethyl acetate was added, and the mixture was washed successively with 100 ml of 5% saline and 100 ml of saturated saline, dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, p-methoxybenzyl 7β-phenylacetamide-3-[(Z) -3
-(2,2-Difluoroethylidene) aminooxy-1
1.0 g of -propenyl] -3-cephem-4-carboxylate was obtained.

IR (Nujol, cm ^-1 ): 3250,
1775, 1720, 1655. ¹ H-NMR (DMSO-d ₆ , δppm): 3.54
_{(Brs, 4H, C 2 -H} 2, -CH 2 CO -), 3.
_{74 (s, 3H, -OCH 3} ), 4.20~4.80
_{(M, 2H, -CH 2 ON} =), 5.06,5.19
(ABq, J = 10.0Hz, 2H , -CO 2 CH
₂₋ ), 5.16 (d, J = 5.0 Hz, 1H, C ₆ −
H), 5.50~5.90 (m, 2H , C 7 -H, = C
H−), 6.33 (d, J = 12.0 Hz, 1H, C ₃
-CH =), 6.48 (dxt, J = 5.5, 53.0
_{Hz, 1H, -CHF 2),} 6.92,7.32 (AB
q, J = 9.0 Hz, 4H, Ph), 7.24 (s, 5)
H, Ph), 7.78 (q, J = 5.5 Hz, 1H,-
N = CH-), 9.09 (d, J = 8.0 Hz, 1H,
-CONH-).

(2) 0.98 g of phosphorus pentachloride was dissolved in 20 ml of methylene chloride, 0.38 g of pyridine was added at 0 ° C, and the mixture was stirred at 0-5 ° C for 1 hour. The compound of (1) 0.
After adding 9 g and stirring at the same temperature for 1 hour, it cooled at -5 degreeC, 0.9 ml of isobutanol was dripped, and it stirred at -5 to 0 degreeC for 1 hour. Add 0.9 ml of water and add 2 at the same temperature.
After stirring for 0 minutes, the mixture was washed with 10% brine (30 ml) and the aqueous layer was extracted with methylene chloride (30 ml). The methylene chloride layers were combined, washed with 30 ml of 10% saline and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and diethyl ether 7
After pouring into 0 ml, the precipitate was collected by filtration to obtain 0.5 g of the title compound powder.

IR (Nujol, cm ^-1 ): 1780,
1720. ¹ H-NMR (DMSO-d ₆ , δppm): 3.70
_{(S, 2H, C 2 -H} 2), 3.75 (s, 3H, -O
_{CH 3), 4.20~4.80 (m,} 2H, -CH 2 O
N =), 5.00~5.40 (m, 4H, C 6, 7 -
_{H, -CO 2 CH 2 -)} , 5.60~5.90 (m, 1
H, = CH-), 6.41 (d, J = 12.0 Hz, 1
H, C ₃ -CH =), 6.49 (d × t, J = 5.5,
_{53.5Hz, 1H, -CHF 2),} 6.89,7.3
0 (ABq, J = 9.0 Hz, 4H, Ph), 7.78
(Q, J = 5.5 Hz, 1H, -N = CH-), 8.0
^{0~11.00 (br, 3H, -N +} H 3).

Example 11 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -3- (2,2-Difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylic acid sodium salt (1) p-methoxybenzyl 7β-amino-3-
[(Z) -3- (2,2-Difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylate hydrochloride 0.49 g and (Z) -2- (2
-Tritylaminothiazol-4-yl) -2-trityloxyiminoacetic acid dicyclohexylamine salt 0.93
g was suspended in 15 ml of methylene chloride and cooled to -10 ° C. Pyridine 0.18 ml, phosphorus oxychloride 0.13 m
1 was sequentially added and stirred at the same temperature for 30 minutes. Ethyl acetate (100 ml) was added, and the mixture was washed successively with 10% citric acid water, saturated sodium hydrogen carbonate solution and saturated saline (100 ml each), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and p-methoxybenzyl 7β-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoa Cetamide] -3-[(Z) -3- (2,2-difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylate (0.83 g) was obtained.

IR (Nujol, cm ^-1 ): 3320,
1785, 1730, 1690. ¹ H-NMR (DMSO-d ₆ , δppm): 3.58
_{(Brs, 2H, C 2 -H} 2), 3.74 (s, 3H,
_{-OCH 3), 4.20~4.70 (m,} 2H, -CH
₂ ON =), 5.00 to 5.20 (m, 2H, -CO ₂
CH ₂ −), 5.26 (d, J = 5.0 Hz, 1H, C
_{6 -H), 5.50~6.00 (m,} 2H, C 7 -H,
= CH-), 6.32 (d, J = 12.0 Hz, 1H,
_{C 3 -CH =), 6.56 (} d × t, J = 5.5,5
_{3.0Hz, 1H, -CHF 2),} 6.60 (s, 1
H, thiazoleC ₅ -H), 6.80~7.50
(M, 34H, Ph), 7.80 (q, J = 5.5H
z, 1H, -N = CH-), 8.72 (brs, 1H,
_{thiazoleC 2 -NH -), 9.86 (} d, J =
8.0 Hz, 1H, -CONH-).

(2) 0.74 g of the compound of (1) was suspended in 0.74 ml of anisole, 2.3 ml of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. n
-Hexane 70 ml was added, the oily substance was separated by decantation, and 100 ml of a mixed liquid of n-hexane-isopropyl ether (3: 1) was added to solidify the mixture to give a powder of 0.
4 g were obtained. To the obtained powder, 80% formic acid (1.6 ml) was added, and the mixture was stirred at room temperature for 1 hour. After pouring into 70 ml of a mixed solution of ethyl ether-isopropyl ether (1: 1), the precipitate was collected by filtration to obtain 0.3 g of powder. The obtained powder was suspended in 30 ml of water, adjusted to pH = 7.5 with sodium bicarbonate and dissolved, and then adsorbed on Diaion HP-21 (30 ml). After washing with water, eluting with 5% acetonitrile water, the target fraction was concentrated under reduced pressure and freeze-dried to give the title compound powder 2
10 mg was obtained.

IR (Nujol, cm ^-1 ): 3300,
1760, 1675. ¹ H-NMR (DMSO-d ₆ , δppm): 3.48
_{(Brs, 2H, C 2 -H} 2), 4.30~4.70
_{(M, 2H, -CH 2 ON} =), 5.05 (d, J =
_{5.0Hz, 1H, C 6 -H)} , 5.50~5.90
_{(M, 2H, C 7 -H} , = CH -), 6.38 (d, J
_{= 12.0Hz, 1H, C 3 -CH} =), 6.60 (d
Xt, J = 5.5, 53.0 Hz, 1H, -CH
F ₂ ), 6.72 (s, 1H, thiazoleC ₅ −
H), 7.10 (brs, 2H , -NH 2), 7.75
(Q, J = 5.5 Hz, 1H, -N = CH-), 9.3
6 (d, J = 8.0 Hz, 1H, -CONH-). 1
1.00-12.50 (br, 1H, -OH).

Example 12 1-Isopropoxycarbonyloxyethyl 7β-
[(Z) -2- (2-L-alanylaminothiazole-
4-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylate hydrochloride (1) 1-isopropoxycarbonyloxyethyl 7
β-amino-3-[(Z) -3,3-difluoro-1-
Propenyl] -3-cephem-4-carboxylate hydrochloride 1.0 g and (Z) -2- [2- (Boc-L-
Alanyl) aminothiazol-4-yl] -2-trityloxyiminoacetic acid dicyclohexylamine salt 1.94
g was suspended in 30 ml of methylene chloride and cooled to -10 ° C. Pyridine 0.40 ml, phosphorus oxychloride 0.30 m
1 was sequentially added and stirred at the same temperature for 30 minutes. 150 ml of ethyl acetate was added, and the mixture was washed successively with 10% citric acid water, saturated aqueous sodium hydrogen carbonate and saturated saline 150 ml each, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and 1-isopropoxycarbonyloxyethyl 7β-{(Z) -2-
[2- (Boc-L-alanyl) aminothiazole-4
-Yl] -2-trityloxyiminoacetamide} -3
-[(Z) -3,3-difluoro-1-propenyl]-
1.5 g of 3-cephem-4-carboxylate was obtained.

IR (Nujol, cm ^-1 ): 1785
1750, 1710. ¹ H-NMR (DMSO-d ₆ , δppm): 1.24
(D, J = 6.0Hz, 6H , - (CH 3) 2), 1.
35 (s, 9H, -C ( CH 3) 3), 1.46 (d,
_{J = 6.0Hz, 3H, -CH 3} ), 1.48 (d, J
_{= 5.5Hz, 3H, -CH 3)} , 3.50,3.72
(ABq, J = 16.0Hz, 2H , C 2 -H 2),
4.00-4.40 (m, 1H, -COCH <), 4.
_{60~5.00 (m, 1H, -OCO 2} CH <), 5.
31 (d, J = 5.0Hz, 1H, C 6 -H), 5.6
_{0~6.10 (m, 2H, C 7} -H, = CH -), 6.
52 (d × t, J = 6.0, 55.0 Hz, 1H, −C
_{HF 2), 6.60~7.00 (m,} 1H, -CO 2 C
H <), 6.71 (d, J = 12.0 Hz, 1H, C ₃
-CH =), 7.00 to 7.50 (m, 16H, Ph,
thiazoleC ₅ -H), 7.80~8.50 (b
r, 1H, -NH-), 10.05 (d, J = 8.0H
z, 1H, -CONH-), 12.50 (brs, 1
H, thiazoleC ₂ -NH-).

(2) 1.45 g of the compound of (1) was dissolved in 7.25 ml of formic acid, and 8.6N hydrogen chloride-2 at 0 ° C.
-Add 0.85 ml of propanol solution and add 1 at the same temperature.
Stir for 5 minutes. After pouring into 250 ml of isopropyl ether, the precipitate was collected by filtration to obtain 0.8 g of the title compound powder.

IR (Nujol, cm ^-1 ): 3300,
1785, 1740, 1700. ¹ H-NMR (DMSO-d ₆ , δppm): 1.24
(D, J = 6.0Hz, 6H , - (CH 3) 2), 1.
46 (d, J = 5.5Hz, 6H, -CH 3 × 2),
3.50, 3.75 (ABq, J = 16.0 Hz, 2
_{H, C 2 -H 2),} 4.00~4.40 (m, 1H, -
COCH <), 4.60 to 5.00 (m, 1H, -OC
O ₂ CH <), 5.30 (d, J = 5.0 Hz, 1H,
_{C 6 -H), 5.60~6.00 (m} , 2H, C 7 -
H, = CH-), 6.51 (dxt, J = 6.0, 5
_{5.0Hz, 1H, -CHF 2),} 6.60~7.00
_{(M, 1H, -CO 2 CH} <), 6.71 (d, J = 1
_{2.0Hz, 1H, C 3 -CH =} ), 7.50 (s, 1
H, thiazoleC ₅ -H), 7.90~10.0
^{0 (br, 3H, -N +} H 3), 9.75 (d, J =
8.0 Hz, 1H, -CONH-), 11.70 (br
_{s, 1H, thiazoleC 2 -NH -} ), 12.3
6 (brs, 1H, -OH).

The following compounds are prepared by any of the methods of Examples 1-12. (1) 7β-[(Z) -2- (2-aminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
[(Z) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylic acid and its sodium salt (2) 7β-[(Z) -2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-[(Z) -3,3-difluoro-1
-Propenyl] -3-cephem-4-carboxylic acid and its sodium salt (3) 7β-[(Z) -2- (5-amino-1,2,4
-Thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-[(Z) -3,3-difluoro-1-
Propenyl] -3-cephem-4-carboxylic acid and its sodium salt (4) 7β-[(Z) -2- (2-aminothiazole-
4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylic acid (5) 7β-[(Z) -2- (2-aminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
[(E) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylic acid and its sodium salt

(6) 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-[(E) -3 , 3-Difluoro-1-propenyl] -3-cephem-4-carboxylic acid and its sodium salt (7) 7β-[(Z) -2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-[(E) -3,3-difluoro-1-
Propenyl] -3-cephem-4-carboxylic acid and its sodium salt (8) 7β-[(Z) -2- (2-aminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
[(2,2-Difluoroethylidene) aminooxy] methyl-3-cephem-4-carboxylic acid and its sodium salt (9) 7β-[(Z) -2- (5-amino-1,2,4)
-Thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-[(2,2-difluoroethylidene) aminooxy] methyl-3-cephem-4-carboxylic acid and its sodium salt (10) 7β- [(Z) -2- (5-amino-1,2,
4-Thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-[(2,2-difluoroethylidene) aminooxy] methyl-3-cephem-4-carboxylic acid and its sodium salt

(11) 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(Z) -3- (2,2-difluoro) Ethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylic acid and its sodium salt (12) 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoa Cetamide] -3
-[(E) -3- (2,2-Difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylic acid and its sodium salt (13) 7β-[(Z) -2- (2 -Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-
[(E) -3- (2,2-Difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylic acid sodium salt (14) 7β-[(Z) -2- (5-amino- 1, 2,
4-thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-[(Z) -3- (2,2-difluoroethylidene) aminooxy-1-propenyl] -3
-Cephem-4-carboxylic acid and its sodium salt (15) 7β-[(Z) -2- (5-amino-1,2,2
4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-[(Z) -3- (2,2-difluoroethylidene) aminooxy-1-propenyl] -3-
Cephem-4-carboxylic acid and its sodium salt

(16) 7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-[(E) -3 −
(2,2-Difluoroethylidene) aminooxy-1-
Propenyl] -3-cephem-4-carboxylic acid and its sodium salt (17) 7β-[(Z) -2- (5-amino-1,2,
4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-[(E) -3- (2,2-difluoroethylidene) aminooxy-1-propenyl] -3-
Cephem-4-carboxylic acid and its sodium salt (18) 7β-amino-3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylic acid (19) Benzhydryl 7β-amino -3-[(Z)
-3,3-Difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (20) pivaloyloxymethyl 7β-amino-3-
[(Z) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylate and its hydrochloride

(21) 1-acetoxyethyl 7β-amino-3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (22) 1-cyclohexyl Oxycarbonyloxyethyl 7β-amino-3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (23) 7β-amino-
3-[(E) -3,3-difluoro-1-propenyl]
-3-Cephem-4-carboxylic acid (24) Benzhydryl 7β-amino-3-[(E)
-3,3-Difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (25) 1-isopropoxycarbonyloxyethyl
7β-amino-3-[(E) -3,3-difluoro-1
-Propenyl] -3-cephem-4-carboxylate and its hydrochloride

(26) Pivaloyloxymethyl 7β-
Amino-3-[(E) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (27) 1-acetoxyethyl 7β-amino-3-
[(E) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylate and its hydrochloride (28) 1-cyclohexyloxycarbonyloxyethyl 7β-amino-3-[(E) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxy Rate and its hydrochloride (29) 7β-amino-3-[(2,2-difluoroethylidene) aminooxy] methyl-3-cephem-4-
Carboxylic acid (30) 7β-amino-3-[(Z) -3- (2,2-
Difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylic acid

(31) 7β-amino-3-[(E) -3
-(2,2-Difluoroethylidene) aminooxy-1
-Propenyl] -3-cephem-4-carboxylic acid (32) benzhydryl 7β-amino-3-[(2,2
2-difluoroethylidene) aminooxy] methyl-3
-Cephem-4-carboxylate and its hydrochloride (33) Benzhydryl 7β-amino-3-[(Z)
-3- (2,2-Difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (34) Benzhydryl 7β-amino-3-[(E)
-3- (2,2-Difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (35) 1-isopropoxycarbonyloxyethyl
7β-Amino-3-[(2,2-difluoroethylidene) aminooxy] methyl-3-cephem-4-carboxylate and its hydrochloride

(36) 1-isopropoxycarbonyloxyethyl 7β-amino-3-[(Z) -3- (2,
2-Difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (37) 1-isopropoxycarbonyloxyethyl
7β-amino-3-[(E) -3- (2,2-difluoroethylidene) aminooxy-1-propenyl] -3-
Cephem-4-carboxylate and its hydrochloride (38) pivaloyloxymethyl 7β-amino-3-
[(2,2-Difluoroethylidene) aminooxy] methyl-3-cephem-4-carboxylate and its hydrochloride (39) pivaloyloxymethyl 7β-amino-3-
[(Z) -3- (2,2-Difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (40) pivaloyloxymethyl 7β-amino-3-
[(E) -3- (2,2-Difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride

(41) 1-isopropoxycarbonyloxyethyl 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide]
-3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate (42) 1-isopropoxycarbonyloxyethyl
7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(Z)
-3,3-Difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (43) 1-isopropoxycarbonyloxyethyl
7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-[(Z) -3,3-difluoro-1 -Propenyl] -3-cephem-4-carboxylate and its hydrochloride (44) 1-acetoxyethyl 7β-[(Z) -2-
(2-Aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (45) 1-acetoxyethyl 7β-[(Z) -2-
(2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride

(46) 1-acetoxyethyl 7β-
[(Z) -2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetamide]
-3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (47) pivaloyloxymethyl 7β-[(Z) -2
-(2-Aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloric acid Salt (48) Pivaloyloxymethyl 7β-[(Z) -2
-(2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(Z) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloric acid Salt (49) Pivaloyloxymethyl 7β-[(Z) -2
-(5-Amino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylate and its hydrochloride (50) 1-isopropoxycarbonyloxyethyl
7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylate and its hydrochloride

(51) 1-isopropoxycarbonyloxyethyl 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide]-
3-[(E) -3,3-difluoro-1-propenyl]
-3-Cephem-4-carboxylate and its hydrochloride (52) 1-isopropoxycarbonyloxyethyl
7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-[(E) -3,3-difluoro-1 -Propenyl] -3-cephem-4-carboxylate and its hydrochloride (53) 1-acetoxyethyl 7β-[(Z) -2-
(2-Aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride salt (54) 1-acetoxyethyl 7β-[(Z) -2-
(2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride salt (55) 1-Acetoxyethyl 7β-[(Z) -2-
(5-Amino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-
[(E) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylate and its hydrochloride

(56) Pivaloyloxymethyl 7β-
[(Z) -2- (2-aminothiazol-4-yl)-
2-Hydroxyiminoacetamide] -3-[(E)-
3,3-Difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (57) pivaloyloxymethyl 7β-[(Z) -2
-(2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloric acid Salt (58) pivaloyloxymethyl 7β-[(Z) -2
-(5-Amino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-
[(E) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylate and its hydrochloride (59) 1-isopropoxycarbonyloxyethyl
7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-hydroxyiminoacetamide] -3-[(2,2-difluoroethylidene) aminooxy] Methyl-3-cephem-4-carboxylate and its hydrochloride (60) 1-isopropoxycarbonyloxyethyl
7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(Z)
-3- (2,2-difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride

(61) 1-isopropoxycarbonyloxyethyl 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide]-
3-[(E) -3- (2,2-difluoroethylidene)
Aminooxy-1-propenyl] -3-cephem-4-
Carboxylate and its hydrochloride (62) 1-isopropoxycarbonyloxyethyl
7β-[(Z) -2- (2-L-alanylaminothiazol-4-yl) -2-methoxyiminoacetamide]-
3-[(Z) -3,3-difluoro-1-propenyl]
-3-Cephem-4-carboxylate and its hydrochloride (63) 1-isopropoxycarbonyloxyethyl
7β-[(Z) -2- (2-L-alanylaminothiazol-4-yl) -2-hydroxyiminoacetamide]
-3-[(E) -3,3-difluoro-1-propenyl] -3-cephem-4-carboxylate and its hydrochloride (64) 1-isopropoxycarbonyloxyethyl
7β-[(Z) -2- (2-L-alanylaminothiazol-4-yl) -2-methoxyiminoacetamide]-
3-[(E) -3,3-difluoro-1-propenyl]
-3-Cephem-4-carboxylate and its hydrochloride

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Takayoshi Mori 13-153 Yamada-Hamuro-cho, Nishikyo-ku, Kyoto (72) Inventor Nobuharu Kakeya 3-10-10 Takadai, Nagaokakyo, Kyoto Prefecture

Claims (7)

[Claims] 1. A compound of the general formula (I)[In formula, A is -CH = CH-, -CH = CH-CH_TwoO
N = CH- or -CH _TwoON = CH-, R¹Is hydrogen
An atom, an alanyl group or an amino protecting group, R^TwoIs hydrogen
A child, a lower alkyl group or a hydroxy protecting group, R^ThreeIs
Carboxyl group or esterified carboxyl group
And Z represents = CH- or = N-. ] Represented by
Pharosporin compound or its pharmaceutically acceptable
salt. 2. The cephalosporin compound according to claim 1, which is selected from the following compounds, or a pharmaceutically acceptable salt thereof. 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylic acid sodium salt 1-isopropoxycarbonyloxyethyl 7β-
[(Z) -2- (2-aminothiazol-4-yl)-
2-Hydroxyiminoacetamide] -3-[(Z)-
3,3-Difluoro-1-propenyl] -3-cephem-4-carboxylate hydrochloride 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide]- 3-
[(Z) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylic acid 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylic acid sodium salt 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(2,2-Difluoroethylidene) aminooxy] methyl-3-cephem-4-carboxylic acid sodium salt 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoaceta Mido] -3-
[(Z) -3- (2,2-Difluoroethylidene) aminooxy-1-propenyl] -3-cephem-4-carboxylic acid sodium salt 1-isopropoxycarbonyloxyethyl 7β-
[(Z) -2- (2-L-alanylaminothiazole-
4-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylate hydrochloride 3. A prophylactic / therapeutic agent for infectious diseases, which comprises the cephalosporin compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. The preventive and therapeutic agent for infectious disease according to claim 3, which is an oral preventive and therapeutic agent for infectious disease. 5. In the general formula (I) according to claim 1,
An oral prophylactic / therapeutic agent for infectious diseases, comprising a cephalosporin compound in which R ³ is an esterified carboxyl group or a pharmaceutically acceptable salt thereof as an active ingredient. 6. A compound represented by the general formula (II):[In formula, A is -CH = CH-, -CH = CH-CH_TwoO
N = CH- or -CH _TwoON = CH-, R^ThreeIs Cal
Indicates a voxyl group or an esterified carboxyl group
You. ] The 7-amino cephalosporin compound represented by
Or salt. 7. The cephalosporin compound according to claim 6, which is selected from the following compounds, or a pharmaceutically acceptable salt thereof. p-methoxybenzyl 7β-amino-3-[(Z)-
3,3-Difluoro-1-propenyl] -3-cephem-4-carboxylate hydrochloride (Compound A) and p-
Methoxybenzyl 7β-amino-3-[(E) -3,
3-Difluoro-1-propenyl] -3-cephem-4
-Carboxylate hydrochloride (Compound B) 1-isopropoxycarbonyloxyethyl 7β-amino-3-
[(Z) -3,3-difluoro-1-propenyl] -3
-Cephem-4-carboxylate hydrochloride p-methoxybenzyl 7β-amino-3-[(2,2
-Difluoroethylidene) aminooxy] methyl-3-
Cephem-4-carboxylate hydrochloride p-methoxybenzyl 7β-amino-3-[(Z)-
3- (2,2-difluoroethylidene) aminooxy-
1-propenyl] -3-cephem-4-carboxylate hydrochloride