JPH11322757A - Novel cephem compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel cephem compound showing strong antimicrobial effects against a wide range of bacteria, including methicillin resistant Staphylococcus aureus, and useful for prevention and/or treatment of infection diseases. SOLUTION: This compound is a cephem compound shown by formula I [R<1> is a (protected) amino; R<2> is a halogen; R<3> is H or a hydroxy-protecting group; R<4> is (protected) carboxy; R<5> is hydroxy, amidinothio or the like; and (n) is an integer of 1 to 6], e.g. 7β-[2- (Z)-hydroxyimino}-2-(2-amino-5- chlorothiazol-4-yl)acetamido]-3-[4-carbamoylmethylthiazol-2-ylthio]-3- cephem-4- carboxylic acid. The compound shown by formula I can be obtained by, e.g. reacting a compound shown by formula II with a compound shown by formula III. It can be expected to show high antimicrobial activity against wide varieties of pathogenic microbes.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to novel cephem compounds and pharmaceutically acceptable salts thereof. More specifically, the present invention relates to novel cephem compounds having antimicrobial activity and pharmaceutically acceptable salts thereof, methods for producing them, pharmaceutical compositions containing them, and preventing infectious diseases in humans and animals And / or methods of treating.

[0002]

BACKGROUND OF THE INVENTION Over the past decades, many types of antibiotics have been discovered and used in medical settings for treatment and prevention. Above all, cephalosporin antibiotics have been remarkably developed and are effective against a wide range of bacteria such as gram-positive bacteria and gram-negative bacteria, and are therefore used for treatment and prevention of various infectious diseases. Unfortunately, however, the frequent use of such antibiotics has led to the emergence of bacteria that have acquired antibiotic resistance, making treating patients infected with such bacteria an important issue. I have. In particular, the emergence of methicillin-resistant Staphylococcus aureus (MRSA) poses a serious problem. Cephem compounds with high antimicrobial activity against a wide variety of pathogenic microorganisms, including Gram-positive and Gram-negative microorganisms, are known for example in EP-A-3066863, but they are methicillin-resistant Staphylococcus aureus ( (MRSA) and Pseudomonas aeruginosa are still inadequate as antimicrobial agents. MRSA infections are generally intractable and, due to lack of effective treatments,
The emergence of antibiotics effective for MRSA is strongly desired.
Against this background, the search for antibiotics effective for MRSA has been continued. For example, JP-A-5-202665 and JP-A-10-45766 disclose cephalosporin compounds effective for MRSA. Has been
Not enough yet.

[0003]

Under such a background,
Strong antibacterial activity against a wide range of bacteria, and MRSA
Therefore, the appearance of a cephalosporin compound having a strong antibacterial activity has been desired.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above problems, and as a result, a novel cephem compound represented by the following general formula [I] or a salt thereof has been widely used. The present inventors have found that they have an antibacterial spectrum and a strong antibacterial activity, and particularly have a strong antibacterial activity against MRSA, and completed the present invention. That is, an object of the present invention is to provide the cephem compounds highly active against many pathogenic microorganisms, especially methicillin-resistant Staphylococcus aureus (MRSA), and pharmaceutically acceptable salts thereof. Another object of the present invention is to provide a method for producing the cephem compound and a salt thereof. Another object of the present invention is to provide a pharmaceutical composition containing the cephem compound or a salt thereof as an active ingredient.
It is a further object of the present invention to provide a method for preventing and / or treating an infectious disease caused by a pathogenic microorganism, comprising administering the cephem compound to an infected human or animal.

[0005]

DETAILED DESCRIPTION OF THE INVENTION The cephem compounds aimed at by the present invention are new and can be represented by the following general formula [I]:

[0006]

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Wherein R ¹ is amino or protected amino, R ² is halogen, R ³ is hydrogen or hydroxy protecting group, R ⁴ is carboxy or protected carboxy, R ⁵ Is hydroxy; amidinothio; carbamoyl optionally substituted by lower alkyl; or a leaving group, and n is an integer of 1-6. And their pharmaceutically acceptable salts. The target compound [I] of the present invention can be produced by the following processes.

Process 1

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Process 2

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Process 3

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Process 4

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Process 5

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[0013] ^{wherein, R 1, R 2, R} 3, R 4, R 5 and n are as defined on each, R ³ _a is a hydroxy protecting group, R ⁴ _a is protected carboxy, R ⁵ _a is a leaving group, R ⁵ _b is amidinothio. Starting compound [II] can be prepared by the following processes.

Process A

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Process B

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[0016] Here, R ^4, R ⁵ and n are as defined on each, X is acid residue, R ⁷ is amino or protected amino, R ⁷ _a is protected Amino. Compounds (I), (Ia), (Ib), (I
For c), (Id), (Ie), (If), (Ig) and (III), the compounds are syn (Z) isomers,
It is to be understood that the anti (E) isomers and mixtures thereof are included. For example, with respect to the target compound (I), the syn (Z) isomer means one geometric isomer having a partial structure represented by the following formula:

[0017]

Embedded image Wherein R ¹ , R ² and R ³ are each as defined above. The anti (E) isomer means the other geometric isomer having a partial structure represented by the following formula:

[0018]

Embedded image Wherein R ¹ , R ² and R ³ are each as defined above. All such isomers and mixtures thereof are within the scope of this invention.

In the present specification and claims, the partial structures of these geometric isomers and mixtures thereof are represented by the following formula for convenience:

Embedded image Wherein R ¹ , R ² and R ³ are each as defined above. Compound (I) and other compounds may include one or more stereoisomers with asymmetric carbon atom (s), and all such isomers and mixtures thereof are included in the scope of the present invention. Please understand that it is.

In the above and following description of the present specification, preferred examples and specific examples of various definitions included in the scope of the present invention are described in detail below. The term "lower" shall mean from 1 to 6 carbon atoms unless otherwise specified. Preferred "lower alkyl" are methyl,
It includes linear or branched ones such as ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc., more preferably C1-C4 alkyl, particularly preferably methyl, Ethyl or propyl.

The term "halogen" with respect to R ² means chlorine, bromine, fluorine or iodine. Preferred "protected amino groups" include acyl as defined below, organic silyl groups optionally having suitable substituent (s) (eg mono-, di- or tri-lower alkylsilyl groups). Etc.), ar lower alkyl optionally having a suitable substituent (s) (eg, benzyl,
Amino groups substituted by conventional amino protecting groups that can be easily removed, such as trityl, p-nitrobenzyl and the like.

Suitable "acyl" includes carbamoyl, aliphatic acyl groups and acyl groups containing an aromatic or heterocyclic ring. As the aliphatic acyl,
Saturated or unsaturated, acyclic or cyclic, such as lower alkanoyl (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.);
Lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (eg, mesyl, ethanesulfonyl, propanesulfonyl, Isopropanesulfonyl, butanesulfonyl, etc.). Examples of the acyl group containing an aromatic ring or a heterocyclic ring include arelsulfonyl (eg, benzenesulfonyl, tosyl, etc.); aroyl (eg, benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indanecarbonyl, etc.); Phenylacetyl, phenylpropionyl, etc.); al-lower alkoxycarbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.) and the like. The above-mentioned acyl moieties may have a suitable substituent (s) such as halogen (eg, chlorine, bromine, iodine or fluorine), lower alkyl as defined above.

Suitable "protected carboxy" includes esterified carboxy and the like. Preferred examples of the ester include a lower alkyl ester (eg, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.); Lower alkenyl esters (eg, vinyl esters, allyl esters, etc.); lower alkynyl esters (eg, ethynyl esters, propynyl esters, etc.); lower alkoxyalkyl esters (eg, methoxymethyl esters, ethoxymethyl esters, isopropoxymethyl esters, 1-methoxyethyl esters) , 1-ethoxyethyl ester, etc.); lower alkylthioalkyl esters (eg, methylthiomethyl ester, ethylthiomethyl ester) Mono (or di- or tri) halo lower alkyl esters (eg, 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy Lower alkyl esters (eg, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-acetoxyethyl ester , 1-propionyloxyethyl ester, etc.); cyclo-lower alkylcarbonyloxy lower alkyl esters (eg, 1- (cyclohexylcarbonyloxy) ethyl ester, etc.); Grade alkoxycarbonyloxy lower alkyl esters (e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxy methyl ester, 1- (or 2-) [methoxycarbonyloxy] ethyl ester, 1- (or 2
-) [Ethoxycarbonyloxy] ethyl ester, 1
-(Or 2-) [propoxycarbonyloxy] ethyl ester, 1- (or 2-) [isopropoxycarbonyloxy] ethyl ester, etc.); cyclo lower alkyloxycarbonyloxy lower alkyl ester (for example, 1- (cyclohexyloxycarbonyloxy) )
Lower alkanesulfonyl lower alkyl ester (for example, mesyl methyl ester, 2-
Mesylethyl esters, etc.); ar lower alkyl esters, for example, phenyl lower alkyl esters optionally having one or more suitable substituents (eg, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl) Esters, trityl esters, benzhydryl esters, bis (methoxyphenyl) methyl esters, 3,4-dimethoxybenzyl esters, 4-hydroxy-3,5-di-t-butylbenzyl esters and the like; substituted or unsubstituted phenyl esters ( One or more suitable substitutions such as, for example, phenyl ester, tolyl ester, t-butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc. May be a have ant - glycol ester; tri-lower alkyl silyl ester; lower alkyl thio ester (e.g. methylthio ester, such as ethyl thio ester) include the like.

Suitable "hydroxy protecting groups" include the above-mentioned acyl, cyclo-lower alkenyl (preferable examples of cyclo-lower alkenyl are cyclo (C3-C8) alkenyl such as cyclopentenyl and cyclohexenyl),
Phenyl lower alkyl (eg, benzyl, 4-methoxybenzyl, trityl, etc.) optionally having one or more suitable substituents, substituted silyl (eg, trimethylsilyl, t-butyldimethylsilyl, etc.), tetrahydropyranyl, etc. And those that can be easily removed.

Suitable "acid residues" include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), and acyloxy, such as those mentioned above as the acyl moiety. More preferred acyloxy include sulfonyloxy (eg, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, tosyloxy, etc.), lower alkanoyloxy (eg, acetyloxy, propionyloxy, etc.).

Suitable "leaving groups" include reactive groups derived from hydroxy and the like. Suitable “reactive groups derived from hydroxy” include the acid residues described above.

Suitable pharmaceutically acceptable salts of the target compound [I] are conventional non-toxic salts, such as alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts. Metal salts such as salts (eg, calcium salts, magnesium salts, etc.), ammonium salts, organic base salts (eg, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N, N′-dibenzylethylenediamine salts, etc.) , Organic acid salts (eg, acetate, maleate,
Tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate and the like; inorganic acid salts (for example, hydrochloride, hydrobromide, hydroiodide, thiocyanate, sulfate, And salts with amino acids (eg, arginine, aspartic acid, glutamic acid, etc.).

Preferred specific examples of the target compound [I] are as follows. R ¹ is amino or lower alkanoylamino; R ² is halogen; R ³ is hydrogen or lower alkanoyl; R ⁴ is carboxy or esterified carboxy; R ⁵ is hydroxy, amidinothio, carbamoyl or Acyloxy wherein n is an integer of 1 to 6; More preferred embodiments of the target compound [I] are as follows. R
¹ is amino, R ² is halogen, R ³ is hydrogen, R ⁴ is carboxy, R ⁵ is hydroxy,
Amidinothio, carbamoyl or sulfonyloxy wherein n is an integer 1 or 2.

The process for producing the target compound and the starting compound of the present invention will be described in detail below.

Process (1) Compound (I) or a salt thereof is prepared by combining compound (II) or a reactive derivative at the amino group or a salt thereof with compound (III) or a reactive derivative at the carboxy group or a salt thereof. It can be produced by reacting. Suitable reactive derivatives at the amino group of compound (II) include Schiff base imino compounds formed by the reaction of compound (II) with carbonyl compounds such as aldehydes and ketones, or enamine-type tautomers thereof. Isomers; silyl derivatives formed by the reaction of compound (II) with silyl compounds such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide [eg N- (trimethylsilyl) acetamide], bis (trimethylsilyl) urea; Derivatives formed by the reaction of II) with phosphorus trichloride or phosgene, and the like. Compound (III)
Suitable reactive derivatives at the carboxy group of
Examples include acid halides, acid anhydrides, active amides, active esters, and the like. Preferred examples of those reactive derivatives are
Acid chlorides; acid azides; substituted phosphoric acids [eg dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid,
Halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (eg, methanesulfonic acid), aliphatic carboxylic acid (eg, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentane) Acid, trichloroacetic acid or the like] or a mixed acid anhydride with an aromatic carboxylic acid (eg, benzoic acid or the like); symmetric acid anhydride; imidazole, 4-substituted imidazole, 1-hydroxy-1H-benzotriazole, Dimethylpyrazo-
Activated amides with triazole, triazole or tetrazole;
Or an active ester (eg, cyanomethyl ester,
Methoxymethyl ester, dimethyliminomethyl [(C
H _{3) 2} N ⁺ = CH-] ester, vinyl ester, propargyl ester, p- nitrophenyl ester,
2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester,
p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.) or N
-Hydroxy compounds [for example, N, N-dimethylhydroxylamine, 1-hydroxy-2 (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazo-
And the like). These reactive derivatives can be arbitrarily selected from them according to the type of compound (III) used. The reaction is usually
Conventional solvents such as water, alcohols (eg, methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, methyl acetate, N, N-dimethylformamide, pyridine and the like; The reaction is performed in any other organic solvent that does not adversely affect the reaction. These conventional solvents may be used by mixing with water. In this reaction, when compound (III) is used in the form of a free acid or a salt thereof, N, N′-dicyclohexylcarbodiimide; N-cyclohexyl-N′-morpholinoethylcarbodiimide; N-cyclohexyl-N ′-( 4-
Diethylaminocyclohexyl) carbodiimide;
N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide; N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis (2-methylimidazole); pentamethyleneketene- N-cyclohexylimine, diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1
-Alkoxy-1-chloroethylene; trialkyl phosphite; polyethyl phosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [eg, ethyl chloroformate, chloroform; Isopropyl formate and the like]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; 1- (p
-Chlorobenzenesulfonyloxy) -6-chloro-1
H-benzotriazole; reaction in the presence of a conventional condensing agent such as the so-called Filsmeier reagent prepared by reacting N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride and the like. Is preferably performed. Alkali metal bicarbonate, tri-lower alkylamine (eg, triethylamine, diisopropylethylamine, etc.), pyridine, N
The reaction can also be carried out in the presence of an inorganic or organic base such as lower alkylmorpholine, N, N-dilower alkylbenzylamine. The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating.

Process 2 The target compound [Ib] or a salt thereof can be produced by an elimination reaction of the hydroxy protecting group of the compound [Ia] or a salt thereof. Suitable methods for the elimination reaction include hydrolysis,
Conventional methods such as reduction may be mentioned. (I) In the case of hydrolysis: The hydrolysis is preferably carried out in the presence of a base or an acid including a Lewis acid.
Suitable bases include metal hydroxides (eg, sodium hydroxide, magnesium hydroxide, etc.), metal alkoxides (eg, sodium methoxide, potassium methoxide, etc.), metal carbonates or bicarbonates, trialkylamines (eg, Trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo [4.
3.0] nona-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene, and other inorganic and organic bases. Can be Suitable acids include organic acids (eg, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, ammonium chloride, etc.) Is mentioned. The elimination using a Lewis acid such as trihaloacetic acid (eg, trichloroacetic acid, trifluoroacetic acid, etc.) is preferably carried out in the presence of a cation scavenger (eg, anisole, phenol, etc.). The reaction is usually carried out in a solvent such as water, alcohol (eg, methanol, ethanol, etc.), methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating. (Ii) In the case of reduction: The reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction. Suitable reducing agents to be used for chemical reduction are metals (eg, tin, zinc, iron, etc.) or metal compounds (eg, chromium chloride, chromium acetate, etc.)
And an organic acid or an inorganic acid (for example, formic acid, acetic acid, popopionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). Suitable catalysts to be used for catalytic reduction include platinum catalysts (eg, platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (eg, spongy palladium, palladium black, palladium oxide, Palladium charcoal, colloidal palladium, palladium / barium sulfate, palladium /
A nickel catalyst (eg, reduced nickel, nickel oxide, Raney-nickel, etc.), a cobalt catalyst (eg, reduced cobalt, Raney-cobalt, etc.),
Conventional catalysts such as iron catalysts (eg, reduced iron, Raney-iron, etc.) and copper catalysts (eg, reduced copper, Raney-copper, Ullman copper, etc.). This reduction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, methanol, ethanol, propanol, dioxane, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof. . When the above-mentioned acids used for chemical reduction are liquid, they can be used as a solvent. The reaction temperature for this reduction is not particularly limited, but the reaction is usually carried out under cooling or heating. The invention also includes within the scope where the amino group protected at R ¹ and / or the carboxy group protected at R ⁴ is converted to an amino group and / or a carboxy group respectively during this reaction. Things.

Process 3 The compound [Id] or a salt thereof can be produced by subjecting the compound [Ic] or a salt thereof to an elimination reaction of a carboxy protecting group. This reaction can be carried out in the same manner as the elimination reaction of the hydroxy protective group in the process 2, therefore, reagents and reaction conditions (e.g. solvent, reaction temperature, etc.) to be used for, referring to those processes 2 Good. The present invention includes within its scope the case where the amino group protected at R ¹ and / or the hydroxy group protected at R ³ is converted to an amino group and / or a hydroxy group during this reaction. It is.

Process 4 Compound [If] or a salt thereof is obtained by converting compound [Ie] to-
It can be produced by subjecting a hydroxy group bonded to (CH ₂ ) _n- to an exchange reaction with a leaving group. This reaction usually involves water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, acetonitrile,
N, N-dimethylformamide, methanol, ethanol
The reaction is carried out in toluene, ether, tetrahydrofuran or any other conventional solvent which does not adversely influence the reaction. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. When a compound [If] having an amino at R ¹ , a hydroxy at OR ³ , and / or a carboxy at R ⁴ is used in this reaction,
It is preferable that the amino and the hydroxy and / or carboxy group in OR ³ of the compound [If] be protected in advance.

Process 5 Compound [Ig] or a salt thereof can be produced by reacting compound [If] or a salt thereof with thiourea [VI]. This reaction usually involves water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride,
The reaction is carried out in a solvent such as acetonitrile, N, N-dimethylformamide, methanol, ethanol, ether, tetrahydrofuran or any other solvent which does not adversely influence the reaction. The reaction temperature is not particularly limited.
The reaction is carried out under cooling or heating. When a compound [If] having an amino for R ¹ , a hydroxy for OR ³ , and / or a carboxy for R ⁴ is used in this reaction, the amino, OR,
It is preferred that the hydroxy and / or carboxy groups in ³ be protected in advance.

Process A The compound [IIa] can be prepared by reacting the compound [III] or a salt thereof with the compound [IV] or a reactive derivative at the mercapto group or a salt thereof. Suitable reactive derivatives in the mercapto group of compound [IV] include metal salts such as alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.). . This reaction is usually carried out in a solvent such as water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran or any other which does not adversely affect the reaction. Conventional solvents,
It is preferably carried out in a substance having a strong polarity, and they can also be used as a mixture with water. Compound [II
When the compound [I] and / or the compound [IV] are used in a free form in the reaction, an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, a trialkylamine,
The reaction is preferably carried out in the presence of a base such as pyridine or a Lewis acid such as boron trifluoride under near neutral conditions. The reaction temperature is not particularly limited, but usually the reaction is carried out at ambient temperature or under heating.

Process B Compound [II] or a salt thereof can be prepared by subjecting compound [V] or a salt thereof to an amino-protecting group elimination reaction. This reaction can be carried out in similar to that of the aforementioned Process 2, and therefore, the reagents and reaction conditions to be used (e.g. solvent, reaction temperature, etc.) of Process 2
Of them. Suitable salts of the target compounds and the starting compounds and the reactive derivatives thereof in Processes 1 to 5, A and B include compounds [I]
Can be mentioned. The object compound [I] of the present invention or a salt thereof exhibits high antimicrobial activity and inhibits the growth of many microorganisms including pathogenic Gram-positive and Gram-negative bacteria. The target compound [I] of the present invention or a salt thereof has a strong antimicrobial activity particularly against methicillin-resistant bacteria or other antibiotic-resistant bacteria such as vancomycin-resistant or ampicillin-resistant bacteria.

In order to show the usefulness of the target compound (I),
MIC (minimum inhibitory concentration) of representative compounds of this invention
The test data for the following are shown below.

(A) Minimum growth inhibitory concentration test method : A glass was obtained by the following two-fold dilution agar plate method.
The antibacterial activity in the vessel was measured. One of the overnight cultures of viable cells (10 ⁸ / ml) in Trypticase soy broth of each test strain
Platinum loops were streaked on hot injection agar (HI agar) containing graded concentrations of representative test compounds, incubated at 37 ° C. for 20 hours, and then subjected to a minimum inhibitory concentration (MI).
C) was expressed in μg / ml. Test compound : (1) 7β- [2-{(Z) -hydroxyimino} -2- (2-amino-5-chlorothiazol-)
4-yl) acetamido] -3- [4-carbamoylmethylthiazol-2-ylthio] -3-cephem-4-
Carboxylic acid (2) 7β- [2-{(Z) -hydroxyimino} -2
-(2-Amino-5-chlorothiazol-4-yl) acetamido] -3- [4- (2-carbamoylethyl)
Thiazol-2-ylthio] -3-cephem-4-carboxylic acid

Test results :

[Table 1]

For the purpose of therapeutic administration, the desired compound [I] of the present invention and a pharmaceutically acceptable salt thereof are orally or percutaneously administered.
It is used in the form of conventional pharmaceutical preparations containing the compound as active ingredient in a mixture with a pharmaceutically acceptable carrier, such as a solid or liquid organic or inorganic excipient suitable for parenteral administration or external use. The pharmaceutical preparation may be in solid form such as tablets, granules, powders and capsules or in liquid form such as solutions, suspensions, syrups, emulsions and limonade. In the above preparations, if necessary, auxiliary substances (adjuvants),
Stabilizers, humectants and other common additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, clay, sucrose, corn starch, talc, gelatin, agar, pectin, peanut Oil, olive oil, cocoa butter, ethylene glycol and the like can also be contained. The dose of compound [I] varies depending on the age and condition of the patient, the type of disease, the type of compound [I] to be applied, and the like, and depends on them, but is generally 1 mg to about 4000 mg per day. Or higher doses can be administered to each patient. About 50 mg of the target compound of the present invention,
100mg, 250mg, 500mg, 1000mg,
An average dose of 2000 mg can be used for the treatment of infections by pathogenic microorganisms.

The following production examples and examples are provided to explain the present invention in more detail.

Production Example 1 7β-Formamido-3-methanesulfonyloxy-3
-Cephem-4-diphenylmethyl carboxylate (5.0
To a solution of g) in 25 ml of tetrahydrofuran and 25 ml of dimethoxyethane at 0 ° C. was added 4-carbamoylmethyl-2-mercaptothiazole (1.78 g) and potassium tert-butoxide (1.15 g). After stirring overnight, the reaction mixture was diluted with water to stop the reaction,
Extracted with ethyl acetate and tetrahydrofuran, washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was washed with a small amount of ethyl acetate to give 7β-formamido-3- [4-carbamoylmethylthiazol-2-ylthio] -3-cephem-4-carboxylate diphenylmethyl. 3.12 g were obtained. IR (KBr): 3296, 1776, 1666 cm ^-1 NMR (DMSO-d ₆ , δ): 3.54, 3.78
(2H, ABq, J = 17.6 Hz), 3.56 (2
H, s), 5.29 (1H, d, J = 5.0 Hz),
5.91 (1H, dd, J = 5.0 Hz, 8.9H
z), 6.96 (1H, s), 7.00 (1H, b
s), 7.27-7.41 (11H, m), 7.56.
(1H, s), 8.15 (1H, s), 9.20 (1
H, d, J = 8.9 Hz) MAS (APCI) m / z: 567 (M ⁺ )

Production Example 2 Methanol 32 of 7β-formamido-3- [4-carbamoylmethylthiazol-2-ylthio] -3-cephem-4-carboxylate (3.12 g)
At room temperature, 3.2 ml of concentrated hydrochloric acid was added dropwise to the ml solution.
After 4.5 hours, the reaction mixture was diluted with water and the pH was adjusted to 5.8 with aqueous sodium bicarbonate to give 7β-amino-3- [4-carbamoylmethylthiazol-2-ylthio]-. Diphenylmethyl 3-cephem-4-carboxylate (2.66 g) was obtained as a precipitate. IR (KBr): 3412, 1776, 1678 cm ^-1 NMR (DMSO-d ₆ , δ): 3.48, 3.77
(2H, ABq, J = 17.8 Hz), 3.56 (2
H, s), 4.93 (1H, d, J = 5.2 Hz),
5.15 (1H, d, J = 5.2 Hz), 6.94 (1
H, s), 7.00 (1H, bs), 7.26-7.4.
3 (13H, m), 7.53 (1H, s) MAS (APCI) m / z: 539 (M ⁺ )

Production Example 3 7β-Formamido-3-methanesulfonyloxy-3
-Cephem-4-diphenylmethyl carboxylate (5.0
g) and 4- (2-carbamoyl) ethyl-2-mercaptothiazole (1.93 g) in the same manner as in Production Example 1 to give 7β-formamido-3- [4- (2-carbamoylethyl) thiazo- Ru-2-ylthio] -3-cephem-4-carboxylate (2.2 g, 37
%). IR (KBr): 1780, 1662 cm ^-1 NMR (DMSO-d ₆ , δ): 2.43 (2H,
m), 2.91 (2H, m), 3.52, 3.77 (2
H, ABq, J = 17.7 Hz), 5.30 (1H,
d, J = 5.0 Hz), 5.92 (1H, dd, J =
5.0 Hz, 8.9 Hz), 6.81 (2H, bs),
6.96 (1H, s), 7.28-7.44 (10H,
m), 8.15 (1H, s), 9.21 (1H, d, J
= 8.9 Hz) MAS (APCI) m / z: 578.94 (M ⁺ −
2), 580.94 (M ⁺ )

Production Example 4 7β-Formamido-3- [4- (2-carbamoylethyl) thiazol-2-ylthio] -3-cephem-4
7β-amino-3- [4- (2-carbamoylethyl) thiazol-2-ylthio] -3-cephem-4-carboxylic acid from diphenylmethylcarboxylate (2.2 g) in the same manner as in Production Example 2. Diphenylmethyl acid (1.81
g, 86%). IR (KBr): 3415, 1
780, 1666 cm ^-1 NMR (DMSO-d ₆ ,
δ): 2.43 (2H, m), 2.89 (2H, m),
3.54, 3.76 (2H, ABq, J = 15.5H
z), 4.91 (1H, d, J = 5.2 Hz), 5.1
4 (1H, d, J = 5.2 Hz), 6.80 (2H, b
s), 6.93 (1H, s), 7.27-7.42 (1
3H, m) MAS (APCI) m / z: 553 (M ⁺ )

Production Example 5 To a suspension of lithium aluminum hydride (2.0 g) in 100 ml of tetrahydrofuran was added 4-methoxycarbonylmethyl-2-mercaptothiazole at 0 ° C. After 20 minutes, the reaction was quenched by dilution with aqueous sodium sulfate and water, and the resulting precipitate was removed by filtration.
The pH of the filtrate was adjusted to 3, and extracted with ethyl acetate and tetrahydrofuran. The organic phase was washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography,
4- (2-Hydroxyethyl) -2-mercaptothiazole (1.28 g) was obtained. IR (KBr): 3219, 1603, 1477 cm ^-1 NMR (DMSO-d ₆ , δ): 2.59 (2H, t,
J = 6.4 Hz), 3.61 (2H, dt, J = 6.4)
Hz, 5.3 Hz), 4.77 (1H, t, J = 5.3)
Hz), 6.59 (1H, s), 13.08 (1H, b
s) MAS (APCI) m / z: 162 (M ⁺⁺ 1)

Production Example 6 7β-Formamido-3-methanesulfonyloxy-3
-Cephem-4-carboxylate diphenylmethyl (3.8
8 g) in a solution of 19 ml of tetrahydrofuran and 19 ml of dimethoxyethane at 0 ° C. with 4- (2-hydroxyethyl) -2-mercaptothiazole (1.28 g).
And potassium tert-butoxide (0.89 g) was added. After stirring overnight, the reaction mixture was quenched by diluting with water, extracting with ethyl acetate and tetrahydrofuran,
Washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give 7β-formamide-3- [4
Diphenylmethyl- (2-hydroxyethyl) thiazol-2-ylthio] -3-cephem-4-carboxylate (2.23 g) was obtained. IR (KBr): 3429, 1784, 1686 cm ^-1 NMR (DMSO-d ₆ , δ): 2.86 (2H, t,
J = 6.7 Hz), 3.53, 3.78 (2H, AB
q, J = 17.5 Hz), 3.69 (2H, td, J =
6.7 Hz, 5.4 Hz), 4.67 (1 H, t, J =
5.4 Hz), 5.30 (1H, d, J = 5.0H)
z), 5.91 (1H, dd, J = 5.0 Hz, 8.8)
Hz), 6.96 (1H, s), 7.27-7.46
(10H, m), 7.49 (1H, s), 8.15 (1
H, s), 9.20 (1H, d, J = 8.8 Hz) MAS (APCI) m / z: 554 (M ⁺ )

Production Example 7 7β-formamido-3- [4- (2-hydroxyethyl) thiazol-2-ylthio] -3-cephem-4-
Methanol of diphenylmethyl carboxylate (2.23 g)
2.3 ml of concentrated hydrochloric acid was added dropwise to the 22 ml solution at room temperature. After 2 hours, the reaction mixture was diluted with water, the pH was adjusted to 6.5 with aqueous sodium hydrogen carbonate and extracted with ethyl acetate and tetrahydrofuran. The organic phase was washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 7β-amino-3- [4- (2-hydroxyethyl) thiazol-2-ylthio] -3-cephem-4-.
Diphenylmethyl carboxylate (2.01 g) was obtained. IR (KBr): 3342, 1778, 1739 cm ^-1 NMR (DMSO-d ₆ , δ): 2.85 (2H, t,
J = 6.8 Hz), 3.46, 3.77 (2H, AB
q, J = 17.7 Hz), 3.69 (2H, m), 4.
67 (1H, m), 4.91 (1H, bd, J = 5.2)
Hz), 5.14 (1H, d, J = 5.2 Hz), 6.
93 (1H, s), 7.27-7.39 (12H,
m), 7.44 (1H, s ) MAS (APCI) m / z: 526.13 (M + +
1), 548.13 (Na salt)

Example 1 7β-amino-3- [4-carbamoylmethylthiazo-
2-[(Z) -chloride was added to a solution of diphenylmethyl di-2-methylthio-2--3-thiophene-4-carboxylate (2.0 g) and N- (trimethylsilyl) acetamide (2.92 g) in 54 ml of tetrahydrofuran. [Acetoxyimino] -2- (2-formylamino-5-chlorothiazol-4-yl) acetyl (1.50 g) was added in small portions. After 2 hours, the reaction was quenched by diluting the reaction mixture with water and ethyl acetate and adjusting the pH to 6. The organic phase was washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain 7β- [2-｛(Z)-
Acetoxyimino {-2- (5-chloro-2-formylaminothiazol-4-yl) acetamido] -3-
[4-carbamoylmethylthiazol-2-ylthio]
2. diphenylmethyl-3-cephem-4-carboxylate
25 g were obtained. IR (KBr): 3197, 1786, 1670 cm ^-1 NMR (DMSO-d ₆ , δ): 2.21 (3H,
s), 3.53, 3.82 (2H, ABq, J = 16.
0 Hz), 3.58 (2H, s), 5.38 (1H,
d, J = 5.0 Hz), 6.02 (1H, dd, J =
5.0Hz, 8.6Hz), 6.97 (1H, s),
7.0 (1H, bs), 7.28-7.41 (11
H, m), 7.56 (1H, s), 8.56 (1H,
s), 10.11 (1H, d, J = 8.6 Hz), 1
2.99 (1H, s) MAS (MALD-TOF) m / z: 833.708
(Na salt)

Example 2 7β- [2-{(Z) -acetoxyimino} -2- (5
-Chloro-2-formylaminothiazol-4-yl)
33 ml of methanol of diphenylmethyl acetamido] -3- [4-carbamoylmethylthiazol-2-ylthio] -3-cephem-4-carboxylate (3.25 g)
2.3 ml of concentrated hydrochloric acid was added dropwise to the solution at room temperature. 2.5
After time, the reaction mixture was diluted with water and the pH was adjusted to 6 with aqueous sodium bicarbonate solution to give 7β- [2-{(Z)-
Hydroxyimino {-2- (2-amino-5-chlorothiazol-4-yl) acetamido] -3- [4-carbamoylmethylthiazol-2-ylthio] -3-cephem-4-carboxylate diphenyl Methyl (2.37 g)
Was obtained as a precipitate. IR (KBr): 3315, 1780, 1676 cm ^-1 NMR (DMSO-d ₆ , δ): 3.56 (2H,
s), 3.4-3.7 (2H, m), 5.29 (1H,
d, J = 5.0 Hz), 5.94 (1H, dd, J =
5.0Hz, 8.6Hz), 6.96 (1H, s),
7.0 (1H, bs), 7.28-7.40 (13H,
m), 7.55 (1H, s), 9.55 (1H, d, J
= 8.6 Hz), 11.79 (1H, s) MAS (MALD-TOF) m / z: 763.82 (N
a salt), 779.781 (K salt)

Example 3 7β- [2-{(Z) -hydroxyimino} -2- (2
-Amino-5-chlorothiazol-4-yl) acetamido] -3- [4-carbamoylmethylthiazol-2
To a solution of diphenylmethyl-3-ylthio] -3-cephem-4-carboxylate (2.37 g) in 12 ml of dichloromethane at 0 ° C. was added stepwise anisole (2.4 ml) and trichloroacetic acid (4.8 ml). Was. After 2 hours, the reaction mixture was added dropwise to isopropyl ether to form a precipitate, which was purified by preparative liquid chromatography using ODS resin and column chromatography using HP-20 resin. And desalted by 7β-
[2-{(Z) -hydroxyimino} -2- (2-amino-5-chlorothiazol-4-yl) acetamide]
3- [4-Carbamoylmethylthiazol-2-ylthio] -3-cephem-4-carboxylic acid was obtained as a precipitate. IR (KBr): 3257, 1772, 1672, 16
53 cm ^-1 NMR (DMSO-d ₆ , δ): 3.45, 3.73
(2H, ABq, J = 17.6 Hz), 3.55 (2
H, s), 5.23 (1H, d, J = 5.0 Hz),
5.85 (1H, dd, J = 5.0 Hz, 8.5H
z), 6.98 (1H, s), 7.28 (2H, b
s), 7.44 (1H, bs), 7.51 (1H,
s), 9.50 (1H, d, J = 8.5 Hz), 11.
70 (1H, s) MAS (MALD-TOF) m / z: 575.8825
(M ⁺ ), 577.804 (M ⁺ +2) Elemental analysis Calculated for C ₁₇ H ₁₄ ClN ₇ O ₆ S ₄ .2.5H ₂ O: C 32.88; H 3.08; N 15.7
9 found: C 32.87; H 3.05; N 15.6.
9

Example 4 7β-amino-3- [4- (2-carbamoylethyl)
Example 1 was prepared from diphenylmethyl thiazol-2-ylthio] -3-cephem-4-carboxylate (1.81 g).
7- [2-{(Z) -acetoxyimino} -2- (5-chloro-2-formylaminothiazo-
4- (4-yl) acetamido] -3- [4- (2-carbamoylethyl) thiazol-2-ylthio] -3-cephem-4-carboxylate diphenylmethyl (1.52
g, 56.2%). IR (KBr): 3462, 1782, 1664 cm ^-1 NMR (DMSO-d ₆ , δ): 2.21 (3H,
s), 2.43 (2H, m), 2.91 (2H, m),
3.60 (2H, m), 5.38 (1H, d, J = 5.
0 Hz), 6.03 (1H, dd, J = 5.0 Hz,
8.7 Hz), 6.81 (2H, bs), 6.97 (1
H, s), 7.27-7.49 (10H, s), 8.5.
6 (1H, s), 10.11 (1H, d, J = 8.7H)
z), 13.00 (1H, bs) MAS (MALD-TOF) m / z: 847.78 (N
a salt)

Example 5 7β- [2-{(Z) -acetoxyimino} -2- (5
-Chloro-2-formylaminothiazol-4-yl)
Acetamide] -3- [4- (2-carbamoylethyl) thiazol-2-ylthio] -3-cephem-4-
Methanol of diphenylmethyl carboxylate (1.52 g)
1.07 ml of concentrated hydrochloric acid was added dropwise to the 15 ml solution. 2
After time, the reaction mixture was diluted with water and ethyl acetate to quench the reaction and the pH was adjusted to 5.5. The organic phase was washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 7β- [2-{(Z) -hydroxyimino}-
2- (2-amino-5-chlorothiazol-4-yl)
Acetamide] -3- [4- (2-carbamoylethyl) thiazol-2-ylthio] -3-cephem-4-
Diphenylmethyl carboxylate (1.25 g, 89.9)
%). IR (KBr): 3346, 1782, 1664 cm ^-1 NMR (DMSO-d ₆ , δ): 2.43 (2H,
m), 2.90 (2H, m), 3.60 (2H, m),
5.30 (1H, d, J = 5.1 Hz), 5.9-6.
0 (1H, m), 6.81 (2H, bs), 6.96
(1H, s), 7.28-7.43 (11H, m),
9.56 (1H, d, J = 8.7 Hz), 11.72
(1H, s) MAS (MALD-TOF) m / z: 777.83 (N
a salt)

Example 6 7β- [2-{(Z) -hydroxyimino} -2- (2
-Amino-5-chlorothiazol-4-yl) acetamido] -3- [4- (2-carbamoylethyl) thiazol-2-ylthio] -3-cephem-4-carboxylate diphenylmethyl (1.25 g) ) To 7β- [2-{(Z) -hydroxyimino}-
2- (2-amino-5-chlorothiazol-4-yl)
Acetamide] -3- [4- (2-carbamoylethyl) thiazol-2-ylthio] -3-cephem-4-
The carboxylic acid (0.22 g, 22.6%) was obtained. IR (KBr): 3406, 1778, 1672 cm ^-1 NMR (DMSO-d ₆ , δ): 2.43 (2H, t,
J = 8.0 Hz), 2.90 (2H, t, J = 8.0H)
z), 3.43, 3.72 (2H, ABq, J = 17.
6 Hz), 5.24 (1H, d, J = 5.0 Hz),
5.85 (1H, dd, J = 5.0 Hz, 8.6H
z), 6.80 (1H, bs), 7.34 (2H, b
s), 7.40 (1H, s), 9.51 (1H, d, J
= 8.6 Hz), 11.71 (1H, s) MAS (MALD-TOF) m / z: 589.77 (M
⁺⁾ Elemental analysis _{C 18 H 16 ClN 7 O 6} S 4 · 3H 2 calculated for O: C 33.57; H 3.44; N 15.2
2 Found: C 33.46; H 3.30; N 14.9.
2

Example 7 Example 1 was prepared from diphenylmethyl 7β-amino-3- [4- (2-hydroxyethyl) thiazol-2-ylthio] -3-cephem-4-carboxylate (2.01 g). 7- [2-{(Z) -acetoxyimino} -2- (5-chloro-2-formylaminothiazo-
4- (4-yl) acetamido] -3- [4- (2-hydroxyethyl) thiazol-2-ylthio] -3-cephem-4-carboxylic acid diphenylmethyl (3.0 g, 9
8%). IR (KBr): 3392,1782,1686,15
49 cm ^-1 NMR (DMSO-d ₆ , δ): 2.21 (3H,
s), 2.85 (2H, m), 3.55, 3.83 (2
H, ABq, J = 17.7 Hz), 3.69 (2H,
m), 4.67 (1H, m), 5.39 (1H, d, J
= 5.0 Hz), 6.02 (1H, dd, J = 5.0H)
z, 8.4 Hz), 6.97 (1H, s), 7.28-
7.41 (10H, m), 7.48 (1H, s), 8.
56 (1H, s), 10.10 (1H, d, J = 8.4)
Hz) MAS (MALD-TOF) m / z: 798.848
(M ⁺ ), 82.823 (Na salt)

Example 8 7β- [2-{(Z) -acetoxyimino} -2- (5
-Chloro-2-formylaminothiazol-4-yl)
Acetamide] -3- [4- (2-hydroxyethyl)
Starting from diphenylmethyl thiazol-2-ylthio] -3-cephem-4-carboxylate (1.0 g), 7β- [2-{(Z) -hydroxyimino} -2- (2-amino-5-chlorothiazol-4-
Yl) acetamido] -3- [4- (2-hydroxyethyl) thiazol-2-ylthio] -3-cephem-4
-Diphenylmethyl carboxylate (0.85 g, 93%)
I got IR (KBr): 3373, 1782, 1664 cm ^-1 NMR (DMSO-d ₆ , δ): 2.80-2.88
(2H, m), 3.53-3.70 (4H, m), 4.
64-4.69 (1H, m), 5.30 (1H, d, J
= 5.3 Hz), 5.94 (1H, dd, J = 5.3H)
z, 8.6 Hz), 6.95 (1H, s), 7.28-
7.47 (13H, m), 9.54 (1H, d, J =
8.6 Hz) MAS (MALD-TOF) m / z: 728.94 (M
⁺ ), 750.90 (Na salt)

Example 9 7β- [2-{(Z) -hydroxyimino} -2- (2
-Amino-5-chlorothiazol-4-yl) acetamido] -3- [4- (2-hydroxyethyl) thiazo-
From β-yl-2-ylthio] -3-cephem-4-carboxylate (0.85 g), 7β- [2-{(Z) -hydroxyimino} -2 was obtained in the same manner as in Example 3.
-(2-Amino-5-chlorothiazol-4-yl) acetamido] -3- [4- (2-hydroxyethyl) thiazol-2-ylthio] -3-cephem-4-carboxylic acid (245 mg, 37%). IR (KBr): 3294, 1770, 1653 cm ^-1 NMR (DMSO-d ₆ , δ): 2.84 (2H, t,
J = 6.7 Hz), 3.48-3.76 (4H, m),
4.66 (1H, m), 5.24 (1H, d, J = 4.
9 Hz), 5.84 (1H, dd, J = 4.9 Hz,
8.6 Hz), 7.30 (2H, bs), 7.43 (1
H, s), 9.49 (1H, d, J = 8.6 Hz), 1
1.69 (1H, s) MAS (MALD-TOF) m / z: 562.83 (M
⁺⁾ Elemental analysis _{C 17 H 15 ClN 6 O 6} S 4 · 1.5H calculated for _{2 O: C 34.60; H 3.07} ; N 14.2
4 Observed: C 34.46; H 3.07; N 13.9.
4

Example 10 7β- [2-{(Z) -acetoxyimino} -2- (5
-Chloro-2-formylaminothiazol-4-yl)
Acetamide] -3- [4- (2-hydroxyethyl)
To a solution of diphenylmethyl thiazol-2-ylthio] -3-cephem-4-carboxylate (1.0 g) in 15 ml of dichloromethane at -50 ° C was added trifluoromethanesulfonic anhydride (0.24 ml) and diisopropylethylamine (0. .25 ml) was added. After 2 hours, the reaction was stopped by diluting the reaction mixture with water and adjusting the pH to 6.
The mixture was extracted with ethyl acetate and tetrahydrofuran, the organic phase was washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain 7β- [2-｛(Z)-
Acetoxyimino {-2- (5-chloro-2-formylaminothiazol-4-yl) acetamido] -3-
[4- (2-trifluoromethanesulfonyloxyethyl) thiazol-2-ylthio] -3-cephem-4-
Diphenylmethyl carboxylate (1.06 g) was obtained. NMR (DMSO-d ₆ , δ): 2.21 (3H,
s), 2.85 (2H, m), 3.69 (4H, m),
5.39 (1H, d, J = 5.0 Hz), 6.02 (1
H, dd, J = 5.0 Hz, 8.4 Hz), 6.96
(1H, s), 7.28-7.48 (11H, m),
8.56 (1H, s), 10.10 (1H, d, J =
8.4 Hz), 12.99 (1 H, s)

Example 11 7β- [2-{(Z) -acetoxyimino} -2- (5
-Chloro-2-formylaminothiazol-4-yl)
Acetamide] -3- [4- (2-trifluoromethanesulfonyloxyethyl) thiazol-2-ylthio]
Thiourea (87 mg) was added to a solution of diphenylmethyl-3-cephem-4-carboxylate (1.06 g) in 10 ml of acetonitrile. After 3 hours, the solvent of the reaction mixture is evaporated under reduced pressure to give 7β- [2-{(Z) -acetoxyimino} -2- (5-chloro-2-formylaminothiazol-4-yl). Acetamide] -3- [4-
Diphenylmethyl (2-isothioureidoethyl) thiazol-2-ylthio] -3-cephem-4-carboxylate (1.06 g) was obtained. NMR (DMSO-d _6,
δ): 2.21 (3H, s), 2.85 (2H, m),
3.66 (4H, m), 5.39 (1H, d, J = 5.
0 Hz), 6.02 (1H, dd, J = 5.0 Hz,
8.5 Hz), 6.96 (1H, s), 7.0 (3H,
br), 7.28-7.48 (11H, m), 8.56.
(1H, s), 10.10 (1H, d, J = 8.5H
z), 12.98 (1H, s) MAS (MALD-TOF) m / z: 856.81 (M
⁺ ), 858.81 (M ⁺⁺ 2)

Example 12 7β- [2-{(Z) -acetoxyimino} -2- (5
-Chloro-2-formylaminothiazol-4-yl)
Acetamide] -3- [4- (2-isothioureidoethyl) thiazol-2-ylthio] -3-cephem-4
-A solution of diphenylmethyl carboxylate (1.06 g) in 5.3 ml of dichloromethane at 0 ° C. was added to anisole (1.
1 ml) and trifluoroacetic acid (2.1 ml) were added stepwise. After 2.5 hours, the reaction mixture was added dropwise to isopropyl ether to give 7β- [2-{(Z) -acetoxyimino} -2- (5-chloro-2-formylaminothiazole-4). -Yl) acetamide] -3- [4-
(2-Isothioureidoethyl) thiazol-2-ylthio] -3-cephem-4-carboxylic acid (0.77 g)
Was obtained as a precipitate. IR (KBr): 3315, 1774, 1674 cm-1 MAS (MALD-TOF) m / z: 690.60 (M
⁺ ), 692.63 (M ⁺⁺ 2)

Example 13 7β- [2-{(Z) -acetoxyimino} -2- (5
-Chloro-2-formylaminothiazol-4-yl)
Acetamide] -3- [4- (2-isothioureidoethyl) thiazol-2-ylthio] -3-cephem-4
To a solution of carboxylic acid (0.77 g) in 8 ml of methanol was added dropwise 0.65 ml of concentrated hydrochloric acid at room temperature. After 2 hours, the reaction mixture was added dropwise into ethyl acetate to give a precipitate, which was purified by preparative liquid chromatography using ODS resin and column chromatography using HP-20 resin. After desalting, 7β- [2-
{(Z) -hydroxyimino} -2- (2-amino-5
-Chlorothiazol-4-yl) acetamido] -3-
[4- (2-isothioureidoethyl) thiazol-2
-Ylthio] -3-cephem-4-carboxylic acid 0.11
g was obtained as a precipitate. IR (KBr): 3392, 1770, 1651 cm ^-1 NMR (DMSO-d ₆ , δ): 2.79 (2H, t,
J = 6.6 Hz), 3.23, 3.68 (2H, AB
q, J = 17.1 Hz), 3.70 (2H, t, J =
6.6 Hz), 5.09 (1H, d, J = 5.0H)
z), 5.66 (1H, dd, J = 5.0 Hz, 8.5)
Hz), 7.23 (1H, s), 7.30 (2H, b
s), 9.42 (1H, d, J = 8.5 Hz) MAS (MALD-TOF) m / z: 620.83 (M
⁺ ), 622.80 (M ⁺⁺ 2)

Claims (8)

[Claims] 1. The formula: embedded image Wherein R ¹ is amino or protected amino, R ² is halogen, R ³ is hydrogen or a hydroxy protecting group, R ⁴ is carboxy or protected carboxy, R ⁵ is hydroxy Amidinothio; carbamoyl optionally substituted with lower alkyl; or a leaving group, n is an integer of 1 to 6], and pharmaceutically acceptable salts thereof. 2. R ¹ is amino or lower alkanoylamino; R ³ is hydrogen or lower alkanoyl; R ⁴ is carboxy or esterified carboxy; R ⁵ is hydroxy, amidinothio, carbamoyl or acyloxy. A compound of claim 1. 3. R ¹ is amino, R ² is halogen, R ³ is hydrogen, R ⁴ is carboxy, R ⁵ is hydroxy, amidinothio or carbamoyl, and n is an integer 1 or 2. 3. The compound of claim 2, which is 4. 7β- [2-{(Z) -hydroxyimino} -2- (2-amino-5-chlorothiazol-4-)
Yl) acetamido] -3- [4-carbamoylmethylthiazol-2-ylthio] -3-cephem-4-carboxylic acid, 7β- [2-{(Z) -hydroxyimino}-
2- (2-amino-5-chlorothiazol-4-yl)
Acetamide] -3- [4- (2-carbamoylethyl) thiazol-2-ylthio] -3-cephem-4-
Carboxylic acid, 7β- [2-{(Z) -hydroxyimino} -2- (2-amino-5-chlorothiazol-4-
Yl) acetamido] -3- [4- (2-hydroxyethyl) thiazol-2-ylthio] -3-cephem-4
-Carboxylic acid and 7β- [2-{(Z) -hydroxyimino} -2- (2-amino-5-chlorothiazol-
4. The compound of claim 3 selected from the group consisting of 4-yl) acetamido] -3- [4- (2-isothioureidoethyl) thiazol-2-ylthio] -3-cephem-4-carboxylic acid. 5. The formula: embedded image Wherein R ¹ is amino or protected amino, R ² is halogen, R ³ is hydrogen or a hydroxy protecting group, R ⁴ is carboxy or protected carboxy, R ⁵ is hydroxy Amidinothio; carbamoyl optionally substituted by lower alkyl; or a leaving group, n is an integer of 1 to 6] and a pharmaceutically acceptable salt thereof, ) Formula: embedded image Wherein R ⁴ , R ⁵ and n are each as defined above, or a reactive derivative at the amino group thereof, or a salt thereof, having the formula: Wherein R ¹ , R ² and R ³ are each as defined above, or a reactive derivative at the carboxy group or a salt thereof to form a compound of the formula: Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are each as defined above, or a salt thereof, or (2) a compound of the formula: ^{Wherein, R 1, R 2, R} 4, R 5 and n are as defined on each, R ³ _a is a is hydroxy protecting group to the compound or a hydroxy protecting group elimination reaction of a salt thereof With the formula: Wherein R ¹ , R ² , R ⁴ , R ⁵ and n are each as defined above, or a salt thereof, or (3) a compound of the formula: ^{Wherein, R 1, R 2, R} 3, R 5 and n are as defined on each, R ⁴ _a is a is protected carboxy The compound or a carboxy protecting group elimination reaction of a salt thereof And the formula: Wherein R ¹ , R ² , R ³ , R ⁵ and n are each as defined above, or a salt thereof, or (4) a compound of the formula: Wherein R ¹ , R ² , R ³ , R ⁴ and n are each as defined above, or a salt thereof, is subjected to an exchange reaction of the hydroxy with a leaving group to give a compound of the formula: 11] ^{Wherein, R 1, R 2, R} 3, R 4 and n are as defined on each, R ⁵ _a is a leaving group] or to produce a compound or a salt thereof, (5) : Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ _a and n are each as defined above, or a salt thereof, with thiourea to form a compound of the formula: ^{Wherein, R 1, R 2, R} 3, R 4 and n are as defined on each, R ⁵ _b is amidinothio] further characterized in that to produce a compound or a salt thereof . 6. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a mixture thereof with a pharmaceutically acceptable carrier. 7. A method for treating an infectious disease, comprising administering the compound of claim 1 or a pharmaceutically acceptable salt thereof to a human or animal. 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof for use as an antimicrobial agent.