KR0157589B1 - Novel cephalosporin antibiotics and process for preparation thereof - Google Patents

Abstract

The present invention relates to novel cepilosporin-based compounds, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates and solvates and isomers thereof, as indicated by the following general formula (I) useful as antibiotics: .

Wherein R ¹ represents hydrogen or an aminoprotecting group,

R ² is hydrogen, C _1-4 alkyl group, C _3-4 alkenyl group, C _3-4 alkynyl group or —C (R ^a ) (R ^b ) COOR ^c , where R ^a and R ^b may be the same or different Each of which represents hydrogen or a C _1-4 alkyl group, or R ^a and R ^b together with the carbon atom to which they are attached represent a C _3-7 cycloalkyl group and R ^c represents hydrogen or a carboxyl protecting group.) ego,

R ³ is Ions or carboxylic acid protecting groups,

R ⁴ and R ⁵ are the same or different and each represent a hydrogen substituted or unsubstituted amino group, hydroxy group or alkoxy group, C _1-4 alkyl group, carboxy group or alkoxy carboxyl group, or R ⁴ and R ⁵ are Form a C _3-7 ring together with the attached carbon atom,

R ⁶ represents a substituted or unsubstituted amino group or a C _1-4 alkyl group,

Q represents CH or N.

Description

New cephalosporin antibiotics and preparation method

The present invention relates to novel cepilosporin compounds of the general formula (I) which are useful as antibiotics, more specifically (Z) -2- (2-aminothiazole (or aminothiadiazole) -4 at the 7-β position -Yl) -2- (alkyl (or carboxyalkyl) oxyimino) acetamido group and at the same time a Cefme compound into which a 3-phenyl substituted propenyl group is introduced, ie 4-amino- at 3-position of the propenyl group Cephalosporin compounds with potent microbial activity substituted with trisubstituted pyrimidinium (or disubstituted pyrimidine) thio groups, broad antimicrobial spectrum and improved pharmacokinetic properties, pharmaceutically acceptable non-toxic salts thereof, physiologically active Degradable esters, hydrates and solvates and isomers thereof, and pharmaceutical compositions comprising them.

In the above formula,

R ¹ represents hydrogen or an aminoprotecting group,

R ² is hydrogen, C _1-4 alkyl group, C _3-4 alkenyl group, C _3-4 alkynyl group or —C (R ^a ) (R ^b ) COOR ^c , where R ^a and R ^b may be the same or different Each of which represents hydrogen or a C _1-4 alkyl group, or R ^a and R ^b together with the carbon atom to which they are attached represent a C _3-7 cycloalkyl group and R ^c represents hydrogen or a carboxyl protecting group.) ego,

R ³ represents a -ion or a carboxylic acid protecting group,

R ⁴ and R ⁵ are the same or different and each represents a hydrogen substituted or unsubstituted amino group, a hydroxy or alkoxy group, a C _1-4 alkyl group, a carboxyl group or an alkoxy carboxyl group, or a carbon to which R ⁴ and R ⁵ are attached Together with the atoms to form a C _3-7 ring,

R ⁶ represents a substituted or unsubstituted amino group or a C _1-4 alkyl group,

Q represents CH or N.

Cephalosporin antibiotics are widely used to treat diseases of pathogenic bacteria in humans and animals, and are particularly useful for treating diseases caused by bacteria that are resistant to other antibiotics, such as penicillin compounds, and for treating penicillin-sensitive patients. .

In many cases, it is desirable to use antibiotics that are active against both Gram-positive and Gram-negative microorganisms, and the antimicrobial activity of these cephalosporin antibiotics is greatly affected by the substituents at the 3 or 7 position of the cefe ring. This is a well known fact.

Thus, 7-β has been shown to be highly stable against β-lactamase produced by various Gram-negative bacteria as well as high antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria. Numerous cephalosporin antibiotics have been developed with various substituents introduced at the 3-position of the acylamido group and the cefe ring.

For example, British Patent No. 1,399,086 describes a broad and comprehensive description of cephalosporin derivatives represented by the following general formula (A).

In the above formula,

R ^a is hydrogen or an organic group,

R ^b is an etherified monovalent organic group linked to oxygen through carbon,

B is -S- or S → 0,

P is an organic group.

Since these compounds have been invented, many attempts have been made to develop antibiotics with improved antimicrobial properties, particularly against Gram-negative bacteria. As part of these attempts, British Patent No. 1,522,140 describes cephalosporin antibiotics of In which the compound is syn-isomer or is present as a mixture of syn- and cmti-isomers containing at least 90% or more of syn-isomers.

In the above formula,

R ^c is a furyl or thienyl group,

R ^d is a C _1-4 alkyl, C _3-4 cycloalkyl, furylmethyl or thienylmethyl group,

R ^e is hydrogen or carbamoyl, carboxymethyl, silfonyl or methyl group.

Since then, numerous attempts have been made to develop antibiotics having a broad antimicrobial spectrum with enhanced antimicrobial activity to gram-positive bacteria as well as to gram-negative bacteria. As a result, many cephalosporin antibiotics having similar structures of general formula (B) have been developed.

This development led to a number of changes, such as the introduction of acylamido groups and specific groups at the C-3 position at the 7-position of the cephem nucleus of Formula (B).

For example, Belgian Patent No. 852,427 discloses that in Formula (A) R ^a is substituted with various other organic groups, including 2-aminothiazol-4-yl, and the oxygen atom of the oxyimino group is attached to an aliphatic hydrocarbon group. And a cephalosporin antibiotic compound in which the aliphatic hydrocarbon group itself may be substituted with a carboxyl group, wherein in the compound, the substituent at the C-3 position is acyloxymethyl, hydroxymethyl, formyl or heterocyclic ring Thiomethyl group, and the like.

Of course, the compounds described in the above patent documents are completely distinguished in the structure from the compounds according to the present invention.

Recently, many efforts have been made to develop compounds that exhibit strong activity against a wide range of pathogens, as well as strong antimicrobial activity against some Gram-negative bacteria producing β-lactamase. In particular, numerous attempts have been made to introduce specific groups into P of compounds of general formula (A) wherein R ¹ is 2-aminothiazol-4-yl, and as a result of this effort, P has been shown that cefem compounds have strong activity against a wide range of pathogens. It has been found that it is visible and seperm compounds having these structures are described in the following Japanese Patent JP 03,173,894 and the like.

That is, Japanese Patent JP 03,173,894 describes seperm compounds having the structure of the following general formula (C).

In the above formula,

R ^f is hydrogen or substituted or unsubstituted hydrocarbyl,

R ^g represents a carboxyl group or an esterified carboxyl group,

R ^h is a substituted or unsubstituted heterocyclic group, or hydrocarbyl,

Q is N, CH or CCI.

The above patent also describes an optionally substituted thiazole, thiadiazole, tetrazole, triazole, and the like in the above-described substituted or unsubstituted heterocyclic group in the definition of R ^h that describes the C-3 substituent. There is no mention or suggestion of optionally molar pyrimidinium groups.

Based on this prior art, the present inventors have repeatedly attempted to develop a cephalosporin compound having not only strong antimicrobial activity against a wide range of pathogens, including Gram-negative bacteria producing β-lactimase, but also having improved pharmacokinetic properties. Efforts have resulted in (Z) -2- (2-aminothiazole (or aminothiadiazol) -4-yl) -2- (alkyl (or carboxyalkyl) oxyimino) acetamido groups at the 7β-position. The present invention was completed by discovering that cephalosporin compounds in which a pyrimidinium) thio propenyl group optionally substituted at the same time in the C-3 position meet these goals.

It is an object of the present invention to provide novel cephalosporin compounds of formula (I), pharmaceutically acceptable nontoxic salts thereof, physiologically hydrolysable esters, hydrates and solvates and isomers thereof.

In the above formula,

R ¹ represents hydrogen or an aminoprotecting group,

R ² is a C _1-4 alkyl group, C _3-4 alkenyl group, C _3-4 alkynyl group or —C (R ^a ) (R ^b ) COOH, wherein R ^a and R ^b may be the same or different, Each represents hydrogen or a C _1-4 alkyl group, or R ^a and R ^b represent a C _3-7 cycloalkyl group together with the carbon atom to which they are attached, and R ^c represents hydrogen or a carboxyl protecting group.

R ³ is-or a carboxyl protecting group,

R ⁴ and R ⁵ are the same or different and each represents hydrogen, a substituted or unsubstituted amino group, a hydroxy, or an alkoxy group, a C _1-4 alkyl group, a carboxyl group or an alkoxy carbonyl group, or R ⁴ and R ⁵ Together with the attached carbon atom to form a C _3-7 ring,

R ⁶ represents a substituted or unsubstituted amino group or a C _1-4 alkyl group,

Q represents CH or N.

In the above general formula, when R ² is-(R ^a ) (R ^b ) CO ₂ H, when R ^a and R ^b are different, the carbon to which they are attached is asymmetric center and these compounds form diastereomers. The present invention includes diastereoisomers of each of these compounds and mixtures thereof. The compounds of the present invention may also form tautomers, and the present invention also includes these tautomers. In addition, depending on the geometry of the double bond in the propenyl group which is part of the C-3 substituent, there are cis- and trans- isomers, and each of these geometric isomers and mixtures thereof is included in the present invention.

Compounds of general formula (I) according to the present invention are geometric isomers, including syn- and anti-isomers containing 90% or more of syn-isomers, and also of the general formula (I) Hydrates and solvates are also included within the scope of this invention.

In addition, since the aminothiazole group may form tautomers with iminothiazoline groups when Q is CH in the compound of formula (I), such tautomers are included in the scope of the present invention.

When Q is N, aminothiadiazole groups form tautomers with iminothiadiazoline groups and these tautomers are also included in the scope of the present invention.

In addition, cis- and trans-isomers exist as follows depending on the geometry of the double bond of the propenyl group which is part of the C-3 molar.

In the present invention, each of these geometric isomers and mixtures thereof is also included, and trans- is more preferable in terms of antimicrobial activity.

Pharmaceutically acceptable non-toxic salts of the compounds of formula (I) include hydrochloric acid, bromic acid, phosphoric acid, salts of sulfuric acid with inorganic acids, acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, hydroxyl, succinic acid, benzoic acid, tartaric acid Salts of organic carboxylic acids such as fumaric acid, manderic acid, ascorbic acid, dried acid, or sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid, and salts of penicillin with other acids known in the art. Include. These acid addition salts are prepared by conventional techniques. The compounds of formula (I) may also form nontoxic salts with bases. In this case, the base used may include alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g. sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate), and an alkaline earth metal carbonates (e.g. calcium carbonate) Inorganic bases) and organic bases such as amino acids.

Examples of physiologically hydrolyzable esters of the compound of general formula (I) include indanyl phthalidyl, metholoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, 5-methyl-2 Oxo-1, 3-dioxoene methyl and other physiologically hydrolysable esters known and used in the art of penicillin and cephalosporin. Such esters can be produced by known methods.

Compounds of the following general formula (I) according to the present invention, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates or solvates thereof may be prepared by the following general formula (II) in the presence of a solvent By reacting with the compound of (III) and, if necessary, by removing the amino protecting group or the acid protecting group before or after the reaction or reducing the S-oxide [s- (0) m].

In the above formula,

R ¹ -R ⁶ and Q are as described above,

X is a halogen element,

m is 0 or 1;

In the above general formula, R ¹ , an amino protecting group, is acyl, substituted or unsubstituted ar (lower) alkyl (eg benzyl, diphenylethyl, triphenylmethyl, 4-methoxybenzyl, etc.), halo (lower) alkyl (eg : Trichloromethyl, tricoloethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloidene, and the like. Acyls suitable as amino protecting groups may be aliphatic and aromatic acyl groups or acyl groups having a heterocycle. Examples of such acyl groups include C _1-5 lower alkanoyls (eg formyl, acetyl, etc.), C _2-6 alkoxycarbonyls (eg methoxycarbonyl, ethoxycarbonyl, etc.), lower alkyl sulfides. Phenyl (eg methylsulfonyl, ethylsulfonyl etc.) or ar (lower) alkoxycarbonyl (eg benzyloxycarbonyl etc.) etc. are mentioned. The acyl described above may have suitable substituents such as 1-3 halogens, hydroxy, cyano, nitro and the like. In addition, the reaction product of silane, boron, phosphorus compound and amino group may be an amino protecting group.

R ^{3, which} is a carboxyl protecting group, is usually suitable as long as it is easily removed under mild conditions, such as (lower) alkyl esters (eg methyl esters, t-butyl esters, etc.), (lower) alkenyl esters (eg Vinyl esters, allyl esters, etc.), (lower) alkoxythio (lower) alkyl esters (e.g., methoxyomethyl esters, etc.), halo (lower) alkyl esters (e.g., 2,2,2-trichloroethyl esters, etc.), Substituted or unsubstituted aralkyl esters such as benzyl esters, P-nitrobenzyl esters, P-methoxybenzyl esters, and the like, or silyl esters.

The amino protecting group and the carboxyl protecting group can be easily removed under mild reaction conditions such as hydrolysis and reduction to form a free amino group or a carboxyl group. The amino protecting group and carboxyl protecting group may be appropriately selected and used according to the chemical properties of the compound of general formula (I).

Leaving group X represents a halogen element such as chlorine, fluorine and iodine.

The meaning represented by the dotted line in the structure of the compound of formula (II) means that the compound of formula (II) alone represents the compound of formula (II-a) or a compound of formula (II-b) Or a mixture of a compound of Formula (II-a) with a compound of Formula (II-b).

In the above formula,

R ¹ , R ² , R ³ , m, Q and X are as described above.

The compound of formula (II), which is a starting material of the present invention, may be prepared according to the following reaction scheme. That is, the compound of formula (IV) or a salt thereof is activated with an acylating agent and reacted with the compound of formula (V) to obtain a compound of formula (VI), and C- of the compound of formula (VI) It can be prepared by introducing a 3-halogenated-propenyl group at the 3 position.

In the above scheme,

Q, m, R ¹ , R ² , R ³ and X are as described above.

In the structural formulas of the general formulas (V) and (VI) and the following general formulas (VII) and (VII), the dotted lines represent 2-cefem or 3-cefem compounds of the respective general formula compounds, respectively. Or a mixture thereof.

In preparing the compounds of formula (VI), the active acyl derivatives of formula (IV) are acid chlorides, acid anhydrides, mixed acid anhydrides (preferably methylchloroformate, mesylenesulfonyl chloride, p-toluene Acid anhydrides formed with sulfonyl chloride or chlorophosphate) or activated esters (preferably those formed in the reaction with N-hydroxy benzotriazole in the presence of a condensing agent such as dicyclohexyl carbodiimide). . The acylation reaction may also proceed with the free acid of formula (IV) in the presence of a condensing agent such as dicyclohexyl carbodiimide, carbonyl diimidazole. On the other hand, the acylation reaction usually proceeds well in the presence of organic bases such as tertiary aman (preferably triethylamine, dimethylaniline, pyridine) or inorganic bases such as sodium bicarbonate and sodium carbonate, and methylene chloride and chloroform are used as solvents. Solvents such as halogenated carbon, tetrahydrofuran, acetotritrile, dimethylformamide or dimethylacetamide. Also mixed solvents of the above solvents may be used and may be used in the form of an aqueous solution. The temperature of the acylation reaction is -50 degreeC-50 degreeC, Preferably it is about -30 degreeC-20 degreeC. The acylating agent of the compound of formula (IV) may use the equivalent or slight excess (1.05 to 1.2 equivalents) with respect to the compound of formula (V).

Compounds of formula (II) are prepared according to the general method from the compounds of formula (VI). That is, first, the compound of general formula (VI) is obtained by a commercial method (e.g., Wittig reaction) to obtain an intermediate of general formula (i), and then react the halogenated acetaldehyde with general formula ( II) compounds can be prepared.

Wherein R ¹ , R ² , Q, m and R ³ are as described above.

The compound of formula (II) can also be prepared by activating a compound of formula (IV) or a salt thereof with an acylating agent and directly reacting the compound of formula (VII). Here, the activation and acylation reaction of the general formula (IV) are according to the method described above.

In the above formula,

m, X and R ³ are as described above.

In addition, conversion of the halogen element represented by X in general formula (II) to another halogen element can be performed by a commercial method. For example, the compound of general formula (II) in which X is an iodine element can be obtained by reacting the compound of general formula (II) in which X is a chlorine element with an alkali metal iodide.

In preparing the compound of formula (I), the amino protecting group and the acid protecting group of the compound of formula (II) can be removed by conventional methods well known in the art of cephalosporin. That is, the protecting group can be removed by a hydrolysis or reduction method, and when including an amido group as the protecting group, it is preferable to undergo hydrolysis through amino halogenation and amino etherification. Acid hydrolysis is useful for the removal of tri (di) phenylmethyl or alkoxycarbonyl groups and is carried out using inorganic acids such as formic acid, organic acids such as trifluoro acetic acid, p-toluenesulfone or hydrochloric acid.

The preparation method of the compound of general formula (III) used in the present invention is described in detail in the preparation examples below.

Meanwhile, in the present invention, in the preparation of the compound of the general formula (I) by substituting the compound of the general formula (III) at the C-3 position of the compound of the general formula (II), the solvent is preferably anhydrous solvents. The solvents include lower alkylnitriles such as acetonitrile and propionitrile, lower halogenated alkanes such as chloromethane, dichloromethane and chloroform, ethers such as tetrahydrofuran, dioxane and ethyl ether, amides such as dimethylloanaamide, ethyl Esters such as acetates, ketones such as acetone, hydrocarbons such as benzene, alcohols such as methanol and ethanol, sulfoxides such as dimethyl sulfoxide, and the like, and mixed solvents of these solvents can also be used. The reaction temperature is appropriately -10 ° C to 80 ° C, preferably 20 ° C to 40 ° C, and the compound of formula (III) is 0.5 to 2 equivalents, preferably 1.0 to 1.1, based on the compound of formula (II). Equivalents can be used.

The desired compound of formula (I) can be separated or purified from the reaction product of the reaction by various methods such as recrystallization, iontophoresis, silica gel column chromatography or ion exchange resin chromatography.

As described above, the compound of general formula (I) exhibits a broad antimicrobial spectrum and stronger antimicrobial activity against pathogens including various gram-positive and gram-negative bacteria, and this activity also applies to many gram-negative bacteria producing β-lactamase. It can be effectively used for the prevention and treatment of bacterial infection in animals including humans.

The compounds of formula (I) of the present invention may be formulated in a known manner using known pharmaceutical carriers and excipients and injected into unit dose forms or multidose containers.

The formulation form may be in the form of a solution, suspension or emulsifier in an oil or aqueous medium, and may contain conventional dispersants, suspensions or stabilizers. In addition, for example, it may be in the form of a dry powder that is used as a sterile, depyrogenated water is dissolved before use. The compounds of formula (I) may also be formulated into suppositories using conventional suppository bases such as cocoa butter or other glycerides. If desired, the compounds of the present invention can also be administered in combination with other antibacterial agents such as penicillin or cefalphosphorin.

When formulating a compound of the present invention in unit dosage form, it is preferred that this unit dosage form contains about 50 to 1,500 mg of the active ingredient of the compound of general formula (I). The dosage of the compound of formula (I) depends on the doctor's prescription depending on factors such as the patient's weight, age and the particular nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 500 to 5,000 mg per day, depending on the frequency and intensity of administration. A total dosage of about 150-3,000 mg per day, usually separated by anecdotal doses for intramuscular or intravenous administration to adults, will be sufficient, but for some strains of infection higher doses may be desirable.

Compounds of general formula (I) according to the invention and their non-toxic salts (preferably salts with alkali metal salts, alkaline earth metal salts, inorganic acid salts, organic acid salts and amino acids) are used in a wide range of hospitals, including a variety of Gram-positive and Gram-negative bacteria. Because of its strong antimicrobial activity against adult bacteria, it is very useful for the prevention and treatment of diseases caused by bacterial infection in animals including humans.

Examples of major compounds according to the invention are summarized below.

The following Preparation Examples and Examples are intended to further illustrate the present invention, but do not limit the present invention.

[Production Example 1]

Paramethoxybenzyl, 7-[(Z) -2 [(SR) -1- (diphenylmethoxycarbonyl) eth-1-oxyimino] -2- [2- (triphenylmethyl) aminothiazole- 4-yl] acetamido] -3-[(Z) -3-chloro-1-propen-1-yl] -3-cefe-4-carboxylate

Paramethoxybenzyl, 7-[(Z) -2 [1- (diphenylmethoxycarbonyl) eth-1-oxyimino] -2- [2- (triphenylmethyl) aminothiazol-4-yl] Acetamido] -3-chloromethyl-3-cepem-4-carboxylate 101.9 g was dissolved in 750 ml of acetone, and then 27.5 g of triphenylphosphine and 15.8 g of sodium iodide were sequentially added, followed by stirring at room temperature for 40 minutes. After completion of the reaction, the solvent in the reaction solution was distilled off under reduced pressure, 750 ml of dichloromethane and 750 ml of distilled water were added to the remaining residue, and the mixture was shaken well to separate the layers. The organic layer was separated, dried over anhydrous magnesium sulfate, and distilled under reduced pressure. Was removed. The obtained solid was washed with 800 ml of diethyl ether, dried, and then dissolved in a mixed solvent of 1 L of chloroform and 1 L of saturated salt. Then, 110 ml of 1N sodium hydroxide solution was added thereto, followed by stirring at 15 ° C. for 20 minutes. 250 ml of distilled water was added to the reaction solution, and the mixture was separated, and 74.5 g of 40% -chloroacetaldehyde aqueous solution was added to the organic layer, which was then stirred at room temperature for 30 minutes. 1 L of distilled water was added to the reaction solution, the mixture was shaken well, and the organic layer obtained by layer separation was dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained solid was separated and purified through silica gel column chromatography to obtain 91.7 g of the title compound as a pale yellow solid.

[Production Example 2]

Paramethoxybenzyl, 7-[(Z) -2 [(S, R) -1- (diphenylmethoxycarbonyl) prop-1-oxyimino] -2- [2- (triphenylmethyl) amino Synthesis of Thiazol-4-yl] acetamido] -3-[(Z) -3-chloro-1-propen-1-yl] -3-cefe-4-carboxylate

Paramethoxybenzyl, 7-[(Z) -2- [1- (diphenylmethoxycarbonyl) prop-1-oxyimino] -2- [2- (triphenylmethyl) aminothiazole-4- 10] g of acetamido] -3-chloromethyl-3-cepem-4-carboxylate was dissolved in 750 ml of acetone, and then 27.5 g of triphenylphosphine and 15.8 g of sodium iodide were added in order, followed by stirring at room temperature for 40 minutes. . After completion of the reaction, the solvent in the reaction solution was distilled off under reduced pressure, 750 ml of dichloromethane and 750 ml of distilled water were added to the remaining residue, and the mixture was shaken well to separate the layers. Was removed. The obtained solid was washed with 800 ml of diethyl ether, dried, and then dissolved in a mixed solvent of 1 L of chloroform and 1 L of saturated salt. Then, 110 ml of 1N sodium hydroxide solution was added thereto, followed by stirring at 15 ° C. for 20 minutes. 250 ml of distilled water was added to the reaction solution, and the mixture was separated, and 74.5 g of 40% -chloroacetaldehyde aqueous solution was added to the organic layer, which was then stirred at room temperature for 30 minutes. 1 L of distilled water was added to the reaction solution, the mixture was shaken well, and the organic layer obtained by layer separation was dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained solid was separated and purified through silica gel column chromatography to obtain 92.1 g of the title compound as a pale yellow solid.

[Manufacture example 3]

Paramethoxybenzyl, 7-[(Z) -2- (2-tert-butoxycarbonylprop-2-oxyimino) -2- [2- (triphenylmethyl) aminothiazol-4-yl ] Acetamido] -3-[(Z) -3-chloro-1-propen-1-yl] -3-cefe-4-carboxylate

Paramethoxybenzyl, 7-[(Z) -2- [2-tert-butoxycarbonylprop-2-oxyimino] -2- [2- (triphenylmethyl) aminothiazol-4-yl ] Acetamido] -3-chloromethyl-3-cepem-4-carboxylate 92.4g was dissolved in 750 ml of acetone, and then 27.5 g of triphenylphosphine and 15.8 g of sodium iodide were added in order, followed by stirring at room temperature for 40 minutes. After completion of the reaction, the solvent in the reaction solution was distilled off under reduced pressure, 750 ml of dichloromethane and 750 ml of distilled water were added to the remaining residue, and the mixture was shaken well. The layers were separated. The organic layer was separated, dried over anhydrous magnesium sulfate, and distilled under reduced pressure. Was removed. The obtained solid was washed with 800 ml of diethyl ether, dried, and then dissolved in a mixed solvent of 1 L of chloroform and 1 L of saturated salt. Then, 110 ml of 1N sodium hydroxide solution was added thereto, followed by stirring at 15 ° C. for 20 minutes. 250 ml of distilled water was added to the reaction solution, the mixture was left to stand, and 74.5 g of 40% -chloroacetaldehyde aqueous solution was added to the organic layer obtained by layer separation, and the mixture was stirred at room temperature for 30 minutes. 1 L of distilled water was added to the reaction solution, the mixture was shaken well, and the organic layer obtained by layer separation was dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained solid was separated and purified through silica gel column chromatography to obtain 81.7 g of the title compound as a pale yellow solid.

[Production Example 4]

Paramethoxybenzyl, 7-[(Z) -2- [1- (diphenylmethoxycarbonyl) cyclopentoxyamino] -2- [2- (triphenylmethyl) aminothiazol-4-yl] acet Amido] -3-[(Z) -3-chloro-1-propen-1-yl] -3-cefe-4-carboxylate

Paramethoxybenzyl, 7-[(Z) -2- [1- (diphenylmethoxycarbonyl) cyclopentoxyamino] -2- [2- (triphenylmethyl) aminothiazol-4-yl] acet Amido] -3-chloromethyl-3-cepem-4-carboxylate 105.9g was dissolved in 750ml of acetone, and then 27.5g of triphenylphosphine and 15.8g of sodium iodide were sequentially added, followed by stirring at room temperature for 40 minutes. After completion of the reaction, the solvent in the reaction solution was distilled off under reduced pressure, 750 ml of dichloromethane and 750 ml of distilled water were added to the remaining residue, and the mixture was shaken well. The layers were separated. The organic layer was separated, dried over anhydrous magnesium sulfate, and distilled under reduced pressure. Was removed. The obtained solid was washed with 800 ml of diethyl ether, dried, and then dissolved in a mixed solvent of 1 L of chloroform and 1 L of saturated salt. Then, 110 ml of 1N sodium hydroxide solution was added thereto, followed by stirring at 15 ° C. for 20 minutes. 250 ml of distilled water was added to the reaction solution, the mixture was left to stand, and 74.5 g of 40% -chloroacetaldehyde aqueous solution was added to the organic layer obtained by layer separation, and the mixture was stirred at room temperature for 30 minutes. 1 L of distilled water was added to the reaction solution, the mixture was shaken well, and the organic layer obtained by layer separation was dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained solid was purified by silica gel column chromatography to obtain 92.3 g of the title compound as a pale yellow solid.

Production Example 5

Paramethoxybenzyl, 7-[(Z) -2-ethoxyimino-2- [2- (triphenylmethyl) aminothiazol-4-yl] acetamido] -3-[(Z) -3- Synthesis of Chloro-1-propen-1-yl] -3-cepem-4-carboxylate

Paramethoxybenzyl, 7-[(Z) -2-ethoxyimino-2- [2- (triphenylmethyl) aminothiazol-4-yl] acetamido] -3-chloromethyl-3-cepem- After dissolving 81.1 g of 4-carboxylate in 750 ml of acetone, 27.5 g of triphenylphosphine and 15.8 g of sodium iodide were added sequentially, followed by stirring at room temperature for 40 minutes. After completion of the reaction, the solvent in the reaction solution was distilled off under reduced pressure, 750 ml of dichloromethane and 750 ml of distilled water were added to the remaining residue, and the mixture was shaken well. The layers were separated. The organic layer was separated, dried over anhydrous magnesium sulfate, and distilled under reduced pressure. Was removed. The obtained solid was washed with 800 ml of diethyl ether, dried, and then dissolved in a mixed solvent of 1 L of chloroform and 1 L of saturated salt. Then, 110 ml of 1N sodium hydroxide solution was added thereto, followed by stirring at 15 ° C. for 20 minutes. 250 ml of distilled water was added to the reaction solution, the mixture was left to stand, and 74.5 g of 40% -chloroacetaldehyde aqueous solution was added to the organic layer obtained by layer separation, and the mixture was stirred at room temperature for 30 minutes. 1 L of distilled water was added to the reaction solution, the mixture was shaken well, and the organic layer obtained by layer separation was dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The solid obtained here was purified by silica gel column chromatography to obtain 73.9 g of the title compound as a pale yellow solid.

[Manufacture example 6]

Paramethoxybenzyl, 7-[(Z) -2-methoxyimino-2- [2- (triphenylmethyl) amino-thiazol-4-yl] acetamido] -3-[(Z) -3 Synthesis of -chloro-1-propen-1-yl] -3-cepem-4-carboxylate

Paramethoxybenzyl, 7-[(Z) -2-methoxyimino-2- [2- (triphenylmethyl) amino-thiazol-2-yl] acetamido] -3-chloromethyl-3-cepem After dissolving 81.2 g of 4-carboxylate in 750 ml of acetone, 27.5 g of triphenylphosphine and 15.8 g of sodium iodide were sequentially added thereto, followed by stirring at room temperature for 40 minutes. After completion of the reaction, the solvent in the reaction solution was distilled off under reduced pressure, 750 ml of dichloromethane and 750 ml of distilled water were added to the remaining residue, and the mixture was shaken well. The layers were separated. The organic layer was separated, dried over anhydrous magnesium sulfate, and distilled under reduced pressure. Was removed. The obtained solid was washed with 800 ml of diethyl ether, dried, and then dissolved in a mixed solvent of 1 L of chloroform and 1 L of saturated salt. Then, 110 ml of 1N sodium hydroxide solution was added thereto, followed by stirring at 15 ° C. for 20 minutes. 250 ml of distilled water was added to the reaction solution, the mixture was left to stand, and 74.5 g of 40% -chloroacetaldehyde aqueous solution was added to the organic layer obtained by layer separation, and the mixture was stirred at room temperature for 30 minutes. 1 L of distilled water was added to the reaction solution, the mixture was shaken well, and the organic layer obtained by layer separation was dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The solid obtained here was purified by silica gel column chromatography to obtain 71.6 g of the title compound as a pale yellow solid.

Example 1

7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyate-1-oxyimino) acetamido] -3-[(E ) -3- (1,4-diaminopyridinium-2-yl) thio-1-propen-1-yl] -3-cepem-4-carboxylic acid (I-1a) and (I-1b) Synthesis of

17.24 g of the compound obtained in Preparation Example 1 was dissolved in 200 ml of acetone, and 11.32 g of sodium iodide was added, followed by stirring at 15 ° C. to 20 ° C. for 2 hours. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove the solvent, and the obtained residue was extracted with 300 ml of ethyl acetate, washed three times with 300 ml of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and concentrated by removing the solvent. The concentrated solution obtained herein was slowly added dropwise to 300 ml of diethyl ether to solidify, filtered, washed with 200 ml of diethyl ether, and dried to give 15.3 g of a white white solid. 5.0 g of this compound is aliquoted, dissolved in 20 ml of dimethylformamide, 1.69 g of 1,4-diaminopyrimidine-2-thione is added thereto, and the mixture is stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with 200 ml of ethyl acetate, washed three times with 200 ml of saturated salt water, dried over 50 g of anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The concentrated solution obtained herein was slowly added dropwise to 300 ml of diethyl ether to solidify, and the solid obtained by filtration was washed with 20 ml of diethyl ether and dried to give 4.55 g of a white powder. 4.55 g of the solid obtained was dissolved in 15 ml of anisole, and the temperature of the reaction solution was cooled to 0 ° C to 4 ° C. Then, 30 ml of trifluorotoacetic acid was slowly added dropwise and stirred at room temperature for 1 hour, and then the temperature of the reaction solution was -10 ° C. To 15 ° C., 180 ml of diethyl ether was slowly added dropwise to solidify, filtered, washed sequentially with 150 ml of acetone and 150 ml of diethyl ether, and dried to yield 2.15 g of a white white solid. Each diastereoisomer was separated using the graphy (μ-Bondpak C18 Steel Column, 30mm × 30mm) obtained here to obtain 440mg and 430mg of the title compound I-1a (S) and I-1b (R), respectively, as a white solid. do.

Example 2

7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyate-1-oxyimino) acetamido] -3-[(E ) -3- (7-amino-1-methyl-1H-imidazo- [1,2, -C] pyrimidinium-5-yl) thio-1-propen-1-yl] -3-cepem- Synthesis of 4-carboxylic acid (I-2b)

7-amino-1-methyl-1H-imidazo [1,2-c] pyrimidine in place of 5.0 g of the compound obtained in Preparation Example 1 and 1,4-diaminopyrimidine-2-thione used in Example 1 1.85 g of 2-thione was used in the same manner as in Example 1 to obtain 420 mg and 425 mg of the title compound I-2a (R) as a white solid, respectively.

Example 3

7-[(Z) -2-((2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyate-1-oxyimino) acetamido] -3-[( E) -3- (2,7-diamino-1-methyl- [1,2,4] triazol [1,5, -C] pyriminium-5-yl) thio-1-propen-yl] Synthesis of -3-cepem-4-carboxylic acid (I-3a) and (I-3b)

2,7-amino-1-methyl [1,2,4] triazolo- [1 instead of 5.0 g of the compound obtained in Preparation Example 1 and the 1,4-diaminopyrimidine-2-thione used in Example 1 Using 1.85 g of, 5, -C] pyrimidine-2-thione, 420 mg and 425 mg of the title compound I-3a (S) and I-3b (R) were obtained as white solids, respectively. .

Example 4

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (S, R) -1-carboxyate-1-oxyimino) acetamido] -3-[(E) -3- (1,4-diamino-5,6-cyclopentapyrimidin-2-yl) thio-1-propen-yl] -3-cefe-4-carboxylic acid (I-4a) and Synthesis of (I-4b)

5.0 g of the compound obtained in Preparation Example 1 and 1.85 g of 1,4-diamino-5,6-cyclopentapyrimidine-2-thione instead of 1,4-diaminopyrimidine-2-thione used in Example 1 In the same manner as in Example 1 using 420 mg, 425 mg of the title compound I-4a (S) and I-4b (R) as white solids were obtained, respectively.

Example 5

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (S, R) -1-carboxyprop-1-oxyimino) acetamido] -3-[(E ) -3- (1,4-diaminopyrimidin-2-yl) thio-1-propen-1-yl] -3-cepem-4-carboxylic acid (I-5) and (I-5b ) Synthesis

5.0 g of the compound obtained in Preparation Example 2 and 2.0 g of 1,4-diaminopyrimidine-2-thione used in Example 1 were similarly prepared in Example 1 to obtain the title compound I-5a (S) as a white solid. 420 mg and 430 mg of I-5b (R) are obtained, respectively.

Example 6

7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyprop-1-oxyimino) acetamido] -3-[( E) -3- (7-amino-1-methyl-1H-imidazo [1,2-c] pyriminium-5-yl) thio-1-propen-yl] -3-cepem-4-carboxyl Synthesis of Acids (I-6a and I-6b)

7-amino-1-methyl-1H-imidazo [1,2-c] pyrimidine in place of 5.0 g of the compound obtained in Preparation Example 2 and the 1,4-diaminopyrimidine-2-thione used in Example 5 2.0 g of 2-thione was used in the same manner as in Example 1 to obtain 430 mg and 425 mg of the title compound I-6a (S) and I-6b (R), respectively, as a white solid.

Example 7

7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyprop-1-oxyimino) acetamido] -3-[( E) -3- (2,7-diamino-1-methyl- [1,2,4] triazol [1,5, -c] pyrinium-5-yl) thio-1-propene-1- Synthesis of Il] -3-cepem-4-carboxylic acid (I-7a) and (I-7b)

2,7-diamino-1-methyl [1,2,4] triazolo- [instead of 5.0 g of the compound obtained in Preparation Example 2 and 1,4-diaminopyrimidine-2-thione used in Example 1 2.0 g of 1,5, -c] pyrimidine-2-thione was prepared in the same manner as in Example 1 to obtain 430 mg and 425 mg of the title compounds I-7a (S) and I-7b (R) as white solids, respectively. do.

Example 8

7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyprop-1-oxyimino) acetamido] -3-[( E) -3- (1,4-diamino-5,6-cyclopentapyrimidin-5-5-yl) thio-1-propen-1-yl] -3-cefe-4-carboxylic acid (I -8a) and Synthesis of (I-8b)

2.0 g of 1,4-diamino-5,6-cyclopentapyrimidine-2-thione instead of 5.0 g of the compound obtained in Preparation Example 2 and 1,4-diaminopyrimidine-2-thione used in Example 1 In the same manner as in Example 1, using the title compound I-8a (S) and I-8b (R) as a white solid to obtain 430 mg and 425 mg, respectively.

Example 9

7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyprop-1-oxyimino) acetamido] -3-[( E) -3- (5-methyl-14,6-triaminopyrimidin-2-yl) thio-1-propen-1-yl] -3-cepem-4-carboxylic acid

2,7-diamino-1-methyl [1,2,4] triazolo- [instead of 5.0 g of the compound obtained in Preparation Example 2 and 1,4-diaminopyrimidine-2-thione used in Example 1 2.0 g of 1,5, -c] pyrimidine-2-thione was prepared in the same manner as in Example 1 to obtain 430 mg and 425 mg of the title compounds I-7a (S) and I-7b (R) as white solids, respectively. do.

Example 10

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclopentoxyimino) acetamido] -3-[(E) -3- (1, Synthesis of 4-diaminopyrimidin-2-yl) thio-1-propen-1-yl] -3-cefe-4-carboxylic acid (I-10)

5.0 mg of the compound obtained in Preparation Example 4 and 2.0 g of 1,4-diaminopyrimidinium-2-thione were prepared in the same manner as in Example 1 to obtain 450 mg of the title compound (I-10) as a white solid. do.

Example 11

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclopentoxyimino) acetamido] -3-[(E) -3- (7- Amino-1-methyl-1H-imidazol [1,2-c] pyrimidin-5-5-yl) thio-1-propen-1-yl] -3-cepem-4-carboxylate (I-11 ) Synthesis

7-amino-1-methyl-1H-imidazo [1,2-c] pyriin instead of 5.0 g of the compound obtained in Preparation Example 4 and the 1,4-diaminopyrimidinium-2-thione used in Example 1 1.86 g of midine-5-thione was used in the same manner as in Example 1 to obtain 400 mg of the title compound (I-11) as a white solid.

Example 12

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclopentoxyimino) acetamido] -3-[(E) -3- (2, 7-diamino-1-methyl [1,2,4] triazole [1,5-c] pyrimidinium-5-yl) -thio-1-propen-1-yl] -3-cepem-4 Synthesis of Carboxylate (I-12)

2,7-diamino-1-methyl [1,2,4] triazole [1] instead of 5.0 g of the compound obtained in Preparation Example 4 and the 1,4-diaminopyrimidine-2-thione used in Example 1 , 5-c] pyrimidinium-5-thione was prepared in the same manner as in Example 1 to obtain 390 mg of the title compound (I-12) as a white solid.

Example 13

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxyprop-2-oxyimino) acetamido] -3-[(E)-(1, Synthesis of 4-diamino-5,6-cyclopentamiridinium-2-yl) thio-1-propen-1-yl] -3-cef-4-carboxylate (I-13)

5.0 g of the compound obtained in Preparation Example 3 and 2.29 g of 1,4-diamino-5,6-cyclopentapyrimidine-2-thione instead of 1,4-diaminopyrimidine-2-thione used in Example 1 405 mg of the title compound (I-13) was obtained as a white solid, in the same manner as in Example 1.

Example 14

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxyprop-2oxyimino) acetamido] -3-[(E) -3- (1 Synthesis of, 4,6-triamino-5-methylpyrimidin-2-yl) thio-1-propen-1-yl] -3-cef-4-carboxylate (I-14)

Instead of 5.0 g of the compound obtained in Preparation Example 3 and 1,4-diaminopyrimidine-2-thione used in Example 1, 1.85 g of 1,4,6-triamino-5methylpyrimidine-2-thione was used. In the same manner as in Example 1, 420 mg of the title compound (I-14) was obtained as a white solid.

Example 15

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3-[(E) -3- (1,4-diaminopyri Synthesis of midinium-2-yl) thio-1-propen-1-yl] -3-cef-4-carboxylate (I-15)

5.0 g of the compound obtained in Preparation Example 5 and 1.85 g of 1,4-diaminopyrimidine-2-thione were prepared in the same manner as in Example 1 to synthesize 420 mg of the title compound (I-15) as a white solid. It was.

Example 16

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-[(E) -3- (1,4-diaminopyri Synthesis of midin-2-yl) thio-1-propen-1-yl] -3-cef-4-carboxylate (I-16)

5.0 g of the compound obtained in Preparation Example 6 and 1.85 g of Example 1,4-diaminopyrimidine-2-thione were used in the same manner as in Example 1 to obtain 425 mg of the title compound (I-16) as a white solid. To obtain.

Example 17

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-[(E) -3- (1,4,6-tri Synthesis of Amino-5-methylpyrimidin-2-yl) thio-1-propen-1-yl] -3-cepem-4-carboxylate (I-17)

1,4,6-triamino-5-methylpyrimidine-5-methylpyrimidine- in place of 5.0 g of the compound obtained in Preparation Example 6 and 1,4-diaminopyrimidine-2-thione used in Example 1 1.85 g of 2-thione was used in the same manner as in Example 1 to obtain 420 mg of the title compound (I-17) as a white solid.

The usefulness of the compounds according to the present invention is to test standard strains, clinically isolated strains, strains resistant to some antibiotics, and strains producing β-lactamase using the known compound ceftazidime as a control agent. As the strains, the minimum inhibitory concentrations (Minimum Inhibitiory Concentration) for these strains were obtained, and at the same time, the pharmacokinetic parameters of the rats were obtained and evaluated. In other words, the minimum inhibitory concentration was obtained by diluting the test compounds by a 2-fold dilution method, dispersing them in Muller-Hinton Agar medium, and then inoculating 2 ul of a test strain having 10 ⁷ CFU (Colory Forming Unit) per ml. Incubated at 37 ℃ for 20 hours and the results are shown in Table 2. Pharmacokinetic parameters for rats were obtained using SD rats (♂) weighing about 230 ± 10 g. That is, the samples were administered through the femoral vein at a dose of 20 mg / kg for 4 to 5 mice, and 1, 2.5, 5, 10, 20, 40, 60, 120, 180 minutes after administration through the femoral artery Blood was collected and blood concentration was determined by Agar Well Method, and the calculated pharmacokinetic parameters, T _½ and AUC (Area Under the Curve), are shown in Table 3. .

Claims (6)

New cephalosporin compounds represented by the following general formula (I), pharmaceutically acceptable nontoxic salts thereof, physiologically hydrolysable esters, hydrates and solvates and isomers thereof. Wherein R ¹ represents hydrogen or an aminoprotecting group, R ² represents hydrogen, a C _1-4 alkyl group, a C _3-4 alkenyl group, a C _3-4 alkynyl group or —C (R ^a ) (R ^b ) COOR ^c Wherein R ^a and R ^b may be the same or different and each represent hydrogen or a C _1-4 alkyl group, or R ^a and R ^b together with a carbon atom to which they are attached a C _3-7 cycloalkyl group R ^c represents hydrogen or a carboxyl protecting group.), And R ³ represents Ions or carboxyl protecting groups, R ⁴ and R ⁵ are the same or different and each represents a hydrogen substituted or unsubstituted amino group, hydroxy or alkoxy group, C _1-4 alkyl group, carboxyl group or alkoxy carboxyl group, or R ⁴ and R ⁵ together with the carbon atom to which they are attached may form a C _3-7 ring, R ⁶ represents a substituted or unsubstituted amino group or a C _1-4 alkyl group, and Q represents CH or N. A compound of formula (I) according to claim 1 selected from the group consisting of: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyate-1-oxyimino) acetamido] -3-[(E ) -3- (1,4-diaminopyridinium-2-yl) thio-1-propen-1-yl] -3-cepem-4-carboxylic acid: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxylate-1-oxyimino) acetamido] -3-[(E) -3- (7-amino- 1-Methyl-1H-imidazo- [1,2, -C] pyrimidin-5-5-yl) thio-1-propen-1-yl] -3-cepem-4-carboxylic acid: 7- [ (Z) -2-((2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyate-1-oxyimino) acetamido] -3-[(E)- 3- (2,7-diamino-1-methyl- [1,2,4] triazole [1,5, -C] pyriminium-5-yl) thio-1-propen-yl] -3- Cefem-4-carboxylic acid: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxy-1--1-oxyimino) acetami Fig.]-3-[(E) -3- (1,4-diamino-5,6-cyclopentapyrimidin-2-yl) thio-1-propen-yl] -3-cepem-4- Carboxylic acid: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyprop-1-oxyimino ) Acetamido] -3-[(E) -3- (1,4-diaminopyriminium-2-yl) thio-1-propen-1-yl] -3-cepem-4-carboxylic acid : 7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyl-1-oxyimino) acetamido] -3-[( E) -3- (7-amino-1-methyl-1H-imidazo [1,2-c] pyriminium-5-yl) thio-1-propen-yl] -3-cepem-4-carboxyl Acid: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyprop-1-oxyimino) acetamido] -3- [(E) -3- (2,7-diamino-1-methyl- [1,2,4] triazol [1,5, -c] pyrinium-5-yl) thio-1-propene- Yl] -3-cepem-4-carboxylic acid: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyprop-1 -Oxyimino) acetamido] -3-[(E) -3- (1,4-diamino-5,6-cyclopentapyridinium-5-yl) thio-1-propen-1-yl ] -3-cepem-4-carboxylic acid: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-[(S, R) -1-carboxyprop-1- Oxiimino) acetamido] -3-[(E) -3- (5-methyl-1,4,6-triaminopyrimidin-5-5-yl) O-1-propen-1-yl] -3-cepem-4-carboxylic acid: 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxy Cyclopentoxyimino) acetamido] -3-[(E) -3- (1,4-diaminopyrimidin-2-yl) thio-1-propen-1-yl] -3-cepem- 4-carboxylic acid: 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclopentoxyimino) acetamido] -3-[(E) -3- (7-amino-1-methyl-1H-imidazol [1,2-c] pyrimidinium-5-yl) thio-1-propen-1-yl] -3-cepem-4-car Voxylate: 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclopentoxyimino) acetamido] -3-[(E) -3- (2,7-diamino-1-methyl [1,2,4] triazole [1,5-c] pyrimidinium-5-yl) -thio-1-propen-1-yl] -3- Sepem-4-carboxylate: 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxyprop-2-oxyimino) acetamido] -3- [(E)-(1,4-Diamino-5,6-cyclopentamiridinium-2-yl) thio-1-propen-1-yl] -3-cepem-4-carboxylate: 7- [(Z) -2- (2-aminothia -4-yl) -2- (2-carboxyprop-2oxyimino) acetamido] -3-[(E) -3- (1,4,6-triamino-5-methylpyrimidinium- 1-yl) thio-1-propen-1-yl] -3-cepem-4-carboxylate: 7-[(Z) -2- (2-aminothiazol-4-yl) -2- ( Ethoxyimino) acetamido] -3-[(E) -3- (1,4-diaminopyrimidin-2-yl) thio-1-propen-1-yl] -3-cepem-4 -Carboxylate: 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-[(E) -3- (1, 4-diaminopyrimidin-2-yl) thio-1-propen-1-yl] -3-cepem-4-carboxylate: or 7-[(Z) -2- (2-aminothiazole- 4-yl) -2- (methoxyimino) acetamido] -3-[(E) -3- (1,4,6-triamino-5-methylpyrimidin-2-yl) thio-1- Propen-1-yl] -3-cepem-4-carboxylate. The compound of formula (II) is then reacted with the compound of formula (III) in the presence of a solvent and, if necessary, is removed an amino protecting group or an acid protecting group before or after the reaction or S-oxide [s- (0) m ] A process for the preparation of a compound of formula (I), a pharmaceutically acceptable non-toxic salt thereof, a physiologically hydrolysable ester, hydrate or solvate thereof, wherein Wherein R ¹ represents hydrogen or an aminoprotecting group, R ² represents hydrogen, a C _1-4 alkyl group, a C _3-4 alkenyl group, a C _3-4 alkynyl group or —C (R ^a ) (R ^b ) COOR ^c Wherein R ^a and R ^b may be the same or different and each represent hydrogen or a C _1-4 alkyl group, or R ^a and R ^b together with a carbon atom to which they are attached a C _3-7 cycloalkyl group R ^c represents hydrogen or a carboxyl protecting group.), And R ³ represents Ions or carboxyl protecting groups, R ⁴ and R ⁵ are the same or different and each represents a hydrogen substituted or unsubstituted amino group, hydroxy or alkoxy group, C _1-4 alkyl group, carboxyl group or alkoxy carboxyl group, or R ⁴ and R ⁵ together with the carbon atom to which it is attached may form a C _3-7 ring, R ⁶ represents a substituted or unsubstituted amino group or a C _1-4 alkyl group, Q represents CH or N, and X Is a halogen element, and m is 0 or 1. The solvent of claim 3 wherein the solvent is acetonitrile, propionitrile, chloromethane, dichloromethane, chloroform, tetrahydrofuran, dioxane, ethyl ether, N, N-dimethylformamide, ethyl acetate, acetone, benzene, methanol, At least one selected from ethanol and dimethylsulfone. The method of claim 3, wherein the reaction temperature is -10 ℃ to 80 ℃. The method according to claim 1, wherein the amount of the compound of formula (III) is 0.5 to 2 equivalents based on the compound of formula (II).