KR0154903B1 - Novel cephalosporin antibiotics - Google Patents

Abstract

The present invention relates to cephalosporin compounds represented by the following general formula (I), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolyzable esters, hydrates and solvates and isomers thereof, useful as antibiotics.

Wherein R ¹ represents hydrogen, a C _1-4 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group or —C (R ^a ) (R ^b ) COOH, and R ^a and R ^b are the same or May be different and each represent hydrogen or a C _1-4 alkyl group, or together with the carbon atoms to which they are attached form a C _3-7 cycloalkyl group, R ² represents a C _1-4 alkyl group, and R ³ represents hydrogen Or a methyl group.

Description

New Cephalosporin Antibiotic (I)

The present invention provides novel cephalosporin compounds of Formula (I), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates and solvates and isomers thereof, useful as antibiotics, and their It relates to a weak composition.

Wherein R ¹ represents hydrogen, C _1-4 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group or —C (R ^a ) (R ^b ) COOH, wherein R ^a and R _b are the same or May be different and each represent hydrogen or a C _1-4 alkyl group, or together with the carbon atoms to which they are attached form a C _3-7 cycloalkyl group, R ² represents a C _1-4 alkyl group, and R ³ represents hydrogen or A methyl group is shown.

In the above formula, when R ^a and R ^b are different, the carbon atom to which they are attached becomes an asymmetric center. Such compounds are diastereomers and the present invention includes diastereo isomers of each of these compounds and mixtures thereof. These compounds may also form tautomers, and these tautomers are included in the present invention.

As shown in the above general formula, the present invention provides a potent microorganism by introducing a (2,3-disubstituted-6-aminopyrimidin-4-yl) thiomethyl group in quarternary form at the C-3 position of the cefe ring. It is an object to provide cephalosporin antibiotics with activity and a broad antimicrobial spectrum.

Cephalosporin antibiotics are widely used to treat diseases of pathogenic bacteria in humans and animals, and are particularly useful for the treatment of 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. Therefore, 7-β has been shown to have high antibacterial activity against a wide range of Gram-negative and Gram-negative bacteria, and to attempt to find antibiotics that are not only very stable against β-lactamase produced by various Gram-negative bacteria but also in vivo. Numerous cephalosporin antibiotics have been developed with various substituents introduced at the 3-position of the acylamido group and the cefe ring.

For example, Japanese Patent Laid-Open Publication No. 54-9296 describes very broadly about cephalosporin derivatives of the following general formula (A) having a substituent A at the 3-position of the cefe ring.

In the description of the present invention, hydrogen, optionally substituted alkyloxy or alkenyloxy group, halogen or -CH ₂ Y group with respect to the substituent A in the 3-position, wherein Y is a nucleophilic compound including a hydrogen, halogen or -SR group And the residues are described very broadly and comprehensively to include substitutable 5- to 8-membered heterocycles, especially when Y is -SR, in which specific examples of substitutable pyridyl or pyrimidyl And the like, but there is no reference or example to the pyrimidinium group in the amino-substituted quaternary form as in the present invention described above.

On the other hand, French Patent No. 2,426,694 describes 7-[(2-aminothiazol-4-yl) -2oxyiminoacetamino] represented by the following general formula (B) having a substituent appropriately selected at 7β- and 3 positions. Reference is made to cefem derivatives.

Wherein R ₅ and R ₆ represent a C _3-7 cycloalkylidene group together with the carbon atom to which they are attached, Z is a 5-6 membered heterocycle which is bonded to carbon and contains one or more nitrogen atoms, It may have a small sulfur atom and / or be substituted with a C _1-4 alkyl group.

The specification of the patent discloses a compound having a substituent in the quaternary form, such as a pyrimidinium thiomethyl group, at the 3 position of the cefe ring, but these substituents also have a pyrimidinium having at least one amino group, which is a core substituent of the present invention. It is different from thiomethyl group.

In addition, Mitsubishi et al. Describe the cephalosporin compound represented by the following general formula (C) in European Patent Application No. 87304896.1.

In the formula, R ₈ represents the following general formula (Ca-1) or (Ca-2).

Wherein R ₉ represents a lower alkenyl, a substitutable 5 or 6 membered nitrogen-containing heterocyclic group, an acylamino or a substitutable lower alkyl group, and R ₁₀ and R ₁₁ may be the same or different, respectively, hydrogen, lower alkyl , Amino, acylamino, carboxyl, carbamoyl, thiocarbamoyl or lower alkoxycarbonyl group, R ₁₂ and R ₁₃ are each lower alkyl, V 'and W' may be the same or different, and -CH = or- N = group.

In the application specification of the present invention, various heterocyclic moieties including the general formulas (D-1), (D-2), etc. are represented as substituents at the C-3 position, and these are substituted with hydrogen, lower alkyl, amino groups, and the like. Although there is a general description that it may be, but there is only an example of a pyrimidinium thiomethyl group substituted with an alkyl group, as in the above-described known techniques, specific reference to a pyrimidinium thiomethyl group having one or more amino groups at a specific position And no substitution at the 7β-position is completely distinct from that of the compounds according to the invention.

Accordingly, the present inventors have conducted much research on cephalosporin antibiotics having stronger antimicrobial activity and broad antimicrobial spectrum, and have the following general formulas having various 4,6-diamino pyrimidinium residues at the C-3 position. Has succeeded in developing cephalosporin compounds, and has already obtained a number of patents, including Korean Patent Nos. 47528, 47754, 47755 and 47756.

Wherein R ₁₄ is C _1-4 alkyl, C _3-4 alkenyl, C _3-4 alkynyl or C (R ^A ) (R ^B ) COOH, R ₁₅ is C _1-4 alkyl, C _{3- A 4} alkenyl, a C _3-4 cycloalkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted phenyl group, R ₁₆ represents hydrogen or an alkyl group of C _1-4 , and Q is CH or N.

However, in the specification of the known patent by the present inventors, the compound of the general formula (I) according to the present invention is excluded because the connection position of the pyrimidinium group is completely different.

In addition, the present inventors filed with the Republic of Korea Patent Application No. 91-6494 dated April 23, 1991 for the Sepem compound of the general formula (E), currently pending.

Wherein R ₁₇ and R ₁₈ are the same as defined for substituents R ¹ and R ² of the compounds according to the invention; Q represents N or CH.

However, the substituent at the C-3 position of the compound (e) is limited to the 3-substituted-2,6-diaminopyrimidinium ring, and according to the present invention, the 2,3-disubstituted-6-aminopyrimidinium ring There is a difference from the compound of the general formula (I) having

Accordingly, the present invention provides a strong antimicrobial activity against a wide range of pathogens of the compound of the general formula (I) having introduced a (2,3-disubstituted-6-aminopyrimidin-4-yl) thiomethyl group at the C-3 position of the cefe ring. The present invention has been completed by discovering the fact that.

Accordingly, an object of the present invention is to provide a novel cephalosporin compound of the general formula (I) wherein a thiomethyl group is introduced at the C-3 position (2,3-disubstituted-6-aminopyrimidin-4-yl) thiomethyl group of the cefe ring; To provide pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates and solvates and isomers thereof.

Wherein R ¹ represents hydrogen, a C _1-4 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group or —C (R ^a ) (R ^b ) COOH, wherein R ^a and R ^b are the same Or different and each represent hydrogen or a C _1-4 alkyl group, or together with the carbon atom to which they are attached form a C _3-7 cycloalkyl group, R ² represents a C _1-4 alkyl group, and R ³ is Hydrogen or a methyl group is represented.

In the general formula (I), the C _1-4 alkyl groups of R ¹ and R ² are preferably methyl and ethyl groups, alkenyl groups are preferably allyl groups, and alkynyl groups are preferably propargyl groups.

Compounds of formula (I) according to the invention are geometric isomers, including mixtures of syn and anti-isomers, and hydrates and solvates of compounds of formula (I) are also included in the scope of the invention.

In addition, since the aminothiazole group in the compound of general formula (I) can form a tautomer with an iminothiazoline group, such tautomers are also included in the scope of the present invention.

Pharmaceutically acceptable non-toxic salts of the compounds of formula (I) are salts with inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, hydroxyl, succinic acid, benzoic acid Salts with organic carboxylic acids such as tartaric acid, fumaric acid, manderic acid, ascorbic acid, dried acid or sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid, and other acids known and used in the art of penicillin and cephalosporin Contains salts. These acid addition salts are prepared by conventional techniques. Alternatively, the compound of formula (I) may form a nontoxic salt with a base depending on the R ¹ group. In this case, inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. calcium hydroxide), sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, etc. Organic bases such as bases and amino acids are included.

Examples of physiologically hydrolyzable esters of the compounds of formula (I) include indanyl, phthalidyl, methoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycosyloxymethyl, 5-methyl-2 Oxo-1,3-dioxoren-4-yl methyl ester and other physiologically hydrolysable esters known and used in the art of penicillin and cephalosporin. Such esters can be produced by known methods.

According to the present invention, the compound of formula (I), a pharmaceutically acceptable non-toxic salt thereof, a physiologically hydrolyzable ester, hydrate or solvate thereof may be prepared by the following compound of formula (II) in the presence of a solvent: By reacting with a compound of III), if necessary before or after the reaction, by removing the aminoprotecting or acid protecting groups or by reducing the S-oxide [S → (O) n].

Wherein R ¹ , R ² and R ³ are as defined above and R ⁴ is hydrogen or an amino protecting group; R ⁵ is hydrogen or a carboxyl protecting group; R ⁶ is hydrogen, a C _1-4 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group, or a —C (R ^a ) (R ^b ) CO ₂ (R ^c ) group wherein R ^a and R ^b are May be the same or different and each represent hydrogen or a C _1-4 alkyl group, or represent a C _3-7 cycloalkyl group together with the carbon atom to which they are attached, and R ^c is hydrogen or a carboxyl protecting group; L is a leaving group; n is 0 or 1;

Wherein the aminoprotecting group R ⁴ is acyl, substituted or unsubstituted ar (lower) alkyl (eg benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, etc.), halo (lower) alkyl (eg trichloro) Romethyl, trichloroethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloidene and the like. Acyls suitable as aminoprotecting groups may be aliphatic and aromatic acyl groups or acyl groups having a heterocycle. Examples of such acyl groups include C _1-6 lower alkanoyl (eg formyl, acetyl, etc.), C _2-6 alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, etc.), lower alkanesul Phenyl (for example, methanesulfonyl, ethanesulfonyl etc.) or ar (lower) alkoxycarbonyl (for example, 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 the silane, boron, phosphorus compound and amino group can be an amino protecting group.

The carboxyl protecting group R ⁵ 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) alkoxy (lower) alkyl esters (e.g., methoxymethyl esters, etc.), (lower) alkylthio (lower) alkyl esters (e.g., methylthiomethyl esters, etc.), halo (lower) Alkyl esters (e.g., 2,2,2-trichloroethyl ester, etc.), substituted or unsubstituted aralkyl esters (e.g., benzyl esters, P-nitrobenzyl esters, esters of P-methoxybenzyl, etc.) or silyl esters Etc.

The amino protecting group and 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 or carboxyl protecting group can be appropriately selected and used according to the chemical properties of the compound of general formula (I).

The leaving group L is, for example, arenesulfonyls such as halogens such as chlorine and fluorine, (lower) alkanoyloxy such as acetoxy, and methanesulfonyloxy such as methanesulfonyloxy, and paratoluenesulfonyloxy. Oxy or alkoxycarbonyloxy.

The meaning represented by the dotted line in the structure of the compound of formula (III) 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).

Wherein n, R ⁴ , R ⁵ , R ⁶ and L are as described above.

The compound of general formula (II) which is a starting material of the present invention can be prepared according to the following reaction scheme as a known compound. That is, it can be prepared by activating a compound of formula (IV) or a salt thereof with an acylating agent and reacting with a compound of formula (V).

In the above scheme, n, R ⁴ , R ⁵ , R ⁶ and L are as described above, and the meaning represented by the dotted line in the compound of the general formula (V) means that the compound of the general formula (V) is the following general formula ( Each of Va) or a compound of formula (Vb) or a mixture of a compound of formula (Va) and a compound of formula (Vb).

Wherein n, R ⁵ and L are as described above.

In preparing the compounds of formula (II), the active acylated derivatives of formula (IV) are acid chlorides, acid anhydrides, mixed acid anhydrides (preferably methylchloroformate, mesitylenesulfonyl chloride, P-toluene Acid anhydrides formed with sulfonyl chloride or chlorophosphate) or activated esters (preferably those formed in the reaction with N-hydroxybenzotriazole 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 an organic base such as tertiary amine (preferably triethylamine), diethyl aniline, pyridine and the like, and an inorganic base of sodium bicarbonate, sodium carbonate, and the solvent used is methylene chloride and chloroform. Solvents such as halogenated carbon, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, and the like. Also mixed solvents of the above solvents can be used and can be used as an aqueous solution.

The temperature of the acylation reaction is about -50 ° C to 50 ° C (preferably -30 ° C to 20 ° C), and the acylating agent of the compound of formula (IV) is equivalent to or slightly excess ( 1.05 to 1.2 equivalents).

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 cephalosporins. 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 trifluoroacetic acid, P-toluenesulfonic acid or hydrochloric acid.

The compound of formula (III) used in the present invention is a novel substance and its preparation method is described in detail in the preparation examples below.

On the other hand, in the present invention, the compound of the general formula (III) is substituted in the C-3 position of the compound of the general formula (II) in the preparation of the compound of the general formula (I), the solvent is dimethylformamide, dimethyl sulfoxide, Polar solvents such as dimethyl acetamide and the like can be used. The reaction temperature is in the range of 10 ° C. to 80 ° C. (preferably 20 to 40 ° C.), and the compound of formula (III) is 0.5 to 2 equivalents, preferably 0.9 to 2, based on the compound of formula (II). 1.1 equivalents may be used. In addition, salts such as sodium or potassium iodide, bromo sodium or potassium, or potassium thiocyanate may be used to stabilize the reaction intermediates and products.

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 mentioned above, the compounds of formula (I) exhibit a broad spectrum of antimicrobial spectrum and more potent antimicrobial activity against pathogens including various Gram-positive and Gram-negative bacteria, and this activity also affects 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 incorporated into unit dose forms or in multidose containers. The formulation form may be in the form of a solution, suspension or emulsion of 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 may be administered in combination with other antibacterial agents such as penicillin or cephalosporin.

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 boom of the compound of formula (I). The dosage of the compound of general formula (I) is according to the doctor's prescription depending on factors such as the patient's weight, age and the specific nature and severity of the disease. However, dosages required for adult treatment typically range from about 500 to 5,000 mg per day, depending on the frequency and route of administration. A total dosage of about 150 to 3,000 mg per day, usually separated by a single dose for intramuscular or intravenous administration to adults, will be sufficient, but a higher daily diathermy may be desirable for some strains of infection.

Compounds of general formula (I) according to the invention and their nontoxic names (preferably salts with alkali metal salts, alkaline earth metal salts, inorganic acid salts, organic acid salts and amino acids) are a wide variety of pathogenic bacteria, including various Gram-positive and Gram-negative bacteria. Because of its potent antimicrobial activity, it is very useful for the prevention and treatment of vaginal disease caused by bacterial infection in animals including humans.

Examples of major compounds according to the invention are shown in Table 1 below.

The following preparations and examples are intended to further illustrate the invention and do not limit the invention.

[Production Example 1]

Synthesis of 6-amino-3-methylpyrimidine-4-thione

A) Synthesis of 4-amino-6-hydroxy pyrimidine

To a solution of 14.3 g of 4-amino-6-hydroxy-2-mercaptopyrimidine suspended in 200 ml of distilled water, 30 g of Raney nickel was added and heated to reflux for 6 to 10 hours. After cooling the reaction solution to 50-60 ° C., the Ranickel is filtered, the filtrate is concentrated under reduced pressure and left at 0-5 ° C. for 1 hour. The resulting solid was filtered, washed with 10 ml of distilled water and dried under reduced pressure to give 10.3 g of the title compound as a white solid.

B) Synthesis of 4-amino-6-chloropyrimidine

10.1 g of the solid obtained in 1) was added to a mixed solution of 50 ml of phosphorus oxychloride and 10 ml of N, N-dimethylaniline, heated to reflux for 3 hours, and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, added to 100 ml of cold ice water, and the aqueous layer from which N, N-dimethylaniline was removed was neutralized with ammonia water and extracted with 200 ml of ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and the organic solvent is removed under reduced pressure to give 6.3 g of the title compound as a yellow solid.

C) Synthesis of 6-amino-3-methylpyrimidine-4-thione

15 g of methyl iodide was added to a solution of 6.1 g of the solid obtained in b) in 100 ml of tetrahydrofuran, heated to reflux for 10 hours, and cooled to room temperature. The resulting solid was filtered, washed with 20 ml of tetrahydrofuran and To dry. The dried solid is suspended in 50 ml of methyl alcohol and the reaction solution to which 3 g of 70% sodium sulfide is added is heated to reflux until no bubbles are generated. The reaction solution is cooled to 0 ° C. and the resulting solid is filtered, washed and dried with 20 ml of distilled water and 20 ml of acetone to give 4.3 g of the title compound as an off white solid.

[Production Example 2]

Synthesis of 6-amino-3-ethylpyrimidine-4-thione

The solid obtained in b) of Preparation Example 1 was subjected to analogous method of Preparation 1) using ethyl iodide to obtain the title compound as a white solid.

[Manufacture example 3]

Synthesis of 6-amino-2,3-dimethylpyrimidine-4-thione

A) Synthesis of 4,6-dihydroxy-2-methylpyrimidine

6.9 g of metallic sodium was added to 100 ml of ethyl alcohol and heated to reflux until a clear solution was added. 16 g of diethyl malonate and 7.95 g of acetamidine hydrochloride were further heated to reflux for 10 hours, and then cooled to room temperature. Filter the solids. The filtered solid was dissolved in 50 ml of distilled water, neutralized with concentrated hydrochloric acid, and the resulting solid was filtered, washed with 20 ml of acetone, and dried under reduced pressure to obtain 10.5 g of the title compound as a white solid.

B) Synthesis of 4-amino-6-chloro-2-methylpyrimidine

10 g of the solid obtained in a) was suspended in 50 ml of phosphorus oxychloride by heating to reflux for 3 hours, and the reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrated residue was added to 100 ml of cold ice water, neutralized with ammonia water, and the solution was extracted with 200 ml of ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and the organic solvent is removed under reduced pressure to give a yellow solid. The solid obtained is added to a mixed solution of 100 ml of ethyl alcohol and 100 ml of ammonia water and heated to reflux for 5 hours. The reaction solution is cooled to room temperature, ethyl alcohol is removed under reduced pressure, the resulting solid is filtered, washed with 20 ml of ethyl ether and dried under reduced pressure to give 7.8 g of the title compound as a white solid.

C) Synthesis of 6-amino-2,3-dimethylpyrimidine-4-thione

7.5 g of the solid obtained in b) was added to 15 g of methyl iodide in a solution of 100 ml of tetrahydrofuran, heated to reflux for 10 hours, cooled to room temperature, the resulting solid was filtered, washed with 20 ml of tetrahydrofuran and To dry. The dried solid is suspended in 50 ml of methyl alcohol and the reaction solution added with 3 g of 70% sodium hydrogen sulfide is heated to reflux until no bubbles are generated. The reaction solution is cooled to 0 ° C. and the resulting solid is filtered, washed with 2 ml of distilled water and 20 ml of acetone and dried to give 5.1 g of the title compound as a pale yellow solid.

m, p: decomposition above 213 ℃

[Production Example 4]

Synthesis of 6-amino-3-ethyl-2-methylpyrimidine-4-thione

The solid obtained in b) of Preparation Example 3 was subjected to analogous method of Preparation 3) using ethyl iodide to obtain the title compound as a pale yellow solid.

m, p: decomposition above 210 ℃

Example 1

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (6-amino-3-methyl Synthesis of Pyrimidinium-4-yl) thiomethyl-3-cepem-4-carboxylate

Paramethoxybenzyl 3-chloromethyl-7- (Z) -2 (2-tert-butoxy carbonylprop-2-oxyimino) -2- [2- (triphenylmethyl) aminothiazole-4 Dissolve 1 g of acetamino-3-cefe-4-carboxylate in 10 ml of dimethylsulfoxide, add 200 g of 6-amino-3-methylpyrimidine-4-thione obtained in Preparation 1, and then at room temperature for 2 hours. Was stirred. 50 ml of diethyl ether was added to the reaction solution, followed by vigorous stirring. 15 ml of dichloromethane was dissolved in the residue from which diethyl ether was removed, and 100 ml of ethyl ether was slowly added dropwise thereto. The resulting solid was filtered, washed with 5 ml of ethyl ether and dried.

The dried solid was added to a mixed solution of 6 mL of trifluoroacetic acid and 3 mL of anisole cooled to -30 ° C, the reaction solution was allowed to warm to room temperature, stirred for 1 hour, and the reaction solution was cooled to -50 ° C. 5 ml of methyl ether was added dropwise for 10 minutes. The resulting solid was filtered, washed with 20 ml of ethyl ether and dried, and then separated and purified using preparative liquid chromatography (μ-Bondapak C18 steel column: 19 mm x 30 cm) using 10% aqueous methanol solution as eluent. 310 mg of the title compound was obtained.

EXAMPLES 2-4

Paramethoxybenzyl 3-chloromethyl-7- (Z) -2 (2-tert-butoxycarbonylprop-2-oxyimino) -2- [2- (triphenylmethyl) aminothiazole-4 Compounds were obtained in the same manner as in Example 1 using -yl] acetamino-3-cepem-4-carboxylate and thion synthesized in Preparation Examples 2, 3 and 4.

7- (Z) -2 (2-aminothiazol-4-yl) -4- [2-carboxyprop-2-oxyimino) acetamido] -3- (6-amino-3-ethylpyrimidy Nium-4-yl) thiomethyl-3-cepem-4-carboxylate

7-[(Z) -2 (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (6-amino-2,3- Dimethylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate

7-[(Z) -2 (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamido] -3- (6-amino-3-ethyl- 2-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate

Example 5

7- (Z) -2 (2-aminothiazol-4-yl) -2- (1-carboxyprop-1-oxyimino) acetamido] -3- (6-amino-3-methylpyrimidy Nium-4-yl) thiomethyl-3-cepem-4-carboxylate synthesis

Paramethoxybenzyl 3-chloromethyl-7-{(Z) -2 (l-tert-butoxycarbonyleth-1-oxyimino) -2- [2- (triphenylmethyl) aminothiazole-4 -Yl] acetamido} -3-cepem-4-carboxylate 1g was dissolved in 10ml of dimethyl sulfoxide and 200mg of 6-amino-3-methylpyrimidin-4-thione obtained in Preparation Example 1 was added thereto at room temperature. Stir for 2 hours.

50 ml of diethyl ether was added to the reaction solution, followed by vigorous stirring. 15 ml of dichloromethane was dissolved in the residue from which diethyl ether was removed, and then 100 ml of ethyl ether was slowly added dropwise. The resulting solid was filtered, washed with 50 ml of ethyl ether and dried. The dried solid was added to a mixed solution of 6 ml of trifluoroacetic acid and 30 ml of anisole cooled to -30 ° C., the temperature was raised to room temperature, stirred for 1 hour, and the reaction solution was cooled to -50 ° C. 50 ml of ethyl ether was added dropwise for 10 minutes. The resulting solid was filtered, washed with 20 ml of ethyl ether and dried, and then purified by preparative liquid chromatography (μ-Bondapak C18 Stell column: 19 mm x 30 cm) using 50% methanol solution as eluent to obtain a white solid. 290 mg of the title compound was obtained.

Example 6

7-[(Z) -2 (2-aminothiazol-4-yl) -2- (1-carboxyprop-1-oxyimino) acetamido] -3- (6-amino-2,3- Dimethylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate synthesis

Paramethoxybenzyl 3-chloromethyl-7- (Z) -2- (l-tert-butoxy carbonyleth-1-oxyimino) -2- [2- (triphenylmethyl) aminothiazole-4 -Il] acetamido-3-cepem-4-carboxylate and thion synthesized in Preparation Example 3 were run in the same manner as in Example 5 to obtain the title compound.

Example 7

7-[(Z) -2 (2-aminothiazol-4-yl) -2- (1-carboxymeth-1-oxyimino) acetamido] -3- (6-amino-3-methylpyrimidy Nium-4-yl) thiomethyl-3-cepem-4-carboxylate synthesis

Paramethoxybenzyl 3-chloromethyl-7- (Z) -2- (l-tert-butoxy carbonyleth-1-oxyimino) -2- [2- (triphenylmethyl) aminothiazole-4 Dissolve 1 g of acetamido-3-cepem-4-carboxylate in 10 ml of dimethyl sulfoxide and add 200 mg of 6-amino-3-methylpyrimidine-4-thione obtained in Preparation 1 to 2 at room temperature. Stir for hours.

50 ml of diethyl ether was added to the reaction solution, followed by vigorous stirring. 15 ml of dichloromethane was dissolved in the residue from which diethyl ether was removed, and 100 ml of ethyl ether was slowly added dropwise thereto. The resulting solid was filtered, washed with 50 ml of ethyl ether and dried. The dried solid was added to a mixed solution of 6 ml of trifluoroacetic acid and 3 ml of anisole cooled to -30 ° C., the temperature was raised to room temperature, stirred for 1 hour, and the reaction solution was cooled to -50 ° C. 50 ml of methyl ether was added dropwise for 10 minutes. The resulting solid was filtered, washed with 20 ml of ethyl ether and dried, and then separated and purified using preparative liquid chromatography (μ-Bondapak c18 Steel column: 19 mm x 30 cm) using 5% aqueous methanol solution as eluent. 310 mg of the title compound was obtained.

Example 8

7-[(Z) -2 (2-aminothiazol-4-yl) -2- (1-carboxycyclopent-1-oxyimino) acetamido] -3- (6-amino-3-methylpyri Midinium-4-yl) thiomethyl-3-cepem-4-carboxylate synthesis

Paramethoxybenzyl 3-chloromethyl-7- (Z) -2- (1-diphenylmethoxycarbonyl) cyclopent-1-oxyimino) -2- [2- (triphenylmethyl) aminothiazole- Dissolve 1 g of 4-yl] acetamido-3-cepem-4-carboxylate in 10 ml of dimethyl sulfoxide and add 200 mg of 6-amino-3-methylpyrimidine-4-thione obtained in Preparation 1 at room temperature. Stir for 2 hours.

50 ml of diethyl ether was added to the reaction solution, followed by vigorous stirring. 15 ml of dichloromethane was dissolved in the residue from which diethyl ether was removed, and 100 ml of ethyl ether was slowly added dropwise thereto. The resulting solid was filtered off, washed with 50 ml of ethyl ether and dried. The dried solid was added to a mixed solution of 6 ml of trifluoro acetic acid and 3 ml of anisole cooled to -30 ° C., the temperature was raised to room temperature, stirred for 1 hour, and the reaction solution was cooled to -50 ° C. 50 ml of methyl ether was added dropwise for 10 minutes. The resulting solid was filtered, washed with 20 ml of ethyl ether and dried, and then purified by preparative liquid chromatography (μ-Bondapak C18 Steel column: 19mm x 30cm) with 10% aqueous methanol solution as eluent. 25 mg of the title compound was obtained.

Example 9

7-[(Z) -2 (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (6-amino-3-methylpyrimidin-4-yl) Thiomethyl-3-cepem-4-carboxylate Synthesis

Paramethoxybenzyl 3-chloromethyl-7- (Z) -2- (1-diphenylmethoxycarbonyl) cyclopent-1-oxyimino) -2- [2- (triphenylmethyl) aminothiazole- Dissolve 1 g of 4-yl] acetamido-3-cepem-4-carboxylate in 10 ml of dimethyl sulfoxide, add 200 mg of 6-amino-3-methylpyrimidine-4-thione obtained in Preparation Example 1, and then at room temperature. Stir for 2 hours. 50 ml of diethyl ether was added to the reaction solution, followed by vigorous stirring. 15 ml of dichloromethane was dissolved in the residue from which diethyl ether was removed, and 100 ml of ethyl ether was slowly added dropwise thereto. The resulting solid was filtered, washed with 50 ml of ethyl ether and dried. The dried solid was added to a mixed solution of 6 mL of trifluoro acetic acid and 3 mL of anisole cooled to -30 ° C, the reaction solution was allowed to warm to room temperature, stirred for 1 hour, and the reaction solution was cooled to -50 ° C. Add 50 ml of methyl ether dropwise for 10 minutes. The resulting solid was filtered, washed and dried with 20 ml of ethyl ether, and purified by preparative liquid chromatography (μ-Bondapak C18 Steel column: 19 mm x 30 cm) using 25% aqueous methanol solution as eluent. 330 mg of the title compound was obtained.

Example 10

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (6-amino-2,3-methylpyrimidin-4 -Yl) thiomethyl-3-cepem-4-carboxylate synthesis

Paramethoxybenzyl 3-chloromethyl-7-{(Z) -2- (methoxyimino) -2- [2- (triphenylmethyl) aminothiazol-4-yl] acetamido} -3-cepem The title compound was obtained in the same manner as in Example 9 using -4-carboxylate and thion synthesized in Preparation Example 3.

[Antibacterial Test]

Using the known compound Ceftazidme as a control agent for the usefulness of the compounds according to the present invention, the minimum inhibitory concentration (Minimum Inhibitory concentration) for the standard strain was determined and evaluated.

The minimum inhibitory concentration was obtained by diluting the test compound by a 2-fold dilution method, and then dispersing it in Muller-Hinton agar medium, inoculating 2 μl of a standard test strain having 10 CFU / ml and then 20 ° C. at 37 ° C. Obtained by time incubation, the results are shown in Table 2.

Claims (2)

Cephalosporin compounds represented by the following general formula (I), pharmaceutically acceptable non-toxic salts thereof, physiological hydrolysable esters, hydrates and solvates and isomers thereof. Wherein R ¹ represents hydrogen, a C _1-4 alkyl group, a C _2-4 alkenyl group, a C _2-4 alkynyl group or —C (R ^a ) (R ^b ) COOH, and R ^a and R ^b are the same or May be different and each represent hydrogen or a C _1-4 alkyl group, or together with the carbon atoms to which they are attached form a C _3-7 cycloalkyl group, R ² represents a C _1-4 alkyl group, and R ³ represents hydrogen Or a methyl group. The compound of claim 1, wherein R ¹ is a —C (R ^a ) (R ^b ) COOH group, wherein R ^a and R ^b are each independently hydrogen, methyl or ethyl, or cyclobutyl together with the carbon atom to which they are attached , A cyclopentyl or cyclohexyl group is formed.