KR0177900B1 - New cephalosporin antibiotics - Google Patents

Abstract

The present invention has a (Z) -2- (2-aminothiazol-4-yl) -2- (α-carboxy-3,4-substituted benzyloxyimino) acetamide group at the 7-β position and a C- A compound in which an ethene group substituted by a heterocyclic ring is introduced at position 3, a cephalosporin-based compound of formula (I) having strong microbial activity, broad antibacterial spectrum, and improved pharmacokinetic properties, and a pharmaceutically acceptable nontoxicity thereof Salts, physiologically hydrolysable esters, solvates, isomers thereof, and antimicrobial compositions containing them as active ingredients.

Wherein Q represents CH or N, R ₁ represents hydrogen or an aminoprotecting group, R ₂ and R ₃ are the same or different and each independently represents a hydrogen or hydroxy protecting group, or R ₂ and R ₃ are Together can form a cyclic diol protecting group, R ₄ and R ₅ represent hydrogen or a carboxyl protecting group, R ₆ represents a heterocyclic compound of the following general formula,

Wherein R ₇ and R ₈ each independently represent hydrogen, substituted or unsubstituted amino, hydroxy, alkoxy, C ₁ -C ₄ alkyl, carboxyl, alkoxycarbonyl or halogen and R ₉ is C ₁ -C ₄ Alkyl, C ₃ -C ₄ alkenyl, carboxymethyl or amino.

Description

New cephalosporin antibiotics

The present invention is a novel cephalosporin-based compound useful as an antibiotic, more specifically (Z) -2- (2-aminothiazol-4-yl) -2- (α-carboxy-3,4- at the 7-β position A compound having a substituted benzyloxyimino) acetamide group and a ethene group substituted by a heterocyclic ring at the C-3 position, having strong microbial activity, broad antibacterial spectrum, and improved pharmacokinetic properties, The present invention relates to cephalosporin-based compounds, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, solvates, isomers thereof, and antimicrobial compositions containing them as active ingredients.

In the above formula,

Q represents CH or N,

R ₁ represents hydrogen or an aminoprotecting group,

R ₂ and R ₃ are the same or different and each independently represent a hydrogen or hydroxy protecting group, or R ₂ and R ₃ together may form a cyclic diol protecting group,

R ₄ and R ₅ represent hydrogen or a carboxyl protecting group,

R ₆ represents a heterocyclic compound of the following general formula,

here,

R ₇ and R ₈ each independently represent hydrogen, substituted or unsubstituted amino, hydroxy, alkoxy, C ₁ -C ₄ alkyl, carboxyl, alkoxycarbonyl or halogen,

R ₉ represents a C ₁ -C ₄ alkyl, C3-C ₄ alkenyl, carboxy-methyl or amino.

Cephalosporin antibiotics are widely used to treat diseases of pathogenic bacteria in humans and animals, and in particular, to treat diseases caused by bacteria that are resistant to other antibiotics such as penicillin and to treat penicillin-sensitive patients. In most cases, it is desirable to use antibiotics that are active against both Gram-positive and Gram-negative microorganisms. The antimicrobial activity of these cephalosporin-based antibiotics is greatly affected by substituents at the 3 or 7 position of the cefe ring. It is true of the base. Therefore, it has shown high antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria, and is very stable against β-lactamase produced by various Gram-negative bacteria and has been tried to find antibiotics that are very stable in vivo. Numerous cephalosporin antibiotics have been developed with various substituents introduced at the 3-position of the β-acylamido group and the cefe ring.

For example, in British Patent No. 1,399,086, cephalosporin derivatives represented by the following general formula (A) are described broadly and collectively.

In the above formula,

R ₁₀ is hydrogen or an organic group,

R ₁₁ is an etherified monovalent organic group that is linked to oxygen through carbon,

B is -S- or S-O,

P is an organic group.

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

In the above formula,

R ₁₂ is a furyl or thienyl group,

R ₁₃ is a C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, furylmethyl or thienylmethyl group,

R ₁₄ is hydrogen or carbamoyl, carboxymethyl, sulfonyl or methyl group.

Since then, many attempts have been made to develop antibiotics of a broad spectrum of antimicrobial spectrum that show enhanced antimicrobial activity in gram-positive bacteria as well as gram-negative bacteria. As a result, acylamido groups are introduced at the Cempec nucleus 7-position of general formula (B) and C- Various changes, such as the introduction of specific groups at the 3 position, have led to the development of many cephalosporin antibiotics with structures similar to those of the general formula (B).

For example, Belgian Kingdom Patent No. 852,427 discloses that in the compound of general formula (A), the R ₁₀ substituent is substituted with various other organic compounds including 2-aminothiazol-4-yl and the oxygen atom of the oxyamino group is an aliphatic hydrocarbon. A cephalosporin-based antibiotic compound is described, in which the aliphatic hydrocarbon group itself is substituted with a carboxyl group, wherein the substituent at the C-3 position is acyloxymethyl, hydroxymethyl, formyl or optionally Substituted heterocyclic thiomethyl group; and the like. However, the compounds described in the above patents are, of course, completely distinguished from the compounds of the present invention and their structures.

Recently, many efforts have been made to develop compounds having strong antibacterial activity against a wide range of pathogens as well as some Gram-negative bacteria producing β-lactamase. Substituents, in particular, R ₁₁ of the general formula (A) compound in which R ₁₀ is 2-aminothiazol-4-yl, may be introduced into various heterocyclic groups such as aryl or alkylsulfonylacyl, aryl, aralkyl, etc. Many attempts have been made. As a result of these efforts, it has been found that the cefem compounds in which R ₁₁ is an α-carboxy-3,4-substituted benzyl group show strong activity against a wide range of pathogens. / 00140 and European Patent Application 87308525,2.

That is, PCT / JP86 / 00140 describes cefem compounds of the following general formula (C).

In the above formula,

R ₁₅ is hydrogen or an aminoprotecting group,

E and G represent hydrogen, methyl, carboxyl groups, protected carboxyl or oxygen atoms,

L and M represent hydrogen or oxygen atom,

R ₁₆ is hydrogen or a carboxyl protecting group,

a, b, c are integers of 0 or 1,

X is hydrogen or hydroxyl or

It is defined as.

In this patent, (Z) -2- (2-aminothiazol-4-yl) -2- (α-carboxy-3,4-substituted benzyloxyamino) acetate described in the invention at the 7-β position Although extensively described to include an amide group, -CH ₂ Y describing the C-3 position is a hetero atom (S or N) in Y connected to the C-3 position of the cefe nucleus through a methylene group. It is different from the structure connected through the ethene group as in the invention.

European Patent Application No. 87308525,2 also describes cefem compounds of the following general formula (D).

In the above formula,

R ₂₁ represents hydrogen or an aminoprotecting group,

R ₂₂ and R ₂₃ hydroxy or substituted hydroxy groups or R ₂₂ and R ₂₃ together represent a diol group cyclically protected,

R ₂₄ and R ₂₅ represent hydrogen or a carboxyl protecting group,

R ₂₆ represents hydrogen or a C ₁ -C ₄ alkyl group substituted by 1 to 3 halogen atoms,

Z is S or S-O and the dashed line represents a 2-cefem or 3-cefem compound.

However, in the above European patent, the substituent introduced at the C-3 position is different from the C-3 substituent of the present invention.

In addition, WO 94/10177 describes cefem compounds of the general formula (E).

In the above formula,

R ₂₇ is an amino or protected amino group,

R ₂₈ is hydrogen, a hydroxyprotecting group or lower alkyl, lower alkyl substituted by 1 to 3 halogen atoms,

R ₂₉ represents a carboxyl or protected carboxyl group

R ₃₀ represents an optionally substituted pyridyl vinyl group.

In the above patent, a pyridyl vinyl group, which is one of the 2-ene ring substituted ethene groups introduced in the present invention at the C-3 position, is introduced, but the (Z) -2- ( There is no mention or suggestion that it may include a 2-aminothiazol-4-yl) -2- (α-carboxy-3,4-substituted benzyloxyimino) acetamide group.

On the other hand, the present inventors have made many attempts to achieve a desired purpose by introducing a new specific group at the C-7 position, and as a result (Z) -2- (2-aminothiazol-4-yl at the C-7 position It has been found that cefem compounds incorporating) -2- (α-carboxy-3,4-substituted benzyloxyimino) acetamide groups show excellent antimicrobial activity against various pathogens. No. 93-18319, 93-18320, 93-18321.

Based on the prior art as described above, the present inventors have shown a cephalosporin compound that exhibits strong antibacterial activity against a wide range of pathogens, including Gram-negative bacteria producing β-lactamase, as well as further improved pharmacokinetic properties. Efforts have been made to develop, resulting in (Z) -2- (2-aminothiazol-4-yl) -2- (α-carboxy-3,4-substituted benzyloxyimino) acet at the 7-β position. The present invention has been accomplished by discovering that the cephalosporin compound having an amide group and introduced with an ethene group substituted by a heterocyclic ring at the C-3 position meets this purpose.

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

In the above formula,

Q represents CH or N.

R ₁ represents hydrogen or an aminoprotecting group,

R ₂ and R ₃ are the same or different and each independently represent a hydrogen or hydroxy protecting group, or R ₂ and R ₃ together may form a cyclic diol protecting group,

R ₄ and R ₅ represent hydrogen or a carboxyl protecting group,

R ₆ represents a heterocyclic compound of the following general group,

here,

R ₇ and R ₈ each independently represent hydrogen, substituted or unsubstituted amino, hydroxy, alkoxy, C ₁ -C ₄ alkyl, carboxyl, alkoxycarbonyl or halogen,

R ₉ represents a C ₁ -C ₄ alkyl, C3-C ₄ alkenyl, carboxy-methyl or amino.

A strong microbial activity, broad antibacterial spectrum and improved pharmacokinetic preferred compounds among the compounds of the formula (I) having the characteristics are R _1, R ₄ and R ₅ are hydrogen, R ₂ and R ₃ are each independently hydrogen or Acetyl, R ₇ and R ₈ are each independently hydrogen, halogen or methyl, and R ₉ is methyl;

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

In the compound of general formula (I) according to the present invention, since the carbon atom to which the 3,4-substituted phenyl group is attached is asymmetric, the compound of general formula (I) exists as diastereomer, and the present invention Isomers and mixtures thereof. In addition, the compounds of the general formula (I) include geometric isomers, including syn- and anti-isomers containing at least 90% of syn-isomers.

Since the aminothiazole of the compound of general formula (I) can form a tautomer with iminothiazoline, as can be seen by the following structural formula, such tautomers are included in the scope of the present invention.

Since aminothiadiazole when Q is N can also form a tautomer with iminothiadiazoline as follows, these tautomers are also included in the scope of the present invention.

In addition, since the following cis- and trans-isomers may exist depending on the geometry of the double bond in the ethene group which is part of the C-3 substituent, the present invention includes the respective geometric isomers and mixtures thereof, provided that the antimicrobial activity is From the standpoint the cis-isomer is more preferred.

In addition, solvates including pharmaceutically acceptable non-toxic salts of the general formula (I) compounds, physiologically hydrolysable esters, and hydrates are also included in the scope of the present invention.

Pharmaceutically acceptable non-toxic salts of the compounds of formula (I) according to the invention are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or the like or acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, oxalic acid, succinic acid , Organic carboxylic acids such as benzoic acid, tartaric acid, fumaric acid, manderic acid, ascorbic acid, dried acid or salts with sulfonic acids such as methanesulfonic acid, paratoluene sulfonic acid and penicillin and cephalosporin-based compounds Salts with other acids being used. These acid addition salts can be prepared by conventional conversion processes. Compounds of formula (I) may also form non-toxic salts with bases, which bases can be used include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium bicarbonate And inorganic bases such as potassium bicarbonate, potassium carbonate and calcium carbonate or organic bases such as amino acids.

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

In addition, the compounds of formula (I) according to the present invention, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, solvates including hydrates may optionally contain a compound of formula (II) as a solvent and It can be prepared by a method characterized by reacting with a compound of the general formula (III) in the presence of a base and, if necessary, removing the amino protecting group or acid protecting group before or after the reaction.

In the above formula,

R ₁ to R ₉ and Q are as defined above,

R ₃₁ represents lower alkyl or aryl.

The reaction of the compound of formula (II) and compound of formula (III) is water, alcohol (for example, methanol, ethanol, etc.), benzene, dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylenedichloride, chloroform , Solvents such as dioxane, diethyl ether, or a mixed solvent of water and other solvents, and may be performed at a wide range of temperatures from low to high temperatures.

Bases used in the reaction may include organic or inorganic bases, and examples thereof include alkali metal or alkaline earth metal hydroxides such as sodium and potassium (eg sodium hydroxide and potassium hydroxide) and alkali metal hydrogencarbonates (eg Sodium bicarbonate, potassium bicarbonate), alkali metal carbonates (e.g. sodium carbonate, calcium carbonate), tri (lower) alkylamines (e.g. trimethylamine, triethylamine, diisopropylethylamine), alkali metal hydrides (e.g. hydrogenation Sodium), alkali metal (lower) alkoxides (e.g. sodium methoxide sodium ethoxide), pyridine, picoline, dimethylaminopyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine And N, N-di (lower) alkylaniline. If the base and / or starting material are liquid, they can also act as solvents.

Wherein the aminoprotecting group R ₁ is acyl, substituted or unsubstituted ar (lower) alkyl (e.g. benzyl, dipanylmethyl, 4-methoxybenzyl, etc.), halo (lower) alkyl (e.g. trichloromethyl , Trichloroethyl and the like), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloidene and the like can be used. Here, acyl suitable as an aminoprotecting group may be an acyl group having an aliphatic, aromatic or heterocyclic ring, for example C ₁ -C ₅ lower alkanoyl (eg formyl, acetyl, etc.), C ₂ -C ₆ alkoxycarbonyl (E.g., methoxycarbonyl, ethoxycarbonyl, etc.), lower alkanesulfonyl (e.g. methylsulfonyl, ethylsulfonyl, etc.) or ar (lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.) Can be mentioned. The aforementioned acyl may be substituted by suitable groups such as 1 to 3 halogens, hydrogen, cyano, nitro and the like. In addition to those mentioned above, the reaction product of silanes, boron, phosphorus compounds and amino groups can also be aminoprotecting groups.

The carboxyl protecting groups R ₄ and R ₅ are suitable as long as they can be easily removed under ordinary mild conditions, and are (lower) alkyl esters (e.g. methyl ester, t-butyl ester, etc.), (lower) alkenyl esters ( Examples: vinyl esters, allyl esters, etc.), (lower) alkoxy (lower) alkyl esters (e.g. methylomethyl esters, etc.), halo (lower) alkyl esters (e.g. 2,2,2-trichloroethyl esters, etc.) Substituted or unsubstituted aralkyl esters (e.g., benzene esters, p-nitrobenzyl esters, p-methoxybenzyl esters, etc.) or silyl esters.

The hydroxy protecting groups R ₂ and R ₃ are acyl (e.g. formyl or COR ^a , where R ^a represents C ₁ -C ₈ alkyl, preferably methyl), alkoxycarbonyl (e.g. CO ₂ R ^a , where R ^a is C ₁ -C ₈ alkyl), silyl (eg C ₁ -C ₄ alkyl) silyl, in particular trimethylsilyl or (t-butyldimethylsilyl), boride (-B (OR ^b )) , Hosate (-P (O) (OR ^b ) ₂ , where R ^a is C ₁ -C ₄ alkyl), and the like, wherein R ₂ and R ₃ may be formed together as a cyclic diol protecting group. Is C ₁ -C ₇ alkylidenedioxy (eg methylenedioxy, ethylenedioxy or isopropylidenedioxy), alkylidenedioxy with one or more substituents (eg methoxymethylenedioxy, di Phenylmethylenedioxy or carbonyldioxy), cyclic borate (e.g. -OB (OH) O-), cyclic phosphate (e.g. -OP (O) (OH) O- or -OP (O) (OR ^b ) O-, where R ^b is as defined above or di (C ₁ -C ₄ alkyl) silyldioxy (eg dimethylalkyldioxy) and the like.

The amino protecting group, hydroxy protecting group, cyclic diol 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, hydroxy group or carboxyl group. I) Select appropriately according to chemical property of compound.

In preparing the compound of formula (I), the amino protecting group or the acid protecting group of the compound of formula (II) may be removed by conventional methods commonly known in the cephalosporin-based art. That is, the protecting group can be removed by a hydrolysis or reduction method, and in the case where an amido group is included as the protecting group, it is preferable to undergo hydrolysis through aminohalogenation and aminoetherization. Acid hydrolysis is useful for the removal of tri (di) phenylmethyl groups or alkoxycarbonyl groups and is carried out using organic acids such as formic acid, trifluoroacetic acid, p-toluenesulfonic acid or inorganic acids such as hydrochloric acid.

The synthesis method mentioned above will be described in more detail in the following Preparation Examples and Examples.

As mentioned above, the compounds of formula (I) according to the invention and their non-toxic salts (preferably with alkali metal salts, alkaline earth metal salts, salts of inorganic acid salts, organic acid salts and amino acids) are characterized by various gram positive and It has a broad spectrum of antimicrobial spectrum and stronger antimicrobial activity against pathogens containing gram-negative bacteria, and this activity is also applied to many gram-positive bacteria producing β-lactamase, which is used for the prevention of bacterial infection in animals including humans and for the treatment of diseases. This can be very useful.

Accordingly, the present invention aims to provide an antimicrobial composition containing the novel compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. The compound of formula (I) is for It may be formulated in a known manner using a carrier or excipient and incorporated into unit dose forms or multidose containers. Formulation forms may be in the form of solutions, suspensions or emulsions in oils or aqueous media, and may contain conventional dispersing agents, suspending agents or stabilizers. Or, for example, it may be in the form of a dry powder used by dissolving before use with sterile, pyrogen-free water. The compounds of formula (I) may also be formulated into suppositories using conventional suppository bases such as cocoa butter or glycerides, and may be administered in combination with other fungicides such as penicillin or cephalosporin as necessary.

Preferred pharmaceutical preparations are in unit dose form. In such form, the formulation preferably contains about 50 to 1500 mg of the active ingredient.

For the purpose of treating bacterial infections, the dosage of the compounds used in the pharmaceutical methods of the present invention may vary depending on factors such as the patient's weight, age, and the particular nature and severity of the disease, and according to the doctor's prescription . Generally, dosages in the range of about 500 to 5,000 mg per day are preferred, depending on the frequency and intensity of administration during adult treatment, and an overall dosage of about 150 to 3,000 mg per day is usually sufficient for intramuscular or intravenous administration to adults. Higher doses may be required for infection with some strains.

Hereinafter, the present invention will be described in more detail based on the following Examples. However, these examples are only intended to help the understanding of the present invention, the scope of the present invention in any sense is not limited to these examples.

[Production Example 1]

Paramethoxybenzyl, 7-[(Z) -2- (α-t-butoxycarbonyl-3,4-dihydroxybenzyloxyimino) -2- [2- (triphenylmethyl) aminothiazole- 4-yl] acetamino] -3- (triphenylphosphino) methyl-3-cepem-4-carboxylate

Paramethoxybenzyl, 7-[(Z) -2- (α-t-butoxycarbonyl-3,4-dihydroxybenzyloxyimino) -2- [2- (triphenylmethyl) aminothiazole- 20 g of 4-yl] acetamino] -3- (triphenylphosphino) methyl-3-cepem-4-carboxylate was dissolved in 100 ml of acetone, and 4 g of sodium iodide was added thereto, followed by stirring at room temperature for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dissolved in 300 ml of ethyl acetate and washed with 300 ml of distilled water and 300 ml of saturated brine, respectively. The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was dissolved in 200 ml of acetone and 7 g of triphenylphosphine were added, followed by stirring at room temperature for 3 hours. After the reaction was completed, 300 ml of diethyl ether was added dropwise to the reaction solution, and the resulting solid was filtered, washed with 200 ml of diethyl ether and dried to give 22 g of the title compound as a white powder.

[Production Example 2]

Synthesis of N-methyl-4-formyl-pyridinium iodide

15 g of 4-pyridine carboxaldehyde was dissolved in 100 ml of tetrahydfuran, and 50 g of methyl iodide was added thereto, followed by stirring for 4 hours while heating to reflux. After the reaction was completed, the solid formed during the reaction was filtered, washed with 200 ml of diethyl ether and dried to give 13 g of the title compound as a reddish brown solid.

Example 1

7-[(Z) -2- (α-carboxy-3,4-dihydroxybenzyloxyimino) -2- (2-aminothiazol-4-yl] acetamido] -3-[(Z) Synthesis of 2- (2-furyl) ethenyl] -3-cepem-4-carboxylate (I-IS and I-IR)

Paramethoxybenzyl synthesized in Preparation Example 1, 7-[(Z) -2- (α-t-butoxycarbonyl-3,4-dihydroxybenzyloxyimino) -2- [2- (triphenyl 1 g of methyl) aminothiazol-4-yl] acetamido] -3- (triphenylphosphino) methyl-3-cepem-4-carboxylate was dissolved in 5 ml of methylenedichloride, cooled to 0 ° C., and then 53 mg of sodium hydroxide dissolved in 2.5 ml of distilled water was added dropwise. After stirring for 1 hour while maintaining the temperature of the reaction mixture at 0 to 4 ℃ 10ml methylene dichloride and 5ml of distilled water was added to the reaction mixture and stirred well mixed. Sufficient organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. 50 ml of diethyl ether was added to the residue, followed by washing with stirring to obtain 700 mg of a royal blue solid. The obtained solid was dissolved in 20 ml of dimethylformamide, 180 mg of 2-furaldehyde was added thereto, and then the temperature was raised and stirred for 1 hour. After the reaction was completed, 100 ml of methylene dichloride and 100 ml of distilled water were added to the reaction mixture, and the mixture was mixed well. The organic layer was sufficiently washed with 100 ml of saturated brine, dried over magnesium sulfate and distilled under reduced pressure to obtain 500 mg of the title compound as a white solid.

Example 1 Paramethoxybenzyl obtained in step 1, 7-[(Z) -2- (α-t-butoxycarbonyl-3,4-dihydroxybenzyloxyimino) -2- [2- (Triphenylmethyl) aminothiazol-4-yl] acetamido] -3-[(Z) -2- (2-furyl) ethenyl] -3-cepem-4-carboxylate 500 mg of anisole 1 ml The solution was dissolved in, cooled to 0 ° C., 2 ml of trifluoroacetic acid was added dropwise, and then heated to room temperature and stirred for 40 minutes. After the reaction was completed, the reaction solution was cooled to -10 ° C again, and 10 ml of diethyl ether was added dropwise thereto, and the resulting solid was filtered and dried. The obtained solid was separated and purified by preparative liquid chromatography (μ-Bondapak C18 steel column, 19mm x 30mm) using 20% methanol as eluent to obtain 45 mg and 40 mg of the title compound S isomer and R isomer as white solid, respectively. It was.

Example 2

7-[(Z) -2- (α-carboxy-3,4-dihydroxybenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamino] -3-[(Z)- Synthesis of 2- (2-pyridyl) ethenyl] -3-cepem-4-carboxylate (I-2S and I-2R)

Paramethoxybenzyl, 7-[(Z) -2- (α-t-butoxycarbonyl-3,4-, similar to Step 1 of Example 1 using 2-thiophene carboxaldehyde Dihydroxybenzyloxyimino) -2- [2- (triphenylmethyl) aminothiazol-4-yl] acetamido] -3-[(Z) -2- (2-thiophenyl) ethenyl]- 550 mg of 3-cefem-4-carboxylate were obtained, and the same procedure as in Example 2 was carried out to give 55 mg and 45 mg of the title compound S isomer and R isomer as a white solid, respectively.

Example 3

7-[(Z) -2- (α-carboxy-3,4-dihydroxybenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3-[(Z) Synthesis of 2- (2-pyridyl) ethenyl] -3-cepem-4-carboxylate (I-3S and I-3R)

Paramethoxybenzyl, 7-[(Z) -2- (α-t-butoxycarbonyl-3,4-di, was carried out in analogy to Example 1 using 2-pyridine carboxaldehyde Hydroxybenzyloxyimino) -2- [2- (triphenylmethyl) aminothiazol-4-yl] acetamido] -3-[(Z) -2- (2-thiophenyl) ethenyl] -3 -550 mg of cefem-4-carboxylate were obtained, and were carried out in the same manner as in Step 2 of Example 1 to obtain 45 mg and 45 mg of the title compound S isomer and R isomer of the white solid, respectively.

Example 4

7-[(Z) -2- (α-carboxy-3,4-dihydroxybenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3-[(Z) Synthesis of 2- (N-methylpyridinium-4-yl) ethenyl] -3-cepem-4-carboxylate (I-4S and I-4R)

N-methyl-4-formyl-pyridinium iodide synthesized in Preparation Example 2 was carried out in the same manner as in Example 1, Step 1, paramethoxybenzyl, 7-[(Z) -2 -(α-t-butoxycarbonyl-3,4-dihydroxybenzyloxyimino) -2- [2- (triphenylmethyl) aminothiazol-4-yl] acetamido] -3-[( Z) -2- (N-methylpyridinium-4-yl) ethenyl] -3-cepem-4-carboxylate 550 mg was obtained, and was carried out in the same manner as in step 2 of Example 1, to obtain a white solid. 45 mg and 45 mg of the title compound S isomer and R isomer were obtained, respectively.

Example 5

7-[(Z) -2- (α-carboxy-3,4-dihydroxybenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamino] -3-[(Z)- Synthesis of 2- (2-pyrrolyl) ethenyl] -3-cepem-4-carboxylate (I-5S and I-5R)

Paramethoxybenzyl, 7-[(Z) -2- (α-t-butoxycarbonyl-3,4-, similar to step 1 of Example 1 using 2-pyrrole carboxyaldehyde Dihydroxybenzyloxyimino) -2- [2- (triphenylmethyl) aminothiazol-4-yl] acetamido] -3-[(Z) -2- (2-pyrroline) ethenyl]- 550 mg of 3-cefem-4-carboxylate were obtained, and the same procedure as in Example 2 below was carried out to obtain 45 mg and 45 mg of the title compound S isomer and R isomer of white solid, respectively.

Example 6

7-[(Z) -2- (α-carboxy-3,4-dihydroxybenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamino] -3-[(Z)- Synthesis of 2- (N-methylpyrrole-2-yl) ethenyl] -3-cepem-4-carboxylate (I-6S and I-6R)

Paramethoxybenzyl, 7-[(Z) -2- (α-t-butoxycarbonyl-3), similarly to step 1 of Example 1, using N-methylpyrrole-2-carboxylate , 4-dihydroxybenzyloxyimino) -2- [2- (triphenylmethyl) aminothiazol-4-yl] acetamido] -3-[(Z) -2- (N-methylpyrrole-2 550 mg of -yl) ethenyl] -3-cepem-4-carboxylate were obtained, followed by the same procedure as in Step 2 of Example 1, to obtain 45 mg and 45 mg of the title compound S isomer and R isomer of the white solid, respectively. It was.

Example 7

7-[(Z) -2- (α-carboxy-3,4-dihydroxybenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamino] -3-[(Z)- Synthesis of 2- (2-imidazoline) ethenyl] -3-cepem-4-carboxylate (I-7S and I-7R)

Using 2-imidazole carboxaldehyde similar to step 1 of Example 1, paramethoxybenzyl, 7-[(Z) -2- (α-t-butoxycarbonyl-3, 4-dihydroxybenzyloxyimino) -2- [2- (triphenylmethyl) aminothiazol-4-yl] acetamido] -3-[(Z) -2- (2-imidazoline) 550 mg of tenyl] -3-cepem-4-carboxylate was obtained, and the same procedure was followed as in the step 2 of Example 1, to obtain 45 mg and 45 mg of the title compound S isomer and R isomer, respectively, as a white solid.

Example 8

7-[(Z) -2- (α-carboxy-3,4-dihydroxybenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamino] -3-[(Z)- Synthesis of 2- (N-methylimidazol-2-yl) ethenyl] -3-cepem-4-carboxylate (I-8S and I-8R)

Paramethoxybenzyl, 7-[(Z) -2- (α-t-butoxycart), similar to step 1 of Example 1, using N-methylimidazole-2-carboxaldehyde Bonyl-3,4-dihydroxybenzyloxyimino) -2- [2- (triphenylmethyl) aminothiazol-4-yl] acetamido] -3-[(Z) -2- (2-thio 535 mg of phenyl) ethenyl] -3-cefe-4-carboxylate were obtained, and were carried out in the same manner as in Step 2 of Example 1 to obtain 45 mg and 45 mg of the title compound S isomer and R isomer of the white solid, respectively. .

Biological Example 1: In vitro Antimicrobial Activity Assay

The usefulness of the compound according to the present invention is a standard compound, a clinically isolated strain, a strain resistant to some antibiotics, and a strain producing beta lactamase, using the known compound ceftazidime as a control agent. Minimum Inhibitory Concentration (MIC, μg / ml) was obtained and evaluated. The minimum inhibitory concentration was obtained by diluting the test compound by a 2-fold dilution method, dispersing it in Mueller-Hinton agar medium, and inoculating 2 μl of the test strain having 10 ⁷ CFU (Colony Forming Unit) per ml. It was obtained by incubating for 20 hours at 37 ℃, the results are shown in Table 2.

Biological Example 2: Pharmacokinetic Experiments

Pharmacokinetic parameters for rats were obtained from SD rats (males) weighing approximately 230 ± 10 g. That is, the compounds according to the present invention were administered through the femoral vein at a dose of 20 ml / kg to 4 to 5 mice, 1, 2.5, 5, 10, 20, 40, 60, 120 and 180 minutes after administration Later, blood was collected from the femoral artery and blood concentration was obtained by Agar Well Method, and the calculated pharmacokinetic parameters, half-life (T), and area under the curve (AUC) were calculated. ) Values are shown in Table 3.

Claims (3)

The compounds of formula (I), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, solvates and isomers; Wherein Q represents CH or N, R ₁ represents hydrogen or an aminoprotecting group, R ₂ and R ₃ are the same or different and each independently represents a hydrogen or hydroxy protecting group, or R ₂ and R ₃ are Together can form a cyclic diol protecting group, R ₄ and R ₅ represent hydrogen or a carboxyl protecting group, R ₆ represents a heterocyclic compound of the following general formula, Wherein R ₇ and R ₈ each independently represent hydrogen, substituted or unsubstituted amino, hydroxy, alkoxy, C ₁ -C ₄ alkyl, carboxyl, alkoxycarbonyl or halogen, R ₉ is C ₁ -C ₄ alkyl, C ₃ -C ₄ alkenyl, carboxymethyl or amino. The compound of claim _1, wherein R _1, R ₄ and R ₅ are hydrogen, R ₂ and R ₃ are each independently hydrogen or acetyl, and R ₇ and R ₈ are each independently hydrogen, halogen or C ₁ -C ₄ alkyl and R ₉ is methyl. The method of claim 1,