KR0136053B1 - Novel cephalosprin an tibiotics - Google Patents

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Description

New cephalosporin antibiotics and preparation method thereof

The present invention provides novel cephalosporin-based compounds represented by the following general formula (1) useful as antibiotics, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates and solvates and isomers thereof, It relates to a method for preparing and a pharmaceutical composition containing them.

Wherein R ₁ is hydrogen, C _1-4 alkyl group, C _3-4 alkenyl group, C _3-4 alkynyl group or —C (R ^a ) (R ^b ) COOH where R ^a and R ^b are the same Or may represent hydrogen or a C _1-4 alkyl group, respectively, 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 ₂ and R ₃ are Together with hydrogen, a C _1-4 alkyl group, a substituted or unsubstituted amino group, a hydroxy group or a carbon to which they are attached may form a C _3-5 ring, R ₄ is hydrogen, a C _1-4 alkyl group, an amino group, or And a hydroxy group, Q is CH or N.

Cephalosporin-based 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, therefore, considerable research has been made in the development of various types of cephalosporin antibiotics.

For example, British Patent No. 1.399,086 describes a broad and comprehensive description of cephalosporin derivatives represented by the following general formula (A).

Wherein R is hydrogen or an organic group, R ^a is an etherified monovalent organic group linked to oxygen through a carbon atom, B is S or S-O, and P is an organic group.

The discovery of this class of compounds has led to attempts in this area to find compounds with improved properties, for example, improved properties for certain classes of bacteria, in particular Gram-negative bacteria.

British Patent 1,522,140 describes cephalosporin antibiotics of the general formula (I), wherein the compounds are syn isomers, or exist as a mixture of syn and anti isomers containing at least 90% or more syn isomers.

Wherein R 'is a furyl or thienyl group, R''is a C _1-4 alkyl group, C _3-7 cycloalkyl group, furylmethyl or thienyl methyl group, and R''' is hydrogen, carbamoyl, carboxymethyl , Sulfonyl or methyl group.

These compounds show high antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria, and are very stable against β-lactamase produced by various Gram-negative bacteria as well as in vivo. In an attempt to find antibiotics with enhanced broad spectrum antimicrobial activity and strong activity against Gram-negative bacteria, other compounds with similar structures have been developed. This development led to various changes such as introducing a specific group at the 3-position of the 7-β acyl amido group and cephalosporin derivative of the general formula (I).

For example, Belgian Kingdom Patent No. 852,427 discloses that R in the general formula (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. Cephalosporin-based antibiotic compounds are described in which the aliphatic hydrocarbon group itself can be substituted with a tarboxyl group.

In such compounds, the substituent at the C-3 position is acyloxymethyl, hydroxymethyl, formyl or an optionally substituted heterocyclic thiomethyl group.

Also. Tsudomu Derachi et al. Disclose in US Pat. No. 4,390,534 a cefem and cefam compound of the following general formula (C).

Wherein R ¹ is an amino or protected amino group: R ² is hydrogen, acyl, optionally substituted allyl, substituted alkyl, alkenyl, 0-substituted with optionally substituted cycloalkyl, cycloalkynyl or oxo group Or an S-containing 5-membered heterocyclic ring: R ⁴ is acyloxyalkyl, acylthioalkyl, optionally substituted pyridinium alkyl, optionally substituted heterocyclicthioalkyl, alkyl, halogen, hydroxy or optionally substituted Thiazolium alkyl, R ⁵ is carboxy or protected carboxy, with the proviso that R ⁵ is COO- when R ⁴ is optionally substituted pyridinium alkyl or optionally substituted thiazlium alkyl: --- dotted line is single bond or double Indicates that it is a bond.

Of course, the compounds described in the above patents are completely chemically distinct from the compounds described in the present invention.

Based on these prior arts, the present inventors have conducted numerous studies to develop cephalosporin compounds that exhibit not only strong antimicrobial activity against a wide range of pathogens, including Gram-negative bacteria producing β-lactamase, but also have improved pharmacokinetic properties. As a result of the experiments, the present inventors have found that cephalosporin compounds having a pyrimidinium methyl group optionally substituted at the C-3 position and several groups specific at the 7-β position meet these objectives, thereby completing the present invention. It became.

An object of the present invention is to provide a novel cephalosporin compound represented by the following general formula (1), a pharmaceutically acceptable non-toxic salt thereof, physiologically hydrolysable esters, hydrates and solvates and isomers thereof. .

Wherein R ¹ , R ² , R ³ , R ⁴ and Q are as described above, respectively.

Compounds of formula (1) according to the invention are geometric isomers, including syn- or mixtures of syn- and anti-isomers containing at least 90% of syn-isomers, and are also solvents of compounds of formula (1) Cargo (including luggage) is also included in the scope of the present invention.

In addition, when R ₁ is represented by C (R ^a ) (R ^b ) CO ₂ H in the compound of formula (1), if R ^a and R ^b are different, the carbon atoms to which they are attached become asymmetric centers to form diastereoisomers. In the present invention, diastereo isomers of each of these compounds and mixtures thereof are also included in the scope of the present invention.

Pharmaceutically acceptable non-toxic salts of the compounds of formula (1) are salts with inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid or acetic acid, trifluoro acetic acid, citric acid, formic acid, maleic acid, hydroxyl acid, succinic acid, benzo Organic carboxylic acids such as phosphoric acid, tartaric acid, fumaric acid, manderic acid, ascorbic acid, dried acid, or salts with sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid, and others known and used in the art of penicillin and cephalosporin Salts with acids. These acid addition salts are prepared by conventional techniques. The compound of formula (1) may also form non-toxic salts with bases, depending on the R ¹ group. Bases used herein include alkali metal hydroxides (e.g. sodium or potassium hydroxide), alkaline earth metal hydroxides (e.g. calcium hydroxide). Inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and calcium carbonate and organic bases such as amino acids.

Examples of physiologically hydrolysable eschers of the compound of formula (1) include indanyl, phthalidyl, methoxymethyl, pivaloyl oxymethyl, glycyloxymethyl, phenylglyciyloxymethyl, 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 are prepared by known methods.

The compound of formula (1) exhibits high antimicrobial activity against various Gram-positive and Gram-negative bacteria and is used for the prevention and treatment of bacterial infection in animals including humans.

The compound of formula (1) is formulated in a known manner using known pharmaceutical carriers and excipients and contained in unit dosage form or in multidose containers. Such pharmaceutical compositions are in the form of solutions, suspensions or emulsions in oils or aqueous media and may contain conventional dispersants, suspending agents or stabilizers. In addition, the pharmaceutical composition of the present invention may be present in the form of a dry powder which is dissolved before use, for example, in sterile, pyrogen-free water. The compounds of formula (1) may also be formulated into suppositories using conventional suppository bases such as cocoa butter or other glycerides. If necessary, the compound of formula (1) of the present invention may be administered in combination with other antibacterial agents such as penicillin or cephalosporin.

In the case of a unit dosage form, it is preferable to contain about 50 to 1,500 mg of the active ingredient of the compound of formula (1). The dosage of the compound of general formula (1) depends on the prescription of the doctor depending on factors such as the weight and age of the patient and the specific characteristics 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 route of administration. The total dosage of about 150 to 3,000 mg per day will usually be sufficient, divided into one dose for intramuscular or intravenous administration to adults, but a higher daily dosage is preferred for some strains of infection.

The general formula (1) compound according to the present invention exhibits a wide range of antimicrobial activity, and generally has high activity against gram negative bacteria, and this activity is also applied to many gram negative bacteria producing β-lactamase. In particular, the compounds according to the invention show very high activity against Pseudomonas strains.

Compound (1) according to the present invention, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates or solvates thereof may be prepared by the following formula (II) in the presence of a solvent It is prepared by reacting with a compound of formula (III), removing the amino protecting group or acid protecting group before or after the reaction if necessary or reducing the S-oxide [S- (O) n].

Wherein R ¹ , R ² , R ³ and R ⁴ are each as described above: n is 0 or 1: R ⁵ is hydrogen or an amino protecting group: R ⁶ is hydrogen, a C _1-4 alkyl group, hydroxide Roxy protecting group, C _3-4 alkenyl group, C _3-4 alkynyl group or -C (R ^a ) (R ^b ) CO ₂ (R ^c ) group, where R ^a and R ^b may be the same or different, Each represent hydrogen or a C _1-4 alkyl group, or R ^a and R ^b together with the carbon atom to which they are attached form a C _3-7 cycloalkyl group, R ^c is hydrogen or a carboxyl protecting group: R ⁷ is Hydrogen or a carboxyl protecting group: X is a leaving group: Q is CH or N.

Wherein the amino protecting group is acyl, substituted or unsubstituted ar (lower) alkyl (e.g. benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, etc.), halo (lower) alkyl (e.g. trichloro Methyl, trichloro ethyl and the like), tedrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloidene and the like. Acyls suitable as aminoprotecting groups may be aliphatic acyl groups and acyl groups having aromatic or heterocycles. Examples of such acyl groups include lower alkanoyls having 1 to 6 carbon atoms (eg formyl, acetyl, etc.), alkoxycarbonyl having 2 to 6 carbon atoms (eg methoxycarbonyl, ethoxycarbonyl, etc.). Lower alkanesulfonyl (such as methinesulfonyl, ethanesulfonyl and the like), or ar (lower) alkoxycarbonyl (such as benzyloxycarbonyl and the like). The above-mentioned acyl may have 1 to 3 suitable substituents such as halogen, hydroxy, cyano, nitro and the like. In addition, the reaction product of silane, boron, phosphatides and amino groups may also be an amino protecting group. Carboxyl protecting group of R ⁶ and R ⁷ in R ^c is typically suitable as would any as long as it is readily removed under mild conditions and examples of him (lower) alkyl ester (eg methyl ester t- butyl ester, etc.), (lower Alkenyl esters (e.g. vinyl esters, allyl esters, etc.), (lower) alkoxy (lower) alkyl esters (e.g. methoxymethyl esters, etc.), (lower) alkylthio (lower) alkyl esters (e.g. methylthiomethyls) Esters), halo (lower) alkyl esters (e.g. 2, 2, 2-trichloroethyl ester, etc.), substituted or unsubstituted aralkyl esters (e.g. benzyl esters, p-nitrobenzyl esters, p-methoxy Benzyl esters, etc.) or silyl esters. The amino protecting group and carboxyl protecting group can be easily removed under mild reaction conditions such as hydrolysis or reduction to form a free amino group or carboxyl group. The amino protecting group or carboxyl protecting group can be appropriately selected and used according to the properties of the compound of the general formula (1). X is a leaving group, for example, halogen such as chlorine, fluorine, iodine, (lower) alkanoyloxy such as acetoxy, (lower) alkane sulfonyloxy such as methanesulfonyloxy, paratoltuenesulfonyl oxy, etc. Arenesulfonyloxy or alkoxy carbonyloxy.

In the structure of the compound of formula (II), the dotted line means that the compound of formula (II) alone represents the following compound of formula (II-a), or compound of formula (II-b), or II-a) means a mixture of a compound and a general formula (II-b) compound.

Wherein R ⁵ , R ⁶ , R ⁷ , n, Q and X are the same as described above.

Compounds of the general formula (II) which are the starting materials of the present invention are known compounds and are prepared according to the following scheme. That is, it is prepared by activating the following compound of formula (IV) or a salt thereof with an acylating agent and then reacting with a compound of formula (V).

Scheme

In the scheme,

R ⁵ , R ⁶ , R ⁷ , n, Q and X are as described above, respectively.

The meaning of the dotted line in the compound of Formula (V) means that the compound of Formula (V) alone represents the following Formula (V-a), or each compound of Formula (V-b) The mixture of (V-a) compound and a general formula (V-b) compound is shown.

In the above formula,

n, R ⁷ and X are as described above, respectively.

In preparing compounds of formula (II), the active acylated derivatives of formula (IV) are acid chlorides, acid anhydrides, mixed acid anhydrides (preferably methylchloroformate or mesitylenesulfonyl chloride, p- Acid anhydrides formed with toluenesulfonyl chloride or chlorophosphate) or activated esters (preferably formed in reaction with N-hydroxy benzotriazole in the presence of a condensate such as dicyclo hexyl carbodiimide) Etc.

The acylation reaction may also proceed with the free acid of formula (IV) in the presence of condensates such as dicyclo hexyl carbodiimide, carbonyl diimidazole.

On the other hand, the acylation reaction usually proceeds well in the presence of organic bases such as tertiary amines (preferably triethylamine, dimethylaniline or 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, acetonitrile, dimethyl formamide 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 ° C to 50 ° C, preferably about -30 ° C to 20 ° C. The acylating agent of the compound of formula (IV) may use an equivalent or slight excess (1.05 to 1.2 equivalents) relative to the compound of formula (V).

In addition, the conversion of the halogen element represented by X of general formula (II) to another halogen element can be carried out by a conventional method. For example, the compound of general formula (II) in which X is an iodine element can be obtained by reacting a 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 groups or alkoxy garbonyl groups, and is carried out using inorganic acids such as formic acid, organic acids such as trifluoro acetic acid, p-fluenesulfonic acid 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 solvent, and an organic solvent that can be used. Examples 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 N and N-dimethylformamide, Esters such as ethyl acetate, 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 -10 ° C to 80 ° C, preferably 20 ° C to 40 ° C. The compound of formula (III) may be used in an amount of 0.5 to 2 equivalents, preferably 1.0 to 1.1 equivalents, based on the compound of formula (II).

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

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

The compound of formula (I) according to 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. Formulation forms may be in the form of solutions, suspensions or emulsions in oil or aqueous media, may be in the form of conventional dispersants, suspensions or emulsions, 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 formula (I) according to the 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 formula (I). The dosage of the compound of general formula (I) depends on the doctor's prescription depending on factors such as the patient's weight, age, and the specific nature and severity of the disease. However, the dosage required for adult gyro usually 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 a single dose for intramuscular or intravenous administration to an adult, will be sufficient, but a higher daily dose may be desirable for some strains of infection.

Compounds of general formula (I) according to the present invention and their nontoxic salts (preferably with alkali metal salts, alkaline earth metal salts, inorganic acid salts, organic acid salts and salts with amino acids) are a wide variety of pathogenic bacteria, including various Gram weak and Gram negative bacteria. Because of its potent antimicrobial activity, 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 shown as follows.

TABLE 1 Main compound

Preparation Example 1 Synthesis of 4-aminopyrimidine

157.07 g of 2-mercapto-4-aminopyrimidine was dissolved in 1007 ml of 1.5 N aqueous sodium hydroxide solution, the reaction solution was cooled to 0-4 ° C., and 267.55 g of 30% aqueous hydrogen peroxide solution was slowly added dropwise thereto. After completion of the dropwise addition, the reaction solution was heated to room temperature and stirred at this temperature for 1 hour. After the reaction was completed, 170 ml of acetic acid was slowly added dropwise to the reaction solution, and the resulting solid was filtered and washed with 200 ml of distilled water, 200 ml of methanol and 400 ml of diethyl ether, and dried to obtain 173.62 g of a white powder. The solid obtained here was slowly added dropwise to 1 L of concentrated hydrochloric acid cooled to 0 to 4 ° C., stirred at this temperature for 1 hour, and the reaction solution was then heated to room temperature and stirred for 8 hours. The solid produced during the reaction was filtered, washed with 1 L of acetone and 1 L of diethyl ether and dried to obtain 102.16 g of the title compound in the form of a hydrochloride salt. 102.16 g of the solid obtained was suspended in 400 ml of distilled water, 200 ml of 15% aqueous sodium hydroxide solution was added thereto, stirred at room temperature for 1 hour, filtered and washed with 400 ml of ethanol to obtain 91.24 g of a white powder.

NMR (δ, DMSO-d6): 6.42 (d, 1H), 6.85 (s, 2H), 8.04 (d, 1H), 8.36 (s, 1H)

Preparation Example 2 Synthesis of 4-amino-5,6-cyclopentapyrimidine

Instead of 2-mercapto-4-aminopyrimidine used in Preparation Example 1, 210.25 g of 2-mercapto-4-amino-5,6-cyclopentapyrimidine was used to carry out a white powder. 124. 32 g of the title compound were obtained.

NMR (δ, DMSO-d6): 1.96 (m. 2H), 2.62 (t, 2H0, 2.68 (t, 2H), 6.56 (S, 2H), 8.13 (s, 1H)

Preparation Example 3 Synthesis of 4-amino-2-methylpyrimidine

5.6 g of acetamidine hydrochloride salt was dissolved in 70 ml of methanol, and 22.8 g of sodium methoxide 28% solution was added dropwise while stirring at room temperature, followed by dropwise addition of 11.5 g of 3-ethoxy acrylonitrile. After completion of the dropwise addition, the reaction solution was stirred at 80 ° C for 15 hours. After the reaction was completed, the reaction solution was cooled to room temperature, neutralized with 5N-hydrochloride solution, and the solution was distilled under reduced pressure to obtain a solid title compound with salt. The compound was dissolved in 30 ml of methyl alcohol and filtered. The solution was distilled under reduced pressure and concentrated to 10 ml. Then, 50 ml of diethyl ether was slowly added dropwise to solidify, filtered and washed with 20 ml of diethyl ether to give the title compound 2.14. g was obtained.

NMR (δ, DMSO-d6): 2.27 (s, 3H), 6.21 (d, 1H), 6.69 (bs, 2H), 7.92 (d, 1H)

Example 1

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [4-aminopyrimidinium] methyl-3-cepem-4 Synthesis of Carboxylate

Paramethoxybenzyl, 3-chloromethyl-7-[(Z) -2- {2- (triphenylmethyl) aminothiazol-4-yl} -2- (triphenylmethoxyimino) acetamido]- 4 g of 3-cefe-4-carboxylate was dissolved in 50 ml of acetone (compound obtained in Preparation Example 1), 526 ml of 4-aminopyrimidine was added thereto, and then 1.11 g of sodium iodide was added dropwise at room temperature over 30 minutes. , And stirred at room temperature for 6 hours. After the reaction was completed, acetone was distilled under reduced pressure, extracted with 80 ml of ethyl acetate, washed three times with 60 ml of saturated brine, dried over 5 g of anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The concentrated solution obtained herein was slowly added dropwise to 30 ml of diethyl ether to solidify, and the solid obtained by filtration was washed with 10 ml of diethyl ether and dried to give 3.32 g of a white powder. 3.32 g of the solid obtained was dissolved in 9 ml of anisole, and the reaction solution was cooled to 0-4 DEG C., 18 mL of trifluoroacetic acid was slowly added dropwise, and the reaction solution was allowed to rise to room temperature. Stir further. After the reaction, the reaction solution was cooled to -10 to 15 ° C., and 100 ml of diethyl ether was slowly added dropwise to solidify. The mixture was filtered, washed three times with 20 ml of diethyl ether, and dried to obtain 1.35 g of a white white solid. 1.35 g of the solid obtained was separated using preparative liquid chromatography (μ-Bondapak C18 Steel Column, 19 mm x 30 mm) using a 5% methanol solution as an eluent. MG is obtained.

MS (FAB, M + 1): 477

NMR (δ, D ₂ O + NaHCO ₃ ): 3.46 (ABq, 2H). 4.98 (ABq, 2H), 5.28 (d, 1H), 5.89 (d, 1H), 6.85 (d, 1H), 7.01 (s, 1H), 8.08 (d, 1H), 8.62 (s, 1H)

IR (KBr, cm ^-1 ): 1770 (β-lactam), 1680, 1635, 1570

Example 2

7-[(Z) -2- (2 aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [4-amino-5,6-cyclopentapyrimidin] methyl Synthesis of 3-Cefem-4-carboxylate

534 mg of the title compound (I-2) as a white solid, was prepared in the same manner as in Example 1 but using 749 mg of 4-amino-5,6-cyclopentapyrimidine prepared in Preparation 2 instead of 4-aminopyrimidine. To obtain.

MS (FAB, M + 1): 517

NMR (δ, D ₂ O + NaCHO ₃ ): 2.31 (t, 2H), 2.91 (t, 2H), 3.20 (m, 2H), 3.44 (ABq, 2H), 5.12 (ABq, 2H), 5.28 (d , 1H), 5,91 (d, 1H), 6.97 (s. 1H), 8.71 (s, 1H)

IR (KBr, cm ^-1 ): 1775 (β-lactam), 1670, 1610, 1530

Example 3

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- [4-amino-pyrimidinium] methyl-3-cepem- Synthesis of 4-carboxylate

Paramethoxybenzyl, 3-chloromethyl-7-[(Z) -2-2- (triphenylmethyl) aminothiazol-4-yl-2- (methoxyimino) acetamido] -3-cepem- 4 g of 4-carboxylate and 515 mg of the compound 4-aminopyrimidine obtained in Preparation 1 were used in the same manner as in Example 1 to obtain 612 of the title compound (I-3) as a white solid.

MS (FAB, M + 1): 491

NMR (δ, D ₂ O): 3.45 (ABq, 2H), 3.97 (s, 3H), 4.97 (ABq, 2H), 5.26 (d, 1H), 5.82 (d, 1H), 6.81 (d, 1H) , 6.97 (s, 1H), 8.01 (d, 1H), 8.69 (s, 1H)

IR (KBr, cm ^-1 ): 1775 (β-lactam), 1670, 1610, 1530

Example 4

7-[(Z) -2- (aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [4-amino-5,6-cyclopentapyrimidinium] methyl- Synthesis of 3-Cefem-4-carboxylate

A white solid title compound (1-4) was obtained in the same manner as in Example 3, except that 4-1amino-5,6-cyclopentapyrimidine 712 prepared in 2 was prepared instead of 4-aminopyrimidine. .

MS (FAB, M + 1): 531

NMR (δ, D ₂ O): 2. 21 (t, 2H), 2.08 (t, 2H), 3.08 (m, 2H), 3.36 (ABq, 2H), 3.97 (s, 3H), 5.05 (ABq, 2H), 5.20 (d, 1H), 5.82 (d, 1H), 6.97 (s, 1H), 8.52 (s, 1H)

IR (KBr, cm ^-1 ): 1775 (β-lactam), 1680, 1630, 1570

Example 5

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- [4-aminopyrimidinium] methyl-3-cepem-4 Synthesis of Carboxylate

Paramethoxy benzyl, 3-chloromethyl-7-[(Z) -2-2- (triphenylmethyl) aminothiazol-4-yl-2- (ethoxyimino) acetamido] -3-cepem- Using 4 g of 4-carboxylate and 530 mg of the compound 4-aminopyrimidine obtained in Preparation 1, 635 mg of a white solid compound (I-5) was obtained in the same manner as in Example 1.

MS (FAB, M + 1): 505

NMR (δ, D ₂ O): 1.30 (t, 3H), 3.46 (ABq, 2H), 4.28 (q, 2H), 4.99 (ABq, 2H), 5.28 (d, 1H), 5.85 (d, 1H) , 6.85 (d, 1H), 6.99 (s, 1H), 8.24 (d, 1H), 8.70 (s, 1H)

IR (KBr, cm ^-1 ): 1765 (β-lactam), 1660, 1630, 1550

Example 6

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- [4-amino-5,6-cyclopentapyrimidinium]

Synthesis of Methyl-3-cepem-4-carboxylate

Performing similarly to Example 5, but instead of 4-aminopyrimidine, 593 mg of white solid title compound (I-6) was obtained using 722 mg of 4-amino-5,6-cyclopentapyrimidine prepared in Preparation Example 2. do.

MS (FAB, M + 1): 545

NMR (δ, D ₂ O): 1.28 (t, 3H), 2.20 (t, 2H), 2.80 (t, 2H), 3.08 (m, 2H), 3.35 (ABq, 2H), 4.22 (q, 2H) , 5.03 (ABq, 2H), 5.20 (d, 1H), 5.84 (d, 1H), 6.92 (s, 1H), 8.51 (s, 1H)

IR (KBr, cm ^-1 ): 1775 (β-lactam), 1670, 1610, 1530

Example 7

7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- [4-amino-2-methylpyrimidinium] methyl-3 Synthesis of Cefem-4-carboxylate

567 mg of white solid title compound (I-7) is obtained by carrying out similarly to Example 5 but using 750 mg of 4-amino-2-methyl mipimidine prepared in Preparation 3 in place of 4-aminopyrimidine.

MS (FAB, M + 1): 519

NMR (δ, D ₂ O): 1.33 (t, 3H), 2.61 (s, 3H), 3.40 (ABq, 2H), 4.35 (q, 2H), 5.01 (ABq, 2H), 5.27 (d, 1H) , 5.90 (d, 1H), 6.83 (d, 1H), 6.94 (s, 1H), 8.10 (d, 1H)

IR (KBr, cm ^-1 ): 1770 (β-lactam), 1670, 1620, 1560

Example 8

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- [4-amino-pyrimidy Nium] Synthesis of Methyl-3-cepem-4-carboxylate

Paramethoxybenzyl, 3-chloromethyl-7-[(Z) -5-amino-1,2,4-thiadiazol-3-yl-2- (ethoxyimino) acetamido] -3-cepem 652 mg of a white solid compound (I-8) was obtained in the same manner as in Example 1 using 3 g of 4-carboxylate and 527 mg of the compound 4-aminopyrimidine obtained in Preparation Example 1.

MS (FAB, M + 1): 506

NMR (δ, D ₂ O): 1.32 (t, 3H), 3.45 (ABq, 2H), 4.35 (q, 2H), 4.98 (ABq, 2H), 5.28 (d, 1H), 5.89 (d, 1H) , 6.88 (d, 1H), 8.21 (d, 1H), 8.70 (s, 1H)

IR (KBr, cm ^-1 ): 1775 (β-lactam), 1670, 1640, 1550

Example 9

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- [4-amino-5, Synthesis of 6-cyclopentapyrimidinium] methyl-3-cepem-4-carboxylate

685 mg of the title compound (I-9) as a white solid using 553 mg of 4-amino-5,6-cyclopentapyrimidine prepared in Preparation Example 2 was used in the same manner as in Example 8, instead of 4-aminopyrimidine. To obtain.

MS (FAB, M + 1): 546

NMR (δ, D ₂ O): 1.32 (t, 3H), 2.21 (t, 2H), 2.79 (t, 2H), 3.08 (m, 2H), 3.37 (ABq, 2H), 4.39 (q, 2H) , 5.05 (ABq, 2H), 5.21 (d, 1H), 5.88 (d, 1H), 8.52 (s, 1H)

IR (KBr, cm ^-1 ): 1775 (β-lactam), 1680, 1610, 1540

Example 10

7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- [4-amino-2- Methylpyrimidinium] Synthesis of Methyl-3-cepem-4-carboxylate

In the same manner as in Example 8, instead of 4-aminopyrimidine, 642 mg of the title compound (I-10) as a white solid was obtained using 513 mg of 4-amino-2-methylpyrimidine prepared in Preparation Example 3.

MS (FAB, M + 1): 520

NMR (δ, D ₂ O): 1.39 (t, 3H), 2.65 (s, 3H), 3.42 (ABq, 2H), 4.36 (q, 2H), 5.04 (ABq, 2H), 5.04 (ABq, 2H) , 5.28 (d, 1H), 5.90 (d, 1H), 6.85 (d, 1H), 8.10 (d, 1H)

IR (KBr, cm ^-1 ): 1765 (β-lactam), 1680, 1630, 1570

The fluidity of the compounds according to the present invention was tested using standard known compounds ceftazidime as a control agent, strains producing standard strains, clinically isolated strains, strains resistant to some antibiotics, and strains producing lactamase. The minimum inhibitory concentrations (Minimum Inhibitory Concentration) for these strains were obtained, and at the same time, the pharmacokinetic parameters of rats were 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 2 μl of the test strain having 10 ⁷ CFU (Colory Forming Unit) per ml. After inoculation and incubation at 37 ° C. for 20 hours, the results are shown in Table 2.

TABLE 2 Minimum Inhibitory Concentration for Test Strains (㎍ / ㎖)

Claims (7)

New cephalosporin-based compounds represented by the following general formula (I), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates and solvates and isomers thereof. In the above formula, R ¹ may be 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 ) 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; R ² and R ³ may each form a C _3-5 ring with hydrogen, a C _1-4 alkyl group, a substituted or unsubstituted amino group, a hydroxy group or the carbon to which they are attached, R ⁴ is hydrogen, a C _1-4 alkyl group, an amino group, or a hydroxy group, Q is 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- (hydroxyimino) acetamido] -3- [4-aminopyrimidinium] methyl-3-cepem-4 Carboxylates; 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [4-amino-5,6-cyclopentapyrimidinium] Methyl-3-cefe-4-carboxylate; 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- [4-amino-pyrimidinium] methyl-3-cepem- 4-carboxylate; 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3- [4-amino-5,6-cyclopentapyrimidinium] Methyl-3-cefe-4-carboxylate; 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- [4-aminopyrimidinium] methyl-3-cepem-4 Carboxylates; 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- [4-amino-5,6-cyclopentapyrimidinium] Methyl-3-cefe-4-carboxylate; 7-[(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3- [4-amino-2-methylpyrimidinium] methyl-3 -Cefem-4-carboxylate; 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- [4-amino-pyrimidy Nium] methyl-3-cepem-4-carboxylate; 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- [4-amino-5, 6-cyclopentapyrimidinium] methyl-3-cepem-4-carboxylate; 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- [4-amino-2- Methylpyrimidinium] methyl-3-cepem-4-carboxylate; The compound of the following general formula is reacted with the compound of the following general formula (III) in the presence of a solvent and, if necessary, the amino protecting group or the acid protecting group is removed before or after the reaction or the S-oxide [S- (O) n] is reduced. A process for preparing a compound of formula (I), a pharmaceutically acceptable non-toxic salt thereof, a physiologically hydrolysable ester, hydrate or solvate thereof, characterized by In the above formula, R ¹ may be 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 ) 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; R ² and R ³ may each form a C _3-5 ring with hydrogen, a C _1-4 alkyl group, a substituted or unsubstituted amino group, a hydroxy group or the carbon to which they are attached, R ⁴ is hydrogen, a C _1-4 alkyl group, an amino group, or a hydroxy group, n is 0 or 1; R ⁵ is hydrogen or an amino protecting group; R ⁶ is hydrogen, a C _1-4 alkyl group, hydroxy protecting group, C _3-4 alkenyl group, C _3-4 alkynyl group or —C (R ^a ) (R ^b ) CO ₂ (R ^c ) group, where 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 the carbon atom to which they are attached form a C _3-7 cycloalkyl group, R ^c is hydrogen or a carboxyl protecting group; R ⁷ hydrogen or carboxyl protecting group, X is a leaving group; 4. 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 , Ethanol and dimethyl sulfonide, characterized in that one or two or more selected from. The method of claim 3 wherein the reaction temperature is -10 to 80 ° C. 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). An antibiotic composition comprising a therapeutically effective amount of a compound of formula (I) as defined in claim 1 and a pharmaceutically acceptable carrier, excipient and other antimicrobial agent.