KR20030071311A - Novel cephalosporin compounds and process for preparing the same - Google Patents

Abstract

PURPOSE: Provided are cephalosporin compounds and a preparation process thereof, which compounds have strong antimicrobial activity, especially to methicillin resistant Staphylococcus aureus(MRSA). CONSTITUTION: Cephalosporin compounds represented by the formula (1) are provided, wherein R1 and R2 are independently hydrogen, halogen, C1-6 alkyl, C1-6 alkylthio, aryl, arylthio or C5-6 heteroaryl containing 1 to 2 hetero atoms selected from nitrogen and oxygen; R3 is hydrogen or carboxy protecting group; R4, R5 and R6 are independently hydrogen, hydroxy, C1-6 alkyl, C1-6 alkyloxy or C1-6 alkylamino; R7 is hydrogen, hydroxy, amino, C1-6 alkyl, C1-6 alkyloxy, C1-6 alkylamino, or amino or hydroxy substituted or unsubstituted C1-6 alkylthio; Q is sulfur, oxygen or carbon; W and Y are independently C or N, provided that R4 and R6 are not present when W or Y is N; and olefin positioned at the C-3 site where heteroarylthio is substituted comprises cis or trans forms. A process for preparing the cephalosporin compounds of the formula (1) comprises the steps of: activating a compound of the formula (6) or salts thereof with an acylating agent; reacting the activated compound of the formula (6) with a compound of formula (5) to prepare a compound of the formula (11); and reducing the compound of the formula (11) from S to oxide, wherein p is 0 or 1; and a double bond positioned at the C-3 site comprises trans and cis forms.

Description

Novel cephalosporin compounds and process for preparing the same

The present invention relates to novel cephalosporin compounds useful as antibiotics. More specifically, the present invention is a novel cephalosporin compound of formula (1) below, which is useful as an antimicrobial agent and particularly has a strong activity against strains such as methicillin resistant Staphylococcus aureus (MRSA), pharmaceutically acceptable Non-toxic salts thereof, physiologically hydrolysable esters thereof, hydrates, solvates and isomers thereof.

[Formula 1]

Where

R1 And R2 are each hydrogen, halogen, C_1-6Alkyl, C_1-6C containing 1 to 2 heteroatoms selected from the group consisting of alkylthio, aryl, arylthio or nitrogen and oxygen atoms_5-6Heteroaryl,

R3 represents hydrogen or a carboxy protecting group,

R4, R5 and R6 represent hydrogen, a hydroxy group, an amino group, a C _1-6 alkyl group, a C _1-6 alkyloxy or a C _1-6 alkylamino group,

R7 represents hydrogen, a hydroxy group, an amino group, a C _1-6 alkyl group, a C _1-6 alkyloxy, a C _1-6 alkylamino group, or a C _1-6 alkylthio group unsubstituted or substituted with an amino group or a hydroxy group,

Q represents sulfur, oxygen or carbon,

W and Y represent C or N, respectively, provided that when W or Y represents N, R4 and R6 are absent;

The olefin at the position where the heteroarylthiol at the C-3 position is substituted includes both cis- or trans.

The invention also relates to a process for the preparation of compounds of formula (1) and to antibiotic compositions containing them as active ingredients.

Cephalosporin antibiotics are widely used in the treatment of infectious diseases caused by pathogenic bacteria in humans and animals, especially in the treatment of diseases caused by bacteria that are resistant to other antibiotics, such as penicillin compounds, and in the treatment of penicillin-sensitive patients. useful. In the treatment of these infectious diseases, in most cases it is preferable to use antibiotics that exhibit antimicrobial activity against both Gram-positive and Gram-negative microorganisms, and the antimicrobial activity of these cephalosporin antibiotics is 3 or 7 positions of the cefe ring. It is well known that it is greatly influenced by the kind of substituents present in. Thus, numerous attempts have been made to develop cephalosporin antibiotics in which various substituents have been introduced at the 3- or 7-position in an attempt to develop antibiotics that exhibit potent antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria.

For example, British Patent No. 1,399,086 describes the cephalosporin derivatives represented by the following formula (2) in a broad and comprehensive manner.

Where

R8 is hydrogen or an organic group,

R9 is an etherified monovalent organic group which is linked to oxygen through carbon,

A is -S- or> S-> O,

B is an organic group.

Since the invention of these compounds, numerous attempts have been made to develop antibiotics with a broad antimicrobial spectrum, and as a result many corresponding cephalosporin antibiotics have been developed. With this development, various studies have been attempted such as introducing an acyl amido group and a specific group at the C-3 position at the 7-position of the cefe nucleus of the formula (2).

Recently, Gram-positive bacteria, especially methicillin-resistant Pseudomonas aeruginosa (MRSA), have become a serious problem of intestinal infection and have been attempted to introduce thiovinyl groups at the C-3 position as cephalosporin-based compounds that can exhibit strong activity against them. .

That is, Japanese Patent Application No. Hei 10-182655 describes cephalosporin derivatives of the following formula (3) in detail, and introduces a low-toxic compound having high activity against Gram-positive pathogens by introducing a thiovinyl chain at the C-3 position. Suggesting.

Where

Ar is or ego,

R10 represents acylamino,

R11 represents a carboxyl group,

R12 represents a sulfo lower alkyl group,

B ^- represents an anion,

f represents 0 or 1,

The ring represented by C represents a 5-membered ring having 4 or less nitrogen atoms.

As a cephalosporin-based compound capable of exhibiting strong activity against methicillin-resistant Pseudomonas aeruginosa (MRSA) as described above, an attempt was made to introduce an acyl group at position 7 and a pyridine series at C-3. An example is a compound of formula (4) as described in EP 0727426 (1996):

Where

Acyl substituent is Ar-S-CH ₂ -CO-, wherein Ar represents a hydrophobic substituted phenyl, pyridyl or vanzthiazole group,

R13 and R14 each represent hydrogen, alkyl or aminoalkylcarbonylamino,

R15 represents a group having a substituted aliphatic, aromatic, arylaliphatic or sugar moiety.

Although the above patents introduce various heteroaromatic rings in the thiovinyl chain or thiomethyl chain of C-3, they are completely different from the substituents in the thiovinyl chain of C-3 in the present invention.

That is, in the present invention, various pyrimidinyl groups substituted or unsubstituted at the C-3 position are introduced into a chain such as thiovinyl, but the above patents do not mention any of them.

Therefore, the present inventors focused on developing a cephalosporin compound exhibiting a wide range of antimicrobial activity against Gram-positive bacteria including MRSA, and the cephalosporin compounds represented by pyrimidinyl groups optionally substituted at the C-3 position are directed to these targets. It has been found that this is the case and the present invention has been completed.

Accordingly, an object of the present invention is to provide a compound of formula (1), a pharmaceutically acceptable non-toxic salt thereof, a physiologically hydrolysable ester, a hydrate, a solvate, and an isomer thereof.

The present invention also aims to provide a method for preparing a compound of formula (1) and an antibiotic composition characterized by containing the compound of formula (1) as an active ingredient.

It is an object of the present invention to provide novel cephalosporin compounds of formula (1), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates, solvates and isomers thereof.

[Formula 1]

Where

R1 And R2 are each hydrogen, halogen, C_1-6Alkyl, C_1-6C containing 1 to 2 heteroatoms selected from the group consisting of alkylthio, aryl, arylthio or nitrogen and oxygen atoms_5-6Heteroaryl,

R3 represents hydrogen or a carboxy protecting group,

R4, R5 and R6 represent hydrogen, a hydroxy group, an amino group, a C _1-6 alkyl group, a C _1-6 alkyloxy or a C _1-6 alkylamino group,

R7 represents hydrogen, a hydroxy group, an amino group, a C _1-6 alkyl group, a C _1-6 alkyloxy, a C _1-6 alkylamino group, or a C _1-6 alkylthio group unsubstituted or substituted with an amino group or a hydroxy group,

Q represents sulfur, oxygen or carbon,

W and Y represent C or N, respectively, provided that when W or Y represents N, R4 and R6 are absent;

The olefin at the position where the heteroarylthiol at the C-3 position is substituted includes both cis- or trans.

Pharmaceutically acceptable non-toxic salts of the compounds of formula (1) include 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, Organic carboxylic acids such as tartaric acid, fumaric acid, manderic acid, ascorbic acid, malic acid or salts with methanesulfonic acid, para-toluenesulfonic acid and salts with other acids known and used in the art of penicillin and cephalosporin . These acid addition salts can be prepared by conventional techniques. The compounds of formula (1) may also form non-toxic salts with bases. Bases used here include inorganic metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, and alkali metal carbonates such as sodium carbonate, potassium carbonate and calcium carbonate. Organic bases such as bases and amino acids are included.

Examples of physiologically hydrolyzable esters of the compound of formula (1) include indanyl, phthalidyl, methoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, 5-methyl-2 Oxo-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 produced by known methods.

Representative examples of the compound of formula (1) according to the present invention are as follows.

I-1: 3-{(E) -2-[(2,6-diamino-4-pyrimidinyl) sulfanyl] ethenyl} -7-({2-[(2,5-dichlorophenyl) Sulfanyl] acetyl} amino) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid;

I-2: 7-({2-[(2,5-dichlorophenyl) sulfanyl] acetyl} amino) -3-{(E) -2-[(4,6-dimethyl-2-pyrimidinyl) Sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid;

I-3: 7-({2-[(2,5-dichlorophenyl) sulfanyl] acetyl} amino) -3-((E) -2-{[2- (ethylsulfanyl) -6-methyl- 4-pyrimidinyl] sulfanyl} ethenyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid;

I-4: 3-{(E) -2-[(4-amino-2-pyrimidinyl) sulfanyl] ethenyl} -7-({2-[(2,5-dichlorophenyl) sulfanyl] Acetyl} amino) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid;

I-5: 3-{(E) -2-[(4,6-diamino-2-pyrimidinyl) sulfanyl] ethenyl} -7-({2-[(2,5-dichlorophenyl) Sulfanyl] acetyl} amino) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

Compounds of formula (1) according to the present invention, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates, solvates or isomers thereof are acylating compounds of formula (6) or salts thereof After activation, the compound is reacted with a compound of the following formula (5), and if necessary, an acid protecting group is removed before or after the reaction, or S → oxide [S-> (O) _p ] of the formula (11) is reduced to It can be prepared by obtaining the compound of (1).

Where

R1, R2, R3, R4, R5, R6, R7, Q, W and Y are as described above,

p is 0 or 1,

Double bonds in the C-3 position include both trans and cis.

In the above, the carboxy protecting group R 3 is usually suitable as long as it is easily removed under mild conditions, and examples thereof include (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. methyloxymethyl 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, p-methoxybenzyl esters, etc.) or silyl esters Etc.

The carboxy protecting group described above can be easily removed under mild reaction conditions such as hydrolysis and reduction to form a free carboxy group, and is appropriately selected and used in accordance with the chemical properties of the compound of formula (1).

In preparing the compounds of formula (1), the active acylated derivatives of formula (6) are acid chlorides, acid anhydrides, mixed acid anhydrides (preferably methylchloroformate, mesitylenesulfonyl chloride, p-toluenesulfonyl Acid anhydrides formed with chlorides or chlorophosphates) or activated esters (preferably esters formed in reaction with N-hydroxy benzotriazole in the presence of a condensing agent such as dicyclo hexyl carbodiimide). The acylation reaction may also proceed with the free acid of formula (8) in the presence of a condensing agent such as dicyclohexyl carbodiimide, carbonyl diimidazole. If necessary, the active form of formula (6) may be separated by distillation. On the other hand, the acylation reaction usually proceeds well in the presence of organic bases such as tertiary amines, preferably triethylamine, dimethylaniline, pyridine or inorganic bases such as sodium bicarbonate and sodium carbonate, and the solvent used is methylene chloride and chloroform. Solvents such as halogenated carbon, tetrahydrofuran, acetonitrile, dimethylformamide or dimethyl acetamide and the like. Also mixed solvents of the above solvents may be used and may be used in the form of an aqueous solution. If necessary, 1 to 10 equivalents of bistrimethylsilyl acetamide or trimethylsilyl chloride can be used as an additive with respect to 1 equivalent of the compound of formula (5).

The reaction temperature of this acylation step is about -50 to 50 DEG C, preferably about -30 to 20 DEG C, and the acylating agent of the compound of the formula (6) is equimolar or slightly excess relative to one equivalent of the compound of the formula (6). That is, 1.05 to 1.5 equivalents can be used.

The compound of formula (1) also reacts the compound of formula (8) with a compound of formula (9) to give a compound of formula (7), after which the aminoprotecting group A of the compound of formula (7) is removed, It can be prepared by activating the carboxylic acid or salt thereof (6) with an acylating agent and then reacting with the compound of formula (5) from which A is removed.

[Formula 5]

[Formula 6]

In the above formulas,

R1, R2, R3, R4, R5, R6, R7, Q, W and Y are as defined above,

p is 0 or 1,

A is an aminoprotecting group,

Double bonds in the C-3 position include both trans and cis.

Looking at the above manufacturing process of the compound of formula (1) in detail.

Compounds of formula (5), which are intermediates of the invention, are prepared by deprotecting aminoprotecting groups from compounds of formula (7) using organic or inorganic acids.

[Formula 5]

[Formula 7]

In the above formulas,

R3, R4, R5, R6, R7, W, p and Y are as described above,

A represents an aminoprotecting group

Double bonds in the C-3 position include both trans and cis.

Wherein the aminoprotecting group A is acyl, substituted or unsubstituted ar (lower) alkyl (e.g. benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, etc.), halo (lower) alkyl (e.g. trichloro Romethyl, trichloroethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloidene and the like. Acyls suitable as amino protecting groups may be aliphatic and aromatic acyl groups or acyl groups having a heterocycle. Examples of such acyl groups include C _1-5 lower alkanoyl (eg formyl, acetyl, etc.), C _2-6 alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, etc.), lower alkanesulfonyl ( Examples thereof include methylsulfonyl, ethylsulfonyl, and the like, or ar (lower) alkoxycarbonyl (for example, benzyloxycarbonyl and the like). The acyl described above may have suitable substituents, such as 1-3 halogens, hydroxy, cyano, nitro and the like. In addition, the reaction product of silane, boron, phosphorus compound and amino group may be an amino protecting group.

The acid used to prepare the compound of formula (5) by the above process may be an organic acid (trifluoromethanesulfonic acid, trifluoroacetic acid, formic acid or acetic acid) or mineral acid (hydrochloric acid or sulfuric acid), and the like. As halogenated carbon, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide, alcohol, etc. are mentioned. It can also be hydrolyzed only with acid without solvent. The reaction temperature of the process is -50 ° C to 50 ° C, preferably 0 ° C to 15 ° C.

In addition, the compound of formula (7) may be prepared by substituting the compound of formula (9) instead of X at the C-3 vinyl position of the compound of formula (8).

[Formula 7]

[Formula 8]

[Formula 9]

In the above formulas,

A, R3, R4, R5, R6, R7, p, W and Y are as described above,

X represents a halogen and sulfonyloxy group

Double bonds in the C-3 position include both trans and cis.

Organic solvents usable in the reaction 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, dimethylformamide and the like. Amides, 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 mixtures of these solvents may be used. The leaving group X here represents a chlorine, fluorine, iodine and sulfonyloxy group (for example para-toluenesulfonyloxy, methanesulfonyloxy and trifluorosulfonyloxy). The reaction temperature is -10 ° C to 80 ° C, preferably 20 ° C to 40 ° C, and the compound of formula (6) is 0.5 to 2 equivalents, preferably 1.0 to 1.1, based on 1 equivalent of the compound of formula (5) It can be used in the equivalent weight.

Compounds of formula (8) wherein X is chlorine can be prepared with reference to European Patent Nos. 154354 (1985) or 553538 (1982), wherein compounds of formula (8) wherein X is a sulfonyloxy group are The aldehyde at the C-3 position of the compound of 10) can be prepared by converting it into a vinyloxysulfonyl group. This manufacturing method is performed according to a commercial method.

Where

A, R3 and p are as described above,

Double bonds in the C-3 position include both trans and cis.

The compound of formula (10) may be reacted with an active form of sulfonic acid (sulphonic anhydride or sulfonic chloride) in the presence of a base to prepare a compound of formula (8). The base used at this time is usually a tertiary amine, preferably an organic base such as triethylamine, dimethylaniline, pyridine. Specific examples of the active form of sulfonic acid include para-toluenesulphonic chloride, methanesulphonic chloride, methanesulphonic anhydride, trifluoromethanesulphonic anhydride and the like. The active form of sulfonic acid is usually used in 1 to 3 equivalents relative to 1 equivalent of the compound of formula (10). Examples of the solvent used in this reaction include halogenated carbons such as methylene chloride and chloroform, tetrahydrofuran, acetonitrile, dimethylformamide or dimethylacetamide, and mixtures thereof. The reaction temperature is preferably -78 ° C to 0 ° C.

Compounds of formula (10) having various amino protecting groups can be prepared from the starting material 7-amino-decacetioxycephalosporonic acid with reference to US Pat. No. 4,622,393.

The dotted line in the structural formulas of the compounds of the formulas (5), (7), (8) and (10) represents each of the 2-cefem or 3-cefem compounds of the formulas, or a mixture thereof.

The meaning indicated by the dotted line in the compound of the formula (8) indicates that the compound of the formula (8) is present alone or in a mixture of the compound of the formula (8a) or the formula (8b).

In the above formulas,

A, R3, p and X are as described above.

In preparing the compound of formula (1), the acid protecting group of the compound of formula (5) may 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 acid hydrolysis is useful for removing tri (di) phenylmethyl group or alkoxy carbonyl group, and organic acids such as formic acid, trifluoroacetic acid, and p-toluenesulfonic acid Or inorganic acids such as hydrochloric acid.

From the reaction product of the reaction, the desired compound of formula (1) can be separated or purified by various methods such as recrystallization, iontophoresis, silica gel column chromatography or ion exchange resin chromatography.

Another object of the present invention is to provide an antibiotic composition containing a compound of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.

The compounds of the present invention can be administered in injectable and oral formulations as desired.

The compounds of formula (1) of the present invention may be formulated by known methods using known pharmaceutical carriers and excipients and incorporated into unit dose forms or multidose containers. The formulation form may be in the form of a solution, suspension or emulsion in an oil or aqueous medium and may contain conventional dispersants, suspensions or stabilizers. In addition, for example, it may be in the form of a dry powder which is dissolved before use with 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. Solid dosage forms for oral administration may be capsules, tablets, pills, powders, and granules, and capsules and tablets are particularly useful. Tablets and pills are preferably prepared with enteric coatings. Solid dosage forms can be prepared by mixing the active compounds of formula (1) according to the invention with one or more inert diluents such as sucrose, lactose, starch and the like and carriers such as lubricants such as magnesium stearate, disintegrants, binders and the like. Can be.

If desired, the compound of the present invention may be administered in combination with an antibacterial agent such as penicillin or other cephalosporins.

When formulating a compound of the present invention in unit dose form, it is preferred that the unit dose form contains about 50 to 1500 mg of the active ingredient of the compound of formula (1). The dosage of the compound of formula (1) depends on the doctor's prescription depending on factors such as the patient's weight, age and the particular nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 500 to 5,000 mg per day, depending on the frequency and intensity of administration. A total dosage of about 150-3,000 mg per day, usually separated by a single dose for intramuscular or intravenous administration to adults, will be sufficient, but for some strain infections a higher daily dosage may be desirable.

Compounds of formula (1) according to the 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 potent antimicrobial agents against a wide range of pathogenic bacteria, including various Gram-positive bacteria. Because of its active and broad antimicrobial spectrum, it is very useful for the prevention and treatment of diseases caused by bacterial infection in animals including humans.

The following Preparation Examples and Examples are merely to aid the understanding of the present invention, but they do not limit the present invention.

Preparation Example 1

Benzhydryl 7-[( t -butoxycarbonyl) amino] -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia Synthesis of -1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Benzhydryl 7-[( t -butoxycarbonyl) amino] -8-oxo-3- (2-oxoethyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene- 2.57 g (5.06 mmol) of 2-carboxylate was dissolved in 17 ml of distilled dichloromethane. After cooling the temperature of the reactor to -78 ° C, 1.32 ml (7.59 mmol) of N, N -diisopropyl ethyl amine and 1.28 ml (7.59 mmol) of trifluoromethanesulphonic anhydride were slowly added dropwise. Stirring for 20 minutes while maintaining the temperature of the reactor at -78 ℃. The reaction was diluted with excess dichloromethane and water and washed with brine. After drying over anhydrous magnesium sulfate, the mixture was filtered, and the filtrate was distilled under reduced pressure to obtain 3.0 g (yield 98.0%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.43 to 7.25 (10H, m), 7.00 (1H, d, J = 13.2 Hz), 6.95 (1H, d, J = 13.2 Hz), 6.94 (1H, s), 5.68 (1H, m), 5.23 (1H, d, J = 10.0 Hz), 5.03 (1H, d, J = 5.2 Hz), 3.73-3.69, 3.61-3.57 (2H, Abq, J = 17.4 Hz), 1.49 (9H, s)

Mass (m / e) 641 (M + H ⁺ )

Preparation Example 2

7-amino-3-{( E ) -2-[(2,6-diamino-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2 .0] synthesis of oct-2-ene-2-carboxylic acid

Benzhydryl 7-[( t -butoxycarbonyl) amino] -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia 3 g (4.97 mmol) of -1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate were dissolved in 30 ml of dimethyl formamide. 1.23 g (6.46 mmol) of 2,4-diamino-6-mercapto pyrimidine 1/2 sulfate was added to the reactor and allowed to react at room temperature for 24 hours. Excess ethyl acetate was added and washed with brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was distilled under reduced pressure. The residue was purified by column chromatography.

1.39 g of the solid obtained above was deprotected with trifluoroacetic acid, anisole and triethylsilane, and then purified by diethyl ether and filtered. The solid thus obtained was dried under nitrogen to give 886 mg (two step yield 38.6%) of the title compound.

¹ H NMR (D ₂ O, 400 MHz) δ 6.62 (1H, d, J = 10.4 Hz), 6.35 (1H, d, J = 10.4 Hz), 5.81 (1H, s), 5.07 (1H, d, J = 5.2 Hz), 4.93 (1H, d, J = 4.8 Hz), 3.63-3.50 (1H, m)

Mass (m / e) 367 (M + H ⁺ )

Example 1

3-{( E ) -2-[(2,6-diamino-4-pyrimidinyl) sulfanyl] ethenyl} -7-({2-[(2,5-dichlorophenyl) sulfanyl] acetyl } Synthesis of amino) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

7-amino-3-{( E ) -2-[(2,6-diamino-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2 .0] oct-2-ene-2-carboxylic acid 340 mg (0.74 mmol) was dissolved in 8 ml of dichloromethane. 0.91 ml (3.68 mmol) of N, O -bis (trimethyl silyl) acetamide was added and stirred at room temperature for 2 hours. After cooling the reactor to 0 ^° C., 0.09 ml (1.10 mmol) of pyridine and 281 mg (1.10 mmol) of 2-[(2,5-dichlorophenyl) sulfanyl] acetyl chloride were added. The temperature of the reactor was slowly raised to room temperature and stirred at room temperature for 1 hour. A small amount of water was added dropwise, purified with diethyl ether and filtered. The solid thus obtained was dried under nitrogen. Purified by high pressure preparative liquid chromatography to give 21 mg (4.9%) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.18 (1H, d, J = 8.4 Hz), 7.51-7.47, 7.26-7.24 (3H, m), 7.10 (1H, d, J = 11.2 Hz), 6.68 (1H, d, J = 11.2 Hz), 6.30 (2H, s), 6.07 (2H, s), 5.66 (1H, s), 5.49 (1H, m), 4.99 (1H, d, J = 4.0 Hz) , 3.93 (2H, s), 3.78-3.74, 3.67-3.63 (2H, Abq, J = 16.4 Hz)

Mass (m / e) 585 (M + H ⁺ )

Preparation Example 3

7-amino-3-{( E ) -2-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2. 0] Synthesis of Oct-2-ene-2-carboxylic Acid

See Benzhydryl 7-[( t -butoxycarbonyl) amino] -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulphate as reference to US Pat. No. 4,622,393. Phenyl] oxy} ethenyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate benzhydryl 7-[( t -butoxycarbonyl) amino] -3-(( E ) -2-{[(4-methylphenyl) sulfonyl] oxy} ethenyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene- The title compound (68 mg) was obtained in the same manner as in Preparation Example 2 using 2-carboxylate (150 mg, 0.22 mmol) and 4,6-dimethyl-2-pyrimidinethiol (41 mg, 0.29 mmol). (47% yield in two steps)

Mass (m / e) 365 (M + H ⁺ )

Example 2

7-({2-[(2,5-dichlorophenyl) sulfanyl] acetyl} amino) -3-{( E ) -2-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] Synthesis of Tenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

7-Amino-3-{( E ) -2-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1 in the same manner as in Example 1 Azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (53 mg, 0.14 mmol) gave the title compound (6 mg). (Yield 7.1%)

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.97 (1H, d, J = 8.4 Hz), 7.28-7.25, 7.06-7.01 (3H, m), 7.04 (1H, d, J = 15.6 Hz), 6.77 (1H, s), 6.62 (1H, d, J = 15.6 Hz), 5.27 to 5.33 (1H, m), 4.78 (1H, d, J = 4.8 Hz), 3.93 (2H, s), 3.70 (2H, s), 3.33 (2H, m), 2.14 (6H, s)

Mass (m / e) 583 (M + H ⁺ )

Preparation Example 4

7-amino-3-(( E ) -2-{[2- (ethylsulfanyl) -6-methyl-4-pyrimidinyl] sulfanyl} ethenyl) -8-oxo-5-thia-1- Synthesis of Azabicyclo [4.2.0] oct-2-ene-2-carboxylic Acid

See Benzhydryl 7-[( t -butoxycarbonyl) amino] -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulphate as reference to US Pat. No. 4,622,393. Phenyl] oxy} ethenyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate benzhydryl 7-[( t -butoxycarbonyl) amino] -3-(( E ) -2-{[(4-methylphenyl) sulfonyl] oxy} ethenyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene- In the same manner as in Preparation Example 2, using 2-carboxylate (300 mg, 0.45 mmol) and 2- (ethylsulfanyl) -6-methyl-4-pyrimidinylhydrosulfide (109 mg, 0.58 mmol) Compound (231 mg) was obtained. (Two-step yield 75%)

Mass (m / e) 411 (M + H ⁺ )

Example 3

7-({2-[(2,5-dichlorophenyl) sulfanyl] acetyl} amino) -3-(( E ) -2-{[2- (ethylsulfanyl) -6-methyl-4-pyrimidy Synthesis of nil] sulfanyl} ethenyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

7-Amino-3-(( E ) -2-{[2- (ethylsulfanyl) -6-methyl-4-pyrimidinyl] sulfanyl} ethenyl) -8-oxo in the same manner as in Example 1 The title compound (8 mg) was obtained using -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (118 mg, 0.28 mmol). (Yield 4.4%)

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.37 (1H, d, J = 8.4 Hz), 7.66-7.7.6, 7.42-7.39 (3H, m), 7.53 (1H, d, J = 16.0 Hz), 7.23 (1H, s), 6.85 (1H, d, J = 16.0 Hz), 5.68 to 5.64 (1H, m), 5.18 (1H, d, J = 4.8 Hz), 4.08 (2H, s), 3.83 to 3.79, 3.73 to 3.69 (2H, Abq, J = 17.2 Hz), 3.27 to 3.21 (2H, q, J = 7.2 Hz), 2.65 (3H, s), 1.46 (3H, t, J = 7.2 Hz)

Mass (m / e) 629 (M + H ⁺ )

Preparation Example 5

7-amino-3-{( E ) -2-[(4-amino-2-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] Synthesis of Oct-2-ene-2-carboxylic Acid

Benzhydryl 7-[( t -butoxycarbonyl) amino] -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulfonyl] oxy} in the same manner as in Preparation Example 2 Ethenyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (1.3 g, 1.6 mmol) and 4-amino-2-pyrimidinethiol (343 mg, 2.7 Mmol) gave the title compound (61 mg). (2-step yield 7.6%)

Mass (m / e) 352 (M + H ⁺ )

Example 4

3-{( E ) -2-[(4-amino-2-pyrimidinyl) sulfanyl] ethenyl} -7-({2-[(2,5-dichlorophenyl) sulfanyl] acetyl} amino) Synthesis of -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

7-Amino-3-{( E ) -2-[(4-amino-2-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-aza in the same manner as in Example 1 Bicyclo [4.2.0] oct-2-ene-2-carboxylic acid (61 mg, 0.17 mmol) gave the title compound (11 mg). (Yield 12.2%)

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.20 (1H, d, J = 8.0 Hz), 7.93-7.90 (1H, m), 7.50-7.46, 7.26-7.18 (3H, m), 7.18 (1H, d, J = 16.8 Hz), 7.04 (2H, bs), 6.86 (1H, d, J = 16.8 Hz), 6.16 (1H, d, J = 6.0 Hz), 5.49-5.45 (1H, m), 4.99 ( 1H, d, J = 4.4 Hz), 3.92 (2H, s), 3.50 (2H, m)

Mass (m / e) 570 (M + H ⁺ )

Preparation Example 6

7-amino-3-{( E ) -2-[(4,6-diamino-2-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2 .0] synthesis of oct-2-ene-2-carboxylic acid

Benzhydryl 7-[( t -butoxycarbonyl) amino] -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulfonyl] oxy} in the same manner as in Preparation Example 2 Ethenyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (1.58 g, 2.6 mmol) and 4,6-diamino-2-pyrimidinethiol sulfate (646 mg, 3.4 mmol) gave the title compound (258 mg). (Two step yield 26.9%)

Mass (m / e) 367 (M + H ⁺ )

Example 5

3-{( E ) -2-[(4,6-diamino-2-pyrimidinyl) sulfanyl] ethenyl} -7-({2-[(2,5-dichlorophenyl) sulfanyl] acetyl } Synthesis of amino) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

7-Amino-3-{( E ) -2-[(4,6-diamino-2-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia- in the same manner as in Example 1 The title compound (8 mg) was obtained using 1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (195 mg, 2.7 mmol). (Yield 2.5%)

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.19 (1H, d, J = 8.0 Hz), 7.50-7.48, 7.26-7.31 (3H, m), 7.01 (1H, d, J = 12.0 Hz), 6.94 (1H, d, J = 12.0 Hz), 6.23 (4H, m), 5.51-5.57 (1H, m), 5.18 (1H, s), 5.00 (1H, d, J = 4.8 Hz), 3.92 (2H, s), 3.76 to 3.72, 3.66 to 3.62 (2H, Abq, J = 16.4 Hz)

Mass (m / e) 585 (M + H ⁺ )

Experimental Example 1: MIC

The usefulness of the compound according to the present invention is minimal to the standard strains of the compounds (I-1 to I-5) prepared in the above examples using vancomycin, which has an excellent effect on Gram-positive bacteria, as a control agent. Inhibitory concentration (Minimum Inhibitory Concentration) was obtained and evaluated. In other words, the minimum inhibitory concentration was diluted by a 2-fold dilution method and dispersed in Mueller-Hinton agar medium, followed by inoculating 2 μl of the test strain having 10 ⁷ cfu (colony forming unit) per ml. Incubated at 37 ℃ for 20 hours and the results are shown in Table 1. As a result of the minimum inhibitory concentration test for the strains, the compounds according to the present invention were found to have excellent activity against the main in vitro reduction bacteria including MRSA strains.

Susceptibility test results for the standard strain (㎍ / ㎖) Staphylococcus aureusgiorgio Staphylococcus aureus 77 Staphylococcus aureus K311 (S. aureus K311) Staphylococcus epidermis R005 (S. epidermidis R005) this. Facalilis 2009 (E. faecalis2009) I-1 <0.008 0.25 0.5 0.5 0.5 I-2 0.031 0.5 0.5 0.5 0.5 I-3 0.031 One One 0.5 0.25 I-4 0.016 0.25 0.25 0.13 0.5 I-5 <0.008 0.25 0.25 0.25 0.5 Vancomycin One One 2 One > 64

Claims (6)

Cephalosporin compounds of formula (1), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates, solvates or isomers thereof: [Formula 1] Where R1 And R2 are each hydrogen, halogen, C_1-6Alkyl, C_1-6C containing 1 to 2 heteroatoms selected from the group consisting of alkylthio, aryl, arylthio or nitrogen and oxygen atoms_5-6Heteroaryl, R3 represents hydrogen or a carboxy protecting group, R4, R5 and R6 is hydrogen, hydroxyl, C _1-6 alkyl, C _1-6 alkyloxy or C _1-6 represents an alkylamino group, R7 represents hydrogen, a hydroxy group, an amino group, a C _1-6 alkyl group, a C _1-6 alkyloxy, a C _1-6 alkylamino group, or a C _1-6 alkylthio group unsubstituted or substituted with an amino group or a hydroxy group, Q represents sulfur, oxygen or carbon, W and Y represent C or N, respectively, provided that when W or Y represents N, R4 and R6 are absent; The olefin at the position where the heteroarylthiol at the C-3 position is substituted includes both cis- or trans. The method of claim 1, 3-{(E) -2-[(2,6-diamino-4-pyrimidinyl) sulfanyl] ethenyl} -7-({2-[(2,5-dichlorophenyl) sulfanyl] acetyl } Amino) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid; 7-({2-[(2,5-dichlorophenyl) sulfanyl] acetyl} amino) -3-{(E) -2-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] Tenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid; 7-({2-[(2,5-dichlorophenyl) sulfanyl] acetyl} amino) -3-((E) -2-{[2- (ethylsulfanyl) -6-methyl-4-pyrimidy Nil] sulfanyl} ethenyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid; 3-{(E) -2-[(4-amino-2-pyrimidinyl) sulfanyl] ethenyl} -7-({2-[(2,5-dichlorophenyl) sulfanyl] acetyl} amino) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid; 3-{(E) -2-[(4,6-diamino-2-pyrimidinyl) sulfanyl] ethenyl} -7-({2-[(2,5-dichlorophenyl) sulfanyl] acetyl } A compound of formula (1) selected from the group consisting of amino) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. After activating a compound of formula (6) or a salt thereof with an acylating agent, the compound is reacted with a compound of formula (5) to obtain a compound of formula (11), or S → oxide of formula (11) is reduced. A process for the preparation of the compound of formula (1) according to claim 1 characterized in that: [Formula 5] [Formula 6] [Formula 11] Where R1, R2, R3, R4, R5, R6, R7, Q, W and Y are as defined in claim 1, p is 0 or 1, Double bonds in the C-3 position include both trans and cis. The method of claim 3 further comprising removing the acid protecting group. After reacting a compound of formula (8) with a compound of formula (9) to obtain a compound of formula (7), the aminoprotecting group A of the compound of formula (7) is removed, and A method for preparing a compound of formula (1) according to claim 1 characterized by activating a carboxylic acid or a salt thereof with an acylating agent and then reacting with a compound of formula (5) wherein A is removed: [Formula 5] [Formula 6] [Formula 7] [Formula 8] [Formula 9] In the above formulas, R1, R2, R3, R4, R5, R6, R7, Q, W and Y are as defined in claim 1, p is 0 or 1, A is an aminoprotecting group, Double bonds in the C-3 position include both trans and cis. An antibiotic composition comprising as an active ingredient a compound of formula (1) and a pharmaceutically acceptable carrier.