KR100453713B1 - Novel cephalosporin compounds and process for preparing same - Google Patents

Abstract

The present invention provides novel cephalosporin compounds of formula (1), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters thereof, hydrates and solvates and isomers thereof, pharmaceutical compositions containing them and their It relates to a manufacturing method.

Wherein A, Q, R ₁ , R ₂ and Ar are each as mentioned in the specification.

Description

Novel cephalosporin compounds and process for preparing 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), which is a compound useful as an antimicrobial agent and particularly has a strong antibacterial activity against strains such as methicillin resistant Staphylococcus aureus (MRSA), pharmaceutical To non-toxic salts thereof, physiologically hydrolysable esters thereof, hydrates and solvates thereof, and isomers thereof.

[Formula 1]

Where

A represents hydrogen or an amino protecting group,

R ₁ represents hydrogen or C _1-6 alkyl, C _3-4 alkynyl, C _3-6 cycloalkyl or C _3-6 cycloalkyl-methyl which may comprise one to three oxygen or halogens ,

R ₂ represents hydrogen or a carboxyl protecting group,

Ar is or Indicates

From here,

R _3, R _4, R ₅ and R ₇ are each hydrogen, hydroxyl, C _1-6 alkyl, unsubstituted or substituted amino substituted by C _1-6 alkyl, C _1-6 hydroxyalkyl or C _1-6 Alkylthio,

R ₆ is hydrogen, hydroxyl, unsubstituted or substituted by C _1-6 alkylamino, C _1-6 alkyl, or Indicates,

From here,

I represents S, NH, CH ₂ or O,

n represents 0, 1, 2, 3 or 4,

J represents amino, hydroxy or C _1-6 alkoxy unsubstituted or substituted by C _1-6 alkyl,

R ₈ and R ₉ represent hydrogen, C _1-6 alkyl, C _1-6 alkylamino, hydroxy or C _1-6 alkoxy,

W and Y each represent N or C, provided that when W or Y represents N, R ₃ , R ₅ , and R ₈ are absent;

Z represents CH or N,

Q represents CH, C-G, or N, where G represents halogen,

Ethenyl at the position where the heteroarylthio at the C-3 position is substituted may exist in cis or trans form.

The present invention also relates to a process for preparing the compound of formula (1) and an antimicrobial composition containing the compound as an active ingredient.

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 at position 3 or 7 of the cefe ring. It is well known that it is greatly influenced by the kind of substituents present at the position. 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.

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

For example, US Pat. No. 4,719,206 describes cephalosporin derivatives represented by the following formula (2).

Where

R ₁₀ and R ₁₁ represent amino or acylamino, or

R ₁₁ is Indicates

From here,

R ₁₂ represents an organic group,

X represents CH or N,

Z represents an acid,

Y represents CH or N, n represents 0, or

Y represents N ⁺ -R ₁₂ , wherein R ₁₂ represents an organic group, n represents 1, or

Y represents -AN ⁺ (R ₁₃ ) ₃ , wherein R ₁₃ represents lower alkyl,

A represents lower alkylene.

As another example, the cephalosporin derivative represented by the following general formula (3) is described in Japanese Patent No. 733,777.

Where

R ₁₄ is an amino group or a protected amino,

R ₁₅ is hydrogen or an organic group,

R ₁₆ is -COO-, a carboxy group or a protected carboxy group,

-A- is -CH ₂ -or -CH = CH-

X, Y and Z are CH or N,

Q represents CH, N or N ⁺ -R ₁₇ , wherein R ₁₇ represents lower alkyl.

In addition, 3-thio vinyl cephalosporin derivatives having antibacterial activity against JP10,182,655, JP5,345,787, JP6,135,972 and US Pat. No. 4,622,393 are known.

Compared to the present patent, these inventions have a similar double bond at the C-3 position but completely different substituents linked to the C-3 double bond.

Accordingly, the present inventors have conducted repeated studies to develop a cephalosporin compound having a broad antimicrobial activity against Gram-positive bacteria including MRSA, and as a result, a pyrimidinyl or heterobicycle substituent optionally substituted at the C-3 position It has been found that the thiovinyl cephalosporin compounds having are in line with these aims and have completed the present invention.

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 and solvates, and isomers thereof.

[Formula 1]

Where

A represents hydrogen or an amino protecting group,

R ₁ represents hydrogen or C _1-6 alkyl, C _3-4 alkynyl, C _3-6 cycloalkyl or C _3-6 cycloalkyl-methyl which may comprise one to three oxygen or halogens ,

R ₂ represents hydrogen or a carboxyl protecting group,

Ar is or Indicates

From here,

R _3, R _4, R ₅ and R ₇ are each hydrogen, hydroxyl, C _1-6 alkyl, unsubstituted or substituted amino substituted by C _1-6 alkyl, C _1-6 hydroxyalkyl or C _1-6 Alkylthio,

R ₆ is hydrogen, hydroxyl, unsubstituted or substituted by C _1-6 alkylamino, C _1-6 alkyl, or Indicates,

From here,

I represents S, NH, CH ₂ or O,

n represents 0, 1, 2, 3 or 4,

J represents amino, hydroxy or C _1-6 alkoxy unsubstituted or substituted by C _1-6 alkyl,

R ₈ and R ₉ represent hydrogen, C _1-6 alkyl, C _1-6 alkylamino, hydroxy or C _1-6 alkoxy,

W and Y each represent N or C, provided that when W or Y represents N, R ₃ , R ₅ , and R ₈ are absent;

Z represents CH or N,

Q represents CH, C-G, or N, where G represents halogen,

Ethenyl at the position where the heteroarylthio at the C-3 position is substituted may exist in cis or trans form.

The compounds according to the invention can be administered in injectable and oral formulations as desired.

The compound of the formula (1) according to the present invention is a geometric isomer, wherein the imino group of the Cefme ring 7-position contains syn- or anti-isomers containing 90% or more of syn-isomer or syn-isomer. Also included are mixtures of isomers. In addition, hydrates and solvates of the compound of formula (1) are also included in the scope of the present invention. In addition, the aminothiazole group of the compound of formula (1) may form a tautomer with an iminothiazoline group as follows,

2-aminothiazol-4-yl 2-iminothiazolin-4-yl

In addition, when Q is N, the aminothiadiazole group can form an iminothiadiazoline group and tautomer as follows.

Therefore, such tautomers are also included in the scope of the present invention.

In addition, the following trans- and cis-isomers exist depending on the geometry of the double bond of the thiovinyl group which is part of the C-3 substituent.

The present invention also encompasses each of these geometric isomers and mixtures thereof.

Pharmaceutically acceptable non-toxic salts of the compounds of formula (1) are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, hydroxyl acid, succinic acid, benzoic acid, Organic carboxylic acids or salts of methanesulfonic acid, para-toluenesulfonic acid, such as tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, and salts of penicillin with other acids known and used in the art. 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 bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkali metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, calcium carbonate), etc. And organic bases such as amino acids.

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

In the present invention,

G represents a halogen selected from Cl and F,

R ₁ represents hydrogen, methyl or cyclopentyl,

Preference is given to compounds in which R ₃ , R ₄ , R ₅ and R ₇ each represent hydrogen, hydroxyl or amino.

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

I-1: (6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3 -{( E ) -2-[(6-amino-2-hydroxy-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] Oct-2-ene-2-carboxylic acid,

I-2: (6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] 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,

I-3: (6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3 -{( E ) -2-[(2-amino-6-hydroxy-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] Oct-2-ene-2-carboxylic acid,

I-4: (6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3 -{( E ) -2-({2-[(2-aminoethyl) sulfanyl] -4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [ 4.2.0] oct-2-ene-2-carboxylic acid,

I-5: (6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3 -{( E ) -2-({2-[(2-aminoethyl) sulfanyl] -6-methyl-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1- Azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid,

I-6: (6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3 -{( E ) -2-[(4-amino-1 H-pyrazolo [3,4-d] pyrimidin-6-yl) sulfanyl] ethenyl} -8-oxo-5-thia-1-aza Bicyclo [4.2.0] oct-2-ene-2-carboxylic acid,

I-7: (6R, 7R) -3-[( E ) -2-({6-amino-2-[(2-aminoethyl) sulfanyl] -4-pyrimidinyl} sulfanyl) ethenyl] -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1- Azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid,

I-8: (6R, 7R) -7-{[2- (2-amino-1,3-thiazol-4-yl) -2- (methoxyimino) acetyl] 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,

I-9: (6R, 7R) -7-{[2- (2-amino-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] 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,

I-10: (6R, 7R) -7-({2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2-[(cyclopentyloxy) imino] acetyl} 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,

I-11: (6R, 7R) -3-{( E ) -2-[(2-amino-6-hydroxy-4-pyrimidinyl) sulfanyl] ethenyl} -7-{[2- ( 5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct -2-ene-2-carboxylic acid,

I-12: (6R, 7R) -3-{( E ) -2-[(6-amino-2-hydroxy-4-pyrimidinyl) sulfanyl] ethenyl} -7-{[2- ( 5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct -2-ene-2-carboxylic acid,

I-13: (6R, 7R) -7-{[2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -3- {( E ) -2-[(2,6-diamino-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2 -En-2-carboxylic acid,

I-14: (6R, 7R) -3-[( E ) -2-({6-amino-2-[(2-aminoethyl) sulfanyl] -4-pyrimidinyl} sulfanyl) ethenyl] -7-{[2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-aza Bicyclo [4.2.0] oct-2-ene-2-carboxylic acid,

I-15: (6R, 7R) -3-[( E ) -2-({2-[(2-aminoethyl) sulfanyl] -6-methyl-4-pyrimidinyl} sulfanyl) ethenyl] -7-{[2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyiminoacetyl] amino} -8-oxo-5-thia-1-azabi Cyclo [4.2.0] oct-2-ene-2-carboxylic acid,

I-16: (6R, 7R) -3-[( E ) -2-({2-[(2-aminoethyl) sulfanyl] -4-pyrimidinyl} sulfanyl) ethenyl] -7- { [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-azabicyclo [4.2 .0] oct-2-ene-2-carboxylic acid, and

I-17: (6R, 7R) -3-{( E ) -2-[(4-amino-1H-pyrazolo [3,4-d] pyrimidin-6-yl) sulfanyl] ethenyl}- 7-{[2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-azabi Cyclo [4.2.0] oct-2-ene-2-carboxylic acid.

Compounds of formula (1) according to the invention, pharmaceutically acceptable non-toxic salts, physiologically hydrolysable esters, hydrates or solvates thereof are prepared by the compounds of formula (4) in the presence of a solvent React with a compound of to obtain a compound of formula (1a), and if necessary, before or after the reaction, an amino protecting group or an acid protecting group is removed, or S → oxide of formula (1a) in which m is 1 is reduced. It can be prepared by obtaining a compound of.

[Formula 1]

HS-Ar

Where

A, R ₁ , R ₂ , Ar and Q are as mentioned above,

X represents halogen or sulfonyloxy (eg para-toluenesulfonyloxy, methanesulfonyloxy or trifluoromethylsulfonyloxy),

m is 0 or 1,

Double bonds at the C-3 position may exist as trans or cis.

Wherein the amino protecting group A is acyl, substituted or unsubstituted aryl (lower) alkyl (e.g. benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, etc.), halo (lower) alkyl (e.g. trichloro Chloromethyl, trichloroethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted arylalkylidene, substituted cycloalkylidene, 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 alkanesul And aryl (lower) alkoxycarbonyl (for example, benzyloxycarbonyl, etc.), etc. are mentioned. The acyl described above may have suitable substituents, such as 1-3 halogens, hydroxy, cyano, nitro and the like. In addition, the reaction product of a silane, boron, phosphorus compound, and an amino group can also be an amino protecting group.

The carboxy protecting group R ² is usually suitable as long as it is easily removed under mild conditions, such as (lower) alkyl esters (eg, methyl esters, t -butyl esters, etc.), (lower) alkenyl esters (eg, vinyl esters, Allyl esters, etc.), (lower) alkylthio (lower) alkyl esters (eg, methylthiomethyl esters), (lower) alkoxy (lower) alkyl esters (eg, methyloxymethyl esters, etc.), halo (lower) alkyl esters (E.g., 2,2,2-trichloroethyl ester, etc.), substituted or unsubstituted arylalkyl esters (e.g., benzyl esters, p-nitrobenzyl esters, p-methoxybenzyl esters, etc.) or silyl esters, and the like. .

The amino protecting group and the carboxyl protecting group can be easily removed under mild reaction conditions such as hydrolysis and reduction to form a free amino group or a carboxyl group. The amino protecting group and carboxyl protecting group may be appropriately selected and used according to the chemical properties of the compound of formula (1).

Leaving group X represents a halogen or sulfonyloxy group (for example para-toluenesulfonyloxy, methanesulfonyloxy and trifluoromethylsulfonyloxy).

In the present specification, the dashed line in the structure of a compound denotes a compound represented by the following formula (6a) or a compound of formula (6b) as a compound alone or a mixture of a compound of formula (6a) and a compound of formula (6b). do.

Where

m is as mentioned above.

Organic solvents usable in the above process for preparing the compound of formula (1) by substituting the compound of formula (5) at the C-3 position of the compound of formula (4) 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 dimethylformamide, esters such as ethyl acetate, ketones such as acetone, benzene and Hydrocarbons, alcohols such as methanol and ethanol, sulfoxides such as dimethyl sulfoxide, and the like, and mixtures of these solvents may be used.

The reaction temperature is -10 ~ 80 ℃, preferably 20 ~ 40 ℃ suitable, the compound of formula (5) may be used in 0.5 to 2 equivalents, preferably 1.0 to 1.1 equivalents relative to the compound of formula (4) have.

In preparing the compound of formula (1), the amino protecting group or acid protecting group of the compound of formula (4) can be removed by conventional methods well known in the cephalosporin art. 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 hydrolyze through amino halogenation and amino etherification. Acid hydrolysis is useful for the removal of tri (di) phenylmethyl groups or alkoxy carbonyl 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 desired compound of formula (1) can be separated or purified from the reaction product of the reaction by various methods such as recrystallization, electrophoresis, silica gel column chromatography or ion exchange resin chromatography.

The compound of formula (4) which is an intermediate of the present invention can be prepared as follows. Next, the compound of formula (7) or a salt thereof is activated with an acylating agent, and then reacted with a compound of formula (8) to obtain a compound of formula (9), and the vinyl at the C-3 position of the compound of formula (9) The compound of formula (4) can be prepared by introducing a group.

Where

A, R ₁ , R ₂ , Q and m are as mentioned above.

The meaning represented by the dotted line in the compound of formula (8) means that the compound of formula (8) alone represents the compound of formula (8a) or the compound of formula (8b) or the compound of formula (8c), or It is a mixture of the compound of, the compound of Formula (8b), and the compound of Formula (8c).

In which R is₂ And m are as mentioned above.

In preparing compounds of formula (9), the active acylated derivatives of formula (7) 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 dicyclohexyl carbodiimide).

The reaction of the compound of formula (7) with the compound of formula (8) may proceed in the presence of a condensing agent such as dicyclohexyl carbodiimide, carbonyl diimidazole, and the compound of formula (7) may also be used in free acid form. Can be. This 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 halogenated such as methylene chloride and chloroform. Solvents such as hydrocarbons, 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. The reaction temperature is -50 to 50 ° C, preferably -30 to 20 ° C, and the compound of formula (7) may be used in an equivalent to slight excess, that is, 1.05 to 1.2 equivalents, relative to the compound of formula (8). .

In order to synthesize the compound of the formula (4) from the compound of the formula (9), it is necessary to introduce a vinyl group at the C-3 position, and for this purpose, the compound of the formula (9) is a bis (dialkylamino) methane compound Reaction with (10) gives an enamine compound of the formula (11).

Where

A, R ₁ , R ₂ , Q and m are as mentioned above,

R ₁₇ represents OR ₂₁ , wherein R ₂₁ represents lower alkyl or phenyl,

R ₁₈ represents OR ₂₁ or NR ₁₉ R ₂₀ ,

R ₁₉ and R ₂₀ independently represent lower alkyl or phenyl,

Double bonds in the C-3 position may exist in trans or cis.

Solvents used in preparing the compound of formula (11) include dimethylformamide, hexamethylphosphorotriamide, dimethylacetamide, acetonitrile, ethyl acetate, dioxane or halogenated hydrocarbons and the like. The reaction temperature is 20 to 100 ^o C, preferably 40 to 80 ^o C and the amount of the compound represented by the formula (10) is 1 to 5 equivalents based on the compound of the formula (9).

Acid hydrolysis of the compound of formula (11) produces a compound of formula (12).

Wherein A, R ₁ , R ₂ , Q and m are as mentioned above.

The acid used to prepare the compound of formula (12) is an organic acid (formic acid or acetic acid) or mineral acid (hydrochloric acid or sulfuric acid), and the solvent is halogenated hydrocarbon, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide or alcohol. Etc. may be used and may be hydrolyzed only with acid without solvent. The reaction temperature is -20 to 100 ^o C, preferably 20 to 30 ^o C.

To prepare a compound of formula (4), the aldehyde at position C-3 of the compound of formula (12) must be converted to a vinyloxysulfonyl group. This manufacturing method is performed according to a conventional method. That is, the compound of formula (12) can be prepared by reacting the compound of formula (12) with an active form of sulfonic acid (sulphonic anhydride or sulfonylchloride) in the presence of a base. The base used here is usually a tertiary amine, preferably an organic base such as triethylamine, dimethylaniline, pyridine, and specific examples of active forms of sulfonic acid are para-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulphonic Anhydride, trifluoromethanesulphonic anhydride, and the like. The active amount of sulfonic acid is usually 1 to 3 equivalents of the compound of formula (12), and the solvent used is halogenated hydrocarbons such as methylene chloride and chloroform, tetrahydrofuran, acetonitrile, dimethylformamide or dimethylacetamide, etc. There are kinds and mixed solvents of the above solvents may be used. The reaction temperature is appropriately -78 ~ 0 ^o C.

Another method for preparing a compound of formula (1) according to the present invention is as follows. The compound of formula (13) is reacted with a compound of formula (7) or a carboxyl group-activated derivative in the presence of a solvent to obtain a compound of formula (1a), if necessary, before or after the reaction, if necessary. Or by removing the acid protecting group or reducing S → oxide of formula (1a) in which m is 1.

[Formula 7]

[Formula 1a]

Where

Ar, A, R ₁ , R ₂ , Q and m are as mentioned above,

Double bonds at the C-3 position may exist as trans or cis.

In the above method for preparing the compound of formula (1), the active acylated derivatives of formula (7) are acid chlorides, acid anhydrides, mixed acid anhydrides (preferably methylchloroformate, mesitylenesulfonyl chloride, p- Acid anhydrides formed with toluenesulfonyl chloride or chlorophosphate) or activated esters (preferably those formed in the reaction with N-hydroxy benzotriazole in the presence of a condensing agent such as dicyclohexyl carbodiimide) There is this.

The reaction of the compound of formula (7) with the compound of formula (13) can proceed in the presence of a condensing agent such as dicyclohexyl carbodiimide, carbonyl diimidazole, and the compound of formula (7) can also be used in free acid form. Can be. This 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 halogenated such as methylene chloride and chloroform. Solvents such as hydrocarbons, 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. The reaction temperature is -50 to 50 ° C, preferably -30 to 20 ° C, and the compound of formula (7) may be used in an equivalent to slight excess, that is, 1.05 to 1.2 equivalents, relative to the compound of formula (13). .

The acylation reaction may also proceed with the free acid of formula (7) in the presence of a condensing agent such as dicyclohexyl carbodiimide, carbonyl diimidazole. On the other hand, the acylation reaction usually proceeds well in the presence of organic bases such as tertiary amines, preferably triethylamine, dimethylaniline, pyridine or inorganic bases such as sodium bicarbonate and sodium carbonate, and methylene chloride and chloroform as solvents to be used. Solvents such as halogenated hydrocarbons, 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. The temperature of the acylation reaction is -50 to 50 ° C, preferably -30 to 20 ° C, and the acylating agent of the compound of formula (7) is equivalent to or slightly excess, i.e., 1.05 to the compound of formula (13). 1.2 equivalents may be used.

In preparing the compound of Formula (1), the amino protecting group or acid protecting group 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 carbonyl groups and is carried out using organic acids such as formic acid, trifluoro acetic acid, p-toluenesulfonic acid or inorganic acids such as hydrochloric acid.

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

Compounds of formula (13) which are intermediates of the invention are obtained by deprotecting amino protecting groups from the following compounds (14) with organic or inorganic acids.

Where

R ₂ , m and Ar are as mentioned above,

P represents an amino protecting group,

Double bonds in the C-3 position may exist in trans or cis.

Wherein the amino protecting group P is acyl, substituted or unsubstituted aryl (lower) alkyl (e.g. benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, etc.), halo (lower) alkyl (e.g. trichloro Chloromethyl, trichloroethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted arylalkylidene, substituted cycloalkylidene, 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 alkanesul Phenyl (for example, methylsulfonyl, ethylsulfonyl etc.) or aryl (lower) alkoxycarbonyl (for example, benzyloxycarbonyl etc.) etc. are mentioned. The acyl described above may have suitable substituents, such as 1-3 halogens, hydroxy, cyano, nitro and the like. In addition, the reaction product of silane, boron, phosphorus compound and amino group may be an amino protecting group.

The acid used to prepare the compound of formula (13) is an organic acid (trifluoromethanesulfonic acid, trifluoroacetic acid, formic acid or acetic acid) or mineral acid (hydrochloric acid or sulfuric acid) and the solvent is a halogenated hydrocarbon, ethyl acetate, tetra Hydrofuran, acetonitrile, dimethylformamide, alcohols and the like can be used and can be hydrolyzed only with acid without solvent. The reaction temperature is -50 to 50 ^o C, preferably 0 to 15 ^o C.

The compound of formula (14) can be prepared by substituting the compound of formula (5) for X at the C-3 vinyl position of the compound of formula (15).

Where

P, m, R ₂ and X are as mentioned above,

Double bonds in the C-3 position may exist in trans or cis.

Organic solvents that can be used 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, and dimethylformamide and the like. Drew, 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 trifluoromethylsulfonyloxy). The reaction temperature is -10 ° C to 80 ° C, preferably 20 ° C to 40 ° C, and the compound of formula (5) is 0.5 to 2 equivalents, preferably 1.0 to 1.1 equivalents, relative to the compound of formula (15) Can be used.

Compounds of formula (15) wherein X is chlorine may be prepared by reference to European Patent No. 154354 or 553538, and to prepare compounds of formula (15) wherein X is a sulfonyloxy group, The aldehyde at position C-3 must be converted to a vinyloxysulfonyl group. This manufacturing method is made according to a conventional method and is as follows.

Where

P, R ₂ and m are as mentioned above,

Double bonds in the C-3 position may exist in trans or cis.

The compound of formula (16) may be reacted with an active form of sulfonic acid (sulphonic unhydride or sulfonylchloride) in the presence of a base to prepare the compound of formula (15), wherein the base used is usually a tertiary amine , Preferably triethylamine, dimethylaniline, pyridine, and specific examples of the active form of sulfoic acid include para-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulphonic anhydride, trifluoromethane Sulfonic anhydrides and the like. The amount of active form of sulfoic acid is generally 1 to 3 equivalents of the compound of formula (16), and solvents used include halogenated hydrocarbons such as methylene chloride and chloroform, tetrahydrofuran, acetonitrile, dimethylformamide or dimethylacetamide. And the like and a mixed solvent of the above solvents may also be used. The reaction temperature is appropriately -78 ~ 0 ^o C.

Compounds of formula (16) having various amino protecting groups can be prepared from the starting material 7-amino-deacetyloxycephalosporanic acid with reference to US Pat. No. 4,622,393.

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 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 compounds of the present invention can also be administered in combination with other antibacterial agents such as penicillin or cephalosporin.

When formulating a compound of the present invention in unit dose form, it is preferred that this 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 prescription of the doctor 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 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 an adult, will be sufficient, but higher daily dosages may be desirable for some strains of infection.

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 resistant to a wide range of pathogenic bacteria, including various Gram-positive and Gram-negative bacteria. Its strong antimicrobial activity and broad antimicrobial spectrum make it very useful for the prevention and treatment of diseases caused by bacterial infection in animals including humans.

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

Preparation Example 1

Benzhydryl (6R, 7R) -7-({2- {2-[( t -Butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[(trityloxy) imino] acetyl} amino) -3-methyl-8-oxo-5 Synthesis of -thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Dichloromethane 750 distilled from 60 g (0.16 mol) of benzhydryl 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate Dissolved in mL and 2- {2-[( t -butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[(trityloxy) imino] acetic acid 97.84 g (0.17 mol) was added. After the reactor was cooled to -30 ° C, 32.1 ml (0.39 mol) of pyridine and 19.2 ml (0.21 mol) of phosphoryloxy chloride were slowly added dropwise. Stirring for 3 hours while gradually raising the temperature of the reactor to -10 ~ -5 ^o C. Diluted with excess ethyl acetate and washed once each with saturated ammonium chloride solution, 5% sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. The residue was purified by column chromatography to give 97.73 g (yield 66.9%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.28 (1H, s), 7.49 to 7.24 (25H, m), 6.94 (1H, s), 6.01 to 5.97 (1H, m), 5.04 (1H, d, J = 8.0 Hz), 3.38 to 3.33, 3.07 to 3.02 (2H, ABq, J = 20.0 Hz), 2.11 (3H, s), 1.50 (9H, s).

Mass (m / e) 926 (M + H ⁺ ).

Preparation Example 2

Benzhydryl (6R, 7R) -7-({2- {2-[( t -Butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[(trityloxy) imino] acetyl} amino) -8-oxo-3- (2- Synthesis of oxoethyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Benzhydryl (6R, 7R) -7-({2- {2-[( t -butoxycarbonyl) amino] -5-chloro-1,3 after heating 150 ml of dimethylformamide to 50 ^° C. -Thiazol-4-yl} -2-[(trityloxy) imino] acetyl} amino) -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2 50 g (53.96 mmol) of ene-2-carboxylate were added. 33.4 mL (161.9 mmol) of t -butoxy-bis (dimethylamino) methane was added dropwise to the reaction and stirred at 50 ^° C. for 25 minutes. Diluted with excess ethyl acetate and washed with brine. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. 600 ml of ethyl acetate and 400 ml of 1N hydrochloric acid were added to the residue, followed by stirring at room temperature for 2 hours. Again diluted with excess ethyl acetate and washed with brine. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. The residue was dissolved in a small amount of diethyl ether, purified with n-hexane, filtered and dried under nitrogen to give 47.42 g (yield 92.1%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 9.56 (1H, s), 8.26 (1H, bs), 7.47-7.33 (25H, m), 6.90 (1H, s), 6.11-6.07 (1H, m), 5.08 (1H, d, J = 4.8 Hz), 3.70 to 3.66, 3.53 to 3.49 (2H, ABq, J = 16.0 Hz), 3.51 to 3.46, 3.16 to 3.11 (2H, ABq, J = 20.0 Hz), 1.50 (9H , s).

Mass (m / e) 954 (M + H ⁺ ).

Preparation Example 3

Benzhydryl (6R, 7R) -7-({2- {2-[( t -Butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[(trityloxy) imino] acetyl} amino) -8-oxo-3-(( E Synthesis of) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Benzhydryl (6R, 7R) -7-({2- {2-[( t -butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[( Trityloxy) imino] acetyl} amino) -8-oxo-3- (2-oxoethyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate 27.3 g (28.6 mmol) was dissolved in 87.4 mL of distilled dichloromethane. After the reactor was cooled to -30 ~ 35 ^o C, 37.4 mL (214.6 mmol) of pyridine and 7.22 mL (42.9 mmol) of trifluoromethanesulphonic anhydride were added thereto, followed by stirring for 15 minutes. Diluted with excess ethyl acetate, neutralized with 1N hydrochloric acid and washed with brine. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. The residue was purified by column chromatography to give 10.0 g (32.2% yield) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.17 (1H, bs), 7.46-7.24 (25H, m), 7.13 (1H, d, J = 12.0 Hz), 7.00 (1H, s), 6.88 (1H, d , J = 12.0 Hz), 6.05 (1H, m), 5.09 (1H, d, J = 4.0 Hz), 3.45-3.41, 3.23-3.19 (2H, ABq, J = 16.0 Hz), 1.50 (9H, s) .

Mass (m / e) 1086 (M + H ⁺ ).

Preparation Example 4

Benzhydryl 7-({2- (methoxyimino) -2- [2- (tritylamino) -1,3-thiazol-4-yl] acetyl} amino) -3-methyl-8-oxo- Synthesis of 5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

The title compound in the same manner as in Preparation Example 1 using 2- (methoxyimino) -2- [2- (tritylamino) -1,3-thiazol-4-yl] acetic acid (12.82 g, 29 mmol) (16.6 g) was obtained (yield 78%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.46-7.26 (25H, m), 6.92 (1H, s), 6.80 (1H, s), 6.04 (1H, d, J = 4.4 Hz), 4.09 (3H, s ), 3.52-3.47, 3.23-3.19 (2H, ABq, J = 18.4 Hz), 2.13 (3H, s).

Mass (m / e) 806 (M + H ⁺ ).

Preparation Example 5

Benzhydryl 7-({2- (methoxyimino) -2- [2- (tritylamino) -1,3-thiazol-4-yl] acetyl} amino) -8-oxo-3- (2 Synthesis of -oxoethyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Benzhydryl 7-({2- (methoxyimino) -2- [2- (tritylamino) -1,3-thiazol-4-yl] acetyl} amino) -3-methyl-8-oxo- Using the 5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (10 g, 12.4 mmol), the title compound (5.6 g) was obtained in the same manner as in Preparation Example 2 (yield) 54%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 9.56 (1H, s), 7.49-7.20 (25H, m), 6.90 (1H, s), 6.82 (1H, s), 5.98-5.91 (1H, m), 5.05 (1H, d, J = 4.0 Hz), 4.09 (3H, s), 3.72 to 3.68, 3.55 to 3.51 (2H, ABq, J = 16.0 Hz), 3.53 to 3.48, 3.18 to 3.13 (2H, ABq, J = 20.0 Hz).

Mass (m / e) 834 (M + H ⁺ ).

Preparation Example 6

Benzhydryl 7-({2- (methoxyimino) -2- [2- (tritylamino) -1,3-thiazol-4-yl] acetyl} amino) -8-oxo-3-(( E Synthesis of) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Benzhydryl 7-({2- (methoxyimino) -2- [2- (tritylamino) -1,3-thiazol-4-yl] acetyl} amino) -8-oxo-3- (2 -Oxoethyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (5.6 g, 6.7 mmol) in the same manner as in Preparation Example 3 g) was obtained (yield 38.4%).

Mass (m / e) 966 (M + H ⁺ ).

Preparation Example 7

Benzhydryl 7-({2- {2-[( t -Butoxycarbonyl) amino] -1,3-thiazol-4-yl} -2-[(trityloxy) imino] acetyl} amino) -3-methyl-8-oxo-5-thia-1 Synthesis of azabicyclo [4.2.0] oct-2-ene-2-carboxylate

2- {2-[(t-butoxycarbonyl) amino] -1,3-thiazol-4-yl} -2-[(trityloxy) imino] acetic acid (10 g, 18.8 mmol) In the same manner as in Preparation Example 1, the title compound (9.26 g) was obtained (yield 55%).

Mass (m / e) 892 (M + H ⁺ ).

Preparation Example 8

Benzhydryl 7-({2- {2-[( t -Butoxycarbonyl) amino] -1,3-thiazol-4-yl} -2-[(trityloxy) imino] acetyl} amino) -8-oxo-3- (2-oxoethyl)- Synthesis of 5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Benzhydryl 7-({2- {2-[(t-butoxycarbonyl) amino] -1,3-thiazol-4-yl} -2-[(trityloxy) imino] acetyl} amino ) -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (10 g, 11.2 mmol) in the same manner as in Preparation Example 2 The title compound (10 g) was obtained (yield 97.0%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 9.55 (1H, s), 7.47-7.25 (25H, m), 7.05 (1H, s), 6.89 (1H, s), 6.11-6.07 (1H, m), 5.09 (1H, d, J = 4.0 Hz), 3.70 to 3.66, 3.54 to 3.50 (2H, ABq, J = 16.0 Hz), 3.49 to 3.45, 3.16 to 3.12 (2H, ABq, J = 16.0 Hz), 1.51 (9H , s).

Mass (m / e) 920 (M + H ⁺ ).

Preparation Example 9

Benzhydryl 7-({2- {2-[( t -Butoxycarbonyl) amino] -1,3-thiazol-4-yl} -2-[(trityloxy) imino] acetyl} amino) -8-oxo-3-(( E Synthesis of) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Benzhydryl 7-({2- {2-[(t-butoxycarbonyl) amino] -1,3-thiazol-4-yl} -2-[(trityloxy) imino] acetyl} amino Preparation Example Using 8-oxo-3- (2-oxoethyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (10 g, 10.8 mmol) In the same manner as 3, the title compound (3.2 g) was obtained (yield 27.0%).

Mass (m / e) 1052 (M + H ⁺ ).

Preparation Example 10

Benzhydryl 7-({2- {2-[( t -Butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[(cyclopentyloxy) imino] acetyl} amino) -3-methyl-8-oxo-5 Synthesis of -thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

2- {2-[(t-butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[(cyclopentyloxy) imino] acetic acid (1.53 g, 3.9 Mmol) to give the title compound (4.76 g) in the same manner as in Preparation Example 1 (yield 62%).

Mass (m / e) 752 (M + H ⁺ ).

Preparation Example 11

Benzhydryl 7-({2- {2-[( t -Butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[(cyclopentyloxy) imino] acetyl} amino) -8-oxo-3- (2- Synthesis of oxoethyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Benzhydryl 7-({2- {2-[(t-butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[(cyclopentyloxy) imino ] Acetyl} amino) -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (4.76 g, 6.3 mmol) In the same manner as in the 2, the title compound (2.45 g) was obtained (yield 49.0%).

Mass (m / e) 780 (M + H ⁺ ).

Preparation Example 12

Benzhydryl 7-({2- {2-[( t -Butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[(cyclopentyloxy) imino] acetyl} amino) -8-oxo-3-(( E Synthesis of) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Benzhydryl 7-({2- {2-[(t-butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[(cyclopentyloxy) imino ] Acetyl} amino) -8-oxo-3- (2-oxoethyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (2.45 g, 3.14 mmol) Using the same method as in Preparation Example 3 to obtain the title compound (2.5g) (yield 73.0%).

Mass (m / e) 912 (M + H ⁺ ).

Preparation Example 13

Benzhydryl 7-[( t -Butoxycarbonyl) amino] -8-oxo-3-(( E Synthesis of) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-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 were dissolved in 17 ml of distilled dichloromethane. After the reactor was cooled to -78 ^° C., 1.32 mL (7.59 mmol) of N, N -diisopropylethyl amine and 1.28 mL (7.59 mmol) of trifluoromethanesulphonic anhydride were slowly added dropwise. Stir for 20 minutes while maintaining the temperature of the reactor at -78 ^o C. Diluted with excess dichloromethane and water and washed with brine. After drying over anhydrous magnesium sulfate, the filtrate was filtered 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 14

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

Benzhydryl 7-[(t-Butoxycarbonyl) amino] -8-oxo-3-((E) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate 3 g (4.97 mmol) was dissolved in 30 ml of dimethylformamide. 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 the filtrate was filtered 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 ⁺ ).

Preparation Example 15

Benzhydryl (6R, 7R) -7- (2- {5-[( t -Butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2-{[(trityloxy) imino] acetyl} amino) -3-methyl-8-oxo-5 Synthesis of -thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Benzhydryl 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (5.61 g, 14.74 mmol) and 2- { 5-[( t -butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2-[(trityloxy) imino] acetic acid (7.83 g, 14.75 mmol) In the same manner as in Preparation Example 1, the title compound (13.2 g) was obtained (yield 99%).

¹ H NMR (CDCl ₃ , 500 MHz) δ 7.5 to 7.1 (25H, m), 6.92 (1H, s), 6.04 to 6.02 (1H, m), 5.04 (1H, d, 5.0 Hz), 3.34 (1H, d , 18.3 Hz), 3.04 (1H, d, 17.9 Hz), 2.1 (3H, s), 1.51 (9H, s).

Mass 893 (M + H ⁺ ).

Preparation Example 16

Benzhydryl (6R, 7R) -7- (2- {5-[( t -Butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2-{[(trityloxy) imino] acetyl} amino) -8-oxo-3- (2- Synthesis of oxoethyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Benzhydryl (6R, 7R) -7- (2- {5-[( t -butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2-{[(tri Tyloxy) imino] acetyl} amino) -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (13.2 g, 14.78 mmol) And t -butoxy-bis (dimethylamino) methane (7.6 g, 43.6 mmol) gave the title compound (11.8 g) in the same manner as in Preparation Example 2 (yield 86%).

¹ NMR (CDCl ₃ 400 MHz) δ 9.53 (1H, brs), 7.50 to 7.01 (25H, m), 6.91 (1H, s), 6.06 to 6.03 (1H, m), 5.07 (1H, d, 5.2 Hz), 3.62 (1H, d, 16.4 Hz), 3.50 (1H, d, 16.4 Hz), 3.43 (1H, d, 18.4 Hz), 3.12 (1H, d, 18 Hz), 1.53 (9H, s).

Mass 922 (M + H ⁺ ).

Preparation Example 17

Benzhydryl (6R, 7R) -7- (2- {5-[( t -Butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2-{[(trityloxy) imino] acetyl} amino) -8-oxo-3-((E Synthesis of) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Benzhydryl (6R, 7R) -7- (2- {5-[( t -butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2-{[(tri Tyloxy) imino] acetyl} amino) -8-oxo-3- (2-oxoethyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (11.8 g, 12.8 mmol) to give the title compound (4 g) in the same manner as in Production Example 3 (yield 29%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.61 to 7.1 (26H, m), 7.00 (1H, s), 6.83 (1H, d, 12.4 Hz), 6.05 to 5.99 (1H, m), 5.09 (1H, d , 4.4 Hz), 3.42 (1H, d, 17.6 Hz), 3.21 (1H, d, 18.0 Hz), 1.50 (9H, s).

Mass 1053 (M + H ⁺ )

Example 1

(6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3-{( E ) -2-[(6-amino-2-hydroxy-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- Synthesis of En-2-carboxylic Acid

Benzhydryl (6R, 7R) -7-({2- {2-[( t -butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[( Trityloxy) imino] acetyl} amino) -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabi 11.33 g (10.4 mmol) of cyclo [4.2.0] oct-2-ene-2-carboxylate were dissolved in 35 ml of dimethylformamide and 17 ml of dimethyl sulfoxide. 3.01 g (15.7 mmol) of 4-amino-6-mercapto-2-pyrimidinol 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 the filtrate was filtered under reduced pressure. The residue was purified by column chromatography.

7.93 g of the solid obtained above was deprotected with trifluoroacetic acid and triethylsilane and separated and purified by high pressure preparative liquid chromatography to give 780 mg (two step yield 13.1%) of the title compound.

¹ H NMR (D ₂ O, 400 MHz) δ 7.07 (1H, d, J = 15.2 Hz), 6.63 (1H, d, J = 15.2 Hz), 5.88 (1H, d, J = 4.8 Hz), 5.86 (1H , s), 5.28 (1H, d, J = 4.8 Hz), 3.80-3.76, 3.72-3.68 (2H, ABq, J = 17.2 Hz).

Mass (m / e) 571 (M + H ⁺ ).

Example 2

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

Benzhydryl (6R, 7R) -7-({2- {2-[(t-butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[( Trityloxy) imino] acetyl} amino) -8-oxo-3-((E) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabi Example 1 using cyclo [4.2.0] oct-2-ene-2-carboxylate (7.7 g, 7 mmol) and 2,6-diamino-4-pyrimidinethiol sulfate (2.0 g, 10.4 mmol) In the same manner as the title compound (574 mg) was obtained (two-step yield 14%).

¹ H NMR (D ₂ O, 400 MHz) δ 6.84 (1H, d, J = 15.6 Hz), 6.64 (1H, d, J = 15.6 Hz), 5.72 (1H, d, J = 4.8 Hz), 5.12 (1H , d, J = 4.8 Hz), 3.66-3.62, 3.57-3.53 (2H, Abq, J = 17.6 Hz).

Mass (m / e) 570 (M + H ⁺ ).

Example 3

(6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3-{( E ) -2-[(2-amino-6-hydroxy-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- Synthesis of En-2-carboxylic Acid

Benzhydryl (6R, 7R) -7-({2- {2-[(t-butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[( Trityloxy) imino] acetyl} amino) -8-oxo-3-((E) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabi Example using cyclo [4.2.0] oct-2-ene-2-carboxylate (10 g, 9.3 mmol) and 2-amino-6-mercapto-4-pyrimidinol sulfate (2.67 g, 13.9 mmol) The title compound (1.0 g) was obtained in the same manner as 1 (two-step yield 20%).

¹ H NMR (D ₂ O, 400 MHz) δ 7.00 (1H, d, J = 15.6 Hz), 6.78 (1H, d, J = 15.6 Hz), 5.88 (1H, d, J = 2.8 Hz), 5.75 (1H , d, J = 2.0 Hz), 5.27-5.26 (1H, m), 3.82-3.78, 3.72-3.68 (2H, ABq, J = 16.8 Hz).

Mass (m / e) 571 (M + H ⁺ ).

Example 4

(6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3-{( E ) -2-({2-[(2-aminoethyl) sulfanyl] -4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] Synthesis of Oct-2-ene-2-carboxylic Acid

Benzhydryl (6R, 7R) -7-({2- {2-[(t-butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[( Trityloxy) imino] acetyl} amino) -8-oxo-3-((E) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabi Cyclo [4.2.0] oct-2-ene-2-carboxylate (2 g, 1.8 mmol) and 2-{[2- (tritylamino) ethyl] sulfanyl} -4-pyrimidinethiol (1.0 g, 2.3 Mmol) to give the title compound (25 mg) in the same manner as in Example 1 (two-step yield 2.2%).

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 8.32 (1H, d, J = 5.0 Hz), 7.37 (1H, d, J = 15.6 Hz), 7.20 (1H, d, J = 5.0 Hz), 6.67 ( 1H, d, J = 15.6 Hz), 5.68 (1H, m), 5.04 (1H, d, J = 5.1 Hz), 3.68-3.64, 3.54-3.50 (2H, ABq, J = 20.0 Hz), 3.37 (2H , m), 3.19 (2H, m), 1.80 (2H, s).

Mass (m / e) 615 (M + H ⁺ ).

Example 5

(6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3-{( E ) -2-({2-[(2-aminoethyl) sulfanyl] -6-methyl-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [ 4.2.0] Synthesis of Oct-2-ene-2-carboxylic Acid

Benzhydryl (6R, 7R) -7-({2- {2-[(t-butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[( Trityloxy) imino] acetyl} amino) -8-oxo-3-((E) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabi Cyclo [4.2.0] oct-2-ene-2-carboxylate (2.0 g, 1.8 mmol) and 6-methyl-2-{[2- (tritylamino) ethyl] sulfanyl} -4-pyrimidinethiol (1.1 g, 2.4 mmol) was used to obtain the title compound (20 mg) in the same manner as in Example 1 (two-step yield 1.7%).

¹ H NMR (D ₂ O, 400 MHz) δ 6.78 (1H, d, J = 16.0 Hz), 6.72 (1H, d, J = 16.0 Hz), 6.64 (1H, s), 5.57 (1H, d, J = 4.8 Hz), 4.97 (1H, d, J = 4.8 Hz), 3.48-3.44, 3.40-3.36 (2H, ABq, J = 17.2 Hz), 3.19 (2H, t, J = 6.4 Hz), 3.05-2.96 ( 2H, m), 2.01 (3H, s), 1.59 (2H, s).

Mass (m / e) 629 (M + H ⁺ ).

Example 6

(6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3-{( E ) -2-[(4-amino-1 H -Pyrazolo [3,4- d ] Pyrimidin-6-yl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Benzhydryl (6R, 7R) -7-({2- {2-[(t-butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[( Trityloxy) imino] acetyl} amino) -8-oxo-3-((E) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabi Cyclo [4.2.0] oct-2-ene-2-carboxylate (2.0 g, 1.8 mmol) with 4-amino-1H-pyrazolo- [3,4-d] pyrimidine-6-thiol (833 mg , 4.9 mmol) gave the title compound (188 mg) in the same manner as in Example 1 (two-step yield 17.1%).

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 13.10 (1H, s), 11.55 (1H, s), 9.21 (1H, d, J = 8.0 Hz), 7.85 (1H, s), 7.16 (2H, s ), 7.06 (1H, d, J = 16.4 Hz), 6.80 (1H, d, J = 16.4 Hz), 5.47 to 5.53 (1H, m), 4.91 (1H, d, J = 4.8 Hz), 3.44 to 3.35 (2H, m).

Mass (m / e) 595 (M + H ⁺ ).

Example 7

(6R, 7R) -3-[( E ) -2-({6-amino-2-[(2-aminoethyl) sulfanyl] -4-pyrimidinyl} sulfanyl) ethenyl] -7-{[2- (2-amino-5-chloro -1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2 Synthesis of Carboxylic Acids

Benzhydryl (6R, 7R) -7-({2- {2-[(t-butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[( Trityloxy) imino] acetyl} amino) -8-oxo-3-((E) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabi Cyclo [4.2.0] oct-2-ene-2-carboxylate (566 mg, 0.52 mmol) and t-butyl 6-mercapto-2-{[2- (tritylamino) ethyl] sulfanyl} -4 The title compound (84 mg) was obtained by the same method as Example 1 using pyrimidinylcarbamate (471 mg, 0.86 mmol) (two step yield: 25.5%).

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 9.38 (1H, d, J = 7.8 Hz), 7.32 (2H, s), 7.06 (1H, d, J = 15.6 Hz), 6.99 (1H, s), 6.66 (1H, d, J = 15.6 Hz), 6.07 (1H, s), 5.65-5.63 (1H, m), 5.06 (1H, d, J = 5.1 Hz), 3.53-3.47 (2H, m), 3.20 ˜3.14 (2H, m), 3.07-3.03 (2H, m).

Mass (m / e) 630 (M + H ⁺ ).

Example 8

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

Benzhydryl 7-({2- (methoxyimino) -2- [2- (tritylamino) -1,3-thiazol-4-yl] acetyl} amino) -8-oxo-3-(( E) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (2.8 g, 2.6 mmol) and 2,6-diamino-4-pyrimidinethiol sulfate (1.93 g, 10 mmol) gave the title compound (200 mg) in the same manner as in Example 1 (two-step yield 14.1%).

¹ H NMR (D ₂ O, 400 MHz) δ 6.82 (1H, s), 6.79 (1H, d, J = 15.6 Hz), 6.59 (1H, d, J = 15.6 Hz), 5.74 (1H, s), 5.62 (1H, d, J = 4.8 Hz), 5.07 (1H, d, J = 4.8 Hz), 3.79 (3H, s), 3.61-3.57, 3.53-3.49 (2H, ABq, J = 16.4 Hz).

Mass (m / e) 550 (M + H ⁺ ).

Example 9

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

Benzhydryl 7-({2- {2-[(t-butoxycarbonyl) amino] -1,3-thiazol-4-yl} -2-[(trityloxy) imino] acetyl} amino ) -8-oxo-3-((E) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabicyclo [4.2.0] oct-2- Title compound (240 mg) in the same manner as in Example 1 using en-2-carboxylate (3.2 g, 3.0 mmol) and 2,6-diamino-4-pyrimidinethiol sulfate (3.2 g, 16.7 mmol) Was obtained (two step yield 15.0%).

¹ H NMR (D ₂ O, 500 MHz) δ 7.01 (1H, d, J = 15.6 Hz), 6.99 (1H, s), 6.77 (d, J = 15.6 Hz), 5.92 (1H, s), 5.86 (1H , d, J = 5.0 Hz), 5.30 (1H, d, J = 5.0 Hz), 3.81-3.77, 3.73-3.69 (2H, ABq, J = 17.4 Hz).

Mass (m / e) 536 (M + H ⁺ ).

Example 10

(6R, 7R) -7-({2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2-[(cyclopentyloxy) imino] acetyl} amino) -3 -{( E ) -2-[(2,6-diamino-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene- Synthesis of 2-carboxylic Acid

Benzhydryl 7-({2- {2-[(t-butoxycarbonyl) amino] -5-chloro-1,3-thiazol-4-yl} -2-[(cyclopentyloxy) imino ] Acetyl} amino) -8-oxo-3-((E) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia-1-azabicyclo [4.2.0] The title compound in the same manner as in Example 1 using oct-2-ene-2-carboxylate (2.5 g, 2.7 mmol) and 2,6-diamino-4-pyrimidinethiol sulfate (901 mg, 4.7 mmol) (200 mg) was obtained (two steps yield 13.0%).

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.45 (1H, d, J = 8.4 Hz), 7.38 (2H, s), 7.21 (1H, d, J = 16.0 Hz), 6.58 (1H, d, J = 16.0 Hz), 6.22 (2H, s), 5.98 (2H, s), 5.64 (1H, s), 5.57 to 5.54 (1H, m), 5.64 (1H, d, J = 5.2), 4.67 (1H, t, J = 2.8), 3.59-3.45, 3.51-3.47 (2H, ABq, J = 17.2), 1.93-1.64 (6H, m), 1.48-1.46 (2H, m).

Mass (m / e) 638 (M + H ⁺ ).

Example 11

(6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3-{( E ) -2-[(2,6-diamino-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene- Synthesis of 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 (trimethylsilyl) 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 t -butyl 5-chloro-4- {2-[(diethoxyphosphorothioyl) oxy] -2-oxoethaneimidoyl} 788 mg (1.10 mmol) of -1,3-thiazol-2-yl carbamate 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.

The solid obtained above was deprotected with trifluoroacetic acid, anisole and triethylsilane, and then purified by diethyl ether and filtered. Separation and purification by high pressure preparative liquid chromatography gave 21 mg (4.9%) of the title compound.

¹ H NMR (D ₂ O, 400 MHz) δ 6.84 (1H, d, J = 15.6 Hz), 6.64 (1H, d, J = 15.6 Hz), 5.72 (1H, d, J = 4.8 Hz), 5.12 (1H , d, J = 4.8 Hz), 3.66-3.62, 3.57-3.53 (2H, ABq, J = 17.6 Hz).

Mass (m / e) 570 (M + H ⁺ ).

Example 12

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

Benzhydryl (6R, 7R) -7- (2- {5-[( t -butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2 obtained in Production Example 17. -{[(Trityloxy) imino] acetyl} amino) -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia- Using 1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (2 g, 1.9 mmol) and 2-amino-6-mercapto-4-pyrimidinol sulfate (430 mg, 2.2 mmol) In the same manner as in Example 1, the title compound (179 mg) was obtained (yield 0.2%).

¹ H NMR (DMSO, 400 MHz) δ 9.39 (1H, d, 6.6 Hz), 8.03 (2H, brs), 7.24 (1H, d, 12.8 Hz), 6.94 (1H, brs), 6.53 (1H, d, 12.8 Hz), 5.65 to 5.82 (1H, m), 5.45 (1H, s), 5.03 (1H, d, 4.0 Hz), 3.65 (1H, d, 13.2 Hz), 3.48 (1H, d, 13.5 Hz).

Mass 538 (M + H ⁺ ).

Example 13

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

Benzhydryl (6R, 7R) -7- (2- {5-[( t -butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2 obtained in Production Example 17. -{[(Trityloxy) imino] acetyl} amino) -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia- Using 1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (2 g, 1.9 mmol) and 4-amino-6-mercapto-2-pyrimidinol sulfate (450 mg, 2.3 mmol) In the same manner as in Example 1, the title compound (158 mg) was obtained (yield 0.15%).

Mass 538 (M + H ⁺ ).

Example 14

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

Benzhydryl (6R, 7R) -7- (2- {5-[( t -butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2 obtained in Production Example 17. -{[(Trityloxy) imino] acetyl} amino) -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia- 1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (2 g, 1.9 mmol) and 2,6-diamino-4-pyrimidinethiol sulfate (440 mg, 2.3 mmol) In the same manner as in Example 1, the title compound (184 mg) was obtained (yield 0.2%).

Mass 537 (M + H ⁺ )

Example 15

(6R, 7R) -3-[( E ) -2-({6-amino-2-[(2-aminoethyl) sulfanyl] -4-pyrimidinyl} sulfanyl) ethenyl] -7-{[2- (5-amino-1,2 , 4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2- Synthesis of Carboxylic Acids

Benzhydryl (6R, 7R) -7- (2- {5-[( t -butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2 obtained in Production Example 17. -{[(Trityloxy) imino] acetyl} amino) -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia- 1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (2 g, 1.9 mmol) and t -butyl 6-mercapto-2-{[2- (tritylamino) ethyl] sulfanyl } -4-pyrimidinylcarbamate (1.5 g, 2.7 mmol) gave the title compound (82 mg) in the same manner as in Example 1 (yield 7%).

Mass 597 (M + H ⁺ )

Example 16

(6R, 7R) -3-[( E ) -2-({2-[(2-aminoethyl) sulfanyl] -6-methyl-4-pyrimidinyl} sulfanyl) ethenyl] -7-{[2- (5-amino-1,2 , 4-thiadiazol-3-yl) -2- (hydroxyiminoacetyl] amino} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid Synthesis of

Benzhydryl (6R, 7R) -7- (2- {5-[( t -butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2 obtained in Production Example 17. -{[(Trityloxy) imino] acetyl} amino) -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia- 1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (2 g, 1.9 mmol) and 6-methyl-2-{[2- (tritylamino) ethyl] sulfanyl} -4- Using pyrimidinethiol (1.2 g, 2.7 mmol), the title compound (102 mg) was obtained in the same manner as in Example 1 (yield 9%).

Mass 596 (M + H ⁺ )

Example 17

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

Benzhydryl (6R, 7R) -7- (2- {5-[( t -butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2 obtained in Production Example 17. -{[(Trityloxy) imino] acetyl} amino) -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia- 1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (2 g, 1.9 mmol) and 2-{[2- (tritylamino) ethyl] sulfanyl} -4-pyrimidinethiol ( 1.1 g, 2.5 mmol) was used in the same manner as in Example 1 to obtain the title compound (90 mg) (yield 8%).

Mass 582 (M + H ⁺ )

Example 18

(6R, 7R) -3-{( E ) -2-[(4-amino-1H-pyrazolo [3,4-d] pyrimidin-6-yl) sulfanyl] ethenyl} -7-{[2- (5-amino-1,2, 4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid Synthesis of

Benzhydryl (6R, 7R) -7- (2- {5-[( t -butoxycarbonyl) amino] -1,2,4-thiadiazol-3-yl} -2 obtained in Production Example 17. -{[(Trityloxy) imino] acetyl} amino) -8-oxo-3-(( E ) -2-{[(trifluoromethyl) sulfonyl] oxy} ethenyl) -5-thia- 1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (2 g, 1.9 mmol) and 4-amino-1 H-pyrazolo [3,4-d] pyrimidine-6-thiol (700 mg , 4.1 mmol) was used in the same manner as in Example 1 to obtain the title compound (122 mg) (yield 11%).

Mass 562 (M + H ⁺ )

Experimental Example 1) Minimum Inhibition Concentration (MIC)

The usefulness of the compound according to the present invention is the standard of the compounds (I-1 to I-6, I-10) prepared in the above examples using Vancomycin as a control agent having excellent effects on Gram-positive bacteria among known compounds. Minimum Inhibitory Concentration of the strain was obtained and evaluated. In other words, the minimum inhibitory concentration was diluted by a 2-fold dilution method, dispersed in Mueller-Hinton agar medium, and then inoculated with 2 μl of a test strain having 10 ⁷ cfu (colony forming unit) per ml. Incubated at 37 ^o C 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 major in vitro infectious bacteria including MRSA strains.

Susceptibility test results for the standard strain (㎍ / ㎖) S. aureus giorgio S. aureus 77 S. aureus K311 S.epidermidis Q033 E. faecalis 2168 I-1 0.13 0.25 0.5 0.063 0.5 I-2 0.13 One One 0.063 One I-3 0.13 0.5 0.5 0.063 0.5 I-4 0.25 One 2 0.13 One I-5 0.25 One 2 0.13 0.25 I-6 0.13 0.5 0.5 0.031 0.5 I-10 0.5 2 2 0.063 4 Vancomycin One One 2 One > 64

Claims (7)

Compounds of formula (1), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates, solvates and isomers: [Formula 1] Where A represents hydrogen or an amino protecting group, R ₁ represents hydrogen or C _1-6 alkyl, C _3-4 alkynyl, C _3-6 cycloalkyl or C _3-6 cycloalkyl-methyl which may comprise one to three oxygen or halogens , R ₂ represents hydrogen or a carboxyl protecting group, Ar is or Indicates From here, R _3, R _4, R ₅ and R ₇ are each hydrogen, hydroxyl, C _1-6 alkyl, unsubstituted or substituted amino substituted by C _1-6 alkyl, C _1-6 hydroxyalkyl or C _1-6 Alkylthio, R ₆ is hydrogen, hydroxyl, unsubstituted or substituted by C _1-6 alkylamino, C _1-6 alkyl, or Indicates, From here, I represents S, NH, CH ₂ or O, n represents 0, 1, 2, 3 or 4, J represents amino, hydroxy or C _1-6 alkoxy unsubstituted or substituted by C _1-6 alkyl, R ₈ and R ₉ represent hydrogen, C _1-6 alkyl, C _1-6 alkylamino, hydroxy or C _1-6 alkoxy, W and Y each represent N or C, provided that when W or Y represents N, R ₃ , R ₅ , and R ₈ are absent; Z represents CH or N, Q represents CH, C-G, or N, where G represents halogen, Ethenyl at the position where the heteroarylthio at the C-3 position is substituted may exist in cis or trans form. The method of claim 1, G represents a halogen selected from Cl and F, R ₁ represents hydrogen, methyl or cyclopentyl, R ₃ , R ₄ , R ₅ and R ₇ each represent hydrogen, hydroxyl or amino. The method of claim 1, I-1: (6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3 -{( E ) -2-[(6-amino-2-hydroxy-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] Oct-2-ene-2-carboxylic acid, I-2: (6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] 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, I-3: (6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3 -{( E ) -2-[(2-amino-6-hydroxy-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] Oct-2-ene-2-carboxylic acid, I-4: (6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3 -{( E ) -2-({2-[(2-aminoethyl) sulfanyl] -4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [ 4.2.0] oct-2-ene-2-carboxylic acid, I-5: (6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3 -{( E ) -2-({2-[(2-aminoethyl) sulfanyl] -6-methyl-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1- Azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, I-6: (6R, 7R) -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -3 -{( E ) -2-[(4-amino-1 H-pyrazolo [3,4-d] pyrimidin-6-yl) sulfanyl] ethenyl} -8-oxo-5-thia-1-aza Bicyclo [4.2.0] oct-2-ene-2-carboxylic acid, I-7: (6R, 7R) -3-[( E ) -2-({6-amino-2-[(2-aminoethyl) sulfanyl] -4-pyrimidinyl} sulfanyl) ethenyl] -7-{[2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1- Azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, I-8: (6R, 7R) -7-{[2- (2-amino-1,3-thiazol-4-yl) -2- (methoxyimino) acetyl] 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, I-9: (6R, 7R) -7-{[2- (2-amino-1,3-thiazol-4-yl) -2- (hydroxyimino) acetyl] 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, I-10: (6R, 7R) -7-({2- (2-amino-5-chloro-1,3-thiazol-4-yl) -2-[(cyclopentyloxy) imino] acetyl} 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, I-11: (6R, 7R) -3-{( E ) -2-[(2-amino-6-hydroxy-4-pyrimidinyl) sulfanyl] ethenyl} -7-{[2- ( 5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct -2-ene-2-carboxylic acid, I-12: (6R, 7R) -3-{( E ) -2-[(6-amino-2-hydroxy-4-pyrimidinyl) sulfanyl] ethenyl} -7-{[2- ( 5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct -2-ene-2-carboxylic acid, I-13: (6R, 7R) -7-{[2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -3- {( E ) -2-[(2,6-diamino-4-pyrimidinyl) sulfanyl] ethenyl} -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2 -En-2-carboxylic acid, I-14: (6R, 7R) -3-[( E ) -2-({6-amino-2-[(2-aminoethyl) sulfanyl] -4-pyrimidinyl} sulfanyl) ethenyl] -7-{[2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-aza Bicyclo [4.2.0] oct-2-ene-2-carboxylic acid, I-15: (6R, 7R) -3-[( E ) -2-({2-[(2-aminoethyl) sulfanyl] -6-methyl-4-pyrimidinyl} sulfanyl) ethenyl] -7-{[2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyiminoacetyl] amino} -8-oxo-5-thia-1-azabi Cyclo [4.2.0] oct-2-ene-2-carboxylic acid, I-16: (6R, 7R) -3-[( E ) -2-({2-[(2-aminoethyl) sulfanyl] -4-pyrimidinyl} sulfanyl) ethenyl] -7- { [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-azabicyclo [4.2 .0] oct-2-ene-2-carboxylic acid, and I-17: (6R, 7R) -3-{( E ) -2-[(4-amino-1H-pyrazolo [3,4-d] pyrimidin-6-yl) sulfanyl] ethenyl}- 7-{[2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (hydroxyimino) acetyl] amino} -8-oxo-5-thia-1-azabi A compound selected from cyclo [4.2.0] oct-2-ene-2-carboxylic acid. The compound of formula (4) is reacted with a compound of formula (5) in the presence of a solvent to give a compound of formula (1a), or S → oxide of formula (1a) in which m is 1 Process for preparing a compound of formula (1) according to claim 1, characterized by obtaining a compound: [Formula 1] [Formula 4] [Formula 5] HS-Ar [Formula 1a] Where A, R ₁ , R ₂ , Ar and Q are as defined in claim 1, X represents halogen or sulfonyloxy, m is 0 or 1, Double bonds at the C-3 position may exist as trans or cis. An amide bond reaction of a compound of formula (13) with a compound of formula (7) or a carboxyl group thereof activated derivative in the presence of a solvent to give a compound of formula (1a), or A process for preparing the compound of formula (1) according to claim 1 characterized in that the oxide is reduced to give the compound of formula (1): [Formula 1] [Formula 13] [Formula 7] [Formula 1a] Where A, R ₁ , R ₂ , Ar and Q are as defined in claim 1, m is 0 or 1, Double bonds at the C-3 position may exist as trans or cis. An antibiotic composition comprising the compound of formula (1) as an active ingredient and a pharmaceutically acceptable carrier. 7. The antibiotic composition according to claim 6, formulated into a formulation for oral administration containing 50 to 1500 mg of the compound of formula (1).