JPS62167784A - Novel cephalosporin derivative, production thereof and antimicrobial agent containing said derivative as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is H or amino- protecting group; R<2> and R<3> are H, OH or protected OH; R<4> is H or carboxy- protecting group; R<5> is H, halogen, methoxy or -CH2R<6> (R<6> is H, azido, acyloxy, carbamoyloxy, etc.); the bond of wavy line is anti-form or syn-form bond], salt, hydrate thereof or hydrate of the salt thereof. EXAMPLE:(6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-[Z-[carboxy(3,4-dihydroxy phenyl) methyl]oxyimino]acetamido]-3-acetomethyl-8-oxo-5-thia-1-azabicyclo[4.2 .0]oct-2- ene-2-carboxylic acid. USE:An antimicrobial agent against Gram-negative and Gram-positive bacteria. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by formula III.

Description

Detailed Description of the Invention "Industrial Application Field" The present invention relates to the general formula (1) (wherein R1 represents a hydrogen atom or an amino protecting group, and R
2 and R3 represent a hydrogen atom, a hydroxyl group or a protected hydroxyl group, R4 represents a hydrogen atom or a carboxy protecting group, and R5 represents a hydrogen atom, a halogen atom, a methoxy group or a group -CH2R6 (in the formula.

R6 is a hydrogen atom, an azido group, an acyloxy group, a carbamoyloxy group, a pyridinium group, a substituted pyridinium group, a substituted or unsubstituted li ring, or a condensed heterocyclic thio group (however, a heterocycle is a group containing 1 to 4 oxygen atoms) , represents a 5- to 6-membered heterocyclic ring having a sulfur and/or nitrogen atom. ], and the wavy line represents anti(
represents a bond in the anti) or syn (s y n) form. ), salts thereof, hydrates thereof, hydrates of salts, and methods for producing them. The present invention further relates to a formulation for the treatment and prevention of infectious diseases, characterized by containing the cephalosporin derivative.

"Conventional technology J The development of cephalosporin derivatives has been remarkable.

Products with excellent antibacterial activity against Durham-negative bacteria have been developed. However, the antibacterial activity of these cephalosporin derivatives against Durum-positive bacteria is generally weak, and Durum-positive bacteria that are resistant to cephalosporin antibiotics, which have been frequently used to treat Durum-positive bacterial infections (e.g., methicillin Resistant Staphylococcus aureus (MR3A) is increasing year by year.

"Problems to be Solved by the Invention" In view of this background, the present inventors have developed Durham-negative bacteria, particularly tiii, which is frequently isolated as a causative agent of refractory infections.
As a result of intensive research to develop a cephalosporin derivative that retains sufficient antibacterial activity against Bacillus Serratia and also has strong antibacterial activity against Durham-positive bacteria, the general formula (
The present invention was completed by discovering that the cephalosporin derivative represented by 1) satisfies these conditions.

"Means for Solving the Problems" The present invention is based on selecting a substituent having an allylcarboxyalkyloxyimino structure as the substituent at the 7-position of the cephasporin skeleton.

In the cephalosporin derivative of the present invention represented by general formula (1), the aminothiazole moiety at the 7-position substituent is as shown below: (It has the same meaning as above.) It is known that there is a tautomeric relationship, and since both are generally treated as the same substance, in the present invention, the aminothiazole moiety including both isomers It is expressed as Therefore, the compound of the present invention represented by general formula (I) includes both of these tautomers.

Examples of salts of the compound represented by general formula (r) include the following. For example, alkali metal salts such as sodium salts, potassium salts, alkaline earth metal salts such as calcium salts, ammonium salts.

Examples include salts with organic bases such as benzylamine salts and diethylamine salts, and pharmaceutically acceptable salts such as arginine salts and lysine salts. The salts of the compounds may be mono-, di- or tri-salts.

In the case of monosalts or di-salts, the carboxyl group at the 2-position of the cephem skeleton, the carboxyl group of the substituent at the 7-position of the cephem skeleton,
It may be any salt of a carboxyl group or a hydroxysulfonyl group contained in the 3-position substituent of the cephem skeleton.

The compounds of general formula (I) can also form acid adducts with pharmaceutically acceptable organic acids or non-acid acids.

Examples of these salts are hydrochloride.

Mineral acid salts such as hydrobromide, sulfate, phosphate, etc.

Also included are organic acid salts such as acetate, citrate, maleate, tartrate, benzoate, ascorbate, ethanesulfonate, and toluenesulfonate. The salt of the compound may be a mono-salt or a di-salt. In the case of a monosalt, the aminothiazole moiety contained in the substituent at the 7-position of the cephem skeleton may form a salt, and the base 1 contained in the substituent at the 3-position of the cephem skeleton, such as a triazolopyrimidine ring, may form a salt. You can leave it there.

The compound of the present invention represented by the general formula N) can be used as a syn isomer: (in the formula, R1, R2, R3, R4 have the same meanings as above), or as anL i isomer; (in the formula, R1
, R2, R3, and R4 have the same meanings as above. ) or as a mixture of these isomers.

Particularly preferred are the syn isomers, and also mixtures in which the syn isomers predominate.

In the compound of the present invention represented by general formula (I).

Examples of amino protecting groups include formyl, acetyl,
Chloroacetyl, t-butoxycarbonyl.

Examples include acyl groups such as benzyloxycarbonyl, and aralkyl groups such as benzyl, diphenylmethyl, and triphenylmethyl. Examples of carboxy protecting groups include protection of carboxy by esterification, where esters include 1, for example, alkyl esters such as methyl ester and ethyl ester, or benzyl esters,
Examples include aralkyl esters such as diphenylmethyl ester and triphenylmethyl ester. Examples of hydroxy protecting groups include 1, for example, aralkyl groups such as benzyl,
Examples include alkoxyalkyl groups such as methoxymethyl and 1-methoxy-1-methylethyl, and acyl groups such as acetyl, chloroacetyl, t-butoxycarbonyl, and benzyloxycarbonyl. Among these protecting groups, when considering various operations, synthesis of protected bodies, deprotection conditions, etc., triphenylmethyl group is used as an amino protecting group, diphenylmethyl ester is used as a carboxy protecting group, and acetyl group is used as a hydroxy protecting group. Preference is given to using groups.

The compound of the present invention represented by general formula (1) can generally be produced as follows. Namely.

Method A General formula (II) (In the formula, R4 and R5 have the same meanings as above.)
Manufactured by reacting the compound represented by the formula (nI)^1 (in the formula, R1, R2, R3, R4 and the bonds of the wavy line have the same meanings as above). I can do something.

In this production method, the amino group of the compound represented by general formula (II) can be converted into a suitable reactive derivative, if desired.

Furthermore, a compound represented by the general formula (II[), that is, an acid, and a suitable condensing agent 1, such as N,N-dicyclohexylcarbodiimide or N-ethyl-5=phenyl-isoxazolium-3''-sulfonate, etc. The acid can also be used to react with a compound of general formula (II), or the acid can be converted into a suitable reactive derivative and then reacted with a compound of general formula (n).

Suitable reactive derivatives include acid halides (eg acid chlorides), azides, acid anhydrides, active esters (eg N-hydroxysuccinimide ester) and active amides (eg imidazolides).

Examples include triazolides).

The reaction of a compound of general formula (n) with a compound of general formula (n[) is generally carried out in an inert solvent 1 such as dioxane, tetrahydrofuran, acetonitrile.

The reaction is carried out in an organic solvent such as chloroform, methylene chloride, ethyl acetate, or dimethylformamide, and if desired, in water or a mixture of water and an organic solvent, preferably in the presence of a deoxidizing agent. As a deoxidizing agent.

Triethylamine, diethylaniline, etc. are used in organic solvent systems, and aqueous alkalis are used in aqueous systems.

Preferably, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate, etc. are used.

These reactions can be carried out at about -30°C to room temperature;
Preferably it is carried out at -10°C to 10°C.

The protecting group of the cephalosporin derivative represented by the general formula (I) thus obtained can be removed if desired.

Method B A compound represented by the general formula (rV) , , OH (in the formula, R1, R4, R5 and the bonds of the wavy line have the same meanings as above).

General formula (V) (wherein R2, R3 and R4 have the same meanings as above, and X represents a halogen atom or a hydroxyl group.

) can be produced by reacting with a compound represented by: In this production method, when the compound represented by general formula (V) is alcohol.

This is treated with a suitable condensing agent 1 such as triphenylphosphine and ethyl azodicarboxylate using the general formula (TV
), or the compound of general formula (V) can be converted into a suitable reactive derivative 5, for example a tosylate, and then reacted with a compound of general formula (TV). From the viewpoint of reactivity and operability, the compound represented by the general formula (■) is preferably a halide, and a method of reacting this with a compound of the general formula (TV) is preferred.

The reaction of a compound of general formula (rV) with a compound of general formula (V) is generally carried out in an inert solvent 1 such as dioxane, tetrahydrofuran, acetonitrile.

The reaction is carried out in an organic solvent such as chloroform, methylene chloride, ethyl acetate, or dimethylformamide, and if desired, in water or a mixture of water and an organic solvent, preferably in the presence of a deoxidizing agent. As a deoxidizing agent.

Are there any? In the g-medium system, triethylamine,
Diethylaniline etc. are aqueous alkalis in aqueous systems.

Preferably, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate, etc. are used.

These reactions can be carried out at about -30°C to room temperature, but -
Preferably, it is carried out at 10°C to 10'C.

The protecting group of the cephalosporin derivative represented by the general formula (1) thus obtained can be removed if desired. The compound represented by the general formula (IV) used in this production method can be synthesized according to the production method described in Japanese Patent Application No. 59-249193.

Method C A compound represented by the general formula (V[) (in the formula, R1, R2, R3, R4 and the bonds of wavy lines have the same meanings as above) and a substituted or unsubstituted monocyclic or condensed ring. (However, heterocycle refers to a 5- to 6-membered heterocycle having 1 to 4 oxygen, sulfur, and/or nitrogen atoms.) or substituted or unsubstituted pyridine. It can be manufactured by This reaction can be carried out using an organic solvent such as alcohol, dimethylformamide or acetonitrile, or water as a solvent.

When carrying out using an organic solvent, it is preferable to carry out in the presence of a Lewis acid such as boron trifluoride/ether complex.

In addition, when water is used as a solvent, in the presence of a predetermined amount of aqueous alkali (e.g., sodium bicarbonate, potassium carbonate, etc.)
! i: Night can be used as a solvent. This reaction is about 40°
C to 80°C, preferably about 55°C.
Performed between 65°C and 65°C.

The protecting group of the compound represented by the general formula (1) thus obtained can be removed if desired.

Effects of the Invention The compounds of the present invention have a broad antibacterial spectrum against Durham-positive bacteria and Gram-negative bacteria including Pseudomonas aeruginosa, and also exhibit strong antibacterial activity against methicillin-resistant Staphylococcus aureus. It is extremely useful as a treatment for this disease.

Next, in order to demonstrate the usefulness of the compounds of the present invention, data on the anti-yam activity of one representative compound will be shown.

Test compound Compound 1: (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-C carboxy(3
,4-dihydroxydiphenyl)methyl]oximino]
acetamido)-3-((7-methyl-5-1-riazoloN,5-c)pyrimidin-5-yl)thiomethyl28
-oxo-5-thia-1-azabicyclo(4,2,O,
) Oct-2-ene-2-carboxylic acid compound 2 :' (6R,7R)-L-(2-(2-amino-4-thiazolyl)-2-(Z-C carboxy(3
,4-dihydroxyphenyl)methyl]oximino]
Acetamide)-3-((2-carboxy-7-methyl-
5-) Riazolo(1,5-C]pyrimidin-5-yl)
Thiomethyl-8-oxo-5-thia-1-azabicyclo(4,2゜0,)oct-2-ene-2-carboxylic acid compound 3: (6R,7R)-7-(2-(2-amino-4 -thiazolyl)-2-(Z-(carboxy(3
,4-dihydroxyphenyl)methyl]oximino]
acetamide)-3-((8-carpoxytetraduro(1)
,5-b]pyridazin-6-yl)thiomethyl2-8-
Oxo-5-thia-1-azabicyclo(4,2,0,)
Oct-2-ene-2-carboxylic acid compound 4: (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-(carboxy(3
,4-dihydroxyphenyl)methyl]oximino]
acetamido)-3-((6-carpoxy7-hydroxy-S-triazolo[1°5-a]pyrimidin-2-yl)thiomethyl-8-oxo-5-thia-1-azabicyclo[4°2.0.)octo -2-ene-2-carboxylic acid Experimental Example I The in vitro antibacterial activity was determined by the agar plate dilution method. Namely, Mineral Hinton Floss (Muelle)
A loopful of the test bacterial strain (106 bacteria (solid/m+)) cultured in 1 linton broth was applied to Mueller-Hinton agar (MH-agar) containing the test compound at various concentrations. After culturing at 37°C for 20 hours, the minimum inhibitory concentration (MIC, 827ml) was determined.

The results are shown in Table 1.

Experimental Example 2 In vivo infection prevention ability was measured as follows. A group of 10 ICR 4-week-old mice were intraperitoneally infected with the test bacteria as an aqueous suspension. One hour after infection, test compounds were administered intravenously. The number of surviving animals was counted after − weeks and the dose H (EDso; mg/k
g) was calculated.

The results are shown in Table 2.

Next, Table 3 shows the LDSO of a representative example of the compound of the present invention. In addition, LD5. is Probit
It was determined by the method.

Table 3 Compounds of the invention are suitable for use in Durham positive bacteria such as Staphylococcus aureus, Streptococcus, or for example Escherichia coli.

Klebsiella pneumoniae, M. 9 morgan, M. marcescens, Citrobacter
It is used to treat infections caused by infections caused by Durham-negative bacteria such as , Enterobacter, and Flavobacter.

The cephalosporin derivatives provided by the present invention are:
As pharmaceutical compositions 9 they can be used, for example, in the form of formulations containing them together with suitable pharmaceutically acceptable carrier substances 9 such as lactose, carboxymethyl cellulose and the like. Examples of formulations can be solid (eg, tablets, capsules, etc.) or liquid (eg, injections, etc.) form. In addition, the preparation can be sterilized, and auxiliary agents commonly used in pharmaceuticals such as sodium bicarbonate, citric acid, propylene glycol, twin 8
0 (Tveen80) and the like.

Furthermore, the compound is in the form of a lyophilized product or a dry powder.
It is also preferable to use a conventional dissolving agent 1, for example, by dissolving it in water or physiological saline before use. The compound can be used orally or parenterally, depending on the patient's age, condition,
Disease f! ! The daily dosage for one adult can be approximately 0.01 g to approximately 10 g, although it varies depending on the type and disease state.
Preferably a dosage of about 0.1 g to about 5 g is used.

Also.

Parenteral administration of the compounds provided by the invention is particularly preferred.

Examples of the present invention are shown below, but the present invention is not limited to the following examples.

The following is a list of the gloss of Margin Kagugo 421 Example 1 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-C carboxy(3°4-dihydroxyphenyl) Methyl]oxyimino]acetamide]-3
-Acetoxymethyl-8-oxo-5-thia-1-azabicyclo(4,2゜0)oct-2-ene-2-carboxylic acid manufacturing process 1 (6R,7R) -7-(2-(2- 1-diphenylmethylamino-4-thiazolyl)-2-(Z-[diphenylmethyloxycarbonyl(3,4-diacetoxyphenyl)methyl]oxyimino]acetamide]-3-acetoxymethyl-8-oxo-5-thia- Preparation of 1-azabicyclo(4,2,0)oct-2-ene-2-carboxylic acid diphenylmethyl ester 2-(2-)diphenylmethylamino-4-thiazolyl)-2-(Z-diphenylmethyloxycarbonyl (3
,4-diacetoxyphenyl)methyl]oximino #
3.0 g of acid and diphenylmethyl (6R,7R)-7-amino-3-acetoxymethyl-8-oxo-5-thia-1-azabicyclo(4,2,0]oct-2-ene-2-carboxylate 1.58g of ester and 90m of methylene chloride
1 and dicyclohexylcarbodiimide 0 under water cooling.
．． 74 g was added and stirred at room temperature for 4 hours.

Insoluble materials were collected by filtration, the filtrate was concentrated, ethyl acetate was added to the residue, the precipitated insoluble materials were collected by filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain 2.42 g of the title compound.

NMR spectrum (DMSO-ds; ppm)9
．． 7 (LH, m) 8.9 (LH, s) 7.6 to 6.8 (41H, m) 5.9 (LH, s) 5.8 (IH, m) 5.2 (LH, m) 4.8 (2H,ABq) 3.6 (2H,ABq) 2.3 (3H,s) 2, 2 (3H,s) 2, 0 (3H,S) Step 2 (6R,7R)-7- (2-(2-amino-4-thiazolyl) -2-(Z-(carboxy(3゜4-diacetoxyphenyl)methyl)oxyimino]acetamide]
-3-acetoxymethyl-8-oxo-5-thia-1-
Production process of azabicyclo(4,2゜0)oct-2-ene-2-carboxylic acid 2.4 g of the compound obtained in step 1 was dissolved in 18 ml of dichloroethane and cooled on ice.To this solution was added 1.21 ml of anisole. ) Lifluoroacetic acid 2.42
After adding m1, the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated, and the resulting residue was crystallized from ether.

After further washing with methylene chloride, the crystals were crystallized again from ether to obtain 0.74 g of the above-mentioned title compound.

IR spectrum (KB r ; cm-1) 1773.
1684.1637.1374゜1219.1213,
1210, 1184° NMR spectrum (DMSO-d
a; ppm) 9, 7 (IH, m) 7, 4-6. 8 (4H, m) 5, 8 (IH, m) 5, 6 (LH, s) 5, 1 (IH, m) 4, 8 (2H, ABq) 3, 5 (2H, ABq) 2, 3 ( 6H,s) 2, O(3H,s) Step 3 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-(carboxy(3°4-dihydroxyphenyl) methyl)oxyimino]acetamide]-3
-Acetoxymethyl-8-oxo-5-thia-1-azabicyclo(4,2゜0)oct-2-ene-2-carboxylic acid production process 0.26 g of the compound obtained in 2 was added to 9 9 of water.
1 per ml? ! If cloudy, add sodium bicarbonate to dissolve.

The pH was adjusted to 8.0 to 8.5, the atmosphere was replaced with nitrogen, and the mixture was stirred at room temperature. After 4 hours, one reaction solution was adsorbed onto Diaion HPIO, eluted with water, and fractions containing the target compound were collected and lyophilized to obtain 0.059 g of the title compound.

IR spectrum (KB r ; cm4) 1772.
1762,1751.1617°NMR spectrum (D
20; pp pm) 7.0 to 6.9 (4H, m) 5.8 (LH, m) 5.4 (IH, s) 3, 4 (2H, ABq) 2.1 (3
H, s) Example 2 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-C carboxy(3°4-dihydroxydiphenyl)methyl]oxyimino]acetamide) −
3-((1,2,3-thiadiazol-5-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo(
4,2,0) Production process of oct-2-ene-2-carboxylic acid 1 (6R,7R)-7-(2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-[diphenylmethyl oxycarbonyl(3,4-diacetoxyphenyl)methyl]oxyimino]acetamide)-3-((1,
2,3-thiadiazol-5-yl)thiomethyl28
-oxo-5-thia-1-azabicyclo(4,2,0)
Preparation of oct-2-ene-2-carboxylic acid diphenylmethyl ester 2-(2-)diphenylmethylamino-4-thiazolyl)-2-(Z-diphenylmethyloxycarbonyl(3,4-diacetoxyphenyl)methyl) 1.0 g of oxyiminoacetic acid and (6R,7R)-7-amino-3-(
(1,2,3-thiadiazol-5-yl)thiomethyl-8-oxo-5-thia-1-azabicyclo(4,2
,0) 0.59 g of oct-2-ene-2-carboxylic acid diphenylmethyl ester was added to 3 Q ml of methylene chloride.
0.27 g of dicyclohexylcarbodiimide was added to the solution under water cooling, and the mixture was stirred at room temperature for 15 hours. Insoluble materials were collected by filtration, the filtrate was concentrated, ethyl acetate was added to the residue, the precipitated insoluble materials were collected by filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (0.74 g).
I got g.

IR spectrum (KBr; cm-1) 1780,. 1774.1?35,1523°1250
．． 1212, 1180. 70ONMR spectrum (
DMSO-d6; ppm) 9.7 (IH, m) 8.9 (IH, s) 8.8 (IH, S) 7.5-6.8 (41H, m) 5.8 (IH, s) 5.6-(I H, m) 5.2 (LH, m) 4.2 (2H, bs) 3.6 (2H, ABq) 2.3 (3H, s) 2, 2 (3H, S) Step 2 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-(carboxy(3°4-diacetoxyphenyl)methyl]oxyimino]acemide)-3
-((1,2,3-thiadiazol-5-yl)thiomethyl-8-oxo-5-thia-1-azabicyclo(4
, 2,0) Production process of oct-2-ene-2-carboxylic acid 0.69 g of the compound obtained in 1 was dissolved in dichloroethane 1
ml and cooled on ice. This solution contains 0.0% anisole.
After adding 1.5 ml of refluoroacetic acid, the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated, and the resulting residue was crystallized with ether to obtain 0.35 g of the title compound.

rR spectrum (KB r ; cm'l ) 1772
．． 1684, 1637, 1210° NMR spectrum <
DMSO-d6; ppm) 9.6 (IH, m) 8, 9 (IH, s) 7, 5-7. 2 (3H, m) 6, 82. 6. 78 (LH,s)5, 8
(IH, m) 5, 6 (IH, s) 5, 2 (LH, m) 4, 3 (2H, bs) 3, 7 (2H, ABq) 2, 3 (6H, s) Step 3 (6R, 7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-(carboxy(3°4-dihydroxyphenyl)methyl]oxyimino]acetamide)-3
-((1,2,3-thiadiazol-5-yl)thiomethyl-8-oxo-5-thia-1,-azabicyclo(
4,2,0) Production process of oct-2-ene-2-carboxylic acid 0.33 g of the compound obtained in 2 was suspended in 9 ml of water, and sodium hydrogen carbonate was added to dissolve it.

The pH was adjusted to 8.4-8.5 and stirred at room temperature.

After 6 hours, 1 reaction solution was adsorbed on Diamond Ion HPIO,
After washing with 250 ml of water, it was eluted with water-methanol=5:1, and fractions containing the target compound were collected and lyophilized to obtain 0.3 g of the title compound.

IR spectrum (KB r ; cm-1) 1773.
1597.1529, 1.39° 0° NMR spectrum (D20; pp pm) 8.7 (IH, s) 7.0-6.8 (4H, m) 5.7 (IH, m) 3.4 ( LH,s) 5.0 (IH,m) 4.3 (2H,ABq) 3.3 (2H,AB'q) Example 3 (6R,7R)-7-(2-(2-amino-4 -thiazolyl')-2-(Z-(carboxy(3゜4-dihydroxyphenyl)methyl]oxyimino)acetamide)-
3-((8-carboxytetracylo(1,5-b,)pyridazin-6-yl)thiomethyl-8-oxo-5-
Production process of thia-1-azabicyclo(4,2,0)oct-2-ene-2-carboxylic acid 1 (6R,7R)-7-(2-(2-)lifelemethylamino-4-thiazolyl) -2-(Z-[diphenylmethyloxycarbonyl(3,4-diacetoxyphenyl)methyl]oxyimino]acetamide] -3-((8
-diphenylmethyloxycarbonyltetrazolo (1,
5-b) Preparation of pyridazin-6-yl)thiomethyl2-8-oxo-5-thia-1-azabicyclo(4,2,0)oct-2-ene-2-carboxylic acid diphenylmethyl ester 2-(2-tri phenylmethylamino-4-thiazolyl)-2-(Z-diphenylmethyloxycarbonyl(3
,4-diacetoxyphenyl)methyl]oxyiminoacetic acid 1. Og and (6R,7R)-7-amino-3-((8
-diphenylmethyloxycarbonyltetrazolo (1,
5-b) 0.90 g of pyridazin-6-yl)thiomethyl2-8-oxo-5-thia-1-azabicyclo(4,2,03oct-2-ene-2-carboxylic acid diphenylmethyl ester) in 50 ml of methylene chloride 0.24 g of dicyclohexylcarbodiimide was added to the solution under water cooling, and the mixture was stirred overnight at room temperature. Insoluble matter was collected by filtration, and the filtrate was concentrated. Acetone was added to the residue, and the precipitated insoluble matter was collected by filtration. was concentrated and the residue was purified by silica gel column chromatography to obtain 0.75 g of the above title compound.

IR spectrum (KBr; cm-1) 1774.1?34,1363,1297°1225.
1083. 70O NMR spectrum (CDC13; pp pm) 8.1~
6.7 (55H, m) 6.1, 6.0 (IH, s) 5.9 (IH, m) 4.9 (LH, m) 4.7 (2H, ABq) 3, 2 (2H, ABq) 2, 3 (6H,s) Step 2 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-C carboxy(3°4-diacetoxyphenyl)methyl [oximino]acetamide)-3
-((8-carboxytetracylo(1,5-b)pyridazin-6-yl)thiomethyl-8-oxo-5-thia-1-azabicyclo(4,2,0)oct-2-ene-
2-Carboxylic acid manufacturing process 0.75 g of the compound obtained in step 1 was dissolved in 3 ml of dichloroethane and cooled on ice. In this solution, anisole o, 5
ml,) After adding 3 ml of refluoroacetic acid, 3.
Stirred for 5 hours. The reaction solution was concentrated, and the resulting residue was
ml of dichloroethane was added and left to stand for 30 minutes. Decant the supernatant.

After washing the residue with 1Qml of dichloroethane, the residue was crystallized from ether to obtain 0.27g of the title compound.

IR spectrum (KB r ; cm-1) 17?3.
1676, 1638. 1374° NMR spectrum (DMSO-da; ppm) 9, 7 (I
H, m) 8, 1 (IH, s) 7, 4-7. 0 (3H, m) 6, 81. 6. 76 (LH,s)5, 8
(IH, m) 5, 6 (IH, 51) 5, 1 (IH, m) 4゜ 3 (2H, ABq) 3, 6 (2H, ABq) 2, 3 (6H, S) Step 3 (6R, 7R) -7-(2-(2-amino-4-thiazolyl') -2-(Z-(carboxy(3°4-dihydroxyphenyl)methyl]oxyimino]acetamide)
-3-((8-carboxytetracylo(1,5-b)pyridazin-6-yl)thiomethyl]-8-oxo5-
Production process of Chiryo-1-azabicyclo(4,2,0)oct-2-ene-2-carboxylic acid 0.25 g of the compound obtained in 2 was suspended in 6 ml of water, and sodium hydrogen carbonate was added to dissolve it. .

The pH was adjusted to 8.5, the atmosphere was replaced with nitrogen, and the mixture was stirred at room temperature.

After 5 hours, 1 reaction solution was adsorbed on Diamond Ion HPIO,
Elution was performed with water, and fractions containing the target product were collected and lyophilized to obtain 0.15 g of the above-mentioned title compound.

fR spectrum (KB r ; cm-1) 1766.
1589.1388 NMR spectrum (D20: ppm) 7-8
(LH, s) 7.2~6.8 (4H, m) 5.7 (IH, m) 5.4 (IH, s) 5.0 (IH, m) 4.1 (2H, ABq) 3 .4 (2H,ABq) Example 4 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-(carboxy(3°4-dihydroxyphenyl)methyl)oxyimino) acetamide) −
3-((5-methyl-5-triazolo(1,5-a)pyrimidin-7-yl)thiomethyl-8-oxo-5-
Production of thia-1-azabicyclo(4,2,0)oct-2-ene-2-carboxylic acid The above title compound was obtained in the same manner as in Example 2.

IR spectrum (KB r ; cm-1) 1763.
1596, 1513, 1399° NMR spectrum (D
20; pl)m) 8.5.8.3 (LH, s) 7.2-6.8 (5H, m) 5.6 (LH, m) 5.4 (lH, s) 5.0 ( LH, m) 3.4 (2H, ABQ) 2, 6. 2. 4 (3H,S) Example 5 (6R,7R)-7-(2-(2-amino-4-thiazolyl")-2-(Z-C carboxy(3°4-dihydroxyphenyl)methyl)oxyimino] acetamide) −
3-((5-methyl-2-sulfoxy-3-triazolo(1,5-a)pyrimidin-7-yl)thiomethyl-8-oxo-5-thia-1-azabicyclo(4,2,0
) Preparation of oct-2-ene-2-carboxylic acid The above title compound was obtained in the same manner as in Example 2.

IR spectrum (KB r ; cm-1) 1763.
1596.1509,1397°NMR spectrum (D
20; pp pm) 7.2 (IH, s) 7, 0 to 6. 9 (48, m) 5.7
(IH, m) 5.4 (IH, s) 5, 0 (LH, m) 4. 3 (2H,ABq) 3, 4 (2H,ABq) 2, 6 (3H,s) Example 6 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z -(carboxy(3゜4-dihydroxyphenyl)methyl]oxyimino]acetamide)-3
-((7-methyl-8-triazolo(1,5-C]pyrimidin-5-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo(4,2,0)oct-2-ene-2 -Production of carboxylic acid The above title compound was obtained in the same manner as in Example 2.

TR spectrum (KB r ; crrrl ) 176
3.161.2,1533,1475° NMR spectrum (D20; ppm) 8.4 (IH,s) 7, 3 (IH,S') 7, 0-6. 9 (4H, m) 5, 7 (IH, m) 5, 4 (IH, S) 5, 0 (LH, m) 4, . 3 (2H,ABq) 3, 4 (2H,ABq) 2, 6 (3H,S) Example 7 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z -(carboxy(3゜4-dihydroxyphenyl)methyl)oxyimino]acemide)-3
-((2-carboxy-7-methyl-s-triazolo(
1,5-c)pyrimidin-5-yl)thiomethylcou8
-oxo-5-thia-1-azabicyclo(4,2,0)
Preparation of oct-2-ene-2-carboxylic acid The above title compound was obtained in the same manner as in Example 2.

TR spectrum (KBrHcm″1) 1763, 161?, 1534. 1458°1
397, 1368. 1318 NMR spectrum (D20; ppm) 7, 4 (IH,s) 7, 0-6. 9 (4H, m) 5, 7 (IH, m) 5, 4 (IH, S”) 5, 0 (it(, m) 4, 3 (2H, ABci) 3, 4 (2H, ABq) 2, 6 (3H,s) Example 8 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-(carboxy(3°4-dihydroxyphenyl)methyl)oxyimino]acetamide )-3
-((6-carboxyz-hydroxy-,S-triazolo(1,5-a)pyrimidin-2-yl)thiomethyl]-8-oxo5-thia-1-azabicyclo(4,2
, O) Production of oct-2-ene-2-carboxylic acid The above title compound was obtained in the same manner as in Example 2.

TR spectrum (KB r ; cm-1) 1763.
1597.1523.1396 NMR spectrum (D2
0; ppm) 8.6 (IH, s) 7.0 to 6.8 (4H, m) 5.6 (IH, m) 5.4 (LH, s) 3.4 (2H, AB(1) Example 9 (6R,7R)-7-(2-(2-amino-4-thiazolyl')-2-(Z-C carboxy(3°4-dihydroxyphenyl)methyl]oxyimino]acetamide)-
3-((1-methyl-IH-tetrazol-5-yl)
Preparation of thiomethyl]-8-oxo-5-thia-1-azabicyclo(4,2,0]oct-2-ene-2-carboxylic acid The above title compound was obtained in the same manner as in Example 2.

IR spectrum (KB r ; cm-1) 1773.
1637. 1560. 140ONMR spectrum (D20; ppm) 7, 0-6. 9 (4
H, m), 5, 6 (IH, m) 5, 4 (IH, 5) 5- 1 (IH, m) 4, 0 (3H, s) 3, 4 (2H, ABq) Example 10 (6R ,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z,-(carboxy(3゜4-dihydroxyphenyl)methyl]oxyimino]acetamide)
=3-((1-carboxymethyl-IH-tetrazol-5-yl)thiomethyl]-8-oxo5-thia-
1-Azabicyclo(4,2,0)oct-2-ene-2
-Production of carboxylic acid The above title compound was obtained in the same manner as in Example 2.

IR spectrum (KBr; cm-I) 1772
, 1610. 1508. 1384 NMR spectrum (D20; ppm) 7, 0-6. 9 (4H, m) 5, 7 (IH, m) 5, 4 (IH, s) 5, 0 (2H, s) 4, 2 (2H, ABq) 3, 4 (2H, ABq) Example 11 ( 6R, 7R) -7-(2-(2-amino-4-thiazolyl)-2-(Z-(carboxy(3゜4-dihydroxyphenyl)methyl]oxyimino]acetamide)-
3-((2-methyl-1,3゜4-thiadiazole-5
-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4°2.0]oct-2-ene-2-carboxylic acid The above title compound was obtained in the same manner as in Example 2.

IR spectrum (KB r ; cm-1) 1765,
1597. 1531. 1388NMR spectrum (D20; ppm)? , (1~6.9 (
4H, m) 5, 7 (IH, m) 5, 4 (IH, s) 5, 0 (LH, m) 4, 2 (2H, ABq) 3, 4 (2H, ABq) 2, 7 (3H, s) Example 12 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-C carboxy(3<4-dihydroxyphenyl)methyl]oxyimino)acetamide)-3
-(1-pyridiniummethyl)-8-oxo-5-thia-1-azabicyclo(4,2,0)oct-2-ene-
Preparation of 2-carboxylic acid 0.76 g of sodium iodide was dissolved in 0.22 ml of water, and pyridine and 0.25 g of the compound obtained in Step 2 of Example 1 were added and stirred at 50°C.

After 1.5 hours, the temperature was returned to room temperature, acetone IQ m 1 was added, and the precipitated crystals were collected by filtration, dissolved in water, adsorbed on Diamond Ion HPIO, and eluted with water.

Fractions containing the target compound were collected and lyophilized to obtain the above title compound 0.
．． 05g was obtained.

IR spectrum (KBr; cm () 1762.1624.1533.1397 NMR spectrum (D20; pp pm) 9.0-8.0 (5H
;m) 7.2-7.0 (4HHm) 5.7-5.1 (5Hsm) 3.4 (2H;AB(1) Example 13 (6R,7R)-7-(2-(2- Amino-4-thiazolyl)-2-(Z-(carboxyphenylmethyl)oximino)acetamide)-3-((2-carboxy-
5-Methyl-3-triazolo(1,5-a)pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1
-Azabicyclo(4,2,0)oct-2-ene-2-
Production process of carboxylic acid 1 (6R,7R)-7-(2-(2-)liphenylmethylamino-4-thiazolyl')-2-(Z-[(diphenylmethyloxycarbonyl)phenylmethyl]oxyimino]acetamide )-3-((2-diphenylmethyloxycarbonyl-5-methyl-5-)riazolo(1,5
-a) Preparation of pyrimidin-7-yl)thiomethylgo 8-oxo-5-thia-1-azabicyclo(4,2,01oct-2-ene-2-carboxylic acid diphenylmethyl ester) 2-(2-triphenylmethyl 1.06 g of amino-4-thiazolyl')-2-(Z-(diphenylmethyloxycarbonyl)phenylmethyl]oxyiminoacetic acid and (6
R,7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-3-triazolo(1
,5-a)pyrimidin-7-yl)thiomethylgo8-
Oxo-5-thia-1-azabicyclo(4,2,0)oct-2-ene-2-carboxylic acid diphenylmethyl ester (1.0 g) was dissolved in 30 ml of methylene chloride, and 0.3 g of dicyclohexylcarbodiimide was added under water cooling. The mixture was added and stirred at room temperature for 15 hours. After filtering off the insoluble matter and concentrating the filtrate,
Ethyl acetate was added to the residue, the precipitated insoluble matter was collected by filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain 1.39 g of the above-mentioned title compound.

IR spectrum (KB r ; cm・I) 1793
．． 1741.1?35.1508°1498.1202
．． 1181. 699NMR spectrum (DMSO-
d6; pPm) 9.7 (IH, m) 8.9 (IH, s) 7.6 to 6.7 (55H, m) 5.8 (IH, s) 5.7 (IH, m) 5. 2 (IH, m) 4.3 (2H, bs) 3, 5 (2H, ABq) 2, 5 (3H, s) Step 2 (6R,7R)-7-(2-(2-amino-4- thiazolyl)-2-(Z-(carboxyphenylmethyl)oxyimino]acetamide)-3-((2-carboxy-5
-Methyl-5-)riazolo(1,5-a)pyrimidine-
7-yl)thiomethylgo8-oxo-5-thia-1-
Production process of azabicyclo(4,2,0)oct-2-ene-2-carboxylic acid 1.0 g of the compound obtained in step 1 was added to 1 part of dichloroethane.
．． It was dissolved to 5 ml and cooled on ice. This solution contains 0.0% anisole.
After adding 2 ml of refluoroacetic acid, the mixture was stirred at room temperature for 5 hours at 1°. The reaction solution was concentrated, 30 ml of dichloroethane was added to the resulting residue, the supernatant was removed by decantation, the residue was washed with 30 ml of dichloroethane, and the residue was crystallized with ether to obtain 0.54 g of the above jM title compound.

Summer R spectrum (KBr; cm-1) 1778, 1?22. 1675. 1636°15
97, 1509. 120O NMR spectrum (DMSO-d6il)I)m)
9, 5 (IH, m) 7, 5-7. 0 (6H, m) 6, 83. 6. 80 (LH,s)5, 8
(LH, m) 5- 6 (IH, s) 5, 2 (LH, m) 4, 4 (2H, bs) 3, 7 (2H, ABQ・) 2, 6 (3H, s)

Claims (1)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) {In the formula, R^1 represents a hydrogen atom or an amino protecting group,
R^2 and R^3 represent a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, R^4 represents a hydrogen atom or a carboxy protecting group, and R^5 represents a hydrogen atom, a halogen atom, a methoxy group, or a group -CH_2R^ 6 [Wherein, R^6 is a hydrogen atom, an azide group, an acyloxy group, a carbamoyloxy group, a pyridinium group, a substituted pyridinium group, or a substituted or unsubstituted monocyclic or condensed heterocyclic thio group (however, a heterocyclic ring and represents a 5- to 6-membered heterocycle having 1 to 4 oxygen, sulfur and/or nitrogen atoms. ], and the wavy line represents an anti-type or syn-type bond. } Cephalosporin derivatives, salts thereof, hydrates thereof, and hydrates of salts. (2) A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of the salt according to claim 1, wherein R^5 is an acetoxymethyl group. (3) Cephalosporin derivatives, salts thereof, hydrates thereof, and hydration of salts according to claim 1, wherein R^2 and R^3 are hydroxyl groups, and R^5 is an acetoxymethyl group. thing. (4) A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of the salt, according to claim 1, wherein R^5 is a group ▲a mathematical formula, a chemical formula, a table, etc.▼. (5) R^2 and R^3 are hydroxyl groups, and R^5 is a group ▲ Numerical formula, chemical formula, table, etc.▼ Hydrates and salt hydrates. (6) A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of the salt, according to claim 1, wherein R^5 is a group ▲a mathematical formula, a chemical formula, a table, etc.▼. (7) R^2 and R^3 are hydroxyl groups, and R^5 is a group ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The cephalosporin derivatives, salts thereof, and Hydrates and salt hydrates. (8) A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of the salt according to claim 1, wherein R^5 is a group ▲a mathematical formula, a chemical formula, a table, etc.▼. (9) R^2 and R^3 are hydroxyl groups, and R^5 is a group ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The cephalosporin derivatives, salts thereof, and Hydrates and salt hydrates. (10) A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of a salt thereof according to claim 1, wherein R^5 is a group ▲a mathematical formula, a chemical formula, a table, etc.▼. (11) R^2 and R^3 are hydroxyl groups, and R^5 is a group ▲A mathematical formula, a chemical formula, a table, etc.▼ Hydrates and salt hydrates. (12) A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of a salt thereof according to claim 1, wherein R^5 is a group ▲a mathematical formula, a chemical formula, a table, etc.▼. (13) R^2 and R^3 are hydroxyl groups, and R^5 is a group ▲ Numerical formula, chemical formula, table, etc. ▼ Cephalosporin derivatives, salts thereof, and Hydration of hydrates and salts (14) R^
5 is a group ▲A mathematical formula, a chemical formula, a table, etc.▼ The cephalosporin derivative, its salt, its hydrate, and the hydrate of the salt according to claim 1, wherein (15) R^2 and R^3 are hydroxyl groups, and R^5 is a group ▲A mathematical formula, a chemical formula, a table, etc.▼ Hydrates and salt hydrates. (16) A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of the salt according to claim 1, wherein R^5 is a group ▲a mathematical formula, a chemical formula, a table, etc.▼. (17) R^2 and R^3 are hydroxyl groups, and R^5 is a group ▲ Numerical formula, chemical formula, table, etc. ▼ Cephalosporin derivatives, salts thereof, and Hydrates and salt hydrates. (18) A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of the salt according to claim 1, wherein R^5 is a group ▲a mathematical formula, a chemical formula, a table, etc.▼. (19) R^2 and R^3 are hydroxyl groups, and R^5 is a group ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The cephalosporin derivatives, salts thereof, and Hydrates and salt hydrates. (20) A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of the salt according to claim 1, wherein R^5 is a group ▲a mathematical formula, a chemical formula, a table, etc.▼. (21) R^2 and R^3 are hydroxyl groups, and R^5 is a group ▲ Numerical formula, chemical formula, table, etc. ▼ Cephalosporin derivatives, salts thereof, and Hydrates and salt hydrates. (22) A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of a salt thereof according to claim 1, wherein R^5 is a group ▲a mathematical formula, a chemical formula, a table, etc.▼. (23) R^2 and R^3 are hydroxyl groups, and R^5 is a group ▲A mathematical formula, a chemical formula, a table, etc.▼ Hydrates and salt hydrates. (24) A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of the salt according to claim 1, wherein R^5 is a 1-pyridinium methyl group. (25) A cephalosporin derivative, a salt thereof, a hydrate and a salt thereof according to claim 1, wherein R^2 and R^3 are hydroxyl groups, and R^5 is a 1-pyridinium methyl group. Hydrate. (26) R^2 and R^3 are hydrogen atoms, and R^5
A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of the salt according to claim 1, wherein is a group ▲ has a mathematical formula, a chemical formula, a table, etc. ▼. (27) The cephalosporin derivative according to claim 1, wherein R^2 is a hydroxyl group, R^3 is a hydrogen atom, and R^5 is a group ▲ Numerical formula, chemical formula, table, etc. ▼ , its salts, its hydrates and hydrates of salts. (28) The cephalosporin derivative, the salt thereof, the hydrate thereof, and the water of the salt according to any one of claims 1 to 27, wherein the bond indicated by the wavy line is a syn-type bond. Japanese item. (29) General formula (II) ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ (II) {In the formula, R^4 represents a hydrogen atom or a carboxy protecting group, and R^5 represents a hydrogen atom, a halogen atom, or a methoxy group or a group -CH_2R^6 [wherein R^6 is a hydrogen atom, an azide group, an acyloxy group, a carbamoyloxy group, a pyridinium group, a substituted pyridinium group, or a substituted or unsubstituted monocyclic or condensed heterocyclic thio group ( However, the term "heterocycle" refers to a 5- to 6-membered heterocycle having 1 to 4 oxygen, sulfur, and/or nitrogen atoms. ]
represents. }, their reactive derivatives, or their salts have the general formula (III) ▲mathematical formula, chemical formula, table, etc.▼(III) (wherein, R^1 represents a hydrogen atom or an amino protecting group. represents,
R^2 and R^3 represent a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, R^4 represents a hydrogen atom or a carboxy protecting group, and the wavy line bond is an anti-type or syn-type bond. represents. ) or a reactive derivative at the carboxyl group or a salt thereof, and optionally removing the amino-, hydroxy- and/or carboxy-protecting group. Formula (I)▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1, R^2, R^3, R^4, R^5, R
The combination of ^6 and the wavy line has the same meaning as above. )
A method for producing a cephalosporin derivative represented by (30) General formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) {In the formula, R^1 represents a hydrogen atom or an amino protecting group,
R^4 represents a hydrogen atom or a carboxy protecting group, R^
5 is a hydrogen atom, a halogen atom, a methoxy group or a group -C
H_2R^6 [wherein R^6 is a hydrogen atom, an azide group, an acyloxy group, a carbamoyloxy group, a pyridinium group, a substituted pyridinium group, or a substituted or unsubstituted monocyclic or condensed heterocyclic thio group (however, a heterocyclic thio group) The ring represents a 5- to 6-membered heterocyclic ring having 1 to 4 oxygen, sulfur and/or nitrogen atoms. ],
Bonds with wavy lines are anti-type or syn-type.
) represents a combination of shapes. } or their salts have the general formula (V) ▲Mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R^2 and R^3 are hydrogen atoms, hydroxyl groups, or protected hydroxyl groups. , R^4 represents a hydrogen atom or a carboxy protecting group, and X represents a halogen atom or a hydroxyl group. General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (Formula Medium, R^1, R^2, R^3, R^4, R^5, R
The combination of ^6 and the wavy line has the same meaning as above. )
A method for producing a cephalosporin derivative represented by (31) General formula (VI) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) (In the formula, R^1 represents a hydrogen atom or an amino protecting group,
R^2 and R^3 represent a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, R^4 represents a hydrogen atom or a carboxy protecting group, and the wavy line bond is an anti-type or syn-type bond. represents. ) or their salts, substituted or unsubstituted monocyclic or condensed heterocyclic thiol (heterocycle refers to 5- to 4-oxygen, sulfur, and/or nitrogen atoms having 1 to 4 oxygen, sulfur, and/or nitrogen atoms) Represents a 6-membered heterocycle.)
or by reacting a salt thereof or a substituted or unsubstituted pyridine, and optionally removing an amino-protecting group, a hydroxy-protecting group and/or a carboxy-protecting group (I) ▲Numerical formula, There are chemical formulas, tables, etc. ▼ (I) (In the formula, R^1, R^2, R^3, R^4, R^5, R
The combination of ^6 and the wavy line has the same meaning as above. )
A method for producing a cephalosporin derivative represented by (32) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) {In the formula, R^1 represents a hydrogen atom or an amino protecting group,
R^2 and R^3 represent a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, R^4 represents a hydrogen atom or a carboxy protecting group, and R^5 represents a hydrogen atom, a halogen atom, a methoxy group, or a group -CH_2R^ 6 [Wherein, R^6 is a hydrogen atom, an azide group, an acyloxy group, a carbamoyloxy group, a pyridinium group, a substituted pyridinium group, or a substituted or unsubstituted monocyclic or condensed heterocyclic thio group (however, a heterocyclic ring and represents a 5- to 6-membered heterocycle having 1 to 4 oxygen, sulfur and/or nitrogen atoms. ], and the wavy line represents an anti-type or syn-type bond. } A preparation for the treatment and prevention of infectious diseases, characterized in that it contains a cephalosporin derivative represented by the following formula, a salt thereof, a hydrate thereof, and/or a hydrate of the salt as an active ingredient. (33) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oxyimino]acetamide]-3-acetoxymethyl-8-oxo-
5-thia-1-azabicyclo[4.2.0]octo-2
-ene-2-carboxylic acid, its salts, its hydrates and/or
or a hydrate of a salt thereof. (34) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oxyimino]acetamide]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0 ] Octo-2-en-
33. The preparation according to claim 32, which is a 2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (35) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oxyimino]acetamide]-3-[(1-carboxymethyl-1H
-tetrazol-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]octo-
33. The preparation according to claim 32, which is 2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (36) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oximino]acetamide]-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]octo-2
-ene-2-carboxylic acid, its salts, its hydrates and/or
or a hydrate of a salt thereof. (37) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oxyimino]acetamide]-3-[(1,2,3-thiadiazol-5-yl)thiomethyl]-8-oxo-5-thia-1
-Azabicyclo[4,2,0]oct-2-ene-2-
33. The preparation according to claim 32, which is a carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (38) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oximino]acetamide]-3-[(5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-
8-oxo-5-thia-1-azabicyclo [4.2.0
] The preparation according to claim 32, which is oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (39) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oxyimino]acetamide]-3-[(5-methyl-2-sulfoxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5 -thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt; formulation. (40) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oximino]acetamide]-3-[(7-methyl-s-triazolo[1,5-c]pyrimidin-5-yl)thiomethyl]-
8-oxo-5-thia-1-azabicyclo [4.2.0
] The preparation according to claim 32, which is oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (41) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oxyimino]acetamide]-3-[(2-carboxy-7-methyl-s-triazolo[1,5-c]pyrimidin-5-yl)thiomethyl]-8-oxo-5 -thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt; formulation. (42) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oximino]acetamide]-3-[(8-carboxytetrazolo[
1,5-b]pyridazin-6-yl)thiomethyl]-8
-oxo-5-thia-1-azabicyclo[4.2.0]
Claim 3 is oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt.
The formulation according to item 2. (43) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oxyimino]acetamide]-3-[(6-carboxy-7-hydroxy-s-triazolo[1,5-a]pyrimidine-2-
yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, its salts, its hydrates and/or hydrates of its salts. A formulation according to certain claim 32. (44) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oxyimino]acetamide]-3-(1-pyridiniummethyl)-8
-oxo-5-thia-1-azabicyclo[4.2.0]
33. The formulation according to claim 32, which is oct-2-ene-2-carboxylate, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (45) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-(carboxyphenylmethyl)oxyimino]acetamide]-3-[(
2-carboxy-5-methyl-s-triazolo[1,5
-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, its salts, its hydrates and/or or a hydrate of a salt thereof. (46) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl-2-[Z-[carboxy(
3-hydroxyphenyl)methyl]oximino]acetamide]-3-[(2-carboxy-5-methyl-s-
triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[
4.2.0] The preparation according to claim 32, which is oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt.