JPH0269485A - Cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H, (substituted) lower alkyl, (substituted) cycloalkyl, (substituted) lower alkenyl, (substituted) aryl, etc.; R<2> is (substituted) lower alkyl, (substituted) cycloalkyl, (substituted) alkenyl, etc.; R<3> is H or ester residue hydrolyzable in living body]. EXAMPLE:Sodium 7beta-[2-(2-aminothiazol-4-yl)-(z)-2-methoxyiminoacetamido]-3-(2- cyanoethoxy)-3-cephem-4-carboxylate. USE:An antibacterial agent useful for the remedy and prevention of infectious diseases of respiratory organ, infectious diseases of urinary tract, purulent diseases, surgical infectious diseases, etc. PREPARATION:The objective compound can be produced by reacting a com pound of formula II (R<11> is OH-protecting group, etc.; R<31> is R<3> or carboxyl- protecting group; R<4> is H or amino-protecting group) with a compound of formu la HO-R<21> (R<21> is R<2>, etc.) and, as necessary, subjecting the resultant compound of formula III to the removal of the protecting group, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel cephalosporin derivative useful in the medical field, a method for producing the same, and its use as an antibacterial agent.

BACKGROUND OF THE INVENTION Traditionally, cephalosporin antibiotics have been widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals, such as the treatment of diseases caused by bacterial infections resistant to penicillin antibiotics. Cephalosporin antibiotics are particularly useful in the treatment of bacterial infections in penicillin-sensitive patients, and are also low in toxicity, making them excellent in terms of safety. Against this background, numerous attempts have been made to create cephalosporin antibiotics that have stronger antibacterial activity and are superior in terms of safety.

Among these attempts, a derivative in which the 3-position of the cephalosporin nucleus was directly substituted with an oxygen atom was known, and was published in JP-A-49-5.
No. 5687, No. 50-108287, No. 51-564
No. 89, No. 5]-63191, No. 53-103493
No. 59-76089, etc.

However, the compounds described in these documents are merely used as production intermediates, or have a simple lower alkoxy group such as a methoxy group as a substituent at the 3-position. No. 62-19
No. 594 has an alkynylalkyloxy group at the 3-position,
Compounds having carboxymethoxy and alkoxycarbonylmethoxy groups are disclosed. However, as is clear from the claims of these publications, regarding the substituent at the 7-position, the 2(2-aminothiazol-4-yl)-2-substituted and unsubstituted oxyiminoacetamide groups of the compounds of the present invention are Not included. Japanese Patent Publication No. 61-130293
The publication discloses a compound having a fluorinated alkoxy group at the 3-position. However, regarding the substituent at the 7-position, the detailed explanation in this publication only provides general descriptions without specific disclosure, and the examples disclose only a phenylacetamide group, substituted and unsubstituted phenyl Only glycylamide and cyclohexagenylglycylamide groups.

The problem that 6mei aims to solve is to provide a compound that has excellent antibacterial activity against pathogenic bacteria and also has excellent properties in terms of safety.

Means for Solving the Problems Conventionally, in cephalosporin derivatives, it is widely known that the combination of substituents at the 3- and 7-positions of the cephalosporin nucleus is important and greatly affects the antibacterial activity. As a result of intensive research aimed at creating cephalosporin derivatives with excellent antibacterial activity, the present inventors found that 2-(2-aminothiazol-4-yl)-2-
The present invention was completed based on the discovery that a series of cephalosporin derivatives having a substituted or unsubstituted oxyiminoacetamide group and a substituted alkoxy group at the 3-position have excellent antibacterial activity.

The present invention is directed to - maximum (wherein R' is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group).

an optionally substituted lower alkynyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, R3 is an optionally substituted lower alkyl group,
an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, or an optionally substituted lower alkynyl group, R゛ is a hydrogen atom or a nontoxic ester that can be hydrolyzed in vivo The present invention relates to a cephalosporin derivative or a non-toxic salt thereof, a method for producing the same, and an antibacterial agent containing the compound as an active ingredient.

Next, various terms mentioned in this specification and appropriate examples thereof will be explained.

Halogen atoms include fluorine atoms, chlorine atoms, bromine atoms,
means an iodine atom.

Examples of the optionally substituted lower alkyl group include halogen atom, hydroxyl group, methoxy group, ethoxy group, n-
Propoxy group, isopropoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, formyloxy group, acetoxy group, fluoroacetoxy group, carbamoyl group, N-methylcarbamoyl group, N, N
-dimethylcarbamoyl group, carbamoyloxy group, N
-Methylcarbamoyloxy group, N,N-dimethylcarbamoyloxy group, amino group, methylamino group, dimethylamino group, formamide group, acetamide group, fluoroacetamide group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, sulfo group, One or more selected from the group consisting of sulfamoyl group, cyano group, formyl group, acetyl group, fluoroacetyl group, methylthio group, ethylthio group, fluoromethylthio group, ■-fluoroethylthio group, 2-fluoroethylthio group, etc. Optionally substituted with the above substituents, for example, a methyl group,
Ethyl group, rhopropyl group, isopropyl group, n-butyl group, isobutyl group, 5ec-butyl group, tert-butyl group.

Examples include alkyl groups having 1 to 6 carbon atoms such as pentyl group or hexyl group.

Examples of the optionally substituted cycloalkyl group include one or more groups selected from the group consisting of carboxyl group, carbamoyl group, amino group, methylamino group, dimethylamino group, sulfo group, hydroxyl group, cyano group, etc. For example, a cycloalkyl group having 3 to 6 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group may be substituted with a substituent.

Examples of the optionally substituted lower alkenyl group include one or more substituents selected from the group consisting of a halogen atom, a carboxyl group, an amino group, a sulfo group, a hydroxyl group, a carbamoyl group, a cyano group, etc. For example, a vinyl group, allyl group, l-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 1-pentenyl group, or 1-hexenyl group having 2 carbon atoms.
to 6 alkenyl groups.

Examples of the optionally substituted lower alkynyl group include a halogen atom, a hydroxyl group, an amino group, a carboxyl group,
Optionally substituted with one or more substituents selected from the group consisting of carbamoyl group, sulfo group, cyano group, etc., such as ethynyl group, 1-propynyl group, propargyl group, 1-butynyl group, 1- pentynyl group or l-
Examples include alkynyl groups having 2 to 6 carbon atoms such as hexynyl group.

Examples of the optionally substituted aryl group include a halogen atom, methyl group, ethyl group, fluoromethyl group, trifluoromethyl group, aminomethyl group, carboxymethyl group, carbamoylmethyl group, sulfomethyl group, hydroxyl group, methoxy group, Fluoromethoxy group, acetoxy group, amino group, methylamino group, dimethylamino group, acetamido group, carboxyl group, methoxycarbonyl group, carbamoyl group, N-methylcarbamoyl group, N,N-dimethylcarbamoyl group, carbamoyloxy group, sulfonate an aryl group having 6 to 10 carbon atoms, such as a phenyl group or a naphthyl group, which may be substituted with one or more groups selected from the group consisting of a sulfamoyl group, a cyano group, a nitro group, etc. can be mentioned.

Examples of optionally substituted aralkyl groups include halogen atoms, methyl groups, ethyl groups, fluoromethyl groups,
trifluoromethyl group, aminomethyl group, carboxymethyl group, carbamoylmethyl group, sulfomethyl group, hydroxyl group, methoxy group, fluoromethoxy group, acetoxy group,
Amino group, methylamino group, dimethylamino group, acetamido group, carboxyl group, methoxycarbonyl group, carbamoyl group, N-methylcarbamoyl group, N,N-dimethylcarbamoyl group, carbamoyloxy group, sulfo group, sulfamoyl group, cyano group Examples include aralkyl groups having 7 to 12 carbon atoms such as benzyl group, phenethyl group, or naphthylmethyl group, which may be substituted with one or more substituents selected from the group consisting of .

- R in the target compound of the present invention represented by maximum (T)
Preferred examples of ``1'' include hydrogen atom, methyl group, ethyl group, carboxymethyl group, 1-carboxy-1-methylethyl group, 1-carboxycycloprobyl group, 1-
Carboxycyclobutyl group, 1-carboxycyclopentyl group, l-carboxyvinyl group, 2-carboxyvinyl group, 2-carboxyethynyl group, fluoromethyl group,
2-fluoroethyl group, 2,2-difluoromethyl group,
Chlormethyl group, 2-chloroethyl group, bromomethyl group, 2-bromoethyl group, vinyl group, ethynyl group, 3.4
-dihydroxybenzyl group, α-carboxy-3,4-
Examples include dihydroxybenzyl group and benzyl group.

Suitable examples of R1 include, for example, cyanomethyl group, 1-
Cyanoethyl group, 2-cyanoethyl group, 3-cyanopropyl group, 2-cyano-1-methylethyl group, 2-chloroethyl group, 2-fluoroethyl group, 2,2.2-trifluoroethyl group, 2-hydroxyethyl group group, 2-methoxyethyl group, 2-carbamoylethyl group.

2-aminoethyl group, 2-acetylaminoethyl group, carboxymethyl group, l-carboxyethyl group, 2-carboxyethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, l-carboxycarbonylethyl group, 2-ethoxycarbonyl Ethyl cloud, carbamoylmethyl group, ■-carbamoylethyl group, 2-carbamoylethyl group, N-methylcarbamoylmethyl group, N, N
-dimethylcarbamoylmethyl group, 2-N-methylcarbamoylethyl group, 1-N-ethylcarbamoylethyl group, methylthiomethyl group, ethylthiomethyl group, 2-oxopropyl group, cyclopropyl group, vinyl group, furyl group, ethynyl group and propargyl group.

Examples of ester residues that can form nontoxic esters that can be hydrolyzed in vivo include lower alkanoyloxymethyl groups such as acetoxymethyl, propionyloxymethyl, and piparoyloxymethyl groups, and 1-(methoxycarbonyloxy). Ethyl group, 1-(lower alkoxycarbonyloxy)ethyl group such as 1-(ethoxycarbonyloxy)ethyl group or 1-(tert-butoxycarbonyloxy)ethyl group, (5-methyl-2-
(5-substituted-2-oxo-1,3 -dioxol-4-yl)methyl group or 1-
Examples include vine ester residues that are easily hydrolyzed in vivo to form vine esters, such as phthalidyl groups and 5-cyano-1-phthalidyl groups.

- Non-toxic salts of the object compound of the present invention represented by maximum [1) include, for example, salts with alkali metals such as sodium, potassium or lithium, salts with alkaline earth metals such as calcium or magnesium, N, Salts with organic amines such as N-dibenzylethylenediamine, ethanolamine or triethylamine, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid, salts with organic acids such as acetic acid, citric acid or tartaric acid, methanesulfone Examples include salts with acids or organic sulfonic acids such as p-toluenesulfonic acid, or salts with amino acids such as aspartic acid, glutamic acid or lysine.

The compound of the present invention has geometric isomers cE form and 2 form 3 derived from the oximino group in the 7-position side chain, both of which are included in the present invention, but preferably 7 forms.

Next, a method for producing the compound of the present invention will be explained.

- Maximum (wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, r!! A lower alkynyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, R
1 represents an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, or an optionally substituted lower alkynyl group; R' represents a hydrogen atom or a hydrogen atom; The compounds of the present invention represented by -max (respectively representing ester residues capable of forming non-toxic esters that can be hydrolysed in the body) are - maximum (wherein R'' is a hydroxyl protecting group, the above-mentioned R'' or A substituent in which the functional group of R" is protected, R1" is a carboxyl protecting group or the above-mentioned R1, and R4 is a compound represented by hydrogen 7I? (representing a child or a protecting group for an amino group) or its The salt is reacted with a compound represented by the formula %() (wherein RN+ represents R1 or a substituent in which the functional group of R1 is protected) (wherein 1 is a R", R'° and R4 have the above-mentioned meanings), and then, if desired, (i) removing the protecting group (ii) converting into a non-toxic salt (ui) It is produced by performing one or more steps of converting it into a non-toxic ester that can be hydrolyzed in the body.

The process of reacting the compound of the general formula [old compound with the compound of the general formula (III) to produce a compound of -maximum [TV] is performed using aromatic hydrocarbons such as benzene or toluene,
In a solvent that does not adversely affect the reaction, such as ethers such as ethyl ether, tetrahydrofuran or dioxane, chlorinated hydrocarbons such as methylene chloride or chloroform, or acid amides such as dimethylformamide or dimethylacetamide, the azodicarboxylate reagent and the It can be carried out in the presence of an alkylphosphine or a triarylphosphine.

In this step, the azodicarboxylate reagent used is, for example, dimethyl azodicarboxylate, diethyl azodicarboxylate or diisopropylazodicarboxylate, preferably diethyl azodicarboxylate, Examples of the alkylphosphine and triarylphosphine include triethylphosphine, tributylphosphine or triphenylphosphine, and triphenylphosphine is preferred.

As for the implementation conditions of this step, the amounts of each raw material and each reagent to be used can be selected as appropriate, but preferably, compound (n)
The molar ratio of compound [II+], azodicarboxylate reagent, and phosphine is approximately 1.1:1:l, and the reaction temperature can be appropriately selected from -50°C to the reflux temperature of the solvent. However, the temperature is preferably -30°C to room temperature, and the reaction time is 5 minutes to 24 hours.

If a protective group for a functional group is present in the product of the above two steps, removal of the protective group may be carried out by Protective Groups in Organic Synthesis, depending on the type of the protective group. Groupsi
This can be carried out by selecting a known method such as that published in 1981 (Organic Synthesis), published in 1981. Specifically, the removal of the protecting group of the amino group is performed, for example, by tert-
The butoxycarbonyl group is caused by the acid, and the 2,2,2-trichloroethoxycarbonyl group is! With IIE lead and acid, p
-The nitrobenzyloxycarbonyl group is produced by catalytic reduction. In addition, the protective groups of hydroxyl groups can be removed, for example, with potassium bicarbonate in aqueous methanol for formyl and trifluoroacetyl groups, with dilute hydrochloric acid for tetrahydropyranyl groups, and with zinc and acid for 2,2,2-trichloroethoxycarbonyl groups. be exposed. Removal of protective groups such as carboxyl groups, such as benzhydryl groups and p-methoxybenzyl groups, can be carried out using acids such as trifluoroacetic acid in the presence of anisole.
Butyldimethylsilyl groups and the like are reduced with water or hydrous alcohol, 2,2,2-trichloroethyl groups are reduced with zinc and acid, and p-nitrobenzyl groups are reduced.

The products obtained in each of the above steps can be purified, for example, by column chromatography, solvent extraction, precipitation, recrystallization, or the like. Further, if necessary, it can be converted into a desired salt or ester by a method known per se.

Among the raw material compounds used in the method for producing the compounds of the present invention, compounds represented by the general formula (Ill) include, for example, HelveticaChim, Chimiki, Acta
ica Acta) Volume 57, Page 1919 (1974
7-amino-3-hydroxy-3-cephem-4-carboxylic acid or its derivatives produced by the method described in It can be produced by reacting the represented compound or a reactive derivative of its carboxyl group.

7-Amino-3-hydroxy-3-cephem-4-carboxylic acid or a derivative thereof is reacted with a compound represented by the general formula [■] or a reactive derivative of its carboxyl group to obtain the compound represented by the general formula [■]. The process for producing the represented compounds includes, for example, water, acetone, dioxane, ether, tetrahydrofuran, ethyl methyl ketone, chloroform, methylene chloride, dichloroethane, ethyl acetate, ethyl formate, N
, N-dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof, which does not affect the reaction, at a reaction temperature of from cooling to room temperature, and a reaction time of 1 to 10 hours. . Examples of reactive carboxyl derivatives of the compound represented by formula [V] include dehydrating agents such as N,N'-dicyclohexylcarbodiimide, and N-hydroxysuccinimide or 1-hydroxyhencytriazole. active esters formed with active esters, acid halides formed with halogenating agents such as thionyl chloride, phosphorus pentachloride or oxalyl chloride, deoxidizing agents such as triethylamine or N-methylmorpholine and in turn methyl chloroformate. Alternatively, mixed acid anhydrides formed from chlorocarbonate such as isobutyl chloroformate may be mentioned. Further, depending on the type of the reactive derivative of the carboxylic acid used, it may be preferable to carry out the reaction in the presence of a base in order to allow the reaction to proceed smoothly. Such bases include, for example, potassium hydrogen carbonate,
Inorganic bases such as sodium carbonate or potassium carbonate or e.g. trimethylamine, triethylamine, N, N
-Organic bases such as dimethylaniline or pyridine. In addition, when using the compound represented by -maximum (V) in the form of free carboxylic acid, it is recommended to use a condensing agent such as N,N'-dicyclohexylcarbodiimide or N,N-diethylcarbodiimide. preferable. In addition,
- Compounds with maximum [V] can be found, for example, in the Chemical and Pharmaceutical Bulletin (Chea
p, Pharm, Bull, ), Volume 25, 311
5 pages (1977) and Journal of the Chemical Society of Japan, page 785 (1977)
981), etc. Also,
- As for the compound represented by maximum ('III), commercially available products or those easily produced by known methods can be used.

The compounds of the present invention exhibit excellent antibacterial activity and are useful as medicines, and can be used for the treatment and prevention of bacterial infections, such as respiratory infections, urinary tract infections, purulent diseases, and surgical infections. can. Administration methods include parenteral administration such as intravenous injection, intramuscular injection, skewering, etc., or tablets, powders, etc.
Oral administration via capsules, syrups, etc. is applicable. For formulation, conventional methods in this field may be used, and commonly used additives such as auxiliaries, stabilizers, wetting agents, and emulsifiers may be included. The dosage is determined by the doctor, taking into consideration age, sex, body weight, sensitivity differences, administration method, time and interval of administration, degree of illness, physical condition, properties of the pharmaceutical preparation, type of preparation, type of active ingredient, etc. It is usually used in the range of 1 to 100 mg/kg per day, preferably 5 to 30 mg/kg per day, divided into 2 to 4 doses.

In order to more specifically demonstrate the usefulness of the compounds of the present invention, in vitro antibacterial activity against various bacteria was measured by the agar plate dilution method described below. One platinum loop of each test strain cultured overnight in Mueller-Hinton broth (inoculum amount: 10@
CFU/mΩ) were inoculated onto Mueller-Hinton agar. This medium contains antibacterial agents at various concentrations, 37
After culturing at ℃ for 16 hours, the minimum inhibitory concentration (℃
2 μs/mu) was measured.

The results are shown in the table below.

Ru.

Examples include 7β-(2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamide)-
3-Hydroxy-3-cephem-4-carboxylic acid p-methoxybenzyl ester 762+ng (1mmo Q
) and triphenylphosphine 327+og (1,25
mmoff ) in 16 mQ of tetrahydrofuran, and add a solution of 88.9 mg (1,25 mmo Q ) of β-hydroxypropionitrile in tetrahydrofuran (8 mG) at -20°C under a nitrogen stream. Rate 0.19mQ(1,
A solution of 23 mmoQ) in tetrahydrofuran (8 mQ) was added at the same temperature, and after stirring for 30 minutes, ethyl acetate was added to the reaction mixture that was left overnight at the same temperature, and water, IN hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and then saturated brine were added. After washing with water and drying with magnesium sulfate, the solvent is distilled off. The residue was subjected to silica gel column chromatography (Fucco-
gel C-300, eluting with chloroform) to give 7β-(2-(2-tritylaminothiazole-4
-yl)-(Z)-2-methoxyiminoacetamide)-3-(2-cyanoethoxy)-3-cephem-4-
Carboxylic acid p-methoxybenzyl ester 480mg (
Yield: 58.9%). This powder 478mg (0,5
87 mmo Q) was dissolved in 3.3 mD of dichloromethane and 0.68 mQ of anisole (1.5 mm), and 5.1 mQ of trifluoroacetic acid was lowered to 11°C under cooling with water and heated to 11' for 1 hour at the same temperature. The solvent was distilled off. After that, isopropyl ether is added to the residue, and the resulting precipitate is filtered. Dissolve this in water, adjust to pl! 6.5 with aqueous sodium hydrogen carbonate solution,
Reverse column chromatography (Chemco LC-5ORB
.

5P-B-ODS, eluted with 10% methanol aqueous solution) and lyophilized to obtain 95.6 mg (yield 34.4%) of the title compound.

mp: 155-160℃ (Decomposition IR (KBr) am-': 2250, 1760, 16
]0,1535.1365NMR(DMSO-d, )
δ: 2.82 (211, t, J=611z), 3.40
(311, s).

3.84 (311, s), 3.9-4.1 (2] 1.m
), 4.97 (ltl, d, J=5ilz), 5.
46 (III, dd, J=5&8tlz), 6
．． 71 (ill, s), 7, 18 (211, b
r), 9.44 (III, d, J=811z) The following compounds of Examples 2 to 4 were synthesized in the same manner as in Example 1.

Example 2 mp: 165-t70℃ (decomposition) IR (KBr)
cm-': 1760, 1610, 1530.136O
NMR (DMSO-d, )δ: 3.4 (m), 3.8
5 (311, s), 4.95-5.05 (311, m)
, 5.5 (III, m), 6.72 (III
, s), 7.2 (211, br).

9.46 (III, d) Example 3 2''-mp: 175-180°C (decomposition) IR (KBr) cm-' +1760, 1620, 15
30.136ONMR(DMSO-d,')δ: 1
．． 51 (311, d, J=8Hz), 3.4(m)
, 3.83 (311, s), 4.98 (III,
d, J=511z), 5.4~5.7(2+1
, m).

6.70 (111, s), 7.18 (211, br)
, 9.48 (III, d, J = 8 Hz) Example 4 mp: 190-195°C (decomposition) 11i (KBr) cm-': 1760, 1660, 1
620.153ON)IR(DMSO-d, )δ:3
．． 5(m), 3.86(311,s), 4.1-4.
2 (211゜m>, 4.5-4.6 (211, m), 4
．． 98 (Ill, d, J lightning 5Hz), 5.50 (III
, dd, J=5&811z), 6.72(l
it, s), 7.22 (211, br).

9.44<III, d, J=8! Iz) Example 5 7β-[2-(2-tritylaminothiazol-4-yl)(Z)-2-diphenylmethoxycarbonylmethoxyiminoacetamide]-3-hydroxy-3-cephem-4-carvonel1p-methoxybenzyl ester 9
72 mg (Immo Q) and triphenylphosphine 327 mg (1,25 mmoQ) were dissolved in 16 IIlfl of tetrahydrofuran, and 71.4 mg (1,2
A solution of 5 mmoQ) in tetrahydrofuran (8 mQ) is added. Next, a tetrahydrofuran (8 mQ) solution of diethyl azodicarboxylate 0.19 mf:t (1,23 mtnoQ ) was added to this solution at the same temperature, stirred for 1 hour, and then left at the same temperature overnight.

Ethyl acetate is added to the reaction mixture, which is washed with water, IN hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over magnesium sulfate, and then the solvent is distilled off. The residue was subjected to silica gel column chromatography (Wakogel C-3
00, dichloromethane-chloroform) to give 7β-(2-(2-tritylaminothiazol-4-yl)-(Z )-2-diphenylmethoxycarbonylmethoxyiminoacetamide]-3-cyanomethoxy-3 -Cephem-4-carvoneffl! 873 mg (yield 86.3%) of p-methoxybenzyl ester is obtained. 554 mg (0,548 mmo Q) of this powder is mixed with 3 mQ of dikuO/lzmethane and 0.64 mQ of anisole.
4.6 mfl of trifluoroacetic acid was added dropwise under water cooling, and the mixture was stirred for 1 hour at the same temperature. After distilling off the solvent, isopropyl ether was added to the residue to obtain the triple fluoroacetate salt of the title compound. Obtained as a powder. Dissolve this in water, adjust the pH to 6.5 with an aqueous sodium hydrogen carbonate solution,
Reversed phase column chromatography (Chemco LC-8○12
13,5P-B-ODS, eluted with water) and lyophilized to give 70.6 mg (yield 42.5%) of the title compound. -' :1760.1610.15
30.141ONMR(DMSO-d, )δ:3.4
(+ll), 4.28 (2+I, ll), 4.9-5,
05 (311, m), 5.5 (III, m), 6.82
(ill, s), 7.2 (2H, br) Example 6 Mu-4-carboxylade was synthesized in the same manner as in Example 5.

mp: 150-155°C (decomposition) IR (KBr) cIO-': 2250, 1760, 1
600.153ONMR (DlfSO-d, +D, 0)
δ: 2.80 (2+1.t, J=71Jz), 3.3
2 (211°), 3. ! 11-4.2 (211, m)
, 4.30 (211, s), 5.01 (III, d.

J=511z), 5.50(III, d, J=511z
), 6.82 (Ill, s) Example full ester chloromethyl bivalate 45.31!1 g (0.3 m+
No.
After removing the insoluble matter, the solvent was distilled off and the residue was dissolved in 1 mQ of N,N-dimethylformamide to obtain the product obtained in Example 2. 7β-[2-(2-aminothiazole-4-
yl)-(Z)-2-methoxyiminoacetamide]
Dissolve sodium -3-cyanomethoxy-3-cephem-4-carboxylate (100100ta, 217mmon) in N,N-dimethylformamide 1IIQ, add the above solution under water cooling, and stir at room temperature for 15 minutes to form a reaction solution. Water and ethyl acetate are added, and the ethyl acetate layer is separated, washed with water and saturated brine, dried over magnesium sulfate, and the solvent is distilled off. Trituration of the residue with ether gives 17.6 mg (14.7% yield) of the title compound.

mp: 120-123℃ (decomposition) IR (Mar) am-': 1780, 1750, 16
75,1620.153ONMR (DMSO-d, )
δ: 1.16 (911, s), 3.78 (211, s)
, 3.86 (311°s), 5.11 (211,s),
5.23 (Ill, d, J = 4Hz), 5.73 (IH
.

dd, J=4 & 811z), 5.79, 5.89 (2+
1. ABq, J=6Hz), 6.81 (III, s),
7.24 (211, br), 9.64 (III, d, J
=811z) Effect of the Invention The compound of the present invention exhibits excellent antibacterial activity and is therefore useful as a therapeutic agent for bacterial infections in mammals including humans.

Claims (3)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [ I ] (In the formula, R^1 is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group,
An optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, R^
2 is an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, or an optionally substituted lower alkynyl group, and R^3 is a hydrogen atom or A cephalosporin derivative or a nontoxic salt thereof, each representing an ester residue capable of forming a nontoxic ester that can be hydrolyzed in vivo. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] The group is a protected substituent, R^3^1 is R^3 of the general formula [I] described later or a carboxyl group protecting group, R^4 is a hydrogen atom or an amino group protecting group, respectively) The compound or its salt represented by the general formula HO-R^2^1 [III] (wherein, R^2^1 is R^2 of the general formula [I] to be described later)
or the functional group of R^2 represents a protected substituent), the general formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ [IV] (In the formula, R^1^1 , R^2^1, R^3^1 and R^
4 has the above-mentioned meaning), and then, if desired, (i) removing the protecting group, (ii) converting into a non-toxic salt, (iii) a non-toxic compound that can be hydrolyzed in vivo. There are general formulas that are characterized by performing one or more steps beyond the step of converting into a sex ester ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼〔I〕 optionally substituted lower alkyl group, optionally substituted cycloalkyl group,
An optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, R^
2 is an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, or an optionally substituted lower alkynyl group, and R^3 is a hydrogen atom or A method for producing a cephalosporin derivative or a nontoxic salt thereof, each of which represents an ester residue capable of forming a nontoxic ester that can be hydrolyzed in vivo. (3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [I] (In the formula, R^1 is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group,
An optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, R^
2 is an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, or an optionally substituted lower alkynyl group, and R^3 is a hydrogen atom or An antibacterial agent containing a cephalosporin derivative or a nontoxic salt thereof as an active ingredient, each representing an ester residue capable of forming a nontoxic ester that can be hydrolyzed in vivo.