JPH0699448B2 - New cephalosporin compounds and antibacterial agents - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel β-lactam antibacterial agent. More specifically, the present invention relates to novel cephalosporin compounds having antibacterial activity, as well as pharmaceutically acceptable salts or esters thereof.

(Problems to be Solved by Conventional Techniques and Inventions) Cephalosporin antibiotics show a wide range of antibacterial activities against Gram-positive and Gram-negative bacteria, and various semi-synthetic cephalosporin compounds have already been marketed It is clinically used as a therapeutic agent for infectious diseases. However, among these compounds, few therapeutic agents exhibit antibacterial activity against Pseudomonas aeruginosa and Pseudomonas aeruginosa. Further, many of these compounds are unstable with respect to β-lactamase produced by a resistant bacterium, and have drawbacks such as low antibacterial activity against Pseudomonas aeruginosa, which is currently clinically problematic. (WEWick, “Cep
halosporins and Penicillins, Chemistry and Biolog
y ", EHPlynn, Academic Press, New York, N, Y., 1972,
Chapter 11).

(Means for Solving the Problems) The present inventors have already disclosed JP-A-62-492 and JP-A-62-174083.
Japanese Patent Application Laid-Open No. 62-238290, Japanese Patent Application No. 62-108227, and Japanese Patent Application No. 62-108227.
-284634, a novel cephalosporin derivative having a 1-substituted-5-hydroxy-4-pyridon-2-yl group in a part of the 7-amide side chain of the cephem ring has a strong activity against a wide range of pathogens. Is heading.

Further, this time, further research was conducted focusing on the 5-hydroxy-4-pyridone structure, and the resulting novel cephem compound represented by the following general formula (I) was widely used for Gram-positive and Gram-negative bacteria. Has a strong antibacterial activity,
In particular, the present invention was completed by discovering that it exhibits extremely strong antibacterial activity against Pseudomonas aeruginosa, further exhibits strong antibacterial activity against various β-lactamase-producing bacteria, and has low toxicity and is well absorbed. did. Therefore, the present invention provides a compound of general formula (I) [In the formula, R ₁ represents a lower alkyl group which may have a substituent. ] The novel cephalisporin compound represented by these, its pharmacologically acceptable salt, or its ester body, and the antibacterial agent containing them as an active ingredient. Examples of the pharmacologically acceptable salt of the compound represented by formula (I) of the present invention include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt. ; Salts with organic bases,
Examples thereof include organic amine salts such as triethylamine salt, pyridine salt, ethanolamine salt, triethanolamine salt and dicyclohexylamine salt; and basic amino acid salts such as lysine and arginine.

R ₁ of the compound of the general formula (I) represents an alkyl group having 1 to 4 carbon atoms, which may have one or more substituents. Examples of the substituent include a hydroxyl group; a lower alkoxy group such as a methoxy group and an ethoxy group; an amino group; a mono- and di-lower alkyl-substituted amino group such as a methylamino group and a dimethylamino group;
Formyl group, acyl group such as acetyl group; lower alkoxycarbonyl group; carboxyl group; carbamoyl group; cyano group; fluorine atom; chlorine atom; nitro group; sulfonic acid group; sulfonic acid amide group; thiol group; alkylthio group; alkylsulfonyl Group; an alkylsulfinyl group and the like.

The compound (I) of the present invention can be produced by the following method. That is, the following equation (II) [In the formula, R ₂ represents a hydrogen atom or a protecting group for a carboxyl group, R ₃
Represents a hydrogen atom or a protective group for a hydroxy group. ] The compound shown by these, or the reactive derivative in the amino group thereof, or their salt, is added to the following formula (III) [In the formula, R ₄ represents a hydrogen atom or an amino group protecting group, and R ₅ represents a lower alkyl acid which may have a protected substituent. ]
It can be produced by reacting a compound represented by or a reactive derivative of the carboxyl group or a salt thereof.

A suitable example of the reactive derivative at the amino group of compound (II) is a Schiff base type imino produced by the reaction of compound (II) with a carbonyl compound such as an aldehyde or a ketone, or a tautomer thereof. Enamine type isomers; silyl derivatives such as compound (II) and bis (trimethylsilyl) acetamide; and derivatives formed by reacting compound (II) with phosphorus trichloride or phosgene.

Suitable salts of the compounds (II) and (III) include salts with organic acids (for example, acetate, maleate, tartrate,
Acid addition salts such as benzene sulfonate, toluene sulfonate, etc.) or salts with inorganic acids (eg hydrochloride, hydrobromide, sulphate, phosphate etc.); alkali metal salts or alkaline earth salts Metal salts such as metal salts (eg sodium salt, potassium salt, calcium salt, magnesium salt etc.); ammonium salts; organic amine salts (eg triethylamine salt, dicyclohexylamine salt etc.) and the like.

Suitable examples of the reactive derivative at the carboxyl group of the compound (III) include acid halogen compounds, acid azides, acid anhydrides, active azides, active esters and the like, and more specifically, acid chlorides and acid bromides. Substituted phosphoric acid (eg, dialkyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonate (eg, methyl carbonate, ethyl carbonate, etc.), aliphatic carboxylic acid (eg, Pivalic acid,
Valeric acid, isovaleric acid, 2-ethylacetic acid, trichloroacetic acid, etc.) or aromatic carboxylic acid (eg benzoic acid, etc.)
Mixed anhydrides with acids such as; active amides with imidazole, dimethylpyrazole, triazole or tetrazole; or active esters (eg cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl,
_{[(CH 3) 2 N =} CH-] ester, vinyl ester, propargyl ester, p- nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester , Phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc., or N-hydroxy compound (for example, N, N-dimethyl). Hydroxyamine, 1-hydroxy-2- (1H) -pyridone, N-
Esters with hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole and the like can be mentioned. These reactive derivatives are appropriately selected depending on the kind of the reactant compound (III) to be used.

The reaction between the compounds (II) and (III) is usually carried out with water, acetone, dioxane, acetonitrile, chloroform,
Methylene chloride, tetrahydrofuran, ethyl acetate, N, N
Carried out in a conventional solvent such as dimethylformamide, pyridine or other organic solvent which does not adversely influence the reaction. These solvents may be used as a mixture with water.

In this reaction, when the compound (III) is used in the form of a free acid or a salt, examples of the condensing agent include N, N '
-Dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl)
Carbodiimide; N, N'-diethylcarbodiimide; N,
N'-diisopropylcarbodiimide; N-ethyl-N '
-(3-Dimethylaminopropyl) carbodiimide; N, N
-Carbonylbis (2-methylimidazole); pentamethylene ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1
-Alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride; phosphorus oxychloride; thionyl chloride; oxalyl chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxa Zolium salt; 2-ethyl-5- (m-
Sulfophenyl) -isoxazolium hydroxide inner salt; 1- (p-chlorobenzenesulfonyloxy) -6
-Chloro-1H-benzotriazole; so-called Vilsmeier reagent obtained by the reaction of dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride and the like can be mentioned.

This reaction may also be carried out in the presence of an inorganic base or an organic base, and examples of such a base include alkali metal hydrogencarbonates (eg sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), alkaline earth metal carbonates ( Examples thereof include calcium carbonate), tri (lower) alkylamines (eg, triethylamine, trimethylamine, etc.), pyridine, N- (lower) alkylmorpholine, N, N-di (lower) -alkylbenzylamine and the like.

The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

Also the general formula (IV) [In the formula, Y is an acetoxy group, a halogen atom, R ₂ or R ₂ .
₄ and R ₅ have the same meaning as described above. ] To the compound represented by the general formula (V) [In the formula, R ₃ represents a hydrogen atom or a protective group for a hydroxy group. ] It is also possible to produce a compound of the general formula (I) by reacting a nucleophilic compound represented by The product obtained by these methods is the objective compound (I) of the present invention, or a protected form of the amino group, the carboxyl group and the hydroxyl group on the pyridone ring of the objective compound (I), and therefore, if necessary. Each protecting group is removed by a conventional method. The method for removing the carboxyl protecting group and the amino protecting group is appropriately selected depending on the type of the protecting group to be eliminated. For the elimination reaction of the amino protecting group, hydrolysis, reduction, and a method in which an imino halogenating agent and then an imino etherifying agent are allowed to act on a compound in which the protecting group is an acyl group, and then hydrolysis is carried out if necessary Any conventional method such as can be applied. The hydrolysis method using an acid is one of the general formulas, and is applied to elimination of groups such as alkoxycarbonyl group, formyl group and trityl group. The acid used is appropriately selected from formic acid, trifluoroacetic acid, hydrochloric acid and the like according to the type of amino protecting group. The reaction can be carried out without solvent or in the presence of water, a hydrophilic organic solvent or a mixed solvent thereof. When trifluoroacetic acid is used, the reaction may be performed in the presence of anisole. For the elimination reaction of the carboxyl protecting group, any conventional method such as hydrolysis and reduction can be applied. Hydrolysis using an acid is one of the general methods and is applied to elimination of silyl group, p-methoxybenzyl group, diphenylmethyl group and the like. As for the elimination reaction of the protective group for the hydroxyl group on the pyridone ring, any conventional method such as hydrolysis or reduction can be applied. Hydrolysis using acid or base is one of the general methods, for example p-
An acid is applied to eliminate a methoxybenzyl group, a diphenylmethyl group and the like, and a base is applied to eliminate an acyl group such as an acetyl group and a benzoyl group.

The compound of general formula (I) thus obtained is collected in the reaction mixture by a conventional method.

For example, purification, precipitation method, crystallization with an absorptive resin such as Amberlite XAD-2 (manufactured by Rohm and Haas), Diaion HP-20 (manufactured by Mitsubishi Kasei) or SepaBeads SP207 (manufactured by Mitsubishi Kasei) This can be achieved by appropriately combining the methods.

The antibacterial agents containing the compound represented by the general formula (I) or a salt thereof as a main component are mainly injections such as intravenous injection and intramuscular injection, oral preparations such as capsules, tablets and powders, or rectal preparations, oily and fatty substances. It is used in various dosage forms such as suppositories and water-soluble suppositories. These various formulations are commonly used excipients,
Conventional methods using fillers, binders, wetting agents, disintegrating agents, surface-active agents, lubricants, dispersants, buffers, preservatives, solubilizing agents, preservatives, flavoring agents, soothing agents, etc. Can be manufactured by. Specific examples of the formulation method will be described in more detail by the later-mentioned examples.

The dose is appropriately determined according to the individual case in consideration of symptoms, age, sex, etc., but is usually 250-3000 per adult per day.
mg, which is administered in 1 to 4 divided doses daily.

The LD ₅₀ of the acute toxicity test results using the compound of the present invention in mice was
The toxicity was 2g / kg or more.

(Effects of the Invention) The object compound (I) of the present invention or a salt thereof is a novel compound and exhibits high antibacterial activity for inhibiting the growth of a wide range of pathogenic microorganisms including Gram-positive bacteria and negative bacteria. In order to show the usefulness of the compound represented by the general formula (I), Table 1 shows antibacterial activity (minimum inhibitory concentration) measured by agar dilution method for some of them.

The present invention is further described in detail in the following reference examples and examples, but these are not intended to limit the present invention, and various changes and modifications can be made without departing from the scope of the present invention. Needless to say.

The NMR data in the examples used 90 MHz unless otherwise noted, in the case of heavy water, showing the δ value when the water peak is δ value 4.82, in the case of other deuterated solvents , And the δ value based on TMS.

Reference Example 1 2-Hydroxymethyl-5-p-methoxybenzyloxy-4-pyrone Kojic acid (4.26 g) was dissolved in N, N-dimethylformamide (35 ml), and anhydrous potassium carbonate (8.3 g) and p-methoxybenzyl chloride (5.5 g) were dissolved therein. And stir at 70-75 ° C for 1.5 hours. After completion of the reaction, the reaction solution was concentrated to about half volume, 70 ml of water was added thereto under ice-cooling, the resulting precipitate was collected by filtration, washed with water and ethyl acetate, and dried to obtain 6 g of the title compound.

NMR (δ value, CDCl ₃ ) 3.80 (3H, s), 4.43 (2H, s), 4.96 (2
H, s), 6.50 (1H, s), 6.88 (2H, d), 7.30 (2H, d), 7.51
(1H, s) Reference Example 2 5-p-methoxybenzyloxy-4-pyrone-2-carboxylic acid 2-hydroxymethyl-5-p-methoxybenzyloxy-4-pyrone 10 g was dissolved in 200 ml of 50% acetonitrile water. , Nickel peroxide, and Ni ₂ O ₃ 10 g are added, and the mixture is stirred at room temperature for 2 hours. After completion of the reaction, nickel is removed, the filtrate is concentrated under reduced pressure, 50 ml of water is added, and the pH is adjusted to 1.5 with 20% hydrochloric acid under ice cooling. The crystals are collected by filtration, washed with water and dried to obtain 9.6 g of the title compound.

NMR (δ value, DMSO-d ₆ ) 3.77 (3H, s), 4.90 (2H, s), 6.92
(1H, s), 6.96 (2H, d), 7.37 (2H, d), 8.34 (1H, s) Reference Example 3 5-hydroxy-4-pyrone-2-carboxylic acid 5-p-methoxybenzyloxy-4 -Pyrone-2-carboxylic acid 10 g was suspended in water 70 ml, and concentrated hydrochloric acid 150 ml was added.
Stir at 70 ° C. for 2 hours. After completion of the reaction, the reaction solution is concentrated and the precipitated crystals are collected by filtration, washed with a small amount of water and dried to obtain 6.2 g of the title compound.

mp> 200 ° C NMR (δ value, DMSO-D ₆ ) 5.40 (2H, bs), 6.96 (1H, s), 8.2
0 (1H, s) Reference Example 4 3-Hydroxy-4-pyrone 5-Hydroxy-4-pyrone-2-carboxylic acid (5 g) is dissolved in diphenyl ether (30 ml) and stirred at 250 to 260 ° C. for 1 hour. After completion of the reaction, the mixture is cooled and 100 ml of n-hexane is added, and the resulting precipitate is filtered and powder distilled. White crystals of the title compound
Get 6g.

bp 230 ° C mp 132-135 ° C NMR (δ value, CDCl ₃ ) 6.45 (1H, d, J = 6.4Hz), 7.72 (1H, d
d, J = 6.4 Hz, J = 1 Hz), 7.82 (1H, d, J = 6.4 Hz) Reference Example 5 3-diphenylmethyloxy-4-pyrone 3-hydroxy-4-pyrone 5 g was dissolved in 50 ml of methanol, Add 18 g of diphenyldiazomethane and stir at room temperature for 20 hours. After completion of the reaction, methanol was distilled under reduced pressure, and the precipitated crystals were collected by filtration, washed with isopropyl ether and dried to obtain 10 g of the title compound.

mp131-132 ° C IR (Nujol) 1630,1610,1560cm ^-1 NMR (δ value, CDCl ₃ ) 6.30 (1H, d, J = 5.6Hz), 6.36 (1H,
s), 7.15-7.45 (10H, m), 7.42 (1H, d, J = 1Hz), 7.50 (1
H, dd, J = 5.6 Hz, J = 1 Hz) Reference Example 6 3-diphenylmethyloxy-4-pyridone 3-diphenylmethyloxy-4-pyrone 1 g was suspended in concentrated ammonia water 10 ml, and methanol 3 ml was added to dissolve it. Let After stirring for 72 hours at room temperature, the solvent is distilled off under reduced pressure after completion of the reaction, the residue is added to a mixed solution of 20 ml of methylene chloride and 10 ml of water, and the organic layer is washed with water. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure to obtain the title compound (684 mg).

mp> 200 ° C IR (Nujol) 1620,1550,1530cm ^-1 NMR (δ value, CDCl ₃ ) 6.15 (2H, d, J = 6.4Hz), 6.58 (1H,
s), 7.15-7.55 (12H, m) Example 1 (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamide] -3- (3-Diphenylmethyloxy-4-pyridon-1-yl) methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (6R, 7R) -7-[(Z) -2- (2-tritylamino) (Thiazol-4-yl) -2-methoxyiminoacetamido] -3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (400 mg) was dissolved in acetone (10 ml) under nitrogen substitution, and sodium iodide (100 mg) was added at room temperature. Stir for 1 hour. The solvent is distilled off under reduced pressure, the residue is added to a mixed solution of 30 ml of ethyl acetate and 10 ml of water, washed with water, and dried over magnesium sulfate. Separately, 170 mg of 3-diphenylmethyloxy-4-pyridone was suspended in 10 ml of ethyl acetate, and BSTFA ((N, O-bis-Trimethylsilyl) trifluoro
acetamido) 0.2 ml is added and the mixture is stirred for 20 minutes to dissolve. This solution is added to the previously obtained reaction solution and stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and the residue was diluted with 50 ml of methylene chloride.
Dissolved in water, washed with water and 5% aqueous sodium hydrogen sulfite, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography [Wakogel C-300 (Wagel
ko), CHCI ₃ —CH ₃ OH)] to obtain 230 mg of the title compound.

NMR (δ value, CDCl ₃ ) 2.45, 2.92 (2H, ABq, J = 16Hz), 3.72
(3H, s), 4.00 (3H, s), 4.15,4.80 (2H, ABq, J = 14Hz),
4.82 (1H, d, J = 5Hz), 5.16 (2H, s), 5.85 (1H, dd, J = 5H)
z, J = 8Hz), 6.32 (1H, d, J = 6Hz), 6.40 (1H, s), 6.62
(1H, s), 6.78 (1H, d, J = 8Hz), 6.80 (2H, d, J = 6Hz),
6.92 (1H, s), 7.30 (27H, m) Example 2 (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-t-butoxycarbonylmethoxy Iminoacetamide] -3- (3-diphenylmethyloxy-4-pyridon-1-yl) methyl-3-
Cephem-4-carboxylic acid p-methoxybenzyl ester (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-t-butoxycarbonylmethoxyiminoacetamide] -3 -Chloromethyl-3
Treatment with 450 mg of cephem-4-carboxylic acid p-methoxybenzyl ester as in Example 1 gives 355 mg of the title compound.

NMR (δ value, CDCl ₃ ) 1.35 (9H, s), 2.48,5.93 (2h, ABq, J
= 16Hz), 3.78 (3H, s), 4.18,4.78 (2H, ABq, J = 13Hz),
4.70 (2H, s), 5.16,5.20 (2H, ABq, J = 9Hz), 4.82 (1
H, d, J = 5Hz), 5.82 (1H, dd, J = 5Hz, J = 8Hz), 6.35 (1H,
d, J = 6Hz), 6.40 (1H, s), 6.76 (1H, s), 6.82 (2H, d, J)
= 8Hz), 7.00 (1H, bs), 7.3 (27H, m), 8.52 (1H, d, J = 8
Hz) Example 3 (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamide]- 3- (3-Diphenylmethyloxy-4-pyridon-1-yl) methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (6R, 7R) -7-[(Z) -2- (2- Tritylaminothiazol-4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamido] -3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester In the same manner as in Example 1, 300 mg of the title compound is obtained.

NMR (δ value, CDCl ₃ ) 1.65 (3H, s), 1.68 (3H, s), 2.45, 2.
82 (2H, ABq, J = 16Hz), 3.75 (3H, s), 4.25,4.72 (2H, AB
q, J = 12Hz), 4.80 (1H, d, J = 5,2Hz), 5.15,5.26 (2H, AB
q, J = 9Hz), 5.90 (1H, dd, J = 5.2Hz, J = 8Hz) 6.35 (1H,
d, J = 8Hz), 6.42 (1H, s), 6.55 (1H, s), 6.85 (2H, d, J
= 6.4 Hz), 6.98 (1H, d, J-8Hz), 7.3 (27H, m) Example 4 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) 2-Methoxyiminoacetamide]-
3- (3-hydroxy-4-pyridon-1-yl) methyl-3-cephem-4-carboxylic acid sodium salt (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazole-4) -Yl) -2-methoxyiminoacetamido] -3- (3-diphenylmethyloxy-4-pyridone-1-yl) methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 230 mg in methylene chloride
Dissolve in 0.5 ml, add 0.5 ml of anisole and cool with ice. Add 3 ml of trifluoroacetic acid and stir at 5 ° C for 1 hour. After completion of the reaction, 50 ml of isopropyl ether was added and the precipitate was collected by filtration, washed with isopropyl ether, suspended in 1.5 ml of ice water and adjusted to pH 7.2 with 5% sodium hydrogen carbonate water under ice cooling to dissolve. Diaion HP-20 (manufactured by Mitsubishi Kasei) 20m
Develop in 1 and lyophilize the eluate to give 86 mg of the title compound.

NMR (δ value, D ₂ O) 3.20,3.52 (2H, ABq, J = 14.4Hz), 4.00
(3H, s), 4.90 (2H, s), 5.25 (1H, d, J = 5.0Hz), 5.85
(1H, d, J = 5.0Hz), 6.60 (1H, d, J = 6.4Hz), 7.00 (1H,
s), 7.71 (1H, s), 7.75 (1H, d, J = 6.4Hz) Example 5 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl)- 2-Methoxyiminoacetamide]-
3- (3-hydroxy-4-pyridon-1-yl) methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (6R, 7R) -7-[(Z) -2- (2-amino Thiazol-4-yl) -2-methoxyiminoacetamide]-
30 mg of 3- (3-hydroxy-4-pyridon-1-yl) methyl-3-cephem-4-carboxylic acid sodium salt
Dissolve in 1 ml of N, N-dimethylformamide and cool to -20 ° C. Add 20 mg of pivaloyloxymethyl iodide,
Stir for 10 minutes at -20 ° C to -5 ° C. 30 ml of methylene chloride,
It is poured into a mixed solution of 10 ml of water, washed with water and 5% aqueous sodium hydrogen sulfite, and the organic layer is dried over magnesium sulfate. Add 50 ml of isopropyl ether, replace and concentrate, then add 50 ml of isopropyl ether and collect the deposited precipitate by filtration.
Dissolve in 1 ml. After adding 10 ml of water and concentrating the suspension by half, lyophilization gives 21 mg of the title compound.

NMR (δ value, CDCl ₃ ) 1.10 (9H, s), 3.80 (3H, s), 4.72 (2
H, s), 5.20 (1H, d, J = 5.0Hz), 5.80,5.90 (2H, ABq, J =
4.8Hz), 5.82 (1H, dd, J = 5Hz, J = 8.0Hz), 6.12 (1H, d, J
= 6.4Hz), 6.68 (1H, s), 7.10 (2H, bs), 7.28 (1H, s),
7.60 (1H, d, J = 6.4Hz), 9.52 (1H, d, J = 8Hz) Example 6 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) 2-Carboxymethoxyiminoacetamide] -3- (3-hydroxy-4-pyridone-1-
Iyl) methyl-3-cephem-4-carboxylic acid sodium salt (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-t-butoxycarbonylmethoxyiminoacetamide ] -3- (3-Diphenylmethyloxy-4-pyridon-1-yl) methyl-3-
Treatment with cephem-4-carboxylic acid p-methoxybenzyl ester 360 mg as in Example 4 gave 103 mg of the title compound.

NMR (δ value, D ₂ O) 3.22,3.52 (2H, ABq, J = 14,4Hz), 4.60
(2H, s), 4.92 (2H, s), 5.26 (1H, d, J = 5Hz), 5.88 (1
H, d, J = 5Hz), 6.60 (1H, d, J = 6.4Hz)), 7.08 (1H, s),
7.70 (1H, s), 7.72 (1H, d, J = 6.4Hz) Example 7 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- ( 1-methyl-1-carboxy)
Ethoxyiminoacetamido] -3- (3-hydroxy-4-pyridon-1-yl) methyl-3-cephem-4
-Carboxylic acid sodium salt (6R, 7R-7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (1-methyl-1-diphenylmethoxycarbonyl) ethoxyiminoacetamide] -3 Example 4 using 300 mg of-(3-diphenylmethyloxy-4-pyridon-1-yl) methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester.
Treated in the same manner as to give 103 mg of the title compound.

NMR (δ value, D ₂ O) 1.52 (6H, s), 3.20,3.52 (2H, ABq, J =
16Hz), 4.92 (2H, s), 5.25 (1H, d, J = 5.0Hz), 5.85 (1
H, d, J = 5.0Hz), 6.62 (1H, d, J = 6.4Hz), 7.00 (1H, s),
7.70 (1H, s), 7.75 (1H, d, J = 6.4Hz)

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Seiji Shibahara 760 Meiji Seika Co., Ltd., Kohoku Ward, Yokohama City, Kanagawa Prefecture Meiji Seika Co., Ltd. (72) Inventor Shigeharu Inoue 760 Meiji-Seika Co., Ltd.

Claims (2)

[Claims] 1. The following formula (I) [In the formula, R ₁ represents a lower alkyl group which may have a substituent. ] The cepharisporin compound represented by these, and its pharmacologically acceptable salt or ester. 2. An antibacterial agent containing the compound according to claim 1 as an active ingredient.