JPH0633282B2 - New cephalosporin compounds and antibacterial agents - Google Patents

Description

The present invention relates to a novel cephalosporin compound having a wide range of antibacterial activity, including Pseudomonas aeruginosa, and more specifically to the 7-position (Z) -2.
-(2-Aminothiazol-4-yl) -2- (1,5
-Dihydroxy-4-pyridon-2-yl) alkoxyiminoacetamide group-containing novel cephalosporin derivative, which has an excellent therapeutic effect on diseases caused by human and animal pathogens, and medical and veterinary drugs Is useful as

[Problems to be Solved by Prior Art and Invention]

Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria, but their antibacterial activity and spectrum
In addition, it is hard to say that the clinical therapeutic effect is sufficient.

The inventors of the present invention previously disclosed Japanese Patent Application No. 60-140989 and Japanese Patent Application No. 61-77893.
And Japanese Patent Application No. 61-77894, a novel cephalo having a 2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridone-2-carboxamido) acetamide group at the 7-position. It was found that the sporin derivatives have strong activity against a wide range of pathogenic bacteria. Although these derivatives have excellent antibacterial activity against Pseudomonas aeruginosa, the origin of their activity is considered to be due to the 1,5-dihydroxy-4-pyridone-2-carboxamide substituent at the 7-position. , 1,5-dihydroxy-4-pyridone structure was developed and various studies were conducted on the side chain at the 7-position. As a result, the novel cephalosporin compound represented by the formula (I) includes gram-positive and Pseudomonas aeruginosa. The present invention has been completed by finding that it has a wide range of antibacterial activity against Gram-negative bacteria, and particularly has a strong activity against various β-lactamase-producing bacteria.

[Means for solving problems]

The present invention has the general formula (I) useful as an antibacterial agent. [In the formula, R ¹ and R ² may be the same or different, a hydrogen atom, or a lower alkyl group having 1 to 5 carbon atoms or a substituted or unsubstituted phenyl group, A is a hydrogen atom, a hydroxyl group, an azido group,
Alkanoyloxy group having 2 to 5 carbon atoms or lower alkyl group having 1 to 3 carbon atoms as a substituent, hydroxyl group, alkoxy group, oxo group, hydroxyalkyl group, halogen atom, dialkylaminoalkyl group, alkylthio group, cycloalkylthio group A cycloalkyl-alkylthio group, a carbamoyl group, a phenylthio group with or without a phenyl group or an alkoxycarbonyl group, a thiazolylthio group, an oxazolylthio group, a thiadiazolylthio group,
Tetrazolylthio group, triazinylthio group, 1,2,
It shows a 4,6-thiatriazinylthio group, a benzothiazolylthio group, a pyridinium group or an isoquinolinium group. ] The present invention relates to a novel cephalosporin compound, a pharmacologically acceptable salt thereof, and an antibacterial agent containing the same as an active ingredient.

The compound of the general formula (I) is a syn-isomer, and when an asymmetric carbon is present in the side chain at the 7-position, D-form and L-form are possible. Include.
Further, the (1,5-dihydroxy-4-pyridon-2-yl) alkoxyimino moiety of the 7-position substituent can have the following tautomers, and the present invention includes both of them. And the structure description is of pyridone type.

The pharmacologically acceptable salts of the compound of the formula [I] of the present invention include medically acceptable salts, especially conventional non-toxic salts such as alkali metal salts such as sodium salts and potassium salts, calcium salts, magnesium salts. Alkaline earth metal salts such as salts, ammonium salts, organic salts with organic bases such as triethylamine salt, pyridine salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt and other organic amine salts and lysine and arginine Basic amino acid salts such as

Examples of the group represented by A in the compound of formula (I) include (1-methyl-1H-tetrazol-5-yl) thio, (1,2,3-thiadiazol-5-yl) thio,
1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl) thio, 1- (2-hydroxyethyl)-
1H-tetrazol-5yl) thio, 4,5-dihydro-4-methyl-5-oxo-6-hydroxy-1,2,
4-triazin-3-yl) thio, (2,5-dihydro-2-methyl-5-oxo-6-hydroxy-1,2,
4-triazin-3-yl) thio, (2,3-dihydro-3-methyl-2-oxo-6-hydroxy-1,3
5-triazin-4-yl) thio, pyridinium, acetoxy, 4-methylthiopyridinium, 4-cyclopropylthiopyridinium, 4-cyclopropylmethylthiopyridinium, (1,2,3-thiadiazol-5-yl) thio, (4 -Methyloxazol-2-yl) thio, (benzothiazol-2-yl) thio, (1,3,
4-thiadiazol-2-yl) thio, (4-methyl-
1,2,3-thiadiazol-5-yl) thio, (4-
Phenylthiazol-2-yl) thio, (thiazol-
2-yl) thio, (3,4-dihydro-4-methyl-
1,1,3-Trioxo-2H-1,2,4,6-thiatriazin-5-yl) thio, (4-hydroxyphenyl) thio, (4-fluorophenyl) thio, (4-carpamoylthiazole- 5-yl) thio, (thiazole-
5-yl) thio, (2-methyl-1,3,4-thiadiazol-5-yl) thio, (4-ethoxycarbonyl-
1,2,3-thiadiazol-5-yl) thio, (4-
Carbamoyl-1,2,3-thiazol-5-yl) thio, (2-ethoxy-1,3,4-thiadiazole-5)
-Yl) thio, (2-ethylthio-1,3,4-thiadiazol-5-yl) thio, (2-ethoxycarbonyl-1,3,4-thiadiazol-5-yl) thio, (2
-Carbamoyl-1,3,4-thiadiazol-5-yl) thio, (4-ethoxycarbonylthiazol-5-
Yl) thio, (1,2,4-thiadiazol-5-yl) thio, (3-methyl-1,2,4-thiadiazol-5-yl) thio, 4-carbamoylpyridinium, isoquinolinium-2-yl, hydrogen , Hydroxy, azide and the like.

Synthesis of a protected form of 2-hydroxymethyl-1,5-dihydroxy-4-pyridone, which is one of the constituents of the 7-position substituent, is disclosed in Japanese Patent Application No. 60-140989 of the present inventors. It was carried out according to.

That is, it can be obtained by reacting the protected form (II) of kojic acid with hydroxylamine hydrochloride or R ⁹ ONH ₂ and its salt in the presence of pyridine and the like.

(In the formula, R ⁸ and R ⁹ are benzyl, p-nitrobenzyl,
In the reaction of the compound of formula (III) and R ⁹ X (X represents a halogen atom or a diazo group), o-nitrobenzyl, p-methoxybenzyl, a benzhydryl group and the like can be eliminated. It can be obtained as (IVa) or (IVb) or a mixture thereof depending on the reaction conditions such as the type of R ⁹ X, reaction solvent and temperature.

The cephalosporin compound of the general formula (I) of the present invention can be produced by the following methods A and B.

A) General formula (Va) or (Vb) (In the formula, R ¹⁰ is a hydrogen atom or a protecting group of an amino group, R ¹ , R ² and R
⁽⁸ and R ⁹ are as defined above) or a reactive derivative of a carboxylic acid thereof represented by the general formula (VI) (In the formula, R ¹¹ is a hydrogen atom or a protective group for a carboxyl group,
A is produced by reacting the compound represented by the above meaning) or a salt or silyl compound thereof, and then removing the protecting group.

B) General formula (VIIa) or (VIIb) (In the formula, Y is an acetoxy group or a halogen atom, R ⁸ is a hydrogen atom or R ⁸ and R ⁹ are hydrogen atoms or R ⁹ , R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁰ and R
¹¹ is the above-mentioned meaning) and a nucleophilic compound is reacted with the compound, and then the protecting group is removed if necessary to produce the compound of the general formula (I). Here, the nucleophilic compound is a compound corresponding to A in the general formula (I).

As the protecting group for the amino group and the carboxyl group in the above general formula, β-lactam and those used for this purpose in the field of peptide synthesis are appropriately adopted.

Examples of the protecting group for the amino group include phthaloyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethyloxy. Carbonyl, methoxymethyloxycarbonyl, trityl, trimethylsilyl and the like can be mentioned, while examples of the protective group for the carboxyl group include t-butyl, t-amyl, allyl,
Benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, phenyl, p-nitrophenyl,
Methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl, methylthiomethyl, trityl,
Examples include trichloroethyl, trimethylsilyl, dimethylsilyl and the like.

General formula (Va) or (Vb) and (VI) in production method A
For the condensation reaction with, the general method of acylation used for penicillin and cephalosporin is applied.

Examples of the reactive derivative include acid halides, acid anhydrides, active amides, active esters and the like. Preferred examples include acid chlorides, acid bromides, acetic acid, pivalic acid, isovaleric acid, mixed acid anhydrides such as trichloroacetic acid, active amides with pyrazole, imidazole, dimethylpyrazole, benzotriazole, and p-nitrophenyl ester. , 2,4-dinitrophenyl ester, trichlorophenyl ester, 1-hydroxy-1H-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide and the like active esters.

In this reaction, when the compounds of the general formulas (Va) and (Vb) are used in the form of free acid, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of the condensing agent include N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide,
Of N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide and other carbodiimide compounds, N-methylformamide, N, N-dimethylformamide and other amide compounds with thionyl chloride, phosphorus oxychloride, phosgene and other halides It can be performed in the presence of a reagent (so-called Vilsmeier reagent) produced by the reaction.

Among the reactive derivatives in this reaction, acid halides,
The reaction in the acid anhydride requires the presence of an acid binder, and examples of the acid binder include triethylamine, trimethylamine, ethyldiisoproviramine, N, N-.
Examples thereof include organic bases such as dimethylamine, N-methylmorpholine and pyridine, alkali metal compounds such as sodium, potassium or calcium hydroxides, carbonates and bicarbonates, and oxiranes such as ethylene oxide and propylene oxide.

This reaction is usually carried out in a solvent that does not adversely influence the reaction, and as the solvent, water, acetone, acetonitrile, dioxane, tetrahydrofuran, ethyl acetate, methylene chloride, chloroform, dichloroethane, N, N-dimethylformamide, N, N are used. -Dimethylacetamide, dimethylsulfoxide, or a mixed solvent thereof is used.

The reaction temperature is not particularly limited, but it is usually -30 to 40 ° C, and the reaction time is 30 minutes to 10 hours until the completion of the reaction.

As a method for removing the protecting group of the acylated product thus obtained, a method using an acid depending on the type of the protecting group,
A method using a base, a method using hydrazine and the like can be employed, and these can be performed by appropriately selecting a conventional method used in the field of β-lactam and peptide synthesis.

The compounds of the general formulas (Va) and (Vb) have the general formula (VIII) (Wherein R ¹⁰ and R ¹¹ have the above-mentioned meanings) and a compound represented by the formula (IXa) or (IXb) (In the formula, Z represents a halogen atom or a sulfonate group such as mesyloxy, tosyloxy, trifluoromesyloxy group). After reacting a compound represented by the formula, the protecting group for carboxylic acid is removed if necessary. It is obtained by

This condensation reaction is carried out in the presence of a base, if necessary, in a solvent at −50 to −50.
It can be performed within the range of 70 ° C. As the base and solvent used in this reaction, the base and solvents used in the acylation reaction of Method A are used. The reaction of the general formula (VIIa) or (VIIb) with the nucleophilic compound in the production method (B) can be carried out by a method commonly used in the chemistry of cephalosporins. That is, in the general formulas (VIIa) and (VIIb), when Y is an acetoxy group, the reaction is usually water, phosphate buffer, acetone, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide. , Tetrahydrofuran, dimethyl sulfoxide, dioxane, methanol, ethanol and the like, or a mixed solvent with water is preferably used.

The reaction is preferably carried out in the vicinity of neutrality, and the reaction temperature is not particularly limited, but it is usually suitable to carry out from room temperature to around 80 ° C.

The time required for this reaction varies depending on the reaction conditions, but is usually 1 to 10 hours.

Further, this reaction is promoted by carrying out in the presence of an alkali metal halide such as sodium iodide or potassium iodide.

Further, in the case where Y of the general formulas (VIIa) and (VIIb) produces a target compound from a compound of halogen, acetone, dioxane, tetrahydrofuran, ethyl acetate,
Acetonitrile, N, N-dimethylformamide, N,
The reaction is preferably carried out in a solvent such as N-dimethylacetamide or dimethylsulfoxide under non-aqueous conditions. The reaction is usually carried out at 0 to 50 ° C., and the reaction is completed in 1 to 5 hours.

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

For example, purification using an adsorbent resin such as Amberlite XAD-2 (manufactured by Rohm and Haas), Diaion HP-20 (manufactured by Mitsubishi Kasei Co., Ltd.), precipitation method, crystallization method, etc. Achieved by combining.

Antibacterial agents containing a 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 agents. It is used in various dosage forms such as suppositories and water-soluble suppositories. These various preparations include commonly used excipients, fillers, binders, wetting agents, disintegrating agents, surfactants, lubricants, dispersants, buffers, preservatives, solubilizing agents, preservatives. , A flavoring agent, a soothing agent, etc. can be used for the production by a conventional method. A specific example of the formulation method will be described in more detail with reference to Examples below.

The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, etc., but is usually 250 to 300 per adult per day.
It is 0 mg, which is administered in 1 to 4 divided doses daily.

〔Example〕

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

The NMR data in the examples are 400 MHz NMR. In the case of heavy water, the δ value is shown when the water peak is set to δ value of 4.82, and in the case of other heavy solvents, TMS is used as a reference. The δ value at each time is shown.

Reference Example 1 5-p-Methoxybenzyloxy-1-hydroxy-2
-Hydroxymethyl-4-pyridone (a) 42.6 g of kojic acid was added to N, N-dimethylformamide 350
82.8 g of anhydrous potassium carbonate and p-
Add 55 g of methoxybenzyl chloride, and add 1.
Incubate for 5 hours. After completion of the reaction, the reaction solution is concentrated to about half volume, and this is added dropwise to 700 m of water under ice cooling. The precipitate formed is collected by filtration, washed with water and ethyl acetate and dried to give 5-p
-Methoxybenzyloxy-2-hydroxymethyl-4
-Obtain 59.9 g of pyrone.

NMR (CDCl ₃ ) δ; 3.80 (3H, s), 4.43 (2H, s), 4.96 (2H, s), 6.50 (1H, s), 6.88 (2
H, d), 7.30 (2H, d), 7.51 (1H, s) (b) 5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyrone (39.3 g) was dissolved in pyridine (600 m) to give hydroxylamine hydrochloride. Add 52.2g, 70 ~ 75 ℃
Incubate for 2.5 hours. After the reaction is completed, the reaction liquid is about 100 m
The mixture is concentrated to 100 ml, and 100 m of water is added to the mixture. After adjusting the pH to 2 to 2.5, the mixture is stirred at the same temperature for 30 minutes. The resulting crystals are collected by filtration, washed with water and dried to give 16.6 g of the title compound.

_{^{NMR (DMSO - d 6) δ}} ; 3.76 (3H, s), 4.46 (2H, s), 5.03 (2H, s), 6.86 (1H, s), 6.93 (2
H, d), 7.37 (2H, d), 7.97 (1H, s) Reference Example 2 4-diphenylmethyloxy-5-p-methoxybenzyloxy-2-hydroxymethylpyridine-N-oxide 5-p-methoxybenzyl Oxy-1-hydroxy-2
-Hydroxymethyl-4-pyridone 44.3 g was suspended in 320 ml of methyl cellosolve (2-methoxyethanol),
Add 33.4m of triethylamine and dissolve. Methyl cellosolve solution containing 46.6 g of diphenyldiazomethane
Add 150 m and react at 60 ° C. for 5 hours.

After completion of the reaction, the reaction solution is concentrated to about 100 m, and 200 m of a mixed solution of ethyl acetate-isopropyl ether 1: 1 is added thereto. The resulting crude crystals are collected by filtration, washed with a mixture of ethyl acetate-isopropyl ether 1: 1 and isopropyl ether, and dried. This is suspended in 500 m of dichloromethane and the insoluble matter is filtered off. The dichloromethane solution was concentrated to a small amount, ethyl acetate was added thereto, and the resulting crystals were collected by filtration and dried to obtain 42 g of the title target compound.

NMR (CDCl ₃ ) δ; 3.82 (3H, s), 4.57 (2H, s), 5.06 (2H, s), 6.28 (1H, s), 6.69 (1
H, s), 6.89 (2H, d), 7.2-7.5 (12H, m), 7.91 (1H, s) Reference Example 3 1,5-di-p-methoxybenzyloxy-2-hydroxymethyl-4-pyridone 5-p-methoxybenzyloxy-1-hydroxy-2
-Hydroxymethyl-4-pyridone (27.7 g) was suspended in N, N-dimethylformamide (300 m), and anhydrous potassium carbonate (27.7 g) and p-methoxybenzyl chloride (1) were added to the suspension.
Add 7.3 g and react at room temperature for 4 hours. After concentrating the reaction solution to a small amount, add 600 m of chloroform, wash with water, dry over anhydrous magnesium sulfate, and concentrate to about 200 m. To this, 200m of isopropyl ether was added, and the resulting crystals were collected by filtration, dried and the title target compound 3
8.9 g are obtained.

NMR (CDCl ₃ ) δ; 3.75 (3H, s), 3.80 (3H, s), 4.49 (2H, s), 4.90 (2H, s), 5.01 (2
H, s), 6.47 (1H, s), 6.82 (2H, d), 6.87 (2H, d), 6.98 (1H, s),
7.20 (2H, d), 7.23 (2H, d) Reference Example 4 1-diphenylmethyloxy-5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyridone 5-p-methoxybenzyloxy-1-hydroxy- Two
5.54 g of -hydroxymethyl-4-pyridone was suspended in 40 m of N, N-dimethylformamide, and 2.24 g of potassium t-butoxide was added and dissolved under ice cooling. Benzhydryl bromide (4.94 g) is added to this, and the mixture is reacted at room temperature for 2.5 hours.

After completion of the reaction, the reaction solution is concentrated to about 20 m, and this is added dropwise under ice cooling to a mixed solution of ethyl acetate (200 m) and water (100 m). The resulting precipitate is collected by filtration, washed with water and ethyl acetate, and dried to give the title object compound (7.29 g).

NMR (CDCl ₃ ) δ; 3.78 (3H, s), 4.51 (2H, s), 4.59 (2H, s), 6.18 (1H, s), 6.58 (1
H, s), 6.63 (1H, s), 6.82 (2H, d), 7.16 (2H, d), 7.3 ~ 7.5 (10
H, m) Example 1 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) Methoxyiminoacetamide] -3-
(1,2,3-Thiadiazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid (a) 4-diphenylmethyloxy-5-p-methoxybenzyloxy-2-hydroxymethylpyridine-N- 2.2 g of oxide is suspended in 50 m of dichloromethane, 1 m of thionyl chloride and 1 drop of N, N-dimethylformamide are added under ice cooling, and the mixture is reacted at the same temperature for 3 hours. 40m saturated aqueous sodium hydrogen carbonate solution and dichloromethane
Add 50m. The dichloromethane layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to dryness. The residue was dissolved in 40 m of N, N-dimethylformamide and added with (Z) -2- (2-tritylaminothiazole-4).
-Yl) -2-hydroxyiminoacetic acid allyl ester 2.
Add 1 g and 1.24 g of anhydrous potassium carbonate and allow to react overnight at room temperature. Add 200 m of chloroform to the reaction mixture.
Wash sequentially with water, diluted hydrochloric acid and water, dry over anhydrous magnesium sulfate, and concentrate to dryness under reduced pressure.

The residue is purified by silica gel column chromatography, (Z)-
2- (2-Tritylaminothiazol-4-yl) -2
2.18 g of-(4-diphenylmethyloxy-5-p-methoxybenzyloxypyridin-N-oxide-2-yl) methoxyiminoacetic acid allyl ester are obtained.

NMR (CDCl ₃ ) δ; 3.83 (3H, s), 4.89 (2H, d), 5.04 (2H, s), 5.37 (2H, dd), 5.38
(2H, s), 6.0 (1H, m), 6.40 (1H, s), 6.57 (1H, s), 6.90 (2H, d),
6.93 (1H, s), 6.96 (1H, s), 7.1-7.5 (27H, m), 7.87 (1H, s) (b) (a) 1.74 g of the allyl ester compound obtained in 15 ml of dichloromethane and ethyl acetate Dissolve in 15m and add to it 2-
450 mg of potassium ethylhexanoate and 60 mg of tetrakistriphenylphosphine palladium are added, and the mixture is reacted at room temperature for 1 hour. Add 150 m of chloroform to the reaction solution. Water 5
Add 0 m and wash with 6N hydrochloric acid so that the pH of the aqueous layer becomes 2. Then, it is washed with water, dried over anhydrous magnesium sulfate, and concentrated to a small amount. Ether was added thereto, and the resulting crystals were collected by filtration, washed with a mixed solution of ether-dichloromethane (4: 1) and dried to give (Z) -2- (2-tritylaminothiazol-4-yl) -2. -(4-diphenylmethyloxy-5-p-methoxybenzyloxypyridine-N
1.36 g of -oxide-2-yl) methoxyiminoacetic acid are obtained.

_{^{NMR (DMSO - d 6) δ}} ; 3.76 (3H, s), 5.01 (2H, s), 5.16 (2H, s), 6.80 (1H, s), 6.96 (2
H, d), 7.1-7.5 (29H, m), 8.06 (1H, s) (c) Of these, 1.15g was dissolved in 30m of dichloromethane, and under this, at -5 ° C (6R, 7R) -7-amino. -3-chloromethyl-ceph-3-em-4-carboxylic acid p-toluenesulfonate 730 mg of p-methoxybenzyl ester
And 0.54 m of pyridine are added and stirred for 10 minutes. Then -10
Phosphorus oxychloride (0.14 m) is added at -15 ° C and the reaction is continued for 1 hour. After the reaction is completed, 100 m of ethyl acetate is added, and the mixture is washed twice with 50 m of 15% saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated to dryness, and (6R, 7R) -7-[(Z) -2- (2
-Tritylaminothiazol-4-yl) -2- (4-
Diphenylmethyloxy-5-p-methoxybenzyloxypyridin-N-oxide-2-yl) methoxyiminoacetamido] -3-chloromethyl-ceph-3-em-4-carboxylic acid p-methoxybenzyl ester 1.6
get g.

NMR (CDCl ₃ ) δ; 3.36 (2H, ABq), 3.80 (3H, s), 3.83 (3H, s), 4.45 (2H, ABq), 4.
97 (1H, d), 5.02 (2H, ABq), 5.21 (2H, ABq), 5.82 (1H, dd), 6.9
0 (4H, m), 7.1-7.5 (31H, m), 7.87 (1H, s) (d) (c) The 3-chloromethyl derivative 293mg obtained in dimethylsulfoxide 0.5m was dissolved in this, 43 mg of sodium salt of mercapto-1,2,3-thiadiazole is added, and the mixture is reacted at room temperature for 1.5 hours. Ethyl acetate 30 in the reaction solution
m, and washed twice with 10 m of 15% saline. After drying over anhydrous magnesium sulfate, concentrating to dryness, (6R, 7R)-
[(Z) -2- (2-tritylaminothiazole-4-
Yl) -2- (4-diphenylmethyloxy-5-p-
Methoxybenzyloxypyridine-N-oxide-2-
) Methoxyiminoacetamide] -3- (1,2,
3-thiadiazol-5-yl) thiomethyl-cef-3
-M-4-carboxylic acid p-methoxybenzyl ester
You get 275 mg. This is dissolved in 0.32 m of anisole, 0.94 m of trifluoroacetic acid is added, and the mixture is reacted at room temperature for 30 minutes. The reaction solution was dropped into 6 m of isopropyl ether,
The precipitate formed is filtered off, washed with isopropyl ether and dried. 170 mg of the obtained precipitate is suspended in 3 m of water, 1.5 m of saturated aqueous sodium hydrogencarbonate is added under ice cooling, and the mixture is stirred for 10 minutes. This was purified by HP-column chromatography (elution with 5% acetone water) to give the title compound as a sodium salt.
You get 77 mg.

NMR (D ₂ O) 8; 3.47 (2H, ABq), 4.16 (2H, ABq), 5.13 (1H, d) 5.32 (2H, ABq),
5.76 (1H, d), 6.81 (1H, s) 7.09 (1H, s), 7.68 (1H, s), 8.74 (1
H, s) 1-methyl-5-mercapto-in (d) of Example 1
The compounds of Examples 2 to 7 are obtained by the same treatment except that the reagent of [A] is used instead of 1,2,3-thiadiazole.

Example 2 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(1-Methyl-1H-tetrazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-1-methyl-1H-tetrazole NMR (D ₂ O) δ; 3.43 (2H , ABq), 4.05 (3H, s), 4.29 (2H, ABq), 5.13 (1H, d), 5.
30 (2H, ABq), 5.74 (1H, d), 6.70 (1H, s), 7.02 (1H, s), 7.61 (1
H, s) Example 3 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) Methoxyiminoacetamide] -3-
[1- (2-Dimethylaminoethyl) -1H-tetrazol-5-yl] thiomethyl-ceph-3-em-4carboxylic acid [A] 5-mercapto-1- (2-dimethylaminoethyl) -1H-tetrazole NMR (D ₂ O) δ; 2.64 (6H, s), 3.38 (2H, t), 3.51 (2H, ABq), 4.23 (2H, ABq), 4.
72 (2H, m), 5.14 (1H, d), 5.31 (2H, ABq), 5.76 (1H, d), 6.73 (1
H, s), 7.08 (1H, s), 7.64 (1H, s) Example 4 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- ( 1,5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
[1- (2-Hydroxyethyl) -1H-tetrazol-5-yl] thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-1- (2-hydroxyethyl)
-1H- tetrazole _{NMR (D 2 O) δ;} 3.26 (1H, d), 3.72 (1H, d), 4.05 (2H, m), 4.09 (1H, d), 4.40 (1
H, d), 4.57 (2H, m), 5.14 (1H, d), 5.30 (1H, d), 5.38 (1H, d),
5.79 (1H, d), 6.89 (1H, s), 7.09 (1H, s), 7.78 (1H, s) Example 5 (6R, 7R) -7-[(Z) -2- (2-aminothiazole) -4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(4,5-Dihydro-4-methyl-5-oxo-6-hydroxy-1,2,4-triazin-3-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 3-mercapto- 4,5-dihydro-4-methyl-5-oxo-6-hydroxy-1,2,4-triazine NMR (D ₂ O) δ; 3.23 (1H.d), 3.49 (3H, s), 3.73 (1H , d), 3.82 (1H, d), 4.54 (1
H, d), 5.10 (1H, d), 5.25 (1H, d), 5.37 (1H, d), 5.77 (1H, d),
6.75 (1H, s), 7.08 (1H, s), 7.66 (1H, s) Example 6 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2 -(1,5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(2,5-Dihydro-2-methyl-5-oxo-6-hydroxy-1,2,4-triazin-3-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 3-mercapto- 2,5-Dihydro-2-methyl-5-oxo-6-hydroxy-1,2,4-triazine NMR (D ₂ O) δ; 3.43 (2H, ABq), 3.69 (3H, s), 4.22 (2H , ABq), 5.16 (1H, d), 5.
33 (2H, ABq), 5.85 (1H, d), 6.86 (1H, s), 7.11 (1H, s), 7.74 (1
H, s) Example 7 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) Methoxyiminoacetamide] -3-
(2,3-Dihydro-3-methyl-2-oxo-6-hydroxy-1,3,5-triazin-4-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 4-mercapto- 2,3-dihydro-3-methyl-2-oxo-6-hydroxy-1,3,5-triazine.

NMR (D ₂ O) δ; 3.45 (3H.s), 3.53 (2H, ABq), 4.27 (2H, ABq), 5.22 (3H, m), 5.
82 (1H, d), 6.69 (1H, s), 7.10 (1H, s), 7.65 (1H, s) Example 8 (6R, 7R) -7-[(Z) -2- (2-aminothiazole) -4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
Pyridinium methyl-ceph-3-em-4-carboxylate (a) In (a) of Example 1, (Z) -2- (2-tritylaminothiazol-4-yl) -2-hydroxyiminoacetic acid allyl ester In place of (Z) -2- (2-tritylaminothiazol-4-yl) -2- (4-diphenylmethyloxy-5-p-methoxybenzyloxy) obtained by the same method using ethyl ester. Pyridine-N-oxide-2-yl) methoxyiminoacetic acid ethyl ester 4.41 g is dissolved in ethanol 30 m and tetrahydrofuran 10 m. To this, 10m of 2N sodium hydroxide aqueous solution and 5m of water are added, and the reaction is carried out at room temperature for 4 hours.

The crystals formed are collected by filtration, washed with a mixed solution of tetrahydrofuran-ethanol-water (1: 3: 1.5), and then suspended in 30 m of water. Under ice cooling, 5 ml of 1N HCl is added, and the mixture is stirred for 30 minutes. The precipitate was collected by filtration, washed with water and dried to obtain (Z) -2- (2
-Tritylaminothiazol-4-yl) -2- (4-
2.55 g of diphenylmethyloxy-5-p-methoxybenzyloxypyridin-N-oxide-2-yl) methoxyiminoacetic acid are obtained.

The spectral data of this compound was in agreement with those obtained in Example 1 (b).

(b) To 8.1 m of dichloromethane, under ice-cooling, 0.87 m of N, N-dimethylformamide and 1.03 m of phosphorus oxychloride are added and stirred for 1 hour. (Z) -2- (2 obtained in (a)
-Tritylaminothiazol-4-yl) -2- (4-
Dissolve 855 mg of diphenylmethyloxy-5-p-methoxybenzyloxypyridin-N-oxide-2-yl) methoxyiminoacetic acid in 8.5 m of dichloromethane, and add 1 m of the previously prepared dichloromethane solution at -15 ° C to the same temperature. Then react for 1 hour. Next, this reaction solution was suspended in advance at room temperature with 720 mg of (6R, 7R) -7-amino-3-pyridiniummethyl-cef-3-em-4-carboxylate dihydrochloride in 12 m of acetonitrile, and bistrimethylsilyltrichloride. Fluoroacetamide (1.44 m) was added and dissolved and then added dropwise at -30 ° C, and the mixture was reacted for 1 hour under ice cooling. After completion of the reaction, 100 m of dichloromethane is added, and the mixture is washed twice with 50 m of 15% saline.

After drying over anhydrous magnesium sulfate, concentrate and ether 50m
The precipitate formed by filtration was collected by filtration, washed with ether, and dried (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (4- Diphenylmethyloxy-5-p-methoxybenzyloxypyridine-
N-Oxido-2-yl) methoxyiminoacetamido] -3-pyridiniummethyl-ceph-3-em-4-
1.15 g of carboxylate hydrochloride are obtained.

(c) 600 mg of the 3-pyridinium methyl derivative obtained in (b) is suspended in 1 m of anisole, 2.25 m of trifluoroacetic acid is added under ice cooling, and the reaction is carried out for 30 minutes. The reaction solution is poured into 40 m of isopropyl ether, and the formed precipitate is collected by filtration, washed with isopropyl ether and dried. The obtained precipitate (470 mg) was suspended in water (8 m) and neutralized with a saturated aqueous sodium hydrogen carbonate solution under ice-cooling to dissolve it, and this was dissolved in Diaion HP-20 column chromatography (water and 5% acetone water elution) and Purified by Sephadex LH-20 column chromatography (eluted with 50% methanol in water), the title compound as sodium salt, 84
get mg.

NMR (D ₂ O) δ; 3.27 (2H, ABq), 5.21 (1H, d), 5.29 (2H, ABq), 5.48 (2H, ABq),
5.86 (1H, d), 6.73 (1H, s), 7.06 (1H, s), 7.54 (1H, s), 8.16 (2
H, m), 8.64 (1H, m), 8.99 (2H, d) Example 9 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- ( 1,5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
Acetoxymethyl-ceph-3-em-4-carboxylic acid (a) 4.04 g of the carboxylic acid obtained in Example 1 (b) and (6R, 7R)
1.55 g of -7-amino-3-acetoxymethyl-cef-3-em-4-carboxylic acid t-butyl ester are dissolved in 80 m of dichloromethane and cooled to -15 ° C.

Add pyridine 1.53m and phosphorus oxychloride 0.49m,-
Stir for 30 minutes at 15 ° C to -10 ° C. Brine (120 m) is added, and the mixture is extracted with ethyl acetate (300 m). 2 times with saline, N
Wash once with aqCO ₃ solution and once with brine. After dehydration with magnesium sulfate, concentration and purification of the residue by silica gel column chromatography (250 g) (CHCl ₃ : MeOH = 30: 1), (6
R, 7R) -7-[(Z) -2- (2-Tritylaminothiazol-4-yl) -2- (4-diphenylmethyloxy-5-p-methoxybenzyloxypyridine-N-oxide-2- ) Methoxyiminoacetamide] -3
3.56 g of -acetoxymethyl-ceph-3-em-4-carboxylic acid t-butyl ester were obtained.

(b) 3.56 g of the compound obtained in (a) was suspended in 3 m of anisole, and 10 m of trifluoroacetic acid was added under ice-cooling at room temperature.
Incubate for 2.5 hours. The reaction solution is isopropyl ester 80
The resulting precipitate is collected by filtration, washed with isopropyl ether and dried. 2.21 g of the obtained precipitate was added to 20 m of water.
It is suspended in and dissolved in saturated aqueous sodium hydrogen carbonate to a pH of 8. This solution is purified by HP-20 (220m). The fraction containing the desired product was concentrated and lyophilized from the eluate containing water to 5% acetone to give 1.06 g of the title compound as a sodium salt.

NMR (D ₂ O) δ; 2.15 (3H, s), 3.22 (1H, d), 3.63 (1H, d), 4.74 (1H, d), 4.94 (1
H, d), 5.19 (1H, d), 5.32 (1H, d), 5.40 (1H, d), 5.84 (1H, d),
6.94 (1H, s), 7.11 (1H, s), 7.82 (1H, s) Example 10 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2 -(1,5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
120 mg of (4-methylthiopyridinium) methyl-cef-3-em-4-carboxylate (a) 3-chloromethyl derivative (Example 1 (c)) was dissolved in 1 m of acetone, and then 18 mg of sodium iodide was added to 0.5 ml of acetone. m solution is added and reacted at room temperature for 45 minutes.
After distilling off acetone, 1 m of methylene chloride is added and the insoluble portion is filtered off to remove the salt. After distilling off methylene chloride, 1 m of acetonitrile and 38 mg of 4-methylthiopyridine were added to the residue, and the mixture was reacted at room temperature for 1.5 hours with stirring. After adding 0.05 m of acetic acid and 10 m of toluene to the reaction solution, the solvent is evaporated to dryness. 8m of ethyl acetate as residue
, 2 ml of isopropyl ether were added, and the insoluble portion was filtered off after stirring, and (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2- (4-diphenyl). Methyloxy-5-p-methoxybenzyloxypyridin-N-oxide-2-yl) methoxyiminoacetamido] -3- (4-methylthiopyridinium) methyl-ceph-3-em-4-carboxylic acid p-methoxybenzyl 100 mg of ester are obtained.

(b) 100 mg of the 3-substituted product obtained in (a) was added with 0.07 m of anisole.
, Suspended in 1 m of trifluoroacetic acid, added with 0.5 m of formic acid and stirred at room temperature for 1 hour. The insoluble portion is filtered off, removed, and then dropped into 30 cc of isopropyl ether, and the formed precipitate is filtered off. Then, this product was dissolved in 1 m of water, saturated aqueous sodium hydrogen carbonate was added under ice cooling to neutralize, and the product was purified by HP-20 column chromatography (eluting with 10% acetone water) to give the title compound as a sodium salt. As 16m.

NMR (D ₂ O) δ; 3.24 (2H, AB, q), 5.13 (1H, d), 5.21 (1H, d), 5.22 (1H, d), 5.3
6 (1H, d), 5.38 (1H, d), 5.83 (1H, d), 6.71 (1H, s), 7.01 (1H,
s), 7.54 (1H, s), 7.81 (2H, d), 8.56 (2H, d) Example 11 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) ) -2- (1,5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(4-Cyclopropylthiopyridinium) methyl-cef-3-em-carboxylate (6R, 7R) -7-[(Z) -2- (2) obtained in Example 9
-Aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) methoxyiminoacetamido] -3-acetoxymethyl-ceph-3-em-4-carboxylic acid sodium salt 200 mg Was dissolved in 1 m of acetonitrile and 1 m of water, to which 525 mg of sodium iodide and 160 of 4-cyclopropylthiopyridine were added.
mg is added, pH is adjusted to 6.5-7.0 with 10% phosphoric acid aqueous solution, and it is made to react at 65 degreeC for 3 hours. After the reaction was completed, acetone 10
m is added and the precipitate formed is filtered off. This was purified by HP-20 column chromatography (elution with 5% acetone water) and Sephadex LH-20 (50% methanol water) column chromatography to obtain 15 mg of the title compound as a sodium salt.

NMR (D ₂ O) δ; 0.84 (2H, bs), 1.35 (2H, m), 2.42 (1H, m), 3.31 (1H, ABq), 5.1
~ 5.5 (5H, m), 5.84 (1H, d), 6.71 (1H, s), 7.02 (1H, s), 7.55
(1H, s), 7.99 (2H, d), 8.56 (2H, d) Example 12 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(4-Cyclopropylmethylthiopyridinium) methyl-cef-3-em-4-carboxylate Instead of 4-cyclopropylthiopyridine of Example 11,
The title object compound was obtained as a sodium salt by treating in the same manner with 4-cyclopropylmethylthiopyridine.

NMR (D ₂ O) δ; 0.42 (2H.m), 0.72 (2H, m), 1.24 (1H, m), 3.03 (2H, d), 3.31 (2
H, ABq), 5.1 ~ 5.4 (5H, m), 5.84 (1H, d), 6.72 (1H, s), 7.04 (1
H, s), 7.60 (1H, s), 7.84 (2H, d), 8.56 (2H, d) Example 13 (6R, 7R) -7-[(Z) -2- (2-aminothiazole-4 -Yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide-3-
(1,2,3-Thiadiazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid (a) 1-diphenylmethyloxy-obtained in Reference Example 4
Using 13.29 g of 5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyridone, (Z) -2- (2-
Tritylaminothiazol-4-yl) -2- (1-diphenylmethyloxy-5-p-methoxybenzyloxy-4-pyridon-2-yl) methoxyiminoacetic acid 19.0
Get 5 g.

NMR (CDCl ₃ ) δ; 3.75 (3H, s), 4.51 (2H, s), 5.08 (2H, s), 6.33 (1H, s), 6.56 (1
H, s), 6.67 (1H, s), 6.79 (2H, d), 7.00 (1H, s), 7.09 (2H, d),
7.2 ~ 7.4 (26H, m) (b) Compound 854mg obtained in (a) was added to dichloromethane 20m.
Dissolve in, and under ice-cooling, 540 mg of (6R, 7R) -7-amino-3-chloromethyl-ceph-3-em-4-carboxylic acid p-methoxybenzyl ester p-toluenesulfonate and 0.4 m of pyridine. Add.

Phosphorus oxychloride (0.1 m) was added dropwise at -10 to -15 ° C, and the mixture was reacted at the same temperature for 30 minutes.

After completion of the reaction, saturated saline (20 m) and ethyl acetate (40 m) are added, and the organic layer is washed twice with saturated saline. Dry over anhydrous magnesium sulfate and concentrate to dryness under reduced pressure to give (6R, 7R) -7.
-[(Z) -2- (2-tritylaminothiazole-4
-Yl) -2- (1-diphenylmethyloxy-5-p
-Methoxybenzyloxy-4-pyridon-2-yl)
1.58 g of crude powder of p-methoxybenzyl ester of methoxyiminoacetamide] -3-chloromethyl-cef-3-em-4-carboxylic acid are obtained.

(c) The obtained chloromethyl compound was added to dimethyl sulfoxide 2
After dissolving in m, 175 mg of sodium salt of 5-mercapto-1,2,3-thiadiazole is added, and the mixture is reacted at room temperature for 1 hour. Hereinafter, the title compound was treated as a sodium salt by treating in the same manner as in (d) of Example 1,
You get 203 mg.

The obtained NMR data of this compound corresponded with that of Example 1.

The compounds of Examples 14 to 34 are obtained by the same treatment as in Example 13 (c) except that the reagent [A] is used instead of 5-mercapto-1,2,3-thiadiazole. .

Example 14 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(4-Methyloxazol-2-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 2-mercapto-4-methyloxazole NMR (D ₂ O) δ 2.13 (3H, s), 3.47 (2H , ABq), 4.18 (2H, ABq), 5.08 (1H, d), 5.
30 (2H, ABq), 5.74 (1H, d), 6.72 (1H, s), 7.07 (1H, s), 7.64 (1
H, s) Example 15 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) Methoxyiminoacetamide] -3-
(Benzothiazol-2-yl) thiomethyl-cef-3
-Em-4-carboxylic acid [A] 2-mercaptobenzothiazole NMR (D ₂ O) δ 3.37 (2H, ABq), 4.32 (2H, ABq), 4.94 (1H, d), 5.25 (2H, ABq),
5.72 (1H, d), 6.67 (1H, s), 7.04 (1H, s), 7.42 (1H, t), 7.54 (1
H, t), 7.57 (1H, s), 7.86 (1H, d), 7.91 (1H, d) Example 16 (6R, 7R) -7-[(Z) -2- (2-aminothiazole-4 -Yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(1,3,4-thiadiazol-2-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 2-mercapto-1,3,4-thiadiazole NMR (D ₂ O) δ 3.49 (2H, ABq), 4.28 (2H, ABq), 5.10 (1H, d), 5.29 (2H, ABq),
5.75 (1H, d), 6.72 (1H, s), 7.07 (1H, s), 7.65 (1H, s), 9.43 (1
H, s) Example 17 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) Methoxyiminoacetamide] -3-
(4-Methyl-1,2,3-thiadiazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-4-methyl-1,2,3-thiadiazole NMR (D ₂ O) δ 2.67 (3H, s), 3.23 (1H, d), 3.72 (1H, d), 3.79 (1H, d), 4.34 (1
H, d), 5.12 (1H, d), 5.24 (1H, d), 5.36 (1H, d), 5.74 (1H, d), 6.72 (1H, s), 7.08 (1
H, s), 7.62 (1H, s) Example 18 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4) -Pyridon-2-yl) methoxyiminoacetamide] -3-
(4-Phenylthiazol-2-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 2-mercapto-4-phenylthiazole NMR (D ₂ O) δ 3.43 (2H, ABq), 4.22 (2H , ABq), 5.00 (1H, d), 5.28 (2H, ABq),
5.72 (1H, d), 6.69 (1H, s), 7.06 (1H, s), 7.47 ~ 7.54 (3H, m),
7.62 (1H, s), 7.78 (1H, s), 7.86 (2H, d) Example 19 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2 -(1,5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(Thiazol-2-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 2-mercaptothiazole NMR (D ₂ O) δ 3.50 (2H, ABq), 4.19 (2H, ABq), 5.09 (1H , d), 5.31 (2H, ABq),
5.74 (1H, d), 6.73 (1H, s), 7.09 (1H, s), 7.34 (1H, s), 7.64 (1
H, s), 7.81 (1H, s) Example 20 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4) -Pyridon-2-yl) methoxyiminoacetamide] -3-
(3,4-Dihydro-4-methyl-1,1,3-trioxo-2H-1,2,4,6-thiatriazin-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A ] 3,4,5,6-Tetrahydro-4-methyl-
1,1,3-Trioxo-2H-1,2,4,6-thiatriazine-5-thione NMR (D ₂ O) δ 3.41 (3H, s), 3.51 (2H, ABq), 4.12 (2H, ABq ), 5.17 (1H, d), 5.
31 (2H, ABq), 5.81 (1H, d), 6.75 (1H, s), 7.09 (1H, s), 7.68 (1
H, s) Example 21 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) Methoxyiminoacetamide] -3-
(4-Hydroxyphenyl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 4-hydroxythiophenol NMR (D ₂ O) δ 3.14 (1H, d), 3.44 (1H, d), 3.66 (1H , d), 4.37 (1H, d), 4.98 (1
H, d), 5.26 (1H, d), 5.33 (1H, d), 5.67 (1H, d), 6.69 (1H, s),
6.84 (2H, d), 7.07 (1H, s), 7.37 (2H, d), 7.60 (1H, s) Example 22 (6R, 7R) -7-[(Z) -2- (2-aminothiazole) -4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(4-Fluorophenyl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 4-fluorothiophenol NMR (D ₂ O) δ 3.15 (1H, d), 3.52 (1H, d), 3.70 (1H , d), 4.44 (1H, d), 4.97 (1
H, d), 5.23 (1H, d), 5.34 (1H, d), 5.65 (1H, d), 6.71 (1H, s),
7.10 (3H, m), 7.45 (2H, m), 7.63 (1H, s) Example 23 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2 -(1,5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(4-carbamoylthiazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-4-carbamoylthiazole NMR (D ₂ O) δ 3.20 (1H, d), 3.73 (1H , d), 3.74 (1H, d), 4.45 (1H, d), 5.06 (1
H, d), 5.29 (2H, ABq), 5.74 (1H, d), 6.71 (1H, s), 7.07 (1H,
s), 7.62 (1H, s), 8.92 (1H, s) Example 24 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1, 5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(Theazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercaptothiazole NMR (D ₂ O) δ 3.20 (1H, d), 3.52 (1H, d), 3.80 (1H , d), 4.33 (1H, d), 5.13 (1
H, d), 5.31 (2H, ABq), 5.70 (1H, d), 6.73 (1H, s), 7.08 (1H,
s), 7.62 (1H, s), 7.86 (1H, s) 9.02 (1H, s) Example 25 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(2-Methyl-1,3,4-thiadiazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-2-methyl-2-1,3,4-
Thiadithiazole NMR (D ₂ O) δ 2.75 (3H, s), 3.28 (1H, d), 3.74 (1H, d), 3.94 (1H, d), 4.50 (1
H, d), 5.10 (1H, d), 5.31 (2H, ABq), 5.76 (1H, d), 6.72 (1H,
s), 7.08 (1H, s), 7.63 (1H, s) Example 26 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1, 5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(4-Ethoxycarbonyl-1,2,3-thiadiazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-4-ethoxycarbonyl-1,
2,3-thiadiazole NMR (D ₂ O) δ 1.43 (3H, t), 3.23 (1H, d), 3.58 (1H, d), 4.11 (1H, d), 4.41 (1
H, d), 4.48 (2H, q), 5.11 (1H, d) 5.27 (2H, ABq), 5.80 (1H, d), 6.71 (1H, s) 7.01 (1H, s), 7.59 (1H, s ) Example 27 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide ] -3-
(4-carbamoyl-1,2,3-thiadiazole-5
-Yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-4-carbamoyl-1,2,3
-Thiadiazole NMR (D ₂ O) δ 3.21 (1H, d), 3.60 (1H, d), 4.07 (1H, d), 4.38 (1H, d), 5.10 (1
H, d), 5.26 (2H, ABq), 5.78 (1H, d), 6.70 (1H, s), 7.02 (1H,
s), 7.58 (1H, s) Example 28 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridone -2-yl) methoxyiminoacetamide] -3-
(2-Ethoxy-1,3,4-thiadiazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-2-ethoxy-1,3,4-thiadiazole NMR (D ₂ O) δ 1.46 (3H, t), 3.22 (1H, d), 3.76 (1H, d), 3.83 (1H, d), 4.44 (1
H, d), 4.54 (2H, q), 5.12 (1H, d) 5.29 (2H, ABq), 5.74 (1H, d), 6.71 (1H, s), 7.07 (1H, s), 7.63
(1H, s) Example 29 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) ) Methoxyiminoacetamide] -3-
(2-ethylthio-1,3,4-thiadiazole-5-
Il) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-2-ethylthio-1,3,4-
Thiadiazole NMR (D ₂ O) δ 1.41 (3H, t), 3.22 (1H, d), 3.26 (2H, q), 3.72 (1H, d), 3.95 (1
H, d), 4.50 (1H, d), 5.10 (1H, d) 5.28 (2H, ABq), 5.74 (1H, d), 6.71 (1H, s), 7.07 (1H, s), 7.62
(1H, s) Example 30 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) ) Methoxyiminoacetamide] -3-
(2-Ethoxycarbonyl-1,3,4-thiadiazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-2-ethoxycarbonyl-1,
3,4-thiadiazole NMR (D ₂ O) δ 1.41 (3H, t), 3.47 (2H, ABq), 4.35 (2H, ABq), 4.50 (2H, q), 5.
12 (1H, d), 5.28 (1H, ABq), 5.77 (1H, d), 6.72 (1H, s), 7.04 (1
H, s), 7.63 (1H, s) Example 31 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4) -Pyridon-2-yl) methoxyiminoacetamide] -3-
(2-carbamoyl-1,3,4-thiadiazole-5
-Yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-2-carbamoyl-1,3,4
-Thiadiazole NMR (D ₂ O) δ 3.48 (2H, ABq), 4.33 (2H, ABq), 5.11 (1H, d), 5.28 (2H, ABq),
5.76 (1H, d), 6.70 (1H, s), 7.06 (1H, s), 7.60 (1H, s) Example 32 (6R, 7R) -7-[(Z) -2- (2-aminothiazole) -4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(4-Ethoxycarbonylthiazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-4-ethoxycarbonylthiazole NMR (D ₂ O) δ 1.45 (3H, t), 3.28 (1H, d), 3.72 (1H, d), 3.90 (1H, d), 4.47 (2
H, q), 4.57 (1H, d), 5.10 (1H, d), 5.32 (2H, ABq), 5.78 (1H, d), 6.72 (1H, s), 7.10 (1H, s), 7.63
(1H, s), 8.93 (1H, s) Example 33 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy- 4-Pyridone-2-yl) methoxyiminoacetamide] -3-
(1,2,4-thiadiazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-1,2,4-thiadiazole NMR (D ₂ O) δ 3.31 (1H, d), 3.77 (1H, d), 4.20 (1H, d), 4.67 (1H, d), 5.16 (1
H, d), 5.34 (2H, ABq), 5.83 (1H, d), 6.75 (1H, s), 7.13 (1H,
s), 7.65 (1H, s), 8.66 (1H, s) Example 34 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1, 5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(3-Methyl-1,2,4-thiadiazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-3-methyl-1,2,4-thiadiazole NMR (D ₂ O) δ 2.63 (3H, s), 3.29 (1H, d), 3.72 (1H, d), 4.14 (1H, d), 4.61 (1
H, d), 5.16 (1H, d), 5.34 (2H, ABq), 5.82 (1H, d), 6.77 (1H,
s), 7.11 (1H, s), 7.67 (1H, s) Instead of the 4-methylthiopyridine of Example 10, each reagent [A] was used and treated in the same manner as in Examples 35 to 36.
To obtain the compound of

Example 35 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(4-carbamoylpyridinium) methyl-cef-3-
M-4-carboxylate [A] isonicotinamide NMR (D ₂ O) δ: 2.94 (1H, d), 3.58 (1H, d), 5.17 (1H, d), 5.34 (2H, ABq), 5.40
(1H, d), 5.66 (1H, d), 5.83 (1H, d), 6.76 (1H, s), 7.02 (1H,
s), 7.49 (1H, s), 8.43 (2H, d), 9.14 (2H, d) Example 36 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) ) -2- (1,5-Dihydroxy-4-pyridon-2-yl) methoxyiminoacetamide] -3-
(Isoquinolinium-2-yl) methyl-ceph-3-em-4-carboxylate [A] isoquinoline NMR (D ₂ O) δ: 2.94 (1H, d), 3.55 (1H, d), 5.15 (1H, d ), 5.32 (1H, d), 5.48 (1
H, d), 5.67 (1H, d), 5.83 (1H, d), 6.64 (1H, s), 7.03 (1H, s),
7.37 (1H, s), 8.07 (1H, m), 8.25 (2H, m), 8.45 (3H, m), 8.62 (1
H, d) Example 37 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) Methoxyiminoacetamide] -3-
Methyl-ceph-3-em-4-carboxylic acid (a) (Z) -2- (2-tritylaminothiazole-4)
-Yl) -2- (1-diphenylmethyloxy-5-p
-Methoxybenzyloxy-4-pyridon-2-yl)
Methoxyiminoacetic acid (427mg) and (6R, 7R) -7-amino-
3-Methyl-ceph-3-em-4-carboxylic acid t-butyl ester (135 mg) is dissolved in methylene chloride (10 m) and cooled to -10 ° C. Pyridine (0.17m) in this solution
Phosphorus oxychloride (52 μl) was then added, and -10 ° C to -5
Stir at 45 ° C for 45 minutes. Saturated saline is added, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed once each with brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the ethyl acetate is evaporated under reduced pressure. The residue was subjected to silica gel (50 g) column chromatography and CHCl.
Elution with ₃ : MeOH (30: 1) gave (6R, 7R) -7-[(Z)-
2- (2-Tritylaminothiazol-4-yl) -2
-(1-Diphenylmethyloxy-5-p-methoxybenzyloxy-4-pyridon-2-yl) methoxyiminoacetamido] -3-methyl-cef-3-em-4-
276 mg of carboxylic acid t-butyl ester was obtained.

(b) The compound (276 mg) obtained in (a) was added to anisole (0.25 m
), And trifluoroacetic acid (1 m) is added under ice cooling, and the mixture is stirred at room temperature for 2.5 hours. The reaction solution is added to diisopropyl ether (30 m), and the precipitate is collected by filtration. After drying, suspend in water (10 m) and dissolve with saturated aqueous sodium hydrogen carbonate solution to pH 8.2. HP-20 (100m, water elution),
Purify with LH-20 (50 m), freeze-dry the fraction containing the desired product, and use the title target compound as the sodium salt.
mg was obtained.

NMR (D ₂ O) δ 1.93 (3H, s), 3.05 (1H, d), 3.53 (1H, d), 5.12 (1H, d), 5.27 (1
H, d), 5.36 (1H, d), 5.74 (1H, d), 6.78 (1H, s), 7.09 (1H, s),
7.69 (1H, s) Example 38 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridone-2- ) Methoxyiminoacetamide] -3-
Hydroxymethyl-ceph-3-em-4-carboxylic acid (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-) Pyridon-2-yl) methoxyiminoacetamide] -3-
Acetoxymethyl-ceph-3-em-4-carboxylic acid sodium salt (100 mg) is dissolved in 50% aqueous methanol (2 m) and cooled to -20 ° C. Add 1N-NaOH (0.2m),
Stir for 30 minutes at -20 ° C to -25 ° C. 1N-NaOH (0.2m)
Is further added and the mixture is stirred for 1 hour at the same temperature. The pH is adjusted to 6 with 1N-HCl, and methanol is distilled off under reduced pressure. Adjust the pH to 8 with a saturated aqueous solution of sodium hydrogen carbonate, HP-20 (70 m, water elution section),
Purification by LH-20 (50% aqueous methanol) gave 54 mg of the title compound as a sodium salt.

NMR (D ₂ O) δ 3.27 (1H, d), 3.59 (1H, d), 4.27 (1H, d), 4.31 (1H, d), 5.15 (1
H, d), 5.25 (1H, d), 5.35 (1H, s), 5.78 (1H, d), 6.73 (1H, s),
7.08 (1H, s), 7.64 (1H, s) Example 39 (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy -4-Pyridone-2-yl) methoxyiminoacetamide] -3-
Azidomethyl-ceph-3-em-4-carboxylic acid (6R, 7R) -7-[(Z) -2- (2) obtained in Example 9
-Aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridon-2-yl) methoxyiminoacetamido] -3-acetoxymethyl-cef-3-em-4-carboxylic acid sodium salt 58 mg It is dissolved in 1 m of water, 20 mg of sodium azide is added, the pH is adjusted to 6.5 to 6.8 with a saturated aqueous sodium hydrogen carbonate solution, and the mixture is reacted at 60 to 65 ° C for 4.5 hours. The reaction solution as it is, purified by HP-20 column chromatography (water elution) and LH-20 (50% methanol),
The title compound is obtained as the sodium salt.

NMR (D ₂ O) δ 3.42 (2H, ABq), 4.11 (2H, ABq), 5.17 (1H, d), 5.30 (2H, ABq),
5.80 (1H, d), 6.70 (1H, s), 7.08 (1H, s), 7.61 (1H, s) Example 40 (6R, 7R) -7-{(Z) -2- (2-aminothiazole) -4-yl) -2-[(RS) -1- (1,5-dihydroxy-4-pyridon-2-yl) ethoxyimino] acetamido} -3- (1,2,3-thiadiazol-5-yl) ) Thiomethyl-ceph-3-em-4-carboxylic acid (a) 1,5-di-p-methoxybenzyloxy-2-hydroxymethyl-4-pyridone 2 g was added to acetonitrile 50
dissolved in m, added 10 g of active manganese dioxide, at 50 ° C
Incubate for 3.5 hours.

After completion of the reaction, manganese dioxide is filtered off, washed with acetonitrile, and the filtrate is concentrated under reduced pressure. The residue is dissolved in 100 ml of dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

This was purified by silica gel column chromatography (chloroform-methanol = 50: 1), and 2-formyl-1,5-
Di-p-methoxybenzyloxy-4-pyridone 1.15 g
To get

NMR (CDCl ₃ ) δ 3.81 (3H, s), 3.82 (3H, s), 5.00 (2H, s), 5.08 (2H, s), 6.72 (1
H, s), 6.84 (2H, d), 6.89 (2H, d), 7.05 (2H, d), 7.10 (1H, s),
7.31 (2H, d), 9.60 (1H, s) (b) 1.09 g of formyl compound is suspended in 20 m of THF, and under ice cooling, methyl magnesium bromide 1M tetrahydrofuran solution
Add 7.5 m and react at the same temperature for 1 hour. To the reaction mixture was added dilute ammonium chloride solution (30 m), and ethyl acetate was 120 m.
Extract with. After washing with water, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1),
1,5-di-p-methoxybenzyloxy-2-[(RS)
530 mg of -1-hydroxyethyl] -4-pyridone are obtained.

NMR (CDCl ₃ ) δ 1.44 (3H, d), 3.79 (3H, s), 3.80 (3H, s), 4.87 (2H, ABq), 4.95
(1H, q), 5.04 (2H, ABq), 6.54 (1H, s), 6.80 (2H, d), 6.90 (2H,
d), 6.99 (1H, s), 7.21 (2H, d), 7.25 (2H, d) (c) using the alcohol body 495 obtained in (b), (6R, 7R)-
7-{(Z) -2- (2-tritylaminothiazole-
4-yl) -2-[(RS) -1- (1,5-di-p-methoxybenzyloxy-4-pyridon-2-yl) ethoxyimino] acetamido} -3-chloromethyl-ceph-
320 mg of 3-M-4-carboxylic acid p-methoxybenzyl ester are obtained.

(d) 150 mg of the obtained chloromethyl compound is dissolved in 0.4 m of dimethyl sulfoxide, 30 mg of 5-mercapto-1,2,3-thiadiazole is added, and the mixture is reacted at room temperature for 1 hour. Then, the same treatment as in (d) of Example 1 was carried out to obtain 51 mg of the title object compound as a sodium salt.

NMR (D ₂ O) δ 1.57 (3 / 2H, d), 1.62 (3 / 2H, d), 3.48 (1H, ABq), 3.60 (1H, AB
q), 4.11 (1H, ABq), 4.16 (1H, ABq), 5.12 (1 / 2H, d), 5.21 (1/2
H, d), 5.75 (1 / 2H, d), 5.78 (1 / 2H, d), 5.81 (1H, q), 6.61 (1/2
H, s), 6.71 (1 / 2H, s), 7.02 (1 / 2H, s), 7.04 (1 / 2H, s), 7.54 (1
/2H,s),7.56(1/2H,s),8.72(1H,s) Instead of the 5-mercapto-1,2,3-thiadiazole of Example 40 (d), the reagents of [A] were used respectively. The compounds of Examples 41 to 45 are obtained by treating in the same manner except using.

Example 41 (6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2-[(RS) -1- (1,5-dihydroxy-4-pyridone-2 -Yl) ethoxyimino] acetamido} -3- [1- (2-dimethylaminoethyl)-
1H-tetrazol-5-yl) thiomethyl-cef-3
- em-4-carboxylic acid [A] 5-mercapto-1- (2-dimethylaminoethyl)-1H-tetrazole _{NMR (D 2 O) δ 1.61} (3H, t), 2.40 (3H, s), 2.41 ( 3H, s), 3.10 (2H, m), 3.33 (1
/2H,d),3.52(1/2H,d),3.77(1/2H,d),3.83(1/2H,d),4.13
(1 / 2H, d), 4.15 (1 / 2H, d), 4.38 (1 / 2H, d), 4.41 (1 / 2H, d), 4.
60 (2H, m), 5.15 (1 / 2H, s), 5.26 (1 / 2H, d), 5.80 (2H, m), 6.63
(1 / 2H, s), 6.73 (1 / 2H, s), 7.04 (1H, s), 7.59 (1H, s) Example 43 (6R, 7R) -7-{(Z) -2- (2 -Aminothiazol-4-yl) -2-[(RS) -1- (1,5-dihydroxy-4-pyridon-2-yl) ethoxyimino] acetamido} -3- (1,2,4-thiadiazole- 5-yl) thiomethyl-ceph-3-em-4-carboxylic acid [A] 5-mercapto-1,2,4-thiadiazole NMR (D ₂ O) δ 1.61 (3H, t), 3.28 (1 / 2H, d), 3.49 (1 / 2H, d), 3.70 (1 / 2H, d),
3.80 (1 / 2H, d), 4.13 (1 / 2H, d), 4.17 (1 / 2H, d), 4.63 (1 / 2H,
d), 4.67 (1 / 2H, d), 5.12 (1 / 2H, d), 5.23 (1 / 2H, d), 5.80-5.
90 (2H, m), 6.64 (1 / 2H, s), 6.76 (1 / 2H, s), 7.03 (1H, s), 7.62
(1 / 2H, s) 7.63 (1 / 2H, s), 8.60 (1H, s) Example 43 (6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2-[(RS) -1- (1,5-dihydroxy-4-pyridon-2-yl) propoxyimino] acetamido} -3- (1,2,3-thiadiazole-5-
Il) thiomethyl-ceph-3-em-4-carboxylic acid The title compound is obtained by the same procedure as in Example 48 [b] except that ethyl magnesium bromide is used instead of methyl magnesium bromide.

NMR (D ₂ O) δ 1.03 (3H, t), 2.0 (2H, m), 3.40 (1 / 2H, d), 3.51 (1 / 2H, d), 3.7
7 (1 / 2H, d), 3.83 (1 / 2H, d), 3.97 (1 / 2H, d), 4.01 (1 / 2H, d),
4.43 (1 / 2H, d), 4.46 (1 / 2H, d), 5.20 (1 / 2H, d), 5.27 (1 / 2H,
d), 5.68 (1H, m), 5.83 (1H, d), 6.61 (1 / 2H, s), 6.72 (1 / 2H, s) 7.08 (1H, s), 7.62 (1H, s), 8.77 ( 1H, s) Example 44 (6R, 7R) -7-{(Z) -2- (2-aminothiazol-4-yl) -2-[(RS) -1-phenyl-1- (1,
5-Dihydroxy-4-pyridon-2-yl) methoxyimino] acetamido} -3- (1,2,3-thiadiazol-5-yl) thiomethyl-ceph-3-em-4-
Carboxylic acid The title compound is obtained by the same treatment as in Example 40 [b] except that phenylmagnesium bromide is used instead of methylmagnesium bromide.

NMR (D ₂ O) δ 3.10 (1 / 2H, d), 3.15 (1 / 2H, d), 3.51 (1 / 2H, d), 3.64 (1 / 2H,
d), 3.97 (1 / 2H, d), 4.02 (1 / 2H, d), 4.25 (1 / 2H, d), 4.31 (1/2
H, d), 5.07 (1 / 2H, d), 5.12 (1 / 2H, d), 5.68 (1 / 2H, d), 5.73 (1
/2H,d),6.68(1/2H,s),6.76(1/2H,s) 6.82 (1 / 2H, s), 6.95 (1 / 2H, s), 7.11 (1 / 2H, s), 7.12 (1 / 2H,
s), 7.40 (5H, s), 7.77 (1 / 2H, s), 7.82 (1 / 2H, s), 8.74 (1 / 2H,
s), 8.75 (1/2 H, s) Example 45 Injectable formulation Aseptically dispensed to contain 1000 mg (potency) of the compound of Example 1 in 1 vial.

Example 46 Capsules Compound of Example 1 250 parts (potency) Lactose 60 parts (potency) Magnesium stearate 5 parts (potency) These are evenly mixed into capsules to give 250 mg (potency) / capsule. Filled.

Example 47 Soft capsule for rectal administration Olive oil 160 parts Polyoxyethylene lauryl ether 10 parts Sodium hexametaphosphate 5 parts To a uniform base, 25 parts (potency) of the compound of Example 1 was added and uniformly mixed to give 250 mg (force). Value) / capsule was filled into a soft capsule for rectal administration.

〔The invention's effect〕

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 and negative bacteria. In order to show the usefulness of the target compound (I), the compound (I) of the present invention
Table 1 below shows the antibacterial activity of representative ones.

(Z) -2- (2-aminothiazol-4-yl) -2- (1,5-dihydroxy-4-pyridone-2) at the 7-position
The compound having an -yl) alkoxyimino group is a (5-hydroxy-4-pyridon-2-yl) alkoxyimino compound lacking a hydroxyl group at the 1-position (N-position) or 4,5-
Antibacterial activity compared to dihydroxybenzyloxyimino body, especially far superior antibacterial activity against Gram-negative bacteria including Pseudomonas aeruginosa, and excellent solubility in water, which is an important requirement as an injection. Have.

As a result of the acute toxicity test using the compound of the present invention in mice, LD ₅₀
Has a low toxicity above 2 g / kg.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical display location C07D 501/46 8829-4C (72) Inventor Kiyoaki Katano 760 Mojioka-cho, Kohoku-ku, Yokohama-shi Kanagawa Haruka Seika Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor Akira Nakabayashi, 760, Shimooka-cho, Kohoku-ku, Yokohama, Kanagawa Meiji Seika Chemicals Laboratories, (72) Inventor, Yuko Ogino, 760, Shimooka-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture Meiji Seika Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor Takashi Yoshida, 760 Shimooka-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture Meiji Seika Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor, Shoji Sezaki 760, Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Address Meiji Confectionery Co., Ltd. Pharmaceutical Research Laboratory (72) Inventor Shinichi Kondo 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Confectionery Co., Ltd. The laboratory (56) Reference Patent Sho 63-146887 (JP, A)

Claims (2)

[Claims] 1. A formula [In the formula, R ¹ and R ² may be the same or different hydrogen atoms, or a lower alkyl group having 1 to 5 carbon atoms or a substituted or unsubstituted phenyl group, A is a hydrogen atom, a hydroxyl group, an azido group,
Alkanoyloxy group having 2 to 5 carbon atoms or lower alkyl group having 1 to 3 carbon atoms as a substituent, hydroxyl group, alkoxy group, oxo group, hydroxyalkyl group, halogen atom, dialkylaminoalkyl group, alkylthio group, cycloalkylthio group , A cycloalkyl-alkylthio group, a carpamoyl group, a phenylthio group with or without a phenyl group or an alkoxycarbonyl group, a thiazolylthio group, an oxazolylthio group, a thiadiazolylthio group,
Tetrazolylthio group, triazinylthio group, 1,2,
4,6-thiatriazinylthio group, benzothiazolylthio group, pyridinium group or isoquinolinium group]
A cephalosporin compound represented by and a pharmacologically acceptable salt thereof. 2. A formula [In the formula, R ¹ and R ² may be the same or different hydrogen atoms, or a lower alkyl group having 1 to 5 carbon atoms or a substituted or unsubstituted phenyl group, A is a hydrogen atom, a hydroxyl group, an azido group,
Alkanoyloxy group having 2 to 5 carbon atoms or lower alkyl group having 1 to 3 carbon atoms as a substituent, hydroxyl group, alkoxy group, oxo group, hydroxyalkyl group, halogen atom, dialkylaminoalkyl group, alkylthio group, cycloalkylthio group A cycloalkyl-alkylthio group, a carbamoyl group, a phenylthio group with or without a phenyl group or an alkoxycarbonyl group, a thiazolylthio group, an oxazolylthio group, a thiadiazolylthio group,
Tetrazolylthio group, triazinylthio group, 1,2,
4,6-thiatriazinylthio group, benzothiazolylthio group, pyridinium group or isoquinolinium group]
An antibacterial agent containing, as an active ingredient, a cephalosporin compound represented by: and a pharmacologically acceptable salt thereof.