JPH03204885A - New cephalosporin based compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1 and R2 are H or (protected) carboxyl; A is nucleophilic residue; n and m are 0-3]. EXAMPLE:7-[2-(2-Tolytylaminothiazol-4-yl)-2-(3-diphenylmethoxy-4-pyrid on-1-yl) ethoxyiminoacetamido]-3-(1,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-c arboxylic acid p-methoxybenzyl ester. USE:A antimicrobial agent. PREPARATION:A compound expressed by formula II (R3 is H or carboxyl protecting group) or reactive derivative in amino group thereof or salt thereof is reacted with a compound expressed by formula III (R4 is H or amino protecting group; R5 is H or OH protecting group) or reactive derivative in carboxyl group thereof or salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel β-lactam compound, pharmaceutically acceptable salts and esters of the compound, and an antibacterial agent containing this compound as an active ingredient.

[Conventional technology]

Cephalosporin antibiotics exhibit a wide range of antibacterial activity against Durham-positive and Durham-negative bacteria, and various semi-synthetic cephalosporin antibiotics are already commercially available and are used clinically as therapeutic agents for various infectious diseases. ing. However, among these compounds, there are only a few therapeutic agents that exhibit antibacterial activity against Pseudomonas aeruginosa and Proteus. Furthermore, many of these compounds are unstable against β-lactamases produced by resistant bacteria, and have drawbacks such as low antibacterial activity against Pseudomonas aeruginosa, which is currently a clinical problem.

The present inventors have already reported in Japanese Patent Application No. 1-40188 that (3-hydroxy-4-pyridone-
It has been disclosed that novel cephalosporin derivatives having a 1-yl)methyl group have strong activity against a wide range of pathogenic bacteria.

[Problem to be solved by the invention]

The present invention also has a wide range of strong antibacterial activities against Durham-positive bacteria and Durham-negative bacteria, and in particular extremely strong antibacterial activity against Pseudomonas aeruginosa and strong antibacterial activity against various β-lactamase producing bacteria. The object of the present invention is to provide a novel cephalosporin compound, a pharmacologically acceptable salt or ester thereof, and an antibacterial agent containing the same as an active ingredient.

[Means to solve the problem]

The present inventors focused on the 3-hydroxy-4-pyridone structure bonded to the 3-position side chain of the cephem nucleus, which the present inventors had previously invented, and demonstrated the structural activity of the 3-position and 7-position side chains of cephalosporins. As a result of research on the correlation, it was discovered that a new cephalosporin compound having a 3-hydroxy-4-pyridone group at the 7-position side chain site of the cephem nucleus achieves the above object, and the present invention was completed.

[In the formula, R3 and R2 are hydrogen atoms or optionally protected carboxyl groups, A is a nucleophilic residue, and n and m are 0 or an integer of 1-3. ] A novel cephalosporin compound represented by the above formula, a pharmacologically acceptable salt or ester thereof, and an antibacterial agent containing them as active ingredients.

The pharmacologically acceptable salts of the compound represented by formula (I) of the present invention include medically acceptable salts, particularly conventional non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, calcium salts. , alkaline earth metal salts such as magnesium salts, ammonium salts, salts with organic bases, such as organic amine salts such as triethylamine salts, pyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, and salts such as lysine and arginine. Examples include basic amino acid salts.

In addition, pharmacologically acceptable ester groups include acyloxyalkyl esters such as pivaloyloxymethyl ester, carbonate esters such as ethoxycarbonyloxyethyl ester, and proteins that are easily deesterified by enzymes after absorption in the body. Examples include esters, which are called drugs.

The nucleophilic compound residue represented by A in formula (■) includes a hydroxyl group, a mercapto group, a carbamoyloxy group, an azide group, a pyridinio group which may have a substituent, quinolinium, and inquinolinium.

It represents a quaternary ammonium group such as thiazolium, a heterocyclic ring bonded via S, ie, a heterocyclic thio group.

Here, the heterocycle refers to pyridyl, N-oxypyridyl, pyrimidyl, pyridazinyl, N-oxypyridazinyl, pyrazolyl, diazolyl, and thiazolyl.

5-6 membered rings containing 1-4 hetero atoms selected from 0.8 or N such as thiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl, 2 such as cycloalkenopyridyl, benzoxacylyl, triazaintridinyl, etc. Represents a cyclic heterocycle, and on these heterocycles, for example, 1-
3 lower alkyl groups, halogen atom, alkoxy group,
It may have a substituent such as a hydroxyl group, a mercapto group, an amine group, a carboxyl group, a carbamoyl group, a dialkylamino group, a carboxymethyl group, a hydroxyalkyl group, or a sulfoalkyl group.

The compound represented by formula (I) of the present invention can be produced by the method shown below.

The following formula (II) [wherein R2 is a hydrogen atom or a carboxyl group protecting group,
A has the same meaning as above. ] or a reactive derivative thereof at the amino group or a salt thereof, the following formula (III) p.

[In the formula, R1 is a hydrogen atom or an amino group-protecting group, R2 is a hydrogen atom or a hydroxyl group-protecting group, and R1, R2, n and m have the same meanings as above. It can be produced by reacting a compound represented by the following formula, a reactive derivative thereof in the carboxyl group, or a salt thereof. Suitable examples of reactive derivatives at the amine group of the compound of formula (It) include Schiff base-type derivatives produced by the reaction of the compound of formula (II) with carbonyl compounds such as aldehydes, ketones, etc. Imino or its tautomeric enamine type isomer, compounds of the formula (previously) and bis(
Examples include silyl derivatives such as trimethylsilyl)acetamide, and derivatives produced by the reaction of the compound represented by formula (n) with phosphorus trichloride or phosgene.

Suitable salts of the compounds represented by formulas (II) and (III) include, for example, acetates, maleates, and tartrates.

Acid addition salts such as salts with organic acids such as benzenesulfonates, toluenesulfonates, or salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates, phosphates, e.g. Sodium salt, potassium salt.

Examples include metal salts such as alkali metal salts or alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, and organic amine salts such as triethylamine salts and dicyclohexylamine salts.

Suitable examples of reactive derivatives at the carboxyl group of the compound represented by formula (III) include acid halides,
Examples include acid azides, acid anhydrides, active amides, active esters, etc. More specifically, acid chlorides, acid bromides, substituted phosphoric acids such as dialkyl phosphoric acids, dibenzyl phosphoric acids, halogenated phosphoric acids, dialkyl phosphorous acids, etc. acids, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonates such as methyl carbonate, ethyl carbonate, etc., such as pivalic acid, valeric acid, isovaleric acid, 2-
mixed acid anhydrides with acids such as aliphatic carboxylic acids such as ethyl acetic acid, trichloroacetic acid or aromatic carboxylic acids such as benzoic acid, activated amides with imidazoles, tetrazoles, dimethylpyrazoles, triazoles or cyanomethyl esters, for example; Methoxymethyl ester, dimethyliminomethyl ((CH3)x N=CH-) ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, )! ll clophenyl ester. Active esters such as nittachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester, etc. , for example, N-hydroxy compounds such as N,N-dimethylhydroxylamine, 1-hydroxy-2-(LH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-IH-benzotriazole, etc. Examples include esters of and the like. These reactive derivatives are appropriately selected depending on the type of reactant compound to be used.

Reactions with compounds of these formulas (old and formula (II)) are usually carried out using water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, etc. It is carried out in customary solvents or other organic solvents which do not adversely affect the reaction.These solvents may be used in admixture with water.

In this reaction, when the compound represented by formula (I[I) is used in the form of a free acid or a salt, as a condensing agent,
For example, N, N'-dicyclohexylcarbodiimide,
N-cyclohexyl-No-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N.

No-diisopropylcarbodiimide or the like is used.

Other examples include so-called Wilsmeier reagents obtained by reacting dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, and the like. The Willsmeier reaction may also be carried out in the presence of an inorganic or organic base, such as, for example, sodium hydrogen carbonate.

Alkali metal hydrogencarbonates such as potassium hydrogencarbonate, alkaline earth metal carbonates such as calcium carbonate, tri(lower)alkylamines such as triethylamine and trimethylamine, pyridine, N-(lower)alkylmorpholine, N,
Examples include N-si(lower)-alkylbenzylamine.

The reaction temperature in these reactions mentioned above is not particularly limited, and is usually carried out under cooling or heating.

Moreover, the reaction is carried out in an organic solvent and a water-containing solvent.

Also, general formula (IV) Q.

[Wherein, Y is an acetoxy group or a halogen atom, R3 is a hydrogen atom or a carboxy protecting group, RI+ L, R4, R
5゜n and m have the same meanings as above. ] The compound represented by general formula (I) can also be produced by reacting the compound represented by formula (I) with a nucleophilic compound and then removing the protective group if necessary.

The products obtained by these methods have the formula (I
), or is a protected form of the amino group, carboxyl group, and hydroxyl group on the pyridone ring of the same compound. Therefore, if necessary, each protecting group is removed by a conventional method.

The method for removing carboxyl and amino protecting groups is as follows:
It is appropriately selected depending on the type of protecting group to be removed. The elimination reaction of amino protecting groups involves hydrolysis and reduction.For compounds whose protecting group is an acyl group, an iminohalogenating agent and then an iminoetherifying agent are applied, followed by hydrolysis as necessary. Any commonly used method can be applied. A hydrolysis method using an acid is one of the general methods, and is applied, for example, to the elimination of groups such as an alkoxycarbonyl group, a formyl group, and a trityl group. Further, as the acid used, formic acid, trifluoroacetic acid, hydrochloric acid, etc. are appropriately selected depending on the type of amino protecting group.

The reaction can be carried out either in the absence of a solvent or in the presence of water, a hydrophilic organic solvent, or a mixed solvent thereof. Furthermore, when trifluoroacetic acid is used, the reaction may be carried out in the presence of anisole. Any commonly used method such as hydrolysis or reduction can be applied to the elimination reaction of the carboxyl protecting group. Hydrolysis using an acid is one of the general methods and is applied, for example, to eliminate silyl groups, p-methoxybenzyl groups, diphenylmethyl groups, etc. Any commonly used methods such as hydrolysis and reduction can be applied to the elimination reaction of the protecting group for the hydroxyl group on the pyridone ring. Hydrolysis using an acid or a base is one of the common methods. The base is applied.

The compound of general formula (r) obtained as described above is collected from the reaction mixture by a conventional method.

For example, Amberlite XAD-2 (manufactured by Rohm and Haas), Diaion HP-20 or Sepabeads 5P
This can be achieved by appropriately combining purification using adsorption resins such as 207 (manufactured by Mitsubishi Kasei ■), precipitation methods, crystallization methods, and the like.

Antibacterial agents containing the compound represented by general formula (I) or a salt thereof as a main component are mainly injectables such as intravenous and intramuscular injections,
It is used in various dosage forms such as oral or rectal preparations such as capsules, tablets, and powders, oil-based suppositories, and water-soluble suppositories. These various preparations contain commonly used excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizing agents, and preservatives. It can be manufactured by conventional methods using agents, flavoring agents, soothing agents, and the like. Specific examples of the formulation method will be explained in more detail in Examples below.

The dosage is determined depending on the individual case, taking into account the symptoms, age, gender, etc., but it is usually 250 mg per day for adults.
-3000 mg, administered in 181-4 doses.

〔Example〕

The present invention will be further explained in detail in the following synthesis examples and examples, but these do not limit the present invention, and it is understood that various changes and modifications can be made without departing from the scope of the present invention. Needless to say.

Note that the NMR data in the examples are 90M unless otherwise specified.
IIz, in the case of heavy water, the δ value is shown when the peak of water is set to 4.82, and in the case of other heavy solvents, the δ value is shown based on TMS. .

Reference Example 1 l-(2-Hydroxyethyl)-3-diphenylmethoxy-4-pyridone 1 g of 3-diphenylmethoxy-4-pyrone was dissolved in 20 ml of ethanol, and monoethanolamine 2
．． 2 g was added and stirred at room temperature for 20 hours. The reaction solution was concentrated, and 20 grams of ethyl acetate was added to the residue. The precipitated crystals were collected by filtration and dried under reduced pressure. 410 mg of the title compound was obtained as pale yellow crystals.

NMR (DMSO-d,) δ: 3.50 <28.
m), 3.75 (2)1. m).

6, 07 (1)1. d, J=6Hz), 6.
65 (IH,s), 7.30 (IIH,m) Reference Example 2 2-(3-diphenylmethoxy-4-pyridon-1-yl)-4-hydroxybutyric acid DL-homoserine (10 g) was dissolved in water (10). , 8.3 g of caustic soda was added under water cooling, and 20 g of methanol containing 1 g of 3-diphenylmethoxy-4-pyrone was further added. After stirring the reaction solution at 80° C. for 10 hours, the reaction solvent was distilled off under reduced pressure. Dissolve the residue in 1 rnl of water and add Diaion H
Purified by column chromatography on P20 resin 200 rnl (eluent: water, 50% methanol water),
The eluate was concentrated under reduced pressure to remove methanol, and then lyophilized to obtain 530 mg of the sodium salt of the title compound as a pale yellow powder.

NMR (1) 20) δ: 1.8-3.4 (4)1.
m>, 4.60 (1)1. m＞.

6,48 (IH,s), 6.65 (IH,d,
J=6.4)1z), 7.40 (12)1.
m) Reference Example 3 3-(3-diphenylmethoxy-4-pyridon-1-yl)-2-hydroxypropionic acid DL-isoserine 1
g was dissolved in 2 ml of water, 420 mg of caustic soda was added under water cooling, and 20 ml of methanol containing 3-diphenylmethoxy-4-pyrone Ig was further added. After stirring the reaction solution at room temperature for 2 days, the reaction solvent was distilled off under reduced pressure. Add 1 part of the residue to water
-Dissolve in 200 ml of Diamond Ion HP20 resin
By O column chromatography (eluent: water, 50
% methanol in water), the eluate was concentrated under reduced pressure to remove methanol, and then lyophilized to obtain 1 g of the sodium salt of the title compound as a pale yellow powder.

NMR (020) δ: 4.10 (3H, m),
6.42 (IH,s).

6, 60 (1)1. d, J=6.4Hz),
7.50 (12H, m) Reference Example 4 1.4-dihydro-1-(2-hydroxyethyl)-5
-1-methoxybenzyloxy-4-oxo-2-pyridinecarboxylic acid 2 g of 5-p-methoxybenzyloxy-4-pyrone-2-carboxylic acid was suspended in 20 d of ethanol, and 4.7 g of monoethanolamine was added and dissolved. did.

The reaction mixture was stirred at 70°C for 1 hour, and the reaction solvent was distilled off under reduced pressure. Dissolve the residue in 1 rnl of water and add Diaion H
Purified by column chromatography on P20 resin 200 rnl (eluent: water, 50% methanol water),
The eluate was concentrated under reduced pressure to remove methanol, and then lyophilized to obtain 2.4 g of the monoethanolamine salt of the title compound as a pale yellow powder.

NMR (DMSO-d,) δ: 2.50 (21(,
m), 3.30-3.55 (4H, m).

3,75 (3H,s), 4.00 (2H,m)
, 4.80 (2H, bs), 6.10 (IH
,s)6,70.7.10 (4H,^Bq, J=7
Hz), 7.30 (LH,s) Reference Example 5 2-(3-diphenylmethoxy-4-pyridon-1-yl)-4-hydroxybutyric acid diphenylmethyl ester 2-(3-diphenylmethoxy-4-pyridone- 1-yl)-4-hydroxybutyric acid sodium salt 500 μm water 1
f)tf! and methylene chloride (20 ml) and cooled on ice. 300 mg of diphenyldiazomethane was added, the pH was adjusted to 3.0 with 5% hydrochloric acid at 0-5°C, and the mixture was stirred at the same temperature for 1 hour. The organic layer was separated, washed successively with water, 7% aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was purified using Wakogel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) (100 g)
The product was separated and purified by Frassini column chromatography (eluent: chloroform: methanol = 20:1) to obtain 600 ml of the title compound as a pale yellow powder.

NMR (CDC13) δ: 1.7-3.4 (4H, +
n), 4.65 (IH, m).

6, 15 (1)1. d, J=6Hz), 6.3
5 (1)1. s), 6.75 (LH, s).

7.3 (21fl, m) According to Reference Example 5, a compound of Reference Example 6-7 was obtained.

Reference Example 6 3-(3-diphenylmethoxy-4-pyridon-1-yl)-2-hydroxypropionic acid diphenylmethyl ester NMR (CDC1,) δ: 3.70 (2H, m), 4.
30 (IH, m).

6,0O(18,d, J=6Hz), 6.30
(IH,s), 6.82 (IH,s).

7, 30 (12)1. m) Reference Example 7 1.4-dihydro-1-(2-hydroxyethyl)--
5-p-methoxybenzyloxy-4-oxo-2-pyridinecarboxylic acid diphenylmethyl ester NMR (CDCIs) δ: 3.85 (2H, m)
, 4. TO(2H, m).

5.12 (2)! , bs), 6.46 (1)1. s
), 6.85 (2H, d, J=8Hz).

7.30 (12H, m), 7.50 (IH, s)
, 8.05(1)1. s) Reference Example 8 l-(2-phthalimidoxyethyl)-3-diphenylmethyloxyl 4-pyridone N-hydroxyphthalimide 22O4ff1 and 1-
(2-hydroxyethyl)-3-diphenylmethoxy-
400 mg of 4-pyridone and 20 m of tetrahydrofuran
f and DMF4+al! It was dissolved in a mixed solution of and cooled on ice.

Add 320 mg of triphenylphosphine to this solution,
Furthermore, 210 μm of diethyl azodicarboxylate was added, and o-5
Stirred at ℃ for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified using Wakogel C-300 (100g).
The product was separated and purified by flash column chromatography (eluent: chloroform:methanol = 40:1) to obtain 250 mg of the title compound as a pale yellow powder.

NMR (CDCIs) δ: 3.55 (2H, m)
, 4.30 (28,m).

7, 10-7.20 (16H, m) Compounds of Reference Examples 9-11 were obtained according to Reference Example 8.

Reference Example 9 2-(3-diphenylmethoxy-4-pyridon-1-yl)-4-phthalimidoxybutyric acid diphenylmethyl ester NMR (CDC1a) δ: 2.45 (2H, m>
, 3.45 (2H, m>.

5, 10 (1) 1. m), 6.35 (LH, d, J
=61(z), 6.75(IH,s).

6.90-7.70 (26H, m) Reference Example 10 3-(3-diphenylmethoxy-4-pyridon-1-yl)-2-phthalimidoxypropionic acid diphenylmethyl ester NMR (CDC13) δ: 4.15 (2H, m)
, 4.80 (2H,t).

6, 20 (1) 1. 'd, J=6Hz), 6.4
2 (IH, s), 6.80 (1) 1. s).

6, 90-7. TO(26)1. m) Reference Example 11 1.4-dihydro-5-p-methoxybenzyloxy-
4-oxo-1-(2-phthalimidooxyethyl)-
2-Pyridinecarboxylic acid diphenylmethyl ester NMR (CDCI,) δ: 3.72 (3H,s)
, 4.65 (2H, m).

4, 95 (2H, m), 5.22 (2H, s), 6
．． 55 (IH, S).

6, 75 (2)1. d, J=8)1z), 7.
2C1-7,90(17)1. m) Reference example 12 2(2-)! J thylaminothiazol-4-yl)-2
-(3-diphenylmethoxy-4-pyridon-1-yl)ethoxyiminoacetic acid 1-(2-phthalimidoxyethyl)-3-diphenylmethoxy-4-pyridone (680 mg) in methylene chloride 1
It was dissolved in 5ml and cooled on ice. An ethanol solution 1- containing 312 mg of hydrazine hydrate was added dropwise to this solution under water cooling.
Stirred for 0 minutes. After the reaction was completed, insoluble matter was removed by filtration, and the reaction solution was washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Obtained here (3-diphenylmethoxy-
4-Pyridon-1-yl)ethoxyamine was dissolved in ethanol 10- without purification to give 2-(2-)dithylaminothiazol-4-yl)-2-oxoacetic acid 54
3 mg in chloroform solution 2OrrIi. When the reaction mixture was stirred at room temperature for 2 hours, crystals precipitated. Ethyl acetate 10- was added to the reaction mixture, and the crystals were collected by filtration to obtain 600 mg of the title compound as white crystals.

NMR (CDC+3) δ: 3.90 (2)! , m
> , 4.20 (2)1. m＞.

6, 40 (IH, s), 6.60 (LH, s), 6
．． 65 (LH, s).

6,80 (LH,s), ? , 30 (27)i
, +I+) Compounds of Reference Examples 13-15 were obtained according to Reference Example 12.

Reference Example 13 2-(2-)ditylaminothiazol-4-yl)-2
-(3-(3-diphenylmethoxy-4-pyridone-1
-yl)-3-diphenylmethoxycarbonyl]propoxyiminoacetic acid NMR (CDCIs) δ: 2.80 (28, m), 4.
15 (IH, m).

5, 10 (2H, m), 6.25 (IH, s)
, 6.70 (lft, s).

6,80 (IHd, J=6Hz), 7.00-
7.40 (36H, m) Reference Example 14 2-(2-)ditylaminothiazol-4-yl)-2
-C2-(3-diphenylmethoxy-4-pyridone-1
-yl)-1-diphenylmethoxycarbonyl]ethoxyiminoacetic acid NMR (CDCIs) δ: 4.15 (2H, m)
, 5.00 (IH, m).

6,20 (IH,s), 6.60 (IH,d,
J=6)lz) , 6.70 (1t(,s).

6,80 (IH,s), 7.10-7.70 (
318, m) Reference Example 15 2-(2-)ditylaminothiazol-4-yl)-2
-(3-p-methoxybenzyloxy-6diphenylmethoxycarbonyl-4-pyridon-1-yl)ethoxyiminoacetic acid NMR (CDC13) δ: 3.75 (3H, s)
.

3,85 (2H,m), 5.12 (2H,s)
.

5.70 (2H, ff1), 6.55 (IH, S), 6
．． 70 (IH, S).

6,80 (IH,S), 6.91 (IH,S),
7.00-7.70 (25H, m).

8,05 (1)1. s) Example 1? -(2-(2-)ditylaminothiazol-4-yl)-2-(3-diphenylmethoxy-4-pyridon-1
-yl)ethoxyiminoacetamide) -3-(1,
2,3-thiadiazol-5-yl)thiomethyl-3-
Cephem-4-carboxylic acid p-methoxybenzyl ester 7-amino-3-(1,2,3-thiadiazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid p
-methoxybenzyl ester 216 mg and 2-(2
-) dithylaminothiazol-4-yl)-2-(3-
366 mg of diphenylmethoxy-4-pyridon-1-yl)ethoxyiminoacetic acid was dissolved in 10 bottles of dimethylformamide and cooled on ice. 80 mg of l-hydroxybenztriazole hydrate was added and dissolved in this solution, and 110 mg of dicyclohexylcarbodiimide was further added and stirred for 1 hour under water cooling. After the reaction was completed, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to flashini column chromatography using Wakogel C-300 (50 g) (eluent:
Separation and purification using chloroform:methanol=20:1) gave 500 ml of the title compound as a pale yellow powder.

NMR (CDC1,) δ: 3.40 (2H,b
s), 3.72 (3H, s).

3, 90-3.95 (4H, m>, 4.25 (
2)1. m), 4.75 (ift, d, J
=5Hz).

5,05 (2H, bs), 5.65 (1)1.
dd, J=5Hz, 8Hz), 6.45 (I
H,s).

6,55 (IH,s), 6.75 (2H,d,
J=8t(z), 7.05-7.80 (31H,
m) According to Example 1, the compound of Example 2-4 was obtained.

Example 2 7-(2-(2-)ditylaminothiazol-4-yl)-2-(3-p-methoxybenzyloxy-6-diphenylmethoxycarbonyl-4-pyridon-1-yl)
ethoxyiminoacetamide)-3-(1,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-
4-Carboxylic acid p-methoxybenzyl ester NMR (CDC13) δ: 3.36 (2tl, b
s), 3.70 (3H, s).

3,72 (3H,s), 3.85-4.45 (
4H, m), 4.60 (2H, m).

4,80 (IH, d, J=5)1z), 5.1
0 (4H, bs).

5, 50 (ltl, dd, J=5Hz, 8)1
z), 6.50-6.85 (8H, m).

7, 10-7.50 (29H, m), 9.10
(LH, d, J=8Hz) Example 3 7-(2-(2-)ditylaminothiazol-4-yl)-2-(2-(3-diphenylmethoxy-4-pyridon-1-yl)- 1-diphenylmethoxycarbonyl)ethoxyiminoacetamide) -3-(1,2,3
-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester N
! JR (CDCIs) δ: 3.40 (28, bs),
3.75 (3)1. s) 3, 90-4.18 (
4H, m), 4.82 (LH, d, J=5Hz
>.

5゜10 (3H, m), 5.70 (IH, dd)
, 6.50-7.30 (46tl, m).

8, 30 (IH, bs) Example 4 7-[2-(2-)Ritylaminothiazol-4-yl)-2-(3-(3-diphenylmethoxy-4-pyridon-1-yl)-3 -diphenylmethoxycarbonyl)
propoxyiminoacetamide) -3-(1,2,3
-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester NMR (CDCl2) δ: 2.50 (2) 1. m),
3.50 (2H, ABq).

3.75(3)1. s), 3.90 (3H, m),
4.95 (IH, d).

5,05 (2H, bs), 5.70 (IH, m
), 6.25-7.80 (46H, m).

8,30 (IH,d) Example 5 7-C2-<2-aminothiazol-4-yl)-2-
(3-hydroxy-4-pyridon-1-yl)ethoxyiminoacetamide) -3-(1,2゜3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 1-C2-(2- ) dithylaminothiazol-4-yl)-2-(3-diphenylmethoxy-4-pyridon-1
-yl)ethoxyiminoacetamide]-3-(1,2
, 3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 400+y+g was dissolved in anisole 1-, and trifluoroacetic acid 2- was added under water cooling.

After stirring at the same temperature for 1 hour, 40ml of water-cooled isopropyl ether! is added, and the resulting trifluoroacetate of the title compound is collected by filtration and dried under reduced pressure. Suspend this in water 1-,
While cooling with water, add a 7% aqueous sodium hydrogen carbonate solution to adjust the pH to 7.
5 to form a solution. It was purified by column chromatography on Diaion) IP20 resin 20- (eluent: water, 30% methanol/water), the desired fractions were collected, methanol was removed under reduced pressure, and lyophilized to obtain 164 mg of the sodium salt of the indicated compound. Obtained as a yellow powder.

NMR (D, 0) δ: 3.25.3.70 (2)1.
^Bq, J=16H2).

3,95 (IH, d, J=16Hz), 4.30-
4.70 (58, m).

5, 10(IH, d, J=5)1z), 5.70(
LH, d, J=5Hz).

6, 55 (IH, d, J=6.4Hz), 7.05
(1)1. s), 7.60 (2H, bs).

8, 70 (ift, s) According to Example 5, the compound of Example 6-8 was obtained.

Note that the compound of Example 7.8 is a 1:1 mixture of diastereomers derived from the 7-position side chain oxime substituent.

Example 6 l-C2-<2-aminothiazol-4-yl)-2-
(3-hydroxy-6-carboxy-4-pyridone-1
-yl)ethoxyiminoacetamide) -3-(1,
2,3-thiadiazol-5-yl)thiomethyl-3-
Cephem-4-carboxylic acid sodium salt NMR (D, 0) δ: 3. ao, 3.70 (2)
1. ABq, J=16Hz).

4,05 (IH, d, J=16Hz), 4.3
0-4.80 (5H, m).

5, 10 (IH, d, J=5Hz), 5.70 (I
H, d, J=5)1z).

6, 70 (IH, s), 7.00 (IH, s), 7
．． 70 (LH, s).

8,70 (IH,s) Example 7 7-(2-(2-aminothiazol-4-yl)-2-
(2-(3-hydroxy-4-pyridon-1-yl)-
1-carboxy)ethoxyiminoacetamide: ] −
3-(1,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt NMR (D20) δ: 3.48.3.80 (2H,A
Bq, J=16flz).

4.00 (LH, d, J=16Hz), 4.3
0-5.10 (4H, m).

5, 20 (1)1. d, J=5Hz>, 5.8
0 (LH, d, J=5Hz).

5, 60 (I H, d, J=6.4Hz), 7
．． 10 (IH, s), 7.65 (2H, bs)
.

8,75 (1)! , s) Example 8 7-(2-(2-aminothiazol-4-yl)-2-
(3-(3-hydroxy-4-pyridon-1-yl)-
3-carboxypropoxy)iminoacetamide) −
3-(1,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt NMR (D, O) δ: 2.60. (2H, m), 3
．． 25-4.45 (7H, m).

5, 18 (IH, d, J=5Hz), 5.75 (L
H, d, J=5Hz).

6, 55 (IH, d, J=6Hz), 7.00 (L
H,s), 7.60(it(,S).

7, 65 (LH, d, J=6.4) lz), 8.
70 (LH,s) Example 9 Injection preparation 1000+ng (potency) of the compound of Example in 1 vial
Dispense aseptically to make an injectable preparation.

Example 10 Capsule Example Compound 250 parts (potency) Lactose
Fill capsules with 60 parts of magnesium stearate to 5 parts to prepare capsules.

Example 11 Soft capsules for rectal administration To a homogeneous base consisting of 160 parts of olive oil, 10 parts of polyoxyethylene lauryl ether, and 5 parts of sodium hexametaphosphate, 25 parts (potency) of the compound of the example was added and mixed uniformly to give 250 mg ( Fill soft capsules for rectal administration to the desired strength (potency)/capsules to obtain soft capsules for rectal administration.

The target compound represented by formula (1) or its salts of the present invention is a new compound and exhibits high antibacterial activity that inhibits the growth of a wide range of pathogenic microorganisms including Durham-positive and -negative bacteria.

In order to demonstrate the usefulness of the compounds, Table 1 shows the antibacterial activity of some of the compounds measured by the agar dilution method.

The numbers in Table 1 indicate the minimum inhibitory concentration (μg/+n) [
Effects of the Invention The present invention provides a novel cephalosporin compound that has strong antibacterial activity against bacteria, including an extremely wide range of resistant bacteria, and a novel cephalosporin compound that contains this compound as an active ingredient and can be effectively used in mammals including humans. This is a useful invention that provides an antibacterial agent.

Claims (1)

[Claims] 1. The following formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ [In the formula, R_1 and R_2 are hydrogen atoms or optionally protected carboxyl groups, and A is a nucleophilic residue. , n and m each represent an integer of 0 or 1-3. ] A novel cephalosporin compound and its pharmacologically acceptable salt or ester. 2. An antibacterial agent containing the compound according to claim 1 as an active ingredient.