JPS62158289A - Novel cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [Q represents formula II or III (R<1> represents OH; P is 0-2); q is 0-2], salt thereof and physiologically hydrolyzable ester thereof. EXAMPLE:7-[2-(2-Aminothiazol-4-yl)-2-(3, 4-dihydroxybenzyloxyimino)acetamido]- 3-(2-methyl-2-isoindolinio)methyl-3-cephem-4-carboxylate (syn-isomer). USE:An antimicrobial agent against Gram-positive bacteria and Gram-negative bacteria with sensitivity and resistance. PREPARATION:A compound expressed by formula IV (R<3> represents OH or protected OH: R<4> represents H or carboxyl-protecting group; R<5> represents H or amino-protecting group; X represents halogen atom or eliminating group; Y represents S or SO) or salt thereof is reacted with a compound expressed by formula V or VI (R<6> represents H or methyl) to form a compound expressed by formula VII (Q' represents formulae VIII or IX, etc.), as necessary, followed by methylation and/or reduction, and further deprotection, as necessary.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing the same and an antibacterial agent containing the same as an active ingredient.

Prior art - Conventionally, 2-(2-aminothiazol-4-yl)-2-substituted oximinoa in the 7-position side chain of the cephalosporin core has a doamide group, and compounds having an ammoniomethyl group in the 3-position have been extremely difficult to find. Examples of published techniques that have been synthesized and described are, for example, Japanese Patent Application Laid-open Nos. 154786 and 55.
- No. 59196, No. 57-192394, No. 58-
174387M, 5B-198490, 59-
No. 219292 and No. 60-97983, etc., and include Durham-positive bacteria and Pseudomonas aeruginosa.
It also shows activity against cephalosporin-resistant Durham-negative bacteria, including cephalosporin-resistant bacteria, suggesting that it has excellent antibacterial activity and a broad antibacterial spectrum.

β-lactam antibiotics exhibit selective toxicity only to bacteria;
Because it does not affect animal cells, it is a highly useful antibiotic that has few side effects and is widely used in the treatment of bacterial infections.

However, in recent years, the frequency of isolation of resistant Durum-positive bacteria and resistant non-glucose-fermenting Durum-negative bacilli has tended to increase, and there is a desire to enhance antibacterial activity against these bacteria.

Means for Solving the Problems The present invention aims to provide a novel cephalosporin derivative having excellent antibacterial activity, with an ammoniomethyl group at the 3-position and a 2-(2-aminothiazole- As a result of intensive research on a new cephalosporin derivative having a -2-benzyloylominoacetamide group, it was discovered that it has strong antibacterial activity against Durham-negative bacteria and Durham-positive bacteria, and the present invention has been made. completed.

Function The present invention is based on the general formula (I) (wherein, R1 is a hydroxyl group, and P is an integer from O to 2).
, R2 is a hydroxyl group, and q is an integer from O to 2], its nontoxic salt or physiologically hydratable nontoxic ester thereof, its production method, and an antibacterial agent containing it as an active ingredient. .

Next, various symbols and terms described in this specification will be explained.

Examples of the substituent Q of the compound of general formula (I) include a pyrrolidinio group and an isoindolinio group which may be substituted with a hydroxyl group.

One or two hydroxyl groups can be substituted on the isoindoline nucleus, but the substitution positions are not particularly limited.

Specific examples of the substituted Q include a 1-methyl-1-pyrrolidinio group, a 2-methyl-2-isoindolinio group, a 2-methyl-5,6-cyhydroxy-2-methylisoindolinio group, and the like.

Furthermore, the phenyl nucleus of the benzyloxyimino group of general formula (I) may be substituted with one or two hydroxyl groups. However, the substitution position is not particularly limited. Specific examples of the benzyloxyimino group include a benzyloxyimino group and a 3,4-dihydroxybenzyloxyimino group.

Furthermore, substitutions on oximino groups generally include syn isomers and anti isomers, but the present invention includes both syn isomers and anti isomers. In particular, the syn isomer exhibits excellent antibacterial activity.

Examples of the compounds of the present invention include the compounds shown below.

7-[2-(2-aminothiazol-4-yl)-2-
benzyloxyiminoacetamide]-3-(1-methyl-1-pyrrolidinio)methyl-3-refem-4-carboxylate 7-[2-(2-aminothiazol-4-yl)-2-
benzyloxyiminoacetamide]-3-(2-methyl-2-isoindolinio)methyl-3-refem-4
-Ruboxylate 7-[2-(2-aminothiazol-4-yl)-2-
benzyloxyiminoacetamide]-3-(5,6-
cyhydroxy-2-methyl-2-isoindolinio)methyl-3-cephem-4-carboxylate 7-[2-
(2-aminothiazol-4-yl)-2-(3,4-
Dihydroxybenzyl A ximino)acetamide l-
3-(1-Methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate 7-[2-(2-aminothiazol-4-yl)-2-
(3,4-dihydroxybenzyloxyimino)acetamide]-3-(2-methyl-2-isoindolinio)
Methyl-3-cephem-4-carboxylate 7-[2
-(2-aminothiazol-4-yl)-2-(3,4
-dihydroxybenzyloxyimino)acetamide]
-3-(5,6-cyhydroxy-2-methyl-2-isoindolinio)methyl-3-cephem-4-carboxylate The compound of general formula (I) can be hydrolyzed into its non-toxic salt or physiologically by a conventional method. It can be made into a non-toxic ester.

Non-toxic salts of the compound of general formula (I) include conventional pharmaceutically acceptable salts, such as metal salts of sodium, potassium, calcium, magnesium, aluminum, N,N'-dibenzylethylenediamine, Organic amine salts such as procotylene, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,
Inorganic acid salts such as perchloric acid, organic acid salts such as acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, etc., sulfuric acids such as methanesulfonic acid, isethionic acid, p-toluenesulfonic acid, etc. 1 (amino acid salts such as phosphate, glutamic acid, aspartic acid, lysine, arginine, etc.).

In addition, as a non-toxic ester of general formula (I), pharmaceutically acceptable (meaning a member) in the carboxyl group, for example, an acetoxymethyl group, a pivaloyloxymethyl group, etc. ) J/yl A° xymethyl group, 1-
Alkoxycarbonyl A° xyalkyl group such as (ethoxycar/11-nylmethoxy)ethyl group, phthalidyl group,
5-Methyl-2-oxo-1,3-dioxo-4
5-substituted-2-oxo such as -ylmethyl group 1.3-
Dioxol-4-ylmethyl group etc. b; “l-tf
It will be done.

Next, regarding the method for producing the compound of the present invention, FJ2 will be explained at 1/1.
Ru.

The compound of general formula (I) can be prepared as follows: B It can be manufactured using either method.

General formula (IV) (wherein, R3 is a hydroxyl group or a protected hydroxyl group, R4 is a hydrogen atom or a carboxyl group, R5 is a hydrogen atom or an amino protecting group, X is a halogen atom or a leaving group, Y represents an integer from S or So, l, tO to 2) or a salt thereof, a compound represented by the general formula (III) [wherein R1 is a hydroxyl group, R6 is a hydrogen atom or a methyl group, p G, t o to 2
(indicates an integer of O to 2) is reacted with a compound represented by the general formula (II), where X () is an anion, and p is an integer of O to 2).
, R3, R4, R5, Y and q have the above meanings]
After methylating and/or reducing this as necessary, if necessary, preserve p! Compound (I) of the present invention can be produced by removing one group.

In the general formula (IV), , iodine and other halogen atoms are preferred.

Examples of the amine represented by the general formula (I [ can be mentioned.

Production method B General formula (■1) acid group, xO is an anion, p is an integer from 0 to 2),
R4 is a hydrogen atom or carboxyl protecting group, Y is S or S
A compound represented by the general formula (V
) (wherein, R3 is a hydroxyl group or a protected hydroxyl group, R5 is a hydrogen atom or an amino-protecting group, qG, an integer from to to 2) or its reactivity y, acylated by a conductor. , having the meaning of general formula (II)), methylate and/or reduce this as necessary, and then remove the protecting group if necessary,
Compound (I) of the present invention can be produced.

As the protecting groups for the carboxyl group, amino group and hydroxyl group in the above general formula, protecting groups commonly used in the field of β-lactam synthesis can be appropriately selected and used.

As the carboxyl group protecting group, t-butyl group, 2,
2.2-trichloroethyl group, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group, 1-propionyloxyethyl group, 1-(ethoxycarbonyloxy)ethyl group,
Phthalidyl group, benzyl-14-methoxybenzyl group,
3.4-dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group, his(4-methoxyphenyl)methyl group, 5-methyl-2-ohalfo-1,3-dioxo-
Examples include a 4-yl-methyl group, a trimethylsilyl group, a t-butyldimethylsilyl group, and particularly a benzhydryl group, a t-butyl group, a silyl group, and the like are preferred.

As protecting groups for amino groups, trityl group, formyl group,
Examples include chloroacetyl group, trifluoroacetyl group, [-butoxycarbonyl group, trimethylsilyl group, t-butyldimethylsilyl group, and the like.

As protecting groups for hydroxyl groups, 1-oxymethyl group on 2-methoxy group, methoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, phenacyl group, isopropyl group, (
-butyl group, benzyl group, 4-nitrobenzyl group, acetyl group, 2,2.2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, acetonide, trimethylsilyl group, t-butyldimethylsilyl group, and the like.

Next, the manufacturing method A and the manufacturing method B of the compound (I) of the present invention will be explained in detail.

Production method A The reaction between the compound of general formula (IV) and the amine of general formula (III) can be carried out using methylene chloride, chloroform, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethylsulfochloride, The reaction can be carried out in an organic solvent such as a side dish or in a mixed solvent thereof. As the amine of general formula (III), amine salts such as hydrochloride, hydrobromide, sulfate, nitrate, and acetate may be used.

In this case, the reaction is carried out in the presence of a neutralizing amount of a deoxidizing agent such as triethylamine, diisopropylethylamine, N,N-dimethylaniline, or tomethylmorpholine. Furthermore, the amine of general formula (nl) is N,O-bistrimethylsilyl acetate.
It can also be used after being silylated with a silylating agent such as cetamide.

In the reaction, 1 to 2 mol of the amine of general formula (III) is used per 1 mol of the compound of general formula (IV), and the reaction temperature and reaction time are 0 to 40°C and 0.5 to 5 hours.

When using the amine of the general formula (III) in which R6 is a hydrogen atom, the N-methylation reaction is further carried out to form the (tel) ammonio compound (It). Methyl reaction (1 to 30 moles of methyl iodide in the above organic solvent per 1 mole of the tertiary amine compound of general formula (II) or using excess methyl iodide in place of the solvent) (The degree of X0 reaction is -30 to 35°C, and the reaction is completed in several hours to several days.

The compound of the general formula (IV) in which the group Y is SO is also an amine of the general formula (l[I), as in the case of r1c, and 11. Ammonio compound (n) is produced by reaction with methyl Gf-ioC')
can also be manufactured.

Ammonio compounds in which the group Y is SO (IIN, Journal of Organic Chemist 1, No.
al of Organic Cbemistry)
35, p. 2430 (1974) etc., it is possible to reduce the sulf/1-noid group. That is, the ammonio compound (II) in which the group Y is SO can be reduced with iodine in an acetone solvent. Sodium chloride or potassium iodide σ
As an example, acetyl chloride is added dropwise at -40 to 0 DEG C. and reacted for 1 to 2 hours. In the reaction, 3.5 to 10 moles of iodide and 1.5 to 5 moles of acetyl chloride are used per 1 mole of compound (II,) in which group Y is SO.

Furthermore, the compound (I) of the present invention can be produced by removing a protecting group from a compound of general formula (II) in which the group Y is S, if necessary.

Depending on the type of protecting group, the method for removing the protecting group is as follows: Protective Groups in Organic Synthesis
The method can be carried out by appropriately selecting a commonly used method described in 1981 (1981, etc.). For example, protective groups such as l-lythyl group, polmyl group, t-butoxycarbonyl group, benzhydryl group, [-butyl group, and 2-methoxyethoxymethyl group can be removed using hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid, p - It can be made of an inorganic acid such as toluenesulfonic acid or an organic acid, and trifluoroacetic acid is particularly suitable.

Note that when trifluoroacetic acid is used as the acid, the reaction is accelerated by adding anisole.

Further, the reaction can be carried out in a solvent that does not participate in the reaction, such as water, methylene chloride, chloroform, ethylene chloride, benzene, etc., or in a mixed solvent thereof.

The reaction temperature and reaction time are appropriately selected depending on the chemical properties of the compound (l[) and the compound (I) of the present invention and the type of protecting group, and it is particularly recommended to carry out the reaction under mild conditions such as ice-cooling or heating. preferable.

In addition, the raw material compound (IV) of production method A can be produced as follows. The lid formula (I
V) (7) Compound C, benzhydryl 1 described in JP-A No. 50-76089 and JP-A No. 56-8G187
- Reacting amino-3-chloromethyl-3-cephem-4-carboxylate with a carboxylic acid of general formula (V) or a reactive derivative thereof (e.g., acid halide, mixed acid anhydride, active ester, etc.) can be manufactured.

Compounds of general formula (IV) in which the group Y is SO are those compounds in which the group Y is S
A compound of general formula ([V) which is
It can be produced by oxidizing it with an equimolar amount of tochloroperbenzoic acid while cooling with water.

The compound (IV) in which the group X is an iodine atom is a compound of the general formula (IV) in which the group X is a chlorine atom.
It can be produced by reacting with an iodide such as sodium iodide in a solvent such as , N-dimethylformamide, etc. at water cooling or at room temperature, and may be isolated or used as it is in the next reaction without nu.

Production method B The compound of general formula (II) and the compound of general formula (Vl) are mixed in water, acetone, dioxane, ace]-nitrile, tetrahydrofuran, methylene chloride, chloroborum, ethylene chloride, benzene, ethyl acetate, N, N- In a solvent that does not adversely affect the reaction such as dimethylformamide or dimethyl sulfoxide, or in a mixed solvent thereof, the general formula (V)
It can be produced by reacting carboxylic acids or reactive derivatives thereof (for example, acid halides, mixed acid anhydrides, active esters, etc.).

The reaction is carried out using the general formula (V) for 1 mol of the compound of the general formula (I).
1 to 1.5 mol of the reactive derivative are used, and the reaction temperature is -40 to 40°C.

When using an acid halide as the reactive derivative of general formula (V), a deoxidizing agent such as triethylamine, tomethylmorpholine, N,N-dimethylaniline, pyridine, etc. is required.

In the acid halide formation reaction, 1 to 1 mol of a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, or phosgene is added to 1 mole of norvonic acid (v). 10 moles preferably 1-1
．． 5 mol is used, the reaction temperature is -40 to 100°C, preferably -20 to 20°C, and the reaction time is completed in several hours.

In the mixed acid anhydride formation reaction, triethylamine, N-methylmorboline, N, N
- In the presence of 1 to 1.2 moles of a deoxidizing agent such as dimethylaniline or pyridine, 1 to 1.2 moles of a chlorocarbonate such as methyl chloroformate, ethyl chloropormate, or isobutyl chloroformate are used. , the reaction temperature is -40~
The temperature is 20°C, preferably -20~5°C, and the reaction time is 10~5°C.
The duration is 60 minutes.

In the active ester formation reaction, an N-hydroxy compound (e.g., tohydroxysuccinimide, 1-hydroxybenzotriazole, etc.) or a phenol compound (e.g., 4-21-0 phenol, 1 to 1.2 moles of 2,4-dinitrophenol, trichlorophenol, etc.) and 1 to 1.4 moles of N,N'-dicyclohexylcarbodiimide were used, the reaction temperature was -10 to 50°C, and the reaction time was is 30 to 120 minutes.

In addition, in the acylation reaction, when the carboxylic acid of general formula (V) is used in the form of a free acid, carbodiimides such as N,N'-dicyclohexylcarbodiimide, phosphorus oxychloride, N,N-dimethylformamide/oxychloride, etc. The compound of general formula (II) can also be produced in the presence of a condensing agent such as a phosphorus adduct. The production of the compound (I) of the present invention from the general formula (II) is the same as the production method A described above.

In addition, the raw material compound (Vl) of production method B can be produced as follows. The compound of the general formula (l) is a compound of the general formula (DI )
by reacting the amine of the general formula acid group, XO is an anion, p is an integer from O to 2),
R4 is a hydrogen atom or carboxyl protecting group, Y is S 5
O1acyl can be produced by using a compound represented by j representing an acyl group and then deacylating it.

Deacylation reactions are already known in the art, e.g.
Methods include iminochlorination using phosphorus pentachloride or the like, followed by iminoetherification and hydrolysis using methanol or the like, or a method using acylase.

Examples of the acyl group include phenylacetyl group, phenoxyacetyl group, and aminoadipyl group.

Next, the in vitro antibacterial activity of the compounds of the present invention against various bacteria was measured by the agar plate dilution method described below.

Hueller Hinton Bros.
Hueller 1linton
agar). This medium contained antibacterial agents at various concentrations, and after culturing at 31° C. for 16 hours, the minimum inhibition temperature (HfC: 埒/d) was measured. Cefataxime was used as a comparative compound. The results are shown in the table below.

The compound of the present invention showed strong antibacterial activity against sensitive and resistant Gram-negative bacteria and Gram-negative bacteria.

Therefore, the compounds of general formula (I), their non-toxic salts and their physiologically hydrolysable non-toxic esters can be antibacterial agents.

The compounds of the invention can be mixed with solid or liquid excipient carriers known in the art and used in the form of pharmaceutical formulations suitable for parenteral, oral or external administration. Pharmaceutical preparations include liquid preparations such as injections, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as soft blue and half-open forms. These preparations may also contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption enhancers, and surfactants, as required.

Examples of additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, and talc.

Furthermore, the compounds of the invention can be used as antibacterial agents in the treatment of bacterial infections in humans. The dosage varies depending on the condition of the patient, such as age and sex, but it is usually used in the range of 2 to 250 mg/H per day for adults, divided into 2 to 5 doses at 1 to SOmy/Ky per dose. is preferred.

Next, the present invention will be further explained with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 7-[2-(2-aminodeazol-4-yl)-2
-(3,4-dihydroxybenzyloxyimino)acetamide] Production of -3-(2-methyl-2-isoindolinio)methyl-3-ceph-1-4-carboxylate (syn isomer) <A) Benzhydryl 3-chloro Methyl-7-(2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino) ] -2-(2-
tritylaminodeazol-4-yl)acetamide)
-3-cephem-4-carboxylene 1 (syn isomer) 5.169 (4,59 mmol) in methylene chloride 100Ird1. 986 mg (5.7 mmol) of m-chloroperbenzoic acid was added in several portions under ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution is washed with saturated water and then with saturated saline. The organic layer is separated, dried over sodium sulfate, and then the solvent is distilled off under reduced pressure. Diethyl ether was added to the residue to obtain powdered benzhydryl 3-chloromethyl-7-(2-[3,4-di(2-
methoxyethoxymethoxy)benzyloxyimino)]
-2-(2-tritylaminothiazol-4-yl)
Acetamide)-3-cephem-4-carboxylene 1
-1-oxide (syn 1 isomer) 4.99 g (
(Yield 93.6%) was obtained and used for the next reaction without purification.

(B) 4.9 g (4.3 mmol) of the compound obtained in (A) above was dissolved in 100 ml of acetone, and after adding 1.37 (j (9.1 mmol)) of sodium iodide while cooling with water, the mixture was heated to room temperature. Stir for 1 hour at
00d, and then washed with saturated saline. After dehydrating and concentrating the extract, it was subjected to silica gel column chromatography (
Purified with ethyl acetate:hexane=1:2) and purified with benzhydryl 3-iodomethyl-7-(2-[3,4-di(2
-methoxyethoxymethoxy)benzyloxyimino)
]-2-(2-]-]lithiaminothiazol-4-ylacetamide)-3-cephem-4-carboxylene 1-(syn isomer) 3.6 g (yield 68%) are obtained.

NMR (DMSO-d6) δ: 3.22 (311,
s), 3.25 (311, s).

3, 36 (211, brs), 3.38 (411゜m
), 3.7(i (411,m), 4.45(211
, 8 Bq), 5.1 (211, brs).

5.25 (211, s), 5.9 (ill, cld.

J=4.5 and 7.5112).

6.81 (111, s), 7.05 (211, m).

7.2-7.6 (28+1), 8.13 (III, s
), 8.95 (III, d.

J=7.511z) (C) 1.249 (1 mmol) of the compound obtained in (B) above was dissolved in a solution of 20 Inl of methylene chloride and 20 m of N,N-dimethylformamide, and N-methylisomer was added at 0°C. Add 260++ g (2 mmol) of indoline,
Stir at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue to obtain 1.31 g of powder. 830 mg (5 mmol) of potassium iodide and 20 m of acetone were added to this powder, and 0.18 d (2.5 mmol) of acetyl chloride was added dropwise at -20°C.
Stir at 0°C for 4 hours. Add 100 methylene chloride to the reaction solution.
-, washed with 5% aqueous sodium pyrosulfite solution and saturated saline, and dehydrated with sodium sulfate. Solvent 1 was distilled off under reduced pressure, diethyl ether was added to the residue, and benzhydryl 7-(2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino)]-2-(2-1
-cutylaminothiazol-4-yl)at? t~amide)-3-(2-methyl-2-isoindolinio)methyl-3-cephem-4-carboxylate iodo salt (
Syn isomer) 700#1g (yield 52%) was obtained and used for the next reaction without purification.

(D) 700 rng (0
, 52 mmol) in methylene chloride 7- and anisole 1
．． 4 mL of trifluoroacetic acid and cooled to -15℃.
- and methylene chloride (7d) all at once, and at 0℃
The solvent is distilled off under reduced pressure and diethyl ether is added to the residue to obtain 400 mg of a crude product. This crude product is dissolved in 100 d of water, the insoluble matter is filtered off, and the For column chromatography, f=J, 30
% methanol aqueous solution and freeze-drying to obtain 70 mg (yield 22%) of the title compound.

mp 145°C (decomposition) IR (KBr) cM: 1540.1620.
1785N M R (CD30D ・020) δ: 3
．． 15 (311, S), 3.6 (211, ABq).

4.7-5.1 (711), 5.7 (111, d, J=
511z), 6.75(211,s), 6.79(II
I, s), 13.9 (111, s), 7.39 (4
11,s) Compounds of Examples 2 to 4 are obtained by the same method as in Example 1.

Example 2 7-[2-(2-aminothiazol-4-yl)-2-(3,4-dihydroxybenzyloxyimino)acetamide]-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem -4-carboxylate (syn isomer) mp 135°C (decomposition) IR (1 (Br) cM: 1540.1630
．． 1785NMR(CD300-D20)δ:
2.2 (411, brs), 3.0 (311, s).

3.5 (411, brs), 3.8 (211, brs)
, 4.35 (211, brs).

4.9 (111, s), 5.05 (311, brs),
6.75 (211, S).

6.82 (111, s), 6.9 (1 tl, s) Example 3 7-[2-(2-aminothiazol-4-yl)-
2-benzyloxyiminoacetamide] -3-(1
-Methyl-1-pyrrolidinio)methyl-3-cephem-
4-carboxylate (syn isomer) mp 155℃ (decomposition) rR (to Br ) to i (: 1535. 1620
．． 1775N M R (DMSO-d6) δ:
2.1(411,brs), 2.95(311,brs)
s), 3.6 (411, brs), 3.9 (211
,brs).

4.6 (211, brs), 4.85 (111, brs
), 4.9 (1tl, d.

J=7.5Hz), 5.15(211,S), 6.
75 (11I, S), 7.23 (211, brs)
, 7.35 (511, S), 9.65 (111, d
, J=7.5112) Example 4 7-[2-(2-aminothiazol-4-yl)-2-benzyloxyiminoacetamide] -3-(2-methyl-2-isoindolinio)methyl-3-t ? Femu 4-carboxylate (syn isomer) mp 135°C (decomposition) IR (KBr) cM: 1540.1620.
178ON MR (DMSO-d6) δ: 3.1
(311,brs), 3.5(211,brs), 4
．． 4 (2tl, brs), 4.85 (2tl, b
rs).

4, 95 (211, brs), 5.1 (ill, d
, J=4.511z), 5.15(2N,s), 5
．． 7 (111, dd, J=4.5 and 7.511z).

6.7 (1tl, s), 7.2 ~ 7.6 (1111,
m).

9.65 (111, d, J=7.511z) Example 5
7-[2-(2-7minothiazol-4-yl)-2-
(3,4-dihydroxybenzyloxyimino)acetamide]-,-3-(5゜6-hydroxy-2-methyl-2-isoindoliniA)methyl-3-cephem-4
- Preparation of carboxylate (syn isomer) (A> In Example 1 (B) (Rida benzhydryl 3
-iodomethyl-7-(2-[3,4-di(2-methoxy 1-xymethoxy)benzyloxyimino)]-2
-(2-tridelaminothiazol-4-yl)ace1
hairamide)-3-cephem-4-carboxylate 1
- Oxinide (syn isomer) 1.29 g (1,
04 mmol) was dissolved in N,N-dimethylbormamide 20, and 5,6-cyhydroxyisoindoline 23f was dissolved.
Add AF (1,56 mmol) and stir at air temperature for 3 hours. Then, the solvent was distilled off and diethyl ether was added to give powdered benzhydryl 3-(5,6-cyhydroxyisoindolin-2-yl)methyl-7-(
2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]]-2-(2-tritylaminethiazole-4
-yl)aledamide)-3-cephem-4-carboxylate 1-oxide (syn isomer> 1.1B
9 (yield 93.6%) was obtained and used in the next reaction without purification.

(B) 1.18 g of the above compound (A> is 14) (0,
94 mmol) was dissolved in 12 m of methyl iodide and stirred for 17 hours at heat temperature. Then diethyl ether is added to obtain a powder of 1.32 (j).
．． 66 g (10 mmol) and 20 d of acetone were added thereto, and 0.36 d (5 mmol) of acetyl chloride was added dropwise at -20°C, followed by stirring at -10°C for 4 hours. Add 100 methylene chloride to the reaction solution, wash with 5% aqueous sodium pyrosulfite solution and saturated saline, and dehydrate over sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and benzhydryl 3-(5,6-dihydroxy-2-methyl-2-isoindolinio)methyl-7
-(2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino)]-2-(2-1~lythylaminothiazol-4-yl)at? +・amide) −3−
Cephem-4-carboxylate salt (syn isomer>
650 m9 (50% yield) of 11 was used in the next reaction without purification.

(C) Compound 65h+y (6
41 mmol) in methylene chloride 7d and anisole 1.
4mek: Dissolve and cool to -15°C. To this solution was added at once a mixture of 14 d of trifluoroacetic acid and 7 d of methylene chloride, which had been previously cooled at -15°C.
Stir for 1 hour at °C. The solvent was distilled off under reduced pressure and diethyl ether was added to the residue to obtain 400rn of the crude product.
get g. This crude product was dissolved in 100% water, filtered to remove insoluble matter, and purified by reverse phase column chromatography (25% methanol/water) to yield 90mg of the title compound (
A yield of 28.6%) is obtained.

mp 135℃ (decomposition) IR (Br) citl: 1540, 162
0. 1785NMR (D20) δ: 3.12 (3
11,brs), 3.7(211,^Bq).

5, 05 (211, s), 5.2 (IH, d, J=4.
511z), 5.75 (III, d, J=4.511
z), 6.7 to 6, 8 (511), 6. 9 (II
I, s) Reference Example 1 Production of 5,6-simethoxy-2-(p)-tolylsulfonylisoindoline 1.89 g (11 mmol) of p-toluenesulfonamide was added to N,N-dimethylformamide 20-, and the mixture was heated to room temperature. 3.3 g (24 g) of potassium carbonate crushed while stirring with
2.09 mmol) and 2.09 mmol of 4.5-bis-(chloromethyl)veratrol (8.5 mmol) were added. After stirring at room temperature for 20 hours, 40% of water was added and extracted with methylene chloride. The extract was washed with water, then dehydrated with anhydrous sodium hydroxide solution, and the solvent was distilled off under reduced pressure. The crystal residue was washed with diisopropyl ether to obtain 2.7 g of the title compound (yield: 95
．． 2%).

Re-crystallized from N,N-dimethylformamide, melting point 16
7-168°C was obtained.

IRν (Br): 525, 550,
605, 670, 810.

1110, 1160, 1340, 1460, 1
519c eyebrow N M R (CDCl2) δ: 2.
38 (311, s), 3.82 (611, s).

4, 56 (411, S), 6.65 (211, S).

7, 29 (211, d, J = 6.211z).

7, 49 (211, d, J = 6. 211z) Reference Example 2 Production of 5,6-dihydroxyisoindoline/embodied water M salt 5,6-Simethoxy 2-(D)-tolylsulfonylisoindoline 60 g ( o.18 mol) to 41% hydrogen bromide 13607. Phenol 45InI! and 60 me of propimenic acid were added, and the mixture was refluxed for 4 hours with vigorous stirring in a nitrogen stream. The reaction solution was dried under reduced pressure, and the residue was 47% hydrogen bromide W! 1120In1 was added, and the mixture was refluxed again for 3 hours in a nitrogen stream. The reaction solution was soaked in cold water, 300 d of water and 300 d of chloroborum were added, and the aqueous layer was separated and treated with activated carbon. The aqueous layer was dried under reduced pressure, and the crystalline residue was washed with ether/ethanol to obtain 25% of the title compound.
．． 62 g (yield 61.4%) was obtained.

Melting point 251℃ (decomposition) IRν (Br): 1290.1330.141
0.1450.1460°1510, 1610cji NMR(0830-c+6)δ: 4.40(
411, brs).

6.85 (211,s), 8.80 (211,b
), 9.55 (2H, b) Reference Example 3 Production of 5.6-cyhydroxy-2-methylisoindoline/hydrobromide 5.6-cyhydroxyisoindoline/hydrobromide 1
5.39 g (66 mmol) and sodium formate4.
48 g (66 mmol) in 50% formic acid aqueous solution 100-
After dissolving in water, add 17 m of 37% Polmarine water and
It was heated at ℃ for 4 hours. After the reaction solution was concentrated to dryness under reduced pressure, 200 m of 23% hydrobromic acid was added to the residue and treated with activated carbon. The solution was dried again under reduced pressure, and the crystalline residue was recrystallized from water to obtain 11.74 g (yield: 12.3%) of the title compound.

Melting point 205°C (decomposition) [R1/(K8r): 635. 855
．． 1175. 72H, 1320° 1445, 146
0.1505.1605cfflN M R(OH3O
-c+6) δ: 2.99 (311, S), 4.
1-4.8 (411,brd), 6.78(211,s
).

9.0 (III, b).

10, 83 (ill, brs) Reference Example 4 Production of 3.4-di(2-methoxyethoxymethoxy)benzaldehyde 6.9 g (50
26 mmol) of diimpropylethylamine was dissolved in 140 d of methylene chloride. Add IId (150 mmol, 2-methoxyethoxymethyl chloride 1 at 0°C.
7 m (150 mmol) is added dropwise. The reaction solution was heated to 0°C.
After stirring for 1 hour, the mixture was washed successively with 50ml of water, 50ml of 0.5N aqueous sodium hydroxide solution, and saturated saline.

After dehydrating the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 15.7 g (yield: 100%) of the title compound.

NMR(CDCl2) δ: 3.40(6
11,s), 3.60 (411,m).

3, 89 (41f, m), 5.39 (211, S)
, 5.42 (211, S), 7.30 (111, d
, J=711z), 7.55(ill, dd, J=1
and 7112).

7.70 (III, d, J=111z), 9.86 (
fil, s) Reference Example 5 3. Production of 4-di(2-methoxyethoxymethoxy)benzyl alcohol 3. 15.7 g (50 mmol) of 4-di(2-methoxyethoxymethoxy)benzaldehyde was dissolved in methanol 30
Liumium borohydride is dissolved in 0d and heated under cooling.
After adding 89 g (50 mmol) in several portions,
Stir for 30 minutes. Add 2.86- of acetic acid to the reaction solution and add 1
After stirring for 0 minutes, the solvent was distilled off under reduced pressure.

Dissolve the residue in 300 ml of ethyl acetate, wash the extract with saturated brine, dehydrate over anhydrous sulfuric acid, and distill off the solvent to obtain the title compound 15.09 (yield 94.8%). .

NMR(CDCl2)δ:
3.5 (III, s), 3.35 (611, s).

3,55 (411, m), 3.85 (411, m),
4.55 (211,S), 5.26 (411,S)
, 6.9 (III, dd, J=1 and 711z)
, 7.13(III, d, J=i'1lz), 7
．． (3(fll, d, J=, l11z) Reference Example 6 Production of 3.4-di(2-methoxyethoxymethoxy)benzyl chloride 3.4-di(2-methoxyethoxymethoxy)benzyl alcohol 12.9 g (40 , 8 mmol) and 16.1 g (203.7 mmol) of pyridine in methylene chloride 2
Add 30d of thionyl chloride and add 5.8ml of thionyl chloride (8ml) under water cooling.
80 ml of methylene chloride solution containing 1.6 mmol) are added dropwise and stirred for 2 hours. The reaction solution was washed successively with water, saturated sodium chloride water, and saturated brine, and then dehydrated with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 11.5 g (yield: 83.4%) of the title compound.

NMR(DH3O-d6)δ: 3.3(6H,
s), 3.5 (411, m).

3.8 (411, m), 4.73 (211, s), 5.
3 (411, s), 7.1 to 7.2 (311, m) Reference Example 7 2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino)]-2-(2-tritylamino Preparation of ethyl 2-hydroxyimino-2-(2-tritylaminothiazol-4-yl) acetate (syn isomer) 6 g (13.2 mmol) of N .

Dissolved in 120d of N-dimethylbormamide and heated at 0°C for 5
Add 761 mg (15.9 mmol) of 0% oily hydride and stir for 15 minutes. 3.4 in the solution
-Add 4.42 g (13.2 mmol) of di(2-methoxyethoxymethoxychloride,
Stir at room temperature for 17 hours. The solvent was distilled off under reduced pressure, and 150 ml of ethyl acetate was added to the residue. Saturate the solution with 80 In of soda water! , and 80 rIdl of saturated saline, anhydrous 111! ! Dehydrate with I-lium acid. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 7.5 g (yield: 75.1%) of the title compound.

NMR (0830-d6)δ: 1.13 (311
, t), 3.25 (611, s).

3, 5 (411, m), 3.75 (411, m), 4.
0 (211, q), 5.15 (211, S), 6
．． 95 (III, S), 7, 08 (III, s)
, 7. 2-7.4 (1711, m), 8.76 (1
11,s) Reference Example 8 Production of 2-[3.4-di(2-methoxyethoxymethoxy)benzyloxy]-2-(2-tritylaminothiazol-4-yl)acetic acid (syn isomer) 2- [ 3.4-di(2-methoxyethoxymethoxy)
5.27 g (6.97 mmol) of ethyl benzyloxyimino]-2-(2-1-lotylaminothiazol-4-yl) acetate (syn isomer) was added with 100 d of ethanol and 3.2 N aqueous sodium hydroxide solution. 5-
was added and subjected to distant flow for 1 hour. Furthermore, 0.4-liter of 2N aqueous sodium hydroxide solution was added, and the mixture was refluxed for 30 minutes. The solvent is distilled off under reduced pressure to obtain a crystalline residue. After dissolving the crystal residue in tetrahydrofuran/water (1:1) 100, 1N
Adjust the pH to 4.0 with hydrochloric acid and extract with 100 d of ethyl acetate (3 times). After washing the extract with saturated brine, it was dehydrated and the solvent was distilled off under reduced pressure to obtain 5.0 g of the title compound (yield 98.6%).
get. Use in the next reaction without purification.

Reference Example 9 Benzhydryl 3-chloromethyl-7-(2-[3
．． 4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(2-to1notylaminothiazol-4-yl)acetamide 1:)-3-cephem-4-carpoxylate (synrI) ) Preparation of 2- [3.4-di(2-methoxy-1hexymethoxy)benzyloxyimino] -2- (2-tritylaminethiazol-4-yl) vinegar! (Syn isomer) 3
．． 3g (4.34 mmol) and benzhydryl 7-
Amino-3-chloromethyl-3-cephem-4-carpoxylate-1-1.859 (4.46 mmol) is dissolved in 100 methylene chloride. N.

After adding 2.54 mal (20 mmol) of N-dimethylaniline and cooling to 0°C, 0.54 mal (20 mmol) of N-dimethylaniline was added.
4rd (4.34 mmol) is added dropwise. After stirring at room temperature for 1 hour, it was washed successively with 0.1N hydrochloric acid aqueous solution and saturated saline, dehydrated, and condensed.
- The title compound was purified by 4.27 (j (yield: 80
．． 5%).

NMR(CDCl2) δ: 3.2(31
1, s), 3.23 (311, s).

3.45 (611, m), 3.8 (411, m),
4.33 (211, s), 4. ! J8 (ltl, d, J
=4.511z), 5.25(611,s), 5.8
6 (III, dd.

J=4.5 and 911z), 6.7(ill,s), 6
．． 9 to 7.5 (301t, m) Effects of the invention The compound of the present invention is a new compound that has not been described in any literature, and has strong antibacterial activity against sensitive and resistant Gram-negative bacteria and Gram-negative bacteria, so it can be used as an antibacterial agent. This is what is expected.

Patent applicant Banyu Pharmaceutical Co., Ltd. Procedural amendment (voluntary) March 27, 1988 1, Case indication 1985 Patent 1Q1 No. 29346
No. 6 No. 2, Title of the invention 3, t + li correct 廿4, Number of inventions increased by amendment 05, Subject of amendment "Claims" column of the specification and "Detailed explanation of the invention" Column 6, Contents of the amendment As per the attached amendment statement aI 7, Attached document list correction specification 1, Title of the invention New Cef 10 Sporin derivative 2, Claims (1) General formula (I) (However, R1 is a hydroxyl group, p is an integer from 0 to 2)
, R2 is a hydroxyl group, and q is an integer of O to 2," a non-toxic salt or a physiologically hydrolyzable non-toxic ester thereof.

(2) General formula ([V) (wherein, R3 is an optionally protected hydroxyl group, R4 is a hydrogen atom or a carboxyl protecting group, R5 is a hydrogen atom or an amino group, X is a halogen atom or a leaving group, Y is S or So, C1 is an integer of 0 to 2), or a salt thereof, is added to a compound represented by the general formula (I[l) (wherein, R1 is water lS
! %, R6 is a hydrogen atom or a methyl group, and p is an integer from O to 2) to form the general formula (I
I) Acid group, XO is an anion, p is. (indicates an integer from 2 to 2),
R3, R4, R5, Y and q have the above-mentioned meanings], and after optionally methylating and/or reducing the compound, the protective group is removed if necessary. General formula (Il (where R1 is a hydroxyl group and ρ is an integer from 0 to 2)
, R2 is a hydroxyl group, q is not an integer from O to 2, and a method for producing a nontoxic salt or physiologically hydrolyzable nontoxic ester thereof.

(3) General formula (VI) acid group, xO is an anion, ρ is an integer from O to 2),
R4 is a hydrogen atom or carboxyl protecting group, Y is S or S
A compound represented by the general formula (V
) (In the formula, R3 is an optionally protected hydroxyl group, R5 is a hydrogen atom or an amino protecting group, and q is an integer from O to 2)
Acylated with a compound represented by or a reactive derivative thereof to form a compound represented by general formula (I) (wherein Q-1R3, R4, R5, Y and q have the above-mentioned meanings) and , the compound is methylated and/or reduced if necessary, and then the protecting group is removed if necessary. (However, R1 is a hydroxyl group, and p is an integer of O to 2. )
, R2 is a hydroxyl group, and q is an integer of O to 2], a nontoxic salt thereof, or a method for producing a physiologically hydrolyzable nontoxic ester thereof.

(4) General formula (1) (wherein, R1 is a hydroxyl group, and p is an integer from O to 2)
, R2 is a hydroxyl group, and q is an integer from O to 2. An antibacterial agent containing as an active ingredient a compound represented by 1, a nontoxic salt thereof, or a physiologically hydrolyzable nontoxic ester thereof.

DETAILED DESCRIPTION OF THE INVENTION L1 The present invention relates to a novel Cef-10 sporin derivative, a method for producing the same, and an antibacterial agent containing the compound as an active ingredient.

Prior Art Conventionally, compounds having both a 2-(2-aminothiazol-4-yl)-2-rllllll ratio shiiminoacetamide group in the 7-position side chain of the cephalosporin nucleus and an ammoniomethyl group in the 3-position are extremely rare. Many of the techniques synthesized and described include, for example, Japanese Patent Application Laid-open No. 54-154786.
No. 55-59196, No. 57-192394, No. 58-174387, No. 58-198490,
Publications No. 59-219292 and No. 60-97983 are listed, and they are related to Gram-positive bacteria and Pseudomonas aeruginosa.
It has been suggested that it also exhibits activity against cephalosporin-resistant Gram-resistant bacteria, including P. ossa), and has excellent antibacterial activity and a broad antibacterial spectrum.

1. β-lactam antibiotics show selective toxicity only to bacteria,
Because it has no effect on animal cells, it is a highly useful drug that is widely used in the treatment of bacterial infections as an antibiotic with few side effects.

However, in recent years, the frequency of isolation of resistant Gram-positive bacteria and resistant non-glucose-fermenting Durham-negative bacilli has tended to increase, and there is a desire to enhance antibacterial activity against these bacteria.

Means for Solving the Problems The present invention aims to provide a novel cephalosporin derivative having excellent antibacterial activity, with an ammoniomethyl group at the 3-position and a 2-(2-aminothiazole- As a result of intensive research on novel cephalosporin derivatives having a -2-(substituted benzyloxyimino)acetamide group, we discovered that they have strong antibacterial activity against Gram-positive bacteria and Gram-positive bacteria, and have thus developed the present invention. completed.

The present invention is based on the general formula (I) (wherein, R1 is a hydroxyl group, and P is an integer from O to 2).
, R2 is a hydroxyl group, and q is an integer of O to 2], its nontoxic salt or physiologically hydratable nontoxic ester, its production method, and an antibacterial agent containing the compound as an active ingredient. .

Next, various symbols and terms described in this specification will be explained.

Examples of the group Q of the compound of general formula (I) include a pyrrolidinio group and an isoindolinio group in which the hydroxyl group may be @-substituted. One or two hydroxyl groups can be substituted on the isoindoline nucleus, but the substitution positions are not particularly limited. Specific examples of group Q include 1
-Methyl-1-pyrrolidinio group, 2-methyl-2-isoindolinio group, 2-methyl-5,6-cyhydroxy-2-isoindolinio group, and the like.

Furthermore, the benzene ring of the benzyloxyimino group of general formula (I) may be substituted with one or two hydroxyl groups. However, the substitution position is not particularly limited. Specific examples of the substituted benzyloxyimino group include a benzyloxyimino group and a 3,4-dihydroxybenzyloxyimino group.

Furthermore, although there are generally syn-isomers and anti-isomers in the configuration of the oximino group, the present invention includes both syn-isomers and anti-isomers. In particular, the syn isomer has excellent antibacterial activity.

Examples of the compounds of the present invention include the compounds shown below.

7-[2-(2-aminothiazol-4-yl)-2-
benzyloxyiminoacetamide]-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate 7-[2-(2-aminothiazol-4-yl)-2-
benzyloxyiminoacetamide]-3-(2-methyl-2-isoindolinio)methyl-3-cephem-4
-Rupoxylate 7-[2-(2-aminothiazol-4-yl)-2-
benzyloxyiminoacetamide]-3-(5,6-
cyhydroxy-2-methyl-2-isoindolinio)methyl-3-cephem-4-carboxylate 7-[2-
(2-aminothiazol-4-yl)-2-(3,4-
dihydroxybenzyloxyimino)acetamide]-
3-(1-Methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate 7-[2-(2-aminothiazol-4-yl)-2-
(3,4-dihydroxybenzyloxyimino)acetamide]-3-(2-methyl-2-isoindolinio)
Methyl-3-cephem-4-carboxylate 7-[2
-(2-aminothiazol-4-yl)-2-(3,4
-dihydroxybenzyloxyimino)acetamide]
-3-(5,6-cyhydroxy-2-methyl-2-isoindolinio)methyl-3-cephem-4-carboxylate The compound of general formula (I) can be hydrolyzed into its non-toxic salt or physiologically by a conventional method. It can be made into a non-toxic ester.

Examples of non-toxic salts of the compound of general formula (I) include conventional pharmaceutically acceptable salts, such as metal salts of sodium, potassium, calcium, magnesium, aluminum, N,N'-dibenzyl J ethylene, etc. Organic amine salts such as diamines and protylene, inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, etc., acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid. Organic acid salts such as acids, methanesulfonic acid, isethionic acid, p
Examples include sulfonic acid salts such as -h luenesulfonic acid, amino acid salts such as glutamic acid, aspartic acid, lysine, and arginine.

In addition, the non-toxic ester of general formula (I) means a conventional pharmaceutically acceptable ester in its carboxyl group, such as an alkanoyloxymethyl group such as acetoxy, methyl group, pivaloyloxymethyl group, etc. , alkoxycarbonyloxyalkyl groups such as 1-(ethoxycarbonyloxy)ethyl groups, phthalidyl groups, 5-methyl-
5-substituted-2-oxo-1,3-dioxo-4 such as 2-oxo-1,3-dioxo-4-ylmethyl group
-ylmethyl group and the like.

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

The compound of general formula (I) can be produced by either production method A or B shown below.

Production method A General formula (1, V) (wherein, R3 is a hydroxyl group that may be protected, R4 is a hydrogen atom or a carboxyl protecting group, R5 is a hydrogen atom or an amine protecting group, and X is a halogen atom or a leaving group) , Y is S or So, and q is an integer from O to 2), or a salt thereof, is added to the compound represented by the general formula (III), where R1 is a hydroxyl group, RG is a hydrogen atom or a methyl group, and p is a General formula (II) can be produced by reacting a compound represented by (representing an integer from 0 to 2).

In general formula (IV), A halogen atom such as iodine or an acetoxy group is preferred.

Examples of amines represented by the general formula ([[) include pyrrolidine, isoindoline, 5,6-dihydroxyisoindoline, 1-methylpyrrolidine, 2-methylisoindoline, 5,6-cyhydroxy-2-methylisoindoline, etc. can be mentioned.

Production method B General formula (Vl) acid group, Xθ is an anion, p is an integer from O to 2),
R4 is a hydrogen atom or carboxyl protecting group, Y is S or S
A compound represented by the general formula (V
) (In the formula, R3 is an optionally protected hydroxyl group, R5 is a hydrogen atom or an amino protecting group, and q is an integer from O to 2)
Acylation with a compound represented by or a reactive derivative thereof to form a compound of the general formula (I[) (wherein, Q', R3, R
The compound of the present invention ( I) can be produced.

As the protecting groups for the carboxyl group, amino group and hydroxyl group in the above general formula, protecting groups commonly used in the field of β-lactam synthesis can be appropriately selected and used.

As the carboxyl group 51, t-butyl group, 2,
2.2-trichloroethyl group, acetoxymethyl group, propionyloxyethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group, 1-propionyloxyethyl group, 1-(ethoxycarbonyloxy)ethyl group,
Phthalidyl group, benzyl group, 4-methoxybenzyl! ,
3.4-dimethoxybenzyl group, 4-diI-lovenzyl group, benzhydryl group, bis(4-methoxyphenyl)
Methyl group, 5-methyl-2-oxo-1,3-dioxo-4-yl-methyl group, trimethylsilyl group, t-
Examples include butyldimethylsilyl group, and particularly preferred are benzhydryl group, t-butyl group, and silyl group.

As protective groups for amine groups, trityl group, formyl group,
Examples thereof include a chloroacetyl group, a trifluoroacetyl group, a tobutoxycarbonyl group, a trimethylsilyl group, and a t-butyldimethylsilyl group.

Protecting groups for hydroxyl groups include 2-methoxyethoxymethyl group, methyl-oxymethyl group, methylthiomethyl group, tetrahydropyranyl group, phenacyl group, isopropyl group, thi-butyl group, benzyl group, 4-nitrobenzyl group, acetyl group. group, 2,2.2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, acetonide, trimethylsilyl group, t-butyldimethylsilyl group, and the like.

Next, the manufacturing method A and the manufacturing method B of the compound (I) of the present invention will be explained in detail.

Production method A The reaction between the compound of general formula (IV) and the amine of general formula ([ The reaction can be carried out in an organic solvent such as sulfoxide or a mixed solvent thereof. The amine of general formula (I[I) is a hydrochloride,
Amine salts such as hydrobromide, sulfate, nitrate, acetate, etc. may also be used.

In this case, the reaction was performed using moderate doses of triethylamine, diisopropylethylamine, N,N-dimethylaniline, N-
It is carried out in the presence of a deoxidizing agent such as methylmorpholine. The amine of general formula (II[) can also be used after being silylated with a silylating agent such as N,0-bis(trimethylsilyl)acetamide.

In the reaction, 1 to 2 moles of the amine of the general formula (II) are used per 1 mole of the compound of the general formula (IV), and the reaction temperature and reaction time are 0 to 40°C and 0.5 to 5 hours. .

When using the amine of the general formula (I[I) in which R6 is a hydrogen atom, an N-methylation reaction is further performed to obtain the ammonio compound (II). The methylation reaction is carried out in the above organic solvent with respect to 1 mole of the tertiary amine compound of general formula (n),
1 to 30 moles of methyl iodide or excess methyl iodide may be used in place of the solvent. Reaction temperature is -30~35℃
The reaction is completed in 10 to 20 hours.

The compound of the general formula (IV) in which the group Y is SO can also be reacted with the amine of the general formula (III), if necessary, with methyl iodide, to produce the ammonio compound (II) in the same manner as described above.

Ammonio compounds (n) in which the group Y is So are listed in the Journal of Organic Chemistry.
of Organic Chemistry) 35
By the method described in Vol., p. 2430 (1974), etc.
Sulfoxide groups can be reduced. That is, the ammonio compound (II) in which the group Y is SO is prepared by -4 in the presence of sodium iodide or potassium iodide in an acetone solvent.
An example of this is reduction by dropping acetyl chloride at 0 to 0°C and reacting for 1 to 4 hours. The reaction is for a compound where the group Y is S0 (■)
3.5 to 10 mol of iodide and 1.5 to 5 mol of aredel chloride are used per 1 mol.

Furthermore, the compound (I) of the present invention can be produced by removing a protecting group from a compound of general formula (II) in which the group Y is S, if necessary.

The method for removing the protective group depends on the type of the protective group.Protective Groups in Organic Synthesis
The method can be suitably selected from the commonly used methods described in 1981 and the like.

For example, protective groups such as tridel group, polmyl group, t-butoxycarbonyl group, benzhydryl group, t-butyl group, and 2-methoxyethoxymethyl group can be removed using hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-1 - It can be made of free acids such as luenesulfonic acid or talic acids, and trifluoroacetic acid is particularly suitable.

Note that when trifluoroacetic acid is used as the acid, the reaction is accelerated by adding anisole.

Further, the reaction can be carried out in a solvent that does not participate in the reaction, such as water, methylene chloride, chloroform, ethylene chloride, benzene, etc., or in a mixed solvent thereof.

The reaction temperature and reaction time are appropriately selected depending on the chemical properties of compound (II) and the compound (I) of the present invention and the type of protecting group, and it is particularly preferable to carry out the reaction under mild conditions such as ice cooling or heating. .

In addition, the raw material compound (IV) for the production method can be produced as follows. General formula (IV) in which the group Y is S
(7) The compound is disclosed in JP-A No. 50-76089, JP-A No. 5
The benzhydryl 7-amino-3-dimethyl-3-cephem-4-carboxylate 1-described in Publication No. 6-86187 is treated with a compound of general formula (V) or a reactive derivative thereof (e.g., an acid halide, a mixed acid anhydride). active esters, etc.) can be produced without reacting.

Compounds of bifurcated formula (IV) in which the group Y is SO are compounds in which the group Y is S
It can be produced by oxidizing the compound of general formula (IV) with an equimolar amount of tochloroperbenzoic acid in a solvent that does not participate in the reaction, such as methylene chloride, ethylene chloride, or chloroborm, under cooling with water.

The compound (IV) in which the group X is an iodine atom is a compound of the general formula (IV) in which the group
It can be produced by reacting with an iodide such as sodium iodide in a solvent such as N-dimethylformamide at water cooling or room temperature, and may be isolated or used as it is in the next reaction without isolation.

Production method B The compound of general formula (n) is prepared by mixing the compound of general formula (Vl) with water,
In a solvent that does not adversely affect the reaction, such as ace1-one, dioxane, ace1-nitrile, tetrahydrofuran, methylene chloride, chloroform, ethylene chloride, benzene, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, etc. Or in a mixed solvent thereof, general formula (V)
or its reactive derivatives (eg, acid halides, mixed acid anhydrides, active esters, etc.).

The reaction is carried out using the general formula (V) for 1 mol of the compound of the general formula (I).
1 to 1.5 mol of the compound or its reactive derivative is used, and the reaction temperature is -40 to 40°C.

When an acid halide is used as the reactive derivative of general formula (V), it is preferably carried out in the presence of a deoxidizing agent such as triethylamine, N-methylmorpholine, N,N-dimethylaniline, or pyridine.

In the acid halide formation reaction, 1 to 10 halogenating agents such as thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, phosgene, etc. are added to 1 mole of compound (v). The mole used is preferably 1 to 1.5 mol, the reaction temperature is -40 to 100°C, preferably -20 to 20°C, and the reaction time is completed in 10 to 120 minutes.

In the mixed acid anhydride formation reaction, for 1 mol of compound (V),
In the presence of 1 to 1.2 moles of a deoxidizing agent such as triethylamine, N-methylmorne, N,N-dimethylaniline, and pyridine, 1 to 1 to 1.2 moles of a chlorocarbonate such as methyl chloropormate, ethyl chloroformate, and isobutyl chloroformate 1.2 mol is used, the reaction temperature is -40-20°C, preferably -20-5°C, and the reaction time is 10-60 minutes.

In the active ester formation reaction, for 1 mole of compound (■),
N-hydroxy compounds (e.g., N-hydroxysuccinimide, 1-hydroxybenzo-1-lyazole, etc.) or phenolic compounds (e.g., 4-21-phenol, 2,4-dinitrophenol, 1-helichlorophenol, etc.) 1 to 1.2 mol and 1 to 1.4 mol of N,N'-dicyclohexylcarbodiimide are used, the reaction temperature is -10 to 50°C, and the reaction time is 30 to 120 minutes.

In the acylation reaction, when the compound of general formula (V) is used in the form of a free acid, N,N'-dicyclohexylcarbodiimides, phosphorus oxychloride, N,N-dimethylformamide,
The compound of general formula (II) can also be produced in the presence of a condensing agent such as a phosphorus oxychloride adduct.

From the general formula <Il), @lt6 of the compound (I) of the present invention is the same as in the production method A above.

Note that the raw material compound F) of production method B can be produced as follows. The compound of the general formula (l) is
7-acylamino-3-halomethyl-3-cephem-4-carboxylate derivatives described in 72590, 58-154588 Tan, etc., the general formula (III
) with the general formula acid group, XO is an anion, p is an integer from O to 2),
R4 is a hydrogen atom or carboxyl protecting group, Y is S or S
o, acyl can be produced by using a compound represented by 1 representing an acyl group and then deacylating it.

Deacylation reactions are already known in the art.

For example, there is a method consisting of iminochlorination with phosphorus pentachloride or the like, followed by iminochlorination with methanol or the like, and hydrolysis, or a method using acylase.

Examples of the acyl group include a phenylacetyl group, a phenoxyacetyl group, and an aminoadipyl group.

Next, the in vitro antibacterial activity of the compounds of the present invention against various bacteria was measured by the agar plate dilution method described below.

Mi] − ”) − L: Nton broth (Huc
One loopful of each test starter strain (inoculation opening: 106 CFU) cultured overnight in
/Kai) Miko, -Ra Hinton Aka- (Huell)
Erllington Aquar). This medium contains antibacterial agents at various concentrations, and after culturing at 37'C for 16 hours, the minimum inhibitory concentration (HIC: l
J! g/Inl) was measured. Cefotaxime was used as a comparative compound. The results are shown in the table below.

The compound of the present invention showed strong antibacterial activity against sensitive and resistant Gram-negative bacteria and Gram-negative bacteria.

Accordingly, compounds of general formula (I), non-toxic salts and physiologically hydrolyzable non-toxic esters are useful as antimicrobial agents.

The compounds of the present invention can be mixed with solid or liquid flocculent carriers known in the art and used in the form of pharmaceutical formulations suitable for parenteral, oral or external administration. Pharmaceutical preparations include injections, liquid preparations such as syrups and emulsions, solid preparations such as tablets, capsules, and granules, and external preparations such as ointments and half-open tablets. These preparations may also contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption enhancers, surfactants, etc., if necessary.

Examples of additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, and talc.

Furthermore, the compounds of the invention can be used as antibacterial agents in the treatment of bacterial infections in humans. The dosage varies depending on the patient's age, gender, etc., but it is usually 1 dose per day.
Used in the range of ~100 mg 7 Kg, 5 per dose
It is preferable to administer in 2 to 4 doses at ~30 Rg/Kg.

Next, the present invention will be further explained with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Participant Example 1 7-[2-(2-aminothiazol-4-yl)-2
-(3,4-dihydroxybenzyloxyimino)acetamide]-3-(2-methyl-2-isoindolinio)methyl-3-cephem-4-carboxylate (syn isomer) production (A) Benzhydryl 3-chloromethyl -7-(2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino)] -2-(2-tritylaminothiazol-4-yl)acetamide)-
3-cephem-4-carboxylate (syn isomer>
5.16 g (4.59 mmol) of methylene chloride
00d and cooled with water to m-black perbenzoin M98.
After adding h+y (5.7 mmol) in several portions,
Stir for 30 minutes. The reaction solution is washed with saturated heavy-duty water and then with saturated brine. The organic layer is separated, dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. Add diethyl ether to the residue to obtain powdered benzhydryl 3-
Chloromethyl-7-(2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2=(2
-tritylaminothiazol-4-yl)acetamide)-3-cephem-4-carboxylate 1-oxide (syn isomer) 4.99 ff (yield 93.6
%) and used in the next reaction without purification.

(B) Compound obtained in (A) above 4.99 (4,3
(mmol) was dissolved in 100 d of acetic acid, 1.379 mmol (9.1 mmol) of sodium iodide was added while cooling with water, and the mixture was stirred at room temperature for 1 hour. Add 5 ethyl acetate to the reaction solution.
00d, 5% bisulfite 1 helium aqueous solution 200
d. Then wash with saturated saline. After dehydrating and concentrating the extract, it was subjected to silica gel column chromatography (Wa
kO (lel C-300, ethyl acetate:hexane = 1
: 2>, benzhydryl 3-iodomethyl-7
-(2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino] -2-(2-tritylaminothiazol-4-yl)ace1-amide)-3-cephem-4-carboxylate 1 - 3.6 g (yield 68%) of oxide (syn isomer) is weighed 1 q.

NMR(D)IsO-d6)δ: 3.22(3
11, s), 3.25 (311, s).

3, 36 (2H, brs), 3.38 (4H.

m), 3.76 (411', m), 4.45 (21
1, ABQ), 5.1 (211, brs).

5.25 (211, s), 5.9 (111, dd.

J.4.5 and 7.511z).

6.81 (111, S), 7.05 (2+1.m).

7.2-7.6 (2811, m), 8.73 (ill,
s), 8.95 (III, d.

J=7.511z) (C) The above (B) r: ln compound 1.24'? (
1 mmol) was dissolved in a solution of 20 d of methylene chloride and 20 d of N,N-dimethylformamide, 260 μm (2 mmol) of N-methylisoindoline was added at O'C, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue to obtain 1.31 grams of powder. To this powder, 830q (5 mmol) of potassium iodide and 1 acetate were added.
7 cetyl chloride was added at -20°C.
After dropping 18 d (2.5 mmol), the temperature was further increased to -10°C.
Stir for 4 hours. Add 100 Id of methylene chloride to the reaction solution.
, washed with 5% aqueous sodium pyrosulfite solution and saturated brine, and dehydrated with anhydrous sodium sulfate. The solvent was distilled off from the reaction solution under reduced pressure, diethyl ether was added to the residue, and benzhydryl 7-(2-[3,4-di(2
-methoxyethoxymethoxy)benzyloxyimino]
-2-(2-tritylaminothiazol-4-yl)acetamide)-3-(2-methyl-2-isoindolinio)methyl-3-cephem-4-carboxylate iodide (syn isomer) 700 ~ (yield ’$52%),
Use in the next reaction without purification.

(D) Compound 700 (0,52
7 m of methylene chloride and 1.4 d of anisole
and cooled to -15°C. Add 15% to this solution in advance.
A mixed solution of 14M1 of trifluoroacetic acid and 7d of methylene chloride, which had been cooled to 0°C, was added all at once, and the mixture was stirred at 0°C for 1 hour. The solvent is distilled off under reduced pressure and diethyl ether is added to the residue to obtain a crude product 400Irtg.

Dissolve this crude product in 100 ml of water, filter out insoluble matter,
Reversed phase column chromatography (LC5orb RP
-18, Kemco), eluted with a 30% methanol aqueous solution, and the eluted fraction containing the target compound was concentrated and lyophilized to obtain 70 mg (yield 22%) of the title compound.

mp 145℃ (decomposition) [R (Br) cM: 1540.1620.1
785N MR (CD300-Q20) δ:
3.15 (3 tl, s), 3.6 (211,8 Bq).

4, 7-5.1 (711, m), 5.7 (Ill,
d, J=511z), 6.75(211,s),
6.79 (ill, s), 6.9 (itl, s),
7.39 (411,s) Compounds of Examples 2 to 4 are obtained in the same manner as in Example 1.

Example 2 7-[2-(2-aminodeazonezyloxyimino)acetamide]-3-<1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate (syn isomer) mo 135°C (Decomposition) r R (KBr) cM: 1540.1630.
1785N M R (CD30O-020) δ: 2
．． 2 (411, brs), 3.0 (3H, s).

3.5 (411, brs), 3.8 (211, brs)
, 4.35 (211, brs).

4.9 (111, s), 5.05 (3tl, brs),
6.75 (211, s).

6.82 (111, s), 6.9 (1 tl, s) Example 3 7-[2-(2-aminothiazol-4-yl)-
2-benzyloxyiminoacetamide] -3-(1
-Methyl-1-pyrrolidinio)methyl-3-cephem-
4-carboxylate (syn isomer) mp 155°C (decomposition) IR (KBr) cri: 1535. 16
20. 1775N M R (DMSO-d6) δ
: 2.1(411,brs), 2.95(3
11, brs), 3.6 (411, brs), 3.
9 (2fl, brs).

4.6 (211, brs), 4.85 (1tl, b'r
s), 4.9(ill, d.

J=7.511z), 5.15(211,s), 6.7
5 (IH, s), 7.23 (211, brs), 7.
35 (51t, s), 9.65 (Ill, d,
J=7.51! z) Example 4 7-[2-(2-aminothiazol-4-yl)-2-benzyloxyiminoace1-amide]-3-(2-methyl-2-isoindolinio)methyl-3-cephem-4 -carboxylate (
syn isomer) mp 135℃ (decomposition) IR (KBr) cM: 1540.1620.1
γ8°NMR (DMSO-d6) δ: 3.1 (31
1,brs), 3.5(2t(,brs), 4.4(
2H, brs), 4.85 (2H, brs).

4.95 (211,brs), 5. Hllll, d
, J=4.511z), 5°15(211,s),
5.7 (IH, dd, J=4.5 and 07.511z).

6.7 (Ill, s), 7.2 ~ 7.6 (11H, m
).

9.65 (111, d, J=7.511z) Example 5
7-[2-(2-aminothiazol-4-yl)-2-
(3,4-dihydroxybenzyloxyimino)acetamide] -3-(5゜6-hydroxy-2-methyl-2-isoindolinio)methyl-3-cephem-4-
Production of carboxylate (syn isomer) (A) Benzhydryl obtained in Example 1 (B) 3-
Iodomethyl-7-(2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino] -2-(
1.29 g (1.04 mmol) of 1-oxide (syn isomer) to 2-tritylaminethiazol-4-yl)acetamide)-3-cephem-4-carboxylate 1 was dissolved in 20 d of N,N-dimethylformamide. and 236 mg (1
, 56 mmol) and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and diethyl ether was added to give powdered benzhydryl 3-(5,6-cyhydroxyisoindolin-2-yl)methyl-7-(2-[
3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(2-tridelaminothiazol-4-yl)ace1-amide)-3-cephem-4-
Carboxylate 1'-oquinide (syn isomer) 1
．． 18 g (yield 93.6%) +1 was used in the next reaction without purification.

(B) Compound 1.1847(0,
94 mmol) to methyl iodide 12Inf! dissolved in
Stir at room temperature for 17 hours. Diethyl ether is then added to obtain 1.32 g of powder. 1.669 (10 mmol) of potassium iodide and 20 g of acetate were added to this powder, and 0.36 d of acetyl chloride (1) was added at -20°C.
5 mmol) was added dropwise, and the mixture was stirred at -10°C for 4 hours. Add 100 ml of methylene chloride to the reaction solution, wash with 5% aqueous sodium pyrosulfite solution and saturated brine, and dehydrate over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and benzhydryl 3-(5
,6-dihydro1]xy2-methyl-2-isoindolinio)methyl-7-(2-'[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino] -2-
650 mg (yield 50%) of (2-tritylaminothiazol-4-yl)acetamide)-3-cephem-4-carboxylene 1-iodide (syn isomer) was obtained and used in the next reaction without purification. .

(C) Compound 65h+y (0,
47 mmol) is dissolved in methylene chloride 7rd and anisole 1.4- and cooled to -15°C. To this solution, a mixed solution of 14 d of trifluoroacetic acid and 7 rd of methylene chloride, which had been cooled in advance to -15° C., was added all at once, and the mixture was stirred at 0° C. for 1 hour. The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue to obtain 400 μl of a crude product. This crude product was dissolved in 100 d of water, the insoluble matter was filtered off, and the insoluble matter was filtered out using a reversed phase column chroma 1 to Graphie (LC5orb PR-
18, Kemco: eluted with 25% methanol aqueous solution)
The title compound 90Irtg (yield 28.6
%).

mp 135℃ (decomposition) IR (Br) cM: 1540.1620.1
785NMR(020)δ: 3.12(3+1.b
rs), 3.7 (2+1.ABQ).

5.05 (211, s), 5.2 (111, d, J=4
．． 511Z), 5.75(ill, d, J=4.51
1z), 6.7-6.8 (5H, m).

6,9(ill,s) Reference Example 1 Production of 5.6-simethoxy-2-(p)-tolylsulfonylisoindoline 1.89 g (11 mmol) of p-toluenesulfonamide was added to 20 volumes of N,N-dimethylformamide. ) and pulverized 3.3 g (24 g) of potassium carbonate while stirring at room temperature.
2.0 g (8.5 mmol) of 4,5-bis-(chloromethyl)veratrol are added. 2 at room temperature
After stirring for 0 hours, 40% of water was added and extracted with methylene chloride. After washing the extract with water, it is dehydrated with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Wash the remaining crystals with diisopropyl ether to obtain 2.7 g of the title compound (yield 95.2%).
).

Recrystallized from N,N-dimethylformamide, melting point 16
Obtain 1-168°C.

IR (KBr) cM: 525. 550. 60
5. ．． 670°810, 1110.1160.134
0.1460.1519NMR(CDCl2)δ
: 2.38(311,s), 3.82(611,s)
s).

4.56 (4H, s), 6.65 (2H, s).

7.29 (211, d, J=6.211z).

7.49 (2H, d, J = 6.2 Hz) Reference Example 2 Production of 5.6-dihydroxyisoindoline hydrobromide 5.6-Simethoxy 2- (p-tolylsulfonyl)
Isoindoline 60y (0.18 mol) with 47% hydrobromic acid 360d, phenol 457 and propionic acid 6
Add 0d, and while vigorously stirring in a nitrogen stream, old!
・5-minute long distance J. The reaction solution was dried under reduced pressure, 120 rnl of 47% hydrobromic acid was added to the residue, and the mixture was heated again in a nitrogen stream for 3 hours. After cooling the reaction solution, 300% of water and 300% of chloroform are added, and the aqueous layer is separated and treated with activated carbon. The aqueous layer was dried under reduced pressure, the crystalline residue was washed with ether/ethanol, and the title compound was obtained at 25.62%
g (yield 61.4%).

Melting point 215°C (decomposition) I II (KBr) ciA: 1290.133
0.1410.1450°? 460.1510.161
O NMR(DH3O-d6)δ: 4,40(4+
1. brs).

6.85 (211, s), 8.80 (2H, br),
9.55 (2 tl, br) Reference Example 3 Production of 5.6-cyhydroxy-2-methylisoindoline/hydrobromide 5.6-cyhydroxyisoindoline/hydrobromide 1
5.39 q (66 mmol) and 1-lium formate 4.48 g (66 mmol) in 50% formic acid aqueous solution 10
After dissolving in 0d, 17ml of 37% formalin water was added and heated at 80°C for 4 hours. After the reaction solution was concentrated to dryness under reduced pressure, 200 ml of 23% hydrobromic acid was added to the residue and treated with activated carbon. The solution was again dried under reduced pressure, and the crystalline residue was recrystallized from water to give the title compound 11.749 (yield: 12
．． 3%).

Melting point 205°C (decomposition) I R (KBr) cM: 635. 855.1
175.1280゜1320, 1445.1460.1
505.1605NMR(DH3O-d6)δ:
2.99 (311,s), 4.1~4.8 (4H
,brd), 6.78 (2tl, s).

9.0 (1+1.br).

10.83 (111, brs) Reference Example 4 Production of 3.4-di(2-methoxyethoxymethoxy)benzaldehyde 6.9 g (50
2-methoxyethoxymethyl chloride was dissolved at 0°C.
7++j! (150 mmol) was added dropwise. After stirring the reaction solution at 0°C for 1 hour, 50ml of water, 50ml of 0.5N aqueous sodium hydroxide solution/nf! and saturated saline. After dehydrating the organic layer with anhydrous 1-lium sulfate,
The solvent was distilled off under reduced pressure to give the title compound 15.77 (yield: 8-1).
00%).

NMR(CDCl2) δ: 3.40(61
1,s), 3.60 (411,m).

3.89 (411, m), 5.39 (211, s), 5
．． 42 (211, s), 7.30 (ill, d, J
=711z), 7.55 (111,dd, J=1 and 7112).

7, 70 (ill, d, J=111z). 9.8G(
111,S) Reference Example 5 3. Production of 4-di(2-methoxyethoxymethoxy)benzyl alcohol 3. 4-di(2-methoxymethoxy)benzaldehyde is,yg (50 mmol) in methanol 300d After dissolving and cooling, 1.89 g (50 mmol) of helium borohydride was added in several portions, followed by stirring for 30 minutes. 2.86 d of acetic acid was added to the reaction solution, stirred for 10 minutes, and the solvent was distilled off under reduced pressure.

The residue was dissolved in 300 d of ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 15.0 g (yield: 94.8%) of the title compound.

NMR(CDCl2) δ: 3.5(111
, s), 3.35 (611, s).

3.55 (411,, m), 3.85 (411, m),
4.55 (2H, s), 5.26 (411, s), 6
．． 9 (III, dd, J=1 and 711z), 7.
13 (1tl, d, J=711z), 7.6 (ill
, d, J=111z) Reference Example 6 Production of 3.4-di(2-methoxyethoxymethoxy)benzyl chloride 12.9 g (40.8 mmol) of 3.4-di(2-methoxyethoxymethoxy)benzyl alcohol and To 16.1z (203.7 mmol) of pyridine was added 230 m (!
A methylene chloride solution f3 (7) containing /5.8d (81.6 mmol) was added dropwise and stirred for 2 hours.The reaction solution was washed successively with water, saturated aqueous sodium bicarbonate, and saturated brine, and then diluted with anhydrous sulfuric acid solution 1 ~ Liumium dehydration. The solvent is distilled off under reduced pressure,
Silica gel column chromatography (Wakooel
C-300, ethyl acetate:hexane=1:1) to obtain 11.5 g (yield: 83.4%) of the title compound.

NMR(Ko So −IJ[,) δ:
3.3 (611,s), 3.5 (411,m).

3.8 (411, m), 4.73 (211, s), 5.
3 (411, s), 7.1 - 7.2 (311, m) Reference Example 7 Ethyl 2-[3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(2-tritylamino Preparation of thiazol-4-yl) acetate (syn isomer) Ethyl 2-hydroxyimino-2-(2-trideryl)7minodiazol-4-yl) acetic acid: 1 Nistyl (syn isomer) 6 g (13,2 mmol) to N.

Dissolved in 120d of N-dimethylformamide and incubated at 0°C for 5
0% oily sodium hydride 7G'Im'J (15,9
mmol) and stir for 15 minutes. Add 3. to the solution.
Add 4.429 (13.2 mmol) of 4-di(2-methoxyethoxymethoxy)benzyl chloride and stir at room temperature for 17 hours. The solvent is distilled off under reduced pressure, and 150 ml of ethyl acetate is added to the residue. The solution was sequentially washed with 80 mQ of saturated sodium bicarbonate water and 37 g of saturated food and 80 ml of water.
After i, anhydrous lii! Dehydrate with 1-lium I acid. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chroma 1-Graphie (WakoOel C-300,
Ethyl acetate:hexane=1:2) to give the title compound 7.
．． 1 q of 5 g (yield 75.1%).

NMR(DH3O-d6)δ: 1.13(3
11, t), 3.25 (611, s).

3.5 (411, m), 3.75 (411, m), 4.
0 (211, Q), 5.15 (211, s), 6.
95(ill, S), 7.08(ill, s),
7.2-7.4 (1711, m), 8.76 (III
, s) Reference Example 8 Production of 2-[3,4-di(2-methoxyconitoxine 1-xy)benzyloxy]-2-(2-tritylaminothiazol-4-yl)acetic acid (syn isomer) 2 - [3,4-di(2-meI-xie1~kisime1-
xy)benzyloxyimino 1-2- (2-trideraminodeazole- Nisdel (syn isomer) 5.27':i (6.
97 mmol)] to 100 nr (l
and 3.5 g of 2N-sulfurium hydroxide aqueous solution,
Reflux for 1 hour. Add 2N-hydroxide (・Ryu1) to the reaction solution.
8 aqueous solution o. Add 4nIl and reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the crystalline residue was separated by 1.7%. After dissolving the crystal residue in 10 (1 m) of tetrahydrofuran/water (1:1), the pH was adjusted to 4.0 with 1N hydrochloric acid and 100 ml of ethyl acetate was added.
Extract with In1 (3 times). After washing the extract with saturated brine, diluting with water and distilling off the solvent under reduced pressure, the title compound 5 was obtained.
．． 0 g (yield 98.6%) is obtained. Used in the next reaction without cleavage.

Reference Example 9 Benzhydryl 3-chloromethyl-7-(2-[3
．． vA of 4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(2-1~lydylaminodiazol-4-yl)acetamide)-3-cephem-4-carboxylate (syn isomer) 2-[3.4-di(2-methoxy 1-xymethoxy)
benzyloxyimino]-2-(2-trideraminothiazol-4-yl)a acid (syn isomer> 3.3 g
(4.34 mmol) and benzhydryl 7-amino-3-chloromethyl-3-t? 1.85 g < 4.4 + 3 mmol) of "Femu 4-carboxylate" is dissolved in 100 rnf! of methylene chloride, N.

Add 2.54 d (20 mmol) of N-dimethylaniline' and cool to 0°C. I) After that, phosphorus oxychloride 0. 4d (4.34 mmol) is added dropwise. After stirring at room temperature for 1 hour, it was washed successively with 0.1N aqueous hydrochloric acid and saturated brine, dehydrated and concentrated, and then added to a silica gel column (Wakogcl C-3).
00, Vinegar M:, r Ni-Blue: Heki Sign Nan- 3:2)
4.27 g (yield: 80.5%) of the title compound is obtained.

NMR(CDCl2) δ: 3.2(311
, s), 3.23 (311, s).

3.115 (Gll, m), 3°8 (411, m),
4.33 (211, s), 4.98 (111, d, J=
4.511z), 5.25(Gll,s), 5.8G
(111, dd.

J=4.5 and 911z), 0.7(III, s)
, 6.9 to 7,5 (30 + 1.m) The compound of the present invention is a new compound that has not been described in any literature, and has particularly strong antibacterial activity against sensitive and resistant Durum-positive bacteria and Durum-negative bacteria. Therefore, it is expected to be an antibacterial agent.

Claims (4)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, Q is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ (where R^1 is a hydroxyl group, p is an integer from 0 to 2), R^2 is a hydroxyl group, and q is an integer from 0 to 2] , its non-toxic salts or physiologically hydrolyzable non-toxic esters thereof. (2) General formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R^3 is a hydroxyl group or a protected hydroxyl group, R^4
is a hydrogen atom or a carboxyl protecting group, R^5 is a hydrogen atom or an amino protecting group, X is a halogen atom or a leaving group, Y is S or SO, q is an integer from 0 to 2), or The salt has the general formula (III) ▲ mathematical formula, chemical formula, table, etc. ▼ (III) (In the formula, R^1 is a hydroxyl group, R^6 is a hydrogen atom or a methyl group, and p is an integer from 0 to 2. ) is reacted to form the general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, Q' is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^1 is a hydroxyl group, X^■ is an anion, p is 0 (indicates an integer between 2 and 2)
, R^3, R^4, R^5, Y and q have the above-mentioned meanings], and after methylating and/or reducing this as necessary, protecting A general formula characterized by the removal of (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I)
There are mathematical formulas, chemical formulas, tables, etc. ▼ (where R^1 is a hydroxyl group, p is an integer from 0 to 2), R^2 is a hydroxyl group, and q is an integer from 0 to 2] , a non-toxic salt thereof or a physiologically hydrolyzable non-toxic ester thereof. (3) General formula (VI) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) [In the formula, Q' is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^1 is a hydroxyl group, X^■ is an anion, p is 0 to (indicates an integer of 2)
, R^4 is a hydrogen atom or a carboxyl protecting group, Y is S or SO), or its salt is represented by the general formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (Formula Inside, R^3 is a hydroxyl group or a protected hydroxyl group, R^5
is a hydrogen atom or an amino-protecting group, and q is an integer from 0 to 2). II) (wherein Q', R^3, R^4, R^5, Y and q have the above meanings), and methylate and/or reduce this as necessary. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, Q is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Or ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ (where R^1 is a hydroxyl group, p is an integer from 0 to 2), R^2 is a hydroxyl group, and q is an integer from 0 to 2] , a non-toxic salt thereof or a physiologically hydrolyzable non-toxic ester thereof. (4) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, Q is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ (where R^1 is a hydroxyl group, p is an integer from 0 to 2), R^2 is a hydroxyl group, and q is an integer from 0 to 2] , a nontoxic salt thereof, or a physiologically hydrolyzable nontoxic ester thereof as an active ingredient.