JPH01268692A - 3-(1-substituted pyridinium-4-yl)thiomethylcepharosporin derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is (halogen- substituted)-lower alkyl; R<2> is H, negative electron charge or ester residue capa ble of forming a physiologically hydrolyzable ester] or salt thereof. EXAMPLE:7beta-{(Z)-2-(2-Aminothiazol-4-yl)-2-[(alpha-carboxy-3,4-dihyr oxybenzyl)oxyi- mino]acetamide}-3-{[1-(2-fluoroethyl)pyridin ium-4-yl]thiomethyl}-3-cephem-4- carboxylate. USE:An antimicrobial agent. PREPARATION:A compound expressed by formula II (R<3> is H or amino protecting group; R<4> and R<5> are H or OH protecting groups; R<6> and R<7> are carboxyl protecting groups; X is halogen) is reacted with a compound expressed by formula III and as necessary the resultant reaction product is subjected to a process eliminating a protecting group, process converting the eliminated product into salt thereof and process converting the eliminated product into a hydrolyzable ester derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel cephalosporin derivatives useful in the pharmaceutical field. That is, the present invention relates to a novel cephalosporin derivative, a method for producing the same, and an antibacterial agent containing the compound as an active ingredient.

Until now, a large number of compounds having a 2-(2-aminothiazol-4-yl)-2-substituted oxyiminoacetamide group in the 7-position side chain of the cephem nucleus have been synthesized, and there have been no published publications describing them. As for the technology, for example, Japanese Patent Application Laid-Open No. 55-154
No. 980, No. 56-86187, No. 57-59895
No. 57-99592, No. 57-192394,
Publications No. 58-174387, No. 61-134390, No. 62-77392, and No. 62-126189 are listed, and include Durham-positive bacteria and Pseudomonas aeruginos.
It is also shown to be active against cephalosporin-resistant Durham-negative bacteria, including a), and is suggested to have excellent antibacterial activity and a broad antibacterial spectrum.

However, the antibacterial activity of these compounds is limited to Durham-positive bacteria such as methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa.
uginosa), Pseudomonas cepacia (Ps.
eudomonas cepacia), Pseudomonas maltophilia (Pseudomonas
maltophilia) and Acinetobacter calc
glucose non-fermentative bacilli such as P. oaceticus
6 Problems to be Solved by the Invention β-lactam antibiotics exhibit selective toxicity only to bacteria;
Since it does not affect animal cells, it is a highly useful antibiotic that is widely used in the treatment of bacterial infections with few side effects.

However, in recent years, glucose non-fermenting Durum-negative bacilli,
In particular, Pseudomonas aeruginosa and, moreover, methicillin-resistant Staphylococcus aureus are often isolated from patients with weakened immune systems as causative agents of intractable infections, and they pose various problems. Therefore, it is desired to develop an antibacterial agent having improved antibacterial activity against these bacteria.

Means for Solving the Problems The present inventors have created a cephalosporin derivative that has strong antibacterial activity against both Gram-negative bacteria such as methicillin-resistant Staphylococcus aureus and Gram-negative bacteria such as Ha bacteria. As a result of intensive research, we found that a new cephalosporin derivative represented by formula (I) below has excellent antibacterial activity against Gram-negative bacteria including methicillin-resistant Staphylococcus aureus and Gram-negative bacteria including Pseudomonas aeruginosa. The present invention was completed based on the discovery that R' is a lower alkyl group which may be substituted with a halogen atom, and R2 is a hydrogen atom. , each representing a negative charge or an ester residue forming a physiologically hydrolyzable nontoxic ester), its nontoxic salt, a method for producing the compound, and the use of the compound as an antibacterial agent. It is something.

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

A lower alkyl group that may be substituted with a halogen atom is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group that may be substituted with a halogen atom such as a chlorine atom, a bromine atom, or a fluorine atom. It means an alkyl group having 1 to 4 carbon atoms, such as a group, an isobutyl group, a 5ee-butyl group, or a tert-butyl group. Specific examples include fluoromethyl group, 2-fluoroethyl group, 1-fluoroethyl group, 2-chloroethyl group, l-
Chloroethyl group, 2-bromoethyl group, l-bromoethyl group, 3-fluoropropyl group, 3-bromopropyl group, 3-chloropropyl group, 1-bromo-1-methylethyl group, 1-fluoro-1-methylethyl group, 1-chloro-1-methylethyl group, 4-fluorobutyl group, 4-bromobutyl group, 4-chlorobutyl group, 3-fluoro-1
, agemethylpropyl group.

Examples include 3-bromo-1,1-dimethylpropyl group, 3-bromo-1,1-dimethylpropyl group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, and tert-butyl group. , preferably ethyl group, 2-fluoroethyl group, 2-bromoethyl group or 2-chloroethyl group.

Non-toxic salts of the compound (1) of the present invention include addition salts with bases or acids that can be used as pharmaceuticals.

Addition salts with the base include, for example, alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, ammonium salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanol salts, etc. Aliphatic amine salts such as amine salts, jetanolamine salts, triethanolamine salts or brocaine salts, such as N,N
- Aralkylamine salts such as dibenzylethylenediamine salts, such as heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; 5 such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts; Salts include quaternary ammonium salts such as benzyltributylammonium salt, methyltrioctylammonium salt or tetrabutylammonium salt, and basic amino acid salts such as arginine salt or lysine salt.

Addition salts with the acid include inorganic acid salts such as hydrochlorides, hydrobromides, sulfur salts, nitrates, phosphates, carbonates, hydrogen carbonates, and perchlorates, such as acetates, propion salts, etc. Organic acid salts such as acid salts, lactate, maleate, fumarate, tartrate, malate, citrate or ascorbate, such as methanesulfonate, isethionate, benzenesulfonate or p - Sulfonates such as toluenesulfonate, acidic amino acid salts such as aspartate or glutamate.

Ester residues that form physiologically hydrolyzable non-toxic esters include, for example, lower alkoxymethyl groups such as methoxymethyl groups, lower alkoxymethyl groups such as atosekidimethyl groups, propionyloxymethyl groups, or pivaloyloxymethyl groups. Alkanoyloxymethyl groups, e.g. lower alkoxycarbonyloxyalkyl groups such as 1-(ethoxycarbonyloxy)ethyl or 1-(isobroboxycarbonyloxy)ethyl, phthalidyl groups or e.g. (5-methyl-2-oxo-1, (5-substituted-2-oxo-1 such as 3-dioxol-4-yl)methyl group
, 3-dioxol-4-yl) methyl group, which binds to the carboxyl group at the 4-position of the cephem nucleus to form a nontoxic ester that can be hydrolyzed in vivo.

The compound (I) of the present invention has a syn isomer (Z configuration) and an anti isomer (E configuration) in the oximino group,
In general, syn isomers exhibit superior antibacterial activity.All compounds of the present invention are syn isomers.

The E/Z nomenclature is based on the Journal of the American Chemical Society (J, Am, Chem.

Soc, Volume 90, page 509 (1968). (Leaving space below) Next, the method for producing the compound of the present invention will be explained 9. Compound (1) of the present invention is produced by the following formula:
and Ro represent a protecting group for a hydrogen atom or a hydroxyl group, which may be the same or different, Ro and Ro represent a protecting group for a carboxyl group, which may be the same or different, and X represents a halogen atom, respectively. reacting the compound represented by the formula - (in the formula, R1 represents a lower alkyl group optionally substituted with a halogen atom), and then, if necessary, (i) dissociating the protecting group. (it) converting the educt into its non-toxic salt;
) It is produced by performing at least one of the above steps of converting the educt into its physiologically hydrolyzable non-toxic ester.

The compound represented by the general formula ([1)] is represented by the formula (III
), for example, methylene chloride, chloroform, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, N, N-
In dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof, using 1 to 2 equivalents of 4-pyridothione derivative (III) relative to the compound represented by formula (II) at 0°C to 40°C for 0.5 hours to This can be carried out by reacting for 5 hours. In addition, in the above step, if necessary, an iodide such as sodium iodide or potassium iodide is added in an amount of 0.1 to 3 equivalents to the compound represented by the general formula (II), It can be carried out efficiently without side reactions.

Next, the process of removing the protecting group will be explained.

The step of removing the protecting group is carried out depending on the type of the protecting group.
For example, TJ, Genee, published by Wiley in 1981.
) by Protective Groups in Organic Synthesis.
19 from InOrganic 5ynthesis and Plenum Press.
Protective Groups in Organic Chemistry by J.F. WlMcOwie, published in 1973.
Protective GroupsOrganic
This can be carried out by appropriately selecting a method described in ``Chemistry'' and the like.

As the protecting groups for the carboxyl group, amino group, and hydroxyl group of the compound represented by formula (n) above, protective groups that are commonly used in the field of chemistry of β-lactam compounds can be used. Specific examples of carboxyl protecting groups include the following: tert-butyl group, 2,2,2-)lichloroethyl group, acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-( ethoxycarbonyloxy)ethyl group, phthalidyl group, benzyl group, 4-methoxybenzyl group, 3.4-dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group, bis(4-methoxyphenyl)methyl group, (5-methyl -2-oxo-1,3-dioxo-4-yl)methyl group.

Examples include trimethylsilyl group or tert-butyldimethylsilyl group, particularly benzhydryl group, tert-butyldimethylsilyl group, etc.
A butyl group or a tri-lower alkylsilyl group is preferred.

Examples of protecting groups for amino groups include trityl group, formyl group, chloroacetyl group, trifluoroacetyl group, t
Examples include ert-butoxycarbonyl group, trimethylsilyl group, and tert-butyldimethylsilyl group.

Examples of protecting groups for hydroxyl groups include 2-methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, phenacyl group, isopropyl group, tert-butyl group, benzyl group, 4-nitrobenzyl group, and acetyl group. , 2,2.2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, acetonide, trimethylsilyl group, or tert-butyldimethylsilyl group.

To explain specifically how to remove a protecting group, for example, protecting groups such as a trityl group, a formyl group, a tert-butoxycarbonyl group, a benzhydryl group, a tert-butyl group, and a 2-methoxyethoxymethyl group can be removed using hydrochloric acid, It can be carried out with an inorganic or organic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid or p-toluenesulfonic acid, and trifluoroacetic acid is particularly preferred. When trifluoroacetic acid is used as the acid, By adding anisole, thioanisole or phenol, the reaction is accelerated and side reactions are also suppressed. The reaction can be carried out in water, methylene chloride, chloroform, ethylene chloride, benzene, or a mixed solvent thereof. The reaction temperature and reaction time are appropriately selected depending on the chemical properties of the reaction product and the compound (1) of the present invention, and the type of protecting group, and it is particularly preferable to conduct the reaction under mild conditions such as ice cooling or heating. The step of converting the educt of the compound (1) of the present invention into its nontoxic salt can be carried out, for example, by applying a salt-forming reaction commonly used in the art to the educt produced by the above-mentioned production method. can.

The step of converting the free form of the compound (1) of the present invention into its physiologically hydrolyzable non-toxic ester form is described, for example, in JP-A-56-160782, JP-A-56-147789, and JP-A-53-21192. It can be easily carried out by the method described in or a method similar thereto.

The compound (T) of the present invention and its non-toxic salts produced by the above steps can be isolated and purified by known methods such as crystallization or column chromatography.

The method for producing the raw material compound used for producing the compound of the present invention will be explained below.

(wherein, X and R? have the above meanings), a compound represented by the general formula [,] (wherein,
R', R', R'' and R'' have the above meanings) or a reactive derivative of its carboxyl group. For example, water, acetone, dioxane, ether, tetrahydrofuran, ethyl methyl ketone, chloroform, methylene chloride, diglolethane, ethyl acetate, ethyl formate, N, N
- in a solvent that does not adversely affect the reaction, such as dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof,
The reaction can be carried out under the conditions of cooling to room temperature and reaction time of 1 to 10 hours.

Examples of the reactive derivative of the carboxyl group of compound (V) include a condensing agent such as N,N'-dicyclohexylcarbodiimide and an active ester formed by, for example, N- and droxysuccinimide or 1-hydroxybenzotriazole; Acid halides formed by halogenating agents such as thionyl chloride, phosphorous pentachloride or oxalyl chloride; deoxidizing agents such as triethylamine or N-methylmorpholine and Examples include mixed acid anhydrides formed by formate. Further, depending on the type of the reactive derivative of the carboxylic acid used, it may be preferable to carry out the reaction in the presence of a base in order to allow the reaction to proceed smoothly. Such bases include:
Examples include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate, or organic bases such as trimethylamine, triethylamine, N,N-dimethylaniline or pyridine. In addition, when using the compound represented by general formula (V) in the form of a free carboxylic acid, it is recommended to use a condensing agent such as N,N'-dicyclohexylcarbodiimide or N,N'-diethylcarbodiimide. preferable.

The raw material compound (II) produced in the above step can be prepared by a known method such as crystallization or column chromatography, but in some cases it may be used in the next step without separation and purification. It can also be used as a raw material.

The compound represented by the general formula (IV) can be prepared by known methods such as JP-A-50-76089, JP-A-56-86187, Journal of Antibiotics (J.

Antibiotics), Volume 38, Page 1738 (
1985) and Tetrahedron Letters (Tetr
ahedron Lett, ), vol. 22, 3915
(1981) and others.

The compound represented by the general formula (III) can be prepared by known methods such as those published in the Journal of the Chemical Society (J,
Chem.

The compound represented by general formula (V) can be prepared by known methods such as Chemical and Pharmaceutical Bulletin (
Chem, PharIo, Bull), Volume 25,
2-(2-aminothiazol-4-yl)glyoxylic acid derivatives or 2-(2- Aminothiazole-4
-yl)-2-hydroxyiminoacetic acid ester derivative.

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. Mueller Hinton Bros.
One loopful of each test strain (broth) cultured overnight
Inoculum amount: 10@CFU/m Q ) was inoculated onto Mueller Hinton Agar (MHagar). This medium contained antibacterial agents at various concentrations, and after culturing at 37°C for 16 hours, the minimum inhibitory concentration (MIC: μg/l) was measured.As a comparative example, cefotaxime (cefota
xime) and ceftazidime (ceftazidim)
e) was used. The results are shown in the table below.

(Test compound) Compound ■・Diastereomer A compound of Example 1 ■
: Diastereomer A of Example 2 (blank below) Table 1 Minimum inhibitory concentration Note) 1) β-lactamase producing bacteria 2) Staphylococcus aureus JSI is resistant to methicillin.

3) CAZ: Ceftazidiime 4) CTX: Cefotaxime The compound (1) of the present invention is effective against Durham-positive bacteria and Clam-negative bacteria resistant to β-lactam antibiotics, including methicillin-resistant Staphylococcus aureus, especially Pseudomonas aeruginosa and Pseudomonas cepacia. and Acinetobacter
Against non-glucose-fermenting crumb-negative rods such as Calcoaceticus.

It showed excellent antibacterial activity and broad antibacterial spectrum.

Therefore, the compound of formula (1) and its non-toxic salts are useful as antibacterial agents.

The compounds of the present invention can be mixed with solid or liquid excipient carriers known in the art and used in the form of pharmaceutical formulations suitable for O, oral, or external administration. Examples of pharmaceutical preparations include injections.

1. Liquid preparations such as syrups or emulsions; 1. Solid preparations such as tablets, capsules or granules; and eg ointments.

Examples include external preparations such as layer preparations. These preparations may also contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption enhancers or 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, steered butymaglucium, or talc.

When the compound (1) of the present invention is used as an antibacterial agent, the dosage varies depending on the patient's age, gender, symptoms, etc.

Usually used in the range of 1 to 100 μg/kg per day,
It is preferable to administer 5 to 30 micrograms per day in 2 to 4 divided doses.

The present invention will be further explained in detail with reference to the following examples and reference examples, but these examples are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. You may change it by

In the Examples and Reference Examples, the thin layer chromatography (TLC) used was a Merck (Merc) plate as a TLC plate.
Rck) Kieselgel 60F, 4,
A U■ detector was used as the detection method. In addition, the silica gel for the column is Wako Gel C-300 manufactured by Wako Pure Chemical Industries, Ltd. or LC-5ORB RP-1 manufactured by Kemco.
8 was used. NMR spectra are internally referenced with tetramethylsilane (TMS) when measuring with deuterated dimethyl sulfoxide (DMSO-d) or deuterated chloroform (CDCI) solution, and with 2, when measuring with deuterated water (D, O) solution. Vrian using 2-dimethyl-2-silapentane-5-sulfonate (DSS)
Measurements were made with an XL-200 (200 MHz> manufactured by Hitachi, Ltd.) or an R-40 (90 MHz) type spectrometer manufactured by Hitachi, Ltd., and all δ values were expressed in ppm. The symbols in the NMR measurement data have the following meanings. .

S: Singlet d: Doublet t ゛ Triblet (tr
iplet)q: quartet
ABq: AB type
quartet) dd: double doublet (d
doublet) m: multiplet (multiplet) br: broad (broa)
d) J ゛ coupling constant (coupling con
stunt) Hz: Hertz DMSO-d, , heavy dimethyl sulfoxide CDC
l,: Deuterated chloroform D20: Heavy water Example 1 7β-((Z)-2-(2-aminothiazole-4-
yl)-2-((α-carboxylade-3,4-dihydroxybenzyl)oxyimino]acetamide 1-3
- ((1-(2-fluoroethyl)pyridinium-4
-ylcothiomethyl)-3-cephem-4-carboxilade sodium salt benzhydryl 7β-(((Z) -2-(α-benzhydryloxycarbonyl-3,4-di(2-methoxyethoxymethoxy)benzylcooxyimino ]-2-
(2-Tritylaminothiazol-4-yl)acetamide)-3-chloromethyl-3-cephem-4-carboxylade 670 mg (0,5 aamo fl) was added to N
, dissolved in 6.7 mQ of N-dimethylformamide, 200 mg of sodium iodide (1,33ff1mof2
), then 157 mg (1 ma+o Q ) of 1-(2-fluoroethyl)-4-pyridothione are added. After stirring at room temperature for 1 hour, 30 fflΩ of ethyl acetate was added to the reaction mixture, and the mixture was washed with water and then with 20 ml of saturated brine.

After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was mixed with 5 mQ of methylene chloride and 1+ anisole.
Dissolve in a mixture of ff and add 5 mQ of trifluoroacetic acid under water cooling.
drip. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and diisopropyl ether was added to the residue. The resulting insoluble matter is taken out in a furnace, suspended in water 5IIIQ, and adjusted to a diameter of 17.0 mm using saturated sodium bicarbonate solution. After removing the insoluble materials, reverse phase column chromatography (LC-sorb RP-18,
Loom Q), diastereomer A of the title compound was eluted with a 2.5% methanol aqueous solution and diastereomer B was eluted with a 5% methanol aqueous solution, and the mixture was concentrated and lyophilized to give 80.6 mg (yield 23.2%)
and 65.4 mg (yield 18.8%).

Diastereomer Amp: 160-170°C (decomposition) IR(KBr)an-' + 3400.1760,1
630, 1600, 1530, 1390°1360.1
280,1200.1100NMR(DllooN,
+D, O) δ: 3.30 & 3.49 (2H, AB
q, J=18Hz), 4.39 & 4.56 (2'H, A
Bq, JI114)1z), 4.50-5.00(
4H, m), 5.05 (18, d, J=5Hz), 5.
19 (IH, s), 5.67 (IH, d, J=5Hz)
,6.67(11(,d,J=88Z) ,6.79(
IH, S).

6.90 (2H, br s), 8.30 (2H, br s)
s), 8.70 (2H, br s) diastereomer B mp: 160-170°C (decomposition) rR(KBr)an-': 3400,1760,1
630, 1620, 1530, 1390°1360.1
5 to 280,1200,1110.103O103ON
o-d, +D, O): 3.21 & 3.39 (2H,
ABq, J=18)1z).

4.39 & 4.55 (2H, ABq, J=14Hz),
4.55-4.90 (4H, m).

4.95 (IH, d, J=5Hz), 5.14 (LH,
s), 5.47 (IH, d, J=5Hz), 6.53 (
LH, d, J = 8 Hz), 6.68 (IH, d, J = 8
Hz).

6.85 (LH, s), 6.89 (LH, s), 8.2
4(2)1. d, J=6Hz).

8.61 (2H, d, J = 6Hz) Example 2 7β-((Z) -2-(2-aminothiazole-4-
yl)-2-((α-carboxylade-3,4-dihydroxybenzyl)oxyimino]acetamide) −
3-((1-ethylpyridinium-4-yl)thiomethyl]-3-cephem-4-carboxylade sodium salt benzhydryl 7β-(((Z) -2-(α
-benzhydryloxycarbonyl-3,4-di(2-
methoxyethoxymethoxy)benzylcooxyimino]
-2-(2-tritylaminothiazol-4-yl)acetamide)-3-chloromethyl-3-cephem-4-
200 mg (0.15 mmoQ) of carboxylade are dissolved in 4 mΩ of N,N-dimethylformamide and 124 μm of potassium iodide (0.75 mmo I2) are added. After stirring at room temperature for 30 minutes, 31.3 mg (0,225 mmo Q ) of 1-ethyl-4-pyridothione is added, and the mixture is further stirred for 1 hour. Add 30ml of ethyl acetate to the reaction mixture.
Add Q and wash with water and then with 20 m of saturated saline. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue is dissolved in a mixed solution of methylene chloride 51IIQ and anisole l+nQ, and 5mR of trifluoroacetic acid is added dropwise to the solution while cooling with water. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and diisofurovir ether was added to the residue. The resulting insoluble matter was taken out, suspended in 5Q liters of water, and adjusted to pH 7.0 using saturated sodium bicarbonate solution. After separating the insoluble matter in a furnace,
The reactor liquid was subjected to reverse phase column chromatography (LC-sorb
RP-18,100mQ), and diastereomer A of the title compound was purified by 5
Diastereomer B was eluted with an aqueous methanol solution of 12% each, concentrated, and lyophilized.
8 mg (yield: 12.1%) and 10.8 mg (yield: 10.1%) are obtained.

Diastereomer Amp: 170-175°C (decomposition) rR(KBr)an-': 3400,1760,1
630,1600. +530.1390°1360.1
280,1190.111ONll10N14R(D,
+D, O) δ: 1.53 (3H, t, J=7Hz),
3.40 & 3.60 (2H, ABq, J=17Hz),
4.1 (2H, q, J=7Hz).

5.07 (IH, d, J = 5Hz), 5.13 (Ifl
, s), 5.70(l)! , d.

J=5Hz), 6.76 (IH, d, J=8Hz), 6
．． 86 (IH, s), 6.98 (2H, br s), 8
．． 05 (2H, d, J=7Hz), 8.58 (2H, d
, J=7Hz) Diastereomer B mp: 170-175°C (decomposition) rR(KBr)am-': 3400,1760,1
630, 1600, 1530, 1390°1360.1
280,1190.111ONMR (DMSO-d,
+D, O) δ: 1.53 (3H, t, J=7Hz)
, 3.38 & 3.60 (2H, ABq, Jl117Hz
), 4.2 (2H, q, Jg7Hz).

5.06 (IH, d, J=5Hz), 5.10(l)l
, s), 5.70 (LH, d.

J=5Hz), 6.78 (IH, d, J=8Hz),
6.85 (IH, s), 6.95 (2H, br s),
8.04 (2■, d, J = 7) 1z), 8.58 (2H
, d, J=7Hz) Reference Example 1 l-(2-fluoroethyl)-4-pyridone (i) 4-
Hydroxypyridine 700mg (7,36mmon
) N,N-dimethylformamide 7 mΩ dissolved in 1.22 g of potassium carbonate (8,83 mmoQ) and 1.12 g of 1-bromo-2-fluoroethane (8,82 m
mon) and stirred at room temperature for 17 hours. After separating the insoluble matter in the furnace, the solvent in the furnace liquid is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 5% methanol-chloroform).

1-(2-fluoroethyl)-4-pyridone 750mg
(yield 72.2%).

NMR (CDCI, ) δ co 4.04 (IH, d
t, J = 5 & 2.6 Hz).

4.60 (2H, dt, J 5 & 46Hz), 6.3
0 (28, d, J = 8Hz), 7.30 (2H, d, J
=8Hz) (ii) 1-(2-fluoroethyl)-
Dissolve 2.93 g of 4-pyridone (20.76 mmo (1) in 30 mQ of pyridine, and dissolve 6.9 g of phosphorus trisulfide (
30.1 mmoff) and stirred at 55°C for 3 hours. After separating the insoluble matter in the furnace, the solvent in the furnace liquid is completely distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (4-
The residue was purified with 5% methanol-chloroform (eluted with 5% methanol-chloroform) to obtain 2.0 g (yield: 61.3%) of the title compound, 1-(2-fluoroethyl)-4-pyridothione.

IR(KBr)an-': 1830,1510,1
470,1220.120 hunger 1110.1030,82
0,54O NMR (CDCI,) δ: 4.35 (2H, d5J=
5 & 28 Hz), 4.59 (2H, dt, J = 5 & 46
Hz), 7.40 (2H, d, J=8Hz).

7.45 (2H, d, J = 81 (Z) Reference Example 2 Benzhydryl 7β-((Z)' -2-CCα-benzhydryloxycarbonyl-3,4-di(2-methoxyethoxymethoxy)benzylco Oximino]-2
-(2-tritylaminothiazol-4-yl)acetamide)-3-chloromethyl-3-cephem-4-carboxylade 2-[[α-benzhydryloxycarbonyl-3,4
-di(2-methoxyethoxymethoxy)benzylcooxyimino) -2-(2-tritylaminothiazole-
4-yl)acetic acid 4.37g (5,19mmoff) and benzhydryl 7β-amino-3-chloromethyl-
3-cephem-4-carboxilade 2.34 g (
5,64 mmo Q) was dissolved in 90 mΩ of methylene chloride, and 3.2 mm of N,N-dimethylaniline (
25,4nIIlon) and phosphorus oxychloride 0.6
3rnQ (6.77 mmon) was added dropwise and stirred for 1 hour.

The reaction solution was poured into IN hydrochloric acid and extracted with methylene chloride, and then the organic layer was washed with IN aqueous sodium hydroxide solution and saturated brine. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound.

NMR (DMSO-d, )δ: 3.20 (3H,S
), 3.21 (3H, S), 340 (6H, m), 3.
68 (4H, m), 4.42 (2H, m), 5.15 (
2H, m).

5.25 (2+(, m), 5.66 (IH, br s)
, 6.74 (IH, s), 6.82 (LH, s), 6.
95(1)1. s), 7.00-7.80 (38H, m
) Effects of the invention The compound of the present invention is a new compound that has not been described in any literature, and is effective against Durum-positive bacteria resistant to β-lactam antibiotics, including methicillin resistance, and Durum-negative bacteria, including non-glucose-fermenting Durum-negative rods. It has strong antibacterial activity and a broad antibacterial spectrum, making it useful as an antibacterial agent.

Claims (5)

[Claims] (1) General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is a lower alkyl group that may be substituted with a halogen atom, and R^2 is a hydrogen atom, a negative charge or A compound represented by (respectively an ester residue forming a physiologically hydrolyzable non-toxic ester) or a non-toxic salt thereof. (2) 7β-((Z)-2-(2-aminothiazole-
4-yl)-2-[(α-carboxy-3,4-dihydroxybenzyl)oxyimino]acetamide)-3-
A compound according to claim 1, characterized in that it is ([1-(2-fluoroethyl)pyridinium-4-yl]thiomethyl)-3-cephem-4-carboxilade. (3) 7β-{(Z)-2-(2-aminothiazole-
4-yl)-2-[(α-carboxy-3,4-dihydroxybenzyl)oximino]acetamide}-3-
[(1-ethylpyridinium-4-yl)thiomethyl]
-3-cephem-4-carboxylade. (4) General formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^3 is a hydrogen atom or a protecting group for an amino group,
^4 and R^5 may be the same or different, and represent a protecting group for a hydrogen atom or a hydroxyl group; R^6 and R^7 may be the same or different, a protecting group for a carboxyl group; X is a halogen A compound represented by the general formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents a lower alkyl group that may be substituted with a halogen atom.) React with the compound represented by
If necessary, (i) a step of removing the protecting group (ii) a step of converting the educt into its non-toxic salt (iii)
) General formula [I] ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼[I] (wherein R^1 has the above meaning, R^2 represents a hydrogen atom, a negative charge, or an ester residue forming a physiologically hydrolyzable non-toxic ester, respectively) A method for producing the represented compound or its non-toxic salt. (5) General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R^1 is a lower alkyl group that may be substituted with a halogen atom, R^2 is a hydrogen atom, An antibacterial agent containing as an active ingredient a compound represented by a negative charge or an ester residue forming a physiologically hydrolyzable nontoxic ester, or a nontoxic salt thereof.