JPH06510523A - Novel cephem compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] This invention relates to novel cephem compounds and pharmaceutically acceptable salts thereof. It is something that More specifically, this invention provides a novel cephemyl compound with antibacterial activity. compounds and their pharmaceutically acceptable salts, their production methods, and pharmaceuticals containing them. It relates to pharmaceutical compositions and methods of treating infectious diseases in humans and animals.

Therefore, one purpose of this invention is to provide a therapeutic agent that has high activity against many pathogenic bacteria. It is an object of the present invention to provide emem compounds and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for producing the above-mentioned cephem compounds and salts thereof. It is to provide.

Yet another object of this invention is to use the above cephem compounds or An object of the present invention is to provide a pharmaceutical composition containing pharmaceutically acceptable salts thereof.

Yet another object of this invention is to infect infected humans or animals with the above-mentioned cephems. and administering the compound. Provides a method to treat infections caused by pathogenic bacteria Is Rukoto.

The cephem compound targeted by this invention is novel and has the following general formula % formula % In the formula, R' is an amine group or a protected amino group, Z is N or CHl R2 is hydrogen or an organic residue R3 represents a hydroxy group or a protected hydroxy group.

(Hereafter, margin) The object compound (I) of this invention is produced by the following method.

(eea) or reactive derivatives or salts thereof at the amino group Destruction”ヱ1 or its salts (I) or its salts A Dan L (Ia) or its salts (Than) or its salts Manufacturing method” 41 (IC) or its salts (Eng. d) or its salts In the formula, R', R'', R'' and Z each have the same meaning as before, and R= is a protected R is a carboxy (lower) alkyl group, R is a carboxy (lower) alkyl group, R is a carboxy (lower) alkyl group, 2 is a protected hydroxy group, X represents a leaving group.

Starting compounds (IIa) and (V) are produced by the following method.

Manufacturing method 1m (VI) or reactive derivatives or salts thereof at the amino group (V) Manufacturing method”-) or its salts (eee) or its salts Regarding compounds (I), (Ia) to (Id), (III) and (rV), the above Compounds are understood to include syn-isomers, anti-isomers and mixtures thereof. Ru.

For example, with respect to the target compound (I), the syn isomer has the following formula: (wherein R', R ” and Z have the same meanings as before). It refers to a chemical isomer, and an anti-isomer has the following formula: (In the formula, R', R'' and Z each have the same meaning as before) and all such geometric isomers. and mixtures thereof are included within the scope of this invention.

In this specification and claims, the partial structures and and mixtures thereof are represented by the following formula for convenience: (In the formula, R', R'' and Z each have the same meaning as before).

In the foregoing and subsequent descriptions of this specification, various definitions included within the scope of the invention are explained. Preferred examples and explanations of the meanings are described below.

The term "lower" means atoms containing 1 to 6 carbon atoms unless otherwise specified.

Suitable "protected amine groups" include acylamino groups or preferred substituents. Al(lower)alkyl group which may have (e.g. benzyl group, trityl group) Examples include amino groups substituted with commonly used protecting groups such as It will be done.

Preferred "acyl moieties" in the term "acylamino group" include carbamoyl acyl groups, aliphatic acyl groups, and acyl groups containing aromatic rings or heterocycles.

Further, preferable examples of the above acyl group include lower alkanoyl groups (for example, holyl groups). Mil group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group group, isovaleryl group, oxalyl group, succinyl group, pivaloyl group, etc.); lower Alkoxycarbonyl group (e.g. methoxycarbonyl group, ethoxycarbonyl group) group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group group, tertiary butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, (oxycarbonyl group, etc.); lower alkanesulfonyl group (e.g., mesyl group, ethyl group, etc.); sulfonyl group, propanesulfonyl group, isopropanesulfonyl group, butanes sulfonyl group, etc.); arenesulfonyl group (e.g., benzenesulfonyl group, sil group, etc.); aroyl group (e.g., benzoyl group, toluoyl group, xyloyl group, group, naphthoyl group, phthaloyl group, indancarbonyl group, etc.); Al (lower) Alkanoyl group (e.g., phenylacetyl group, phenylpropionyl group, etc.) ; Al(lower) alkoxycarbonyl group (e.g. benzyloxycarbonyl group) , phenethyloxycarbonyl group, etc.). The acyl part mentioned above with a suitable substituent such as halogen (e.g. chlorine, bromine, iodine or fluorine) may have.

Suitable "organic residues" include lower alkyl groups (for example, methyl, ethyl, and Lopyl group, isopropyl group, butyl group, isobutyl group, tertiary butyl group, pentyl group group, neopentyl group, tertiary pentyl group, hexyl group, etc.), mono(or di- or tri-halo(lower) alkyl group (e.g., chloromethyl group) , dichloromethyl group, trichloromethyl group, bromomethyl group, chloroethyl group, Dichloroethyl group, trichloroethyl group, fluoroethyl group, trifluoroethyl group ), lower alkenyl groups (such as vinyl, l-propenyl, allyl), lower alkenyl (such as vinyl, l-propenyl, group, ■-methylallyl group, l or 2 or 3-butenyl group, l or 2 or 3 or 4-pentenyl group, 1 or 2 or 3 or 4 or 5-hexenyl group), lower alkynyl group (e.g. ethynyl group, ■-propynyl group, Lugyl group, l-methylpropargyl group, l or 2 or 3-butynyl group, or 2 or 3 or 4-pentynyl group, ■ or 2 or 3 or 4 or 5 -hexynyl group, etc.), aryl group (e.g., phenyl group, naphthyl group, etc.), Al(lower)alkyl groups such as phenyl(lower)alkyl groups (e.g., benzyl groups, phenethyl groups, phenylpropyl groups, etc.), lower alkyl moieties are exemplified above. Carboxy (lower) alkyl group, lower alkyl moiety is as above. The protected carboxy moiety is as shown in the example below. protected carboxy (lower) alkyl groups, etc.

A suitable [protected carboxy(lower)alkyl group] esterified carboxy group” and “protected carboxy group” Examples include carboxy groups.

Preferable examples of the above esters include lower alkyl esters (for example, metal esters). Tyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester Tyl ester, isobutyl ester, tertiary butyl ester, pentyl ester , tertiary pentyl ester, hexyl ester, etc.) - lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester ( (e.g., ethynyl ester, propynyl ester, etc.) -lower alkoxyalkyl esters (e.g., methoxymethyl ester, ethoxymethyl ester, Propoxymethyl ester, l-methoxyethyl ester, ■-ethoxyethyl esters, etc.); lower alkylthioalkyl esters (e.g., methylthiomethyl ethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylene ester, pylthiomethyl ester, etc.); mono(or di- or trihalo(lower) alkyl); Kyl esters (e.g. 2-iodoethyl ester, 2,2.2-1-dichloro (e.g. ethyl ester); lower alkanoyloxy (lower) alkyl ester (e.g. For example, acetoxymethyl ester, propionyloxymethyl ester, butyl valeryloxymethyl ester, valeryloxymethyl ester, bivaloyloxime Tyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester (2-propionyloxyethyl ester, etc.)-lower alkanesulfonyl (lower) alkynyl esters (e.g. mesyl methyl ester, 2-mesylethyl ester) (lower) alkyl esters, e.g. one or more suitable Phenyl (lower) alkyl esters that may be substituted with substituents (e.g. nitrobenzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester , phenethyl ester, trityl ester, benzhydryl ester, bis(metal) toxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4- hydroxy-3,5-ditertiary butylbenzyl ester, etc.); substituted or substituted with one or more suitable substituents such as unsubstituted phenyl esters aryl esters (e.g., phenyl esters, tolyl esters, Tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.) ; tri(lower)alkylsilyl ester; lower alkylthioester (e.g. methylthioester, ethylthioester, etc.).

Suitable "protecting groups" in the "protected hydroxy group" include the above-mentioned acyl groups. phenyl(lower)alkyl optionally substituted with one or more suitable substituents groups (e.g., benzyl group, 4-methoxybenzyl group, etc.), tetrahydropirani and the like.

Suitable "leaving groups" include halogen [e.g. chlorine, fluorine.

iodine, etc.], acyloxy groups such as sulfonyloxy groups [e.g. (benzenesulfonyloxy group, tosyloxy group, mesyloxy group, etc.), lower alkyl Kanoyloxy group [e.g. acetyloxy group, propionyloxy group, etc.] Which can be mentioned.

Preferred examples of pharmaceutically acceptable salts of target compound (I) include 1, commonly used salts; Examples include alkali metal salts [e.g. sodium salts, potassium salts, etc.] and alkaline earth metal salts [e.g. Metal salts such as sium salts, magnesium salts, ammonium salts, organic base salts [ For example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, Dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt 1 , organic acid salts [e.g., formate, acetate, trifluoroacetate, maleate, alcohol Stone salt, methanesulfonate, benzenesulfonate, toluenesulfonate etc. ], inorganic acid salts [e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.], Salts with amino acids [e.g. alginate, aspartate, glutamate, etc. ] etc.

(Hereafter, margin) Preferred embodiments of the target compound (I) are as follows.

R1 is an amino group or a protected amino group (more preferably an acylamino group).

Z is N or CHl R2 is a lower alkyl group, a carboxy(lower) alkyl group, or a protected carboxyl group. xy(lower)alkyl group [more preferably esterified carboxy(lower) an alkyl group, most preferably a lower alkoxycarbonyl (lower) alkyl group], R7 is a hydroxy group or a protected hydroxy group [more preferably one or more represents a phenyl (lower) alkoxy group which may be substituted with an appropriate substituent.

The method for producing the target compound and starting compound of this invention will be described in detail below.

Temporary”] J- Compound (I) or a salt thereof is a compound (Ha) or a reaction compound at its amino group. reactive derivative and the reactive derivative at the compound (nr) or its carboxy group. or their salts.

Suitable examples of reactive derivatives at the amino group of the above compound (Ila) include the above compound (Ila). Compound (IIa) and a carbonyl compound such as an aldehyde or ketone Schiff base type imino group or tautomeric enamine produced by the reaction of isomers of the above compound (Ila) and e.g. bis(trimethylsilyl)a Cetamide, mono(trimethylsilyl)acetamide [e.g. N-(trimethylsilyl) silyl)acetamide], bis(trimethylsilyl)urea, etc. A silyl derivative produced by the reaction of the above compound (IIa) and, for example, Examples include derivatives produced by reactions such as phosphorus trichloride or phosgene.

Suitable examples of reactive derivatives at the carboxy group of the compound (m) include β - those commonly used in the field of handling lactam compounds, i.e. acid halogens; Examples include compounds, acid anhydrides, activated amides, and activated esters. reactivity induction Suitable examples of compounds include acid chlorides; acid azides; e.g. substituted phosphoric acids [e.g. For example, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid , halogenated phosphoric acid, etc.], dialkyl phosphorous acid, sulfite, thiosulfate, sulfur acids, sulfonic acids [e.g. methanesulfonic acid], aliphatic carboxylic acids [e.g. , acetic acid, propionic acid, butyric acid, isobutyric acid, bibaric acid, valeric acid, isovaleric acid, 2- ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acids [e.g., benzoic acid, mixed acid anhydrides with acids such as [Nato]; symmetrical acid anhydrides; imidazole, C-IH-benzotriazole, 4-substituted imidazole, dimethylpyrazole, amides activated with triazoles or tetrazole; Esters [e.g., cyanomethyl ester, methoxymethyl ester, dimethyl Iminomethyl [(CH-)z　N　”=CH-]ester, vinyl ester, plastic Lopargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, meshi ruphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenyl thioester, p-cresyl thioester, benzothiazolyte ruthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or N- Esters with hydroxy compounds [e.g., N,N-dimethylhydroxyamine, 1-Hydroxy-2-(IH)-pyridone, N-hydroxysuccinimide, N -hydroxyphthalimide, 1-hydroxy-IH-benzotriazole, etc.] Examples include. These reactive derivatives are used in the above compound (III) be arbitrarily selected from among them depending on the type.

This reaction typically involves water, alcohol [e.g., methanol, ethanol, etc.], Setone, dioxane, acetonitrile, chloroform, methylene chloride, ethyl chloride Ren, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyri Commonly used solvents such as gin, or anything else that does not adversely affect the reaction in an organic solvent. These commonly used solvents can also be used mixed with water. may be used.

In this reaction, when the above compound (■r) is used in the free acid form or its salt form , the above reaction preferably involves N,N'-dicyclohexylcarbodiimide:N- Cyclohexyl-No-morpholinoethylcarbodiimide; N-cyclohexyl -N'-(4-diethylaminocyclohexyl)carbodiimide, N, N'- Diethylcarbodiimide, N,N'-diisopropylcarbodiimide; Chil-N'-(3-dimethylaminopropyl)carbodiimide; N.

No-carbonyl-bis(2-methylimidazole); pentamethylene ketene- N-cyclohexylimine; diphenylketene-N-cyclohexylimine; Toxyacetylene; 1-alkoxy-1-chloroethylene; Trialkylphosphite ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphorus chloride) Phosphorus trichloride; Thionyl chloride; Oxalyl chloride; Lower alkyl haloformate ster [e.g., chloroformate ethyl ester, chloroformate isopropyl ester] etc.] nitriphenylphosphine; 2-ethyl-7-hydroxybenzisiodine Sazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium salt Inner salt of droxide; 1-(p-chlorobenzenesulfonyloxy)-6-k Rolo-IH-benzotriazole, N,N-dimethylformamide and thionichloride by reaction with chlorine, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. The presence of commonly used concentrating agents such as the so-called Vilsmeier reagent, which is prepared by done below.

This reaction also works with alkali metal bicarbonates, tri(lower)alkylamines, pyridine N, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzyl alkyl It is carried out in the presence of an inorganic or organic base such as amine.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to heating.

Made in 1L Ren U Compound (I) or a salt thereof, compound (IV) or a salt thereof, and compound (V ) or its salts.

The above reaction uses acetone, chloroform, acetonitrile, methylene chloride, and ethyl chloride. Tyrene, formamide, N,N-dimethylformamide, methanol, ethanol diethyl ether, tetrahydrofuran, dimethyl sulfoxide or the above It is carried out in a solvent such as any other organic solvent that does not adversely affect the reaction. this The reaction temperature is not particularly limited, and the above reaction is usually performed under cooling, room temperature, or heating. Ru. The above reaction also involves alkali metals [e.g., sodium, potassium, etc.], alkali metals [e.g., sodium, potassium, etc.], alkaline earth metals [e.g. magnesium, calcium etc.], their hydroxides or carbonates or bicarbonates, tri(lower)alkylamines [e.g. triamine, triethylamine, diisopropylethylamine, etc.], picoline, alkali metal salts of alkanoic acids [e.g., sodium 2-ethylhexane, etc.], N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine It is carried out in the presence of inorganic and organic bases such as.

1st class Yudanri Compound (Ib) or a salt thereof is compound (Ia) or a salt thereof. It can be produced by subjecting it to an elimination reaction of a ruboxy protecting group. Detachment above Suitable reaction methods include commonly used methods such as hydrolysis and reduction. It will be done.

(il hydrolysis: The above hydrolysis is preferably carried out in the presence of a base or an acid including a Lewis acid.

Suitable bases include alkali metals [e.g. sodium, potassium, etc.], alkaline earth metals [e.g. magnesium, calcium etc.], their hydroxides or carbonates or bicarbonates, trialkylamines [e.g. trimethylamine , triethylamine, etc.], picoline, 1,5-diazabicyclo[4,3,Ol -non-5-ene, 1.4-diazabicyclo[2,2,2,]octane, 1.8 - Inorganic bases such as diazabicyclo[5,4,O,]undec-7-ene and organic Examples include machine bases.

Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, trichloroacetic acid, acids, trifluoroacetic acid, etc.] and inorganic acids [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. trioctoacetic acid [e.g., trichlorovine vinegar In the elimination reaction using a Lewis acid such as trifluoroacetic acid, trifluoroacetic acid, etc., preferably It is carried out in the presence of a cation scavenger [eg, anisole, phenol, etc.].

This reaction typically involves water, alcohol [e.g., methanol, ethanol, etc.], and salts. methylene chloride, tetrahydrofuran, mixtures thereof, or those that adversely affect the above reactions. It is carried out in a solvent such as any other solvent that does not degrade. Liquid bases or acids also dissolve It can be used as a medium. The reaction temperature is not particularly limited, and the reaction is usually cooled. ~Performed under heating.

(iii reduction: The reduction reaction is carried out by commonly used methods and includes chemical reduction and catalytic reduction.

Suitable reducing agents used in the above chemical reduction include metals (e.g. tin, zinc, iron, etc.) or metal compounds (e.g., chromium chloride, chromium acetate, etc.) and organic Acids or inorganic acids [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p- ) luenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

Suitable catalysts used in the above catalytic reduction include platinum catalysts (e.g., platinum plates, platinum gold sponge, platinum black, platinum colloid, platinum oxide, platinum wire, etc.), palladium catalyst (For example, palladium sponge, palladium black, palladium oxide, palladium charcoal) Colloidal palladium, palladium/barium sulfate, palladium/barium carbonate nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel) cobalt catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced cobalt, Raney cobalt, etc.), catalysts (e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g. reduced copper, Raney copper, Commonly used materials include Le Mans steel, etc.). The above reduction reaction is usually Water, methanol, ethanol, propatool, N,N-dimethylformamide or or a mixture of these, in a commonly used solvent that does not adversely affect the reaction. be exposed. Furthermore, if the above acids used in chemical reduction are liquids, they are also solvents. It can be used as Furthermore, as a suitable solvent used in chemical reduction is the solvent mentioned above and other commonly used solvents (e.g. diethyl ether, (dioxane, tetrahydrofuran, etc., or mixtures thereof).

The reaction temperature of the above reduction reaction is not particularly limited, and the reaction is usually carried out under cooling to heating. .

Manufacturing method Yuma L Compound (Id) or a salt thereof is a compound (Ic) or a salt thereof It can be produced by subjecting it to an elimination reaction of a roxy protecting group. The above reaction is , is carried out in the same manner as the above-mentioned manufacturing method (3). Therefore, the reagents used and For reaction conditions (e.g. solvent, reaction temperature, etc.), please refer to the one for production method (3). stomach.

Benita 1 Compound (Vl) or its salts are compound (Vl) or its amino group Reactive derivatives or salts thereof and compound (■) or its carboxy group It can be produced by reacting reactive derivatives.

This reaction is carried out in the same manner as the production method (I) described above. Therefore, used For reagents and reaction conditions (e.g., solvent, reaction temperature, etc.), refer to those in the manufacturing process. do it.

Manufacturing method A11 Compound (formerly or its salts) is a combination of compound (■) or its salts and compound (V) or its salts. or its salts.

This reaction is typically performed with an alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methic chloride Ren, dimethylacetamide, N,N-dimethylformamide or the above reaction carried out in commonly used solvents such as all other organic solvents without adverse effects. It will be done. Among these solvents, a hydrophilic solvent may be used in combination with water.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to heating.

This reaction usually occurs with alkali metals [e.g., sodium, potassium, etc. Lithium metals [e.g. magnesium, calcium etc., their hydroxides or carbonates or bicarbonates, tri(lower)alkylamines [e.g. triethylamine, diisopropylethylamine, etc.], picoline, etc. It is carried out in the presence of inorganic and organic bases.

Manufacturing method The compound (ITcl) or its salts is the compound (Ilb) or its salts. It can be produced by subjecting it to an elimination reaction of a hydroxy protecting group. This anti The reaction is carried out in the same manner as the production method (3) described above. Therefore, the reagents used For the reaction conditions (e.g. solvent, reaction temperature, etc.), please refer to production method (3). Bye.

1st category Compound (Ilal) or its salts is compound (IId) or its salts. It can be produced by subjecting it to an elimination reaction of an amino protecting group. This reaction is , is carried out in the same manner as the above-mentioned manufacturing method (3). Therefore, the reagents used and For reaction conditions (e.g. solvent, reaction temperature, etc.), please refer to the one for production method (3). stomach.

Target compounds and starting compounds in production methods (1) to (4) and production methods (A) to (D) and these reactive derivatives, please refer to those exemplified for compound (I). Bye.

The objective compound (I) and its pharmaceutically acceptable salts are novel and have strong It exhibits antibacterial activity and supports the growth of a wide range of pathogenic bacteria, including Gram-negative bacteria and Gram-negative bacteria. It is useful as an antibacterial agent because it inhibits growth.

In addition, in order to demonstrate the usefulness of the target compound (I), the MI of the representative compound of this invention C (minimum inhibitory concentration) data are shown below.

Ward Nezumi: In vitro antibacterial activity was measured by the following agar plate multiple dilution method.

Each test strain was cultured in Tryptocase Soy Pross overnight. Heart infusion containing the test compound at each concentration level Streak on agar (HI agar) and incubate for 20 hours at 37°C. Minor inhibitory concentration (MIC) was expressed in μg/ml.

ward examination department Aβ-(2-(5-amino-1,2,4-thiadiazol-3-yl)-2- (1-carboxy-1-methylethoxyimino)acetamide]-3-[3- ((5-hydroxy-4-oxo-l.

4-dihydropyridin-2-yl)carboxyamino)-1-pyridinio Jmethy Ru-3-cephem-4-carboxylic acid (syn isomer) (hereinafter referred to as the margin) Trial Ju Song: MIC (μg/ml) For therapeutic administration, the object compound (I) of this invention and a pharmaceutically acceptable Its salts may be organic or organic, suitable for oral, parenteral and topical administration. is a pharmaceutically acceptable carrier such as an inorganic, solid or liquid excipient. used in the form of conventional pharmaceutical preparations containing the above compounds as active ingredients, mixed with It will be done.

Pharmaceutical formulations may be in solid form such as tablets, granules, powders, capsules, It may be in liquid form, such as a solution, suspension, syrup, emulsion, lemonade, etc. stomach.

If necessary, solubilizing agents, stabilizers, wetting agents, columns, clay, Sucrose, cornstarch, talc, gelatin, agar, pectin, peanut oil, ori Contains commonly used additives such as oil, cocoa butter, ethylene glycol, etc. It may be

The dosage of the above compound (I) should be determined depending on the age and condition of the patient, the type of disease, and the compound to be applied. It changes depending on the type of object (I). Generally, 1 mg per day and about 4, Amounts between 0.000 mg or more may be administered to the patient. The eye of this invention Compound (I) is administered at an average single dose of about 50 mg, 100 mg, 250 mg, 50 mg, 0mg and 1000mg may be used to treat pathogenic bacterial infections.

The following Preparations and Examples are included for the purpose of illustrating the invention in more detail. It is something that was given.

Toyoko Shikarata 5-(4-methoxybenzyloxy)-2-carboxy-4(IH)-pyridone (115g), 3-aminopyridine (39,35g) and anhydrous l-hydroxy Benzotriazole (62,3g) in N,N-dimethylformamide (1,1 To 5L suspension, l-ethyl-3-(3-dimethylaminopropyl)carbodiyl Mido hydrochloride (88.2 g) was added at 25°C. After stirring at the same temperature for 1 hour, The reaction mixture was stirred at 43°C for 4 hours. After cooling to 20°C, the mixture was diluted with ice water (4 , 6 L), diisopropyl ether (1,15 L), ethyl acetate (2,3 L), and sodium chloride (4,00 g). Stir this mixture for 30 minutes The resulting precipitate was collected by filtration. This precipitate was mixed with tetrahydrofuran (4 L) suspended in aqueous IN sodium hydroxide solution (200 ml) and sodium chloride. (loog) was added. The separated tetrahydrofuran phase was dissolved in magnesium sulfate (1 kg) and dried under reduced pressure to obtain a dried product. The resulting residue By adding chloroform, grinding, and drying, 5-(4-methoxy benzyloxy)-2-(3-pyridylcarbamoyl)-4(LH)-pyridone (105.5 g) was obtained.

(Hereafter, margin) Installation Ga 1 5-(4-methoxybenzyloxy)-2-(3-pyridylcarbamoyl)-4 (LH)-pyridone (63,65 g) and diisopropylethylamine (31,5 g) Add 78-form to 640 ml of N,N-dimethylformamide solution of m1). Amido-3-chloromethyl-3-cephem-4-carboxylic acid (50 g) at -5°C I added it. After stirring for 2 hours at 5°C, the reaction mixture was dissolved in ethyl acetate (6.4L). I poured it. The resulting precipitate is collected by filtration, washed with ethyl acetate, and dried under reduced pressure. The crude 7B-formamide-3-[3-[(5-(4-methylbenzene) Zyloxy)-4-oxol,4-dihydropyridin-2-yl)carbonyl Aminoco-1-pyridinio-1methyl-3-cephem-4-carboxylic acid (84g) was gotten. Methylene chloride (160ml), anisole (80ml) and trichloride The compound obtained above (84 g) was added to an ice-cooled mixture of fluoroacetic acid (320 ml). I added it little by little. This reaction mixture was stirred for 2 hours under water cooling. Dilute the resulting solution Pour into sopropyl ether (2.8 L) to obtain a precipitate. Filter this precipitate was collected, washed with diisopropyl ether and ethyl acetate, and dried under reduced pressure. 7β-formamide-3-[3-((5-hydroxy-4-oxo-1,4 -dihydropyridin-2-yl)carbonylamino)-1-pyridiniocomethyl Trifluoroacetate (70 g) of -3-cephem-4-carboxylic acid was obtained.

Concentrated hydrochloric acid was added to a suspension of the obtained compound (69.5 g) in methanol (695 ml). (44.7ml) was added under water cooling. This solution was stirred at 22°C for 4 hours. Obtained Pour the aqueous solution into a mixture of acetone (1.85 L) and ethyl acetate (1.85 L). A precipitate was obtained. This precipitate was collected by filtration, washed with ethyl acetate, and dried under reduced pressure. By doing so, the crude target compound (56 g) was obtained. This crude compound ( 56g) was dissolved in water (560ml). This aqueous solution was adjusted to pH 1.0 with 6N hydrochloric acid. Diaion HP-20 (trademark: manufactured by Mitsubishi Chemical Industries, Ltd.) (560ml) It was subjected to packed column chromatography and eluted with water. Fraction containing target compound Collected. To the collected aqueous solution (925 ml) was added isopropyl alcohol ( 2.3 L) was added little by little. The resulting precipitate was collected by filtration and diluted with isopropyl By washing with alcohol and drying under reduced pressure with phosphorus pentachloride, 7β-amino-3 -[3-+ (5-hydroxy-4-year-old xo-1,4-dihydropyridine-2- carbonylamino)-1-pyridiniocomethyl-3-cephem-4-cal Bonic acid dihydrochloride (19.2 g) was obtained, 5.23 + 11 (, d, J = 41 (z), S, '35 LIH, d, J = 4Hz).

5.41.5.66 (2H, ABq, J=14Hz), 7.42 (LH ,s).

7.91 (1B, s), 8.09 +LH, dd, J=6Hz and 9Hz).

8.64 [IH, d, J=9Hzl, 8,77 (IH, d, J=6H z).

9.64 (LH, sl Husband Gotoyoni Aβ-amino-3-[3-((5-hydroxy-4-oxo-1,4-dihydro pyridin-2-yl)carbonylamino)-1-pyridinioJ methyl-3-ceph Em-4-carboxylic acid dihydrochloride (15,46 g) in tetrahydrofuran (30 g) 9ml) suspension, N-(trimethylsilyl)acetamide (78.75g) was added to the suspension. and the mixture was heated to 38°C. 2-(5-amino-1, 2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methyleth ximino) mixed acid anhydride of acetic acid and methanesulfonic acid (syn isomer) (10,5 7g) was added at 7°C. After stirring for 40 minutes at 3-5°C, the reaction mixture was diluted with acetic acid ether. It was poured into a mixture of chill (2.5 L) and acetic acid (37.78 ml). Pour this mixture into the chamber Stir at room temperature for 1.5 hours, collect the resulting powder by filtration, and add ethyl acetate (300 m 1) and dried under reduced pressure. Dissolve this powder (27.9 g) in water (279 ml). The pH was adjusted to 8 with IN aqueous sodium hydroxide solution. Add this solution to IN hydrochloric acid. The pH was adjusted to 6.5 and the resulting precipitate was removed by filtration. Diamond the filtrate Apply column chromatography using HP-20 (140 ml) and dissolve with water. I put it out. The pH of this eluate (1290 ml) was adjusted to 1 with 6N hydrochloric acid, and the obtained The precipitate was removed by filtration, and the filtrate was poured into a Diaion HP-20 (420ml) bottle. It was subjected to column chromatography. The column was washed with water (4.2L).

The target compound was eluted with a 30% aqueous solution of tetrahydrofuran, and the eluate (1,26 The solvent was evaporated from L) to 850ml and cooled to 7°C. Filter the powder obtained. 7β-[2-(5-amino-1,2, 4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxy) ciimino)acetamide]-3-[3-([5-hydroxy-4-oxo-1 ,4-dihydropyridin-2-yl)carboxyamino)-1-pyridiniocome Chil-3-cephem-4-carboxylic acid (syn isomer) (9.82 g) was obtained. .

Nujoll: 1770cm""Nujoll 1 7β-Amino-3-[3-((5-hydroxy-4-oxo-1,4-dihydro pyridin-2-yl)carbonylamino)-1-pyridiniocomethyl-3-ceph dihydrochloride (670 mg) of em-4-carboxylic acid in tetrahydrofuran (13 m l) Add N-(trimethylsilyl)acetamide (3.41 g) to the suspension, This mixture was warmed to 40°C. 2-(5-amino-1,2, 4-thiadiazol-3-yl)-2-methoxyiminoacetic acid chloride hydrochloride (334 mg) was added at 7°C.

After stirring for 30 minutes at 20°C, the reaction mixture was diluted with ethyl acetate (104 ml) and vinegar. Poured into a mixture of acid (1.64 ml). This mixture was stirred at room temperature for 1 hour, and the obtained The powder was collected by filtration, washed with ethyl acetate (26ml), and dried under reduced pressure. . Dissolve this powder (1.12 g) in water (25 ml) and add IN sodium hydroxide solution. The pH of the solution was adjusted to 9, and the pH of this solution was adjusted to 1 with 6N hydrochloric acid. obtained The precipitate was removed by filtration, and the filtrate was poured into a container filled with Diaion HP-20 (25 ml). It was subjected to ram chromatography. The column was washed with water (200ml).

The target compound was eluted with 35% methanol aqueous solution, and from this eluate (112 ml) The solvent was eluted to 18ml and cooled to 5°C. Filter and collect the resulting powder and dried under reduced pressure to obtain 7β-[2-(5-amino-1゜2.4-thiadiazide). azol-3-yl)-2-methoxyiminoacetamide]-3-[3-(( 5-Hydroxy-4-year-old xo-1,4-dihydropyridin-2-yl)carbonylate -1-pyridiniocomethyl-3-cephem-4-carboxylic acid (180 mg) was obtained.

IR (Nujoll: 1760 cm-1HMR (D20-NaHCO3, 61: 3.19 and 3.68 (21 (, ABq.

J=17.8Hz), 3.92 (3H, sl, 5.25 and 5-6 3 (2H, ABq.

J=14.8) 1zl, 5.29 (1-H, d, J=4.8Hz), 5 ．． 87 (IJt, ti.

J=4.8Hzl, 7.10 (IH, sl, 7.59 (LH, sl, 7.89 (LH.

da, J=5.8Hz and 9.51(z), 8.43+1)1.　 d, J=9.5)1z).

8.61 (IH, d, J=5.8Hzl, 9.48 (LH, s) Fire Blood Alliance Yu 5-(4-methoxybenzyloxy)-2-(3-pyridylcarbamoyl)-4 (IH)-pyridone (441 mg) and sodium 2-ethylhexanoate (1,2 7β-[2-(5 -amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy- 1-methylethoxyimino)acetamide 1-3-chloromethyl-3-cephem Trifluoroacetate of -4-carboxylic acid (2.33 g) was added at 5°C. at 5℃ After stirring for 4 hours, the reaction mixture was added dropwise to ethyl acetate (80 ml). added. The obtained powder was collected by filtration and dried under reduced pressure. This powder (2.28g ) in a mixture of water (30 ml) and acetone (120 ml), and the solution was added to the silica. It was subjected to column chromatography packed with Kagel (45.5 g). target compound By eluting with 80% acetone aqueous solution and freeze-drying the eluate, 7β -[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1- Carboxy-1-methylethoxyimino)acetamide]-3-[3-[(5 -(4-methoxybenzyloxy)-4-oxo-1,4-dihydropyridine- 2-yl)carbonylamino]-1-pyridinio]methyl-3-cephem-4- A carboxylic acid (syn isomer) was obtained. A solution of this compound (250 mg) in formic acid , 35% hydrochloric acid (0,177ml) was added at room temperature. After stirring for 1.5 hours at room temperature This solution was added dropwise to a mixture of ethyl acetate (20 ml) and acetone (10 ml). I added while doing so. The obtained powder was collected by filtration and dried under reduced pressure. obtained powder was dissolved in water (13 ml) and the pH was adjusted to 8 with IN aqueous sodium hydroxide solution. . The pH of this solution was adjusted to 1 with 6N hydrochloric acid, and the resulting precipitate was removed by filtration. . This filtrate was applied to a column chromatograph packed with Diaion HP-20 (6.5ml). I applied it to the fee. The column was washed with water (32.5ml). 3 target compounds By eluting with 5% methanol aqueous solution and freeze-drying the eluate, 7β -[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1- Carboxy-1-methylethoxyimino)acetamide]-3-[3-((5 -Hydroxy-4-xo-1,4-dihydropyridin-2-yl)carbonyl amino)-1-pyridiniocomethyl-3-cephem-4-carboxylic acid (synisomer (79 mg) was obtained.

ER (Nuol);'3-170 cm-1 (2H, ABq, J=14 ．． 4Hzl, 5jl (LH, d, J=4.8Hz), 5.90 (IH, d, J=4.8Hzl, 7.20+:LH,s), 7.71-(IH ,s).

7.96 +LH, dd, J=5.7Hz and 8.3Hz), 8.5 2 (IL d.

J=8.31(z), 8.66 (1B, d, J=5.7Hz), 9. 53　(LH,s)剉1danA- 7β-Amino-3-[3-((5-hydroxy-4-oxo-1,4-dihydro pyridin-2-yl)carbonylamino)-1-pyridiniocomethyl-3-ceph Em-4-carboxylic acid dihydrochloride (780 mg) in tetrahydrofuran (15, 6ml) suspension, add N-(trimethylsilyl)acetamide (3.98g). The mixture was then warmed to 38°C. 2-(2-aminothia) was added to the resulting aqueous solution. sol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxy) 2-benzothiazolyl ester (syn isomer) of (shiimino)-3-thioacetic acid (8 67 mg) was added at 7°C.

After stirring at room temperature for 1 hour, the reaction mixture was mixed with ethyl acetate (125 ml) and acetic acid ( It was poured into a mixed solution of 1.9 ml (1.9 ml). This mixture was stirred at room temperature for 30 minutes. obtained The powder was collected by filtration and mixed with ethyl acetate (30 ml), water (22 ml) and acetic acid. 7B-[2-(2-amino Thiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethyl) Toxiimino)acetamide] -3-[3-((5-hydroxy-4- -1,4-dihydropyridin-2-yl) carbonylamino 1-1-pyridinio Comethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained. This compound Trifluoroacetic acid (2,5 m1) was added dropwise at 7°C. After stirring at room temperature for 2 hours, the resulting solution was Poured into diisopropyl ether (50ml). Filter and collect the resulting powder and dried under reduced pressure. Dissolve this powder in water (15 ml) and add IN sodium hydroxide. The pH was adjusted to 7 with an aqueous solution. The pH of this solution was adjusted to 1 with 6N hydrochloric acid, and the obtained The precipitate was removed by filtration. Transfer this filtrate to Diaion HP-20 (15ml) It was subjected to packed column chromatography. This column was washed with water (75ml). Washed. Elute the target compound with a 50% isopropyl alcohol aqueous solution, and The eluate (120ml) was evaporated to 50ml and cooled to 5°C. profit The resulting powder was collected by filtration and dried under reduced pressure to obtain 7β-[2-(2-alpha). Minothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimide) ) Acetamide] -3-[3-((5-hydroxy-4-oxol, 4- dihydropyridin-2-yl)carbonylamino)-1-pyridiniocomethyl- 3-cephem-4-carboxylic acid (syn isomer) (89 mg) was obtained.

Engineering R (Nujol): 1770 cm-15,30-5,54 (2H, m) , 5.87 (1) 1. d, J=4.8Hz), 6.96+LH,s) , 7.18 +LH,sl, 7.55 +1)1. s3.7.90-8. 00+LH, ml, 8.40-8.6012H, ml, 9.25 TLH, s)Tenhou Masuji (1) 7B-[2-(5-amino-1,2,4-thiadiazol-3-yl)- 2-(1-carboxy-1-methylethoxyimino)acetamide]-3-[ 3-((5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl) carbonylamino)-1-pyridiniocomethyl-3-cephem-4-carboxylic acid (syn isomer) (900 mg) in 4N sulfuric acid (3 ml) was added ethanol ( 6 ml) was added at 5° C. with stirring. This mixture was stirred at 5°C for 0.5 h. . Ethanol (14 ml) was added dropwise to this solution while stirring at 5°C. . The obtained precipitate was collected by filtration and dried to give 7β-[2-(5- amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1 -methylethoxyimino)acetamide] -3-[3-((5-hydroxy- 4-oxo-1,4-dihydropyridin-2-yl)carbonylamino)-1- Pyridiniocomethyl-3-cephem-4-carboxylic acid sulfate (syn isomer) (4 80 mg) was obtained.

Engineering RT Nujol): 1770.1670 (sh) cm-1HMRfD Mso-d6.6): 1.43 +6H,s), 3.44 and 3. 59 (2H.

ABq, J=18Hz), 5.22 (LH, d, J=5Hz), 5.58a nd 5.70 (2H78Bq, J=44)1z), 7. '7B (IH,s) , 8.08-8.18 +2H+18, ml, 8.21 (LH,s), 8.8 5 (IH, d, J=6Hz), 8J8 (IH, d, J=8Hzl, 9.71 fLH,s) The following compounds were obtained in the same manner as in Example 5-(1).

(2) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)- 2-(1-carboxy-1-methylethoxyimino)acetamide]-3-[ 3-, ((5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl ) carbonylamino)-1-pyridiniocomethyl-3-cephem-4-'carbo Phosphate hydrochloride (syn isomer) Engineering R (Nujol): 1770.1670 am-1J=14Hz), 5 ．． 95 (IH, dd, J=5Hz, 8Hz), 7.63 (IH.

s), 8.13 (1) 1. sl, 8.10-8.20 + koH, m), 8. 7B (IH.

a, J=6Hz), 8.95 +IH, d, J=9Hz), 9.56 (IH, (1°J=8Hz), 9.69 (LH, br　s) International search report international search report JP9200685 S^　59657

Claims (1)

[Claims] 1. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1 is an amino group or a protected amino group, Z is N or CH, R2 is hydrogen or an organic residue, R3 means a hydroxy group or a protected hydroxy group) A compound represented by or a pharmaceutically acceptable salt thereof. 2. R1 is an amino group or an acylamino group, R2 is hydrogen, a lower alkyl group, a carboxyl group, Boxy(lower)alkyl group or protected carboxy(lower)alkyl group, R 3 is a hydroxy group or a phenyl group optionally substituted with one or more suitable substituents; 2. The compound according to claim 1, which is a (lower) alkoxy group. 3. R2 is hydrogen, lower alkyl group, carboxy(lower) alkyl group or ester carboxy (lower) alkyl group, R3 is a hydroxy group or a lower alkyl group, Koxyphenyl (lower) alkoxy group The compound according to claim 2. 4. R2 is hydrogen, lower alkyl group, carboxy(lower) alkyl group or lower alkyl group 4. The compound according to claim 3, which is a alkoxycarbonyl (lower) alkyl group. 5. R1 is an amino group, Z is N, R2 is a carboxy (lower) alkyl group, R3 is a hydroxy group 5. The compound according to claim 4. 6.7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2 -(1-carboxy-1-methylethoxyimino)acetamide]-3-[3- {(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)cal bonylamino}-1-pyridinio]methyl-3-cephem-4-carboxylic acid 6. The compound according to claim 5, which is a pharmaceutically acceptable salt thereof. . 7. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1 is an amino group or a protected amino group, Z is N or CH, R2 is hydrogen or an organic residue, R3 means a hydroxy group or a protected hydroxy group) Manufacture the compound shown or its salts by any of the methods (1) to (4) below. how to. (1) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R3 has the same meaning as before) Compounds represented by or reactive derivatives thereof at the amino group or salts thereof And the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R1, R2 and Z each have the same meanings as before) or By reacting reactive derivatives or salts thereof at the carboxy group, the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by (wherein R1, R2, R3 and Z each have the same meaning as before) or obtain its salts; or (2) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1, R2 and Z each have the same meaning as before, and X means a leaving group. do) Compounds shown or their salts and formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R3 has the same meaning as before) By reacting the compound shown by or its salt, the formula: ▲ has a mathematical formula, chemical formula, table, etc. I'm here▼ (In the formula, R1, R2, R3 and Z each have the same meaning as before) obtain a compound represented by or a salt thereof; or (3) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1, R3 and Z each have the same meaning as before, and R2a is protected carboxy (lower) alkyl group) The compound represented by or its salts is subjected to an elimination reaction of its carboxy protecting group. ,formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1, R3 and Z each have the same meaning as before, and R2b is carboxylic acid. to obtain a compound represented by ((lower) alkyl group) or a salt thereof; or (4) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R1, R2 and Z each have the same meaning as before, R3a is protected hydroxy group) or its salts. Following the elimination reaction of the protecting group, the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R1, R2 and Z each have the same meanings as before) or Get the salts. 8. formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R3 means a hydroxy group or a protected hydroxy group) The compound shown in 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. and a pharmaceutically acceptable carrier. 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof is administered to humans or or methods of treating infectious diseases administered to animals. 11. The compound or pharmaceutically acceptable compound according to claim 1 used as an antibacterial agent The salts.