JPH02134384A - Cephalosporin compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [X represents -CH=or -N=; Y represents (protected) amino; Z represents H, methoxy or formamino; R<1> represents (substituted) sulfoalkyl; R<2> and R<3> represents H or acyl; W represents substituent; n is 0-5]. EXAMPLE:Sodium (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2- sulfonatomethoxyiminoacetamido]-3-(6,7-dihydroxy-2-isoquinolinium)meth yl-3- cephem-4-carboxylate. USE:An antibacterial agent against Gram-positive bacteria and Gram-negative bacteria, especially Gram-negative bacteria, more specifically Pseudomonas aeruginosa. PREPARATION:A compound expressed by formula II (R<5> represents group eliminative by reaction with an isoquinoline compound; R<4> represents carboxyl- protecting group; p is 0 or 1) is reacted with an isoquinoline compound expressed by formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION a. Field of Industrial Application The present invention relates to a novel cephalosporin compound and a method for producing the same. More specifically, 2-sulfoalkoxyimino-2-(2-aminothiazol-4-yl)acetamide group or 2-sulfoalkoxyimino-
It has a 2-(2-amino-1,3-thiadiazol-4-yl)acetamide group and a 6,7-hydroxyisoquinolinium methyl group (or an acylated form of its hydroxyl group) at the 3-position. The present invention relates to a novel cephalosporin compound, a pharmaceutically acceptable salt thereof, and a method for producing the same.

The Cefa-Osporin compound and its pharmaceutically acceptable salts of the present invention have extremely strong antibacterial activity and have activity that can strongly inhibit the growth of a wide range of Durum-positive and Durham-negative bacteria. It has particularly excellent antibacterial activity against Durham-negative bacteria, especially Pseudomonas aeruginosa.

b. Prior Art Cephalosporin compounds having, for example, a 2-substituted imino-2-(2-aminothiazol-4-yl)acetamide group at position 7 of the sporin skeleton are known as compounds with antibacterial properties. For example, various compounds as shown below have already been proposed.

(i) JP-A-58-57386 This publication describes 2-substituted imino-2-(2-aminothiazole-4-
Cephalosporin compounds have been proposed that have a group represented by an acetamide group at the 7-position and an isoquilinonium methyl group that may be substituted with a specific substituent at the 3-position.

(ii) JP-A-59-130294 This publication describes 2-substituted imino-2-(2-aminothiazole-
Disclosed is a cephalosporin compound having a 4-yl)acetamido group at the 7-position and a quinolinium methyl group or an isoquilinonium methyl group optionally substituted with a specific substituent at the 3-position. .

(Machi JP-A-63-10793) This publication describes 2-L2-aminothiazole-4- substituted at the 2-position with an alkyl group, an alkenyl group, or an alkynyl group which may be substituted with a carboxy group at the 7-position. Sefa-Osporin compounds having an ircineacetamide group and a dihydroxyisoquinolinium methyl group at the 3-position are disclosed.

C0 Object of the Invention The present invention provides a novel cephalic acid compound having a 6,7-cycloisoquinolinium methyl group (or its acylated form with respect to a hydroxyl group) at the 3-position and a sulfoalkyloxyimino group at the 7-position. An object of the present invention is to provide a 10sporin compound.

Another object of the present invention is to provide novel Cephasporin compounds with a broad antibacterial spectrum and strong antibacterial activity.

Still another object of the present invention is to provide a cephalosporin compound having extremely strong antibacterial activity against Gram-negative bacteria and Gram-negative bacteria.

Still another object of the present invention is to provide a cephalosporin compound having extremely strong antibacterial activity, particularly against Gram-negative bacteria such as Pseudomonas aeruginosa, Salmonella typhi, and Enterobacter.

Still another object of the present invention is to provide a novel Cephasporin compound with excellent water solubility and low toxicity.

Still another object of the present invention is to provide a novel method for producing Cephasporin compounds and their pharmaceutical uses.

Other objects and advantages of the invention will become apparent from the description below.

d6 Components of the Invention Research in the present invention has shown that these objects and advantages are achieved by the following Cephalosporin compounds.

That is, according to the present invention, a Cephasporin compound represented by the following general formula (1) and a pharmaceutically acceptable salt thereof are provided.

One of the features of the Cefa-Osporin compound of the present invention is that it has an isoquinoline skeleton having the following structure at the 3-position.

This isoquinoline skeleton has 10RB at the 6,7-position.
, -0R3 has at least a hydroxyl group or an acyloxy group.

In addition, the characteristics of the cephalosporin compound of the present invention are as follows.
The reason is that it has a 7cetamido group with the following structure at the position.

It shows extremely strong activity.

The cephalosporin compound (I>) of the present invention will be explained in more detail below.

The Sephaosporin compound of the present invention represented by the above formula 1 has the acetamido group having an imino group in which R1 is an optionally substituted sulfoalkyl group, and further has a 2-amino (or protected amino) thiazole -4-yl group or 2-amino (or protected amino) thiadiazole-
It is characterized by having a 4-yl group.

The Cefa-Osporin compound of the present invention having such characteristics has a broad antibacterial spectrum and has excellent physiological activity with extremely strong antibacterial activity. It is particularly strong against Durham-negative bacteria, and can inhibit the growth of bacteria with a surprisingly small amount. Of particular note is that the 2-aminothiazol-4-yl skeleton or the 2-7-minothiadiazol-4-yl skeleton, which has not been found in conventional commercially available cephalosporin compounds against Pseudomonas aeruginosa, is partially removed. has. This skeleton is easily isomerized to a 2-aminothiazolin-4-yl skeleton or a 4-aminothiadiazolin-4-yl skeleton represented by the formula. In the present invention, any of these tautomers or a mixture of the two may be used, and any embodiment is included.

The cephalosporin compound of formula (1) is represented by the formula and partially has imino groups. The imino group moiety to which this R1-0- group is bonded may be either a syn-type or an anti-type, or it may be a mixture of both types. However, the thin type is often preferable because it has stronger antibacterial activity.

Y in the above formula 1 is an optionally protected amino group, and therefore means an amine group itself or an amine group protected by a protecting group. In the case of a protected amino group, those commonly used as amino groups are preferred, and examples of the protecting group include an acyl group and an optionally substituted alkyl group. Examples of such acyl groups include formyl, acetyl, and propionyl.

Lower alkanoyl groups such as butyryl, 1so-butyryl, valeryl, 1so-valeryl, oxalyl, succinyl, pivaloyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, is.

-Propoxycarbonyl, butoxycarbonyl.

Lower alkoxycarbonyl groups such as pentyloxycarbonyl: Lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, 1so-propanesulfonyl, butanesulfonyl; Aroyl groups such as benzoyl, toluoyl, naphthoyl, phthaloyl; phenylacetyl, phenylpropionyl, etc. Aralkayl group: Examples include 7-aralkoxycarbonyl groups such as benzoyloxycarbonyl. Such an acyl group may have one or more suitable substituents. Examples of the substituent include halogen atom diano groups such as chlorine, bromine, iodine, and fluorine; lower alkyl groups such as methyl, ethyl, propyl, and butyl, and the like. Examples of the aralkyl group which may have a substituent include benzyl, 4-methoxybenzyl, phenethyl, trityl, 3,4-dimethoxybenzyl, and the like.

In the cephalosporin compound of the present invention, R1 in Formula 1 is an optionally substituted sulfoalkyl group.

In this case, the unsubstituted sulfoalkyl group includes sulfomethyl, 1-sulfoethyl, 2-sulfoethyl, 1-sulfopropyl, 2-sulfopropyl, 3-sulfopropyl, 4-sulfo-n-butyl, sulfo-tert-butyl, sulfopentyl, sulfohexyl, sulfoheptyl,
Straight chain or branched 01-Coo such as sulfooctyl
Sulfoalkyl groups or C3-Coo cyclic sulfoalkyl groups such as 1-cyclopropyl, 1-cyclobutyl, 1-cyclopentyl, and 1-cyclohexyl are mentioned.

When such a sulfoalkyl group has a substituent, examples of the substituent include halogen atoms such as chloro and bromine, aromatic groups such as amine group, hydroxy group, and phenyl group,
Carbamoyl group, carboxyl group, lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, imidazolyl.

Examples include heterocyclic groups such as 2-aminothiazolyl and 1-methyl-1-day-tetrazolyl.

Preferred examples of R1 include sulfomethyl group, 1-sulfo-ethyl group, 1-sulfo-1-methyl-ethyl group, 1
-sulfo-1-cyclopentyl group and the like.

In the CefaOsporin compound of the present invention, X in Formula 1 is -C1-1= or -N=, forming a thiazole ring or a thiadiazole ring, respectively.

There is no problem with either.

Further, 7 in the formula (1) is a hydrogen atom, a methoxy group or a formylamide group, and among these, a hydrogen atom or a methoxy group is preferable, and a hydrogen atom is particularly preferable.

As described above, the cef-10 sporine compound of the present invention has an isoquinoline skeleton at the 3rd position, which has at least 10R2 and 10R3 groups at the 6th and 7th positions, as shown by the formula (3). Here, R2 and R3 are each independently a hydrogen atom or an acyl group, and the acyl group is preferably an aliphatic acyl group. As R2 and R3, a hydrogen atom or an acyl group having 2 to 4 carbon atoms is advantageous, and a hydrogen atom or an acetyl group is particularly preferred.

The isoquinoline skeleton only needs to contain two substituents, 10R2 and 10R3, at the 6 and 7 positions, and may further contain other substituents [-(W)n] at other positions. do not have. In this case, the number of substituents (n) is 0 to 5, and O to
2 is preferable, and O-1 is particularly preferable. This substituent (−
W) may be any of a variety of substituents, but may be the same as the substituent for R1 described above for R1.

Examples of W include: amino group; alkylamino group having 1 to 4 carbon atoms; di(alkyl having 1 to 4 carbon atoms) amino group; hydroxyl group; alkoxy group having 1 to 4 carbon atoms; rubamoyl group: Carbamoyloxy group: thiocarbamoyl group; acyloxy group having 2 to 4 carbon atoms, diano group, halogen atom, halogenated alkyl group having 1 to 4 carbon atoms: sulfo group, aminosulfonyl group; alkanoyl group having 2 to 4 carbon atoms; number of carbon atoms 1 to 4 alkyl group: carboxyl group: alkoxycarbonyl group having 1 to 4 carbon atoms; hydroxy carbon number 1
-4 alkyl group; formyl group and the like.

Furthermore, in the Cepha and Rosporin compounds of formula (1) of the present invention, the cation at the 3-position forms salts with various anions. Examples of the anions include Cf), -, Br
-, CH3COO-, CCj! :+COO-.

Examples include -basic acid ions such as CF3CO0-.

Other salts of the cephalosporin compound of formula 1 include salts at the carboxyl group (-Cooe) at the 4-position. Examples of such salts include alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), ammonium salts, salts with organic bases (triethylamine salts, methylmethylamine salts, pyridine salts, etc.). salt, etc.).

The cephalosporin compound of formula (1) may also be an ester in which the carboxyl group at the 4-position is esterified. Such esters are preferably physiologically easily hydrolyzed. Such esters include, for example, flukoxyalkyl esters such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl ester; acetoxymethyl, propioxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl Furucyloxyalkyl esters such as esters: indanyl, phthalidyl, glycyloxymethyl, phenylglycyloxymethyl esters, and the like.

The Cephasporin compound, its salt, or its ester of the present invention is chemically stable if it is in the form of a crystal. Therefore, crystalline cef-10 sporin compounds, salts thereof or esters thereof are preferred when used as active ingredients in pharmaceutical compositions.

Such crystals may be anhydrous or hydrates such as 3/4-hydrate, 1-hydrate, 1,5-hydrate, 3-hydrate, and 5-hydrate. .

Preferred specific examples of the cephalosporin compound of the present invention are as follows. These are merely examples;
The present invention is not limited to these.

(1) (6R,7R)-7-[(Z)-2-(2aminothiazol-4-yl)-2-sulfonatomethoxyimino-acetamide]-3-(6°7-hydroxy-2
-isoquinolinium) methyl-3-cephem-4-carboxylate sodium (2) (6R,7R)-7-[Z-2-(2~amino-
Sodium 1,3-thiadiazol-4-yl)-2-sulfonatomethoxyimino-acetamide]3-(6,7-cyhydroxy-2-isoquinolinium)methyl-3-cephem-4-carboxylate (3) (6R,7R ) −7−[(Z) −2
-(2aminothiazol-4-yl)-2-(2-sulfonatoethoxyiminoacetamidoco-3-(6,7
-cyhydroxy-2-inquinolinium)methyl-3-
Cephem-4-carboxylate sodium (4) (6R,7R) -7-i: (Z) -2
-(2-7minothiazol-4-yl)-2-(1-sulfonato-1-methyl-ethoxyimino-acetamide]-3-(6,7-dihydroxy-2-isoquinolinium)methyl-3-cephem-4-carboxylate Sodium<5)(6R,7R)-7-[(Z)-2-(2-amino-1,3-thiadiazol-4-yl)-2-(2-
sulfonatoethoxyimino-acetamide]-3-(6
,7-hydroxy-2-isoquinolinium)methyl-
Sodium 3-cephem-4-carboxylate (6) (6R,7R)-7-[(Z)-2-amino-1
,3-thiadiazol-4-yl)-2-(1-sulfonato-1-methyl-ethoxyimino-acetamide]-
3-(6,7-cyhydroxy-2-isoquinolinium)
Sodium methyl-3-cephem-4-carboxylate (7) (6R,7R)-7-[(Z) -2-(2-
aminothiazol-4-yl)-2-(1-sulfonatoethoxyimino-acetamido]-3-(6,7-cyhydroxy-2-isoquinolinium)methyl-3-cephem-4-carboxylate sodium (8) (6R, 7R)-7-[(Z)-2-(2-amino-1,3-thiadiazol-4-yl)2-(1-sulfonatoethoxyimino-acetamide]-3-(6,
7-hydroxy-2-isoquinolinium)methyl-3
- Sodium cephem-4-carboxylate The cephalosporin compound (1) of the present invention, its salts and its esters can be obtained by various synthetic methods.

Some of them will be explained below, but the cephalosporin compound of the present invention is not limited to these synthesis methods.

叉辉戎Al This reaction formula A is a method in which a Cephasporin compound of formula (2) is reacted with an isoquinoline compound of formula (3). The reaction product (1) can be subjected to deprotection, salt formation, esterification and/or reduction reactions as required.

In formula (2), X, Y, Z and R1 are represented by the above formula (1
), and R5 is an acyloxy group.

represents a carbamoyloxy group or a halogen atom, p
represents O or 1, and R4 represents a hydrogen atom or a protective group.

Preferred examples of the acyloxy group in R include acetyloxy, trifluoroacetyloxy, trichloroacetyloxy, propionyloxy, 3-oxobutyloxy, 3-carboxypropionyloxy, and 2-carboxybenzoyloxymanzolyloxy. , 2-(carboethoxycarbamoyl)benzoyloxy, 2-(carboethoxysulf7moyl)benzoyloxy, 3-ethoxycarbamoylpropionyloxy, and the like.

Examples of halogen atoms include iodine and bromine.

Examples include chlorine.

Examples of protecting groups for R4 include methyl and ethyl.

Propyl, iso-propyl, butyl, pentyl.

Lower alkyl groups such as hexyl; alkanoyloxyalkylmethoxymethyl such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl; flukoxyalkyl such as ethoxymethyl, methoxyethyl, ethoxyethyl Group: optionally substituted aralkyl group such as benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, diphenylmethyl, bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl; 2-iodoethyl, 2 , 2. 2-trichloroethyl and other halogenated furkyl groups: vinyl.

Alkenyl groups such as allyl: optionally substituted allyl groups such as phenyl, 4-chlorophenyl, tolyl, xylyl, mesityl; trialkylsilyl groups such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tributylsilyl, etc. It will be done. Among these, R4 is preferably a trialkylsilyl group. When R4 is a trialkylsilyl group, in the reaction of reaction scheme A, Δ2- of the cephalosporin derivative of formula (1)
Since the production of isomers is suppressed, the desired cephalosporin compound of formula (1) can be obtained in high yield.

The cephalosporin compound of formula (2) may be a salt thereof. Preferred salts include the same salts as those exemplified in the cephalosporin compound of formula (1).

In the isoquinoline compound (3) in the reaction formula A, R2 and R3 are the same or different and represent a hydrogen atom or an acyl group, but these may be a phenolic hydroxyl group or a protective group normally used for catechol.

Acyl groups used include acetyl, trifluoroacetyl, trichloroacetyl, propionyl, and 3-oxybutyl.

Examples include 3-carboxypropionyl, 2-carboxyacetyl, 2-carboxybenzoyl, 4-carboxybutyryl)benzoyl, 2-(carboethoxysulf7moyl)benzoyl, 3-ethoxycarbamoylpropionyl, and the like. As the protecting group, one selected is one which is normally used for phenol or catechols and which gives the desired product (1) through a mild elimination reaction. Such protecting groups include methyl, methoxymethyl, 2-methoxyethoxymethyl, methoxythiomethyl, tetrahydropyranyl, phenacyl, aryl, cyclohexyl.

Ethers such as t-butyl, benzyl, 0-nitrobenzyl, 4-picolyl; trimethylsilyl.

Silyl ethers such as t-butyldimethylsilyl, carbonates such as methyl carbonyl, 2,2,2-trichloroethyl carbonyl, and benzyl carbonyl; sulfonates such as methanesulfonyl and p-toluenesulfonyl; and used as protective groups for catechol. Examples include methylene acetal, diphenylmethylene ketal, and cyclic carbonate, and these protecting groups can be selected and used as required.

In formula (3), W and n mean the same groups, atoms, and numbers as defined in formula (1) above.

Furthermore, the compound of formula (3) may be a salt thereof, and preferred salts include, for example, inorganic acid salts (hydrochloride, hydrobromide, sulfate, phosphate, etc.).

Examples include organic acid salts (acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.).

The cephalosporin compound of formula (2) or its salt and the formula (
The reaction 3) with the isoquinoline compound or its salt is carried out by bringing the two into contact in an inert organic solvent.

Examples of inert organic solvents include methylene chloride, dichloromethane, chloroform, carbon tetrachloride, 1,2
-Hydrogen halides such as dichloroethane, diethyl ether, and tetrahydrofuran.

Ether compounds such as dioxane and dimethoxyethane; hydrocarbons such as hexane, benzene, toluene, and xylene; acetonitrile, dimethylformamide, diethylacetamide, dimethyl sulfoxide, and ethyl acetate.

The compound of formula (3) may be a salt thereof, and preferred salts include, for example, inorganic acid salts (hydrochloride, hydrobromide, sulfate, phosphate, etc.).

Examples include organic acid salts (acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.).

A Cephasporin compound of formula (2) or a salt thereof and a formula (
The reaction 3) with the isoquinoline compound or its salt is carried out by bringing the two into contact in an inert organic solvent.

Examples of inert organic solvents include methylene chloride, dichloromethane, chloroform, carbon tetrachloride, 1,2
-Hydrogen halides such as dichloroethane, diethyl ether, and tetrahydrofuran.

Examples include ethers such as dioxane and dimethoxyethane; hydrocarbons such as hexane, benzene, toluene, and xylene; acetonitrile; dimethylformamide: diethylacetamide; dimethyl sulfoxide; and ethyl acetate.

The reaction temperature is preferably room temperature or lower, and is usually carried out in the range of -30°C to +50°C.

A Cephasporin compound of formula (2) or a salt thereof;
Equimolar amounts react with the isoquinoline compound of formula (3) or its salt, but when carrying out the reaction, usually
The isoquinoline compound of formula (3) or a salt thereof is 0.
It is used in an amount of 7 to 10 times the mole, preferably 1.0 to 10 times the mole.

The reaction proceeds by simply stirring the two, and the reaction time varies depending on the reaction solvent, reaction site, etc., but is usually 5 minutes to 3 hours.

The reaction product can be isolated and purified by known means such as solvent extraction, crystallization, and chromatography.

In this reaction formula A, the compound (2
), the target compound (1) of the syn isomer is increased by 1. When a mixture of syn and anti isomers of compound (2) is used as a raw material, the desired product (
A mixture of syn and anti isomers of 1) is obtained. Such mixtures can be separated by conventional means such as crystallization, chromatography, etc.

The reaction product is deprotected and salted as necessary.

Subjected to esterification and/or reduction reactions.

The deprotection reaction is a well-known reaction per se, and the protecting group for a carboxyl group can be removed by a hydrolysis reaction in the presence of an acid or an alkali. The protecting group for the amine group can be removed by acid or catalytic reduction (see US Pat. No. 4,152,433 and US Pat. No. 4,298,606).

The salt-forming reaction is a known reaction per se, and for example, the compound having the betaine structure of formula (1) obtained by the above reaction is treated with hydrochloric acid, hydrobromic acid, @ acid, phosphoric acid, or acetic acid.

An acid such as trifluoroacetic acid: or betaine in the presence of an acid, sodium chloride, or sodium iodide.

This is done by treatment with a salt such as potassium chloride.

The esterification reaction is a reaction known per se, and the resulting cephalosporin compound of formula (1) or a salt thereof and an alkanoyloxyalkyl halide.

acetone with alkoxyalkyl halide, etc.

This is carried out by reaction in an inert organic solvent such as dimethylformamide (UK Patent No. 240921).
(see specification).

The reduction reaction is a known reaction per se, and is carried out by treating a cephalosporin compound in formula (1) where p is 1 with acetyl chloride, etc., and then reducing it with iodide ions, sodium diionite, etc. (See above-mentioned British patent specification).

For example, the following method can be used to obtain the crystalline cephalosporin compound of the present invention.

An amorphous powder of the cephalosporin compound of formula (1) is mixed with water: an organic solvent such as methanol, ethanol, acetone, tetrahydrofuran, dioxane, and acetonitrile:
Alternatively, a method of dissolving the powder in a mixed solvent of these and leaving it to precipitate as a crystal; a method of recrystallizing an amorphous powder using these solvents; or a method of dissolving the amorphous powder in water and then precipitating it as a crystal using the above organic solvent. There is a method of adding i12 to precipitate it as crystals.

On the other hand, as another method, the acid addition salt of the cephalosporin compound of formula (1) is added to water or methanol.

There is also a method of obtaining crystals by dissolving it in an organic solvent such as ethanol, propatool, or a mixed solvent thereof, and then neutralizing it with a base such as triethylamine or sodium hydroxide.

As mentioned above, when crystallizing or recrystallizing in water or a solution containing water, a crystalline hydrate is usually obtained. When crystallized in an organic solvent, a crystalline anhydride or solvate can be obtained. Solvates are easily converted to anhydrides. A crystalline anhydride or solvate can be converted into a hydrate by standing in a gas containing water vapor.

In Reaction Formula B, a compound of formula (4), a salt thereof, or a reactive derivative thereof, and a compound of formula (5), a salt thereof.

React with the ester or its reactive derivative. The reaction product is subjected to deprotection, salt formation, esterification and/or reduction reactions as necessary.

In formula (4), X, Y and R1 are the same as defined in (1) above.

The compound of formula (4) may be a salt, and examples of the salt include acid addition salts. Examples of such acid addition salts include those exemplified as the acid addition salt of the compound of formula (3) in reaction formula A.

Examples of reactive derivatives of the compound of formula (4) include acid halides, acid anhydrides, mixed acid anhydride-activated amides, and activated esters.

Examples of acid halides include acid chloride.

Acid bromides are mentioned. Examples of mixed acid anhydrides include dialkyl phosphoric acid and phenyl phosphoric acid.

Examples include mixed acid anhydrides with acids such as pivalic acid and pentanoic acid. Examples of activated amides include amides activated with imidazole, triazole, tetrazole, dimethylpyrazole, and the like. Examples of activated esters include cyanomethyl ester and methoxymethyl ester.

Examples include dimethyliminomethyl ester, p-nitrophenyl ester, mesylphenyl ester, and the like.

In formula (5), Z, R2, R3, W and 0 are the same as defined in (1) above. Salts of the compound of formula (5) include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; organic bases such as trimethylamine salts, triethylamine salts, and pyridine salts. and the same acid addition salts as mentioned above.

Examples of the ester of the compound of formula (5) include compounds esterified with the same group as exemplified as the protecting group for R4 in the compound of formula (2) of reaction formula A.

Reactive derivatives of the compound of formula (5) include, for example, Schiff base-type imino compounds formed by reaction with carbonyl compounds such as acetoacetic acid or their enamine-type isomers: bis(trimethylsilyl)acetamide, trimethylchlorosilane. , silyl derivatives produced by reaction with silyl compounds such as tert-butyldimethylchlorosilane; derivatives obtained by reaction with phosphorus trioxide and phosgene, and the like.

The compound of formula (5) can be produced by the following method.

Synthesis method of (5) (0)p (5'') (0)p The above reaction is carried out in the same manner as the reaction between the compound of formula (2) shown in reaction formula A and the isoquinoline compound of formula (3). It can be carried out.

The reaction of compound (4), a salt thereof, or a reactive derivative thereof with compound (5), a salt thereof, an ester thereof, or a reactive derivative thereof is carried out in an inert organic solvent, if necessary in the presence of a condensing agent or a base. This is done by bringing the two into contact.

Examples of inert organic solvents include methylene.

Halogenated hydrocarbons such as chloride, dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; Ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; Hydrocarbons such as hexane, benzene, toluene, and xycin; Examples include acetonitrile; dimethylformamide; diethyl sulfoxide and the like.

A base may be added during the reaction. Such bases include, for example, alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal carbonates, trialkylamines, N, N-
Dialkylbenzylamine.

Examples include organic or inorganic bases such as pyridine and N-furkylmorpholine. The amount of such a base to be used is usually equivalent to three times the mole of compound (4), its salt, or a reactive derivative thereof.

When compound (4) or a salt thereof is used in the reaction, a condensing agent may be added. Examples of the condensing agent include N,
Examples thereof include N'-dicyclohexylcarbodiimide, N-cyclohexyl N'-morpholinoethylcarbodiimide, trimethylphosphite, triphenylphosphine, and 2-ethyl-7-hydroxybenzisoxazolium salt. The amount of such a condensing agent used is usually 1 to 3 times the amount of compound (4) or its salt.

Compound (4), a salt thereof, or a reactive derivative thereof and compound (5), a salt thereof, an ester thereof, or a reactive derivative thereof are usually reacted in approximately equimolar amounts.

The reaction temperature is usually carried out under cooling or at room temperature.

The reaction usually completes in several minutes to several tens of hours.

The reaction product can be isolated and purified by known means such as solvent extraction, crystallization, and chromatography.

Deprotection, salt formation, esterification and/or reduction of the reaction product can be carried out in the same manner as shown in Reaction Formula A. Reaction formula A is also used when obtaining crystals of the target product.
This can be done in the same manner as shown in .

In this reaction, when the syn isomer of compound (4) is used as the starting compound, the target compound (1) of the syn isomer is
is obtained. When a mixture of syn and anti isomers of compound (4) is used as a raw material, a mixture of syn and anti isomers of target compound (1) is obtained. Such mixtures can be separated by conventional means such as crystallization, chromatography, etc.

Reaction Formula C (0) p + 82 N -OR+ In Reaction Formula C, a compound of formula (6), a salt thereof, or an ester thereof is reacted with a compound of formula (7), a protected compound thereof, or a salt thereof. The reaction product is subjected to deprotection, salt formation, esterification and/or reduction reactions as necessary.

In formula (6), X. Y, Z, R2, R3,
W, n and p are the same as defined above.

Examples of the salt of the compound of formula (6) include acid addition salts. or alkali metal salts, alkaline earth metal salts, ammonium salts, or salts with organic bases. Specific examples of these salts include the same salts as described for the compound of formula (1).

Examples of the ester of the compound of formula (6) include compounds esterified with the same group as exemplified as the protecting group for R4 of the compound of formula (2) in reaction formula A.

The compound of formula (6) can be produced by the following method.

... Synthesis method of process (6) (0)p (6゛) (0)p The above reaction is a reaction between the compound of formula (2) and the isoquinoline compound of formula (3) shown in reaction formula A. It can be carried out in the same manner as the reaction.

In formula (7), R1 is the same as defined above.

Examples of the protected compound (7) include, when R1 has an active substituent such as a carboxy group, a compound in which these substituents are protected with a commonly used protecting group.

Examples of the salt of compound (7) include acid addition salts, and specific examples thereof include those mentioned above.

A part of the compound of formula (7) is a known compound, and a known method using halogenoalkyl sulfonic acid (JP-A-59-1999)
88462).

Compound (6), its salt or its ester and compound (7)
), the reaction with the protected compound or its salt is carried out by bringing the two into contact in an inert organic solvent, if necessary in the presence of a base.

Examples of inert organic solvents include methanol.

Examples include alcohols such as ethanol, propatool, and butanol. These inert organic solvents may contain water.

Examples of the base that may be added if necessary include the same bases as those used in the reaction of Reaction Formula B.

The amount of the base to be used is usually 1 to 3 times the amount of the compound of formula (6), its salt, or its ester. formula(
The compound of formula (6), its salt or its ester, and the compound of formula (7), its protected compound.

or a salt thereof, and the reaction is usually carried out using equimolar amounts of each.

The reaction temperature is usually carried out under cooling or at room temperature.

The reaction time is usually several minutes to several tens of hours. The reaction product can be isolated and purified by known means such as solvent extraction, crystallization, and chromatography.

In this reaction, a mixture of syn and anti isomers of the compound is obtained.

Such mixtures can be separated by conventional means such as crystallization, chromatography, etc.

Deprotection, salt formation, esterification and/or reduction reactions can be carried out analogously to the reaction formula. When obtaining a crystalline anhydride or hydrate of the target product, the same method as shown in Reaction A can be used.

In the reaction formula, a compound of formula I-(1), a salt thereof, or an ester thereof is reacted with a compound of formula (10). The reaction product is subjected to deprotection, salt formation, esterification and/or reduction reactions as necessary.

In formula I-(1), X, Y, Z, R1, R2
, R3°w, n, and o are the same as defined above.

The salt of the compound of formula I-(1) is an acid addition salt.

Or alkali metal salts, alkaline earth metal salts.

Examples include ammonium salts and salts with organic bases. Specific examples of these salts include the same salts as described for the compound of formula (1).

Examples of the ester of the compound of formula I-(1) include compounds esterified with the same group as the protecting group for R4 in the compound of formula (2) of reaction formula A.

The compound of formula I-(1) can be produced by the following method.

L2 (1) Goshokujou (0) p (0) p 0■ (4゛) In the above reaction, the reaction between the compound of formula (5') and the compound of formula (3) is expressed by reaction formula A. The reaction between the compound of formula (5) and the compound of formula (4°) can be carried out in the same manner as the reaction described in reaction formula B. The compound of formula (4'') is a known compound and can be produced by a known method (US Pat. No. 4,298,606).

In formula (10), Hai represents a halogen atom such as chlorine, bromine, or iodine. Compounds of formula (10) can be obtained by halogenating the corresponding aromatic hydrocarbon by conventional means.

The reaction of the compound of formula I-(1), its salt or ester thereof with the compound of formula (10) is carried out by bringing the two into contact in an inert solvent, optionally in the presence of a base. .

Examples of inert solvents include alcohols such as methanol, ethanol, propatool, and butanol; methylene chloride, and dichloromethane.

Examples include halogenated hydrocarbons such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; dimethylformamide and diethylacetamide; ethyl acetate; and water.

If necessary, the reaction may be carried out in the presence of a base.

Examples of such bases include alkali metal hydroxide, alkali metal hydrogen carbonate, alkali metal carbonate, trialkylamine, N,N-dialkylbenzylamine, pyridine,
Examples include organic or inorganic bases such as N-alkylmorpholine.

The amount of such base to be used is usually determined by the amount of the compound of formula I-(1),
The molar amount is 1 to 3 times that of the salt or ester.

The compound of formula (10) is usually used in an amount of 1 to 3 times the mole of the compound of formula I-(1), its salt, or its ester.

Although the reaction temperature is not particularly limited, it is usually carried out under cooling to heating to about the boiling point of the solvent.

The reaction time is usually several minutes to several tens of hours.

The reaction product can be isolated and purified by known means such as solvent extraction, crystallization, and chromatography. In this reaction, when the syn isomer of compound I-(1) is used as the starting compound, the syn isomer of compound I-(1) is obtained. When a mixture of syn and anti isomers of compound I-(1) is used, compound I-(1)
A mixture of syn and anti isomers of ) is obtained. Such mixtures can be separated by means such as crystallization and chromatography.

Deprotection, salt formation, esterification, and reduction reactions can be carried out in the same manner as shown in reaction formula A. Also when obtaining a crystalline anhydride or hydrate of the target product, reaction formula A
This can be done in the same manner as shown in .

Reaction formula E (0) p + YNH-C-NH2→ This reaction formula E shows a method for synthesizing a compound when X is 10H= in the general formula (2).

In reaction formula E, a compound of formula (8), a salt thereof, or an ester thereof is reacted with a compound of formula (9) or a salt thereof. The reaction product is subjected to deprotection, salt formation, and
Subjected to esterification and/or reduction reactions.

In formula (8), Y, Z, R', R2, R3,
W, n and p are the same as defined above, and R6 is chlorine.

Represents a halogen atom such as bromine or iodine.

Examples of the salt of the compound of formula (8) include alkali metal salts, alkaline earth metal salts, and ammonium salts.

There are salts with organic bases or acid addition salts. Specific examples of these salts include the same salts as described for compound (1).

As the ester of the compound of formula (8), for example, reaction A
Examples include compounds esterified with the same group as the protecting group for R4 of the compound in (2).

The compound of formula (8) is produced as follows.

Synthesis method of (8) (0)p ↑ (0)p (8') (0)p In the above reaction, the reaction between the compound of formula (5') and the compound of formula (3) is performed in reaction formula A. It is carried out analogously to the reaction described. The reaction between the compound of formula (5) and the compound of formula (8°) is carried out in the same manner as the reaction described in reaction formula B. The compound of formula (8°) is a known compound and can be prepared by a known method (for example, British Patent No. 2,012,276).
(No. 2003).

In formula (9), R1 represents a hydrogen atom or a protective group. The compound of formula (9) is a known compound (US Pat. No. 4,298,606).

Examples of the salt of the compound of formula (9) include acid addition salts,
Specific examples of such acid addition salts include acid addition salts similar to those described for the compound of formula (1).

A compound of formula (8), a salt thereof or an ester thereof and formula (9)
) with the compound or its salt in an inert solvent,
This is done by bringing the two into contact.

Examples of inert solvents include water:methanol.

Examples include alcohols such as ethanol, propatool and butanol; ethers such as diethyl ether; tetrahydrofuran and dioxane; dimethylformamide; dimethylacetamide; methylpiperidone; and the like. Mixtures of these solvents can be used as well.

The compound of formula (9) or its salt is usually used in a molar amount of 1 to 3 times the amount of the compound of formula (8), its salt, or its ester.

Although the reaction temperature is not particularly limited, it is usually carried out at a temperature from room temperature to about the boiling point of the solvent.

The reaction time is usually about 1 to 10 hours.

The reaction product can be isolated and purified by known means such as solvent extraction, crystallization, and chromatography.

Deprotection, salt formation, esterification and/or reduction reactions can be carried out in the same manner as shown in Reaction Scheme A. When obtaining a crystalline anhydride or hydrate of the target product, the same method as shown in Reaction Formula A can be used.

The cephalosporin compound of formula (1) of the present invention, particularly the cephalosporin compound of formula (1) in which Y is an amino group, or a pharmaceutically acceptable salt thereof or an ester thereof, can be used to treat a wide range of Durum-positive bacteria and Durum-positive bacteria. It shows high antibacterial activity against negative bacteria and is useful for treating bacterial infections in animals including humans. The cef-10 sporin compound of the present invention has strong antibacterial activity against Durum-negative bacteria such as Pseudomonas aeruginosa, Salmonella typhi, and Enterobacter, and against Durum-positive bacteria such as Staphylococcus aureus, Streptococcus pyogenes, and Bacillus subtilis. . Furthermore, the Cefa-Osporin derivative of the present invention is characterized by a long duration of action.

The cephalosporin compounds of the present invention, pharmaceutically acceptable salts thereof, or esters thereof are administered parenterally or orally. Examples of dosage forms for parenteral administration include intravenous or intramuscular injections, academic regulations, and the like. Injections can take the form of aqueous or oily solutions, suspensions, and the like.

It may also be in the form of powders or crystals that are reconstituted with sterile water before administration. The academic regulations include preparations made of ordinary excipients such as cocoa butter and glycerides and, if necessary, absorption enhancers.

When administered orally, conventional capsules.

There are tablets, granules, etc., and these include absorption enhancers.

It may contain a preservative or the like.

These various formulations can be manufactured by methods well known in the art.

The dosage of the cephalosporin compound, its pharmaceutically acceptable salt, or its ester of the present invention varies depending on the age, symptoms, and mode of administration, but is usually 10 to 2000 mM per day.

The present invention will be explained in more detail below with reference to Examples.

Example 1 (6R,7R)-7-[2-(2-tolylaminothiazol-4-yl)-2-oxoacetamide]-3-(
6,7-dihydroxyisoquinolinium)methyl-3
- 385 ma of cephem-4-carboxylate in a mixture of 50 d of methanol and 12 min of aminooxymethane sulfone.
Add 54 mg and 10 Inl of water and dissolve. Add 230 μl of concentrated hydrochloric acid to this and react at room temperature for 48 hours. Methanol was distilled off under reduced pressure and the pH was adjusted to 6.5 with 0.1-N caustic soda aqueous solution.
And so.

Next, this reaction solution was added to 1007 acetone to obtain a precipitate. The obtained compound was subjected to liquid chromatography [
Column: RP-18, elution solvent: water-methanol mixed solvent, detection: UV wavelength at 260] to obtain the target compound (70 ma >. (Compound ■) IR (cm-'): 1775 NMR (d6-DMSO) δ: 3.462H,brs), 4.62(2H,brs)
.

5.21111. d, J=5.4Hz), 5.51(
2N,brS).

5.851H, dd, J=5.4Hz, 8.3Hz),
6.82 (1N, S).

7.461H,S), 7.61(IH,S).

8.181H, d, J=7.3H2), 8.34(I
H, d, J = 7.3Hz).

9.481H,S), 9.69(IH,d, J=8.
3Hz).

Example 2 In vitro antibacterial activity In vitro antibacterial activity was measured by the agar plate dilution method.

Various test bacteria were cultured overnight in Tryptocase-Soypros, and the platinum loops (viable bacterial count: 106/7) were streaked onto Mueller-Hinton agar containing various concentrations of the compound of the present invention.
Incubate at 7°C for 16 hours and increase the minimum inhibitory concentration (IVLIc).
, μ0/ml). The results are shown in Table I, It.

table ■ CAZ (Sectazigym) table ■ Special permission Out wish Man Teijin Corporation

Claims (1)

[Claims] 1. The following general formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼... I [Here, X is -CH= or -N=, Y is an optionally protected amino group, and Z is Hydrogen atom, methoxy group or formamino group, R^1 is an optionally substituted sulfoalkyl group, R^2 and R^3 are the same or different hydrogen atom or acyl group, W is a substituent, n is 0 to Represents an integer of 5. ] A compound represented by or its salts. 2. General formula (2) below ▲Mathematical formulas, chemical formulas, tables, etc.▼...(2) [Here, X is -CH= or -N=, Y is an optionally protected amino group, and Z is a hydrogen atom , methoxy group or formamino group, R^1 is an optionally substituted sulfoalkyl group or a salt thereof, R^5 is a group that can be removed by reaction with the isoquinoline compound (3) described below, R^4 is carboxyl The group protecting group p represents 0 or 1. ] Compounds represented by the following general formula (3) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼... (3) Here, R^2 and R^3 are the same or different, hydrogen atom or acyl group, W is a substituent , n represents an integer from 0 to 5. The following general formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼... I [Here, X, Y , Z, R^1, R^2, R^3, W and n have the same meanings as above. ] A method for producing a cephalosporin compound and its salts. 3. General formula (4) below ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(4) [Here, X is -CH= or -N=, Y is an optionally protected amino group, and R^1 is Represents an optionally substituted sulfoalkyl group. ] Compounds represented by, salts thereof, or reactive derivatives thereof, and the following general formula (5) ▲ Numerical formulas, chemical formulas, tables, etc.▼...(5) [Here, Z is a hydrogen atom, a methoxy group, or a formylamino group, R^2 and R^3 are the same or different hydrogen atoms or acyl groups, W is a substituent, n is an integer of 0 to 5, p
represents 0 or 1. ], a salt thereof, an ester thereof, or a reactive derivative thereof is reacted with the following general formula I ▲Mathematical formula, chemical formula, table etc. ▼... I [Here, the definitions of X, Y, Z, R^1, R^2, R^3, W and n have the same meanings as above. ] A method for producing a cephalosporin compound and its salts. 4. General formula (6) below ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼... (6) [Here, X is -CH= or -N=, Y is an optionally protected amino group, and Z is a hydrogen atom , a methoxy group or a formamino group, R^2 and R^3 are the same or different and represent a hydrogen atom or an acyl group, W represents a substituent, and n represents an integer of 0 to 5. p is 0 or 1. ] A compound, its salt or ester represented by the following general formula (7) NH_2O-R^1...(7) [Here, R^1 represents an optionally substituted sulfoalkyl group. ] The following general formula I ▲Mathematical formulas, chemical formulas, tables, etc. are included▼ ... I [Here, the definitions of X, Y, Z, R^1, R^2, R^3, W and n have the same meanings as above. ] A method for producing a cephalosporin compound and its salts. 5. The following general formula I - (1) ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼... (1) [Here, X is -CH= or -N=, Y is an optionally protected amino group, and Z is A hydrogen atom, a methoxy group or a formamino group, R^2 and R^3 are the same or different and are a hydrogen atom or an acyl group, W is a substituent, n is an integer of 0 to 5, and p is 0 or 1. [Here, R^1 is an optionally substituted sulfoalkyl group or a salt thereof, and Hal is a halogen. represents an atom. ] The following general formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼... I [Here, X, Y , Z, R^1, R^2, R^3, W and n have the same meanings as above. ] A method for producing a cephalosporin compound and its salts.