JPH04112890A - New thiazole derivative and antimicrobial agent containing the same derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> to R<3> are H, alkyl, acyl, etc.; R<4> is (protected) amino; R<5> is H or ester residue or carboxy-protecting group; X is H, halogeno, alkyl, etc.] or a salt thereof. EXAMPLE:(Z)-2-(2-Aminothiazol-4-yl)-2-(3,4,5- trimethoxyethoxymethoxybenzyloxyimino)acetic acid. USE:An antimicrobial agent. PREPARATION:First, a compound shown by formula II is reacted with a compound shown by formula III in the presence of a condensation agent N,N'- dichlorohexylcarbodiimide in a solvent such as THF at -50 to 30 deg.C and acylated. Then, the prepared compound shown by formula IV is reacted and alkylated with a compound shown by the formula R<6>OH (R<6> is group shown by formula V) in a solvent such as THF in the presence of a base such as pyridine generally at -30 to 100 deg.C.

Description

Detailed Description of the Invention [Second Industrial Application Fields] The present invention provides novel thiazole derivatives useful as antibiotics,
The present invention relates to intermediates for producing the same and antibacterial agents containing the compound as an active ingredient.

2 Conventional techniques The development of cephalosporin derivatives has been remarkable, and Clam-positive bacteria and Pseudomonas aeruginosa (Pseudomonas aeruginosa) have been rapidly developed.
The antibacterial activity against Clam-negative bacteria including Monas aeruginosa has also been improved. However, resistant Clam-positive bacteria such as methicillin-resistant Staphylococcus aureus (MR5A) and Pseudomonas aeruginosa (Ps.
eudamana Saeruginosa), Pseudomonas cep
acia) and Serratia marcesc
It could not be said that the antibacterial activity against such substances as ens) was still sufficient.

[Problem to be solved by the invention]

An object of the present invention is to provide a new thiazole derivative, an intermediate for producing the same, and an antibacterial agent that has more excellent antibacterial activity than conventionally known compounds.

Two ways to solve the problem: 2) A wide range of applications against Clam-positive bacteria such as methicillin-resistant Staphylococcus aureus and Clam-negative bacteria such as Pseudomonas aeruginosa - 1) Efforts to create cephalosporin derivatives with antibacterial activity As a result of investigation, the present invention was completed based on the knowledge that 2-aminothiazole derivatives having a 3,4゜5-trihydroxyphenylmethyloxyimino group as the 7-position substituent have excellent antibacterial activity. be.

That is, the present invention provides a thiazole derivative represented by the following general formula [I] or a nontoxic salt thereof, and an antibacterial agent containing the compound.

(wherein R', R2, and R3 may be the same or different), hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted acyl group, a hydroxyl protecting group, or R
1 and R2 or R2 and R3 may be taken together to form a cyclic diol protecting group, R4 is an amino group or a protected amine group, and R5 represents hydrogen, an ester residue or a carboxy protecting group. , X is hydrogen, halogeno group, alkoxy group, alkyl group, vinyl group, or CH2Y (Y
is hydrogen or a nucleophilic residue). ) The compound of the above formula [I] can be efficiently produced from the compound of the following general formula [■].

It's the taste. ) In the above formula, the alkyl group in R' R2 and R3 is, for example, a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, te
It means an alkyl group having 1 to 10 carbon atoms such as rt-butyl group. Examples of acyl groups include formyl, acetyl, propionyl, butyryl, which have 1 to 10 carbon atoms.
It means an aromatic carboxylic acid acyl group such as a lower aliphatic carboxylic acid acyl group, benzoyl, p-chlorobenzoyl, p-methylbenzoyl, and manzoloyl. The substituents used for the substituted alkyl and substituted acyl groups are usually 1 to 4 substituents selected from among the amino group, carboxy group, halogeno group, cyano group, hydroxy group, alkoxy group, alkyl group, acyl group, and phenyl group. can do. As the hydroxy protecting group, any commonly used protecting groups known per se can be used. For example, methoxymethyl, 2-methoxyethoxymethyl, ■-ethoxyethyl, tetrahydropyranyl, alinobe t-butyl, (wherein R'-R5 has the same meaning as in formula CIL, benzyl, trimethylsilyl, t-butyldimethylsilyl,
It means formyl, acetyl, chloroacetyl, pyaroyl, benzoyl, 2,2.2-)lichloroethoxycarbonyl, and the like. The cyclic diol protecting group means, for example, methylene, ethylidene, impropylidene, cyclohexylidene, diphenylmethylene, carbonyl, hydroxyborane, and the like.

In the protected amino group of R4, any commonly used protecting group known per se can be used as the protecting group for the amino group, such as an aliphatic carboxylic acid acyl group which may be substituted with a halogen. (For example, formyl,
acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, etc.), lower alkoxycarbonyl groups having 2 to 7 carbon atoms optionally substituted with halogen (e.g. , methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarpho'
lower alkanesulfonyl groups (e.g. methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl) ), aromatic sulfonyl groups (e.g., benzenesulfonyl, toluenesulfonyl, etc.), aromatic acyl groups (e.g., benzoyl,
toluoyl, naphthoyl, phthaloinobeindane carbonyl, etc.), al(lower) alkanoyl groups (e.g., phenylacetyl, phenylpropionyl, etc.), cyclo(lower)alkyl(lower)alkanoyl (e.g., cyclohexylacetyl, cyclopentylacetyl, etc.), Al (
(lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p
-methoxybenzyloxycarbonyl, phenethyloxycarbonyl, etc.), monohetriphenyl(lower)alkyl (e.g. benzyl, phenethyl, diphenylmethyl, triphenylmethyl, etc.), lower alkoxycarbonyl(lower)alkylidene or its enamine tautomer (
For example, 1-methoxycarbonyl-1-propene-2-
), di(lower) alkylaminomethylene (e.g., dimethyl phosphinomethylene, etc.), aromatic phosphinyl group (e.g., diphenylphosphinyl, etc.), aromatic phosphinothioyl group (e.g., diphenylphosphinothioyl group) ), aromatic sulfenyl groups (e.g. 3-nitro-
2-pyridine sulfenyl group, etc.).

Examples of the ester residue in R5 include lower alkyl groups such as methyl, ethyl, and t-butyl, lower alkoxymethyl groups such as methoxymethyl, lower alkanoyloxymethyl groups such as acetoxymethyl and pivaloyloxymethyl, and l-( Lower alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxy)ethyl, phthalidyl groups, (5-methyl-2-oxo-1,3-dioxo-
(5-substituted-2-oxo-1 such as
, 3-dioxol-4-yl)methyl group, active ester residues such as benzotriazolyl, and the like.

As the carboxyl protecting group, any commonly used protecting group known per se can be used, for example,
Lower alkanoyloxy (lower) alkyl esters (e.g. acetoxymethyl ester, propionyloxymethyl ester, phthyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.), lower alkanesulfonyl (lower) alkyl ester (e.g., 2-mesylethyl ester, halo(lower) alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.) ), which may have at least one substituent (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, 1 cyclopropylethyl ester, etc.), lower alkenyl esters (e.g., vinyl esters, allyl esters, etc.), lower alkynyl esters (e.g., ethynyl ester, propynyl ester, etc.), even if they have at least one suitable substituent. Good alkyl esters [e.g. mono (or di or tri) phenyl (lower) alkyl esters] (e.g. benzyl esters, 4-
Methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.)
, aryl esters which may have at least one suitable substituent (e.g. t!f, phenyl ester, 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl esters, etc.).

Nucleophilic compound residues in Y include, for example, a hydroxyl group, a mercapto group, a cetyloxy group, a probionyl group, a 3-oxbutyryloxy group, a 3-carboxypropionyloxy group, a 3-ethoxycarbamoylpropionyloxy group, Optionally substituted lower aliphatic carboxylic acid acyloxy group having 2 to 4 carbon atoms such as 4-carboxybutyryloxy group, manzolyloxy group, 2-carboxybenzoyloxy group, 2-(carboethoxycarbamoyl)benzoyloxy group, 2- Protection of optionally substituted aromatic carboxylic acid acyloxy groups such as (carboethoxysulfamoyl)benzoyloxy groups, carbamoyloxy groups, cyano, azide, amino, carbe'moylthio, thiocarbamoyloxy, and amino groups (e.g., N-mono-, di- and trihalogenoacetylcarbamoyloxy groups such as N-chloroacetylcarbamoyloxy group, N-dichloroacetylcarbamoyloxy group, N-trichloroacetylcarbamoyloxy group, N-chloroacetylcarbamoyloxy group, etc.) Examples include sulfonylcarbamoyloxy group, N-)IJ methylsilylcarbamoyloxy group), and phenylglycyloxy group. Alternatively, these nucleophilic compound residues may further contain an alkyl group (e.g., 1 carbon number such as methyl, ethyl, propyl, etc.).
~3 lower alkyl groups), acyl groups (e.g., lower aliphatic carboxylic acid acyl groups having 2 to 4 carbon atoms such as acetyl, propionyl, butyryl, etc., aromatic groups such as benzoyl, p-chlorobenzoinoperumethylbenzoyl, manzoloyl, etc.) (carboxylic acid acyl group), and in this case, the number of substituents is usually 1 to 2. Alternatively, the nucleophilic compound residue may be a quaternary ammonium group. Examples of quaternary ammonium groups include pyridinium, quinolinium, picolinium, lutidinium, substituted pyridinium, substituted quinolinium, substituted picolinium, and substituted lutidinium (herein, substituents include, for example, alkyl groups, acyl groups, halogeno groups, hydroxy groups, mercapto group, cyano group, carboxy group, amino group, carbamoyl group, carbamoyloxy group, sulfo group, hydroxymethyl group, carboxymethyl group, sulfoethyl group, trifluoromethyl group, N-methylcarbamoyl group, N,N-diethylcarbamoyl group The nucleophilic compound residue also represents a betero ring bonded via S, that is, a petero ring thio group. Here, the petero ring is 1 to 4 selected from 0, S, or N. 5~ containing 5 different atoms
It is a 6-membered ring or a fused heterocycle thereof, and the nitrogen atom may be oxidized. Examples of these heterocyclic rings include pyridyl, N-oxytopyridyl, pyrimidyl, pyridazinyl, N-oxytopyridazinyl, pyrazolyl, diazolyl, thiazolyl, 1. 2. 3-
Thiadiazolyl, 1.2.4-thiadiazolyl, ■.

3.4-thiadiazolyl, 1,2.5-thiadiazolyl, 1,2.3-oxadiazolyl, 1,2°4-oxadiazolyl, 1. 3. 4-oxadiazolyl, I,
2.5-oxadiazolyl, l, 2゜3-triazolyl, 1.2.4-triazolyl, IH-tetrazolyl, 2
H-tetrazolyl, S triazolo L 11 D
a J Pyrimidin-7-yl and the like are frequently used. In addition, on these heterocycles, for example, lower alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, propyl, methoxy,
Lower alkoxy groups having 1 to 3 carbon atoms such as ethoxy and propoxy, lower alkenyl groups, lower alkynyl groups, chloro,
Halogen atoms such as bromine, trihalogen-substituted lower alkinobenzoyl groups such as trifluoromethyl and trichloroethyl, hydroxyl groups, mercapto groups, amino groups, carboxyl groups, carbamoyl groups, and carbon atoms having 1 to 3 carbon atoms such as dimethylaminoethyl and dimethylaminomethyl. Di-lower alkylamino lower alkyl group, carboxy lower alkyl group such as carboxymethyl group, lower acyl group such as acetyl, amino lower alkyl group, carbamoyl lower alkyl group, aryl lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxycarbonyl (-) may have a substituent such as a nitro group, a sulfo group, or a sulfoalkyl group such as ethylnato. When these substituents are substituted on the petero ring, the number of substituents is usually 1 to 4.

Addition salts with the base as non-toxic salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts such as trimethylamine salts, triethylamine salts, Aliphatic amine salts such as dicyclohexylamine salts, ethanolamine salts, jetanolamine salts, triethanolamine salts, etc., aralkylamine salts such as N,N-dibenzylethylenediamine, such as pyridine salts, picoline salts, quinoline salts or isoquinoline. Heterocyclic aromatic amine salts such as salts, such as quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, methyltrioctylammonium salt or tetrabutylammonium salt,
Examples include basic amino acid salts such as arginine salts and lysine salts.

Examples of addition salts with nucleic acids include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate, and sulfate; for example, acetate. , propionate, lactate, maleate, tartrate, fumarate, malate, citrate, ascorbate, organic acid salts such as methanesulfonate, benzenesulfonate, p-toluene. Examples include sulfonate salts such as sulfonate salts, and acidic amino acid salts such as aspartic acid and glutamic acid.

Furthermore, the oxime in the formula represented by a wavy line represents either a syn-axis (yn) isomer, an anti-isomer, or a mixture thereof.

In addition, although the 2-amino-1,3-thiazolyl group is thought to have a tautomeric structure as shown below, it will be expressed as a 2-amino-1,3-thiazole compound throughout this specification, and thereby 2-imino-1,3-thiazoline bodies are also included.

(I) (IV) Next, a method for producing the compound of the present invention will be explained.

- The derivative represented by formula [1] can be produced, for example, by method (1) or method (H) shown below.

In the above formula, R6 is a group represented by the following formula (R', R2, and R' have the same meanings as above).

X2 is a halogen atom, methanesulfonyl, p-
h Represents a leaving group such as luenesulfonyl. In addition, in the above formula, any one or more of a carboxyl group protecting group, a hydroxyl group protecting group, an amino group protecting group is It shall be possible to include a step of removing. Further, the above formula can include a step of protecting one or more of a carboxyl group, a hydroxyl group, an amino group, or a plurality of these groups at an appropriate step in the formula.

In the above formula, R', R5, R6, An optionally substituted lower aliphatic carboxylic acid acyloxy group having 2 to 4 carbon atoms such as butyryloxy group, 3-carboxypropionyloxy group, 3-ethoxycarbamoylpropionyloxy group, 4-carboxybutyryloxy group, manzolyloxy basis,
2-carboxybenzoyloxy group, 2(carboethoxycarbamoyl)benzoyloxy group, 2-(carboethoxysulfamoyl)benzoyloxy group, etc., optionally substituted aromatic carbonated acyloxy group, carbamoyloxy group, amino group protected carbamoyloxy group (e.g., N-chloroacetylcarbamoyloxy group, N-dichloroacetylcarbamoyloxy group, N
−)! J dichloroacetylcarbamoyloxy group which N
-mono-, di- and trihalogenoacetylcarbamoyloxy groups, N-chlorosulfonylcarbamoyloxy groups, N-)IJ methylsilylcarbamoyloxy groups),
Examples include phenylglycyloxy group. Alternatively, these nucleophilic compound residues may further contain an alkyl group (e.g.
lower alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, and propyl), acyl groups (e.g., acetyl, propionyl,
(lower aliphatic carboxylic acid acyl group having 2 to 4 carbon atoms such as butyryl, aromatic carboxylic acid acyl group such as benzoyl, p-chlorobenzoyl, p-methylbenzoyl, manzoloyl); in this case, The number of substituents is usually 1 to 2.

In addition, in the above formula, any one or more of a carboxyl group protecting group, a hydroxyl group protecting group, an amino group protecting group is It shall be possible to include a step of removing. In addition, in the above formula, a carboxyl group,
The method may include a step of protecting either a hydroxyl group or an amino group, or a plurality of them.

(2) The compound represented by formula (XI) can be produced, for example, by the methods (1) and (2) shown below.

(XXVI) The compound represented by (XXVI+>) can be produced, for example, by the method shown below.

(XI) (XXIX) H, N0R6 Conventional methods can be used for the reactions in each of the above production methods. More specifically, the following methods may be mentioned.

(a) Three-position conversion reaction (1) A compound of the general formula (XXm) is stirred with a compound of the formula (Vl) in a solvent.

For (XXIV) or (VI), salts thereof can be used. Salts with basic groups include, for example, salts with mineral acids such as hydrochloric acid, nitric acid or sulfuric acid; oxalic acid,
Salts with organic carboxylic acids such as succinic acid, formic acid, trichloroacetic acid or trichloroacetic acid; methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (2゜4.8-)! J methylbenzenesulfonic acid), naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, phenylmethanesulfonic acid, benzene-1,
3-disulfonic acid, toluene-3,5-disulfonic acid,
naphthalene-1,5-disulfonic acid, naphthalene-2,
6-disulfonic acid, naphthalene 2,7-disulfonic acid,
Benzene-1,3,5=trisulfonic acid, benzene-1
,2,4-) disulfonic acid, naphthalene-1,3,5-
Salts with sulfonic acids such as trisulfonic acid, and salts with acidic groups include, for example, salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium or magnesium; ammonium salts; Powerin, dibenzylamine, N-benzyl-β
-Phenethylamine, N+N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine and other salts with nitrogen-containing organic bases can be mentioned.

Moreover, these salts may be isolated beforehand and used.
Alternatively, it may be prepared within the reaction system. Examples of the solvent used include water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, dimethylformamide, formamide, N-methylformamide, acetamide, N-methylacetamide, methanol, and ethanol. Moreover, a mixture of these can also be used. This reaction is
carried out at 0°C to 150°C, preferably room temperature to 100°C,
It can be completed in a few minutes to several tens of hours. Furthermore, in the case of an aqueous reaction solvent, it is desirable to control the pH of the reaction solution during the reaction.

(2) The compound of general formula (XXIV) and the compound of general formula (VI) are stirred in a solvent in the presence of an acid or an acid complex.

The acid or acid complex used in this reaction includes, for example, a protonic acid, a Lewis acid, or a Lewis acid complex. Examples of protonic acids include sulfuric acids, sulfonic acids, and super strong acids (super strong acid means an acid stronger than 100% sulfuric acid, and also includes some of the above-mentioned sulfuric acids and sulfonic acids); Specifically, sulfuric acids such as sulfuric acid, fluorosulfuric acid, and fluorosulfuric acid; alkyl (mono- or di)sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid, or aryl(s) such as p-)luenesulfonic acid; Sulfonic acids such as mono-, di- or tri-sulfonic acids; perchloric acid, magic acid (FSO3H-5bF5), FS
OJ-AsFs, CH35O3H-3bF5゜HF
-BF3. Examples include super strong acids such as H2SO, -3o, and the like.

Furthermore, examples of the Lewis acid include boron trifluoride. In addition, examples of complex compounds of Lewis acids include dialkyl ether complex salts of boron trifluoride and diethyl ether, di-n-propyl ether, di-n-butyl ether, etc.; ethylamine, n-propylamine, n-butylamine; , amine complex salts with triethanolamine, etc.; carboxylic acid ester complex salts with ethyl formate, ethyl acetate, etc.; fatty acid complex salts with acetic acid, propionic acid, etc.;
Examples include IJ complex salts.

In addition, it is preferable to use an organic solvent in this reaction, and examples of organic solvents that can be used include all organic solvents that are inert to the reaction, such as nitromethane, nitroethane, nitropropane, natononitroalkanes; formic acid, acetic acid, and Organic carboxylic acids such as fluoroacetic acid, dichloroacetic acid, and propionic acid; acetone, methyl ethyl ketone,
Ketones such as methyl isobutyl ketone; ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole, dimethyl celsolve; ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate,
These include esters such as ethyl acetate and butyl acetate; nitriles such as acetonitrile and butyronitrile; halokenated hydrocarbons such as methylene chloride, chloroform, and 2-dichloroethane; and sulfolanes such as sulfolane; You may use a mixture of two or more types. Moreover, a complex compound formed by these organic solvents and a Lewis acid can also be used as a solvent.

The amount of the acid or acid complex compound to be used may be at least equimolar to the compound of the general formula (XXI) or its salt, and can be increased or decreased as appropriate depending on the individual case. When using an acid complex compound, it can be used itself as a solvent, or two or more kinds of complex compounds can be used as a mixture.

Further, the amount of the nucleophilic compound of the general formula (VI) or its salts may be at least equimolar to the general formula (XXm) or its salts, but is particularly 1.0 to 5.0 times the molar amount. It is preferable to use

This reaction is usually carried out at 0 to 80°C and is completed in several minutes to several tens of hours.

If moisture is present in the reaction system, undesirable side reactions such as lactonization of the raw material or product and cleavage of the β-lactam ring may occur, so it is desirable to maintain the reaction system in an anhydrous state. In order to satisfy this condition, a suitable dehydrating agent is added to the reaction system, such as phosphorus pentoxide, poIJ
Phosphorus compounds such as IJ acid, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride; Organic silylating agents such as N,O-bis(trimethylsilyl)acetamide, trimethylsilylacetamide, trimethylchlorosilane, dimethyldichlorosilane; acetyl chloride, p - Organic acid chlorides such as toluenesulfonyl chloride; acid anhydrides such as acetic anhydride and trifluoroacetic anhydride; inorganic drying agents such as anhydrous magnesium sulfate, anhydrous calcium chloride, molecular sieves, and calcium carbide, etc. may be added.

(b) Acylation reaction A compound of the general formula (Va) or (Vb) or a reactive derivative thereof at the amino group or a salt thereof is treated with the compound of the general formula (■), (■), (IX), (X) or ( XI)
The reaction is carried out by reacting a compound, a reactive derivative in its carboxyl group, or a salt thereof.

General formula (Va), (Vb), (■), (■), ([X)
, (X) or (XI) include salts in basic groups or acidic salts similar to those explained for the salts of (XXIV) or (VI) in (a).

As the reactive derivative at the amino group of the compound of general formula (Va) or (Vb), those used in general acylation reactions are used. For example, isocyanates, compounds of general formula (Va) or (Vb) or their salts, silyl compounds such as bis(trimethylsilyl)acetamide, trimethylsilylacetamide, trimethylsilyl chloride, phosphorus trichloride, (CH2CH2O)2PCβ, (CH3CH2)2
Phosphorus compounds such as P[1,A or (C1H3>35
Examples include silyl derivatives, phosphorus derivatives, and tin derivatives produced by reaction with tin compounds such as ncl.

General formula (■), (■), (IX), (X) or (XI
) As the reactive derivative at the carboxyl group of the compound, those used in general acylation can be used. For example, acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, and general formula (■)
, (■), (IX), (x) or (XI) and reactive derivatives of the Vilsmeier reagent. Examples of mixed acid anhydrides include mixed acid anhydrides with carbonic acid monoalkyl esters such as carbonic acid monoethyl ester and carbonic acid monoisobutyl ester, and lower alkanoic acids which may be substituted with halogen such as pivalic acid and trichloroacetic acid. Mixed acid anhydrides and the like are used. Examples of active acid amides include N-acylsaccharin, N
-acylimidazole, N-acylbenzoylamide,
N, N'-dicyclohexyl-N-acylurea, N-
Acylsulfonamide and the like are used. Next, as the active ester, for example, cyanomethyl ester,
Substituted phenyl esters, substituted benzyl esters, substituted thienyl esters, benzotriazole esters, sufushiimide esters, and the like are used.

In addition, as a reactive derivative with Vilsmeier reagent,
Acid amides such as N,N-dimethylformamide, N,N-dimethylacetamide, phosgene, thioninochloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethylchloroformate, oxalyl chloride, etc. Examples include derivatives reactive with Vilsmeier's reagent obtained by the action of a halogenating agent.

General formula (■), (■), (IX) (X) or (x
If the compound of l) is used in the form of a free acid or salt, a suitable condensing agent is used. As such a condensing agent,
For example, N,N'-disubstituted carbodiimides, such as N,N'-dicyclohexylcarbodiimide; N,
Azolide compounds such as N'-thionyldiimidazole; N-ethoxycarbonyl-2-ethoxy-1,2
- Dehydrating agents such as hydroxyquinoline, phosphorus oxychloride, and alkoxyacetylene; 2-halogenopyridinium salts such as 2-chloropyridinium methyl iosito and 2-fluoropyridinium methyl iosito; and the like are used.

This acylation reaction is generally carried out in a suitable solvent in the presence or absence of a base. As a solvent, e.g.
Halogenated hydrocarbons such as chloroform and methylene chloride; Aromatic hydrocarbons such as benzene and toluene; Ethers such as tetrahydrofuran and dioxane: N,
N-dimethylformamide, N,N-dimethylacetamide, acetone, water, or mixtures thereof can be used. In addition, as a base, inorganic bases such as alkali hydroxide, alkali hydrogen carbonate, alkali carbonate or alkali acetate; trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine, 4-dimethyl Examples include organic bases such as tertiary amines such as aminopyridine and secondary amines such as dicyclohexylamine and diethylamine.

The reaction temperature is not particularly limited, but is usually -78°C to 60°C,
The reaction is preferably carried out at -50°C to 30°C, and the reaction is usually completed in several minutes to several tens of hours.

(c) Alkylation reaction ■ - Formula (■), (XIX), (XX), (XXI
II) or (XXVI) with general formula (HV)
This is carried out by reacting a compound of 1 in the presence of a base.

Any solvent may be used as long as it does not inhibit this reaction, such as tetrahydrofuran, dioxane,
Methanol, ethanol, chloroform, methylene chloride, ethyl acetate, butyl acetate, NN-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, water, etc., or mixtures thereof, etc. are used. Examples of bases used include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and tertiary bases such as triethylamine, pyridine, and N,N-dimethylaniline. Examples include organic salts such as amines or secondary amines such as dicyclohexylamine and diethylamine.

The reaction is generally carried out at -30°C to 100°C and is completed in several minutes to several tens of hours.

■ - Formula (Xll), (XIX), (XX), (XX
III) or (XX~i) and the compound of general formula (Xll
1) by subjecting it to a commonly used dehydration reaction.

Examples of reagents used in the dehydration reaction include tri-substituted phosphine and azodicarboxylic acid ester.

Examples of the trisubstituted phosphine used include triarylphosphines such as triphenylphosphine, triaryloxyphosphine such as triphenoxyphosphine, trialkoxyphosphine such as triethoxyphosphine, or trialkylphosphine such as triethylphosphine. . Examples of the azodicarboxylic acid esters used include diethyl azodicarboxylate and diisopropyl azodicarboxylate.

Examples of the solvent include ether solvents such as tetrahydrofuran, dioxane, and diethyl ether, aromatic solvents such as benzene and toluene, hexamethylphosphoric triamide, and mixtures thereof.

General formula (Xll), (XIX), (XX), (XXII
[), 1 is for the compound of (XXVI) - formula (
The compound of
, 8 to 1.2 times the mole, trisubstituted phosphine is used 1 to 3 times the mole, preferably 1 to 1.5 times the mole, and azodicarboxylic acid ester is used 1 to 3 times the mole, preferably 1 to 1.5 times the mole. It will be done.

The reaction temperature is -50°C to 80°C, preferably 30°C to 30°C.
It is ℃. The reaction is completed in 1 to several tens of hours.

(d) General formula for ring-closing reaction, (Xll) (XV), (XX) and (XX
I) the compound or its salt, - formula (XVII)
This is done by reacting the following compounds.

This reaction is usually carried out in a solvent. Any solvent may be used as long as it does not inhibit this reaction, and examples thereof include water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, and N.

N-dimethylformamide, N,N-dimethylacetamide, N-methylpyridone, or a mixed solvent of two or more of these is used. Although it is not particularly necessary to add a deoxidizing agent, the reaction may proceed smoothly if the deoxidizing agent is added in an amount within a range that does not change the cephalosporin skeleton. Examples of deoxidizers used in this reaction include inorganic or organic bases such as alkali metal hydroxides, alkali metal hydrogencarbonates, triethylamine, pyridine, and N,N-dimethylaniline.

The reaction is generally carried out at a temperature in the range of 0 to 100°C.

Usually, the general formula (Xll), (XV), (XX) MariL!
(XVII) is used in an amount of one to several times the mole of the compound (XXI) or its salt. The reaction time is usually
The time is from 1 to several tens of hours, preferably from 1 to 10 hours.

(e) Oxime formation reaction The reaction is carried out by reacting a compound of general formula (X), (XV[), or (xxII) or a salt thereof with a compound of general formula (XVIII) or a salt thereof.

Examples of the salts of the compound of general formula (XVIII) include hydrochloride, hydrobromide, and sulfate. This reaction is usually carried out in a solvent such as water or alcohol, a solvent inert to the reaction, or a mixed solvent thereof, and the reaction is usually carried out at a temperature of 0 to 100°C, preferably 10°C.
It is carried out at a temperature of ~50°C and is completed in 10 minutes to 48 hours.

The compound of general formula (XVIII) is used in an amount of 1 to several times the molar amount of the compound of general formula (X), (XVI) or its salt.

(f) Defthaloyl reaction The dephthaloyl reaction of the compound of general formula (XXIX) is carried out using a conventional dephthaloyl reaction, for example, using hydrazine such as hydrazine hydrate or N-methylhydrazine.

Although it is not necessary to use a solvent, methanol, ethanol, methylene chloride, etc. are usually used as the solvent, and the reaction is usually carried out at a temperature of 0 to 100°C and is completed in a few minutes to several days.

Isolation of the derivative of the present invention synthesized as described above is as follows:
This may be carried out by appropriately utilizing isolation methods known per se (extraction method, column chromatography method, recrystallization method, etc.).

Further, some of the derivatives of the present invention have optical isomers, and in this case, each of these isomers and mixtures thereof are also included in the present invention. It was confirmed by elemental analysis, infrared absorption spectrum, nuclear magnetic resonance spectrum, mass spectrometry, etc. that the compound of the present invention has the chemical structure described above.

The compound of general formula (1) or its salts obtained as described above can be administered to humans and animals in the form of free forms, non-toxic salts, and compounds that can be converted into these in vivo. . In that case, it may be prepared in the form usually applied to cephalosporin drugs, such as solid dosage forms such as tablets, capsules, powders, granules, and pills, or solutions, suspensions, and emulsions. Examples of liquid column types include: When preparing the above formulations, if necessary, excipients such as starch, lactose, glucose, calcium phosphate, binders such as starch, microcrystalline cellulose, carboxymethyl cellulose, lubricants such as talc, magnesium stearate, and disintegrating Agents, diluents, additives, etc. may also be used.

Administration can be carried out either orally or parenterally.

Examples of parenteral administration include intravenous administration, intramuscular administration,
Examples include subcutaneous administration or halving.

The dosage varies depending on the age, sex, weight, symptoms, etc. of the subject, but it is usually about 50 mg per adult per day.
~5000 mg may be administered in 1 to 4 divided doses.

Next, the present invention will be explained with reference to examples.

〔Example〕

Reference Example 1 Gallic acid (340 mg, 2.0 mmole) and
Methoxyethoxymethyl chloride (2,2m+j!,
19.3 mmole) in THF solution (8 mn) at 0°C.
Diisopropylethylamine (2,8+
nj! , 16, 1 mmole) was added dropwise. 6 at room temperature
After stirring for an hour, the mixture was diluted with water and ethyl acetate.

Extracted twice with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in THF (15 mβ), and LM LAH ether solution (6 mj!, 6 mmole) was added dropwise while stirring at 0°C under argon. 1
Stir for an hour, dilute with water and ethyl acetate. The reaction solution was filtered, extracted twice with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (Si20
10 g of ethyl acetate) to obtain 809 mg (yield: 96%) of the title compound as a colorless oil.

NMR: δ1.6-1.7 (LH,br), 3
．． 36(3)1. s).

3.38(6H,s), 3.56(6)1. m
), 3°82 (4H1m).

3.98 (2H, m), 4.58 (2H, s), 5
．． 19 (2H, s).

5.27 (4H,s), 6.90 (IH,s)M
S: 420 (M”) Reference Example 2 7 I:/ (94 mg, 0.36 mmole) and N-hydroxyphthalimide (60.5 mg, 0.3
After stirring for 10 minutes, diethyl azodicarboxylic acid was added dropwise over 3 minutes at -20°C. After stirring at the same temperature for 30 minutes, the mixture was returned to room temperature over 30 minutes, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was collected using a Roper column (manufactured by Merck & Co., Ltd., 5160.5ize A).

Hexane: Ac0Et=3:1-1:
1-+1: 2-+Ac0Etonly),
184 mg of the title compound was obtained as a colorless oil.

NMR: δ3.36(3H,s), 3.38(
6H,s), 3.55(6H,m), 3.8H
4H,m), 3.96 (2H,m).

5.12 (2 days, s) 5.20 (2tl, s
), 5.28 (4H,s).

7.06(2)1. s ), 7.73 (2H, m
), 7. lH(2)(,m)MS: 565(M
”) Reference Example 3 Compound of Reference Example 1 (126 mg, 0.30 mole)
The compound of triphenylphos Reference Example 2 (171 mg, 0.30 mmol) was added to a THF solution (3+y+j7) at room temperature.
Hydrazine hydrate (35 μβ, 0.72 mole) was added to 3 mjl of the methylene chloride solution (e) at room temperature, and 1
Stir for hours. Water was added to the reaction solution, the methylene chloride layer was washed twice with water, and then dried with anhydrous sulfuric acid. After dehydration with IJium, the solvent was distilled off under reduced pressure to obtain 130 mg of the title compound (yield 100%).
) was obtained as a colorless oil.

NMR: δ3.38(9)1. s), 3.5
7 (6H, m ), 3.82 (4H, m ), 3.
98 (2H, m), 4.60 (2H, s).

5.20 (2H,s), 5.28 (4H,s),
5. '42 (1) 1. br, s).

6.90 (2H,s) Example 1 Compound of Reference I13 (65 mg, 0.15 mmole
) in methanol solution (1 mA) of (2-amino-4-thiazolyl)-glyoxylic acid (26 mg, 0.15 mm
After stirring at room temperature for 1 hour, the reaction solution was filtered. The filtrate was concentrated to obtain 85 mg (yield 97%) of the title compound as a colorless oil.

NMR: δ3.28 (9H, m), 3.57 (6
day, m), 3.81 (4H, m), 3.9
8 (2H, m), 5.10 (2H, s).

5.18 (2H, m >, 5.24 (4H, m )
, 6.80 (IH,s).

6.90 (2N, s) Example 2 Compound of Reference Example 3 (28 mg, 0.06 mmole)
methanol solution (1+r+j) of (2-tritylamino-4-thiazolyl)-glyoxylic acid (27 mg).

After stirring at room temperature for 30 minutes, the reaction mixture was added with ethyl acetate and washed successively with a 5% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Compound 52 mg (yield 9
8%) was obtained as a colorless oil.

NMR: δ3.3B(3H,s), 3.39(6
H,s), 3.543.61(6H,m), 3
．． 79-3.82 (4) 1. m ), 3.96 (2
H.

m) 5.18(21(,s), 5.20(2)
1. s), 5.22 (4H.

s ), 6.62(it(,s), 6.96(2
H,s), 7.24-7.32 (15H,m) Example 3 Methyl Compound of Example 1 (80 mg, 0.14 mmole)
methylene chloride solution (7β-amino-
3-[[2-(diphenylmethoxycarbonyl)-5-
Diphenylmethyl methyl[1,2,4])riazolo[1゜5-a]pyrimidin-7-yl]thiomethyl]3-cephem-4-carboxylate (purity 88%, 116 mg,
0.14 mmole), DCC (34 mg, 0.1
6 mmole), methanesulfonic acid (8.8 μi, 0
．． 16 mmole) and stirred at room temperature for 1 hour.

The resulting insoluble matter (dicyclohexylurea) was filtered, and the filtrate was diluted with ethyl acetate, washed with a 5% aqueous citric acid solution and 5% hydrogen carbonate, washed sequentially with an aqueous solution of IJ and saturated saline, and dissolved with anhydrous sulfuric acid. After dehydration, the solvent was distilled off under reduced pressure. The resulting residue was transferred to a Rover column (manufactured by Merck & Co., Ltd., 5
i60.5ize A, [fl[J 3only-C
H[l:A 3: ! , 1eOfl=20:1
) to obtain 128 mg (yield 71%) of the title compound as a reddish brown solid.

NMR: δ252(3H,s), 3.24(6H
, s ), 3.30 (3H,' s ), 3.42
-3.52 (6H, m), 3.84-3.88 (4
Day.

m) 3.92-3.96 (2H, m), 4.2
8 (IH, ABq).

4.31 (LH,ABq), 5.08(1)1.
d), 5.15-5.20 (48m), 5,2
2(4)1. s ), 5.62 (2H, m ),
5.94 (LH.

dd ), 6.78(LH,s >, 6.88(L
H,s), 6.90 (IH6), 6.92 (IH
,s), 7.20-7.42 (16H,m).

7.48-7.52 (4H, m) MS (FAB): 1326 (MH”) [R (KBr)
: 1790.1740 cm Example 4 7β[(Z)-2-(2-)Ritylaminothiazol-4-yl)-2-(3,4,5-)rimethoxyethoxymethoxybenzyloxyimino) Example 2 Compound (5
3 mg, 0.06 mmole) in methylene chloride solution (
Diphenylmethyl 7-β-amino-3-[(1-methyltetrazol-5-yl)thiomethyl]-3-cephemu-4-carboxylate (32 mg, 0
．． 06 +u+ole), DCC (16mg, 0.08
mmole) and stirred at room temperature overnight. The resulting insoluble matter (dicyclohexylurea) was filtered, and the filtrate was diluted with ethyl acetate, washed with a 5% aqueous citric acid solution and 5% hydrogen carbonate, washed sequentially with an aqueous solution of IJ and saturated saline, and dissolved with anhydrous sulfuric acid. The solvent was distilled off under reduced pressure. The resulting residue was collected using a Roper column (Merck 5160.5).
ize A, Hexane:Ac0Et=3:1
-1:1) to give the title compound 44 mg (yield: 52
．． 8%) was obtained as a reddish-brown solid.

NMR: δ3.22 (6H,s), 3.38 (3
)1. s ), 3.463.50 (4H, m ),
3.52-3.56 (2H, m), 3.64 (2
H.

d) 3.74-3.78 (4H, m), 3
．． 82(3H,s), 3.94-3y98(2H
,m),' 4.22(1)1. ABq),
4.40 (1tlABq), 5.02 (LH,
d), 5.16(2H,s), 5.22(
4H,s), 5.94(IH,dd), 6
．． 74 (LH,s).

6.88 (2H, s >, 6.92 (18, s )
, 7.22-7.36 (231(.

m), 7.40-7.44 (2H, m) MS (
FAB): 13080. IH”)IR(CHCβ3
) 1790. 1720cm Example 5 Compound of Example 1 (44 mg, 0.08 mmole)
3-acetoxymethylmethyl-7-β-reduced minnow 3-cephem = 4- in methylene chloride solution (1mj2) under water cooling.
Diphenylmethyl carboxylate (33 mg.

0.08 mmole), DCC (19 mg, 0.09
mmole), methanesulfonic acid (4.9 μn, 0.
09 mmole) and stirred at room temperature for 1 hour. The resulting insoluble matter (dicyclohexylurea) was filtered, the filtrate was diluted with ethyl acetate, washed successively with 5% citric acid aqueous solution, 5% sodium bicarbonate aqueous solution, and saturated saline, and after dehydration with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.

The resulting residue was collected using a Rover column (manufactured by Merck & Co., Ltd., 5i6
0, s+ze A, Hexane=AcOE
t: 3: 1 → 1: 1-+
1:2-+Ac0Et only) to obtain 52 mg (yield 69.3%) of the title compound as a reddish-brown solid.

NMR: δ2.07 (3H,s), 3.26 (6
H,s), 3.36(3H,s), 3.44-
3.50 (4ft, m), 3.52-3.58 (
2H.

m), 3.74-3.79 (4H, m), 3.
95-3.99 (2H, m).

4.79 (IH, ABq ), 5.00 (IH, AB
q), 5.06 (LH.

d), 5.18-5.21 (4H, m), 5.
22 (4H, s), 5.50 (2H, br, s)
, 5.96 (LH, dd ), 6.92 (3H, m
).

6.97 (LH,s), 7.28-7.40 (8H
, m), 7.42-7.46 (2H, m) MS (FAB): 1010 (MH-)IRlolo (
: 1790 1730 cm Example 6 Compound of Example 3 (44 mg, 0.03 mmole)
Anisole (72 μA, 0.66 mmol) was added under ice cooling.
e), Todorifluoroacetic acid (307 μf, 3.98 m
mole) and stirred at room temperature for 2 hours. After concentrating this under reduced pressure, isopropyl ether was added, and the resulting powder was collected by filtration and dried under reduced pressure. Water (approximately 0.5 ml) was added to the obtained crude product, and p
The temperature was adjusted to H7 and a solution was obtained. This was subjected to Mitsubishi Kasei's adsorption resin Diaion HP-20 column chromatography (resin amount 40 ml 1.10 mβ/3 ml n/1 fr), sequentially eluted with water and a 10% methanol aqueous solution, and 3
Fractions with UV absorption at 00 nm were collected, concentrated, and lyophilized to obtain 10.7 mg of the title compound (yield: 40 nm).

N! JR (020): δ2.63 (3H, s).

3.63 (Ift, ABq), 4.16 (IH.

ABq>, 5.00-5.10 (3H, m).

6.94(2H,s), 7.17(LH,s!5
(FAB): 774(λ)Ho)IR(KBr):
1760 cm Example 7 1%) with a white solid and 3.32(1)1. ABq).

ABq), 4.49 (IH.

5.71(LH,d) Compound of Example 4 (44 mg, 0.03 mmole)
Anisole (73 μA', 0.67 mmo) was added under ice cooling.
le), trifluoroacetic acid (311 μ!, 4.04 m
mole) was added thereto, and the mixture was stirred for 30 minutes under water cooling and for 1.5 hours at room temperature. After concentrating this under reduced pressure, isopropyl ether was added, and the resulting powder was collected by filtration and dried under reduced pressure. Water (approximately 0.5 ml) was added to the obtained crude product, and the mixture was heated to 1N under water cooling.
The pH was adjusted to 7 with a Na leaf aqueous solution to form a solution.

This was applied to Mitsubishi Kasei's adsorption resin Diaion HP20 column chromatography (resin amount 40ml, 1.10ml!
/ 3 min/ 1 fr,) and sequentially eluted with water, 20% methanol aqueous solution, and 50% methanol aqueous solution, and collected and concentrated fractions with UV absorption at 300 nm.
By freeze-drying, 14.9 mg of the title compound (
Yield: 67.7%) was obtained as a white solid.

NMR (020): δ3.35 (LH, ABq >
, 3.68 (IH,ABq).

4.00-4.08 (4H, m), 4.30 (LH
,ABq), 5.045.10(3H,m),
5.70 (LH, d), 6.60 (2H, s).

7.00 (LH,s) MS (FAB): 658 (MH”) IR (KBr): 1760 cm Example 8 Compound of Example 5 (50 mg, 0.05 mmole)
under water cooling, anisole (108uL 1.00mmol
e), trifluoroacetic acid (463μA, 6.OOmm
ole) and stirred at room temperature for 2 hours. After concentrating this under reduced pressure, isopropyl ether was added, and the resulting powder was collected by filtration and dried under reduced pressure. The obtained crude product was added with water (approximately 0
．． 5+y+A>, and with lNNa leaf aqueous solution under water cooling,
The pH was adjusted to 7 to form a solution. This was applied to Mitsubishi Kasei's adsorption resin Diaion HP-20 column chromatography (resin amount 40m+j!, 10mβ/3m1n/1 f
r,) and sequentially eluted with water, 20% methanol aqueous solution, and 50% methanol aqueous solution, and collected both fractions with UV absorption at 300 nm, concentrated, and lyophilized to obtain 19.3 mg of the title compound (yield). 64.8%) was obtained as a white solid.

NMR (020): δ2.12 (3H,s),
3.28 (LH, 80q).

3.58 (LH, ABq), 4.76 (IH, AB
q), 4.88 (LH.

ABq ), 5.06 (2H,s ), 5.12 (
IH, d), 5.87 (LH, d), 6.62
(2H,s), 7.00(IH,s >MS(FA
B): 602 (MH") IR (KBr): 1760 cm Example 9 An antibacterial activity test was carried out using the representative compound of the present invention: Kotsu 1-1 using the Japanese Society of Chemotherapy Standard Method I. Obtained The antibacterial activity is shown in Table 1.

Claims (3)

[Claims] (1) A thiazole derivative represented by the following general formula [I] or a non-toxic salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・〔I
] (In the formula, R^1, R^2, R^3 may be the same or different, and are hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted acyl group, a hydroxyl protecting group, Alternatively, R^1 and R^2 or R^2 and R^3 may be combined to form a cyclic diol protecting group, R^4 is an amino group or a protected amino group, and R^ 5 is hydrogen,
It represents an ester residue or a carboxy protecting group, and X is hydrogen, a halogeno group, an alkoxy group, an alkyl group, a vinyl group or a group represented by CH_2Y (Y is hydrogen or a nucleophilic residue). ) (2) A thiazole derivative or a salt thereof represented by the following general formula (II). ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[II] (In the formula, R^1 to R^5 are the same as in the formula [I] of claim 1.) (3) An antibacterial agent containing a thiazole derivative represented by formula [I] according to claim 1 or a nontoxic salt thereof as an active ingredient.