JPS63192780A - Cephalosporin compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [X is CH or N; Y is amino which may be protected; Z is H, methoxy or formylamino; R<1> is (substituted) alkyl or H; R<2> and R<3> are H or acyl; W is substituent group; n is 0-5] and a salt thereof. EXAMPLE:(6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido ]-3-(3,4- dihydro-6,7-dihydroxy-2-isoquinolinium)methyl-3-cephem-4-carboxylate. USE:An antimicrobial agent having a wide range of antimicrobial spectrum, extremely strong antimicrobial power and strong antimicrobial activity against Pseudomonas aeruginosa. PREPARATION:A compound shown by formula II (R<4> is carboxyl protecting group; R<5> is eliminable group; p is 0 or 1) is reacted with a dihydroquinoline compound shown by formula III to give a compound shown by formula I.

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, 3,4-dihydro, 6,7-cyhydroxyin, 1,000-norlinium methyl group (
The present invention relates to a novel 77 axvorin compound having a hydroxyl group or an acylated form of its hydroxyl group), a pharmaceutically acceptable salt thereof, and a method for producing the same.

The cephalosporin compounds and pharmaceutically acceptable salts thereof of the present invention have extremely mild antibacterial activity and have activity that can strongly inhibit the growth of a wide range of Durham-positive and Durham-negative bacteria. It has excellent antibacterial activity, especially against gram-negative bacteria, especially against aeruginosa.

b. Conventional technology Seraph 0 Sporin? Cephalosporin compounds having, for example, a 2-substituted imino-2-(2-7minothiazol-4-yl)acetamide group at the @0 position are known as compounds having antibacterial properties, such as those shown below. Numerous compounds have already been proposed.

(1) Japanese Patent Publication No. 58-58353 The cephalosporin compounds described in this publication mainly contain 2-! It is a compound having a substituted imino-2-(2-7minothiazol-4-yl)acetamide group, and the 3rd position thereof is a methyl group substituted with a nucleophilic compound residue.

till JP-A-58-57386 This publication describes a compound having a group represented by a 2-1ill-substituted imino-2-(2-amino/thiazol-4-yl)acetamido group at the 7th position, and a group at the 3rd position. Cephasporin compounds having optionally substituted inquinolinium methyl esters have been proposed.

(110 Japanese Unexamined Patent Publication No. 59-130294) This publication describes a compound having 2-substituted imino-2-(2-7minothiazol-4-yl)7cetamido i at the 7-position and directly substituted with a specific direct substituent group. It is disclosed to be a Sephalosporin compound with a good Sep Norini 9methyl I or Inn Senno LJ Neumethyl Red in third place.

C0 Object of the Invention The present invention provides a compound having a 3,4-dihydro-16,7-dihydroxyinquinolinium, methyl group (or an acylated form of its hydroxyl group) at the 3-position, and a specific substituent at the 7-position. An object of the present invention is to provide a novel cephalosporin compound having the following properties.

Another object of the present invention is to have a broad antibacterial spectrum and a powerful anti-I! The object of the present invention is to provide a novel cephalosporin compound having gt8 properties.

Yet another object of the present invention is to provide a cephalosporin compound that has strong antibacterial activity against Durham-positive and Durham-negative cases.

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

Yet another object of the present invention is to provide novel Cepha I:I sporin compounds with improved water solubility and low toxicity.

Still another object of the present invention is to provide a method for producing *yit Seraph-Osporin compound and its pharmaceutical use.

Other objects and advantages of the invention will become apparent from the description below. - d1 Construction of the Invention According to the research of the present invention, it has been found that these objects and advantages are achieved by the following cephalosporin compounds.

That is, according to the present invention, a cephalosporin compound represented by the following general formula I and a pharmaceutically acceptable salt thereof are provided.

The cephalosporin compound of the present invention has one characteristic in that it has a dihydroisoquinoline skeleton of the lower Um structure at the 3rd position of the 7th position.

This dihydroinquinoline skeleton has at least human a-f syloxy or 7-siloxy groups represented by -OR", -OR" at its 6 and 7-positions.

Another feature of the cephalosporin compound of the present invention is that it has the following Sakaki 7cetamido group at the 7th position.

This acetamido group has an optionally substituted furkyl group or an imino group which is a hydrogen atom, and further has a 2-7mino(or homanami/)thiazol-4-yl group or a 2-7mino( It is characterized by having a thiadiazol-4-yl group.

The cephalosporin compound of the present invention having such characteristics has a broad antibacterial spectrum and has excellent physiological activity such as extremely strong anti-boxing power. In particular, it has a broad antibacterial spectrum and extremely strong antibacterial activity against Durham-negative bacteria, and can inhibit the growth of bacteria with surprisingly little violet. Of particular note is the fact that the previously commercially available cephalosporin compound KFid exhibits surprisingly strong activity against Pseudomonas aeruginosa.

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

The cephalosporin compound of the present invention represented by the above formula I partially has a 2-7 minothiazol-4-yl skeleton or a 2-7 minothiazol-4-yl skeleton represented by the formula. This skeleton is a 2-7 minothiazolin-4-yl skeleton or a 4-7 minothiadiazolin-4
It is easily isomerized to -yl skeleton. In the present invention, any of these tautomers may be used, or a mixture of both may be used (all embodiments are also included).

Further, the cef7-kusborinated compound of formula 1 is represented by the formula C-2 and partially has an imino group. This R'-
The imino group moiety to which the 0-group is bonded may be either a syn-type or an anti-type, or may be a mixture of both types. However, the thin type is often preferable because it has stronger antibacterial activity.

The above formula If')Y is an amino group which may be protected, and therefore it is intended to be the amino group itself or an amino group protected by a protecting group. When it is a protected amino group, it is preferably used as an amino group-holding group, and examples of the holding group include acylmi, an optionally substituted aralkyl group, and the like. An example of such a 7-sil turnip is formyl.

acetyl, flopionyl, futidyl. Lower furkayl groups such as 1so-styryl, valeryl, 1ao-valeryl, oxalyl, succinyl, pivaloyl; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1so-propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl; mesyl, Lower furkanesulfonyl groups such as ethanesulfonyl, propanesulfonyl, 1so-7'ropanesulfonyl, butanesulfonyl; benzoyl,
70yl group such as toluoyl, 7toyl, phthaloyl; phenylacetyl.

Examples include 7ralkanoyl groups such as phenylpropionyl; 7ralkoxycarbonyl groups such as benzoyloxycarbonyl; and the like. Such a 7-syl group can be substituted with a suitable substituent 1
You may have more than one. Examples of substituents include halogen atoms such as chlorine, bromine, chlorine, and fluorine; cyano groups;
Examples include lower alkyl groups such as methyl, ethyl, propyl, and butyl. Examples of the aralkyl group that the tit substituent may have include benzyl, 4-methoxybenzyl, phenethyl, trityl, and 3,4-dimethoxybenzyl.

In the cef7c2 sporin compound of the present invention, the formula
R1 is a hydrogen atom or an optionally substituted furkyl group. In this case, the unsubstituted alkyl group is, for example, methyl or ethyl.

n-propyl + 1ao-propyl, n-butyl.

5eC-butyl, tart-butyl, pentyl, hexyl, heptyl, octyl, nonyl, tetyl
1111 or a branched C1-CIO alkyl group. Examples of substituents in cases where the furkyl group has a substituent include a carboxy group; a flukoxyl group such as methoxycarbonyl, ethoxycarbonyl, tert-gutoxycarbonyl, and pentyloxycarbonyl; imitazolyl, 5- Methylimidazolyl, 1-methylimidazolyl. 2-Methyl-5-nitro-3-imidazolyl. 2-7 Minothiazolyl.

IH-natozolyl. 2H-tetrazolyl, thiazolyl,
1-Methyl-1) 1-tetrazolyl, pyrrolidone-3-
Examples include heterocyclic groups such as yl.

R1 is methyl, ethyl, propyl.

Lower alkyl groups such as 1so-propyl, butyl* t@rt-butyl, hexyl; carboxymethyl.

2-carboxyethyl, 2-carboxy-2-propyl, 2-carboxy-2-butyl, 3-carboxy-3-
In the cephalosporin compound of the present invention, in which a lower alkyl group substituted with a carboxyl group such as pentyl is preferable, X in formula I is 10H= or -N=, and each represents a thiazole ring or a thiadiazole ring. will be formed. There is no problem with either.

Further, 2 in the above 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 mentioned above, the cephalosporin compound of the present invention has a 3,4-dihydroinquinoline skeleton having at least 10)ζ2 and -OR'' groups at the 6- and 7-positions as shown in Formula I. where R2 and R3
are each independently a hydrogen atom or an acyl group, and the acyl group is preferably an aliphatic 7-syl group. R1 and R1 are hydrogen atoms or acyl m having 2 to 4 carbon atoms;
are preferred, particularly a hydrogen atom or an acetyl group.

The dihydroin quinoline skeleton has -OR at the 6 and 7 positions.
As long as it contains the two substituents “and -OR” (,
There is no problem even if other substituents (-(w)n) are further included at other positions. In this case, the number (n) of substituents is 0 to 5, preferably θ to 2, and particularly preferably 0 to 1. This substituent (-W) may be of various types, but it may be the same as the substituent for R1 explained in al.

Examples of this W include: amino group; fulkylamino group having 1 to 4 carbon atoms; hydroxyl; alkoxy group having 1 to 4 carbon atoms; carbamoyl group; carbamoyloxy group; Carbamoyl group; 7-syloxy group having 2 to 4 carbon atoms; cyano group, halogen atom, halogenated alkyl group having 1 to 4 carbon atoms; sulfo group; aminosulfonyl group; furucyl 2 having 62 to 4 carbon atoms
! IiI; alkyl group having 1 to 4 carbon atoms; carbothousyl group; flukoxycarponyl group having 1 to 4 carbon atoms; hydrogen alkyl group having 1 to 4 carbon atoms; formyl group.

Also in the cephalosporin compounds of formula I of the present invention,
The cation (■) at the 3rd position forms salts with various anions. Examples of the anion include CI-, Br-, C
Examples include -chloric acid ions such as HsCOO-, CC15COLJ-1CF, and COO-.

Furthermore, other salts of the Cepha I:+sporin compound of formula l include salts at carboxyl &(-CO(J'')) at position 4. Such salts include, for example, alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal a (calcium salt, magnesium salt, etc.), ammonicum salt.

Salts with organic bases (triethylamine salt, trimethylamine salt, pyridine salt, etc.) $4.

The cephalosporin compound of formula I 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, flukoxyfurkyl esters such as methoxymethyl, ethoxymethyl, methquinethyl, ethoxyethyl ester; acetoxymethyl, propoxymethyl, butyryloxymethyl, valeryloxymethyl, bivalyloxymethyl Furucyloxyalkyl esters such as esters; examples include tantanyl, phthalidyl, glycyloxymethyl, and phenylglycyloxymethyl esters.

The cephalosporin compound, its salt, or its ester of the present invention is chemically stable if it is in the form of a crystal.

Therefore, crystalline cephalosporin compounds, their salts or their esters are preferred when used as active ingredients in pharmaceutical compositions. Such crystals can be anhydrous or 3/4
- hydrate, l-hydrate, 1,5-aqueous phase, 3-hydrate,
It may also be a hydrate such as a pentahydrate.

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

+11 (6R,7K)-7-((Z)-2-(2-
7minothiazol-4-yl)-2-methoxyimino 7
cetamido)-3-(3,4-dihydroC1-617-dihydrocI,2-isoquinolini'lam)methyl-3
-cephem-4-carboxylate (21(6,7R) -7-(IZ)-2-(2-7
minot7zol-4-yl)-2-dithodiiminoacetamide)-3-(3,4-dihydro-6,7-cyhydroxy-2-yn-?/linium)methyl-3-cephem-4-carboxy Rate (31(6R,7R) -7-((Z)-2-(2-7
minot7ol-4-yl)-2-carfoxymethothendiiminoacetamide)-3-(3,4-dihydro I:l
-6,7-cyhydroyaci 2-inquinolinium) methyl-3-cephem-4-carboxylate 14+ (6R,7R)-7-((Z)-2-(2-
7minothiazol-4-yl)-2-(2-carpoxypucubi-2-yloxyimino)acetamide)-3
-(3,4-dihydro-6,7-cyhydroxy-2-ink/linium)methyl-3-cephem-4-carboxylate+51 (6LL,7R)-7-((Z)-2-(2
-7minothiazol-4-yl)-2-(2-carbamoylpropyl-2-yloxyimino)acetamide 3
-3-(3,4-dihydro-6,7-cyhydroxy-2
-inquinolinium) methyl-3-cephem-4-carboxylate (6) (6R,71()-7-((Z)-2-(2
-7minothiazol-4-yl)-2-7lyloxyiminoacetamide)-3-(3,4-dihydro-6
,7-cyhydroxy-2-inchimerinium)methyl-
3-cephem-4-carboxylate (71(6R,7R)-7-((Z)-2-(2-7minothiazol-4-yl)-2-(phenylthiomethoxyimino)acetamide"-3-(: L4-dihydro a-
5,7-cyhydroxy-2-inquinolinium)methyl-3-cephem-4-carboxylate (81(6R,7K)-7-((Z)-2-(2-7minothiazol-4-yl)-2- (1-methyltetrazole-5-thioyl)methoxyiminoacetamide)-
3-(3,4-dihydro0-6.7-cyhydroxy-2-
inquinolinium) methyl-3-cephem-4-carboxylate t9+ (6R,7R)-7F-((Z)-2-(2
-7minothiazol-4-yl)-2-(5-methylimidazol-4-ylmethoxyimino)acetamide)
-3-(3,4-dihydro-a-6,7-cyhydroxy-2
-inquinolinium) methyl-3-cephem-4-carboxylate (111(6R,7R)-7-[(Z) -2-(2-
7minothy7zol-4-yl)-2-(2-carboxypropyl-2-thioyl-methoxyimino)acetamide)-3-(3,4-dihydocl-6,7-cyhydroxy-2-isoquinolinium)methyl-3- Cephem-4
- Carbo-dried sylate αυ (6R, 7R) -7-((Z) -2-(2-7
Minothiazol-4-yl)-2-methoxyiminoacetamide)-3-(2-carboxy-3,4-dihydro-6,7-dihyde eI!? Sea 2-ink/Linitum)
Methyl-3-cephem-4-carboxylate u3 (6,7K) -7-((Z)-2-(2-
7thiazol-4-yl)-2-coolmethylthiomethyloxyiminoacetamide]-3-(3,4-dihydro a-6,7-dihydradfc2-inquinolinium)methyl-3-cephem- 4-carboxylate α3 (6R,7R) -7-((Z)-2-(2-
7mi/thiazol-4-yl)-2-(5-methylimidazol-4-ylmethoxy)acetamide)-3-(
3,4-dihydro-6,7-dihydro-thc(2-yn)-linium)methyl-3-cephem-4-carboxylate α41 (6R,7tt)-7-((Z)-2
-(2-7minoti7zol-4-yl)-2-(2-bid')door-3-yloxyimino)acetamide)-
3-(3,4-dihydro' b + 7-dihytocl xy-2-inquinolinium)methyl-3-cephem-4
-carboxylate BS (6R,7R)-7-((Z)-2-(2-7
Minnow 1,3-thiadiazol-4-yl)-2-methoxyimino7cetamido)-3-(3,4-dihydro-
6,7-cyhydroxy-2-inquinolinium)methyl-3-cephem-4-carboxylate fil (6R,7R) -7-((Z)-2-(2
-7 minnow 1,3-thiadiazol-4-yl)-2-
ethoxyiminoacetamide)-3-(3,4-diL-doC1-6,7-dihydro-thc-2-inquinolinium)
Methyl-3-cephem-4-carboxylate me? + (6R,7R)-7-((Z)-2-(2-
amino-1,3-thiadiazol-4-yl)-2-(
2,2,2-)lichloroethoxyimino)acetamide 3-3-(3,4-di-6,7-dihyde I:lx-2-inquinolinium)methyl-3-cephem-4
-Carboxylate u! 9(6R,7R)-7-((Z)-2-(2-7minor-1,3-thiadiazol-4-yl)-2-(carpomethoxyiminone 7cetamido)-3-(3,4- dihydro-6,7-dihydro-2-inquinolinium)methyl-3-cephem-4-carboxylate C19(6R,7)L)-7-((Z)-2-(2-7
Minnow 1,3-thiadiazol-4-yl)-2-(2
-carboxypropyl-2-yloxyimino)acetamide) -3-(314-dihydro-6,7-cyhydroxy-2-inquinolinium)methyl-3-cephem-4-carboxylate (6R,7R)- 7-((Z)-2-(2-aminothiapour-4-yl)-2-hydroxyiminoacetamide) -3-(3,4-:)hydro-6,7-
dihydroxy-2-ink/linium)methyl-3-cephem-4-carboxylate@j) (6R,7R)-7-((Z)-2-(2
-7 minnow 1,3-thiadiazol-4-yl-2-hydroxyiminoacetamide)-3-(3,4-dihydro6,7-cyhydroxy-2-inquinolinium)methyl-3-cephem-4-carboxy Rate of Cephalosporin Compounds of the Invention 1. That salt.

The esters can be obtained by various synthetic methods. The method will be explained below, but the cephalosporin compound of the present invention is not limited in any way to these synthesis methods.

Reaction formula A R' This reaction formula A is a method in which the cephalosporin compound of formula (2) and the inquinolinated compound of formula (3) are reacted. The reaction product (1) can be subjected to deprotection, salt formation, esterification and/or reduction reactions as necessary.

In formula (2), X, Y, Z and R1 are represented by the above formula (1
It is the same as the definition of 1, and gl can be a group that can be separated when reacted with the dihydroisoquinoline compound of (3) (for example, a 7-syloxy group, a carba-7yloxy group, or a halogen atom, and p is Select O or 1, R4
represents a hydrogen atom or a cyclic group.

Preferred examples of the 7-syloxy group in V include acetyloxy, trifluoroacetyloxy, and trichloroacetyloxy.

Propionyloxy, 3-okifugutyryloxy. 3-
Carboxypropionyloxy, 2-carpoxybenzoyloxy, 4-carboxybutyryloxy, manzolyloxy, 2-(carboethoxycarbamoyl)benzoyloxy.

Examples include 2-(carboethoxysulfamoyl)benzoyloxy and 3-ethoxycarbamoylpropionyloxy.

Examples of the halogen atom include iodine, bromine, and chlorine.

Examples of protecting groups for R4 include methyl and ethyl.

Propyl, 1ao-propyl, butyl, pentyl.

Lower alkyl groups such as hexyl; furucyloxyfurkyl groups such as acetoxymethyl, propylonyloxymethyl, butyryloxymethyl, vanlyloxydimethyl, and pivaloyloxymethyl; dimethyl, engineering) −
? Dimethyl.

Substitution of flufukidialkyls such as methoxyethyl and etho v-diethyl; benzyl, 4-methoxybenzyl, 4-nitrobenzyl, 7enethyl, trityl, diphenylmethyl, bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl, etc. Aralkyl group which may be halogenated; 2-iodoethyl+2+2+2) 'J halogenated alkyl group such as chloroquethyl; fulgunyl group such as vinyl, allyl; phenyl, 4-chlorophenyl.

Optionally substituted allyl groups such as tolyl, xylyl, mesityl; trimethylsilyl, triethylsilyl +
tart -7' methyldimethylsilyl.

Examples include trialkylsilyl groups such as 1-leptylsilyl. Among these, R4 is preferably a trialkylsilyl group. When W is a trialkylsilyl group, the formation of the Δ-isomer of the 70-sporin sieve conductor of formula (1) in the reaction of Scheme A is suppressed, so that the desired formula (1) is suppressed. of cephalosporin compounds are obtained in high yield straw.

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 (11).

The dihydroisoquinoline compound (3
), R1 and RA are the same or different and represent a hydrogen atom or an acyl group, but these may also be a phenolic hydroxyl group or a protective group normally used for catechol. Examples of the acyl groups used include 7-cetyl group, trifluoroacetyl, trichloroacetyl, fropionyl, 3-oxybutyryl, 3-carboxypropionyl, 2-carboxyacetyl, 2-carboxybenzoyl, and 4-carboxybutyryl.

2-(carboethoxycarbamoyl)benzoyl, 2-
(carboethoxysulfamoyl)benzoyl, 3-ethoxylbamoylpionyl, and the like. In addition, as a protecting group, it is usually used for phenol or catechols, and the target compound (il
Those that give will be selected. Such protecting groups include methyl, methoxymethyl, 2-metho? jetoxymethyl,
Methoxythiomethyl, tetrahydropyranyl, 7-enacyl, aryl, cyclohexyl.

t-/'chill, benzyl, 0-nitrobenzyl.

Ethers such as 4-picolyl, trimethylsilyl, t-
Silifrethers such as gtylddimethylsilyl, methyl carbonyl 121212 1'! J Carbonates such as chloroethyl carbonyl and benzyl carbonyl, sulfonates such as methanesulfonyl and p-)luenesulnyl, and methylene acetal used as a protective group for catechol.

Examples include diphenylmethylene ketal and cyclic carbonate, and these protecting groups can be selected and used according to necessity.

In formula (3), W and n are defined in formula (1) above and mean the same group, atom, and number as in ash.

Further, the compound of formula (3) may be a salt thereof (preferred salts include, for example, inorganic acid salts (hydrochloride, hydrobromide, sulfate, phosphate, etc.), organic acid salts, etc. (Acetate,
maleate, I-stone salt, benzenesulfonate, toluenesulfonate, etc.).

The Cefa 0 sporin compound of formula (2) or its salt and the formula (3
The reaction of ) with the dihydroin-1,000-chloride 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, and chloroform.

710 Genated hydrocarbons such as carbon tetramide, l,2-dichloroethane; ethers of diethyl ether, tetrahydrofuran, dioxane, dimethoxyethanato; hexane, benzene, toluene. Examples include hydrocarbon fi such as xylene; 7cetonitrile; dimethylformamide; diethylacetamide; dimethyl sulfoxide;

6 temperature is preferably room temperature or lower;
It is usually best to carry out the process at a temperature in the range of -30°C to +50°C.

A cephalosporin compound of formula (2) or a salt thereof,
The di-droisoquinoline compound of formula (3) or its salt reacts in a very small amount, but when carrying out the reaction,
Usually, the dihydroisoquinoline compound of formula (3) or its salt is 0.7 to 10 times the mole of the cephalosporin compound of formula (2) or its salt, preferably 1.0
~10 times the molar amount is used.

The reaction proceeds by simply stirring the two, and the reaction time varies depending on the reaction solvent, reaction temperature, 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 2A, compound (2
), the desired compound (1) of the syn isomer QU is obtained. When a mixture of syn and anti isomers of compound (2) is used as a raw material, the target compound (1
A mixture of syn and anti isomers of ) is obtained. Such mixtures can be separated by conventional means such as crystallization, chromatography, etc. The reaction products can be subjected to debinding, salt formation, esterification, and/or reduction reactions, if necessary. .

The debinding reaction is a known reaction per se, and the protecting group for the carboxyl group can be removed by a hydrolysis reaction in the presence of an acid or an alkali. The protecting group for ami7 group can be removed by acid or catalytic reduction (see US Pat. Nos. aIJ 4,152.433 and 4,298,606).

This reaction is known per se. For example, the compound having the betaine structure of formula (11) obtained by the above reaction is mixed with hydrochloric acid, hydrobromic acid, acetic acid, or phosphoric acid.

Acids such as acetic acid, trifluorohexacic acid; etc. are carried out by treating betaine with a salt such as sodium chloride, sodium diuride, potassium chloride, etc. in the presence of an acid.

The esterification reaction is a reaction known per se, and the resulting cef 7 o sporin compound of the formula (1+) or its salt and a fluoro/yloxyalkylno^ride, alkoxyfurkylpalite, etc. are mixed with acetone, dimethylformamide, etc. (see British Patent No. 240,921).

The reduction reaction is a well-known reaction in itself, and is carried out by treating a cephalosporin compound of formula (11, where p is 1) with acetyl chloride, etc., and then reducing it with iodide ion, sodium di)ionite, etc. (see the 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 Seraph 0 sporin compound of formula (1) was mixed with water; methanol, ethanol, acetone, and tetrahydrofuran. An organic solvent such as dioxane or acetonitrile; or a mixture of these solvents (solvent K111) is dissolved and left to precipitate as a crystal; a method of recrystallizing an amorphous powder using these solvents; There is a method of dissolving a powder in water and then adding the above-mentioned organic bath agent to form VCG as crystals.

On the other hand, as another method, an acid addition salt of a cephalosporin compound of formula ill 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 crystallized or recrystallized 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.

Reaction 2 B In Reaction Scheme B, the compound of formula (4), its salt, or its reactive derivative is reacted with the compound of formula (5), its salt, its ester, or its reactive derivative. The reaction product is subjected to deprotection, salt formation, esterification and/or reduction reaction 55 as required.

In formula (4), X, Y and R1 are the same as in the foot table of (11) 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...ride, acid anhydride, mixed acid anhydride, activated amide,
There are activated esters, etc.

Examples of acid parite include acid chloride.

Examples include acid chlorides. Examples of the mixed acid anhydride include mixed acid anhydrides with acids such as dialkyl phosphoric acid, phenyl phosphoric acid, pivalic acid, and pentanoic acid.

Examples of the activated amide include 7mide activated with imidazole, triazole, tetrazole, dimethylpyrazole, and the like. Examples of activated esters include cyano-methyl ester, methoxymethyl ester, dimethyliminomethyl ester, p-nide.
Examples include lophenyl ester and mesylphenyl ester.

In formula (5), Z, R'', R'', W and n are the same as defined for the auxiliary fi+. 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 retention group for R4 in the compound of formula (2) of reaction formula A.

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

The compound of formula (5) was obtained using Hisashi's method.

Synthesis method of (5) (3) The above reaction can be carried out in the same manner as the reaction between the compound of formula (2) shown in Reaction formula A and the dihydroisoquinoline compound of formula (3).

The reaction between compound (4), a salt thereof, or a reactive derivative thereof and compound (5), a salt thereof, an ester thereof, or a reactive derivative thereof is carried out in an inert organic solvent, optionally 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 chloride, dichloromethane, and chloroform.

Hexogenated hydrocarbons such as carbon tetrachloride and 1,2-dichloroethane; diethyl ether, tetrahydro-7rane,
Dioxane, dimethoxyethane natonoethers; hydrocarbons such as hexane, benzene, toluene and xylene; acetonitrile; dimethylformamide: diethyl sulfoxide and the like.

A base may be added during the reaction. Such bases include, for example, alkali metal hydroxides.

Examples include organic or inorganic bases such as alkali metal hydrogen carbonate, alkali metal carbonate, trialkylamine, N,N-dialkylbenzylamine, pyridine, and N-furkylmorpholine. The use of such bases is usually compound (
4), equimolar -3 to the salt or reactive derivative thereof.

When compound (4) or a salt thereof is used in the reaction, a condensing agent may be added. As the condensing agent, for example, N, N
'-Dicyclohexylcarbodiimide/N-cyclohexyl N'-morpholinoethylcarbodiimide, N, N
'-diethylcarbodiimide.

Trimethylphosphite, triphenylphosphine, 2
-ethyl-7-hydroxybenzisoxazolium salt and the like. The amount of such condensing agent used is usually 1 to 3 times the molar 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 using an equimolar compound.

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

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

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

The deprotection, salt formation, esterification and/or d-reduction reaction of the anti-core product can be carried out in the same manner as shown in Section 6-8. Crystal of the object? In the case of obtaining it, it can be carried out in the same manner as shown in reaction formula A.

In this reaction, compound (4) is used as a raw material
Purpose of syn isomer-11 when using the syn isomer of
) 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 〇+ H,N -OR'R' 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 reaction as necessary.

In formula (61, X, Y, Z, R", R",
W, no! The hip is the same as the front of the foot.

Salts of the compound of formula (6) include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts,
Alternatively, there is a salt with T4 base.

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 in the same manner 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 left behind by the following method.

Synthesis method of (6) The above reaction can be carried out in the same manner as the reaction between the compound of formula (2) and the dihydroinquinoline compound of formula (3) shown in reaction formula A.

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 by a conventionally used bonding method.

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

The compound of formula (7) is a known compound, and can be prepared by a known method using hydroxyphthalimide (Bulletin 5ociety, 833.19).
76) or a method using 3,4-dinitrophenol hydroxylamine (see 4 Kokai No. 60-169446).

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

An example of an inert organic solvent is methanol.

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

As for the base to be added as necessary, the same base as used in the reaction of Reaction Formula B can be mentioned.

The amount of base to be used is usually 1 to 3 times the amount of the compound of formula (6), its salt, or its ester. Formula (6
), a salt thereof, or an ester thereof and a compound of formula (7), a bound compound thereof, or a salt thereof are usually reacted 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 minutes. The reaction product can be isolated and produced by known means such as solvent extraction, crystallization, chromatography and the like.

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 in the same manner as in Reaction Formula A. When obtaining a crystalline anhydride or hydrate of the target product, the same method as shown in Reaction A can be used.

Anti-Jca2〇I -+11 + Had-ni' -1→l E' In reaction formula 〇, the compound of formula I-(1), its salt or its ester, and the compound of formula αQ, dialkyl sulfate or diazoflucan Make it react. The reaction product is subjected to deprotection, ring formation, esterification and/or reduction reactions, as required.

Formula I -(IIK Oi-1(X@YI Z, R'
l R”, R”lWl n.

p is the same as defined above.

The salt of the compound of formula 1-(11) is an acid addition salt.

Or alkali metal salts, alkaline earth metal salts.

Ammonium salts, salts with organic bases, etc. Specific examples of these salts include salts similar to those described for the compound of μ formula (1).

Examples of esters of the compound of formula I-(1) include compounds esterified in the same manner as the d-group of R4 in the compound of formula (2) of reaction formula A.

The compound of formula I-(llO) can be prepared by the method of Hisashi.

IEI (3)I -111 In the above reaction, the reaction between the compound of formula (octopus) and the compound of formula (3) can be carried out in the same manner as the reaction described in reaction formula A, and the reaction of the compound of formula (5) The reaction between the compound of formula (4'l) and the compound of formula (4'l) can be carried out in the same manner as the reaction described in reaction formula B. The compound of formula (41) is a known compound,
Known method (U.S. Pat. No. 4,298,606)
In formula (11), Hhl is
Represents halogen atoms such as chlorine, bromine, and iodine. Formula 1
Compound 1 can be obtained by halogenating the corresponding alkyl or tIL-substituted alkyl by conventional means.

Examples of the dialkyl sulfate include dimethyl sulfate and diethyl sulfate.

Examples of the diazoalkane include diazomethane.

The reaction of a compound of formula I-(11, a salt thereof, or a derivative thereof with a compound of formula 4, dialkyl sulfuric acid, or diazoalkane is carried out in an inert solvent, optionally in the presence of a base.
This is done by bringing the two into contact.

Examples of inert solvents include methanol.

Alcohols such as ethanol, propatool, methanol; halogenated hydrocarbons such as methylene chloride, methane, chloroform, carbon tetrachloride, l,2-dichloroethane; diethyl ether, ketolahydride O7
Examples include ether attack such as Ran, dioxane and dimethoxyethane; dimethylformamide, 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 hydroxides, alkali hydrogen carbonates, alkali metal carbonates, trialkylamines, N,N-dialkylbenzylamines, pyridine,
Examples include organic or inorganic bases such as N-furkylmorpholine. The amount of such base to be used is usually determined by formula I-(1)
The molar amount is 1 to 3 times that of the compound, its salt or ester.

The compound of formula t11, dialkyl sulfate, or diazoalkane is usually used in an amount of 1 to 3 times the mole of the compound of formula I-tl+, 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 M can be isolated and purified by known means such as solvent extraction, crystallization, and chromatography. In this reaction, the compound '@1-t
When the syn isomer of l+ is used, the compound I-ft
+ syn isomer is obtained.

When a mixture of syn and anti isomers of compound 1-(ll is used, a mixture of syn and anti isomers of compound I-Fll is obtained. Such a mixture can be separated by means such as crystallization or chromatography. can.

Deprotection, salt formation, esterification, and i1-unit reaction can be carried out in the same manner as in the method shown in Reaction Formula A. When obtaining a crystalline anhydride or hydrate of the target product, the same method as shown in Reaction Formula A can be used.

Reaction formula E R1 + Y-C-Nl(,--→ (Tsuno R') This reaction formula E shows a method for synthesizing a compound when X is -C)1= in general formula I.

In reaction 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 optionally subjected to deprotection, salt formation, esterification and/or RI reduction.

In formula (8), Y* Z+ R'+ R'', R3
, W, n and p are the same as the above footrest, and R'
represents a halogen atom such as chlorine, bromine, or iodine.

Examples of the salt of the compound of formula 18+ 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 compound ester of formula (8), for example, reaction A
In the same way as the protective group for R4 in the compound (2), esterified compounds can be mentioned.

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

Synthesis method of (8) (octopus (3)) In the above reaction, the reaction between the compound of formula (octopus) and the compound of formula (3) is carried out in the same manner as the reaction described in reaction formula A.Formula (5) The reaction between the compound of Formula 181 and the compound of Formula 181 is carried out in the same manner as the reaction described in Reaction Scheme B. The compound of Formula (8) is a known compound, and can be carried out by a known method (for example, British National tfF No. 2. Ll 12,276
(No. 2003).

In formula (9), R1 represents a hydrogen atom or a protective group. The compound of formula (9) is a known compound (Koku 1st Permit No. 4.2981606 Specification).

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+).

The compound of formula (8), its salt or its ester and formula (9)
RI reaction with a compound or a salt thereof is carried out by contacting the two in an inert solvent.

Inert solvents include, for example, water: alcohols such as methanol, ethanol, furopanol, and phthanol;
Examples include ethers such as diethyl ether, tetrahedral e+7 run, 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 1 to 3 times that of the compound of formula (8), its salt, or its ester.

The reaction temperature is not particularly limited, but the reaction is carried out at a temperature ranging from room temperature to the boiling point of the solvent.

The reaction time is usually 1 to 10 hours mK.

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

Decontamination, bottle formation, esterification and/or reduction reactions are carried out in the same manner as shown in Reaction Formula A. When obtaining the desired crystalline anhydride or hydrate, the same method as shown in Reaction Formula A can be used.

The cephalosporin compounds of formula fl) of the present invention, especially the cephalosporin compounds of formula (1) in which Y is an amino group, or their pharmaceutically IFF-containing salts or esters, can be used to treat a wide range of Gram-positive bacteria and It exhibits antibacterial activity against Gram-positive bacteria and is useful for treating M. bacterium infections in animals including humans. The Cefa 0 sporin compound of the present invention is green A[,
It has strong antibacterial activity against gram-positive bacteria such as typhoid fever, endea bacterium, yellow budworm, yellow budworm, and hay fever.

Furthermore, the cephalosporin enzyme conductor of the present invention is characterized by a long duration of action.

The cephalosporin compounds of the present invention, their pharmaceutically acceptable salts or esters thereof, are administered parenterally or orally. Dosage forms for parenteral administration include, for example, intravenous or intramuscular injection suppositories. Injections can take the form of an aqueous or oily solution, a sulfur solution, or the like.

It is also a powder that must be reconstituted with sterile water before administration.

It may be a crystal. Examples of suppositories include preparations made of ordinary excipients such as cocoa butter and glycerides, and, if necessary, an absorption enhancer.

When administered orally, 9 tablets of regular capsules;
There are granules and the like, which can contain absorption enhancers, preservatives, etc.

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

The cephalosporin compound of the present invention, its pharmaceutical properties! FF
The dosage of the salt or its ester is determined by age, symptoms,
Although it varies depending on the dosage form, it is usually 10-2000~/day.

The present invention will be explained in more detail below using examples.

Example 1 7 →; In tonitrile 5 lLt
(6R,7R)-7-ami/-3-iodomethyl-3-
Cephem-4-carbonal O,34,9 was turbidly mixed with bistrimethylsilylacetamide O,65au under water cooling.
was dripped. Stir for another 1 hour under water cooling (68.7R
)-7-pisdrimethylsilylamino-3-iodomethyl-3-cephem-4-carboxylic acid trimethylsilyl ester bath fL was obtained. This was cooled to -20°C and dissolved in 0.1639r of 3,4-dihydro-6,7-di8hydroxyisoquinoline and 1tLt of bistrimethylsilylacetamide and 1tLt of bistrimethylsilylacetamide. (Dripping pump (6R,
7R)-7-pisdrimethylsilylami7-3-(3,
An acetonitrile solution of 4-dihydroD-6,7-dihydroxy-2-inquinolinium)methyl-3-cephem-4-carbothousylate was obtained.

The obtained solution was heated to water-cooled temperature and separately CH, CJt.
(Z)-2-Methoxyimino-2-(2-)ditylaminothiazole-4 of 3 rut K O, 45 Mr
Add a solution prepared by stirring for 30 minutes under water cooling from acetic acid and 0.22% of phosphorus pentachloride, raise the temperature to room temperature, stir for an additional hour, and then distill off most of the solvent under reduced pressure. 9
3μ of 9% formic acid was added and stirred at Nff1 for 2 hours. The reaction mixture was poured into 3 Q at of diethyl ether under pressure, and the resulting precipitate was separated from P and extracted with about 1 ION of water. The extract was concentrated, and the concentrate was bathed in a CklP-20 resin column while gradually changing the ratio of water to methanol from 10:1 to 7:3.Bathed with water to methanol = 8:2.7
The target (6m, +a)-
7-((Z)-2-(2-7minothiazol-4-yl)-2-methoxyiminoacetamide)-3-(3
, 4-dihydro-6,7-dihyde c7,000 C2-ink/linium) 0.181% of methyl-3-cephem-4-carboxylate, Q was obtained [Compound 1].

NMRS (010d a DMSO)
a (LM”): 3.93 (3H, s), 5.20 (
15, d).

5.55(1)1. d), 6.80 (IK, s).

7.20 (1M, s), 7.80 (IH, a).

8.60 (lft, 5) IR spectrum (cllL-1): Example 2 3-cephem-4-carboxylate; (6R,7R)
-7-((Z) -2(2-) -F-ruaminothiazole-t-butoxycarponylbu-a-2-yloximi/)acetamidocou 3-iodomethyl-3-cephem-4-carvone yoshibenhydryl ester Q. 2 7
Dissolve lr in ether 25ajK and add 3,4-dihydro-6,7-dihydro-diisoquinoline to 0.08
2 Mr and bistrimethylsilylacedo S do 0.
45d' and stirred at room temperature for 30 minutes. Add another 5 Q ml of ether to dilute the resulting precipitate, filter the precipitate, add 5 m of 90% truffle OA vinegar #R, and stir at room temperature for 2
Stir for hours.

The truffle acetic acid was distilled off using Makabe, and the residue was crushed with ether to obtain a solid powder. Add 10 ml of water to this solid powder.
After adding 1 and stirring for a while, the water increase was separated and concentrated.
HP-2011 fat column with water/acolumn 10:1-6:
The fraction was collected while gradually increasing the ratio of 7 setone/water up to 4. The fraction was eluted with water:acetone = 8:2 (concentrate the fraction, and fractionated by high performance liquid chromatography in the same manner as in Example 1. !
I [Compound U] obtained by drying the target compound * as a solid of 64 mg [Compound U] NMR spectrum (
D, O-dσDMSCI) δ(-); 1, 48 (6H.
s), 5.20 (IH, d).

5, 54 (IH.d), 6.69 (IH.a).

7, 42 (IH.s), 7.62 (IH, a).

8, 55 (1) 1. s) IR spectrum (3-'); Example 3 (Z) - 0.5 instead of 2-methoxyimi/-2-(2-)lythyl 7minot7ol-4-yl)butyric acid 0)
(6R
．． 7R)-7-((Z)-2-(2-7minothiazol-4-yl)-2-7enylthiomethoxyimi/acetamide)-3-(3.4-dihydroCl-6.7
-di8hydroxy-2-inquinolinium)methyl-3
-Cephem-. 4-carboxylene) 0.2 2
J was obtained [compound ■].

NMR (DtO da DMSO) a (folding) ”5, 28 (lkf.d), 5.60 (2H.s)
.

5, 77 (IH.s), 6.95 (IH.s).

7, 18 (1) f. a), 7.28 (5H.b
road. s).

7, 75 (IH, a), 8.55 (IH.s) IR spectrum (cm-'): Example 4 (Z) -2-methoxyimino-2-(2-tritylaminothiazol-4-yl acetic acid Instead of KO, 60/
(7) (Z) -2-(2-t-gutoxycarponyl-2-propyl)naomethoxyimino-2-(2-
) Dithylaminothiapour-4-yl)acetic acid was used in the same manner as in Example 1.
, )-2-(2-ami/thiazol-4-yl)-2-
(2-carboxyprop-2-yl)thiomethoxyiminoacetamide)-3-(3,4-dihydro -tit
7-dihydroxy(2-inquinolinium)methyl-
3-cephem-4-carboxylate 0.20! I got y. [Compound ■] NMR spectrum (D, 0-dIf) MSO) δ (ferment: 1.48 (6) (, s), 5.30 (l) i, d).

5.50 (2H+ a), 5.80 (l) i, d).

6.64 (IH, s), 7.43 (1) 1. s).

7.65(l)i,s),s,6o(LH,s
) IR spectrum (CIIL-'): 177B arrow Example 5 yk
1. Make bistrimethylsilylacetamide cloudy under water cooling.
The mixture was further stirred for 1 hour under water cooling for 1 hour. This *g was cooled to -20°C and 3,4-dihydro-6,7-
A solution of 0.3269 cyhydroxyinquinoline and 1.82517 bistrimethylsilyl 7cetamide dissolved in 2.78 d of N,N-dimethylformamide was slowly added dropwise, and the mixture was further stirred at 0°C for 30 minutes.

On the other hand, 2-7 minnow 1,3-thiadiazole-methoxyimino-mVVO24U 4 MY Jig C1/L-1
Phosphorus pentachloride L), 44.9 and -10°C in 20at
The solution obtained by reacting for 30 minutes was obtained, and this was converted into the jtG obtained above.
The mixture was added to M at once under water cooling and stirred at room temperature for 1 hour.

After distilling off the low point solvent under reduced pressure, diethyl ether 5
In addition, about 1.7 y of a solid containing the target product was obtained.

This solid was extracted with 10 atm of warm water, and the extract 11 was fractionated by high-speed fL chromatography (clear phase 0 L) SC-18 column) using water-methanol to obtain about 10 μm of the title compound [Samurai Compound]. ■〕.

NMR (D, 0-1), L) MSO) 3.95 (3) 1. s), 5.2Ll(l)l,
d).

5.75 (IH, d), 6.82 (l) 1. s).

7.25 (IH, s), 7.85 (IH, s).

8.60 (If(,s)) Example 6 In vitro anti-1 activity was measured by the agar plate dilution method.

Each yuzu test plate was cultured overnight in a medium-night culture, and the platinum loop (viable count of 10'/aj) was transferred to a Mueller-Hinton tube enriched with the compound of the present invention at %8IvIk.
! The cells were cultured at 37° C. for 16 hours, and the minimum inhibitory concentration (MIC, μl/at 2 ) was determined. The result is 6-■
As shown in

Example 71 The MIC values of 10 resistant Pseudomonas aeruginosa for compound ① and CAZ were 't*. The results are shown below.

<Industrial Application Fields> The Seraph-0 skirin compounds and their salts of the present invention have strong anti-hidden properties and inhibit the growth of a large number of Durum-positive bacteria and especially Gram-like bacteria, including Pseudomonas aeruginosa. It is a powerful inhibitor and is used for the treatment and prevention of various infectious diseases.

Special applicant Teijin Ltd.

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 Z is hydrogen atom, methoxy group or formylamino group, R^1 is an optionally substituted alkyl group or hydrogen atom, R^2 and R^3 are the same or different hydrogen atom or acyl group, W is a substituent, n is Indicates an integer from 0 to 5. ] A cephalosporin compound and 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, Z is hydrogen atom, methoxy group or formylamino group, R^1 is an optionally substituted alkyl group or hydrogen atom, R^3 is a group that can be removed by reaction with the isoquinoline compound (3) described below, R^4 is a carboxyl group p indicating a protecting group is 0 or 1] Compounds represented by the following general formula (3) ▲ Numerical formulas, chemical formulas, tables, etc.▼…………(3) [Here, R^2 and R^3 are The same or different hydrogen atoms or acyl groups, W represents a substituent, and n represents an integer of 0 to 5. ] The following general formula I ▲There are mathematical formulas, chemical formulas, tables, 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. 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, R^ 1 is a compound represented by an optionally substituted alkyl group or a hydrogen atom, a salt thereof, or a reactive derivative thereof, and the following general formula (5) ▲There are mathematical 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 from 0 to 5, p is 0 or 1] 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. 4. General formula (6) below ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼... (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 formylimino group, R^2 and R^3 are the same or different and are a hydrogen atom or an acyl group, W is a substituent, and n is an integer of 0 to 5. p is 0 or 1] A compound represented by the following general formula (7) NH_2-R^1…………(7) [Here, R^1 is an optionally substituted alkyl group or a hydrogen atom], its protected compound or salt, and if necessary, deprotection, salt formation, esterification,
The following general formula that is characterized by reduction I ▲There are mathematical formulas, chemical formulas, tables, etc.▼... I [Here, the definitions of X, Y, Z, R^1, R^2, R^3, W and n means the same as above. ] A method for producing a cephalosporin compound and its salts. 5. General formula below I-(1) ▲Mathematical formulas, chemical formulas, tables, etc. are included▼... I-(1) [Here, X is -CH= or -N=, Y is an optionally protected amino group , Z is a hydrogen atom, a methoxy group or a formylamino 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 from 0 to 5, and p is 0 or 1. ] A compound represented by the following general formula (10) Hal-R^1…………(10) where R^1 is an optionally substituted alkyl group or a hydrogen atom, Hal indicates a halogen 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 meaning. ] A method for producing a cephalosporin compound and its salts.