JPS6351389A - Cephalosporin derivative, production thereof and composition having antimicrobial activity - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is H or protecting group; R<2> is (substituted)phenyl; R<3> is 5--6-membered ring hetero aromatic cation capable of containing O, S and N hetero atom in a ring and condensing with other ring]. EXAMPLE:(6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-phenoxyiminoacetamido ]-3-pyri diniummethyl-3-cephem-4-carboxylate. USE:An antimicrobial agent against Gram-positive and Gram-negative bacteria. PREPARATION:A cephalosporin compound (salt) expressed by formula III (R<4> is H or protecting group; Q is acyloxy, carbamoyloxy or halogen; p is 0 or 1) is reacted with a compound (salt) expressed by the formula R<3>' (R<3>' is base corresponding to R<3>) and, as necessary, followed by deprotecting, salt forming, esterification and reductive reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to a CefaOspoli/derivative, a method for producing the same, and an antibacterial active composition. More specifically, the present invention relates to a novel Cef70sporin derivative that has strong antibacterial activity and strongly inhibits the growth of a large number of Durum-positive and Durum-negative bacteria, a method for producing the same, and an antibacterial active composition.

<Background technology> 2-phenoxyimide/
Cephalosporin derivatives having a -2-(2-7 minothi-7zol-4-yl)acetamide group are known, and an example of a phenoxyimino group is disclosed in JP-A-54-9296. However, the substituent at the 3-position is specifically limited to a very narrow range, and the quaternary ammonium methyl group is not synthesized or even specifically disclosed in the specification.

On the other hand, many heptaph 7I:I sporin fatty conductors having a quaternary heptammonicum methyl group at the 3-position are known, such as JP-A-58-210093 and JP-A-59-1490+59-
No. t0593 + 59 13786°13787.13
No. 788 + No. 59-21695, No. 59-31791,
No. 59-82390, No. 59-130888, 59-
130294.130295 + 59-176293
No. 59-1.90994 + No. 60-81186, 6
〇-67484, 60-78988, 60-105
No. 684.

No. 60-97982, No. 60-94984, 60-1
No. 20889, No. 60-136586.136587,
No. 60-166689, No. 60-16388, 60-
No. 163816, No. 60-181090, No. 60-188
No. 389, No. 60-197692, No. 60-224694
No. 60-226884.226885, 60-2
No. 28487, No. 60-237090, No. 6o-2524
No. 85, No. 61-7280 + No. 61-17515.

61-22089, 61-63685, 61-78
No. 792, No. 61-91192, No. 61-97291,
61-115087 and the like. However, these are all 777g sporin derivatives having a 7-lyloxyimino group in the 7-syl substituent at the 7-position (no mention is made of them).

<Disclosure of the Invention> The object of the present invention is to provide a 7-aryl oxyimide 7 with a specific structure at the 7th position.
It is an object of the present invention to provide novel Cephalosporin derivatives having a 7-syl substituent with a quaternary aromatic ammonium methyl group in the 3-position.

Still another object of the present invention is to provide a novel cephalosporin derivative having strong antibacterial activity against Durum-positive and Durum-negative bacteria.

Still another object of the present invention is to develop cephalosporins/derivatives that have sufficient antibacterial activity against methicillin-resistant Staphylococcus aureus, etc., which are resistant to cephalosporin antibiotics that have been used to treat Durham-positive infections in recent years. It is about providing.

Still another object of the present invention is to provide a novel method for producing cephalosporin derivatives and an antibacterial active composition.

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

According to the present invention, these objects and advantages are achieved by the following cephalsporin fat conductor.

That is, the present invention is based on the following formula (1) It is a 777p sporin derivative represented by

<BEST MODE FOR CARRYING OUT THE INVENTION> The cephalosporin derivative of formula (1) has a partial structure of a 2-7 minothi7zol-4-yl group represented by the formula. This partial structure can be easily isomerized to a 2-aminothiazolin-4-yl group. Therefore, the Cefa-Osporin derivative of formula (1) of the present invention may be any of these tautomers, and the present invention includes any of these tautomers.

The cephalosporin derivative of formula (1) has a partial structure represented by the formula. The partial structure may be a syn-type represented by the formula %, an anti-type represented by the formula CR"O', or a mixture of these two isomers in any proportion.

Among the Cefa-Osporin derivatives of the present invention, the syn-type is preferred because it has strong antibacterial activity.

In formula (1), R1 represents a hydrogen atom or a protecting group for an amine group. As a protecting group for the amine 7 group, a 7 syl group and an optionally substituted 7 ralkyl group are used.

Trialkylsilyl groups, etc. are exposed. Examples of such 7-syl group include formyl and acetyl.

Propionyl, butyryl, 1so-butyryl tvaleryl + iso /C lower furucyl groups such as leryl, oxalyl, succinyl, pivaloyl; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Lower alkoxycarbonyl groups such as 1so-propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl; mesyl, ethanesulfonyl, propanesulfonyl, 1so-7'ropanesulfonyl, butanesulfonyl natono lower alkanesulfonyl groups; benzoyl, toluoyl, naphthoyl, phthaloyl, etc. Examples include 70yl group; 7lakanoyl group such as phenyl 7cetyl and phenylpropionyl; 7ralkoxycarbonyl group such as benzoyloxycarbonyl; and the like. Such an acyl group may have one or more suitable substituents. Examples of the substituent include Hagun atoms such as chlorine, bromine, iodine, and fluorine; cyano groups; and lower furkyl groups such as methyl, ethyl, propyl, and butyl.

Examples of the 7ralkyl group which may have a substituent include benzyl and 4-methoxybenzyl.

Examples include phenethyl, trityl, 3,4-methoxybenzyl and the like. Examples of the triflukylsilyl group include trialkylsilyl groups such as trimethylsilyl v triethylsilyl, tributylsilyl, and t-butyldimethylsilyl.

In the formula (1), R'' is a substituted or unsubstituted phenyl group, and when it has 1g1 substituent, an example thereof is a linear or branched C1-C4 furkyl group such as methyl9ethinu, propyl, 1so-propyl, etc. Groups: fluoromethyl, trifluoromethyl, 2-fluoroethyl!trippmethylvdichloromethyl, lower halogenofurkyl groups such as Ig-methyl, bromomethyl, iodomethyl; C-ol C, alkenyl groups such as vinyl 7-lyl; ethynyl, 2
-C such as propynyl! ~C, alkynyl group; C5-C such as cyclopropyl, cyclopentyl, cyclohexyl,
Dichlorofurkyl group; cyano group; carboxyl group; carboxymethyl group; carboxymethyloxy group; sulfo group;
Sulfomethyl group; Sulfoethyl group; Carbamoyl group; Carbamoyloxy group; Hydroxy group; Hydroxymethyl group; Halogen atoms of chlorine, bromine, iodine, and fluorine; Lower fulkylcarbonyloxy group; Amino group; 7minomethyl group; Formyl 7m7 group ; lower alkyl carbonino L-7 group; sulfone 7 group; lower furkyl carbonyl group;
Lower alkoxy group; examples include thiocarbamoyl group and substituted or unsubstituted 7-aryl group, preferably those of formula 6Xn
[Here, X is a halogen atom or a lower furkyl group.

Lower alkoxy group, hapgeno lower furkyl group.

Lower fulkenyl group, lower alkynyl group, dichlorofurkyl group having 3 to 7 carbon atoms, phenyl group, Schiff) group 1-CONH
, or -〇)l(CL)m C00Y (where Y
is a hydrogen atom or a lower furkyl group, 1. m represents 0 or 1) and n represents an integer of 1 to 5].

Gen atom, halogeno lower furkyl group, -CON) (.

Alternatively, it is a substituted phenyl group represented by (OIAI(CHrimcooy) (where Y represents a hydrogen atom or a lower alkyl group, and 1.m represents 0 or 1).

In particular, halogen atoms such as fluorine are particularly preferred since they significantly improve the activity against methicillin-resistant Staphylococcus aureus.

Further, a carboxyl group and a carbamoyl group improve the water solubility of the Cephasporin derivative, so vfK is preferable for use as an injection.

The heteroaromatic cation represented by ~○ in R1 is a quaternary ammonium group derived from a nitrogen-containing aromatic amine, and the corresponding base includes, for example, pyrazole, imidazole, triazole? Tetrazole, inxazole, oxazole.

Thiazole, thiadiazole, inthiazole.

Examples include oxadiazole, pyrin, pyridazine, pyrimidine, pyrazine, triazine and the like.

Furthermore, these ammonium groups may be substituted with one or more of the same or different substituents, and the ru substituent may be a substituted or unsubstituted furkyl group; a cyano group; a carboxy group; an alkoxycarbonyl group; a carbamoyl group. ; carbamoyloxy group; heterocyclic group; hydroxyl group; alkoxy group; or halogen atom.

Examples of the unsubstituted furkyl group include linear or branched C+-Co furkyl groups such as methyl, ethyl, propyl+1so-propyl, butyl, 5ee-butyl, tert-butyl, and benzylhexyl. Examples of substituents for such a furkyl group include, for example,
Hydroxyl group; Cyano group; Carbamoyloxy group; Methoxy,
C, -C, lower alkoxy groups such as phthoxy, butoxy, pentyloxy, hexyloxy; carboxy group; 2
15-dihydroq -2-methyl-5-oxotri7din-3-yl, 2,5-dihydroq -6-hydropx-2
Examples include heterocyclic groups such as -methyl-5-oxotrifudin-3-yl.

Examples of the full;oxycarbonyl group include methoxycarbonyl, ethoxycarbonyl p-poxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like.

Examples of the heterocyclic group include 2,5-dihydro-2-methyl-5-oxotriazin-3-yl, 2,5-dihydro-6-hydro-poxy-2-methyl-5-oxotriazin-3-yl , 2-7minothi7sol-4-yl, and the like.

Examples of alkoxy groups include methoxy.

Examples include ethoxy, pupoquine, butoxy, pentyloxy and the like.

/% Iff gene atom [ is, for example, chlorine, bromine.

Examples include iodine.

The condensed ring may be the above-mentioned heteroaromatic ring, or may be an aromatic hydrocarbon ring such as a benzene ring or a naphthalene ring, a saturated aliphatic hydrocarbon ring such as a cyclopentane ring, or an unsaturated aliphatic hydrocarbon ring such as a cyclopentene ring. It's okay.

Further, these saturated or unsaturated aliphatic hydrocarbon rings may be further substituted with an oxygen atom, a sulfur atom, or a nitrogen atom.

Examples of preferred heteroaromatic cations include the virazolium, thiazolium, oxazolium or viridinic moo cations.

Although the seven-sporin derivative of formula (1) has a betaine structure, the Cepha I:I sporin derivative of the present invention may be, for example, a salt derived from these betaine structures. Such salts include l'L f3 addition salts, such as hydrochloride, hydrobromide.

Inorganic acid salts such as sulfates and phosphates: acetic acid salts, trichloroacetic acid salts, trifluoroacetic acid salts, g salts.

Organic acid salts such as fumarate, maleate, tartrate, methanesulfonate, benzenesulfone WR salt + toluenesulfonate; 7 ruginate! Examples include amino acid salts such as aspartate and glutamate.

These acid addition salts are, for example, represented by the following formula (1') l (1"
) (In the following formula, % R' is exemplified as a 7-mino group.) 5 OOH Formula (1') + (1") K i =: Ite, Ar
'? Ha, Cle, Bre.

CH,Coo", CCl,Cooe, CF,COO
etL,! l' represents no [a acid) anion, and AQ is so! AQ represents an anion of a dibasic acid such as e, c, oρ, etc., and AQ represents an anion of a tribasic acid such as po:e.

Other formulas for the Cephasporin derivative of formula (11) are:
Examples include salts at the jJ lupoxy group at the 4-position. Examples of such salts include alkali metal salts (sodium salts, potassium salts, etc.), heptadium salts, salts with organic bases (triethylamine salts, trimethylamine salts, pyridine salts, etc.), and the like.

The cephalosporin conductor of formula (1) may be an ester in which the carboxy group at the 4-position is nisfurated. Such esters are preferably those that are easily hydrolyzed from a biochemical standpoint. Such esters include, for example, methoxymethyllaethoxymethyl, methoxyethyl,
Flukoxyfurkyl esters such as ethoxyethyl ester; 7-cetoxymethyl, propionyloxymethyl,
Examples include flucyloxyalkyl esters such as butyryloxymethyl, valeryloxymethyl, and pivaloyloxymethyl ester; indanyl, fucridyl, glycyloxymethyl, and phenylglycyloxymethyl ester.

The Cefa-Osporin derivative, its salt, or its ester of the present invention is chemically stable if it is in the form of a crystal.

Therefore, crystalline cephalosporin derivatives, their salts or their nitrite are preferred when used as active ingredients in pharmaceutical compositions. Such crystals may be anhydrous or hydrated.

Preferred specific examples of the cephalosporin derivatives of the present invention are listed below.

1, (6R,7R)-7-((Z)-2-(2-7
Minothiazol-4-yl)-2-phenoximino 7
ceto7mido]-3-pyrazolinium methyl-3-cephem-4-carboxylate 2, (6R,7R)-7-((Z)-2-(2-7
(6R,7R)-7-(E)-2 -(2-7minothiazol-4-yl) -2-(m-methoxyphenoxyimino)7ceto7mido]-3-year-old xazolium methyl-3-cephem-4-carboxylate 4, (6R,7R)- 7-((3)-2-(2-7
(sRt7R)-'y-CI:t )-2-(2
-7minothi7zol-4-yl)-2-(p-bromophenoximino)7cetamido]-3-(2,3-cyp
qbentenoviridinicum) methyl-3-cephem-4-
Carboxylate 6, (6R,7R)-7-((Z
)-2-(2-7minotizol-4-yl)-2-
(o-fluorophenoxyimino)7ceto7mido]-3
-(4-carboxybilinium)methyl-3-cephem-4-carboxylate? , (6R,7R
-7-[G Otsu]-2-(2-7 Minochi 7zoru-4
-yl)-2-(p-fluorophenochlorideξ))7ceto7mid]-3-(4-carbamoylviridinium)methyl-3-cephem-4-carboxylate s,
(6R17R) 7 (l-2-(2-7minotizol-4-yl) -2-(m-trifluoromethylphenoximino)aceto7mido-3-(3-sulfopyridinium)methyl-3-cephem- 4-carboxylate 9, (6R,7R)-7-((2)l-
2-(2-7minotizol-4-yl)-2-(p-
phenylphenoximino)7ceto7mido]-3-(4
-sulfoethylvinium)methyl-3-cephem-
4-carboxylate 10, (GR,7R)-7-
((Zl-2-(2-7minona7zol-4-yl)
-2-(m-methoxyluponylphene/sacyimino)acetamide]-3-11, (6R+7R)-7-((Z)-2-(2-7minothi7zol-4-yl)-2-(p-methoxy carbonylmethylphenoximino)-3-cheno(2,3-
b) Pyridinium methyl-3-cephem-4-carboxylate 12, (6R,7R)-7-((Z)-2-(1
-7 minothi7zol-4-yl)-2-(m-7cetoxyphenoximino)7cetamido]-3-inquinolinium methyl-3-dimethyl-4-carxylate 13, (6R,7R)- 7-(ri-2-(27minothiazol-4-yl)-2-(p-cyanophenoximino)7cetamido)-3-(m-hydroxymethyl)bilinium-3-cephem-4-carpoxylate 14, (6R,7R)-7-(ri)-2-(2-naphthyloxyimino)7cetamido)-3-(4-(tetrazol-5-yl)methylpyridinium methylcou 3-cephem-4-carboxylate 1s , (6R,7R)-7-[:(Z)-2-(
3,4=difluorophenoxyimino)acetamide]
3 (1+2+4) lyazole-1-io)methyl-3-cephem-4-carboxylate 16, (6R,7R)-7-[(Z)-2-(2
-7thiazol-4-yl)-2-(3,5-difluorophenoxyimino)7ceto7mido]-3-(1,
3,4-thiadiazole-4-io)methyl-3-cephem-4-carboxylate 17, (6R,7R)-7-(transl-2-(2-
7minoti7zol-4-yl) -2-(m-rubamoylphenoximine/)7ceto7mido]-3-(3-methyl1,3.4-)su7zol-1-io)methyl −
3-cephem-4-carboxylate 18, (6R,7R)-7-(ri)-2-(2-
7minothy7zol-4-yl)-2-(p-carbamoylmethylphenoximino)acetamide)-3-(biladyl-1-io)methyl-3-cephem-4-carboxylate 19, (6R,7R)=7 −((Z)
-2-(2-7minoti7zol-4-yl) -2-(
m-lupoxyphenoxyimino)7set7mido((
4-(215dihydrot=-6-hydroxy-2-methyl-5-oxotrifudin-3-yl)-thiomethyl]
Pyridinium methyl]=3-cephem-4-carboxylate The method for producing the cephalosubosone derivative of the present invention will be described in detail below.

The CefaOsporin derivative of the present invention can be prepared by various methods (reaction formulas A to E) K described in detail below.

Reaction Formula A In Reaction Formula A, the cephalosporin compound of formula (2) or its salt is reacted with the compound of formula (3) or its salt. The reaction product is subjected to deprotection, ring formation, esterification and/or reduction reactions as necessary.

In formula (2), R1 and R are the same as defined in formula (1), Q represents a 7-syloxy group, a carbamoyloxy group, or a halogen atom, %p represents 0 or l, and R
4 represents a hydrogen atom or a protective group.

Preferred examples of the 7-syloxy group include 7-cetyloxy, trifluoroacetyloxy, Tric I:+
p-acetyloxy, propionyloxy, 3-ocymptyryloxy, 3-carboxypropionyloxybenzoyloxy, 4-carboxybutyryloxy, manzolyloxy +2 (carboethoxycarbamoyl)benzoyloxy +2 (carboethoxysulf7
(moyl)benzoyloxy, 3-ethoxycarbamoylprobionyloxy, and the like.

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

Examples of protective groups include methyl and ethyl.

Propyl, iso-propyl, butyl, pentyl.

Lower furkyl groups such as hexyl; 7-furkyloxyfurkyl groups such as cetoxymethyltupropionyloxymethyl, butyryloxymethyl, valeryloxymethyl, piparoyloxymethyl: methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, etc. Flucoxyalkyl group; benzyl, 4-methoxybenzene, 4
-Optionally substituted aralkyl group such as -ditopbenzyl, phenethyl, trityl, diphenylmethyl, bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl; 2-iodoethyl+2+2,2)! Genated furkyl groups such as J dichlorotyl; fulkenyl groups such as vinyl and allyl: phenyl, 4-chlorophenyl.

Optionally substituted allyl groups such as tolyl, xylyl, mesityl; trimethylsilyl, triethylsilyl,
tert -stildimethylsilyl.

Examples include trifurkylsilyl groups such as tributylsilyl. Among these, R is preferably a triflukylsilyl group. When R4 is a trialkylsilyl group, reaction formula A
△ of the cephalosporin derivative of formula (1) in the reaction of
Since the formation of 8-isomer is suppressed, the desired formula (1
) are obtained in high yield.

The cephalosporin compound of formula (2) may be a salt thereof. A preferred salt is formula 1 (1').

Regarding the Cefa-Osporin derivative (1''), salts similar to the exemplified salts may be mentioned.

In formula (3), the compound represented by R'' is a base corresponding to It3. The compound of formula (3) may be a salt thereof (preferable salts include, for example, an inorganic acid salt ( Examples include hydrochloride, Ahydrone salt, sulfate, phosphate, etc.), organic acid salts (acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.).

The cephalosporin derivative of formula (2) or its salt and the formula (3)
) with the 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, diprxmethane, and chloroform.

Halogenated hydrocarbons such as carbon tetrachloride, l,2-dichloroethane; diethyl ether, tetrahydrofuran,
Examples include dioxane, dimethoxyethane natonoethers; second class hydrocarbons such as -xane, benzene, toluine, and xylene; acetonitrile; dimethylformamide; diethylacetamide; dimethyl sulfoxide; and ethyl acetate.

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

7p 7p sporin compound of formula (2) or a salt thereof and 1
Equimolar amounts of the compound of formula (3) or its salt are reacted, but when carrying out the reaction, usually the cephalosporin compound of formula (2) or its salt is reacted with the compound of formula (3) or its salt.
The compound or its salt is used in an amount of 0.7 to 10 times the mole, preferably i':tl, 0 to 10 times the mole.

The reaction proceeds by simply stirring the two, and the reaction time varies depending on the reaction solvent, reaction 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 polymerography.

In this reaction, when the syn isomer of compound (2) is used as the starting compound, the target compound of the syn isomer (1
) is obtained. When a mixture of Schiff and anti isomers of compound (2) 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 of crystallization, chromatography).

The reaction product is subjected to tax protection, salt formation, esterification, and/or reduction reactions as required.

The deprotection 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 of amine 7 group can be removed by acid or catalytic reduction (U, S, Patent No. 4,152,
433; U, S, Patent Nn4.298,6
06).

The salt-forming reaction is a well-known reaction in itself. For example, the compound having the betaine structure of formula (1) obtained by the above reaction is treated with ζ-ugly, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, etc. acid; or by treating betaine with a salt such as sodium chloride, sodium iodide, potassium chloride, etc. in the presence of an acid.

The esterification reaction is a reaction known per se, and the resulting cephalosporin derivative of formula (1) or a salt thereof is mixed with acetone, dimethylformamide, etc. (United Kingdom Patent
Nn240,921).

The reduction reaction is a well-known reaction in itself, and is carried out by treating the Cephasporin derivative in which p is 1 in formula (1) with 7 cetyl chloride, etc., and then reducing it with iodide ions, sodium dithionite, etc. (
United KingdomPatent Nn24
0,921).

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

The amorphous powder of the formula (1) 7+=+sporin derivative is mixed with water;
Te) organic solvents such as hydrofuran, dioxane + 7cetonitrile; or a method of dissolving it in a mixed solvent of these and leaving it to precipitate as a crystal; a method of recrystallizing an amorphous powder using these solvents; or a method of recrystallizing an amorphous powder using these solvents; There is a method of dissolving the powder in water and then adding the above-mentioned organic solvent to precipitate it as crystals.

On the other hand, as another method, the acid addition salt of the cephalsporin derivative of formula (1) is dissolved in water, an organic solvent such as methanol, ethanol, purpanol, or a mixed solvent thereof, and then triethylamine and sodium hydroxide are added. There is also a method of obtaining crystals by neutralizing with a base such as sodium carbonate. As mentioned above, when crystallizing or recrystallizing in water or a solution containing water, a crystalline hydrate is usually obtained. . When crystallized in an organic solvent, a crystalline anhydride or solvate can be obtained. Solvates are easily converted to anhydrides. A crystalline anhydride or solvate can be converted into a hydrate by standing in a gas containing water vapor.

Reaction Formula B In Reaction Formula B, a compound of formula (4), a salt thereof, or a reactive derivative thereof is reacted with a compound of formula (5), a salt thereof, an ester thereof, or a reactive derivative thereof. The reaction product is subjected to deprotection, salt formation, esterification and/or reduction reactions as necessary.

In formula (4), R1 and R2 are the same as defined above.

The compound of formula (4) may be a salt, and examples of the salt include acid addition salts. As such an acid addition salt, the formula of reaction formula A (
Those exemplified as the acid addition salts of the compounds in 3) can also be mentioned.

Examples of reactive derivatives of the compound of formula (4) include halides, acid anhydrides, mixed acid anhydrides, activated 7amides, activated esters, and the like.

Examples of the acid halide include acid chloride and acid bromide. Examples of the mixed acid anhydride include mixed acid anhydrides with acids such as dialkyl phosphoric acid, phenyl phosphoric acid, piparic acid, and pentanoic acid. Examples of activated amides include amides activated with imidazole, triazole, tetrazole, dimethylpyrazole, and the like. Examples of the activated ester include cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester, p-ditophenyl ester, and mesylphenyl ester.

In formula (5), R3 and p are the same as defined above. Salts of the compound of formula (5) include alkali metal salts such as sodium salts and potassium salts; alkaline earth gold iA salts such as calcium salts and magnesium salts; heptammonium salts and nitrimethylamine salts.

Examples include salts with organic bases such as triethylamine salts and pyridine salts; and acid addition salts similar to those mentioned above.

Examples of the ester of the compound of formula (5) include compounds esterified with the same groups as those exemplified as the protecting group of R4 in the compound of formula (2) of the reactor.

As the reactive O1 conductor of the compound of formula (5), for example,
Schiff base-type imino compounds or their enamine-type isomers formed by reaction with carbonyl compounds such as 7cetoacetic acid; silyl compounds such as bis(trimethylsilyl)7ceto7mide, trimethylchloromilane + tert-butyldimethylcuprosilane Examples include silyl visiting conductors produced by reactions with compounds; derivatives obtained by reactions with phosphorus trichloride and phosgene, and the like.

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

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

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

Examples of inert organic solvents include methylene chloride, dichloromethane, and chloroform.

Carbon tetrachloride, l,2-dichlorohydrocarbons such as ++:I ethane; ethers of diethyl ether, tetrahydrofuran, dioxane, dimethoxyethanat: hexane, benzene! Hydrocarbons such as toluene and xylene; Acetonitrile: Dimethylform 7mide;
Examples include diethyl 7ceto7mide; dimethyl sulfoxide.

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, potash metal carbonate, triflukyl amine, N,N-difurkylbenzylamine, pyridine, and N-furkylmorpholine. The amount of the base to be used is usually equivalent to three times the mole of the compound (4), its salt, or its reactive derivative.

When compound (4) or a salt thereof is used in the reaction, a condensing agent may be added. As a condensing agent, for example) lN,
N'-dicyclohexylcarbodiimide.

N-cyclohexyl-N'-morpholinoethylcarbodiimide, N,N'-diethylcarbodiimide.

Trimethylphosphite, triphenylphosphine, 2
-Ethyl-7-hydro p-oxybenzin oxacillium salt and the like. The amount of such a condensing agent used is usually 1 to 3 times the mole 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 equimolecular compound.

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

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

The reaction product can be subjected to single mMIA by known means such as solvent extraction, crystallization, chromatography, etc.

Deprotection, salt formation, esterification and/or reduction of the reaction product can be carried out in the same manner as shown in Reaction Formula A. The same method as shown in Reaction Formula A can be used to obtain crystals of the target product.

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

Reaction formula C (6) (For reaction formula C, the compound of formula (6), its salt, or its Nisdel is reacted with the compound of formula (7), its protected compound, or its salt. The reaction product is , and subjected to deprotection, ring formation, esterification and/or reduction reactions as necessary.

In formula (6), R'' and p are the same as defined above.

Salts of the compound of formula (6) include acid addition salts, alkali gold g4 salts, alkaline earth metal salts, ammonium salts, and salts with organic bases.

Specific examples of these salts include the same salts as described for the compound of formula (1).

Examples of the ester of the compound of formula (6) include compounds esterified with the same group as exemplified as the I group of It' of the compound of formula (2) in reaction formula A.

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

(6') (3) The above reaction is performed by combining the compound of formula (2) and the formula (3) shown in Reaction Bujin.
) can be carried out in the same manner as the reaction with the compound.

In formula (7), R2 is the same as defined above.

As the protected compound of compound (7), when R2 represents an active substituent such as a carboxy group, compounds in which these substituents are protected with a conventionally used protecting group are preferred.

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 (13ulletin S
ociety, 833.1976) and 2.4-dinitroph x2/L.

A known method using hydroxylamine (Japanese Unexamined Patent Publication No. 1983-
169446).

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

Examples of inert organic solvents include methanol.

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

As the base added as necessary, Reactio
n The same bases as those used in the reaction in Scheme B can be mentioned.

The amount of such base to be used is determined based on the compound of formula (6), its group or
The amount is usually L to 3 times the mole of the masono ester. formula(
The reaction is usually carried out using equimolar amounts of the compound of formula (6), its salt, or its ester and the compound of formula (7), its protected compound, or its salt.

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

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

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

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

Deprotection, ring 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 Formula A can be used.

Reaction formula D (8) (“)) In the reaction formula, 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 Depending, it is subjected to deprotection, ring formation, esterification and/or reduction reactions.

Formula (8) K oiite, R', R", R' and hip lt
The same is true for E constant MK, and R represents a halogen atom such as chlorine, bromine, or iodine.

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

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

Examples of the ester of the compound of formula (8) include:

Examples include compounds esterified with a group similar to the R4 retaining group of the compound of formula (2) in Reaction Formula A.

The compound of formula (8) (2) is produced as follows.

In the above reaction, the reaction between the compound of Formula 1 (5') and the compound of Formula (3) is carried out in the same manner as the reaction described in 1 Reaction Scheme A. The reaction between the compound of formula (5) and the compound of formula (8') is carried out using the same fJ K reaction as described in Reaction Schema B.

The compound of formula (8') is a known compound and can be prepared by a known method (United Kingdom Patent m2
, 012, 276).

In formula (9), R1 represents a hydrogen atom or a hydroxyl group. Compound JX of formula (9) is a known compound (LS, P
agent m4, 298.606).

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

The compound of formula (8), its salt or its ester and formula (9)
The reaction with the compound or its salt is carried out by bringing the two into contact in an inert solvent.

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

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

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

The reaction time is usually about 1 to 10 hours.

The reaction product can be isolated fR1JJ by known means such as solvent extraction, crystallization, and chromatography.

In this reaction 1, when the syn isomer of compound (8) is used as the starting compound, the syn isomer of compound (1) is obtained. If syn and anti isomers of compound (8) are used, a mixture of syn and anti isomers of compound Q) is obtained. Such mixtures can be separated by conventional means such as crystallization, chromatography, etc.

Detachment 11! Bonding salt formation, esterification and/or reduction reactions can be carried out in the same manner as shown in Reaction Scheme A.

1 also when obtaining the crystalline anhydride or hydrate of the target product.
This reaction can be carried out in the same manner as shown in Reaction Scheme A.

Reaction formula E (1″
(11 In reaction formula E, a compound of formula 1, its salt, or its ester is reacted with a compound of formula α1, difurkyl sulfate, or diazoflucan. The reaction product must be vK
Depending, it is subjected to deprotection, ring formation, esterification and/or reduction reactions.

In the formula (l//ri, R1, Rm and p are the same as defined above.

Examples of the salt of the compound of formula (1///) include acid addition salts, alkali metal salts and alkaline earth metal salts.

Examples include ammonium salts and salts with organic bases.

Specific examples of these salts include the same salts as described for the compound of formula (1).

Formula <111As an ester of one compound, reaction formula A
Examples include compounds esterified with the same group as the protecting group for R4 in the compound of formula (2).

A compound of formula (l///li) can be produced by the following method.

In the above reaction, the reaction between the compound of formula (5') and the compound of formula (3) can be carried out in the same manner as the reaction described in reaction formula A. The reaction with the compound can be carried out in the same manner as the reaction described in Reaction Scheme B.

Formula (the four compounds are known compounds, and the known method (
U,S,Patent Nn4,298,606)
It is possible to make a kimono from K.

In the formula (1 (1), nu represents a substituted or unsubstituted furkyl group, a substituted or unsubstituted dichlorofurkyl group, or a substituted or unsubstituted heterocyclic group. Represents a gen atom.Formula (
(to) can be obtained by converting the corresponding aliphatic hydrocarbon, cycloaliphatic hydrocarbon or heterocyclic compound into
It can be obtained by p-genation.

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

Examples of diazoflucan include diazomethane.

The reaction of the compound of formula (1//f), its salt, or its ester with the compound of formula (g), dialkyl sulfuric acid, or diazoalkane is carried out in an inert solvent, if necessary 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, butanol; methylene chloride 1 dit'yp methane! Chloroform, carbon tetrachloride, l,2-diazomethane, etc./
Non-hydrocarbons; ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; dimethylformamide, diethylamide; ethyl acetate; water and the like.

If necessary, the reaction may be carried out in the presence of a base (・
. Examples of such bases include organic or inorganic bases such as alkali metal hydroxide, alkali metal hydrogencarbonate, alkali metal carbonate, triflukylamine, N,N-furkylpenzylamine, pyridine, and N-furkylmorpholine. It will be done. The amount of such base to be used is 1 normal formula (1/
//) for the compound, its salt or ester, 1 to 3
It is twice the mole.

The compound of formula (111), dialkyl sulfate, or diazoflucan is usually used in a molar amount of 1 to 3 times the amount of the compound of formula (l), its salt, or its ester.

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

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

The reaction product can be isolated and purified by known means such as solvent extraction, crystallization, and polymerography. In this reaction, when a compound (1" syn isomer) is used as a starting compound, a compound (1" syn isomer) is obtained.

When a mixture of syn and anti isomers of compound (1'//) is used, a mixture of syn and anti isomers of compound (1'//) is obtained. Such a mixture can be prepared by crystallization, lipography, etc. can be separated by conventional means.

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

Cephasporin derivatives of formula (1) of the present invention, especially R1
The Sepha I:+sporin derivative of formula (1), or a pharmaceutically acceptable salt thereof, or an ester thereof, wherein is a hydrogen atom,
It exhibits high antibacterial activity against a wide range of Durham-positive and Durham-negative bacteria and is useful for treating bacterial infections in animals, including humans. The Cefa-Osporin derivative of the present invention is Pseudomonas aeruginosa, Pseudomonas aeruginosa,
It has strong antibacterial activity against Durham-negative bacteria such as Salmonella typhi and Enterobacter, and against Durham-positive bacteria such as Staphylococcus aureus, Streptococcus pyogenes, and S. subtilis. Furthermore, the cephalosborin derivative of the present invention is characterized by a long duration of action.

The cephalosporin derivatives, pharmaceutically acceptable salts or esters thereof of the present invention are administered parenterally or orally. Examples of dosage forms for parenteral administration include intravenous or intramuscular injections, suppositories, and the like. Injectables can be in the form of aqueous or oily solutions, suspensions, and the like.

Also, the powder is reconstituted with Kff bacteria water before administration.

It may be a crystal. Examples of suppositories include preparations containing ordinary excipients such as Coff7 butter and glyceride, and absorption enhancers as required.

When administered orally, 1 regular capsule 1 tablet;
There are granules and the like, and these K can contain absorption enhancers, preservatives, etc.

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

The dosage of the Cephasporin derivative of the present invention, its pharmaceutically acceptable salt, or its ester is determined based on age, symptoms,
It varies depending on the dosage form, but usually -20 to 2ooow/
It is day.

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

Example 1 (6R, 7R)-7-(eot)-2-(2-) lythyl 7minothi7zol-4-yl)-2-phenoxyiminoacetamide]-3-tomethyl-3-cephem-4-
Carboxylic acid benzhydryl ester 530■? Add ether 30jt64KM to turbidity and add 79cm at room temperature to 1.5cm.
Stir well for a while.

The precipitate was filtered, 3 ml of trifluoroacetic acid was added to F (500~), and the mixture was stirred at room temperature for 1.5 hours.

Next, trifluoroacetic acid was removed under reduced pressure at 20°C or below, the resulting residue was triturated with ether and collected by filtration, and this was dissolved in a small amount of methanol and purified with a water-methanol mixed solvent using an HP-20 ion exchange resin column. Purification was carried out using the system while increasing the methanol volume ratio from 0% to 40%.

The fraction eluted with 20% to 40% methanol was lyophilized to obtain the target (6R,7R)-7-[(2))-2-7dinoxy-2-(2-7minothiazol-4-yl)7set. 7mido]-3-pyridiniummethyl-3-cephem-
28 ml of powder containing 4-carboxylate was obtained.

IR (Box-1) Near 76 NMR (D, DMS 0-D20) δ:5.1
0 1 H (d15.8 5
1 H (d16.9-8.1
11H Example 2 (1) Acetonitrile 250MK(6R,7R)-
20.9 g of 7-amino-3-iodomethyl-3-cephem-4-carboxylic acid was suspended, and 44 g. of bistrimethylsilyl 7cetamide was added dropwise while cooling on a water bath. After the dropwise addition, the mixture was further stirred for 1 hour.

In another reaction vessel, 100 m/CH, CJ, medium, 30.2
1 of (Zl-2-phenoximino-2-(2-)lytyl-7minothiazol-4-yl)acetic acid and 13.2 g of PCI s were reacted at room temperature, and after quickly washing with ice water,
Dry magnesium sulfate and filter to obtain (8)-2-phenoximino-2-(2-)lythyl 7minotizole-4-
A CH, C1t solution of 112 chloride was obtained. This solution was slowly added to the above 7 settonitrile solution under ice cooling. After the addition was completed, stirred at room temperature for 3θ minutes, (6R,
7R)-7-[ri-2-(2-trityl7minotizol-4-yl)-2-phenoximide/7ceto7mide]-3-iodomethyl-3-cephem-4-carboxylic acid trimethylsilyl ester 7 Setonitrile 1 dikp
A mixed solution of lomethane was obtained.

(iii) Cool the mixed solution to -20°C, add 5.5°C of 4-carbamoylpyridine and 5°I of 7cetonitrile.
The dissolved LIK was slowly added dropwise. After the dropwise addition was completed, the mixture was stirred at the same temperature for an additional 2 hours, and the temperature was gradually raised to room temperature.

The 1c solvent was distilled off under reduced pressure, and then 50 ml of trifluoroacetic acid containing 10% water was added, followed by vigorous stirring at room temperature for about 2 hours. After stirring, the resulting precipitate was poured into 500 ml of diethyl ether, filtered, and dried to obtain about 41 g of solid.

The obtained solid was crushed, extracted with water, the water was concentrated, and then ethanol was added.

When the ethanol solution was left to cool with water, a precipitate formed. The precipitate was filtered to obtain 21 g of (6R,7R)-7-[(3)-2
-(2-7minothi7zol-4-yl)-2-phenoximino7cetamido]-3-pyridiniummethyl-3
-cephem-4-carboxylate 2-trifluoroacetate was obtained. Dissolve this in a small amount of methanol and HP
Purification was carried out using a -20 ion exchange resin column in a water-methanol mixed solvent system while gradually increasing the methanol volume ratio from O to 40%.

Fractions eluted with methanol 20%-40% were collected.

(iii) The trifluoroacetate solution was passed through a 7-Amberlite IRA-410 ion exchange resin column and lyophilized to obtain the desired (6R+7R)-7-[(
5.0.9
I got it.

IR(crn-”): 1775NMR(d,-
DMSO-D, O) δ:5.15 1
H(d1 5.90 1H(d) 6.9-7.5 6 H 8,352) 1(d1 9.15 2H(d) Example 3 (6R,7R)-7- in 7cetonitrile 2! 7 minnow 3-iodomethyl-3-cephem-4-carboxylic acid 20
0.9 was suspended, and 435 Ill of bistrimethylsilyl 7cetamide was added dropwise while cooling on a water bath. After dripping,
After stirring for 1 hour under water cooling, the mixture was cooled to -20°C to obtain (6R97R)-7-pisdrimethylsilylamino-3-iodomethyl-3-cephem-4-carboxylic acid trimethylsilyl ester. Add to this while stirring,
4-carbamoylpyridine 56I to 7cetonitrile 40
Slowly drop the solution dissolved in 0 rql (6R
,7R)-7-pisdolymethylsilyl7minnow3- (
A solution of 4-carbamoylpyridinium) methyl-3-cephem-4-carboxylic acid trimethylsilyl ester in 7cetonitrile was obtained.

(11) The temperature of the obtained solution was raised to room temperature.

Separately, 300.9 (3)-2 in 1 l of jig 2 methane
-phenoxyimino-2-(2-methoxyimino-2-(2-)lythyl 7) prepared from 2-(2-tythylaminothiapur-4-yl)acetic acid and 132.9 phosphorus pentachloride A solution of minotizol-4-yl) acetic acid trichloride was added to the solution all at once. After stirring for 1 hour at room temperature,
Most of the solvent was removed under reduced pressure, and 60 Q at of trifluoroacetic acid containing 10 at of water was added, followed by stirring at room temperature for 2 hours. Most of the trifluoroacetic acid was distilled off under reduced pressure, and Jethiether 51 was added while stirring vigorously. The resulting precipitate was separated and extracted with approximately 1.51 liters of water.

After concentrating the extract, add about 21 ml of ethanol, leave to cool, and filter the resulting precipitate (6R, 7R)
-7-[(2))-2-(2-7 minotizole-4-
yl)-2-phenoxyimino7ceto7mid]-3-(
2-trifluoroacetate of 4-cut hamoylpyridinium) methyl-3-cephem-4-carboxylate was obtained.

010 The trifluoroacetate was dissolved in water and lyophilized through an IRA-410 ion exchange resin column to obtain the desired (6R,7R)-7-[l-2-(2)]. -Aminothiazol-4-i/L, )phenoximino]7cet7ξdo]-3-(4-carbamoylpyridinium)methyl]3-cephem-4-carboxyle) 285.1i' was obtained.

Spectral data (IR, NMR) were consistent with those obtained in Example 2.

Example 4 Similarly to Example 3 (i), (6R,7R)-7-7mi/-3-iodomethyl-3-cephem-4-carboxylic acid 50.5' in tonitrile with 500 it of 7 f! :
suspend, 110. ? bistrimethylsilylacetamide and 14. ? from 4-carbamoylpyridine (6
R,7R)-7-pisdrimethylsilylamino-3-(
A solution of 4-carbamoylpyrinium) methyl-3-cephem-4-carboxylic acid trimethylsilyl ester in 7cetonitrile was obtained. Add 300 r of methylene to the above solution.
In R/, an acid chloride solution prepared from 35 g of (2-1'pI:y7-t=+ruaminothiazol-4-yl)glyoxylic acid and 32 g of phosphorus pentachloride was added under water cooling.

After the addition was completed, the mixture was stirred at room temperature for 30 minutes. Subsequently, the solvent was distilled off to obtain a solid residue. methanol 700ml
Dissolve in ml! 6.5.9 O-phenylhydroxy-Zleamine was added and reacted at room temperature for 16 hours → t
Closed.

After the reaction, the solvent was distilled off under reduced pressure, 100 rrl of N N'-dimethylformamide was added to dissolve again, 21N of 1,000 urea was added, and the mixture was stirred at room temperature for 3 hours.

Next, this reaction solution was added to 7 liters of setone to obtain a precipitate.

The obtained solid was purified using H-P-20 ion exchange resin.
Setone water-mixed solvent system with a quantitative ratio of 77 tons from 0 to 40%
Powder 16F containing the title compound was purified with increasing granularity until
I got it. The obtained compound was fractionated by liquid chromatography (column: RP-18, elution solvent: water-methanol mixed solvent ν detection: UV at 260 nm) to obtain the target compound. Spectral data (IR, NMR) were consistent with those obtained in Example 2.

Example 5 Synthesis of lupoxylate according to reaction formula DK (1) In the same manner as (r+) in Example 3, (6R,7
R)-7-7 minnow 3-iodomethyl-3-cephem-
4-carboxylic acid 3.4 g + 7 from setonitrile 50d and 4-carbamoylpyridine 1.1.9 (6R, 7
R)-7-pisdrimethylsilylamino-3-(4-carbamoylpyridinium)methyl-3-cephem-4-
An acetonitrile solution of carboxylic acid trimethylsilyl ester was obtained.

On the other hand, 2.2 g of 4-chloro-3-okine-(2)]-]2-phenoximinoacetic acid was reacted with 2.2 g of phosphorus pentachloride in 50 U' of dichloromethane at room temperature to produce 4-Cup.
A dipar methane solution of -2-phenoxyiminoacetic acid trilide was prepared in advance, and this was slowly added to the acetonitrile solution obtained earlier at -20°C. After the addition, the temperature was gradually raised to room temperature, and the mixture was further stirred for 1 hour. After the reaction, the solvent was distilled off under reduced pressure to form a foamy solid.
3.0 g was obtained.

+i) The foamy solid is dimethylformamide 60i
dK was dissolved, thiourine fi 1.9.9 was added thereto, and the mixture was stirred at room temperature overnight.

When the reaction solution was directly poured into 500 ml of diethyl ether, a viscous liquid was separated, and after the ether was removed by decantation, 50 ml of acetone was added and stirred to obtain a solid.

The obtained solid was dissolved in water, and a HP-20 ion exchange resin column was used, and a water-77 ton mixed solvent system was added to the mixture, and the acetone ratio was gradually increased from 0 to 40. A white solid of 480 η was obtained as a residue containing the title compound. This was checked by high performance liquid chromatography and the estimated purity was outside 8G.

Example 6 In vitro antibacterial activity In vitro tft bacterial activity was measured by the agar plate dilution method.

Various test bacteria were cultured overnight in Tryptocase-Soypros, and a platinum loop (viable bacterial count IQ'/ml) was streaked onto Mueller-Hinton agar containing various concentrations of the compound of the present invention, and incubated at 37°C for 16 hours. The minimum inhibitory concentration (M
IC, μg/ml) was determined.

The results are shown in Table I.

Table-I MIC (μg/pigment) Example 7 Methicillin-resistant yellow P1! - In vitro activity against cocci was determined.

Table-II MIC (μm/xi) Chi CAD (Ceftazidim) LH.

Example 8 Next, other inventive compounds were shown to be active against methyleneline-resistant Staphylococcus aureus (6R97R)-7-[(2
)-2-(2-7minothi7zol-4-yl)-2-phenoxyiminoacetamide]-3-'acetoxymethyl-3-cephem-4-carboxylic acid (comparative compound A).

Compound 1: (6R,7R)-7-(ri)-2-(2-7
(mi/thianol-eyl)-2-phenoximino 7
(6Rl 7R) -7-C(Z)-2-(2
-aminothiazol-4-yl)2-(o-fluorophenoxyimino)acetamide-3-pyridiniummethyl-3-cephem-4-carboxylate Compound 111; (6R,7R)-7-((Zl-2
-(2-7minothi7p-4-yl)-2-(p-fluorophenoxyimino)7cetamido]-3-pyridiniummethyl-3-cephem-4-carboxylate compound ■; (θR, 71 tons) -7 -(ni)-2-(2-
(6R,7R)-7- C(2)-2-(
2-7minothi7zol-4-yl)-2-(p-fluorophenoxyimino)7cetamido]-3-(4-carbamoylpyridinium)methyl-3-cephem-4-carboxylate compound ■; (6R,7R) -7-C-2-(2-7minothiazol-4-yl) -2-
(m-trifluoromethylphenoximino)acetamide) -3-(4-carboxypyridinium)methyl-3-cephem-4-carboxylate compound ■;(
6RT7R) 7 (C12(2-7minothi7zol-4-yl)-2-(m-trifluoromethylphenoximino)acetamide)-3-(4-carbamoylpyrinium)methyl-3-cephem-4-carboxylate compound ■; (6R,7R)-7-((Z)-2-(2
-aminethiazol-4-yl) -2-(m-trifluoromethylpheno or soimino)7cetamido)-3
-(4-sulfoethylpyridinium)methyl-3-cephem-4-carboxylate compound IX; (GR,7R)-7-C)-2-(
2-7 minothi7zol-4-yl)-2-(p-fluorophenoxyimino)acetamide]-3-(3-sulfopyridinium)methyl-3-cephem-4-carboxylate <Industrial field of application> The present invention Seven F70 sporini/derivatives, their salts, or their Nisdels have strong antibacterial properties, strongly inhibiting the growth of many Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus, and Gram-positive bacteria, and are effective against various infections. It is useful for the treatment and prevention of J-symptoms.

Claims (1)

[Claims] 1. The following formula (1) ▲There are numerical formulas, chemical formulas, tables, etc.▼ (1) [In the formula, R^1 represents a hydrogen atom or a protective group. R^2
is a substituted or unsubstituted phenyl group, R^3 is ▲ formula,
Chemical formulas, tables, etc. are available.A substituted or unsubstituted 5- to 6-membered ring heteroaromatic cation represented by ▼, which can further contain a heteroatom selected from oxygen, sulfur, and nitrogen in the ring. It can also be fused with other rings. ] A cephalosporin derivative represented by 2. R^2 is a formula ▲ Numerical formula, chemical formula, table, etc. ▼ [Here, cycloalkyl group, phenyl group, cyano group, -CONH_2 or -(O)_l
(CH_2) m-COO_Y (where Y represents a hydrogen atom or a lower alkyl group, l and m represent 0 or 1), and n represents an integer of 1 to 5] is a substituted phenyl group represented by A cephalosporin derivative according to claim 1. 3. R^2 is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Here, X' is a halogen atom, a halogen lower alkyl group, -
CONH_2 or -(O)_l(CH_2)m-CO
OY (where Y is a hydrogen atom or a lower alkyl group,
2. The cephalosporin derivative according to claim 1, which is a substituted phenyl group represented by (l and m represent 0 or 1). 4. The cephalosporin derivative according to claim 1, wherein R^3 is a substituted or unsubstituted pyrazolium-thiazolium-, oxazolium- or pyridinium-cation. 5. Formula (2) below ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (2) [In the formula, R^1 and R^2 are the same as defined above, and R^4 represents a hydrogen atom or a protective group. Q represents an acyloxy group, a carbamoyloxy group or a halogen atom. p is 0
Or represents 1. ] A cephalosporin compound or a salt thereof represented by the following formula (3) R^3' (3) [wherein R^3' is a quaternary alkylammonium group R^
3] The following formula (1) is characterized by reacting with a compound represented by or a salt thereof, and subjecting it to deprotection, salt formation, esterification and/or reduction reaction as necessary ▲ Formula, There are chemical formulas, tables, etc.▼(1) [In the formula, R^1, R^2, and R^3 are the same as the definitions above. ]
A method for producing cephalosporin derivatives, their salts and esters. 6. Formula (4) below ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (4) [In the formula, R^1 and R^2 are the same as the definitions above. ], its salt or its reactive derivative and the following formula (
5) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(5) [In the formula, R^3 and p are the same as the above definitions. ], a salt thereof, an ester thereof, or a reactive derivative thereof is reacted with the following formula (1), which is subjected to deprotection, salt formation, esterification and/or reduction reaction as necessary. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1) [In the formula, R^1, R^2, and R^3 are the same as the above definitions. ]
A method for producing a cephalosporin derivative, a salt thereof, or an ester thereof. 7. The following formula (6) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (6) [In the formula, R^1, R^3 and p are the same as the above definitions. ] A cephalosporin derivative, its salt, or its ester represented by the following formula (7) H_2N-OR^2 (7) [wherein R^2 is the same as the above definition. ] The following formula (1) is characterized by reacting the compound represented by the formula, its protected compound or its salt, and subjecting it to deprotection, salt formation, esterification and/or reduction reaction as necessary. , chemical formulas, tables, etc.▼(1) [In the formula, R^1, R^2, and R^3 are the same as the above definitions. ]
A method for producing a cephalosporin derivative, a salt thereof, or an ester thereof. 8. The following formula (8) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (8) [In the formula, R^2, R^3 and p are the same as the above definitions. ^5
represents a halogen atom. ] The compound represented by, its salt, or its ester and the following formula (9) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (9) [In the formula, R^1 is the same as the above definition. ] The following formula (1) is characterized by reacting with a compound represented by or a salt thereof and subjecting it to deprotection, salt formation, esterification, and/or reduction reaction as necessary ▲ Numerical formula, chemical formula, table, etc. ▼(1) [In the formula, R^1, R^2, and R^3 are the same as the above definitions. ]
A method for producing a cephalosporin derivative, a salt thereof, or an ester thereof. 9. The following formula (1''') ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (1''') [In the formula, R^1, R^3, R^4, R^5, l, m, n
, X and p are the same as defined above. ] A cephalosporin derivative represented by the following formula (10) Hal-R^2' (10) [wherein R^2' is a substituted or unsubstituted alkyl group,
Hal representing a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted heterocyclic group represents a halogen atom. ] The following formula (1″″) is characterized by reacting with a compound represented by and subjecting it to deprotection, salt formation, esterification, and/or reduction reaction as necessary. Yes▼(1″″) [In the formula, R^1, R^2', and R^3 are the same as the above definitions. ] A method for producing a cephalosporin derivative, a salt thereof, or an ester thereof. 10. An antibacterial active composition comprising the cephalosporin derivative according to claim 1, a salt thereof or an ester thereof as an active ingredient, and optionally a pharmaceutically acceptable carrier.