JPS61200995A - Cephalosporin derivative, production and pharmaceutical use thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> is H, or protecting group; R<2> is H, (substituted) alkyl, (substituted) cycloalkyl, or (substituted) heterocyclic ring; R<3> is H, (substituted) alkyl, CN, COOH, alkoxycarbonyl, etc.; R<4> and R<5> are H, or alkyl: l is 0-2; m and n are 1, or 2 when l is 0, and 0 when lis 1 or 2; X is methylene when l is 0 or 1, and (substituted) methylene or oxo, when l is 2: with the proviso that X is not methylene, when R<3>, R<4>, and R<5> are H], its salt and its ester. EXAMPLE:(6R,7R)-7-([(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino-aceto-a mi-do]-3-(1- azabicyclo[3,3,0]octan-1-itheta)-methyl-3-cephemn-car-boxylate. USE:An antibacterial agent. PREPARATION:A cephalosporin compound shown by the formula II is reacted with a compound shown by the formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to cephalosporin derivatives, their production methods, and their pharmaceutical uses. More specifically, the present invention relates to a novel cephalosporin derivative that has strong antibacterial activity and strongly inhibits the growth of a large number of Durum-positive and Durham-negative bacteria, its production method, and its pharmaceutical use.

<Background technology> 2-methoxyimino-
Cefrosborin derivatives having a 2-(2-7minothiazol-4-yl)acetamide group are widely known as third-generation antibiotics, and are currently considered important in the medical field as therapeutic agents for various infectious diseases. There is.

Such cephalosporin derivatives include, for example, 7 at the 3-position.
A cephalosporin derivative (cefmetuxime) having a cetoxime cow group is known, and is characterized by being stable against β-lactamases. Also 1st in 3rd place
-Methyl-IH-tetrazol-5-yl-cephalosporin derivative with thiomethyl group (cefmetuxime)
It is also known to have strong antibacterial activity against Gram-negative and Gram-positive bacteria.

On the other hand, cephalosporin derivatives having a quaternary ammonium methyl group at the 3-position are known, such as U, S, P
Atant A4,27 L671 includes pyridinium methyl and quinolium methyl.

Cephalosporin derivatives having 84117 ammonicum methyl groups, such as vicolium methyl, have been disclosed. Furthermore, in Japanese Patent Application Laid-Open No. 59-219292, 1-(1
Cephalosporin derivatives having quaternary ammonium methyl groups such as -7zabicyclo(2,2,2)-octane-1-io)methyl groups have been described.

However, 1-(l-7zabicyclo(3,
Cephalosporin derivatives having a specific quaternary ammonium methyl group such as 3,0)-octane-1-io)methyl group have not been known so far.

<Disclosure of the Invention> The object of the present invention is to place 1-(1-7 Zabishik a-(
It is an object of the present invention to provide novel cephalosporin derivatives having specific quaternary ammonium methyl groups, such as 3,3,03-octane-1-io)methyl groups.

Another object of the present invention is to provide novel cephalosporin derivatives with potent antibacterial activity.

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

Still another object of the present invention is, in particular, Pseudomonas III, Salmonella typhi,
Gram-negative bacteria such as Enterobacter.

The present invention provides cephalosporin derivatives that have strong antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus, Streptococcus pyogenes, and Bacillus subtilis.

Yet another object of the present invention may be to provide novel cephalosporin derivatives with long-lasting antibacterial activity.

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

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

According to the invention, these objects and advantages are achieved by the following cephalosporin derivatives.

That is, the present invention is a cephalosporin derivative represented by the following formula (1), a salt thereof, or an ester thereof.

<Best mode for carrying out the invention> The cephalosporin derivative of formula (1) has L, m.

Depending on the definition of n and X, it is classified into three types as described below.

(1-1) t is 0, m and n are 1 or 2, and X is a derivative In this case, the cephalosporin derivative of the present invention has the following formula (
1-1) In formula (1-t)&c, m and n each represent 1 or 2.

In this case, the cephalosporin derivative of the present invention has the following formula (
1-2) %Formula% In this case, the cephalosporin derivative of the present invention has the following formula (
1-3) Represents a ren group, a methylene group having a substituent, or an oxo group. When Ra, R4 and R1 are hydrogen atoms, X is not a methylene group.

Examples of the substituents of the methylene group having substituents include:
Hydroxyl group; Amino group; Chlorine, Bromine.

Halogen atoms such as iodine; methyl, ethyl.

propyl, 1so-propyl, butyl, tert-
Examples include alkyl groups such as butyl, pentyl, and hexyl.

The cephalosporin derivatives of formula (1) I(1-1), (1-2) and (1-3) have a partial structure of a 2-7 minothiazol-4-yl group represented by the formula. The core structure can be easily isomerized into a 2-7 minothousazolin-4-yl group represented by the formula.

Therefore, the cephalosporin derivatives of formulas (1) I(]-1) 1(1-2) and (1-3) of the present invention may be any of these tautomers; In invention,
Any tautomeric p-pillar is included.

The cephalosporin derivatives of formulas (1), (1-1)I(1-2), and (1-3) have partial structures represented by the formulas. The partial structure may be a syn type represented by the formula, an anti type represented by the formula C-WO2, or a mixture of these chive isomers in any proportion. Among the cephalosporin derivatives of the present invention, the syn-type is preferred because it has strong antibacterial activity.

In formula (1) I(1-1), (1-2) and (1-3), R14 represents a hydrogen atom or a protective group. Examples of the protective group include an acyl group and an optionally substituted aralkyl group. Such acyl groups include, for example, formyl, acetyl, propionyl, butyryl, 1so
- lower alkanoyl groups such as butyryl, valeryl, l80-valeryl, oxalyl, succinyl, piparoyl;
Methoxycarbonyl, ethoxycarbonyl.

Lower alkoxycarbonyl groups such as propoxycarbonyl, 1so-propoxycarbonyl, phthoxycarbonyl, pentyloxycarbonyl; mesyl, ethanesulfonyl, boopanesulfonyl, 1so-propanesulfonyl.

Examples include lower alkanesulfonyl groups such as butanesulfonyl; aryl groups such as benzoyl, toluoyl, naphthoyl, and phthaloyl; aralcamyl groups such as phenylacetyl and phenylbupionyl; and 7-raloxycarbonyl groups such as benzoyloxycarbonyl. Such an acyl group may have one or more suitable substituents. Examples of the substituent include helogne atoms such as chlorine, bromine, iodine, and fluorine; cyano groups; and lower furkyl groups such as methyl, ethyl, propyl, and butyl.

Examples of the aralkyl group which may have an am group include benzyl, 4-methoxybenzyl, phenethyl, trityl, and 3,4-dimethoxybenzyl.

In formula (1) L(1-1) I(1-2) and (1-3), R represents a hydrogen atom, a substituted or unsubstituted furkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted cycloalkyl group. Represents a substituted heterocyclic group.

Examples of unsubstituted alkyl groups include methyl, ethyl, propyl, and 1so-propyl.

butyl, 5ee-butyl, tart-butyl,
Straight-chain or branched C1-C11 alkyl groups such as pentyl, hexyl, heptyl, octyl, nonyl, and decyl are mentioned. As substituents for such alkyl groups,
For example, carboxy group; methoxycarbonyl, ethoxycarbonyl, tart-7')oxycarbonyl,
Flucoxycarbonyl groups such as pentyloxycarbonyl; imidazolyl, 5-methylimidazolyl.

1-methylimitazolyl, 2-methyl-5-2) I=1
Examples include heterocyclic groups such as -3-imidazolyl, 2-7minothi7zolyl, IH-tetozolyl, 2H-tetrazolyl, thiazolyl, 1-methyl-IH-tetrazolyl, and pyrrolyF-3-yl.

Examples of the unsubstituted cycloalkyl group include C, -C, dicyclofurkyl groups such as cyclopropyl, cyclobutyl, cyclopenthyl, and cyclohexyl. Examples of substituents for the dichlorofurkyl group include the same substituents as for the alkyl group described above.

Examples of the unsubstituted heterocyclic group include IH-tetrazolyl, 2H-tetrazolyl, virridon-3-yl, 2-
Examples include 7minogyu azolyl. Examples of substituents for such heterocyclic groups include methyl, ethyl, and propyl.

Examples include alkyl groups such as butyl; alkoxy groups such as methoxy, ethoxy, propoxy, and butoxy; halogen atoms such as fluorine, bromine, and chlorine.

R8 is methyl, ethyl, propyl.

Lower furkyl groups such as 1so-propyl, gutyl, tert-butyl, hexyl; carboxymethyl, 2-
Carboxyethyl, 2-carboxy-2-propyl, 2
A lower furkyl group substituted with a carboxy group such as -carboxy-2-butyl or 3-carboxy-3-pentyl is preferred.

In formulas (1), (1-1), (1-2) and (1-=3), B& is a hydrogen atom, a substituted or unsubstituted furkyl group; a cyano group; a carboxy group; an alkoxycarbonyl group; a carbamoyl group represents a carbamoyloxy group; a heterocyclic group; a hydroxyl group; an alkoxy group; or a halogen atom.

Examples of unsubstituted alkyl groups include methyl, ethyl, propyl, and 18o-propyl.

Straight chain or branched C1 such as butyl, 1I6e-butyl, tert-butyl, pentyl, hexyl, etc.
-C, an alkyl group. Examples of substituents for such alkyl groups include hydroxyl group; cyano group; carbamoyloxy group; and methoxy.

C1-C6 lower alkoxy group such as ethoxy, butoxy, pentyloxy, hexyloxy: Carboxy group:
2,5-dihydro-2-methyl-5-oxotriazin-3-yl, 2,5-dihydro-6-hydroxy-2
Examples include heterocyclic groups such as -methyl-5-oxotriazin-3-yl.

Examples of the alkoxycarbonyl group include methoxycarbonyl and ethoxycarbonyl.

Propoxy carbonyl, butoxycarbonyl.

Examples include pentyloxycarbonyl and hexyloxycarbonyl.

Examples of the heterocyclic group include 2,5-dihydro ts -2
-Fukyl-5-oxotriazin-3-yl, 2,5-
Examples include dihydro-6-hydroxy-2-methyl-5-oxotriazin-3-yl and 2-7minothiazol-4-ylnatoca.

Examples of the alkoxy group include methoxy.

Ethoxy, propoxy, butoxy, pentyloxy, etc. h=includes.

Examples of halogen atoms include chlorine and bromine.

Examples include eye drops.

Rm is preferably a hydrogen atom, a substituted or unsubstituted methyl group, a cyano group, or an alkoxycarbonyl group.

In formulas (1), (1-1), (1-2) and (1-3), R4 and RA are the same or different and each represents a hydrogen atom or an alkyl group. Examples of alkyl groups include methyl, ethyl, and propyl.

1so-propyl, butyl,! l@e-butyl.

Examples include straight-chain or branched C8-C, alkyl groups such as tert-butyl, pentyl, and hexylnato.

Ha and Rm are each preferably a hydrogen atom.

The cephalosporin derivatives of formulas (1), (1-1), (1-2) and (1-3) have a betaine structure, and the cephalosporin derivative of the present invention can be derived from, for example, these betaine structures. Salt may also be used. Such salts include acid addition salts, such as inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate; acetate, trichloroacetate, trifluoroacetate, maleate; Tartrate, methanesulfonate.

Examples include organic acid salts such as benzenesulfonate and toluenesulfonate; amino acid salts such as alginate, aspartate, and glutamate.

These acid addition salts are, for example, represented by the following formulas (1') and (1''
).

h L represents an anion of an acid, and An:e represents an anion of a tribasic acid such as po:''.

Other salts of the cephalosporin derivatives of formulas (1), (z-1), (x-2) and (]-3) include salts at the carboxy group at the 4-position. Examples of such salts include alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), ammonium salts, salts with organic bases (triethylamine salts, trimethylamine salts, pyridine salts, etc.). salt, etc.).

The cephalosporin derivative of formula (1) e(1-1)+(1-2)+(1-3) may 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, flufky dialkyl esters such as methoxymethyl, ethoxymethyl, methoxyethyl, and ethoxyethyl esters; acetoxymethyl.

Furukayloxyalkyl esters such as propioxymethyl, butyryloxymethyl, valeryloxymethyl, and pivaloyloxymethyl ester; indanyl, phthalidyl, glycyloxymethyl, phenylglycyloxymethyl ester, and the like.

The cephalosporin derivatives, salts thereof, or esters thereof of the present invention are chemically stable if they are in the form of crystals.

Therefore, crystalline cephasporin derivatives, their salts or their esters are preferred when used as active ingredients in pharmaceutical compositions. Such crystals can be anhydrous or 3/4
- hydrate, 1-hydrate, 1.5-hydrate, 3-hydrate,
It may also be a hydrate such as a pentahydrate.

Preferred specific examples of the cephalosporin derivatives of the present invention are as follows.

Cephasporin derivative (1oo) of formula (1-1) (6
R,7R) -7-((Z) -2-(2--yminothiazol-4-yl)-2-methoxyiminoacetamide)-3- (1-7zabicyclo(3,3,0)octane- 1-io)methyl-3-cephem-4-carboxylate (102) (6R,7R)-7-C(z)-2-(
2-7 MinoJF-7Zol-4-yl)-2-methoxyiminoacetamide)-3- (1-7ZabisikR(4,3,O)nonane-1-io)
Methyl-3-cephem-4-rupoxylate (104) (6R,7R)-7-((Z)-2-(
2-7minothi7zol-4-yl)-2-methoxyimino7cetamido]-3- (1-7zabicyclo(4,4,0)decane-1-io)
Methyl-3-cephem-4-carboxylate (106) (6R,7R)-7-((Z)-2-(
2-7minothiazol-4-yl)-2-methoxyiminoacetamide)-3-(l-aza-8-methylbicyclo[3°3.0] octane-1-io)methyl-3-cepham-4-carboxylate (log) (1,7R)-7-((Z)-2-(2
--rminothiazol-4-yl)-2-methoxyiminoacetamide)-3- (1-aza-8-cyanobicyclo[3°3.0] octane-1-io)methyl-3-cephem-4- Carboxylate (no) (6R,7R)-7-((z) -2-(
2-yminothiazol-4-yl)-2-methoxyiminoacetamide)-3-(1-aza-8-hydroxymethylbiscif ρ(3,3,0)octane-1-io)methyl-3
-cephem-4-carboxylate (112) (6R,7R)-7-((Z)-2-(
2-7minothiazol-4-yl)-2-methoxyiminoacetamide)-3-(1-7zar8-carbamoylbicyclo(3,3,0)octane-1-io)methyl-3-cephem-4-carboxylate (114) (6R,7R)-7-((Z)-2-(
2-7minothiazol-4-yl)-2-methoxyiminoaceto7mido]-3-(1-aza-8-carbamoyloxybicycloa (3,3,0)octane-1-io)methyl-3-cephem -4-carboxylate (116) (6R,7R)-7-((Z)-2-(
2-7minothiazol-4-yl)-2-(2-carboxypropyl-2-yloxyimino)acetamide)-3-(1-7zabicyclo(3,3,03octane-1-io)methyl-3-cephem - 4-carboxylate (118) (6R,7R)-7-((Z)-2-(
2-rminothiazol-4-yl)-2-(5-methylimidazol-4-ylmethoxyimino)7cetamido]-3-(1-7zabicyclo(3,3,0)octane-1-io) Methyl-3-cephem-4-carboxylate (120) (6R,7R) -7-((Z) -2
-(2--rminothiazol-4-yl)-2-carboxymethoxyimino7cetamido]-3-(1-7
Zabicic R (3,3,0)octane-1-io)methyl-3-cephem-4-carboxylate (122) (6R,7R)-7-((Z)-2-(
2-7minothiazol-4-yl)-2-(2-carboxyethoxyimino)acetamide)-3-(1-7zabicyclo(3,3,0)octane-1-io)methyl-3-cephem-4-carboxy Rate (124) (6R,7R) -7-((Z)-2-
(2-7minothiazol-4-yl)-2-(imidazol-4-ylmethoxyimino)acetamide)-3-(1-7 zabicyclo(3,3,0)octane-1-io)methyl-3-cephem- 4-carboxylate (126) (6R,7R)-7-((z)-2-(
2-rminothiazol-4-yl)-2- (2-7minothiazol-4-ylmethoxyimino)acetamide)-3- (1-7zabicyclo(3,3,0)octane-1-io)methyl- 3-cephem-4-carboxylate (12B) (6R,7R)-7-((Z)-2-(
2-7minothiazol-4-yl)-2- (IH-tetrazol-5-ylmethoxyimino)7cetamido]-3- (1-7zabicyclo(3,3,0)octane-1-io)methyl-3- Cephem-4-carboxylate (130) (6R,7R) -7-((z)-2-
<2-7minothiazol-4-yl)-2-(1-methylimidazol-5-ylmethoxyimino)acetamide]-3-(1-azabisicq(3,3,0)octane-1-
Io) Mel 3-cephemu 4-carboxylate (132) (6R,7R)-7-((Z)-2-
(2-7minothiazol-4-yl)-2-(pyrrolidon-3-ylmethoxyimino)acetamide)-3-(1-7zabicyclo(3,3,0)octane-1-io)methyl-
3-cephem-4-carboxylate (134) (6R,7R)-7-C(z)-2-<
2-rminothiazol-4-yl)-2- (2-carboxypropyl-2-yloxyimino)acetamide)-3- (1-7zabicyclo(4,3,0)nonane-1-io)
Methyl-3-cephem-4-carboxylate (136) (6R,7R)-7-((Z)-2-
(2-7minothiazol-4-yl)-2- (2-carboxypropyr-2-yloxyimino)7cetamido)-3- (1-7zabisic a [4,4,0]decane-1-io) Methyl-3-cephem-4-carboxylate (138) (6R,7R)-7-[(Z)-2-(
2-7minothiazol-4-yl)-2-(2-carboxypropyl-2-yloxyimino)acetamido)-3-(1-aza-8-hydroxymethyl(3,3,03octane-1-io)methyl -3-cephem-4-carboxylate (200) (6R,7R) -7-(-(Z) -
2-(2-7ζnotiazol-4-yl)-2-methoxyiminoacetamide)-3-(l-7zabicyclo(2,2,1)hebutan-1-io)methyl-3-cephem-4- Carboxylate (202) (6R,7R) -7-((Z) -2
-(2-7minothiazol-4-yl)-2- (2-carboxypropyl-2-yloxyimino)acetamide)-3- (1-7zabisigulo(2,2,1)hebutan-1-io)methyl -3-cephem-4-carboxylate (204) (6R,7R) -7-((z) -2
-(2-7minothiazol-4-yl)-2-carboxymethoxyiminoacetamide]-3-(1-7
Zabicyclo(2,2,1)hebutane-1-io)methyl-3-cephem-4-carboxylate (206) (6R,7R)-7-((Z)-2-(
2-7minothiazol-4-yl)-2-(2-carboxyethoxyimino)acetamide)-3-(1-7zabicyclo(2,2,1)hebutan-1-io)methyl-3-cephem-4- Carboxylate (208) (6R,7R)-7-((Z)-2-(2-
7minothousandazol-4-yl)-2-(imidazol-4-ylmethoxyiminoacetamide)-3-(1-7zabicyclo(2,2,1)hebutan-1-io)methyl-
3-cephem-4-carboxylate (21G) (6R,7R)-7-((z) -2-
(2-7minothiazol-4-yl)-2-(5-methylimidazol-4-ylmethoxyimino)acetamide]-3-(1-7zabicyclo(2,2,1)hebutan-1-io)methyl- 3-cephem-4-carboxylate (212) (6R,?R)-7-((Z)-2-(
2-7minothiazol-4-yl)-2-methoxyiminoacetamide)-3-(1-aza-4-methylvicp[2°2.1] hebutan-1-io)methyl-3-cephem-4-carboxy Rate (214) (6R,7R)-7-((Z)-2-(
2-7minochenazol-4-yl)-2-methoxyiminoacetamide)-3-(1-aza-4-hydroxymethylbicyclo(2,2,1')hebutan-1-io)methyl-
3-cephem-4-carboxylate (216) (6R,7R)-7-((Z)-2-(
2-7minothiazol-4-yl)-2-methoxyiminoacetamide]-3- (1-7f-4-chloromethylbicyclo(2,2,1)hebutan-1-io)methyl-3-cephem-4- Carboxylate (300) (6R,7R)-7-((z)-2-
(2-7minothiazol-4-yl)-2-methoxyiminoacetamide)-3- (1-aza-3-oxobicyclo[2°2.2] octane-1-io)methyl-3-cephem-4-carboxy Rate (302'l (6R,7R) -7-((Z) -
2-(2-7minothiazol-4-yl)-2-methoxyiminoacetamide)-3-(1-aza-3-hydroxybicycou(2,2,2)octane-1-io)methyl-3-cephem- 4-carboxylate (304) (6R,7R) -7-C(Z)-2-
(2=7minothiazol-4-yl)-2-methoxyiminoacetamide)-3- (1-aza-3-chlorobicyclo[2°2.2] octane-1-io)methyl-3-cephem-4-carboxy Rate (306) (SR,7R) -7-((Z)-2-
(2-7minothiazol-4-yl)-2-me)ximinoacetamide)-3- (1-aza-3-7minobicyclo[2°2.2] octane-1-io)methyl-3-cephem-4 -carboxylate (308) (6R,7R)-7-((Z)-2-(
2-7minothousazol-4-yl)-2-carboxypropyl-2-yloxyimino)acetamide)-3-(1-aza-3-oxobicyclo(2,2,2)octane-1-
io) Methyl-3-cephem-4-carboxylate (310) (6R,7R)-7-((Z)-2-(
2-7minothi7zol-4-yl)-2-(2-carboxyethoxyimino)acetamide)-3-(1-aza-3-oxobicyclo(2,2,2)octane-1-io)methyl-3 -cephem-4-carboxylate (312) (6R,7R)-7-((Z)-2-(
2-7minothiazol-4-yl)-2-(imidazol-4-yloxyimido)7cetamido)-3-(1-azadi3-oxobicyclo(2,2,2)octane-1-io)methyl- 3-cephem-4-carboxylate (314) (6R,7R)-7-((z) -2-
(2-7minothiazol-4-yl)-2- (5-methylimidazol-4-ylmethoxyiminoacetamide)-3- (1-aza-3-oxobicyclo[2°2.2] octane-1-io) Methyl-3-cephem-4-carboxylate (316) (6R,7R) -7-((Z)-2-
(2-7minoti7zol-4-yl)-2-methoxyiminoacetamide)-3-(1-aza-4-methylbicyclo[2°2.2]octane-1-io)methyl-3-cephem-4 -carboxylate (318) (6R,7R) -7-((Z)-2-
(2-7minothi7zol-4-yl)-2-methoxyiminoacetamide)-3- (1-aza-4-cyanobicycou[2°2.2] octane-1-io)methyl-3-cephem-4- Carboxylate (320) (6R,7R)-7-((Z)-2-(
2-7(314) (6R,7R)-7-C(z)-
2-(2-7minothiazol-4-yl)-2- (5-methylimidazol-4-ylmethoxyiminoacetamide)-3- (1-aza-3-oxobicyclo[2°2.2] octane-1- io) Methyl-3-cephem-4-carboxylate (31B) (6R,7R) -7-C(Z) -2-(
2-7minotizol-4-yl)-2-methoxyiminoacetamide)-3- (1-7-4-methylbicyclo[2°2.2] octane-1-io)methyl-3-cephem-4- Carboxylate (3t8) (6R,7R)-7-((Z)-2-
(2-7mi/thiazol-4-yl)-2-methoxyiminoacetamide]-3- (1-7zar4-cyanobicycou[2°2.2] octane-1-io)methyl-3-cephem-4 -carboxylate (320) (6R,7R)-7-((Z)-2-(
2-aminothiazol-4-yl)-2-methoxyiminoacetamide)-3- (1-7zar4-ethoxycarbonylbicyclo[2,2,2)octane-1-io)methyl-
3-cephem-4-carboxylate (322) (6R,7R) -7-((z) -2
-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamide)-3- (Niaza-4-human-oxymethylbicyclo[2,2,2]octane-1-io)methyl-3
-cephem-4-carboxylate (324) (6R,7R)-7-((Z)-2-(
2-7minothiazol-4-yl)-2-methoxyiminoacetamide]-3-[1-aza-4-(2,5-di-L-do-2-methyl-5
-oxotriazin-3-yl) 1,000omethylbicyclo(2,2,23octane-1-io]methyl-3-cephemu-4-carboxylate (325) (6R,7R)-7-, ((Z)-2 −
(2-7minothiazol-4-yl)-2-methoxyiminoaceto7mido]-3- (1-7zar4-carboxybicyclo(2,2,23octane-1-io)methyl-3-cephem-4- Carboxylate 1326) (6R,7R)-7-((Z)-2-
(2-7minoti7zol-4-yl)-2-methoxyiminoacetamide)-3-(1-aza-4-methylbicyclo(2,2,2)off-turn-1-io)methenru3-cephemu4 -Carboxylate The method for producing the cephalosporin derivative, salt or ester thereof of the present invention will be described in detail below. The cephalosporin derivative, salt thereof, or ester thereof of the present invention can be produced by various methods (reaction schemes A to E) detailed below.

(2) (s) Reaction scheme: The cephalsporin compound of formula (2) or a salt thereof is reacted with the compound of formula (3) or a salt thereof. The reaction product is deprotected, salted, and
Subjected to esterification and/or reduction reactions.

In the formula (2), R1 and R1 are the same as defined in the formula (1), Q represents an acyloxy group, a carb7yloxy group, or a halogen atom, p represents 0 or 1, and R
・represents a hydrogen atom or a protective group.

Preferred examples of the acyloxy group include acyloxy, trifluoroacetyloxy, trichloroa7tyloxy, propionyloxy, and 3-oxinthyloxy.

3-carboxypropionyloxy, 2-carboxybenzoyloxy, 4-carboxybutyryloxy, manzolyloxy, 2-(carboethoxycarbamoyl)benzoyloxy, 2-(carboethoxysulfamoyl)benzoyloxy, 3-ethoxycarbamoylbu Examples include pionyloxy.

Examples of halogen atoms include iodine.

Examples include bromine and chlorine.

Examples of protecting groups for R6 include lower alkyl groups such as methyl, ethyl, furoyl, pentaso-propyl, phtyl, pentyl, and hexyl; acetoxymethyl, propylonyloxymethyl, butyryloxymethyl, and valeryloxymethyl. , alkanoyloxyalkyl groups such as pivaloyloxymethyl; methoxymethyl.

Flucoxyalkyl groups such as ethoxymethyl, methoxyethyl, ethoxyethyl; benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, diphenylmethyl, bis(methoxyphenyl)methyl.

3. An optionally @-substituted aralkyl group such as 4-dimethoxybenzyl; 2-iodoethyl.

2.2.2-)! Halogenated alkyl group of J Crozier Mas Lunat; Alkenyl group such as vinyl, allyl; Allyl group which may be exchanged such as phenyl, 4-chlorophenyl, tolyl, xylyl, mesityl; trimethylsilyl, triethylsilyl, t@rt- Glythyldimethylsilyl.

Trialkylsilyl groups such as tributylsilyl and the like can be used. Among these, W is preferably a triplekylsilyl group. When W is a trialkylsilyl group, Cephasporin 111 of formula (1) in the reaction of Reaction Scheme A
Since the production of the 14-novae isomer is suppressed, the desired cephalosporin derivative of formula (1) can be obtained in high yield.

The cephasporin compound of formula (2) may be a salt thereof. Preferred salts include formula (1).

Examples of the cephalsporin derivatives (1-1), (1-2) and (1-3) include salts similar to the exemplified salts.

The cephalsporin compound of formula C2) is a known compound and can be prepared by a known method (U, S, Pat@nt A 4+29
8.606. U, S, Pat@nt A 4t406
,899. U,S.

Patent A 4.39'L131).

Equation (3) R', R', R', tlrn
ln and X are the same as defined in formula (1). The compound of formula (3) may be a salt thereof (preferred salts are).

For example, inorganic acid salts (hydrochloride, hydrobromide).

sulfates, phosphates), organic acid salts (acetates).

maleate, tartrate, benzenesulfonate, toluenesulfonate/acid, etc.).

The compound of formula (3) is a known compound and can be prepared by a known method (
J, Org, Ch*m, 46.1737-1738, 1
981;5ynthesis@701. S@ptemb
er, 1978).

Cefa ρsporin♂ conductor of formula Q) or its salt and formula (3)
The reaction with the compound or its salt is carried out by bringing the two into contact in an inert organic solvent.

Examples of the inert organic I@ medium include methylene chloride, dichloromethane, ritya form, carbon tetrachloride,
, 2-dichloroethane and other halogenated hydrocarbons; diethyl ether.

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

The reaction temperature is preferably room temperature or lower, and it is generally preferred to carry out the reaction in a range of -30°C to +50°C.

A cephalosporin compound of formula (2) or a salt thereof,
The cephalosporin compound of formula (3) or its salt reacts with the compound of formula (3), but when carrying out the reaction, the cephalosporin compound of formula (2) or its salt is usually reacted with the compound of formula (3).
The compound or its salt is 0.7 to 10 times larger, preferably .

1.0 to 10 times more is used.

The reaction proceeds by simply stirring the two, and at the time of reaction rrr
l 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, 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 syn 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 a mixture.

It can be separated by conventional means such as crystallization and chromatography.

The reaction product is subjected to deprotection, ring formation, esterification, and/or reduction reactions as necessary. The deprotection reaction is a known reaction per se, and the protective group of 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 44m152,433; U, S, Pa
tent A 4,298,606).

The salt-forming reaction is itself a well-known reaction, and for example, a compound with the betaine structure 2α) obtained in the above reaction is converted into salt #!
, hydrobromic acid, sulfuric acid, phosphoric acid, vinegar, trifluoroacetic acid and other acids; or betaine in the presence of an acid, sodium chloride.

This is done by treatment with salts such as sodium iodide and potassium chloride.

The esterification reaction is a reaction known per se, in which the resulting Cephasporin derivative of formula (1) or a salt thereof is mixed with flucyloxyfurkyl halide, alkoxyalkyl nolide, etc., using 7setone, dimegyolformamide, etc. cr> carried out by reaction in an inert organic solvent (LJnlted Klngdom P+a
tent A 240+921).

The reduction reaction is a well-known reaction in itself, and is carried out by treating a cephalosporin 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 Kingdom Patent A
2401921).

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

The Cephasporin gzJHF Noah Seven Rufus powder of formula (1) was mixed with water, methanol, and ethanol.

Organic solvents such as acetone, tetrahydrofuran, dioxane and acetonitrile; or a method in which a mixed solvent of these is dissolved and allowed to stand to precipitate as crystals; a method in which an amorphous powder is crystallized using these solvents; or an amorphous powder There is a method of dissolving it 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 cephalosporin derivative in 20) is dissolved in water, methanol, ethanol, propatool tx organic solvent, or a mixed solvent thereof, and then triethylamine and sodium hydroxide are added. There is also a method to obtain crystals by neutralizing with a base such as.

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. The crystalline anhydrous solvate can be converted into a hydrate by evaporation in a gas containing water vapor.

In reaction scheme 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 deboilerization, salt formation, 1-stellation and/or reduction reactions as required.

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

The compound of formula (4) may be a salt (such as an addition salt). Examples of such acid addition salts include those exemplified as the acid addition salt of the compound of formula (3) in Reaction Scheme A. are commonly mentioned.

Examples of reactive derivatives of the compound of formula (4) include acid halides, r11 anhydrides, mixed acid anhydride-activated amides,
There are activated esters, etc.

Examples of acid halides include iron chloride and acid bromide. Examples of the mixed acid anhydride include mixed acid anhydrides with acids such as dialkylphosphoric acid, phenylphosphoric acid, pivalic acid, and pentanoic acid. Activated amides include imidazole, triazole,
Examples include amido groups activated with tetrazole, dimethylvirazole, etc. Examples of activated esters include sand ++, sheath cow ester, and methoxy methyl ester.

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

The compound of formula (4) is a known compound and can be prepared by a known method (
U, S, Patant A 4,298+606) K
Therefore, it can be manufactured.

In formula (5), R Hatake, R', R', t, m, n
, X 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; calcium salts and magnesium salts (Q
Examples thereof include flukaline earth metal salts; ammonium salts; salts with organic bases such as trimethylamine salts, 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 group as exemplified as the protecting group for R' in the compound of formula (2) of reaction scheme A.

Examples of reactive derivatives of the compound of formula (5) include 7
A basic imino compound or its enamine-type isomer formed by reaction with a carbonyl compound such as cetoacetic acid; bis(trimethylsilyl)7adoamide.

Silyl derivatives produced by reaction with silyl compounds such as trimethylchlorosilane and tert-7'methyldimethylc99silane; phosphorus trichloride.

Examples include derivatives obtained by reaction with phosgene.

The compound of formula (5) is produced by the following method.3) (5') The above reaction is 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. can be done.

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, if necessary in the presence of a condensing agent or a base. This is done by bringing the two into contact.

Examples of inert organic solvents include methylene chloride, dichloromethane, 9g form, carbon tetracarbon, 1
, 2-dichloroethane and other halogenated hydrocarbons; diethyl ether.

Ethers such as tetrahydrofuran, dioxane and dimethoxyethane; hydrocarbons such as hexane, benzene, toluene and xylene; 7cetonitrile: dimethylform; diethyl sulfoxide and the like.

A base may be added during the reaction. Such bases include, for example, alkali metal hydroxides, alkali metal hydrogen carbonates, carbon R alkali gold JL) realkylamines, N, N-
:) Examples include organic or inorganic bases such as furkylbenzylamine, pyridine, and N-furkylmorpholine.

The amount of the base to be used is usually equimolar to three times the molar amount of the compound (4), its salt, or its reactive derivative.

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

Examples include triphenylphosphine and 2-ethyl-7-hydroxypenzisoxazolium salt. 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 in approximately equimolar amounts.

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

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

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

Deprotection, ring formation, esterification and/or reduction of the reaction product can be carried out in the same manner as shown in Reaction Scheme A.

The same method as shown in Reaction Scheme 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 chromatography.

(6) R'' (7) In reaction scheme C, a compound of formula (6), a salt thereof or an ester thereof, and a compound of formula (7).

React with the protected compound or its salt. Reaction products are deprotected if necessary.

Subjected to ring formation, esterification and/or reduction reactions.

In formula (6), R'', Rj, R', R'
, L, m+n+X and p are as defined above.

Examples of the salt of the compound of formula (6) include addition salts.

Alternatively, there are alkali metal salts, alkaline earth metal salts, ammonium salts, or salts with organic bases. Specific examples of these salts include the same salts as described for the compound of formula (1).

Examples of the ester of the compound of formula (6) include compounds esterified with the same group as exemplified as the protecting group for R1 of the compound of formula (2) in reaction scheme AK.

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

(6') (3)R'' The compound of formula (6') is a known compound and can be prepared by a known method (U, S, Patent A 4,201,779;
U,S.

PatsntA 42851436; U-
S, P a tent A 4+41 L898)
! ? : Therefore, it can be manufactured.

The above reaction is carried out by the formula (2
) can be carried out in the same manner as the reaction of the compound of formula (3).

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

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

The compound of formula (7) is a known compound and can be prepared by a known method using hydroxyphthalimide (Bulletin 5
oeiety, 833.1976) IIC.

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

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

As a base to be added as necessary, reaction scheme B
Examples include the same * groups used in the N reaction.

The amount of the base used is the compound of formula (6).

The amount is usually 1 to 3 times the mole of the salt or ester thereof. The compound of formula (6), its salt or its ester and the formula (
The reaction is usually carried out using equimolar amounts of the compound (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.

It is known that deprotection, ring formation, esterification and/or reduction reactions are carried out in the same manner as in Reaction Scheme A. When obtaining a crystalline anhydride or hydrate of the target product, the same method as shown in Reaction Scheme A can be used.

R' In reaction scheme D, the compound of formula (8), its base, or its ester is reacted with the compound of formula (9) or its salt. The reaction product is subjected to deprotection, salt formation, esterification and/or reduction reactions as necessary.

In formula (8), R'', R'', R', R
' r X + t + m.

n and p are the same as defined above, and R7 represents a halogen atom such as chlorine, bromine, or iodine.

Examples of the salt of the compound of formula (8) include alkali metal salts, alkaline earth metal salts, ammonium salts, salts with organic bases, and acid addition salts. Specific examples of these salts include the same salts as those described for compound (1).

Examples of the ester of the compound of formula (8) include a compound esterified with a group similar to the protecting group of R6 of the compound (2) in reaction scheme A.

The compound of formula (8) is produced as follows. In the above reaction, the reaction between the compound of formula (5') and the compound of formula (3) is carried out in the same manner as the reaction described in reaction scheme A. Ru.

The reaction between the compound of formula (5) and the compound of formula (8') is carried out in the same manner as described in reaction scheme B. The compound of formula (8') is a known compound and can be prepared by a known method (United Kingdom Patent A
2.012,276).

In formula (9), R1 represents a hydrogen atom or a hydroxyl group. The compound of formula (9) is a known compound (U, S,
Patent A 4.298.606).

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

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, propatool, and butanol;
diethyl ether.

Examples include ethers such as tetrahydrofuran and dioxane; dimethylformamide; dimethylacetamide; and methylpiperidone. 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.

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

The reaction time is usually about 1 to 10 hours.

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

In this reaction, when the syn isomer of compound (8) is used as the starting compound, the syn isomer of compound (1) is obtained. When syn and anti isomers of compound (8) are used, a mixture of syn and anti isomers of compound (1) 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 under pressure in the same manner as in reaction scheme A. When obtaining a crystalline anhydride or hydrate of the target product, the same method as shown in Reaction Scheme A can be used.

s (1"') αQ(1"') In reaction scheme E, a compound of formula (1"'), a salt thereof or an ester thereof, and a compound of formula (10).

React with dialkyl sulfuric acid or diazoalkane.

The reaction product should be subjected to membrane removal, salt formation, esterification and/or reduction reactions, depending on the IK.

In formula (1"'), R" + R", R',
R', t, m*n+X and p are as defined above.

The salt of the compound of formula (1'') and R7 are acid addition salts.

Alternatively, there are alkali metal salts, alkaline earth metal salts, ammonium salts, salts with organic bases, etc. Specific examples of these salts include the same salts as described for the compound of formula (1).

As the ester of the compound of formula (1#'), there can be mentioned a compound esterified with the same group as the eye-holding group of R6 in the compound of formula (2) of reaction scheme A.

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

Rs (ge) 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 scheme A, and the compound of formula (5) and Formula (4')
The reaction with the compound can be carried out in the same manner as the reaction described in Reaction Scheme B. The compound of formula (4') is a known compound and can be prepared by a known method (U, S, Patent
No. 4°298, 606).

In formula (10), R1/ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. Hat is
Represents halogen atoms such as chlorine, bromine, and iodine. formula(
The compound 10) can be obtained by halogenating the corresponding aliphatic hydrocarbon, cycloaliphatic hydrocarbon or heterocyclic compound by a conventional method.

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

Examples of the diazoalkane include diazomethane.

A compound of formula (1''), a salt thereof or an ester thereof and a compound of formula (1'')
The reaction with the compound 10), dialkyl sulfuric acid, or diazoalkane is carried out by bringing the two into contact in an inert solvent, optionally in the presence of a base.

Examples of inert solvents include methanol, ethanol,
Alcohols such as propatool and butanol; methylene chloride, dichloromethane, dichloroform, and carbon tetrachloride.

1. Halogenated hydrocarbons such as 2-dichloroethane;
diethyl ether, tetrahydrofuran, dioxane,
Examples include ethers such as dimethoxyethane; dimethylformamide, diethylacetamide; dithyl acetate; and water.

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

Such bases include, for example, alkali metal hydroxides and alkali metal hydrogen carbonates.

Alkaline carbonate, triflukylamine.

Examples include organic or inorganic bases such as N,N-dialkylbenzylamine, pyridine, N-alkylheptasphorine, and the like. The amount of such base to be used is usually 1 to 3 times the amount of the compound of formula (III), its salt or ester.

The compound of formula (10), dialkyl sulfate, or diazoalkane is usually used in an amount of 1 to 3 times the amount of the compound of formula (1''), its salt, or its ester.

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

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

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

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

Cephalosporin derivatives of formula (1) of the present invention, especially VcR
The cephalosporin derivative of formula (1) or its pharmaceutically acceptable salt or ester thereof, in which ' is a hydrogen atom, exhibits high antibacterial activity against a wide range of Gram-positive bacteria and Gram-negative bacteria, including humans. Useful in treating bacterial infections in animals. The cefadisporin derivatives of the present invention include Pseudomonas aeruginosa, Pseudomonas aeruginosa,
Typhoid fever! , Gram-negative bacteria such as Enterobacter, Staphylococcus aureus, Streptococcus pyogenes, and Gram-negative bacteria such as Subtilis.
It has strong antibacterial activity against bacteria. Furthermore, the cephasporin derivative of the present invention is characterized by a long duration of action.

The cefadisporin 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. Injections can take the form of aqueous or oily solutions, suspensions, and the like. It may also be in the form of powder or crystals that are reconstituted with sterilized water before administration. Examples include preparations made by adding absorption enhancers to normal excipients such as suppositories such as Hakokoa Putter and Glyclide, depending on the fee.

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

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

Cefadisporin derivative of the present invention, its pharmaceutical K11
l! The dosage of F-acceptable salt or its ester is determined by age,
Varies depending on symptoms and dosage form, but usually 20 to 20,001
19/day.

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

Example 1 Synthesis of (6R,7R)-7-(CZ)-2-(2-) dithylaminothiazol-4-yl)-2-methoxyiminoacetamide]-3-iodomethyl-3-cephem-4
-Carbon-brewed benzhydryl ester 468■ ether 30t/1cIIIl! Once cloudy, add 1-7 Zabicyclo (3,3,01 octane 111119) and boil at M temperature for 1.
The mixture was stirred well for 5 hours.

The precipitate was filtered, and 3 Int of triflic acetic acid was added to F (4s5+rli) [stirred at room temperature for 1.5 hours].

Next, trifluoroacetic acid was removed under reduced pressure at 20°C or below, and the resulting residual liquid was crushed with ether and collected by filtration. This was dissolved in a small amount of methanol and added to a water-methanol mixed solvent using an HP-20 ion exchange resin column. Purification was carried out in the system while increasing the methanol volume ratio from 0 to 404.

The fraction eluted with 20% to 40% methanol was freeze-dried to obtain the desired (6R,7R)-7-((Z)-2-methoxy-2-(2-amigthiazol-4-yl)acetamide). -3-(1-azabicyclo (3,3,0)
A powder 4711y containing octane-1-io)methyl-3-cephem-4-carboxylate was obtained.

IR (t=l-"Phoenix"): 1770, 1668, 1630, 1220, 1130.
104ONMR (D6104ONδ: 1.7-2.3 (8H, broad).

3.2~4.0 (5H, broad)+3.85(3
H,+)+4.7~4.7 (4H,multiple
t).

5.27 (IH, d), 5.89 (IH, d+d
).

6.84 (IH9s), 7.26 (2H+
Chess Example 2 (i) (6R, 7R)-7-(■)-2-(2-aminethiazol-4-yl)-2-methoxyiminoacetamide)-3-(1-7zabisichu(3, 3,0) Octane-1-io) Methyl-3-cephem-4-carboxylate (betaine) 3.01 crude crystals were dissolved in 7 dK of water, and 10 g of sulfur #6+d was added dropwise while stirring under water cooling.

Approximately 15 d of ethanol was added and allowed to stand, and the precipitated crystals were treated with F. The sample was washed with ethanol and dried to obtain the title compound (6
R17R)-? -Il, (2))-2-(2-7minothiazol-4-yl)-2-methoxyiminoacetamide)-3-(1-7zabicyclo(3,3,0)octan-1-io)methyl-3 -Cephem-4-carboxylate sulfate [sulfate of compound (100)] 2.5
I got t.

IR (α-re: 3370 + 1788 * 1640 + ] 54
5 * 1070 + 10 J ONMR(+), 0
) δ: 1.8-2.3 (8H, broad).

3.2-3.8 (5H, broad).

4.0 (3H, singlet).

4.0-4.7 (4H, broad).

5.3 (H, doublet), 5.8 (IH,
doublet).

7.05 (IHtsingl*t) (ii) (6R, 7R) -7-((2))-2-
(2-7minothiazol-4-yl)-2-methoxyiminoacetamide)-3-(1-7zabisikR(3,3
,0]]Octane-1-iomethyl-3-cephem-4
- Carboxylate 2 fist triflo p acetate [Compound (1
oe) trifluoroacetate) 4. Dissolve Of in 15% of water and add 8.51 nt of 10% sulfuric acid while cooling on ice.
added. When 50% of ethanol was added to this and kept at -200 overnight, white crystals were obtained. - When overdried, the title compound (6Rt7R)-7-[isomer]-2-(2-7minothiazol-4-yl)-2-methoxyiminoacetamide]-3-(1-azabicyclo(3,3,0 ) octane-1-io)methyl-3-cephem-4-rupoxylate sulfate [sulfate of compound (100)] 3.3
F was obtained.

Example 3 (6R,7R)-7-((phantom-2-(2-aminothiazol-4-yl)-2-methoxyimino7cetamide)
-3-(1-7zabicyclo(3,3,0)octane-1
-io) Methyl-3-cephem-4-carboxylate (hetaine) 3.0 g in water and methanol 5 g 1 t
Dissolve 4N HC6 in a mixed solvent of
added. After the addition was completed, 200 ml of ethanol was added, the mixture was kept under water cooling overnight, and the resulting crude crystals were recrystallized from water to obtain the title compound 2.22.

IR (Kiichi 1): 3390.177G, 1709,1650,1036 Example 4 (i) (6R, 7R) -7-C form) -2-methoxyimino-2-(2-7minothiazol-4-yl) acetamido)-3-(1-azabicyclo(3,3,0:
]] Octane-1-iomethyl-3-cephem-4-carboxylate [Compound (1oO): l (amorphous) 5
．． Of was dissolved in 20 d of methanol at room temperature and stirred for 2 hours.

4. The precipitated crystals are separated from each other, washed with methanol, and dried.
I got 8f.

As a result of X#1 diffraction measurement of this product, the following relative intensity was obtained, which indicates the presence of crystals.

Diffraction angle (2θ0) Relative intensity (chi) 6.4 1
3 57.2 8
7 21 3.4 6
3 61 3.8 8
2 71 4.2
9 2 01 7
．． 8 5 1 0 01
9.0 2 4
02 0.4 5 3
02 2.4 0
9 52 3.2 3
2 12 3.0 1
2 22 3.9 7
2 42 5.8 0
2 82 6.4 3
2 62 8.2 2
1 92 8.7 5
2 5 Also, in the infrared absorption spectrum, unlike the amorphous type, absorption was observed at the following wave numbers.

3300.3190, 1763, 1675, 1617,
1350, 1300° 1210.1182, 1098,
1015,961.926,889,860°823.
781,762,737 (cm-') (ii)
(6R,7R)-7-(@)-2-methoxyimino-2
-(2-aminethiazol-4-yl)acetamide)
-3-(1-7zabicyclo(3,3,0)octane-1
-io) Methyl-3-cephem-4-carboxylate sulfate [sulfate of compound (100)] 6. Or was dispersed in methanol 15 dK and triethylamine 2.77 Nt
was added dropwise at room temperature, and the compound gradually dissolved. After stirring for 5 hours, the precipitated crystals were separated in a furnace to obtain 4.9f.

The X-ray diffraction and infrared absorption spectra of this crystal matched the crystal obtained in (i).

(i) Instead of the sulfate of (ii) [the sulfate of compound (100)], use 2-hydrochloride [hydrochloride of compound (100)] 5.8 f, and the rest is the same as in (ii). 4.81 crystals were obtained. ′ (iψ 2-trifluoroacetate [compound (100)) instead of the sulfate of (11) [sulfate of compound (100)]
trifluoroacetate) 7.3 Using f, the rest is (ii
) A similar crystal 4.91 was obtained.

(v) The crystallized product obtained in (i) was placed in the atmosphere overnight. The relative humidity during the run was about 50-60%. The thus obtained hydrate (3-hydrate) had the following characteristics by X-ray diffraction.

Example 5 (1) Acetonitrile 250- to (6R,7R)-
7-Amino-3-iodomethyl-3-cephem-4-carboxylic acid 209 was suspended, and while cooling on a water bath, 7-methylsilylacetoamide 44- was added dropwise.

After the dropwise addition, the mixture was further stirred for 1 hour.

In another reaction vessel, in C4 of 100-26.31
)-2-Methoxyimino-2-(2-)dithylaminothiazol-4-yl)acetic acid and 13.2 f of PCl3 were reacted at room temperature, washed with ice water, dried with magnesium sulfate, and filtered. 6)-2-methoxyimino-2-
CI of (2-) dithylaminothiazol-4-yl) acetic acid chloride (C4, solution) was prepared. This solution was slowly added to the acetonitrile solution under water cooling. After the addition was completed, it was kept at room temperature for 30 minutes. Stir 6)t, 7R)-7-
(◇7.>-2-(2-) dithylaminothiazol-4-yl)-2-methoxyiminoacedo, mid]
A mixture of -3-iodomethyl-3-cephem-4-carboxylic acid trimethylsilyl ester in 7cetonitrile-dichlorop-methane was obtained.

(ii) The M mixed solution was cooled to -20°C, and a solution of 5.11 1-7zabicyclo(3,3,O)octane dissolved in 50°C of acetonitrile was slowly added dropwise. After the dropwise addition was completed, the mixture was further stirred at the same temperature for 2 hours and 1,141 hours, and the temperature was gradually raised to room temperature.

The solvent was distilled off under reduced pressure, and then 50-trituacetic acid containing 10'l of water was added and stirred vigorously at room temperature for about 2 hours. After the stirring was completed, the precipitate was poured into 500 ml of diethyl ether and the resulting precipitate was filtered and dried to obtain about 41 tons 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 212 (6R,7R)-7-((Z)-2
-(2--rminoq-7zol-4-yl)-2-methoxyiminoacetamide)-3-(1-azabicyclo(
3,3,0)octane-1-io)methyl-3-cephem-4-carboxylate 2-trifluoroacetate [
A solid solvate of the trifluoroacetate of compound (100) was obtained.

(b) Dry the solid, suspend the dry powder in about 50% dry methanol, and neutralize with triethylamine while stirring under water cooling to obtain the desired product (6R,
7R) -7-(■)-2-(2-7minothiazol-4-yl)methoxyiminoacetamide)-3-(1-
(1-7zabicyclo(3,3,0)]octane-1-iomekyl)3-cephemu-4-carboxylate5.2
I got 2.

High performance liquid chromatography [Column: Richroa
orb RP-18, eluate; H, OM@0I (
=85-15) It was confirmed from K that the purity was 98.2%.

Example 6 Phthiazol-4-yl)-2-methoxyiminoacetamide)-3-(1-7zabicyclo(3,3,0)octane-1-io)methyl-3-cephem-4-carboxylate [Compound ( Synthesis of 100)) according to reaction scheme B (i) 7 c) 2) ! 7 Le 2 L Medium K (
6R,7R)-7-Amino-3-iodomethyl-3-cephem-4-carboxylic acid (200 t) was clouded under Pa and cooled on an ice bath while bistrimethylsilylacetamide 4351
! 1 t was dropped. After the dropwise addition, the mixture was further stirred for 1 hour under water cooling, and then cooled to -20°C to obtain (6R,7R)-7-pisdrimethylsilylamino-3-iodomethyl-3-cephem-4-carboxylic acid trimethylsilyl ester. Ta. This C (, while stirring, 1-7 Zabishik a (3,
3,0) Slowly drop a solution of octane 519 in acetonitrile 400- to (6Rt 7 R)
? -bistrimethylsilylamino-3-(t-7zabicyclo(3,3,0)octane-1-io)methyl-3
A 7-cetonitrite solution of -cephem-4-carboxylic acid trimethylsilyl ester was obtained.

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

Separately, 2632 ■)-2-methoxyimine/-2-(2-)ditylaminothiazole- in 1 t of dichloromethane.
A solution of (gradient-2-methoxyimino-2(2-trithyl-aminothousazol-4-yl)) acetic acid pride prepared from phosphorus pentachloride (4-yl) acetic acid and 1321 phosphorus pentachloride was added to the solution f.
ig added at once. After stirring at room temperature for 1 hour, most of the solvent was removed under reduced pressure, and 600ml of trifluoroacetic acid mixed with 1 inch 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 5 tons of diethyl ether was added while stirring vigorously. The obtained precipitate was taken from house to house and extracted with about 1.5 tons of water from the F sieve. After concentrating the extract, add about 2 tons of ethanol and leave to cool.
When the obtained precipitate is filtered, (6R,7R)-7-C■
)-2-(2-7minothiazol-4-yl)-2-methoxyiminoacetamide)-3-(1-azabicic c
y (3,3,Q )] octane-1-iomethyl-3
270t of a solvate of 2-triple-oacetate of -cephem-4-carboxylate [trifluoroacetate of compound (100)] was obtained.

(iii) The obtained solvate was dried in vacuo, and the solid powder 1402 was suspended in methanol 500rdK, and while stirring under water cooling, triethylamine was added dropwise and neutralized while monitoring with a pH meter.

At the neutralization point, KfiNL was stirred for 1 hour, and when stirring was continued, crystals precipitated. The crystalline (6R,7R)-7- was filtered, washed with methanol, and dried.
((2))-2-(2-7minothiazol-4-yl)
-2-Methoxyiminoacetamide)-3-(1-azabicyclo(3,3,O)octane-1-io)Megyu-3-cephemu-4-carboxylate [Compound (100
)) 74μ was obtained. The purity of this product was measured by high-performance liquid chromatography [column: PR-ts, elution solvent: water-methanol mixed solvent, detection: UV at 28
0 nm) was 99 or more.

Spectral data (IR, NMR) were consistent with those obtained in Example 1.

Example 7 Similar to Example 6 (i), suspend K(6R,7R)-7-amino-3-iodomethyl-3-cephem-4-carboxylic acid 502 in acetonitrile,
110F bistrimethylsilylacetamide and 132
1-7zabisic G = (3,3,0)octane and (6R17R)-7-pisdrimethylsilylamino 3
An acetonitrile solution of -(1-azabicyclo(3,3,0)octane-1-io)methyl-3-cephem-4-carboxylic acid trinotylsilyl ester was prepared. Add 62F (2-tritylaminobo-azol-4-yl)glyoxylic acid and 32F to the above solution in 300 mZ of methylene chloride.
An acid succilide solution prepared from phosphorus pentachloride was added under water cooling. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. Subsequently, the solvent was distilled off to obtain a solid residue. methanol 7
00d& was dissolved, 7.19 of O-methylhydroxyimine 7.11 was added, and the mixture was reacted at room temperature for 16 hours.

After removing most of the solvent under reduced pressure in the reaction wave, 10%
Trifluoroic acid C11150- containing water was added thereto, and the mixture was vigorously stirred at room temperature for 4 hours.・Next, add 1 t of this reaction solution
into diethyl ether to obtain a precipitate. This precipitate was filtered and treated in the same manner as in Example 6 (11) to obtain solid 342 of the trifluoroacetate of the title compound [trifluoroacetate of compound (100)].

The obtained compound (6) was mixed with HP-20 ion exchange resin in an acetone water-mixed solvent system at an acetone ratio of O to 40.
Powder 15 containing the title compound was refined in increasing amounts until
．． 4 f was obtained. The obtained compound was confirmed to be the title compound by liquid chromatography [column: RP-181 elution solvent: water-methanol mixed solvent, detection: UV at 280 nm], and its purity was 6.
It was 8%.

Example 8 (3,3,O)octane-1-io)methyl-3-(1
) In the same manner as in Example 6 (1), (6R, 7It)-
7-7 minnow 3-iodomethyl-3-cephem-4-carvone fi3.4F, acetonitrile 50g and 1-azabicic9 (3,3,0)octane 1. From Of(6
R,7R)-7-pisdrimethylsilylamino-3-(
1-7 sahicyclo(3,3,0)octane-1-io)
An acetonitrile solution of methyl-3-cephem-4-carboxylic acid trimeryl silyl ester was obtained.

On the other hand, 1.62 t of 4-chloro-3-oxo-(i)-2-methoxyiminoacetic acid was reacted with 2.2 t of phosphorus pentachloride in 50 ml of dichloromethane at room temperature. 6) A dichloromethane solution of -2-methoxyiminoacetic acid chloride was prepared in advance, and this was slowly added to the previously obtained acetonitrile m11 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 and a foamy solid was obtained.
I got it.

(11) The foamy solid was dissolved in dimethylformamide 6°+dK, 1.92 ml of 1,000 urea was added thereto, and the mixture was stirred overnight at room temperature.

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

The obtained solid was dissolved in 1 c of water, and using an HP-20 ion exchange resin column, using a water-7 7 ton mixed solvent system,
Purification was carried out while gradually increasing the quantitative ratio of 7 setone from 0 to 40%, and a white solid of 415 to 415 was obtained as a compound residue of IflA compound. This was confirmed by high performance liquid coomadography and the estimated purity was 75%.

Example 9 (i) 3.4 t of (eat7a)-7-rmino-3-iodomethyl-3-cephem-4-carboxylic acid was suspended in 50 mjlCM of acetonitrile, and 7.52 g of bistrimethylsilylacetamide was added at room temperature and stirred for 1 hour under VC. After that, it was cooled by -20CK and 1-7 Zabishik 9 (3,
3,0) Slowly add 1.01 octane and add 1.01 octane at the same temperature.
After stirring for an hour, the truffle of (6R,7R)-7-pisdrimethylsilylamino-3-(1-7zabicyclo(3,3,O)octane-1-io)methyl-3-cephem-4-carboxylic acid was added. An acetonitrile solution of tilsilyl ester was prepared at tJI of 4 m. Separately, (6)-2-hydroxyimino-2-(2-trigylaminothiazol-4-yl)6
Acid 4.2f in 50-dichloromethane, 2.1 r
-2-Hydroxyimino-2-(2-)lythyl 7-minothiazol-4-yl) acetic acid chloride was reacted with PC4 at room temperature, and this was added to the above solution at room temperature to react. Ta. After stirring for 1 hour at room temperature, the solvent was distilled off under reduced pressure to leave a foamy solid 13 as a residue.
．． Obtained 5 F.

(ii> Dissolve the fm-like solid in 200-dimethyl sulfoxide, add 2.0-iodomethyl and 5-potassium carbonate.
．． The mixture of 5f was stirred at room temperature for 2 days. After the reaction, 750 ml of water was poured, and the precipitate formed was poured into 50% trifluoroacetic acid containing 10% water.
Stir vigorously for 3 hours at room temperature. The reaction solution was neutralized with 500-diethyl ether, and the resulting precipitate was collected by filtration, washed with acetone, and then dried.

The precipitate was thoroughly reslurried with 100 ml of water at 40°C and then extracted by filtration. The extract was concentrated, and the acetone ratio was adjusted to 0 to 0 using a water-acetone mixed solvent using an HP-20 ion exchange side fat column. M-manufactured was made by gradually increasing the percentage up to 40%. A solid of 320 η was obtained from the fraction mainly containing the title compound, and the estimated purity was 57% as confirmed by high performance liquid chromatography.

Implementation f1110 Synthesis (6R,7R) -7,-((2))-2-()lytylaminothiazol-4-yl)-2-(2-t-ptoxycarponylp-pyrr-2-yloxyyξ)) acetamido-3-iodomethyl-3-cephem-4-carboxylic acid benzhydryl 540η dichloromethane 10,
8- Dissolve at room temperature and 1-azabicyclo(3,3,O)
85 μm of octane was added and the resulting mixture was stirred as it was at room temperature for 30 minutes. After the reaction, 80 rnt of ether was added, the resulting precipitate was taken out in a furnace, 4.2 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in phosphorus at pH=7.
The product was purified by column chromatography using a column of HP-20 ion-exchange oil using 50 +dVC and eluting with a water-a7tone system as a solvent while increasing the volume ratio of acetone from 0% to 40%. acetone 20
~40'% fractional freeze-dried (6R,7R)-7-
[(2))-2-(2-aminothiazol-4-yl)
-2-(2-carboxypropyl-2-yloxyimino)acetamide)-3-(1-azabishikj (3,
3,03octane-1-io)methyl-3-cephem-
About 38 μ of 4-carboxylate [compound (116)] was obtained.

IR (cnt-'): 1760.1660.1605 NMR (D, DMSO) δ: 1.48 (6H, s), 18 ~ 2.2
(8H,broad)3.0~4.0 (6H,b
road).

4.0-4.5 (3H, broad).

5.4 (IH), 6.7 5 (IH), 7.3
(IH, s).

7.2 8 (2H), 9.3 (IH) Example 1
Synthesis of (6R,7R)-7-C@-2-(2-toditylami/thiazol-4-yl)-2-methoxyiminoacetamide]-3-iodomethyl-3-17! A-4-
Carboxylic acid benzhydryl ester 46811v was suspended in ether 301+17, 1-7 Zabicic c-(4,3,0)nonane 125119 was added at room temperature, and then stirred at room temperature for 1.5 hours. Discard the precipitate and remove it (2
74~) K) Add 3 refluoroacetic acids and stir at room temperature for 1.5 hours. 6. Distill the truffle c20 acetic acid under vacuum at room temperature (20°C) or below. Add 20 vre of ether to the ahiro and stir. An oil separated. The ether layer was removed by decantation, and the oil was dissolved in a small amount of methanol and mixed with water and methanol using HP-20 ion exchange resin f! Separation was carried out using a # medium system while increasing the methanol volume ratio from 0 to 40.

Fractions ranging from 20% to 30% methanol are collected and lyophilized to obtain the desired (jR, 7R)-7-[■)-2.
-(2-7minothiazol-4-yl)-2-methoxyiminoacetamide]-3-(1-azabicycou(4,
3,0) Nonane-1-io)methyl-3-cephem-4
- Powder 4 containing carboxylate [compound (102)]
0 cape was obtained.

NMR (D, DMSO) δ: 1.8-2.2 (IOH, broad).

3, 1-3, 6 (4) 1 r b r o a
d) + 3.6 (2Hv d+d) +3.9
5 (2H, d+d), 4.0 (3H, s).

5.35 (IH, d), 5.85 (IH, d).

7.05 (IH,a) Synthesis of Example 12 (6R,7R)-7-(◇')-2-(2-)rithylaminothianazol-4-yl)-2-methoxyiminoacetamide]-3-iodomethyl -3-Cephem-4
-Carboxylic acid benzhydryl ester 468~ was converted into 1-7 Zabisikq C4,4 in the same manner as in Example 11.
, 0) was reacted with decane 1401rq and treated with trifluoroacetic acid and ether in the same manner to obtain 45■ as crude crystals. This was purified using a column of HP-20 ion exchange resin and eluted with a mixed solvent of water and methanol.
The target (6R
,7R)-7-((Z)-'2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide)
-3-(1-7zabicyclo(4,4,O)decane-1-
io) Methyl-3-cephem-4-carboxylate [
About 5 q of powder of Compound (104)] was obtained.

IR(cyst-'): 1760.1540,1130,1090Example 13 Amide)-3-(1-7zabisikO(4,3,0)nonane-1-io)Megyurou3-cephemu4sei( 6m, 7R)-7-COself)-2-(2
-ditylaminothiazol-4-yl')-2-(
2-1-Butoxycarbonylpropyl-2-yloxyimino)acetamide]-3-iodomethyl-3-cephem-4-carvone! Shunpenthydryl ester 270
Dissolve 1119 into ether 25-, 1-7 Zabisikq
50 μm of (4,3,0)nonane was added and stirred at 16° C. for 45 minutes. The mixture was diluted with an additional 50 ml of ether and filtered. The obtained precipitate (approximately 200 Mf) was added with K90% trifluoro vinegar #4.5 and stirred at room temperature (20°C) for 1 hour.

Trifluoroacetic acid was distilled off in vacuo, and the residue was dissolved in acetone and phosphorous d buffer (pH 7.6) and dissolved in HP-20.
Using an ion-exchange resin column, purification was carried out in an acetone-water mixed solvent system, increasing the ratio of 77 tons from 0% to 40%. The fractions bathed in acetone at a ratio of 10% to 20% were lyophilized to obtain the desired (6R97R)-7-[
(6)-2-(2-7mi/4-azol-4-yl)-
2-(2-carboxypurpyr-2-yloxyimino)acetamide)-3-(1-azabicyclo(4,3,
O]]nonane-1-iomethyl-3-cephem-4-carboxylate [compound (134)] powder 24η was obtained.

nt(硼-9=176G,1640,1540,1130.1090Example 14 (6R,7a)-7-(Q)-2-(2-dithylaminothiazol-4-yl)-2-methoxyimino Acetamide]-3-iodomethyl-3-cephem-4-
702 kg of carboxylic acid benzhydryl ester was suspended in 45 me K of ether, and 187.511 g of 1-aza-8-methylbicif El (3,3,O]octane was added thereto and stirred at room temperature for 3 hours. The precipitate was filtered. ,P 6
92111P with triple ol vinegar $4.5- and water 0.
45- was added and stirred at room temperature for 1 hour. Trifluoroacetic acid was distilled off at 15°C under vacuum, and the residual liquid was crushed in ether, filtered, and dissolved in a small amount of methanol. *W was performed while increasing the methanol volume ratio from θ to 40.

Freeze-dry 2 volumes of methanol and target (61t, 7R)-7-[■)-
2-(2-7minothiazol-4-yl)-2-methoxyacetamide)-3-(1-aza-8-methylbiscifR (3.3.0)octane-1-io)methyl-
3-cephem-4-carboxylate [compound? +(10
A powder 422Ili containing 6)) was obtained.

NMR (D, O) δ: 1, 5 (3H, aingl@t) + 2.1 ~ 2.
3 (8H, broad).

3,3~3.9 (6Jbroad).

3, 9 ~ 4.2 (2H, d+d), 4.0 (
311. I).

5, 3 5 (IH, d), 5.8 5 (IH, d
), 6, 7 5 (IH9I)y 7.1 (IH
, Hatake) Example 15 (6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide)-3-(1-aza-8-cyanobicif a (3.3
．． 0) octane-1-io)fukyru-3-cephem-
Synthesis of 4-carboxylate [compound (108)) (SR, 7 R )-7 = CC B) - 2-(
2-) dithylaminothiazol-4-yl)
-2-Methoxyiminoacetamide] -3-Iodomethyl-3-cephem-4-carboxylic acid benzhydryl ester 420q dried ether 42-Ks cloudy, 1-
7f-8-'/7/hi. ,7 ria(3
．． 3.0) 114~ of octane was added and stirred at room temperature for 1.5 hours. Additional ether 42-mL was added and the precipitate was filtered.

Obtained door size 16-(1!1q, trifluoroacetic acid 3,
5- was added and stirred at room temperature for 1 hour. After removing trifluoroacetic acid under reduced pressure in the same manner as in Example 6, the residue was purified using HP-20
N was prepared using an acetone-water mixed solvent by column chromatography using an ion exchange resin. Acetone: water; 2:
The fraction bathed in 8 is also the target (6R,7R)-7-
((Z)-2-(2-7minothiazol-4-yl)-
2-methoxyiminoacetamide)-3-(l-aza-
8-Cyano(3.3.0)octane-1-io)methyl-3-cephem-4-carboxylate [Compound (
Powder 7,5119 containing 108)) was obtained.

tfL (prepared: 2 2 3 0 + 1 7 7 0 + 1 5 3
5 t 114 0 , 10 8 5 Example 16 (6R1 7R)-7-i)-2-(2-
dithylaminothiazol-4-yl)-2-(2-
t-Butoxycarbonylpropyl-2-yloxyimino)acetamidocou 3-iodomethyl-3-cephem-4-carboxylic acid penthydryl 270■ ether 2
1-aza-8-hydroxymethyl (
3.3.0) 150η of octane was added and the mixture was stirred at room temperature for 2 hours. 2.5-trifluoroacetic acid was added to the reaction graded precipitate, and the mixture was stirred at room temperature for 2 hours.

Trifluoroacetic acid was distilled off under reduced pressure, the residue was triturated with ether, filtered, and the sample was washed with a mixed solvent of water and acetone using a HP-20 ion exchange column (fatty column) to remove the volume of acetone.
Elution was carried out while increasing sequentially from tO to 50 parts. The obtained fraction is freeze-dried to obtain the desired ( 6 R, 7 R)-7-
((Z)-2-(2-7minothousazol-4-yl)-
2-(2-carboxypropyl-2-yloxyimino)acetamide)-3-(1-asa-8-hydroxybicycR(3,3,0)octane-1-io)methyl-3
-Cephem-4-carboxylate [Compound (138)
) was obtained.

I K (z-'): 3400.1760. l600.1535.1140 Example 17 Synthesis of (200)) (6R,7R) -7-((Z)-2-(2-)
1-azabicyclo(2,2, 1) 97 μm of butane was added to the mixture and stirred at room temperature for 1 hour. The precipitate was filtered and treated with trifluoroacetic acid 3-
Then, 0.3-liter of water was added and stirred at room temperature for 1 hour.

Trifluoroacetic acid was distilled off under vacuum at a temperature below room temperature, ether was added to the residue to crush the crystals, and the crystals were collected by filtration. The obtained crystals were dissolved in a small amount of methanol and purified using an HP-20 ion exchange resin column in a water-methanol mixed solvent system while increasing the methanol volume ratio from 0 to 40. The fraction eluted with methanol:water at 2=8 to 3 nia was freeze-dried to obtain the desired (6R97R)-7-(
(Z)-2-(2-7minothiazol-4-yl)-2
-methoxyimino7cetamido)-3-(1-7zabicyclo(2,2,1)hebutan-1-io)methyl-3-
Cephem-4-carboxylate [Compound (200)]
A powder 81q containing the following was obtained.

NMR (DtO) δ: 2.1 (4H, broad), 3.0 (IH, b
road).

3.3 (2Jmulpl@t).

3.3-3.6 (4H, broad).

:L7-4.0 (2H, broad).

4.0 (3H9minlet) 15.3 (IJd
oubl@t).

5.85 (IH, doublet), 6', 87
(IH, mlnglet) Example 18 Synthesis (6R, 7R)-7-((z)-2-(2-) lythylami7+azol-4-yl)-2-(2-1-butoxycarbonylbuvir-2- yloxyimino)acetamido-3-iodomethyl-3-cefemuchicarboxylic acid penthydryl 540~ dissolved in ether 50-1-7zabicyclo(2,2,1)butane 97 at room temperature
~ was added and the mixture was left to stir at room temperature for 1 hour.

After the reaction, 3.5 L of trifluoroacetic acid and 0.35 L of water were added to the precipitate, and the mixture was vigorously stirred at room temperature for 1.5 hours. K under reduced pressure) +7 fluoroacetic acid and water under reduced pressure Vcff! and the residue was triturated with ether. The sample was dissolved in a mixed solvent of water and methanol, and purified using a column of HP-20 ion exchange resin with a mixed solvent of water and methanol while gradually increasing the volume of methanol. The fraction eluted with 10-20% methanol was lyophilized and used for the purpose (6H7 weight>-7
-Cφ)-2-(2-7minothiazole-4-ijb
) -2-(2-carpoxyprobyl-2-yloxyimino)acetamide]-3-(I-azabicyclo[2
, 2, 1] to] butane-1-iomethyl-3-cephem-4-carboxylate [compound (202)] was obtained.

rR(cIn-'): 1760.1660.1160 Example 19 (6R,7R)-7-(CZ)-2-(2-) dithylaminothiazol-4-yl)-2-methoxyiminoacetamide]-3 -iodomethyl-3-cef! A-4
-Carboxylic acid benzhydryl ester 468F+9 was suspended in 30 trt of ether, 127111i of 1-aza-3-oxobicycloC2,2,21 octane was added, and the mixture was stirred at room temperature for 1 hour and mixed. F-saiju triflo p acetic acid 3
The mixture was stirred at room temperature for 2 hours. Trifluoroacetic acid was removed under reduced pressure, washed with ether, extracted with water, and HP-2
Using a water-methanol mixed solvent system, the methanol volume ratio was sequentially rubbed and separated from 0 to 50 using a 0 ion exchange resin. The active fractions were collected and lyophilized to obtain the compound (3
00) was obtained.

IR(crR-'): 1768 HMR (ppm, D, O) δ: 1.7-2.3 (6H, broad).

2.7-3.0 (11 (, broad).

3.2-4.0 (6H, broad), 4.00
(31(,a).

5.36 (11(+d)e 5-86 (11(td)
L7.01 (H+s) Example 20 (6R,7R)-7,-(Kaoru)-2-(2-7minothiazol-4-yl-2-methoxyiminoacetamide)-3-(1-ab-3-human Compound (,302) was obtained from 1-aza-3-hydroxybicyclo(2,2,2)octane in the same manner as in Example 19.

IR (α-'): 1765 NMR (PprFl*DtO) δ: 1.7-2.
3 (6H, broad).

2.9-4.0 (6H, broad), 4.00
(3H, s).

5.35 (14(,d), 5.86 (IH,d)
.

7.02 (IHta) Example 21 [Oe of compound (318)).

In the same manner as in Example 19, compound (318) was obtained from 1-aza-4-cyanobisiph t:x (2,2,2)octane.
I got it.

IR(”-’): 177 O NMR (ppm+D*o)δ: 2.1~L6 (6H1broad).

3.2~3.7 (61(1broad), 4.00
(3H,s)+5.36 (IH+d)+5-86
(IH+d)+7.01 (IHta) Example 22 In the same manner as in Example 19, compound (304) was obtained from l-aza-3-chlorobicyclo(2°L2.2) octane.

TRCcm-li: 1770.1660, 1610.1030 Example 23 Compound (320) was obtained from l-aza-4-ethoxycarponylbisic+:+ (2,2,2)octane in the same manner as in Example 19. Ta.

IR(α-'): 1765.1730.1670,1620.1025 Example 24 Noacetamide)-3-(1-Aza-4-Human Example 1
9, 1-aza-4-human pxibisic+=
+ Compound (322) was obtained from (2,2,2)octane.

IR (cPn-'): 1763.1665, 1620.1020 Example 25 In the same manner as in Synthesis Example 19, l-aza-4-(2,5-dihydro-2-methyl-5-oxotriazine-3- Compound (324) was obtained from thiamethylbicyclo(2,2,2)octane.

IR (cy++-'): 1780.1665, 1630.1620 Example 26 Methyl-3-cephem-4-carboxylate [Synthesis of compound (325) In the same manner as in Example 19, 1-aza-4-carboxybicyclo ( 2,2,2) Compound (325) from octane
I got it.

I R(tTn-'): 1770.1605, 1255.1028 Example 27 Compound (326) was obtained from 1-aza-4-methylbicyclo(2,2,2)octane in the same manner as in Example 19. .

IR(ctn-'): 1762.1660, 1355.1018 Example 28 In vitro antibacterial activity In vitro antibacterial activity was determined by the agar plate dilution method.

Various test bacteria were cultured overnight in Tryptocase-Soypros, and the platinum loops (viable bacteria count 106/d) were streaked onto Mueller-Hinton agar containing various concentrations of the compounds of the present invention.
The culture was incubated at 7°C for 16 hours, and the minimum inhibitory concentration (MIC, μ
f/me) was determined.

The results are shown in Table-1.

Table-I MIC (μm) Comparative Compound A: CH@ Comparative Compound B: Example 29 In vitro antibacterial activity of other compounds of the present invention was measured in the same manner as in Example 28.

The results are as shown in Table ○.

Table-! I MIC (μ2 Hawk) Example 30 The in vitro antibacterial activity of the compound (326) of the present invention was measured in the same manner as in Example 28.

The results are shown in Table-■.

Table-1it MIC (μP/d).

Example 31 An experiment was conducted using 1CR male mice (body weight 22 to 25 f, 5 weeks old) in a group of 10 mice.

The strain E. eoli 81 was cultured on Mueller-Hinton agar at 37° C. overnight, and suspended in Ikuto saline to prepare a bacterial solution (5×10′ cells/m/m).

Bacterial solution 1- was administered intraperitoneally to mice, and 15 minutes later, the compounds of the present invention were administered subcutaneously at various concentrations. The survival of the mice was observed for 4 days, and the survival rate after 4 days was determined.

The results are shown in Table-PIVC.

Table -■ Example 32 The duration of antibacterial activity of compound (100) was measured.

The mice used were ICR strain, 5 weeks old, and 10 male mice per group. A bacterial solution of E. coli 81 was intraperitoneally administered to mice at a dose of 5 x 10' c@ll/head to infect them.

1 hour or 3 hours before infection, K, compound (1,OO
) was administered subcutaneously at It O,5119/h@ad.

The survival rate of the mice was determined 4 days after infection. The results are in Table-VK
As shown.

Table V As is clear from Table 4, the compound (100) of the present invention has excellent durability of antibacterial activity.

Example 33 Soomp crystalline (6B, 7R) -7-[ψ)-
2-(2-7 minoxazol-4-yl)-2-methoxyiminoacetamide)-3-(1-7
,3,0)octane-1-io)methyl-3-cephem-4-carboxylate in a nitrogen atmosphere under sterile conditions,
Filled into vials. The vial was closed using a rubber disc. This preparation is used by dissolving it in a suitable carrier before administration.

Claims (1)

[Claims] 1. The following formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. are included. It represents an alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocyclic group. R^2 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a cyano group, a carboxy group, an alkoxycarbonyl group, a carbamoyl group, a carbamoyloxy heterocyclic group, a hydroxyl group, an alkoxy group, or a halogen atom. R^4 and R^5 are the same or different and represent a hydrogen atom or an alkyl group. l represents 0, 1 or 2. m and n are 1 when l is 0
Or represents 2. m and n are 0 when l is 1 or 2
represents. X represents a methylene group when l is 0 or 1. When 1 is 2, X represents a methylene group, a methylene group having a substituent, or an oxo group, provided that R^3, R^4
and when R^5 represents a hydrogen atom, X is not a methylene group. ] A cephalosporin derivative, a salt thereof, or an ester thereof. 2. The following formula (1-1) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^3, R^4, R^5, m
and n are the same as defined above. ] The cephalosporin derivative, salt or ester thereof according to claim 1, represented by: 3. The following formula (1-2) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1, R^2, R^3, R^4 and R^5 are the same as the above definitions] A cephalosporin derivative, a salt thereof, or an ester thereof according to claim 1. 4. Formula (1-3) below ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^3, R^4 and R^5 are the same as the above definitions. X represents a methylene group, a methylene group having a substituent, or an oxo group, provided that R^3, R^
When 4 and R^5 are hydrogen atoms, X is not a methylene group. ] A cephalosporin derivative, a salt thereof, or an ester thereof according to claim 1, represented by: 5. The cephalosporin derivative, its salt, or its ester according to any one of claims 1 to 4, wherein R^2 is a lower alkyl group or a lower alkyl group substituted with a carboxy group. 6. The cephalosporin derivative according to any one of claims 1 to 5, a salt thereof, or That ester. 7. The cephalosporin derivative, its salt, or its ester according to any one of claims 1 to 6, wherein R^4 and R^5 are hydrogen atoms. 8. Salt is the following formula (1') or (1'') ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ An^■_1, 1/2A^2n^■_2, or 1/3A
^3n^■＿3▲There are mathematical formulas, chemical formulas, tables, etc.▼ 2An^■＿1, An^2^■＿2, or 2/3A^3
n^■_3 [In the formula, R^1, R^2, R^3, R^4,
R^5, l, m, n and X are the same as defined above. An^■
_1 represents an anion of a monobasic acid, A^2n^■_2 represents an anion of a dibasic acid, and A^3n^■_3 represents an anion of a tribasic acid. ] Claims 1 to 7
The salt according to any one of paragraphs. 9. A cephalosporin derivative, a salt thereof, or an ester thereof according to any one of claims 1 to 8, which is in the form of a crystal or a hydrate thereof. 10. Formula (2) below ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (2) [In the formula, R^1 and R^2 are the same as the definitions above. R^6 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 its salt represented by the following formula (3) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (3) [In the formula, R^3, R^4, R^5, l, m, n and X are the same as defined above. ] 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. Yes▼(1) [In the formula, R^1, R^2, R^3, R^4, R^5, l
, m, n and X are the same as defined above. ] A method for producing a cephalosporin derivative, a salt thereof, or an ester thereof. 11. The method for producing a cephalosporin derivative, a salt thereof, or an ester thereof according to claim 10, wherein R^6 in the above formula (2) is a trialkylsilyl group. 12. 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, R^4, R^5, m, l, n, X, and p are the same as the above definitions. ] The following formula ▲, which is characterized by reacting a compound represented by, a salt thereof, an ester thereof, or a reactive derivative thereof, and subjecting it to deprotection, salt formation, esterification and/or reduction reaction as necessary. There are chemical formulas, tables, etc.▼(1) [In the formula, R^1, R^2, R^3, R^4, R^5, l
, m, n, and X are the same as defined above. ] A method for producing a cephalosporin derivative, a salt thereof, or an ester thereof. 13. Formula (6) below ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (6) [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, 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, R^3, R^4, R^5, l
, m, n and X are the same as defined above. ] A method for producing a cephalosporin derivative, a salt thereof, or an ester thereof. 14. Formula (8) below ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (8) [In the formula, R^2, R^3, R^4, R^5, l, m, n
, X and p are the same as defined above. R^7 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. There is ▼ (1) [In the formula, R^1, R^2, R^3, R^4, R^5, l
, m, n, X and p are the same as defined above. ] A method for producing a cephalosporin derivative, a salt thereof, or an ester thereof. 15. 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,
It represents a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted heterocyclic group. Hal represents a halogen atom. ] The following formula (1″″) ▲, which is characterized by reacting a compound represented by, dialkyl sulfuric acid, or diazoalkane, and subjecting it 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', R^2, R^4, R^6,
l, m, n and X are the same as defined above. ] A method for producing a cephalosporin derivative, a salt thereof, or an ester thereof. 16. The following formula (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (1) [In the formula, R^1 represents a hydrogen atom or a protective group. R^2 is a hydrogen atom, a substituted or unsubstituted alkyl group,
Represents a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted heterocyclic group. R^3 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a cyano group, a carboxy group, an alkoxycarbonyl group, a carbamoyl group, a carbamoyloxy group, a heterocyclic group, a hydroxyl group, an alkoxy group, or a halogen atom. R^4 and R^5 are the same or different and represent a hydrogen atom or an alkyl group. l represents 0, 1 or 2. m and n represent 1 or 2 when l is 0. m and n represent 0 when l is 1 or 2. When l is 0 or 1, X represents a methylene group. When 1 is 2, X represents a methylene group, a methylene group having a substituent, or an oxo group, provided that R^3, R
When ^4 and R^5 represent a hydrogen atom, X is not a methylene group. An antibacterial agent containing a cephalosporin derivative represented by the following, its salt, or its ester as an active ingredient.