JPH1036375A - New cephalosporin derivative or its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new cephalosporin derivative being the specific one, having a wide range antimicrobial spectrum and a strong antibacterial activities and useful as an antimicrobial agent effective in methicillin resistant Staphylococcus aureus(MRSA). SOLUTION: This new cephalosporin derivative is the new one of formula I [R<1> is a (substituted) alkylthio, an aryl, an arylthio, an aryloxy or a heterocyclic ring; A is a (protected) amino, a (protected) OH or a (substituted) methylene; R<2> is a halogen, cyano, amidino, azido, nitro, a (substituted) alkyl, a (substituted) aryl, a (substituted) alkoxy, a (substituted) pyrimidyl, a (substituted) purinyl, a (substituted) quinazolinyl, etc.; R<3> is a (protected) carboxyl, carboxylato; (n) is 0 or 1] and useful as an antimicrobial agent, etc., against the MRSA. This compound is obtained by reacting a cephalosporin derivative of formula II (X is an eliminable group) with mercaptans of the formula R<2> -SH in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel cephalosporin derivative or a salt thereof. More specifically, the following general formula [1]

Embedded image [Wherein, R ¹ represents an optionally substituted alkylthio,
A represents an aryl, arylthio, aryloxy or heterocyclic group; A represents an optionally protected amino, hydroxyl or hydroxyimino group or a methylene group optionally substituted by an alkoxyimino group; R ² represents a halogen atom , Cyano group, amidino group, guanidino group, azide group, nitro group, optionally substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, acyl, carbamoyl, carbamoyloxy,
Alkoxyimino, ureido, alkylsulfinyl,
An alkylsulfonyl or sulfamoyl group or an optionally protected amino, imino, hydroxyl, hydroxyimino or carboxyl group
Pyrimidinyl, quinazolinyl, purinyl, pyrazolo [3,4-d] pyrimidinyl, pyrazolo [4,3-d] pyrimidinyl, [1,2,
3] a triazolo [4,5-d] pyrimidinyl or pteridinyl group; R ³ is a carboxyl group or a carboxylate group which may be protected; n is 0 or 1
Are respectively shown. ] Or a salt thereof.

[0002]

2. Description of the Related Art Many cephalosporin antibiotics having a broad antibacterial spectrum and strong antibacterial activity have been developed, but methicillin-resistant Staphylococcus aureus (MRS) has been developed.
The antimicrobial activity against A) is still insufficient.

[0003]

Under such circumstances, it has been desired to develop a cephalosporin derivative having a strong antibacterial activity against MRSA.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, at the 3-position of the cephalosporin ring, pyrimidinylthio, quinazolinylthio,
Purinylthio, pyrazolo [3,4-d] pyrimidinylthio, pyrazolo [4,3-d] pyrimidinylthio, [1,
A novel cephalosporin derivative represented by the general formula [1] having a [2,3] triazolo [4,5-d] pyrimidinylthio or pteridinylthio group or a salt thereof is MRS
It has a strong antibacterial activity against A and has been found to be useful as a pharmaceutical for humans and animals, and has completed the present invention.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
In the present specification, unless otherwise specified, a halogen atom means, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkyl group means, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec. -Butyl,
A linear or branched C _1-12 alkyl group such as isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and undecyl; a lower alkyl group is, for example, methyl, ethyl, Propyl,
Isopropyl, n-butyl, sec-butyl, isobutyl, te
rt- butyl and straight-chain or branched C _{1 -5} alkyl group, such as pentyl; and the alkenyl group, for example,
Vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, a C _2-12 alkenyl group such as octenyl; Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, C _3, such as cyclohexyl _-6 cycloalkyl group; acyl group is, for example, formyl group,
Acetyl, propionyl, butyryl, isobutyryl, valeryl and other C _2-5 alkanoyl groups and aroyl groups such as benzoyl and naphthoyl;
Phenyl and naphthyl groups and the like;

[0006] Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, se
linear or branched C _1-12 alkyl such as c-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and undecyloxy;
O-group; a lower alkoxy group includes, for example, methoxy,
Ethoxy, propoxy, isopropoxy, n-butoxy,
a linear or branched C _1-5 alkyl-O— group such as sec-butoxy, isobutoxy, tert-butoxy and pentyloxy; an alkylthio group is, for example, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutylthio,
linear or branched C such as tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio, nonylthio, decylthio and undecylthio;
_A lower alkylthio group means, for example, a straight or branched chain such as methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, isobutylthio, tert-butylthio and pentylthio; branch chain C _{1 -5} alkyl -S- group; and alkyl amino groups, e.g., methylamino, ethylamino, propylamino, isopropylamino, n- butylamino, sec- butylamino, isobutylamino, tert-
Mono- such as butylamino, pentylamino, hexylamino, heptylamino, octylamino, nonylamino, decylamino, undecylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethylamino, methylpropylamino and ethylbutylamino Or an amino group substituted with a di-C _1-12 alkyl group; a lower alkylamino group includes, for example, methylamino, ethylamino, propylamino,
Isopropylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, pentylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethylamino,
Amino groups substituted with mono- or di- _C1-5 alkyl groups such as methylpropylamino and ethylbutylamino;

[0007] The arylthio group is, for example, an aryl-S- group such as phenylthio and naphthylthio; the aryloxy group is, for example, an aryl-O- group such as phenyloxy and naphthyloxy; For example, methoxyimino, ethoxyimino,
Propoxyimino, isopropoxyimino, n-butoxyimino, sec-butoxyimino, isobutoxyimino, te
linear or branched C _1-12 alkyl such as rt-butoxyimino, pentyloxyimino, hexyloxyimino, heptyloxyimino, octyloxyimino, nonyloxyimino, decyloxyimino and undecyloxyimino; O-imino group; iminoalkyl group includes, for example, iminomethyl, 1-iminoethyl,
A linear C _1-5 alkyl group substituted by an imino group such as -iminopropyl, 2-iminopropyl, 1-iminobutyl, 2-iminobutyl and 1-iminopentyl;

The alkylsulfinyl group includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl,
Linear or branched C _1-12 such as heptylsulfinyl, octylsulfinyl, nonylsulfinyl, decanylsulfinyl and _{undecanylsulfinyl}
An alkylsulfonyl group means, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, nonylsulfonyl, decanylsulfonyl and unsulfonyl; Linear or branched C _1-12 alkyl-SO such as decanylsulfonyl
_{A 2} -group;

The alkoxycarbonyl group includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl , heptyloxy carbonyl, octyloxycarbonyl, nonyloxycarbonyl, C _1-12 straight-chain or branched, such as decyloxycarbonyl and undecyloxy carbonyl
An alkyl-O-CO- group;

The heterocyclic group includes, for example, azetidinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,
Isoxazolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, 1,3,4-oxadiazolyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiatriazolyl, pyridyl, pyrazinyl, pyrimidinyl, Pyridazinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, 1,2,4-triazinyl, benzothienyl, naphthothienyl, benzofuryl, isobenzofuryl, chromenil, indolizinyl, isoindolyl, indolyl, indazolyl, prunyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, naphthyridinyl , Quinazolinyl, sinolinyl, phthalidinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, benzoxazolyl, triazolopyridyl, tetrazolopyridazinyl, tetrazo Pyrimidinyl, thiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, benzothiazolyl, 1,2,3,4-tetrahydroquinolyl, imidazo [1,2-b] [1 , 2,4] triazinyl, quinuclidinyl and the like, a 4- to 6-membered heterocyclic group or a fused heterocyclic group containing at least one heteroatom atom selected from an oxygen atom, a nitrogen atom and a sulfur atom; I do.

Hereinafter, the compound represented by formula (1) will be described in detail. Alkylthio group of R ^1, lower alkylthio group, an aryl group, an arylthio group, an aryloxy group, a phenyl group, a phenyl group, a heterocyclic group, a thienyl group, a thiazolyl group and a thiadiazolyl group; the R ² alkyl,
Alkenyl, cycloalkyl, aryl, alkoxy,
Examples of the substituent of the aryloxy, alkylthio, arylthio, alkylamino, acyl, carbamoyl, carbamoyloxy, alkoxyimino, ureido, alkylsulfinyl, alkylsulfonyl and sulfamoyl groups include a halogen atom, an optionally protected hydroxyl group, An optionally substituted amino group, an optionally protected imino group and a lower alkoxy group.

The protecting group used when the compound of the present invention and its intermediates for production have an amino group, an imino group, a hydroxyl group, a hydroxyimino group and a carboxyl group are conventionally known in the field of cephem compounds. Amino, hydroxyl and carboxyl protecting groups. Specifically, Protective Groups in Organic Synthesis [Theodora.W.Green], (1981)
Year) John Wiley & Sons
Sons, Inc.)] and JP-B-60-52755.

The amino-protecting group includes all groups which can be usually used as an amino-protecting group, such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromo. Benzyloxycarbonyl, (mono-, di-, tri-) chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert
-Butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl,
2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl,
Isopropoxycarbonyl, phthaloyl, succinyl,
Acyl groups such as alanyl, leucyl, 1-adamantyloxycarbonyl and 8-quinolyloxycarbonyl; al-lower alkyl groups such as benzyl, diphenylmethyl and triphenylmethyl; 2-nitrophenylthio and 2,4-dinitrophenylthio Aryl-thio groups such as, for example; alkyl- or aryl-sulfonyl groups such as methylsulfonyl and p-tolylsulfonyl;
Di-lower alkylamino-lower alkylidene groups such as N, N-dimethylaminomethylene; al-lower alkylidene groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene and 2-hydroxy-1-naphthylmethylene; 3-hydroxy-4
Nitrogen-containing heterocyclic alkylidene groups such as -pyridylmethylene; cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene and 3,3
Cycloalkylidene groups such as -dimethyl-5-oxocyclohexylidene; diaryl- or dial-lower alkyl-phosphoryl groups such as diphenylphosphoryl and dibenzylphosphoryl; 5-methyl-2-oxo-
Examples include an oxygen-containing heterocyclic alkyl group such as 2H-1,3-dioxol-4-yl-methyl, and an alkyl-substituted silyl group such as trimethylsilyl.

The hydroxyl-protecting group includes all groups which can be usually used as a hydroxyl-protecting group,
For example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4
-Dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2 , 2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2
-(Phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy- 1
Acyl groups such as naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl and benzoyl; methyl, tert-butyl, Lower alkyl groups such as 2,2,2-trichloroethyl and 2-trimethylsilylethyl; lower alkenyl groups such as allyl; benzyl, p-methoxybenzyl,
Aralkyl groups such as 4-dimethoxybenzyl, diphenylmethyl and trityl; oxygen- and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl and tetrahydrothiopyranyl; methoxymethyl, methylthiomethyl, benzyloxymethyl, 2- Methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl and 1
Lower alkoxy- and lower alkylthio-lower alkyl groups such as ethoxyethyl; methylsulfonyl and
alkyl- or aryl-sulfonyl groups such as p-tolylsulfonyl; substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and diphenylmethylsilyl; Can be

The carboxyl-protecting group includes all groups which can be used as ordinary carboxyl-protecting groups, such as methyl, ethyl, n-propyl, iso-propyl, 1,1-dimethylpropyl and n-butyl. And tert
Lower alkyl groups such as -butyl; aryl groups such as phenyl and naphthyl; aralkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and bis (p-methoxyphenyl) methyl; Benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl and p
Acyl lower alkyl groups such as -methanesulfonylbenzoylmethyl; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; 2,2,2-
A halogeno lower alkyl group such as trichloroethyl; 2-
Lower alkylsilylalkyl groups such as (trimethylsilyl) ethyl; alkylcarbonyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl; nitrogen-containing heterocyclic-lower alkyl groups such as phthalimidomethyl and succinimidomethyl; cyclohexyl Cycloalkyl groups such as methoxymethyl, methoxyethoxymethyl and 2- (trimethylsilyl) ethoxymethyl; lower alkoxy lower alkyl groups such as benzyloxymethyl; al-lower alkoxy lower alkyl groups such as benzyloxymethyl;
Lower alkylthio lower alkyl groups such as methylthioethyl; arylthio lower alkyl groups such as phenylthiomethyl; lower alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butynyl and allyl; and trimethylsilyl, triethylsilyl, And substituted silyl groups such as triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and diphenylmethylsilyl.

Examples of the salt of the compound represented by the general formula [1] include a commonly known salt or an inner salt of a basic group such as an amino group or an acidic group such as a carboxyl, sulfo or hydroxyl group. As the salt in the basic group, for example, a salt with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid; a salt with an organic carboxylic acid such as formic acid, trichloroacetic acid or trifluoroacetic acid; Acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalene-
Salts with sulfonic acids such as 2-sulfonic acid or naphthalene-1,5-disulfonic acid; salts with acidic amino acids such as glutamic acid or aspartic acid; and salts in the acidic group include, for example, sodium or potassium. Salts with alkaline earth metals such as calcium or magnesium; ammonium salts; trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine or N-methylmorpholine. And a salt with a basic amino acid such as lysine or arginine. In the compound of the general formula [1] and a salt thereof, isomers (for example, optical isomer, geometric isomer,
When tautomers exist, the invention embraces all such isomers as well as all hydrates, solvates and various crystalline forms.

In the compounds of the present invention, R ¹ is a lower alkylthio, phenyl, phenyloxy or thienyl group optionally substituted with a halogen atom, a thiazolyl group or amino group optionally substituted with a halogen atom or amino group. A thiadiazolyl group which may be substituted with; a methylene group which may be substituted with an optionally protected hydroxy or hydroxyimino group or an alkoxyimino group; R ² may be a cyano group or an optionally substituted Pyrimidinyl, quinazolinyl, purinyl, pyrazolo [3,4-d] which may be substituted with one or more groups selected from good alkyl, alkoxy, alkylthio or alkylamino groups or optionally protected amino or hydroxyl groups Pyrimidinyl, pyrazolo [4,3-d] pyri Compounds which are a midinyl, [1,2,3] triazolo [4,5-d] pyrimidinyl or pteridinyl group are preferred, and R ¹ is a lower alkylthio group substituted with a halogen atom, a phenyl group or a halogen atom or an amino group. An optionally substituted thiazolyl group; R ² is substituted by one or more groups selected from a cyano group, an optionally substituted lower alkyl or lower alkylamino group or an optionally protected amino or hydroxyl group; Compounds which are optionally pyrimidinyl, quinazolinyl, purinyl, pyrazolo [3,4-d] pyrimidinyl, [1,2,3] triazolo [4,5-d] pyrimidinyl or pteridinyl groups are more preferred.

3- (4-aminopyrimidin-2-ylthio) -7-phenylacetamido-3-cephem-4
-Sodium carboxylate 7-phenylacetamido-3- (pyrimidine-2-
Sodium thiol-3-cephem-4-carboxylate 3- (4-methylpyrimidin-2-ylthio) -7-
Sodium phenylacetamido-3-cephem-4-carboxylate 3- (4-hydroxypyrimidin-2-ylthio)-
7-Phenylacetamido-3-cephem-4-carboxylate sodium 3- (4-amino-6-hydroxypyrimidine-2-
(Ilthio) -7-phenylacetamido-3-cephem-4-carboxylate sodium

.3- (4,6-diaminopyrimidine-2)
-Ylthio) -7-phenylacetamido-3-cephem-4-carboxylate sodium 3- [4- (1-iminoethylamino) pyrimidine-
2-ylthio] -7-phenylacetamido-3-cephem-4-carboxylate sodium 3- (5-cyanopyrimidin-4-ylthio) -7-
Sodium phenylacetamido-3-cephem-4-carboxylate · Sodium 7-phenylacetamido-3- (purin-6-ylthio) -3-cephem-4-carboxylate · 3- (6-aminopurin-2-ylthio) Sodium -7-phenylacetamido-3-cephem-4-carboxylate

.3- (2-aminopurin-6-ylthio) -7-phenylacetamido-3-cephem-4-
Sodium carboxylate 3- (6-hydroxypurin-2-ylthio) -7-
Sodium phenylacetamide-3-cephem-4-carboxylate 3- (2-hydroxypurin-6-ylthio) -7-
Sodium phenylacetamido-3-cephem-4-carboxylate ・ Sodium 3- (9-aminopurin-6-ylthio) -7-phenylacetamido-3-cephem-4-carboxylate ・ 7-phenylacetamido-3- (pyrazolo [3,4
-D] pyrimidin-4-ylthio) -3-cephem-4
-Sodium carboxylate

.3- (4-aminopyrazolo [3,4-
d] Pyrimidin-6-ylthio) -7-phenylacetamido-3-cephem-4-carboxylate sodium 3- (4-hydroxyquinazolin-2-ylthio)-
7-Phenylacetamido-3-cephem-4-carboxylate sodium 3- (4-aminoquinazolin-2-ylthio) -7-
Sodium phenylacetamido-3-cephem-4-carboxylate 3- (2-aminopteridin-4-ylthio) -7-
Sodium phenylacetamido-3-cephem-4-carboxylate 3- (5-amino [1,2,3] triazolo [4,5-
d] Sodium pyrimidin-7-ylthio) -7-phenylacetamido-3-cephem-4-carboxylate

.3- (4-aminopyrazolo [3,4-
d] pyrimidin-6-ylthio) -7- (difluoromethylthio) acetamido-3-cephem-4-carboxylate sodium 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- [ (Z) -2-Hydroxyimino-2-phenylacetamido] -3-cephem-4-
Sodium carboxylate 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-[(R) -2-hydroxy-2
-Phenylacetamide] -3-cephem-4-carboxylate sodium 7- [2- (2-amino-5-chlorothiazole-4)
-Yl)-(Z) -2-hydroxyiminoacetamido] -3- (4-aminopyrimidin-2-ylthio)-
Sodium 3-cephem-4-carboxylate 3- (4-aminopyrimidin-2-ylthio) -7-
[2- (2-aminothiazol-4-yl)-(Z)-
2-methoxyiminoacetamide] -3-cephem-4
-Sodium carboxylate

.3- (4-aminopyrazolo [3,4-
d] pyrimidin-6-ylthio) -7-phenyloxyacetamido-3-cephem-4-carboxylate sodium 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (thiophene- Sodium 2-yl) acetamido-3-cephem-4-carboxylate 7- [2- (2-amino-5-chlorothiazole-4)
-Yl)-(Z) -2-hydroxyiminoacetamido] -3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -3-cephem-4-carboxylate sodium 3- (4- Aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid Sodium 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- [2- (5-amino-1,2,4
-Thiadiazol-3-yl)-(Z) -2-hydroxyiminoacetamido] -3-cephem-4-carboxylate sodium 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7 -[2- (5-amino-1,2,4
-Thiadiazol-3-yl)-(Z) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate sodium

Next, a method for producing the compound of the present invention will be described. The compound of the present invention can be synthesized, for example, according to the following production method.

[0025]

(Equation 1)

[0026]

(Equation 2)

[0027]

(Equation 3)

Wherein R ¹ , R ² , R ³ , A and n are
Each has the same meaning as described above, and R ⁴ represents a hydrogen atom or an amino protecting group; and X represents a leaving group. Examples of the amino protecting group for R ⁴ include the same amino protecting groups as described for A and R ² . Examples of the leaving group for X include a halogen atom, a lower alkylsulfonyloxy group such as methylsulfonyloxy and ethylsulfonyloxy; a halogeno lower alkylsulfonyloxy group such as trifluoromethylsulfonyloxy and an arylsulfonyloxy group such as p-tolylsulfonyloxy. And the like.

The general formulas [1a], [1b], [2],
Examples of the salt of the compound of [3], [4], [5] and [6] include the same salts as those described for the salt of the compound of general formula [1].

The reactive derivative of the compound of the general formula [4] or a salt thereof includes, for example, trimethylsilanyl, dimethylsilanediyl, isopropyldimethylsilanyl, trimethoxysilanyl, dimethoxymethylsilanyl, dimethylmethoxysilanyl or Organic silyl groups such as dimethoxysilanediyl or dimethoxyphosphinyl,
1,3,2-dioxophosphoran-2-yl, 4-methyl-1,3,2-dioxophosphoran-2-yl or 1,3,2-dioxophosphorinan-2-yl and the like Examples include compounds in which an organic phosphorus group is bonded to an amino group that is a reaction site.

The reactive derivative of the compound of the formula [5] or a salt thereof includes, for example, acid halides, acid anhydrides, mixed acid anhydrides, active acid amides described in JP-A-59-93085 and the like. Active esters, active thioloesters or acid azides or reactive derivatives of the compound of the general formula [5] with the Vilsmeier reagent are mentioned. Next, a method for producing the compound of the general formula [1] or a salt thereof will be described in detail.

Production Method 1 The compound of the general formula [3] or a salt thereof is reacted with a compound of the general formula [3] or a salt thereof in the presence or absence of a base or a deoxidizing agent to give a compound of the general formula [2] 1] or a salt thereof can be obtained. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include water; ethers such as tetrahydrofuran, diethyl ether and dioxane; and halogenated hydrocarbons such as methylene chloride and chloroform. Alcohols such as methanol and ethanol; N, N-dimethylformamide and N, N;
Amides such as N-dimethylacetamide; aromatic hydrocarbons such as benzene and toluene; esters such as ethyl acetate and butyl acetate; ketones such as acetone and methyl ethyl ketone; dimethyl sulfoxide;
1,3-dimethylimidazolidinone; hexamethylphosphoric triamide; and nitriles such as acetonitrile and propionitrile. These solvents may be used alone or in combination of two or more. Examples of the base used as necessary in this reaction include, for example, alkali hydroxide, alkali carbonate, alkali hydrogen carbonate, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, 2,6-lutidine , Tetramethylguanidine, lithium bistrimethylsilylamide, sodium hydride, 1,8-diazabicyclo [5.
4.0] -7-undecene or 1,5-diazabicyclo [4.3.0] -5-nonene.

The deoxidizing agent used as needed includes, for example, propylene oxide.
The amount of the compound of the general formula [3] or a salt thereof to be used is at least equimolar to the compound of the general formula [2] or a salt thereof. The amounts of the base and the deoxidizing agent used as needed are 0.5 to 2 moles and 1 mole or more with respect to the compound of the general formula [2] or a salt thereof, respectively. In addition, the reaction temperature and the reaction time are not particularly limited, but the reaction may be usually performed at -20 ° C to 100 ° C for 5 minutes to 50 hours.

Production Method 2 A compound of the general formula [4], a salt thereof or a reactive derivative thereof is converted into a compound of the general formula [5], a salt thereof or a reactive derivative thereof in the presence or absence of a base. By reacting, a compound of the general formula [1] or a salt thereof can be obtained. Examples of the solvent used in this reaction include the same solvents as described in Production method 1. Examples of the base optionally used in this reaction include sodium acetate, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine, N, N-dimethylaniline, N , N-diethylaniline, dicyclohexylamine, 2,6-lutidine, tetramethylguanidine,
Lithium diisopropylamide, lithium bistrimethylsilylamide, 1,8-diazabicyclo [5.4.0]
-7-undecene and 1,5-diazabicyclo [4.3.
Organic bases such as 0] -5-nonene; and inorganic bases such as sodium hydride, alkali hydroxide, alkali carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.

In order to use the compound of the formula [5] in the form of a free acid or a salt thereof, an appropriate condensing agent is used. Such condensing agents include, for example, N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide. The amount of the compound of the general formula [5] or a salt thereof or a reactive derivative thereof to be used is 0.9 times or more, preferably 0.9 mol or more, with respect to the compound of the general formula [4] or a salt or a reactive derivative thereof. , 0.9-
It is 1.5 times mol. The amounts of the base and the condensing agent used as needed are, for the compound of the general formula [4] or a salt thereof or a reactive derivative thereof, respectively:
It is 0.5 to 2 times mol and equimolar or more. The reaction temperature and the reaction time are not particularly limited, but are usually -50 to 8
It may be carried out at 0 ° C. for 5 minutes to 30 hours.

Production Method 3 (1) Isomerization A compound of the general formula [1b] or a salt thereof can be obtained by reacting a compound of the general formula [6] or a salt thereof with a base. This reaction, for example,
Of the American Chemical Society (JA
m. Chem. Soc.) Vol. 88, pp. 852-853 (1966) or a method analogous thereto.

(2) Oxidation / Reduction Alternatively, the compound of general formula [1a] or its salt is subjected to an oxidation reaction conventionally used in the field of cephem-based compounds to obtain a compound of general formula [1a] Or a salt thereof, and subjecting the compound of the general formula [1a] or a salt thereof to a reduction reaction conventionally used in the field of cephem-based compounds.
Compound b) or a salt thereof can also be obtained. These oxidation and reduction reactions are described, for example, in The Journal of
Organic Chemistry (J.Org.Chem.) Volume 35,
2430-2433 (1970), Journal of the Chemical Society [J. Chem. Soc. (C)] 1142-11151
Page (1966) and JP-A-52-48683, or a method analogous thereto.

The compound of the general formula [4] or [5] or a salt thereof or a reactive derivative thereof in the above-mentioned production method; and the compound of the general formula [2], [3] or [6] or a compound thereof Isomers (eg, optical isomers, geometric isomers, tautomers, etc.)
When is present, all these isomers can be used and all hydrates, solvates and various crystal forms can be used. The thus-obtained compound of the general formula [1] of the present invention or a salt thereof can be isolated and purified according to a conventional method such as extraction, crystallization, recrystallization, and column chromatography.

Next, a compound of the general formula [2] or a salt thereof as a raw material for producing the compound of the present invention; a compound of the general formula [3] or a salt thereof; a compound of the general formula [4] or a salt thereof or The method for producing the reactive derivative thereof; and the compound of the general formula [6] or a salt thereof will be described.

(A) The compound of the general formula [2] or a salt thereof, which is a starting compound in the production method 1, can be produced according to a known method or a method analogous thereto. The Journal of Organic Chemistry (J.Org.Chem.) 54, 4962
4966 (1989), Vol. 59, pp. 1606-1607 (1994)
Year), Pure and Applied Chemistry (Pure Appl. Chem.) Vol. 59, pp. 1041-1046 (1987)
And the like, or a method analogous thereto.

(B) The compound of the general formula [3] or a salt thereof, which is a starting compound in the production method 1, can be produced according to a known method or a method analogous thereto. Chemical Pharmaceutical Bulletin (Chem. Pharm. Bull.) Vol. 25, No. 1811
, Page 1821 (1977) or a method analogous thereto. In addition to the reactions described in these documents, it is possible to further apply ordinary alkylation reactions, substitution reactions, acylation reactions, oxidation reactions, reduction reactions, and the like to further induce other target raw material compounds. it can.

(C) The compound of the general formula [4], which is a starting compound in the production method 2, or a salt thereof or a reactive derivative thereof; It can be produced by combining Method 1 and a method known per se.

In the production method of the compound of the present invention and the production method of the starting compound described above, when an active group such as an amino group or a hydroxyl group is present in addition to the reaction site, these groups are protected in advance by a conventional method. Aside
After the reaction, elimination may be carried out according to a conventional method. After completion of the reaction, the reaction target product can be used for the next reaction without isolation, and can be isolated and purified according to a conventional method such as extraction, crystallization, recrystallization, and column chromatography. You may.

When the compound of the present invention is used as a medicament, excipients usually used for formulation, usual pharmaceutical carriers, and formulation auxiliaries such as diluents may be appropriately mixed. , Tablets, soft or hard capsules, powders, syrups, granules, pills, suspensions, emulsions,
It can be administered orally or parenterally in the form of a solution, powder formulation, suppository, ointment or subcutaneous, intramuscular, intravenous or drip injection. In addition, the administration method, dosage and number of administrations can be appropriately selected according to the age, weight, and condition of the patient. Usually, for adults, oral or parenteral (eg, injection, infusion, or rectal site) ) Can be administered in a dose of 0.1 to 100 mg / kg per day in one to several divided doses.

Next, the antibacterial activity of the representative compounds of the present invention will be described. Test method Japanese Society of Chemotherapy standard method [CHEMOTHERAPY
Vol. 29, No. 1, pp. 76-79 (1981)], the test bacterium cultured overnight in a growth medium was adjusted to 10 ⁶ cells / ml, and one platinum loop was added to the Muller containing drug. Hinton Agar (M
ueller Hinton agar) medium (Difco) and inoculate
After culturing at 18 ° C. for 18 to 20 hours, the presence or absence of the growth of the bacteria was observed, and the MIC (μg / ml) was defined as the minimum drug concentration at which the growth of the bacteria was inhibited. Table 1 shows the results.

[0046]

[Table 1] MIC (μg / ml) ─────────────────────────── Example No. S. aureus FDA 209P S. aureus F -597 ^* ─────────────────────────── 53 0.2 3.13 57 0.2 3.13 62 0.2 3.13 63 0.2 3.13 68 0.2 1.56 70 0.2 3.13 71 0.2 3.13 74 0.78 6.25 76 0.78 6.25 ─────────────────────────── *: MRSA

Next, the method for producing the compound of the present invention will be described specifically with reference to Reference Examples and Examples, but the present invention is not limited thereto. The carrier used in column chromatography was silica gel (BW-127ZH; manufactured by Fuji Silysia Chemical Ltd.), and the carrier used in reversed-phase column chromatography was LC-SORB SP-B-ODS (manufactured by Chemco). Was. All mixing ratios in the eluent are volume ratios. The abbreviations in the table have the following meanings. Ph: phenyl

Reference Example 1 6.00 g of 7-phenylacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester was suspended in a mixed solvent of 180 ml of methylene chloride and 180 ml of acetonitrile, and cooled under ice-cooling. After addition of 2.30 g of m-chloroperbenzoic acid (purity 70%), the mixture is stirred at 20 ° C. for 90 minutes. Saturated aqueous sodium hydrogen carbonate solution 20
Add 0 ml and separate the organic layer. The separated organic layer is sequentially washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration.
5.70 g of phenylacetamide-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide are obtained. IR (KBr) cm ^-1 ; 1795,1735,1685

Reference Example 2 2.00 g of 7-phenylacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester was suspended in 40 ml of methylene chloride, 750 mg of pyridine and pentachloride at -30 ° C. 1.32 g of phosphorus was added, and the mixture was stirred for 1 hour under ice-cooling.
And stirred for 30 minutes under ice cooling. 40 ml of water is added to the reaction solution, and the organic layer is separated. After adding 40 ml of water to the separated organic layer and adjusting the pH to 5 with a saturated aqueous solution of sodium hydrogen carbonate, the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was added with 40 ml of tetrahydrofuran and 450 m of (difluoromethylthio) acetic acid.
g, 1-hydroxybenzotriazole 480 mg and dicyclohexylcarbodiimide 650 mg were sequentially added, and the mixture was added at 20 ° C for 1 hour.
Stir for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; toluene: ethyl acetate = 4: 1) to give 7- (difluoromethylthio) acetamido-3-trifluoromethyl. 1.47 g of sulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester are obtained. IR (KBr) cm ^-1 ; 1790,1730,1695

The following compounds are obtained in the same manner. 7-[(Z) -2-hydroxyimino-2-phenylacetamido] -3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1780,1735, 1680 7-[(R) -2-formyloxy-2-phenylacetamido] -3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735 , 1695

Reference Example 3 7- (Difluoromethylthio) acetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-
1.47 g of carboxylic acid diphenylmethyl ester was dissolved in 30 ml of methylene chloride, and m-chloroperbenzoic acid (purity 7
(0%) and then stirred at the same temperature for 10 minutes. 30 ml of a saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent; toluene: ethyl acetate = 1: 1).
7- (difluoromethylthio) acetamido-3-trifluoromethylsulfonyloxy-3-
Cephem-4-carboxylic acid diphenylmethyl ester-
780 mg of 1β-oxide are obtained. IR (KBr) cm ^-1 ; 1800,1735,1660

The following compounds are obtained in the same manner. 7-[(Z) -2-hydroxyimino-2-phenylacetamido] -3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1670 7-[(R) -2-formyloxy-2-phenylacetamido] -3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr ) cm ^-1 ; 1805,1730,1675

Example 1 4-Aminopyrimidine-2-thiol (39 mg) was dissolved in methanol.
The suspension is suspended in 1 ml, and thereto is added a solution of 59% of 28% (W / W) sodium methoxide in methanol under ice-cooling, followed by stirring at the same temperature for 10 minutes. Then, 2 ml of N, N-dimethylformamide was added, and at -30 ° C., 200 ml of 7-phenylacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide was added.
After adding g, stir at -10 ° C for 10 minutes. The reaction solution is added to a mixture of 20 ml of ethyl acetate and 20 ml of water, adjusted to pH 5 with 2N hydrochloric acid, and then the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and diethyl ether was added to the obtained residue.
160 mg of (4-aminopyrimidin-2-ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide are obtained. IR (KBr) cm ^-1 ; 1795,1735,1685

Examples 2 to 20 In the same manner as in Example 1, the compounds shown in Tables 2 to 4 are obtained.

[0055]

[Table 2]

[0056]

[Table 3]

[0057]

[Table 4]

The names and properties of the compounds No. 2 to No. 20 in the table are shown below. No. 2; 7-phenylacetamido-3- (pyrimidin-2-ylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ⁻¹ ; 1790, 1710, 1660 No. 3 3- (4-methylpyrimidin-2-ylthio)
-7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1785,1720,1650 No.4; 3- (4-hydroxypyrimidin-2-ylthio) -7-Phenylacetamido-3-cephem-4-
Carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1665 No. 5; 3- (4-amino-6-hydroxypyrimidin-2-ylthio) -7-phenylacetamido-3- Cephem-4-carboxylic acid diphenylmethyl ester-1
β-oxide IR (KBr) cm ^-1 ; 1800,1735,1660 No. 6; 3- (4,6-diaminopyrimidin-2-ylthio) -7-phenylacetamido-3-cephem-4
-Carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1685 No. 7; 3- [4- (1-Iminoethylamino) pyrimidin-2-ylthio] -7-phenylacetamide -3
-Cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1670

No. 8; 3- (5-cyanopyrimidine-4
-Ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-
Oxide IR (KBr) cm ^-1 ; 1790,1735,1655 No. 9; 7-phenylacetamido-3- (purine-6)
-Ylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1685 No. 10; 3- (6-aminopurin-2-ylthio) -7
-Phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1735,1655 No. 11; 3- (2-aminopurin-6-ylthio) -7
-Phenylacetamide-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1675,1635 No. 12; 3- (6-hydroxypurin-2-ylthio)
-7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1790,1735,1685 No.13; 3- (2-hydroxypurin-6-ylthio)
-7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1655

No. 14; 3- (9-aminopurin-6-ylthio) -7-phenylacetamido-3-cephem-
4-Carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1685 No. 15; 7-phenylacetamido-3- (pyrazolo [3,4-d] pyrimidin-4-ylthio) -3-Cephem-4-carboxylic acid diphenylmethyl ester-1β
-Oxide IR (KBr) cm ^-1 ; 1795,1735,1655 No. 16; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-phenylacetamide-3
-Cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1735,1655 No. 17; 3- (4-hydroxyquinazolin-2-ylthio) -7-phenylacetamide-3 -Cephem-4-
Carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1790,1735,1685 No.18; 3- (4-aminoquinazolin-2-ylthio)
-7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1730,1670 No. 19; 3- (2-aminopteridin-4-ylthio)
-7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1735,1670 No. 20; 3- (5-amino- [1,2, 3] triazolo [4,5-d] pyrimidin-7-ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1655

Example 21 63 mg of 4-aminopyrimidine-2-thiol was dissolved in methanol
The suspension was suspended in 2 ml, and after adding 96 mg of a methanol solution of 28% (W / W) sodium methoxide under ice-cooling, the mixture was stirred at the same temperature for 10 minutes. Then, 4 ml of N, N-dimethylformamide and 1 ml of tetrahydrofuran were added, and 7- [2- (2-
t-butoxycarbonylamino-5-chlorothiazole-
4-yl)-(Z) -2-triphenylmethoxyiminoacetamide] -3-methylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester 500 m
After adding g, stir at 20 ° C. for 2 hours. The reaction solution is added to a mixed solution of 20 ml of ethyl acetate and 20 ml of water, adjusted to pH 2 with 2N hydrochloric acid, and then the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, and the precipitated crystal was collected by filtration.
-(4-Aminopyrimidin-2-ylthio) -7- [2
-(2-t-butoxycarbonylamino-5-chlorothiazol-4-yl)-(Z) -2-triphenylmethoxyiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester and 3- (4- Aminopyrimidin-2-ylthio) -7- [2- (2-t-butoxycarbonylamino-5-chlorothiazol-4-yl)-(Z) -2-triphenylmethoxyiminoacetamide] -2-cephem-4 380 mg of a mixture of diphenylmethyl carboxylate are obtained. IR (KBr) cm ^-1 ; 1785,1720

Example 22 The following compounds were obtained in the same manner as in Example 21. 3- (4-aminopyrimidin-2-ylthio) -7-
[2- (2-t-butoxycarbonylaminothiazole-
4-yl)-(Z) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester and 3- (4-aminopyrimidin-2-ylthio) -7- [2- (2-t -Butoxycarbonylaminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -2-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1750,1720,1685

Example 23 3- (4-aminopyrimidin-2-ylthio) -7-
[2- (2-t-butoxycarbonylamino-5-chlorothiazol-4-yl)-(Z) -2-triphenylmethoxyiminoacetamide] -3-cephem-4-carboxylic acid diphenylmethyl ester and 3- ( 4-Aminopyrimidin-2-ylthio) -7- [2- (2-t-butoxycarbonylamino-5-chlorothiazole-4-
Yl)-(Z) -2-triphenylmethoxyiminoacetamide] -2-cephem-4-carboxylic acid diphenylmethyl ester mixture (380 mg) was dissolved in methylene chloride (5 ml), and m-chloroperbenzoic acid (purity 70) was added under ice-cooling. %), And stirred at the same temperature for 15 minutes. 10 ml of a saturated aqueous solution of sodium hydrogen carbonate is added to the reaction solution, and the organic layer is separated. The separated organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: ethyl acetate).
Purification by 3- (4-aminopyrimidin-2-ylthio) -7- [2- (2-t-butoxycarbonylamino-5-chlorothiazol-4-yl)-(Z) -2-triphenyl Methoxyiminoacetamide] -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-
90 mg of oxide are obtained. IR (KBr) cm ^-1 ; 1800,1720

Example 24 The following compounds were obtained in the same manner as in Example 23. -3- (4-aminopyrimidin-2-ylthio) -7-
[2- (2-t-butoxycarbonylaminothiazole-
4-yl)-(Z) -2-methoxyiminoacetamide] -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1720,1685

Example 25 77 mg of 4-aminopyrazolo [3,4-d] pyrimidine-6-thiol were suspended in 2 ml of methanol, and 28% (W / W
W) After adding 88 mg of a methanol solution of sodium methoxide, the mixture is stirred at the same temperature for 10 minutes. Next, 5 ml of N, N-dimethylformamide was added, and 300 mg of 7- (difluoromethylthio) acetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide was added at −30 ° C. After that,-
Stir at 10 ° C for 10 minutes. The reaction solution is added to a mixture of 30 ml of ethyl acetate and 30 ml of water, adjusted to pH 5 with 2N hydrochloric acid, and then the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, and the precipitated crystal was collected by filtration to give 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio).
-7- (Difluoromethylthio) acetamide-3-cephem-4-carboxylic acid diphenylmethyl ester-1
180 mg of β-oxide are obtained. IR (KBr) cm ^-1 ; 1785,1730,1655

Example 26 The following compounds were obtained in the same manner as in Example 25. -3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-[(Z) -2-hydroxyimino-2-phenylacetamido] -3-cephem-4-
Carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1685

Example 27 The following compounds were obtained in the same manner as in Example 25. -3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-[(R) -2-formyloxy-2-phenylacetamido)]-3-cephem-4-
Carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1730,1635

Example 28 160 mg of 3- (4-aminopyrimidin-2-ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide was added to N, N
-Dissolve in 2 ml of dimethylformamide, add 87 mg of phosphorus trichloride at -30 ° C, and stir at the same temperature for 1 minute. The reaction solution is added to a mixture of 20 ml of ethyl acetate and 20 ml of water, adjusted to pH 5 with a saturated aqueous solution of sodium hydrogen carbonate, and then the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration to give 3- (4-aminopyrimidin-2-ylthio) -7-phenylacetamido-3-cephem- 4-carboxylic acid diphenylmethyl ester 120m
get g. IR (KBr) cm ^-1 ; 1780,1720,1670

Examples 29 to 50 In the same manner as in Example 28, the compounds shown in Tables 5 to 8 are obtained.

[0070]

[Table 5]

[0071]

[Table 6]

[0072]

[Table 7]

[0073]

[Table 8]

The names and properties of the compounds No. 29 to No. 50 in the table are shown below. No. 29; 7-phenylacetamido-3- (pyrimidin-2-ylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785, 1705, 1660 No. 30; 3- ( 4-methylpyrimidin-2-ylthio)
-7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790, 1730, 1660 No. 31; 3- (4-hydroxypyrimidin-2-ylthio) -7-phenyl Acetamide-3-cephem-4-
Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1795,1735,1685 No. 32; 3- (4-amino-6-hydroxypyrimidin-2-ylthio) -7-phenylacetamido-3-cephem-4- Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1655 No.33; 3- (4,6-diaminopyrimidin-2-ylthio) -7-phenylacetamido-3-cephem-4
-Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1735,1670 No. 34; 3- [4- (1-Iminoethylamino) pyrimidin-2-ylthio] -7-phenylacetamide-3
-Cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1740,1685

No. 35; 3- (5-cyanopyrimidine-4
-Ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1655 No.36; 7-phenylacetamido-3- (purine-6)
-Ylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1735,1675 No.37; 3- (6-aminopurin-2-ylthio) -7
-Phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1675 No.38; 3- (2-aminopurin-6-ylthio) -7
-Phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1675 No.39; 3- (6-hydroxypurin-2-ylthio)
-7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1685 No.40; 3- (2-hydroxypurin-6-ylthio)
-7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1650 No.41; 3- (9-aminopurin-6-ylthio) -7
-Phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1670 No. 42; 7-phenylacetamido-3- (pyrazolo [3,4-d] pyrimidine- 4-ylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1670

No. 43; 3- (4-aminopyrazolo [3,4
-D] pyrimidin-6-ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1735,1660 No.44; 3- (4-hydroxyquinazoline -2-ylthio) -7-phenylacetamido-3-cephem-4-
Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1795,1735,1685 No.45; 3- (4-aminoquinazolin-2-ylthio)
-7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1730,1655 No. 46; 3- (2-aminopteridin-4-ylthio)
-7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1670 No.47; 3- (5-amino- [1,2,3] triazolo [ 4,5-d] pyrimidin-7-ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1685 No.48; 3- (4 -Aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (difluoromethylthio)
Acetamide-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1735,1655 No.49; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio)- 7-[(Z) -2-hydroxyimino-2-phenylacetamido] -3-cephem-
4-Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1655 No.50; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-[(R) -2-formyloxy-2-phenylacetamide] -3-cephem-4
-Diphenylmethyl carboxylate IR (KBr) cm ^-1 ; 1790,1730,1635

Example 51 3- (4-aminopyrimidin-2-ylthio) -7-
[2- (2-t-butoxycarbonylamino-5-chlorothiazol-4-yl)-(Z) -2-triphenylmethoxyiminoacetamide] -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide 90mg
Was dissolved in 2 ml of N, N-dimethylformamide,
After adding 29 mg of phosphorus trichloride, the mixture is stirred at -20 ° C for 30 minutes. The reaction solution is added to a mixture of 20 ml of ethyl acetate and 20 ml of water, adjusted to pH 5 with a saturated aqueous solution of sodium hydrogen carbonate, and then the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration to give 3- (4
-Aminopyrimidin-2-ylthio) -7- [2- (2
-T-butoxycarbonylamino-5-chlorothiazol-4-yl)-(Z) -2-triphenylmethoxyiminoacetamide] -3-cephem-4-carboxylic acid diphenylmethyl ester 90 mg is obtained. IR (KBr) cm ^-1 ; 1790,1715,1655

Example 52 The following compounds were obtained in the same manner as in Example 51. -3- (4-aminopyrimidin-2-ylthio) -7-
[2- (2-t-butoxycarbonylaminothiazole-
4-yl)-(Z) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1720,1655

Example 53 3- (4-Aminopyrimidin-2-ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester (120 mg) was dissolved in methylene chloride (2.5 ml) and anisole (0.5 ml), and dissolved in ice. After adding 2.5 ml of trifluoroacetic acid under cooling, the mixture is stirred at the same temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and diethyl ether 10
After adding ml, the precipitated crystals are collected by filtration. The precipitated crystals are dissolved in 20 ml of a 10% aqueous acetonitrile solution, adjusted to pH 7 with a saturated aqueous sodium hydrogen carbonate solution, and the solvent is concentrated to about half under reduced pressure. Purification of the concentrate by reverse phase column chromatography (eluent; 15% acetonitrile aqueous solution) gives 3-
23 mg of sodium (4-aminopyrimidin-2-ylthio) -7-phenylacetamido-3-cephem-4-carboxylate are obtained. IR (KBr) cm ^-1 ; 1770,1620 NMR (D ₂ O) δ value; 3.54 (1H, d, J = 17 Hz), 3.70 (2H, s), 3.89 (1
(H, d, J = 17Hz), 5.21 (1H, d, J = 5Hz), 5.65 (1H, d, J = 5Hz), 6.36
(1H, d, J = 6Hz), 7.35 (5H, s), 7.92 (1H, d, J = 6Hz)

Examples 54 to 74 In the same manner as in Example 53, the compounds shown in Tables 9 to 12 are obtained.

[0081]

[Table 9]

[0082]

[Table 10]

[0083]

[Table 11]

[0084]

[Table 12]

The names and properties of the compounds No. 54 to No. 74 in the table are shown below. No. 54; sodium 7-phenylacetamido-3- (pyrimidin-2-ylthio) -3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1770,1670,1615 NMR (D ₂ O) δ value; 3.53 (1H, d, J = 18Hz), 3.70 (2H, s), 3.85 (1
(H, d, J = 18Hz), 5.24 (1H, d, J = 5Hz), 5.67 (1H, d, J = 5Hz), 7.10
7.67.60 (6H, m), 8.57 (2H, d, J = 5 Hz) No. 55; 3- (4-methylpyrimidin-2-ylthio)
-7-Phenylacetamido-3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1770,1655,1610 NMR (D ₂ O) δ value; 2.45 (3H, s), 3.52 (1H, d, J = 18Hz), 3.70 (2
H, s), 3.85 (1H, d, J = 18Hz), 5.26 (1H, d, J = 5Hz), 5.66 (1H, d,
J = 5Hz), 7.12 (1H, d, J = 5Hz), 7.37 (5H, s), 8.37 (1H, d, J = 5H
z) No. 56; 3- (4-hydroxypyrimidin-2-ylthio) -7-phenylacetamido-3-cephem-4-
Sodium carboxylate IR (KBr) cm ^-1 ; 1770, 1660, 1615 NMR (D ₂ O) δ value; 3.50 (1H, d, J = 17 Hz), 3.70 (2H, s), 3.89 (1
H, d, J = 17Hz), 5.25 (1H, d, J = 5Hz), 5.66 (1H, d, J = 5Hz), 6.26
(1H, d, J = 7 Hz), 7.35 (5H, s), 7.92 (1 H, d, J = 7 Hz) No. 57; 3- (4-amino-6-hydroxypyrimidin-2-ylthio) -7- Phenylacetamido-3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1775,1630 NMR (D ₂ O) δ value; 3.52 (1H, d, J = 17 Hz), 3.69 (2H, s), 3.84 (1
H, d, J = 17Hz), 5.21 (1H, d, J = 5Hz), 5.24 (1H, s), 5.67 (1H, d,
J = 5Hz), 7.37 (5H, s) No. 58; 3- (4,6-diaminopyrimidin-2-ylthio) -7-phenylacetamido-3-cephem-4-
Sodium carboxylate IR (KBr) cm ^-1 ; 1765,1620 NMR (D ₂ O) δ value; 3.59 (1H, d, J = 17 Hz), 3.70 (2H, s), 3.83 (1
H, d, J = 17Hz), 5.21 (1H, d, J = 5Hz), 5.49 (1H, s), 5.65 (1H, d,
J = 5Hz), 7.38 (5H, s) No. 59; 3- [4- (1-Iminoethylamino) pyrimidin-2-ylthio] -7-phenylacetamide-3
- cephem-4-carboxylate ^{IR (KBr) cm -1; 1770,1615} NMR (D 2 O) δ value; 2.23 (3H, s), 3.43 (1H, d, J = 17Hz), 3.71 (2
H, s), 3.78 (1H, d, J = 17Hz), 5.19 (1H, d, J = 5Hz), 5.61 (1H, d,
J = 5Hz), 6.78 (1H, d, J = 6Hz), 7.37 (5H, s), 8.37 (1H, d, J = 6H
z)

No. 60; 3- (5-cyanopyrimidine-4
-Ylthio) -7-phenylacetamido-3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1775,1670,1655 NMR (D ₂ O) δ value; 3.48 (1H, d, J = 18Hz) , 3.70 (2H, s), 3.96 (1
(H, d, J = 18Hz), 5.28 (1H, d, J = 5Hz), 5.70 (1H, d, J = 5Hz), 7.37
(5H, s), 8.84 (1H, s), 9.00 (1H, s) No. 61; 7-phenylacetamido-3- (purine-6
-Ylthio) -3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1770,1655 NMR (D ₂ O) δ value; 3.46 (1H, d, J = 18Hz), 3.69 (2H, s) , 3.86 (1
(H, d, J = 18Hz), 5.29 (1H, d, J = 5Hz), 5.68 (1H, d, J = 5Hz), 7.35
(5H, s), 8.41 (1H, s), 8.67 (1H, s) No. 62; 3- (6-aminopurin-2-ylthio) -7
-Phenylacetamide-3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1770,1635 NMR (D ₂ O) δ value; 3.59 (1H, d, J = 17 Hz), 3.70 (2H, s) , 3.90 (1
(H, d, J = 17Hz), 5.25 (1H, d, J = 5Hz), 5.67 (1H, d, J = 5Hz), 7.37
(5H, s), 8.05 (1H, s) No. 63; 3- (2-aminopurin-6-ylthio) -7
-Phenylacetamido-3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1775,1610 NMR (D ₂ O) δ value; 3.45 (1H, d, J = 17 Hz), 3.68 (2H, s) , 3.85 (1
(H, d, J = 17Hz), 5.24 (1H, d, J = 5Hz), 5.66 (1H, d, J = 5Hz), 7.34
(5H, s), 8.03 (1H, s) No. 64; 3- (6-hydroxypurin-2-ylthio)
-7-Phenylacetamido-3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1770,1685,1615 NMR (D ₂ O) δ value; 3.54 (1H, d, J = 17Hz), 3.69 ( 2H, s), 3.86 (1
(H, d, J = 17Hz), 5.25 (1H, d, J = 5Hz), 5.67 (1H, d, J = 5Hz), 7.35
(5H, s), 8.09 (1H, s) No. 65; 3- (2-hydroxypurin-6-ylthio)
-7-phenylacetamido-3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1770,1615 NMR (D ₂ O) δ value; 3.54 (1H, d, J = 17 Hz), 3.72 (2H, s), 3.91 (1
(H, d, J = 17Hz), 5.30 (1H, d, J = 5Hz), 5.69 (1H, d, J = 5Hz), 7.38
(5H, s), 8.01 (1H, s) No. 66; 3- (9-aminopurin-6-ylthio) -7
-Phenylacetamide-3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1770,1635 NMR (D ₂ O) δ value; 3.53 (1H, d, J = 17 Hz), 3.70 (2H, s) , 3.91 (1
(H, d, J = 17Hz), 5.31 (1H, d, J = 5Hz), 5.69 (1H, d, J = 5Hz), 7.37
(5H, s), 8.30 (1H, s), 8.63 (1H, s) No. 67; 7-phenylacetamido-3- (pyrazolo [3,4-d] pyrimidin-4-ylthio) -3-cephem- Sodium 4-carboxylate IR (KBr) cm ^-1 ; 1770,1655 NMR (D ₂ O) δ value; 3.49 (1H, d, J = 18 Hz), 3.71 (2H, s), 3.89 (1
(H, d, J = 18Hz), 5.31 (1H, d, J = 5Hz), 5.70 (1H, d, J = 5Hz), 7.37
(5H, s), 8,34 (1H, s), 8.64 (1H, s)

No. 68; 3- (4-aminopyrazolo [3,4
-D] pyrimidin-6-ylthio) -7-phenylacetamido-3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1770,1645 NMR (D ₂ O) δ value; 3.57 (1H, d, J = 18Hz), 3.68 (2H, s), 3.85 (1
(H, d, J = 18Hz), 5.23 (1H, d, J = 5Hz), 5.67 (1H, d, J = 5Hz), 7.34
(5H, s), 7.98 (1H, s) No. 69; 3- (4-hydroxyquinazolin-2-ylthio) -7-phenylacetamido-3-cephem-4-
Sodium carboxylate IR (KBr) cm ^-1 ; 1770,1665 NMR (D ₂ O) δ value; 3.45 (1H, d, J = 17 Hz), 3.66 (2H, s), 3.82 (1
(H, d, J = 17Hz), 5.21 (1H, d, J = 5Hz), 5.66 (1H, d, J = 5Hz), 7.20
-8.10 (4H, m), 7.32 (5H, s) No.70; 3- (4-aminoquinazolin-2-ylthio)
-7-Phenylacetamido-3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1770,1665 NMR (D ₂ O) δ value; 3.57 (1H, d, J = 17 Hz), 3.70 (2H, s), 3.84 (1
(H, d, J = 17Hz), 5.23 (1H, d, J = 5Hz), 5.67 (1H, d, J = 5Hz), 7.20
-8.10 (4H, m), 7.37 (5H, s) No.71; 3- (2-aminopteridin-4-ylthio)
-7-Phenylacetamido-3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1770,1615 NMR (D ₂ O) δ value; 3.59 (1H, d, J = 17 Hz), 3.70 (2H, s), 3.93 (1
(H, d, J = 17Hz), 5.30 (1H, d, J = 5Hz), 5.70 (1H, d, J = 5Hz), 7.36
(5H, s), 8.45 (1H, d, J = 2 Hz), 8.83 (1H, d, J = 2 Hz) No. 72; 3- (5-amino- [1,2,3] triazolo [4.5] -d] pyrimidin-7-ylthio) -7-phenylacetamido-3-cephem-4-carboxylate ^{IR (KBr) cm -1; 1770,1670,1655} NMR (D 2 O) δ value; 3.63 (1H, d, J = 17Hz), 3.71 (2H, s), 3.93 (1
(H, d, J = 17Hz), 5.31 (1H, d, J = 5Hz), 5.71 (1H, d, J = 5Hz), 7.38
(5H, s) No. 73; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (difluoromethylthio)
Acetamido-3-cephem-4-carboxylate ^{IR (KBr) cm -1; 1785,1735,1655} NMR (D 2 O) δ value; 3.64 (1H, d, J = 17Hz), 3.71 (2H, s) , 3.96 (1
(H, d, J = 17Hz), 5.32 (1H, d, J = 5Hz), 5.73 (1H, d, J = 5Hz), 6.19
(1H, t, J _HF = 56 Hz), 7.12 (1H, s) No. 74; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-[(Z) -2- Hydroxyimino-2-phenylacetamide] -3-cephem-
Sodium 4-carboxylate IR (KBr) cm ^-1 ; 1775,1655 NMR (D ₂ O) δ value; 3.68 (1H, d, J = 17 Hz), 3.98 (1H, d, J = 17 Hz),
5.28 (1H, d, J = 5Hz), 5.81 (1H, d, J = 5Hz), 7.50 (5H, s), 8.05
(1H, s)

Example 75 3- (4-Aminopyrazolo [3,4-d] pyrimidine-
6-ylthio) -7-[(R) -2-formyloxy-
2-phenylacetamide] -3-cephem-4-carboxylic acid diphenylmethyl ester (100 mg) in methylene chloride
Dissolve in 2.5 ml and 0.5 ml of anisole, add 2.5 ml of trifluoroacetic acid under ice-cooling, and stir at the same temperature for 15 minutes.
The reaction solution was concentrated under reduced pressure, and methanol was added to the resulting residue.
After adding 1 ml and 1 ml of 1N hydrochloric acid and stirring at 20 ° C. for 1 hour,
The pH is adjusted to 6.5 with a saturated aqueous sodium hydrogen carbonate solution, and the solvent is concentrated under reduced pressure to about half the volume. Purification of the concentrate by reverse phase column chromatography (eluent; 5% aqueous acetonitrile solution) gives 3- (4-aminopyrazolo [3,4-d].
Pyrimidin-6-ylthio) -7-[(R) -2-hydroxy-2-phenylacetamido] -3-cephem-
5 mg of 4-carboxylic acid sodium salt are obtained. IR (KBr) cm ^-1 ; 1770,1655 NMR (D ₂ O-CD ₃ CN) δ value; 3.61 (1H, d, J = 17 Hz), 3.89 (1H, d, J =
17Hz), 5.27 (1H, d, J = 5Hz), 5.28 (1H, s), 5.69 (1H, d, J = 5H
z), 7.47 (5H, s), 8.10 (1H, s)

Example 76 3- (4-Aminopyrimidin-2-ylthio) -7-
90 mg of [2- (2-t-butoxycarbonylamino-5-chlorothiazol-4-yl)-(Z) -2-triphenylmethoxyiminoacetamide] -3-cephem-4-carboxylic acid diphenylmethyl ester was methylene chloride. 2.
After dissolving in 5 ml and 0.5 ml of anisole, adding 2.5 ml of trifluoroacetic acid under ice-cooling, and stirring at 20 ° C. for 30 minutes. The reaction solution is concentrated under reduced pressure, and the obtained residue is dissolved in a 90% aqueous formic acid solution, followed by stirring at 20 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was treated with diethyl ether (10 ml).
Is added, and the precipitated crystals are collected by filtration. The precipitated crystals are dissolved in 20 ml of a 10% aqueous acetonitrile solution, adjusted to pH 7 with a saturated aqueous sodium hydrogen carbonate solution, and the solvent is concentrated to about half under reduced pressure. Purification of the concentrated solution by reversed-phase column chromatography (eluent; 5% acetonitrile aqueous solution) gives 7- [2
-(2-amino-5-chlorothiazol-4-yl)-
(Z) -2-Hydroxyiminoacetamide] -3-
29 mg of (4-aminopyrimidin-2-ylthio) -3-cephem-4-carboxylic acid sodium salt are obtained. IR (KBr) cm ^-1 ; 1765, 1665, 1620 NMR (D ₂ O) δ value; 3.60 (1 H, d, J = 17 Hz), 3.92 (1 H, d, J = 17 Hz),
5.36 (1H, d, J = 5Hz), 5.92 (1H, d, J = 5Hz), 6.35 (1H, d, J = 6H
z), 7.92 (1H, d, J = 6Hz)

Example 77 3- (4-aminopyrimidin-2-ylthio) -7-
[2- (2-t-butoxycarbonylaminothiazole-
4-yl)-(Z) -2-methoxyiminoacetamide] -3-cephem-4-carboxylic acid diphenylmethyl ester 70 mg in methylene chloride 1.25 ml and anisole 0.1%.
Dissolve in 25 ml, add 1.25 ml of trifluoroacetic acid under ice-cooling, and stir at 20 ° C for 1 hour. The reaction solution is concentrated under reduced pressure, 5 ml of diethyl ether is added to the obtained residue, and the precipitated crystals are collected by filtration. The precipitated crystals are dissolved in 10 ml of a 10% aqueous solution of acetonitrile, adjusted to pH 7 with a saturated aqueous solution of sodium hydrogen carbonate, and concentrated under reduced pressure to about half the solvent.
Purification of the concentrate by reverse-phase column chromatography (eluent; 5% acetonitrile aqueous solution) gives 3- (4-aminopyrimidin-2-ylthio) -7- [2- (2-aminothiazol-4-yl). -(Z) -2-Methoxyiminoacetamide] -3-cephem-4-carboxylic acid sodium salt, 11 mg, is obtained. IR (KBr) cm ^-1 ; 1785, 1720, 1655 NMR (D ₂ O) δ value; 3.61 (1 H, d, J = 17 Hz), 3.96 (1 H, d, J = 17 Hz),
3.99 (3H, s), 5.35 (1H, d, J = 5Hz), 5.84 (1H, d, J = 5Hz), 6.37
(1H, d, J = 6Hz), 7.03 (1H, s), 7.92 (1H, d, J = 6Hz)

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Minami Shinsaburo 3-15-10 Higashi Toyama Kotobukicho, Toyama City, Toyama Prefecture (72) Inventor Yasuo Watanabe 1-247, Toyama City Town, Toyama Prefecture

Claims (6)

[Claims] [Claim 1] [Wherein, R ¹ represents an optionally substituted alkylthio,
A represents an aryl, arylthio, aryloxy or heterocyclic group; A represents an optionally protected amino, hydroxyl or hydroxyimino group or a methylene group optionally substituted by an alkoxyimino group; R ² represents a halogen atom , Cyano group, amidino group, guanidino group, azide group, nitro group, optionally substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, acyl, carbamoyl, carbamoyloxy,
Alkoxyimino, ureido, alkylsulfinyl,
An alkylsulfonyl or sulfamoyl group or an optionally protected amino, imino, hydroxyl, hydroxyimino or carboxyl group
Pyrimidinyl, quinazolinyl, purinyl, pyrazolo [3,4-d] pyrimidinyl, pyrazolo [4,3-d] pyrimidinyl, [1,2,
3] triazolo [4, 5-d] pyrimidinyl or pteridinyl a; R ³ is a protected or unprotected carboxyl group or a carboxylate group; n is 0 or 1
Are respectively shown. ] The cephalosporin derivative represented by these, or its salt. Is wherein R ^2, cyano, alkyl optionally substituted, alkoxy, substituted with one or more groups selected from alkylthio or alkylamino group or a protected or unprotected amino or hydroxyl group Pyrimidinyl, quinazolinyl, purinyl, pyrazolo [3,4-d] pyrimidinyl, pyrazolo [4,3-
d] pyrimidinyl, [1,2,3] triazolo [4,5
-D] The cephalosporin derivative or a salt thereof according to claim 1, which is a pyrimidinyl or pteridinyl group. 3. R ¹ is substituted by lower alkylthio, phenyl, phenyloxy or thienyl group optionally substituted by a halogen atom, thiazolyl group or amino group optionally substituted by a halogen atom or amino group. The cephalosporin derivative or a salt thereof according to claim 1 or 2, which is a thiadiazolyl group that may be substituted. 4. The cephalosporin derivative according to claim 3, wherein R ¹ is a lower alkylthio group substituted with a halogen atom, a phenyl group or a thiazolyl group optionally substituted with a halogen atom or an amino group. . 5. The cephalosporin derivative or a salt thereof according to claim 1, wherein A is a hydroxy or hydroxyimino group which may be protected or a methylene group which may be substituted with an alkoxyimino group. 6. A compound according to claim 1, wherein R ² is substituted with one or more groups selected from a cyano group, an optionally substituted lower alkyl or lower alkylamino group, and an optionally protected amino or hydroxyl group. Good pyrimidinyl, quinazolinyl, purinyl, pyrazolo [3,4-d]
Pyrimidinyl, [1,2,3] triazolo [4,5-d]
A pyrimidinyl or pteridinyl group.
The cephalosporin derivative or a salt thereof according to the above.