JPH11279180A - New cephalosporin derivative or its salt and antimicrobial agent containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having strong antimicrobial activity to methicillin resistant Staphylococcus aureus and useful as a medicine, especially an antimicrobial agent to human and animals by binding a specific group to 3 position of cephalosporin ring. SOLUTION: This compound is represented by formula I R<1> is H, a halogen, cyano or the like; A is a halogen, a (protected)amino, a (protected)OH, vinylidene or the like; R<2> is a group of a (substituted) formula II or (substituted) formula III [G<1> to G<4> are each C or N; D ring is a 5-6 membered carbon ring (containing N in the ring); broken line is a direct bond binding to C in the ring]; R<3> is a (protected)COOH or carboxylate; (n) is 0 or 1}, e.g. 3-[4- aminopyrazolo(3,4-d)pyrimidin-6-ylthio]-7-cyanoaceamide-3-cephem-4-car boxylic acid diphenylmethyl ester-1β-oxide. The compound of formula I is obtained by reacting, e.g. a compound (salt) of formula IV with a compound (salt) of the formula R<2> -SH in the presence of a base or deacidifying agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel cephalosporin derivative or a salt thereof useful as a medicine.

[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 made intensive studies to solve the above-mentioned problems, and as a result, the following formula was added to the 3-position of the cephalosporin ring.

[0005]

Embedded image Or

Embedded image

Wherein G ¹ , G ² , G ³ and G ^{4 each} represent a carbon atom or a nitrogen atom; Ring D is a 5- or 6-membered carbon ring which may contain a nitrogen atom in the ring. ); The dashed line indicates a bond bonded to the carbon atom in the ring.) The novel cephalosporin derivative or a salt thereof to which the group represented by The present invention has been found to be useful as a pharmaceutical for humans and animals, and has completed the present invention.

That is, the present invention provides a compound represented by the general formula [1]:

Embedded image Wherein R ¹ is a hydrogen atom, a halogen atom, a cyano group,
A represents an optionally substituted alkyl, alkoxy, alkylcarbonyloxy, alkylthio, aryl, arylthio, aryloxy, heterocyclic thio or heterocyclic group; A represents a halogen atom, an optionally protected amino group, An optionally substituted hydroxyl group, an optionally protected hydroxyimino group or a methylene group optionally substituted by an alkoxyimino group, a cycloalkylidene group, a vinylidene group and an ethynylene group;
² is the following formula which may be substituted,

[0008]

Embedded image Or

Embedded image Wherein G ¹ , G ² , G ³ , G ⁴ , D and the dashed line have the same meaning as described above; R ³ represents a carboxyl group or a carboxy group which may be protected. A rat group; n represents 0 or 1, respectively. ] The cephalosporin derivative represented by these, or its salt is provided.

Further, the present invention provides a drug, particularly an antibacterial agent, containing the cephalosporin derivative represented by the above general formula [1] or a salt thereof.

[0010]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below 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,
A C _2-12 alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl and the like; an alkynyl group is, for example, a C _2-12 such as ethynyl, propargyl or the like;
_2-12 alkynyl group; cycloalkyl group is, for example,
Cyclopropyl, cyclobutyl, cyclopentyl, C _{3- 6} cycloalkyl group such as cyclohexyl; and cycloalkylidene group, for example, cyclopropylidene, cyclobutylidene, cyclopentylidene, C _3-6 cycloalkylidene, such as cyclohexylidene An acyl group is, for example, a C _2-5 alkanoyl group such as formyl group, acetyl, propionyl, butyryl, isobutyryl, valeryl and an aroyl group such as benzoyl and naphthoyl; an aryl group is a phenyl and naphthyl group; ;

The alkoxy group includes, 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,
linear or branched C _1-5 alkyl-O— groups such as sec-butoxy, isobutoxy, tert-butoxy and pentyloxy;

The alkylthio group includes, for example, methylthio, ethylthio, propylthio, isopropylthio, n-
Butylthio, sec-butylthio, isobutylthio, tert-
A linear or branched C _1-12 alkyl-S- group such as butylthio, pentylthio, hexylthio, heptylthio, octylthio, nonylthio, decylthio and undecylthio; a lower alkylthio group is, for example, methylthio, ethylthio, propylthio; , Isopropylthio, n-butylthio, sec-butylthio, isobutylthio,
a linear or branched C _1-5 alkyl-S— group such as tert-butylthio and pentylthio; an alkylamino group is, for example, methylamino, ethylamino, propylamino, isopropylamino, n-butyl amino,
sec-butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino, heptylamino, octylamino, nonylamino, decylamino, undecylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethylamino, methyl Amino groups substituted with mono- or di-C _1-12 alkyl groups such as propylamino and ethylbutylamino;

The lower alkylamino group includes, for example, methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, pentylamino, dimethylamino, diethylamino, An amino group substituted by a mono- or di-C _1-5 alkyl group such as dipropylamino, diisopropylamino, methylethylamino, methylpropylamino and ethylbutylamino; an alkylcarbonyloxy group is, for example, acetyloxy; A linear or branched _C1-12 alkyl-CO-O- group such as, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, hexanoyloxy, octanoyloxy and decanoyloxy; Carbonyloxy The group, for example, acetyloxy, propionyloxy, butyryloxy, a straight-chain or branched C _1-5 alkyl -CO-O- groups such as iso-butyryloxy and valeryloxy;

An arylthio group is, for example, an aryl-S-group such as phenylthio and naphthylthio; an aryloxy group is, for example, an aryl-O- group such as phenyloxy and naphthyloxy; an alkoxyimino group is 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 Linear or branched C _1-12 such as, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl and _{undecyloxycarbonyl}
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, chromenyl, indolizinyl , Isoindolyl, indolyl, indazolyl, prunyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl,
Quinazolinyl, sinolinyl, phthalidinyl, isochromanil, chromanil, indolinyl, isoindolinyl,
Benzoxazolyl, triazolopyridyl, tetrazolopyridazinyl, tetrazolopyrimidinyl, thiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, benzothiazolyl,
1,2,3,4-tetrahydroquinolyl, imidazo [1,2
-B] a 4- to 6-membered heterocyclic group or fused heterocyclic group containing at least one heteroatom atom selected from an oxygen atom, a nitrogen atom and a sulfur atom such as [1,2,4] triazinyl and quinuclidinyl; A heterocyclic thio group,
For example, the aforementioned heterocyclic group such as thiadiazolylthio group-
An S-group;

Hereinafter, the compound represented by formula (1) will be described in detail. R ² is the following formula:

[0019]

Embedded image and

Embedded image

(Wherein G ¹ , G ² , G ³ and G ^{4 each} represent a carbon atom or a nitrogen atom; ring D is a 5- or 6-membered carbon ring which may contain a nitrogen atom in the ring) , A broken line indicates a bond bonded to a carbon atom in the ring.). More specifically, a group represented by the following formula can be mentioned.

[0021]

Embedded image (In the formula, the ring D has the meaning described above.)

The above [ia], [ib], [ic], [id], [ie], [ii]
Specific examples of the bicyclic heterocyclic group represented by a] and [iib] include a quinolinyl group; an isoquinolyl group; a naphthydinyl group; a pyrrolopyrimidinyl group; a pyrazolopyrimidinyl group;
Quinazolinyl group; pyridopyrimidinyl group; pteridinyl group; pyrimidopyrimidinyl group, pyrimidopyridazinyl group, indolyl group and benzimidazolyl group.

Specific examples thereof include quinolin-2-yl, isoquinolin-3-yl, 1,8-naphthyridin-2-yl, quinazolin-2-yl, pyrrolo [2,3- d] pyrimidin-2-yl group, pyrrolo [3,
2-d] pyrimidin-2-yl group, pyrrolo [3,4-d] pyrimidin-2-yl group, purin-2-yl group, purine-
A 6-yl group, a pyrazolo [3,4-d] pyrimidin-6-yl group, a pyrazolo [3,4-d] pyrimidin-4-yl group,
A pyrazolo [4,3-d] pyrimidin-5-yl group, [1,2,
3] a triazolo [4,5-d] pyrimidin-5-yl group,
[1,2,3] triazolo [4,5-d] pyrimidin-7-yl group, pyrido [2,3-d] pyrimidin-2-yl group, pyrimido [4,5-d] pyrimidin-2-yl , Pyrimide
[5,4-d] pyrimidin-2-yl group, pyrimido [4,5
-C] pyridazin-7-yl group, pyrimido [4,5-d] pyridazin-2-yl group, pteridin-2-yl group, pteridin-4-yl group, indol-2-yl group and benzimidazole-2 -Yl group and the like.

R ^{1 is} an alkyl group, an alkoxy group, an alkylcarbonyloxy group, an alkylthio group, an aryl group,
Examples of the substituent of the arylthio group, the aryloxy group, the heterocyclic thio group or the heterocyclic group include a halogen atom, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, an amino group which may be protected and a protected group. And a guanidino group.

The groups represented by [I] and [II] in R ² include a halogen atom, a cyano group, an amidino group, a guanidino group, an azide group, a nitro group, an oxo group, an amino group which may be protected; An optionally protected hydroxyl group; an optionally substituted alkyl, alkenyl, cycloalkyl,
Aryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, acyl, carbamoyl, carbamoyloxy, alkoxyimino, ureido, alkylsulfinyl, alkylsulfonyl and sulfamoyl groups or optionally protected amino,
It may be substituted with one or more groups selected from imino, hydroxyl, hydroxyimino or carboxyl groups. Further, among those groups, alkyl, alkenyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, acyl, carbamoyl, carbamoyloxy, alkoxy An imino group, a ureido group, an alkylsulfinyl group, an alkylsulfonyl and a sulfamoyl group are a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, an optionally protected imino group and a lower alkoxy group. It may be replaced by, for example.

As the protecting group used when the compound of the present invention and its production intermediate have an amino group, an imino group, a hydroxyl group, a hydroxyimino group and a carboxyl group, conventionally known protecting groups in the field of cephem compounds. Amino, hydroxyl and carboxyl protecting groups. Specifically, Protective Groups in Organic Synthesis [Theodora.W.Green], (1991
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, alanyl, leucyl, 1-adamantyloxycarbonyl and 8-
Acyl groups such as quinolyloxycarbonyl; benzyl,
Al-lower alkyl groups such as diphenylmethyl and triphenylmethyl; 2-nitrophenylthio and 2,
Arylthio groups such as 4-dinitrophenylthio; alkyl- or aryl-sulfonyl groups such as methylsulfonyl and p-tolylsulfonyl; di-lower alkylamino-lower alkylidene groups such as N, N-dimethylaminomethylene; benzylidene, 2-hydroxy Al-lower alkylidene groups such as benzylidene, 2-hydroxy-5-chlorobenzylidene and 2-hydroxy-1-naphthylmethylene; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene; cyclohexylidene; -Ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-
Acetylcyclohexylidene and 3,3-dimethyl-
Cycloalkylidene groups such as 5-oxocyclohexylidene; diaryl- or dial-lower alkyl- such as diphenylphosphoryl and dibenzylphosphoryl
Phosphoryl group; 5-methyl-2-oxo-2H-1,3
Oxygen-containing heterocyclic alkyl groups such as -dioxol-4-yl-methyl; and alkyl-substituted silyl groups 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 p
Alkyl- or aryl-sulfonyl groups such as -tolylsulfonyl; substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and diphenylmethylsilyl. .

The carboxyl-protecting group includes all groups which can be used as ordinary carboxyl-protecting groups, and includes, for example, methyl, ethyl, n-propyl, iso-propyl, 1,1-dimethylpropyl, n-butyl Lower alkyl groups such as and tert-butyl; aryl groups such as phenyl and naphthyl; benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and bis
aralkyl groups such as (p-methoxyphenyl) methyl; acyl lower alkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl;
Oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; halogeno lower alkyl groups such as 2,2,2-trichloroethyl; lower alkylsilylalkyl groups such as 2- (trimethylsilyl) ethyl;
Alkylcarbonyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl; nitrogen-containing heterocyclic-lower alkyl groups such as phthalimidomethyl and succinimidomethyl; cycloalkyl groups such as cyclohexyl; methoxymethyl, methoxyethoxymethyl And lower alkoxy lower alkyl groups such as 2- (trimethylsilyl) ethoxymethyl; al-lower alkoxy lower alkyl groups such as benzyloxymethyl; lower alkylthio lower alkyl groups such as methylthiomethyl and 2-methylthioethyl; arylthio groups such as phenylthiomethyl Lower alkyl group; 1,1-
Lower alkenyl groups such as dimethyl-2-propenyl, 3-methyl-3-butynyl and allyl; and trimethylsilyl, triethylsilyl, triisopropylsilyl,
And substituted silyl groups such as 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. Examples of the salt in the basic group include 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-2
A salt with a sulfonic acid such as sulfonic acid or naphthalene-1,5-disulfonic acid; or a salt with an acidic amino acid such as glutamic acid or aspartic acid.
Examples of the salt in the acidic group include a salt with an alkali metal such as sodium or potassium; a salt with an alkaline earth metal such as calcium or magnesium; an ammonium salt; trimethylamine, triethylamine, tributylamine, pyridine, N, N -A salt with a nitrogen-containing organic base such as dimethylaniline, N-methylpiperidine or N-methylmorpholine; or a salt with a basic amino acid such as lysine or arginine. Of the above salts, physiologically acceptable salts are preferred.

In the compound of the general formula [1] and salts thereof, isomers (for example, optical isomers, geometric isomers,
When tautomers exist, the invention embraces all such isomers as well as all hydrates, solvates and various crystalline forms.

In the compound of the present invention, R ¹ is a halogen atom, an alkyl group optionally substituted with a halogen atom,
An aryl group optionally substituted with an alkoxy group or an amino group; an alkylthio group optionally substituted with a halogen atom, cyano group, amino group, guanidino group, alkenyl group or alkynyl group; substituted with a halogen atom or amino group which may be thienyl, furyl, thiazolyl, or thiadiazolyl group; thiadiazolylthio group; R ² is optionally substituted with amino group or hydroxyl group quinazolinyl, purinyl, pyrazolo [3,
4-d] pyrimidinyl, pyrazolo [4,3-d] pyrimidinyl, [1,2,3] triazolo [4,5-d] pyrimidinyl,
Compounds which are quinolinyl, pyrrolo [2,3-d] pyrimidinyl, naphthyridinyl, pyrido [2,3-d] pyrimidinyl or pteridinyl groups are preferred. Hereinafter, Tables 1 to 8
Examples of typical compounds of the present invention are shown below.

[0033]

Embedded image

[Table 1] ---------------------------------------------- ----------------------- No. R¹ R^Two  -------------------------------------------------- ------------------- 1. Phenylfurin-6-yl 2. 3-methoxyphenylfurin-6-yl 3. 4-methoxyphenylfurin-6-yl 4 4-aminophenylfurin-6-yl 5. furan-2-yl furin-6-yl 6. thiophen-2-yl furin-6-yl 7. cyanomethylthiofurin-6-yl 8. 2-aminoethylthio Furin-6-yl 9.2-Quadinoethylthiofurin-6-yl 10.Fluoralkyrthiofurin-6-yl 11. (1,3,4-Thiathiazole-2-yl) thiofurin-6-yl 12. Fluoromethylthiofurin-6-yl 13. Hydrogenfurin-6-yl 14. Methylfurin-6-yl 15. n-Butylfurin-6-yl 16. tert-Butylfurin-6-yl 17. Trifluoromethylfurin- 6-yl 18. Chlorofurin-6-yl 19. methylcarboxynyloxy Furin-6-yl 20. Methoxyfurin-6-yl 21. Hensothiazol-2-yl furin-6-yl 22. Cyanofurin-6-yl

23. Phenyl 2-aminofurin-6-yl 24. 3-methoxyphenyl 2-aminofurin-6-yl 25. 4-methoxyphenyl 2-aminofurin-6-yl 26. 4-aminophenyl 2- Aminofurin-6-yl 27. furan-2-yl 2-aminofurin-6-yl 28. thiophen-2-yl 2-aminofurin-6-yl 29. cyanomethylthio 2-aminofurin-6-yl 30. 2-aminoethylthio 2-aminofurin-6-yl 31.2-quadinoethylthio 2-aminofurin-6-yl 32.fluoroalkylthio 2-aminofurin-6-yl 33. (1,3,4- Thiaziasopropyl-2-yl) thio 2-aminofurin-6-yl 34. Difluoromethylthio 2-aminofurin-6-yl 35. Hydrogen 2-aminofurin-6-yl 36. Methyl 2-aminofurin-6-yl 37 n-Butyl 2-aminofurin-6-yl 38.tert-Butyl 2-aminofurin-6-yl 39. Trifluoromethyl 2-aminofurin-6-yl 40. Chloro-2-aminofurin-6-yl 41. Methylcarboxyloxy 2-aminofurin-6-yl 42. Methoxy 2-aminofurin-6-yl 43. Hensothiazole-2-yl 2-aminofurin-6-yl 44. Cyano 2-aminofurin-6-yl

45. Phenyl 2-human peroxyfurin-6-yl 46. 3-Methoxyphenyl 2-human peroxyfurin-6-yl 47. 4-Methoxyphenyl 2-human peroxyfurin-6-yl 48. 4-aminophenyl 2- Human peroxyfurin-6-yl 49. furan-2-yl 2-human peroxyfurin-6-yl 50. thiophen-2-yl 2-human peroxyfurin-6-yl 51. cyanomethylthio 2-human peroxyfurin-6-yl 52. 2-Aminoethylthio 2-humanoxyfurin-6-yl 53.2-Quadinoethylthio 2-humanoxyfurin-6-yl 54.Fluoralkyrthio 2-humanperoxyfurin-6-yl 55. (1,3,4- Thiocyanate-2-yl) thio 2-human peroxyfurin-6-yl 56. Perfluoromethylthio 2-human peroxypurin-6-yl 57. Hydrogen 2-human peroxyfurin-6-yl 58. Methyl 2-human peroxy Furin-6-yl 59.n-Butyl 2-human peroxyfurin-6-yl 60.tert-Butyl 2-human peroxyfurin-6-yl 61.Trifluoromethyl 2-human peroxyfurin-6-yl 62.Chloro 2-human peroxy Furin-6-yl 63. Methylcarboxynyloxy 2-human peroxyfurin-6-yl 64. Methoxy 2-human peroxyfurin-6-yl 65. Hensothiazol-2-yl 2-human peroxyfurin-6-yl 66. Cyano 2- Human peroxyfurin-6-yl

67. Phenyl 9-aminofurin-6-yl 68. 3-Methoxyphenyl 9-aminofurin-6-yl 69. 4-Methoxyphenyl 9-aminofurin-6-yl 70. 4-Aminophenyl 9- Aminofurin-6-yl 71. Furan-2-yl 9-aminofurin-6-yl 72. Thiophene-2-yl 9-aminofurin-6-yl 73. Cyanomethylthio 9-aminofurin-6-yl 74. 2-Aminoethylthio 9-aminofurin-6-yl 75.2-Quadinoethylthio 9-aminofurin-6-yl 76.Fluoralkyrthio 9-aminofurin-6-yl 77. (1,3,4- Thiocyanas-2-yl) thio 9-aminofurin-6-yl 78. Difluoromethylthio 9-aminofurin-6-yl 79. Hydrogen 9-aminofurin-6-yl 80. Methyl 9-aminofurin-6-yl 81 n-butyl 9-aminofurin-6-yl 82. tert-butyl 9-aminofurin-6-yl 83. Trifluoromethyl 9-aminofurin-6-yl 84. Chloro 9-aminofurin-6-yl 85. Methylcarbonyloxy 9-aminofurin-6-yl 86. Methoxy 9-aminofurin-6-yl 87. Hensothiazole-2-yl 9-aminofurin-6-yl 88. Cyano 9-aminofurin-6-yl

89. Phenylfurin-2-yl 90. 3-Methoxyphenylfurin-2-yl 91. 4-Methoxyphenylfurin-2-yl 92. 4-Aminophenylfurin-2-yl 93. Furan-2- Yl furin-2-yl 94. thiophen-2-yl furin-2-yl 95. cyanomethylthiofurin-2-yl 96. 2-aminoethylthiofurin-2-yl 97. 2-quadinoethylthiofurin-2 -Yl 98. Fluoralkyrthiofurin-2-yl 99. (1,3,4-thiathiazole-2-yl) thiofurin-2-yl 100. Fluoromethylthiofurin-2-yl 101. Hydrogenfurin-2-yl 102 Methylfurin-2-yl 103. n-butylfurin-2-yl 104. tert-butylfurin-2-yl 105. trifluoromethylfurin-2-yl 106. chlorofurin-2-yl 107. Methylcarbonyloxy Furin-2-yl 108. Metho Shi-purin-2-yl 109. benzo Chiaso Bu Lumpur-2-yl-purin-2-yl 110. cyano-purin-2-yl

111. Phenyl 6-aminofurin-2-yl 112. 3-Methoxyphenyl 6-aminofurin-2-yl 113. 4-Methoxyphenyl 6-aminofurin-2-yl 114. 4-Aminophenyl 6- Aminofurin-2-yl 115. furan-2-yl 6-aminofurin-2-yl 116. thiophen-2-yl 6-aminofurin-2-yl 117. cyanomethylthio 6-aminofurin-2-yl 118. 2-Aminoethylthio 6-aminofurin-2-yl 119. 2-Quadinoethylthio 6-aminofurin-2-yl 120.Fluoralkyrthio 6-aminofurin-2-yl 121. (1,3,4- Thiocyanasyl-2-yl) thio 6-aminofurin-2-yl 122. Difluoromethylthio 6-aminofurin-2-yl 123. Hydrogen 6-aminofurin-2-yl 124. Methyl 6-aminofurin-2-yl 125 n-butyl 6-aminofurin-2-yl 126. tert-butyl 6-aminophenyl Perlin-2-yl 127. Trifluoromethyl 6-aminofurin-2-yl 128. Chloro 6-aminofurin-2-yl 129. Methylcarboxyloxy 6-aminofurin-2-yl 130. Methoxy 6-aminofurin 2-yl 131. Hensothiazol-2-yl 6-aminofurin-2-yl 132. Cyano 6-aminofurin-2-yl

133. Phenyl 6-human peroxyfurin-2-yl 134. 3-Methoxyphenyl 6-human peroxyfurin-2-yl 135. 4-Methoxyphenyl 6-human peroxyfurin-2-yl 136. 4-Aminophenyl 6- Human peroxyfurin-2-yl 137. Furan-2-yl 6-human peroxyfurin-2-yl 138. Thiophene-2-yl 6-human peroxyfurin-2-yl 139. Cyanomethylthio 6-human peroxyfurin-2-yl 140. 2-Aminoethylthio 6-human peroxyfurin-2-yl 141.2-Quadinoethylthio 6-human peroxyfurin-2-yl 142.Fluoralkyrthio 6-human peroxyfurin-2-yl 143. (1,3,4- Thiocyanasyl-2-yl) thio 6-human peroxyfurin-2-yl 144. Perfluoromethylthio 6-human peroxyfurin-2-yl 145. Hydrogen 6-human peroxyfurin-2-yl 146. Methyl 6-h Peroxyfurin-2-yl 147. n-butyl 6-human peroxyfurin-2-yl 148. tert-butyl 6-human peroxyfurin-2-yl 149. trifluoromethyl 6-human peroxyfurin-2-yl 150. chloro 6- Human peroxyfurin-2-yl 151. Methylcarbonyloxy 6-human peroxyfurin-2-yl 152. Methoxy 6-human peroxyfurin-2-yl 153. Hensothiazol-2-yl 6-human peroxyfurin-2-yl 154. Cyano 6 -Humanoxyfurin-2-yl

155. Phenyl quinazolin-2-yl 156. 3-Methoxyphenyl quinazolin-2-yl 157. 4-Methoxyphenyl quinazolin-2-yl 158. 4-Aminophenyl quinazolin-2-yl 159. Furan-2- Il quinazodolin-2-yl 160. thiophen-2-yl quinazodolin-2-yl 161. cyanomethylthio quinazodolin-2-yl 162. 2-aminoethylthio quinazodolin-2-yl 163. 2-quinacinoethylthio quinazodulin-2 -Ill 164. Fluoralkarylthioquinazolin-2-yl 165. (1,3,4-thiadiazol-2-yl) thioquinazolin-2-yl 166. Fluoromethylthioquinazolin-2-yl 167. Hydrogen quinazolin-2-yl 168 Methyl quinazolin-2-yl 169. n-butyl quinazolin-2-yl 170. tert-butyl quinazolin-2-yl 171. trifluoromethyl quinazolin-2-yl 172. Chloroquinazodolin-2-yl 173. Methylcarbonyloxy quinazolin-2-yl 174. Methoxyquinazolin-2-yl 175. Hensothiazol-2-yl quinazolin-2-yl 176. Cyanoquinazolin-2-yl

177. Phenyl 4-aminoquinazodolin-2-yl 178. 3-Methoxyphenyl 4-aminoquinazodolin-2-yl 179. 4-Methoxyphenyl 4-aminoquinazodolin-2-yl 180. 4-aminophenyl 4- Aminoquinazodolin-2-yl 181. Furan-2-yl 4-Aminoquinazolin-2-yl 182. Thiophene-2-yl 4-Aminoquinazolin-2-yl 183. Cyanomethylthio 4-aminoquinazodolin-2-yl 184. 2-Aminoethylthio 4-aminoquinazolin-2-yl 185.2-Quadinoethylthio 4-aminoquinazolin-2-yl 186.Fluoralkyrthio 4-aminoquinazolin-2-yl 187. (1,3,4- Thiocyanate-2-yl) thio 4-aminoquinazolin-2-yl 188. Difluoromethylthio 4-aminoquinazolin-2-yl 189. Hydrogen 4-aminoquinazolin-2-yl 190. Methyl 4-aminoquinazolin-2-yl 181 . n -Butyl 4-aminoquinazolidin-2-yl 192. tert-Butyl 4-aminoquinazolidin-2-yl 193. Trifluoromethyl 4-aminoquinazolidin-2-yl 194. Chloro 4-aminoquinazolidin-2-yl 195. Methyl Carboxyloxy 4-aminoquinazolidin-2-yl 196. Methoxy 4-aminoquinazolidin-2-yl 197. Benzodithiazol-2-yl 4-aminoquinazolidin-2-yl 198. Cyano 4-aminoquinazolidin-2-yl

199. Phenyl 4-human peroxyquinazolidin-2-yl 200. 3-Methoxyphenyl 4-human peroxyquinazolidin-2-yl 201. 4-Methoxyphenyl 4-human peroxyquinazolidin-2-yl 202. 4-aminophenyl 4- Human peroxyquinazolin-2-yl 203. furan-2-yl 4-human peroxyquinazolin-2-yl 204. thiophen-2-yl 4-human peroxyquinazolin-2-yl 205. cyanomethylthio 4-human peroxyquinazolin-2-yl 206. 2-Aminoethylthio 4-humanquinoxyquinazolin-2-yl 207. 2-Quadinoethylthio 4-humanoxyquinazolin-2-yl 208.Fluoralkenylthio 4-humanoxyquinazolin-2-yl 209. (1,3,4- Thiocyanate-2-yl) thio 4-humanoxyquinazolin-2-yl 210. Perfluoromethylthio 4-humanoxyquinazolin-2-yl 211 Hydrogen 4-Hydroxyquinazolidin-2-yl 212. Methyl 4-Hydroxyquinazolin-2-yl 213. n-Butyl 4-Hydroxyquinazolin-2-yl 214. tert-Butyl 4-Hydroxyquinazolin-2-yl 215. Tri. Fluoromethyl 4-human peroxyquinazolin-2-yl 216. Chloro 4-human peroxyquinazolin-2-yl 217. Methylcarbonyloxy 4-human peroxyquinazolin-2-yl 218. Methoxy 4-human peroxyquinazolin-2-yl 219. Benzothiazole 2-yl 4-Hydroxyquinazolidin-2-yl 220. Cyano 4-Hydroxyquinazolidin-2-yl

221. Phenylphthalicin-2-yl 222. 3-Methoxyphenylphthalicin-2-yl 223. 4-Methoxyphenylphthalicin-2-yl 224. 4-Aminophenylphthalicin-2-yl 225. Furan-2- Il phthalicin-2-yl 226. Thiophene-2-yl phthalicin-2-yl 227. Cyanomethylthio phthalicin-2-yl 228. 2-Aminoethylthio phthalicin-2-yl 229. 2-Quadinoethylthio phthalicin-2 -Il 230. Fluoroalkylthio phthalicin-2-yl 231. (1,3,4-thiathiazol-2-yl) thiophthalicin-2-yl 232. Fluoromethylthio phthalicin-2-yl 233. Hydrogen phthalicin-2-yl 234 Methyl phthal-2-yl 235. n-Phyl phthal-2-yl 236. tert-Phyl phthal-2-yl 237. Tri Fluoromethyl-2-yl 238. Chlorophthalicin-2-yl 239. Methyl carboxyoxyphthalicin-2-yl 240. Methoxy phthalicin-2-yl 241. Hensothiazol-2-yl phthalicin-2-yl 242. Cyano-phthalicin- 2-Il

243. Phenyl 5-amino [1,2,3] triaspero [4,5-d] perimidin-7-yl 244.4-Methoxyphenyl 5-amino [1,2,3] triaspero [4,5 -d] Hyrimicidin-7-yl 245. 4-Methoxyphenyl 5-amino [1,2,3] triazolo [4,5-d] hyrimidin-7-yl 246.4-Aminophenyl 5-amino [1,2 , 3] Triazodolo [4,5-d] pyrimicidin-7-yl 247. Furan-2-yl 5-amino [1,2,3] triasolo [4,5-d] pyrimicidin-7-yl 248. Thiophene- 2-yl 5-amino [1,2,3] triaspero [4,5-d] perimidin-7-yl 249. Cyanomethylthio 5-amino [1,2,3] triaspero [4,5-d] perimidicin- 7-yl 250. 2-Aminoethylthio 5-amino [1,2,3] triaspero [4,5-d] perimidin-7-yl 251. 2-Quadinoethylthio 5-amino [1,2,3 ] Triazodolo [4,5-d] pyrimicidin-7-yl 252. No [1,2,3] triazodolo [4,5-d] pyrimidin-7-yl 253. (1,3,4-thiadiazol-2-yl) thio 5-amino [1,2,3] triazodolo [4 , 5-d] Primicidin-7-yl 254. Perfluoromethylthio 5-amino [1,2,3] triazolo [4,5-d] perimidin-7-yl 255. Hydrogen 5-amino [1,2,3] Triazolo [4,5-d] pyrimicidin-7-yl 256. Methyl 5-amino [1,2,3] triazolo [4,5-d] hyrimicidin-7-yl 257. n-butyl 5-amino [1, 2,3] Triazolo [4,5-d] pyrimicidin-7-yl 258. tert-butyl 5-amino [1,2,3] triazolo [4,5-d] hyrimicidin-7-yl 259. Trifluoromethyl 5-Amino [1,2,3] triazolo [4,5-d] pyrimicidin-7-yl 260. Chloro 5-amino [1,2,3] triazolo [4,5-d] hyrimidin-7-yl 261 Methylcarboxynyloxy 5-amino [1,2,3] triazolo [4,5-d] hyrimidin-7-yl 262. 5-Amino [1,2,3] triazodolo [4,5-d] pyrimidin-7-yl 263. Hensothiazol-2-yl 5-amino [1,2,3] triazodolo [4,5-d] Polyimidin-7-yl 264. Cyano 5-amino [1,2,3] triazolo [4,5-d] polyimidin-7-yl

265. Phenyl [1,2,3] triaspero [4,5-d] perimidin-5-yl 266. 3-Methoxyphenyl [1,2,3] triaspero [4,5-d] perimidin-5 -Yl 267. 4-methoxyphenyl [1,2,3] triaspero [4,5-d] perimidicin-5-yl 268. 4-aminophenyl [1,2,3] triaspero [4,5-d] perimidicin -5-yl 269. Furan-2-yl [1,2,3] triaspero [4,5-d] perimidin-5-yl 270. Thiophen-2-yl [1,2,3] triaspero [4,5] 271. Cyanomethylthio [1,2,3] triaspero [4,5-d] perimidin-5-yl 272. 2-Aminoethylthio [1,2,3] triaspero [4, 5-d] Hyrimicidin-5-yl 273. 2-Quadinoethylthio [1,2,3] triazolo [4,5-d] hyrimisin-5-yl 274. Fluoralkyrthio [1,2,3] triazolo [ 4,5-d] Primicidin-5-yl 275. (1,3,4-thiathiazole-2- Le) Thio [1,2,3] triazolo [4,5-d] pyrimicidin-5-yl 276. Perfluoromethylthio [1,2,3] triazolo [4,5-d] hyrimicidin-5-yl 277. Hydrogen [1,2,3] triazolo [4,5-d] hyrimicidin-5-yl 278. Methyl [1,2,3] triazolo [4,5-d] hyrimicidin-5-yl 279. n-butyl [1 , 2,3] Triazolo [4,5-d] pyrimicidin-5-yl 280. tert-butyl [1,2,3] triazolo [4,5-d] hyrimicidin-5-yl 281. Trifluoromethyl [1 , 2,3] Triazolo [4,5-d] pyrimicidin-5-yl 282. Chloro [1,2,3] triazolo [4,5-d] hyrimicidin-5-yl 283. Methylcarbonyloxy [1,2 , 3] Triazolo [4,5-d] hyrimicidin-5-yl 284. Methoxy [1,2,3] triazolo [4,5-d] hyrimicidin-5-yl 285. Hensothithiazole-2-yl [1, 2,3] Triazodolo [4,5-d] pyrimidin-5-yl 286. Cyano [1,2,3] trio Zorro [4,5-d] Pi Rimijin-5-yl

287. Phenyl perazolo [3,4-d] perimidin-4-yl 288. 3-Methoxyphenyl perazolo [3,4-d] perimidicin-4-yl 289. 4-methoxyphenyl perazolo [3,4- d] Hyperimidin-4-yl 290. 4-Aminophenyl hirazolin [3,4-d] hyrimidin-4-yl 291. Furan-2-yl hirazolin [3,4-d] hyrimidin-4-yl 292. Thiophene- 293. Cyanomethylthio thiazolo [3,4-d] pyrimicidin-4-yl 294. 2-Aminoethylthio thiazolo [3,4-d] hyrimidine- 4-Iil 295. 2-Quadinoethylthiohydrazolo [3,4-d] hyrimisin-4-yl 296.Fluoralkyrthiohyrazoro [3,4-d] hyrimisin-4-yl 297. (1,3,4- Thiazoasole-2-yl) thioperazole [3,4-d] perimidin-4-yl 29 8. Perfluoromethylthio peri [3,4-d] perimidin-4-yl 299. Hydrogen peri [3,4-d] perimicin-4-yl 300. Methyl peri [3,4-d] perimidin-4-yl 301 n-butyl hydro [3,4-d] hyrmicin-4-yl 302. tert-hyphthrhydro [3,4-d] hyrmicin-4-yl 303. trifluoromethyl hydro [3,4-d] hyrmicin- 4-yl 304. Chlorohydro [3,4-d] perimidin-4-yl 305. Methyl carboxyloxyperazolo [3,4-d] perimidicin-4-yl 306. Methoxy hydro [3,4-d] perimidin- 4-Il 307. Hensothiazol-2-yl Hydrazol [3,4-d] hyperimidin-4-yl 308. Cyano Hydrazol [3,4-d] hyrimidin-4-yl

309. Phenyl 6-aminodiazolo [3,4-d] perimidicin-4-yl 310. 3-Methoxyphenyl 6-aminodiazolo [3,4-d] perimidicin-4-yl 311. 4-methoxyphenyl 6- Aminohydro [3,4-d] perimidicin-4-yl 312. 4-Aminophenyl 6-aminohydro [3,4-d] perimidicin-4-yl 313. Furan-2-yl 6-aminohydro [3,4-d ] Hyrimicidin-4-yl 314. Thiophene-2-yl 6-aminohirasolo [3,4-d] hyrimisin-4-yl 315. Cyanomethylthio 6-aminohirasolo [3,4-d] hyrimisin-4-yl 316.2 -Aminoethylthio 6-aminohydro [3,4-d] perimicin-4-yl 317. 2-Quadinoethylthio 6-aminohydro [3,4-d] perimicin-4-yl 318. Fluorochlorothio 6-aminohydro [] 3,4-d] Primetic 4-yl 319. (1,3,4-thiathiazol-2-yl) thio 6-aminodiazolo [3,4-d] pyrimicidin-4-yl 320. Fluoromethylthio 6-aminodiazolo [3,4-d] hyrimidin-4-yl 321. Hydrogen 6-amino diazo [3,4-d] perimidicin-4-yl 322. Methyl 6-amino diazo [3,4-d] perimidicin-4-yl 323. n-butyl 6-amino diazo [3,4-d] perimidic -4-yl 324. tert-butyl 6-aminohydro [3,4-d] hyrimidin-4-yl 325. trifluoromethyl 6-aminohydro [3,4-d] hyrimidine-4-yl 326. chloro 6-aminohyperoro [3,4-d] pyrimicidin-4-yl 327. Methylcarbonyloxy 6-aminopyrazolo [3,4-d] hyrimidin-4-yl 328. Methoxy 6-aminopyrazolo [3,4-d] hyrimidin-4-yl 329. Hensothiazole-2-yl 6-amino ° Razoro [3,4-d] Pi Rimijin 4-yl 330. cyano 6- Aminohi ° Razoro [3,4-d] Pi Rimijin 4-yl

331.Phenyl 6-human hydroxyperazole [3,4-d] perimidicin-4-yl 332.3-methoxyphenyl 6-humanperoxyperazole [3,4-d] perimidicin-4-yl 333. 4- Methoxyphenyl 6-human hydroxyperazole [3,4-d] perimicin-4-yl 334. 4-Aminophenyl 6-humanperoxyperazole [3,4-d] perimicin-4-yl 335.furan-2-yl 6 -Hydroxyperoxy [3,4-d] perimicin-4-yl 336. Thiophen-2-yl 6-Hydroxyperoxy [3,4-d] perimicin-4-yl 337. Cyanomethylthio 6-Hyperoxyperazole [ 3,4-d] Hyrimicidin-4-yl 338. 2-Aminoethylthio 6-Hetoxyhydroxyl [3,4-d] Hyrimicidin-4-yl 339. 2-Quarinoethylthio 6-Hydroxyhydroxyrolo [3 , 4-d] Primicin-4-yl 340. LUTHIO 6-HYDROXYPERISORED [3,4-d] PERIMICIN-4-YL 341. (1,3,4-THIATHISOSOL-2-YL) THIO 6-HYDROXYPERISORED [3,4-d] perimidin-4-yl Ill 342. Perfluoromethylthio 6-Hydroxyperoxy [3,4-d] perimicin-4-yl 343. Hydrogen 6-Hydroxyperhydro [3,4-d] perimicin-4-yl 344. Methyl 6-humanperoxyperol [3,4-d] Hypermicin-4-yl 345. n-Phthyl 6-Hydroxyperoxyl [3,4-d] Hypermicin-4-yl 346. tert-Phthyl 6-Hydroxyperoxyl ] Primicidin-4-yl 347. Trifluoromethyl 6-human peroxyperoxy [3,4-d] perimicin-4-yl 348. Chloro 6-human peroxyperazole [3,4-d] perimicin-4-yl 349. Methylcarboxyloxy 6-human hydroxyperazole [3,4-d] Rimicidin-4-yl 350. methoxy 6-humanhydroxyperazole [3,4-d] perimicin-4-yl 351. benzothiazol-2-yl 6-humanhydroxyperazole [3,4-d] hyrimidine-4-yl 352. Cyano 6-Hydroxyperazolo [3,4-d] perimicin-4-yl

353. Phenyl perazole [3,4-d] perimidin-6-yl 354. 3-Methoxyphenyl perazole [3,4-d] perimidin-6-yl 355. 4-methoxyphenyl perazole [3,4- d] Hyrimicidin-6-yl 356. 4-Aminophenyl hyrazolo [3,4-d] hyrimidin-6-yl 357. Furan-2-yl hyrazolo [3,4-d] hyrimidin-6-yl 358. Thiophene- 2-yl perazo [3,4-d] perimidicin-6-yl 359. Cyanomethylthio peri [3,4-d] perimidicin-6-yl 360. 2-aminoethylthio peri [3,4-d] perimidic- 6-Ill 361. 2-Quadinoethylthiohydrazolo [3,4-d] hyrimisin-6-yl 362.Fluoralkyrthiohyrazolo [3,4-d] hyrimisin-6-yl 363. (1,3,4- Thiashiasor-2-yl) thiothiazolazole [3,4-d] pyrimidin-6-yl 36 4. Perfluoromethylthio diazo [3,4-d] hyrimidin-6-yl 365. Hydrogen hydoro [3,4-d] hyrimidin-6-yl 366. Methyl hydoro [3,4-d] hyrimidin-6-yl 367 n-Phylhydrazolo [3,4-d] hyperimidin-6-yl 368. tert-Hydroxyperazolo [3,4-d] hyrimicidin-6-yl 369. Trifluoromethylhyperazo [3,4-d] hyperimidin 6-yl 370. Chlorohydrazolo [3,4-d] perimidicin-6-yl 371. Methylcarbonyloxyperioduro [3,4-d] perimicin-6-yl 372.Methoxy hydrazolo [3,4-d] perimidic- 6-Il 373. Hensothiazol-2-yl Hydrazol [3,4-d] hyperimidin-6-yl 374. Cyano Hydrazol [3,4-d] hyrimidin-6-yl

375.Phenyl 4-aminoperazolo [3,4-d] perimidicin-6-yl 376.3-Methoxyphenyl 4-aminoperazolo [3,4-d] perimidicin-6-yl 377.4-methoxyphenyl 4- Aminohydro [3,4-d] perimidicin-6-yl 378. 4-Aminophenyl 4-aminohydro [3,4-d] perimidicin-6-yl 379. Furan-2-yl 4-aminohydro [3,4-d ] Hyrimicidin-6-yl 380. Thiophene-2-yl 4-aminopyrazolo [3,4-d] hyrimicidin-6-yl 381. Cyanomethylthio 4-aminohirasolo [3,4-d] hyrimicidin-6-yl 382.2 -Aminoethylthio 4-aminopyrazol [3,4-d] hyrimicidin-6-yl 383. 2-Quadinoethylthio 4-aminopyrazol [3,4-d] hyrimicidin-6-yl 384. Fluoralkyrthio 4-aminopyrazol [ 3,4-d] Primetic 6-yl 385. (1,3,4-thiadiazol-2-yl) thio 4-aminodiazolo [3,4-d] hyrimidin-6-yl 386. Fluoromethylthio 4-aminodiazolo [3,4-d] hyrimidin-6-yl 387. Hydrogen 4-Aminohydro [3,4-d] perimidicin-6-yl 388. Methyl 4-Aminohydro [3,4-d] perimidicin-6-yl 389. n-butyl 4-Aminohydro [3,4-d] perimidicin -6-yl 390. tert-Butyl 4-aminopyrazol [3,4-d] hyrimidin-6-yl 391. Trifluoromethyl 4-aminopyrazol [3,4-d] hyrimidin-6-yl 392. Chloro 4-aminopyrazol [3,4-d] pyrimicidin-6-yl 393. Methylcarbonyloxy 4-aminopyrazolo [3,4-d] hyrimidin-6-yl 394. Methoxy 4-aminopyrazolo [3,4-d] hyrimidine-6-yl 395. Hensothiazole-2-yl 4-amino ° Razoro [3,4-d] Pi Rimijin 6-yl 396. cyano 4- Aminohi ° Razoro [3,4-d] Pi Rimijin 6-yl

397. Phenylquinolin-2-yl 398. 3-methoxyphenylquinolin-2-yl 399.4-methoxyphenylquinolin-2-yl 400. 4-aminophenylquinolin-2-yl 401. furan-2- Il quinolin-2-yl 402. thiophen-2-yl quinolin-2-yl 403. cyanomethylthio quinolin-2-yl 404. 2-aminoethylthio quinolin-2-yl 405. 2-quadinoethylthio quinoline-2 -Il 406. Fluoroalkirthiothioquinolin-2-yl 407. (1,3,4-thiadiazol-2-yl) thioquinolin-2-yl 408. Difluoromethylthioquinolin-2-yl 409. Hydrogenquinolin-2-yl 410 Methylquinolin-2-yl 411. n-butylquinolin-2-yl 412. tert-butylquinolin-2-yl 413. trifluoromethylquinolin-2-yl 414. chloroquinolin-2-yl 415. methylcarbonyloxy Quinolin-2-yl 4 16. Methoxyquinolin-2-yl 417. Benzodithiazol-2-yl quinolin-2-yl 418. Cyanoquinolin-2-yl

419. Phenyl 1,8-naphthyridin-2-yl 420. 3-Methoxyphenyl 1,8-naphthyridin-2-yl 421. 4-Methoxyphenyl 1,8-naphthyridin-2-yl 422.4-Amino Phenyl 1,8-naphthyridin-2-yl 423. furan-2-yl 1,8-naphthyridin-2-yl 424. thiophen-2-yl 1,8-naphthyridin-2-yl 425. cyanomethylthio 1,8- Naphthyricin-2-yl 426.2-Aminoethylthio 1,8-naphthyricin-2-yl 427.2-Quadinoethylthio 1,8-naphthyricin-2-yl 428.Fluoralkyrthio 1,8-naphthyricin-2- Il 429. (1,3,4-thiathiazol-2-yl) thio 1,8-naphthyridin-2-yl 430. Difluoromethylthio 1,8-naphthyridin-2-yl 431. Hydrogen 1,8-naphthyridin-2-yl Yl 432. Methyl 1,8-naphthyridin-2-yl 433. n-butyl 1,8-naphthyridin-2-yl 434. te rt-butyl 1,8-naphthyridin-2-yl 435. trifluoromethyl 1,8-naphthyridin-2-yl 436. chloro 1,8-naphthyridin-2-yl 437. methyl carboxyloxy 1,8-naphthyridin-2 -Yl 438. Methoxy 1,8-naphthyricin-2-yl 439. Hensothithiazol-2-yl 1,8-naphthyricin-2-yl 440. Cyano 1,8-naphthyricin-2-yl

441. Phenyl Pyritol [2,3-d] Primicidin-2-yl 442. 3-Methoxyphenyl Piritol [2,3-d] Primicidin-2-yl 443. 4-Methoxyphenyl Piritol [2,3- d] Primidin-2-yl 444. 4-Aminophenyl pyridin [2,3-d] pyrimidin-2-yl 445. Furan-2-yl pyridin [2,3-d] pyrimidin-2-yl 446. Thiophene- 2-ylpyridin [2,3-d] pyrimicidin-2-yl 447. Cyanomethylthio pyridin [2,3-d] pyrimidin-2-yl 448. 2-aminoethylthiopyridin [2,3-d] pyrimidin- 2-yl449. 2-Quadinoethylthiopyritol [2,3-d] pyrimicidin-2-yl 450.Fluoralkyrthiopyritol [2,3-d] pyrimicidin-2-yl 451. (1,3,4- Thiaceasol-2-yl) thiopyrido [2,3-d] pyrimicidin-2-yl 452. Fluoromethylthio Operito [2,3-d] perimidicin-2-yl 453. Hydrogen perito [2,3-d] perimidisin-2-yl 454. Methyl perito [2,3-d] perimidisin-2-yl 455. n- Butyl-pyri [2,3-d] pyrimicidin-2-yl 456. tert-butyl-pyri [2,3-d] pyrimicidin-2-yl 457. 458. Chloropyrito [2,3-d] pyrimicidin-2-yl 459. Methylcarboxynoxypyrito [2,3-d] hirimicidin-2-yl 460. Methoxypyrito [2,3-d] hirimicidin-2-yl 461. Hensothiazol-2-yl pyrimidin-2-yl 462. Cyano pyridol [2,3-d] pyrimidin-2-yl

463. Phenyl 7-human peroxypyrido [2,3-d] perimidicin-2-yl 464. 3-methoxyphenyl 7-human peroxypyrido [2,3-d] perimidicin-2-yl 465.4. Methoxyphenyl 7-human peroxypyrido [2,3-d] perimicin-2-yl 466. 4-Aminophenyl 7-human peroxypyrido [2,3-d] perimicin-2-yl 467.furan-2-yl 7 -Hydroxypyritol [2,3-d] pyrimicidin-2-yl 468. Thiophene-2-yl 7-Hydroxypyritol [2,3-d] Hyrimicidin-2-yl 469. Cyanomethylthio 7-Hydroxypyritol [ 2,3-d] Perimidin-2-yl 470. 2-Aminoethylthio 7-human peroxypyritol [2,3-d] perimidin-2-yl 471. 2-Quadinoethylthio 7-human peroxypyritol [2 , 3-d] Primicin-2-yl 472. Fluoralkyrthio 7-Hydroxy Cyperito [2,3-d] pyrimicidin-2-yl 473. (1,3,4-thiathiazol-2-yl) thio 7-Hetoxyhydroxy [2,3-d] perimicin-2-yl 474. Perfluoromethylthio 7-Hydroxypyrido [2,3-d] perimicin-2-yl 475. Hydrogen 7-Hydroxyperitritol [2,3-d] perimicin-2-yl 476. Methyl 7-Hydroxyperituri [2,3- d] Hypermicin-2-yl 477. n-Phthyl 7-Hydroxypyritol [2,3-d] Hypermicin-2-yl 478. tert-Phthyl 7-Hydroxypyritol [2,3-d] Hyperimidin-2- Il 479. Trifluoromethyl 7-human peroxypyrido [2,3-d] perimicin-2-yl 480. Chloro 7-human peroxypyrido [2,3-d] perimicin-2-yl 481. Methyl carboxyloxy 7- Human peroxypyrito [2,3-d] pyrimicidin-2-yl 482. Methoxy 7-human peroxy Xypyridyl [2,3-d] pyrimicidin-2-yl 483. Hensothiazol-2-yl 7-Hydroxypyritol [2,3-d] Pyrimicin-2-yl 484. Cyano 7-Hydroxypyritol [2,3 -d] Primicin-2-yl

485. Phenyl 4-aminohydroxy [2,3-d] perimidin-2-yl 486.3-methoxyphenyl 4-aminohydroxy [2,3-d] perimidisin-2-yl 487. 4-methoxyphenyl 4- Aminochloro [2,3-d] pyrimicidin-2-yl 488. 4-Aminophenyl 4-aminopyrrolo [2,3-d] pyrimicidin-2-yl 489. Furan-2-yl 4-aminopyrrolo [2,3-d ] Hyrimicidin-2-yl 490. Thiophene-2-yl 4-aminohydro [2,3-d] hyrimidin-2-yl 491. Cyanomethylthio 4-aminohydro [2,3-d] hyrimidin-2-yl 492.2 -Aminoethylthio 4-aminohydro [2,3-d] perimicin-2-yl 493. 2-Quadinoethylthio 4-aminohydro [2,3-d] perimicin-2-yl 494. 2,3-d] Primicidin-2-yl 495. (1,3,4-thiadiazol-2-yl) thio-4-amido Nohydrolo [2,3-d] pyrimicidin-2-yl 496. Difluoromethylthio 4-aminohydrolo [2,3-d] pyrimicidin-2-yl 497. Hydrogen 4-aminochloro [2,3-d] hirimicidin-2-yl 498. Methyl 4-aminohydroxy [2,3-d] pyrimicidin-2-yl 499. n-butyl 4-aminohydroxy [2,3-d] hyrimicidin-2-yl 500. tert-butyl 4-aminohydroxy [2,3] -d] Primidin-2-yl 501. Trifluoromethyl 4-aminopropyl [2,3-d] pyrimidin-2-yl 502. Chloro-4-aminopropyl [2,3-d] pyrimidin-2-yl 503. Methylcarbonyl Oxy 4-aminohydroxy [2,3-d] perimidin-2-yl 504. Methoxy 4-aminohydroxy [2,3-d] perimidicin-2-yl 505. Hensothiazole-2-yl 4-aminohydroxy [2,3- d] Pyrimidin-2-yl 506. Cyano 4-aminopyrrolo [2,3-d] pyrimidin-2-yl Le

507. Phenyl 2-aminophthalicin-4-yl 508. 3-Methoxyphenyl 2-aminophthalicin-4-yl 509. 4-Methoxyphenyl 2-aminophthalicin-4-yl 510. 4-aminophenyl 2- Aminophthalicin-4-yl 511. Furan-2-yl 2-Aminophthalicin-4-yl 512. Thiophene-2-yl 2-Aminophthalicin-4-yl 513. Cyanomethylthio 2-aminophthalicin-4-yl 514. 2-aminoethylthio 2-aminophthalicin-4-yl 515. 2-quacinoethylthio 2-aminophthalicin-4-yl 516.fluoroalkylthio 2-aminophthalicin-4-yl 517. (1,3,4- Thiaceasol-2-yl) thio 2-aminophthalicin-4-yl 518.Fluoromethylthio 2-aminophthalicin-4-yl 519.Hydrogen 2-aminophthalicin-4-yl 520.Methyl 2-a Nophthalicin-4-yl 521. n-Phthyl 2-aminophthalicin-4-yl 522. tert-Butyl 2-aminophthalicin-4-yl 523. Trifluoromethyl 2-aminophthalicin-4-yl 524. Chloro-2-amino Phthalicin-4-yl 525. Methylcarboxyloxy 2-aminophthalicin-4-yl 526. Methoxy 2-aminophthalicin-4-yl 527. Hensothiazol-2-yl 2-aminophthalicin-4-yl 528. Cyano 2- Aminophateric-4-yl -------------------------------------------- -------------------------

[0057]

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[0058]

[Table 2] ---------------------------------------------- ----------------------- No. R¹ R^Two  -------------------------------------------------- ------------------- 529. Phenylfurin-2-yl 530. Phenyl 6-aminofurin-2-yl 531. Phenyl 4-aminoquinazodolin-2-yl 532 Phenyl 4-Hydroxyquinazolin-2-yl 533. Phenyl 4-Aminohydroxy [3,4-d] perimidin-6-yl 534. Phenyl 7-Hydroxyquinazolin-2-yl 535. Phenyl 4-aminophenyl [2,3-d] pyrimidin-2-yl 536. Phenyl 2-aminophthalicin-4-yl ----------------------- ----------------------------------------------

[0059]

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[0060]

[Table 3] ---------------------------------------------- ----------------------- No. R¹ R^Two  -------------------------------------------------- ------------------- 537. Phenylfurin-2-yl 538. Phenyl 6-aminofurin-2-yl 539. Phenyl 4-aminoquinazolidin-2-yl 540 Phenyl 4-Hydroxyquinazolin-2-yl 541.Phenyl 4-Aminopyrazo [3,4-d] perimidin-6-yl 542.Phenyl 7-Hydroxyquinazolin-2-yl 542. Phenyl 4-aminohydroxy [2,3-d] perimidin-2-yl 544. Phenyl 2-aminophthalicin-4-yl 545. Hydrogen furin-2-yl 546. Hydrogen 6-aminofurin-2-yl 547. Hydrogen 4 -Aminoquinazodolin-2-yl 548.Hydrogen 4-Hydroxyquinazodolin-2-yl 549.Hydrogen 4-Aminopyrazolo [3,4-d] pyrimicidin-6-yl 550. ] Primidin-2-yl 551. Hydrogen 4-aminopyrrolo [2,3-d] Remisin-2-yl 552. Hydrogen 2-aminophthalicin-4-yl ---------------------------------- -----------------------------------

[0061]

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[0062]

[Table 4] ---------------------------------------------- ----------------------- No. R¹ R^Two  -------------------------------------------------- ------------------- 553. Phenylfurin-2-yl 554. Phenyl 6-aminofurin-2-yl 555. Phenyl 4-aminoquinazolidin-2-yl 556 Phenyl 4-Hydroxyquinazolin-2-yl 557.Phenyl 4-Aminopyrazolo [3,4-d] perimidin-6-yl 558. Phenyl 4-aminohydroxy [2,3-d] perimidin-2-yl 560. Phenyl 2-aminophenyl-4-yl ----------------------- ----------------------------------------------

[0063]

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[0064]

[Table 5] ---------------------------------------------- ----------------------- No. R¹ R^Two  -------------------------------------------------- ------------------- 561. Phenylfurin-2-yl 562. Phenyl 6-aminofurin-2-yl 563. Phenyl 4-aminoquinazolin-2-yl 564 Phenyl 4-Hydroxyquinazolin-2-yl 565.Phenyl 4-Aminopyrazolo [3,4-d] perimidin-6-yl 566.Phenyl 7-Hydroxyquinazolin-2-yl 566. Phenyl 4-aminohydroxy [2,3-d] pyrimidin-2-yl 568. Phenyl 2-aminophthalicin-4-yl 569. 2-Amino-5-chlorothiazol-4-yl furin-2-yl 570. 2- Amino-5-chlorothiazol-4-yl 6-aminofurin-2-yl 571. 2-Amino-5-chlorothiazol-4-yl 4-aminoquinazolidin-2-yl 572. 2-Amino-5-chlorothiazol -4-yl 4-Hydroxyquinazodolin-2-yl 573. 2-amino-5-chlorothia Ethyl-4-yl 4-aminopyrazolo [3,4-d] pyrimicidin-6-yl 574. 2-Amino-5-chlorothiazol-4-yl 7-humanhydroxypyritol [2,3-d] pyrimicidin- 2-yl 575. 2-Amino-5-chlorothiazol-4-yl 4-aminohydro [2,3-d] pyrimidin-2-yl 576. 2-Amino-5-chlorothiazol-4-yl 2-aminophthalicin -4-yl ---------------------------------------------- -----------------------

[0065]

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[0066]

[Table 6] ---------------------------------------------- ----------------------- No. R¹ R^Two  -------------------------------------------------- ------------------- 577. 2-Aminothiazol-5-ylfurin-2-yl 578. 2-Aminothiazol-5-yl 6-aminofurin-2 -Yl 579. 2-Aminothiazol-5-yl 4-aminoquinazolidin-2-yl 580. 2-Aminothiazol-5-yl 4-Hydroxyquinazodolin-2-yl 581. 2-Aminothiazol-5-yl 4- Aminopyrazol [3,4-d] pyrimicidin-6-yl 582. 2-Aminothiazol-5-yl 7-Hthoxyhydroxy [2,3-d] pyrimicidin-2-yl 583. 2-Aminothiazol-5-yl 4-Aminofluoro [2,3-d] perimidin-2-yl 584. 2-Aminothiazol-5-yl 2-Aminophthalicin-4-yl ----------------- -------------------------------------------------- -

[0067]

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[0068]

[Table 7] ---------------------------------------------- ----------------------- No. R¹-A- R^Two  -------------------------------------------------- ------------------- 585. Phenylfurin-2-yl 586. Phenyl 6-aminofurin-2-yl 587. Phenyl 4-aminoquinazolin-2-yl 588 Phenol 4-Hydroxyquinazolin-2-yl 589. Phenol 4-Aminohydrazol [3,4-d] perimidin-6-yl 590. Phenyl 4-aminophenol [2,3-d] pyrimidin-2-yl 592. Phenyl 2-aminophenyl-4-yl ----------------------- ----------------------------------------------

[0069]

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[0070]

[Table 8] ---------------------------------------------- ----------------------- No. R¹-A- R^Two  -------------------------------------------------- ------------------ 593. ethynylfurin-2-yl 594. ethynyl 6-aminofurin-2-yl 595. ethynyl 4-aminoquinazolin-2-yl 596. Ethynyl 4-Hydroxyquinazolin-2-yl 597. Ethynyl 4-aminopyrazolo [3,4-d] pyrimidin-6-yl 598. Ethynyl 7-Hydroxypyrido [2,3-d] pyrimicidin-2-yl 699. Ethynyl 4-Aminochloro [2,3-d] perimidin-2-yl 600. Ethynyl 2-aminophthalicin-4-yl ------------------------ ---------------------------------------------

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.

Production method 1

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Production method 2

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Production method 3

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Wherein R ¹ , R ² , R ³ , A and n are
Each has the same meaning as described above, and R ^3a represents a protected carboxyl group; 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 .

The leaving group for X includes a halogen atom; a lower alkylsulfonyloxy group such as methylsulfonyloxy and ethylsulfonyloxy; a halogeno lower alkylsulfonyloxy group such as trifluoromethylsulfonyloxy and benzenesulfonyloxy and toluenesulfonyloxy. And an arylsulfonyloxy group.

The general formulas [1a], [1b], [2],
The compounds of [3], [4], [5] and [6] can also be used as salts, and the salts thereof are the same as those described for the salts of the compound of general formula [1]. Is mentioned.

As the compound of the formula [4] or a salt thereof, a reactive derivative thereof can be used. For example, trimethylsilanyl, dimethylsilanediyl, isopropyldimethylsilanyl, trimethoxysilanyl, dimethoxymethylsilyl Organic silyl groups such as dimethyl, dimethylmethoxysilanyl or dimethoxysilanediyl or dimethoxyphosphinyl, 1,3,2-dioxophosphorane-
2-yl, 4-methyl-1,3,2-dioxophosphoran-2-yl or 1,3,2-dioxophosphorinane-
Examples include compounds in which an organic phosphorus group such as 2-yl is bonded to an amino group that is a reaction site.

As the compound of the formula [5] or a salt thereof, a reactive derivative thereof can be used. For example, acid halides, acid anhydrides, mixed acids described in JP-A-59-93085 and the like can be used. Examples thereof include anhydrides, active acid amides, active esters, active thioloesters, or acid azides, or reactive derivatives of the compound of the general formula [5] with the Vilsmeier reagent. Next, a method for producing the compound of the general formula [1] or a salt thereof will be described in detail.

Production Method 1 A compound of the general formula [2] 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 of the solvent include water; ethers such as tetrahydrofuran, diethyl ether and dioxane; halogenated compounds such as methylene chloride and chloroform. Hydrocarbons; alcohols such as methanol and ethanol; amides such as N, N-dimethylformamide and N, 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. The solvent may be used as a mixture.

The base optionally used in this reaction includes, for example, alkali hydroxide, alkali carbonate, alkali hydrogencarbonate, 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 and the like. In addition, as a deoxidizing agent used as needed,
For example, propylene oxide and the like can be mentioned.

The amount of the compound represented by the general formula [3] or a salt thereof is at least equimolar to the compound represented by 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. Further, the reaction temperature and the reaction time are not particularly limited, but usually, the reaction may be carried out at −20 ° C. to 100 ° C. for 5 minutes to 50 hours.

Production Method 2 A compound of the general formula [4] or a salt thereof or a reactive derivative thereof is reacted with a compound of the general formula [5] or 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. As the base used as necessary in this reaction, for example, 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 diisopropyl Amide, lithium bistrimethylsilylamide, 1,8-diazabicyclo [5.4.0] -7-
Undecene and 1,5-diazabicyclo [4.3.0]-
Organic bases such as 5-nonene; and inorganic bases such as sodium hydride, alkali hydroxide, alkali carbonate, sodium bicarbonate and potassium bicarbonate.

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 represented by the general formula [5] or a salt thereof or the reactive derivative thereof is 0.9 times or more, preferably 0.9 mol or more with respect to the compound of the general formula [4] or the salt or the reactive derivative thereof. ~ 1.5
It is twice the mole. The amounts of the base and the condensing agent used as required are 0.5 to 2 with respect to the compound of the general formula [4] or a salt thereof or a reactive derivative thereof, respectively.
More than twice and equimolar. The reaction temperature and the reaction time are not particularly limited, but usually, the reaction may be carried out at −50 to 80 ° C. for 5 minutes to 30 hours.

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

(2) Oxidation and Reduction Alternatively, the compound of the general formula [1a] or its salt is subjected to an oxidation reaction conventionally used in the field of cephem compounds to obtain the compound of the 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 compounds, to obtain a compound of the general formula [1a].
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.

Compounds of general formula [4] or [5] or their salts or reactive derivatives thereof in the above-mentioned production method; and compounds of general formula [2], [3] or [6] or their 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; a compound of the general formula [3] or a salt thereof; a compound of the general formula [4] or a salt thereof or a raw material for producing the compound of the present invention. 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 (P
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
, P. 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 starting material compounds. it can.

(C) The compound of general formula [4] which is a starting compound in the production method 2 or a salt thereof or a reactive derivative thereof; , Production 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, a carboxyl group or a hydroxyl group is present in addition to the reaction site, these groups are previously converted to a conventional method. Therefore, it may be protected and then eliminated after the reaction 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. Is also good.

When the compound of the present invention is used as a medicament, excipients usually used in the preparation of pharmaceutical preparations, usual pharmaceutical carriers and formulation auxiliaries such as diluents may be mixed as appropriate. , 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. When the compound of the present invention is used as a medicine, particularly as an antibacterial agent, it is preferable to make it into an injection form. For the production of injections, it may be carried out by a conventional method in the field,
For example, the compound of the present invention may be dissolved in water, filtered aseptically, dispensed into vials, and lyophilized to give a lyophilized preparation for injection. In addition, the administration method, dosage and number of administrations can be appropriately selected according to the age, body weight and condition of the patient. Usually, for adults, oral or parenteral (for example, injection, drip or rectal site Etc.)
Depending on the administration, 0.1 to 100 mg / kg per day may be administered once or several times.

Next, the antibacterial action 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
(Mueller Hintonagar) medium (manufactured by Difco) at 37 ° C
After 18 to 20 hours of culture, the presence or absence of bacterial growth was observed, and the MIC was used with the minimum drug concentration at which bacterial growth was inhibited.
(μg / mL). Table 9 shows the results.

[0096]

[Table 9]

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

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. , M-
After adding 2.30 g of chloroperbenzoic acid (purity 70%), 90 ° C at 90 ° C
Stir for minutes. Saturated aqueous sodium bicarbonate solution
Add 200 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 -phenylacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide are obtained. IR (KBr) cm ^-1 ; 1795,1735,1685

Reference Example 2 (1) 7-phenylacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (1.00 g) was suspended in methylene chloride (20 mL) and pyridine (370 mg) was added at -30 ° C. And phosphorus pentachloride 660mg
And stirred for 1 hour under ice-cooling.
Add 6 mL and stir for 1 hour under ice cooling. 20 mL of water is added to the reaction solution, and the organic layer is separated. After adding 20 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. (A solution) (2) 200 mg of 2-furanacetic acid was dissolved in 10 mL of tetrahydrofuran, and 1-hydroxybenzotriazole 240
mg and dicyclohexylcarbodiimide (320 mg) are sequentially added, and the mixture is stirred at 20 ° C. for 1 hour. (B solution) (3) The B solution is added to the A solution under ice cooling, and the mixture is stirred at 20 ° C. for 12 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; toluene: ethyl acetate = 20: 1) to give 7- (furan-2-yl) acetamido-3-. Trifluoromethylsulfonyloxy-
400 mg of 3-cephem-4-carboxylic acid diphenylmethyl ester are obtained. IR (KBr) cm ^-1 ; 1775,1765,1735,1700

Reference Example 3 The following compounds were obtained in the same manner as in Reference Examples 2 (1) to (3). 7- (difluoromethylthio) acetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-
Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1730,1695 7-[(R) -2-formyloxy-2-phenylacetamido] -3-trifluoromethylsulfonyloxy-3-cephem-4 -Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1695 7- (4-methoxyphenylacetamido) -3-trifluoromethylsulfonyloxy-3-cephem-4-
Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1773,1734,1697 7- (3-methoxyphenylacetamido) -3-trifluoromethylsulfonyloxy-3-cephem-4-
Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1773,1733,1695 7-[(Z) -2-hydroxyimino-2-phenylacetamido] -3-trifluoromethylsulfonyloxy-3-cephem-4 -Carboxylic acid diphenylmethyl ester IR (KBr) cm-1; 1782,1733,1678

Reference Example 4 (1) 7-phenylacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (2.00 g) was suspended in methylene chloride (40 mL) and pyridine (740 mg) was added at -30 ° C. And 1.32 g of phosphorus pentachloride
And stirred for 1 hour under ice-cooling.
Add 12 mL and stir for 1 hour under ice cooling. 40 mL of water in 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. (A2 solution) (2) 513 mg of 1-phenyl-1-cyclopropanecarboxylic acid
Was dissolved in 10 mL of methylene chloride, and under ice-cooling, 401 mg of oxalyl chloride and 0.2 m of N, N-dimethylformamide
L are added in sequence and stirred at 20 ° C. for 1 hour. (B2 solution) (3) The B2 solution is added to the A2 solution under ice cooling, and the mixture is stirred at 20 ° C for 12 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; toluene: ethyl acetate = 30: 1) to give 7- (1-phenyl-1-cyclopropanecarboxamide). 830 mg of -3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester are obtained. IR (KBr) cm ^-1 ; 1810,1735,1685,1655

Reference Example 5 The following compounds were obtained in the same manner as in Reference Examples 4 (1) to (3). .7- (2,2-difluoro-2-phenylacetamide)
-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KB
r) cm ^-1 ; 1785,1736,1708 7- (4-t-butoxycarbonylaminophenylacetamido) -3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1780,1730,1696 7- (3-methoxyphenylacetamido) -3-trifluoromethylsulfonyloxy-3-cephem-4
Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1773,1733,1695

Reference Example 6 (1) 1.00 g of 7-phenylacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester was suspended in 20 mL of methylene chloride, and 370 mg of pyridine was added at -30 ° C. And phosphorus pentachloride 660mg
And stirred for 1 hour under ice-cooling.
Add 6 mL and stir for 1 hour under ice cooling. 20 mL of water is added to the reaction solution, and the organic layer is separated. After adding 20 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. (A3 solution) (2) thiophene-2-carboxylic acid 220 mg in methylene chloride 4m
Then, 156 mg of N-methylmorpholine and 280 mg of 2-chloro-4,6-dimethoxy-1,3,5-triazine are sequentially added under ice cooling, and the mixture is stirred at 20 ° C. for 2 hours. (B3 solution) (3) The B3 solution is added to the A3 solution under ice cooling, and the mixture is stirred at 20 ° C for 12 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; toluene: ethyl acetate = 30: 1) to give 7- (thiophen-2-yl) acetamido-3-. 830 mg of trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester are obtained.

Reference Example 7 7-phenylacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (5.00 g) was suspended in methylene chloride (100 mL). 3.3 g of phosphorus chloride was added, and the mixture was stirred under ice-cooling for 30 minutes, and then methanol at 30 ° C.
Add L and stir for 1 hour under ice cooling. 100 mL of water is added to the reaction solution, and the organic layer is separated. After adding 20 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. To this solution, at -20 ° C, 670 mg of cyanoacetic acid and 1.1 g of pyridine
And 1.6 g of phosphorus oxychloride, and the mixture is stirred at the same temperature for 30 minutes. 100 mL of water is added to the reaction solution, and the organic layer is separated. After adding 20 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, diethyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration to give 7-cyanoacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylate diphenylmethyl. 3.8 g of the ester are obtained. IR (KBr) cm ^-1 ; 1800,1745,1685,1655

The following compounds are obtained in the same manner. 7-cyanomethylthioacetamide-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1775,1736,1685 7-propargylthioacetamide-3-trifluoro Methylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1794,1774,1736,1686 7- (1,3,4-thiadiazol-2-ylthio) acetamide- 3-trifluoromethylsulfonyloxy-3
-Cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1794,1735,1686

Reference Example 8 1.00 g of 7-cyanoacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester was dissolved in 10 mL of methylene chloride and 10 mL of acetonitrile, and m-chloroform was added under ice-cooling. After adding 400 mg of perbenzoic acid (purity 70%), the mixture is 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, diethyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration to give 7-cyanoacetamido-3-trifluoromethylsulfonyloxy-
1.2 g of 3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide are obtained. IR (KBr) cm ^-1 ; 1802,1734,1664

The following compounds are obtained in the same manner. 7- (furan-2-yl) acetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1802,1735,1686,1655 7- (difluoromethylthio) acetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-
Carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1662 7-[(R) -2-formyloxy-2-phenylacetamido] -3-trifluoromethylsulfonyloxy-3 -Cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1802,1727,1673 7- (4-methoxyphenylacetamido) -3-trifluoromethylsulfonyloxy-3-cephem- 4-
Carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1792,1734,1654 7-[(Z) -2-hydroxyimino-2-phenylacetamido] -3-trifluoromethylsulfonyloxy-3 -Cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1802,1734,1670 7- (1-Phenyl-1-cyclopropanecarboxamide) -3-trifluoromethylsulfonyloxy- 3
-Cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1810,1735,1684

7- (2,2-difluoro-2-phenylacetamido) -3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1801,1735,1696 ・ 7- (4-t-butoxycarbonylaminophenylacetamide) -3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ⁻¹ 1796,1734,1700,1664,1654 7- (3-methoxyphenylacetamido) -3-trifluoromethylsulfonyloxy-3-cephem-4
-Carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1792,1735,1684,1653,16007- (thiophen-2-yl) acetamido-3-trifluoromethylsulfonyloxy-3-cephem -4-
Carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1801,1735,1655 7-cyanomethylthioacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β- Oxide IR (KBr) c
m ^-1 ; 1802,1735,1654 7-propargylthioacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide-7-
(1,3,4-thiadiazol-2-ylthio) acetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β
-Oxide IR (KBr) cm ^-1 ; 1803,1735,1685

Reference Example 9 15.00 g of 7-phenylacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester was suspended in 300 mL of methylene chloride, and 5.8 g of pyridine and pentane were added at -30 ° C. After adding 9.9 g of phosphorus chloride and stirring for 1 hour under ice cooling, 90 mL of methanol at -30 ° C
And stirred under ice cooling for 1 hour. 225 mL of water is added to the reaction solution, and the organic layer is separated. After adding 200 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. To this solution are added 6.2 g of heptanoic acid, 6.4 g of pyridine and 9.5 g of phosphorus oxychloride at −20 ° C., and the mixture is stirred at the same temperature for 1 hour. 200 mL of water is added to the reaction solution, and the organic layer is separated. 100 mL of water is added to the separated organic layer, the pH is adjusted to 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, and the obtained residue was purified by silica gel chromatography (eluent; toluene: ethyl acetate = 15: 1) to give 7-hexylcarboxamide-3-trifluoromethylsulfonyloxy-3. 5.2 g of cephem-4-carboxylic acid diphenylmethyl ester are obtained. IR (KBr) cm ^-1 ; 1780,1736,1686

In the same manner, the following compound is obtained. 7-trifluoromethylacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1798,1736,1703 7-ethynylcarboxamide-3-trifluoro Methylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1794,1735,1654 7-methoxyacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid Diphenylmethyl ester IR (KBr) cm ^-1 ; 1794,1736,1686,1677 7-acetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1788,1728,1670 7-cyclopropanecarboxamide-3-trifluoromethylsulfonyloxy-3-cephem-4- Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1779,1735,1679

7-acetoxyacetamide-3-trifluoromethylsulfonyloxy-3-cephem-4-
Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1772,1752,1738,1709 3-trifluoromethylsulfonyloxy-7-vinylcarboxamide-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1793,1734,1685,1676 7-neopentylcarboxamide-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1775,1734,1679 7-chloroacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1793,1734,1684 7-propionamido-3-trifluoromethylsulfonyloxy -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1795,1734,1655,1522

Reference Example 10 480 mg of 7-acetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester was dissolved in 5 mL of methylene chloride, and m-chloroperbenzoic acid (purity: After adding 234 mg (70%), the mixture is stirred at the same temperature for 10 minutes. 20 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, diisopropyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration to give 7-acetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylate diphenylmethyl. 420 mg of ester-1β-oxide are obtained. IR (KBr) cm ^-1 ; 1790,1735,1655

In the same manner, the following compound is obtained. 7-trifluoromethylacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1794,1734,1670 7-hexylcarboxamide- 3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1792,1736,1654 7-cyclopropanecarboxamide-3-trifluoromethylsulfonyloxy -3-Cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1794,1735,1654 7-ethynylcarboxamide-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid Acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1799,1726,1640 7-acetoxya Cetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1802,1735,1685,1676

3-trifluoromethylsulfonyloxy-7-vinylcarboxamide-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1793,1736,1664 7-neopentyl Carboxamide-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1735,1655 7-chloroacetamido-3-trifluoromethylsulfonyl Oxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1798,1734,1667 7-methoxyacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4- carboxylic acid diphenylmethyl ester -1β- oxide ^{IR (KBr) cm -1; 1802,1735,1686,1676,1655} · 7- propionic Bromide 3 trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester -1β- oxide IR (KBr) cm ^-1; 1794,1735,1655

Example 1 140 mg of 4-aminopyrazolo [3,4-d] pyrimidine-6-thiol was suspended in 5 mL of methanol, and 28% (W / W
W) After adding 160 mg of a methanol solution of sodium methoxide, the mixture is stirred at the same temperature for 10 minutes. Then, N, N-dimethylformamide (20 mL) and acetonitrile (10 mL) were added, and at -30 ° C, 7-cyanoacetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide (500 mg)
And then stirred at −10 ° C. for 10 minutes. The reaction solution was added to a mixture of 50 mL of ethyl acetate and 50 mL of water, and pH was adjusted with 2 mol / L hydrochloric acid.
After adjusting to 5, 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, ethyl acetate was added to the obtained residue, and the precipitated crystals were collected by filtration to give 3- (4
-Aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-cyanoacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide 23
Obtain 0 mg. IR (KBr) cm ^-1 ; 1785,1730,1665

Examples 2 to 30 In the same manner as in Example 1, the compounds shown in Tables 10 to 14 are obtained.

[0117]

[Table 10]

[0118]

[Table 11]

[0119]

[Table 12]

[0120]

[Table 13]

[0121]

[Table 14]

The names and properties of the compounds No. 2 to No. 30 in the table are shown below. No. 2; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1
β-oxide IR (KBr) cm ^-1 ; 1795,1735,1655 No. 3; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-[(Z) -2-hydroxy Imino
2-phenylacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1685 No.4; 3- (4-aminopyrazolo [3,4-d ] Pyrimidin-6-ylthio) -7- (difluoromethylthio) acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1785,1730,1655 No.5; 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 No.6; 3- (4-aminopyrazolo [3,4-d] Pyrimidin-6-ylthio) -7- (4-methoxyphenylacetamido) -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1785,1720,1655 No.7; 3 -(4-Aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (1-phenyl-1-cyclopropanecarboxamide) -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR ( KBr) cm ^-1 ; 1795,1720,1670

No. 8; 3- (4-aminopyrazolo [3,4-
d] pyrimidin-6-ylthio) -7- (2,2-difluoro-2-phenylacetamido) -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1785,1720 , 1655 No. 9; diphenylmethyl 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (4-t-butoxycarbonylaminophenylacetamide) -3-cephem-4-carboxylate Ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1720,1650 No.10; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (3-methoxyphenylacetamide ) -3-Cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1735,1655 No. 11; 3- (4-aminopyrrolo [2,3-d] pyrimidine-2 -Ylthio) -7-phenylacetamido-3-cef Beam-4-carboxylic acid diphenylmethyl ester -1
β-oxide IR (KBr) cm ^-1 ; 1794,1734,1654 No.12; 3- (quinolin-2-ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1794,1732,1684,1653 No.13; 3- (naphthyridin-2-ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1735,1655

No. 14; 3- (4-aminopyrazolo [3,4-
d] pyrimidin-6-ylthio) -7- (thiophen-2
-Yl) acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1794,1735,1654 No.15; 3- (4-aminopyrazolo [3,4-d] Pyrimidin-6-ylthio) -7- (furan-2-yl) acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ⁻¹ ; 1793,1734,1670,1654,1636 No. 16; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-cyanomethylthioacetamide-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1790, 1735, 1655 No. 17; diphenylmethyl 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (propargylthio) acetamido-3-cephem-4-carboxylate Ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1735,1655 No. 18; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (1,3,4-thiadiazole-
2-ylthio) acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide

No. 19: 7-phenylacetamido-3-
(Purin-6-ylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1685 No. 20; 3- (6-aminopurine-2- Ilthio) -7-
Phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1735,1655 No. 21; 3- (2-aminopurin-6-ylthio) -7-
Phenylacetamide-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1675,1635 No.22; 3- (6-hydroxypurin-2-ylthio)-
7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1790,1735,1685 No.23; 3- (2-hydroxypurin-6-ylthio)-
7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1655 No. 24; 3- (9-aminopurin-6-ylthio)- 7-
Phenylacetamide-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1800,1735,1685

No. 25; 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. 26; 3- (4-hydroxyquinazolin-2-ylthio) -7-phenylacetamide-3 -Cephem-4-
Carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1790,1735,1685 No.27; 3- (4-aminoquinazolin-2-ylthio)-
7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1730,1670 No.28; 3- (2-aminopteridin-4-ylthio)-
7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1795,1735,1670 No. 29; 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 No. 30; 7-phenyl Acetamide-3- (7-hydroxypyrido [2,3-d] pyrimidin-2-ylthio) -3
-Cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide

Example 31 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-cyanoacetamido-3-cephem-4
-Dissolve 200 mg of carboxylic acid diphenylmethyl ester-1β-oxide in 2 mL of N, N-dimethylformamide, add 120 mg of phosphorus trichloride at -30 ° C, and stir at the same temperature for 1 minute. The reaction solution is added to a mixed solution 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, methylene chloride was added to the obtained residue, and the precipitated crystals were collected by filtration to give 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio)-.
100 mg of 7-cyanoacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester are obtained. IR (KBr) cm ^-1 ; 1786,1654,1578

Examples 32 to 60 In the same manner as in Example 31, the compounds shown in Tables 15 to 19 are obtained.

[0129]

[Table 15]

[0130]

[Table 16]

[0131]

[Table 17]

[0132]

[Table 18]

[0133]

[Table 19]

The names and properties of the compounds No. 32 to No. 60 in the table are shown below. No. 32; 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.33; 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.34; 3- (4-aminopyrazolo [3 , 4-d] Pyrimidin-6-ylthio) -7- (difluoromethylthio) acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1735,1655 No.35; (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-[(R) -2-formyloxy-
2-phenylacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1730,1635 No.36; 3- (4-aminopyrazolo [3,4-d] pyrimidine-6 -Ylthio) -7- (4-methoxyphenylacetamido) -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1655 No.37; 3- (4-aminopyrazolo [3 , 4-d] Pyrimidin-6-ylthio) -7- (1-phenyl-1-cyclopropanecarboxamide) -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1795,1735,1655

No. 38; 3- (4-aminopyrazolo [3,4-
d] pyrimidin-6-ylthio) -7- (2,2-difluoro-2-phenylacetamido) -3-cephem-4-
Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1795,1735,1655 No.39; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (4-t-butoxy) Carbonylaminophenylacetamido) -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1793,1734,1718,1686,1654,1648,1638 No.40; 3- (4-aminopyrazolo [3 , 4-d] Pyrimidin-6-ylthio) -7- (3-methoxyphenylacetamido) -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1735,1655 No.41; 3- (4-aminopyrrolo [2,3-d] pyrimidin-2-ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester No. 42; 3- (quinolin-2-ylthio)- 7-phenylacetamido-3-cephem-4-carbo Acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1734,1663 No.43; 3- (naphthyridin-2-ylthio) -7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester

No. 44; 3- (4-aminopyrazolo [3,4-
d] pyrimidin-6-ylthio) -7- (thiophen-2
-Yl) acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1784,1734,1636,1590 No.45; 3- (4-aminopyrazolo [3,4-d] pyrimidine- 6-ylthio) -7- (furan-2-yl) acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1735,1655 No. 46; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-cyanomethylthioacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1720,1655 No.47; (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (propargylthio) acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1720,1655 No. 48; 3- (4-aminopyrazolo [3,4-d] pyrimidine- - ylthio) -7- (1,3,4-thiadiazole -
2-ylthio) acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1780,1735,1655

No. 49; 7-phenylacetamido-3-
(Purin-6-ylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1735,1675 No. 50; 3- (6-aminopurin-2-ylthio) -7 −
Phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1675 No.51; 3- (2-aminopurin-6-ylthio) -7-
Phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1675 No.52; 3- (6-hydroxypurin-2-ylthio)-
7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1685 No.53; 3- (2-hydroxypurin-6-ylthio)-
7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1650 No.54; 3- (9-aminopurin-6-ylthio) -7-
Phenylacetamide-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1670

No. 55; 7-phenylacetamido-3-
(Pyrazolo [3,4-d] pyrimidin-4-ylthio) -3
-Cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1670 No. 56; 3- (4-hydroxyquinazolin-2-ylthio) -7-phenylacetamido-3-cephem-4 −
Carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1795,1735,1685 No.57; 3- (4-aminoquinazolin-2-ylthio)-
7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785, 1730, 1655 No. 58; 3- (2-aminopteridin-4-ylthio)-
7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1790,1735,1670 No.59; 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.60; 7-phenylacetamido-3- (7-hydroxypyrido [2,3-d] pyrimidin-2-ylthio) -3
-Cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1735,1670

Example 61 3- (4-aminopyrazolo [3,4-d] pyrimidine-6
(Ilthio) -7-cyanoacetamido-3-cephem-
4-Carboxylic acid diphenylmethyl ester (100 mg) is dissolved in methylene chloride (4.0 mL) and anisole (1.0 mL), trifluoroacetic acid (2.0 mL) is added under ice cooling, and the mixture is stirred at the same temperature for 10 minutes. The reaction solution is concentrated under reduced pressure, 10 mL of diisopropyl ether is added to the obtained residue, 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 concentrated under reduced pressure to about half the solvent. Purification of the concentrated solution by reverse phase column chromatography (eluent; 5% acetonitrile aqueous solution) gives 3- (4-aminopyrazolo [3,4-
d] Pyrimidin-6-ylthio) -7-cyanoacetamido-3-cephem-4-carboxylate 42 mg are obtained. IR (KBr) cm ^-1 ; 1770,1760

Examples 62 to 90 The compounds of Tables 20 to 24 are obtained in the same manner as in Example 61.

[0141]

[Table 20]

[0142]

[Table 21]

[0143]

[Table 22]

[0144]

[Table 23]

[0145]

[Table 24]

The names and properties of the compounds No. 62 to No. 90 in the table are shown below. No. 62; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-phenylacetamido-3-
Sodium cephem-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. 63: 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-[(Z)- 2-Hydroxyimino-2-phenylacetamide] -3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1755,1655 NMR (D ₂ O) δ value; 3.68 (1H, d, J = 17 Hz) , 3.98 (1H, d, J = 17Hz),
5.28 (1H, d, J = 5Hz), 5.81 (1H, d, J = 5Hz), 7.50 (5H, s), 8.05
(1H, s) No. 64; sodium 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 = 17 Hz), 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, JHF = 56Hz), 7.12 (1H, s) No.65; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-[(R) -2-hydroxy -2-
Phenylacetamide] -3-cephem-4-carboxylate sodium 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) No. 66; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (4-methoxyphenylacetamide)- Sodium 3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1770,1655 No.67; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (1-phenyl) -1-cyclopropanecarboxamide) -3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1775,1760,1655

No. 68; 3- (4-aminopyrazolo [3,4-
d] pyrimidin-6-ylthio) -7- (2,2-difluoro-2-phenylacetamido) -3-cephem-4-carboxylic acid sodium IR (KBr) cm ^-1 ; 1775,1720,1655 No.69; Sodium 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (4-aminophenylacetamido) -3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1765,1595 No. 70; sodium 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (3-methoxyphenylacetamido) -3-cephem-4-carboxylate IR (KBr) cm ^-1 1770,1595 No.71; 3- (4-aminopyrrolo [2,3-d] pyrimidin-2-ylthio) -7-phenylacetamido-3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1763,1589 No. 72; 3- (quinolin-2-ylthio) -7-phenylacetamido-3-se E beam 4-carboxylate ^{IR (KBr) cm -1; 1774,1763,1655,1648,1610} No.73; 3- ( naphthyridin-2-ylthio) -7-phenylacetamido-3-cephem-4 Sodium carboxylate IR (KBr) cm ^-1 ; 1775,1655,1600

No. 74; 3- (4-aminopyrazolo [3,4-
d] pyrimidin-6-ylthio) -7- (thiophen-2
-Yl) acetamide-3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1765,1654,1594 No.75; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) Sodium -7- (furan-2-yl) acetamido-3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1775,1750,1635 No.76; 3- (4-aminopyrazolo [3,4-d ] Pyrimidin-6-ylthio) -7- (cyanomethylthio) acetamido-3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1770,1655,1595 No.77; 3- (4-aminopyrazolo [3 , 4-d] pyrimidin-6-ylthio) -7- (propargylthio) acetamido-3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1760,1655,1595 No.78; 3- (4 -Aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7- (1,3,4-thiadiazole-
Sodium 2-ylthio) acetamido-3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1775,1685,1595

No. 79; 7-phenylacetamido-3-
Sodium (purine-6-ylthio) -3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1770,1655 NMR (D ₂ O) δ value; 3.46 (1H, d, J = 18 Hz), 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. 80; 3- (6-aminopurin-2-ylthio) -7-
Sodium 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. 81; 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 = 17Hz), 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. 82; 3- (6-hydroxypurin-2-ylthio)-
7-Phenylacetamido-3-cephem-4-carboxylate sodium 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. 83; 3- (2-hydroxypurin-6-ylthio)-
7-Phenylacetamido-3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1770,1615 NMR (D ₂ O) δ value; 3.54 (1H, d, J = 17Hz), 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. 84; 3- (9-aminopurin-6-ylthio) -7-
Phenylacetamido-3-cephem-4-carboxylate sodium 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. 85; 7-phenylacetamido-3-
(Pyrazolo [3,4-d] pyrimidin-4-ylthio) -3
- cephem-4-carboxylate ^{IR (KBr) cm -1; 1770,1655} NMR (D 2 O) δ value; 3.49 (1H, d, J = 18Hz), 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.86; 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.87; 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 = 17Hz), 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.88; 3- (2-aminopteridin-4-ylthio)-
7-Phenylacetamido-3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 ; 1770,1615 NMR (D ₂ O) δ value; 3.59 (1H, d, J = 17Hz), 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. 89; 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. 90; 7-phenylacetamido-3- (7-hydroxypyrido [2,3-d] pyrimidin-2-ylthio) -3
-Cephem-4-carboxylate IR (KBr) cm ^-1 ; 1775,1665

Example 91 117 mg of 4-aminopyrazolo [3,4-d] pyrimidine-6-thiol was suspended in 3 mL of methanol, and 28% (W / W
W) After adding 135 mg of a methanol solution of sodium methoxide, the mixture is stirred at the same temperature for 10 minutes. Next, 7 mL of N, N-dimethylformamide and 2 mL of acetonitrile were added, and -3 was added.
After adding 400 mg of 7-acetamido-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide at 0 ° C.,
Stir at 10 ° C for 10 minutes. The reaction solution is added to a mixed solution of 50 mL of ethyl acetate and 50 mL of water, adjusted to pH 2 with 2 mol / L 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, diethyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration to give 7-acetamido-3- (4-aminopyrazolo [3,4-d] pyrimidine-
260 mg of 6-ylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide are obtained. IR (KBr) cm ^-1 ; 1793,1734,1684,1670,1654

Examples 92 to 103 The compounds of Tables 25 to 26 are obtained in the same manner as in Example 91.

[0153]

[Table 25]

[0154]

[Table 26]

The names and properties of the compounds No. 92 to No. 103 in the table are shown below. No. 92; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-trifluoromethylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1786,1726,1664 No. 93; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-hexylcarboxamide-3
-Cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1794,1734,1654 No.94; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-cyclopropanecarboxamide-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1782,1734,1654 No.95; 3- (4-aminopyrazolo [3,4- d] pyrimidin-6-ylthio) -7-neopentylcarboxamide-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1794,1735,1685,1654,1639 No.96 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-chloroacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β
-Oxide IR (KBr) cm- ¹ ; 1783,1685, 1670, 1654, 1648, 1638 No. 97; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-propionamide- 3-cephem-4-carboxylic acid diphenylmethyl ester-1β-
Oxide IR (KBr) cm ^-1 ; 1781,1734,1654,1648

No. 98: 3- (4-aminopyrazolo [3,4-
d] pyrimidin-6-ylthio) -7-ethynylcarboxamide-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ⁻¹ ; 1794,1654,1648,1637,1578 No.99; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-acetoxyacetamide-3-
Cephem-4-carboxylic acid diphenylmethyl ester-
1β-oxide IR (KBr) cm ^-1 ; 1793,1734,1685,1654,1636,1587 No.100; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-vinylcarboxamide -3-
Cephem-4-carboxylic acid diphenylmethyl ester-
1β-oxide IR (KBr) cm ^-1 ; 1794,1654,1643,1637,1629,1578 No. 101; 7-acetamido-3- (4-aminopyrrolo
[2,3-d] pyrimidin-2-ylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1793,1654,1648,1637,1571 No.102; 7-acetamido-3- (4-amino-2-quinazolylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide IR (KBr) cm ^-1 ; 1793,1654,1648,1637,1617,1534 No. 103; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-methoxyacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1
β-oxide IR (KBr) cm ^-1 ; 1794,1685,1676,1654,1648,1637,1578

Example 104 3- (4-aminopyrazolo [3,4-d] pyrimidine-6
(Ilthio) -7-acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester-1β-oxide 27
0 mg was dissolved in N, N-dimethylformamide 3 mL, and -30
After adding 94 mg of phosphorus trichloride at 0 ° C, the mixture is stirred at the same temperature for 1 minute. The reaction solution is added to a mixed solution 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, methylene chloride was added to the obtained residue, and the precipitated crystals were collected by filtration to give 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-. 210 mg of acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester are obtained. IR (KBr) cm ^-1 ; 1785,1734,1685,1654,1648

Examples 105 to 116 The compounds of Tables 27 to 28 are obtained in the same manner as in Example 104.

[Table 27]

[0159]

[Table 28]

The names and properties of the compounds No. 105 to No. 116 in the table are shown below. No. 105; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-trifluoromethylacetamide-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1786,1701,1685,1654,1638 No.106; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-hexylcarboxamide-3
-Cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1786,1735,1654 No.107; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-cyclo Propanecarboxamide-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1786,1734,1654,1637 No.108; 3- (4-aminopyrazolo [3,4-d] pyrimidine-6- (Irthio) -7-neopentylcarboxamide-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1786,1735,1719,1686,1654,1638 No.109; 3- (4-aminopyrazolo [ 3,4-d] pyrimidin-6-ylthio) -7-chloroacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1786,1734,1685,1676,1654,1637 No. 110; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7 -Propionamide-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1786,1735,1654

No. 111; 3- (4-aminopyrazolo [3,4
-D] pyrimidin-6-ylthio) -7-ethynylcarboxamide-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1785,1654,1578 No.112; 3- (4-aminopyrazolo [ 3,4-d] pyrimidin-6-ylthio) -7-acetoxyacetamide-3-
Cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1786,1735,1686,1654,1637,1578 No.113; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio ) -7-Vinylcarboxamide-3-
Cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1786,1735,1654,1629,1578 No.114; 7-acetamido-3- (4-aminopyrrolo
[2,3-d] pyrimidin-2-ylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1782,1654,1648,1637,1570,1560 No.115; Acetamide-3- (4-amino-2-quinazolylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1782,1654,1648,1637,1618,1541,1534 No.116; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-methoxyacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; 1786,1654,1648, 1637,1589

Example 117 3- (4-aminopyrazolo [3,4-d] pyrimidine-6
(Ilthio) -7-acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester (200 mg) was dissolved in methylene chloride (4.0 mL) and anisole (1.0 mL), and trifluoroacetic acid (2.0 mL) was added under ice-cooling. Stir for minutes. The reaction solution is concentrated under reduced pressure, 10 mL of diethyl ether is added to the obtained residue, 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 concentrated under reduced pressure to about half the solvent. Purification of the concentrate by reverse phase column chromatography (eluent: 2.5% acetonitrile aqueous solution) gives 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-acetamido-3-cephem-
45 mg of sodium 4-carboxylate are obtained. IR (KBr) cm ^-1 ; 1774,1594 NMR (D ₂ O) δ value; 2.11 (3H, s), 3.61 (1H, d, J = 16 Hz), 3.97 (1H,
d, J = 16Hz), 5.29 (1H, d, J = 5Hz), 5.71 (1H, d, J = 5Hz), 8.00 (1
H, s)

Examples 118 to 129 The compounds of Tables 29 to 30 are obtained in the same manner as in Example 117.

[0164]

[Table 29]

[0165]

[Table 30]

The names and properties of the compounds No. 118 to No. 129 in the table are shown below. No. 118; sodium 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-trifluoromethylacetamide-3-cephem-4-carboxylate IR (KBr) cm ^-1 ; 1773, 1685,1654,1636,1595 NMR (D ₂ O) δ value; 3.2-4.2 (4H, m), 5.32 (1H, d, J = 5 Hz), 5.75 (1
H, d, J = 5Hz), 7.92 (1H, s) No. 119; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-hexylcarboxamide-3
- cephem-4-sodium IR (KBr) carboxylic acids _{^{cm -1; 1763,1654,1590 NMR (D 2}} O) δ value; 1.4-2.6 (13H, m), 3.2-4.2 (2H, m), 5.0- 6.0
(2H, m), 7.97 (1H, s) No. 120; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-cyclopropanecarboxamide-3-cephem-4-carboxylic acid Sodium IR (KBr) cm ^-1 ; 1764,1594 NMR (D ₂ O) δ value; 0.6-1.2 (4H, m), 1.5-2.0 (1H, m), 3.59 (1H,
d, J = 17Hz), 3.96 (1H, d, J = 17Hz), 5.29 (1H, d, J = 5Hz), 5.74
(1H, d, J = 5Hz), 7.93 (1H, s) No. 121; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-neopentylcarboxamide-3-cephem- sodium 4-carboxylic acid ^{IR (KBr) cm -1; 1773,1762,1752,1670,1654,1595} NMR (D 2 O) δ value; 1.05 (9H, s), 2.25 (2H, brs), 3.5-4.2 (2H,
m), 5.2-5.5 (1H, m), 5.7-5.9 (1H, m), 7.99 (1H, s) No.122; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) 7-chloroacetamide-3-cephem-4-carboxylate ^{IR (KBr) cm -1; 1764,1648,1638,1594} NMR (D 2 O) δ value; 3.61 (1H, d, J = 17Hz), 3.98 (1H, d, J = 17Hz),
4.27 (2H, s), 5.34 (1H, d, J = 5Hz), 5.77 (1H, d, J = 5Hz), 7.95
(1H, s) No. 123; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-propionamide-3-cephem-4-carboxylate sodium IR (KBr) cm ^-1 _{; 1772,1654,1595 NMR (D 2 O)} δ value; 1.16 (3H, t, J = 7Hz), 2.38 (2H, q, J = 7Hz), 3.5
9 (1H, d, J = 17Hz), 3.96 (1H, d, J = 17Hz), 5.28 (1H, d, J = 5Hz),
5.70 (1H, d, J = 5 Hz), 7.94 (1 H, s) No. 124; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-ethynylcarboxamide-3
- cephem-4-carboxylate ^{IR (KBr) cm -1; 1764,1654,1648,1593} NMR (D 2 O) δ value; 3.4-4.2 (3H, m), 5.32 (1H, d, J = 5Hz ), 5.79 (1
(H, d, J = 5Hz), 7.91 (1H, s)

No. 125; 3- (4-aminopyrazolo [3,4
-D] pyrimidin-6-ylthio) -7-acetoxy acetamide-3-cephem-4-carboxylate ^{IR (KBr) cm -1; 1772,1648,1637,1596} NMR (D 2 O) δ value: 2.22 ( 3H, s), 3.60 (1H, d, J = 17Hz), 3.8-4.2
(1H, m), 4.7-5.2 (2H, m), 5.32 (1H, d, J = 5Hz), 5.77 (1H, d, J =
5Hz), 7.95 (1H, s) No. 126; 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-vinylcarboxamide-3-
Cephem-4-carboxylate ^{IR (KBr) cm -1; 1763,1654,1647,1595} NMR (D 2 O) δ value; 3.2-4.2 (2H, m), 5.33 (1H, d, J = 5Hz) , 5.7-6.
1 (2H, m), 6.33 (2H, d, J = 6Hz), 7.95 (1H, s) No.127; 7-acetamido-3- (4-aminopyrrolo
[2,3-d] pyrimidin-2-ylthio) -3-cephem-4-carboxylate ^{IR (KBr) cm -1; 1764,1589} NMR (D 2 O) δ value; 2.12 (3H, s), 3.48 (1H, d, J = 17Hz), 3.87 (1H,
d, J = 17Hz), 5.24 (1H, d, J = 5Hz), 5.69 (1H, d, J = 5Hz), 6.35 (1
H, d, J = 3 Hz), 7.01 (1 H, d, J = 3 Hz) No. 128; sodium 7-acetamido-3- (4-amino-2-quinazolylthio) -3-cephem-4-carboxylate IR ( KBr) cm ^-1 ; 1764,1655,1618,1572,1535 NMR (D ₂ O) δ value; 2.13 (3H, s), 3.51 (1H, d, J = 17 Hz), 3.94 (1H,
d, J = 17Hz), 5.28 (1H, d, J = 5Hz), 5.72 (1H, d, J = 5Hz), 7.1-7.
8 (4H, m) No.129; 3- (4- aminopyrazolo [3,4-d] pyrimidine-6-ylthio) -7-methoxy-acetamide-3-cephem-4-carboxylate IR (KBr) cm ^{- 1} ; 1774,1763,1654,1596 NMR (D ₂ O) δ value; 3.3-4.3 (7H, m), 5.33 (1H, d, J = 5 Hz), 5.79 (1
(H, d, J = 5Hz), 7.96 (1H, s)

Formulation Example 1 3- (4-aminopyrazolo [3,4-d] pyrimidine-6
Dissolve 15.7 g of sodium (Ilthio) -7-[(R) -2-hydroxy-2-phenylacetamido] -3-cephem-4-carboxylate in water for injection at Japan Pharmaceutical Co., Ltd. to make a total volume of 100 mL [in terms of free carboxylic acid] 15% (W / V)]. The solution obtained is sterile filtered. Dispense 2 mL of the filtrate into 10 mL vials and immediately freeze-dry. After lyophilization and sealing, in a vial, 300 mg of 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-[(R) in terms of free carboxylic acid in one vial.
-2-hydroxy-2-phenylacetamide] -3-
A lyophilized formulation for injection containing sodium cephem-4-carboxylate is obtained.

Formulation Example 2 3- (4-aminopyrazolo [3,4-d] pyrimidine-6
(Ilthio) -7-cyanoacetamido-3-cephem-
Dissolve 15.8 g of sodium 4-carboxylate in Japanese Pharmacopoeia water for injection to make the total amount 100 mL [15% (W /
V)]. The solution obtained is sterile filtered. Dispense 2 mL of the filtrate into 10 mL vials and immediately freeze-dry. After freeze-drying and sealing, 30 vials equivalent to free carboxylic acid in one vial
A lyophilized formulation for injection containing 0 mg of sodium 3- (4-aminopyrazolo [3,4-d] pyrimidin-6-ylthio) -7-cyanoacetamido-3-cephem-4-carboxylate is obtained.

[0170]

According to the present invention, a quinazolinylthio group, a purinylthio group, a pyrazolopyrimidinylthio group, a triazolopyrimidinylthio group, a quinolinylthio group, a pyrrolopyrimidinylthio group, a naphthyridinylthio group, a pyridopyrimidinylthio group are located at the 3-position of the cephalosporin ring. A cephalosporin derivative represented by the general formula [1] or a salt thereof having a nitrogen-containing bicyclic thio group such as a pteridinylthio group or the like has a strong antibacterial activity against MRSA,
Because of its high in vivo stability, it is useful as a pharmaceutical for humans and animals.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Keisuke Suzuki 1-27-27 Shimookui, Toyama City, Toyama Prefecture (72) Minami Shinsaburo 16-54, Eimachi, Toyama City, Toyama Prefecture (72) Inventor Yasuo Watanabe Toyama Prefecture 1-247 Toyama Municipality

Claims (6)

[Claims] [Claim 1] Wherein R ¹ is a hydrogen atom, a halogen atom, a cyano group,
A represents an optionally substituted alkyl, alkoxy, alkylcarbonyloxy, alkylthio, aryl, arylthio, aryloxy, heterocyclic thio or heterocyclic group; A represents a halogen atom, an optionally protected amino group, An optionally substituted hydroxyl group, an optionally protected hydroxyimino group or a methylene group optionally substituted by an alkoxyimino group, a cycloalkylidene group, a vinylidene group and an ethynylene group;
² is the following formula which may be substituted: Or (Wherein G ¹ , G ² , G ³ and G ⁴ represent a carbon atom or a nitrogen atom; Ring D represents a 5- or 6-membered carbocyclic ring which may contain a nitrogen atom in the ring; Represents a bond bonded to a carbon atom in the ring.); R ³ represents a carboxyl group or a carboxylate group which may be protected; n represents 0 or 1; Show. The cephalosporin derivative represented by these, or its salt. 2. R ¹ is a cyano group, an optionally substituted alkylthio, aryl, arylthio, aryloxy, heterocyclic thio or heterocyclic group; and A is a halogen atom, which may be protected. amino group, an optionally protected hydroxyl group, protected methylene group which may be substituted in good hydroxyimino group or alkoxyimino group optionally or 1,1 cycloalkylidene group; R ² is replaced The following formula, which may be: Or (Wherein B represents a carbon atom or a nitrogen atom; Ring D represents a 5- or 6-membered carbon ring which may contain a nitrogen atom in the ring). 2. The cephalosporin derivative or a salt thereof according to 1. 3. A method according to claim 1, wherein R ¹ is a methylthio group or a phenyl group substituted with a fluorine atom, and A is substituted with an optionally protected hydroxyl group or an optionally protected hydroxyimino group. a good methylene group, R ² is optionally substituted with amino group or hydroxyl group quinazolinyl, purinyl, pyrazolo [3,
3. The cefaro according to claim 1, wherein a compound which is a 4-d] pyrimidinyl, pyrazolo [4,3-d] pyrimidinyl, [1,2,3] triazolo [4,5-d] pyrimidinyl or pteridinyl group is excluded. A spolin derivative or a salt thereof. (4) Wherein R ¹ is a hydrogen atom, a halogen atom, a cyano group,
A represents an optionally substituted alkyl, alkoxy, alkylcarbonyloxy, alkylthio, aryl, arylthio, aryloxy, heterocyclic thio or heterocyclic group; A represents a halogen atom, an optionally protected amino group, An optionally substituted hydroxyl group, an optionally protected hydroxyimino group or a methylene group optionally substituted by an alkoxyimino group, a cycloalkylidene group, a vinylidene group and an ethynylene group;
² is the following formula which may be substituted: Or (Wherein G ¹ , G ² , G ³ and G ⁴ represent a carbon atom or a nitrogen atom; Ring D represents a 5- or 6-membered carbocyclic ring which may contain a nitrogen atom in the ring; Represents a bond bonded to a carbon atom in the ring.); R ³ represents a carboxyl group or a carboxylate group which may be protected; n represents 0 or 1; Show. An antibacterial agent containing a cephalosporin derivative represented by the formula or a salt thereof. 5. R ¹ is a cyano group, an optionally substituted alkylthio, aryl, arylthio, aryloxy, heterocyclic thio or heterocyclic group; and A is a halogen atom, which may be protected. amino group, an optionally protected hydroxyl group, an optionally protected hydroxyimino group or alkoxyimino methylene group which may be substituted with a group or 1,1 cycloalkylidene group; R ² is substituted The following formula, which may be: Or (Wherein B represents a carbon atom or a nitrogen atom; Ring D represents a 5- or 6-membered carbon ring which may contain a nitrogen atom in the ring). An antibacterial agent containing the cephalosporin derivative or a salt thereof according to 4. 6. A compound according to claim 1, wherein R ¹ is a methylthio group or a phenyl group substituted with a fluorine atom, and A is substituted with an optionally protected hydroxyl group or an optionally protected hydroxyimino group. a good methylene group, R ² is optionally substituted with amino group or hydroxyl group quinazolinyl, purinyl, pyrazolo [3,
The compound which is a 4-d] pyrimidinyl, pyrazolo [4,3-d] pyrimidinyl, [1,2,3] triazolo [4,5-d] pyrimidinyl or pteridinyl group is excluded.
Or an antibacterial agent containing the cephalosporin derivative or a salt thereof according to 5.