JPH06135972A - New cephem compound - Google Patents

Abstract

PURPOSE:To provide a new compound useful as an antibacterial agent for Gram-positive bacteria, Gram-negative bacteria, etc. CONSTITUTION:The compound of formula I [R<1> is (protected) amino; R<2> is H or organic group; R<3> is (protected) carboxy; R<4> is 1,2,3-thiazolyl, triazolyl or tetrazolopyridazinyl; Z is N or CH], e.g. 7beta-[2-(2-aminothiazol-4-yl)-2- acetoxyiminoacetamido]-3-[(E)-2-[(1,2,3-thiadiazol-5-yl)thio]vinyl]-3- cephem-4- carboxylic acid diphenylmethyl ester. The compound of formula I can be produced by reacting a compound of formula II with a compound of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel cephem compound having high antibacterial activity and is used in the medical field.

[0002]

BACKGROUND OF THE INVENTION Many cephem compounds are known, but the cephem compound represented by the following general formula (I) of the present invention is not known.

[0003]

Although many cephem compounds having antibacterial activity and useful as medicines are known,
This invention was made with the intention of developing a further excellent drug product.

[0004]

The cephem compound which is the object of the present invention is novel and can be represented by the following general formula (I).

General formula:

[Chemical 3] [Wherein R ¹ is an amino group or a protected amino group,
R ² is hydrogen or an organic group, R ³ is a carboxy group or a protected carboxy group, R ⁴ is a 1,2,3-thiadiazolyl group, a triazolyl group or a tetrazolopyridazinyl group, and Z is N or CH. means]

The cephem compound (I) of the present invention is described below.
It can be manufactured by the manufacturing method described. Manufacturing method 1

[Chemical 4]

Manufacturing method 2

[Chemical 5]

Manufacturing method 3

[Chemical 6]

Manufacturing method 4

[Chemical 7]

Manufacturing method 5

[Chemical 8] [Wherein R ¹ , R ² , R ³ , R ⁴ and Z have the same meanings as described above,
R ¹ _a means a protected amino group, R ² _a means a hydroxy protecting group, R ³ _a means a protected carboxy group, R ³ _b means an esterified carboxy group] Raw material compound (IIa)
Can be produced by the following method.

Manufacturing method A

[Chemical 9]

Production method B

[Chemical 10] [Wherein R ³ and R ⁴ have the same meanings as described above, R ⁵ represents an amino group or a protected amino group, R ⁵ _a represents a protected amino group, and X ¹ represents an acid residue]

The compounds (I), (Ia) to (Ig) and (III) include syn isomers, anti isomers and mixtures thereof. Taking the target compound (I) as an example, the syn isomer has the following formula

[Chemical 11] (Wherein R ¹ , R ² and Z are as defined above) means a geometric isomer having a partial structure, and the anti isomer is represented by the following formula

[Chemical 12] (Wherein R ¹ , R ² , and Z are as defined above), and means a geometrical isomer having a partial structure, and such geometrical isomers and mixtures thereof are all also present in the present invention. It is included in the range of.

In the present specification, the partial structures of these geometric isomers and their mixtures are represented by the following formulas for convenience.

[Chemical 13] (Wherein R ^1, R ² and Z are as defined above).

Suitable pharmaceutically acceptable salts of compound (I) are conventional non-toxic salts, such as salts with inorganic bases such as alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth salts. Metal salts (eg calcium salt, magnesium salt etc.), ammonium salts; salts with organic bases such as organic amine salts (eg triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-
Dibenzylethylenediamine salt etc.); Inorganic acid addition salt (eg hydrochloride, hydrobromide, sulfate, phosphate etc.); Organic carboxylic acid addition salt or organic sulfonic acid addition salt (eg formate, acetate) , Trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, etc.); salts with bases such as salts with basic or acidic amino acids (eg arginine, aspartic acid, glutamic acid, etc.) Or it may include acid addition salts.

In the above and subsequent descriptions of the present specification, suitable examples and explanations of various definitions included within the scope of the present invention will be explained in detail below.

The term "lower" means 1 to 6 carbon atoms (preferably 1 to 4) unless otherwise specified.

A suitable "protected amino group" is
Examples thereof include an amino group substituted with a conventional protecting group such as an acylamino group or an ar (lower) alkyl group which may have a suitable substituent (eg, benzyl group, trityl group, etc.).

Suitable "acyl" moiety of "acylamino group" includes carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring represented by aromatic acyl or a heterocycle represented by heterocyclic acyl.
Suitable examples of the acyl are shown below: lower alkanoyl (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkylsulfonyl (eg, mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, etc.); arylsulfonyl ( Aroyl (eg, benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, a, etc.) Dan carbonyl, etc.); ar (lower) alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.); can be exemplified Al a (lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl carbonyl, etc.).

Suitable organic groups include lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, etc.), a hydroxy protecting group such as the acyl ( For example, lower alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc., mono (or di or tri) halo (lower) alkyl (eg fluoromethyl, difluoromethyl, chloromethyl, Dichloromethyl, trichloromethyl, bromomethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, trifluoroethyl, etc.), lower alkenyl (for example, vinyl, 1-propenyl, allyl, 1-methyl acrylate) Le, 1 or 2 or 3
Butenyl, 1 or 2 or 3 or 4-pentenyl,
1 or 2 or 3 or 4 or 5-hexenyl, etc.), lower alkynyl (eg ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-).
Pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl etc.), aryl (eg phenyl, naphthyl etc.), ar (lower) such as phenyl (lower) alkyl
Alkyl (eg benzyl, phenethyl, phenylpropyl, etc.), lower alkyl moiety is as previously described carboxy (lower) alkyl, lower alkyl moiety is as previously described, wherein the protected carboxy moiety is And protected carboxy (lower) alkyl and the like.

Suitable "protected carboxy group" includes esterified carboxy group and the like. Preferable examples of the ester include lower alkyl ester (eg, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.). ;
Lower alkenyl ester (eg vinyl ester, allyl ester etc.); Lower alkynyl ester (eg ethynyl ester, propynyl ester etc.); Lower alkoxyalkyl ester (eg methoxymethyl ester,
Ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester and the like); lower alkylthioalkyl ester (for example, methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester and the like); Mono (or di or tri) halo (lower) alkyl ester (eg 2-iodoethyl ester, 2,2,2-trichloroethyl ester etc.);
Lower alkanoyloxy (lower) alkyl ester (eg acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1 or 2
-Acetoxyethyl ester, 2-propionyloxyethyl ester, etc.); lower alkylsulfonyl (lower)
Alkyl ester (eg mesyl methyl ester, 2-
Mesylethyl ester, etc.); ar (lower) alkyl ester, eg phenyl (lower) alkyl ester optionally having one or more suitable substituents (eg benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl Ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); heterocyclic oxycarbonyl Oxy (lower) alkyl ester [eg 1 or 2- (tetrahydropyran-4-yloxycarbonyloxy) ethyl ester etc.]; aryl ester optionally having one or more suitable substituents, eg substituted Or unsubstituted phenyl ester (eg For example, phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); cyclo (lower) alkylcarbonyloxy (lower) alkyl ester ( For example, cyclohexylcarbonyloxymethyl ester, etc.); lower alkyl thioesters (eg, methyl thioester, ethyl thioester, etc.) and the like can be mentioned.

Suitable "1,2,3-thiadiazolyl" is 1,2,3-thiadiazol-5-yl, 1,
2,3-thiadiazol-4-yl etc. can be mentioned. Suitable "tetrazolopyridazinyl" may include tetrazolo [1,5-b] pyridazin-7-yl, tetrazolo [1,5-b] pyridazin-6-yl and the like.

Suitable "triazolyl" includes:
2,3-triazolyl, 1,2,5-triazolyl,
1,2,4-triazolyl, 1,3,4-triazolyl and the like can be mentioned.

Suitable "acid residue" is halogen (eg chlorine, bromine, iodine etc.), sulfonyloxy [eg tosyloxy, lower alkylsulfonyloxy (eg methylsulfonyloxy, ethylsulfonyloxy etc.).
Etc.] etc. can be mentioned.

Suitable "hydroxy protecting group" may be the same as those mentioned above.

Suitable "esterified carboxy group"
Can be the same as those mentioned above. The method for producing the target compound and the starting compound of the present invention will be described in detail below.

Production Method 1 The object compound (I) or its salt is the compound (IIa)
Alternatively, it can be produced by reacting the reactive derivative at the amino group or a salt thereof with compound (III) or the reactive derivative at the carboxy group or a salt thereof. Suitable reaction derivatives at the amino group of compound (IIa) include Schiff base type imino compounds formed by the reaction of compound (IIa) with carbonyl compounds such as aldehydes and ketones, or tautomeric enamine type isomers thereof. Compound, a silyl derivative formed by the reaction of a compound (IIa) with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide [eg, N- (trimethylsilyl) acetamide], bis (trimethylsilyl) urea, etc .; Mention may be made of derivatives and the like formed by the reaction of IIa) with phosphorus trichloride or phosgene.

Suitable examples of the reactive derivative at the carboxy group of the compound (III) include acid halides,
An acid anhydride, an active amide, an active ester, etc. can be mentioned. Suitable examples thereof include acid chlorides; acid azides;
Substituted phosphoric acid (eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, lower alkanesulfonic acid (eg, methanesulfonic acid, ethanesulfonic acid, etc.), sulfurous acid, thiosulfuric acid, sulfuric acid, fat With an acid such as a group carboxylic acid (for example, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid) or an aromatic carboxylic acid (for example, benzoic acid) Mixed anhydrides; symmetrical anhydrides; active amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or active esters (eg cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ )) ₂ N ⁺ = CH-] ester, vinyl ester Propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxy Methyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester etc.) or N-hydroxy compound (eg N,
N-dimethylhydroxylamine, 1-hydroxy-2
-(1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1
H-benzotriazole etc.) and the like. These reactive derivatives can be appropriately selected from these depending on the type of compound (III) to be used. The reaction is usually water, alcohol (eg methanol, ethanol etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N.
-In a conventional solvent such as dimethylformamide, pyridine or any other organic solvent that does not adversely influence the reaction. These conventional solvents may be used as a mixture with water.

When the compound (III) is used in this reaction in the form of a free acid or a salt thereof, the reaction is a conventional condensing agent,
For example, N, N'-dicyclohexylcarbodiimide; N
-Cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide;N-ethyl-N'-(3 -Dimethylaminopropyl) carbodiimide; N, N'-carbonylbis-
(2-methylimidazole); pentamethylene ketene-
N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkylphosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; Thionyl chloride; oxalyl chloride; lower alkyl haloformates (eg ethyl chloroformate, isopropyl chloroformate, etc.); triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfo Phenyl) isoxazolium hydroxide inner salt; 1-
(P-Chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; conventional condensation such as so-called Vilsmeier reagent prepared by reacting N, N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride and the like. It is desirable to carry out in the presence of the agent. The reaction includes alkali metal hydrogen carbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine,
It can also be carried out in the presence of an inorganic or organic base such as N, N-di (lower) alkylbenzylamine. The reaction temperature is not particularly limited and is usually under cooling or heating.

Production Method 2 The object compound (Ib) or a salt thereof can be produced by subjecting the compound (Ia) or a salt thereof to a elimination reaction of a hydroxy protecting group. This reaction is carried out by a conventional method such as hydrolysis or reduction. The hydrolysis is preferably carried out in the presence of a base or an acid (including a Lewis acid). Suitable bases include alkali metals (eg sodium,
Potassium, etc.), alkaline earth metals (eg magnesium, calcium etc.), hydroxides or carbonates or hydrogen carbonates thereof, trialkylamines (eg trimethylamine, triethylamine etc.), picoline, 1,5-
Diazabicyclo [4.3.0] non-5-ene, 1,4
There may be mentioned inorganic bases or organic bases such as -diazabicyclo [2.2.2] octane and 1,8-diazabicyclo [5.4.0] -undec-7.

Suitable acids include organic acids such as formic acid,
Examples thereof include acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc.) and inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, ammonium chloride, etc.). The elimination reaction using a Lewis acid such as trihaloacetic acid (eg, trichloroacetic acid, trifluoroacetic acid, etc.) is preferably carried out in the presence of a cation scavenger (eg, anisole, phenol, etc.). The reaction is usually water, alcohol (for example, methanol,
Ethanol, etc.), tetrahydrofuran, methylene chloride,
It is carried out in a solvent such as these mixtures or in any other solvent that does not adversely influence the reaction. A liquid base or acid can also be used as a solvent. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating. Examples of the reduction method that can be used in the elimination reaction include:
Mention may be made of chemical reduction and catalytic reduction. Suitable reducing agents used for chemical reduction include metals (eg tin, zinc, iron etc.) or metal compounds (eg chromium chloride, chromium acetate etc.) and organic or inorganic acids (eg formic acid, acetic acid, propionic acid, trifluoro). A combination of acetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). Suitable catalysts used for catalytic reduction include platinum catalysts (eg platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (eg palladium sponge, palladium black, palladium oxide,
Palladium-carbon, colloidal palladium, palladium-
Barium sulfate, palladium-barium carbonate, etc.), nickel catalyst (eg reduced nickel, nickel oxide, Raney-nickel etc.), cobalt catalyst (eg reduced cobalt, Raney-cobalt etc.), iron catalyst (eg reduced iron, Raney-iron etc.) ), A copper catalyst (for example, reduced copper, Raney copper, Ullmann copper, etc.) and the like. The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, methanol, ethanol, propanol, N, N-dimethylformamide, or a mixture thereof. Further, when the acid used for chemical reduction is liquid, these can be used as a solvent. Suitable solvents for the catalytic reduction include the above-mentioned solvents and other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran and the like or a mixture thereof. The reaction temperature for reduction is not particularly limited, but the reaction is usually performed under cooling or heating.

Production Method 3 The object compound (Id) or a salt thereof can be produced by subjecting the compound (Ic) or a salt thereof to a reaction for eliminating a carboxy-protecting group. This reaction can be carried out by the method shown in Production method 2 or a method similar thereto.

Production Method 4 Compound (Ie) or a salt thereof can be produced by subjecting compound (Id) or a salt thereof to an esterification reaction. Examples of the esterifying agent used in this reaction include conventional ones such as alcohol or its reactive equivalent (for example, halide such as iodide, sulfonic acid ester, sulfuric acid ester, diazo compound, etc.). The reaction is usually carried out in a conventional solvent such as acetone, dioxane, alcohol, ethylene chloride, n-hexane, tetrahydrofuran, ethyl acetate, N, N-dimethylformalide or other solvent which does not adversely influence the reaction. Be seen. The reaction temperature is not particularly limited, and the reaction is usually performed in the range of cooling or heating.

Production Method 5 The object compound (Ig) or a salt thereof can be produced by subjecting the compound (If) or a salt thereof to an elimination reaction of an amino-protecting group. This reaction usually involves hydrolysis,
It is carried out by a conventional method such as reduction. The method of hydrolysis and reduction, and the reaction conditions such as reaction temperature and solvent are
Since it is substantially the same as the one described in the elimination reaction of the hydroxy protecting group of compound (Ia) in production method 2, its explanation can be incorporated.

Production Method A Compound (II) or a salt thereof can be produced by reacting compound (IV) or a salt thereof with compound (V) or a salt thereof. This reaction can be carried out by the method shown in the following Production Example or a method similar thereto.

Production Method B Compound (IIa) or a salt thereof can be produced by subjecting compound (IIb) or a salt thereof to an elimination reaction of an amino-protecting group. This reaction can be carried out by the method shown in the following Production Example or a method similar thereto. Suitable salts of the target compound and the starting compound and their reactive derivatives in the production methods 1-5 and AB include:
Reference can be made to those described for compound (I).

The object compound (I) and its pharmaceutically acceptable salts are novel and have high antibacterial activity and inhibit the growth of a wide range of pathogenic bacteria including Gram-positive and Gram-negative bacteria and are useful as antibacterial agents. Is.

In order to show the usefulness of the target compound (I), the test results for MIC (minimum inhibitory concentration) of representative compounds belonging to the compound (I) are shown below. Test method : In vitro antibacterial activity was measured by the following agar plate multiple dilution method. Each test strain was cultured overnight in tryptocase-soy-broth to give 1 platinum loop (10 ⁸ viable cells /
ml) was inoculated on Heart Infusion Agar (HI-Agar) containing representative test compounds at each concentration step, 37
After incubating at 20 ° C. for 20 hours, the minimum inhibitory concentration (MIC) was expressed in μg / ml. Test compound 7β- [2- (2-aminothiazol-4-
Il) -2-Methoxyiminoacetamide] -3-
[(E) -2-[(1,2,3-thiadiazole-5-
Yiel] thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer) test results MIC (μg / ml)

[Table 1]

For administration therapeutically, the object compound (I) of the present invention and pharmaceutically acceptable salts thereof are organic or inorganic solid or liquid forms suitable for oral, parenteral and topical administration. It is used in the form of a conventional pharmaceutical preparation containing the compound as an active ingredient in admixture with a pharmaceutically acceptable carrier such as an agent. Pharmaceutical formulations include solid forms such as tablets, granules, powders, capsules, or solutions, suspensions, syrups, emulsions,
It may be in the form of liquid such as lemonade. Auxiliary agents, stabilizers, wetting agents and others in the above-mentioned preparations as needed, lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, white clay, sucrose, corn starch,
Additives commonly used such as talc, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol and the like may be included.

The dose of the compound (I) varies depending on the patient's age, condition, type of disease, type of compound (I) used, and the like. Generally 1 mg to about 4,0 per day
The range of 00 mg or more may be administered to the patient. The object compound (I) of the present invention is an average single dose of about 5
0 mg, 100 mg, 250 mg, 500 mg, 100
0 mg may be used to treat pathogenic infections. Hereinafter, the present invention will be described in more detail with reference to Examples.

Production Example 1 7β-t-Butoxycarbonylamino-3-[(E) -2- (tosyloxy) vinyl]
-3-Cephem-4-carboxylate diphenylmethyl (2
0.0 g) of N, N-dimethylformamide solution (12
0 ml) solution is cooled to 5 ° C. Sodium = 1,2,3-thiadiazole-5-thiolate (6.35 g) is added to this solution, and the mixture is stirred for 2.5 hours while being kept at 5 ° C. The reaction mixture was mixed with ethyl acetate (1000 ml)
Pour into a mixture of water and water (1000 ml). The organic layer is separated, washed with water and brine, dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. The formed crystals were washed with a mixed solution of ethyl acetate-n-hexane (2: 1), collected by filtration, and 7β-t-butoxycarbonylamino-3-.
[(E) -2-[(1,2,3-thiadiazole-5-
Yil) thio] vinyl] -3-cephem-4-carboxylate diphenylmethyl is obtained. IR (Nujol, cm ^-1 ): 3300, 178
0, 1690, 1510 NMR (DMSO-d ₆ ) δ: 1.42 (9H,
s), 3.68 and 4.04 (2H, ABq, J =
18Hz), 5.18 (1H, d, J = 5Hz),
5.59 (1H, d, J = 5.9Hz), 6.95
(1H, s), 7.02 (1H, d, J = 15H
z), 7.19 (1H, d, J = 15 Hz), 7.
2-7.6 (10H, m), 8.11 (1H, d, J
= 9 Hz), 9.03 (1H, s)

Production Example 2 The following compound was obtained in the same manner as in Production Example 1. 7β-t-butoxycarbonylamino-3-[(Z)-
2-[(1,2,3-thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylate diphenylmethyl. IR (Nujol, cm ^-1 ): 3300, 178
0, 1710, 1500 NMR (DMSO-d ₆ ) δ: 1.41 (9H,
s), 3.76 (2H, s), 5.19 (1H,
d, J = 5 Hz), 5.61 (1H, dd, J = 5.
9Hz), 6.64 (1H, d, J = 10Hz),
6.77 (1H, d, J = 10 Hz), 6.89 (1
H, s), 7.2-7.5 (10H, m), 8.09.
(1H, d, J = 9Hz), 8.87 (1H, s)

Production Example 3 7β-t-Butoxycarbonylamino-3-[(E)-
2- (Tosyloxy) vinyl] -3-cephem-4-carboxylate Diphenylmethyl (3.31 g) and N, N-dimethylformamide (16.6 ml) in a solution of 6-mercaptotetrazolo [1,5-b]. Pyridazine (847m
g) and N, N-diisopropylethylamine (0.87)
ml) at 5 ° C. The mixture is stirred at 5 ° C. for 3 hours and then left overnight. The reaction mixture was diluted with ethyl acetate (200
(ml) and ice water (200 ml). The organic layer is separated, washed with diluted saline (twice), dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. A mixed solution of ethyl acetate-n-hexane (1: 1) was added to the residue, and the crystalline substance was collected by filtration to give 7β-t-butoxycarbonylamino-3-.
[(E) -2-[(tetrazolo [1,5-b] pyridazin-6-yl) thio] vinyl] -3-cephem-4-carboxylate diphenylmethyl (580 mg) is obtained. The solvent of the filtrate is distilled off under reduced pressure. The residue was dissolved in ethyl acetate and triturated with n-hexane to give the same compound (2.28g)
To get IR (Nujol, cm ^-1 ): 1770, 170
0, 1500 NMR (DMSO-d ₆ ) δ: 1.42 (9H,
s), 3.78 and 4.11 (2H, ABq, J =
18Hz), 5.22 (1H, d, J = 5Hz),
5.62 (1H, dd, J = 5.9Hz), 6.99
(1H, s), 7.11 (1H, d, J = 16H
z), 7.3-7.5 (1H, m), 7.88 (1
H, d, J = 10 Hz), 8.13 (1H, d, J =
9Hz), 8.70 (1H, d, J = 10Hz)

Production Example 4 7β-t-Butoxycarbonylamino-3-[(E)-
2-[(1,2,3-Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylate diphenylmethyl (10.0 g) in acetonitrile (100 m
p-Toluenesulfonic acid monohydrate (6.24 g) is added to the mixed solution of l), and the mixture is stirred at 40 ° C. for 2.5 hours.
The reaction mixture was mixed with ethyl acetate (150 ml) and water (150 m).
Pour into the mixture of l). P with saturated aqueous sodium hydrogen carbonate solution
Adjust to H7. The organic layer is separated, washed with water and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Ethyl acetate-n-hexane mixed solution (2: 1)
Was added, the crystalline compound was collected by filtration, and 7β-amino-3-
There is obtained [(E) -2- (1,2,3-thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylate diphenylmethyl (4.44 g). IR (Nujol, cm ⁻¹ ): 1760, 173
0, 1600 NMR (DMSO-d ₆ ) δ: 2.41 (2H,
s), 3.64 and 4.004 (2H, ABq, J
= 18 Hz), 4.09 (1H, d, J = 5 Hz),
5.10 (1H, d, J = 5Hz), 6.96 (1
H, d, J = 15 Hz), 6.95 (1 H, s),
7.12 (1H, d, J = 15Hz), 7.2-7.
6 (10H, m), 9.01 (1H, s)

Production Example 5- (1) In the same manner as in Production Example 4, the following compound is obtained. 7β-Amino-3-[(Z) -2-[(1,2,3-thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylate diphenylmethyl IR (Nujol, cm ⁻¹ ). : 1755, 172
0, 1600 NMR (DMSO-d ₆ ) δ: 2.37 (2H,
s), 3.73 (2H, s), 4.92 (1H, d
-Like), 5.11 (1H, d, J = 5Hz),
6.59 (1H, d, J = 10 Hz), 6.72
(1H, d, J = 10 Hz), 6.89 (1H,
s), 7.2-7.5 (10H, m), 8.86
(1H, s)

Production Example 5- (2) In the same manner as in Production Example 4, the following compound is obtained. 7β-amino-3-[(E) -2-[(tetrazolo [1,5-b] pyridazin-6-yl) thio] vinyl]
-3-Cephem-4-carboxylic acid diphenylmethyl IR
(Nujol, cm ⁻¹ ): 1770, 1705 NMR (DMSO-d ₆ ) δ: 2.59 (2H, br)
s), 3.74 and 4.10 (2H, ABq, J
= 18 Hz), 4.92 (1H, d, J = 5 Hz),
5.13 (1H, d, J = 5Hz), 6.98 (1
H, s), 7.04 (1H, d, J = 16Hz),
7.2-7.5 (11H, m), 7.87 (1H,
d, J = 10 Hz), 8.69 (1H, d, J = 10H)
z)

Production Example 6 7β-t-Butoxycarbonylamino-3-[(E)-
2-[(Tetrazolo [1,5-b] pyridazin-6-yl) thio] vinyl] -3-cephem-4-carboxylate diphenylmethyl (12.9 g) in methylene chloride (65 m
l) Add anisole (13 ml) to the suspension.
After cooling the mixture to 5 ° C., trifluoroacetic acid (26
ml) is added. The mixture is stirred at 5 ° C. for 2.5 hours. The solvent of the reaction mixture is distilled off under reduced pressure and the residue is triturated with diisopropyl ether. The precipitate was collected by filtration, dried, and 7β-amino-3-[(E) -2-[(tetrazolo [1,5-b] pyridazin-6-yl) thio] vinyl].
-3-Cephem-4-carboxylic acid / trifluoroacetic acid salt (10.1 g) is obtained. _{NMR (DMSO-d 6) δ} : 3.80 and 4.0
9 (2H, ABq, J = 17Hz), 5.02 (1
H, d, 5Hz), 5.18 (1H, d, J = 5H
z), 7.34 (2H, s), 7.89 (1H,
d, J = 10 Hz), 8.70 (1H, d, J = 10H
z)

Production Example 7 In the same manner as in Production Example 1, the following compound is obtained. 7β-t-butoxycarbonylamino-3-[(E)-
2-[(1,2,3-triazol-4-yl) thio]
Vinyl] -3-cephem-4-carboxylate diphenylmethyl. IR (Nujol, cm ⁻¹ ): 1780, 170
0, 1500 NMR (DMSO-d ₆ ): δ 1.41 (9H,
s), 3.64 and 3.87 (2H, ABq,
J = 17.0 Hz), 5.14 (1H, d, J = 4.
7Hs), 5.49 (1H, dd, J = 9.0 an
d4.7Hx), 6.86 (1H, d, J = 15,6H
x) 6.81 (1H, s), 7.11 (1H, d, J
= 15.6 Hz), 7.2-7.5 (10H, m),
8.05 (1H, d, J = 9.0Hx), 8.18 (1
H, hrs)

Production Example 8 The following compound was obtained in the same manner as in Production Example 6. 7β-amino-3-[(E) -2-[(1,2,3-triazol-4-yl) thio] vinyl] -3-cephem-4-carboxylic acid / trifluoroacetic acid salt. IR (Nujol, cm ^-1 ): 1790, 163
0, 1520 NMR (DMSO-d ₆ ): δ 3.60 and 3.85 (2H, ABq, J = 17.5 Hz), 4.8.
2 (1H, d, J = 5.0Hx), 5.02 (1H,
d, J = 5.0Hx), 6.5-7.0 (2H, m),
8.20 (1H, s)

Example 1 Diphenylmethyl (4) of 7β-amino-3-[(E) -2-[(1,2,3-thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylate To a solution of 0.2 g) in methylene chloride (63 ml) is added bis (trimethylsilyl) acetamide (6.12 ml). 1 at room temperature
Stir for 0 minutes and cool to 5 ° C. 2-in the reaction mixture
(2-Aminothiazol-4-yl) -2-acetoxyiminoacetyl chloride hydrochloride (syn isomer) (2.
82 g) is added and the mixture is stirred at 5 ° C. for 3.5 hours.
The reaction mixture was mixed with ethyl acetate (60 ml) and water (60 ml).
Of the crystalline compound was collected by filtration, dried over phosphorus pentoxide under reduced pressure to give 7β- [2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamide].
-3-[(E) -2-[(1,2,3-thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylate diphenylmethyl (syn isomer) (4.90 g)
Get IR (Nujol, cm ^-1 ): 3300, 177
0, 1700, 1650, 1530 NMR (DMSO-d ₆ ) δ: 2.23 (3H,
s), 3.75 and 4.11 (2H, ABq, J =
18Hz), 5.35 (1H, d, J = 5Hz),
5.97 (1H, dd, J = 5.8Hz), 6.97
(1H, s), 7.02 (1H, d, J = 15H
z), 7.21 (1H, s), 7.22 (1H,
d, J = 15 Hz), 7.2-7.5 (12H,
m), 9.05 (1H, s), 10.06 (1H,
d, J = 8Hz)

Example 2- (1) In the same manner as in Example 1, the following compound is obtained. 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
[(1,2,3-Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (Nujol, cm ^-1 ): 3300-310
0, 1760, 1640, 1530 NMR (DMSO-d ₆ ) δ: 3.68 and 4.0.
2 (2H, ABq, J = 18Hz), 5.23 (1
H, d, J = 5 Hz), 5.82 (1H, dd, J =
5.8 Hz), 6.82 (1H, s), 7.09
(1H, d, J = 15 Hz), 7.20 (1H, d,
J = 15 Hz), 9.05 (1H, s), 9.72
(1H, d, J = 8Hz)

Example 2- (2) In the same manner as in Example 1, the following compound is obtained. 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(Z) -2-
[(1,2,3-Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (Nujol, cm- ¹ ): 3200, 177.
0, 1660, 1620, 1530 NMR (DMSO-d ₆ ) δ: 3.80 (2H,
s), 3.84 (3H, s), 5.23 (1H,
d, J = 5 Hz), 5.83 (1H, dd, J = 5.
8Hz), 6.72 (1H, d, J = 10Hz),
6.75 (1H, s), 6.89 (1H, d, J = 10)
Hz), 7.25 (2H, br s), 8.99
(1H, s), 9.65 (1H, d, J = 8Hz)

Example 2- (3) In the same manner as in Example 1, the following compound is obtained. 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
[(Tetrazolo [1,5-b] pyridazin-6-yl)
Thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer) IR (Nujol, cm ^-1 ): 3400-320
0, 1765, 1660-1600, 1520 NMR (DMSO-d ₆ ) δ: 3.77 and 4.0.
8 (2H, ABq, J = 18Hz), 3.86 (3
H, s), 5.26 (1H, d, J = 5 Hz), 5.8
4 (1H, dd, J = 5.8Hz), 6.77 (1
H, s), 7.24 (2H, br s), 7.31
(2H, s), 7.89 (1H, d, J = 10H
z), 8.69 (1H, d, J = 10 Hz), 9.
69 (1H, d, J = 8Hz)

Example 3 Diphenylmethyl (syn) 7β-amino-3-[(Z) -2-[(1,2,3-thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylate Isomer)
To a solution of (2.50 g) in methylene chloride (38 ml) was added bis (trimethylsilyl) acetamide (3.64 mg).
Add. The reaction mixture is stirred at room temperature for 10 minutes and then cooled to 5 ° C. 2- (2-Aminothiazol-4-yl) -2-acetoxyiminoacetyl chloride hydrochloride (syn isomer) (1.95 g) is added to the reaction mixture, and the mixture is stirred at 5 ° C for 2.5 hr. The reaction mixture is poured into a mixture of ethyl acetate (80 ml) and water (80 ml). The mixture was adjusted to pH 6 and the insoluble material was filtered off,
β- [2- (2-aminothiazol-4-yl) -2-
Acetoxyiminoacetamide] -3-[(Z) -2-
[(1,2,3-Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylate diphenylmethyl (syn isomer) (925 mg) is obtained. The organic layer of the filtrate is separated, washed with water and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to column chromatography using silica gel. Ethyl acetate was added to the fraction containing the target compound, insoluble material was collected by filtration,
7β- [2- (2-aminothiazol-4-yl) -2
-Hydroxyiminoacetamide] -3-[(Z) -2
-[(1,2,3-thiadiazol-5-yl] thio]
Vinyl] -3-cephem-4-carboxylate diphenylmethyl (syn isomer) (509 mg) is obtained. 7β- [2- (2-aminothiazol-4-yl) -2
-Acetoxyiminoacetamide] -3-[(Z) -2
-[(1,2,3-thiadiazol-5-yl) thio]
Vinyl] -3-cephem-4-carboxylate diphenylmethyl (syn isomer) IR (Nujol, cm ^-1 ): 3300, 177
0, 1650, 1530 NMR (DMSO-d ₆ ) δ: 2.21 (3H,
s), 3.82 (2H, s), 5.35 (1H,
d, J = 5 Hz), 5.99 (1H, dd, J = 5.
8Hz), 6.67 (1H, d, J = 10Hz),
6.77 (1H, d, J = 10 Hz), 6.9 (1
H, s), 7.18 (1H, s), 7.2-7.5.
(12H, m), 8.88 (1H, s), 10.0
(1H, d, J = 8Hz) 7β- [2- (2-aminothiazol-4-yl) -2
-Hydroxyiminoacetamide] -3-[(Z) -2
-[(1,2,3-Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylate diphenylmethyl (syn isomer) IR (Nujol, cm- ¹ ): 3400-320
0, 1780, 1710, 1660, 161
0, 1520 NMR (DMSO-d ₆ ) δ: 3.77 (2H,
s), 5.29 (1H, d, J = 5 Hz), 5.9
5 (1H, dd, J = 5.8Hz), 6.64 (1
H, d, J = 10 Hz), 6.68 (1H, s),
6.76 (1H, d, J = 10Hz), 6.90 (1
H, s), 7.1-7.5 (12H, m), 8.87.
(1H, s), 9.54 (1H, d, J = 8Hz),
11.3 (1H, s)

Example 4 7β-Amino-3-[(E) -2-[(tetrazolo [1,5-b] pyridazin-6-yl) thio] vinyl]
To a suspension of -3-cephem-4-carboxylic acid / trifluoroacetic acid salt (4.91 g) in methylene chloride (150 ml) was added bis (trimethylsilyl) acetamide (7.4
2 ml), and the mixture is stirred at room temperature for 20 minutes. After cooling to 5 ° C, 2- (2-aminothiazole-
4-yl) -2-acetoxyiminoacetyl chloride
Add the hydrochloride salt (syn isomer) (3.41 g) and add 1 at 5 ° C.
Stir for hours and at room temperature for 5 hours. The reaction mixture is triturated with diisopropyl ether, the precipitate is filtered off and dried under reduced pressure. A suspension of the precipitate in water (400 ml) was added with ammonium chloride (1.61 g) and methanol (2
0 ml) and the mixture is adjusted to pH 8 and 2.
Stir for 8 hours. After filtering the insoluble matter, the filtrate is adjusted to pH 6
Adjustment, the methanol is distilled off under reduced pressure, chromatography is carried out using Diaion HP-20 (trademark: manufactured by Mitsubishi Kasei Co.), and eluted with 10% aqueous isopropyl alcohol solution. Concentrate the eluate under reduced pressure and use Diaion H
Chromatography is performed using P-20 (trademark: manufactured by Mitsubishi Kasei) and eluted with 5% isopropyl alcohol aqueous solution. The eluate is concentrated under reduced pressure to 50 ml, cooled to 5 ° C. and then adjusted to pH 3. The precipitate was collected by filtration and dried under reduced pressure with phosphorus pentoxide to give 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -2- [. (Tetrazolo [1,5-
b] Pyridazin-6-yl) thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer) (847 mg) is obtained. IR (Nujol, cm ^-1 ): 3300, 178
0, 1760, 1660-1600, 1530 NMR (DMSO-d ₆ ) δ: 3.76 and 4.0.
6 (2H, ABq, J = 17Hz), 5.25 (1
H, d, J = 5 Hz), 5.85 (1H, dd, J =
5.8 Hz), 6.68 (1H, s), 7.14
(2H, br s), 7.31 (2H, s), 7.8
8 (1H, d, J = 10 Hz), 8.69 (1H,
d, J = 10 Hz), 9.54 (1H, d, J = 8H
z), 11.3 (1H, s)

Example 5 7β- [2- (2-aminothiazol-4-yl) -2
-Acetoxyiminoacetamide] -3-[(E) -2
-[(1,2,3-thiadiazol-5-yl) thio]
Vinyl] -3-cephem-4-carboxylate diphenylmethyl (syn isomer) (4.0 g) in methylene chloride (20
Anisole (4 ml) is added to the mixture in (ml) and the mixture is cooled to 5 ° C. The mixture is stirred at 5 ° C for 1 hour.
The reaction mixture is added dropwise to diisopropyl ether (550 ml). The precipitate was collected by filtration to give 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E) -2-[(1,2,3-thiadiazole- 5-yl) thio] vinyl] -3-cephem-4-carboxylic acid trifluoroacetate salt (syn isomer) is obtained. Water (500 ml) and methanol (50 ml) are added to this salt, and the mixture is stirred at pH 8-8.3 at room temperature for 2.5 hours. The reaction mixture is adjusted to pH 6 and the organic solvent is distilled off under reduced pressure. The insoluble material was removed by filtration, the filtrate was gradually adjusted to pH 4.7, and subjected to chromatography with Diaion HP-20 (trademark: manufactured by Mitsubishi Kasei Co., Ltd.).
Elute with a 1% aqueous solution of isopropyl alcohol. The eluate is concentrated, cooled to 5 ° C, adjusted to pH 3 and adjusted to 30 ° C at 5 ° C
Stir for minutes. The precipitate was collected by filtration, and 7β- [2- (2-
Aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-[(E) -2-[(1,2,3-
Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer) (865 mg) is obtained. IR (Nujol, cm ^-1 ): 3200, 175
0, 1640-1580, 1520 NMR (DMSO-d ₆ ) δ: 3.65 and 3.9.
9 (2H, ABq, J = 18Hz), 5.22 (1
H, d, J = 5 Hz), 5.82 (1H, dd, J =
5.8 Hz), 6.67 (1H, s), 7.07
(1H, d, J = 15Hz), 7.15 (2H,
s), 7.19 (1H, d, J = 15 Hz), 9.0
4 (1H, s), 9.51 (1H, d, J = 8H
z), 11.33 (1H, s)

Example 6 7β- [2- (2-aminothiazol-4-yl) -2
-Hydroxyiminoacetamide] -3-[(Z) -2
-[(1,2,3-thiadiazol-5-yl) thio]
Anisole (0.7 ml) is added to a mixture of vinyl] -3-cephem-4-carboxylate diphenylmethyl (syn isomer) (700 mg) in methylene chloride (3.5 ml) and cooled to 5 ° C. Add trifluoroacetic acid (1.4 ml) to the mixture and stir at 5 ° C. for 2 hours. The reaction mixture is added dropwise to diisopropyl ether (100 ml). The insoluble material was collected by filtration to give 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(Z) -2-[(1,2,3-thiadiazole- 5-yl) thio] vinyl] -3-cephem-
4-carboxylic acid / trifluoroacetic acid salt (syn isomer)
(675 mg) is obtained. This salt is dissolved in water at pH 7-7.5. The aqueous solution is gradually adjusted to pH 4.9 with 1N hydrochloric acid. The aqueous solution is chromatographed on Diaion HP-20 (trademark: manufactured by Mitsubishi Kasei) and eluted with a 10% aqueous isopropyl alcohol solution. Concentrate the eluate,
Cool to 5 ° C, adjust to pH 2.9 and stir at 5 ° C for 30 minutes. The insoluble material is filtered off and 7β- [2-
(2-Aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(Z) -2-[(1,
2,3-thiadiazol-5-yl) thio] vinyl]-
3-Cephem-4-carboxylic acid (syn isomer) (244
mg) is obtained. IR (Nujol, cm ^-1 ): 3300, 176
0, 1660-1520 NMR (DMSO-d ₆ ) δ: 3.78 (2H,
s), 5.22 (1H, d, J = 5 Hz), 5.8
4 (1H, dd, J = 5.8Hz), 6.66 (1
H, s), 6.71 (1H, d, J = 10 Hz),
6.89 (1H, d, J = 10Hz), 7.14 (2
H, s), 8.99 (1H, s), 9.51 (1
H, d, J = 8 Hz, 11.3 (1H, s9

Example 7 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
[(1,2,3-Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer)
(300 mg) of N, N-dimethylformamide (3 m
l) To the solution is added potassium carbonate (43 mg) and the mixture is cooled to 5 ° C. Iodomethyl pivalate (138 mg) is added to the mixture, and the mixture is stirred at 5 ° C for 1 hr. The reaction mixture is poured into a mixture of ethyl acetate (50 ml) and ice water (50 ml). The organic layer is separated, washed with water and brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was triturated with diisopropyl ether to give 7β-
[2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(E) -2-
[(1,2,3-Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylate pivaloyloxymethyl (syn isomer) (270 mg) is obtained. IR (Nujol, cm ^-1 ): 1770, 175
0, 1660, 1520 NMR (DMSO-d ₆ ) δ: 1.16 (9H,
s), 3.70 and 4.10 (2H, ABq, J =
18 Hz), 3.84 (3 H, s), 5.26 (1
H, d, J = 5 Hz), 5.81 and 5.92 (2
H, ABq, J = 6 Hz), 5.9 (1H, m),
6.77 (1H, s), 7.06 (1H, d, J = 1
5Hz), 7.23 (1H, d, J = 15Hz),
7.24 (2H, s), 9.07 (1H, s),
9.67 (1H, d, J = 8Hz)

Example 8- (1) In the same manner as in Example 7, the following compounds are obtained. 7β- [2- (2-aminothiazol-4-yl) -2
-Hydroxyiminoacetamide] -3-[(E) -2
-[(1,2,3-thiadiazol-5-yl) thio]
Vinyl] -3-cephem-4-carboxylic acid pivaloyloxymethyl (syn isomer) IR (Nujol, cm ⁻¹ ): 1770, 175
0, 1660, 1520 NMR (DMSO-d ₆ ) δ: 1.16 (9H,
s), 3.69 and 4.08 (2H, ABq, J =
18Hz), 5.26 (1H, d, J = 5Hz),
5.81 and 5.92 (2H, ABq, J = 6H
z), 5.86 (1H, dd, J = 5.8Hz),
6.68 (1H, s), 7.06 (1H, d, J = 1
5 Hz), 7.14 (2H, br s), 7.23
(1H, d, J = 15hZ9, 9.07 (1H,
s), 9.53 (1H, d, J = 8Hz), 11.3
(1H, s)

Example 8- (2) In the same manner as in Example 7, the following compounds are obtained. 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
[(1,2,3-Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylate acetoxymethyl (syn isomer) IR (Nujol, cm ^-1 ): 1765, 167
0, 1610, 1525 NMR (DMSO-d ₆ ) δ: 2.09 (3H,
s), 3.69 and 4.11 (2H, ABq, J =
18 Hz), 3.85 (3 H, s), 5.26 (1
H, d, J = 5 Hz), 5.83 (1 H, m),
5.80 and 5.87 (2H, ABq, J = 6H
z), 6.76 (1H, s), 7.09 (1H,
d, J = 15 Hz), 7.24 (2H, s), 7.
24 (1H, d, J = 15Hz), 9.08 (1H,
s), 9.67 (1H, d, J = 8Hz)

Example 8- (3) In the same manner as in Example 7, the following compounds are obtained. 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
[(Tetrazolo [1,5-b] pyridazin-6-yl)
Thio] vinyl] -3-cephem-4-carboxylic acid pivaloyloxymethyl (syn isomer) IR (Nujol, cm ^-1 ): 3450, 330
0-3200, 1775, 1750, 1660,
1610, 1530 NMR (DMSO-d ₆ ) δ: 1.17 (9H,
s), 3.81 and 4.17 (2H, ABq, J =
18Hz), 3.86 (3H, s), 5.29 (1
h, d, J = 5 Hz), 5.9 (1H, m), 5.
84 and 5.95 (2H, ABq, J = 6Hz),
6.77 (1H, s), 7.18 (1H, d, J = 1
6Hz), 7.24 (2H, s), 7.48 (1
H, d, J = 16 Hz), 7.92 (1H, d, J =
9 Hz), 8.71 (1H, d, J = 9 Hz).
9.69 (1H, d, J = 8Hz)

Example 9- (1) In the same manner as in Example 7, the following compounds are obtained. 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
[(1,2,3-Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylate 1-acetoxyethyl (syn isomer). IR (Nujol, cm ^-1 ): 1765, 166
0, 1610, 1520 NMR (DMSO-d ₆ ): δ 1.46 and 1.
48 (total 3H, dx2, J = 5Hx),
2.06 (3H, s), 3.68 and 4.10
(2H, ABq, J = 18Hx), 3.84 (3
H, s), 5.24 and 5.27 (total 1
H, dx2, J = 4 Hz), 5.8-5.9 (1H,
m), 6.75 and 6.76 (total 1H,
sx2), 6.90 and 6.99 (total
1H, qx2, J = 5 Hz), 7.03 and 7.
05 (total 1H, dx2, J = 15H
z), 7.25 and 7.26 (total 1H,
dx2, J = 15 Hz), 7.23 (2H,
brs), 9.07 (1H, s), 9.66 (1
H, d, J = 8Hz)

Example 9- (2) In the same manner as in Example 7, the following compounds are obtained. 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
[(1,2,3-Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylic acid 1- (tetrahydropyran-4-yloxycarbonyloxy) ethyl (syn isomer). IR (Nujol, cm ^-1 ): 3300, 178
0, 1750, 1670, 1610, 1520 NMR (DMSO-d ₆ ): δ 1.49 and 1.51 (total 3H, d, J = 5 Hz),
1.5-1.7 (2H, m), 1.8-2.0 (2H,
m), 3.3-3.5 (2H, m), 3.7-3.9.
(2H, m), 3.84 (3H.s), 3.80 and 4.10 (2H, ABq, J = 17Hx), 4.
8-4.9 (1H, m), 5.25 and 5.27.
(Total1H, d, J-5Hx), 5.8-
5.9 (1H ,,), 6.75 (1H, s.), 6.
83 and 6.90 (total 1H, q, J
= 5Hx), 7.04 (1H, d, J = 15Hx),
7.19 (1H, d, J = 15Hz), 7.23 (2
H, brs), 9.09 (1H, s), 9.65 and 9.66 (total 1H, d, J = 8Hz)

Example 9- (3) In the same manner as in Example 7, the following compounds are obtained. 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -2-
[(1,2,3-Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylic acid cyclohexylcarbonyloxymethyl (syn isomer). IR (Nujol, cm ^-1 ): 1780, 176
0, 1680, 1620, 1530 NMR (DMSO-d ₆ ): δ 1.1-1.9 (1
0H, m), 2.3-2.4 (1H, m), 3.70
And 4.10 (2H, ABq, J = 18H
z), 3.85 (3H.s), 5.26 (1H,
d, J = 5 Hz), 5.81 and 5,90 (2
H, ABq, J = 6 Hz), 5.85 (1H, d
d, J = 5, 8 Hz), 6.77 (1H, s),
7.07 (1H, d, J = 15 Hz), 7.23
(1H, d, J = 15Hx), 7.24 (2H, br
s), 9.07 (1H, s), 9.66 (1H, d, J
= 8Hz)

Example 10- (1) In the same manner as in Example 1, the following compound is obtained. 7β- [2- (5-amino-1,2,4-thiadiazo-
L-3-yl) -2-ethoxyiminoacetamide]-
3-[(E) -2-[(1,2,3-thiadiazole-
5-yl) thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer). IR (Nujol, cm ^-1 ): 1760, 166
5, 1505 NMR (DMSO-d ₆ ): δ 1.27 (3H,
t, J = 7 Hz), 3.64 and 4.02 (2
H, ABq J = 18 Hz), 4.19 (2H,
q, J = 7 Hz), 5.22 (1H, d, J = 5)
Hz), 5.85 (1H, dd. J = 5.8H
z), 7.06 (1H, d, J = 15 Hz), 7.1
9 (1H, d, J = 15Hz), 8.16 (2H,
brs), 9.04 (1H, s), 9.62 (1H,
d, J = 5.8 Hz)

Example 10- (2) In the same manner as in Example 1, the following compounds are obtained. 7β- [2- (2-triphenylmethylaminothiazo-
Lu-4-yl) -2-difluoromethoxyiminoacetamide] -3-[(E) -2-[(1,2,3-thiadiazol-5-yl) thio] vinyl] -3-cephem-
4-carboxylic acid (syn isomer). IR (Nujol, cm ^-1 ): 1770, 168
0, 1520 NMR (DMSO-d ₆ ): δ 3.65 amd
4.00 (2H, ABq, J = 18Hz), 5.22
(1H, d, J = 5Hz), 5.74 (1H, dd, J
= 5.8 Hz), 6.99 (1H, s), 6.7-7.
8 (19H, m), 9.14 (1H, s), 9.15
(1H, s), 9.94 (1H, d, J = 8Hz)

Example 10- (3) In the same manner as in Example 1, the following compounds are obtained. 7β- [2- (5-triphenylmethylamino-1,1,
2,4-thiadiazol-3-yl) -2-difluoromethoxyiminoacetamide] -3-[(E) -2-
[(1,2,3-Thiadiazol-5-yl) thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer). IR (Nujol, cm ^-1 ): 1770, 168
0, 1520 NMR (DMSO-d ₆ ): δ 3.63 and 4.01 (2H <ABq, J = 18 Hz), 5.
21 (1H, d, J = 5Hx), 5.82 (1H, d,
J = 5,8 Hz), 7.21 (1H, t, J = 7
0 Hz), 7.0-7.4 (17 H, m), 9.0
4 (1H, s), 9.90 (1H, d, J = 8H
z), 10.17 (1H, brs)

Example 11 7β- [2- (2-triphenylmethylaminothiazo-
Lu-4-yl) -2-difluoromethoxyiminoacetamide] -3-[(E) -2-[(1,2,3-thiadiazol-5-yl) thio] vinyl] -3-cephem-
4-carboxylic acid (syn isomer) in dichloromethane (10
ml) and anisole (2 ml) solution (1.89 g) at 5 ° C. with trifluoroacetic acid (4 ml). The mixture is stirred at 5 ° C. for 1.5 hours. The reaction mixture is dropped into diisopropyl ether, the precipitate is filtered off and dried under reduced pressure. A suspension of the precipitate in water (70 ml) is adjusted to pH 7, dissolved and adjusted to pH 5.8. Solution
Chromatograph using HP-20 (70 ml), eluting with 7% aqueous isopropyl alcohol. Remove the organic solvent of the eluent and concentrate to 60 ml. The aqueous solution was adjusted to pH 3 at 5 ° C, the precipitate was filtered off, washed with ice water, dried over phosphorus pentoxide under reduced pressure,
7β- [2- (2-aminothiazol-4-yl) -2
-Difluoromethoxyiminoacetamide] -3-
[(E) -2-[(1,2,3-thiadiazole-5-
Yil) thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer) is obtained. IR (Nujol, cm- ¹ ): 1770, 1760,
1660, 1620, 1520 NMR (DMSO-d ₆ ): δ 3.67 and 4.02 (2H, ABq, J = 18 Hz), 5.25.
(1H, d, J = 5Hz), 5.84 (1H, d
d, J = 5.8 Hz), 7.02 (1H, s),
7.08 (1H, d, J = 15Hz), 7.14
(1H, t, J = 71 Hz), 7.21 (1H,
d, J = 15 Hz), 7.38 (2H, brs),
9.05 (1H, s), 10.00 (1H, d,
J = 8Hz)

Example 12 In the same manner as in Example 11, the following compound is obtained. 7β- [2- (5-amino-1,2,4-thiadiazo-
Lu-3-yl) -2-difluoromethoxyiminoacetamide] -3-[(E) -2-[(1,2,3-thiadiazol-5-yl) thio] vinyl] -3-cephem-
4-carboxylic acid (syn isomer). IR (Nujol, cm ⁻¹ ): 1775, 1760,
1660, 1615, 1520 NMR (DMSO-d ₆ ): δ 3.65 and 4.00 (2H, ABq, J = 18 Hz),
5.23 (1H, d, J = 5Hz), 5.86 (1
H, dd, J = 5.8 Hz), 7.04 (1H,
d, J = 15 Hz), 7.22 (1H, d, J =
15Hz), 7.25 (1H, t, J = 71Hz),
8.31 (2H, brs), 9.03 (1H, s),
9.95 (1H, d, J = 8Hz)

Example 13 The following compound was obtained in the same manner as in Example 4. 7β- [2- (2-aminothiazol-4-yl) -2
-Hydroxyiminoacetamide] -3-[(E) -2
-[(1,2,3-Triazol-4-yl) thio] vinyl] -3-cephem-4-carboxylic acid (syn isomer). IR (Nujol, cm ^-1 ): 1750, 163
0 NMR (DMSO-d ₆ ): δ 3.45 and 3.60 (2H, ABq, J = 16.8 Hz),
5.04 (1H, d, J = 4.9Hz), 5.63
(1H, dd, J = 8.2 and 4.9 Hz),
6.38 (1H, d, J = 15.7Hz),
6.65 (1H, s) 7.15 (2H, br
s), 7.24 (1H, d, J = 15.7Hz),
8.03 (1H, s), 9.45 (1H, d, J =
8.2 Hz)

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Claims (2)

[Claims] 1. A general formula: [Wherein R ¹ is an amino group or a protected amino group, R 1
² is hydrogen or an organic group, R ³ is a carboxy group or a protected carboxy group, R ⁴ is a 1,2,3-thiadiazolyl group, a triazolyl group or a tetrazolopyridazinyl group, and Z is N or CH. The novel cephem compound and a salt thereof. 2. A general formula: [Wherein R ³ represents a carboxy group or a protected carboxy group, and R ⁴ represents a 1,2,3-thiadiazolyl group, a triazolyl group or a tetrazolopyridazinyl group], and a novel cephem compound represented by the following: Its salt.