JPH09278778A - Anti-mrsa cephalosporin compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new anti-MRSA [anti-methicillin-resistant Staphylococcus aureus (MRSA)] cephalosporin compound, having strong antimicrobial activities against the MRSA and high safety and useful as a therapeutic agent for infectious diseases caused by the MRSA. SOLUTION: This anti-MRSA cephalosporin compound is represented by formula I X is O or S; R<1> H, a metallic atom, a carboxyl-protecting group or an ester group hydrolyzable in vivo together with carboxyl; R<2> is phenylacetyl group or a group represented by formula II [R<4> is a (protected) amino; R<5> is H, methyl, etc.]; R<3> is 2- or 4-pyridyl, 3,4-dihydrioxyphenyl, etc.; (n) is 0 or 1}, e.g. diphenylmethy 7β-phenylacetamido-3-[5-(pyridin-2-y1)-1,3,4-oxadiazol-2- yl 9147/28} thio-3-cephem-4-carboxylate. The compound represented by formula I is obtained by reacting a compound represented by formula III (Y is an eluminable group) with a compound represented by formula IV (M is H, a metallic atom, etc.).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel cephalosporin compound useful as an antibacterial agent, a pharmaceutically acceptable salt thereof, a method for producing the same, and an antibacterial agent containing these as active ingredients.

[0002]

2. Description of the Related Art In recent years, the frequency of isolation of Gram-positive bacteria has increased in clinical settings, and the frequency of isolation of methicillin-resistant Staphylococcus aureus (hereinafter abbreviated as MRSA) has increased remarkably. MRSA infections are generally extremely intractable, and their causes include a decrease in the immune capacity of patients and the lack of effective antibacterial agents. At present, vancomycin is widely used as a therapeutic drug for MRSA infection, but it may cause serious side effects and is difficult to use for all MRSA infections. Further, since vancomycin-resistant bacteria tend to increase, a new drug effective for MRSA is desired.

[0003] Cephalosporin antibacterial agents have broad antibacterial activity against Gram-positive and Gram-negative bacteria and have been widely used in clinical settings as highly safe drugs. However, these cephalosporin compounds have no antibacterial activity against MRSA and cannot be used for treating MRSA infections, which have been increasing in recent years.

Under these circumstances, a cephalosporin compound effective for MSRA infection has been sought, and some compounds have already been reported. A cephalosporin effective for MRSA includes a 2- (2-aminothiazol-4-yl) -2-alkoxyiminoacetamide group or 2- (5-amino-1,2,4-) at the 7-position of cephalosporin.
A thiadiazol-3-yl) -2-alkoxyiminoacetamide group and a substituted benzothiazolylthio group at the 3-position of cephalosporin (European Patent EP56036).
5) or a substituted thiazolylthio group (JP-A-4-321)
No. 691), a compound having a thienopyridinium methyl group (JP-A-5-262777), 2- (N-carbamoylmethylpyridinium-4-).
Yl) thiovinyl group (JP-A-6-206886)
Although a compound having is reported, a substituted 1,3,4-oxadiazolylthio group at the 3-position of cephalosporin,
Substituted 1,3,4-thiadiazolylthio group, substituted 1,2,
A compound having a 4-thiadiazolylthio group is neither disclosed nor suggested in the specification, let alone its synthesis.

[0005]

Under these circumstances, in MRSA infections, which are expected to increase in the future,
There is a demand for new cephalosporin antibacterial agents that are safer and have a strong antibacterial activity against MRSA.

[0006]

Means for Solving the Problems In order to solve the above problems, the present inventors have conducted extensive studies on cephalosporin derivatives, and as a result, substituted cephalosporins at the 3-position with 1,3,4-
A novel cephalosporin derivative represented by the general formula (1) having an oxadiazolylthio group or a substituted 1,3,4-thiadiazolylthio group and a salt thereof, or a substitution 1 at the 3-position of cephalosporin It was found that the novel cephalosporin derivative represented by the general formula (5) having a 2,4, thiadiazolylthio group and a salt thereof exhibit a strong antibacterial activity against MRSA, and thus the present invention is completed. I arrived.

That is, the present invention relates to a novel cephem compound represented by the general formula (1), a pharmacologically acceptable salt thereof and a physiologically hydrolyzable carboxylic acid ester. [Wherein, X is an oxygen atom or a sulfur atom, R ¹ is a hydrogen atom, a metal atom, a protecting group for a carboxyl group or an ester group which is hydrolyzable in vivo in cooperation with a carboxyl group, R ²
Is a phenylacetyl group or (In the formula, R ⁴ represents an optionally protected amino group, R ⁵ represents a hydrogen atom, a methyl group, an allyl group, a cycloalkylmethyl group, a cycloalkyl group or a 2-fluoroethyl group.), R ³ represents 2-pyridyl group, 3-pyridyl group, 4-
Pyridyl group, 3,4-dihydroxyphenyl group, 3-hydroxy-4-pyridon-6-yl group, N-methylpyridinium-3-yl group, phenyl group, 2-thienyl group,
1-naphthyl group, 2-naphthyl group, 3,4,5-trimethoxyphenyl group or benzothiophen-2-yl group,
n represents 0 or 1. Or a novel cephem compound represented by the general formula (5), a pharmacologically acceptable salt thereof, and a physiologically hydrolyzable carboxylic acid ester. [Wherein R ¹ is a hydrogen atom, a metal atom, a protective group for a carboxyl group or an ester group that can be hydrolyzed in vivo in cooperation with a carboxyl group, and R ² is a phenylacetyl group or (In the formula, R ⁴ represents an optionally protected amino group, R ⁵ represents a hydrogen atom, a methyl group, an allyl group, a cycloalkylmethyl group, a cycloalkyl group or a 2-fluoroethyl group.), R ³ represents 2-pyridyl group, 3-pyridyl group, 4-
Pyridyl group, 3,4-dihydroxyphenyl group, 3-hydroxy-4-pyridon-6-yl group, N-methylpyridinium-3-yl group, phenyl group, 2-thienyl group,
1-naphthyl group, 2-naphthyl group, 3,4,5-trimethoxyphenyl group or benzothiophen-2-yl group,
n represents 0 or 1. ].

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Next, the symbols and terms used in this specification will be described.

R ^{1 in} the compounds of the general formulas (1) and (5) means a hydrogen atom, a metal atom, a protecting group for a carboxyl group or an ester group which can be hydrolyzed in vivo in cooperation with a carboxyl group. Here, the metal atom means an alkali metal such as sodium and potassium, an alkaline earth metal such as calcium and magnesium, and preferable examples include sodium and potassium. As an ester group which can be hydrolyzed in vivo in cooperation with a carboxyl group, R ¹ may have a lower alkoxycarbonyloxyalkyl group, an alkanoyloxymethyl group and a substituent (2-oxo-
1,3-dioxolen-4-yl) methyl group and the like, and particularly preferred examples are 1- (ethoxycarbonyloxy) ethyl group, acetoxymethyl group, pivaloyloxymethyl group and 5-methyl-2-oxo. A -1,3-dioxolen-4-ylmethyl group may be mentioned.

R ² of the compounds of the general formulas (1) and (5) is a phenylacetyl group or (In the formula, R ⁴ represents an optionally protected amino group, and R ⁵ represents a hydrogen atom, a methyl group, an allyl group, a cycloalkylmethyl group, a cycloalkyl group, or a 2-fluoroethyl group.). Here, the cycloalkylmethyl group refers to a methyl group having a cyclic alkyl group having 3 to 6 carbon atoms as a substituent, and specific examples thereof include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, and a cyclohexylmethyl group. To be The cycloalkyl group refers to a cyclic alkyl group having 3 to 6 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

R ³ of the compounds of the general formulas (1) and (5) is 2-pyridyl group, 3-pyridyl group, 4-pyridyl group,
3,4-dihydroxyphenyl group, 3-hydroxy-4
-Pyridone-6-yl group, N-methylpyridinium-3
-Yl group, phenyl group, 2-thienyl group, 1-naphthyl group, 2-naphthyl group, 3,4,5-trimethoxyphenyl group and benzothiophen-2-yl group.

In R ² in the general formulas (1) and (5), the formula Partial structure of oxyimino group represented by Is a syn isomer And anti isomer In general, syn isomers show excellent antibacterial activity, and the compounds of the present invention are all syn isomers. The E / Z nomenclature is based on Journal of the American Chemical Society (J. Am. Chem. Soc.) Vol. 90, p. 509 (1968).
It is described in.

The compounds of the general formulas (1) and (5) can be converted into their pharmaceutically acceptable salts or physiologically hydrolyzable carboxylic acid esters by a conventional method. The non-toxic salts of the compounds of the general formulas (1) and (5) are the pharmaceutically acceptable conventional ones, and the salts of carboxylic acid at the 4-position of the cephem skeleton and the acyl group at the R ² group at the 7-position of the cephem skeleton. Examples thereof include an ammonium salt at the 2-aminothiazole group and a pyridinium salt at the 3-position of the cephem skeleton. Examples of salts of carboxylic acids include metal salts such as sodium, potassium, magnesium, and aluminum, organic amine salts such as triethylamine salt, pyridine salt, and ethanolamine salt, or ammonium salts, such as pyridinium salts such as hydrochloric acid and hydrobromic acid. Inorganic acid salts such as nitric acid, sulfuric acid and perchloric acid, organic acid salts such as acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid, malic acid, tartaric acid and citric acid, for example, methanesulfonic acid, isethionic acid, p-toluene Examples thereof include sulfonic acid salts such as sulfonic acid and amino acid salts such as glutamic acid, aspartic acid, lysine and arginine. The physiologically hydrolyzable carboxylic acid ester may have, for example, a lower alkoxycarbonyloxyalkyl ester, an alkanoyloxymethyl ester, and a substituent (2-oxo-1,3-dioxolene-).
4-yl) methyl ester and the like, and particularly preferred examples are 1- (ethoxycarbonyloxy) ethyl ester, acetoxymethyl ester, pivaloyloxymethyl ester, and 5-methyl-2-oxo-1,3-
Dioxolen-4-ylmethyl ester may be mentioned.

The compound of the general formula (1) can be produced by the following production method. Production method Compound represented by general formula (2) [Wherein Y is a leaving group, R ¹ is a hydrogen atom, a metal atom, a protecting group for a carboxyl group or an ester group that can be hydrolyzed in vivo in cooperation with a carboxyl group, R ² is a phenylacetyl group or (In the formula, R ⁴ represents an optionally protected amino group, R ⁵ represents a hydrogen atom, a methyl group, an allyl group, a cycloalkylmethyl group, a cycloalkyl group or a 2-fluoroethyl group.), N is 0. Or 1 is shown. ] The compound represented by general formula (3) [In the formula, M is a hydrogen atom, a metal atom or a quaternary ammonium, R ³ is a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 3,4-dihydroxyphenyl group, a 3-hydroxy-4-pyridone- 6-yl group, N-methylpyridinium-3-yl group, phenyl group, 2-thienyl group, 1-
A naphthyl group, a 2-naphthyl group, a 3,4,5-trimethoxyphenyl group or a benzothiophen-2-yl group is shown. ], And conversion of the side chain R ² if necessary,
After forming and reducing the sulfoxide, the protecting group is removed from the reaction product to produce the compound of the general formula (1).

As the leaving group Y of the compound of the general formula (2), specifically, a halogen atom such as a chlorine atom, a bromine atom, an iodine atom or an acetoxy group, a carbamoyloxy group,
Examples thereof include a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, an acetoxymethylcarbamoyloxy group and a methanesulfonyloxy group, and a chlorine atom, a bromine atom, an iodine atom, a trifluoromethanesulfonyloxy group and a methanesulfonyloxy group are particularly preferable.

Further, M in the compound of the general formula (3) means a hydrogen atom, a metal atom or a quaternary ammonium, and examples of the metal atom include sodium, potassium, calcium, magnesium and aluminum. Among them, particularly preferable examples include sodium and potassium. Examples of the quaternary ammonium include triethyl hydrogen ammonium, tri-n-butyl hydrogen ammonium, tripropyl hydrogen ammonium, triisopropyl hydrogen ammonium, diisopropyl hydrogen ammonium, diisopropyl hydrogen ammonium, tetra-n-butyl ammonium and hydro. Examples thereof include genpyridinium, and particularly preferable examples include triethylhydrogenammonium, tri-n-butylhydrogenammonium, and hydrogenpyridinium.

In the general formula (3), when M is a hydrogen atom, it has the following tautomeric structure, but the present invention includes any tautomeric structure.

The reaction between the compound of the general formula (2) and the compound of the general formula (3) is carried out, for example, with methylene chloride, chloroform,
It can be carried out in an organic solvent such as ether, ethyl acetate, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, acetone, or a mixed solvent thereof. In the reaction, 1 to 2 mol of the compound of the general formula (3) is used per 1 mol of the compound of the general formula (2), the reaction temperature is 0 to 40 ° C., and the reaction time is preferably 0.5 to 10 hours.

The compounds of the general formulas (1) and (2) in which n is 0 can be prepared by the method described in The Journal of Organic Chemistry (J. Org. Chem.), Vol. 35, page 2430 (1970). Similarly, it can be produced by reducing the sulfoxide group. That is, the compounds of the general formulas (1) and (2), in which n is 1, are added in the presence of sodium iodide or potassium iodide in an acetone solvent at −40 to 0.
Acetyl chloride is added dropwise at ℃ and reacted for 1 to 5 hours, or the compounds of the general formulas (1) and (2) in which n is 1 are placed in a solvent such as N, N-dimethylformamide, methylene chloride or ethyl acetate. It can be reduced by adding phosphorus tribromide or phosphorus trichloride dropwise at -40 ° C to 0 ° C and reacting for 0.5 to 5 hours. In the reaction, iodide is added to 1 mol of the compound of the general formula (1) or (2) in which n is 3.5.
.About.10 mol and 1.5 to 5 mol of acetyl chloride or 1.1 to 6 mol of phosphorus trichloride or phosphorus tribromide are used.

The compounds of the general formulas (1) and (2) in which n is 1 are prepared according to the method described in The Journal of Organic Chemistry (J. Org. Chem.), Vol. 35, page 2430 (1970). And n is 0, the compounds of the general formulas (1) and (2) are treated with, for example, methylene chloride, ethylene chloride,
Oxidize with an equimolar amount of m-chloroperbenzoic acid, hydrogen peroxide or metaperiodic acid in an organic solvent that does not participate in the reaction such as chloroform, ether, acetic acid, or a mixed solvent thereof under ice cooling or room temperature. Can be manufactured.

Side chains R of the compounds of the general formulas (1) and (2)
² can be converted if needed. In the above general formula, a compound in which R ² is a phenylacetyl group can be produced by removing the phenylacetyl group according to the method described in JP-B-49-20319 and further condensing it with a desired carboxylic acid derivative. That is, the compound is present in benzene, toluene, ethyl acetate, methylene chloride, ethylene chloride or a mixed solvent thereof, for example, the presence of a deoxidizing agent such as N, N-dimethylaniline, pyridine, triethylamine, sodium hydrogen carbonate or potassium hydrogen carbonate. Under phosphorus pentachloride or phosphorus oxychloride at -80 to 50 ° C, preferably-
After reacting at 65 ° C to 0 ° C for 0.5 to 2 hours, the phenylacetyl group of R ² can be removed by treatment with a lower alcohol such as methanol, ethanol or propanol, followed by hydrolysis. (6) The compound can be represented by

The compound represented by the general formula (7) in the general formula (6) or its reactive derivative at the amino group or a salt thereof. [Wherein R ⁴ is an optionally protected amino group, R ⁵ is a hydrogen atom, a methyl group, an allyl group, a cycloalkylmethyl group, a cycloalkyl group or a 2-fluoroethyl group, and Z is a hydroxyl group or a reactive residue. And n represents 0 or 1. ] Or a salt thereof and, if necessary, R ² is converted from a phenylacetyl group by reduction or removal of a protecting group. [Wherein, X is an oxygen atom or a sulfur atom, R ¹ is a hydrogen atom, a metal atom, a protective group for a carboxyl group or an ester group which is hydrolyzable in vivo in cooperation with a carboxyl group, R ⁴
Is an optionally protected amino group, R ⁵ is a hydrogen atom, a methyl group, an allyl group, a cycloalkylmethyl group, a cycloalkyl group or a 2-fluoroethyl group, R ³ is a 2-pyridyl group, a 3-pyridyl group, 4-pyridyl group, 3,4-dihydroxyphenyl group, 3-hydroxy-4-pyridone-
6-yl group, N-methylpyridinium-3-yl group, phenyl group, 2-thienyl group, 1-naphthyl group, 2-naphthyl group, 3,4,5-trimethoxyphenyl group or benzothiophene 2-yl group , N represents 0 or 1. ] The compound represented by these can be manufactured.

More specifically, the compound of the general formula (6) is used to influence the reaction of, for example, water, acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, benzene, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide and the like. Can be produced by reacting the compound of the general formula (7) or a reactive derivative thereof (for example, acid halide, mixed acid anhydride, active ester, etc.) in a solvent that does not give it can.

The reaction is carried out by reacting 1 mol of the compound of the general formula (6) with the compound of the general formula (7) or its reactive derivative 1 to
1.5 mol is used, the reaction temperature is -40 to 40 ° C, and the reaction time is
0.5 to 10 hours.

When an acid halide is used as the reactive derivative of the compound of the general formula (7), it is carried out in the presence of a deoxidizing agent such as triethylamine, N-methylmorpholine, N, N-dimethylaniline or pyridine. Is preferred.

The acid halide formation reaction is carried out according to the general formula (7)
1 to 10 moles, preferably 1 to 1.5 moles of a halogenating agent such as methylene chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, phosgene, etc. per 1 mole of the compound of The reaction temperature is -40 to 100
The reaction time is 10 to 180 minutes, and the reaction time is 10 to 180 minutes.

In the mixed acid anhydride forming reaction, 1 to 1.2 mol of a deoxidizing agent such as triethylamine, N-methylmorpholine, N, N-dimethylaniline or pyridine is used per 1 mol of the compound of the general formula (7). For example, 1 to 1.2 mol of chloroformates such as methyl chloroformate, ethyl chloroformate and isobutyl chloroformate, or 1 to 2 mol of sulfonyl chlorides such as methanesulfonyl chloride and p-toluenesulfonyl chloride are used. However, the reaction temperature is -40 to 20 ° C, preferably -20 to 5 ° C, and the reaction time is 10 to 120 minutes.

The active ester forming reaction is carried out by reacting 1 mol of the compound of the general formula (7) with an N-hydroxy compound (for example,
N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc.) or a phenol compound (for example, 4
-Nitrophenol, 2,4-dinotrophenol,
1,4,5 mol of 2,4,5-trichlorophenol and 1 to 1.2 mol of N, N-dicyclohexylcarbodiimide.
Using 1.4 mol, the reaction temperature is -10 to 50 ° C, and the reaction time is 0.
5 to 2 hours.

In the acylation, when the compound of the general formula (7) is used in a free acid form, carbodiimides such as N, N-dicyclohexylcarbodiimide, phosphorus oxychloride, N, N-dimethylformamide / oxychloride. The compound of the general formula (8) can be produced even in the presence of a condensing agent such as a phosphorus adduct.

If desired, the compound of the present invention can have a protecting group removed. As the protecting group for the carboxyl group, amino group and hydroxyl group in the general formula (1), a protecting group usually used in the field of β-lactam synthesis can be appropriately selected and used.

The method of introducing and removing the protecting group depends on the type of the protecting group, for example, Protective Groups in Organic Synthesis (Protective Groups in
Organic Synthesis: TW Green, published by Wily 1981
The method described in (Year) etc. can be appropriately selected and performed.

Examples of the protective group for the carboxyl group include t-butyl group, 2,2,2-trichloroethyl group,
Acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 1-acetoxyethyl group, benzyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 4-nitrobenzyl group, benzhydryl group, bis ( 4-methoxyphenyl) methyl group, trialkylsilyl group and the like, and particularly 4-methoxybenzyl group, benzhydryl group, 4-nitrobenzyl group, trimethylsilyl group, t-butyldimethylsilyl group and the like can be mentioned.

Examples of the hydroxyl-protecting group include 2-methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, phenacyl group,
Isopropyl group, t-butyl group, benzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, acetyl group,
2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, trimethylsilyl group, t-butyldimethylsilyl group and the like can be mentioned.

Examples of the amino group-protecting group include a trityl group, a formyl group, a chloroacetyl group, a trifluoroacetyl group, a t-butoxycarbonyl group, a trimethylsilyl group and a t-butyldimethylsilyl group.

The method of removing the protective group will be specifically described below.
Trityl group, formyl group, t-butoxycarbonyl group,
Benzhydryl group, 2-methoxyethoxymethyl group, 4
The protective group such as -methoxybenzyl group can be formed with an inorganic acid or an organic acid such as hydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., and trifluoroacetic acid is particularly preferable. When trifluoroacetic acid is used as the acid, the reaction is promoted by adding anisole, thioanisole or phenol, and side reactions are also suppressed. The reaction is, for example,
It can be carried out in a solvent such as water, methylene chloride, chloroform, benzene or the like which does not participate in the reaction or a mixed solvent thereof. The reaction temperature and the reaction time are appropriately selected according to the chemical properties of the compound of the general formula (1) and the kind of the protective group, and it is particularly preferable to carry out the conditions of ice cooling or heating.

Some of the compounds of the general formula (3) are novel compounds and can be derived from the known compound (9). That is, the hydrazide compound (10) is reacted with hydrazine in an inert solvent such as alcohol, tetrahydrofuran, methylene chloride, chloroform, benzene, dimethylformamide, dimethylsulfoxide or the like or a mixed solvent thereof as follows. ) And then reacting with carbon disulfide in the presence of a suitable base such as potassium hydroxide, sodium hydroxide or triethylamine at a temperature of 0 to 100 ° C.
Can be converted to a compound represented by. At this time, after carbon disulfide is added to (9), it can be converted to a 1,3,4-oxadiazole body (3) in which X = O by a desulfurization reaction treatment with an acid treatment such as hydrochloric acid. it can. on the other hand,
By performing a dehydration reaction treatment with an acid such as sulfuric acid, X
= S, 1,3,4-thiadiazole body (3) can be obtained. The compound (3) is a thiol type (3)
And a thione-type (3 ′) tautomeric structure, but any tautomeric structure is included in the present invention.

[Biological Activity] The compound of the general formula (1) or (5) is a novel compound and has a high antibacterial activity for inhibiting the growth of a wide range of pathogenic microorganisms including Gram-positive and Gram-negative bacteria. . In particular, MRSA, which has been increasing in recent years
The excellent antibacterial activity against methicillin-resistant Staphylococcus which is a causative agent of infectious diseases is extremely useful for treating MRSA infectious diseases with few therapeutic agents. In order to show the usefulness of the compounds (1) and (5) of the present invention below, 7β- was used as a comparative compound.
[2- (5-amino-1,2,4-thiadiazole-3
-Yl) -2-methoxyiminoacetamide] -3-
(Benzothiazol-2-yl) thio-3-cephem-
4-Carboxylic acid sodium salt: Comparative compound A, imipenem: Comparative compound B, ciprofloxacin: Comparative compound C
The following tests were carried out by using and the results are shown in the table.

1. In vitro antibacterial activity (MIC) Measured according to the standard method of the Japanese Society of Chemotherapy. (Table 1) 2. In vitro antibacterial activity against quinolone-resistant Staphylococcus was measured according to the standard method of the Japanese Society of Chemotherapy. (Table 2)

[0039]

[Table 1]

[0040]

[Table 2]

As shown in Table 1, the compounds of the general formulas (1) and (5) and their pharmacologically acceptable salts or physiologically hydrolyzable non-toxic esters are useful as antibacterial agents. That is, the novel compound of the present invention in which a substituted 1,3,4-oxadiazole group, a substituted 1,3,4-thiadiazole group, and a substituted 1,2,4-thiadiazole group are sulfide-bonded to the 3-position of cephalosporin is MRSA. Comparative compound B and potent anti-M widely used as therapeutic agents for infectious diseases including infectious diseases
Compared with comparative compound A, which has RSA activity and is currently under development, it shows excellent antibacterial activity against MRSA. Also, not only Gram-positive bacteria including MRSA,
It also shows excellent antibacterial activity against Gram-negative bacteria such as Escherichia coli.

Further, as shown in Table 2, it was found that the quinolone type antibacterial agent, which has become remarkably resistant to the increase in the amount used in recent years, has an extremely excellent antibacterial activity against quinolone resistant MRSA, and the compound of the present invention causes social problems. Advanced MRS
It was shown to be extremely useful as a therapeutic agent for A infection.

The compounds of the present invention can be used in the form of pharmaceutical preparations suitable for parenteral administration, oral administration or external administration, by mixing them with carriers of solid or liquid excipients known in the art. Examples of the pharmaceutical preparation include injections, syrups, liquids such as emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories. In addition, these preparations may optionally contain additives such as auxiliary agents, stabilizers, lubricants, emulsifiers, absorption promoters and surfactants which are usually used. Examples of the additive include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, talc and the like. Further, the compound of the present invention can be used as an antibacterial agent for the treatment and prevention of human or animal bacterial infections. The dose varies depending on the circumstances such as age and sex of the patient, but normally, it is preferable to administer 1 to 2000 mg / kg per day in 1 to 5 divided doses.

[0044]

EXAMPLES Example 1 7β-Phenylacetamide-3- [5- (pyridine-
2-yl) -1,3,4-oxadiazol-2-yl] thio-3-cephem-4-carboxylic acid diphenylmethyl

60% sodium hydride, oily (75.6 mg, 1.
89 mmol) in tetrahydrofuran (8 ml) suspension
(Pyridin-2-yl) -1,3,4-oxadiazole-2-thiol (339 mg, 1.89 mmol) was added, and the mixture was allowed to stand at room temperature.
Stirred for 10 minutes. This is 7β-phenylacetamide-
Diphenylmethyl 3- (trifluoromethylsulfonyloxy) -3-cephem-4-carboxylate (1.00 g, 1.
58 mmol) in tetrahydrofuran (16 ml),
The mixture was stirred at room temperature for 3.5 hours. The insoluble material was filtered through Celite, and the solvent was evaporated. The obtained residue is subjected to silica gel column chromatography [methylene chloride-ethyl acetate = 1.
0: 1] to obtain 623 mg of yellow amorphous. This was dissolved in methylene chloride (9 ml), m-chloroperbenzoic acid (232 mg, 941 μmol) was added, and the mixture was stirred under ice cooling for 1 hr. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue obtained was treated with N, N-dimethylformaldehyde (9 ml).
After dissolution in, the mixture was added dropwise with phosphorus tribromide (89.4 μl, 941 μmol) under ice cooling and stirred at the same temperature for 1 hour. The reaction solution was diluted with methylene chloride, washed 3 times with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography [methylene chloride-ethyl acetate = 10: 1] to obtain 506 mg of an orange amorphous title compound (yield 48%).

¹ H-NMR (CDCl ₃ , δ): 3.47
(1H, d, J = 17.6Hz), 3.61 (1H, d, J = 1
6.1Hz), 3.67 (1H, d, J = 16.1Hz), 3.84
(1H, d, J = 17.6Hz), 5.05 (1H, d, J =
4.9Hz), 5.92 (1H, dd, J = 9.3, 4.9H
z), 6.20 (1H, d, J = 8.9Hz), 6.95 (1H,
s), 7.20-7.52 (16H, m), 7.91 (1H, t, J =
7.8Hz), 8.22 (1H, d, J = 7.8Hz), 8.78
(1H, d, J = 4.4Hz)

Examples 2 to 13 Using 5-aryl-1,3,4-oxadiazole-2-thiol or 5-aryl-1,3,4-thiadiazole-2-thiol, in the same manner as in Example 1 By treatment, the compounds shown in Table 3 below were obtained.

[0048]

[Table 3]

Example 2 ¹ H-NMR (CDCl ₃ , δ): 3.51 (1H, d, J
= 18.1Hz), 3.62 (1H, d, J = 16.1Hz), 3.68
(1H, d, J = 16.1Hz), 3.85 (1H, d, J = 1
7.6Hz), 5.06 (1H, d, J = 5.4Hz), 5.93
(1H, dd, J = 8.8, 5.4Hz), 6.24 (1H,
d, J = 8.8Hz), 6.97 (1H, s), 7.20-7.40
(15H, m), 7.48 (1H, dd, J = 7.8, 4.9H
z), 8.27 (1H, dd, J = 9.8, 2.0Hz), 8.80
(1H, d, J = 8.8Hz), 9.20 (1H, s)

Example 3 ¹ H-NMR (CDCl ₃ , δ): 3.50 (1 H, d, J
= 18.1Hz), 3.61 (1H, d, J = 16.1Hz), 3.67
(1H, d, J = 16.1Hz), 3.87 (1H, d, J = 1
8.1Hz), 5.07 (1H, d, J = 5.4Hz), 5.94
(1H, dd, J = 8.8, 5.4Hz), 6.27 (1H,
d, J = 8.8Hz), 6.97 (1H, s), 7.19-7.38
(15H, m), 7.82 (2H, dd, J = 4.4, 1.5H
z), 8.83 (2H, d, J = 5.9Hz)

Example 4 ¹ H-NMR (CDCl ₃ , δ): 3.43 (1 H, d, J
= 17.6Hz), 3.60 (1H, d, J = 16.1Hz), 3.67
(1H, d, J = 16.1Hz), 3.71 (1H, d, J = 1
8.0Hz), 3.80 (3H, s), 3.81 (3H, s), 5.0
1 (1H, d, J = 4.9Hz), 5.13 (2H, s), 5.1
5 (2H, s), 5.91 (1H, dd, J = 9.3, 4.9H
z), 6.13 (1H, d, J = 9.3Hz), 6.89 (2H,
d, J = 8.8Hz), 6.90 (2H, d, J = 8.8H)
z), 6.96 (1H, s), 6.99 (1H, d, J = 8.8H
z), 7.22-7.43 (19H, m), 7.49 (1H, dd, J
= 8.3, 2.0Hz), 7.58 (1H, d, J = 2.0Hz)

Example 5 ¹ H-NMR (CDCl ₃ , δ): 3.51 (1H, d, J
= 17.6Hz), 3.61 (1H, d, J = 16.1Hz), 3.68
(1H, d, J = 16.1Hz), 3.83 (1H, d, J = 1
7.6Hz), 5.06 (1H, d, J = 5.4Hz), 5.93
(1H, dd, J = 8.8, 5.4Hz), 6.10 (1H,
d, J = 8.8Hz), 6.99 (1H, s), 7.23-7.44
(15H, m), 7.59-7.63 (2H, m), 7.91 (1H,
d, J = 7.8Hz), 7.95 (1H, d, J = 5.9H)
z), 7.97 (1H, d, J = 8.3Hz), 8.07 (1H,
dd, J = 8.8, 2.0Hz), 8.49 (1H, s)

Example 6 ¹ H-NMR (CDCl ₃ , δ): 3.55 (1 H, d, J
= 18.1Hz), 3.62 (1H, d, J = 16.1Hz), 3.68
(1H, d, J = 16.1Hz), 3.87 (1H, d, J = 1
8.1Hz), 5.06 (1H, d, J = 4.9Hz), 5.93
(1H, dd, J = 9.3, 4.9Hz), 6.13 (1H,
d, J = 9.3 Hz), 6.98 (1H, s), 7.21-7.43
(15H, m), 7.55-7.64 (2H, m), 7.67-7.70
(1H, m), 7.95 (1H, d, J = 8.3Hz), 8.07
(1H, d, J = 8.3Hz), 8.09 (1H, dd, J =
7.3, 1.0Hz), 9.17 (1H, d, J = 8.8Hz)

Example 7 ¹ H-NMR (CDCl ₃ , δ): 3.49 (1H, d, J
= 17.6Hz), 3.61 (1H, d, J = 16.1Hz), 3.67
(1H, d, J = 16.1Hz), 3.82 (1H, d, J = 1
7.6Hz), 5.05 (1H, d, J = 4.9Hz), 5.92
(1H, dd, J = 8.8, 4.9Hz), 6.14 (1H,
d, J = 8.8Hz), 6.98 (1H, s), 7.21-7.51
(17H, m), 7.88-7.91 (2H, m), 7.94 (1H,
s)

Example 8 ¹ H-NMR (CDCl ₃ , δ): 3.46 (1H, d, J
= 18.1Hz), 3.64 (2H, d, J = 7.8Hz), 3.78
(1H, d, J = 17.6Hz), 3.80 (3H, s), 3.81
(3H, s), 5.02 (1H, d, J = 5.4Hz), 5.17
(2H, s), 5.22 (2H, s), 5.91 (1H, dd,
J = 9.3, 4.9Hz), 6.22 (1H, d, J = 9.3H)
z), 6.89 (2H, d, J = 8.3Hz), 6.93 (2H,
d, J = 8.8Hz), 6.95 (1H, s), 7.21-7.41 (1
9H, m), 7.87 (1H, s), 8.12 (1H, s)

Example 9 ¹ H-NMR (CDCl ₃ , δ): 3.50 (1H, d, J
= 18.1Hz), 3.62 (1H, d, J = 16.1Hz), 3.68
(1H, d, J = 16.1Hz), 3.84 (1H, d, J = 1
8.1Hz), 5.05 (1H, d, J = 4.9Hz), 5.92
(1H, dd, J = 9.3, 4.9Hz), 6.14 (1H,
d, J = 9.3 Hz), 6.97 (1H, s), 7.23-7.44
(16H, m), 7.87 (1H, td, J = 7.8, 2.0H
z), 8.29 (1H, d, J = 7.8Hz), 8.64 (1H,
dd, J = 4.9, 1.0 Hz)

Example 10 ¹ H-NMR (CDCl ₃ , δ): 3.50 (1H, d, J
= 18.1Hz), 3.61 (1H, d, J = 16.1Hz), 3.68
(1H, d, J = 16.1Hz), 3.80 (1H, d, J = 1
8.1Hz), 5.04 (1H, d, J = 4.9Hz), 5.91
(1H, dd, J = 9.3, 4.9Hz), 6.09 (1H,
d, J = 9.3 Hz), 6.98 (1H, s), 7.22-7.40
(15H, m), 7.47-7.53 (3H, m), 7.88 (2H,
dd, J = 7.8, 1.5Hz)

Example 11 ¹ H-NMR (CDCl ₃ , δ): 3.48 (1 H, d, J
= 18.1Hz), 3.61 (1H, d, J = 16.1Hz), 3.67
(1H, d, J = 16.1Hz), 3.77 (1H, d, J = 1
8.1Hz), 5.02 (1H, d, J = 4.9Hz), 5.91
(1H, dd, J = 9.3, 4.9Hz), 6.09 (1H,
d, J = 8.8 Hz), 6.97 (1H, s), 7.14 (1H,
dd, J = 4.9, 3.9 Hz), 7.25-7.40 (15H,
m), 7.49 (1H, dd, J = 3.9, 1.0Hz), 7.53
(1H, dd, J = 4.9, 1.0Hz)

Example 12 ¹ H-NMR (CDCl ₃ , δ): 3.53 (1 H, d, J
= 18.1Hz), 3.62 (1H, d, J = 16.1Hz), 3.68
(1H, d, J = 16.1Hz), 3.83 (1H, d, J = 1
8.1Hz), 5.05 (1H, d, J = 4.9Hz), 5.92
(1H, dd, J = 9.3, 4.9Hz), 6.07 (1H,
d, J = 9.3 Hz), 6.99 (1H, s), 7.22-7.41
(15H, m), 7.56-7.60 (2H, m), 7.88-8.03
(4H, m), 8.32 (1H, s)

Example 13 ¹ H-NMR (CDCl ₃ , δ): 3.49 (1 H, d, J
= 18.6Hz), 3.61 (1H, d, J = 16.1Hz), 3.68
(1H, d, J = 16.6Hz), 3.80 (1H, d, J = 1
8.1Hz), 3.93 (3H, s), 3.94 (6H, s), 5.0
4 (1H, d, J = 4.9Hz), 5.91 (1H, dd, J
= 9.3, 4.9Hz), 6.03 (1H, d, J = 8.8H
z), 6.98 (1H, s), 7.11 (2H, s), 7.24-7.
41 (15H, m)

Example 14 7β-Phenylacetamide-3- {5- [3,4-bis (4-methoxybenzyloxy) pyridin-2-yl] -1,3,4-oxadiazol-2-yl} Diphenylmethyl thio-3-cephem-4-carboxylic acid

60% sodium hydride, oily (75.6 mg, 1.
89 mmol) in tetrahydrofuran (8 ml) suspension
[3,4-bis (4-methoxybenzyloxy) pyridin-2-yl] -1,3,4-oxadiazole-2-
Thiol (853 mg, 1.89 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. This is 7β-phenylacetamido-3- (trifluoromethylsulfonyloxy) -3-cephem-
4-Carboxylic acid diphenylmethyl (1.00 g, 1.58 mmol)
Was added to a tetrahydrofuran (16 ml) suspension at room temperature,
Stirred for hours. The insoluble material was filtered through Celite, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography [methylene chloride-ethyl acetate = 10: 1] to obtain 567 mg of a pale brown amorphous title compound (yield 38%).

¹ H-NMR (CDCl ₃ , δ): 3.41
(1H, d, J = 17.6Hz), 3.60 (1H, d, J = 1
6.1Hz), 3.67 (1H, d, J = 16.1Hz), 3.77
(1H, d, J = 17.6Hz), 3.80 (3H, s), 3.81
(3H, s), 5.02 (1H, d, J = 5.4Hz), 5.20
(2H, s), 5.21 (2H, s), 5.91 (1H, dd,
J = 8.8, 5.4Hz), 6.13 (1H, d, J = 8.8H
z), 6.89 (2H, d, J = 8.8Hz), 6.93 (2H,
d, J = 9.3 Hz), 6.94 (1H, s), 7.20-7.41
(19H, m), 7.78 (1H, s), 8.24 (1H, s)

Examples 15 to 17 Using 5-aryl-1,3,4-oxadiazole-2-thiol or 3-phenyl-1,2,4-thiadiazole-2-thiol as Examples 14 to 17 By the same treatment, the compounds shown in Table 4 below were obtained.

[0065]

[Table 4]

Example 15 ¹ H-NMR (CDCl ₃ , δ): 3.47 (1 H, d, J
= 17.6Hz), 3.61 (1H, d, J = 16.1Hz), 3.68
(1H, d, J = 16.1Hz), 3.79 (1H, d, J = 1
7.6Hz), 5.05 (1H, d, J = 4.9Hz), 5.92
(1H, dd, J = 9.3, 4.9Hz), 6.09 (1H,
d, J = 9.3 Hz), 6.97 (1H, s), 7.23-7.43
(15H, m), 7.50-7.58 (3H, m), 7.99-8.01
(2H, m)

Example 16 ¹ H-NMR (CDCl ₃ , δ): 3.46 (1 H, d, J)
= 18.1Hz), 3.61 (1H, d, J = 16.1Hz), 3.68
(1H, d, J = 16.1Hz), 3.76 (1H, d, J = 1
7.6Hz), 5.04 (1H, d, J = 5.4Hz), 5.92
(1H, dd, J = 9.3, 4.9Hz), 6.14 (1H,
d, J = 9.3 Hz), 6.96 (1H, s), 7.19 (1H,
dd, J = 4.9, 3.9 Hz), 7.24-7.43 (15H,
m), 7.60 (1H, dd, J = 4.9, 1.0Hz), 7.73
(1H, dd, J = 3.9, 1.0Hz)

Example 17 ¹ H-NMR (CDCl ₃ , δ): 3.53 (1 H, d, J
= 18.1Hz), 3.63 (1H, d, J = 16.1Hz), 3.69
(1H, d, J = 16.1Hz), 3.90 (1H, d, J = 1
8.1Hz), 5.10 (1H, d, J = 4.9Hz), 5.94
(1H, dd, J = 9.3, 4.9Hz), 6.15 (1H,
d, J = 8.8 Hz), 6.99 (1H, s), 7.18-7.40
(15H, m), 7.45-7.55 (3H, m), 8.20-8.22
(2H, m)

Example 18 7β- [2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -3- [5-
(Pyridin-2-yl) -1,3,4-oxadiazol-2-yl] thio-3-cephem-4-carboxylic acid diphenylmethyl

Compound of Example 1 (506 mg, 765 μmol)
Solution of methylene chloride (7.6 ml) under ice-cooled phosphorus pentachloride (2
39mg, 1.15mmol) and pyridine (149μl, 1.84mmo)
l) were sequentially added, and the mixture was stirred at the same temperature for 1.5 hours. Methanol (1.9 ml) was added to this, and water (
7.6 ml) was added and the mixture was stirred for 1 hour. The water layer was removed, water (7.6 ml) was added, and the pH was adjusted with saturated aqueous sodium hydrogen carbonate solution.
7, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was evaporated and the residue obtained was treated with 2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid (339 mg, 765 μmol) and dicyclohexylcarbodiimide (174 mg, 843 μmol). In addition, after dissolving in tetrahydrofuran (7.6 ml), the mixture was stirred at room temperature for 3 hours, the solvent was distilled off, ethyl acetate was added, and the insoluble matter was filtered off,
The solvent was distilled off. The obtained residue was purified by silica gel column chromatography [methylene chloride-ethyl acetate = 10: 1] to obtain 172 mg of a pale yellow amorphous title compound (yield 23%).

¹ H-NMR (CDCl ₃ , δ): 3.52
(1H, d, J = 18.1Hz), 3.90 (1H, d, J = 1
8.1Hz), 4.06 (3H, s), 5.17 (1H, d, J =
5.4Hz, 6.02 (1H, dd, J = 9.3, 4.9H
z), 6.73 (1H, s), 6.85 (1H, d, J = 8.8H
z), 6.98 (1H, s), 6.99 (1H, s), 7.23-7.
44 (25H, m), 7.50 (1H, ddd, J = 7.3, 4.
9, 1.0Hz), 7.92 (1H, td, J = 7.8, 1.5H
z), 8.23 (1H, d, J = 4.8Hz), 8.78 (1H,
dd, J = 4.9, 1.0 Hz)

Examples 19 to 28 Using the compounds of Examples 2 to 6, 8, 9, and 14 to 16,
By treating in the same manner as in 18, the compounds shown in Table 5 below were obtained.

[0073]

[Table 5]

Example 19 ¹ H-NMR (CDCl ₃ , δ): 3.55 (1 H, d, J
= 18.1Hz), 3.91 (1H, d, J = 18.1Hz), 4.07
(3H, s), 5.18 (1H, d, J = 4.9Hz), 6.03
(1H, dd, J = 8.8, 4.9Hz), 6.74 (1H,
s), 6.88 (1H, d, J = 9.3Hz), 6.97 (1H,
s), 6.99 (1H, s), 7.23-7.42 (25H, m), 7.
48 (1H, dd, J = 8.3, 4.9Hz), 8.28 (1H,
dt, J = 7.8, 2.0Hz), 8.81 (1H, dd, J =
4.9, 1.5Hz), 9.21 (1H, d, J = 2.4Hz)

Example 20 ¹ H-NMR (CDCl ₃ , δ): 3.55 (1 H, d, J
= 18.1Hz), 3.93 (1H, d, J = 18.1Hz), 4.07
(3H, s), 5.19 (1H, d, J = 4.9Hz), 6.03
(1H, dd, J = 9.3, 4.9Hz), 6.73 (1H,
s), 6.92 (1H, d, J = 9.3Hz), 6.99 (2H,
s), 7.23-7.41 (25H, m), 7.83 (2H, d, J =
6.4Hz), 8.83 (2H, d, J = 6.4Hz)

Example 21 ¹ H-NMR (CDCl ₃ , δ): 3.48 (1 H, d, J
= 18.1Hz), 3.77 (1H, d, J = 18.1Hz), 3.80
(3H, s), 3.81 (3H, s), 4.06 (3H, s),
5.13 (2H, s), 5.14 (1H, d, J = 4.4Hz),
5.16 (2H, s), 6.01 (1H, dd, J = 8.8,4.9
Hz), 6.73 (1H, s), 6.82 (1H, d, J = 8.8
Hz), 6.89 (2H, d, J = 8.3Hz), 6.90 (2
H, d, J = 8.3Hz), 6.98 (1H, s), 7.01 (1
H, s), 7.24-7.45 (30H, m), 7.50 (1H, d
d, J = 8.3, 2.0 Hz), 7.59 (1H, d, J = 2.4)
Hz)

Example 22 ¹ H-NMR (CDCl ₃ , δ): 3.46 (1 H, d, J
= 17.6 Hz), 3.80 (3H, s), 3.81 (3H, s),
3.83 (1H, d, J = 17.6Hz), 4.06 (3H, s),
5.14 (1H, d, J = 4.9Hz), 5.206 (2H,
s), 5.213 (2H, s), 6.01 (1H, dd, J =
8.8, 4.9Hz), 6.73 (1H, s), 6.84 (1H,
d, J = 8.8Hz, 6.89 (2H, d, J = 8.8H)
z), 6.93 (2H, d, J = 8.8Hz), 6.96 (1H,
s), 6.99 (1H, s), 7.23-7.44 (29H, m), 7.
79 (1H, s), 8.25 (1H, s)

Example 23 ¹ H-NMR (CDCl ₃ , δ): 3.52 (1 H, d, J
= 18.1Hz), 3.85 (1H, d, J = 18.1Hz), 4.06
(3H, s), 5.16 (1H, d, J = 4.9Hz), 6.02
(1H, dd, J = 9.3, 4.9Hz), 6.73 (1H,
s), 6.84 (1H, d, J = 9.3Hz), 6.99 (2H,
s), 7.24-7.58 (28H, m), 7.99-8.01 (2H,
m)

Example 24 ¹ H-NMR (CDCl ₃ , δ): 3.51 (1 H, d, J
= 18.1Hz), 3.82 (1H, d, J = 18.1Hz), 4.06
(3H, s), 5.15 (1H, d, J = 5.4Hz), 6.01
(1H, dd, J = 9.3, 4.9Hz), 6.73 (1H,
s), 6.85 (1H, d, J = 8.8Hz), 6.99 (2H,
s), 7.19 (1H, dd, J = 5.4, 3.9Hz), 7.25
-7.45 (25H, m), 7.60 (1H, dd, J = 5.4,
1.0Hz), 7.73 (1H, dd, J = 3.9, 1.0Hz)

Example 25 ¹ H-NMR (CDCl ₃ , δ): 3.56 (1 H, d, J
= 18.1Hz), 3.88 (1H, d, J = 18.1Hz), 4.06
(3H, s), 5.17 (1H, d, J = 4.9Hz), 6.02
(1H, dd, J = 9.3, 4.9Hz), 6.73 (1H,
s), 6.85 (1H, d, J = 9.3Hz), 6.99 (1H,
s), 7.01 (1H, s), 7.23-7.46 (25H, m), 7.
59-7.63 (2H, m), 7.91 (1H, d, J = 7.8H
z), 7.96 (1H, d, J = 5.9Hz), 7.98 (1H,
d, J = 8.8Hz), 8.08 (1H, dd, J = 8.8,
2.0Hz), 8.50 (1H, s)

Example 26 ¹ H-NMR (CDCl ₃ , δ): 3.60 (1H, d, J
= 18.1Hz), 3.93 (1H, d, J = 18.1Hz), 4.06
(3H, s), 5.18 (1H, d, J = 4.9Hz), 6.03
(1H, dd, J = 9.3, 4.9Hz), 6.73 (1H,
s), 6.85 (1H, d, J = 9.3Hz), 6.99 (1H,
s), 7.01 (1H, s), 7.22-7.45 (25H, m), 7.
56-7.72 (3H, m), 7.95 (1H, d, J = 7.8H
z), 8.07 (1H, d, J = 8.3Hz), 8.10 (1H,
d, J = 7.3Hz), 9.19 (1H, d, J = 8.8Hz)

Example 27 ¹ H-NMR (CDCl ₃ , δ): 3.50 (1 H, d, J
= 18.1 Hz), 3.79 (3H, s), 3.80 (3H, s),
4.06 (3H, s), 5.13 (1H, d, J = 5.4Hz),
5.18 (2H, s), 5.22 (2H, s), 6.00 (1H, d
d, J = 8.8, 4.9 Hz), 6.73 (1H, s), 6.88
(2H, d, J = 8.8Hz), 6.90 (1H, d, J =
8.8Hz), 6.92 (2H, d, J = 8.8Hz), 6.98
(1H, s), 7.01 (1H, s), 7.21-7.41 (29H,
m), 7.88 (1H, s), 8.12 (1H, s)

Example 28 ¹ H-NMR (CDCl ₃ , δ): 3.54 (1 H, d, J
= 18.1Hz), 3.88 (1H, d, J = 18.1Hz), 4.07
(3H, s), 5.16 (1H, d, J = 4.9Hz), 6.02
(1H, dd, J = 9.3, 4.9Hz), 6.74 (1H,
s), 6.86 (1H, d, J = 9.3Hz), 6.99 (1H,
s), 7.00 (1H, s), 7.23-7.43 (26H, m), 7.
87 (1H, td, J = 7.8, 1.5Hz), 8.30 (1H,
d, J = 8.3Hz), 8.64 (1H, d, J = 3.9Hz)

Example 29 7β-Amino-3- [5- (pyridin-3-yl)-
1,3,4-oxadiazol-2-yl] thio-3-
Cephem-4-carboxylic acid diphenylmethyl

A solution of the compound of Example 2 (2.63 g, 3.97 mmol) in methylene chloride (40 ml) was added with phosphorus pentachloride (1.24) under ice cooling.
g, 5.96 mmol) and pyridine (771 μl, 9.53 mmol)
Were sequentially added, and the mixture was stirred at the same temperature for 1.5 hours. Methanol (10 ml) was added to this, and water (40 ml) was added at the same temperature for 3 hours and the mixture was stirred for 1 hour. The water layer was removed, water (40 ml) was newly added, the pH was adjusted to 7 with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography [methylene chloride-ethyl acetate = 10: 1].
1.09 g of a yellowish brown amorphous title compound was obtained (yield 50
%).

¹ H-NMR (CDCl ₃ , δ): 3.55
(1H, d, J = 17.6Hz), 3.94 (1H, d, J = 1
7.6Hz), 4.80-4.90 (1H, br), 5.07 (1H,
d, J = 5.4Hz), 7.00 (1H, s), 7.23-7.43
(10H, m), 7.48 (1H, dd, J = 8.3,4.9H
z), 8.28 (1H, d, J = 7.8Hz), 8.80 (1H,
dd, J = 4.9, 1.5 Hz), 9.20 (1H, d, J = 1.
5Hz)

[0087] Using the compound of Example 30 to 36 Examples 7,10～13,16 and 17, Example
By treating in the same manner as in 29, compounds shown in Table 6 below were obtained.

[0088]

[Table 6]

Example 30 ¹ H-NMR (CDCl ₃ , δ): 3.51 (1 H, d, J
= 17.6Hz), 3.86 (1H, d, J = 18.1Hz), 4.83
(1H, d, J = 4.9Hz), 5.04 (1H, d, J =
5.4Hz), 6.99 (1H, s), 7.18 (1H, dd, J
= 4.9, 3.9Hz), 7.23-7.46 (10H, m), 7.59
(1H, dd, J = 4.9, 1.0Hz), 7.72 (1H, d
d, J = 3.9, 1.0Hz)

Example 31 ¹ H-NMR (CDCl ₃ , δ): 3.54 (1 H, d, J
= 17.6Hz), 3.92 (1H, d, J = 17.6Hz), 4.84
(1H, brs), 5.06 (1H, d, J = 5.4Hz), 7.
01 (1H, s), 7.22-7.50 (12H, m), 7.89-7.92
(2H, m), 7.95 (1H, s)

Example 32 ¹ H-NMR (CDCl ₃ , δ): 3.53 (1 H, d, J
= 18.1Hz), 3.87 (1H, d, J = 18.1Hz), 4.75
-4.90 (1H, d-like br), 5.04 (1H, d, J =
4.9Hz), 7.01 (1H, s), 7.22-7.41 (10H,
m), 7.46-7.52 (3H, m), 7.86-7.89 (2H,
m)

Example 33 ¹ H-NMR (CDCl ₃ , δ): 3.51 (1 H, d, J
= 18.1Hz), 3.85 (1H, d, J = 18.1Hz), 4.83
(1H, d, J = 5.4Hz), 5.03 (1H, d, J =
5.4Hz), 7.01 (1H, s), 7.13 (1H, dd, J
= 4.9, 3.9Hz), 7.22-7.41 (10H, m), 7.47
(1H, dd, J = 3.9, 1.0Hz), 7.52 (1H, d
d, J = 4.9, 1.0Hz)

Example 34 ¹ H-NMR (CDCl ₃ , δ): 3.55 (1 H, d, J
= 18.1Hz), 3.90 (1H, d, J = 18.1Hz), 4.84
(1H, brs), 5.05 (1H, d, J = 5.4Hz), 7.
03 (1H, s), 7.22-7.42 (10H, m), 7.56-7.61
(2H, m), 7.88-7.95 (3H, m), 8.02 (1H,
dd, J = 8.3, 1.5Hz), 8.31 (1H, s)

Example 35 ¹ H-NMR (CDCl ₃ , δ): 3.51 (1 H, d, J
= 18.1Hz), 3.86 (1H, d, J = 18.1Hz), 3.92
(3H, s), 3.94 (6H, s), 4.84 (1H, brs
), 5.04 (1H, d, J = 4.9Hz), 7.02 (1H,
s), 7.11 (2H, s), 7.23-7.41 (10H, m)

Example 36 ¹ H-NMR (CDCl ₃ , δ): 3.59 (1 H, d, J
= 18.1Hz), 3.92 (1H, d, J = 18.1Hz), 4.87
(1H, brs), 5.10 (1H, d, J = 5.4Hz), 7.
02 (1H, s), 7.15-7.32 (10H, m), 7.48 (3
H, t, J = 3.4 Hz), 8.22 (2H, dt, J = 5.
9, 2.0Hz)

Example 37 3- [5- (pyridin-3-yl) -1,3,4-oxadiazol-2-yl] thio-7β- [2- (2-tritylaminothiazol-4-yl) ) -2-Trityloxyiminoacetamide] -3-cephem-4-carboxylic acid diphenylmethyl

The compound of Example 29 (180 mg, 331 μmol
), 2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetic acid (267 mg, 397 μ
mol) and dicyclohexylcarbodiimide (81.9m
g, 397 μmol) was dissolved in tetrahydrofuran (7 ml), and the mixture was stirred at room temperature for 5 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography [methylene chloride-ethyl acetate = 10: 1], and then by preparative thin layer chromatography [methylene chloride-ethyl acetate = 10: 1]. 48.9 mg of the yellow amorphous title compound was obtained (yield 12%).

¹ H-NMR (CDCl ₃ , δ): 3.35
(1H, d, J = 18.1Hz), 3.83 (1H, d, J = 1
7.6Hz), 5.17 (1H, d, J = 5.4Hz), 6.16
(1H, dd, J = 8.8, 5.4Hz), 6.42 (1H,
s), 6.74 (1H, s), 7.00 (1H, s), 7.22-7.
48 (42H, m), 8.28 (1H, dt, J = 7.8, 2.0H
z), 8.80 (1H, dd, J = 4.9, 1.5Hz), 9.22
(1H, d, J = 2.0Hz)

Example 38 7β- [2-Cyclopentyloxyimino-2- (2-
Tritylaminothiazol-4-yl) acetamide]
-3- [5- (2-thienyl) -1,3,4-oxadiazol-2-yl] thio-3-cephem-4-carboxylic acid diphenylmethyl

Compound of Example 30 (200 mg, 365 μmol)
And 2-cyclopentyloxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid (363 mg, 7
Phosphorus oxychloride (51.1 μl, 548 μmol) and pyridine (104 μl, 1.28 mmol) were added to a suspension of 30 μmol) in methylene chloride (2 ml) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Water (2 ml) was added, and the mixture was further stirred for 1 hour, then the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography [methylene chloride-ethyl acetate = 10: 1] to obtain 203 mg of a pale brown amorphous title compound (yield 54
%).

¹ H-NMR (CDCl ₃ , δ): 1.54-
1.91 (8H, m), 3.50 (1H, d, J = 18.1Hz),
3.82 (1H, d, J = 18.1Hz), 4.92-4.96 (1H,
m), 5.14 (1H, d, J = 4.9Hz), 6.03 (1H,
dd, J = 9.3, 4.9 Hz), 6.72 (1H, s), 6.85
(1H, d, J = 9.3Hz), 6.97 (1H, s), 6.98
(1H, s), 7.19 (1H, dd, J = 4.9,3.9H
z), 7.25-7.46 (25H, m), 7.60 (1H, dd, J
= 4.9, 1.0Hz), 7.73 (1H, dd, J = 3.9,
1.0Hz)

Examples 39-58 Using the compounds of Examples 30-36 and the iminoacetic acid derivatives,
By treating in the same manner as in Example 38, the compounds shown in Table 7 below were obtained.

[0103]

[Table 7]

Example 39 ¹ H-NMR (CDCl ₃ , δ): 3.49 (1 H, d, J
= 18.1Hz), 3.81 (1H, d, J = 17.6Hz), 4.78
(2H, dd, J = 5.9, 1.5Hz), 5.15 (1H,
d, J = 5.4Hz), 5.23 (1H, dd, J = 10.3,
1.5Hz), 5.32 (1H, dd, J = 8.6, 1.5H
z), 5.97-6.04 (2H, m), 6.73 (1H, s), 6.
85 (1H, d, J = 9.3Hz), 6.97 (1H, s), 6.
98 (1H, s), 7.18 (1H, dd, J = 4.9,3.9H
z), 7.23-7.46 (25H, m), 7.60 (1H, dd, J
= 4.9, 1.0Hz), 7.73 (1H, dd, J = 3.9,
1.0Hz)

Example 40 ¹ H-NMR (CDCl ₃ , δ): 0.27-0.31 (2H,
m), 0.52-0.57 (2H, m), 1.10-1.20 (1H,
m), 3.50 (1H, d, J = 18.1Hz), 3.82 (1H,
d, J = 17.6Hz), 4.05-4.15 (2H, m), 5.16
(1H, d, J = 5.4Hz), 6.05 (1H, dd, J =
9.3, 4.9 Hz), 6.76 (1H, s), 6.96 (1H,
s), 6.99 (1H, s), 7.19 (1H, dd, J = 4.
9, 3.9Hz), 7.24-7.38 (23H, m), 7.45 (2
H, d, J = 7.3 Hz), 7.60 (1 H, dd, J = 4.
9, 1.0Hz), 7.73 (1H, dd, J = 3.9, 1.0H
z)

Example 41 ¹ H-NMR (CDCl ₃ , δ): 3.54 (1 H, d, J
= 18.1Hz), 3.89 (1H, d, J = 18.1Hz), 4.07
(3H, s), 5.18 (1H, d, J = 4.9Hz), 6.03
(1H, dd, J = 9.3, 4.9Hz), 6.74 (1H,
s), 6.82 (1H, d, J = 9.3Hz), 6.98 (1H,
s), 7.00 (1H, s), 7.22-7.52 (27H, m), 7.
89-7.92 (2H, m), 7.96 (1H, s)

Example 42 ¹ H-NMR (CDCl ₃ , δ): 1.60-2.00 (6H,
m), 3.54 (1H, d, J = 18.1Hz), 3.89 (1H,
d, J = 17.6Hz), 4.90-5.00 (1H, m), 5.17
(1H, d, J = 4.9Hz), 6.04 (1H, dd, J =
9.3, 4.9Hz), 6.73 (1H, s), 6.84 (1H,
d, J = 8.8 Hz), 6.96 (1H, s), 7.00 (1H,
s), 7.22-7.49 (27H, m), 7.89-7.92 (2H,
m), 7.96 (1H, s)

Example 43 ¹ H-NMR (CDCl ₃ , δ): 1.50-2.00 (8H,
m), 3.51 (1H, d, J = 18.1Hz), 3.83 (1H,
d, J = 18.1Hz), 4.93-4.96 (1H, m), 5.13
(1H, d, J = 5.4Hz), 6.02 (1H, dd, J =
9.3, 5.4Hz), 6.72 (1H, s), 6.83 (1H,
d, J = 9.3 Hz), 6.97 (1H, s), 6.99 (1H,
s), 7.13 (1H, dd, J = 4.9, 3.9Hz), 7.26
-7.42 (25H, m), 7.49-7.54 (2H, m)

Example 44 ¹ H-NMR (CDCl ₃ , δ): 3.50 (1 H, d, J
= 18.1Hz), 3.81 (1H, d, J = 18.1Hz), 4.78
(2H, d, J = 5.9Hz), 5.14 (1H, d, J =
4.9Hz), 5.22 (1H, dd, J = 10.3, 1.5H
z), 5.32 (1H, d, J = 8.1Hz), 5.96-6.06
(2H, m), 6.73 (1H, s), 6.81 (1H, d, J
= 9.3 Hz), 6.97 (1H, s), 6.99 (1H, s),
7.14 (1H, dd, J = 4.9, 3.9Hz), 7.24-7.42
(25H, m), 7.49 (1H, dd, J = 3.9,1.0H
z), 7.53 (1H, dd, J = 4.9, 1.0Hz)

Example 45 ¹ H-NMR (CDCl ₃ , δ): 0.27-0.31 (2H,
m), 0.52-0.56 (2H, m), 1.15-1.30 (1H,
m), 3.51 (1H, d, J = 18.1Hz), 3.82 (1H,
d, J = 18.1Hz), 4.11 (2H, d, J = 6.8H)
z), 5.15 (1H, d, J = 4.9Hz), 6.04 (1H,
dd, J = 8.8, 4.9 Hz), 6.76 (1H, s), 6.96
(1H, s), 7.00 (1H, s), 7.14 (1H, dd,
J = 4.9, 3.9Hz), 7.27-7.42 (25H, m), 7.49
(1H, dd, J = 3.9,1.0Hz), 7.53 (1H, d
d, J = 4.9, 1.0Hz)

Example 46 ¹ H-NMR (CDCl ₃ , δ): 3.54 (1 H, d, J
= 18.1Hz), 3.85 (1H, d, J = 18.1Hz), 4.06
(3H, s), 5.15 (1H, d, J = 5.4Hz), 6.01
(1H, dd, J = 8.8, 4.9Hz), 6.73 (1H,
s), 6.81 (1H, d, J = 8.8Hz), 6.99 (1H,
s), 7.00 (1H, s), 7.25-7.42 (25H, m), 7.
47-7.53 (3H, m), 7.89 (2H, dd, J = 7.8,
1.5Hz)

Example 47 ¹ H-NMR (CDCl ₃ , δ): 3.41 (1 H, d, J
= 18.1Hz), 3.74 (1H, d, J = 18.1Hz), 5.12
(1H, d, J = 5.4Hz), 5.89 (2H, brs), 6.0
1 (1H, dd, J = 8.8, 4.9Hz), 6.61 (1H,
s), 6.66 (1H, d, J = 8.8Hz), 7.01 (1H,
s), 7.28-7.52 (28H, m), 7.87 (2H, dd, J
= 7.8, 1.0Hz)

Example 48 ¹ H-NMR (CDCl ₃ , δ): 1.50-2.00 (8H,
m), 3.53 (1H, d, J = 18.1Hz), 3.86 (1H,
d, J = 18.1Hz), 4.93-4.96 (1H, m), 5.14
(1H, d, J = 4.9Hz), 6.02 (1H, dd, J =
9.3, 4.9 Hz), 6.72 (1H, s), 6.82 (1H,
d, J = 9.3 Hz), 6.97 (1H, s), 7.00 (1H,
s), 7.23-7.42 (25H, m), 7.46-7.54 (3H,
m), 7.88 (1H, dd, J = 7.8, 1.5Hz)

Example 49 ¹ H-NMR (CDCl ₃ , δ): 3.53 (1 H, d, J
= 18.1Hz), 3.82 (1H, d, J = 18.1Hz), 4.06
(3H, s), 5.14 (1H, d, J = 4.9Hz), 6.00
(1H, dd, J = 8.8, 4.9Hz), 6.73 (1H,
s), 6.80 (1H, d, J = 8.8Hz), 6.99 (1H,
s), 7.00 (1H, s), 7.14 (1H, t, J = 4.4H)
z), 7.29-7.42 (25H, m), 7.49 (1H, d, J =
3.9Hz), 7.53 (1H, d, J = 4.9Hz)

Example 50 ¹ H-NMR (CDCl ₃ , δ): 3.57 (1 H, d, J
= 18.1Hz), 3.98 (1H, d, J = 18.1Hz), 4.06
(3H, s), 5.17 (1H, d, J = 4.9Hz), 6.02
(1H, dd, J = 9.3, 4.9Hz), 6.74 (1H,
s), 6.80 (1H, d, J = 9.3Hz), 6.98 (1H,
s), 7.02 (1H, s), 7.23-7.43 (25H, m), 7.
57-7.60 (2H, m), 7.88-7.96 (3H, m), 8.02
(1H, dd, J = 8.3, 1.5Hz), 8.33 (1H,
s)

Example 51 ¹ H-NMR (CDCl ₃ , δ): 3.44 (1 H, d, J
= 18.1Hz), 3.78 (1H, d, J = 18.1Hz), 5.14
(1H, d, J = 4.9Hz), 5.65-5.80 (2H, b
r), 6.04 (1H, dd, J = 8.8, 4.9Hz), 6.62
(1H, s), 6.72 (1H, d, J = 7.8Hz), 7.02
(1H, s), 7.22-7.45 (25H, m), 7.55-7.61
(2H, m), 7.86-7.96 (3H, m), 8.01 (1H,
dd, J = 8.3,1.5Hz), 8.30 (1H, s)

Example 52 ¹ H-NMR (CDCl ₃ , δ): 1.60-2.00 (6H,
m), 3.56 (1H, d, J = 18.1Hz), 3.88 (1H,
d, J = 18.1Hz), 4.90-5.00 (1H, m), 5.16
(1H, d, J = 4.9Hz), 6.03 (1H, dd, J =
9.3, 4.9Hz), 6.73 (1H, s), 6.83 (1H,
d, J = 9.3 Hz), 6.96 (1H, s), 7.01 (1H,
s), 7.23-7.43 (25H, m), 7.57-7.60 (2H,
m), 7.88-7.96 (3H, m), 8.02 (1H, dd, J
= 8.8, 1.5Hz), 8.32 (1H, s)

Example 53 ¹ H-NMR (CDCl ₃ , δ): 3.53 (1 H, d, J
= 18.1Hz), 3.84 (1H, d, J = 18.1Hz), 3.92
(3H, s), 3.94 (6H, s), 4.06 (3H, s),
5.15 (1H, d, J = 5.4Hz), 6.01 (1H, dd,
J = 9.3, 4.9Hz), 6.74 (1H, s), 6.78 (1
H, d, J = 8.8Hz), 6.98 (1H, s), 7.01 (1
H, s), 7.12 (2H, s), 7.23-7.43 (25H, m)

Example 54 ¹ H-NMR (CDCl ₃ , δ): 3.40 (1 H, d, J
= 18.1Hz), 3.75 (1H, d, J = 17.6Hz), 3.91
(6H, s), 3.92 (3H, s), 5.12 (1H, d, J
= 4.9 Hz), 5.76 (2H, brs), 6.02 (1H, d
d, J = 8.3, 4.9Hz), 6.62 (1H, s), 6.74
(1H, d, J = 8.3Hz), 7.01 (1H, s), 7.10
(2H, s), 7.28-7.45 (25H, m)

Example 55 ¹ H-NMR (CDCl ₃ , δ): 1.60-2.00 (6H,
m), 3.52 (1H, d, J = 18.1Hz), 3.85 (1H,
d, J = 18.1Hz), 3.92 (3H, s), 3.94 (6H,
s), 4.90-4.95 (1H, m), 5.14 (1H, d, J =
4.9Hz), 6.02 (1H, dd, J = 9.3, 4.9H
z), 6.72 (1H, s), 6.80 (1H, d, J = 8.8H
z), 6.96 (1H, s), 7.00 (1H, s), 7.12 (2
H, s), 7.23-7.43 (25H, m)

Example 56 ¹ H-NMR (CDCl ₃ , δ): 3.59 (1 H, d, J
= 18.1Hz), 3.96 (1H, d, J = 18.1Hz), 4.09
(3H, s), 5.22 (1H, d, J = 5.4Hz), 6.04
(1H, dd, J = 9.3, 4.9Hz), 6.75 (1H,
s), 6.83 (1H, d, J = 8.8Hz), 7.00 (1H,
s), 7.01 (1H, s), 7.17-7.31 (25H, m), 7.
45-7.55 (3H, m), 8.20-8.25 (2H, m)

Example 57 ¹ H-NMR (CDCl ₃ , δ): 3.49 (1 H, d, J
= 18.1Hz), 3.88 (1H, d, J = 18.1Hz), 5.18
(1H, d, J = 4.9Hz), 5.70-5.85 (2H, b
r), 6.06 (1H, dd, J = 8.8, 4.9Hz), 6.55
-6.65 (1H, br), 6.64 (1H, s), 7.02 (1H,
s), 7.17-7.33 (25H, m), 7.43-7.52 (3H,
m), 8.20-8.25 (2H, m)

Example 58 ¹ H-NMR (CDCl ₃ , δ): 1.60-2.00 (6H,
m), 3.59 (1H, d, J = 18.1Hz), 3.96 (1H,
d, J = 18.1Hz), 4.95-5.00 (1H, m), 5.21
(1H, d, J = 5.4Hz), 6.06 (1H, dd, J =
9.3, 4.9Hz), 6.74 (1H, s), 6.91 (1H,
d, J = 8.8 Hz), 6.98 (1H, s), 7.01 (1H,
s), 7.18-7.31 (25H, m), 7.45-7.55 (3H,
m), 8.20-8.25 (2H, m)

Example 59 7β-Phenylacetamide-3- [5- (pyridine-
4-yl) -1,3,4-oxadiazol-2-yl] thio-3-cephem-4-carboxylate sodium salt

Compound of Example 3 (69.0 mg, 104 μmol)
Of anisole (0.5 ml) in trifluoroacetic acid (0.5
ml) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into diisopropyl ether (50 ml), and the precipitated crystals were collected by filtration and air dried. After suspending this in water (4 ml), the pH was adjusted to 7.4 with a saturated aqueous sodium hydrogen carbonate solution, and the low bar column LiChro was used.
After purification with prep RP-8 [water-acetonitrile = 4: 1],
Lyophilization gave the title compound as a colorless powder, 40.7
mg was obtained (yield 76%).

¹ H-NMR (DMSO-d6 + D ₂ O,
δ): 3.40 (1H, d, J = 16.6Hz), 3.84 (1H,
d, J = 17.1Hz), 5.10 (1H, d, J = 4.9H)
z), 5.58 (1H, d, J = 4.9Hz), 7.22-7.30
(5H, m), 7.95 (2H, d, J = 5.9Hz), 8.82
(2H, d, J = 5.9Hz) MS (FAB +, m / z): 518 [M + H] IR (KBr, cm ^-1 ): 3434, 2361, 1769, 1657, 16
18, 1537, 1462, 1393, 1348, 1262, 1179

Examples 60 to 62 The compounds of Examples 5, 15 and 16 were used and treated in the same manner as in Example 59, to give compounds of Table 8 below.

[0128]

[Table 8]

Example 60 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.38
(1H, d, J = 17.1Hz), 3.57 (1H, d, J = 1
3.7Hz), 3.79 (1H, d, J = 16.6Hz), 5.09
(1H, d, J = 4.9Hz), 5.56 (1H, d, J =
4.9Hz), 7.20-7.31 (5H, m), 7.58-7.64 (3
H, m), 8.01 (2H, dd, J = 7.8, 1.5Hz) MS (FAB +, m / z): 517 [M + H] IR (KBr, cm ^-1 ): 3422, 1769, 1620, 1549, 14
93, 1470, 1393, 1346, 1263, 1177, 1082

Example 61 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.36
(1H, d, J = 17.1Hz), 3.49 (1H, d, J = 1
3.7Hz), 3.56 (1H, d, J = 13.7Hz), 3.75
(1H, d, J = 17.1Hz), 5.07 (1H, d, J =
4.9Hz), 5.55 (1H, d, J = 4.9Hz), 7.20-
7.31 (6H, m), 7.86 (1H, t, J = 1.5Hz),
7.94 (1H, d, J = 4.9Hz) MS (FAB +, m / z): 523 [M + H] IR (KBr, cm ^-1 ): 3422, 1769, 1620, 1535, 14
95, 1472, 1393, 1348, 1177, 1086

Example 62 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.57
(1H, d, J = 13.7Hz), 3.83 (1H, d, J = 1
6.6Hz), 5.12 (1H, d, J = 4.9Hz), 5.58
(1H, d, J = 4.9Hz), 7.21-7.31 (5H,
m), 7.63-7.69 (2H, m), 8.02-8.18 (4H,
m), 8.64 (1H, s) MS (FAB +, m / z): 567 [M + H] IR (KBr, cm ^-1 ): 3420, 1769, 1620, 1539, 14
74, 1395, 1352, 1269, 1179, 1128, 1074, 1005

Example 63 Sodium 7β-phenylacetamide-3- [5- (1-naphthyl) -1,3,4-oxadiazol-2-yl] thio-3-cephem-4-carboxylate

Compound of Example 6 (71.1 mg, 100 μmol)
Trifluoroacetic acid (1 ml) in anisole (1 ml) solution
Was added and stirred at room temperature for 1 hour. The reaction solution was poured into diisopropyl ether (50 ml), and the precipitated crystals were collected by filtration and air dried. This was suspended in water (4 ml) and adjusted to pH 7.6 with a saturated aqueous sodium hydrogen carbonate solution. The precipitated crystals were collected by filtration, washed with water and then freeze-dried to give the title compound as a colorless powder.
32.6 mg was obtained (yield 57%).

¹ H-NMR (DMSO-d6 + D ₂ O,
δ): 3.86 (1H, d, J = 17.1Hz), 5.11 (1H,
d, J = 4.9Hz), 5.57 (1H, d, J = 4.9H)
z), 7.22-7.29 (5H, m), 7.66-7.78 (3H,
m), 8.10 (1H, d, J = 7.8Hz), 8.22 (2H,
d, J = 7.3 Hz), 9.06 (1H, d, J = 8.8 Hz) MS (FAB +, m / z): 567 [M + H] IR (KBr, cm ^-1 ): 3424, 3057, 1769, 1663, 16
22, 1532, 1474, 1395, 1348, 1262, 1179, 1123, 1007

Example 64 7β-Phenylacetamido-3- [5- (2-thienyl) -1,3,4-thiadiazol-2-yl] thio-
3-Cephem-4-carboxylate sodium

Compound of Example 11 (150 mg, 220 μmol)
Trifluoroacetic acid (1 ml) in anisole (1 ml) solution
Was added and stirred at room temperature for 1 hour. The reaction solution was poured into diisopropyl ether (50 ml), and the precipitated crystals were collected by filtration and air dried. After suspending this in water (4 ml), the pH was adjusted to 7.4 with a saturated aqueous sodium hydrogen carbonate solution, and the adsorbent HP-20 [water → water-
Acetonitrile (20: 1) → water-acetonitrile (4: 1)]
After purification in, and freeze-drying, 71.6 mg of the title compound was obtained as a yellowish white powder (yield 61%).

¹ H-NMR (DMSO-d6 + D ₂ O,
δ): 3.37 (1H, d, J = 17.1Hz), 3.50 (1H,
d, J = 14.1Hz), 3.57 (1H, d, J = 13.7H)
z), 3.80 (1H, d, J = 17.1Hz), 5.08 (1H,
d, J = 5.4Hz, 5.59 (1H, d, J = 4.9H)
z), 7.20-7.32 (6H, m), 7.68 (1H, d, J =
3.9 Hz), 7.82 (1 H, d, J = 4.9 Hz) MS (FAB +, m / z): 539 [M + H] IR (KBr, cm ^-1 ): 3420, 1767, 1620, 1537, 14
97, 1445, 1393, 1350, 1261, 1179, 1049

Example 65 7β-Phenylacetamide-3- (3-phenyl-
Sodium 1,2,4-thiadiazol-5-yl) thio-3-cephem-4-carboxylate

By treating with the compound of Example 17 in the same manner as in Example 64, 11.6 of the title compound was obtained as a yellowish white powder.
mg was obtained (yield 15%).

¹ H-NMR (DMSO-d6 + D ₂ O,
δ): 3.51 (1H, d, J = 13.7Hz), 3.59 (1H,
d, J = 13.7Hz), 3.93 (1H, d, J = 17.1H)
z), 5.15 (1H, d, J = 4.9Hz), 5.62 (1H,
d, J = 5.4 Hz), 7.22-7.33 (5H, m), 7.45-
7.60 (3H, m), 8.10-8.20 (2H, m) MS (FAB +, m / z): 533 [M + H] IR (KBr, cm ^-1 ): 3430, 1769, 1618, 1528, 14
64, 1433, 1391, 1348, 1319, 1277, 1179, 1113, 1073

Example 66 7β- [2- (2-aminothiazol-2-yl) -2
-Methoxyiminoacetamide] -3- [5- (pyridin-2-yl) -1,3,4-oxadiazole-2-
Il] thio-3-cephem-4-carboxylic acid sodium salt

Compound of Example 18 (78.3 mg, 80.8 μmol)
Trifluoroacetic acid (1 ml) in anisole (1 ml) solution
Was added and stirred at room temperature for 1 hour. The reaction solution was poured into diisopropyl ether (30 ml), and the precipitated crystals were collected by filtration and air dried. After suspending this in water (4 ml), adjust the pH to 7.4 with saturated aqueous sodium hydrogen carbonate solution, and apply to the row bar column LiChroprep.
After purification with RP-8 [water-acetonitrile = 4: 1] and freeze-drying, 32.5 mg of the title compound was obtained as a colorless powder (yield 69%).

¹ H-NMR (DMSO-d6 + D ₂ O,
δ): 3.39 (1H, d, J = 16.6Hz), 3.83 (3H,
s), 5.15 (1H, d, J = 4.9Hz), 5.68 (1H,
d, J = 4.9 Hz), 6.75 (1H, s), 7.65 (1H,
dd, J = 7.3, 4.9 Hz), 8.06 (1H, td, J =
7.8, 1.5Hz), 8.17 (1H, d, J = 7.8Hz),
8.78 (1H, d, J = 3.9Hz) MS (FAB +, m / z): 583 [M + H] IR (KBr, cm ^-1 ): 3426, 1771, 1620, 1534, 14
62, 1389, 1348, 1181, 1090, 1038

[0144] Using the compound of Example 67 to 74 Examples 19～22,27,28,37 and 39, it was treated in the same manner as in Example 66 to give the compounds of Table 9, wherein.

[0145]

[Table 9]

Example 67 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.38
(1H, d, J = 16.6Hz), 3.83 (3H, s), 3.84
(1H, d, J = 16.6Hz), 5.16 (1H, d, J =
4.9Hz), 5.68 (1H, d, J = 4.9Hz), 6.74
(1H, s), 7.64 (1H, dd, J = 7.8,4.9H
z), 8.39 (1H, d, J = 7.8Hz), 8.80 (1H,
d, J = 4.9 Hz), 9.17 (1 H, s) MS (FAB +, m / z): 583 [M + H] IR (KBr, cm ⁻¹ ): 3426, 1775, 1615, 1537, 14
68, 1391, 1348, 1181, 1127, 1088, 1038

Example 68 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.33
(1H, d, J = 17.1Hz), 3.71 (1H, d, J = 1
7.1Hz), 3.83 (3H, s), 5.13 (1H, d, J =
4.9Hz), 5.66 (1H, d, J = 4.9Hz), 6.74
(1H, s), 6.88 (1H, d, J = 8.3Hz), 7.31
(1H, dd, J = 8.3, 2.0Hz), 7.36 (1H,
d, J = 2.0 Hz) MS (FAB +, m / z): 614 [M + H] IR (KBr, cm ^-1 ): 3428, 1769, 1659, 1611, 15
74, 1537, 1493, 1391, 1350, 1319, 1285, 1208, 118
1, 1123, 1088, 1042

Example 69 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.31
(1H, d, J = 16.6Hz), 3.70 (1H, d, J = 1
7.1Hz), 3.83 (3H, s), 5.13 (1H, d, J =
4.9Hz), 5.65 (1H, d, J = 4.9Hz), 6.74
(1H, s), 7.14 (1H, s), 7.75 (1H, s) MS (FAB +, m / z): 615 [M + H] IR (KBr, cm ^-1 ): 3426, 1775, 1616, 1535, 15
01, 1474, 1391, 1348, 1181, 1088, 1038

Example 70 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.38
(1H, d, J = 17.1Hz), 3.83 (3H, s), 3.85
(1H, d, J = 18.1Hz), 5.17 (1H, d, J =
4.9Hz), 5.68 (1H, d, J = 4.9Hz), 6.74
(1H, s), 7.95 (2H, d, J = 6.3Hz), 8.82
(2H, d, J = 5.9Hz) MS (FAB +, m / z): 583 [M + H] IR (KBr, cm ^-1 ): 3426, 1775, 1667, 1615, 15
41, 1466, 1393, 1350, 1263, 1179, 1094, 1038, 1001

Example 71 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.36
(1H, d, J = 16.6Hz), 3.83 (1H, d, J = 1
6.6Hz), 5.16 (1H, d, J = 5.4Hz), 5.69
(1H, d, J = 4.9Hz), 6.67 (1H, s), 7.64
(1H, dd, J = 7.8, 4.9Hz), 8.38 (1H, d
t, J = 8.3, 2.0 Hz), 8.80 (1H, dd, J =
4.9, 1.5 Hz), 9.17 (1 H, d, J = 1.5 Hz) MS (FAB +, m / z): 569 [M + H] IR (KBr, cm ⁻¹ ): 3422, 1769, 1618, 1532, 14
68, 1389, 1354, 1188, 1086, 1044

Example 72 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.32
(1H, d, J = 16.6Hz), 3.83 (3H, s), 5.14
(1H, d, J = 5.4Hz), 5.68 (1H, d, J =
4.9Hz), 6.73 (1H, s), 7.31 (1H, s), 7.7
0 (1H, s) MS (FAB +, m / z): 631 [M + H] IR (KBr, cm ^-1 ): 3443, 1765, 1659, 1620, 15
39, 1443, 1393, 1356, 1314, 1182, 1044

Example 73 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.38
(1H, d, J = 17.1Hz), 3.84 (3H, s), 3.86
(1H, d, J = 18.1Hz), 5.16 (1H, d, J =
5.4Hz), 5.71 (1H, d, J = 5.4Hz), 6.74
(1H, s), 7.55 (1H, dd, J = 7.3, 4.9H
z), 8.02 (1H, td, J = 8.2, 2.0Hz), 8.20
(1H, d, J = 8.3Hz), 8.66 (1H, d, J =
4.9 Hz) MS (FAB +, m / z): 599 [M + H] IR (KBr, cm ^-1 ): 3426, 1771, 1620, 1534, 14
35, 1389, 1352, 1262, 1181, 1038, 1007

Example 74 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.35
(1H, d, J = 17.1Hz), 3.81 (1H, d, J = 1
6.6Hz), 4.58 (2H, d, J = 5.4Hz), 5.14-
5.18 (2H, m), 5.31 (1H, dd, J = 17.6, 2.0
Hz), 5.70 (1H, d, J = 4.9Hz), 5.93-6.00
(1H, m), 6.72 (1H, s), 7.22 (1H, dd,
J = 4.9, 3.4Hz), 7.67 (1H, dd, J = 3.4,
1.0Hz), 7.82 (1H, dd, J = 4.9, 1.0Hz) MS (FAB +, m / z): 630 [M + H] IR (KBr, cm ^-1 ): 3424, 1769, 1620, 1534, 14
45, 1385, 1262, 1182, 1022

Example 75 7β- [2- (2-aminothiazol-2-yl) -2
-Methoxyiminoacetamido] -3- (5-phenyl-1,3,4-oxadiazol-2-yl) thio-3
-Cephem-4-carboxylate sodium

Compound of Example 23 (348 mg, 359 μmol)
Trifluoroacetic acid (1 ml) in anisole (1 ml) solution
Was added and stirred at room temperature for 1 hour. The reaction solution was poured into diisopropyl ether (50 ml), and the precipitated crystals were collected by filtration and air dried. After suspending this in water (4 ml), the pH was adjusted to 7.6 with a saturated aqueous sodium hydrogen carbonate solution, and the adsorbent HP-20P [water → water-
Acetonitrile (20: 1) → water-acetonitrile (4: 1
)] And lyophilized to give 223 mg of the title compound as a colorless powder (quantitative yield).

¹ H-NMR (DMSO-d6 + D ₂ O,
δ): 3.83 (3H, s), 5.16 (1H, d, J = 4.9H)
z), 5.66 (1H, d, J = 4.9Hz), 6.74 (1H,
s), 7.58-7.64 (3H, m), 8.00-8.02 (2H,
m) MS (FAB +, m / z): 582 [M + H] IR (KBr, cm ^-1 ): 3424, 1773, 1620, 1534, 14
70, 1389, 1346, 1264, 1179, 1040

Examples 76-98 Examples 24-26, 38-43, 45-58
By treating in the same manner as in 75, the compounds shown in Table 10 below were obtained.

[0158]

[Table 10]

Example 76 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.35
(1H, d, J = 16.6Hz), 3.76 (1H, d, J = 1
7.1Hz), 3.83 (3H, s), 5.14 (1H, d, J =
4.9Hz), 5.66 (1H, d, J = 4.9Hz), 6.74
(1H, s), 7.30 (1H, dd, J = 4.9,3.9H
z), 7.86 (1H, dd, J = 3.9, 1.0Hz), 7.95
(1H, dd, J = 4.9, 1.0Hz) MS (FAB +, m / z): 588 [M + H] IR (KBr, cm ^-1 ): 3426, 1771, 1622, 1532, 14
72, 1389, 1348, 1263, 1179, 1036

Example 77 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.83
(3H, s), 5.18 (1H, d, J = 5.4Hz), 5.68
(1H, d, J = 4.9Hz), 6.74 (1H, s), 7.63
-7.69 (2H, m), 8.03-8.18 (4H, m), 8.64
(1H, s) MS (FAB +, m / z): 632 [M + H] IR (KBr, cm ⁻¹ ): 3426, 1773, 1622, 1534, 14
72, 1389, 1348, 1267, 1179, 1128, 1038

Example 78 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.55
(1H, d, J = 16.6Hz), 3.83 (3H, s), 3.87
(1H, d, J = 16.1Hz), 5.18 (1H, d, J =
4.9Hz), 5.68 (1H, d, J = 4.9Hz), 6.75
(1H, s), 7.66-7.78 (3H, m), 8.10 (1H,
d, J = 8.3Hz, 8.23 (2H, d, J = 7.8H)
z), 9.07 (1H, d, J = 8.8Hz) MS (FAB +, m / z): 632 [M + H] IR (KBr, cm ^-1 ): 3428, 1771, 1620, 1534, 14
76, 1391, 1348, 1263, 1179, 1123, 1038

Example 79 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 1.40-
1.55 (2H, m), 1.60-1.90 (6H, m), 3.33 (1
H, d, J = 16.6Hz), 3.77 (1H, d, J = 16.6H)
z), 4.62-4.65 (1H, m), 5.14 (1H, d, J =
5.4Hz), 5.66 (1H, d, J = 4.9Hz), 6.69
(1H, s), 7.29 (1H, dd, J = 4.9,3.9H
z), 7.86 (1H, dd, J = 3.9, 1.0Hz), 7.95
(1H, dd, J = 4.9, 1.0Hz) MS (FAB +, m / z): 642 [M + H] IR (KBr, cm ^-1 ): 3439, 2959, 2866, 1769, 16
24, 1532, 1474, 1393, 1352, 1177, 1034

Example 80 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.34
(1H, d, J = 16.6Hz), 3.76 (1H, d, J = 1
6.6Hz), 4.57 (2H, d, J = 5.4Hz), 5.14-
5.19 (2H, m), 5.30 (1H, dt, J = 17.6,1.5
Hz), 5.68 (1H, d, J = 4.9Hz), 5.91-6.01
(1H, m), 6.73 (1H, s), 7.29 (1H, dd,
J = 4.9, 3.9 Hz), 7.86 (1H, dd, J = 3.9,
1.0 Hz), 7.95 (1 H, d, J = 4.9 Hz) MS (FAB +, m / z): 614 [M + H] IR (KBr, cm ⁻¹ ): 3428, 1773, 1622, 1532, 14
72, 1389, 1348, 1263, 1179, 1022

Example 81 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 0.24−
0.27 (2H, m), 0.46-0.50 (2H, m), 1.09-1.
15 (1H, m), 3.34 (1H, d, J = 16.6Hz), 3.
76 (1H, d, J = 17.1Hz), 3.83-3.91 (2H,
m), 5.14 (1H, d, J = 4.9Hz), 5.68 (1H,
d, J = 5.4Hz), 6.71 (1H, s), 7.29 (1H,
dd, J = 4.9, 3.9 Hz), 7.86 (1H, dd, J =
3.9, 1.0Hz), 7.95 (1H, dd, J = 4.9, 1.0
Hz) MS (FAB +, m / z): 628 [M + H] IR (KBr, cm ^-1 ): 3432, 1769, 1624, 1532, 14
72, 1393, 1348, 1179, 1026

Example 82 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.83
(3H, s), 3.84 (1H, d, J = 16.6Hz), 5.16
(1H, d, J = 4.9Hz), 5.68 (1H, d, J =
4.9Hz), 6.74 (1H, s), 7.49-7.54 (2H,
m), 8.02 (1H, d, J = 8.3Hz), 8.12 (1H,
d, J = 7.3 Hz), 8.25 (1 H, s) MS (FAB +, m / z): 638 [M + H] IR (KBr, cm ⁻¹ ): 3428, 1773, 1620, 1532, 14
68, 1389, 1348, 1263, 1157, 1038

Example 83 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 1.40-
1.55 (2H, m), 1.60-1.90 (6H, m), 3.84 (1
H, d, J = 16.6Hz), 5.17 (1H, d, J = 4.9H)
z), 5.68 (1H, d, J = 4.9Hz), 6.70 (1H,
s), 7.48-7.55 (2H, m), 8.02 (1H, d, J =
6.8Hz), 8.12 (1H, d, J = 7.3Hz), 8.25
(1H, s) MS (FAB +, m / z): 692 [M + H] IR (KBr, cm ⁻¹ ): 3432, 2959, 1765, 1657, 16
22, 1535, 1468, 1391, 1352, 1157

Example 84 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 1.40-
1.55 (2H, m), 1.60-1.90 (6H, m), 3.38 (1
H, d, J = 18.1Hz), 3.81 (1H, d, J = 17.1H)
z), 4.64-4.66 (1H, m), 5.15 (1H, d, J =
5.4Hz), 5.68 (1H, d, J = 4.9Hz), 6.69
(1H, s), 7.23 (1H, dd, J = 5.4,3.9H
z), 7.66 (1H, dd, J = 3.9, 1.0Hz), 7.82
(1H, dd, J = 5.4, 1.0Hz) MS (FAB +, m / z): 658 [M + H] IR (KBr, cm ^-1 ): 3432, 2957, 1769, 1620, 15
34, 1445, 1385, 1352, 1179, 1046

Example 85 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 0.25-
0.28 (2H, m), 0.45-0.50 (2H, m), 1.05-1.
20 (1H, m), 3.35 (1H, d, J = 17.1Hz), 3.
80 (1H, d, J = 17.1Hz), 3.88 (2H, dd, J
= 6.8, 4.9Hz), 5.14 (1H, d, J = 5.4H
z), 5.70 (1H, d, J = 5.4Hz), 6.71 (1H,
s), 7.22 (1H, dd, J = 4.9, 3.9Hz), 7.67
(1H, dd, J = 3.9, 1.0Hz), 7.82 (1H, d
d, J = 4.9, 1.0 Hz) MS (FAB +, m / z): 644 [M + H] IR (KBr, cm ^-1 ): 3424, 1769, 1620, 1534, 14
45, 1389, 1348, 1262, 1181, 1026

Example 86 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.83
(3H, s), 3.84 (1H, d, J = 17.1Hz), 5.15
(1H, d, J = 5.4Hz), 5.69 (1H, d, J =
4.4Hz), 6.73 (1H, s), 7.50-7.60 (3H,
m), 7.85-7.95 (2H, m) MS (FAB +, m / z): 598 [M + H] IR (KBr, cm ^-1 ): 3422, 1773, 1618, 1534, 14
58, 1387, 1348, 1262, 1181, 1042

Example 87 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.83
(1H, d, J = 17.1Hz), 5.15 (1H, d, J =
4.9Hz), 5.70 (1H, d, J = 4.9Hz), 6.65
(1H, s), 7.50-7.60 (3H, m), 7.85-7.95
(2H, m) MS (FAB +, m / z): 584 [M + H] IR (KBr, cm ^-1 ): 3428, 1767, 1620, 1530, 14
58, 1383, 1262, 1182, 1127, 1047, 1001

Example 88 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 1.40-
1.55 (2H, m), 1.60-1.90 (6H, m), 3.84 (1
H, d, J = 16.6 Hz), 4.60-4.70 (1 H, m), 5.
16 (1H, d, J = 5.4Hz), 5.68 (1H, d, J =
4.9Hz), 6.69 (1H, s), 7.50-7.60 (3H,
m), 7.85-7.95 (2H, m) MS (FAB +, m / z): 652 [M + H] IR (KBr, cm ^-1 ): 3426, 2959, 1769, 1620, 15
30, 1456, 1391, 1350, 1262, 1179, 1044

Example 89 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.36
(1H, d, J = 16.6Hz), 3.81 (1H, d, J = 1
7.6Hz), 3.83 (3H, s), 5.14 (1H, d, J =
4.9Hz), 5.69 (1H, d, J = 4.9Hz), 6.73
(1H, s), 7.22 (1H, dd, J = 4.9,3.9H
z), 7.68 (1H, dd, J = 3.9, 1.0Hz), 7.82
(1H, dd, J = 4.9, 1.0Hz) MS (FAB +, m / z): 604 [M + H] IR (KBr, cm ^-1 ): 3428, 1771, 1620, 1534, 14
45, 1385, 1348, 1260, 1179, 1042

Example 90 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.84
(3H, s), 5.17 (1H, d, J = 4.9Hz), 5.70
(1H, d, J = 4.9Hz), 6.74 (1H, s), 7.59
-7.64 (2H, m), 7.99-8.10 (4H, m), 8.47
(1H, s) MS (FAB +, m / z): 648 [M + H] IR (KBr, cm ^-1 ): 3422, 1771, 1618, 1532, 13
85, 1262, 1181, 1128, 1040

Example 91 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.86
(1H, d, J = 16.6Hz), 5.17 (1H, d, J =
4.9Hz), 5.72 (1H, d, J = 4.9Hz), 6.75
(1H, s), 7.59-7.64 (2H, m), 8.01-8.10
(4H, m), 8.47 (1H, s) MS (FAB +, m / z): 634 [M + H] IR (KBr, cm ^-1 ): 3424, 1767, 1618, 1530, 13
73, 1192, 1128, 1046

Example 92 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 1.40-
1.50 (2H, m), 1.60-2.00 (6H, m), 3.87 (1
H, d, J = 17.1Hz), 5.18 (1H, d, J = 5.4H)
z), 5.69 (1H, d, J = 4.9Hz), 6.70 (1H,
s), 7.60-7.64 (2H, m), 7.99-8.09 (4H,
m), 8.46 (1H, s) MS (FAB +, m / z): 702 [M + H] IR (KBr, cm ^-1 ): 3430, 2959, 1769, 1622, 15
30,1362,1192,1128

Example 93 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.73
(3H, s), 3.825 (1H, d, J = 16.6Hz),
3.831 (3H, s), 3.87 (6H, s), 5.15 (1H,
d, J = 4.9Hz), 5.68 (1H, d, J = 4.9H)
z), 6.74 (1H, s), 7.16 (2H, s) MS (FAB +, m / z): 688 [M + H] IR (KBr, cm ^-1 ): 3426, 1773, 1620, 1532, 14
64, 1408, 1331, 1242, 1173, 1127, 1040

[0177]Example 94 ¹ H-NMR (DMSO-d6 + D_TwoO, δ): 3.73
(3H, s), 3.82 (1H, d, J = 16.6Hz), 3.87
(6H, s), 5.15 (1H, d, J = 4.9Hz), 5.69
(1H, d, J = 4.9Hz), 6.65 (1H, s), 7.16
(1H, s) MS (FAB +, m / z): 674 [M + H] IR (KBr, cm^-1): 3430, 1769, 1620, 1514, 14
66, 1408, 1331, 1242, 1171, 1127, 1047

Example 95 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 1.40-
1.55 (2H, m), 1.60-1.90 (6H, m), 3.34 (1
H, d, J = 16.6 Hz), 3.73 (3 H, s), 3.83 (1
H, d, J = 17.1 Hz), 3.87 (6 H, s), 4.60-4.
70 (1H, m), 5.16 (1H, d, J = 4.9Hz), 5.
68 (1H, d, J = 4.9Hz), 6.69 (1H, s), 7.
16 (1H, s) MS (FAB +, m / z): 742 [M + H] IR (KBr, cm ^-1 ): 3426, 2953, 1771, 1620, 15
14,1464,1408,1331,1242,1171,1127

Example 96 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.85
(3H, s), 3.96 (1H, d, J = 16.6Hz), 5.22
(1H, d, J = 5.4Hz), 5.73 (1H, d, J =
4.9Hz), 6.75 (1H, s), 7.50-7.60 (3H,
m), 8.10-8.20 (2H, m) MS (FAB +, m / z): 598 [M + H] IR (KBr, cm ^-1 ): 3424, 1771, 1620, 1530, 14
64, 1433, 1387, 1346, 1319, 1277, 1179, 1113, 1036

Example 97 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 3.95
(1H, d, J = 17.1Hz), 5.22 (1H, d, J =
5.4Hz), 5.74 (1H, d, J = 4.9Hz), 6.67
(1H, s), 7.50-7.60 (3H, m), 8.10-8.20
(2H, m) MS (FAB +, m / z): 584 [M + H] IR (KBr, cm ^-1 ): 3426, 1769, 1618, 1530, 14
64, 1433, 1389, 1348, 1319, 1277, 1181, 1113, 1044

Example 98 ¹ H-NMR (DMSO-d6 + D ₂ O, δ): 1.40-
1.55 (2H, m), 1.60-1.95 (6H, m), 3.95 (1
H, d, J = 17.1 Hz), 4.60-4.70 (1 H, m), 5.
23 (1H, d, J = 4.9Hz), 5.73 (1H, d, J =
4.9Hz), 6.70 (1H, s), 7.50-7.60 (3H,
m), 8.10-8.20 (2H, m) MS (FAB +, m / z): 652 [M + H] IR (KBr, cm ^-1 ): 3426, 2959, 1771, 1620, 15
30, 1464, 1433, 1389, 1348, 1319, 1277, 1177, 1113

Example 99 7β- [2- (2-aminothiazol-2-yl) -2
-Methoxyiminoacetamido] -3- [5- (1-methylpyridinium-3-yl) -1,3,4-oxadiazol-2-yl] thio-3-cephem-4-carboxylate

Compound of Example 19 (64.6 mg, 66.7 μmol)
In acetonitrile (1 ml) solution of iodomethane (41.5μ
l, 667 μmol) was added and the mixture was stirred at 4 ° C. for 14 hours and then at room temperature for 24 hours. The residue obtained by distilling off the reaction solution was dissolved in anisole (1 ml) and then trifluoroacetic acid (1 ml).
Was added and stirred at room temperature for 1 hour. The reaction solution was poured into diisopropyl ether (50 ml), and the precipitated crystals were collected by filtration and air dried. After suspending this in water (4 ml), adjust the pH to 7.4 with saturated aqueous sodium hydrogen carbonate solution, and apply to the row bar column LiChroprep.
After purification with RP-8 [water-acetonitrile = 4: 1] and freeze-drying, 19.1 mg of the title compound was obtained as a pale yellow powder.
Obtained (yield 50%).

¹ H-NMR (DMSO-d6 + D ₂ O,
δ): 3.83 (3H, s), 4.45 (3H, s), 5.15 (1)
H, d, J = 4.9Hz, 5.70 (1H, d, J = 4.9H)
z), 6.74 (1H, s), 8.29 (1H, t, J = 8.3H)
z), 9.08 (1H, d, J = 8.8Hz), 9.12 (1H,
d, J = 6.8 Hz), 9.70 (1 H, s) MS (FAB +, m / z): 575 [M + H] IR (KBr, cm ⁻¹ ): 3424, 1771, 1620, 1534, 14
62, 1385, 1346, 1169, 1034

Example 100 5- (1-naphthyl) -1,3,4-oxadiazole-2-thiol

To a solution of naphthalene-1-carboxylic acid hydrazide (1.34 g, 7.20 mmol) in ethanol (7.2 ml) was added potassium hydroxide powder (808 mg, 14.4 mmol) and then carbon disulfide (1.52 ml, 25.2 mmol) at room temperature. It was stirred for 15 minutes. The reaction solution was heated under reflux for 5 hours, the solvent was evaporated, and the resulting residue was dissolved in water and adjusted to pH 4 with 2N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, dried in air, and recrystallized from 50% methanol to obtain 254 mg of the title compound as colorless needle crystals (yield 15%).

¹ H-NMR (DMSO-d6, δ): 7.6
6-7.77 (3H, m), 8.11 (1H, d, J = 7.8H
z), 8.14 (1H, dd, J = 7.3, 1.0Hz), 8.24
(1H, d, J = 7.8Hz), 8.85 (1H, d, J =
8.8Hz) MS (EI +, m / z): 228 (M ⁺ )

Example 101 5- (2-naphthyl) -1,3,4-oxadiazole-2-thiol

The same treatment as in Example 100 was carried out using naphthalene-2-carboxylic acid hydrazide (1.83 g, 9.83 mmol) to obtain 345 mg of the title compound as pale yellow needles (yield 15%).

¹ H-NMR (DMSO-d6, δ): 7.6
3-7.70 (2H, m), 7.94 (1H, dd, J = 8.8,
2.0Hz), 8.03 (1H, d, J = 7.3Hz), 8.10
(1H, t, J = 8.3Hz), 8.17 (1H, d, J =
8.3Hz), 8.54 (1H, s) MS (EI +, m / z): 228 (M ⁺ )

Example 102 5- (3,4,5-trimethoxyphenyl) -1,3
4-thiadiazole-2-thiol

To a solution of 3,4,5-trimethoxybenzoic acid hydrazide (7.95 g, 35.1 mmol) in ethanol (35 ml) was added potassium hydroxide powder (2.36 mg, 42.1 mmol) and then carbon disulfide (7.40 ml, 123 mmol). After heating under reflux for 4 hours, the solvent was distilled off. The resulting residue was concentrated under ice cooling with concentrated sulfuric acid (70
After dissolving in ice water (500 ml), the precipitated crystals were collected by filtration, washed with water and air dried. This was digested with ethanol, cooled, and the precipitated crystals were collected by filtration to give 1.
07 g was obtained (11% yield).

¹ H-NMR (DMSO-d6, δ): 3.7
3 (3H, s), 3.85 (6H, s), 7.20 (2H, br
s), MS (EI +, m / z): 284 (M ⁺ )

Claims (5)

[Claims] 1. A novel cephem compound represented by the general formula (1), a pharmacologically acceptable salt thereof, and a physiologically hydrolyzable carboxylic acid ester. [Wherein, X is an oxygen atom or a sulfur atom, R ¹ is a hydrogen atom, a metal atom, a protecting group for a carboxyl group or an ester group which is hydrolyzable in vivo in cooperation with a carboxyl group, R ²
Is a phenylacetyl group or (In the formula, R ⁴ represents an optionally protected amino group, R ⁵ represents a hydrogen atom, a methyl group, an allyl group, a cycloalkylmethyl group, a cycloalkyl group or a 2-fluoroethyl group.), R ³ represents 2-pyridyl group, 3-pyridyl group, 4-
Pyridyl group, 3,4-dihydroxyphenyl group, 3-hydroxy-4-pyridon-6-yl group, N-methylpyridinium-3-yl group, phenyl group, 2-thienyl group,
1-naphthyl group, 2-naphthyl group, 3,4,5-trimethoxyphenyl group or benzothiophen-2-yl group,
n represents 0 or 1. ] 2. A compound represented by the general formula (2) [Wherein Y is a leaving group, R ¹ is a hydrogen atom, a metal atom, a protecting group for a carboxyl group or an ester group that can be hydrolyzed in vivo in cooperation with a carboxyl group, R ² is a phenylacetyl group or (In the formula, R ⁴ represents an optionally protected amino group, R ⁵ represents a hydrogen atom, a methyl group, an allyl group, a cycloalkylmethyl group, a cycloalkyl group or a 2-fluoroethyl group.), N is 0. Or 1 is shown. ] The compound represented by general formula (3) [In the formula, M is a hydrogen atom, a metal atom or a quaternary ammonium, R ³ is a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 3,4-dihydroxyphenyl group, a 3-hydroxy-4-pyridone- 6-yl group, N-methylpyridinium-3-yl group, phenyl group, 2-thienyl group, 1-
A naphthyl group, a 2-naphthyl group, a 3,4,5-trimethoxyphenyl group or a benzothiophen-2-yl group is shown. ], And conversion of the side chain R ² if necessary,
The method for producing a novel cephem compound according to claim 1, wherein the protecting group is removed from the reaction product after the formation and reduction of the sulfoxide. 3. An intermediate represented by the general formula (4) [Wherein, when X is an oxygen atom, R ⁶ is a 1-naphthyl group,
It represents a 2-naphthyl group or a benzothiophen-2-yl group, and when X is a sulfur atom, it represents a 3,4,5-trimethoxyphenyl group. ] 4. A novel cephem compound represented by the general formula (5), a pharmacologically acceptable salt thereof and a physiologically hydrolyzable carboxylic acid ester. [Wherein R ¹ is a hydrogen atom, a metal atom, a protective group for a carboxyl group or an ester group that can be hydrolyzed in vivo in cooperation with a carboxyl group, and R ² is a phenylacetyl group or (In the formula, R ⁴ represents an optionally protected amino group, R ⁵ represents a hydrogen atom, a methyl group, an allyl group, a cycloalkylmethyl group, a cycloalkyl group or a 2-fluoroethyl group.), R ³ represents 2-pyridyl group, 3-pyridyl group, 4-
Pyridyl group, 3,4-dihydroxyphenyl group, 3-hydroxy-4-pyridon-6-yl group, N-methylpyridinium-3-yl group, phenyl group, 2-thienyl group,
1-naphthyl group, 2-naphthyl group, 3,4,5-trimethoxyphenyl group or benzothiophen-2-yl group,
n represents 0 or 1. ] 5. An antibacterial agent containing the novel cephem compound according to claim 1 or 4 or a pharmacologically acceptable salt thereof as an active ingredient.