WO1992002523A1

WO1992002523A1 - Novel cephalosporin compound

Info

Publication number: WO1992002523A1
Application number: PCT/JP1991/001026
Authority: WO
Inventors: Shigeo Shimizu; Hiroyuki Takano
Original assignee: Sankei Pharmaceutical Company Limited; Nippon Pharmaceutical Development Institute Company Limited
Priority date: 1990-08-02
Filing date: 1991-07-31
Publication date: 1992-02-20
Also published as: KR0178011B1; KR920702364A

Abstract

A novel cephalosporin compound represented by general formula (I), which has a wide antibacterial spectrum, wherein A represents a group of the formula -N=CH-, -NHCO-(CH=CH)m-, -CH2- or -O-CH2; m represents 0 or 1; R?1, R2 and R3¿ represent independently hydrogen or lower alkyl; R4 represents hydrogen or a group of the formula -OR6, wherein R6 represents hydrogen, lower alkyl or a protective group; and R5 represents hydrogen or an organic group.

Description

Specification

New Cephalosborane Compounds “Technical Field”

The present invention relates to a novel cephalosborin compound having a wide range of antibacterial properties.

"Background technology"

Conventionally, it has been known that Cephalosporin antibiotics have antibacterial activity against Gram-positive bacteria and negative bacteria, and many compounds have been actually used. Above all, compounds called third-generation cephalosporin antibiotics have a very wide spectrum of antibacterial spectrum and are especially valued clinically.

However, all have poor antibacterial activity against bacteria, and some are very effective against gram-negative bacteria other than Pseudomonas aeruginosa, but have poor antibacterial activity against gram-positive bacteria. There is a drawback that the cephalosporin resistance-obtaining strain, which is gradually increasing with the increase in the use frequency of aarosporin compounds, shows cross-resistance.

In view of these circumstances, various cephalosporin compounds have been studied, and for example, the following cephalosporin compound is disclosed in Japanese Patent Application Laid-Open No. Sho 63-152386. You.

(Wherein, R represents a hydrogen halogen or an organic group)

"Disclosure of the invention"

The present inventors have conducted intensive studies on compounds having a strong antibacterial activity against a very wide range of pathogenic bacteria, and as a result, the compound having the following general formula (I) was found to be an excellent drug for treating bacterial infectious diseases. They have found that they have characteristics, and have completed the present invention.

The present invention provides a compound represented by the general formula (I):

(Where A is the formula: N = CH—, NHCO— (CH = CH) _m— , —CH 2 One or One 0—CH ₂ —: m represents 0 or 1: R ¹ , R ² and R ³ each independently represent a hydrogen atom or a lower alkyl group: R ⁴ represents a hydrogen atom or a formula 10 R ⁶ (R ⁶ represents a hydrogen atom, a lower alkyl group or a protecting group): R ⁵ represents a hydrogen atom or an organic group)

And a salt or ester thereof.

In addition, with respect to the oxime represented by the general formula (I), a compound, hydrate, or organic solvate of a Syn configuration or an Auti configuration is naturally included in the present invention. In the above formula (I), examples of the lower alkyl group of R ¹ , R ² and R ³ include a linear or branched alkyl group having 1 to 3 carbon atoms. For example, methyl, ethyl, n- or isopropyl, and the like.

When R ⁴ represents the formula OR ⁶ , the lower alkyl group for R ⁶ includes a straight-chain or branched alkyl group having 1 to 4 carbon atoms. For example, methyl, ethyl, n- or isopropyl, n-butyl and the like can be mentioned. Examples of the protecting group for R ⁶ include benzyl, p-methoxybenzyl, diphenylmethyl, trityl, 2-methoxymethoxymethyl and the like.

As the organic group for R ⁵ , many groups are known, and as the substituent at the 3-position, those obtained by fermentation or those easily derived therefrom are commonly used. . For example, lower alkyl groups such as methyl and ethyl, vinyl groups, alkoxy groups having 1 to 3 carbon atoms such as methoxy and ethoxy, and methoxymethyl and ethoxymethyl. A lower alkoxymethyl group having 1 to 3 carbon atoms, an acyloxymethyl group such as acetoxymethyl, propionyloxymethyl, etc., a carbamoyloxymethyl group, 1 rubumoiru 1 1 carboxymethylidene 1, 3-Dichetan-1 2-- In some cases, R ⁵ is a group represented by the formula CH ₂ —T, where T is a quaternary ammonium group or SR ⁷ (R ⁷ is a substituted or unsubstituted heterocyclic group. ).

The quaternary ammonium groups include triethylamine, trimethylamine, 1-methylbiperidine, 1-methylpyrrolidine, 1-methylpyrrolidin, —Methyl-3—Ammonia of aliphatic tertiary amines or nitrogen-containing saturated heterocyclic compounds such as pyrrolidinol, 1-amino carbonyl and 4-methylpyrazine, quinuridine Or pyridin, 2—methylpyridin, 3—methylpyridin, 41-methylpyridin, 41-ethylpyridin, 2,3—dimethylpyridin, 2 , 3 — Cyclopentenoviridine, 4-Aminoviridine, 3 — Cyanopyridine, Nicotinic acid, Nicotinic acid amide, Isonicotinic acid, Isonicotinic acid amide, 3 — Pyridinesulfonic acid, 4-Pyridine sulfonic acid, 3—Hydroxypyridin, 4-Hydroxypyridin, 5,6,7,8—Tetra Hydroi soquinoline, 5.6, 7, 8 — Tetrahydroquinoline, thiazo , 5-methylthiol, 4-methylthiazole, quinoline, isoquinoline, 4, 5, 6.7-tetrahydropyrazo [1.5-a] pyridine, Examples include quaternary ammoniums of nitrogen-containing unsaturated hetero compounds such as triazole, pyrazole and 1,2.4-triazolo [1.5-a] pyrimidine.

As the substituted or unsubstituted heterocyclic group for R ⁷ , a 5- to 6-membered monocyclic or condensed ring having 1 to 4 heteroatoms selected from 0, S or N in the ring can be used. A heterocyclic group, such as a tetrazolyl group, a triazolyl group, a thiazolyl group, a thiadiazolyl group, an oxadiazolyl group, a pyridyl group, or a pyridyl group; Midyl group, pyridazinyl group, pyrazolyl group, tetrazolo [1.5-b] pyridazinyl group, 1,2,4,1-triazolo [1.5-a] pyridyl Midinyl group, pyrazo opening [1.5—a] pyrimidinyl group, imidazolyl group, triazinyl And an isothiazolyl group. Examples of the substituent on these hetero groups include a lower alkyl group such as methyl and ethyl, and a halogen-substituted lower alkyl group such as a nitrogen atom, trifluoromethyl, and trichloroethyl. Group, cycloalkyl group, lower alkoxy group, carboxymethyl group, carboxyethyl group, carboxy group, sulfoxymethyl group, sulfoxethyl group, amino group, di-lower alkylamino group, di-lower alkyl group Aminoethyl group, cyano group, lower alkylthio group, sulfonic acid group, sulfonic acid amide group, azide group, hydroxyxamic acid group, carbamoyl group, hydroxyl group, hydroxymethyl group, It may have a hydroxyloxy group or the like.

Preferred correct Examples of R ⁵ are methylation, § Se Bok Kishimechiru, (1 over main switch ruthenate Bok Razoru 5- I le) Chiome chill, [1 - (2 - arsenate de Loki Shechiru) Te Bok Razoru 5- I leチオ Thiomethyl, (1-carboxymethyltetrazol-5-yl) thiomethyl, (1.2.3-triazoyl-5-yl) thiomethyl, (1,3,4-thia) Diazo 2 -yl) Chi-methyl, (5-methyl 1, 3-3.4-Asia di 2- 2-) Thiomethyl, (1 .2-3-Thiadiazol 5 -yl) Thiome Thiol, (4-pyridyl) thiomethyl, (1-methyl pyridine) 2-thiol, thiomethyl,

(2-carboxy-5-methyl-s-triazolo [1.5-a] pyrimidine-1 7-yl) thiomethyl, (3-carboxy-5-methylpyrazolo [1.5-a] Pyrimidine-1 7-yl) thiomethyl, (2-hydroxymethyl 5-methyl s-triazolo

[1.5-a] pyrimidine-1 7-yl) thiomethyl and the like. The carboxy group at the 4-position of the cephalosporin compound of the formula (I) may be left undissociated, but may be, for example, an alkali metal salt such as sodium or potassium, or triethylamine or diamine. Organic amine salts such as isopropylamine and cyclohexylamine may be formed.

The group forming an ester is a protecting group in a reaction such as a lower alkyl group such as tertiary butyl; an aralkyl group such as benzyl, diphenylmethyl, and p-2-trobenzyl. Lower alkoxymethyl groups such as methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, t-butoxymethyl, etc .: 2—methoxymethoxymethyl Lower alkoxymethyl group such as lower alkoxymethyl group; 2.2.2—halogenated lower alkoxymethyl group such as trichloro ethoxymethyl group: acetoxymethyl, propionyl group xymethyl Aliphatic oxymethyl groups such as, for example, petilyl xymethyl, and vivaloy oxymethyl, 1-methoxycarbonylcarbonyl Such as ethyl, 1-ethoxycarbonyloxy, 1-propoxycarbonyl, 1-hydroxycarbonyl, 1-cyclohexyloxycarbonyl, etc. 1—Lower-alkoxy force Luponyloxityl group, phthalidyl group, (2-oxo-5-methyl-1,3-, dioxolen-4-yl) methyl group A group that forms an ester that is easily hydrolyzed in a living body for pro-dragging during administration.

The protecting group in the reaction of these carboxy groups can be removed by treatment with an acid or a base. When the protecting group is diphen In the case of an aralkyl group such as nilmethyl, it is removed by reacting with trifluoroacetic acid or by a reducing agent such as zinc monoacetic acid or by catalytic reduction.

The cephalosporin compound of the present invention can be synthesized, for example, according to the following three methods.

Method A

(Wherein, M represents a hydrogen atom or a protecting group for a carboxy group, and R ^s has the same meaning as described above.)

And a compound represented by

(Wherein, R ⁷ represents a hydrogen atom or an amino-protecting group, R ⁸ represents a hydrogen atom or a hydroxyl-protecting group, and R ¹ R ² , R ³ and R have the same meanings as described above.)

By reacting with a carboxylic acid represented by or a reactive derivative thereof, and, if necessary, removing the protecting group. B method ~ n ~ C CON, ",,

And a compound represented by

NH ₂ -0- (V)

(The symbols in the formula are as defined above.)

The compound can be obtained by reacting with the compound represented by and, if necessary, removing the protecting group.

C method

(The symbols in the formula are as defined above.

And a compound represented by

OHC

(νπ) (νπΐ) (In the formula, m represents 0 or 1, and other symbols have the same meanings as described above.)

The compound can be obtained by reacting with the compound of formula (I) and removing a protecting group as necessary.

Hereinafter, the method for producing the novel cephalosporin compound of the present invention will be described in more detail.

Method A

In general, the reaction between compound (II) and compound (III) is preferably performed using a reactive derivative of compound (III). In this case, an acid halide, a mixed acid anhydride, an active ester, an active thioester, or the like is used as a reactive inducer. Alternatively, a free carboxylic acid can be used as it is, but in that case, a condensing reagent is preferably used. As the reagent, for example, N, N′-dicyclohexylcarpoimide, N, N′-carbonyldiimidazole, Cyanur chloride, Vilsmeier reagent and the like are used.

Such reactions are known in the fields of penicillin chemistry, cephalosporin chemistry, and peptide chemistry.

These reactions are usually carried out in a suitable solvent, such as dichloromethane, chloroform-form, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, acetate. The reaction is carried out at 110 to 30 ° C. for 0.5 to 2 hours in toluene, acetate, water or a mixed solvent thereof. After the reaction, the protecting group is removed, if necessary, followed by separation and purification by a method well known in the art.

The protecting group for the amino group of R ⁷ is used in general peptide chemistry Easily removable protecting groups for amino groups, for example, alkanol groups such as formyl and trifluoracetyl: t-butoxycarbonyl, and alkoxyoxy groups such as trichloroethoxycasolevonyl. Carbonyl group: an aralkyloxycarbonyl group such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl: or protected by proton. The method for removing these amino-protecting groups can be carried out, for example, by the method described in JP-B-58-583533.

The protecting group for the hydroxyl group of R ⁸ is benzyl, a — (or 3 —) naphthylmethyl, difuunylmethyl, triphenylmethyl, 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 4 Aralkyl groups in which the aryl ring is substituted with lower alkoxy, such as chlorobenzyl and 4-cyanobenzyl, ditoro, halogen, and cyano: acetyl, propionyl, trichloroacetyl, Benzyl, and acyl groups such as 412-trobenzoyl. When the hydroxyl-protecting group is an aralkyl group, it can be removed by contacting with a reducing agent, and when the hydroxyl-protecting group is an acyl group, it can be removed by treating with a base. .

B method

In the reaction between compound (IV) and compound (V), compound (V) can be used as it is, but preferably a salt with a mineral acid, for example, hydrochloride or P-toluene sulfonate An organic sulfonate such as the following is used. Such salts are preferably used in about equimolar amounts or in slight excess. The reaction is preferably carried out with a polar organic solvent, such as dimethyl The reaction is performed in a solvent such as lilleform amide, dimethyl acetate amide, N-methylpyrrolidone, dimethyl sulfoxide, or acetonitril. The temperature for this reaction is 0 ° C to 50 ° C. After the reaction, the protecting group may be removed and separated and purified by the method described above, if necessary, according to a method well known in the art.

C method

The reaction between compound (VI) and compound (VII) is usually carried out in a suitable solvent, for example, methanol, ethanol, ibropanol, tetrahydrofuran, dioxane. The reaction is carried out at 0 to 30 ° C. for 1 to 5 hours in acetonitril, etc. or a mixed solvent thereof.

In addition, the reaction between compound (VI) and compound (VIII)

The reaction is performed using the reactive derivative of (VIII). As the reactive derivative, for example, an acid halide, a mixed acid anhydride, an active ester and the like are used. Also, free carboxylic acid can be used as it is. In that case, an appropriate condensation reagent may be used. As the reagent, for example, N.N'-dicyclohexyl rubodiimide, cyanochloride, Vilsmeier reagent and the like are used. Compound

The reaction between (VI) and compound (VIII) is usually used in an equimolar amount. These reactions are usually carried out in a suitable solvent, such as dichloromethane, macroform, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, The reaction is carried out at 110 to 30 ° C for 0.5 to 2 hours in acetonitrile, acetone, water or a mixed solvent thereof. After the reaction, the protecting group may be removed by a method well-known in the art, if necessary, according to the method described above. To make.

The salt or ester of the present invention obtained by each of the above methods may be further converted to a free carboxylic acid by a known method, if necessary, and the free carboxylic acid obtained by each of the above methods may be converted to a free carboxylic acid as necessary. It can also be converted to a pharmaceutically acceptable salt or ester by a known method.

The novel cephalosporin compound of the present invention can be orally or parenterally administered to a human or animal in various known modes of administration. The compound may be used alone or in combination with a pharmaceutically acceptable carrier, liquid diluent, binder, lubricant, humectant, etc., for example, for injections, tablets, granules, dragees, It is used in the form of general pharmaceutical compositions such as powders, capsules, gels, dry syrups, suspensions, solutions, emulsions, ointments, pastes, creams, suppositories and the like. Furthermore, as other additives that can be blended, dissolution retardants, absorption promoters, surfactants and the like can be mentioned. In any case, any known pharmaceutically acceptable substances can be used.

The novel cephalosporin compounds of the present invention can be used alone or as a mixture of two or more different derivatives, the amount of which is about 0.1 based on the weight of the total drug composition. ~ 99.5%, preferably in the range of 0.5-95.0%. In the pharmaceutical composition containing the compound of the present invention, other pharmacologically active compounds can be further mixed as an active ingredient in addition to the compound or a mixture thereof.

The daily dose of the novel cephalosporin compound of the present invention to patients varies depending on the human or the type of animal, its body weight and disease state. Weight per kg It is in the range of 1-1.000 mg, preferably 5-80 mg. It is orally or parenterally administered in 3 to 4 times a day.

"Best mode for carrying out the invention"

Examples are shown below, but the present invention is not limited to these examples.

Reference example 1

2—Holmyl 1—Hydroxy 5— (4-Methoxybenzyloxy) 1-41 Pyridone

(a) Dissolve 50 g (0.352 mol) of kojic acid in 400 ml of DMF, add 97.3 g (0.704 mol) of potassium carbonate and 4 ml of chloride. 66.2 g (0.422 mol) of 1-methoxyxybenzyl was added, and the mixture was stirred at 70 to 75 ° C for 1.5 hours. The reaction solution was poured into 2000 ml of water, extracted with 3.0000 ml of chloroform, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Ether was added to the residue, and the mixture was stirred. The crystals were collected by filtration and dried to give 2-hydroxymethyl 5-(4-methoxypentyloxy)-propylene 8 I got 3.2.

(b) 2-hydroxymethyl-5- (4-methylxybenzyloxy) obtained in (a), 11.7 g (65 mmol) of virion, was added to 200 ml of pyridine. Dissolved in water, and then added with hydroxylamine hydrochloride 13.9 g (0.2 mol) was added and the mixture was stirred at 70 ° C for 10 hours. The residue obtained by distilling off the solvent was dissolved in 100 ml of methanol, this was added dropwise to 900 ml of water, and the mixture was stirred for 1 hour. The precipitate was collected by filtration, washed with water. The residue was dried to give 7.67 g of 1-hydroxyl 2-hydroxymethyl-5- (4-methoxybenzyloxy) -141 pyridone.

(c) 1-Hydroxy 2—Hydroxymethyl-5— (4-Methoxybenziloxoxy) obtained in (b) 14-pyridone 7.6 g (27.4 mmol) ) Was suspended in 300 ml of DMF, and 7.6 g (55 mmo 1) of carbonated lithium and 5.2 g (33.2 mmol) of sodium chloride ) Was added and the mixture was stirred at 70 ° C. for 1.5 hours. After the reaction solution was concentrated to 13, it was poured into 50 O ml of water, and extracted with 300 ml of ethyl acetate. After washing with water, it was further washed with saturated saline and dried over anhydrous magnesium sulfate. Ether was added to the residue obtained by concentrating the mixture, and the mixture was stirred. The crystals were collected by filtration, dried, and dried to give 2-hydroxymethyl-1,5-di (4-methoxybenzyloxy) 14. 8.54 g of one pyridone was obtained.

(d) 2-Hydroxymethyl-1,5-di (41-methoxybenzoyloxy) obtained in (c), 1,4-pyridone 8.5 g (21.4 mmol) A mixture of 150 ml of dioxane and 4.3 g (50 mmol) of activated manganese dioxide was stirred under reflux for 5 hours. Further, 4.3 g of activated manganese dioxide was added, and the mixture was stirred under reflux for 2 hours. The reaction solution was allowed to cool and then filtered, and the solvent was distilled off. The obtained oily residue was subjected to silica gel chromatography and subjected to chromatography on a gel. The residue obtained by evaporating the solvent was stirred with ether, and the resulting crystals were collected by filtration and dried to obtain 2.66 g of the title compound. Was.

Ή Customer (d _e -DMS0) δ:

3.84 (S, 3Η),

5.33 (S. 2Η).

7.06 (d.J = 9Hz.2H).

7.48 (S. 1H),

7.57 (d, J = 9Hz.2H),

8.51 (S. 1H),

9.96 (S, 1H)

Reference example 2

2-Holmyl 1.5-di (4-methoxybenzyl) 4-pyridone

Dissolve 18.9 g (47.5 ramol) of 2-hydroxymethyl-1,5-di (4-methoxybenzyloxy) -141 pyridone in 400 ml of methanol. , activated manganese dioxide 6 2 g (0. 7 1 3 mol) of pressurized forte and stirred for 3 h at 5 0 ^e C. The reaction solution was filtered, the solvent was distilled off, and the residue obtained was crystallized by adding isopropyl ether. The crystals were collected by filtration and dried to obtain 17.8 g of the title compound. 6

Ή NMR (CDCla) δ:

3.78 (S. 3H).

3.80 (S. 3H).

5.15 (S. 2H).

5.34 (S. 2H).

6.72 to 6.94 (m, 6H).

6.97 (S, 1H),

7.10 (S. 1H).

7 ・ 22〜 7.34 (m, 2H).

9.64 (S. 1H)

Reference example 3

2—Holmyl-1 5— (4-Methoxyxybenzyloxy) 1-4-Pyridone

(a) Dissolve 21 g (80 mmol) of 2-hydroxymethyl-5- (4-methoxybenzyloxy) pyrone in 300 ml of dioxane, and add 25% Then, 30 O ml of ammonia water was added, and the mixture was stirred in an autoclave at 60 ° C for 4 hours. The reaction mixture is concentrated to 1/4, and the precipitated crystals are collected by filtration and dried to give 2-hydroxymethyl-5- (4-methoxybenzyloxy) -141 pyridine. Don 1 2 .01 g Obtained.

(b) 2-Hydroxymethyl-5- (4-methoxybenzyloxy) -14 obtained in (a) 8.2 g (31.4 mmol) of 4-pyridone, dioxane 1 A mixture of 70 mi and 3.0 g (34.5 mmol) of activated manganese dioxide was stirred under reflux for 6 hours. The reaction solution was allowed to cool and then filtered to obtain a filtrate, which was concentrated. The residue obtained was crystallized by adding ethyl acetate and ether, and the crystal was collected by filtration and dried. 2.0 3 g of the compound was obtained.

画 picture (de-DMSO) δ:

3.83 (S. 3Η).

5.33 (S. 2Η),

7.09 (d, J = 9Hz.2H),

7.51 (S, 1Η).

7.59 (d, J = 9Hz.2H).

8.53 (S. 1H).

10.03 (S. 1H)

Reference example 4

2—Holmyl 1 1-Methoxy 5— (4-Methoxybenzyloxy) 1-4-Bilidon

a) 1 — Hydroxy 2 — Hydroxime Chill 5 — (4 Toxibenziloxy) 5.6 g (20 mmol) of 141 pyridone, 8 O ml of DMF, 5.5 g (40 mmol) of carbonic acid rim and 3.42 g of yowimethyl (24 mmol) was stirred at room temperature for 1 hour. 50 ml of water was added to the residue from which DMF was distilled off, and the mixture was extracted with 200 ml of methylene chloride. This was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was crystallized by adding ether, filtered and dried. 2-hydroxymethyl 1-methoxy 5- (4-methoxybenzyloxy) 1-41 12 g of pyridone δ.12 g were obtained.

(b) 2-Hydroxymethyl-1 1-methoxy-1-5- (4-methoxyxylbenzene) obtained in (a) 5.1-g (1 (7.5 mmol) was dissolved in 350 ml of methanol, 30 g (350 mmo 1) of activated manganese dioxide was added, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was filtered, the solvent was distilled off, and the obtained residue was mixed with ether, crystallized, filtered and dried to obtain 4.62 g of the title compound.

'Η N R (CDCla) δ:

3.77 (S, 3H),

3.99 (S, 3Η),

δ.14 (S. 2Η),

6.80 (S. 1Η).

6.78 to 6.88 (m, 2Η),

7.25 (S. 1Η).

7.23-7.35 (m, 2Η).

9.90 (S. 1Η) Example 1

7 — {2-(2 — Amino 1.3. 3 — Thiazo 1-4 1) 1 2-[1 1 (1, 5 — Dihydroxy 4-1 Pyridone 1 2-ィL-methylidenecarbazole) 1-11-Methylethoxyminodiacetamide} 1-3— (5—Methyl-1.3,4,4-Thiadiazole-2—I-Luthiomethyl) 1-3—Sefmu 4 One-strength rubonic acid j Field Goe-义 ^ COOH

(a) 7-[2-(2-amino 1, 3-thiazol-4-yl) 1-2-(1-rubazoi-1-1-methylethoxyminino)-acetamide] 1 3 — (5 — methyl 1.3.4 — thiadiazol 2 — dithiothiomethyl) 1 3 — cefeu 4 4 diphenyl methyl methyl diester dihydrochloride dihydrochloride 4.9 g (5.75 mniol) And 2-formyl-1-hydroxy-5- (4-methoxybenzyloxy) -14-pyridone (1.58 g, 5.75 mmol) was added to 5 ml of methanol. After stirring at room temperature for 1.5 hours, the reaction solution was added dropwise to 1.0000 ml of ether, the resulting precipitate was collected by filtration, washed with ether, and dried. This was applied to silica gel column chromatography, eluted with a mixture of formaldehyde and methanol, concentrated, and then treated with ether to give 7— {2— (2-amino 1.3—Thiazole-41) 1 2— [1- (1—Hydroxy-1 5— (4-Methoxyxybenzyloxy) 1-41Pyridone 1—2— Ridenecarnozyl) 1 1 1-Methylethoxyminino] acetamide} 1 3 — (5—Methyl-1.3,4-th-a-z-yl) 4 3.3 g of powder of difuninyl methyl ester hydrochloride hydrochloride was obtained.

(b) The powder obtained in (a) was suspended in 10 ml of anisol, 20 ml of trifluoroacetic acid was added with stirring under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. The resulting precipitate was collected by filtration, washed with ether, and dried to obtain a powder of a compound from which hydroxyl and carboxy group protecting groups were eliminated.

(c) The powder obtained in (b) was suspended in 50 ml of water, adjusted to pH 7.0 with a 5% aqueous sodium hydrogen carbonate solution, and dissolved. The solution was adjusted to pH 2.5 with 2N hydrochloric acid under ice-cooling and stirring, and the resulting precipitate was collected by filtration, washed with water and dried to obtain 1.92 g of the title compound.

Awake (d ₆ -DMS0) δ:

1.62 (S, 6Η),

2.72 (S, 3Η),

3.82 (S, 2Η),

4.38. 4.55 (d.J = 14Hz.1H),

5.33 (d.J = 5Hz, 1H),

5.85 to 6.24 (m, 1H).

7.15, 7.62, 8.24, 8.52 (S, 1H)

Example 2 (sodium salt of the compound of Example 1) 7-{2-(2-amino 1.3-thiazol-41-yl) 1 2-[1-1 (1.5-dihydroxyl-4-pyridone-1 2-il-methylene 3-(5-methyl 1.3.4. 4-thiadiazol 2-i-luciomethyl) 1 3-cefume 4 Rubonic acid sodium salt

1.0 g of the compound obtained in Example 1 was suspended in 30 ml of water, adjusted to pH 7.0 with a 5% aqueous sodium hydrogen carbonate solution, and dissolved. This solution is applied to a column chromatograph on an adsorption resin (Mitsubishi Kasei Diaion HP-20), eluted with a mixture of water and methanol, and the fraction containing the target compound is concentrated, followed by freezing. Drying afforded 0.63 g of the title compound.

'Η picture (de-D SO + DzO) δ:

1.62 (S, 6Η),

2.75 (S. 3Η).

5.25. 5.90 (d, J = 5Hz. 1H),

7.08 (S. 2H),

7.88, 8.42 (S, 1H)

Example 3

7- {2— (2—Amino 1.3—Third Zol 4-D) 1 2— [1 D 1 (5—Hydroxy 1—Methoxy 4—Pyridoneー 2 — リゾ 1 1 1 3 1 3 1 一一メメ 3 3 3 3 3 （3 （— — 2 メチルルーチオ 2 1) 3—Sefmu 4) 1-Carbonic acid

The title compound was obtained according to the method of Example 1.

麗 Rei (d ₆ -DMS0) δ:

1.61 (S. 6Η).

2.74, 4.34 (S. 3Η),

3.82 (S, 2Η).

5.33 (d, J = 5Hz.1H).

5.82〜6.22 (m.1H),

7.12, 7.68 (S, 1H),

8.88 (S. 2H)

Example 4

7-{2-(2 -amino 1, 3 -thiazol 4 -yl) 1 2-[1-(5 -hydroxy 4-1 pyridone 1-2-dimethylene denka rubazoi A) Acetamide} — 3 — (5 — methyl 1.3, 4 — thiadiazol 2 — iluthiomethyl)-3 — cefum 4 acid

The title compound was obtained according to the method of Example 1.

Ή Awake (de-DMSO) δ:

1.64 (S. 6Η),

2.75 (S. 3Η).

3.82 (S. 2Η),

4.28. 4.68 (d. J = 14Hz. 1H),

5.34 (d.J = 5Hz.1H).

5.87 to 6.24 (m, 1H).

7.12.68. 8.30. 8.67 (S, 1H)

The following compounds are produced according to the method of Example 1.

a) 7 — {2 — (2 — amino 1, 3 — thiazole 4 yl) 1 2 — [1 (1.5-dihydroxy 6-methyl 4 bidon 1 2 — 1-methylethylethoxymino] acetamido} 1-3— (5—methyl1.3.4.4—thiadiazol2—2-chlorothiomethyl) 1-3—cefumu (4) Rubonic acid

b) 7 — {2-(2 — amino 1, 3 — thiazol-4-yl) 1 2 — [1 1 (1, 5 — dihydroxy 6 — methyl 4-pyridone 1 2) 1-Methylethoxyminino] acetamido} -3— (1-Methyl-1H—Tetrazol-5—I-Luthiomethyl) 1-3—Sefume 4 One strength le Bon

c) 7-{2-(2-amino 1.3-thiazo-1-4-yl)-2-[1-(1.5-dihydroxy 6-methyl-4-pyridone-1) 2 — (methylidenecarbazolyl) 1 1 1-methylethoxyminino] acetamide} 1 3 — (2—carboxy-5—methyl s—triazolo [1.5—a] Pyrimidin 1 7 —Luchio methyl) 1 3 —Sefume 4

d) 7 — {2-(2 — Amino 1, 3 — Thiazol-4-yl) 1 2 — [1-(1, 5 — Dihydroxy 6-Methyl 4-Viridone 1) 2 — i-methylidenecarbazolyl) 1-1-methylethoxymino] acetamide} 1 3-(2-hydroxymethyl-5-methyl-s-trisazolo [1. 5 — a] pyrimidine 1 7 — i-Luthiomethyl) 1 3 — sefume 4 rubonic acid

e) 7 — {2 — (2 — Amino 1.3 — Thiazol-4-yl) 1 2 — [1 1 (5 — Hydroxy 1 — Metric 6 — Methyl 4) Pyridone-1—2-methylidenecarbazolyl) -111-methylethoxymethylamino-acetamide}-3- (5—methyl-1-1.3,4-thiadiazole-2 —I-Luthiomethyl) I 3 —Sefume 4 Irurubonic acid

f) Ryoichi {2-(2-Amino 1, 3-Thiazo-1-4-yl) 1 2-[1 1 (5-Hydroxy 1-Methoxy 1 6-Methyl-1) 4 1 pyridone 1 2 — dimethyl dimethyl carbazole) 1 1 1 methyl ethoxymino] acetate amide} 1 3 — (1-methyl 1H-tetrazole 5- Iru tiomethyl) I 3 — SEFM

4 One-stroke rubonic acid

g) 7 — {2-(2 — Amino 1.3. 3 — Thiazo- 1-4-yl) 1 2 — [1-(5 — Hydroxy 1-Methoxy 6-Methyl 4 1-pyridone 1—2-methylidene carbazole) 1—11-methyl ethoxymino] acetamide} 1 3— (2—carboxy 5—methyl-s—triazolo [1.5-a] pyrimidine 1-7-thiothiomethyl) 1-3-cefume 4 rubonic acid

h) 7 — {2-(2 — Amino 1.3. 3 — Thiazol-4-yl) 2 — [1 (5 — Hydroxyl 1 — Metoxie 6 — Methyl — 4 1- 2-dimethylmethyl carbazoyl) 1-1 -methylethoxymino] acetamide} 1-3-(2-hydroxymethyl 5-methyl s-troazolo) 1.5 — a] pyrimidine 1 7 — dithiothiol) 1 3 — cefume 4 — carboxylic acid

Reference example 5

5-1 4-Methoxy benzyloxy) 1-Methoxy 4-Pyridone 2 Molar rubonic acid

2-formyl-1-metoxy-5- (4-methoxybenzyloxy) -141 pyridone 2.89β (10 mmol) was added to methanol 50 The mixture was suspended in a mixed solution of 20 ml of water and 20 ml of water, and 6 ml of an aqueous solution of sodium monohydroxide was added to obtain a uniform solution. 2.8 g (12 mmol) of silver oxide was added thereto, and the mixture was stirred at room temperature for 1.5 hours. After filtering the reaction solution, methanol was distilled off, and the resulting aqueous solution was adjusted to pH 2 with 2N hydrochloric acid under ice-cooling and stirring. The precipitate was collected by filtration, washed with water, and dried to obtain 2.44 g of the title compound.

Ή NMR (d ₆ -DMS0) δ:

3.77 (S. 3Η).

4.10 (S. 3Η).

5.02 (S, 2Η),

6.45 (S. 1H).

7.03 (d.J = 9Hz.2H).

7.38 (S. 1H),

7.46 (d.J = 9Hz.2H),

8.20 (S. 1H)

Reference example 6

1,5-di- (4-methoxybenzyloxy) -1-41-pyridone-2 mono-rubonic acid

2-formyl 1,5-di- (4-methoxybenzyl) 3.95 g (10 mmol) of pyridone was dissolved in 50 ml of methanol and water. The suspension was suspended in 20 ml, and 6 ml of a 2N-sodium hydroxide aqueous solution was added to obtain a uniform solution. 2.8 g (12 mniol) of silver oxide was added thereto, and the mixture was stirred at room temperature for 23 hours. After the reaction solution was filtered, the aqueous solution obtained by distilling off methanol was adjusted to pH 2 with 2N monohydrochloric acid under ice-cooling and stirring. The precipitate was collected by filtration, washed with water, and dried to give the title compound (3.64 g).

画 picture (de-DMSO) δ:

3.78 (S. 3Η).

3.82 (S, 3Η).

5.08 (S, 2Η).

5.26 (S. 2Η),

6.77 to 7.05 (m. 6H).

7.08 (S. 1H).

7.15 (S. 1H).

7.25 to 7.40 (m.2H)

Reference Example 7

2 — (2 — Amino 1, 3-Thiazol-4 yl) 1 2 —

[1- (5-Hydroxyl-methoxy-4,1-pyridone-12-ylcarbonylcarbazole) -11-Methylethoxymino] acetate hydrochloride

a) 5 — (4-methoxybenzyl) 1-1-methoxy 4 1-pyridone-2-fluorocarboxylic acid 2.44 g (8 mmol), 2- (2-amino1.3-thiazole-41-yl) 1-2- (1-carnozoic) 1.75 g (8 mmol) of t-butylester acetate and 1.23 g (8 mmol) of 1-hydroxyxenzozotriazole ) Was dissolved in 100 ml of DMF, and 2.06 g (10 mmol) of N, N'-dicyclohexylcarpoimide was added and stirred for 2 days. The reaction mixture was filtered and added dropwise to ether. The resulting precipitate was collected by filtration, washed with ether, dried and dried to give 2 '-(2-amino 1.3-thiazole) 4 1-yl) ー 2 — [1 1- (5- (4-methyl xybenzyl) 1 1-methyl xy 4 4-pyridone 2—yl) 1 1 1-methyl ethoxy G) A powder of t-butyl acetate was obtained.

() The powder obtained in (a) was dissolved in a mixture of 10 ml of anisol and 30 ml of trifluoroacetic acid and stirred for 1.5 hours. A mixture of 5 ml of methanol and 0.55 ml of oxine salt was added thereto, and the mixture was added dropwise to ether, and the resulting precipitate was collected by filtration and washed with ether. After drying, 2.66 g of the title compound was obtained.

^J H NMR (de-DMSO) δ:

1.62 (S. 6H),

4.41 (S. 3Η),

7.34. 7.68. 9.08 (S, 1Η)

Example 5

7-{2-(2-amino 1, 3-thiazole-4-1) 1 2-[1-1 (5-hydroxy 1-methoxy 4-pyridone 1 2—I-Carbonylcarbazolyl) 1 1 1-Methylethoxyminino] acetamide} —3— (5—Methyl-1.3.4.4—Thiadiazol2—Isothiothiomethyl) 1 3— Sef-Emu 4 Ichiban Lubon

(a) 2— (2-amino-1,3—thiazol-4-yl) 1-2— [1- (1-hydroxy-5-hydroxy) obtained in Reference Example 7 2- (2-hydroxycarbonylcarbazole) 111-methylethoxymininoacetic acid hydrochloride 2.55 g (5.2 mmol), 7-amino3— (5 —Methyl-1,3,4 —Thiadiazol-2 —Diruthiomethyl) 1-3 —Cefume 4 2.66 g (5.2 mmol) of diphenylmethyl ester of rubonic acid and 1-hydroxybenzoate Dissolve 0.8 g (5.2 mmol) of lyazole in 30 ml of DMF, cool on ice, and add 1.28 g (6,6 g) of N, N'-dicyclohexylhexylcyclodiimide. .2 mmol), and the mixture was stirred for 30 minutes while cooling with ice, and further stirred at room temperature for 1 hour. After the reaction solution was filtered, an equal amount of a form of chloroform was added, and the mixture was added dropwise to vigorously stirred ether. The resulting precipitate was collected by filtration, washed with ether, and dried. This was applied to silica gel chromatography, eluted with a mixture of black form, methanol and formic acid, compressed, and then treated with ether. 1.43 g of the title compound powder obtained by protecting the carboxyl group of the title compound with a diphenylmethyl group was obtained.

(b) The powder obtained in (a) was suspended in 3 ml of anisol, 10 ml of trifluoroacetic acid was added under ice-cooling and stirring, and the mixture was stirred for 30 minutes under ice-cooling. The resulting precipitate was collected by filtration, washed with ether, and dried to obtain a powder of the hydrochloride of the title compound.

(c) The powder obtained in (b) was suspended in 3 O ml of water, adjusted to pH 7.0 with a 5% aqueous sodium hydrogen carbonate solution, and dissolved. The solution was adjusted to pH 2.5 with 2N hydrochloric acid while stirring under ice-cooling, and the resulting precipitate was collected by filtration, washed with water and dried to obtain 0.84 g of the title compound.

'Η NMR (de-DMSO) δ:

1.60 (S. 6H),

2.73. 4.35 (S, 3Η),

3.80 (S. 2H),

5.40 (d.J = 5Hz, 1H).

5.80 to 6.18 (m, 1H),

7.14. 7.45, 8.90 (S, 1H)

Reference Example 8

2 — (2 — Amino 1,3-thiazoyl 4-yl) 1 2 — [1 1 (1, 5 — dihydroxy 4-1 pyridone 1-2 — carbonyl carbonylcarbazole) [1-1-methylethoxymino] acetic acid · hydrochloric acid

(a) 1.5-di (4-methoxybenzyloxy) -14-pyridone-12-caprolubonic acid 3.56 g (8.65 mmol), 1-hydroxybenzo A mixture of 1.59 g of triazole ((10.38 mmol) and 100 ml of DMF was stirred under ice-cooling with N.N'-dicyclohexylcarbodiimide 2.14 g (10. The mixture was stirred for 30 minutes under ice-cooling and then for 2.5 hours at room temperature.The reaction solution was filtered, and then 2— (2—amino 1,3—thiophene) was added. Azoyl 4-yl) 1 2 — (1 liter rubazoyl 1-methyl ethoxymino) acetic acid t-methyl ester was added, and the mixture was stirred at room temperature for 3 days. The precipitate was collected by filtration, dried, and the resulting powder was applied to silica gel chromatography to obtain a black foam.醆 mixture The resulting oily residue was treated with ether to form a powder, which was collected by filtration and dried to give 2- (2-amino1.3-thiazole-4-1). 1) 2- (1- (1,5-di (4-methyoxybenzyloxy)) 141-pyridone-12-yl-carbazolyl) 1-1-methylethoxyimino] acetic acid 2.08 g of powder of t-butyl ester was obtained.

(b) The powder obtained in (a) was dissolved in a mixture of 10 ml of anisol and 20 ml of trifluoroacetic acid and stirred at room temperature for 2.5 hours. this The resulting precipitate was collected by filtration, washed with ether and dried, and then dried. 2- (2-amino1.3-thiazo-l-41-yl) 1—2— [1—1—1.5—dihydroxy-4—1 pyridone—1—2-carboncarbazyl) —1-1-methylethoxycarboxylic acid] Acetate / trifluoroacetate powder 1.5 1 g I got

(c) 20 ml of methanol was cooled with ice, and 0.77 g of oxylin chloride was added dropwise. The powder obtained in (b) was added thereto and stirred to obtain a solution. This was added dropwise to 1.000 ml of ether, and the resulting precipitate was collected by filtration, washed with ether, and dried to obtain 1.45 g of the title compound.

Ή NMR (de-DMSO) δ

1.65 (S, 6Η)

7.38 (S, 1H)

7.77 (S. 1H)

8.43 (S, 1H)

Example 6

7- {2- (2—amino 1,3—thiazo-one-41-yl) one 2-[one-one (1.5-di-hydroxy-4-1-pyridone-one two-) L-carbonylcarbazolyl) 1 1 1-methylethoxymino] acetamido} 1 3 — (5—methyl-1,3,4—thiadiazol 2—dichlorothiomethyl) 1—3—cefume 4 One-stroke rubonic acid

The title compound was obtained according to the method of Example 5.

Ή NMR (de-D SO) δ:

1.58 (S. 6Η).

2.75 (S. 3Η).

3.18 (S. 2Η),

4.35〜4.92 (m, 2H),

5.21 (d, J = 5Hz.1H).

5.78 to 6.14 (m, 1H).

7.08 (S. 1H).

7.38 (S. 1H)

The following compound is produced according to the method of Example 5.

a) 7 — {2 — (2 — amino 1.3-thiazol-4-yl) 1 2 — [1 1 (1.5-dihydroxy 4-pyridone 1 2- Rucarbazolyl) 1 1 1-methylethoxyminino] acetamide} 1 3 — (1,3,4—thiadiazole-2—diluthiomethyl) 13—cefumeu 4

b) 7-{2-(2-amino 1, 3-thiazol-4-yl) 1-2-[1-(1, 5-dihydroxy 4-pyridone-1-2-carbazole carbazoy) 1) Methyl ethoxymino] acetamide} 1 3 — (1.2, 3 — thiadiazole 5 — i-Luthiomethyl) — 3 — seveum 4

c) 7 — {2-(2 — amino 1, 3 — thiazol-4-yl) 1 2 — [1 1 (1.5-dihydroxy 4-pyridone 1 2- Rucarbazolyl) 1- 1-methylethoxymino] acetamide} 1 3— [1- (2—hydroxyxethyl) tetrazol-5-i-luciomethyl] 13-sefu-emu 4 Lebon

d) 7-{2-(2-amino 1.3-thiazo-1-4-yl) 1-2-[1-1-(1.5-dihydroxy 4-pyridone-1-2- Nilcasoleno'zyl) 1-Methylethoxyoximino] Acetatomid} 1 3 — (3—Carboxy 5—Methylpyrazo mouth [1.5-a] Bilimidine 7-Irethiothiol) 1-3-se-fumeu 4 One-stroke rubonic acid

e) 7 — {2 — (2 — Amino 1, 3 — Thiazo 1-4-4) 1 2 — [1 1 (1.5-Dihydroxy 4-pyridone 1-2-Carbo) 1-Methylethoxyminino] acetamide} 1-3— (3—carboxy-5-methyl-s-triazolo [1.5—a] pyrimidine-1 7— Luci-Methyl) 1 3 — Sefmu 4 4 Rubonic acid COOH

f) 7-{2-(2-amino 1.3-thiazol-4-yl) 1 2-[1 (1, 5-dihydroxy-1-4-pyridone-1- L-carbyl carbazole) 1-1-methylethoxymino] acetamide}-3-(2-hydroxymethyl relay 5-methyl s-triazolo [1.5-a] Limidine 1 7 — ryumemethyl) 1 3 — sefume 4

Reference Example 9

5 —Bromo-4-hydroxy 6 —Methyl nicotinic acid methyl ester CHaOCO

(a) 4-Hydroxy 6-Methylnicotinic acid 15.3 g (0.1 mol) was suspended in 1.0 ml of acetic acid and heated to 50 ° C. And dissolved. To this, 32 g (0.2 mol) of bromine was added dropwise over 30 minutes, followed by stirring at 60 ° C for 22 hours. The reaction solution was allowed to cool, and the precipitated crystals were collected by filtration, washed with ether, and dried to obtain crystals of 5-bromo-4-hydroxy-6-methylnicotinic acid.

(b) The crystals obtained in (a) were suspended in 1.00 ml of methylene chloride, and 20.2 g (0.2 mol) of triethylamine was added to form a solution. This Reoｰ2 0 cooled to ^e C chloride Chioniru 2 3. 8 g of (0. 2 mol) was added dropwise over 2 0 minutes. The reaction solution was stirred for 1 hour under ice-cooling and further for 1.5 hours at room temperature, and then reduced to about 1 to 3 to obtain the acid chloride (a).

(c) To the concentrated solution obtained in (b) was added 1.0000 ml of methylene chloride, and the mixture was stirred under ice cooling. Add 16 ml (0.4 mol) of methanol to this, then add 20.2 g (0.2 mol) of triethylamine dropwise over 10 minutes and then at room temperature for 12 hours Stirred. The precipitate was collected by filtration, washed with methylene chloride and methylene chloride, and dried to give the title compound 20.3 as a powder.

'Η NMR (de-DMSO) δ:

2.38 (S. 3H).

3.73 (S. 3H). 8.30 (S, 1H)

Reference example 10

4.5—Dihydroxy 6—Methylnicotinic acid

OH

. .

N ヽ CH ₃

(a) A suspension of 19.2 g (78 mmol) of 5-bromo-4-hydroxy-6-methyl nicotinate methyl ester obtained in Reference Example 9 in 200 ml of DMF was added. 1.9 g (10 mmol) of cuprous iodide and then 47 ml (0.26 mol) of a sodium methylate 28% methanol solution were added. The mixture was stirred at 100 ° C for 2 hours, cooled with ice, and adjusted to pH 3 with 2N monohydrochloric acid while pouring into 400 ml of ice-cold water. The mixture was extracted with 5,000 ml of a porcelain form, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was triturated with isopropyl ether and n-hexane, collected by filtration and dried to obtain 4-hydroxy-5-methoxy-6-methylnicotinic acid methyl ester.

(b) The powder obtained in (a) was dissolved in 70 ml of glacial acetic acid, 200 ml of a 47% aqueous solution of hydrobromic acid was added, and the mixture was stirred at 100 ° C for 20 hours. After concentrating the reaction solution to about 1/2, add 2N aqueous sodium hydroxide solution under ice-cooling and stirring to adjust the pH to 0.5, stir under ice-cooling for 1 hour, and filter the precipitate. 6 g of the title compound was obtained by drying, washing and drying. Obtained as a powder.

lH Difficulty (de-D SO) 5:

Reference example

2 — (4 ill) 1 2 —

[41- (pyridone-3-yl) cal] acetic acid

(a) 8.46 g (50 mmol) of 4,5-dihydroxy-6-methyldiconic acid obtained in Reference Example 1 ° was suspended in 30 ml of pyridine, and acetic anhydride was stirred under ice-cooling with stirring. 14 ml (150 mmol) was added dropwise over 10 minutes, followed by stirring at room temperature for 3 hours. The reaction solution was poured into 400 ml of water, adjusted to pH 1 with 6 N hydrochloric acid under ice cooling and stirring, and stirred for 1 hour under ice cooling.The precipitate was collected by filtration, washed with water, and dried. A powder of 4-hydroxy-5-acetoxy-6-methylnicotinic acid was obtained.

(b) The powder obtained in (a) and 2-(2-amino1.3-thiazol-41-yl) 12-force rubazoi-lumoxy-xymininoacetic acid tert-butyl ester. 6 Dissolve 1 g (40 mmol) and 7-35 g (48 mmol) of 1-hydroxybenzotriazole in 700 ml of DMF, and stir with ice-cooled N, Ν'-dicyclohexane. Hexilka ruposiimid 9.9 g (48 mmol) was added, and the mixture was stirred for 30 minutes under ice cooling, and then stirred at room temperature for 24 hours. After filtering the reaction solution, the solvent was distilled off, and 100 ml of ethyl acetate was added to the residue, and the mixture was stirred to obtain a powder. The powder was collected by filtration, dried, and dried to give 2- (2-amino-1, 3-thiazole-4-yl) 1 2— [4- (5—acetoxy 6—methyl-4—pyridone 1—3—yl) carboxyl carbazoi lumet xyminino] t-butyl acetate An ester powder was obtained.

(c) A mixture of the powder obtained in (b) and 40 ml of trifluoroacetic acid was stirred at room temperature for 2 hours, and trifluoracetic acid was distilled off. A 8% aqueous solution of triturate was added, and the mixture was stirred at room temperature for 1 hour. This was adjusted to pH 1 with 2 N hydrochloric acid under ice-cooling and stirring, and the precipitate was collected by filtration, washed with water, and dried to obtain 6.06 g of the title compound.

! HNR (d ₆ -D S0) 5:

2.35 (S, 3H).

4.83 (S. 2H).

7.09 (S. 1H).

8.34 (S. 1H)

Example 7

7 — {2 — (2—Amino 1, 3—Thiazo 1-4-1) 1 2-[(4- 1 (5-Hydroxy 6—Metyl 4—Pyridone 1 3) —Yl) Carbonylcarbazolyl) methoxymino] acetamido} 1 3 — (2-Hydroxymethyl-5-methyl-s-triazolo [1,5—a] pirimi Gin 1 7 — i-Ruthiomethyl) 1 3 — Cefm 4 4

The title compound was obtained according to the method of Example 5.

Ή N R (de-DMSO) δ:

2.31 (S. 3Η).

2.64 (S. 3Η),

3.79 (S. 2Η).

4.53 to 5.14 (m.2H).

4.75 (S, 2H).

5.92 to 6.24 (m, 1H).

7.12 (S. 1H).

7.38 (S. 1H),

8.36 (S. 1H)

Reference example 1 2

1-Diphenylmethyloxy 2-Hydroxymethyl 5-4 -Methoxybenzyl HOCH ₂ _ (, N, ° ^{cH2 -D-} O CH

, '-(O

1-Hydroxyxy 2—Hydroxymethyl-5— (4-Methoxyxyloline) 1-4-Pyridone 32.9 g (0.119 mo1) in DMSO 45 Dissolve in 0 ml, and add 25 g (0.18 mol) of potassium carbonate, 27 g (0.18 mol) of sodium iodide and chlorodiphenylmethane 3 6.5 g (0.18 mol) was added, and the mixture was stirred at room temperature for 23 hours. The reaction solution was slowly cooled with ice-cooling, and 300 g of fine ice and 500 ml of water were slowly added. The precipitate was collected by filtration, washed with water and washed with isopropyl ether, and dried to obtain 50.74 g of the title compound.

'Η Awake (de-DMSO) δ:

3.82 (S. 3Η)

4.35 (S. 2Η)

4.74 (S, 2Η)

6.18 (S. 1H)

6.60 (S. 1H)

7.03 (d, J = 9Hz. 2H),

7.38 (d.J = 9Hz.2H),

7.42 to 7.73 (m. 11H)

Reference Example 1 3

2-aminomethyl 1 diphenylmethyloxy 5 — (41-methoxybenzyl) 1-41 pyridone NH _a CH.

(a) 1-diphenylmethyloxy 2 -hydroxymethyl 5-(4-methoxybenzyloxy) 1 -41 pyridone 2 2.17 g (50 mmol) of methylene chloride 400 The suspension was suspended in 0.1 ml of DMF, and 0.6 ml of DMF was added thereto. After 20.8 g (175 mmol) of thionyl chloride was added dropwise thereto over 10 minutes, the mixture was stirred at 110 to 115 ° C for 3 hours. The reaction mixture was poured into a mixture of 800 ml of ice-cooled saturated sodium bicarbonate solution and 200 ml of methylene chloride, and after stirring, an organic layer was obtained, and further 200 ml of methylene chloride was added. Extracted. These are combined, washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to give 2-chloromethyl-1-diphenylmethyloxy-5- (4-methoxybenzyloxy) -14-pyridine. Oil was obtained.

(b) The oil obtained in (a) was dissolved in 150 ml of DMF, 14.8 g (80 mmol) of phthalimidocadium was added, and the mixture was stirred at 60 ° C for 30 minutes. . After cooling this with ice, 600 ml of water was added. This was extracted with 400 ml of chloroform, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain an oil. To this, add 100 ml of isopropyl ether and stir, repeat the operation of discarding the isopropyl ether layer three times, distill off the remaining solvent, and distill the 2-phthalimidethyl-1-diphenyl. An oily product of 4- (4-methylxybenzyloxy) -141 pyridone was obtained. (c) The oil obtained in (b) was dissolved in a mixture of 150 ml of methylene chloride and 100 ml of methanol and cooled with ice, and hydrazine hydrate (1 (0%) was added, and the mixture was stirred for 1 hour under ice-cooling. The residue obtained by distilling off the solvent was dissolved in 400 ml of chloroform, left to stand overnight.The precipitate was filtered off, and the oil obtained by distilling off the solvent was purified by silica gel chromatography. The mixture was eluted with lamin chromatography on a mixture of chloroform and a mixture of formaldehyde and methanol, and the solvent was distilled off to obtain 10.5 g of the title compound as an oil. .

* H Awake (CDCla) δ:

3.62 (S. 2Η),

3.83 (S, 3Η).

4.81 (S. 2Η),

6.17 (S. 1H).

6.40 (S. 1H).

6.80 to 7.68 (m. 15H)

Reference example 1 4

1 1 [5 — (4-Methoxybenzyloxy) 1 1 1-Diphenyl meth- yloxy 1 4-Pyridone 1- 2—Dimethyl carbamoyl] 1-1 1-Methylethoxyamine

(a) 2-methyl 2-phthalimide g (23 mmol) and 3.52 g (23 mmol) of 1-hydroxybenzotriazole were dissolved in 100 ml of tetrahydrofuran and stirred under ice-cooling with stirring. 5.78 g (28 mmol) of N'-dicyclohexylcarpoimide was added, and the mixture was stirred for 30 minutes under ice cooling, and then stirred at room temperature for 2 hours. The filtrate obtained by filtering off the precipitate was used to obtain 2-aminomethyl 1-diphenylmethyl-5-(4-methoxybenzyloxy) 14-pyridone obtained in Reference Example 13 10. 5 g (23.7 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was filtered, the solvent was distilled off, and the oily substance obtained was subjected to silica gel column chromatography, eluted with a mixture of chloroform and ethanol, and the solvent was distilled off. By doing so, one diphenyl methacrylate 5 — (4-meth oxybenzene) one 2 — (2 — methyl 2 — phthalimidoxib mouth pionylami (Nomethyll) An oily substance of 141 pyridone was obtained.

(b) 8.0 g of the oily substance obtained in (a) was dissolved in 40 ml of ethanol, and 0.58 ml of hydrazine hydrate (100%) was added under ice-cooling and stirring. 2 mmol) and stirred for 1 hour under ice cooling. After the reaction solution was filtered, the solvent was distilled off. The residue was dissolved in 50 ml of close-up form and left for several hours, followed by filtration, and the filtrate was concentrated. To the obtained oily residue, isopropyl ether was added, and the mixture was stirred to form a powder. The powder was collected by filtration and dried to obtain 4.68 g of the title compound as a powder.

_{'Η NR (CDC1 3) δ} :

1.38 (S, 6H).

3.82 (S, 3H).

4.37 (d.J = 5Hz.2H), 4.56 (S, 2H),

6.15 (broad S, 2H).

6.37 (S, 1H),

6.57 (S. 1H),

6.74 (S. 1H),

6.88 (S, 1H),

7.03 (S. 1H).

7.25 (S, 1H),

7.40 (S. 1H),

7.54 (S, lOH),

8.10 (d.J = 5Hz.1H)

Reference example 1 5

2 — (2 — Hormylamino 1.3. 3 — Thiazole-4-yl) 1 2 — {1-[5 — (4-Methoxybenzyloxy) 1 1 1 Diphenylmethyl 4 1 pyridone 1 2 —methyl methylcarbamoyl] 1 1 1-methylethoxyiminoacetic acid

Reference Example 14 1 [5 — (4-Methoxymethoxy) 1 – 1 diphenylmethyloxy 4 – 1 pyridone 1 – 2 – methylethylcarnomoyl] 1 – 1 1 Methylethoxy 3.3.6 1 g (6.64 mmol) was dissolved in 100 ml of ethanol, and 100 ml of water was added. To this were added 0.7 g of sodium acetate and 1.2 g (6 mmol) of 2-((2-formylamino-1,3-thiazol-41-yl) glyoxylic acid. To this mixture was added a 2N-sodium hydroxide aqueous solution to adjust the pH to 6.5, and the mixture was stirred at room temperature for 24 hours. After ethanol was distilled off from the reaction solution, the pH was adjusted to 2.5 with a 2N hydrochloric acid aqueous solution while stirring with ice cooling. The precipitate was collected by filtration, washed with water, and dried to give 2.99 g of the title compound.

N R (de-DMSO) 5:

1.52 (S. 6H).

3.38 (S. 3H).

4.30 (S. 2H).

4.83 (S, 2H).

6.32 to 7.88 (m. 18H),

8.75 (S. 1H)

Example 8

7 — {2 — (2-amino 1.3-thiazol-41) 1 2— [1 (1,5—dihydroxy 4—1 pyridone 1—2— Circarno \ 'mille) 1 1 1 Methyl ethoxyminoacetamide} 1 3 — (5—Methyl 1.3, 4—Thiadiazol 2—I-Luthiomethyl) 1 3—Cef-emu 4 One-stroke rubonic acid

(a) 2— (2-formylamino 1,3—thiazol-4-yl) obtained in Reference Example 1-5—2— {1— [5— (4-methoxybenzil) —— 1-diphenylmethyloxy-4-pyridone-1-2- (methylmethylcarbamoyl) -111-methylethoxyimino} acetic acid 2.99 g (4.12 mmol) of 7-amino-3— (5-Methyl 1.3.3.4 —Thiadiazol 2 —Diruthiomethyl) 13 —CefM 4 Diphenylmethylester Rilebonate 2.3 1 g ( 4.53 mmol) and 0.63 g (4.12 mmol) of 1-hydroxybenzotriazole are dissolved in 30 ml of DMF, cooled with ice, and cooled with N .'- dicyclohexylcarboximide. 1. ◦ 2 g (4.944 mmol) was added, and the mixture was stirred for 30 minutes while cooling with ice, and further stirred at room temperature for 2 hours. After filtration, the reaction mixture was added dropwise to 180 ml of isopropyl ether, and the resulting precipitate was collected by filtration and dried. This was subjected to silica gel chromatography, eluted with a mixture of black form and methanol, concentrated, and then treated with isopropyl ether to obtain a compound of formula (2) -(2-Hormylamine 1, 3-Thiazolyl 41-1) 1 2-[1-(1.5-Dihydroxy 4-pyridone 1-2-methylmethylcarbamoyl) 1 1 Ichimichiru Toxie Minodiacetamide} 1-3- (5-methyl-1.3,4-thiaziazole-2-ylthiothiomethyl) -13-cefmue 4-Carbonic acid powder (3.04 g) was obtained. .

(b) Dissolve 2.97 g of the powder obtained in (a) in 24 ml of methylene chloride, add 15 ml of anisol, cool on ice, and add 3 Q ml of trifluoroacetic acid. The mixture was stirred for 1 hour while cooling with ice. This was added dropwise to isopropyl ether 75 O inl, the resulting precipitate was collected by filtration and dried, and 7- {2- (2-formylylreamino 1.3-thiazo-l-4-1) 1) 2-[1-diphenylmethyloxy 5-(4-methoxybenzyloxy) 1-4-pyridone 1-2-ylmethylcarbamoyl] 1-1 -methylethoxyamino Acetamide} 1- (5-Methyl 1.3, 4-Thiadiazol 2-Iruchi-Methyl) 1-3-Cefume 4 A powder of divinylmethylester of rubonic acid was obtained.

(c) 20 ml of methanol was ice-cooled, and 0.45 ml of oxine chloride was added dropwise thereto. The powder obtained in (b) was added thereto, and the mixture was stirred for 2.5 hours while cooling with ice. This reaction solution was added dropwise to 450 ml of ether, and the resulting precipitate was collected by filtration and dried to obtain a powder of the hydrochloride of the title compound.

The powder obtained in (d) (c) was suspended in water 5 0 ml, adjusted to _P H 7. 0 with 5% bicarbonate Na Application Benefits um solution and dissolved. The solution was adjusted to pH 2.5 with 2N-hydrochloric acid under ice-cooling and stirring, and the resulting precipitate was collected by filtration, washed with water, and dried to obtain 1.74 g of the title compound.

! HNR (d ₆ -D S0 + D ₂ 0) 1.63 (S. 6H).

2.75 (S. 3H).

3.84 (S, 2H).

4.67 (S. 2H).

5.98 (d.J = 5Hz.1H),

7.25 (S. 1H),

7.32 (S, 1H),

8.52 (S. 1H)

The following compound is produced according to the method of Example 8.

a) 7- {2- (2-Amino-1,3-thiazol-4-yl) -1-2- [1- (1- (1.5-dihydroxy-pyridone-one 2-dimethyl carbamoyl) 1 1 1 Methyl ethoxymino] acetamide} 13- (5-Methyl-1.3,4-thiathiol-2-l-thiothiomethyl) 1-3-Cefume-4

b) 7-{2-(2-amino 1, 3-thiazol-4-yl) 1 2-[1-1 (1.5-dihydroxy 4-pyridone 1-2-i-dimethylmethylcarbamoy 1) 11- (methyl ethoxymino) acetamide} 13- (methyl 1H-tetrazol-5-i-luc- ometyl) 13-cefmu 4 δ 3

c) 7 — {2-(2 — Amino 1.3. 3 — Thiazol-4-yl) 1 2 — [1 — (1, 5 — dihydroxy 4 1 pyridone 1 2 — Zilume Tylcarbamoyl) 1 1 1 methyl ethoxymino] acetamide} — 3 — (2-carboxy-5 — methyl s-triazo mouth [1.5 — a〗 pyrimidine] 7 — i-Luthiomethyl) 1 3 — cefum 4 4 rubonic acid

d) 7-{2-(2-amino 1, 3-thiazole-4-yl) 1 2-[1-(1, 5-dihydroxy 4-pyridone-1 2-zylume Tylcarbamoyl) 1-11-methylethoxyminino] acetamide} 13- (2-hydroxymethyl-5-methyl-s-triazolo [1.5-] pyrimidine-1 7 —I-Luthiomethyl) I 3 —CefM 4

e) 7 — {2-(2 — Amino 1.3. 3 — Thiazol-4-yl) 1 2 — [1-(5 -Hydroxy 1 1-Methyl xy 4 1 Pyridone 1 2 — 1-methylethyl oximino] acetamido} 1-3— (5-methyl-1.3.4-thiadiazol-2—diluthiomethyl) 1-3-sefmue 4 power rubons

f) 7 — {2-(2 — amino 1, 3-thiazole-4-yl) 1 2 — [1 (5—hydroxy 1 -methoxy 4 -pyridone 2 — 1-methylethyloxymino] acetamide} 13- (1-methylethyl 1H-tetrazole)

5—Luthiomethyl) 1—3—Sfuemu 4

g) 7-{2 — (2 — Amino 1.3-Thiazo-1-4-yl) 1 2 — [1-(5-Hydroxy 1-Methoxy 4-Pyrid 1-methyl-2-ethoxyminino] acetamide} 1-3— (2-carboxy-5-methyl-s—triazolo [1.5-a] Pyrimidine 1 7 — thiol thiomethyl) 1 3 — sefum 4 4 rubonic acid

h) 7-{2-(2-amino 1.3-thiazol-4-yl) 1 2-[1-1 (5-hydroxy 1-methoxy-14-pyridone-2) —I relay methyl carbamoyl) 1-11 methyl ethoxymino] acetamide} 1 3 — (2 — Hydroxymethytyl 5 — Methyl s — Tro azolo “1.5 — a〗 Birimidine 1 7 — ルーチチ 3 3 セフムームー 4 4 rubonic acid

Reference Example 1 6

2—Amino oxime chill 1 (4-Methoxyxylbenzyloxy) 1-41 pyridone

(a) 1 diphenyl methoxy

20 g (45 mmol) of 5- (4-methoxybenzyloxy) -141 pyridone was suspended in 250 ml of methylene chloride, and 0.6 ml of DMF was added. The mixture was stirred under cooling to 11 ° C. To this, 19 g (160 mmol) of chlorinated chloride was added dropwise over 10 minutes, and the mixture was stirred at 110 to 115 ° C for 3 hours. The reaction solution was poured into a mixture of ice-cooled saturated sodium bicarbonate solution (750 ml) and methylene chloride (200 ml), and stirred. After stirring, an organic layer was obtained, and methylene chloride (200 ml) was further added. Extracted. These are combined, washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off to give 2-chloromethyl 1-diphenylmethyloxy 5-(4-methoxybenzyloxy)-4-pi. A red oil was obtained.

(b) The oil obtained in (a) was dissolved in 100 ml of DMS, and 8.16 g (50 mmol) of N-hydroxyphthalimide and 8.3 g of carbon dioxide were dissolved. (60 mmol) and 1 g (6 mmo 1)

The mixture was stirred at 60 ° C for 1 hour. After cooling with ice, the mixture was poured into 700 ml of water and extracted with 300 ml of ethyl acetate. After washing with water, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain an oil. This oily substance was applied to silica gel chromatography, eluted with a mixture of black mouth and methanol, and the solvent was distilled off to obtain 2 — An oily product of phthalimidoxymethyl 1-diphenylmethyloxy 5— (4-methoxybenzoyloxy) -4-pyridone was obtained.

(c) The oil obtained in (b) was dissolved in a mixture of 150 ml of methylene chloride and 100 ml of methanol, cooled on ice, and hydrazine hydrate was added thereto. (100%) 4.4 nil (90 mmol) was added, and the mixture was stirred for 1 hour under ice cooling. The residue obtained by distilling off the solvent was dissolved in 400 ml of black form and left overnight, and then the precipitate was filtered off. The product was eluted with chloroform-methanol mixture on Kagelkalam chromatograph, and the solvent was distilled off to give 16.4 g of the title compound as an oil. I got it.

Ή N R (CDCla) 6:

3.79 (S. 3Η).

4.49 (S, 2Η),

4.71 (S. 2Η).

5.68 (S. 2Η).

6.18 (S. 1H).

6.48 (S. 1H),

6.75 (S. 1H),

6.83 (S. 1H).

6.98 (S. 1H).

7.21 (S. 1H).

7.38-7.73 (m, 11H)

Reference Example 1 7 1 1 [5 — (4-methoxybenzyloxy) 1 1 diphenylmethyloxy 4 1-pyridone 1 2-dimethyloxycarbonyl N

The title compound was obtained according to the method of Reference Example 14.

Ή Painting (CDCls) δ:

1.38 (S. 6Η).

3.83 (S. 3Η).

4.62 (S. 2Η),

4.85 (S. 2Η),

6.65 (S. 1H).

6.82 (S. 1H).

G.88 (S. 1H),

7.03 (S. 1H).

7.23 (S. 1H),

7.38 (S. 1H).

7.46 to 7.74 (m, 11H)

Reference Example 1 8

2-(2-holminamino 1.3-thiazol-4-yl) 1 2-{2-[5-(4-methoxybenzyl) 1-1 diphenylmethyl Kissy 4 1 Pyridon 1 2 Lubamoyl] 1-methyl ethoxymino) Acetic acid

The title compound was obtained according to the method of Reference Example 15.

'Η N R (de-DMSO) δ:

1.48 (S. 6H).

3.86 (S. 3H),

4.62 to 4.93 (m, 4H),

6.62 to 7.85 (m, 18H),

8.78 (S. 1H)

Example 9

7 — {2-(2—Amino 1.3-Thiazo-one 41-yl) 1 2 — [1 1- (1.5-Dihydroxie 4—Pyridone 1 2 — 1-methylethylethoxymino] acetamido} 1 3 — (5—methyl-1,3,3.4—thiadiazol 2 —diluthiomethyl) 1 3—cefumeu 4 One-stroke rubonic acid

The title compound was obtained according to the method of Example 8. Ή picture (d ₆ -DMS0 + D ₂ 0) δ:

1.53 (S. 6H).

2.74 (S, 3H).

3.83 (S. 2H),

4.54 (ABq, J = 14Hz. 2H),

5.95 (d.J = 5Hz.1H),

7.32 (S, 1H),

7.63 (S. 1H).

8.63 (S. 1H)

Example 10

7 — {2-(2—Amino 1.3 .3—Thiazo 4 -yl) 1 2 — [1 1 (1, 5 —Dihydroxy 4 -Pyridone 1 2 —Iru Methoxycarbamoyl) -1-methylethoxyminino] acetamide} 1-3— (2—carboxy5—methylyls—triazolo [1.5—a] pyrimidine-1 7 —Luthiothiol 3 1 —Sefume 4 1Rubonic acid

The title compound was obtained according to the method of Example 8.

'Η NMR (d ₆ -DMS0 + D ₂₀ ) δ:

1.48 (S. 6H). 2.63 (S. 3H).

3.78 (S. 2H).

4.38 to 4.85 (m, 2H).

5.88 (d, J = 5Hz. 1H),

7.05 (S. 1H).

7.36 (S, 1H).

7.48 (S. 1H).

8.33 (S. 1H)

The following compound is produced according to the method of Example 8.

a) 7-{2-(2-amino 1.3-thiazol-4-yl) 1 2-[1-1 (1, 5-dihydroxy 4-viridone 1-2-relay methoxycarbamoy 1) 1 1 1 Methyl ethoxymino) Acetamide 1 3 — (1-Methyl-1 H-Tetra-1-5-Lu-Michi) 1-3-Sefmu 4 Rubonic acid

b) 7-{2-(2-amino 1, 3-thiazol-4-yl) 1 2-[1-1 (1.5-dihydroxy 4-pyridone 1-2-) 1-methylethoxyethoxymino] acetamido} -3- (2-hydroxymethyl-5-methyl-s-triazolo [1.5-a ] Pyrimidine 1 7 3) 3-Sefmu 4 One-stroke relevonic acid

c) 7-{2-(2-amino 1.3-thiazol-4-yl) 1 2-[1-(5-hydroxy 1-meth-oxy 4-pyridone-1 2 1-methyloxyethoxymino] acetamido} 13- (5-methyl-1.3.4-thiaziazole-2-dichlorothiol) 13-cefumeu 4 Monocarboxylic acid

d) 7 — {2-(2 — Amino 1.3-Thiazole-4-yl) 1 2 — [1 (5-Hydroxy 1-Methoxy 1-4-Pyridone 2 1-Methylethoxymino] acetamid} 1-3— (1-Methyru1H—Tetrazolu5—Y-Luthiomethyl) 1-3—Sefumu 4 rubonic acid

e) 7 — {2-(2 — Amino 1.3. 3 — Thiazo 1-4-yl) 1 2 — [1-(5-Hydroxy 1-Methoxy 4-Pyridone 2) —Alu-methoxycarbamoyl) 11 1-methylethoxyminino] acetamide} 1 3— (2—Carboxy 5—Methyl s-triazolo [1.5—a] Birimidine 1 7 — ryumemethyl) 1 3 — sefume 4

f) 7 1 I 2-(2-amino 1, 3-thiazol-4-yl) 1 2-[1-1 (5-hydroxy 1-methoxy 4-pyridone 2- 1-methylethoxyethoxymino] acetamido} 1-3— (2-hydroxymethyl-5-methyl-5-methyl-s-triazolo) a〗 Pyrimidine 1 7 — ィ Lucio methyl) 1 3 — Sefmu 4

Example 1 1

7-{2-(2-amino-1, 3-thiazol-4-yl) 1 2-[1 1-(1.5-dihydroxyl 4-1 pyridone 1-2-il carilepo Nilkasolevasil) 1 1 1-Methylethoxyminino] acetamide} 1 3 — (4 1 pyridyl) thiomethyl 3 — Cefm 4

The title compound was obtained according to the method of Example 5.

麗 Rei (de-DMSO) δ:

1.57 (S. 3Η).

3.55 (broad S. 2H),

4.48 (broad S, 2H).

5.13 (d.J = 4Hz, 1H).

5.77 (d, J = 4Hz.1H).

6.98 (S, 1H), 7.20 (S. 1H).

7.48 (d.J = 5Hz.2H),

8.44 (d.J = 5Hz.2H)

Example 1 2

7 — {2-(2-amino 1, 3-thiazol 41-1) 1 2-[1 1-(1.5-dihydroxy 4-1 pyridone 1-2-carbonyl carbazole 1 1 1 1 Methylethoxyminodiacetamide} 1 3 — Acetoximethyl 3 — Cefume 4 1% sodium rubonate sodium salt CHa

According to the method of Example 5, 7— {2 -— (2-amino-1,3-thiazole-4-yl) 1-2— [1-1 (1,5—dihydroxy-4-pi) Ridone-1 2-divinylcarbazole) 1-1-methyl thiocyano] acetamid} 1-3-acetoximetyl 3-cefume 4 Then, the title compound was obtained according to the method of Example 2.

Ή NMR (d _e -DMS0) δ:

1.52 (S. 6Η),

2.05 (S. 3Η), 3.48 (broad S, 2H),

4.85 to 5.38 (m. 3H).

5.75 (d.J = 5Hz.1H),

7.01 (S. 1H).

7.23 (S, 1H)

Example 13

7-{2-(2-amino 1, 3-thiazol-41-yl) 1 2-[1 (1, 5-dihydroxy 4-pyridone-1 2-yl-carbone Rucarbazole) 1 1 1 methyl ethoxymino] acetamide} 1 3 — (1 methyl pyridinium 2 — チチチ 3) 1 3 —

7— {2— (2-amino-1,3—thiazolue 4-one-irile) obtained in Example 1 2 1-2— [1-1- (1,5-dihydroxy-4-pyridone) 2—Divinylcarbazole) 1 1-methyl thiocyano] acetamido} 1 3—acetoximetyl 3—cefum 4 1-sodium rubonate sodium salt 2.3 g (3.32 mmol) was dissolved in 16 ml of water, and 16 ml of sodium acetate, 5 g (33.4 mmol) of sodium hydroxide and 1-medium were dissolved. Chill 2 — Choporyridone 0.82 g (6. δ mmol) was added. The solution was adjusted to pH 7 by adding 2N-hydrochloric acid, and then stirred at 65 ° C for 5 hours. The reaction solution was stirred while dropping into 4 ml of acetate, and the precipitate was collected by filtration and dried to obtain a powder. This powder was dissolved in water, subjected to reverse phase preparative chromatography, eluted with a mixture of water and methanol, concentrated, and lyophilized to give 0.52 g of the title compound. Obtained.

^J HNR (d ₆ -DMS0) δ:

1.48 (S. 3H).

3.42 (broad S, 2H),

4.22 (S. 3H).

4.44 (broad S. 2H),

5.08 (d, J = 4Hz.1H).

5.82 to 6.08 (m. 1H),

7.02 (S. 1H),

7.34 (S. 1H).

7.56-8.64 (m, 3H),

8.93 (d, J = 6Hz.1H)

(Sensitivity test)

Example 1, 3, 4 and the minimum deter concentration of the obtained the following compounds 1-4 in 6 [MIC (m / ml: 1 0 6 CFU / ml)] is shown in Table 1.

Compound 1 (Example 1) ··· 7-{2-(2 -amino 1.3 -thiazol-4-yl) 1 2-[1-1 (1.5-dihydroxy 4 1-Pyridone 1 2 —methyl methyl carbazole) 1 1 1 Methyl ethoxymin acetamide amide} ー 3 — (5—methyl 1,3,4-thiadiazol-2—I-Luthiomethyl) 1—3-Sefum 4

Compound 2 (Example 3) · ·-7-{2-(2-amino 1.3-thiazole-4-yl) 1 2-[1-(5-hydroxy 1- Toxie 41-pyridone 1- 2-methylidene carbazole) 1- 1-methylethoxyminino] acetamido} 1 3- (5-methylethyl 1.3, 4-thiazia) Zol-2 — thiol-methyl) 1 3 — sefume 4 rubonic acid

Compound 3 (Example 4) · * · 7— {2— (2—Amino 1,3-thiazol-4-isole) 1 2— [1 (5—hydroxyl 4-pyridine) 1 2 — i-methylidenecarbazole) 1- 1-methyloxymethylene acetate amide}-3-(5-methyl 1.3, 4-thiadiazol 2-dithiothiomethyl) One 3-Sefume 4 One-strength rubonic acid

Compound 4 (Example 6) ··· -7- {2- (2-amino1.3-thiazol-41-yl) 1 2— [1- (1,5-dihydroxy-41-pi) REDON 1 2 — YL CARBONYL CARBAZOLE) 1 1 1 METHYL ETXY MINI] ACE AMID} 1 3 — (5 — METHYLUM 1,3,4THIADIAZOLE 2 — Chill) 1-3-Se-fume 4 table 1

CAZ: Cefu taz id ime

"Industrial applicability"

According to the present invention, a novel cephalosporin compound can be provided. The compound of the present invention represented by the above formula (I) exhibits excellent antibacterial activity against a wide range of Gram-negative bacteria and Gram-positive bacteria.

Therefore, the novel cephalosporin compounds of the present invention can be effectively used for humans or animals for the prevention or treatment of the above-mentioned bacterial infectious diseases. it can.

Claims

Claims General formula (I

I)

(Where A represents the formula: N = CH—, NHC 0— (CH = CH) _m— , CH ₂ — or 0—CH ₂ —; m represents 0 or 1; R ¹ , R ² and R ³ each independently represent a hydrogen atom or a lower alkyl group: R ⁴ represents a hydrogen atom or a formula 10 R ^e (R ⁶ represents a hydrogen atom, a lower alkyl group or a protecting group); R ⁵ represents a hydrogen atom or an organic group), a novel cephalosporin compound represented by the formula: or a salt or ester thereof.

2. The cephalosporin-based compound according to claim 1, wherein in the formula (I), A is a formula (1) NHC0—, or a salt or ester thereof.

3. The cephalosporin-based compound according to claim 1, wherein A in the formula (I) is represented by the formula: N = CH—, or a salt or ester thereof.

4. The cephalosporin-based compound according to claim 1, wherein in the formula (I), A is a formula CH ₂ —, or a salt or ester thereof.

5. The cephalosborin-based compound according to claim 1, wherein in the formula (I), A is a formula 10—CH ₂ —, or a salt or ester thereof.

6. In the formula (I), R ¹ and R ² are lower alkyl groups having 1 to 3 carbon atoms. 4. The cephalosporin-based compound according to claim 1 or a salt or ester thereof.

7. The cephalosporin compound according to claim 6, wherein R ¹ and R ² are a methyl group, or a salt or ester thereof.

8. The cephalosporin-based compound according to claim 1, wherein in the formula (I), R ³ is a hydrogen atom, or a salt or ester thereof.

9. The cephalosporin compound according to claim 1, wherein in the formula (I), R ⁴ is a hydrogen atom, a hydroxy group or a methoxy group, or a salt or ester thereof.

10. The cephalosporin-based compound according to claim 1, wherein in the formula (I), R ^s is a 5-methyl-1.3.4-thiadiazol-2-ylthiothiomethyl group. Salts or esters thereof.

1 1. In the formula (I), R ⁵ is a 2-methylhydroxy-5-methyl-s-triazolo [1.5-a] pyrimidine-17-dichloromethyl group. 2. The cephalosporin compound according to item 1, a salt or ester thereof.

1 2. In the formula (I), R ⁵ is 2 -carboxy-5 -methyl- s -triazolo [1.5 -a] pyrimidine-1 7 -dimethyl group. The cephalosporin compound according to claim 1, a salt or an ester thereof.

13. The cephalosporin according to claim 1, wherein in the formula (I), R ^{5 is} s 1 —methyl-1H—tetrazol-5-ylthiomethyl group. Compounds, salts or esters thereof.

1 4. In the formula (I), R ⁵ force 5 1, 3. 2. The cepfa spolin-based compound according to claim 1, which is a luthiomethyl group, or a salt or ester thereof.

1 5. Formula (I) in, only ^five 5 1, 2. 3-thiadiazole over 5 I routine Saime ceph § Rosubo Li emissions based compound methyl group and is described first aspect, a salt thereof or ester.

1 6. In the formula (I), R ⁵ force si — (2-hydroxyshetyl) tetrazo 5 — i is a methyl group of cephalosporium according to claim 1. Compounds, salts or esters thereof.

17. The cepha according to claim 1, wherein in the formula (I), R ⁵ is a 3 -carboxy-5-methylpyrazo opening [1.5-a] pyrimidine-17-ylthiomethyl group. Losporin-based compounds, salts or esters thereof.

1 8. The cephalosporin-based compound according to claim 1, wherein R ^{5 is a} 5- (4-pyridyl) thiomethyl group in the formula (I), or a salt or ester thereof.

1 9. formula (I), Joseph § Rosupo Li down compounds of claims claim 1 wherein R ⁵ is 3-§ Seto Kishime butyl group, a salt thereof or ester le.

2 in 0. formula (I), R ⁵ Power 51 - main Chirubi Li Jiniumu 2 I Lou Chiome ceph § Rosupo Li down compounds of claims claim 1 wherein a butyl group, a salt or ester.

2 1. The following equation:

4. The cephalosporin-based compound according to claim 1, which is represented by the following: or a salt or ester thereof.

2 2.

NH

The cephalosporin-based compound according to claim 1, which is represented by:

2 3.

O

C -CONH -N = CH

/ \. H

2. The cephalosborane compound according to claim 1, which is represented by CH ₃ CH, or a salt or ester thereof.

2 4. The following formula:

The cephalosporin-based compound according to claim 1, which is represented by the following: or a salt or ester thereof.

2 5.

4. A cefolin spolin-based compound according to claim 1 represented by: or a salt or ester thereof.

2 6. The following equation:

2 7. The following formula:

2 8. The following formula: H:

2 9. The following formula:

2. The cephalosporin-based compound according to claim 1, wherein the salt or ester is represented by the formula:

30. Next equation

4. The cephalosporin-based compound according to claim 1, which is represented by: or a salt or ester thereof.

3 1. The following equation:

32. Next equation: