JPS62492A - Novel cephalosporin derivative and antimicrobial agent - Google Patents

Abstract

NEW MATERIAL:A cephalosporin compound shown by the formula I (A is 2-5C alkanoyloxy, carbamoyloxy, azido, etc.). EXAMPLE:(6R,7R) 7-[(RS)2-(2-Aminothiazol-4-yl)-2-(1, 5-dihydroxy-4-pyridone--2- carb oxamido)acetamido]-3-acetoxymethyl-cef-3-em-4-carboxylic acid. USE:An antibacterial agent. PREPARATION:A compound shown by the formula II (R<7> is H or protecting group; R<8> is H or protecting group) or its salt or silylated compound is reacted with a compound shown by the formula III (R<6> and R<9> are H, eliminable protecting group such as benzyl, p-nitrobenzyl, etc.).

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a novel cephalosporin derivative having a broad antibacterial spectrum including Pseudomonas aeruginosa. -yl)-2-(1,
This relates to a new cephalosporin derivative having a 5-dihydroxy-4-pyridone-2-carboxamide) acetamide group, which has excellent therapeutic effects against diseases caused by pathogenic bacteria in humans and animals, and is useful as a medical and veterinary drug. be.

[Prior Art and Problems to be Solved by the Invention] Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria, and are commonly used to treat diseases caused by pathogenic bacteria. However, the so-called third-generation cephem antibiotics that have recently appeared as antibacterial agents against Gram-negative bacteria, including opportunistic bacteria, cannot be said to have sufficient clinical therapeutic effects.

For example, an amide substituted with dihydroxybenzoic acid for the amino group at the 2-position of an aminothiazolylglycyl group substituted at the 7-position of a cephalosporin exhibits particularly strong antibacterial activity against Pseudomonas aeruginosa (Japanese Patent Application Laid-Open No. 139387-1982). O-methylated molecules have the disadvantage of being easily deactivated in vivo.

JP-A-59-118792 discloses a 5-hydroxy-4-pyridone-2-carboxamide derivative of the 2-amino group of an aminothiazolylglycyl group as an example of the compound of the invention. are the main ones, and no specific example of the 1,5-dihydroxy-4-pyridone-2-carboxamide substituted product of the present invention is shown.

Synthesis of 1,5-dihydroxy-4-pyridone-2-carboxylic acid, which is a component of the 7-position substituent of the present invention, is not so easy. In other words, the reaction between kojic acid and hydrazine yields almost no N-aminopyridone 1. Ichimoto et al. Agricultural Biological Chemistry Vol. 31, pp. 979-989, 1967 (1, Ichi
a+oto atcs Agr, Biol, Chemv
ol, 31979-989.1967),
Generally, when a pyrone ring is reacted with hydroxylamine,
Hydroxylamine substitution of the carbonyl moiety is observed simultaneously with hydroxylamine substitution of the desired oxygen atom. Heterocyclic Compounds, Pyridine and It's Derivatives Volume 14 Part, Interscience Paprisi Social Ltd.

(Heterocyclic Con+pounds,
Pyridine and 1tsDerivative
es vol 14 Part 21interscie
nce public-4shers LTD).

As a result of various studies in the present invention, the compound was obtained in relatively good yield by carrying out this reaction in the presence of pyridine or the like.

The compound of the present invention is characterized by having this 1,5-dihydroxy-4-pyridone-2-carboxamide group in the 7-position substituent, and compared with the 5-hydroxy-4-pyridone-2-carboxamide substituted product. , antibacterial activity, especially against Pseudomonas aeruginosa, was found to be more enhanced than expected, and it also has excellent solubility in water, which is an important requirement for injectables.

The present invention specifically discloses the usefulness of the compounds of the invention.

[Means for solving problems]

The present invention aims to provide novel derivatives and pharmacologically acceptable salts thereof that overcome the drawbacks of existing cephalosporin antibiotics.

That is, the present invention relates to the general formula (1), where A is an alkanoyloxy group having 2 to 5 carbon atoms, a carbamoyloxy group, an azide group, "(n is 0 or an integer of 3 to 5, R1, Rt are the same - or Pyridylthio and substituted pyridylthio groups represented by a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 5 carbon atoms which may contain a halogen atom, which may be different, [n and R+, Rz have the above meanings, R3 has 1 to 5 carbon atoms
Straight chain or branched alkyl group, halogen-substituted alkyl group, cyclopropyl group, cyclopropylmethyl group, alkenyl group, oxygen atom, or -(CHz) mB (m is 0
An integer of ~3, B is a hydroxyl group, an alkoxy group, an acino group, an alkyl-substituted amino group, a carboxyl group, a carbamoyl group, a sulfonic acid group, a sulfonic acid amide group, a cyano group, a thiol group, an alkylthio group, a methanesulfonylaminocarbonyl group, or an acetamidosulfonyl group), a pyridiniumthio group represented by ], and a substituted pyridiniumthio group, or a substituted pyridiniumthio group, or a group represented by the formula (n is 0 or 3 to
an integer of 5, R' and R' may be the same or different, a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, a carboxyl group, a carbamoyl group, a sulfonic acid group, a sulfonic acid amide group, Indicates a straight-chain or branched alkylthio group having 1 to 5 carbon atoms, a halogen-substituted alkylthio group, a cycloalkanotio group, a cycloalkanomethylthio group, a carboxyalkylthio group, a carbamoylalkylthio group, an alkoxyalkylthio group, an alkyl-substituted aminoalkylthio group) The present invention relates to a novel cephalosporin compound having the following pyridinium and a substituted pyridinium group, a pharmacologically acceptable salt thereof, and an antibacterial agent containing the same as an active ingredient.

The α carbon of the aminothiazolylglycyl substituent in the general formula (2) can exist in the 0 form and the L form, and the present invention includes both of them and the DL form.

Furthermore, the following tautomers can exist for the 1,5-dihydroxy-4-pyridone-2-carboxamide moiety of the 7-position substituent, and the present invention includes both of them, but the naming and structural description are It has a pyridone type.

The pharmacologically acceptable salts of the compounds of formula I according to the invention include medically acceptable salts, especially the customary non-toxic salts, and inorganic salts include salts with inorganic bases, such as sodium salts. , alkali metal salts such as potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, and organic salts such as salts with organic bases, such as triethylamine salts, pyridine salts, ethanolamine salts,
Examples include organic amine salts such as triethanolamine salt and dicyclohexylamine salt, and basic amino acid salts such as lysine and arginine.

Specific examples of the substituent at the 3-position of the compound of formula (1) of the present invention include, but are not limited to, the following.

(pyridin-4-yl)thiomethyl, (pyridin-3-
yl)thiomethyl, (pyridin-2-yl)thiomethyl, (3-methylpyridin-4-yl)thiomethyl, (2
,3-dimethylpyridin-4-yl)thiomethyl, (2
-carboxypyridin-4-yl)thiomethyl, (2-
Carbamoylpyridin-4-yl)thiomethyl, (2,
3-cyclobenzenobiridin-4-yl)thiomethyl,
(pyridine-N-oxide-4-yl)thiomethyl, (
2,3-cyclopentenopyridine-N-oxide-4-
yl)thiomethyl, (5,6-cyclobentenopyridin-2-yl)thiomethyl, (2゜3-cyclohexenopyridin-4-yl)thiomethyl, (5,6-cyclohexenopyridin-2-yl)thiomethyl, (1-Methylpyridinium-4-yl)thiomethyl, (l-methylpyridinium-3-yl)thiomethyl, (1-methylpyridinium-2-yl)thiomethyl, (1-ethylpyridinium-4-yl)thiomethyl, (l -allylpyridinium-4-yl)thiomethyl, [1-(2,2,2-trifluoroethyl)viridinylam-4-yl)thiomethyl, (1-carboxylmethylpyridinium-4-yl)
Thiomethyl, (1-carbamoylpyridinium-4-yl)thiomethyl, (1-hydroxyethylpyridinium-4-yl)thiomethyl, (1-dimethylaminoethylpyridinium-4-yl)thiomethyl, (1-cyclopropylpyridinium-4-yl) yl)thiomethyl, (1-
Cyclopropylmethylpyridinium-4-yl)thiomethyl, (1-methylthiomethylpyridinium-4-yl)thiomethyl, (1-cyanomethylpyridinium-4-yl)
yl)thiomethyl, (2,3-cyclopenteno-1-methylpyridinium-4-yl)thiomethyl, (2゜3-
cyclopenteno-1-ethylpyridinium-4-yl)
Thiomethyl, (2,3-cyclopenteno-1-allylpyridinium-4-yl)thiomethyl [2,3-cyclopenteno-1-(2,2゜2-trifluoroethyl)pyridinium-4-ylkothiomethyl, (2,3- Cyclopenteno-1-carboxymethylpyridinium-4-yl)thiomethyl, (2,3-cyclopenteno-1-carbamoylpyridinium-4-yl)thiomethyl, [2,3
-cyclopenteno-1-(2-hydroxyethyl)pyridinium-4-ylcothiomethyl, (2,3-cyclopenteno-1-dimethylaminoethylpyridinium-4
-yl)thiomethyl, (2,3-cyclopenteno 1
-cyclopropylpyridinium-4-yl)thiomethyl, (2,3-cyclopenteno-1-cyclopropylmethylpyridinium-4-yl)thiomethyl, (2,3-cyclopenteno-1-cyanomethylpyridinium-4-yl)thiomethyl, (5,6-cyclopenteno-1-methylpyridinium-2-yl)thiomethyl, (5,6-cyclopenteno-1-carboxyethylpyridinium-2)
-yl)thiomethyl, [5,6-cyclopenteno-1-
(2-Hydroxyethyl)pyridinium-2-ylcothiomethyl, (2,3-cyclohexeno-1-methylpyridinium-4-yl)thiomethyl, (2,3-cyclohexeno-1-carboxyethylpyridinium-4-yl) Thiomethyl, (2,3-cyclohexeno-1-carbamoylpyridinium-4-yl)thiomethyl, C2,
3-cyclohexeno-1-(2-hydroxyethyl)
Pyridinium-4-ylkothiomethyl, [2,3-cyclohexeno-1-(dimethylaminoethyl)pyridinium-4-ylkothiomethyl, pyridiniummethyl, 4-
Methylpyridinium methyl, 2.3. -dimethylpyridinium methyl, 2,3-cyclopentenopyridinium methyl, 2,3-cyclohexenopyridinium methyl, 4
-Carbamoylpyridiniummethyl, 3-carbamoylpyridiniummethyl, 4-methylthiopyridiniummethyl, 3-methylthiopyridiniummethyl, 2-methylthiopyridiniummethyl, 4-ethylthiopyridiniummethyl, 4-allylthiopyridiniummethyl, 4-cyclopropylmethylthiopyridiniummethyl , 3-cyclopropylmethylthiopyridiniummethyl, 4-cyclopropylthiopyridiniummethyl, 4-cyclopentylthiopyridiniummethyl, 4-(2,2,2-trifluoroethyl)thiopyridiniummethyl, 4-(2-hydroxyethyl)thio Pyridinium methyl, 3-(2-hydroxyethyl)thiopyridinium methyl, 4-, (2
-fluoroethyl)thiopyridinium methyl, 4-carboxyethylthiopyridinium methyl, 4-carbamoylethylthiopyridinium methyl, 4-(N,N-dimethylaminoethyl)thiopyridinium methyl, 2.3
-Cyclopenteno-4-methylthiopyridinium methyl, 2.3-cyclopenteno-4-ethylthiopyridinium methyl, 2゜3-cyclopenteno-4-allylthiopyridinium methyl, 2.3-cyclopenteno-4-cyclopropylmethylthiopyridinium methyl, 2 .3-cyclopenteno-4-cyclopropylthiopyridinium methyl, 2,3-cyclopenteno-4-pentylthiopyridinium methyl, 2,3-cyclopenteno-4-(2,
2,2-trifluoroethyl)thiopyridinium methyl, 2.3-cyclopenteno-4-(2-hydroxyethyl)thiopyridinium methyl, 2.3-cyclopenteno-4-(2-fluoroethyl)thiopyridinium methyl, 2. 3-cyclopenteno-4-carboxymethylthiopyridinium methyl, 2,3-cyclopenteno-4-
Carbamoylmethylthiopyridinium methyl, 2,3-
Cyclopenteno-4-(N.

N-dimethylaminomethyl)thiopyridinium methyl,
2.3-cyclohexeno-4-methylthiopyridinium methyl, 2.3-cyclohexeno-4-cyclopropylmethylthiopyridinium methyl, 2.3-cyclohexeno-4-(2,2,2-trifluoroethyl ) Thiopyridinium methyl.

The above-mentioned substituent at the 3-position can be synthesized using the known method "Heterocyclic Compounder Pyridine Andisotuderivade Novus Parts 1 to 4 Interscience Publications Ltd., J rHeteroc-ycljc
Compounds+Pyridine and i
ts Derivativesvol 14 Part
0neA+Four rnterscience p
However, in particular, the synthesis of cycloalkanotiopyridones containing a cyclo ring and substituted alkylthiocycloalkanopyridines is described in Japanese Patent Applications No. 59-33747 and No. 59-138 of the present inventors.
206, according to the method disclosed in Publication No. 59-254518.

1,5-dihydroxy-4, which is a component of the 7-position substituent
-Pyridone-2-carboxylic acid or its protected form is synthesized by a) reacting a protected form of 5-hydroxy-4-pyrone-2-carboxylic acid with a hydroxyl amino acid salt in the presence of pyridine or the like.

H (in the formula, R' is a removable protecting group such as benzyl, p-nitrobenzyl, 0-nitrobenzyl group, phenacyl group) or b) halogen-substituted product of 5-hydroxy-4-pyridone-2-carboxylic acid It can also be obtained by hydrolysis of N-oxide obtained by oxidizing with hydrogen peroxide or the like.

The cephalosporin compound of general formula (11) of the present invention can be produced by the following methods A, B, and C. That is, A) General formula (wherein R7 is a hydrogen atom or a protecting group for an amino group, R (@ is a hydrogen atom or a protecting group for a carboxyl group, A is the meaning described above), or a salt or silylated product thereof. - Removable protecting groups such as nitrobenzyl, 0-nitrobenzyl, methoxyethoxymethyl, phenacyl group>
It is produced by reacting the compound represented by or a reactive derivative of carboxylic acid, and then removing the protective group if necessary.

B) Reaction of a compound represented by the general formula (V) (R', R', R'' are the above-mentioned meanings) or its carboxylic acid with a compound represented by the general formula (R' and A are the above-mentioned meanings) After reacting the sexual derivative,
By removing the protecting group, if present, general formula 1
The compound is obtained.

C) General formula (Vl) (R', R', R', R' are the above-mentioned meanings, X is an acetoxy group or a halogen atom) to a compound represented by the general formula [■
] (R', R", n have the above meanings) General formula [■] (R', R", R3, n have the above meanings) or general formula (I
X) (R'+R'+n has the above-mentioned meaning) A compound represented by formula (1) is obtained by reacting the compound represented by the formula (R'+R'+n) and then removing the protecting group if necessary.

As the protecting group for the amino group and carboxyl group in the above general formula, those used for this purpose in the field of β-lactam and peptide synthesis can be appropriately employed.

Examples of protecting groups for amino groups include phthaloyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and diphenyl. Methyloxycarbonyl, methoxymethyloxycarbonyl, trityl, trimethylsilyl, etc. are mentioned, and examples of protecting groups for lopoxyl groups include t-butyl, t-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, and benzhydryl. , phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl.

Methylthiomethyl, trityl, trichloroethyl.

Examples include trimethylsilyl, dimethylsilyl, dimethylaminoethyl, and the like.

The basic reaction of both production methods A and B) is a condensation reaction by acylation, and the general acylation method used for penicillins and cephalosporins is applied.

Examples of the reactive derivative include acid halides, acid anhydrides, active amides, and active esters. Preferred examples include acid chlorides, acid bromides, mixed acid anhydrides such as acetic acid, pivalic acid, isovaleric acid, and trichloroacetic acid, pyrazole, activated amides of imidazole 5-dimethyl and lazole, benzotriazole, etc., and p-nitrophenyl. ester.

2.4-dinitrophenyl ester, trichlorophenyl ester, 1-hydroxy-IH-2-pyridone, N
-Hydroxysuccisoimide. Examples include active esters with N-hydroxyphthalimide and the like.

In addition, in this reaction, when the compounds (I[I) and (V) are used in the form of free acids, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of the condensing agent include, for example:
N,N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide,
Carbodiimide compounds such as N-cyclohexyl-N″-(4-diethylaminocyclohexyl)carbodiimide, amide compounds such as N-methylformamide, N,N-dimethylformamide, and halides such as thionyl chloride, phosphorus oxychloride, and phosgene. This can be carried out in the presence of a reagent (so-called Vilsmeier reagent) produced by the reaction of

Among the reactive derivatives in this reaction, acid halides,
The reaction with acid anhydrides and acid anhydrides requires the presence of an acid condensing agent, and examples of acid binding agents include tritylamine, trimethylamine, ethyldiisopropylamine, N,N-dimethylamine, N-methylmorpholine, and pyridine. Examples include bases, alkali metals such as sodium, potassium or calcium hydroxides, carbonates and monobicarbonates, and oxiranes such as ethylene oxide and propylene oxide.

This reaction is usually carried out in a solvent that does not adversely affect the reaction, and examples of the solvent include water, acetone, acetonitrile, dioxane, tetrahydrofuran, methylene chloride, chloroform, dichloroethane, and N.

N-dimethylformamide or a mixed solvent thereof is used.

Although the reaction temperature is not particularly limited, it is usually carried out at -30 to 40°C, and the reaction time reaches completion in 30 minutes to 10 hours.

If the acylated product thus obtained has a protecting group, removal of the protecting group will be necessary. Methods for removing protecting groups include methods using acids, bases, and hydrazine, depending on the type of the protecting group. It can be selected and carried out as appropriate.

The compound of general formula (■), which is a synthetic intermediate of production method A, is published in Journal of Antibiotics, Vol. 35, 1022.
Page (198-O) (J, Antibiotics 3
5, 1022 (1980)), etc.

General formula (Vl) and general formula [■] in manufacturing method (C),
For the reaction with [■] and (IX), a method commonly used in cephalosporin chemistry is usually employed.

That is, when X is an acetoxy group in general formula (Vl), the reaction usually involves water, phosphate buffer, acetone,
acetonitrile, N,N-dimethylformamide, N,
It is preferable to conduct the reaction in a polar solvent such as N-dimethylacetamide, tetrahydrofuran, dimethyl sulfoxide, dioxane, methanol, ethanol, or a mixed solvent with water. It is preferable to carry out the reaction near neutrality, and the reaction temperature is not particularly limited, but it is usually suitable to carry out the reaction from room temperature to around 70°C.

The time required for this reaction varies depending on the reaction conditions, but is usually 1 to 10 hours. Further, this reaction is promoted by performing it in the presence of an alkali metal halide such as sodium iodide or potassium iodide.

Further, when the desired compound is produced from a compound in which X in the general formula (Vl) is a halogen, examples of the halogen include chlorine, bromine, and iodine, but iodine is generally preferred from its reactivity. A compound in which X in the general formula (VI) is iodine can be prepared by a known method (for example, JP-A-56-13159
According to No. 0), the above-mentioned X is easily prepared from a protected form of an amino group or a carboxyl group of a compound in which the acetoxy group is present.

This reaction usually involves acetone, dioxane, tetrahydrofuran, ethyl acetate, acetonitrile, and N.

It is preferable to carry out the reaction under non-aqueous conditions in a solvent such as N-dimethylformamide or N,N-dimethylacetamide. The reaction is normally preferably carried out at 0 to 50°C, and is completed in 1 to 5 hours.

The compound of general formula [1) obtained as described above is collected from the reaction mixture by a conventional method.

For example, purification using adsorbent resins such as Amberlite

This can be achieved by appropriately combining precipitation methods, crystallization methods, etc.

Antibacterial agents containing the compound represented by formula (1) or its salt as a main ingredient are mainly administered intravenously or intramuscularly.

It is used in various dosage forms such as injections, capsules and tablets, oral preparations such as powders, rectal preparations, oil-based suppositories, and water-soluble suppositories. These various preparations contain commonly used excipients, fillers, binders, wetting agents, disintegrants, 1 surface active agent, 1 lubricant, 1 dispersant, buffering agents, preservatives, solubilizing agents, and preservatives. , flavoring agent.

It can be manufactured by a conventional method using a soothing agent and the like.

Specific examples of the formulation method will be explained in more detail in Examples below.

The dosage is determined on a case-by-case basis, taking into account symptoms, age, gender, etc., but it is usually 250 to 250 mg per day for adults.
3000 ml, which is administered in 1 to 4 divided doses a day.

〔Example〕

The present invention will be further explained in detail in the following examples, but these examples are merely illustrative and do not limit the present invention, and various changes and modifications can be made without departing from the scope of the present invention. Needless to say, it is.

In addition, the NMR data in the examples is 100 MHz or 40 MHz.
Using 0 MHz NMR, unless otherwise specified, in the case of heavy water, the δ value is shown when the peak of water is set to 4.82, and in the case of other heavy solvents, TMS
The δ value is shown based on .

Reference example 1.5-dihydroxy-4-pyridone-2-force4A sputum θ
! +a+ Sodium 3.4 in anhydrous methanol 200-
Add 5 g to prepare a sodium methoxide solution.

After adding 21.3 g of kojic acid to this at room temperature and lubricating it with benzyl chloride 191n1, the mixture was reacted under heating under reflux for 4 hours.

After the reaction is completed, the reaction solution is concentrated, 200 g of water is added to the residue, and the precipitated crystals are collected by filtration, washed with water and ether, and dried to obtain 29 g of 5-pendioloxy-2-hydroxymethyl-4-pyrone.

Of this, 16 g was dissolved in 600 g of methanol, 100 g of activated mangala dioxide was added, and the mixture was reacted under heating under reflux for 1 hour. After the reaction is completed, the insoluble portion is filtered off, and the filtrate is concentrated under reduced pressure to about 200 ml. Add to this 200% water +n1 and IN Na
01l 69- and 15.9 g of silver oxide were added, and the mixture was allowed to react at room temperature for 30 minutes. After the completion of the reaction, the insoluble portion was filtered off, concentrated under reduced pressure to remove methanol, and washed with dichloromethane.
IN HCI 77.5- was added, the resulting precipitate was collected by filtration, washed with water, dried, and 5-benzyloxy-4=pyrone-
13 g of 2-carboxylic acid are obtained.

NMR (DMSO-di) δ4.99 (2H, s)
, 7.41 (5H, m).

6.92 (IH, s), 8.35 (IH, s) mountain] 5
-benzyloxy-4-pyrone-2-carboxylic acid 4.9
2 g was dissolved in 70-pyridine, 7 g of hydroxylamine hydrochloride was added, and the mixture was reacted at 80° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 250 rnl of water was added to the residue, and the mixture was cooled with 6N IC! Adjust the pH to 1.5 to 2.0 and stir at the same temperature for 30 minutes. The resulting precipitate is collected by filtration, washed with water, and then dried to obtain 2.5 g of 5-benzyloxy-1-hydroxy-4-pyridone-2-carboxylic acid.

NMR (DMSO-d6) δ 5.26 (2) 1. s), 7.35-7.55 (5H,
m).

7.57 (LH, s), 8.55 (LH, 5) (C) 5
-benzyloxy-1-hydroxy-4-pyridone-2
-2g of carboxylic acid to 100% of 50% methanol water? A
It becomes cloudy, then IN NaOH1,53- is added to it and dissolved.
500 μm of 5% palladium carbon powder was added to this, and the mixture was subjected to catalytic reduction at room temperature in a hydrogen stream. After the reaction is completed, the 5% palladium charcoal powder is filtered off, washed with 50% methanol water, concentrated under reduced pressure to remove methanol, and l1iHc18Tnl is added.

The formed precipitate was collected by filtration, washed with water and dried to obtain the title compound 1.
．． Obtain 2g.

NMR (DMSO-db) δ 7.55 (01,s), 8.05 (ILs).

Example 1 Mutual Earthwork Z Momme (Method A) (a) 780 μ of 5-benzyloxy-1-hydroxy-4-pyridone-2-carboxylic acid was added to 1 of tetrahydrofuran.
2-, and add and dissolve 0.54- triethylamine.

To this, 624 liters of phosphorus pentachloride was added at -15°C and reacted for 1 hour. On the other hand, (612,711) 7-C(R
5) 2-(2-aminothiazol-4-yl)-2-
Aminoacetamide]-3-acetoxymethyl-cef-
3-M-4-carboxylic hydrochloride 920 Akebono was dissolved in 50% aqueous tetrahydrofuran solution 30- and triethylamine was added under water cooling to adjust the pH to 8.

Add the above tetrahydrofuran solution little by little to this.

During this time, the pH of the reaction solution is maintained at 8 to 8.5.

After the reaction is completed, the pH of the reaction solution is adjusted to 6.5, concentrated under reduced pressure to remove tetrahydrofuran, water is added to the residual aroma, and the pH is adjusted to 2 with IN HCl under water cooling.

The resulting precipitate was collected by filtration and dried, (6R, 7R) 7
-((R5) 2- (2-aminothiazol-4-yl)-2-(5-benzyloxy-1-hydroxy-4
-pyridone-2-carboxamide) acetamide two 3
1.25 g of crude powder of -acetoxymethyl-cef-3-em-4-carboxylic acid is obtained. This was suspended in 50% methanol 20- and adjusted to pH 6.5 with saturated NaHCO:+water.
~7.0, dissolved, purified by LH-20 column chromatography (50% methanol water), (6R, 7.
R) 7- ((R5) 2-(2-aminothiazol-4-yl)-2-(5-benzyloxy-1=hydroxy-4-pyridone-2-carboxamide)acetamido-3-acetoxymethyl-cef- 3-M-4-
500 μ of sodium salt of carboxylic acid are obtained.

(bl) Next, this was added to an aqueous solution 30- containing palladium black 500, and acetic acid was added to adjust the pH to 5.
Subject to catalytic reduction at room temperature and pressure. After the reaction, palladium black was removed by filtration, concentrated to a small amount and pu was adjusted to 7.0, and this was subjected to HP-20 column chromatography (H20-5
% acetone water) to obtain 250 ml of the title compound as a sodium salt.

NMR (DzO) δ 2.1.1+2.12 (each 38It3)+3.
48('/1X2H,ABq), 3.55('/z
X2H, ABq).

4.79 ('to X2H, ABq), 4.82 (18X
2)1. ABq).

5.11 ('/f)1. d), 5.15('/J, d
),? , 60 (Wat) I, s).

7.62 ('to H, s), 5.65 ('/zH, d).

5.75 ('to H, d), 6.75 ('/J, s),
6.80 ('/J, s).

7.48 (IH, s), 7.60 (IH, s) (Method B
) ((6R,7R) 7- ((RS) obtained with al
2-(2-7minothiazol-4-yl")-2-(
5-benzyloxy-1-hydroxy-4-pyridone-
2-carboxamide) acetamido-3-acetoxymethyl-ceph-3-em-4-carboxylic acid (350 g) suspended in 2.5 g of anisole and 2.5 g of nitromethane;
Under water cooling, the mixture was lubricated with nitromethane l- containing 450 W of aluminum chloride, and then allowed to react at room temperature for 30 minutes. After the reaction is completed, water-cooled sewage 5- is added to the reaction solution, and the formed precipitate is collected by filtration. This was washed with water and ethyl acetate, and then dried to obtain 170 μg of a crude powder of the title compound.

This was suspended in a small amount of 50% methanol water, and saturated NaH
Dissolved at pH 6.5 with COs water, purified by LH-20 column chromatography (50% methanol),
65 lbs of sodium salt of the title object product is obtained. The spectral data for this compound was consistent with that obtained with Method A.

(Method C) 171 cm of 1,5-dihydroxy-4-pyridone-2-carboxylic acid is suspended in 5 cm of tetrahydrofuran, 0.18 cm of triethylamine and 208 cm of phosphorus pentachloride are added under cooling with water, and the mixture is allowed to react at room temperature for 1 hour. . On the other hand, (611,7R)
7- ((R5) 2-(2-aminothiazole-
4-yl)-2-aminoacetamide]-3-acetoxymethyl-cef-3-em-4-carboxylic hydrochloride 3
00■ is dissolved in 50% aqueous tetrahydrofuran solution 10-, and the pH is adjusted to 7.5 with saturated NaHCO1 water. Add the above tetrahydrofuran solution little by little to this while cooling with water. During this time, the 9H of the reaction solution was adjusted to 8.0. After the reaction was completed, the pH of the reaction solution was adjusted to 6.0, concentrated under reduced pressure to remove tetrahydrofuran, and the remaining perfume solution was adjusted to pH with INHα.
2.0, the resulting precipitate was collected by filtration, dried, and purified by HP-20 and LH-20 column chromatography in the same manner as described above. The spectral data of the resulting compound was consistent with that obtained in Method-A.

Example 2 (6R,7R)7-((R5
) 2-(2-aminothiazol-4-yl)-2-(
1゜5-dihydroxy-4-pyridone-2-carboxamide)acetamide]-3-acetoxymethyl-ceph-
120 μ of 3-M-4-carboxylic acid sodium salt to 50
Dissolve 2% acetonitrile in water, add 300% sodium iodide and 1-methyl-cyclopentano [b]
Add 50 μ of 4-thiopyridone, adjust +)H to 6.8 with 25% phosphoric acid water, and react at 70°C for 3 hours. After the reaction is complete, add the reaction solution to acetone and collect the formed precipitate by filtration. Wash with acetone and dry. This was dissolved in a small amount of water and subjected to HP-20 column chromatography (20I
The product was purified by eluting with n1.5 to 10% acetone water (1iiiI) to obtain the title target compound 45■.

This was further subjected to LH-20 column chromatography (15
〇-150% methanol) to obtain the target compound 30
■ Get.

NMR (020) δ 2.28 (2H, +m), 3.88 (28, m), 3.
21 (2H, m).

3.55('/z X 21(, ABq), 3.60
('/2 X 2H, ABq), 4.04 (3H
,s).

4.26('/l x 2H,ABq)4.28('/
z X2H, ABq).

5.09('/zH,d), 5.13('/z)I,s
), 5.62('/zH,d).

5.63 (IH, s), 5.72 ('/zH, d),
6.75('/zH,s).

6.79('/)H,s),? , 26 ('to〇, S),
7.31 ('/2H, 3).

7.53 (IH, d), 7.54 ('/zo, s)
, 7.57('/J,s).

8.15(In,d) In Example 2, 1-methyl-cyclopentano (b
)-4-thiopyridone and the compounds of Examples 3 to 8 are obtained by the same treatment except that each reagent (A) is used.

Example 3 acid.

(A) Cyclopentano [b] 4-thiopyridone NMR (020) δ 2.16 (2H, m) + 2.82 (211, m), 3.
01 (2H, m).

3.49('/z X2H, ABq), 3.55('/
l X2H, ABq).

4.17 ('/1x2H, ABq), 4.20 ('/z
X2H, ABq).

5.02 ('/J, d) 5.07 ('/J, d),
5.60 ('/zH, d).

5.62 (IH, s), 5.70 ('H, d), 6
．． 75 ('H+3) + 6.80 ('/g) I, s),
7.21 (IH, d), 7.37 ('/J, s).

7.39 ('/J, s), 7.61 ('/J, s),
7.62('/lH,s).

8.22(1)1. d) Example 4 Upper [A] 1-methyl-4-thiopyridone NMR (ozo
) δ 3.54 ('to X2H, ABQ), 3.58 ('to x2
H, ABq).

4.29 (weight/zX2H,ABq), 4.32('/z
X2H, ABq).

4.22 (3H, s), 5.09 ('to H, d), 5
．． 13 ('/zH, d).

5.62 (IH, s), 5.62 ('/J, d).

6.73 ('/zo, d), 6.76 ('/J, d)
, 6.81 ('/zH1s) + 7°39 ('to H,s
), 7.40('/zH,s),? ,63('/zH,
s).

7.64('/lH,s), 7.81(28,d)
, 8.40 (2H, d) Example 5 [A] 4-Mercaptopyridine NMR (DzO) δ 3.50 ('to X2H, ABq), 3.57 ('to
2H, ABq).

4.15 ('to x2H, ABq), 4.17 ('to
2H, ABq).

5, ON' 80 d), 5.05 (' 〇, d), 5
．． 58 ('to II, d).

5.60 (LH, s), 5.67 ('/J, d), 6
．． 74 ('/lH,s).

6.79 ('to〇, s), 7.40 (2H, d), 7.
42 (LH, s).

7.62 (LH, s), 8.33 (2H, d) Example 6 1-pyridone-2-carboxamido)acetamide]-3
-(23-cyclobennopyridinium) (A) 2.3
-Cyclopentinoviridine NMR (020) δ 2.33 (2) 1. m), 3.20 (3H, m), 3.
35 (2H, m).

3.45('/!H,d), 3.48('/ZH,d
), 5.15 (IhH, d).

5.18 ('/zH, d), 5.32 (IH, m) 5
．． 48 (lH, m).

5.61 (LH, s), 5.68 ('/J, d), 5.
78 ('/J, d).

6.75 ('/J, s), 6.79 ('H, s),
7.43 (IH, s).

7.69 ('to〇, s), 7.70 ('/zH, s)
, 7.80 (IH, m).

8.30 (18, m), 8.53 ('/J, d), 8.
56('/J, d) Example 7 [A) 2.3-cyclopenteno-4-methylthiopyridine NMR (Ox○) δ 2.33 (2H, m), 2.68 (38 old S), 2 ．．
69 ('3/2H, S).

2.95 (2H, m), 3.27 (2H, m), 3.1
5-3.50 (2H, m) 5.15 ('/J, d), 5
．． 18 ('/2H, d), 5.10. ~5.35(
2H, m) 5.60 (lH9s), 5.67 ('/z1
1. a), 5.78 ('/zH, d).

6.75 ('/J, s), 6.79 ('/J, s),
7.37 (LH,s).

7.50 ('/2H, d), 7.52 ('H, d)
, 7.62 (IH, s).

8.32 ('/J, d), 8.34 ('/!H, d).

Example 8 [A] 4-Methylthiopyridine NMR (020) δ 2.62 (3/zH, s), 2.64 ('to, s),
3.35 ('/zX2H, 8Bq).

3.40 ('to x2H, ABq), 5.10 (IH, m
), 5.18('/zH,d).

5.20 ('to H, d), 5.36 (IH, m), 5.
57('/zH,s).

5.58 ('to〇, s), 5.67 ('/zH, d)
, 5.78('/zH,d).

6, γO('H1s)+6.74('/2H1s)+
7-33 (IH5s).

7.60 (IH, s), 7.70 (LH, d), 7
．． 74 (LH, d).

8.53 (28, m) Example 9 (a) Suspend 520 q of 5-benzyloxy-1-hydroxy-4-pyridone-2-carboxylic acid in tetrahydrofuran 7- and add and dissolve z triethylamine 36-. do. To this was added 416 cm of phosphorus pentachloride at -10'C, and the mixture was allowed to react for 1 hour to prepare an acid chloride solution.

On the other hand, (R5)2-(2-)ditylaminothiazole-
600 μm of 4-yl)glycine is dissolved in 20 μm of 50% aqueous tetrahydrofuran solution.

Under water cooling, adjust the pH of the reaction solution to pH 8-8 with triethylamine.
．． While maintaining the temperature at 5, add the above acid chloride solution little by little.

After the reaction is completed, the reaction solution is concentrated under reduced pressure to remove tetrahydrofuran, 6N HCl is added to the residue to adjust the pH to 2, and the mixture is extracted with chloroform (100 m x 2).

After washing with water, drying with magnesium sulfate, concentrating to dryness, (R
3) 2-(2-)ditylaminothiazol-4-yl)
1.0 g of -2-(5-benzyloxy-1-hydroxy-4-pyridone-2-carboxamide)acetic acid is obtained.

(bl) Of this, 660■ is added to 5m of tetrahydrofuran.
Triethylamine 0.15 m
Add Z and 210 cm of phosphorus pentachloride, and react at the same temperature for 1 hour.

On the other hand, 270 μl of 7-amino-3-(2,3-cyclopentinoviridin-4-yl)thiomethyl-cef-3-em-4-carboxylic acid was suspended in a 50% aqueous solution of tetrahydrofuran, and triethylamine was added under water cooling. Add to pH 8 and dissolve. Add the above reaction solution little by little to this. During this time, triethylamine was added to adjust the pH of the reaction solution to pl+8 to 8.
Keep it at 5.

After the reaction is completed, the reaction solution is concentrated to a small amount. Water was added to this, the pH was adjusted to 2 with 6N HCl, and the mixture was extracted with ethyl acetate. After washing with water, drying with magnesium sulfate, concentrating to dryness,
(6R,7R) 7- ((R3)-2-(2-)gutylaminothiazol-4-yl) -2-(5-benzyloxy-1-hydroxy-4-pyridone-2-carboxamide)acetamide]- 3-(2,3-cyclopentenopyridin-4-yl)thiomethyl-cef-3-
640 ml of em-4-carboxylic acid are obtained.

(C1 Dissolve this in 5+ sl of formic acid, add 0.2-sl of concentrated hydrochloric acid, and react for 1 hour at room temperature. After the reaction is complete, the formed precipitate is filtered off, the filtrate is concentrated to a small volume, and washed with ether.

A small amount of water was added to the residue, the pH was adjusted to 7 with a saturated aqueous sodium bicarbonate solution, and this was subjected to HP-20 column chromatography, eluted with 10-20% acetone water, concentrated under reduced pressure, and then lyophilized. , (6R,7R)7- ((
IIS)-2-(2-aminothiazol-4-yl)-
2-(5-benzyloxy-1-hydroxy-4-pyridone-2-carboxamide)acetamide 3-3-(2
,3-cyclopentenopyridin-4-yl)thiomethyl-cef-3-em-4-carboxylic acid sodium salt 22
Get 0 mir.

This is then subjected to catalytic reduction in the same manner as method A-(b) of Example 1 to obtain the title compound.

, the spectral data of this compound was consistent with that of Example 3.

Example 10 An injection preparation was aseptically dispensed so that each vial contained 1000 μg (potency) of the compound of Example 2.

Example 11 Capsule Compound of Example 2 250 parts (potency) Lactose
60 parts Magnesium stearate 5 parts These were mixed uniformly and filled into capsules at a concentration of 250 ml (potency)/capsule.

Example 12 Soft capsules for rectal administration 25 parts (potency) of the compound of Example 2 were added to a homogeneous base consisting of 160 parts of olive oil, 10 parts of polyoxyethylene lauryl ether, and 5 parts of sodium hexametaphosphate, and mixed uniformly.
The solution was filled into soft capsules for rectal administration so that the concentration was 0 (potency)/capsule.

〔Effect of the invention〕

The object compound (1) of the present invention or its salts is a new compound and exhibits high antibacterial activity that inhibits the growth of a wide range of pathogenic microorganisms, including Durham-positive and -negative bacteria. In order to demonstrate the usefulness of the target compound (1), the compound (1) of the present invention was prepared.
Table 1 below shows the antibacterial activity measured for representative substances among the following.

2-(2-aminothiazol-4-yl) to 2-(1,5-dihydroxy-4-pyridon-2-
Cephalosporin derivatives having a carboxamide) acetamide group, combined with the effect of the 3-position substituent, exhibit a wide range of antibacterial activity, with particularly strong activity against Pseudomonas aeruginosa, and low solubility in water, which is an important requirement for injectables. Excellent in sex.

As a result of an acute toxicity test using mice of the compound of the present application, LD
50 is less toxic than Ig/kg.

Patent applicant Meiji Seika Co., Ltd. Agent
Tsutomu Arai (and 1 other person) Procedural amendment April 3, 1986 Director-General of the Patent Office Mr. Ka Michibe I τ- and 1, 19 Cattle 1985 Patent Application No. 140989 2 New title of invention Cephalosporin derivatives and antibacterial agents 3, relationship with the case of the person making the amendment Patent applicant name (609) Meiji Seika Co., Ltd. 4, agent 6, content of amendment (1) Page 31 of the specification, line 14 “Reference "Example" is corrected to "Reference Example 1."

(2) Insert the following sentence below the last line on page 33.

Reference Example 2 (a) 34.5 g of 5-benzyloxy-4-pyrone-2-carboxylic acid is suspended in concentrated hydrochloric acid 500- and Lo 250- and reacted at 80°C for 1 hour. The reaction solution is cooled on ice. The resulting crystals were collected by filtration, washed with water, dried, and 5-hydroxy-
16.6 g of 4-pyrone-2-carboxylic acid are obtained.

NMR (DMSO-di) δ 6.96 (1)1. s), 8.17 (1) 1,5
) (b) 39.3 g of 5-hydroxy-4-pyrone-2-carboxylic acid is dissolved in DMF 700-, and 62.5 g of potassium t-butoxide is added under water cooling. 30 minutes later,
Add p-methoxybenzyl chloride 75-, stir at room temperature for 30 minutes, and then react at 60°C for 24 hours.

After the reaction was completed, the reaction solution was added to 2.5 l of dichloromethane, washed with water (800 rn1x3), dried over magnesium sulfate, concentrated to a small amount under reduced pressure, added ether 350 to the residual aroma, and collected the precipitated crystals by filtration. 5-p-methoxybenzyloxy-4-pyrone-2
-75 g of carboxylic acid p-methoxyhensyl ester are obtained.

NMR (CD (Jz) 6 3.80 (3H, s), 3.82 (3H, s),
5.02 (2H, s).

5.29 (2H, s), 6.88 (2H, d),
6.92 (2H, d).

7.17 (II(,s), 7.30 (2H,d)
, 7.34 (2H, d).

7.60 (1B, 5) (c) Of this, 70g is tetrahydrofuran 1.87
1, add water 476- and IN NaOH 264-, and react at room temperature for 30 minutes. After removing tetrahydrofuran under reduced pressure, water 600 TR1 was added to the residual fragrance.
After washing with dichloromethane, IN H (J 26
5- was added, and the resulting precipitate was collected by filtration, washed with water, and dried to give 5-p-methoxybenzyloxy-4-pyrone-2.
-34.9 g of carboxylic acid are obtained.

NMR (DMSO-di) δ 3.77 (3H, s), 4.90 (28,
s), 6.92 (LH, s).

6.96 (2H, d), 7.37 (2H,
d), 8.34 (LH,5) (d) 5-p-methoxybenzyloxy-4-pyrone-2-carboxylic acid 3
3.2 g was dissolved in pyridine 500-, 41.7 g of hydroxylamine hydrochloride was added thereto, and the mixture was reacted at 80° C. for 1 hour. After concentrating the reaction solution to a small amount under reduced pressure, add 80% water to the residual aroma.
0- was added, and the pH was adjusted to 2 with 6N HHCf under ice cooling, and the resulting precipitate was collected by filtration, washed with water, and dried to obtain the title object 17.2.
Obtain 5g.

NMR (DMSO-di) δ 3.80 (3H, s), 5.22 (2H, s),
7.00 (21, d).

7.43 (2H, d), 7.59 (11, s),
8.59 (IH,s) Reference Example 3 1-Cyclopropyl-4-thiopyridone (a) Pyran-
4.5 g of 4-one was dissolved in 100% of benzene, and Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,
Add 10.6 g of 3-dithia-2,4-diphosphethane-2,4-disulfide and stir at 80°C for 30 minutes. After cooling, the insoluble portion was removed by filtration, and the filtrate was concentrated, followed by silica gel column chromatography (250 g, toluene-ethyl acetate = 5:1).
5.18 g (98%) of pyran-4-thione is obtained.

N? IRCCDCI2 > 6 7.14 (2)1. d), 7.48 (2H, d)
(b) Dissolve 1.12 g of pyran-4-thione in 20 - of ethanol, and dissolve 1.05 g of cyclopropylamine under water cooling.
- and react at room temperature for 15 minutes. After the reaction was completed, the reaction solution was concentrated and the residual aroma was subjected to silica gel column chromatography (chloroform-methanol = 20:1) to obtain 1.32 g of the title compound as crystals.

NI'lR(CDcj, ) δ j, 17 (2H, m), 1.17 (2H, m),
3.49 (1B, m).

1.21 (28,d), 7.38 (2H,d) Reference Example 4 ■-(2-Hydroxyethyl)-4-thiopyride In the same manner as in Reference Example 3(b), using ethanolamine, the title compound I got it.

NMR (DzO) δ 4.12 (2H, m), 4.42 (2H,
■), 7.69 (2H, d).

7.95 (2H, d) Reference Example 5 l-(2-dimethylaminoethyl)-4-thiopyridone The title compound was obtained in the same manner as in Reference Example 3(b) using N,N-dimethylethylenediamine.

NMR (CD(Js) 6 2.24 (6H, s), 2.65 (2H, t),
3.96 (28,t).

7.25 (2H, d), 7.42 (2)1. d)
Reference Example 6 l-(2-70loethyl)-4-thiopyridonepyran-
Dissolve 1.12 g of 4,000 ions in 20 W#l of ethanol and 10 liters of pyridine, add 2 g of 2-fluoroethylamine hydrochloride to the dirt, and react at 60°C for 3 hours. After concentrating the reaction solution, chloroform was added and the insoluble portion was filtered off. The filtrate was concentrated to a small amount and purified by silica gel column chromatography (chloroform-methanol = 20:1) to obtain the title compound 89.
Get 0 ■.

NMI? (CDcl, ) 6 4.17 (2o, tt), , 4.73 (2
n, tt), 7.18 (2u, d).

7.42 (2H, d) Reference Example 7 l-(2-sulfoethyl)-4-thiopyridonepyran-
Dissolve 1.12 g of 4-thione in 20-mL of ethanol,
-Aminoethanesulfonic acid 1.25g and IN Mai
l (10-) and reacted at 70°C for 1.5 hours. After the reaction, ethanol was removed and purified using HP-20 column chromatography to give the title compound as a sodium salt with 2.1
get g.

NMR (Dgo) δ 3.46 (2)1. t), 4.57 <2
Lt), 7.56 (2)1. d).

7.88 (2H, d) Reference Example 8 1.12 g of l-(2-sulfamoylethyl)-4-thiopyridonebira:,/-4-thione was dissolved in ethanol 10-
2-sulfamoylethylamine 2
．． Lubricate with a solution obtained by dissolving 48 g in a mixture of 10-1 ethanol and 51 R1 water. After reacting for 1 hour at room temperature, further 50 ~
React at 60°C for about 1.5 hours. After the reaction is completed, the reaction solution is concentrated to dryness, and the residue is washed with methylene chloride.

30 mZ of water was added to the residue, and while cooling, the precipitated crystals were collected by filtration, washed with water and ether, and dried to obtain the title compound 490.
get.

NMR (da-DMSO) δ 3.52 (2H, t), 4.35<2H, t).

7.08 (2H, br, s), 7.14 (2Ld)
, 7.63 (2H, d).

Reference Example 9 1-Ruboxymethyl-4-thiopyridone (a) 14.25 g of 4-pyridone was dissolved in DMF 250 mZ,
This is followed by 25% of ethyl bromoacetate and 31% of potassium carbonate.
Add 1 g and react at 60°C for 2.5 hours. After the reaction is complete, the insoluble portion is filtered off and the filtrate is concentrated. The remaining residue was subjected to silica gel column chromatography (chloroform-methanol = LO:
1 to 5:1) to obtain 22.8 g of 1-ethoxycarbonylmethyl-4-pyridone. This was dissolved in 400 mj of dimethoxyethane, 30 g of Lawesson's reagent was added, and the mixture was reacted under heating under reflux for 30 minutes. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (chloroform-methanol = 20:1), and further crystallized from dichloromethane-ether to obtain 13.6 g of ■-ethoxycarbonylmethyl-4-thiopyridone. obtain.

NMR (CD(Ji) δ 1.32 (3H, t), 4.29 (2H, q),
4.65 (2H, s).

7.13 (2H, d), 7.37 (2H, d) (
b) Dissolve 9.6 g of 1-ethoxycarbonylmethyl-4-thiopyridone in 120% of ethanol and
Add H68mZ and react at room temperature for 20 minutes. After completion of the reaction, concentrate to remove ethanol, and add 68 m of IN hydrochloric acid under water cooling.
1 was added, and the resulting precipitate was collected by filtration and dried to obtain 5.23 g of the title compound.

NMR (d, -DMSO) δ 4.86 (2H, s), 7.18 (2H, d),
7.55 (2H, d) Reference Example 10 - Rubamoylmethyl-4-thiopyridone 1.57 g of 1-ethoxycarbonylmethyl-4-thiopyridone is added to water-cooled T1 ammonia water 15 and allowed to react for 1 hour.

The reaction solution was concentrated to dryness under reduced pressure, water was added, and the precipitate was collected by filtration.
After washing with water and drying, the title compound 980■ is obtained.

NMR (d6-DMSO) δ 4.70 (2H, s), 7.16 (28, d),
7.42 (IH, s).

7.50 (2H, d), 7.84 (IH, s) Reference Example 11 5.3 g of 3-benzoylthiopyridine was dissolved in acetone 30-
9.4- of 2-iodoethanol was added, and the mixture was reacted for 16 hours under heating and reflux. After completion of the reaction, the reaction solution was concentrated, and the residue was washed with ether and then with a 2:1 mixed solution of methylene chloride and ether, and the residue was dried to obtain 1-hydroxyethyl-3=benzoylthiopyridinium iodo salt5. Obtain 3g.

Of this, 2.58g was dissolved in 6NFIC135yd,
After the reaction was completed for 1 hour under heating and reflux, the reaction solution was concentrated to dryness, dissolved in water 2θ-, and IR-120
(H", 40 ml") was purified by column chromatography, and the title objective compound 1.17 was obtained from the 3NHC1 eluate.
get g.

NMR (020) δ 4.03 (211,t), 4.63 (2H,t)
, 7.87 (ill, dd).

8.43 (IH, d), 8.57 (18, d),
8.79 (], H, s)'' (3) Insert the following sentence between lines 12 and 13 on page 38.

(Method D) (a) 7.1 g of 51)-methoxybenzyloxy-1-hydroxy-4-pyridone-2-carboxylic acid was suspended in 100% of tetrahydrofuran, and 4.4 g of triethylamine
Add 1 nl and dissolve. Next, 5.33 g of phosphorus pentachloride was added in 4 portions at -10 to 15°C, and 1
Allow time to react and prepare acid chloride solution.

On the other hand, syn-7-C2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide] = 11.9 g of 3-acetoxymethyl-3-cephem-4-carboxylic acid sodium salt in 250 Tnl of formic acid and 20 + J of water.
11 g of zinc powder is added little by little while cooling with water.
After 30 minutes of reaction, the zinc dust is filtered off, washed with formic acid, and the filtrate is concentrated under reduced pressure. 250ml of water is added to the residue, hydrogen sulfide gas is passed through it for 10 minutes under water cooling, and the precipitate formed is filtered off.

After concentrating the filtrate under reduced pressure, water was added and 2001s! Then, add 100% tetrahydrofuran + R1, (6R, 7R)
? -((R5) Z-(2-aminothiazole-
A solution of 4-yl)-2-aminoacetamido-3-acetoxymethyl-ceph-3-em-4-carboxylic acid is obtained.

While cooling with water, add triethylamine to adjust the pH to 8-8.
．． Add the above acid chloride solution while maintaining the temperature at 1.
Allow time to react. After the reaction, tetrahydrofuran was removed under reduced pressure, the pH was adjusted to 2 with 6NHCl under water cooling, and the resulting precipitate was collected by filtration, washed with water, and dried to obtain (6R, 7R).
7- ((RS) 2- (2-aminothiazole-4
-yl)-2-(5-p-methoxybenzyloxy-1
9.2 g of crude powder of -hydroxy-4-pyridone-2-carboxamido)acetamido-3-acetoxymethyl-cef-3-em-4-carboxylic acid are obtained.

(b) Suspend this in 22 rnl of anisole, add 97-7 trifluoroacetic acid dropwise under water cooling, react for 30 minutes at room temperature, and then add dropwise into diisopropyl ether 700 IIIf.

The formed precipitate is collected by filtration, washed with diisopropyl ether, and then dried.

The resulting precipitate is saturated with hydrogen carbonate) IJum aqueous solution (approximately 6 ml)
0+af4: dissolved, (pH 7, 2-4) IIP
-20 column chromatography to obtain 3.34 g of the title compound as a sodium salt. The spectral data of this compound was consistent with that obtained with Method A. ”(
4) Add the following sentence before the 10th line of page 49 [Effects of the invention].

[Example 14 monoyl)thiomethyl-cef-3-em-4-carboxylate [A] 1-carboxymethyl-4-thiopyridone NM
R(D*O) δ 3.38 (zH, d), 3.43 (!4H, d)
, 3.66 (!4H, d).

3.70 (!/GH,d), 4.15 (!101
．． d), 4.17 (%H, d).

4.40 (VlH, d), 4.43 (%H, d),
5.06 (2H, s).

5.08 (zH, d), 5.1104)1. d),
5.62 (LH,s).

5.63 (!4H, d), 5.73 (zH, d)
, 6.74 (zH,s).

6.78 (%H,s), 7.40 (l)I,s)
, 7.66 (LH,s).

7.81 (2+1.d), 8.37 (21,d
) Example 15 Omethylcef-3-M-4-carboxylate [A] 3-Mercapto-1-methylpyridinium chloride NMR (DtO) δ 3.38 (!411.d), 3.43 (!/GH
, d), 3.62 (!4H, d).

3.64 (zH, d), 3.96 (zH, d),
3.99 (each H, d).

4.19 (IH, d), 4.30 ('to〇, s
), 4.31 (380, s).

5.01 (!4H, d), 5.04 (+AI, d
), 5.51 (!4+1.d).

5.58 (VRH,s), 5.59 (AH,s)
, 5.60 (!101.d).

6.69 (lH,s), 6.74 (!/iH,s
), 7.33 (LH,s).

7.57 (zH,s), 7.58 (!4H,s)
, 7.85 (LH, m).

8.37 (LH, +m), 8.57 (IH, d
), 8.85 (IH,s) Example 16 (A) 1-(2-Hydroxyethyl)-4-thiopyridone NMR ((h O) δ 3.37 (!4H,d), 3.43 (! /S,d
), 3.63 (%H,d).

3.68 (!48.d), 4.01 (2H,t)
, 4.14 (!/U, d).

4.17 (!/U, d), 4.37 (!/GH,
d), 4.40 (zH, d).

4.53 (2)1. m), 5.07 (!4H,
d), 5. 'll (%H,d).

5.60 (LH, s), 5.61 (〃H, d)
, 5.70 (〃H, d).

6.73 (!/SH,S), 6.77 (!48.
's), 7.29 (!4H,s).

7.30 (〃H,s), 7.52 (!II,s)
, ? , 54 ('45H, s).

7.79 (2H, m), 8.43 (28, m
) Example 17 CA) 1-Carbamoylmethyl-4-thiopyridone NMR (Dz O) δ 3.40 (zH,d), 3.45 (!/G
H, d), 3.65 (!4B, d).

3.71 (%H,d), 4.17 (!4H
, d), 4.22 (!/SH, d).

4.41 (zH, d), 4.45 (!zf, d
), 5.08 ('zf, d).

5.11 (!4H,d), 5.33 (2H
, br, s), 5.6'l (IH, s).

5.71 (!4Q, d), 6.74 (!4
H,s), 6.79 (%H,s).

7.37 (IH,s), 7.59 1'4H,
s), 7.60 (zH,s).

7.85 (2H, m), 8.40 (2H,
II+) Example 18 (A) 1-(2-dimethylaminoethyl)-4-thiopyridone NMR (DzO) δ 2.47 (3H,s), 2.50 (3H,s)
, 3.20 (2H, m).

3.37 (!?SH,d), 3.41 (!4H,
d), 3.64 (+AH, d).

3.68 (%H, d), 4.14 (18, d),
4.38 (IH, d).

4.65 (2H, +*), 5.08 (!l, d
), 5.12 (!l,d).

5.60 (!'SH,d), 5.61 (IH,s
), 5.71 (zH,d).

6.72 (!11.s), 6.77 (!4H,s
), 7.31 (%H,s).

7.35 (!4H,s), 7.54 (zH,s)
, 7.58 (!l(,s).

7.82 (2H, a), 8.47 (2H, m)
Example 19 Xylate (A) 1-cyclopropyl-4-thiopyridone NMR (
Dz O) δ 1.30 (4H, m), 3.36 (+AH, d
), 3.42 (+All, d).

3.63 (zH,d), 3.67 (!101.d
), 4.15 (21(,m).

4.38 (!, 4H, d), 4.42 ('41 (
, d), 5.05 (%l(, d).

5.09 (V2Ld), 5.57 (IH,s),
5.58 (AH, d).

5.68 (!/!, d), 6.73 (zlI, s
), 6.77 (zH,s).

7.37 (!411.s), 7.38 (zH,s
), 7.59 (!4H,s).

7.60 (Vll(,s), 7.76 (2H,m
>, 8.52 (2H, d) Example 20 (A) 1-(2-fluoroethyl)-4-thiopyridone NMR (D, O) δ 3.37 (!4H, d), 3.43 (zH, d)
, 3.65 (zH,d).

3.68 (V2O,d), 4.13 (!4
)1. d), 4.17 (V2O, d).

4.42 ('/Sll, d), 4.45 (
V21+, d), 4.7 to 4.95 (4H, m)
.

5.05 (%H, d), 5.10 (%H,
d), 5.57 (III, s).

5.58 (V2O,d), 5.68 (!4
H,d), 6.73 (%lI,s).

6.78 ('zU, s), 7.38 (IH, s)
, 7.62 (lH,s).

7.87 (2H, m), 8.48 (2H,
d) Example 21 (A) 1-(2-hydroxyethyl)-3-mercaptopyridinium chloride NMR (DzO) δ 3.40 (%H, d), 3.47 (VzH, d)
, 3.70 (zH,d).

3.71 (%H, d), 4.03 (2H, m),
4.10 (2)1. ABq).

4.65 (2H, quiet), 5.04 (!/dl,
d), 5.07 (!, 4tl, d).

5.50 (lH, d), 5.58 (LH, s),
5.61 (!/l, d).

6.71 (!zU,s), 6.76 (Vz
H,s>, 7.37 (!411.s).

7.38 (lAH,s), 7.60 (18
,s), 7.94 (LH,m).

8.50 (IH, m), 8.68 (IH,
m), 8.99 (IH, br, s) Example 22 (A) 1-(2-sulfoethyl)-4-thiopyridone NMR (Dz O) δ 3.36 (!48.d), 3.42 ( '/U, d
), 3.54 (2H, t).

3.64 (!411.d), 3.68 (V2O,
d), 4.13 (!4H, d).

4.15 (zH, d), 4.37 (!zHI, d
), 4.41 (%ll, d).

4.82 (2H, m), 5.07 (!101.
d), 5.10 (!/f, d).

5.58 (%H, s), 5.59 (Wll, s)
, 5.61 (V2O,d).

5.70 (V2O, d), 6.73 (%H, s)
, 6.77 (V2O,s).

7.38 (%tl,s), 7.39 (%II,s
), 7.62 (V2O,s).

7.63 (zH,s), 7.78 (IH,
d), 7.80 (IH, d).

8.49 (Ill, d), 8.51 (IH
, d).

Example 23 (A) 1-(2-sulfamoylethyl)-4-thiopyridone N units R (D20) δ 3.35 (+ALd), 3.39 (+AH, d)
, 3.60 (zH,d).

3.67 (!/S11.d), 3.93 (2H,
L), 4.17 (V2O,d).

4.18 (zH, d), 4.34 (!/U, d)
, 4.38 (zH,d).

4.92 (2H, br, s), 5.06 (!/H
1,d), 5.09 (%H,d).

5.59 (!l(,s), 5.59 (!41(,
s), 5.60 (!/U, d).

5.69 (zH, d), 6.71 (MH, s),
6.75 (+AH,s).

7.35 (zH,s), 7.36 (zH,s),
7.59 (V2)1. s).

7.60 (!41(,s), 7.80 (IH,d
), 7.81 (IH, d).

8.5], (2+1.d) Example 24 Duplex (a) (R5) 1.03 g of 2-(2-tritylaminothiazol-4-yl)-2-(t-butoxycarbonylamino)acetic acid in DMF 1-Hydroxyhencytriazole 270 μm and N dissolved in IOd.

Add 412 lbs of No-dicyclohexylcarbodiimide and react at room temperature for 1 hour.

To this was added a 10 volume solution of DMPI containing 740 μl of 7-amino-3-chloromethyl-cef-3-em-4-carboxylic acid benzhydryl ester, and the mixture was allowed to react at room temperature for 5 hours. After the reaction, the insoluble portion was filtered off, and the filtrate was diluted with ethyl acetate.
20- was added, washed sequentially with powdered sodium hydrogen carbonate solution, diluted hydrochloric acid solution and saturated saline solution, and dried over magnesium sulfate.
Concentrate to dryness under reduced pressure.

The residue was purified by silica gel column chromatography (Hensen:ethyl acetate = 8:1) to obtain (6R,7R) 7-((R
S)-2-(2-aminothiazol-4-yl)-2-
(t-butoxycarbonylamino)acetamide two 3
1.3 g of -chloromethyl-cef-3-em-4-carboxylic acid benzhydryl ester are obtained.

(b) Dissolve 1.05g of this in 15rnl of tetrahydrofuran and dissolve 180ml of 1-methylthiopyridone.
and react at room temperature for 5 hours. After the reaction is completed, the reaction solution is concentrated, 20-ethyl acetate is added to the residue, the resulting precipitate is collected by filtration, washed with ethyl acetate, and then collected by filtration to obtain (6R,7
R) 7- ((Rs) -2-(2-)cutylaminothiazol-4-yl)-2-(t-butoxycarbonylamino)acetamide)-3-(1-methylpyridinium-4-yl)thiomethyl- Cef-3-M-4-
1 g of carporic acid benzhydryl ester is obtained.

(C) Of these, 980 μm was suspended in 3.3 μg of anisole, and while cooling with water, 15 m/ml of trifluoroic acid was added, and the mixture was allowed to react at room temperature for 30 minutes. After completion of the reaction, the reaction solution was lubricated with diisopropyl ether 100, nI, and the resulting precipitate was collected by filtration and dried to give (6R,7R) 7-((
RS>-2-(2-aminothiazol-4-yl)-2
-acetamide)-3-l(+-methylpyridinium-
720 tsp of 4-yl)thiomethyl-cef-3-em-4-carboxole 1-trifluoroacetate are obtained.

NMR (D, O) δ 3.49 (+AH, d), 3.56 (%ll, d
), 3.75 (!4tl,d).

3.77 (+AH, d), 1.22 (3H, s)
, 4.3~4.5 (2H, m) 5.16 ('AH
, d), 5.18 (!41+, d), 5.32
(!4tl,s).

5.33 (!11.s), 5.65 (%H,d)
, 5.77 (!/U, d).

7.12 (IH, s), 7.81 (2H, m)
, 8.43 (2B,d)(d)5-1)-methquinhensyloxy-1-hydroxy-4-pyridone-2
- 380 nv of carboxylic acid in 6 ml of tetrahydrofuran
and add 0.24% of triethylamine to dissolve. To this, at -10~=15℃, phosphorus pentachloride 220■
was added and reacted for 1 hour at the same temperature.
Make 9 rounds.

(61?, 71?) 7-[(R
3) -2-(2-aminothiazol-4-yl)-2
670 μm of amino-acetamido)-3-(1-methylpyridinium-4-yl)thiomethyl-cef-3-em-4-carboxylate trifluoroacetate was dissolved in 3 mf of tetrahydrofuran and 9 μm of water, and dissolved in triethylamine under water cooling. Add the above acid chloride solution while maintaining the pH at 8-8.5. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and this was heated with water for 6 hours.
Add NHfJ to make pl+2, and collect the resulting precipitate by filtration. After washing with water and drying, (6R, 7R)? −((R
5) -2-(2-aminothiazol-4-yl)-2
-(5-p-Methoxyhensyloxy-1-hydroxy-4-pyridone-2-carboxamide)-3-(1-methylpyridinium-4-yl)thiomethyl-cef-3-
550 µm of coarse powder of Em-4-carboxylate is obtained.

(e) QQ this to anisole 1,5-, add 6 ml of trifluoroacetic acid under water cooling, and react for 30 minutes at room temperature.

After the reaction is completed, the reaction solution is added to 60.7 g of diisopropyl ether, and the resulting precipitate is collected by filtration and dried.

Suspend this in a small amount of water and add 7 mL of saturated sodium bicarbonate water.
Dissolve the solution in caroene (pH 7-7.2) L, HP -2
Purified by 0 column chromatography (5% acetone water elution),
The title target compound 240■ is obtained.

The spectral data of this compound matched that of Example 4. ” Procedural Amendment November 1, 1985 Mr. Michibu Uga, Director-General of the Agency, Hanyu's Novel Cefa 0 Sporin Derivative and Antibacterial Agent 3, Relationship with the person making the amendment Hogyu Patent applicant address and name (609) Meiji Seika Co., Ltd. 4, Agent's Specification 6, Contents of amendment fi+ Page 27 of the specification, lines 1 to 2: ``Tritylamine J is amended to ``triethylamine.''

(2) "rN,N-dimethylamine" in the third line of page 27 is corrected to "rN,N-dimethylaniline".

(3) Page 36, line 10 r7.60 (!4H,
s) Correct J to r5.60(%H,s)J.

(4) Page 36, line 11, 1”7.62 (!/!
, s) J is corrected to r5.62(!4Ls)J.

(5) Page 40, line 1 r 5.13 ('A I
+, s) J to r5. Correct to I3(!4H, d)J.

(6) Page 41, line 6 r8.22 (lu, d)
J to r8. Correct to l2 (Ill, d).

(7) 1st line from the bottom of page 41 r6.73 (!/H
Correct (,d)J to r5.13 ('AH,d)J.

(8) 1st line from the bottom of page 41 r6.76 (!zl
+, d) Correct J to r6.76 (!4H, s) J.

(9) The following sentence is added before page 49, line 10 [effects of the invention].

“Example 13 In Example 2, l-methylone clopentano (b
) -4-Thiopyridone was replaced with 4-rupoxymethyl-cyclopentano [b] The title compound was obtained by the same treatment except that 4-thiopyridone was used.

NMR (DzO) δ 2.30 (2H, m), 2.98 (2H, m),
3.17 (2H, m).

3.53 (V2X2H, ABq), 3.58 (%
X2H, ABq).

4.30 (lAx2JI, ABq), 4.32 1
x2H, ABq).

4.94 (2Ls), 5.06 (!/H1,d
), 5.10 (!411.d).

5.60 (E, s), 5.61 (%lI, d)
, 5.71 (zH,d).

6.75 (%Ls), 6.79 (%H,s
), 7.40 (lAH,s).

7.41 (V2H,s), 7.60 (1)
1. m), 7.65 (%H,s).

Claims (1)

[Claims] 1. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, A is an alkanoyloxy group having 2 to 5 carbon atoms, a carbamoyloxy group, an azide group, Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (n is 0 or an integer of 3 to 5, R^1, R^2 may be the same or different hydrogen atom, halogen atom, carbon number 1 to 5
pyridylthio and substituted pyridylthio groups (lower alkyl group that may contain a halogen atom), ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [n, R^1, R^2 have the above meanings, R^ 3 is a linear or branched alkyl group having 1 to 5 carbon atoms, a halogen-substituted alkyl group, a cyclopropyl group, a cyclopropylmethyl group,
Alkenyl group, oxygen atom, or -(CH_2)mB(
m is an integer of 0 to 3, B is a hydroxyl group, an alkoxy group, an amino group, an alkyl-substituted amino group, a carboxyl group, a carbamoyl group, a sulfonic acid group, a sulfonic acid amide group, a cyano group, a thiol group, an alkylthio group, a methanesulfonylamino group carbonyl group or acetamidosulfonyl group)
pyridiniumthio and substituted pyridiniumthio groups represented by ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (n is 0 or an integer from 3 to 5 R^4, R^5 is Hydrogen atoms, which may be the same or different, straight chain or branched alkyl groups having 1 to 5 carbon atoms, carboxyl groups, carbamoyl groups, sulfonic acid groups, sulfonic acid amide groups, straight chain or branched chains having 1 to 5 carbon atoms alkylthio group, halogen-substituted alkylthio group,
Cycloalkanothio group, cycloalkanomethylthio group,
Indicates a carboxyalkylthio group, a carbamoylalkylthio group, an alkoxyalkylthio group, and an alkyl-substituted aminoalkylthio group. ) and substituted pyridinium groups. A novel cephalosporin compound and a pharmacologically acceptable salt thereof. 2. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, A is an alkanoyloxy group with 2 to 5 carbon atoms, a carbamoyloxy group, an azide group, Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (n is 0 or Integers R^1 and R^2 of 3 to 5 may be the same or different, hydrogen atom, halogen atom, lower alkyl group having 1 to 5 carbon atoms, which may contain a halogen atom), and pyridylthio and substitutions. Pyridylthio group, formula ▲ Numerical formula, chemical formula, table, etc. ▼ [n, R^1, R^2 have the meanings above, R^3 is a straight or branched alkyl group having 1 to 5 carbon atoms, halogen substitution Alkyl group, cyclopropyl group, cyclopropylmethyl group,
Alkenyl group, oxygen atom, or -(CH_2)mB(
m is an integer of 0 to 3, B is a hydroxyl group, an alkoxy group, an amino group, an alkyl-substituted amino group, a carboxyl group, a carbamoyl group, a sulfonic acid group, a sulfonic acid amide group, a cyano group, a thiol group, an alkylthio group, a methanesulfonylamino group carbonyl group or acetamidosulfonyl group)
There are pyridiniumthio and substituted pyridiniumthio groups represented by ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (n is 0 or an integer from 3 to 5, R^4, R^5 may be the same or different, a hydrogen atom, a straight chain or branched alkyl group having 1 to 5 carbon atoms, a carboxyl group, a carbamoyl group, a sulfonic acid group, a sulfonic acid amide group, a straight chain or branched chain having 1 to 5 carbon atoms. Pyridinium and substituted pyridinium groups represented by branched alkylthio groups, halogen-substituted alkylthio groups, cycloalkanotio groups, cycloalkanomethylthio groups, carboxyalkylthio groups, carbamoylalkylthio groups, alkoxyalkylthio groups, and alkyl-substituted aminoalkylthio groups. An antibacterial agent containing a novel cephalosporin compound and a pharmacologically acceptable salt thereof as active ingredients.