JPS59118792A - Cephem compound - Google Patents

Abstract

NEW MATERIAL:A beta-lactam compound shown by the formula I [X is methylene, S or O; A is phenyl, 4-hydroxyphenyl, 2-aminothiazolyl; B is any of groups shown by the formulas II-IV (Y is H, OH, or 1-6C alkanoyloxy; Z is H, OH, amino, or 1-12C alkyl); R1 is H, OH, 1-6C alkoxy, or 1-6C alkyl; R2 is H, halogen, or CH2R2'(R2' is H, azido, 2-6C alkanoyloxy, etc.); R3 is H, alkaline (earth) metal, organic ammonium, or ester residue]. EXAMPLE:(6R, 7S)7-[ (S)-2-( 2-Aminothiazol-4-yl )-2-( 5-hydroxy-4- pyridone-2-carboxyamido)-acetamido]-1-azabicyclo[4,2,0]oct-2-en-8-oxo- 2-carboxylic acid. USE:An antibacterial agent against Gram-positive and Gram-negative bacteria, etc. PROCESS:An amino compound shown by the formula V is condensed with a carboxylic acid shown by the formula VI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cephem compounds. More specifically, the present invention relates to the general formula (I) (wherein, a hydrogen atom, a hydroxyl group, or a linear or branched lower alkanoyloxy group having 1 to 6 carbon atoms, and Z represents a hydrogen atom, a hydroxyl group, an amine group, or a linear or branched alkyl group having 1 to 12 carbon atoms; ), R] is a hydrogen atom, a hydroxyl group, a carbon number of 1 to 6
a straight-chain or branched lower alkoxy group, or a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms, R2 is a hydrogen atom, a halogen atom, or a group represented by Cn2R, [wherein R2' is hydrogen] Atom, azide group, carbon number 2~
6 lower alkanoyloxy group, carbamoyloxy group, pyridinium group, substituted pyridinium group, or substituted or unsubstituted heterocyclic thio group (however, heterocycle refers to 1 to 4
R3#-1: hydrogen atom,
alkali metal, alkaline earth metal, organic ammonium-based or ester residue)
Concerning lactam compounds.

Many β-lactum antibiotics are being developed to provide excellent chemotherapeutic agents for the treatment of various bacterial infections. The present inventors have made a great deal of effort to search for useful compounds that have been extensively eroded. Many acylated β-lactam compounds have been synthesized. Among them, the general formula (
It has been discovered that the β-lactam compound represented by I) has a strong antibacterial effect over a wide range of Durham-negative bacteria, including not only Durum-positive bacteria, but also Pseudomonas aeruginosa, Pseudomonas sepatia, and various Enterobacteria, and the present invention I was able to complete it.

The group can assume two tautomeric structures by isomerization as shown in the following formula.

a) When Z=H (hydrogen atom) b) When Z=OH (hydroxyl group) It changes fluidly depending on the type. 75; The naming and structure description of the compound represented by the general formula (I) may use the pyridone type, the idroxypyridinium nodine type, or the idroxyviridinium Hg isomer. However, in the present invention, the -1-pyridone type is used for naming. The present invention is intended to include all tautomers.

The halogen atom in the R2 group of the compound represented by general formula (I) represents chlorine or bromine, and the substituents for the monosubstituted pyridinium group include a carnocumoyl group, a cyano group, (CH2
) ncO2H5 (CH2) nsO3H etc. 75 Two examples are given. However, n represents an integer from 1 to 3.

Substituents for the heterocyclic thio group include a lower alkyl group having 1 to 6 carbon atoms, a hydroxyl group, an amino group, a nitro group, (CHz)nc
Oz'H, (CHz)nsOa'H, (C'Hz)n-
Examples include N (lower alkyl group) 2 (lower alkyl refers to a group having 1 to 4 carbon atoms). The heterocycle may be any 5- or 6-membered rare heterocyclic group containing 1 to 4 N, O, or S atoms, but preferred are a tetrazolyl group, thiadiazolyl group, triazolyl group, and thiazole group. group, triazinyl group, pyridyl group, pyridinium group, etc.

The alkali metals and alkaline earth metals in the R3 group are metals that form the counter cation of carboxylate anidine (COO-), and the former include sodium, potassium, etc., and the latter include magnesium, calcium, Barium A
Can you give an example? Examples of counter-cation groups include ammonium groups of organic amines such as basic amino acids.

Examples of the ester residue represented by R3 include the following formula: -CHoCR5 (wherein, R4 is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R5 is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms;
(represents a lower alkyl group or phenyl group), which is relatively easily dissociated in vivo.

The β-lactam compound represented by general formula (I) can be produced by the following method A), method B) or method C).

Method A) 02R3 (II) (1) The amine compound represented by the general formula (II) is converted into the amine compound represented by the general formula (U
A compound represented by the general formula (I) can be produced by combining it with a carboxylic acid represented by the formula (I). General condensation methods in peptide synthesis are applied, and the main methods include the acid halide method, acid anhydride method, dicyclocarbodiimide method, mixed acid anhydride method, active ester method, and acid azide method. Among them, the active ester method is preferred. Examples of the active ester include N-hydroxysuccinimide, 1-hydroxybenzotriazole, and P-nido-lophenylmercabutane.

Amine compounds (If) can be used as such or as inorganic acid salts such as hydrochloride, aqueous bromide or organic acid salts such as trifluoroacetate, or as N-silyl derivatives. . The acylation (condensation) reaction is carried out in an aqueous or non-aqueous solvent at a temperature of -50°C to +50°C, if necessary in the presence of a base or other acid scavenger.

As a solvent, ethers such as tetrahydrofuran,
Amides such as dimenalformamide, sulfoxides such as dimethyl sulfoxide, acetone, acetonitrile, water, etc. may be used alone or in combination. Bases include tertiary amines such as triethylamine and dimethylaniline, inorganic bases such as sodium hydrogen carbonate and potassium carbonate, and other acid scavengers such as ethylene oxide,
Oxirane compounds such as propylene oxide may be used.

Among the compounds represented by the general formula (11), the compound where X is S is J, Antibiot soil c6 aim 1022 (19
80), and oxacephalosborins in which X is 0 were prepared by the method described in J. Med. Chem.
977), J, Am, C'hem, Soc, ±:
114403 (1979) etc., and further the corresponding compound represented by the general formula (II) can be produced according to the method for cephalosporins (X=S). . Regarding carbacephems in which X is CH2, a method for producing the carbacephems is described in Japanese Patent Application No. 156752/1983.

Compounds represented by the general formula (Kawa) are known, Journal of the Japanese Society of Agricultural Chemistry 16 253 (1940), Chem.

Ber, 87 1440 (1954), etc.

Method B) (AI) (V) Decapturing group 1111--→ Compound represented by general formula (I) (:
However, A' represents phenyl, 4-hydroxyphenyl, or w (Nl (however, W represents a protected amine group))] A carboxylic acid represented by general formula (IV) and general formula (V)
By condensing the 7-amine compound represented by the formula (I), a compound represented by the general formula (I) can be produced.

General methods for acylation of henicillin and cephalosporin are applied, and the main methods include acid halide method, acid anhydride method, mixed acid anhydride method, active ester method or acid azide method. Among them, the mixed acid anhydride method is preferred. Typical mixed acid anhydrides include a compound represented by the general formula (IV) and methyl chlorocarbonate in the presence of a base.
Examples include anhydrides produced by reaction with ethyl chlorocarbonate, isobutyl chlorocarbonate, pivaloyl chloride, and the like.

The 7-amino compound (■) can be used by itself or with the general formula (
It can be used as a salt similar to the amine compound represented by 1) or as a crocodile conductor.

The acylation (condensation) reaction is carried out in an aqueous or non-aqueous medium at a temperature of -50°C to +50°C, if necessary in the presence of a polybase. The solvent and base used in the reaction are exactly the same as those used in method A).

If necessary after condensation, the protective group (amine protective group) can be removed by a conventional method.

The desorption method is McOmieiifi's 'Protec'.
tive Groupsin Organic Che
mistry N (1973, Plenum Press
) can be carried out according to the method detailed in .

Among the compounds represented by the general formula (■), 1. Cephalosporins in which χ is S are widely known compounds, and oxacephatetrasporins in which X is 0 are available from JlMed-Chem,
, 20551 (1977), same day 757 (1979)
It can be produced by the method described in
The carbacephems of , are disclosed in JP-A-54-128591,
No. 55-87791, No. 55-108872, No. 5
It can be manufactured by the method described in JP 6-61377 and the like.

The compound represented by general formula (b) can be produced by the method described below.

This condensation reaction is performed on the compound v#! represented by the general formula (1). It can be carried out in the same manner as manufacturing method A).

That is, the condensation can be carried out in the solvent used in method A) at a temperature of -50°C to +50°C in the presence of a base if necessary.

Note that, if desired, L-(Vl), D-
By using (Vl), each corresponding L
-(IV), D-(IV) can be produced, and if method B) is applied using these, the corresponding L-(
I) and D-(I) can be produced.

The compound represented by the general formula (Vl) is also known and can be produced by the method described in Japanese Patent Application No. 56-156752.

Method C) (In the case of a group represented by R2=CH+Rffi) (■) Compound A -11-→ Compound represented by general formula (I) [wherein,
Compounds include pyridine, substituted pyridine, or substituted or unsubstituted heterocyclic thiols (heterocycle refers to 1 to 4 ○
, S, and H atoms).

R4 represents a group that can be substituted by the reaction of Compound A, which is a nucleophilic reagent, with a compound represented by the general formula (■), preferably an alkanoyloxy group having 2 to 6 carbon atoms].

The compound represented by the general formula (I) is the method A) or the method B
It can be produced by reacting a compound represented by the general formula (■) which can be produced by method (method) with compound A or a salt thereof.

This substitution reaction can be carried out using, for example, water, phosphate buffer, acetone,
It can be carried out in solvents such as chloroform, acetonitrile, nitrhencene, methylene chloride, dimethylformamide, methanol, ethanol, tetrahydrofuran, dimethyl sulfoxide, but is preferably carried out in strongly polar spraying 3. It is also carried out, if necessary, in the presence of an inorganic base such as sodium bicarbonate or an organic base such as triethylamine. The reaction temperature is not particularly limited,
The reaction is usually carried out at room temperature, under heating, or under heating. This reaction is preferably carried out using alkali metal halides (e.g. sodium iodide, potassium iodide, etc.), alkali metal thiocyanates (e.g. sodium thiocyanate,
potassium thiocyanate, etc.).

The compound of the present invention has strong antibacterial activity against Durum-positive bacteria and Durum-negative bacteria, and is useful as an insecticide for the treatment of various infectious diseases and as a component of Hushunri, and is similar to general cephalosporin agents. It is formulated using various vertebral carrier materials, excipients, diluents, etc., and administered as an injection, an oral drug, or a crude drug depending on the dosage form.

The present invention will be specifically illustrated in Examples below.

Example 1゜(6R,78)7-((S)-2-(2-aminothiazol-4-yl)-2-(5-71 idroxy-4-pyridone-2-carboxyamide)-acetamidocy 1-
Azabicyclo(4,2,0,1oct-2-ene-8-
Production of oxo-2-carboxylic acid; 5-hydroquine-4-pyridone-2-carboxylic acid 31
0-■ and 1-) Hydroxybenzotriazole 260
(1) was dissolved in 4+IL1 of dimethyl sulfoxide, and while stirring, 410 (2) N,N'-dicyclohexylcarbodiimide was added and reacted at room temperature for 1 hour to prepare an active ester solution.

(6R,7s)7-((s)-2-(2-aminothiazol-4-yl)-2-aminoacetamidocou-1-azabicyclo(:4.2.0:)oct-2-ene- 8
370 ml of -oxo-2-carboxylic hydrochloride is added to 24 ml of dimethyl sulfoxide, and 0.3 d of triethylamine is added and dissolved. The above-mentioned active ester solution was added to this and reacted at room temperature for 2 hours. Insoluble materials were removed from the reaction mixture, 5 drops of water were added, the pH was adjusted to 2 with IN hydrochloric acid, and the mixture was purified by column chromatography using Diaion HP-10100m (elution solvent, water:
methanol=1:1) 260 kg of the title compound was obtained. (
(Yield 52.9%) 210 pieces of the above powder were mixed with 1 part of saturated sodium bicarbonate solution.
Purification by column chromatography using P-1050d (elution solvent, water:methanol = 5:1) gave a light gray powder of 200η.This had the physical properties shown below. Based on the value, it was identified as the sodium salt of the listed compound.

IRνmax(KBr)6n-1:1755.1670
．． 1650°1600.1570.152O NMR (D20) δ: 7.67 (IH, 8), 7.
23 (IH, s).

6.73 (IH, B), 6.2 (IH, m), 5.
60 (IH.

s), 5.34 (IH, d, J=5), 3
．． 9 (IH, m).

2.4 (2H, m), 2.2 to 1.5 (2H, m
) Example 2 (6R,78)7-(,(S)-2-(2-aminothiazol-4-yl)-2-(3-)1 hydroxy 2
-Pyridone-6-carboxyamide°)-acetamido-1-azabicyclo(4,2,0)oct-2-ene-
Production of 8-oxo-2-carboxylic acid: 3-hydroxy-2- instead of 5-7-idroxy-4-pyridone-2-carboxylic acid used in Example 1.
When the same operation as in Example 1 was performed except for using pyridone-6-carbo/acid, a pale yellow powder of 190πZ was obtained, which was identified as the title compound. (Yield 3a, 7X) NMR(D20)δ: 7.16(IH,d)
, 6.65 (IH, s).

6.50 (IH, d), 6.2 (LH, m), 5.55
(IH.

e), 5.33 (IH, d), 3.9 (IH, m)
, 2.4 (2H,m), 2.3-1.5 (2H
,m) Example 3, (6R,78)7-[('R)=2-(P-hydroxyphenyl)-2-(s-hydroxy-4-pyridone-
Preparation of the sodium salt of octo-2-ene-8-okine-2-carboxylic acid: 5-hydroxy-4-pyridone-2-carbo7fl13
74v-y and N-hydroxysuccinimide)”278
77p was dissolved in 4.5 d of dimethyl sulfoxide,
While stirring, 507 μm of N,N'-dicyclohexylcarbodiimide was added and reacted at room temperature for 1 hour to prepare an active ester solution.

(6R,7S)7-((R)-2-(P-hydroxyphenyl)-2-aminoacetamide] = 1-azabicyclo[4,2,01oct-2-ene-8-oxo-2-
Carboxylic acid 600Td;i is added to 4.5-dimethyl sulfoxide, and 0.34-triethylamine is added and dissolved.

The above-mentioned active ester solution was added to this and reacted at room temperature for 2 hours. Add 1 d of water to the reaction mixture, and dilute with IN hydrochloric acid.
After adjusting to H1.5 and removing insoluble matter, add Diamond Ion H.
When purified by column chromatography using P-10180*J, (elution solvent, water:methanol-2=1
~1:1) 900 f1v of white powder was obtained.

Further, the above powder was dissolved in 5 liters of saturated sodium bicarbonate solution and purified by column chromatography using Diaion HP-101001 liters (eluent: water:methanol = 10:1) to obtain a pale yellow powder of 840,711p (
yield 899%).

IT(νmax(KBr)Cn+-': 3350.
1750.1680°1660.1640,1600,
1570,152ON MR(D20)δ: 7
．． 68 (LH, s), 7.29 (2H, d.

J=8.5H2), 7.17 (IH,8:), +
3. sa C2H.

(1, J=9.OH2), 6.02~6.20 (I
H, m).

5.45 (IH, s), 5.38 (LH, d, J
=5. IH2).

3.65-4.0 (IH, m), 2.05-2.40
(2H, m).

0.85-2.05 (2H,m) Example 4゜7-[(R)-2-(P-hydroxyphenyl)-2-
Preparation of the sodium salt of (5-hydroxy-4-pyridone-2-carboxyamido)-acetamido]-3-(1,2,3-)lyazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.

H 5-hydroxy-4-pyridone-2-carboxylic acid 436
ty and N-hydroxysuccinimide 3231P4
is dissolved in 5-dimethyl sulfoxide and while stirring,
N,N'-dicyclohexylcarbodiimide of Cape 579 was added and reacted at room temperature for 1 hour to prepare an active ester solution.

7-((R)-2-(P-hydroxyphenyl)-2-
Athanoacetamide: ]-3-(1,23-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic hydrochloride 12 was added to 6-dimethylsulfoxide,
Add and dissolve 0.6 ag of triethylamine to this. Add the above-mentioned active ester solution to this and let it cool for 2 hours at room temperature.
Allowed time to react. Add 1,5 ml of water to the reaction mixture and add IN
The pH was adjusted to 2.0 with hydrochloric acid, and the insoluble matter was removed by column chromatography using Diaion UP-1023 (HD). A white powder of t:2)11y was obtained.

Furthermore, the above powder was dissolved in 5 liters of saturated M carbon dioxide solution and purified by column chromatography using Diaion HP-10110m (eluent: water: methanol = 1
0:1 to 5:1) 1.04f of pale pink powder was obtained (yield 77.5%).

IRνmax (KBr)It~': 3250,
1765,1690゜1670.1645,1600,
1570,152ONMR(D2Sδ: 7.78(I
H,s), 7.75 (IH,s).

7.4 (2H, d, J ~8.4Hz), 7.
25 (IH, e).

6.90 (2H,a, J=8.2Hz), s,
6s (IH.

d, J=4.5H2), 5.54 (IH,s)
, 5.00 (IH, a, J=4.5H2) L V,
= 3゜50, l'u = 4.11 (2H, ABq, J
AB=13.5H2), V person=3.17 and 1)
n=3.60 (2H, AEq, 'JAB=18H
z) Example 5 (6R, 7R)? -(2-(2-aminothiazole-4
-yl)-2-(5-hydroxy-4-pyridone-2-
Preparation of carboxamide)acetami)')-3~acetoxymethyl-3-cephem-4-carboxylic acid sodium salt: 5-hydroxy-4-pyridone-2-carboxylic acid 1.0
? (6,48 mmole), N-hydroxysuccinimide (750 μm) (6,48 mmole) was dissolved in dimethyl sulfoxide (4.34 mmole), and N, N'-dicyclohequinlecarbodiimide (1.342 mmole) (6,48 mmole) was dissolved in dimethyl sulfoxide (4.34 mmole).
ole) and stirred at room temperature for 1 hour to obtain a solution of active ester.

On the other hand, (6R,7R)7-[2-(2-aminothiazol-4-yl)-2-aminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylic hydrochloride 2
．． 0? (4.32 mmole), add 6.41 ml of dimethyl sulfoxide, and add 1.2 ml of triethylamine.
(8.64 mmole) to form a solution. The above active ester solution was added to this, and the mixture was stirred at room temperature for 3 hours. Add 2N hydrochloric acid to the reaction solution to adjust the pH to 2, and filter out the precipitate. P liquid with Diamondion HP-10460m
Attach to 10 column chromatography. After washing with 1.5 t of water and 5:11.7 t of water: methanol, the two fractions eluted with 2:1 water: methanol were combined and concentrated under reduced pressure to obtain 1 yellow solid.
．． Obtain 08f. Of this, 770 ml was dissolved in an aqueous sodium bicarbonate solution and subjected to column chromatography using Diaion HP-1070-. Develop with water, combine the two fractions containing the target product, and concentrate under reduced pressure to obtain a yellow powder 4'7 o7? ;, (o
,s.

mmole) (yield: 26.09 g).

IR￥)max(KBr)cn+-”: 3350.
1770.1660°1610.1520.124O NMR (D2S δ: 7.73 (IH, S), 7.2
0 (IH, 8).

to 6°75 ('72H, s), 6.72 (1/2H, s)
, 5.7-5.5 (IH, m), 5.59 (IH
, 8), 5.1-5.0 (IH, m), 4.9-4
．． 5 (2H, m), 3.7-3.1 (2H, m), 2
．． 04(3/2H,8), 2.08(”/2H,
El) Example 6゜(6R,7s)7-[(s)-2-(2-aminothiazol-4-yl)-2-(5-hydroxy-1-methyl-4-pyridone-2rcarboxamide) -acetamidocy1-azabicyclo[4,2,0:]]octo2
-Production of ene-8-oxo-2-carboxylic acid: To the 5-hydroxy-4-pyridone-2-carboxylic acid used in Example 1, 5-hydroxy-1-dimether-4-pyridone-2- When the same operation as in Example 1 was carried out except for using 33 oyy of carboxylic acid, 210 μ of pale yellow powder was obtained, which was identified as the title compound (yield: 42.3
X).

IR))max(KBr)cn+” :1765.1
700.1660°1635.1560.154O NMR (DMSO-d6-CD30D) δ: 7.43
(IH,s).

6.53 (IH, ε), 6.33 (IH, 8), 6.3
(IH.

m), 5.47 (IH, B), 5.32 (IH, 1
), 3.8(IH,nx), 3.67(3H,s
), 2.4 (2H, m).

2.0-1.4 (2H,m) Example 7゜(4S, 6R, 7S) 7-(2-(2-aminothiazol-4-yl)-2-(5-hydroxy-4-pyridone- 2-carboxamide) acetamidocy4-hydroxy-1-'azabicyclo[4,2,0)-oct-2-
Production of ene-8-oxo-2-carboxylic acid: 5-hydroxy-4-pyridone-2-carboxylic acid 776
q and N-hydroxysuccinimide 580q are dissolved in dimethyl sulfoxide 5-, N,N'-dicyclohexylcarbodiimide 105 (llp) is added, and the mixture is stirred at room temperature for 1 hour.

Apart from this, (4S,6R,78)7-[,2-amino-2-(2-aminothiazol-4-yl)acetamidocy4-hydroxy-1-azabicyclo(4,2
,0) To a solution of 12002t17 of oct-2-ene-8-oxo-2-carboxylic hydrochloride in 54 parts of dimethyl sulfoxide and 1.7 m of triethylamine, the above solution is added under stirring. After stirring at room temperature for 2 hours, 5 d of water was added, the pH was adjusted to 15 with hydrochloric acid, and insoluble matter was filtered off.

The filtrate was subjected to column chromatography using DiaioyHp-1o (Mitsubishi Kasei Corporation) 1t, developed with water-mhethanol, and the relevant fractions were concentrated to dryness to obtain the title compound 540q (yield: 35, 8%).

IR ax (KBr) crn-”: 3270.17
70.1755°1660.1620,1550,15
20.1355NMR(DMSOd6)δ: 9.03
~8.83 (IH, m).

8.74-8.53 (IH, m), 8.00 (IH,
s), 7.47 (1n, 8), 7.02 (2H, b
s), 6.51 and 6.49 (II (, 8 each), 6
°25 and 6.23 (IH.

Each d), 5.57 to 5.27 (2H, m), 4.3
3-4.15 (IH, m), 4.03-3.70 (IH
, m), 1. ．． 83-L15 (2H, m) Heart 1, Indication of the case Patent Application No. 2!30738 of 1982, Name of the invention Cephem Compound 3, Relationship with the case to be amended Patent Applicant Postal Code 100 Address Tokyo 6-14 Otemachi-chome, Chiyoda-ku, Miyako
(102) Column 5 of Detailed Description of the Invention in the Specification of Kyowa Hakko Kogyo Co., Ltd., Contents of Amendment + 1) The following example is added after the description of Example 7 on page 29.

Example 8゜(6R,7R)-7-(2-(2-aminothiazole-
4-yl)-2-(5-hydroxy-4-pyridone-2
-carboxamido)acetamide]-3-(1-methyl-4-pyridiniothiomethyl)-3-cephem-4-carboxylate -υH (6R,7R)-7- obtained in Example 5 r, 2-(2
2.133 g of -aminothiazol-4-yl)-2-(5-hydroxy-4-pyridone-2-carboxamido)acetamide]-3-acetokyremethyl-3-cephem-4-carboxylic acid was suspended in 38 ml of water. To this, 318 μm of sodium hydrogen carbonate and 1-methylpyrido-4-
Add Thione 663■ and stir at 80°C for 3.5 hours. After the reaction was completed, the mixture was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution was added to the three reaction mixtures to form a homogeneous solution, which was then subjected to column chromatography on a Diaion HP-10, 700ml. Ice 21. Water/methanol-5/12.1β
After washing with water, the two fractions eluted with water/methanol (2/1) were combined and concentrated under reduced pressure to obtain 730 mg (yield: 31%) of the title compound.

IR: 1/)1'B'(am-'): 330
0.1780.1670.1640°TIQX 1610, 1560.153O NMR: (D2 o-Na oD) δppm:
8.2 (2H, m), 7.6 (211, m)
, 7.59 (!/M11.S).

7.58 (%11.S), 7.09 (%11.S)
．． S), 7.07 (!/S11.S).

6.71 (!/S11.S), 6.68 (z
H,S), 5.66 (zH,d.

J = 5Hz), 5.56 (z)(,d, J
=5H2).

5.54 (IIl, S), 5.0 (IIl,
m), 4.08 (3H,S).

3.8-3.0 (2It, m> Example 9゜(6R,7R)-7-(2-(2-aminothiazole-
4-yll-2-(5-cedroxy4-pyridone-2
-carboxamide)acetamide)-3-(1-carpoxymedy-4-pyridiniothiomethyl)-3-cephem-4-carboxylate sodium salt: 11 (3) Obtained in Example 5 ( 6R,7R)-7-(2-(2-
aminothiazol-4-yl)-2-5-hydroxy-
4-Pyridone-2-carboxamide) acetamido-3-acetoxymethyl-3-cephem-carboxylic acid 83
3■, 1-carphokidimethylpyrido-4-thione 300
■ 273 ■ of sodium bicarbonate was dissolved in 15 ml of water, and 290 ■ of the title compound (yield: 2) was obtained according to the method of Example 8.
8%).

IR→Journey history (am'): 3300.1765.1
670.1630°52O NMR: (D 2 o) δp p m : 8
．． 33 (211, d, J = Hz) 7.75 (214
, d, J = 7H, Z), 7.71 (IH, S
).

7.18 (Ill, S), 6.71 (II(,
S), 5.7-5.5 (LH, m), 5.60
(IH,S), 5.01 (211,5).

4.6-4.0 (211, m), 4.0-3.
2 (211,m) Example 10゜(6R,7R)-'l-(2-(2-aminothiazol-4-yl)-2-(5-hydroxy-4-pyridone-
Production of (2-carboxamide)-3=(1-carbamoylmethyl-4-pyridiniothiomethyl)-3-cephem-4-carboxylate: υH (6R,7R)-7-(obtained in Example 5) 2-(2-
aminothiazol-4-yl)-2-(5-hydroxy-4-pyridone-2-carboxamide)acetamide 3-acetoxymethyl-3-cephem-4-carboxylic acid 750■, 1-carhamonimethylpyrido 4 -thione 246 ■.

112 ml of sodium hydrogen carbonate was dissolved in 13 ml of water.

According to the method of Example 8, the title compound 2ΩOnw (yield 2
2%).

IR: p kB (cm-'): 33
00. 1?65. 1690. +630°1'1
'TQx 52O NMR: (D2o-NaoD) δppm
: 8.28 (2H, m), 7.72 (2H, m)
, 7.65 (IH,S).

7.14 (%11.S), 7.13 (!/i
ff, S), 6.73 (zH, S).

6.70 (+AH,S), 5.68 (zH,d
, J = 5Hz).

5.58 (1, d, J = 5H2), 5.56
(IH,S).

5. 07 (Item), 4.5-4.0 (
, 211, m), 3.9-3.1 (2+1.m) Example 11゜(6R,7R)-7-C2-(2-aminothiazole-
4-yl)-2-(5-hydroxy-4-pyridone-2
-carboxamide)acetamide]-3-(1-carpoxymedy-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid disodium salt: (6R, 7R) obtained in Example 5 -7-C2-(2~
aminothiazol-4-yl)-2-(5-hydroxy-4-pyridone-2-alpoxate)acetamide]
-2.252 g of -3~acetoxymethyl-3-cephem-4-carboxylic acid and 950 g of 1-carpoxymedyru-5-mercaptotetrazole were suspended in 40 ml of water, j#,
Add 176 g of sodium oxyhydrogen L to make a homogeneous solution.

This is stirred at 65° C. for 1.5 hours and then cooled to room temperature.

Add 6N hydrochloric acid to adjust the pal of the reaction solution to about 3.

After the precipitated insoluble matter is dissolved by adding dimethyl sulfoxide, it is subjected to column chromatography using Diaion HP 10.10100O. Water 2β, water/methanol-
After washing with 4/1 2A, the fractions eluted with water/methanol-2/1 were combined and concentrated under reduced pressure.

590 mg of yellow powder is obtained. This thing HP -1,
Powder 230■ obtained by repurifying using 0100ml
Suspend it in water, add saturated aqueous sodium bicarbonate solution,
Adjust pH to 6.0. The obtained solution was concentrated under reduced pressure.
The title compound 260■ is obtained. (Yield 9%) ■R: 1/) kBhi (cm'): 3400.
+770.1620.1560°VYloIx.

52O NMR: (D20) 699m: 7.75
(IH,S).

7.19 (111,5), 6.78 and 6.
74 (I I+, each S).

5.8-5.5 (Ill, m), 5.59 (
IIl, S).

5.2-4.9 (L H, m), 5.00 (
211,5).

4.5-3.9 (2H, m), 3.9-3.2
(211,m) Example] 2゜(6R,7R)-7-(2-(2-aminothiazole-
4-yl)-2-(5-hyroxy4-pyridone-2-carboxamide)acetamide]-3-(4-β-sul;j-ethylpyridium)-methyl-3-cephem-4-carboxylate・Manufacture of strium salt: Lll+ (6R,7R)-1 to [2-(2-
aminothiazol-4-yl)-2-(5-hydroxy-4-pyridone-2-carboxamide)acemide]-
2.815 g of 3-a7toxymethyl-3-cephem-4-carboxylic acid was suspended in 20 ml of water, 1.4 g of 4-(β-sulfoethyl)pyridine, and 1.4 g of sodium bicarbonate.
Add 05g of sodium iodide to the resulting solution.
and stir at 270°C for 2 hours. After cooling to room temperature 2
The reaction solution was added to 250 ml of cold acetone, and the precipitated insoluble matter was filtered. This product was dissolved in 30 ml of water, and the pH was adjusted to about 3 with 6N hydrochloric acid. After filtering out the precipitated insoluble matter and dissolving it in dimethyl sulfoxide, 7 Tire Ion HP
-10,1000mlO column chromatography. After washing with water 10100O, water/methanol-3/
1. Concentrate both eluted fractions under reduced pressure.

300 mg of yellow powder is obtained. Suspend this in water.

Add saturated aqueous sodium hydrogen carbonate solution and reduce p1 to 6.5
Adjust to. The obtained solution was concentrated under reduced pressure to obtain 1 compound 3.
00■ (yield 9%) is obtained.

IR: tu vagina (cm-'): 3400.178
0.1660.1620°1520, 1105 ON R: (D 2 o) 699m: 8.
80 (211,d, J=7Hz).

8.1-7.8 (211, m), 7.71 (
1tl, S).

7,'17 (IH,S), 6.71 (Ill,
S), 5.9-5.0 (3H, m), 5.5
6 (I HyS), 3.8-3.0 (211
, m).

3.35 (411,5) Procedural amendment filed in 1982, Mr. Commissioner of the Japan Patent Office, 1. Indication of the case, Patent Application No. 230738, filed in 1983. 2. Name of the invention, cephem compound 3. Person making the amendment. Related Patent applicant postal code 100 Address 6-1 Otemachi, Chiyoda-ku, Tokyo Name
(102) Column 5 of Detailed Description of the Invention of Kyowa Hakko Kogyo Co., Ltd. Specification, Contents of Amendment (1) V D2o -Na on page 3, line 5 and line 6 directly below 5
Correct oD J to rD2o-NaODJ.

(2) Correct "cedroxy" to "hydroxy" on page 3, line 14.

(3) "D2" on page 4, line 12, page 7, line 12, and page 9, line 4
o” is corrected to “D20”.

(4) Correct "J=H2" on page 4, line 12 to mJ=7H2J.

(5) Correct "carboxamide" in the three lines directly below 4 to "carboxamide acetamide."

(6) Correct the structural formula on page 5 as follows.

H (Power 5.
Corrected to "carbamoylmethylpyrido".

(8) Change “95o1Ag” in the 6th line directly below 6 to “960+9J”
Correct.

(9) Change “sulfoethylpyridium” in the 3 lines directly below 7 to “
Corrected to ``sulfoethylpyridinium.''

OQ: Correct the structural formula on page 8 as follows.

Claims (1)

[Claims] (1) General formula (I) (wherein, X is a methylene group, sulfur atom or oxygen atom, A is a phenyl group, 4-hydroxyphenyl group or 2-aminothiazolyl). A branched lower alkanoyloxy group, Z represents a hydrogen atom, a hydroxyl group, an amino group, or a straight-chain or branched alkyl group having 1 to 12 carbon atoms) is a group represented by a hydrogen atom, a hydroxyl group, a carbon number % R2 is a hydrogen atom, a halogen atom, or cH2R:
, [wherein R2' is a hydrogen atom, an azide group, a lower alkanoyloxy group having 2 to 6 carbon atoms, a carbamoyloxy group, a pyridinium group, a substituted pyridium group, or a substituted or unsubstituted heterocyclic thio group] (Heterocycle represents a 5- or 6-membered heterocycle having 1 to 4 0.S, N group atoms)], R3 is a hydrogen atom, an alkali metal, an alkali A β,-lactam compound represented by an earth metal, an organic ammonium group, or an ester residue.