JPH0228185A - Cephalosporin compound and synthetic intermediate thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is H, (carboxy substituted) lower alkyl or oxopyrrolidyl; R<2> is phenyl having 1-3 substituent group such as OH; A is formula II or formula III, whose N-6 membered ring part is occasionally substituted by <=2 carboxyl groups : B is bond hand, -CH2-, -CH2-CH2- or formula IV]. EXAMPLE:7beta-[2-(2-Aminothiazol-yl)-2(Z)-(2-carboxypropyl-2-oxyimino) acetamide]-3-[1-(3,4-dihydroxyphenyl)-4-pyridinio]thiomethyl-3-cephem-4- carboxylate monosodium salt. USE:An antimicrobial agent. PREPARATION:A compound expressed by formula V [R<3> is (protected)amino; X<1> is reactive residue] is reacted with a thiopyrrolidone expressed by formula VI or thiopyridine expressed by formula VII.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel cephalosporin compound having excellent antibacterial activity and intermediates for its synthesis.

[Conventional technology]

Conventionally, many cephalosporin antibiotics have been known as antibacterial agents, such as 7β-(2-<2-aminothiazol-4-yl)2-[(2-oxopyrrolidine-
3-yl)oximino]acetamide l-3-(1-
pyridinio)methyl-3-cephem-4-carboxylate or its 3-(3- or 4-hydroxymethyl-
It has been reported that the 1-pyridinio)methyl compound has strong antibacterial activity (Japanese Patent Application Laid-Open No. 59-51292).

[Structure and effects of the invention]

The present invention relates to a novel cephalosporin compound represented by the following general formula and a pharmacologically acceptable salt thereof.

(The following is a blank space) (However, R1 is a hydrogen atom, a lower alkyl group which may be substituted with a carboxy group, or an oxopyrrolidyl group, R2
has 1 to 3 substituents selected from hydroxyl group, carboxy group, amino group, formylamino group, and carboxy lower alkanoylamino group, and the N-6 membered ring group can be substituted with up to 2 carboxyl groups. B is a bond, -CH--CH-CH2-1 or the novel cephalosporin compound (I) of the present invention or a salt thereof is effective against a wide variety of microorganisms including Durham-positive bacteria and Durham-negative bacteria. It has excellent antibacterial activity, especially in comparison with the above-mentioned known compounds, against Pseudomonas aeruginosa (Pseudo IIonas aeru).
It is a useful pharmaceutical compound that has the excellent feature of exhibiting strong antibacterial activity against S. glnosa. For example, Pseudomonas aeruginosa
Aeruginosa) P
-2-((2-oxopyrrolidin-3-yl)oxyimino]acetamide] -3-(1-(3,4-dihydroxyphenyl group-4-hyridinio)thiomethyl-3-cephem-4-carboxylate) It exhibits antibacterial activity that is 15 times or more superior to the above-mentioned known compounds.

Specific examples of the object compound of the present invention include, in general formula (I), R1 is a hydrogen atom, a methyl group optionally substituted with a carboxy group, an ethyl group, a propyl group, an isopropyl group, a butyl group, etc. Examples include compounds that are lower alkyl groups, oxopyrrolidyl groups such as 2-oxopyrrolidyl groups, and 3-oxopyrrolidyl groups. Among these, pharmaceutically preferable compounds have general formula (I) in which RL is a carboxyisopropyl group or a 2-oxopyrrolidyl group, and R
A compound in which 2 is a 2,3-dihydroxyphenyl group or a 3,4-dihydroxyphenyl group, and B is a bond or an ethylene group.

In addition, the partial structure represented by the formula % in the present invention means a geometric isomer represented by the formula % (Z)-isomer or (E)-isomer, or a mixture thereof, unless otherwise specified. It shall be. However, when used as a medicine, the object compound (1) of the present invention, in which the oquinimino group is in the (Z)-configuration, has particularly excellent biological properties.

According to the present invention, a theoretically acceptable salt of the target compound (1) has the general formula or a drug thereof (wherein R3 is an optionally protected amino group, Xl represents a reactive residue, and R1 has the same meaning as above) or a salt thereof, and a compound represented by the general formula (wherein R2 and B have the same meaning as above, and in some cases, the N-6M ring portion thereof has up to two carboxyl groups. R
When 3 is a protected amino group, it can be produced by removing the protecting group for the amino group from the product.

As the salts of the raw material compounds (n), (III) and (■), for example, alkali metal salts, alkaline earth metal salts, quaternary ammonium salts, etc. can be used as appropriate. In the starting compound (II), the protecting group for the amino group in R3 includes, for example, a lower alkanoyl group, a mono-, di- or trihalogeno-lower alkanoyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted phenyl-lower alkyl group, Examples of the reactive residue X1 include a triphenyl-lower alkyl group, and examples of the reactive residue X1 include a carbamoyloxy group, a lower alkanoyloxy group, and a halogen atom.

Raw material compound (n) and raw material compound (III) or (IV)
The reaction with can be suitably carried out in a solvent at room temperature to heating. As the reaction solvent, water, a hydrophilic solvent (for example, acetonitrile), or a mixture thereof can be suitably used, and the reaction is carried out under weak acid to neutral conditions (
It is preferred to carry out at a pH of 2 to 8, especially 5 to 8). If desired, in order to improve the reactivity, an alkali metal halide, an alkali metal thiocyanate, an alkali metal hydrogen carbonate, a quaternary ammonium salt having a surfactant action (for example, a tri-lower alkylbenzylammonium salt), or a phosphoric acid A buffer solution or the like may be added. Furthermore, when R3 is a protected amino group, removal of the protecting group can be carried out according to conventional methods, for example, by hydrolysis, catalytic reduction, acid treatment, etc., depending on the type of protecting group; It can be done in combination.

The object compound (I) of the present invention or a pharmacologically acceptable salt thereof has excellent antibacterial activity against Durum-positive bacteria and Gram-negative bacteria, and can be used as a therapeutic agent for various infectious diseases in mammals including humans. It can be used as a chemotherapeutic agent or as an additive in animal feed. For example, the compound of interest (1) is inter alia Pseudomonas aeruginosa (P, ae
Pseudomonas including Pseudomonas ruginosa
It has a strong antibacterial effect against bacteria belonging to the genus Staphylococcus, Escherlchla, and Salmonella.
Lionel Ia) genus, Klebsiella (Klebsl)
It also exhibits excellent antibacterial activity against a wide variety of bacteria belonging to the genus Ella, Proteus, Citrobaeter, Enterobacter, and Serrat Ia. . In addition, the target compound (1) or a pharmacologically acceptable salt thereof is derived from the genus Shigela or Enterococcus (
It also shows excellent antibacterial activity against bacteria belonging to the genus Enterococcus.

The target compound (1) or a pharmacologically acceptable salt thereof can also be used, for example, in Escherichia coli (E, colt) ML.
-1410-RGNl123 +,: YoQ production saleyy
It exhibits high stability against various β-lactamases including β-lactamases, exhibits an excellent long-lasting infection-preventing effect, and exhibits high antibacterial activity in vivo. In addition, the target compound (I) or a pharmacologically acceptable salt thereof has low toxicity and exhibits high safety as a pharmaceutical.

When the object compound (I) of the present invention is used as a medicine,
It can be used both as a free compound and as a pharmaceutically acceptable salt thereof. Such salts include, for example, non-toxic metal salts such as sodium, potassium, calcium, magnesium, aluminum salts, nitrialkylamines (e.g. triethylamine), non-toxic amines such as pyridine, ethanolamine, triethanolamine, dicyclohexylamine. Salts with inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; Salts with organic acids such as oxalic acid and tartaric acid; Salts with amino acids such as glycine, lysine, arginine, aspartic acid, and glutamic acid. can give. In addition, the salt of the target compound (I) may be in the form of a salt formed with a polystyrene resin containing an amino group, a quaternary amino group, or a sulfonic group, or a resin containing a carboxyl group, such as a polyacrylic acid resin. You can.

Furthermore, it may be a double salt with an alkali metal or alkaline earth metal salt such as sodium chloride, potassium chloride, sodium sulfate, calcium chloride, or an ammonium salt such as ammonium chloride. Therefore, the objective compound (I) of the present invention and its pharmacologically acceptable salts should be interpreted to include any of its inner salts, adducts, double salts, solvates, hydrates, etc. be.

The target compound (1) or a pharmacologically acceptable salt thereof can be administered orally or parenterally (eg, intravenously, intramuscularly, subcutaneously). The daily dose of the target compound (I) or a pharmacologically acceptable salt thereof varies depending on the age, weight, condition, and type of disease of the patient, but usually the daily dose is 1 kg body weight. Approximately 0.
002 to about 0.2g.

Preferably, 0.01-0.04g is appropriate. Furthermore, when the target compound (1) or a pharmacologically acceptable salt thereof is used as a medicine, it can be used together with pharmaceutical excipients, binders, lubricants, etc. suitable for oral or parenteral administration. Pharmaceutical preparations may be solid preparations such as tablets, granules, and capsules, or liquid preparations such as solutions, suspensions, and emulsions. These pharmaceutical preparations may be sterile and/or may contain adjuvants such as stabilizers, wetting agents, emulsifiers.

The raw material compounds (III) and (IV) of the present invention are new compounds, and among them, the raw material compound (Iff) is composed of chelidonic acid and the general formula % (wherein R4 is an optionally protected hydroxyl group, (representing a phenyl group having 1 to 3 substituents selected from a carboxyl group and an amino group, a formylamino group, and a carboxy lower alkanoylamino group, and B has the same meaning as above) under heating. After preparing a pyridone compound represented by the general formula (however, the symbols have the same meanings as above), if the group R4 is not protected, it is protected and treated with a conventional sulfurizing agent (e.g. , Lawesson's reagent) and then removing the protecting group from the product.

At this time, if the reaction between the chelidonic acid and the amine compound (V) is heated to a high temperature (for example, 130 to 200°C), the pyridone compound (V
On the other hand, if the reaction is carried out at a lower temperature than this, a pyridone compound in which the N-6 membered ring is substituted with up to two carboxyl groups can be obtained.

On the other hand, the raw material compound (IV) consists of 4-mercaptopyridine and a phenyl compound represented by the general formula % (where X2 represents a reactive residue and the other symbols have the same meanings as above). react or 4-
It can be produced by reacting a halogenopyridine with a thiol compound represented by the general formula % (in which the symbols have the same meanings as above) and, if desired, removing a protecting group from the product.

Furthermore, starting compounds (1111) and (TV) in which R2 is a phenyl group substituted with a formylamino group or a carboxy lower alkanoylamino group, the corresponding aminophenyl compound is prepared by a conventional method, for example, with formic acid or lower alkoxycarbonyl-lower fatty acid. It can also be produced by reacting with a halide and, if necessary, hydrolyzing the product.

Experimental Example Experimental Method The minimum inhibitory concentration (M, 1, C,, g/ml) of the specimen was added to Sensitivity Disk Medium-N using agar plate dilution method (Japanese Society of Chemotherapy Standard Method) ).

Experimental results Pseudomonas aeruginosa of the compounds listed in Table 1 below
P IO2 and Escherichia coli (Escherlc)
hla colt) ML-1410・RG N-82
M for 3, 1. C, are all 0.05gg/na
It was less than l.

Table 1 (I) (However, in the formula, (Z) indicates that the imino group has a (Z)-configuration, and (β) indicates that the 7th carbon atom of the cephalosporin skeleton is In the table below, (S) represents 2-oxopyrrolidine-3
- indicates that the carbon atom at position 3 of the -yl group has the (S)-configuration. Same below. ) Examples ] (1) 18.72 g of chelidonic acid, 15.58 g of 4-aminoveratrol and 100 g of dimethyl sulfoxide
After heating m1 to 160-170°C, the solvent is distilled off. Add chloroform to the residue, extract with diluted hydrochloric acid, make the extract alkaline, and re-extract with chloroform.

After washing and drying the extract, the solvent was distilled off, chloroform-ethyl acetate was added to the residue, and the crystals were collected to give 1-(3
,4-dimethoxyphenyl)-4-pyridone 1B, 38
I got g.

11.1), 168-170°C (2) Product of (1) above 8. Og to methylene chloride 10
After cooling, 17.38 g of boron tribromide was added dropwise. After stirring at the same temperature and at room temperature, the mixture is cooled again, methanol is added to the residue, and the solvent is distilled off. The residue was recrystallized from methanol-ethyl acetate to obtain 9.40 g of 1-(3,4-dihydroxydiphenyl)-4-hydroxypidinium bromide.

1.1), 260-265°C (decomposition) (3) Above (
After stirring 9.40 g of the product from 2), 10.1 g of acetic anhydride, and 100 ml of pyridine at room temperature, the solvent was distilled off. The residue was dissolved in chloroform, washed with water, dried, and the solvent was distilled off. Ethyl acetate-hexane was added to the residue, and the precipitated crystals were collected in a furnace to give 1-(3,4-diacetoxyphenyl)-4-
7.06 g of pyridone was obtained.

Melon, p, l [i2 - 165 °C (4) 7.0 g of the product from (3) above, 120++ dimethoxyethane solution, 1, and 30 ml of pyridine were heated, and then Lawson's reagent [2,4-bis(4-methoxy phenyl)-1,3-dithia-2,4-diphosphethane-2
, 4-disulfide) and reflux.

The solvent was distilled off from the reaction solution, the residue was purified by silica gel chromatography [solvent: chloroform-methanol (15:1)], and the product was washed with ethyl acetate to obtain 1-(3,4-
diacetoxyphenyl)-4-thiopyridone 4.67g
I got it.

111.1), 193-19B”C(5) above (4
), 4 ml of water, 6 ml of methanol and 0.35 g of sodium bicarbonate are stirred under a stream of argon. Hydrochloric acid was added to the reaction solution, the solvent was distilled off, the residue was purified by silica gel chromatography [solvent: chloroform-methanol (5:1)], and the product was washed with ethyl acetate to obtain 1-(3,4- Dihydroxyphenyl)-4-thiopyridone o,aoK was obtained.

m, p, 259-261°C (decomposition) (I3) 0.444 g of the product of (5) above, 7β-[2
-(2-aminothiazol-4-yl)-2(Z)-(
2-Carboxyprobu-2-oximino)acetamide] Cephalosporanic acid disodium salt 0.858s
- and 2.25 i of sodium iodide are added to a mixture of 15 ml of water and 15 ml of acetonitrile. The mixture was stirred at 65-70° C. for 7 hours under an argon stream, and then concentrated under reduced pressure. The concentrated solution is adsorbed on a column filled with a nonionic adsorption resin [trade name: Diaion HP-20, manufactured by Mitsubishi Chemical Industries, Ltd.], washed with water, and eluted with 20% methanol. After concentrating the eluate, the residue was lyophilized to give 7β-(2-(2-aminothiazol-4-yl)-2(Z)-(2-carboxyprobu-2-oximino)acetamide]-3[
1-(3,4-dihydroxyphenyl)-4-pyridiniocothiomethyl-3-cephem-4-carboxylate monosodium salt 0. 1130g was obtained.

1.1), 200℃ (gradual decomposition) I RJ/nuj0'(a++-1): 3350
(br), 178 groups, 18X 1B20, 60O NMR (D20) δ: 1.47 (S, OH), 3.5
2 (d, LH.

J”17.5Hz), 3.70(d, LH, J-17
,5Hz>,5.22(d,LH,J-4,8H
z), 5.73 (d, LH, J-4, 8Hz), 8.8
8 (s, lH), 7.90 (d, 2H, J-[f, 3)
12), 8.50 (d, 28.J-8, 3H2) Example 2 7β-(2-(2-aminothiazol-4-yl)
-2(Z)-[((3S)-2-oxopyrrolidine-3
-yl)oximino]acetamido]cephalosboranic acid 0.787. 15 ml of water and 15 ml of acetonitrile
Add to the mixture of m1 and p! with sodium hydrogen carbonate. 16.4
Adjust to. 0.439 g of 1-U,4-dihydroxyphenyl)-4-thiopyridone and 2.25 g of sodium iodide are added to the mixture, and the mixture is stirred at 65-70° C. for 7.5 hours under an argon stream. The reaction solution is concentrated under reduced pressure, water is added to the residue to remove the precipitate, and the precipitate is washed with tetrahydrofuran. The precipitate was suspended in 20 ml of methanol, stirred at room temperature for 1 hour, heated to 45-50°C, and then ? The number of houses is 7
β-(2-(2-aminothiazol-4-yl)-2
(Z)-(((as)-2-oxopyrrolidin-3-yl)oximino]acetamide) -3-(1-(
3,4-dihydroxyphenyl)-4-pyridiniocothiomethyl-3cephem-4-carboxylate 0.39
2 g was obtained as a yellow powder.

■, p, 220℃ (gradual decomposition) nujol -1 1Rν (am): 3300 (br), 1770
S1690, 18X 62O NMR (DMSO-d6) δ: 2.10-2.50 (
n.

2H), 4.72 (t, IH, J”7.8Hz)
, 5.03 (cl, IH, no 4.9Hz), 5.8
0 (dd, IH, J-4, 9 and 8.3Hz), 6.7
7 (s, IH), 8.18 (d, 2H, J-6, 0H
z), 8.76(d, 2i(, J-6, 0Hz)
Examples 3 to 8 (1) Corresponding raw material compounds to Example 1-(1) to (5)
), the compounds listed in Table 2 below were obtained.

(However, in Example 4-(1), 4-aminophenol was used instead of 4-aminoveratol, and Example 5-(1)
) Since tyramine hydrochloride was used in Example 1-(
Step 2) was not performed. Also, Example 8-(1)
Since methyl 2-acetoquine-5-aminobenzoate was used as the raw material compound, the steps of Example], -(2) and (3) were not performed. ) (The following is a blank space) Table S CN-B-R2 (II[) (2) By treating the product of (1) above in the same manner as in Example 1-(8) or Example 2, Table 3 below is obtained. The described compound was obtained.

(However, during the reaction, adjust the pH to 6.1 to 6 with sodium hydrogen carbonate.
．． I adjusted it to 5. Further, in Example 6-(2), the reaction was carried out without adding sodium iodide. ) (hereinafter blank) Example 9 (1) 5-amino-2-phenylbenzoxazole,
Example 1-(1) of chelidonic acid and dimethyl sulfoxide
) and (4) to obtain 1-(2-phenylbenzoxazol-5-yl)-4-thiopyridone.

m, p, 270-272°C (2) Add concentrated hydrochloric acid to the product of (1) above and reflux it. After cooling, add activated carbon and filter. After concentrating the solution, the residue is neutralized with a saturated aqueous sodium bicarbonate solution, and the precipitated crystals are taken to the bottom of the furnace. The crystals were purified by silica gel chromatography [solvent: chloroform-methanol (15:2)], and the product was washed with ethanol to obtain 1.511 g of 1-(3-amino-4-hydroxyphenyl)-4thiopyridone. .

i, p, 222-226°C (3) The product of (2) above and 7β-[2-(2aminothiazol-4-yl)-2C'l')-CC<3
8) -2-oxopyrrolidin-3-yl)oxyimino]acetamido]cephalosporanic acid in Example 1-<8
) or treated in the same manner as in Example 2 to obtain 7β(2-(2-aminothiazol-4-yl)2(Z)-(((3S)-
2-oxopyrrolidin-3-yl)oximino]acetamido)-3-(1(3-amino-4-hydroxyphenyl)-4pyridinio]thiomethyl-3-cephem-
4-carboxylate was obtained.

m, p, 210°C (gradual decomposition) NMR (DMSO-d6+D20) 6:4.38 (d,
1. ) I, J-14H2), 4.58 (d, LH, J
-14)1z), 4.85(t,lH,J-6,8)1
2), 5.05 (d, LH, j-4, 4H2), 5.6
5 (t, iH, J-4, 4H2), L04. (d, 2)
1. J-61 (Z), 8.88 (d, 21 (, no 61
(z) Example 10 (1) 1. - (3-Amino-4-hydroxyphenyl)-4-thiopyridone is refluxed in formic acid, ethyl acetate is added and the precipitate is counted. The crystals were recrystallized from dimethylformamide-isopropyl ether to give 1-
(3-formylamino-4-hydroxyphenyl)-
4-thiopyridone was obtained.

n, p, 239-240 (decomposition) (2) The product of (1) above and 7β-C2-C2-aminothiazol-4-yl)-2(Z)-[((3S
)-2-oxopyrrolidin-3-yl)oximino]
Acetamide] Cephalosporanic acid Example 1-(6)
Or treated in the same manner as in Example 2 to obtain 7β-[2-(2-aminothiazol-4-yl)2(Z)-[((3S)-
2-oxopyrrolidin-3-yl)oxyimino]acetamide)-3-(1(3-formylamino-4-hydroquinphenyl)-4-pyridiniocothiomethyl-3-
Cephem-4-carboxylate was obtained.

i, p, 190°C (gradual decomposition) NMR (DMSO-d6+D20) δ: 4.44 (d,
lH, J-15! (z) , 4.60 (d, LH, J-
15Hz), 4.77 (t, IH, J-6, 8H2),
5.02 (d, LH, J-4, 4112), 5.81 (
d, IH, J-4, 4Hz), 6.82 (s, LH),
8.16 (d, 2H, 8, 3Hz), 8.37 (s, I
H), 8.74 (d, 2H.

J-6,3Hz) Example 11 (1) 6-amino-2-phenylbenzoxazole was added to Example 1-(1) and (4) and Example 9-(2
) to obtain 1-(4-amino3-hydroxyphenyl)-4-thiopyridone.

1! , p, 2JB~219℃ (decomposition) (2) above (1
) and 7β-C2-C2 aminothiazole-4
7β- [2(2-aminothiazol-4-yl)-2(Z)(((3S)-2-oxopyrrolidine-
3-yl)oximino]acetamido)-3-(1-
(4-Amino-3-hydroxyphenyl)-4-pyridiniocothiomethyl-3-cephem-4.carboxylate was obtained.

m, p, 245°C (gradual decomposition) NMR (DMSO-d6) δ: 4.50 (m, 211), 4.72 (t-
11ke, l11), 5.03(d, 1HJ=4.9H
z), 5.60 (dd-11ke, LH),
8.77 (s, IH), 8.14 (d, 2H,
J=6.4Hz), 8.73(d, 2H, J-6,
4H2), 9.54 (d, IH, J-7, 8H2) Example 12 (1) 1-(4-amino-3-hydroxyphenyl)-
4-Thiopyridone was treated in the same manner as in Example 1O-(1) to obtain 1-(4-formylamino-3-hydroxyphenyl)-4-thiopyridone.

i, p, 232-234°C (decomposition) (2) The product of (1) above and 7β-C2-C2-aminothiazol-4-yl)-2(Z)-[((3S
)-2-oxopyrrolidin-3-yl)oximino]
Acetamide]cephalosporanic acid was treated in the same manner as in Example 1 (6) or Example 2 to obtain 7β-[2-(2-aminothiazol-4-yl)-2(Z)C(<38>-2-
Oxopyrrolidin-3-yl)oxyimino]acetamido)-3-(1-(4-formylamino-3-hydroxyphenyl)-4pyridinio]thiomethyl-3-cephem-4-carboxylate was obtained.

m, p, 230°C (gradual decomposition) NMR (DMSO-d6) δ: 2.0 to 2.6 (+s, 2H), 4.72 (t-1
1ke, 111), 5.05 (d, 111.J-4,
911z), 5.63 (dd, lH, J-7,8 and 4.9Hz), 6.77 (s, LH), 7.09
~7.27 (+, 3) 1) , 8.13 (d, 2)
1. J-8, 4) 1z), 8.85 (d, 2H, J-
6,4Hz) Example 13 (1) 1-(3-amino-4-hydroxyphenyl)-
4-thiopyridone 1.12g, potassium carbonate 1.22g
, 10 ml of dimethylformamide and 1.0 ml of ethylmalonyl chloride. ．． After reacting 23 g at room temperature for 1 hour, the solvent was distilled off, water was added to the residue, and after washing, 2.0 g of potassium carbonate was added to the aqueous layer.
Add Og and heat. 1. Make the reaction solution acidic with hydrochloric acid. The precipitated product was separated, treated with an aqueous sodium hydrogen carbonate solution, and then acidified with hydrochloric acid. .

111.1), 244-247°C (decomposition) (2) The product of (1) above and 7β-[2-(2~aminothiazol-4-yl)-2(Z)-[((3S)- 2-oxopyrrolidin-3-yl)oximino]acetamide]cephalosporanic acid was treated in the same manner as in Example 1-(6) or Example 2 to obtain 7β-[2-(2-aminothiazol-4-yl). -2(Z)(((3S)-'2-oxopyrrolidin-3-yl)oximino]acetamide)
-3-N-(3~(carboxyacetylamino)-4
-hydroxyphenyl)-4-pyridiniocothiomethyl-3-cephem-4-carboxylate monosodium salt was obtained.

1-p, > 200°C (gradual decomposition) NMR (DMS
O-d6) δ: 4.513 (rI, 2H), 5.04 (
d, 11 (, no 4.9Hz), 5.81 (dd
, LH, J-8,3 and 4.9H2), 8.77 (s
.

LH), 7.1-7.3 (m, 5H), 8.22 (
d, 2H, J-8, 4Hz), 8.78 (d, 2H,
J-6) 1z) Example 14 (1) 6.2 g of 4-mercaptopyridine, 2.3 g of 62% sodium hydride and 40 m of dimethylformamide
1 is stirred at 5-10°C. 17.6 g of toluenesulfonic acid 3,4-dimethoxyphenethyl ester was added dropwise to the reaction mixture, and after stirring at room temperature, the mixture was poured into water and extracted with ethyl acetate. The solvent was distilled off from the extract, and the residue was purified by silica gel chromatography (solvent: ethyl acetate) to obtain 9.89 g of 4-(3,4-dimethoxyphenethyl)thiopyridine.

m, p, 42-44°C (2) 9.4 g of the product from (1) above was added to Example 1- (2
) to obtain 7.58 g of 4-(3,4-dihydroxyphenethyl)thiopyridine.

rA, p, 128-129°C (3) The product of (2) above and 7β-[2-(2-aminothiazol-4-yl)-2(Z)-(2-carboxyprobu-2-oximino) Acetamide] Cephalosporanic acid sodium salt was treated in the same manner as in Example 1-(8) or Example 2 to obtain 7β[2-(2-aminothiazol-4-yl)2(Z)-(2-carboxylic acid). Probu-2-oximino)acetamide] -3-(4-
(3,4-dihydroxyphenethylthio)-1-pyridiniocomethyl-3-cephem-4-carboxylate was obtained.

m, p, 200°C (gradual decomposition) NMR (DMSO-d6) δ: 1.46 (s, 8) 1), 5.04 (d, 1.H
, J=14Hz), 5.30(d, IH, J-14H
z), 5.24 (d, IH, J=4.8Hz), 5.
78 (d, IH, J-4, 8Hz), fi, 8B
(s, IH), 7.48 (d, 2H, J=6Hz)
, 8.38 (d, 211.J-[111z) Example
15 (1) 4-chloropyridine 3.00. , 3.4-dimethoxythiophenol 3.40g, potassium carbonate 5.6C
1 g and 40 ml of dimethylformamide are reacted at room temperature.

The reaction solution was poured into water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off, and the residue was chromatographed on silica gel (
Solvent: ethyl acetate) to obtain 4.67 g of 4(3,4-dimethquinphenyl)thiopyridine.

11.1), 59-61°C (2) Product of (1) above 4.87. Example 1- (
It was treated in the same manner as in 2) to obtain 3.92 g of 4-(3,4-dihydroxyphenyl)thiopyridine.

m, p, 192-193°C (3) The product of (2) above and 7β-(2-(2aminothiazol-4-yl)-2(Z)-(2-carboxyprobu-2-oximino)acetamide ] Cephalosporanic acid disodium salt was treated in the same manner as in Example 1-(6) or Example 2 to obtain 7βC2-C2-aminothiazol-4-yl)2(Z)-(2-carboxyprob-
2-oximino)acetamide) -3-(4-(
3,4-dihydroxyphenylthio)-1-pyridiniocomethyl-3-cephem-4-carboxylate was obtained.

ffi, 190℃ (gradual decomposition) NMR (D20
) δ: 1.45 (s, 8H), L12 (d, IHj-1
7) 1z), 3.58 (d, IH, J=I7Hz),
5.0 [i (d, IH, J-15Hz), 5.25 (d
, IH,J=4.9Hz), 5.34(d,IH,J-
+511z), 5.81(d, IILJ-4,9Hz)
, 6.90 (s, IH) , 7.43 (d, 211
J”611z), 8.45(d, 211.J-6H
z) Example 16 (1) 4-methoxythiophenol, 4-chloropyridine hydrochloride and sodium hydrogen carbonate were added to Example 15-(1
) and Example 1-(2) to produce 4-(4
-hydroxyphenyl)thiopyridine was obtained.

+! , p, 236-239°C (2) The product of (1) above and 7β-[2-(2aminothiazol-4-yl)-2(Z)[((33) -
2-oxopyrrolidin-3-yl)oximino)acetamido]cephalosporanic acid was treated in the same manner as in Example 1-(6) or Example 2 to obtain 7β-[:2-(2-aminothiazol-4yl)- 2(Z) −(((3
S) -2-oxopyrrolidin-3-yl)oximino]acetamido)-3-C4-(4-hydroxyphenylthio)-1-pyridinio]methyl-3-cephem=4-carboxylate was obtained.

m, p, 200°C (gradually decomposed) NMR (D O + DMSO-d6) δ: 4.84 (
t, Ill, J-811z), 5.10 (d,
IH, I-4, 811z), 5.72 (d, IH
, J-4,8Hz), 6.82 (s.

III), 7.45 (d, 211.J-61
1z), 8.68 (d, 211°j-611z) Examples 17 and 18 (1) By treating the corresponding raw material compounds in the same manner as in Example 14-(1) and Example 1-(2), The compounds listed in Table 4 below were obtained.

(However, in Example 17, 4-methoxybenzyl chloride was used instead of toluenesulfonic acid 3,4-dimethoxyphenethyl ester, and in Example 18, methanesulfonic acid 4-
Methoxyphenethyl ester was used as the starting compound. ) (The following is a blank space) Table (2) The product of (1) above was treated in the same manner as in Examples 1-(6) or Example 2 to obtain the compounds listed in Table 5 below.

(However, in Example 1.7-(2), the reaction was carried out by adjusting the pH of the reaction solution to 6.1 to 6.5 with sodium hydrogen carbonate.) (Hereinafter, blank spaces) Examples 19 to 25 By treating the corresponding raw material compounds in the same manner as in Example 1-(6) or Example 2, the compounds listed in Table 6 below were obtained.

(However, in Examples 21, 24 and 25, the pH of the reaction solution was adjusted to 6°1 to 6.5 with sodium hydrogen carbonate,
In Examples 20 and 23, the pH was adjusted to 6.5 with a phosphate buffer solution.
The reaction was carried out by adjusting the ) (Left below) Example 26 (1) To a solution of 22.2 g of 2,3-dimethoxy-5-nitrobenzaldehyde in 100 ml of acetone was added 21.1 g of potassium permanganate in 200 ml of water. After adding the solution dropwise while keeping the internal temperature at 35-45℃,
(2) Stir at 60°C for 5 hours. Add 15 methanol to the reaction solution.
After adding m1 and separating excess potassium permanganate, it was filtered to remove insoluble matter, the filtration was concentrated, acetone was distilled off, the p was adjusted to 11 with concentrated hydrochloric acid, and the precipitated crystals were
The residue was taken out, washed with water, and dried to obtain 21.4 g of 2,3-dimethoxy-5-nitrobenzoic acid.

11, I), 176-177°C (2) 10% palladium-carbon (wet catalyst) 2.0% in a solution of 20.4 g of 2,3-dimethoxy-5-nitrobenzoic acid dissolved in 330 ml of ethanol and 70 ml of acetic acid.
g was added, stirred for 3 hours under hydrogen pressure of 2.0 to 3.8 atm, filtered off the catalyst, concentrated the furnace solution, and washed the obtained crystals with a hexane-isopropyl ether mixture.
17.2 g of 3-dimethoxy-5-aminobenzoic acid was obtained.

s, p, 151-152 °C (3) Hydrogen chloride gas was bubbled into a solution of 17.1 sr of 2,3-dimethoxy-5-aminobenzoic acid in 400 ml of methanol for 1 hour while cooling with water, and then 3 hours at room temperature.
Stir for hours. Add 1.5 g of ethyl acetate to the residue obtained by distilling off methanol, adjust the pH to 8 to 9 with a saturated aqueous sodium bicarbonate solution, separate the ethyl acetate layer, wash with water,
After drying over magnesium sulfate, ethyl acetate was distilled off to give methyl 2.3-dimethoxy-5-amino-benzoate l1
1.1 g was obtained.

■、9. 81-62°C (4> Example 1-(
1) to obtain 1-(3,4-dimethoxy-5
-methoxycarbonylphenyl)-4-pyridone14.
9g was obtained.

m, p, 137-138°C (5) 14.6 g of 1-(3,4-dimethoxy-5-methoxycarbonylphenyl)-4-pyridone and 48%
A mixture of 200 ml of hydrobromic acid was heated under reflux for 4 hours, concentrated to half a volume, and the precipitated crystals were filtered out, washed with ether, and dried to give 1-(3,4-dihydroxy-5-carboxyphenyl). )-4-pyridone hydrobromide (14.2 g) was obtained.

Lp, 273-274.5℃ (6) 1- (3,4-
Chlorine hydrogen gas was blown into a solution of 14.1 g of dihydroxy-5-carboxyphenyl)-4-pyridone hydrobromide for 1 hour while cooling with water, and the mixture was then heated under reflux overnight. To the residue obtained by distilling off the solvent, an aqueous sodium bicarbonate solution was added to adjust the pH to 8-9, and this was diluted with chloroform-
Extracted with methanol. After drying the organic layer over magnesium sulfate, the solvent was distilled off to obtain 0.6 g of 1-(3,4-dihydroxy-5-methoxycarbonylphenyl)-4-pyridone I.

m, p, 254-255°C (7) 10.5 g of 1-(3,4-dihydroxy-5-methoxycarbonylphenyl)-4-pyridone.

A mixture of 53 ml of acetic anhydride and 110 ml of pyridine was added to 6
After stirring for two nights at 0°C, the solvent was distilled off. The residue was dissolved in chloroform, washed with water, dried, and then the solvent was distilled off. The residue obtained was purified with a silica gel column using chloroform-methanol to obtain caramel-like 1. - (3,4-
diacetoxy-5-methoxycarbonylphenyl)-4
-9.2 g of pyridone were obtained.

(g) After stirring a mixture of 3.06 g of 1-(3,4-diacetoxy-5-methoxycarbonylphenyl)-4-pyridone and 10.2 ml of phosphoryl trichloride at 70°C for 15 minutes, excess phosphoryl trichloride was completely removed. Distilled into.

This product was added with 41 ml of chloroform and 18% chloroform under water cooling.
Add 41 ml of sodium hydrogen sulfide water, stir vigorously for 15 minutes, and then separate the layers. The organic layer obtained is washed with water, dried over magnesium sulfate, and the solvent is distilled off to give a caramel-like 1-
2.65 g of (3,4-diacetoxy-5-methoxycarbonylphenyl)-4-thiopyridone was obtained.

(9) To a suspension of 0.72 g of 1-(3,4-diacetoxy-5-methoxycarbonylphenyl)4-thiopyridone in 20 ml of acetonitrile, 10 ml of IN sodium hydroxide was added while cooling with water under a stream of argon. After stirring at room temperature for 3.5 hours, the pH was adjusted to 7.0 with 10% hydrochloric acid, and 7β-[2-(2-aminothiazole-
4-yl) -2(Z) -[((3S)2-oxopyrrolidin-3-yl)oxyimino]acetamide]
Add 0.81 g of Cepharosporanic acid, 2.25 g of sodium iodide and 10 ml of water, and adjust the pH to 6.8 with acetic acid.
7 and reacted in the same manner as in Example 1-(6).
β-[2-(2-aminothiazol-4-yl) -
2(Z) -(((3S)-2-oxopyrrolidin-3-yl)oxyimino)]acetamide) -
3-[1-(3,4-dihydroxy-5-carboxyphenyl)-4-pyridiniothio]methyl-3-cephem-4-carboxylate monosodium salt 0.36 g
I got it.

11.1), > 220°C (decomposition) nujol -1 1Rν (cm): 3330.1760.169
0, 1ax 1620.1600 Mass (F A B ) m/z: 750 (MH”
), 72g(Mt(''-Na)NMR(D,,O
)δ.

2.30 (LH, m), 2.52 (IH, m)
, 3.37 (LH, d.

J-17,6Hz), 3.42 (2H,i)
, 3.71 (IH, d.

J=17.6Hz), 4.25 (lH,d,J-
14.6Hz), 4.35 (IH, d, J=14.6H
z), 4.99 (IH, dd, J-7, 5Hz),
5.20 (lit, d, J=4.611z), 5
．． 75 (III, d, J-4,611z), 6.
93 (ltl, s), 7.12 (hl, s)
, 7.41 (LH, S), 7.84 (211, dJ
-8,1Ilz), 8.46(2)I.

d, J=8.111z) Example 27 (1) A mixed solution of 2 g of chelidonic acid IG and 12.3 g of 4-aminoveratrol in 700 ml of water is gently heated under reflux for 24 hours, and then concentrated under reduced pressure. Add methanol to the residue, filter and remove the precipitate, dissolve the precipitate in 400 ml of warm water, treat with activated carbon, concentrate again, add methanol, filter the precipitated crystals, remove and dry. 1-(3,4-dimethoxyphenyl)
17.2 g of -2,6-dicarpoxy 4-pyridone was obtained.

m, p, 170-175°C (2) 1-(3,4-dimethoxyphenyl)-2,
Example 1: 3.19 g of 6-dicarpoxy 4-pyridone
- The product obtained by the same treatment as in (2) and (3) was dissolved in 30 ml of dimethylformamide and cooled on ice. To this, 11.4 g of methyl iodide and 6.9 g of potassium carbonate
After stirring at room temperature for 18 hours, ethyl acetate and water were added to separate the layers. The ethyl acetate layer was washed with water, dried over magnesium sulfate, the solvent was distilled off, and the resulting residue was purified using a silica gel column (eluent: ethyl acetate-chloroform). acetoxyphenyl)-2
,8-dimeI-xycarbonyl-4-pyridone! , 55
．． I got it.

m, p, 110-112°C (3) 1-(3,4-diacetoxyphenyl)-2
, 6-Simethoxycarbonyl-4-pyridone 5.35g
was processed in the same manner as in Example 1-(4) to obtain 1-(3,4-
5.04 g of diacetoxyphenyl-2,6-simethoxycarbonyl-4-thiopyridone was obtained.

Table, 9.150~151℃ (4) 15ml of methanol - 1 in 10ml of water (3
A solution of 2.10 g of ,4-diacetoxyphenyl)-2,8-dimethoxycarbonyl-4-thiopyridone and 2.78 g of potassium carbonate is heated under reflux for 4 hours and then concentrated under reduced pressure. The residue was purified by chromatography to obtain crude 1-(3,4-dihydroxyphenyl)-2,
1.38 g of 6-dicarpoxy 4-thiopyridone was obtained.

(5) 0.8 g of crude 1-(3,4-dihydroxyphenyl)-2,8-dicarboxy-4-thiopyridone obtained as above and 7β-[2-(2-aminothiazole-4- ) −2(Z)−[((3S) −
2-oxopyrrolidin-3-yl)oxyimino]acetamido]cephalosporanic acid 1.05. Example 1
- 7β-(2-(2-aminothiazol-4-yl)-2(Z)(((3S)
-2-oxopyrrolidin-3-yl)oxyimino)
] 0.66 g of disodium salt of acetamido)-3-(1-(3,4-dihydroxyphenyl)-2,6-dicarpoxy 4-pyridiniocothiomethyl-3-cephem-4-carboxylate was obtained.

gl, I), 160°C (decomposition) I Rνnu"'(cm-'): 3300-32
00.1780, ax 1680.1640.1595 Mass (F A B ) s/z: 794 (MH-
Na + H) NMR (δ, D20): 2.2-2.4 (IH, m), 2.5-2.7 (LH,
a), 3.3-3.5 (211, rA), 3.48 and 3.77 (2H, ABq, J-18Hz), 4.
25 and 4.34 (2H, ABq, J-14Hz), 5
．． 06 (111, dd, J-7 and 811z), 5.2
5 (111, d, J-511z), 5.82 (11Ld
, J-512), 6.84 (111, dd, J-1,5
and 811z), 6.96 (111,d, J-1,51
12), 6.98 (111, d, J-8112), 7.
07(211,8), 7.08(lIl,s) Example
28 (1) A mixture of 20 g of 4-hydroxypyridine, 49.1 g of potassium carbonate and 40.3 g of bromoacetic acid methyl ester in 270 ml of acetone was heated under reflux for 5 hours. After cooling, inorganic substances were removed by filtration, and the solvent was distilled off from the furnace solution. Chloroform-ethyl acetate was added to the obtained residue to elute soluble substances. The crystals obtained by distilling off chloroform-ethyl acetate were recrystallized from chloroform-methanol-isopropyl ether to obtain 11.5 g of 1-methoxycarbonylmethyl-4-pyridone.

m, p, 184-167 °C (2) 1.6 M n- in 60 ml of tetrahydrofuran
In a solution of lithium diisopropylamide prepared from 44.3 ml of butyllithium and 7,0 g of diisopropylamine, 11.0 ml of 1-methoxycarbonylmethyl-4-pyridone was dissolved in 10 ml of hexamethylphosphoryltriamide at -40° C. under a stream of argon. ．． A solution of was added dropwise, and after the addition, the temperature was gradually raised to room temperature. This solution was cooled again to -40°C and heated to 60°C in tetrahydrofuran.
3.4-dimethoxybenzyl chloride H in m1, 3g
A solution of was added dropwise, and after the addition, the mixture was stirred at room temperature overnight. Water was added to the mixture, extracted with chloroform, the chloroform layer was washed with water, dried over magnesium sulfate, the solvent was distilled off, and the resulting residue was purified using a silica gel column (
The eluent was chloroform-methanol)l, 1-[1-
5.7 g of methoxycarbonyl-2-(3,4-dimethquinphenyl)ethyl]-4-pyridone was obtained as crystals.

ffi, p, 193-195°C (3) 1-[1-methoxycarbonyl-2-(3,4-
dimethquinephenyl)ethyl] -4-pyridone was treated in the same manner as in Example 1- (2) and (3) to produce 1[1-methquinecarbonyl-2-(3,4-diacetoxyphenyl)ethyl] - 665 g of 4-pyridone were obtained as a powdered product.

(4) 1-[1-methoxycarbonyl-2-(3,
4-Diacetoxyphenyl)ethyl]-4-pyridone (4.9 g) was treated in the same manner as in Example 1-(4) to obtain 1[1
-Methoxycarbonyl-2-(3,4-diacetoxyphenyl)ethyl] 3.2 g of -4-thiopyridone was obtained as crystals.

m, p, 121-123°C (5) 0.7 1-[1-methoxycarbonyl-2-(3,4-diacetoxyphenyl)ethyl J-4-thiopyridone dissolved in 20 ml of water and 15 ml of acetonitrile
A solution of 8 g and 0.58 g of sodium hydrogen carbonate was stirred for 2 hours at 60°C under an argon stream, and after cooling, the pH was adjusted to 6.70 with acetic acid.
．． 7β-[2(2-aminothiazol-4yl)-2(Z)(((3S)
A solution of 0.79 g of -2-oxopyrrolidin-3-yl)oximino[acetamide]cephalosporanic acid and 2.25 g of sodium iodide were added, and the pH was adjusted to 6 with acetic acid.
As 30, 7β was reacted in the same manner as in Example 1-(6).
-C2-(2-aminothiazol-4-yl) -2
(Z) -[((3S)-2-oxopyrrolidin-3-yl)oximino]acetamide)-3-(1
-(1-carbonyl-2-(3,4-dihydroxyphenyl)ethyl)-4-pyridinio] -thiomethyl-3
-Cephem-4-carboxylate monosodium salt 0.42 g was obtained as a mixture of diastereomers.

1! , p, > 200℃ (decomposition) I Rν""'(am-'): 3300 (br)
, 1780, own aX 1690.1625 (br) Mass (F A B ) TI/z: 800 (MN
a), 778 (Ml white NMR (DMSO-d6) δ
: 2.00-2.80 ('2H, +a), 3.
10~3.60 (f3H, 11), 4.30~
5.10 (5H, m), 5.60 (LH, Shin)
, 8.30 (LH, t-11kc), θ, 42~6
．． 54 (2H, m), 6.75 and 6.77 (L
H, 5X2), 7.28 (2Lbr), 7,99 (3
H, m), 8.50 (2H, d, J-5,9Hz
), 8.60-9.20 (2H, br, +g),
9,53 and 9.57 (IH, dX2゜J-7,8H
z and 7.8f (z) Patent applicant Tanabe Pharmaceutical Co., Ltd.

Claims (6)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (However, R^1 is a hydrogen atom, a lower alkyl group that may be substituted with a carboxy group, or an oxopyrrolidyl group, R
^2 is a phenyl group having 1 to 3 substituents selected from a hydroxyl group, a carboxy group, an amino group, a formylamino group, and a carboxy lower alkanoylamino group, and A is a ▲ mathematical formula, chemical formula, table, etc. ▼ or ▲ mathematical formula , chemical formulas, tables, etc. A group shown by ▼, whose N-6-membered ring moiety may be substituted with up to two carboxyl groups, and B is a bond or -CH_
2-, -CH_2-CH_2-, or ▲ mathematical formula, chemical formula,
Cephalosporin compounds or pharmacologically acceptable salts thereof. (2) The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R^1 is a hydrogen atom, a methyl group, a carboxyisopropyl group, or a 2-oxopyrrolidyl group. (3) Claim 2, wherein R^1 is a carboxyisopropyl group or a 2-oxopyrrolidyl group, and R^2 is a 2,3-dihydroxyphenyl group or a 3,4-dihydroxyphenyl group.
The described compound or a pharmaceutically acceptable salt thereof. (4) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (However, R^1 is a hydrogen atom, a lower alkyl group that may be substituted with a carboxy group, or an oxopyrrolidyl group, R
^3 represents an optionally protected amino group, X^1 represents a reactive residue) or its salt, and the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (III) or ▲ Mathematical formula , chemical formulas, tables, etc.▼(IV) (However, R^2 is a phenyl group having 1 to 3 substituents selected from a hydroxyl group, a carboxy group, an amino group, a formylamino group, and a carboxy lower alkanoylamino group,
Is B a bond, -CH_2-, -CH_2-CH
_2-, or ▲ represents a group shown by ▼, which has a mathematical formula, chemical formula, table, etc., and the N-6-membered ring portion thereof may optionally be substituted with up to 2 carboxyl groups) Thiopyridone represented by or react with a thiopyridine compound or a salt thereof, and when R^3 is a protected amino group, remove the protecting group of the amino group from the product,
Then, if necessary, by converting the product into a pharmacologically acceptable salt, a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (However, R^1, R^2 and B are the same as above) A is a group represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and in some cases, the N-6-membered ring group moiety has up to two A method for producing a cephalosporin compound or a pharmacologically acceptable salt thereof. (5) General formula ▲ Numerical formulas, chemical formulas, tables, etc. a phenyl group having
Is B a bond, -CH_2-, -CH_2-CH
_2-, or ▲Represents a group shown by ▼, which has a mathematical formula, chemical formula, table, etc., and whose N-6-membered ring portion may optionally be substituted with up to 2 carboxyl groups) Thiopyridone compound or its salt. (6) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^2 has 1 to 3 substituents selected from hydroxyl group, carboxy group, amino group, formylamino group, and carboxy lower alkanoylamino group) a phenyl group having
Is B a bond, -CH_2-, -CH_2-CH
_2-, or ▲Represents a group shown by ▼, which has a mathematical formula, chemical formula, table, etc., and whose N-6-membered ring portion may optionally be substituted with up to 2 carboxyl groups) Thiopyridine compound or its salt.