JPS5850206B2 - New derivatives of cephalosporin compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel cephalosporin derivative represented by the general formula or a salt thereof.

In the compound of the above general formula, A is an isothiazolyl group represented by the formula ((in the formula, Ra and Rb each mean a hydroxyl group, a carboxy group, or a cyano group)), and R is a hydrogen atom or a lower alkyl group. means base.

Among the isothiazolyl groups represented by A, those having a hydroxyl group at the 31-position include keto-enol isomers represented by the following formula, and the present invention includes both of these.

The enol form, the keto form, and the salt of the compound represented by the above general formula (I) include pharmaceutically acceptable non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, ammonium salts, and synchromesh salts. Examples include salts with organic bases such as hexylamine salts, cyclohexylamine salts, trimethylamine salts, triethylamine salts, ethanolamine salts, ornithine salts, and lysine salts.

Cephalosporin derivatives (I) provided by the present invention
) or its salts are new compounds that have antibacterial activity against both Duram positive and negative bacteria, and are particularly effective against the latter, making them useful as pharmaceuticals, feed additives, preservatives for foods, and chemical products. It is.

The compound represented by the general formula (I) can be produced by the following method.

(In the formula, X means a halogen atom.

Moreover, A and R have the above-mentioned meanings.

) The reaction for producing the object compound (I) of the present invention by the above method involves using an alkali metal salt of mercaptoisothiazole, which may have a substituent on the 7-valoacetamidocephalosporin derivative (II-a) or a salt thereof. It is done by making it work.

The reaction is usually carried out in a solvent.

The solvent is not particularly limited as long as it does not participate in the reaction; for example, water, methanol, acetone, tetrahydrofuran, dimethylformamide, or a mixed solvent thereof may be used.

The reaction is also preferably carried out at room temperature or under cooling in the presence of a base.

For the compound (III-a), the mercapto group of mercaptoisothiazole can usually be used as an alkali metal salt, but when used as is, it can be used as a base such as triethylamine, N.N--)methylaniline, N-
The presence of aliphatic, aromatic or heterocyclic bases such as ethylmorpholine, pyridine, collidine, 2,6-lutidine or alkali metal carbonates or bicarbonates such as sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc. It is done below.

Examples of the halogen atom for X in the 7-valoacetamidosephalosporin derivative (II-a) include a chloro atom, a prohyroatom, and a fluorine atom.

The ratio of compounds (II-a) and (m-a) used in this reaction is 1 mole of (II-a) to 1 mole of In-a).
~2 mol is suitable.

Isolation of the product from the reaction solution is carried out by conventional methods, such as separation by chromatography or extraction with a solvent.

These compounds can be converted into their non-toxic salts by conventional methods.

A commonly used method is, for example, by adding an n-butanol solution of alkali metal 2-ethylhexanoate to these compounds, and then adding an organic solvent with different solubility such as ether or ethyl acetate. Alkali metal salts of compounds, also dicyclohexylamine,
By adding and reacting an organic base such as triethylamine, cyclohexylamine, trimethylamine, arginine, lysine, ornithine, or jetanolamine in an equal or small excess amount, the organic base of the target compound of the present invention can be further added with aqueous ammonia. There is a method to obtain ammonium salt.

Next, the manufacturing method of the present invention will be specifically explained with reference to Examples.

Although most of the isothiazole derivatives used as raw materials in the following examples are compounds that have not been described in literature, they are based on 4-cyano-3-hydroxy-5-mercaptoisothiazole, which is a known isothiazole derivative. Manufacturing method (W
, RoHatchard et al., J.Org., Chem.
, (28), 2164), or by further treating the thus obtained isothiazole derivative by a conventional method.

Example 1 Disodium salt of 4-cyano-3-hydroxy-5-mercaptoisothiazole 150 mI? methanol 5m
A solution of 250 ml of 7-bromoacetamido-3-(1-methyltetrazo*-54l)thiomethyl-A3-cephem-4carboxylic acid dissolved in 4 methanol was added dropwise to this solution under water cooling.

Stir at the same temperature for 1 hour, then at room temperature for another 1 hour.

After the reaction, the reaction solvent was distilled off under reduced pressure, and a small amount of water was added to make a 5%
Adjust the pH to 1 with hydrochloric acid.

Extraction is performed with a mixture of n-butanol and ethyl acetate (volume ratio 1:1), and the organic layer is washed with water and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate.

The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography and eluted with a mixture of chloroform-methanol-formic acid (volume ratio 80:20:3) to obtain 7-
120 ml of (4-cyano-3-hydroxyisothiazol-5-yl)thioacetamido-3-(1-methyltetrazol-5-yl)thiomethyl-A3-cephem-4-carboxylic acid are obtained.

Example 2 Suspend 270 μ of 4-carboxy-5-ethylthio-3-hydroxyisothiazole in 10 μm of liquid ammonia, cool to −50° C., add ioo μ of metallic sodium, and stir at −50 to −33° C. Stir for 30 minutes.

Liquid ammonia was distilled off, the resulting residue was dissolved in 20 rnl of methanol, and 562 μl of 7-promoacetamido-3-(1-methyltetrazol-5-yl)thiomethyl-A3cephem-4-carboxylic acid was dissolved in methanol under water cooling. 1 oml of the solution was added dropwise, stirred for 30 minutes under water cooling, and then returned to room temperature and stirred for 30 minutes.

After the reaction is completed, the pH is adjusted to 4 with 4N hydrochloric acid, and the reaction solvent is distilled off under reduced pressure.

Water was added to the residue, the pH was adjusted to 1 with 4N hydrochloric acid, and the mixture was extracted with 50 ml of a mixture of butanol and ethyl acetate (volume ratio 1:1).

The organic layer was washed twice with water, then once with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

Add 3 Q ml of ether to the residue, filter the precipitate, wash with 20 ml each of ether three times, and dry under reduced pressure to obtain 7-(4-carboxy-3-hydroxyisothiazol-5-yl)thioacetamide 3. -(1-methyltetrazol-5-yl)thiomethyl-A3-cephem-4-
Carboxylic acid powder 529rn9 is obtained.

Nuclear magnetic resonance spectrum (D6-DMSO) δ (ppm)
; 3.32 (2H), 3.66 (2H) 3.90
(2H), 4.26 (2H) 5.04 (IH), 5.62 (2H)

Claims (1)

[Scope of Claims] 1. An isothiazolyl group represented by the general formula (wherein Ra and Rb each independently mean a hydroxyl group, a carboxy group, or a cyano group); A novel cephalosporin derivative represented by (representing a hydrogen atom or a lower alkyl group). 2 A is 4-cyano-3-hydroxyisothiazole-
The compound according to claim 1, which is a 5-yl group. 3. The compound according to claim 1, wherein A is 4-carboxy-3-hydroxyisothiazol-5-yl group.