JPS5835198B2 - New antibacterial compound - 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 above general formula CI, 1, R means a hydrogen atom or a 1-methyltetrazol-5-ylthio group.

Compound CI) provided by the present invention is a completely new cephalosporin derivative with a chemical structure in that it has a 1,3-dichetane ring in the side chain at position 7 of the cephalosporin core, and has excellent antibacterial activity. Therefore, it is promising as an antibacterial agent.

In particular, it has been shown to have excellent efficacy against several important pathogenic bacteria belonging to Durham-negative bacteria.

Therefore, the compound [■] of the present invention is suitable for pharmaceuticals, especially antibacterial agents,
It is useful as a feed additive and preservative.

The compound of the present invention is available as it is or as a salt thereof.

Suitable salts include salts with pharmaceutically acceptable non-toxic bases, such as alkali metal salts such as sodium salts and potassium salts; ammonium salts; dicyclohexylamine salts, cyclohexylamine salts;
Examples include salts with organic bases such as trimethylamino salt, triethylamine salt, ethanolamine salt, ornithine salt, and lysine salt.

: The compound of the present invention or a salt thereof is administered orally or parenterally as an antibacterial agent.

The dosage varies depending on symptoms, body weight, etc., but for adults, one mouthful is usually about 250 to 3000 m9, divided into 3 to 4 doses.

Dosage forms suitable for administration include injections, tablets, capsules, syrups, etc., but when preparing these dosage forms, excipients, preservatives, stabilizers, etc. used in pharmaceuticals must be added. , can be carried out by conventional methods.

According to the present invention, the compound CI) can be produced by the following method.

First method (In the formula, R has the above meaning.

) This method is carried out by treating a cephalosporin compound CI[) having a (4-carboxy-3-hydroxyisothiazol-5-yl)thioacetamide group in the 7-position with a base.

Suitable bases include weakly basic substances such as sodium hydrogen carbonate, potassium hydrogen carbonate, and sodium carbonate.

This reaction is usually carried out in a solvent at room temperature or under cooling.

The solvent is not particularly limited as long as it does not participate in the reaction, but preferably water or water-miscible methanol, acetone, tetrahydrofuran, dimethylformamide, etc. are used alone or in appropriate mixtures.

Isolation and purification of the product from the reaction solution was carried out according to conventional methods.
Extraction with organic solvents, crystallization, and separation and purification by column chromatography are used.

Second method This method is shown by the following reaction formula.

(In the formula, R1 means a hydrogen atom or a protecting group for a carboxy group.

Moreover, R has the above-mentioned meaning. ) The reaction for producing the target compound [I] of the present invention by the second method is a reaction in which a 7-aminocephalosporin derivative [I[) or a salt thereof is reacted with 4-
(carbamoylcarphokymethylene)-1,3-dichetane-2carboxylic acid (IV, 1 or a reactive derivative of the carboxylic acid) to prepare a compound [v], in which R1 is a protecting group for the carboxyl group. Sometimes this is done by then removing it.

In the reaction of the above compounds (III) and (IV), the compound [■] can be converted into a reactive derivative of its carboxylic acid and then subjected to the reaction.

Suitable reactive derivatives include acid norides, mixed acid anhydrides, active esters, active amides, acid anhydrides, acid azides, and the like.

When compound (IV) is used in a free state, a condensing agent may be used.

Suitable condensing agents include N-N'-dicyclohexylcarbodiimide and N-N'-diethylcarbodiimide.

Furthermore, since compound (IV) also has a carboxyl group in the methylene group, this carboxyl group and compound (II
In order to avoid side reactions with I), it is preferable to protect this carboxyl group in advance with a protecting group such as a tert-butyl group or a benzhydryl group.

The reaction between compound [■] and compound (IV) or its reactive derivative is carried out under heating or cooling.

The thus generated cephalosporin compound (V) having a 4-(carbamoylcarboxymethylene)-1,3-dicetan-2-carboxamide group at the 7-position is then led to the target compound CI,l by removing the protecting group. Can be done.

Third method The target compound CI,1 of the present invention can also be produced by the reaction of the following formula.

(In the formula, R2 represents an acetyl group or a carbamoyl group.

) This method involves adding 1-methyl-IH-tetrazol-5-thiol or This is carried out by reacting an alkali metal substituent on the hydrogen of the mercapto group.

The reaction is carried out at room temperature to elevated temperature, usually in a solvent.

Solvents that do not participate in this reaction include, for example, acetone, methylformamide, methanol, ethanol, water, and phosphate buffer*, but these may be used in combination if necessary.

The reaction is preferably carried out near neutrality. As a starting material, ■−
When methyl-IH-tetrazole-5-thiol is used in its free state, it is preferably carried out in the presence of a base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate, a trialkylamine, pirine 7, or dimethylaniline. be.

In order to isolate the product after the reaction is completed, the reaction solution is made acidic and the precipitated product is collected, or a method using solvent extraction is used.

Example 1 7-(4-carboxy-3-hydroxyisothiazol-5-yl)thioacetamido-3(1-methyltetrazol-5-yl)thiomethyl-j3-cephem-4-
300 μl of carboxylic acid in 5% sodium bicarbonate aqueous solution 1
Dissolve in 5ml and 2ml of methanol and stir at room temperature for 6 hours.

After washing this solution with 10rfLl of ethyl acetate, the aqueous layer was separated and acidified with 10% hydrochloric acid solution.
Phanol (volume ratio 1:1) mixture 207711 each
Extract times.

The extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

Ether was added to the residue to solidify it, and the residue was taken and washed with ether to give 7-(4-(carbamoylcarboxymethylene)-1,3-dicetan-2-yl)carboxamide-3-(1-methyltetrazole- 200 μl of 5-yl)thiomethyl-j3-cephem-4-carboxylic acid are obtained.

Nuclear magnetic resonance spectrum (DMSOda) δ (ppm
); 3.72 (2H) H*7-(4-carboxy-3-hydroxyisothiazol-5-yl) of C2
Thioacetamido-3-methyl-J3-cephem-4-
Carboxylic acid 1. (L is 5% sodium bicarbonate aqueous solution 5
Dissolved in 0rfLl and 5rnl of methanol, 1 mL at room temperature.
Stir the time.

After washing this solution with 20 ru of ethyl acetate, the aqueous layer was separated.

The resulting precipitate is acidified with a 10% hydrochloric acid solution and the resulting precipitate is separated from P, washed with water and then with ether.

The obtained crude product was dissolved in a 5% aqueous sodium hydrogen carbonate solution, then reprecipitated by adding a 10% hydrochloric acid solution, washed with water and ether, and dried to obtain 7-(4-(carbamoylcarboxymethylene)-1,3-dichetane). -2yl)carboxamido-3-methyl-J3-cephem-4-carboxylic acid 0.5P is obtained.

Claims (1)

[Claims] (In the formula, R is a hydrogen atom or 1-methyltetrazole-5
- means an ylthio group. ) or its salt with a pharmaceutically acceptable non-toxic base**.