ITMI941228A1 - cephalosporins - Google Patents

Abstract

New cephalosporins of formula I (FORMULA I) in which R represents hydrogen, a cation or an ester group, are prepared from the p-nitrobenzyl ester of 7-phenylacetamido-3-trifluorome tansulfonyloxy-3-cefem-4- acid carboxylic acid by reaction with furan in the presence of a base, subsequent catalytic hydrogenation and any pharmaceutically acceptable salification or esterification. The new products thus obtained are antibiotics with excellent activity.

Description

Description of the industrial invention

The present invention relates to new cephalosporins. More particularly, the invention relates to cycloaddition products of formula I

wherein R represents pharmaceutically acceptable hydrogen, cation or ester group.

Adducts of cephalosporins with furan are described by R. L. Elliott et al. in J. Org. Chem. 1994, 59, 1606-1607, but this reaction always leads to compounds having an unsaturation in the 4,5 position of the cyclohexane.

It has now been found that the corresponding product of cycloaddition which, by removal of the p-nitrobenzyl group by catalytic hydrogenation, gives the compound of formula I (R = H) which can in turn be converted into a pharmaceutically acceptable salt or ester thereof.

It has also been surprisingly found that the compound of formula I, as such or in the form of a salt thereof, has an antibacterial activity higher than that of the unsaturated product described in the literature, at least on most microorganisms.

According to another of its aspects, the present invention relates to a process for the preparation of the compounds of formula I, characterized in that:

(a) it is the p-nitrobenzyl ester of 7-phenylacetami do-3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylic acid of formula II

with furan in the presence of an organic base;

(b) the so obtained cycloaddition product of formula III is submitted

to a catalytic hydrogenation and the compound of formula I thus obtained is optionally transformed into an ester thereof or into a drug salt thereof which is quite acceptable.

Step (a) is carried out at a temperature ranging from 0 to 40 ° C, usually at room temperature, in an ethereal organic solvent such as dioxane or tetrahydrofuran, or of the hydrocarbon type, possibly halogenated, such as hexane, toluene, dichloromethane or 1,1, 1-trichloroethane.

A tertiary amine such as triethylamine, diisopropylethylamine, 4-methylmorpholine, 1-methylpiperidine is preferably used as the organic base.

The reaction is rapid and is completed in 10 + 30 minutes; however, it can be followed by thin layer chromatography (TLC) using a hexane / ethyl acetate mixture (1: 1 v / v). The cycload diction product of formula III is isolated according to the usual techniques, for example by eliminating the by-products by washing with water and evaporating the solvent.

Step (b) is carried out by carrying out a catalytic hydrogenation in the presence of a conventional hydrogenation catalyst. The hydrogen pressure can range from 6.9-103 to 6.9-105 pascals, preferably from 1.4-105 to 3.5-105 pascals.

The hydrogenation takes place in an inert organic solvent of the alcoholic type such as methanol, ethanol or isopropanol, of the etheric type such as dioxane, tetrahydrofuran, or of the saturated hydrocarbon type such as hexane or cyclohexane. The catalysts used are based on palladium, preferably 10% Pd / C.

After 2-6 hours, the removal of the p-nitrobenzyl group and the simultaneous reduction of the double bond of the product of formula III thus obtained is complete. In any case, the progress of the reaction can be followed by TLC and the hydrogenation can be stopped at the end of the reaction.

The product of formula I is thus isolated by conventional techniques, filtering the catalyst, evaporating the solvent, taking up the residue with a suitable solvent, for example ethyl acetate. From this solution the product of formula I, in which R is hydrogen, contained therein is isolated by previous salification with an aqueous solution of a mineral base, for example carbonate or sodium bicarbonate, and subsequent acidification of the mineral salt, for example sodium, thus obtained with an acid, for example hydrochloric acid.

The free acid thus prepared can be salified according to the methods known in the literature, for example transformed into its sodium salt by reaction with sodium ethylhexanoate.

The compound of formula I (R = H) can be transformed into its salts with alkali metals such as sodium or potassium, with alkaline earth metals such as calcium or magnesium, with organic bases such as ethanolamine or tromethamine, or with amino acids such as lysine or arginine.

The esters can be prepared according to conventional techniques starting from the sodium salt or from a salt with an organic base, for example triethylamine, and a suitable chloride or bromide. The methyl ester can be easily prepared from the free acid by reaction with diazomethane.

The cycloaddition product of formula III is a new intermediate useful for the preparation of the saturated compound I, and constitutes another aspect of the present invention.

Some compounds of the invention have been the subject of a preliminary pharmacological investigation. In the "in vitro" tests the compound of formula I (R = H) shows a significant activity towards microorganisms such as Sarcina lutea, Staphylococcus aureus, Bacillus subtilis, Moraxella catarrhalis, Streptococcus pyogenes with an M.I.C. 0.25 to 1 mcg / mg.

The compounds of the present invention have an excellent antibacterial activity and can therefore be used, also thanks to their low toxicity, for the preparation of pharmaceutical compositions for the treatment of Gram-positive and Gram-negative bacterial infections and, to this purpose, they are formulated with conventional excipients for the preparation of tablets, capsules, granules for reconstitution in syrups or drinkable solutions, or injectable solutions for intramuscular administration.

Unit administration doses include from 1 to 5000 mg, advantageously from 20 to 3000 mg, preferably from 50 to 2000 mg of active ingredient each and can be administered from 1 to 5 times a day depending on the severity of the infection.

The following examples illustrate the invention without, however, limiting it.

EXAMPLE 1

(a) In a 250 ml flask, treat at room temperature 3 g (5 mmoles) of 7-phenylacetamido-3-trifluoromethanesulfonyloxy-3-cefem-4-carboxylate of p-nitrobenzyl (formula II) in 50 ml of dichloromethane with 1.45 ml (20 mmol) of furan and 1.02 ml (6 mmol) of diisopropylethylamine. The reaction, controlled by TLC (eluent: hexane / ethyl acetate = 1: 1 v / v), is completed in 15 minutes. The reaction mixture is then diluted with dichloromethane, washed with acidulated water and the organic phase is concentrated, separated and dried on anhydrous sodium sulphate. The product is purified by chromatography on a silica gel column eluting with hexane / ethyl acetate (7: 3 v / v). 1.56 g of product of formula III are obtained. Yield: 60%.

(b) To a solution of 1.4 g (2 mmoles) of the compound obtained at the end of the previous step in 20 ml of ethyl alcohol, 1 g of 10% Pd / C is added, then the mixture is subjected to hydrogenation with a 24-10 <4> pascal hydrogen pressure for 4 hours. At the end of the reaction, after control on TLC, the catalyst is filtered, the ethyl alcohol is evaporated, taken up with ethyl acetate and the acid is salified with an aqueous solution of Si, the aqueous phase is separated and, after acidification at a pH of approximately 2, it is extracted with ethyl acetate. The organic phase is evaporated, after dehydration with

anhydrous, and 0.7 g of product of formula I (R = H) are obtained. Yield: 92%.

IR (KBr): 1770, 1737 and 1647 cm <-1>.

EXAMPLE 2

0.5 g of the compound obtained in Example 1 are treated, dissolved in 10 ml of methylene chloride, with an ethereal solution of diazomethane no. After evaporation under vacuum, 0.55 g of methyl ester of formula I (R = CH3) are obtained.

Claims (8)

CLAIMS 1. Cephalosporins of formula I wherein R represents hydrogen, a cation or a pharmaceutically acceptable ester group. 2. Salts of the compound of formula I, where R is hydrogen, with alkali, alkaline earth metals or pharmaceutically acceptable organic bases. 3. Salts of the compound of formula I, according to claim 2, characterized in that tromethamine, ethanolamine or amino acids such as lysine or arginine are used as organic bases. 4. Esters of the compound of formula I, where R is an acetoxymethyl, acetoxyethyl, pivaloyloxymethyl, pivaloyloxyethyl group. 5. Process for the preparation of the compounds according to claim 1, characterized in that: (a) it is the p-nitrobenzyl ester of 7-phenylacetami do-3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylic acid of formula II with furan in the presence of a base; (b) the so obtained cycloaddition product of formula III is submitted to a catalytic hydrogenation and the compound of formula I thus obtained is optionally transformed into an ester thereof or a pharmaceutically acceptable salt thereof. 6. Compound of formula III 7. Pharmaceutical composition containing as active principle a compound according to claim 1, together with the common vehicles and excipients. 8. Composition according to claim 3, characterized in that the active principle is formulated in unit doses containing from 1 to 5000 mg of said active principle.