GB2101581A - Cephalosporin derivatives - Google Patents

Description

SPECIFICATION Cephalosporin derivatives The present invention is concerned with novel cephalosporin derivatives of the general formula

in which R represents the pivaloyloxymethyl or acetoxymethyl group, as well as acid addition salts of these compounds and hydrates of the compunds of formula I or of their acid addition salts.

The compounds of formula I form addition salts with organic or inorganic acids. Examples of such salts are hydrohalides (e.g. hydrochlorides, hydrobromides and hydroiodides) as well as other mineral acid salts such as sulphates, nitrates, phosphates and the like, alkylsulphonates and monoarvlsulphonates such as ethanesulphonates, toluenesulphonates, benzensulphonates and the like and also other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

The compounds of formula I as well as their acid addition salts can by hydrated. The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of the hygroscopic properties of an initially anhydrous product.

The products in accordance with the invention can be present in the syn-isomeric form

or in the anti-isomeric form

or as a mixture of these two forms. The syn-isomeric form or mixtures in which the syn-isomeric form predominates is/are preferred.

Preferred products are Methylene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyiminoj-acetamido]-3-[[[2-methyl-5- [[(pivaloyloxy) methoxy]ca rbonyl]-2 H-l ,2,4-triazol-3-yl]thio] methyl]-8-oxo-5-thia- - azabicyclo[4.2 .0]oct-2-ene-2-carboxylate pival ate and its acid addition salts as well as the corresponding hydrates.

The above cephalosporin derivatives can be manufactured in accordance with the invention by subjecting the corresponding dicarboxylic acid, i.e. the (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2- [methoxyiminoaceta mido]-3-[[3-carboxy- -methyl-l H-l ,2,4-triazol-5-yl)thio] methyl]-8-oxo-5-thia- 1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (compound II), or a salt of this compound to a corresponding esterification and, if desired, converting the product obtained into an acid addition salt or hydrate or into a hydrate of this acid addition salt.

The dicarboxylic acid (compound II) used in the above process can be prepared as follows starting from 7-aminocephalosporanic acid.

The 7-aminocephalosporanic acid is reacted in aqueous solution with 4,5-dihydro-1-methyl-5 thioxo-l H-l ,2,4-triazole-3-carboxylic acid (compound Ill), for example at a temperature between about 40 and 800C, conveniently at about 600 C. The solution is preferably buffered at a pH of about 6 to 7, preferably 6.5.

The thus-obtained (6 R,7R)-7-amino-3-/[(3-carboxy- 1 -methyl-l ,2,4-triazol-5-yl)thio] methyl/-8 oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (compound IV) is subsequently reacted with a carboxylic acid of the general formula

wherein R' represents a cleavable group, or with a reactive functional derivative of this acid, whereby there is obtained a compound of the general formula

wherein R' has the above significance.

Possible R'-protecting groups are, for example, protecting groups which are cleavable by acid hydrolysis such as, for example, t-butoxycarbonyl or trityl, or protecting groups which are cleavable by basic hydrolysis such as, for example, trifluoroacetyl. Preferred R'-protecting groups are chloroacetyl, bromoacetyl and iodoacetyl, especially chloroacetyl. The last-mentioned protecting groups can be cleaved off by treatment with thiourea.

As reactive functional derivatives of carboxylic acids of formula V there come into consideration, for example, halides (i.e. chlorides, bromides and fluorides), azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters (e.g. N-hydroxysuccinimide esters) and amides (e.g.

imidazolides).

The reaction of the 7-amino compound IV with the carboxylic acid of formula V or a reactive functional derivative thereof can be carried out in a manner known per se. Thus, for example, an acid halide, preferably the chloride, of a carboxylic acid of formula V can be reacted with the amine IV. The reaction is preferably carried out in the presence of an acid-binding agent, for example in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium carbonate or in the presence of a lower alkylated amine such as triethylamine. As the solvent there is preferably used water, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxan.The reaction can also be carried out in an aprotic organic solvent such as, for example, dimethylformamide, dimethyl sulphoxide or hexamethylphosporic acid triamide. The reaction can conveniently be carried out at temperatures between about -40"C and room temperature, for example at about 0-i 00C.

Subsequently, the amino protecting group R' in the resulting compound of formula VI is cleaved off, whereby the desired dicarboxylic acid (compound 11) is obtained. Protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used.This cleavage is generally carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature, for example a temperature in the range of about OOC to +400 C. Protecting groups which are cleavable under alkaline conditions are generally hydrolyzed with dilute aqueous caustic alkali at OOC to 300 C. The chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved off by means of thiourea in acidic, neutral or alkaline medium at about O-300C. Hydrogenolytic cleavage (e.g. cleavage of benzyl) is unsuitable in this case, since the oxime function would be reduced to the amino group during the hydrogenolysis.

The dicarboxylic acid II obtained can subsequently be converted into a salt, for example into an acid addition salt as described above for the end products of formula I, or also into salts with bases, for example alkali metal salts such as the sodium and potassium salt, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as salts with amines (e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, alkylamines or diaikylamines) as well as salts with amino acids such as, for example, salts with arginine or lysine. The salts can be mono-salts or also di-salts. The salts are manufactured in a manner known per se; for example, by reacting the dicarboxylic acid II with an equivalent amount of the desired acid or base, conveniently in a solvent such as water or in an organic solvent such as ethanol, methanol, acetone etc.

When a second equivalent of base is used, salt formation is also effected on the second carboxy function. The temperature at which the salt formation is carried out is not critical. It is generally carried out at room temperature, but it can also be carried out at a temperature slightly above or below room temperature (e.g. in the range of OOC to +500C).

The 4,5-dihydro-l -methyl-5-thioxo-l H-l ,2,4-triazole-3-carboxylic acid is in tautomeric equilibrium with the corresponding thiol as shown in the following formulae

The preparation of this compound is described in Example 1.

The esterification in accordance with the invention of the dicarboxylic acid II is carried out by reaction with an agent yielding the pivaloyloxymethyl or acetoxymethyl group, preferably by reaction with the corresponding halide, especially with the iodide. The reaction can be accelerated with the aid of a base, for example an alkali metal hydroxide or carbonate or an organic amine such as triethylamine.

An excess of the corresponding halide is preferably used. The esterification is preferably carried out in an inert organic solvent, optionally in admixture with water, examples of such solvents being dimethylacetamide, hexamethylphosphoric acid triamide, dimethyl sulphoxide or, preferably, dimethylformamide. The temperature preferably lies in the range of about 0--40"C.

The manufacture of the acid addition salts and hydrates of the compounds of formula I or the hydrates of these salts can be carried out in a manner known per se; for example, the acid addition salts can be manufactured by reacting the compound of formula I with an equivalent amount of the desired acid, conveniently in a solvent such as water or in an organic solvent such as ethanol, methanol, acetone etc. The temperature at which the salt formation is carried out is not critical. It is generally carried out at room temperature, but it can also be carried out at a temperature slightly above or below room temperature (e.g. in the range of OOC to +500C).

The manufacture of the hydrates usually takes place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially anhydrous product. For the controlled manufacture of a hydrate, a completely or partially anhydrous product can be exposed to a moist atmqsphere (e.g. at about +100C to +400C).

A syn/anti mixture of a compound of formula I which may be obtained can be separated into the corresponding syn- and anti- forms in the customary manner, for example by recrystallization or by chromatographical methods using a suitable solvent or solvent mixture. However, the compound of formula I in the syn-isomeric form is preferably obtained by using a compound of formula V in the synform.

The compounds of formula I as well as the corresponding acid addition salts of the hydrates of these products have antibiotic, especially bactericidal, activity. They possess a broad spectrum of activity against gram-positive bacteria (e.g. Streptococci) and against gram-negative bacterial (e.g.

Neisseria meningitidis) as well as against various /3-lactamase-forming gram-negative pathogens such as Escherichia coli and Serratia marcescens.

The compounds of formula I as well as the corresponding acid addition salts or the hydrates of these products can be used for the treatment and prophylaxis of infectious diseases. A daily dosage of about 0.1 g to about 4 g, especially about 0.25 g to about 2 g, comes into consideration for adults.

Enteral or parenteral administration is possible, a particular advantage lies in the suitability of the products in accordance with the invention for enteral (e.g. oral) administration.

The oral antimicrobial activity of the products in accordance with the invention can be demonstrated on the basis of in vivo tests on mice. The curative dosage (CD50, mg/kg) referred to hereinafter signifies that dosage at which 50% of the tested mice survive.

Test compounds: Product A: Methylene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamidoj-3-[[[2- methyl-5-[[(pivaloyloxy) methoxy]ca rbonyl]-2H- 1 ,2,4-triazol-3-yl]thio] methyl]-8-oxo-5-thia 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate Cephalexin (previously known, recognized orally active cephalosporin) Results (CD50, mg/kg)

Product A Cephalexin Pathogen p.o. s.c. p.o. s.c.

Escherichia coli 0.047 0.002 3.2 2.1 Serratia marcescens 0.68 0.05 > 50 > 50 Neisseria meningitidis 0.14 1.2 Streptococcus pyrogenes 0.95 0.044 1.8 1.2 Product A is significantly more active than cephalexin not only after peroral administration but also after subcutaneous administration.

The blood level values attained after oral administration are shown in the following comparison in rats.

Antibiotic concentration in the blood Oral dosage in ,ug/ml after minutes mg/kg 15 30 45 60 90 150 ProductA 20 6 12 12 10 8 5 Cephalexin 50 ' 8 12 14 18 5 Product A is at least as non-toxic as cephalexin (LDso p.o. in mice after 24 hours: > 4000 mg/kg for Product A, 1 600-4500 mg/kg for cephalexin).

The products in accordance with the invention can be used as medicaments, for example in the form of pharmaceutical preparations which contain them in admixture with a pharmaceutical, organic or inorganic inert carrier material which is suitable for enteral or parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, Vaseline etc. The pharmaceutical preparations can be made up in solid form (e.g. as tablets, drawees, suppositories or capsules) or in liquid form (e.g. as solutions, suspensibns or emulsions). If necessary, they can be sterilized and/or can contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure, anaesthetics or buffers.

They can also contain still other therapeutically valuable substances.

The following Examples illustrate the invention: EXAMPLE 1 Manufacture of methylene (6R,7 R)-7-[2-(2-amino-4-thiazolyji-2-[(Z)-methoxyiminoj-acetamidoj- 3-[[[2-methyl-5-[[(pivaloyloxy)methoxy]carbonyl]-2H-i ,2,4-triazol-3-yl]thio]methyl]-8-oxo-5-thia- 1 - azabicylo[4.2.0]oct-2-ene-2-carboxylate pivalate: 3.9 g of the disodium salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyiminojacetamido]- 3-[[3-carboxy- i-methyl-i H- 1 ,2,4-triazol-5-yl]thio]methyl]-8-oxo-5-t 1 -azabicyclo[4.2.0]oct-2-ene- carboxylic acid are dissolved in a mixture of 100 ml of dimethylformamide and 25 ml of water. This solution is treated at 0--50C with 3.13 g of iodomethyl pivalate while gassing with nitrogen.The mixture is stirred at 0--5 0 C for 30 minutes, then poured into 500 ml of water and extracted three times with 200 ml of ethyl acetate each time. The aqueous phase is discarded. The combined ethyl acetate phases are washed successively with water, dilute aqueous sodium hydrogen carbonate solution and again with water, dried over sodium sulphate and concentrated strongly at 400C in vacuo. After adding low-boiling petroleum ether, the precipitated product is filtered off under suction, washed with lowboiling petroleum ether and dried at 400C in a high vacuum. There is obtained beige coloured, amorphous, crude product. For purification, this product is chromatographed on a column of 100 g of silica gel (0.2-0.5 mm) using ethyl acetate as the elution agent. There is obtained pure, beige coloured, amorphous title substance with Rf = 0.31 in thin-layer chromatography on Kieselgel-60F-254 plates with ethyl acetate as the running agent. The specific rotation is [aC]D5 = --121.60 (c = 0.4924 in acetone); the nuclear resonance spectrum and the microanalysis correspond to the given structure.

The compound used as the starting material in the above process can be prepared as follows: (a) Preparation of 4,5-dihydro-l -methyl-5-thioxo-l H-l ,2,4-triazole-3-carboxylic acid methyl ester: 12.9 g of 1 -methoxyoxalyl-2-methyl-thiosemicarbazide are added to a solution of 1.6 g of sodium in 200 ml of methanol. The mixture is boiled under reflux for 4 hours. The substance which precipitates after 1/2 hour is separated. The mother liquor is evaporated at 400C in vacuo. The evaporation residue is dissolved in 100 ml of water and acidified with concentrated hydrochloric acid.The crystallizate which thereby separates out yields, after recrystallization from water, pure, colourless 4,5-dihydro-1 methyl-5-thioxo-l H-1 ,2,4-triazole-3-carboxylic acid methyl ester of melting point 1 88-1 900C (decomposition).

(b) Preparation of 4,5-dihydro-l -methyl-5-thioxo-l H-i ,2,4-triazole-3-carboxylic acid: 3.46 g of 4,5-dihydro-1 -methyl-5-thioxo-l H-i ,2,4-triazole-3-carboxylic acid methyl ester are dissolved in 50 ml of 1 N sodium hydroxide. After stirring for 1/2 hour at 250C, the solution is made acid with 25 ml of 2N hydrochloric acid and concentrated at 400C in vacuo, the desired acid crystallizing.

This acid is filtered off under suction, washed with ice/water and dried at 450C in a high vacuum. There is obtained colourless 4,5-dihydro-l -methyl-5-th ioxo-l H-i ,2,4-triazole-3-carboxylic acid of melting point 177-1 780C (decomposition).

(c) Preparation of (6R,7R)-7-amino-3-[[(3-carboxy- 1 methyl ,2,4-triazol-5-yl)thio]methyl]-8-oxo-5- thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid: 34 g of 7-aminocephalosporanic acid are suspended together with 25.5 g of 4,5-dihydro-1 methyl-5-thioxo-l H-i ,2,4-triazole-3-carboxylic acid in 500 ml of water. The pH is adjusted to 6.5 with 3N sodium hydroxide. The mixture is stirred at 550C for 4 hours while gassing with nitrogen, the pH being held constant at 6.5 with 3N sodium hydroxide with the aid of an autotitrator. The dark solution is cooled to 250C and adjusted to pH 3.5 with concentrated hydrochloric acid.After 1 5 minutes, the precipitated material is filtered off under suction, suspended in 500 ml of water and brought into solution at pH 7 with 3N sodium hydroxide. The orange-red solution is adjusted to pH 3 with concentrated hydrochloric acid. The precipitated substance is filtered off under suction, washed successively with 250 ml of water, 500 ml of acetone and 500 ml of low-boiling petroleum ether and dried at 40-450C overnight in vacuo. There is obtained (6R,7 R)-7-a mino-3-[[(3-ca rboxy-l -methyl 1 ,2,4-triazol-5-yl)thio] methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-carboxylic acid as a beige coloured powder.

(d) Manufacture of (6R,7 R)-3-[[(3-carboxy-1 -methyl-l H- ,2,4-triazol-5-yl)thio] methyl]-7-[2-[2-(2 chloroacetamido)-4-thiazolyl]-2-[(Z)-methoxyimino]acetamido]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2ene-2-carboxylic acid: 75 g of phosphorus pentachloride are added to 600 ml of methylene chloride dried over calcium chloride. The suspension is cooled to -1 00C while stirring and 1 38 ml of N,N-dimethylacetamide are added dropwise during about 5 minutes, the temperature rising to -50C. The suspension is cooled to -i 50C and stirred for 1 5 minutes.After cooling to --200C, 100 g of 2-(2-chloroacetamido-4-thiazolyl)2-(Z)-methoxyimino-acetic acid are added and the mixture is stirred at 50C for 45 minutes, a yelloworange solution resulting. This solution is cooled to -300C, treated with 1 50 g of ice and stirred at -50C for 10 minutes.The methylene chloride phase containing the acid chloride formed is separated and stored initially at about-i 50C. This acid chloride solution is added dropwise during 30 minutes while stirring vigorously to a solution, cooled to 0--50C, which has been prepared by treating 111.5 g of (6R,7R)-7-amino-3-[[(3-carboxy-l methyl ,2,4-triazol-5-yl)thio]methyl]-8-oxo-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid with 3N sodium hydroxide to pH 8.2 in 500 ml of water, the pH value being held at 8.0-8.2 with 3N sodium hydroxide with the aid of an autotitrator. The mixture is stirred at 250C for 2 hours. Thereafter, 900 ml of methylene chloride and 6 1 of n-butanol are added.The pH is re-adjusted to 2 with 3N hydrochloric acid while stirring vigorously. The organic phase is separated, washed three times with 3 1 of water each time, stirred for 1 5 minutes with 60 g of decolourizing charcoal and filtered. The light yellow filtrate is concentrated strongly at 600C in vacuo, the reaction product precipitating. The precipitated product is filtered off under suction, washed successively with n-butanol, ether and low-boiling petroleum ether and dried at 400C overnight in vacuo. There is obtained crude, beige (6R,7 R)-3-[[(3-carboxy-l -methyl-l H-l ,2,4-triazol-5- yl)thio] methyl]-7-[2-(2-chloroacetamido)-4-thiazolyl]-2-[(Z)-methoxyimino]acetamido]-8-oxo-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

(e) Preparation of the disodium salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)- methoxyimino]acetamido]-3-[[(3-carboxy-1 -methyl-l H- ,2,4-triazol-5-yl)thio]methyl]-8-oxo-5-thia- 1 azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid: 53 g of (6 R,7 R)-3-[L(3-ca rboxy-l -methyl-l H-i ,2,4-triazol-5-yl)thio]methylj-7-[2-[2-(2- chloroacetamido)-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-8-oXo-5-thia-1 -azabicyclo[4.2.0]oct-2ene-2 carboxylic acid are suspended in 11 of water together with 34 g of thiourea. The pH is adjusted to 7 by the dropwise addition of 1 N sodium hydroxide, a dnrk brown solution resulting. This solution is stirred at pH 7 overnight while gassing with nitrogen, the pH being held constant with 1 N sodium hydroxide with the aid of an autotitrator. The pH of the solution is re-adjusted to 3.5 with 1 N hydrochloric acid while stirring. The precipitated substance (fraction I) is filtered off under suction, washed with 250 ml of water and dried at 400C in vacuo. Fraction I is brown in colour and very much impure; it is discarded. The orange mother liquor is re-adjusted to pH 2.65 with 1 N hydrochloric acid while stirring. The precipitated material is filtered off under suction and washed with 250 ml of water.

The beige coloured filter material is azeotropically distilled with ethanol under reduced pressure, filtered off under suction, washed with ethanol and low-boiling petroleum ether and dried at 400C in vacuo.

There is thus obtained a beige-brown fraction Il which, for purification and conversion into the disodium salt, is suspended in 2 l of methanol, treated with 50 ml of a 2N solution of sodium 2-ethyl-caproate in ethyl acetate and subsequently stirred with 200 ml of water for 30 minutes. A small amount of insoluble brown material is filtered of and discarded. About 1 I is removed from the orange coloured filtrate by evaporation at 400C in vacuo, then 1 l of ethanol is added and the mixture is concentrated in vacuo to a volume of about 500 ml. The solution is decanted off from the viscous brown resin, a heavy mixture, which thereby separates. The decanted-off yellow-orange solution is treated with 11 of ethanol and concentrated strongly at 400C in vacuo, substance partially precipitating.After adding 2.5 1 of methanol, there is obtained a yellow solution which is concentrated strongly at 400C in vacuo. The thereby precipitated disodium salt is filtered off under suction, washed with methanol and low-boiling petroleum ether and dried at 350C in a high vacuum. There is obtained the pure, beige coloured disodium salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamidoj-3-[[(3-carboxy- l-methyl-l H- ,2,4-triazol-5-yl)thio]methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid with [a]25 = 38.70 (e = 1 in water).

EXAMPLE 2 Manufacture of methylene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido]- 3-[[[2-methyl-5-[[(acetoxy)methoxy]carbonyl]-2 H- ,2,4-triazol-3-yl]thio] methyl]-8-oxo-5-thia- 1 - azabicyclo[4.2.0]oct-2-ene-2-carboxylate acetate: 5.98 g of the disodium salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)- methoxyimino]acetamido]-3-[[(3-carboxy-l i-methyl-i ,2,4-triazol-5-yl)thio] methylj-8-oxo-5-thia- 1 - azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are dissolved in a mixture of 70 ml of dimethylformamide and 25 ml of water. The solution is treated at 0--5 OC with 6.12 g of bromomethyl acetate while gassing with nitrogen and stirred at 0--5 0 C for 3 hours.The mixture is poured into 500 ml of water and extracted twice with ethyl acetate with the addition of a small amount of acetone. The combined organic phases are washed successively with dilute aqueous sodium hydrogen carbonate solution and water, dried over sodium sulphate and concentrated strongly at 400C in vacuo. After adding low-boiling petroleum ether, the substance which precipitates in amorphous form is filtered off under suction, washed with low-boiling petroleum ether and dried at 250C overnight in a high vacuum. There is obtained a beige crude product which, for purification, is chromatographed on a column of 80 g of silica gel (0.2-0.5 mm diameter) using ethyl acetate as the elution agent.There is obtained pure beige amorphous title substance (from ethyl acetate/low boiling petroleum ether) with [a]025 - 107 160 (c = 1.0358 in acetone). The nuclear resonance spectrum and the microanalysis correspond to the given structure.

EXAMPLE 3 An interlocking gelatin capsule containing the following ingredients is manufactured in the usual manner: Methylene (6R,7R)-7-[2-(2-amino-4-thiazolyl) 2-[(Z)-methoxyimino]-acetamido-3-[[[2 methyl-5-[[(pivaloyloxy) methoxy]ca rbonyl]- 2H-1 ,2,4-triazol-3-yl]thio]methyl]-8-oxo- 5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2- carboxylate pivalate 500 mg Luviskol (water-soluble polyvinylpyrrolidone) 20 mg Mannitol 20 mg Talc 15 mg Magnesium stearate 2 mg 557 mg EXAMPLE 4 Tablets of the following composition are manufactured in the usual manner Methylene (6R,7R)-7-[2-(2-amino-4-thiazolyl)- 2-[(Z)-methoxyimino]-acetamido-3 methyl-5-[[(pivaloyloxy) methoxy]carbonyl]- 2H- 1 ,2,4-triazol-3-yl]thio] methyl]-8-oxo- 5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2 carboxylate pivalate 250 mg Lactose 70 mg Maize starch 65 mg Polyvinylpyrrolidone 10 mg Magnesium stearate 5 mg 400 mg A granulate is manufactured in the usual manner using the active substance, the lactose, the polyvinylpyrrolidone and 40 parts by weight of the maize starch. This granulate is mixed with the remaining 25 parts by weight of maize starch and the 5 parts by weight of magnesium stearate and the resulting mixture is pressed to tablets.

Claims (14)

1. Cephalosporin derivatives of the general formula

in which R represents the pivaloyloxymethyl or acetoxymethyl group, as well as acid addition salts of these compounds and hydrates of the compounds of formula i or of their acid addition salts.

2. Cephalosporin derivatives in accordance with claim 1 in the syn-isomeric form or in the form of mixtures in which the syn-isomeric form predominates.

3. Methylene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido]-3-[[[2-methyl- 5-[[(pivaloyloxy)methoxy]ca rbonylj-2H- 1 ,2,4-triazol-3-yl]thio] methyl]-8-oxo-5-thia- 1- azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate as well as acid addition salts of this compound and hydrates of this compound or acid addition salts.

4. Methylene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[[2-methyl- 5-[[(acetoxy)methoxy]carbonyl]-2H- 1,2,4-triazol-3-yl]thio] methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct2-ene-2-carboxylate acetate as well as acid addition salts of this compound and hydrates of this compound or acid addition salts.

5. Compounds in accordance with any one of claims 1-4 as pharamceutically active substances.

6. Compounds in accordance with any one of claims 1-4 as pharmaceutically active substances for the enteral (e.g. oral) treatment and prophylaxis of infectious diseases.

7. Methylene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido]-3-[[[2-methyl- 5-[[(pivaloyloxy)methoxy]carbonyl]-2H-1 ,2,4-triazol-3-yl]thio] methyl]-8-oxo-5-thia-1 - azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate as well as acid addition salts of this compound and hydrates of this compound or acid addition salts for the enteral (e.g. oral) treatment and prophylaxis of infectious diseases.

8. Pharmaceutical preparations, which contain a compound in accordance with any one of claims 1-4.

9. Pharmaceutical preparations for the enteral (e.g. oral) treatment and prophylaxis of infectious diseases, which contain a compound in accordance with any one of claims 1-4.

10. Pharmaceutical preparations in accordance with claim 9 which contains methylene (6R,7R)-7 [2-(2-a mino-4-thiazolyl)-2-[(Z)-methoxyimino]-aceta mido]-3-[[[2-methyl-5- [[(pivaloyloxy) methyoxyjcarbonyl]-2H-i ,2,4-triazol-3-yl]thiojmethyl]-8-oxo-5-thia- 1 azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate or an acid addition salt of this compound or a hydrate of this compound or of one of its acid addition salts.

ii. A process for the manufacture of compounds in accordance with any one of claims 1-4, which process comprises subjecting the corresponding dicarboxylic acid, i.e. (6R,7R)-7-[2-(2-amino-4- thiazolyl)-2-[methoxyimino]acetamido]-3-[[3-carboxy-1-methyl-1 H-l ,2,4-triazol-5-yl)thia]methyl]-8- oxo-5-thia-l -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, or a salt of this compound to a corresponding esterification and, if desired, converting the product obtained into an acid addition salt or a hydrate or into a hydrate of this acid addition salt.

12. A process according to claim wherein a pivaloyloxymethyl halide, especially the iodide, is used as the esterifying agent.

13. The use of compounds in accordance with any one of claims 1-4 in the treatment of prophylaxis of illnesses.

14. The use of compounds in accordance with any one of claims 1 -4 in the enteral (e.g. oral) treatment of prophylaxis of infectious diseases.

1 5. The use of methylene (6R,7 R)-7-[2-(2-a mino-4-thiazolyl)-2-[(Z)-methoxyiminoj-acetamido]-3- [[[2-methyl-5-[[(pivaloyloxy)methoxy]carbonylj-2 H-i ,2,4-triazol-3-yl]thio] methylj-8-oxo-5-thia-i azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate as well as of acid addition salts of this compound and of hydrates of this compound or acid addition salts in accordance with claim 14.

1 6. Compounds as claimed in any one of claims 1-4 whenever prepared according to the process claimed in claim ii or 12 or by an obvious chemical equivalent thereof.

1 7. Methylene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido]-3-[[[2- methyl-5-[[(pivaloyloxy)methoxy]carbonyl]-2 H- ,2,4-triazol-3-yl]thio] methyl]-8-oxo-5-thia- 1 azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate as well as acid addition salts of this compound and hydrates of this compound or acid addition salts whenever prepared according to the process claimed in claim 11 or 12 or by an obvious chemical equivalent thereof.

1 8. The invention as hereinbefore described.