SE437522B - (6R, 7R) -7- / 2- (2-AMINO-4-THIAZOLYL) -2- (Z-METOXIIMINO) -ACETAMIDO / -3- (SUBSTITUTED THIOMETHYL) -Cephalosporinic Acid AND LOWER ALKANOYLALKYL ESTAR / ETHAR - Google Patents

Abstract

Compounds of the general formula <IMAGE> [wherein X represents the 1,2,5,6- tetrahydro-2-methyl-5,6-dioxo-as- triazin-3-yl group, the 2,5-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3- yl group of the 1,4,5,6-tetrahydro-4- methyl-5,6-dioxo-as-triazin-3-yl group] and readily hydrolysable esters, readily hydrolysable ethers and salts thereof and hydrates of these compounds have broad-spectrum anti-bacterial activity.

Description

7904682-7 as readily hydrolyzable esters, ethers and salts of this compound and hydrates of the compound of formula I or of its esters, ethers and ointments By readily hydrolysable ester of the compound of formula I are meant compounds corresponding to formula I, whose carboxy group is in the form of an easily hydrolyzable ester group. Examples of such esters which may be common are the lower alkanoyloxyalkyl esters, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl esters; the lower alkoxycarbonyloxyalkyl esters, e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl esters; lactonyl esters, e.g. phthalidyl and thiophthalidyl esters; lower alkoxymethyl esters, e.g. methoxymethyl esters; and the lower alkanoylaminomethyl esters, e.g. acetamidomethyl esters. Other esters can also be used, e.g. benzyl and cyanomethyl esters.

As readily hydrolyzable ethers of the compound of formula I are meant compounds corresponding to formula I, wherein X represents the group 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-5-yl, the enolic OH group of which is in the form of an easily hydrolyzable ether group.

Such ether groups are those mentioned above for the readily hydrolyzable ester groups. Examples of such ethers are also, for example, the lower alkanoyloxyalkyl ethers, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ethers; the lower alkoxycarbonyloxyalkyl ethers, e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl ethers; lactonyl ethers, e.g. phthalidyl and thiophthalidyl ethers; the lower alkoxymethyl ethers, e.g. methoxymethyl ethers; and the lower alkanoylaminomethyl ethers, e.g. acetamidomethyl ethers.

Examples of elements or the compound of formula 1 are alkali metal salts such as sodium and potassium salts; ammonium salts; alkaline earth metal salts such as calcium salts; salts with organic bases such as salts with amines, e.g. salts with N-ethylpiperidine, procaine, dibenzylamine, N, N'-dibenzylethylethylene diamines, alkylamines or dialkylamines as well as salts with amino acids, e.g. salts with arginine or lysine. The salts may be monosalts or disalts. The second salt formation may occur in compounds with the hydroxy group of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group.

The compound of formula I likewise forms addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, for example hydrochlorides, hydrobromides, hydroiodides as well as other mineral acid salts such as sulfate, nitrate, phosphate and the like, alkyl and monoaryl sulfonate such as ethanesulfonate, toluenesulfonate, benzenesulfonate and the like and also other organic acid salts such as acetate, tartrate, maleate, citrate, benzoate, salicylate, ascorbate and the like.

The compound of formula I and its salts, readily hydrolysable esters and ethers may be hydrated. The hydration can take place in connection with the manufacturing process or after some time due to their hygroscopic properties using an initially anhydrous product.

The products according to the invention may be present in the synisomeric form 7 \ Ü-CONH-g HN / QN 2 s \\ OCH3 or in the anti-isomeric form HzN / (N fl aofvra-šg cH3o 7904682-7 or as mixtures of these two The syn isomer is preferred or mixtures in which the syn isomer form predominates.

Preferred products are the following: (6R, 7R) -7- [2- (2-amino-H-thiazolyl) -2- (Z-methoxyimino) -acetamido] -3 - [[2,5-dihydro -6-hydroxy-2-methyl-5-oxo-as-triazin-5-yl) thio] -methyl] -8-oxo-5-thia-1-azabicyclo- [U.2.0] oct-2-ene- 2- carboxylic acid and its salts as well as the corresponding hydrate.

The above-mentioned acyl derivatives are prepared according to the invention in such a way that a) in a compound having the general formula uuuI 1 uuuI CH3ON =: c-CoNH- r N »- II w OM f Ce-SX RHN S - COOH wherein X has the meaning given above, R denotes a cleavable protecting group and the carboxy group may be in protected form, the protecting group R cleaves, possibly also an existing carboxy protecting group, or that b) for the preparation of an easily hydrolysable ester resp. ether of the compound of formula I submits a carboxylic acid resp. an enol of the formula I a corresponding esterification resp. etherification, or that c) for the preparation of salts or hydrates of the compound of formula I resp. hydrate of these salts converts the compound of formula I to a salt or a hydrate resp. a hydrate of 7904682-7 this salt.

The carboxy group present in the starting compound of formula II can optionally be protected, for example by esterification to an easily cleavable ester, e.g. a silyl ester, e.g. the trimethylsilyl ester. The easily hydrolyzable esters highlighted above also come into consideration. The carboxy group can also be protected by salt formation with an inorganic or tertiary organic base such as triethylamine. Possible R-protecting groups are, for example, acid hydrolytically cleavable protecting groups, e.g. t-butoxycarbonyl or trityl, or also base hydrolytically cleavable protecting groups, e.g. trifluoroacetyl. Preferred R-protecting groups are chloro-, bromo- and iodoacetyl, especially chloroacetyl.

The latter protecting groups can be cleaved by treatment with thiourea.

The starting compounds of formula II can be prepared, for example, by N-acylation of the corresponding 7-amino compound and more particularly by reacting a compound having the general formula H Hw- '2' I III _ 0 // - N / CHg- SX COOH wherein X is as defined above and the carboxy group and / or amino group may be in protected form, with an acid having the general formula oH3oN == c-coon 7 \ IV RHN 7904682-7 wherein R is as defined above, or react with a reaction-functional functional derivative of this acid and optionally cleave an existing carboxy-protecting group.

The carboxy group present in the 7-amino compound of formula III can be optionally protected and in particular in the manner indicated above for the preparation of the starting compound of formula II.

The amino group of the compound of formula III can be protected, for example, with a silyl protecting group such as trimethylsilyl.

Suitable reactive functional derivatives of acids of formula IV are, for example, halides, i.e. chlorides, bromides and fluorides; azides; anhydrides, especially mixed anhydrides with strong acids; reactive esters, e.g.

N-hydroxysuccinimide esters, as well as amides, e.g. imidazolid.

The reaction of the 7-amino compound of formula III with the acid of formula IV or a reaction-prone functional derivative thereof can be carried out in a manner known per se. Thus, for example, one can condense a free acid of formula IV with one of the mentioned esters corresponding to formula III with a carboxidiimide such as dicyclohexylcarbodiimide, in an inert solvent such as acetic ester, acetonitrile, dioxane, chloroform, methylene chloride, benzene and then dimethylform cleave the ester group. Instead of the carbodiimides, oxazolium salts can also be used as condensing agents, e.g.

N-ethyl-5-phenyl-isoxazolium-3'-sulfonate.

According to another embodiment, a salt of an acid of formula III is reacted, e.g. a trialkylammonium salt such as triethylammonium salt, having a reaction-prone functional derivative of an acid of formula IV as mentioned above in an inert solvent, e.g. one of the above.

According to a further embodiment, an acid halide is preferably reacted with the chloride of an acid of formula IV, with the enine of formula III. The reaction preferably takes place in the presence of an acid-binding agent, e.g. in the presence of aqueous alkali, preferably sodium hydroxide solution, or in the presence of an alkali metal carbonate such as potassium carbonate, or in the presence of a lower alkylated amine, e.g. triethylamine. As the solvent, water is preferably used, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxane. It is also possible to work in an aprotic organic solvent such as, for example, dimethylformamide, dimethylsulfoxide or hexamethylphosphoric acid triamide. Using silylated starting compounds of formula III, work in anhydrous medium.

The reaction of the 7-amino compound of formula III with the acid of formula IV or a reaction-prone functional derivative thereof may conveniently take place at a temperature between about -4000 and room temperature, for example at about 0 - 1000.

According to process variant a) according to the invention, the amino-protecting group R is cleaved in a starting compound of the formula II. By acid hydrolysis, cleavable protecting groups are preferably removed with the aid of a lower alkanecarboxylic acid, which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The temperature is usually room temperature even if you can use slightly raised or slightly lowered temperatures, e.g. in the range of approximately 0 ° C to + 140 ° C. Aixally cleavable protecting groups are generally hydrolyzed with dilute aqueous solution of lye at 0 ° C to 3000. Chloroacetyl, bromoacetyl or iodoacetyl protecting groups can be cleaved by thiourea in acidic, neutral or alkaline environment at about 0 - BOOC. Hydrogenolytic cleavage (eg benzyl cleavage) is unsuitable here, since the oxime function of the hydrogenolysis is reduced to an amino group.

After carrying out the process variant a), a carboxy-protecting group present in the reaction product may be removed. When the protecting group is a silyl group (silyl ester), this group can be particularly easily cleaved by treating the reaction product with water. Lower alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, lactonyl, alkoxymethyl and alkanoylaminomethyl esters are preferably cleaved off enzymatically by means of a suitable esterase (at about 20 - 0 ° C). When the carboxyl group is protected by salt formation (eg with triethylamine), the cleavage of this salt-forming protecting group4 can take place by treatment with acid. As acid, one can use, for example, hydrochloric acid, sulfuric acid, phosphoric acid or citric acid.

The carboxy protecting group can be cleaved off in the same way as described above even before cleavage of the protecting group R.

To prepare the easily hydrolyzable esters of the carboxylic acid of formula I according to variant b), the carboxylic acid is preferably reacted with the corresponding halide containing the ester group, preferably with the iodide. The reaction can be accelerated by means of a base, e.g. an alkali metal hydroxide or carbonate or an organic amine such as triethylamine. The 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X with its enolic function is etherified to give corresponding, readily hydrolysable ethers. The products thus obtained, co-esterified or etherified, are referred to above and below as "readily hydrolysable esters / ethers". Preferably an excess of the corresponding halide is used. The esterification / etherification reaction is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylphosphine. formic acid triamide, dimethylsulfoxide or preferably dimethylformamide, the temperature preferably being in the range of about 0-40 ° C.

Preparation of the salts and hydrates of the compound of formula I resp. hydration of these salts can take place in a manner known per se, e.g. by reacting the carboxylic acid of formula I with an equivalent amount of the desired base, suitably in a solvent such as water or in an organic solvent such as ethanol, methanol, acetone and others. When a second equivalent of the base is used, salt formation also takes place in the tautomeric enol form (2,5-dihydro-6- ..-_ _.. .._....-.._.._-. ~ ._ 7904682-7 hydroxy-2-methyl-5-oxo-as-triazin-5-yl group X) to form a disalt. The temperature of the salt formation is not critical.

It is generally at room temperature but may also be slightly above or below, approximately in the range 0o to + 5o ° C.

The hydrates are usually prepared automatically in connection with the manufacturing process or as a result of hydroscopic properties of an initially anhydrous product. For the intended preparation of a hydrate, a completely or partially anhydrous product (carbonic acid according to the formula I or ester, ether or salt thereof), may be exposed to the action of a humid atmosphere, e.g. at about + 10 ° C to + & 0 ° C.

The 1-amino compounds of formula III used above can be prepared from a compound having the formula HQN-¶ a / r- * NX / "nu I ~ uII 9% CH _, ___ Y vi: COOH wherein Y represents a leaving group, by reaction with a thiol having the general formula HS- VI X VI wherein X has the meaning given above.

Suitable leaving groups Y in a compound of formula V are, for example, halogens, e.g. chlorine, bromine or iodine, acyloxy groups, e.g. lower alkanoyloxy groups such as acetoxy, lower alkyl or arylsulfonyloxy groups such as mesyloxy or tosyloxy or an azido group. The reaction of the compound having the formula V with a thiol having the formula VI can take place in a manner known per se, e.g. at a temperature between about 40 and BOOC, preferably at about GOOC, in water or in a buffer solution having a pH of about 6-7, preferably 6.5.

An obtained sight / anti-mixture of the compound having the formula I can be divided into corresponding sight and anti-forms in the usual way, for example by recrystallization or by chromatographic methods using a suitable solvent resp. a solvent mixture.

The compounds of formulas I and II as well as the corresponding readily hydrolysable esters / ethers and salts and the hydrates of these products are antibiotically active, in particular bactericidal. They show a wide spectrum of action against gram-positive and gram-negative microorganisms, including staphylococci that form β-lactamase and various β-lactamase-forming gram-negative bacteria, such as Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Prerleusellac species.

The compounds of formulas I and II as well as the corresponding easily hydrolysable esters / ethers and salts resp. The hydrates of these products can be used for the treatment and prophylaxis of infectious diseases. For adults, a daily dose of about 0.1 g to about 2 g is in question. Parenteral administration of the compounds of the invention is particularly preferred.

To demonstrate the antimicrobial activity of the aforementioned products, the following representative compounds were tested: 79134682- “7 ll Product A: (6R, 7R) -7 ~ [2- (2-amino-H-thiazolyl) -2- (Z -methoxy-imino) acetamido] -3 - [[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl] -8-oxo-5-thia -1-azabicyclo [2..0] oct-2-ene-2-carboxylic acid Product B: (6R, YR) -7- [2- [2- (2-chloroacetamido) -H-thiazolyl] -2- (Z-methoxyimino ) acetamido [-5 - [[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] -methyl] -8-oxo-5-thia-1- azabicyclo [H.2.0] oct-2-ene-2-carboxylic acid Activity in vitro: 7904682-7 12 minimum inhibitory concentration (Hg / ml) AB Haemophilus influenzae Strain 1 0.08 1.2 V Strain 2 0.005 0.3 Strain 3 0.005 0.16 Strain 4 0.005 0.16 Strain 5 o, oo25 0.08 Strain 6 0.0025 0.16 Strain 7 0.0025 0.16 Klebsiella pneumoniae 1.2 10 Escherichia coli Strain 0.02 0.16 Strain 2 0.6 5 Proteus mirabilis Strain 1 50.01 0.08 strain 2 '~ _o, o1 0.16 Proteus vulgaris 50.01 0.16 Proteus rettgeri 50.01 0.16 Staphylococcus aureus Strain ATCC 6538 2.5 2.5 Penic illin- resistant Strain 2.5 5 | Pseudomonas aeruginosa Stam l 0.3 1.2 š Stam. 2 10> 80 i Strain 3 2.5 40 ¿.tribe 4 80 i I Strain 5 80 2 strain e lo ao strain 7 s ao l Serratia marcescens 0.08 2.5 ih »- 7904632" 7 13 Groups of five mice was infected with an aqueous suspension of Escherichia coli intraperitoneally Three times, ie 1 hour, 2.5 hours and H hours after the infection, the test substance was added subcutaneously in physiological saline solution.The number of surviving animals was determined on the fourth day.Different dosages were used and by interpolation, the dose at which 50% of the experimental animals survived (CDSO, mg / kg) was determined.

Test substance A B CDSO, mg / kg $ 0.005 0.16 Toxicity .cdi Test substance A B LD5O, mg / kg i.v. 250-500 250-500 s.c. > HOOO 2000-UOOO p.o. > 5000> 5000 In the Swedish patent applications no. 7701964-4, 7702909-8 and 7704233-1 disclose cephalosporins which, like the cephalosporins of the invention, have a 7-12- (2-amino-4-thiazolyl) -2- - (Z-methoxyimino) -acetamide Q7 group. However, the cephalosporins of the invention differ characteristically from those previously known by the configuration of the substituents in the 3-position, whereby new compounds with surprising efficiencies are obtained. Thus, a comparison with a structurally closely comparable compound from the above-mentioned prior art (the compound which in the 3-position as well as the cephalosporins according to the invention, shows a 6-membered N-heterocyclic thiomethyl group, more specifically a (6 -methyl-1-oxido-pyridazin-3-yl) -thiomethyl group), that the cephalosporin of the invention of formula I, wherein X represents a 1,2,5,6-tetrahydro-2-methyl-5,6- dioxo-as-triazin-3-yl group or its corresponding tautomeric form, the group 2,5-dihydro-6-hydroxy-2-methyl-PQQLIR ~ 7904682-7 14 -5-oxo-as-triazin-3 -yl, a massive (more than 50-fold) superiority in effect in in vivo prophylactic testing on mice against the pathogenic microorganisms Serratia marcescens, Klebsiella pneumoniae, Proteus mirabilis and Proteus vulgaris.

The products according to the invention can be used as medicaments, for example in the form of pharmaceutical preparations, which contain the products or their salts in admixture with a pharmaceutical, organic or inorganic inert carrier suitable for enteral or parenteral administration, e.g. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations may be in solid form, e.g. as tablets, dragees, suppositories, capsules; or in liquid form, e.g. such as solutions, suspensions or emulsions.

They may be sterilized and / or contain excipients such as preservatives, stabilizers, wetting agents or emulsifiers, salts for altering the osmotic pressure, anesthetics or buffer substances. They may also contain other therapeutically valuable substances. The compounds of formula I and their salts and hydrates are suitable for parenteral administration and are prepared for this purpose preferably as lyophilisate or dry powder for dilution with common agents such as water or isotonic saline solution. The readily hydrolyzable esters or ethers of the compounds of formula I and their salts resp. hydrates are also questionable for enteral administration.

The invention is further described by the following examples.

Example 1 Preparation of the disodium salt of (6R, 7R) -7 ¥ [2- (2-amino-H-thiazolyl) -2- (Z-methoxyimino] -3 - [[2,5-dihydro-6-hydroxy] 2-methyl-5-oxo-as-triazin-3-yl) thio] -methyl-8-oxo-5-thia-1-azabicyclo [H.2.0] oct-2-ene-2-carboxylic acid. 15.3 g (6R, 7R-7- [2- [2- (2-chloroacetamido) -α-thiazolyl] -2- (Z-methoxyimino) acetamido] -3- [[2,5-dihydro -6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thiolmethyl-8-oxo-5-thia-1-azabicyclo- [H.2.0] oct-2-en-2- Carboxylic acid (fraction I, see below) was suspended together with 5 g of thiourea in 150 ml of water, and under good nitrogen supply and stirring the pH was adjusted with saturated sodium bicarbonate solution to 6.8 - 7.0, forming an orange solution. autotitrator with the addition of sodium bicarbonate solution, the pH of the reaction solution was kept constant at 6.8 for 6 hours, then an additional 2.5 g of thiourea was added and the solution was stirred for a further 3 hours, the pH being maintained at 6.8 with the addition of saturated sodium bicarbonate. a red solution overnight in the refrigerator, making it darker. The pH of the solution was adjusted to 2.0 - 2.5 by adding 100% formic acid, whereupon the substance precipitated. This was filtered off and washed with 100 ml of 10% formic acid. The mother liquor was discarded. The brownish suction substance was suspended in 200 ml of water and adjusted to 7 with triethylamine to give a brown solution. This solution was stirred for 30 minutes with 2 g of activated carbon, after which the carbon was filtered off and the still brown filtrate was adjusted to pH 3.5 with 100% formic acid with thorough stirring. The resulting precipitate was filtered off with suction, washed with 50 ml of 10% formic acid and discarded. The dark yellow filtrate was adjusted to pH 2 - 2.5 with 100% formic acid, the substance precipitating.

This was filtered off, washed with ice water and dried. The resulting cephalosporinic acid was suspended for transfer to the disodium salt in a mixture of HO ml acetone and HO ml water and added with 20 ml of a 2N solution of 2-ethylcaproic acid sodium salt in acetic ester. To the orange solution thus formed was added 50 ml of acetone, whereupon a brown resin precipitated, which was separated by filtration. The yellow filtrate was stirred for 50 minutes, during which the disodium salt crystallized.

The mixture was further added portionwise with 50 ml of acetone and stored overnight in a refrigerator. The crystallizate was filtered off with suction, washed one after the other with an acetone / water mixture (85:15), pure acetone and low-boiling petroleum ether and dried over all mtlï-'gßllwï v * 1.53 "'~ 1 ~ -Å1"' "> fl = f 7904682-7 16 over vacuum overnight at HOOC. The title substance was obtained in the form of beige crystals. [alšo = -lüho (c = 0.5 in water). Nuclear resonance spectrum and microanalysis corresponded to the indicated structure.

The starting material used as starting material (6R, 7R) -7- [2- [2- (2-chloro-acetamido) -α-thiazolyl] -2- (Z-methoxyimino) acetamido] -3- / [(2,5- dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -tic] methyl] -8-oxo-5-thia-1-azabicyclo [.2.2,0loct-2-en-2 The carboxylic acid could be prepared as follows: 22.2 H g of 2- (2-chloroacetamido-thiazol-H-yl) -2- (Z-methoxyimino) -acetic acid were suspended in 2 ml of methylene chloride. This suspension was added with 13.39 ml of triethylamine to give a light brown solution. This solution was cooled to 0-500 and added with 16.72 g of phosphorus pentachloride, stirred for 5 minutes at 0-5 ° C and 20 minutes without cooling. The yellow solution was evaporated in vacuo at 3500. The evaporation residue was shaken twice with n-heptane and the latter was decanted off.

The resinous residue was treated with 20 ml of tetrahydrofuran and the undissolved triethylamine hydrochloride was filtered off. The yellow filtrate contained the acid chloride. 22 g (TR) -7-amino-3-desacetoxy-3-1- (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio] -cephalosporanic acid suspension was dissolved in a mixture of 300 ml of water and 150 ml of tetrahydrofuran. For suspension, 2N sodium hydroxide solution was added dropwise with careful nitrogen supply by means of an autotitrator until a brown-red solution with a pH of 8 was formed. This was cooled to 0-5 ° C and added dropwise over 15 minutes with the solution of the acid chloride in tetrahydrofuran prepared above. The mixture was then stirred for 2.5 hours at 2500 DEG C. The pH of the acylation mixture was kept constant at 8 by the addition of 2N sodium hydroxide solution. The substantially black solution was liberated in vacuo at HOOC from tetrahydrofuran. Then 100 ml of 2N sulfuric acid was added. The resulting substance was filtered off with suction, washed with water and carefully filtered off with suction. The moist brown suction substance was dissolved in 1.5 l of acetone. The dark solution was liberated over "Hyflo" from ............._.._....._.....__.._. . . . i,. -._......... .__ if '1.1 .: t _.- _, - 1 .7904682-7 17 a small amount of dark undissolved material, added to charcoal, stirred for 30 minutes and then filtered again over "Hyflo".

The orange-red filtrate was dried over sodium sulfate, evaporated in vacuo and evaporated with ethyl acetate. A black resin precipitated, which was filtered off and discarded. The 2-phase filtrate still containing water was azeotroped three times with benzene in vacuo at 100 ° C. The resulting precipitate was filtered off with suction and dried in vacuo at HOOC.

The latter was stirred twice with 1 liter of acetone each, leaving a brown resin, which was discarded. The combined orange acetone extracts were evaporated in vacuo at HOOC to about 150 ml, whereupon a brown resin was filtered off and discarded. The filtrate was charged with 1 liter of acetic ester and evaporated in vacuo at HOOC. The resulting precipitate was filtered off with suction, washed with ethyl acetate and then with ether to give [(6R, 7R) -7 - [[2- (2-chloroacetamido) -H-thiazolyl] -2- (Z-methoxyimino) acetamido] 3 - [(2,5-Dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] -methyl-8-oxo-5-thia-1-azabicyclo [U .2.G1oct-2-ene-2-carboxylic acid, fraction 1: a beige amorphous acid]. This fraction I could be used directly to prepare the desired end product. The acetic ester mother liquor was strongly evaporated in vacuo at 100 ° C, diluted with ether and the precipitated substance was filtered off with suction [(6R, 7R) -7- [2- [2- (2-chloroacetamido) -H-thiazolyl] -2- (Z-methoxyimino) ) acetamido [3 - [[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-astriazin-3-yl) thio] -methyl] -8-oxo-5-thia-1 -azabicyclo [H.2.0] oct--2-ene-2-carboxylic acid, fraction II: a light beige amorphous acid, thin layer chromatographically slightly purer than fraction I].

To prepare the disodium salt, 3.5 g of acid (fraction II) was dissolved in a mixture of 20 ml of acetone and 11 ml of water. The solution was added with 7 ml of a 2N solution of 2-ethylcaproic acid sodium salt in acetic ester, whereby the disodium salt crystallized. Then an additional portion of 25 ml of acetone was added and the mixture was stored in a freezer for 2 hours. The crystals were then filtered off with suction, washed successively with 25 ml of slave, an ice-cold mixture of acetone and water (80:20), pure acetone and low-boiling petroleum ether and dried overnight in high vacuum at 0 ° C. The sodium site of (6R, 7R) -7- [2- - [2-chloroacetamido) -U-thiazolyl] -2- (Z-methoxyimino) -acetamido [-5- [[2,5-dihydro- 6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio] -methyl-8-oxo-5-thia-1-azabicyclo [2.2.0] oct-2-ene * 2-carbon- š ° = -142.7 ° c (c = 1 in water). Nuclear resonance spectrum and microanalysis corresponded to the acid in the form of light yellow crystals. [a] specified structure.

Example 2 Preparation of methylene- (6R, 7R) -7 * [2- (2-amino-H-thiazolyl) -2- (z-methoxyimino) α] ethamino] -3- [II2,5-hydro] -2- methyl-5-OXO- -6 - [(pivaloyloxy) methoxy] -as-triazin-3-yl] -thio] methyl] -8-oxo-5-thia-1-azabicyclo [H.2.0] oct-2- a 2-carboxylate pivalate. 1.85 g of the cephalosporin disodium salt prepared in Example 1 were suspended in 50 ml of dimethylformamide and added under nitrogen supply at 0 DEG-5 DEG C. with 1.35 g of pivaloyloxymethyl iodide. The reaction mixture was stirred for 50 minutes at 0-5 ° C and then poured onto 500 ml of ethyl acetate.

The mixture was washed three times with water, twice with 5% sodium bicarbonate solution and finally further with water. The solution was dried over sodium sulfate and evaporated vigorously in vacuo at 3506. After addition of ether, the title substance precipitated amorphous. This was filtered off, washed with ether and low boiling petroleum ether and dried in a high vacuum at 25 ° C overnight. The title substance was obtained in the form of a beige amorphous powder. Nuclear resonance spectrum and microanalysis were consistent with the indicated structure. 7904682-7 19- Example Preparation of dry ampoules for intramuscular administration: In the usual way, a lyophilisate of 1 g of the disodium salt of (5R, 7R) -7- [2- (2-amino---thiazolyl) -2- (Z-methoxyimino) acetamido] -3 - [[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl] -8-oxo-5- thia-1-azabicyclo- - [ü.2.0] oct-2-ene-2-carboxylic acid and filled into an ampoule. Prior to administration, the lyophilisate was charged with 2.5 ml of a 2% aqueous solution of lidocaine hydrochloride.

Example In the usual way, a gelatin capsule having the following composition was prepared: methylene (6R, 7R) -7- [2- (2-amino-U-thiazolyl) -2- (Z-methoxyimino) acetamido] -3 - [[[2, 5-dihydro-2-methyl-5-oxo-6-1- (pyvaloyloxy) methoxy] -astriazin-5-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 Mon

Claims (5)

7904682-7 to CLAIMS 1. 1. Acyl derivative, characterized in that it has the general formula çHapN-i-comn-š 5 IN '_ a Å-š / GHz-s x HZN _ S' _ COOH wherein X represents the group l, 2 , 5,6-tetrahydro-2-methyl-5,6-dioxo-1-triazin-3-yl resp. 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as--triazin-3-yl, and lower alkanoyloxyalkyl esters / ethers and salts of this compound and hydrates of the compound of formula I resp. of its esters / ethers and salts. Compounds according to claim 1, characterized in that they are in syn-isomeric form resp. mixtures in which the syn-isomeric form predominates. 3. (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) -acetamide] -3- [12,5-dihydro-6-hydroxy-2 -methyl-5-oxo-as-triazin-3-yl) -thio] -methyl] -8-oxo-5-thia-1-azabicyclo [.2.2.Q] oct-2-ene-2-carboxylic acid as well as salts and hydrates of this compound resp. the salts thereof. B fl igtIu fi vet1. Lower alkanoyloxyalkyl esters / ethers of acyl derivatives of formula I according to any one of claims 1-3 as well as salts of these esters / ethers and hydrates of these esters / ethers and salts. 5. Methylene- (6R, 7R) -7- [1- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) -acetamide] -3- [IZ2,5-dihydro-2-methyl-5 -oxo-6-L-pivaloyloxy) methoxy] -as-triazin-3-yl] -thi] methyl] -8-oxo-5-thia-1-azabicyclo [.2.2.Q] - oct-2-ene -2-carboxylate pivalate as well as salts of this compound and hydrates of this compound and salts.EWHgt h¶vet1.