DK149283B - ANALOGY PROCEDURE FOR PREPARING CEPHALOSPORINE DERIVATIVES - Google Patents

Description

1Λ9283

The present invention relates to an analogous process for the preparation of therapeutically effective cephalosporin derivatives of the general formula I

Η H

5 IIs

CH3ON = rC-COHH -r-N

ri r ^ nAs /.

10 COOH

wherein X represents a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or the tautomeric 2,5-dihydro-6-hydroxy-2-methyl group. 5-oxo-as-triazin-3-yl group, and R ° represents hydrogen or a leaving group which may be tert-butoxycarbonyl, trityl, trifluoroacetyl or chloro, bromo or iodoacetyl, or pharmaceutically tolerable salts or hydrates of compounds of formula I wherein R ° represents hydrogen, or hydrates of these salts.

20

Examples of pharmaceutically tolerable salts of compounds of formula I are alkali metal salts, e.g. the sodium and potassium salt; the ammonium salt; alkaline earth metal salts, e.g. calcium salt; salts with organic bases, e.g. salts with amines such as, salts with N-ethylpiperidine, procaine, dibenzylamine, Ν, Ν'-dibenzylethylethylenediamine, alkylamines or dialkylamines, and salts with amino acids, e.g. salts with arginine or lysine. The salts may be monosaltic or disaltic. The second salt formation can occur in compounds with the hydroxy group of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group.

The compounds of formula I also 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 and phosphates, alkyl and mono-aryl sulphonates such as ethane sulphonates, toluene sulphonates and benzene sulphonates and other organic acid salts such as acetates, tartrates, malates, citrates, benzoates, benzoates, .

The compounds of formula I (including their salts) may be hydrated. The hydration can be carried out during the manufacturing process or eventually due to hygroscopic properties of an initially anhydrous product.

10

The products in question may be in the syn-isomeric form N - C-CONH_? 15 'JCS u * OCH 3 or in the anti-isomeric form 20 v CH, O

25 J

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

Preferred products are (6R, 7R) -7- [2- (2-amino-4-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-[4.2.0] oct-2-en-2 -carboxylic acid and its salts as well as the corresponding hydrates.

The process of the invention for the preparation of the above-mentioned acyl derivatives I is characterized in that:

translates a compound * ed into the general formula XII Η H

5 H2N - [- [^ J— * ch2— s— x 111

COOH

Wherein X is as defined above and carboxy

the group and / or the amino group may be in protected form, with an acid of the general formula IV

CHjONrsrC-COOH

Å RHN / where R represents a leaving group as defined above, or with a reactive functional derivative of this acid, if necessary, protecting group R and / or any carboxy protecting group present and if desired to prepare salts or hydrates of a compound of formula I wherein R ° represents hydrogen, or 25 of hydrates of these salts convert a compound of formula I into a salt or hydrate or hydrate of this salt.

The 3q carboxy group present in the starting compound of formula III may, if desired, be protected, e.g. by esterification to a readily cleavable ester, e.g. a silyl ester such as the trimethylsilyl ester. Speech hydrolyzable esters may also be present. By easily hydrolyzable esters is meant compounds whose carboxy group is in the form of a readily hydrolyzable ester group. Examples of such esters which may be of a conventional nature are the lower alkanoyloxyalkyl esters, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester; the lower alkoxycarbonyloxyalkyl esters, e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl esters; lactonyl esters, e.g. phthalidyl and thiophthalidyl esters; the lower alkoxymethyl esters, e.g. methoxymethyl ester; and the lower alkanoylaminomethyl esters, e.g. acetamidomethylester. The carboxy group may also be protected by salt formation with an inorganic or tertiary organic base such as triethylamine. The amino group of the compound of formula III can e.g. be protected with a silyl protecting group such as trimethylsilyl. Possible R protecting groups in the starting compounds of formula IV are e.g. by acid hydrolysis, cleavable protecting groups, e.g. tert-butoxycarbonyl or trityl, or by basic hydrolysis leaving protective groups, e.g. trifluoroacetyl. Preferred R protecting groups are chloro, bromo and iodoacetyl, especially chloroacetyl. The last protecting groups can be split off by treatment with thiourea.

As reactive functional derivatives of acids of formula IV, e.g. are mentioned halides, i.e. chlorides, bromides and fluorides; azides; anhydrides, especially mixed anhydrides with strong acids; reactive esters such as N-hydroxysuccinimide ester; and amides such as imidazolides.

25

The reaction between the 7-amino compound of formula III and the acid of formula IV or a reactive functional derivative thereof can be carried out in a manner known per se.

Thus, e.g. a free acid of formula IV is condensed 2Q with one of said esters corresponding to formula III by a carbodiimide, e.g. dicyclohexylcarbodiimide, in an inert solvent, e.g. ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide and the ester group is decomposed. Instead of carbodiimides, oxazolium salts, e.g. N-ethyl-5-phenyl-isoxazolium-3'-sulfonate.

5 149283

In another embodiment, a salt of an acid of formula III is reacted, e.g. a trialkylammonium salt, e.g. the triethylammonium salt, with a reactive functional derivative of an acid of formula IV as mentioned above in an inert solvent, e.g. one of the above.

In a further embodiment, an acid halide, preferably the chloride, of an acid of formula IV is reacted with the amine of formula III. The reaction is preferably carried out in the presence of an acid binding agent, e.g. in the presence of aqueous base, preferably sodium hydroxide solution, or in the presence of an alkali metal carbonate, e.g. potassium carbonate, or in the presence of a lower alkylated amine, e.g. triethylamine. Preferably water is used as solvent, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxane. An aprotic organic solvent, e.g. dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide. Using silylated starting compounds of formula III, it is worked in anhydrous medium.

The reaction between the 7-amino compound of formula III and the acid of formula IV or a reactive functional derivative thereof can conveniently be carried out at temperatures between -40 ° C and room temperature, e.g. at about.

0 - 10 ° C.

Reaction of the compounds of formula III with the carboxylic acids of formula IV or a reactive functional

derivatives thereof leading to cephalosporin derivatives redden the general formula II

Η H

CH3ON = C-CONH--

// c ^> nJ-CH2_s_-x II

ς / i

COOH

6 149283 where X has the meaning given above and R represents a leaving group protecting group. These compounds of formula II can be converted to compounds of formula I, wherein R hydrogen represents hydrogen, by cleavage of the amino-protecting group R. Preferably, acidic hydrolysis of cleavable protecting groups is removed by means of a lower alkane carboxylic acid, which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The temperature is usually room temperature, although XO can be used slightly higher or slightly lower temperature, e.g. in the range between 0 and + 40 ° C. Alkaline cleavable protecting groups are generally hydrolyzed with dilute aqueous bases at 0 - 30 ° C. Chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved by thiourea in an acidic, neutral or alkaline environment at approx. 0 - 30 ° C. Hydrogenolytic cleavage (e.g. benzyl cleavage) is unsuitable here as the oxime function of the hydrogenolysis is reduced to an amino group.

20

After cleavage of the amino protecting group R, if desired, a carboxy protecting group present in the reaction product may be cleaved off. When the protecting group is a silyl group (silyl ester), this group can be split off particularly easily by treating the reaction product with water. Lower alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, lactonyl, alkoxymethyl and alkanoylaminomethyl esters are preferably enzymatically cleaved by a suitable esterase (at about 20 - 40 ° C). When the carboxyl group is protected by salt formation (e.g. with triethylamine), the cleavage of this salt-forming protecting group can be effected by treatment with acid. As an acid, for this purpose e.g. hydrochloric acid, sulfuric acid, phosphoric acid or citric acid are used.

The carboxy protecting group can be cleaved in a similar manner as described above even before the cleaving of the protecting group R.

The preparation of the salts and hydrates of compounds of formula I wherein R ° represents hydrogen or the hydrates of these salts can be made in a manner known per se, e.g. by reacting the carboxylic acid of formula I wherein R ° represents hydrogen, with an equivalent amount of the desired base, conveniently in a solvent such as water or in an organic solvent such as ethanol, methanol or acetone. Using an additional equivalent base, salt formation also occurs on the possibly tautomeric enol form (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X), thereby forming a disalt.

The temperature of the salt formation is not critical. It is usually at room temperature, but may also lie slightly above or below, e.g. in the range between 0 and + 50 ° C.

The hydrates are often made automatically during the manufacturing process or due to the hygroscopic properties of an initially water free product. A hydrate can be prepared from a completely or partially anhydrous product (carboxylic acid of formula I or ester, ether or salt thereof) by exposing it to a humid atmosphere, e.g. at about. 10 - 40 ° C.

The above 7-amino compounds of formula III may be prepared from compounds of general formula VII 30

Η H

: Ice.

h2n - ^ - y J — K ^ —cs ^ VI1

35 I

COOH

8 149283

wherein Y represents a leaving group and the carboxy group may be in protected form by reaction with a thiol of general formula VI

5 HS - X VI

where X has the meaning given above, in the presence of water.

As a leaving group Y in a compound of formula VII 10, e.g. are mentioned 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 azido. Compounds VII may be protected by the carboxy group in the manner described for the starting compound of formula III.

The reaction of the compound of formula VII with the thiol of formula VI can be carried out in a manner known per se, e.g. at a temperature between ca. 40 and 80 ° C, conveniently at approx. 60 ° C, in water or in a buffer solution with a pH of approx. 6-7, preferably 6.5.

An optionally obtained syn / anti-blend of a compound of formula I can be split in the usual manner into the corresponding syn and anti forms, e.g. by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture. 1 2 3 4 5 6

The compounds of formula I as well as the corresponding salts or hydrates 2 of these products are antibiotic, especially bactericidal activity 3. They have a broad spectrum of action against gram-positive 4 and gram-negative microorganisms, including β-lactamase-forming Staphylococci and various β-lactamase-forming 6 gram-negative bacteria, e.g. Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marcescens, Proteus and Klebsiell species.

9 149283

The compounds of formula I as well as the corresponding salts or hydrates of these products can be used for the treatment and prophylaxis of infectious diseases. For adults, one daily dose of approx. 0.1 - approx. The parenteral administration of the compounds of this invention is particularly preferred.

To detect the antimicrobial activity of the products in question, the following representative compounds 10 have been tested:

Product A: (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z- methoxyimino) acetamido] -3 - ([(2,5-dihydro-6-hydroxy) -2-methyl-5-oxo-az-triazin-3-yl) thio] -15-methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0.] Oct--2-en-2 carboxylic acid.

Product B: (6R, 7R) -7- (2- [2- (2-chloroacetamido) -4- -thiazolyl] -2- (Z-methoxyimino) acetamido) -3-20 - ([(2,5- dihydro-6-hydroxy-2-methyl-5-oxo-asa-triazin-3-yl) thiolmethyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 carboxylic acid.

In vitro activity: Minimum inhibitory concentration (, µg / ml) 25 10 149283 ___________A__B_

Haemophilus influenzae Strain 1 0.08 1.2 5 Strain 2 0.005 0.3

Strain 3 '0.005 0.16

Strain 4 0.005 0.16

Strain 5 0.0025 0.08

Strain 6 0.0025 0.16 10 __Strain 7 0.0025 0.16

Klebsiella pneumoniae 1,2 10

Escherichia coli Strain 1. 0.02 0.16

Strain 2 0.6 5 15 Proteus mirabilis Strain 1 ^ 0.01 0.08

Strain 2 ^ 0.01 0.01

Proteus vulgaris ^ 0.01 0.01

Proteus Straightening 0.01 0.01 16 Staphylococcus aureus Strain ATCC 6538 2.5 2.5

Penicillin resistant strain 2.5 5

Pseudomonas aeruginosa Strain 1 0.3 1.2

Tribe 2 10 ^ 80 25 Tribe 3 2.5 40

Tribe 4 5 80

Tribe 5 5 80

Strain 6 10 80

Strain 7 '5 80 30 "- -" "-1- —-" "

Serratia marcescens 0.08 2.5

In vivo activity.

35 groups of every 5 mice are infected intraperitoneally with an aqueous suspension of Escherichia coli. Three times, ie At 1 hour, 2 1/2 hours and 4 hours after infection, the test substance is administered subcutaneously in physiological boiling salt solution. The number of surviving animals is determined on the 4th day.

Various dosages are administered and, when interpolated, the dose at which 50% of the test animals survive is determined (CD5q, mg / kg).

Test substance A B

CD50, mg / kg £ 0.005 0.16 10

Toxicity ....

Test substance A B

ης LD, .n, mg / kg intra-250 - 500 250 - 500 venous subcu-> 4000 2000 - 4000 aunt pero-> 5000 ^ 5000 altogether 20 German presentation no. 27 15 385 and 27 07 565 cephalosporin derivatives are described. which, like the cephalosporins prepared by the process of the present invention, contains a 7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] group. However, the cephalosporins prepared according to the present invention differ in a distinct manner from the known compounds in the configuration of the substituent in 3-position, and thus novel compounds with surprising effects have been provided. Thus, a comparison with a structurally close, comparable compound of the prior art (the only compound which, at the 3-position, similar to the subject cephalosporins, contains a 6-membered N-heterocyclic thiomethyl group, namely a ( -methyl-1-oxido-pyridazine-3-yl) thiomethyl group, shown to represent a representative compound of the ce-g phalosporins of formula I of the invention wherein X is a 1,2,5,6 hydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or its corresponding tautomeric form, a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3 -yl group, has a massive (over 50 times more potent) efficacy superior in a prophylactic in vivo test on mice against the pathogenic microorganisms Serratia marcescens, Klebsiella pneumoniae, Proteus mirabilis and Proteus vulgaris.

The products in question can be used as pharmaceuticals, e.g.

in the form of pharmaceutical compositions containing them or their salts in admixture with a pharmaceutically, organically or inorganically inert carrier suitable for enteral or parenteral application.

2q The process according to the invention is further illustrated by the following examples:

Example 1.

Preparation of (6R, 7R) -7- (2- [2- (2-chloroacetamido) -4- -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-l-azabicyclo [4.2.0] oct-2-ene 2-carboxylic acid. 22.24 g of 2- (2-chloroacetamido-thiazol-4-yl) -2- (Z-methoxy 2-imino) acetic acid are suspended in 240 ml of methylene chloride.

3

To this suspension is added 13.39 ml of triethylamine, 4 of which forms a light brown solution. This solution of 5 is cooled to 0 - 5 ° C, 16.72 g of phosphorus pentachloride 6 is added and stirred for 5 minutes at 0 - 5 ° C and for 20 minutes without cooling. The yellow solution is evaporated in vacuo at 35 ° C. The evaporation residue is shaken twice with n-heptane which is decanted off. The resinous residue is treated with 240 ml of tetrahydrofuran and the undissolved triethylamine hydrochloride is filtered off. The yellow filtrate contains the acid chloride.

22 g (7R) -7-amino-3-desacetoxy-3- [(2,5-dihydro-6-hydroxy- - 2-methyl-5-oxo-az-triazin-3-yl) thio] cephalosporanoic acid is suspended in a mixture of 300 ml of water and 150 ml of tetrahydrofuran. To the suspension, drop under a good cover of nitrogen gas 2N sodium hydroxide solution by using an autotitrator until a tan solution of pH 8 is formed. of the acid chloride in tetrahydrofuran. Then stir for 2 1/2 hours at 25 ° C. The pH of the acylation mixture is kept constant at 8 by the addition of 2N sodium hydroxide solution. The practically black solution is frozen for tetrahydrofuran in vacuo at 40 ° C. 100 ml of 2N sulfuric acid solution is then added. The thus precipitated substance is isolated by suction filtration, washed with water and thoroughly aspirated. The moist brown filtration product is dissolved in 1.5 liters of acetone. The dark solution is filtered off a small amount of dark undissolved material over "Hyflo" S / charcoal, stirred for 30 minutes and filtered again over "Hyflo" ®. The orange-red filtrate is dried over sodium sulfate, evaporated in vacuo and evaporated with ethyl acetate.

Thereby a black resin is precipitated which is filtered off and discarded. The 2-phase, still aqueous filtrate is subjected to azeotropic distillation 3 times with benzene in vacuo at 40 ° C. The precipitate thus obtained is isolated by suction filtration and dried in vacuo at 40 ° C. The substance is stirred twice with 1 liter of acetone each time, whereby as a residue a brown resin is obtained, which is discarded. The combined orange colored acetone extracts are evaporated in vacuo to 150 ml at 40 ° C, whereupon a brown resin is filtered off and discarded. To the filtrate is added 1 liter of ethyl acetate and evaporated in vacuo at 40 ° C. The precipitate thus obtained is isolated by suction filtration, washed with ethyl acetate and then with ether [(6R, 7R) -7- (2- [2- (2-chloroacetamido) - 14 149283 -4-thiazolyl] -2- (Z-methoxyimino ) acetamido) -3 - ([(2,5-di-hydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl - 8-oxo-5-thia- 1-azabicycloί4.2.0] oct-2-ene-2-carboxylic acid, fraction I: a beige colored, amorphous acid] This fraction I 5 can be used directly to prepare the desired final product.

The ethyl acetate mother liquor is vaporized vigorously in vacuo at 40 ° C and diluted with ether, and the precipitate is isolated by suction filtration [(6R, 7R> -7- (2- [2- (2-chloroacetamido) - 4-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 [4.2.0] oct-2-ene-2-carboxylic acid, fraction II: a light beige, amorphous acid, thin layer chromatographic] _5 somewhat purer than fraction I].

To prepare the disodium salt, 3.5 g of acid (fraction II) is dissolved in a mixture of 20 ml of acetone and 11 ml of water.

To this solution is added 7 ml of a 2N solution of 2-ethylcaproic acid sodium salt in ethyl acetate, thereby crystallizing the sodium salt. Then 25 ml of acetone is added portionwise and the mixture is stored in the freezer for 2 hours. Then, the crystallate is isolated by suction filtration, washed with 25 ml of an ice-cold acetone-water mixture (80:20), pure acetone and low-boiling petroleum ether in the order given and dried overnight in high vacuum at 40 ° C. There is obtained the disodium salt of (6R, 7R) -7 - (2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) -acetamido) -3 - ([(2.5- dihydro-6-hydroxy-2-methyl-5-oxo-as-30-triazin-3-yl) thio] methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] - oct-2 -an-2-carboxylic acid in the form of light yellow crystals.

= -142.7 ° (c = 1 in water), Nuclear resonance spectrum and microanalysis correspond to the structure indicated.

35

Example 2.

Preparation of the disodium salt of (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] -3- ([2,5- 149283-dihydro-6 -hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thiol - methyl) -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-car -boxylsyre.

15/3 g (6R, 7R) -7- (2- [2- (2-chloroacetamido) -4-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 [4.2.0] oct-2-ene 2-Carboxylic acid (Fraction I, see above) is suspended together with 5 g of 10 thiourea in 150 ml of water. Under good nitrogen gasification and stirring, the pH of 6.8 - 7.0 is adjusted with saturated sodium hydrogen carbonate solution to give an orange solution. Using autotitrate br, the pH of the reaction solution is kept constant at 6.8 for 6 hours while adding sodium hydrogen carbonate solution.

Then an additional 2.5 g of thiourea is added and the solution is stirred for an additional 3 hours while maintaining the pH of 6.8 with the addition of saturated sodium hydrogen carbonate solution. Then the red 20 solution is stored in the refrigerator overnight, thereby darkening. The pH of this solution is adjusted to 2.0 - 2.5 by the addition of 100% formic acid, whereby the substance precipitates. This is isolated by suction filtration and washed with 100 ml of 10% formic acid solution. The mother liquor is discarded.

The brownish suction filtration product is suspended in 200 ml of water and the pH is adjusted to 7 with triethylamine to give a brown solution. This solution is stirred with 2 g of activated charcoal for 30 minutes, the charcoal is filtered off and the still brown filtrate is adjusted with vigorous stirring to pH 3.5 with 100% formic acid. The thus precipitated substance is isolated by suction filtration, washed with 50 ml of 10% formic acid solution and discarded. The dark yellow filtrate is adjusted to pH 2-2.5 with 1001 formic acid, whereby the substance precipitates. This is isolated by suction filtration, washed with ice water and dried. The cephalosporic acid obtained is suspended for conversion to the disodium salt in a mixture of 40 ml of acetone and 40 ml of water and 20 ml of a 2-N solution of

Claims (7)

149283 2-Ethylcaproic acid sodium salt in ethyl acetate. To the orange solution thus formed is added 50 ml of acetone, which precipitates a brown resin which is separated by filtration. The yellow filtrate is stirred for 30 minutes to crystallize the disodium salt. To the mixture is added 50 ml of acetone in portions and the mixture is stored in the refrigerator overnight. The crystallate is isolated by suction filtration, washed with an acetone-water mixture at a ratio of 85:15, pure acetone and low-boiling petroleum ether in the order indicated and dried overnight in vacuo at 10 DEG C. 40 C. The title compound, in the form of 20 o of beige crystals, is obtained = -144 (c = 0.5 in water). Nuclear resonance spectrum and microanalysis correspond to the structure indicated. 15 Patent claims. 1. Analogous Process for the Preparation of Therapeutic Activity-2Q Some Cephalosporin Derivatives of General Formula I Η H 5. s CH30N = tC-conh -i-'N. 1 // - l KNJ-CH2-S-X R ° HN ^ \ S /. ] COOH where X represents a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-2Φ-as-triazin-3-yl group or the tautomeric 2,5-dihydro-6-hydroxy-2 -methyl-1-oxo-as-triazin-3-yl group, and R ° represents hydrogen or a leaving group which may be tert-butoxycarbonyl, trityl, trifluoroacetyl or chloro, bromo or iodoacetyl, or pharmaco-22 tally tolerable salts or hydrates of compounds of formula I wherein R ° represents hydrogen, or hydrates of these salts. 149283 characterized by reacting a compound of the general formula III Η H 5 in h2n —— r J— ^ s ~ x 111 COOH wherein X is as defined above and the carboxy group and / or amino group may be in protected form, with an acid of the general formula IV CH 3 NO = -C COOH RHN / 20 wherein R represents a leaving group as defined above, or having a reactive functional derivative of this acid, if. if necessary, the protecting group R and / or the peel off. a carboxy protecting group optionally present and, if desired, for the preparation of salts or hydrates of a compound of formula I wherein R R represents hydrogen, or of hydrates of these salts convert a compound of formula I into a salt or hydrate or hydrate of this salt. A process according to claim 1 for the preparation of compounds of the general formula II H H CH3ON = pCONH- | --j ^> j "jj oJ — N S— X RHN" \ / I s COOH