DE2529425A1 - 7-(2-(4-hydroxy-3-nitrophenyl)-2-aminoacetamido)-cephalosporins - with broad-spectrum antibacterial activity - Google Patents

Abstract

Cephalosporin cpds. of formula (I): (where R1 is H or CHO; R2 is H, Cl, Br or NO2; R3 is H, OCOMe or S-Het; Het is 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1-methyltetrazol-5-yl or 1,2,3-triazol-5-yl), esters and salts, are prepd. by reacting a 3-CH2R3-7-amino-3-cephem-4-carboxylic acid of formula (II): or a functional deriv. with a substd. phenylacetic acid of formula (III): or an activated deriv. (in the form of an acid addn. salt when R1 = H) or by treating a cpd. corresp. to formula (I) but contg. a functionally modified OH or NH2 gp. with a solvolysing or hydrogenolysing agent, and opt. converting R3 = OCOMe into R3 = S-Het-by reaction with Het-SH, and/or converting R1 = H into R1 = CHO by reaction with a formylating agent, and/or converting COOH into an ester or salt or vice versa, and/or isolating a pure epimer from an epimer mixt. of formula (I). (I) are antibacterial agents active against Gram-positive and -negative bacteria.

Description

Cephem derivatives and processes for their preparation The invention relates to the new cephem derivatives of the general formula I. wherein R¹ is H or CHO, R² is H, Cl, Br or NO2, R³ is H, OCOCH3 or -S-Het, and Het is 1,3,4-thiadiazolyl-2,5-methyl-1,3,4-thiadiazolyl-2 , 3-methyl-1,2,4-thadiazolyl-5, 1-methyltetrazolyl-5 or 1,2,3-triazolyl-5 mean, as well as their easily cleavable esters and their physiologically harmless salts.

The invention was based on the object of finding new compounds that can be used to manufacture drugs. This task was solved by providing the compounds of formula I.

These compounds have excellent antibacterial activity against gram-negative and against gram-positive germs. Compared with known semi-synthetic obtained cephalosporins, they show clear differences in terms of sensitivity of the individual germs. In numerous cases, known cephalosporins are used by the significantly outperformed new products, so that they can be used in the fight against certain Bacterial infections have crucial therapeutic advantages. That's how it is minimal inhibitory concentration of 7-f2-amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] -3- (1-methyltetrazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid and the sodium salt of this acid for a number of disease-causing agents, including Escherichia coli, Sarmonella tyhphimurium, Shigella kruso and Klebiella pneumoniae remarkably low.

7- [2-Amino-2- (3-bromo-5-nitro-4-hydroxyphenyl) acetamido] -3ephalos.poranic acid shows, for example, excellent activity (measured as DC50) against mice Staphylococcus aureus.

The compounds can accordingly be used as medicaments in particular can be used to combat bacterial infections. They can also be saved as Intermediate products can be used to manufacture other drugs.

The invention thus relates to the new compounds of the formula I and their easily cleavable esters and their physiologically harmless salts.

In addition to forinyl, the radical R1 preferably denotes H.

In addition to hydrogen and Cl, R2 is preferably Br or NO2.

preferably means H or OCOCH3 and in particular 3-methyl-1,2,4-thiadiazolyl-5-mercapto, 5-methyl-1,3,4-thiadiazolyl-2-mercapto or 1-methyl-tetrazolyl-5-mercapto before grad but 1,2,3-triazolyl-5-mercapto; however, R3 can also be 1,3,4-thiadiazolyl-2-mercapto Act.

1,2,3-Triazolyl-5-thiol is tautomeric to 1,2,3-Triazolyl-4-thiol. Both connections cannot be distinguished from one another, especially in solution pastures The same applies to the residues 1,2,3-triazolyl-5- (mercapto) and 1,2,5-triazolyl-4- (mercapto), which are derived from the two thioleii mentioned and which are also not can be distinguished from each other. Hiex and subsequently 1,2,3-triazolyl-5- or 1,2,3-triazolyl-5-mercapto also the 1,2,3-triazolyl-4- or 1,23-triazolyl-4-mercapto radical Understood.

Easily cleavable esters of the compounds of the formula I are in first and foremost the tert-butyl esters also mentioned, for example, the trimethylsilyl, benzyl, Benzhydryl, trichloroethyl, benzoylmethyl, p-methoxybenzyl or methoxymethyl esters, also the pivaloyloxymethyl esters.

Accordingly, the invention particularly relates to those Compounds of the formula I in which at least one of the radicals mentioned is one of the has preferred meanings given above. Some of the preferred groups of compounds can be expressed by the following sub-formulas Ia to Ih, which correspond to the formula I and in which the radicals unspecified in the of the formula I have given meanings, in which, however, in Ia R³ is OCOCH3; in Ib R3 is 3-methyl-1,2,4-thiadiazolyl-5-mercapto; in Ic R3 5-methyl-1,3,4-thiadiazolyl-2-mercapto means; in I d R³ is 1-methyl-terazolyl-5-mercapto; in Ie R³ 1,2,3-triazolyl-5-mercapto means; in If R3 is H; in Ig R1 denotes H and R2 Br or NO2; in lh R1 H, R2 is Br or NO2 and R³ is -S-Huet; imm Ii R1 H, R2 Br or NO2 and R3 H means; in Ij R1 is H and R3 1,2,3-triazolyl-mercapto.

The α-C atom of the substituted phenylacetyl radical, which Forming the side chain in a compound of Formula I is asymmetrical The invention therefore covers pure epimers in which this C atom has the D configuration and those pure epimers in which this carbon atom has the L configuration.

But also the epimer mixtures of the formula I in which the a-C atom of the side chain is D- and L-configured in approximately equal parts are the subject the invention. Such compounds of the formula I are particularly preferred, in particular of the formulas Ia to Ij, in which the α-C atom of the side chain has the D configuration having.

The invention also relates to a process for the preparation of the compounds of formula I and their easily cleavable esters and their physiologically insignificant salts, which is characterized in that a 3-CH2R³-7-amino-3-cephem-4-carboxylic acid is used general formula II wherein R³ has the meaning given, or one of its functional derivatives with a substituted phenylacetic acid of the general formula III wherein R¹ and R² have the meanings given, or reacts one of their activated derivatives, the acid II or its activated derivative being present as an acid addition salt if R¹ is hydrogen, or that functionally modified OH contained in an otherwise corresponding to the formula I prior bond - or NH2 groups by treatment with solvolyzing or hydrogenolyzing agents and that, if necessary, in the product obtained, the substituent R³ is exchanged for another substituent R³ by treating an acetoxy group with a thiol of the formula Het-SH or a corresponding one Mercaptide converts into the radical -S-Het and / or converts an amino group into a formylamino group by treatment with a formylating agent and / or converts a carboxyl group into an easily cleavable carboxylic acid ester group by treatment with an esterifying agent and / or from a salt or ester obtained Acid in freedom set Zt and / or an acidic or acidic compound of the formula I obtained is converted into one of its physiologically acceptable salts by treatment with a base or acid and, if desired, a pure epimer is isolated from an epimer mixture of the formula I.

All of these conversions proceed according to methods such as those used in cephalosporin chemistry are known and described in the literature.

The invention also relates to a process for the production of pharmaceutical preparations, characterized in that a compound of general formula I and / or one of its easily cleavable esters and / or one their physiologically harmless salts together with at least one solid. liquid or semi-liquid carrier or excipient and optionally together with another Bringing the active ingredient into a suitable dosage form.

Finally, there are also pharmaceutical preparations containing one Compound of the general formula I and / or one of its easily cleavable esters and / or one of their physiologically harmless salts, the subject of the invention.

Some of the starting materials for the process according to the invention are known, partly new. You can use known methods analogously known compounds getting produced.

For example, the acids II (R = -S-Het) can be obtained from 7-aminocephalosporanic acid (7-ACS; II, R = -OCOCH3) by reaction with the known heterocyclic thiols of the formula Het-SH, or the associated metal mercaptides, e.g.

by reaction of the corresponding alkali metal salts in hot aqueous Acetone.

As functional derivatives of an acid of the formula Ii are suitable in primarily the easily cleavable esters, e.g. the tert-butyl esters, the trimethylsilyl esters (e.g. those formed in situ from II and N-trimethylsilyl-acetamide) and the others esters given above. Furthermore, the salts, especially the neutral salts these acids are suitable. The alumina metal (e.g. sodium, Potassium), alkaline earth metal (e.g. magnesium, calcium) and ammonium salts. Under the the latter are those of amines, especially tertiary amines, e.g. triethylamine, Triethanolamine, pyridine, collidine, derived salts are preferred.

These salts can be used as such in the reaction; they can also be made up of an acid II and a base, e.g. NaHCO3, Na2HPO4 or triethylamine.

The activated derivatives of the acids III are particularly suitable Halides, preferably the chlorides and bromides, furthermore the anhydrides and mixed Anhydrides as well as azides and activated esters, e.g. those with p-nitrophenol, 2,4-dinitrophenol, p-nitrophenyl mercaptan, methylene cyanohydrin or N-hydroxysuccinimide. As mixed Anhydrides of acids III are e.g. on the one hand those with lower alkanoic acids, in particular acetic acid and substituted acetic acids such as trichloroacetic acid, Pivalic acid or cyanoacetic acid and on the other hand anhydrides with Carbonic acid half-esters, which e.g. by reacting the acids III with chloroformic acid benzyl ester, -p-nitro-benzyl ester, isobutyl ester, ethyl ester and allyl ester are available. All of these functional derivatives of III are preferably generated in situ.

If an activated derivative of a compound of the formula III (R1 = H) is used, it is always used as an acid addition salt, the Proton acts as an amino blocking group and prevents self-acylation.

The acid addition salts used are mainly those with strong acids in question, preferably with strong mineral acids such as HCl, HBr; HJ, H SO, or HNO3, but optionally also with strong organic acids, for example trichloroacetic acid or trifluoroacetic acid. It is particularly advantageous to acylate a compound of formula II or

one of their functional derivatives is the hydrochloride of acid chloride to use a compound of formula III.

In general, the implementation of the cephem derivatives II (or their functional derivatives) with the compounds of the formula III (or with their activated Derivatives) in the presence of an inert solvent. Suitable solvents are especially chlorinated hydrocarbons, e.g., methylene chloride, chloroform; Ether, such as diethyl ether, tetrahydrofuran, dioxane; Ketones such as acetone, butanone; Amides like Dimethylformamide (DMF), dimethylactamide, hexamethylphosphoric acid triamide; Sulfoxides, such as dimethyl sulfoxide (DO); Water; also organic or aqueous inorganic Basel. Mixtures of the solvents mentioned can also be used. Provided a salt of a compound of formula I is to be prepared is as a solvent in particular an excess of the base used to form this salt is suitable, e.g. triethylamine or aqueous sodium hydroxide solution.

The reaction of a compound of formula II with a compound of the formula III (or one of its activated derivatives) usually occurs at Temperatures between -70 and + 80 °, preferably between -50 and + 30 °, in particular between -40 and 10 °. The reaction time depends on the type of starting materials selected and the reaction temperature dependent; it is usually between 5 minutes and 72 hours.

In particular, it is particularly useful to have a first, preferably a tert-butyl ester of acid II with the free phenylacetic acid III (R¹ = CHO) to implement, advantageously adding a water-binding agent. As such, come e.g. carbodiimides, especially dicyclohexylcarbodiimide (DCO). So lets for example 7-ACS-tert-ethyl ester, the acid III (R¹ = CHO) and DCC in approximately equimolar amounts Shares and react with cooling in an inert solvent, in particular in methylene chloride, DMF, DMSO or solvent mixtures.

The implementation of II with activated derivatives (or their salts) the acids II is preferably carried out in the presence of a basic catalyst. Suitable basic catalysts are inorganic metal hydroxides, preferably Alkali metal or alkaline earth metal hydroxides, basic salts, as well as organic ones Amines, preferably tertiary organic amines. In particular, NaHCO3 is used, KHCO3, Na2CO3, K2CO3, NaOH, KOH, pyridine or a base of low nucleophiles, e.g. a tertiary amine such as triethylamine, N-methylmorpholine, ethyldiisopropylamine or Potassium tert-butoxide.

The cephem derivatives of the formula I are also available by one contained in a compound otherwise corresponding to formula I functionally sets modified OH or NH2 groups according to known methods in freedom.

The starting materials for this process variant are e.g.

obtainable analogously to the methods described above, but with sensitive functional groups during synthesis by protecting groups functional modifies.

Functionally modified OH groups are, for example, in Consideration: etherified or esterified hydroxyl groups e.g. benzyloxy or acetoxy.

Functionally modified NH2 groups have special meanings. The corresponding compounds are obtained, which otherwise correspond to formula I, by reacting compounds of the formula II or their functional derivatives with compounds which otherwise correspond to formula III (or their activated derivatives), but in which the amino group is replaced by a protective group known from peptide chemistry is blocked. Suitable protecting groups are e.g. tert-butoxycarbonyl, carbobenzyloxy, 2-hydroxy-1-naphthylcarbonyl, trichloroethoxycarbonyl, 2-ethoxycarbonyl-1-methylvinyl and 2-methoxycarbonyl-1-methylvinyl and the formyl group.

; If you use the t-butoxycarbonyl, ß-ketoester, ß-diketone or β-ketoamide protecting groups (see British Patent 1,123,333 or U.S. Patents 3,325 479 and 2 316 247 resp.

Japanese Patent 71/24714), it is preferably used as an activated one Derivative of the acylating acid which, apart from the protected amino group, the Formula III corresponds to a mixed anhydride, e.g. with a carbonic acid half-ester the Acylation of a 7-amino group of a cephalosporin is a known reaction, and every functional equivalent of a compound of the formula III, as blicherweise used as an acylating agent for primary amino groups can be used. Examples of suitable acylating derivatives of the free acid have already been mentioned been.

The free acid can be coupled with compound II if one first has reacted the free acid with N, N'-Dimethylchlorformimi niumchlorid, or through the use of enzymes or an N, N'-carbonyldiimidazole or a N, N'-carbonylditriazole or a carbodiimide reagent, e.g.

N, N'-diisopropylcarbodiimide, N, N'-dicyclohexylcarbodiimide or N-cyclohexyl-N '- (2-morpholinoethyl) -carbodiimide or with the help of an isoxazolium salt. Another activated derivative is a Corresponding azolide, i.e. an amide of the corresponding acid, its amide nitrogen Is a member of a quasi-aromatic 5-membered ring containing at least 2 nitrogen atoms contains, e.g. an imidazole, pyrazole, triazole, benzimidazole or benzotriazole ring. Another suitable derivative of the substituted phenylglycine acid of the formula III is N-carboxy anhydride (Leuchs' anhydride). Here is the group that serves activates the carboxyl group, also to protect the amino group.

The functionally modified groups can according to known, methods described in the literature solvolytic, especially hydrolytic, or set free by hydrogenolysis. A solvolysis, preferably hydrolysis, in particular also a formylamino group, e.g. with trifluoroacetic acid or with aqueous mineral acids, e.g. hydrochloric acid, at temperatures between 100 and 50 ° carried out. Hydrogenolysis of functionally modified groups, in particular an elimination of benzyl, tert-butoxycarbonyl and carbobenzyloxy radicals is possible by hydrogenation in the presence of noble metal catalysts, such as 5-50 one Palladium on carbon, or palladium oxide.

It is advisable to hydrogenolyze at temperatures between 10 and + 50 °, especially at room temperature, and at pressures between 1 and 10 at, preferably at normal pressure.

Particularly mild hydrogenation conditions must be selected in order to to avoid the undesired reduction of a NO2 group.

If desired, one can in the product of the formula I obtained according to per se known from the literature methods a substituent R³ against one exchange other substituents R.

It is particularly advantageous to use a cephalosporanic acid obtained Formula I (R3 = OCOCH3) by reaction with a mercaptan of the formula Het-SH in to convert the corresponding thioether (R3 = -SHet). One uses appropriately Salt of cephalosporanic acid with a salt of thiol in aqueous acetone at temperatures between 20 and 1000 and pH values between 4 and 8 µm. Particularly suitable salts are the alkali metal salts, especially the sodium salts.

This synthetic route is particularly suitable for the production of compounds of the formula I (R1 = CHO).

As already explained, the compounds of formula I have in the with the side chain linked to the ß-lactam ring an asymmetry center. you will be therefore mostly obtained as a mixture of two epimeric forms, which due to their different physical properties isolated from the mixture and pure can be obtained, for example, by recrystallization from suitable solvents (In particular, instead of the compounds themselves, well-crystallizing derivatives can be used), but especially with the help of chromatographic methods, both adsorption chromatographic or partition chromatographic methods as well as mixed forms are possible.

Furthermore, it is of course possible to use pure diastereomeric compounds of the formula I according to the methods described, by adding compounds the formula TTI (resp.

their activated Derivatej used as starting materials that already are cptically active.

The optically active compounds of the formula III or their activated ones Derivatives can be based on a variety of well-known methods, as they are in the literature, in particular also given for the cleavage of racemic α-amino acids are made from the racemates. The method of chemical separation is to be preferred. Thereafter, from the racemic mixture by reaction with an optically active auxiliary formed diastereomers. So you can if necessary an optically active base with the carboxyl group of a compound of the formula III realize. For example, one can use diastereomeric salts of compounds of the formula III with optically active amines such as quinine, brucine, morphine or 1-phenylethylamine form.

The amino group can be reacted with an optically active acid such as (+) - and (-) - tartaric acid, camphoric acid or ß camphorsulphonic acid for the formation of more suitable diastereomeric salts are used, preferably an ester of the Amino acid used.

The difference in the solubility of the diastereomers produced in each case Salt allows the selective crystallization of one form and regeneration the respective optically active compounds from the mixture.

You can also a free carboxylic acid I by esterification into a convert easily cleavable carboxylic acid ester.

For example, the tert-butyl esters are obtained by reacting the acids with Isobutylene.

Conversely, the acid I can be set free from an ester obtained e.g. by solvolysis, in particular by acid hydrolysis. The one in the synthesis tert-butyl esters obtained particularly advantageously are, for example, with trifluoroacetic acid cleaved at temperatures between 0 and 40 °.

The new cephem derivatives are solid crystalline or amorphous products. They form solid, often crystalline, alkali metal, ammonium and alkaline earth metal salts as well as salts with organic bases such as diethylamine, triethylamine, diethanolamine, N-ethyl-diethanolamine, pyrrolidine, piperidine, N-ethylpiperidine, 1- (2-hydroxyethyl) piperidine, Morpholine, procaine, benzylamine, dibenzylamine, 1-phenyl-2-propylamine and others Amines, such as those commonly used for the production of cephalosporin salts Find.

Of the alkali metal salts, the sodium and potassium salts are in particular significant. They can be made by adding a solution of an acid I in an organic solvent with a solution of the sodium or potassium salt a fatty acid, e.g. diethylacetic acid or 2-ethylcaproic acid, in a solvent, e.g. acetone or n-butanol, or mixed with a solvent mixture. The one with it or salts which precipitate on the addition of ether can be filtered off.

Basic compounds of the formula I can be mixed with acids in the usual way Way can be converted into the associated acid addition salts, e.g. into the hydrochlorido or citrate.

Since the compounds I have no sharp melting points, will appropriately characterized by other physical indicators, especially advantageous due to their nuclear magnetic resonance spectra. You can also use the thin layer chromatogram be characterized. For this purpose, Merck TLC precast silica gel plates can be used F254 is used (superplasticizer e.g. dioxane / water 8: 151.

The new compounds can be mixed with solid, liquid and / or semi-liquid pharmaceutical carriers as pharmaceuticals in human or veterinary medicine be used.

The carrier substances used are organic or inorganic Substances in question that are used for enteral, preferably oral, e.g. but also for parenteral or topical application are suitable and those with the new compounds do not react, such as water, vegetable oils, benzyl alcohols, polyethylene glycols, Gelatin, lactose, starch, magnesium U-earat, talc, petroleum jelly, cholesterol. For the enteral application are e.g. tablets, capsules, coated tablets, syrups, juices or Suppositories. Solutions, preferably, are used in particular for parenteral application oily or aqueous solutions, as well as suspensions, emulsions or implants, for the topical application of ointments, creams or powders. These preparations can be sterilized or with auxiliaries, emulsifiers, salts to influence the osmotic pressure, Buffer substances, dyes are added. You can also use other active ingredients contain.

The compounds of general formula I and their easily cleavable Esters and their physiologically acceptable salts can essentially be used in the same way as the known compounds cephalexin and cephalotin to combat used by infections; they are preferably used in dosages between 1 and 5000; administered in particular between 200 and 2000 mg per dosage unit. The daily dosage is preferably between 4 and 100, in particular between 10 and 40 mg / kg body weight.

Each of the compounds of the formula mentioned in the following examples I is particularly suitable for the production of pharmaceutical additives.

The IR spectra were measured in KBr.

The NMR spectra are recorded in methyl sulfoxide.

DMF = dimethylformamide, 7-ACS - 7-aminocephalosperanic acid.

DCC = dicyclohexylcarbodiimide.

Unless otherwise stated, the following examples the substituted 2-NMR¹-2-phenylacetic acids of the formula II (or their derivatives) used as racemates; accordingly, the compounds of formula I are then obtained as mixtures of two epimers.

Example 1 a) A mixture of 3.28 g of 3-deacetoxy-7-ACS-tert-butyl ester is stirred, 3.29 g of 2-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetic acid, 2.5 g of DCC, 10 ml of dry DMF and 15 ml of dry methylene chloride for 1 hour at room temperature, filtered, the filtrate soaks in on a silica gel column, eluted with ethyl acetate, we obtain from the eluate after distilling off the solvent 7- [2-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetoamido] -3-methyl-3-cephem-4-carboxylic acid-tert.- butyl ester as residue, NMR: signals at 1.5 ppm (9 protons), 2 ppm (3 protons), 3.1 - 3.7 ppm (2 protons), 4.9-5.1 ppm (1 proton), 5.4-5.8 ppm (2 protons), 7.8 - 7.9 ppm (2 protons), 8.9 - 9.1 ppm (1 proton), 9.3 - 9.5 ppm (1 proton).

The correspondingly substituted 2-phenyl-2-formylaminoacetic acids are analogous obtainable by reaction with 3-deacetoxy-7-ACS-tert-butyl ester in the presence of DCC: 7- [2-Formylamino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid tert-butyl ester 7- [2-Formylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido] -3-methyl-3-cephem-4-carboxylic acid tert-butyl ester 7- [2-Formylamino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid tert-butyl ester.

b) 1.4 g of 7- [2-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-cerbonic acid tert-butyl ester are dissolved in 15 ml of dry trifluoroacetic acid, stirred for 15 minutes at room temperature, distilled the trifluoroacetic acid is removed and 7- [2-formylamine-p-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid is obtained as the residue.

The corresponding cephem-4-carboxylic acid tert-butyl esters are analogous hardenable by treatment with dry trifluoroacetic acid: 7- [2-formylamino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid 7- [2-Formylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid 7- [2-Formylamino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid.

c) A mixture of 0.5 g of 7- [2-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid tert .-butyl ester, Stand 30 ml of THF and 4 ml of concentrated aqueous HCl at 5 ° overnight, pour extracted in water with ethyl acetate and obtained after distilling off the organic Solvent 7- [2-Amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamido] -3-methyl-3-cephem-4-carboxylic acid tert-butyl ester as a residue.

Analogously from the corresponding formylamino compounds through Treatment with HCl available in TlIF: 7- [2-Amino-2- (3-nitro-4-hydroxylphenyl) acetamido] -3-methyl-3-cephem-4-cerbonic acid tert-butyl ester 7- [2-Amino-2- (3-bromo-5-nitro-4-hydroxyphenyl) acetamido].

3-methyl-3-cephem-4-cerbonic acid tert-butyl ester 7- [2-amino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4- tert-butyl carboxylate.

d) 1.2 g of 7- [2-amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido-3-methyl-3-cephem-fi-carboxylic acid tert-butyl ester are stirred, dissolved in 15 ml of trifluoroacetic acid for 30 minutes at 5 °, the solvent is distilled and the residue obtained is the trifluoroacetate of 7- [2-amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetatnidoJ-3-methyl-3-eephem-4-carboxylic acid. This salt, dissolved in 40 ml of water, is stirred for 1 hour at 250 with 20 g of a polystyrene-amine ion exchange resin (Amberlite IR-45), separates the ion exchanger and lyophilises the aqueous Solution. 7- [2-Amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] -3-methyl is obtained.

3-cephem-4-carboxylic acid (betaine form).

The corresponding tert-butyl esters are analogously treated by treatment obtainable in betaine form with trifluoroacetic acid: 7- [2-Amino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid 7-E2-Amino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido7 3-methyl-3-cephem-4-carboxylic acid 7- [2-Amino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4 carboxylic acid.

The substituted 2-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetic acid used as the starting material can be prepared as follows: A mixture of 1.8 g of 2-amino-2- (3-chloro-4-hydroxyphenyl) acetic acid is stirred, 4 ml of acetic anhydride and 14 ml of formic acid for 3 hours at 0 °, the solvent is distilled and receives 2-formylamino-2- (3-chloro-4-hydroxyphenyl) acetic acid as a residue.

300 mg of 2-formylamino-2- (3-chloro-4-hydroxyphenyl) acetic acid are added at 0 °, dissolved in 10 ml glacial acetic acid and 5 ml acetic anhydride 0.2 ml aqueous nitric acid (density = 1.5). After 10 minutes, the precipitate formed is of 2-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetic acid filtered off and dried.

Analogously, formylation and nitration at 0 ° give 2-amino-2- (3-bromo-4-hydroxyphenyl) acetic acid the 2-formylamino- (3-bromo-5-nitro-4-hydroxyphenyl) acetic acid and correspondingly 2-Amino-2- (4-hydroxyphenyl) acetic acid 2-Formyamino-2- (3-nitro-4-hydroxyphenyl) acetic acid.

Is the nitration of 2-formylamnino-2- (4-hydroxyphenyl) acetic acid carried out at room temperature, 2-formylamino-2- (3,5-dinitro-4-hydroxyphenyl) acetic acid is obtained.

The free substituted aminophenylacetic acids are selected from the substituted Formylaminophenylacetic acids by treatment with EICl in THF at room temperature manufacturable.

Example 2 2.4 g of 7- [2-tert-butoxycarbonylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido] -cephalosporanic acid are stirred 30 minutes at 250 in a mixture of 10 ml of trifluoroacetic acid and 5 ml of anisole, the solvent is distilled off and 7- [2-amino- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido-7-cephalosporic acid is obtained as trifluoroacetate. The free acid can therefrom as described in Example 1d as Betaine can be obtained.

The starting material is obtained by reacting 2-tert-butoxycarbonylamino-2- (3-brcm-5-nitro-4-hydroxyphenyl) acetic acid (obtainable from 2-amino-2- (3-bromo-5-nitro-4-hydroxyphenyl) acetic acid by reacting with tert-butoxycarbonylazide in the presence of MgO) with 7-ACS in the presence of ethyl chloroformate.

Analogous are by solvolysis of the corresponding N-tert-butoxycarbonyl derivatives available: 7- [2-Amino-2- (3-nitro-4-hydroxyphenyl) -acetamido] -cephalosporanic acid 7- [2-Amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamido] -cephalosporanic acid 7- [2-Amino-2- (3,5-dinitro-4-hydroxyphenyl) -acetamido] -oophalosporanic acid.

Example 3 a) 1.45 g of 7- [2-formylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido] -cephalosporanic acid are suspended and 232 mg of 1-methyltetrazole-5-thiol in 8 ml of water at room temperature the reactants thereby adding NaNCO3 in solution, whereby the pH value between 4 and 7 is, heated for 3 hours at 70 °, brings the reaction mixture after cooling with concentrated hydrochloric acid to piI 2, filtered and the precipitate dried. 7- [2-Formylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) acetamido] -3- (1-methyl-tetrazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid is obtained.

Analogously, they can be obtained by reacting the corresponding cephalosporanic acid with 1-methyltetrazol-5-thiol: 7- [2-formylamino-2- (3-mitro-4-hydroxyphenyl) acetamido] -3- (1-methyl-tetrazolyl-5-mercaptomethyl) -3-cephem-4 -carboxylic acid 7- [2-Formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamido] -3- (1-methyl-tetrazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid 7- g -Formylamino-2- (3,5-dinitro-4-hydroxypnenyl) -acetamido] -3- (1-methyl-tetrazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid.

b) 0.6 g of 7- [2-formylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) acetamido] -3- (1-methyl-tetrazolyl-5-mercaptomethyl2-3-cephem) is stirred -4-carboxylic acid overnight at room temperature in a mixture of 20 ml of THF and 3 ml of concentrated Hydrochloric acid, most of the solvent is distilled off, 5 ml of H20 are added to the residue, brings to pH 4 with dilute aqueous NaHCO3 solution, lets stand for 4 hours at 0 °, filtered and dried the precipitate. 7 g -amino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido] -3- (1-methyl-tetrazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid are obtained.

Analogous are by solvolysis of the corresponding formylamino compounds of the formula I available: 7-S-amino-2- (3-nitro-4-hydroxyphenyl) -acetamido7-3- (1-methyl-tetrazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid 7- [2-Amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamido] -3- (1-methyl-tetrazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid 7- [2-Amino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3- (1-methyl-tetrazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid.

Example 4 a) Analogously to Example 3a, the corresponding cephalosporanic acids are obtained obtainable by reaction with 1,3,4-thiadiazol-2-thiol: 7-L2-formylanzino-2- (3-nitro-4-hydroxyphenyl) -acetamidov-3- (1,3,4-thiadiazolyl-2-mercaptomethyl ) -3-cephem-4-carboxylic acid 7- [2-Formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamido / -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -5-cephc. ~ -4- carboxylic acid 7-E2-Formylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid 7- [2-Formylamino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid; and by reacting with 5-methyl-1,3,4-thiadiazol-2-thiol: 7- [2-formylamino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3- (5-methyl-1 , 3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid 7- [2-Formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamido] -3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem- 4-carboxylic acid 7- [2-Formylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamide S-3- (5-methyl-1,3,4-thiadiasolyl-2-mercaptomethyl) -3-cephem- 4-carboxylic acid 7-E-Formylamino-2- (3, 5-dinitro-4-hydroxyphenyl) -acetamido] -3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid .

b) Analogous to example 1d are from the cephem derivatives mentioned in example 4a obtainable by reaction with trifluoroacetic acid: 7-g2-amino-2- (3-nitro-4-hydroxyphenyl) -acetamido7-3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid 7-E2-Amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamidoJ-3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid 7- [2-Amino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido] -5- (1,3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid 7- [2-Amino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid 7- [2-Amino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thiadiazolyl-2-mercaplomethyl) -3-cephem-4-carb onic acid 7- [2-amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -3- cephem-4-carboxylic acid 7- [2-Amino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido] -5- (5-methyl-1,3,4-thiadiaz.olyl-2-mercaptomethyl) -3- cephem-4-carboxylic acid 7- [2-Amino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4- carboxylic acid.

Example 5 a) 2.85 g of 2-formylamino-2- (3,5-dinitrophenyl) acetic acid are added and 1.1 ml of triethylamine, dissolved in 50 ml of anhydrous THF with stirring, 1.15 ml of isobutyl chloroformate, 4.45 g of 7-amino-3- (3-methyl-1,2,4-thiadiazole-5-mercaptomethyl) -3-cephem-4-carboxylic acid triethylamine salt are added dropwise at -10 °, dissolved in 20 ml of THF and 20 ml of water, stirred for 1 hour at 0 ° and one more hour Hour at 250, the THF is distilled off, 20 ml of water are added to the residue, and the mixture is added with HCl to pH 3, extracted with ethyl acetate, the organic phase dries over MgSO4, the solvent is distilled off and 7- [2-formylamino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3- (3-methyl-1,2,4-thiadiazolyl-5) is obtained as residue -mercaptomethyl) -3-cephem-4-carboxylic acid.

The corresponding 2-formylaminophenylacetic acids are analogous by reacting with 7-amino-3- (3-methyl-1,2,4-thia diazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid or the salts of these acids available in the presence of isobutyl chloroformate: 7- [2-Formylamino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid ? -F2-Formylamino-2- (3-chloro-5-nitro-4-hydroxyheny1) -acetamido] -3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -3-cephem-4 -carboxylic acid 7- [2-Formylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido] -3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -3-cephem- 4-carboxylic acid 7- [2-Formylamino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -3-cephem-4- carboxylic acid.

b) Analogously to example id are from the cephem derivatives mentioned in example 5a obtainable by reaction with trifluoroacetic acid: 7- [2-Amino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3- (3-methyl-1,2,4-thioadiazolyl-5-mercaptomethyl) - 3-cephem-4-carboxylic acid 7- [2-Amino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3- (3-methyl-1,2,4-thioadiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid 7- [2-Amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamido] -3- (3-methyl-1,2,4-thioadiazolyl-5-mercaptomethyl) -3-cephem- 4-carboxylic acid 7- [2-Amino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido] (3-methyl-1,2,4-thioadiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid .

Example 6 a) A mixture of S2.8 g is stirred for 3 hours at 400 7-ACS-tert formyl ester, 25 g DCC and 32.9 2-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetic acid in 150 ml of dioxane and 50 ml of DMF, the reaction mixture is filtered and the distillation is carried out Solvent off, bring the residue with ethyl acetate on a silica gel column, eluted with ethyl acetate, the eluate is dried over Na2SO4, the solvent is distilled and receives as residue 7- [2-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] cephalosporanic acid tert-butyl ester.

The corresponding substituted 2-formylamino-2-phenylacetic acids are analogous by implementing with 7-ACS-tert. Butyl ester available: 7- [2-Formylamino-2- (3-nitro-4-hydroxyphenyl) acetamido] cephalosporanic acid tert-butyl ester 7- [2-Formylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido] -cephalosporanic acid, tert-butyl ester 7- [2-Formylamino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] cephalosporanic acid tert-butyl ester.

b) Analogously to Example 1b, from the tert-butyl esters mentioned in Example 6a obtainable by treatment with dry trifluoroacetic acid: 7- [2-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamido] -cephalosporanic acid 7- [2-Formylamino-2- (3-nitro-4-hydroxyphenyl) -acetamido] -cephalosporanic acid 7- [2-Formylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido] -cephalosporanic acid 7- [2-Formylamino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] cephalosporanic acid.

c) 5.2 g of 7- [2-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] cephalosporanic acid are dissolved and 1.3 g of 5-methyl-1,3,4-thiadiazole-2-thiol by adding NaHCC3 in 40 ml of water and adjusts the pH to 5.2. The mixture is stirred for 2 hours with constant pH control at 75 °, precipitate with concentrated HCl, filtered and dry the filter cake. 7- [2-Formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -3- is obtained cephem-4-carboxylic acid.

The other cephalosporanic acids mentioned in Example 6b are analogous obtainable by reaction with 5-methyl-1,3,4-thiadiazol-2-thiol: 7- [2-formylamino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3- (5-methyl-1 , 3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid 7-E-Formylamino-2 (3-bromo-5-nitro-4-hydroxyphenyl) -actamido] -3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl 3-cephem-4-carboxylic acid 7- [2-formylamino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -3-cephem-4-carboxylic acid.

Example 7 Analogously to Example 6a, conversion of 7-ACS-tert Butyl ester with 2-D-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetic acid (available from the racemic acid by resolution with the help of cinchonine in water): 7- [2-Formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] -cephalosporanic acid tert-butyl ester.

Example 8 A solution of 2.8 g of 2-L-formylamino-2- (3,5-dinitrophenyl) acetic acid is added (obtainable from the racemic acid by cleavage with the help of (+) - α-naphthylethylamine in ethanol) and 1.15 g of N-hydroxysuccinimide in 30 ml of dry TIIF at 00 2.1 g DCC and stir for 5 hours at 00, filtered, the solvent is distilled off and gives the residue at 0 ° to a solution of 3.4 g of '7-Amin.o-3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid and 1 g of triethylamine in 80 ml of dry pyridine.

The mixture is stirred for 3 hours at 40 °, poured into 180 ml of water, brought with aqueous HCl to pH 2, filtered and dried the precipitate. 7- [2-L-formylamino-2- (3,5-dinitrophenyl) acetamido] -3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -3-cephem-4- is obtained carboxylic acid.

Example 9 a) 3.4 g of 7-amino-3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid are suspended in 50 ml of dry acetonitrile, gives 1 g of triethylamine and 2 ml of N, N-dimethylaniline to, cools to 5 ° and 12.7 g of trimethylchlorosilane are added dropwise. It is left to stand for 10 minutes, then add within 15 minutes at 50 3 g of 2-amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetyl chloride hydrochloride (obtainable from a suspension of 2-amino-2- (3-chloro-5-nitro-4-hydroyphenyl) -acetic acid in dry dioxane by successive introduction of dry Phosgene and dry HCl gas), the mixture is stirred for 1 hour at 12.degree Stir 40 ml of water. Adds Na2CO3 until a pH of 2p5 is reached, separates the organic phase, brings the aqueous phase with HCl to a pH of 2, washes with diethyl ether, brings the aqueous phase with NaOH (dilute aqueous Solution) to pH 4 and concentrated until crystals form. Leave at 50 overnight stand, filtered and dried the precipitate. 7- [2-Amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamido] -3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -3- is obtained cephem-4-carboxylic acid.

The epimer mixture obtained can phisch thin-layer chromatography (Kleselgel / dioxane: water = 85:15) can be separated into the pure epimers.

b) Nan stirs 2.2 g of 7- [2-amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] -3- (3-methyl-1,2,4-thiadiazolyl-5) -mercaptomethylj-5-cephem-4-carboxylic acid 2 hours at 5 ° in a mixture of 15 ml of formic acid and 4 ml of acetic anhydride, the solvent is largely distilled off (about 16 ml of distillate), gives Add 20 ml of water to the residue, leave to stand at 0 ° for 1 hour, filter and dry the precipitation. 7-Z> -Formylamino-2- (3-chloro-5-nitrc 4-hydroxyphenyl) -acetamidov-3- (3-methyl-1,2,4-thiadiazolyl-5-r.ercaptomethyl) -3- is obtained cephem-4-carboxylic acid.

c) An autoclave (volume approx. 100 ml) is filled at -10 ° a solution of 0.6 g of 7-g2-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamidol-3- (3-meth.yl-1,2,4-thiadiazolyl-5- mercaptomethyl) -3-cephem-4-carboxylic acid (Mixture of two epimers) in 22 ml of dry dioxane, which concentrated 1 drop Contains sulfuric acid and 5 ml isobutylene. Shake for 2 hours at room temperature, poured into 200 ml of a dilute aqueous NaHCO3 solution and extracted with ethyl acetate. After drying over MgSO4, the solvent is distilled off. 7- [2-Formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] -3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) is obtained -3-cephem-4-carboxylic acid tert. -butyl ester as a mixture of two epimers, which chromatographic (silica gel ready-to-use columns from E. Merck, Darmstadt / ethyl acetate) can be separated into the pure epimers.

Example 10 a) A mixture of 600 mg of 7- [2-D-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamido-cephalosporanic acid is added (obtainable from the tert-butyl ester prepared according to Example 7 by reaction with trifluoroacetic acid analogous to Example 2), 200 mg 1,2,3-triazolyl-5-thiol and 20 ml of water with saturated aqueous NaHCO3 solution to pH = 5.5, stir for 2 hours at 800, pour into 30 ml of water, precipitate with concentrated HC1, filtered, brings the filtrate to pH 1 with concentrated HCl, extracted with a mixture from THF and ethyl acetate (7: 8), the organic phase is dried over MgSO4, distilled the solvent and the residue recrystallized from diethyl ether. You get 7- [2-D-Formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] -3- (1,2,3-thiazolyl-5-mercaptomethyl) -3-cephem-4- carboxylic acid.

The other cephalosporanic acids mentioned in Example 6b are analogous available: 7-2-D-formylamino-2- (3-nitro-4-hydroxyphenyl) -acetamido2 3- (1,2,3-thiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid, 7-E2-D-formylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamidol-3- (1,2,3-triazolyl-5-nlercaptomethyl) -3-cephem-4-carboxylic acid, 7 - [2-Formylamino-2- (3,5-dinitro-4-hydroxyphenyl) .- acetamidol-3- (1,2,3-tri2zolyl-5-mercaptometh) rl) -3-cephem-4-carboxylic acid.

b) 323 mg of 7- [2-D-formylamino-2- (3-chloro-5-nitro-4-hydrOxyphenyl) -acetamidol-.S- (1j253-triazol.yl-5-mercaptomethyl) -3- are dissolved cephem-4-carboxylic acid and 42 mg of NaHCO3 in 6 ml of water, stirred for 30 minutes at room temperature and obtained after freeze-drying the solution, the sodium salt of 7- [2-D-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamidol-3- (l, Z, S-triazolyl-5-mercaptomethyl) - 3-cephem-4-carboxylic acid.

The other cephem derivatives mentioned in Example 10 a are analogous obtainable by reaction with NaHCO3: the sodium salt of the 7 - D-formylamino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3- (1,2,3-thiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid the sodium salt of 7- [2-D-formylamino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamidol-3- (1,2,3-triazolyl-5-mercaptomethylf3-cephem-4-carboxylic acid the sodium salt of 7- [2-formylamino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] -3- (1,2,3-thiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid .

cj Analogously to Example 3 b, hydrolysis of D-formylamino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] -3- (1,2,3-thiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid with THF / hydrochloric acid 7-g2-D-amino-2- (3-chloro-5-nitro -4-hydroxyphenyl) acetamidoi'-3- (1 ", 3-triazoiyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid.

The others mentioned in Example 10 a are analogous by hydrolysis Cephem derivatives available: 7-r2-D-amino2- (3-nitro-4-hydroxyphenyl! -Acetamido7-3- (1,2,3-thiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid 7- [2-D-Amino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido] -3- (1,2,3-thiazolyl-5-mercaptomethyl) -3-cephem-4- carboxylic acid 7-12-D-Amino-2- (3,5 dinitro-4-hydroxyphenyl) -acetamidol-3- (1,2,3-thiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid.

d) Analogously to Example 10 b, by reacting amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamido7-3-3- (1,2,3-thiazolyl-5-mercaptomethyl) -3-cephem-4-carboxylic acid with NaHCO3 the sodium salt of 7-12-D-amino-2- (3- chloro- 5-nitro-4-hydroxyphenyl) -acetamida7-3- (1,2,3-triazolyl-S-mercaptomethyl) -3-cephem-4-carboxylic acid, IR: bands at 1765, 1695, 1605, 1540, 1505, 1405, 1360, 1260, 1190, 1100, 1070, 1020, 980 and 780 cm are analogous from the others in example 10 c mentioned cephem derivatives by reaction with NaHCO 3 obtainable: the sodium salt the 7- £ 2-D-amino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3- (1,2,3-thiazolyl-5-mercaptomethyl) -3-cephem-4-carbons acid the sodium salt of 7- [2-D-amino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido-3- (1,2,3-triazolyl-5-mercaptomethyl) -3-cephem -4-carboxylic acid the sodium salt of 7- [2-D-amino-2- (3,5-dinitro-4-hydroxyphenyl) -acetamido-3- (1,2,3-triazolyl-5-mercaptomethyl) -3-cephem-4- carboxylic acid.

The active ingredients of the formula I can be according to methods that are derived from the Literature are known to process into pharmaceutical preparations such as the following Example shows: Example A: ampoules A solution of 100 g of 7- [2-amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) acetamido] cephalosporanic acid, sodium salt is dissolved in 0.3 l of double-distilled water, sterile filtered, in ampoules bottled, lyophilized under sterile conditions and sealed under sterile conditions. Every Ampoule contains 1 g of active ingredient.

The solution ampoules are obtained by adding 50 g of lidocaine hydrochloride Dissolves in 3 l of double-distilled water and, after sterile filtration, in ampules which are sterilized at 1200 for 20 minutes. Each solution ampule contains 50 mg lidocaine hydrochloride in 3 ml water.

Example B: Tablets A mixture consisting of 100 g of 7- [2-amino-2- (3-bromo-5-nitro-4-hydroxyphenyl) -acetamido7-3- (5-methyl-1,3,4-thiadiazolyl- 2-mercaptomethyl) -3-cephem-4-carboxylic acid, sodium salt 500 g milk sugar, 180 g wheat sugar, 10 g cellulose powder and 10 g magnesium stearate becomes Tpletter in the usual way.

compressed in such a way that each tablet contains 50 mg of the active ingredient.

Claims (9)

Patent claims: 1. Compounds of the general formula I wherein R¹ is H or CHO, R2 is H, C1, Br or NO2, R3 is H, OCOCH3 or -5-Het, and Het is 1,3,4-thiadiazolyl-2,5-methyl1,3,4-thiadiazolyl-2 3- Methyl-1,2,4-thiadiazolyl-5, 1-methyl-tetrazolyl-5 or 1,2,3-thiadiazolyl-5 as well as their easily cleavable esters and their physiologically harmless salts. 2. 7- [2-Amino-2- (3-nitro-4-hydroxyphenyl) acetamido] cephalosporanic acid and their sodium salt. 3. 7- [2-Amino-2- (3-bromo-4-hydroxyphenyl) acetamido] cephalosporanic acid and their sodium salt. 4. 7- [2-Amino-2- (3-chloro-5-nitro-hydroxyphenyl) -acetamido] -cephalosporanic acid and their sodium salt. 5. 7- [2-Amino-2- (3,5-dinitro-4-hydroxyphenyl) acetamido] cephalosporanic acid and their sodium salt. 6. 7- [2-Amino-2- (3-chloro-5-nitro-4-hydroxyphenyl) -acetamido] -3- (1,2,3-triazoylyl-5-mercaptomethyl) -3-cephem-4- carboxylic acid and their sodium salt. 7. Process for the preparation of a compound of the general formula 1 wherein R1 is H or CHO, R2 is H, Cl, Br or NO2, R3 is H, OCOCH3 is -S-Het, and Het is 1,3,4-thiadiazolyl-2,5-methyl-1,3,4-thiadiazolyl-2 , 3-methyl-1,2,4-thiadiazolyl-5, 1-methyl-tetrazolyl-5 or 1,2,3-triazolyl-5 mean, and their easily cleavable esters and their physiologically acceptable salts, characterized. that men a 3-CH2R³-7-amino-3-cephem-4-carboxylic acid of the general formula II in which R³ has the meaning given, odes one of its functional derivatives with phenylacetic acid of the general formula III which is substituted worn R¹ and R² have the meanings given, or converts one of their activated derivatives, which 5 is present as Säreadditionsallz when R¹ is hydrogen, or that functionally modified OH or NH2 groups contained in a compound otherwise corresponding to formula I can be treated with solvolyzing or hydrogenolyzing agents are set free and that, if necessary, the substituent R³ in the product obtained is exchanged for another substituent R³ by converting an acetoxy group into the radical -S-Het by treating with a thiol of the formula Het-SH or a corresponding mercaptide converts and / or converts an amino group into a formylamino group by treating with a formylating agent and / or converts a carboxyl group into an easily cleavable carboxylic acid ester group by treatment with an esterifying agent and / or sets the acid free from a salt or ester obtained and / or a obtained acidic or b Asic compound of the formula I by treating a base or acid is converted into one of its physiologically acceptable salts and, if desired, a pure epimer is isolated from an epimer mixture of the formula I. 8. Process for the manufacture of pharmaceutical preparation, thereby characterized in that a compound of general formula I and / or a their easily cleavable esters and / or one of their physiologically harmless ones Salts together with at least one solid, liquid or semi-liquid carrier or adjuvant and optionally together with a further active ingredient in one brings appropriate dosage form. 9. Pharmaceutical preparation containing a compound of the general Formula I and / or one of its easily cleavable esters and / or one of its physiologically harmless salts.