DE2444103A1 - CEPHEMDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Merck Patent Society

Limited Liability September 5, 1974

Darmstadt 2444103

Cephem derivatives
and methods of making them

The invention relates to new cephem derivatives of the general formula I.

Z-CH ₂ CO-NH

COOH

wherein

Z is a 4-hydroxyphenyl radical substituted identically or unequally in the 3- and 5-positions by F, Cl, Br, NO ₂ , NH _{2 or NHCHO,}

R -OCOCH ₅ or -S-Het and

Het 3-methyl-1,2,4-thiadiazolyl-5, 5-methyl-1,3,4-thiadiazolyl-2, 1-methyl-tetrazolyl-5 or 1,3,4-thiadiazolyl-2

mean,

as well as their easily cleavable esters and their physiologically harmless ones. Salts.

609813/1005

The invention was based on the object of finding new compounds which can be used for the production of medicaments can be. This object was achieved by providing the compounds of the formula I. '

It has been found that these compounds have excellent antibacterial activity against gram-negative and against gram-positive germs. Show in comparison with known semisynthetically obtained cephalosporins there are clear differences with regard to the sensitivity of the individual germs. In numerous cases they are known Cephalosporins are significantly outperformed by the new products, making them useful in fighting certain bacterial infections have decisive therapeutic advantages. So is the minimum inhibitory concentration of ^ -acetoxymethyl-Y- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid and 3- (i-methyltetrazolyl-5-mercaptomethyl) -7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid or the sodium salts of these acids for a number of pathogens, including Escherichia coli, Salmonella typhimurium, Shigella krusei and Klebsie11a pneumoniae remarkably low. These compounds show in vivo and 7- (3-amino-5-bromo-4-hydroxyphenyl-acetamido) -cephalosporanic acid excellent activity in mice (measured as DC 50) against Staphylococcus aureus, Streptococcus pyogenes, Diplococcus pneumoniae, Salmonella newport, Klebsiella pneumoniae and Escherichia coli. Further remarkably good serum concentrations were found after parenteral administration of these substances to dogs. The compounds can accordingly be used as medicaments, in particular for combating bacterial infections will. They can also be used as intermediate products for the production of other drugs.

609813/1005

2U41Q3

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

The radical Z means one disubstituted in the 3- and 5-positions 4-hydroxyphenyl radical. In detail are preferred Residues Z called 3,5-dibromo, 3,5-diamino, 3,5-diformylamino, 3-fluoro-5-chloro, 3-fluoro-5-bromo, 3-fluoro-5-nitro, 3-fluoro-5-amino-, 3-fluoro-5-formylamino-, 3 ~ chloro-5-bromo-, 3-bromo-5-formylamino- and 3-nitro-5-amino-4-hydroxyphenyl. However, 3> 5-difluoro, 3,5-dinitro, 3-chloro-5-nitro, 3-chloro-S-EmInO, 3-chloro-5-formylamino, 3-bromo-5-nitro- and 3-bromo-5-amino-4-hydroxyphenyl. The group Z also stands for 3,5-dichloro-, 3-iOrmylamino-5-nitro- and 3-amino-5-formylamino-4-hydroxyphenyl,

Among the heterocyclic radicals Het are the 1-methyltetrazolyl-5 radical, the 3-methyl-1,2,4-thiadiazolyl-5 radical and the 5-methyl-1,3,4-thiadiazolyl-2 radical is preferred.

Easily cleavable esters of the compounds of the formula I are primarily the tert-butyl esters e.g. the trimethylsilyl, benzyl, benzhydryl, trichloroethyl, 'benzoylmethyl, p-methoxybenzyl or methoxymethyl ester, also the pivaloyloxymethyl esters.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings given above. Some of the preferred groups of compounds can be expressed by the following sub-formulas Ia to In, which correspond to formula I. and in which the radicals unspecified have the meanings given for formula I, but in which

609813/1005

in Yes R. in You R. in Ic R. in Id R. in Ie Z

2'4U103

-OCOCH, means;

3-methyl-1, 2,4-thiadiazolyl-5-inereapto "means; 5 ~ methyl-1,3,4-thiadiazolyl-2-mercapto"means; i-methyl-tetrazolyl-5-mercapto "means _;

3,5-difluoro-4-hydroxyphenyl, 3,5-dinitro-4-hydroxyphenyl, 3-chloro-5-nitro-4-hydroxyphenyl, 3-chloro-5-amino-4-hydroxyphenyl, 3-bromo-5-nitro-4-hydroxyphenyl or is 3-bromo-5-amino-4-hydroxyphenyl;

in If Z has the meanings given for Ie and R is OCOCH ₅ ;

in Ig Z has the meanings given for Ie and R is 3-methyl-1,2,4-thiadiazolyl-5-mercapto;

in Ih Z has the meanings given for Ie and R is 5-methyl-1,3,4-thiadiazolyl-2-mercapto;

in Ii Z has the meanings given for Ie and R is i-methyl-tetrazolyl-5-mercapto;

in Ij Z 3> 5-diamino-4-hydroxyphenyl, 3,5-dibromo-4-hydroxyphenyl, 3,5-diformylamino-4-hydroxyphenyl, 3-I ¹ IuOr-S-Mtro-4-hydroxyphenyl, 3-fluoro -5-amino-4-hydroxyphenyl, 3-bromo-5-iOrmylamino-4-hydroxyphenyl or 3-nitro-5-amino-4-hydroxyphenyl;

in Ik Z has the meanings given for Ij and R is OCOCH ₅ ;

in Il Z has the meanings given for I3 and R is 3-methyl-1 ^^ - thiadiazolyl-S-mercapto;

in Im Z has the meanings given for Ij and R is 5-methyl-1,3,4-thiadiazolyl-2-mercapto;

in In Z has the meanings given for Ij and R is i-methyl-tetrazolyl-5-mercapto.

609813/100 5

24U103

The invention also relates to a process for preparing the compounds of the formula I and their easily cleavable esters and their physiologically acceptable salts, which is characterized in that a 3-CH ₂ 7-amino-3-cephem-4-carboxylic acid is used general formula II

II CH ₂ R

COOH
where R has the meaning given,

or one of its functional derivatives with a substituted phenylacetic acid of the general formula III

Z-CH ₂ COOH III where Z has the meaning given,

or one of its activated derivatives is reacted, or that one otherwise corresponds to the formula I compound functionally modified OH or EHp groups contained therein by treatment with solvolyzing or hydrogenolyzing agents sets free and that one optionally replaces one or both substituents R and / or Z for other substituents R and / or Z in the product obtained, by getting a nitro group by treating with a reducing agent is reduced to an amino group and / or an amino group is reduced by treating with a formylating agent Converts agent to a formylamino group and / or an acetoxy group by treatment with a thiol of the formula Het-SH or a corresponding mercaptide is converted into the radical -S-Het and / or a carboxyl group by treatment with

609813/1005

an esterifying agent into an easily cleavable carboxylic acid ester group converts and / or sets the acid free from a salt or ester obtained and / or a acidic or basic compound of the formula I obtained by treatment with a base or acid in one of its physiological transferred harmless salts.

All of these reactions proceed according to methods that are known in cephalosporin chemistry and that are detailed in the literature are described.

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

The invention also relates to pharmaceutical preparations, containing a compound of the general formula I and / or one of its easily cleavable esters and / or an inrer physiologically harmless salt.

The starting materials for the process according to the invention are either known, or they can be known per se Methods analogous to known compounds can be prepared. For example, the acids II (R = -S-Het) are available from 7-aminocephalosporanic acid (7-ACS; II; R = -OCOCEU) 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. The phenylacetic acids III are

609813/1005

24U103

as far as they are not known, by. Introduce the desired Substituents in the "known 4-hydroxyphenylacetic acid" according to per se "known methods, for example by electrophiles Substitution can be produced.

The easily cleavable esters, for example the tert-butyl esters, the trimethylsilyl esters (which are formed in situ from II and H-trimethylsilyl acetamide, for example) and the other esters indicated above, are primarily suitable as functional derivatives of the acids II. The salts, in particular the neutral salts, of these acids are also suitable. The alkali metal (eg sodium, potassium), alkaline earth metal (eg magnesium, calcium) and ammonium salts are particularly suitable. Among the last are those of amines, especially tertiary amines; eg ■ triethylamine, triethanolamine, pyridine, collidine, derived salts are preferred. These salts can be used as such in the reaction; they can also be generated in situ from the acid II and a base, for example NaHCO. ,, ITa ₂ HPC ^ or triethylamine.

The halides, preferably the chlorides and bromides, are particularly suitable as activated derivatives of the acids III, also the anhydrides and mixed anhydrides and azides and activated esters, e.g. those with p-nitrophenol, 2,4-dinitrophenol, p-nitrophenyl mercaptan, methylene cyanohydrin or H-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-nitrobenzyl ester, isobutyl ester, ethyl ester or allyl ester are available. All of these activated derivatives of III are preferred generated in situ.

609813/1005.

2UA103

In general, the implementation of the cephem derivatives II takes place (or their functional derivatives) with the phenylacetic acids III (or with their activated derivatives) in the presence an inert solvent. Particularly suitable solvents are chlorinated hydrocarbons, e.g. Methylene chloride, chloroform; Ethers such as diethyl ether, tetrahydrofuran, dioxane; Ketones such as acetone, butanone; Amides like Dimethylformamide (DJIP), dimethylacetamide, hexamethylphosphoric acid triamide; Sulfoxides such as dimethyl sulfoxide (DMSO); Water; also organic or aqueous inorganic bases. Mixtures of the solvents mentioned can also be used. If a salt of a compound of the formula I is to be prepared is, as a solvent, in particular an excess of the base used to form this salt suitable, e.g. triethylamine or aqueous sodium hydroxide solution.

The implementation of II with III (or their functional or activated derivatives) usually takes place at temperatures between -70 and + 80 °, preferably between -50 and + 30 °, especially between -40 and 0. The reaction time depends on the type of starting materials chosen and the Reaction temperature dependent; it is usually between 5 minutes and 72 hours.

In particular, it is particularly useful to use an ester, preferably to react a tert-butyl ester of acid II with the free phenylacetic acid III, advantageously a adding water-binding agent. Carbodiimides, in particular dicyclohexylcarbodiimide (DCC), can be used as such Consideration. For example, 7-ACS-tert-butyl ester, acid III and DCC are left in approximately equimolar proportions and below React cooling in an inert solvent, especially in methylene chloride, DMP, DMSO or solvent mixtures.

609813/100 5

2UU03

The reaction of II with activated derivatives of the acids III is preferably carried out in an alkaline medium. A base is added to the reaction mixture, in particular KaHCO ₃ , KHCO ₃ , Fa ₂ CO ₃ , K ₂ CO ₃ , NaOH, KOH, pyridine or a base of low nucleophilicity, for example a tertiary amine such as triethylamine, N-methylmorpholine, ethyldiisopropylamine or potassium tert-butoxide.

The cephem derivatives of the formula I are still available, by functionally modified OH or UHp groups contained in a compound otherwise corresponding to formula I sets in freedom according to methods known per se. The starting materials for this process variant are e.g. obtainable analogously to the methods described above, but sensitive functional groups during the Functionally modifies synthesis by protecting groups.

Functionally modified groups are, for example: etherified or esterified hydroxyl groups, e.g. Benzyloxy or acetoxy; benzylated or acylated amino groups, e.g. benzylamino, benzyloxycarbamoyl, tert-butoxycarbamoyl, Acetylamino, the protective groups that should be mentioned in particular are those customary in peptide chemistry. In particular Formy! amino groups are also possible.

The functionally modified groups can be solvolytic by methods known per se and described in the literature, in particular hydrolytically or hydrogenolytically, are set free. Solvolysis, preferably Hydrolysis is carried out e.g. with trifluoroacetic acid or with aqueous mineral acids, e.g. hydrochloric acid, at temperatures carried out between -10 ° and 50 °. Functional hydrogenolysis Modified groups, in particular the splitting off of benzyl or carbobenzoxy radicals, mainly takes place by hydrogenation in the presence of noble metal catalysts,

6 0 9 8 13/1005

24U1Q3

like 5-50 fig palladium on charcoal; or palladium oxide. The hydrogenolysis is expediently carried out at temperatures between -10 and + 50 °, in particular at room temperature, and at pressures between 1 and 100 at, preferably at normal pressure.

If desired, you can in the product obtained Formula I one substituent R against another substituent R according to methods known per se from the literature and / or exchange one substituent Z for another substituent Z.

For example, it is possible to reduce a nitro group on the phenyl ring to an amino group. Basically you can for this purpose, all methods known per se suitable for the reduction of nitro groups can be used, provided they do not cause undesirable changes in the molecule. Catalytic hydrogenation is particularly suitable e.g. can be carried out on noble metal catalysts such as palladium at room temperature and normal pressure.

60981 3/1005

24-4103

It is also possible, for example, to convert an amino group to convert to a formylamino group with a formylating agent. Formic acid is used as a formylating agent, preferably in the presence of a solvent. As a rule, one works in the presence of a dehydrating agent Means. As such, carboxylic acid anhydrides are particularly suitable, which at the same time act as solvents can serve. It is particularly advantageous to use excess formic acid in the presence of acetic anhydride as the formylating acid Funds to use. The reaction temperatures are between about -25 ° and room temperature, preferably between about -5 ° and + 5 °.

It is also possible to use a cephalosporanic acid obtained of the formula I (R = -OCOCH *) by reaction with a mercaptan to convert the formula Het-SH into the corresponding thioether I (R = -SHet). A salt is expediently used of cephalosporanic acid with a salt of thiol in aqueous acetone at temperatures between 20 and 100 ° and pH values between 4 and 8 µm. Particularly suitable salts are the alkali metal, especially the sodium salts.

A free carboxylic acid I can also be converted into an easily cleavable carboxylic acid ester by esterification. E.g. the tert-butyl esters are obtained by reacting the acids with isobutylene.

Conversely, the acid I can be set free from a salt or ester obtained, e.g. by solvolysis,

0 9 8 13/1005

especially by acid hydrolysis. The one in the synthesis tert-butyl esters obtained particularly advantageously are, for example, with trifluoroacetic acid at temperatures between 0 and split 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 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 other amines such as are commonly used for the preparation of cephalosporin salts.

Of the alkali metal salts, in particular the sodium and the potassium salts matter. They can be prepared by making a solution of an acid I in an organic Solvent with a solution of the sodium or potassium salt of a fatty acid, e.g. diethyl acetic acid or 2-ethylcaproic acid in a solvent such as acetone or n-butanol, or mixed with a solvent mixture. Those precipitating in the process or on the addition of ether Potassium salts can be filtered off. But you can too e.g. the solution of an acid I in water with the calculated amount of an alkali metal carbonate or hydrogen carbonate such as NapCO-, or KHCO ,, dissolved in water, react and receive then the desired salt, for example after evaporation of the solvent, as a residue.

Basic compounds of the formula I can be converted into the associated acid addition salts with acids in the customary manner e.g. in the hydrochloride or citrate.

60981 3/1005

2UA103

Since the compounds I have no sharp melting points, they are appropriately characterized by other physical parameters, particularly advantageously by their infrared spectra. In the infrared spectrum they show the absorption band of the ß-lactam ring at 1760-1800 cm. she can also be characterized by their nuclear magnetic resonance spectra and by the thin-layer chromatogram. For this It is advisable to use Merck TLC precast silica gel iV> 54 can be used (eluent e.g. dioxane / water 85:15).

The new compounds can be used as medicaments in a mixture with solid, liquid and / or semi-liquid excipients used in human or veterinary medicine. The carrier substances used are organic or inorganic Substances in question that are intended for enteral, e.g. oral, but preferably for parenteral or topical application are suitable and which do not react with the new compounds, such as water, vegetable oils, benzyl alcohols, Polyethylene glycols, gelatin, lactose, starch, magnesium te ar at, talc, petroleum jelly, cholesterol. For enteral use, e.g. tablets, capsules, coated tablets, Syrups, juices or suppositories. Solutions, preferably oily, are used in particular for parenteral administration or aqueous solutions, as well as suspensions, emulsions or implants, for topical application ointments, creams or Powder. These preparations can be sterilized or with auxiliaries, emulsifiers, salts to influence the osmotic pressure, buffer substances, dyes are added. They can also contain other active ingredients.

The compounds of general formula I and their easily cleavable esters and their physiologically acceptable salts can be used to fight infections in essentially the same way as the well-known compound cephalotin will; they are preferably given in dosages

6D9813 / 100S

-H-

2U4103

between 1 and 5000, especially between 200 and 2000, mg administered per dosage unit. The daily dosage is preferably between 4 and 100, in particular between 10 and 40 mg / kg body weight. Parenteral (e.g. intravenous or intramuscular) administration is preferred.

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

The IR spectra are recorded in KBr. DMF = dimethylformamide, 7-ACS = 7-aminocephalosporanic acid, DCC = dicyclohexylcarbodiimide.

example 1

a) 100 g of 7-ACS are suspended in 1 liter of methylene chloride at -10 ° and brings the acid into solution by adding 129 ml of triethylamine. A solution of 3-bromo-5-nitro-4-hydroxyphenylacetic acid chloride is added dropwise at -10 ° in DMP (prepared from 104 g of 3-bromo-5-nitro-4-hydroxyphenylacetic acid, dissolved in 400 ml of DMF, by adding 26.8 ml of thionyl chloride -10 °), then the methylene chloride is distilled off, the residue is poured into water, filtered and the precipitate dries. 7- (3-Bromo-5-nitro-4-hydroxyphenyl-acetamido) -cephalosporanic acid is obtained,

IR: 1780, 1740, 1670, 1550, 1250, 1160, 1110, 1080, 1040 cm ^-1 .

60981 3/1005

Chlorides of chlorides are obtained analogously by reacting the acid produced in situ

3-fluoro-5-nitro-4-hydroxyphenylacetic acid 3-chloro-5-nitro-4-hydroxyphenylacetic acid, 3,5-dinitro-4-hydroxyphenylacetic acid 3,5-dibromo-4-hydroxyphenylacetic acid 3,5-dichloro-4-hydroxyphenylacetic acid 3,5-difluoro-4-hydroxyphenylacetic acid

with 7-ACS

7- (3-Fluoro-5-nitro-4-hydroxyphenyl-acetamido) -cephalosporanic acid

7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -cephalosρoranoic acid

7- (3,5-dinitro-4-hydroxyphenyl-acetamido) -cephalosporanic acid,

IR: 1760, 1680, 1640, 1550, 1425, 1350, 1260 cm "¹;

7- (3,5-dibromo-4-hydroxyphenyl-acetamido) -cephalosporanic acid

7- (3,5-dichloro-4-hydroxyphenyl-acetamido) -cephalosporanic acid,

IR: 1770, 1720, 1650, 1530, 1485, 1410, 1230 cm "¹;

7- (3,5-I> ifluoro-4-hydroxyphenyl-acetamido) -cephalosporanic acid.

b) 1.06 g of 7- (3-bromo-5-nitro-4-hydroxyphenylacetamido) -cephalosporanic acid are suspended and 232 mg of 1-methyltetrazole-5-thiol in 8 ml of water at room temperature and brings the

Reactants by adding NaHCO, in solution, keeping the pH is between 4 and 7. The mixture is heated to 70 ° for 3 hours, acidified strongly with aqueous HCl, filtered and dried

609813/1005

2U4103

the featherfall. 3- (i-Methyltetrazolyl-5-mercaptomethyl) is obtained -7- (3- "bromo-5-nitro-4-hydroxyphenyl-acetamido) 3-cephem-4-carboxylic acid,

IR: 1785, 1730, 1670, 1630, 1545, 1470-, 1425, 1360, 1330, 1270, 1180, 1110 cm " ¹ .

Analogously are obtainable by reacting the in Example 1a named cephalosporanic acids with i-methyltetrazole-5-thiol

3- (1-methyltetrazolyl-5-mercaptomethyl) -7- (3-fluoro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (1-Methyl-tetrazolyl-5-mercaptomethyl) -7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -3-eephem-4-carboxylic acid

3- (i-Meth3 "l-tetrazolyl-5-mercaptomethyl) -7- (3,5-dinitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid, IR: 3400, 1770, 1670, 1635, 1545 , 1345, 1240 cm "¹;

3- (i-Methyltetrazolyl-5-mercaptomethyl) -7- (3,5-dibromo-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3-Ci-methyltetrazolyl-5-mercaptomethyl) -7- (3,5-dichloro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (i-Methyltetrazolyl-5-mercaptomethyl) -7- (3,5-difluoro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid.

c) Analogously to Example 1b, 7- (3-bromo-5-nitro-4-hydroxyphenyl-acetamido) -cephalosporanic acid is obtained by reacting with 5-Methy1-1,3,4-thiadiazol-2-thiol in water at 70 ° in Presence of NaHCO, 3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-bromo-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid,

IR: 1785, 1725, 1680, 1630, 1545, 1430, 1330, 1265, 1110cm " ¹ 609813/1005

2U4103

Analogously are obtainable by reacting the in Example 1a
named cephalosporanic acids with 5-methyl-1,3,4-thiadiazole-2-thiol

3- (5-Methy1-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-fluoro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephein-4-carboxylic acid

3- (5-Methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3,5-dinitro-4-hydroxypheny1-ac e tamido) -3-c ephem-4-carbonic acid,

IR: 3400, 1760, 1630, 1610, 1550, 1340, 1240 cm "¹;

3- (5-Methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3,5-dibromo-4-hydroxyphenyl-acetamido) -3-cephem-4-cart) onic acid

• 3- (5-Methyl-1 _; 3,4-thiadiazolyl-2-mercaptomethyl) -7- (3,5 ~ dichloro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (5-Methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3,5-difluoro-4-hydroxyphenyl-acetamido) -3-cephem-4-cart) onic acid.

d) Analogously to Example 1b, 7- (3-bromo-5-nitro-4-hydroxyphenyl-acetamido) -cephalosporanic acid is obtained by reacting with
3-methyl-1,2,4-thiadiazole-5-thiol in water at 70 ° in
Presence of NaHCO ₅ 3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-bromo-5-nitro-4-hydroxyphenyl-acetamido) 3-cephem-4-carboxylic acid,

IR: 1785, 1730, 1660, 1630, 1445, 1430, 1365, 1330,
1300, 1260, 1180, 1110 cm " ¹ .

609813/1005

Analogously are obtainable by reacting the in Example 1a named cephlosporanic acids with 3-methyl-i, 2,4-thiadiazole-5-thiol

3- (3-Methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-fluoro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-c art ons acid e

3- (3-Methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (3 ~ methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3,5-dinitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid,

IR: 3400, 1755, 1630, 1610, 1545, 1340, 1235 cm ""¹;

3- (3-Methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3,5-dibromo-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (3-Methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3,5-dichloro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3,5- <3.ifl-u.or-4-liydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid.

e) Analogously to Example 1b, they can be obtained by reacting the cephalosporanic acids mentioned in Example 1a with 1,3,4-thiadiazole-2-thiol

3- (1,3,4-Thiadiazolyl-2-mercaptomethyl) -7- (3-bromo-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

5- (i, 3,4-Thiadiazolyl-2-mercaptomethyl) -7- (3-fluoro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

609813/100 5

2U41Q3

3- (i, 3,4-Thiadiazolyl-2-mercaptomethyl) -7- (3-clilor-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (i, 3,4-Thiadiazolyl-2-mereaptomethyl) -7- (3,5-dinitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (1,3,4-Thiadiazolyl-2-mercaptomethyl) -7- (3,5-dibromo-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (1,3,4-Thiadiazolyl-2-mercaptomethyl) -7- (3,5-dichloro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3,5-di-drom-4-hydroxyplienyl-acetamido) -3-cepliem-4-carboxylic acid.

Example 2

a) Dissolve 463 mg of 3-chloro-5-nitro-4-hydroxyphenylacetic acid, 65-6 mg of 7-ACS-tert-butyl ester and 412 mg of DOC in a mixture of 5 ml of methylene chloride and 5 ml of DMP. It is allowed to stand for 30 minutes at room temperature and the reaction mixture is purified by chromatography on silica gel (ethyl acetate). 7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -cephalosporic acid tert-butyester is obtained.

Analogously, they can be obtained by reacting the 3-and 5-position disubstituted 4-hydroxyphenylacetic acids mentioned in Example 1a with 7-ACS-tert-butyl ester in the presence of DCC, the tert-butyl esters of Example 1a as end products called cephalosporic acids.

b) 5.5 g of 7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -cephalosporanic acid tert-butyl ester are dissolved in 200 ml of methanol and hydrogenated "at room temperature and atmospheric pressure in the presence

6 0 9 8 1 3/1 0 0 B.

24U103

from 3 g of Raney nickel to the uptake of the theoretical calculated amount of hydrogen. The catalyst is filtered off, the solvent is distilled off and the residue Purified by chromatography (silica gel / ethyl acetate). 7- (3-Amino-5-chloro-4-hydroxyphenyl-acetamido) -cephalosporanic acid tert-butyl ester is obtained.

Analogously, hydrogenation of the tert-butyl esters in Example 1a as end products mentioned nitro derivatives of substituted cephalosporanic acids available:

7- (3-Amino-5-fluoro-4-hydroxyphenyl-acetamido) -cephalosporanic acid tert-butyl ester

7- (3-Amino-5-bromo-4-hydroxyphenyl-acetamido) -cephalosporanic acid tert-butyl ester

7- (3-Amino-5-nitro-4-hydroxyphenyl-acetamido) -cephalosporanic acid tert-butyl ester

7- (3,5-Diamino-4-hydroxyphenyl-acetamido) -cephalosporanic acid tert-butyl ester.

c) 1 g of 7- (3-amino-5-chloro-4-hydroxyphenyl-acetamido) -cephalosporanic acid tert-butyl ester is dissolved in 10 ml of trifluoroacetic acid, left to stand for 20 minutes at room temperature, distilled the trifluoroacetic acid and, after recrystallization of the residue from diethyl ether, 7- (3-amino-5-chloro-4-hydroxyphenyl-acetamido) -cephalosporanic acid,

IR: 3320, 1780, 1730, 1670, 1540, 1500, I400, 1200, 1080, 1050 cm "" ¹ .

13 / 100B

24U1Q3

Analogous to those mentioned in Example 2b as end products Cephalosporanic acid tert-butyl esters by reacting with Trifluoroacetic acid available:

7- (3-Amino-5-fluoro-4-hydroxyphenyl-acetamido) ~ cephalosρoranoic acid

7- (3-Amino-5-bromo-4-hydroxyphenyl-acetamido) -cephalosporanic acid,

IR: 3320, 3090, 2650, 1780, 1670, 1545, 1500, 1200 cm "¹;

7- (3-imino-5-nitro-4-hydroxyphenyl-acetamido) -cephalosporanic acid

7- (3,5-diamino-4-hydroxyphenyl-acetamido) -cephalosporanic acid.

d) Analogously to Example 1b, the cephalosporanic acids mentioned in Example 2c are obtained by reaction with 1-methyl-tetrazole-5-thiol in the presence of NaHCO., available:

3- (1-methyltetrazolyl-5-mercaptomethyl) -7- (3-amino-5-chloro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (1-methyltetrazolyl-5-mercaptomethyl) -7- (3-amino-5-fluor-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (1-Methyltetrazolyl-5-mercaptomethyl) -7-C3-amino-5-bromo-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (1-methyltetrazolyl-5-mercaptomethyl) -7- (3-amino-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (1-methyltetrazolyl-5-mercaptomethyl) -7- (3,5-diamino-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid.

e) Analogously to Example 1c, the cephalosporanic acids mentioned in Example 2c are obtained by reaction with 5-methyl-1,3,4-thiadiazole-2-thiol in the presence of RaHCO, available:

6098 13/1005

3- (5-Methy1-1, 3,4-thiadiazolyl-2-mercaptoniethyl) -7- (3-amino-5-chloro-4-hydrOxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (5-Methy1-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-amino-5-fluoro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (5-Methy1-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-amino-5-13rom-4-hydroxyphenyl-acetalido) -3-cepheni-4-carboxylic acid

3- (5-Methy1-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-amino-5-nitr o-4-hydroxyphenyl-ac e tamido) -3-c e phem-4-carboxylic acid

3_ (5_Methyl1-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3,5-diamino-4-hydroxypheny! -Acetamido) -S-acid.

f) Analogously to Example 1d, the cephalosporanic acids mentioned in Example 2c can be obtained by reacting with 3-methyl-1,2,4-thiadiazole-5-thiol in the presence of NaHCO-:

3- (3-Methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-amino-5-chloro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (3-Methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-amino-5-fluoro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (3-Methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-amino-5-bromo-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (3-Methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-amino-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3,5-diamino-4-hydroxyphenyl-acetamido) -3-cephem-4-carbon- acid. 609313/100 5

g) Analogously to Example 1e, the cephalosporanic acids mentioned in Example 2c are obtained by reaction with 1,3 »4-thiadiazole-2-thiol in the presence of UaHCO, available:

3- (i, 3,4-Thiadiazolyl-2-mercaptomethyl) -7- (3-amino-5-chloro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (1,3,4-Thiadiazolyl-2-mercaptomethyl) -7- · (3-ainino-ί5-fluoro-4-hydroxyphenyl-acetalnido) -3-cephem- · 4-car · bonic acid

3- (1,3,4-Thiadiazolyl-2-mercaptomethyl) -7- (3-amino-5-bromo-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (i, 3 _> 4-thiadiazolyl-2-mercaptomethyl) -7- (3-amino-5-nitro-4-hydroxyphenyl-acetamido) -3 · ■ - · cephem-4-carbonic acid

3- (1,3,4-Thiadiazolyl-2-mercaptomethyl) -7- (3,5-diamino-4-hydroxyphenyl-acetamido) -3-eephem-4-carboxylic acid.

Example 3

One -rührt 200 mg of 7- (3-amino-5-t ^i> rom-4-hydroxyphenyl-acetamido) cephalosporanic acid 2 hours, "at 5 ° in a mixture of 10 ml of dry formic acid and 2 ml of acetic anhydride, the solvent is distilled and obtained after purification of the residue by chromatography (silica gel / dioxane: water = 9: T) 7- (3-bromo-5-formylamino-4-hydroxyphenyl-acetamido) -cephalosporanic acid.

Example 4

a) 1.20 g of 3-chloro-5-formylamino-4-hydroxyphenylacetic acid are dissolved, 1.72 g of 7-ACS tert-butyl ester and 1.07 g of DCC in a mixture of 15 ml of chloroform, 10 ml of dry dioxane and 10 ml of dry acetone, boiled for 30 minutes, distilled

609 8 1-3 Ί ΟΠΒ

24U103

the solvent and after chromatographic purification of the residue (silica gel / ethyl acetate) 7- (3-chloro-5-formylamino-4-hydroxyphenyl-acetamido) -cephalosporanic acid tert-butyl ester.

The corresponding substituted pormylamino-4-hydroxyphenylacetic acids are analogous by reaction with 7-ACS tert-butyl ester available in the presence of DOC:

7- (3-Bromo-5-formylamino-4-hydroxyphenyl ~ acetamido) -cephalosporanic acid tert-butyl ester

7- (3-Fluoro-5-formylamino-4-hydroxyphenyl-acetamido) -cephalosporanic acid tert-butyl ester

7- (3-Formylamino-5-nitro-4-hydroxyphenyl-acetamido) -cephalosporanic acid tert-butyl ester

7- (3,5-Diformylamino-4-hydroxyphenyl-acetamido) -cephalosporanic acid tert-butyl ester.

The substituted formylamino-4-hydroxyphenylacetic acids used as starting materials can be obtained by electrophilic bromination, chlorination or nitration, for example in glacial acetic acid at room temperature, reduction with hydrogen in the presence of Raney nickel (analogous to Example 2b) and pormylation with formic acid in the presence of acetic anhydride (analogous to Example 3). The 3-i ^1- luoro-5-formylamino-4-hydroxyphenylacetic acid can be obtained from 3,5-dinitro-4-hydroxyphenylacetic acid, reduction of a nitro group (analogous to Example 2b), diaziotization of the 3-amino-5-nitro-4-hydroxyphenylacetic acid obtained , Exchange of the diazonium group for fluorine by means of HBI \ (Schiemann reaction), reduction of the 3-fluoro-5-nitro-4-hydroxyphenylacetic acid obtained (analogous to Example 2b) to 3-amino-5-fluoro-4-hydroxyphenylacetic acid and pormylation of this compound with Formic acid (analogous to example 3).

609813/1005

b) 1.2 g of 7- (3-chloro-5-formylamino-4-hydroxyphenylacetamido ^ cephalosporanic acid tert-butyl ester are dissolved in 12 ml of dry trifluoroacetic acid, stir for 30 minutes at room temperature with the exclusion of moisture, the Trifluoroacetic acid and after treatment of the residue with diethyl ether, 7- (3-chloro-5-formylamino-4-hydroxyphenyl-acetamido) -cephalosporanic acid is obtained.

The other tert-butyl esters mentioned in Example 4a are analogous obtainable by reaction with dry trifluoroacetic acid:

7- (3-Bromo-5-formylamino-4-h.ydroxyph.eny 1-acetamido) -cephalosporanic acid

7- (3-fluoro ~ 5-formylamino-4-hydroxyphenyl-acetamido) -c ephalos porans acid

7- (3-i ¹ ormylamino-5-nitr o-4-hydroxyphenyl-ac e tamido) cephalosporanic acid

7- (3,5-Diformylamino-4-hydroxyphenyl-acetamido) -cephalosporanic acid.

c) 0.8 g of 7- (3-chloro-5-formylamino-4-hydroxyphenylacetamido) -cephalosporanic acid tert-butyl ester is dissolved in 10 ml of trifluoroacetic acid, add 5 ml of water while cooling with ice, stir for 1 hour at room temperature, the solvent is distilled off and 7- (3-amino-5-chloro-4-hydroxyphenylacetamido) -cephalosporanic acid is obtained as a residue.

d) Analogously to Example 4c, 7- (3-chloro-5-formylamino-4-hydroxypheny1-acetamido) -cephalosporanic acid is obtained by reaction with aqueous trifluoroacetic acid 7- (3-amino-5-chloro-4-hydroxyphenyl-acetamido) -cephalosporanic acid available.

609813/1005

24U103

Example 5

a) 2.72 g of 7-ACS are dissolved in 40 ml of dry dioxane at -10 ° by adding diethylamine, 2.9 g of 3-bromo-5-chloro-4-hydroxyphenylacetic acid azide (obtainable from 3-bromo-5- nitro-4-hydroxyphenylacetic acid by reduction with hydrogen in the presence of Raney nickel, diazotization in dilute aqueous HCl at 0 with NaNOp, reaction of the diazonium compound with Cu ₂ CIp, reaction of the 3-bromo-5-chloro-4-hydroxyphenylacetic acid obtained with SOC1 _?, and reacting the obtained oily acid chloride with NaN.,) dissolved in 30 ml of dry acetonitrile, the solvent is distilled largely, the residue is poured into ice-water, filtering and drying the precipitate. 7- (3-Bromo-5-chloro-4-hydroxyphenyl-acetamido) -cephalosporanic acid is obtained.

Analog are available from

3-bromo-5-fluoro-4-hydroxyphenylacetic acid azide and 3-chloro-5-fluoro-4-hydroxyphenylacetic acid azide

by implementing with 7-ACS

7- (3-Bromo-5-fluoro-4-hydroxyphenyl-acetamido) -cephalosporanic acid and

7- (3-chloro-5-fluoro-4-hydroxyphenyl-acetamido) -cephalosporanic acid.

b) It is added to a well-stirred suspension of 519 mg of 7- (3-bromo-5-chloro-4-hydroxyphenyl-acetamido) -cephalosporanic acid in 20 ml of water 84 mg of NaHCO ™, dissolved in 10 ml of water, stirred for 1 hour, lyophilized and obtained as residue the sodium salt of 7- (3-bromo-5-chloro-4-hydroxyphenyl-acetamido) -cephalosporanic acid.

609813/1005

24U1Q3

Those mentioned in the above examples are analogous Cephalosporanic acids or 3-cephem-4-carboxylic acids the corresponding Sodium salts available. Instead of NaHCO, can also be used with KHCO, in which case the appropriate Potassium salts are available.

Example 6

A solution of 437 mg of 7- (3-benzylamino-5-chloro-4-hydroxyphenyl-acetamido) -cephalosporanic acid tert-butyl ester (obtainable from 3-benzylamino-5-chloro-4-hydroxyphenylacetic acid and 7-ACS-tert-butyl ester) in 100 ml of methanol is used 300 mg of 5% Pd-charcoal at 25 ° and formal pressure until the end hydrogen uptake of hydrogen. It is filtered and evaporated, and tert-butyl 7- (3-amino-5-chloro-4-hydroxyphenyl-acetamido) -cephalosporanate is obtained.

Example 7

3.44 g of 3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -7-amino-3-cephem-4-carboxylic acid are dissolved (obtainable analogously to Example 1c by reacting 7-ACS with 5-methyl-i, 3,4-thiadiazole-2-thiol) in 60 ml of dry dioxane at -5 ° by adding morpholine, 2.95 g of 3-bromo-5-nitro-4-hydroxyphenylacetic acid chloride are added dropwise, dissolved in 25 ml of dry dimethylformamide, stirred for 3 hours at room temperature, the dioxane is distilled off, the residue is stirred in water, filtered and the precipitate is dried. 3- (5-Methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-bromo-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid is obtained,

IR: 1785, 1725 ,. 1680, 1630, 1545, H30, 1330, 1265, 1110 cm " ¹ .

6 0 9 θ 1 3/1 0 0 p

24U1Q3

They can be obtained analogously by reacting the corresponding 3-het-mercaptomethyl-7-amino-3-cephem-4-carboxylic acids with 3-Bromo-5-nitro-4-hydroxyphenylacetic acid chloride:

3- (1-Methyltetrazolyl-5-mercaptomethyl) -7- (3-bromo-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-bromo-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

and by reacting with 3-chloro-5-nitro-4-hydroxyphenylacetic acid chloride

3_ (5_Methy1-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (1-methyltetrazolyl-5-mercaptomethyl) -7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid

3- (3-Methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid.

The compounds of formula I may be prepared by methods which are known from the _(literature, to pharmaceutical preparations - ^ work out, as the following example shows:

Example A: ampoules

A solution of 100 g of 7- (3-chloro-5-nitro-4-hydroxyphenylacetamido) -cephalosporanic acid, sodium salt is dissolved in 0.3 l of double-distilled water, sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each 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 is filled into ampoules which last 20 minutes long sterilized at 120 °. Each solution ampoule contains 50 mg lidocaine hydrochloride in 3 ml water.

609813/1005

Claims (20)

Patent claims: 1. Compounds of the general formula I Z-CH ₀ CO-ITH 0 ^ S ^^ ^CH 2 ^R COOH wherein Z is a 4-hydroxyphenyl radical substituted identically or unequally by F, Cl, Br, NO ₂ , ITH _{2 or NHCHO in the 3- and 5-positions,} R -OCOCH ₅ or -S-Het and Het 3-methyl-1,2,4-thiadiazolyl-5, 5-methyl-1,3,4-thiadiazolyl-2, 1-methyl-tetrazolyl-5 or 1,3,4-thiadiazolyl-2 mean, as well as their easily cleavable esters and their physiologically harmless salts. 609813/1005 2. Compounds of general formula I according to claim 1, wherein Z is a 3,5-difluoro, 3,5-dichloro, 3,5-dibromo, 3,5-dinitro, 3-chloro-5-nitro, 3-bromo-5-nitro, 3-amino-5-chloro, ^ -Formylamino - ^ - chlorine, 3-formylamino-5-bromo- or 3-amino-5-bromo ~ 4-hydroxyphenyl radical, as well as their easily cleavable esters and their physiologically harmless ones Salts. 3. Compounds of general formula I according to claim 1, wherein R is an OCOCH, radical, as well as their easy cleavable esters and their physiologically harmless salts. 4. Compounds of general formula I according to claim 2, where R is an OCOCH, radical, as well as their easy cleavable esters and their physiologically harmless salts. 5. Compounds of general formula I according to claim 2, wherein R -S-Het and Het 3-methyl-1,2,4-thiadiazolyl-5, 5-methyl-1,3,4-thiadiazolyl-2, 1-methyl-tetrazolyl-5 or 1,3,4-Th-iadiazolyl means, as well as their easily cleavable Esters and their physiologically harmless salts. 6. 3-Acetxymethyl-7- (3-bromo-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid and their sodium salt. 7. 3-Ethoxymethyl-7- (3,5-dinitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid and their sodium salt. 8. 3-Acetoxymethyl-7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid and their sodium salt. 60 9 B 1 3/1 005 24AA103 9. 3- (5-Methy 1-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3 ■ bromo-5-nitro-4-hydroxypheny! -Acetamido) ^ -eephem- ^ acid and its sodium salt. 10. 3- (5-Methy1-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-chloro-5-n.itro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid and their sodium saltζ. 3- (5-Methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3,5-dinitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid and their sodium salt. 12. 3- (1 -Methyltetrazolyl-5-mercaptomethyl) -7- (3- "bromo-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-cart> onic acid and its sodium salt. 13. 3- (1-Methyltetrazolyl-5-mercaptomethyl) -7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid and their sodium salt. 14. 3- (1-Methyl-tetrazolyl-5-mercaptomethyl) -7- (3,5-dinitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carldonic acid and their sodium salt. 15 x 3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-hrom-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carl3onic acid and their sodium salt. 16. 3- (i, 3,4-Thiadiazolyl-2-mercaptomethyl) -7- (3-chloro-5-nitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid and those. Sodium salt. 17. 4- (i, 3,4-Thiadiazolyl-2-mercaptomethyl) -7- (3,5-dinitro-4-hydroxyphenyl-acetamido) -3-cephem-4-carboxylic acid and their sodium salt. 13/1005 2U41Q3 18. Process for the preparation of compounds of the general formula I. , CO-WH ^ • o ^ COOH wherein Z is a 4-hydroxyphenyl radical substituted in the 3- and 5-positions identically or unequally by P, Cl, Br, NO ₂ , EH _{2 or EHCHO,} R -OCOCH ₃ or -S-Het and Het 3-methyl-1,2,4-thiadiazolyl-5, 5-methyl-1,3,4-thiadiazolyl-2, 1-methyl-tetrazolyl-5 or 1,3,4-thiadiazolyl mean, and their easily cleavable esters and their physiologically acceptable salts, characterized in that a 3-CH ₂ R-7-amino-3-cephem-4-carboxylic acid of the general formula II II COOH
where R has the meaning given, 60981 ^ / 100 5 or one of its functional derivatives with a substituted one Phenylacetic acid of the general formula III Z-CH ₂ COOH III ■ where Z has the meaning given, or one of its activated derivatives is reacted, or that one otherwise corresponds to the formula I compound functionally modified OH or NHp-G groups contained by treatment with solvolysing or sets hydrogenolysing agents in freedom and that one, if necessary, in the product obtained one or both substituents E and / or Z are exchanged for other substituents R and / or Z by adding a group reduced to an amino group by treatment with a reducing agent and / or an amino group by treatment converted to a formylamino group with a formylating agent and / or an acetoxy group by treating with converts a thiol of the formula Het-SH or a corresponding mercaptide into the radical -S-Het and / or a Carboxyl group is converted 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 an acidic or basic one obtained Compound of the formula I by treatment with a base or acid in one of its physiologically acceptable salts convicted. 19. A process for the manufacture of pharmaceutical preparations, characterized in that a compound of the general Formula I and / or one of its easily cleavable 609813/100 5 Esters and / or one of their physiologically harmless salts together with at least one solid, liquid or semi-liquid carrier or excipient and optionally brings together with another active ingredient into a suitable dosage form. 20. A pharmaceutical preparation containing a compound of the general formula I and / or one of its easy cleavable esters and / or one of their physiologically acceptable salts. 609813/1005