DE2507834A1 - CEPHEMDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Merck Patent Limited Liability Company

Darmstadt February 7th 1975

Ce phemde derivatives and methods of making them

(Addition to P 23 45 402)

The invention relates to the novel cephemic derivatives in general Formula I.

Z-CH ₂ GO-KE

COOH

wherein

Z is an unsubstituted or one or more alkyl having 1 to 4 carbon atoms, Alkoxy with 1 to 4 carbon atoms, OH, P, Cl, Br, J, NO «, WHp and / or acylamino with 1 to 4 carbon atoms substituted 1,4-dihydro-4-oxo-1-pyridyl radical,

609836/0926

night; -; "/:" oh

geänc'orl:

R 1,3,4-thiadiazolyl-2-thio or, if Z is a 1,4-dihydro-4-oxo-1-pyridyl radical substituted by acylamino with 1 to 4 carbon atoms, also H, -OCOCH ₃ or - S-het and

■ Eel 3-methyl-1,2,4-thiadiazolyl-5, 5-Kethyl-1,3,4-oxadiazolyl-2, 5-hydroxymethyl-1,3,4-oxadiazolyl-2, 5-methyl-1 , 3,4-thiadiazolyl-2, 5-hydroxymethyl-1,3,4-thiadiazolyl-2, tetrazolyl-5, 1-methyl-tetrazolyl-5, 1,2,3-triazolyl-4, 4-methyl-oxazolyi -2 or 1-0xidopyridinio-2

mean,

As well as their easily cleavable esters and their physiologically harmless salts.

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.

The present application is an additional application to the DBP (German patent application P 23 45 402.6).

It has been found that these compounds have an excellent antibacterial activity against gram-negative and against gram-positive germs. In comparison with known semisynthetically obtained cephalosporins, they show clear differences with regard to the sensitivity of the individual germs. In numerous cases, known cephalosporins are considerably surpassed by the new products, so that they have decisive therapeutic advantages in combating certain bacterial infections. The minimum inhibitory concentration of 3- (i, 2,4-thiadiazolyl-2-thiomethyl) -7- (3,5-dichloro-1,4-aihydro-4-oxo-1-pyridyl-acetamido) -3- cephem-4-carboxylic acid and 3-0, 2,4-thiadiazolyl-2-thiomethyl) -7- (3-amino-5-chloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3 -cephem-4-carboxylic acid or the potassium salts of these acids for

609836/0926

a number of pathogens, including Escherichia coli, Salmonella typhimurium, Shigella krusei and Klebsiella pneumoniae lower by a factor of 2-8 than that of cephalothin and cephalexin. In vivo showed this Compounds and 7 ~ (3-chloro-5-formylamino-1,4-'iihydro-4-OXO-1-pyridyl-acetamido) -cephalosporanic acid 1 to 20 times more potent than cephalothin in mice (measured as DC 50) against Staphylococcus aureus, Streptococcus pyogenes, Diplococcus pneumoniae, Salmonella newport, Klebsiella pneumoniae and Escherichia coli. In addition, after parenteral administration of these substances to dogs, serum concentrations were found which correspond to were comparable to those determined for cephalothin; $ 80-100 was found in the urine within 24 hours administered active substance detected.

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.

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 primarily denotes a single, double or quadruple, preferably a double substituted, but also an unsubstituted or trisubstituted 1,4-dihydro-4-oxo-1-pyridyl radical. In the case of single substitution, the substituents in the radical Z are preferably in the 3-position, in the case of twofold in the 3- and 5- or 2-position in the 6-position, in the case of threefold in the 2-, 3- and 5-position. Preferred substituents are Cl, Br and NH ₂ . Further substituents are OH, F, J, NOg, alkyl with 1 to 4 carbon atoms, primarily methyl, but also ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl or tert-butylj

■ 609836/0 9 26

25w834

Alkoxy with 1 to 4 carbon atoms, preferably methoxy, but also ithoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; Acylamino with 1 to 4 Carbon atoms, preferably alkanoylamino with 1 to 4 carbon atoms, especially formylamino, but also acetyl, propionyl or butyrylamino. Acylamino can also be alkylsulfonylamino with 1 to 4 carbon atoms, preferably methylsulfonyl or ethylsulfonylamino, but also propylsulfonyl, Isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, Isobutylsulfonyl- or tert-butylsulfonylamino,

Specifically, as preferred radicals are Z in addition to the unsubstituted 1,4-dihydro-4-oxo-1-pyridyl called: 3,5-diehlor-, 3,5-dibromo-, 3-amino-5-chloro-, 3-amino-5-bromo-, ^ -Chlor-S-formylamino-, 3-bromo-5-formylamino-, 3-chloro-5-acetylamino, 3-bromo-5-acetylamino, 3-chloro-5-methylsulfonylamino, 3-bromo-5-methylsulfonylamino, also 3,5-difluoro-, 3,5-diiodine-, 3,5-dinitro-, 3,5-dihydroxy-, 3,5-dimethoxy, 3,5-diamino, 3-chloro, 3-bromo, 3-nitro, 3-nitro, 3-amino, 3-hydroxy, 3-methoxy, 2,6-dimethyl-, 2,6-dimethyl-3,5-dichloro-, 2,6-dimethyl-3,5-dibromo-, 2,6-dimethyl-3,5-di3od-, 3-chloro-5-nitro-, 3-bromo-5-nitro-, 3-chloro-5-amino-, 3-bromo-5-amino-, 3-chloro-5-hydroxy- and 3-bromo-5-hydroxy-1,4-dihydro- 4-oxo-1-pyridyl. The group Z also stands for the following radicals, for example: 3-fluorine, 3-iodine, 3-ethoxy, 3-n-butoxy, 3-methyl, 3-ethyl, 3-n-butyl, 2,6-dimethyl-3-fluoro, 2,6-dimethyl-3-chloro-, 2,6-dimethyl-3-bromo-, 2,6-dimethyl-3-iod-, 2,6-dimethyl-3-hydroxy-, 2,6-dimethyl-3-nitro-, 2,6-dimethyl-3-amino-, 2,6-dimethyl-3-methoxy-,

2,6-dimethyl-3,5-difluoro-, 3-chloro-5-butylsulfonylamino-1,4-dihydro-4-oxo-1-pyridyl.

RQ903B / 092 6

ORIGINAL INSPECTED

2bUVS34

R is preferably the 1,3,4-thiadiazolyl-2-thio radical and if Z is a 1,4-dihydro-4-oxo-1-pyridyl radical substituted by acylamino having 1 to 4 carbon atoms, also H, OCOCH, and Het, being among the heterocyclic Residues Het the 1-methyl-tetrazolyl-5-residue, the 3-methyl-1,2,4-thiadiazolyl-5-residue and the 5-methyl-1,3,4-thiadiazolyl-2 radical are preferred.

Easily cleavable esters of the compounds of the formula I are primarily the tert-butyl esters, also e.g. the trimethylsilyl, benzyl, benzhydryl, trichloroethyl, Benzoy, methyl, p-kethoxybenzyl or methoxymethyl esters, also the pivaloyloxymethyl esters.

Those compounds of the formula I are preferred in which at least one of the symbols R and Z is one of the above has given preferred meanings.

Some of these preferred groups of compounds can be represented by the sub-formulas Ia to Ij below are, which otherwise correspond to the formula I, and in which the unspecified symbols in the Formula I have given meaning, but in which

in Ia R is 1,3,4-thiadiazolyl-2-thio;

in. Tb Z, a 1,4-dihydro-4-oxo-1-pyridyl radical substituted by at least one acylamino radical having 1 to 4 carbon atoms means;

in Ic Z one by at least one alkanoylamino radical 1,4-dihydro-4-oxo-1-pyridyl radical substituted with 1 to 4 carbon atoms means;

in Id Z one by at least one formylamino radical substituted 1,4-dihydro-4-oxo-1-pyridyl radical means;

609836/0 926

in Ie Z one by at least one acetylamino radical substituted 1,4-dihydro-4-oxo-1-pyridyl radical "means;

in If Z one by at least one alkylsulfonyl

amino radical with 1 to 4 carbon atoms is 1 _f 4-dihydro-4-oxo-1-pyridyl radical;

in Ig Z one by at least one methylsulfonylamino radical substituted 1,4-dihydro-4-oxo-1-pyridyl radical means;

in Ih Z 3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-

pyridyl,
R 1,3,4-thiadiazolyl-2-thio, H, OCOCH ₅ or

-S-Het and
• Het 1 -Methyltetrazolyl-5, 3-Methyl-1,2,4-thia-

diazolyl-5 or 5-methyl-1,3,4-thiadiazolyl-2 "mean;

in Ii Z 3-bromo-5-formylamino-1 ^ -dihydro ^ -oxo-ipyridyl- and
R 1,3,4-thiadiazolyl-2-thio, H, OCOCH ₃ or

-S-Het, and
Het 1-methyltetrazolyl-5, 3-methyl-1,2,4-thia-

diazolyl-5 or 5-methyl-1,3,4-thiadiazolyl-2 "mean;

in I3 Z 3-chloro, 3-bromo, 3-amino, 3-iOrmylamino, 3,5-dichloro, 3,5-dibromo, 3-amino-5-chloro, 3-amino-5-bromo-, ^ -chloro-S-methyl-, 3-bromo-5-methyl-, 3-chloro-5-methoxy-, 3-bromo-5-methoxy, 3-chloro-5-hydroxy-, 3-bromo-5-hydroxy-1,4-dihydro-5-oxo-1-pyridyl and E is 1,3,4-thiadiazolyl-2-thio.

The invention also relates to a process for the preparation of the compounds of the formula I and their easily cleavable esters and their physiologically harmless salts, which is characterized in that a compound of the general formula II

OOOH

wherein

R has the meaning given,

or one of its functional derivatives with a pyridone acetic acid of the general formula III

Z-CH ₂ COOH III

wherein

Z has the meaning given,

or converts one of its functional derivatives,

or that a compound of the general formula IV

«L ^

IV

CH ₂ R

COOH wherein ^v

X means Cl, Br or a reactive esterified OH group ,

• -60 9 838/092 fi

or one of its functional derivatives with a pyridone of the general formula V

ZH V

or one of its functional derivatives, or a compound of the formula VI

Z ¹ -CH ₂ -CO-NH

VI

I ₂ OCOCH ₅

COOH

wherein

Z is an unsubstituted or mono- or polysubstituted 1,4 by alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, OH, F, Cl, Br, I, NO ₂ and / or NH ₂ -Dihydro- 4-0X0-1 -pyridyl radical,

with 2-mercapto-1,3,4-thiadiazole or one of its alkali metal salts,

or that functionally modified OH, NHp or oxo groups contained in a compound otherwise corresponding to the formula I are set free by treatment with solvolyzing or hydrogenolyzing agents and that one or both of the substituents R and / or Z are optionally opposed in the product obtained exchanging other substituents R and / or Z and / or converting a carboxyl group into an easily cleavable carboxylic acid ester group by treatment with an esterifying agent and / or releasing the acid from a salt or ester obtained and / or a obtained acidic or basic compound of the Formula T converted into one of its physiologically harmless salts by treatment with a base or acid.

609836/0926

2507334

The conversion of one or "both of the substituents R and / or Z against other substituents R and / or Z takes place, for example, by treating a hydroxy group with a Alkylating agent alkylated and / or a nitro group or an acetoxymethyl group by treating with a Reducing agent reduced to an amino group or to a methyl group and / or a MEL group by reaction converts with an acylating agent into an acylamino group with 1 to 4 carbon atoms and / or an ethoxy group is converted into the radical -S-Het by treatment with a thiol of the formula Het-SH or a corresponding mercaptide.

All of these reactions proceed according to methods as they are known in cephalosporin chemistry and in the literature are described in detail.

The starting materials for the process according to the invention are either known or they can be prepared by methods known per se analogously to known compounds. For example, the acids II (R = -S-Het or 1,3,4-thiadiazolyl-2-thio ) obtainable from 7-aminocephalosporanic acid (7-ACS; II; R = -OCOCEU) by reaction with the mostly known heterocyclic TM oils of the formula Het-SH or with 2-mercapto-T, 3,4-thiadiazole or the associated metal mercaptides, e.g. by reaction of the corresponding alkali metal salts in hot aqueous acetone. The pyridone acetic acids III are available from the pyridones V and. Chloroacetic acid or hydroacetic acid. The acids IV can be obtained by methods known per se, for example from the acids II with a substituted acetic acid of the formula X-CHpCOOH or a functional derivative of such an acid, for example chloroacetyl chloride or bromoacetyl bromide. The radical X is preferably bromine, but it can also stand for Cl or a reactive esterified OH-G group, in particular for alkylsulfonyloxy with 1 to 6 carbon atoms or arylsulfonyloxy

G 0 9 8 3 6/0 9 2 B.

with 6 to 10 carbon atoms such as p-toluenesulfonyloxy. The substituted ones Pyridones Y are usually made by substituting 4-pyridone.

The easily cleavable esters, for example the tert-butyl esters, the trimethylsilyl esters (which, for example, arise in situ from II or IY and H-trimethylsilyl acetamide) and the .other esters given above. The salts, in particular the neutral salts, of these acids are also suitable. The alkali metal (for example sodium, potassium), alkaline earth metal (for example magnesium, calcium) and ammonium salts are particularly suitable. Among the latter, the salts derived from amines, in particular from tertiary amines, for example triethylamine, triethanolamine, pyridine, eollidine, are preferred. These salts can be used as such in the reaction; they can also be prepared in situ from the acid II or IY and a base, for example ITaHCO ₅ , Fa ₂ HPO. or triethylamine.

The halides, preferably the chloride and chloride derivatives, are particularly suitable as functional derivatives of the acids III Bromides, also the anhydrides and mixed anhydrides as well as azides and activated esters, e.g. those with p-ltitrophenol, 2,4-dinitrophenol, p-nitrophenyl mercaptan, methylene cyanohydrin or N-hydroxysuccinimide. As mixed anhydrides of the acids III, on the one hand, those are also suitable lower alkanoic acids, especially 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-star, e.g. III with benzyl chloroformate, p-nitrobenzyl ester, isobutyl ester, ethyl ester or allyl ester available are. All of these functional derivatives of III are preferably generated in situ.

'6 09036/0926

Puncture derivatives of Pyridone V are preferred their salts, e.g. the Na and K salts. These can be made of V e.g. with metallic Na or K in a high boiling point inert solvents such as toluene or in the cold with NaH.

In general, the implementation of the cephem derivatives II takes place "or IV (or their functional derivatives) with the pyridone derivatives III or V (or with their functional derivatives) in the presence of an inert solvent. As a solvent particularly suitable are chlorinated hydrocarbons, e.g. methylene chloride, chloroform; Ether how Diethyl ether, tetrahydrofuran, dioxane; Ketones such as acetone, butanone; Amides such as dimethylformamide (DMP), dimethylacetamide, Hexamethylphosphoric triamide; Sulfoxides such as dimethyl sulfoxide (DMSO); Water; also organic or aqueous inorganic bases. Mixtures of the mentioned solvents are used. If a salt of a compound of the formula I is to be produced, is an excess of the base used to form this salt, e.g. triethylamine, is particularly suitable as a solvent or aqueous sodium hydroxide solution.

The implementation of II with III or IV with V (or their functional derivatives) usually takes place at temperatures between -70 and + 80 °, preferably between -40 and + 30 °, especially between 0 ° and room temperature. 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 pyridone-acetic acid III, which is advantageous adding a water-binding agent. As such, e.g.

B Π Π η 3 R / Π 9 2 R

Carbodiimides, especially dicyclohexylcarbodiimide (DGG) into consideration. For example, 7-ACS-tert-butyl ester, the Acid III and DGC in approximately equimolar proportions and react with cooling in an inert solvent, especially in methylene chloride, DME, DMSO or solvents mix oil.

The reaction of II with functional derivatives of the acids III and the reaction of IY and V are preferably carried out in an alkaline medium. Either the pyridone V is used in the form of a salt, for example an alkali metal salt, or a base is added to the reaction mixture, in particular NaHCO 1, KHGO ₃ , Na ₂ GO ₅ , K ₂ CO ₃ , NaOH, KOH, pyridine or one base less Nucleophilicity, for example a tertiary amine such as triethylamine, N-methylmorpholine, ethyldiisopropylamine or potassium tert-butoxide.

You can also a cephem derivative VI by reacting with 2-mercapto-1,3,4-thiadiazole in the. transfer the corresponding thioether (R = 1,3,4-thiadiazolyl-2-thio). The reaction conditions correspond to those given below for the reaction of a obtained cephalosporanic acid of the formula I (R. = -OGOGH ₃ ) with a thiol Het-SH.

The cephem derivatives of the formula I can also be obtained by releasing functionally modified OH, NH ₉ or oxo groups contained in a compound otherwise corresponding to the formula I according to methods known per se. The starting materials for this process variant are obtainable, for example, analogously to the methods described above, but sensitive functional groups are functionally modified during the synthesis by protective groups.

Functionally modified groups are, for example: etherified or esterified hydroxyl groups,

609836/0926

e.g., benzyloxy or acetoxy; benzylated or acylated amino groups, e.g. benzylamino, benzyloxycarbamoyl, tert-butoxycarbamoyl, Acetylamino, in particular those customary in peptide chemistry should be mentioned as protective groups are. The oxo group of the pyridone ring can be functionally modified in the form of a derivative of the corresponding enol form e.g. in the form of quaternary salts of the general formula VII

Q-O - \ -

! c- ι _{r λ}

A ~ 0 ^^ V ^ CH ₂ R

COOH

worxn

Q is a solvolytic, hydrogenolytic or

catalytically removable residue, in particular an easily cleavable ether or ester group and

a "any anion, preferably chloride or Mean bromide and the pyridine ring can be substituted in analogy to the radical Z,

as well as their easily cleavable esters, especially the corresponding benzyl and tert-butyl esters. Instead of from VII a corresponding zwitterion comes into consideration, which can arise from HA by splitting off from VII.

The functionally modified groups can after themselves known methods described in the literature by solvolytic, in particular hydrolytic or hydrogenolytic be set free. Solvolysis, preferably

6 0 P, 8 3 6/0 9 2 F,

-H-

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 °. Hydrogenolysis sanctions modified groups, especially one Cleavage of benzyl and carbobenzoxy radicals takes place mainly by hydrogenation in the presence of noble metal catalysts, such as 5-50 ^ igem palladium on carbon, or Palladium oxide. It is expedient to hydrogenolyze at temperatures between -10 and + 50 °, in particular at room temperature, as well as at pressures between 1 and 100 at, preferably at normal pressure. It is possible and often desired direct the hydrogenolysis in such a way that further reductive changes occur in the molecule at the same time; e.g. a Acetoxymethy! group located in the 3-position to form a Methyl group are reduced.

If desired, the product of the formula I obtained can be used by methods known per se from the literature one substituent R against another substituent R and / or a substituent Z against another substituent Replace Z.

For example it is possible to alkylate a hydroxy group by treatment with an alkylating agent, e.g. with diazomethane, methyl bromide, methyl iodide, dimethyl or Diethyl sulfate, ethyl, n-propyl or n-butyl chloride, bromide or iodide.

It is also possible, for example, to create a nitro group on the pyridone ring to reduce to the amino group. In principle, all known per se for the reduction of nitro groups can be used for this purpose Appropriate methods are used, provided they do not cause undesirable changes in the molecule. Particularly Catalytic hydrogenation is suitable, e.g. on noble metal catalysts such as palladium at room temperature and normal pressure can be carried out.

6 0 9 8 3 6/0926

The reductive conversion of an acetoxymethyl group into a methyl group can also be hydrogenated Carry out on noble metal catalysts such as palladium, where appropriate "at low temperatures, but something elevated pressures (between 2 and 10 at) works.

Palis desired, several of the reduktiyen described can also be used Conversions can be performed in one step. So you can by hydrogenation of a cephalosporanic acid I (R = -OCOCH,) substituted in the radical Z by a nitro group is the corresponding deacetoxycephalosporanic acid I (R = H), which is substituted in the radical Z by an amino group is to manufacture.

It is also possible to acylate an amino group on the pyridone ring by treatment with an acylating agent. Acylating agents are alkanoic acids with 1 to 4 carbon atoms or alky! Sulfonic acids with 1 to 4 carbon atoms or the reactive ones Derivatives of these acids, e.g. their halides, preferably their chlorides or bromides, or their anhydrides. Preferred aylating agents are formic acid, acetic acid, acetic anhydride, acetyl chloride, acetyl bromide, methanesulf onyl bromide and methanesulfonyl chloride.

It is particularly advantageous to obtain a cephalosporanic acid of the formula I (R = -OCOCH,) by reaction with a To convert mercaptan of the formula Het-SH into the corresponding thioether I (R = -S-Het). 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.

609836/0926

For example, 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, especially by acid hydrolysis. The tert-butyl esters obtained particularly advantageously in the synthesis are E.g. cleaved with trifluoroacetic acid 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 Salts with organic bases such as diethylamine, triethylamine, diethanolamine, N-ethyl-diethanolamine, pyrrolidine, piperidine, N-ltliy! Piperidine, 1- (2-hydroxyethyl) piperidine, morpholine, Procaine, benzylamine, dibenzylamine, 1-phenyl-2-propylamine and other amines, as are commonly used for Find production of cephalosporin salts use.

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.

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.

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2507334

Since the compounds I have no sharp melting points, they are expediently replaced by other physical ones
Key figures characterized, particularly advantageous by
their infrared spectra. In the infrared spectrum they show the absorption band of the ß-lactam ring at 1760-1800 cm ~. They can also be characterized by their nuclear magnetic resonance spectra and by the thin-layer chromatogram. Merck TLC pre-fabricated silica gel Focja plates can be used for this purpose (flow agent eg dioxane / water 85:15).

The new compounds can be used in admixture with solid, liquid and / or semi-liquid excipients as medicaments in human or veterinary medicine. The carrier substances used are organic or
inorganic substances in question, which are suitable for enteral, e.g. oral, but preferably for pax-enteral or topical application and which do not react with the new compounds, such as water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, 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 or aqueous solutions, and suspensions, emulsions or implants are used in particular for parenteral administration, while ointments, creams or ointments are used for topical application
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 new compounds can also be lyophilized in a manner known per se and the lyophilizates obtained can be used, for example, for the production of injection preparations.

The substances are preferably used in dosages between 1 and 5000, in particular between 200 and 2000 mg administered per dosage unit. The daily dosage is up preferably between 2 and 100 mg / kg, in particular between 8 and 40 mg / kg of body weight. In addition, the connections of the formula I and / or their salts can be used in accordance with the known compound cephalotin. Parenteral (e.g. intravenous or intramuscular) administration is preferred.

The compounds of formula I mentioned in the following examples are for the production of pharmaceutical Preparations particularly suitable.

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

example 1

a) A solution of 12.5 g of 7-ACS-tert-butyl ester and 8.9 g

DCC in 100 ml of methylene chloride / DMF 1: 1 is cooled to 0 °. 9.1 g of 3,5-dichloro-4-pyridone-1-acetic acid are added, removed after 5 minutes the ice bath and stirred for a further 30 minutes at 25 °. The urea formed is filtered off and the filtrate is filtered through silica gel (mobile phase: ithyl acetate / 1 ^ methanol). The solvent is evaporated and the 7- (3,5-dichloro-1,4-dihydro-4-oxo-1-pyridylacetamido) -cephalosporanic acid-tert-butyl ester obtained crystallized from ether.

600336 / 092B

b) 22 g of the tert-butyl ester are dissolved in 30 ml of trifluoric acid solved. To. It is evaporated for 30 minutes and the 7- (3,5-dichloro-1, 4-dihydro-4-oxo-1-pyridyl-acetamido) -eephalosporanoic acid obtained crystallized from ether.

IR: 1780, 1680, 1630, 1590, 1220 cm " ¹ .

c) 5j7 g of the 7- (3,5-dichloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanic acid obtained are in 60 ml of 0.01N aqueous sodium hydrogen carbonate solution a pH below 7 and dissolved with 1.2 g of 2-mercapto-1,3,4-thiadiazole added in 20 ml of acetone. The reaction solution is stirred for 2 hours at 80 ° and pH 6.3 under nitrogen. The acetone is then removed, the solution is washed with ether and acidified to pH 2, and the 3- (1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3,5-dichloro-1,4-dihydro) obtained -4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid filtered off and dried,

IR: 1765, 1680, 1615, 1365, 1230 cm " ¹ .

Analogous to example 1c are from the corresponding cephalosporanic acids the compounds of formula I given in Examples 2 to 34 below by reaction with 2-mercapto-1,3,4-thiadiazole available:

609836/0926

example

CD

O
CO
OO
CO

cn

O
CO

ro

4 5 β

. 7 8 9

10 11 12 13 H 15 16

Compound of formula I.

3- (1,3,4-th.iadiazolyl-2-tmomethyl) -7- (1,4-dihydr 0-4-0X0-1-pyridyl-acetamido) -

3-cephem-4-carboxylic acid

3- (i, 3,4-thiadiazolyl-2 ~ thiomethyl) -7- (2,6-dimethyl-1,4-dihydro-4-oxo-1-pyridyl-

acetamido) -3-cephem-4-carboxylic acid

3- (1,3,4-thiadiazolyl-2-thiomethyl) -7- (3-methoxy-1,4-dihydro ~ 4-oxo-1-pyridyl-

acetamido) -3-cepnem - 4-carboxylic acid

3- (1,3,4-TMadiazolyl-2-thiomethyl) -7- (3-n-butoxy-1 _; 4-di] iydro-4-oxo-1-pyridyl-

acetamido) -3-cepnem-4-cart) on acid

3- (1,3,4-TMadiazolyl-2-thiomethyl) -7- (3-hydroxy-1,4-dihydro-4-oxo-1-pyr.i '. ^; !' L-

acetamido) -3-cepnem-4-carboxylic acid

3- (1,3,4-TMadiazolyl-2-tmomethyl) -7- (3-fluoro-1,4-dihydro-4-oxo-1-pyrid; / l-aoet-

amido) -3-cephera-4-carbonic acid

3- (i, 3,4-TMadiazolyl-2-tmomethyl) -7- (3-chloro-1,4-dih.ydro-4-oxo-1-pyr.iciy! -Acetamido ) ~ 3-cephem-4-carboxylic acid

3- (i, 3,4-TMadiazolyl-2-tmomethyl) -7- (3-bromo-1,4-dihydro-4-oxo-1-pyridyl-aoet-

amido) -3-cepnem-4-carbonic acid

3- (i, 3,4-thiadiazolyl-2-thiomethyl) -7- (3-; iodo-1,4-dihydro-4-oxo-1-pyridyl-aoet-

amido) -3-cepnem-4-carboxylic acid

3- (1,3,4-TMadiazolyl-2-tliiomethyl) -7- (3,5-difluoro-_1, 4-dihydro-4-oxo-1-pyridyl-

acetamido) -3-cepliem-4-carboxylic acid

3- (i, 3,4-TMadiazolyl-2-tmomethyl) -7- (3,5-dibromo-1,4-dihydro-4-oxo-1-pyridyl-

ac e tamido) -3-c e ph.em-4-oarb ons aur e

3- (1,3,4-thiadiazolyl-2-thiomethyl) -7- (3,5-diiod-1, 4-dihydro-4-oxo-1 »pyridyl-

acetamido) -3-cephem-4-carboxylic acid

3- (i, 3,4-thiadiazolyl-2-thiomethyl) -7- (2,6-dimethyl-3,5-diohlor-1,4-dihydro-4-oxo-

1-pyridyl-acetamido) -3-cepliem-4-carboxylic acid

3- (1,3,4-thiadiazolyl-2-thiomethyl) -7- (2,6-dimethyl-3,5-dibromo-1,4-dihydro-4-oxo-

1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

3- (1,3,4-TMadiazolyl-2-tmomethyl) -7- (3-nitro-1,4-dihydro-4-oxo-1-pyridyl-acet-

amido) -3-cephem-4-carboxylic acid

ro cn o -j oo

example

Compound of formula I.

17 18 19 20 21

22 23 24 25 26 27 28 29

-Thiadiazolyl-2-tM. omethyl) -7- (3,5-dinitro-1,4-dihydro-4-oxo-1-pyridylacetamidο) -3-cephem-4-carboxylic acid

3-0.3.4

3- (1,3,4-thiadiazolyl-3- (1,3,4-thiadiazolyl-3- (1,3,4-thiadiazolyl 3- (1,3,4-thiadiazolyl-

2-tMomethyl) 7- (3-clilor-5-nitro-1,4-dih. Hydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

2-th.iomethyl) -7- (3-'bromo-5-nitro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

2-thiomethyl) -7- (3-chloro-5-amino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cepliem-4-carboxylic acid

• 2-tmomethyl) -7- (3-'bromo-5-amino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cepheiii-4-carboxylic acid,

IR: 1770, 1630, 1660, 1600, 1550, 1365, 1270, 1240, 1190, 1065 cm " ¹

3-0.3.4 3-0.3.4 3-0.3.4 3-0.3.4 3-0.3.4 3-0.3.4 3-0.3.4 3-0.3.4

-Tlliadiazolyl-2-thiomeΐl·lyl) -7- (3-chloro-5-l·lydroxy-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

-TMadiazolyl-2-tmomethyl) -7- (3-TDrom-5-hydroxy-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

-TMadiazolyl-2-thiomethyl) -7- (3-bromo-5-chloro-1,4-di] iydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-cart) acids

-Tliiadiazolyl-2-tliiomethyl) -7- (3-chloro-5-methyl-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-cart) onic acid

-Th.iadiazolyl-2-th.iomethyl) -7- (3-13roni-5-methyl-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-oarbonsä- are

-TMadiazolyl-2-tmomethyl) -7- (3-chloro-5-metlioxy-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

-TMadiazolyl-2-tliiomethyl) -7- (3-bromo-5-methoxy-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

-TMadiazolyl-2-thiomethyl) ~ 7- (3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

CTJ

OO

10

to

CT.

example

30th

31 32 33 34

Compound of formula I.

3- (1,3,4-TMadiazolyl-2-thiomethyl) -7- (3-bromo-5-formylamino-1,4-dibydro-4-oxo-

1-pyridyl-acetaraido) -3-cepliem-4-carboxylic acid »

IR: 1780, 1690, 1630, 1550, 1480, 1370, 1255, 1190, 1065 at " ¹

3- (1,3,4-th.iadiazolyl-2-thiomethyl) -7- (3-chloro-5-acetylamino-1,4-dihydro-4-

oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

3- (1,3,4-TMadiazolyl ~ 2-tmomethyl) -7- (3-bromo ~ 5-acetylamino-1,4-dihydro-4-oxo-

1 ~ pyridyl ~ acetamido) -3-cepliem-4-carboxylic acid

3- (1,3,4-TMadiazolyl-2-t-momethyl) -7- (3-chloro-5-methylsulfonylamino-1,4-dihydro-

4-0X0-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

3- (1,3,4-TMadiazolyl-2-thiomethyl) -7- (3-bromo-5-methylsulfonylamino-1,4-dihydro-

4-0X0-1-pyridyl-acetamido) - 3-cephem-4-carboxylic acid

O i

The compounds of the formula I given in Examples 35 and 44 below can be obtained analogously to Example 1c by reacting 7- (3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosρoranoic acid with

3-methyl-1 ^^

5-methyl-1,3,4-oxadiazole ~ 2-thiol, 5-hydroxymethyl-1,3,4-oxadiazol-2-thiol, 5-methyl-1,3,4-thiadiazol-2-thiol, 4-hydroxymethyl-1,3,4-thiadiazol-2-thiol, Tetrazole-5-thiol,

1,2,3 ~ triazole-4-thiol, 4-methyl-oxazole-2-thiol, 2-mercaptopyridine-IT-oxide and 1-methyl-tetrazole-5-thiol:

609836/0926

example

CC '
CT 35 5 ZD
te
ro 36
37 38 39 20th 40
41 42 43 44

Verb inching of Formula I.

3- (3-Methyl-1,2,4-thiadiazolyl-5-thiomethyl) -7- (3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3- cephem-4 ~ carboxylic acid

3- (5-Methyl-1,3,4-oxadiazol-2-thiomethyl) -7- (3-chloro-5-formylamino -1,4-dihydro-4-0X0-1-pyridyl-acetamido ) -3-ceph.em-4-carboxylic acid

3- (5-Hydroxymethyl-1, 3,4-oxadia.zol-2-thiomethyl) -7- (3-chloro-5-formylamino- -1,4-dihydro-4-oxo-1-pyridyl-acetamido ) -3-cephem-4-carboxylic acid "e

3- (5-Methyl-1, 3,4-th.iadia2ol-2-thiomethyl) -7- (3-chloro-5-formylaminu'-1, i-dihydro-4-0X0-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

3- (5-Hydroxym.eth.yl-1,3,4-th.iadiazol-2-thiomethyl) -7- (3-ch.lor-5-formylamino-1,4-dihydr0-4-0X0- 1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

3- (Tetrazo3.yl-5-thiomethyl) -7- (3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-pyi'idylacetamido) -3-cephem-4-carboxylic acid

3- (1,2,3-Triazolyl-4-thiomethyl) -7- (3-chloro-5-formylamino »1,4-dihyA: < ^s o-4-oxo-1 pyridyl-acetamido) -3- cephem-4-carboxylic acid

3- (4-Meth.yl-oxazolyl-2-thiomethyl) -7- (3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4- carboxylic acid

3- (1-0xido-pyridinio-2-thiomethyl) -7- (3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

3- (i-Methyl-tetrazolyl-2-th.iomethyl) -7- (3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4- carboxylic acid

ro

cn σ -4 00 co

The compounds of the formula I given in Examples 45 "to 59 below are analogous to Example 1c by reacting 7- (3-bromo-5-formylamino-1,4-dihydro-4-OXO-1-pyridyl-acetamido) -cephalosporanic acid, 7- (3-Chloro-5-acetylamino-1,4-cLiliycLro-4-oxo-1 -pyridyl-acetamido) -cephalosporanic acid, 7- (3-bromo-5-acetylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanic acid, 7- (3-chloro-5-methylsulfonylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanic acid and 7- (3-bromo-5-methylsulfonylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamidο) -cephalosporic acid with 3-Methy1-1,2,4-thiadiazole-5-thiol, 5-methyl-1,3,4-thiadiazol-2-thiol and 1-methyltetrazolyl-5-thiol available:

609836/0926

example

5 CT
O
'.D 46 3- (3-methyl Ca?
CT, 47 3- (3-methyl 10 48
49 3- (3-methyl
3- (3-methyl 50 3- (5-methyl 15th 51 3- (5-methyl 52 3- (5-methyl 20th 53 3- (5-methyl 54 3- (5-methyl 25th 55 3- (1-methyl 56 3- (1-methyl 57 3- (1-methyl 58 3- (1-methyl 59 3- (1-methyl

Compound of formula I.

3- (3-Methyl-1,2,4-thiadiazolyl-5-thiomethyl) -7- (3-Bromo-5-formylamino-1,4-dihydro-4-0X0-1-pyridyl-acetamido) -3- cephem-4-carboxylic acid,

IR: 1790, 1690, 1640, 1555, 1485, 1375, 1260, 1200 cm " ¹

• 1,2,4-thiadiazolyl-5-thiomethyl) -7- (3-chloro-5-acetylamino-1,4-dihydro-4-0X0-1-pyridyl-acetamido) -3-cephem-4-carbolic acid

■ 1,2,4-thiadiazolyl-5-thiomethyl) -7- (3-bromo-5-acetylamino-1,4-dihydro-4-0X0-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

L-1,2,4-thiadiazolyl-5-thiomethyl) -7- (3-chloro-5-methylsulfonylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid ⁱ ure

-1,2,4-thiadiazolyl-5-thiomethyl) -7- (3-bromo-5-methylsulfonylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

-1,3,4-thiadiazolyl-2-thiomethyl) -7- (3-bromo-5-formylamino-1,4-dihydro-4-0X0-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid, IR: 1780, 1695, 1640, 1550, 1480, 1380, 1275, 1200 cm- ¹

-1,3,4-thiadiazolyl-2-thiomethyl) -7- (3-chloro-5-acetylamino-1,4-dihydro-4-0X0-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

-1,3,4-thiadiazolyl-2-thiomethyl) -7- (3-bromo-5-acetylamino-1,4-dihydro-4-0X0-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

-1,3,4-thiadiazolyl-2-thiomethyl) -7- (3-chloro-5-methylsulfonylamino-1,4-dihydro-4-oxo ~ 1-pyridyl-acetamido) -3-cephem-4-carboxylic acid ure

.-1,3,4-thiadiazolyl-2-thiomethyl) -7- (3-bromo-5-methylsulfonylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid 'u.re

-tetrazoly1-5-thiomethyl) -7- (3-bromo-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid,

IR: 1785, 1695, 1640, 1550, 1480, 1380, 1260, 1190 cm " ¹

Tetrazolyl-5-thiomethyl) -7- (3-chloro-5-acetylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

-tetrazolyl-5-thiomethyl) -7- (3-bromo-5-acetylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

-tetrazolyl-5-thiomethyl) -7- (3-chloro-5-methylstilphonylamino-1,4-dihydro-4-0X0-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid

-tetrazolyl-5-thiomethyl) -7- (3-bromo-5-methylsulfonylamino-1,4-dihydro-4-0X0-1-pyridy! -acetamido) -3-cephem-4-carboxylic acid

Example 60

Analogously to Example 1, "b obtained by acidic hydrolysis of the 7- (3-bromo-5-formylamino-1,4 ~ dihydro-4-oxo-1-pyridyl acetamido) cephalosporanic acid tert '-buty.! Ester (available analogous to Example 1a from 7-A0S-tert-butyl ester and 3-bromo-5-formylamino-4-pyridone-1-acetic acid in the presence of DCO) 7- (3-bromo-5-formylamino-1,4-dihydro- 4-oxo-1-pyridyl-acetamido) -cephalosporanic acid, IE: 1780, 1680, 1635, 1550, 1480, 1380, 1240, 1200, 1080, 1045 cm " ¹ .

Analogously to Example 60, from the corresponding tert-butyl esters (obtainable from 7-ACS-tert-butyl ester and the corresponding 4-pyriaeon-1-acetic acids of the formula III) the gephalosporan acids of the formula I specified in Examples 61 "to 68 below by acidic saponification available:

609836/0926

example

Compound of formula I.

10

62 63

64

65 66

67 68

15th

7- (3-chloro-5-ormylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) ~ cephalQ "~ sporic acid

7- (3-3? Ormylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -eephalosporanic acid

7- (3-Acetylamino-5 ~ bromo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalo ~ sporic acid

7- (3-Acetylamino-5-chloro-1,4-dihydro-4-oxo-1-pyridyl-acetainido) ™ cepii £ .lo-> sporic acid

7- (3-Acetylamino-1,4-dihydro-4-oxo ~ 1-pyridyl-acetaiaido) -cephalosporanic acid

7- (3-Bromo-5-methylsulfonylamino-1,4-dihydro-4-oxo-1-pyridyl-aoetitmido) -ceplialosporanic acid

7- (3-Chloro-5-methylsulfonylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamid, u) -cephalospora, acid

7- (3-methylsulfonylamino-1,4-dih.yero-4-oxo-1-pyridyl-acetamido) -cephalosporanic acid

ω ι

K)

--3 OO

Example 69

a) 23 mg of T-aminodeacetoxycephalosporanic acid tert-butyl ester (obtainable from the acid and isobutylene in dioxane / HpSO. at 25 °), 34 mg of ^ -Bromo-S-formylamino- ^ pyridon-acetic acid and 38 mg of DCG are dissolved in 2 ml of absolute methylene chloride while cooling with ice and are kept for a further 2 hours

• 25 stirred. The reaction mixture is purified over silica gel with ethyl acetate / methane oil, and the eluate is evaporated and crystallized with ether. 7- (3-Bromo-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -desacetoxy-cephalosporanic acid tert-butyl ester is obtained.

b) The tert-butyl ester obtained according to 69a is analogous to Example 1b saponified. 7- (3-Bromo-5-formylainino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -desacetoxycephalosporanic acid is obtained,

IR: 1780, 1680, 1640, 1560, 1480, 1380, 1200 cm " ¹ .

Analogous to example 69b are from the corresponding tert-butyl esters (available from desacetoxy-7-ACS-tert-butyl ester and the corresponding 4-pyridone-1-acetic acids of the formula III) the deacetoxycephalosporanic acids of IOrmel I specified in Examples 70 to 77 below by acidic saponification available:

0 ['. 3 3 B / (j 9 2 b

example

CC
ω 15th 70 5 ^ 10 71 co
to. 72 73 74 75 76 77

VerMn.du.ng of the formula I.

7- (3-chloro-5-formylamino-1,4-dih.ydro-4-oxo-1-pyridyl-acetamido) -desacetoxyoeph.alosporansau.re

7- (3-Formylamino-1, 4-dihydro-4-oxo-1-pyridyl-aeetamido) -desaeetoxy-ceph.a, lo-

7- (3 ~ acetylamino-5-'bromo-1,4-dih. Hydro-4-oxo-1-pyridyl-acetamido) - ™ desacetoxy ~ oephalosporanic acid

7- (3-acetylamino-5-chloro-1,4-dihydro-4-oxo-1-pyridyl-aoetamido) -desacetoxyoephalosporanic acid

7- (3 ~ acetylamino-1,4-dihydro-4-oxo-1-pyridy! -Acetamido) -desacetoxycephalosporanic acid

7- (3-Bromo-5-meth.ylsulfonylamino-1,4-dih. Hydro-4-oxo-1-pyridyl-acetamido) -desacetoxy-cephalosporanic acid

7- (3-Ch.lor-5-methylsulfonylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -desacetoxycephalosporanic acid

7- (3-Meth.ylsulfonylamino-1,4-dih. Hydro-4-oxo-1-pyridyl-acetamido) -desacetoxycephalosporanic acid

K) Cn O · <! OO CO

Example 78

200 mg of the tert-butyl ester of 3-0,3,4-thiadiazolyl-2-thiomethyl) -7- (3-nitro-1,4-dihydr'o-4-oxo-1-pyridylacetamido) -3-eephem-4-carboxylic acid are taken up in 60 ml of methanol and with the addition of 200 mg of 5% Pd-charcoal Hydrogenated for 15 minutes at 25 ° and normal pressure. The catalyst is filtered off, the solution evaporated and the Residue crystallized with ether. 3- (1,3,4-Thiadiazolyl-2-thiomethyl) -7- (3-amino-1,4-dihydro-4-oxo-1 is obtained -pyridyl-aeetamido) -3-cephem-4-carboxylic acid tert. -butyl ester.

Example 79

To 451 mg · 3-chloro-5-formylamino-4-pyridone-1-acetic acid in. 10 inl of absolute DMP v / ground 0.224 ml with ice cooling Trichloroacetyl chloride given. After stirring for 30 minutes, a solution of 554 mg of 7-ACS and 1 g of N-trimethylsilylacetamide is added in 5 ml of DMF. It is stirred for another 30 minutes while cooling with ice, then poured into water and added pH adjusted to 5. It is washed with ether, adjusted to pH 2, extracted with ethyl acetate, dried, evaporated, crystallizes with ether and gives 7- (3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-aeetamido) -cephalosporanic acid.

609836/0926

Example 80

To 451 mg of 3-chloro-5 ™ formylamino-4-pyridone-1-acetic acid in 5 ml of absolute TMF , 0.224 ml of triehloroacetyl chloride are added. After stirring for 30 minutes, a solution of 554 mg of 7-ACS and 0.84 ml of triethylamine in 20 ml of methylene chloride is added. The mixture is stirred for a further 30 minutes, then poured into water and adjusted to pH 6. It is washed with methylene chloride, worked up as usual, and 7- (3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanic acid is obtained.

Example 81

A solution of 272 mg of 7-ACS and 1 ml of triethylamine in 10 ml of methylene chloride is added in portions at 0 ° Stir with 336 mg of 3-bromo-5-methylsulfonylamino-1,4-dihydro-4-oxo-1-pyridyl acetazide offset. The mixture is stirred for a further 1 hour, filtered off with suction and 7- (3-bromo-5-methylsulfonylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosρoranoic acid is obtained.

Example 82

10 g of 7-ACS are suspended in 95 ml of absolute methylene chloride, cooled to -10 °, brought into solution with stirring with 12.9 ml of triethylamine and stirred for a further 45 minutes at -30 ° - then one is added dropwise at a temperature below -20 ° Freshly prepared solution of 3-chloro-5-formylamino-4-pyridon-i-acetyl chloride (obtained by adding dropwise 2.68 ml of thionyl chloride to a solution of 8.12 g of 3-chloro-5-formylamino-4-pyridon-1 -acetic acid in 40 ml IMF

609836/0926

at -40 °), stir for 45 minutes at -20 °, leaves on Warm up to 0 ° and extract several times with sodium bicarbonate solution. The separated aqueous phases are acidified with hydrochloric acid and with tetrahydrofuran / ethyl acetate extracted. The organic phases are dried over sodium sulfate and evaporated, and 7- (3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanic acid is obtained.

Example 83

a) A solution of 684 mg of 3-0,3,4-thiadiazolyl-2-thiomethyl) -7- (3-benzylainino-5-bromo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) - 3-cephem-4-carboxylic acid tert-butyl ester (obtainable from 3-benzylamino-1,4-dihydro-4-oxo-1-pyridyl-acetic acid and 7-amino-3- (i, 3,4-thiadiazolyl- 2-thiomethyl) -3-cephem-4-carboxylic acid tert-butyl ester) in 100 ml of methanol is hydrogenated on 300 mg of 5 ° lgex Pd-carbon at 25 ° and normal pressure until the hydrogen uptake has ended. It is filtered, evaporated and 3- (1,3,4-thiadiazolyl-2-tb.iolethyl-7- ^ -amino ^ -bromo-1,4-dihydro-4-oxo-1-pyridylacetamido) -3- cephem-4-carboxylic acid tert-butyl ester.

b) The tert-butyl ester obtainable according to Example 83a is analogous to Example 1b for 3rO53,4-thiadiazolyl-2-thiomethyl) -7- (3-amino-5-bromo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid saponified.

c) It is added to a mixture of 185 ml of formic acid and 52 ml acetic anhydride with ice cooling 50 g 3- (1,3,4-thiadiazolyl-2-thiomethyl) -7- (3-amino-5-bromo-1,4-cLihydro-4-0X0-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid,

60 Oa 38/0926

stir for one hour "at 0 °, the solvent is distilled and obtained as residue 3- (1,3,4-thiadiazolyl-2-thioIII ^ thyl) -7- (3-bromo-5-f ormylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid.

d) 150 mg of the acid obtainable according to Example 83c dissolved in a little methanol, with methanolic diethyl acetic acid-potassium salt solution added and precipitated with diethyl ether. The associated potassium salt is obtained.

The active ingredients of the formula I can be converted into pharmaceutical preparations by methods which are known from the literature process as the following example shows:

Example A: ampoules

A solution of 1 kg of 7- (3-chloro-5-formylamino-1,4-dihydro-4-OXO-1-pyridyl-acetamido) -cephalosporanic acid, potassium salt is dissolved in 3 l of double-distilled water, sterile filtered, filled into ampoules, under sterile conditions lyophilized and sterile closed. 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.

Analogously to Example A, ampoules can be obtained which contain one or more of the other active ingredients of the formula I or their physiological contain harmless salts or their easily cleavable esters.

609836/0926

Claims (17)

Patent claims: Z is an unsubstituted or a · - or polysubstituted by alkyl of 1 "to 4 carbon atoms, alkoxy having 1 his 4 carbon atoms, OH, P ₅ 03 _Br, T ₅ IFOP, IiHp and / or acylamino with 1 Ms 4 carbon atoms substituted 1,4-Mhydro-4-o: xo-1-pyridyl radical, R 1,3,4-thiadiazolyl-2-thio or, if Z is a 1,4-dihydro-4-oxo-1-pyridyl radical substituted by acylamino with 1 to 4 carbon atoms, also H, -OCOCH ₅ or -S- Het and Het 3-methyl-1,2,4-thiadiazolyl-5,5-methyl-1,3,4- oxadiazolyl-2, 5-hydroxymsthyl-1,3,4-oxadiazolyl-2, 5-methyl-i, 3,4-thiadiazolyl-2, 5-hydrosymethyl-1,3,4-thiadiazolyl-2, Tetrazolyl-5, 1-methyltetrazolyl-5, 1,2,3-triazolyl-4,4-methyl-oxazolyl-2 or 1-oxidopyridinio-2 mean, as well as their easily cleavable esters and their physiologically harmless salts. 6 0 9 8 3 6/0926 2. 3- (1,3,4-Thiadiasolyl-2-thiomethyl) ~ 7- (3,5-dichloro-1,4-dihydro-4-oxo-1-pyriayl-acetamido) -3-cephem-4- carboxylic acid, 3- 3- (1,3,4-thiadiazolyl-2-thiomethyl) -7- (3-amino-5-'bromo ~ 1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephein-4-carboxylic acid. 4. 3- (1,3,4-Thiadiazolyl-2-thiomethyl) -7- (3-bromo-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem- 4-carbonsä "u.re . 5. 7- (3-Bromo-5-forinylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -desacetoxy-cephalosporanic acid. 6. 7- (3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -ceplialosporanate. 7. 7- (3-Bromo-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporarLsätire. 8. 3- (3-Methyl-1,2,4-thiadiazolyl-5-tmomethyl) -7- (3-chloro-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-acetamido ) -3-cephem-4-carboxylic acid. 9. 3- (3-Methyl-1,2,4-t-madiazolyl-5-thiomethyl) -7- (3-bromo-5-formylamino-1,4-dihydro-4-oxo-1-pyridyl-aoetamido) - 3-cephem-4-carl) onic acid. 10. 3- (5-Methyl-1,3,4-thiaaiazolyl-2-tmomethyl) -7- (3-clilor-5-formy! Amino-1,4-dihydro-4-oxo-1-pyridy! - acetamido) -3-cephem-4-carboxylic acid. 11. 3- (5-Methyl-1,3,4-t-madiazolyl-2-tliio! Net] b.yl) -7- (3-'bromo-5-f'ormylamino-1,4-diyydro-4- oxo-1 -pyridyl-acetamido) -3- oe phe: <n- 4 - ο arts ons äiire e ■. naia υ -: 5 s, > 3 o J 4 12. 3- (1-Methyl-tetrazolyl-5-th.iometliyl) -7- (3-chloro-5-formylamino-1,4-diylium-4-oxo-1 -pyridyl-acetamido) -3-cephem-4-car "bonic acid. 13. 3- (i-Methyl-tetrazolyl-5 ~ t] iomethyl) -7-C3-'broni-5-formylamino-1,4- hydro-4-oxo-1 -pyridyl-acetamido) -3-cepliem - 4-carboxylic acid. 6 03836/0926 14- Process for the preparation of compounds of general Formula I. Z-CH ₂ COlTH CH ₂ R COOH worm Z is an unsubstituted or one or more alkyl having 1 to 4 carbon atoms, Alkoxy with 1 to 4 carbon atoms, OH, F, Cl, Br, J, KOp, KHp and / or acylamino with 1 to 4 C-atoms substituted 1, 4 ~ dihydro - 4 ~ oxo-1-pyridyl radical, R 1,3-4-thiadiazolyl-2-thio or, if Z is a 1,4-I-ihydric-4-oxo-1-pyridyl radical substituted by acylamino having 1 to 4 carbon atoms, also H, -OCOCH ₅ or -S-Het and Het 3-methyl-1,2,4-thiadiazolyl-5,5-methyl-1,3,4- oxadiazolyl-2, 5-hydroxymethyl-1,3,4-oxadiazolyl-2. 5-methyl-1,3,4-thiadiazolyl-2, 5-hydroxymethyl-1,3,4-thiadiazolyl-2, Tetrazolyl-5, 1-methyl-tetrazolyl-5, 1,2,3-triazolyl-4,4-methyl-oxazolyl-2 or 1-oxidopyridinio-2 mean, and their easily cleavable esters and their physiologically acceptable salts, characterized in that one Compound of the general formula II 6 03836/0926 2 5 G 7 8 3 A O ^ II COOH wherein R has the meaning given, or one of its functional derivatives with a pyridone acetic acid of the general formula III Z-CH ₂ COOH III wherein Z has the meaning given, or converts one of its functional derivatives, or that a compound of the general formula IV X-CHo-CO-NH ^ O <** ^X \ ^ CH ₂ R COOH wherein X means Cl, Br or a reactive esterified OH-G group, or one of their functional derivatives with a pyridone of the general formula V Z-H V SUN 9 »36/0926 or one of its functional derivatives reacts »or that a compound of the formula VI Z ¹ -CH ₀ GOIiH CH ₂ OCOCH, COOH worm Z 'is an unsubstituted or a single or. 1,4-dihydro-4-OXO-1- substituted several times by alkyl with 1 "to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, OH, F, Cl, Br, J, NOp and / or KH ₂ pyridyl radical means, with 2-mercapto-1,3,4-thiadiazole or one of its alkali metal salts implements, or that functionally modified OH-, NHp- or oxo groups by treatment with solvolysing-n or hydrogenolysing agents are set free and that you optionally in the product obtained one or exchanges both substituents R and / or Z for other substituents R and / or Z, and / or that a carboxyl group can be converted into an easily cleavable one by treatment with an esterifying agent Converts carboxylic ester group and / or sets the acid free from a salt or ester obtained and / or an acidic or obtained basic compound of the formula I by treatment with a base or acid in one of its physiologically harmless Salts transferred. 609Ö36 / 0926 15 · The method according to claim 14, characterized in that the substituent R in a product of the formula I obtained is exchanged for another substituent R, by adding an acetoxy group by treatment with a thiol of the formula Het-SH or an equivalent Converts mercaptide into the radical -S-Het, Het each having the meaning given in claim 14. 16. 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 esters and / or one of its physiologically harmless ones Salts together with at least one solid, liquid or semi-liquid carrier or auxiliary, and optionally brings together with another active ingredient into a suitable dosage form. 17. A pharmaceutical preparation containing a compound of the general formula I and / or one of its easily cleavable esters and / or one of its physiologically acceptable Salts. 609836/0926 ORIGINAL INSPECTED