IE42709B1 - 7-(1,4-dihydro-4-oxo-1-pyridyl)-cephem derivatives and processes for their preparation - Google Patents

Abstract

Procedure for obtaining cefem derivatives of general formula I ** (Formula) ** where Z means an unsubstituted 1,4-dihydro-4-oxo-1-pyridyl moiety or substituted once or several times by alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, OH, F, Cl, Br, I, NO2, NH2 and / or acylamino with 1 to 4 carbon atoms, R means 1,3,4-thiadiazolyl-2-thio and , when Z is a 1,4-dihydro-4-oxo-1-pyridyl moiety substituted by acylamino with 1 to 4 carbon atoms, also H, -OCOCH3 or -S-Het and Het means 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-oxidopyridinium-2, as well as its easily dissociable esters and physiologically compatible salts.

Description

This invention is concerned with certain novel cephem derivatives, with processes for their preparation, and with compositions containing them.

We have found that cephem derivatives of formula I: ch2R wherein Z is an unsubstituted l,4-dihydro-4-oxo-l-pyridyl radical or a 1,4-dihydro-4-oxo-l-pyridyl radical which is mono- or polysubstituted by alkyl having 1 to 4 C atoms, alkoxy having 1 to 4 C atoms, OH, F,. Cl, Br, 1, N02, NH2 and/or acylamino having 1 to 4 C atoms, R is l,3,4-thiadiazol-2-yl-thio and additionally if the I , 4-il i hyilt I-μ/r i il'/l radical onnlaiii.·; .icy I mino having I lo 4 C .ιΙοιιι.ί, κ in ll, —OCOCII^ or —S—Uct, where Het is J-methyl-1,2,4-thiadiazol-5-yl, 5-methyl-l,3,4-oxadiazol - 2 - yl, 5 - hydroxymethyl - 1,3,4 - oxadiazol - 2 - yl, 5 - methyl - 1,3,4thiadiazol -2- yl, 5 - hydroxymethyl - 1,3,4 - thiadiazol - 2 yl, tetrazol -5-yl, 1 - methyl -tetrazol - 5 -yl, 1,2,3 triazol - 4 - yl, 4 - methyl - oxazol - 2 - yl or l-oxido-2pyridyl, and their readily hydrolysable esters (as hereinafter defined) and physiologically acceptable salts, have excellent antibacterial activity against both Gram-negative and Gram-positive bacteria. Compared with known semi-synthetic cephalosporins, these compounds exhibit differences with respect to the sensitivity of individual bacteria. In numerous cases, these compounds are considerably more active than known cephalosporins, so that they have decisive therapeutic advantages in combating certain bacterial infections. Thus the minimum inhibitory concentrations of 3 - (1,3,4 - thiadiazol -2-yl - thiomethyl) - 7 - (3,5 dichloro - 1,4 - dihydro - 4 - oxo - pyridyl - acetamido) - 3 cephem - 4 - carboxylic acid and 3 - (1,3,4 - thiadiazol - 2 yl-thiomethyl) - 7 - (3 - amino - 5 - chloro - 1,4 - dihydro 4 - oxo - 1 - pyridyl - acetamido) - 3 - cephem - 4 - carboxylic acid or of their alkali metal salts with respect to a number of pathogens, including Escherichia coli, Salmonella typhimurium, Shigella krusei and Klebsiella pneumoniae, is lower than that of Cephalothin and Cephalexin by a factor of from 2 to 8. In vivo, these compounds and 7-(3- chloro - 5 - formylamino - 1,4 dihydro - 4 - oxo - 1 - pyridyl - acetamido) - cephalosporanic acid have an activity (measured as the DC50) in mice which is 1 to 2.0 times that of Cephalothin against Staphlococcus ureus, Streptococcus pyrogenes, Diplococcus pneumoniae, Salmonella newport, Klebsiella pneumoniae and Escherichia coli. Serum concentrations comparable with those determined similarly for Cephalothin have also been found after parenteral administration of these compounds to dogs; 80 to 100% of the active compound administered was detected in the urine within 24 hours.

The above compounds can, therefore, be used as medicaments, particularly for combating bacterial infections. They can also be used as intermediates for the preparation of other medicaments.

The compounds of formula I and their readily hydrolysable 0 esters and physiologically acceptable salts are novel and constitute one aspect of the present invention.

The Z radical is preferably a l,4-dihydro-4-oxo-l-pyridyl radical which is mono-,di- or tetra-substituted, more preferably di-substituted, but may also be unsubstituted or tri-substituted.

If it is mono-substituted, the substituent in the Z radical is preferably in the 3-position; if it is disubstituted, they ate preferably in the 3- and 5- or in the 2- and 6-position, and if it is tri-substituted, they are preferably in the 2-, 3- and 5-position. Preferred substituents are Cl, Br and NH2 Other substitu3 ents are OH, F, I, N02 and alkyl having 1 to 4 C atoms, preferably methyl, but also ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl; alkoxy having 1 to 4 c atoms, preferably methoxy, but also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy; and acylamino having 1 to 4 j C atoms, preferably alkanoylamino having I to 4 C atoms, particularly formylamino, but also acetylamino, propionylamino or butyrylamino. Acylamino may also be alkylsulphonylamino having 1 to 4 C atoms, preferably methylsulphonylamino or ethylsulphonylamino, but also prqpylsulphonylamino, isopropylsulphonylamino, butylsulphony) lamino, sec.-butylsulphonylamino, isobutylsulphonylamino or tert.butylsulphonylamino.

In addition to unsubstituted l,4-dihydro-4-oxo-l-pyridyl, the following are preferred Z radicals: 3,5-dichloro-, 3,5-dibromo-, 3-amino-5-chloro-, 3-amino-5-bromo-, 3-chloro-5-formylamino-, 3-bromo-5-formylaminO“, 3-chloro-5-acetylamino-, 3-bromo-5-acetylamino-, 3-chloro-5-methylsulphonylamino-, 3-bromo-5-methylsulphonylamino-, 3,5-difluoro-, 3,5-diiodo-, 3,5-dinitro-, 3,5-dihydroxy-, 3,5-dimethoxy-, 3,5-diamino-, 3-chloro-, 3-bromo-, 3-nitro-, 3-amino-, 3-hydroxy-, 3-methoxy-, 2,6-dimethyl-, 2,6-dimethy1-3,5dichloro-, 2,6-dimethyl-3,5-dibromo-, 2,6-dimethy1-3,5-diiodo-, 3-chloro-5-nitro~, 3-bromo-5-nitro-, 3-chloro-5-hydroxy- and 3bromo-5-hydroxy-l,4-dihydro-4-oxo-l-pyridyl. The Z radical may also be, for example, one of the following radicals: 3-fluoro-, 3-iodo-, 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-3bromo-, 2,6-dimethyΙ-3-iodo-, 2,6-dimethyΙ-3-hydroxy-, 2,6-dimethyl-3-nitro-, 2,6-dimethyl-3-amino-, 2,6-dimethyl-3-methoxy-, 2,6dimethyl-3,5-difluoro- or 3-chloro-5-butylsulphonylamino-l,4-dihydro-4-oxo-l-pyridyl.

R is preferably the l,3,4-thiadiadiazol-2-yl-thio radical and, if Z is a l,4-dihydro-4-oxo-l-pyridyl radical substituted by acylamino having 1 to 4 C atoms, is also H, OCOCH^ and —S— Het, the l-methyl-tetrazol-5-yl radical, the 3-methyl,-1,2,4-thiadiazol-5-yl radical and the 5-methyl-l,3,4-thiadiazol-2-yl radical being preferred among the heterocyclic radicals Het.

The expression readily hydrolysable ester is used herein to refer to a tert.-butyl, trimethylsilyl, benzyl, benzhydryl, trichloroethyl, bcnzoyImethyl, p-mcthoxybenzyl, metliox/nioi hyl, or pivaloyloxymethyl ester.

Preferred compounds according to the invention are those compounds of formula I in which at least one of the R and Z raai5 cals has one of the preferred meanings indicated above.

Some of the preferred groups of compounds can be represented by the partial formulae Xa to Xj which follow and which correspond in other respects to formula I and in which the radicals not designated in greater detail have the meaning indicated in formula I, but in which in Ia, R is l,3,4-thiadiazOl-2-yl-thio; in lb, Z is a l,4-dihydro-4-oxo-l-pyridyl radical which is substituted by at least one acylamino radical having 1 to 4 C atoms in Ic, Z is a l,4-dihydro-4-oxo-l-pyridyl radical which is substituted by at least one alkanoylamino radical having 1 to 4 C atoms; in Id, Z is a l,4-dihydro-4-oxo-l-pyridyl radical which is substituted by at least one formylamino radical; in Ie, Z is a l,4-dihydro-4-oxo-l-pyridyl radical which is substituted by at least one acetylamino radical; in If, Z is a l,4-dihydro-4-oxo-l-pyridyl radical which is substituted by at least one alkylsulphonylamino radical having 1 to 4 C atoms; in Ig, Z is a l,4-dihydro-4-oxo-l-pyridyl radical which is substituted by at least one methylsulphonylamino radical; in Ih, Z'is 3-chloro-5-formylamino-l,4-dihydro-4-oxo-l-pyridyl, R is l,3,4-thiadiazol-2-yl-thio, H, OCOCH^ or —S—Het, and Het is l-methyltetrazol-5-yl, 3-methy1-1,2,4-thiadiazol-5yl or 5-methyl-l,3,4-thiadiazol-2-yl; in Ii, Z is 3-bromo-5-formylarnino-l,4-dihydro-4-oxo-l-pyridyl, and R is 1,3,4-thiadiazol-2-yl-thio, H, OCOCH-j or —S—-Het, and Het is l-methyltetrazol-5-yl, 3-methyl-l,2,4-thiadiazol~5yl or 5-methy1-1,3,4-thiadiazol-2-yl; and in Ij, Z is 3-chloro-, 3-bromo-, 3-amino-, 3-formylamino-, 3,56 II ........N ^H2R diclilotu-, 3,5-(1.1 bromo-, 3-amino-5-chloro-, 3-amtno-5bromo-, 3-chloro-5-nu;thyl-, 3-bromo-5-niethyl-, 3-chloro5-methoxy-, 3-bromo-5-methoxy-, 3-chloro-5-hydroxy- or 3-bromo-5-hydroxy-l,4-dihydro-5-oxo-l-pyridyl, and R is l,3,4-thiadiazol-2-yl—thio.

The present invention also comprises a process for the preparation of a compound according to the invention, which comproses: (i) reacting a compound of formula II: Π2Ν·,.. i σ· wherein R has the above-stated meaning for formula I, or a readily hydrolysable ester (as herein defined) thereof or a physiologically acceptable salt thereof, with a pyridone-acetic acid of formula III: Z·—ch2cooh III wherein Z has the above-stated meaning for formula I, or a chloride or bromide thereof, or (ii) reacting a compound of formula IV: COOH X—CH2CO—NH x IV ch2R COOH wherein X is Cl, or an alkylsulphonyloxy group with 1 to 6 C atoms or an arylsulphonyloxy group with 6 to 10 C atoms, and R has the above-stated meaning for formula I, or a readily hydrolysable ester (as herein defined) thereof or a physiologically acceptable salt thereof, with a pyridone Of formula Vs Z—Η V wherein Z has the above-stated meaning for formula 1, or a sodium or potassium salt thereof or, (iii) treating a compound which in other respects corresponds to formula I, but which contains at least one etherified or esterified hydroxyl group, benzylated or acylated amino group and/or an oxo group in the corresponding enol form, with a solvolysing or hydrogenolysing agent to liberate the OH, NH2 and/or oxo group(s).

The present invention also comprises a process for the preparation of a compound of formula I in which Z has any of the above-stated meanings except a l,4-dihydro-4-oxo-l-pyridyl radical substituted by acylamino having 1 to 4 C atoms, which comprises reacting a compound of formula VI: Z—CH2CO—HH Xi?· VI :h2ococh3 cooh wherein Z1 is an unsubstituted l,4-dih.ydro-4-oxo-l-pyridyl radical or a l,4-dihydro-4-oxo~l-pyridyl radical which is mono- or poly8 substituted by alkyl having 1 to 4 C atoms, alkoxy having 1 to 4 C atoms, OH, F, Cl, Br, I, 8¾ and/or NH2, with 2-mercapto- 1,3,4-thiadiazole or an alkali metal salt thereof.

If desired, the R substituent in the resulting compound of formula I may be replaced by another R substituent and/or the Z substituent may be converted into another Z substituent and/or a carboxyl group may be esterified to form a corresponding readily hydrolysable ester group.

When a salt or ester is obtained by any of the foregoing processes, the corresponding acid may be liberated therefrom or a resulting acid or basic compound of formula I may be converted by treatment with a base or an acid into a physiologically acceptable salt thereof.

The conversion of a Z substituent into another Z substituent is carried out, for example, by alkylating a hydroxyl group by treatment with an alkylating agent and/or reducing a nitro group to an amino group by treatment with a reducing agent and/or by converting a NH2 group into an acylamino group having 1 to 4 C atoms by reaction with an acylating agent, the conversion of an R substituent into another R substituent is carried out, for example, by reducing an acetoxymethyl group to a methyl group by trecitment with a reducing agent or by converting an acetoxy group into the —S—Het radical by treatment with a thiol of formula Het—SH or a corresponding mercaptide.

All these reactions may be carried out in accordance with methods which are known in cephalosporin chemistry and are described in detail in the literature.

The starting materials for the processes according to the invention are either known or can be prepared analogously to known compounds by known methods. For example, the acids II (R=—S— 43709 Het or l,3,4-thiadiazol-2-yl-thio) can be obtained from 7-aminocephalosporanic acid (7—ACA; II; R=—OCOCH^) by reaction with a heterocyclic thiol of the formula Het-SH, which are for the most part known, or with 2-mercapto-l,3,4-thiadiazole or the corresponding metal mercaptides, for example by reacting the corresponding alkali metal salts in hot aqueous acetone. The pyridone-acetic acids III can be obtained from a pyridone V and chloroacetic acid or bromo-acetic acid. The acids IV can be obtained by known methods, for example from an acid II using a substituted acetic acid of the formula X—CH2COOH or a reactive derivative thereof, for example chloroacetyl chloride or bromoacetyl bromide. The X radical is preferably bromine, but it can also be- Cl or a reactive esterified OH group, preferably alkylsulphonyloxy having 1 to 6 C atoms or arylsulphonyloxy having 6 to 10 C atoms, such as p-toluenesulphonyloxy. The substituted pyridones V are generally prepared by substitution of 4-pyridone.

Among the readily hydrolysable esters of the acids II and IV which may be used, the trimethylsilyl esters may be formed, for example, in situ from II or IV and N-trirnethylsilyl-acetamide.

When an ammonium salt is used, it is preferably derived from an amine, particularly from a tertiary amine, for example triethylamine, triethanolamine, pyridine or collidine. The specified salts can be employed as such in the reaction; they can also be generated in situ from the acid II or IV and a base, for example NaHCO-j Na2HP0^ or triethylamine.

The Na and K salts of the pyridones V can be obtained by sa· lifying V, for example using metallic Na or K in a high-boiling, inert solvent, such as toluene, or even in the cold using NaH.

In general, the reaction of the cephem derivatives II or IV (or their specified derivatives or salts with the pyridone deri- 10 42709 vatives III or V or their specified derivatives or salts) is carried out in the presence of an inert solvent. Suitable solvents are, for example, chlorinated hydrocarbons, for example methylene chloride or chloroform; ethers, such as diethyl ether, tet5 rahydrofuran and dioxan,-ketones,such as acetone and butanone;amides,, such as dimethylformamide (DMF), dimethylacetamide and hexamethylphosphoric acid triamide; sulphoxides, such as dimethylsulphoxide (DMSO); water; and also organic or aqueous inorganic bases. Mixtures of two or more of the solvents mentioned can also be used. If a salt of a compound of formula I is to be prepared, an excess, of the base, for example triethylamine or aqueous sodium hydroxide solution, employed for the formation of this salt is particularly suitable for use as the solvent.

The reaction of II with III or IV with V (or their speci15 fied derivatives or salts) is generally carried out at a temperal.ute of from —'/<» to + 0., preferably from —4() to ι 1OU 0., more preferably from 0u to room temperature. The reaction time depends on the nature of the starting materials used and on the reaction temperature ; it is normally from 5 minutes to 72 hours.

It is especially preferred to react an ester, preferably a tert.-butyl ester of the acid II, with the free pyridoneacetic acid III, and it is advantageous to carry out this reaction in the presence of a water-binding agent. Suitable water-binding agents include, for example, carbodiimides, particularly dicyclohe25 xylcarbodiimide (DCC). Thus, for example, 7—ACA tert.-butyl ester, the acid III and DCC are reacted in approximately equimolar proportions and with cooling in an inert solvent, preferably methylene chloride, DMF, DMSO or mixture of solvents.

The reaction of II with a chloride or bromide of the acid III, and the reaction of IV 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^, KHCO3, Na2CO3,' K2CO3, NaOH, KOH, pyridine or a base of low nucleophilic character, for example a tertiary amine, such as triethylamine, N-methylmorpholifte, ethyldiisopropylamine or potassium tert.-butylate.

A cephem derivative VI can also be converted into the corresponding thioether (R=l,3,4-thiadiazol-2-yl-thio) by reaction with 2-mercapto-1,3,4-thiadiazole. The reaction conditions corr> espond to those indicated below for the reaction of a cephalosporanic acid of formula I (R= —OC0CH3) with a thiol Het-SH.

The cephem derivatives of formula I can also be obtained by liberating OH, NH2 and/or oxo groups, by methods which are in themselves known, from the derivatives thereof specified above in ι a compound which in other respects corresponds to formula I. The starting materials for this process variant can, for example, be obtained analogously to the methods described above, but sensitive groups are protected by means of removable protective groups during the synthesis.

Starting compounds for this procedure contain etherified or esterified hydroxyl groups, for example, benzyloxy, trimethylsilyloxy or acetoxy; and/or benzylated or acylated amino groups, for example benzylamino, benzyloxycarbamoyl, tert.-butoxy-carbamoyl and acetylamino, and the protective groups which should be mentioned are, preferably, those which are conventionally used in peptide chemistry. The oxo group of the pyridone ring can be functionally modified in the form of a derivative of the corresponding enol form, for example in the form of quaternary salts of the general formula VII COOH wherein Q is a radical which can be removed solvolytically, hydrogenolytically or catalytically, and is preferably a readily Θ hydrolysable ether or ester group and A is any suitable anion, preferably chloride or bromide, and the pyridine ring can be substituted analogously to the Z radical, and of their readily hydrolysable esters, preferably the corresponding benzyl esters and tert.-butyl esters. A corresponding zwitterion, which can be formed by elimination of HA from VII, can also be used instead of VII.

The protected groups can be liberated solvolytically, preferably hydrolytically, or hydrogenolytically, by known methods which are described in the literature. Solvolysis, preferably hydrolysis, is carried out, for example, using trifluoroacetic acid or using aqueous mineral acids, for example hydrochloric acid, at a temperature of from —10° to 50° C. Hydrogenolysis of functionally modified groups, in particular elimination of benzyl and carbobenzoxy radicals, may be carried out by hydrogenation in the presence of a noble metal catalyst, such as 5 to 50'4 palladium-oncharcoal, or palladium oxide. It is preferred to carry out hydrog20 enolysis at a temperature of from —10 to + 50° C., more preferably at room temperature, at a pressure of from 1 to 100 atmosp13 heres, more preferably at normal pressure. It is possible, and is frequently desired, to direct the hydrogenolysis in such a way that other reductive changes take place in the molecule at the same time; for example an acetoxymethyl group located in the 3-position can be reduced to a methyl group.

If desired, an R substituent in the resulting product of formula I can be replaced by another R substituent and/or a Z substituent can be converted into another z substituent by known methods which are described in the literature.

For example, it is possible to alkylate a hydroxyl group by treatment with an alkylating agent, for example with diazomethane, methyl bromide, methyl iodide, dimethyl sulphate or diethyl sulphate, ethyl chloride, bromide or iodide, n-propyl chloride bromide or iodide or n-butyl chloride, bromide or iodide.

It is also possible, for example, to reduce a nitro group on the pyridone ring to an amino group. In principle, all the suitable known methods for the reduction of nitro groups can be used for this purpose, provided that they do not produce undesired changes in the molecule. Catalytic hydrogenation, which can be carried out, for example, in the presence of a noble metal catalyst, such as palladium, at room temperature and at normal pr essure, is preferred.' The reductive conversion of an acetoxymethyl group into a methyl group can also be carried out by hydrogenation in the presence of a noble metal catalyst, such as palladium, the reaction preferably being carried 'out at low temperatures, but at somewhat elevated pressures (from 2 to 10 atmospheres).

If desired, several of the reductive conversions described can be carried out in one stage. Thus it is possible, by hydrogenating a cephalosporanic acid I (R=OCOCHg) which is substituted 43709 in the Z radical by a nitro group, to prepare the corresponding desacetoxy-cephalosporanic acid I (R=H) which is substituted in the Z radical by an amino group.

An amino group on the pyridone ring can also be acylated by treatment with an acylating agent. Suitable acylating agents are alkanoic acids having 1 to 4 C atoms or alkylsulphonic acids having 1 to 4 C atoms or the reactive derivatives of these acids, for example their halides, preferably their chlorides or bromides, or their anhydrides. Preferred acylating agents are formic acid, acetic acid, acetic anhydride, acetyl chloride, acetyl bromide, methanesulphonyl bromide and methanesulphonyl chloride.

It is particularly advantageous to convert a cephalosporanic acid of formula I (R= —OCOCH^) into the corresponding thioether I (R= —S—Het) by reaction with a mercaptan of formula Het—SH. It is preferred to react a salt of cephalosporanic acid with a salt of the thiol in aqueous acetone at a temperature of from 20 to 100° C. and at a pH of from 4 to 8. The preferred salts are the alkali metal salts, particularly the sodium salts.

A free carboxylic acid I can be converted by esterification into a readily hydrolysable carboxylic acid ester. Por example, the tert.-butyl esters can be obtained by reacting the acids with isobutylene.

Conversely, the acid I can be liberated from a resulting salt or ester, for example by solvolysis, preferably acid hydrolysis. The tert.-butyl esters, which are particularly advantageously obtained in the synthesis, can, for example, be hydrolysed by means of trifluoroacetic acid at a temperature of from 0 to 40° C.

The new cephem derivatives are solid, crystalline or amorphous compounds. They form solid, and frequently crystalline, alkali metal salts, ammonium salts and alkaline earth metal salts -is well as salts with organic bases such as diethylamine, triethylamine, diethanolamine, N-ethyldiethanolamine, pyrrolidone, piperidine, N-ethylpiperidine, 1-(2-hydroxyethyl)piperidine, morpholine, procaine, benzylamine, dibenzylamine, l-phenyl-2-propylamine and other amines such as are conventionally used' for the preparation of cephalosporin salts, Among the alkali metal salts the sodium and potassium salts are of particular importance. They can be prepared by treating a solution of an acid I in an organic solvent with a solution of the sodium salt or potassium salt of a fatty acid, for example diethylacetic acid or 2-ethylcaproic acid, in a solvent, for example acetone or h-butenol, or a mixture of solvents. The alkali metal salt which is thereupon precipitated or upon adding diethyl ether, is then filtered off. The alkali metal salts can also be prepared by lyophilisation or spray drying of their neutralised aqueous solutions.

Basic compounds of formula I can be converted in conventional manner into the corresponding acid addition salts, for example into the hydrochlorides or citrates, by treatment with the appropriate acid. : , Since the compounds I do not have sharp melting points, they are preferably characterised by other physical data, particularly advantageously by means of their infra-red spectra. In’the infrared spectrum, they display the absorption band of the 3-lactam ring located at 1,760—1,800 cm”1* They can also be characterised by their nuclear magnetic resonance spectra and by the Lr thin layer chromatogram. Silica gel F254 PrePared thin layer chromatographic plates (manufactured by E. Merck, Darmstadt) are preferably used for this purpose (with, for example, 85:15 dioxan/water as the developing agent). 42700 The compounds according to the invention are used in human or veterinary medicine in admixture with solid, liquid and/or semi-liquid inert, physiogically acceptable carriers or excipients. Suitable carriers are organic or inorganic substances which are suitable for enteral, for example oral, administration, or, preferably for parenteral administration or topical application and which do not react with the new compounds, such as water, vegetable oils, benzyl alcohol, polyethylene glycols, gelatine,lactose, starch, magnesium stearate, talc, petroleum jelly and cholestrol. Compositions in the form of tablets, capsules, dragees, syrups, elixirs or suppositories are, for example, suitable for enteral use. Solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants are used for parenteral administration, and ointments, creams or powders are used for topical application. These compositions may be sterilised and/or may additionally contain adjuvants, emulsifiers, salts for controlling the osmotic pressure, buffer substances or dyestuffs. They can also contain other active compounds. The new compounds can also be lyophilised in known manner and the resulting lyophilisates can be used, for example, for the production of compositions for injection.

The compounds according to the invention can, in general, be used in the same manner as the known compound Cephalothin. Parenteral administration (for example, intravenous or intramuscular) is preferred. Suitable daily dosages are from 2 to 100,’ preferably from 8 to 40, mg/kg of body weight. When compositions according to the invention are formulated in dosage unit form, they preferably contain from 1 to 5000, more preferably 200 to 2000, mg of the active compound(s) per dosage unit.

Each of the compounds of formula I mentioned in the Examples which follow is particularly suitable for the production of pharmaceutical compositions. . 42709 In order that the invention may be more fully understood, the following Examples are given by way of illustration only.

In these Examples, all temperatures are in degrees centigrade. The IR spectra were determined in KBr. DMP=dimethylformamide, 7—ACA=7-amino cephalosporanic acid and DCC=dicyclohexylcarbodiimide.

Example 1. a) A solution of 12.5 g of 7—ACA tert.-butyl ester and 8.9 g of DCC in 100 ml of 1:1 methylene chloride/DMF is cooled to 0°. 9.1 g of 3,5-dichloro-4-pyridone-l-acetic acid are added, the ice bath is taken away after 5 minutes and stirring is continued for a further 30 minutes at 25°. The urea formed is filtered off and the filtrate is filtered through silica gel (developing agent: ethyl acetate/1% methanol). The solvent is evaporated and the resulting 7-(3,5-diohloro-l,4-dihydro-4-oxo-l-pyridyl-acetamido)cephalosporanic acid tert.-butyl ester is crystallised from diethyl ether. b) 22 g of the tert.-butyl ester are dissolved in 30 ml of trifluoroacetic acid. The mixture is evaporated after 30 minutes and the resulting 7-(3,5-dichloro-l,4-dihydro-4-oxo-l-pyridyl-acetamido)ce phalospqranic acid is crystallised from diethyl ether.

IR: 1,780, 1,680, 1,630, 1,590, 1,220 cm-1· c) 5.7’ g of 7-(3.5-dichloro-l,4-dihydro-4-oxo-l-pyridyl-acetamido) cephalosporanic acid obtained are dissolved in 60 ml of 0.01 N aqueous sodium bicarbonate solution at a pH value below 7 and 1.2 g of 2-mercapto-l,3,4-thiadiazole in 20 ml of acetone are added. The reaction solution is stirred under nitrogen for 2 hours at 80° and a pH of 6.3. The acetone is then removed, the solution is washed with diethyl ether, acidified to pH 2 and the resulting 3- 18 (1,3,4-thiadiazol-2-yl-thiomethyl)-7-(3,5-dichloro-l,4-dihydro4-oxo-l-pyridyl-acetamido)-3-cephem-4-carboxylic acid is filtered off and dried, IR: 1,765, 1,680, 1,615, 1,365, 1,230 cm-15 The compounds of the formula I indicated in Examples 2 to which follow can be obtained, analogously to Example 1 o, from the corresponding cephalosporanic acids by reaction with 2-mercapto thiadiazole: 427( 9 examplej Compound of the formula i S Φ P CM Φ O I co I Ή *ϋ •rt ε rt P Φ ϋ rt I rd >1 *0 Ή >t Oj I rd I X I Ν’ I Cl Ό >1 Χί •rt Ό I Ν' 0 If0 0 Ν' 1 •rt 1 Ν' ε •rt ε 1 β £ φ ε P rt 1 Ρ φ φ P Ν' Oj Ρ o Φ 1 Φ Oj rt □ ε □ Φ 1 rt φ 1 ϋ I—1 1 Ρ π 1 >1 rrt Oj 1 (*} , >1 Φ 1 •rt Ό ϋ 3 Xte •rt 1 Ό 0 >1 Cl CO rt Ό Oj >1 1 ε •rt t Oj rt ε rrt I 0 Ρ rt 1 rd Ό φ Ρ 0 1 •rt ϋ φ X 0 £ rt υ 0 X rt rt 1 0 Ρ ι—Ι ι Ν' 1 Φ >1 rrt 1 Ν' α Τ5 >1 0 1 rt •rt τί Jrt 0 ι Ρ •rt ffi M rrt Cl >t •fi Oj >1 P ! 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J, rH tn 1 m 1 1 rH 4-) 2 ( in I in in W 0 1 fc 0 | 0 *0 1 1 fc R MH 0 in S4 0 M •H 0 Ό 0 O ε Γ' 0 g 0 0 g ‘H fi CO 1 fl) 0 ro rH 0 1—1 nj0 9 0 co XJ H *» Λ Sh xi u ra y - fc tn 44 Λ rH 0 Λ υ u ? 0 X) rH m co ro ro ro rH η Ή to fc 0 03 in 03 '-'rtf *—» >1 *·* rH fc-r ίζ O o 1 •r| CQ wH 1 ’rl t X 1 !>i 1 -r 00 •H 'd r- 0 sp r> 0. r- o b· 0 t- X S t sP χί n 1 nJ fc 1 rtj 1 nJ I Λ 1 0 1 n 44 3 rH <—x r—* Sh rfc Λ x—» H 0 o rH 0 rH 0 rH nJ rH SH rH I ! ft >1 fc >1 iH >1·Η >, ϋ >1 ra *r fc s XJ in xi H XJ rH 43 I x: 0 xi r- O m ,, 0 44 >1 in y >1 y >i 44 sp 44 1 44 > 1 m r-ί O in as X 4) X fl) 1 fl) sp Si Ϊ in 1 0 g 0 fc g 0 g 0 g g e · fi C •rH 0 43 rH 0 1) 0Λ 0 3 0 β0 ί H fl) Χί •H SH ♦rl SH •H Sh •rl X! •Η Q) •rl S· rH 44 XJ (rt fc •G nJ h ra X! ft -13 -s Xi fl fc o 44 ϋ O 44. ϋ 44 o 44 0) y ft 44 u 0 N I I sp 1 1 1 1 | ϋ 1 a) | | Sp flj IO rH sp rH sp rH 1 rH ϋ rH sp ID •H rH ix 1 fc >1 1 >1 1, tx co ix 1 >1 I fc Φ ix 1 g rH g 1 1 1 co 1 g rH nJ in Φ in Q) in 3 in fc tn t CM fl •rl 1 . 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ID I I nJ 1 nJ 1 nJ 1 nJ 3 β 3 nJ 1 fc ro rH ro •rl CO •rl 44 *rl 44 •rH r rH sp rH 03 | 03 1 03 a) d 03 1 Q nJ fc nJ nJ rfc nJ 0 ra o nj ***. * CH •H 0 0 •r| 0 •rl 0 •rl nJ •rl nJ •rl C 0 XJ 03 σι h 03 Xi t) xi 1 X! 1 Xi t 00 44 ‘rl r- 44 •rl 44 *rl 44 rH 44 rH 44 T 44 1 g fc 1 g I g 2?1 £· t g fc 1 QJ Ξ rH sP co sp ns sp 03 M> 13 sp n rH 44 K 44 fc +) *•44 fc •rl fc «rl fc 4J rH rH CM (1) · CM fl) CM 0) CM M CM M m a «· «, ϋ fc ϋ > ϋ fc >1 ·«· ix c X! & rH nJ H rH nJ rH nJ rH ft rH ft rH nJ H 44 Q) 44 QJ 1 H rH H 1 rl J rH g g ix >i >1 ix X! xi X! χί XJ x; 1 1 44 44 44 y 44 44 fl) fl) fl) fl) fl) φ CO rH s g f s g s ro co ro ro co in *—» γ «-χ <^* 1 ro co ro ro co to Q) ft in ID b· co 0 ε sp sp sp sp sp in nJ κ ω .4.227.09 a G rn tf ω (5-Methyl-l,3,4-thiadiazol-2-yl-thiomethyl)-7-(3-chloro-5-acetylamino-l,4-dihydro-4-oxo-l-pyridylό Ή P >1 a ι o tf I tf I o o *0 -P 0) υ ιΰ ο •ϋ •Η β d Ο) □ (0 I Ο Ό •Η β «ΰ -μ 0) □ ίΰ 1 Ό Ρ 1 ιΗ 1 rH >1 'ϋ •Η ΪΗ ιΗ 1 tp >1 TJ >1 0 •Η nJ •Η Ό tf •Η •Η Ρ •Η ο ι Ό Ρ ί>1 Ρ t ’tf 1 ίρ a >1 tf k. tf 0« I a 1 Η *. 1 rH ι 0 1 ι—ί <Η 1 «Η ρ χ: •Η Ό I Ο £ Ή I Ο tf ο I tf Ο tf ο I tf I ι ο tf ο ι tf 1 (Η 1 | rH 0 I tf tp «Η 0 } Ρ 0 £ >1 Ρ te *£ Ρ «Η 0 £ Ό ϋ >1 | 43 0 >1 χ: >1 0 a Χί ,£ ο •Η χί £ rH a •Η <3\ d •Η •Η £ ^4 τι γΗ 1 nJ β W £ I Η χί* 1 £ •Η ιη xr rH •k χρ ιΗ «Η * rp κ >1 44 >1 «Η *. 1 «Η -Ρ -Ρ Χί 1 Ο 0 I φ φ -Ρ 0 kO « 0 υ nJ ι ιη ι ο β Ο μ ro I Η υ r nJ β I ιη 0 Ό 1 'ΰ rH κ Μ •Η 0 •Η ο Ο Ο β Ο β 00 ι—1 nj 0 ίΰ Μ ΓΟ 44 Ρ 0 κ 0 α 43 □ Ψί rH 1 •Η 1 •Η 1 ΓΟ . ιΗ ΓΟ ι—1 ιη κ. *-* S *-* Ν I ο 1 tf | tf 0 00 r* 0 Ρ' 0 β xt* ι fi 1 43 0 * ρ d >ι ο Μ I ΓΟ Ή β ίΰ Γ—ί >1 +J Φ ϋ ίΰ ι ιη ι Ο ρ ο χ: ο ι r—I ΪΗ •Ρ Φ □ ίΰ ι m ι ο g Μ I >1 >1 •Ρ tp -Ρ tf 44 tf ιη tf φ tf φ 1 φ 1 1 ιη 1 1 0 β 0 β β β β Γ* κ >· 43 0 43 0 φ 0 Φ 1 rtf (Η 1 Ό 1 T3 Ρ -Η Ρ Ή χ: •Η 43 •Η X—» •H X-χ •H <ΰ fi ιϋ 44 a Χί a ιΗ 0 *. rp ϋ rp ϋ ϋ -Ρ Q +> φ 44 φ >1 φ Ο >1 Φ >1 £ ι 1 1 1 υ I α 44 tf 44 fi χτ ιΗ tf rH I rH 1 44 0 ko 44 ο 44 ϋ ι >1 1 >1 ΓΟ tp ΓΟ Φ •Η k. 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Ή ·» •Η Ρ φ P φ P Φ Φ ΓΟ Φ ΓΟ Ρ Γ0 Ρ 44 υ .· 44 ο 44 o ϋ ·. 0 k. >1 Η >1 φ ι Pi Φ ι Φ 1 d rH ίΰ Η | a rH a 44 Γ0 H 44 I Γ0 44 | ro I rH 1 γΗ 1 «Η ιΗ 1 pp pp tp >1 >. tp tp >1 χ; Χί 44 Χί .£ 44 -Ρ 44 44 44 44 44 φ Φ Φ Φ Φ Φ £ £ I £ £ | s | £ ιη 1 ιη ιη ιΗ iH pp — I ΓΟ ι ΓΟ I ΓΟ ΓΟ 1 ro 1 ro (l-Methyl-tetrazol-5-yl-thiomethyl)-7-(a-chlora-S-methylsulphonylamino-l,4-dihydro-4-oxo-l-pyridylacetamido) -3-cephera-4-carboxylic acid ιη ιη I ΓΟ - 27 48709 φ rd & -(l-Methyl-tetrazol-5-yl-thiomethyl)-7-(3-bromo-5-methylsulphonylainino-l,4-dihydro-4-oxo-l-pyridylχί Ή ϋ ro ο •Η rd X ο ί ro ο ι ι £ Φ β ft Φ ϋ Φ I rd β ro fi 1 β 0 rd μ Φ β α) b 1 0 1 rd id fi ·» 1 β μ μ ro •H rd g 0 μ Q i 0 6 Χί fi β ro 0 CO 0 fi μ 0 rd fi ιη 10 id ro >4 μ μ £ £ ο 0 id . rd id H ro ·» μ fi φ Φ 0 H μ o μ £ μ μ >1 μ •id to id to 1 10 μ Φ 0 Φ in H ο ro μ 1 0 00 10 υ μ 1 rd 0 μ Ο φ μ >1 in >1 £ | μ μ μ 1 μ 0 m μ ft μ α 0 fi u 1 £ fi β £ β β 0 κ ro ο 1 0 I 1 £ Ο χ ft • id ro 0 Ο W ro μ β μ CM tn Μ «· Η xi β — fi xi Φ r—k ro φ fi 1 μ μ μ H μ ro co μ μ i »—· *» «, χί υ «J H r- Χί id i ο Φ ro ο ro μ φ Γ- μ *a* μ Ud ϋ μ 0 CM ro N I μ 0 ro (0 ΙΟ ro κ ο β 1 β φ Φ μ μ Γ- g fi 0 > 0 χί κ. id 0 ♦id rd μ μ fi O £ 0 •id fi >1 tn fi ο μ. vo Ο μ μ ro μ ro CO Μ ro Μ fi Μ ΓΟ Η Φ μ Φ 0 0 β υ 0 Η μ β μ ft o ft μ ro & φ μ « Ud to . Q to μ £ μ ο •rl 0 μ 0 β ro β μ ΙΟ fi rd i-t μ μ Ο £ X ro Ο 0 ro Φ 0 ro 00 Μ w fi Φ ft β μ β Μ· ο μ ΙΛ rd ro ft φ ft * μ 0 ro χί ft tn φ (TO 0 φ μ μ μ μ 0 σ fi υ φ β ϋ XJ 1 *4 φ I Μ. β 0 ro X •id 1 tn ζ-» Ο μ »•*4 *-* ο W ϋ Q 1 Φ 0 ιη r> to g ro Γ* id Χί ιη μ ω μ id ft μ •κ Ο id μ β 1 Φ μ to V cn r* φ μ Φ ϋ rd μ id β μ χί U μ ro t* W ro Φ μ μ Φ ιη μ Φ I Φ υ υ ΓΟ U μ rd ro ro fi ro νο ro M ro μ ι ft 1 rd μ ι ί>4 rd μ μ 0 K μ fi ro N Φ xf >1 μ xi β ρ X xi rd μ χί fi φ β χί w •id ft υ *Η Ο ro fi ι μ id ro Μ 00 id μ • Μ 0 >1 ro >4 ιο ο ro μ >1 μ ft X 0 ft ft μ id ft I w μ 1 μ to β φ I >1 rd μ μ 0 0 μ rf rd | 0 Φ ι •k rH tn 0 μ υ 0 Ο <β Φ tn tn fi X ro Η 00 b β fi fi 0 0 >1 | 0 t- Di μ μ cn | rd μ | «» V fi XJ χί 0 v to | μ O ro fi fi rd 1 fi φ 1 ο Ο ο ro 0 0 fi 0 ·· ft ft c i-i Cn 0 id fi! 43 & (0 (A r 0 Χί Χί Η E4 0 φ Φ >4 H μ >4 μ id id β ro μ β μ id id •id fi >4 μ 0 0 0 XJ ro ft Χί μ ϋ υ in o μ ΙΛ β e μ UH Example Compound of the Φ •μ ϋ Φ ϋ •μ φ •μ □ Φ □ •μ β 03 β Φ •H 03 Φ μ φ 0 Φ •μ μ ο •μ nJ -μ ϋ ο ft ϋ υ Φ ft ιη Φ ϋ φ ω Ο •rH ϋ 0 μ Ο β ϋ •μ μ Φ •μ nJ •μ β Φ χ: β μ Φ β Φ Χί ft Φ 0 •rl Φ μ Φ a φ μ ft Ο μ ο •μ φ ο 0 ω Φ 0 ft □ ϋ ι ft 0 ft ω Φ ι ω rH ϋ tfl 0 —— 0 0 Φ •rH 0 ι—Η ϋ 0 φ μ Χί β rl Φ •μ φ •μ Φ ft Φ Φ Λ β •μ ε ,β Φ μ ,β ft Φ ε φ Ω-Ι 0 0 Οι Φ μ Φ μ Φ 1 ft Φ Ω Ω μ Φ 0 w υ 1 ft Φ υ 1 o 0 1 -fc ω ω Πί -fc OJ ι~Η -fc. 0 ο Φ 1 Ω •rH Φ ο φ γΉ I μ Φ ε -β φ •μ Φ r*H >1 •μ Φ Ω, -μ § Χί ίχ Φ ε μ Φ ε Φ Ω» Φ •μ φ Φ 0 φ μ Φ •μ μ μ ϋ 1 μ fl) ϋ μ >1 Φ Φ Φ ϋ I ίχ Ωι ϋ 1 ο ϋ Φ ζ™*, Ωη 1 Φ rH 03 φ I 0 I μ I ίχ •rH ι «μ φ rH | μ OJ g «-Η Ιχ •μ t 0 ίχ •rH φ ίχ Φ £ 0 X Φ μ -μ 03 •μ Φ X 0 •μ ix Φ -Η μ μ 0 | μ ft υ μ ίχ Φ 1 sp ίχ 1 Φ ίχ ft ϋ sp | ft μ ι ft ι Φ 1 Ο | 1 rH 1 μ I 0 μ μ 0 ίχ r-H 1 μ μ φ I X Φ 1 Ο ίχ φ ίχ 0 0 •Η 0 X Φ ίχ χ; X 1 μ X 0 •μ Χί •μ 0 sp ίχ 1 μ •μ Φ 1 1 ft ρ sp ίχ Φ 1 Sp 0 I sp 1 ft ι sp 1 μ r-l t 0 ι sp fc 0 Φ 1 ο μ rH »< μ μ ίχ 0 μ φ | μ I φ •β X φ ίχ 0 1 0 ίχ •μ 0 ίχ ,α X 0 β λ OJ I r* •μ ο β •μ •Η 1 SP •μ Φ 1 •μ £ Φ Sp 1 03 1 Sp ε Φ 1 fc 0 1 sp 1 φ μ sp rH μ Τ «. o rl fc 1 ϋ fc rH μ ίχ β r-l 0 ix .μ 1 φ β 0 1 β c. ι 0 Ω .β 0 •Η Η 0 μ Χί .γ: 04 β Π Φ ( 0 •μ Ωι μ •μ 1 ό rl Φ μ β £ rH SP μ ,β 1 β ϋ) Φ ίχ fc μ 0 sP Μ μ μ ε rH ι 1 κ. μ ίχ ίχ μ I ιη in Η ίχ .β β 0 0 ι 1 ί X μ 0 Uh β 0 0 0 μ Φ Φ | •Η β c β Φ ε ft ιη g •μ •μ •μ β 1 μ 1 φ § £ £ I m β Ο ι-Η Φ Φ φ ιη I ϋϊ μ ίχ «-Η μ rH 1 0 μ 0 ε ίχ X ίχ Ο μ ίχ r-i μ μ μ μ ε 0 Γ* Χί 0 Φ Φ Φ 0 μ μ ο ft ϋ ϋ ϋ μ Χί Φ I ι < rij cq U ί^ ΓΩ ΡΩ ι 1 1 1 ι 1 «—· ·—- ΓΩ ΡΩ ΡΩ ΡΩ ΡΩ ΡΩ | I »—' fc— ·«-- fc— •fc- fc-· b b 1 1 1 1 1 1 b b b b b b rHf\lfOspLniDb»0O KOKOkOKOkOkOKO'-O ε ϋ ΙΛ 0 0 1 Φ Φ •μ £ μ sp β Φ 0 Uh 1 Φ μ φ μ 0 μ μ Λ Φ β ίχ φ φ 1 r-| •μ χί Χί β ΡΩ Xi £ μ &Η μ —· φ Φ Φ Φ 1 β μ £ • b •μ ίχ ο Φ Φ ε Φ m Χί φ μ μ μ CM μ Φ Λ 0 β > 0 Uh μ μ * •μ 1 0 Φ μ tn ιη Φ 0 μ 1 X) ω β φ σ φ μ Φ •μ μ £ β Χί χί (Α 0 ΜΗ 0 μ ΕΗ Φ μ 0 χί Φ Λ £ • μ ι μ CM μ ΡΩ ε Φ φ υ μ 43 Χί β ΜΗ (Μ ο Φ μ Λ 0 Χί μ φ Ιί μ φ « tn •Η μ Ω μ μ ε β Φ ίχ Κι 03 ut .β φ Sp Φ μ 4J μ ΡΩ > Φ ίχ Φ μ χί μ Φ ·. 0 μ μ Φ •μ Φ 0 Φ ϋ ο tfl μ £ φ ιη •μ tn 0 CM Φ Φ β μ ϋ Φ •μ Μη •μ μ φ μ ω β Φ μ μ β 03 Φ φ •μ Φ μ SP μ μ Φ 0 Ο υ W Φ -μ ft U) ο tn «μ W CM α Φ μ 0 « μ φ Φ • μ Ή Φ ϋ μ σ. Φ β ο •μ υι κο Χί φ φ μ ίχ ft X tn β «μ μ φ φ 0 ε φ W 0 Η ϋ •μ ft ϊι Φ co Φ μ ω £ X ΡΩ □ Φ •μ Φ 0 β ♦μ X μ •μ 03 6 μ ω Φ β β ϋ υ Φ Φ •μ φ β φ β φ Φ W Φ Φ tn •μ 0 Φ μ •Η β UH μ Φ ίχ 0 •Η •μ ft 0 μ Φ μ μ β β Ω β φ •μ ,Ω Ω 0 ft •β £ 0 •μ Ω 4J cd Φ μ ιη ι •μ Φ Φ •μ '0 b α μ β Φ Φ •rl φ Φ UH β 1 ,β μ 0 Φ r-H £ β Φ 1 μ Φ tT» Φ φ Φ X μ ε μ β Φ •μ Φ □ 0 •μ ε μ 00 Φ Φ μ 0 CM •μ ο β a Φ μ μ 0 φ --, χί ίχ χί •Η > Φ μ ft ο μ φ ιη - 29 4870θ rd B Md m rt rd rt X Gi QJ ϋ .ert.-butyl ester obtained in accordance with 69a is saponified analogously to lb. This gives 7-(3-bromo-5-formylamino-l,4-dihydro-4-oxo-l-pyridyl-acetamido)x qj x Ed tt M kJ •id G rt o •μ β rt μ ο Gi ω Ο rd Gi QJ G >1 tt O X QJ O rt rt Q) kJ I o οE o o o OJ χ w β ♦μ KJ QJ X rt O id KJ β •μ β O id X rt G •μ Md id β Gi rt rt KJ id rt x <—ι >1 X 3 X X μ QJ X o rt rd X σι οι >1 tt o X QJ rt rt QJ KJ E O μ H H H rt rd Md QJ X X 3 QJ Md O rd E rd μ Ot QJ rt ta 0 g rd KJ o Md rt X •μ co X rt G cn 0) H β rt X id rd X 0 rt G +> X •μ ta Md X X o 0 0 QJ co rd ta-» G it· rt rt rt % KJ 3 rt 1 rd •μ 0 μ rd 0 tn OJ 1 ta rt 0 X QJ o rd ω β 0 rt QJ 0 o ip β rt rd •μ rt >1 μ μ ta X >1 0 KJ 3 Gi G< QJ X 1 ω β | iP 0 •μ • rd rt X tn rt X μ β X X QJ •μ Gi 0 X KJ OJ β G Q) tn 0 ft X β Gi tt id rt 0 β KJ QJ X rt β μ QJ o 0 μ G Gi 0 rt Ϊ rt ϋ fti H 0) rd μ QJ KJ rd μ X 0 0 X QJ Md ο X KJ Ed X QJ β 0 X rt •μ X X μ S Ε 0) 0 χ o- μ rt o- Md 0) o rd kJ id G rt G id β KJ rt KJ kJ •μ μ id ♦id G 0 G G rt Ut rt rt rt O 0 o 0 id rd •μ •μ β rt β β rt 43 rt KJ rt Jh KJ Ot μ •μ μ G •μ QJ ο ο 0 Ut 0 G Gi rt Ul rt rt I rt rt o O ϋ 0 rd ϋ tt rd •μ rd rt •μ 0 rt β rt 43 a X Λ rt 43 Ut rt QJ Gi μ Ut QJ μ G 0) ο QJ G 0 rt G Gi U Ul rt & rt >1 rt 0) tt Ο >1 tt G KJ 0 rd tt G rd 1 X rt G X rt m QJ X X QJ 43 | o (It QJ G Ut rt (1) O rt Φ O to ϋ rt rt O KJ QJ 1 cn QJ 1 ♦μ KJ >1 QJ kJ >, g 1 tt KJ tt 3 m ϋ cn G X 1 X cn X QJ qj QJ G 0 ϋ ,-s. 0 G rt KJ rt 0 KJ rt 1 rt KJ ♦μ co rd g QJ •μ g QJ >1 Pd rt KJ g rt KJ KJ X 3 X •μ rt QJ cn +> Q) cn μ rd G 1 0) G 1 >1 3 rt Xta 0 rt Ot s I 0 rt 0 I μ rd KJ rd. KJ rd 0 >1 •μ r-i id 1 Md kJ g >1 KJ g 0 •μ 3 kJ •μ 3 tt Φ μ X •μ μ X σ Si ί» QJ μ >1 QJ 1 +) Οι CJ >1 Ui G iP 1 rt Ut rt 1 Md r-d 1 rd 0 O | rd rd rd μ Ο >1 o >1 KJ; KJ tt KJ O tt KJ >t a 0 •μ tt 0 •μ X & | μ 0 μ •μ 0 ip >1 ip !>ι KJ & 1 Ut *P. | Ut I e 0 1 I 0 1 iP 0 μ rd 0 μ rd ta υ KJ μ kJ rd Ν 0 kJ >1 G 1 43 tt >1 43 tt 0 •μ 0 43 0 β KJ •rd KJ •μ ι -P kJ ip g ιΡ ip 3 ta O ip ta O rd Η μ μ >1 1 kJ rd kj β Ο 0 >1 0 β X 0 n X X •μ •μ .fi o •μ Ut Ε KJ 0 rd KJ rd rt 1 μ 43 t 3 rd ip X- G -P rt ta rd in tn rd >1 μ 1 1 X ο 0 G G 0 X Md β β C β 0 1 •μ •μ •μ •μ fi tn e g fi g 1 I rt 3 rt 3 in Ο rd rd H 1 μ d >, >1 >1 0 ο g X X X E rd μ Q) QJ QJ 0 43 n CJ O G μ υ Cm rtj CQ m cn cn cn cn cn ο- O' O' O' O' O' oJ rd Gi ο rd OJ cn iP in 3 ο- o- O' O' O' O' tt w § tf w (3-Chloro-5-methylsulphonylamino-l,4-dihydro-4-oxo-l-pyridyl-acetamido)-3-desacetoxy-cephalosporanio '0 •P u £ O £ ϋ •P q £ P a rn rp £ Χί a φ o ι t”! tf p Φ o £ co nJ I ro I Ή nJ β £ P Φ o £ I >1 nJ P >1 a ι «-i I tf o tf P nj rd ι tf r-i I q xP C Γ) .q a >-P tf) ►P r£ P Φ V ro i I kD r· r· p** tn χ-^ q Ό ι—1 Ο 1 •P q Ο Ό o rp nJ £ Ν •Ρ P β Ό £ β P £ nJ •Ρ £ Ή Ο Φ nJ Ρ q kO P 44 £ Φ Φ £ •Ρ ϋ ro q 44 Ρ ,β £ *—· •Ρ 44 Ο Ρ I £ a I r*~ a £ 1 1 £ Φ > f-4 P Φ tf >1 rP q £ κ nJ tP φ ω ω ΓΟ •Ρ Χί 44 ω •Ρ k Ρ 44 £ Φ rP >1 Φ 44 ρ q k-’ a β a 0 Ο Φ •Ρ I ι •Ρ Ρ rP 44 X! £ £ £ ro ι-Ρ 44 β γΡ 1 Ό Ρ 0 cn I rP •Ρ Ο ω φ >1 ϋ β > 0 1 £ φ •P tf (Ν 44 Χί tn 0 1 ϋ £ 44 rP •Ρ cn 1 ο ι-4 nJ «. •P Ν >1 q 44 χί tf £ tf £ 44 EH •Ρ 0 Ο I nJ fi C3 a £ Ρ ΙΛ •α P 0 •Ρ £ CN φ Φ Ρ a Χί ϋ Ρ Χί nJ Ρ 44 1 44 φ 44 >1 φ 1 tf £ 44 Φ χ: Ρ tf 1 rp •Ρ ω «. β (ft -Ρ «Η nJ φ ΓΟ φ Φ 4ρ tP k χί 44 Χί I Η γΡ a £ ω 44 tP kx- φ q •ρ Φ tf Ρ f □ •Ρ •Ρ k £ ΓΟ ι β X» nj rp Λ γΟ ω < 44 1 in ίρ 44 1 Ρ ο χ-^. rP γΡ 0 Ρ 0 £ 0 φ Ρ nJ Ρ 44 ω q Ρ φ *Ρ 0 £ β •P 44 β 44 ϋ £ β nj ω £ Φ £ •Ρ Φ 44 nJ Φ β ϋ Φ φ Χί 1 £ γ4 ϋ 44 Ε4 >1 tp £ £ Λ CO ϋ 44 1 q a ·<_- •Ρ £ γΡ φ γΡ nJ rp fi >1 tP £ φ 1 >1 1 nJ 0 Ο ω tf •Η ρ ϋ Ή r* Ο Ρ Ρ nJ Ρ γΡ Λ Ρ >1 tP £ r-f 1 Ρ Φ a Χί ,β £ £ 44 I Ο Ρ x—» ϋ rP φ I ω r4 Φ I Ρ β tp tp ι Χί 0 £ 0 Ρ Χί Ρ tf I ϋ 44 tf 0 nJ nJ Φ 44 I q a Φ ε t Ο tf £ •Ρ 0 I Ρ β φ 0 Η in φ Χί φ β Ρ Ο £ Ρ χ: nj q 44 nj a Ο tp £ Ο •Ρ r4 φ Ο χί ,q (Λ tp ϋ ΓΜ •Ρ Ρ tn Φ '0 Φ β Ρ 1 I tf β Ο Φ rM ΓΟ Ί ! Ο Λί »4 Γ) ΓΊ 4* 1 1 ΐΠ Example 79. 0.224 ml of trichloroacetyl chloride are added, while cool ing in ice, to 451 mg of 3-chloro-5-formylamino-4-pyridone-lacetic acid in 10 ml of absolute DMF. After stirring for 30 minutes, a solution of 554 mg of 7—ACA and 1 g of N-trimethylsilylacetamide.in 5 ml of DMF is added. The mixture is stirred for a further 30 minutes while cooling in ice and is then poured into Water and adjusted to pH 5. The mixture is washed with diethyl ether, adjusted to pH 2 and extracted with ethyl acetate, the ext ract is dried and evaporated and the residue is crystallised by means of ether to give 7-(3- chloro - 5 - formylamino - 1,4 dihydro - 4 - oxo - 1 - pyridyl - acetamido)-cephalosporanic acid.

Example 80. 0.224 ml of trichloroacetyl chloride are added to 451 mg 5 of 3-chlorO-5-formylamino-4-pyridone-l-acetic acid in 5 ml of absolute DMF. After stirring for 30 minutes, a solution of 554 mg of 7—ACA and 0.84 ml of triethylamine in 20 ml of methylene chloride is added. The mixture is stirred for a further 30 minutes and is then poured into water and adjusted to pH 6. The mixture ’ is washed with methylene chloride and worked up in the customary manner to give 7-(3-chloro-5-formylamino-l,4-dihydro-4-oxo-l-pyridylacetamido)-cephalosporanic acid.

Example 81. 336 mg of 3-bromo-5-methylsulphonylamino-l,4-dihydro-45 oxo-l-pyridylacetazide are added in portions to a solution of 272 mg of 7—ACA and 1 ml of triethylamine in 10 ml of methylene chloride at 0°, while stirring. The mixture is stirred for a further 1 hour and the product is filtered off, giving 7-(3-bromo-532 42703 methylsulphonylamino-1,4-dihydro-4-oxo-l-pyridyl-acetamido) cephalosporanic acid.

Example 82. g of 7—ACA are suspended in 95 ml of absolute methylene chloride, the mixture is cooled to —-1O0, 12.9 ml of triethylamine are dissolved while stirring and the mixture is stirred for a further 45 minutes at —30°. A freshly prepared solution of 3-chloro-5-formylamino-4-pyridone-l-acetyl chloride (obtained by dropwise addition of 2.68 ml of thionyl chloride to a solution of 8,12 g of 3-chloro-5-formylamino-4-pyridone-l-acetic acid in 40 ml of DMF at —40°) is then added dropwise at a temperature of below —20° and the mixture is stirred for a further 45 minutes at —20°, allowed to warm up to 0° and extracted several times with sodium bicarbonate solution. The aqueous phases are separated off, acidified with hydrochloric acid and extracted with tetrahydrofuran/ethyl acetate. The organic phases are dried over sodium sulphate and evaporated to give 7-(3-chloro-5-formylamino-1,4-dihydro-4-oxo-l-pyridyl-acetamido) - cephalosporanic acid.

Example 83. a) Λ solution of 684 mg of 3 - (1,3,4 - thiadiazol -2-yl. - thiomethyl) - 7 - (3 - benzylami.no - 5 - bromo - 1,4 - dihydro - 4 oxo - 1 - pyridyl - acetamido) - 3 - cephem - 4 - carboxylic acid tert.-butyl ester (obtainable from 3 - benzylami.no - 1,4 - dihydro - 4 - oxo - 1 - pyridylacetic acid and 7 - amino - 3 - (1,3,4 thiadiazol-2-yl-thiomethyl)-3-cephem-4-carboxylic acid tert.-butyl ester) in 100 ml of methanol is hydrogenated at 25° and at normal pressure over 300 mg of 5% Pd-on-charcoal until absorption of hyd33 rogen ceases. The mixture is filtered and evaporated to give 3- (1,3,4-thiadiazol -2-yl - thiomethyl - 7 - (3 - amino - 5 bromo - 1,4 - dihydro - 4 - oxo-l-pyridyl-acetamido)-3-cephem4- carboxylic aoid tert.-butyl ester. b) The tert.-butyl ester which can be obtained in accordance with Example 83a is saponified, analogously to Example lb, to give 3-(l,3,4-thiadiazol-2-yl-thiomethyl)-7-(3 - amino - 5 - bromo 1,4 - dihydro - 4 - oxo - 1 - pyridyl - acetamido) - 3 - cephem 4 - carboxylic acid. c) .50 g of 3 - (1,3,4 - thiadiazol -2-yl - thiomethyl) - 7 (3 - amino - 5 - bromo - 1,4 - dihydro - 4 - oxo - 1 - pyridyl acetamido) - 3 - cephem - 4 - carboxylic acid are added to a mixture of 185 ml of formic acid and 52 ml of acetic anhydride while cooling in ice, the mixture is stirred for one hour at 0°, the solvent is distilled off and 3 - (1,3,4 - thiadiazol - 2 - yl thiomethyl) - 7 - (3 - bromo - 5 - formylamino - 1,4 - dihydro 4 - oxo - 1 - pyridylacetamido) - 3 - cephem - 4 - carboxylic acid is obtained as the residue. d) 150 mg of the acid which can be obtained in accordance with Example 83c are dissolved in a little methanol, a methanolic solution of the sodium salt of diethylacetic acid is added and the product is precipitated with diethyl ether. The corresponding sodium salt is obtained.

All the other free acids of formula I specified in the foregoing Examples can be similarly converted into their sodium salts.

The following Example describing the preparation of a pharmaceutical composition containing a compound according to the invention, is given by way of illustration only:— - 34 42709 Example Λ: Ampoules.

Kg of the potassium salt of 7-(3-chloro-5-formylaminol,4-dihydro-4-oxo-l-pyridyl-acetamido)-cephalosporanic acid is dissolved in 3 1. of twice distilled water, and the solution is filtered under sterile conditions, filled into ampoules, lyophilised under sterile conditions and sealed in a sterile manner. Each ampoule contains 1 g of active compound.

In order to provide an injectible solution, ampoules of aqueous solution for dissolving the above lyophilisate are also provided. This solution is prepared by dissolving 50 g of lidocaine hydrochloride in 3 1. of twice distilled water and filling the solution, after filtration under sterile conditions, into ampoules which are sterilised at 120° for 20 minutes. Each solution ampoule contains 50 mg of lidocaine hydrochloride in 3 ntl of water.

Ampoules which contain one or more of the other active compounds of formula I or their physiologically acceptable salts or their readily hydrolysable esters can be obtained analogously to Example A.

Claims (23)

CL A I M S

1. Cephem derivatives of formula I Z — CH 2 CQ—NH .S CH 2 R wherein Z is an unsubstituted l,4-dihydro-4-oxo-l-pyridyl radical or a 1,4-dihydro-4-oxo-1-pyridyl radical which .is mono- or poly-substituted by alkyl having 1 to 4 C atoms, alkoxy having 1 to 4 C atoms, OH, F, Cl, Br, I, N0 2 , NH 2 and/or acylamino having 1 to 4 C atoms, R is l,3,4-thiadiazol-2-yl-thio and, additionally, if the l,4-dihydro-4-oxo-l-pyridyl radical contains acylamino having 1 to 4 C atoms, R is H, —OCOCH^ or —S—Het, where Het is 3 - methyl - 1,2,4 - thiadiazol -5-yl, 5 - methyl 1,3,4 - oxadiazol i- 2 - yl, 5 - hydroxymethyl - 1,3,4 - oxadiazol - 2 - yl, 5 - methyl - 1,3,4 - thiadiazol - 2 - yl, 5 - hydroxymethyl - 1,3,4 - thiadiazol - 2 - yl, tetrazol -5-yl, 1 - methyl - tetrazol - 5 - yl, 1,2,3 - triazol - 4 - yl, 4 - methyl - oxazol - 2 - yl or l-oxido-ϊί-pyridyl, and their readily hydrolysable esters as herein defined and physiologically acceptable salts.

2. 3 - (1,3,4 - Thiadiazol -2-yl - thiomethyl) - .7 (3,5 - dichloro - 1,4 - dihydro - 4 - oxo - 1 - pyridyl - acetamido) - 3 - cephem - 4 - carboxylic acid.

3. 3' - (1,3,4 - Thiadiazol -2-yl - thiomethyl) - 7 (3 - amino - 5 - bromo - 1,4 - dihydro - 4 - oxo - 1 - pyridyl acetamido) - 3 - cephem - 4 - carboxylic acid.

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

5. 7 - (3 - Bromo - 5 - formylamino - 1,4 - dihydro - 4 - oxo - 1 - pyridyl - acetamido) - 3 - desacetoxy - cephalosporanic acid.

6. 7 - (3 - Chloro - 5 - formylamino - 1,4 - dihydro - 4 - oxo - 1 - pyridyl - acetamido) - cephalosporanic acid.

7. 7 - (3 - Bromo - 5 - formylamino - 1,4 - dihydro - 4 - oxo - 1 - pyridyl - acetamido) - cephalosporanic acid.

8. 3 - (3 - Methyl - 1,2,4 - thiadiazol - 5 - yl - thiomethyl) - 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 - thiadiazol - 5 - yl - thiomethyl) - 7 - (3 - bromo - 5 - formylamino - 1,4 - dihydro - 4 oxo - 1 - pyridyl - acetamido) - 3 - cephem - 4 - carboxylic acid.

10. 3 - (5 - Methyl - 1,3,4 - thiadiazol -2-yl - thiomethyl) - 7 - (3 - chloro - 5 - formylamino - 1,4 - dihydro - 4 oxo - 1 - pyridyl - acetamido) - 3 - cephem - 4 - carboxylic acid.

11. 3 - (5 - Methyl - 1,3,4 - thiadiazol -2-yl - thiomethyl) - 7 - (3 - bromo - 5 - formylamino - 1,4 - dihydro - 4 oxo - 1 - pyridyl - acetamido) - 3 - cephem - 4 - carboxylic acid.

12. 3 - (1 - Methyl - tetrazol - 5 - yl - thiomethyl) - 7 -(3- chloro - 5 - formylamino - 1,4 - dihydro - 4 - oxo - 1 pyridyl - acetamido) - 3 - cephem - 4 - carboxylic acid.

13. 3 - (1 - Methyl - tetrazol - 5 - yl - thiomethyl) - 7 - (3 - bromo - 5 - formylamino - 1,4 - dihydro - 4 - oxo - 1 pyridyl - acetamido) - 3 - cephem - 4 - carboxylic acid.

14. A process for the preparation of a cephem derivative of formula I specified in claim 1, or a readily hydrolysable ester (as herein defined) or physiologically acceptable salt thereof which comprises reacting a compound of formula II: II wherein R has the meaning specified in claim 1, or a readily hydrolysable ester (as herein defined) Or a physiologically acceptable salt thereof, with a pyridone acetic acid of formula III: Z-ch 2 cooh III wherein Z has the meaning specified in claim 1, or a chloride 3 or bromide thereof.

15. A process for the preparation of a cephem derivative of formula I specified in claim I, or a readily hydrolysable ester ( as herein defined) or physiologically acceptable salt thereof, which comprises reacting a compound of formula IV: X — CII 2 CO —NH J. IV \ch 2 r COOH wherein X is Cl, Br or an alkylsulphonyloxy group with 1 to 6 C atoms, or an arylsulphonyloxy group vzith 6 to 10 atoms, and R lias the meaning specified in claim 1, or a readily hydrolysable ester (as herein defined) or a physiologically acc5 eptable salt thereof, with a pyridone of formula V: Z-Η V wherein Z has the meaning specified in claim 1, or a sodium or potassium salt thereof.

16. A process for the preparation of a compound of fo10 rmula I specified in claim 1 in which Z has any of the meanings specified in claim 1 except a l,4-dihydro-4-oxo-l-pyridyl radical substituted by acylamino having 1 to 4 C atoms, which comprises reacting a compound of formula VI: Z 1 -CH 2 C0—NH o> COOH 15 wherein is an unsubstituted l,4-dihydro-4-oxo-l-pyridyl radical or a l,4-dihydro-4~oxo-l-pyridyl radical which is monoor poly-substituted by alkyl having 1 to 4 C atoms, alkoxy having 1 to 4 C atoms, OH, F, Cl, Br, I, N0 2 and/or NH 2 , with 2-mercapto-l,3,4-thiadiazole or an alkali metal salt thereof. 20

17. A process for the preparation of a cephem derivative of formula I specified in claim 1, or a readily hydroly39 4270 9 sable ester (as herein defined) or physiologically acceptable salt thereof «which comprises treating a compound which in other respects corresponds to formula I, but which contains at least one etherified or esterified hydroxyl group, benzy1ated or acylated amino group and/or an oxo group in the correspond ing enol form with, a solvolysing or hydrogenolysing agent to liberate the OH, NH 2 and/or oxo group(s).

18. A process according to any one of claims 14 to 17, in which the R substituent in the compound of formula I obtained in which R is acetoxy is replaced by another R substituent by converting an acetoxy group into the —S—Het radical by treatment with a thiol of the formula Het—SH or a corresponding mercaptide.

19. A processaccording to any one.of claims 14 to 18, in which, when a salt or ester of a compound of formula I is obtained, it, is treated to liberate the corresponding acid of formula I therefrom or, when an acid or basic compound of formula I is obtained, it is treated with a base or an acid to form a physiologically acceptable salt thereof.

20. A process for the preparation of a cephem derivative according to claim 1, substantially as herein described in any one of Examples 1 to 83.

21. A pharmaceutical composition comprising at least one compound as claimed in any of claims 1 to 13 and an inert, physiologically acceptable carrier.

22. A pharmaceutical composition according to claim 21 which is in dosage unit form, each dosage unit containing from 200 to 2000 mg of said compound(s).

23. A pharmaceutical composition substantially as herein described in Example A.