GB1581460A - Process for the preparation of a-(2-oxoimidazolidin-1-yl-carbonylamino)-acetamidocephalosporin derivatives and analogues and their use as medicaments - Google Patents

Description

(54) A PROCESS FOR THE PREPARATION OF a-(2-OXO-IMIDAZOLIDIN-1-YL CARBONYLAMINO)-ACETAMIDO-CEPHALOSPORIN DERIVATIVES AND ANALOGUES AND THEIR USE AS MEDICAMENTS (71) We, BAYER AKTIENGESELLSCHAFT, a body corporate organised under the laws of Germany, of Leverkusen, Bayerwerk, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to a process for the preparation of a-(2-oxo-imidazolidin-1yl-carbonylamino)-acetamido-cephalosporin derivatives and analogues and their use as medicaments, especially as antibacterial agents and as agents for promoting the growth and improving the feedstuff utilisation in animals.

It has already been disclosed that certain a-(2-oxo-imidazolidin-1-yl-carbonylamino)- benzylpenicillins and corresponding cephalosporins with a 2-oxo-imidazolidin- 1-yl- carbonylamino side chain have an actibacterial action (see German Offenlegungsschriften (German Published Specifications) 2,104,580, 2,152,967, 2,258,973, 2,402,465 and 2,428,139).

According to the present invention we provide a process for the preparation of a compound of the formula I

in which A represents hydrogen or methoxy, B represents phenyl; phenyl which is substituted by hydroxyl, halogen, methoxy, cyano and/or by CH3-SO2; thienyl; cyclohexenyl or 1,l-cyclohexadien-1-yl T represents hydroxyl; pyridinium, 4-aminocarbonyl-pyridinium or aminopyridinium in which case the carbonyl group at the 4-position takes the form of a carbonyl anion; azido; cyano; thiocarbamoylthio as hereinafter defined; the group -S-phenyl, which can be substituted; or the group -S-Het, in which Het represents an optionally substituted heterocyclic 5-membered or 6-membered ring, U represents oxygen, sulphur or the group -CH2- and Z represents the group

wherein R' and R2 are identical or different and denote hydrogen, optionally substituted alkyl (for example optionally substituted aralkyl) or alkenyl, optionally substituted cycloalkyl, cycloalkenyl or cycloalkadienyl, optionally substituted aryl, optionally substituted heterocyclyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, nitro, lower alkylcar bonyl, -CONH2, -CONHCH3, -CON(CH3)2, -SO2NH2, -SO2-NHCH3 or -SO2N(CH3)2 or Rl and R2, conjointly with the carbon atom to which they are bonded, form a 3-membered to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring, which can be substituted, the said compound being in either of the two possible diastereomeric configurations, that is the R and S configurations, with respect to the chirality centre C*, or in the form of a mixture of the diastereomers resulting therefrom, and, when Z represents the group

and R' and R2 are different, being either in the syn-form or in the anti-form, with respect to the imino group, or a hydrate or salt thereof, which process comprises reacting a compound of the formula II:

wherein A, B, U, Z and C* have the meaning indicated above, or a salt thereof with an inorganic or organic base, with a compound of the general formula III T - H III in which T has the meaning indicated above.

or with a salt thereof with an inorganic or organic base, in the presence or in the absence of a catalyst except where T is hydroxyl when a specific acylane is employed, and in the presence of a solvent, and converting the resulting compound into a salt, or, if desired into a free acid.

The compounds prepared according to the invention (i.e. the compounds of the formula I and the salts and hydrates thereof) exhibit strong antibacterial actions and have the property of promoting the growth and the feedstuff utilisation in animals. Of those compounds of the invention which are salts, therefore, the pharmaceutically acceptable salts are most important and preferred.

Surprisingly, these (3-lactam antibiotics display a very good action against a broad spectrum of pathogens. coupled with good tolerance.

If 7-{D-a-[(2-Oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylamino]- phenylacetamido} -3-acetoxymethyl-ceph-3-em-4-carboxylic acid and 2-methyl-5-mercapto1,3,4-thiadiazole are used as the starting materials, the course of the reaction according to the process of the invention can be represented by the following equation:

In the general formulae, the preferred optionally substituted alkyl groups for the radicals Rl and R are straight-chain or branched alkyl with 1 to 6 and, in particular, 1 to 4 carbon atoms. Examples which may be mentioned are optionally substituted methyl, ethyl, n- and i-propyl and n-, i- and t-butyl.

The preferred optionally substituted alkenyl groups for the radicals R' and R2 are straight-chain or branched alkenyl with 2 to 6 and in particular 2 to 4 carbon atoms.

Examples which may be mentioned are optionally substituted ethenyl, propen-1-yl, propen-2-yl and buten-3-yl.

The preferred optionally, substituted cycloalkyl, cycloalkenyl and cycloalkadienyl groups for the radicals R and R- are mono-, bi- or tri-cyclic groups containing 3 to 10, and in particular 3, 5 or 6, carbon atoms. Examples which may be mentioned are optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, bicyclo-[2. 2. 1]-heptyl, bicyclo-[2.2.2. ]-octyl and adamantyl.

The preferred optionally substituted aryl groups for the radicals R and R2 are aryl groups which have 6 to 10 carbon atoms in the aryl part. Examples which may be mentioned are optionally substituted phenyl or naphthyl. Substituents in the phenyl ring may be in the o-, m- or p-position.

The preferred optionally substituted aralkyl groups for the radicals Rl and R2 are aralkyl groups which is optionally substituted in the aryl part and/or the alkyl part and having 6 or 10, and in particular 6, carbon atoms in the aryl part and 1 to 4, and in particular 1 or 2, carbon atoms in the alkyl part and in which the alkyl part can be straight-chain or branched.

Examples which may be mentioned are optionally substituted benzyl and phenyl-ethyl.

The preferred optionally substituted heterocyclyl groups for the radicals Rl and R2 are hetero-paraffinic, hetero-aromatic and hetero-olefinic 5-membered to 7-membered, especially 5-membered or 6-membered, rings with 1 to 3, and in particular 1 or 2, identical or different hetero-atoms. Examples of typical hetero-atoms are oxygen, sulphur or nitrogen.

Examples which may be mentioned are optionally substituted thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoly, pyrrolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxtriazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, tetrahydrofuranyl, dioxanyl, pyrrolidinyl, piperidinyl, morpholinyl and 2- and 4-pyronyl. There may also be mentioned the radicals:

When Rl or R2 represents an alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl or aralkyl group, it can carry one or more, preferably 1 to 3, and in particular 1 or 2, identical or different radicals R3. Very particularly preferentially, the said radicals R' and R2 are unsubstituted or contain one substituent.

When R' or R2 represents a heterocyclyl radical, it can carry one or more, preferably 1 to 3, and in particular 1 or 2, identical or different radicals R4. Very particularlv preferentially, heterocyclyl Rl and R2 is unsubstituted or contains one substituent Rt.

In the statements which follow, the expression "lower alkyl" in all cases, even in combination with other atoms or groups [for example lower alkoxy and HCON-(lower alkyl), denotes straight-chain or branched alkyl with 1 to 6, in particular 1 to 4 and preferably 1, 2 or 3, carbon atoms. Examples which may be mentioned are optionally substituted methyl, ethyl, n- and i-propyl and n-, i- and t-butyl. "Lower alkyl" also includes groups which are substituted by 1 to 5, and in particular 1 to 3, identical or different halogen atoms and the halogen atoms are preferably fluorine, chlorine and bromine and in particular fluorine and chlorine. Examples which may be mentioned are trifluoromethyl, chloro-di-fluoromethyl, bromomethyl, 2,2,2-tri-fluoroethyl and pentafluoroethyl.

R3 preferably denotes halogen, preferably fluorine, chlorine, bromine or iodine and in particular fluorine, chlorine or bromine; amino; mono-lower alkylamino, preferably methylamino or ethylamino and in particular methylamino; di-lower alkylamino, preferably dimethylamino or diethylamino and in particular dimethylamino; pyrrolidyl; piperidyl; HCO-NH-; lower alkyl-CO-NH-, preferably CH3-CO-NH-; H-CO-N(lower alkyl)-, preferably H-CO-N(CH)-or H-CO-N(CHs)-, lower alkyl-CO-N-(lower alkyl)-, preferably CH3-CO-N(CH)-; (lower alkyl),C=N-; lower alkyl-SO2-NH-, preferably CH3-SO2-NH- or C2H5-SO2-NH- and in particular CH3-SO2-NH-; lower alkyl-SO2-N(lower alkyl)-, preferably CH3-SO2-N(CH3)-; HO-SO2-NH-; HO-SO2-N(lower alkyl)-, preferably HO-SO2 N(CH3)- or HO-SO2-N(C2H5)-; amidino; (lower alkyl)2-N-CH=N-, in particular (CH)2N- CH=N

guanidino, nitro, azido, hydroxyl, lower alkyl-oxy-, preferably CH3-O- or C2Hs-O- and in particular CH3O-; H-CO-O; lower alkyl-CO-O-, preferably CH-CO-O- or (CH3)3C-CO- 0; lower alkyl-O-CO-O-, preferably CH3-O-CO-O-, C2H5-O-CO-O- or (CH)C O-CO- O-; H2N-CO-O-; lower-alkyl-NH-CO-O-, preferably CH3-NH-CO-O- or C2H5-NH-CO-O- ; (lower alkyl)2N-CO-O-, preferably (CH)2N-CO-O- or (C2H5)2N-CO-O;

H2N-SO,-O-; lower alkyl-NH-SO2-O-, preferably CH3-NH-SO2-O- or C2HS-NH-SO2-O-; (lower alkyl)2 N-SO,-O-, preferably (CH)2N-SO,-O- or (C2H5)2N-SO2-O-: HOOC-, H2N-CO-; (lower alkyl)2N-CO-, especially (CH3)2N-CO- or (C2H5)2N-CO-; OHC-; HO-SO2-O-, HS-; lower alkyl-S-, preferably CH3-S-, CF3-S-, C2H5-S or (CH3)2CH-S-, lower

alkyl-S-, preferably CH3-S 0 0 or

lower alkyl-SO,-, preferably CH3-SO-, CFASO,- or C2H5-SO2-; the group H2N-SO2-; lower alkyl-NH-SO2- preferably CH3-NH-SO2- or C2H5-NH-SO2-; (lower alkyl)2N-SO2-, preferably (CH3)2N-SO2- or (C2H5)2N-SO2-;

the group HO-SO2-; straight-chain or branched alkyl with 1 to 6 carbon atoms, especially methyl, ethyl, propyl, isopropyl, n-butyl, sec.-butyl or tert.-butyl, preferably methyl; 2-furyl; phenyl; or phenoxy.

When R4 is attached to a carbon atom in heterocyclyl Rl and R2, R4 preferably denotes lower alkyl, preferably methyl, ethyl or isopropyl and in particular methyl; cycloalkyl with 3 to 7, and preferably 3 to 6. carbon atoms, especially cyclopropyl; the trifluoromethyl group; halogen, preferably fluorine, chlorine or bromine; nitro; amino; lower alkylamino, preferably CH3-NH- or C2H5-NH-; di-lower alkylamino preferably (CH3)2N- or (C2H5)2N- formylamino; acetylamino; CH-O-CO-NH-, C2H5O-CO-NH-; CH-SO2-NH, hydroxyl; methoxy, ethoxy; methylthio. ethylthio; CH3-SO2-; CH3-SO-; lower alkyl-N4-SO2, preferably CH3-NH-SO2; lower alkyl-oxy-CH2-, especially CH30-CH7- and C2H5O-CH2-; heterocyclyl-aldimino (definition of heterocyclyl as for R' and R2), especially furyl-2aldimino; 'alkenyl (definition as for Rl and IR-'), especially allyl;

HOOC-: HO3S-; (lower alkyl)2NSO2-, in particular (CH3)2NSO2; NCO-; lower alkyl-CO-, preferably CH3-CO-; lower alkyl-O-CO-, preferably CH3-O-CO- or C2HsO-CO-; -CN; lower alkyl-O-CO-CH2-, preferably CH3-O-COCH2- or C2HOCOCH2-; (lower alkyl0)2CH-, preferably (C2H,9O)2CH-; HO-lower alkyl-, preferably HO-CH2-,

thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxatriazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, tetrahydrofuranyl, dioxanyl, pyrrolidinyl, piperidinyl or morpholinyl and preferably furyl.

When R4 is a substituent on one or more nitrogen atoms in a nitrogen-containing heterocyclyl R' and R2, R4 preferably denotes lower alkyl, preferably methyl, ethyl, propyl or isopropyl and especially methyl and ethyl; the group -C=-N; -CHO; -COO-lower alkyl, preferably -COO-CH3, -COOC2Hs, -COOCHtCH3)2 or -COO-C(CH3)3; -CO-NH2; -CO-NH-lower alkyl, preferably -CO-NH-CH3, -CO-NH-C2Hs or -CO-NH-CH(CH3)2; and -CO-lower alkyl, preferably -CO-CH3, -CO-C2Hs or -CO-CH(CH3)2.

The rings which can be formed by Rl and R2 conjointly with the carbon atom to which they are bonded may be saturated or unsaturated. Unsaturated rings preferably contain 1 or 2 double bonds. The rings can contain 1 or more, preferably 1 or 2 and in particular 1 hetero-atom or hetero-group. Hetero-atoms which may be mentioned are oxygen, sulphur and/or nitrogen. Examples of hetero-groups which may be mentioned are the SO2 group and the lower alkyl-N-group and in the case of 6-membered rings, a hetero-atom or a hetero-group is preferably in the 4-position (relative to the carbon atom to which Rl and R2 are bonded . Particularly preferred rings which may be mentioned are:

The rings which are formed by Rl and R2 conjointly with the carbon atom to which they are bonded can contain one or more. preferably 1 to 3. and especially 1 or 2, identical or different substituents R R' preferably denotes halogen, preferably fluorine, chlorine or bromine; hydroxyl; lower alkoxy. preferably methoxy and ethoxy: lower alkythio, preferably methylthio or ethylthio: amino; lower alkylamino, preferably CH-NH- or C2H5-NH-: di-lower alkylamino. preferably dimethylamino and diethylamino; the groups -CN, -COOH. -COOCH3 or -COOC2H > , or straight cahin or branched lower alkyl, preferably methyl or ethyl.

Particularly preferentially, at least one of the radicals R' and R2 represents hydrogen.

Particularly preferentially, Z represents the group

Compounds which contain the radical

are formed when this radical is already contained in the compounds of the formula II or, inter alia, can be formed when the reaction is carried out in water-containing solvents.

Phenyl B can carry one or more, preferably 1 to 3 and in particular 1 or 2, identical or different substituents. The substituents can be in the o-, m- and/or p-position. Preferably, one substituent is in the p- or m-position and most preferably there is a single substituent in the p-position. Examples of substituents which may be mentioned are halogen, such as fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, and in particular fluorine and chlorine; alkyl of 1 to 6, preferably 1 to 4 and.in particular 1 or 2, carbon atoms; cyano and methylsulphonyl. Substituted phenyl radicals B which may be mentioned in particular are the hydroxyphenyl radical (preferably p-hydroxyphenyl), the methylphenyl radical (preferably p-methylphenyl), the cyanophenyl radical (preferably mand p-cyanophenyl), the methylsulphonylphenyl radical (preferably pmethylsulphonylphenyl) and the fluorophenyl radical (preferably o-fluorophenyl and m-fluorophenyl).

The heterocyclic ring Het in -S-Het (definition of T) consists of 5 or 6 ring members and may contain 1 to 4, and preferably 1 to 3, identical or different hetero-atoms, the hetero-atoms being oxygen sulphur and nitrogen. The heterocyclic ring is preferably unsaturated and particularly preferentially contains 2 double bonds. The heterocyclic ring can contain one or more, preferably 1 or 2, and in particular one, substituent. Examples of substituents which may be mentioned are: halogen, such as fluorine, chlorine, bromine and iodine, preferably chlorine and bromine, amino, lower alkylamino, di-lower alkylamino, lower alkyl, cycloalkyl (with 3 to 7 and preferably 5 or 6, carbon atoms in the cycloalkyl part), lower alkoxy, trifluoromethyl, phenyl, benzyl and acylamino with preferably 2 to 5 and in particular 2 or 3, carbon atoms. The following may be mentioned as S-Het which are particularly preferred:

The thiocarbamoylthio radical in the definition of T can be substituted on the N atom by one or two lower alkyl radicals. Furthermore, this N atom can be a constituent of a pyrrolidine, piperidine, morpholine or N4-lower alkyl-piperazine ring.

The -S-phenyl radical in the definition of T can carry one or more, preferably 1 to 3, and in particular 1 or 2, identical or different substituents, preferred substituents being those which are listed above as possible substituents of the radical -S-Het.

Particularly preferentially, B represents phenyl, 4-hydroxyphenyl or 1,4-cyclohexadien 1-yl.

Suitable pharmaceutically acceptable salts of the compounds of the formula I and of the starting compounds of the formulae II and III are salts of these compounds with inorganic or organic bases at the acid carboxyl group or, respectively, at the acid carboxyl and sulphonic acid groups. Bases which can be employed for this purpose are all the bases customarily used in pharmaceutical chemistry, especially in the chemistry of antibiotics.

Examples of inorganic bases which may be mentioned are: alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates and alkali metal bicarbonates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate; aluminium hydroxide and ammonium hydroxide.

Organic bases which can be employed are primary, secondary and tertiary aliphatic amines as well. as heterocyclic amines. Examples which may be mentioned are: di- and tri-lower alkylamines, for example diethylamine and triethylamine, tri-B-hydroxyethylamine, procaine, dibenzylamine, N ,N' -dibenzylethylene-diamine, N-benzyl-P-phenyl-ethylamine, Nmethylmorpholine, N-ethylmorpholine, l-ephenamine, dehydroabietylamine, N ,N '-his- dehydroabietylethylenediamine and N-lower alkylpiperidine. So-called basic aminoacids, such as lysine and arginine, can also advantageously be used as bases. Particularly preferred salts are the sodium salts.

Particularly preferred compounds of the general formula I prepared by the process of the invention are those in which A represents hydrogen, B represents phenyl, hydroxyphenyl (particularly preferentially p-hydroxyphenyl) or 1 ,4-cyclohexadien-1-yl) U represents sulphur, T denotes OH, 1-methyl-tetrazol-5-yl-thio, lH-1 ,2 ,3-triazol-5-yl-thio, 2-methyl-1,3,4- thiadiazol-5-yl-thio, 3-methyl-1,2,4-thiadiazol-5-yl-thio, 2-tri-fluoromethyl- 1,3,4- thiadiazol-5-yl-thio, pyridin-2-yl-thio, the N-oxide of pyridin-2-yl-thio, pyridin-4-yl-thio or 3-hydroxy pyridin-2-yl-thio, Z represents the groups

wherein R' denotes hydrogen, and R2 denotes phenyl which is optionally substituted by halogen (especially fluorine, chlorine and bromine), alkyl with 1 to 4 carbon atoms (especially methyl), alkoxy with 1 to 4 carbon atoms (especially methoxy), nitro, cyano, alkylsulphonyl with 1 to 4 carbon atoms (especially methylsulphonyl) or CHlOOC-, or denotes furyl or thienyl which are optionally substituted, preferably in the 4- or 5-position. by halogen (especially chlorine or bromine), NO2, alkyl or alkoxycarbonyl with 1 to 4 carbon atoms or CH3COOCH2-, the furyl ring and thienyl ring preferably being bonded in the 2- and 3- position; or denotes pyridyl (preferably 3-pyridyl), and C* is in the D- = (R-) configuration, as well as the pharmaceutically acceptable salts, preferably the sodium salts, of these compounds.

All crystal forms and hydrate forms of the compounds prepared according to the process of the invention, of the general formula I, and their salts are antibacterially active in the same way.

The compounds of the general formula II, which are used as starting materials, can be obtained as follows: Compounds of the formula IV

in which A, B, C and U have the abovementioned meaning, or their salts, for example sodium salts, are reacted with approximately equimolar amounts of compounds of the formula V

in which Z has the meaning indicated above and W represents halogen, especially chlorine, at temperatures of between preferably 0 and 25"C, for example whilst cooling with ice/water. During the reaction the pH value is kept in the range of 7.0 to 7.5 by adding to base, for example triethylamine. A solvent which can be used is, for example, 20% (parts by volume) aqueous tetrahydrofurane (THF).

The mixture is subsequently stirred until no further triethylamine has to be added in order to maintain this pH. It is then diluted with 40 parts by volume of water, if necessary the pH is brought to 7.0, the tetrahydrofuran is substantially removed in a rotary evaporator, the residual solution is washed once with ethyl acetate, then covered with a layer of fresh ethyl acetate and acidified to pH 2.0 with dilute hydrochloric acid, whilst stirring and cooling, the organic phase is separated off, the aqueous phase is once more extracted by shaking with ethyl acetate and the combined ethyl acetate extracts, after washing with a saturated solution of sodium chloride, are then dried with MgSO4. After removing the desiccant, the solution is diluted with an equal volume of diethyl ether and the sodium salt of the compound of the formula II is then precipitated by adding an approximately 1 molar solution of sodium 2-ethylhexanoate in diethyl ether (which contains about 10% of methanol) and is filtered off an dried.

The compounds of the formula IV are already known or are obtainable according to known methods (compare, for example, E.H.Flynn, Cephalosporins and Penicillins, Academic Press, New York and London, 1972).

The compounds of the formula V are known or are obtainable according to known methods. They can be prepared, for example, in the customary manner by reacting the heterocyclic compounds of the general formula VI:

in which Z has the meaning indicated above, with, for example, molar amounts of phosgene in inert organic solvents, such as, for example, tetrahydrofuran, or in mixtures of water and inert organic solvents, such as, for example, chloroform, at temperatures off) to 25"C, in the absence or in the presence of the molar amount of a base, such as, for example, triethylamine, and working up, and purifying, the products in the customary manner.

The following general formula Ila covers one preferred class of starting materials used in the process of the invention:

Such starting materials are exemplified by those specific materials of formula Ila illustrated in Table A, part B, of Specification No. 1,486,349. Other starting materials of formula Ila are those wherein Rl, R2 and B are as follows:

B C6H5 C6H5 C6H5 Cyclohexa1,4-dien-1-yl Another class of useful compounds used as starting materials in the process of the invention is represented by the formula IIb. Individual compounds of this formula are exemplified in the following table:

Z and B are as follows:

B Phenyl Phenyl Phenyl Phenyl All crystal forms, hydrate forms and salts of the compounds of the general formula II (a and b) are suitable as starting materials for the process according to the invention.

The compounds of the general formula III, which are used as starting materials, are nucleophilic reagents which are obtainable according to known methods. In the process according to the invention, these nucleophilic reagents replace the acetoxy group in the reactants of the general formula II.

Reactions of this type are already known, for example with pyridines (Hale et al., Biochem. J., 79 (1961) 403 and Spencer et al, J. Org. Chem. 32 (1967) 500), with pseudo-aromatic mercapto-heterocyclic compounds (Hale et al., see citation above, Kariyone et al., J. Antibiotics, 23, (1970), 131 and Spencer et al., see citation above) and with dithiocarbamates (Van Heyningen et al., J. Chem. Soc. (London) 1965, 5015) as the nucleophilic reactant.

Especially preferred starting materials of the general formula III which may be mentioned are: 2-methyl-5-mercapto-1, 3,4-thiadiazole, 3-methyl-5-mercapto-1,2,4thiadiazole, 2-mercapto-1,3,4-thiadiazole, 5-mercapto-1,2,4-thiadiazole, 1-methyl-5mercapto-tetrazole, 1 -methyl-2-mercapto- 1,3 ,4-triazole, 2-methyl-5-mercapto- 1,3,4oxadiazole, 1-H-5-mercapto-1.2,3-triazole, 2-mercaptopyridine, the N-oxide of 2mercaptopyridine, 4-mercaptopyridine, 2-mercapto-3-hydroxy-pyridine and water (for the preparation of compounds in which T represents OH when there is used also a specific acylase)., Diluents which can be used for the process according to the invention (reaction of the compounds of the general formula II with the compounds of the general formula III) are, above all, water but other solvents may also be used.

Examples of organic solvents which may be mentioned are: acetone, tetrahydrofuran, dioxane, acetonitrile, dimethyl-formamide, isopropanol, ethanol and dimethylsulphoxide and other water-miscible solvents, on their own or as mixtures with one another. Mixtures of these solvents with water can also be employed.

The pH value for the reaction according to the invention can be varied within wide limits, for example between 2 and 9, by adding acids or bases or buffer mixtures; a pH value of 4-7 is preferred and a pH value of 5 is particularly preferred. Bases which can be used are all the inorganic and organic bases customarily used in organic chemistry, such as alkali metal hydroxides, alkaline earth metal hydroxides, alkaline earth metal oxides, alkali metal carbonates and bicarbonates, alkaline earth metal carbonates and bicarbonates, ammonia, primary, secondary and tertiary aliphatic and aromatic amines and also heterocyclic bases.

Examples which may be mentioned are sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium oxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ethylamine, methyl-ethylamine, triethylamine, hydroxyethylamine, aniline, pyridine and piperidine.

Examples of buffer mixtures which may be mentioned are phosphate buffers and citrate buffers.

The reaction temperatures can be varied within a relatively wide range. In general, the reaction is carried out at between +20"C and 100"C, and preferably between 35"C and 75"C.

The reaction can be carried out under normal pressure, but also under reduced pressure or elevated pressure. In general, the reaction is carried out under normal pressure.

For the reaction according to the invention it is frequently advantageous to employ catalysts, such as alkali metal iodides (for example NaI or KI), alkali metal thiocyanates (for example NaSCN or KSCN), Lewi (Enterococci), Str. agalactiae, Str. lactis, Str. equi, Str. anaerobis and Diplococcus pneumoniae (Pneumococci) (Str. = Streptococcus); Neisseriaceae, such as Neisseriae, for example Neisseria gonorrhoeae (Gonococci), N.

meningitidis (Meningococci), N. catarrhalis and N. flava (N. = Neisseria); Corynebacteriaceae, such as Corynebacteria, for example Corynebacterium diphtheriae, C. pyrogenes, C. diphtheroides, C. acnes, C. parvum, C. bovis, C. renale and C. ovis, Enterobacteriaceae, such as Escherichiae bacteria of the Coli group, Escherichia bacteria, for example Escherichia coli, Enterobacter bacteria, for example E. aerogenes and E.

cloacae, Klebsiella bacteria, for example K. pneumoniae, Serratia, for example Serratia marcescens (E. = Enterobacter) (K. = Klebsiella), Proteae bacteria of the Proteus group, Proteus, for example Proteus vulgaris, Pr. organic, Pr. rettgeri and Pr. mirabilis (Pr. = Proteus), Providencia, for example Providencia sp. Salmonelleae, Salmonella bacteria, for example salmonella paratyphi A and B, S. typhi, S. enteritidis, S. cholerae suis and S.

typhimurium (S. = Salmonella), and Shigella bacteria, for example Shigella dysenteriae (SH. = Shigella); Pseudomonadaceae, such as Pseudomonas bacteria, for example Pseudomonas aeruginosa and Ps. pseudomallei (Ps. = Pseudomonas), and Aeromonas bacteria, for example Aeromonas Liquefacuens and A. hydrophila (A. = Aeromonas); Spirillaceae, such as Vibrio bacteria, for example Vibrio cholerae and V. proteus (V. = Vibrio); Parvobacteriaseae or Brucellaceae, such as Pasteurella bacteria, for example Pasteurella multocida, Past. pestis (Yersinia), Past. pseudotuberculosis (Past. = Pasteurella), Haemophilus bacteria, for example Haemophilus influenzae, (H. = Haemophilus), Bordetella bacteria, for example B. bronchiseptica (B. = Bprdetella); Bacterioidacea, such as Bacteroides bacteria, for example Bacteroides fragilis and B.

serpens (B. = Bacteroides), Fusiforme bacteria, for example Fusobacterium fusiforme and Sphaerophorus bacteria, for example Sphaerophorus necrophorus, Sph. necroticus and Sph. pyrogenes (Sph. = Sphaerophorus); Bacillaceae, such as aerobic spore-forming Bacillaceae, for example Bacillus anthracis, B. subtilis and B. cereus (B. = Bacillus), anaerobic spore-forming Chlostridia, for example Clostridium perfringens, Cl. tetani and Cl. botulinum (Cl. = Clostridium); The above list of pathogens is purely illustrative and is in no way to be interpreted as restrictive.

Examples which may be mentioned of diseases which can be prevented, alleviated and/or cured by the active compounds prepared according to the invention are: diseases of the respiratory passages and of the pharyngeal cavity, otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infections, bronchitis and arthritis.

The present invention also provides a pharmaceutical composition containing as active ingredient a compound prepared according to the invention in admixture with a solid or liquid diluent or carrier.

This pharmaceutical composition may contain the active ingredient in a sterile or isotonic aqueous solution.

The invention also provides a medicament in dosage unit form comprising a compound prepared according to the invention either alone or in admixture with a diluent.

This medicament may be in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a compound prepared according to the invention either alone or in admixture with the diluent.

"Medicament" as used in this Specification means physically discrete coherent portions suitable for medical administration. "Medicament in dosage unit form" as used in this Specification means physically discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or sub-multiple (down to a fortieth) of a daily dose of the compound prepared according to the invention in association with a carrier and/or enclosed within an envelope. Whether the medicament contains a daily dose or, for example, a half, a third, or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.

The pharmaceutical compositions according to the invention may, for example, take the form of ointments, gels. pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granules or powders.

The diluents to be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees, capsules and pills include the following: (a) fillers and extenders, e.g. starch, sugars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g.

agar-agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution e.g. paraffin; (f) resorption accelerators, e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol and glycerol monostearate; (h) adsorptive carriers, e.g. kaolin and bentonite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols.

The tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time.

The coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.

The ingredient can also be made up in microencapsulated form together with one of several of the above-mentioned diluents.

The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can. for example, be the usual water-soluble or water-insoluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high esters (e.g. C14-alcohol with C16- fatty acid)) or mixtures of these diluents.

The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.

The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydrocarbons.

The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents such as solvents, dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide oils (for example ground nut oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.

For parenteral administration, the solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.

The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols. polyoxyethylene sorbit and sorbitane esters), microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.

All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g.

peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).

The pharmaceutical compositions according to the invention usually contain from 0.1 to 99.5, preferably from 0.5 to 95cue of the active ingredient by weight of the total composition.

In addition to a compound prepared according to the invention, the pharmaceutical compositions and medicaments according to the invention can also contain other pharmaceutically active compounds. They may also contain a plurality of compounds prepared according to the invention.

Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention. Such medicaments may include solvents of molecular weight less than 20() as sole diluent.

The discrete coherent portions constituting the medicament according to the invention will generally be adapted by virtue of their shape or packaging, for medical administration and may be, for example, any of the following: tablets. (including lozenges and granules), pills, dragees, capsules, suppositories and ampoules. Some of these forms may be made up for delayed release of the active ingredient. Some, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.

The preferred daily dose for administration of the medicaments of the invention is 0.3g to 80g of active ingredient.

The production of the above mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).

This invention further provides a method of combating (including prevention, relief and cure of) the above-mentioned diseases in non-human animals, which comprises administer ing to the animals a compound prepared according to the invention alone or in admixture with a diluent or in the form of a medicament according to the invention.

It is envisaged that these active compounds will be administered perorally, parenterally (for example intramuscularly, intraperitoneally or intravenously), rectally or locally, preferably parenterally, especially intravenously or intramuscularly. Preferred pharmaceutical compositions and medicaments are therefore those adapted for parenteral administration.

In general, it has proved advantageous both in human medicine and in veterinary medicine to administer the active compound or compounds prepared according to the invention in total amounts of 6 to 800, preferably 15 to 300, mg/kg of body weight every 24 hours, optionally in the form of several, for example 3, individual administrations, in order to achieve the desired results. An individual administration contains the active compound or compounds prepared according to the invention, preferably in amounts of 2 to 300, especially 10 to 150, mg/kg of body weight. However, it can be necessary to deviate from the dosages mentioned and in particular to do so as a function of the nature and the body weight of the subject to be treated, the nature and the severity of the illness, the nature of the formulation and of the administration of the medicine, and the time or interval over which the administration takes place. Thus it can suffice in some cases to manage with less than the abovementioned amount of active compound, whilst in other cases the above-mentioned amount of active compound must be exceeded. The particular optimum dosage required and the type of administration of the active compounds can easily be determined by anyone skilled in the art, on the basis of his expert knowledge.

The invention also includes a medicated fodder comprising a compound prepared according to the invention and a nutritious material. Examples of suitable nutritious materials are oil cake, grains (e.g. barley), fish meal, soya bean meal, extracted sugar beet, silage, hay and skimmed milk.

When used as feedstuff additives, the compounds prepared according to the invention can be administered in the customary manner together with the feedstuff or with feedstuff formulations or with the drinking water. By this means it is possible to prevent an infection by Gram-negative or Gram-positive bacteria and also to achieve better utilisation of the feedstuff.

The P-lactam antibiotics prepared according to the invention are distinquished by powerful antibacterial actions, which have been tested in vivo and in vitro, and by oral resorbability.

The -lactam antibiotics prepared according to the invention can, in order to broaden the spectrum of action or to achieve a more powerful action, also be combined with, for example, aminoglycoside antibiotics, such as gentamycin, sisomycin, kanamycin, amicacin or tobramycin.

The activity of the -lactam antibiotics prepared according to the invention can be demonstrated, by way of example, by the following in vitro and in vivo experiments: 1. In vitro experiments Examples two, five and eight, which can be regarded as typical representatives of the compounds prepared according to the invention, were diluted to a content of 100ELg/ml with Muller-Hinton nutrient broth. In each case, the nutrient solution contained 1 x 105 to 2 x 105 bacteria per millilitre. The small tubes containing this batch were in each case incubated for 24 hours and the degree of turbidity was then determined. Freedom from turbidity indicates action. At a dosage of 100 g/ml, the following bacterial cultures were free from turbidity (sp. = species): Klebsiella pneumoniae, Enteribacter aerogenes sp., Providencia; Serratia marcescens, E coli BE, Salmonella sp., Shigella sp., Proteus, indole-negative and indole-positive, Pasteurella psuedptuberculosis, Haemophilus influenzae, Bordetella bronchiseptica, Staphylococcus aureus 133. Neissera catarrhalis sp., Diplococcus pneumoniae sp., Streptococcus pyogenes W., Enterococcus sp., Lactobacillus sp., Corynebacterium diphteriae gravis, Corynebacterium pyrogenes M, Closfrifium tetani and Pseudomonas aeruginosa sp.

2. In vivo experiments Table 1 which follows shows the dose of one of the compounds prepared according to the invention against several bacteria in an animal experiment using white mice. White mice of the CF, strain were infected intraperitoneally with the particular strain of bacteria indicated.

TABLE 1 Animal experimetits with white mice Determination of the EDl after 24 hours Germ Dose in mg of the p-lactam antibiotic of Examples 1.3., 2.3. and 2.4. per kg/body weight (subcutaneously) Escherichia coli C165 2 x 150 Klebsiella 63 2 x 150 Therapy: 2 administrations: 30 minutes and 90 minutes after infection. The EDloo is the dose at which 100% of the infected animals still survive after 24 hours.

The process according to the invention is illustrated with the aid of the examples which follow.

Unless otherwise stated, the NMR spectra of the compounds prepared according to the invention were recorded in CD,OD solution. The notations in brackets have the following meanings: s = singlet d = doublet t .= triplet q = quartet m = multiplet Unless otherwise stated. the IR spectra of the compounds prepared according to the invention were recorded in liquid paraffin (Nujol - registered Trade Mark) suspensions.

Explanation of the abbreviations used in the examples: vol. = volume pts. by wt. = parts by weight in grams pts. by vol. = parts by volume in ml.

hours = hours hr. = hour THF = tetrahydrofuran DMF = dimethylformamide ether = diethvl ether room temperature = about 20"C abs. = absolute decomp. pt. = decomposition point The % data for the yields denotes yields in % of theory. All the temperatures are given in "C.

EA'AIWlple 1

2.0 pts. by wt. of sodium 7-{D-(i-[(2-oxo-3-furylideneamino-imidazolidin-t-yl)- carbonylaminoj-phenylicetamide}-3-acetoxymethyl-ceph-3-em-4-carboxylate are dissolved in 15 pts. by vol. of water and 2() pts. by vol. of citrus acetyl esterase solution (prepared according to DAS (German Published Specification) 1,161,276 of 11.4.61) are added. The reaction mixture is warmed at 350C for 7 hns. and the pH value is kept at 6.8 by the dropwise addition of 0.1 N sodium hydroxide solution.

The solution is filtered. with the addition of a filter aid (Celite - registered Trade Mark), and the filtrate is extracted several times with ethyl acetate. The pH of the aqueous phase is brought to 2.6 with 5 N HC1 and the precipitate which has separated out is filtered off and washed with water. The precipitate is digested with acetone, the mixture is filtered and the filtrate is concentrated. The residue is suspended in 20 pts. by vol. of water and the pH is brought to 7 with ().1 N sodium hydroxide solution, whereupon a clear solution forms. This solution is lyophilised and ().3 pt. by wt. of sodium 7-D-a-(2-oxo-3-furylideneamino- imidazolidin- 1-yl)-carbonylaminoJ-phenylacetamido}-3-hydroxymethylceph3em4 carboxylate is obtained.

NMR (CD30D): 7.80 (s, 1H), 7.70 (s, 1H), 6.97 (q. 1H), 5.75 (d, 1H), 5.63 (s, 1H), 5.37 (overlapped by the replaceable protons), 4.4 (s, 2H) and 3.95 (s, broad, 4H), the C-2 protons are overlapped by the solvent peak (in 6).

Example 2

1.0 pt. by wt. of 7-{D-a-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylamino] phenylacetamido}-3-acetoxy-methyl-ceph-3-em-4-carboxylic acid and 0.4 pt. by wt. of 5-mercapto-1-methyltetrazole are suspended in 50 pts by vol. of a phosphate buffer of pH 7, the pH is brought to 5 and the suspension is stirred for 5 hrs. at 70"C whilst nitrogen is passed and this pH value is maintained. After cooling the pH .of the reaction mixture is brought to 7 with 2 N sodium hydroxide solution and the mixture is extracted several times with ethyl acetate. The pH of the aqueous phase is slowly brought to 1.8 with 0.1 N hydrochloric acid, whereupon 0.8 Put. by wt. of 7-{D-a-l (2-oxo-3-fury!ideneamino- imidazolidin-1-yl)-carbonylamino-phenylacetamido}-3- (1-methyltetrazol-5-yl)- thiomethyl]-ceph-3-em-4-carboxylic acid precipitates; this precipitate is washed with water and dried over P4O10 in a desiccator. The acid is dissolved in 100 pts. by vol. of absolute acetone, the solution is filtered and 20 pts. by vol. of water are added to the filtrate. The acetone is stripped off and the acid precipitates again.

As well as 1.0 N sodium hydroxide solution is added dropwise to this suspension until a clear solution forms and the mode of addition is such that the pH does not rise above 7.8.

This solution is lyophilised and 0.7 pt. by wt. of the sodum salt with a decomp. pt. of 210-220"C is obtained.

IR (KBr): 1760, 1720, 1660, 1610, 1520, 1475, 1410 and 1230 cm-l.

NMR (CD3OD): 7.73 (s, 1H), 7.63 (d, 1H), 7.38 (m, 5H), 6.88 (d, 1H), 6.54 (q, 1H), 5.67 (d, 1H), 5.56 (s, 1H), 4.9 (overlapped by the replaceable protons), 4.32 (s, 2H), 3.95 (s, 3H), 3.85 (s, broad, 4H) and 3.45 (overlapped by the solvent peak).

Example 3

6.5 pts. by wt. or sodium 7-{D-a-[(2-oxo-3-furylideneamino-imidazolin-1-yl) carbonylamino]-phenylacetamido}-3-acetoxymethyl-ceph-3-em-4-carboxylate and 2.7 pts.

by wt. of 5-mercapto-3-methyl- 1,2,4-thiadiazole are dissolved in 250 pts. by vol. of phosphate buffer (pH 7) and the reaction and working up are carried out as in Example 2.

This gives 3.9 ts. by wt. of sodium 7-{D-a-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)- carbonylamino-phenylacetamido}-3- (3-methyl-thiadiazol-5-yl)-thiomethyl -ceph-3-em-4carboxylate with a decomp. pt. of 200-210 C.

IR (KBr): 1760, 1720, 1660, 1595, 1525, 1475, 1410, 1275 and 1230 em NMR (CD3OD): 7.70 (s, 1H), 7.64 (d, 1H), 7.33 (m, 5H), 6.86 (d, 1H), 6.50 (dd, 1H), 5.65 (d, 1H), 5.55 (s, 1H), 4.90 (d, 1H), 4.02 (pseudo-d, 2H), 3.85 (s, broad, 4H), 3.4 (overlapped by solvent peak) and 2.52 (s, 3H).

Example 4

7-{D-α-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylamino]-phenylacetamido}- 3-acetoxymethyl-ceph-4-em-4-carboxylic acid (1.2 pts. by wt.) is dissolved in phosphate buffer of pH 7 (20 pts. by vol.), 2-mercapto-5-trifluoromethyl-1,3,4-thiadiazole (0.9 pt. by wt.) is added and the mixture is warmed to 70 C for 6 hrs. and during this time the pH is kept at 5.1 by means of 0.1 N sodium hydroxide solution. After cooling and removing a little decomposition product, the mixture is acidified to pH 1 and the free cephalosporin acid is filtered off, washed with water and dried (yield: 0.9 pt. by wt., IR bands in Nujol at 1780, 1730, 1670 and 1540 cm- l) This acid is then dissolved in a little dimethylformamide and, after adding 1.4 pts. by vol. of a 1 molar solution of sodium 2-ethyl-hexanoate in ether, the sodium salt is precipitated with ether. Yield: 0.5 pt. by wt. of sodium 7--{D-a[(2-oxo-3- furylidene-amino-imidazolidin-1-yl]-carbonylamino}-phenylacetamido-3-[(5- trifluoromethyl-1,3,4-thiadiazol-2-yl)-thiomethyl]-ceph-3-em-4-carboxylate.

Melting point = decomposition above 220"C; no clear melt up to 2600C (Kofler bench).

-Lactam content: 76% IR spectrum (carbonyl region): 1765, 1720, 1660, 1600 and 1530 cm-' Example 5

5.0 pts by wt. of sodium 7-{D-a-[(2-oxo-3-furylidene-aminoimidazolidin-1-yl)- carbonylamino]-phenylacetamido}-3-acetoxymethyl-ceph-3-em-4-carboxylate and 1.6 pts.

by wt. of 2-methyl-5-mercapto-1,3,4-thiadiazole are reacted, and the product is worked up, as in Example 3. This gives 2.7 pts. by wt. of sodium 7-{D-a-[(2-oxo-3-furylideneamino imidazolidin-1-vl)-carbonylamino]-phenylacetamido}-3-[(2-methyl- 1,3 ,3,4-thiadiazol-5-yl)- thiomethyl]-ceph-3-em-4-carboxylate with a decomp. pt. of 214-222"C.

IR (KBr): 3400. 1755, 1720. 1660. 1595, 1520, 1470 and 1405 cm-X.

NMR (d6-DMSO): d 9.50 (1H), d 9.20 (1H), s and d between 7.90-7.88 (2H). m at about 7.5 (5H), d 6.94 (1H), dd 6.70 (1H), m at about 5.7 (3H), AB 5.00 (2H), s (broad) 3.91 (4H). at about 3.6 replaceable protons overlapped by AB system and s 2.76 (3H) ppm.

Exaenple 6

21.4 pts by wt. of sodium 7-{D-a-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)- carbonylamino]-phenylacetamido}-3-acetoxymethyl-ceph-3-em-4-carboxylate and 8.0 pts.

by wt. of 5-mercapto-1.3.4-thiadiazole are dissolved in 500 pts. by vol. of phosphate buffer (pH 7) and the reaction and working up are carried out as in Example 2. This gives 1.6 pts.

by wt. of sodium 7-{D-α-[2-oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylamino]- phenylacetamido)-3-(1,3,4-thiadiazol-5-yl-thio-methyl)-ceph-3-em-4-carboxylate with a decomp. pt. of 211-223"C IR (KBr): 34()(). 1760. 1770. 166). 1610, 1520. 1475 and 1410 cm-'.

NMR (CD3OD): s X.68 (1H). s 7.75 (lH). d 7.63 (lH). mat about 7.4 (5H), d 6.90(1H). dd 6.55 (1H). m at about 5.6 (3H). AB 5.10 (2H), pseudo-s 3.9 (4H) overlapped by AB system (2H) ppm.

Example 7

Yield: 1.7 pts by wt.

Melting point: about 230"C with decomposition. -I IR (carbonyl region): 1760, 1725, 1670, 1610 and 1530 cm-'.

NMR (d? DMF/CDXOD): d 8.3 (1H),- m 7.85-7.05 (1OH), 6.85 (1H), 6.55 (1H), 5.6-5.8 (2H), 4.85-5.0 (1H), q 4.0-4.5 (2H), 3.9 (4H) and q 3.2-3.6 ppm (2H) (6).

Example 11

3.0 pts. by wt. of 7-{D-a-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylamino]- phenylacetamido}-3-acetoxy-methyl-ceph-3-em-4-carboxylic acid and 1.2 pts. by wt. of 2-mercapto-3-hydroxypyridine are reacted, and the product is worked up, in the manner described in Example 4 (except that the reaction is carried -out for 16 hours at 70 and pH 5.1). This gives 2.8 pts. by wt. of sodium 7-{D-a-[(2-oxo-3-furylideneamino-imidazolidin-1yl)-carbonylamino]-phenylacetamido}-3-(3-hydroxypyridin-2-yl-thiomethyl)-ceph-3-em-4carboxylate with a decomposition point of about 240"C.

IR (carbonyl region): 1765, 1730, 1670, 1630 and 1550-1530 cm-l.

B-Lactam content (according to analysis and NMR): 90% Example 12

5.0 pts. by wt. of sodium 7-{D-a-[(2-oxo-3-furylideneamino-imidazolidin-l-yl) carbonylamino]-phenylacetamido}-3-acetoxymethyl-ceph-3-em-4-carboxylate and 2.6 pts.

by wt. of 1-carboxymethyl-5-mercapto-tetrazole are reacted, and the product is worked up as in example 5. This gives 2.9 pts. by wt. of sodium 7-(D-a-[(2-oxo-3-furylideneamino- imidazolidin-1-yl)-carbonylamino]-phenylacetamido}-3-[(1-carboxymethyl-tetrazol-5-yl)- thiomethyl]-ceph-3-em-4-carboxylate with a decomp. pt. of 203-208"C.

IR (KBr): 1765, 1715, 1670, 1535, 1480, 1410, 1270, 1235 cm- WHAT WE CLAIM IS:1. A process for the preparation of a compound of the formula

in which A represents hydrogen or methoxy; B represents phenyl; phenyl which is substituted by hydroxyl, halogen, methoxy, cyano and/or by CHR-SO,, thienyl; cyclohexenyl or 1 ,4-cyclohexadien- 1-yl; T represents hydroxyl; pyridinium, 4-aminocarbonylpyridium or aminopyridinium in which case the carboxyl group at the 4-position takes the form of a carbonyl anion; azido; cyano; thiocarbamoylthio as hereinbefore defined; the group -S-phenyl, which can be substituted; or the group -S-Het, in which Het represents an optionally substituted heterocyclic 5-membered or 6-membered ring, U represents oxygen, sulphur or the group -CH2- and Z represents the group 0.8 pt by wt. of sodium 7-{D-a-[(2-oxo-3-furylidene-amino-imidazolidin-1-yl)- carbonylamino] -4-hydroxy-phenylacetamido}-3-acetoxymethyl-ceph-3-em-4-carboxylate and 0.5 pt. by wt. of lH-5-mercapto-1,2,3-triazole are reacted, and the product is worked up, as in Example 3. This gives 0.9 pt. by wt. of sodium 7 {D-a-[(2-oxo-3-furylideneamino- imidazolidin- 1-yl)-carbonylaminoj-4-hydroxy-phenylacetamido}-3-(1 ,2 ,3-triazol-5-yl- thiomethyl)-ceph-3-em-4-carboxylate with decomp. pt. of 230"C.

IR (KBr): 3420, 1755, 1720, 1660, 1590, 1510, 1470 and 1410 cm-l.

NMR (d6-DMSO): s 7.82 (1H), d 7.80 (1.H), s 7.50 (1H), A2B2 7.08 and 6.70 overlapped by the 2- and 3-furane proton (6H), m at about 5.7 (3H), d 5.10 (2H) and pseudo-s overlapped by AB system at about 3.9 (6H) ppm.

Example 8

2.0 pts by wt. of sodium 7-{D-a-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)- carbonylamino]-phenylacetamido}-3-acetoxymethyl-ceph-3-em-4-carboxylate and 0.7 pt.

by wt. of 2-mercaptopyridine are reacted with one another, and the product is worked up, in the manner described in Example 4. This gives 1.9 pts by wt. of sodium 7-(D-a-[(2-oxo-3 furylideneamino-imidazolidin- 1-yl)-carbonylamino- phenylacetamido}-3-(pyridin-2-ylthiomethyl)-ceph-3-em-4-carboxylate with a decomp. pt. of 234"C.

IR (carbonyl region): 1750, 1720, 1660, 1600 and 1530 cm-'.

NMR (d7-DMF/CD3OD): d 8.4 (1H), m 7.85-7.20 (9H), d 7.15 (1H), 6.85 (1H), 6.6 (1H), 5.8 (1H), d 5.65 (1H), d 4.9 (1H), q 4.63-4.3 (2H), 3.85 (broad) (4H) and q 3.6-3.2 ppm (2H) ( ) The free acid (1.9 pts. by wt.) of the cephalosporin which is obtained as an intermediate during working up, was crystalline and had a melting point of 248-252"C (decomposition).

IR (carbonyl region): 1760, 1720, 1660 and 1505 elm . The triethanolamine salt is obtained by dissolving the free acid of the cephalosporin in a little DMF, adding the calculated amount of triethanolamine (for example in the form of a 1 molar solution in butanol) and precipitating the salt with ether.

Example 9

2.0 pts. by wt. of sodium 7-{D-a-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)- carbonylamino]-phenylacetamido}-3-acetoxymethyl-ceph-3-em-4-carboxylate and 0.7 pt.

by wt. of 4-mercaptopyridine are reacted, and the product is worked up, in the manner described in Example 4. This gives 1.3 pts. by wt. of the free acid (decomposition point about 210 C, on rapid heating 258"C), which was then converted into sodium 7-(D-a-[(2- oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylamino]-phenylacetamido}-3-(pyridin-4- yl-thiomethyl)-ceph-3-em-4-carboxylate. decomposition point about 1900C.

IR (carbonyl region); 1750, 1720, 1660, 1620 and 1510-1525 cm1.

Example 10

3.0 pts. by wt. of 7-{D-a-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylamino]- phenylacetamido}-3-acetoxy-methyl-ceph-3-em-4-carboxylic acid and 1.5 pts by wt. of the N-oxide of 2-mercaptopyridine were reacted with one another in the manner described in Example 4 and the resulting free acid (1.8 pts. by wt.) was converted into the Na salt: sodium 7-(D-o-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylamino]- phenylacetamido)-3-( l-oxidopyridin-2-yl -thiomethyl) -ceph-3-em-4-carboxylate .

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (20)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   0.8 pt by wt. of sodium 7-{D-a-[(2-oxo-3-furylidene-amino-imidazolidin-1-yl)- carbonylamino] -4-hydroxy-phenylacetamido}-3-acetoxymethyl-ceph-3-em-4-carboxylate and 0.5 pt. by wt. of lH-5-mercapto-1,2,3-triazole are reacted, and the product is worked up, as in Example 3. This gives 0.9 pt. by wt. of sodium 7 {D-a-[(2-oxo-3-furylideneamino- imidazolidin- 1-yl)-carbonylaminoj-4-hydroxy-phenylacetamido}-3-(1 ,2 ,3-triazol-5-yl- thiomethyl)-ceph-3-em-4-carboxylate with decomp. pt. of 230"C.

   IR (KBr): 3420, 1755, 1720, 1660, 1590, 1510, 1470 and 1410 cm-l.

   NMR (d6-DMSO): s 7.82 (1H), d 7.80 (1.H), s 7.50 (1H), A2B2 7.08 and 6.70 overlapped by the 2- and 3-furane proton (6H), m at about 5.7 (3H), d 5.10 (2H) and pseudo-s overlapped by AB system at about 3.9 (6H) ppm.

   Example 8

   2.0 pts by wt. of sodium 7-{D-a-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)- carbonylamino]-phenylacetamido}-3-acetoxymethyl-ceph-3-em-4-carboxylate and 0.7 pt.

   by wt. of 2-mercaptopyridine are reacted with one another, and the product is worked up, in the manner described in Example 4. This gives 1.9 pts by wt. of sodium 7-(D-a-[(2-oxo-3 furylideneamino-imidazolidin- 1-yl)-carbonylamino- phenylacetamido}-3-(pyridin-2-ylthiomethyl)-ceph-3-em-4-carboxylate with a decomp. pt. of 234"C.

   IR (carbonyl region): 1750, 1720, 1660, 1600 and 1530 cm-'.

   NMR (d7-DMF/CD3OD): d 8.4 (1H), m 7.85-7.20 (9H), d 7.15 (1H), 6.85 (1H), 6.6 (1H),

   5.8 (1H), d 5.65 (1H), d 4.9 (1H), q 4.63-4.3 (2H), 3.85 (broad) (4H) and q 3.6-3.2 ppm (2H) ( ) The free acid (1.9 pts. by wt.) of the cephalosporin which is obtained as an intermediate during working up, was crystalline and had a melting point of 248-252"C (decomposition).

   IR (carbonyl region): 1760, 1720, 1660 and 1505 elm . The triethanolamine salt is obtained by dissolving the free acid of the cephalosporin in a little DMF, adding the calculated amount of triethanolamine (for example in the form of a 1 molar solution in butanol) and precipitating the salt with ether.

   Example 9

   2.0 pts. by wt. of sodium 7-{D-a-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)- carbonylamino]-phenylacetamido}-3-acetoxymethyl-ceph-3-em-4-carboxylate and 0.7 pt.

   by wt. of 4-mercaptopyridine are reacted, and the product is worked up, in the manner described in Example 4. This gives 1.3 pts. by wt. of the free acid (decomposition point about 210 C, on rapid heating 258"C), which was then converted into sodium 7-(D-a-[(2- oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylamino]-phenylacetamido}-3-(pyridin-4- yl-thiomethyl)-ceph-3-em-4-carboxylate. decomposition point about 1900C.

   IR (carbonyl region); 1750, 1720, 1660, 1620 and 1510-1525 cm1.

   Example 10

   3.0 pts. by wt. of 7-{D-a-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylamino]- phenylacetamido}-3-acetoxy-methyl-ceph-3-em-4-carboxylic acid and 1.5 pts by wt. of the N-oxide of 2-mercaptopyridine were reacted with one another in the manner described in Example 4 and the resulting free acid (1.8 pts. by wt.) was converted into the Na salt: sodium 7-(D-o-[(2-oxo-3-furylideneamino-imidazolidin-1-yl)-carbonylamino]- phenylacetamido)-3-( l-oxidopyridin-2-yl -thiomethyl) -ceph-3-em-4-carboxylate .

   wherein

   R' and R2 are identical or different and denote hydrogen; optionally substituted alkyl or alkenyl; optionally substituted cycloalkyl, cycloalkenyl or cycloalkadienyl; optionally substituted aryl; optionally substituted heterocyclyl; carboxyl; methoxycarbonyl; ethoxy carbonyl; cyano; nitro; lower alkylcarbonyli -CONH2; -CONHCH3; -CON(CH3)2; -SO2NH2; -SO2-NHCHS or -SO2N(CH3)2 or R and R2, conjointly with the carbon atom to which they are bonded, can form a 3-membered to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring, which can be substituted, or a salt or hydrate thereof, which process comprises reacting a compound of the formula: -

   in which A, B, U and Z are as defined above, or a salt thereof, with a compound of the formula T-H wherein T is as defined above, or a salt thereof, optionally in the presence of a catalyst except where T is hydroxyl when a specific acylase is employed, and in the presence of a solvent, and converting the resulting compound into a salt, or into a tree acid.
2. 2. A process according to claim 1, in which A represents hydrogen, B represents phenyl, hydroxyphenyl or 1,4-cyclohexadien-1-yl, U represents sulphur, T denotes hydroxyl, l-methyl-tetrazol-5-yl-thio , 1H-1 ,2,3-triazol-5-yl-thio, 2-methyl 1,3 ,4-thiadiazol-5-yl-thio, 3-methyl-1,2,4-thiadiazol-5-yl-thio, 2-trifluoromethyl-1 3,4- thiadiazol-5-yl-thio, pyridin-2-yl-thio, the N-oxide of pyridin-2-yl-thio, pyridin-4-yl thio or 3-hydroxypyridin-2-yl-thio, Z represents the groups

   wherein R2 denotes phenyl or phenyl which is substituted by halogen, alkyl with 1 - 4 C atoms, alkoxy with 1 - 4 C atoms, nitro, cyano, alkylsulphonyl with 1 - 4 C atoms, or CH3OOC-, or R2 denotes furyl or thienyl either of which are substituted by halogen, nitro, alkyl with 1-4 C atoms, alkoxycarbonyl with 1-4 C atoms or CH3COOCH2-, or R2 denotes pyridyl, and the C atom bonded to the radical B is in the R-configuration.
3. 3. A process according to claim 1 when used to prepare a compound of the formula

   or a salt or a hydrate thereof.
4. 4. A process according to claim 1 when used to prepare a compound of the formula

   or a salt or a hydrate thereof.
5. 5. A process according to claim 1 when used to prepare a compound of the formula

   or a salt or a hydrate thereof.
6. 6. A process according to claim 1 when used to prepare a compound of the formula

   or a salt or hydrate thereof.
7. 7. A process according to claim 1 when used to prepare a compound of the formula

   or a salt or hydrate thereof.
8. 8. A process according to claim 1 when used to prepare a compound of the formula

   or a salt or hydrate thereof.
9. 9. A process according to claim 1 when used to prepare a compound of the formula

   or a salt or hydrate thereof.
10. 10. A process according to any one of the preceding claims wherein a resulting free acid is converted into its sodium salt.
11. 11. A process according to claim 1.

    wherein T is hydroxyl and the reaction is effected with an aqueous solution of citrus acetyl esterase.
12. 12. A process according to any one of the preceding claims, in which the reaction is carried out at a temperature of from +20 C to +1000C.
13. 13. A process according to any one of the preceding claims, in which the reaction is carried out at a pH value of from 2 to 9.
14. 14. A process according to claim 1 substantially as hereinbefore described specifically.
15. 15. A process according to claim 1 substantially as hereinbefore described in any one of the specific Examples.
16. 16. A compound as defined in claim 1 when prepared by a process according to any one of the preceding claims.
17. 17. A pharmaceutical composition containing as an active ingredient a compound according to claim 16 in admixture with a solid or liquid diluent or carrier.
18. 18. A medicament in dosage unit form comprising a compound according to claim 16.
19. 19. A method of combating bacterial diseases in non-human animals which comprises administering to the animals an active compound according to claim 16 either alone or in admixture with a diluent or in the form of a medicament according to claim 18.
20. 20. A medicated fodder comprising a compound according to claim 16 and a nutritious material.