IE43814B1 - -lactam antibiotics,process for their preparation and their use as medicaments - Google Patents

Abstract

The present invention relates to new β-lactam antibiotics, a process for their preparation and their use as medicaments, especially as anti-bacterial agents and as agents for promoting the growth and improving the feed5 stuff utilisation in animals.

Description

The present invention relates to new β-lactam antibiotics, a process for their preparation and their use as medicaments, especially as anti-bacterial agents and as agents for promoting the growth and improving the feed5 stuff utilisation in animals.

It has already been disclosed that certain a-(imidazolidin-2-oxo-l-yl-carbonylamino)-benzylpenicillins are anti-bacterially active (compare Belgian Patent Specifications 767,647 and 767,648, Netherlands Patent Specification 7,114,254 and German Offenlegungsschrift (German Published Specification) 2,152,968).

The new β-lactam antibiotics according to the invention differ chemically from the known compounds of the state of the art above all by the fact that the N3 of the imidazolidinone radical is bonded to the N atom of an imino or amino group.

The present invention provides β-lactam antibiotics of the formula I II 438 1 d in which R represents hydrogen Z represents the groups C=N- or R2- C-NHOH wherein 2 R and R are identical or different and denote hydrogen, optionally substituted alkyl or alkenyl, optionally substituted cycloalkyl, cycloalkenyl and cycloalkadienyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heterocyclyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, nitro, lower alkylcarbonyl, -conh2, -conhch3, -con(ch3)2, -so2nh2, -S02-NHCH3 or -SO2N(CH3)2 or ί ο R and R 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, A represents -CH2-CH2~, -CH2~CH2-CH2- or B represents optionally substituted phenyl cyclohexenyl or cyclohexadienyl, X represents S, and y represents the group 14 ?H2 ^-ch2-t COOH in which the carbon atom which carries the carboxyl group is bonded to the nitrogen atom of the β-lactam ring, and T denotes hydrogen, alkyl-CO-Ο-, pyridinium, aminopyridinium, carbamoyloxy, azido, cyano, hydroxyl, the -S-phenyl group, which can be substituted, or the -S-Het group, in which Het represents an optionally substituted heterocyclic 5membered or 6-membered ring; it being possible for these compounds of the formula I to be present in the two possible R- and S-configurations of the chirality centre C*, as well as in the form of mixtures of the diastereomers resulting therefrom, it also being possible for the compounds of the formula I, if Z represents the group C=N1 2 and R and Rz are different, to be present in the syn20 form or in the anti-form with regard to the imino group, and it further being possible for these compounds of the formula X also to be present in the various hydrate forms, 42814 - 5 and their salts. The compounds of the invention i.e. the compounds of the formula I and their salts exhibit powerful anti-bacterial properties and possess the property of improving the growth and feedstuff utilisation of animals Of the compounds of the invention which are salts therefore, those which are pharmaceutially acceptable are more important and are preferred.

The compounds of the invention may be obtained by reacting compounds of the formula II R in which R, B, C, X and Y have the abovementioned meaning, or their salts, with compounds of the formula III Z-N N-CO-W (III) in which Z and A have the abovementioned meaning and W represents halogen, azido or another leaving group which is eliminated under the reaction conditions, in the presence of a solvent and optionally of an acidbinding agent, at temperatures of from -20°C to +50°C, and the resulting β-lactam antibiotics are optionally converted into their salts, or, if desired, the free acids are prepared from the salts obtained.

Surprisingly, the compounds according to the invention exhibit a substantially greater and above all broader antibacterial action, that is to say an action against more families of bacteria of the Gram-negative type, than, for example, the β-lactam antibiotics known from the state of the art. The compounds according to the invention thus represent an enrichment of pharmacy.

If, for example, a D-a-aminobenzylcephalosporin and l-chlorocarbonyl-3-benzylidenimino-imidazolidin-2-one are used as starting materials, the course of the reaction can be represented by the following equation: . CO, / x . />-CH=N-N N-C0-C1 + ff \_J (R) ,/-CH-CO-NH\ V I NH2 nZ COOH Tetrahydrofuran/H^O 0-20uC pH = 6.5 - 7.5 COOH In the general formulae, optionally substituted alkyl R1 and R2 is straight-chain or branched alkyl with, preferably, 1 to 6, especially 1 to 4, carbon atoms. Optionally substituted methyl, ethyl, n- and i-propyl and η-, i- and t-butyl may be mentioned as examples. - 7 1 2 Optionally substituted alkenyl R and R is straight chain or branched alkenyl with, preferably, 2 to 6, especially 2 to 4, carbon atoms. Optionally substituted ethenyl, propenyl-(1), propenyl-(2) ai,d butenyl-(3) may be mentioned as examples.

Optionally substituted cycloalkyl, cycloalkenyl 1 2 and cycloalkadienyl R and R is monocyclic, bicyclic and tricyclic and preferably contains 3 to 10, especially 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.T7-heptyl, bicyclo-/2~.2.27~octyl and adamantyl. 2 Optionally substituted aryl R and R is aryl with, preferably, 6 to 10 carbon atoms in the aryl part. Optionally substituted phenyl or naphthyl may be mentioned as examples. Substituents in the phenyl ring are in the ο-, m- or p-position. Further, the radicals may be mentioned. 2 Optionally substituted aralkyl R and R is aralkyl which is optionally substituted in the aryl part and/or alkyl part and which has preferably 6 or 10, especially 6, carbon atoms in the aryl part and preferably 1 to 4, especially 1 or 2, carbon atoms in the alkyl part, and wherein the alkyl part may be straight-chain or branched. Optionally substituted benzyl and phenylethyl may be mentioned as examples. 2 Optionally substituted heterocyclyl R and R are hetero-saturated, hetero-aromatic or hetero-unsaturated 43814 - 8 5-membered to 7-membered, preferably 5-membered or 6membered, rings with, preferably, 1 to 3, especially 1 or 2, identical or different hetero-atoms. Hetero-atoms are oxygen, sulphur or nitrogen. Optionally substituted thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxdiazolyl, thiadiazolyl, triazolyl, oxatriazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, tetrahydrofuranyl, dioxanyl, pyrrolidinyl, piperidinyl, morpholinyl, pyronyl-2 and pyronyl-4 may be mentioned as examples.

Alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalka 12 dienyl, aryl and aralkyl R and R can carry one or more, preferably 1 to 3, especially 1 or 2, identical or different radicals R . It is very particularly preferred 1 2 that the said radicals R and R should be unsubstituted or contain one substituent. 2 Heterocyclyl R and R can carry one or more, preferably 1 to 3, especially 1 or 2, identical or different radicals R . It is very particularly preferred 1 2 that heterocyclyl R and R should be unsubstituted or 4 contain one substituent R .

In the explanations which follow, the term lower alkyl11 denotes throughout also in conjunction with other atoms or group (for example lower alkoxy, HCON-(lower alkyl), and the like), straight-chain or branched alkyl with preferably 1 to 6, especially 1 to 4, carbon atoms. Optionally substituted methyl, ethyl, n- and i-propyl and η-, i- and t-butyl may be mentioned as examples. Lower alkyl can be substituted by 1 to 5, especially 1 to 3, identical or different halogen atoms, the halogen atoms preferably being fluorine, chlorine and bromine especially fluorine and chlorine. Trifluoromethyl, chlorodifluoromethyl, bromomethyl, 2,2,2-trifluoroethyl and pentafluoroethyl may be mentioned as examples. *3814 - 9 3 R preferably denotes halogen, preferably fluorine, chlorine, bromine and iodine, especially fluorine, chlorine and bromine; amino; mono-lower alkylamino, preferably methylamino and ethylamino, and especially methylamino,di-lower alkylamino, preferably dimethylamino and diethylamino, especially dimethylamino; pyrrolidinyl; piperidinyl; HCO-NH-; lower alkyl-CO-NH-; preferably CH^-CO-NH-; H-C0-N(lower alkyl)- i preferably H-CON(CH3)- or H-CO-N^Hg) -; lower alkyl-CO-N( lower alkyl)-; preferably CH^-CO-N(CH^)-; (lower alkyl)2C=N-; lower alkyl-SO2-NH-, preferably CH3-SO2-NH- and C2H5“ SO2~NH-, and especially 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)- and HO-SO2-N(C2H5)-; amidino; (lower alkyl)^N-CH=K-, especially (CH3)2N-CH=N-; j^^N-CII=Nguanidino, nitro, azido, hydroxyl, lower alkoxy, preferably CH3-O- and C2Hg-O-, especially CHgO-; H-CO-O-; lower alkyl-CO-Ο-, preferably CHj-CO-O, CgHg-CO-O- and (CH3)3C-CO-O-; lower alkyl-O-CO-O-, preferably CHj-O-CO0-, C2H5-O-CO-O- and (CH3)3C-O-CO-O-; H2N-CO-O-; lower alkyl-NH-CO-O, preferably CH3-NH-CO-O- and CjHg-NH-CO-O-; (lower alkyl)2N-CO-O-, preferably (CH3)2N-CO-O-, (c2h5)2n-co-o-, £^\l-C0-0and H2N-SO2~O-; lower alkyl-NH-SO2-O-, preferably CHj-NHS02~0- and C2H5-NH-SO2-O-; (lower alkyl)2N-SO2~O-, preferably (O^N-SC^-O and (C2H5)2N-SO2-O-; HOOC- and 814 - 10 H^N-CO- ; (lower alkyl)2N-CO-, especially (CH3)2N-COand (C2H5)2N-CO-; OHC-j HO-SO2~Oand HS-; lower alkyl-S-, preferably CH3-S-, CF3-S~, C2Hs-S- and (CHg)2CH-S-j lower alkyl-S-, preferably CH,-S- and C0H,--S-; HO,S-; lower alkyl-SO--, ! J preferably CHj-SOj-, CF3SO2- and C2H5-S02-j the group H2N-SO2~; lower alkyl-NH-SO2-, preferably GHj-NH-SOjand CjHg-NH-SOj-; (lower alkyl)2U-SO2-, preferably (CH3)2N-SO2- and (C2H5) 2N-SO2-,xo 0^’ the HO-SO2-S- group; 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; furyl-2, and phenyl or phenoxy.

In. the case where R is present on one or more i 2 4 carbon atoms in the heterocyclyl radical R and R , R preferably denotes lower alkyl, preferably methyl, ethyl and isopropyl and especially methyl; cycloalkyl with 3 to 7, preferably 3 to 6, carbon atoms, especially cyclopropyl; the trifluoromethyl group; halogen, preferably fluorine, chlorine or bromine; nitro; amino; lower alkylamino, preferably CH3-NH- and C2Hg-NH~; dilower alkylamino, preferably (CH3)2N- and (C^HgJ-jN-; formylamino; acetylamino; CH3~O-CO-NH- and CjHgO-CO-NH-; >5 CH3-SO2-NH-; hydroxyl, methoxy and ethoxy; methylthio and ethylthio; CH3-SO2-; CHg-SO-; lower alkyl-NH-SO2“, preferably CH3-NH-SO2-; lower alkoxy-CH2-, especially CH3O-CH2~ and C2HgO-CH2-; heterocyclyl-aldimino (heterocyclyl being defined as for R1 and R2), especially furyl1 2 2-aldimino; alkenyl (defined as for R and R ), especially allyl; and CH=CHthe groups H00C-; HOgS-; lower alkyl-NHSO^-f especially CHj-NH-SOj-; (lower alkyl)2NSO2-, especially (CH3)2NSO2~5 HCO-; lower alkyl-CO-, preferably CH^-CO-; lower alkyl0-C0-, preferably CHg-O-CO- and CgHgO-CO-; and -CN, lower alkyl-O-CO-CH2-, preferably CH3-O-COCH2“ or C2H5OCOCH2~; (lower alkyl-O)2CH-, preferably (C2HgO)2CH-; HO-lower alkyl-, preferably HO-CH,-, (CH,),C- and Z J Z | OH CH,-CH-; thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, J I OH isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxatriazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, tetrahydrofuranyl, dioxanyl, pyrrolidinyl, piperidinyl and morpholinyl, preferably furyl.

In the case where R is present as a substituent on one or more nitrogen atoms in a nitrogen-containing 1 2 4 heterocyclyl radical R and R , R preferably denotes lower alkyl, preferably methyl, ethyl, propyl and isopropyl, especially methyl and ethyl; the -C^N group; -CHO; -COO-lower alkyl, preferably -COO-CH3, -COOCgHg, -COOCH(CH3)2 and -COO-C(CH3)3; -CO-NH2; -CO-NH-lower alkyl, preferably -CO-NH-CH3, -CO-NH-C2H5 and -CO-NHCH(CH3)2; and -CO-lower alkyl, preferably -CO-CH3, -CO-C2H5 and -CO-CH(CH3)2. 2 The rings which may be formed by R and R conjointly with the carbon atom to which they are bonded are saturated or unsaturated. Unsaturated rings preferably contain 1 or 2 double bonds. The rings can contain 1 or more, preferably 1 or 2, especially 1, hetero-atom or hetero-group. Oxygen, sulphur and/or nitrogen may be mentioned as hetero-atoms. Examples of hetero-groups which may be mentioned are the S02~ group as well as the lower alkyl-N-group, and in the case of 6-membered rings preferably one hetero-atom or one hetero-group is in the 4-position (relative to the carbon atom to which R1 and 2 R are bonded). The following may be mentioned as particularly preferred rings: h3c CH, |j>= ' , S lower alkyl -N and lower °2 • ( ' S ' °2S alkyl 2 The rings which are formed by R and R conjointly with the carbon atom to which they are bonded can contain one or more, preferably 1 to 3, especially 1 or 2, identical or different substituents R . R preferably denotes halogen, preferably fluorine, chlorine and bromine; hydroxyl; lower alkoxy, preferably methoxy and ethoxy; lower alkylthio, preferably methylthio and ethylthio; amino lower alkylamino, preferably CH^-NH- and C2Hg-NH-; dilower alkylamino, preferably dimethylamino and diethylamino; the -CN; -COOH; -COOCH^ and -COC^Hg groups; and straight-chain or branched lower alkyl, preferably methyl and ethyl.

Particularly preferentially, at least one of the 1 2 radicals R and R represents hydrogen.

Particularly preferentially, Z represents the R. '1 C=N~ R' ,2 group. 2 Compounds which contain the radical R R C-NHOH are produced when this radical is already contained in the compounds of the formula III, or can be produced if the reaction is carried out in aqueous solvents.

Phenyl B can carry one or more, preferably 1 to 3, especially 1 or 2, identical or different substituents.

The substituents can be in the 0-, m- and/or p-position. Preferably, one substituent is in the p- or m-position. Examples of substituents which may be mentioned are halogen, such as flourine, chlorine, bromine and iodine; preferably fluorine, chlorine and bromine; alkyl with 1 to 6, preferably 1 to 4, especially 1 or 2, carbon atoms; cyano and methylsulphonyl. Substituted phenyl radicals B - 14 which may be mentioned in particular are the hydroxyphenyl radical (preferably p-hydroxyphenyl), the methylphenyl radical (preferably p-methylphenyl), the cyanophenyl radical (preferably m- and p-cyanophenyl), the methylsulpho nyl radical (preferably p-methylsulphonylphenyl) and the fluorophenyl radical (preferably o-fluorophenyl and mfluorophenyl).

In the definition of T, alkyl in alkyl-CO-O-preferably denotes alkyl with 1 to 4, especially 1 or 2, carbon atoms. Examples which may be mentioned are methyl and ethyl, methyl being particularly preferred.

The heterocyclic ring Het in -S-Het (definition of T) consists of 5 or 6 ring members and contains 1 to 4, preferably 1 to 3, identical or different hetero-atoms, the hetero-atoms being oxygen, sulphur and nitrogen. Preferably, the heterocylcic ring is unsaturated, and particularly preferentially contains 2 double bonds. The heterocyclic ring can contain one or more, preferably 1 or 2, especially 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, preferably 5 or 6, carbon atoms in the cycloalkyl part), lower alkoxy (for the meaning of lower alkyl, see above), trifluoromethyl, phenyl, benzyl and acylamino with, preferably, 2 to 5, especially 2 or 3, carbon atoms. The following may be mentioned as particularly preferred meanings of -S-Het: CH, z NN '3 CH.

— S.

S. ch3 The -S-phenyl radical in the definition of T can carry one or more, preferably 1 to 3, especially 1 or 2, identical or different substituents, preferred substituents being those which are listed above as possible substituents of the radical -S-Het. 4c Compounds according to the invention in which C is in the D- = R-configuration are very particularly preferred.

All crystal forms and hydrate forms of the compounds 10 according to the invention, of the general formula I, and of their salts, are anti-bacterially active in the same way.

Halogen W represents fluorine, chlorine and bromine, preferably bromine or chlorine, especially chlorine.

Leaving groups in the definition of W are to be 15 understood as all nucleofugic groups usually employed in organic chemistry (i.e. leaving groups which can be eliminated under the reaction conditions) and above all those which are described in Angewandte Chemie, 81 (1969), page 543.

Non-toxic, pharmaceutically tolerated salts of the compounds of the formula X are salts of these compounds with inorganic and organic bases at the acid carboxyl group or at the acid carboxyl and sulphonic acid groups. Bases 3814 which can. be employed for this purpose are all bases usually employed in pharmaceutical chemistry especially in the chemistry of the antibiotics. Examples of inorganic bases which may be mentioned are alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates and alkali metal bicarbonates, such as sodium hydroxide and potassium hydroxide, calcium hydroxide and magnesium hydroxide, sodium carbonate and potassium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate; aluminium hydroxide and ammonium hydroxide. As organic amines it is possible to use primary, secondary and tertiary aliphatic amines as well as heterocyclic amines. Examples which may be mentioned are: di- and tri-lower alkylamines, for example N,N'dibenzylethylenediamine. N-benzyl-g-phenylethylamine, N-methylmorpholine and N-ethylmorpholine, 1-ephenamine, dehydroabietylamine, N,N'-bis-dehydroabietylethylenediamine, and N-lower alkylpiperidine. So-called basic aminoacids such as lysine or arginine can also be used advantageously as bases. Particularly preferred salts are the sodium salts.

Very particularly preferred compounds of the formula I are those in which the definition of the radicals is as follows.

R represents hydrogen; Z represents the groups RR' ,1 ,1 C=Nor R‘ ,2 R' ,2 OH wherein R1 denotes hydrogen; and denotes phenyl which is optionally substituted by R 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 CH^OOC-? or furyl or thienyl which are optionally substituted, preferably in the 4- or 5- position, by halogen (especially chlorine or bromine), N02, alkyl or alkoxycarbonyl with 1 to 4 carbon atoms or CHjCOOCI^-, the furyl and thienyl ring preferably being bonded in the 2- and 3position; or pyridyl (preferably pyridyl-3); and A represents -CHj-CHj-? and B represents phenyl, hydroxyphenyl (preferably phydroxyphenyl) or cyclohexadienyl (preferably cyclohexa-l,4-dien-l-yl); and Y represents the group CH. '2 c-ch2-t COOH wherein T represents hydrogen, -O-CO-CH^, hydroxyl or thiadiazolylthio or tetrazolylthio which is optionally substituted by alkyl with 1 to 4 carbon atoms or CF^; and ★ C is in the D- = R-configuration; as well as the sodium salts of these compounds.

The compounds of the general formula II used as starting materials are already known or are obtainable according to known methods.

All crystal forms, hydrate forms and salts of the compounds of the general formula II are suitable for use as starting materials for the process according to the invention.

Examples which may be mentioned are 7~(a~amino10 phenylacetamido)-3-methyl-ceph-3-em-4-carboxylic acid and 7-(α-amino-phenylacetamido)-3-acetoxymethyl-ceph-3-em4-carboxylic acid.

As salts of the compounds of the formula II it is preferably possible to employ salts with bases which have been listed as being suitable for forming salts with compounds of the formula I. The sodium salts are particularly preferred.

The compounds of the general formula III used as starting materials are obtainable according to known methods They can be obtained, for example, in the following manner (compare also J. A. C. S. 78, (1956) 5349): 3 8 11 /C0\ _^JH NaNO2/H (+) CO / \ O=N-^_ sT-/ CO Zn/H (+) H2N-N NH /ncc2h5)3 βΐ4 - 20 The following may be mentioned as examples of starting compounds according to the invention, of the general formula III: 1-chlorocarbonyl-2-oxo-3-benzalimino-imidazolidine, l-azidocarbonyl-2-oxo-3-benzaliminoimidazolidine, l-chlorocarbonyl-2-oxo-3-(4-chloro)benzalimino-imidazolidine, l-chlorocarbonyl-2-oxo-3(4-methoxy)benzalimino-imidazolidine, 1-chlorocarbonyl2-ΟΧΟ-3-(4-nitro)benzalimino-imidazolidine, 1-chlorocarbonyl-2-oxo-3-(4-cyano)benzalimino-imidazolidine 1- chlorocarbonyl-2-oxo-3-(4-methylsulphonyl)benzaliminoimidazolidine, l-chlorocarbonyl-2-oxo-3-(thiophen-2aldimino)-imidazolidine, l-azidocarbonyl-2-oxo-3-(thiophen- 2 -aldimino) -imidazolidine, l-chlorocarbonyl-2-oxo-3(furan-2-aldimino)-imidazolidine and 1-azidocarbonyl2- ΟΧΟ-3-(furan-2-aldimino)-imidazolidine.

Those compounds of the general formula III in which W is azide are obtained in the usual manner, for example from the corresponding compounds III, in which W is halogen, by reaction with, for example, alkali metal azides.

Diluents which can be used in the process according to the invention are water and all inert organic solvents, preferably those which are water-miscible. These include, above all, lower dialkyl ketones, for example acetone and methyl ethyl ketone, and cyclic ethers, for example tetrahydrofuran and dioxane; nitriles, for example acetonitrile; lower dialkylformamides, for example dimethylformamide; lower alkyl alcohols, for example ethanol and isopropanol, as well as dimethylsulphoxide. These solvents can also be used as mixtures with one another and also as any desired mixtures of one or more of these solvents with water. The process according to the invention can thus be carried out in the presence of (a) exclusively water, (b) exclusively one or more organic solvents or (c) water and one or more organic solvents.

If, because of the presence of water, it is possible to measure the pH during the reaction according to the invention, the pH of the reaction mixture is preferably kept at between 5.5 and 7.5 by adding bases or by using buffer mixtures. The process according to the invention can, however, also be carried out very readily in a different pH range, for example between 4.5 and 9.0, or at pH 2.0 to 4.5. Furthermore it is possible to carry out the reaction in water-immiscible solvents, for example halogenated hydrocarbons, such as chloroform or methylene chloride, with the addition of organic bases, preferably lower alkylamines, for example triethylamine or diethylamine, or cyclic bases, for example N-ethylpiperidine. The reaction can also be carried out in a mixture of water and a waterimmiscible solvent such as, for example, lower alkyl ethers, such as diethyl ether; halogenated hydrocarbons, such as chloroform and methylene chloride; carbon disulphide; isobutyl methyl ketone; esters, such as ethyl acetate; and aromatic hydrocarbons, such as benzene; in these cases it is advisable to stir the mixture vigorously and to keep the pH value between 4.5 and 9.0 or, for example, 2.0 and 4.5, by adding bases or by using customary buffer solutions, for example phosphate, acetate or citrate buffers. The reaction can, however, also be carried out in water alone, in the absence of organic solvents, in the presence of an organic or inorganic base, or with addition of customary buffer substances.

All acid-binders usually employed in the chemistry of the antibiotics can be used as the acid-binding agents. These include inorganic bases and organic bases which are difficult to acylate, for example as a result of steric hindrance. Sodium hydroxide and potassium hydroxide may be mentioned as examples of inorganic bases. Organic bases which can be used are practically all open-chain or cyclic amines, and also hetero-aromatic bases, which cannot be acylated or are difficult to acylate. Examples of bases which may be mentioned are tertiary amines, preferably lower alkylamines, for example triethylamine and/or cyclic bases, for example pyridine, and, as a secondary amine which is difficult to acylate, dlcyclohexylamine.

The addition of a base in the process according to the invention is only necessary if acid compounds are produced during the reaction, for example if W represents halogen or azide.

The reaction temperatures can be varied within a substantial range. In general, the reaction is carried out between -20°C and +50°C, preferably between 0 and +20°C. However, as with most chemical reactions, higher or lower temperatures can also be used in principle.

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

In carrying out the processes according to the invention, the proportions of the reactants of the formula II and III can be varied within wide limits without adversely influencing the result. For example, the starting materials can be reacted with one another in equimolecular amounts. However, it can be expedient to use one of the two reactants in excess in order to facilitate the purification, or preparation in a pure form, of the desired cephalosporin, and to increase the yield.

For example, the reactants of the general formula II can be employed in an excess of 0.1 to 0.3 mol equivalents and diminished decomposition of the reactants of the general formula III in an aqueous solvent mixture can thereby be achieved. The excess of the reactants of the general formula II can easily be removed on working up the reaction mixture, because of the ready solubility in aqueous mineral acids.

On the other hand, however, it is also possible, with advantage, to employ the reactants of the general 3 8 1 4 formula II in an excess of, for example, 0.1 to 1.0 mol equivalent. This results in better utilisation of the reactants of the general formula II and compensates for the decomposition of the reactants of the general formula III which takes place as a side-reaction in aqueous solvents. Since the compounds of the general formula III added in excess are rapidly converted, in water, to neutral nitrogen-containing heterocyclic compounds, which can easily be removed, the purity of the antibiotics is hardly impaired thereby.

The amount of the bases which may be used is decided, for example, by the desired maintenance of a particular pH value. Where a pH measurement and adjustment is not carried out, or is not possible, or not meaningful, because of the absence of sufficient amounts of water in the diluent, 2 mol equivalents of base are preferably added.

The working up of the reaction batches in order to prepare the compounds according to the invention and their salts is throughout carried out in the manner generally known for these compounds. The isolation and purification of the compounds according to the invention, and the liberation of the free acids from salts or the conversion of the free acids into salts are also carried out in accordance with generally customary methods of organic chemistry which are familiar to any expert.

The compounds of the general formula I, in the form of the free acid, have the same type of anti-bacterial action whether they are crystalline or amorphous and whether they are anhydrous or in various hydrated forms. Equally, the compounds of the general formula I have the same type of anti-bacterial action in the form of their salts, for example the sodium salts, whether they are crystalline or amorphous and whether they are anhydrous or contain water, for example through being in the form of a hydrate. 438 14 The compounds identified in the following table are Examples of new active compounds.

TABLE A.

(R) •C=N-N N-CO-NH-CH-CO-NH· ' V_/ I B Z 0 n COOH :h2t (B) (V) (Β) I) R represents hydrogen; T represents -O-COCH^ „2 „ (1) H (2) 4-C1 (3) 4-CH3O (4) 4-NO2 (5) 4-CN (6) 4-CH3SO, (7) 4-CH3SO, 4-HO 3 8 14 - 25 (B) lb) r7 (1) Η (2) Η (3) Η (4) Η (5) Η (6) Η (7) Η (8) Η (9) Η (10) Η (11) Η (12) Η (13) Η (14) Η (15) Η (16) Η (17) Η (18) Η (19) Η (20) Η (21) Η (22) Η χ υ3 7 r CH3OCH2C2HSOCH2 (Ο2Η5°)2ΟΗ ch3s ch3° c2h5° 0HCo2n CH3SO2 CH3CO CH3OCOCH2 ch3oco c2h5oco F Cl Br H H H H H H H H H H H H H H H H H H H H H -OH 4381426 (23) Η ch3so2nh Η (24)i-C3H7 Η Η (25) Η hoch2 Η (26) Η ch3nhso2 Η (27) Η Η (28) Η C- Η (Β) II) R1 represents hydrogen; Β represents phenyl: Τ represents -O-CO-CH3; 2 R represents: (1) (2) (3) (4) fl Xi - n k N ii . n (5) (6) (7) CH3 (8) Q ’ a , o a (9) (10) (11) (12) Br u Λ—f ; lx o ' X Ν' jct η3Λ°- - 27 (13) (14) (15) ¢16) 0H3 (17) (18) (19) (20) (21) (22) (23) (24) (Β) ί-Ο^Ηγ; Ill) Β CH3-CH=CH (CH3)2NCO-; represents phenyl; T represents -O-CO-CH3 (1) ch3 (2) CH3 (3) 0 0 oA (4) CF3 (5) Cyclohexyl ch3 CO43814 (Β) IV) Β represents cyclohexa-l,4-dien-l-yl; Τ represents -O-COCH^ (1) H (2) H (3) H 4-ΟΗ3Ο°6Η4 4-CH3SO2CgH4 (Β) V) B represents phenyl; T represents -O-COCH3 C=N- represents: (Β) VI) R1 R2 (1) Η C6H5 OH (2) Η C6H5 OH (3) Η C6H5 OH CH-S (4) Η Cyclohexa-l,4-dien-l-yl H (Β) VII) B represents phenyl ; R1 C=N- The active compounds according to the invention couple a low toxicity with a strong and broad antimicrobial activity. These properties permit their use as chemotherapeutic active compounds in medicine and as compounds for preserving inorganic and organic materials, in particular organic materials of all kinds, for example polymers, lubricants, paints, fibres, leather, paper and timber, foodstuffs and water.

The active compounds according to the invention are active against a very broad spectrum of microorganisms. They can be used to combat Gram-negative and Gram-positive bacteria and bacteria-like micro-organisms and to prevent, ameliorate and/or heal illnesses caused by these pathogens.

The active compounds according to the invention are particularly active against bacteria and bacterialike micro-organisms. They are therefore particularly suitable for the prophylaxis and chemotherapy of local and systemic infections, caused by these pathogens, in human medicine and veterinary medicine.

For example, local and/or systemic illnesses caused by the following pathogens or by mixtures of the following pathogens can be treated and/or prevented: Micrococcaceae, such as Staphylococci, for example Staphylococcus aureus, Staph, epidermidis, Staph, aerogenes and Gaffkya tetragena (Staph. = Staphylococcus); Lactobacteriaceae, such as Streptococci, for example Streptococcus pyogenes, a- or (3-haemolytic Streptococci, non-(γ)-haemolytic Streptococci, Str. viridans, Str. faecalis (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. pyogenes, C. diphtheroides, C acnes, C. parvum, C. bovis, C. renale, C. ovis and - 31 C. murisepticum, Listeria bacteria, for example Listeria monocytogenes, Erysipelothrix bacteria, for example Erysipelothrix insidiosa and Kurthia bacteria, for example Kurthia zopfii (C. = Corynebacterium); Mycobacteriaceae, such as pathogens of mycobacterioses, for example Mycobacterium tuberculosis, M. bovis, M. avium, and so-called atypical mycobacteria of the Runyon groups I, II, III and IV, and M. leprae (M. = Mycobacterium); Enterobacteriaceae, such as Escherichiae bacteria of the Coli group: Escherichia bacteria, for example Escherichia coli, Enterobacteria, for example E. aerogenes and E. cloacae, Klebsiella bacteria, for example K. pneumoniae, and K. ozaenae, Erwiniae, for example Erwinia spec., Serratia, for example Serratia marcescens (E, = Enterobacter) (K. = Klebsiella), Proteae bacteria of the Proteus group: Proteus, for example Proteus vulgaris, Pr. morganii, Pr. rettgeri and Pr. mirabilis, Providencia, for example Providencia sp. (Pr.

= Proteus), Salmonelleae: Salmonella bacteria, for example Salmonella paratyphi A and B, S. typhi, S. enteritidis, S. cholerae suis and S. typhi murium (S. = Salmonella, and Shigella bacteria, for example Shigella dysenteriae, Sh. ambigua, Sh. flexneri, Sh. boydii and Sh. sonnei (Sh. = Shigella); Pseudomonadaceae, such as Pseudomonas bacteria, for example Pseudomonas aeruginosa and Ps. pseudomallei (Ps. = Pseudomonas), and Aeromonas bacteria, for example Aeromonas liguefaciens and A. hydrophilia (A. = Aeromonas); Spirillaceae, such as Vibro bacteria, for example Vibrio cholerae, V. proteus and V. fetus (V = Vibrio), and Spirillum bacteria, for example Spirillum minus; Parvobacteriaceae or Brucellaceae, such as Pasteurella bacteria, for example Pasteurella multocida, Past, pestis (Yersinia), Past, pseudotuberculosis and Past. tularensis (Past. = Pasteurella), Brucella bacteria, for example Brucella abortus, Br. melitensis and Br. suis (Br. = Brucella), Haemophilus bacteria, for example Haemophilius influenzae, H. ducreyi, H. suis, H. canis and H. aegypitcus (H. = Haemophilius), Bordetella bacteria, for example Bordetella pertussis and B. Bronchiseptica (B. = Bordetella) and Moraxella bacteria, for example Moraxella lacunata; Bacterioidaceae, 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 organisms, for example Bacillus anthracis (B. subtilis and B. cereus) (B. = Bacillus) and anaerobic spore-forming Clostridia, for example Clostridium perfringens, Cl. septicium, Cl. oedematien, Cl. histolyticum, Cl. tetani and Cl. botulinum (Cl. = Clostridium); Spirochaetaceae, such as Borrelia bacteria, for example Borrelia recurrentia and B. vincentii (B. = Borrelia), Treponema bacteria, for example Treponema pallidum, Tr.. pertinue and Tr. carateum (Tr. = Treponema) and Leptospira bacteria - Leptospira interrogans, for example Leptospira icterohaemorrhagiae, L. canicola, L. grippotyphosa, L. pomona, L. mitis and L. bovis (L. = Leptospira); The above list of pathogens is purely illustrative and is in no way to be interpreted as restrictive.

The following may be mentioned as examples of illnesses which can be prevented, ameliotated and/or healed by the active compounds according to the invention.

Illnesses of the respiratory passages and of the pharyngeal cavity; otitis; pharyngitis; pneumonia; - 33 peritonitis; pyelonephritis; cystitis; endocarditis; systemic infections; bronchitis; arthritis; local infections.

The present invention provides a pharmaceutical composition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence of a surface active agent.

The invention further provides a pharmaceutical composition containing as active ingredient a compound of the invention in the form of a sterile or isotonic aqueous solution.

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

The invention also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a compound of 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 portions 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 of the invention. 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 respecti35 vely. - 34 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, glycerol monostearate; (h) adsorptive carriers, e.g. kaolin and bentonite; (i) lubricants, e.g. talc, calcium and magnesium stearates 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 or several of the abovementioned 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 C^g-fatty acidj) 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 (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), 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-butane diol, dimethylformamide, oils /for example ground nut oil/, 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, bloodisotonic.

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 sorbite 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 preferably contain about 0.1 to 99.5, more preferably from about 0.5 to 95% of the active ingredient by weight of the total composition.

In addition to a compound of 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 of 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 200 as sole diluent.

The discrete coherent portions constituting the medicament according to the invention (whether in dosage unit form or not) 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 50 mg to 25 g of active ingredient.

The production of the above-mentioned pharmaceutical - 37 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 administering to the animals a compound of 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 orally or parenterally.

Preferred pharmaceutical compositions and medicaments are therefore those adapted for oral and parenteral administration.

The invention also includes, for use in veterinary nedicine, medicated fodder comprising a compound 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, exhausted sugar beet chips, silage, hay and skimmed milk.

In general it has proved advantageous both in human medicine and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of from 5 to 1,000, preferably 20 to 300, mg/kg of body weight every 24 hours, optionally in the form of several individual administrations, in order to achieve the desired results. An individual administration contains the active compound or the active compounds according to the invention, preferably in amounts of from 1 to 250, especially of 10 to 100, 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 body weight of the subject to be treated, the nature and the severity of the illness, the nature of the preparation 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 above-mentioned amount of active compound whilst in other cases the abovementioned amount of active compound must be exceeded.

The particular required optimum dosage and the type of administration of the active compounds can easily be decided by anyone skilled in the art, on the basis of his expert knowledge.

When used as additives to feedstuffs, the new compounds, in the usual concentrations and preparations, can be administered together with the feedstuff or the feedstuff preparations, or in the drinking water. By this means, an infection by Gram-negative or Gram-positive bacteria can be prevented, ameliorated and/or cured and equally a promotion of growth and improvement of feedstuff utulisation can be achieved.

The new cephalosporins are distinguished by strong antibacterial effects, which were demonstrated in vivo and in vitro, and by oral resorbability.

The cephalosporins according to the invention can, in order to broaden the spectrum of action and to achieve a boosting of the action, especially in the case of β-lactamase-forming bacteria, be combined with other antimicrobial active compounds, for example with penicillins which are particularly penicillinaseresistant. An example of such a combination would be a combination with oxacillin or dicloxacillin.

To broaden the spectrum of action and to achieve a boosting of the action, the- cephalosporins according to the invention can also be combined with 3 8 14 amino-glycoside antibiotics, such as, for example. Gentamicin, Sisomicin, Kanamicin, Amikacin or Tobramicin.

The activity of the β-lactam antibiotics 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 1.3., 2.3. and 2.4., which can be regarded as typical representatives of the compounds according to the invention, were diluted with Muller-Hinton nutrient broth, with addition of 0.1% of glucose, to a content of 100 ug/ml. In each case, the nutrient solution 5 5 contained 1 x 10 to 2 x 10 bacteria per millilitre. The tubes containing this mixture were in each case incubated for 24 hours and the turbidity was then determined. Freedom from turbidity indicates that the compound is active. At a dosage of 100 ug/ml the following bacterial cultures were free from turbidity (sp. = species): Klebsiella pneumoniae; Enterobacter aerogenes sp.; Providencia; Serratia marcescens; E.coli BE; Salmonella sp.; Shigella sp.; Proteus, indole-negative and indolepositive; Pasteurella pseudotuberculosis; Brucella sp.; Haemophilus influenzae; Bordetella bronchiseptica; Staphylococcus aureus 133; Neisseria catarrhalis sp; Diplococcus pneumoniae sp.; Streptococcus pyogenes W.; Enterococcus sp.; Lactobacillus sp.; Corynebacterium diphteriae gravis; Corynebacterium pyogenes M; Clostridium tetani; Pseudomonas aeruginosa sp.; Bacteroides fragilis sp.; 2. In vivo experiments Table 1 which follows shows the action of one of the compounds according to the invention against a range of bacteria in animal experiments with white mice. The - 40 white mice, of the CF^ strain, were infected intraperitoneally with the species of bacteria stated in each case.

Table 1.

Animal experiments with white mice.

Determination of the Εϋ^θθ after 24 hours Germ Dose in mg of the β-lactam antibiotic from Examples 1.3., 2.3. and 2.4. per kg of body weight (administered subcutaneously) Escherichia coli C 165 2 x 150 Klebsiella 63 2 x 150 Therapy: administered twice, 30 and 90 minutes after infection. The Ed^0Q is the dose at which 100% of the infected animals still survive after 24 hours.

The process according to the invention is illustrated 10 by the examples which follow.

The 7-(α-amino-phenylacetamido)-3-methyl-ceph-3em-4-carboxylic acid used in the examples contained about 5% of water but anhydrous 7-(α-aminophenylacetamido)-3methyl-ceph-3-em-4-carboxylic acid can be used equally well.

The 7-(α-amino-phenylacetamido)-3-acetoxymethylceph-3-em-4-carboxylic acid used in the examples contained 8% of water but anhydrous 7-(a-amino-phenylacetamido) -3-acetoxymethyl-ceph-3-em-4-carboxylic acid can be used equally well.

The water content of the starting compounds is immaterial with regard to carrying out the process according to the invention.

Cefalexin denotes the particular 7~(a-aminophenylacetamido)-3-methyl-ceph-3~em-4-carboxylic acid with the D = R-configuration in the side chain and cephaloglycine denotes the particular 7-(a-aminophenylacetamido)-3-acetoxymethyl-ceph-3-em-4-carboxylic acid with the D = R-configuration in the side chain.

The NMR spectra of the compounds according to the invention were recorded in CD3OD solution, unless stated otherwise. The designation in brackets denotes the following: s = singlet q = quartet d = doublet m = multiplet t = triplet AB = AB system The IR spectra of the compounds according to the invention were recorded in paraffin oil suspensions, unless stated otherwise.

Explanation of the abbreviations used in the examples: vol. pts. by wt. pts. by vol. hrs. hr.

THF DMF ether = volume = parts by weight = parts by volume - hours = hour = tetrahydrofuran = dimethylformamide = diethyl ether room temperature = approx. 20°C abs. = absolute dec. pt. = decomposition point The yields quoted in % denote yields in % of theory. - 42 Insert Β Preliminary examples A, B and C, which do not relate to compounds of the invention, are given here to illustrate procedures used in some of the subsequent numbered examples and indicated therein only by reference to examples A, B and C.

Example A.

Ampicillin (14 pts. by wt.) is suspended in 80% strength aqueous tetrahydrofuran (140 pts. by vol.) and dissolved by means of the minimum amount of triethylamine required (the pH is then 8.0); l-chlorocarbonyl-2-oxo-3-benza!iminoimidazolidine (7.8 pts. by wt.) (see example 1.2.) is introduced slowly, whilst stirring, and at the same time the pH is kept at 7.0 - 7.5 by appropriate addition of triethylamine. The mixture is then stirred further for as long as triethylamine still has to be added in order to maintain the stated pH range (about 1-2 hrs.). The mixture is diluted with water (200 pts. by vol.), the pH is adjusted to 6.5, the tetrahydrofuran is largely evaporated off in vacuo, the aqueous solution which remains is washed once with ether in a separating funnel, then covered with ethyl acetate, and acidified to pH 2 with dilute HC1, whilst stirring. The organic phase is then separated off, washed with saturated NaCl solution, dried over MgSO, diluted with an equal volume of ether, and treated with an approx. 1-molar sodium 2-ethylhexanoate solution in ether containing methanol, until precipitation ceases. The sodium 6{D-a-/72-oxo-3-benzaliminoimidazolidin-l-yl)-carbonylaminq7-phenylacetamido}-penicillanate is filtered off, washed with ether and then with a mixture of ether and methanol (5 - 10%) and isopropanol, and dried.

Example B. -' _ _ A penicillin is prepared in the manner described under example A from amoxicillin trihydrate (6.0 pts. by wt.) and l-chlorocarbonyl-2-oxo-3-benzalimino-imidazolidine (3.6 pts. by wt.) (see example 1.2.). On acidifying the aqueous reaction solution with dilute hydrochloric acid (about 20% by weight) to pH 1.5, a part of the penicillin-acid liberated is not taken up by the ethyl acetate. This part is filtered off, washed with water and dried (yield 5.2 pts. by wt.). Thereafter, some sodium salt of the penicillin can still be precipitated from the ethyl acetate phase by means of sodium 2ethylhexanoate.

Example C.

A penicillin is prepared in the manner described in example A from ampicillin trihydrate (2.0 pts. by wt.) and l-chlorocarbonyl-2-oxo-3-(4-methylsulphonyl) benzalimino-imidazolidine (1.6 pts. by wt.). The penicillin-acid separates out as a crystalline precipitate which is insoluble in water and ethyl acetate (1.6 pts. by wt.). This penicillin-acid is dissolved in a little dimethylformamide, the calculated quantity of sodium 2-ethylhexanoate solution (in ether containing methanol) is added and the sodium salt of the penicillin is precipitated by pouring the mixture into a large amount of ether.

Example 1. 1.1 CH = N - N NH 2-Oxo-imidazolidine (31.5 pts. by wt.) is dissolved in 2N sulphuric acid (1,000 pts. by vol.), the solution is cooled to 3-6°C, a solution of sodium nitrite (25.25 pts. by wt.) in water (50 pts. by vol.) is added dropwise over the course of 13 minutes whilst stirring, and continuing to cool, the mixture .is then stirred for a further 1.5 hrs. in an ice bath and purified zinc dust (55 pts. by wt.) is then introduced in the course of one hour. The mixture is stirred for a further 0.5 hr. whilst cooling with ice and then for a further hr. at room temperature. The unconverted zinc is then filtered off and washed with a little water, benzaldehyde (35 pts. by wt.) is added to the combined filtrates and the mixture is stirred vigorously for 0.5 hr. The 1-benzalimino-2-oxo-imidazolidine Which has precipitated is then filtered off and recrystallised, after drying (49.2 pts. by wt.; melting point = 194-200°C) from ethanol.

Yield 41,4 pts. by wt., melting point = 2O2°C.

IR spectrum: 1,720 cm-1(C=0) calculated: C63.5 H 5.9 N 22.2 found: C64.1 H 5.7 N 22.7 1.2 CH = N - N N - CO - Cl A mixture of l-benzalimino-2-oxoimidazolidine (11.7 pts. by wt.)(see 1.1.), benzene (120 pts. by vol.) and triethylamine (13.8 pts. by vol.) is heated to the boil and a solution of triethylchlorosilane (10 pts. by wt.) in benzene (50 pts. by vol.) is then added dropwise over the course of 1 hr., whilst stirring. The mixture is then kept at the boil for a further 5.5 hrs., and the triethyl amine hydrochloride which has separated out is filtered off hot and washed with hot benzene. A solution of phosgene (6.2 pts. by wt.) in benzene (30 pts. by vol.) is added to the cooled, combined benzene filtrates. The mixture is left standing well-sealed overnight at room temperature. Excess phosgene present is then very largely removed by means of a dry stream of air. The 3 814 l-chlorocarbonyl-2-oxo-3-benzalimino-imidazolidine is filtered off and dried.

Yield 8.9 pts. by wt., melting point = 250-252°, with decomposition.

IR spectrum: calculated: C 52.5 found: C 51.8 1,800 cm-1 (-C0-C1) H 4.0 Cl 14.1 N 16.7 H 5.6 Cl 14.6 N 16.8 Q = H or Na 2.25 pts. by wt. of cephaloglycine dihydrate are suspended in 50 ml of 80 per cent strength aqueous THF and reacted with 12.6 pts. by wt. of 1-chlorocarbonyl2-oxo-3-benzalimino-imidazolidine, and worked up, as in Example A. On acidifying with dilute hydrochloric acid (for example 2 N HC1), 7-{D-a-/“(2-oxo-3-benzaliminoimidazolidin -1-yl) - carbonylamino/ - phenylacetamido} - 3 - acetoxymethyl-ceph-3-em-4~carboxylic acid precipitates (1.9 pts. by wt., corresponding to 61.4%), This material is dissolved in 5 pts. by vol. of dimethyl20 acetamide, 3 pts. by vol. of a methanolic 1 M sodium 2ethyl-hexanoate solution are added and the mixture is added, whilst stirring, to 30 pts. by vol. of a 10 : 1 mixture of ether and methanol, whereupon 1.7 pts. by wt. of sodium 7-{D-a-/(2-oxo-3-benzalimino-imidazolidin - 1 25 yl) - carbonylamino/ - phenylacetamido} - 3 - acetoxymethyl - ceph-3-em-4-carboxylate of dec. pt. 18O-185°C precipitates. 438^-4 The ethyl acetate phase is worked up as in Example A, whereby further 0.9 pt. by vol. (corresponding to 28.0%) of the sodium salt is obtained.

C29H27N6NaO8S · H2° calculated: C 52.72 H 4.42 N 12.71 S 4.85 found: 52.5 4.9 12.2 4.6 XR (KBr): 1,760, 1,725, 1,670, 1,605 and 1,520 cm-1.

NMR(CD30D/D20) : 7.75 and 7.40 (m,HH) , 5.75 (d,lH) , 5.57 (s,lH), 5.00 (d,lH), 4.87 (on which is superposed the signal of the exchangeable protons), 3.82 (m,4H) and 2.08(s,3H) fi.

The CD3OD solvent peak is superposed on the signals of the G-2-protons.

The β-lactam content is between 80 and 85%. .8 pts. by wt. of 2-oxo-imidazolidine, 12.6 pts. of sodium nitrite and 27.5 pts. by wt. of zinc dust are processed as in Example 1.1. and stirred with 23.2 pts. by wt. of 4-chlorobenzaldehyde overnight. .5 pts. by wt. of 1-(4-chloro)benzalimino-2oxo-imidazolidine of melting point 233-235°C.

C10H10C1N3° calculated: C 53.70 H 4.51 N 18.79 Cl 15.85 found: 53.9 4.5 18.7 16.0 IR (KBr): 3,250, 3,130, 1,735, 1,705 and 1,595 cm-1. - 47 NMR(dg-DMSO): 7.66 and 7.45 (AB,4H), 7.60 (s,lH), 7.15 (s, broad, 1H) , m, centred at 3.6 (4H)fi.

A solution of 31.0 pts. by wt. of trimethylchloro5 silane in 100 pts. by vol. of absolute dioxane is added dropwise over the course of 1 hr., whilst stirring, to a boiling solution of 21,4 pts. by wt. of 1-(4-chloro)benzalimino-2-oxo-imidazolidine and 31.0 pts. by wt. of triethylamine in 240 pts. by vol. of absolute dioxane. 1° The mixture is then heated overnight under reflux, the triethylamine hydrochloride which has separated out is filtered off hot and washed with hot dioxane, and after cooling a solution of 9.9 pts. by wt. of phosgene in'60 pts. by vol. of abs. dioxane is added.

After standing for 12 hrs. at room temperature, excess phosgene is flushed out by means of dry air. The precipit· ate is filtered off, the filtrate is concentrated and the residue is recrystallised from abs. acetonitrile. 8.9 pts by wt. of l-chlorocarbonyl-2-oxo-3-(4-chloro)benzalimino20 imidazolidine of dec. pt. 188-192°C.

IR (paraffin oil) : 1,800 and 1,700 cm Q = H or Na 2.25 pts. by wt. of cephaloglycine dihydrate in 40 pts. by vol. of 80% strength by volume THF are reacted with 3.5 pts. by wt. of l-chlorocarbonyl-2-oxo-3-(4chloro)-benzalimino-imidazolidine as in Example 1.3. 0.6 pt. by wt. of sodium 7-{D - a /(2 - oxo - 3 - {4 chloro} benzalimino - imidazolidin - 1 - yl) - carbonyl - amino/ - phenyl - acetamido} - 3 - acetoxymethyl - ceph - 3 - em - 4 - carboxylate of β-lactam content 80-85% is obtained.

IR(KBr): 1,760, 1,720, 1,660 and 1,595 cm-1.

NMR(CD3OD): 7.7 and 7.4 (m,10H), 5.65 (d,lH), 5.60 (s,lH), 5.0-4,8 m (on which is superposed the signal of the exchangeable protons) 3.88 and 3.70 (superposed multiplets), 2.03 (s,3H) δ, C2gH2gClNgNaOgS . 1¾ H20 . dimethylacetamide calculated: C 50.25 H 4.22 N 11.72 S 4.48 found: 50.1 4.5 11.1 5.4 Example 3. .8 pts. by wt. of 2-oxo-imidazolidine, 12.6 pts. by wt. of sodium nitrite and 27.5 pts. by wt. of zinc dust are processed as in example 2.1. and reacted with 22.4 pts. by wt. of 4-methoxybenzaldehyde. 15.8 pts. by wt. of 1-(4-methoxy)benzalimino-2-oxo-imidazolidine of melting point 179-181°C are obtained.

IR(KBr): 3,250, 3,130, 1,725, 1,700 and 1,605 cm-1.

NMR(dg-DMSO): 7.56 and 6.92 (AB,4H), 7.52 (s,lH), - 49 7.04 (s,lH), CHH13N3°2 calculated: found: 3.72 (s,3H), m centred at 3.52 (4H) δ.

C 60.27 H 5.97 60.3 5.9 N 19,17 18.9 3.2 CH3O // CH=N-N N-COCl A solution of 20.0 pts. by wt. of trimethylchlorosilane in 50 pts. by vol. of abs. benzene is added dropwise to a boiling solution of 13.6 pts. by wt. of 1-(4methoxy)-benzalimino-2-oxo-imidazolidine and 27.6 pts. by vol. of triethylamine in 120 pts. by vol. of abs. benzene, and the mixture is reacted and worked up as in Example 1.2. 6.2 pts. by wt. of l-chlorocarbonyl-2-oxo-3-(4-methoxy)benzalimino-imidazolidine of melting point 2O4-2O8°C are obtained.

IR (paraffin oil): 1,800 cm X 3.3 CH-O CH=N-N (R) N-CONH-CH-CONH- / N \>i>CH2OCOCH3 COOQ Q = H or Na - 50 1.41 pts. by wt, of l-chlorocarbonyl-2-oxo-3-(4methoxy)benzalimino-imidazolidine are reacted with 2.25 pts by wt. of cephaloglycine dihydrate suspended in 40 pts. by vol. of 80% strength by volume THF, and worked up, as in Example 1.3.

On acidification, 7-{D-a-/(2-oxo-3-{4-methoxy}benzalimino-imidazolidin-l-yl) carbonylaminq7 - phenylacetamido - 3 - acetoxymethyl - ceph - 3 - em - 4 - carboxylic acid precipitates (1.2 pts. by wt.) and is reacted, as in Example B, with 1.9 pts. by vol. of a 1 M sodium 2-ethylhexanoate solution to give sodium 7-(0-0,-/(2 - oxo - 3 {4 - methoxy} benzalimino - imidazolidin - 1 - yl) carbonylaminq/ - phenylacetamido} - 3 - acetoxymethyl ceph - 3 - em - 4 - carboxylate (0.7 pt. by wt.).

The ethyl acetate phase is worked up as in Example A, whereby a further 1.6 pts, by wt. of the sodium salt of dec. pt. 22O-23O°C and of 80% β-lactam content are obtained. IR(KBr): 1,770, 1,730, 1,660 and 1,610 cm-1.

NMR(CD3OD/D2O): 7.55 and 6.85 (AB,4H), 7.40 (s, superposed on the AB system, 1H), 5.67 (d,lH), 5.47 (s,lH), 5.15-4.85 (m, on which is superposed the signal of the exchangeable protons), 3.76 (broad s, 4H), 2.05 (s,3H)6, C30H29N6Na09S * H2° 690·6 calculated: C 52.18 H 4.52 N 12.17 S 4.65 found: 51.9 4.4 11.8 5.1 Example 4. .8 pts. by wt. of 2-oxo-imidazolidine, 12.6 pts. by wt. of sodium nitrite and 27.5 pts. by wt. of zinc dust, as well as 24,9 pts. by wt. of 4-nitrobenzaldehyde are reacted as in Example 2.1. The resulting 1-(4-nitro)benzalimino-2-oxo-imidazolidine is freed from impurities by boiling with ethanol; 37.6 pts. by wt. of melting point 265-267°C.

IR(KBr): 3,430, 3,260, 1,720, 1,595 and 1,570 cm-1.

NMR(d.-DMSO): 8.20 and 7.88 (AB,4H), 7.68 (S,1H), 7.37 (broad s,lH), m, centred at 3.65 (4Η)δ. calculated: C 51.28 H 4.31 N 23.92 found: 51.2 4.3 23.9 4.2.

N-C0C1 8.8 pts. by wt. of 1-(4-nitro)benzalimino-2-oxoimidazolidine, 12.1 pts. by wt. of triethylamine, 12.0 pts. by wt. of trimethylchlorsilane and 3.9 pts. by wt. of phosgene are reacted as in Example 2.2. The 1-chloro· carbonyl-2-oxo-3-(4-nitro)benzalimino-imidazolidine is recrystallised from abs. acetonitrile; 2.6 pts. by wt. of the title compound,dec. pt. 188-192°C result.

IR (paraffin oil): 1,800, 1,760 and 1,700 cm \ 4.3 COONa 6.5 pts. by wt. of cephaloglycine dihydrate in 80 pts. by vol. of 80 per cent strength aqueous THF are reacted with 4.4 pts. by wt. of l-chlorocarbonyl-2-oxo3-(4-nitro)benzalimino-imidazolidine as in Example 3.3. 9.3 pts. by wt. of sodium 7-{D-a-/’(2 - oxo - 3 {4 - nitro} benzalimino - imidazolidin - 1 - yl) carbonyl - aminq7 - phenylacetamido} - 3 - acetoxymethyl ceph - 3 - em - 4 - carboxylate of dec. pt. 22O-5°C are obtained. IR (KBr): 1,760, 1,730, 1,660 and 1,605 cm 'C29H26K7Na010S · 2 H2° calculated: C 48.13 H 4.19 N 13.56 S 4.42 found: C 48.0 H 4.1 N 13.4 S 4.4 12.6 pts. by wt. of 2-oxo-imidazolidine, 10.1 pts by wt. of sodium nitrite and 21.8 pts. by wt. of zinc dust are processed as in Example 2.1. and reacted with 17.3 pts. by wt. of 4-cyanobenzaldehyde. 26.2 pts. by wt. of 1-(4cyano) benzalimino-2-oxo-imidazolidine are obtained and are freed from impurities by successive washing with water, ethanol and ether. Melting point 265-267°C.

IR(KBr): 3,210, 3,120, 2,220, 1,720 and 1,590 cm1, NMR(d,-DMSO): 7.88 (s,4H), 7.66 (s,lH), 7.30 (broads, lH), m centred at 3.7 (4H)δ. calculated: C 61.68 H 4.71 N 26.15 found: 59.8 4.6 .9 438 14 .2.

NC CH=N-N N-COCl 7.5 pts. by wt. of 1-(4-cyano)benzalimino-2-oxo-imidazolidine and 12.1 pts. by Wt. of triethylamine in 60 pts. by vol. of abs. dioxane, 12.0 pts. by wt. of trimethylchlorosilane in 25 pts. by vol. of abs. dioxane and 3.9 pts. by wt. of phosgene are reacted as in Example 2.2. The l-chlorocarbonyl-2-oxo-3-(4-cyano)benzalimino-imidazolidine is recrystailised from abs. acetonitrile; 4.7 pts. by wt. are obtained. of melting point 260-264 C 10 IR (paraffin oil): 1,800 cm calculated: C 52.09 H 3.28 N 20.25 Cl 12.82 found: 52.0 3.3 .3 12.5 Example 6. 6.1. ch3-so2 /C°\ -CH=N-N_^IH This Substance is prepared in the manner described 15 in Example 1.1. except that the reaction is carried out in a 1:1 (by volume) mixture of water and dichloromethane from 15.8 pts. by wt. of imidazolidine and 31.0 pts. by wt. of 4-methylsulphonylbenzaldehyde. The crude product is recrystailised from nitromethane. Yield: 9.2 pts. by wt. of 1-(4-methylsulphonyl)benzalimino-2-oxoimidazolidine, melting point = 264°C.

NMR signals at τ = 2.0 (4H), 2.2 (1H), 5.9-6.65 (4H) and 6.7 ppm (3H). - 54 calculated: C 49.4 H 4.9 N 15.7 0 18.0 S 12.0 found: 48.6 5.0 15.7 18.3 12.1 2 /co\ This substance is prepared in the manner described 5 in Example 1.2. from 9.2 pts. by wt. of 1-(4-methylsulphonyl) -benzalimino-2-oxo-imidazolidine. The crude product is recrystallised from nitromethane and acetonitrile. Yield 5.4 pts. by wt. of l-chlorocarbonyl-2oxo-3-(4-methylsulphonyl)benzalimino-imidazolidine.

Melting point = 2O8-213°C calculated: C 43.7 H 3.6 Cl 10.8 N 12.8 S 9.7 found: 43.8 4.9 10.2 12.5 9.5 COON a This cephalosporin is obtained in the manner 15 described in Example A and C from cephaloglycine (1.5. pts. by wt.) and l-chlorocarbonyl-2-oxo-3-(4-methylsulphonyl)benzalimino-imidazolidine (1.0 pts. by wt.), in part initially as the crystalline acid (the portion which is insoluble in ethyl acetate and water) (1.0 pt. by wt.) and in 20 part immediately as the sodium salt (the portion dissolved - 55 in ethyl acetate, from which it is precipitated as the sodium salt (0.75 pt. by wt.). Further sodium salt is then prepared from the cephalosporin-aCid as described in Example C. Total yield: 1.85 pts. by wt. of sodium 7/2-oxo-3-(4-methylsulphonyl) benz a limino· imidazolidin - 1 - yl7 “ carbonyl - amino } - phenylacetamidq7 - 3 - acetoxymethyl-ceph-3-em-4-carboxylate. g-Laotam content: 84%.

According to the NMR spectrum, this cephalosporin contains about 1.7 mols of water, 0.4 mol of dimethylformamide, 0.4 mol of ethyl acetate and 0.16 mol of sodium 2-ethylhexanoate. This was taken into account in the calculated analytical data: calculated: C 47.4 H 4.6 N 10.5 S 7.5 found: 47.3 4.2 10.8 8.1 NMR signals at τ = 2.1 (4H), 2.25 (IH), 2.5-2.9 (5H) , 4.3-4.6 (2H) , 5.05-5.3 (3H), 6.0-6.3 (4H), 6.7 (2H) , 6.9 (3H) and 8.0 ppm (3H). Example 7. .8 pts. by wt. of 2-oxo-imidazolidine, 12.6 pts. by wt. of sodium nitrite and 27.5 pts. by wt. of zinc dust, and 18.5 pts. by wt. of thiophen-2-aldehyde are reacted as in Example 1.1. The resulting l-(thiophen2-aldimino)-2-oxo-lmidazOlidine is freed from impurities by boiling with ethanol, or is recrystallised from dimethylformamide. 22.4 pts. by wt. of melting point 263-265°C.

IR(KBr): 3,240 and 1.705 (broad) cm-1.

NMR(dg-DMSO): 7.88 (s,lH), 7.3-7.0 (heteroaromatic protons, as well as NH,4H), m, centred at 3.6 (4H) . centred at 3.6 (4H) calculated: C 49.22 H 4.65 N 21.52 S 16.42 7.2 . found: 49.4 '4.6 21.4 H=N-N N-COCl S 21.4 16.1 9.8 pts. by wt. of (1-(thiophen-2-aldimino)-2-oxoimidazolidine , 16.2 pts. by wt. of triethylamine, 16.1 pts. by wt. of trimethylchlorosilane and 5.1 pts. by wt. of phosgene are reacted as in Example 1.2. 7.7 pts. by wt. of l-chlorocarbonyl-2-oxo-3-(thiophen-2-aldimino)imidazolidine of dec. pt. 184-188°C are obtained.

IR (paraffin oil): 1,830 and 1,720 cm \ The chlorocarbonyl compound still contains starting material which was not removed, since it does not interfere with the subsequent reactions. 7.3 .

CH=N-N N-CONH-CH-CONH0 COOQ Q = H or Na 1.50 pts. by wt. of l-chlorocarbonyl-2-oxo-3(thiophen-2-aldimino)-imidazolidine and 2.25 pts. by wt. of cephaloglycine dihydrate in 40 pts. by vol. of 80% strength by volume THF are reacted as in Example 1.3.

On acidification, 7-{D - a - /”(2 - oxo - 3 - {thiophen 2 - aldimino} - imidazolidin - 1 - yl) - carbonyl aminQ7_phenyl-acetamido}-3-acetoxymethyl-ceph-3-em-4carboxylic acid (0.6 pt. by wt.) precipitates and this is reacted, as in Example B, with 3 pts. by vol. of a 1 M sodium 2-ehhyl-hexanoate solution to give sodium 7{D-tx-/(2-oxo-3-{thiophen-2-aldimino} - imidazolidin 1 - yl)carbonylaming7 ” phenylacetamido} - 3 - acetoxy methyl - ceph - 3 - em - 4 - carboxylate.

The β-lactam content is 75-80%.

IR(KBr): 1,755, 1,720, 1,660 and 1,600 cm-1.

NMR(CD3OD): 7.95 (s,lH), 7.5-6.8 (aromatic and heteroaromatic protons, 8H), 5.75-5.00 (m,3H), 4.8 (on which is superposed the signal of the exchangeable protons), 3.82 (broad s, 4H), 2.00 (s, 3Η)δ.

Example 8. .8 pts. by wt. of 2-oxo-imidazolidine, 12.6 pts. by wt. of sodium nitrite and 27.5 pts. by wt. of zinc dust, and 15.8 pts. by wt. of furan-2-aldehyde, are reacted as in Example 1.1. 17.5 pts. by wt. of 1-furfurylideneamino-2-oxo-imidazolidine of melting point 218-22O°C are obtained.

IR(KBr): 3,200, 3,110, 1,715 and 1,585 cm \ NMR(dg-DMSO): 7.70 (m,lH), 7.50 (s,lH), 7.15 (broad s, IH), 6.50-6.75 (m,2H), m centred at 3.55 (4H)6. ,8 1-4 calculated: C 53.63 H 5.06 N 23.45 found: 53.7 5.0 23.2 8.2 .

CH=N-N N-C0C1 11.5 pts. by wt. of furfurylideneamino-2-oxo5 imidazolidine, 10.0 pts. by wt. of triethylamine 13.2 pts. by wt. of trimethylchlorosilane and 6.2 pts. by wt. of phosgene are reacted as in Example 1.2. 3.8 pts. by wt. of l-chlorocarbonyl-2-oxo-3-furfurylideneaminoimidazolidine of dec. pt. 188-192°C are obtained.

IR (paraffin oil): 1,800 and 1,700 cm \ 8.3. ^y_CH=N-l υ Λ ί V_7 CH2OCOCH3 .0 pts. by wt. of cephaloglycine dihydrate in 100 pts. by vol. of 80 per cent strength aqueous THF and 6.1 pts. by wt. of l-chlorocarbonyl-2-oxo-3-fur15 furylideneamino-imidazolidine are reacted, and worked up, as in Example 1.3. On Slowly acidifying With 0.1 N HCI at 5-10°C, 13.1 pts. by wt. of crystalline acid (Q=H) precipitate. The acid is dissolved in 500 pts. by vol. of acetone, small amounts of insoluble matter are filtered off and the filtrate is concentrated. The - 59 residue is suspended in 120 pts. by vol. of water and 1.5 N sodium hydroxide solution is added until the material has dissolved, the pH being kept at between 7.5 and 8.0. The solution is filtered, 940 pfs. by vol. of acetone followed by 190 pts. by vol. of ethyl acetate are added and the sodium salt is then precipitated by dropwise addition of 380 pts. by vol. of ether. 7.8 pts. by wt. of crystalline sodium 7-{D-a-/(2oxo - 3 - furfurylideneamino - imidazolidin - 1 - yl)carbonylamino7 - phenyl - acetamido} - 3 - acetoxymethyl - ceph - 3 - em - 4 - carboxylate of dec. pt. 215-22O°C, and of 95% β-lactam content, are obtained.

IR (KBr)! 1,765, 1,730, 1,670, 1,615, 1,530, 1,480, 1,390, 1,265, 1,230, 1,020, 740 and 695 cm1.

NMR (D2O/CD3OD): 7.50 (s,2H), 7.30 (s,5H), 6.65 (IH), 6.45 (IH), 5.56 (d,lH), 5.38 (s,lH), 4.91 (pseudo-d, on which is superposed the signal of the exchangeable protons), 3.76 (6H), 2.03 (s,3H)i C27H25N6NaO9S · H2° calculated: C 49.84 H 4.18 N 12.91 S 4.92 18.9 pts. by wt. of 2-oxo-imidazolidine, 15.2 pts. by wt. of sodium nitrite and 33.2 pts. by wt. of zinc dust are processed as in Example 2.1. and reacted with 29.1 pts. by wt, of 2-chlorothiophen-5-aldehyde. 36.0 pts. by wt. of l-(2-chlorothiophen-5-aldimino)-2-oxo4 3 814 - 60 imidazolidine are obtained, and the material was purified by successive washing with water, ethanol and ether. Melting point 194-197°C.

IR(KBr): 3,260, 1,700 (broad), 1,580 cm-1.

NMR(dg-DMSO): 7.92 and 7.78 (s, together 1H, syn- and anti-form), 7.16 and 7.10 (AB with superposed NH, 3H), m centred at 3.6 (4Η)δ. calculated: C 41.84 9.2.

H 3.51 3.8 N 18.28 18.0 S 13.96 14.3 N-C0C1 8.6 pts. by wt. of 1-(2-chlorothiophen-5-aldimino) ' -2-oxo-imidazolidine and 12.1 pts. by wt. of triethylamine in 60 pts. by vol. of abs. dioxane, and 12.0 pts. by wt. of trimethylchlorosilane in 25 pts. by vol. of abs. dioxane, and 3.9 pts. by wt. of phosgene, are reacted as in Example 2.2. The precipitate which has separated out after driving off the excess phosgene is filtered off and dried. 5.1 pts. by wt. of 1-chlorocarbonyl-2-oxo-3-(2-chlorothiophen-2-aldimino)-imidazoli20 dine of dec. pt. 215-220°C are obtained.

IR (paraffin oil): 1,800 cm (R) N-CONH-CH-CONH- COONa - 61 2.5 pts. by wt. of cephaloglycine dihydrate in 50 pts. by vol. of 80 per cent strength THF are reacted with 1.7 pts by wt. of l-chlorocarbonyl-2-oxo3-(2-ehlorothiophen-5-aldimino)-imidazolidine as in Example 1.3. and the mixture is worked up. 2.5 pts. by wt. of sodium 7-{D-a-/”(2-oxo-3-{2-chlorothiophen-5aldimino} - imidazolidin - 1 -yl) - carbonylamine/ phenylacetamido} - 3 - acetoxymethyl - ceph - 3 em-4-carboxylate are obtained.

IR(KBr) : 1,760, 1,730, 1,670 and 1,600 cm-1·.

NMR (CD30D/D20): 7.87 (s, IH), 7.50 (s,5H), 7.18 (d,lH), 6.93 (d,lH), 5.65 (d, IH), 5.53 (s,lH), 5.05 (on which is superposed the signal of the exchangeable protons), 3.83 (6 H), 2.10 (s, 3H)6.

C27H24C1N6°8S2 1 H2° calculated: C 46.26 H 3.74 N 11.99 S. 9.14 Cl 5.07 found: C 46.3 H 3.9 N 11.9 S 9.5 Cl 5.0 Example 10. Λ SI NH 1_I FT .8 pts. by wt. of 2-oxo-imidazolidine, 12.6 pts. by wt. of sodium nitrite and 27.5 pts. by wt. of zinc dust are processed as in Example 2.1. and reacted with 31.5 pts. by wt. of 3-bromothiophen-5-aldehyde. 41.2 pts. by wt. of 1-(3-bromothiophen-5-aldimino)-2-oxoimidazolidine are obtained and this material is purified by successive washing with water, ethanol and ether and is recrystallised from DMF. - 62 Melting point 253-255°C.

IR(KBr): 3,230 and 1,710cm-1.

NMR(dg-DMSO): 7.77 (s,lH), 7.60 (s,lH), 7.28 (s, 1H), 7.24 (s, 1H), m centred at 3.6 (4H). calculated: C 35.04 H 2.93 N 15.33 S 11.70 Br 29.15 found: 34.7 2.9 15.5 11.8 29.1 Br .2 El· CH=N-N N-COCl 12,2 pts. by wt. of 1-(3-bromothiophen-5-aldimino) 2-oxo-imidazolidine and 14.1 pts. by wt. of triethyl10 amine in 120 pts. by vol. of abs. dioxane, and 14.0 pts. by wt. of trimethylchlorosilane in 50 pts. by vol. of abs. dioxane and 4.6 pts. by wt. of phosgene, are reacted as in Example 2.2. The precipitate which has separated out after driving off the excess phosgene is filtered off, the filtrate is concentrated and the residue is triturated with abs. ether and filtered off. 7.5 pts. by wt, of l-chlorocarbonyl-2-oxo-3-(3-bromothiophen-5-aldimino)-imidazolidine of melting point 165-170 are obtained; this product still contains a proportion of starting material.

IR (paraffin oil): 1,780 and 1,690 cm I - 63 6.5 pts. by wt. of cephaloglycine dihydrate in 80 pts. by vol. of 80 per cent strength aqueous THF are reacted with 5.0 pts. by wt. of l-chlorocarbonyl-2oxo-3-(3-bromothiophen-5-aldimino)-imidazolidine and worked up, as in Example 1.3. 4.2 pts. by wt. of sodium 7-{D-a-/'(2-oxo-3-{3-bromothiophen-5-aldimino}-imidazolidin - 1 - yl) - carbonylamino/ - phenylacetamido} - 3 acetoxymethyl - ceph - 3 - em - 4 - carboxylate of dec. pt. 190-5°C are obtained.

IR (KBr): 1,760, 1,725, 1,670 and 1,605 cm-1.

C27H24BrN6NaO8S2· IJ2° calculated: C 43.50 H 3.52 N 11.28 S 8.59 found: C 43.8 H 3.8 N 10.8 S 8.1 Example 11.

Cinnamaldehyde (18.5 pts. by wt.) are added to a solution of l-amino-2-oxo-imidazolidine hydrochloride (21 pts. by wt.) in 1 N sodium hydroxide solution (150 pts. by vol.) at 20°C, whilst stirring, and the mixture is then stirred for a further 90 minutes at the same temperature, after which it is left to stand for 16 hrs. The precipitate which has separated out is filtered off, well washed with water and dried over Ρ4θ]_θ in a desiccator.

Yield: 29.9 pts. by wt.

Melting point = 209-210°C (Kofler bench).

The substance still contains 0.28 mol equivalent of water. This is taken into account in the following - 64 - calculated analytical data: calculated: : C 65.4 H 6.1 N 19.1 found: C 65.5 H 6.1 N 19.1 11.2.

•CH=CH-CH=N-N ΙΊ-CO-Cl \_y A solution of phosgene (4.3 pts. by vol.) in benzonitrile (15 pts. by vol.) is added dropwise to a mixture of 1-(cinnamylidene-amino)-2-oxo-imidazolidine (10 pts. by wt.), benzonitrile (50 pts. by vol.) and triethylamine (7.7 pts. by vol.), whilst stirring, and cooling with ice/water. The mixture is then stirred for a further 4.5 hrs. whilst continuing the cooling.

The precipitate formed is then filtered off, stirred in about 30 pts. by vol. of methylene chloride for 2 hrs. at 20°C, again filtered off and then dried over in a desiccator.

Yield: 8.2 pts. by wt.

Melting point = 227-23O°C (Kofler bench).

The substance still contains triethylamine hydrochloride, but this does not interfere with the further reaction.

IR spectrum (-C0-C1): 1,800 cm 1 (in paraffin oil). 11.3 h3c-oc-o Ο This cephalosporin is prepared analogously to the manner described in Examples A. and 1.3., from cephaloglycinedihydrate (1.5 pts. by wt.) and l-chlorocarbonyl5 2-oxo-3-(cinnamylidene-amino)-imidazolidine (1.08 pts. by wt.; an excess is used since the substance still contains triethylamine hydrochloride). After removing the tetrahydrofuran at pH 7.0, a precipitate which is insoluble in water and ethyl acetate is filtered off and is stirred with a mixture of ethyl acetate and water at pH 2.0. After filtering off, the product is stirred with 10 pts. by vol. of dimethylformamide, insoluble matter is filtered off, and after diluting the filtrate with 150 pts. by vol. of ether the sodium salt is precipitated.

Yield: 0.5 pt by wt. of sodium 7-{D-a-/(2-oxo-3cinnamylidene-amino-imidazolidin - 1 - yl) - carbonylamino/ “ phenyl - acetamido} - 3 - acetoxymethyl - ceph3-em-4-carboxylate. 8-Lactam content: 80%.

According to the NMR, this cephalosporin contains about 3 mol equivalents of water and 0.65 mol equivalent of sodium 2-ethylhexanoate. This was taken into account in the following calculated analytical data: calculated: C 52.3 H 5.4 N 10.1 S 3.9 found: C 52.4 H 5.6 N 10.3 S 3.8 IR spectrum (in paraffin oil) (carbonyl region): 1,770, 1,730, 1,668, 1,612 and 1,540 cm-1. - 66 43814 NMR signals (in deuterated DMF) at τ = 2.1-2.9 (13H), 3.9-C2H), 4.75-5.1 (3 H), 4.0 (4 H), 6.6 (2 H) and 7.9 ppm (3 H) .

Example 12.

Pyridin-3-aldehyde (10.7 pts. by wt.) is added to a solution of l-amino-2-oxo-imidazolidine (10.1 pts. by wt.) in a mixture of methanol and water (50 pts. by vol. each) and the mixture is then stirred for about 20 hrs. at 20°C. The precipitate formed is then filtered off, washed with water and a little methanol and dried over Ρ^Ο^θ in vacuo at 60°C.

Yield: 16.5 pts. by wt.

Melting point = 195°C (Kofler bench). calculated: C 56.9 H 5.3 N 29.5 0 8.4 found: C 56,9 H 5.2 N 30.0 0 8.0 12.2.

N-COCl HC1 A solution of phosgene (1.35 pts. by vol.) in tetrahydrofuran (10 pts. by vol.) is added to a suspension of 1-(3-pyridyl-methyleneamino)-2-oxoimidazolidine (3.0 pts. by wt.) in a mixture of benzonitrile (30 pts. by vol.) and triethylamine (2.6 pts. by vol.), whilst cooling with ice water. After 20 minutes, the mixture is allowed to come to 20°C and is then stirred at this temperature overnight. The precipitate - 67 present is then filtered off, washed with ether and then with dichloromethane and dried.

Yield: 4.2 pts. by wt.

IR spectrum (CO.Cl): 1,800 cm (in paraffin oil) Melting point = 252°C (Kofler bench) Example 13. h3c 3-Methylbenzaldehyde is added to a mixture of 1amino-2-oxo-imidazolidine hydrochloride (14.0 pts. by wt.) and 1 N sodium hydroxide solution (100 pts. by vol.) and the mixture is then stirred for a further 5 hrs. at 20°C. The precipitate formed is then filtered off, washed with water and dried.

Yield; 20.3 pts. by wt. Melting point = 2O5-2O7°C (Kofler bench).

A solution of trimethylchlorosilane (9.65 pts. by wt.) in benzene (50 pts. by vol.) is added dropwise over the course of one hour to a gently boiling mixture of 1-(3-methylbenzylideneamino)-2-oxo-imidazolidine (12.1 pts. by wt.), benzene (150 pts. by vol.) and triethylamine (13,4 pts. by vol.). The mixture is then - 68 boiled under reflux for 20 hrs. and the triethylamine hydrochloride is filtered off hot and rinsed with hot benzene. A solution of phosgene (4.7 pts. by vol.) in benzene (30 pts. by vol.) is added to the combined filtrates which have been cooled to 10°C and the mixture is then left to stand for 48 hrs. at 20°C. Thereafter the precipitate formed is filtered off, washed with benzene, then triturated with ethylene chloride (40 pts. by vol.), and then dried.

Yield: 3.2 pts, by wt. Melting point = 2O9-21O°C (Kofler bench). calculated: C 54.3 H 4.5 Cl 13.4 N 15.8 found: C 54.5 H 4.6 Cl 13.5 N 15.4 IR spectrum (CO.Cl) : 1,810 cm1 (in paraffin oil).

This cephalosporin is obtained when cephaloglycine dihydrate (1.0 pt. by wt.) is reacted with 1-chlorocarbonyl-2-oxo-3-(3-methylbenzylideneamino)-imidazolidine (0.69 pts. by wt.) in the manner described in Examples A and 1.3. The sodium salt separated out as a gel-like precipitate which could not be filtered off. For this reason, all volatile matter was stripped off and the residue was treated with dry ether. This gave the cephalo sporin salt as a loose white powder.

Yield: 1.2. pts. by wt. of sodium 7-{0-α-/·(2-οχο69 3-m-methylbenzylideneamino - imidazolidin - 1 - yl)carbonylaminq7 - phenylacetamido} - 3 - acetoxymethyl - ceph - 3 - em - 4 - carboxylate. g-Lactam content: 90%.

The cephalosporin salt contains about 2.9 mol equivalents of water. This was taken into account in the calculated analytical data: Calculated: C 51.2 H 4.9 N 11.9 S 4.6 found: C 51.4 H 5.5 N 11.7 S 4.7 IR spectrum (in paraffin oil) (carbonyl region): 1,765 -1 (shoulder), 1,740, 1,660, 1,610 and 1,535 cm NMR signals ( in dy-DMF) at τ = 1.85-2,8 (10 H) 3.9-4.3 (2 H), 4.7-5.0 (3 H), 5.8-6.1 (4 Η), 6.4-6.7 (2 Η), 7.5 (3 H) and 7.8 ppm (3 H).

Example 14. 14.1.

CH=N-N, N-H \_7 This substance is obtained in the manner described in Example 13.1. from l-amino-2-oxo-imidazolidine hydrochloride (14.0 pts. by wt.) and 4-fluorobenzaldehyde (12.8 pts. by wt.).

Yield: 20.4 pts, by wt. Melting point = 229-230°C (Kofler bench). 14.2. ΓΛ // CH=N-N N-C0-C1 \_7 - 70 A solution of phosgene (4.2 pts. by vol.) in benzonitrile (10 pts. by vol.) is added dropwise to a mixture of 1-(4-fluorobenzylideneamino)-2-oxo-imidazolidine (6.0 pts. by wt.), benzonitrile (50 pts. by vol.) and triethylamine (8 pts. by vol.) whilst cooling with ice/ water, and stirring, and the mixture is then stirred for a further 3 hrs. at 20°C. The precipitate is then filtered off, suspended in methylene chloride (240 pts. by vol.) again filtered off and dried.

Yields 0.9 pts. by wt. (the mother liquor contains some more of this substance).

The substance is not quite free from triethylamine hydrochloride, but this did not interfere with the further reaction.

IR spectrum (CO.Cl): 1,820/1,810 cm 1 (in paraffin oil).

Melting point = 240-247°C, with decomposition (Kofler bench). 14.3.

This cephalosporin is obtained when cephaloglycine dihydrate (1.0 pt. by wt.) is reacted with 1-chlorocarbonyl-2-oxo-3-(4-fluorobenzylideneamlno)-imidazolidine (0.7 pt. by wt.) in the manner described in Examples A and 1.3. Since the sodium salt separated out as a gel and was difficult to filter in this form, all volatile material was removed in vacuo and the residue was treated with a mixture of ether and methanol (10/1).

As a result of this treatment, the sodium salt was converted to a loose white powder. - 71 43814 Yield: 0.5 pt. by wt. of sodium 7-{D-a-/(2-oxo-3p-fluorobenzylideneamino-imidazolidin-l-yl)-carbonylamino7-phenylacetamido}-3-acetoxymethyl“ceph-3-em-4carboxylate. β-Lactam content: 91%.

According to the NMR spectrum, the cephalosporin contains about 0.13 mol equivalent of sodium 2-ethylhexanoate and 1.7 mol equivalents of water. This was taken into account in the calculated analytical data: calculated: C 50.7 H 4.4 N 11.8 S 4.5 found: H 50.7 H 4.4 N 11.8 S 4.6 IR spectrum (in paraffin oil) (carbonyl region): 1,775 (shoulder), 1,760 (shoulder), 1,735, 1,680, 1,610 and 1,550-1,520 cm-1.

NMR signals (in CD3OD) at τ = 2.1-2.9(10), 4.2-4.35 (1 H), 4.4 (1 H), 5.0-5.2 (3 H), 6.1 (4 H), 6.5-6.7 (2 H) and 8.0 ppm (3 H).

Example 15. .1.

\\ // CH=N-N P This substance is obtained as in Example 13.1 from l-amino-2-oxo-imidazolidine hydrochloride (14.0 pts. by wt.) and 2-fluorobenzaldehyde (12.7 pts. by wt,) in a yield of 17.6 pts. by wt.

Melting point 214-216°C (Kofler bench).

F - 72 A solution of phosgene (4.2. pts. by vol.) in benzonitrile (10 pts. by vol.) is added dropwise to a mixture of 1-(2-fluorobenzylideneamino)-2-oxo-imidazolidine (6.0 pts by wt.)., benzonitrile (50 pts. by vol.) and trimethylamine (8 pts. by vol.) whilst stirring and cooling with ice/water. The mixture is then stirred for a further 3 hrs. at 20°C. The product is then filtered off and washed with ether and the precipitate is suspended in about 120 pts. by vol. of methylene chloride again filtered off and dried.

Yield: 5.6 pts. by wt.

Melting point = 230°C (Kofler bench) IR spectrum (CO.Cl): 1,800 (with a shoulder at about 1,815) cm The substance contains a little trimethylamine hydrochloride but this did not interfere with the further reaction.

This cephalosporin is obtained from cephaloglycine dihydrate (1.5 pts. by wt.) and l-chlorocarbonyl-2-oxo3-(2-fluorobenzylideneamino)-imidazolidine (1.07 pts. by wt.) in accordance with the process of preparation described in Examples A and 1.3.

On working up, acidification to pH 2 gives a part of the cephalosporin as free acid which is insoluble in water and ethyl acetate (0.2 pt. by wt.; IR spectrum /carbonyl regioo7: 1,780, 1,745, 1,670 and 1,540 om in paraffin oil). To the extent that the cephalosporin formed is dissolved in the organic phase, it is obtained - 73 43814 therefrom in a yield of 0.8 pt. by wt. as sodium 7-{D-a/(2-oxo-3-o-fluorobenzylideneamino - imidazolidin - 1 yl) - carbonylamino7 - phenylacetamido} - 3 - acetoxymethyl - ceph - 3 - em - 4 - carboxylate.

The data which follow relate to the sodium salt. β-Lactam content: 91%.

According to the NMR spectrum, the cephalosporin contains about 2.8 mol equivalents of water and 0.05 mol equivalent of sodium 2-ethylhexanoate. This was taken into account in the calculated analytical data: calculated: found: C 49.2 C 49.1 H 4.5 H 4.3 N 11.7 S N 11.7 S 4.5 4.9 IR spectrum (in paraffin oil) (carbonyl region) 1,730, 1,670, 1,610 and 1,530 cm .

NMR signals (in d?-DMF) at τ = 1.8-2.9(10 H), 4.0-4.4(2 H) ’4.8-5.1 (3 H), 5.8-6.2(4 H), 6.5-6.75(2 H) and 7.95 ppm (3 H) .

Example 16.

Cl 47.5 pts. by wt. of 2-oxo-imidazolidine, 38.0 pts. by wt. of sodium nitrite and 82.5 pts. by wt. of zinc dust are processed as in Example 2.1. and reacted with 64.0 pts. by wt. of 2-chlorobenzaldehyde. 65.0 pts. by wt. of 1-(2-chloro)benzalimino-2-oxo-lmidazolidine are obtained and are recrystallised from ethanol. Melting point 216-17°C. 16.2 CH=N-N Cl v_y N-COCl 50.0 pts. by wt. of 1-(2-chloro)benzalimino-2oxo-imidazolidine and 73.0 pts. by wt. of triethylamine in 400 pts. by vol. of abs. dioxane, and 72.7 pts. by wt. of trimethylchlorosilane in 150 pts. by vol. of abs. dioxane, and 44.5 pts. by wt. of phosgene, are reacted as in Example 2.2. 37.2 pts. by wt. of 1-chlorocarbonyl2-ΟΧΟ-3-(2-chloro)benzalimino-imidazolidine are obtained and are recrystallised from acetonitrile. Melting point 233-7°C.

IR (paraffin oil): calculated: C 46.18 found: C 46.1 1,800 cm H 3.17 H 3.2 N 14.68 Cl 24.78 N 14.6 Cl 24.7 16.3 CH=N-N ,N-CONH-CH-CONH ,5 pts. by wt. of cephradin in 100 pts. by vol. of 80 per cent strength aqueous THF are reacted with .7 pts. by. wt. of l-chlorocarbonyl-2-oxo-3-(2-chloro)benzalimino-imidazolidine as in Example A. 10.9 pts. by wt. of sodium 7-{D-a-/(2-oxo-3-{2-chloro}benzaliminoimidazolidin-l-yl)-carbonylaminq7-cyclohex-l,4-dienyl(1)20 acetamido}-3-methyl-ceph-3-em-4-carboxylate of dec. pt. 222°C are obtained.

IR (KBr): 1,770, 1,735, 1,665 and 1,590 cm C27H26C1N6NaO6S · 2H2° calculated: C 49.36 H 4.66 N 12.79 S 4.88 Cl 5.39 25 found: C 48.9 H 4.5 N 12.4 S 4.4 Cl 5.3 3 814 16.4. Ο .0 pts. by wt. of cephaloglycine dihydrate in 100 pts. by vol. of 80 per cent strength aqueous THF are reacted with 3.3 pts. by wt. of l-chlorocarbonyl-2-oxo5 3-(2-chloro)benzalimino-imidazolidIne.as in Example 1.3. 6.7 pts. by wt. of sodium 7 - {D - a - /(2 - oxo - 3 {2 - chloro} benzalimino - imidazolidin - 1 - yl) carbonyl - amino7-phenylacetamido}-3-acetoxymethyl-ceph3-em-4-carboxylate of dec. pt. 195-2OO°C are obtained.

IR (KBr): 1,760, 1,725, 1,670 and 1,600cm1.

NMR (CD30D/D20): 7.2-8.0(aromatic protons and -CH=N-), .65 (d, 1 H), 5.50 (s, 1 H), 5.05 (3, on which is superposed the signal of the exchangeable protons), 3.8 (6 H), 2.10 (s, 3H)6.

C29H26C1N6NaO8S - H2° C 50.11 H 4.21 N 12.09 S 4.63 C 50.1 H 4.1 N 12.1 S 4.8 calculated: found: 17.1.

Example 17. - 76 47.6 pts. by wt. of 2-oxo-imidazolidine, 34.5 pts. by wt. of sodium nitrite and 78.4 pts. by wt. of zinc dust are processed as in Example 1.1. and stirred with 77.0 pts. by wt. of 3-chlorobenzaldehyde overnight. 65.7 pts. by wt. of l-(3-ohloro)benzalimino-2-oxo-imidazolidine of melting point 210-212°C are obtained.

IR (KBr): 3,230, 3,120, 1,715, 1,475 and 1,405 cm NMR (dg-DMSO): m. centred about 7.5 (aromatic protons, -CH=N- and NH;6 H), 3.65 (m, 4 H)5. calculated: C 53.70 H 4.51 N 18.79 Cl 15.85 found: C 54.0 H 4.7 N 18.4 Cl 16.2 17.2 CH=N-N^_^N-COC1 Cl A solution of 43.3 pts. by wt. of tri-methylchlorosilane in 80 pts. by vol. of abs. dioxane is added dropwise to a boiling solution of 30.0 pts. by wt. of 1-(3-chloro)benzalimino-2-oxo-imidazolidine and 43.4 pts. by wt. of triethylamine in 250 pts. by vol. of abs, dioxane, and the mixture is reacted with 26.4 pts. by wt. of phosgene as in Example 2.2. 16.2 pts. by wt. of l-chlorocarbonyl-2-oxo3-(3-chloro)benzalimino-imidazolidine of dec. pt. 190°C are obtained; this product still contains a small quantity of starting material. ch2ococh3 lONa 3.3 pts. by wt. of cephaloglycine dihydrate in 100 pts. by vol. of 80 per cent strength aqueous THF are reacted with 2.5 pts. by wt. of l-chlorocarbonyl-2-oxo3-(3-chloro)benzalimino-imidazolidine as in Example 1.6. 2.1 pts. by wt of sodium 7 - {D - a - /(2 - oxo - 3 {3 - chloro} benzalimino - imidazolidin - 1 - yl) carbonylaminq7 - phenylacetamido} - 3 - acetoxymethyl ceph-3-em-4-carboxylate of melting point 212-218°C (with decomposition) are obtained.

IR (KBr): 1,765, 1,735, 1,665 and 1,610cm-1.

C29H26C1N6NaO8S · 3H2° calculated: C 47.65 H 4.42 N 11.49 found: C 47.6 H 4.8 N 11.5 Example 18. 18.1.

Cl CH=N-N v_y Cl 47.6 pts. by wt. of 2-oxo-imidazolidine, 34.5 pts. by wt. of sodium nitrite and 78.4 pts. by wt. of zinc dust, and 87.5 pts. by wt. of 3,4-dichlorobenzaldehyde are reacted as in Example 1.1. 50.4 pts. by wt. of 1(3,4-dichloro)benzalimino-2-oxo-imidazolidine of melting point 178-181°C are obtained.

IR (KBr): 3,240, 1,710 (broad), 1,470, 1,400 and 1,260 cm-1.

NMR(dg-DMSO): 7.95(s, IH), 7.7(m, 3 H), 7.37(s, broad, 1 H), m centred at 3.7 (4 H). calculated: C 46.46 il 3.52 N 36.28 Cl 27.47 found: C 46.4 H 3.6 N 16.1 Cl 27.4 4381^ 18.2 Cl0 Λ :h=n-n, n-coci C1 .0'pts. by wt. of 1-(3,4-dichloro)benzalimino2-oxo-imidazolidine and 37.8 pts. by wt. of triethylamine in 250 pts. by vol. of abs. dioxane, and 37.7 pts. by wt. of trimethylchlorosilane in 80 pts. by vol. of abs. dioxane, and 32.1 pts. by wt. of phosgene are reacted as in Example 2.2. 11.2 pts. by wt. of l-chlorocarbonyl-2oxo-3-(3,4-dichloro)benzalimino-imidazolidine of dec. pt. 224-23O°C are obtained.

IR (paraffin oil): 1,800 cm . calculated: C 41.80 H 2.82 N 13.07 Cl 33.07 found: C 41.9 H 2.8 N 12.9 Cl 32.8 COONa 7.0 pts. by wt. of cephaloglycine dihydrate in 100 pts. by vol. of 80 per cent strength aqueous THF are reacted with 5.0 pts. by wt. of l-chlorocarbonyl-2-oxo3-(3,4-di-chloro)benzalimino-imidazolidine as in Example 1.3. 7.7 pts by wt. of sodium 7 - {D - a -/(2 - oxo - 3 {3,4 - dichloro} benzalimino - imidazolidin - 1 - yl) carbonylamino7 - phenylacetamido} - 3 - acetoxymethyl ceph - 3 obtained. em - 4 - carboxylate of dec. pt. 190-5 C are IR (KBr): 1,765, 1,740, 1,665 and 1,615 cm calculated; C 48.95 N 11.80 0 17.99 found: C 49.0 N 11.7 0 18.1 »3814 Example 19. 27.8 pts. by wt. of 2-oxo-imidazolidine, 20.0 pts. by wt. of sodium nitrite and 38.0 pts. by wt. of zinc dust, and 54.0 pts. by wt. of 4-bromobenzaldehyde are reacted as in Example 1.1. 22.4 pts. by wt. of 1-(4bromo)benzaUmino-2-oxo-imidazolidine of melting point 25O-2°C are obtained.

IR (KBr): 3,240, 3,120, 1,740, 1,705, 1,595, 1,475, 1,415 and 1,270 cm X NMR (dg-DMSO): 7.67 (aromatic protons and -CH=N-), 7.30 (s, broad, 1 Η), m centred at 3.6 (4 Η)δ. calculated: C 44.80 H 3.76 N 15.67 found: C 44.9 H 3.7 N 15.3 21.7 pts. by wt. of 1-(4-bromo)benzalimino-2oxo-imidazolidine and 26.3 pts. by wt. of triethylamine in 250 pts. by vol. of abs. dioxane, and 26.2 pts. by wt. of chlorotrimethylsilane in 80 pts. by vol. of abs. dioxane, and 16.0 pts. by wt. of phosgene are reacted as in Example 2.2. 4.2 pts. by wt. of l-chlorocarbonyl-2-oxo-3-(4bromo)benzalimino-imidazolidine of melting point 177-180° C are obtained.

IR (paraffin oil): 1,700 cm 19.3.

(R) N-C0NH-CH-C0NH- .7 pts. by wt. of cephaloglycine dihydrate and 4.2 pts. by wt. of l-chlorocarbonyl-2-oxo-3-(4-bromo)benzalimino-imidazolidine are reacted as in Example A. 3.5 pts. by wt. of sodium 7-{D-a-/72-oxo-3-{4-bromo}benzalimino-imidazolidin - 1 - yl) - carbonylamino/ phenylacetamido} - 3 - acetoxymethyl - oeph - 3 - em 4-carboxylate of dec. pt. 19O-3°C are obtained.

XR (KBr): 1,760, 1,725, 1,655 and 1,600cm1. 47.6 pts. by wt. of 2-oxo-imidazolidine, 34.5 pts. by wt. of sodium nitrite and 78.4 pts. by wt. of zinc dust and 60.1 pts. by wt. of 4-methylbenzaldehyde are reacted as in Example 1.1. 52.2 pts. by wt. of 1-(4-methyl)benzalimino-2-oxo-imidazolidine of melting point 235-6°C are obtained.

IR(KBr): 3,230, 3,110, 1,710 (broad), 1,475, 1,410, 1,270 (broad) cm1 NMR (dg-DMSO): 7.2-7.8(aromatic protons, -CH=N-,NH;6H), m centred at 3.7(4 H), 2.40 (s,3 Η)δ. calculated: C 65.00 H 6.45 N 20.68 found: C 65.00 H 6.3 N 20.8 0 /=\ A 20.2. CH,—(\ /)- -CH=N-N, .. \_i N-COCl .3 pts. by wt. of 1-(4-methyl)benzalimino-2-oxoimidazolidine, 33.3 pts. by wt. of triethylamine, 32.1 pts. by wt. of chlorotrimethylsilane and 19.8 pts. by wt. of phosgene are reacted as in Example 19.2. 19.6 pts. by wt. of l-chlorocarbonyl-2-oxo3-(4-methyl)benzalimino-imidazolidine of melting point 265-8°C are obtained. IR (paraffin oil): 1,800 cm-1. calculated: C 54.24 H 4.55 N 15.82 Cl 13.34 found: C 54.2 H 4.5 N 15.8 Cl 13.6 .3. Λ -CH=N-N N-CONH-CH-CONH^ L_/ CH„-OCOCH, COONa .0 pts. by wt. of cephaloglycine dihydrate in 50 pts. by vol. of 8o per cent strength aqueous THF are reacted with 3.0 pts. by wt. of l-chlorocarbonyl-2-oxo3-(4-methyl)benzalimino-imidazolidine as in Example 1.3. 5.5 pts. by wt. of sodium 7 - {D - a - /(2 - oxo - 3 {4 - methyl} benzalimino - imidazolidin - 1 - yl) carbonyl - amino7 - phenylacetamido} - 3 - acetoxymethyl - ceph - 3 - em - 4 are obtained. carboxylate of dec. pt. 178 -80 C IR (KBr): 1,760, 1,725, 1,660 and 1,615 cm C3OH29N6Na°8S calculated: found: h2o C 53.41 C 53.4 N 12.47 N 12.5. 21.1, CI!300C —\\ Example 21. 47.6 pts. by wt. of 2-oxo-imidazolidine, 34.5 pts. by wt. of sodium nitrite and 78.4 pts. by wt. of zinc dust, and 77.1 pts. by wt. of 4-carboxybenzaldehyde, are reacted as in Example 1.1. 82.8 pts. by wt. of 1-(4carboxy)benzaiimino-2-oxo-imidazolidine are obtained; this is suspended in 200 pts. by vol. of methanol and a solution of diazomethane in ether is added until a yellow colouration persists. A short time after a clear solution has formed, l-(4-methoxycarbonyl)benzalimino-2-oxoimidazolidine of melting point 245-6°C crystallises out.

IR (KBr): 2,240, 1,700 with shoulder at 1,720 cm 1.

NMR (dg-DMSO): 7.6-7.1{AB system and s at 8.63;5 H), 7.20(s,broad, 1 H), 3.88(s, 3 H), m centred at 3.7 (4 Η) δ. calculated: C 58.29 H 5.30 N 17.00 0 19.41 found: C 58.7 H5.2 N17.3 019.6 /=\ Λ 21.2. ch3ooc- -<x CH=N-N N-C0C1 VJ \_Z 17.4 pts. by wt. of 1-(4-methoxycarbonyl)benzalimino-2-oxo-imidazolidine, 22.8 pts. by wt. of triethylamine, 22.7 pts. by wt. of ohlorotrimethylsilane and 13.9 pts. by wt. of phosgene are reacted as In Example 19.2. 21.0 pts. by wt. of l-chlorocarbonyl-2-oxo-3(4-methoxycarbonyl)benzalimino-imidazolidine of dec. pt. 21O-15°C are obtained.

IR (paraffin oil): 1,800 cm \ 2.3 pts. by wt. of cephaloglycine dihydrate in 40 pts. by vol. of 80 per cent strength aqueous THF are reacted with 2.2 pts. by wt. of l-chlorooarbonyl-2-oxo5 3-(4-methoxycarbonyl)benzalimino-imidazolidine as in Example 1.3, 1.0 pts. by wt. of sodium 7-{D-a-/(2-oxo3-{4-methoxycarbonyl Jbenzalimino-imidazolidin-l-yl)carbonylaminq/-phenylacetamido}-3-acetoxymethyl-ceph-3em-carboxylate is obtained.

IR (KBr): 1,755, 1,725, 1665 and 1,600cm1.

C31H29N6Na010S · 3 H2° calculated: C 49.34 H 4.67 N 11.14 S 4.25 found: C 49.1 H 4.5 N 11.1 S 4.4 Example 22. 22.1 CH3-C0-0-CH2 π A 1' j CH=N~N NH A solution of l-amlno-2-oxo-imidazolidine (3. 0 pts. by wt) in water (30 pts. by vol.) is added to a suspension of 5-acetoxymethyl-furan-2-aldehyde (5.0 pts. by wt.) in water (50 pts. by vol.) over the course of minutes, whilst stirring and cooling with ice/water.

The mixture is then stirred for a further 20 hrs. at 20°C, and thereafter the precipitate is filtered off and washed with isopropanol. The substance was dried at 3 814 - 84 70°C over Ρ^Ο^θ in vacuo.

Yield: 6.6 pts. by wt. Melting point = 146°C. calculated: C 52.6 H 5.2 N 16.7 0 25.5 found: C 52.6 H 5.3 N 16.8 0 25.8 22.2.

CH3-CO-OCH N-CO-Cl A solution of trimethylchlorosilane (3.2 pts. by wt.) in benzene is added dropwise to a mixture, boiling under reflux, of l-(5-acetoxymethyl-furfurylideneamino)-2-oxo-imidazolidine (6.6 pts. by wt.), benzene (60 pts. by vol.) and triethylamine (4.1 pts by vol.) and the mixture is then boiled for a further 20 hrs. The triethylamine hydrochloride is then filtered off whilst the mixture is still hot, and is rinsed with benzene, and a solution of phosgene (1.6 pts. by vol.) in benzene (10 pts. by vol.) is added to the combined filtrates, whilst cooling. The mixture is left to stand for 20 hrs. at 20°C and the product is then filtered off.

Yield: 4.3 pts. hy wt. Melting point = 184-85°C.

IR spectrum (in paraffin oil) (carbonyl region): 1,810 and 1,745 cm \ calculated: C 45.9 H 3.8 Cl 11.3 N 13.4 0 25.5 found: C 46.4 H 3.9 Cl 11.1 N 13.4 0 25.3 22.3 CH. ch2ococh3 438 14 o-co-ch3 This cephalosporin is obtained when cephaloglycine dihydrate (2.0 pts. by wt) and l-chlorocarbonyl-2-oxo-3-(5-acetoxymethyl-furfurylidene amino)-imidazolidine (1.5 pts. by wt.) are reacted with one another in the manner described in Examples A and 1.3. On acidification, a part of the cephalosporin is obtained as a precipitate which is insoluble in water and in the organic phase (ethyl acetate): (Yield: 0.1 pt. by wt.; melting point = sticky at 2O5°C, progressive decomposition up to 260 C, but no clear melt; IR spectrum in· the carbonyl region: 1,770, 1,726, 1,678, 1,600 and 1,528 cm in paraffin oil).

The cephalosporin can then be precipitated from the organic phase as described before.

Yield: 2.7 pts. by wt. of sodium 7-D-a-(/2-oxo3-(5-acetoxymethyl-furfurylidene amino) - imidazolidin - 1 - yl7 carbonylamino} - phenylacetamido - 3 acetoxymethyl - ceph - 3 - em - 4 - carboxylate. β-Lactam content: 86%.

IR spectrum (carbonyl region): 1,770 (shoulder), 1,760 (shoulder), 1,730, 1,668, 1,610, 1,550 (shoulder) and 1,530 cm \ NMR signals at τ = 2.33(1 Η), 2.45-2.85(5 Η), 3.15-3.25 (1 Η), 3.4-3.52(1 Η), 4.24-4.48(2 Η), 4.92(2 Η), 5.05.22 (3 Η), 6.0-6.27(4 Η), 6.55-6.75 (2 Η), 7.96(3 Η) - 86 and 8.02 ppm (3 H).

Melting point = from 22O°C, dropping and with decomposition.

Example 23 23.1 Λ CH=N-N NH 2-Chlorofuran-5-aldehyde is reacted with 1-amino2-oxo-imidazolidine as in Example 1.1. l-(5-Chlorofurfurylidene amino) “2-oxo-imidazolidine of melting point 173-175°C is obtained.

NMR (dg-DMSO): 7.45(s, IH), 7.26(s, broad, IH), 6.77 (d, IH), 6.6O(d, IH), 3.55(m, 4H) δ calculated: C 45.0 H 3.7 N 19.7 Cl 16.6 found: C 45.5 H 3.8 N 20.0 Cl 16.2 23.2 Cl· 0· CH=N-N N-COCl \_/ .0 pts. by wt. of l-(5-ohlorofurfurylideneamlno)15 2-oxo-imidazolidine, 31.8 pts. by wt. of triethylamine, 31.8 pts. by wt. of chloromethylsilane and 18.6 pts. by wt. of phosgene are reacted as in Example 1.2.

After recrystallisation from acetonitrile, 16.5 pts. by wt. of l-chlorooarbonyl-2-oxo“3-(5-ohlorofurfurylidene20 amino)-imidazolidine of dec. pt. 193-196°C are obtained, calculated: Cl 25.68 found: Cl 25.7 .0 pts. by wt. of cephaloglycine dihydrate in 100 pts. by vol. of 80 per cent strength aqueous THF and 3.5 pts. by wt. of l-chloroearbonyl~2~oxo-3-(5-chloro-fur5 furylideneamino)-imidazolidine are reacted as in Example 1.3. 4.3 pts. by wt. of sodium 7 - {D - a - /*(2 - oxo 3 - {5 - chlorofurfurylideneamino } - imidazolidin - 1 yl) - carbonylamino/ - phenylacetamido} - 3 - acetoxymethyl - ceph - 3 - em - 4 - carboxylate of dec. pt. 18510 190°C are obtained.

IR (KBr); 1,765, 1,720, 1,660, 1,595, 1,520, 1,405 and 1,225 cm F NMR (CD30D/D20): 7.48(s) and 7.37(m, total 6H), 6.78 (IH), 6.34(1 H), 5.65(1 H), 5.43(IH), 4.95(on which is superposed the signal of the exchangeable protons), 3.8(s, broad, 4h), 3.6 (on which is superposed the solvent peak), 2.06(s, 3Η)δ.

Example 24, 33.5 pts. by wt. of 2-bromofuran-5-aldehyde, dissolved in 100 pts. by vol. of THF, are added to a solution of l-amino-2-oxo-imidazolidine hydrochloride in 350 pts. by vol. of water, which has been adjusted to pH 5 with sodium hydroxide solution, and the mixture is stirred overnight. The precipitate is filtered off, washed with water and recrystallised from methanol. 30.0 pts. by wt. of 1-(5-bromofurfurylideneamirr)-2-oxo-imidazoli dene of dec. pt. 153-158°C are obtained.

IR (KBr): 1,720, 1,580, 1,410, 1,265 and 1,245 cm-1.

NMR (dg-DMSO): 7.55(s, IH), 7.31(s, IH), 6.8O(AB, 2H), m about 3.6 (4H)δ. 24.2.

CH=N-N N-COCl .0 pts. by wt. of l-(5-bromofurfurylideneamino)2-oxo-imidazoline, 37.8 pts. by wt. of triethylamine, 36.8 pts. by wt. of chlorotrimethylsilane and 23.0 pts. by wt. of phosgene are reacted as in Example 1.2.

After recrystallisation from acetonitrile, 21.6 pts. by wt. of l-chlorocarbonyl-2-oxo-3-(5-bromofurfuryli deneamino)-imidazolidine of dec. pt. 19O-184°C are obtained.

IR (paraffin oil): 1,815 cm X 24.3.

S ch2ococh3 COONa,H 4.5 pts. by wt. of cephaloglycine dihydrate and 3.3 pts. by wt. of l-chlorocarbonyl-2-oxo-3-(5-bromofurfuryli deneamino)-imidazolidine in 100 pts. by vol. of 80 per cent strength aqueous THF are reacted as in Example 1.3. 3.3 pts. by wt. of sodium 7 - {D - a - /(2 - oxo 89 4 3 8 l.j -{5 -brctnofurfurylidene - amino} - imidazolidin - 1 - yl) - carbonylaminq/ - phenylacetamido} - 3 - acetoxymethyl ceph - 3 - em - 4 - carboxylate of dec. pt. 187-196°C. IR(KBr): 1,775, 1,715, 1,655, 1,450 and 1,275cm1.

NMR (CD3OD/D2O): 7.55(s, 1H), 7.4(m, 5H), 6.80(d, 1H), 6.50(d, 1H), 5.68(d, 1H), 5.5O(s, 1H), 4.96(d, 1H), 4.92 (on which is superposed the signal of the exchangeable protons), 3.80(3, broad, 4H) , 3.4 (on which is superposed the solvent peak), 2.08(s, 3Η)δ.

Example 25. r\ .1.

CH, —1> Jl—CH=N-N NH 3 oZ^ \_J 98.3 pts. by wt. of 2-methylfuran-5-aldehyde are added to a solution of l-amino-2-oxo-imidazolidine hydrochloride in 1,000 pts. by vol. of water which has been brought to pH 4.5 with sodium hydroxide solution and the mixture is stirred overnight. The precipitate is filtered off, washed with water and recrystallised from ethanol. 126 pts. by wt. of 1-(5-methylfurfurylideneamino) 2-oxo-imidazolidine of melting point 194-6°C are obtained.

IR (KBr) . 3,320, 1,735, 1,710, 1,480, 1,420, 1,395 and 1,245 cm 1.

NMR (d,-DMS0)z 7.57(s, 1H), 7.22(s, broad, 1 H), 6.67 and 6.25 (Ab system, 2H), 3.65(m, 4H), 2.38 (s, 3H)δ . calculated: C 55.95 H 5.74 N 21.75 found: C 5 6.0 H 5.8 N 21.3. .2.

CH. // w •Οχ CH=N-N N-COCl \_7 50.0 pts. by wt. of 1-(5-methylfurfurylideneamino)-2 oxo-imidazolidine, 84.3 pts. by wt. of triethylamine, 84.0 pts. by wt. of chloromethylsilane and 51.4 pts. by wt. of phosgene are reacted as in Example 1.2. After recrystallisation from acetonitrile, 50.7 pts. by wt. of l-chlorocarbonyl-2-oxo-3-(5-methylfurfurylideneamino)imidazolidine of dec. pt. 180-186°C are obtained.

IR (paraffin oil): 1,815 cm-1. 4.4 pts. by wt. of cephaloglycine dihydrate and 2.6 pts. by wt. of l-chlorocarbonyl~2-oxo-3-(5-methylfurfuryli deneamino)-imidazolidine in 80 pts. by'vol. of 80 per cent strength aqueous THF are reacted as in Example 1.3. 4.4 pts. by Wt. of sodium 7 - {D - a -/(2 - oxo - 3 15 {5 - methylfurfurylideneamino} - imidazolidin - 1 - yl) carbonylamino7 - phenylacetamido} - 3 - acetoxymethyl ceph - 3 - em - 4 - carboxylate are obtained.

IR (KBr): 1,760, 1,725, 1,660, 1,600, 1,525, 1,405 and 1,225 cm A NMR (CD3OD): 7.7O(s, 1H), 7.4O(m, 5H), 6.80(d, 1H), 6.20(4, 1H), 5.75(4, 1H), 5.68 (s, 1H), 4.95 (m, on which is superposed the signal of the exchangeable protons), 3.88 (s, broad, 4H), 3.45 (on which is superposed the solvent peak), 2.35 (s, 3H), 2.04 (s,3H)5. - 91 26.1.

CH Example 26. Λ -jj-CH=N-N\_NH 14.0 pts. by wt. of 5-methyl-3-formyl-isoxazole are reacted with 25.6 pts. by wt. of l-amino-2-oxo-imidazolidine hydrochloride in 100 pts, by vol. of water as in Example 25.1. After 90 minutes, the precipitate is filtered off, washed with water, dried and recrystallised from absolute acetonitrile. 12.5 pts. by wt. of 1-(5methylisoxazol-3-yl-methyleneamino)-2-oxo-imidazolidine of melting point 195-7°C are obtained.

IR (paraffin oil): 3,220, 1,695 and 1,610 em NMR (CD30D) : 7.65(s, IH), 7.47 (s, broad, IH), 6.53 (s, IH), 3, . 7(m, 4H), 2. 50(s, 3H) fi. calculated: C 49.48 H 5.19 N 28.85 found: C 49.6 H 5.2 N 29.2. 0 26.2.

-CH=N-N CH, \_7 N-COCI 12.0 pts. by wt. of 1-(5-methyl-isoxazol-3-ylmethyleneamino)-2-oxo-imidazolidine, 21.0 pts. by wt. of triethylamine, 20.8 pts. by wt. of chlorotrimethylsilane and 12.3 pts. by wt. of phosgene are reacted as in Example 1.2. 19.8 pts. by wt. of l-chlorocarbonyl-2-oxo-3-(5methyl-isoxazol-3-yl-methyleneamino)-imidazolidine of - 92 melting point 199-2O3°C are obtained. The compound still contains small amounts of triethylamine hydrochloride which do not have to be removed since they do not interfere with the subsequent reaction.

IR (paraffin oil): 1,790 cm-1. 18.1 pts. by wt. of cephaloglycine dihydrate and 9.5 pts. by wt. of l-chlorocarbonyl-2-oxo-3-(methylisoxazol-3-yl-methyleneamino)-imidazolidine in 150 pts. by vol. of 80 per cent strength aqueous THF are reacted as in Example 1.3. 2.2 pts. by wt. of sodium 7-{D-a-/72-oxo-3-{5methylisoxazol-3-yl-methyleneamino} - imidazolidin - 1 yl) - carbonylaminq7 - phenylacetamido} - 3 - acetoxy15 methyl - ceph - 3 - em - 4 - carboxylate are obtained. Dec. pt. 215-22O°C.

IR(KBr): 1,760, 1,730 (shoulder), 1,670, 1,595 and 1,395 cm-1.

NMR(CD30D/D20): 7.74(s, 1H), 7.38(s, 5H), 6.63(s, 1H), .65 (d, IH), 5.5O(s, 1H), 4.95 (on which is superposed the signal of the exchangeable protons, 3.90 (s, broad, 4H), 3.4 (on which is superposed the solvent peak, 2.45 (s, 3H), 2.05 (s, 3Η)δ. 27.1 - 93 1-(Diacetoxymethyl)-5-nitrofuran (48.6 pts. by wt.) in a mixture of water (216 pts. by vol.) and concentrated H2SO4 (108 pts. by wt.) is boiled for 15 minutes under N2, the mixture is then cooled, the 5-nitro-furfural formed is taken up in ether and, after removing the ether, is dissolved in 100 pts. by vol. of methanol. A solution of l-amino-2-oxo-imidazolidine hydrochloride (27.5 pts. by wt.) in water (100 pts. by vol.) is added to this solution. After 4.5 hrs. the product which has separated out is filtered off, washed with water and dried.

Yield: 42.1 pts. by wt.

Melting point = 259-26O°C (Kofler heating bench). calculated: C 42.9 H 3.6 N 25.0 0 28.6 found: C 42.8 H 3.7 N 25.2 0 29.1 27.2. 0oN—il J— 2 o x CH=N- 0 Λ •Ν N· \_J 8.0 pts. by wt. of the product described above (27.1) are silylated in the manner described in Example 1.2. and then reacted with phosgene (2.6 pts. by vol.).

Yield: 5.2 pts. by wt.

Melting point = 188-19O°C (Kofler bench).

The substance still contains a little triethylamine hydrochloride - the bulk of the triethylamine hydrochloride is removed by washing with methylene chloride but this does not interfere with the subsequent reaction. 27.3. Ο V_7 0θ_£πτ_Γ»ΐϊ_ηη_·Μΐτ C00Na,H CH2-O-CO-CH3 This cephalosporin is obtained when cephaloglycine dihydrate (4.0 pts. by wt.) and l-chlorocarbonyl-2-oxo3-(5-nitro-furfurylideneamino )-imidazolidine (2.5 pts. by wt.) are reacted with one another in the manner described in Examples A and 1.3. On acidifying the reaction mixture which has been freed from tetrahydrofurane, only a part of the cephalosporanic acid dissolves in the ethyl acetate. The other part precipitates. The sodium salt is then obtained from both fractions in the manner already described.

Yield: 2.8 pts. by wt. of sodium 7-{D-a-/l2-oxo-3/5-nitro- furfurylideneamin^-imidazolidin - 1 - yl) carbonylaming7 - phenylacetamido} - 3 - acetoxymethyl 15 ceph - 3 - em - 4 - carboxylate. Melting point = decomposition from about 230°C to 26O°C, but no clear melt (Kofler heating bench). β-Lactam content (determined iodometrically): 84%.

NMR signals (in dg-DMF) at τ = 1.95-2.9(8H), 4.1-4.5(2H), 4.9-5.2(3H), 6.0(4H), 6.6-6,85(2H and 8.0 ppm/3H).

IR spectrum (carbonyl region): 1,765 (shoulder), 1,725, 1,670, 1,600 and 1,510 cm F (in Nujol). 28.1, Example 28.

This substance is obtained from l-amino-2-oxoimidazolldine (1.2 pts. by wt.) and 5-methoxycarbonylfurfural (1.8 pts. by wt.) in aqueous methanol (1:1;12 pts. by vol.) in 60 minutes at 20°C.

Yield: 2.7 pts. by wt.

Melting point = sticks firmly from 88°C (Kofler bench). 28.2.

N-C0-C1 2.6 pts. by wt. of the product described above (29.1) 10 are silylated in the manner described in Example 1.2. and then reacted with phosgene (0.8 pt. by vol.).

Yield: 1.5 pts. by wt.

Melting point = (crude product - still contains some triethylamine hydrochloride) = decomposition at about 220° C (Kofler bench).

Example 29. 29.1. η Λ C-Hc0-C0 —IL 21—CH=N-N 2 5 0'^ \_! NH This substance is obtained from l-amino-2-oxo-imidazolidine (1.3 pts. by wt.) and 5-ethoxycarbonyl-furfural (2.6 pts. by wt.) in aqueous methanol.

Yield: 3.1 pts. by wt.

Melting point (crude product) = 135-138°C (Kofler bench). 29.2.

CH=N-N N-C0-C1 \_J 2.85 pts. by wt. of the product described above (30.1.) are silylated in the manner described in Example 1.2. (but using dioxane as the solvent) and then reacted with phosgene (0.9 pt. by vol.).

Yield: 1.1 pts. by wt.

Melting point = 23O-33°C (Kofler bench)(crude product) .

Example 30. .1. (ΟΗ3)3Ο. // \_J CH=N-N NH This intermediate product is obtained when l-amino-2 oxo-imidazolidine hydrochloride (6.9 pts. by wt.) is dissolved in 1 N sodium hydroxide solution (50 pts. by vol)·, 4-tertiary butyl-benzaldehyde (8.0 pts. by wt.) is added and the mixture is stirred for 24 hrs. at 20°C.

The product which has precipitated is recrystallised from acetonitrile.

Yield: 5.9 pts. by wt.

Melting point = 208°C (Kofler bench). .2 (CH -CO-CI This substance is obtained by the procedure descri· - 97 bed in Example 1.2. from the product described above (Example 30.1) (5.5 pts. by wt.), after silylation with triethylchlorosilane (4.4 pts. by wt.) and subsequent reaction with phosgene (2.1 pts. by vol.), using dioxane as the solvent.

The substance still contained some triethylamine hydrochloride.

IR spectrum (COCI): 1,808 cm A (Nujol).

Example 31.

To prepare this cephalosporin, cephaloglycinedihydrate (1.5 pts. by wt.) and l-chlorocarbonyl-2oxo-3-(3-pyridyl-methyleneamino)-imidazolidine (0.8 pt.by wt.) are reacted in the manner described in Examples A. and 1.3. After removing the tetrahydrofuran and acidifying the mixture to pH 1.5, the free cephalosporanic acid separates out as a precipitate which is insoluble in water and in ethyl acetate (0.8 pt. by wt.); melting point: decomposition from about 200°C onwards no clear melt up to 26O°C /Kofler heating bench/; IR bands at 1,770, 1,745, 1,675 and 1,520-1,550 cm-1.

/Nujol7- This acid is dissolved in a little dimethylformamide, 1.3 pts, by vol. of an approximately 1 molar sodium 2-ethylhexanoate solution in ether containing methanol are added and the sodium salt of the cephalosporin is precipitated with ether.

Yield; 0.6 pt. by wt. of sodium 7-{D-a-/(2-oxo3-/3-pyridyl-methyleneaminq7 - imidazolidin - 1 - yl) - carbonylamino7 - phenylacetamido} - 3 - acetoxymethyl - ceph - 3 - em - 4 - carboxylate. Melting point = on sprinkling the finely powdered substance on the Kofler heating bench, from 242°C onwards, the material briefly forms a clear melt, and then immediately decomposes and solidifies and does not melt again below 26O°C.

IR spectrum (carbonyl region): 1,770(shoulder), 1,760,1,730, 1,670, 1,605 and 1,530-50 cm (in Nujol).

According to the NMR spectrum the substance contains 10 about 5.5 mol equivalents of water and 0.26 mol equivalets of sodium 2-ethylhexanoate. This was taken into account in the following calculated analytical data: calculated: C 45.9 fi 5.2 N 12.5 found: C45.9 H 5.3 N 1?.4 β-Lactam content: (determined iodometrically) 82%.

Example 32. ΓΛ (R) aC >-CH=N-N , N-CONH-CH-CONH-r\_I S' “N -00Q CH20H Q=H or Na 11.0 pts. by wt. of 7-(D-a-amino-phenylacetamido)3-hydroxymethyl-ceph-3-em-4-carboxylic acid in 100 pts. by vol. of 80 per cent strength aqueous THF and 6.1 pts. by wt. of l-chlorocarbonyl-2-oxo-3~furfurylideneaminaimidazolidine are reacted, and worked up, as in Example 1.3. 6.9 pts. by wt. of sodium 7-{D-a/~(2- oxo - 3 furfurylideneamino - imidazolidin - 1 - yl) - carbonylaminq7 - phenyl - acetamido}-3-hydroxymethyl-ceph-3-em-425 carboxylate of dec. pt. 215-22O°C are obtained.

NMRCCD3OD) : 7.8O(s, IH) , 7.7O(s, IH) , 6.97(q, IH) , .75 (d, IH), 5.63(s, IH), 5.37(on which are superposed the exchangeable protons), 4.4O(s, 2H), 3.95(s, broad 4H), the solvent peak (in δ) is superposed on the C-2-protons.

Example 33 7.5 pts. by wt. of 7-(D-a-amino-phenylacetamido)-3/(3-methyl-l,2,4-thiadiazol-5-yl)-thiomethyl7-ceph-3-em-4carboxylic acid in 100 pts. by vol. of 80 per cent strength aqueous THF and 6.1 pts. by wt. of 1-chlorocarbonyl-2-oxo-3-furfurylidene-amino-imidazolidine are reacted, and worked up, as in Example 1.3. .2 pts. by wt. of sodium 7-{D-a-/(2-oxo-3-furfurylidene-amino-imidazolidin-l-yl)-carbonylaminq7-phenylacet15 amido) - 3-/(3-methy1-1,2,4-thiadiazol-5-yl)-thiomethyl7~ceph 3-em-4-carboxylate of dec. pt. 21O-215°C are obtained.

IR(KBr): 1,760, 1,720, 1,660, 1,595, 1,525, 1,475, 1,410, 1,275 and 1,230 cm-1.

NMR(CD3OD): 7.7O(s, IH), 7.64(d, IH), 7.33(m, 5H), 6.86 (d, IH), 6.5O(dd, IH), 5.65(d, IH), 5.55(s, IH), 4.9O(d, IH), 4.02(pseudo-q, 2H), 3.85(s, broad, 4H), 3.4(on which is superposed the solvent peak), 2.52 (s, 3Η)δ. - 100 Example 34.

CH, Q-H or Na .0 pts. by wt. of 7-(D-ot-amino-phenylaoetamido)-3/(l-methyl-tetrazol-5-yl)-thiomethyl7-ceph-3-era-4carboxyllc acid in 100 pts. by vol. of 80 per cent strength aqueous THE and 6.1 pts. by wt. of 1-chlorocarbonyl-2-oxo-3-furfurylideneamino-imidazolidine are reacted, and worked up, as in Example 1.3. 3.2 pts by wt. of sodium 7 - {D - a - /(2 - oxo - 3 - furfurylidene amino - imidazolidin - 1 - yl) - carbonyl amino/ 10 phenylacetamido} -3-/(1- methyl - tetrazol - 5 yl) - thiomethyl7 - ceph - 3 - era-4-carboxylate of dec. pt. 210-220°C are obtained.

IR(KBr): 1,760, 1,720, 1,660, 1,610, 1,520, 1,475, 1,410 and 1,230 cm \ NMR (CD3OD): 7.73(s, IH), 7.63(d, 1H) , 7.38(m, 5H), 6.88(d, IH), 6.54(q, IH), 5.67(d, IH), 5.56(s, IH), 4.9 (on which are superposed the exchangeable protons), 4.32(s, 2H), 3.95(s, 3H), 3.85 (s, broad, 4H), 3.45 (on which is superposed the solvent peak)δ.

Example 35.

Q=H or Na - 101 8.0 pts. by wt. of 7-(D-a-amino-phenylacetamido)3-/(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-thiomethyl7~ ceph-3-em-4-carboxylic acid in 100 pts. by vol. of 80 per cent strength aqueous THF and 6.1 pts. by wt, of 15 chlorocarbonyl-2-oxo-3-furfurylideneamino-imidazolidine are reacted, and worked up, as in Example 1.3. 7.8 pts. by wt. of sodium 7-{D-a-/(2-oxo-3-furfurylideneamino-imidazolidin-l-yl) - carbonylaminq7 - phenylacetamino} - 3 - /(5 - trifluoromethyl - 1/3,4 - thiadiazol 2-yl)-thiomethyl7-ceph-3-em-4-carboxylate of dec. pt. 22O°C, and of 76% β-Lactam content, are obtained.

IR (paraffin oil): carbonyl region: 1,765, 1,720, 1,660, 1,600 and 1,530 cm A

Claims (20)

1. CLAIMS;1. A β-Lactam of the formula (I) Z-N N-CO-NH-CH-CO-NH-C- CH I N (I) in which 5 R represents a hydrogen atom Z represents a group of the formula wherein 1 2 R and R are identical or different and each denotes 10 hydrogen; an optionally substituted alkyl or alkenyl group; an optionally substituted cycloalkyl, cycloalkenyl or cycloalkadienyl group; an optionally substituted aralkyl group; an optionally substituted aryl group; an optionally substituted heterooylyl group; a carboxyl, L5 methoxycarbonyl, ethoxycarbonyl-, cyano, nitro, lower alkylcarbonyl group; or a group of the formula -C0NH 2 , -C0NHCH 3 , -C0N(CH 3 ) 2 ; -SO 2 NH 2 ; -SO 2 ~NHCH 3 or -SO 2 -N(CH 3 ) 2 or 4 3814 - 103 1 2 R and R conjointly with the carbon atoms to which they are bonded form a 3-membered to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring which can be substituted, 5 A represents -C^-CHj - , -CHg-C^-C^- or B represents an optionally substituted phenyl, cyclohexenyl or cyclohexadienyl group and X represents S, 10 Y represents a group of the formula C-CH O - T \Z c I COOH in which the carbon atom which carries the carboxyl group is bonded to the nitrogen atom of the β-lactam ring, and T 15 denotes a hydrogen atom; or an alkyl-CO-O-, pyridinium, amino-pyridinium, carbamoyloxy, azido, cyano or hydroxyl group, an -S-phenyl group, which can be substituted, or an -S-Het group, in which 20 Het represents an optionally substituted heterocyclic 5-membered or 6-membered ring; the compound being in either of the two possible R- and S- configurations with respect to the chirality centre 43S14 - 104 C, or in the form of a mixture of the diastereomers resulting therefrom, and, when Z represents the group R 1 \ C=N1 2 and R and R are different, in either the syn-form or 5 in the anti-form with regard to the imino group, or a hydrate form or salt thereof.

2. A compound according to claim 1, wherein Z represents a group of the formula 10 wherein R 1 denotes hydrogen and R denotes phenyl optionally substituted by halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, nitro, cycno, alkylsulphonyl with 1 to -5 4 carbon atoms or by CH^OOC-, or denotes a furyl, thienyl or pyridyl group, optionally substituted by halogen, N0 2 , alkyl or alkoxycarbonyl with 1 to 4 carbon atoms or by CH^COOCI^-; A represents -CHj-CHg-; θ B represents phenyl, hydroxyphenyl or cyclohexadienyl; - 105 and Y represents a group of the formula CH„ c-ch 2 -t X I COOH wherein 5 T represents hydrogen, -O-CO-CHj, hydroxyl or a thiadiazolylthio or tetrazolylthio group optionally substituted by alkyl with 1 to 4 carbon atoms or by CF^; and * C is in the D- = R-configuration 10

3. A compound according to claim 2 wherein R 2 denotes phenyl optionally substituted by halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, nitro, cyano, alkylsulphonyl with 1 to 4 carbon atoms or by CH^OOC-, or denotes a furyl, thienyl, pyridyl 15 group optionally substituted by halogen or CH 3 COOCH 2 ~; and T represents hydrogen, -O-CO-CH 3 or hydroxyl,

4. A compound according to claim 1 wherein x R, A, B and Y are as defined in claim 1; 20 R 1 and R are identical or different and each denotes hydrogen; optionally substituted alkyl or alkenyl; optionally substituted cycloalkyl, cycloalkenyl or cycloalkadienyl; optionally substituted aryl or optionally substituted heterocyclic group; and - 106 T represents hydrogen, alkyl-CO-O-(1)-pyridinium, amino pyridinium, carbamoyl, azido, cyano, the -S-phenyl group, which may be substituted, or the -S-Het group in which Het represents an optionally substituted hetero5 cyclic 5- or 6-membered ring.

5. A compound according to claim 1, wherein A and B are as defined in claim 2; R denotes phenyl optionally substituted by halogen, alkoxy with 1 to 4 carbon atoms, nitro, cyano or by alkyl 10 sulphonyl with 1 to 4 carbon atoms, or represents a furyl or thienyl group optionally substituted by halogen; and T represents -O-CO-CHj.

6. A compound of the formula

7. A compound of the formula Cl- (R) CH=N-N N-CONH-CH-CONH1_I CH 2 OCOCH 3 COOH - 107

8. A compound of the formula COOH

9. A compound of the formula >20. CH 3 -SO 2 —ί / CH=N-N N-CO-NH-CH-CO-NH. \__y COOH CO-CH,

10. A compound of the formula

11. A compound of the formula v_/ (R) N-CO-NH-CH-CONH CH 2 OCOCH 3 COOH - 108

12. A compound of the formula 4 3 814

13. A pharmaceutically acceptable salt of a compound according to any one of claims 5 to 12. 5

14. A pharmaceutically acceptable salt of a compound according to any one of claims 9 to 12.

15. A sodium salt of a compound according to any one of claims 6 to 10.

16. A sodium salt of a compound according to any 10 one of claims 9 to 12.

17. Any compound according to claim 1 specifically described herein.

18. A compound according to claim 1 and described in Table A. L5

19. A compound according to claim 1 identified in Table A by any one of the numbers BI (a) (1), (3) and (6), Bib (1); BII (19) and BV (1), (6) and (7). 20. A compound according to claim 1 as described in any one of examples 2.3; 3.3; 4.3; 6.3 and 7.3. 21. A compound according to claim 1 as described in any one of examples 8.3; 9.3; 10.3; 11.3; 13.3; 14.3; 15.. 3; 16.3; 16.4; 17.3; 18.3; 19.3; 20.3; 21.3 and 22.3. 22. A compound according to claim 1 as described 4381/j 109 in any one of examples 23.3; 24.3; 25.3; 26.3; 27.3 and 31 to 35. 23. A process for preparing a compound according to claim 1 which comprises reacting a compound of the 5 formula (II) R in which * R, B, C, X and Y are as defined in claim 1, or a salt thereof with a compound of the formula (III) :0 in which Z and A are as defined in claim 1 and W represents halogen, azido or another leaving group which is eliminated under the reactions conditions, 15 in the presence of a solvent and optionally in the presence of an acid-binding agent and, optionally either converting the resulting β-lactam into a salt or, converting the resulting salt into the free acid. 24. A process according to claim 23, wherein the - 110 reaction is conducted at a temperature of from -20 to +50°C. 25. A process according to claim 23 or claim 24 wherein the compound is as defined in claim 2 or claim 22. 26. A process according to claim 25 wherein the compound is as defined in any one of claims 3, 11, 12 and 22. 27. A process according to claim 23 wherein the compound is as defined in any one of claims 4, 10, 19 and 20. 28. A process for preparing a compound according to claim 1 substantially as hereinbefore described in any one of the Examples listed in claim 20. 29. A process for preparing a compound according to claim 1 substantially as hereinbefore described in any one of the Examples listed in claim 21. 30. A process for preparing a compound according to claim 1 substantially as hereinbefore described in any one of the Examples listed in claim 22. 31. A compound according to claim 1 prepared by a process according to any one of claims 23 to 30. 32. A pharmaceutical composition containing as an active ingredient a compound according to any one of claims 1 to 22 and 30 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent. 33. A pharmaceutical composition containing as an active ingredient a compound according to any one of - Ill claims 1 to 22 and 31 in the form of a sterile or isotonic aqueous solution. 34. A composition according to claim 32 or 33 containing from 0.5 to 95% by weight of the said active ingredient. 35. A composition according to any one of claims 32 to 34 wherein the active ingredient is a compound according to any one of claims 3, 11, 12, 14, 16, 18 and 21. 36. A composition according to any one of claims 32 to 34 wherein the active ingredient is a compound according to any one of claims 4 to 10, 13, 15, 19 and 20. 37. A medicament in dosage unit form comprising a compound according to any one of claims 1 to 22 and 31 either alone or in admixture with a diluent. 38. A medicament in the form of tablets, pills, dragees, capsules, ampoules, or suppositories comprising a compound according to any one of claims 1 to 22 and 31 either alone or in admixture with a diluent. 39. A medicament according to claim 37 or 38 wherein the said compound is a compound according to any one of claims 3, 11, 12, 14, 16, 18 and 21. 40. A medicament according to claim 37 or 38 wherein the said compound is a compound according to any one of claims 4, 13, 15, 19 and 20. 41. A method of combating bacterial illness in non-human animals which comprises administering to the animals an active compound according to any one of claims 1 to 22 and 31 either alone or in admixture with a diluent or in the form of a medicament according to claim 37 or 38. - 112 42. A method according to claim 41 in which the active compound is administered in an amount of from 20 to 200 mg per kg body weight per day. 43. A method according to claim 41 or 42 in which 5 the active compound is administered orally or parenterally. 44. A method according to any one of claims 41 to 43 wherein the active compound is a compound according to any one of claims 3, 11, 12, 14, 16, 18 and 21. 45. A method according to any one of claims 41 10 to 43 in which the active compound is a compound according to any one of claims 4 to 10, 13, 15, 19 and 20. 46. A medicated fodder comprising a nutritious material and, as active ingredient, a compound according to claim 1 or claim 2. 15 47. A medicated fodder according to claim 46 wherein the active ingredient is a compound according to any one of claims 3, 11, 12, 14, 16, 18 and 21. 48. A medicated fodder according to claim 46 wherein the active ingredient is a compound according to

20. Any one of claims 4 to 10, 13, 19 and 20.