Cephalosporins, processes for their preparation and pharmaceutical compositions containing them

Abstract: Cephalosporin derivatives having a 3-position substituent of the formula I are described: wherein R¹ is hydrogen, alkenyl or optionally substituted alkyl, Het is a 5- or 6-membered heterocyclic ring bonded via a carbon atom to the amide linkage, wherein Het is selected from a group of the formulae II - III: wherein A is CH or a nitrogen atom; B is oxygen, sulphur or a group NR⁴; one or two of D, E, F and G are nitrogen atoms and the remainder are CH groups: or Het is a pyrazinone, pyridinone, pyridazinone or pyrimidinone ring, or is a thione equivalent of such a ring, said rings having a substituent R⁴ on one nitrogen atom, or is pyranone, or pyranthione; the ring Het being fused by any two adjacent carbon atoms to the benzene ring; and Het being attached to the -CH₂NR¹CO- group via a carbon atom; R² is hydroxy or an in vivo hydrolysable ester thereof; R³ is ortho to R² and is hydroxy or an in vivo hydrolysable ester thereof; and R⁴ has various values. The use of such compounds as antibacterial agents is described as are processes for their preparation and intermediates therefor.

Description: The present invention relates to cephalosporins and in particular to such compounds comprising an amide group. This invention further relates to processes for their preparation, to intermediates in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them. The compounds of this invention are antibiotics and can be used in the treatment of any disease that is treated with antibiotics for example in the treatment of bacterial infection in animals, in particular in mammals including humans. The compounds of this invention also have non-therapeutic uses as they can be used in conventional manner in industry as is known to those in the art. The compounds of this invention, however, are primarily of therapeutic interest as they show a desirable profile of activity and duration in their antibacterial effect. Investigation into new cephalosporin derivatives has been intense over the past 25 years with many thousands of patents and scientific papers having been published. A particular problem associated with the commercially available cephalosporins is the lack of potency against strains of Pseudomonas including Ps. aeruginosa. The present invention provides cephalosporin derivatives having novel 3-position substituents, which derivatives possess good antibacterial activity against a wide range of organisms and show good stability to β-lactamases. These compounds are particularly advantageous in that they have excellent activity against strains of Ps. aeruginosa. GB-B-2089339 and GB-B-2148282 disclose compounds wherein the 3-position substituent of a cephalosporin is of the formula: - CH₂R² wherein R² is a substituted or unsubstituted aryl, acylamino, aromatic heterocyclic, triazolyl or tetrazolyl group. In the above mentioned references the substituent "acyl" is able to have a variety of meanings but there is no teaching or suggestion of the compounds of the present invention which comprise specific ring systems having hydroxy groups or related substituents ortho to one another. Accordingly the present invention provides a cephalosporin compound of the formula IV: or salt or ester thereof, wherein: R¹ is hydrogen, C₁₋₆alkyl optionally substituted by halo, hydroxy, C₁₋₄alkoxy, carboxy, amino, cyano, C₁₋₆alkanoylamino, phenyl or heteroaryl wherein heteroaryl is a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulphur and may be optionally substituted, for example by the substituents described hereinafter with respect to the fused Het-benzene ring system, or R¹ is C₂₋₆alkenyl; Het is a 5- or 6-membered heterocyclic ring selected from a group of the formulae II -III: wherein A is CH or a nitrogen atom; B is oxygen, sulphur or a group NR⁴; one or two of D, E, F and G are nitrogen atoms and the remainder are CH groups: or Het is a pyrazinone, pyridinone, pyridazinone or pyrimidinone ring, or is a thione equivalent of such a ring, said rings having a substituent R⁴ on one nitrogen atom: or Het is a pyranone or pyranthione ring: the ring Het being fused by any two adjacent carbon atoms to the benzene ring; and Het being bonded via a carbon atom to the -CH₂NR¹CO- group; R² is hydroxy or an in vivo hydrolysable ester thereof; R³ is ortho to R² and is hydroxy or an in vivo hydrolysable ester thereof; R⁴ is hydrogen or hydroxy, or C₁₋₆alkoxy, phenoxy, C₂₋₆alkenyl or C₁₋₆alkyl, (any of these groups being optionally substituted by hydroxy, C₁₋₆alkoxy, cyano, amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, carboxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoyloxy, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, C₁₋₆alkoxycarbonylamino, phenyl, phenylC₁₋₆alkyl, carboxyaminocarbonyl, C₁₋₆alkoxycarbonylaminocarbonyl, benzoyl or C₃₋₈cycloalkyl) or R⁴ is phenyl, C₃₋₈ cycloalkyl, amino, C₁₋₆alkylamino or di-C₁₋₆alkylamino: wherein the fused Het-benzene ring system and/or any phenyl group is further optionally substituted by at least one substituent selected from C₁₋₆alkyl, halo, hydroxy, hydroxy C₁₋₆alkyl, cyano, trifluoromethyl, nitro, amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, phenyl C₁₋₆alkylamino, C₁₋₆alkanoyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkanoyloxy, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkyl carbamoyl, carboxy, carboxy C₁₋₆alkyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl, sulpho, sulphoC₁₋₆alkyl, sulphonamido, C₁₋₆alkylsulphonamido, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoylamino, thioureido and amidino: X is sulphur, oxygen, methylene or sulphinyl; R⁶ is hydrogen, methoxy or formamido; R⁵ is 2-aminothiazol-4-yl or 2-aminooxazol-4-yl each optionally substituted in the 5-position by fluorine, chlorine or bromine, or R⁵ is 5-aminoisothiazol-3-yl, 5-amino-1,2,4-thiadiazol-3-yl, 3-aminopyrazol-5-yl, 3-aminopyrazol-4-yl, 2-aminopyrimidin-5-yl, 2-aminopyrid-6-yl, 4-aminopyrimidin-2-yl, 2-amino-1,3,4-thiadiazol-5-yl or 5-amino-1-methyl-1,2,4-triazol-3-yl; R⁷ is of the formula =N.O.R⁸ (having the syn configuration about the double bond) wherein R⁸ is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (1-3C)alkyl(3-6C)cycloalkyl, (3-6C)cycloalkyl(1-3C)alkyl, (3-6C)alkenyl optionally substituted by carboxy, (5-8C)cycloalkenyl, (3-6C)alkynyl, (2-5C)alkylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, (1-4C)alkylcarbamoyl(1-4C)alkyl, di(1-4C)alkylcarbamoyl(1-4C)alkyl, (1-4C)haloalkylcarbamoyl(1-4C)alkyl, (1-3C)haloalkyl, (2-6C)hydroxyalkyl, (1-4C)alkoxy(2-4C)alkyl, (1-4C)alkylthio(2-4C)alkyl, (1-4C)alkanesulphinyl(1-4C)alkyl, (1-4C)alkanesulphonyl(1-4C)alkyl, (2-6C)aminoalkyl, (1-4C)alkylamino(1-6C)alkyl, (2-8C)dialkylamino(2-6C)alkyl, (1-5C)cyanoalkyl, 3-amino-3-carboxypropyl, 2-(amidinothio)ethyl, 2-(N-aminoamidinothio)ethyl, tetrahydropyran-2-yl, thietan-3-yl, 2-oxopyrrolidinyl, or 2-oxotetrahydrofuranyl, or R⁸ is of the formula V:- -(CH₂) q -C(COOH)=CR⁹R¹⁰ V wherein q is one or two and R⁹ and R¹⁰ are independently hydrogen or C₁₋₄alkyl; or R⁸ is of the formula VI:- -CR¹¹R¹²-(CH₂) r -COR¹³ VI wherein r is 0-3, R¹¹ is hydrogen, (1-3C)alkyl or methylthio, R¹² is hydrogen (1-3C)alkyl, (3-7C)cycloalkyl, cyano, carboxy, (2-5C)carhoxyalkyl or methanesulphonylamino, or R¹¹ and R¹² are joined to form, together with the carbon to which they are attached, a (3-7C)carbocyclic ring, and R¹³ is hydroxy, amino, (1-4C)alkoxy, (1-4C) alkylamino or of the formula NHOR¹⁴ in which R¹⁴ is hydrogen or (1-4C)alkyl; or R⁷ may be of the formula =CH.R¹⁵ wherein R¹⁵ is hydrogen, halogen, (1-6C)alkyl, (3-7C)cycloalkyl, (2-6C)alkenyl, (3-7C)cycloalkenyl, phenyl or benzyl. In one aspect R¹ may be C₁₋₆alkyl substituted by heteroaryl as defined above. For example R¹ may be pyridinylmethyl or furanylmethyl. Particular meanings for R¹ are hydrogen, C₁₋₆alkyl for example methyl, ethyl or propyl, hydroxy C₁₋₆alkyl for example 2-hydroxyethyl, halo C₁₋₆alkyl for example 2-chloroethyl or 2-fluoroethyl, C₁₋₆alkoxy C₁₋₆alkyl for example 2-methoxyethyl, 2-ethoxyethyl or methoxymethyl, carboxy C₁₋₆alkyl for example carboxymethyl, phenyl C₁₋₆alkyl for example benzyl or phenethyl, or C₂₋₆alkenyl for example allyl. Preferably R¹ is hydrogen, methyl or ethyl. Most preferably R¹ is hydrogen. In one aspect Het is a ring of the formula II as hereinbefore described, that is Het is an imidazole, thiazole, oxazole, pyrrole, furan or thiophen ring. In particular the Het-benzene fused ring system is benzimidazol-2-yl, benzthiazol-2-yl or indol-2-yl. In another aspect Het is a ring of the formula III as hereinbefore described, that is the Het-benzene fused ring system represents quinoline, isoquinoline, quinazoline, cinnoline, quinoxaline or phthalazine. In a further aspect Het is a pyrazinone, pyridinone, pyridazinone or pyrimidinone ring, or the thione equivalent of such rings, said rings having a substituent R⁴ on one nitrogen atom. For example the Het-benzene fused ring system may be of the sub-formula i)-ix): Particular meanings of the group R⁴ are hydrogen, hydroxy, C₁₋₆alkoxy for example methoxy or ethoxy, C₁₋₆alkyl for example methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, C₃₋₈cycloalkyl for example cyclopropyl, hydroxy C₁₋₆alkyl for example hydroxymethyl or hydroxyethyl, phenyl, phenylC₁₋₆alkyl for example benzyl or phenethyl, C₂₋₆alkenyl for example allyl, aminoC₂₋₆alkyl for example aminoethyl or aminopropyl, carbamoylC₁₋₆alkyl for example carbamoylmethyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl for example ethoxycarbonylmethyl or ethoxycarbonylethyl and carboxyC₁₋₆alkyl for example carboxymethyl or carboxyethyl. Preferably R⁴ is hydrogen, methoxy, ethoxy, methyl, ethyl, isopropyl, butyl or benzyl. Preferred values for the Het-benzene fused ring system are those of the sub-formulae i), ii) and iii). For the avoidance of doubt, thione equivalents of ring systems i) - ix) are those wherein the oxo group (=O) is replaced by the thioxo group (=S). In another aspect the Het ring is a pyranone ring so that values of the Het-benzene fused ring system include sub-formulae x)-xii): The ring systems of the sub-formulae xi) are preferred, that is the chroman-2-one ring system. The present invention also covers the related ring systems wherein the oxo group (=O) is replaced by a thione group (=S). R² is hydroxy or an in vivo hydrolysable ester thereof. In vivo hydrolysable esters are those pharmaceutically acceptable esters that hydrolyse in the human or animal body to produce the parent hydroxy compound. Such esters can be identified by administering, e.g. intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters include C₁₋₆ alkanoyloxy for example acetoxy, propionyloxy, pivaloyloxy, C₁₋₄alkoxycarbonyloxy for example ethoxycarbonyloxy, phenylacetoxy and phthalidyl. Conveniently both R² and R³ have the same value and are both hydroxy or are both in vivo hydrolysable esters, for example they are both acetoxy or pivaloyloxy. As stated hereinbefore the fused Het-benzene ring system may be further optionally substituted, on either ring, by one or more atoms or groups. Particular substituents are C₁₋₆alkyl for example methyl or ethyl, halo for example chloro, fluoro or bromo, hydroxy, hydroxyC₁₋₆alkyl for example hydroxyethyl, nitro, amino, C₁₋₆alkylamino for example methylamino or ethylamino, di-C₁₋₆alkyl amino for example dimethylamino or diethylamino, phenylC₁₋₆alkylamino for example benzylamino, C₁₋₆alkoxy for example methoxy or ethoxy, carboxyC₁₋₆alkyl for example carboxymethyl, C₁₋₆alkanoylamino for example acetamido, trifluoromethyl, carboxy, carbamoyl, C₁₋₆alkylcarbamoyl for example methylcarbamoyl, di-C₁₋₆alkylcarbamoyl for example dimethylcarbamoyl, C₁₋₆alkanoyl for example acetyl, C₁₋₆alkylthio for example methylthio, cyano and C₁₋₆alkoxycarbonyl for example methylcarbonyl. In a particularly preferred aspect the 3-position substituent for the cephalosporins of the present invention is of the sub-formula xiii): wherein R² and R³ are as hereinbefore defined, R⁴¹ is hydrogen or C₁₋₆ alkyl for example methyl, ethyl, propyl or butyl and R⁴² is hydrogen, nitro, cyano, chloro, bromo, carboxy or C₁₋₆ alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl. In a further particularly preferred aspect the 3-position substituent for the cephalosporins of the present invention is of the sub-formula xiv): wherein R⁴³ is hydrogen, chloro, bromo, carboxy, C₁₋₆ alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl, amino, C₁₋₆ alkylamino for example methylamino or ethylamino or phenyl C₁₋₆alkylamino for example benzylamino. In another particularly preferred aspect the 3-position substituent for the cephalosporins of the present invention is of the sub-formula xv) or xvi): wherein R², R³ and R⁴² are as hereinbefore defined. Particular meanings for R⁸ are hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, allyl, cyclopentenyl, cyclohexenyl, propargyl, methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, methylcarbamoylmethyl, 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 2-ethoxyethyl, 2-methylthioethyl, 2-methanesulphinylethyl, 2-methanesulphonylethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 2-dimethylaminoethyl, cyanomethyl, 2-cyanoethyl, azidomethyl, 2-azidoethyl, ureidomethyl, 3-amino-3-carboxypropyl, 2-(amidino)ethyl, 2-(N-aminoamidino)ethyl, tetrahydropyran-2-yl, thietan-3-yl, 2-oxopyrrolidinyl and 2-oxo-tetrahydrofuran-3-yl, or, when R⁸ is of the formula V in which q is 1 or 2, a particular meaning for R⁸ is when R⁹ and R¹⁰ are hydrogen or methyl, or, when R⁸ is of the formula VI, a particular meaning for R⁸ is when r=0 and R¹¹ is hydrogen, methyl or methylthio, R¹² is hydrogen, methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyano, carboxy, carboxymethyl, 2 carboxyethyl or methanesulphonylamino, or when R¹¹ and R¹² are joined to form, together with the carbon to which they are attached, a cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane ring and R¹³ is hydroxy, amino, methoxy, ethoxy, methylamino, ethylamino, or of the formula NHOR¹⁴ in which R¹⁴ is hydrogen, methyl or ethyl. Preferably R⁸ is C₁₋₆alkyl for example methyl or ethyl,1-carboxycyclobutyl, 1-carboxycyclopentyl, or 2 carboxyprop-2-yl. In particular R⁸ is 2-carboxyprop-2-yl. Particular meanings for R¹⁵ are hydrogen, methyl, ethyl or chlorine. A particularly preferred class of cephalosporins of the present invention is that wherein R⁵ is 2-aminothiazol-4-yl, R⁷ is a group =NOR⁸ wherein R⁸ is C₁₋₆ alkyl, 1-carboxycyclobutyl,1-carboxycyclopentyl or 2-carboxyprop-2-yl, R⁶ is hydrogen, X is sulphur and the 3-position substituent is of the sub-formula xiii) - xvi). Particular compounds of the present invention include: 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-methyl-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-4- oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-n-butyl-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-5-nitro-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-5-cyano-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7 [2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-5-chloro-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid. 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-methoxy-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dipivaloyloxy-1-ethyl-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-4-oxocinnolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(5-carboxy-1,4-dihydro-6,7-dihydroxy-1-ethyl-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(5-carboxy-1,4-dihydro-6,7-dihydroxy-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(6,7-dihydroxy-2-methylaminoquinoxalin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(2-bromo-6,7-dihydroxyquinoxalin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino) acetamido]-3-(2-chloro-6,7-dihydroxyquinoxalin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(2-benzylamino-6,7-dihydroxyquinoxalin -3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(6,7-dihydroxy-2-methoxycarbonylquinoxalin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(7,8-dihydroxy-2-oxo-2H-benzopyran-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, and 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamidol-3-(1,4-dihydro-6,7-dihydroxy-2-methyl-1-oxo-isoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid. The cephalosporin derivatives referred to herein are generally named in accordance with the 'cephem' nomenclature and numbering system proposed in J.A.C.S. 1962, 84 ,3400. It should be realised, of course, that the present invention covers all tautomeric forms, for example the sub-formulae i)-ix) are depicted in the keto form; where possible these may exist and be depicted in the enol form. Such tautoners are, of course, within the scope of the present invention. Furthermore the Het ring may be optionally substituted by hydroxy and this may exist in the tautomeric keto form. As stated hereinbefore the compounds of this invention at primarily intended for use in therapy. Therefore in a preferred aspect the present invention provides a cephalosporin compound of the formula IV or a pharmaceutically acceptable salt or ester thereof. Suitable salts include acid addition salts formed with hydrochloric, hydrobromic, citric, maleic, phosphoric and sulphuric acids. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, or N,N-dibenzylethylamine. In order to use a compound of the present invention or a pharmaceutically acceptable salt or ester thereof for the therapy of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a cephalosporin compound having a 3-position substituent of the formula I or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier. The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal, topical, local or parenteral administration. For these purposes it may be formulated by means known to the art into the form of, for example, tablets, capsules, syrups, aqueous or oily solutions or suspensions, emulsions, dispersible powders, suppositories and sterile injectable aqueous or oily solutions or suspensions. In addition to the pharmaceutically acceptable cephalosporin derivative of the present invention the pharmaceutical composition of the invention may also contain, or be co-administered with, one or more known drugs selected from other clinically useful antibacterial agents (for example other beta-lactams or aminoglycosides), inhibitors of beta-lactamase (for example clavulanic acid), renal tubular blocking agents (e.g. probenicid) and inhibitors of metabolising enzymes (for example inhibitors of peptidases, for example Z-2-acylamino-3-substituted propenoates). A preferred pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection, for example a sterile injectable containing between 1 and 50% w/w of the cephalosporin derivative, or one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg. and 1 g. of the cephalosporin derivative. The pharmaceutical compositions of the invention will normally be administered to man in order to combat infections caused by bacteria, in the same general manner as that employed for cephalothin, cefoxitin, cephradine, ceftazidime and other known clinically used cephalosporin derivatives, due allowance being made in terms of dose levels for the potency of the cephalosporin derivative of the present invention relative to the known clinically used cephalosporins. Thus each patient will receive a daily intravenous, subcutaneous or intramuscular dose of 0.05 to 30 g., and preferably 0.1 to 10 g., of the cephalosporin derivative, the composition being administered 1 to 4 times per day, preferably 1 or 2 times a day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose. Thus a preferred daily oral dose is 0.5 to 10 g. of the cephalosporin derivative, the composition being administered 1 to 4 times per day. In a further aspect the present invention provides a process for preparing a cephalosporin compound having a 3-position substituent of the formula IV, which process comprises: a) reacting a cephalosporin compound of the formula wherein R¹, R⁵, R⁶, R⁷ and X are as defined hereinabove with a compound of the formula VII: wherein Het, R² and R³ are as defined in hereinabove and L is a leaving group; or b) reacting a compound of the formula VIII with a compound of the formula IX or a reactive derivative thereof: wherein R¹, R², R³, X, Het, R⁵, R⁶ and R⁷ are as hereinbefore defined; or c) for compounds wherein R⁷ is a group =NOR⁸, reacting a compound of the formula X: wherein R¹, R², R³, R⁵, R⁶, X, and Het are as hereinbefore defined, with a compound of the formula: R⁸ONH₂ wherein R⁸ is as hereinbefore defined; or d) for compounds wherein R⁷ is a group =NOR⁸ and R⁸ is other than hydrogen, reacting a compound of the formula IV as hereinbefore defined wherein R⁷ is a group =NOH with a compound of the formula XI: L¹ - R¹⁶ XI wherein L¹ is a leaving group and R¹⁶ is a group R⁸ other than hydrogen: or e) forming a group R⁵ by cyclizing an appropriate precursor thereof: wherein any functional groups are optionally protected: and thereafter, if necessary: i) removing any protecting group, ii) for preparing in vivo hydrolysable esters, esterifying corresponding hydroxy groups, iii) converting compounds wherein X is S to compounds wherein X is sulphinyl and vice versa, iv) forming a pharmaceutically acceptable salt. In the reaction between a cephalosporin compound having a 3-position substituent of the formula: -CH₂NHR¹ and a compound of the formula VII, conveniently L is a leaving group such as halo for example chloro, bromo or iodo. Most suitably the reaction is performed under conditions conventional for the reaction of acid halides with amines for example in the presence of an organic amine such as triethylamine. Suitably the reaction is performed at an ambient or lower temperature in a substantially inert solvent such as dimethylformamide and/or dichloromethane. In an alternative aspect the leaving group L is part of an activated ester formed with the acid precursor of the compound of the formula VII, i.e. a compound wherein L is -OH provides an activated ester, e.g. dicyclohexylcarbodi-imide provides an activated ester of the formula VII wherein L is -OC(NHC₆H₁₁)=NC₆H₁₁, which group is displaced by the cephalosporin having a 3-position substituent of the formula: -CH₂NHR¹. Formation and reaction of the active ester is performed in conventional manner in the presence of reaction promotors such as hydroxybenzotriazole and triethylamine, for example in a substantially inert organic solvent such as dimethylformamide at a non-extreme temperature such as 10°C-50°C. The cephalosporin starting-materials for this reaction are known from the art, or are made by methods analogous to those of the art. See for example EP-A-127992 and EP-A-164944. The compounds of the formula VII are either known in the art or are made by methods analogous thereto. For example compounds wherein L is chloro are conveniently prepared from the corresponding acids of the formula (VII A): wherein Het, R² and R³ are as hereinbefore defined. The acids are known or are prepared by methods of heterocyclic chemistry known to those skilled in the art, for example as in the hereinafter described Examples. Many of the acids of the formula VII A are novel and as such form another aspect of the present invention; in particular wherein R² and R³ are both hydroxy. Suitable and preferred acids of the formula VII A are those that give rise to the suitable and preferred cephalosporin compounds of the present invention. In particular the present invention provides specific, novel heterocyclic carboxylic acids (and precursors thereto) described in the experimental section hereinafter. The reaction between compounds of the formulae VIII and IX is performed under conditions conventional in the cephalosporin art, for example under standard acylation conditions wherein for example the acid is activated as an acid bromide, acid chloride, anhydride or activated ester, or the reaction is performed in the presence of a coupling reagent such as dicyclohexylcarbodi-imide. The compounds of the formula VIII can be prepared in a manner analogous to that described for the compounds having the 3-substituent of the formula IV, with the 7-amino group being optionally protected. The reaction between the compound of the formula X and R⁸ONH₂ is performed under conditions standard in the general chemical and/or cephalosporin art. The compounds of the formula X can be prepared in a manner analogous to that described for the compounds having the 3-substituent of the formula IV. The reaction between the compound of the formula IV wherein R⁷ is a group =NOH and a compound of the formula XI is performed under conditions standard in the general chemical and/or cephalosporin art. A group R⁵ may be formed by cyclizing an appropriate precursor. For example compounds of the formulae XII and XIII: NH₂CSNH₂ (XIII) wherein R⁷, R⁶, X, R¹, R², R³ and Het are as hereinbefore defined and L² is a leaving group, may be reacted to form a 2-aminothiazol-4-yl group. A nitrogen atom of the thiourea may be optionally protected during this cyclization. The compounds of the formula XII can be prepared in a manner analogous to that described for the compounds having a 3-substituent of the formula IV. The compounds of the formulae IX, XI and R⁸ONH₂ are known from, or can be made by the methods of, the general chemical and/or cephalosporin art. The compounds of the formulae VIII, X and XII are novel and as such form a further aspect of the present invention. In the process of this invention any functional group can be optionally protected, if appropriate. Such protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. Specific examples of protecting groups are given below for the sake of convenience, in which "lower" signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention. A carboxyl protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming phenol, silanol or stannanol (the said alcohol, phenol, silanol or stannanol preferably containing 1-20 carbon atoms). Examples of carboxyl protecting groups include straight or branched chain (1-12C)alkyl groups (eg isopropyl, t -butyl); halo lower alkyl groups (eg 2-iodoethyl, 2,2,2-trichloroethyl); lower alkoxy lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (eg 1-methoxy-carbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg p-methoxybenzyl, o -nitrobenzyl, p -nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (eg trimethylsilylethyl); and (2-6C)alkenyl groups (eg allyl and vinylethyl). Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis. Examples of hydroxyl protecting groups include lower alkanoyl groups (eg acetyl); lower alkoxycarbonyl groups (eg t -butoxycarbonyl); halo lower alkoxycarbonyl groups (eg 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, p -methoxybenzyloxycarbonyl, o -nitrobenzyloxycarbonyl, p -nitrobenzyloxycarbonyl); tri lower alkylsilyl (eg trimethylsilyl, t -butyldimethylsilyl) and aryl lower alkyl (eg benzyl) groups. In addition two hydroxy groups substituted on adjacent carbon atoms, for example in the catechol moiety, may be protected in the form of a cyclic acetal such as the methylenedioxy moiety. Examples of amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg p -methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di- p -anisylmethyl and furylmethyl groups; acyl (eg alkoxycarbonyl and aralkoxycarbonyl eg t -butoxycarbonyl and benzyloxycarbonyl); trialkylsilyl (eg trimethylsilyl and t -butyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups; and the phthalimido group. The following biological test methods, data and Examples serve to illustrate this invention. Antibacterial Activity The pharmaceutically acceptable cephalosporin compounds of the present invention are useful antibacterial agents having a broad spectrum of activity in vitro against standard laboratory microorganisms, both Gram-negative and Gram-positive, which are used to screen for activity against pathogenic bacteria. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system. In particular, the cephalosporins of the present invention show good stability to β-lactamases reinforcing the broad spectrum potency. In a further advantageous aspect. The present compounds typically have particularly high activity in vitro against strains of Pseudomonas aeruginosa and other Gram-negative aerobic bacteria. The antibacterial properties of the compounds of the invention may also be demonstrated in vivo in conventional mouse protection tests. In addition representative compounds of this invention show prolonged duration, as evidenced by half-life values, in test animals. Cephalosporin derivatives have generally been found to be relatively non-toxic to warm-blooded animals, and this generalisation holds true for the compounds of the present invention. Compounds representative of the present invention were administered to mice at doses in excess of those required to afford protection against bacterial infections, and no overt toxic symptoms or side effects attributable to the administered compounds were noted. The following results were obtained for representative compounds on a standard in-vitro test system using Isosensitest agar medium. The antibacterial activity is described in terms of the minimum inhibitory concentration (MlC) determined by the agar-dilution technique with an inoculum size of 10⁴ CFU/spot (CFU represents colony forming units). Example 1 7-[2-(2-Aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4 dihydro-1-ethyl-6,7-dihydroxy-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid. i) 1.4-Dihydro-1-ethyl-6,7-methylenedioxy-4-oxoquinoline-3-carboxylic acid (3.9g) and boron tribromide (15ml) were heated at 50°C for 15 hours. The reaction mixture was cooled and added slowly to water (100ml) at 0°C. The pH was adjusted to 11 with concentrated potassium hydroxide, the mixture was filtered and the filtrate taken to pH1, whereupon the precipitate was collected by filtration, washed with water and dried to give 1,4-dihydro-6,7-dihydroxy-1-ethyl-4-oxoquinoline-3-carboxylic acid (3.13g); δ ((CD₃)₂SO) 1.42(3H,t); 4.46(2H,q); 7.23(1H,s); 7.66(1H,s); 8.82(1H,s)ppm. ii) Part of the product from i) (1.0g) was dissolved in acetonitrile (15ml) by the addition of 1,8-diazabicyclo-[5.4.0]undec-7-ene (1.2g). The solution was cooled to 0°C, phenacyl chloride (1.3ml) added and stirred at ambient temperature for 72 hours. HCl solution in ether (40ml; 40g/l) was added; the solvents were evaporated and the resultant residue was dissolved in dichloromethane, filtered, concentrated and dissolved in methanol to give 6,7-diphenylacetoxy-1,4-dihydro-1-ethyl-4-oxoquinoline-3-carboxylic acid (0.414g) as a precipitate; δ(CDCl₃) 1.54(3H,t); 3.56 and 3.68(4H,2s); 4.27(2H,q); 7.35(10H,s); 7.52 and 8.28(2H,ss); 8.73(1H,s)ppm. iii) Part of the product from ii) (0.286g) was dissolved in anhydrous dichloromethane (10ml) and treated with thionyl chloride (1.1 equivalents) for 90 minutes to give 6,7-diphenylacetoxy-1,4-dihydro-1-ethyl-4-oxoquinoline-3-carboxylic acid chloride. iv) The product from iii) was used without purification. To 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (0.446g) in dimethylformamide (10ml), at -20°C, was added triethylamine (3 equivalents) followed by the product of iii) above in dichloromethane (10ml). The reaction temperature was allowed to reach 0°C over a period of 60 minutes whereupon the solvents were evaporated to give, as a residue, the 6,7-diphenylacetoxy precursor of the title compound. This residue was dissolved in aqueous methanol, the pH was adjusted to 8.5 using ammonium hydroxide and maintained at this value for 60 minutes. 2N HCl was added to take the mixture to pH6.5 whereupon the crude product was purified by HPLC chromatography on silica using gradient elution (methanol:water:acetic acid 30:69:1 45:54:1). Collection of the appropriate fractions and evaporation gave the title compound (0.110g); δ ((CD₃)₂SO/CD₃COOD/CF₃COOD) 1.4(3H,t); 1.54(6H,s); 3.6(2H,s); 4.24(2H,q); 4.4(2H,m); 5.2(1H,d); 5.82(1H,d); 7.06(1H,s); 7.12, 7.65 and 8.69(3H,3s)ppm. EXAMPLES 2 - 63 The following general procedure was used for the preparation of the compounds of Examples 2 - 63. To a solution of the appropriate 3-aminomethylcephalosporin in dimethylformamide, at a temperature in the range +10° to -20°C (generally -20°C), was added triethylamine (about 2 or 3 equivalents) followed by at least one equivalent of the appropriate heterocycle in the form of an acid chloride in dichloromethane (or an activated este in dimethylformamide where indicated). The reaction was allowed to proceed to completion (typically 1 to 5 hours), for example as judged by thin layer chromatography or HPLC. The solvent was evaporated under reduced pressure to give the corresponding 3-heterocyclic carboxamidomethyl cephalosporin which was purified by: i) column chromatography on HP2OSS resin using gradient elution with methanol/water/acetic acid (1%) and/or ii) preparative HPLC on C₁₈ reverse phase silica using acetonitrile/water/trifluoroacetic acid (0.1%) or methanol/ammonium carbonate buffer. In certain cases, indicated by footnotes, the hydroxy groups on the heterocycle are protected. In such cases the coupling reaction provides a cephalosporin wherein the hydroxy groups are protected. This may be subjected to standard deprotection (as indicated in footnotes). Particulars of the compounds prepared are given in Table 1. NMR characterising data are given in Table 2. PREPARATION OF STARTING MATERIALS Cephalosporins Reference may be made to EP-A-127992 and EP-A-164944 for general descriptions of methods suitable for the preparation of cephalosporin starting materials. The starting materials for the Examples of the present invention including: 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid; 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-ethoxyimino)acetamido]ceph-3-em-4-carboxylic acid; and 3-ethylaminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-ethoxyimino)acetamido]ceph-3-em-4-carboxylic acid; are specifically described in EP-A-164944. Preparation of heterocyclic carbonyl chlorides or activate esters. The carbonyl chlorides (for reacting with the 3-aminomethyl cephalosporins) are prepared in conventional manner from the corresponding acids. Examples of conventional methods include dissolving the corresponding acid in anhydrous dichloromethane with thionyl chloride (at least one equivalent) and stirring for 1-3 hours at room temperature. In certain Examples the heterocyclic acid is dissolved in dichloromethane in the presence of trimethylsilylchloride and triethylamine (e.g. Examples 4-14, 16, 17 and 59). In Example 15, the heterocycle (306mg) was heated at reflux for 2.5 hours with hexamethyldisilazane (1.26ml) and saccharin (20mg) in chloroform (10ml). The reaction mixture was evaporated under reduced pressure and then converted to the acid chloride as described above. In Examples 45, 51-58, the heterocyclic acid was converted to the corresponding acid chloride with PCl₅ in dichloromethane at a temperature in the range 20-40°C for up to 2 hours. The solvents were evaporated and the residue triturated in toluene to give the solid acid chloride. The activated esters (for reacting with the 3-aminomethylcephalosporins) are prepared in conventional manner from the corresponding acid. Examples of conventional methods include dissolving the corresponding acid in dimethylformamide, adding triethylamine (1 equivalent), o-hydroxybenzotriazole and dicyclohexylcarbodi-imide; stirring for about 90 minutes and filtering (to remove urea). The carbonyl chloride and activated esters were reacted with the appropriate cephalosporin without further purification. Preparation of Heterocyclic carboxylic acids The heterocyclic carboxylic acids (for preparing the carbonyl chlorides or activated esters) are known or are prepared as described below:

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A cephalosporin compound of the formula (IV): or salt or ester thereof, wherein: R¹ is hydrogen, C₁₋₆alkyl optionally substituted by halo, hydroxy, C₁₋₄alkoxy, carboxy, amino, cyano, C₁₋₆alkanoylamino, phenyl or heteroaryl wherein heteroaryl is a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulpur and may be optionally substituted by the substitents described hereinafter with respect to the fused Het-benzene ring system, or R¹ is C₂₋₆ alkenyl; Het is a 5- or 6-membered heterocyclic ring selected from a group of the formulae II -III: wherein A is CH or a nitrogen atom; B is oxygen, sulphur or a group NR⁴; one or two of D, E, F and G are nitrogen atoms and the remainder are CH groups: or Het is a pyrazinone, pyridinone, pyridazinone or pyrimidinone ring, or is a thione equivalent of such a ring, said rings having a substituent R⁴ on one nitrogen atom: or Het is a pyranone or pyranthione ring: the ring Het being fused by any two adjacent carbon atoms to the benzene ring; and Het being bonded via a carbon atom to the -CH₂NR¹CO- group; R² is hydroxy or an in vivo hydrolysable ester thereof; R³ is ortho to R² and is hydroxy or an in vivo hydrolysable ester thereof; R⁴ is hydrogen or hydroxy, or C₁₋₆alkoxy, phenoxy, C₂₋₆alkenyl or C₁₋₆alkyl, (any of these groups being optionally substituted by hydroxy, C₁₋₆alkoxy, cyano, amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, carboxy, C₁₋₆alkoxycarbonyl, C₁₋₆alyanoyloxy, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, C₁₋₆alkoxycarbonylamino, phenyl, phenylC₁₋₆alkyl, carboxyaminocarbonyl, C₁₋₆alkoxycarbonylaminocarbonyl, benzoyl or C₃₋₈cycloalkyl) or R⁴ is phenyl, C₃₋₈ cycloalkyl, amino, C₁₋₆alkylamino or di-C₁₋₆alkylamino: wherein the fused Het-benzene ring system and/or any phenyl group is further optionally substituted by at least one substituent selected from C₁₋₆alkyl, halo, hydroxy, hydroxy C₁₋₆alkyl, cyano, trifluoromethyl, nitro, amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, phenyl C₁₋₆alkylamino, C₁₋₆alkanoyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkanoyloxy, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkyl carbamoyl, carboxy, carboxy C₁₋₆alkyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl, sulpho, sulphoC₁₋₆alkyl, sulphonamido, C₁₋₆alkylsulphonamido, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoylamino, thioureido and amidino: X is sulphur, oxygen, methylene or sulphinyl; R⁶ is hydrogen, methoxy or formamido; R⁵ is 2-aminothiazol-4-yl or 2-aminooxazol-4-yl each optionally substituted in the 5-position by fluorine, chlorine or bromine, or R⁵ is 5-aminoisothiazol-3-yl, 5-amino-1,2,4-thiadiazol-3-yl, 3-aminopyrazol-5-yl, 3-aminopyrazol-4-yl, 2-aminopyrimidin-5-yl, 2-aminopyrid-6-yl, 4-aminopyrimidin-2-yl, 2- amino-1,3,4-thiadiazol-5-yl or 5-amin-1-methyl-1,2,4-triazol-3-yl; R⁷ is of the formula =N.O.R⁸ (having the syn configuration about the double bond) wherein R⁸ is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (1-3C)alkyl(3-6C)cycloalkyl, (3-6C)cycloalkyl(1-3C)alkyl, (3-6C)alkenyl optionally substituted by carboxy, (5-8C)cycloalkenyl, (3-6C)alkynyl, (2-5C)alkylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, (1-4C)alkylcarbamoyl(1-4C)alkyl, di(1-4C)alkylcarbamoyl(1-4C)alkyl, (1-4C)haloalkylcarbamoyl(1-4C)alkyl, (1-3C)haloalkyl, (2-6C)hydroxyalkyl, (1-4C)alkoxy(2-4C)alkyl, (1- 4C)alkylthio(2-4C)alkyl, (1-4C)alkanesulphinyl(1-4C)alkyl, (1- 4C)alkanesulphonyl(1-4C)alkyl, (2-6C)aminoalkyl, (1-4C)alkylamino(1- 6C)alkyl, (2-8C)dialkylamino(2-6C)alkyl, (1-5C)cyanoalkyl, 3-amino-3-carboxypropyl, 2-(amidinothio)ethyl, 2-(N-aminoamidinothio)ethyl, tetrahydropyran-2-yl, thietan-3-yl, 2-oxopyrrolidinyl, or 2-oxotetrahydrofuranyl, or R⁸ is of the formula V:- -(CH₂) q -C(COOH)=CR⁹R¹⁰ V wherein q is one or two and R⁹ and R¹⁰ are independently hydrogen or C₁₋₄alkyl; or R⁸ is of the formula VI:- -CR¹¹R¹²-(CH₂) r -COR¹³ VI wherein r is 0-3, R¹¹ is hydrogen, (1-3C)alkyl or methylthio, R¹² is hydrogen (1-3C)alkyl, (3-7C)cycloalkyl, cyano, carboxy, (2-5C)carboxyalkyl or methanesulphonylamino, or R¹¹ and R¹² are joined to form, together with the carbon to which they are attached, a (3- 7C)carbocyclic ring, and R¹³ is hydroxy, amino, (1-4C)alkoxy, (1-4C) alkylamino or of the formula NHOR¹⁴ in which R¹⁴ is hydrogen or (1- 4C)alkyl; or R⁷ may be of the formula =CH.R¹⁵ wherein R¹⁵ is hydrogen, halogen, (1-6C)alkyl, (3-7C)cycloalkyl, (2-6C)alkenyl, (3-7C)cycloalkenyl, phenyl or benzyl. A compound according to claim 1 wherein the fused Het-benzene system is quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine or is a ring system of the sub-formulae i) - xii): wherein R⁴ is hydrogen, hydroxy, C₁₋₆alkoxy, C₁₋₆alkyl, C₃₋₈cycloalkyl, hydroxyC₁₋₆alkyl, phenyl, phenylC₁₋₆alkyl, C₂₋₆alkenyl, aminoC₂₋₆alkyl, carbamoylC₁₋₆alkyl, C₁₋₆alkoxycarbonyl C₁₋₆alkyl or carboxyC₁₋₆alkyl: and either ring of the Het-benzene ring system is optionally substituted by one or more atoms or groups selected from C₁₋₆alkyl, halo, hydroxy, hydroxyC₁₋₆alkyl, nitro, amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, phenylC₁₋₆alkylamino, C₁₋₆alkoxy, carboxyC₁₋₆alkyl, C₁₋₆alkanoylamino, trifluoromethyl, carboxy, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, C₁₋₆alkanoyl, C₁₋ ₆alkylthio, cyano and C₁₋₆alkoxycarbonyl. A compound according to either claim 1 or 2 wherein R² and R³ are both hydroxy. A compound according to any one of claims 1 to 3 wherein the cephalosporin compound has a 3-position substituent of the sub-formula xiii): wherein R⁴¹ is hydrogen or C₁₋₆alkyl and R⁴² is hydrogen, nitro, cyano, chloro, bromo, carboxy or C₁₋₆ alkoxycarbonyl. A compound according to any one of claims 1 to 3 wherein the cephalosporin compound has a 3-position substituent of the sub-formula xiv): wherein R⁴³ is hydrogen, chloro, bromo, carboxy, C₁₋₆alkoxycarbonyl, amino, C₁₋₆alkylamino or phenylC₁₋₆alkylamino. A compound according to any one of claims 1 to 3 wherein the cephalosporin compound has a 3-position substituent of the sub-formulae xv) or xvi): wherein R⁴² is hydrogen, nitro, cyano, chloro, bromo, carboxy or C₁₋₆alkoxycarbonyl. A compound according to claim 1 wherein R⁵ is 2-aminothiazol-4-yl, R⁷ is a group =NOR⁸ wherein R⁸ is C₁₋₆alkyl, 1-carboxycyclobutyl, 1-carboxycyclopentyl or 2-carboxyprop-1-yl, R⁶ is hydrogen, X is sulphur and the 3-position substituent is of the sub-formulae xiii) - xvi): wherein R⁴¹ is hydrogen or C₁₋₆alkyl, R⁴² is hydrogen, nitro, cyano, chloro, bromo, carboxy or C₁₋₆alkoxycarbonyl and R⁴³ is hydrogen, chloro, bromo, carboxy, C₁₋₆alkoxycarbonyl, amino, C₁₋₆alkylamino or phenylC₁₋₆alkylamino. A compound according to claim 7 wherein R⁸ is 2-carboxyprop-2-yl. A compound according to claim 1 which is: 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-methyl-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-n-butyl-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-5-nitro-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-5-cyano-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-5-chloro-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamid]-3-(1,4-dihydro-6,7-dihydroxy-1-methoxy-4- oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamid]-3-(1,4-dihydro-6,7-dipivaloyloxy-1-ethyl-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-4-oxocinnolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(5-carboxy-1,4-dihydro-6,7-dihydroxy-1-ethyl-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(5-carboxy-1,4-dihydro-6,7-dihydroxy-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(6,7-dihydroxy-2-methylaminoquinoxalin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(2-bromo-6,7-dihydroxyquinoxalin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(2-chloro-6,7-dihydroxyquinoxalin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(2-benzylamino-6,7-dihydroxyquinoxalin -3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(6,7-dihydroxy-2-methoxycarbonyl-quinoxalin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(7,8-dihydroxy-2-oxo-2H-benzopyran-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, or 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-2-methyl-1-oxo-isoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, A pharmaceutical composition which comprises a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier. A process for preparing a compound according to claim 1 which process comprises: a) reacting a cephalosporin compound of the formula: wherein R¹, R⁵, R⁶, R⁷ and X are as defined in claim 1 with a compound of the formula VII: wherein Het, R² and R³ are as defined in claim 1 and L is a leaving group; or b) reacting a compound of the formula VIII with a compound of the formula IX or a reactive derivative thereof: wherein R¹, R², R³, X, Het, R⁵, R⁶ and R⁷ are as defined in claim 1; or c) for compounds of the formula IV wherein R⁷ is a group =NOR⁸, reacting a compound of the formula X: wherein R¹, R², R³, R⁵, R⁶, X, and Het are as defined in claim 1, with a compound of the formula: R⁸ONH₂ wherein R⁸ is as defined in claim 1; or d) for compounds of the formula IV wherein R⁷ is a group =NOR⁸ and R⁸ is other than hydrogen, reacting a compound of the formula IV as hereinbefore defined wherein R⁷ is a group =NOH with a compound of the formula XI: L¹ - R¹⁶ XI wherein L¹ is a leaving group and R¹⁶ is a group R⁸ other than hydrogen; or e) forming a group R⁵ by cyclizing an appropriate precursor thereof: wherein any functional groups are optionally protected: and thereafter, if necessary: i) removing any protecting group, ii) for preparing in vivo hydrolysable esters, esterifying corresponding hydroxy groups, iii) converting compounds wherein X is S to compounds wherein X is sulphinyl and vice versa, iv) forming a pharmaceutically acceptable salt. A compound of the formula (VIII) or (X) as defined in claim 11 or a compound of the formula (XII): wherein L² is a leaving group and R⁶, R⁷, R¹, R², R³, X and Het are as defined in claim 11. A compound of the formula: wherein Het is a 5- or 6-membered heterocyclic ring selected from a group of the formulae II-III: wherein A is a nitrogen atom; B is oxygen, sulphur or a group NR⁴; one or two of D, E, F and G are nitrogen atoms and the remainder are CH groups: or Het is a pyrimidinone ring, or is a thione equivalent of such a ring, said rings having a substituent R⁴ on one nitrogen atom: wherein R⁴ is hydrogen or hydroxy, or C₁₋₆alkoxy, phenoxy, C₂₋₆alkenyl or C₁₋₆alkyl, (any of these groups being optionally substituted by hydroxy, C₁₋₆alkoxy, cyano, amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, carboxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoyloxy, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, C₁₋₆-alkoxycarbonylamino, phenyl, phenylC₁₋₆alkyl, carboxyaminocarbonyl, C₁₋₆alkoxycarbonylaminocarbonyl, benzoyl or C₃₋₈cycloalkyl) or R⁴ is phenyl, C₃₋₈cycloalkyl, amino, C₁₋₆alkylamino or di-C₁₋₆alkylamino: or Het is a pyranthione ring: the ring Het being fused by any two adjacent carbon atoms to the benzene ring; and Het being bonded via a carbon atom to the LCOgroup; R² and R³ are as defined in claim 1; wherein the fused Het-benzene ring system and/or any phenyl group is further optionally substituted by at least one substituent selected from C₁₋₆alkyl, halo, hydroxy, hydroxy C₁₋₆alkyl, cyano, trifluoromethyl, nitro, amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, phenyl C₁₋₆alkylamino, C₁₋₆alkanoyl,C₁₋₆alkoxy, C₁₋₆alkythio, C₁₋₆alkanoyloxy, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alklcarbamoyl, carboxy, carboxy C₁₋₆alkyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl, sulpho, sulphoC₁₋₆alkyl, sulphonamido, C₁₋₆alkylsulphonamido, C₁₋₆-alkoxycarbonyl, C₁₋₆alkanoylamino, thioureido and amidino: and L is a leaving group or hydroxy group. A compound according to claim 13 wherein L is hydroxy or halo. A compound according to either of claims 13 or 14 wherein R² and R³ are both hydroxy. A compound according to any one of claims 13 to 15 wherein L is hydroxy. Claims for the following Contracting States : ES, GR A process for preparing a cephalosporin compound of the formula (IV): or salt or ester thereof, wherein: R¹ is hydrogen, C₁₋₆alkyl optionally substituted by halo, hydroxy, C₁₋₄alkoxy, carboxy, amino, cyano, C₁₋₆alkanoylamino, phenyl or heteroaryl wherein heteroaryl is a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulphur and may be optionally substituted by the substituents described hereinafter with respect to the fused Het-benzene ring system, or R¹ is C₂₋₆alkenyl; Het is a 5- or 6-membered heterocyclic ring selected from a group of the formulae II -III: wherein A is CH or a nitrogen atom; B is oxygen, sulphur or a group NR⁴; one or two of D, E, F and G are nitrogen atoms and the remainder are CH groups: or Het is a pyrazinone, pyridinone, pyridazinone or pyrimidinone ring, or is a thione equivalent of such a ring, said rings having a substituent R⁴ on one nitrogen atom: or Het is a pyranone or pyranthione ring: the ring Het being fused by any two adjacent carbon atoms to the benzene ring; and Het being bonded via a carbon atom to the -CH₂NR¹CO- group; R² is hydroxy or an in vivo hydrolysable ester thereof; R³ is ortho to R² and is hydroxy or an in vivo hydrolysable ester thereof; R⁴ is hydrogen or hydroxy, or C₁₋₆alkoxy, phenoxy, C₂₋₆alkenyl or C₁₋₆alkyl, (any of these groups being optionally substituted by hydroxy, C₁₋₆alkoxy, cyano, amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, carboxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoyloxy, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, C₁₋₆alkoxycarbonylamino, phenyl, phenylC₁₋₆alkyl, carboxyaminocarbonyl, C₁₋₆alkoxycarbonylaminocarbonyl, benzoyl or C₃₋₈cycloalkyl) or R⁴ is phenyl, C₃₋₈ cycloalkyl, amino, C₁₋₆alkylamino or di-C₁₋₆alkylamino: wherein the fused Het-benzene ring system and/or any phenyl group is further optionally substituted by at least one substituent selected from C₁₋₆alkyl, halo, hydroxy, hydroxy C₁₋₆alkyl, cyano, trifluoromethyl, nitro, amino, C₁₋₆alkylamino. di-C₁₋₆alkylamino, phenyl C₁₋₆alkylamino, C₁₋₆alkanoyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkanoyloxy, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkyl carbamoyl, carboxy, carboxy C₁₋₆alkyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl, sulpho, sulphoC₁₋₆alkyl, sulphonamido, C₁₋₆alkylsulphonamido, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoylamino, thioureido and amidino: X is sulphur, oxygen, methylene or sulphinyl; R⁶ is hydrogen, methoxy or formamido; R⁵ is 2-aminothiazol-4-yl or 2-aminooxazol-4-yl each optionally substittited in the 5-position by fluorine, chlorine or bromine, or R⁵ is 5-aminoisothiazol-3-yl, 5-amino-1,2,4-thiadiazol-3-yl, 3-aminopyrazol-5-yl, 3-aminopyrazol-4-yl, 2-aminopyrimidin-5-yl, 2-aminopyrid-6-yl, 4-aminopyrimidin-2-yl, 2- amino-1,3,4-thiadiazol-5-yl or 5-amino-1-methyl-1,2,4-triazol-3-yl; R⁷ is of the formula =N.O.R⁸ (having the syn configuration about the double bond) wherein R⁸ is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (1-3C)alkyl(3-6C)cycloalkyl, (3-6C)cycloalkyl(1-3C)alkyl, (3-6C)alkenyl optionally substituted by carboxy, (5-8C)cycloalkenyl, (3-6C)alkynyl, (2-5C)alkylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, (1-4C)alkylcarbamoyl(1-4C)alkyl, di(1- 4C)alkylcarbamoyl(1-4C)alkyl, (1-4C)haloalkylcarbamoyl(1-4C)alkyl, (1- 3C)haloalkyl, (2-6C)hydroxyalkyl,(1-4C)alkoxy(2-4C)alkyl, (1- 4C)alkylthio(2-4C)alkyl, (1-4C)alkanesulphinyl(1-4C)alkyl, (1- 4C)alkanesulphonyl(1-4C)alkyl, (2-6C)aminoalkyl, (1-4C)alkylamino(1- 6C)alkyl, (2-8C)dialkylamino(2-6C)alkyl, (1-5C)cyanoalkyl, 3-amino-3- carboxypropyl, 2-(amidinothio)ethyl, 2-(N-aminoamidinothio)ethyl, tetrahydropyran-2-yl, thietan-3-yl, 2-oxopyrrolidinyl, or 2- oxotetrahydrofuranyl, or R⁸ is of the formula V:- -(CH₂) q -C(COOH)=CR⁹R¹⁰ V wherein q is one or two and R⁹ and R¹⁰ are independently hydrogen or C₁₋₄alkyl; or R⁸ is of the formula VI:- -CR¹¹R¹²-(CH₂) r -COR¹³ VI wherein r is 0-3, R¹¹ is hydrogen, (1-3C)alkyl or methylthio, R¹² is hydrogen (1-3C)alkyl, (3-7C)cycloalkyl, cyano, carboxy, (2-5C)carboxyalkyl or methanesulphonylamino, or R¹¹ and R¹² are joined to form, together with the carbon to which they are attached, a (3-7C)carbocyclic ring, and R¹³ is hydroxy, amino, (1-4C)alkoxy, (1-4C) alkylamino or of the formula NHOR¹⁴ in which R¹⁴ is hydrogen or (1-4C)alkyl; or R⁷ may be of the formula =CH.R¹⁵ wherein R¹⁵ is hydrogen, halogen, (1-6C)alkyl, (3-7C)cycloalkyl, (2-6C)alkenyl, (3-7C)cycloalkenyl, phenyl or benzyl: which process comprises: a) reacting a cephalosporin compound of the formula wherein R¹, R⁵ R⁶ R⁷ and X are as defined hereinabove with a compound of the formula VII: wherein Het, R² and R³ are as defined in hereinabove and L is a leaving group; or b) reacting a compound of the formula VIII with a compound of the formula IX or a reactive derivative thereof: wherein R¹, R², R³, X, Het, R⁵, R⁶ and R⁷ are as defined hereinabove; or c) for compounds wherein R⁷ is a group =NOR⁸, reacting a compound of the formula X: wherein R¹, R², R³, R⁵, R⁶, X, and Het are as defined hereinabove, with a compound of the formula: R⁸ONH₂ wherein R⁸ is as defined hereinabove; d) for compounds wherein R⁷ is a group =NOR⁸ and R⁸ is other than hydrogen, reacting a compound of the formula IV as hereinbefore defined wherein R⁷ is a group =NOH with a compound of the formula XI: L¹ - R¹⁶ XI wherein L¹ is a leaving group and R¹⁶ is a group R⁸ other than hydrogen; or e) forming a group R⁵ by cyclizing an appropriate precursor thereof: wherein any functional groups are optionally protected: and thereafter, if necessary: i) removing any protecting group, ii) for preparing in vivo hydrolysable esters, esterifying corresponding hydroxy groups, iii) converting compounds wherein X is S to compounds wherein X is sulphinyl and vice versa, iv) forming a pharmaceutically acceptable salt. A process according to claim 1 for preparing a compound wherein the fused Het-benzene system is quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine or is a ring system of the sub-formulae i) - xii): wherein R⁴ is hydrogen, hydroxy, C₁₋₆alkoxy, C₁₋₆alkyl, C₃₋₈cycloalkyl, hydroxyC₁₋₆alkyl, phenyl, phenylC₁₋₆alkyl, C₂₋₆alkenyl, aminoC₂₋₆alkyl, carbamoylC₁₋₆alkyl, C₁₋₆alkoxycarbonyl C₁₋₆alkyl or carboxyC₁₋₆alkyl: and either ring of the Het-benzene ring system is optionally substituted by one or more atoms or groups selected from C₁₋₆alkyl, halo, hydroxy, hydroxyC₁₋₆alkyl, nitro, amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, phenylC₁₋₆alkylamino , C₁₋₆alkoxy, carboxyC₁₋₆alkyl, C₁₋₆alkanoylamino, trifluoromethyl, carboxy, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, C₁₋₆alkanoyl, C₁₋₆alkylthio, cyano and C₁₋₆alkoxycarbonyl. A process according to any one of claims 1 to 2 for preparing a compound wherein R² and R³ are both hydroxy. A process according to any one of claims 1 to 3 for preparing a compound wherein the cephalosporin compound has a 3-position substituent of the sub-formula xiii): wherein R⁴¹ is hydrogen or C₁₋₆alkyl and R⁴² is hydrogen, nitro, cyano, chloro, bromo, carboxy or C₁₋₆ alkoxycarbonyl. A process according to any one of claims 1 to 3 for preparing a compound wherein the cephalosporin compound has a 3-position substituent of the sub-formula xiv): wherein R⁴¹ is hydrogen or C₁₋₆alkyl and R⁴² is hydrogen, nitro, cyano, chloro, bromo, carboxy or C₁₋₆ alkoxycarbonyl. A process according to any one of claims 1 to 3 for preparing a compound wherein the cephalosporin compound has a 3-position substituent of the sub-formulae xv) or xvi): wherein R⁴² is hydrogen, nitro, cyano, chloro, bromo, carboxy or C₁₋₆alkoxycarbonyl. A process according to claim 1 for preparing a compound which is: 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-methyl-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-n-butyl-4 -oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-5-nitro-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-5-cyano-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-5-chloro-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-methoxy-4 -oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dipivaloyloxy-1-ethyl -4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-1-ethyl-4-oxoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(5-carboxy-1,4-dihydro-6,7-dihydroxy-1 -quinoxalin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(7,8-dihydroxy-2-oxo-2H-benzopyran-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid, or 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(1,4-dihydro-6,7-dihydroxy-2-methyl-1-oxo-isoquinolin-3-carboxamidomethyl)ceph-3-em-4-carboxylic acid. A process for preparing a pharmaceutical composition which comprises bringing into associatior a cephalosporin compound having a 3-position substituent as defined in claim 1 and a pharmaceutically acceptable carrier. A compound of the formula (VIII) or (X) as defined in claim 1 or a compound of the formula (XII): wherein L² is a leaving group and R⁶, R⁷, R¹, R², R³, X and Het are as defined in claim 1. A compound of the formula: wherein Het is a 5- or 6-membered heterocyclic ring selected from a group of the formulae II -III: wherein A is a nitrogen atom; B is oxygen, sulphur or a group NR⁴; one or two of D, E, F and G are nitrogen atoms and the remainder are CH groups: or Het is a pyrimidinone ring, or is a thione equivalent of such a ring, said rings having a substituent R⁴ on one nitrogen atom: wherein R⁴ is hydrogen or hydroxy, or C₁₋₆alkoxy, phenoxy, C₂₋₆alkenyl or C₁₋₆alkyl, (any of these groups being optionally substituted by hydroxy, C₁₋₆alkoxy, cyano, amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, carboxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoyloxy, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, C₁₋₆-alkoxycarbonylamino, phenyl, phenylC₁₋₆alkyl, carboxyaminocarbonyl, C₁₋₆alkoxycarbonylaminocarbonyl, benzoyl or C₃₋₈cycloalkyl or R⁴ is phenyl, C₃₋₈cycloalkyl, amino, C₁₋₆alkylamino or di-C₁₋₆alkylamino: or Het is a pyranthione ring: the ring Het being fused by any two adjacent carbon atoms to the benzene ring; and Het being bonded via a carbon atom to the LCO-group; R² and R³ are as defined in claim 1; and the fused Het-benzene ring system and/or any phenyl group is further optionally substituted by at least one substituent selected from C₁₋₆alkyl, halo, hydroxy, hydroxy C₁₋₆alkyl, cyano, trifluoromethyl, nitro, amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, phenyl C₁₋₆alkylamino, C₁₋₆alkanoyl, C₁₋₆alkoxy, C₁₋₆alkythio, C₁₋₆alkanoyloxy, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, carboxy, carboxy C₁₋₆alkyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl, sulpho, sulphoC₁₋₆alkyl, sulphonamido, C₁₋₆alkylsulphonamido, C₁₋₆-alkoxycarbonyl, C₁₋₆alkanoylamino, thioureido and amidino; and L is a leaving group or hydroxy group. A compound according to claim 10 wherein L is a hydroxy or halo. A compound according to either of claims 10 or 11 wherein R² and R³ are both hydroxy. A compound according to any one of claims 10 to 12 wherein L is hydroxy.

Inventors: ARNOULD JEAN CLAUDE, BOUCHEROT DOMINIQUE, DAVIES DAVID HUW, JUNG FREDERICK HENRI, STRAWSON COLIN JOHN, ARNOULD, JEAN CLAUDE, BOUCHEROT, DOMINIQUE, DAVIES, DAVID HUW, JUNG, FREDERICK HENRI, STRAWSON, COLIN JOHN
Applicants: ICI PHARMA, ICI PLC, IMPERIAL CHEMICAL INDUSTRIES PLC
Application year: 1988
Main classification: C07D501
IPC codes: C07D241, C07D501, C07D215, C07D239, C07D471, C07D311, C07D209, C07D251, A61K31, A61P31, C07D217, C07D237