GB2209524A - Chemical compounds - Google Patents

Abstract

Cephalosporin antibiotics of formula (I) are disclosed <IMAGE> wherein R<1> represents a hydrogen atom or an amino protecting R<2> represents a hydrogen atom or a carboxyl blocking group; R<3> represents a hydrogen atom or a C1-C4 alkyl group optionally substituted by one to three halogen atoms; R<4> and R<5> which may be the same or diferent each represents a hydrogen atom, a C1-4 alkyl group, or together with the carbon atom to which they are attached form a C3-C-7 cycloalkyl group; R<6> and R<7> which may be the same or different each represents a hydroxy group, a substituted hydroxy group or R<6> and R<7> together represent a cyclic protected diol group; Z is >S or >S->0 ( alpha - or beta -); the dotted line bridging the 2- ,3- and 4- positions indicates that the compound is a ceph-2-em or ceph-3-em compound; and non-toxic salts, and solvated forms, including hydrated forms, thereof.

Description

CHFMT rnl rnMPnl lnns The present invention relates to cephalosporin derivatives, to processes for their preparation, to pharmaceutical preparations comprising them and to intermediates for use in the preparation of suostances having valuable antioacterial activity.

The cephalosporin compounds in this specification are named with reference to 'cepham' after J. Amer. Chem. Soc., 1962, 84, 3400, the term 'cephem' referring to the basic cepham structure with one douDle fond.

Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in human beings and animals.

Cephalosporins are especially useful in the treatment of diseases caused by bacteria which are resistant to other antibiotics such as penicillin compounds, and in the treatment of penicillin-sensitive patients. In many instances it is desirable to employ a cephalosporin antibiotic which exhibits activity against both Gram-positive and Gram-negative microorganisms, and a significant amount of research has been directed to the development of various types of broad spectrum cephalosporin antibiotics.

Thus, for example, in our British Patent Specification No.

1399086, we describe a novel class of cephalosporin antibiotics containing a 7ss-(a-etherified oxyimino)acylamido side chain, the oxyimino group having the syn configuration. This class of antibiotic compounds is characterised by high antioacterial activity against a range of Cram-positive and Gram-negative organisms coupled with particularly high stability to ss-lactamases produced by various Gram-negative organisms.

The discovery of this class of compounds has stimulated further research in the same area in attempts to find compounds which have improved properties, for example against particular classes of organisms, especially Gram-negative organisms. This interest is reflected in the very large number of patent applications which have been filed relating to cephalosporin antibiotics havina particular substituents both on the 7ss-acylamido side chain and at the 3-position of the cephalosporin nucleus.

for example, Brithish Patent Specification No. 1576625 centeins a generic definition of cephalosporin antibiotics having a etherified oxyimino)acetamido side chain wherein the etherifying group is an aliphatic hydrocarbon group which may have suitable substituents. The side chain is further a-suDstituted oy a group which inter alia may be an aminothiazolyl group. The 3-position group may also De selected from a large number of alternatives and a possible 3-suDstituent within the generic definition is an optionally substituted caroamoyloxymethyl group.

In British Patent Specification No. 1604971 a wide variety of cephalosporin antibiotics are generally disclosed in which the 7ss-position side chain may be selected from inter alia a 2-(2-aminothiazol-4-yl)-2-(etherified oxyimino)acetamido group, in which the etherifying group, amongst very many possible meanings, may be a substituted alkyl group although the preferred etherifying group is stated to be an unsubstituted methyl group. The 3-position group may also be selected from a large number of alternatives and possible 3-substituents within the generic definition include an optionally substituted carbamoyloxymethyl group.

European Patent Application No. 189287 discloses penicillin and cephalosporin antibiotics in which the 7ss-position side chain is inter alia a 2-(2-aminothiazol-4-yl)-2-(etherified oxyimino)acetamido group.

The oxyimino etherifying group, amongst several possibilities, may be a substituted benzoylcaroazoylalkyl group. The 3-position of the cephalosporin nucleus may, according to the generic definition, inter alia be a carbamoyloxymethyl group.

We have now discovered that by the selection of a substituted benzopyranylcarbonylcarbazoyl-alkoxyimino group as the etherified oxyimino grouping of a (Z)-2-(2-aminothiazol-4-yl)-2-(etherified oxyimino)acetamido group at the 7ss-position in combination with particular groups as herein defined at the 3-position, cephalosporin derivatives are obtained that have a particularly advantageous profile of activity (described in more detail below) against a wide range of commonly encountered pathogenic organisms and/or the compounds may be of use as intermediates in the preparation of other active compounds.

Accordingly, the present invention provides cephalosporin compounds of the general formula (I)

wherein Rl represents a hydrogen atom or an amino protecting group; R2 represents a hydrogen atom or a carboxyl blocking group; R3 represents a hydrogen atom or a C1-C4 alkyl group optionally substituted by one to three halogen atoms; R4 and R5 which may be the same or different each represents a hydrogen atom, a Cl-C4 alkyl group, or together with the carbon atom to which they are attached form a C3 C7 cycloalkyl group; R6 and R7 which may be the same or different each represents a hydroxy group, a substituted hydroxy group or R6 and R7 together represent a cyclic protected diol group; Z is > S or > S+O (a- or P-);; the dotted line bridging the 2-, 3- and 4positions indicates that the compound is a ceph-2-em or ceph-3-em compound; and non-toxic salts, and solvated forms, including hydrated forms, thereof.

In the compounds of formula (I), C1-4 alkyl groups may oe straight chain or Dranched chain, for example, a methyl, ethyl, propyl, isopropyl or n-butyl, iso-butyl, sec-butyl or t-butyl group.

Where R1 is an amino protecting group, the protecting group may be for example a C7-20 aralkyl group (for example a triphenyl methyl or 4-methoxybenzyl group), an acyl group, such as an optionally substituted C16 alkanoyl group (for example a formyl or chloroacetyl group) or an optionally substituted C16 alkoxycarbonyl group (for example a t-butoxycarbonyl or 2,2,2-trichloroethoxycarbonyl group), or a C7-lOaralkyloxycarbonyl group (for example a benzyloxycarbonyl group) or a silyl group (for example a tri-methylsilyl group).

Where R2 represents a carboxyl blocking group, the blocking group may be for example 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 from 1 to 20 carbon atoms) or a symmetrical or mixed anhydride blocking group derived from an appropriate acid. Particular examples of R2 include t-butyl, diphenylmethyl, 2,2,2-trichloromethyl and p-nitrobenzyl.

Where R3 is a substituted alkyl group it may contain one, two or three halogen atoms e.g. chlorine or bromine atoms.

In general R3 preferably represents a hydrogen atom or a methyl, ethyl or 2-chloroethyl group.

In general each of R4 and R5 preferably represents a hydrogen atom, a methyl group, or together with the carbon atom to which they are attached a cyclobutyl group.

When R6 or R7 represents a substituted hydroxy group it may be for example an alkoxy group [e.g. a group of formula OR8 (where R8 is a C1-Cs alkyl group, for example a methyl or ethyl group)], an arylalkoxy group (e.g. an O-benzyl group), an acyloxy group (e.q. a formyloxy group or a group of formula -OCOR8, where R8 is as defined above, for example, an acetoxy group), an alkyl carbonate group (e.g. a group of formula -OC02R8, where R8 is as defined above), or a silyloxy group tfor example a (C14-alkyl)3silyloxy group such as a trimethylsilyloxy or a t-butyldimethylsilyloxy group].

Where R6 and R7 together form a cyclic protected diol grouping, this may be a carbonate group, an alkylidenedioxy group, preferably having 1-20 carbon atoms, e.g. a methylenedioxy, ethylenedioxy or isopropylidenedioxy group which may carry one or more substituents e.g. phenyl, C14-alkoxy, or oxo substituents, for example methoxymethylenedioxy, diphenylmethylenedioxy or carbonyldioxy groups; a cyclic borate group, for example -OB(OH)O-, or -OB(OR9)0-, a cyclic phosphate group, for example -OP(O)(OH)O-, or -OP(0)(OR9)0- (where R9 represents a Cl~salkyl group), and a cyclic silyl ether group, e.g. a di(cl-4alkyl)silyldioxy group for example a dimethylsilyldioxy group.

In general, such silyloxy, borate or phosphate groups represent protected hydroxy groups which may be cleaved to provide a compound of formula (I) having free hydroxyl groups.

In the compounds of formula (I), Z is preferably > S.

Ceph-3-em compounds of the invention are particularly preferred.

Where the compound is to be used in medicine any ester function should be a non-toxic metabolically labile ester function. Examples of non-toxic metabolically labile ester derivatives include acyloxyalkyl esters, for example, lower alkanoyloxy-methyl or -ethyl esters such as acetoxy-methyl or -ethyl or pivaloyloxymethyl esters, and alkoxycarbonyloxyethyl esters, for example, lower alkoxycarbonyloxyethyl esters such as the ethoxycarbonyloxyethyl ester.

In addition to the above ester derivatives, the present invention includes within its scope the active compounds of the invention in the form of other physiologically acceptable equivalents, i.e. physiologically acceptable compounds which like the metabolically labile esters are converted in vivo into the parent antibiotic compounds of the invention.

Non-toxic salt derivatives of compounds of formula (I) include inorganic base salts such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.q. calcium salts); amino acid salts (e.g. lysine and arginine salts); organic base salts (e.g. procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and N-methylglucosamine salts). Other non-toxic salt derivatives include acid addition salts, e.g. formed with hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, formic, citric, tartaric and trifluoroacetic acids. The salts may also be in the form of resinates formed with, for example, a polystyrene resin or cross-linked polystyrene divinylbenzene copolymer resin containing amino or quaternary amino groups or sulphonic acid groups, or with a resin containing carboxyl groups, e.g. a polyacrylic acid resin.

Soluble base salts (e.g. alkali metal salts such as the sodium salt) of the compounds of formula (I) may be used in therapeutic applications because of the rapid distribution of such salts in the body upon administration. Where, however, insoluble salts of compounds (I) are desired in a particular application, e.g. for use in depot preparations, such salts may be formed in conventional manner, for example with appropriate organic amines.

The compounds according to the invention are syn isomers. The syn isomeric form is defined by the configuration of the O-substituent with respect to the carboxamido group. In this specification, the syn configuration is denoted structurally as shown in formula (Ia)

It will be understood that since the compounds according to the invention are geometric isomers, some admixture with the corresponding anti isomer may occur.

It will further be appreciated that in the oxime etherifying group, the carbon atom adjacent to the oxy group may be chiral and may therefore exist in either R or S configuration. The invention thus includes within its scope individual isomeric forms of the compounds of formula (I) as well as mixtures thereof.

The compounds according to the present invention may exist in different tautomeric forms (for example in respect of the 2-aminothiazolyl group) and it will be understood that all such tautomeric forms, e.g. the 2-iminothiazolinyl form, are included within the scope of the invention.

As indicated previously, the compounds of the invention are active against a wide range of commonly encountered pathogenic organisms and/or are of use as intermediates for the preparation of other active compounds. In general, when the compounds of the invention are to be used as intermediates the group R2 will often be a carboxyl blocking group; the group R1 will be an amino protecting group, and the groups R6 and R7 will often be protected hydroxy groups such as alkoxy, silyloxy, or together will be a cyclic protected diol group.

In general active compounds of the invention will be ceph-3-em compounds of formula (I) in which R1 and R2 each represent hydrogen atoms, Z represents > S and R6 and R7 which may be the same or different represent hydroxy or C1C4 acyloxy groups e.g. acetoxy groups.

Important active compounds according to the invention have the formula (In)

wherein R3, R4, R5 and Z are as defined for formula (I); R6a is a hydroxy or acetoxy group; R7a is a hydroxy or acetoxy group; and the non-toxic salts, solvates(including hydrates) and metabolicelly labile esters thereof.

Particularly preferred compounds of the invention are: (6R,7R,2 'Z)-7-[2-(2-Amino-4-thiazolyl)-2-[ (3-( (6,7-dihydroxy4-oxo-4H- oenzopyran-3-yl ) carbonyl) carbazoyl ) methox yimino] ac etamido] -3 - (carnamoyloxymethyl)ceph-3-em-4-carboxylic acid; (6R,7R,2iZ)-7-t2-(2-Amino-4-thiazolyl)-2-[2-(5-((6,7-diacetoxy-4-oXo- 4H-benzopyr an-3-yl) carbonyl) carbazoyl) prop-2-oxyimino] acetamido]-3- (carbamoyloxymethyl) ceph-3-em-4-carboxylic acid; and the non-toxic salts, solvates (including hydrates) and metabolically labile esters thereof.

Active compounds according to the invention exhibit broad spectrum antibiotic activity both in vitro and in vivo. They have high activity against both Gram-positive and Gram-negative organisms, including many & actamase producing strains. The compounds also possess high stability to & actamases produced by a range of Gramnegative and Gram-positive organisms.

Compounds acccording to the invention have been found to exhibit high activity against strains (including penicillinaseproducing strains) of Gram-positive bacteria such as Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus species. This is coupled with excellent activity against Pseudomonas species, and also with high activity against various members of the Enterobacteriaceae (e.g. strains of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis and indole-positive Proteus organisms such as Proteus vulgaris, Proteus morganii and Providence species), and strains of Haemophilus influenzae and Acinetobacter calcoaceticus. This combination of high activity against Gram-positive organisms with high activity against Gram-negative organisms, more particularly against Pseudomonas, that is possessed by the compounds of the invention is unusual and particularly advantageous.

Cephalosporin derivatives described herein have been found to possess a desirable long serum elimination half life in vivo.

Compounds of the invention may be used for treating a variety of diseases caused by pathogenic bacteria in human beings and animals, such as respiratory tract infections and urinary tract infections.

The antibiotic compounds of the invention may be formulated for administration in any convenient way, by analogy with other antibiotics and the invention therefore includes within its scope pharmaceutical compositions comprising an antibiotic compound in accordance with the invention adapted for use in human or veterinary medicine. Such compositions may be presented for use in conventional manner with the aid of any necessary pharmaceutical carriers or excipients.

The antibiotic compounds according to the invention may be administered in combination with one or more other pharmaceutically active substances, for example another antibacterial substance especially one having a B-lactam ring e.g. a penicillin or another cephalosporin.

The antibiotic compounds according to the invention may be formulated for injection and may be presented in unit dose form, in ampoules, or in multi-dose containers, if necessary with an added preservative. The compositions may also take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

If desired, such powder formulations may contain an appropriate non-toxic base in order to improve the water-solubility of the active ingredient and/or to ensure that when the powder is reconstituted with water, the pH of the resulting aqueous formulation is physiologically acceptable. Alternatively the base may be present in the water with which the powder is reconstituted. The base may be, for example, an inorganic base such as sodium carbonate, sodium bicarbonate or sodium acetate, or an organic base such as lysine or lysine acetate.

The composition may also be presented in a form suitable for absorption by the gastro-intestinal tract, for example, tablets, capsules, syrups or suspensions for oral adminstration, and suppositories.

Compositions for veterinary medicine may, for example, be formulated as intramammary preparations in either long acting or quick-release bases.

The compositions may contain from 0.1 > upwards, e.g. 0.1-99 of the active material, depending on the method of administration. When the compositions comprise dosage units, each unit will preferably contain 100-3000 mg of the active ingredient e.g. 200-2000 mg. The daily dosage for adult human treatment will preferably range from 200 to 12000 mg e.g. 1000-9000 mg per day, depending inter alia on the nature of the infection and the route and frequency of administration.

In general, intravenous or intramuscular administration will be employed, for example using 400 to 4000 mg per day of the active ingredient in adult human treatment. It will be appreciated that in some circumstances, for example, in the treatment of neonates, smaller dosage units and daily dosages may be desirable.

The compounds of the invention may be prepared by a number of processes, discussed below.

Thus, according to another embodiment of the invention we provide a process for the preparation of an antibiotic compound of formula (I) as hereinnefore defined or an ester, non-toxic salt, solvate (including hydrate) thereof which comprises acylating a compound of formula (II)

wherein Rl, R2, R4, R5, Z and the dotted line are as defined above and R3a is the group R3 as defined above or a N-protecting group, (e.g. a labile group such as an acyl group, especially a lower alkanoyl group such as acetyl, a halosubstituted lower alkanoyl group such as mono-, di- or trichloroacetyl, or a haloqenated alkoxycarbonyl group such as 2,2,2-trichloroethoxycarbonyl) or a salt, e.g. an acid addition salt (formed with, for example, a mineral acid such as hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid or an organic acid such as methanesulphonic or toluene-p-sulphonic acid) or an N-silyl derivative thereof, with an acid of formula (III)

wherein R6 and R7 are as defined above or a salt thereof or with an acylating agent corresponding thereto; whereafter, if necessary and/or desired in each instance, any of the following reactions, in any appropriate sequence, are carried out: (i) conversion of a A2-isomer into a desired A3-isomer, (ii) reduction of a compound wherein Z is > S+O to form a compound wherein Z is > S, (iii) conversion of a carboxyl group into a non-toxic metabolically labile ester function, (iv) formation of a non-toxic salt or solvate, (v) removal of any carboxyl blocking and/or N-protecting groups, and (vi) removal of any hydroxy blocking groups.

The above reactions (i) to (vi) may be carried out in conventional manner.

In the above-described process the starting material of formula (II) is preferably a compound wherein Z is > S and the dotted line represents a ceph-3-em compound.

Acylating agents corresponding to the acids of formula (III) which may be employed in the preparation of compounds of formula (I) include acid halides, particularly acid chlorides or bromides. Such acylating agents may be prepared by reacting an acid of formula (ZIT) or a salt thereof with a halogenating agent e.g. phosphorus oxychloride, thionyl chloride or oxalyl chloride.

Acylations employing acid halides may be effected in aqueous and non-aqueous reaction media, conveniently at temperatures of from -50 to +500C, preferably -10 to +300C, if desired in the presence of an acid binding agent. Suitable reaction media include aqueous ketones such as aqueous acetone, aqueous alcohols such as aqueous ethanol, esters such ethyl acetate, halogenated hydrocarbons such as methylene chloride, amides such as dimethylacetamide, nitriles such as acetonitrile, or mixtures of two or more such solvents.Suitable acid binding agents include tertiary amines (e.g. triethylamine or dimethylaniline), silylated amides (e.g. bistrimethylsilylacetamide), inorganic bases (e.g. calcium carbonate or sodium bicarbonate), and oxiranes such as lower 1,2-alkylene oxides (e.g. ethylene oxide or propylene oxide) which bind the hydrogen halide liberated in the acylation reaction.

Acids of formula (III) may themselves be used as acylating agents in the preparation of compounds of formula (I). Acylations employing acids of formula (III) are desirably conducted in the presence of a condensing agent, for example a carbodiimide such as N, N '-dicyclohexylcarbod iimide or N-ethyl-N '-y-dimethyl aminopropyl carbodiimide; a carbon compound such as carbonyldiimidazole; or an isoxazolium salt such as N-ethyl-5- phenylisoxazolium perchlorate; or N-ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline.

Acylation may also be effected with other amide-forming derivatives of acids of formula (III) such as, for example, an activated ester, a symmetrical anhydride or a mixed anhydride (e.g.

formed with pivalic acid or with a haloformate, such as a lower alkyl haloformate). Mixed anhydrides may also be formed with phosphorus acids (for example phosphoric or phosphorous acids), sulphuric acid or aliphatic or aromatic sulphonic acids (for example toluene-p-sulphonic acid). An activated ester may conveniently be formed in situ using, for example, 1-hydroxybenzotriazole in the presence of a condensing agent as set out above. Alternatively, the activated ester may be preformed.

A > la.-o reaction involvir the fr9 soidc nr their above-mentioned amide-forming derivatives are desirably effected in an anhydrous reaction medium, e.g. methylene chloride, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylacetamide or dimethyl sulphoxide.

An alternative method of activation is, for example, by reacting an acid of formula (III) with a solution or suspension preformed by adding a carDonyl halide, in particular oxalyl chloride or phosgene, or a phosphoryl halide such as phosphorus oxychloride to a solvent such as a halogenated hydrocarbon, for example methylene chloride, containing a lower acyl tertiary amide such as N,N-di-methylformamide. The activated form of the acid of formula (III) may then be reacted with a carDazoyl compound of formula (II) in a suitable solvent or mixture of solvents for example halogenated hydrocarbons e.g. dichloromethane; alcohols such as an alkanol, e.g.

ethanol or industrial methylated spirits; esters, e.g. ethyl acetate; ethers, e.g. tetrahydrofuran or dioxan; ketones, e.g. acetone; amides, e.g. dimethylacetamide; acetonitrile; water and mixtures thereof. The acylation reaction may conveniently be effected at temperatures of from - 500 to 500C, preferably -400 to +300C, if desired in the presence of an acid binding agent, for example as described above (e.g. dimethylaniline, triethylamine or sodium bicarbonate).

If desired, the above acylation reactions may be carried out in the presence of a catalyst such as 4-dimethylaminopyridine.

The reaction product may be separated from the reaction mixture, which may contain, for example, unchanged cephalosporin starting material and other substances, by a variety of processes including recrystallisation, ionophoresis, column chromatography, high pressure liquid chromatography, ion-exchange chromatography or chromatography on macroreticular resins.

A A2-cephalosporin ester derivative obtained in accordance with the process of the invention may be converted into the corresponding desired A3-derivative by, for example, treatment of the A2-ester with a base, such as pyridine or triethylamine.

A ceph-2-em reaction product may also be oxidised to yield the corresponding ceph-3-em 1-oxide, for example by reaction with a peracid, e.g. peracetic or m-chloroperbenzoic acid; the resulting sulphoxide may subsequently be reduced as described hereinafter to yield the corresponding desired ceph-3-em sulphide.

Where a compound is obtained in which Z is > S+O this may be converted into the corresponding sulphide by, for example, reduction of the corresponding acyloxysulphonium or alkoxysulphonium salt prepared in situ by reaction with e.g. acetyl chloride in the case of an acetoxysulphonium salt, reduction being effected by, for example, sodium dithionite or by iodide ion as in a solution of potassium iodide in a solvent e.g. acetic acid, acetone, tetrahydrofuran, dioxan, dimethylformamide or dimethylacetamide. The reaction may be effected at a temperature of from -20 to +500C.

In the oxidation and reduction processes described above, the groups R6 and R7 in the starting materials are desirably other than hydroxyl groups.

Metabolically labile ester derivatives of the compounds of formula (I) may be prepared by reacting a compound of formula (I) or a salt or protected derivative thereof with the appropriate esterifying agent such as an acyloxyalkyl halide or alkoxycarbonyloxyalkyl halide (e.g. iodide) conveniently in an inert organic solvent such as dimethylformamide or acetone, followed, where necessary, by removal of any protecting groups.

Base salts of the compounds of formula (I) may be formed by reacting an acid of formula (I) with an appropriate base. Thus, for example, sodium or potassium salts may be prepared using the respective acetate, 2-ethylhexanoate or hydrogen carbonate salt. Acid addition salts may be prepared by reacting a compound of formula (I) or a metabolically labile ester derivative thereof with the appropriate acid.

A salt may be produced directly from an ester by splitting of the ester group under suitable reaction conditions, for example, catalytic reduction of an ester, in an aqueous/organic solvent, in the presence of a metal salt, to yield the salt directly.

Starting materials for the preparation of compounds of general formula (I) according to the invention, are preferably in their syn isomeric form or in the form of mixtures of the syn isomers and the corresponoing anti isomers containing at least 90 > of the syn isomer.

Where a compound of formula (I) is obtained as a mixture of isomers, the syn isomer may be obtained by, for example, conventional methods such as crystallisation or chromatography.

Compounds of formula (II) may be prepared by deprotection of the corresponding N-protected carbazoyl compounds (IIa)

wherein R10 represents a nitrogen protecting group and Rl, R2, R3a, R4, R5 and the dotted line are as defined above, using standard methods described in the literature.

Carbazoyl compounds of formula (IIa) may be obtained by acylation of an amino compound of formula (IV)

wherein R2, R3a, Z and the dotted line are as defined above, or a salt e.g. an acid addition salt (formed with, for example, a mineral acid such as hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid or an organic acid such as methanesulphonic or toluene-p-sulphonic acid) or a 7-N-silyl derivative thereof, with an acid of formula (V).

wherein R1, R4, R5 and R10 are as defined above or a salt thereof, or with an acylating agent corresponding thereto.

An acid of formula (V) may be derived from the corresponding ester derivative of formula (Va)

wherein R1, R4, R5 and R10 are as defined above and R11 represents a carboxylic acid blocking group such as a methyl or ethyl ester, by de-esterification using conventional means e.g. a base such as sodium hydroxide in an aqueous solvent such as aqueous methanol or ethanol.

Compounds of formula (Va) may be produced using conventional methods from the corresponding acids of formula (VI)

wherein Rl, R4, R5 and R11 are as defined above, by reaction of the acid or activated derivative thereof with a hydrazine derivative (VII) H2NNHR10 (VII) where R10 is as defined above and represents for example a formyl group.

Starting materials of formula (III) and the corresponding acid halides may be prepared according to the methods described in British Patent Application No. 2051810.

It should be appreciated that in some of the above transformations it may be necessary to protect any sensitive groups in the molecule of the compound in question to avoid undesirable side reactions. Examples of suitable protecting groups are given in "Protective Groups in Organic Synthesis" by Theodora W. Greene (John Wiley and Sons, 1981).

For example, during any of the reaction sequences referred to above it may be necessary to protect the NH2 group of the aminothiazolyl moiety, for example by tritylation, acylation (e.g.

chloroacetylation or formylation), protonation or other conventional methods. The protecting group may thereafter be removed in any convenient way which does not cause breakdown of the desired compound, e.g. in the case of a trityl group by using an optionally halogenated carboxylic acid, e.g. acetic acid, formic acid, chloroacetic acid or trifluoroacetic acid or using a mineral acid, e.g. hydrochloric acid or mixtures of such acids, preferably in the presence of a protic solvent such as water, or, in the case of a chloroacetyl group, by treatment with thiourea.

Similarly, any hydroxy groups of the chromone moiety may need to be protected during any of the above reaction sequences. Hydroxy protecting groups which may be removed under mild conditions will generally be suitable, for example acetyl or silyl groups. Such groups may be introduced in conventional manner and, when desired, removed such that breakdown of the product does not occur. For example in the case of an acetyl group, the group may be removed by solvolysis with an aqueous solvent such as aqueous methanol or aqueous ethanol in the presence of a base, for example sodium bicarbonate, ammonium hydroxide, ammonium carbonate or ammonium carbamate. A silyl group, for example a trimethylsilyl group may be cleaved by treatment with a dilute aqueous acid.

Carboxyl blocking groups used in the preparation of compounds of formula (I) or in the preparation of necessary starting materials are desirably groups which may readily be split off at a suitable stage in the reaction sequence, conveniently at the last stage. It may, however, be convenient in some instances to employ non-toxic metabolically labile carboxyl blocking groups such as acyloxy-methyl or -ethyl groups (e.g. acetoxy-methyl or -ethyl or pivaloyloxymethyl) and retain these in the final product to give an appropriate ester derivative of a compound of formula (I).

Suitable carboxyl blocking groups are well known in the art, a list of representative blocked carboxyl groups being included in British Patent No. 1399086. Preferred blocked carboxyl groups include aryl lower alkoxycarbonyl groups such as p-methoxybenzyloxyzarbonyl, e-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; lower alkoxycarbonyl groups such as t-butoxycarbonyl; and lower haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. The carboxyl blocking group may subsequently be removed by any of the appropriate methods disclosed in the literature; thus, for example, acid catalysed hydrolysis or reduction is applicable in many cases, as is photolysis and enzymically-catalysed hydrolysis.

The present invention also provides the intermediate compounds of the general formulae (II), (liy), (V) and (Va).

The following Examples illustrate the invention.

Temperatures are in OC. Dichloromethane was dried by passage through basic alumina and standing over 4A molecular sieves.

N,N-dimethylformamide was dried by passage through acidic alumina and standing over 4A molecular sieves. Nujol is a registered trade mark.

Intermediate 1 Ethyl(Z)-2-(2-Triphenylmethylamino-4-thiazolyl)-2-C(3- formylcarbazoyl)methoxyimino }acetate To a stirred suspension of (Z)-2-(2-triphenylmethylamino-4 thiazolyl)-2-(carboxymethoxyimino) acetic acid ethyl ester (5.156g) in anhydrous dichloromethane (50ml) were added a drop of anhydrous N,N-dimethylformamide and triethylamine (1.81ml). The resulting solution was cooled under nitrogen to -5 and then a solution of oxalyl chloride (1.14ml) in anhydrous dichloromethane (6ml) was added dropwise. The solution was stirred for 1 hour and then formylhydrazine (3.09) in anhydrous N,N-dimethylformamide (13ml) was added slowly.The mixture was stirred at OO for a further 2 hours and then the temperature was allowed to rise to 180 over 1)4 hours. The reaction mixture was poured into ethyl acetate (300ml), 2N hydrochloric acid (200ml) and ice. The aqueous phase containing some suspended solid was shaken with ethyl acetate (200ml), the solid was filtered off and the layers were separated. The combined organic phases were washed with 2N hydrochloric acid (2x200ml), water (2x200ml) and saturated brine (10Dml), dried over magnesium sulphate and evaporated to give a foam (4.56g). The crude product was chromatographed on silica gel (250g) eluting with 3 < methanol - chloroform. Appropriate fractions were combined and evaporated to give the title ester (1.25g) as a foam.

smax(CHBr3) 3395, 1728, 1700 (sh), 1650 and 1530 cm-l, 6 (DMSO-d6) mixture of rotamers 1.11 (3H,t), 3.98 (2H,m), 4.56 (1H,s), 6.95 and 6.97 (1H,s), 7.15-7.4 (15H,m), 7.88 and 8.01 (1H,s), 8.84 and 8.87 (1H,s) and 9.9 (2H, broad s).

Intermediate 2 (Z)-2-(2-Triphenylmethylamino-4-thiazolyl)-2-[(3-formylcarbazoyl) methoxyimino)]acetic Acid To a solution of (Z)-2-(2-triphenylmethylamino-4-thiazolyl)-2 [(3-formylcarbazoyl)methoxyimino) acetic acid ethyl ester (1.219) in dioxan (15ml) was added 1M aqueous sodium hydroxide (4.5ml). The solution was stirred at 210 for 32 hours and was then poured into ethyl acetate (lOOml) and shaken with 2N hydrochloric acid (50ml).

The aqueous phase was separated and extracted with ethyl acetate (50ml) and the combined organic phases were washed with water (2x50ml) and saturated brine (50ml), dried over magnesium sulphate and evaporated to give the title acid (963mg).

vmax (CHBr3) 1712, 1630cm-1; 6 (cDcl3) Mixture of rotamers. 4.64 (2H,broad t), 6.64 and 6.69 (1H, broad s), 7.2-7.45 (15H, broad s), 7.76 and 7.94 (1H, broad s), 8.5-10.8 (4H, broad signals).

Intermediate 3 Ethyl (Z)-2-(2-Triphenylmethylamino-4-thiazolyl)-2-(Z-carboxyprop -2- oxy-imino ) acetate Ethyl (Z)-2-(2-triphenylmethylamino-4-thiazolyl)-2-[2-(ethoxy carbonyl) prop-2-oxyimino] acetate (147.59) was twice dissolved in toluene (600ml) and the solvent was evaporated under reduced pressure.

The resulting solid was dissolved in trifluoroacetic acid (680ml) and the solution was stirred for 1 hour. The solvent was evaporated off under reduced pressure and the residue was partitioned between ethyl acetate (5ûOml) and aqueous 2M potassium hydrogen carbonate (50ûml).

The aqueous layer was back-extracted with ethyl acetate (lOOml) and the organic layers combined and set aside. The resulting precipitate was filtered off and dried under reduced pressure to give the title compound (39.659). On cooling, the filtrate yielded a further crop of the title compound (61.779).

Vmax(CHBr3) 3230, 1730 and 1537cm-1; 6(CDCl3)1.3Z (3H,t), 1.58 (6H, s), 4.36 (2H,q), 6.40 (1H, s), 7.3 (15H, m), 8.5 (1H, broad s) and 9.40 (1H, broad s).

Intermeciate 4 Ethyl (Z)-2-(2-Triphenylmethylamino-4-thiazolyl)-2-[2-(3-formyl carbazoyl ) prop2-oxyimino] acetate Method 1 To a solution of ethyl (Z)-2-(2-triphenylmethylamino-4-thia zolyl)-2-(2-carboxyprop-2-oxyimino)acetate (5.439) in acetonitrile (250ml) and anhydrous dimethylformamide (20ml) were added N-hydroxybenzotriazole monohydrate (200mg), 4-(N,N-dimethylamino)pyridine (150mg) and dicyclohexylcarbodiimide (2.39). The resulting mixture was stirred for 25 minutes and then a solution of N-formylhydrazine (1.29) in acetonitrile (60ml) was added and stirring continued for a further 19 hours.A few drops of glacial acetic acid were added and the solution was filtered, diluted with ethyl acetate (500ml), washed sequentially with 2N hydrochloric acid (3x100ml), water (100ml) and saturated brine (100ml), dried over magnesium sulphate and evaporated to give a foam (89). The crude product was chromatographed under medium pressure on silica eluting with chloroform-methanol (97:3).

Appropriate fractions were combined and evaporated under reduced pressure to give the title hydrazide (4.149) as a foam.

Method 2 To a solution of ethyl (Z)-2-(2-triphenylmethylamino-4-thia- zolyl)-2-(2-carboxyprop-2-oxyimino)acetate (2.09) in dry tetrahydrofuran (15ml) and dichloromethane (15ml) containing N-methylmorpholine (0.4ml) cooled to 230 was added 2-methylpropyl chloroformate (0.48ml) and the solution was stirred at -20 for 30 minutes. N-Formyl hydra- zine (265mg) was added and the solution was stirred at -200 for 1 hour, allowed to warm to room temperature and then stirred for a further hour. The solution was filtered and evaporated under reduced pressure to give a foam (2.39). The crude product was chromatographed under medium pressure on silica eluting with dichloromethane-ethyl acetate (3:2).Appropriate fractions were combined and evaporated under reduced pressure to give the title compound (1.139) as a foam.

vmax(CHBra) 3398, 1736, 1668 and 1529cm1; 6 (CDCl3) 1.32 (3H, t), 1.57 (6H, s), 4.36 (2H, q), 6.60 (1H, s), 7.33 (15H, m), 7.70 (1H broad s), 8.13 (1H, s), 8.6 (1H, broad s) and 9.98 (1H, broad s).

Intermediats 5 (z)-2-(2-Triphenylmethylamino-4-thiazolyl)-2-t2-(3-ormylcar-b-a-zoyl) prop-2-oxyimino]acetic Acid A suspension of ethyl (Z)-2-(2-triphenylmethylamino-4-thia zolyl)-2-[2-(3-formylcarbazoyl)prop-2-oxyimino]acetate (3.959) in dioxan (6Dml) and 1M sodium hydroxide solution (14ml) was stirred for 16 hours.The resulting solution was diluted with ethyl acetate (200ml) and shaken with 2N hydrochloric acid (100ml). The aqueous phase was extracted with ethyl acetate (100ml) and the combined organic phases were washed with water (2x100ml) and saturated brine (100ml), dried over magnesium sulphate and evaporated to give a foam (3.89). This was triturated with ether (circa 20ml) to give a solid which was filtered off, washed with n-hexane and dried under reduced pressure to give the title acid (2.969).

v 3600-2100 (broad) and 1750-1660 (broad) cmii max 6 (DMSO-d6) Major rotamer. 1.42 (6H, s), 6.92 (1H, s) 7.1-7.5 (15H,m), 8.02 (1H, s), 8.91 (1H, s), 9.16 (1H, s) and 9.93 (1H, s) Minor rotamer. 1.42 (6H, s), 6.91 (1H, s), 7.1-7.5 (15H, m), 7.77 (1H, d), 8.86 (1H, s), 9.45 (1H, d) and 9.63 (1H, s).

Intermediate 6 Diphenylmethyl (6R ,7R ,2 'Z)-3-(Carbamoyloxymethyl )-7-[2-(2-triphenyl- methylamino-4-thiazolyl)--2-[ (3-formylcarbazoyl)methoxyimino]- acetamido]ceph-3-em-4-carboxylate To a solution of (Z)-2-(2-triphenylmethylamino4-thiazolyl)-2- [(3-formylcarbazoyl)methoxyimino]acetic acid (736mg) in anhydrous N,N-dimethylformamide (7ml) cooled in ice were added diphenylmethyl (6R,7R)-7-amino-3-(carDamoyloxymethyl)ceph-3-em-4-carboxylate (571mg) N-hydroxybenzotriazole monohydrate (256mg) and dicyclohexylcarbodiimide (344mg). After stirring the reaction mixture in an ice bath for 1 hour the solid which separated out was filtered off and washed with N,N-dimethylformamide (2ml). The filtrate was diluted with ethyl acetate (100ml), washed sequentially with 2N hydrochloric acid (4x50ml), water (5ûml) and saturated brine (2x5ûml), dried over magnesium sulphate and evaporated to give a foam (1.29). The crude product was chromatographed on silica gel (1209) eluting initially wih 4% methanol-chloroform and then 7% methanol-chloroform.

Appropriate fractions were combined and evaporated to give the title cephalosporin ester (844mg) as an amorphous solid.

#max 3520, 3380, 3260, 1785, 1728 and 1679 cm 6 (DMSO-d6) Mixture of rotamers.3.52 (1H,d), 3.67 (1H,d), 4.65 (3H,m), 4.83 (1H,d), 5.26 (1H,d), 5.86 (1H,dd), 6.7 (2H, broad s), 6.91 and 6.92 (1H,s), 6.95 (1H,s), 7.20-7.60 (25H,m), 7.92 and 8.08 (1H,s and d), 8.98 and 9.02 (1H,s) and 9.55-9.80 (2H,m).

Intermediate 7 Diphenylmethyl (6R,7R,2'Z)-3-(Carbamoyloxymethyl)-7- [2-(2 triphenylmethylamino-4-thiazolyl )-2- (carbazoylmethoxyimino) acetamido]ceph-3-em-4-carboxylate Hydrochloride Phosphoryl chloride (0.93ml) was added slowly to methanol (20ml) at around OOC and the solution was stirred for 15 minutes.An aliquot (5ml) was added to diphenylmethyl(6R ,7R,2'2)-3- (carbamoyloxymethyl)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2 (3-formylcarbazoyl)methoxyimino)acetamido]ceph-3-em-4-carboxylate (785mg) and the mixture was stirred in ice for 1ss4 hours. The resulting solution was added dropwise with stirring to isopropyl ether (50ml) and the precipitated solid was filtered off, washed with isopropyl ether and dried under reduced pressure to give the title hydrazide (745mg).

V 1789 1728 and 1678 cm-l; max 6 (DMSO-d6) 3.8-5.2 (3H,broad s), 3.52 and 3.66 (each 1H,s), 4.63 (1H,d), 4.75 (2H,s), 4.81 (1H,d), 5.25 (1H,d), 5.85 (1H,dd), 6.70 (2H, broad s), 6.93 (1H,s), 6.95 (1H,s), 7.2-7.6 (25H,m), 9.30 (1H,broad s) and 9.72 (1H,d).

Intermediate 8 Diphenylmethyl (6R,7R,2'Z )-3-iCarbamoyloxymethyl)-7-t2-(2-triphenyl- methylamino-4-thiazolyl)-2-[2-(3- formylcarbazoyl)prop-2- oxyiminoj- acetamido]ceph-3-em-4-carboxylate To a solution of (Z)-2-(2-triphenylmethylamino4-thiazolyl)-2 [2-(3-formylcarbazoyl)prop-2-oxyimino]acetic acid (2.8669) in anhydrous N,N-dimethylformamide (35ml) stirred in ice were added diphenylmethyl (6R, 7P)-7-amino-3-carbamoyloxymethylceph-3-em-4- carboxylate (2.1539), N-hydroxybenzotriazole monohydrate (865mg) and dicyclohexylcarbodiimide (1.339). The resulting suspension was stirred in an ice bath for 1 hour and then a few drops of glacial acetic acid were added.The solid was filtered off and washed with N,N-dimethylformamide (3ml) and ethyl acetate (20ml). The filtrate was partitioned between ethyl acetate (200ml) and 2N hydrochloric acid (100ml). The aqueous phase was extracted with ethyl acetate (100ml) and the combined inorganic phases were washed sequentially with 2N hydrochloric acid (3x100ml), water (100ml) and saturated brine (2x100ml), dried over magnesium sulphate and concentrated under reduced pressure to give a foam (5.2g). The crude product was chromatographed under medium pressure on silica (5009) eluting initially with 2 ó methanol-chloroform and then with 4% methanolchloroform. Appropriate fractions were combined and evaporated to give the title cephalosporin ester (2.1479) as a foam.

V (C 6max H8r3) 3510, 3385, 3260, 1780, 1722, 1660 and 1523cm-1; # (DMSO-d6) Mixture of rotamers.1.48 (3H, s), 1.50 (3H, s), 3.56 (1H, d), 3.68 (1H, d), 4.63 (1H, d), 4.82 (1H, d), 5.28 (1H, d), 5.79 (1H, dd), 6.70 (2H, broad s), 6.94 (1H, s), 6.96 (1H, s), 7.2-7.6 (25H, m), 7.82 (minor rotamer) and 8.0 (1H, s major rotamer), 8.94 (minor rotamer) and 8.98 (1H, s major rotamer), 9.20 (major rotamer) and 9.45 (1H, s minor rotamer), 9.56 (m, minor rotamer ) and 9.87 (1H, s major rotamer).

Intermediate 9 Diphenylmethyl (6R,7R,2'Z)-3-(Carbamoyloxymethyl)-7-[2-(2-triphenyl- methylamino-4-thiazolyl)-2-(2-carbazoylprop-2-oxyimino)acetamido]ceph -3-em-4-carboxylate Hydrochloride To methanol (20ml) stirred in ice under nitrogen was added phosphoryl chloride (0.93ml) dropwise and the solution was stirred for a further 15 minutes. Diphenylmethyl (6R,7R,2'Z)-3-(carbamoyloxy- methyl)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(2-(3-formyl- carbazoyl)prop-2-oxyimino)acetamido]ceph-3-em-4-carDoxylate (2.109) was dissolved in a portion of this solution (13ml) and stirred in an ice Dath for 1 hours.The solution was then dripped into stirred isopropyl ether (150ml) and the resulting precipitate was filtered off, stirred with isopropyl ether (100ml), filtered off and dried under reduced pressure to give the title compouna tZulag 210 0 [a]0 +31 (c 1.053 in chloroform), x (chloroform) 266nm(E: 171); max V 3700-2300 (broad), 1788, 1720, 1678, 1572 and 1590cm-1; max 6 (DMSO-d6) 1.50 (3H, s), 1.52 (3H, s), 3.52 (1H, s), 3.65 (1H, s), 4.60 (1H, d), 4.79 (1H, d), 5.24 (1H, d), 5.80 (1H, dd), 6.65 (2H, broad) 6.92 (1H, s), 6.96 (1H, s), 7.1-7.6 (25H, m), 9.65 (1H, broad s), 9.72 (1H, d) and 10.55 (1H, s).

Example 1 Diphenylmethyl (6R,7R,2'Z)-3-(Carbamoylaxymethyl)-7-[2-[3-((6,7- dihydroxy-4-oxo-4H-benzopyran-3-yl)carbonyl)carbazoyl)methoxyimino] -2-(2-triphenylmethylamino-4-thiazolyl)acetamido3ceph-3-em-4 carboxylate To a solution of diphenylmethyl (6R,7R,2'Z)-3-(carbamoyloxy methyl)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(carbazoylmethoxy- imino)acetamido]ceph-3-em-4-carboxylate hydrochloride (708mg) in anhydrous dichloromethane (10ml) stirred under nitrogen in ice was added bis-trimethylsilylacetamide (1.93ml) and the mixture was stirred for 30 minutes. 6,7-Dihydroxy-4-oxo-4H-benzopyran-3-carbonyl chloride (282mg) was added and stirring continued for 1 hours. The solution was added stirred to isopropyl ether (50ml)-methanol (lml) and the precipitated solid (1.219) was filtered off, chromatographed on silica gel (1009) eluting initially with 10 > methanol-chloroform and then with chloroform-methanol-acetic acid (90:10:1). Pure fractions were combined, concentrated and added to stirred isopropyl ether to precipitate the title cephalosporin (370mg).

max (Nujol) 1787, 1720 and 1665 cm-1; 6 (DMSO-d6) 3.54, (1H,d), 3.68 (1H,d), 4.62 (1H,d), 4.71 (2H,s), 4.82 (1H,d), 5.26 (1H,d), 5.86 (1H,broad s), 6.57 (1H,s), 6.72 (2H,broad s), 6.91 (1H,s) 6.95 (1H,s), 7.1-7.6 (26H,m), 8.81 (1H,s), 9.02 (1H,broad s), 9.68 (1H,broad s), 11.53 and 12.51 (4H,broad signals).

Example 1 (6R,7R,2'Z)-7- [2-(2-Amino-4-thiazolyl)-2-[(3-((6 ,7-dihydroxy-4-oxo 4H-Denzopyrsn-3-yl)carbonyl)carDazoyl)methoxyimino]acetamido]-3- (carbamoyloxymethyl)ceph-3-em-4-carboxylic Acid Trifluoroacetate Salt To a mixture of diphenylmethyl (6R,7R,2'Z)-3 (carbamoyloxymethyl)-7- [2-[(3-((6,7-dihydroxy-4-oxo-4H-benzopyran-3- yl) carbonyl) carbazoyl) methoxyimino]-2-(2-triphenylmethylamino-4- thiazolyl) acetamido ]ceph-3-em-4-caroxylate (350mg) and anisole (0.5ml) was added trifluoroacetic acid (2.3ml) and the solution was stirred for 7 minutes.A drop of water was added and the mixture was poured into stirred isopropyl ether (30ml). The resulting precipitate was filtered off, washed thoroughly with isopropyl ether and dried to give the title compound (260mg).

(pH6) 233.6(Ei 454) and 319nm (Ei 142); 6 (DMSO-d6) 3.4-3.8 (2H,m), 4.63 (1H,d), 4.69 (2H,s), 4.91 (1H,d), 5.20 (1H,d), 5.85 (1H,dd), 6.64 (2H,broad s), 6.88 (1H,s), 7.02 (1H,s), 7.34 (3H,broad s), 7.44 (1H,s), 8.94 (1H,s), 9.67 (1H,d), 10.14 (1H,broad s), 10.30 (1H,d), 10.89 (1H,broad s) and 11.11 (1H,d).

Example 3 Diphenylmethyl (6R ,7R,2'Z)-3- (cartamoyloxymethyl)-7-[2-(2-triphenyl- methylamino-4-thiazolyl)-2-[2-(3-((6,7-diacetoxy-4-oxo-4H-benzopyran- 3-yl)carbonyl)carbazoyl)prop-2-oxyimino]acetamido]ceph-3-em-4-carb late To a solution of diphenylmethyl (6R,7R,2'Z)-3-(carbamoyloxy- methyl)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(2-carbazoylprop- 2-oxyimino) acetamido]ceph-3-em-4-carboxyl ate (291mg) in dichloro methane (5ml) stirred under nitrogen was added bis-trimethylsilylacetamide (0.75ml) and the solution was stirred for 45 minutes. 6,7 Diacetoxy-4-oxo-4H-benzopyran-3-carbonyl chloride (119mg) was added and stirring continued for 1 hour.The solution was added to a stirred mixture of isopropylether (loom) and methanol (lmi) to precipitate a solid (295mg) which was filtered off and chromatographed under medium pressure on silica eluting with chloroform-methanol (95:5). Appropriate fractions were combined and evaporated to give the title compound (100mg).

6 (DMSO-d6) 1.45 (3H, s), (3H, s), 2.35 (3H, s), 2.38 (3H, s), 3.52 (1H, d), 3.67 (1H, d), 4.60 (1H, d), 4.77 (1H,d), 5.27 (1H, d), 5.79 (1H, dd), 6.65 (2H, broad s), 6.92 (1H, s), 7.1-7.4 (15H, m), 7.91 (1H, s) and 8.10 (1H, s).

Example 4 (6R,7R,2'Z)-7-[2-(2-Amino-4-thiazolyl)-2-[2-(3-((6,7-diacetoxy-4-oxo- 4H-benzopyran-3-yl)carbonyl)carbazoyl)prop-2-oxyimino]acetamido]-3- (caramoyioxymethyl)ceph-3-em-4-carboxylic acid Diphenylmethyl (6R,7R,2'Z)-3-(carbamoyloxymethyl)-7-[2-(2- triphenylmethylamino-4-thiazolyl)-2-[2-(3-((6,7-diacetoxy-4-oxo-4H- benzopyran-3-yl)carbonyl)carbazoyl) prop-2-oxyimino]acetamido]ceph-3- em-4-carboxylate (90mg) was treated with anisole (O.lml) and trifluoroacetic (0.4ml) and the solution was stirred for 20 minutes.

A drop of water was added and the solution added to stirred isopropyl ether (SOml). The resulting precipitate was filtered off, washed with isopropylether and dried under reduced pressure to give the title compound (48mg).

Vmax (Nujol) 3600-2220 (broad), 1776, 1670 and 1625cm1; 6 (CDCl3) 1.53 (3H, s), 1.58 (3H, s), 2.36 (3H, s), 2.40 (3H, s), 4.65 (1H, d), 4.92 (1H, d), 5.27 (1H, d), 5.93 (1H, dd), 6.68 (2H, broad s), 6.94 (1H, s), 7.94 (1H, s) and 8.13 (1H, s).

Claims (3)

Claims

1. Compounds of formula (I)

where in R1 represents a hydrogen atom or an amino protecting group; R2 represents a hydrogen atom or a carboxyl blocking group; R3 represents a hydrogen atom or a C1-C4 alkyl group optionally substituted by one to three halogen atoms; R4 and R5 which may be the saine or different each represents a hydrogen atom, a C1-4 alkyl group, or together with the carbon atom tu which they are attached form a C3 -C7 cycloalkyl group; R6 and R7 which may be the Swine or different each represents a hydroxy group, a sdbstituted hydroxy group or R6 and R7 together represent a cyclic protected diol group; Z is > S or > S4O (a- or ss-j;; tiiz dotted line bridging the 2-, 3- and 4- positions indicates that the compound is a ceph-2-e!l or ceoh-3-em compound; and non-toxic salts, and solvated forms including hydrated forms, thereof.

2. Compounds as claimed in claim 1 of formula (Ib)

wherein R3, R4, R5 and Z are as defined in claim 1 R6a is a hydroxy or acetoxy group; 7a is a hydroxy or acetoxy group; and the non-toxic salts, solvates (including hydrates) and metabolically labile esters thereof.

3. Compounds as claimed in claim 2 being (6R,7R,2'Z)-7-[2-(2-amino-4-thiazolyl)-2- [(3-((6,7-dihydroxy-4-oxo-4H-benzopyran-3-yl)carbonyl) carbazOyl)methoxyimino]acetamido]-3-(carbamoylOxymethyl) ceph-3-em-4-carboxylic acid; and (6P,7R,2'Z)-7-[2-(2-amino-4-thiazolyl)-2- [2-(3-((6,7-diacetoxy-4-oxo-4H-benzopyran-3-yl)carbonyl) carbazoyl)prop-2-oxyimino]acetamj3oj-3-(carbamoyloxymethyl) ceph-3-em-4-carboxylic acid.