GB1604723A

GB1604723A - 7-(2-aminothiazol-4-yl)-2-oxyimino-acetamido)-cephem derivatives

Info

Publication number: GB1604723A
Application number: GB23041/78A
Authority: GB
Original assignee: Glaxo Operations UK Ltd
Current assignee: Glaxo Operations UK Ltd
Priority date: 1978-05-26
Filing date: 1978-05-26
Publication date: 1981-12-16
Also published as: JPS54154787A; KR830000698A; BE876539A; KR830001130B1; ZA792582B

Description

(54) 7-[2-AMINOTHIAZOL-4-YL)-2-OXYIMINO ACETAMIDO]-CEPHEM DERIVATIVES (71) We, GLAXO OPERATIONS UK LIMITED, formerly known as Glaxo Laboratories Limited, a British Company of Greenford, Middlesex do hereby declare the invention for which we pray that a patent may be performed, to be particularly described in and by the following statement:- This invention is concerned with cephalospo.rin compounds possessing valuable antibiotic properties.

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 double bond.

Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in human beings and animals, and 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. 1,399,086, we describe a novel class of cephalosporin antibiotics containing a 7 - (a - etherified oximino) - acylamido group, the compounds being syn isomers or mixtures of svn and anti isomers wherein -the syn isomer predominates. This class of antibiotic compounds are characterised by high antibacterial activity against a range of grampositive and gram-negative organisms coupled with particularly high stability to A- 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.

For example, in our British Patent Specification No. 1,496,757, we describe cephalosporin antibiotics containing a 7p-acylamido group of the formula

(wherein R is a thienyl or furyl group; RA and RB may be inter alia C14 alkyl groups or together with the carbon atom to which they are attached form a C37 cycloalkylidene group; and m and n are each 0 or I such that the sum of m and n is 0 or 1), the compounds being syn isomers or mixtures of syn and anti isomers containing at least 90% of the syn isomer. These compounds have been found to have particularly good activity against gram-negative organisms.

Other compounds of similar structure have been developed from these compounds in further attempts to find antibiotics having improved broad spectrum antibiotic activity and/or high activity against gram-negative organisms. Such developments have involved variations in not only the aromatic groups (R' and R) and the oximino etherifying groups in the above formulae but also the introduction of particular groups in the 3-position of the cephalosporin molecule.

Thus, for example, in Belgian Patent Specification No. 852,427, there are described cephalosporin antibiotic compounds falling within the general scope of our British Patent Specification No. 1,399,086 and wherein the group R in the above formula may be replaced by a variety of different organic groups, including 2 - aminothiazol - 4 - yl, and the oximino group is an aliphatic hydrocarbon group which may be substituted by, for example, car oxy, while the 3-position contains certain specific groups.

We have now discovered that by an appropriate selection of groups constituting the 78- and 3-positions compounds having particularly good activity against a wide range of gram-negative organisms may be obtained.

The present invention provides antibiotics of the general formula

(wherein Ra and Rb, which may be the same or different, each represent a C14 alkyl group and Y represents a C-linked 5- or 6-membered heterocyclic ring containing at least one nitrogen atom, which ring may also contain one or more sulphur atoms and/or may be substituted by a C, alkyl group) and non-toxic salts and non-toxic metabolically labile esters thereof.

Examples of heterocyclic rings which may be represented by Y in formula (I) above include pyridyl and tetrazolyl groups. When the heterocyclic ring is substituted by a C,, alkyl group this may, for example, be methyl.

The compounds according to the present invention, which compounds are svn isomers, may exist in tautomeric forms (in respect of the 2-aminothiazolyl group) and it will be understood that such tautomeric forms, i.e. 2-aminothiazolyl and 2 iminothiazolinyl, are included within the scope of the invention.

When the group Y is in a quaternary form, e.g. an N-alkyl pyridinium group, the compounds of formula (I) may exist in the form of a bentaine containing a --COOB group.

The compounds according to the invention exhibit good broad spectrum antibiotic activity. The compounds exhibit activity against microorganisms which produce p-lactamases, and also possess very high stability to p-lactamases produced by a range of gram-negative organisms. Furthermore they have been found to exhibit good activity against various members of the enterobacteriaceae (e.g.

strains of Escherichia coli, Klebsiella aerogenes and especially Proteus mirabilis, Proteus organ it and Proteus vulgaris), as well as against Pseudomonas organisms e.g. strains of Pseudomas aeruginosa.

As mentioned above, the compounds of the invention are syn isomers. The syn isomeric form is defined by the configuration of the group

with respect to the carboxamido group. In this specification the syn configuration is denoted structurally as

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

Non-toxic salt derivatives which may be formed from the compounds of general formula (I) include inorganic base salts such as alkali metal salts (e.g.

sodium and potassium salts) and alkaline earth metal salts (e.g. 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); and, where appropriate, acid addition salts, e.g.

with hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, formic, trifluoroacetic, toluene - p - sulphonic and methane - sulphonic 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, where appropriate, sulphonic acid groups, or, again where appropriate, with a resin containing carboxyl groups, e..apolyacrylic acid resin. Use of highly soluble base salts (e.g. alkali metal salts such as the sodium salt) of compounds of formula I is generally advantageous 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 a conventional manner, for example with appropriate organic amines.

Non-toxic metabolically labile ester derivatives which may be formed from the compounds of general formula (I) and which on administration are converted in vivo into the antibiotic compound of formula (I) include, for example, acyloxymethyl esters, e.g. (c,~ alkanoyl)oxymethyl esters such as acetoxymethyl, acetoxyethyl and pivaloyloxymethyl esters.

Preferred compounds according to the present invention by virtue of their high activity against Pseudomonas organisms, e.g. strains of Pseudomonas aeruginosa include those compounds of formula (I) wherein Ra and Rb both represent methyl groups and Y represents a 1 - methylpyridinium - 2 - yl or I - methyltetrazol - 5 yl group.

The compounds of formula (I) may be used for treating a variety of diseases caused by pathogenic bacteria in human beings and animals, such as respiratory tract and urinary tract infections.

The compounds according to the invention may be prepared by any convenient method, for example by techniques analogous to those described in British Patent Specification No. 1,399,086.

Thus according to one embodiment of the invention we provide a process for the preparation of an antibiotic compound of formula (I) as hereinbefore defined or a non-toxic salt or non-toxic metabolically labile ester thereof which comprises either (A) condensing a compound of the formula

[wherein Y is as defined above; B is > S or > S .O (- or A-); R3 represents hydrogen or a carboxyl blocking group, e.g. the residue of an ester-forming aliphatic or araliphatic alcohol or an ester-forming phenol, silanol or stannanol (the said alcohol, phenol, silanol or stannanol preferably containing 1--20 atoms) or a symmetrical or mixed anhydride group derived from an appropriate acid; and the dotted line bridging the 2-, 3- and 4positions indicates that the compound is a ceph-2-em or ceph-3-em compoundl, or a salt, e.g. an acid addition salt such as a hydrochloride, hydrobromide, sulphate, nitrate, phosphate, methane-sulphinate or tosylate, or an N-silylated derivative thereof with an acid of formula

(wherein R" and Rb are as defined above; and R4 represents a carboxyl blocking group, e.g. as defined above for R4 and R5 iS an amino or protected amino group) or with an acylating agent corresponding thereto; or (B) reacting a compound of formula

(wherein Ra, Rb, R5, B and the dotted line are as defined above; R3 and R3" may independently represent hydrogen or a carboxyl blocking group; and X is a replaceable residue of a nucleophile, e.g. an acetoxy or dichloroacetoxy group or a halogen atom such as chlorine, bromine or iodine) with a sulphur nucleophile serving to form a group of formula CH2-SY (wherein Y is as defined above) at the 3-osition; whereafter, if necessary and/or desired in each instance, any of the following reactions (C) in any appropriate sequence, are carried out: (i) conversion of a A2-isomer into the desired A3-isomer, (ii) reduction of a compound wherein B is > S < O to form a compound wherein B is > S, (iii) conversion of a carboxyl group into a non-toxic metabolically labile ester function, and (iv) removal of any carboxyl blocking and/or N-protecting groups; and finally (D) recovering the desired compound of formula (I) or a non-toxic salt or non-toxic metabolically labile ester thereof, if necessary after separation of isomers.

Base salts of compounds of formula (I) may be formed by reaction of the cephalosporin acid with, for example, sodium 2-ethylhexanoate or potassium 2ethylhexanoate. Non-toxic metabolically labile ester derivatives may be formed using conventional esterifying agents.

Acylating agents 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 (III) or a salt thereof with a halogenating agent e.g. phosphorus pentachloride, thionyl chloride or oxalyl chloride.

Acylations employing acid halides may be effected in aqueous and nonaqueous reaction media, conveniently at temperatures of from -50 to +500 C, preferably -20 to +30"C, if desired in the presence of an acid binding agent.

Suitable reaction media include aqueous ketones such as aqueous acetone, esters such as 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), inorganic bases (e.g. calcium carbonate or sodium bicarbonate), and oxiranes such as C26 1 ,2-alkylene oxides (e.g. ethylene oxide or propylene oxide) which bind 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 (III) are desirably conducted in the presence of a condensing agent, for example a carbodiimide such as N,N' - diethyl - , dipropyl- or diisopropylcarbodiimide, N,N' - dicyclohexyl - carbodiimide or N - ethyl - N' - V dimethylaminopropylcarbodiimide; a carbonyl compound such as carbonyldiimidazole; or an isoxazolinium salt such as N- ethyl - 5phenylisoxazolinium perchlorate.

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. with pivalic acid or formed with a haloformate such as a C16 alkylhaloformate). An activated ester may conveniently be formed in situ using, for example, 1 - hydroxy - benzotriazole in the presence of a condensing agent as set out above.

Mixed anhydrides may be formed with phosphorus acids (for example phosphoric or phosphorous acids), sulphuric acid or aliphatic or aromatic sulphonic acids (for example p-toluene sulphonic acid).

Acylation reactions involving the free acids or their above-mentioned amide forming derivatives are desirably effected in an anhydrous reaction medium, e.g.

methylene chloride, dimethylformamide or acetonitrile.

The acids of formula (III) may, if desired, be employed in the form of their acid addition salts e.g. their hydrochlorides.

In addition to the general methods described in British Patent Specification No. 1,399,086 referred to above, compounds of formula I may also be prepared by the reaction of a corresponding 3-acetoxymethyl cephalosporin compound with an appropriate sulphur nucleophile, for example, in an analogous manner to that described in British Patent Specification Nos. 1,012,943 and 1,206,305.

Compounds of formula I may also be prepared by the reaction of a corresponding 3 - halomethylcephalosporin with an appropriate sulphur nucleophile disclosed in the above references, such a process being described in British Patent Specification No. 1,241,657, or by the reaction of a 3halomethylcephalosporin sulphoxide with any appropriate sulphur nucleophile disclosed in the above references, such a process being described in British Patent Specification No. 1,326,531.

Appropriate sulphur nucleophiles include those of formula YSH in which Y is as defined above. However, when Y is a 1 - methylpyridinium - 2 - yl group, the corresponding N - methyl - pyrid - 2 - thione is preferably employed, the reaction being advantageously effected in the presence of sodium iodide.

A2-Cephalosporin ester derivatives obtained in accordance with the process of the invention may be converted into the corresponding At derivative by, for example, treatment of the 2 ester with a base.

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

Where a compound is obtained in which B is > SeO this may be converted to the corresponding sulphide by, for example, reduction of the corresponding acyloxy-sulphonium or alkyloxysulphonium 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 water miscible solvent e.g. acetic acid, acetone, tetrahydrofuran, dioxan, dimethylformamide or dimethylacetamide. The reaction may be effected at a temperature of -20" to +50"C.

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.

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 ctystallisation or chromatography. Syn and anti isomers may be distinguished by appropriate techniques, e.g. by their ultraviolet spectra, by thin layer, paper, or high pressure liquid chromatography or by their proton magnetic resonance spectra.

For use as starting materials for the preparation of compounds of general formula (I) according to the invention, compounds of general formula (III) and acid halides and anhydrides corresponding thereto in their syn isomeric form or in the form of mixtures of the syn isomers and the corresponding anti isomers containing at least 90% of the syn isomer are preferably used.

Acids of formula III may be prepared by etherification of a compound of formula.

(wherein R5 is as hereinbefore defined and R re resents hydrogen or a carboxyl blocking group) by reaction with a compound of general formula

[wherein Ra, Rb, and R4 are as hereinbefore defined, and T is halogen such as chloro, bromo or iodo; sulphate; or sulphonate such as tosylate] followed by removal of any carboxyl blocking group RB. Separation of isomers may be effected either before or after such etherification. The etherification reaction is desirably carried out in the presence of a base, eg. potassium carbonate or sodium hydride, and is preferably conducted in an organic solvent, for example dimethylsulphoxide, a cyclic ether such as tetrahydrofuran or dioxan, or an N,N-disubstituted amide such as dimethylformamide. Under these conditions the configuration of the oximino group is substantially unchanged by the etherification reaction.

The reaction should be effected in the presence of a base if an acid addition salt of a compound of formula (V) is used. The base should be used in sufficient quantity to rapidly neutralise the acid in question.

Acids of general formula (III) may also be prepared by reaction of a compound of formula

(wherein R5, and Re are as hereinbefore defined) with a compound of formula

(wherein R", Rb and R4 are as defined for formula (III). followed by removal of any carboxyl blocking group R6.

Compounds of formula (VIII) may be prepared in conventional manner.

Reaction of (VII) with (VIII) may be followed where necessary by the separation of syn and anti isomers.

The acids of formula (III) may be converted to the corresponding acid halides and anhydrides and acid addition salts by conventional methods.

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 t - butoxycarbonylation, protonation or other conventional method. 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 aqueous solution of an optionally halogenated carboxylic acid, e.g. acetic acid, formic acid, chioroacetic acid or trifluoroacetic 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 as the last stage. It may, however, be convenient in some instances to employ nontoxic, metabolically labile carboxyl blocking groups such as acyloxymethyl groups (e.g. acetoxymethyl, acetoxyethyl and pivaloyloxymethyl groups) and retain these in the final product to give a non-toxic 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 Specification No. 1,399,086. Preferred blocked carboxyl groups include aryl C2a akoxycarbonyl groups such as p- methoxybenzyl- oxycarbonyl, pnitrobenzyloxycarbonyl and diphenylmethoxy - carbonyl; C2e alkoxycarbonyl groups such as t - butoxy - carbonyf; and C e haloalkoxycarbonyl groups such as 2,2,2 - trichloroethoxycarbonyl. Carboxyl blocking group(s) may subsequently be removed by any of the appropriate methods disclosed in the literature; thus, for example, acid or base catalysed hydrolysis is applicable in many cases, as are enzymically-catalysed hydrolyses.

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 formulated for injection and may be resented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may 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.

The antibiotic compounds may also be presented in a form suitable for absorption by the gastro-intestinal tract, e.g. as tablets or capsules. The antibiotic compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

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%, preferably from 1060% of the active material, depending on the method of administration.

When the compositions comprise dosage units, each unit will preferably contain 501500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 250 to 6000 mg per day, depending on the route and frequency of administration, although in treating Pseudomonas infections higher daily doses may be required.

The antibiotic compounds according to the invention may be administered in combination with other therapeutic agents such as antibiotics, for example, cephalosporins or other penicillins.

The following Examples illustrate the invention. All temperatures are in "C.

'Petrol' means petroleum ether (b.p. 40 60 ).

Preparation 1 Ethyl (Z)-2-(2-aminothiazol-4yl)-2-(hydroxyiminoNacetate To a stirred and ice-cooled solution of ethyl aceto-acetate (292 g) in glacial acetic acid (296 ml) was added a solution of sodium nitrite (180 g) in water (400 ml) at such a rate that the reaction temperature was maintained below 10 C. Stirring and cooling were continued for about 30 min., when a solution of potassium chloride (160 g) in water (800 ml) was added. The resulting mixture was stirred for one hour. The lower oily phase was separated and the aqueous phase was extracted with diethyl ether. The extract was combined with the oil, washed successively with water and saturated brine, dried, and evaporated. The residual oil, which solidified on standing, was washed with petrol and dried in vacuo over potassium hydroxide, giving ethyl (Z) - 2 - (hydroxyimino) - 3 - oxobutyrate (309 g).

A stirred and ice-cooled solution of ethyl (Z)- 2 - (hydroxyimino) - 3 oxobutyrate (150 g) in dichloromethane (400 ml) was treated dropwise with sulphur chloride (140 g). The resulting solution was kept at room temperature for 3 days, then evaporated. The residue was dissolved in diethyl ether, washed with water until the washings were almost neutral, dried, and evaporated. The residual oil (177 g) was dissolved in ethanol (500 ml) and dimethylaniline (77 ml) and thiourea (42 g) was added with stirring. After two hours, the product was collected by filtration, washed with ethanol and dried to give the title compound (73 g); m.p.

188 (decomp.).

Preparation 2 Ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4yl)-acetate, hydrochloride, Trityl chloride (16.75 g) was added portionwise over 2 hours to a stirred and cooled (-30") solution of the product of Preparation 1 (12.91 g) in dimethylformamide (28 ml) containing triethylamine (8.4 ml). The mixture was allowed to warm to 150 over one hour, stirred for a further 2 hours and then partitioned between water (500 ml) and ethyl acetate (500 ml). The organic phase was separated, washed with water (2x500 ml) and then shaken with IN HCI (500 ml). The precipitate was collected, washed successively with water (100 ml), ethyl acetate (200 ml) and ether (200 ml) and dried in vacuo to provide the title compound as a white solid (16.4 g); m.p. 184 to 1860 (decomp).

Preparation 3 Ethyl (Z)-2-(2-t-B utoxycarbonylprop-2-oxyimino)-2-(2-trityl-aminothiazol- 4-yl)acetate Potassium carbonate (34.6 g) and t-butyl 2 - bromo - 2 - methylpropionate (24.5 g) in dimethylsulphoxide were added to a stirred solution under nitrogen of the product of Preparation 2 (49.4 g) in dimethylsulphoxide (200 ml) and the mixture was stirred at room temperature for 6 hours. The mixture was poured into water (2 1), stirred for 10 mins., and filtered. The solid was washed with water and dissolved in ethyl acetate (600 ml). The solution was washed successively with water, 2N hydrochloric acid, water, and saturated brine, dried, and evaporated.

The residue was recrystallised from petrol to give the title compound (34 g), m.p.

123.5 to 1250.

Preparation 4 (L)-2 < 2-t-B utoxycarbonylprop-2-oxyimino)-2-(2-tritylamino-thiazol-4-yl) acetic acid The product of Preparation 3 (2 g) was dissolved in methanol (20 ml) and 2N sodium hydroxide (3.3 ml) was added. The mixture was refluxed for 1.5 hours and then concentrated. The residue was taken up in a mixture of water (50 ml), 2N hydrochloric acid (7 ml), and ethyl acetate (50 ml). The organic phase was separated, and the aqueous phase extracted with ethyl acetate. The organic solutions were combined, washed successively with water and saturated brine, dried, and evaporated. The residue was recrystallised from a mixture of carbon tetrachloride and petrol to give the title compound g), m.p. 152 to 156 (decomp).

Example 1 a) t-Butyl (6R, 7R)-3-Acetoxymethyl-7-[(Z)-2-(2-t-butoxy-carbonylprop-2 oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamidol ceph-3-em-4- carboxylate A stirred solution of the product of Preparation 4 (572 mg) and t-butyl (6R, 7R) - 3 - acetoxymethyl - 7 - aminoceph - 3 - em - 4 - carboxylate (328 mg) in dimethylformamide (10 ml) was cooled to 0 . and I - hydroxybenzotriazole (150 mg) was added, followed by dicyclohexylcarbodiimide (225 mg). The mixture was warmed to room temperature, stirred for 5 hours, and allowed to stand overnight.

The mixture was filtered, and the white solid washed with a little ether. The filtrate and washings were diluted with water (50 ml) and extracted with ethyl acetate. The organic extracts were combined, washed successively with water, 2N hydrochloric acid, water, sodium bicarbonate solution, and saturated brine, dried and evaporated. The residue was eluted through a silica column with ether. The product-containin (b) (6R, 7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2.(2-carboxyprop-2- oxyimino)acetamido] -34 1 -methyltetrazol-5-ylthiomethyl)-ceph-3em-4- carboxylic acid The product of stage (a) (2.0 g) in anisole (10 ml) was stirred with trifluoroacetic acid (20 ml) at 250. After 2.5 h, the volatile solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was evaporated to give the title compound (920 mg), [a] (DMSO) 58 , AmaX (pH 6 buffer) 232 (inf) (E 17,860), 256 nm (inf) (E 16,280).

WHAT WE CLAIM IS: 1. Cephalosporins of the general formula

(wherein Ra and Rb, which may be the same or different, each represent a C14 alkyl group and Y represents a C-linked 5-or 6- membered heterocyclic ring containing at least one nitrogen atom, which ring may also contain one or more sulphur atoms and/or may be substituted by C14 alkyl alkyi group) and non-toxic salts and non-toxic metabolically labile esters thereof.

2. Compounds as claimed in claim 1 wherein Ra and Rb both represent methyl groups.

3. Compounds as claimed in claim I or claim 2 wherein the said heterocyclic ring in the group Y is a pyridyl or tetrazolyl group.

4. Compounds as claimed in any of the preceding claims wherein the said heterocyclic ring is substituted by a methyl group.

5. Compounds as claimed in claim 4 wherein Y represents an Nmethylpyridinium group.

6. (6R, 7R) - 7 - [(Z) - 2 - (2 - Aminothiazol - 4 - yl) - 2 - (2 - carboxy prop - 2 - oxyimino)acetamidol - 3 - (1 - methylpyridinium - 2 - ylthio methyl)ceph - 3- em - 4- carboxylate and non-toxic salts and non-toxic metabolically labile esters thereof.

7. (6R, 7R) - 7 - [(Z) - 2 - (2 - Aminothiazol - 4 - yl) - 2 - (2 - carboxy prop - 2 - oxyimino)acetamidol - 3 - (1 - methyltetrazol - 5 - ylthio methyl)ceph - 3 - em - 4 - carboxylic acid and non-toxic salts and non-toxic metabolically labile esters thereof.

8. A process for the preparation of a compound of formula I (as defined in claim 1) or a non-toxic salt or non-toxic metabolically labile ester thereof which comprises either (A) condensing a compound of the formula

[wherein Y is as defined in Claim 1; B is > S or > SO (a, or A-); R3 represents hydrogen or a carboxyl blocking group; and the dotted line bridging the 2-, 3- and 4- positions indicates that the compound is a ceph-2-em or ceph-3-em compoundl, or a salt or an N-silylated derivative thereof with an acid of formula

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

Claims

**WARNING** start of CLMS field may overlap end of DESC **. (b) (6R, 7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2.(2-carboxyprop-2- oxyimino)acetamido] -34 1 -methyltetrazol-5-ylthiomethyl)-ceph-3em-4- carboxylic acid The product of stage (a) (2.0 g) in anisole (10 ml) was stirred with trifluoroacetic acid (20 ml) at 250. After 2.5 h, the volatile solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was evaporated to give the title compound (920 mg), [a] (DMSO) 58 , AmaX (pH 6 buffer) 232 (inf) (E 17,860), 256 nm (inf) (E 16,280). WHAT WE CLAIM IS:

1. Cephalosporins of the general formula

(wherein R" and Rb are as defined in claim 1; R4 represents a carboxyl blocking group; and R5 is an amino or protected amino group) or with an acylating agent corresponding thereto; or (B) reacting a compound of formula

(wherein Ra, Rb, R5, B and the dotted line are as defined above; R3 and R3" may independently represent hydrogen or a carboxyl blocking group; and X is a replaceable residue of a nucleophile) or an acid addition salt thereof, with a sulphur nucleophile serving to form a group of formula CH2-SY (wherein Y is as defined in claim 1 at the 3-position; whereafter, if necessary and/or desired in each instance, any of the following reactions (C) in any appropriate sequence, are carried out: (i) conversion of a A2 isomer into the desired A3 isomer, (ii) reduction of a compound wherein B is > S < O to form a compound wherein B is > S.

(iii) conversion of a carboxyl group into a non-toxic metabolically labile ester function, and (iv) removal of any carboxyl blocking and/or N-protecting groups; and finally (D) recovering the desired compound of formula (I) or a non-toxic salt or non-toxic metabolically labile ester thereof, if necessary after separation of isomers.

9. A process as claimed in claim 8 wherein a compound of formula (II) is condensed with an acid halide corresponding to the acid of formula (III).

10. A process as claimed in claim 9 wherein the condensation is effected in the presence of an acid binding agent comprising a tertiary amine, an inorganic base or an oxirane.

11. A process as claimed in claim 8 wherein a compound of formula (II) is condensed with an acid of formula (III) in the presence of a condensing agent comprising a carbodiimide carbonyldiimidazole or an isoxazolinium salt.

12. A process as claimed in claim 8 substantially as herein described.

13. A process as claimed in claim 8 substantially as herein described with reference to the Examples.

14. Compounds of the general formula I (as defined in claim 1) whenever prepared by a process as claimed in any of claims 8 to 13.

15. Pharmaceutical compositions comprising a compound of formula I (as defined in claim 1) or a non-toxic salt or non-toxic metabolically labile ester thereof in association with a pharmaceutical carrier or excipient.