IE47335B1

IE47335B1 - Oxime derivatives of 7-amino-thiazolyl-acetamidocephalosporanic

Info

Publication number: IE47335B1
Application number: IE1450/78A
Authority: IE
Original assignee: Roussel Uclaf
Priority date: 1977-07-19
Filing date: 1978-07-19
Publication date: 1984-02-22
Also published as: GB2005660A; ATA522878A; ES471647A2; IE781450L; JPS5422392A; CH632503A5; SE7807274L; DE2831332A1; DK320578A; FR2408613B2; NL7807741A; GB2056988A; DK162094C; IT1156871B; AU3813378A; BE869079R; CA1123824A; IT7850356A0; GB2005660B; AU527621B2

Abstract

The compounds of general formula: wherein Ra represents a hydrogen atom or a trityl group and A represents a hydrogen atom or an alkali metal atom, an equivalent of an alkaline- earth metal atom or a magnesium atom, or a substituted ammonium group, the compounds being in the form of the syn or anti isomers, are new anti-bacterial compounds for use in the treatment of diseases caused by microorganisms in animals or humans. The compounds are prepared from 7-amino-cephalosporanic acid by reaction with 2-(2-tritylamino-4-thiazolyl)- 2-vinyloxyimino-acetic acid or a functional derivative thereof, followed by salification and/or removal of the trityl group, if appropriate. The intermediate 2-(2-tritylamino- 4-thiazolyl)-2-vinyloxyimino-acetic acid and certain related compounds employed in its preparation are also new.

Description

This invention relates to various oxime derivatives of 7-amino-thiazolyl-acetamido-cephalosporanic acid.

In our Patent Specification Mo. 45015 we describe and claim a group of novel oxime derivatives of 7-amino-thiazolyl5 acetamido-cephalosporanic acid defined by the general formula: (I) OR' ch2 o-c % 0 wherein R represents a hydrogen atom or a group removable by acid hydrolysis or by hydrogenolysis, R‘ represents a hydrogen atom, a group removable by acid hydrolysis lo or by hydrogenolysis or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, A represents a hydrogen atom, an alkali metal atom, an equivalent of an alkaline-earth metal atom, an equivalent of a magnesium atom or a substituted ammonium group, with the provisos that when R' represents a group removable by acid hydrolysis or by hydrogenolysis R represents the same or a different group removable by acid hydrolysis or by hydrogenolysis, and that when R1 represents a hydrogen atom R also represents a hydrogen atom, the compounds being in the form of the syn isomer.

The compounds of general formula I possess anti-bacterial activity, and our aforesaid Specification sets out several specifically preferred compounds having outstanding activity. We have now found however that certain other compounds of general formula I not specifically mentioned in our aforesaid Specification, and the corresponding anti isomers thereof possess remarkable anti-bacterial activity.

In one aspect therefore, this invention provides the compounds of general formula: NH — Ra ~^2 CO2A 4733S wherein R represents a hydrogen atom or a trityl group and a A represents a hydrogen atom or an alkali metal atom, an equivalent of an alkaline-earth metal atom or a magnesium atom, or a substituted ammonium group, the compounds being in the form of the syn or anti isomers.

By substituted ammonium group is meant a group derived from an organic amine; typical examples of such amines are methylamine, propylamine, trimethylamine, triethylamine, Ν,Ν-dimethylethanolamine, tris-(hydroxyroethy 1)-aminomethane, arginine or lysine.

The syn isomers of the compounds of general formula 1’ are preferred.

A preferred group of compounds falling within general formula 1' are the syn isomers of those wherein R, represents a hydrogen atom. —— a 3-acetoxymethyl-7- |_2-(2-tritylami no-4-thi azolyl)-2-vi ny115 oxyimino-acetamidoj -ceph-3-eme-4-carboxylic acid, syn isomer, and its sodium salt, and 3-acetoxymethy1-7-[z-(Z-amino-4-thiazolyl)-2-vinyloxyimino-acetamido]-ceph3-eme-4-carboxyTic acid, syn isomer, and its sodium salt, are specifically preferred compounds of general formula I1.

As mentioned Hereinbefore, the compounds of general formula 1' may exist in the form of a syn or an anti isomer.

The syn isomers of general formula 1' are of the formula: the anti isomers of general formula 1' are of the formula.

NH —R wherein R, and A are as defined hereinbefore. The compounds of general formula I1 are also tautomeric about the 2-atom in the thiazolyl ring and adjacent nitrogen atoms. One of the tautomeric structures is as depicted in general formula I'. The other tautomeric structure is: wherein R, and A are as defined hereinbefore, a This invention also extends to a process for preparing the compounds of general formula I'.

In another aspect therefore, this invention provides a process for preparing a compound of general formula !<.: (Ic) (wherein A represents a hydrogen atom or an alkali metal atom, an equivalent of an alkaline-earth metal or a magnesium atom, or a substituted ammonium group) in which process 7-amino-cephalosporanic acid of structural formula: is reacted with an acid of structural formula: or a functional derivative thereof, to obtain a compound of general formula I wherein A represents a hydrogen atom, which compound may optionally be salified to obtain a compound of general formula I wherein A represents an alkali metal atom, an equivalent of an alkaline earth or a magnesium atom, or a substituted ammonium group.

The process is preferably performed using, as a functional derivative of the acid of fonnula II , an anhydride formed in situ 3 ' by the action of dicyclohexyl carbodiimide on the acid of formula IIa10 Where it is desired to prepare a compound of general formula I wherein A represents a sodium atom, the salification is preferably performed by treating the compound of general formula I wherein A represents a hydrogen atom with sodium bicarbonate.

A compound of general formula: nh2 (wherein A represents a hydrogen atom or an alkali metal atom, an equivalent of an alkaline-earth metal or magnesium atom, or a substituted ammonium group) may thereafter be prepared by reacting a compound of general formula I obtained from the above general process with an acid to obtain the compound of general formula wherein A represents a hydrogen atom, which compound may optionally be salified to obtain a compound of general formula wherein A represents an alkali metal atom, an equivalent of an alkaline-earth metal or magnesium atom, or a substituted ammonium group.

The acid with which the compound of general formula I is reacted is preferably formic acid.

Where it is desired to prepare a compound of general formula Id wherein A represents a sodium atom, the salification is preferably performed by treating the compound of general formula Id wherein A represents a hydrogen atom with sodium bicarbonate.

The compound of structural formula Ha, used as starting material in the above process, may be prepared by treating a compound of structural formula: NH -C(C6H5)3 C02a1k N (ΠΙ') (wherein alk represents an alkyl radical of from 1 to 4 carbon atoms and X represents a chlorine, bromine or iodine atom) with a strong base to obtain a compound of structural formula: (mb) - CH — CHg (wherein alk is as defined hereinbefore) which compound is thereafter treated with a base, and then with an acid, to obtain the desired compound of structural formula II . α The strong base with which the compound of structural formula III1 is treated is pteferably an alkali metal alkylate such as potassium tert-butyl ate, in a dialkyl sulphoxide solvent such as dimethyl sulphoxide. The treatment is best performed at ambient temperature.

The base with which the compound of structural formula 111^ is treated may be a mineral base such as barium oxide or sodium or potassium hydroxide, and the preferred base is potassium hydroxide in a mixture of a cyclic ether such as dioxan and an alcohol such as ethanol. 4733 The acid used subsequent to the base may be an organic acid such as formic or acetic acid, although it is preferred to use a dilute mineral acid such as dilute hydrochloric acid.

The compound of general formula III1, employed in the above 5 process may be prepared by reacting, in the presence of a base, a compound of general formula X-CHg-CHg-X (wherein X represents a chlorine, bromine or iodine atom) with a compound of general formula f, (Va> wherein alk represents an alkyl radical having from 1 to 4 carbon atoms, lo The compound of general formula XCHg-CHgX is preferably 1,2-dibromoethane.

The base employed in the reaction may be a tertiary amine such as triethylamine, or an alkali metal alkalate such as potassium tert-butyl ate in a polar solvent such as dimethyl formamide or tetrahydrofuran. The preferred base is however an alkali metal carbonate such as potassium carbonate in dimethyl formamide.

The compounds of general formula Va may be prepared by reacting thiourea with a compound of general formula: Cl-CHg-C — C —C02alk (VHa) (wherein alk is as hereinbefore defined) to obtain a compound of 5 general formula: (wherein alk is as hereinbefore defined) which compound is treated wicn an equivalent amount of trityl chloride to obtain the desired compound of general formula V,. a The compounds of general formula 1' are preferably syn isomers, which isomers may be prepared simply by following the process described above, but always using a starting material (by which is meant a compound of general formula I , II , III1 or V,) which is a syn isomer. The syn configuration will then be maintained throughout the various process steps described above, and a syn isomer of a compound of general formula I or Id will result.

The syn isomer of the starting material of general formula V, may, as might be expected, be prepared as above but from the syn isomer of the corresponding compound of general formula IVc, and in this invention a compound of general formula IVC is prepared from the corresponding compound of general formula VII . Specific reaction a conditions should however preferably be employed if it is wished to prepare a syn isomer of a compound of general formula IVC from the corresponding compound of general formula VII . a Accordingly, to obtain a syn isomer of a compound of general formula Va, the reaction of thiourea with the corresponding compound of general formula VII, should preferably take place a) a in an aqueous solvent such as aqueous acetone or aqueous ethanol; b) at ambient temperature, using a substantially stoichiometric amount of thiourea and a relatively short reaction time of from one to three hours; or c) using a combination of a) and b).

An example of such a reaction is set out below in the Examples.

As has been mentioned hereinbefore, the compounds of general formula 1' possess remarkable anti-bacterial activity not only against Gram positive bacteria such as staphylococci, streptococci and especially penicillin-resistant staphylococci, but also against Gram negative bacteria, especially coliform bacterial, Klebsiella, Salmonella and Proteus.

The activity of the compounds of general formula 1' indicates their use as medicaments in the treatment of diseases caused by sensitive miroorganisms and especially in the treatment of staphylococcal infections such as staphylococcal septicaemia, malignant facial or skin staphylococcal infections, pyodermatitis, septic or suppurating sores, anthrax, phlegmons, erysipelas, acute primary or post-influenza staphylococcal infections, bronchopneumonia and pulmonary suppurations.

The compounds of general formula I1 may also be used as medicaments in the treatment of colon bacillus infections and associated infections, in infections caused by Proteus, by Klebsiella and Salmonella and in other diseases caused by Gram negative bacteria.

Before using them in medicine however, it is preferred to form the compounds of general formula 1' into pharmaceutical compositions, by association with suitable pharmaceutical vehicles.

Accordingly, in yet another aspect, this invention provides pharmaceutical compositions containing as active ingredient one or more of the compounds of general formula Γ, in association with a pharmaceutically acceptable vehicle.

The compositions of the invention preferably contain those compounds mentioned hereinbefore as being particularly preferred.

The description pharmaceutically acceptable is used herein to exclude any possibility that the nature of the vehicle, considered of course in relation to the route by which the composition is to be administered, could be harmful to a patient to be treated. The choice of a suitable vehicle or acid is believed to be within the competence of those accustomed to the preparation of pharmaceutical formulations.

The compositions may be administered bucally, rectally, parenterally or locally by topical application to the skin or mucous membranes. In respect of these routes the pharmaceutical vehicle is preferably: a) the ingestible excipient of a plain or sugar-coated tablet; the ingestible container of a gelatin capsule; or the ingestible pulverulent solid carrier of a powder or granules; b) the solid or liquid medium of a paste, cream, ointment, gel or ungent; c) a sterile injectable liquid solution or suspension medium; or d) a base material of a suppository.

Whilst the pharmacuetital forms just listed represent those most likely to be employed, they do not necessarily exhaust the possibilities.

The vehicles employed will generally be those excipients commonly employed in the formulation of pharmaceutical compositions.

Such excipients may be solid or liquid as appropriate to the pharmaceutical form chosen, and may include a wide range or organic and inorganic solids, and aqueous and non-aqueous liquids; examples include talc, gum arabic, starch, lactose, magnesium stearate or fatty substances cf animal or vegetable origin such as cocoa butter, paraffin derivatives or glycols. These excipients may be compounds with one or more wetting, dispersing or emulsifying agents and/or one or more preservatives.

The dosage of the active ingredient to be administered to a patient will of course vary with the compound concerned, the complaint and the patient being treated and the route of administration chosen. By way of illustration it may be said that a desirable dosage in an adult of the compound of Example 3 below would be from 0.5 g to 1.0 g administered three times daily by an intramuscular route.

In a yet further aspect, this invention provides the compounds and the compositions of the invention for use in a method of treatment of nonhuman animals to combat diseases caused by bacteria.

Certain of the intermediates employed in the processes of this invention are new, and are claimed in our British Patent Specification No. 2,056,988 B. These novel intermediates are : (a) the compounds of general formula III1: (wherein X represents a chlorine, bromine or iodine atom and alk represents an alkyl radical having from 1 to 4 carbon atoms); and (b) the compounds of general formula: - 16 47335 wherein R represents a hydrogen atom or an alkyi radical of from 1 to 4 carbon atoms.

The following Examples and Formulations are given, through only by 5 way of illustration, to show some preferred aspects of this invention.

EXAMPLE 1 3-acetoxymethyl-7- £2-(2-tritylamino-4-thiazolyl)-2-vinyloxyiminoacetamido]-ceph-3-eme-4-carboxylic acid, syn isomer Stage A; ethyl 2-(2-bromoethoxyimino)-2-tritylamino-4-thiazolyl)acetate, syn isomer.

Under argon, at ambient temperature and over 3 minutes, 4.14 g of potassium carbonate were introduced into a mixture of 4.94 g of ethyl 2-hydroxy-imi no-2-(2-tri tylami no-4-thi azolyl)-acetate hydrochlori de, □ syn isomer, in 10 cm of dimethyl formamide. The whole was agitated for 20 minutes at 20°C, after which 8.65 cm^ of 1,2-dibromoethane were added. After further agitation for 30 hours, the whole was poured 3 3 into a medium comprising 100 cm of distilled water and 20 cm of methylene chloride. After decanting, re-extracting with methylene chloride, washing with distilled water and re-extracting, the organic solutions were dried, vacuum-filtered, rinsed and distilled to dryness. A crude product was obtained which was chromatographed on silica, eluting with benzene containing 5% of ether, to recover a first fraction. This v/as recrystallised from methanol after dissolution at 50-60°C and vacuum-filtered at 0°C - + 5°C. 1.16 g of creamy white product were obtained. M.Pt = 117°C.

A homogeneous fraction of 1.258 g was then obtained.

NMR = p.p.m. (CDC1-) triplet = 3.55 J = 7 H2CH2-Br triplet = 4.51 J = 6 Η N - 0 - CH2 singlet = 6.55, proton of the thiazole ring.

Stage B: ethyl 2-(2-tritylamino-4-thiazolyl)-2vinyloxyimino acetate, syn isomer. 6.9 g of ethyl 2-(2-bromoethoxyimino)-2-(2-tritylamino-4thiazolyl)-acetate, syn isomer, prepared in Stage A, v/as placed in cn? of dimethyl sulphoxide. At 20-25°C and over 5 minutes, cm^ of a ι m solution of potassium tert-butylate in tetrahydrofuran were introduced, after v/hich the whole v/as agitated for 30 minutes before the introduction, at ambient temperature, of a further o cm of IM solution of potassium tert-butylate tetrahydrofuran.

Agitation was continued for a further 30 minutes, and then again 3 cnr of the same solution of potassium tert-butylate was introduced, followed, after another 30 minutes, by a third 3 cm of the solution.

After the last introduction the whole v/as agitated again for minutes and then poured into a mixture of 350 cm of water and ice and 90 cm of methylene chloride.

□ The whole was acidified to pH 2 with 28 cm of normal hydrochloric acid, then after decanting and re-extracting with 3 times 50 cm of methylene chloride, washing with distilled water, drying vacuum-filtering and rinsing, the product-containing liquid was distilled to dryness.

A black resin was obtained which was purified by chromatography on a column of silica, eluting with methylene chloride, to give 3.227 g of expected product. This was used without further purification in the following stage.

NMR p.p.m. = (CDClg) range of peaks from 4.16 to 4.83 p.p.m. = CHg range of peaks from 6.66 to 7.33 p.p.m. = CH singlet at 6.65 - proton of the thiazole ring.

After recrystallisation from absolute ethanol a product was obtained of melting point 114°C.

Analysis (C28R25°3N3S^ Calculated: C% 69.54 H% 5.21 N% 8.69 S% 6.36 Found: 69.2 5.2 8.3 6.6 Stage C: 2-(2-tritylamino-4-thiazolyl)-2-vinyloxyimino acetic acid, syn i somer. 3.227 g of ethyl 2-(2-tritylamino-4-thiazolyl) 2-vinyloxyimino 0 acetate, syn isomer, prepared in Stage B, was placed in 3.2 cm of dioxan. At ambient temperature, 20 cm of a 0.5 M solution of ο potassium hydroxide in absolute ethanol were added, followed by 12 cm of absolute ethanol. Under argon, the whole was brought to 50°C with agitation and maintained there for 1 hour; the potassium salt then crystallised out. The temperature was lowered to 20°C, and after vacuum-filtration and rinsing with ethanol, the product was taken up with a mixture of 50 cm3 of ethyl acetate and 50 cm3 of distilled water.

The taken-up product was acidified using 6 cm3 of 2N hydrochloric acid, and the whole was agitated until two homogeneous phases were obtained. After decanting, washing with three times cm of distilled water, re-extracting with ethyl acetate, drying and vacuum-filtering, the resultant product-containing liquor was rinsed with ethyl acetate, concentrated to 15 cm3, chilled to 0°C -+ 5°C, vacuum-filtered and rinsed with ethyl acetate. After drying 2.53 g of the expected product were obtained. The product was used without further purification in the following stage, but after reerystallisation, a purified sample had a melting point of 150°C.

Stage D· 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-vinyloxyiminoacetamidoj-ceph-3-eme-4-carboxylic acid, syn isomer. 2.53 g of 2-(2-tritylamino-4-thiazolyl)-2-vinyloxyimino acetic acid, syn isomer, prepared in Stage C, was introduced into 20 cm3 of methylene chloride. The whole was cooled to + 5°C and, all at once, 0.632 g of dicyclohexylcarbodiimide were added. Back at room temperature, the whole was agitated under argon for 1 hour to obtain suspension A.

Quite separately 0.718 g of 7-amino-cephalosporanic acid were, under argon, introduced into 10 cm3 of methylene chloride. The whole was cooled to + 10°C, and 1.1 cm3 of triethylamine were added to obtain solution B.

Suspension A, over 10 minutes and at +5-+ 10°C was then introduced into solution B, and the whole was agitated whilst being allowed to return to ambient temperature (over 35 minutes). It was then agitated for 3 hours at 20-25°C, after which 0.6 cm3 of acetic acid were added. The whole was agitated for a further ten minutes and then the dicyclohexylurea formed was vacuum-filtered. The organic solution remaining was washed with water, dried and distilled under vacuum to give a yellow resin. This was taken up with ethyl acetate and a slight amount of insoluble matter was filtered off. The solution was brought to dryness to obtain 3.475 g of the expected product.

The ethyl 2-hydroxyimino-2-(2-tritylamino-4-thiazolyl) acetate, hydrochloride syn isomer, used at the start of Example 1 was prepared as follows:Ethyl 2-hydroxyimino-2-(2-amino-4-thiazolyl)-acetate, syn isomer. 0.8 g of thiourea were dissolved in 2.4 cm of ethanol and 4.8 cm3 of water. Over 5 minutes, a solution of 2 g of ethyl 4-chloro-2-hydroxyimino-acety1-acetate were added and the whole was agitated for one hour at ambient temperature. The major part of the ethanol was driven off under partial vacuum and the pH was brought to 6 by adding solid solution sodium acid carbonate. After chilling, vacuum-filtering, washing with water and drying under vacuum at 40°C, 1.32 g of expected product were obtained.

M.Pt. = 232°C.

Analysis: CgH,}03N3S Calculated: C% 39.06 H3£ 4.21 N% 19.52 S% 14.9 Found: 38.9 4.4 19.7 14.6 Ethyl 2-(2-tritylaniino-4-thiazoTyl )-2-hydroxyimino-acetate hydrochloride, syn isomer. 43.2 g of ethyl 2-(2-anrino-4-thi azolyl )-2-hydroxyimino-acetate, syn isomer, prepared above were introduced into 120 cm of dry dimethyl S formamide.

The whole was cooled to -35°C and 32 cm3 of triethylamine were introduced, followed over 30 minutes, by 60 g of trityl chloride in portions The temperature was allowed to rise again and total dissolution of the solid matter was observed. The solution was then heated to 30°C, and 1θ after one hour was poured into 1.2 litres of iced water containing cm3 of 22° Be hydrochloric acid.

The whole was agitated in a bath of iced water, and after vacuumfiltration and rinsing with normal hydrochloric acid, the product was made into a paste with ether. 69.3 g of the hydrochloride were obtained.

EXAMPLE 2 Sodium salt of 3-acetoxymethyl-7- [^2-(2-tritylamino-4-thiazolyl) -2-vinyloxyimino-acetamido]-ceph-3-eme-4-carboxylic acid, syn isomer.

At ambient temperature, 2.628 g of the product obtained in 20 Example 1 in tha form of a resin were dissolved in 5.2 cm3 of acetone.

All at once, 10.4 cm of a molar solution of sodium acid carbonate in water were acded, and the whole was left for one hour at 20°C.

The formed sodium salt was then vacuum-filtered and rinsed twice with 2 cm3 of a mixture of water and acetone (1:1) and once with 2 cm3 of distilled water. The salt was dried under vacuum at 40°C to give 1.612 g of expected crude product.

EXAMPLE 3 3-acetoxymethy1-7-[2-(2-ami no-4-thi azolyl)-2-vi nyloxyi mi noacetami do]-ceph-3-eme-4-carboxylic acid, syn isomer. 1.612 g of the sodium salt of 3-acetoxymethyl 5 7-[2-(2-tri ty 1 ami no-4-thi azolyl)-2-vi nyloxyi mi no-acetami do] -ceph-3eme-4-carboxylic acid, syn isomer, obtained in Example 2, was placed in 4 cm3 of 98% formic acid. Immediately afterwards 4 cm3 of distilled water were added, and the whole was agitated at 40°C for 15 minutes. The heterogeneous suspension resulting was then triturated for 30 minutes at ambient temperature, before being vacuumfiltered at 20°C. The filtrate was rinsed twice with 1.6 cm3 of 50% formic acid and distilled to dryness; the residue was taken up 0 with 5 cm of distilled water, vacuum-filtered at ambient temperature, and rinsed with distilled water then with ether. After drying 300 mg of expected product were obtained.

By re-treating the insoluble matter in the same manner as above using 50% formic acid, another 0.214 g of the acid were obtained. Analysis: (C^yH^OyNgSg) Calculates CSS 43.68 H% 3.66 N% 14.98 S% 13.72 Found: 44.2 3.9 15.1 13.0 NMR p.p.m. (DMSO) 6.91 (proton of the thiazole ring) 7.28 (free amine NH2) EXAMPLE 4 Sodium salt of 3-acetoxymethyl-7-[2-(2-anrino-4-thiazolyl)-2vinyloxyimino-acetamidoj -ceph-3-eme-4-carboxylic acid, syn isomer.

To 5.08 g of 3-acetoxymethyl-7-[2-(2-aniino-4-thiazoly1 )-2vinyloxyimino-acetamido]-ceph-3-eme-4-carboxylic acid, syn isomer, prepared according to Example 3, were added 5 cm of ethanol followed 3 by, under agitation in a bath of iced water, 10 cm of an aqueous molar solution (1M) of sodium acid carbonate. After dissolution, cm3 of ethanol were added, and the whole was concentrated at 30°C under vacuum, taken up with ethanol and dried to a constant weight. The expected product was obtained.

FORMULATION 1 An injectable preparation was made up according to the formula: 3-acetoxymethyl-7-[2-(2-ami no-4-thi azolyl)-2-vi nyloxyimi no10 acetamidif] -ceph-3-eme-4-carboxylic acid, syn isomer 500 mg sterile aqueous excipient q.s.v. 5 cm FORMULATION 2 A gelating capsule was made up according to the formula: 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)15 2-vinyloxyimino-acetamidoj-ceph-3-eme-4-carboxylic acid, syn isomer 250 mg excipient q.s. for one gelatin capsule up to 400 mg

Claims

1. The compounds of general formula: wherein R g represents a hydrogen atom or a trityl group and 5 A represents a hydrogen atom or an alkali metal atom, an equivalent of an alkaline-earth metal atom or a magnesium atom, or a substituted ammonium group, the compounds being in the form of the syn or anti isomers.

2. The syn isomers of the compounds of general formula 1' as 10 defined in Claim 1.

3. A compound as claimed in Claim 2, wherein R g represents a hydrogen atom. 47333

4. 3-acetoxymethyl-7-[2-(2-tri tylami no-4-thi azolyl)-2-vi nyloxyiminoacetanridq] -ceph-3-eme-4-carboxylic acid, syn isomer and its sodium salt.

5. 3—acetoxymethyl-7- jl·- (2-ami no-4-thi azolyl )-2-vinyloxyimino5 acetamido]-ceph-3-eme-4-carboxylic acid, syn isomer, and its sodium salt.

6. A process for preparing a compound of general formula I c : (wherein A represents a hydrogen atom or an alkali metal atom, an equivalent of an alkaline-earth metal or a magnesium atom, or a 10 substituted ammonium group) in which process 7-amino-cephalosporanic acid of structural formula: is reacted with an acid of structural formula: (a) or a functional derivative thereof, to obtain a compound of general 5 formula I wherein A represents a hydrogen atom, which compound may optionally be salified to obtain a compound of general formula I wherein A represents an alkali metal atom, an equivalent of an alkaline-earth or a magnesium atom, or a substituted anmonium group.

7. A process as claimed in Claim 6, in which an anhydride formed 10 in situ by the action of dicyclohexy! carbodiimide on the acid of formula II, is employed as a functional derivative of the acid of a formula II . a

8. A process as claimed in Claim 7, in which where it is desired to prepare a compound of general formula I wherein A represents a 15 sodium atom, the salification is performed by treating the compound of general formula I c wherein A represents a hydrogen atom with sodium bicarbonate.

9. A process for preparing a compound of general formula: (wherein A represents a hydrogen atom or an alkali metal atom, an equivalent of an alkaline-earth metal or magnesium atom, or a substituted ammonium group) in which a compound of general formula I 5 prepared according to any of Claims 6 to 8 is reacted with an acid to obtain the compound of general formula Ij wherein A represents a hydrogen atom, which compound may optionally be salified to obtain a compound of general formula wherein A represents an alkali metal atom, an equivalent of an alkaline-earth metal or magnesium atom, or a 1° substituted ammonium group.

10. A process according to Claim 9 in which the acid vrith which the compound of general formula I is reacted is formic acid.

11. A process according to Claim 9 or Claim 10, in which where it is desired to prepare a compound of general formula wherein 15 A represents a sodium atom, the salification is performed by treating the compound of general formula Ij wherein A represents a hydrogen atom with sodium bicarbonate.

12. A process according to any of Claims 6 to 11, in which the compound 20 of structural formula II , used as starting material in the preparation a of the compound of general formula I c , is prepared by treating a compound of structural formula: (wherein alk represent an alkyl radical of from 1 to 4 carbon atoms and X represents a chlorine, bromine or iodine atom) with a strong base to obtain a compound of structural formula: (wherein alk is as defined hereinbefore) which compound is thereafter treated with a base, and then with an acid, to obtain the desired compound of structural formula II . a

13. A process according to Claim 12, in which the strong base with f 10 which the compound of structural formula III is treated is potassium tert-butylate in dimethyl sjlphoxide.

14. A process according to Claim 13, in which the treatment is performed at ambient temperature.

15. A process according to any of Claims 12 to 14, in which the base with which the compound of structural formula III g is treated is potassium hydroxide in a mixture of dioxan and ethanol.

16. A process as claimed in any of Claims 12 to 15, in which the acid used subsequent to the base with which the compound of structural formula Illg is treated is dilute hydrochloric acid.

17. A process as claimed in any of Claims 12 to 15, in which the I compound of general formula III is prepared by reacting, in the presence of a base, a compound of general formula X-CH 2 -CH 2 -X (wherein X represents a chlorine, bromine or iodine atom) with a compound of general formula: C0 2 alk (Va) li \ TH wherein alk represents an alkyl radical having from 1 to 4 carbon atoms.

18. A process as claimed in Claim 17, in v/hich the compound of ]g general formula XCH 2 _ CH 2 X is 1,2-dibromoethane.

19. A process as claimed in Claim 17 or Claim 18, in which the base employed is potassium carbonate in dimethyl formamide.

20. A process as claimed in any of Claims 17 to 19, in which the compound of general formula V fl is prepared by reacting thiourea with a compound of 5 general formula: Cl — CH, - C li -C —CO ? alk S t” 1 .) \o„ (wherein alk is as hereinbefore defined) to obtain a compound of general formula (wherein alk is as hereinbefore defined) which compound is treated with 10 an equivalent amount of trityl chloride to obtain the desired compound of general formula V a<

21. A process according to Claim 20, in which the' syn isomer of the compound of general formula V a is obtained by reacting thiourea with a corresponding compound of general formula VII a a) in an aqueous solvent; b) at ambient temperature, using a substantially stoichiometric amount of thiourea and a relatively short reaction time of from one to three hours; or c) using a combination of a) and b), thereby to obtain the syn isomer of the compound of general formula IV c , which compound is treated with an equivalent amount of trityl chloride so as to obtain the desired syn isomer of the compound of general formula V,. Q

22. A process for preparing a compound of general formula I or substantially as described herein with reference to any one of the Examples.

23. A pharmaceutical composition containing as active ingredient one or more of the compounds claimed in Claim 1, in association with a pharmaceutically acceptable vehicle.

24. A composition as claimed in Claim 23, in which the active ingredient is one or more of the compounds claimed in Claim 3.

25. A composition as claimed in Claim 23, in which the active ingredient is one or more of the compounds claimed in Claim 4 or Claim 5.

26. A composition as claimed in Claim 23, and substantially as described herein with reference to the Formulations,

27. A method of treatment of non-human animals to combat diseases caused by bactena, which method comprises administering an effective amount of a compound as claimed in any one of claims 1 to 5 or a composition as claimed in any ote of Claims 23 to 26.