IE45865B1 - New oxime derivatives of 3-carbamoyloxymethyl-7-amino-thiazolyl-acetamido-cephalosporanic acid, processes for preparing them and pharmaceutical compositions containing them - Google Patents

Abstract

The syn isomers of the compounds of formula: , in which R1 represents a saturated or unsaturated C1-C4 alkyl and A represents hydrogen or one equivalent of an alkali metal or alkaline-earth metal or of an amine organic base, are prepared from the syn isomers of the corresponding compounds in which the amino group of the thiazolyl radical is substituted by a group which can be removed by acid hydrolysis or by hydrogenolysis, or by a chloroacetyl group; in the first case, an acid hydrolysis or a hydrogenolysis is carried out, in the second case treatment is carried out with thiourea. The compounds obtained have antibacterial properties; they can be used in the treatment of infectious diseases, especially of staphylococcias and of colibacilloses.

Description

This invention relates to new oxime derivatives of - carbamoyloxymethyl - 7 - aminothiazolylacetamido - ceph - 3 em 4 - carboxylic acid, processes for preparing them and pharmaceutical compositions containing them. In particular it concerns certain derivatives of 3 - carbamoyloxymethyl -7-^2-(2- amino - 4 - thiazolyl) - 2 imino -. acetami do] - ceph - 3 - em - 4 - carboxylic acid that may be of use in medicine.

Accordingly this invention provides the oxime derivatives of · - carbamoyloxymethyl - 7 - aminothiazolylacetamido - ceph - 3 10 em - 4 - carboxylic acid of the general formula: 4S86S in which R represents a hydrogen atom or a group removable by acid hydrolysis or by hydrogenolysis, R-j represents a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, A represents either 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, the compounds being in the form of the syn isomer.

The expression a group removable by acid hydrolysis or by hydrogenolysis is used herein to mean a group that may be cleaved from the remainder of the molecule without otherwise affecting its structure (other than cleaving other groups removable by acid hydrolysis or by hydrogenolysis, where more than one is present). Thus for example R may represent a t-butoxycarbonyl, trityl, benzyl, benzhydryl, trichloroethyl, carbobenzyloxy or formyl group, or an equivalent of a phthaloyl group. Of those groups, R preferably represents a t-butoxycarbonyl, trityl, benzhydryl, tri chloroethyl or carbobenzyloxy group. r may be an alkyl, alkenyl or an alkynyl group, and examples of suitable groups include the methyl, ethyl, propyl, isopropyl, sec-butyl, t-butyl, vinyl, propenyl, butenyl, ethynyl and propargyl radicals.

When A represents an equivalent of an alkaline-earth metal atom or an equivalent of a magnesium atom, or when R represents an equivalent of a phthaloyl group, each molecule of the syn isomer shown in general formula I contains, as A or R, the fraction of the metal atom or phthaloyl group corresponding to a single valence. 43863 When A represents a metal atom (and thus the compounds of general formula I are metal salts) A is preferably a sodium, potassium, lithium, calcium or magnesium atom. When A represents a substituted ammonium group (and thus the compounds of general formula I are amine salts) A is preferably derived from methylamine, propylamine, diethylamine, trimethylamine, triethylamine, Ν,Ν-dimethylethanolamine or tris-(hydroxymethyl)-aminomethane.

It will be appreciated that when R represents a group removable by acid hydrolysis or hydrogenolysis, the amine group at the 2-position of the thiazoyl ring is protected by the group removable by acid hydrolysis or hydrogenolysis. The amine group is released from protection when the group removable by acid hydrolysis or hydrogenolysis is cleaved from the molecule.

Thus the syn isomers of general formula I comprise the protected syn isomers of the general formula N (Ia) (wherein R' represents a group removable by acid hydrolysis or hydrogenolysis and Rj and A are as defined hereinbefore); and the unprotected syn isomers of the general formula: (wherein Rj and A are as defined hereinbefore).

A particularly preferred class of unprotected syn isomers falling within general formula Ib' are those wherein Rj represents a methyl radical and A represents a hydrogen atom or a sodium atom.

Amongst the unprotected syn isomers of general formula Ib' the 10 following are especially preferred: - carbamoyloxymethyl -7-(2-(2- amino - 4 - thiazolyl) - 2 (methoxyimino)-acetamido] - ceph - 3 - em - 4 - carboxylic acid syn isomer; - carbamoyloxymethyl -7-(^2-(2- amino - 4 - thiazolyl - 2 5 (methoxyimino) - acetamido] - ceph - 3 - em - 4 - carboxylic acid, syn isomer, as obtained according to the process described in Example 2; and the sodium salt of 3 - carbamoyloxymethyl - 7 - [j? - (2 - amino 4 - thiazolyl) - 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 carboxylic acid, syn isomer.

It should be understood that by virtue of tautomerism the syn isomers of general formula I can exist: a) either in the form indicated by general formula I; b) or in the form as shown in the following general formula: R - wherein R, R-, and A are as defined hereinbefore. All references herein to the syn isomers of general formula I and other compounds in which such tautomerism is possible should be construed as extending to both tautomeric forms, unless othenvise specified.

In another aspect this invention provides a process for the preparation of the protected syn isomer of the general formula: (wherein R' is as defined hereinbefore, A1 represents an alkali-metal or a hydrogen atom and Rg represents a group removable by hydrolysis) is treated with a hydrolysis agent effective at hydrolysing the group Rg and not the group R*, and in the case where a basic hydrolysis agent is employed thereafter the hydrolysis product is treated with an acid, to give the desired product of the general formula: wherein J?' and Rj are as defined hereinbefore.

The hydrolysis of the syn isomer of general formula II is carried out in a manner that will remove the group Rg and not the group R1, and naturally the group Rg is chosen accordingly. It is believed to be within the competence of one skilled in the art to choose both suitable substituents and reaction conditions, but by way of illustration it is pointed out that a basic medium such as sodium bicarbonate in water is preferably employed, although potassium bicarbonate or an alkali-metal carbonate in either water or a water/alcohol mixture may be employed. When such basic hydrolysis agents are employed the hydrolysis product is treated with an acid and dilute hydrochloric acid is preferred. However, other mineral acids such as sulphuric or phosphoric acid can also conveniently be used. 48865 Alternatively, an acidic medium may be used to effect the hydrolysis of the group Rg provided the group R' is not also removed. A slightly acidic buffered medium is preferred to effect this hydrolysis.

By way of indication the substituent R2 is preferably a tri chloroethyl, benzyl, ^-methoxybenzyl or chlorosulphony radical.

The syn isomers of general formula II used in the above preparation are desirably prepared by reacting an appropriate syn isomer of the general formula (wherein R', A' and R^ are as defined hereinbefore) with an isocyanate of the general formula: R2— N = C = 0 (wherein Rg is as defined hereinbefore) to give the desired product 15 of general formula II. 43865 The reaction to form the desired syn isomer of general formula II is preferably carried out in an inert solvent or mixture of inert solvents. Particularly preferred solvents are methylene chloride and chloroform, but dimethylformamide, tetrahydrofuran or pyridine may be used with advantage. If no solvent is used the reaction is carried out in the pure isocyanate.

The syn isomers of general formula III used in the above preparation wherein A’ represents an alkali-metal atom are preferably prepared by reacting 7 - aminocephalosporanic acid of the formula with an alkali-metal alcoholate in an alcohol, product with a syn isomeric acid of the general and treating the formed formula: nhr' (IV) c -COgH OR, 4586S (wherein Rj and R' are as defined hereinbefore) or a functional derivative thereof to give the desired product of general formula III. 7-Aminocephalosporanic acid is preferably reacted with the alkali-metal alcoholate in a lower alcohol containing from 1 to 3 carbon atoms.

In a particularly preferred process the alcoholate is sodium methylate and it is employed in methanol. However, other alcoholates such as potassium t-butylate may be used. The product of the reaction with the alcoholate is then treated with the acid of general formula IV or a functional derivative thereof. Preferably a derivative such as the acid chloride or the acid anhydride is used, and the latter may be formed in situ, by the action of isobutyl chloroformate on the free acid. Other halides or other anhydrides formed in situ by the action of other alkyl chloroformates, of a dialkyl earbodiimide or of a dicycloalkyl earbodiimide such as dicyclo-hexyl earbodiimide may also be used. Still further acid derivatives such as the acid azide, the acid amide or an acid ester formed, for example, with hydroxysuccinimide, £-nitrophenol or 2,4-dinitrophenol may also be used. ί In the case where the reaction is carried out with a halide of the acid of general formula IV or with an anhydride thereof, the work is preferably carried out in the presence of a basic agent. Preferred basic agents include the alkali-metal bi carbonates and carbonates, and tertiary organic bases such as N-methyl-morpholine, pyridine or a trialkylamine such as triethylamine.

In an alternative process the syn isomers of general formula III wherein A' represents an alkali-metal atom may be prepared by treating an appropriate syn isomer of the general formula: 45365 (wherein Rj, R1 and A are as defined hereinbefore) with an alkali-metal alcoholate in an alcohol to obtain the desired product of general formula III In this alternative process the alkali-metal alcoholate is again preferably sodium methylate. The reaction is advantageously carried out in a lower alcohol containing from 1 to 3 carbon atoms.

The syn isomers of general formula III wherein A1 represents a hydrogen atom may be prepared by treating an appropriate syn isomer of the general formula: NHR 4S865 (wherein R1 and R^ are as defined hereinbefore) with a deacetylation enzyme to obtain the desired product of general formula III.

The substituent R' in the above formulae is preferably a t-butoxycarbonyl, trityl, benzyl, benzhydryl, tri chloroethyl, carbobenzyloxy or formyl group, or an equivalent of a phthaloyl group. The deacetylation enzyme is preferahly a wheatgerm enzyme, employed at a temperature of substantially 37°C and at a substantially neutral pH.

The invention also provides an alternative process for preparing 10 the protected syn isomers of general formula Ia, in which the compound of the formula: is treated with an appropriate acid of general formula IV (as defined hereinbefore) or with a functional derivative thereof to obtain the desired product of general formula Ia.

In a preferred method of carrying out the process the compound of formula VI is treated with a functional derivative of the acid of general formula IV and preferred functional derivatives and preferred reaction conditions are as described hereinbefore in relation to the reaction of derivatives of the acid of general formula IV in the preparation of the syn isomers of general formula III wherein A' represents an alkali-metal atom.

This invention also provides a process for preparing the unprotected syn isomers of general formula lb1 wherein A represents a hydrogen atom, in which process an appropriate syn isomer of general formula Ia is subjected to acid hydrolysis or hydrogenolysis as necessary to remove the substituent R1 and so form the desired product of the general formula: wherein R·] is as defined hereinbefore. 45365 It is believed to be within the competence of one skilled in the art to determine whether acid hydrolysis or hydrogenolysis will be effective at removing a given substituent R‘, and to choose appropriate reaction conditions.

Preferred acid hydrolysis agents include trifluoroacetic acid, formic acid and acetic acid. These acids can be used in anhydrous form or in the presence/water. A preferred hydrogenolysis agent is zinc-acetic^ acid system.

Preferably acid hydrolysis, using an agent such as anhydrous trifluoroacetic acid or aqueous formic or acetic acid, is used to eliminate t-butoxycarbonyl or trityl groups as substituent R'.

However, the zinc-acetic acid system is preferably used to eliminate the tri chloroethyl group and catalytic hydrogenation to eliminate benzyl, benzhydryl and carbobenzyloxy groups.

The invention also provides an alternative process for the preparation of the unprotected syn isomers of general formula lb, in which an appropriate syn isomer of the general formula: (wherein Rj is as defined hereinbefore) is treated with thiourea to obtain the desired product of general formula Ib.

The action of thiourea on the syn isomer of general formula VII is preferably carried out in an neutral or an acidic medium. A similar type of reaction is described by Masaki in J.A.C.S. 90, 4508 (1968).

The starting materials of general formula VII are conveniently prepared in a manner analogous to the preparation of the protected syn isomers of general formula Ia from the syn isomers of general formula V by the route V —>111-5» II-r>Ia. That is to say, the preferred multi-stage route is as follows: an appropriate syn isomer of the general formula co2h (VIII) is reacted with a deacetylation enzyme to obtain the corresponding product of the general formula: 43865 which product of general formula IX is treated with an isocyanate of the general formula: r2 — n = C — 0 to obtain a product of the general formula: which product is treated with a hydrolysis agent, and when a basic hydrolysis agent has been used also treated with an acid, to obtain the desired product of general formula VII.

In the above sequence the substituent groups and Rg are 5 as defined hereinbefore, and the. preferred substituents and reaction conditions for the various steps are also as previously described. However, it has been found desirable to use the preferred wheatgerm enzyme at a lower dilution than that employed in converting the syn isomers of general formula V into the syn isomers of general formula III.

The invention also provides a process for preparing the protected or unprotected syn isomers of general formula I wherein A represents an alkali-metal atom, an equivalent of an alkaline-earth metal atom, an equivalent of magnesium or a substituted ammonium group, in which process an appropriate syn isomer of general formula Ia or lb is salified by reaction with a suitable base to give the desired salt.

The salification can be effected in a conventional manner, for example, the salts may be obtained by the action on the syn isomers of general formulae Ia and lb of a mineral base such as, for example, sodium or potassium hydroxide, sodium carbonate or bicarbonate or of an organic base such as triethylamine.

The salification is preferably carried out in one or more solvents such as water, methanol, ethanol, acetone and dioxan.

The invention extends of course to the syn isomers of general 25 formula I whenever prepared by a process as described herein.

The syn isomers of general formula I and especially those of general formula lb' possess very good antibiotic activity on the one hand against the Gram-positive bacteria such as the staphylococci and the streptococci, especially against the penicillin-resistant staphylococci, and on the other hand against the Gram-negative bacteria especially against the coliform bacteria, the klebsiella, the proteus and salmonella.

These properties may make the pharmaceutically-acceptable syn isomers of the invention suitable for use as medicaments in the treatment of diseases caused by sensitive microorganisms, particularly 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-influenze staphylococcal infections, bronchopneumonia and pulmonary suppurations.

The products may also be useful as medicaments in the treatment of colon bacillus and associated infections, of infections caused by Proteus, by Klebsiella and Salmonella and of other diseases caused by Gram-negative bacteria.

However, before any of the syn isomers of this invention may be used in medicine, they should preferably be formed into pharmaceutical compositions by association with suitable pharmaceutical vehicles.

The term pharmaceutical 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 intended to be administered, could render the composition harmful rather than beneficial. 3 8 6 5 The choice of a suitable mode of presentation, together with an appropriate vehicle, is believed to be within the competence of those accustomed to the preparation of pharmaceutical formulations.

Accordingly, in yet another aspect this invention provides A ’ pharmaceutical compositions containing as active material one or more syn isomers of general formula lb1, in association with a suitable pharmaceutical vehicle.

Preferably the active material is a syn isomer of a general formula lb' wherein R1 represents a methyl radical and A represents a hydrogen or sodium atom. · Amongst these preferred active materials the following are especially mentioned: - carbamoyloxymethyl - 7 -J_2 - (2 - amino - 4 - thiazolyl) 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 - carboxylic acid, syn isomer; - carbamoyloxymethyl -7-^2- (2 - amino - 4 - thiazolyl) 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 - carboxylic acid, syn isomer, obtained according to the process described in Example 2; and the sodium salt of 3 - carbamoyloxymethyl -7-^2- (2 - amino 4 - thiazolyl) - 2 - (methoxyimino) - acetamidoj- ceph - 3 - em 4 - carboxylic acid, syn isomer.

The compositions of this invention may be administered by buccal, rectal or parenteral route or by local route using a topical application to the skin or mucous membranes. For these and other applications the preferred vehicles are: a) the ingestible excipient of a plain or coated tablet, sublingual tablet or pill; the ingestible container of a capsule or cachet; the ingestible pulverent solid carrier of a powder or a granular preparation; or the ingestible liquid medium of a syrup, solution, suspension or elixir; b) the solid or liquid medium of a paste, lotion, cream ointment or gel; c) a sterile injectable liquid solution or suspension medium, or d) a base material of low melting point capable of releasing the active material to perform its pharmacological function, which base material when appropriately shaped forms a suppository.

The compositions of the invention may be solid or liquid depending upon the particular form of presentation selected. Preferred forms of administration include plain or sugar-coated compressed tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams and gels; these forms may be prepared according to the usual methods. The vehicle employed generally comprises one or more of the excipients customarily employed in these pharmaceutical compositions, and thus may include one or more of talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or nonaqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols and various wetting, dispersing or emulsifying agents and/or preservatives.

The dose of the active material administered may be varied according to the complaint treated, the person concerned, the route of 8 6 5 administration and the product under consideration. By way of illustration only, it can be from 0.250 g to 4 g per day for the product described in example 2 administered by oral route or from 0.500 g to 1 g for the products described in examples 2 and 5 administered three times daily by intra-muscular route.

It is believed that certain of the intermediates used in the preparation of syn isomers of general formula I are themselves new. These novel intermediates are: a) the syn isomers of the general formula: wherein R a hydrogen , R^ and A1 are as defined hereinbefore and B represents atom or the radical: — C — NH — R, I wherein R^ is as defined hereinbefore; and b) the syn isomers of general formula NKCOCH2C1 wherein is as defined hereinbefore and D or a radical represents a hydrogen atom in which R'g represents a hydrogen atom or a group removable by hydrolysis.

The syn isomeric acids of general formula IV and the syn isomers of general formulae V and V can be prepared by the processes described in the our Patent Specification No. 45015. 4S8Ga The coinpound of formula VI is described in German Patent Application No. 2,203,653, and the syn isomers of general formula VIII are described in French Patent Application No. 77 - 01713, published as Specification No. 2,384,781.

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

Example 1 3-carbamoyloxymethyl-7-{l·-(2-tritylamino-4-thiazolyl)-2(methoxyimino)-acetamido|-ceph-3-em-4-carboxylic acid, syn isomer Stage A: Sodium salt of 3 - hydroxymethyl -7-(2-(2- tritylamino - 4 - thiazolyl) - 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 - carboxylic acid, syn isomer o cm of methanol and 1.7 g of the diethylamine salt of 3 - acetoxymethyl -7-(^2-(2- tritylamino - 4 - thiazolyl) - 2 15 (methoxyimino) - acetamido] - ceph - 3 - em - 4 - carboxylic acid, syn isomer were mixed under nitrogen. The formed solution was cooled to -25°C and over 2 minutes, 380 mg of sodium methylate were added, and the whole was agitated at -20°C for 4 hours 30 minutes, then 126 mg of sodium methylate were added and the agitation continued for 4 hours. The reaction medium was then saturated with dry ice and poured at -20°C into 680 cm2 of ether.

After one night in the refrigerator the whole was vacuum-filtered and washed with ether to obtain 1.89 g of white product. M.Pt. = 210230°C (with decomposition).

Stage Β: 3 - carbamoyloxymethyl -7-(2-(2- tritylamino 4 - thiazolyl) - 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 - carboxylic acid, syn isomer cm of methylene chloride and 0.75 cm of tri chloroacetyl 5 isocyanate were mixad under nitrogen. The formed mixture was brought to between 0 and +5°£ and, over four minutes, 1.5 g of product obtained in stage A were added. About half way through this addition, a further 0.25 cm^ of trichloroacetyl isocyanate were added, with an additional ο 0.25 cm at the end of the introduction. After 10 minutes 10 agitation at between 0 and +5°C, 1 cm3 of methanol were added, and the mixture was concentrated almost to dryness under vacuum, before being redissolved in 30 cm3 of methanol. A solution of 915 mg of sodium 3 acid carbonate in 22.5 cm of water was added, and the mixture was agitated for 3 hours at ambient temperature, decanted, concentrated and then acidified to pH 2 with 1M hydrochloric acid. The formed precipitate was vacuum-filtered, washed with water, then ether, and finally made into a paste with ether and dried under vacuum. 600 mg of a solid (M.Pt. = approximately 210°C with decomposition) were obtained. Rf =0.28 (ethylacetate, ethanol, water 7:2:1).

The diethylamine salt of 3 - acetoxymethyl -7-(2-(2- trityl amino - 4 - thiazolyl) - 2 - (methoxyimino)-acetamido] - ceph - 3 - em 4 - carboxylic acid, syn isomer, was prepared as follows: 5865 Ethyl 2-(2-amino-4-thiazolyl)-2-methoxyimino-acetate, syn isomer g of ethyl γ - chloro - a - methoxyimino - acetyl acetate, cm of absolute ethanol and 0.42 g of crushed thiourea were placed in a reaction vessel, which was agitated at ambient temperature for about ο two hours. The mixture was diluted with 60 cm of ether, causing the hydrochloride to crystallise out, and agitated. The crystals were vacuum-filtered, washed and dried to give 685 mg of the hydrochloride, which were then dissolved in 4 cm3 of water at 50°C. Potassium acetate was added until pH 6 caused the desired amine salt to crystallise out, and the mixture was cooled. The crystals were recovered by vacuumfiltration, washed with water and dried to give 270 mg of the expected product. M.Pt. = 161°C.

Ethyl 2-(2- tritylamino - 4 - thiazolyl) - 2 - methoxyimino acetate, syn isomer 4.6 g of product prepared according to the previous stage were dissolved at 30°C in 92 cm3 of methylene chloride. The solution was cooled to -10°C, when 2.9 cm3 of triethylamine were added, and cooled again to -35°C. 6.1 g of trityl chloride were then introduced over 15 minutes and the mixture was allowed to return to ambient temperature, taking two hours, thirty minutes in all. The mixture was washed with water, then with 0.5 N hydrochloric acid, and sodium acetate in water, before being dried and concentrated. The residue was taken up with ether, concentrated again and dissolved in methanol. Next, water and ether were added, and the mixture was allowed to crystallise. The crystals were recovered by vacuum-filtration and washed with ether to obtain 6.15 g of the expected product. . M.Pt. = 120°C. 4S86S 2-(2-tri tylami no-4-thi azolyl)-2-methoxyimi no-aceti c acid, syn isomer o 7.01 g of the ester obtained above were dissolved in 35 cm of dioxan. The solution was brought to 110°C in an oil bath, then over five minutes, 9 cm of 2N sodium hydroxide were added. The mixture was refluxed for 30 minutes under agitation, during which time the sodium salt crystallised out, and then cooled. The crystals were recovered by vacuum-filtration, and washed with dioxan and then ether to give a first yield of 5.767 g of salt. The mother liquor was concentrated to give a second yield of 1.017 g: a total yield of 6.784 g of salt. □ 3.06 g of the salt were placed in a mixture of 65 cm of methylene chloride and 6.5 cm3 of 2N hydrochloric acid, and the mixture was washed with water, dried and concentrated to dryness to give the free acid quantitatively.

Diethylamine salt of 3-acetoxymethyl-7-[/-(2-tritylannno4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-em-4carboxylic acid, syn isomer The acid obtained as in the previous stage (from 153.6 g of q sodium salt) was dissolved in 450 cm of methylene chloride under an inert atmosphere. The solution was cooled with an ice bath, and at +5°C 36 g of dicyclohexylcarbodiimide were added. The mixture was agitated for 40 mintues at +5°C, and then for 30 minutes at +20°C. The precipitated dicyclohexylurea was vacuum-filtered. The filtrate was cooled to between -10°C and -15°C, then a solution, at -10°C, of 40.8 g of 7-amino-cephalosporanic acid 3 in 600 cm of methylene chloride and 41 cm of triethylamine was introduced. The mixture was allowed to return to ambient temperature, agitated, and washed twice with normal hydrochloric acid and three times with water, before being dried and concentrated.

The residue was taken up with ethyl acetate, which was evaporated off to dryness. This residue was dissolved in 350 cm of dioxan, after 3 which 350 cm of ether were added slowly, followed by 33 cm of diethylamine. The mixture was agitated for 20 minutes, filtered and the filtrate was concentrated before the addition of about 2.5 litres of ether. The ether was agitated and vacuum-filtered to give 110.3 g of the expected salt..

The ethyl γ - chloro - a - methoxyimino - acetyl acetate used as the start of this preparation was prepared as follows: 22.5 g of ethyl γ - chloro - a - oximino - acetyl acetate was placed q in 100 cm of methylene chloride. The mixture was placed on an ice bath and, under agitation, 275 cm of fresh solution of diazomethane (concentration 21.6 g/1) were slowly added. The mixture was left for five minutes, after which the excess diazomethane was destroyed with a little alumina. Finally, the mixture was concentrated, and then purified by eluting over silica with methylene chloride to give 11.93 g of the expected product.

Example 2 3-carbamoyloxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino)acetamidoj-ceph-3-etti-4-carboxylic acid, syn isomer. q 500 mg of product obtained in Example 1 were mixed with 5 cm of 8? acetic acid in water. The formed mixture was agitated for two hours 4586s minutes at 50°C and cooled to ambient temperature when a precipitate 3 was thrown down by the addition of 40 cm of ether. The precipitate was vacuum-filtered and rinsed with ether to give 290 mg of impure cream solid. 270 mg of this impure solid were dissolved in 4 cm of 8% acetic acid in water, and 4 cm of ethyl acetate were added. The mixture was filtered, washed with a mixture of 8% acetic acid in water and ethyl acetate (1:1), and agitated with 270 mg of silica. After filtering and washing, a precipitate was thrown down by the addition of ether, which was vacuum-filtered and washed with ether to give 136 mg of product. M.Pt. > 260°C.

Rf = 0.35 (ethyl acetate-ethanol-water 6:2:2).

Example 3 3-carbamoyloxymethyl-7-(2-(2-tritylami no-4-thiazolyl)-2|5 methoxyimino)-acetamido]-ceph-3-em-4-carboxylic acid, syn isomer Stage A: Sodium salt of 3 - hydroxymethyl - 7 -[(2 -(2- tritylamino - 4 - thiazolyl) - 2 - (methoxyimino) - acetamidiT] - ceph - 3 - em 4 - carboxylic acid, syn isomer a) 15 cm3 of dry methanol and 272 mg of 7-amino-cephalosporanic acid 20 were mixed under nitrogen. The formed mixture was cooled to -20°C, and a total of 136 mg of sodium methylate were introduced, in three additions. The mixture was agitated for 7 hours 30 minutes at immediately -15°C and then used / in stage c) below. b) 1 g of th,e sodium salt of 2-(2-tritylamino - 4 - thiazolyl) 2 - methoxyimino - acetic acid, syn isomer, was introduced into a 3 3 mixture of 8 cm of methylene chloride, 1 cm of ether and 4 cm of normal hydrochloric acid. The formed mixture was agitated until dissolution, decanted and re-extracted with methylene chloride. The extracts were washed tyith water, dried and evaporated to dryness, and the residue obtained was redissolved in 4 cm of dry methyl chloride. 235 mg of dicyclohexylcarbodiimide were added, and the mixture was agitated for 30 minutes at ambient temperature, after which the dicyclohexylurea formed was separated by vacuum-filtration and rinsed with methylene chloride. c) The solution prepared at b) was added to the mixture a) which had been previously saturated with dry ice. The mixture was agitated for 30 minutes at -15°C, and then left for a night at +5°C.

The product was precipitated by the addition of isopropyl ether, and 800 mg of a product identical to that obtained in Stage A of Example 1 were obtained.

Stage B: 3 - carbamoyloxymethyl -7-(^2-(2- tritylamino - 4 thiazolyl) - 2 - (methoxyimino) - acetamido) - ceph - 3 - em - 4 20 carboxylic acid, syn isomer.

The method of Stage B of Example 1 was employed to obtain the expected product.

Example 4 3-carbamoyloxymethyl-7-[g- (2-tri tylami no-4-thi azolyl)-225 (methoxyimino)-acetamidoJ-ceph-3-em-4-carboxylic acid, syn isomer Some 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino acetic acid obtained as described above (from 1.81 g of the sodium salt) was 4S865 dissolved in 20 cm of dry chloroform. 0.48 g of dicyclohexylcarbodiimide were added and the mixture was agitated for 45 minutes at ambient temperature. The urea formed was separated by vacuumfiltration, and the filtrate was cooled to -10°C before the addition of 0.5 g of 3 - carbamoyloxymethyl - 7 - amino - ceph - 3 em-4 - carboxylic acid in 8 cm of chloroform and 0.5 cm of triethylamine.

After one night at +5°C the mixture was extracted with a 4% solution of bicarbonate. The aqueous solution was washed with ether and acidified to pH 2. The precipitate formed was recovered by vacuum-filtration, washed with water and then ether and dried to give a product identical to that obtained in Example 1.

Example 5 3-carbamoyloxymethyl-7-(2-(2-amino-4-thiazolyl)-2-(niethoxyimino)acetamid]-ceph-3-em-4-carboxylic acid, syn isomer Stage A: 3 - hydroxymethyl -7-(2-(2- chloroacetamido - 4 thiazolyl) - 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 carboxylic acid, syn isomer. *3 240 cm of distilled water at 37°C and 40 g of cleansed wheatgerm were mixed. The mixture was agitated for 30 minutes at 37°C and centrifuged at +5°C to give 205 cm3 of supernatent enzyme solution at pH 6.6 Separately, 1.6 g of 3 - acetoxymethyl -7-^-(2chloroacetamido - 4 - thiazolyl) - 2 - (methoxyimino) - acetamidoj ceph - 3 - em - 4 - carboxylic acid, syn isomer were introduced into 4S865 cnr of distilled water. A suspension at pH 4.3 was obtained, which o was brought to pH 6.7 by the addition of 11.9 cm of 0.2N potassiym hydroxide. The solution became clear.

Under agitation, at 37°C, and in an atmosphere of nitrogen, 192 cm3 of the fresh enzyme solution prepared as above were mixed with the above acid solution at pH 6.7. The pH was then maintained at 6.5 by addition of 0.2N potassium hydroxide, as required, and the progress of the reaction was followed by means of thin layer chromatography The reaction was stopped at the end of 4 hours, when the mixture was centrifuged at +5°C. The residue formed was triturated with 19 cm3 of iced water and centrifuged at 5°C for 30 minutes, after which the supernatant layers were combined and concentrated to 67 cm . 168 cm of acetone were added to precipitate the proteins, which were separated by filtration and then washed 3 times by formation of a paste with 16 cm portions of a water-acetone solution (1:2:5).

The filtrate and washing waters were combined and 640 mg of carbon black were added to the mixture, which was agitated for 1 hour at ambient timperature and then filtered. The precipitate was washed with a water-acetone mixture, and the washing waters and filtrate were united and concentrated in a water bath. 5 cm of formic acid were added to cause crystallisation. The mixture was left for one night at 5°C, after which the crystals were recovered by vacuumfiltration and washed with water to give 76.1 g of the expected product, which was reerystallised as follows: g 727.4 mg of the product obtained above were added to 28 cm of I distilled water. 134 mg of sodium bicarbonate were introduced, and the mixture formed was agitated. The insoluble matter was separated and 50 mg of sodium bicarbonate were added to the mixture, which was agitated for another 15 minutes. 142 mg of carbon black were added, and the mixture was agitated for 30 minutes at ambient temperature.

The carbon black was then separated by filtration and washed 3 times with 2 cm Qf water. The washing waters and filtrate were combined, and o 3 cm of acetic acid and 0.5 cm of formic acid were added. The product slowly crystallised out, and was recovered by vacuum-filtration and washed with distilled water to give 635.9 mg of product, after drying. = + 63.4°, with 0.5% product in 0.5 M sodium acid carbonate.

NMR (DMSO 60 MHz): 7.48 p.p.m: - proton of the thiazole ring, 3.91 p.p.m. - methoxy of the oxime, 4.28 p.p.m. - methylene of the group -CHgOH. i Stage B: 3 - carbamoyloxymethyl - 7 - [2-(2- chloroacetamido - 4 - thiazolyl) - 2 - (methoxyimino) - acetamido] - ceph 3 - em - 4 - carboxylic acid, syn isomer 1.56 g of 3 - hydroxymethyl - 7 - [_2 - (2 - chloroacetamido - 4 20 thiazolyl) - 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 carboxylic acid, syn isomer (as prepared in Stage A), 18 cm of pyridine and 60 cm of tetrahydrofuran were mixed. The mixture formed was cooled to -25°C, and 3 cm3 of trichloroacetyl isocyanate were added in one portion. The temperature rises to -18°C then falls 4-58 6 5 back, when 600 cm of a saturated solution of sodium bicarbonate in water, diluted to half concentration, were added. The mixture was agitated at ambient temperature and extracted 4 times with 25 cm portions ο of ethyl acetate. Each extract was then washed with 125 cm of a saturated solution of sodium acid carbonate, diluted to half concentration. The basic aqueous phases were combined, brought to neutrality with 2N hydrochloric 0 acid and extracted twice with 250 cm. portions of ethyl acetate, which were washed with a saturated solution of sodium chloride. The product was then re-extracted with tetrahydrofuran and washed again. The organic phases were combined, washed with salt water, dried and evaporated under reduced pressure. The gum obtained was triturated with ether, agitated at ambient temperature and vacuumfiltered to give a solid that was rinsed and dried to give 1.020 g of a white powder. M.Pt. = 246°C (with decomposition) Rf = 0.37 (ethyl acetate-acetic acid water 80:15:5).

Stage C: 3 carbamoyloxymethyl -7-^2-(2- amino - 4 thiazolyl) - 2 - (methoxyimino) acetamidoj - ceph 3 - em - 4 - carboxylic acid, syn isomer 950 mg of the product obtained in Stage B above and 171 mg of thiourea 3 were introduced into 2 cm of distilled water. The mixture formed was placed in an ice bath and 190 mg of potassium bicarbonate were added in several portions. The mixture was allowed to return to ambient temperature and left under agitation for 5 hours 30 minutes, after which formic acid and 6.7 cm of water were added until neutrality.

Next, the mixture was triturated in an ice bath and vacuum-filtered.

The solid was ringed with 3.8 cm of water containing 10% of formic acid, taken up with 5.7 cm of water and maintained in an ice bath with the addition of triethylamine so as to ensure good dissolution. 0.6 cm of formic acid were added before vacuum-filtration and two subsequent washings with 3.8 cm3 of water containing 10% of formic acid. A dark brown gum was eliminated. The aqueous phases were combined and treated b with 10.25 g of ammonium sulphate, and the precipitate formed was recovered by vacuum-filtration, made into a paste with water, then ether, and dried to give a first yield of 470 mg. By saturating the mother liquors with ammonium sulphate a second yield of 52 mg was obtained.

The product was purified as follows: 46 mg of crude product containing formic acid and 0.12 cm3 of absolute ethanol containing 0.1 millimole of pyridine were together agitated for 2 hours. The solid was recovered by vacuum-filtration, rinsed with absolute ethanol and dried to give 32 mg of purified white powder.

NMR (60 MHz (DMSO) p.p.m.: 6.75 - proton of the thiazolyl ring, 6.58 - OCO NHg.

The 3 - acetoxymethyl - 7 - [2 - (2 - chloracetamido - 4 - thiazolyl) - 2 - (methoxyimino) - acetamido J - ceph - 3 - em - 4 - carboxylic acid, syn isomer used at the start of this Example was prepared as follows: Ethyl 2-(2- chloracetamido - 4 - thiazolyl) - 2 - (methoxyimino) acetate, syn isomer 45.8 g of ethyl 2-(2- amino - 4 - thiazolyl) - 2 - (methoxyimino) acetate, syn isomer prepared as indicated in Example 1) were mixed •3 0 with 200 cm of methylene chloride. 20 cm of liquor were distilled 25 therefrom to effect drying, and the mixture was cooled to 10°C before the addition of 50 cm of pyridine. 41 g of monochloracetic anhydride were further added, with slight heating until dissolution, and the mixture was left for six hours at 20°C under nitrogen, after which ο cm of water were added. The mixture was agitated, poured into q 300 cm of chilled 2M hydrochloric acid and then decanted. The product was extracted with methylene chloride, and the extracts were washed with water, sodium bicarbonate and again with water, then dried, passed over active charcoal and concentrated. 300 cm of isopropyl ether were added to the residue, and the product crystallised out. The mixture was then concentrated until a thick paste was obtained, chilled and vacuum-filtered. The solid obtained was washed with isopropyl ether and dried to obtain 45.4 g of product. M.Pt. = 113°C.

A pure sample was obtained by recrystallisation from a mixture of methylene chloride and isopropyl ether. M.Pt. = 118°C. 2-(2- chloroacetamido - 4 - thiazolyl) - 2 - (methoxyimino) acetic acid, syn isomer g of the product obtained in the previous stage were introduced into 230 cm3 of5abso)ute ethanol, followed by, at 20°C under nitrogen, cm of pure sodium hydroxide solution. The product dissolved,' the sodium salt began to crystallise out, and the medium congealed into a mass. After sixteen hours a solid was separated by vacuum-filtration and washed with ethanol. The salt thus obtained was dissolved in water and chilled before the addition of 100 cm of 2N hydrochloric acid. Next, the formed solution was saturated with sodium chloride and the product was extracted with the ethyl acetate containing 10% ethanol.

The extracts were dried, passed over active charcoal, distilled under vacuum, and the water present was entrained with benzene. The residue formed was taken up with methylene chloride, distilled to dryness, taken up again with methylene chloride, chilled and vacuum-filtered.

The solid separated was washed with methylene chloride and dried to give 34.5 g of the expected product. M.Pt. = about 200°C. The product was purified by recrystallisation from an acetone-isopropyl ether mixture. Analysis: -C8H8°4N3C1S = 277.68 Calculated: C% 34.60 H% 2.90 N% 15.13 Cl% 12.77 S% 11.55 Found: C% 34.8 H% 2.8 N% 14.8 Cl% 12.6 S% 11.5 - acetoxymethyl -7-(2-(2- chloracetamido - 4 - thiazolyl) 2 - (methoxyimino) - acetamido(j - ceph - 3 - em - 4 - carboxylic acid, syn isomer. .3 g of the product obtained in the above stage were introduced into 80 cm3 of methylene chloride. At 5°C, 8 cm3 of triethylamine were added, then at 0°C and under nitrogen, 3.8 cm3 of thionyl chloride and 26 cm of methylene chloride were added. The mixture formed was left for fifteen minutes at 0°C and then 7 cm3 of triethylamine were introduced, followed, at 0°C under nitrogen, by 13.6 g of 3 7-amino-cephalosporanic acid in 100 cm of methylene chloride and 14 cm of triethylamine. The temperature was allowed to rise to 20°C, and after one hour's agitation, the solution was distilled to dryness under vacuum at about 30-35°C. The residue was dissolved in 250 cm3 of water and passed over active charcoal before the addition of 50 cm of 2N hydrochloric acid. A precipitate was formed which was separated by vacuum-filtration and washed with water. The crude product thus 3 obtained was put into a suspension in 80 cm of ethanol, and at 5 +5°C, 7 cm3 of triethylamine were added, followed by 15 cm3 of 4N sulphuriq acitj in a single addition, under agitation. The product crystallised out, and after fifteen minutes this was recovered by vacuum-filtration, washed with ethanol by making into a paste, washed with ether and dried under vacuum to give 18.6 g of the expected product. = + 26° + 1° (concentration: 1% in dimethylformamide).

• X * Example 6 Sodium spit of 3-carbamoyloxymethyl-7- ^2-(2-amino-4-thiazolyl)2-(methoxyimino)-acetamido] -ceph-3-em-4-carboxylic acid, syn isomer mg of 3 - carbamoyloxymethyl - 7 -[^2 - (2 - amino - 4 thiazolyl) - 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 carboxylic acid, syn isomer, prepared as in Example 5, were introduced into 0.2 cm of distilled water. 12 mg of sodium bicarbonate were added in small amounts and a solution was gradually formed before ' % taking up with 2.4 cm of acetone and triturating. A gum was formed, which was separated by decanting and taken up with 2.4 cm of acetone, before triturating and agitating for 10 minutes at ambient temperature 'to give fraction A. ο 2.4 cm of acetone were then added to the mother liquors, and the mixture was triturated and agitated for 10 minutes at ambient temperature to give fraction B. Fractions A and B were combined and made into 3 a paste with, and successively, 0.2 cm of ethanol, 0.2 cm of isopropyl ether and 0.2 cm of acetone. The product was placed in a dissicator until a constant weight was obtained, giving 65 mg of a creamy white powder. M.Pt. >272°C.

Rf. = 0.16 (eluant:ethyl acetate-acetic acid-water: (80:15:5).

Formulation 1 A preparation for injection was prepared of formula: - carbamoyloxymethyl - 7 - [j! - (2 - amino 4 - thiazolyl) - 2 - (methoxyimino) - acetamidoQceph - 3 - em - 4 - carboxylic acid, syn isomer 500 mg Sterile aqueous excipient....q.s.v. 5 cm Formulation 2 Gelatin capsules were prepared corresponding to the formula: - carbamoyloxymethyl -7-(2-(2- amino - 4 thiazolyl) - 2 - (methoxyimino) - acetamido] 20 ceph - 3 - em - 4 - carboxylic acid, syn isomer 250 mg Excipient q.s. for one gelatin capsule up to 400 mg Formulation 3 A composition for injection was prepared by:the formula: Sodium salt of 3 - carbamoyl oxymethyl - 7 - £2 (2 - amino - 4 - thiazolyl) - 2 - (methoxyimino) 5 acetamidoj - ceph - 3 - em - 4 - carboxylic acid, syn isomer 500 mg Sterile aqueous excipient....q.s.v. 5 cm Formulation 4 Gelatin capsules were prepared corresponding to the 10 formula: Sodium salt of 3 - carbamoyloxymethyl - 7 (j! - ( 2- amino - 4 - thiazolyl) - 2 (methoxyimino) - acetamidoj - ceph - 3 - em 4 - carboxylic acid, syn isomer 250 mg Excipient q.s. for one gelatin capsule up to 400 mg • In the following claims all substituents and formulae are as first defined, unless otherwise stated.

Claims (1)

1. An oxime derivative of 3 - carbamoyloxymethyl - 7 - amino thiazolyl - acetamido - ceph - 3 - em-4 - carboxylic acid of the general formula: (wherein R-| represents a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms and A represents either a hydrogen atom, an alkali-metal atom, an equivalent of an alkaline-earth metal atom, an equivalent of a magnesium atom, or 10 a substituted ammonium group) the compound being in the form of the syn isomer. 2. · A syn isomer as claimed in Claim wherein A represents a sodium, potassium, lithium, calcium or magnesium atom. 3. A syn isomer as claimed in Claim 1, wherein A represents a substituted ammonium group derived from methylamine, propylamine, diethylamine, trimethylamine, triethylamine, N,N - dimethylethanolamine or tris(hydroxymethyl) - aminomethane. V 5 4. A syn isomer as claimed in Claim 1, wherein R^ represents a methyl radical and A represents a hydrogen atom or a sodium atom. 5. 3 - Carbamoyloxymethyl - 7 - |_2 - (2 - amino - 4 - thiazolyl) 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 - carboxylic acid, syn isomer. 10 6. 3 - Carbamoyloxymethyl -7-^2-(2- amino - 4 - thiazolyl) 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 - carboxylic acid, syn isomer, as obtained according to the process described in Example 2. 7. The sodium salt of 3 - carbamoyloxymethyl - 7 - [2 - (2 - amino - 4 - thiazolyl) - 2 - (methoxyimino) - acetamido] - ceph - 3 - em 15 4 - carboxylic acid syn isomer. 8. An oxime derivative of 3 - carbamoyloxymethyl - 7 - amino thiazolyl - acetamido - ceph - 3 - em - 4 - carboxylic acid of the general formula: NHR* (wherein R 1 represents a group removable by acid hydrolysis or by hydrogenolysis) the compound being in the form of the syn isomer. 9. A syn isomer as claimed in Claim 8, wherein R' represents a jt-butoxyca rbony!, trityl, benzhydryl, trichloroethyl or carbobenzyloxy 5 group. 10. A process for preparing a syn isomer of general formula lb 1 wherein A represents a hydrogen atom, in which process an appropriate syn isomer of general formula Ia 1 , wherein A represents a hydrogen atom, is subjected to acid hydrolysis or hydrogenolysis as necessary 10 to remove the substituent R 1 and so form the desired product of the general formula ' «865 Π. A process as claimed in Claim 10, in v/hich the acid hydrolysis is effected with trifluoroacetic acid, formic acid or acetic acid. 12. A process as claimed in Claim 10, in which the hydrogenolysis is effected with a zinc-acetic acid system. 5 13. A process for preparing the syn isomers of general formula la* wherein A represents a hydrogen atom, in which process an appropriate syn isomer of the general formula: (wherein A 1 represents an alkali-metal atom or a hydrogen atom and 10 Rg represents a group removable by hydrolysis) is treated with a hydrolysis agent effective at hydrolysing the group Rg and not the group R 1 , and in the case where a basic hydrolysis agent is employed 4586s thereafter the hydrolysis product is treated with an acid, to give the desired product of the general formula: 14. A process as claimed in Claim 13, in which the hydrolysis of 5 the syn isomer of general formula II is carried out using aqueous sodium bicarbonate. 15. A process as claimed in Claim 13, in which the hydrolysis of the syn isomer of formula II is carried out using potassium bicarbonate or an alkali-metal carbonate in a medium of water or a 10 water/alcohol mixture. 16. A process as claimed in Claim 14 or Claim 15, in which the hydrolysis product is treated with dilute hydrochloric, sulphuric or phosphoric acid. 17. A process as claimed in any of Claims 13 to 15, in which the substituent Rg is a trichloroethyl, benzyl, j)-methoxybenzyl or chiorosulphonyl radical. 18. A process as claimed in any of Claims 13 to 17, in which the 5 syn isomer of the general formula II is prepared by reacting an appropriate syn isomer of the general formula: with an isocyanate of the general formula: r 2 —N = C=tO to give the desired product of general formula II. 19. A process as claimed in Claim 18, in which the reaction is carried out in one or more inert solvents. 20. A process as claimed in Claim 19, in which the reaction is carried out in one or more of methylene chloride, chloroform, 5 dimethylformamide, tetrahydrofuran and pyridine. 21. A process as claimed in any of Claims 18 to 20, in which a syn isomer of general formula III wherein A' represents an alkali-metal atom is prepared by reacting 7-aminocephalosporanic acid of the formula: with an alkali-metal alcoholate in an alcohol, and treating the formed product with an appropriate syn isomeric acid of the general formula: NHR 1 c — co 2 h OR, (IV) N 4. 5 a ο «> or a functional derivative thereof to give the desired product of general formula III. 22. A process as claimed in Claim 21, in which the 7-aminocephalosporanic acid is reacted with the alkali-metal alcoholate in an 5. Alcohol containing from 1 to 3 carbon atoms. 23. A process as claimed in Claim 22, in which the alcoholate is sodium methylate and the reaction is carried out in methanol. 24. A process as claimed in any of Claims 21 to 23, in which the acid of general formula IV is employed as its acid chloride or acid 6. 10 anhydride. 25. A process as claimed in Claim 24, in which the anhydride is formed in situ by the action of isobutyl chloroformate on the free acid. 26. A process as claimed in Claim 24 or Claim 25, in which the reaction is-carried out in the presence of a basic agent. 7. 15 27. A process as claimed in Claim 26, in which the basic agent is an alkali-metal bicarbonate or carbonate, N-methylmorpholine, pyridine or a trialkylamine. 28. A process as claimed in any of claims 18 to 20, in which a syn isomer of general formula III wherein A' represents an alkali-metal 8. 20 atom is prepared by treating an appropriate syn isomer of the general formula: with an alkali-metal alcoholate in an alcohol to obtain the desired product of general formula III. 29. A process as claimed in Claim 28, in which the alkali-metal 5 alcoholate is sodium methylate, and the alcohol contains from 1 to 3 carbon atoms. 30. A process as claimed in any of Claims 18 to 20, in which a syn isomer of general formula III wherein A 1 represents a hydrogen atom is prepared by treating an appropriate syn isomer of the general 10 formula: NHR' COgH (V) CH? - O-C - CH. II with a deacetylation enzyme to obtain the desired product of general formula III. 31. A process as claimed in Claim 30, in which the substituent 5 R 1 is a t-butoxycarbonyl, trityl, benzyl, benzhydryl, trichioroethyl, carbobenzyloxy or formyl radical or the equivalent of a phthaloyl group. 32. A process as claimed in Claim 30 or Claim 31, in which the enzyme is a wheatgerm enzyme, employed at a temperature of substantially 10 37°C and at a substantially neutral pH. 33. A process for preparing the syn isomers of general formula Ia, in which the compound of the formula: (VI) is treated with an appropriate acid of general formula IV or with a functional derivative thereof to obtain the desired product of general formula Ia. 5 34. A process as claimed in Claim 33, in which a functional derivative of the acid of general formula IV as defined in Claim 24 or Claim 25 is employed. 35. A process as claimed in Claim 33or Claim 34, in which the reaction conditions are as defined in Claim 26 or Claim 27. 10 36. A process for the preparation of the syn isomers of general formula Ib, as claimed in any of Claims 10 to 12, in which process the syn isomer of general formula Ia 1 wherein A represents a hydrogen atom is prepared by a process as claimed in any of Claims 13 to 35. 37. A process for preparing the syn isomers of general formula Ib, 15 in which an appropriate syn isomer of the general formula: 458 0 5 is treated with thiourea to obtain the desired product of general formula lb 38. A process as claimed in Claim 37, in which the reaction is carried out in a neutral or an acidic medium. 5 39. A process as claimed in Claim 37 or Claim 38, in which the starting material of general formula VII is prepared by reacting an appropriate syn isomer of the general formula: with a deacetylation enzyme to obtain the corresponding product of the general formula: co 2 h which product of general formula IX is treated with an isocyanate of the general formula: R - N=-C»O to obtain a produgt of the general formula (X) - C - NHR 2 II 458 6 5 which product is treated with a hydrolysis agent, and in the case when a basic hydrolysis agent has been used thereafter treated with an acid, to obtain the desired product of general formula VII. 40. A process as claimed in Claim 39, in which the substituent group Rg is as defined in Claim 17. 41. A process as claimed in Claim 39 or Claim 40, in which the reaction conditions employed are as defined in Claims 32, 19, 20 and 14 to 16. 42. A process for preparing the syn isomers of general formula la' or Ib 1 wherein A represents an alkali-metal atom, an equivalent of an alkaline-earth metal atom, an equivalent of magnesium or a substituted ammonium group, in which process an appropriate syn isomer of general formula Ia or Ib is salified by reaction with a suitable base to give the desired product. 43. A process as claimed in Claim 42, in which the salification is carried out in a solvent comprising one or more of water, methanol, ethanol, acetone and dioxan. 44. A process as claimed in Claim 42 or Claim 43, in which the syn isomer of general formula Ia or Ib is prepared by a process as claimed in any of Claims 10 to 41. 45. A process for the preparation of a syn isomer of general formula la' or Ib' substantially as described herein with reference to any one of the Examples. 46. A syn isomer of general formula la* or Ib', whenever prepared by a process as claimed in any of Claims 10 to 45. 47. A pharmaceutical composition containing as active material one or more syn isomers of general formula Ib 1 , in association with a suitable' pharmaceutical vehicle. 48. A composition as claimed in Claim 47, in which the active material is a syn isomer of general formula Ib' wherein R·, represents 5 a methyl radical and A represents a hydrogen or sodium atom. 49. A composition as claimed in Claim 47, in which th'e active material is: 3 - carbamoyloxymethyl -7-^2-(2- amino - 4 - thiazolyl) - 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 - carboxylic acid, 10 syn isomer; 3 - carbamoyloxymethyl - 7 - [^2-(2- amino - 4 - thiazolyl) 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 - carboxylic acid, syn isomer, obtained according to the process described in Example 2; or the sodium salt of 3 - carbamoyloxymethyl -7-(2-(2- amino 15 4 - thiazolyl) - 2 - (methoxyimino) - acetamido] - ceph - 3 - em - 4 carboxylic acid, syn isomer. 50. A composition as claimed in any of Claims 47 to 49 and substantially as described herein with reference to any one of the Formulations. 20 51. The syn isomers of general formula VII.