GB1572683A

GB1572683A - Oxime derivatives of 7-aminothiazolyl-acet-amido-cephalosporanic acid processes for preparing them and pharmaceutical compositions containing them

Info

Publication number: GB1572683A
Application number: GB11580/78A
Authority: GB
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1977-03-25
Filing date: 1978-03-23
Publication date: 1980-07-30
Also published as: IT1103477B; SE7802834L; CH629815A5; JPS53119888A; HU182738B; AU3447278A; ATA213178A; ZA781613B; FR2384779B1; AT355723B; BE865299A; NL7803165A; FR2384779A1; DE2812570A1; LU79313A1; DK129678A; AU520450B2; IT7848605A0

Abstract

The compounds correspond to the formula: <IMAGE> in which the symbols R, R1 and A have the meaning given in Claim 1. They are prepared by reacting compounds of formula II and III: <IMAGE> or a functional derivative of III, in which A' represents H or an ester which can be removed by acid hydrolysis or by hydrogenolysis, R<2> represents a group which can be removed in the same way or a chloroacetyl group and R'1 is defined like R2 or represents a saturated or unsaturated C1-C4 alkyl and when R'1 represents ClCH2CO-, R2 also represents this group; the removable groups A', R2 and R'1 are then removed by acid hydrolysis, hydrogenolysis and/or treatment with thiourea. The compounds and their salts of the carboxylic group have a good antibiotic activity and can be used for the treatment of various infectious diseases.

Description

(54) NEW OXIME DERIVATIVES OF 7 AMINOTHIAZOLYL-ACETAMIDO-CEPHALOSPORANIC ACID, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM (71) We, ROUSSEL-UCLAF, a French Body Corporate, of 35 Boulevard des Invalides, Paris 7eme, France, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to new oxime derivatives of 7 - amino - thiazolyl .acetamido - cephalosporanic acid, processes for preparing them and compositions contining them.

In one aspect this invention provides the compounds of the general formula:

wherein R, represents a hydrogen atom or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, Ra represents a chlorine atom, a methoxy radical, an alkylthio radical having from I to 4 carbon atoms or a radical R4-CO-NH- in which R4 represents an alkyl radical having from 1 to 4 carbon atoms, and A represents a hydrogen atom, an alkali-metal atom, an equivalent of an alkaline-earth metal atom, an equivalent of a magnesium atom or an equivalent of an ammonium or a substituted ammonium group, the group OR, being in the sytt position.

Thus, the invention extends to compounds of the general formula:

in the form of the syn isomer, wherein R, and A are as defined hereinbefore, and R represents a chlorine atom or a methoxy radical; and compounds of the general formula:

in the form of the syn isomer, wherein R, and A are as defined hereinbefore and R3 represents an alkylthio radical having from 1 to 4 carbon atoms or a radical R4-CO-NH-, in which R4 represents an alkyl radical having from 1 to 4 carbon atoms.

When R, represents a hydrocarbyl radical this may be an alkyl, alkenyl or alkynyl radical-for example, R, may be a methyl ethyl, propyl, isopropyl, n-butyl, secbutyl, tbutyl, vinyl, propenyl, butenyl, ethynyl or propargyl radical.

When Ra or R3 represents an alkylthio radical, this may be, for example, a methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio or tbutylthio radical. When either of these groups represents a R4-CO-NH- group this may be an acetamido, propionylamino, butyrylamino or isobutyrylamino radical that is to say, a group wherein RA represents a methy; ethyl, propyl or isopropyl radical.

R4 may also represent an n-butyl, sec-butyl or t-butyl radical.

When A represents "an equivalent of an alkaline-earth metal atom", "an equivalent of a magnesium atom" or "an equivalent of an ammonium or substituted ammonium group" each molecule of the compound shown in general formula IAS I or I' contains, as A, the fraction of the atom or group corresponding to a single valence.

Thus, the compounds of the invention may either be in the form of free acids or in the form of salts thereof formed with alkalimetals, alkaline-earth metals, magnesium, ammonia or organic amines.

A preferably represents sodium, potassium, lithium or ammonium, or an equivalent of calcuim or magnesium, or A is derived from an organic amine such as trimethylamine, triethylamine, diethylamine, methylamine, n-propylamine, N,N-dimethyl-ethanolamine, tris(hydroxymethyl)aminomethane, argine or lysine.

A preferred group of compounds of general formula 1A is that corresponding to general formula I' wherein Rl represents a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, R3 represents a methylthio radical or an acetamido radical and A represents a hydrogen atom or a sodium atom.

The following compounds of general formula 1A are especially preferred.

7 -[2 -(2 -amino - thiazol - 4 -yl) -2 methoxyimino - acetamido] 3 - methoxy ceph - 3- em- 4- carboxylic acid, synisomer, and its salts formed with alkali metals, alkaline-earth metals, magnesium, ammonia and organic amines; 7 -[2 -(2 -amino - thiazol - 4 - yl) - 2 methoxyimino - acetamido - 1 - 3 - chloro ceph - 3 - em - 4 - carboxylic acid, syn isomer, and its salts formed with alkali metals, alkaline-earth metals, magnesium, ammonia and organic amines; and 7 -[2 -(2 -amino - thiazol - 4 - yl) - 2 methoxyimino - acetamido] - 3 acetamido - ceph - 3 - em - 4 - carboxylic acid, syn isomer, and its salts formed with alkali metals, alkaline-earth metals, magnesium, ammonia and organic amines.

It is to be understood that the compounds of general formula 1A may exist either in the form indicated by formula IA, or in the form of compounds of the general formula:

wherein Ra, R, and A are as defined hereinbefore.

This invention also provides a process for preparing the compounds of general formula 1A wherein A represents a hydrogen atom, in which a compound of the general formula:

in the form of the syn-isomer, (wherein R. is as defined hereinbefore, R2 represents a group removable by acid hydrolysis or by hydrogenolysis or a chloracetyl group, R', represents a group removable by acid hydrolysis or by hydrogenolysis, a chloracetyl group or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, with the proviso that when R', represents a chloracetyl group R2 also represents a chloracetyl group, and A' represents a hydrogen atom or an ester-forming group removable by acid hydrolysis or by hydrogenolysis) is treated with one or more appropriate agents selected from acid hydrolysis agents, hydrogenolysis agents and thiourea so as to obtain a compound of the general formula:

in the form of the syn isomer, wherein Ra and R, are as defined hereinbefore.

By the expression "a group removable by acid hydrolysis or hydrogenolysis" is meant a group that can be cleaved from the remainder of the molecule without otherwise affecting its structure (other than cleaving other such groups where more than one is present). Examples of such groups that R', and R2 may represent include the tbutoxycarbonyl, trityl, benzyl, benzhydryl, trichloroethyl, benzyloxycarbonyl, formyl, trichloroethoxycarbonyl and 2tetrahydropyranyl groups.

When A' represents an ester-forming group removable by acid hydrolysis or by hydrogenolysis this may be a benzhydryl, tbutyl, benzyl, p-methoxybenzyl or trichloroethyl radical.

The aim in the conversion of the compounds of general formula II into compounds of general formula 1,A is to replace the substituent R2 with a hydrogen atom, and also, when R', represents a group removable by acid hydrolysis or by hydrogenolysis or a chloracetyl radical and/or when A' represents a group removable by acid hydrolysis or by hydrogenolysis, to replace R', and/or A' with a hydrogen atom.

In order to do this the compound of general formula II is treated with one or more acid hydrolysis agents when R', and R2 each represent a group removable by acid hydrolysis and when A' represents a hydrogen atom or a group removable by acid hydrolysis.

The compound of general formula II is treated with one or more hydrogenolysis agents when R', and R2 each represent a group removable by hydrogenolysis and A' represents a hyrogen atom or a group removable by hydrogenolysis.

The compound of general formula II is treated with one or more acid hydrolysis agents and with one or more hydrogenolysis agents when at least one of the substituents R'" R2 or A' represents a group removable by acid hydrolysis and at least one of these substituents represents a group removable by hydrogenolysis.

The compound of general formula II is treated with thiourea when R2 represents a chloracetyl group and when R'l represents a chloracetyl group or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms; in addition the aforementioned compound II is treated with an acid hydrolysis agent or a hydrogenolysis agent as appropriate when A' does not represent a hydrogen atom.

Acid hydrolysis agents which may be used include formic acid, trifluoroacetic acid and acetic acid. These acids can be used in anhydrous form or in aqueous solution. In addition the zinc/acetic acid system may be used as an acid hydrolysis agent.

Preferably an acid hydrolysis agent such as anhydrous trifluroroacetic acid, aqueous formic acid or aqueous acetic acid is used to eliminate a t-butoxycarbonyl or trityl group as substituent R', or Rz, or to remove a benzhydryl, t-butyl or p-methoxybenzyl group as substituent A'.

Preferably the zinc/acetic acid system is used to eliminate a trichloroethyl group as substituent R'" R2 or A'.

Hydrogenolysis agents such as hydrogen in the presence of a catalyst may be used to eliminate a benzhydryl or carbobenzyloxy group as substituent R', or R2, or to remove a benzyl group as substituent R'" R2 or A'.

The reaction of thiourea with the compound II, wherein R2 represents a chloracetyl radical and R', represents a chloracetyl radical or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, is preferably carried out in a neutral or acidic medium.

This type of reaction is described by Masaki in J.A.C.S., 90, 4508 (1968).

The starting materials of general formula II are preferably prepared by a process in which a compound of the general formula:

(wherein Ra and A' are as defined hereinbefore) is treated with an acid of formula:

in the form of the syn isomer (wherein R', and R2 are as defined hereinbefore) or a functional derivative thereof.

In a preferred aspect the invention relates to a process for preparing certain of the compounds of general formula 1,A starting from compounds of general formula III wherein Ra represents a chlorine atom or a methoxy radical.

Preferably the compound of general formula III is treated with a functional derivative of the acid of formula IV such as the acid chloride, or the anhydride, the anhydride advantageously being formed in situ by the action of isobutyl chloroformate or of dicyclohexylcarbodiimide on the free acid. Alternatively, it is possible to employ other halides or other anhydrides formed in situ by the action of other alkyl chloroform ates of other dicycloalkylcarbodiimides or of a dialkycarbodiimide. It is also possible to employ other acid derivatives such as the acid azide, the acid amide or an activated acid ester formed, for example, with hydroxysuccinimide, p - nitrophenol or 2,4 - dinitrophenol.

When a compound of general formula III is reacted with a halide of the acid of general formula IV or with an anhydride formed with isobutyl chloroformate, the reaction is preferably carried out in the presence of a base. Suitable bases include alkali-metal carbonates or a tertiary organic base such as N- methyl - morpholine, pyridine or a trialkylamine such as triethylamine or tri - n - butylamine.

The compounds of the general formula IV used in the above process are known, being described in Belgian Patent No. 850,662.

The compounds of general formula III wherein Ra represents an alkylthio radical may be prepared by a process as described in French Patent 2,282,895. The compounds of general formula II wherein Ra represents a R4-CO-NH- radical may be prepared by the process described in German Patent 2,553, 912, but they may also be prepared by acylation of an appropriate compound of the general formula:

(wherein Rb represents a protecting group for the amine and R'b represents a hydrogen atom or a removable ester-forming group) the acylation being followed by removal of the protecting group on the amine and, if necessary, on the carboxylic group. Such a preparation is described hereinafter in the Examples.

The products of general formula B are described, for example, in French Patent 2,301,260.

The products of general formula 1,A formed by the process described hereinafter may be salified to form the corresponding compounds of general formula 1A wherein A does not represent a hydrogen atom. This salification may be effected by any of the usual methods. The salification may be carried out, for example, by reacting the acids with a mineral base for example; sodium or potassium hydroxide or sodium bicarbonateor with a salt of a substituted or unsubstituted aliphatic carboxylic acid such as diethylacetic acid, dimethylacetic acid, ethyl-hexanoic acid or, more especially, acetic acid.

The preferred mineral salts of general formula 1A are the sodium salts.

The salification may also be achieved by reacting the compounds of general formula 1,A with ammonia or an organic base such as trimethylamine, triethylamine, diethylamine, methylamine, propylamine, N,N-dimethyl-ethanolamine, tris (hydroxymethyl)aminomethane, arginine or lysine.

In preparing the salts the solvates of the free acids may be used as starting products in place of the free acids.

The salification is preferably carried out in one or more solvents selected from water, diethyl ether, methanol, ethanol and acetone.

The salts are obtained in amorphous or crystalline form according to the reaction conditions employed. The crystalline salts are preferably prepared by reacting the free acids with one of the salts of aliphatic carboxylic acids mentioned hereinbefore, and most preferably with sodium acetate.

In the preparation of sodium salts the salification reaction is preferably carried out in a suitable organic solvent such as methanol, which is a solvent capable of containing only small amounts of water.

The compounds of general formula 1A 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 Salmonella and the Proteus.

These properties may make the pharmaceutically-acceptable compounds of general formula I suitable for use as medicaments, particularly as antibiotic medicaments in the treatment of diseases caused by sensitive microorganisms 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, bronchopnuemonia and pulmonary suppurations.

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

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

Accordingly, in a further aspect, this invention provides pharmaceutical compositions containing as active ingredient of one or more pharmaceuticallyacceptable compounds of general formula 1A in association with a pharmaceuticallyacceptable vehicle.

The compositions of the invention preferably contain those compounds of general formula 1A described hereinbefore as being preferred.

The term "pharmaceutically-acceptable" is used herein to exclude any possibility that the vehicle or the active material, considered of course in relation to the route by which the composition is to be administered, could be harmful to the patient being treated.

The choice of a suitable vehicle is believed to be within the competence of those accustomed to the preparation of pharmaceutical formulations. The compositions are preferably administered buccally, rectally, by a parenteral route or intramuscular route, or locally by topical application to the skin or mucous membranes. In respect of these routes the pharmaceutical vehicle may be, for example: a) the ingestible excipient of a tablet or pill, such as a plain or sugar-coated compressed tablet; the ingestible container of a capsule or cachet and particularly a gelatine capsule; the ingestible pulverulent solid carrier of a powder or granules; or the ingestible liquid medium of a syrup, solution, suspension or elixir; b) the solid or liquid medium of a paste, cream, ointment or gel, or the liquified propellant gas of an aerosol; c) a sterile injectable liquid solution or suspension medium; or d) the base material of a suppository.

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

The vehicles will generally be prepared from those materials commonly employed in the formulation of pharmaceutical compositions. Such materials may be solid or liquid as appropriate to the pharmaceutical form chosen, and may include a wide range of organic and inorganic solids, and aqueous and nonaqueous liquids; examples include talc, gum arabic, starch, lactose, magnesium stearate or fatty substances of animal or vegetable origin such as cocoa butter, paraffin derivatives or glycols. These materials may be compounded 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 would be from 0.250 g to 4 g administered by the oral route for the compounds described in Examples 2, 4 and 6, or from 0.500 g to 1 g when administered 3 times daily by an intramuscular or intravenous route.

The intermediates of general formula II described hereinbefore are new, and in another aspect this invention provides these compounds as their syn isomers per se, together with processes for preparing them.

In order that the invention may be well understood the following examples will now be given, only by way of illustration: Example 1: Diphenylmethyl 7 - [2 - (2 - tritylamino thiazol - 4 - yl) - 2 - methoxyimino acetamido] - 3 - methoxy - ceph - 3 em - 4 - carboxylate, syn isomer.

One mixes 1.02 g of sodium salt of 2 - (2 tritylamino - thiazol- 4- yl)- 2 methoxyimino - acetic acid, syn isomer, described in Belgian Patent No. 850,662, in 10 cm3 of methylene chloride and 5 cm3 of 2N hydrochloric acid. One agitates for 5 minutes, decants, washes with water, dries, filters and brings to dryness under vacuum.

One obtains 0.980 g of free acid.

These 0.980 g of acid are dissolved in 20 cm3 of dry methylene chloride and one adds at ambient temperature 0.232 g of dicyclohexylcarbodiimide. One agitates for one hour and vacuum-filters the precipitate of dicyclohexylurea, that is 0.175 g. One cools the filtrate to -100C and adds a solution at -100C, of 0.396 g of diphenylmethyl 7 - amino - 3 - methoxy ceph - 3 - em - 4 - carboxylate in 5 cm3 of methylene chloride. One allows to return to ambient temperature, decants, washes with normal hydrochloric acid and with water, dries, filters and brings under vacuum. One obtains 1.2 g of product in the form of a resin. This product is purified by chromatography on silica, eluting with a mixture of benzene and ethyl acetate (6:4).

One obtains 0.220 g of expected product (Rf=0.3).

Ultra-violet spectrum in ethanol +N/10 aqueous HCI.

--max 275 nm Eft=233 E=19130 inflexion 290 nm E,=202 NMR (CDCL3, 60 MHz) p.p.m.=3.69 (-O-CH3) 4.06 (=N-OCH3) 6.8 (proton of the thiazole) 6.9

Example 2: 7 - [2 - (2 - amino - thiazol - 4 - yl) - 2 methoxyimino - acetamido] - 3 methoxy - ceph - 3 - em - 4 carboxylic acid, syn isomer.

One mixes, under nitrogen at OOC, 0.415 g of diphenyl- methyl 7- [2 - (2 tritylamino - thiazol - 4- yl)- 2methoxyimino - acetamido] - 3 methoxy - ceph - 3 - em - 4 - carboxylate prepared according to Example 1, 2 cm3 of anisole, then 20 cm3 of trifluoroacetic acid.

One agitates for 15 minutes at OOC, then pours into 50 cm3 of water. One washes with methylene chloride, then brings the aqueous phase to dryness. One takes up several times with a few cm3 of ethyl acetate, then concentrates to dryness under vacuum. One obtains 0.267 g of trifluoroacetate of the expected product. This trifluoroacetate is dissolved in 10 volumes of acetone containing 20% of water. One adds 0.04 cm3 of pyridine. One brings to dryness, takes up the residue with 1 cm3 of acetone and precipitates by the addition of ethyl ether.

One vacuum-filters and washes with ethyl acetate, then with ether. One obtains a first yield of 0.126 g, then a second yield of 0.025 g. The product is purified as follows: one combines the two yields, adds 1.5 cm3 of ethyl acetate and leaves for 30 minutes under agitation. One vacuum-filters, washes with ether and dries for one night under vacuum. One obtains 0.123 g of purified product. M.Pt=1700C.

NMR (DMSO, 60 MHz) p.p.m.: 3.85 (NOME) 3.76 (OME), 6.86 (proton of the thiazole), 7.16 (NH,).

Example 3: 7 - [2 - (2 - tritylamino - thiazol - 4 - yl) 2 - methoxyimino - acetamidoj - 3 chloro - ceph - 3 - em -4 - carboxylic acid, syn isomer.

One suspends 1.548 g of sodium salt of 2 (2 - tritylamino - thiazol - 4 - yl) - 2methoxyimino - acetic acid, syn isomer, in 50 cm3 of methylene chloride. One adds 6 cm3 of 2N hydrochloric acid, agitates, decants, washes with water and distils to dryness. One obtains 1.477 g of expected acid.

The acid obtained above is put into a solution in argon in 25 cm3 of anhydrous methylene chloride.

One adds, all at once, 0.376 g of dicyclohexylcarbodiimde, agitates at 200C under argon for one hour and one filters under argon the dicyclohexylurea formed.

One cools the chloromethylenic solution of anhydride to --100C.

On the other hand one suspends 0.390 g of 7 - amino - 3 - chloro - ceph - 3 - em 4 - carboxylic acid in 5 cm3 of methylene chloride. One adds 0.46 cm3 of triethylamine. One adds a further 10 cm3 of methylene chloride. This solution is cooled and poured into the above solution of anhydride at -100C. One agitates and adds 5 cm3 of anhydrous dimethylsulphoxide so as to obtain total dissolution of the reaction mixture. One agitates for 10 minutes at -10 C, then allows the temperature to rise again to200C. One agitates for two hours at 20"C. One washes the organic solution twice with 20 cm3 of 2N hydrochloric acid, then three times with distilled water. The chloromethylenic phase is distilled to dryness at a temperature below 300 C.

One obtains 1.715 g of crude product. By thin layer chromotography the product has an Rf of 0.4 (eluant acetone/water 100:10).

The product is purified by passing twice over silica eluting with acetone containing 10% of water.

One thus recovers 0.485 g of purified expected product.

Ultra-violet spectrum: (Ethanol) (Ethanol+N/10 HCI) Inflection at 235 nm E'=341 E=17800 Max at 273 nm El=277 E=18300 Inflection at 259 nm E'=270 Inflection at 290 nm E'=213 Inflection at 264 nm E1=257 Inflection at 300 nm E;=144 Inflection at 300 nm E'=85 E=5600 Example 4: 7 -2[2 -(2 -amino - thiazol - 4 - yl) - 2 methoxyimino - acetamido] - 3 chloro - ceph - 3 - em -4 - carboxylic acid, syn isomer.

0.385 g of acid prepared in Example 3 are made into a paste at 550C with 4 cm3 of aqueous formic acid containing 50 /a of water. One triturates the product. The product breaks up at the end of about 10 minutes with partial dissolution and precipitation of the triphenyl carbinol formed. One agitates for 20 minutes in all at 55"C. one adds 4 cm3 of distilled water, vacuum-filters, washes with water 3 times and isolates 0.135 g of triphenyl carbinol.

The clear filtrate is brought to dryness under vacuum by means of successive azeotropes formed by the addition of ethyl acetate.

One obtains a powder which one triturates in 25 cm3 of ethyl ether. One vacuum-filters, washes with ether and dries at 20"C. One obtains 0.265 g of product, Rf=0.55 (acetone/acetic acid 100:10).

NMR spectrum (DMSO, 60 MHz)

(a): two doublets centred at 3.42 and 3.9 p.p.m. J=18 Hz (b): singlet at 3.84 p.p.m.

(c): doublet at 5.12 p.p.m.

(d): two doublets at 5.58 and 5.72 p.p.m.

J=4.5 H 5.5 (e): singlet at 6.72 p.p.m.

(f): singlet at 7.8 p.p.m.

(g): doublet at 9.6 p.p.m. J=7. Hz.

Example 5: 7 - [2 - (2 - amino - thiazol - 4 - yl) - 2 (methoxyimino)- acetamido] - 3 methylthio - ceph - 3 - em - 4 carboxylic acid, syn isomer.

Stage A: 7 - [2 - (2 - tritylamino - thiazol 4 - yl) - 2' - (methoxyimino) acetamido] - 3 - methylthio - ceph - 3 - em - 4 - carboxylic acid, syn isomer.

One places 790 mg of sodium salt of 2 [(2 - tritylamino - thiazol - 4- yl)- 2- (methoxyimino)l - acetic acid, syn isomer, in a mixture of 8 cm3 of methylene chloride and 4 cm3 of 2N hydrochloric acid. One agitates for 5 minutes, decants, washes with water, dries, filters and brings to dryness under reduced pressure. One obtains 755 mg of acid which one dissolves in 3 cm3 of methylene chloride. One adds, at ambient temperature, 185 mg of dicyclohexylcarbodiimide. One agitates for one hour at ambient temperature and vacuum-filters the precipitate of dicyclohexylurea formed (one recovers 140 mg thereof). One cools the filtrate to -100C and adds a solution, also cooled to --100C, of 300 mg of 7 - amino 3 - methylthio ceph - 3 - eme 4 - carboxylic acid in the form of trifluoroacetate in 3 cm3 of dry methylene chloride and 0.6 cm3 of triethylamine. One leaves for one hour at -10 C then allows to return over one hour to ambient temperature. One washes with 2N hydrochloric acid then with water, dries, filters and obtains 1.02 g of expected crude product. The product is purified by chromatography on silica, eluting with a mixture of ethyl acetate, ethanol and water (70:20:10). One obtains 100 mg of pure product. This product is added to a first yield of 160 mg of pure product obtained under identical conditions.

Stage B: 7 - [2 - (2 - amino - thiazol - 4 yl) - 2 - (methoxyimino) - acetamido] - 3 methylthio - ceph - 3 - em - 4 - carboxylic acid,syn isomer.

One places 260 mg of product obtained in Stage A above in 4 cm3 of 50% aqueous formic acid. One leaves for 35 minutes under agitation at 55--600. One vacuumfilters the precipitate formed, washes it with aqueous formic acid and dries it. One thus obtains 60 mg of triphenyl carbinol. The filtrate is brought to dryness under reduced pressure. The residue is taken up several times with a little ethanol. One distils again then adds a little ether. One vacuum-filters the precipitate, washes with ether then dries. One obtains 122 mg of expected product.

NMR spectrum (CD3)2SO

(a) doublet 2 p.p.m. J=l lHz(b) singlet 3.83 p.p.m.

(c) singlet 6.75 p.p.m.

(d) singlet 7.16 p.p.m.

(e) from 5 to 5.6 p.p.m.

Example 6: 7 - [2 - (2 - amino - thiazol - 4 - yl)- 2 (methoxyimino)- acetamido] - 3 acetamido - ceph - 3 - em - 4 - carboxylic acid, syn isomer.

Stage A: 7[2 - (2 - tritylamino - thiazol 4 - yl) - 2 - (methoxyimino) - acetamido] 3 - acetamido - ceph - 3 - em - 4 - 0.2 cm3 of triethylamine. One agitates for 30 minutes and adds 2 cm3 of dimethyl formamide. One then observes total dissolution. The solution is agitated at 200C for 1 hour 30 minutes then washed with dilute hydrochloric acid and with water.

After evaporation to dryness under reduced pressure one obtains 3.187 g of expected crude product. The product is purified by passing twice over silica, eluting with acetone containing 10% of water. One recovers 0.789 g of purified product.

NMR CDCI3 6.7 p.p.m., proton of the thiazole 7.26 p.p.m. proton of the trityl group.

Stage B: 7 - [2 - (2 - amino - thiazol - 4 yl) - 2 - (methoxyimino) - acetamido] - 3 acetamido - ceph - 3 - em - 4 - carboxylic acid, syn isomer.

0.68 g of product obtained in Stage A are put into solution under argon, in 8 cm3 of 50% aqueous formic acid. One heats to about 55"C using a bath and triturates the product formed. One obtains a white precipitate of triphenyl carbinol. One agitates for 20 minutes in all, adds 8 cm3 of distilled water and vacuum-filters the triphenyl carbinol (one obtains 0.26 g thereof). The formic solution is brought to dryness. The formic acid is eliminated by the formation of azeotropes, after addition of a mixture of ethanol and ethyl acetate.

One obtains 0.44 g of expected crude product. The product is made into a paste at 20"C in 5 cm3 of ethyl ether. After vacuumfiltration and washing with ether one recovers 0.425 g of product.

Analysis: C15H16N6O6S2, HCO2H Calculated: C% 39.50 H , 3.72 N% 17.27 Found: C39.48 H%3.71 N% 16.90 NMR spectrum (CD3)2SO

(a) singlet: 2 p.p.m.

(b) singlet: 3.83 p.p.m.

(c) singlet: 6.82 p.p.m.

(d) doublet: 5.45-5.55 p.p.m.

(e) doublet: 5.0W5.1 p.p.m.

The 7 - amino - 3 - acetamido - ceph 3 - em - 4 - carboxylic acid, in the form of the trifluoroacetate, was prepared as follows: A) Diphenylmethyl 7- [triphenylmethylamino] - 3 - amino - ceph - 3em - 4 - carboxylate.

One introduces 7.3 g of diphenylmethyl 7 - [triphenyl - methylamino] - 3 hydroxy - ceph - 3 - em - 4 - carboxylate, in an inert atmosphere, into 180 cm3 of absolute ethanol. One adds 3.1 g of pure ammonium chloride and 7.1 cm3 of pyridine. One agitates at 500C for 20 hours. The mixture is cooled poured into 500 cm3 of distilled water and extracted with methylene chloride.

One washes and brings to dryness One obtains 7.1 g of product which one purifies by chromatography on silica (eluants:benzene and ethyl acetate 8:2).

One recovers the fractions of Rf: 0.35 and obtains 3.1 g of purified product.

M.Pt.=255 C.

B) Diphenylmethyl 7- [triphenylmethylamino] - 3 - acetamido - ceph - 3 em - 4 - carboxylate.

One introduces 3.1 g of ester obtained in A into 100 cm3 of anhydrous benzene. One adds 1.41 cm3 of acetyl chloride and 2.13 cm3 of diisopropyl ethylamine. One agitates for 17 hours at 500C. One cools and washes the aqueous solution with sodium bicarbonate, then with water. The organic phase is evaporated and obtains 3.6 g of crude product which contains a mixture of ceph - 3 - eme and ceph - 2 - eme isomers.

To prepare these products one chromatographs on silica, eluting with a mixture of benzene and ethyl acetate (9: 1).

One recovers 2.259 g of expected ceph - 3 eme product. Rf=0.4. m.Pt.=180 C.

C) 7 - amino - 3 - acetamido - ceph 3 - em - 4 - carboxylic acid.

One dissolves in an inert atmosphere 2.21 g of product obtained at B in 17.5 cm3 of methylene chloride and 2.5 cm3 of anisole.

One cools to about 0 C and adds 17.5 cm3 of pure trifluoroacetic acid. One agitates for 30 minutes. One adds 50 cm3 of distilled water.

One extracts with ethyl acetate and brings to dryness. One obtains 0.953 g of expected product in the form of the trifluoroacetate.

Rf=0.35 (acetone and acetic acid 9:1) M.Pt.=2600C.

Example 7; One made up a preparation for injection of formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido] - 3 - chloro - ceph 3 - em - 4 - carboxylic acid, synisomer 500 mg Sterile aqueous excipient q.s.v. 5 cm3 Example 8: One made up a preparation for injection of formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido]- 3- methoxy ceph - 3 - em - 4 - carboxylic acid, syn isomer 500 mg Sterile aqueous excipient q.s.v. 5 cm3 Example 9: One made up gelatine capsules corresponding to the formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido] - 3 - chloro - ceph 3 - em - 4 - carboxylic acid, syn isomer 250 mg Excipient q.s. for one gelatine capsule up to 400 mg Example 10: One made up gelatin capsules corresponding to formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido]- 3- methoxy ceph - 3 - em - 4 - carboxylic acid, syn isomer 250 mg Excipient q.s. for one gelatin capsule up to 400 mg Example 11: One made up a preparation for injection of formula: 7 - [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido] - 3 - methylthio ceph - 3 - em - 4 - carboxylic acid, syn isomer 500 mg Sterile aqueous excipient q.s.v. 5 cm3 Example 12: One made up a preparation for injection of formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamidot - 3 - acetamido - ceph - 3 - em - 4 - carboxylic acid, syn isomer 500 mg Sterile aqueous excipient q.s.v. 5 cm Example 13: One made up gelatin capsules corresponding to the formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido] - 3 - methylthio - ceph - 3 - em - 4 - carboxylic acid, syn isomer 250 mg Excipient q.s. for one gelatin capsule up to 400 mg Example 14: One made up gelatin capsules corresponding to the formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido] - 3 - acetamido ceph - 3 - em - 4 - carboxylic acid. syn isomer 250 mg Excipient q.s. for one gelatin capsule up to 400 mg.

WHAT WE CLAIM IS:1. A compound of the general formula:

wherein R, represents a hydrogen atom or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, Ra represents a chlorine atom, a methoxy radical, and alkylthio radical having from 1 to 4 carbon atoms or a radical R,--COO-NNH- in which R4 represents an alkyl radical having from 1 to 4 carbon atoms, and A represents a hydrogen atom, an alkali-metal atom, an equivalent of an alkaline-earth metal atom, an equivalent of a magnesium atom, or an equivalent of an ammonium or a substituted ammonium group, the group ORt being in the syn position.

2. A compound of the general formula:

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

Claims

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

Example 8: One made up a preparation for injection of formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido]- 3- methoxy ceph - 3 - em - 4 - carboxylic acid, syn isomer 500 mg Sterile aqueous excipient q.s.v. 5 cm3 Example 9: One made up gelatine capsules corresponding to the formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido] - 3 - chloro - ceph

3 - em - 4 - carboxylic acid, syn isomer 250 mg Excipient q.s. for one gelatine capsule up to 400 mg Example 10: One made up gelatin capsules corresponding to formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido]- 3- methoxy ceph - 3 - em - 4 - carboxylic acid, syn isomer 250 mg Excipient q.s. for one gelatin capsule up to 400 mg Example 11: One made up a preparation for injection of formula: 7 - [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido] - 3 - methylthio ceph - 3 - em - 4 - carboxylic acid, syn isomer 500 mg Sterile aqueous excipient q.s.v. 5 cm3 Example 12: One made up a preparation for injection of formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamidot - 3 - acetamido - ceph - 3 - em - 4 - carboxylic acid, syn isomer 500 mg Sterile aqueous excipient q.s.v. 5 cm Example 13: One made up gelatin capsules corresponding to the formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido] - 3 - methylthio - ceph - 3 - em - 4 - carboxylic acid, syn isomer 250 mg Excipient q.s. for one gelatin capsule up to 400 mg Example 14: One made up gelatin capsules corresponding to the formula: 7- [2 - (2 - amino - thiazol - 4- yl)- 2 methoxyimino - acetamido] - 3 - acetamido ceph - 3 - em - 4 - carboxylic acid. syn isomer 250 mg Excipient q.s. for one gelatin capsule up to 400 mg.

WHAT WE CLAIM IS:1. A compound of the general formula:

wherein R, represents a hydrogen atom or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, Ra represents a chlorine atom, a methoxy radical, and alkylthio radical having from 1 to 4 carbon atoms or a radical R,--COO-NNH- in which R4 represents an alkyl radical having from 1 to 4 carbon atoms, and A represents a hydrogen atom, an alkali-metal atom, an equivalent of an alkaline-earth metal atom, an equivalent of a magnesium atom, or an equivalent of an ammonium or a substituted ammonium group, the group ORt being in the syn position.
2. A compound of the general formula:

in the form of the syn isomer, wherein R1 and A are as defined in Claim 1, and R represents a chlorine atom or a methoxy radical.
3. A compound of the general formula:

in the form of the syn isomer, wherein k1 and A are as defined in Claim 1, and R3 represents an alkylthio radical having from 1 to
4 carbon atoms or a radical R4-CO-NH, in which R4 represents an alkyl radical having from 1 to 4 carbon atoms. 4. A compound as claimed in any of the preceding claims, wherein R1 represents a methyl, ethyl, propyl, isopropyl, n-butyl, secbutyl, t-butyl, vinyl, propenyl, butenyl, ethynyl or propargyl radical.
5. A compound as claimed in any of the preceding claims, wherein A represents sodium, potassium, lithiums or ammonium, or an equivalent of calcium or magnesium, or A is derived from trimethylamine, triethylamine, diethylamine, methylamine, n-propylamine, N,N-dimethyl ethanolamine, tris(hydroxymethyl) - aminomethane, arginine or lysine.
6. A compound as claimed in Claim 3, wherein R1 represents a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, R3 represents a methylthio radical or an acetamido radical and A represents a hydrogen atom or a sodium atom.
7.7 -[2 -(2 -Amino - thiazol - 4 - yl) - 2- methoxyimino - acetamido]- 3methoxy - ceph - 3 - em - 4 - carboxylic acid, syn isomer, and its salts formed with alkali metals, alkaline-earth metals, magnesium, ammonia and organic amines.
8.7 -[2 -(2-Amino - thiazol - 4 - yl) - 2- methoxyimino - acetamido]- 3chloro - ceph - 3 - em - 4 - carboxylic acid, syn isomer, and its salts formed with alkali metals, alkaline-earth metals, magnesium, ammonia and organic amines.
9. 7 - [2 - (2 - Amino - thiazol - 4 - yl) 2- methoxyimino - acetamido] - 3 acetamido - ceph - 3 - em - 4 - carboxylic acid, syn isomer, and its salts formed with alkali metals, alkaline-earth metals, magnesium, ammonia and organic amines.
10. A process for preparing the compounds of general formula 1A wherein A represents a hydrogen atom, in which a compound of the general formula:

in the form of the syn isomer, (wherein Ra is as defined in Claim 1, R3 represents a group removable by acid hydrolysis or by hydrogenolysis or a chloracetyl group, R', represents a group removable by acid hydrolysis or by hydrogenolysis, a chloracetyl group or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms, with the proviso that when R', represents a chloracetyl group R2 also represents a chloracetyl group, and A' represents a hydrogen atom or an ester-forming group removable by acid hydrolysis or by hydrogenolysis) is treated with one or more appropriate agents selected from acid hydrolysis agents, hydrogenolysis agents and thiourea so as to obtain a compound of the general formula:

wherein Rl and Ra are as defined in claim 1.
11. A process as claimed in Claim 10, in which Ra represents a chlorine atom or a methoxy radical.
12. A process as claimed in Claim 10 or Claim 11, in which R', and/or R2 represents a t - butoxycarbonyl, trityl, benzyl, benzhydryl, trichloroethyl, benzyloxycarbonyl, formyl, trichloroethoxycarbonyl or 2 tetrahydropyranyl group.
13. A process as claimed in any of Claims 10 to 12, in which A' represents a benzhydryl, t - butyl, benzyl, p methoxybenzyl, or trichloroethyl radical.
14. A process as claimed in any of Claims 10 to 13, in which anhydrous trifluoroacetic acid, aqueous formic acid or aqueous acetic acid is used to eliminate a t butoxycarbonyl or trityl group present as substituent R't or R2, or to remove a benzhydryl, t - butyl or p - methoxybenzyl group present as substituent A'.
15. A process as claimed in any of Claims 10 to 13, in which a zinc/acetic acid system is used to eliminate a trichloroethyl group present as substituent R'l, R2 or A'.
16. A process as claimed in any of Claims 10 to 15, in which hydrogen in the presence of a catalyst is used to eliminate a benzhydryl or carbobenzyloxy group present as substituent R', or R2, or to remove a benzyl group present as substituent R'r, R2 or A'.
17 A process as claimed in any of Claims 10 to 16, in which a compound of general formula II wherein R2 represents a chloroacetyl radical and R' represents a chloracetyl radical or a saturated or unsaturated hydrocarbyl radical having from 1 to 4 carbon atoms is reacted with thiourea in a neutral or acidic medium.
18. A process as claimed in Claim 10, in which the starting material of general formula II is prepared by a process in which compound of the general formula:

(wherein Ra is as defined in Claim 1 and A' is as defined in Claim 10) is treated with an acid of formula:

in the form of the syn isomer (wherein R', and R2 are as defined in Claim 10) or a functional derivative thereof.
19. A process as claimed in Claim 18, in which Ra represents a chlorine atom or a methoxy radical.
20. A process as claimed in Claim 18 or Claim 19, in which the compound of general formula III is treated with a halide of the acid of general formula IV or with an anhydride of the acid of general formula IV formed with isobutyl chloroformate, the reaction being carried out in the presence of a base.
21. A process as claimed in Claim 20, in which the base is an alkali-metal carbonate, N-methyl-morpholine, pyridine or a trialkylamine.
22. A process as claimed in Claim 10 or Claim 18, in which the product of general formula IZA is salified to form the corresponding compounds of general formula 1A wherein A does not represent a hydrogen atom.
23. A process as claimed in Claim 22, in which Ra represents a chlorine atom or a methoxy radical.
24. A process as claimed in Claim 22 or Claim 23, in which a solvate of the compound of general formula 1,A is salified.
25. A process as claimed in Claim 22 or Claim 23, carried out in one or more solvents selected from water, diethyl ether, methanol, ethanol and acetone.
26. A process for preparing the compounds of general formula I as defined in claim 2, substantially as described hereinbefore with reference to any one of Examples 1 to 4.
27. A process for preparing the compounds of general formula I' as defined in claim 3, substantially as described herein with reference to either of Examples 5 and 6.
28. A compound of general formula I as defined in claim 2, whenever prepared by a process as claimed in any of Claims 11, 19, 23 and 26.
29. A compound of general formula I' as defined in claim 3, whenever prepared by a process as claimed in any of Claims 10, 18,
30. A/ pharmaceutical composition containing an active ingredient of one or more pharmaceutically-acceptable compounds of general formula 1A as defined in claim 1 in association with a pharmaceutically-acceptable vehicle.
31. A composition as claimed in Claim 30, in which the active ingredient is one or more compounds as claimed in any of Claims 2, 7 and 8.
32. A composition as claimed in Claim 30, in which the active ingredient is one or more compounds as claimed in any of Claims 3, 6 and 9.
33. A pharmaceutical composition substantially as described herein with reference to any of Examples 7 to 10.
34. A pharmaceutical composition substantially as described herein with reference to any of Examples 11 to 14.
35. A compound of general formula II as defined in claim 10, wherein Ra represents a chlorine atom or a methoxy radical.
36. A compound of general formula II as defined in claim 10, wherein Ra represents an alkylthio radical having from I to 4 carbon atoms or a radical R4-CO-NH- in which R4 is as defined in Claim 1.