FR2505338A1 - 3-Substd. thio-vinyl 1-oxa-ceph-3-em-4-carboxylic acid antibacterials - esp. having 7-2-2-amino-4-thiazolyl-2-methoxy:imino-acetamido Gp., 3-thio substits. include thiadiazolyl and triazinyl Gps. - Google Patents

Abstract

7-Beta-R1-NH 7-alpha-R2 3-SR-CH=CH- 1-oxa-ceph-3-em-4- carboxylic acid derivs. of formula (I), as the E or Z form or their mixtures, as the syn or antiform or their mixtures and their metallic salts, nitrogen-base addition salts and acid addition salts are new. In the formulae R is e.g. (1) 2-, 3- or 4-pyridyl including their N-oxides; (2) 2-pyrimidyl; (3) 6-methyl 3-pyridazinyl-1-oxide; (4) 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, substd. in position 4 by (a) 1-2C alkyl opt. substd. by alkoxy, alkylthio or formyl, (b) allyl, 2,3-dihydroxy-propyl, 1,3-dihydroxy-2- propyl or 2-formyl-2-hydroxy-ethyl, (c) 2-3C alkyl, substd. by hydroxy, carbamoyloxy, acyloxy or acylamino (the acyl gps. are opt. substd. by amino), alkylsulphonylamino ureido, alkylureido or dialkylureido; 1 are opt. substd. by formyl; 1-2C alkoxy; (10) (a) 1-alkyl-1,2,4-triazol-5-yl opt. substd. in position 3 by alkoxycarbonyl, where alkyl and alkoxy gps. are 1-2C or (b) 1-alkyl-1,3,4-triazol-5-yl; R1 is 3-amino-4-thiazolyl-C(=N -OR3)-CO-gp. (Gp. A) or R6-CH(COOH)-CO, R3 is H, alkyl, vinyl or -CR4R5-COOH; R4, R5 independently are H or alkyl or together are 2-3C alkylene; R6 is opt. para hydroxy substd. phenyl or 2- or 3-thienyl and R2 is H or methoxy. Unless specified alkyl or acyl gps. above are 1-4C, opt. branched. Antibacterials active against gram-positive and gram-negative bacteria. In vitro (I) are active at 1-15 microgram/cc against Staph.aureus Smith sensitive to penicillin G and at 0.01-1 microgram/cc against E.coli N1HJ, and in vivo against the same organisms (I) are active at 0.5-15 mg/kg s.c and 0.01-10 mg/kg s.c. respectively in mice. The s.c. LD50 in mice is 1.5-2.5 g/Kg.

Description

leur préparation et leur utilisation.The present invention relates to novel oxacephalosporins of the general formula

their preparation and use.

tdont la fonction amine est libre ou protégée et dans laquelle RO est un atome d'hydrogène, un radical protecteur, un radical alcoyle ou vinyle ou un radical carboxyalcoyle libre ou protégé représenté par la formule générale

dans laquelle les radicaux Ra et Rb, qui sont identiques ou différents, représentent des atomes d'hydrogène ou des radicaux alcoyle, ou forment ensemble un radical alcoylène contenant 2 ou 3 atomes de carbone7, ou
R4 représente un radical a-carboxyarylacétyle dont le groupement carboxy peut être libre ou protégé et dans lequel aryle représente phényle éventuellement substitué (par un radical p.hydroxy libre ou protégé) ou thiényle-2 ou -3, et le symbole R" représente un atome d'hydrogène ou un radical méthoxy en position 7a, ou bien b) le symbole R1 représente un radical protecteur facilement éliminable, le symbole R4 est un radical facilement éliminable, et le symbole R" est un atome d'hydrogène ou un radical méthoxy en 7a, ou un atome d'hydrogène en 7ss, et le symbole R2 représente un radical de formule générale:
O-SO2-R3 (IVa)
ou -OCO-R'3 (ive) sedans lesquelles R3 est un radical alcoyle1 tvrifluorométhyle, trichlorométhyle ou un radical phényle éventuellement substitué par un atome d'halogène ou par un radical alcoyle ou nitro, et R'3 est défini comme
R3 ou représente un radical acylméthyle, acyl-2 éthyle1 acyl-2 propyle, alcoyloxycarbonylméthyle, alcoyloxycarbonyl-2 éthyle ou alcoyloxycarbonyl-2 propyle] ou un atome d'halogène choisi parmi le chlore, le brome et l'iode.The products of general formula (I) are in the form of bicyclooctene-2 or -3 (according to the chemical nomenclature
Abstracts) and the substituent on the carbon atom at the 3-position of bicyclooctene has cis or trans stereoisomerism (hereinafter referred to as Z or E respectively), and a) the symbol R1 represents a hydrogen atom or a radical easily removable protector (for example methoxymethyl, t-butyl, benzhydryl, benzyl> p.nitrobenzyl or p.methoxybenzyl), the symbol R4 represents a hydrogen atom or a radical of general formula

wherein the amine function is free or protected and in which R 0 is a hydrogen atom, a protective radical, an alkyl or vinyl radical or a free or protected carboxyalkyl radical represented by the general formula

wherein the radicals Ra and Rb, which are the same or different, represent hydrogen atoms or alkyl radicals, or together form an alkylene radical containing 2 or 3 carbon atoms7, or
R4 represents an α-carboxyarylacetyl radical, the carboxy group of which may be free or protected and in which aryl represents optionally substituted phenyl (with a free or protected p-hydroxy radical) or thienyl-2 or -3, and the symbol R "represents a hydrogen atom or a methoxy radical at position 7a, or b) the symbol R1 represents an easily removable protecting radical, the symbol R4 is an easily removable radical, and the symbol R "is a hydrogen atom or a methoxy radical in 7a, or a hydrogen atom in 7ss, and the symbol R2 represents a radical of general formula:
O-SO2-R3 (IVa)
or -OCO-R'3 (ive) in which R3 is an alkyl trifluoromethyl, trichloromethyl or a phenyl radical optionally substituted by a halogen atom or by an alkyl or nitro radical, and R'3 is defined as
R 3 or represents an acylmethyl, 2-acylethyl 2-acylpropyl, alkyloxycarbonylmethyl, 2-alkyloxycarbonylethyl or 2-alkylpropylpropyl] or a halogen selected from chlorine, bromine and iodine.

 It is understood that the alkyl or acyl portions or radicals mentioned above (or which will be mentioned below) are (unless otherwise stated) straight or branched and contain 1 to 4 carbon atoms.

 It is also understood that the substituent in position (-3) of the products of general formula (I) may be in cis or trans form or as a mixture of cis and trans forms.

ou Ar Se- (IX) dans lesquelles le reste Ar est un radical alcoyle ou phényle ou phényle substitué par un ou plusieurs atomes d'halogène ou radicaux nitro ou alcoyle et n est égal à O ou 1, ou 5) tel que R4NH est remplacé par un radical diméthylaminométhylèneamino ou par un radical de formule générale
Ar' - CH = N - (x) dans laquelle Ar' est un groupe phényle éventuellement substitué par un ou plusieurs radicaux tels que méthode, nitro, alcoyle ou hydroxy.By easily removable radical R4 is meant a radical chosen from 1) benzhydryl or trityl, 2) an acyl radical of general formula
R5CO- (v) in which R5 represents
a) a hydrogen atom, an alkyl radical containing 1 to 7 carbon atoms, alkenyl containing 3 to 7 carbon atoms, cyanomethyl or halomethyl
b) a phenyl radical (which can be up to 3 times substituted by hydroxyl, nitro, cyano, trifluoromethyl, alkyl or alkyloxy radicals) or a thienyl-2 or -3 radical
c) a radical of general formula
Where R'5 is a radical as defined in b) and Y is a sulfur or oxygen atom
d) an arylalkyl radical of general formula:
R "5 CH 2 - (VIb) in which R" 5 is a pyhenyl radical (which can be up to 3 times substituted by hydroxy, alkyl or alkyloxy radicals) or a heterocyclyl radical such as thienyl-2 or -3 or furyl- 2 or 3) a radical of general formula
Wherein R 6 is an unsubstituted branched alkyl radical, a straight or branched alkyl radical bearing one or more substituents such as halogen atoms or cyano, phenyl or substituted phenyl radicals (by one or more halogen atoms or alkyl, alkyloxy, nitro or phenyl radicals), a trimethylsilyl-2 ethyl radical, a vinyl or allyl radical or a quinolyl radical, and 4) a radical of general formula

or Ar Se- (IX) wherein the radical Ar is an alkyl or phenyl radical or phenyl substituted by one or more halogen atoms or nitro or alkyl radicals and n is 0 or 1, or 5) such that R4NH is replaced by a dimethylaminomethyleneamino radical or by a radical of general formula
Ar '- CH = N - (x) in which Ar' is a phenyl group optionally substituted by one or more radicals such as method, nitro, alkyl or hydroxy.

 Furthermore, it is understood that the ORO group of the radical of general formula (II) may be in one of the syn or anti positions and that these isomers and their mixtures fall within the scope of the present invention.

The syn form can be represented by the formula

The anti form can be represented by the formula

 When R 4 represents a radical of general formula (II), among the preferred meanings of the symbol RO, mention may in particular be made of: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, vinyl, free or protected carboxymethyl, carboxy-2 free or protected propyl, or protective radical For example, selected from trityl, tetrahydropyranyl, 2-methoxy-2-propyl, alkyloxycarbonyl (such as t-butoxycarbonyl) or aryloxycarbonyl (such as benzyloxycarbonyl).

 When R contains a protected carboxy radical, the protective radical may be chosen for example from methoxymethyl, t-butyl, benzhydryl, benzyl-p-nitrobenzyl or p-methoxybenzyl.

 When R 4 is a radical of general formula (II) the amine function of this radical may be protected by a radical such as t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trichloroacetyl, trityl, benzyl> dibenzyl, benzyloxycarbonyl, p. nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, chloroacetyl, formyl or trifluoroacetyl.

 When R.sup.4 represents an α-carboxyarylacetyl radical whose carboxy group is protected, the latter may be protected by an acid-protecting radical, for example as mentioned above for RO.

 When R.sup.4 represents a p-hydroxyphenylacetyl α-carboxy radical whose hydroxy group is protected, the latter may be protected, for example, by an oxime-protecting radical as cited above for RO.

According to the invention, the products of general formula (I) in which R 1, R 2, R 4 and R "are defined as above, with the exception that R 4 represents a hydrogen atom, can be prepared by reacting an activated derivative of R3SO3H and R'3COOH acids of the type

(ou un mélange de ses isomères) dans laquelle,R' étant défini conne R1 précédemment en b), le produit se présente sous forme bicyclooctène-2 ou -3 ou oxoéthylidène-3 bicyclooctane et soit R'4 est défini comme R4 dans la formule générale (I) en a), étant entendu que lorsqu'il représente un radical de formule générale (II), l'amine de ce dernier est protégée, et R" est un atome d'hydrogène ou un radical méthoxy en position 7 , soit R' est défini comme R4 dans la formule générale (I) en b) et R"
4 est un atome d'hydrogène ou un radical méthoxy en 7a ou un atome d'hydrogène en 7ss, suivie éventuellement de l'élimination des radicaux protecteurs.<tb> (R3SO2) <SEP> (a)
<tb> R3S02Hal <SEP> (b) <SEP> (xI) <SEP>
<tb>(R'3C0)<SEP> 20 <SEP> (c)
<tb>R'3COHal<SEP> (d)
<tb> (R3 and R'3 being defined as above and Hal being a halogen atom), or a halogenating agent, on a product of general formula

(or a mixture of its isomers) wherein, R 'being defined as R1 previously in b), the product is in the form of bicyclooctene-2 or -3 or oxoethylidene-3 bicyclooctane and R'4 is defined as R4 in the general formula (I) in a), it being understood that when it represents a radical of general formula (II), the amine of this latter is protected, and R "is a hydrogen atom or a methoxy radical in position 7 or R 'is defined as R4 in the general formula (I) in b) and R "
4 is a hydrogen atom or a methoxy radical at 7a or a hydrogen atom at 7ss, optionally followed by removal of the protective radicals.

 When it is desired to use a product of general formula (XI) in which R '4 is a radical of general formula (II), the remainder R of which is a hydrogen atom, it is necessary to protect the oxime beforehand. .

 When it is desired to use an aldehyde of general formula (XI) in which R '4 contains a carboxy group, this radical may be free or protected if an activated derivative of R 3 SO 3 H or R' 3 COOH is activated; on the other hand, it is necessary to protect it beforehand if a halogenating agent is activated.

 When it is desired to use an aldehyde in which the radical R '4 is alpha-carboxy (p-hydroxyphenyl) acetyl, it is necessary to protect the hydroxyl radical.

 Radical protection is carried out under the conditions described above.

[dans laquelle X1, Y1 et Z1 représentent des radicaux alcoyle ou phényle, ou éventuellement deux d'entre eux forment un cycle avec l'atome d'azote auquel ils sont rattachés], par exemple la triéthylamine ou la NN-diméthylaniline,dans un solvant organique chloré (par exemple dichlorométhane), dans un ester (acétate d'éthyle), dans un éther (par exemple dioxanne, tétrahydrofuranne), dans un amide (par exemple diméthylacétamide, diméthylformamide), dans l'acétonitrile ou la N-méthylpyrrolidone ou dans un mélange de ces solvants, ou directement dans un solvant basique comme la pyridine, ou bien lorsque R2 est autre qu'un atome dthalogène, on peut opérer en milieu hydroorganique en présence d'un agent alcalin de condensation (par exemple bicarbonate alcalin, soude ou potasse), à une température comprise entre -78 C et la température de reflux du mélange réactionnel.It is generally carried out in the presence of a tertiary base as defined by the general formula

[in which X1, Y1 and Z1 represent alkyl or phenyl radicals, or optionally two of them form a ring with the nitrogen atom to which they are attached], for example triethylamine or NN-dimethylaniline, in a chlorinated organic solvent (for example dichloromethane), in an ester (ethyl acetate), in an ether (for example dioxane, tetrahydrofuran), in an amide (for example dimethylacetamide, dimethylformamide), in acetonitrile or N-methylpyrrolidone or in a mixture of these solvents, or directly in a basic solvent such as pyridine, or else when R2 is other than a halogen atom, it is possible to operate in a hydroorganic medium in the presence of an alkaline condensation agent (for example alkaline bicarbonate) sodium hydroxide or potassium hydroxide) at a temperature between -78 ° C. and the reflux temperature of the reaction mixture.

 Optionally, the operation is carried out under nitrogen.

 it is not absolutely necessary to have purified the intermediate of general formula (XI) to implement this reaction.

When it is desired to prepare a product of general formula (I) in which R 2 is a halogen atom, the halogenating agent may be chosen from halogenated derivatives of phosphorus, in particular - halogen addition compounds and triarylphosphite, or - phosphorus trichloride, phosphorus oxychloride,
phosphorus pentachloride, dichlorotriphenylphosphorane or
catechyltrichlorophosphorane when R2 is a chlorine atom, or - phosphorus tribromide, phosphorus oxybromide, phosphorus pentabromide or catechylbromophosphorane when R2 is a bromine atom.

 Eurehyltrichloro (or tribromo) phosphorane, which can be further prepared in situ, can be obtained according to the method described by H. GROSS and U. KARSH, J. Prakt. Chem., 29, 315 (1965).

The halogen and triarylphosphite addition compounds, which can be prepared in situ, are described by US Pat.
HN RYDON and BL SONGE, J. Chem. Soc., 3043 (1956), by
J. MICHALSKI et al., J. Org. Chem., 42, 3122 (1980) or in Belgian Patent 881,424 and may be prepared according to the methods mentioned in these documents.

The preparation of halogenated derivatives of genetically
general (I) is carried out in an anhydrous medium.

[dans laquelle R", R'4, R'1, et R2 étant définis comme ci-dessus, le produit présente la même isomérie que le produit de formule générale (I)] qui est ensuite déhydrohalogéné.When According is intended to prepare a product of general formula (I), in which B2 is a chlorine or bromine atom, depending on the operating conditions, it is possible to isolate the dihalogenated intermediate of general formula

[wherein R ", R'4, R'1, and R2 being defined as above, the product has the same isomerism as the product of general formula (I)] which is then dehydrohalogenated.

When it is desired to isolate the dihalogenated intermediate, the reaction is carried out by the action of a halogenating agent in an organic solvent such as a chlorinated solvent (for example dichloromethane, chloroform, carbon tetrachloride, dichloro-1, ethane). ). an ether (for example ethyl ether, propylene oxide, tetrahydrofuran, dioxane), an amide (for example dimethylscetamide, dimethylpropionamide, dimethylformamide, N-acetylmorpholine,
N-acetylpiperidine, N-methylpyrrolidone) or a mixture of these solvents, at a temperature slightly lower than that for separating the corresponding halogenovinyl derivative, that is to say between -78 and 30 C.

 it is also possible to operate in the presence of a base such as pyridine in a solvent mentioned above, b a temperature between -78 and OOC.

 The dehydrohalogenation is carried out in the presence of a tertiary base as defined above, an aromatic amine (for example pyridine, picoline, quinoline) or a mineral base (such as sodium hydroxide, potassium hydroxide, a carbonate or a alkaline or alkaline earth bicarbonate), in organic or hydroorganic medium in the solvents mentioned above, b a temperature of between -20 ° C. and the reflux temperature of the reaction mixture.

 It is not absolutely necessary to have purified the dihalogenated intermediate to prevent dehydrohalogenation.

 The elimination of the different protective radicals can be carried out simultaneously or successively.

For exemple,
The elimination of amine protecting groups takes place when it is a t-butoxycarbonyl, trityl, p-methoxybenzyloxycarbonyl or formyl radical: by treatment in an acidic medium. Preferably, trifluoroacetic acid is used at a temperature of between 0 ° and 20 ° C., or anhydrous or aqueous formic acid or para-toluenesulphonic or methanesulphonic acid in acetone or acetonitrile is used. at a temperature between 200C and the reflux temperature of the reaction mixture. In these circumstances when
R 4is a radical of general formula (II) the product of general formula (I) can be obtained in the form of trifluorecetate, solvate with formic acid, methanesulphonate or para-toluenesulphonate, the amine function of which can be released by any method known per se to obtain an amine from one of its salts without affecting the rest of the molecule. It is carried out in particular by placing in contact with an ion exchange resin or by the action of an organic base; when it is a 2,2,2-trichloroethoxycarbonyl or p-nitrobenzyloxycarbonyl radical: by reduction (in particular treatment with zinc in acetic acid) - when it is a chloroacetyl radical or trichloroacetyl by application of the method described in the French patent published under No. 2,243,199 - when it is a benzyl, dibenzyl or benzyloxycarbonyl radical: by catalytic hydrogenation - when it is a radical trifluoroacetyl: by treatment in a basic medium.

 2 / The elimination of the protective groups of the carboxy radical is effected - when it is a tert-butyl, methoxybenzyl or benzhydryl group: by tral tenierlt in acid medium, under the conditions described above for removal of the amino trityl protecting radical. In the case of the benzhydryl radical, it is possible to operate in the presence of anisole; in the case of a methoxymethyl group: by treatment in a dilute acidic medium; in the case of a p-nitrobenzyl group: by reduction (in particular treatment with zinc in acetic acid or by hydrogenolysis).

 3 / The elimination of the protective groups of the oxime or of the hydroxy radical is effected - when it is a trityl or tetrahydropyranyl group: by acidolysis, for example by trifluoroacetic acid, formic acid, aqueous or otherwise or para-toluenesulfonic acid - when it is the 2-methoxypropyl-2 group: according to the method described in Belgian Patent 875,379; in the case of the alkyloxycarbonyl or aryloxycarbonyl groups: according to the methods described in Belgian Patent 871,213.

dans laquelle R", R'1 et R'4 étant définis comme précédemment pour la formule générale (XII) (étant entendu que, le cas échéant, les radicaux amino et/ou carboxy contenus par R'4 sont protégéa), le produit se présente sous forme bicyclooctène-2 ou -3, le substituant sur l'atome de carbone en position -3 du bicyclooctène présente la stéréoisomérie E ou Z, et
R7 et K8 qui Soîit identiques ou différents représentent des radicaux alcoyle (éventuellement substitués par un radical alcoyloxy ou dialcoylamino) ou phényle, ou forment ensemble avec l'atome d'azote auquel ils sont rattachés un hétérocycle saturé à 5 ou 6 chaînons, contenant éventuellement un autre hétéroatome choisi parmi l'azote, l'oxygène ou le soufre et éventuellement substitué par un radical alcoyle.The products of general formula (XII) can be obtained by hydrolysis of the enamine (or of the mixture of isomeric 4namines) of general formula:

in which R ", R'1 and R'4 being defined as above for the general formula (XII) (it being understood that, where appropriate, the amino and / or carboxy radicals contained by R'4 are protected), the product is in the bicyclooctene-2 or -3 form, the substituent on the carbon atom at the 3-position of the bicyclooctene has E or Z stereoisomerism, and
R7 and K8 which are identical or different represent alkyl radicals (optionally substituted by an alkyloxy or dialkylamino radical) or phenyl, or together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle, optionally containing another heteroatom selected from nitrogen, oxygen or sulfur and optionally substituted by an alkyl radical.

 Preferably, a famine of general formula (XV) is hydrolysed in which R7 and R8 each represent a methyl radical.

 It is generally carried out in an organic acid (for example formic acid, acetic acid) or mineral acid (for example hydrochloric acid, sulfuric acid) in the presence or absence of a solvent, in an aqueous or organic medium, at a particular temperature of between -2 ° C. and the reflux temperature of the reaction mixture. When operating in an organic medium, the hydrolysis is carried out by adding water to the reaction mixture and then optionally treated with a mineral base (for example alkaline bicarbonate) or an organic base (for example tertiary amine or pyridine).

 When operating in the presence of a solvent, it is not necessary that the solvent is miscible with the acidic aqueous phase. The contact is then carried out by vigorous stirring.

 Among the solvents that may be used, mention may be made of chlorinated solvents, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide and alcohols. It is not absolutely necessary to have purified the intermediate of general formula (XV) to implement this reaction.

 When it is desired to obtain an aldehyde of general formula (XII) in which R '4 contains a free acid function, it is necessary to operate from an amine in which R' 1 and the protective group of the acid function of R'4 are different and selectively eliminable.

 The removal of the protective radical is carried out under the conditions described above.

The products of general formula (XV) can be obtained by the action of a product of general formula

dans laquelle R12 et R13 sunt définis corme R7 et soit encore Rg et R10 représentent chacun un radical de formule gjn- rale (XVIIb)] sur un dérivé d'oxacéphalosporine de formule générale

dans laquelle, R',R'1, et R'4 étant définis comme précédemment dans la fomule générale (XV), la produit se présente sous forme méthyl-3 bicyclooctène-2 ou -3 ou méthylène-3 bicyclooctane.optionally prepared in ai Lu, [for which R7 and R8 are defined
as before and Rg and R10 which are identical or different,
either represent groups of general formula
-X2 R11 (XVIIa) wherein X2 is an oxygen atom and R11 represents an alkyl or phenyl radical, or represents a radical of general formula (XVIIa) (wherein X2 represents an oxygen or sulfur atom and R 11 is alkyl or phenyl), and the other an amino group of the general formula

wherein R12 and R13 are defined as R7 and either R8 and R10 are each a radical of the general formula (XVIIb) on an oxacephalosporin derivative of the general formula

wherein, R ', R'1, and R'4 being defined as above in the general formula (XV), the product is in the form of 3-methyl-2-bicyclooctene or 3-methylene-3-bicyclooctane.

When a product of general formula (XVI) in which the radical (XVIIb) is different from -NR7R8 is chosen, it is preferable to choose such a product so that the ammine HNk12R13 is more volatile than HNR7R8,
We usually operate. in an organic solvent such as dimethyllormand or hexamethylphosphorotriamide, or in a mixture of solvents (for example dimethylamine tetrahydrofuran, dimethylformamide-dimethylacetamide, dimethylformamide-ether or dimethylformamide dioxane) at a temperature between 200C and the reflux temperature. of the reaction mixture.

 it is understood that when R'4 is a radical of general formula (II) in which R is a hydrogen atom, it is preferable that the oxime is protected under the conditions described above.

 It is also understood that when R'4 contains a hydroxy substituent, it is preferable to protect the latter.

 Protection and elimination of the protective radicals are carried out under the conditions described above.

 The products of general formula (XVI) can be prepared according to the methods described by H. BREDERECK et al., Chem. Ber. 41 (1968), Chem. Ber. 101, 3058 (1968) and Chem. Ber. 106, 3725 (1973).

dans laquelle R'l est défini comme précédemment et R1 > est un atome d'hydrogène ou un radical méthoxy en position 7a, en opérant par action d'un acide de formule générale
R'4 - OH (xx) dans laquelle R'4 est défini comme ci-dessus, ou d'un dérivé réactif de cet acide, en opérant dans les conditions décrites ci-après pour la préparation des produits de formule générale (I) au moyen d'un acide de formule générale (XXa) ou d'un de ses dérivés réactifs.The oxacéphalosporine derivatives of general formula (XVIII) in which R'4 represents a radical of general formula (II) or a radical &alpha; -carboxyarylacétyle whose amine and / or acid functions are protected can be prepared from the products of general formula

in which R'l is defined as above and R1> is a hydrogen atom or a methoxy radical in position 7a, acting by action of an acid of general formula
R'4-OH (xx) in which R'4 is defined as above, or a reactive derivative of this acid, under the conditions described below for the preparation of the products of general formula (I) using an acid of general formula (XXa) or a reactive derivative thereof.

 The conditions for deblocking the substituents are as previously described for the preparation of oxacephalosporins of general formula (I).

dans laquelle R" est défini comme précédemment par analogie avec les méthodes employées en chimie des cAphalo8porinea, et décrites par exemple par S. SEKI et coll., Tet. Lett., 33, 2915 (1977),
R.R. CHAUVETTE et coll., J. Org. Chem., 38 (17), 2994 (1973),
J.C. SHEEHAN et coll., J. Amer. Chem. Soc. 80, 1156 (1958),
E.H.FLYNN, Cephalosporins and Penicillins, Ac. Pressa (1972),
L. HORODER et coll., Hoppe Seyler's Z. Physiol. Chem. 357 1651 (1976),
J. UCI et coll., Angew. Chem. Int. Ed. Engl. 17 (5), 361 (1978),
Helv. Chim. Acta, 51, 924 (1968),
L. ZERVAS et coll., J. Amer. Chem. Soc., 85, 3660 (1963),
J.F. FITT, J. Org.Chem., 42 (15), 2639 (1977), ou dans le brevet belge 788 885 ou - lorsque R'4 est diphénylméthoxycarbonyle par action de l'azidoformiate correspondant en milieu hydroorganique, en présence d'un bicarbonate alcalin, - lorsque R'4 est quinolyl-8 oxycarbonyle ou allyloxycarbonyle: par action du carbonate correspondant en milieu hydroorganique basique, - lorsque R'4N11- est remplacé par nitro-4 benzylidèneamino ou diméthoxy-3,4 benzylidèneamino : selon la méthode décrite par R.A. SIRESTONE, Tetrahedron
Lett., 375 (1972).The oxacephalosporins of general formulas (XVIII) and (XIX) may be prepared according to the methods described in the literature, for example in Belgian patents 863,998 and 848,288, in US Pat. No. 4,108,992 or by Y. HAMASHIMA et al. , Tet. Let. 4,943 (1979), and by CL BRANCH et al., JCS Perkin I, 2,268 (1979) or from an oxacephalosporin of the general formula

in which R "is defined as above by analogy with the methods employed in the cephalosporein chemistry, and described for example by S. SEKI et al., Tet Lett., 33, 2915 (1977),
RR CHAUVETTE et al., J. Org. Chem., 38 (17), 2994 (1973),
JC SHEEHAN et al., J. Amer. Chem. Soc. 80, 1156 (1958),
EHFLYNN, Cephalosporins and Penicillins, Ac. Pressa (1972),
L. HORODER et al., Hoppe Seyler's Z. Physiol. Chem. 357, 1651 (1976),
J. UCI et al., Angew. Chem. Int. Ed. Engl. 17 (5), 361 (1978),
Helv. Chim. Acta, 51, 924 (1968),
L. Zervas et al., J. Amer. Chem. Soc., 85, 3660 (1963),
JF FITT, J. Org.Chem., 42 (15), 2639 (1977), or in Belgian Patent 788,885 or - when R'4 is diphenylmethoxycarbonyl by action of the corresponding azidoformate in hydroorganic medium, in the presence of an alkaline bicarbonate, when R'4 is 8-quinolyloxycarbonyl or allyloxycarbonyl: by the action of the corresponding carbonate in a basic hydroorganic medium, - when R'4N11- is replaced by 4-nitrobenzylideneamino or 3,4-dimethoxybenzylideneamino: according to the method described by RA SIRESTONE, Tetrahedron
Lett., 375 (1972).

obtenue selon la demande de brevet allemand 2 531 843.Oxacephalosporins of general formula (XXI) in which
R "is a methoxy radical at position 7a can be obtained by methoxylation of an oxacephalosporin of formula

obtained according to German Patent Application 2,531,843.

The products of general formula (XX) can be prepared by the method described in Belgian Patent 850,662, or by application of the method described in Belgian Patent 877,884, when R'4 is a radical of general formula (II) in where R is hydrogen or alkyl,
The products of general formula (xx) can be prepared according to the method described in Belgian Patent 869,079 when R'4 is a radical of general formula (II) in which R is vinyl.

 The products of general formula (xx) can be prepared according to the methods described in the Belgian patents 864 810, 865 298, 876 541 and 876 542 when R'4 is a radical of general formula (II) in which R is a substituent of general formula (III).

The products of general formula (XX) when R'4 is an α-carboxyarylacetyl radical, may be prepared according to the following methods: when the aryl group represents a phenyl or p-hydroxyphenyl group: by application of the methods described by D. IVANOV and G. VASSILEV
Compt. Makes. Acad. Bulgarian Sci., O, 3942 (1956) or in Belgian Patent 852,912.

when the group aryl represents a thienyl-2 group: according to
D. IVANOV and N. MAREKOV: Compt. Makes. Acad. Bulgarian Sci., 8 (11), 29 (1955).

when the aryl group represents a thienyl-3 group: according to British Patent 1,125,557.

According to the invention, the products of general formula (I) in which R1, R2 and R "are defined as previously in a) and
R4 is a hydrogen atom, can be obtained by removal of the protective radical R4 from a product of general formula (I) in which R1> R2 and R4 are defined as previously in b) and R "is located in position 7a ( or possibly by simultaneous elimination of the protective radicals R 1 and R 4 when it is desired to obtain a product of general formula (I) for which R 1 and R 4 are hydrogen atoms).

 The removal of the protective radical R4 is carried out by any known method to release an amine function without affecting the rest of the molecule.

 By way of example, the methods may be mentioned. R4 is trityl, benzhydryl, trichloroacetyl, chloroacyl, t-butoxycarbonyl, trichloroethoxycarbonyl, bensyloxycarbonyl, p-methoxybenzyloxycarbonyl and p-nitrobenzyloxycarbonyl: according to the methods mentioned above for the liberation of the amino radical from the product of the formula general (I) - when R4 represents formyl, 2-chloro-dimethyl-1, 1-ithoxycarbonyl, 2-cyano-dimethyl-1, 1-thoxycarbonyl, 3,5-dimethoxy-benzyloxycarbonyl, diphenylmethoxycarbonyl, (biphenylyl-4) -2-isopropyloxycarbonyl, vinyloxycarbonyl allyloxycarbonyl, 8-quinolyloxycarbonyl, o.nitrophinylthio, p.nitrophenylthio, and when R4NH- is replaced by dimethylaminomethyleneamino, 3,4-dimethoxybenzylideneamino or 4-nitro benzylideneamino: by hydrolysis in acidic medium; when R4 represents 2,2,2-trichloroethyl or 2,2,2-trichloro-1,1-dimethyl-ethoxycarbonyl by treatment with zinc in acetic acid, when R4 represents acetyl, benzoyl, phenylacetyl or phinoxyacetyl; : according to the method described in the Belgian patent BE 758 800 or according to the method described by YOSHIOKA, Tet. Letters 351 (1980), when R4 represents trimethylsilylethoxycarbonyl: according to the method described by Il. GERLACH, Helv. Chim. Acta 60 (8), 3039 (1977), when R4 represents p.nitrobenzyloxycarbonyl and benzyl: by hydrogenolysis in the presence of palladium.

 When R "is a methoxy group, the following methods may be used in preference to the preceding methods: 1) In the case where R 4 represents benzhydryl or trityl: hydrogenolysis in the presence of palladium.

2) In the case where R4 represents radicals of general formulas (VIII) or (IX): by the methods described by E. M. CORDON, J. Am. Chem. Soc.

102 (5), 1690 (1980); T. KOBAYASHI, Bull. Chem. Soc. Japan 52 (11), 3366 (1979) and T. KOBAYASHI, Chem. Pharm. Bull. 27, 2718 (1979).

3) In the case where R4 represents a radical of general formula (X): by treatment with Girard T reagent by analogy with the method described in Belgian Patent 863,998.

According to the invention, the products of general formula (I) in which R1, R2, R4 and R "are defined as previously in a) (except for R4 to represent a hydrogen atom) can also be obtained by action of an acid of general formula
R4-OH (XXa) 5 whose amino function is protected beforehand when R4 is a radical of general formula (II) 3, or by action of one of its reactive derivatives, on an amino-7 oxacephalosporin of general formula (I) in wherein R4 is a hydrogen atom and R1, R2 and R "are defined as in a), and optionally removal of the protective groups.

a) When the product of general formula (XXa) is used in acid form, the condensation of this product (the amine and / or oxime functions of which have previously been protected) on amino-7 is generally carried out. oxacéphalosporine of general formula (I) wherein R1 represents an easily removable protecting radical, operating in an organic solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane or chloroform, in the presence of a condensing agent such as a carbodiimide (for example dicyclohexylcarbodiimide), NN'-carbonyldiimidazole or 2-ethoxyethoxycarbonyl-1-dihydro-1,2-quinoline, at a temperature of between -20 and 40 ° C., and then the protective groups present in the If necessary, the reaction is carried out in the presence of a catalytic amount of N, N-dimethylamino-4-pyridine.

b) When using a reactive derivative of the acid of general formula (XXa), it is possible to use anhydride, a mixed anhydride or a reactive ester of general formula
R4-OZ (xXa ') wherein R4 is defined as above and Z is succinimido, benzotriazolyl-1, 4-nitrophenyl, 2,4-dinitrophenyl, pentachlorophenyl or phthalimido. When R4 is a radical of general formula (II), the amine function of such derivatives is protected beforehand (for example as described above). The protection conditions of the various substituents are as previously described.

 It is also possible to use a reactive derivative such as an acid halide. In the latter case, when R 4 is a radical of general formula (II), it is possible, for example, to react the hydrochloride of the acid chloride with the 7-aminocaacephalosporin of general formula (I), and when R 4 is a α-carboxy (p.hydroxyphenyl) acetyl radical, it is necessary to protect the hydroxy group.

 When using the anhydride, a mixed anhydride or an acid halide (which can be prepared in situ, the condensation is carried out in an inert organic solvent such as an ether (for example tetrahydrofuran or dioxane), an chlorinated solvent (for example chloroform or methylene chloride), an amide (for example dimethylformamide or dimethylacetamide) or a ketone (for example acetone), known in mixtures of the above solvents in the presence of an acid acceptor such as an epoxide (for example propylene oxide) or a nitrogenous organic base such as pyridine, dimethylaminopyridine, N-methyl-morpholine or a trialkylamine (for example triethylamine), or in a hydroorganic medium in the presence of an alkaline condensing agent such as sodium bicarbonate, and the operation is carried out at a temperature between -40 and + 400CI then the protective groups are eventually replaced by hydrogen atoms.

 When a reactive ester of general formula (XXa ') is used, it is generally carried out in the presence of a trialkylamine (for example triethylamine) in an organic solvent such as dimethylformamide at a temperature of between 0 and 400.degree. we replace the groups.

protectors by hydrogen atoms.

 If necessary, the elimination of the protective radicals can be carried out under the conditions described above.

dans laquelle le symbole R est choisi parmi les significations : 1) pyridyle-2,-3 ou -4 éventuellement N-oxydés 2) pyrimidinyle-2 3) méthyle oxyde-l pyridazinyle-3 4) dioxo-5,6 tétrahydro-1,4,5,6 triazine-1,2,4 yle-3 substitué en position -4 par
a) un radical alcoyle contenant 1 ou 2 atomes de carbone eventuellement substitué par un radical alcoyloxy, alcoylthio, formyle,
b) un radical allyle, dihydroxy-2,3 propyle, dihydroxy-1,3 propyle-2 ou fornyl-2 hydroxy-2 éthyle,
c) un radical alcoyle contenant 2 ou 3 atomes de carbone substitué par hydroxy, carbamoyloxy, acyloxy ou acylamino (dont les portions acyles Sont non substituées ou substituées par anino), alcoylsulfonylamino, uréldo, alcoyluréido ou dialcoyluréido.The new products of general formula (I) are useful as intermediates for the preparation of oxacephalosporins of general formula

in which the symbol R is chosen from the meanings: 1) pyridyl-2, -3 or -4 optionally N-oxidized 2) pyrimidinyl-2 3) methyl-1-oxide pyridazinyl-3 4) dioxo-5,6 tetrahydro-1 , 4,5,6 1,2,4-triazine-3-yl substituted in the -4 position by
a) an alkyl radical containing 1 or 2 carbon atoms, optionally substituted with an alkyloxy, alkylthio or formyl radical,
b) an allyl, 2,3-dihydroxypropyl, 1,3-dihydroxypropyl-2 or 2-fornyl-2-hydroxyethyl,
c) an alkyl radical containing 2 or 3 carbon atoms substituted by hydroxy, carbamoyloxy, acyloxy or acylamino (whose acyl portions are unsubstituted or substituted by anino), alkylsulphonylamino, ureldo, alkylureaido or dialkylureido.

5) dioxo-5,6 1,4,5,6-tetrahydro-1,2,4-triazine-1,3-yl-3-yl or 5,6-dioxo-1,2,5,6-tetrahydro-triazine-1, 2,4-yl-3 substituted in the -2 position by an alkyl radical containing 1 or 2 carbon atoms optionally substituted with a formyl radical 6) 2-alkyl-2,5-dihydro-5-oxo-1,2-triazin-1,2-yl 3 optionally substituted at position -6 by an alkyl, alkyloxy radical, the portions and alkyl radicals of which contain 1 or 2 carbon atoms; 7) amino-1-dihydro-1,2-oxo-2-pyrimidinyl-4 (8) -thiadiazol-1,3, 4-alkyl substituted 5-alkyl, dialkylaminoalkyl or acylaminoalkyl, or 9) 5-tetrazolyl substituted in the -1-position with
a) an alkyl radical containing 1 or 2 carbon atoms optionally substituted with a formyl radical,
b) an alkyl radical containing 2 or 3 carbon atoms gubstitu-by hydroxy, acylamino, or dialkylamino, or
c) with a 2,3-dihydroxypropyl or 1,3-dihydroxy-2-propyl 10) a) 1-alkyl-1,2,4-triazol-5-yl optionally substituted in the -3 position by an alkyloxycarbonyl radical whose radicals alkyl and alkyloxy contain 1 or 2 carbon atoms,
b) alkyl-1-triazol-1,3,4-yl-5, the symbol R 'represents a radical of general formula (II) in which R is a hydrogen atom, an alkyl, vinyl or carboxyalkyl radical as defined by the general formula (III) or represents a radical &alpha; -carboxyarylacetyl wherein aryl represents phenyl (optionally substituted by a p.hydroxy radical) or thienyl-2 or -3 and the symbol R "represents a hydrogen atom or a radical methoxy at 7a, and wherein the substituent at the -3 position is in E or Z forms.

zanis lesquelles alk est un radical alcoylène contenant 1 à 4 atomes de carbone, X&alpha; et Y&alpha; sont identiques et représentent des atomes d'oxygène ou de soufre, et R&alpha; repréaente un radical alcoyle, ou bien X&alpha; et Y&alpha;; sont identiques ou différents et représentent des stomes d'oxygène ou de soufre, et les radicaux R&alpha; forment ensemble un radical alcoylène contenant 2 ou 3 atomes de carbone], lorsque l'on veut obtenir une oxacéphalosporine de formule générale (XXIII) dans laquelle R contient un radical formyl sur un dérivé d'oxacéphalosporine (ou le cas échéant sur un mélange des isomères de ce dérivé) de formule générale (I) dans laquelle R1,
R2, R4 et t" sont définis comme précédemment en a), à l'exception pour
R4 de représenter un atome d'hydrogène, suivie éventuellement de l'élimination des radicaux protecteurs.The products of general formula (XXIII) can be obtained from the products of general formula (I) by operating as follows: The oxacephalosporins of general formula (XXIII) can be prepared by the action of a thiol of general formula
R-S11 (xxiv) (or an alkali or alkaline earth salt thereof) wherein R is defined as above [R being protected in the form of an acetal, in the form of a radical of the general formula

wherein alk is an alkylene radical containing 1 to 4 carbon atoms, X &alpha; and Y &alpha; are identical and represent oxygen or sulfur atoms, and R &alpha; represents an alkyl radical, or X &alpha; and Y &alpha;; are identical or different and represent oxygen or sulfur stomes, and the radicals R &alpha; together form an alkylene radical containing 2 or 3 carbon atoms], when it is desired to obtain an oxacephalosporin of general formula (XXIII) in which R contains a formyl radical on an oxacéphalosporine derivative (or, if appropriate, on a mixture of isomers of this derivative) of general formula (I) in which R1,
R2, R4 and t "are defined as previously in a), with the exception of
R4 represents a hydrogen atom, followed eventually by the elimination of the protective radicals.

 When the radical R of the product of general formula (xxiv) is capable of interfering with the reaction, it is preferable to protect this group (especially when R contains an amino, alkylamino, hydroxy or carboxy radical).

 The protection and the elimination of all these radicals are, for example, effected by one of the groups defined above and under the conditions described above.

 The 2,3-dihydroxypropyl or 1,3-dihydroxypropyl-2 radicals may be (or are) protected in the form of a 2,2-dimethyl-4-dioxolanylmethyl or 2,2-dimethyl-5-dioxanyl radical.

 When the radical R 'represents a group of general formula (II), the amino radical is free or protected, when R represents a hydrogen atom, the oxime is preferably protected and when R contains a carboxy group it is free or protected.

 When the radical R 'represents an α-carboxyarylacetyl group, it is preferable to protect the hydroxy radical when the aryl substituent represents p.hydroxyphenyl; the carboxy group can be free or protected.

 The operation is generally carried out in the presence of an organic base, such as a pyridine or a tertiary organic base of general formula (xiii) such as diisopropylethylamine or diethylphenylamine.

 When an alkali or alkaline earth salt of the thiol of general formula (XXIV) * is reacted, it is not necessary to operate in the presence of an organic base as defined above.

 The reaction is advantageously carried out in an organic solvent such as dimethylformamide, tetrahydrofuran or acetal nitrile or a mixture of the solvents mentioned above.

 it is also possible to operate in the presence of alkaline bicarbonate in a solvent as mentioned above, optionally in the presence of water.

It operates at a temperature between -200C and the
reflux temperature of the reaction mixture, the chosen temperature
being variable according to the thiol used. Similarly, according to the thiol used,
the reaction time can vary from 5 minutes to 48 hours.

 Optionally, the operation is carried out under nitrogen.

Preferably, when it is desired to use a 3-bicyclooctene
of general formula (I), it implements such a product for which
is other than hydrogen.

 The removal of the protective radical of R is carried out before, simultaneously with or after the removal of the other protective groups.

 When the 2,3-dihydroxypropyl or 1,3-dihydroxypropyl-2 radicals are protected in the form of cyclic acetals, the liberation of the protected radicals is carried out by acidolysis, for example with trifluoroacetic acid, aqueous or non-aqueous formic acid or p-toluenesulfonic acid. When aqueous or non-aqueous formic acid is used, the liberation of the protected hydroxy radicals in the cyclic acetal state can lead at least partially to the corresponding mono or diesters, which can be separated, if appropriate, by chromatography.

 The deblocking of the groups of general formula (XXVa or b) (when it is desired to obtain a product of general formula (XXIII) in which R contains a formylalkyl radical) is carried out in the presence of a sulphonic acid (for example methanesulphonic acid or p-toluenesulphonic acid in an organic solvent (for example acetonitrile or acetone), optionally in the presence of water and optionally in the presence of an acetalisable reactant such as acetone, glyoxylic acid, benzaldehyde or pyruvic acid; at a temperature between 200 ° C. and the reflux temperature of the reaction mixture, or else when the radical R is a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl radical; 3, by the action of aqueous formic acid (preferably containing less than 10% of water), either in the presence or absence of silica, or by transacetalization, the presence of an acetalisable reagent as defined above.

The thiols of general formula (XXIV), which can be used in their tautomeric form, can be prepared by applying one of the following methods according to the meaning of the radical R: when R is a pyridyl-3 radical: the method described by
HM WUEST and EH SAKAL, J. Am. Chem. Soc., 73, 1210 (1951), when R is a 1-oxide-3-pyridyl radical: according to the method described by B. BLANK et al., J. Med. Chem. 17, 1065 (1974), when R is a 1-oxide pyridyl-4 radical: according to the method described by RAY JONES et al., J. Chem. Soc. 2937 (1960).

when R is a 6-methyl-1-oxide-3-pyridazinyl radical: according to the method described in Belgian Pat. No. 787,635.

[dans lesquelles RY a la définition donnée ci-dessus en 1 ) et R$' est un substituant définici-dessus en 20)7,en présence d'un alcoolate alcalin, par exemple l'éthylate ou le méthylate de sodium ou le t.butylate de potassium, par application de la méthode décrite par M. PESSON et M.- when R is
10) a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 radical substituted in the 4-position with an R @ radical chosen from
a) an allyl radical, alkyl (1 or 2 carbon atoms), itself optionally substituted by an alkyloxy or alkylthio radical,
b) a 2,3-dihydroxypropyl or 1,3-dihydroxypropyl-2 radical (optionally protected in the form of a cyclic acetal)
c) an alkyl radical (2 or 3 carbon atoms) itself substituted [by hydroxy, carbamoyloxy, dialkylamino, alkyloylphonylamino, acylamino (optionally substituted), ureido, alkylureaido or dialkylureido]
d) a radical of general formula (XXVa) or (XXVb),
20) a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-substituted in the -1-position, or dioxo-5,6-tetrahydro-1,2,5,6-triatomine -1,2,4-yl-3substituted in position -2 by an alkyl radical containing 1 or 2 carbon atoms or by a radical of general formula (XXVa); by having an alkyl oxalate act on a thiosemicarba: ide of general formula
RY NH NH-NH 2 NH (XXXVIa)
H2N CS NH NH-RY '(XXVIb)

[in which RY has the definition given above in 1) and R 'is a substituent defined above in 20) 7, in the presence of an alkali alkoxide, for example sodium ethoxide or methoxide or t potassium butylate, using the method described by M. PESSON and M.

ANTOINE, Bull. Soc. Chim. France 1590 (1970).

 It is not absolutely necessary to purify the product obtained (or release the protected radicals) to implement it for the preparation of the products of general formula (XXIII).

 The thiosemicarbazide of general formula (XXVIa), (XXVIb) or (XXVIc) can be prepared according to one of the methods described by K.A.

Jensen et al., Acta Chem. Scand., 22, 1 (1968), or by application of the method described by Y. KAZANDV and J.Y. POTOVSKII, Doklady Acad. Nauk.

SSSR, 134, 824 (1960), it being understood that when Rr contains an amino radical, the latter is protected.

 The protrection of the amino radical and the elimination of the protective radical are carried out according to the usual methods which do not affect the rest of the molecule. In particular, the t-butoxycarbonyl group is used, which can be removed by acid hydrolysis.

When R is an alkyl-1-triazol-1,3,4-yl-5 radical: by application of one of the methods described by M. PESSON and M. ANTOINE, Bull. Soc.

Chim. France 1590 (1970).

When R is a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-radical substituted in the 4-position with acyloxyalkyl (optionally substituted): by acylation of the dioxo-5, 6-hydroxyalkyl-3-mercapto-1,4,5,6-tetrahydro-1,2,4 1,2,4-triazine, the mercapto radical of which was previously protected [for example according to CG KRUSE et al., Tet.

Lett. 1725 (1976) 7, by any known method for acylating an alcohol without touching the rest of the molecule, then release of the mercapto group in an acidic medium.

When R is an alkyl-2-dioxo-5,6-tetrahydro-1,2,5,6-triazine-1,2,4-yl-3-alkyl-1-triazol-1,2,4-yl or 1-alkyl-3-alkyloxycarbonyl-triazol -1,2,4 yl-5: according to the method described by M. PESSON and M. ANTOINE,
CR Acad. Sci., Series C, 267 (25), 1726 (1968).

When R is a 2-alkyl-2,5-dihydro-5-oxo-1,2,4-triazin-3-yl radical substituted at the -6-position with an alkyl or alkyloxy radical according to the method described in J. Antibiotics, 33, 783 (1980).

When R is a 1,2-amino-1,2-dihydro-2-oxo-4-pyrimidinyl radical: according to the method described in European Patent Application EP 00005.

When R is a 1,3,4-thiadiazol-5-radical optionally substituted by alkyl: according to the methods described in Belgian Patent 830,821.

- When R is a 1,3-thiadiazol-5-yl substituted by dialkylaminoalkyl according to the method described in German Patent Application 2,446,254.

When R is a thiadiazol-1,3,4-yl radical substituted by an acylaminoalkyl radical: according to the method described in Japanese Patent Application 76 80857.

- When R is a tetrazolyl-5-optionally substituted in position -1 by alkyl or hydroxyalkyl: according to the methods described in Belgian Patent 830 821.

- When R is a tetrazolyl-5 radical substituted in the -1 position by a dialkylaminoalkyl radical: by application of the method described in the German patent application 2,738,711.

When R is a tetrazolyl-5 radical substituted by an acylaminoalkyl radical: according to the method described in US Pat. No. 4,117,123.

Loraque R is a tetrazolyl-5 radical substituted in the -1 position by a 2,3-dihydroxypropyl radical: according to the method described in the patent
U.S. 4,064,242.

When R is a tetrazolyl-5-radical substituted in the -1-position with a 1,3-dihydroxypropyl-2-radical: by addition of sodium azide to a 2,2-dimethyl-1,3-dioxolane-1,3-isothiocyanate (possibly due to the release of the hydroxy groups).

- When R is a tetrazolyl-5 radical substituted in position -1 by a radical of general formula (XXVa): by action of sodium azide on the corresponding isothiocyanate, by analogy with the method described by RE ORTH, J. Pharm . Sci. 52 (9), 909 (1963).

dans laquelle R1, R4 et R" sont définis comme pour les produits de formule générale (I) en b) et R est défini comme précédemment.2 - Oxacephalosporins of general formula (XXIII) can also be obtained in the following manner
A thiol of general formula (XXIV), the radical R of which is optionally protected, or an alkali or alkaline earth salt thereof, is reacted with an oxacéphalosporine derivative (or optionally a mixture of bicyclooctene-2 isomers) and 3 of such a derivative) of general formula (I) in which R1, R2, R4 and R "are defined as previously in b), then the protective radicals of R are optionally removed to prepare a product of general formula

in which R1, R4 and R "are defined as for the products of general formula (I) in b) and R is defined as above.

 The reaction is generally carried out under the conditions described above for obtaining a 3-thiovinyl oxacephalosporin of general formula (XXIII) from a thiol of general formula (XXIV) and a product of general formula (I) ).

tdans laquelle R est défini comme précédemment, R" est soit un atome d'hydrogène ou un radical méthoxy en 7a, soit un atome d'hydrogène en 7ss et R1 est un atome d'hydrogène ou un radical protecteuXl, à partir d'un produit de formule générale (XXVII) par élimination du radical
R4 (ou éventuellement élimination successive ou simultanée des radicaux ou groupements protecteurs R4 et R1, lorsque l'on veut obtenir un produit de formule générale (XXVIII) dans laquelle R1 est un atome d'hydrogène.An amino-7 oxacephalosporin of general formula is prepared

in which R is defined as above, R "is either a hydrogen atom or a methoxy radical at 7a, or a hydrogen atom at 7ss and R1 is a hydrogen atom or a protecteuX1 radical, from a product of general formula (XXVII) by elimination of radical
R4 (or optionally successive or simultaneous removal of the radicals or protective groups R4 and R1, when it is desired to obtain a product of general formula (XXVIII) in which R1 is a hydrogen atom.

 The procedure is generally carried out under the conditions described above for obtaining a product of general formula (I) in which R 4 is a hydrogen atom.

When the radical R "of the product of general formula (XXVIII) is a hydrogen atom at 7B, and optionally when the radical
R "of the product of general formula (XXVIII) is a hydrogen atom at 7a, a product of general formula (XXVIII) is prepared by methoxylation in which R" is a methoxy radical at position 7.

 The methoxylation is carried out under the conditions described in the Belgian patents 871 213 and 863 998.

dans laquelle R est défini comme précédemment, R" est un atome d'hydrogène en position 7a et R1 représente un atome d'hydrogène ou un radical protecteur facilement éliminable, suivie de l'élimination des radicaux protecteurs.An oxacephalosporin of general formula (XXIII) is then prepared by the action of an acid represented by the general formula
R'-OH (xxIx) in which R 'is defined as precededentunent (it being understood that when R' is a radical of general formula (II), the amine function of this radical is protected) or a reactive derivative of this acid on an amino-7 oxacephalosporin of the general formula

wherein R is defined as above, R "is a hydrogen atom at position 7a and R1 represents a hydrogen atom or an easily removable protecting group, followed by removal of the protective groups.

- When R 'represents a radical of general formula (II), the acid of general formula (XXIX), in syn or anti form or mixtures thereof, respectively leads to the products of general formula (XXIII) of syn or anti form or their mixtures.

 It is understood that the oxime is protected when R represents a hydrogen atom.

 When R contains a carboxy radical, it is also protected.

When R 'represents an α-carboxyarylacetyl radical, the protection of the carboxy group is not mandatory; he can therefore be free or protected.

 It is the same for the hydroxy radical when the aryl group represents p.hydroxyphenyl.

- When B contains an amino or alkylamino substituent, this group is protected, and when it contains a hydroxy substituent, the latter is free or preferably protected.

 It is understood that the amino, alkylamino, carboxy and hydroxy groups which exist in certain radicals are (or may be) protected by any protective groups normally used for the protection of amines, carboxylic acids, alcohols or oximes and whose use does not alter the rest of the molicle.

 When it is desired to obtain a product of general formula (XXIII) in which R contains a formylalkyl radical, this radical may be protected in the form of an acetal in the form of a radical of general formula (XXVIa) or (XXVIb) .

 The reaction is carried out under the conditions described above for the acylation of the products of general formula (I) in which R 4 is a hydrogen atom.

 The removal of the protective radicals is carried out under the conditions described above.

 The isomers of the products of general formulas (I), (XII), (xIII), (XIV), (xv), (xvII), (xvIII), (XVIIIa) and (XIX) can be separated by chromatography or crystallization.

 The novel oxacéphalosporine derivatives of general formula (XXIII) and their pharmaceutically acceptable salts have particularly advantageous antibacterial properties. They exhibit remarkable in vitro and in vivo activity on Gram-positive and Gram-negative organisms.

In vitro, the products of general formula (XXIII) were reported to be active at a concentration of between 1 and 15 μg / cm.sup.3 on strains of penicillin G-sensitive Staphylococcus aureus (Smith), at a concentration of 0.01. and 1 pg / cm3 on
Escherichia coli strain NIHJ.

In vivo, the products of general formula (XXIII) have been shown to be active on experimental infections of the mouse with Staphylococcus aureus Smith (penicillin G sensitive) at a dose of between 0.5 and 15 mg / kg per day over the counter. -cutaneous, and to Escherichia coli (strain
NIHJ) at doses between 0.01 and 10 mg / kg per day subcutaneously.

 Furthermore, the LD50 of the products of general formula (XXIII) is between 1.5 g / kg and doses greater than 2.5 g / kg subcutaneously in mice.

 The following non-limiting example shows how the invention can be put into practice.

dans laquelle R" est en position 7a.In CH example, the products are listed according to the Chemical Abstracts nomenclature. It is understood that, in the absence of any particular mention, the oxacéphalosporine derivatives which are cited have the stereochemistry given by the partial general formula:

wherein R "is in position 7a.

EXAMPLE
2.51 g of 2-benzhydryloxycarbonyl-2-oxo-2-yl) -8-oxo-tritylamino-7-oxa-5-aza-1-bicyclo [4.2.0] octene-2 are dissolved in 20 cm 3 of pyridine. To the resulting solution was added 1.13 g of tosyl chloride and the mixture was stirred at 2000 for 1 hour 25 minutes.

The solution is poured into 150 cm3 of ice water, a gum is deposited on the walls of the container, the aqueous phase is decanted and the gummy substance is dissolved in 45 cm3 of ethyl acetate. The organic solution is washed with twice 50 cm 3 of a 0.1 N solution of hydrochloric acid, 50 cm 3 of a 5% solution of sodium bicarbonate and 30 cm 3 of a semisaturated solution of chloride. sodium chloride, dried over sodium sulphate, filtered and concentrated to dryness at 30 ° C. under reduced pressure (20 mm Hg;
2.7 kPa) 2.4 g of a crude brown product consisting essentially of 2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) -tritylamino-5-oxa-5-azabicyclo [4.2.0] octene are collected. -2, mixture of E and Z forms

Infrared spectrum (KBr), characteristic bands (cm 1)
1790, 1725, 1595, 1490, 1450, 1380, 1190, 1180, 745, 700.

Benzhydryloxycarbonyl-2 (oxo-2-ethyl) -3-oxo-8-trityl
amino-7-oxa-5-azabicyclo [4.2.0] octene-2 can be prepared in the following manner
A solution of 3.0 g of 2-benzhydryloxycarbonyl-2 (2-dimethylamino-vinyl) -8-oxo-tritylamino-7-oxa-5-aza-1-bicyclo [4.2.0] octene-2 forms
E, in 100 cm3 of ethyl acetate is stirred vigorously for 1 hour 30 to 20 C in the presence of 45 cm3 of a 1N hydrochloric acid solution.

The mixture is decanted and the organic phase is washed with 50 cm3 of a 5% solution of sodium bicarbonate and then with 50 cm3 of a half-saturated solution of sodium chloride. The ethyl acetate phase is dried over sodium sulfate, filtered and concentrated to dryness at 30 ° C. under reduced pressure (20 mm Hg, 2.7 kPa). 2.52 g of a crude product consisting mainly of 2-benzhydryloxycarbonyl-2-oxo-2-yl) -8-oxo-tritylamino-7-oxa-5-azabicyclo [4.2.0] octene-2 are obtained in the form a light brown meringue
Infrared spectrum (KBr), characteristic bands (cm-1) 1790, 1720, 1600, 1495, 1450, 1220, 750, 700.

3,81 (d, J - 3,5, 1H, H en 6) ; 3,92 et 4,12 (2d, J ^ 18, 2H, -CH2-O-) ; 4,35 (dd, J r 3,5 et 9, 1H, H en 7) : 6.80 (s, 1H, -COO-CH(C6H5)2) ; 9,49 (s, 1H,

Proton NMR spectrum (350 μM, CDCl 3, ppm, J: Hs): 3.37 and 3.50 (2d, J-16, 2H,

3.81 (d, J - 3.5, 1H, H at 6); 3.92 and 4.12 (2d, J18, 2H, -CH2-O-); 4.35 (dd, 3.5 and 9, 1H, H at 7): 6.80 (s, 1H, -COO-CH (C6H5) 2); 9.49 (s, 1H,

2-Benzhydryloxycarbonyl-2 (2-dimethylamino-vinyl) -8-oxo-tritylamino-5-oxa-4-azabicyclo [4.2.0] octene-2, Form E can be obtained as follows
A solution of 4.25 g of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-tritylamino-5-oxa-5-azabicyclo [4.2.0] octene-2 in 20 cm 3 of dimethylformamide is heated under nitrogen at 80 ° C. under nitrogen. To the solution kept stirring at 800 ° C., 1.55 cm3 of t-butoxybis-dimethylaminomethane is added dropwise during 7 minutes. When the addition is complete, the mixture is stirred at 80 ° C. for 17 minutes. The solution is diluted with 150 cm3 of ethyl acetate, the organic phase is washed with three times 60 cm3 of distilled water and 60 cm3 of a half-saturated solution of sodium chloride, dried over sodium sulfate, filter and concentrated to dryness at 30 ° C. under reduced pressure (20 mm Hg, 2.7 kFa). The residue is triturated in 150 cm3 of ethyl ether, the suspension obtained is filtered and the filtrate is concentrated to dryness at 30 ° C. under reduced pressure (20 mm of mercury, 2.7 kPa). a crude product consisting mainly of 2-benzhydryloxycarbonyl-2 (2-dimethylamino-vinyl) -3-oxo-8-tritylamino-5-oxa-4-azabicyclo [4.2.0 octene-2, form E used without further purification.

 Infrared spectrum (KBr), characteristic bands (cm-1): 1780, 1660, 1615, 1480, 1450, 745, 700.

Proton NMR Spectrum (350 MHz, CDCl3, 6 ppm, Js Hs) 2.77 (s, 6H, -N (CH3) 2); 3.71 (d, J - 3.5, 1H, H at 6); 4.12 and 4.53 (2d, J-17, 2H, -ch2-o-); 4.26 (mf, 1H, H at 7); 6.24 and 6.40 (24,
J - 13, 2H, -CHXCH-); 6.81 (s, 1H, -COO-CH (C6H5) 2).

7.74 g of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-tritylamino-7
oxa-5-azabicyclo [4.2.0] octene-2 are prepared according to a scheme of
synthesis described in US Patent 4,108,992 in which it replaces
t-butyl glyoxylate with benshydryl glyoxylate prepared according to
French Patent 1,495,047.

The expected oxacephalosporin is obtained in the form of a
white solid from 13.2 g of tritylamino-3 (propyn-2-yloxy) -4 oxo-2
axétidine.

Infrared Spactre (KBr). characteristic bands (cm-1):
3340, 1780, 1715, 1620, 1595, 1585, 1490, 1450, 1220, 745, 700.

Proton NMR spectrum (350 NHx, CDCl3, ppm, Nsr)
1.90 (s, 3H, -CH3); 3.75 (d, J - 3.5, 1H, H at 6); 3.87 and 4.08 (2d,
J - 18, 2H, -CH 2 -O-); 4.30 (d, J z 3.5, 1H, H at 7); 6.85 (s, 1H,
-COO-CH (C6H5) 2); 7.15 to 7.4 (mt, 26H, aromatics ee -HN-C (C6H5) 3)
SAMPLE REFERENCE
To a solution of 2.4 g of benzhydryloxycarbonyl-2 oxo-8
(2-toeoxy-vinyl) -3-tritylsmino-5-oxox-exe-1-bicyclo [4.2.0] octene-2
mixture of E and Z forms, in 15% dimethylformamide, 0.28 g of
sodium salt of 5-mercapto-2-methylthiadiaxole-1,3,4, the mixture is
stirred at 20 ° C. for 2 hours, then diluted with 50 cm3 of ethyl acetic acid
The solutou is washed with 5 times 50 cm3 of distilled water and 50 cml of a
semi-saturated solution of sodium chloride, then dried over
sodium.On filter and concentrated to dryness at 20 C under reduced pressure (20 mm
mercury; 2.7 kPa) The residue (2.1 g) is chromatographed on a Merck silica gel column (0.04-0.06) (column diameter, 4.1 cm, height, 20 cm). Catalytic cyclohexane-methyl acetate (70:30 vol) was eluted with 50 kPa pressure to collect 60 cc fractions. Fractions 9 and 10 are concentrated to dryness under
4 kPa) reduced pressure (30 mm Hg, at 30 ° C. 0.13 g of 2-benzhydryloxycarbonyl-2 - [(2-methylthisisol-1,3,4-yl) -5-thio-2-yl] -3-oxo are obtained. 8-tritylamino-5-oxa-5-aza-1-bicyclo [4.2.0] octene-2, E-form as a pale yellow meringue.

 Infra-red spectrum (KBr), characteristic bands (cm-1): 1790, 1720, 1490, 1450, 1210, 745, 700.

KMN spectrum of the proton (350 MHt, CDCl3, δ ppm, J hs) 2.74 (s, 3H, -CH3); 3.76 (d, J = 3.5, 1H, H at 6); 4.16 and 4.62 (2d,
JI 18, 2H, -CH2-0-); 4.37 (d, J - 3.5, 1H, H at 7); 6.84 (s, 1H, -COO-CH (C6H5) 2) 6.96 (d, J = 17, 1H, -CH = CH-S-).

0.12 g of 2-benzhydryloxycarbonyl [(methyl-2
thiadiazol-1,3,4-yl-5-thio-2-vinyl] -3-oxo-8-tritylamino-5-oxa-5-aza-1
bicyclo [4.2.0] octene-2, form E in 1.4 cm3 of acetone and 0.029 g of p-toluenesulphonic acid monohydrate is added to the solution. The solution is refluxed for 45 minutes during which crystals develop on the walls of the container. The suspension is filtered and the
The filtrate is poured into 10 cm3 of a 17% solution of sodium bicarbonate.
sodium. The mixture is extracted with twice 5 cm3 of ethyl acetate, the
organic phase is dried over sodium sulfate, filtered and concentrated
dry at 30 ° C. under reduced pressure (20 mm of mercury, 2.7 kPa).
thus 0.1 g of a crude brown solid consisting essentially of 7-amino
2-Benzhydryloxycarbonyl-2 - [(2-methyl-1,3-thiazolyl-5-yl) -2-thio-vinyl)
oxo-8 oxa-5-azabicyclo [4.2.0] octene-2, form B.

Rf ~ 0.20 [silica gel chromatoplate, eluent
cyclohexane-ethyl acetate 80-20 (by volume)).

 To a solution of 0.1 g of 7-amino-2-benzhydryloxycarbonyl-2 - [(2-methyl-thiadiazol-1,3,4-yl) -5-thio-2-vinyl] -3-oxo-5-oxa-1-axa-bicyclo [ 4.2.0] octene-2, form E in 20 cm3 of dichloromethane, 0.089 g of 2-methoxymino-2 (2-trityamino-4-thiazolyl) acetic acid, syn isomer, 0.041 g of N, N'-dicyclohexylcarbodiimide and 0.001 g of N, N-dimethylamino-4-pyridine. The mixture is stirred at 20 ° C. for 1 hour 30 minutes.

0.1 cm3 of acetic acid is then added; a slight insoluble material is removed by filtration, the filtrate is concentrated to dryness at 30 ° C. under reduced pressure (100 mm Hg) and the residue is dissolved in ethyl acetate (5 cc).

The solution is washed with 2 times 2.5 cm 3 of 0.1 N hydrochloric acid, then with 5 cm 3 of a 1% solution of sodium bicarbonate and with 5 cm 3 of distilled water. It is dried over sodium sulphate, filtered and concentrated to dryness at 30 ° C. under 20 mm of mercury (2.7 kPa). The residue (0.12 g) is fixed on 0.25 g of Merck silica gel (0.05-0.2) and the powder obtained is deposited on a column of 10 g of silica gel (column diameter : 1 cm).

50 cm.sup.3 (in volumes) of cyclohexane-ethyl acetate mixture are successively eluted with 70 cm.sup.3, a mixture of 40-60 and 30 cm.sup.3 of a 20-80 mixture is obtained, and fractions of 2 are collected. 5 cm3. The fractions 22 to 40 are concentrated to dryness at 200 ° C. under reduced pressure (20 mm of mercury, 2.7 kPa) and 0.023 g of 2-benzhydryloxycarbonyl [2-methoxyimino-2-trityamino-4-thiazolyl] acetamido is recovered. 7 [(2-methyl-thiadiazol-1,3,4-yl-5) -thio-2-vinyl [3-oxo-8] aza-1-bicyclo [4.2.0] octene-2 isomer syn, form E in the form of an orange meringue.

 Infra-red spectrum (KBr), characteristic bands (cm # 1795, 1720, 1685, 1520, 1495, 1450, 1210, 1045, 750, 700.

 Proton NMR Spectrum (350 MHz, CDCl3 · in ppm, J in Hz) 2.74 (s, 3H, -CH3); 4.07 (s, 3H, = N-O-CH 3); 4.59 and 4.86 (2d, J-18, 2H, -CH 2 -0-); 5.13 (d, J - 3.5, 1H, -H at 6); 5.81 (dd, J - 3.5 and 9, 1H, -H at 7); 6.78 (s, 1H, -H thiazole); 6.79 (d, J-9, 1H, -CO-NH-); 6.88 (s, 1H, -COO-CH (C6H5) 2); 7.03 (mf, 1H, -NH-C (C6H5) 3); 7.14 and 7.69 (2d, J = 17, 2H, -CH = CH-S-).

 To a solution of 0.023 g of 2-benzhydryloxycarbonyl {2-methoxy-imino-2- (2-trityamino-4-thiazolyl) -acetamido] -7 [(2-methyl-thiadiazol) -3,4-yl) -5-thio-vinyl] - 3 oxa-5 / aza-1 bicyclo [4.2.0] octene-2, syn isomer, form E, with 1 cm3 of formic acid, add 0.5 cm3 of distilled water and heat the mixture to 50 C under stirring for 20 minutes. After cooling, the insoluble material is filtered and concentrated to dryness at 30 ° C. under reduced pressure (20 mm Hg, 2.7 kPa). The residue is taken up twice with 15 cm3 of ethanol, each time dry concentrating at 20 ° C. under 20 mm of mercury (2.7 kPa) and the residue is triturated in 20 cm3 of ethyl ether.

After filtration, 0.010 g of [(2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -7-carboxy-2 - [(2-methyl-thiadiazol-1,3,4-yl-5) thio-2) is obtained after filtration. vinyl] -3-oxo-5-oxa-5-azabicyclo [4.2.0] octene-2, isomer yn, form E in the form of a yellow powder.

 Infrared spectrum (KBr), characteristic bands (cm-1): 1785, 1670, 1620, 1530, 1040.

 Proton NMR spectrum (350 MJ 2, DMSO d 6, ppm, J in Hz): 2.70 (s, -CH 3); 3.83 (s, = N-OCH3); 4.50 and 4.78 (2d, J = 18, -CH 2 -O-, 5.14 (d, J = 3.5, -H at 6), 5.45 (mf, -H at 7); 6.75 (s, -H thiol zole); 7.10 to 7.70 (mt, -NH 2 and -CH = CH-S-); 9.34 (d, J-9, -CO-NH-); ).

Claims (10)

R'3 is defined as R3 or represents an acylmethyl, 2-acylethyl, 2-acylpropyl, alkyloxycarbonylmethyl, 2-alkyloxycarbonylethyl or 2-alkoxycarbonylpropyloxy group, or a halogen atom, it being understood that the radicals and alkyl portions or acyls mentioned above are (except special mention) straight or branched and contain 1 to 4 carbon atoms, in its forms E or Z and mixtures thereof, and where appropriate in its syn on forms and their mixtures.  or -O-COR'3 Sedans in which R3 is a straight or branched alkyl radical containing 1 to 4 carbon atoms, trifluoromethyl, trichloromethyl, or phenyl which is unsubstituted or substituted by a halogen atom or by an alkyl or nitro radical, and  -O-S02R3 R4 represents an α-carboxyarylacetyl radical whose carboxy group may be free or protected and in which aryl represents phenyl (optionally substituted by a free or protected p-hydroxyl radical), or thienyl-2 or -3, and the symbol R "represents a hydrogen atom or a methoxy radical at position 7a, or b) the symbol R1 represents an easily removable protecting radical, the symbol R4 represents an easily removable radical, and the symbol R "is a hydrogen atom or a radical methoxy at 7a, or a hydrogen atom at 7ss and the symbol R2 represents a radical of general formula  wherein the radicals Ra and R which are the same or different represent hydrogen atoms or alkyl radicals, or together form an alkyl radical containing 2 or 3 carbon atoms7, or

 the amine function is free or protected and in which R "is a hydrogen atom, a protective radical, an alkyl, vinyl or free or protected carboxyalkyl radical represented by the general formula

 which is in the bicyclooctene-2 or -3 form and whose substituent at the -3 position has the E or Z stereoisomerism and wherein a) the R1 symbol represents a hydrogen atom or an easily removable protecting group, the R4 symbol represents a hydrogen atom or a radical of general formula

 1 - A new derivative of oxacephalosporin characterized in that it meets the general formula  2 - A novel oxacéphalosporine derivative according to claim 1, characterized in that R1 and R "being defined as in a) in claim 1, R4 is a radical of general formula

 wherein RO is defined according to claim 1, and wherein the amine function is previously protected by a t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trichloroacetyl, chloroacetyl, trityl, dibenzyl, benzyl> benzyloxycarbonyl, p nitrobenzyloxycarbonyl, p methoxybenzyloxycarbonyl, formyl or trifluoroacetyl, and R2 is defined as in claim 1.  3 - A novel oxacéphalosporine derivative according to claim 1 characterized in that, R1 and R "being defined as in a) in claim 1, R4 is a radical of general formula

 whose amine function is free or protected and in which R is a trityl group, tetrahydropyranyl or 2-methoxypropyl-2 protecting the oxime function, and R2 is defined as in claim 1.  4 - A novel oxacéphalosporine derivative according to claim 1 characterized in that, R1 and R "being defined as in a) in claim 1, R4 is a radical of general formula

 whose amine function is free or protected and in which R is a carboxyalkyl group represented by the general formula

 wherein R and Rb are as defined in Claim 12 protected by a radical selected from methoxymethyl, t-butyl, benzyldryl, beuzyl, p-nitrobenzyl and p-methoxybenzyl, and R2 is defined as in claim 1.  5 - A novel oxacéphalosporine derivative according to claim 1 characterized in that, R1 and R "being defined as in a) in claim 1, R4 is an α-carboxyarylacetyl radical whose carboxy group is protected by a radical selected from methoxymethyl, t-butyl, benzhydryl, benzyl, p-nitrobenzyl and p-methoxybenzyl.  6 - A novel oxacéphalosporine derivative according to claim 1 characterized in that, R2, R4 and R "being defined as in claim 1, the easily removable radical represented by R1 is chosen from methoxymethyl, t.butyl, benzhydryl radicals benzyl, p-nitrobenzyl and p-methoxybenzyl.  7 - A novel oxacéphalosporine derivative according to claim 1 characterized in that, R1 and R "being defined as in b) in claim 1, R4 represents an easily removable radical selected from 1) benzhydryl or trityl, 2) a radical acyl of general formula  R5COin which R5 represents  a) a hydrogen atom, an alkyl radical containing 1 to 7 carbon atoms, alkenyl containing 3 to 7 carbon atoms, cyanomethyl or almenomethyl  b) a phenyl radical (which can be up to 3 times substituted by hydroxyl, nitro, cyano, trifluoromethyl, alkyl or alkyloxy radicals) or a thienyl-2 or -3 radical  c) a radical of general formula  R'5 Y CH2 in which R'5 is a radical as defined in b) and Y is a sulfur or oxygen atom  d) an arylalkyl radical of general formula  Wherein R "is a phenyl radical (which may be up to 3 times substituted by hydroxy, alkyl or alkyloxy radicals) or a heterocyclyl radical such as thienyl-2 or -3 or furyl-2 or -3 3) a radical of general formula  Wherein R6 is an unsubstituted branched alkyl radical, a straight or branched alkyl radical bearing one or more substituents selected from halogen atoms or cyano, phenyl or substituted phenyl radicals (by one or more halogen atoms or alkyl, alkyloxy, nitro or phenyl radicals), a trimethylsilyl-2 ethyl radical, a vinyl or allyl radical or a quinolyl radical, and 4) a radical of general formula

 or Ar Sedans in which the radical Ar is an alkyl or phenyl radical or phenyl substituted by one or more halogen atoms or nitro or alkyl radicals and n is equal to O or 1, or 5) such that R4NH is replaced by a dimethylaminomethyleneamino radical; or by a radical of general formula  Wherein Ar 'is phenyl optionally substituted with one or more radicals selected from methoxy, nitro, alkyl or hydroxy.  8 - A process for preparing a product according to claim 1 wherein R1, R2, R4 and R "are defined as in claim 1 except for R4 to represent a hydrogen atom, characterized in that 'is made to act either an activated derivative of the acids R3SO3H and R'3 COOH, chosen from ::  (R3S02) 20  R3S02Hal  (R'3C0) 20  and R'3CO Hal (R3 and R'3 being defined as in claim 1 and Hal being a halogen atom) is a halogenating agent, on a product of general formula

 (or a mixture of its isomers), which is in the form of 2-or 3-bicyclooctene, or 3-oxoethylidene bicyclooctane, and wherein R'1 is an easily removable protecting radical, and R'4 is defined as R4 in claim 1 a) it being understood that when R'4 contains an amino radical the latter is protected, and R "is a hydrogen atom or a methoxy radical at 7a, or R'4 is defined as R4 in the claim 1 in b) and R "is a hydrogen atom or a methoxy radical in the 7-position or a hydrogen atom in the 7ss position, then the protective groups are optionally removed and the isomers optionally separated from the product obtained.  9 - A process for preparing a product according to claim 1, wherein R1> R2 and R "are defined as in claim 1 in a) and R4 is a hydrogen atom, characterized in that it eliminates the radical R4 or optionally in that the radical R4 and the radical R1 of a product according to claim 1, for which R1 and R4 are defined as in claim 1 in b), are removed simultaneously and the product is optionally separated. obtained in its isomers.  - A process for preparing a product according to claim 1 wherein R1, R2, R4 and R "are defined as in claim 1 in a), except for R4 to represent a hydrogen atom, characterized in that it is acylated by means of an acid represented by the general formula R 4 -OH (in which R 4 is defined as above and, where appropriate, the amine function is protected beforehand) or of one of its derivatives reagents an oxacephalosporin according to claim 1 for which R4 is a hydrogen atom, then the protective radicals are optionally removed and the product obtained is optionally separated into its isomers.