FR2469415A2 - 7-Amino-thiazolyl methoxy-imino acetamido 3-thio-vinyl-cephalosporin - antibacterials active against Gram negative and Gram positive bacteria - Google Patents

Abstract

3-Thiovinyl-cephalosporin of formula (I) having syn or anit, E or Z forms and their mixtures including their acid addition, metallic and N-base addition salts are new. In (I) R is e.g. alkyl, L-2-amino-2-carboxy-ethyl; phenyl; 2-, 3- or 4-pyridyl and their (N-oxides) 2-pyrimidinyl; 3-pyridazinyl substd. in position 6 and opt. N-oxidised or tetrazolo(4,5-b)pyridazin-6-cyl; 4) 1,4-dialkyl or 1-alkyl-5,6-dioxo 1,4,5,6-tetrahydro-1, 2,4-trazin-3-yl or 2-alkyl-5,6-dioxo-1,2,5,6-dioxi-1,2,5,6-tetrahydro-1,2,4-triazin-- 3-yl; 6) Ro is H, alkyl, vinyl or cyanomethyl; R1 is H or a group-CH(R2)(OOCR3) (easily removed by enzymes) (where R2=H or alkyl and R3= alkyl or cyclohexyl. The alkyl and acyl radicals above except where specifically specified are opt-branched and contain 1-4C atoms). (I) are a antibacterials active against gram-negative and gram-positive. In vitro tests show (I) are active against penicillin G sensitive Staph aireus (Staph aureus Smith) at 0.5-15 mg/cc and against penicillin G resistant strains (Staph. aureus MB 9) at 1-30 ug/cc. They are active against E. coli Monod at 0.001-ug/cc and against Kledsiella pneumonae at 0.06-30 ug/cc. Some cpds. are active against Proteus morganii (0.01-30ug/cc) and Enterobacter aerogenes (0.1-30ug/cc)sub-cultaneous LD50 of (I) in mice is 1.5-2.5 g/kg. Admin. may be oral, rectat, parenteral or topical.

Description

leurs sels,.leur préparation et les médicaments qui les contiennent.In the main patent have been described new thiovinyl-3 cephalosporins of general formula

their salts, their preparation and the medicines which contain them.

dans laquelle R" représente un atome d'hydrogène ou un radical alcoyle et R"' représente un radical alcoyle ou le radical cyclohexyle, étant entendu que les portions ou radicaux alcoyles ou acyles cités ci-dessus (ou qui seront cités ci-après) sont (sauf Invention spéciale) droits ou ramifiés et contiennent 1 à 4 atomes de carbone.In the general formula (I), the symbol R represents an alkyl, phenyl, thiadiazol-1,3,4-yl-5 (unsubstituted or substituted by alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, trifluoromethyl, alkyloxy, alkylthio, alkylsulphonyl, amino, alkylamino, dialkylamino, acylamino or carboxy), or tetrazolyl-5 (unsubstituted or substituted in the 1-position by an alkyl radical, hydroxyalkyl whose alkyl part contains 2 to 4 carbon atoms, alkyloxyalkyl, carboxyalkyl). sulfoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfamoylaminoalkyl or phenyl); the symbol R "represents a hydrogen atom or an alkyl radical, and the symbol R 'represents a hydrogen atom, or an easily removable enzymatically radical of general formula

in which R "represents a hydrogen atom or an alkyl radical and R"'represents an alkyl radical or the cyclohexyl radical, it being understood that the alkyl or acyl portions or radicals mentioned above (or which will be quoted below) are (except special Invention) 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 a mixture of cis and trans forms.

 In what follows, the trans stereoisomerism will be denoted by E and the cis stereoisomerism will be denoted by Z.

 Furthermore, it is understood that the OR "group 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

dans laquelle R" est défini comme précédemment, et dont la fonction amine est préalablement protégée (ainsi que l'oxime lorsque RO représente l'hydrogène), ou d'un dérivé réactif de cet acide sur une amino-7 céphalosporine de formule générale

dans laquelle R est défini comme précédemment, R1 représente un atome d'hydrogène, un radical de formule générale (II) ou un radical protecteur facilement éliminable, par exemple méthoxyméthyle, t.butyle, benzhydryle, p.nitrobenzyle, p.méthoxybenzyle, et n représente O ou 1, suivie de la réduction du sulfoxyde obtenu lorsque n = 1, puis de l'élimination des radicaux protecteurs.According to the main patent, the products of general formula (I) can be prepared by the action of an acid of general formula

in which R "is defined as above, and whose amine function is protected beforehand (as well as the oxime when RO represents hydrogen), or a reactive derivative of this acid on a 7-amino cephalosporin of general formula

in which R is defined as above, R1 represents a hydrogen atom, a radical of general formula (II) or an easily removable protecting group, for example methoxymethyl, t-butyl, benzhydryl, p-nitrobenzyl, p-methoxybenzyl, and n represents O or 1, followed by reduction of the sulfoxide obtained when n = 1, followed by elimination of the protective radicals.

 It is understood that the acid of general formula (III) in syn or anti form or mixtures thereof, respectively leads to products of general formula (I) of syn or anti form or mixtures thereof.

 When the acid of general formula (III) is used, protection of the amino group is carried out by any method known per se for blocking an amine function without affecting the rest of the molecule. It is necessary to use an easily removable group such as t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, chloroacetyl, trichloroacetyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl or p-methoxybenzyloxycarbonyl.

 When RO represents a hydrogen atom, the protection of the oxime can be carried out by any known method which does not alter the rest of the molecule. In particular, trityl or tetrahydropyranyl groups are used, which can be removed by acidolysis, for example with trifluoroacetic acid, aqueous or non-aqueous formic acid or para-toluenesulphonic acid. The elimination is carried out indifferently before, simultaneously with or after the other protective radicals.

 Generally the condensation of the product of general formula (III), whose acid function is free and whose amine function has been previously protected, on the amino-7 cephalo sporine of general formula (IV) in which, R and n being defined as above, R 1 represents a radical of general formula (II) or an easily removable protecting group such as methoxymethyl, t-butyl, benzhydryl, p-nitrobenzyl or p-methoxybenzyl, operating in an organic solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride or chloroform, in the presence of a condensing agent such as carbodiimide (for example dicyclohexylcarbodiimide), NN'-carbonyldiimidazole or ethoxy-2 ethoxycarbonyl-1 dihydro -1,2 quinoline, at a temperature between -20 and 400C, then reduces the oxide obtained when using a 7-amino cephalosporin of general formula (IV) in which n = 1, and eliminates the protective groups of the amine function and, where appropriate, the acid function.

 It is understood that when in the general formula (IV) the radical R contains a group capable of interfering with the desired reaction (amino or carboxy), it is preferable to protect the group by any method which is known per se and which does not does not alter the rest of the molecule.

 If it is an amino group, protection and elimination are effected by one of the methods described above for the amino radical of the acid of general formula (III).

 In the case of the carboxy group, the protection and elimination is carried out by one of the methods described above for the carboxy radical of the 7-amino cephalosporin of general formula (IV).

 It is also understood that when in the general formula (IV) the radical R contains a hydroxyl or sulfo group, it is preferable to use a product in the formula of which n = 0.

 The elimination of the protective radical of R is carried out after the reduction of the oxide, before, simultaneously with or after the elimination of the other protective radicals.

 The reduction of the S-oxide can be carried out under the conditions described in German Patent Application 2,637,176.

 Depending on the nature of the protective groups, the elimination can be carried out in a single step or in two steps, according to the usual methods.

By way of example 1 / When the protecting group of the amine function is a t-butoxycarbonyl, trityl or p-methoxybenzyloxycarbonyl radical, depending on the nature of the protective group for the acid function, the elimination is carried out
in a single step by treatment in acidic medium when
R 1 is t-butyl, p-methoxybenzyl or benzhydryl. Trifluoroacetic acid is preferably used at a temperature of between 0 and 200 ° C. (and, in the case of the benzhydryl radical, in the presence of anisole) or anhydrous or aqueous formic acid, or else when R 1 is t . In these conditions, the product of general formula (I) is obtained in the form of trifluoroacetate, of solvate with formic acid or of para-toluene sulphate, 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 operates in particular by placing in contact with an ion exchange resin or by the action of an organic base.

 in a single step by treatment in a dilute acid medium, when R 1 is the methoxymethyl group.

 by reduction (in particular treatment with zinc in acetic acid) and then removal of the protective radical of the amine function by treatment in an acid medium as previously, when R 1 represents the p-nitrobenzyl radical.

2 / When the protective group of the amine function is a p.nitrobenzyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl radical, depending on the nature of the protective group R1 the elimination is carried out:
by reduction (in particular treatment with zinc in acetic acid) followed by treatment in an acid medium, preferably with trifluoroacetic acid, anhydrous or aqueous formic acid or para-toluenesulphonic acid when the protective group R 1 is t. butyl, p-methoxybenzyl or benzhydryl, or followed by treatment in dilute acidic medium when R1 is a methoxymethyl radical.

 in a single step by reduction (in particular treatment with zinc in acetic acid) when the protective group R 1 is a p-nitrobenzyl radical.

3 / When the amine function is protected by a chloroacetyl or trichloroacetyl radical, depending on the nature of the protective group R1, the elimination is carried out:
according to the method described in French Pat. No. 2,243,199, when the protective group R 1 is a t-butyl, p-methoxybenzyl or benzhydryl radical (when R 1 represents the benzhydryl radical, the treatment with trifluoroacetic acid is preferably in the presence of anisole).

 by treatment in a dilute acidic medium followed by the treatment described in French Pat. No. 2,243,199, when the group R 1 is a methoxymethyl radical.

according to the method described in French Pat. No. 2,243,199, when the protective group R 1 is a p-nitrobenzyl radical 4 / When the amine function is protected by a benzyl, dibenzyl or benzyloxycarbonyl radical, depending on the nature of the protective group R1 the elimination takes place
by catalytic hydrogenation followed by treatment in an acid medium (for example with trifluoroacetic acid) when the protective group R 1 is a t-butyl, p-methoxybenzyl or benzhydryl radical, or followed by treatment in a dilute acid medium,
R1 is a methoxymethyl radical. (It is also possible to reverse the catalytic hydrogenation and acid treatment steps).

 - In a single step by catalytic hydrogenation, or in two stages by treatment with zinc in acetic acid and catalytic hydrogenation when the protective group R1 is a radical p. nitrobenzyl.

dans laquelle R" est défini comme ci-dessus et Z représente un radical succinimido, benzotriazolyl-l, nitro-4 phényle, dinitro-2,4 phényle, pentachlorophényle ou phtalimido, et dont la fonction amine a été préalablement protégée (par exemple par un groupement protecteur tel que ceux cités précédemment en A/). I1 est également possible de mettre en oeuvre un halogénure d'acide, par exemple le chlorure d'acide en faisant réagir le chlorhydrate du chlorure de l'acide de formule générale (III) sur l'amino-7 céphalosporine de formule générale (IV). B / When a reactive derivative of the acid of general formula (III) is used, it is possible to use anhydride, a mixed anhydride or a reactive ester of general formula

in which R "is defined as above and Z represents a succinimido, benzotriazolyl-1, 4-nitrophenyl, 2,4-dinitrophenyl, pentachlorophenyl or phthalimido radical, and whose amine function has been previously protected (for example by a protective group such as those mentioned above in A /). It is also possible to use an acid halide, for example the acid chloride, by reacting the hydrochloride of the acid chloride of the general formula (III ) on the 7-amino cephalosporin of general formula (IV).

 When the anhydride, a mixed anhydride or an acid halide (which can be prepared in situ) is used, the condensation is carried out in an inert organic solvent such as an ether (tetrahydrofuran or dioxane for example) , a chlorinated solvent (chloroform or methylene chloride, for example), an amide (dimethylformamide or dimethylacetamide for example) or a ketone (acetone for example), as well as mixtures of the above solvents, in the presence of an acceptor of acid such as an epoxide (for example propylene oxide) or a nitrogenous organic base such as pyridine, N-methylmorpholine or a trialkylamine (triethylamine for example), or in a hydroorganic medium in the presence of a alkaline condensation agent such as sodium bicarbonate, and one operates at a temperature between -40 and +400C, then reduced, if necessary, the S-oxide obtained, and one optionally replaces the protective groups with atom of hydrogen.

 When a reactive ester of general formula (seen) is used, it is generally carried out in the presence of a trialkylamine (triethylamine) in an organic solvent such as dimethylformamide at a temperature of between 0 and 400.degree. where appropriate, the S-oxide obtained and replacing the protective groups with hydrogen atoms.

dans laquelle, R , R1 et n étant définis comme précédemment, lorsque n = O le produit se présente sous forme bicyclooctène-2 ou -3 et lorsque n = 1 le produit se présente sous forme bicyclooctène-2 (selon la nomenclature des Chemical Abstracts), le substituant sur l'atome de carbone en position -3 du bicyclooctène présente la stéréoisomérie E ou Z,
R2 représente un atome d'hydrogène ou un radical protecteur du groupement amino, tel que défini précédemment et
R3 représente un radical de formule générale
SO2 - 3 (six)
ou - O - CO - R'3 (x) dans lesquelles R'3 est un radical alcoyle, trifluorométhyle, trichlorométhyle ou phényle substitué par un atome d'halogène, ou un radical alcoyle ou nitro, suivie de la réduction de l'oxyde obtenu (lorsque n = 1) puis éventuellement de l'élimination des radicaux protecteurs.According to the main patent, the products of general formula (I) can also be prepared by the action of a thiol of general formula
R - SH (vII) in which R is defined as above, on a cephalosporin derivative (or if appropriate on a mixture of the isomers of this derivative) of general formula

wherein, R, R1 and n being defined as above, when n = 0 the product is in the form of bicyclooctene-2 or -3 and when n = 1 the product is in the form of bicyclooctene-2 (according to the nomenclature of Chemical Abstracts ), the substituent on the carbon atom at the 3-position of the bicyclooctene has E or Z stereoisomerism,
R2 represents a hydrogen atom or a radical protecting the amino group, as defined previously and
R3 represents a radical of general formula
SO2 - 3 (six)
or - O - CO - R'3 (x) in which R'3 is an alkyl, trifluoromethyl, trichloromethyl or phenyl radical substituted by a halogen atom, or an alkyl or nitro radical, followed by the reduction of the oxide obtained (when n = 1) and eventually the elimination of protective radicals.

 It is understood that when the radical R of the product of general formula (VII) is likely to interfere with the reaction, it is necessary to protect this group under the conditions described above.

 It is also understood that when R represents hydrogen, it is necessary to protect the oxime under the conditions described above.

où 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. On utilise par exemple la diisopropyléthylamine, ou la diéthylphénylamine.The operation is generally carried out in the presence of an organic base, such as a pyridine or a tertiary organic base of the type

where 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, diisopropylethylamine or diethylphenylamine is used.

 The reaction is advantageously carried out in an organic solvent such as dimethylformamide, tetrahydrofuran or acetonitrile 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 or in a hydroorganic medium (dimethylformamide / water, tetrahydrofuran / water, acetonitrile / water, acetone / water for example).

 It operates at a temperature between -20 C and the reflux temperature of the reaction mixture, the chosen temperature being variable according to the thiol employed. Likewise, depending on the thiol employed, the reaction time may 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 (VIII), such a product is used for which
R1 is other than hydrogen.

 The reduction of the oxide and the elimination of the protective groups are carried out according to the methods described above.

 According to the main patent, the products of general formula (I) in which R 'represents a radical of general formula (II) in which R "and R"' are defined as above, can also be obtained by esterification of a product of formula general (I) wherein R 'represents a hydrogen atom and whose amine function has been previously protected, by any method known per se to prepare an ester from an acid without affecting the rest of the molecule.

dans laquelle R" et R"' sont définis comme précédemment et Z2 représente un atome d'halogène, dans un solvant inerte tel que le diméthylformamide, à une température comprise entre O et 300C. In general, an alkali metal salt or a tertiary amine salt of a product of general formula (I) as defined above, the amine function of which has previously been protected and, where appropriate, the radical R, is reacted. and oxime are also protected, on a product of general formula

wherein R "and R"'are defined as above and Z2 represents a halogen atom, in an inert solvent such as dimethylformamide, at a temperature between 0 and 300C.

 The products of general formula (XII) can be prepared according to the method described in German Patent Application 2,350,230.

 The products of general formula (III) can be prepared according to the method described in Belgian Patent BE 850 662.

(dans laquelle R et n sont définis comme précédemment, R'1 est défini comme R1, à l'exception de représenter l'hydrogène et R4 représente un radical facilement éliminable) par élimination du radical R4 ou éventuellement élimination simultanée des radicaux R4 et R'1 lorsque l'on veut obtenir un produit de formule générale (IV) dans lequel R1 est un atome d'hydrogène.The products of general formula (IV) can be obtained from a product of general formula

(in which R and n are defined as above, R'1 is defined as R1, with the exception of representing hydrogen and R4 represents an easily removable radical) by elimination of the radical R4 or optionally simultaneous removal of the R4 and R radicals When it is desired to obtain a product of general formula (IV) in which R 1 is a hydrogen atom.

By easily removable R4 radical is meant a benzhydryl or trityl radical, a 2,2,2-trichloroethyl radical, an acyl radical of general formula
R5 - CO - (xIv) (wherein R5 is a hydrogen atom or an alkyl radical (optionally substituted by one or more halogen atoms or by a phenyl or phenoxyl or phenyl radical), or a radical of general formula
Where R6 is a branched alkyl radical, a straight or branched alkyl radical (bearing one or more substituents chosen from halogen atoms, a cyano, trialkylsilyl, phenyl or substituted phenyl radical) (R 6 O CO - (xv) 6 by one or more alkyloxy, nitro or phenyl)), vinyl, allyl or quinolyl, 7 or nitrophenylthio radicals.

In addition, the radical R 4 NH-may be replaced by a methyleneimino radical in which the methylene radical is substituted by a dialkylamino or aryl group (the latter optionally substituted with one or more methoxy or nitro radicals).

Examples of radicals R4 that may be used include the following radicals formyl, acetyl, chloroacetyl, trichloroacetyl, phenylacetyl, phenoxyacetyl, benzoyl, t. 2-Butoxycarbonyl 2-chloro-1,2-dimethyl-1,2-trichloro-2,2,5-trichloroethoxycarbonyl 2,2,2-trichloro-2,2-dimethyl-1-ethoxycarbonyl 2-cyano-dimethyl-1-ethoxycarbonyl 2-trimethylsilyl ethoxycarbonyl benzyloxycarbonyl p.methoxybenzyloxycarbonyl dimethoxy-3 Benzyloxycarbonyl; nitrobenzyloxycarbonyl diphenylmethoxycarbonyl (biphenylyl-4) -2 isopropyloxycarbonyl vinyloxycarbonyl allyloxycarbonyl-8-quinolyloxycarbonyl o. nitrophenylthio p.nitrophenylthio
Examples of methyleneimino radicals that may be mentioned are 3-thylaminomethyleneimino-3,4-dimethoxybenzylideneimino-4-nitro benzylideneimino.
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, mention may be made of the following methods - when R 4 represents trityl, benzhydryl, trichloroacetyl, chloroacetyl, t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p. methoxybenzyloxycarbonyl and p.nitrobenzyloxycarbonyl, according to the methods mentioned above for the liberation of the amino radical of the product of general formula (I), - when R4 represents formyl, 2-chloro-1,1,1-dimethyl ethoxyearbonyl, 2-cyano dimethyl -1,1-Etoxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, (4-biphenyl) -2-isopropyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 8-quinolyloxycarbonyl, o-nitrophenylthio, p-nitrophenylthio, and when R4NH-is replaced by dimethylaminomethyleneimino, 3,4-dimethoxybenzylideneimino or 4-nitro benzylideneimino, by hydrolysis in acidic medium, - when R4 represents 2,2,2-trichloroethyl or 2,2,2-trichloro-1,1-dimethylethoxycarbonyl, by treatment with zinc in acetic acid, - when R4 represents acetyl, benzoyl, phenylacetyl or phenoxyacetyl, according to the method described in Belgian Patent BE 758,800, - when R4 represents trimethylsilylethoxycarbonyl the, according to the method described by H. GERLACH, Helv. Chim. Acta 60 (8), 3039 (1977), when R4 represents p.nitrobenzyloxycarbonyl, by hydrogenolysis in the presence of palladium.

dans laquelle, R'1, R3, R4 et n étant définis comme précédemment, lorsque n = O le produit se présente sous forme bicyclooctène-2 ou -3, lorsque n = 1 le produit se présente sous forme bicyclooctène-2 et le substituant sur l'atome de carbone en position -3 du bicyclooctène présente la stéréoisomérie E ou Z.The products of general formula (XIII) may be obtained by the action of a thiol of general formula (VII), the radical R of which is optionally protected, on a cephalosporin derivative or, where appropriate, on a mixture of isomers of the derivative of general formula

wherein, R'1, R3, R4 and n being defined as above, when n = 0 the product is in the form of bicyclooctene-2 or -3, when n = 1 the product is in the form of bicyclooctene-2 and the substituent on the 3-carbon atom of bicyclooctene has E or Z stereoisomerism.

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

 The thiols of general formula (VII) can be obtained by applying one of the following methods, depending on the meaning of the radical R - when R is a 1,3,4-thiadiazolyl radical optionally substituted by alkyl, alkyloxy, alkylthio, alkylsulphonyl, amino, alkylamino, dialkylamino or acylamino, according to the methods described in Belgian Patent 830,821, when R is a thiadiazol-1,3,4-yl-5 radical substituted with hydroxyalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl. the method described in German Patent Application 2,446,254, when R is a 1,3-carboxyalkyl-substituted thiadiazol-1-yl radical, by the method described in German Patent Application No. 1,953,861. when R is a 1,3,4-trifluoromethyl-substituted thiadiazol-5-radical, according to the method described in German Patent Application No. 2,162,575, when R is a 1,3,4-thiadiazol radical; substituted yl-5 with a carboxy radical, according to the method described in Japanese Patent Application 77 48666, when R is a tetrazolyl-5 radical optionally substituted in position -1 by alkyl, hydroxyalkyl or phenyl, according to the methods described in Belgian Patent 830,821. when R is a 5-tetrazolyl radical substituted in the 1-position by alkyloxyalkyl, by adding sodium azide to an isothio cyanatoalkylalkylalkyl by operating in an organic solvent such as ethanol, at the reflux temperature of the reaction mixture.

 Isothiocyanatoalkyloxyalkyl can be obtained by application of the method described by E. SCHMIDT et al., Chem. Ber.

73, 286 (1940).

when R is a tetrazolyl-5 radical substituted in the 1-position with a carboxyalkyl radical, according to the method described in Belgian Patent 858,112, when R is a tetrazolyl-5 radical substituted in the -1 position by a sulfoalkyl radical, according to the method described in Belgian Patent 856,498 or described by DA BERGES et al., J. Het.Chem. 15, 981 (1978),
when R is a tetrazolyl-5 radical substituted in the -1-position by an aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl radical, by application of the method described in the German patent application DE No. 2,738,711, when R is a substituted tetrazolyl-5 radical; in position -1 with a sulfamoylaminoalkyl radical, according to the method described in Belgian Patent 856 636.

{dans laquelle, n et R'1 étant définis comme précédemment, lorsque n = O le produit se présente sous forme bicyclooctène-2 ou -3 ou oxoéthylidène-3 bicyclooctane et lorsque n = 1 le produit se présente sous forme bicyclooctène-2 ou oxoéthylidène-3 bicyclooctane et R'4 représente un radical de formule générale

dans laquelle R est défini comme précédemment et R'2 est défini comme R2 > àl l'exception de représenter l'hydrogène, ou R'4 représente un radical R4 tel que défini précédemment}, suivie éventuellement de la réduction du sulfoxyde obtenu et éventuellement de l'élimination des radicaux protecteurs de la fonction amine et de la fonction acide (lorsque l'on veut obtenir un produit de formule générale (VIII) pour lequel R1 et/ou R2 sont hydrogène).The products of general formulas (VIII) and (XVI) may be prepared by the action of an activated derivative of R'3SO3H acids and
R'3 COOH (see formulas (IX) and (X)]. like
(R'3502) 2 O (xvII)
R'3 S02 Hal (xvIII)
(R'3CO) 2 O (XIX)
R'3CO Hal (xx) {in these formulas R'3 is defined as above and Hal represents a halogen atom), on a product (or a mixture of isomers) of general formula

wherein n and R'1 being defined as above, when n = 0 the product is in the form of bicyclooctene-2 or -3 or oxoethylidene-3-bicyclooctane and when n = 1 the product is in the form of bicyclooctene-2 or 3-oxoethylidene bicyclooctane and R'4 represents a radical of general formula

in which R is defined as above and R'2 is defined as R2> with the exception of representing hydrogen, or R'4 represents a radical R4 as defined above}, optionally followed by the reduction of the sulfoxide obtained and optionally elimination of the protective radicals of the amine function and the acid function (when it is desired to obtain a product of general formula (VIII) for which R 1 and / or R 2 are hydrogen).

 It is understood that when R'4 is a radical of general formula (xxii) in which R is hydrogen, it is necessary to protect the oxime. The protection and the release are carried out according to the methods described above.

The operation is generally carried out in the presence of a tertiary base as defined by formula (XI), for example triethylamine or
N, N-dimethylaniline in a chlorinated organic solvent (methylene chloride for example), in an ether (dioxane, tetrahydrofuran, for example), in an amide (dimethylacetamide, dimethylformamide), in acetonitrile or N-methylpyrrolidone, or directly in a basic solvent such as pyridine at a temperature between -78 C and the reflux temperature of the reaction mixture.

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

 Where appropriate, the removal of the protective radicals from the amine function and the acid function is carried out according to the methods described above for obtaining the product of general formula (I).

dans laquelle, R1, R3 et n étant définis comme précédemment, lorsque n = O le produit se présente sous forme bicyclooctène-2 ou -3, lorsque n = 1 le produit se présente sous forme bicyclooctène-2 et le substituant sur l'atome de carbone en position -3 du bicyclooctène présente la stéréoisomérie E ou Z, ou le cas échéant sur un melange des isomères de ce produit, suivie éventuellement de la réduction de l'oxyde obtenu, puis éventuellement de l'élimination des radicaux protecteurs.The products of general formula (VIII) may also be obtained by the action of an acid of general formula (III), the amine function of which is protected beforehand or by the action of one of its reactive derivatives, on a product of general formula

wherein, wherein R1, R3 and n are defined as above, when n = O the product is in the form of bicyclooctene-2 or -3, when n = 1 the product is in the form of bicyclooctene-2 and the substituent on the atom of carbon in the 3-position of the bicyclooctene has the stereoisomerism E or Z, or if appropriate on a mixture of isomers of this product, optionally followed by the reduction of the oxide obtained, then optionally the elimination of the protective radicals.

 The reaction is carried out under the conditions described above for the action of an acid of general formula (III) on a 7-amino cephalosporin of general formula (IV).

 If necessary, the reduction of the oxide and the elimination of the protective radicals can be carried out under the conditions described to obtain the product of general formula (I).

 The product of general formula (XXIII) can be obtained by removal of the protective radical R4 from a product of general formula (XVI), or optionally by simultaneous removal of radicals R4 and R'1 when it is desired to obtain a product of formula general (XXIII) wherein R4 is hydrogen.

 It is generally carried out under the conditions described above for obtaining a product of general formula (IV) from a product of general formula (XIII).

dans laquelle, R'1 et R'4 étant définis comme précédemment, le produit se présente sous forme bicyclooctène-2 ou -, et le substituant sur l'atome de carbone en position -3 du bicyclooctène présente la stéréoisomérie E ou Z, et
R7 et R8 qui sont identiques ou différents représentent des radicaux alcoyle (éventuellement substitués par un radical hydroxy, alcoyloxy, amino, alcoylamino 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 (XXI), in which n is 0, can be obtained by hydrolysis of the enamine (or mixture of isomeric enamines) of general formula

wherein, R'1 and R'4 being defined as above, the product is in the form of bicyclooctene-2 or -, and the substituent on the carbon atom at the 3-position of the bicyclooctene has E or Z stereoisomerism, and
R 7 and R 8, which are identical or different, represent alkyl radicals (optionally substituted by a hydroxy, alkyloxy, amino, alkylamino or dialkylamino radical) or phenyl, or together with the nitrogen atom to which they are attached form a saturated heterocycle with 5 or 6-membered, optionally containing another heteroatom selected from nitrogen, oxygen or sulfur and optionally substituted by an alkyl radical.

 An enamine of general formula (XXIV) in which R7 and R8 are each methyl is preferably hydrolyzed.

 It is generally carried out in an organic acid (formic acid, acetic acid for example) or mineral (hydrochloric acid, sulfuric acid for example) in the presence or absence of a solvent, in aqueous or organic medium, at a temperature between -20 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 (alkaline bicarbonate) or organic (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 (XXIV) to carry out this reaction.

 The products of general formula (XXI) in which n is equal to 1, can be obtained by oxidation of the products of general formula (XXI) for which n is equal to O by application of the method described in German patent application DE 2 637,176.

 Similarly, the products of general formulas (IV), (VIII), (XIII), (XVI) or (XXIII) in which n is equal to 1 can be obtained respectively by oxidation of the products of general formulas (IV), (VIII ), (XIII), (xvi) or (xxIII) in which n is equal to O by application of the method described in German Patent Application DE 2,637,176.

éventuellement préparé in situ, {pour lequel R7 et R8 sont définis comme précédemment et Rg et R10, qui sont identiques ou différents, soit représentent des groupements de formule générale
-X2 R11 (xxvI) dans laquelle X2 est un atome d'oxygène et R11 représente un radical alcoyle ou phényle, soit représentent l'un un radical de formule générale (XXVI) (dans lequel X2 représente un stome d'oxygène ou de soufre et R11 est alcoyle ou phényle), et l'autre un radical amino de formule générale

dans laquelle R12 et R13 sont définis comme R7 et R8, soit encore Rg et R10 représentent chacun un radical de formule générale (XXVII)} sur un dérivé de céphalosporine de formule générale

dans laquelle, R'1 et R'4 étant définis comme précédemment, le produit se présente sous forme bicyclooctène-2 ou -3 ou méthylène-3 bicyclooctane. The products of general formula (XXIV) in which R7 and R8 have the above definition, with the exception of representing alkyl substituted with hydroxy, amino or alkylamino, may be obtained by the action of a product of general formula

optionally prepared in situ, for which R 7 and R 8 are defined as above and R 8 and R 10, which are identical or different, or represent groups of general formula
-X2 R11 (xxvi) wherein X2 is an oxygen atom and R11 represents an alkyl or phenyl radical, or represents a radical of general formula (XXVI) (wherein X2 represents an oxygen or sulfur stome and R 11 is alkyl or phenyl), and the other an amino group of the general formula

in which R12 and R13 are defined as R7 and R8, or else R8 and R10 each represent a radical of general formula (XXVII) on a cephalosporin derivative of general formula

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

 When a product of general formula (XXV) in which the radical (XXVII) is different from -NR7R8 is chosen, it is preferable to choose such a product so that the amine HNR12R13 is more volatile than HNR7R8.

 It is generally carried out in an organic solvent such as dimethylEormamide, or in a mixture of solvents (dimethylformamide-tetrahydrofuran, dimethylformamide-dimethylacetamide, dimethylformamide-ether or dimethylformamide-dioxane, for example) at a temperature of between 20 ° C. and the reflux temperature of 20 ° C. reaction mixture.

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

 The products of general formula (xxiv) in which Ra and R'4 are defined as above and R7 and R8 represent alkyl groups substituted by hydroxy, amino or alkylamino can be obtained by transenamination from a product of general formula (XXIV ) in which R7 and R8 represent alkyl radicals, preferably methyl.

dans laquelle R'7 et R'8, qui sont identiques ou différents, représentent des radicaux alcoyle substitués par hydroxy, amino ou alcoylamino sur le produit de formule générale (XXIV) et l'on opère dans les conditions décrites précédemment pour l'action d'un produit de formule générale (XXV) sur un dérivé de formule générale (XXVIII).The reaction is carried out by the action of an amine of general formula

in which R'7 and R'8, which are identical or different, represent alkyl groups substituted by hydroxy, amino or alkylamino on the product of general formula (XXIV) and it is carried out under the conditions described above for the action a product of general formula (XXV) on a derivative of general formula (XXVIII).

 The products of general formula (XXV) 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'1 est défini comme précédemment en opérant par action d'un acide de formule générale (III) ou d'un de ses dérivés, dans les conditions décrites précédemment pour l'obtention des produits de formule générale (I). The cephalosporin derivatives of general formula (XXVIII) in which R'4 represents a radical of general formula (XXII) may be prepared from the products of general formula

in which R'1 is defined as previously by operating by action of an acid of general formula (III) or a derivative thereof, under the conditions described above for obtaining products of general formula (I).

 The cephalosporin derivatives of general formulas (XXVIII) and (XXX) in which R'1 represents a radical of general formula (II) can be obtained by esterification of the corresponding acids according to the method described above for obtaining a product. of general formula (I) wherein R1 is a radical of general formula (II) from a product of general formula (I) wherein R1 is a hydrogen atom.

dans laquelle la position de la double liaison est définie comme précédemment, selon les méthodes connues ou décrites dans la littérature - lorsqu'e R'4 est un radical formyle, selon J.C. SHERRAN et coll.,
J. Amer. Chem. Soc. 80 1156 (1958), - lorsque R'4 est acétyle, chloracétyle, trichloracétyle, phénylacétyle, phénoxyacétyle ou benzoyle, selon E.H. FLYNN, Cephalosporins and
Penicillins, Ac. Press (1972), - lorsque R'4 est un radical t.butoxycarbonyle, selon L. MORODER et coll., Hoppe Seyler's Z. Physiol. Chem. 357 1651 (1976), - lorsque R'4 est trichloro-2,2,2 diméthyl-l,l éthoxycarbonyle, selon
J.UGI et coll., Angew. Chem. Int. Ed. Engl. 17(5) 361 (1978), - lorsque R'4 est trichloro-2,2,2 éthoxycarbonyle, chloro-2 diméthyl-1,1 éthoxycarbonyle, cyano-2 diméthyl-1,1 éthoxycarbonyle, triméthylsilyl-2 éthoxycarbonyle, benzyloxycarbonyle, p.méthoxybenzyloxycarbonyle, diméthoxy-3,5 benzyloxycarbonyle, p.nitrobenzyloxycarbonyle, vinyloxycarbonyle, par action d'un chloroformiate en milieu hydroorganique en présence d'un bicarbonate alcalin, ou selon le brevet belge 788 885, - lorsque R'4 est diphénylméthoxycarbonyle, par action de 1'azidofor- miate correspondant en milieu hydroorganique, en présence d'un bicarbonate alcalin, - lorsque R'4 est (biphénylyl-4~-2 isopropyloxycarbonyle, par analogie avec la méthode décrite par Helv. Chim.Acta, 51, 924 (1968), - lorsque R' est quinolyl-8 oxycarbonyle ou allyloxycarbonyle, par
4 action du carbonate correspondant en milieu hydroorganique basique, - lorsque R'4 est o.nitrophénylthio ou p.nitrophénylthio, par analogie avec la méthode décrite par L. ZERVAS et coll., J. Amer. Chem. Soc.The introduction of the protective groups R'1 and R'4 of the product of general formula (XXVIII) (Mx) for R'1 can be carried out on a 7-amino cephalosporin of general formula

in which the position of the double bond is defined as above, according to known methods or described in the literature - when R'4 is a formyl radical, according to JC SHERRAN et al.,
J. Amer. Chem. Soc. 80 1156 (1958), - when R'4 is acetyl, chloroacetyl, trichloroacetyl, phenylacetyl, phenoxyacetyl or benzoyl, according to EH FLYNN, Cephalosporins and
Penicillins, Ac. Press (1972), when R'4 is a t.butoxycarbonyl radical, according to L. MORODER et al., Hoppe Seyler's Z. Physiol. Chem. 357, 1651 (1976), when R'4 is 2,2,2-trichloro-1,1-dimethyl-ethoxycarbonyl, according to
J.UGI et al., Angew. Chem. Int. Ed. Engl. 17 (5) 361 (1978), when R'4 is 2,2,2-trichloroethoxycarbonyl, 2-chloro-1,1-dimethylethoxycarbonyl, 2-cyano-1,1-dimethylethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, benzyloxycarbonyl , p.methoxybenzyloxycarbonyl, 3,5-dimethoxy benzyloxycarbonyl, p.nitrobenzyloxycarbonyl, vinyloxycarbonyl, by action of a chloroformate in a hydroorganic medium in the presence of an alkaline bicarbonate, or according to Belgian Patent 788 885, - when R'4 is diphenylmethoxycarbonyl by the action of the corresponding azidoformate in a hydroorganic medium, in the presence of an alkaline bicarbonate, when R'4 is (biphenylyl-4 ~ -2 isopropyloxycarbonyl, by analogy with the method described by Helv Chim.Acta, 51, 924 (1968), when R 'is 8-quinolyloxycarbonyl or allyloxycarbonyl, by
The action of the corresponding carbonate in a basic hydroorganic medium, when R '4 is o.nitrophenylthio or p.nitrophenylthio, by analogy with the method described by L. ZERVAS et al., J. Amer. Chem. Soc.

85, 3660 (1963), when R'4 NH- is replaced by dimethylaminomethyleneimine, by analogy with the method described by J. F. FITT, J. Org. Chem.

42 (15), 2639 (1977), when R'4 NH- is replaced by 4-nitro-benzylidenemino or 3,4-dimethoxybenzilideneimino, according to the method described by RA SIRESTONE,
Tetrahedron Lett., 33, 2915 (1977), when R'1 is methoxymethyl, according to S. SEKI et al., Tetrahedron
Lett., 33, 2915 (1977), when R'1 is t.butyl, according to RJ STEDMAN, J. Med. Chem., 9, 444 (1966), when R'1 is benzhydryl, according to the Dutch patent application 73 03263, when R'1 is p.nitrobenzyl or p.methoxybenzyl, according to
RR CHAUVETTE et al., J. Org. Chem. 38 (17) 2994 (1973).

 The isomers of the products of general formulas (I), (IV), (viii)> (XIII), (XVI), (XXI), (XXIII) and (XXIV) can be separated by chromatography or by crystallization.

The present addition concerns novel products corresponding to the general formula (I) in which R and R 'are defined according to the main patent and R represents an L-amino-2-carboxy-2 ethyl radical, or a heterocyclyl radical chosen from -tetrazolyl -5 substituted in the -1-position by an acylaminoalkyl, -thiadiazol-1,3,4-yl-5 substituted by a hydroxy or acylaminoalkyl radical, -thiadiazol-1,2,4-yl-5 substituted with an alkyl or alkyloxy radical, pyridyl-2, -3 or -4, optionally N-oxidized, triazol-1,2,3-yl-5,1-triazol-1,3,4-yl-5-pyridazinyl-3 substituted in position -6 by a alkyl, methoxy, amino or acylamino radical and optionally N-oxidized, - tetrazolo [4,5-b] pyridazinyl-6,5-dioxo-5> 6-tetrahydro-1,4,5,6-triazine-1,2,4-yl -3 substituted in position -4 by an alkyl, allyl, hydroxyalkyl, alkyloxyalkyl or acylaminoalkyl radical, of formula

 It is understood that, as in the main patent, the alkyl or acyl portions or radicals mentioned above are straight or branched and contain from 1 to 4 carbon atoms.

 It is also understood that the substituent at the -3 position of the products according to the present addition may be in cis or trans form or in the form of a cis-trans mixture.

 As in the main patent, the -OR group of the products according to the present addition may be in one of the syn or anti positions, and these isomers and mixtures thereof fall within the scope of this addition.

 In general, the products of sterebisomerism syn are preferred.

Among the meanings of the symbol R defined according to the present addition, there may be mentioned in particular - (2-acetamidoethyl) -1-tetrazolyl-. 2-Hydroxythiadiazol-1,3,4-yl-5-acetamidomethyl-2-thiadiazol-1,3,4-yl-5 - (2-acetamidoethyl) -2-thiadiazol-1,3,4-yl-5-methyl-3 1,2,4-thiadiazol-5-ethyl-3-thiadiazol-1,2,4-yl-5-methoxy-3-chiadiazol-1,2,4-yl-5-pyridyl-2-pyridyl-3-pyridyl-4 1-oxide-2-pyridyl-1,2,3-aziazol-5-triazol-1,3,4-yl-54-methyl-6-pyrimidinyl-3-methyl-6-oxide-1-pyridazinyl-3-ethyl pyridazinyl- 3-ethyl-6-oxide-1-pyridazinyl-3-methoxy-6-pyridazinyl-3-amino-6-pyridazinyl-3-acetamido-6-pyridazinyl-3-tetrazolo [4,5-b] pyridazinyl-6-dioxo-5,6 4-methyl-1,4,5,6-tetrahydro-1,2,4-triazo-3-yl-5,5-dioxo-4-ethyl-1,4,5,6-tetrahydro-1,2,4-triazo-3-yl 5-dioxo-4-propyl-1,4,5,6-tetrahydro-1,2,4-triazo-3-yl-5-dioxo-4-isopropyl-1,4,5,6-tetrahydro-1, 2,4-yl-3-allyl-4-dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-dioxo-5,6-hydroxymethyl-1,4,5-tetrahydro 1,2,4-triazine-1,3-dioxo-5,6-hydroxy-2-hydroxyethyl-1,4,5,6-tetrahydro-1,2-triazine; 4-yl-3-dioxo-5,6-methoxymethyl-4-tetrahydro-1,4,5,6-triazin-1,2,4-yl-3-dioxo-5,6 (2-methoxyethyl) -4-tetrahydro-1, 4,5,6-triazine-1,2,4-yl-3-dioxo-5,6-ethoxymethyl-4-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-dioxo-5> 6 ( 2-ethoxy-ethyl) -4-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-acetamidomethyl-4-dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2, 4-yl-3 - (2-acetamidoethyl) -4,5,5-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-3-yl
According to the present addiction, the products of general formula (I) in which R is defined according to the present addition, can be prepared according to the method described in the main patent, by the action of an acid of general formula (III) whose function amine is protected beforehand (as well as the oxime when R "represents hydrogen), or a reactive derivative of this acid, on a 7-amino cephalosporin of general formula (IV) in which R1 and n are defined according to main patent and R is defined according to the present addition, followed by the reduction of the sulfoxide obtained when n = 1, then the removal of the protective radicals.

 The reaction of (III) on (IV), the protection of radicals, the elimination of protective radicals and the reduction of sulfoxide are carried out under the conditions described previously in the main patent.

It is understood that (as for the products of the main patent) when in the general formula (IV) the radical
R contains a group capable of interfering with the desired reaction (amino or carboxy), it is preferable to protect this group by any method known per se and which does not alter the rest of the molecule.

 It is also understood that when in the general formula (IV) the radical R contains a hydroxy radical, it is preferable to use a product in the formula of which n = 0.

 According to the present addition, the products of general formula (I) in which R is defined according to the present addition can also be prepared according to the method described in the main patent, by action of a thiol of general formula (VII) in which R is defined according to the present addiction, on a derivative of cephalosporin (or on a mixture of isomers of this derivative) of general formula (VOIE) as defined in the main patent, followed by the reduction of the oxide obtained (when n = 1) and possibly the elimination of the protective radicals.

 The reaction is carried out under the conditions described in the main patent. The protection of the radicals, their elimination and the reduction of the oxide are carried out according to the methods described in the main patent.

 According to the present addition, the products of general formula (I) in which, R being defined according to the present addition and R being defined according to the main patent, R 'represents a radical of general formula (II), may also be prepared by esterification of a product of general formula (I) in which R 'is a hydrogen atom, and whose amine function has been previously protected, by any method known per se for preparing an ester from an acid without affecting the rest of the molecule.

 It operates in particular according to the method described in the main patent.

 The products of general formula (IV) in which R is defined according to the present addition may be prepared from a product of general formula (XIII) in which R is defined according to the present addiction, operating in the same manner as for obtaining products of general formula (IV) in which R is defined according to the main patent.

The products of general formula (XIII) in which R is defined according to the present addition, can be obtained in the same way as the products of general formula (XIII) in which
R is defined according to the main patent, by action of a thiol of general formula (VII), the radical R is optionally protected on a cephalosporin derivative (or a mixture of isomers of this derivative) of general formula (XVI).

 The reaction is carried out under the conditions described in the main patent.

The thiols of general formula (VII) in which R is defined according to the present addition can be obtained by applying one of the following methods - when R is a 5-tetrazolyl radical substituted with an acylaminoalkyl or 1,3-thiadiazole radical, 4 yl-5 substituted with hydroxy according to the method described in US Patent 4,117,123; when R is a thiadiazol-1> 3,4-yl-5 radical substituted by an acylaminoalkyl radical: according to the method described in Japanese Patent Application 76 80857 - when R is a 1,2,4-thiadiazol-5-yl radical; substituted by alkyl or alkyloxy: according to the method described in the patent application
DE 2 806 226 or according to Chem. Ber. 90, 184 (1957) - when R is a pyridyl-3 radical: according to the method described by
HM WUEST and EH SAKAL, J.Am. Chem. Soc., 73, 1210 (1951) - when R is a 1-oxide pyridyl-3 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 triazol-1,2,3-yl-5 radical: according to the method described in the patent application FR 2,215,942 - when R is a 3-pyridazinyl radical substituted with alkyl or methoxy and optionally N-oxidized: according to the method described in patent BE 787 635; when R is a 3-pyridazinyl radical substituted by amino and optionally N-oxidized: according to the method described in patent BE 579,291 - when R is a 3-pyridazinyl radical substituted by acylamino and optionally N-oxidized: by application of the methods described by
Mr. KUMAGAI and Mr. BANDO, Nippon Kagaku Zasshi, 84,995 (1963) and
T. HORDE and T. UEDA, Chem. Pharm. Bull., 11, 114 (1963); when R is a tetrazolo [4,5-b] pyridazinyl-6 radical: according to the method described in patent BE 804 251; when R is a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 radical substituted in the 4-position by alkyl, allyl or alkyloxyalkyl, according to the method described in patent BE 830; 455 - when R is a dioxo-5> 6-tetrahydro-1, h, 5,6-triazine-1,2,4-yl-3 radical substituted in the 4-position with a hydroxyalkyl or acylaminoalkyl radical: by the action of an oxalate d alkyl on a thiosemicarbazide of the general formula
R11-NH-CS-NH-NH2 (XXXIII) in which R11 represents a hydroxyalkyl or acylaminoalkyl radical, in the presence of an alkaline alkoxide, for example ethylate or sodium methoxide, by application of the method described by M. PESSON and M. ANTOINE, Bull. Soc. Chim. France (1970), 1590.

In the case where R is a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 radical substituted in the 4-position, the thiol of general formula (VII) is used. in the form of tautomeric thioxo-3-dioxo-5,6 perhydrotriazine-1,2,4
The isomers of the products of general formulas (I), (IV) or (hIII) in which R is defined according to the present addition may be separated by chromatography or crystallization.

 The new products according to the addition can be converted to addition salts with acids. According to the methods of the present addition the products are generally obtained in the form of trifluoroacetate, solvate with formic acid or para-toluenesulphonate. The products of general formula (I), in which R is defined according to the present addiction, obtained in the form of these salts can be released and converted into salts of other acids according to the usual methods.

 The products according to the addition can also be converted into metal salts or addition salts with the nitrogenous bases according to the methods known per se. These salts can be obtained by the action of a metal base (for example alkaline or alkaline earth), ammonia or an amine on a product according to the addition in one in a suitable solvent such as an alcohol, an ether or water or exchange with a salt of an organic acid. The salt formed precipitates, after optional concentration of its solution, it is separated by filtration or decantation.

 As salts of pharmaceutically acceptable salts may be mentioned the addition salts with mineral acids (hydrochlorides, hydrobromides, sulphates, nitrates, phosphates) or organic acids (succinates, fumarates, maleates, toluenesulphonates) salts with alkali metals (sodium, potassium lithium) or with alkaline earth metals (magnesium, caicium), ammonium salt, nitrogen base salts (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, NN-dimethylethanolamine, benzylamine, dibenzylamine , dicyclohexylamine, N-benzyl-s-phenethylamine, N, N'-benzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine).

 The novel products according to the addition may be optionally purified by physical methods such as crystallization or chromatography.

The new cephalosporin derivatives according to the present addition and their pharmaceutically acceptable salts have particularly advantageous anti-bacterial properties. They exhibit remarkable activity in vitro and in vivo on germs
Gram-positive and Gram-negative.

 In vitro, the products of general formula (I) were active at a concentration of between 0.5 and 15 g / cm 3 on strains of penicillin G-sensitive staphylococci (Staphylococcus aureus Smith), at a concentration of between 1 and 30 μg / cm3 on penicillin G-resistant staphylococcus strains (Staphylococcus aureus MB 9), at a concentration of between 0.0001 and 1 μg / cm3 on Escherichia coli strain Monod and at a concentration of between 0.06 and 30 μg / cm3 on Klebsiella pneumoniae. In addition, some were active at a concentration of between 0.01 and 30 μg / cm3 on Proteus morganii and at a concentration between 0.25 and 30 μg / cm3 on Enterobacter aerogenes.

In vivo, the products of general formula (I) have been shown to be active in experimental infections of the mouse with
Staphylococcus aureus Smith (penicillin G sensitive) at a dose of 0.2 to 15 mg / kg daily subcutaneously, and
Escherichia coli (Monod strain) at doses of between 0.001 and 10 mg / kg per day subcutaneously.

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

 The following examples illustrate the invention.

EXAMPLE 1
A mixture of 5.02 g of 2-benzyl-2-yl-2-dichloro-2-methoxyimino (2-tritylamino-1,3-thiazolyl) -2-acetamido-7-oxo-5-oxo-5-oxo-2-oxyte is stirred under nitrogen for 2 hours. (2-tosyloxy-vinyl) -3-thia-5-aza-bicyclo [4.210] octene-2, syn isomer, E-form, 75 cm3 of dimethylformamide, 2.21 g of Nt.butoxycarbonyl L-cysteine and 2.61 g. cm3 N, N-diisopropylethylamine. After cooling, the mixture is diluted with 500 cm 3 of ethyl acetate and the organic phase is washed with twice 400 cm 3 of water, 250 cm 3 of 0.1 N hydrochloric acid and 250 cm 3 of half-saturated water. sodium chloride, dried over sodium sulfate, filtered and concentrated to dryness at 200C under reduced pressure - (20 mm Hg).

 The residue is dissolved in 50 cm3 of acetonitrile.

A solution of 0.97 g of diphenyl diazomethane in 25 cm3 of acetonitrile is stirred at 200 ° C., stirred for 2 hours at 200 ° C. and diluted with 500 cm 3 of ethyl acetate. 0.05 N hydrochloric acid (100 cc), a 1% solution of sodium bicarbonate and 100 cm3 of a semisaturated solution of sodium chloride are washed in an ampoule, dried over sodium sulfate. sodium, filtered and concentrated to dryness at 20 ° C. under reduced pressure (20 mm Hg). The residue is taken up in 50 cm3 of a cyclohexane-ethyl acetate mixture 60-40 (volumes) and the solution is chromatographed on a column of 300 g of Merck silica gel (0.04-0.06) (diameter of the column: 6 cm, height 30 cm). The mixture is eluted with 4 liters of the above mixture under a pressure of 40 kPa, collecting 115 cm 3 fractions. Fractions 11 to 23 are combined and concentrated to dryness at 200 ° C. under reduced pressure (20 mm Hg) to give 3.57 g of 2-benzhydryloxycarbonyl-2 - [(L-benzhydryloxycarbonyl) -2-tert-butoxycarbonylamino-2-ethyl-2-yl) vinyl] -3 [2-methoxyimino (2-tritylamino-1,3-thiazolyl) -2-acetamide] -7-oxo-5-oxide-5-thia-aza-1-bicyclo [4.2.0] octene-2, isomer syn, form E.

Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3380, 1795, 1710, 1690, 1510, 1495, 1445, 1365, 1045, 940, 750, 740
Proton NMR Spectrum (350 MHz, CDCl3, δ ppm, J in Hz) 1.48 (s, 9H, -C (CH3) 3); 2.95 and 3.75 (2d, 3 = 18, 2H, -S CH 2 -) 3.20 (d, J = 7, 2H, -SCI 1, 4.08 (s, 3H, -OCH 3); 48 (d, J = 4, 1H, 11 at 6), 4.67 (mt, 1H, -CHCOO-), 6.10 (dd, J = 4 and 9, 1H,
H in 7); 6.39 (d, J = 7, 1H, -NH COO-); 6.41 (d, J = 16, 1H, = CHS-); 6.71 (s, 1H, H thiazole); 6.85 (s, 1H, -COOCH-) 6.93 (s, 1H, -COOCII-); 7.10 (s, 1H, -NH C (C6H5) 3).

 To a solution cooled to -10 [deg.] C. of 2-benzhydryloxycarbonyl-2 - [(1-benzhydryloxycarbonyl-2-tert-butoxycarbonylamino-2-ethyl) -2-thio] -vinyl, 2-methoxyimino-2-tritylamino-thiazol 1,3-yl-4) -2-acetamido-7-oxo-8-oxide-5-thia-5-aza-1-bicyclo4.2.0.7-octene-2, syn isomer, E-form, in 45 cm3 of methylene chloride, is added successively 1.35 cm3 of dimethylacetamide and, with stirring, 0.59 cm3 of phosphorus trichloride. Stirred for 1 hour at -10 C, diluted with 600 cm3 of ethyl acetate, washed with 2 times 100 cm3 of a 2% solution of sodium bicarbonate and 2 times 100 cm3 of a half-saturated solution. of sodium chloride, dried over sodium sulphate, filtered and concentrated to dryness at 200 ° C. under reduced pressure (20 mm of mercury). The residue is dissolved in 60 cm 3 of a cyclohexane-ethyl acetate mixture 65-35 (volumes ) and the solution is chromatographed on a column of 250 g of Merck silica gel (0.04-0.06) (column diameter: 5 cm). It is eluted with 2 liters of a cyclohexane-ethyl acetate 65-35 (volumes) at a pressure of 40 kPa, collecting 130 cm3 fractions.

Fractions 5 to 8 are combined and concentrated to dryness at 200 ° C. under reduced pressure (20 mm Hg) and 2.78 g of 2-benzhydryloxycarbonyl-2 - [(L-benzhydryloxycarbonyl-2-t-butoxycarbonylamino-2-ethyl) thio are thus collected. 2-vinyl-3'-methoxyimino-2 (tritylamino-2-thiazol-1,3-yl) -4-acetamide] -7-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form E, in the form of a yellow meringue.

5,36 (s large, 1H, -NH COO-) ; 5,04 (d, J = 4, 1H, H en 6) ; 5,85 (dd, J = 4 et 9, 1H,
H en 7) ; 6,41 (d, J = 16, 1H, =CHS-) ; 6,8 (s, 1H, H du thiazole) 6,88 (s, 1H, -CH COO CH-) ; 6,93 (s, 1H, -GOOCH-) ; 7,03 (s, 1H, -nhc (C6H5)3) ; 7,08 (d, J = 16, 1H, -CH=CHS-).Infra-red spectrum (CHBr3), characteristic bands (cm) 3400, 1780, 1710, 1690, 1515, 1495, 1450, 1390, 1370, 1050, 945, 755, 745
Proton NMR Spectrum (350 MHz, CDCl3, 6 ppm, JHz) 1.43 (s, 9H, (CH3) 3 C-); 3.22 (2 AB limit, 4H, -S Ch 2 -); 4.10 (s, 3H, -OCH 3); 4.70

5.36 (brs, 1H, -NH COO-); 5.04 (d, J = 4.1H, H at 6); 5.85 (dd, J = 4 and 9, 1H,
H in 7); 6.41 (d, J = 16, 1H, = CHS-); 6.8 (s, 1H, H thiazole) 6.88 (s, 1H, -CH COO CH-); 6.93 (s, 1H, -GOOCH-); 7.03 (s, 1H, -NHc (C6H5) 3); 7.08 (d, J = 16, 1H, -CH = CHS-).

 2.71 g of 2-benzhydryloxycarbonyl-2 - [(1-L-benzhydryloxycarbonyl-2-butoxycarbonylamino-2-ethyl) -2-thio-vinyl] -3 [methoxyimino-2 (tritylamino-2-thiazol-1,3-yl)) are dissolved 2-acetamido-7-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form E in 40 cm3 of formic acid, diluted with 40 cm3 of water and stirred at 50 ° C. for 30 minutes. The cooled mixture is filtered to -20 ° C. and concentrated to dryness at 30 ° C. under reduced pressure (0.05 mm Hg). The residue is taken up successively with 3 times 75 cm 3 of ethanol, evaporating in each case dry at 20 ° C. under reduced pressure (20 mm Hg). The solid residue is treated with 200 cm 3 of refluxing ethanol and the cooled suspension is filtered. After washing with 3 times 25 cm 3 of diethyl ether and drying, 1.34 g of [(L-2-amino-2-carboxy) is collected. 2-ethyl-2-thio-vinyl] -2-amino-1,3-thiazolyl-4-yl) -methoxyimino-2-acetamido] -7-carboxy-2-oxo-3-thia-5-azo-1-bicyclo [4.2.0] octene 2, syn isomer, form E.

 Infrared spectrum (kBr), characteristic bands (cm) 3500, 2000, 1750, 1660, 1530, 1035, 940.

 Proton NMR spectrum (350 MHz, DMSO d6.6 ppm, JHz) 3 at 3.70 (bulk, 4H, -SCH2-cephalosporin and side chain); 3.87 (s, 3H, -O CH 3); 5.15 (d, J = 4, 1H, H at 6); 5.65 to 5.72 (solid, 2H, H at 7 and CHOCH); 6.77 (s, 1H, H thiazole) 6.92 (AB ,, 2H, -CH = CH-); 7.20 (s, 3H, -NH 3 +); 9.58 (d, J = 9, 1H, -COMU-).

 2-Benzhydryloxycarbonyl-2-methoxyimino (2-trityamino-1,3-thiazolyl) -2-acetamido] -1-oxo-5-oxide (2-thesyloxyvinyl) thia-5-azabicyclo [4.2. 0] octene-2, syn isomer, form E can be prepared as described in Example 3 of the main patent.

EXAMPLE 2
A mixture of 10.04 g of 2-benzhydryloxycarbonyl [2-methoxyimino-2-tritylamino-1,3-thiazol-4-yl] -2-acetamido] -oxo-8-oxide-5 (10.04 g) is stirred under nitrogen for 6 hours ( 2-tosyloxyvinyl) -5-thia-5-aza-bicyclo [4.2.0] octene-2, syn isomer, E-form, 200 cm3 of dimethylformamide, 3.74 g of (acetamidoethyl) -1-mercapto-5-tetrazole and 3.5 cm3 of diisopropylethylamine. It is diluted with 800 cm3 of ethyl acetate. washed with 3 times 400 cm3 of water, dried over sodium sulphate, filtered and concentrated to dryness at 20 ° C. under 20 mm of mercury. The product previously fixed on 50 g of Merck silica gel (0.05-0.2) is deposited on a column of 100 g of the same silica gel (column diameter: 3 cm). Eluted successively by mixtures cyclohexane-ethyl acetate: 50-50 (vol.) 500 cm3, 25-75 (vol.) 1 liter and 3 liters of ethyl acetate, collecting 125 cc fractions. Fractions 19 to 30 are concentrated to dryness at 20 ° C. under 20 mm of mercury. 5.05 g of {[(2-acetamidoethyl) -1-tetrazolyl-5-thio-3-vinyl-3-benzhydryloxycarbonyl-2-methoxyimino-2 (tritylamino-2-thiazol-1,3-yl) -2-acetamido is collected. ] 7-oxo-5-oxide 5-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form as a brown meringue.

Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3440, 3380, 1800, 1720, 1670, 1510, 1495, 1445, 1370, 1045, 940, 750, 735
Proton NMR Spectrum (350 MHz, CDCl3, 6 ppm, JHz) 1.84 (s, 3H, -COCH3); 3.27 and 4 (2d, J = 18, 2H, -SCU2-); 3.62 (mt, 2H, -CH2NHCO-); 4.05 (s, 3H, -O CH 3); 4.35 (t, 2H,> N CH 2 -) 4.62 (d, J = 4, 1H, H at 6); 6.07 (dd, J = 4 and 9, 1H, H at 7) 6.50 (t, J = 7, 1H, -NHCO-); 6.69 (s, 1H, H thiazole); 6.93 (s, 1H, -COOCH-); 6.96 (d, J = 16, 1H, -CH = CH S-); 7.10 (s, -1H, -NHc (C6H5))
3.

 To a solution cooled to -10 ° C. of 4.99 g of {[(acetamido-2-ethyl) -1-tetrazolyl-5-thio-2-vinyl) -3-benzhydryloxycarbonyl-2 [methoxyimino-2 (tritylamino-2-thiazol-1) 3-yl-4) -2-acetamido-7-oxo-8-oxide-5-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, Form E in 49 cc of methylene chloride, 1.95 cm3 of dimethylacetamide and 0.86 cm3 of phosphorus trichloride. Stirred for 2 hours at -10 C. diluted with 300 cm3 of ethyl acetate, washed with 200 cm3 of a semisaturated solution of sodium bicarbonate and 200 cm3 of a saturated solution of sodium chloride, dried over sodium sulphate, filtered and concentrated to dryness at 200 ° C. under 20 mm of mercury. Chromatography on a column of Merck silica gel (0.04-0.06) (column diameter: 6 cm). 5 liters of a cyclobexane-ethyl acetate mixture 20-80 (vol.) Under a pressure of 40 kPa, collecting 125 cc fractions. Fractions 19 to 32 are evaporated to dryness at 20 ° C. under 20 minutes of mercury and 2.36 g of [2- [2-acetamidoethyl] -2-tetrazolyl] -2-thio-vinyl] benzhydryloxycarbonyl-2L are collected. 2-methoxyimino (2-trityamino-1,3-thiazolyl-4-yl) acetamido] -7-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form in the form of of a yellow meringue.

Infra-red spectrum (CHBr3), characteristic bands (cm) 3440, 3400, 1785, 1720, 1680, 1515, 1495, 1450, 1370, 1040, 945, 755, 740
Proton NMR Spectrum (350 MHz, CDCl 3, 6 ppm, J in Hz) 1.93 (s 3H, -CH 3); 3.54 and 3.60 (2d, J = 18, 2H, -SCH 2 -); 3.70 (m, 2H, -CH2NHCO-); 4.04 (s, 3H, -OCH3); 4.35 (t, J = 5, 2H,> NCH 2 -); 5.10 (d, J = 4.1H, H at 6); 5.94 (dd, J = 4 and 9, 1H, H at 7) 6.40 (t, J = 5, 1H, -NHCOCH 3); 6.73 (s, 1H, H thiazole); 6.93 (s, 1H, -COO ch-); 7 (s, 1H, (C 6 H 5) 3 C NH-).

 2.32 g of {(2-acetamidoethyl) -1-tetrazolyl-2-thio-vinyl) -3-benzhydryloxycarbonyl-2 [2-methoxylimino-2-tritylamino-1,3-thiazol-4-yl] acetamido] are dissolved 7-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form E in 60 cm3 of formic acid, added 60 cm3 of water and heated at 50 ° C. with stirring for 15 minutes. the cooled mixture is filtered towards 20 ° C., concentrated to dryness at 500 ° C. under 0.05 mm of mercury and the residue is taken up with 3 times 150 cm 3 of ethanol, each time driving off the solvent under reduced pressure (at 20 ° C. under 20 mm). mercury) The residue is taken up in 50 cm3 of ethanol, the suspension is stirred at 400 ° C. for 1 hour, allowed to cool to 200 ° C. and filtered, thus affording 0.86 g of tetra (2-acetamidoethyl) -1. Tetra 2-zolyl-2-thio-3-vinyl-3- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -7-carboxy-2-oxo-8-thia-5-azabicyclo [4.2.0 ] octene-2 isomer syn, form E in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3500, 2500, 1775, 1660, 1540, 1040, 945
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 1.90 (s, 3H, -CH3); 3.44 (t, 2H, sN CH 2 -); 3.60 (q, 2H, -CH2NHCO-) 3.64 and 3.76 (2d, J = 18, 2H, -S CH2-); 4.0 (s, 3H, -OCH 3) 5.16 (d, J = 4, 1H, H at 6); 5.82 (dd, J = 4 and 9, 1H, H at 7) 6.60 (s, 3H, -NH3 +); ; 6.78 (s, 1H, H thiazole); 6.96 (d, J = 16, 1H, -CH = CH S-); 7.37 (d, J = 16, 1H, = CHS-); 7.86 (t, J = 5, 1H, -NHCOCH3); 9.50 (d, J = 9, 1H, -CONH-).

 L> (2-acetamidoethyl) -1-mercapto-tetrazole may be prepared according to the method described in US Pat. No. 4,117,123.

EXAMPLE 3
A mixture of 6.02 g of 2-benzhydryloxycarbonyl-2-methoxyimino (2-tritylamino-1,3-thiazolyl) -2-acetamido] -7-oxo-8-oxide is stirred at 60 ° C. under nitrogen for 2 hours. -5 (2-tosyloxyvinyl) -5-thia-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form, 60 cm3 of dimethylformamide, 2.27 g of 2-acetamidomethyl-5-mercapto thiadiazole -1.3,4 and 1,15 cm3 of diisopropylethylamine. The cooled mixture is diluted with 250 cm3 of ethyl acetate, washed with 150 cm3 of water, 100 cm3 of 0.1 N hydrochloric acid, 100 cm3. saturated sodium bicarbonate solution and 2 times 100 cm3 of water, dried over sodium sulphate, filtered and concentrated to dryness at 20 ° C. under reduced pressure (20 min of mercury). The residue, fixed on 20 g of Merck silica gel (0.05-0.2), is deposited on a column of 70 g of silica gel (0.05-0.2) (diameter of the column: 2 5 cm). Eluted with 2.5 liters of ethyl acetate, collecting 100 cm 3 fractions. Fractions 9 to 23 are evaporated to dryness at 20 ° C. under reduced pressure (20 min of mercury) and 3 g of [(2-acetamidomethyl-1,3,4-thiadiazol-5-yl) -3-thio-vinyl] are collected. 2-Benzhydryloxycarbonyl-2-methoxyimino-2 (tritylamino-2-thiazol-4-yl) -2-acetamido] -7-oxo-5-oxide-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E in the form of a brown meringue.

Infra-red spectrum (KBr), characteristic bands (cm) 3400, 1795, 1720, 1670, 1525, 1495, 1450, 1370, 1040, 940, 750, 700
Proton NMR Spectrum (350 MHz, CDCl 3, 6 ppm, J in Hz) 1.97 (s, 3H, -COCH 3); 3.30 and 4.15 (2d, J = 18, 2H, -SCH 2 -); 4.08 (s, 3H, -DCH 3); 4.64 (d, J = 4, 1H, H at 6); 4.72 (AB, 2H, -CH2NHCO-); 6.14 (dd, J = 4 and 9, 1H, H at 7); 6.72 (s, 1H, H thiazole) 6.97 (s, 1H, -COOCH-).

 To a solution cooled to -10 [deg.] C. of 3 g of [(2-acetamidomethyl-1,3-thiadiazol-5-yl) -2-thio-vinyl] -2-benzhydryloxycarbonyl [2-methoxyimino-2-tritylamino-thiazol-1, 3-acetamido-7-oxo-5-oxide-5-thia-aza-1-bicyclo [4.2.0] octene-2, syn isomer, Form E in 29 cc of methylene chloride, is added cm 3 of dimethylacetamide and 0.519 cm 3 of phosphorus trichloride and then stirred for 1 hour at -10 C. The mixture is poured into ethyl acetate (250 cc), washed with saturated sodium bicarbonate solution (250 cc) and twice 100 cm3 of water, dried over sodium sulphate, filtered and concentrated to dryness at 20 ° C. under reduced pressure (20 mm of mercury). The residue is dissolved in 10 cm 3 of methylene chloride and the solution is chromatographed on a gel column. Merck silica (0.04-0.06) (column diameter: 4 cm). The mixture is eluted with 2.5 liters of a mixture of ethyl acetate cyclohexane 80-20 (vol.) Under a pressure of 40 kPa, collecting 100 cm3 fractions. The fractions II to 21 are evaporated to dryness under reduced pressure at 20 ° C. (20 mm Hg) and 2.1 g of [(2-acetamido thiadiazol-1,3,4-yl-5) thio-2) are evaporated off. vinyl] -3-benzhydryloxycarbonyl-2 [2-methoxyimino-2-tritylamino-1,3-thiazol-4-yl] acetamindo] -7-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2-isomer syn, form E in the form of a yellow meringue.

Infrared spectrum (KBr), characteristic bands (cm) 3400, 3280, 1785, 1720, 1670, 1530, 1495, 1450, 1370, 1040, 945, 755, 700
Proten NMR Spectrum (350 MHz, CDCl3, ppm, JHz) 2.0 (s, 3H, -COCH3); 3.58 and 3.68 (2d, J = 18, 2H, -SCH 2 -); 4.08 (s, 3H, -OCH3); 4.75 (d, J = 5.2H, -CH2NHCO-); 5.10 (d, J = 4.1H,
H in 6); 5.97 (dd, J = 4 and 9, 1H, H at 7); 6.55 (t, J = 5, 1H, -NHCO-); 6.76 (s, 1H, H thiazole); 7.0 (s, 1H, -COOCH-); 7.05 (s, 1H, -NH C (C6H5) 3); 7.18 (d, J = 16, 1H, -CH-CHS-).

 2.1 g of [(2-acetamidemethyl-1,3,4-thiadiazolyl) -2-thio-vinyl] -2-benzhydryloxycarbonyl-2-methoxyimino-2-tritylamino-1,3-thiazol-1-yl was dissolved in 4) -2-acetamido-7-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form E in 21 cm3 of formic acid, 12 cm3 of water are added and heated to 500 ° C during 30 minutes. The cooled mixture at 20 ° C. is then filtered and concentrated to dryness at 50 ° C. under reduced pressure (0.05 mm Hg), the residue is taken up in 50 cm 3 of ethanol and the solvent is removed at 200 ° C. under reduced pressure (20 ° C.). mn of mercury); This operation is repeated 2 times, then the residue is taken up in 50 cm3 of ethanol under reflux. A hot filter is used to remove a slight insoluble matter, concentrated to 20 cm 3 under reduced pressure (20 mm Hg) at 200 ° C. and filtered. After drying, 0.75 g of [(2-acetamidomethyl-1,3,4-thiadiazol-5-thio-2-vinyl] -3 [(2-aminothiazol-1,3-yl) -4) is obtained. 2-methoxyimino-acetamido] -7-carboxy-2-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E in the form of a cream-colored powder.

Infrared spectrum (KBr), characteristic bands (cm-1) 3320, 1770, 1660, 1540, 1380, 1040
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 1.90 (s, 3H, -COCH3); 3.68 and 3.92 (2d, J = 18, 2H, -S CH 2 -); 3.87 (s, 3H, -OCH 3); 4.22 (d, J = 4, 1H, H at 6); 4.60 (AB limit, 2H, -CH 2 NHCO); 5.82 (dd, J = 4 and 9, 1H, H at 7); 6.75 (s, 1H, -OCH3); 7.15 (d, J = 16, 1H, -CH = CHS-); 7.20 (s, 3H, -NH 3 +); 7.25 (d, J = 16, 1H, = CHS-); 9.63 (d, J = 9, 1H, -CONHO-).

 2-Acetamidomethyl-5-mercapto-1,3,4-thiadiazole can be prepared by applying the method described in Japanese Patent Application 76 80857.

EXAMPLE 4
A mixture of 4 g of 2-benzhydryloxycarbonyl [2-methoxyimino-2-tritylamino-1,3-thiazolyl-4-yl] acetamido] -7 oxo-8-oxide-5-ol (tosyloxy) is stirred at 60 ° C. under nitrogen for 2 hours. -2 vinyl) -3 thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form, 1.05 g of 5-mercapto-3-methyl-1,2,4 thiadiazole, 0.83 cm3 of N, N-diisopropylethylamine and 50 cm3 of dimethylformamide. The cooled mixture at 20 ° C. is diluted with 600 cm 3 of ethyl acetate and the organic phase is washed with 100 cm 3 of distilled water, 150 cm 3 of 0.1 N hydrochloric acid, 2 × 150 cm 3 of a solution. to 5% of sodium bicarbonate and 2 times 150 cm3 of water saturated with sodium chloride, dried over sodium sulphate, filtered and concentrated to dryness at 20 ° C. under reduced pressure (20 mm of mercury). The brown residue is taken up in 10 cm3 of a cyclohexane-ethyl acetate mixture 40-60 (vol.) and the solution is chromatographed on a column of 150 g of Merck silica gel (0.04-0.06) (diameter of the column : 4 cm). Is eluted with 3 liters of cyclohexane-ethyl acetate 40-60 (vol) at a pressure of 40 kPa collecting 50 cm3 fractions. The fractions 24 to 60 are evaporated to dryness at 20 ° C. under reduced pressure (20 mm of mercury) and 1.8 g of 2-benzhydryloxycarbonyl [2-methoxyimino-2-tritylamino-1,3-thiazolyl-4-yl] are recovered. acetamido] -7- (3-methyl-thiadiazol-1,2,4-yl) -5-thio-vinyl-3-oxo-8-oxy-5-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E.

7,05 (d, J = 14, 1H, -CH=CHS-) ; 7,48 (d, J = 9, 1H, -CONH-) ; 7,58 (d, J = 14, 1H, =cHS-). Proton NMR Spectrum (350 MHz, CDCl 3, 6 ppm, J in Hz) 2.63 (s, 3H, -CH 3); 3.29 and 4.07 (2d, J = 18, 2H, -SCH 2 -); 4.08 (s, 3N, -OCH3); 4.61 (d, J = 4, 1H, H at 6); 6.18 (dd,
J = 4 and 9, 1H, H at 7); 6.71 (s, 1H, H thiazole); 6.89 (s, 1H,

7.05 (d, J = 14, 1H, -CH = CHS-); 7.48 (d, J = 9, 1H, -CONH-); 7.58 (d, J = 14, 1H, = cHS-).

To a solution cooled to -10 ° C. of 1.75 g of 2-benzhydryloxycarbonyl-2-methoxyimino (2-tritylamino-1,3-thiazolyl) -2-acetamidol-7 (3-methyl-1,2,4-thiadiazole) yl-5) 2-thio-vinyl-3-oxo-8-oxide-5-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form and 0.72 cm3 of dimethylacetamide in 40 cm3 of sodium chloride. methylene, 0.35 cm3 of phosphorus trichloride are added in one go.The mixture is stirred for 1 hour at -10 ° C. again 0.17 cm3 of phosphorus trichloride is added, the mixture is stirred for 10 minutes and then treated as follows
It is diluted with ethyl acetate (500 cc), washed twice with 150 cm3 of a 2% solution of sodium bicarbonate and twice with 150 cm3 of a half-saturated solution of sodium chloride, dried over sodium sulfate. sodium, filtered and concentrated to dryness at 200C under reduced pressure (20 min of mercury). The residue is taken up in 15 cm3 of a cyclohexane-ethyl acetate mixture 30-70 (vol.) And the solution is chromatographed on a column of 60 g of Merck silica gel (0.05-0.2) ( diameter of the column: 4 cm). Eluted with 300 cm3 of the above mixture, collecting 20 cm3 fractions. Fractions 6 to 13 are combined and concentrated to dryness at 200 ° C. under reduced pressure (20 minutes of mercury). 1.18 g of 2-benzhydryloxycarbonyl-2-methoxyimino (2-tritylamino-1,3-thiazolyl) is collected. -2-acetamido] -7 [(3-methyl-thiadiazol-1,2,4-yl-5) thio-2-vinyl-3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E.

 Proton NMR Spectrum (350 MHz, CDCl3, 6 ppm, J in Hz) 2.62 (s, 3H, -CH3); 3> 60 and 3.68 (2d, J = 18, 2B, -SCH 2 -); 4.07 (s, 3B, -OCH3); 5.11 (d, J = 4, 1H, H at 6); 5.95 (dd, J = 4 and 9, 1H, H at 7); 6.75 (s, 1H, H thiazole); 6.88 (d, J = 9, 1H, -CONH-); 6.98 (d, J = 16, 1H, -CH = CHS-); 6.99 (s, 1H, -COOCH '); 7.0 (s, 1H, -NH-).

 1.1 g of 2-benzhydryloxycarbonyl [2-methoxyimino-2-tritylamino-1,3-thiazol-4-yl] -7-acetamido (3-methyl-thiadiazol-1,2,4-yl) -5-thio) are dissolved. 2 vinyl] -3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form in 30 cc of formic acid, added 13 cm3 of distilled water and heated at 50 ° C. 30 minutes. The suspension cooled to 20 ° C. is filtered and the filtrate is concentrated at 20 ° C. under reduced pressure (0.05 mm Hg). The residue is taken up in 30 cm3 of ethanol, concentrated at 20 ° C. under reduced pressure and this operation is repeated 3 times. The residual solid is treated at reflux with 100 cm 3 of ethanol, a slight insoluble matter is removed by filtration, and the filtrate is then filtered off. is concentrated to 5 cm3, diluted with 20 cm3 of diethyl ether and cooled to +4 C. After filtration and drying, there is obtained 0.44 g of (2-amino-1,3-thiazol-4-yl) methoxyimino 2-acetamido-7-carboxy-2 (3-methyl-1,2,4-thiadiazol-5-yl) -5-thio-vinyl] -3-oxo-5-thia-5-azabicyclo [44.2.0] octene-2, syn isomer, form E in the form of a yellow powder.

 Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 2.57 (s, 3H, -CH3); 3.65 and 3.95 (2d, J = 18, 2H, -SCH 2 -); 3.86 (s, 3H, -OCH 3); 5.23 (d, J = 4, 1H, H at 6); 5.82 (dd, J = 4 and 9, 1H, H at 7); 6.75 (s, 1H, H thiazole); 7.04 (d, J = 16, 1H, -CH = CHS-); 7.36 (d, J = 16, 1H, = CHS-); 9.63 (d, J = 9, 1H, -CONH-).

 The 5-mercapto-3-methylthiadiazol-1,2,4 can be prepared according to the method described in Chem. Ber. 90, 184 (1957).

EXAMPLE 5
A solution of 6.0 g of 2-benzhydryloxycarbonyl-2-methoxyimino- (tritylamino-2-thiazol-4-yl) -2-acetamido-7-oxo-8-oxide-5-ol (tosyloxy) is stirred at 20 ° C. for 2 hours under nitrogen. -2 vinyl) -3 thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form and 1.33 g of 2-mercaptopyridine in 60 cm3 of dimethylformamide and 2.1 cm3 of N, N-diisopropylethylamine. The mixture is diluted with ethyl acetate (400 cc) and the organic phase is washed with twice 500 cm3 of distilled water and then with 300 cm3 of half-saturated sodium bicarbonate solution and then 300 cm3 of half-saturated solution of chloride. sodium.

It is dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 min of mercury) at 20 ° C. The residue in solution in 25 cm3 of methylene chloride is chromatographed on a column of 300 g of silica MERCI (0.04 -0.06) (diameter of the column 5 cm) eluting with a mixture of methylene chloride-ethyl acetate 80-20 (vol.) And collecting fractions of 100 cm3. Fractions 17 to 34 are combined and concentrated to dryness under reduced pressure (20 mm Hg) at 350 ° C. It is dried for 15 hours under reduced pressure (0.2 mol of mercury) at 20 ° C. 3.9 g of 2-benzhydryloxycarbonyl-2-methoxyimino (2-tritylamino-1,3-thiazolyl-4-yl) are thus obtained. acetamido] -7-oxo-5-oxide-5- (2-pyrimetyl) -2-thio-vinyl-5-thia-aza-1-bicyclo [4.2.0] octene-2, syn-isomer, form E in the form of a yellow meringue .

 A mixture of 3.9 g of 2-benzhydryloxycarbonyl-2-methoxyimino (2-tritylamino-1,3-thiazol-4-yl) -7-acetamido-7-oxo-8-oxide (pyridyl) is stirred at -15 ° C. for 1 hour. 2) 2-thio-vinyl] -3-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn-isomer, E-form, 1.6 cc of dimethylformamide, 40 cc of methylene chloride and 097 cc of phosphorus trichloride . The solution obtained is poured into 600 cm3 of ethyl acetate and the organic phase is washed with twice 200 cm3 of half-saturated sodium bicarbonate solution and then twice with 200 cm3 of half-saturated sodium chloride solution. It is dried over sodium sulphate, filtered and the cake is washed with concentrated ethyl acetate (100 cm3) under reduced pressure (20 mm Hg) at 35 ° C.

The residue is taken up in 30 cm3 of methylene chloride and chromatography on a column of 150 g of MERCK silica (0.04-0.06) (column diameter: 4 cm) eluting with a methylene chloride mixture of methylene chloride. Ethyl 95-5 (vol.) Fractions of 100 cm 3 are collected. Fractions 10 to 40 are combined and concentrated to dryness under reduced pressure (20 mm of mercury) at 35 ° C. It is dried for 15 hours under reduced pressure (0.2 min of mercury) at 20 ° C. This gives 2.4 2-Benzhydryloxycarbonyl-2-methoxyimino-2 (2-tritylamino-1,3-thiazolyl) -2-acetamido] -7-oxo-8 (2-pyridyl) -2-thio-vinyl] -5-thia-5-azabicyclo L4 .2.0 octene-2, syn isomer, form E.

 A solution of 2.40 g of 2-benzhydryloxycarbonyl [2-methoxyimino (2-tritylamino-1,3-thiazolyl) -2-acetamido] -7-oxo (2-pyridyl) thio is stirred at 50 ° C. for 1 hour. -2-vinyl] -3-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form E in 21 cm3 of formic acid and 13 cm3 of distilled water. After cooling, the suspension is filtered and the cake is washed with 20 cm3 of distilled water. It is concentrated under reduced pressure (0.2 mm Hg) at 350 ° C. The residue is taken up with 100 cm3 of ethanol and concentrated under reduced pressure (20 mm Hg). The solid obtained is disintegrated in 20 cm 3 of distilled water at 20 ° C., and the cake is washed with successively 15 cm 3 of distilled water, 12 cm 3 of ethanol and 20 cm 3 of ether. It is dried under reduced pressure (0.2 mm of mercury) at 20 ° C. for 15 hours. 1.05 g of [(2-amino-1,3-thiazolyl) -2-methoxyimino-2-acetamido] are obtained. 7-carboxy-2-oxo-8 (2-pyridyl) -2-thio-vinyl-5-thia-5-aza-1-bicycloL4.2.07 octene-2, syn isomer, E-form.

Infra-red spectrum (KBr), characteristic bands (cm-1) 3500, 2820, 2600, 1775, 1670, 1650, 1630, 1575, 1450, 1415, 1380, 1040, 940, 765
Proton NMR spectrum (350 MHz, DMSO, δ ppm, J in Hz) 3.72 and 3.95 (2d, J = 18, 2H, 4H); 3.85 (s, 3H, -OCH 3) 5.20 (d, J = 4, 1H, H at 6); 5.77 (dd, J = 4 and 9, 1H, H at 7) 6.76 (s, 1H, 1H thiazole); 7.15 (d, J = 17, 1H, -CH = CHSi, 7.18 (s, 2H, amino), 7.44 (d, J = 16, 17, -CH = CHS-), 7.75; and 8.2 (d, t, 1H,
J = 8, H at 4 of the pyridine); 8.50 (t, 1H, J = 4, H2 of pyridine) 9.50 (d, J = 9, 1H, -CONH-).

EXAMPLE 6
To a solution of 3.4 g of 2-benzhydryloxycarbonyl-2-methoxyimino (2-tritylamino-1,3-thiazol-4-yl) -7-acetamido-8-oxo-2-tosyloxy-vinyl-3-thia-5-aza-1 bicyclo [4.2.0] octene-2, syn isomer, form E in 85 cm3 of dry N, N-dimethylformamide is added 0.43 g of 2-mercapto-pyridine N-oxide and 0.6 cm3 of N, N-diisopropylethylamine and stirred for 30 minutes at 25 ° C. A further 0.43 g of 2-mercapto-pyridine N-oxide and 0.6 cm 3 of N, N-diisopropylethylamine are added and the mixture is stirred for a further 10 minutes at 255 ° C. and then diluted by 250 ° C. cm3 of ethyl acetate. Wash twice with 200 cm3 of water and then with 200 cm3 of 0.1 N hydrochloric acid and with 200 cm3 of saturated sodium chloride solution; after drying over magnesium sulphate, the solvent is evaporated under reduced pressure (30 min of mercury) at 40 ° C.The residue (3.5 g) is combined with 0.5 g of product obtained in the same manner and chromatographed on silica gel. Merck silica (0.04-0.06) (diameter of the column: 5 cm) eluting with a mixture of ethyl acetate and methanol 98-2 (vol.) at a pressure of 50 kPa, collecting fractions of 120 cm3. In fractions 2 to 4, 1.1 g of unchanged starting material is recovered. Fractions 45 to 75 are concentrated to dryness under reduced pressure (30 mm of mercury) at 40 ° C. and 1.6 g of 2-benzhydryloxycarbonyl-2-methoxyimino (2-tritylamino-1,3-thiazolyl-4-yl) are obtained. acetamido] -7-oxo-8 (1-oxide-2-pyridyl) -2-thio-vinyl-5-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn-isomer, E-form in the form of a meringue gray.

Infra-red spectrum (CHBr3), characteristic bands (cm 1) 3390, 1780, 1720, 1680, 1585, 1510, 1465, 1420, 1040, 945, 750
Proton NMR Spectrum (350 MHz, CDCl3, δ ppm, J in Hz) 3.60 and 3.69 (AB, J = 18, 2H, -SCH2); 4.08 (s, 3H, = NOCH3); 5.12 (d, J = 4.1H, H at 6); 5.97 (dd, J = 4 and 9, 1H, H at 7); 6.57 (d,
J = 16, 1H, -CH = CHSi; 6.76 (s, 1H, H thiazole); 7.0 (s, 2H, -CHAr2 and (C6H5) 3CNN-); 7.1 to 7.5 (bulk, aromatic); 8.25 (d, J = 9, 1H, -CONH-).

 2.3 g of 2-benzhydryloxycarbonyl-2-methoxyimino (2-trityamino-1,3-thiazolyl) -2-acetamido] -7-oxo-8 (1-oxide-1-pyridyl) -2-thio-vinyl-3-yl are dissolved thia-5-azabicyclo [4.2.0] octene-2, syn isomer, Form E in 54 cc of formic acid. The solution is diluted with 21 cm3 of distilled water and stirred for 20 minutes at 500C. After hot filtration, the solvents are evaporated under reduced pressure (10 mm Hg) at 40 ° C. The residue is triturated with 50 cm3 of ethanol.

It is brought to dryness under reduced pressure (30 min of mercury) at 40 ° C. The operation is repeated once. The residue is taken up in 50 cm3 of ethanol; the solid is drained, washed with 15 cm3 of ethanol and then twice with 25 cm3 of ethyl ether, and then dried under reduced pressure (10 mm of mercury) at 25 ° C. 0.98 g of (2-amino) 1,3-thiazol-4-yl) -2-acetamido-2-carboxypoxo-8 (1-oxide-2-pyridyl) -2-thio-vinyl-3-thia-5-aza-1-bicycloL4.2.02 octene-2, syn isomer form E in the form of a gray powder.

Infrared spectrum (KBr), characteristic bands (cm) 3330, 1770, 1670, 1540, 1470, 1420, 1040, 950, 760
Proton NMR spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 3.75 and 4.16 (AB, J = 18.2H, -SCH2-); 3.88 (s, 3H, = NOCH3); 5.24 (d, J = 4.1H, H at 6); 5.73 (dd, J = 4 and 9, 1H, H at 7); 6.78 (s, 1H, H thiazole); 7.05 and 7.32 (AB, J = 16, 2H, -CH = CH-S-) 7.63 (d, J = 7, 1H, 3H pyridine); 7.1 to 7.5 (solid, 4H, H at 4 and 5 pyridine ± NH 2); 763 (d, J = 7, 1H, H to 3 pyridine); 8.32 (d, J = 6, 1H, 6H pyridine); 9.64 (d, J = 9, 1H, -CONH-).

EXAMPLE 7
To a solution of 4.9 g of 2-benzhydryloxycarbonyl-2-methoxy-imino-2-tritylamino-1,3-thiazol-4-yl) -7-acetamido-8-oxo-2-tosyloxy-3-vinyl-5-thia-aza 1-bicyclo [4.2.0] octene-2, syn isomer, form E in 40 cm3 of dimethylformamide, 0.738 g of 3-mercapto-6-methyl-1-oxide are added successively at 22 ° C., under a nitrogen atmosphere and with stirring. pyridazine and 0.89 cc of N, N-diisopropylethylamine.

Stirred for 15 minutes at 25 ° C., diluted with 600 cm 3 of ethyl acetate, washed successively with twice 120 cm 3 of water, 120 cm 3 of 0.1 N hydrochloric acid, 2 × 120 cm 3 of a solution. 2% sodium bicarbonate and 2 times 120 cm3 of a half-saturated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated to dryness at 200C under reduced pressure (20 min of mercury). The residue is taken up in 10 cm3 of ethyl acetate and the solution is filtered through a column of 50 g of Merck silica gel (0.05-0.2) (diameter of the column 2.4 cm). Elution with 500 cm3 of ethyl acetate, successively collecting a fraction 1 of 100 cm3 colorless, a fraction 2 of 20 cm3 pale yellow and a fraction 3 of 360 cm3. The latter is concentrated to dryness at 20 ° C. under reduced pressure (20 min of mercury). 4 g of 2-benzhydryloxycarbonyl-2-methoxyimino-2 (2-tritylamino-1,3-thiazolyl) -2-acetamido] -7 [ (6-methyl-1-oxide-3-pyridazinyl) 2-thio-vinyl] -3-oxo-5-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, Form E in the form of a brown meringue -orange.

Infra-red spectrum (KBr), characteristic bands (cm-1) 3400, 1780, 1720, 1680, 1530, 1495, 1450, 1330, 1210, 1050, 1040, 1000, 945, 810, 755, 700
Proton NMR Spectrum (35014Hz, CDCl3, 6 ppm, JHz) 2.45 (s, 3H, -CH3); 3.62 and 3.77 (2d, J = 18, 2H, -SCH 2 -); 4.09 (s, 3H, -OCH3); 5.08 (J, J = 4, 1H, H at 6); 5.93 (dd, J - 4 and 9, 1H,
H in 7); 6.03 (s, 1H, (C 6 H 5) 3 CHN-); 6.76 (s, 1H, H thiazole); 6.95 (s, 1H, -COOCH-).

 A solution of 3.9 g of 2-benzhydryloxycarbonyl [2-methoxyimino (2-tritylamino-1,3-thiazolyl) -2-acetamido] -7 [(6-methyl-oxide) is stirred at 50 ° C. for 30 minutes. 1-pyridazinyl-3-thio-vinyl-3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, Form E in a mixture of 60 cm 3 of formic acid and 25 cm 3 of 'distilled water. The cooled mixture is filtered towards 20 ° C. and the filtrate is concentrated to dryness at 30 ° C. under reduced pressure (0.05 nm of mercury). The residue is taken up in 50 cm3 of ethanol, concentrated to dryness at 20 ° C. under reduced pressure (20 mm of mercury) and this operation is repeated twice. The residual solid is treated with 40 cm3 of ethanol at reflux for 5 minutes and the suspension cooled to 20 C is filtered.

After drying, 1.96 g of [(2-amino-1,3-thiazolyl) -2-methoxyimino-2-acetamido] -2-carboxy-2 - [(1-methyl-1-oxide-1-pyridazinyl) thio) were collected after drying. 2-vinyl-3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form as a yellow powder.

Infra-red spec (KBr), characteristic bands (cm-1) 3420, 3320, 3230, 1765, 1675, 1655. 1620, 1535, 1325, 1210, 100, 1000, 810
Proton NMR Spectrum (350 MHz, DMSO d6, d in ppm, J in Hz) 2.33 (s, 3H, -CH3); 3.70 and 3.97 (2d, J = 18, 2H, -SCH 2 -); 3.86 (s, 311, -OcH3); 5.23 (d, J = 4, 1H, H at 6); 5.81 (dd, J = 4 and 9, 1H, H at 7); 6.76 (s, 1H, H thiazole); 7.18 to 7.20 (solid, 5H, -CH = CH- and -NH 3 +); 7.31 and 7.86 (2d, J = 7, H of pyridazine) 9.62 (d, J = 9, 1H, -COH fl-).

 The 3-mercapto-6-methyl-1-oxide pyridazine is prepared according to Belgian Patent 787 635.

EXAMPLE 8
One solution of 5 g of 2-benzhydryloxycarbonyl-2-methoxy-imino-2 (2-tritylamino-1,3-thiazolyl) -2-acetamido-7-oxo-5-oxide (2-tosyloxy-vinyl) -3-thia-5-aza 1-bicyclo [4.2.0] octene-2, syn isomer, E-form and 1.05 g of 6-acetamido-3-mercaptopyridazine in 50 cm3 of dry N, N dimethylformamide is treated with 1.1 cm 3 of
N, N diisopropylethylamine and heated for 1 hour 40 minutes at 60 C. The reaction mixture is diluted with 300 cm3 of ethyl acetate and washed 3 times with 200 cm3 of distilled water and with 250 cm3 of saturated solution of sodium chloride. sodium.After drying over magnesium sulfate
the organic phase is concentrated to dryness under reduced pressure (30 mm Hg) at 400 ° C. and the residue is chromatographed on a column of silica gel (0.06-0.04) (column diameter: 5 cm), eluting with under a pressure of 50 kPa with a mixture of cyclohexane and ethyl acetate 25-75 (vol.). Fractions of about 100 cm3 are collected.

Fractions 10 to 22, containing the pure product, are concentrated under reduced pressure (30 mm of mercury) at 40 ° C. 2.2 g of [(6-actamido-3-pyridazinyl) -2-thio-vinyl] benzhydryloxycarbonyl are obtained. 2-methoxyimino-2 (tritylamino-2-thiazol-1,3-yl-4) -2-acetamidog-7-oxo-5-oxide-5-thia-aza-1-bicyclo [4.2.0g octene-2, syn isomer, E-form under the shape of a brown meringue.

Rf = 0.48, silica gel chromatoplate; cyclohexane / ethyl acetate eluent 20-80 (vol.)
Infra-red spectrum (CHBr3), characteristic bands (cm1)
3380, 3220, 1785, 1715, 1700, 1680, 1450, 1370, 1040, 935, 750
Proton NMR Spectrum (350 MHz, CDCl3, 6 ppm, J in Hz)
2.05 (s, 3H, CH3CONH-); 3.26 and 4.8 (2d, J = 18, 2H, -S (O) CH 2 -); 4.08 (s, 3H, -NOCH3); 4.62 (d, J = 4, 1H, Hen 6); 6.12 (dd, J = 4 and 9, 1H, H at 7); 6.75 (s, 1H, H thiazole); 7.0 (s, 1H, -CHAr2);
7.09 (s, 1H, (C 6 H 5) 3 CNH-); 7.18 (d, J = 4, 1H, 5H pyridazine)
7.12 (d, J = 16, 1H, -CH = Ch-S-); 7.25 to 7.5 (mt, aromatics + -CH = CHS- + H to 4 of pyridazine); 8.30 (d, J = 9, 1H, -CONH-); 9.50 (s, 1H, CH3CONH-).

 A solution of 2.2 g of (6-acetamido-3-pyridazinyl) -2-thio-vinyl] -2-benzhydryloxycarbonyl [2-methoxyimino-2-tritylamino-1,3-thiazol-4-yl] acetamide] -7 8-oxo-5-thia-5-aza-1-bicyclo [4.2.2] oc-2-octene, syn-isomer, E-form in 12 cc of methylene chloride containing 0.47 cc of N, N-dimethylacetamide is cooled to -10 ° C and treated with 0.23 cm3 of phosphorus trichloride. The reaction mixture is stirred for 2 hours at -100C. Another 0.47 cm 3 of N, N dimethylacetamide and 0.23 cm 3 of phosphorus trichloride are added and the mixture is stirred for 1 hour at -10 ° C. and then diluted with 150 cm 3 of saturated sodium bicarbonate solution and 150 cm 3 of sodium acetate. ethyl; the aqueous phase is extracted with 100 cm3 of ethyl acetate.

The combined organic extracts are washed twice with 50 cm3 of saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to dryness under reduced pressure (30 mm Hg) at 40 ° C. and the residue is chromatographed on a column of silica gel (0.04-0.06) (column diameter: 4 cm), eluting with a mixture of cyclohexane and ethyl acetate 40-60 (vol.) under a pressure of 40 kPa. Fractions of about 100 cm3 are collected. Fractions 3 to 10, containing the pure product, are concentrated to dryness under reduced pressure (30 mm Hg) at 400 ° C. 1 g of [(6-acetamido-3-pyridazinyl) -2-thio-vinyl] -2-benzhydryloxycarbonyl [2-methoxyimino-2-tritylamino-1,3-thiazol-4-yl] acetamido] -7-oxoacetate are obtained. 8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form E as a yellow meringue.

 Rf = 0.58, silica gel chromatoplate; cyclohexane / ethyl acetate eluent 30-70 (vol.).

 Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3400, 3360, 2820, 1780, 1715, 1705, 1680, 1580, 1510, 1490, 1445, 1400, 1040, 940, 840, 755.

 1 g of 6-acetamido-6-pyridazinyl-3-thio-vinyl] -3-benzhydryloxycarbonyl-2 [2-methoxyimino-2-tritylamino-1,3-thiazol-4-yl] acetamido] -7-oxo were dissolved 8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form E in 23.5 cm3 of formic acid and added 9 cm3 of distilled water and then heated for 25 minutes at 50 ° C. The precipitate is filtered and the filtrate concentrated under reduced pressure (10 min of mercury) at 40 C. The residue is triturated in 50 cm3 of anol qu. It is evaporated under reduced pressure (30 mm Hg) at 40 ° C. This operation is repeated and the residue is taken up in 50 cm 3 of ethanol and the insoluble material is filtered and washed with 30 cm 3 of ethyl ether. 0.51 g of [(6-acetamido-3-pyridazinyl) -2-thio-vinyl] -3 [(2-amino-thiazol-1,3-yl) -4-methoxyimino-2-acetamido] -7-carboxy are obtained. 2-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn-isomer, form E in the form of a cream-colored solid.

Infrared spectrum (KBr), characteristic bands (cm) 3300, 1760, 1660, 1550, 1510, 1035, 940
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 2.10 (s, 3H, CH3CONH-); 3.72 and 3.98 (AB, J = 17, 2H, -SCH2); 3.86 (s, 3H, = NOCH3); 5.2 (d, J = 4.1H, H at 6); 5.78 (dd, J = 4 and 9, 1H, H at 7); 6.76 (s, 1H, H thiazole); 7.20 (s, 2H, -NH 2) 7.19 (d, J = 10, 1H, -CH = CH-S-); 7.33 (d, J = 10, 1H, -CH = CH-S); 7.78 (d, J = 9, 1H, H on pyridazine); 8.12 (s, 1H, CH3CONU-) 9.65 (d, J = 9, 1H, -CONH-); 8.27 (d, J = 9, 1H, H at 4 on pyridazine) 11.1 (brs, 1H, -CO 2 H).

The 3-acetamido-6-mercaptopyridazine may be prepared according to the method described by Mr. Kumagai and Mr. BANDO, Nippon-Kagaku
Zasshi 84, 995 (1963).

EXAMPLE 9
To a solution of 4 g of 2-benzhydryloxycarbonyl-2-methoxyimino [2-tritylamino-1,3-thiazol-4-yl] acetamido] -7-oxo-8: -5 (2-tosyloxyvinyl) -3 thia-5-azabicyclo [4.2.0] octene-2, 1. Form E in 40 cc of dry N, N dimethylformamide is added 0.7 g of 5-dioxo-4-methyl-3-thioxo-perhydrotriazine-1, 2.4 and 0.77 cm3 of N, N diisopropylethylamine. The reaction mixture is heated for 90 minutes at 60 ° C. and then diluted with 200 cm 3 of ethyl acetate and washed 4 times with 100 cm 3 of distilled water. After drying over magnesium sulphate, filtration and evaporation to dryness under reduced pressure ( 30 mm Hg) at 40 ° C. the residue is chromatographed on silica gel
Merck (0.04-0.06) (column diameter: 4 cm) eluting at 50 kPa with ethyl acetate, collecting 100 cm 3 fractions; the
Fractions 11 to 29 are concentrated to dryness under reduced pressure
(30 mm of mercury) at 40 ° C. 2.8 g of benzhydryloxycarbo are obtained
nyl-2 (5,5-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazine-3-yl)
2-thio-vinyl-3-vinyl [2-methoxyimino-2-tritylamino-1,3-thiazol-4-yl)
7-acetamido-8-oxo-5-thia-5-aza-1-bicyclo [4.2.0] octene-2,
syn isomer, form E.

Infra-red spectrum (CHBr3), characteristic bands (cm)
3360, 3200, 2820, 1795, 1710, 1680, 1590, 1515, 1490, 1450, 1040, 760
Proton NMR Spectrum (350Hz, CDCl3, 6 ppm, JHz) 3.30 (s, 3H, -Ch3 triazine); 3.30 and 4.0 (AB, J = 18, -S (O) CH 2); 3.88
(s, 3H, = NOCh3); 4.65 (d, J = 4, 1H, H at 6); 6.02 (dd, J = 4 and 9,
1H, H at 7); 6.32 (d, J = 16, 1H, -CH = CH-S); 6.68 (s, 1H, H from
thiazole); 6.92 (s, 1H, -CHAr2); 7.15 to 7.55 (massive, aromatic +
CONH + (C6H5) 3CNH- + -CH = CDHS-).

To a cooled solution at 30 ° C. of 2.8 g of benzhydryloxy
2-carbonyl-2- (4,6-dioxo-4-methyl-1,4,5,6-tetrahydro-triazine -1,2,4-yl) -3-thio-vinyl] -3 [methoxyimino-2 (tritylamino-2-thiazol)] 1.3 yl-4) -2
7-acetamido-7-oxo-5-oxide-5-aza-1-azabicyclo [4.2.0] octene-2,
isomer sya, form E in 30 cm3 of methylene chloride and 1.1 cm3
of N, N dimethylacetamide, add 0.53 cm3 of phos trichloride
The mixture is stirred and stirred for 2 hours at -15 ° to -10 ° C. and then diluted with ethyl acetate (250 cc). We wash twice
per 100 cm3 of saturated sodium bicarbonate solution and then
250 cm3 of saturated sodium chloride solution, dried over sulphate
magnesium, filter and evaporate the solvent under reduced pressure
(30 mn of mercury) at 40 ° C. The residue is chromatographed on gel of
silica (0.04-0.06) (column diameter: 4 cm) eluting with a mixture of cyclohexane and ethyl acetate 20-80 (vol.
pressure of 50 kPa by collecting fractions of 100 cm3. The
Fractions 4 to 16 are concentrated to dryness under reduced pressure (30 mm
of mercury) at 40 ° C. 1.75 g of benzhydryloxycarbonyl-2 are obtained.
[(4,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazol-3-yl) thio-z
vinyl] -3 [2-methoxyimino-2-tritylamino-thiazol-1, 3-yl) -2 acetami
7-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form as a cream-colored solid.

Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3380, 1785, 1710, 1680, 1515, 1490, 1445, 1040, 940, 755, 740
Proton NMR Spectrum (350 MHz, CDCl3, 6 ppm, JHz) 3.41 (s, 3H, -CH3 triazine); 3.58 and 3.68 (AB, J = 18, 2H, -SCH2-); 4.04 (s, 3H, = NOCH3); 5.10 (d, J = 4.1H, H at 6); 5.95 (dd, J = 4 and 9, 1H, H at 7); 6.74 (s, 1H, H thiazole); 6.84 (d, J = 17, 1H, -CH = CH-S-); 6.96 (s, 1H, -CHAr2); 7.03 (d, J = 9, 1H, -CONH-); 7.15 to 7.55 (solid, aromatic + (C6H5) 3CNH- + -CH = CHS-); 10.8 (s, 1H, -NH-triazine).

 1.7 g of 2-benzhydryloxycarbonyl-2 (5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazo-1-yl) -thio-2-vinyl] -3 (methoxyimino) 2 (2-tritylamino-1,3-thiazolyl) -2-acetamido-7-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form are dissolved in 24 cm 3 of 98% formic acid; after adding 16 cm3 of distilled water, the reaction mixture is heated for 25 minutes at 50 ° C. and then filtered while hot and concentrated to dryness under reduced pressure (10 nm of mercury) at 400 ° C. The solid is triturated with 40 cm3 of ethanol and is brought to dryness under reduced pressure (30 mm of mercury) at 40 ° C. This operation is repeated once and then the residue obtained is taken up in 30 cm 3 of ethanol. The insoluble material is filtered off, washed with 10 cm3 of ethanol and twice 50 cm3 of ether, and dried under reduced pressure (10 mm Hg) at 250C. 0.85 g of [(2-amino-1,3-thiazolyl) -2-methoxyimino-2-acetamido-7-carboxy-2 - [(4,6-dioxo-4-methyl-1,4,5-tetrahydro) are obtained. , 6-triazine-1,2,4-yl-3-thio-2-vinyl-3-oxo-8-thia-5-aza-1 bicyclo [2.2.2] octene-2, syn isomer, form E in the form of a solid of cream colour.

Rf = 0.37, silica gel chromatoplate; eluent ethyl acetate-water-acetic acid 3-2-2 (vol.)
Infrared spectrum (KBr), characteristic bands (cm) 3300, 3260, 2600, 1770, 1705, 1680, 1630, 1585, 1530, 1375, 1040, 950
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 3.35 (s, 3H, -CH3 triazine); 3.65 and 3.88 (AB, J = 18, 2H, -SCH 2) 3.87 (s, 3H, = NOCH 3); 5.22 (d, J = 4, 1H, H at 6); 5.80 (dde, J = 4 and 9, 1H, H at 7); 6.75 (s, 1H, H thiazole); 6.83 (d, J = 16, -CH = CH-S-); 7.11 (d, J = 16, 1H, -CH = CH-S-); 7.20 (bs, 3H, -NH 3 +, 9.58 (d, J = 9, 1H, -CONH-).

 The 5-dioxo-4-methyl-3-thioxo-perhydrotriazine-1,2,4 may be prepared according to M. PESSON and M. ANTOINE: Bull. Soc. Chim.

Fr., 1590 (1970).

EXAMPLE 10
A mixture of 7.02% of 2-benzhydryloxycarbamoyl [2-methoxyimino-2-tritylamino-1,3-thiazolyl-4-acetamido] -7-oxo-5-oxide-5 is stirred at 60 ° C. for 2 hours under nitrogen. (2-tosyloxy-vinyl) -5-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn-isomer, E-form, 50 cm3 of dimethylformamide, 1.34 cc of diisopropylethylamine and 1.33 g of dioxo-5 6-ethyl-3-thioxo-3-perhydrotriazine-1,2,4. The cooled mixture is diluted with 600 cm 3 of ethyl acetate and the organic phase is washed with twice 125 cm 3 of water 150 cm 3 of 0.5 N hydrochloric acid, twice 125 cm 3 of a half-saturated solution of sodium bicarbonate and 2 times 125 cm3 of water saturated with sodium chloride, dried over magnesium sulphate and concentrated to dryness at 300 ° C. under reduced pressure (20 mm of mercury). The residue is dissolved in 150 cm 3 of sodium acetate. ethyl and chromatography the solution on a Merck silica gel column (0.04-0.06) (column diameter: 7 cm). It is eluted with 3 liters of ethyl acetate under a pressure of 40 kPa, collecting 100 cm 3 fractions. Fractions 10 to 23 are concentrated to dryness at 200C under reduced pressure (20 mm Hg). 5.3 g of 2-benzhydryloxycarbonyl (5,6-dioxo-4-ethyl-1,4,5,6-tetrahydro-1,2,4-triazo-3-yl) -thio-2-vinyl] -3-methoxyimino are thus collected. -2- (2-tritylamino thiazol-1,3-yl) -2-acetamido-7-oxo-5-oxide-5-thia-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E in the form of a light brown solid.

4,0 (s, 3H, -OCH3) ; 4,68 (d, J = 4, 1H,
H en 6) ; 6,04 (dd, J = 4 et 9, 1H, H en7) ; 6,70 (s, 3H, -OCH3); 6,85 (d J = 16, -CH=CHS-) ; 6,97 (s, 1H, -COOCH-).Infrared spectrum (KBr), characteristic bands (cm) 3500, 2000, 1785, 1710, 1685, 1520, 1495, 1450, 1040, 945, 755, 700
Proton NMR Spectrum (350 MHz, CDCl3, 6 ppm, JHz) 1.27 (t, J = 7.3H, -CH3); 3.40 and 4.12 (2d, J = 18, 2H> -SCH 2 -) 3.86 (q, J = 7,

4.0 (s, 3H, -OCH 3); 4.68 (d, J = 4.1H,
H in 6); 6.04 (dd, J = 4 and 9, 1H, H17); 6.70 (s, 3H, -OCH 3); 6.85 (d = 16, -CH = CHS-); 6.97 (s, 1H, -COOCH-).

 To a cooled solution at -14 ° C. of 5.2 g of 2-benzhydryloxycarbonyl (5,6-dioxo-4-ethyl-1,4,5,6-tetrahydro-1,2,4-triazine-3-yl) thio-2 vinyl] -3 [2-methoxyimino (2-tritylamino-1,3-thiazolyl) -2-acetamido] -7-oxo-5-oxide-5-thia-1-axa-bicyclo [4.2.0] octene-2, isomer Syn, form E in 100 cm3 of methylene chloride, is successively added 1.95 cm3 of dimethylacetamide and 1 cm3 of phosphorus trichloride. The mixture is stirred for 1 hour at a temperature in the region of -12 ° C. and then 0.5 cm3 of phosphorus trichloride are added again and the mixture is stirred at -1 ° C. for 15 minutes. The mixture, diluted with 600 cm 3 of ethyl acetate, is washed with 2 times 250 cm 3 of a 2% solution of sodium bicarbonate and 2 times 250 cm 3 of a semisaturated solution of sodium chloride. is dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (20 min of mercury) at 200C. The residual oil is purified by chromatography on a column of 100 g of Merck silica gel (0.05-0.2) (diameter of the column: 4.5 cm), the product being previously fixed on 25 g of gel of silica. Eluted with 500 cm3 of ethyl acetate, collecting 50 cm3 fractions. The fractions 5 to 9 are concentrated to dryness at 200 ° C. under reduced pressure (20 min of mercury) and 5.3 g of 2-benzhydryloxycarbonyl [(4,6-dioxo-4-ethyl-1,4,5,6-tetrahydro-triazine) are recovered. 1,2,4-yl-3-thio-2-vinyl-3-methoxyimino-2 (tritylamino-2-thiazol-1,3-yl) -4-acetamido] -7-oxo-8-thia-5-azabicyclo [4.2. 0] octene-2, syn isomer, form E in the form of an orange meringue.

4,05 (s, 3H, -OCH3) ; 5,12 (d, J = 4, 1H, H en 6) ; 5,94 (dd, J = 4 et 9, 1H, H en 7) ; 6,77 (s, 1H,
H du thiazole) ; 6,87 (d, J = 16, 1H, -CH=CHS-) ; 6,97 (d, J = 9, 1H, -CONH-) ; 6,96 (s, 1H, -COOCHr) ; 8,20 (s, 1H, =NNH CO-). Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3385, 1785, 1710, 1680, 1515, 1490, 1445, 1040, 940, 755, 740
Proton NMR Spectrum (350 MHz, CDCl 3, 6 ppm, J in Hz) 1.34 (t, J = 7.3H, -CH 3); 3.60 and 3.70 (2d, J = 18, 2H, -SCH 2 -) 3.95 (q, J = 7, 2H,

4.05 (s, 3H, -OCH 3); 5.12 (d, J = 4.1H, H at 6); 5.94 (dd, J = 4 and 9, 1H, H at 7); 6.77 (s, 1H,
Thiazole); 6.87 (d, J = 16, 1H, -CH = CHS-); 6.97 (d, J = 9, 1H, -CONH-); 6.96 (s, 1H, -COOCHr); 8.20 (s, 1H, = NNHCO-).

 3 g of 2-benzhydryloxycarbonyl (5,6-dioxo-ethyl-1,4-tetrahydro-1,4,5,6-triazin-1,2,4-yl-3-thio) -2-vinyl-3-methoxyimino-2-tritylamino are dissolved 2-thiazol-1,3-yl) -2-acetamido-7-oxo-5-thia-aza-1-bicyclo [4.2.0] octene-2, syn isomer, Form E in 30 cc of formic acid, diluted 14 cm3 of water and heated at 50 ° C. with stirring for 30 minutes. The mixture cooled to 20 ° C. is filtered and the filtrate is concentrated to dryness at 30 ° C. under reduced pressure (0.05 mm Hg).

The solid is taken up in 100 cm3 of ethanol and concentrated to dryness at 200C under reduced pressure (20 mm Hg), this operation is repeated 3 times and the solid is treated at 600C with 500 cm3 of ethanol. After removal of a slight insoluble matter, the solution is concentrated to 40 cm3 (300 ° C. under 20 mm Hg) and cooled to +4 ° C. After filtering and drying the insolable, 1.49 g of [( 2-amino-1,3-thiazolyl-4-yl] -2-methoxyiminoacetamido] -7-carboxy-2 - [(4,6-dioxo-4-ethyl-1,4,5,6-tetrahydro-1,2,4-triazine) 2 → 4-yl-3-thio-2-vinyl-3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form B.

3,86 (s 3H, -OCH3) ; 5,20 (d, J = 4, 1H, H en 6) n 5,78 (dd, J = 4 et 9, 1H, H en 7) ; 6,75 (s, 1H, H du thiazole) ; 6,95 (d, J = 16, 1H, -CH=CHS-) ; 7,13 (d, J = 16, 1H, =CHS-) ; 7,18 (s, 3H, -NH3+) ; 9,63 (d, J = 9, 1H, -CONH-).Infrared spectrum (KBr), characteristic bands (cm-1) 3500, 2200, 1770, 1700, 1680, 1530, 1040, 940
Proten NMR Spectrum (350 MHz, DMSO d6, δ ppm, J in Hz) 1.22 (t, J = 7.3H, -CH3); 3.65 and 3.80 (2d, J = 18, 2H, -SCH 2 -); 3.80 (q, J = 7, 2H,

3.86 (s 3H, -OCH 3); 5.20 (d, J = 4.1H, H at 6) n 5.78 (dd, J = 4 and 9, 1H, H at 7); 6.75 (s, 1H, H thiazole); 6.95 (d, J = 16, 1H, -CH = CHS-); 7.13 (d, J = 16, 1H, = CHS-); 7.18 (s, 3H, -NH 3 +); 9.63 (d, J = 9, 1H, -CONH-).

 The 5-dioxo-4-ethyl-3-thioxo-1,2,4-perhydrotriazine can be prepared according to the method described in the beige patent 830 455.

EXAMPLE
A mixture of 9.79 g of 2-benzhydryloxycarbonyl [2-methoxyimino-2-tritylamino-1,3-thiazol-4-yl] -acetamido] -7-oxo-8-oxohydrate is stirred at 60 ° C. under nitrogen for 1 hour. (2-tosyloxy-vinyl) -3-thia-5-azabicyclo [4.2.0] octene-2. syn isomer, E-form, 50 cm3 dimethylformamide, 2.28 g dioxo-5,6-isopropyl-3-thioxo-3-perhydrotriazine-1,2,4 and 2,12 cm3 N, M-diisopropylethylamine.The mixture is diluted 600 cm3 of ethyl acetate, washed with 2 times 150 cm3 of water, 100 cm3 of 1N hydrochloric acid, 2 times 150 cm3 of a 2% solution of sodium bicarbonate and 2 liver 150 cm3 of a solution. half-saturated sodium chloride, dried over sodium sulphate, filtered and concentrated to dryness at 20 ° C. under 20 mol of mercury.The purification is carried out by chromatography on a column of 300 g of Merck silica gel (0.05- 0.2) (diameter of the column: 5 cm). The mixture is eluted with a cyclohexane-ethyl acetate mixture 40-60 (vol), collecting 1 liter fractions. Fractions 9 to 14 are concentrated to dryness at 200 ° C. under 20 mm of mercury. 7.4 g of benzhydryloxycarbonyl-2 (dioxo-5,6-isopropyl-4-tetrahydro-1,4,5,6-triazine-1 are collected, 2,4-yl-3-thio-2-vinyl] -3 [2-methoxyimino-2-tritylamino-1,3-thiazol-4-yl] -7-acetamido-5-oxo-5-oxide-5-thia-aza-1-bicyclo [ 4.2.0] octene-2, syn isomer, form E in the form of a yellow-orange meringue.

Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 1.45 (d, J = 7.6H, -CH (CH3) 2); 3.68 and 4.29 (2d, J = 19, 2H, -SCH 2 -); 3.84 (s, 3H, -OCH 3); 4.35 (mt, 1H, -CH (CH 3) 2); 5.05 (d, J = 4.1H,
H in 6); 5.86 (dd, J = 4 and 9, 1H, H at 7); 6.78 (s, 1H, H-thiazole); 6.97 (s, 1H, -COOCH-); 6.96 (d, J = 16, 1H, -CH = CHS-); 7.11 (d, J = 16, 1H, = CHS-); 8.74 (s, 1H, -NH C (C6H5) 3); 9.05 (d,
J = 9, 1H, -CONH-); 12.53 (s, 1H, = NNH CO- or

A solution of 7.3 g of benzhydryloxycarbonyl-2 - [(4,6-dioxo-4-isopropyl-1,4,5,6-tetrahydro-1,2-triazine) is treated at -10 ° C. with stirring for 1 hour 30 minutes. 4-yl-3-thio-2-vinyl] -3-methoxyimino-2 (tritylamino-2-thiazol-1,3-yl-4) -2-acetamido-7-oxo-5-oxide-5-thia-aza-1-bicyclo [4.2. 0] octene-2 isomer syn, form E and 2.73 cm3 of dimethylacetamide in 100 cm3 of methylene chloride per 1.25 cm3 of phosphorus trichloride. The mixture is diluted with 600 cm 3 of ethyl acetate, washed with 2 × 15 cm 3 of a 2 × solution of sodium bicarbonate and twice with 150 cm 3 of a half-saturated solution of sodium chloride, dried over sodium sulphate, filtered and concentrated to dryness at 20 ° C. under reduced pressure (20 min of mercury). The residue is fixed on 50 g of silica gel
Merck (0.05-0.2) and the powder deposited on a column of 200 g of silica gel (column diameter: 4 cm). Eluted with ethyl acetate-cyclohexane 80-20 (vol.), Collecting 200 cm3 fractions. Fractions 3 and 4 are concentrated to dryness at 20 ° C. under a pressure of 20 mm of mercury and 5.3 g of 2-benzhydryloxycarbonyl-2 - [(4,4-dioxo-4,6-isopropyl) -tetrahydro-1,4,5 are collected. 6 1,2,4-triazine-1,2-yl) -3-thio-vinyl] -3 [methoxyimino-2 (tritylamino-2-thiazol-1,3-yl) -4-acetamido] -7-oxo-8-thia-5-aza bicyclo [4.2.0] octene-2, syn isomer, form E in the form of a yellow-orange meringue.

Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3400, 1790, 1720, 1685, 1520, 1495, 1450, 1045, 945, 760, 740
Proton NMR spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 1.46 (d, J = 7.6H, -CH (CH3) 2); 3.64 and 3.84 (2d, J-18, 2H, -SCH2-) 3.82 (s, 3H, -OCH3); 4.36 (mt, 1H, -CH (CH 3) 2); 5.24 (d, J = 4.1H at 6); 5.76 (dd, J = 4 and 9, 1H, H at 7); 6.72 (s, 1H, H thiazole); 6.94 (d, J = 16, 1H, -CH = CHS-); 6.94 (s, 1H, -COOCK <) 7.0 (J, J = 16, 1H, = CHS-); 8.78 (s, 1H, -NHC (C6H5) 3); 9.58 (d, J = 9, 1H, -GONH-); 12.53 (s, 1H, = NNHCO- or

 5.25 g of benzhydryloxycarbonyl-2 - [(4,6-dioxo-4-isopropyl-1,4,5,6,6-tetrahydro-1,2,4-tetrahydro-1-yl) -3-thio-vinyl] -3-methoxyimino are dissolved 2 (tritylamino-2-thiazol-1,3-yl-4) -2-acetamido] -7-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E in 50 cc of acid formic, diluted with 20 cm3 of water and heated at 50 C with stirring for 30 minutes. After cooling to 20 ° C., the mixture is filtered and the solution is concentrated to dryness at 300 ° C. under reduced pressure (0.05 mm Hg). The residue is taken up in 25 cm3 of ethanol, the solvent is stripped at 20 ° C. under a pressure of 20 mm of mercury and these operations are repeated 3 times. The solid is treated under reflux with 600 cm 3 of ethanol, filtered and filtered. concentrated at 50 cm3 at 20 ° C. under 20 minutes of mercury. After filtration and drying of the insoluble material, 2 g of t (2-amino-1,3-thiazol-4-yl) -2-methoxyimino-2-acetamido] -7-carboxy-2 - [(dioxo-5,6-isopropyl) 4-Tetrahydro-1,4,5,6-triazin-1,2,4-yl-3-thio-2-vinyl] -3-oxo-5-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm-1) 3500, 2200, 1775, 1705, 1680, 1530, 1050, 950
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 1.48 (d, J = 7.6H, -CH (CH3) 2); 3.64 and 3.82 (2d, J = 18, 2H, -SCH 2 -) 3.85 (s, 3H, -OCH 3); 4.42 (mt, 1H, -CH (CH3) 2); 5.22 (d, J = 4, 1H, H at 6); 5.78 (dd, J = 4 and 9, 1H, H at 7); 6.74 (s, 1H, H thiazole); 6.93 (d, J = 16, 1H, -CH = CHS-); 7.07 d, J = 16, 1H,
CHS-); 7.18 (s, 3H, -NH 3 +); 9.62 (d, J = 9, 1H, -CONH-); 12.55 (s, 1H, = NNHCO- or = NN =--ON).

 The dioxo-5,6-isopropyl-3-thioxo-3-perhydrotriazine-1,2,4 can be prepared according to the method described in patent BE 830 455.

EXAMPLE 12
A mixture of 10.04 g of 2-benzhydryloxycarbonyl [2-methoxylimino-2-tritylamino-1,3-thiazol-4-yl] -2-acetamido-7-oxo-5-oxide-5 (2 ×) is stirred at 60 ° C. under nitrogen for 3 hours ( 2-tosyloxyvinyl) -5-thia-5-aza-bicyclo [4.2.0] octene-2, syn isomer, E-form, 200 cm3 of dimethylformamide, 2.22 g of 4-allyl-5,6-dioxo thioxide 3 perhydrotriazine-1,2,4 and 2,1 cm3 of N, N-diisopropylethylamine. The mixture is diluted with 600 cm 3 of ethyl acetate, washed twice with 200 cm 3 of water and twice with 100 cm 3 of semisaturated water of sodium chloride, dried over sodium sulfate, filtered and concentrated to dryness. at 200 ° C. under 20 mm of mercury. The residue is taken up in 50 cm 3 of methylene chloride, 20 g of Merck silica gel (0.05-0.2) are added and the mixture is concentrated to dryness at 20 ° C. under 20 minutes of mercury. The powder is deposited on a column of 200 g of Merck silica gel (0.05-0.2) (column diameter: 6.1 cm). The mixture is eluted with cyclohexane-ethyl acetate 2 liters 20-80 (vol), 1 liter 10-90 (vol) and then 2 liters of ethyl acetate, collecting 120 cm3 fractions. Fractions 8 to 28 are evaporated to dryness at 20 ° C. under 20 minutes of mercury. 3.7 g of [(allyl-4-dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,23,4-yl-3) thiovinyl] -3-benzhydryloxycarbonyl-2-methoxyimino-2 (tritylamino) are collected 2-thiazol-1,3-yl-4) -2-acetamido] -7-oxo-5-oxide-5-thia-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E in the form of a orange meringue.

Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3380, 1800, 1720, 1670, 1515, 1045, 940
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 3.60 and 4.29 (2d, J = 18.2H, -SCH2-); 3.85 (s, 3H, -OCH 3); 4.45 (d,
J = 5, 2H,> NCH 2 -); 5.05 (d, J = 4, 1H, H at 6); 5.17 to 5.27 (Mc, 2H, = CH 2); 5.78 to 5.92 (2Mt, 2H, 7H and -CH = CH 2); 6.78 (s, 1H, H thiazole); 6.95 (d, J = 16, 1H, -CH = CHS-); 6.97 (s, 1H, -COOCH #); 7.09 (d, J - 16, 1H, = CHS-); 8.78 (s, 1H, -NHC (C 6 H 5); 9.04 (d,
J = 9, 1H, -CONH-); 12.62 (s, 1H, = N-NH-CO- or

 To a mixture cooled to -10 C of 2.34 g of {E (allyl-3) -4-dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-1] thio -2-vinyl] -2-benzhydryloxycarbonyl [2-methoxyimino-2-tritylamino-1,3-thiazolyl-4-yl] acetamido] -7-oxo-5-oxide-5-thia-bicyclo [4.2.0] octene-2 , syn isomer, form E and 0.85 cm3 of dimethylacetamide in 23 cm3 of methylene chloride, 0.40 cm3 of phosphorus trichloride is added and the mixture is stirred for 30 minutes at 3 ° -10 ° C. The mixture is poured into 250 cm 3 of methyl acetate, washed with 50 cm of water, 50 cm of saturated sodium bicarbonate solution, and 2 times 50 cm of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness at 30 C under 20 minutes of mercury.

The residue, dissolved in 10 cm3 of methylene chloride, is fixed on 10 g of Merck silica gel (0.05-02,) and deposited on a column of 30 g of silica gel (column diameter: 1, 4 cm). Is eluted with 500 cm3 of a cyclohexane-ethyl acetate mixture 20-80 (vol.), Collecting 60 cm3 fractions. Fractions 2 to 4 are evaporated to dryness at 20 ° C. under reduced pressure (20 mm Hg). 1.34 g of {[(allyl-3) -4-dioxo-5,6-tetrahydro-1,4,5,6-triazin-1,2,4-yl] -3-thio-2-vinyl) -3-benzhydryloxycarbonyl (1.34 g) were collected. -2- [2-methoxyimino-2-tritylamino-1,3-thiazolyl-4-yl] acetamido] -7-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form under the shape of a yellow meringue.

Infrared spectrum (CHBr3), characteristics (cm-1) 3380, 1780, 1720, 1680, 1515, 1490, 1445, 1040, 940, 750, 735
Proton NMR Spectrum (350 MHz, CDCl3, 6 ppm, JHz) 3.57 and 3.66 (2d, J = 18, 2H, -SCH2-); 4.03 (s, 3H, -OCH3); 4.52 (d, j = 4, 2H, -NCH 2 -); 5.09 (d, J - 4, 1H, H at 6); 5.26 to 5.38 (2d, 2H = CH 2); 5.78 to 5.88 (mi, 1H, -CH = CH2); 5.92 (dd, J = 4 and 93 1H, H at 7); 6.74 (s, 1H, H thiazole); 6.86 (d, J = 16, -CH = CHS-); 6.96 (s, 111, -COOCH-); 7.05 (d, J = 9, 1H, -CONH-) 11.68 (s, 1H, = NNHCO- or

 1.34 g of {[(allyl-3) -4-diono-5,6-tetrahydro-1,4,5,6-triazin-1,2,4-yl] -3-thio-2-vinyl) -3-benzhydryloxycarbonyl are dissolved. 2- [2-methoxyimino (2-trityamino-1,3-thiazolyl-4-yl) -acetamide] -7-oxo-5-thia-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form in 13 cm3 of formic acid, 6.5 cm3 of water are added and heated with stirring at 50 ° C. for 30 minutes. After cooling, the mixture is filtered and the solution is concentrated to dryness at 30 ° C. under reduced pressure (0.05 ° C.). mn of mercury). The residue is taken up in 50 cm3 of ethanol, the solvent is removed under reduced pressure (20 mm Hg) at 20 ° C. and this operation is repeated 3 times. The residue is refluxed with ethanol (100 cc), a slight insoluble material is removed. by filtration, the filtrate is concentrated to 50 cm3 at 30 ° C. under reduced pressure (20 mm Hg) and cooled for 1 hour at +4 ° C. After filtration and drying of the precipitate, 0.37 g of allyl-3) -4-dioxo-5,6-tetrahydro-1,4,5,6-triazin-1,2,4-yl-3-thio-2-vinyl] -3 [(2-aminothiazol-1,3-yl)) 4) -2-methoxyimino-2-acetamido] -7-carboxy-2-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm-1) 3600, 2300, 1775, 1710, 1680, 1535, 1040, 945
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 3.63 and 3.80 (2d, J = 18, 2H, -SCH2-); 3.88 (s, 3H, -OCH 3); 4.48 (d,
J = 4, 2H, NCH 2 -); 5.19 to 5.27 (mt, 3H, CH 2 and H at 6); 5.74 to 5.92 (mt, 2H, -CH = CH 2 and H at 7); 6.74 (s, 1H, H thiazole) 6.91 (d, J = 16, 1H, -CH = CHS-); 7.09 (d, J = 16, 1H, = CHS-); 7.18 (s, -NH3); 9.60 (d, J = 9, 1H, -CONH-); 12.61 (s, 1H, = N-NHCO

 4-Allyl -5,5-dioxo-3-thioxo-1,2,4-perhydrotriazine can be prepared according to the method described in Belgian Patent 830 455.

EXAMPLE 13
A solution of 0.58 g of f (2-amino-1,3-thiazolyl-4-yl) -2-methoxyimino-7-acetamido-2-carboxy-8-oxo-2-tosyloxyvinyl-3-thia-5-aza-2-yl 1 bicyclo [4.2.0] octene-2, syn isomer, E-form and 0.31 g of dioxo-5,6 (2-hydroxyethyl) -4-thioxo-perhydrotriazine-1,2,4 sodium salt in 10 cm3 of N, N dimethylformamide is heated for 4 hours at 60 C. The cooled reaction mixture is diluted with 150 cm3 of ethyl ether, the precipitate is separated on a filter, washed twice with 25 cm3 of ether and dried. 0.6 g of (2-amino-1,3-thiazol-4-yl) -2-methoxyimino-acetamido-7-carboxy-2 - [[dioxo-5,6-hydroxy-2-ethyl] -4-tetrahydro] are obtained. 1,4,5,6-triazine-1,2,4-yl-3-thio-2-vinyl-3-oxo-8-thia-5-aza-1-bicycloL4.2.0g octene-2, syn isomer, crude form E under the form of an amorphous beige powder.

Rf = 0.42, silica gel chromatoplate, eluent mixture of ethyl acetate, acetic acid and water 60-20-20 (vol.)
The product can be purified as follows. it is dissolved in 50 cm3 of dilute sodium hydroxide solution (pH = 8) and then brought to pH = 5 with dilute hydrochloric acid; after filtration of a slight insoluble material, the solution obtained is chromatographed on a column of XAD-2 resin (diameter: 2.4 cm), successively eluting the impurities with 1 liter of distilled water and then the pure product with 1 liter of mixture water-ethanol 95-5 (vol.) After concentration under reduced pressure (5 mm Hg) at 30 ° C. and drying, 0.2 g of [(2-aminothiazol-1,3-yl-4) - 2-methoxyimino-2-acetamido-7-carboxy-2 {[dioxo-5,6 (hydroxy-2ethyl) -4-tetrahydro-1,4,5,6-triazine-1,2,4-yl-37-thio-2-vinyl) - 3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form as light yellow crystals.

; 3,84 (s, 3H, -NOCH3) ; 3,92 (t,
J = 5, 2H,

; 5,10 (d, J = 4, 1H, H en 6) ; 5,65 (dd,
J = 4 et 9, 1H, H en 7) ; 6,39 (d, J = 16, 1H, -CH=CH-S-) ; 6,73 (s, 1H, H en 5 du thiazole) ; 7,17 (s large, 2H, -NH2) ; 7,37 (d,
J = 16, 1H, -CH=CH-S-) ; 9,54 (d, J = 9, 1H, -CONH-C7).Proton NMR spectrum (350 MHz, DMSO d6> 6 ppm, J = Hz) 3.60 (t, J = 5.2H,

; 3.84 (s, 3H, -NOCH3); 3.92 (t,
J = 5, 2H,

; 5.10 (d, J = 4.1H, H at 6); 5.65 (dd,
J = 4 and 9, 1H, H at 7); 6.39 (d, J = 16, 1H, -CH = CH-S-); 6.73 (s, 1H, H in 5 thiazole); 7.17 (brs, 2H, -NH 2); 7.37 (d,
J = 16, 1H, -CH = CH-S-); 9.54 (d, J = 9, 1H, -CONH-C7).

0.13 g of C (2-amino-1,3-thiazolyl) -2-methoxyimino-2-acetamido] -7-carboxy-2 - [(dioxo-5,6-hydroxy-2-ethyl) -4) 1,2,5-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-thio-viyl) -3-oxo-5-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E in 21 cm3 of solution
N / 100 sodium bicarbonate. The solution is frozen at -80 ° C. and freeze-dried. 0.145 g of the sodium salt of L (2-amino-1,3-thiazol-4-yl) -2-methoxyimino-2-acetamido-7-carboxy-2-hydroxydroxo-5,6 (2-hydroxyethyl) -4-tetrahydro are obtained. 1,4,5,6-triazine-1,2,4-yl-3-thio-2-vinyl-3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form in the form of a white lyophilisate.

 Rf = 0.28, silica gel chromatoplate; eluent mixture of ethyl acetate-acetic acid-water 60-20-20 (vol.).

3,87 (s, 3H, = NOCH3) ; 5,07 (d,
J = 4, 1H, H en 6) ; 5,60 (dd, J = 4 et 9, 1H, H en 7) ; 6,31 (d,
J = 16, 1H, -CH=C11-S-) ; 6,71 (s, 1H, H en 5 du thiazole) ; 7,17 (s large, 2H, -NH2) ; 7,36 (d, J = 16, 1H, -CH-CHS-) ; 9,54 (d, J = 9, 1H, -CONH-).Proton NMR spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 3.50 (AB unsolved, 2H, -SCH2-); 3.60 (t, J = 6.2H,) NCH 2 CH 2 OH 3.91 (t, J = 6.2H,

3.87 (s, 3H, = NOCH 3); 5.07 (d,
J = 4.1H, H at 6); 5.60 (dd, J = 4 and 9, 1H, H at 7); 6.31 (d,
J = 16, 1H, -CH = C11-S-); 6.71 (s, 1H, H in 5 thiazole); 7.17 (brs, 2H, -NH 2); 7.36 (d, J = 16, 1H, -CH-CHS-); 9.54 (d, J = 9, 1H, -CONH-).

The dioxo-5,6-hydroxy-2-ethyl-3-thioxo-3-perhydrotriazine1,2,4 can be prepared by applying the method described by
Mr PESSON and Mr ANTOINE, Bull. Soc. Chim. France 1590 (1970) operating in the following manner
To a solution of sodium methylate (prepared from 0.85 g of sodium) in 37 cm3 of methanol is added 5 g of (hydroxyethyl) -4 thiosemicarbazide and 5.5 cm3 of ethyl oxalate and heated refluxing for 3 hours. After cooling, the precipitate is filtered off and washed twice with 5 cm3 of methanol. The crude sodium salt is obtained, which is then taken up in 25 cm3 of distilled water; the filtered solution is acidified to pH = 2 with 1N hydrochloric acid. The precipitate is separated by filtration, washed with water and dried in air. 2.4 g of 5-dioxo-6 (2-hydroxyethyl) -4-thioxo-3-perhydrotriazine-1,2,4 ( F = 230 ° C).

 The sodium salt can be prepared by treating 4.73 g of 5-dioxo-5,6-hydroxy-2-ethyl-3-thioxo-3-perhydrotriazine-1,2,4 in anhydrous methanol with sodium ethyl-2 hexanoate . 4.7 g of sodium salt are thus obtained.

Infrared spectrum (KBr), main bands (cm) 3420, 3200, 3070, 1655, 1575, 1560, 1395, 1205, 1080, 1045, 835
(2-Hydroxyethyl) thiosemicarbazide can be obtained according to the method described by Y. KAZAKOV and IY POTOVSKII, Doklady
Acad. Nank. SSSR 134, 824 (1960).

EXAMPLE 14
A mixture of 5.8 g of 2-benzhydryloxycarbonyl [2-methoxyimino-2-tritylamino-1,3-thiazol-yl] -2-acetamido] -oxo-8-oxide is stirred at 60 ° C. for 80 minutes under nitrogen. (2-tosyloxy-vinyl) -3-thia-5-aza-1-bicycloc4.2.0-octene-2, syn-isomer, E-form, 58 cm3 of dimethylformamide, 1.3 g of (2-methoxyethyl) -4-dioxo-2-ene 5.6 thioxo-3 perhydrotriazine-1,2,4 and 0,819 mg of diisopropylethylamine. The mixture cooled to 20 ° C. is diluted with 300 cm 3 of ethyl acetate, the organic phase is washed 4 times with 100 cm 3 of water in total, dried over magnesium sulphate, filtered and concentrated to dryness at 20 ° C. under pressure. The residue, dissolved in 250 cm3 of ethyl acetate, is filtered through a column of 32 g of silica gel and eluted with 500 cm3 of ethyl acetate. The eluate is evaporated to dryness under reduced pressure (20 mm of mercury) at 20 ° C. 5.4 g of 2-benzhydryloxycarbonyl-2- [4,6-dioxo-4-methoxyethyl) -tetrahydro-1 are thus obtained. 4,5,6-triazine-1,2,4-yl-3-thio-2-vinyl] -3 [methoxyimino-2 (tritylamino-2-thiazol-1,3-yl) -4-acetamido] -7-oxo-8-oxide; 5-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form, as a beige solid.

3,34 et 4,1 (dd, J = 18, 2H, -S(O)Ch2-) ; 4,00 (s, 3H, = NOCH3) 4,66 (dg J = 4, 1H, H en 6) ; 6,08 (dd, J = 4 et 9, 1H, H en 7) ; 6,71 (s, 1H, H du thiazole) ; 6,85 (d, J = 16, 1H, -CH=CHS-) 6,97 (s, 1H, -COOCH).Infrared spectrum (KBr), characteristic bands (cm) 3400, 2830, 1800, 1720, 1690, 1590, 1525, 1495, 1450, 1370, 1210, 1110, 1040, 945, 755, 700
Proton Rl4N spectrum (350 MHz, CDCl3, δ ppm, J in Hz) 3.32 (s, 3H, -CH2OCH3); 3.60 (t, J = 5.2H, -CH 2 O-); 4.05 (t, J = 5,

3.34 and 4.1 (dd, J = 18, 2H, -S (O) Ch 2 -); 4.00 (s, 3H, = NOCH3) 4.66 (dg J = 4.1H, H at 6); 6.08 (dd, J = 4 and 9, 1H, H at 7); 6.71 (s, 1H, H thiazole); 6.85 (d, J = 16, 1H, -CH = CHS-) 6.97 (s, 1H, -COOCH).

 To a cooled solution at -10 C of 5.3 g of 2-benzhydryloxycarbonyl {[(methoxy-2 ethyl) -4-dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4 3] 2-thio-vinyl] -3 [2-methoxyimino (2-tritylamino-1,3-thiazolyl) -2-acetamido] -7-oxo-5-oxide-5-thia-aza-1-bicyclo [4.2.0] octene -2, syn isomer, form E in 53 cm3 of methyl chloride, 2.06 cm3 of dimethylacetamide and then 0.91 cm3 of phosphorus trichloride are added, stirred for 2 hours at -10 ° C. and then the solution is diluted in 750 cm3. of ethyl acetate, this solution is washed twice with 100 cm 3 of saturated sodium bicarbonate solution, twice with 100 cm 3 of saturated sodium chloride solution, dried over magnesium sulfate, concentrated at 50 cm 3 under reduced pressure (20 min of mercury) at 20 ° C. and 200 cm3 of isopropyl ether are added.

The solid formed is isolated by filtration, washed with 20 cm3 of isopropyl ether and dried. 4.2 g of a cream-colored solid are thus obtained. This solid, dissolved in a mixture ethyl acetate-cyclohexane 70-30 (vol.) Is chromatographed on a column of silica gel
Merck (0.04-0.06) (column diameter: 6 cm). The reaction mixture is eluted with 1500 cm3 of a 70-30 (vol.) Ethyl acetate-cyclohexane mixture under a pressure of 40 kPa, collecting 75 cm 3 fractions. Fractions 9 to 19 are concentrated to dryness under reduced pressure (20 ° C.). mm Hg) at 20 ° C., 2.9 g of 2-benzhydryloxycarbonyl-2 - [[dioxo-5,6 (methoxy-2-ethyl) -4-tetrahydro-1,4,5,6-triazine-1,2,4 are thus obtained. yl-3] -thio-2-vinyl] -3 [2-methoxyimino-2-tritylamino-1,3-thiazol-4-yl] acetamido] -7-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene 2, syn isomer, form E in the form of a cream-colored solid.

3,60 et 3,68 (2d, J = 18, 2H, -SCH2-) ; 4,06 (s, 3H, --NOcH3) ; 5,11 (d, J = 4, 1H, H en 6) ; 5,95 (dd, J = 4 et 9, 1H, H en 7) ; 6,76 (s, 1H, H du thiazole) ; 6,86 (d, J = 16, 1H, -CH=CHS-) ; 6,93 (d, J = 9, 1H, -CONH-) ; 6,97

Infra-red spectrum (KBr), characteristic bands (cm) 3400, 2820, 1785, 1720, 1690, 1590, 1525, 1495, 1450, 1370, 1210, 1110, 1040, 945, 755, 705
Proton NMR Spectrum (350 MHz, CDCl 3, 6 ppm, J in Hz) 3.34 (s, 3H, -CH 2 OCH 3) 3> 65 (t, J = 5.2H, -CH 2 O-); 4.11 (t, J = 5, 2H,

3.60 and 3.68 (2d, J = 18, 2H, -SCH 2 -); 4.06 (s, 3H, --NOcH3); 5.11 (d, J = 4, 1H, H at 6); 5.95 (dd, J = 4 and 9, 1H, H at 7); 6.76 (s, 1H, H thiazole); 6.86 (d, J = 16, 1H, -CH = CHS-); 6.93 (d, J = 9, 1H, -CONH-); 6.97

 2.8 g of 2-benzhydryloxycarbonyl-2 - [{dioxo-5,6 (methoxy-2 ethyl) -4-tetrahydro-1,4,5,6-triazine-1,2,4-yl] -3-thio-2-vinyl} are dissolved 3-methoxyimino-2- (2-trityamino-1,3-thiazolyl) -4-acetamido] -7-oxo-5-thia-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form in 50 cm3 of formic acid, add 25 cm3 of water and heat for 15 minutes at 500 with stirring. The mixture is diluted with 25 cm3 of water, cooled, filtered and concentrated to dryness at 40 ° C. under 0.05 nm of mercury. The residue is taken up three times with 50 cm3 of ethanol, each time evaporating to dryness under reduced pressure (0.05 nm of mercury). The residue is taken up in 200 cm3 of refluxing ethanol, filtered hot on sintered glass, the residue is taken up again with 100 cm3 of refluxing ethanol, filtered while hot, the two combined filtrates are concentrated to 20 cm3, cooled to 0 and the solid thus obtained is filtered and dried. 1.45 g of 2-carboxy-2 - [(2-methoxyethyl) -4-dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-thio-2-vinyl] are thus obtained. 3 [2-methoxyimino-2-aminothiazol-1,3-yl] -4-acetamido] -7-oxo-5-thia-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form under the form of a yellow solid.

3,62 et 3,73 (2d, J = 18, 2H, -SCH2-) ; 3,96 (s, 3H, @NOCH3) ; 5,18 (d, J = 4, 1H, H en 6) ; 5,81 (dd, J = 4 et 9, 1H,
H en 7) ; 6,78 (s, 1H, H du thiazole) ; 6,87 (d, J = 15, 1H, -CH=CH-S-) ; 7,29 (d, J = 15, 1H, -CH=CH-S-) ; 6,70 (s large, 3H, -NH3+) ; 9,55 (d,
J = 9, 1H, -CONH-) ; 12,64 (s, 1H, -OH).Infrared spectrum (KBr), characteristic bands (cm) 3480, 2830, 1775, 1710, 1680, 1635, 1590, 1535, 1380, 1110, 1040, 940
Proton NMR Spectrum (350 MHz, DMSO d6> 6 ppm, JHz) 3.36 (s, 3H, -CH2OCH3); 3.56 (t, J = 5.2H, -CH2O-); 4.10 (t, J = 5,

3.62 and 3.73 (2d, J = 18, 2H, -SCH 2 -); 3.96 (s, 3H, NOCH 3); 5.18 (d, J = 4, 1H, H at 6); 5.81 (dd, J = 4 and 9, 1H,
H in 7); 6.78 (s, 1H, H thiazole); 6.87 (d, J = 15, 1H, -CH = CH-S-); 7.29 (d, J = 15, 1H, -CH = CH-S-); 6.70 (br s, 3H, -NH 3 +); 9.55 (d,
J = 9, 1H, -CONH-); 12.64 (s, 1H, -OH).

 (4-Methoxy-ethyl) -4,6-dioxo-3-thioxo-perhydrotriazine1,2,4 can be prepared according to Belgian Patent 830 455.

EXAMPLE 15
A mixture of 10.04 g of 2-benzhydryloxycarbonyl-2-methoxyimino (2-tritylamino-1,3-thiazol-4-yl) -2-acetamido] -7-oxo-8-oxide is stirred at 60 ° C. for 3 hours under nitrogen. 5 (2-tosyloxy-vinyl) -5-thia-aza-1-bicyclo [4.2.0] -octene-2, syn isomer, E-form, 200 cm3 of dimethylformamide, 2.76 g of (2-acetamidoethyl) dioxo-5,6 thioxo-3 perhydrotriazine-1,2,4 and 2,1 cm3 of diisopropylethylamine.

The cooled mixture is then diluted with 800 cm 3 of ethyl acetate, the organic phase is washed with 1.2 liters of water, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg). at 20 ° C. The residue is triturated in 150 cm3 of ether, the insoluble matter is isolated on the filter and, after drying, 9.5 g of {(4-acetamidoethyl) -4-dioxo-5,6-tetrahydro-1,4 are obtained. , 5,6-triazine-1,2,4-yl-3-thio-2-vinyl-3-benzhydryloxycarbonyl-2 [2-methoxylmiao-2 (tritylamino-1,3-thiazolyl) -2-acetamido] -7-oxo-8 5-oxide 5-thia-5-azabicyclo 4.2.07 octene-2, syn isomer, E-form as a tan solid.

5,26 (d, J = 4, 1H, H en 6)- 5,78 (dd, J = 4 et 9, 1H, H en 7) ; 6,73 (s, 3H, -OCH3) ; 6,92 (d, j = 16, 1H, -CH=CHS) ; 6,95 (s, 1H, -COOCH-) ; 7,0 (d, J = 16, 1H, =CHS-) ; 7,78 (t, J = 6, -NHCOch3) ; 8,81 (s, 1H, -NHC (C6H5)3) 9,60 (d, J = 9, 1H, -CONH-) ; 12,60 (s, 1H, =N-NHCO- ou

Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3370, 1795, 1710, 1680, 1520, 1495, 1445, 750, 735
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 1.75 (s, 3H, -COCH3); 3.65 and 3.90 (2d, J = 18, 2H, -SCH 2 -); 3.86 (s, 3H, -OCH 3); 3.88 (t,

5.26 (d, J = 4.1H, H at 6) - 5.78 (dd, J = 4 and 9, 1H, H at 7); 6.73 (s, 3H, -OCH 3); 6.92 (d, j = 16, 1H, -CH = CHS); 6.95 (s, 1H, -COOCH-); 7.0 (d, J = 16, 1H, = CHS-); 7.78 (t, J = 6, -NHCOch 3); 8.81 (s, 1H, -NHC (C 6 H 5) 3) 9.60 (d, J = 9, 1H, -CONH-); 12.60 (s, 1H, = N-NHCO- or

 To a cooled solution at -10 ° C. of 9.03 g of {[(2-acetamidoethyl) -4-dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl] 2-thio-2-yl] -3-benzhydrolxycarbonyl [2-methoxyimino-2-tritylamino-1,3-thiazol-4-yl] acetamido] -7-oxo-5-oxide-5-thia-aza-1-bicyclo [4.2.0 ] Octene-2, syn isomer, Form E in 85 cm3 of methylene chloride, 3.4 cm3 of dimethylacetamide and then 1.49 cm3 of phosphorus trichloride are added. Stirred for 2 hours at -100C, diluted with 500 cm3 of methylene chloride, washed with 250 cm3 of a semisaturated solution of sodium bicarbonate and 250 cm3 of a saturated solution of sodium chloride, dried over sodium sulfate. sodium and concentrated to dryness under reduced pressure (20 mm Hg) at 20 ° C. The brown solid obtained is dissolved in an ethyl acetate-methylene chloride-methanol (120-120-80 cm 3) mixture and the solution is chromatographed. on a column of Merck silica gel (0.04-0.06) (column diameter: 4 cm). The mixture is eluted with 1.5 liters of ethyl acetate 95-5 (vol.) At a pressure of 40 kPa, collecting 125 cm3 fractions. Fractions 6 to 10 are concentrated to dryness under reduced pressure (20 mm Hg) at 200 ° C. 3.33 g of {[(2-acetamidoethyl) -4-dioxo-5,6-tetrahydro-1,4,5,6-triazin-1,2,4-yl] -3-thio-2-vinyl] -3 are collected. 2-benzhydryloxycarbou-2 [2-methoxyimino (2-tritylamino-1,3-thiazolyl) -2-acetamido] -7-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form the shape of a beige solid.

; 3,86 (s, 3H, -OCH3) 5,05 (d, J =4, 1H, H en 6) ; 5,85 (dd, J = 4 et 9, 1H, H en 7) ; 6,80 (s, 1H, Il du thiazole) ; 6,96 (d, J = 16, 1H, -CH=CHS-) ; 6,97 (s, 1H, -COOCH-) ; 7,12 (d, J = 16, 1H, =CHS-) ; 7,98 (t, J = 6, 1H, -NH COCH3) ; 8,75 (s, 1H, -NHC(C6H5)3) ; 9,04 (d, J = 9, 1H, -CONH-) ; 12,60 (s, 1H, =N-NHCO- ou

Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3380, 1785, 1710, 1680, 1520, 1495, 1445, 755, 740
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 1.75 (s, 3H, -COCH3); 3.32 (mt, 2H, -CH2NHC0); 3.62 and 4.30 (2d,
J = 18, 2H, -SCH 2 -); 3.86

; 3.86 (s, 3H, -OCH 3) 5.05 (d, J = 4, 1H, H at 6); 5.85 (dd, J = 4 and 9, 1H, H at 7); 6.80 (s, 1H, 11 thiazole); 6.96 (d, J = 16, 1H, -CH = CHS-); 6.97 (s, 1H, -COOCH-); 7.12 (d, J = 16, 1H, = CHS-); 7.98 (t, J = 6, 1H, -NH COCH 3); 8.75 (s, 1H, -NHC (C6H5) 3); 9.04 (d, J = 9, 1H, -CONH-); 12.60 (s, 1H, = N-NHCO- or

 3.15 g of {[(2-acetamidoethyl) -4-dioxo-5,6-tetrahydro-1,4,5,6-triazin-1,2,4-yl] -3-thio-2-vinyl} -3 is dissolved 2-benzhydryloxycarbonyl-2 [2-methoxyimino-2-tritylamino-1,3-thiazol-4-yl] acetamido] -7-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form in 80 cm3 of formic acid, 30 cm3 of water are added and the mixture is heated at 60 ° C. with stirring for 30 minutes. The cooled mixture is filtered and concentrated to dryness under reduced pressure (0.05 mm Hg) at 50 ° C. The residue is taken up in 250 cm 3 of ethanol and concentrated to dryness under reduced pressure (20 mm Hg) at 30 ° C. repeat the operation and then take up the solid in 40 cm3 of ethanol with stirring at 40 ° C.

After cooling, filtration and drying 1.56 g of {[(2-acetamidoethyl) -4-dioxo-5,6-tetrahydro-1,4,5,6-triazin-1,2,4-yl] were obtained. 2-thio-vinyl] -3 [(2-amino-thiazol-1,3-yl) -4-methoxyimino-2-acetamido] -7-carboxy-2-oxo-8-thia-5-azabicyclo [4.2.0] octene 2, syn isomer, form E in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3500, 2500, 1775, 1710, 1685 to 1630, 1540, 1045, 950
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 1.90 (s, 3H, -CH3); 3.48 (m, 2H, -CH 2 NH-); 3.62 and 3.73 (2dmH - 18.2H, -SCH 2 -); 4.0 (s, 3H, -OCH 3); 5.15 (d, J = 4.1H, H at 6), 5.82 (dd, J = 4 and 9, 1H, H at 7); 6.78 (s, 1H, H thiazole) 6.86 (d, J = 16, 1H, -CH = CHS-); 7.31 (d, J = 16, 1H, = CHS-); 7.73 (s, 3H, NH3 +); 9.50 (d, J = 9, 1H, -CONH-); 12.54 (s wide, 1H, -CONHN = or

 0.128 g of the above product is dissolved in 2 cm 3 of a 0.1 M solution of sodium bicarbonate, filtered and the solution is lyophilized. 0.127 g of the sodium salt of 4 - [(2-acetamidoethyl) are collected. dioxo-5,6-tetrahydro-1,4,5,6-triazin-1,2,4-yl-3-thio-2-vinyl] -3 [(2-aminothiazol-1,3-yl) -4-methoxyimino) 2-acetamido] -7-carboxy-2-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form.

7,85 (t, 1H, -NHCO-) ; 12,5 (m, 2H, NH du cycle)), à partir de 4,41 g d'(acétamido-2 éthyl)-4 thiosemicarbazide et de 3,4 cm3 d'oxalate d'éthyle en présençe de méthylate de sodium, par application de la méthode décrite par M. PESSON et M. ANTOINE, Bull.3.61 g of 2- (4-acetamidoethyl) -5,6-dioxo-3-thioxo-perhydrotriazine-1,2,4-strong (Kofleri inst.> 260 ° C.) are obtained.
Infrared spectrum (KBr), characteristic bands (cm) 3365, 3050, 2000, 1710> 1630, 1600-1580, 1545, 1350, 1330, 1200
Proton NMR Spectrum (80 MHz, DMSO d6, # in ppm, J in Hz) 1.7 (s, 3H, -CH3); 3-7.7 (mt, -CH2NHCO- and H2O); 4.3 (t, 2H,

7.85 (t, 1H, -NHCO-); 12.5 (m, 2H, NH of the cycle)), starting with 4.41 g of (2-acetamidoethyl) thiosemicarbazide and 3.4 cm3 of ethyl oxalate in the presence of sodium methoxide , by application of the method described by M. PESSON and M. ANTOINE, Bull.

Soc. Chim. France 1590 (1970).

The starting thiosemicarbazide can be obtained by operating as follows
Refluxed for 2 hours a solution of 57.7 g of methyl N- (2-acetamidoethyl) dithiocarbamate and 14.6 cm3 of hydrazine hydrate in 300 cm3 of absolute ethanol. The mixture is cooled to 4 ° C., filtered and the insoluble material is dried at 300 ° C. under 0.05 mm Hg. 39.5 g of (2-acetamidoethyl) thiosemicarbazide are obtained in the form of white crystals (F. inst., RKoflerS = 171 ° C.).

 Infrared spectrum (KBr), characteristic bands (cm) 3280, 3180, 1650, 1560 to 1535, 1360, 1280.

 The present addition also relates to medicaments which contain as active product at least one product of general formula (I) in pure form (in free form or in salt form) or in the form of a composition in combination with one or more pharmaceutically acceptable adjuvants. These drugs can be used orally, parenterally or rectally.

 As solid compositions for oral administration may be used tablets, pills, powders or granules.

In these compositions, the active product according to the invention is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch. These compositions may also comprise substances other than diluents, for example a lubricant such as magnesium stearate.

 As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil may be used. These compositions may also comprise substances other than diluents, for example wetting, sweetening or flavoring products.

 The compositions for parenteral administration may be aqueous or nonaqueous sterile solutions, suspensions or emulsions. As the solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil and injectable organic esters, for example ethyl oleate, may be used. These compositions may also contain adjuvants, in particular wetting agents, emulsifiers or dispersants. Sterilization can be done in several ways, for example by means of a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating.

They can also be prepared as sterile solid compositions which will be dissolved at the time of use in sterile water or any other sterile injectable medium.

 The compositions for rectal administration are suppositories which may contain, in addition to the active product, excipients such as cocoa butter or suppo-wax.

 In human therapy, the drugs according to the present addition are particularly useful in the treatment of bacterial infections.

 In general, the doctor will determine the dosage he considers the most appropriate according to the age, weight, degree of infection and other factors specific to the subject to be treated.

Generally, the doses are between 1 and 10 g per day of active product orally, intramuscularly or intravenously for an adult.

 The following examples, given in a non-limiting manner, illustrate compositions according to the present addition.

EXAMPLE A
An injectable solution is prepared having the following composition - sodium salt of {1- (2-acetamidoethyl) dioxo-5,6
1,4,5,6-tetrahydro-1,2,4-triazine-3-yl] thio-2
vinyl] -3 (2-amino-1,3-thiazolyl) -2-methoxyimino-2
7-acetamido-2-carboxy-8-oxo-5-thia-aza-1-bicyclo
4.2.Q7 octene-2 (syn isomer, form E) 260 mg - sodium chloride ............................... ......... 1.5 mg - injectable solution ...................... 2 cm3
This solution contains 250 mg of active product counted as free acid.

EXAMPLE B
An injectable solution having the following composition - sodium salt of (2-amino-1,3-thiazol-4-yl) -2 is prepared.
2-methoxyiminoacetamido] -7 carboxy-2 [5,5-dioxo]
(2-hydroxyethyl) -4,4,5,6-tetrahydro-1,2,4-triazine
yl-3] thio-2-vinyl] -3-oxo-8-thia-5-azabicyclo [4.2.0]
octene-2 (syn isomer, E-form) .......................... 260 mg - sodium chloride ........ .............................. 1.5 mg - injectable solution ........ ............................. 2 cm3
This solution contains 250 mg of active product counted as free acid.

Claims (9)

 1 - A new thiovinyl-3 cephalosporin characterized in that it meets the general formula

 in which R represents a 2-L-amino-2-carboxy-ethyl or heterocyclyl radical chosen from: tetrazolyl-5 substituted in the -1 position by an acylaminoalkyl radical, thiadiazol-1,3,4-yl-5 substituted with a hydroxyl or acylaminoalkyl radical, thiadiazol -1,2,4-yl-5 substituted with an alkyl or alkyloxy radical, 2-, 3- or 4- pyridyl-optionally N-oxidized, 1,2,3-triazol-5-yl, 1,3-triazol-5-yl, 3-pyridazinyl substituted at the -6 position with an alkyl, methoxy, amino or acylamino radical and optionally N-oxidized> tetrazolo [4,5-b] pyridazinyl-6, dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 substituted in the 4-position with an alkyl, allyl and hydroxyalkyl radical, alkyloxyalkyl or acylaminoalkyl, the symbol R represents a hydrogen atom or an alkyl radical, and the symbol R 'represents a hydrogen atom or an easily removable enzymatically radical of general formula

 in which R "represents a hydrogen atom or an alkyl radical and R" 'represents an alkyl radical or the cyclohexyl radical, it being understood that the radicals and alkyl or acyl portions mentioned above are (unless otherwise stated) straight or branched and contain 1 to 4 carbon atoms, in its syn or anti forms, and E or Z and mixtures thereof, as well as its addition salts with acids, metal salts and addition salts, and the nitrogenous bases.  2 - the method of preparing a product according to claim 1, characterized in that an acid of general formula is made to act

 wherein R is defined according to claim 1, and wherein the amine function is previously protected (as well as the oxime when R "represents hydrogen) or a reactive derivative of this acid, on a 7-amino cephalosporin of general formula

 in which R is defined according to claim 1, R1 represents a hydrogen atom, a radical of general formula ::

 as defined in claim 1, or an easily removable protecting group, and n represents O or 1, then when n = 1 the oxide obtained is reduced and the protective groups are removed and then the product obtained is optionally converted into an addition salt. with an acid, a metal salt, or an addition salt with a nitrogen base.  s - Process according to claim 2, characterized in that an acid of general formula is used

 wherein R "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.nitro group. benzyloxycarbonyl or p.methoxybenzyloxycarbonyl.  4 - Process according to claim 2, characterized in that an acid of general formula is used

 wherein R "is a trityl group or tetrahydropyranyl protecting the oxime function.  5 - Process according to claim 2, characterized in that a 7-amino cephalosporin is used in which the easily removable radical represented by R1 is chosen from methoxymethyl, t.butyl, benzhydryl, p.nitrobenzyl and p. methoxybenzyl.  6 - Process according to claim 2, characterized in that a reactive derivative of the acid of general formula is used

 wherein R "is defined according to claim 1, selected from anhydride, a mixed anhydride, a reactive ester and a halide thereof.  7 - Process according to claim 2, characterized in that, when using a 7-amino cephalosporin whose R radical comprises a substituent hydroxy, amino or carboxy, this group is previously protected.  8 - Process for the preparation of a product according to claim 1, characterized in that a thiol of general formula is made to act.  R - sH wherein R is defined according to claim 1, on a cephalosporin derivative (or, where appropriate, a mixture of isomers) of general formula

 wherein, R being defined according to claim 1, wherein R 1 and n are defined as in claim 2, when n = O this derivative is in the form of bicyclooctene-2 or -3, when n = 1 this derivative is in the form of bicyclooctene; 2, the substituent on the carbon atom at the 3-position of bicyclooctene has E or Z stereoisomerism, R2 represents a hydrogen atom or a radical protecting the amino radical, and R3 represents a radical of general formulas -O-SO2R '  or -O-CO R 'in which R' is a straight or branched alkyl radical containing 1 to 4 carbon atoms, trifluoromethyl, trichloromethyl or phenyl substituted by a halogen atom or by an alkyl or nitro radical, and then when n = The resulting oxide is reduced, the protective groups are optionally removed and the product obtained is optionally converted to the addition salt with an acid, a metal salt or an addition salt with a nitrogen base.  9 - Process according to claim 8, characterized in that the reaction is carried out in the presence of a pyridine or a tertiary organic base.  10 - Process for the preparation of a product according to claim 1, in which R 'represents a radical of general formula

 as defined in claim 1, characterized in that a product according to claim 1 for which R 'is hydrogen is esterified by any method known per se for preparing an ester from an acid, without touching the rest of the molecule, then eventually transforms the product obtained into the addition salt with an acid.  11 - medicine. characterized in that it contains at least one product according to claim 1> in pure form or in the form of a composition with one or more compatible adjuvants and pharmaceutically acceptable adjuvants.