FR2532936A1 - New 2-aminothiazolyl-4-ylacetic acid derivatives containing a substituted oxime functional group and process for their preparation. - Google Patents

Abstract

Products of general formula Vd: in which R2 denotes a hydrogen atom or a protective group for the amino radical and Rd denotes: - either a CHF2 radical; - or a radical -(CH2)n-S-Rc in which n denotes an integer from 1 to 4 and Rc denotes one of the radicals or nitrile, R4 denotes a protective radical for the amino radical, syn isomer, process for preparing these products.

Description

 The present invention, to which Michel VIGNAU and René HEYMES have participated, concerns new substituted alkyl esters derived from 7- (2-amino-4-thiazolyl) acetamido cephalosporanic acid, their preparation process and their application as medications. caments.

isomère syn dans laquelle R représente - ou bien Ra, Ra représentant un radical -(CH2)n-S-R2 dans lequel R2 représente les radicaux

ces radicaux étant éventuellement sous une forme protonée et n représente un entier de 1 à 4; - ou bien R représente Rb, Rb représentant soit un radical -(CH2)n-S-CN dans lequel n représente un entier de 1 a 4, soit un radical CHF2
R1 représents - ou bien un atome d'hydrogène; - ou bien un radical chloro ou méthoxy; - ou bien un radical alkyle, cycloalkyle, alkylthio ayant au plus 5 atomes de carbone;; - ou bien un radical -CH2-S-R' dans lequel R' représente
un radical hétérocyclique substitué ou non substitué, contenant de l'azote,
un radical acyle ayant de 2 a 4 atomes de carbone; - ou bien un radical acétoxyméthyle ou carbamoyloxyméthyle; - ou bien un radical

dans lequel Alk comporte de 1 à 4 atomes de carbone, - ou bien un radical azidométhyle;
A peut représenter soit un atome- d'hydrogène ou un groupement ester facilement clivable, soit lorsque R représente
Ra, le groupement CO2 à peut rapresenter l'anion -CO2e soit, lorsque R représente Rb, A peut representer un équivalent de métal alcalin, alcalino-terreux, de magnésium, d'ammonium ou d'une base organique aminée, ainsi que les sels d'addition des produits de formule I avec les acides organiques ou minéraux.The subject of the invention is products of general formula

syn isomer where R is - or Ra, Ra is - (CH2) nS-R2 wherein R2 is radicals

these radicals being optionally in a protonated form and n represents an integer of 1 to 4; or else R represents Rb, Rb representing a radical - (CH2) nS-CN in which n represents an integer of 1 to 4, or a radical CHF2
R1 represent - or a hydrogen atom; - or a chloro or methoxy radical; or an alkyl, cycloalkyl or alkylthio radical having at most 5 carbon atoms; or a radical -CH 2 -SR 'in which R' represents
a substituted or unsubstituted heterocyclic radical containing nitrogen,
an acyl radical having 2 to 4 carbon atoms; or an acetoxymethyl or carbamoyloxymethyl radical; - or a radical

in which Alk has 1 to 4 carbon atoms, or an azidomethyl radical;
A can represent either a hydrogen atom or an easily cleavable ester group, or when R represents
Ra, the CO2 group can represent the -CO2e anion or, when R represents Rb, A can represent an equivalent of alkali metal, alkaline earth metal, magnesium, ammonium or an organic amino base, as well as addition salts of the products of formula I with organic or inorganic acids.

 Panai the values of R1 include methyl, ethyl, propyl, isopropyl, butyl, isoburyl, tertbutyl, pentyl, pentylsecondary, tert-pentyl, cyclopropyl, cyclobutyl, cyclopentyl.

 Among the values of R 1 there may also be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio or tert-butylthio values.

 Among the values of R 1, there may also be mentioned the substituents -CH 2 -S-R 'in which R' represents the values 1,2,3 - 1,2,5 - 1,2,4 or 1,3,4 - thiadiazolyl; 1-H tetrazolyl, 1,3-thiazolyl; 1,2,3 - 1,2,4 or 1,3,4-triazolyl; 1,2,3 - 1,2,4 or 1,2,5 or 1,3,4-oxadiazolyl, these radicals being unsubstituted or substituted by one or more radicals selected from the group consisting of methyl radicals, ethyl, propyl, isopropyl, methoxy, ethoxy, propyloxy, isopropyloxy, amino, hydroxycarbonylmethyl, dimethylaminoethyl and diethylaminoethyl. R 'can also represent an acetyl, propionyl or butyryl radical.

 Panai the values of R1, one can also quote the values acetamido, propionylamido, butyrylamido, isobutyrylamido, valerylamido.

 As easily cleavable esters, mention may be made of the esters formed with the methoxy-methyl, ethoxy-methyl, isopropoxy-methyl, α-methoxyethyl, α-ethoxyethyl, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl and isobutyryloxymethyl radicals. isovaleryloxymethyl, propionyloxyethyl, isovaleryloxyethyl, 1-acetoxyethyl, 1-acetoxypropyl, 1-acetoxybutyl, 1-acetoxyhexyl, 1-acetoxyheptyl.

 Panal salts formed with bases include those formed with an equivalent of sodium, potassium, lithium, calcium, magnesium, ammonium. It is also possible to mention, among the organic bases, trimethylamine, diethylamine, triethylamine, methylamine, propylamine, N, N-dimethylethanolamine, tris (hydruxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, N ', N'-dibenzylethylenediamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylgincamine.

sous une forme éventuellement protonée, soit un radical -CHF2 et R1 représente un atome d'hydrogène, un radical 1-méthyl 1 (H) tétrazolyl thiométhyle ou 2-méthyl 1,3,4-thiadiazolylthio-méthyle, un radical acétoxyméthyle ou un radical azidométhyle.The products of formula I, mentioned above, may be in the form of organic or inorganic diacid salts since these products contain at least one salifiable amino radical.
The acids with which the products of formula 9 can be salified include, among others, acetic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenasulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like.
The subject of the invention is more particularly the products of formula I as defined above, in which R represents - or a hydrogen atom, or a radical CH 2 -SR - in which R 'represents a radical 1- methyl 1 (H) tetrazolyl or 2-methyl-1,3,4-thiadiazolyl, - or an acetoxymethyl radical, - or an azidomethyl radical, as well as addition salts with organic or mineral acids
The invention relates more particularly to the products of formula I, in which R represents either a radical

in an optionally protonated form, that is a radical -CHF2 and R1 represents a hydrogen atom, a 1-methyl-1 (H) tetrazolylthiomethyl or 2-methyl-1,3,4-thiadiazolylthio-methyl radical, an acetoxymethyl radical or a azidomethyl radical.

 The invention relates in particular to the products described in the examples and especially to 3-acetoxymethyl-7- [2- (2-amino-thiazol-4-yl) -2- (amino-imino-methylthio) -ethoxy] -imino-acetamido acid. ceph-3-th -4-carboxylic acid (syn-isomer) in the form of an internal salt or a salt with a mineral or organic acid and its esters with easily cleavable groups and 3-acetoxymethyl-7- / 2- acid (2-amino thiazol-4-yl) 2- (difluoromethoxyimino) acetyl / amino / ceph-3-ene 4-carboxylic acid, syn isomer, its salts with alkali metals, alkaline earth metals, magnesium, ammonium and organic bases amino and its esters with easily cleavable groups, as well as its salts with mineral or organic acids.

It is understood that the goods of formula I previously mentioned may exist either in the form indicated by the said formula I or in the form of the products of formula I.

dans laquelle R2 représente un atome d'hydrogène ou un groupement protecteur du radical amino, A1 représente un atome d'hydrogène ou un ester facilement clivable, R1 a la-signi- fication indiquée précédemment et R3 représente ou bien un atome d'hydrogène ou bien R'3, R'3 représentant un radical
(CH2)n-Hal dans lequel n représente un entier de 1 à 4 et
Hal représente un atome d'halogène soit lorsque R3 représente un atome d'hydrogène, par un produit de formule Hall CHF2 dans laquelle Ha l1 représente un atome de chlore ou de brome, pour obtenir un produit de formule III

dans laquelle A1 , R1 et R2 ont la signification précédente, - soit lorsque R3 représente R'3 ou bien par la thiourée, ou bien par un produit de formule

dans laquelle R4 représente un groupement protecteur du radical amino ou bien par un produit de formule N=C-S-R5 dans laquelle R5 représente un groupement ammonium ou un atome de métal alcalin pour obtenir un produit de formule
III'

dans laquelle R1 , R2 et A1 ont la signification précédente et Rc représente les radicaux:

ou nitrile; produits de formule III dans laquelle R2 et A1 représentent chacun un atome d'hydrogène et produits de formule III' dans laquelle R2 et A1 représentent chacun un atome d'hydrogène et Rc est différent du radical

produits correspondant à des produits de formule I dans laquelle A représente un atome d'hydrogène et R ne représente pas le radical

que si désiré l'on estérifie ou salifie par une base ou par un acide et produits ce rormule III ou III' dans laquelle l'un au moins des substituants
R2 ou A1 est différent d'un atome d'hydrogène et produits de formule III', dans laquelle Rc représente le groupement

que l'on traite par un ou plusieurs agents choisis panai les agents d'hydrolyse, d'hydrogènolyse et la thiourée pour obtenir des produits de formule générale I'

dans laquelle R et R1 ont la signification indiquée précé gemment et correspondant à un produit de formulé I dans laquelle A représente un atome d'hydrogène, produits de formule I' que si désiré l'on estérifie ou salifie par une base ou par un acide. The present invention also relates to a process for the preparation of the products of formula I, characterized in that a product of formula II is treated.

wherein R2 represents a hydrogen atom or a group protecting the amino radical, A1 represents a hydrogen atom or an easily cleavable ester, R1 has the meaning indicated above and R3 represents either a hydrogen atom or well R'3, R'3 representing a radical
(CH2) n-Hal wherein n represents an integer of 1 to 4 and
Hal represents a halogen atom or when R3 represents a hydrogen atom, with a product of formula Hall CHF2 in which Ha11 represents a chlorine or bromine atom, to obtain a product of formula III

in which A1, R1 and R2 have the above meaning, - either when R3 represents R'3 or else by thiourea, or by a product of formula

in which R4 represents a protecting group of the amino radical or else a product of formula N = CS-R5 in which R5 represents an ammonium group or an alkali metal atom to obtain a product of formula
III '

in which R1, R2 and A1 have the above meaning and Rc represents the radicals:

or nitrile; products of formula III in which R2 and A1 each represent a hydrogen atom and products of formula III 'in which R2 and A1 each represent a hydrogen atom and Rc is different from the radical

products corresponding to products of formula I in which A represents a hydrogen atom and R does not represent the radical

if desired, one esterifies or salifies with a base or an acid and produces this formula III or III 'in which at least one of the substituents
R2 or A1 is different from a hydrogen atom and products of formula III ', wherein Rc represents the grouping

that the hydrolysis, hydrogenolysis and thiourea agents are treated with one or more agents to give products of the general formula I '

in which R and R 1 have the meaning indicated above and corresponding to a product of formula I in which A represents a hydrogen atom, products of formula I ', if desired, esterified or salified by a base or an acid .

 In the product of formula II, the protective group of the amino radical which R2 may represent may be, for example, an alkyl radical of 1 to 6 carbon atoms such as preferably tert-butyl or tert-emyl; R2 may also be an aliphatic acyl group, an aromatic or heterocyolic acyl group or a carbamoyl group.

 Among the aliphatic acyl groups, there may be lower alkanoyl groups such as, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, as well as lower alkoxy or cycloalkoxy carbonyl groups. as for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonylbutoxycarbonyl, tertbutoxycarbonyls, pentyloxycarbonyl, tert-pentoxycarbonyl, hexyloxycarbonyl.

 Among the aromatic acyl groups there may be mentioned benzoyl, toluoyl, naphthoyl, phthaloyl, mesyl, as well as phenylacetyl, phenylpropionyl and arylaldoxycarbonyl groups such as benzyloxycarbonyl.

 The acyl groups may be substituted for example with a chlorine, bromine, iodine or fluorine atom such as, for example, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl or bromoacetyl.

 Substituent R2 may also be lower aralkyl such as benzyl, 4 = methoxy benzyl or phenylethyl, trityl, 3,4-dimethoxy benzyl, benzhydryl.

 Substituent R2 may also represent a haloalkyl group such as trichloroethyl.

 The substituent R2 may also represent a chlorohenzoyl, paranitrobenzoyl, paratert-butylbenzoyl, phenoxyacetyl, caprylyl, n-decanoyl or acryloyl group.

The substituent R2 can also represent a methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl group and the corresponding thiocarbamoyl groups.
The above list is not an exhaustive list. It is obvious that other protective groups of the amines, groups known in particular in peptide chemistry, can also be used.

 The values of -CO2A1 include the ester groups formed with the following easily removable radicals: esters formed with alkyl radicals such as butyl, isobutyl, tert-butyl, pentyl, hexyl esters.

 Acetoxymethyl, propionyloxymethyl, butyzyloxymethyl, valeryloxymethyl, pivaloyloxymethyl, 2-acetoxyethyl, 2-propionyloxyethyl and 2-butyryloxyethyl esters may also be mentioned.

 There may also be mentioned a 2-mesylethyl, 2iodoethyl, ss, ss, ss-trichloroethyl, vinyl, allylic, ethynyl, propynyl, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenylethyl, trityl, diphenylmethyl, 3,4-dimethoxy ester. banzylique.

 Mention may also be made of phenyl, 4-chlorophenyl, tolyl or tert-butylphenyl esters.

 The halogen atom represented by Hal is preferably bromine or iodine.

 The action of a product of formula Hal1CHF2 on a product of formula II in which R3 represents a hydrogen atom is preferably carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, a carbonate or a carbonate sodium or potassium acid.

 It is carried out for example in an organic solvent such as anhydrous ethanol, dioxane, methanol, isopropanol, tetrahydrofuran or a mixture of these solvents.

 The protecting group of the amino radical represented by R4 can be selected from the list indicated above for the substituent R 2.

ou N=C-S-R5 sur un produit de formule II dans laquelle R3 représente un radical -(CH2)n-Hal est ef fectuée de préférence dans un solvant organique tel que l'hexaméthyl phosphoro triamide, le chloroforme, le diméthyl formamide, l'acétone ou le dioxanne.The action of thiourea, a product of fonaule

or N = CS-R5 on a product of formula II in which R3 represents a - (CH2) n-Hal radical is preferably carried out in an organic solvent such as hexamethyl phosphoro triamide, chloroform, dimethyl formamide, acetone or dioxane.

 One can also operate in the presence of a base. In the absence of base, a product of formula III 'is preferably obtained in the form of an H-Hal acid halohydrate corresponding to the halogen represented by the substituent Hal.

a pour but d'éliminer les groupements R2, A1 et R4
L'élimination des groupements R2 et R4 est réalisée par exemple par hydrolyse
L'hydrolyse peut être acide ou basique ou utiliser de l'hydrazine.The transformation of the products of formula III and III 'in which at least one of the groups R2 and A1 represents a removable group, as well as products of formula III' in which the group R c represents

aims to eliminate R2, A1 and R4 groups
The removal of the R2 and R4 groups is carried out for example by hydrolysis
The hydrolysis can be acidic or basic or use hydrazine.

Acidic hydrolysis is preferably used to remove optionally substituted alkoxycarbonyl or cycloalkoxycarbonyl groups such as t-pentyloxycarbonyl or t-butyloxycarbonyl, optionally substituted arylalkoxycarbonyl groups such as benzyloxycarbonyl, trityl, tert-butyl or 4-methoxy groups. benzoyl
The acid which is preferably used may be chosen from the group consisting of hydrochloric acid, benzenesulphonic acid or para-toluenesulphonic acid, or trifluoroacetic acid.

 However, other mineral or organic acids can be used.

 Basic hydrolysis is used preferentially to remove acyl groups such as trifluoroacetyl.

 The base which is preferably used is an inorganic base such as an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.

 It is also possible to use magnesia or barite or an alkali metal carbonate or acidic carbonate such as carbonates and acidic carbonates of sodium or potassium.

It is also possible to use sodium or potassium acetate. Other bases may however be used
Hydrolysis using hydrazine is preferably used to remove groups such as phthaloyl.

 The groups R2 and R4 can also be removed by the zinc-acetic acid system (for example the trichloroethyl group).

 The benzhydryl, benzyloxycarbonyl groups are preferably removed by hydrogen in the presence of a ca talyseu r.

 The chloroacetyl group is removed by the action of thiourea in neutral or acidic medium according to the type of reaction described by MASAKI (JACS, 90, 4508. 1968).

 Other means of amine deprotection known from the literature can also be used.

 The subject of the invention is more particularly the process described above, characterized in that products are used in which R2 is chosen from the group consisting of trityl, chloroacetyl and tert-pentyloxycarbonyl radicals. butyloxycarbonyl, benzyloxycarbonyl.

 The removal of the radical A1 when it is different from a hydrogen atom is carried out under conditions similar to those described above for the removal of R2 or R4. It is possible to use, among other things, acid hydrolysis of or basic. Acid hydrolysis is preferably used to remove radicals such as optionally substituted alkyl or optionally substituted aralkyl.

 An acid selected from the group consisting of hydrochloric, fornic, trifluoroacetic or p-toluenesulphonic acid is preferably used. The other values of the radical A1 are removed according to the methods known to those skilled in the art.

 The operation is preferably carried out under mild conditions, ie at room temperature or by heating the mixture.

Naturally one can, when for example R2, R4 and
A1 are eliminable groups belonging to different types, to act on the products III or III ', several agents envisaged in the preceding enumerations.

 During the reactions described above, a fraction of the products obtained may consist of ceph-2-th products.

In this case, the product fraction # 2 is converted into products # 3. It operates then according to a scheme known in the literature for products with a cephem nucleus
The scheme is as follows: the product containing a portion of # 2 is oxidized to obtain the corresponding sulfoxide. A peracid such as metachloroperbenzoic acid is preferably used. The passage from the sulfoxide of # 2 to the sulfoxide of # 3 is in the presence of a hydroxyl or solvent. water
The reduction of sulfoxide # 3 is carried out in the presence of an acid halide or phosphorus trichloride
This type of passage from products # 2 to products 83 has been described for example by
Kaiser et al. J.Org. 35, 2430 (1970)
SPRY and Coll.J.Org. 40, 2411 (1975) or in patents
- American 3,705,897 or German 1 937 0160
Salification of the products of formula I 'in which
R represents Rb can be carried out according to the usual methods
The salification may for example be obtained by action on these acids or on a solvate (for example the ethanol solvate) or a hydrate of this acid with a mineral base such as sodium or potassium hydroxide, carbonate sodium or potassium acid, sodium or potassium carbonate It is also possible to use the salts of mineral acids such as tri-sodium phosphate. It is also possible to use organic diacid salts.
Examples of organic acid salts which may be mentioned are the linear or branched, saturated or unsaturated aliphatic dicarboxylic acid salts of 1 to 18 and preferably 2 to 10 carbon atoms. These aliphatic radicals may be interrupted by one or more a plurality of heteroatoms, such as oxygen or sulfur, or substituted with aryl radicals, for example phenyl, thienyl or furyl, with one or more hydroxyl radicals or with one or more halogen atoms such as fluorine, chlorine or bromine, preferentially chlorine having one or more carboxylic or lower alkoxycarbonyl radicals, preferably methoxycarbonyl, ethoxycarbonyl or propyloxycarbonyl, with one or more aryloxy radicals, preferably phenoxy.

 In addition, sufficiently soluble aromatic acids such as, for example, substituted benzoic acids, preferably lower allyl radicals, can be used as organic acids.

 Examples of such organic acids are: formic acid, acetic acid, acrylic acid, butyric acid, acipic acid, isobutyric acid, n-caproic acid, isocaproic acid, chloropropionic acid, crotonic acid, phenylacetic acid, 2-thienylacetic acid, 3-thienylacetic acid, 4-ethylphenylacetic acid, glutaric, monoethyl ester of adipic acid, hexanoic, heptanoic, decanoic, oleic, stearic, palmitic, 3-hydroxypropionic, 3-methoxypropionic, 3-methylthiobutyric, 4-chlorobutyric, 4-phenylbutyric, 3-phenoxybutyric, 4 ethylbenzoic, 1-propylbenzoic.

 Sodium acetate, sodium 3-ethyl hexanoate or sodium diethyl acetate are preferably used as sodium salts, however.

 Salification can also be obtained by the action of an organic base such as triethylamine, diethylamine, trimethylamine, propylamine, N, N-dimethyl ethanolamine or tris (hydroxy methyl) amino methane. It can also be obtained by the action of arginine, lysine, methylamine, ethanol amine, pyridine, picolinea, dicyclohexylamine, procaine, histidine, N-methylglucamine, morpholine and benzylamine.

 This salification is preferably carried out in a solvent or a mixture of solvents such as water, ether, ethyl, methanol, ethanol or acetone.

 The salts are obtained in amorphous or crystalline form according to the reaction conditions used.

 The crystallized salts are preferably prepared by reacting the free acids with one of the salts of the above-mentioned aliphatic carboxylic acids, preferably with sodium acetate.

 The salification of the products of formula I 'with a mineral or organic acid can be carried out according to the usual methods.

 The products of formula I may be reacted with such mineral or organic acid.

 The optional esterification of the products of formula I 'is carried out under standard conditions. In general, the acid of formula I 'is reacted with a derivative of formula Z-R20 in which Z represents a hydroxyl radical or a halogen atom such as fluorine, chlorine, bromine, iodine and R20. denotes the ester group to be introduced, a group of which a non-limiting list appears above.

dans laquelle R2 represente un atome d'hydrogene ou un groupement protecteur du radical amino et R2 représente ou bien un atome d'hydrogène ou bien R'3 S R'3 représentant un radi- cal -(CH2)n-Hal dans lequel Hal représente un atome d'halos gene et Il représente un entier de 1 a 4.The subject of the invention is also a process for the preparation of the products of general formula I as defined above, characterized in that a product of formula IV is treated.

wherein R2 represents a hydrogen atom or a group protecting the amino radical and R2 represents either a hydrogen atom or R'3 S R'3 representing a radical - (CH2) n-Hal in which Hal represents a halogen atom and II represents an integer of 1 to 4.

dans laquelle R2 a la signification precedentet
soit, lorsque R3 représente R'3 ou bien par la thiourée ou bien par un Produit de formule

dans laquelle R4 représente un groupement protecteur du radical amino ou bien par un produit de formule N-C-S-R5 dans laquelle R5 représente un groupement ammonium ou un atome de métal alcalin, pour obtenir un produit de formule V'

dans laquelle R2 a la signification précédente et roc représente les radicaux

ou nitrile; produits de formule V et V' que l'on fait agir, tels quels ou sous fonde de dérivé fonctionnel, sur un produit de formule VI

dans laquelle A1 représente un atome d'hydrogène ou un ester facilement clivable et R1 a la signification indiquée précédemment, pour obtenir respectivement les produits de formules
III et III' que l'on traite- si désiré selon le procddé décrit ci-dessus. or, when R3 represents a hydrogen atom, with a product of formula Hall CHF2 in which Hall represents a chlorine or bromine atom to obtain a product of formula

in which R2 has the meaning precedentet
either when R3 represents R'3 or else by thiourea or by a product of formula

in which R4 represents a protecting group of the amino radical or else a product of formula NCS-R5 in which R5 represents an ammonium group or an alkali metal atom, to obtain a product of formula V '

in which R2 has the previous meaning and rock represents the radicals

or nitrile; products of formula V and V 'which are allowed to act, either on their own or as a functional derivative, on a product of formula VI

in which A1 represents a hydrogen atom or an easily cleavable ester and R1 has the meaning indicated above, to obtain respectively the products of formulas
III and III 'which is treated if desired according to the procedure described above.

et des produits de formule NHC-S-R5 sur les produits de formule IV dans laquelle R3 représente un radical -(CH2)n-Hal est effectuée dans les mêmes conditions que celles décrites précédemment pour l'action des meRes produits sur les produits correspondants de formule III. The effect of Hall products CHF2 on the products of formula TV in which R3 represents a hydrogen atom and thiourea, products of formula

and products of formula NHC-S-R5 on the products of formula IV in which R3 represents a - (CH2) n-Hal radical is carried out under the same conditions as those described above for the action of the products produced on the corresponding products. of formula III.

 The functional derivative of the product of formula V or V 'may be a functional derivative such as a halide, a symmetrical or mixed anhydride, an amide or an activated ester.

An example of a mixed anhydride is, for example, that formed with isobutyl chloroformate or tosyl chloride. As an example of an activated ester, there can be mentioned the ester formed with 2,4-dinitrophenol or that formed with 1-hydroxybenzo / 1 / triazole. As an example of this, chloride or bromide may be mentioned.
Acidic acid or amide of acid may also be mentioned.
The anhydride can be formed in situ by the action of N, N'-disubstituted carbodiimides, for example N, N-dicyolohexyl carbodiimide.

The acylation reaction is preferably carried out in an oxganic solvent such as methylene chloride. However, other solvents such as tetrahydrofuran, chloroform or dimethylformamide can be used.
When using an acid halide or a mixed anhydride formed by the action of isobutyl chloroformate, the acylation reaction is preferably carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, carbonates and carbonates. skipjobs of sodium and potassium, sodium acetate, triethylamine, pyridine, morpholine or N-methyl morpholine
The reaction temperature is generally less than or equal to room temperature
The products of formula III and III 'are converted into corresponding products of formula I under the conditions described above.
The invention more particularly relates to the method described above, characterized in that it implements products in which the substituent R2 is selected from the group consisting of trityl radicals, chloroacetyl, tert-pentyloxycarbonyl, tert -butyloxycarbonyl, benzyloxycarbonyl
The products of the general formula I and their addition salts with the mineral or organic acids possess a very good antibiotic activity on the gratta (+) bacteria such as the staphylococci, the streptococci and, in particular, the penicillin-resistant staphylococci. resistant. Their effectiveness on gram (-) bacteria, especially on coliform bacteria, pseudomonas, is particularly remarkable.

 These properties enable said products to be used as medicaments in the treatment of diseases of susceptible genera and, in particular, in the case of staphylococcias such as staphylococcal septicemia, malignant staphylococcal malignancies of the face or cutaneous, pyoderma, septic wounds or the like. fungus, anthrax, phlegmons, eesipeles, primitive or postinfluenza acute staphylococci, bronchopneumonia, pulmonary suppuration.

 These products can also be used as medicaments in the treatment of collibacillosis and associated infections, in Proteus, Klebsiella, Salmonella and Pseudomonas infections and in other conditions caused by gram (-) bacteria.

 The subject of the present invention is therefore also, as medicaments and, in particular, antibiotic medicaments, the products of formula I as defined above, and also their salts with pharmaceutically acceptable inorganic or organic acids.

sous une forme éventuelle ment protonée, soit un radical -CHF2 et R1 représente un atome d'hydrogène, un radical 1-méthyl 1 (H) tétrazolvl thiométhyle ou 2-méthyl 1,3,4-thiadiazolylthiométhyle, un radical acétoxyméthyle ou un radical azidométhyle.The subject of the invention is, in particular, as medicaments and, in particular, antibiotic medicaments, the products of formula I and their pharmaceutically acceptable salts, in which formula R 1 represents
- or a hydrogen atom,
or a radical -CH 2 -SR "in which R" represents a 1-methyl 1 (H) tetrazolyl or 2-methyl-1,3,4-thiadiazolyl radical,
- or an acetoxymethyl radical,
or an azidomethyl radical, as well as the addition salts with organic or inorganic acids as well as the products of formula I in which
R represents either a radical

in a form possibly protonated, a radical -CHF2 and R1 represents a hydrogen atom, a 1-methyl-1 (H) tetrazolylthiomethyl or 2-methyl-1,3,4-thiadiazolylthiomethyl radical, an acetoxymethyl radical or a radical azidomethyl.

 The invention relates more particularly, as medicaments, to 3-acetoxymethyl 7 - [2 - [[2- (aminoimino methylthio) ethoxy] imino [2- (2-aminothiazol-4-yl) acetyl] / ami no / ceph-3-th 4-carboxylic syn isomer in the form of internal salt or salt with a mineral or organic acid and its esters with groups - easily cleavable, pharmaceutically acceptable and 3-acetoxymethyl acid 7- / 2- (2-amino thiazol-4-yl) -2- (difluoronethoxyimino) acetyl / amino / ceph-3-ae 4-carboxylic acid, syn isomer, its salts with alkali metals, alkaline earth metals, magnesium ammonium, and organic amine bases and its esters with easily cleavable groups and its salts with pharmaceutically acceptable inorganic or organic acids.

 The invention extends to pharmaceutical compositions containing as active ingredient at least one of the drugs defined above.

 These compositions can be administered orally, rectally, parenterally, intramuscularly or locally by topical application to the skin and mucous membranes.

 They can be solid or liquid and be in the pharmaceutical forms commonly used in human medicine, for example, tablets, single or coated tablets, capsules, granules, suppositories, injectables, ointments, creams, gels; they are prepared according to the usual methods. The active principle (s) can be incorporated into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or vegetable origin fatty substances, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 These compositions may also be in the form of a powder intended to be dissolved extemporaneously in a suitable vehicle, for example sterile pyrogen-free water.

 The dose administered varies according to the condition being treated, the subject, the route of administration and the product under consideration. It may be, for example, between 0.250 g and 4 g per day orally, in humans, with the product described in Example 1 or 9 or between 0.500 g and 1 g, three times per day per day. intramuscular.

 The products of formula I and their salts can also be used as disinfectants for surgical instruments.

dans laquelle R1 et A1 ont la signification indiquée cidessus et R2 représente un radical protecteur du radical amino.- les produits de formule III',

dans laquelle n, Rc, R1 , A1 ont la signification indiquée ci-dessus et R'2 a la signification précédente, les produits de formule V

dans laquelle R2 a la signification indiquée ci-dessus et les produits du formule V'

dans laquelle R2 et Rc ont la signification indiquée ci-dessus. Les produits de formule Il utilisés an départ peuvent être obtenus, par exemple, de la façon suivante
a) Produits de formule XI dans laquelle R3 représente un atome d'hydrogène.Finally, the object of the invention is, as new industrial products and, in particular, as medial internal products necessary for the preparation of the products of formula I, as defined above, the products of formula IIIa:

in which R1 and A1 have the meaning indicated above and R2 represents a radical protecting the amino radical. The products of formula III ',

in which n, Rc, R1, A1 have the meaning indicated above and R'2 has the above meaning, the products of formula V

in which R2 has the meaning indicated above and the products of formula V '

wherein R2 and Rc have the meaning indicated above. The products of formula II used initially can be obtained, for example, as follows
a) Products of formula XI in which R3 represents a hydrogen atom.

produit décrit par exemple dans le brevet français 2 383 1882 par le 2-méthoxypropène pour obtenir un produit de formule

que l'on fait agir, par exemple sous forme d'un dérive de cet acide tel que l'anhydride symétrique, sur un produit de formule

pour obtenir un produit de formule

que l'on traite par un acide minéral aqueux tel que l'acide chlorhydrique dilué pour obtenir un produit de formule :

correspondant a un produit de formule II dans laquelle R3 représente un atome d'hydrogène.A product of formula A is treated

product described for example in French Patent 2,383,188 by 2-methoxypropene to obtain a product of formula

that is made to act, for example in the form of a derivative of this acid such as symmetrical anhydride, on a product of formula

to obtain a product of formula

that is treated with an aqueous mineral acid such as dilute hydrochloric acid to obtain a product of formula:

corresponding to a product of formula II in which R3 represents a hydrogen atom.

 b) The products of formula II in which R3 represents a radical - (CH2) n-Hal are obtained by reacting a product of formula Hal- (CH2) n-Hal on the product of formula IIa above.

The products of formula IV in which R 3 represents the (CH 2) n-Hal radical are obtained by reacting a product of formula Hal- (CH 2) n-Hal with a product of formula
AT.

dans laquelle A a la signification précédente- et R représen= te

ou -CHF2
EXEMPLE 1 : Trifluoroacétats de l'acide 3-acétoxyméthyl 7 //2-(2-amino thiazol-4-yl) 2-/2-(amino imino méthyl thio) éthoxy/imino/acétamido/céph-3-ème 4-cerboxylique (isomère syn).In addition to the following examples which illustrate but do not limit the invention, the following formulas products are additional substances obtainable by the invention:

in which A has the preceding meaning- and R represents

or -CHF2
EXAMPLE 1 Trifluoroacetates of 3-acetoxymethyl 7H-2- (2-aminothiazol-4-yl) -2- (2-aminoimino-methylthio) -ethoxy-imino-acetamido-ceph-3-en-4-ene cerboxylic (syn isomer).

 STAGE A: 2- (2-Tritylamino-thiazol-4-yl) -2- (2-aminoimino-methylthio) -ethoxy-imino-acetic acid syn isomer (as internal salt).

4.6 g of 2 (2-10-ethoxy) imino-2- (2-tritylamino-thiazol-4-yl) acetic acid syn isomer is stirred for 27 hours at room temperature and protected from light. , dichloroethane promoted sol, 1 g thicurea and 20 cm3 hexamethylphosphorotriamide. The mixture is poured into 320 cm3 of isopropyl ether. The precipitated gum obtained is taken up in isopropyl ether and then with water. It is drained, washed with water, dried and gives 3.59 g of product
Mp = 2600C.

NMR SPECTRUM (CF3 CO2 2H) -CH2S-: triplet centered on 3.57 ppm J = 6 Hz -NO-CH2: triplet centered on 4.72 ppm J = 6 Hz
STAGE B: Benzhydryl 3-acetoxymethyl-7- [2- (2-tritylamino-thiazol-4-yl) 2 - [(2-aminoimino-methylthio) -ethoxy-imino] -acetamido-ceph-3-th -4-carboxylate hydrochloride.

10.63 g of the product obtained above, 4.14 g of pyridine iodhydrate, 8.24 g of dicyclohexylcarbodiimide, 7 g of benzhydryl 7-amino-3-acetoxymethyl ceph-3-th-4-carboxylate and 60 cm 3 are stirred. anhydrous dimethylformanide. After 25 minutes at 150 ° C. and 10 minutes at room temperature, the reaction mixture is drained and the insoluble material is washed with methylene chloride. The methylene chloride is removed from the filtrate under reduced pressure at a maximum of 450 ° C, the liquid residue poured into 1 liter of isopropyl ether and stirred for 2 minutes. Decanted, removed the supernatant, the precipitate is taken up with isopropyl ether and the suspension is stirred for 20 minutes. After decantation, the insoluble matter is dissolved in methanol. It is precipitated with ethyl ether, stirred for 70 minutes, drained, rinsed with ether, dried and gives 18.2 g of product.
F (decomposition): = 194 C.

 STAGE C: 3-Acetoxymethyl-7- [2- (2-amino-thiazol-4-yl) -2- [2- (imino-imino-methyl-thio) -ethoxy] imino] -acetemido / ceph-3-ene trifluoroacetate 4-carboxylic acid (syn isomer).

 7.5 g of the product obtained above and 75 g of trifluoroacetic acid are stirred for 3 minutes at room temperature, the insoluble material is filtered off and the filtrate is collected in 1.2 l of ice-cold ether. After 15 minutes at room temperature, the precipitate is filtered off with suction, dissolved in methanol and reprecipitated by addition of ether, stirred for 15 minutes, filtered off, rinsed with ether and dried to give 2.19 g of the expected product. F (decomposition) = 2560 C.

SPECTER R.M.N. (C2 H3) 2SO-OAC: 2.02 p.p.m. singlet N-O-CH2 -: 4.25 p.p.m.

H5 thiazole: 6.78 ppm singlet
SPECTRUM IR (nujol) ss lactam: 1768 cm-1
Amide II + heterocycle: 1538 cm -1
SPECTRUM UV (EtOH, HCl N / 10) ills. 262 nm E1: 291
The syn isomer 2- (2-iodoethoxyimino) 2- (2-tritylamino thiazol-4-yl) acetic acid used starting from Example 1 was prepared as follows
a) Ethyl 2- (2-bromoethoxyimino) 2- (2-tritylamino-thiazol-4-yl) acetate isomer

 A mixture of 4.94 g of 2-hydroxyimino-2- (2-tritylamino-4-thiazolyl) acetic acid ethyl ester, syn isomer, is introduced under argon into 10 cm3 of dimethylformamide and, at room temperature, is added under argon. room, in 3 minutes, 4.14 g of potassium carbonate. Stirred 20 minutes at 20 ° C and added 8.65 cm3 of 1,2-dibromoethane. Stirred 30 hours and poured into a medium comprising 100 cm3 of distilled water and 20 cm3 of methylene chloride. decanted, re-extracted with methylenechloride, washed with distilled water, reextracted, dried organic solutions, drained, rinsed and distilled to dryness. The crude product is obtained, which is chromatographed on silica, glutinous with benzene. å 5 * ether. A first fraction is recovered which is recrystallized from methanol after dissolution at 50-60 ° C. and draining at 0 ± 5 ° C. and gives 1.16 g of creamy white product F = 117 ° C.

We obtain. then a homogeneous fraction of 1.258 g
b) Ethyl 2- (2-iodoethoxyimino) 2- (2-tritylamino-thiazol-4-yl) acetate isomer

 6 g of 2- (2-bromoethoxyimino) 2- (2-tritylamino-thiazol-4-yl) ethyl isomeric acid prepared above are introduced into 60 cm 3 of methyl ethyl ketone and 2.141 g of 10-ol.

hard sodium. A haircut is refluxed at 10 minutes.

Evaporated under reduced pressure. The residue is taken up in 120 cm3 of methylene chloride and washed five times in 40 cm3 of water. Each wash is re-extracted with 2 cm3 of methylene chloride, the organic phase is dried and evaporated to dryness. The resin obtained is supplemented with ether.

It is dried under reduced pressure and gives 6.22 g of product
F = 1100C.

 c) 2- (2-iodoethoxyimino) 2- (2-tritylamino-thiazol-4-yl) acetic acid isomer syn.

 6.7 g of ethyl ester prepared in stage b) are introduced under an inert atmosphere into 5.5 cm 3 of dioxane and 44 cm 3 of absolute ethanol. 5.5 cm 3 of a 2N solution of sodium hydroxide are then added dropwise. 7 cm3 of absolute ethanol are added, the mixture is stirred overnight at room temperature and the sodium salt is formed. The mixture is rinsed twice with 3 cm 3 of ethanol-dioxane mixture (4-1), and the residue is washed with ether. The product obtained is treated in a separating funnel with 100 cm3 of water and 100 cm3 of chloroform. It is adjusted to pH 2 with normal hydrochloric acid. The organic phase is decanted, washed with saturated sodium chloride solution, dried and evaporated under reduced pressure. The resin obtained is dissolved at 400 ° C. in 35 cm 3 of dichloroethane, the crystallization is initiated, the mixture is left at ambient temperature for 72 hours, the precipitate formed is wrung out, rinsed, dried and 5.4 g of white product are obtained which are solvated with dichloroethane (ie 4, 61 g of pure product) m.p. 161 C.

ANALYSIS
C26 H22O3N3SI = 583.35
Calculated: N% 6.16 S% 4.70
Found: 5.9 4.8
UV SPECTRUM (Ethanol, N hydrochloric acid)
1o
278 nm E1 = 235
NMR SPECTRUM (C2 HCI3): proton at 5 thiazole: 6.58 ppm.

EXAMPLE 2 Trifluoroacetate of 3-Acetoxymethyl 7H-2- (2-aminothiazol-4-yl) -2- (aminoiminomethylthio) ethoxyimino / acetamido / ceph-3-thecarboxylic acid trifluoroacetate (isomer
STAGE A Hydrochloride 3-acetoxymethyl-7- [2- (2-trityl-amino-thiazol-4-yl) -2-amino-2-amino-imino-methyl-thio) ethoxy-imino-acetamido-ceph-3-en-4-carboxylate hydrochloride .

 The mixture is stirred for 32 hours. 870 mg of 3-acetoxymethyl-7- [2- (2-tritylamino-thiazol-4-yl) -2- [(2-iodoethoxy) imino] -acetamido-ceph-3-th -4-carboxylate of benzhydryl, 131 mg of thiourea and 1.7 cm3 of anhydrous hexamethylphosphorotriamide.

75 cm3 of isopropyl ether are added with stirring and then, after decantation, 45 cm3 of ethyl ether and filtered to obtain 1.229 g of solvated product. F = 100 C.

NMR SPECTRUM (C2 HCI3)
OAC: 2.0 ppm singlet
: 3.33 to 3.83 ppm

 OCH2: 4.5 p.p.m.

 OAC OAC: 4.88 - 4.98 p.p.m.

H at position 6: doublet 5.14 ppm J = 5HZ
H at position 7: 5,83 -. 6.08 ppm

H at position 5: (thiazole: syn) 6.78 ppm singlet
STAGE B: 3-Acetoxymethyl 7-2- (2-amino thiazol-4-yl) 2- [2- (amino-imino-methyl-thio) -ethoxy] amino] -acetamido / gep-3-th-4- trifluoroacetate carboxylic acid (syn isomer).

 450 mg of the product obtained above and 4.5 cm 3 of trifluoroacetic acid are stirred for 3 minutes at room temperature, the insoluble material is filtered off, the filtrate is collected in 45 cm3 of ice-cold ethyl ether and the mixture is stirred for 15 minutes.

The mixture is filtered off with suction, rinsed with ether and the precipitate is taken up in 0.8 cm 3 of methanol, 8 cm of ether are added, the mixture is stirred for 15 minutes, drained, rinsed with ether and dried to obtain 100 mg of product.
F (decomposition) 256-258 C.

SPECTRUM R.MN. (C2H3) 2 SO
OAC: 2.02 ppm singlet
proton in 5 thiazole: 6.77 ppm singlet
IR SPECTRUM (nujol)
ss lactam 1769 cm-1
Amide II + heterocycle: 1534 cm -1
UV SPECTRUM (EtOH HCl N / 10)
Max. 259 nm E1 to 327
PREPARATION: 3-Acetoxy-methyl-7- [2- (2-tritylamino-thiazol-4-yl) -2 - [(2-iodoethoxy) imino] -acetyl] -amino-ceph-3-th, 4- (4-acetoxy) benzhydryl ester isomeric carboxylic syn.

1.28 g of 2- (2-iodoethoxyimino) -2- (2-tritylamino-thiazol-4-yl) acetic acid, syn isomerized with dichloroethane (in fact in fact 1.09 g of product) are introduced under an inert atmosphere. pure) and 1.45 g of benzhydryl ester of 7-aminocephalosporanic acid in 22 cm3 of anhydrous methylene chloride,
An ice bath is introduced into an ice bath and 5 cc of a 0.5M solution (ie 103 g / liter) of dicyclohexylcarbodiimide in methylene chloride are introduced dropwise. The mixture is stirred at 0 ° C. for one hour and then for one hour at 25 ° C. The precipitated dicyclohexylurea is filtered off, rinsed with methylene chloride and the filtrate and the washing liquors are evaporated to dryness at a temperature below 40 ° C. under reduced pressure. 2.98 g of product are obtained which is chromatographed on silica eluting with a mixture of methylene chloride and ethyl acetate (92-8). 1.12 g of white product is collected.

UV SPECTRUM (Ethanol N: 10 hydrochloric acid)
max. = 269 nm E1 = 209
SPECTRUM IR (Chloroform) = ss-lactam: 1791 cm-1
C = N-OR; 1042 cm -1; C = C: 1638 cm-1
NMR SPECTRUM (C2HCI3):
Proton in 5 thiazole: 6.75 ppm

EXAMPLE 3: 3-Acetoxymethyl-7- [2- (2-aminothiazol-4-yl) -2 - [(2-amino-imino-methylthio) -ethoxy] imino-acetamido-ceph-3-yl 4-carboxylic acid (in the form of the hydroiodide)
For 30 hours at room temperature 130 mg of 3-acetoxymethyl 7 - [[2- (2-amino thiazol-4-yl) -2- (2-iodoethoxy) imino) trifluoroacetate are stirred at room temperature. acetamido / ceph-3-th 4-carboxylic acid, 28 mg of thiourea and 0.37 cm3 of dimethyl formamide. The solution is precipitated with 3 cm 3 of isopropyl ether, decanted, the gum formed with isopropyl ether, followed by ethyl ether and finally with ethyl acetate. It is filtered off, washed with ethyl acetate and dried to obtain 133 mg of product which is purified in ethyl acetate to obtain 85 mg of expected product F. = 2500 ° C.

NMR SPECTRUM (C2H3) 2SO
OAC: 2.02 ppm singlet
NO-CH2-: triplet 4.28 ppm J = 6 Hz
H at position 6: doublet 5.16 ppm J = 5 Hz
H at position 7: 5.68 to 5.88 ppm

Proton in 5 thiazole: 6.82 ppm singlet
UV SPECTRUM (EtOH HCI N / 10)
Maximum at 220 nm E1 = 444 E 29.800
Inflex at 255 nm E1 = 262 e 17.600
PREPARATION: 3-Acetoxymethyl-7- [2- (2-amino thiazol-4-yl) 2 - [(2-iodoethoxy) imino] -acetamido] -3-thio-4-carboxylic acid trifluoroacetate, syn isomer .

960 mg of the benzyl ester of the corresponding tritylated product, product prepared in Example 2, are introduced into 10 cm 3 of pure trifluoroacetic acid. The mixture is stirred for 3 minutes at room temperature, cooled for one minute in an ice bath and then precipitated by the addition of 100 cm 3 of ice-cold isopropyl ether. The mixture is stirred for 10 minutes at room temperature, the precipitate is filtered off, the isopropyl ether rinsed and then ethyl ether, dried under reduced pressure and gives 460 mg of expected product p # 214 C
ANALYSIS -:
C17H18N5O7 SI, CF3 CO2H
Calculated: N% 9.87 SO 9.06
Found: 9.7 9.2
UV SPECTRUM (Ethanol, N / 10 hydrochloric acid)
Max. : 262 E1 = 290
NMR SPECTRUM / (CD3) 2SO /:
Proton in 5 thiazole: 6.83 ppm

EXAMPLE 4: 3 - [(1-Methyl-1H-tetrazol-5-yl) -thiomethyl] - [2- (2-aminothiazol-4-yl) -2 - [(2-aminoiminomethylthio) -ethoxy] imino] -acetamido / ceph -3-mer 40 carboxylic (.sous form of internal salt)
STANE A: 3 - [(1-methyl-1H-tetrazol-5-yl) -thiomethyl] -7- [2- (2-tritylaminothiazol-4-yl) -2-amino-imino-methylthio) -ethoxy] -imino-acetamido ceph-3-th 4-carboxylic acid (as internal salt).

 660 mg of 7-amino-3 - [(1-methyl-1H-tetra-zol-5-yl) thiomethyl / ceph-3-yl) -carboxylic acid and 10 cm3 of anhydrous dimethylformamide are stirred, stirred for 10 minutes, cooled to 95.degree. C. and 260 ml of triethylenediamine are added in fractions in minutes under stirring. After 3 minutes 1.68 g of pyridine hydroiodide are added rapidly, the mixture is stirred for 2 minutes, 1.06 g of 2- (2-tritylamino-thiazol-4-yl) -2 - ((2-aminoimino-methylthio) ethoxyimino acid are added. / acetic acid, stirred for 5 minutes and at 150C added in one go 840 mg of dicyclohexylcarbodiimide. The mixture is drained after 45 minutes, the filtrate is poured into 250 cm3 of ice water. The mixture is stirred for half an hour, filtered, washed with water and dried to obtain 1.338 g of amorphous product. The mixture is stirred for half an hour. 1.2-3 g of the latter with 10 cm3 of methylene chloride, filtered off the insoluble, treated the filtrate with activated charcoal, filtered, concentrated the filtrate to dryness and obtained 857 mg of product.

NMR SPECTRUM (C2H3) 2SO
-N-CH3: 3.9 ppm

 Protons of trityl: 7.3 p. p.m.

IR SPECTRUM (CHCI3)
ss lactam: 1769 cm-1
Amide: 1674 cm-1
CO2 + aromatic: 1600 cm -1, 1493
Amide II + heterocyl: 1525 cm -1
UV SPECTRUM (EtOH HCI N / 10)
Max. 271 nm E1 = 230
STAGE B: 3 - [(1-methyl-1H-tetrazol-5-yl) -thiomethyl] -7- [2- (2-aminothiazol-4-yl) -2 - [(2-amino-imino-methylthio) -ethoxy] -imino-acetamido ceph-3-th 4-carboxylic acid (as internal salt).

800 mg of the product obtained above is dissolved in 8 cm3 of 92% aqueous acetic acid by heating at 480-500 ° C. and this temperature is maintained for 2 hours 1/4. The insoluble matter is filtered off and 150 cm3 of isopropyl ether are added to the filtrate, the mixture is stirred for 1/2 hour, the mixture is left standing for one hour, filtered, washed with isopropyl ether and then with ethyl ether, dried and 537 mg of product. This is stirred for half an hour with 2 cm3 of ethanol, then with 2.5 cm3 of water, finally the 325 mg obtained with 2 am3 of acetic acid are added and dropwise added 20 mole of methanol and 4 cm3 of water. After stirring for half an hour, the filtrate is filtered off and treated with activated charcoal, filtered, evaporated and a residue is obtained which is repeated several times with ethanol. 175 mg of white product is obtained
Mp = 258 C.

NMR SPECTRUM (C2H3) 2SO
Proton in 5 thiazole (syn) 6.82 ppm singlet
N-CH3: 3.92 ppm

 N-OCH 2 and CH 2 -S--: 4.33 p.p.m.

H in position 6 and 7
H s s lactam: = 5 to 5.83 ppm

amide 1667 cm-1
CO2 1597 cm-1
Amide II:1533 cm-1
SPECTRE U.V. (EtOH HCI N/10)
Inflex. 223 nm E1 = 338
Max. 263 nm E1/1 = 295 e = 17.700
Infl 280 nn E1 = 255
EXEMPLE 5 : Acide 3-azidométhyl 7-//2-(2-aminothiazol-4-yl) 2-/2-(amino imino méthylthio) éthoxy imino/acétamido/cèph3-ème 4-carboxylique (sous forme de sel interne).SPECTRUM -XR (nujol)
ss lactam 1766 cm-1

amide 1667 cm-1
CO2 1597 cm -1
Amide II: 1533 cm-1
UV SPECTRUM (EtOH HCI N / 10)
Inflex. 223 nm E1 = 338
Max. 263 nm E1 / 1 = 295 e = 17,700
Infl 280 nn E1 = 255
EXAMPLE 5: 3-Azidomethyl-7- [2- (2-aminothiazol-4-yl) -2- (2-aminoiminomethylthio) ethoxy] amino / acetamido / ceph-3-yl carboxylic acid (in the form of an internal salt) .

 STAGE A: 3-Azidomethyl-7- [2- (2-tritylaminothiazol-4-yl) -2 - [(2-amino-imino-methylthio) -ethoxy] imino-acetamido] -3-carboxylic acid (as salt internal).

 255 mg of 7-amino-3-azidomethyl ceph-3-yl 4-carboxylic acid are stirred for 5 minutes with 3 cm 3 of anhydrous formamide and 168 parts of triethylenediamine are added in portions. To the resulting solution was added 412 mg pyridine iodhydrate and cooled the mixture to + 150C to add in one go the following solution: 532 mg 2- (2-tritylamino thiazol-4-yl) 2 - / (2-aminoimino-methylthio) -ethoxyiminoacetic acid, 207 mg of pyridine hydroiodide and 3 cm3 of dimethylformamide. 412 mg of di-cyclohexylcarbodiimide are immediately added. and stirred 20 minutes at 15 C, 40 minutes at 200C, wring. 100 cm3 of water are added to the filtrate and the mixture is stirred for half an hour, allowed to stand for half an hour, drained, washed with water and dried to obtain 437 mg of crude product.

432 mg of this latter are purified by stirring with 8.6 cc of chloroform for half an hour. The mixture is filtered off with suction, treated with active charcoal, filtered and evaporated to give 350 mg of product.

IR SPECTRUM (CHCI3)
azide: 2160 cm -1
ss-lactam: 1769 cm -1
amide: 1670 cm-1
CO2: 1600 cm-1
Amide II: 1521 cm
STAGE B: 3-azidomethyl 7- / 2- (2-aminothiazol-4-)
Yl) 2- [2- (amino-imino-methylthio) -ethoxyimino] -acetamido-cep-3-th -4-carboxylic acid (as internal salt)
The mixture is heated at 46-500C for 2h15, 344 mg of the product obtained above and 315 cm3 of acetic acid at 92%. It is treated with activated charcoal and heated for another 30 minutes, filtered hot and 80 cm3 of ethyl ether is added to the filtrate.

After standing for 15 minutes, drained, washed with ether and collected 159 mg of product F = 2384C.

NMR SPECTRUM (C2H3) 2SO
Proton in 5 thiazole: 6.8 ppm singlet
H at position 6: doublet 5.06 ppm J = 5Hz.

H at position 7: after treatment at 2H2O
doublet 5.67 ppm J = 5Hz
IR SPECTRUM (nujol)
ss-lactam 1770 cm-1
C amide 1667 cm-1 #
N3) 2102 cm-1 and CO2
C = C 1600-1535 cm-1
UV SPECTRUM (EtOH HC1 N / 10)
Infl. : 222 nu El = 325
Max. : 261 nu E1 / 1 = 319
Infl. : 280 nu E1 - 271
EXAMPLE 6: 3 - [(2-methyl-1,3,4-thiadiazol-5-yl) -thio-methyl] -7- [2- (2-aminothiazol-4-yl) -2 - [(2-amino) imino] methyl thio) ethoxy / imino / acetamido / ceph-3-th 4-carhoxylic (under internal salt)
STAGE A: 3 - [(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl] -7- [2- (2-tritylaminothiazol-4-yl) -2 - ((2-aminoiminomethylthio) -thoxy] - acid imino / acetamido / ceph-3-th 4-carboxylic acid (as internal salt).

 207 mg of 7-amino-3 - [(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl / ceph-3-th -4-carboxylic acid and 1.8 cm3 of dimethylformamide are stirred for 1/2 hour, 90 mg of triethylenediamine are added at 150 ° C., followed by 252 mg of pyridine hydroiodide. To this mixture is added rapidly the solution obtained by stirring 318 mg of 2- (2-tritylamino-thiazol-4-yl) - (2-amino-imino-methylthio) -ethoxy-imino-acetic acid, 252 mg of pyridine iodhydrate and 1.8 cm3 of dimethylformamide and then 252 mg of dicyclohexyl carbodiimide are added, the mixture is stirred for 15 minutes at 15 ° C. and 30 minutes at 20 ° C. and then the insoluble material is filtered off.The filtrate is treated with 120 cm3 of water and stirred for 15 minutes. The mixture is filtered, washed with water and dried to give 361 mg of crude product which is stirred for half an hour with 20 cm3 of methylene chloride, filtered off and the filtrate is concentrated to dryness. chloroform, treated with activated charcoal and drained The filtrate is brought to dryness under argon and gives 171 mg of product.

IR SPECTRUM (nujol)
ss-lactam: 1764 cm
amide: 1667 cm-1
aromatic and CO2: 1599 cm -1, 1497 cm -1
amide II + heterocycle: 1526 cm -1, 1511 cm -1
UV SPECTRUM (EtOH HCI N / 10)
Max. 271 nm E1 / 1 = 227 z = 19,500
STAGE B: 3 - [(2-methyl-1,3,4-thiadiazol-5-yl) -thio-methyl] -7- [2- (2-aminothiazol-4-yl) -2 - [(2-amino-imino-methylthio) -ethoxy) - acid / imino / acetamido / ceph-3-th 4-carboxylic acid (as internal salt).

 During 2 h / 2, 171 mg of the product obtained above and 1.71 cm3 of acidic acid at 92% are heated at 48 ° C. to 50 ° C. with stirring. The solution is filtered, isopropyl ether (30 cc) is added to the filtrate, the mixture is stirred for 15 minutes, the residue is filtered off after standing for 15 minutes, the mixture is washed with isopropyl ether and then with ethyl ether and is dried to give 93 mg of product. 260 C.

NMR SPECTRUM (C2H3) 2SO
CH3-C: 2.67 ppm singlet
N-OCH2 and CH2S (in 3): 4.33 ppm

H at positions 6 and 7 5.0 5.83 ppm
Thiazole H5: 6.78 ppm singlet
IR SPECTRUM (nujol)
ss-lactam 1760 cm-1
amide 1660 cm-1
CO2 1613-1595 cm-1
amide II + heterocyl 1531 cm-1
UV SPECTRUM (EtOH HCl N / 10) 220 @@ y1
In1. 220 nm E1 = 312
Max. 265 nm E1 = 307
Infl. 280 nm E1 / 1 = 278
EXAMPLE 7: 3-Acetoxymethyl-7- [2- (2-aminothiazol-4-yl) -2- (2-thiocyanatoethoxy) -imino-acetamido] -3-thiocarboxylic acid.

 STAGE A: 2- (2-Tritylamino thiazol-4-yl) 2- (2-thiocyanatoethoxyimino) acetic acid.

 For 139 hours, 6.83 g of 2- (2-iodoethoxy) imino 2- (2-tritylamino thiazol-4-yl) acetic acid isomer syn, solvate, are stirred at + 150 ° C, protected from light. dichloromethane, 7.61 g of ammonium thiocyanate and 35 μl of dimethylacetamide The solution is cooled in an ice-water bath and 400 R 3 of distilled water and 150 cm 3 of saturated solution of chloride are added. sodium. Stir 2 hours, drained, washed with water, dried and obtained 4.55 g of crude product. After two recrystallizations in ethyl acetate, 3.44 g of the expected product are obtained. Fi = 194 C.

 STAGE B: 3-Acetoxymethyl-7- [2- (2-tritylaminothiazol-4-yl) -2- (2-thiocyanatoethoxy) -imino-acetamido-ceph-3-beryl 4-carboxylate benzhydryl.

1.69 g of the product obtained above, 0.685 g of pyridine hydroiodide, 1.16 g of benzhydryl 4-amino-3-acetoxymethyl ceph-3-me-4-carboxylate and 1, -3-6 g are mixed together. of dicyclohexylcarbodiimide. 17 cm 3 of dimethylformamide are immediately added, cooled to 160 ° C. for 30 minutes, the insoluble material is filtered off, 400 cm 3 of ethyl ether are added to the filtrate and the mixture is stirred.
S-minutes and let rest an hour. After decantation, the gum obtained is washed with ether and then 50 cm3 of ether are added and kneaded until concretion. The mixture is filtered off with suction, washed with ether and dried to obtain 1.92 g of crude product which is purified by chromatography on silica eluting with a chloroform-acetonitrile (91-9) mixture.

790 mq of amorphous product is collected
NMR SPECTRUM (C2HCI3)
OAC 2.0 ppm singlet CH-S: 3.17 to 3.65 ppm

NO-CH2: triplet 4.58 pmm J = 6Hz
CH2-OAC: 4.65-4.87 ppm and 4.98-5.2 ppm

H5 thiazole syn: 6.77 ppm singlet
IR SPECTRUM (CHCI3)
C = N: 2156 cm -1
ss-lactam 1793 cm-1
ester + OAC: 1739-1733 cm-1
amide: 1689 cm-1
UV SPECTRUM (EtOH HCl W / 10)
Max. 267 nu E1 = 209 E li 540
STAGE C: 3-Acetoxymethyl-7- (2- (2-aminothiazol-4-yl) -2- (2-thiocyanatoethoxy) -imino-acetamido-3-thi-4-carboxylic acid.

 445 mg of the product obtained above and 4.4 cm3 of trifluoroacetic acid are stirred for 3 minutes at room temperature, 44 ml of ice-cold isopropyl ether are added, the mixture is stirred for 5 minutes, drained, rinsed with a mixture of isopropyl ether and ethyl ether (1-1) then with ethyl ether. The product is dissolved in 0.8 gm 3 of methanol, the solution is precipitated with ethyl ether (8 cc), stirred for 10 minutes, filtered off, rinsed with ether and dried to obtain 199 mg of product F (decomposition) = 200 ° C.

NMR SPECTRUM (C2H3) 2SO
OAC: 2.03 ppm singlet CH2S: 3.17 to 3.83 ppm

H5 thiazole syn: 6.82 ppm singlet
IR SPECTRUM (nujol)
S-CEN: 2153 cm -1
ss-lactam: 1781 cm-1
UV SPECTRUM (EtOH HCI N / 10)
Max. 264 nude # 18,900
EXAMPLE 8 3-Acetoxymethyl-7- (2-aminothiazol-4-yl) -2- (2-imino-hydrazino-methylthio) ethoxy-imino-acetamido-ceph-3-yl carboxylic acid (as internal salt).

 STAGE A: 2- (2-Tritylamino-thiazol-4-yl) -2- (2-tritylhydrazino-imino-methylthio) -ethoxy-imino-acetic acid as internal salt.

 7.5 g of 2- (2-iodoethoxy) imino 2- (2-tert-aminothiazol-4-yl) acetic acid isomer-syn, solvated with dichloroethane, 13.5 g of N-tritylthiosenicarbazide are dissolved in 45 cm3 of anhydrous dimethylformamide. The solution is heated at 30 ° C. to 320 ° C., protected from light for 65 hours, poured into 900 cm 3 of water, stirred for 10 minutes, 60 ml of saturated solution of sodium chloride are added and after half an hour drained, washed with water, dried and obtained 18.14 g of crude product. 5 g of the latter are purified by chromatography on silica by gluing with a chloroform-methanol mixture (85-15), taken up in isopropyl ether and dried, and 1.44 g of product F = 200 ° C. are obtained.

NMR SPECTRUM (C2HCI3)
H5 thiazole: 5.87 ppm singlet
NO-CH2: 4.33 ppm

 H trityles: 7.18 - 7.35 p.p.m.

 H mobile: 5.42 p.p.m.

IR SPECTRUM (CHCl3)
NH: 392 cm-1
UV SPECTRUM (EtOH HCl N / 10)
Max. 278 nu E1 = 180
STAGE B: Benzhydryl 3-acetoxymethyl-7- [2- (2-trityl-amino-thiazol-4-yl) -2- (2-tritylhydrazino-imino-methylthio) ethoxy-imino-acetamido-ceph-3-th -4-carboxylate hydrochloride.

 513 mg of the product obtained above, 134 mg of pyridine hydroiodide, 268 mg of dicyclohexylcarbodiimide, 227 mg of benzhydryl 7-amino 3-acetoxymethyl ceph-3-th-4-carboxylate and 3 mg of benzhydryl 4-carboxylate are stirred for 20 minutes at room temperature. cm3 of dimethylformamide anhydrous. 10 μM of methylene chloride are added, the dicyclohexylurea formed is filtered off, the filtrate is concentrated under reduced pressure and the residue is stirred for 5 minutes with 40 cm3 of isopropyl ether and decant. The resin obtained is taken up in 40 cm3 of a mixture of isopropyl ether and ethyl ether (1-1), triturated, stirred for 20 minutes, drained, rinsed with isopropyl ether and then dried. 680 mg of product F (decomposition) 162 C.

SPECTRUM I.R. (CHCI3).

NH: 3391
C = O: 1782 cm -1
Ester and OAC: 1736-1730 cm-1
Aromatic: 1594 cm -1, 1576 cm -1, 1496 cm -1
STAGE C: 3-acetoxymethyl-7H-amino-thiazol-4-yl) 2- (2-iminohydrazinomethylthio) -ethoxy-imino-acetamido [ceph-3-th -4-carboxylic acid (as internal salt).

For 45 minutes, the product obtained above is stirred at 50 ° C., 0.94 g of the product obtained, 9.4 cm 3 of formic acid and 4.7 cm 3 of water.
It is cooled to room temperature, filtered off and the filtrate is concentrated to dryness. The residue is taken up in 9 cm3 of trifluoroacetic acid, stirred for 4 minutes. The insoluble matter is filtered off, isopropyl ether (90 cc) is added to the filtrate, the mixture is stirred for 5 minutes, the precipitate is filtered off, the isopropyl ether rinsed, and the residue is taken up. the minimum amount of methanol and precipitates with ethyl ether. 282 mg of product are obtained. 558 mg of product prepared as above in 7 cm 3 of water are added in suspension and pyridine is added to pH 6.6.
The light insoluble material is filtered and the filtrate is concentrated to dryness under reduced pressure. The residue is taken up in 5 cm3 of ethyl ether and triturated
The precipitate obtained is filtered off with ether and 500 mg of product is obtained, which is stirred for 10 minutes in 5 cm 3 of methanol, the insoluble material is filtered off, the residue is filtered off with ethyl ether to obtain 96 mg. of product F (decomposition) 210 C.

 Mother liquors are recovered 66 mq of identical product.

NMR SPECTRUM (C2H3) 2SO
OAC 2, Ù3 ppm singlet
NO-CH3 4.25 ppm

H5 thiazole: 6.78 ppm singlet
UV SPECTRUM (EtOH-HCI N / 10)
ax. 262 nm E1 / 1 = 301 # = 16 800
The tritylthiosamicarbazide used from the example was prepared as follows:
100 cm3 of dimethylacetate are rapidly added with 9.11 g of thiosmicarbazide and 27.9 g of trityl chloride. The temperature is maintained at +15 ° C., triethylamine (13 cm3) is added dropwise, the solution is left for one hour at 15 ° C., the pH is adjusted to about 7 with triethylamine and then poured into 2 liters of mixture: water and After stirring for one hour, the mixture is filtered off, washed with water and dried at 500 ° C. under reduced pressure to obtain 31.3 g of product F = 1940 ° C.
29.3 g of the above product are stirred for 30 minutes with ethyl acetate (90 cc), drained, washed with ethyl acetate and then dried. 25.05 g of product are obtained
F = 2080C.

NMR SPECTRUM (CzHCl3)
H mobile: 5.08 ppm 6.92 ppm 6.33 ppm

 Trityl H: a 7.33 p.p.m.

IR SPECTRUM (CHCI3)
= C = NH2 3505 cm-1
UV SPECTRUM (EtOH.HCl N / 10)
Max. 245 nm E1 = 405
EXAMPLE 9: 3-Acetoxymethyl-7- [2- (2-amino-thiazol-4-yl) -2- (difluoromethoxyimino) acetyl] amino-ceph-3-th -4-carboxylic acid isomer syn.

 STAGE A: 2- (2-Tritylamino thiazol-4-yl) 2- (difluoro-methoxy imino) ethyl isomer syn.

 5 g of 2-hydroxyimino-2- (2-tritylamino-thiazol-4-yl) ethyl isomer hydrochloride, 20 ml of 2N sodium hydroxide and 20 cm3 of ethanol 1000 are stirred for 5 minutes.

The sodium salt precipitates. 60 cm3 of dioxane are added to dissolve it and the monochlorodifluoromethane is sparged for 30 minutes with good stirring. 20 cm3 of 2N sodium hydroxide, 20 cm3 of ethanol 100 and 60 cm3 of dioxane are then added and the bubbling is continued for another 30 minutes. 6.7 g of sodium bicarbonate are then added. sodium and stirred for 15 minutes at room temperature. A slight insoluble material is filtered off and the filtrate is concentrated under reduced pressure at a temperature not exceeding 400 ° C. until the consistency of a syrup. It is diluted with chloroform, decanted, washed once with water and then with a saturated aqueous solution of sodium chloride, dried, evaporated to dryness and chromatography on silica eluting with benzene. 652 mg of white resin is collected.

NMR SPECTRUM (C2HCI3)
CH F2: 5.55 - 6.75 - 7.95 ppm

H5 thiazole syn: 6.77 ppm singlet
UV SPECTRUM (EtOH)
Max. 308 nm E1 / 1 = 80 # = 4100 SPECTRUM -1.R.

C = NOR 1141 cm-1
CHF2 = 1145 cm-1 - 1117 cm-1
STAGE B: 2- (2-Tritylamino thiazol-4-yl) 2- (difluoromethoxyimino) acetic acid isomer syn.

 51 mg of the product obtained above, 0.05 cm 3 of dioxane, 0.35 cm 3 of ethanol 100 and 0.1 cm 3 of sodium hydroxide are stirred.

A light gum is formed which is dissolved with 0.1 cm3 of ethanol 100. It is sealed and heated at 40 ° C for 2 1/2 hours and left overnight at room temperature with good agitation. The precipitate formed is filtered off and rinsed with a few drops of a dioxane-ethanol mixture (17) and then with ether to give 25 mg of Na salt which is taken up in 1 cm 3 of chloroform, 1 cm 3 of water and add hydrochloric acid N until pH2. Stir vigorously, decant the chloroform, wash with water, dry, evaporate to dryness and obtain 16 mg of white resin.

NMR SPECTRUM C2HCI3
CHF2: 5.4 - 6.6 - 7.8 ppm

H5 thiazole syn: 6.72 ppm singlet
OH and NH: 9.33 and 10.25 ppm

 STAGE C: 3-Acetoxymethyl 7- [2- (2-tritylamino-thiazol-4-yl) -2- (difluoromethoxy-imino) acetyl-amino-ceph-3-th -4-tert-butyl-4-carboxylate.

 80 mg of tert-butyl 3-acetoxymethyl 7-amino ceph-3-yl-4-carboxylate and 16 μl of chloroform were stirred in an ice bath.

2 cm3 of a chloroform solution containing 309 mg of dicyclohexylcarbodiimide are introduced dropwise.

One hour and a half is left at ambient temperature and then the dicyolohexylurea formed is filtered off. The filtrate is evaporated under reduced pressure, chromatographed on silica-glutinous with a mixture of methylene chloride and ethyl acetate (94-6).

584 mg of white resin are obtained.

NMR SPECTRUM (C2HCl3)
tert-butyl: 1, .54 ppm singlet
OAC: 2.0 ppm singlet
CEF2 e 5.6 - 6.8 - 8.0 ppm

H5 Thiazola syn: 6.92 ppm singlet
UV SPECTRUM (EtOH HCI N / 10)
Max. 262 nm E1-217
STAGE D: 3-Acetoxymethyl 7 - [[2- (2-amino thiazol-4-yl)] - [2- (difluoromethoxyimino) acetyl] amino] ceph-3-en-4-carboxylic acid syn isomer

0.32 g of the product obtained above and 1 .6 cm3 of pure trifluoroacetic acid are stirred for 3 minutes at room temperature. 16 ml of an ice-cold mixture of isopropyl ether and ethyl ether (1-1) are added and the mixture is stirred for 15 minutes.
It is filtered off, rinsed with the ethereal mixture and then with pure ethyl ether and 130 mg of white product is obtained. F decomposition = 176 C.

NMR SPECTRUM (C2H3) 2SO
OAC 2.03 ppm singlet
CH F: 5t95 - 7.13 8.23 ppm

H5 thiazole syn: 7.05 singlet
UV SPECTRUM (EtOH HCI N / 10)
Max. 278 nm E1 / 1 = 265
IR SPECTRUM (nujol)
ss-lactam: 1777 cm -1
OAC: 1726 cm-1
-C = NOR: 1031 cm-1
EXAMPLE 10 Preparations for Injection, Formulas
A - 3-Acetoxymethyl-7- [2- (2-amino thiazol-4-yl) Acid]
2- / 2- (amino imino methylthio) ethoxy imino / acetamido
/ ceph-3-th 4-carboxylic acid (syn isomer) 500 mg
Sterile aqueous excipient.qsp 5 cm3
B - 3-Acetoxymethyl 7 - / 2- (2-Aminothiazol-4) Acid
-yl) 2- (difluoromethoxyimino) acetyl / amino
ceph-3-th 4-carboxylic isomer syn 500 mg
Aqueous sterile excipient qsp ................. 5 cm3
EXAMPLE 11 Capsules having the formula:
A - 3-Acetoxymethyl-7- [2- (2-amino thiazol-4-yl) Acid]
2- / 2- (aino imino methylthio) ethoxyimino / acetamido
/ ceph-3-th 4-carboxylic acid (syn isomer) .......... 250 mg
Excipient qs 1 capsule finished at ........ 400 mg
B - 3-Acetoxymethyl 7 - [2- (2-amino thiazol, 4-yl))
2- (difluoromethoxyimino) acetyl / amino / ceph-3-th
4-carboxylic acid (syn isomer) 250 mg
Excipient qs 1 capsule finished at ....... 400 mg - PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION
I - ACTIVITY IN VITRO, dilutions method in liquid medium.

 A series of tubes are prepared in which the same amount of sterile nutrient medium is distributed. Increasing amounts of the product to be tested are dispensed into each tube, and then each tube is seeded with a bacterial strain. After incubation for twenty-four or forty-eight hours in an oven at 37 ° C., inhibition of growth is assessed by transillumination, which makes it possible to determine the minimum inhibitory concentrations (C.M.I.) expressed in .mu.g / cm.sup.3.

The following results were obtained
EXAMPLES OF EXAMPLES 1, 2 and 3

<tb><SEP> C. <SEP> M. <SEP> I. <SEP> in <SEP> g / ml
<tb><SEP> STRAINS <SEP> 24 <SEP> H <SEP> 48 <SEP> h
<tb> Staphylococcus <SEP> aureus <SEP> ATCC <SEP> 6 <SEP> 538
<tb> Pen-Sensible <SEP> ................................ <SEP> 2 <SEP> 2
<tb> Staphylococcus <SEP> aurens <SEP> UC <SEP> 1 <SEP> 128
<tb> Pen-resistant <SEP> ................................ <SEP> 2 <SEP> 3
<tb> Staphylococcus <SEP> aureus <SEP> exp.n <SEP> 54 <SEP> 146 ........... <SEP> 2 <SEP> 3
<tb> Straptococcus <SEP> pyogenic <SEP> A <SEP> 561 <SEP> ................. <SEP> 0.02 <SEP> 0.02
<tb> Bacillus <SEP> subtilis <SEP> ATCC <SEP> 6 <SEP> 633 <SEP> ................. <SEP> 1 <SEP> 1
<tb> Escherichia <SEP> Coli <SEP> Susceptible <SEP> Tetracy
<tb> cline <SEP> ATCC <SEP> 9 <SEP> 637 <SEP> .............................. <SEP> 1 <SEP> 1
<tb> Escherichia <SEP> Coli <SEP> Resistant <SEP> Tetracy
<tb> cline <SEP> ATCC <SEP> 11 <SEP> 303 <SEP> ............................. <SEP > 0.05 <SEP> 0.05
<tb> Escherichia <SEP> Coli <SEP> Exp. <SEP> TO26B6 <SEP> .................. <SEP> 0.5 <SEP> 0.5
<tb> Escherichia <SEP> Coli <SEP> Resistant <SEP> Gentamy
<tb> cline, <SEP> Tobramycin <SEP> R <SEP> 55 <SEP> 123 <SEP> D <SEP> ................. <SEP> 0, 5 <SEP> 0.5
<tb> Klebsiella <SEP> pneumoniae <SEP> Exp. <SEP> 52 <SEP> 145 <SEP> ............ <SEP> 0.5 <SEP> 0.5
<tb> Klebsiella <SEP> Pneumoniae <SEP> 2 <SEP> 536 <SEP> Resistant
<tb> Gentamycin <SEP> ................................... <SEP> 1 <SEP> 2
<tb> Protaus <SEP> mirabilis <SEP> (indol-1) <SEP> A <SEP> 235 <SEP> .............. <SEP> 0.1 <SEP> 0.1
<tb> Salmonella <SEP> typhimurium <SEP> 420 <SEP> .................... <SEP> 0.5 <SEP> 0.5
<tb> Enterobacter <SEP> cloacae <SEP> 681 <SEP> ....................... <SEP> 2 <SEP> 2
<tb> Providencia <SEP> From <SEP> 48 <SEP> .............................. <SEP> 2 <SEP> 3
<tb> Psendomonas <SEP> 8951 <SEP> Resistant <SEP> Gentamy
<tb> cine <SEP> Tetracycline ............................... <SEP> 20 <SEP> 20
<tb> Serratia <SEP> Resistant <SEP> Gentamycin <SEP> 2 <SEP> 532 <SEP> 0.5 <SEP> 0.5
<Tb>
PRODUCT OF EXAMPLE 4

<tb><SEP> C. <SEP> M. <SEP> I. <SEP> in <SEP> g / ml
<tb><SEP> STRAINS <SEP> 24 <SEP> H <SEP> 48 <SEP> H
<tb> Staphylococcus <SEP> aureus <SEP> ATCC <SEP> 6 <SEP> 538
<tb> Pen-Sensible <SEP> ............................ <SEP> 1 <SEP> 2
<tb> Staphylococcus <SEP> aureus <SEP> UC <SEP> 1 <SEP> 128 <SEP> Pen
<tb> Resistant <SEP> ................................ 2 <SEP> 2
<tb> Staphylococcus <SEP> aureus <SEP> exp. <SEP> n <SEP> 54 <SEP> 146 <SEP> 2 <SEP> 2
<tb> Streptococcus <SEP> pyogenic <SEP> A <SEP> 561 <SEP> ............ <SEP> 0.05 <SEP> 0.05
<tb> Bacillus <SEP> subtilis <SEP> ATCC <SEP> 6 <SEP> 633 <SEP> ............. 0.5 <SEP> 2
<tb> Escherichia <SEP> Coli <SEP> Susceptible <SEP> Tetracy- <SEP>
<tb> cline <SEP> ATCC <SEP> 9 <SEP> 637 <SEP> ........................ <SEP> 2 <SEP> 2
<tb> Escherichia <SEP> Coli <SEP> Resistant <SEP> Tetracy
<tb> cline <SEP> ATCC <SEP> 11 <SEP> 303 <SEP> ...................... <SEP> 0.2 <SEP> 0.2
<tb> Escherichia <SEP> Coli <SEP> Exp.TO26B6 <SEP> ............ <SEP> 1 <SEP> 1
<tb> Escherichia <SEP> Coli <SEP> Resistant <SEP> Gentamy
<tb> cine, Tobramycin <SEP> R <SEP> 55 <SEP> 123 <SEP> D <SEP> .............. <SEP> 1 <SEP> 1
<tb> Klebsiella <SEP> pneumoniae <SEP> Exp. <SEP> 52 <SEP> 145 <SEP> ........... <SEP> 1 <SEP> 1
<tb> Klebsiella <SEP> Pneumoniae <SEP> 2 <SEP> 536 <SEP> Resistant
<tb> Gentamycin <SEP> ................................. <SEP> 5 <SEP> 5
<tb> Proteus <SEP> mirabilis <SEP> (indol-) <SEP> A <SEP> 235 <SEP> ............. <SEP> 0.2 <SEP> 0, 5
<tb> Salmonella <SEP> typhimurium <SEP> 420 <SEP> ................... <SEP> 2 <SEP> 2
<tb> Enterobacter <SEP> cloacae <SEP> 681 <SEP>. <SEP> ........ <SEP> 3 <SEP> 3
<tb> Pseudomonas <SEP> 39 <SEP> 35 <SEP> Exp.Sensitive <SEP> Genta
<tb> mycine ......................................... <SEP> 10 <SEP> 20
<tb> Providencia <SEP> From <SEP> 48 <SEP> ............................. <SEP> 5 <SEP > 10
<tb> Serratia <SEP> Resistant <SEP> Gentamycin <SEP> 2 <SEP> 532 <SEP> 1 <SEP> i <SEP>
<tb> PRODUCT OF EXAMPLE S

<tb><SEP> C. <SEP> M. <SEP> I. <SEP> in <SEP> g / ml
<tb><SEP> STRAINS <SEP> 24 <SEP> H <SEP> 48 <SEP> H
<tb><SEP> Staphylococcus <SEP> aureus <SEP> ATCC <SEP> 6 <SEQ> 538
<tb> Pen-Sensible .................................... <SEP> 1 <SEP> 1
<tb><SEP> Staphylococcus <SEP> aureus <SEP> UC <SEP> 1 <SEP> 128
<tb><SEP> Pen-Resistant <SEP> .................................. <SEP> 1 <SEP> 2
<tb><SEP> Staphylococcus <SEP> at <SEP> reus <SEP> exp.N <SEP> 54 <SEP> 146 <SEP> ........... <SEP> 1 <SEP> 2
<tb><SEP> Streptococcus <SEP> pyogenic <SEP> A <SEP> 561 <SEP> ................... <SEP> 0.02 <SEP> 0.05
<tb><SEP> Bacillus <SEP> subtilis <SEP> ATCC <SEP> 6 <SEP> 633 <SEP> ................... <SEP> 2 <SEP> 3
<tb><SEP> Escherichia <SEP> Coli <SEP> Susceptible <SEP> Tetracy
<tb><SEP> cline <SEP> ATCC <SEP> 9 <SEP> 637 <SEP> ............................ ... <SEP> 2 <SEP> 2
<tb><SEP> Escherichia <SEP> Coli <SEP> Resistant <SEP> Tetracy
<tb> cline <SEP> ATCC <SEP> 11 <SEP> 303 <SEP> .............................. <SEP> 0.2 <SEP> 0.2
<tb> Escherichia <SEP> Coli <SEP> Exp. <SEP> TO26B6 <SEP> ................... <SEP> 0.5 <SEP> 0.5
<tb><SEP> Escherichia <SEP> Coli <SEP> Resistant <SEP> Gentamy
<tb><SEP> cine, <SEP> Tobramycin <SEP> R <SEP> 55 <SEP> 123 <SEP> D <SEP> ................... <SEP> 1 <SEP> 1
<tb> Klabsiella <SEP> pneumoniae <SEP> Exp. <SEP> 52 <SEP> 145 <SEP> .............. <SEP> 1 <SEP> 1
<tb><SEP> Klebsiella <SEP> Pneumoniae <SEP> 2 <SEP> 536 <SEP> Resistant
<tb><SEP> Gentamycin <SEP> .................................... <SEP> 2 <SEP> 3
<tb><SEP> Proceu <SEP> mirabilis <SEP> (indol-) <SEP> A <SEP> 235 <SEP> .............. <SEP> 0.2 <SEP> 0.2
<tb><SEP> Salmonella <SEP> typhimu <SEP> rium <SEP> 420 <SEP> ................... <SEP> 1 <SEP> 1
<tb><SEP> Enterobacter <SEP> cloacae <SEP> 681 <SEP> ...................... <SEP> 3 <SEP> 3
<tb><SEP> Providencia <SEP> From <SEP> 48 <SEP> ............................. <SEP> 10 <SEP> 10
<tb><SEP> Serratia <SEP> Resistant <SEP> Gentamycin <SEP> 2 <SEP> 532 <SEP> .......... <SEP> 1 <SEP> 1
<Tb>
PRODUCT OF EXAMPLE 6

<tb><SEP> C. <SEP> M. <SEP> I. <SEP> in
<tb><SEP> SUCHES
<tb><SEP> 24 <SEP> H <SEP><SEP> 48 <SEP> E <SEP>
<tb> Staphylococcus <SEP> aureus <SEP> ATCC <SEP> 6 <SEQ> 538 <SEP>
<tb> Pen-Sensible <SEP> ............................... <SEP> 1 <SEP> 2
<tb> Staphylococcus <SEP> yr <SEP> reas <SEP> OC <SEP> 1 <SEP> 128
<tb> Pen-Resistant <SEP> .............................. <SEP> 2 <SEP> 2
<tb> Staphylococcus <SEP> at <SEP> xeus <SEP> exp.n <SEP> 54 <SEP> 146 <SEP> ....... <SEP> 2 <SEP> 2
<tb> Streptococcus <SEP> pyogenic <SEP> A <SEP> 561 <SEP> ............... <SEP> 0.05 <SEP> 0.05
<tb> Sacrificial <SEP> subtilis <SEP> ATCC <SEP> 6 <SEP> 633 <SEP> ............... <SEP> 1 <SEP> 2
<tb> Escherichia <SEP> Coli <SEP> Susceptible <SEP> Tetracy
<tb> oline <SEP> ATCC <SEP> 9 <SEP> 637 <SEP> ........................... <SEP> 5 <SEP> 5
<tb> Escherichia <SEP> Coli <SEP> Resistant <SEP> Tetracy
<tb> cline <SEP> ATCC <SEP> 11 <SEP> 303 <SEP> .......................... <SEP> 0, 1 <SEP> 0.1
<tb> Escherichia <SEP> Coli <SEP> Exp. <SEP> TO26B6 <SEP> ............... <SEP> 2 <SEP> 2
<tb> Escherichia <SEP> Coli <SEP> Resistant <SEP> Gentamy- <SEP>
<tb> cine, <SEP> Tobramycin <SEP> R <SEP> 55 <SEP> 123 <SEP> D <SEP> ............... <SEP> 1 <SEP> 1
<tb> Klebsiella <SEP> pneumoniae <SEP> Exp. <SEP> 52 <SEP> 145 <SEP> ......... <SEP> 1 <SEP> 1
<tb> Klebsiella <SEP> Pneumoniae <SEP> 2 <SEP> 536 <SEP> Resistant <SEP>
<tb> Gentamycin <SEP> ............................... <SEP> 5 <SEP> 5
<tb> Proteus <SEP> mirabilis <SEP> (indol-) <SEP> A <SEP> 235 <SEP> ... <SEP> 1 <SEP> 1 <SEP>
<tb> Salmonella <SEP> typhimurium <SEP> 420 <SEP> ................. <SEP> 2 <SEP> 3
<tb> Enterobacter <SEP> cloacss <SEP> 681 <SEP> ................... <SEP> 10 <SEP> 10
<tb> Serratia <SEP> Resistant <SEP> Gentamycin <SEP> 2 <SEP> 532 <SEP> 2 <SEP> 3
<Tb>
PRODUCT OF EXAMPLE 7

<tb><SEP> C. <SEP> M. <SEP> I. <SEP> in <SEP> g / ml
<tb><SEP> STRAINS <SEP> 24 <SEP> H <SEP> 48 <SEP> H
<tb> Staphylococcus <SEP> aureus <SEP> ATCC <SEP> 6 <SEP> 538
<tb> Pen-Sensible <SEP> ...................... <SEP> 1 <SEP> 1
<tb> Staphylococcus <SEP> at <SEP> reus <SEP> UC <SEP> 1 <SEP> 128
<tb> Pen-Resistant <SEP> ..................... <SEP> 1 <SEP> 1
<tb> Staphylococcus <SEP> aureus <SEP> exp.N <SEP> 54 <SEP> 146. <SEP> 1 <SEP> 2
<tb> Streptococcus <SEP> pyogenic <SEP> A <SEP> 561 <SEP> ...... <SEP> 0.02 <SEP> 0.02
<tb> Bacillus <SEP> subtilis <SEP> ATCC <SEP> 6 <SEP> 633 <SEP> ...... <SEP> 1 <SEP> 2
<tb> Escherichia <SEP> Coli <SEP> Susceptible <SEP> Tetracy
<tb> cline <SEP> ATCC <SEP> 9 <SEP> 637 <SEP> .................. <SEP> 5 <SEP> 5
<tb> Escherichia <SEP> Coli <SEP> Resistant <SEP> Tetracy
<tb> cline <SEP> ATCC <SEP> 11 <SEP> 303 <SEP> ................. <SEP> 0.2 <SEP> 0.2
<tb> Escherichia <SEP> Coli <SEP> Exp. <SEP> TO26B6 <SEP> ...... <SEP> 2 <SEP> 2
<tb> Escherichia <SEP> Coli <SEP> Resistant <SEP> Gentamy
<tb> cine, <SEP> Tobramycin <SEP> R <SEP> 55 <SEP> 123 <SEP> D <SEP> ...... <SEP> 1 <SEP> 1
<tb> Klebsiella <SEP> Pneumoniae <SEP> Exp.52 <SEP> 145 <SEP> ... <SEP> 0.5 <SEP> 0.5
<tb> Klebsiella <SEP> Pneumoniae <SEP> 2 <SEP> 536 <SEP> Resistant
<tb> Gentamycin <SEP> ......................... <SEP> 5 <SEP> 5
<tb> Proteus <SEP> mirabilisw <SEP> (indol-) <SEP> A <SEP> 235 <SEP> ... <SEP> 0.2 <SEP> 0.5
<tb> Salmonella <SEP> typhimurium <SEP> 420 <SEP> .......... <SEP> 1 <SEP> 3
<tb> Providencia <SEP> From <SEP> 48 <SEP> ................... <SEP> 10 <SEP> 10
<tb> Serratia <SEP> Resistant <SEP> Gentamycin <SEP> 2 <SEP> 532. <SEP> 2 <SEP> 3
<Tb>
PRODUCT OF EXAMPLE 8

<tb><SEP> C. <SEP> M. <SEP> I. <SEP> in <SEP> g / ml
<tb><SEP> STRAINS <SEP> 24 <SEP> H <SEP> 48 <SEP> H
<tb> Staphylococcus <SEP> aureus <SEP> ATCC <SEP> 6 <SEP> 538
<tb> Pen-Sensible <SEP> .................................. <SEP> 1 <SEP> 2
<tb> Staphylococcus <SEP> aureus <SEP> UC <SEP> 1 <SEP> 128
<tb> Pen-Resistant <SEP> ................................. <SEP> 2 <SEP> 2
<tb> Staphylococcus <SEP> aureus <SEP> exp.N <SEP> 54 <SEP> 146 <SEP>. <SEP> 1 <SEP> 2
<tb> Streptococcus <SEP> pyogenic <SEP> A <SEP> 561 <SEP> ................. <SEP> 0.02 <SEP> 0.02
<tb> Bacillus <SEP> subtilis <SEP> ATCC <SEP> 6 <SEP> 633 <SEP> ................. <SEP> 1 <SEP> 3
<tb> Escherichia <SEP> Coli <SEP> Susceptible <SEP> Tetracy
<tb> cline <SEP> ATCC <SEP> 9 <SEP> 637 <SEP> .............................. <SEP> 2 <SEP> 2
<tb> Escherichia <SEP> Coli <SEP> Resistant <SEP> Tetracy- <SEP>
<tb> cline <SEP> ATCC <SEP> 11 <SEP> 303 <SEP> ............................. <SEP > 0.5 <SEP> 0.5
<tb> Escherichia <SEP> Coli <SEP> Exp <SEP> TO26B6 <SEP> .................. <SEP> 1 <SEP> 1
<tb> Escherichia <SEP> Coli <SEP> Resistant <SEP> Gentamy
<tb> cine, <SEP> Tobramycin <SEP> R <SEP> 55 <SEP> 123 <SEP> D <SEP> .................. <SEP> 1 <SEP> 1
<tb> Klebsiella <SEP> pneumoniae <SEP> Exp. <SEP> 52 <SEP> 145 <SEP> ............. <SEP> 1 <SEP> 1
<tb> Klebsiella <SEP> Pneumoniae <SEP> 2 <SEP> 536 <SEP> Resistant
<tb> Gentamycin <SEP> .................................. <SEP> 5 <SEP> 10
<tb> Proteus <SEP> mirabilis <SEP> (indol) <SEP> A <SEP> 235 <SEP> .. <SEP> 0.2 <SEP> 0.2
<tb> Salmonella <SEP> typhimurium <SEP> 420 <SEP> ................... <SEP> 1 <SEP> 2
<tb> Serratia <SEP> Resistant <SEP> Gentamycin <SEP> 2 <SEP> 532 <SEP> i <SEP> 2 <SEP>
<Tb>
PRODUCT OF EXAMPLE 9

<tb><SEP> C. <SEP> M. <SEP> I. <SEP> in <SEP> g / ml
<tb><SEP> STRAINS <SEP> 24 <SEP> H <SEP> 48 <SEP> H
<tb><SEP> Staphylococcus <SEP> aureus <SEP> ATCC <SEP> 6 <SEQ> 538
<tb><SEP> Pen-Sensitive <SEP> ............................... <SEP> 1 <SEP> 1
<tb><SEP> Staphylococcus <SEP> at <SEP> reus <SEP> UC <SEP> 1 <SEP> 128
<tb><SEP> Pen-Resistant <SEP> ............................. <SEP> 1 <SEP> 2
<tb><SEP> Staphylococcus <SEP> aureus <SEP> exp. <SEP> n <SEP> 54 <SEP> 146 ....... <SEP> 1 <SEP> 2
<tb><SEP> Streptococcus <SEP> pyogenes <SEP> A <SEP> 561 <SEP> ............... <SEP> 0.05 <SEP> 0.05
<tb><SEP> Streptococcus <SEP> faecalis <SEP> 5 <SEP> 432 <SEP> .............. <SEP> 5 <SEP>
<tb><SEP> Bacillus <SEP> subtilis <SEP> ATCC <SEP> 6 <SEP> 633 <SEP> ............. <SEP> 1 <SEP> 5
<tb><SEP> Escherichia <SEP> Coli <SEP> Susceptible <SEP> Tetracy
<tb><SEP> cline <SEP> ATCC <SEP> 9 <SEP> 637 <SEP> ......................... <SEP> 0.5 <SEP> 1
<tb><SEP> Escherichia <SEP> Coli <SEP> Resistant <SEP> Tetracy
<tb><SEP> cline <SEP> ATCC <SEP> 11 <SEP> 303 <SEP> ........................ <SEP> 0 , 05 <SEP> 0,1
<tb><SEP> Escherichia <SEP> Coli <SEP> Exp.TO26B6 <SEP> .............. <SEP> 0.2 <SEP> 0.2
<tb><SEP> Escherichia <SEP> Coli <SEP> Resistant <SEP> Gentamy
<tb><SEP> cina, <SEP> Tobramycin <SEP> R <SEP> 55 <SEP> 123 <SEP> D <SEP> ............. <SEP> 0.2 <SEP> 0.2
<tb><SEP> Klebsiella <SEP> Pneumoniae <SEP> Exp.52 <SEP> 145 <SEP> ......... <SEP> 0.05 <SEP> 0.05
<tb><SEP> Klebsiella <SEP> Pneumoniae <SEP> 2 <SEP> 536 <SEP> Resistant
<tb> Gentemycine <SEP> ............................. <SEP> 0.5 <SEP> 0.5
<tb><SEP> Protaus <SEP> mirabilis <SEP> (indol-) <SEP> A <SEP> 235 <SEP> ........ <SEP> 0.05 <SEP> 0.05
<tb><SEP> Salmonella <SEP> typhimurium <SEP> 420 <SEP> .............. <SEP> 0.5 <SEP> 0.5
<tb> Providencia <SEP> From <SEP> 48 <SEP> ........................ <SEP> 2 <SEP> 2
<tb><SEP> Serratia <SEP> Resistant <SEP> Gentamycin <SEP> 2 <SEP> 532 <SEP> ..... <SEP> 0.5 <SEP> 0.5
<Tb>
II- ACTIVITY IN VIVO
A) Experimental infection with Escherichia Coli TO26B6
The action of the product of Example 1 on the experimental infection of Escherichia coli in the mouse was investigated.

Ten male mice weighing 21.5 g were infested with an intraperitoneal injection of 0.5 cc of a twenty-two hour culture of nutrient broth of the strain. Escherichia coli TO26B6 Pasteur Institute, diluted to 1 / 5th by distilled water.

 One hour, five hours and twenty-four hours after the injection, a given amount of the product was administered by injection.

 Mortality was noted for eight days.

The results were as follows

<tb><SEP> MORTALITY <SEP> AFTER <SEP> MOUSE
<tb><SEP> DOSAGE <SEP> 7H <SEP> 7H15 <SEP> 21H30 <SEP> 24 <SEP> H <SEP> 28 <SEP> H <SEP> 36 <SEP> H <SEP> SURVIVORS
<tb><SEP> at <SEP> 8th <SEP> day
<tb> Witnesses <SEP> 1 <SEP> 1 <SEP> 8 <SEP> 0/10
<tb><SEP> 0.1 <SEP> mg <SEP> 1 <SEP> 1 <SEP> 1 <SEP> 1 <SEP> 6/10
<tb><SEP> 0.25mg <SEP> 10/10
<Tb>
B) Experimental infection with Proteus Mirabilis.

 The action of the product of Example 1 was studied on an experimental Proteus Mirabilis infection of the mouse.

Ten mice of an average weight of 21.5 g were infested by intraperitoneal injection of 0.5 cm 3 of a 22 hour oxoid broth culture of the
Proteus Mirabilis A 235, diluted 1/10.

 Subcutaneous injection, one hour, five hours and twenty four hours after injection, was administered a determined amount of product.

The results have and the following

<tb><SEP> MRTALITE <SEP> AFTER <SEP> MOUSE <SEP> SURVIVAL
<tb><SEP> DOSAGE <SEP> 21:15 <SEP> 23:45 <SEP> 25 <SEP> H <SEP> 31 <SEP> H <SEP> at <SEP> 8th <SEP> DAY
<tb> Cookies <SEP> 9 <SEP> 1 <SEP> 0/10
<tb> 0.025 <SEP> mg <SEP> 1 <SEP> 1 <SEP> 1 <SEP> 7/10
<tb> 0.05 <SEP> mg <SEP> 10/10
<tb> 0.1 <SEP> mg <SEP> 10/10
<tb> 0.25 <SEP> mg <SEP> 10/10
<tb> 0.5 <SEP> mg <SEP> 10/10
<Tb>
C) Experimental infection with Protens Morganii A 236
The action of the product of Example 1 was investigated on experimental infection of Proteus Morganii A 236 of the mouse. Ten mice with an average weight of 20.5 g were infested by intraperitoneal injection of 0.5 cm3 of a culture in pH7 medium, diluted 1/10.

 Subcutaneous injection was administered one hour five hours and twenty-four hours after injection. a specific quantity of the product.

The following results were obtained.

<Tb>

<SEP> DOSAGE <SEP> MORTALITY <SEP> AFTER <SEP> MOUSE <SEP> SURVIVORS
<tb> 4 <SEP> H <SEP> 6 <SEP> H <SEP> 6:15 <SEP> 21:10 <SEP> 45:20 <SEP> at <SEP> 8th <SEP> DAY
<tb><SEP> Witnesses <SEP> 10 <SEP> 0/10
<tb> 0.05 <SEP> mg <SEP> 1 <SEP> 2 <SEP> 1 <SEP> 3 <SEP> 1 <SEP> 2/10
<tb><SEP> 0.1 <SEP> mg <SEP> 10/10
<tb> 0.25 <SEP> mg <SEP> 10/10
<tb> 0.5 <SEP> mg <SEP> 10/10
<Tb>
D) Experimental infection with Klebsiella Pneumoniae
The action of the product of Example 1 on the experimental infection of Klebsiella Pneumoniae Ne 5.2 145 of the mouse was studied. Ten mice of an average weight of 21 g were infested by intraperitoneal injection of 0.5 cm3 of a pH6 culture diluted to 1/1500.

 Subcutaneous injection was administered one hour, five hours and twenty-four hours after injection, a determined amount of the product.

The results. following were obtained:

<tb><SEP> 9Si = i = CP <SEP> ==} <SEP> MOUSE
<tb> POSOLOGIM <SEP> ~ <SEP> XQRTAbITE <SEP> AFTER <SEP> 1 <SEP> SuRVIVANTES
<tb><SEP> where <SEP> rC1 <SEP> o <SEP> s <SEP> o <SEP>
<tb><SEP> Z <SEP> m <SEP> o <SEP> = <SEP> 4 <SEP> J, S <SEP>; ro6 <SEP> I8 <SEP> j <SEP> aU <SEP > 8th <SEP> J
<tb><SEP>:<SEP> t :: <SEP>. <SEP>. <SEP>. <SEP> o <SEP> J: 6 <SEP> J: 8 <SEP> o <SEP> at <SEP> 8th <SEP> DAY
<tb><SEP>:<SEP>:<SEP>:<SEP>.<SEP>:
<tb> Witnesses <SEP> 1 <SEP> 6 <SEP> 1 <SEP> -1 <SEP> 1 <SEP> | <SEP> 0/10
SEP>SEP> SEP > Q ~ <SEP> ts00s <SEP> eoBoooz
<tb><SEP> 0.1 <SEP> mg <SEP> ≈ <SEP> 1 <SEP> 1 <SEP> 1 <SEP> 1 <SEP> 6/10
<tb> 0.1 <SEP> mg <SEP> i <SEP> 1 <SEP> 1 <SEP> o. <SEP> a <SEP> ~ o <SEP> 6/10
<tb> 0.25 <SEP> mg <SEP> 1 <SEP> 1 <SEP> i <SEP> 8/10
<tb> ~~~~~~~ <SEP> ~ 0 ~ <SEP> = ~ 0Y. <SEP> .0 ~~ <SEP> CI <SEP> i <SEP> ~ <SEP> 0w0 <SEP>> e0 <SEP> 9/10
<tb> O, S <SEP> mg <SEP> 1 <SEP> s / ao
<tb> i <SEP> em ~ s <SEP> sz <SEP> D <SEP> ~~ <SEP> o = ~ <SEP>;. ~~ o <SEP> c: mo <SEP> sca ~ oex
<tb> P <SEP> mcr <SEP> - <SEP> as / io
<tb> i1S <SEP> e <SEP> s <SEP> ~ <. <SEP> n <SEP> ~ soo <SEP>3C> COi <SEP> 1 (Lg <SEP> la / b
<tb><SEP> 1 <SEP> tS <SEP> mg <SEP> 1a / 10
<Tb>

Claims (7)

R4 represents a radical protecting the amino radical, syn isomer.  or nitrile

 or a (CH 2) n -S-RC radical in which n represents an integer of 1 to 4 and Rc represents one of the radicals  - a radical CHF2  wherein R2 represents a hydrogen atom or a protecting group of the amino radical and Rd represents

 CLAIMS 1- The products of general formula Vd  2- The products of general formula V

 syn isomer in which R2 has the meaning given in claim 1.  3- The products of general formula V '

 syn isomer wherein n, R2 and Rc are as defined in claim 1.  4- The products. of general formulas V or V 'as defined in any one of claims 2 or 3 wherein the radicals R2 and R4 are selected from the group consisting of trityl, chloroacetyl, tert-pentyloxycarbonyl, tert-butyloxycarbonyl and beizyloxycarbonyle.  5- The products of general formulas V or V 'as defined in any one of claims 2 or 3 in which the radical R2 represents a hydrogen atom  6. The products of general formula V as defined in claim 2 in which R 2 represents a hydrogen atom or a trityl radical.  7- Process for the preparation of the products of formula Vd as defined in claim I, characterized in that a product of formula IV is treated.

 in which R2 represents a hydrogen atom or a group protecting the amino radical and R3 represents either a hydrogen atom or R'3, R3 representing a - (CH2) n -Hal radical in which Hal represents a hydrogen atom; halogen and n represents an integer of 1 to 4.  or nitrile;

 in which R2 has the above meaning and R c represents the radicals

 in which R4 represents a protecting group of the amino radical or else a product of formula N C-S-R5 in which R5 represents an ammonium group or an alkali metal atom, to obtain a product of formula V '

 or, when R3 represents R'3 or else by thiourea or by a product of formula  in which R2 has the previous meaning,

 or, when R3 represents a hydrogen atom, with a product of formula Hal1 CHF2 in which Hal1 represents a chlorine or bromine atom in order to obtain a product of formula