FR2588867A1 - New products derived from the 3-amino-2-oxoazetidine series, process for their preparation and their application - Google Patents

Abstract

The products of formula: Ra = R1 = -(CH2)nX; n = integer from 1 to 4; X = halogen, CN, OR'1; R'1 = H, Alk; or X = S-R"1; R"1 = H, Alk or heterocycle; or X = R"; R' and R" = H, C1-4 Alk or R'+R" = heterocycle or X = N3, SCH or NCS; R1 = optionally esterified or salified carboxyl, or Ra = R1 = in which the functional groups are protected; A = H or SO3H, cis or trans, racemic or optically active, process for their preparation and their application.

Description

 The present invention relates to novel products derived from 3-amino-2-oxoazetidine-1-sulfamic acid, to a process for their preparation, to their use as medicaments and to the intermediate products necessary for their preparation.

dans laquelle R représente un atome d'hydrogène ou un radical alkyle, alkényle ou alkynyle, linéaire ou ramifié, ayant au plus 12 atomes de carbone éventuellement substitue,
R1 représente soit un radical-(CH2)n-X dans lequel n représente un nombre entier de 1 à 4 et X représente un atome d'halogène, un radical cyano1 un radical O-R1 dans lequ-el R'1 représente un atome hydrogène ou un radical alkyle, ou X représente un radical S-R"1 dans lequel R"1 représente un atome d'hydrogène m radical alkyle ou un hétérocycle ou X représente un radical
# dans lequel R' et R" représente un atome d'hydrogène un radical alkyle ayant de 1 à 4 atomes de carbone, ou R' et
R" forment avec l'atome d'azote auquel ils sont liés, un hétérocycle ou X représente un radical azido, thiocyanato ou iso- thiocyanato sot R1 représente un radical carboxyle éventuellement estérifié cu salifié, ainsi que les sels des produits de formule I avec les bases ou les acides, le trait ondulé signifiant que les produits peuvent se trouver sous la forme cis ou trans ou sous forme d'un mélange cis-trans , les produits de formule I étant sous forme racémique ou optiquement active, l'oxime étant sous la forme syn.The subject of the invention is the products of general formula I

in which R represents a hydrogen atom or an alkyl, alkenyl or alkynyl radical, linear or branched, having at most 12 carbon atoms optionally substituted,
R1 represents either a radical- (CH2) nX in which n represents an integer from 1 to 4 and X represents a halogen atom, a cyano radical or an O-R1 radical in which R'1 represents a hydrogen atom or an alkyl radical, or X represents an SR "1 radical in which R" 1 represents a hydrogen atom m alkyl radical or a heterocycle or X represents a radical
# in which R 'and R "represents a hydrogen atom an alkyl radical having 1 to 4 carbon atoms, or R' and
R "form, with the nitrogen atom to which they are bonded, a heterocycle or X represents an azido, thiocyanato or isothiocyanato radical. R1 represents an optionally esterified or carboxylated carboxyl radical, as well as the salts of the products of formula I with bases or acids, the wavy line signifying that the products may be in the cis or trans form or in the form of a cis-trans mixture, the products of formula I being in racemic or optically active form, the oxime being in the form syn.

Among the values of R are: a) methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, decyl, undecyl, dodecyl b) vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl radicals c) ethynyl, propargyl, butynyl radicals
The radicals indicated above in (a) to (c) may themselves be substituted with one or more radicals, such as optionally salified or esterified carboxy radicals, alkoxycarbonyl radicals such as methoxycarbonyl, ethoxycarbonyl, carbamoyl, dimethylcarbamoyl, amino, α-alkylamino such as dimethylamino, diethylamino, alkylamino such as methylamino, halogen such as chlorine, bromine, iodine, alkoxy such as methoxy, ethoxy, propyloxy, alkylthio such as methyl thio, ethylthio, aryl such as phenyl, or heterocyclic aryl such as tetrazolyl, pyridinyl, arylthio such as optionally substituted phenylthio, heterocyclic aryl-thio such as tetra zolylthio, thiadiazolylthio optionally substituted with alkyl such as methyl.

 Among the values of R, the values of hydrogen, methyl, ethyl carbon optionally esterified salified oli, 1-carboxy-1-methyl ethyl, optionally esterified or salified, 2-aminoethyl, may be mentioned above.

 Among the values of R 1 there may be mentioned more particularly the chloromethyl, chloroethyl, chloropropyl, 1 chloro-1-methyl ethyl and chlorobutyl radicals.

 Mention may also be made of the corresponding brominated, iodinated or fluorinated radicals, in particular bromomethyl. Mention may also be made of cyano methyl, cyanoethyl and the corresponding alkyl radicals.

 Among the R'1 values, mention may be made of the alkyl radicals preferably containing 1 to 4 carbon atoms mentioned above in a), in particular the methyl radical.

 Among the values of R "1, mention may also be made of alkyl radicals, preferably having from 1 to 4 carbon atoms, in particular methyl.

 Among the heterocycles that may represent Rb, mention may be made of the radicals 1,2,3-1,2,5-1,2,4 o 1,3,4 thiadiazolyl 1H 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 several radicals selected from the group formed for example by methyl, ethyl propyl, isopropyl, methoxy, ethoxy, propyloxy, isopropyloxy, amino, hydroxycarbonylmethyl, dimethylaminoethyl and diethylaminoethyl.

 There may be mentioned more particularly the radicals 1-methyl tetrazolyl, 2-methyl-1,3,4-thiadiazolyl, 3-methyl-1,2,4-thiadiazolyl, 3-methoxy-1,2,4-thiadiazolyl, 1,3,4 Thiadiazol-5-yl and especially the 1-methyl tetrazolyl radical.

peut représenter notamment un radical amino, diméthylamino, méthylamino, éthylamino, diéthylamino, pipéridino, morpholino.The radical

may especially represent an amino, dimethylamino, methylamino, ethylamino, diethylamino, piperidino, morpholino radical.

 The sulfo group in position 1 and the carboxy group that may contain the radical R may be salified.

Among the salts that can be prepared include the sodium, potassium, lithium, calcium, magnesium and ammonium salts. Mention may also be made of organic base salts such as trimethylamine, diethylamine, triethylamine, methylamine, propylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, N ', N'-dibenzylethylenediamine, morpholine, benzylamine, procaine, lysine, arinine, histidine, N
The products of formula I may be in the form of salts of organic or inorganic acids since these products contain a salifiable amino group in the melt.

 Among the acids with which the amino groups of the products of formula can be salified are, inter alia, acetic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, hydrochloric, hydrobromic, sulfuric and phosphoric acids. The products of formula I can also be in the form of internal salts.

 The preferred products are cis products.

isomères syn, sous forme cis dans laquelle R2 représente un atorne d'hydrogène ou un radical alkyle linéaire ou ramifié éventuellement substitué par un radical carboxyle ou amino, n' représente un nombre entier de 1 a' 2 et X' représente un atome halogène ou un radical hydroxyle, sols forme racémique ou optiquement active ainsi que les sels des produits de formule
I' avec les bases ou les acides.The invention more particularly relates to the products of general formula II

syn isomers, in cis form in which R2 represents a hydrogen atom or a linear or branched alkyl radical optionally substituted with a carboxyl or amino radical, n 'represents an integer of 1 to 2 and X' represents a halogen atom or a hydroxyl radical, racemic or optically active soils as well as the salts of the products of formula
I 'with bases or acids.

 The subject of the invention is more particularly the products described hereinafter in the examples, and especially 4chloromethyl-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-1-sulfamic acid. cis, syn isomer, racemic or optically active.

it is understood that the products of formula I above may be present, either in the form indicated by said formula I, or in the form mine tautomer Iz

The lactam nucleus is numbered as follows

Products referred to as cis are formula products

Trans products are formula products

racémique ou optiquement actif, formule dans laquelle Ra repré- sente R1, R1 ayant la signification indiquée ci-dessus, soit
Ra représente R1 dans lequel'les fonctions réactives sont protégées et A représente un atome d'hydrogène ou un radical sulfo, par un produit de formule III

dans laquelle Rb représente un atome d'hydrogène ou un groupement protecteur du radical amino et R'b représente un groupement protecteur du radical hydroxyle ou R'b représente R, R ayant la signification indiquée ci-dessus , ou R'b représente un radical R dans lequel les fonctions réactives sont protégées, pour obtenir un produit de formule IV

racémlqrle ou optiquement actif dans laquelle Rb, R'b, Ra et A ont la signification précédente, produit que l'on sommet si nécessaire, et si désiré, à l'une quelconque ou plusieurs des réactions suivantes, dans un ordre quelconque o) coupure par hydrolyse, hydrogénolyse ou par action de la thiourée du ou des groupements protecteurs que peuvent représenter Rb et R'b ou comporter R'b et Ra. The invention also relates to a process for the preparation of the products of general formula I as defined above, characterized in that a product of formula II is strained.

racemic or optically active formula in which Ra represents R1, R1 having the meaning indicated above, or
Ra represents R 1 in which the reactive functions are protected and A represents a hydrogen atom or a sulfo radical, with a product of formula III

in which Rb represents a hydrogen atom or a group protecting the amino radical and R'b represents a protecting group of the hydroxyl radical or R'b represents R, R having the meaning indicated above, or R'b represents a radical R in which the reactive functions are protected, to obtain a product of formula IV

racemic or optically active in which Rb, R'b, Ra and A have the above meaning, which product is top-up if necessary, and if desired, at any one or more of the following reactions, in any order o) cut by hydrolysis, hydrogenolysis or by action of the thiourea of the protective group or groups that can represent Rb and R'b or R'b and Ra.

b) esterification or salification of the arboxy radical that may comprise the Rtb radical and salification of the sulfo radical.

c) salification with an acid of the amino radical (s).

d) sulfamation of the products in which the radical A represents a hydrogen atom.

e) splitting the molecule to obtain an optically active product.

 In formula II, Ra may generally represent the radical R1. However, in cases where R1 represents a - (CH2) nX in which x represents in particular a hydroxyl or amino radical, it may be advantageous to protect these radicals by removable protecting groups.

 The protective groups of the amino radical may be, for example, an alkyl radical, preferably tert-butyl or tert-amyl radical, they may also be understood from acyl, aromatic or heterocyclic aliphatic groups or a carbamoyl group.

 Mention may also be made of lower alkanoyl groups such as, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl. R 'may also be lower alkoxy or cycloalkoxycarbonyl such as, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, tert-butyloxycarbonyl pentyloxycarbonyl, hexyloxycarbonyl, benzoyl, toluolyl, naphthoyl, phthaloyl, mesyl, phenylacetyl, phenylpropionyl, aralkoxycarbonyl, such as benzyloxycarbonyl.

 The acyl groups may be substituted for example with a chlorine, bromine, diode or fluorine atom.

Mention may be made of chloroacetyl, dichloroacetyl, trichloroacetyl, bronoacetyl or trifluoroacetyl radicals.

 It is also possible to use a lower aralkyl group such as benzyl, 4-methoxybenzyl or phenylethyl, methyl, 3,4-di-methoxybenzyl or benzhydryl.

 It is also possible to use a haloalkyl group such as trichloroethyl.

 It is also possible to use a chlorobenzoyl, para-nitrobenzoyl, para-tert-butylbenzoyl, phenyloxyethyl, caprrlyl, n-decanoyl, acryloyl or trichloroethoxycarbonyl group.

It is also possible to use a methyl-carbamoyl group,
phenylcarbamoyl, naphthylcarbamoyl, as well as thiocar
corresponding bamcyles.

The list above is not exhaustive, it is evi-
other protective groups of amines, group-
known in particular in the chemistry of peptides, few
can also be used.

The hydroxyl group protecting group can
to be chosen from the list below
It can be an acyl group such as for example for
myl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl,
trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxy
acetyl, benzoyl, benzoylformyl, p-nitrobenzoyl. We can
also include ethoxycarbonyl, methoxycarbonyl
bonyle, propoxycarbonyl, ssssss-trichloroethoxycarbonyl, ben
zyloxycarbonyl, tert-butoxycarbonyl, 1-cyclo-propylethoxy
carbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, methyl
thoxytetrahydropyranyl, trityl, benzyl, 4-methaxybenzyl,
benzhydryl, trichloroethyl, 1-methyl, 1-methoxyethyl, phthaloyl.

 Other acyls such as propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl may also be mentioned.

 Mention may also be made of phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, para-nitrobenzoyl, para-tert-butylbenzoyl, caprylyl, acryloyl, methylcarbamoyl, phenylcarbamoyl and naphthylcarbamoyl radicals.

 3an underst the values of the substituents Rb when this one does not represent a hydrogen atom, as well as the values of the protecting groups which can possibly represent or comprise R'b, in particular when R'b comprises an amine, can be taken in the lists mentioned above.

 In a preferred embodiment of the process, the product of formula (II) is treated with a functional derivative of a product of formula (III). This functional derivative can be, for example, a halide, a symmetrical or mixed anhydride, an amide or an activated ester.

 As an example of a mixed anhydride, mention may be made, for example, of that formed with isobutyl chloroformate and that formed with pivaloyl chloride and mixed carboxylic-sulphonic anhydrides formed, for example, with para-toluene sulphonyl chloride. As an example of an activated ester, mention may be made of the ester formed with 2,4-dinitrophenol and that formed with hydroxybenzothiazole.

 An example of a halide is chloride or bromide.

 There may also be mentioned acid azide or acid amide.

 The anhydride can be formed in situ by the action of substituted carbodiimide NN'di, for example N, N-dicyclohexylcarbodiimide.

 The acylation reaction is preferably carried out in an organic solvent such as methylene chloride.

 However, other solvents such as tetrahydrofuran, chloroform or dimethylformamide can be used.

 When an acid halide is used and generally when a halohydric acid molecule is released during the reaction, the reaction is preferably carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, potassium hydroxide and the like. sodium or potassium carbonates and carbonates, sodium acetate, triethylamine, pyridine, morpholine or N-methylmorpholine.

 The reaction temperature is generally less than or equal to room temperature.

 When% represents a hydrogen atom, a mixed carboxylic sulfonic anhydride is preferably used.

 Depending on the values of E, and R a, the products of formula (IV) may or may not be products of formula (I).

The products of formula (IV) are products of formula (I) when Rb represents a hydrogen atom, when R1b does not represent a protecting group of the hydroxyl radical
or does not represent a radical R with a function
protected, finally when R a does not represent a radical R1
in which a reactive function is protected and A does not
does not represent a hydrogen atom.

In other cases, the action on the product of formula (IV) of one or more hydrolysis, hydrogenolysis or
thiourea is intended to eliminate the radical Rb when
this represents a radical protecting the amino radical.

to eliminate the radical R 'b when it represents a protecting group of the hydroxyl radical and to eliminate the other protective groups that may comprise the radicals a and R'b.

 the nature of the reagents to be used in all these cases is well known to those skilled in the art. Examples of such reactions are given later in the experimental part.

 The following is a non-exhaustive enumeration of the means that can be used to eliminate the different groups.

 the removal of the 2 'group can be carried out by hydrolysis, which is acidic, basic or employs the hydrozine.

 Acidic hydrolysis is preferably used to remove optionally substituted alkoxy and cycloalkoxycarbonyl groups, such as tert-pentyloxycarbonyl or tert-butyloxycarbonyl, optionally substituted aralkoxycarbonyl groups such as benzyloxycarbonyl, trityl, benzhydryl, tert-butyl or 4-methoxybenzyl groups.

 The acice that is preferably used may be selected from the group consisting of hydrochloric, benzene sulfonic or para-toluene sulfonic acid, formic or triluoroacetic acid. However, other mineral or organic acids can be used.

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

 The base which is preferably used is a mineral base such as sodium hydroxide or potassium hydroxide. It is also possible to use magnesia, barite or an alkali metal carbonate or acidic carbonate such as carbonates and acidic carbonates of sodium or potassium or other bases.

 Sodium or potassium acetate can also be used.

 Hydrolysis using hydrazine is preferably used to remove groups such as phthaloyl.

 the group b may also be removed by the zinc-acetic acid system (for the trichloroethyl group), the benzhydryl, benzyloxycarbonyl groups are preferably removed by hydrogen in the presence of a catalyst.

 The chloroacetyl group is removed by the action of thiourea in a neutral or acidic medium according to the reaction method described by MASAKI J.A.C.S., 90, 4508, (4508, (1968).

 It is also possible to use other deprotection methods known in the literature, for example the oxidative cleavage, especially for the benzyl group.

 Among the preferred groups, mention may be made of formyl, acetyl, ethoxycarbonyl, mesyl, trifluoroacetyl, chloroacetyl and trityl groups. Particularly preferred are trityl and chloroacetyl radicals.

 The acid which is preferably used is trifluoroacetic acid or formic acid.

 The removal of the radical Rtb or the protective groups that include R'b or Ra when it is necessary, is carried out under conditions similar to those described above for the removal of Rb.

 Among other things, acid hydrolysis can be used to remove optionally substituted alkyl or aralkyl radicals.

 An acid selected from the group consisting of hydrochloric, formic, trifluoroacetic and para-tcluene sulfonic acids is preferably used.

 The other values of the Rb or R'b radicals or of the protective groups that include R'b or R a are, when desired, removed according to the methods known to those skilled in the art.

It is preferably carried out under moderate conditions, that is to say, at room temperature or by heating slightly.

 Naturally, it is possible for example when Rb or R'b or Ra are or contain removable groups belonging to different types, to act on the products (IV) several agents envisaged in the previous enumerations.

 Salification of the products can be carried out according to the usual methods.

 Salification may, for example, be further obtained on a product in acid form or on a solvate, for example the ethanolic soldier or a hydrate of this acid, a mineral base such as sodium or potassium hydroxide. , carbonate or acidic carbonate of sodium or potassium. Mid-neural acid salts such as tri-sodium phosphate can also be used. Q can also use salts of organic acids.

 A list of such organic acid salts can be found, for example, in the French patent BF 2 476 087.

 Sodium acetate, sodium 2-ethyl hexanoate or sodium diethyl acetate are preferably used as sodium salts.

 Salification can also be obtained by the action of an organic base or an amino acid.

The possible esterification of products in which
R includes an acid function is also performed under conventional conditions.

 The sulphides: any possible products of formula IV in which A represents a hydrogen atom is carried out using sulfur trioxide or a reactive derivative of this anhydride.

 The pyridine sulfuric anhydride complex is preferably used, but other sulfur trioxide complexes may also be used with dioxin or trimethylamine.

 The reaction is carried out in a conventional solvent such as ethyl acetate, chloroform or dimethylformamide. We can operate at room temperature. When using the pyridine-sulfur trioxide complex, the products can be isolated in the form of pyridinium salts.

 The possible splitting of the racemic molecules of formula II or IV can be carried out according to the usual methods.

 An optically active carboxylic or sulphonic organic acid such as tartaric acid, dibenzoyl tartaric acid, camphosulphonic acid or glutamia acid can be used, the decomposition of the salt thus obtained being carried out using a mineral base such as sodium hydrogen carbonate or a base organic such as a tertiary amine, for example triethylamine.

The present invention relates especially to a process as described above, characterized in that, for carrying out the process, a product of formula II in which A represents m hydrogen atom and a product of formula in which R represents. protecting group of the radical amLno and in that the sulphamation is carried out on a product of formula IV in which Rb represents a protective group of the radical am, no
The protecting group represented by b is preferably the trityl radical.

 The sulphamation is preferably carried out with the pyridine-sulfuric anhydride complex.

dans laquelle R a a la signification indiquée ci-dessus et R représente un groupement protecteur du radical imino, avec un produit de formule VI

dans laquelle R'p et R"p représentent l'un, un atome dthydro- gène et l'autre un groupement protecteur du radical amino ou R' et R" représentent ensemble un groupement protecteur divalent et B représente un radical hydroxyle ou halogène, pour obtenir un produit de formule VII ::

dans laquelle Ra, Rp, R'a et R"p ont la signification précédente, produit de formule VII que l'on soumet aux réactions suivantes a) Coupure par hydrolyse, hydrogénolyse ou action de la thiourée du radical Rp ; 'o) Sulfamatation éventuelle de l'amine en position 1 c) Coupure oar hydrolyse, hydrogénolyse ou action de la thiourée des radicaux R'p et R"p ; d) Dédoublement éventuel de la molécule pour obtenir un produit optiquement actif.The subject of the present invention is also a process for the preparation of the products of formula II, characterized in that a product of formula V is allowed to react.

in which R aa has the meaning indicated above and R represents a protective group of the imino radical, with a product of formula VI

in which R'p and R "p represent one, a hydrogen atom and the other a protecting group of the amino radical or R 'and R" together represent a divalent protective group and B represents a hydroxyl or halogen radical, to obtain a product of formula VII ::

wherein Ra, Rp, R'a and R "p have the above meaning, a product of formula VII which is subjected to the following reactions: a) Cleavage by hydrolysis, hydrogenolysis or thiourea action of the radical Rp; (o) Sulfamation optionally amine in position 1 c) Cleavage oar hydrolysis, hydrogenolysis or action of thiourea R'p and R "p radicals; d) Possible duplication of the molecule to obtain an optically active product.

The protective group Rp may be chosen from the list of substituents previously stated for amines
For reasons explained below, however, it is preferred to use a benzyl or 2,4-dimethoxy benzyl radical or the like.

 Similarly, the radicals R'p and R "p may be chosen from the same list of protective radicals mentioned above, and it is preferred to use the phthaloyl radical.

 The group B may represent a halogen atom. Acid chloride is preferred.

 When 3 represents a halogen atom, action of the product V on the product VI is carried out in the presence of a base such as triethylamine or a metal such as zinc.

 When B represents a hydroxyl radical, the reaction is carried out in the presence of a dehydrating agent such as an anhydride, preferably trifluoroacetic anhydride.

 The action of the products of formula V with the products of formula VI preferentially gives cis products. The trans products are obtained by isomerization in a basic medium.

The first deprotection reaction is intended, when it is desired to carry out the sulphamation of the resulting products, the selective release of the Rp radical.
Thus, as indicated above, preferably a benzyl or di-methoxy benzyl radical is used which is released using, preferably an oxidant such as potassium peroxodisulfate.

 It is preferably carried out in a solvent such as water-acetic acid or acetonitrile.

 The possible sulfamation of the products of which the secondary amine in position 1 is free is carried out as indicated above.

 The possible second unlocking operation has the aim of releasing the amine in position 3 by elimination of the radicals R'p and R "p.

When, as indicated above, one operates with a phthalimido radical, the elimination is carried out, as indicated above, with hydrogen, preferably a hydrazine hydrate in a solvent such as dimethylformamide.

Of course, especially in the case where the products of formula IV are not sulfamated, the radicals
R'p, R'p and R "p can be eliminated simultaneously.

 The duplication is counted above, carried out in the usual manner.

dans laquelle A a la signification indiquée ci-dessus, n représente un nombre entier de 1 à 4 et X" représente X,
X ayant la signification indiquée ci-dessus, à ltexception d'un atome d'halogène, soit X" représente X dans lequel une fonction réactive est protégée, caractérisé en ce que l'on traite un produit de formule VIII

dans laquelle R'q et R"q représentent chacun un atome d'hydrogène ou ont la signification de 'p et R"q indiquée ci-dessus par un dérivé réactif du radical cyano, du radical -ORa, -SRb

de formule IX (six) das laquelle X", A, R'q et Rl'a ont les valeurs indiquées précedemment, produit cue l'on soumet si nécessaire et si désiré, à l'une quelconque ou à plusieurs des réactions suivantes a) Coupure par hydrolyse, hydrogénolyse ou par action de la thiourée des groupements représentés par R'q et R"c q lorsque ceux-ci sont différents d'un atome d'hydrogène.The present invention also relates to a process for preparing the products of formula IIa:

in which A has the meaning indicated above, n represents an integer of 1 to 4 and X "represents X,
X having the meaning indicated above, with the exception of a halogen atom, X "represents X in which a reactive function is protected, characterized in that a product of formula VIII is treated

in which R'q and R "q each represent a hydrogen atom or have the meaning of 'p and R' q indicated above by a reactive derivative of the cyano radical, the radical -ORa, -SRb

of the formula IX (six) in which X ", A, R'q and Rl'a have the values indicated above, produced and subjected, if necessary and if desired, to any one or more of the following reactions: ) Cleavage by hydrolysis, hydrogenolysis or by the action of thiourea groups represented by R'q and R "cq when they are different from a hydrogen atom.

b) Sulfamation of the products in which the radical A represents a hydrogen atom.

c) Duplication of the molecule to obtain an optically active product.

 The action, on the product of formula VIII, of the reactive radicals of the radicals which it wishes to substitute for the halogen atom is carried out under the usual conditions.

 The exchange between the halogen atom and a mercaptate is, for example, preferably carried out with the aid of an alkali metal salt of this mercaptan, such as the sodium salt.

 The exchange between the halogen atom and an alkali metal acetate such as sodium or potassium acetate makes it possible to introduce a protected hydroxyl radical which can be released and then etherified if desired.

The action of an amine, optionally protected by one of the radicals indicated above makes it possible to introduce an optionally protected radical.

 An azide of alkali metal, preferably sodium acid, can be used to introduce the azfdo radical. A cyanide or an alkali metal thiocyanate can also be used to produce the products in which X represents these radicals or isothiocyanate.

 Subsequent operations of possible deprotection, sulphamation and also possible splitting are carried out as indicated above.

 The products of general formula (I) have a very good antibiotic activity on gram (-) bacteria, especially on coliform bacteria, klebsiella, salmonella and proteus.

 These products can be used as medicaments in the treatment of colibacillosis and associated infections, in proteus, klebella and salmonella infections and in other conditions caused by gram (-) bacteria.

 The subject of the present invention is therefore also, as medicaments and in particular antibiotic drugs, the products of formula (1) as defined above, as well as their pharmaceutically acceptable salts.

isomère3 syn, sous forme cis dans laquelle R2 représente un atome d'hydrogène ou un radical alkyle linéaire ou ramifié éventuellement substitué par un radical carboxyle ou amino, n' représente un nombre entier de 1 à 2 et X' représente un atome d'halogène ou un radical hydroxyle, sous forme racémique ou optiquement active ainsi que les sels des produits de formule
I' avec les bases ou les acides, pharmaceutiquement acceptables
L'invention a également plus particulièrement pour objet
à titre de médicaments et notamment de médicaments antibioti
ques, les produits décrits dans les exemples et spécialement
- l'acide 4-chlorométhyl-3-/2-(2-amino-4-thiazolyl)2-méthoxy
imino acétamido/2-oxo azétidine-l-sulfamique cis, isomère
syn, racémique ou optiquement actif.the subject of the invention is, as a matter of fact, the products of formula (I '), especially of antibiotic drugs,

syn isomer3, in cis form in which R2 represents a hydrogen atom or a linear or branched alkyl radical optionally substituted by a carboxyl or amino radical, n 'represents an integer of 1 to 2 and X' represents a halogen atom or a hydroxyl radical, in racemic or optically active form, as well as the salts of the products of formula
I 'with bases or acids, pharmaceutically acceptable
The invention also more particularly relates to
as drugs and especially antibiotic drugs
products described in the examples and especially
4-chloromethyl-3- [2- (2-amino-4-thiazolyl) -2-methoxy acid
imino acetamido / 2-oxo azetidine-1-sulfamic cis, isomer
syn, racemic or optically active.

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

These compositions can be administered by
oral, rectal, parenteral or
topically applied to the skin and mucous membranes.

In particular, the products of formula (I) in the
which Δ represents a cleavable ester such as the ester of
propionyloxymethyl can be administered orally.

They can be solid or liquid and present themselves
in the pharmaceutical forms commonly used in
human pills such as, for example, tablets, single or coated, capsules, granules, suppositories, injectables, ointments, creams, gels; they are prepared according to the usual methods. the active ingredient (s) can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or no, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 These compositions may, in particular, be in the form of a powder intended to be dissolved extemporaneously in a suitable vehicle, for example apyrogenic sterile water.

The dose administered varies according to the condition being treated, the subject, the route of administration and the product under consideration. It can be between, for example, understood
between 0.250g and 4g per day, orally in humans,
with the product described in Example 1, or still included
between 0.500g and Ig three times a day, intramus
lar.

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

dans laquelle Rb, R?b, A et Ra ont la signification indiquée cidessus, ainsi que les produits de formule II

dans laquelle A et Ra ont la signification indiquée ci-dessus.The invention finally relates to products
new industrial products and, in particular, as products
intermediaries necessary for the preparation of the products of
formula (I) as defined above, the products of
general formula IV

in which Rb, Rb, A and Ra have the meaning indicated above, as well as the products of formula II

in which A and Ra have the meaning indicated above.

 The products of formula V which are not known can be prepared by the action of an aldehyde of formula RaCHO optionally in the form of hydrate Ra-CH (OH) 2 on a protected amine of formula RpNH2.

 Examples of such preparations are given in the experimental part.

In addition to the products described in the examples which illustrate the invention without however limiting it, the following products constitute products obtainable within the scope of the present invention; substituents
X, R, A and R1 are those indicated in formula (I)

<tb> M-HT1
<tb> -CH2CH3 <SEP> t <SEP> CH2
<tb> 2-I
<tb><SEP> CH <SEP> -CH <SEP> Cl
<tb> 22 <SEP> 3 <SEP> (CH2 <SEP> 2
<tb> -CH <SEP>(<SEP> CH3 <SEP>) <SEP> 2 <SEP> -CE2
<tb> -nC4H9 <SEP> -CH2Cl
<tb> -CHa-CH = CH2 <SEP> -CH2Cl
<tb> -CH2CO2H <SEP> Cl2 <SEP> 1
<tb> L-CO2H <SEP> -CH2Cl
<tb> -C (CH3) 2CO2H <SEP> -CH2Cl
<tb> -CH-c02H <SEP> -CH2Cl
<tb> -CH2C02C2H5 <SEP> -CH2Cl
<tb> -CH2CO2tBu <SEP> -CH2C1
<tb>, -CH-C02H <SEP> -CH2C1
<tb><SEP> 25
<tb>. <SEP> -C <SEP>(<SEP> CH3 <SEP>) <SEP> -CH2Cl
<tb> 33
<tb> -CH2 <SEP> -CrI = CH-CO <SEP> 2H <SEP> CH
<tb>'-CH-CO2H<SEP> -CH2Cl
<tb><SEP> 7
<tb> -CH2CN <SEP> CH2
<tb> - (CH2) 2CN <SEP> -CH2Cl
<tb> I <SEP> -CH2 <SEP> -CONH2 <SEP> -CH2Cl
<tb> (CH2) 2 <SEP> Br <SEP> -CH2Cl
<tb><SEP> - (CH2) 2C1 <SEP> -CH2C1
<Tb>

<tb><SEP> r
<tb><SEP> R <SEP> -. <SEP> R1
<tb> - <SEP>(<SEP> CH2 <SEP>) <SEP> 333r <SEP> CH2Cl
<tb> I <SEP> 2
<tb> - (CH2) 79 <SEP> -CH2Cl
<tb> -H2C-CoCH <SEP> -CH2Cl
<tb> -HC = CH2 <SEP> -CH2Cl
<tb> (CH2) 2 <SEP> t <SEP> -CH2Cl
<tb> - <SEP> (CH2) <SEP> 2-CH3 <SEP> -CH2Cl
<tb><SEP> - (CX2) 2-O <SEP> -CH2Cl
<tb> -CH2-N <SEP> (CH3) 2 <SEP> -CH2Cl
<tb> -CH2-CH2-N (CH3) 2 <SEP> -CH2Cl
<tb><SEP> H <SEP> H <SEP> CH20CH3
<tb><SEP> CH3 <SEP> -CH2OCH3
<tb> -CH2CH2NH2 <SEP> -CH20CHD
<tb> -CH2C02H <SEP>. <SEP> -CH2OCH3
<tb> -C (CH3) 2CO2H <SEP> -CH2oCH)
<tb> -CHzCH2Br <SEP> -CH2OCH3
<tb> -CH2CH2I <SEP> -CH20CH3
<tb> -CH2CO2C2H5 <SEP> -CH2OCH3
<tb> -CH2C02tBu <SEP> -CH2OCH3
<tb> -C <SEP> (CH3) <SEP> 2CO2C2H5 <SEP> -CH2OCH3
<tb> -C (<SEP> H3) 2Co2tBu <SEP> -CH2OCH3
<Tb>

<tb><SEP> R <SEP> R <SEP> | <SEP> R1
<tb> -CH2CH3 <SEP> | -CH2Br
<tb> 2
<tb> - (CH2) 2CH3 <SEP> | CH2
<tb> -CH (CH <SEP> 2 <SEP> -CH <SEP> Br
<tb><SEP> 3
<tb> -nC4Hg <SEP> -CH2Br
<tb> -CH2-CH = CH2 <SEP> CH2
<tb> -CH2CO2H <SEP> -CH2Br
<tb> t-C02H <SEP> -CH2Br
<tb> EfCH3) 2C02E <SEP> -CH2 <SEP> Br
<tb><SEP> 3 <SEP> 2
<tb> C-C92H <SEP> -CH2 <SEP> Br
<tb> -CH2C02C2H5- <SEP> -CH2 <SEP> Br
<tb> -CH2C02tBu <SEP> -CH2Br
<tb> H) O2H <SEP> -CH2 <SEP> 3r
<tb> -C (CH3) 3 <SEP> -CH2Br
<tb> -CH2 <SEP> -CH = CH-CO2H <SEP> CH2
<tb> -CH-CO <SEP> H <SEP> -CH2 <SEP> Br
<tb> iR
<tb> -CH2CN <SEP> -CH2Br
<tb> - (CH2) 2CN <SEP> -CH2 <SEP> Br
<tb> -CH2-CONH2 <SEP> -CH2 <SEP> Br
<tb> - (CH2) 2 <Sep> Er <SEP> -CH2 <SEP> Br
<tb> - (H2) 2cl <SEP> -CH2 <SEP> Br
<Tb>

<tb><SEP> 1 <SEP> I
<tb><SEP> R <SEP> R1
<tb>. ~
<tb><SEP> t <SEP> 293 <SEP> -CH23r
<tb><SEP> i <SEP> 3
<tb><SEP> (CS,), I <SEP> -CH2Br
<tb><SEP> -H2C-C = CH <SEP> -CH2Br
<tb><SEP> -HC = CH2 <SEP> -CH2 <SEP> 3r
<tb><SEP> -CH23r
<tb><SEP> - (CH2) 2 ~ <SEP> C <SEP> 3r
<tb> 1- (CH2) 2-N3O <SEP> -CH-2
<tb><SEP> -CH28-N (C <SEP>(<SEP>) 2 <SEP> -CHa <SEP> Br
<tb><SEP> -CH2-CE2-N (CH3) 2 <SEP> -CFI2Br
<tb><SEP> -Ct <SEP> -CE2 <SEP> Br.
<Tb>

<SEP> 12
<tb><SEP> -CH2CH2NH2 <SEP> -CH2 <SEP> Br
<tb><SEP> H <SEP> -CH2 <SEP> Br
<tb><SEP> H <SEP> -CH2 <SEP> SCH3
<tb><SEP> CH3 <SEP> -CH2 <SEP> SCH3
<tb><SEP> -CH25H2NH2 <SEP> -CH2 <SEP> SCH3
<tb><SEP> -CH2 <SEP> CO2H <SEP> -CH <SEP> SCH3
<tb> F <SEP> --C (CH3 <SEP>) <SEP> 2CO2H <SEP> -CH2- <SEP> SCH3
<tb><SEP> -CH2CH2Br <SEP> CH2 <SEP> 3
<tb><SEP> -CH2CE2I <SEP> -CH2 <SEP> SCH3
<tb><SEP> -CH2CO2C2H5 <SEP> CH2 <SEP> SCH3
<Tb>

<tb> [R <SEP> R1
<tb> t <SEP> R <SEP> R1
<tb> -CH2C02tBu <SEP> -CH2SCH
<tb> fC (CH3) 2CO2C2 <SEP> 5 <SEP> -CE2SCH
<tb> hC (CH3) 2C02tBu <SEP> -CH2SCH
<tb> -CH2CE3 <SEP> -CH2 <SEP> OH
<tb><SEP> - (CH2) 2CH3 <SEP> -CH2 <SEP> OH
<tb> -CH (CH <SEP>) <SEP> -CH2 <SEP> OH
<tb><SEP> 32
<tb><SEP> -nC4Hg <SEP> -CH2 <SEP> OH
<tb><SEP> -CH2-CH = CH2 <SEP> -CH2 <SEP> OH
<tb><SEP> -CH2CO2H <SEP> -CH2 <SEP> OH
<tb><SEP> t-C02H <SEP> -CH2OH
<tb><SEP> - (CH3) 2CO2H <SEP> -CH2 <SEP> OH
<tb><SEP> -C1-C02H <SEP> -CH2 <SEP> OH
<tb><SEP> -CH2CO2C2H5 <SEP> -CH2 <SEP> OH
<tb><SEP> -CH2C02tBu <SEP> -CH2 <SEP> OH
<tb><SEP> C2R5 <SEP> -CH2OH
<tb><SEP> 25
<tb><SEP> -C (CH <SEP>) <SEP> -CH2 <SEP> OH
<tb><SEP> 33
<tb><SEP> -CH2-CH = CH-CO2H <SEP> -CH2 <SEP> OH
<tb><SEP> -CH-C02H <SEP> -CH2OH
<tb><SEP> 37
<tb><SEP> -CH2CN <SEP> -CH2 <SEP> OH
<tb><SEP> - (CH2) 2CN <SEP> -CH2 <SEP> OH
<Tb>

<tb><SEP> R <SEP> tR1
<tb>-CH2-C'ONE2<SEP> -CH2OH
<tb> - (CH2) 2Br <SEP> -CH2OH
<tb> - (Clrg) 21 <SEP> -CH2OH
<tb> - (CH2) 33r <SEP> -CH2OH
<tb><SEP> H <SEP> -CH2SCN
<tb><SEP> CH3 <SEP> -CH2SCN
<tb> -CHCH2NH2 <SEP> -CH2SCN
<tb> -CH2C02H <SEP> -CH2SCN
<tb> -C (CH3) 2CO2H <SEP> -CH2SCN
<tb> - (CH2) 2I <SEP> -CH20H
<tb> -H2C-C = CH <SEP> -CH2oR
<tb> -HC = CH2 <SEP> - <SEP> -CH2OH
<tb> (CH2) 2 <SEP> 2 <SEP> aCH20H
<tb> - (CH2) <SEP> O <SEP> C <SEP>3; NCH, <SEP> -CH20H
<tb> (CE2) 2 <SEP> o <SEP> -N = j3 <SEP> 420H
<tb> -CH2c-N (CH3) 2 <SEP> -CH2H
<tb> -CH2-CH2-N (CH3) 2 <SEP> -CH20E
<tb><SEP> -CH <SEP> OH
<tb><SEP> 3 <SEP> 2
<tb> -CHCF-NH2 <SEP> -CH20H
<tb><SEP> H <SEP> -CH20H
<Tb>

<tb><SEP> R <SEP> Ri
<tb><SEP> H <SEP> CH2NH2
<tb><SEP> CH3 <SEP> CH2NH2
<tb> -CH2CH2NH2 <SEP> CH2NH2
<tb> -CH2CO2H <SEP> CH2NH2
<tb> -C (CH3) 2CO2H <SEP> CH2NH2
<tb> -CH2CH2Br <SEP> CH2NH2
<tb> -CH2CH2I <SEP> CH2NH2
<tb><SEP> H <SEP> CH2N3
<tb><SEP> CH3 <SEP> CH2N3
<tb> -CH2CH2NH2 <SEP> CH2N3
<tb> -CH2CO2H <SEP> CH2N3
<tb> -C (CH3) 2CO2H <SEP> CH2N3
<tb><SEP> H <SEP> CH2NCS
<tb><SEP> CH3 <SEP> CH2NCS
<tb> CH2CH2NH2 <SEP> CH2NCS
<tb> CH2CO2H <SEP> CH2NCS
<tb> CH2CH3 <SEP> CH2SH
<tb> (CH2) 2CH3 <SEP> CH2SH
<tb> CH (CH3) 2 <SEP> CH2SH
<tb><SEP> nC4H9 <SEP> CH2SH
<Tb>

<tb><SEP> R <SEP> R1
<tb><SEP> I
<tb> -CH2-CE - CH2 <SEP> -CH2sH
<tb> -CH2CO2H <SEP> -CH2SH
<tb> -CO2H <SEP> -CH2SH
<tb> - (CH3) 2CO2H <SEP> -CH2 <SEP> SH
<tb> C <SEP> 3 <SEP>-CO> H <SEP> -CH2SH
<tb> H2C02C2H5 <SEP> -CH2 <SEP> 5H
<tb> H2C02tBu <SEP> -CH2SH
<tb> -Ç502H <SEP> -CH2 <SEP> 5H
<tb> C (C5 <SEP>) 3 <SEP> -CH2SH
<tb> -CH2-CH = CH-C02H <SEP><H2SH
<tb><SEP> H-CO <SEP> H <SEP> -CH2SH
<tb><SEP> 2
<tb><SEP> 37
<tb><SEP> H2CN <SEP> 2
<tb> - (CH2) 2CN <SEP> -CH2SH
<tb> -CH2-CONH2 <SEP> -CH2SH.
<Tb>

<SEP> (CH2) 2 <SEP> Br <SEP> -CH2SH
<tb> - <SEP> (CH2 <SEP>) <SEP> 2C1 <SEP> -CH2S-E
<tb> 1- (CH2) 33r <SEP> -CH2SH
<tb> -C <SEP> (CH3 <SEP>) 2CO2H <SEP> -CH2NCS
<tb><SEP> H <SEP> -CH2N (CH3) 2
<tb><SEP> CH3 <SEP> -CH2N (CH3) 2
<Tb>

<tb><SEP> R <SEP> R1
<tb><SEP> I
<tb> -CH2CH2HH2 <SEP> I <SEP> -CH2N <SEP> (CH3) 2
<tb> -CH2C02H <SEP> -CH2N (C) 2
<tb> - (CH2) 2I <SEP> -CHSH
<tb> -H2C-C = CH <SEP> -CH2- <SE> SH
<tb> -HC = CH2 <SEP> -CH2 <SE> SH
<tb> - (CH2) 2- <SEP> -CH2 <SEP> 3H
<tb> - (CH2) 2- <SEP> O <SEP> JCH3 <SEP> - <SEP> -CH2 <SEP> 3H
<tb> - (5H2) 2- <SEP> o <SEP> P <SEP> -CH2SH
<tb> -CH28-N (C <SEP> - <SEP> -CH2SH
<tb> -CH2-CH2-N (CH3) 2 <SEP> -CH2SE
<tb><SEP> CH3 <SEP> -CH2SH
<tb> -CH2CH2NH2 <SEP> wH2SH
<tb><SEP> H <SEP> -CH2sR
<tb> -C (CH3) 2CO2H <SEP> -CH2N (CH3) 2
<Tb>
EXAMPLE 1: cis, syn, racemic 4-chloromethyl-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-1-sulfamic acid

Step A: 4-chloromethyl-3- [2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine syn.

 A suspension of 2.32 g of 2- (2-tritylamino-4-thiazolyl) -2-metioxyimino acetamido isomer svn in 23 cm3 of methylene chloride is cooled and 594 mg of dicyclohexyl carbodiimide are added, the mixture is stirred for 20 minutes and added a solution of 441 mg of 4-chloromethyl-3-amino-2-oxoazetidine hydrochloride in 10 cm3 of methylene chloride and 0.4 cm3 of triethylamine.

The mixture is stirred for 1 hour at room temperature, the dicyclobetylurea formed is filtered off, rinsed with methylene chloride and 10 cm3 of saturated solution of sodium hydrogen carbonate and 20 cm3 of water are added to the filtrate. It is stirred, decanted in an ampoule, washed with water again, the organic phase re-extracted and dried.

 It is concentrated to dryness under reduced pressure, the residue is added with the minimum amount of ethyl acetate, scraped off, the insoluble material is filtered off, rinsed with ethyl acetate and concentrated again to dryness under reduced pressure. The residue is dissolved in 5 cm3 of ethanol and diluted slowly with 10 cm3 of ether. Crystallization is initiated, the mixture is stirred for 2 hours, the crystals formed are filtered off, rinsed with ethanol-ether (1-2) and 688 mg of expected product are obtained.

Analysis: C29H26O3N5 SCI = 560.08
Calculated: CX 62.19 H x 4.68 N x 12.5
Found: 62.4 4.8 12.2
Stage B: 4-Chloromethyl-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-1-sulfamic acid, racemic syn.

a) Sulfamation
To a solution of 1.72 g of pyridine sulfan (pyridine sulfuric anhydride complex) in 17.2 cm3 of dry dimethylformamide is added 2,403 g of the product obtained in the preceding stage. The mixture is stirred for 66 hours at room temperature, the insoluble material is filtered off, rinsed with dimethylformamide, diluted with 300 cm3 of ether, stirred, allowed to stand for 10 minutes, the ether is removed, the residue is washed with ether and the residue is taken up with trin- with 20 cm3 of ethanol.

After dissolution, the expected product crystallizes. It is stirred slowly for 30 minutes, filtered, rinsed with ethanol and then with ether.

 855 mg of expected product is obtained, which is pyridinium 4-chloromethyl-3- [2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-1-sulfamic acid.

b) Unlocking the remaining trityle
A mixture of 360 mg of pyridine sulphamate obtained previously and 1.4 cm3 of formic acid with 332 of water is heated to 500 ° C.

After dissolution, the crystallization of triphenylcarbinol occurs. It is left for 10 minutes at 500.degree. C., cooled, diluted with 0.6 cm.sup.3 of water, the insoluble material is filtered off and rinsed with water. The filtrate is added a little ethanol and concentrated to dryness under reduced pressure. Water and ethanol are added and evaporated in vacuo. 1.2 cc of saturated aqueous sodium hydrogencarbonate solution are added to the residue. The light insoluble material is filtered, rinsed with water and 3 drops of formic acid and scrapes are added to the filtrate.

The expected product crystallizes. Stirred for 10 minutes, filtered, rinsed with water and ether, dried and isolated 113 mg of expected product.

Analvs: C10 H12 6 N5 S2 Cl = 397.82
Calculated: Ci 30.19 H max 3.04
Found: 29.6 3.2 PREPARATION: a) 2-chloro-N-phenylmethylethanimine.

 A solution of 4 cm3 of chloroacetaldehyde in 20 cm3 of deionized water is cooled and a solution of 2.14 g of benzylamine in 10 cm3 of water is introduced with stirring. It is stirred for 5 minutes at 10 / 150C and a gum and a cloudy solution are obtained.

It is extracted with 30 cm3 then 20 cm3 of benzene. The solution is dried, filtered, rinsed and distilled to dryness under vacuum. 3.34 g of product is obtained which is used as it is.

b) N-benzyl 3-phthalimido 4-choromethyl 2-azetidinone cis.

 The solution of 3.34 g of product obtained above is cooled to -50 ° C. in methylene chloride (20 cc) and then triethylamine (2.8 cc) is added all at once. Stirring and temperature are maintained and introduced in 20 minutes. solution of 4 g of phthalimidoacetic acid chloride in 20 cm3 of methylene chloride. The mixture is then stirred for one hour at 0.degree. C., poured into a separating funnel and washed with 50 cm.sup.3 of demineralised water and 5 cm.sup.3 of a molar aqueous solution of sodium hydrogen carbonate and then with demineralized water (twice 30 cm.sup.3). ). The methylene chloride washings are re-extracted (20 cm 3), dried, drained, rinsed and concentrated to dryness under vacuum. A crude resin (6 g) is obtained which is chromatographed on silica using methylene chloride containing 5% sulfuric ether. The fraction of Rf = 0.45 is isolated, brought to dryness and pasted with 10 cm3 of dichloromethane. sulfuric ether, drained, rinsed with 3 times 2 cm3 of sulfuric ether. Dry in vacuo and 1.25 g of product. F = 1490C.

c) cis-3-phthalimido 4-chloromethyl-2-azetidinone

 A mixture of 17.75 g of the product obtained above, 31 g of potassium peroxodisulfate, 110 cm 3 of water and 160 cm 3 of acetic acid is heated under heat for 25 minutes under good agitation in an oil bath at 1200 ° C. It is cooled to room temperature, 50 g of dipotassium phosphate are added to neutralize the acidity formed, the solvents are removed under reduced pressure, 250 cm 3 of water and 150 cm 3 of ethyl acetate are added, the mixture is stirred and then added in small portions of the carbonate. sodium acid until gassing ceased, filter, rinsed with ethyl acetate, decanted in an ampoule, re-extracted with 50 cm3 of ethyl acetate, the organic phase dried, filtered, rinsed and concentrated to dryness under reduced pressure. The residue is chromatographed on 200 g of silica (eluent: methylene chloride 25x of ethyl acetate). The rich fractions are collected, concentrated to dryness, taken up with ether, dissolved, drained, rinsed and dried. 5.4 g of desired product.

Analvse: C12 Hg N2 Cl = 264.67
Calculated: CX 54.46, H, 3.43
Found: 54.7 3.5 d) 4-chloromethyl-3-amino-2-oxoazetidine hydrochloride.

 To a suspension of 5.3 g of the product obtained above in 54 cm 3 of methylene chloride, 12 cm 3 of a solution of hydrazine hydrate in dimethylformamide (2 cm 3 of hydrazine hydrate) is added dropwise. and qs (20 cm3 dimethylformamide).

It is left for 20 minutes at rest after caking and then added to completely dissolve normal hydrochloric acid (about 30 cm 3) so as to bring the pH to 3. It is stirred for 3 hours at room temperature, the phthalhydrazide formed is filtered off, rinsed at room temperature. water then ethanol finally ether. Dry and obtain 2.844 g of product. Dimethylformamide and water are removed under reduced pressure, the residue is taken up twice with ethanol, and the residue is evaporated to give 20 cm 3 of ethanol. Stir 45 minutes, wring the crystals formed, rinse with ethanol and ether.

2.46 g of the expected product are finally obtained.

Example 2: 4- (1-Methyl-5-mercapto-1,2,3,4-tetrazol) methyl-3- [2- (2-amino-4-thiazolyl) -2-methoxy-amino-acetamido] -2-oxo-azetidine-1-sulfamido acid , cis racemic.

Step A: 4- (1-Methyl-5-mercapto-1,2,3,4-tetrazol) methyl 3- [2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-1-sulfamic acid.

a) Condensation;
A mixture of 2.25 g of syn isomeric 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid in 21 cm3 of methylene chloride is stirred cold for 20 minutes in an ice-water bath. 576 mg of dicyclohexylcarbodiimide. The bath is removed and a solution of 597 mg of 4- (1-methyl-5-mercapto-1,2,3,4-tetrazol) methyl-3-amino-2-oxo-azetidine hydrochloride is added in 10 cm3 of methylene chloride and 0.38 g. cm3 of triethylamine. It is stirred at room temperature for 1 hour, concentrated to dryness under reduced pressure, filtered, rinsed with methylene chloride, ether-finished, dried and isolated 1.594 g of product containing dicyclohexylurea.

b) Sulfamation
A mixture of 1.594 g of the product obtained above and 0.66 g of pyridine sulfan (pyridine-anhydride complex) in 6.6 cm3 of dimethylformamide is stirred for 70 hours. The dicyclohexylurea is filtered, rinsed with the minimum amount of dimethylformamide and the filtrate is diluted with approximately 200 cm3 of ether. It is stirred well, filtered insoluble, washed with ether, combined all the products by dissolving them in methanol, the expected product crystallizes. It is filtered, rinsed with methanol, finished with ether and dried to obtain 620 mg of expected product.
Stage B: 4- (1-methyl-5-mercapto-1,2,3,4-tetrazol) methyl-2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido / 2-oxoazetidine-1-sulfamic acid.

 At 60 ° C., a mixture of 620 mg of product obtained in the preceding stage in 0.8 cm 3 of water and 1.62 cm 3 of formic acid is heated for 12 minutes, the triphenylcarbinol crystallizes. Cool, dilute with a little water. The expected product also crystallizes. Stirred for 10 minutes, filtered, rinsed with water and then pasted 3 times with ether. The insoluble material is taken up in water, 2 cm 3 of saturated aqueous sodium hydrogen carbonate is added, the mixture is stirred, the insoluble material is filtered off, rinsed with water, and the usual hydrochloric acid is added q.s. pH 2. The expected product crystallizes. Stir 5 minutes, filter, rinse with water, finish with ether, dry and obtain 294 mg of expected product.

Analvse: C12 H15 O6 N9 S3 1/2 H20 = 486.51
Calculated: C% 29.63 H% 3.31 N% 25.91 S% 19.77
Found: 29.5 3.4 25.8 19.8 Prenaration 1α) 4- (1-Methyl-5-mercapto-1,2,3,4-tetrazol) methyl-3-phthalimido-2-oxo-azedidine cis.

 A suspension of 7.6 g of cis 4-chloromethyl-3-phthalimido-2-oxoazetidine obtained at the preparation of Example 1c) is heated to 100 ° C., 5.48 g of sodium salt of 1-methyl-5-mercapto 1,2,3,4-tetrazole (dihydrate), 4.3 g of sodium iodide and 57 cm3 of dimethylformamide and left stirring for 3 hours at this temperature. Cooled, poured into 0.75 l of water and 150 cm3 of ethyl acetate. Rinsed, stirred vigorously, decanted, reextracted with 75 cm3 and 45 cm3 of ethyl acetate, filter the insoluble which is the expected product. Washed with 150 cm3 of water, re-extracted and dried. After filtering, concentrated to a small volume under reduced pressure and filtered a second jet and rinsed with ethyl acetate. The insoluble products are combined, dried and finally isolated 5.1 g of expected product.

Analvse: C14 H12 03 N6S, 1/4 AcOEt = 366.37
Calculated: C 49.17 H: 3.85 Mi 22.94
Found: 49.2 3.7 23.0 b) 4- (1-Methyl-5-mercapto-1,2,3,4-tetrazol) methyl-3-amino-2-oxo azetidin hydrochloride.

 1 cm3 of hydrazine hydrate is added dropwise to a suspension of 5.845 g of the product obtained above in 18.5 cm.sup.3 of dry dimethylformamide and stirred for 20 minutes at room temperature and then 19 cm.sup.3 of water and 24 cm.sup.3 are added. of normal hydrochloric acid. A final pH of 3 is obtained, the mouth is left stirring overnight at room temperature. The phthalhydrazide formed is then filtered, rinsed with water and concentrated to dryness under reduced pressure, ethanol is added, the slurry is concentrated and the mixture is concentrated to dryness. , add methanol to dissolve hot and concentrate to dryness. The product crystallizes. 20 cm3 of methanol, disintegrant, ice, drain, rinse with ice-cold methanol, end with ether and obtains 2.49 g of expected product in 2 streams.

Example 3: 4-tert-Butoxycarbonol-3- [2- (2-amino-4-thiazolyl) -2-methoximinoacetamido] -2-oxoazetidine-1-sulfamoyl cis racemic isomer.

Step A: Pyridinium 4-tert-butoxycarbonyl 3- [2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine 1-sulfamate.

a) Condensation:
A mixture of 9 g of syn isomer 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid in 90 cm3 of methylene chloride and 2.3 g of dicyclohexylcarbodiimide is stirred for 20 minutes in an ice-water bath. then 1.862 g of 4-tert-butoxycarbonyl-3-amino-2-oxo-azetidine are added. After dissolution, dicyclohexylurea crystallizes. It is left stirring for 45 minutes at room temperature, filtered, rinsed with methylene chloride, 25 cm3 of saturated aqueous sodium hydrogen carbonate and 50 cm3 of water are added to the filtrate. Agitated and observed caking. It is filtered, rinsed 3 times with methylene chloride, decanted the filtrate, reextracted, dried, filtered, rinsed and the filtrate concentrated to dryness under reduced pressure. 20 cm3 of ethyl acetate and scratch are added. The expected product crystallizes. It is stirred for 30 minutes, filtered, rinsed with ethyl acetate and then ether. After drying, 5.16 g of 4-tertbutoxycarbonyl-3- [2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine isomer, syn.

b) Sulfamation
A mixture of 3.38 g of pyridine sulfan (pyridine sulfuric anhydride complex) in 34 cm 3 of dimethylformamide and 5.16 g of the product obtained above is stirred at room temperature for 70 hours. The mixture is poured into 500 cm3 of ether.

The precipitate formed is triturated and the ether is removed after 15 minutes of contact. Released with ether, added ethanol, heated to dissolve and scratch. The expected product crystallizes. Stirred for 15 minutes, filtered, rinsed with ethanol and then with ether, dried and obtained 4.083 g of expected product.

Stage B: 4-tert-butoxycarbonyl-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-1-sulfamic acid cis racemic isomer.

 A solution of 77 product obtained in Stage A and 10 cm 3 of a solution comprising 0.805 cm 3 of dry pyridine, 1 cm 3 of 10N hydrochloric ethanol and q.s. 20 cm3 of methanol. It is then concentrated to dryness under reduced pressure, ether is added, triturated and the ether is removed.

The operation is repeated once more, water is added to the residue, the insoluble material is filtered off, rinsed with water and the filtrate is scraped off, concentrated under reduced pressure. The expected product crystallizes. It is left standing for 15 minutes, filtered, rinsed with water and then with ether and dried. 232 mg of expected product is obtained.

Analysis: C14H19O8N5S2 = 449.36
Calculated: C% 37.41H% 4.26N% 15.58S% 14.27
Found: 37.3 4.2 15.5 14.4
Preparation: a) 1,1-Dimethylethyl 3- (1,3-dihydro-1,3-dioxo-2-isoindol-2-yl) -4-oxo-1-2,4-dimethoxy-phenyl-methyl-2-azetidine carboxylate cis isomer.

 &alpha;) A mixture of 12.25 g of 2,4-dimethoxybenzylamine hydrochloride, 35 cm3 of 2N sodium hydroxide and 100 cm3 of benzene was stirred vigorously, decanted, re-extracted with 10 cm3 of benzene, washed with water, dried and filter. 2,4-Dimethoxy benzylamine is obtained in solution.

 A solution of 8.9 g of tert-butyl glyoxylate and the above filtrate is refluxed and then 3/4 of the benzene distilled. The remainder of the benzene is then removed under reduced pressure at 400C. An oil is obtained which is used as it is.

 &gamma; To a mixture comprising the oil prepared above, 12.3 g of phthalimidoacetic acid, 150 cm 3 of methylene chloride and 24 cm 3 of triethylamine, 8.5 cm 3 of trifluoroacetic anhydride are introduced in small portions and the mixture is stirred for 45 minutes. .

 It is then poured into a separating funnel and 120 cm3 of 0.5M sodium hydrogen carbonate in water are added. It is stirred, decanted, extracted with methylene chloride, dried, filtered and concentrated to dryness under reduced pressure. Ether is added and triturated. The product crystallizes. After wringing, rinsed three times with ether, while stirring, dried and gives 16.5 g of expected product. F = 1400C.

Analysis: C25H2607N2 = 466.49
Calculated C% 64.37H% 5.62 N% 6.0
Found 64.2 5.7 5.9.

1) Cis (1,1-dimethylethyl) cis -3- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -4-oxo-2-azetidine carboxylate;

 Refluxed for two hours a mixture of 11.7 g of the product obtained above, 27 g of potassium persulfate, 13.2 g of dipotassic phosphate, 100 cm3 of acetonitrile and 70 cm3 of water.

It is cooled to 350 ° C. and the acetonitrile is removed under reduced pressure. 100 cm3 of ethyl acetate are then added, the precipitate is filtered off, and the methylene chloride is rinsed off by pasting.
The filtrate is decanted into a vial, reextracted with ethyl acetate, washed with 50 cm3 of 0.5 M aqueous sodium carbonate, washed with molar salt water and re-extracted each time.

 The organic phases are combined, dried, concentrated to dryness and the crystals are taken up with a mixture of 20 cm3 of ethyl acetate-ether. Stirred for 10 minutes, drained, rinsed with the same mixture by pasting and then with ether, dried and obtains 4.55 g of expected product.

Analysis: C16H16 5N2 3136.32
Calculated C% 60.75 H 5 '5.10 N% 8.85
Found 60.7 5.2 8.7.

C) 4-tert-butoxycarbonyl 3-amino-2-oxoazetidine cis -isomer
A mixture of 3.16 g of the product obtained above is stirred at room temperature in 3.2 cm 3 of dry methylene chloride and then 6 cm 3 of a 2M hydrazine hydrate solution are added dropwise thereto. dimethylformamide.

After stirring for 20 minutes, 50 ml of methylene chloride and 2.2 ml of acetic acid are added. Stirred 6 hours, filtered phthalhydrazide formed, rinsed with methylene chloride. 1.023 g of product is recovered. The filtrate is concentrated to dryness, 25 cm 3 of ethyl acetate, 30 cm 3 of saturated aqueous sodium hydrogen carbonate and 20 cm 3 of water are added. The mixture is stirred, ammonium sulphate is added until saturation is complete, and the mixture is filtered off. insoluble, decanting the filtrate into an ampoule, reextracted with ethyl acetate, the organic phase dried, filtered, removal of ethyl acetate and dimethylformamide under reduced pressure at 45-500C,
The residue is chromatographed on silica eluting with ethyl acetate, collecting the main fraction, removing the solvent, crystallizing in a little ether, filter, rinsed with ether and dried.

547 mg of expected product are obtained.

Analysis: C8H1403N2 = 186.21
Calculated C 51.6% H 7.58 N% 15.04
Found 51.9 7.6 14.7.

Example 4: 4-Chloromethyl-3- [2- (2-amino-4-thiazolo- (2-aminoethoxy) imino acetamido] -2-oxoazetidine-1-sulfamoyl cis, racemic syn.

 Step A: 4-Chloromethyl-3- (2- (2-tritylamino-4-thiazlyl) -2- (2-tritylamino-ethoxy) imino-acetamido-2-oxo-azetidine syn.

1.68 g of tosyl chloride are added to a solution of 6.3 g of 2- (2-tritylamino-4-thiazolyl) -2- (2-tritylamino) acid.
ethoxy) imino acetic isomer syn in 40 cm3 of
methylene and 1.24 cc of triethylamine.

Stir for 40 minutes then add all at once
a solution of 1.368 g of 4-chloromethyl hydrochloride
amino 2-oxoazetidine in 40 cm3 of methylene chloride and
2.4 cc of triethylamine. Stir 2 hours at room temperature
ambient, add water, shake vigorously, decant and
re-extracted with methylene chloride. The organic phase is dried,
filter and dry concentrate. The residue is chromatographed on silica (eluent: ether).

 4.9 g of expected product are obtained. Rf = 0.8.

Stage B: 4-chloromethyl-3- (2- (2-tritylamino-4-thiazolyl) 2
(2-Tritylamino ethoxy) imino acetamido / 2-oxo azetidine 1-sulfamate
pyridinium.

 A mixture of 4.9 g of the product obtained in the preceding stage, 2.6 g of pyridine and 25 cm 3 of dimethylformamide is stirred at room temperature for 4 days. Poured into 1 liter of water containing 500 cm3 of ether.

 The insoluble material is triturated, filtered, rinsed with ether and dried to obtain 6.6 g of expected product.

Rf = 0.4 (eluent: methylene chloride, ethyl acetate, ethanol: 65-20-15).

 Stage C: cis, syn, racemic, 4-chloromethyl-3- [2- (2-amino-4-thiazolyl) -2- (2-aminoethoxy) iminoacetamido] -2-oxoazetidine-1-sulfamic acid.

 A suspension of 5.3 g of the product obtained above in 42 cm 3 of formic acid at 33% water is heated at 55 ° C. for 12 minutes.

 Cooled, diluted with 30 cm3 of water, filter triphenyl carbinol formed, rinsed with water and concentrated to dryness in a bath at 400 C. The mixture is taken up twice with a water-ethanol mixture, the residue.

 Concentrate to dryness, add water and sodium hydrogen carbonate in saturated aqueous solution so as to bring the pH slightly alkaline.

 The insoluble material is filtered off, rinsed with water, 2N hydrochloric acid is added so as to bring the pH to 45 ° C. The crystallization is initiated, stirred for one hour, filtered, rinsed with water and then with water. ether.

 700 mg of expected product is obtained.

Analysis: C11H15O6N6S2Cl2
Calculated C% 30.95 H% 3.54
Found 30.9 3.8.

Example 5: Cis, syn, racemic 4-chloromethyl-3- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -2-oxoazetidine-1-sulfamic acid.

 Step A: 4-chloromethyl-3- (2- (2-tritylamino-4-thiazolyl) -2-trityloxyiminoacetamido / 2-oxoazetidine syn.

 A mixture of 1.527 g of sodium salt of 2- (2-tritylamino-4-thiazolyl) -2-trityloxyimino acetic acid and 419 mg of tosyl chloride in 15 cm3 of methylene chloride is stirred for 40 minutes and then a solution is added. 342 mg of 4-chloromethyl-3-amino-2-oxoazetidine hydrochloride in 15 cm3 of methylene chloride and 0. 0 cm3 of triethylamine.

 The mixture is stirred for 2 hours, water is added, stirred, decanted, re-extracted with methylene chloride and the organic phase is dried and filtered. The filtrate is concentrated under reduced pressure and chromatographed on silica (eluent ether).

 After evaporation of the solvent, 736 mg of condensate are collected.

 Sade B: Pyridinium 4-chloromethyl-3- [2- (2-tritylamino-4-thiazolyl) -2-trityloxyiminoacetamido] -2-oxoazetidine-1-sulfamate.

 A solution of 1.248 mg of product obtained as in Step A and 640 mg of pyridine sulfan (pyridine sulfuric anhydride complex) in 6.8 cm3 of dry dimethylformamide is left for 4 hours at room temperature.

 Then poured into 300 cm3 of ether, triturated, filtered insoluble, rinsed with ether, pasted in 10 cm3 of methanol, stirred for 15 minutes, filtered, rinsed with methanol and then with ether, dried, and finally obtained 1.02 g of expected product.

 Stage C: cis, syn, racemic, 4-chloromethyl-3- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -2-oxoazetidine-1-sulfamic acid.

 A suspension of 1.02 g of the product obtained in the preceding stage in 9.1 cm3 of formic acid at 65% is heated to 600 for 15 minutes.

 The procedure is as described above in Step C of Example 4 and obtains 119 mg of expected product.

EXAMPLE 6 PREPARATION FOR FORMULA INJECTION
- cis, syn, racemic 5-chloromethyl-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-1-sulfamic acid 500 mg
- Sterile aqueous excipient ............................. 5 cm3.

Example 7: Capsules having the formula
- cis-4-chloromethyl-3- [2- (2-amino-4-thiazolyl) -2-methoxy-imino-acetamido] -2-oxoazetidine-1-sulfamic acid, racemic 250 mg
- Excipient qs 1 capsule finished at .......... 400 mg.

Pharmacological study of the products of the invention.

In vitro activity, 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 test product are dispensed into each tube and each tube is inoculated with a bacterial strain.

After incubation for twenty-four or forty-eight hours in an oven at 370C, inhibition of growth is assessed by transillumination which allows to determine the minimum inhibitory concentrations (C.M.I) expressed r, g / cm3.

The following results are obtained
Product of Example 1

<tb><SEP> STRAINS <SEP> MIC <SEP> in <SEP> g / ml
<tb> 24 <SEP> H <SEP> 48 <SEP> H
<tb> (Escherichia <SEP> Coli <SEP> Susceptible <SEP>: <SEP>: <SEP><SEP>)<SEP>
<tb> (Tetracycline <SEP> 7624 <SEP>: <SEP> 1.25 <SEP>: <SEP> 1.25
<tb> (Escherichia <SEP> Coli <SEP> Resistant
<tb> Tetracycline <SEP> AT <SEP> CC <SEP> 11 <SEP> 303 <SEP> 0.16 <SEP> 0.16
<tb> (Enterobacter <SEP> Cloacae <SEP> 681 <SEP>: <SEP><SEP> 2.5 <SEP>: <SEP>
<tb> Escherichia <SEP> Coli <SEP> Resistant
<tb> Gentamycin <SEP> Tobramycin <SEP> R55 <SEP> 123 <SEP> D <SEP> 0.62 <SEP> 0.62
<tb> Klebsiella <SEP> Pneumoniae <SEP> Exp. <SEP> 52145 <SEP> 1.25 <SEP> 2.5
<tb> Klebsiella <SEP> Pneumoniae <SEP> 2536
<tb> (Resistant <SEP> Gentamycin <SEP>: <SEP> 2.5 <SEP> 2.5 <SEP>)
<tb> Proteus <SEP> mirabilis <SEP> (indol-) <SEP> A <SEP> 235 <SEP> 0.16 <SEP> 0.16
<tb><SEP> Proteus <SEP> vulgaris <SEP> (indol <SEP> +) <SEP> A <SEP> 232 <SEP> 0.08 <SEP> 0.08
<tb> Salmonella <SEP> typhimurium <SEP> 420 <SEP> 1.25 <SEP> 1.25
<tb> Providencia <SEP> From <SEP> 48 <SEP> 0.62 <SE> 0.62
<tb> Serratia <SEP> Resistant <SEP> Gentamycin
<tb> 2 <SEP> 532 <SEP> 5 <SEP> * <SEP>: <SEP> 5 <SEP>
<Tb>

<tb><SEP> CMI <SEP> in <SEP> g / ml
<tb> STEPS <SEP> Product <SEP> of <SEP> Product <SEP> of
<tb> example <SEP> 4 <SEP> example <SEP> 5
<tb> 24 <SEP> H <SEP> 48 <SEP> H <SEP> 24 <SEP> H <SEP> 48 <SEP> H
<tb> Escherichia <SEP> Coli <SEP> Sensitive
<tb> Tetracycline <SEP> 7624 <SEP> 1,2 <SEP> 1,2 <SEP> 0.6 <SEP> 0.6
<tb> Escherichia <SEP> Coli <SEP> Resistant
<tb> Tetracycline <SEP> AT <SEP> CC <SEP> 11 <SEP> 303 <SEP> 0.6 <SEP> 0.6 <SEP> 0.6 <SEP> 0.6
<tb> Escherichia <SEP> Coli <SEP> Resistant
<tb> Gentamycin <SEP> Tobramycin
<tb> R <SEP> 55 <SEP> 123 <SEP> D <SEP> 1.2 <SEP> 1.2 <SEP> 0.6 <SEP> 0.6
<tb><SEP> Klebsiella <SEP> pneumoniae
<tb><SEP> Exp. <SEP> 52 <SEP> 145 <SEP> 5 <SEP> 10 <SEP> 5 <SEP> 5
<tb><SEP> Klebsiella <SEP> Pneumoniae <SEP> 2 <SEP> 536
<tb><SEP> Resistant <SEP> Gentamycin <SEP> 2.5 <SEP> 2.5 <SEP> 2.5 <SEP> 2.5
<tb><SEP> Proteus <SEP> mirabilis <SEP> (indol-)
<tb> A <SEP> 235 <SEP> 0.6 <SEP> 0.6 <SEP> 0.6 <SEP> 1.2
<tb><SEP> Proteus <SEP> vulgaris <SEP> (indol +)
<tb> A <SEP> 232 <SEP> 1.2 <SEP> 1.2 <SEP> 0.6 <SEP> 0.6
<tb><SEP> Salmonella <SEP> typhimurium <SEP> 420 <SEP> 2.5 <SEP> 5 <SEP> 1,2 <SEP> 2,5
<tb> Providencia <SEP> From <SEP> 48 <SEP> 2,5 <SEP> 2,5 <SEP> 0.6 <SEP> 1,2
<tb> Serratia <SEP> Resistant <SEP> Gentamy
<SEP> cine <SEP> 2 <SEP> 532 <SEP> 2.5 <SEP> 5 <SEP> 5 <SEP> 5
<Tb>

Claims (4)

1. The products of general formula (II) in which Ra represents either R1, R1 representing a radical - (CH2) nX in which n represents an integer from 1 to 4 and X represents an atom of halogen, a cyano radical, an O-R'1 radical in which R'1 represents a hydrogen atom or an alkyl radical, or X represents an SR "1 radical in which R" 1 represents a hydrogen atom, a alkyl radical or a heterocycle or X represents a radical in which R 'and R "represent a hydrogen atom, an alkyl radical having 1 to 4 carbon atoms, or R' and R" form with the nitrogen atom to which they are attached, a heterocycle where X represents an azido, thiocyanato or isothiocyanato radical, or else R1 represents an optionally esterified or salified carboxyl radical, ie Ra represents R1 in which the reactive functions are protected and A represents a hydrogen atom or a sulpho radical, the wavy line signifying that the products can be in the cis or trans form or in the form of a cis-trans mixture, the products of formula II being in racemic or optically active form. 2. The products according to claim 1 of general formula I;

  in cis form wherein n 'is an integer from 1 to 2 and X' represents a halogen atom or a hydroxyl radical, in racemic or optically active form.  3.- The products according to any one of claims 1 or 2 in cis form wherein Ra represents a fluoromethyl radical. 4. Process according to claim 1 for the preparation of the products of formula (II), characterized in that a product of formula (V) is reacted.

 wherein k has the meaning indicated in claim 1 and Rp represents a protective group of the imino radical, with a product of formula VI

 wherein R'p and R "p represent one, a hydrogen atom and the other a protecting group of the amino radical or R 'and R "p together represent a divalent protecting group and B represents a hydroxyl or halogen radical, to obtain a product of formula VII

 in which Ras Rp, R'p and R "p have the above meaning, product of formula VII, which is subjected to the following reactions: cleavage by hydrolysis, hydroyenolysis or thioure-e action of the radical kp; b / Sulfamation of the amine in the 1-position: c) Cleavage by hydrolysis, hydrogenolysis or thiourea action of the radicals R'p and R "pd /. Possible duplication of the molecule to obtain an optically active product. 5. A process according to claim 4 for the preparation of the products of formula (IIa)

 in which A has the meaning indicated in claim 1, n represents an integer of 1 to 4 and X "represents X, X having the meaning indicated in claim 1, with the exception of a halogen atom, X represents X in which a reactive function is protected, characterized in that a product of formula is treated VIII

 in which Rlq and R "q each represent a hydrogen atom or have the meaning of R'p and R" p indicated in claim 4 by a reactive derivative of the cyano radical, the radical ORa, -SRb

 -SCN or -NCS to obtain a product of formula IX

  wherein X ", A, R 'and R" q have the values indicated above, which product is subjected if necessary and if desired, to any one or more of the following reactions a /. Cleavage by hydrolysis, hydrogenolysis or by the action of thiourea of the groups represented by R'q and R "q when they are different from a hydrogen atom, b / Sulfamation of the products in which the radical A represents an atom hydrogen, c / Duplication of the molecule to obtain an optically active product. b. Application of the products of formula II as defined in claim 1, characterized in that a product of formula II as defined in claim 1 is treated with a product of formula III

 wherein Rb represents a hydrogen atom or a protecting group of the amino radical and R'b represents a protecting group of the hydroxyl radical or R'b represents R, R represents a hydrogen atom or an alkyl, alkenyl or akynyl radical, linear or branched having not more than 12 carbon atoms, optionally substituted R'b represents a radical R in which the reactive functions are protected to obtain a product of formula IV

  racemic or optically active in which Rb, R 'b' have the above meaning, Ra and A have the meaning indicated in claim 1, which product is subjected if necessary, and if desired, to any one or more of following reactions in any order a /. cleavage by hydrolysis, hydrogenolysis or by thiourea action of the protective group or groups that may represent Rb and R ', or comprise R'b and R'as b /. esterification or salification of the carboxy radical that may comprise the radical R'b and salification of the sulfo radical, c /. acid salification of the amino radical (s), d /. sulfanation of the products in which the radical A represents a hydrogen atom, e /. resolution of the molecule to obtain an optically active product, to obtain a product of general formula I

 in which R has the above meaning and R1 has the meaning indicated in claim 1 as well as the salts of the products of formula With the bases or the acids, the corrugated line signifying that the products may be in the cis or trans form or in the form of a cis-trans mixture, the products of formula I being in racemic or optically active form, oxime being in the form syn. 7. Application according to claim 6 for the preparation of the products of formula (I), as defined in claim 6, characterized in that a product of formula (II) is used for carrying out the application. in which A represents a hydrogen atom and a product of formula (III) in which Rb represents a protecting group of the amino radical and in that the sulphamation is carried out on a product of formula (IV) in which Rb represents a protective group to the amino radical.