GB2111482A - Azetidine medicaments - Google Patents

Abstract

An azetidine of formula (I): <IMAGE> or a salt thereof, in which R represents a hydrogen atom or a linear or branched, alkyl, alkenyl, or alkynyl radical having at most 12 carbon atoms, which radical is optionally substituted; R1 represents a radical -(CH2)n-X; in which n represents an integer from 1 to 4; and X represents a halogen atom; a cyano radical; a radical O-R'1 in which R'1 represents a hydrogen atom or an alkyl radical; or X represents a radical S-R''1 in which R''1 represents a hydrogen atom, an alkyl radical or a heterocyclic radical; or X represents a radical <IMAGE> in which R' and R'' are the same or different and each represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R' and R'' together with the nitrogen atom to which they are attached form a heterocyclic radical; or X represents an azido, a thiocyanato or an isothiocyanato radical; and the wavy line indicates that the compound is in its cis or transform or in the form of a cis-trans mixture; the oxime group in the compound being in the syn form, and the compound being in the racemic or an optically active form, is a new compound. The azetidine and its pharmaceutically acceptable salts are medicaments particularly antibiotics.

Description

SPECIFICATION Azetidine medicaments The present invention relates to new azetidine compounds, their preparation, the use of such compounds as medicaments, and compositions containing such compounds.

Accordingly, the invention provides a compound which is an azetidine of formula (I):

or a salt thereof, in which R represents a hydrogen atom or a linear or branched, alkyl, alkenyl, or alkynyl radical having at most 1 2 carbon atoms, which radical is optionally substituted; R, represents a radical -(CH2)-X; in which n represents an integer from 1 to 4; and X represents a halogen atom; a cyano radical; a radical O-R'1 in which R'1 represents a hydrogen atom or an alkyl radical; or X represents a radical S-R"1 in which R"1 represents a hydrogen atom, an alkyl radical or a heterocyclic radical; or X represents a radical

in which R' and R" are the same or different and each represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R' and R" together with the nitrogen atom to which they are attached form a heterocyclic radical; or X represents an azido, a thiocyanato or an isothiocyanato radical; and the wavy line indicates that the compound is in its cis or trans form or in the form of a cis-trans mixture; the oxime group in the compound being in the syn form, and the compound being in the racemic or an optically active form.

Among the values for R there can be mentioned: a) Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, sec-pentyl, tertpentyl, neo-pentyl, hexyl, iso-hexyl, sec-hexyl, tert-hexyl, heptyl, octyl, decyl, undecyl, or dodecyl, groups.

b) Vinyl, allyl, 1 -propenyl, butenyl, pentenyl, or hexenyl, groups.

c) Ethynyl, propargyl, or butynyl, groups.

The groups mentioned above in paragraphs a) to c) can themselves be substituted by one or more radicals, such as carboxy radicals, possibly salified or esterified (so that the radical is for example alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl), carbamoyl, dimethylcarbamoyl, amino, dialkylamino (such as dimethylamino or diethylamino), alkylamino (such as methylamino), cyano, halogen (i.e. chlorine, bromine, iodine or fluorine), alkoxy (such as methoxy, ethoxy or proDvioxv).

alkylthio (such as methylthio or ethylthio), aryl (such as phenyl), aryl heterocyclic radicals (such as tl tetrazolyl or pyridinyl), optionally substituted arylthio (such as optionally substituted phenylthio), or aryl heterocyclic-thio radicals (such as tetrazolylthio or thiadiazolylthio) optionally substituted by an alkyl group such as methyl.

Among the values for R there can be mentioned more particularly the values hydrogen, methyl, optionally esterifired or salified carboxyethyl, optionally esterified or salified 1 -carboxy-1 -methylethyl, 2aminoethyl or difluoromethyl.

Among the values for R1, there can be mentioned more particularly chloromethyl, chloroethyl, chloropropyl, 1 -chloro-i -methyl ethyl, or chlorobutyl radicals. There can also be mentioned the corresponding bromine, iodine or fluorine analogues, in particular bromomethyl orfluoromethyl. There can also be mentioned aikylcyano radicals such as methylcyano or ethylcyano.

Among the values for R'1, there can be mentioned the alkyl radicals, preferably having from 1 to 4 carbon atoms, mentioned above in a), in particular the methyl radical.

Among the values for R"1, there can also be mentioned the alkyl radicals, preferably having from 1 to 4 carbon atoms, mentioned above in a), in particular methyl.

Among the heterocyclic radicals which R"1 can represent, there can be mentioned pyridyl, 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 or 1,2,3 1 2,4- 1,2,5- or 1 3,4-oxadiazolyl, these rajicais either being not substituted, or substituted by one or more radicals chosen from the group formed, for example, by methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyloxy, isopropyloxy, amino, hydroxycarbonylmethyl, dimethylaminoethyl and diethylaminoethyl radicals.

There can be mentioned more particularly 1-methyltetrazolyl, 2-methyl-i 3,4-thiadiazolyl, 3 methyl-i ,2,4-thiadiazolyl, 3-methoxy- 1 2,4-thiadiazolyl, 1 ,3,4-thiadiazol-5-yl and, more especially, 1methyltetrazolyl radicals.

The radical

can represent in particular an amino, dimethylamino, methylamino, ethylamino, diethylamino, piperidino, or morpholino radical.

The azetidines of formula (I) can form salts. The azetidines can form salts with bases and acids.

The sulpho group in position 1 as well as the carboxy group which the radical R can contain can be salified.

Among the salts which can be prepared, there can be mentioned the sodium, potassium, lithium, calcium, magnesium, or ammonium salts. There can also be cited the salts with organic bases such as trimethylamine, diethylamine, triethylamine, methylamine, propylamine, N,N-dimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, N',N'dibenzylethylenediamine, morpholine, benzylamine, procaine, lysine, arginine, histidine or N-methyl glucamine.

The present azetidines can be in the form of salts with organic or mineral acids, since the azetidines contain at least one salifiable amino radical.

Among the acids with which the amino groups of the azetidines of formula (I) can be salified, there can be mentioned, among others, acetic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, hydrochloric, hydrobromic, sulphuric, or phosphoric acid. The azetidines of formula (I) can also be in the form of internal salts.

The preferred compounds are the cis compounds.

More particularly, the invention provides a compound which is an azetidine of formula (I')

syn isomer, in the cis form, in which R2 represents a hydrogen atom or a linear or branched alkyl radical containing up to 12 carbon atoms, which radical is optionally substituted by one or more substituents selected from halogen atoms and carboxyl, amino and cyano radicals; n' represents the integer 1 or 2; and X' represents a fluorine atom, a 2-pyridinylthiomethyl radical or a thiocyanato radical; the azetidine being in the racemic or an optionally active form; or a salt of this azetidine.

The invention provides more particularly the azetidines of formula (I') in which n' represents the number 1 and X' represents a fluorine atom, as well as those in which R2 represents a hydrogen atom or a methyl or difluoromethyl radical, an optionally salified or esterified carboxymethyl radical, an aminoethyl or cyanomethyl radical, or an optionally salified or esterified 1 -methyl-1 -carboxyethyl radical.

More particularly, the invention provides the compounds described further on in the Examples, and especially 4-fluoromethyl-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-2-oXo-azetidine-1- sulphonic acid, cis, syn, isomer, racemic or optically active, or a salt thereof, or 4-fluoromethyl-3-[2-(2 amino-4-thiazolyl)-2-difluoromethoxyiminoacetamido]-2-oxo-azetidine-i -sulphonic acid, cis, syn isomer, racemic or optically active, or a salt thereof.

It is to be understood that the present azetidines can be presented, either in the form indicated by the said formula (I), or in the tautomeric imine form lz:

The lactam nucleus is numbered as follows:

The azetidines designated cis have the formula:

The trans products are the products with the formula::

The invention is also concerned with a process for the preparation of the products with the general formula (I) as defined above, characterized in that a product with the formula (II)

racemic or optically active, in which formula either Ra represents R1, R1 having the significance indicated above, or Ra represents R1 in which the reactive functions are protected and A represents a hydrogen atom or a sulpho radical, is treated by a product with the formula (III)

in which Rb represents a hydrogen atom or a protector group for the amino radical and R'b represents a protector group for the hydroxyl radical or R'b represents R, R having the significance indicated above, or R'b represents a radical R in which the reactive functions are protected, so as to obtain a product with the formula (IV):

racemic or optically active, in which Rb, R'b, Ra and A have the previous significances, which product, if necessary and if desired, is submitted to any one or more of the following reactions, in any order whatsoever: a) separation by hydrolysis, hydrogenolysis or by action of thiourea of the protector group or groups which Rb and R'b can represent or which R'b and Ra can include.

b) Esterification or salification of the carboxy radical, which the radical R'b can include and salification of the sulpho radical.

c) salification by an acid of the amino radical or radicals.

d) sulphonation of the products in which the radical A represents a hydrogen atom, e) resolution of the molecule so as to obtain an optically active product.

In the formula (II), Ra can represent generally the radical R1. However in the case where R1 represents a --(CH,),X radical, in which X represents in particular a hydroxyl or amino radical, it can be advantageous to protect these radicals by separable protector groups.

The protector groups for the amino radical can for example be alkyl radicals, preferably tert-butyl ortert-amyl, they can also be included among the acyl, aliphatic, aromatic or heterocyclic groups or the carbamoyl group.

There can also be cited the lower alkanoyl groups, such, for example, as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, Rb can also represent a lower alkoxy or cycloalkoxycarbonyl group such, for example, as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1cyclopropylethoxyca rbonyl, isopropyloxyca rbonyl, butyloxyca rbonyl, tert-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, a benzoyl, toluolyl, naphthoyl, phthaloyl, mesyl, phenylacetyl, phenylpropionyl group, or an aralkoxycarbonyl group such as benzyloxy-carbonyl.

The acyl groups can be substituted for example by a chlorine, bromine, iodine or fluorine atom.

There can be cited the chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl or trifluoroacetyl radicals.

There can also be used a lower aralkyl group such as benzyl, 4-methoxybenzyl or phenylethyl, trityl, 3,4-dimethoxybenzyl or diphenylmethyl.

A haloalkyl group such as trichloroethyl can also be used.

There can also be used a chlorobenzoyl, para-nitrobenzoyl, para-tert-butylbenzoyl, phenoxyacetyl, caprylyl, n-deca noyl, acryloyl, or trichloroethoxycarbonyl group.

There can also be utilized a methyl-carbamoyl, phenylcarbamoyl, naphthylcarbamoyl group, as well as the corresponding thiocarbamoyls.

The above list is not limitative, it is obvious that other amine protector groups, groups known in particular in the chemistry of the peptides, can equally be utilized.

The protection group for the hydroxyl radical can be chosen from the list below: It can be an acyl group such, for example, as formyl, acetyl, chloroacetyi, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl. There can also be cited the ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, / trich loroethoxyca rbonyl, benzoyloxyca rbonyl, tert-butoxycarbonyl, 1 -cyclo-propylethoxycarbonyl, tetra hydropyrannyl, tetrahydrothiopyrannyl, methoxytetrahydropyrannyl, trityl, benzyl, 4-methoxybenzyl, diphenylmethyl, trichloroethyl, 1-methyl 1-methoxyethyl and phthaloyl groups.

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

The radicals phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, para-nitrobenzoyl, para-tert butylbenzoyl, caprylyl, acryloyl, methylcarbamoyl, phenylcarbamoyl and naphthylcarbamoyl can also the cited.

Naturally, the values of the substituents Rb, when these do not represent a hydrogen atom, as well as the values of the protector groups which R'b can possibly represent or include, in particular when R'b includes an amine, can also be taken from the lists mentioned above.

In a preferential manner of carrying out the process, the product with the formula (Il) is treated with a functional derivative of a product with the formula (Ill). This functional derivative can for example be a halide, a symmetric or mixed anhydride, an amide or an activated ester.

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

As example of halide, there can be cited the chloride or bromide.

There can also be cited the acid azide or the acid amide.

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

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

Other solvents can, however, be utilized, such as tetrahydrofuran, chloroform or dimethylformamide.

When an acid halide is utilized, and in a general way when a hydrohalic acid molecule is liberated in the course of the reaction, it is preferable to carry out the reaction in the presence of a base such as sodium hydroxide, potassium hydroxide, carbonates and acid carbonates of sodium and potassium, sodium acetate, triethylamine, pyridine, morpholine or N-methylmorpholine.

The reaction temperature is, in general, less than or equal to the ambient temperature.

When Rb represents a hydrogen atom, it is preferred to use a carboxylic sulphonic mixed anhydride.

According to the values for Rb, R' b and Ra, the products with the formula (lV) may or may not constitute products with the formula (I).

The products with the formula (lV) constitute products with the formula (I) when Rb represents a hydrogen atom, when R'b does not represent a protector group for the hydroxyl radical or does not represent a radical R including a protected function, and finally when Ra does not represent a radical R in which a reactive function is protected and when A does not represent a hydrogen atom.

In the other cases, the action on the product with the formula (lV) of one or more hydrolysis or hydrogenolysis agents or of thiourea has the purpose of eliminating the radical Rb when the latter represents a protector radical of the amino radical, of eliminating the radical R'b when the latter represents a protector group of the hydroxyl radical, and of eliminating the other protector groups which the radicals Ra and R'b can include.

The kind of reagents to be put into action in all these cases is well known to an expert in the subject. Examples of such reactions are given further on in the experimental part.

There is given below a non-exhaustive list of the means which can be employed to eliminate the different groups.

The elimination of the group Rb can be effected by hydrolysis, the latter being acid, basic, or utilizing hydrazine.

It is preferential to utilize acid hydrolysis to eliminate the alkoxy and cycloalkoxycarbonyl groups, possibly substituted, such as tert-pentyloxycarbonyl or tert-butyloxycarbonyl, the aralkoxycarbonyl groups, possibly substituted, such as benzyloxycarbonyl, and the trityl, diphenylmethyl, tert-butyl or 4methoxy-benzyl groups.

The acid which is preferably utilized can be chosen from the group constituted by hydrochloric, benzene sulphonic or para-toluene sulphonic, formic or tri-fluoro acetic acid. Other mineral or organic acids can however also be used.

It is preferred to use basic hydrolysis to eliminate acyl groups such as trifluoroacetyl.

The base which it is preferred to use is a mineral base such as sodium or potassium hydroxide.

There can also be utilized magnesia, baryta, or a carbonate or acid carbonate of an alkali metal such as the carbonates and acid carbonates of sodium or potassium or other bases.

There can also be used sodium or potassium acetate.

Hydrolysis using hydrazine is utilized for preference to eliminate groups such as phthaloyl.

The Rb group can also be eliminated by the zinc-acetic acid system (for the trichloroethyl group), the diphenylmethyl benzyloxycarbonyl groups are preferably eliminated by hydrogen in the presence of a catalyst.

The chloroacetyl group is eliminated by the action of thiourea in a neutral or acid medium, according to the type of reaction described by MASAKI J.A.C.S., 90, 4508, (1 968).

There can also be utilized other methods known in the literature for removing protection, for example separation by oxidizing, particularly for the benzyl group.

Among the preferred groups, there can be cited formyl, acetyl, ethoxycarbonyl, mesyl, trifluoroacetyl, chloroacetyl, trityl. The trityl and chloroacetyl radicals are particularly preferred.

The acid which is used for preference is trifluoroacetic acid or formic acid.

The elimination of the R'b radical or the protector groups which R'b and Ra contain, when this is necessary, is carried out in similar conditions to those previously described for the elimination of Rb.

Acid hydrolysis, among other processes can be used to eliminate alkyl or aralkyl radicals, possibly substituted.

It is preferred to use an acid chosen from the group formed by hydrochloric, formic, trifluoroacetic and para-toluene sulphonic acids.

The other values for the radicals Rb or R'b or the protector groups which R'b or Ra contain are eliminated, when this is desired, according to processes known to the expert. It is preferred to operate in moderate conditions, that is to say, at ambient temperature or on slight heating.

Naturally, when, for example Rb or R'b or Ra are or contain groups which can be eliminated but belonging to different types, several agents included in the previous lists can be made to act on the products (lV).

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

Salification can, for example, be obtained by the action on a product in the acid form or on a solvate, for example, the ethanol solvate or a hydrate of this acid, of a mineral base such as the hydroxide of sodium or potassium, the carbonate or the acid carbonate of sodium or potassium. There can also be utilized the salts of mineral acids such as tri-sodium phosphate. Salts of organic acids can also be used.

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

As salts of sodium it is preferred to utilize the acetate, the 2-ethyl hexanoate or the diethyl acetate.

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

The esterification, if required of the products in which R includes an acid function is also carried out in standard conditions.

The sulphonation of the products with the formula (IV) in which A represents a hydrogen atom is carried out by sulphuric an hydroxide or by a reactive derivative of this anhydride.

It is preferred to utilize the complex pyridine sulphuric anhydride but there can also be utilized other complexes of sulphuric anhydride with dioxan or trimethylamine.

The reaction is carried out in a usual solvent such as ethyl acetate, chloroform or dimethylformamide, and it can be done at ambient temperature. When the complex pyridine-sulphuric anhydride is utilized, the products can be isolated in the form of salts of pyridinium.

The resolution of the racemic molecules with the formula (II) or (IV) if required can be carried out according to the usual methods.

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

The present invention is especially concerned with a process as described above, characterized in that, in order to put it into operation, a product with the formula (Il) in which A represents a hydrogen atom and a product with the formula (III) in which Rb represents a protector group for the amino radical are used, and in that the sulphonation is carried out on a product with the formula (lV) in which Rb represents a protector group of the amino radical.

The protector group which Rb represents is for preference the trityl radical.

It is preferred to carry out the sulphonation with the complex sulphuric pyridine anhydride.

Also a subject of the present invention is a process for the preparation of the products with the formula (II), characterized in that a product with the formula (V):

in which Ra has the significance indicated above and Rp represents a protector group for the imino radical, is made to act on a product with the formula (Vl):

in which R' and R"p represent the one a hydrogen atom and the other a protector group for the amino radical, or R' and R" together represent a divalent protector group and B represents a hydroxyl radical or a halogen, so as to obtain a product with the formula (VII):

in which Ra, Rp, R' and R" have the previous significances, which product with the formula (VII) is submitted to the following reactions:: a) Separation by hydrolysis, hydrogenolysis or action of thiourea of the radical b) Possible sulphonation of the amine in position 1; c) Separation by hydrolysis, hydrogenolysis or action of thiourea of the radicals R' and d) Possible resolution of the molecule so as to obtain an optically active product.

The protector group Rp can be chosen from the list of substituents given previously for amines.

For reasons explained below, it is however preferred to utilize a benzyl radical or 2,4-dimethoxy benzyl or an equivalent.

In addition, the protector group Rp can contain an asymmetric carbon atom and the invention has also in particular as its subject a process as previously defined, characterised in that at the start a product with the formula (V) in which Rp represents a protector group of the imino radical containing an asymmetric group is used and a product with the formula (VII) is isolated in the optically active form.

These optically active products with the formula (VII) lead to optically active products with the formula (I) according to the process previously described.

As protector group, there can be cited particularly the 1 -phenyl ethyl group.

An example of the preparation of an optically active product with the formula (VII) is provided further on in the experimental part.

The radicals R' and R" can be chosen from the same list of protector radicals given above. it is preferred to use the phthaloyl radical.

The group B can represent a halogen atom. The acid chloride is preferred.

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

When B represents a hydroxyl radical, the operation is done in the presence of a dehydratation agent such as an anhydride, preferably trifluoroacetic anhydride.

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

When it is required to sulphonate the resulting products, the object of the first de-protection reaction is the selective de-blocking of the radical Rp. Therefore, as indicated above, it is preferred to utilize a benzyl or di-methoxy benzyl radical, which is preferably de-blocked by an oxidiser such as potassium peroxodisulphate.

It is preferred to operate in a solvent such as a water-acetic acid mixture or acetonitrile.

The sulphonation, if it is required, of products in which the secondary amine in position 1 is free is carried out as indicated above.

The possible second de-blocking operation has the object of liberating the amine in position 3 by elimination of the radicals R' and R"p. When, as indicated above, one is operating with a phthalimido radical, the elimination is effected, as indicated above, by hydrazine preferably a hydrazine hydrate in a solvent such as dimethylformamide.

Naturally, in particular in the case where the sulphamation of the products with the formula (IV) is not carried out, the radicals Rp, R' and R" can be eliminated simultaneously.

Resolution, as indicated above, is carried out in the usual manner.

According the present invention can also be prepared the products with the formula (ilk):

in which A has the significance indicated above, n represents a whole number between 1 and 4 and X" represents X, X having the significance indicated above, with the exception of a halogen atom, or X" represents X in which a reactive function is protected, by a process in that a product with the formula (VIII)::

in which Rlq and Rliq each represent a hydrogen atom or have the significance of R' and R" indicated above, is treated by a reactive derivative of the cyano radical, of the radical -OR'1, -SR"1,

-SCN or --NCS, so as to obtain a product with the formula (IX)

in which X", A, Rlq and Rliq have the values indicated previously, which product is if necessary and if desired, submitted to any one or more of the following reactions:: a) Separation by hydrolysis, hydrogenolysis or by action of thiourea of the groups represented by q and Rliq when these are different from a hydrogen atom, b) Sulphonation of the products in which the radical A represents a hydrogen atom, c) Resolution of the molecule so as to obtain an optically active product.

The action on the product with the formula (VIII) of the reactive derivatives of the radicals which it is wished to substitute for the halogen atom is carried out in the usual conditions.

For example, the exchange between a halogen atom and a mercaptan is preferably carried out by an alkali metal salt of this percaptan such as a sodium salt.

The exchange between the halogen atom and an acetate of an alkali metal such as sodium or potassium acetate enables a protected hydroxyl radical to be introduced which can be liberated and then if desired etherified.

The action of an amine, possibly protected by one of the radicals indicated above enables a radical

possibly protected, to be introduced.

An azide of an alkali metal, preferably sodium azide, can be made to act in order to introduce the azido radical. A cyanide or a thiocyanate of an alkali metal can equally be made to act so as to obtain the products in which X represents these radicals or an isothiocyanate.

The subsequent operations of possible de-protection, of sulphonation and of resolution, also possible, are carried out in the manner indicated above.

The subject of the invention is especially a process for preparing the products with the formula I as defined above, characterized in that Ra represents a fluoromethyl radical.

The products with the general formula (I) possess a very good anti-biotic activity on the Gram negative bacteria, particularly on the coliform bacteria, the klebsiella the salmonella and the proteus.

These products can in particular be utilized as medicaments in the treatment of colibacilloses and associated infections, in proteus, klebsiella and salmonella infections and in other disorders caused by Gram negative bacteria.

Therefore equally a subject of the present invention, as medicaments and in particular as antibiotic medicaments, is the products with the formula (I), as defined above, as well as their pharmaceutically acceptable salts.

The invention has particularly as its subject as medicaments and in particular as antibiotic medicaments, the products with the formula (I'):

syn isomers, in the cis form, in which R2 represents a hydrogen atom or a linear or branched alkyl radical, possibly substituted by one or more halogen atoms, a carboxyl, amino, or cyano radical, n' represents the whole number 1 or 2 an X' represents a fluorine atom, a 2-pyridinylthiomethyl radical or a thiocyanato radical, in the racemic or optically active form, as well as the salts of the products with the formula (I') with pharmaceutically acceptable bases or acids.

The invention also has more particularly as its subject, as medicaments and notably as antibiotic medicaments, the products with the formula (I') as defined above, in which n' represents the number 1 and X' represents a fluorine atom, as well as their pharmaceutically acceptable salts with bases or acids, and the products with the formula (I') as defined above, in which R2 represents a hydrogen atom or a methyl, difluoromethyl, carboxymethyl possibly salified or esterified radical, an aminoethyl, cyanomethyl, or 1-methyl 1 -carboxyethyl possibly salified or esterified radical, as well as their pharmaceutically acceptable salts with bases or acids.

The invention also has more particularly as its subject, as medicaments and notably as antibiotic medicaments, the products described in the Examples and especially 4-fluoromethyl-3-[2-(2-amino-4thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-1 -sulphonic acid, cis, syn isomer, racemic or optically active, and its pharmaceutically acceptable salts, as well as 4-fluoromethyl-3-[2-(2-amino-4 thiazolyl)-2-difluoromethoxyiminoacetamido]-2-oxoazetidine-1 -sulphonic acid, cis, syn isomer, racemic or optically active, and its pharmaceutically acceptable salts.

The invention provides pharmaceutical compositions containing as active principle at least one of the medicaments defined above.

These compositions can be administered by the oral, rectal or parenteral route, or by the local route as topical applications on the skin or the mucosa.

The compositions can be solid or liquid and can be presented in the pharmaceutical forms currently utilized in human medicine, such as plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, and gels. The pharmaceutical forms can be prepared by the usual methods. The active principle can be incorporated with the excipients usually employed in the formulation of pharmaceutical compositions. Such excipients may be solid or liquid as appropriate to the pharmaceutical form chosen, and may include a wide range of organic and inorganic solids, and aqueous and non-aqueous liquids; examples include talc, gum arabic, starch, lactose, magnesium stearate or fatty substances of animal or vegetable origin such as cocoa butter, paraffin derivatives or glycols. The excipients may be compounded with one or more wetting, dispersing or emulsifying agents and/or one or more preservatives.

These compositions can, in particular, be presented in the form of a powder intended to be dissolved when required in an appropriate vehicle, for example in sterile apyrogeneous water.

The dose administered is variable according to the disorder treated, the subject concerned, the administration route and the product considered. It can, for example, be between 0.250 g and 4 g per day by oral route in man with the product described in example 1, or also between 0.500 g and 1 g three times per day, by intramuscular route.

The products with the formula (I) and their salts can also be utilized as disinfectants for surgical instruments.

Finally, a subject of the invention, as new industrial products and, the products with the general formula (IV):

in which Rb, R'b, A and Ra have the significance indicated above, as well as the products with the formula (all):

in which A and Ra have the significance indicated above, it being understood that in the said formula (Il), when A represents a hydrogen atom, Ra can not represent a methylthio, hydroxymethyl, azidomethyl, aminomethyl or alkoxymethyl radical.

The products with the formula (V) which are not known can be prepared by the action of an aldehyde with the formula RaCHO, possibly in the form of the hydrate RaCH(OH)2 on a protected amine with the formula Rp NH2.

Examples of such preparations are given in the experimental part.

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

R R -CH,CH, -CH,CI -(CH2)2OH3 -CH,CI -OH(CH3)2 -OH2CI -nO4H9 -CH,CI -OH2-OHOH2 -CH2Cl -OH2OQH -CH2Cl ACO2H -CH,CI 4 -C(CH3)2CO2H -CH2Cl -OH-CO2H -CH2CI 1H3 CH2CO2C2Hs -OH2C I CH2CO2tBu -CH2Ol -CH-CO,H -CH2C I O2H3 -C(CH3)3 -CH2Cl -OH2-CH-OH-O02H -CH,CI -CH-COLH -CH2Cl O3H7 -OH2CN -CH2CI -(OH2)2CN -CH2Ol -CH2-O0NH2 -CH,CI -(OH2)2 Br -CH2Ol -(CH2)2Cl -OH2Cl

R R1 -(OH2)3Br -CH,CI -(OH2)2l -CH2Ol -H2C-C=-OH -CH,CI -HC=OH2 L7 \ -CH2CI "1 -CH,CI CH) -OH2Cl -cH)Do -OH2Cl -CH3C-N(CH3)3 -CH2Cl 0 -CH3-CH2-N(CH 3)2 -CH,CI H I -OH30CH3 CH 3 -CH,OCH, -OH2CH2NH2 CH2OCH3 -CH,CO,H -CH20CH3 -C(OH3)2CO2H -CH,OCH, -CH3OH2Br -CH30CH2 -OH3CH2l CH2OCH3 ,-CH2O02C2H3 -OH20CH3 -OH2O02tBu -CH2OCH3 -C(CH3)2C02C2H -OH20OH3 -C(OH3)2CO2tBu -OH20CH3

R | R, CH2CH3 -CH2Br -(OH2)2OH3 -OH2Br CH(CH3)2 -OH2Br -nC4H, -OH2Br -CH,-CH=CH2 -CH2Br CH2CO2H -CH2Br -C-C02H -CH2Br C(CH 3)2CO2H -CH2Br -CH-CO,H -CH2Br CH3 CH2CO2C2Hs -CH2Br -CH2C02tBu -CH2Br -CH-COH -CH2Br H1 -'C(CH3)3 -CH2Br -CH2-OH=CH-C02H -CH2Br -CH-CO2H -OH2Br 3H7 -CH2CN -CH2Br -(OH2)2CN -CH2Br -CH2-CONH2 -CH2Br -(CH2)2Br -CH2Br -(CH2)2Ol -CH2Br

R | R -(CH2)3Br CH2Br -(OH2)2l -OH28r -H2O-CaaCH -OH2Br -HO-OH -OH2Br (CH )rZ -CH2Br II --CH,Br CcH) H -OH2Br )a 1' -CH2Br -CH2C-N (OH 3)2 -CH2Br 0 -OH2-CH2-N(CH3)2 -CH2Br CH3 -CH2Br -CH2CH2NH2 -CH2Br H -CH2Br H -OH2SOH3 CH3 -CH2SCH3 -OH2OH2NH2 -CH2SCH3 CH2CO2H -CH2SOH3 C(CH3)2C02H -OH2SCH3 -CH2OH2Br -OH2SCH3 -OH2CH2l -OH2SCH3 -CH200202H5 -CH2SOH3

R R1 CH2CO2tBu -CH,SCH, -C(OHs)2CO2C2H5 -CH2SCH3 C(CH 3)2C02tBu -OH2SCH3 CH2CH -CH20H -(OH2)2CH3 -OH2OH -CH(CH3)2 -CH20H -nC4H9 -CH20H -CH2-CH=OH2 -OH20H CH2'CO2H -OH20H -O-CO2H -CH2OH -(CH)2CO2H -OH20H -CH-O02H -CH20H CH 3 -CH2O02C2H5 -OH20H -CH2OO2tBu -OH20H -OH-CO2H -OH20H O2H5 -C (OH 3)2 -CH20H -CH,-CH=CH-CO,H -OH20H -CH-OO2H -OH20H 3H7 -CH,CN -OH20H -(CH2)2CN -CH20H

R R1 -OH2-CON H2 -OH2OH -(CH2)2Br -CH2OH -(OH2)2Cl -CH20H -(CH2)3Br -CH20H H -CH2SCN CH 3 CH2SCN -CH2OH2NH2 -CH2SON CH2CO2H -CH2SON -O(OH3)2O02H -CH28CN -(OH2)2l -CH20H -H2C-C-OH -CH2OH -HC=CH3 &commat; -OH20H - S < ) -OH2OH W CCH 2) -OH20H ( -CH,OH -CH2C-N(OH 3)2 -CH2OH 0 -OH2-OH3-N(OH3)3 -CH,OH CH3 -CH20H -OH2OH2-NH2 -CH20H H -CH2OH

R R1 R H CH2NH2 CH3 CH2NH2 -OH2OH2NH2 CH2NH2 -CH,CO,H CH2NH2 -C(CH 3)2C02H CH2NH2 -CH2CH2Br CH2NH2 -OH2OH2l CH2NH2 H CH2N3 CH3 CH2N3 -CH2OH2NH2 CH2N3 -CH2002H CH2N3 -C(OH3)2O02H CH2N3 H CH2NCS CH3 CH2NCS -OH2OH3NH2 CH2NCS -CH,CO,H CH2NCS -OH2CH3 CH2SH -(CH2)2OH3 CH2SH -L"H(OH3)3 OH2SH -nC4Ha CH2SH

R Rl R R -CH3-CHH -OH2SH CH2CO2H -CH2SH --CO2H -OH2SH -(CH,),CO,H -CH2SH -OH-CO2H -OH 2SH OH3 -CH2O02C2H 5 -OH2SH CH2CO2tBu -OH2SH -OH-CO2H -CH2SH 12H5 -O(OH3)3 -OH2SH -OH2-CH=OH-O02H -CH2SH -CH-C02H -CH2SH 3H7 -OH2CN -OH2SH -(CH2)2ON -CH3SH -CH,-CONH, -CH2SH -(CH2)3Br -CH,SH -(OH2)2Cl -OH2SH -(OH2)3Br -CH2SH -C(CH3)2CO2H -CH,NCS H -OH2N(CH3)2 CH3 -CH2N(OH3)2

R R, -CH2OH2NH2 ,CH2N(CH3)2 -OH2O02H CH2N(CH3)2 -(OH2)3l -CH2SH -H3O-O C H -CH3SH -HC=CH, &commat; -CH,SH (eH -CH,SH H9) 1 ) 1~OC H) -OH2SH -C( H ) a El( b -CH,SH -OH3O-N(CH3)2 -OH2SH -OH2-0H2-N(CH3)2 -OH2SH CH 3 --CH,SH -CH2CH2NH2 -CH,SH H -OH2SH -C(CH,),CO,H -OH2N(OH3)2 -CH,CN -OH2 F -OH2-O02H -OH2 F H3 -CH -CH P3

EXAMPLE 1 4-chloromethyl 3-[2-(2-amino 4-thiazolyl) 2-methoxyimino acetamido] 2-oxoazetidine 1-sulphonic acid, cis, syn, racemic Stage A: 4-chloromethyl 3-[2-(2-tritylamino 4-thiazolyl) 2-methoxyimino acetamido] 2-oxo azetidine, syn A suspension of 2.32 g of 2-(2-tritylamino 4-thiazolyl) 2-methoxyimino acetic acid, syn isomer, in 23 cm3 of methylene chloride is cooled, and 594 mg of dicyclohexyl carbodiimide is added, and after agitating cold for 20 minutes a solution of 441 mg of 4-chloromethyl 3-amino 2-oxo azetidine hydrochloride in 1 0 cm3 of methylene chloride and 0.4 cm3 of triethylamine are added.After agitating for 1 hour 20 minutes at ambient temperature, the dicyclohexylurea formed is separated, rinsed with methylene chloride, and 10 cm3 of a saturated solution of sodium acid carbonate and 20 cm3 of water are added to the filtrate. This is then agitated, decanted into a flask, washed again with water, the organic phase is re-extracted and dried.

After concentrating to dryness under reduced pressure, the minimum of ethyl acetate is added to the residue, which is scratched, the insoluble matter is filtered, rinsed with ethyl acetate and again concentrated to dryness under reduced pressure. The residue is dissolved in 5 cm3 of ethanol and slowly diluted with 10 cm3 of ether. Crystallization is initiated, with agitation for 2 hours, then the crystals formed are separated and rinsed with an ethanoí-ether (12) mixture, so obtaining 688 mg of the expected product.

Analysis: C29H2603N5SCI = 560.08 Calculated: C % 62.19 H % 4.68 N % 12.5 Found: 62.4 4.8 12.2 Stage B: 4-chloromethyl 3-[2-(2-amino-4-thiazolyl) 2-methoxyAmino acetamido1 2-oxo aze tidine 1 sulphuric acid, cis, syn, racemic a) Sulphonation: 2.403 g of the product obtained at the previous stage is added to a solution of 1.72 g of pyridine sulphan (complex sulphuric pyridine anhydride) in 1 7.2 cm3 of dry dimethylformamide.After agitating for 66 hours at ambient temperature, filtering off the insoluble matter, rinsing with dimethylformamide, diluting with 300 cm3 of ether, agitating, leaving to rest for 1 0 minutes, eliminating the ether, and washing again with ether while triturating, the gum is taken up with 20 cm3 of ethanol. After dissolving and being scratched, the expected product crystallizes out. It is agitated lightly for 30 minutes, filtered, rinsed with ethanol and then with ether.

855 mg of the expected product is obtained, which is pyridinium 4-chloromethyl 3-[2-(2tritylamino 4-thiazolyl) 2-methoxyimino acetamido] 2-oxo azetidine 1-sulphonate.

b) Unblocking the trityl residue: A mixture of 360 mg of pyridine sulphonate previously obtained and 1.4 cm3 of formic acid with 33% water is taken to 50 C. After it has dissolved, crystaliization of triphenylcarbinol occurs. It is left for 10 minutes at 500C, cooled, diluted with 0.6 cm3 of water, the insoluble matter is filtered off and rinsed with water. A little ethanol is added to the filtrate, which is concentrated to dryness under reduced pressure. Water and ethanol are added and then evaporated under vacuum. 1.2 cm3 of a saturated aqueous solution of sodium acid carbonate is added to the residue. After filtering off the light insoluble matter, and rinsing with water, 3 drops of formic acid are added to the filtrate and it is scratched. The expected product crystallizes out.After agitating for 10 minutes, filtering, rinsing with water and with ether and drying, 11 3 mg of the expected product is isolated.

Analysis: O10H12O8N5S2CI = 397.82 Calculated: C % 30.19 H % 3.04 Found: 29.6 3.2 Preparation: a) 2-chloro-N-phenylmethyl ethanimine A solution of 4 cm3 of chloroacetaldehyde in 20 cm3 of demineralized water is cooled and under agitation a solution of 2.14 g of benzylamine in 10 cm3 of water is introduced. After agitation for 5 minutes at 10/15 C, a gum is obtained and a turbid solution, which is extracted with 30 cm3 and then with 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-chloromethyl 2-azetidinone, cis The solution of 3.34 g of product obtained above in 20 cm3 of methylene chloride is cooled to --500C. While maintaining the agitation and the temperature, over 20 minutes, a solution of 4 g of phthalimido acetic acid chloride in 20 cm3 of methylene chloride is introduced; agitating is continued for one hour at 0,+5 C, followed by pouring into a decanting flask, washing with 50 cm3 of demineralized water and 5 cm3 of a molar aqueous solution of sodium acid carbonate, and then with demineralized water (twice 30 cm3). The washings are re-extracted with methylene chloride (20 cm3), dried, separated, rinsed and concentrated to dryness under vacuum.A crude resin is obtained (6 g) which is chromatographed on silica by means of methylene chloride with 5% of sulphuric ether. The fraction with Rf = 0.45 is isolated, taken to dryness, triturated with 10 cm3 of sulphuric ether, separated, rinsed three times with 2 cm3 of sulphuric ether. After drying under vacuum, 1.25 g of product is obtained. M.Pt.

14900.

c) 3-phthalimido 4-chloromethyl 2-azetidinone cis A mixture of 17.75 g of the product previously obtained, 31 g of potassium peroxodisulphate, 110 cm3 of water and 1 60 cm3 of acetic acid is heated for 25 minutes under good agitation in an oil bath at 1 200C. It is then cooled to ambient temperature, 50 g of dipotassium phosphate is added to neutralize the acidity formed, the solvents are expelled under reduced pressure, 250 cm3 of water and 1 50 cm3 of ethyl acetate are added, and after agitation, sodium acid carbonate is added in small quantities until evolution of gas ceases. The medium is filtered, rinsed with ethyl acetate, decanted into a flask, re extracted with 50 cm3 of ethyl acetate, the organic phase is dried, filtered, rinsed and concentrated to dryness under reduced pressure. The residue is chromatographed on 200 g of silica (eluent: methylene chloride with 25% of ethyl acetate). The rich fractions are recovered, concentrated to dryness, taken up with ether, dissolved, separated, rinsed and after drying 5.4 g of the product sought is obtained. Analysis: C12HgN2CI = 264.67 Calculated: C % 54.46 H % 3.43 Found: 54.7 35 d) 4-chloromethyl 3-amino 2-oxo azetidine hydrochlorate To a suspension of 5.3 g of product obtained above in 5.4 cm3 of methylene chloride, 12 cm3 of a solution of hydrazine hydrate in dimethylformamide (2 cm3 of hydrazine hydrate and q.s. for 20 cm3 of dimethylformamide) is added drop by drop. After aggregation, it is left for 20 minutes, then sufficient (about 30 cm3) of normal hydrochloric acid is added to dissolve it completely, in such a way as to bring the pH to 3.After agitating for 1 8 hours at ambient temperature filtering the phthalhydrazide formed, rinsing with water, then with ethanol and finally with ether and drying 2.844 g of product is obtained.

The dimethylformamide and water are expelled under reduced pressure, the residue is taken up twice with ethanol which is expelled and a product is obtained to which 20 cm3 of ethanol is added. After agitating for 45 minutes, separating the crystals formed, rinsing with ethanol and ether, there is finally obtained 2.466 g of the expected product.

EXAMPLE 2 4-(1 -methyl 5-mercapto 1,2,3,4-tetrazol) methyl 3-[2-(2-amino 4-thiazoly) 2-methoxyimino acetamido] 2-oxo azetidine 1-sulphonic acid, cis, racemic Stage A: 4-(l -methyl 5-mercapto 1,2,3,4-tetrazol) methyl 3-[Z-(2-tritylamino 4-thiazolylj 2methoxyimino acetamido] 2-oxo azetidine 1 -sulphonic acid a) Condensation: A mixture of 2.25 g of 2-(2-tritylamino 4-thiazolyl) 2-methoxyimino acetic acid, syn isomer, in 21 cm3 of methylene chloride and 576 mg of dicyclohexylcarbodiimide is agitated cold for 20 minutes in a bath of iced water.The bath is removed and a solution of 597 mg of 4-(1 -methyl 5-mercapto 1,2,3,4tetrazol) methyl 3-amino 2-oxo azetidine hydrochlorate in 10 cm3 in methylene chloride and 0.38 cm3 of triethylamine are added. After agitating at ambient temperature for 1 hour 20 minutes, concentrating to dryness under reduced pressure, filtering, rinsing with methylene chloride, finishing with ether and drying, 1.594 g of product is isolated, containing dicyclohexylurea.

b) Sulphonation: A mixture of 1.594 g of the product obtained above and 0.66 g of pyridine sulphan (complex pyridine sulphuric anhydride) in 6.6 cm3 of dimethylformamide is agitated for 70 hours. The dicyclohexylurea is filtered off, rinsed with the minimum of dimethylformamide, and the filtrate is diluted with about 200 cm3 of ether. After agitating well, filtering off the insoluble matter, washing with ether, joining all the products together and dissolving them in methanol, the expected product crystallizes out.

It is filtered, rinsed with methanol and finished with ether, dried, and 620 mg of the expected product is obtained.

Stage B: 4-(1 -methyl 5-mercapto 1,2,3,4-tetrazol) methyl 3-[2-amino 4-thiazolyl) 2-methoxyimino acetamidoll 2-oxo azetidine 1 -sulphonic acid A mixture of 620 mg of the product obtained in the previous stage in 0.8 cm3 of water and 1.62 cm3 of formic acid is heated to 60"C for 12 minutes, and triphenylcarbinol crystallizes out. By cooling and diluting with a little water, the expected product also crystallizes. The medium is agitated for 10 minutes, filtered, rinsed with water, then triturated three times with ether.The insoluble matter is taken up in water, 2 cm3 of saturated aqueous sodium acid carbonate is added, then after agitating, filtering the insoluble matter, rinsing with water and adding normal hydrochloric acid as required for pH 2, the expected product crystallizes. After agitating for 5 minutes, filtering, rinsing with water and finishing with ether and drying, 294 mg of the expected product is obtained.

Analysis: C12HX506NgS31/2 H20 = 486.51 Calculated: C % 29.53 h % 3.31 25.91 S % 19.77 Found: 29.5 3.4 25.8 19.8 PREPARATION 1 a) 4-(1 -methyl 5-mercapto 1,2,3,4-tetrazol) methyl 3-phthalimido 2-oxo azetidine, cis A suspension of 7.6 g of 4-chloromethyl 3-phthalimido 2-oxo azetidine, cis, obtained by the preparation of example 1 c), 5.48 g of sodium salt of 1-methyl 5-mercapto 1,2,3,4-tetrazole (dihydrated), 4.3 g of sodium iodide and 57 cm3 of dimethylformamide are heated to 1000C and left under agitation for 3 hours at this temperature.It is then cooled, poured into 0.75 1 of water and 1 50 cm3 of ethyl acetate, rinsed, agitated vigorously, decanted, re-extracted with 75 cm3 and then 45 cm3 of ethyl acetate, and the insoluble matter which is the expected product is filtered off. After washing with 1 50 cm3 of water, re-extracting, drying, and filtering, it is concentrated to a small volume under reduced pressure, filtered a second time and rinsed with ethyl acetate. The insoluble products are joined together, dried, and finally 5.1 g of the expected product is isolated.

Analysis: C14H12O3N6S 1/4 AcOEt = 366.37 Calculated: C % 49.17 H % 3.85 N % 22.94 Found: 49.2 3.7 23.0 b) 4-(l -methyl 5-mercapto 1,2,3,4-tetrazol) methyl 3-amino 2-oxo azetidine hydrochloride 1 cm3 of hydrazine hydrate is added drop by drop to a suspension of 5.845 g of the product obtained above in 1 8.5 cm3 of dry dimethylformamide and agitated for 20 minutes at ambient temperature, the 1 9 cm3 of water and 24 cm3 of normal hydrochloric acid are added. After obtaining a final pH of 3, the mixture is stoppered, left for one night under agitation at ambient temperature, then the phthalhydrazide formed is filtered, rinsed with water, and concentrated to dryness under reduced pressure.After adding ethanol, triturating, concentrating to dryness, adding methanol hot to make a solution and concentrating to dryness, the product crystallizes. By adding 20 cm3 of methanol, triturating, chilling, separating, rinsing with iced methanol and finishing with ether, 2.49 g of the expected product is obtained in two lots.

EXAMPLE 3 4-chloromethyl 3-[2-(2-amino 4-thiazolyl) 2-(2-amino ethoxy) imino acetamido] 2-oxoazetidine 1sulphonic acid, cis, syn, racemic Stage A: 4-chloromethyl 3-[2-(2-tritylamino 4-thiazolyl) 2-(2-tritylamino ethoxy) imino acetamido] 2oxo azetidine, syn 1.68 g of tosyl chloride is added to a solution of 6.3 g of 2-(2-tritylamino 4-thiazolyl) 2-(2tritylamino ethoxy) imino acetic acid, syn isomer, in 40 cm3 of methylene chloride and 1.24 cm3 of triethylamine.

After agitating for 40 minutes, a solution of 1.368 g of 4-chloromethyl 3-amino 2-oxo azetidine hydrochloride in 40 cm3 of methylene chloride and 2.4 cm3 of triethylamine is added all at once; agitation is continued for 2 hours at ambient temperature, then water is added with vigorous agitation.

After decanting, re-extracting with methylene chloride, drying the organic phase, filtering and concentrating to dryness and chromatographing the residue on silica (eluent - ether), 4.9 g of the expected product is obtained. Rf = 0.8.

Stage B: Pyridinium 4-chloromethyl 3-[2-(2-tritylamino 4-thiazolyl) 2-(2-trftylamino ethoxy) imino acetamido] 2-oxo azetidine l-sulphonate A mixture of 4.9 g of the product obtained in the previous stage, 2.6 g of pyridine sulphan and 25 cm3 of dimethylformamide is agitated for four days at ambient temperature. It is then poured into 1 litre of water containing 500 cm3 of ether.

The insoluble matter is triturated, filtered, rinsed with ether, dried, and 6.6 g of the expected product is obtained. Rf = 0.4 (eluent: methylene chloride, ethyl acetate, ethanol (65-20-1 5)).

Stage C: 4-chloromethyl 3-[2-12-amino 4-thiazolyl) 2-(2-amino ethoxy) imino acetamido] 2-oxo azetidine l-sulphonic acid, cis, syn, racemic A suspension of 5.3 g of the product obtained above in 42 cm3 of formic acid with 33% water is taken to 55--600C for 12 minutes. After cooling and diluting with 30 cm3 of water, the triphenyl carbinol formed is filtered, rinsed with water and concentrated to dryness in a water-bath at 4000. The residue is taken up twice with a water-ethanol mixture, then concentrated to dryness, water is added and a saturated aqueous solution of sodium acid carbonate so as to bring the pH to a slightly alkaline value.

The insoluble matter is filtered, rinsed with water, 2N hydrochloric acid is added so as to bring the pH to 4-5. Crystallization is initiated, and after agitating for one hour, filtering, rinsing with water and then with ether, 700 mg of the expected product is obtained.

Analysis: C,1H,506N6S2CI Calculated: C % 30.95 H % 3.54 Found: 30.9 3.8 EXAMPLE 4 4-chloromethyl 3-[2-(2-amino 4-thiazolyl) 2-hydroxyimino acetamido] 2-oxo azetidine 1-sulphonic acid, cis, syn, racemic Stage A: 4-chloromethyl 3-[2-(2-tritylamino 4-thiazolyl) 2-trityloxyimino acetamidoj 2-oxo azeticllne, syn A mixture of 1.527 g of the sodium salt of 2-(2-tritylamino 4-thiazolyl) 2-trityloxyimino acetic acid and 419 mg of tosyl chloride in 15cm3 of methylene chloride is agitated for 40 minutes, then a solution of 342 mg of 4-chloromethyl 3-amino 2-oxoazetidine hydrochloride in 1 5 cm3 of methylene chloride and 0.6 cm3 of triethylamine are added.

The mixture is agitated for 2 hours, water is added, then, after agitating and decanting, it is re extracted with methylene chloride, the organic phase is dried and then filtered. The filtrate is concentrated under reduced pressure and chromatographed on silica (eluent: ether).

After evaporation of the solvent, 736 mg of condensate is recovered.

Stage B: Pyridinum 4-chlorome thyl 3-[2-(2-tritylamino 4-thiazolyl) 2-trityloxyimino acetamido] 2-oxo azetidine 1 -sulphonate A solution of 1.248 g of the product obtained as in stage A and 640 mg of pyridine sulphan (complex pyridine sulphuric anhydride) in 6.8 cm3 of dry dimethylformamide is left for 4 hours at ambient temperature.

It is then poured into 300 cm3 of ether, triturated, the insoluble matter is filtered, rinsed with ether, triturated in 10 cm3 of methanol, agitated for 1 5 minutes, filtered, rinsed with methanol and then with ether, dried, and finally 1.02 g of the expected product is obtained.

Stage C: 4-chloromethyl 3-[2 -(2 -amino 4-thiazolyl) 2-hydroxyimino acetamido] 2-oxo azetidine 1 - sulphonic acid, cis, syn, racemic A suspension of 1.02 g of the product obtained in the previous stage in 9.1 cm3 of formic acid at 66% is taken to 600C for 1 5 minutes. By operating as previously described at stage C of example 3, 119 mg of the expected product is obtained.

EXAMPLE 5 4-fluoromethyl 3-[2-(2-amino 4-thiazolyl) 2-methoxyimino acetamido]2-oxo azetidine 1-sulphonic acid, cis, syn, racemic Stage A: 4-fluoromethyl 3-[2-(2-tritylamino 4-thiazolyl) 2-methoxyimino acetamido] 2-oxo azetidine cis, syn, racemic 0.91 5 g of 2-(2-tritylamino 4-thiazolyl) 2-methoxyimino acetic acid, syn isomer, 7 cm3 of acetone and 0.319 g of tosyl chloride are mixed together. After agitating for 50 minutes at 200C, the mixture is filtered and a solution containing 0.216 g of 4-fluoromethyl 3-amino 2-oxo azetidine hydrochloride, cis, 7 cm3 of methylene chloride and 0.42 cm3 of triethylamine is added. After agitating for 45 minutes, then evaporating to dryness, water is added, the solid matter is crumbled and then separated, then triturated with acetone and separated again.The product is purified by trituration in ethyl acetate. 0.654 g of the expected product is obtained.

Analysis: C29H26O3N5SF 543.62 Calculated: C % 64.07 H % 4.82 N % 12.88 S % 5.90 F % 3.49 Found: 64.0 4.9 12.4 5.9 3.4 Stage B: 4-fluoromethyl 3-[2 -(2 -amino 4-thiazolyl) 2-methoxyimino acetamido] 2-oxo azetidine 1sulphonic acid, cis, syn, racemic a) Obtaining pyridinium sulphonate A mixture of 0.564 g of the product obtained in Stage A, 0.410 g of pyridine sulphan and 4.1 cm3 of dimethylformamide is agitated at 200C for 88 hours. It is then poured into 200 cm3 of ether, the product is separated, methanol is added, then by agitating, separating and drying the crystals obtained, 0.473 g of the expected product is obtained.

b) De-tritylation 0.470 g of the product obtained above, is put into suspension in 1.87 cm3 of formic acid with 33% of water, heated to 55--600C for 5 minutes and then to 700C for 1 3 minutes, a further 1.2 cm3 of formic acid is added and it is then heated again to 700C for 1 5 minutes. After cooling to 200C and filtering, ethanol is added to the filtrate which is then concentrated to dryness. Water and ethanol are added to the residue which is again concentrated to dryness. The residue is dissolved in water to which 1.6 cm3 of sodium bicarbonate at 10% is added.After filtering and adding 2N hydrochloric acid to pH 2, evaporating the water, triturating the residue in water, filtering, rinsing with water and then with ether and drying, 0.140 g of the expected product is obtained. M.Pt. (with decomposition) -2400C.

Analysis: CXOH1206NsS2F = 381.36 Calculated: C % 31.50 H % 3.17 N % 18.36 S % 16.81 F % 4.98 Found: 31.6 3.2 18.5 16.5 5.1 Preparation of the hydrochloride of 4-fluoromethyl 3-amino 2-oxo azetidine cis 1) N-methyl N-methoxy fluoroacetamide 27.2 g of fluoroacetyl chloride and 120cm3 of methylene chloride are mixed together, cooled to +50C under inert gas and 50 cm3 of methoxymethylamine is introduced slowly while keeping the temperature below 200C, then the whole is agitated for 2 hours at 200C. After filtering. expelling the solvent under reduced pressure and distilling the residue under reduced pressure, 30.9 g of the expected product is obtained. B.Pt23= 930C 2) fluoroacetaldehyde hydrate 7.8 g of the product obtained in the previous stage is dissolved in 1 33 cm3 of tetrahydrofuran, cooled to 0--+20C, and 74 cm3 of a 1 M solution in hexane of diisobutyialuminium hydride is introduced slowly. After allowing the temperature to return slowly to ambient, pouring into a mixture of 28 cm3 of concentrated hydrochloric acid and 56 cm3 of water while cooling, agitating and then distilling under atmospheric pressure, 38 cm3 of the expected product is obtained diluted in water.

(B.Pt.: 75 to 100.50C) 3) 4-fluoromethyl 3-phthalimido 2-oxo 1-(1-phenyl ethyl azetidine cis 69 cm3 of the solution as obtained in the previous stage is diluted in 1 00 cm3 of water. This is cooled in an ice bath for 1 5 minutes then 8.8 cm3 of a-phenyl ethylamine DL is added, with agitation for 10 minutes, filtering, rinsing with water, and then 130 cm3 of methylene chloride is added to the filtrate.

,The mixture is heated to reflux until solution is complete, cooled, decanted, the organic phase is dried then cooled under inert gas to --500C. 15.4 g of phthalimidoacetyl chloride in 60 cm3 of methylene chloride and 1 0.4 cm3 of triethylamine in methylene chloride are added slowly. The temperature is allowed to return to 200C with agitation for 1 hour. 25 cm3 of sodium bicarbonate at 10% and 60 cm3 of water are added, then by agitating, decanting, extracting with methylene chloride, joining up the organic phases and drying them, concentrating them to dryness, and chromatographing the residue on silica, eluting with methylene chloride with 1 0% of ethyl ether, 13.7 g of the expected product is obtained.

Analysis: C20H1703N2F = 352.37 Calculated: C % 68.17 H % 4.86 N % 7.95 F % 5.39 Found: 68.2 4.9 7.8 5.6 4) 4-fluoromethyl 3-phthalimido 2-oxo azetidine, cis, racemic 1 3.7 g of the product obtained in the previous stage is dissolved in 200 cm3 of acetonitrile and 130 cm3 of water is added. The mixture is taken to reflux, then over 1 5 minutes a solution of 22.2 g of ammonium persulphate in 52 cm3 of water is introduced and the whole is maintained at reflux for 1 hour 25 minutes, it is then cooled, saturated with sodium chloride, decanted, washed with a saturated aqueous solution of sodium chloride, re-extracted with ethyl acetate, the organic phases are joined together and dried and the solvent is evaporated.The residue is chromatographed on silica, eluting with a mixture of methylene chloride and ethyl acetate (75-25), the crystals obtained are rinsed with ethyl ether and 3.756 g of the expected product is obtained.

iR Spectrum (CHCI3) absorptions at 3430 cm NH) and at 1 790, 1770 and 1 725 cm-1 (C = O P lactate and phthalimido) 5) 4-fluoromethyl 3-amino 2-oxo azetidine hydrochloride cis 1.24 g of the product obtained in the previous stage is put into suspension in 1.2 cm3 of dioxan then 1 4 cm3 of a solution of 1 cm3 of hydrazine hydrate in 50 cm3 of dioxan is added. This is maintained for 45 minutes at ambient temperature then 5 cm3 of N hydrochloric acid is added and the whole is maintained under agitation for 1 5 hours.It is then concentrated to dryness, water and 2.3 cm3 of N hydrochloric acid are added, with agitation and then filtered. Ethanol is added to the filtrate which is then concentrated to dryness. Methanol is added to the residue, then ethanol and again it is concentrated to dryness. The crystals are re-crystallised from methanol.

0.391 g of the expected product is obtained. M.Pt. (with decomposition) --2200C.

EXAMPLE 6 4-fluoromethyl 3-[2-(2-amino 4-thiazolyl) 2-(1-carboxy 1-methyl ethoxy)imino acetamido]2-oxo azetidine 1-sulphonic acid, cis, syn, racemic Stage A: 4-fluoromethyl 3-[2-(2-tritylamino 4-thiazolyl) 2-( 1 -tert-butoxycarbonyl 1-methyl ethoxy)imino acetamido]2-oxo azetidine cis, syn, racemic 0.686 g of 2-(2-tritylamino 4-thiazolyl) 2-(1-tert-butoxycarbonyl 1-methyl ethoxy)imino acetic acid syn isomer, 5 cm3 of acetone and 0.17 crn3 of triethylamine are mixed together then 0.229 g of tosyl chloride is added, with agitation for 50 minutes, filtered and under agitation a solution of 0.155 g of 4-fluoromethyl 3-amino 2-oxo azetidine hydrochloride cis in 5 cm3 of methylene chloride and 0.3 cm3 of triethylamine are added to the filtrate.After agitation for 55 minutes at 200 C, the solvents are evaporated, methylene chloride and water are added, 2 cm3 of sodium bicarbonate at 10% is added with agitation. After decanting and extracting with methylene chloride, the organic phases are joined together, dried and concentrated to dryness. The residue is chromatographed on silica, eluting with ethyl ether and 0.613 g of the expected product is obtained.

The thiazol product used at the start is described in the French Application 2,421,906.

Stage B: 4-fluoromethyl3-[2-(2-amino 4-thiazolylJ 2-(1-carboxy 1-methyl ethoxy)imino acetamidol2- oxo azetidine 1-sulphonic acid, cis, syn, racemic a) Obtaining pyridinium sulphonate The product obtained at Stage A and 0.36 g of pyridine sulphan are dissolved in 3.6 cm3 of dimethylformamide.

This is agitated at 200C for 62 hours, poured into water, agitated, separated and the precipitate obtained is dried. 0.518 g of the expected product is obtained.

b) De-tritylation The product obtained at the previous stage is dissolved in 2.9 cm3 of trifluoroacetic acid, maintained at 200C for 1 5 minutes, then 29 cm3 of isopropyl ether is added and the whole is filtered.

The product is triturated in ethyl acetate for 1 5 minutes, filtered and dried then the product is dissolved in a little water containing 1 cm3 of sodium bicarbonate at 10%; it is filtered again, 2N hydrochloric acid is added to the filtrate to pH 2; it is filtered again, part of the water is evaporated, then by cooling, separating the crystals, and rinsing them with ether 0.094 g of the expected product is obtained. M.Pt.

(with decomposition) --2300C.

NMR Spectrum (DMSO ""'90 MHz) Peaks at 1.5 ppm (CH3),3.78 to 4.94 ppm (H4 and CH2F) 5.22-5.27-5.32 and 5.37 ppm (H4), 6.88 ppm (H5 thiazol syn), 9.21 and 9.31 ppm (NHOO).

EXAMPLE 7 4-thiocyanatomethyl 3-[2-amino 4-thiazolyl) 2-methoxyimino acetamido]2-oxo azetidine 1-sulphonic acid, cis, syn, racemic Stage A: 4-thiocyanato methyl 3-[2-f2-tritylamino 4-thiazolyl)2-methoxyimino acetamido]2-oxo azetidine cis, syn, racemic 3.19 g of 2-(2-tritylamino 4-thiazolyl) 2-methoxyimino acetic acid, syn isomer, is put into suspension in 50 cm3 of methylene chloride. Under agitation 1 cm3 of triethylamine and then 1.38 g of tosyl chloride are added. The whole is maintained under agitation at ambient temperature for 40 minutes then over 5 minutes, a solution of 1.162 g of 4-thiocyanatomethyl 3-amino 2-oxo azetidine hydrochloride cis, in 40 cm3 of methylene chloride and 2 cm3 of triethylamine are added.The mixture is maintained under agitation for 4 hours, washed with water, then with water containing 4 cm3 of N hydrochloric acid, dried and concentrated to dryness. The residue is dissolved in ethyl acetate, cooled, the crystals formed are separated, washed with methanol, dried and 0.709 g of the expected product is obtained. The mother liquors are evaporated to dryness, the residue is chromatographed on silica, eluting with a mixture of chloroform and methanol (93-7) and the further 1.069 g of the expected product is obtained.

Stage B: 4-thiocyanatomethyl 3-[2-(2-amino 4-thiazolyl)2-methoxyimino acetamido]2-oxo azetidine 1sulphonic acid, cis, syn, racemic a) Obtaining pyridinium sulphamate At 200C, a mixture of 1.7 g of the product obtained at Stage A, 12 cm3 of dimethylformamide and 1.16 g of pyridine sulphan is agitated for 90 hours. It is then poured into ether under agitation, the precipitate formed is taken up with methanol, cooled, then the crystals are separated. 0.544 g of the expected product is obtained in 2 lots.

b) De-tritylation 4 cm3 of formic acid with 33% of water is heated to 600C then 0.42 g of the product obtained above is added and the whole is agitated at 600C for 20 minutes. After cooling to 200 C, 40 cm3 of ethyl ether is added with agitation for 1 hour at 0--+50C. The precipitate is separated, rinsed with ethyl ether and triturated with a 0.1 N aqueous solution of sodium bicarbonate. After filtering, the filtrate is acidified to pH 2 by N hydrochloric acid, cooled and the crystals formed are separated. These are washed with water, dried and 0.237 g of the expected product is obtained. M.Pt. (with decomposition) = 2650C.

Analysis: C,1Ht2N606S3 (420.54) Calculated: C % 31.42 H % 2.88 N % 19.99 S % 22.88 Found: 31.2 3.2 19.7 22.6 Preparation of4-thiocyanatomethyl 3-amino 2-oxo azetidine hydrochloride, cis 1) 4-iodomethyl 3-phthalimido 2-oxo azetidine, cis, racemic 26.5 g of 4-chloromethyl 3-phthalimido 2-oxo azetidine, cis, 30 g of sodium iodide and 80 cm3 of dimethylformamide are mixed together, taken to 1200C for 2 hours then cooled and poured into a mixture of 800 cm3 of water and 100 cm3 of ethyl acetate under agitation. The crystals formed are filtered, rinsed with water then with ethyl acetate until colourless and finally with ethyl ether. The mother liquors are taken up, decanted, the organic phase is dried, concentrated to dryness, taken up with ethyl acetate, filtered, rinsed with ethyl acetate and dried.In this way 28.4 g of the expected product is obtained in two lots.

2) 4-thiocyanato methyl 3-phthalimido 2-oxo azetidine, cis, racemic Under agitation a mixture of 1.78 g of the product obtained above in 5 cm3 of dimethylformamide is taken to 750C then 1.5 g of potassium thiocyanate is added with agitation for 3 hours 30 minutes.

After pouring into water, the precipitate is separated, washed with water and dried. It is then triturated hot in isopropyl ether, separated and dried. 1.25 g of the expected product is obtained.

3) 4-thiocyanato methyl 3-amino 2-oxo azetidine hydrochloride, cis 1.45 g of the product obtained at the previous stage is mixed in 1 5 cm3 of hot dioxan, cooled, then 0.3 cm3 of hydrazine hydrate is added slowly with agitation at 200C for 50 minutes. Then 7.5 cm3 of N hydrochloric acid is added, the whole is maintained for 1 5 hours under agitation, the precipitate is separated, and rinsed with water; the filtrate is taken up and evaporated to dryness. 0.914 g of the expected product is obtained.

EXAMPLE 8 4-fluoromethyl 3-[2-(2-amino 4-thiazolyl) 2-difluoromethoxyimino acetamido]2-oxo azetidine 1sulphonic acid, cis, syn, racemic Stage A: 4-fluoromethyl 3-[2-(2-tritylamino 4-thiazolyl) 2-difluoromethoxyimino acetamido]2-oxo azetidine, cis, syn, racemic 0.914 g of 2-(2-tritylamino 4-thiazolyl) difluoromethoxyimino acetic acid, syn isomer, 7 cm3 of acetone and 0.25 cm3 of triethylamine are mixed together then 0.339 g of tosyl chloride is added with agitation for 50 minutes. A solution of 0.23 g of 4-fluoromethyl 3-amino 2-oxo azetidine hydrochloride, cis, in 7 cm3 of methylene chloride and 0.45 cm3 of triethylamine are then added with agitation for 1 hour 30 minutes. The solvents are evaporated, methylene chloride and water are added, then 3 cm3 of 10% sodium bicarbonate, with agitation.After decanting, extracting the aqueous phase with methylene chloride, joining the organic phases and drying them, evaporating the solvent, taking up the residue with ethanol, cooling, separating the crystals, rinsing them with ethanol and then with ether and drying them, 0.537 g of the expected product is obtained.

Stage B: 4-fluorometh yl 3-[2-(2-amino 4-thiazolyl) 2-difluoromethoxyimino acetamido] 2-oxo aze tidine 1-sulphonic acid, cis, syn, racemic a) Obtaining pyridinium sulphamate The product obtained at Stage A and 0.37 g of pyridine sulphan are dissolved in 3.7 cm3 of dimethylformamide. The solution is agitated for 72 hours at 200 C, poured into 150 cm3 of ether, filtered, washed with ether and the product is dissolved in ethanol. After agitating, filtering the crystals formed, washing them with ethyl ether and drying them, 0.506 g of the expected product is obtained.

b) De-tritylation 0.76 g of the product obtained above is mixed with 4 cm3 of formic acid with 33% of water. The mixture is taken to 600C for 1 5 minutes, diluted with water, filtered, ethanol is added to the filtrate, taken to dryness, taken up by a mixture of water and ethanol, taken to dryness again, taken up with water and 2 cm3 of 10% sodium bicarbonate is added; the insoluble material is filtered off, 2N hydrochloric acid is added to the filtrate to pH 2, which is then concentrated and allowed to crystallise.

The crystals are filtered, rinsed with water then with ethyl ether and dried, 0.312 g of the expected product is obtained.

Analysis C10H10O6N5S2F3 Calculated: C % 28.78 H % 2.41 N % 16.78 S % 13.66 F % 15.36 Found: 28.9 2.5 16.6 13.4 15.3 NMR Spectrum (DMSO) 90 MHz Peaks at 4.39 and 4.94 ppm (-CH2-F) Peaks at 5.21-5.26-5.3 and 5.35 ppm (H3 cis) Peaks at 6.38-7.15 and 7.93 ppm (-CHF2) Peaks at 7.01 ppm (H5 thiazol) Peaks at 9.66 and 9.76 ppm (-CONH) IR Spectrum (CHCI3) Absorptions at 1 770 cm-1 (C = op-lactame), 1675 cm-l (amide) 1640 cm-1 (amide 11), 1585 cm- (conjugated system) 1 530 crn-1 (thiazol), 1280-1270 cm-1 (-SO3H) and 1052 cm-1

EXAMPLE 9 4-fluoromethyl 3-[2-(2-amino 4-thiazolyl) 2-hydroxyimino acetamido]2-oxo azetidine 1-sulphonic acid, cis, syn, racemic Stage A: 4-fluoromethyl 3-[2-(2-tritylamino 4-thiazolyl) 2-trityloxyimino acetamido]2-oxo azetidine, cis, syn, racemic 0.806 g of 2-)2-tritylamino 4-thiazolyl) 2-trityloxy imino acetic acid, syn isomer, 5 cm3 of acetone and 0.17 cm3 of triethylamine are mixed together, then 0.228 g of tosyl chloride isadded. The mixture is agitated for 1 hour, then 0.1 55 g of 4-fluoromethyl 3-amino 2-oxo azetidine hydrochloride in 5 cm3 of methylene chloride and 0.31 cm3 of triethylamine are added, with agitation for 20 minutes.Methylene chloride is added again, with agitation for a further 1 hour 30 minutes, and after taking to dryness, adding methylene chloride and water, agitating, decanting, drying the organic phase, evaporating the solvent and chromatographing the residue on silica, eluting with ethyl ether, 0.598 g of the expected product is obtained.

Stage B: 4-fluoromethyl 3-[2-(2-amino 4-thiazolyl) 2-hydroxyimino acetamido]2-oxo azetidine 1sulphonic acid, cis, syn, racemic a) Obtaining pyridinium sulphonate By operating as indicated at Stage B of Example 4, starting with the product obtained at Stage A above, the expected product is obtained.

b) De-tritylation By operating as indicated at Stage B of Example 4, starting with the product obtained above, the expected product is obtained.

EXAMPLE 10 3-phthalimido 4-chloromethyl 2-oxo azetidine, cis, optically active Stage A: N-(1 -phenyl)ethyl 3-phthalimido 4-chloromethy! 2-oxo azetidine, cis, optically active 2.5 cm3 of chloroacetaldehyde hydrate at 50% in water is dissolved in 50 cm3 of water. The solution is agitated and 2.55 cm3 of (+) (1-phenyl)ethylamine is added at O--+ 50C. After agitating for 6 minutes the precipitate is separated and rinsed with water. The precipitate is taken up by a mixture of methylene chloride and chloroform and dried. The solution is cooled under inert gas at --500C, then 4.5 g of phthalimido acetic acid chloride in 25 cm3 of methylene chloride and 2.74 cm3 of triethylamine in 20 cm3 of methylene chloride are added slowly and simultaneously.After allowing the temperature to rise and maintaining under agitation for 2 hours 30 minutes, pouring into a mixture of water and sodium bicarbonate, extracting with chloroform, drying, and evaporating the solvent the residue is taken up with ethanol. The insoluble material is filtered and washed with a mixture of ethanol and methylene chloride.

The filtrate is taken up, treated with activated charcoal, concentrated and allowed to crystaliise. There is obtained, in two lots, 1.364 g of crystals. The mother liquors are taken up and chromatographed on silica, eluting with a mixture of chloroform and ethyl acetate (8-2). 1.58 g of crystals is obtained, making a total of 2.944 g of the expected product, constituted by a single diastereoisomer.

Stage B: 3-phthalimido 4-chloromethyl 2-oxo azetidine, cis, optically active 0.3 g of the product obtained at Stage A is mixed in 2 cm3 of acetonitrile and taken to 90--950C under agitation. A solution of 0.502 g of ammonium persulphate in 2 cm3 of water is added slowly with agitation for 1 hour 45 minutes, then by pouring into water, extracting with ethyl acetate, washing the organic phae with an aqueous solution of sodium thiosulphate, drying and evaporating the solvent, 0.058 g of the expected product is obtained. CgD = +10.50 + O (CHCI3) M.Pt = 17200.

By continuing the synthesis as described, for example, at Example 1, 2, 4 or 5, an optically active product corresponding to formula (I) is obtained.

EXAMPLE 11 A preparation for injection has been made up with the formula: -4-fluoromethyl 3-[2-(2-amino 4-thiazolyl) 2-methoxyimino acetamido] 2-oxo azetidine 1-sulphonic acid, cis, syn, racemic 500 mg sterile aqueous excipient 5 cm3 EXAMPLE 12 Capsules have been made up corresponding to the formula: --4-fluoromethyl 3-[2-(2-amino 4-thiazolyl) 2-methoxyimino acetamido] 2-oxo azetidine 1-sulphonic acid, cis, syn, racemic 250 mg -excipient q.s. for a capsule finishing at 400 mg PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION Activity in vitro, method of dilutions in liquid medium A series of tubes is prepared in which the same quantity of sterile nutritive medium is distributed.

There is distributed in each tube increasing quantities of the product under study, then each tube is inoculated with a bacterial strain. After incubation for twenty-four or forty-eight hoursin an oven at 37 OC the inhibition of the growth is evaluated by trans-illumination which enables the minimum inhibiting concentrations (M.l.C.), expressed in ,ug/cm3, to be determined.

The following results were obtained: Product of example 1

M.l.C. in ,ug/ml STRAINS 24 Hr. 48 Hr.

Escherichia Coli Sensitive to Tetracycline 7624 1.25 1.25 Escherichia Coli Resistant to Tetracycline AT CC 11 303 0.16 0.16 Enterobacter Cloacae 681 2.5 2.5 Escherichia Coli Resistant to Gentamycine Tobramycine R55 123 D 0.62 0.62 Klebsiella Pneumoniae Exp. 52145 1.25 2.5 Klebsiella Pneumoniae 2536 Resistant Gentamycine 2.5 2.5 Proteus mirabilis (indol-) A 235 0.16 0.16 Proteus vulgaris (indol+) A 232 0,08 0.08 Salmonella typhimurium 420 1.25 1.25 Providencia Du 48 0.62 0.62 Serratia Resistant to Gentamyci ne 2 532 5 5

M.l.C. in llg/ml Product of Product of example 3 example 4 STRAINS 24 Hr. 48 Hr. 24 Hr. 48 Hr. Escherichia Coli Sensitive to Tetracycline 7624 1.2 1.2 0.6 0.6 Escherichia Coli Resistant to Tetracycline AT CC 11 303 0.6 0.6 0.6 0.6 Escherichia Coij Resistant to Gentamycine Tobramycine R 55123 D 1.2 1.2 0.6 0.6 Klebsiella Pneumoniae Exp. 52 145 5 10 5 5 Klebsiella Pneumonia 2 536 Resistant Gentamycine 2.5 2.5 2.5 2.5 Protus mirabilis (indol-) A 235 0.6 0.6 0.6 1.2 Proteus vulgaris (indol+) A 232 1.2 1.2 0.6 0.6 Salmonella typhimurium 420 2.5 5 1.2 2.5 Providencia Du 48 2.5 2.5 0.6 1.2 Serratia Resistant to Gentamycine 2 532 2.5 5 5 5

Product of example 5

M.l.C. in g/ml Strains 24 Hr. 48 Hr Pseudomonas aeruginosa 1771 m 0.6 1.2 Escherichia coli UC 1894 #0.04 ,0.04 Escherichia coli 078 0.15 0.15 Escherichia coli TEM 0.15 0.15 Escherichia coli 1507 E 0.15 0.15 Escherichia coli DC 0 0.3 0.3 Escherichia coli DC 2 0.15 0,3 Salmonella typhimurium MZ 11 0.08 0.08 Klebsiella pneumoniae Exp. 52 145 0.3 0.3 Klebsiella aerogenes 1082 E 5 5 Klebsiella aerogenes 1522 E 0.15 0.15 Enterobacter cloacae 1321 E 0.08 0.08 Serratia RG 2532 0.06 1.2 Proteus mirabilis (indol -) A 235 0.08 0.08 Proteus vulgaris (indol +) < 0.04 < 0.04 A 232 Providencia Du 48 0.3 0.3 Product of example 6

M.I.C. in g/ml Strains 24 Hr. 48 Hr.

Pseudomonas aeruginosa 1771 m 0.3 0.6 Escherichia coli UC 1894 0.08 0.08 Escherichia coli 0 78 0.3 0.3 Escherichia coli 0.6 0.6 TEM Escherichia coli 1507 E . 0.6 0.6 Escherichia coli 0.6 0.6 DC 0 Escherichia coli DC 2 0.3 0.3 Salmonella typhimurium MZ 11 0.6 0.6 Klebsieila pneumoniae Exp. 52 145 0.6 0.6 Klebsiella aerogenes 1082 E 0.6 0.6 Klebsiella aerogenes 1522 E 0.3 0.3 Enterobacter cloacae 1321 E 0Q3 0.3 Serratia RG 2 532 0.3 0.3 Proteus mirabilis (indol -) A 235 #0.04 40.04 Proteus vulgaris (indol +) A 232 Xû.04 < 0.04 Providencia Du 48 0.15 0.15 Product of example 8

M.I.C. in lig/ml Strains 24 Hr, 48 Hr.

5 5 Escherichia coli UC 1894 .04 0.08 Escheltichia coli 078 0.08 0.08 Escherichia coli TEM 0.15 0.15 Escherichia coli 1507 E o.04 Escherichia coli DC 0 0.08 0.08 Escherichia coli DC 2 XO.Q4 < 0.04 Salmonella typhimurium MZ 11 0.08 0.08 Klebsiella pneumoniae Exp. 52 145 0.3 0.3 r Klebsiella aerogenes 1522 E 0.08 0.08 Enterobacter cloacae 1321E 0.08 0.08 1321 E 0.08 0.08 Serratia RG 2532 0.6 0.6 Proteus mirabilis (indol -) A 235 40.04 40.04 Proteus vulgaris (indol +) A 232 < 0.04 < 0.04 Providencia Du 48 0.3 0.3

Claims (33)

1. A compound which is an azetidine of formula (I):

or a salt thereof, in which R represents a hydrogen atom or a linear or branched, alkyl, alkenyl, or alkynyl, radical having at most 1 2 carbon atoms, which radical is optionally substituted; R1 represents a radical -(CH2)-X; in which n represents an integer from 1 to 4; and X represents a halogen atom; a cyano radical; a radical O--R', in which R' represents a hydrogen atom or an alkyl radical; or X represents a radical S-R"1 in which R"1 represents a hydrogen atom, an alkyl radical or a heterocyclic radical; or X represents a radical

in which R' and R" are the same or different and each represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R' and R" together with the nitrogen atom to which they are attached form a heterocyclic radical; or X represents an azido, a thiocyanato or an isothiocyanato radical; and the wavy line indicates that the compound is in its cis or trans form or in the form of a cis-trans mixture; the oxime group in the compound being in the syn form, and the compound being in the racemic or an optically active form.

2. A compound which is an azetidine of formula (I'):

syn isomer, in the cis form, in which R2 represents a hydrogen atom or a linear or branched alkyl radical containing up to 1 2 carbon atoms, which radical is optionally substituted by one or more substituents selected from halogen atoms and carboxyl, amino and cyano radicals; n' represents the integer 1 or 2; and X' represents a fluorine atom, a 2-pyridinylthiomethyl radical or a thiocyanato radical; the azetidine being in the racemic or an optionally active form; or a salt of this azetidine.

3. A compound according to claim 2 wherein n' represents the number 1 and X' represents a fluorine atom.

4. A compound according to claim 2 or 3 wherein R2 represents a hydrogen atom or a methyl or difluoromethyl radical, an optionally esterified or salified carboxymethyl radical, an aminoethyl or cyanomethyl radical, or an optionally esterified or salified 1 -methyl-1 -carboxyethyl radical.

5. A compound according to claim 1 substantially as described herein.

6. A compound according to claim 1 which is an azetidine of formula (I) which is specifically identified herein.

7. A salt of the azetidine claimed in claim 6.

8. 4-fl uoromethyl-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxo-azetidine-1 - sulphonic acid, cis, syn isomer, racemic or optically active, or a salt thereof.

9. 4-fluoromethyl-3-[2-(2-amino-4-thiazolyl)-2-difluoromethoxyiminoacetamido]-2-oxo- azetidine-1 -sulphonic acid, cis, syn isomer, racemic or optically active, or a salt thereof.

10. Process for the preparation of a compound claimed in any one of the preceding claims, which process comprises reacting an amine of formula (all):

racemic or optically active, in which formula either Ra represents R1, R, being as defined in claim 1, or Ra represents R, in which the reactive functions are protected, and A represents a hydrogen atom or a sulpho radical, with an acid of formula (III):

or an acid functional derivative thereof, in which Rb represents a hydrogen atom or a protective group for the amino radical, and R'b represents a protective group for the hydroxyl radical or R'b represents R, R being as defined in claim 1, or R' b represents a radical R whose reactive functions are protected, so as to obtain an azetidine of formula (IV)::

racemic or optically active, in which Rb, R'b, Ra and A are as defined above, which azetidine if desired is submitted to any one or more of the following reactions in any order: a) separation by hydrolysis, hydrogenolysis or by the action of thiourea of the protective group or groups which Rb and R'b can represent or R'b and Ra can contain, b) esterification or salification of the carboxy radical which the radical R'b can contain or salification of the sulpho radical which A can represent, c) salification by an acid of the amino radical or radicals, d) sulphonation of the azetidine in which A represents a hydrogen atom, e) resolution of the molecule so as to obtain an optically active product.

11. Process according to claim 10 wherein an amine of formula (II) in which A represents a hydrogen atom is reacted with an acid of formula (III) in which Rb represents a protective group for the amino radical to produce an azetidine of formula (IV) in which Rb represents a protective group for the amino radical, and this azetidine of formula (IV) is sulphonated.

12. Process according to claim 10 or 11 wherein the amine of formula (II) is prepared by reacting an imine of formula (V):

in which Ra is as defined in claim 10 and Rp represents a protective group for the imino radical, with a protected amine of formula (VI):

in which one of R' and R"p represents a hydrogen atom and the other a protective group for the amino radical, or R' and R" together represent a divalent protective group, and B represents a hydroxyl radical or a halogen, so as to produce an amine of formula (VII):

in which Rat Rp, R' and Rttp are as defined above, which amine of formula (VII) is submitted to the following reactions:: a) separation by hydrolysis, hydrogenolysis or the action of thiourea of the radical R p; b) optional sulphonation of the amine in position 1; c) separation by hydrolysis, hydrogenolysis or the action of thiourea of the protective radicals R' p and R" p; and d) optional resolution of the molecule so as to obtain an optically active product.

1 3. Process according to claim 1 2 wherein in formula (V) Rp represents a protective group for the imino radical including an asymmetric carbon atom and an amine of formula (VII) is isolated in optically active form.

1 4. Process according to any one of claims 1 0-13 wherein Ra represents a fluoromethyl radical.

15. Process for preparing a compound claimed in any one of claims 1-9, which process is performed substantially as described herein.

16. Process for preparing a compound claimed in any one of claims 1-9, which process is performed substantially as described herein in any one of Examples 1-10.

1 7. A pharmaceutical composition comprising a pharmaceutically acceptable excipient together with a compound which is an azetidine claimed in any one of claims 1-6, 8 and 9 or a pharmaceutically acceptable salt thereof.

1 8. A composition according to claim 1 7 in the form of compressed tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams or gels.

1 9. A composition according to claim 1 7 which is solid.

20. A composition according to claim 17 wherein the excipient is talc, gum arabic, lactose, starch, magnesium stearate, a fatty substance of animal or vegetable origin, a paraffin derivative or a glycol.

21. A composition according to claim 1 7 which contains a wetting, dispersing or emulsifying agent or a preservative.

22. A composition according to claim 17 substantially as described herein.

23. A pharmaceutical composition substantially as described herein in Example 11 or 12.

24. A composition claimed in any one of claims 1 7-23 for use in a method of treatment of the human or animal body by therapy.

25. For use in a method of treatment of the human or animal body by therapy, an azetidine claimed in any one of claims 1-6, 8 and 9 or a pharmaceutically acceptable salt thereof.

26. For use in a method of treatment of the human or animal body by therapy, 4-fluoromethyl-3- [2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamidoj-2-oxo-azetidine- 1 -sulphonic acid, cis, syn isomer, racemic or optically active, or a pharmaceutically salt thereof.

27. For use in a method of treatment of the human or animal body by therapy, 4-fluoromethyl-3- [2-(2-am ino-4-thiazolyl)-2-difl uoromethoxyiminoacetamido]-2-oxo-azetidine- 1 -sulphonic acid, cis, syn isomer, racemic or optically active, or a pharmaceutically acceptable salt thereof.

28. A compound or composition claimed in any one of claims 24-27 substantially as described herein.

29. A compound or composition claimed in any one of claims 24-27 substantially as described herein in any one of the Examples.

30. An azetidine of formula (IV):

in which Rb, R'b, A and Ra are as defined in claim 1 0.

31. An amine of formula (all):

in which A and Ra are as defined in claim 10, with the proviso that when A represents a hydrogen atom, Ra cannot represent a methylthio, hydroxymethyl, azidomethyl, aminomethyl or alkoxymethyl radical.

32. A process for preparing an azetidine claimed in claim 30, which process is performed substantially as described herein.

33. A process for preparing an amine claimed in claim 31, which process is performed substantially as described herein.