CH655317A5 - DERIVATIVES OF 3-AMINO 2-OXO AZETIDINE 1-SULFONIC ACID, THEIR PREPARATION, MEDICAMENTS AND COMPOSITIONS CONTAINING THEM. - Google Patents

Description

The present invention relates to new compounds derived from 3-amino-2-oxo-azetidine-1-sulfonic acid, their preparation process and the medicaments and compositions containing them.

2o The subject of the invention is the compounds of general formula (I):

nh.

25

h2N

(II)

in which A and Ra have the meaning indicated in claim 6, it being understood that when A represents a hydrogen atom, Ra cannot represent a methyl-thio, hydroxymethyl, azidomethyl, aminomethyl or alko-xymethyl radical.

AT

'C0NH \ 3_VR1

\

or oJrk

(i)

s03h 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, Ri 35 represents a radical - (ch2) nX in which n represents a number integer from 1 to 4 and X represents a halogen atom, a cyano radical, an O-R'i radical in which R'i represents a hydrogen atom or an alkyl radical, or X represents an SR "i radical in which R "i represents a hydrogen atom an alkyl radical or a heterocycle or X represents a radical

-N ^ R

in which R 'and R "represent a hydrogen atom or an alkyl radical having from 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 iso-thiocyanato radical, as well as the salts of the compounds of formula (I) with bases or acids, the wavy line signifying that the 50 products can be in the eis or trans form or in the form of 'a cis-trans mixture, the compounds of formula I being in racemic or optically active form, the oxime being in syn form.

Among the values of R we can cite:

55 a) The methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, sec-pen-tyle, tert-pentyl, neo-pentyl, hexyl, iso-hexyl radicals -hexyl, tert-hexyl, heptyl, octyl, decyl, undecyl, dodecyl;

b) vinyl, allyl, 1-propenyl, butenyl, penté-60 nyle, hexenyl radicals;

c) ethynyl, propargyl, butynyl radicals.

The radicals indicated above in paragraphs a) to c) may themselves be substituted by one or more radicals such as optionally salified or esterified carboxy radicals, alkoxycarbonyl such as methoxycarbonyl, ethoxy-carbonyl, carbamoyl, dimethyl-carbamoyl, amino, di-alky-lamino such as dimethyl-amino, diethylamino, alkylamino such as methylamino, halogen such as chlorine, bromine, iodine, fluorine,

655,317

4

alkoxy such as methoxy, ethoxy, propyloxy, alkylthio such as methylthio, ethylthio, aryl such as phenyl, or heterocyclic aryl such as tetrazolyl, pyridinyl, arylthio such as phe-nylthio optionally substituted, heterocyclic-thio aryl such as tetrazolylthio, optionally substituted by an alkyl such as methyl.

Among the values of R, there may be mentioned more particularly the hydrogen, methyl, optionally esterified or salified carboxy ethyl, 1-carboxy-1-methyl-ethyl optionally esterified or salified, 2-amino-ethyl, difluoromethyl values.

Among the Ri values, 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 and fluoromethyl. Mention may also be made of cyanomethyl, cyanoethyl and the corresponding alkyl radicals.

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

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

Among the heterocycles which R "i can represent, mention may be made of the pyridyl, 1,2,3-1,2,5-1,2,4 or 1,3,4-thiadiazo-lyl radicals; 1H tetrazolyl, 1, 3-thiazolyl, 1,2,3-1,2,4 or 1,3,4-triazo-lyle; 1,2,3-1,2,4 or 1,2,5 or 1,3,4- oxidiazolyl, these radicals being unsubstituted or substituted by one or more radicals chosen from the group formed for example by the methyl, ethyl propyl, isopropyl, methoxy, ethoxy, propyloxy, isopropyloxy, amino, hydroxycarbonylmethyl, dime-thylaminoethyl and diethylaminoethyl radicals.

Mention may more particularly be made of the 1-methyl-tetrazolyl, 2-methyl-1,3,4-thiadiazolyl, 3-methyl-1,2,4-thia-diazolyl, 3-methoxy-1,2,4-thiadiazolyl radicals , 1,3,4-thiadiazol-5-yl and more especially the 1-methyl-tetrazolyl radical.

The radical ".

-N ^ "R" ^ R "

may especially represent an amino, dimethyla-mino, methylamino, ethylamino, diethylamino, piperidino, morpholino radical.

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

Among the salts which can be prepared, mention may be made of the sodium, potassium, lithium, calcium, magnesium, ammonium salts. Mention may also be made of organic base salts such as trimethylamine, diethylamine, triethylamine, methylamine, propylamine, N, N-dimethyl-etha-nolamine, tris- (hydroxymethyl) -aminomethane, ethanol-amine, pyridine, picoline, dicyclohexylamine, N ', N'-dibenzylethylenediamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methyl glucamine.

The compounds of formula I can be in the form of salts of organic or mineral acids since these products contain at least one salifiable amino radical.

Among the acids with which the amino groups of the compounds of formula I can be salified, mention may be made, inter alia, of acetic, trifluoroacetic, maleic, tartaric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, hydrochloric, hydrobromic, sulfuric acids. , phosphori-que. The compounds of formula I can also be in the form of internal salts.

The preferred compounds are the eis compounds.

A more particular subject of the invention is the compounds of general formula I '

nh.

AT

CONH / \

Ifr

\

; CH2) n., X '

(I ')

\ NOT

0Ro er \

so3h

syn isomers, in the eis form, in which R2 represents a hydrogen atom or a linear or branched alkyl radical optionally substituted by one or more halogen atoms, a carboxyl, amino or cyano radical, n 'represents the integer 1 or 2 and X ′ represents a fluorine atom, a 2-pyridinylthiomethyl radical or a thiocyanato radical,

in racemic or optically active form, as well as the salts of the compounds of formula (I ') with bases or acids.

A more particular subject of the invention is also the compounds of general formula (I ') as defined above, 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, difluoromethyl, carboxymethyl radical optionally salified or esterified, an aminoethyl, cyanomethyl, 1-methyl-1-carboxy-methyl radical, optionally salified or esterified.

A more particular subject of the invention is the compounds described below in the examples and especially the 4-fluoromethyl-3- / 2- (2-amino-4-thiazolyl) 2-methoxyimino-acetamido / 2-oxo acid -azetidine-1-sulfonic eis, syn, racemic or optically active isomer and its salts, as well as 4-fluoromethyl-3- / 2- (2-amino-4-thiazolyl) 2-difluoromethoxy-imino-acetamido / 2-oxo-azetidine-1-sulfonic eis, syn, racemic or optically active isomer and its salts.

It is understood that the aforementioned compounds of formula I can be present, either in the form indicated by said formula I, or in the tine imine form Iz:

45

GOLD

r ^ 1

dz)

&

% 03H

The lactam nucleus is numbered as follows \ 4

55

CT2 T ^ SO ^ H

The products called eis are the products of formula: \

0 ^ "

^ S03H

Trans products are formula products:

\ <? 1

-NOT.

'S0, H

5

655,317

The invention also relates to a process for the preparation of products of general formula I as defined above, characterized in that a product of formula II is treated

h2n.

0 ^

(II)

Neither racemic nor optically active, formula in which either Ra represents Ri, Ri having the meaning indicated above, or Ra represents Ri in which the reactive functions are protected and A represents a hydrogen atom or a sulfo radical, by a product of formula III

n hr.

(III)

wherein Rb represents a hydrogen atom or a protecting group for the amino radical and R'b represents a protecting group for 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:

nhr.

(iv)

racemic or optically active, in which Rb, R'b, Ra and A have the previous meaning, product which is subjected if necessary, and if desired, to any one or more of the following reactions, in any order:

a) cleavage by hydrolysis, hydrogenolysis or by the action of thiourea of the protective group or groups which may represent Rb and R'b or include R'b and Ra;

b) esterification or salification of the carboxy radical which the radical R'b may comprise and salification of the sulfo radical;

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

d) sulfonation of the products in which the radical A represents a hydrogen atom;

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

In formula II, Ra can generally represent the radical Ri. However, in the cases where Ri 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 protective groups.

The protecting groups of the amino radical can be, for example, alkyl radicals, preferably tert-butyl or tert-amyl, they can also be understood by means of acyl, aliphatic, aromatic or heterocyclic groups and the carbamoyl group.

Mention may also be made of lower alkanoyl groups such as, for example, formyl, acetyl, propionyl, buty-ryle, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl,

pivaloyl. Rb can also represent a lower alkoxy or cycloalkoxycarbonyl group such as, for example, methoxy-carbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopro-pylethoxycarbonyl, isopropyloxycarbonyl, butyloxycarbo-nyl, tert-butyloxycarbonyl, pentyloxycarbonyl, hexyloxy-carbonyl, toluolyl, naphthoyl, phta-loyle, mesyl, phenylacetyl, phenylpropionyl, an aralkoxycarbonyl group, such as benzyloxycarbonyl.

The acyl groups can be substituted, for example, with a chlorine, bromine, iodine or fluorine atom. Mention may be made of the chloroacetyl, dichloroacetyl, trichlo-roacetyl, bromoacetyl or trifluoroacetyl radicals.

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

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

It is also possible to use a chloroben-zoyl, para-nitrobenzoyl, para-tert-butylbenzoyl, phenoxya-2o cetyl, caprylyl, n-decanoyl, acryloyl, trichloroethoxycarbonyl group.

One can also use a methylcarba-moyle group, phenylcarbamoyl, naphthylcarbamoyl, as well as the corresponding thiocarbamoyl.

The above list is not exhaustive, it is obvious that other protective groups for amines, groups known in particular in peptide chemistry, can also be used.

The hydroxyl protecting group can be chosen from the list below.

It can be an acyl group such as for example formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichlo-roacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl. Mention may also be made of the groups ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, ßßß-trichloroöthoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 1-cyclopropylethoxycarbo-nyl, tetrahydropyrannyl, tetrahydrothropyrannyl, methyrhyrethyethyl, methohyryethyl, trichlorothyryryethyl, tetrahydrothiopyrannyl, tetrahydrothiopyranyl, tetrahydrothyryryl trichloroethyl, 1-methyl-1-methoxyethyl, phthaloyl.

Mention may also be made of other acyls such as propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl.

45 Mention may also be made of the phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, paranitrobenzoyl, paratertbutylbenzoyl, caprylyl, acryloyl, methylcarba-moyle, phenylcarbamoyl and naphthylcarbamoyl radicals.

Of course, the values of the substituents Rb when so it does not represent a hydrogen atom, as well as the values of the protective groups which may optionally represent or contain R'b, in particular when R'b comprises an amine, can be taken from 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.

60 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 sulfonic anhydrides formed, for example, with paratoluenesulfonyl chloride. As an example of activated ester 65, there may be mentioned the ester formed with 2,4-dinitro-phenol and that formed with hydroxybenzothiazole.

As an example of a halide, mention may be made of chloride or bromide.

655,317

6

Mention may also be made of the acid azide or the acid amide.

The anhydride can be formed in situ by the action of an NN'-disubstituted carbodii-mide, for example N, N-dicyclohexylcar-bodiimide.

The acylation reaction is preferably carried out in an organic solvent such as methylene chloride. It is however possible to use other solvents such as tetrahy-drofuran, chloroform or dimethylformamide.

When an acid halide is used and generally when a hydrochloric 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, sodium or potassium acid carbonates and carbonates, sodium acetate, triethylamine, pyridine, morpholine or N-methylmorpholine.

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

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

Depending on the values of Rb, R'b and Ra, the products of formula (IV) may or may not constitute products of formula (I).

The products of formula (IV) constitute products of formula (I) when Rb represents a hydrogen atom, when R'b does not represent a group protecting the hydroxyl radical or does not represent a radical R comprising a protected function, finally when Ra does not represent a radical Ri in which a reactive function is protected and that A does not represent a hydrogen atom.

In the other cases, the action on the product of formula (IV) of one or more hydrolysis, hydrogenolysis or thiourea agents is intended to eliminate the radical Rb when the latter represents a protective radical of the amino radical, to eliminate the radical R'b when the latter represents a protective group for the hydroxyl radical and to eliminate the other protective groups which the radicals Ra 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.

A non-exhaustive list of the means that can be used to eliminate the various groupings is given below.

The elimination of the Rb group can be carried out by hydrolysis, this being acidic, basic or using hydrazine.

Acid 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, diphenylmethyl, tert-butyl or 4- methoxy-benzyl.

The acid which is preferably used can be chosen from the group consisting of hydrochloric, benzene sulphonic or paratoluene sulphonic, formic or trifluoroacetic acids. However, other mineral or organic acids can be used.

Basic hydrolysis is used with advantage to eliminate acyl groups such as trifluoroacetyl.

The base which is preferably used is an inorganic base such as sodium or potassium hydroxide. It is also possible to use magnesia, baryte or an alkali metal carbonate or acid carbonate such as sodium or potassium acid carbonates and carbonates or other bases.

Sodium or potassium acetate can also be used.

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

The Rb group can also be eliminated by the zinc-acetic acid system (for the trichloro-5-thyle group), the diphenylmethyl and 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 J.A.C.S. Masaki, 90.4508 (1968).

One can also use other deprotection methods known in the literature, for example oxidative cleavage, for example the benzyl group.

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

The acid which is preferably used is trifluoro-roacetic acid or formic acid.

The elimination of the radical R'b or of the protective groups which comprise R'b or Ra, when this is necessary, is carried out under conditions similar to those described above for the elimination of Rb.

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

Preferably, an acid chosen from the group formed by hydrochloric, formic, trifluoroacetic and paratoluene sulfonic acids is used.

The other values of the radicals Rb or R'b or of the protective groups which comprise R'b or Ra are, when desired, eliminated according to methods known to those skilled in the art. It is preferably carried out under moderate conditions, that is to say, at room temperature or with slight heating.

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

The salification of the products can be carried out according to the 40 usual methods.

Salification can, for example, be obtained by action on a product in acid form or on a solvate, for example the ethanolic solvate, or a hydrate of this acid, of a mineral base such as sodium or potassium hydroxide , sodium or potassium carbonate or acid carbonate. It is also possible to use the salts of mineral acids such as trisodium phosphate. It is also possible to use salts of organic acids.

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

Sodium acetate, sodium 2-ethylhexanoate or sodium diethyl acetate are preferably used as the sodium salts.

Salification can also be obtained by action 55 of an organic base or an amino acid.

The optional esterification of the products in which R contains an acid function is also carried out under conventional conditions.

The sulfonation of the products of formula IV in which A so represents a hydrogen atom is generally carried out using sulfuric anhydride or a reactive derivative of this anhydride.

Preferably the sulfuric anhydride pyridine complex is used, but other sulfuric anhydride complexes with dioxane or trimethylamine can also be used.

The reaction is carried out in a usual solvent such as ethyl acetate, chloroform or dimethylformamide. We can operate at room temperature. When using the

7

655,317

pyridine-sulfuric anhydride complex, products can be isolated in the form of pyridinium salts.

Any duplication of the racemic molecules of formula II or IV can be carried out according to the usual methods.

It is possible to use an optically active organic carboxylic or sulphonic acid such as tartaric, diben-zoyl tartaric, camphosulphonic or glutamic acids, the decomposition of the salt thus obtained being carried out by means of a mineral base such as sodium carbonate or an organic base such as a tertiary amine, for example triethylamine.

The present invention relates specifically to a process as described above, characterized in that one uses, for its implementation, a product of formula II in which A represents a hydrogen atom and a product of formula III in wherein Rb represents a protective group for the amino radical and in that the sulfonation is carried out on a product of formula IV in which Rb represents a protective group for the amino radical.

The protective group which Rb represents is preferably the trityl radical.

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

To prepare the compounds of formula II, one can proceed as follows. We act a product of formula V

H / K

V

ilr

NOT

(v)

in which Ra has the meaning indicated above and Rp represents a group protecting the imino radical, with a product of formula VI:

R "

"Ni -CH-COB

/ 2

(VI)

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

RV

(VII)

in which Ra, Rp, R'p and R "p have the above meaning, product of formula VII which is subjected to the following reactions:

a) Cleavage by hydrolysis, hydrogenolysis or action of the thiourea of the radical Rp;

b) Possible sulfonation of the amine in position 1;

c) Cleavage by hydrolysis, hydrogenolysis or action of the thiourea of the radicals R'p and R "p;

d) Possible splitting of the molecule to obtain an optically active product.

The protective group Rp can be chosen from the list of substituents set out above for the amines.

For reasons explained below, it is nevertheless preferred to use a benzyl or 2,4-dimethoxy-benzyl radical or equivalent.

In addition, the protective group Rp may contain an asymmetric carbon atom. In this case, a process as defined above is applied, in which a product of formula (V) is used at the start in which Rp represents a group protecting the imino radical comprising an asymmetric group and isolates a product of formula ( VII) in optically active form.

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

As a protective group, mention may in particular be made of the 1-phenylethyl group.

i5 An example of preparation of an optically active product of formula (VII) is given below in the experimental part.

The radicals R'p and R "p can be chosen from the same list of protective radicals set out above. It is preferred to use the phthaloyl radical.

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

When B represents a halogen atom, the action of product V on 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 operation 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 preferably gives the products eis. Trans products are obtained by isomerization in basic medium.

The aim of the first deprotection reaction is, when it is desired to carry out the sulfonation of the resulting products, the selective unblocking of the radical Rp.

It is therefore preferable to use, as indicated above, a benzyl or di-methoxy benzyl radical which is released using, preferably, an oxidizing agent such as potassium peroxodisulfate.

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

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

The purpose of the possible second unblocking operation is to release 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, elimination is carried out, as indicated above, preferably by hydrazine a hydrazine hydrate in a solvent such as dimethylformamide 5o Of course, in particular in the case where the sulfonation of the products of formula is not carried out IV, the radicals RP, R'p and R "p can be eliminated simultaneously.

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

55 It is also possible to prepare products of formula (IIa):

^ (CH2) nX "

(n / A)

cr in which A has the meaning indicated above, n represents an integer from 1 to 4 and X "represents X, X having the meaning indicated above, with the exception of a halogen atom, ie X "represents X in which a reactive function is protected, by a process according to which a product of formula VI 11 is treated:

655,317

8

R '

^ CH2) nHal

(VIII)

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

"nrii>

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

R'_

> R "_ />

(IX)

in which X ", A, R'q and R" q have the values indicated above, product which 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 these are different from a hydrogen atom;

b) Sulfonation of 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 derivatives of the radicals which it is desired to substitute for the halogen atom is carried out under the usual conditions.

The exchange between the halogen atom and a mercaptan, for example, is preferably carried out using 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, possibly protected by one of the radicals indicated above, makes it possible to introduce a radical

-R '

-R "

-Born

possibly protected.

An alkali metal azide, preferably sodium azide, can be acted upon to introduce the azido radical. It is also possible to act on a cyanide or an alkali metal thiocyanate to obtain the products in which X represents these radicals or an isothiocyanate.

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

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

The products of general formula (I) have very good antibiotic activity on gram (-) bacteria, in particular on coliform bacteria, klebsiella, Salmonella and proteus.

These products can in particular be used as medicaments in the treatment of colibacillosis and associated infections, in proteus, klebsiella and

Salmonella and other conditions caused by gram (-) bacteria.

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

The subject of the invention is particularly, as medicaments and in particular antibiotic medicaments, the products of formula (I '):

10

f2

A w

Y

V

onhv „(ch2) r, x '

or2 o

(X1)

S03H

syn isomers, in the eis form, in which R2 represents a hydrogen atom or a linear or branched alkyl radical 20 optionally substituted by one or more halogen atoms, a carboxyl, amino or cyano radical, n 'represents the whole number 1 or 2 and X ′ represents a fluorine atom, a 2-pyridinylthiomethyl radical or a thiocyanato radical,

in racemic or optically active form, as well as the salts of the products of formula (I ') with pharmaceutically acceptable bases or acids.

A more particular subject of the invention is also, as medicaments and in particular antibiotic medicaments, the products of formula (I ') as defined above, in which n' represents the number 1 and X 'represents a fluorine atom, as well as their salts with pharmaceutically acceptable bases or acids, and the products of formula (I ') as defined above, in which R2 represents a hydrogen atom or a methyl radical, difluoro- 35 methyl, optionally salified or esterified carboxymethyl, an aminoethyl, cyanomethyl, 1-methyl-1-carboxy-methyl radical optionally salified or esterified, as well as their salts with pharmaceutically acceptable bases or acids.

A more particular subject of the invention is also, "as medicaments and in particular antibiotic medicaments, the products described in the examples and especially 4-fluoromethyl-3- / 2- (2-amino-4-thiazolyl) acid -2-methoxyiminoacetamido / 2-oxo-azetidine-1 -sisonic eis, syn, racemic or optically active isomer and its maceutically acceptable phar-45 salts, as well as 4-fluoromethyl-3- 3- [2- (2 -amino-4-thiazolyI) -2-difluoromethoxyimino-acé-tamido] 2-oxo-azetidine-1-sulfonic acid, syn, racemic or optically active isomer and its pharmaceutically acceptable salts.

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

These compositions can be administered by buccal, rectal, parenteral route or by local route in topical application on the skin and the mucous membranes.

They can be solid or liquid and come in the pharmaceutical forms commonly used in human medicine such as, for example, tablets, simple or coated, capsules, granules, suppositories, pre-injectable drugs, ointments, creams , gels; they are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually used 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.

9

655,317

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

The dose administered is variable depending on the condition treated, the subject in question, the route of administration and the product considered. It can be, for example, between 0.250 g and 4 g per day, orally in humans, with the product described in Example 1, or even between 0.500 g and 1 g three times a day, intramuscular route. io

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

Also new are the compounds of general formula (IV): NHR.

AT

S N

\ - / com.

NOT\

OR 'b

R

X a

(IV)

\

25

in which Rb, R'b, A and Ra have the meaning indicated above, as well as the compounds of formula (II):

H0N d, R

2 N ^ a

AT

(he)

in which A and Ra have the meaning indicated above, it being understood that in said formula (II), when A represents a hydrogen atom, Ra cannot represent a methylthiol, hydroxymethyl, azidomethyl, amino-methyl or alkoxymethyl radical . The compounds of formula (II) form part of the invention as a means for implementing the claimed process.

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 RpNHl.

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 which can be obtained in the context of the present invention; the substituents X, R, A and Ri are those indicated in formula (I).

35

40

45

r v

r r1

-ck2CH3

-ch2ci

- (ch2) 3br

-ch2c1

- (ch2) 2ch3

-ch2c1

- (ch2) 2i

-ch2ci

-ch (ch3) 2

-ch2ci

-hgc-cïch

-ch2c1

"nc4h9

-ch2ci

-hc = ch2

-ch2ci

-ch2-ch = ch2

-ch2c1

- (ch2) 2-n ^

-ch2ci

-ch2co2h

-ch2c1

- (ch2) 2-nqnch3

-ch2ci

- £ -c02h

-ch2c1

- <ch2> 2 <>

-ch2ci

55

60

r r1

r

* 1

-c (ch3) 2c02h

-ch2c1

-ch2g-n (ch3) 2

-chgcl

-ch-co2h ch3

-ch2c02c2h5

-ch2ci

-ch2-ch2-h (ch3) 2

-ch2c1

-ch2ci h

-ch20ch3

-CH2C02tBu

-ch2cx

CH3

-chgochj

-ch-c02h 2h5

-c (ch3) 3

-ch2c1 -ch2c1

-ch2ch2nh2 -ch2co2h

-chgochj

-ch2och3

-ch2-ch = ch-co2h

-ch2c1

-c (ch3) 2co2h

-ch2och3

-ch-co2h

-chgch

-ch2ci

-ch2c1

-CH2CH2Br

-ch2ch2x

-chjochj -chgqchj

- (ch2) 2ch

-chgcx

-ch2co2c2h5

-ch2och3

-ch2-c0nh2

-ch2c1

-CH2C02tBu

-ch2och3

- (ch2) 2 ep

-ch2ci

-c (ch3) 2co2c2h5

-ch2och3

- (ch2) 2v1

-ch2ci

-C (CH3) 2C02tBu

-ch2och3

-ch2ch3

-CHgBr

- (CH2) 5Br

-ch2BV

- (ch2) 2ch3

-CHgBr

- (ch2) 2i

-ch2br

-cn {cn3) 2

-CHgBr

-h2c-cSch

-CH2Br

-nc4h9

1

-CHjBr

-hc = ch2

-CH2Br

-ch2-ch = ch2

-CHgBr

- (ch2) 2- ^ ô)

-CH2Br

-ch2c02h

-CHgBr

- (ch2) 2-n ^) ich3

"ch23r

-% - co2h

-ch23r

- (ch2) 2-nq)

-CH2Er

-cfch ^ îgcogh

-CH2Br

-ch2g-n (ch3) 2

-CH2Br

- £ h-c02h

_CH2 Br

-ch2-ch2-n (ch3) 2

-CH2 Br

-ch2c02c2h5

-CH2Br

VS%

-CHzBr

-CH2C02tBu

-CH2Br

-ch2ch2nh2

-CH2Br

-ch-c02h

-CH2Br

H

-CH2 Br

2h5

-c (chj) 3

-CHgBr

H

_ch2 sch3

-ch;, - ch = ch-c02h

-CH2 3r ch3

-CH2 SCHj

-CH-CO-H

I 2

C3 7 -ch2cn

-CH2 Br -CH2 Br

• -ch2ch2nh2

-CHpC02H

-ch2 sch3 -ch2 sch3

- (CH2) 2CM

-CH2 Br

-CfCH3) 2C02H

-CH2 SCHj

655317

10

R

R1

R

R1

R

Rt

R

R1

-CH-CO-H

-CH.SH

H

CH-N,

-ch2-conh2

-CH2Br

-CH2CH2Br

-CH2 sch3

5

2 3

\ h52

2

- (CH2) 2 Hr

-CH2 Br

-CK2CH2I

-ch2 sch3

CH3

CH2N3

-C (CH3) 3

-ch2sh

- (CH2) 2CI

-CH-CH-SH-

CH-N,

-CH., - CH = CH-CO-H

-CH-SH

-CH2Br

-CH2C02C2K5

-ch2 sch3

2 2 2

2 3

vs. vs

2

10

-ch2co2h

CH-N,

-ÇH-CO-H

-CH SH

-CHgCOgtBu

-ch2sch,

-CH2-C0NH2

-ch2oh

2 3

3 ^ 7

2

-c (ch3) 2co2c2h5

-ch2sch.

- (CH ^ Br

-CH20H

-C (CHj) 2C02H

CH2N3

-ch2cn

-ch2sh

-C (CH3) 2C02tBu

-ch2sch.

- (CH2) 2v1

-ch2oh

15

H

ch2ncs

- (ch2) 2cm

-ch2sh

-ch2ch3

-ch2oh

- (CH2) 3Br

-ch2oh

chj ch2ncs

-ch2-conh2

-CH2SH.

- (ch2) 2ch3

-ch2oh h

-ch2sch

■) fl

-C ^ CH2NH2

ch2ncs

- (CH2) 2 Br

-CH2SH

-chcch ^

-ch2oh ch3

-chgscn zu

-CH2C02H

ch2ncs

-Cch2) 2ci

-ch2sh

-nc4hg

-ch20h

-CHgCHjïlHg

-chgscn

-CH2CH3

ch2sh -

- (CH2) 3Br

-CH2SH

-ch2-ch-ch2

-CHgOH

-ch2co2h

-CI ^ SCN

25

- (CH2) 2CH3

CH2SH

-c (ch3) 2co2h

-ch2ncs

-ch2co2h

-CH20H

-c (ch3) 2co2h

-CH23CN

-CH (CH3) 2

ch2sh

H

-CH2N (CH3) 2

- ^ - CO2H

-ch2oh

- (CHgJgl

-CH2OH

30

-nc ^ Hg ch2sh

ch3

-CH2N (CH3) 2

-h2c-c ^ ch

-ch-ch-nh,

-CH_N (CH,) _ '

- (CH3) 2C02H

-ch2oh

-ch2oh

2 2 2

2 3 2

-çh-co.h

-ch2oh

-hc = ch2

-CH20H

-CH2C02H

CM

sT

0 &

»R ch3

-CH2C02C2H5

-ch2ch

- (ch2) 2- ^ ô)

-chgoh

35

-Cch2) 2i

-CH ^ h

-CH2C02tBu

-ch20H

- (CH ^ -nQNCI ^

-ch2oh

-H2C-C5CH

-CH2 SH

-CH-C02H

-ch2oh

- (ch2) 2-tq3

-CHgDH

40

-hc-ch2

-CH2SH

2H5

-CH2g-N (CH3) 2

- (ch2) _- i (o>

-CH, SH

-c (ch3) 3

-ch2oh

-ch2oh.

^ \ (

- (CH2) 2- / ~; NCH

2

-CH-SH

-CH2-CH = CH-C02H

-CH20H

-ch2-ch2-n (ch3) 2

-ch2or

45

vs. \ / ^

/ v

2

-ch2oh

- (ch2) 2-n ^ jd

-CH-SH

-CH-C02H

-ch2oh

t3H?

-CH20H

-CH2g-N (CH3) 2

-CH-SH

-CH2CN

-CH2CK2-NH2

-ch2oh

£

- (CH2) 2CJT

50

-CH2-CH2-N (CH3) 2

-CH0SH

-CH20H

H

-CH ^ H

e.

CH3

-CH-SH

H

CH2NH2

-ch2-ch-ch2

-ch2sh

2

-CH2CH2KH2

-CH-SH

chj ch2nh2

-CH2C02H

■ -ch2sh

55

2

-CH2SH

H

-CH-SH

-CH2CH2NH2

ch2nh2

- £ -C02H

- (CH3) 2C02H

-ch2sh

-C (CH3) 2C02H

-ch2n (ch3) 2

-ch2co2h

CH2NH2

60

-ch2sh

-ch-cs

-ch, f

-C (CH3) 2C02H

ch2nh2

-CH-CO2H

2

2

ch3

-ch2-c02h

~ CH2F

-chgchjbr ch2nh2

-ch2co2c2h5

-CH2SH

65

-ch3

-ch2-s - ^^

-ch2ch2i chgnhg

-chgcogtbu

-CH2SH

-chf2

-ch2-s "0

Example 1: Acid-4-chloromethyl-3- [2- (2-amino-4-thiazolyl) 2-methoxyimino-acetamido] -2-oxoazetidine-1-sulfonic eis, 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-trityla-mino-4-thiazolyl) -2-methoxyimino-acetamido syn isomer is cooled in 23 cm 3 of methylene chloride and 594 mg of dicyclohexyl carbodiimide is stirred. minutes cold and add a solution of 441 mg of 4-chloromethyl hydrochloride

3-amino-2-oxo-azetidine in 10 cm3 of methylene chloride and 0.4 cm3 of triethylamine. The mixture is stirred for 1 hour 20 minutes at room temperature, the dicyclohexylurea formed is drained, rinsed with methylene chloride, 10 cm 3 of saturated sodium hydrogen carbonate solution and 20 cm 3 of water are added to the filtrate. Stirred, decanted in a vial, washed with water again, re-extracts the organic phase and dries it.

Concentrate to dryness under reduced pressure, add to the residue the minimum amount of ethyl acetate, scrape, filter the insoluble material, rinse with ethyl acetate and concentrate again to dryness under reduced pressure. The residue is dissolved in 5 cm3 of ethanol and diluted slowly with 10 cm3 of ether. The crystallization is started, stirred for 2 hours, the crystals formed are drained, rinsed with an ethanol-ether mixture (1-2) and 688 mg of expected product is obtained.

Analysis: CzoHaaOaNsSCl = 560.08 Calculated (%): C 62.19 H 4.68 N 12.5 Found (%): C 62.40 H 4.80 N 12.2

Stage B: Acid-4-chloromethyl-3- [2- (2-amino-4-thiazolyl) 2-methoxyimino-acetamido] -2-oxo-azetidine-1-sulfonic eis, racemic syn.

a) Sulfonation:

To a solution of 1.72 g of pyridine sulfan (pyridine sulfuric anhydride complex) in 17.2 cm3 of dry dimethylformamide, 2.403 g of product obtained in the preceding stage is added. Agitation is carried out for 66 hours at room temperature, the insoluble material is filtered, rinsed with dimethylformamide, diluted with 300 cm 3 of ether, agitated, left to stand for 10 minutes, eliminates the ether, rewashes with ether by grinding, takes up the gum with 20 cm3 of ethanol. After dissolution, it is scraped, the expected product crystallizes. The mixture is stirred slowly for 30 minutes, filtered, rinsed with ethanol and then with ether.

855 mg of expected product is obtained, which is 4-chloro-methyl-3- [2- (2-tritylamino-4-thiazolyI) -2-methoxyimino-aceta-mido] -2-oxo-azetidine-1-sulfonate pyridinium.

b) Unlocking the remaining trityle:

A mixture of 360 mg of pyridine sulfonate obtained previously and 1.4 cm3 of formic acid containing 33% water is brought to 50 ° C. After dissolution, the crystallization of triphenyl-carbinol occurs. It is left for 10 minutes at 50 ° C., cooled, diluted with 0.6 cm3 of water, filters the insoluble material, rinses with water. A little ethanol is added to the filtrate and concentrated to dryness under reduced pressure. Water and ethanol are added which are evaporated under vacuum. 1.2 cm 3 of saturated aqueous sodium bicarbonate solution are added to the residue. The light insoluble material is filtered, rinsed with water, added to the filtrate 3 drops of formic acid and scraped. The expected product crystallizes. Stir for 10 minutes, filter, rinse with water and ether,

dries and isolates 113 mg of expected product.

Analysis: CioHuOôNsSîC ^ 397.82 Calculated (%): C 30.19 H 3.04 Found (%): C 29.60 H 3.20

Preparation:

a) 2-chloro-N-phenylmethyl-ethanimine.

A solution of 4 cm3 of chloroacetaldehyde in 20 cm3 of demineralized water is cooled and introduced with stirring

655,317

a solution of 2.14 g of benzylamine in 10 cm3 of water. Agitation is carried out for 5 minutes at 10/15 ° C. and a gum and a cloudy solution are obtained. Extraction is carried out with 30 cm 3 then 20 cm 3 of benzene. The solution is dried, filtered, rinsed and distilled to dryness under vacuum. 3.34 g of product are obtained, used as it is.

b) N-benzyl-3-phthalimido-4-chloromethyl-2-azetidinone eis.

The solution of 3.34 g of product obtained above in 20 cm 3 of methylene chloride is cooled to -50 ° C., then 2.8 cm 3 of triethylamine are added at once. Stirring and temperature are maintained and a solution of 4 g of phthalimido acetic acid chloride in 20 cm 3 of methylene chloride is introduced in 20 minutes. Then stirred for one hour at 0, + 5 ° C, pour into a separating funnel and wash with 50 15 cm3 of demineralized water and 5 cm3 of aqueous molar solution of sodium hydrogen carbonate then with demineralized water (2 times 30 cm3). The washes are re-extracted with methylene chloride (20 cm 3), dried, wrung, rinsed and concentrated to dryness under vacuum. A crude resin (6 g) is obtained which is chromatographed on silica using methylene chloride 5% sulfuric ether. The fraction of Rf = 0.45 is isolated, brought to dryness, paste with 10 cm3 of sulfuric ether, wrung, rinsed with 3 times 2 cm3 of sulfuric ether. It is dried under vacuum and 1.25 g of product is obtained. Mp 149 ° C.

25

c) 3-phthalimido-4-chloromethyl-2-azetidinone eis.

A mixture of 17.75 g of product obtained above, 31 g of potassium peroxodisulfate, 110 cm 3 of water and 160 cm 3 of water is heated to hot for 25 minutes with good stirring in an oil bath at 120 ° C. acetic acid. Cool to room temperature, add 50 g of dipotassium phosphate to neutralize the acidity formed, remove the solvents under reduced pressure, add 250 cm3 of water and 150 cm3 of ethyl acetate, stir and then add in small portions of 35 sodium hydrogen carbonate until gas evolution ceases, filter, rinse with ethyl acetate, decant in a vial, reextract with 50 cm3 of ethyl acetate, dry the organic phase, filter, rinse and concentrate to dryness under reduced pressure. The residue is chromatographed on 200 g of silica (eluent: methylene chloride 40% ethyl acetate). The rich fractions are collected, concentrated to dryness, taken up in ether, solved, drained, rinsed, dried and obtained 5.4 g of the desired product.

Analysis: C12H9N2CI = 264.67 Calculated (%): C 54.46 H 3.43 45 Found (%): C 54.70 H 3.50

d) 4-chloromethyl-3-amino-2-oxo-azetidine hydrochloride.

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 qs 20 cm3 dimethylformamide). It is left standing for 20 minutes after solidification 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 18 hours at room temperature, filters the phthalhydrazide formed, rinses with water then with ethanol and finally with ether. Dried and obtained 2.844 g of product. Dimethylformamide and water are removed under reduced pressure, the residue is taken up twice with ethanol, removed and a product is obtained to which 20 cm 3 of ethanol are added. Agitation is carried out for 45 minutes, the crystals formed are drained, rinsed with ethanol and ether. 2.466 g of expected product are finally obtained.

b5 Example 2: Acid-4- (1-methyl-5-mercapto-1,2,3,4-tetrazol) methyl-3- [2- (2-amino-4-thiazolyl) -2-methoxyimino-aceta- mido] 2-oxoazetidine-1-sulfonic, racemic eis.

Stage A: Acid-4- (1-methyl-5-mercapto-1,2,3,4-tetrazol)

655,317

12

methyl-3- [2- (2-tritylamino-4-thiazolyl) -2-methoxyimino-aceta-mido] -2-oxo-azetidine-1-sulfonic.

a) Condensation:

A mixture of 2.25 g of 2- (2-tritylamino-4-thiazo-lyl) -2-methoxyimino-acetic syn isomer in 21 cm3 of chloride is stirred cold for 20 minutes in an ice-water bath. methylene and 576 mg dicyclohexylcarbodii-mide. 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 in 10 cm 3 of methylene chloride and 0.38 cm3 of triethylamine. The mixture is stirred at room temperature for 1 hour 20 minutes, concentrated to dryness under reduced pressure, filtered, rinsed with methylene chloride, finished with ether, dried and isolated 1.594 g of product containing dicy-clohexylurea.

b) Sulfonation:

A mixture of 1.594 g of product obtained above and 0.66 g of pyridine sulfan (pyridine sulfuric anhydride complex) in 6.6 cm 3 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 cm 3 of ether. Stir well, filter the insoluble material, wash with ether, combine all the products by dissolving them in methanol, the expected product crystallizes. Filtered, rinsed with methanol, finished with ether, dried and obtained 620 mg of the expected product.

Stage B: Acid-4- (1-methyl-5-mercapto-1,2,3,4-tetrazol) -

methyl-3- [2- (2-amino-4-thiazolyl) -2-methoxyimino-aceta-

mido] 2-oxo-azetidine-1-sulfonic.

A mixture of 620 mg of product obtained in the preceding stage in 0.8 cm3 of water and 1.62 cm3 of formic acid is brought to 60 ° C. for 12 minutes, the triphenylcarbinol crystallizes. Cool, dilute with a little water. The expected product also crystallizes. Stir for 10 minutes, filter, rinse with water and then paste 3 times with ether. We take up the insoluble matter in water, add 2 cm3 of saturated aqueous sodium hydrogen carbonate, stir, filter the insoluble matter, rinse with water, add normal hydrochloric acid q.s.p. pH 2. The expected product crystallizes. Stirred 5 minutes, filter, rinse with water, finish with ether, dry and obtain 294 mg of the expected product.

Analysis: CnHisObNoSj Vi I-hO = 486.51 Calculated (%): C 29.63 H 3.31 N 25.91 S 19.77 Found (%): C 29.50 H 3.40 N 25.80 S 19.80

Preparation 1:

a) 4- (1-methyl-5-mercapto-1,2,3,4-tetrazol) -methyl-3-phthali-mido-2-oxo-azetidine eis.

A suspension of 7.6 g of 4-chloromethyl-3-phthalimido-2-oxo-azetidine and obtained in the preparation of Example 1 c) is brought to 100 ° C., 5.48 g of sodium salt of 1-methyl-5-mer-capto-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 0.751 water and 150 cm3 of ethyl acetate. Rinsed, stirred vigorously, decanted, reextracted with 75 cm3 then 45 cm3 of ethyl acetate, filtering the insoluble material which is the expected product. Wash with 150 cm3 of water, re-extract and dry. After filtering, the mixture is concentrated to 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 the expected product.

Analysis: C14H12O3N6S, 'A AcOEt = 366.37 Calculated (%): C 49.17 H 3.85 N 22.94 Found (%): C 49.20 H 3.70 N 23.00

b) 4- (1-Methyl-5-mercapto-1,2,3,4-tetrazol) -methyl-3-amino-2-oxo-azetidine hydrochloride.

1 cm3 of hydrazine hydrate is added dropwise to a suspension of 5.845 g of product obtained above in 18.5 cm3 of dry dimethylformamide and the mixture is stirred for 20 minutes at room temperature then 19 cm3 of water and 24 cm3 of normal hydrochloric acid. A final pH of 3 is obtained, mouth, left stirring overnight at room temperature, then filters the phthalhydrazide formed, rinses with water, concentrates at 10 sec under reduced pressure, adds ethanol, disintegrates, concentrates to dryness , add methanol to dissolve when hot and concentrate to dryness. The product crystallizes. 20 cm3 of methanol are added, disintegrated, ice-cold, drained, rinsed with ice-cold methanol, finished with ether and 2.49 g of expected product obtained in 2 jets.

Example 3: acid-4-chloromethyl-3- [2- (2-amino-4-thiazolyl) -2- (2-amino-ethoxy) imino-acetamido] 2-oxoazetidine-1-sulfonic eis, racemic syn.

Stage A: 4-chloromethyl-3- [2- (2-tritylamino-4-thiazolyl) -

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-thiazolyI) 2- (2-tritylamino-ethoxy) imino-acetic acid isomer syn in 40 cm3 of methylene chloride and 1.24 cm3 of triethylamine.

The mixture is stirred for 40 minutes and then a solution of 1.368 g of 4-chloromethyl hydrochloride is added at once

3-amino-2-oxoazetidine in 40 cm3 of methylene chloride and 2.4 cm3 of triethylamine. Shake for 2 hours at room temperature.

30 ture ambient, add water, stir vigorously, decant and reextract with methylene chloride. The organic phase is dried, filtered and concentrated to dryness. The residue is chromatographed on silica (eluent: ether).

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

35

Stage B: 4-chloromethyl-3- [2- (2-tritylamino-4-thiazolyl) 2 (2-tritylamino-ethoxy) imino-acetamido] 2-oxo-azetidine-

1-pyridinium sulfonate.

A mixture of 40 4.9 g of product obtained in the preceding stage, 2.6 g of pyridine sulfan and 25 cm 3 of dimethylformamide is stirred for 4 days at room temperature. Pour into 1 liter of water containing 500 cm3 of ether.

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

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

Stage C: 4-chloromethyl-3- [2- (2-amino-4-thiazolyl) acid

2- (2-amino-ethoxy) imino-acetamido] -2-oxo-azetidine-1-sulfo-5o nique eis, syn, racemic.

A suspension of 5.3 g of product obtained above in 42 cm3 of formic acid at 33% water is brought to 55-60 ° C. for 12 minutes.

Cooled, diluted with 30 cm3 of water, filtered the triphenyl 55 carbinol formed, rinsed with water and concentrated to dryness in a water bath at 40 ° C. The residue is taken up twice with a water-ethanol mixture.

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, rinsed with water, added 2N hydrochloric acid so as to bring the pH to 4-5. The crystallization is started, stirred for one hour, filtered, rinsed with water and then with ether.

65 700 mg of expected product is obtained.

Analysis: C11H15O6N6S2CI Calculated (%): C 30.95 H 3.54 Found (%): C 30.90 H 3.8.

13

655,317

Example 4: Acid-4-chloromethyl-3- [2- (2-amino-4-thiazolyl) 2-hydroxyimino-acetamido] 2-oxo-azetidine-1-sulfonic eis, syn, racemic.

Stage A: 4-chloromethyl-3- [2- (2-tritylamino-4-thiazoIyl) 2-tri-tyloxyimino-acetamido] 2-oxo-azetidine syn.

A mixture of 1.527 g of sodium salt of 2- (2-tritylamino-4-thiazolyl) 2-trityloxy-mino-acetic acid and 419 mg of tosyl chloride in 15 cm 3 of methylene chloride is stirred for 40 minutes. then add a solution of 342 mg of 4-chloromethyl-3-amino-2-oxoazetidine hydrochloride in 15 cm3 of methylene chloride and 0.6 cm3 of triethylamine.

Stir the mixture for 2 hours, add water, stir, decant, re-extract with methylene chloride and dry the organic phase then filter. The filtrate is concentrated under reduced pressure and chromatography on silica (eluent: ether).

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

Stage B: 4-chloromethyl-3- [2- (2-tritylamino-4-thiazolyl) 2-tri-tyloxyimino-acetamido] 2-pyro-nium oxo-azetidine-1-sulfonate.

A solution of 1.248 g of product obtained as in Stage A and 640 mg of pyridine sulfan (pyridine sulfuric anhydride complex) is left at room temperature for 4 hours in 6.8 cm 3 of dry dimethylformamide.

Then poured into 300 cm3 of ether, grind, filter the insoluble material, rinse with ether, paste in 10 cm3 of methanol, stir for 15 minutes, filter, rinse with methanol and then with ether, dry, and finally obtain 1.02 g of expected product.

Stage C: Acid-4-chloromethyl-3- [2- (2-amino-4-thiazolyI) 2-hydroxyimino-acetamido] 2-oxo-azetidine-1-sulfonic eis, syn, racemic.

A suspension of 1.02 g of product obtained in the preceding stage in 9.1 cm 3 of 66% formic acid is brought to 60 ° C. for 15 minutes.

The procedure is as described above in stage C of Example 3 and gives 119 mg of the expected product.

Example 5: Acid-4-fluoromethyl-3- [2- (2-amino-4-thiazolyl) 2-methoxyimino-acetamido] 2-oxo-azetidine-1-sulfonic eis, syn, racemic.

Stage A: 4-fluoromethyl-3- [2- (2-tritylamino-4-thiazolyl) 2-methoxyimino-acetamido] 2-oxo-azetidine eis, syn, racemic.

0.915 g of 2- (2-tritylamino-4-thiazolyl) 2-methoxyimino-acetic acid, syn isomer, 7 cm 3 of acetone and 0.319 g of tosyl chloride are mixed. Stirred for 50 minutes at 20 ° C, filtered and added a solution containing 0.216 g of 4-fluoromethyl-3-amino-2-oxo-azetidine hydrochloride eis, 7 cm3 of methylene chloride and 0.42 cm3 of triethylamine.

Stir for 45 minutes, evaporate to dryness, add water, disintegrate, wring, then paste with acetone and wring. The product is purified by pasting in ethyl acetate. 0.654 g of 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 (%): C 64.00 H 4.90 N 12.40 S 5 , 90 F 3.40

Stage B: Acid-4-fluoromethyl-3- [2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] 2-oxo-azetidine-1-sulfonic eis, syn, racemic.

a) Obtaining pyridinium sulfonate.

The mixture is stirred at 200 ° C. for 88 hours, a mixture of 0.564 g of product obtained in stage A, 0.410 g of pyridine sulfan and 4.1 cm3 of dimethylformamide. Poured into 200 cm3 of ether, wrung the product, added methanol, stirred, wrung and dried the crystals obtained. 0.473 g of expected product is obtained.

b) Detritylation 5 0.470 g of the product obtained above is suspended in 1.87 cm3 of formic acid at 33% water, then heated to 55-60 ° C for 5 minutes then to 70 ° C for 13 minutes, rejuvenates 1.2 cm3 of formic acid and reheats to 70 ° C for 15 minutes. Cool to 20 ° C, filter, add ethanol to the filtrate and then concentrate to dryness. Water and ethanol are added to the residue and then concentrated again to dryness. The residue is dissolved in water supplemented with 1.6 cm 3 of 10% sodium bicarbonate. Filter, add 2N hydrochloric acid since at pH 2, evaporate the water, paste the residue in water, filter, rinse with water, then with ether, dry and obtain 0.140 g of expected product. F (decomposition) = * 240 ° C.

Analysis: CioHi206NsS2F = 381.36 Calculated (%): C 31.50 H 3.17 N 18.36 S 16.81 F4.98 20 Found (%): C 31.60 H 3.20 N 18.50 S 16.50 F 5.10

Preparation of 4-fluoromethyl-3-amino-2-oxo-azetidine hydrochloride eis.

1) N-methyl-N-methoxy-fluoroacetamide.

25.27.2 g of fluoroacetyl chloride and 120 cm3 of methylene chloride are mixed, cooled to + 5 ° C under inert gas and slowly introduced 50 cm3 of methoxymethylamine while keeping the temperature below 20 ° C, then stirred for 2 hours at 20 ° C. Filtered, the solvent is removed under reduced pressure, the residue is rectified under reduced pressure and 30.9 g of expected product are obtained.

Eb 23 = 93 ° C.

2) Fluoroacetaldehyde hydrate.

7.8 g of product obtained in the preceding stage are dissolved in 133 cm3 of tetrahydrofurania, cooled to 0. + 2 ° C and slowly introduced 74 cm3 of a 1M solution in diisobutyl aluminum hydride hexane. The temperature is allowed to slowly return to room temperature, poured into a mixture of 28 cm3 of concentrated hydrochloric acid and 56 cm3 of water while cooling, stirred then distilled at atmospheric pressure. 38 cm3 of expected product are obtained diluted in water (bp: 75 to 100.5 ° C).

3) 4-fluoromethyl-3-phthalimido-2-oxo-1- (1-phenylethyl) -azeti-dine eis.

69 cm3 of solution as obtained in the preceding stage are diluted in 100 cm3 of water. Cooled in an ice bath for 15 minutes then added 8.8 cm3 of a-phenylethylamine so DL, stirred for 10 minutes, filter, rinse with water and add to the filtrate 130 cm3 of methylene chloride. The mixture is heated to reflux until complete dissolution, cooled, decanted, the organic phase is dried and then cooled under inert gas to -50 ° C. 15.4 g of phthalimidoacetyl chloride 55 in 60 cm3 of methylene chloride and 10.4 cm3 of triethylamine in methylene chloride are slowly added thereto. The temperature is allowed to return to 20 ° C and stirred for one hour. 25 cm3 of 10% sodium bicarbonate and 60 cm3 of water are added, stirred, decanted, extracted with methylene chloride, the combined organic phases are dried, concentrated to dryness, the residue is chromatographed on silica eluting with chloride of methylene to 10% ethyl ether and obtains 13.7 g of the expected product.

Analysis: C20H17O3N2 F = 352.37 Calculated (%): C 68.17 H 4.86 N 7.95 F 5.39 65 Found (%): C 68.20 H 4.90 N 7.80 F 5, 60

4) 4-fluoromethyl-3-phthalimido-2-oxo-azetidine eis, racemic.

The 13.7 g of the product obtained in the preceding stage are dissolved

655,317

14

tooth in 200 cm3 of acetonitrile and add 130 cm3 of water. The mixture is brought to reflux, a solution of 22.2 g of ammonium persulfate in 52 cm 3 of water is introduced over 15 minutes and the reflux is maintained for one hour twenty-five minutes. It is cooled, saturated with sodium chloride, decanted, washed with a saturated aqueous solution of sodium chloride, reextracted with ethyl acetate, the combined organic phases are dried and the solvent is evaporated. The residue is chromatographed on silica, eluting with a methylene chloride-ethyl acetate mixture (75-25), rinsing the crystals obtained with ethyl ether and obtaining 3.756 g of the expected product.

IR spectrum (CHCb): Absorption at 3430 cm-1 (-NH) and at 1790.1770 and 1725 cm-1 (C = 0 ßlactam and phthalimido).

5) 4-fluoromethyl-3-amino-2-oxo-azetidine hydrochloride eis.

1.24 g of product obtained in the preceding stage is suspended in 1.2 cm3 of dioxane and then 14 cm3 of a solution of 1 cm3 of hydrazine hydrate in 50 cm3 of dioxane is added. Maintained for 45 minutes at room temperature then added 5 cm3 of N hydrochloric acid and stirred for 15 hours. Concentrate to dryness, add water and 2.3 cm3 of N hydrochloric acid, stir and filter. Ethanol is added to the filtrate and concentrated to dryness. Methanol is added to the residue, then ethanol and concentrated to dryness again. The crystals are recrystallized from methanol.

0.391 g of expected product is obtained. F (dec.) = 220 ° C.

EXAMPLE 6 Acid-4-fluoromethyl-3- [2- (2-amino-4-thiazolyl) -2- (1 -carboxy-1-methyl-ethoxy) imino-acetamido] 2-oxoazeti-dine-1-sulfonic eis, syn, racemic.

Stage A: 4-fluoromethyl-3- [2- (2-tritylamino-4-thiazolyl) -2- (1-terbutoxycarbonyl-1-methyl-ethoxy) imino-acetamido] 2-oxoazetidine eis, syn, racemic.

0.686 g of 2- (2-tritylamino-4-thiazolyl) -2- (1-terbutoxycarbonyl-1-methyl-ethoxy) imino-acetic acid, syn isomer, 5 cm3 of acetone and 0.17 cm3 of triethylamine then add 0.229 g of tosyl chloride, stir for 50 minutes, filter and add to the filtrate with stirring, a solution of 0.155 g of 4-fluoromethyl-3-amino-2-oxo-azetidine hydrochloride and 5 cm3 of chloride methylene and 0.3 cm3 of triethylamine. The mixture is stirred for 55 minutes at 20 ° C., the solvents are evaporated off, methylene chloride and water are added, 2 cm 3 of 10% sodium bicarbonate are added, the mixture is stirred, decanted, extracted with methylene chloride, the organic phases are dried combined and concentrated to dryness. The residue is chromatographed on silica eluting with ethyl ether to obtain 0.613 g of the expected product.

The starting thiazolic product is described in French application 2,421,906.

Stage B: 4-fluoromethyl-3- [2- (2-amino-4-thiazolyl) -2- (l-carboxy-1-methyl-ethoxy) imino-acetamido] -2-oxo-azeti-dine-1 acid -sulfonic eis, syn, racemic.

a) Obtaining pyridinium sulfonate.

The product obtained in Stage A and 0.36 g of pyridine sulfan are dissolved in 3.6 cm 3 of dimethylformamide.

The mixture is stirred at 20 ° C. for 62 hours, poured into water,

stir, wring and dry the precipitate obtained. 0.518 g of expected product is obtained.

b) Detritylation:

The product obtained in the preceding stage is dissolved in 2.9 cm3 of trifluoroacetic acid and maintained at 20 ° C for 15 minutes. 29 cm 3 of isopropyl ether are added, the mixture is filtered and the product is placed in ethyl acetate for 15 minutes. Filter is dried, the product is dissolved in a little water, containing 1 cm3 of 10% sodium bicarbonate, filter, add 2N hydrochloric acid to the filtrate until pH 2, filter, partially evaporate the water , cools, wring the crystals, rinses them with ether and obtains 0.094 g of the expected product. F (dec.) ^ 230 ° C.

NMR spectrum (DMSO - 90 MHz): Peaks at 1.5 ppm (CH3), 3.78 - 4.94 ppm (Hi and CH2F) 5.22 - 5.27 - 5.32 and 5.37 ppm (H4 ), 6.88 ppm (Hs thiazole syn), 9.21 and 9.31 ppm (NHCO).

Example 7: Acid-4-thiocyanatomethyl-3- [2- (2-amino-4-thia-zolyl) -2-methoxyimino-acetamido] 2-oxo-azetidine-1-sulfonic eis, syn, racemic.

Stage A: 4-thiocyanato-methyl-3- [2- (2-tritylamino-4-thiazolyl) 2-methoxyimino-acetamido] 2-oxo-azetidine eis, syn, racemic.

We put 3.19 g of 2- (2-tritylamino-4-thiazolyl) acid -

2-methoxyimino-acetic, syn isomer, suspended in 50 cm3 of methylene chloride. Add with stirring

1 cm3 of triethylamine then 1.38 g of tosyl chloride. Stirring is maintained at ambient temperature for 40 minutes and then added over 5 minutes, a solution of 1.162 g of 4-thiocyanatomethyl-3-amino-2-oxo-azetidine hydrochloride eis in 40 cm3 of methylene chloride and 2 cm3 triethylamine. Stirring is continued for 4 hours, washing with water and then with water containing 4 cm3 of N hydrochloric acid, drying and concentrating to dryness. The residue is dissolved in ethyl acetate, cooled, drained the crystals formed, washed with methanol, dried and obtained 0.709 g of the expected product. The mother liquors are evaporated to dryness, the residue is chromatographed on silica eluting with a chloroform-methanol mixture (93-7) and again 1.069 g of expected product is obtained.

Stage B: 4-thiocyanatomethyl-3- [2- (2-amino-4-thiazo-lyl) 2-methoxyimino-acetamido] 2-oxo-azetidine-1-sulfonic acid eis, syn, racemic.

a) Obtaining pyridinium sulfonate.

The mixture is stirred for 90 hours at 20 ° C., a mixture of 1.7 g of product obtained in stage A, 12 cm 3 of dimethylformamide and 1.16 g of pyridine sulfan. Poured into ether with stirring, the precipitate formed with methanol is taken up, cooled and then the crystals are wrung out. 0.544 g of expected product is obtained in 2 jets.

b) Detritylation:

Heated to 60 ° C, 4 cm3 of formic acid at 33% water, then added 0.42 g of product obtained above and stirred at 60 ° C for 20 minutes. Cool to 20 ° C and then add 40 cm3 of ethyl ether and stir for one hour at 0, + 5 ° C. The precipitate is drained, rinsed with ethyl ether and triturated with a 0.1 N aqueous solution of sodium bicarbonate. Filtered, acidified the filtrate to pH 2 with N hydrochloric acid, cooled and wrung out the crystals formed. They are washed with water, dried and 0.237 g of the expected product is obtained. F (dec.) = 265 ° C.

Analysis: CnHnNsOeSj (420.54)

Calculated (%): C 31.42 H 2.88 N 19.99 S 22.88 Found (%): C 31.20 H 3.20 N 19.70 S 22.60

Preparation of 4-thiocyanatomethyl hydrochloride

3-amino-2-oxo-azetidine eis.

1) 4-iodomethyl-3-phthalimido-2-oxo-azetidine eis, racemic.

26.5 g of 4-chloromethyl-3-phthalimido-2-oxo-azetidine eis, 30 g of sodium iodide and 80 cm 3 of dimethylformamide are mixed. The mixture is brought to 120 ° C. for two hours, cooled, poured into a mixture of 800 cm3 of water and 100 cm3 of ethyl acetate with stirring, filters the crystals formed, rinses them with water and then with acetate ethyl until discoloration and finally with ethyl ether. We take the mother liquors, decant, dry

5

10

15

20

25

30

35

40

45

50

55

60

b5

15

655,317

the organic phase, concentrated to dryness, taken up in ethyl acetate, filtered, rinsed with ethyl acetate and dried. 28.4 g of expected product are thus obtained in 2 jets.

2) 4-thiocyanato methyl-3-phthalimido-2-oxo-azetidine eis, racemic.

A mixture of 1.78 g of product obtained above in 5 cm 3 of dimethylformamide is brought to 75 ° C. with stirring, then 1.5 g of potassium thiocyanate are added and the mixture is stirred for 3 hours 30 minutes. It is poured into water, the precipitate is wrung out, washed with water and dried. It is pasted hot in isopropyl ether, drained and dried. 1.25 g of expected product are obtained.

3) 4-thiocyanato methyl-3-amino-2-oxo-aze-tidine hydrochloride eis.

1.45 g of product obtained in the preceding stage are mixed in 15 cm3 of hot dioxane, cooled then slowly added 0.3 cm3 of hydrazine hydrate and stirred at 20 ° C for 50 minutes. 7.5 cm3 of hydrochloric acid N are then added, the mixture is kept stirring for 15 hours, the precipitate is drained, rinsed with water, the filtrate is taken up and evaporated to dryness. 0.914 g of expected product is obtained.

Example 8: Acid-4-fluoromethyl-3- [2- (2-amino-4-thiazolyl) -2-difluoromethoxyimino-acetamido] 2-oxo-azetidine-1-sulfonic eis, syn, racemic.

Stage A: 4-fluoromethyl-3- [2- (2-tritylamino-4-thiazolyl) -2-difluoromethoxyimino-acetamido] 2-oxo-azetidine eis, syn, racemic.

0.914 g of 2- (2-tritylamino-4-thiazolyl) acid is mixed

2-difluoromethoxyimino-acetic, syn isomer, 7 cm3 of acetone and 0.25 cm3 of triethylamine then add 0.339 g of tosyl chloride and stir for 50 minutes. Then a solution of 0.23 g of 4-fluoromethyl hydrochloride is added.

3-amino-2-oxo-azetidine eis in 7 cm3 of methylene chloride and 0.45 cm3 of triethylamine. The mixture is stirred for an hour and a half, the solvents are evaporated off, methylene chloride and water are added, then 3 cm 3 of 10% sodium bicarbonate, stirred, decanted, the aqueous phase is extracted with methylene chloride, the combined organic phases are dried , the solvent is evaporated, the residue is taken up in ethanol, cooled, the crystals are wrung, rinsed with ethanol and then with ethyl ether and dried. 0.537 g of expected product is obtained.

Stage B: Acid-4-fluoromethyl-3- [2- (2-amino-4-thiazolyl) -2-difluoromethoxyimino-acetamido] 2-oxo-azetidine-1-sulfonic eis, syn, racemic.

a) Obtaining pyridinium sulfonate.

The product obtained in Stage A and 0.37 g of pyridine sulfan are dissolved in 3.7 cm 3 of dimethylformamide. The mixture is stirred for 72 hours at 20 ° C., poured into 150 cm 3 of ether, filtered, washed with ether and the product is dissolved in ethanol. The crystals formed are stirred, filtered, washed with ethyl ether and dried. 0.506 g of expected product is obtained.

b) Detritylation:

0.76 g of product obtained above is mixed with 4 cm 3 of formic acid at 33% water. The mixture is brought to 60 ° C. for 15 minutes, diluted with water, filtered, added ethanol to the filtrate, brought to dryness, taken up in a mixture of water and ethanol, brought up to dry again, taken up at water and add 2 cm3 of 10% sodium bicarbonate, filter an insoluble material, add 2N hydrochloric acid to the filtrate until pH 2, concentrate and leave to crystallize. The crystals are filtered, rinsed with water then with ethyl ether and dried. 0.312 g of expected product is obtained.

Analysis: C10H10O6N5S2F3

Calculated (%): C 28.78 H 2.41 N 16.78 S 13.66 F 15.36 Found (%): C 28.90 H 2.50 N 16.60 S 13.40 F 15.30

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 5.35 ppm (Hj eis). Peaks at 6.38 - 7.15 and 7.93 ppm (-CHF2). Peaks at 7.01 ppm (Hs thiazole). Peaks at 9.66 and 9.76 ppm (-CONH)

IR spectrum (CHCh)

Absorption at 1770 cm-1 (C = O lactam), 1675 cm-1 (amide), 1640 cm-1 (amide II), 1585 cm-1 (conjugated system), 1530 10 cm-1 (thiazole), 1280 - 1270 cm-1 (-SO3H) and 1052 cm-1 (-C = NO-).

Example 9 Acid-4-fluoromethyl-3- [2- (2-amino-4-thiazolyl) -

2-hydroxyimino-acetamido] 2-oxo-azetidine-1-sulfonic eis, 15 syn, racemic.

Stage A: 4-fluoromethyl-3- [2- (2-tritylamino-4-thiazolyl) -2-tri-tyloxyimino-acetamido] 2-oxo-azetidine eis, syn, racemic. 0. 806 g of 2- (2-tritylamino-4-thiazolyl) acid is mixed

3-Trityloxy-imino-acetic, syn isomer, 5 cm3 of acetone and 0.17 cm3 of triethylamine then added 0.228 g of tosyl chloride. The mixture is stirred for one hour and then 0.155 g of 4-fluoromethyl-3-amino-2-oxo-azetidine hydrochloride is added in 5 cm3 of methylene chloride and 0.31 cm3 of triethylamine. Stir for 20 minutes, add methylene chloride, stir again for 1 hour 30 minutes, bring to dryness, add methylene chloride and water, stir, decant, dry the organic phase, evaporate the solvent and chromatograph the residue on silica, eluting with ethyl ether. 0.598 g of expected product is obtained.

30

Stage B: Acid-4-fluoromethyl-3- [2- (2-amino-4-thiazolyl) -2-hydroxyimino-acetamido] 2-oxo-azetidine-1-sulfonic eis, syn, racemic.

a) Obtaining pyridinium sulfonate.

The operation is carried out as indicated in stage B of Example 4, starting from the product obtained in stage A above and the expected product is obtained.

b) Detritylation.

40 The operation is carried out as indicated in stage B of Example 4, starting from the product obtained above and the expected product is obtained.

Example 10: optically active 3-phthalimido-4-chloromethyl-2-oxo-azetidine 45 eis.

Stage A: N- (1-phenyl) ethyl-3-phthalimido-4-chloromethyl-2-oco-azetidine eis, optically active.

2.5 cm3 of 50% chloroacetaldehyde hydrate are dissolved in water, in 50 cm3 of water. Stirred and added at 0.50 + 5 ° C, 2.55 cm3 of (+) - (1-phenyl) ethylamine. The mixture is stirred for 6 minutes and then the precipitate is filtered and rinsed with water. The precipitate is taken up in a methylene chloride-chloroform mixture and dried. The solution is cooled under inert gas to -50 ° C., 4.5 g of phthalimido acetic acid chloro-55 in 25 cm3 of methylene chloride and 2.74 cm3 of triethylamine in 20 cm3 of chloride are added slowly and simultaneously methylene. The temperature is allowed to rise and the mixture is stirred for two hours and thirty minutes. Poured into a water-sodium bicarbonate mixture, extracted with chloroform, dried, the solvent evaporated and the residue taken up in ethanol. The insoluble material is filtered and washed with an etha-nol-methylene chloride mixture. The filtrate is taken up, treated with activated carbon, concentrated and left to crystallize. 1.364 g of crystals are obtained in 2 jets. The mother liquors are taken up and chromatography on silica, eluting with a chloroform-ethyl acetate mixture (8-2). 1.58 g of crystals are obtained, ie a total of 2.944 g of the expected product consisting of a single diastereoisomer.

655,317

16

Stage B: optically active 3-phthalimido-4-chloromethyl-2-oxo-azetidine.

0.3 g of product obtained in stage A is mixed in 2 cm 3 of acetonitrile and brought to 90-95 ° C with stirring. A solution of 0.502 g of ammonium persulfate in 2 cm3 of water is slowly added, the mixture is stirred for one hour forty-five minutes and then poured into water, extracted with ethyl acetate, the organic phase is washed with a solution aqueous sodium thiosulfate, dries and evaporates the solvent. 0.058 g of expected product is obtained. aD = + 10.5 ° ± 1 ° (CHCb). M = 172 ° C.

Continuing the synthesis as described, for example, in example 1,2,4 or 5, a corresponding product of formula I is obtained which is optically active.

Example 11: A preparation for injection of formula was carried out:

- Acid-4-fluoromethyl-3- [2- (2-amino-4-thia- 500 mg zolyl) -2-methoxyimino-acetamido] 2-oxo-azeti-dine-1-sulfonic eis, syn, racemic

- 5 cm3 sterile aqueous excipient

Example 12: Capsules corresponding to the formula were produced:

- Acid-4-fluoromethyI-3- [2- (2-amino-4-thia- 250 mg zolyl) -2-methoxyimino-acetamido] 2-oxo-azeti-dine-1-sulfonic eis, syn, racemic

- Excipient q.s.p. one capsule finished at 400 mg

Pharmacological study of the products of the invention. In vitro activity, dilution method in liquid medium.

A series of tubes is prepared in which the same quantity of sterile nutritive medium is distributed. Increasing quantities of the product to be studied are distributed in each tube, then each tube is seeded with a bacterial strain. After incubation for twenty-four or forty-eight hours in an oven at 37 ° C, the growth inhibition is assessed by transillumination, which makes it possible to determine the minimum inhibitory concentrations (C.M.I.) expressed in ug / cm3.

The following results are obtained:

Product of Example 1

C.M.I. in ag / ml

Strains

24h

48 H

Escherichia coli sensitive tetracycline 7624

1.25

1.25

Tetracycline resistant Escherichia coli

AT CC 11 303

0.16

0.16

Enterobacter cloacae 681

2.5

2.5

Gentamycin resistant Escherichia coli

tobramycin R55 123 D

0.62

0.62

Klebsiella pneumoniae exp. 52145

1.25

2.5

Klebsiella pneumoniae 2536 resistant

gentamycin

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 From 48

0.62

0.62

Serratia resistant gentamycin 2,532

5

5

C.M.I. in (ig / ml

Strains

Product of

Product of

example 3

example 4

24 H 48 H

24 H 48 H

Escherichia coli sensitive tetracycline

7624

1.2 1.2

0.6 0.6

Tetracycline resistant Escherichia coli

AT CC 11 303

0.6 0.6

0.6 0.6

Escherichia coli resistant genta

mycine tobramycin R 55 123 D

1.2 1.2

0.6 0.6

Klebsiella pneumoniae Exp. 52 145

5 10

5 5

Klebsiella pneumoniae 2536

resistant

gentamycin

2.5 2.5

2.5 2.5

Proteus 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 From 48

2.5 2.5

0.6 1.2

Serratia resistant gentamycin 2,532

2.5 5

5 5

Product of Example 5

Strains

C.M.I. in ug / ml

24h

48 H

Pseudomonas aeruginosa 1771 m

0.6

1.2

Escherichia coli UC 1894

<0.04

<0.04

Escherichia coli 0 78

0.15

0.15

Escherichia coli T E M

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 +) A 232

<0.04

<0.04

Providencia From 48

0.3

0.3

Product of Example 6

Strains

C.M.I. in | ig / ml

24h

48 H

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 T E M

0.6

0.6

Escherichia coli 1507 E

0.6

0.6

Escherichia coli DC 0

0.6

0.6

Escherichia coli DC 2

0.3

0.3

Salmonella typhimurium MZ 11

0.6

0.6

Klebsiella 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

0.3

0.3

Serratia RG 2,532

0.3

0.3

Proteus mirabilis (indol -) A 235

<0.04

<0.04

Proteus vulgaris (indol +) A 232

<0.04

<0.04

Providencia From 48

0.15

0.15

.5

10

15

20

25

30

35

40

45

50

55

60

65

17,655,317

Product of Example 8

C.M.I. in ug / ml

24 H '48 H

Escherichia coli UC 1894

<0.04

<0.08

Escherichia coli 0 78

0.08

0.08

Escherichia coli T E M

0.15

0.15

Escherichia coli 1507 E

<0.04

<0.04

Escherichia coli DC 0

0.08

0.08

Escherichia coli DC 2

<0.04

<0.04

Salmonella typhimurium MZ 11

0.08

0.08

Klebsiella pneumoniae Exp. 52 145

0.3

0.3

Klebsiella aerogenes 1522 E

0.08

0.08

Enterobacter cloacae 1321 E

0.08

0.08

Serratia RG 2532

0.6

0.6

Proteus mirabilis (indol -) A 235

<0.04

<0.04

Proteus vulgaris (indol +) A 232

<0.04

<0.04

Providencia From 48

0.3

0.3

Claims (12)

655,317 ^ 1 H2Nv (I). ct2 1 nvs03h 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, Ri represents a radical - (CH2) nX in which n represents a number integer from 1 to 4 and X represents a halogen atom, a cyano radical, an O-R'i radical in which R'i represents a hydrogen atom or an alkyl radical, or X represents an SR "i radical in which R "i represents a hydrogen atom, an alkyl radical or a heterocycle or X represents a radical: -not. • r " .-—- conh. ° r2 ^ -not- so3h (ii) vs/ racemic or optically active, formula in which either Ra represents Ri, Ri having the meaning indicated in claim 1, or Ra represents Ri in which the reactive functions are protected and A represents a sulfo radical, by a compound of formula III: in which R 'and R "represent a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms or R' and R" form with the nitrogen atom to which they are linked, a heterocycle or X represents a azido, thiocyanato or isothio-cyanato radical, as well as the salts of the products of formula I with bases or acids, the wavy line signifying that the compounds may be in the eis or trans form or in the form of a cis- trans, the compounds of formula I being in racemic or optically active form, the oxime being in syn form. 2. Compounds according to claim 1, of general formula (I '): S ^ p-co2H (III) '(ch2) n, x' (i1) Ndr1. 0 Wherein Rb represents a hydrogen atom or a protecting group for the amino radical and R'b represents a protecting group for the hydroxyl radical or R'b represents R, R having the meaning indicated in claim 1 or R'b represents a radical R in which the reactive functions are protected, to obtain a compound of formula IV: • nhrv (iv) 45 syn isomer, in the eis form in which R2 represents a hydrogen atom or an alkyl radical, linear or branched, optionally substituted by one or more halogen atoms, a carboxyl, amino or cyano radical, n 'represents the whole number 1 or 2 and X 'represents a fluorine atom, a 2-pyridinyl thiomethyl radical or a thiocyanato radical, in racemic or optically active form as well as the salts of the products of formula I' with bases or acids. 2 CLAIMS 1. Compounds of general formula (I): nh, 'conh 3 3 655,317 claim 6, to obtain a compound of formula (IV '): shr. AT \ —J -CONK ^ Ra \, O4 nor ' (iv ') NH 13. Medicament consisting of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt of this compound. 14. Medicament according to claim 13, consisting of a compound of formula (I ') according to one of claims 2 to 4. 15. The medicament according to claim 13, consisting of a compound according to claim 5. 16. Pharmaceutical compositions containing, as active ingredient, at least one compound according to one of claims 1 to 5. racemic or optically active, in which Rb, R'b and Ra have the previous meaning, this compound is subjected to a sulfonation, the sulfonated compound is subjected, if necessary, to cleavage by hydrolysis, hydrogenolysis or by the action of thiourea of or protective groups which represent Rb and R'b or which comprise R'b and Ra and, if desired, subject the compound obtained to the salification of the carboxy radical which may comprise the radical R'b and to the salification of the sulfo radical or to the salification by an acid of the amino radical (s). 3. Compounds of the formula according to claim 2 in which n 'represents the number 1 and X' represents a fluorine atom. 4. Compounds of the formula according to one of claims 2 or 3 in which the substituent R2 represents a hydrogen atom or a methyl, difluoromethyl, carbo-xymethyl radical, optionally esterified or salified, a friend-noethyl, cyanomethyl radical , 1-methyl-1-carboxyethyl, optionally esterified or salified. 4-fluoromethyl-3- / 2- (2-amino-4-thiazolyl) 2-difluoromethoxy-imino-acetamido / 2-oxo-azetidine-1-sulfonic eis, syn, racemic or optically active isomer and its salts. 5. Compounds according to claim 3, namely 4-fluoromethyl-3- / 2- (2-amino-4-thiazolyl) 2-methoxyimino -acetamido / 2-oxo-azetidine-1-sulfonic acid eis, syn isomer, racemic or optically active and its salts, as well as acid 55 racemic or optically active in which Rb, R'b, Ra and A have the above meaning, said compound is subjected, if necessary, to cleavage by hydrolysis, hydrogenolysis or by the action of the thiourea of the protective group or groups represented by Rb and R'b or that comprise R'b and Ra and, if desired, subject the compound obtained to the salification of the carboxy radical which the radical R'b may contain and to the salification of the sulfo radical or to the salification by an acid of the or amino radicals. 6. Process for preparing the compounds of formula (I) according to claim 1, characterized in that a compound of formula (II) is treated: 7. Process for preparing the compounds of formula (I) according to claim 1, characterized in that a compound of formula (II ') is treated: h2n- 60 .nh (lï) racemic or optically active, formula in which either 65 Ra represents Ri, Ri having the meaning indicated in claim 1, or Ra represents Ri in which the reactive functions are protected, by a compound of formula (III) above, in which Rb and R'b have the meanings indicated in 8. Method according to claim 7, characterized in that one puts in play a compound of formula (III) in which Rb represents a protective group of the amino radical and in that the sulfonation is carried out on a compound of formula (IV) in which Rb represents a protective group for the amino radical. 9. Process for the preparation of carboxylic esters of the compounds of formula (I) according to claim 1, characterized in that a compound of formula (II) above is treated, racemic or optically active, formula in which either Ra represents Ri, Ri having the meaning indicated in claim 1, or Ra represents Ri in which the reactive functions are protected and A represents a sulfo radical, by a compound of formula (III) above, in which Rb and R'b have the meaning indicated in claim 6 but R'b comprises a carboxy radical, to obtain a compound of formula (IV) above, racemic or optically active, in which Rb, R'b, Ra and A have the preceding meaning , said compound is subjected to an esterification of the carboxy radical, the carboxylic ester obtained is subjected, where appropriate, to cleavage by hydrolysis, hydrogenolysis or by the action of the thiourea of the protective group or groups which Rb represents or which comprises Ra and, if desired, submit the compound obtained upon salification of the sulfo radical or upon salification for an acid of the amino radical (s). 10. A method of preparing the compounds of formula (I) according to claim 1 in optically active form, characterized in that a compound of formula (I) is racemic by the method according to claim 6 and the said subject is subjected racemic compound with the splitting of the molecule. 11. Method according to one of claims 6 to 10, characterized in that the radical Ra represents a fluoromethyl radical. 12. As means for implementing the process according to claim 6, the compounds of formula (II):