IE56521B1 - Azetidines - Google Patents

Abstract

1. Claims : For the contracting states : BE, SE, CH, DE, FR, GB, IT, LI, LU, NL Products of general formula (I) : see diagramm : EP0114128,P43,F6 in which R represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from carboxy radicals, optionally salified or esterified ; amino, methylamino, dimethylamino and diethylamino radicals ; the phenyl radical optionally substituted by one or more radicals chosen from the following radicals : hydroxy, methyl, methoxy, chloro, bromo, fluoro ; fluoro, chloro, bromo or iodo radicals ; nitrile, CONH2 or CONH SO2 R" radicals in which R" represents an alkyl radical having from 1 to 4 carbon atoms ; a phenyl radical, an amino, methyl or dimethylamino radical ; a heterocyclic amino radical chosen from piperidino, morpholino piperazino or 4-ethyl-2,3-dioxo-1-piperazino radicals ; - a cycloalkyl radical having from 3 to 8 carbon atoms or a radical : see diagramm : EP0114128,P44,F1 salified or esterified, in which nc represents a whole number from 0 to 5, - one of the following radicals : acetyl, propionyl or benzoyl, carbamoyl, dimethylamino carbonyl, phenyl or benzyl optionally substituted by alkyl, alkoxy or halogen ; R1 represents a hydrogen atom, an alkyl, alkenyl, alkynyl or thioalkyl radical having a the most 12 carbon atoms, optionally substituted by one or more radicals chosen from azido or alkylthio radicals having from 1 to 4 carbon atoms or a phenylthio radical, optionally salified or esterified carboxy radicals, amino, methylamino, dimethylamino or diethylamino radicals, the phenyl radical, optionally substituted by one or more radicals chosen from hydroxy, halogeno, trifluoromethyl, amino, alkyl or alkoxy radicals having from 1 to 4 carbon atoms ; fluoro, chloro, bromo or iodo radicals, nitrile, CONH2 or CONH SO2 R" radicals in which R" represents an alkyl radical having from 1 to 4 carbon atoms, a phenyl radical, an amino, methyl or dimethylamino radical, a heterocyclic amino radical chosen from piperidino, morpholino, piperazino or 4-ethyl-2,3-dioxo-1-piperazino radicals ; a heterocyclic aryl radical chosen from the following radicals : thienyl, furyl, pyrannyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridinyl or pyrimidinyl ; and the following radicals : acetoxy, propionyloxy, benzoyloxy, acetylamino, benzylcarbonyl, carbamoyloxy, methylaminocarbonyloxy or dimethylaminocarbonyloxy, acetyl, propionyl, and benzoyl, - a free, esterified or salified carboxy radical, - a phenyl radical optionally substituted by one of the following radicals : alkyl, trifluoromethyl, alkoxy, alkylthio, halogen, hydroxyl, amino or hydroxylakyl, a heterocyclic radical chosen from the following radicals : thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolinyl, imidazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl optionally substituted by an alkyl, carboxy, carboxy alkyl, aminoalkyl or dialkylaminoalkyl radical, - an acetyl, propionyl, n-butyryl or benzoyl radical, optionally substituted by alkoxy or hydroxy, - a carbamoyl, methyl or dimethylcarbamoyl radical, - a azido radical. R2 represents a nitrogen-containing heterocycle optionally substituted by one or more of the radicals chosen from the group formed by the following radicals : nitro, carboxy, CF3 , nitrile, halogen, sulpho, alkylsulpho, (CH2 )n SO3 H, (CH2 )n NHSO3 H, (CH2 )n SO2 NH2 , (CH2 )n CO2 H, in which n represents a whole number from 1 to 4 and containing at least one acid hydrogen, X represents a CH radical or a nitrogen atom, the wavy lines indicate that the OR radical can exist in cis or trans form or in the form of a cis-trans mixture, the products of formula (I) being in racemic or optically active form, as well as the salts of the products of formula (I) withthe bases and acids. 1. Claims : For the contracting state AT Process for preparing the products of general formula (I) : see diagramm : EP0114128,P48,F3 in which R represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from carboxy radicals, optionally salified or esterified ; amino, methylamino, dimethylamino and diethylamino radicals ; the phenyl radical optionally substituted by one or more radicals chosen from the following radicals : hydroxy, methyl, methoxy, chloro, bromo, fluoro ; fluoro, chloro, bromo or iodo radicals ; nitrile, CONH2 or CONH SO2 R" raidcals in which R" represents an alkyl radical having from 1 to 4 carbon atoms ; a phenyl radical ; an amino, methyl or dimethylamino radical ; a heterocyclic amino radical chosen from piperidino, morpholino piperazino or 4-ethyl-2,3-dioxo-1-piperazino radicals ; - a cycloalkyl radical having from 3 to 8 carbon atoms or a radical : see diagramm : EP0114128,P48,F1 salified or esterified, in which nc represents a whole number from 0 to 5, - one of the following radicals : acetyl, propionyl, or benzoyl, carbamoyl, dimethylamino carbonyl, phenyl or benzyl optionally substituted by alkyl, alkoxy or halogen ; R1 represents a hydrogen atom, an alkyl, alkenyl, alkynyl or thioalkyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from azido or alkylthio radicals having from 1 to 4 carbon atoms or a phenylthio radical, optionally salified or esterified carboxy radicals, amino, methylamino, dimethylamino or diethylamino radicals, the phenyl radical, optionally substituted by one or more radicals chosen from hydroxy, halogeno, trifluoromethyl, amino, alkyl or alkoxy radicals having from 1 to 4 carbon atoms ; fluoro, chloro, bromo or iodo radicals, nitrile, CONH2 or CONH SO2 R" which R" represents an alkyl radical having from 1 to 4 carbon atoms, a phenyl radical, an amino, methyl or dimethylamino radical, a heterocyclic amino radical chosen from piperidino, morpholino, piperazino or 4-ethyl-2,3-dioxo-1-piperazino radicals ; a heterocyclic aryl radical chosen from the following radicals : thienyl, furyl, pyrannyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridinyl or pyrimidinyl ; and the following radicals : acetoxy, propionyloxy, benzoyloxy, acetylamino, benzylcarbonyl, carbamoyloxy, methylaminocarbonyloxy or dimethylaminocarbonyloxy, acetyl, propionyl, and benzoyl, - a free, esterified or salified carboxy radical, - a phenyl radical optionally substituted by one of the following radicals : alkyl, trifluoromethyl, alkoxy, alkylthio, halogen, hydroxyl, amino or hydroxyalkyl, a heterocyclic radical chosen from the following radicals : thienyl, furyl, pyrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolinyl, imidazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl optionally substituted by an alkyl, carboxy, carboxy alkyl, aminoalkyl or dialkylaminoalkyl radical, - an acetyl, propionyl, n-butyryl or benzoyl radical, optionally substituted by alkoxy or hydroxy, - a carbamoyl, methyl or dimethylcarbamoyl radical, - an azido radical. R2 represents a nitrogen-containing heterocycle optionally substituted by one or more of the radicals chosen from the group formed by the following radicals : nitro, carboxy, CF3 , nitrile, halogen, sulpho, alkylsulpho, (CH2 )n SO3 H, (CH2 )n NHSO3 H, (CH2 )n SO2 NH2 , (CH2 )n CO2 H, in which n represents a whole number from 1 to 4 and containing at least one acid hydrogen, X represents a CH radical or a nitrogen atom, the wavy lines indicate that the OR radical can exist in cis or trans form or in the form of a cis-trans mixture, the products of formula (I) being in racemic or optically active form, as well as the salts of the products of formula (I) with the acids and bases, characterized in that a product of formula (II) : see diagramm : EP0114128,P49,F1 cis or trans, racemic or optically active, in which formula either R1 p represents R1 , R1 having the previously indicated significance, or R1 p represents the substituent R1 in which the reactive functions are protected and either R2 p represents R2 , R2 having the previously indicated significance, or R2 p represents the substituent R2 in which the reactive functions are protected, is treated with a product of formula (III) : see diagramm : EP0114128,P49,F3 syn or anti, in which Rb represents a hydrogen atom or a protector group of the amino radical and Rp represents a protector group of the hydroxyl radical or Rp represents R, R having the significance indicated in claim 1, or Rp represents a radical R in which the reactive functions are protected, so as to obtain a product of formula (IV) : see diagramm : EP0114128,P49,F5 syn or anti, racemic or optically active, in which Rp, R1 p, R2 p and Rb have the previous significance, which product is submitted, if necessary and if desired, to any one of the following reactions, in any order : a) cleavage by hydrolysis, hydrogenolysis or by the action of the thiourea of the protector group or groups which can be represented by Rb and Rp or can be contained in Rp, R1 p and R2 p ; b) esterification or salification of the carboxy or sulpho radicals which can be contained in the radicals Rp, R1 p and R2 p ; c) salification by an acid of the amino radical or radicals ; d) resolution of the molecule so as to obtain an optically active product.

Description

The present invention relates to novel derivatives of 3-amino-2-oxo azetidines having a heterocyclic nitrogenous radical in position 1, a process for their preparation, their application as medicaments and the intermediate products required for their preoaration.

Accordingly, the invention provides products of general formula ('): OA in which R represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from carboxy radicals, optionally sal ified or esterified; amino, methylamino, dimethylamino and diethylamino radicals; the phenyl radical optionally substituted by one or more radicals chosen from the following radicals: hydroxy, methvl, methoxy, -2chloro, bromo, fluoro; fluoro, chloro, bromo or iodo radicals; nitrile, CONHg or CONH SOgR radicals in which RH represents an alkyl radical having from 1 to 4 carbon atoms; a phenyl radical, an amino, methyl or dimethylamino radical; a heterocyclic amino radical chosen from piperidino, morpholino, piperazino or 4-ethyl-2,3-dioxo-l-piperazino radicals; - a cycloalkyl radical having from 3 to 8 carbon atoms or a radical: HjC (CH,)nc sal ified or esterified, in which nc represents a whole number from 0 to 5, - one of the following radicals: acetyl, propionyl or benzoyl, carbamoyl, dimethylamino carbonyl, phenyl or benzyl optionally substituted by alkyl, alkoxy or halogen; Rj represents a hydrogen atom, an alkyl, alkenyl, alkynyl or thioalkyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from azido or alkylthio radicals having from 1 to 4 carbon atoms or a phenylthio radical, optionally salified or esterified carboxy radicals, amino, methylamino, dimethylamino or diethylamino radicals, the phenyl radical, optionally substituted by one or more radicals chosen from hydroxy, halogeno, trifluoromethyl, amino, alkyl or alkoxy radicals having from 1 to 4 carbon atoms; fluoro, chloro, bromo or iodo radicals, nitrile, CONH? or CONH S02R radicals in which R represents an alkyl radical having from 1 to 4 carbon atoms, a phenyl radical, an amino, methyl or dimethylamino radical, a heterocyclic amino radical chosen from piperidino, morpholino, piperazino or 4-ethyl-2,3-dioxo-l-piperazino radicals; a heterocyclic aryl radical chosen from the following radicals: thienyl, furyl, pyrannyl, thiazolyl, thiadizolyl, oxazolyl, oxadiazolyl, pyridinyl or pyrimidinyl; and the following radicals: acetoxy, propionyloxy, benzoyloxy, acetylamino, benzylcarbonyl, V -310 carbamoyloxy, methyl ami nocarbonyloxy or dimethylaminocarbonyloxy, acetyl, propionyl, and benzoyl, - a free, esterified or salified carboxy radical, - a phenyl radical optionally substituted by one of the following radicals: alkyl, trifluoromethyl, alkoxy, alkylthio, halogen, hydroxyl, amino or hydroxyalkyl, a heterocyclic radical chosen from the following radicals: thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl,-isoxazolyl, imidazolinyl, imidazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl optionally substituted by an alkyl, carboxy, carboxy alkyl, aminoalkyl or dialkylaminoalkyl radical, - an acetyl, propionyl, n-butyryl or benzoyl radical, optionally substituted by alkoxy or hydroxy, - a carbamoyl, methyl or dimethylcarbamoyl radical, - a azido radical, represents a nitrogen-containing heterocycle optionally substituted by one or more of the radicals chosen from the group formed by the following radicals: nitro, carboxy, CFp nitrile, halogen, sulpho, alkylsulpho, (CH2)nSO3H, (CH2)nNHSO3H, (CH2)nSO2NH2, (CH2)nCQ2H, in which n represents a whole number from I to 4 and containing at least one acid hydrogen, X represents a CH radical or a nitrogen atom, the wavy lines indicate ,. .. Λη ,. . ., syn or anti form .or tnat .the,prQducts that the OR radical can exist in^cis or trans form or in the form o -xan existM of a cis-trans mixture, the products of formula (I) being in racemic or optionally active form, as well as the salts of the products of formula (I) with bases and acids.

Among the values of R, there may be mentioned: a) methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, decyl, undecyl and dodecyl radicals; b) vinyl, allyl, 1-propenyl, butenyl, pentenyl and hexenyl radicals; and c) ethynyl, propargyl and butynyl radicalsThe radicals mentioned above under a) to c), may be substituted by one or more radicals such as optionally salified or esterified carboxy radicals, for example alkoxycarbonyl radicals, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and tert-amyloxycarbonyl, and optionally substituted benzyloxycarbonyl radicals, such as £-nitrobenzyloxycarbonyl and p-methoxybenzyloxycarbonyl radicals- Among other esterified carboxy radicals there * may be mentioned carboxy radicals esterified by benzhydryl, phenyl and £-nitrophenyl groups. The carboxy group may also be esterified by a group of the V - 5 -CH-O-C-B type in which A represents an alkyl radical I I A 0 containing 1-6 carbon atoms or a hydrogen atom and B represents an alkyl or alkoxy radical containing 1-6 carbon atoms· The radicals mentioned above under a) to c), may also be substituted by an amino, methylamino, dimethylamino, diethylamino or phenyl radical, optionally substituted by one or more radicals selected from hydroxy, methyl, methoxy, chloro, bromo and fluoro radicals.

The radicals mentioned above under a) to c), may also be substituted by one of the halogens : fluoro, chloro, bromo and iodo; by a nitrile radical; or by a CONHg or CONHSO^R substituent in which R may represent an alkyl radical such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, an aryl radical such as phenyl, an amino radical such as amino, methylamino or dlmethylamino or a heterocyclic amino radical such as optionally substituted piperidino, morpholino or piperazino, such as 4-ethyl-2,3-dioxo-l-piperazino.

Among the values of R, carbocylic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, may also be mentioned.

R can also represent a radical of H2C^(CH2 )^CH2 type, salified or esterified, in which -c-co2h nc represents a numeral from 0 to 5.

R can also represent an acyl radical such as alkylcarbonyl for example acetyl or propionyl or an arylcarbonyl radical such as benzoyl; an optionally substituted carbamoyl radical such as - 6 . dimethylaminocarbonyl; or an aryl radical, such as phenyl, optionally substituted by alkyl, alkoxy or halogen, or an aralkyl radical, such as benzyl, optionally substituted in the same way.

The radical R^ may also represent one of the * optionally substituted alkyl, alkenyl or alkynyl radicals as discussed above.

R^ may also represent a thioalkyl radical such as v thiomethyl or thioethyl or a thioalkyl radical derived from another alkyl radical mentioned above for R under a). The thioalkyl radical which R^ may represent may be substituted by tbe same radicals as discussed above for alkyl, alkenyl or alkynyl values. For the thiomethyl radical, the substituent preferred Is carbamoyl, CONHg.

In addition, there may be mentioned alkyl, alkenyl, alkynyl or thioalkyl radicals substituted by one of the following radicals: azido, aryl, such as phenyl, optional ly substituted by halogen, trifluoromethyl, amino, hydroxyl, or alkyl or alkoxy containing 1-^ carbon atoms; and 5 or 6 membered heterocyclic aryl such as thienyl, furyl, pyraqyl, thiazolyl, thiadlazolyl, oxazolyl, oxadlazolyl, pyridinyl or pyrimidinyl.

The alkyl, alkenyl, alkynyl or thioalkyl radicals which the substituent R^ may represent can also be substituted by alkylthio radicals such as methylthio, ethylthio, propylthio, isopropylthio, butylthio or tert-butylthio; arylthio such as phenylthio; an acyl radical such as acetyl, propionyl or benzoyl; acyloxy such as acetoxy, propionyloxy or benzoyloxy; acylamino such as acetylamino; aralkylcarbonyl such as benzylcarbonyl; carbamoyloxy; methylaminocarbonyloxy; or dimethylaminocarbonyloxy.

The values of R^ representing an esterified carboxy group may be selected from such groups discussed above in connection with substituent R.

V - 7 The following values may also be cited for the groups with which the carboxy radical is esterified: methoxymethyl, ethoxymethyl, isopropyloxymethyl, oC-methoxyethyl, oC-ethoxyethyl, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, 4 isobutyryloxymethyl, valeryloxymethyl, isovaleryloxymethyl, tert-butylcarbonyloxymethyl, hexadeoanoyloxymethyl, *propionyloxyethyl, isovaleryloxyethyl, 1-acetyloxyethyl. 1-propionyloxyethyl, 1-butyryloxyethyl, 1-tert-butylcarbonyloxyethyl, 1-acetyloxypropyl, 1-hexadecanoyloxyethyl, 1-propionyloxypropyl, 1-methoxycarbonyloxyethyl, methoxycarbonyloxymethyl, 1- acetyloxybutyl, 1-acetyloxyhexyl, 1-acetyloxyheptyl, phthalidyl, 5,6-dimethoxyphthalidyl, tert-butylcarbonylmethyl, allyl, 2-chloroallyl, methoxycarbonylmethyl, benzyl or tert-butyl, methoxyethoxymethyl, dimethylaminoethyl, cyanomethyl, tert-butyloxycarbonylmethyl, 2,2-ethylenedioxyethyl, cyanoethyl, 2,2-dimethoxyethyl, 2-chloroethoxymethyl, 2-hydroxyethoxyethyl, 2,3-epoxypropyl, 3-dxmethylamino—2-hydroxypropyl, 2-hydroxyethyl, 2-methylaminoethoxymethyl, 2-aminoethoxymethyl, 3-methoxy-2,4-thiadiazol-5-yl, 2-tetrahydropyranyl, 2-methoxyprop-2-yl, 1-hydroxyprop-2-yl, isopropyl, carbamoylmethyl, chloromethyl, 2- chloroethyl, acety lmethyl, 2-methyl thioethyl, thiocyanatomethyl, 2-chloro-l-acetyloxyethyl, 2-bromo-l-acetyloxyethyl, 2-fluoro-l-acetyloxyethyl, 2-methoxy-l-acetyloxethyl, 2-methyl-l-acetyloxypropyl, 2-acetyloxyprop-2-ylt 1-methoxyacetyloxyethyl, 1-acetylcarbonyloxyethyl, 1-hydroxyacetyloxyethyl, 1-formylcarbonyloxyethyl, 1-(2-thieny1)carbonyloxyethy1, 1-(2-fury1)carbonyloxyethyl, l-(5-nitro-2-furyl)carbonyloxyethyl, 1-(2-pyrrolyl)carbony1oxyethyl, 1-(propionyloxy)carbonyloxyethyl, l-(propyloxycarbonyloxy)ethyl, 1-(isopropyloxycarbonyloxy)ethyl, 1-(raethoxyethoxycarbonyloxy)ethyl, l-(allyloxycarbonyloxy)- > ethyl, l-(2,3-epoxy)propyloxycarbonyloxyethyl, 1-(2-furyl)- 8 m ethyl oxycarbonyloxyethyl, 1-(2-fluoro )ethyloxycarbonyloxyethyl, l-(methoxycarbonyloxy )propyl, (2-methoxycarbonyloxy )prop-2-yl, (methoxycarbonyloxy)chloromethyl, 1-(methoxycarbonyloxy >2-chloroethyl, 1-(methoxycarbonyloxy )-2-methoxyethyl, . * 1-(methoxycarbonyloxy)-l-allyl.

When Rj represents an optionally substituted aryl radical, it may be a phenyl radical optionally v substituted by an alkyl, CF^, alkoxy, alkylthio, halogen, hydroxyl, amino or hydroxyalkyl radical, or it may be a heterocyclic radical with 5 or 6 members of which 1 to 4 are hetero-atoms such as N, S or 0. The following radicals may be mentioned as examples: thienyl, furyl, pyrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyi, imidazolinyl, imidazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and triazinyl. The heterocyclic radical, for example these specified radicals, can optionally be substituted by an alkyl, carboxy, earboxyalkyl, aminoalkyl or dialkylaminoalkyl radical.

Among the acyl groups which R^ may represent, there may be mentioned for example acetyl, propionyl, n-butyryl and benzoyl radicals optionally substituted by alkoxy or hydroxy radicals.

Among the substituted carbamoyl groups, methylcarbamoyl or dimethylcarbameyl' groups may be mentioned.

Among the values of R^» there may be mentioned most particularly heterocyclic radicals containing members of which 1 to 4 are nitrogen atoms, such as pyrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl radicals.

The heterocyclic radicals may be substituted by one or more radicals selected from the group consisting * 35 of: nitro, carboxy, CF^, nitrile, halogen, sulpho, alkylsulpho, (CH2 )nSO3H, (CH2 )nNHS(>3H, (CH2 >nS02NH2 and V - 9 (CH^^COgH, in which n represents an integer from 1 to 4.

J Among the salts of the present products of formula (I) with bases, sodium and potassium salts may be mentioned more particularly. These salts may be formed by means of the acid hydrogen which the substituent R2 contains. As the radicals and R can also contain salifiable acid functions, multiple salts may be obtained.

In addition to the sodium and potassium salts mentioned above, lithium, calcium, magnesium and ammonium salts may also be mentioned.

Salts with organic bases may also be mentioned, 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 and N-methylglucamine.

The products of formula (I) may also be presented in the form of salts of acids, since these products contain at least one salifiable amino radical. The acids may be organic or mineral acids.

Among the acids with which the amino groups of the products of formula (I) may be salified, the following acids may be mentioned: acetic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, > ^-toluenesulphonlc, hydrochloric, hydrobromic, sulphuric - 10 and phosphoric. The present compounds may also be presented in the form of internal salts of the azetidine of formula (I).

More particularly, the present invention provides the products 5 comprised in the interior of formula (I) above and corresponding to the general formula (I'): in which R' represents a hydrogen atom or a linear or branched alkyl radical having from I to 6 carbon atoms, optionally substituted by one or more of the radicals chosen from the group formed by the following radicals: free, esterified or salified carboxy radical, amino, monoor dimethylamino, phenyl, halogen, nitrile, CONHSO^R in which R represents an alkyl radical having 1 to 4 carbon atoms, phenyl or amino, mono- or dimethylamino, or R' represents an acetyl, propionyl or phenyl carbonyl radical or a phenyl radical, or R‘ represents a cycloalkyl radical having 3 to 8 carbon atoms or a radical: salified or esterified, in which nc represents a whole number from 0 to 35 5, R'l represents a hydrogen atom or an alkyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from the group formed by the following radicals: halogen, -11azido, hydroxyl, mercapto, phenyl, amino, nitrile, alkylthio having 1 to 4 carbon atoms or optionally oxidized phenylthio, acetyl, propionyl, benzoyl, acetoxy, propionyloxy, benzoyloxy, acetylamino, benzyl carbonyl, carbamoyloxy, methyl or dimethyl carbamoyloxy; or R*l represents an alkenyl or alkynyl radical having at the most 12 carbon atoms, optionally substituted by a phenyl radical or by one or more halogen atoms, or R’| represents a thioalkyl radical optionally substituted by carbamoyl; or R1^ represents a phenyl radical optionally substituted by halogen, a CFp amino, hydroxy, alkyl or ·* alkoxy radical; or R1^ represents an esterified carboxy radical, a carbamoyl radical or an azido radical; R'2 represents one of the following radicals: tetrazolyl, . triazolyl, imidazolyl, purazolyl or pyrrolyl, optionally substituted by one or more of the radicals chosen from the group formed by the following radicals: nitro, carboxy, CFp nitrile, halogen, sulpho, alkylsulpho, (CH2)nSO3H, (CH2)nNHS03H, (CH2)nSO2NH2 or (CH2)nC02H, in which n represents a whole number from 1 to 4, the products having syn isomerism; the wavy line indicates that the products can exist in cis or trans form, or in the form of a cis-trans mixture, the products of formula (I1) being in racemic or optically active form, as well as the salts of the products of fonnula (I*) with bases and acids.

Among che heterocycles which R7 or R'2 may represent the different possible isomers may be mentioned. Thus, each of Rg or % BaZ represent for - . example a pyrrol-2-yl or pyrrol-3-yl radical, a pyrazol-3-yl or pyrazoi-^-yl radical, an Imidazol-2-yI or iaidazol-4-yl radical, or a l,2,3-triazol-4-yl or 1,2,a-triazol-3-yl radical. .

In formula (Ir), more especially Hr represents a hydrogen atom or a methyl, phenyl, difluoromethyl, I-methyl-I-carboxyethyl, cyanomethyl, carboxymethyl cr methylsulphonylcarbamoylaethyl radical; represents a hydrogen atom or a methyl, fluoromethyl, trifluoramechyl,ethoxycarbonyl or carbamoyl radical; and 3'g represents a lH-tetrazol-5-yl or 1,3,u-trlazol-2-yl radical ootionally substituted by a v trifluororaethyl or carboxymethyl radical. Preferably, represents a tetrazolyl radical. - 12 5 tv The present product Is notably: 3-CC2-(2-amInothiazol-fc-yl)*2-mefchoxyIminoacetyl]-amino]-fc-methyl-l-Cl-H-idfrazoI-o-yD-fi-azetldinone, cis or trans, syn Isomer, racemic or optically active; 3-CC2-(2-aminothlazal-fc-yl)-2-oarboxyeeShoxylsinoacefcyl]-aminoj-fc-methy1-1-(L-H-fcetrazoI-5-yI)-2-azetidinone, cis or srana, syn isomer, racemic or optically active; 3-CC2-(2-aminothiazoI-fc-yL )-2-(L-carho xy-l-methyl Jethoxyiainoacecyl]-amino]-fc-methyI-l-(l-H-cetrazol-5-yl)-2-asetidinone, cis or trans, 3yn Isomer, racemic op optically active; 3-C C2-(2-aminot'niacol-fc-yL )-2-methoxylmlnoacec*/l]-amino]-fc-fluoromethyl-Ι-(l-H-tetrazol-5-yi)-2-a3eciC or , syn Isomer, racemic or optically act 3-C £2-( 2-aair.c chia sol* fc-yl )-2-fluorome cho xyiai -aaino]-fc-aechyl-L-Ci-H-£s vazcI-5-yl )-2.-aseti or crans. syr. isomer, racemic or optically act inone, cis ive; or noacetyl]iir.one, cis The present invention is also directed to a process for preparation of products of general formula (I) such as defined above, characterized in that a product of formula (II): (Π) cis or trans, racemic or optically active, in which formula either R^p represents Rp R^ having the significance indicated in Claim 1, or RjP represents the substituent R^ in which the reactive functions are protected and either R2p represents R2, R2 having the significance indicated in Claim 1, or R2p represents the substituent R2 in which the reactive functions are protected, is treated by a product of formula (III): -13NHRb syn or anti, in which Rb represents a hydrogen atom or a protector group of the amino radical, and Rp represents a protector group of the hydroxyl radical, or Rp represents R, R having the significance* indicated in Claim 1, or Rp represents a radical R in which the reactive functions are protected so as to obtain a product of formula (IV): NHRb syn or anti, racemic or optically active, in which X, Rp, R^p, Rgp and Rb have the previous significance, which product is submitted, if necessary and if desired, to any one of the following reactions, in any order: a) cleavage by hydrolysis, hydrogenolysis or by the action of the thiourea of the protector group or groups which can be represented by Rb and Rp or which can be contained in Rp, R^p and R2p; b) esterification or salification of the carboxyl or sulpho radicals which can be contained in the radicals Rp, R^p and R^p; c) salification by an acid of the amino radical or radicals; d) resolution of the molecule so as to obtain an optically active , product. '9 -145 When R^p in formula (II) contains a hydroxyl or amino radical, it may be advantageous to protect these radicals with protective groups which later may be eliminated.

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

Lower alkanoyl groups may be mentioned particularly, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl or pivaloyl. R^p may also contain an alkoxy or lower cycloalkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, •r tert-butyloxycarbonyl, pentyloxycarbonyl or hexyloxy35 carbonyl, a benzoyl, toluolyl, naphthoyl, phthaloyl, mesyl, phenylacetyl or phenylpropionyl group, or an V - 15 aralkoxycarbonyl group such as benzyloxycarbonyl.

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

Chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl or trifluoroacetyl radicals may be mentioned.

A lower aralkyl group may also be employed, such as * benzyl, 4-methoxybenzyl or phenylethyl, trityl, 3,4-dimethoxybenzyl or benzhydryl.

A halo-alkyl group may also be employed, such as > trichloroethyl.

A chlorobenzoyl group may also be employed, or a para-nitrobenzoyl, pg.ra-tert-butvl benzoyl, phenoxyacetyl, caprylyl, n-decanoyl, acryloyl or trichloroethoxycarbonyl group. .

A methylcarbamoyl, phenylcarbamoyl or naphthylcarbamoyl group may-also be employed, as well as the corresponding thiocarbamoyls.

An allyl, benzyloxyalkyl, alkoxyalkoxyalkyl or further a Q-phenylsulphonylalkyl group may equally be employed .

The above list is riot limiting; it is evident that other protective groups of amines, and groups known in particular in the chemistry of peptides, may also be employed .

The protective group of the hydroxyl radical may be selected from the following list: It may be an acyl group, such as formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl or £-nitrobenzoyl. Ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, βββ -trichloroethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 1-cyclopropylethoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxytetrahydropyranyl, trityl, benzyl, 4-methoxybenzyl, benzhydryl, trichloroethyl, 1-methyl-l-methoxyethyl and phthaloyl groups may also be - 16 mentioned.

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

Phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, « para-nitrobenzoyl, para-tert-butylbenzoyl, caprylyl, acryloyl, methylearbamoyl, phenylcarbamoyl, and naphthylcarbamoyl radicals may also be mentioned, κ It will be understood that the values of 10 substitutent Rb when it does not represent a hydrogen atom, as well as the values of protective groups which Rp may possibly represent or contain, in particular when Rp contains an amine, may be taken from the list given above. Likewise for the groups which R2p may contain.

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

As mixed anhydrides, that which is formed with isobutyl chloroformate and that which is formed with pivaloyl chloride and the carboxylic-sulphonic mixed anhydrides formed for example with para-toluenesulphonyl chloride may be mentioned as examples. As an example of an activated ester, the ester formed with 2,4-dinitrophenol and that which is formed with hydroxy benzothiazole may be mentioned , As an example of a halide, chloride or bromide may be mentioned.

Acid azide or acid amide may also be mentioned.

The anhydride may be formed in situ by the action of disubstituted Ν,Ν'-carbodiiraide, for example v N,N’-dicyclohexylcarbodiimide.

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

V - 17 However, other solvents may be used, such as tetrahydrofuran, chloroform or dimethylformamide.

When an acid halide is used, and generally when a hydrohalic acid molecule is freed in the course of the reaction, the reaction is preferably carried out in the presence of a base such as sodium or potassium hydroxide, * carbonates and acid carbonates of sodium or potassium, sodium acetate, triethylamine, pyridine, morpholine or N-methylmorpholine. J The temperature of the reaction is generally less than or equal to ambient temperature.

When Rb represents a hydrogen atom, a carboxyl-sulphonyl mixed anhydride is preferably used.

According to the values of Rb, R^p, R2P and Rp, the products of formula (IV) may or may not be the products formula (I). .

The products of formula (IV) are the products of formula (I) when Rb represents a hydrogen atom, when Rp does not represent a protective group of the hydroxyl radical or does not represent an R radical containing a protected function, when R^p does not represent an R^ radical in which a reactive function is protected and when R^ does not represent a heterocycle containing a protective group.

In the other eases, the action on the product of formula (IV) of one or several hydrolyzing or hydrogenolyzing agents or of thiourea, aims to eliminate the Rb radical when this represents a protective radical of the amino radical, to eliminate the Rp radical when this represents a protective group of the hydroxyl radical and to eliminate the other protective groups which the Rp, R^p and R^p radicals may contain.

The nature of the reagents used in all these cases is well known to those in the art. Examples of * such reactions are given further on in the experimental part.

U - 18 A non-limiting enumeration is now given of the methods which may be used to eliminate the different groups.

Elimination of the Rb group can be carried out 5 by hydrolysis, the latter being basic, acidic or by using hydrazine.

Preferably, acid hydrolysis is used to eliminate optionally substituted alkoxy and cycloalkoxycarbonyl groups, such as tert-pentyloxycarbonyl or tert10 -butyloxycarbonyl, optionally substituted aralkoxycarbonyl groups, such as benzyloxycarbonyl, and trityl, diphenylmethyl, tert-butyl or M-methoxybenzyl groups.

-The acid preferably used may be selected from the group consisting of hydrochloric, benzene sulphonic, para-toluene sulphonic, formic and trifluoroacetic acids. However, other mineral or organic acids may be used .

Basic hydrolysis is preferentially employed to eliminate acyl groups, such as trifluoroacetyl.

The base preferentially used is a mineral base such as sodium or potassium hydroxide. 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 may also be used.

Sodium acetate or potassium acetate may, also be used.

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

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

The chloroacetyl group can be eliminated by thiourea action in a neutral or acid medium according to - 19 the type of reaciton described by MASAKI J.A.C.S., 9£, 4508, (1968).

Other methods of eliminating the protection known in the literature may also be used.

Among the preferred groups, formyl, acetyl, ethoxycarbonyl, mesyl, trifluoroacetyl, chloroacetyl and * trityl groups may be mentioned. Trityl and chloroacetyl radicals are particularly preferred. For the R2p radical, the benzyl group is preferred. > lhe acid which is preferably used is trifluoroacetic acid or formic acid.

The elimination of the Rp radical or of the protective groups which Rp, R^p or R^p contain, when elimination is necessary, can be carried out unde similar conditions to those previously described for the elimination of Rb.

Among others, acid hydrolysis can be used to eliminate the optionally substituted alkyl or aralkyl radicals .

Preferably, an acid is used selected from the group consisting of hydrochloric, formic, trifluoroacetic and para-toiuene sulphonic acids.

The other values of the Rb or Rp radicals or the protective groups which Rp, R^p or R^p contain can be eliminated, when so desired, according to the processes known to those in the art.

The operation is preferably carried out under moderate conditions, that is to say, at ambient temperature or by slight heating.

Elimination of a benzyl radical or of a benzyloxyalkyl radical on the substituent R^p is carried out preferably by hydrogenolysis.

Elimination of an allyl radical on R^p ie carried out for example by action of the complex triphenylphosphine rhodium chloride. T Elimination of an alkoxyalkoxyalkyl radical is V - 20 carried out for example by action of zinc bromide or titanium chloride.

Elimination of an Naturally, when for example Rb, Rp, R^p or RgP are or contain groups to be eliminated belonging to different types, several agents mentioned in the preceding enumerations can be made to act on the products of formula (IV).

Salification of the productscan be carried out according to the usual methods.

Salification of the products in which Rp, R^p or RgP contain a carboxy or sulpho function, may be obtained for example by action on a product in acid form or on a solvate, for example the ethanol solvate'or on a hydrate of this acid, of a mineral base such as sodium hydroxide, potassium hydroxide, or a carbonate or acid carbonate of sodium or potassium. Salts of mineral acids can also be used such as trisodium phosphate. Salts of organic acids may also be used.

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

As sodium salts, sodium acetate, sodium ?-ethylhexanoate or sodium diethylacetate are preferably used.

Salification can also be obtained by action of an organic base or of an amino aci d.

Possible esterification of the products in which RPf rιp or R?p contain an acid function can also be carried out under standard conditions.

Possible resolution of racemic molecules with the formula (II) or (IV) may be carried out according to the usual methods.

An optically active carboxylic or sulphonic organic acid may be used such as tartaric, dibenzoyl - 21 10 tartaric, camphosulphonic or glutamic acids, the decomposition of the salt thus obtained being carried out by means of a mineral base such as acid sodium carbonate or of an organic base such as a tertiary amine, for example triethylamine.

In the present process, especially R^p represents a hydrogen atom or a methyl, f luoromethyl, trif luoromethyl, ethoxycarbonyl or carbamoyl radical; R9p represents a IH-tetrazol-5-yl or l,3,4-triazol-2-yl radical, optionally substituted by a trifluoromethyl or carboxymethyl radical; Rb represents a protective group of the. amino radical; and Rp represents a protective group of the hydroxyl radical, or a methyl, phenyl, difluoromethyl, 1-methyl-I-carboxyethyl, cyanomethyl, carboxymethyl or methyl-sulphonylcarbamoylmethyl radical.

The present invention also provides a preparation process t characterized in that the products of formula (IC): (ΙΌ are prepared by reacting a product of formula (7) * Ap .5.3 in which Rp and R9p have the significance indicated above, in the presence of a scrong base, with a product of formula (VI): Ί5 N w a-as^ :| o (V· -22in which Ap represents a hydrogen atom or an ester group, Rap and R'ap are such that either Rap and R'ap each represents a hydrogen atom, or one represents a hydrogen atom and the other represents a protector group of the amino radical, or Rap and R'ap together form a divalent protector radical of the amino radical, so as to obtain a product of formula (VII): in which Ap, R|p, R?p, Rap and R'ap keep the previous significance and the wavy line indicates that the substituent R|P can exist in alpha or beta position, which product of formula (VII) is submitted, if desired, to one or other of the following reactions, in any order: a) separation of the two isomers; b) protection of the NH? radical when Rap and R'ap each represents a hydrogen atom, which product of formula (VII), in the form of a single isomer or a mixture of isomers, is submitted, when Ap represents an ester group, to a saponification agent, then to a beta-lactamization agent, so as to obtain a product of formula (VIII): (VIII) which product is submitted, if necessary and if desired, to any one of -23the following reactions, in any order: a) separation of the isomers; b) cleavage by hydrolysis, hydrogenolysis or by the action of the 5 thiourea of one of the radicals Rap and R'ap or of these two radicals when one represents a protector group or both represent together a protector group, so as to obtain an expected product of formula (II).

The strong base which is preferably used is butyl-lithium in the presence of a secondary amine such as diisopropylarnine. However, an alkali metal alcoholate may be used such as potassium tert-butylate.

In addition to the protective groups of the amino group mentioned previously, Rap and R'ap may together represent a divalent group such as the benzylidene group or the / \ group. -24Ap may represent one of the ester groups mentioned previously. Among these, a lower alkyl group such as methyl or ethyl is preferred.

If the amino radical of the amino derivative Of the product of formula (VII) is free, either because the operation has been carried out using a product of formula (VI) in which Rap and R’ap each represent a hydrogen atom, or because the protective group which these two substituents represent has been cleaved at the time of the reaction of the products of the formulae (V) and (VI), in that case one proceeds to protect this amino radical. One of the known reactive derivatives of the protective groups mentioned previously can then be used.

In a preferred method for carrying out the process, the amino radical is protected by a trityl radical by using trityl chloride in the presence of abase, preferably an amine such as triethylamine.

Saponification of the -C02Ap group can be carried ?0 out, when Ap represents an ester group, by the action of a base such as sodium or potassium hydroxide in a solvent such as dioxan, followed by acidification, for example by hydrochloric acid .

The cyclisation reaction which enables the products of with formula (VIII) to be obtained is carried out, preferably, in the presence of a ^-lactamisation agent, leading to the preparation of a reactive derivative of the carbonyl.

The sulphonyl-carboxyl mixed anhydride is ' preferably prepared in the presence of tosyl chloride and a base, preferably diazabicyclo-octane or triethylamine. Bromotriphenylphosphine may also be used.

The optional reactions to de-protect the protected amino radical which the R’ap group represents, can be carried out under the conditions indicated above, for example acid hydrolysis. Likewise, it may be preferable to cleave the protective group which the substituent Rgp optionally contains.

The present invention also provides a preparation process characterized in that the products of formula (II) such as described hereinabove are prepared by reacting a beta-lactone of formula (IX): Rap, in which R^p, Rap and R'ap have the significance indicated in Claim 8, with a product of formula (A): (A) in which R?p has the significance indicated in Claim 8, so as to obtain a product of formula (X): R,p (X) R,p -26which product of formula (X) is, if desired, submitted to one or other of the following reactions, in any order: a) separation of the isomers when R.p does not represent a hydrogen atom; b) protection of the NHg radical when Rap and R'ap each represents a hydrogen atom or modification of the protector group represented by one or other of Rap and R'ap or which is formed by Rap and R'ap together, and which product of formula (X), in the form of an isomer or of a mixture of isomers, is submitted to a cyclization reagent so as to obtain a product of formula (VIII): «‘as z N (VIII) i which product of formula (VIII) can be separated into its isomers and 20 which is submitted, when Rap or R'ao represents a protector grouo of the amino radical or when Rap and R’ap together represent a divalent protector radical of the amino radical, to the action of a cleavage reagent by hydrolysis or hydrogenolysis, or to the action of the . thiourea so as to obtain an expected product of formula (':)· The action of the products of formula HyN-R9p on the products of formula (IX) is preferably carried cut in the presence of a trialfcylaluminiufli such as trimethyi-aluminium. The reactant A thus effectively puts into operation a product of formula: R2pNH - Al alkyl alkyl ¥ -27The protection of the amino radical or the optional modification of the protective group can be carried out under the usual conditions described above.

For the remainder of the reaction, it is preferred that the amino radical be protected by a radical such as benzyloxycarbonyl.

The cyclisation reagent which enables the products of formula (X) to become the products of formula (VIII) is preferably diethyl diazodicarboxylate in the presence of triphenylphosphine. However, one could use a dialkylchloramine or carbon tetrachloride also in the presence of triphenylphosphine or of tris dimethylaminophosphine. Lastly, pyridine disulphide could be used. Also, the hydroxy radical of the product (X) may be activated by a group such as mesylate. Cyclisation can then be carried out in the presence Qf a base such as sodium acid carbonate or sodium carbonate., (see Chem. Pharm. Bull. 29, 1063 (1981).

The final possible treatments of the products of formula (VIII) can be carried out under the conditions discussed above.

Like the resolution of the products of formula (II) , , optional or (IV), the/ resolution of racemic molecules of formula (VII) or (X) can be carried out according to the usual methods.

A carboxylic organic acid or optically active sulphonic acid such as tartaric, dibenzoyl tartaric, camphosulphonic or glutamic acid may be used.

Decomposition of the salt thus obtained can be 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. - 28 The present invention is especially directed to a process such as that described hereinabove, characterized in that in order to prepare a product of formula (II) in which the substituent R^p represents a hydrogen atom or a methyl radical, the process described in Claim 8 is put into operation, starting with a product of formula (IX) in which R^p represents a hydrogen atom or a methyl radical.

The present invention is also directed to a preparation process characterized in that the products of formula (II): are prepared by reacting a product of formula: in which ftp, Rap and R'ap are defined as previously, with a product of formula: Y-R2p (XII) in which R2p is defined as previously and Y represents a nucleofugal group in the presence of a base, so as to obtain a product of -29formula (VIII) as defined previously, which can be separated into its isomers and which is submitted, when either Rap or R'ap represents a protector group of the amino radical or when Rap and R'ap together represent a divalent protector radical of the amino radical, to the action of a cleavage reagent by hydrolysis or hydrogenolysis or to the action of the thiourea, so as to obtain an expected product of formula (II).

The nucleofuge group Y is preferably a halogen atom, more particularly a fluorine or chlorine atom, a -O-SOg-CFp -Q-SOg-CgHg or -0-S02-CH3 group or, further, a quaternary ammonium group.

The base utilized may be a metallic hydride, an alkaline alcoholate, an alkaline amide or a tertiary amine. An amide such as sodium or lithium di isopropyl-amide is or sodium or lithium bis-tri-methylsilyl-amide is preferably used. -30The reaction is preferably carried out in a solvent or a mixture of solvents such as ethyl ether, dioxan, tetrahydrofuran, an alkane, a cyclo-alkane, dimethylformamide, dime thylsulphoxide, hexamethylphosphotriamide, toluene , benzene or xylene.

The reaction is most preferably carried out by employing as starting material a product formula (XI) whose amino function is protected.

The Rap and R'ap groups may be those mentioned 10 previously.

The reactions for removing the protection from the amino radical can be carried out under the conditions indicated previously, for example by acid hydrolysis.

If the R^p radical contains a protective group, it is 15 preferable to cleave it by using one of the methods previously mentioned.

The reagents of formula (XII) may further be prepared by converting a reactant of formula (A) as defined above into a corresponding diazo derivative, and reacting this with a metallic halide.

The reagents may further be prepared by a process wherein an isocyanate of formula (a): p-N=C=O (a) in which p is a protective group, is treated with 30 hydrazine, to obtain: II p-NH-C-NH-NH2 (b) - 31 which is then converted into the azide (c): II p-nh-c-n3 (e) The azide is cyclised by the action of phosphorus pentachloride so as to obtain the halotetrazole sought which, if applicable, is submitted to an exchange reaction on the halogen.

An example of such a preparation is given further on in the experimental part.

The reagents of formula (XII) in which Y represents a -O-SC^-CF^, -O-SO^-^J or -O-SO^-CH^ group may be prepared starting with corresponding hydroxylated derivatives, for example by the action of an appropriate sulphonyl chloride.

The reagents of formula (XII) in which Y represents a quanternary ammonium group may be prepared starting with a reactant of formula (A) as defined above, by quaternisation for example by means of an alkyl iodide.

The invention also provides a process characterized in that the^^o? formula (XI) as defined above, with trans configuration, are prepared by reacting a base with a product of formula (XIj): R - 32 9 of cis configuration, in the form of either of the diastereoisomers or of their mixture, in which formula (Xlj), R^p, Rap and R'ap are as defined above and Rc represents a hydrogen atom or a protective group, so as to obtain a lactam of formula (XI?): Rao X R'ap^ ,Rlp (XX2, of trans configuration, in the form of either of the diaestereoisomers or of their mixture, in which formula (XI?), Rj^p, Rap, R'ap and Rc are as defined above, which, if applicable, is submitted to the action of a cleaving agent of the protective group RQ.

In the preferred conditions for carrying out the above-mentioned process: - the base used is an alkaline alcoholate or an alkaline amide, notably potassium tert-butylate, sodium or lithium diisopropylamide or sodium or lithium bis-trimethylsilyl-amide; - the operation is carried out In a solvent or a mixture of solvents such as ethyl ether, dioxan, tetrahydrofuran, an alkane, a cyclo-alkane, dimethylformamide, dimethyl, sulphoxide, hexamethylphosphotriamide, toluene, benzene or xylene; - a product of formula (XI3) is used as starting material In which Rap and R'ap are preferably as defined above and Rc represents a protective group of the amino radical, which may be chosen from the list of protective groups of amines given.previously and may - 33 contain an asymmetrical carbon atom; for example the 1-phenylethyl group may be mentioned.

The cleaving agent of the protective group Rq may be one of those previously described. The cleavage of the protective group Rc may lead, if applicable, to the simultaneous cleaving of groups Rap and R'ap. The 1-phenylethyl group may, for example, be eliminated by the action of ammonium persulphate in acetonitrile.

The compounds of formula (I) and their salts, possess very good antibiotic activity on gram (-) bacteria, notably on coliform bacteria, klebsiella, salmonella and proteus.

These products may notably be utilized as medicaments in the treatment of colibacillosis and associated infections, in proteus, klebsiella and salmonella infections and in other ailments caused by gram (-) bacteria. also The present invention therefore /provides as medicaments, notably as antibiotic medicaments, the products of formula (I), as well as their pharmaceutically acceptable salts.

The invention provides as medicaments, notably antibiotic medicaments, particularly the azetidines of formula (I') (I’) in which R1 represents a hydrogen atom or a linear or branched alkyl radical containing 1 to 6 carbon atoms, optionally substituted by one or more radicals selected from the group consisting of a free, esterified or salified carboxy radical, amino, mono- or dialkylamino, aryl, halogen, nitrile, CONHSOgR in which R1* represents an optionally substituted alkyl, aryl or amino radical, or R1 represents an alkylcarbonyl or arylcarbonyl radical, or a phenyl radical, R'j represents a hydrogen atom or an alkyl radical optionally substituted by one or more radicals selected from the group consisting of halogen atoms, azido, hydroxyl, mercapto, aryl, amino, nitrile, optionally oxidised alkylthio or arylthio, acyl, acyloxy, acylamino, aralkylcarbonyl, carbamoyloxy, alkyl- or dialkyl-carbamoyloxy, or R'j represents an alkenyl or alkynyl radical optionally substituted by a phenyl radical or by one or more halogen atoms; or R'j represents a thioalkyl radical optionally substituted by carbamoyl; or R'j represents a phenyl radical optionally substituted by halogen, CFp amino, hydroxy, alkyl or alkoxy, or R'j represents an esterified carboxy radical, a carbamoyl radical, or an azido radical, R*2 represents a tetrazolyl, triazolyl, imidazolyl, pyrazolyl or pyrrolyl radical, optionally substituted by one or more -35radicals selected from the group consisting of nitro, carboxy, CF3, nitrile, halogen, sulpho, alkylsulpho, (CH2)nS03H, (CH2)nNHS03H, (CH2)nS02NH2, {CH2)nC02H in which n represents an integer from 1 to 4; the products having syn isomerism, the wavy line signifies that the products may be in cis or trans form or in the form of a cis-trans mixture; the products of fonnula (I1) being in racemic or optically active form, as well as the salts of the products of fonnula (I1) with bases and acids. rne invention provides aa medicaments, notably as antibiotic medicaments, more particularly the products described in the Examples and especially: 3-[[2-(2-aminothiazol-4-yl )-2-methoxyiminoacetyl]-amino]-4-methyl-l-(l-H-tetrazol-5-yl)-2-azetidinone, cis or trans, syn isomer, racemic or optically active; 3-[[2-(2-aminothiazol-4-yl )-2-carboxymethoxyiminoacetyl]-amino]-4-methyl-l-(l-H-tetrazol-5-yl)-2-azetidinone, cis or trans, syn isomer, racemic or optically active; 3-C[2-(2-aminothiazol-U-yl)-2-(1-carboxy-1-methyl)ethoxyiminoaeetyI]-amino]-4-methy1-1-(l-H-tetrazol-5-yl)-2-azetidinone, cis or trans, syn isomer, racemic or optically active; 3-CC2-(2-aminothiazol-U-yl )-2-methoxyiminoacetyl]-amino]36 -4-fluoroBethyl-l-(l-H-tetrazol-5-yl)-2-azetidinone, cis trans, syn isomer, racemic or optically active; or 3-[[2-(2-aminothiazol-4-yl )-2-fluoromethoxyiminoacetyl]-amino]-4-methyl-l-(l-H-tetrazol-5-yl )-2-azetidinone, cis or trans, syn isomer, racemic or optically active.

The invention provides pharmaceutical compositions containing as active principle at least one of the present medicaments. The compositions may be administered by the oral, rectal, or parenteral route or by the local route by topical application on the skin or the membranes.

The compositions may be solid or liquid and may be presented in the pharmaceutical forms currently used in human medicine, such as plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams or gels. The pharmaceutical forms can be prepared by the^ usual methods.

The active principle is usually employed in admixture with a pharmaceutically acceptable excipient, which may be an excipient known for use in the formulation of pharmaceutical compositions. Such excipients may be solid or liquid as appropriate to tbe 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.

The compositions may be presented notably in the form of a powder intended for extemporaneous dissolving in an appropriate vehicle, for example apyrogenic sterile water.

The quantity administered varies according to the ailment treated, the person in question, the administration route and the product considered. It may be for* example - 37 between 0.250 and 4 g per day of the product described in Exanple 1 by the oral route in nan, or, further, nay be between 0.500 and lg, three times a day, by the intramuscular route.

The products of formula (Σ) and their salts nay also be used as disinfectants, particularly for surgical instruments.

Lastly, the invention provides as new industrial products the products of general formula (II): H (Π) in which R^p and R2p have the significance indicated hereinabove.

The products of formula (V) which can be used as the starting point in the preparation process may be prepared by reacting an amino of formula (A): (A) with an aldehyde of formula «(3) RtP CHO (3) The intermediate of formula CC) may be obtained, in which alk represents an alkyl radical normally corresponding to the alkanol in which the reaction takes place. The intermediates of formula CC) can be converted into products of formula (II), generally by heiting, for.example in a solvent such as xylene. An example of such a reaction is described in the experimental part. - 38 The reactant of formula R^P NH^ may be prepared by the usual methods. An example of such a reactant, 2-benzyl-5-aminotetrazole, is described in JACS, 76, 923 <1954).

The products of formula (VI) which are derivatives of glycine, may be prepared by the usual methods.

The products of formula (IX) may also be prepared by the usual methods. Notably, when R^p represents a hydrogen atom, the products of formula (IX) is the lactone of serine optionally protected on the amino function When R^p represents a methyl radical, the products of formula (IX) is a derivative of threonine. The lactone of N-trityl L-serine is described in JACS, 81, 6086.

The products of formula (XI^) in which Rc represents a protective group may be prepared from the products of formula (XI) by methods known in the art. They can further be prepared, like the products of formula (XI) themselves, by a process described in Belgian patent no. 894 785.

The invention Is illustrated by the Examples which follow the Table below. The Table below shows products, besides those described in the Examples, which may be obtained within the framework of the present invention; the substituents X, R, R1 and R^ are as indicated in formula (I). ;ί s η a Μ υ J W s S = = ε = = Ε = y τ- α X Cb ΚΛ CM Cm X Ο α Η ω CM Ο Ο CM X Ο ο X κ> X ο κ> U. α Cb -Ρ CMU χ CM ° 8 JM δ ω α m X ο = = S S CM Cb Ο * * * = S χ ο (Μ α 1 /-« **< • * » «Γ S CM Ο υ CM Ξ χ δ Ο CM Cb Ο ίΟ Cu Ο * +, JM ω χ ° 8 *Γ· ·** jn ο ΚΛ Cb Ο α U CM II 12C02if Ε = = = — κΜ χ-ο C W ο ο ι m CM χ = S ϋ α φ χ ·** υ = = = = = = = = = CM α 0- = = = = = - = = = S τ- α X Cb (Λ CM m X I Lu ο ο α Ρ Μ (Μ Ο ϋ CM X δ Ο (Μ tx. EC Ο Cu +* u ω CM Ο ο _£Μ ο ο X <Μ Cb ω | α X — — —== Ε S «Μ • χ ο = S S = = Ε Ε - = S ί\ χ c' = = = = = - = O— ts< s s = = χ m£*. rn X CM U, oxo o •M W _CM O O = mb. X CM O X o m ω o JJ ca rv o o -CM δ o cc CM O mu m X I x 0-0-0 1 = = = = = = = = = S X δ = = = S = . = = = = = = CM az = = = = = = r— CC +> ω cm CM X O X o o o rn . rn X X O O JJ ω CM o o _CM Ξ o o = jn δ 1 i { rw* X o x—w : <»» 1 m ο o = x = = = = m O = t I 1 X 1 tw·» o = AM = = = = = CM az = s = = = <— az b CM »** o CiT' o JJ W CM o O JM o o •M ΛΙ Ck. X o m u, o +» ca CM O o CM ·** δ o az CM Cb< o = = = ~ΪΜ O JF 9 u*> M. MM 0—0—0s s s £ X O s s = = s = = = ο OS u.’’ V , ι X = = = = = X = W i l·? Q = r* tf fa IO CM tf tf tf cj a to fa u +J (4 CM o CJ CM tf tf O CJ »v* Mb* rob ro to tf CM fa tf CJ tf CJ o o 1*1 MM o tf s o CM X = o· = se X = Ml CM O CJ CM Τ- Ο = s = = CM b tf a X tf = CJ = = = = = = = * MM u = CM tf1 ?-»- = «b r1 u H - II Η?9·,1μ> a = = j- T" tf tO +> fa w O CM 8 CM τ* δ CJ •T* ^jto X. CJ ro fa CJ 4-> fa CM O O JM o o ro MM " o b ro (Ufa tf O o * rO tf = a ·' = tf = = = = 3- = = = X s = = δ = = = δ = = = *< = = = = = - = = ' i*1 Hr K 1 *-i« = = ί- α: ro *▼< ·»» ~ o b ~C\J a to Qu O +j ω CM O CJ CM £ a—* a o tf rob tf CM O tf O ro fa O cm' •M +J tf ω o CM O o o tf a: = = = = - δ jAJ δ = = = •M «X* ΓΜ O O 2 CM o o o CM fcRV r :, CM •C CO O ro X •m* £ mm CJ = = = = s = = tf s o s - 42 I <\ CC 1 >-x fi- cc Cn iM X o m fa a P Cd CM O O X Cn m cm X x o o r10 Cb O P Cd CM O O CC CM X X o=o 1 JM O = = = « = = = = X X o = = cm cc . .... iT O/s = = = = = = * > 11 7 = = = X CM jj X ω s o ° o X K\Cx. K\ X CM Ct, OXO O P Cd C\J O o CM s 4~Λ o o •v* I'M = = = x "cm o O = ~i\J X CM -O o cn Ο O s cm m •V· ~Ί = = = = x »r δ CM Cn δ "cm O mo *· X 1 ~ l δ O 0-0 — X s s = = s s = = = = = O X CM CC 0 ?^\Λ = = = = = = = = r~ X X CM ω x ft Cj o •P W CM O O CM £ δ o X δ &* Λ CM -: &· O O +4 W ^JM O O HM · i δ cc _£Πχ = δ = - Cie. δ * = = = II *Ίκ| H203-0- £ 1 kH0 X O = B= * — Λ CC 1 «= S = = 2 Μ ,Ί 2 = = = 0~· = = = r- « -Τ' —· M. o Cu σι Ο Ρ mw Cu CM X s ο ο υ = = = = = = CC * 4 o=o 1 = Of X _ W = = „σι mcu «*» *Γ* χ υ ο "σι ο mo X ι ο-ο1 χ ο Ο σι χ ο — CM X ΣΧ — σι σ w ο ο ο ο ι m σι σι χ X X ο ο X υ = = = = υ s = S = = = — σι a ;-ί Q s = I Im^COjW II = = = = = = -- τ- α: X = = m ρ cu ω -ρ ο σι ω ο ο = = = = = . cc O\ Si υ X ο ο J.M ο σι. Ο "Ο = JM Ο = κ\ •V* Ο _ Χ Cu σι σι ο ο. χ jn ο ο—ο—ο Χ\ί ο X o - = 0 X β = = = = =2H X 8 X = = ί >* - = = = = = τ- ο: Cu X Ch υ υ -Ρ ω CM ο υ CM X ο ο POCu X X CM Ο X Ο m Cu Ο Ρ Cd σι Ο ο •Η m •w< ο Cu σι ο Ol Ο υ _τ-» | -T° = 3—O-U 1 = = σι •Τ· »«4 Μη uh 0=0 1 s σι X ο = = = •J ·* e «/ J = = X ο =' = *** Β ο = = S = = = az 5 2 U kJ kA Q-T = = II II It II II .·' <·> —' u. J J 9' " « r· Ct X o = = - = =w **« = Ot -hj— X X 0=0 1 s CM X o 1 ro cm X &4 O X a PM· •M CM O -v too fO'T' X J X 0-0-0 X = CM o o CM O X CM O X O X- o o 1 CM X o CM CM O X x OT 0=0 Ο 1 IO CM X X X o to X o X o CM X ί Q; = = = = = = = r- x +> s W = = = = = - = - to o 1 cn 1 ·>* WR «** MM CM X- O O α o ru cm »-M —' O O CM "O W X o ~?O bi m "?M o JOO 0-0- 1 A. £ ro ^cu *** *M o o *CM O O CM •v* o ^ΛΙ Ξ-o o=o O OT 1 Ο O CM CM fOX X X o -----o_t -. X X = o = = = = = = CM X Uto ?A 1 ?-x 9 w S = = =φ o’* w W s j/ = =. = «— ot fO P b. W O CM O υ 1 X to X o Gu CM *r* MM a Gu O •P ω CM X o o to X o Cu to CM Cu X O O +j a CM O O OS ^5’ □Γ4 w Mv MM 0=0 = a 1 s = CM m »*« *** 0=0 ^fU ·— o = = s X .- - — o - = - σ α λ ύΓ υ / Ο-. = = = .. H V -x = r· X = m X O s s = X s χ Η* < frM CM <Μ Du Ο χ mo mx Ο X f X ο-ο—ο m cm X Cb O X o »·» "?M X o mo m x t X 0-0—0 I m X o χ X = ο « = s s = £ CM α rv,= = = Γ" χ m χ ο = op α m cu X CM O X o CM O - * X mo m->s o X 1 X CM 0-0-0 X 1 o CM o O _cm o CM X CM Ο X X—O X=O Ο 0Ί 1 Ο O CM ~cm ^mx JL i χ o = = = = = <Μ X At CC τ- α m X X o £b O mp Cm ύ O X m X o Cu CM X O α II = = = ^CM 0=0 = ^CM . £'- = χ X = o = = = = - & X R r2 CH :h2conh h3cso2 -S-CHg 1 2 conh2 /Q 1 H n ;h«-ch 2 II ch2 If II II II II CH-CNH2II 2 0 II II EXAMPLE 1 : (3SR,4RS) 3-//2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl/-amino/-4-methy1-1-(l-H-tetrazol-5-yl)-2-azetidinone syn isomer a) (3SR.4RS) 3-amino-4-methyl-l-(l-H-tetrazol-5-yl)-25 -azetidinone hydrochloride.

A solutiorf of 990 mg of (3SR.4RS) 3-amino-4-methyl-l-Z2-(phenylmethyl)2-H-tetrazol-5-yl7-2-azetidinone 3 hydrochloride in 30 cm of ethanol is taken to reflux then 3 800 mg of palladium at 18% on carbon in 5 cm of ethanol 10 is added.

A current of hydrogen is made to pass for 15 minutes at reflux, then the whole is filtered and evaporated under reduced pressure. 692 mg of the product sought is obtained. b) Mixed paratoluene sulphonic and 2-(2-tritylaminothiazol15 -4-yl)-2-methoxyimino acetic (syn isomer) anhydride· 640 mg of paratoiuene sulphonyl chloride is added to a solution of 1.5 g of 2-(2-tritylaminothiazol-4-yl)-23 -methoxyimino acetic acid, syn isomer in 25 cm of acetone and 0·5 cm of triethylamine. The whole is agitated for 20 half an hour at ambient temperature. - 49 c) (3SR.4RS) 3-//2-/2-tritylaminothiazol-4-yl/-2-methoxyiminoacetyl/-amino/-4-methyl-l-(lH-tetrazol-5-yl)-2-azetidinone, syn isomer.

The solution obtained previously is poured into a solution of 692 mg of (3SR.4RS) 3-amino-4-methyl-l-(l-tetrazol-5-yl)-2-azetidinone hydrochloride in 3 cm of acetonitrile and 1.5 cm of triethylamine. After agitating at ambient 3 temperature for one and a half hours, adding 0.5 cm of acetic acid, separating the precipitate, washing it twice with 2 cm of acetone and drying, a first lot of 460 mg of the product sought is obtained. The filtrate is concentrated 3 3 under reduced pressure to 5 cm then taken up by 50 cm of ethyl acetate. After washing with 10 cm of water, drying the organic phase, concentrating under reduced pressure, taking up the product by 5 cm of ethyl acetate, agitating, cooling, allowing to crystallize for one hour 30 minutes at 0°C, separating and washing the crystals twice with 3 cm of acetone, then with ether, a second lot is obtained of 55 mg of the product sought, identical to the preceding product. ;The two lots .are combined, making a total of 1.015 g of product (m.p. ~ 200°C). d) (3SR,4RS) 3-//2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl/-amino/-4-methyl-l-(l-H-tetrazol-5-yl)-2azetidinone, syn isomer.

Over half an hour, the 1.015 g of product obtained above 1 is heated in 5 cm of 66% formic acid. The triphenyl carbinol precipitate is filtered and washed with 2 cm of 66% formic acid then with 2 cm of water. The filtrate 3 is diluted with 25 cm of water and concentrated under reduced pressure to about 5 cm . The crystals formed are separated and washed with water then three times with 2.5cm of methanol and lastly with ether. The product is dried at 70°C for 4 hours under reduced pressure and finally 471 mg of the product sought is obtained (m.p. 260°C)(Rf-0.25 eluent : ethyl acetate - ethanol - water : 70/20/10). - 50 Analysis : 0χ1 Ηχ3 Ng 03 S = 351.34 Calculated: C% 37.6 H% 3.73 S% 9.12 Found: 372. 3.7 8.8 The (3SR.4RS) 3-amino-4-methyl-l-/2-(phenylmethyl)-2-H-tetrazol-5-yl/-2-azetidinone hydrochloride was prepared as follows: a) N-(1-methoxyethy1)-2-(phenylmethyl)-2H-tetrazol-5-amine.

A mixture of 15 g of 2-benzyl-5-amino tetrazole prepared according to .JACS, 76, 923 (1954), in 300 cm of methanol and 15 cm of pure acetaldehyde is agitated for 18 hours at ambient temperature. After concentrating under reduced pressure to 25 - 30 g and eluting on a 400 g column of silica with ether containing 0.5% of triethylamine, 18.8 g of the product sought is finally obtained, (m.p. ** 60®C) (Rf=0.6 : eluent, ether with 0.5% of triethyl amine). b) N-ethylidene-2-(phenylmethyl)-2H-tetrazol-5-amine. 4.78 g of :the product obtained above is heated to reflux in 100 cm of xylene. The distillation is done at constant 3 volume by adding pure xylene, and in this way 100 cm is distilled off in half an hour. After half an hour, the solvent is evaporated under reduced pressure, and by drying to constant weight under reduced pressure, 4.18 g of the expected product is obtained, which crystallizes. c) (2SR,3SR) and (2SR,3RS) 2-amino-3-'2-(phenylmethyl)-l-H-tetrazol-5-yl-amino/-butanoate of methyl. 3 A solution of 10 cm of diisopropylamine in 100 cm of anhydrous tetrahydrofuran, under argon, is cooled to -60*C, then 40 cm of 15% butyl-lithium in hexane is added over 5 minutes.

The temperature is raised to -30°C, and the mixture is agitated for 5 minutes at this temperature, then the temperature is reduced to -50*C and 11.5 g of methyl ester of N-(benzylidene)glycine, in 30 cm of tetrahydrofuran is - 51 slowly added. After agitation at this temperature for 10 minutes, 13 g of N-ethylidene-2-(phenylmethyl)-2H3 -tetrazol*5-amine in 20 cm of tetrahydrofuran is added.

The temperature is allowed to rise to -30®C and agitation is continued for 30 minutes at this temperature then the solution Is poured into a mixture of 130 cm of 2N hydrochloric acid and 520 cm of water. After agitating for 30 minutes at ambient temperature, washing the solution with ether, adding concentrated ammonia until pH 8.5 - 9, extracting with methylene chloride, drying, and concentrating the filtrate under reduced pressure, 19 g of resin is obtained which is chromatographed under pressure on silica, eluting with a methylene chloride, methanol, concentrated ammonia mixture : 97.5 : 2.5 : 0.4. About 7.22 g of the trans product is obtained and 3.9 g of the cis product. d) (2SR,3RS) 2-/(triphenylmethyl)-amino/-3-(2-phenylmethyl)-2H-tetrazol-5-yl-amino/-butanoate of methyl.

A mixture of 6 g of cis product obtained previously and 3 g of trityl chloride an 60 cm of tetrahydrofuran and 4.2 cm of triethylamine is taken to reflux for 16 hours, then allowed to return to ambient temperature and filtered.

After concentrating under reduced pressure, taking up with 3 200 cm of methylene chloride, washing with water, drying, evaporating to dryness and chromatographing on silica, eluting with a mixture of hexane, ethyl acetate 7 : 3, 7.45 g of the product sought is then isolated (Rf = 0.25 hexane - ethyl acetate 7:3). e) (2SR,3RS) 2-/tritylamino/-3-/2-(phenylmethyl-2H-tetrazol-5-yl-amino/butanoic acid.

A mixture of 7.45 g of the product obtained above, 150 cm 3 of dioxan, 6 cm of sodium hydroxide ION and 12 cm of water is taken to reflux for 40 hours then concentrated under reduced pressure. After taking up by 150 cm of 3 water, 150 cm of ethyl acetate and 30 cm of 2N hydrochloric acid, decanting, extracting with ethyl acetate. - 52 drying, evaporating to dryness, taking up the crystals with ether, cooling, separating, washing with ether and drying at 60°C for 18 hours, 6.22 g of white crystals is then Isolated (m.p. £ 200eC). f) (3SR,4RS) 4-methyl-l-/2-(phenylmethyl)-2H-tetrazol-5-y1/-3-/tritylamino/-2-azetidinone.

A solution of 4.88 g of the acid obtained above in 50 cm of methylene chloride and 2.4 g of diazabicyclo-octane is agitated for 2 minutes at ambient temperature then cooled to -40eC. Over one minute, 9.5 cm of (1M) tosyl chloride in methylene chloride is added and the whole is agitated for 15 minutes at -40°C then the temperature is allowed to rise, over one hour, to 0°C. The whole is washed with water, dried and concentrated under reduced pressure.

The residue is chromatographed on silica, eluting with a mixture of isopropyl ether and methylene chloride 5 : 95, and 1.99 g of the product sought is thus obtained.

(Rf=0.40). g) (3SR.4R5) 3-amino-4-methyl-l-/2-(phenylmethy1)-2H20 -tetrazol-5-yl/-2-azetidinone hydrochloride.

A mixture of 1.97 g of the product obtained above in f), 3 cm of methylene chloride and 1 cm of 8M hydrochloric acid in methanol is agitated for 15 minutes at ambient temperature then concentrated under reduced pressure and 3 taken up by 5 cm of methylene chloride and poured into cm of ether while agitating briskly. The product sought precipitates. After separating, washing with ether and drying under reduced pressure at 60°C for 2 hours, 1.02 g of the product sought is obtained (m.p. 200°C (Rf*0.4 eluent : methylene chloride, methanol, concentrated ammonia : 96 : 4 : 0.5%).

EXAMPLE 2 : (3SR/4SR) 3-//2-(2-aminothiazol-4-yi)-2me thoxy iminoace tyl·/-amino/-4-me thy 1-1 -(l-H-tetrazol-5-yl )-2-azetidinone. - 53 a) (3SR.4SR) 3-amino-4-methyl-l-(l-H-tetrazol-5-yl)-2-azetidinone hydrochloride.

By operating as in stage a) of example 1, starting with 495 mg of (3SR,4SR) 3-amino-4-methy1-1-/2-(phenylmethyl)-2Htetrazol-5-yl/-2-azetidinone hydrochloride, 361 mg' of the product sought is obtained. b) (3SR.4SR) 3-//2-/2-tritylamino/-thiazol-4-yl/-2-methoxyiminoacetyl/-amino/-4-methyl-l-(lH-tetrazol-5-yl)-2-azetidinone.

A suspension of mixed sulphonic and 2-(2-tritylaminothiazol-4-yl)-2-methoxyimino acetic (syn isomer) anhydride prepared as indicated in stage b) of example 1, starting with 450 mg of 2-(2-tritylaminothiazol-4-yl)-2-methoxyimino acetic acid, syn isomer, and 190 mg of paratoluene sulphonyl chloride, is poured into a solution of 209 mg of (3SR,4SR) 3-amino-4-methyl-l-(lH-tetrazol-5-yl)-23 -azetidinone hydrochloride in 25 cm of acetonitrile and 3 0.45 cm of triethylamine. The whole is agitated for 3 hours at ambient temperature then 0.2 cm of acetic acid is added.. After concentrating under reduced pressure, • 3 taking up with 60 cm of ethyl acetate, washing with water then drying the organic phase, evaporating to dryness, taking up with 3 cm of ethyl acetate and agitating, crystals are allowed to form. After 2 hours at 0°C, separating, washing the precipitate with ethyl acetate and then with ether, 0.21 g of the product sought is obtained. (Rf= 0.4 eluent, ethyl acetate - ethanol - water 70 : 20 ; 10). c) (3SR,4SR 3-//2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl/-amino/-4-methy1-1-( lH-tetrazol-5-yl)-2-azetidinone. 190 mg of the product obtained above is heated to 50°C 3 for 15 minutes in 1.5 cm of 66% formic acid. The temperature is allowed to return to ambient over half an hour, then 2 cm of water is added, followed by filtering.

The filtrate is concentrated under reduced pressure, taken 3 up by 4 cm of absolute ethanol, then concentrated under reduced pressure. This operation is repeated three times. then the residue is taken up by 2.5 cm of acetone; solution takes place, then crystals form, and after cooling and separating, these are washed with ether, then dried under reduced pressure at 40°C. In this way, 75 mg of the expected product is obtained (m.p. 220eC) (Rf=O,25, eluent, ethyl acetate - ethanol - water, 70 : 20 : 10).

The (3SR.4SR) 3-amino-4-methyl-l-/2-(phenylmethyl)-2H-tetrazol-5-yl/-2-azetidinone hydrochloride was prepared as follows: a) (2SR,3SR 2-/tri tylamino/-3-/-2-(phenylmethyl)-2Htetrazol-5-yl amino/-butanoate of methyl.

By operating as indicated in stage d) of the preparation following example l, starting with 7 g of trans product obtained at stage c) of the example 1 preparation and with 8 g of trityl chloride, 9.42 g of the expected product is obtained, (m.p. * 160°C)(Rf=0.25, eluent, hexane ethyl acetate 7:3). b) (2SR,3SR) 3-/2-(phenylmethyl/-2H-tetrazol-5-yl-amino/-2-/trityLamino/-butanoic acid.

By operating as indicated at stage e) of the example 1 preparation, starting with 9.42 g of the product obtained above, 8.3 g of the expected product is obtained (m.p. 200°C). c) (3SR,4SR) 4-methyl-l-/2-(phenylmethyl)-2H-tetrazol-5-yl/-3-/(triphenylmethyl)-amino/-2-azetidinone.

By operating as Indicated at stage f) of the example 1 preparation, starting with 8.3 g of the product obtained above, 3 g of the expected product is obtained. d) (3SR,4SR) 3-amino-4-methyl-l-/2-(phenylmethyl)-2H-tetrazol-5-yl/-2-azetidinone hydrochloride.

By operating as indicated at stage g) of the example 1 preparation, starting with 1.7 g of the product obtained above, 790 mg of the expected product is obtained.

EXAMPLE 3 : (3S) 3-//2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl/-amino/-l-(lH-tetrazol-S-yP-Z-azetidinone. - 55 a) (3S) 3-//2-tritylaminothiazol-4-yl)-2-methoxyiminoacetyl/-amino/-l-(!H-tetra2ol-5-yl)-2-azetidinone.

By operating as indicated at stage c) of example 1, starting with 660 mg of (3S) 3-amino-l-(lH-tetrazol-5-yl)-2azetidinone and the mixed paratoluene sulphonic and 2-(2-tritylaminothiazol-4-yl)-2-methoxyimino acetic (syn isomer) anhydride, prepared as in stage b) of example 1, the product expected is obtained, (m.p. ~ 220°C).

(Rf=0.4, eluent: ethyl acetate - ethanol - water 70/20/10). b) (3S) 3-//2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl/-amino/-l-(lH-tetrazol-5-yl)-2-azetidinone.

A mixture of 150 mg of the product obtained at stage a) in 2 cm of 66% formic acid is heated to 50°C for 15 minutes, then allowed to return to ambient temperature and the triphenyl carbinol obtained is filtered and washed with 3 cm of 66% formic acid. The filtrate is concentrated 3 under reduced pressure, taken up by 10 cm of absolute ethanol and evaporated, and this operation is repeated 3 times. The residue is then taken up by 1 cm of acetone, separated, washed with ether, dried under reduced pressure at 60eC for one hour, and 48 mg of the expected product is obtained (m.£.> 260°C)(Rf : 0,1, eluting with ethyl acetate - ethanol - water, 70/20/10).

The 3-amino-l-(lH-tetrazol-5-yl)-2-azetidinone hydrochloride used at the start of example 3 was obtained as follows: a) (2S) 2-tritylamino-3-hydroxy-N(2-phenylmethyl-2H-tetrazol-5-yl)-propionamide.

A mixture of 25 cm of 2M trimethylaluminium in hexane, 3.5 g of 2-phenyimethyl-5-amino-2H-tetrazole and 100 cm of tetrahydrofuran is taken to reflux for 15 minutes, then 6.6 g of N-trityl-L-serine lactone is added. The mixture is taken to reflux for 3 hours, then cooled to 10°C and 3 cm of ethanol is added very slowly while agitating.

After evaporating to dryness, the residue is taken up by 3 300 cm of methylene chloride and 200 cm of water, taken to pH 4 by hydrochloric acid. After decanting and filtering, the organic phase is washed with 200 cm of 0.05 M hydrochloric acid, dried, filtered, and the solvents are - 56 3 evaporated to dryness. The residue ls taken up by 20 cm of ethyl acetate and cooled. The crystals formed are separated, washed with ether and dried under reduced pressure. 5.3 g of the expected product is obtained (m.p. =202-204°C). b) (2S) 2-amino-3-hydroxy-N-(2-phenylmethyl)-2H-tetrazol-5-yi)-propionamide.

A mixture of 3.5 g of the product obtained above, 25 cm 3 of methylene chloride and 1.7 cm of AM hydrochloric acid in methanol is agitated at ambient temperature for 15 minutes. After separating, washing twice with 10 cm of methylene chloride and then twice with 20 cm of ether then drying under reduced pressure, 1.94 g of the expected product is obtained. c) (2S) 2-(phenylmethyloxycarbonylamino)-3-hydroxy-N-(2-phenylmethyl-2H-tetrazol-5-yl)-propionamide.

A mixture of 1.94 g of the product obtained above, 25 cm of water, 2 g of sodium acid carbonate and 25 cm of methyl3 ene chloride is agitated vigorously, then 2.5 cm of benzyl chloroforntate at 50% in: toluene is added. The mixture is agitated at ambient temperature in toluene, then decanted, and extracted once by 25 cm of methylene chloride. The 3 organic phase is washed with 20 cm of 0.05M hydrochloric acid, then dried. After evaporating the solvent under reduced pressure, 2.45 g of the expected product is obtained d) (3S) l-/2-(phenylmethyl-2H-tetrazol-5-yl)-3-(phenylmethyloxycarbonylamino)-2-azetidinone. cm of a molar solution of diethyl diazodicarboxylate in tetrahydrofuran is added at 10°C to a mixture of 2 g of the product obtained at c) and 1.75 g of triphenyl 3 phosphine in 50 cm of tetrahydrofuran. The mixture is agitated for 15 minutes at 10’C, then evaporated under reduced pressure, and chromatographed on silica with a mixture of methylene chloride and ethyl acetate, 85/15. 1.3 g of the expected product is obtained, after triturating with ether (m.p. a. 15O°C). - 57 Analysis : Cig Ηχ0 Νθ Ο0 Calculated: C% 60.3 H% 4.79 N% 22.21 Found: 60.3 4.8 22.0 e) 3-amino-l-(lH-tetrazol-5-yl)-2-azetidinone hydrochloride.

A mixture of 1.3 g of the product obtained above is taken 3 to ref lux in 80 cm of absolute ethanol, then 1 cm of 8M hydrochloric acid in ethanol is added, and then 800 mg of palladium at 18% on carbon. A current of hydrogen is passed until hydrogenation is complete. By filtering and evaporating to dryness, 660 mg of product is obtained.

EXAMPLE 4 : (3SR.4RS) 3-//2-(2-aminothiazol-4-yl)-2-/(difluoromethoxy)imino/-acetyl/-amino/-4-methyl-l-(l-H-tetr.azol-5-yl)-2-azetidinone, syn isomer. α. 2_2ζ^π?ί02ζίζΤΞ£5ϊ2ζ1ζί1ζϊζ£θί£ΒΞ2Αζ5ζϊ22ζ_ -2-azetidinone hydrochloride.

By operating as at stage a) of example 1, using 890 mg of (3SR.4RS) 3-amino-4-methyl-l-/2-(phenylmethyl)-2-H-tetrazol3 -5-yl/-2-azetidinone hydrochloride, 20 cm of ethanol at 70°C and 7.50 mg of palladium at 18% on carbon, after hydrogenating for 15 minutes, the expected product is obtained which is utilized immediately.

B. Mixed_garatoluene^sulphonic and_2-( 2-tritylaminothiazol=4-y 1)2-£difiHoromethoxy)- imino acetic (syn isomer) anhydride.

The operation is done as at stage b) of example 1, utilizing 325 mg of paratoluene sulphonyl and 815 mg of 2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyimino acetic acid, syn isomer, described in the French patent 2,461,713 in 3 cm of acetone and 0.25 cm of triethylamine. ί^-ί225±ή522«2ζΖΖ2ζΖ2ζί£2ίϊ225?2ϊ}2ζί5!ϊΐ2522ζ5ζΣ22ζ2ζ -difluoromethoxyimino/-ace tyl/-amino/-4-methy1-1-(l^H- te t£252iz5zZi2z2z^52ii^i22ne· syn *somer· The suspension obtained at stage B Is added to the solution 3 of the product obtained at stage A in 45 cm of acetonitrile 3 and 0.75 cm of triethylamine. The whole is agitated for - 58 3 hours at ambient temperature, 0.35 cm of acetic acid is added, followed by concentration to dryness under reduced 3 pressure. The residue is taken up by ethyl acetate, 15 cm of a 1M solution of sodium bicarbonate is added, the precipitate is separated, taken up by water, acidified to pH 3-4 by 2N hydrochloric acid, extracted by ethyl acetate, washed with an aqueous solution of sodium chloride, dried and concentrated to dryness under reduced pressure.

The residue is taken up by ethyl acetate, cooled, separated, the crystals are washed with ethyl acetate then with ether, dried under reduced pressure and 308 mg of the expected product is obtained. m.p. 2 220®C.

Si-iSSRiiSSj-a-Z/a^^inothiazol-^-yO-a-^difluoro15 m®t52xZimin°52eSZi/z^!Di02Zz2zrne£5Zizlz^iz3z££££552iz5zZl2z z2-azetidinone, syn isomer. 290 mg of the product obtained at the preceding stage is heated for 15 minutes at 50°C in 2.15 cm of 66% formic acid. The triphenylcarbinol precipitated is separated, washed with 2 cm of 66% formic acid, and the filtrate is concentrated to dryness under reduced pressure. The residue is taken up by ethanol and concentrated again under reduced pressure. This operation is repeated, then the residue is triturated in acetone, separated, washed with acetone and then with ether and dried under reduced pressure. 150 mg of the expected product is obtained. m.p.}260°C.

Analysis: Cu Ηχχ Ng 0g SF2 = 387.33 Calculated: C% 34.11 H% 2.86 F% 9.81 N% 32.55 S% 8.28 Found: 34.1 3.0 . 9.6 32.1 8.2 NMR Spectrum (DMSO) 1.39 - 1.45 ppm : CH3-CH4.6 ppm : .47 to 5.63 ppm : H3 7.04 ppm : of the thiazole 6.4 - 7.15 - 7.95 ppm : CH Fg - 59 7.37 ppm : NH^ 9.7 - 9.8 ppm : NH-CO EXAMPLE 5 : (3SR.4RS) 3-//2-(2-aminothiazol-4-yl)-2-/-(l-pΓopenyl·oxy)imino/-acetyl/-amino/-4-methyl-l-(l-Htetrazol-5-yl)-2-azetidinone, syn Isomer. 0*_5iii2i.2arai2l2®5!:_®2iE5£2l2_32iL2zii:z£ri£yl25!i!22£ni252i -4-yl)-2-(l-propenyloxy)-imino acetic (syn isomer) anhydride The operation is done as at stage b) of example 1, utilizing '265’ mg of paratoluene sulphonyl chloride and 630 mg of 2-(2-tritylaminothiazol-4-yl)-2-(l-propenyloxy)-imino acetic acid, syn isomer (described in French patent 2,361,893) in 3 cm of acetone and 0.2 cm of triethylamine. 5i-i225i4522-.2z^Z2zZ2Zi£ityIa!!ii22zii!iia52iz4ZZi2z2zilz -tetrazol-5-yl)-2-azetidinone, syn isomer.

The o9peration is done as at stage c) of example 1, utilizing the suspension obtained in the preceding stage A and the (3SR,4RS) 3-amino-4-methyl-l-(l-H-tetrazol-5-yl)-2-azetidinone hydrochloride prepared as at stage A of example 4. A first lot of 400 mg of the expected product is obtained, then the mother liquors are concentrated, the residue is taken up by ethyl acetate, and extracted with an aqueous solution of sodium bicarbonate. After decanting, acidifying the aqueous phase, extracting with ethyl acetate, washing with water, drying and concentrating to dryness under reduced pressure, 140 mg of product identical to the first lot is recovered, m.p. 220°C. iiDi22Zz222iZ1^z2£iinoZ"4-rnei!2yiziziI"H‘'£®5ra221*5~Zi )-222^ii2i22n2» syn isomer 380 mg of the product obtained at stage B is heated for minutes at 50°C in 2.8 cm of 66% formic acid, then allowed to return to ambient temperature, and the precipitate is eliminated by filtering. The filtrate is concetrated to dryness under reduced pressure the residue is taken up by water, washed with water, dried at 50°C under reduced pressure and 185 mg of the expected product ia recovered, m.p. 26OeC. - 60 Analysis: 0χ3 Ηχ5 Ng C>3 S = 377.37 Calculated: C% 41.37 H% 4.01 N% 33.40 S% 8.50 Found: 41.3 4.0 33.3 8.5 NMR Spectrum (DMSO) 1 1.38 to 1.45 ppm : CH3-CH 4.58 - 4.64 ppm : N-0CH2 4.61 ppm: .14 to 5.42 ppm : =CH2 .5 to 5.64 ppm : H3 .77 to 6.14 ppm : CH=CH2 6.8 ppm : Hg of the thiazol 7.24 ppm : NH2 9.4 - 9.49 ppm : NHCO EXAMPLE 6 : (3SR,4RS) 3-//2-( ?-aminothiazoI-4-y1)-2-/-(carboxymethoxy)-imino/-acetyl/-amino/-4-methy1-1-(1-H-tetrazol-5-yl)-2-azetidinpne, syn isomer.

A. Mixed_garatolune_sulphonic_and_2=£2-tritylaminothiazol^ zizZilz? zZi£2rtbu£2£X23£!20Mii!!2£!3yi2z22XZziiDi22_a22£i2_ (syn isomer) anhydride7 The operation is done as in example 1, stage b), starting with 480 mg of paratoluene sulphonyl chloride and 1.38 g of 2-(2-tritylaminothiazol-4-yl)-2-(tertbutoxycarbonylmethyl) -oxy/-iminO acetic acid, syn isomer, prepared in the French q 3 patent 2,445,830, in 15 cm of acetone and 0..36 cm of triethylamine. 2χ-.ί223Λ4522*2ζΖΖ2ζί3~££2£Σ22ίΒ2£2£3ΐ2522ζ5ζϊ22ζ2ζΖί£2£ϊζ 52£22Xc2£5°2Xlmeti,Z12'o3tZ>/zi2i£2Z"a2e£^2Zzai?i22zizT2£3^iz -1-(l-H-tetrazol-5-yl)-2-azetidinone, syn isomer.

The operation is done as In stage C of example 4, utilizing the suspension utilized in the preceding stage A and the (3SR,4RS) 3-amino-4-methy1-1-(l-H-tetrazol-5-yl)-2azetidinone hydrochloride prepared at stage A of example 4. 850 mg of the expected product is collected. m.p.A/270°C.

Sx_i225.s.ii322..2zZZ2zi2"amin2£3i—2iz2zZi2z2zZi2££52£Z!D2£!}2*z2z i5i£2Zz3£2£yiZz^!2i22Zz5zSetGZixiziiz3z£2££a£2iz5zZi2’2z -azetidinone, syn isomer. - 61 A solution of 830 mg of the product obtained in the 3 preceding stage B in 2.5 cm of trifluoroacetic acid is agitated for 5 minutes at ambient temperature, then concentrated to dryness under reduced pressure. The residue is taken up by 5 cm of 66% formic acid, heated for 15 minutes at 50°C, cooled, and the precipitate is eliminated by filtering. 3 times successively, the filtrate is concentrated to dryness under reduced pressure, and the residue is taken up by ethanol and then by acetone. Crystallization is initiated, followed by cooling and separating the crystals, washing them with acetone, then with ether and drying them at 50°C under reduced pressure. 240 mg of the expected product is collected, m.p. >26O*C. NMP. Spectrum (DMSO) 1.39 - 1.45 ppm : CH3-CH - 4.58 ppm ; H4 .48 to 5.63 ppm : H3 4.62 ppm : OCH^-CO 6.81 ppm : of the thiazole 7.25 ppm : NH2 9.38 - 9.48 ppm : NHCO EXAMPLE 7 : (3SR.4RS) 3-//2-(2-aminothiazol-4-yl)-2-/(l-carboxy-l-methy 1 ethoxy)-iminoZ-ace tyl/-amino/-4-me thy 1-1-(tetrazol-5-yl)-2-azetidinone, syn i5omer A. Mixed garatoluene sulphonic and 2-(2-tritylaminothiazolίί-toxycarbonyl-l -methylethox^'inji^o.^etic (syn isomer) anhydride.

The operation~isdoneas in stage b) of example 1, starting with 325 mg of paratoiuene sulphonyl chloride and 970 mg of 2-(2-tritylaminothiazol-4-yl)-2-/ (1-tertbutoxycarbonyl-l-methylethyl)-oxy/-imino acetic acid, syn isomer, prepared in French patent no. 2,421,906, in 17.5 cm of acetone and 0.25 cm of triethylamine.

Bie£3SRx4Rs2_32//2-^2^ t£i t^lamino th i azo 1-4-yl2χ2- (1 z£££i52£2iZ22£322^J-zizrn2thZi2£«iZ2ziTi22iz222£ZJ-y,’2mino~ -4-methy1-1-( tetrazol-5-yl)-2-azetidinone, syn isomer.

By operating as in stage C of example 4, utilizing the - 62 suspension obtained in the preceding stage A and (3SR,4RS) 3-amino-4-methyl-1-(1-H-tetrazol-5-y1)-2-azetidinone hydrochloride prepared at stage A of example 4, 1.07 g of the expected product Is obtained. m.p. ~ 220°C.

C. _ (3SR,4RS) 3-//22^22aminothiazol-4-^l2"2-/£l3carboxy-l^methylethoxyl-imino/acet^l/^amihQ/^-meth^l-l-(tetrazol^S^yO-S-azetidinone, syn isomer.

The operation is done as in stage C of example 6, starting with 950 mg of the product obtained in the preceding stage B. The crude product is purified by chromatography on silica, eluting with water. After concentrating to.dryness, the residue is taken up by methanol, and after filtering and eliminating the solvent under reduced pressure, it crystallizes out from acetone. After drying at 50°C, under reduced pressure, 157 mg of the expected product is obtained, m.p. > 26O°C.

NMR Spectrum (DMSO) 1.35 - 1.42 ppm : CH3-CH 1.42 ppm : (CH3>2 4.28 ppm : .28 to 5.43 ppm : 6.75 ppm : of the thiazole 7.15 ppm : NH2 11.34 - 11.44 ppm : NHCO EXAMPLE 8 : (3SR,4RS) 3-//2-(2-aminothiazol-4-yl)-2-(πΐ6ίΝοχγϊίηιηο)-3θ6ίγ1/-Βΐη1ηρ/—4-ethyl-l-( 1-H-tetrazol-5-yl)-2-azetidlnone. ^i-i225if3§2^2z25?i22z5ze£!}XiziziizHz£2££222iz5zZi2z2z z252Si2i2222_!lX5£02i3i2£i3®2.

The operation is done as at stage a) of example 1, starting with 2 g of (3SR.4RS) 3-amino-4-ethyl-l-/2-(phenylmethyl)-2H-tetrazol-5-yl/-azetidinone hydrochloride, but hydrogenating the solution twice successively. - 63 jt B._£3SR,4RS) 3-//2^2-tri tylaminothiazol-4-^1 J^Z-methoxylminoacetyl/-amino/-4-ethyl-l-( l-H-tetrazgl^S-yl)-2azetidinone. cm3 of acetonitrile and 2.85 cm^ of triethylamine are 5 added to the product obtained at stage A, then a suspension of mixed paratoluene sulphonic and 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino acetic (syn isomer) anhydride, prepared as in stage b) of example 1, starting with 2.9 g of 2-(2-tritylaminothiazol-4-yl)-2-methoxyimino acetic acid, syn isomer, and 1.24 g of paratoluene sulphonyl ls added. The whole is agitated for 1 hour 30 minutes at 3 ambient temperature, 0.4 cm of acetic acid is added, and the reaction is continued as in stage b) of example 2. 1.86 g of crude product is obtained which is re-crystallized from acetone. 1 g of the expected product is recovered, m.p. 260°C. Rf = 0.27 (eluent: ethyl acetate, ethanol, water, 7-2-1). z222£ZiZz2Ti22Zziz2thy1z1"£izSz£2££252iz5z2fI2z2z55®£iii2222i 1 g of the product obtained in the preceding stage is heated for 15 minutes at 50eC in 5 cm of 66% formic acid. After allowing the temperature to return to the ambient, filtering, and concentrating the filtrate, 25 cm of water is added, and the mixture is cooled and filtered again. The filtrate is concentrated to dryness under reduced pressure, the residue is taken up by 10 cm of acetone, filtered, the filtrate is concentrated to 3 cm and allowed to crystallize. The crystals are separated, washed with acetone, dried under reduced pressure, and 270 mg of the expected product is obtained, m.p.^210°C. Rf=0.15 (eluent: ethyl acetate - ethanol - water, 7-2-1).

NMR Spectrum (OMSO) 0.9 - 0.98 - 1.05 ppm and 1.67 to 2.22 ppm : Ethyl 3.87 ppm : N-OCH^ 4.22 ppm : H4 4.87 to 4.99 ppm : H3 6.74 ppm: Hg of the thiazole 7.24 ppm : NH2 - 64 9.3 - 9.4 ppm : NH-CO The (3SR,4RS) 3-amino-4-ethy1-1-/2-phenyLmethy1-2H-tetrazol-5-yl/-2-azetidinone hydrochloride used at the start of the example was prepared as follows: a2-.?izilz!D®£!}2iyE£2Bii2z2z£Ei}22yi{B2££Zi2z2z5z£2££a52iz5’ Operating as in stage a) of the preparation following example 1, starting with 2 g of 2-benzyl-5-aminotetrazole and 2 cm of propionaldehyde, 2.72 g of the expected product is obtained. Rf= 0.57 (eluent : ether) b) N-gropy1idene-2-£phenylmethy12-2-H-tetrazol-5-amine Operating as at stage b) of the preparation of example 1, starting with 20 g of the product obtained at stage a) above, 17.5 g of the expected product is obtained. c)-(,2SRi3SR2_and_(2SR±3RS2-2=amino-3-/2r(ghenylmethyl2-2H-tetrazol-5-yl-amino/-gentanoate of methyl.

Operating as in stage c) of the example 1 preparation, utilizing the product obtained in the preceding stage b), 14.07 g of trans product, m.p. 600C, and 6.2 g of 20 c*-s product, m.p. 105°C, are obtained. ί?2-.£215.·.2§32_!!!®£!]χΐ~2ζ££ΐ£χ225ΐΩ2ζ2ζΖ2ζίΕ!}θΕΧ2!!!2£ £xi2z2z zSz£2££az2iz§zZizaniln22zE2E£aE2a£® · Operating as indicated at stage d) of the preparation following example 1, starting with 21 g of trans product, prepared as at stage c) above, 29.8 g of the expected product is obtained, m.p. ~ 190°C. ?2_£S§3»3SR) 22trttylamino-3-/2-(phenylmethyl2322H= tetrazol-5-yl-amino/-gentanoic acid.

Operating as at stage e) of the preparation following example 1, utilizing 29.8 g of the ester prepared above, 26.3 g of the expected product is obtained, m.p. * 175"C. £2-i253x2§Si_5z2£tiZizizZSz£E-22^iiD2i-Xi2zSzHz£2££2S2lz5ziiz z3zi££i£ZiaTi222z2/2"azetldinone· Operating as at 3tage f) of the preparation following example 1, starting with 5.18 g of the acid prepared above, 2.55 g of the expected product is obtained. - 65 Rf-Ο.42 - eluent: methylene chloride-isopropyl ether 95-5). -tetrazol-5-yl/-2-azetidinone hydrochloride.

By operating as in stage g) of the preparation of example 1, utilizing 2.4 g of the trityl derivative prepared above, 1.15 g of the product sought is obtained, m.p. 2O2°C. (Rf*0.52 - eluent: ethyl acetate-ethanol-water 7-2-1). - 66 EXAMPLE 9 : (3SR,JRS) 3-//2-(2-amlnothiazol-4-yl)-2-methoxyimino/-acetyl amino/4»-e thy 1.-1.-(l-H-tetrazol-5-yl) azetidinone. £-_£225.ι2 522-2ζ2ΐί22Ζ-Ζ2£!}Σΐζ£~ (1-H-te t razol^^y 22z The operation is done as at stage a) of example 1, starting with 1.08 g of (3SR.4RS) 3-amino-4-ethyl-l-/2-(phenylmethyl)-2-H-tetrazol-5-yl-2-azetidinone hydrochloride twice hydrogenating the solution for 15 minutes. After filtering, the filtrate is concentrated to dryness, taking up the residue 3 times by ethanol and twice by acetonitrile.

B^_£3SRa4RS2_32//2-£tritylaminothiazol-4-yl2-2-rnethoxyiminoacetyl/-amino/-4-ethyl^l;(1-H-tet£azol-5-yi2zZz Z-52£iSi2222· The operation is done as at stage B of example 8, utilizing the product obtained in the preceding stage A and a suspension of mixed paratoluene sulphonic acid and 2-(2-tritylaminothiazol-4-yl)-2-methoxyimino acetic (syn isomer) anhydride, prepared as at stage b) of example 1, starting with 1.56 g of 2-(2-critylaminothiazol-4-yl)-2-methdxyimino acetic acid, syn isomer and 670 mg of paratoluene sulphonyl chloride. 2g of crude product is obtained which is dissolved in acetone and solidified again by ether. 1.18 g of the expected product is obtained, m.p. = 210eC.

C. (3SR.4RS) 3-//2-(2-aminothiazol-4-yl)-2-£methoxy-_ ii?i22^>.2E2£Xl^zainino/,4'ethX1-z1z^ 1-ίίζ££££252£ζ5ζΧϋζ£ζ -azetidinone.

The operation is done as at stage d) of example 1, starting with 870 mg of the product obtained in the preceding stage B. The crystals are washed with acetone, then with ether. 370 mg of the expected product is obtained, m.p. 260°C (decomposes). Rf = 0.2 (eluent : ethyl acetate35 ethanol-water, 7-2-1).

NMR Spectrum (DMSO) 0.88 - 0.95 - 1.03 ppm : CH^ of the ethyl 3.85 ppm : N-OCH3 - 67 4.33 ppm : H4 .47 to 5.63 ppm : 6.78 ppm : of the thiazole 7.25 ppm : NHg 9.43 - 9.53 ppm : NH-CO The (3SR,4RS) 3-amino-4-ethy1-1-/2-(phenyImethy1)-2-H-tetrazol-5-yl/-2-azetidinone hydrochloride utilized at the start of example 9 was prepared as follows: ^2_l2SR±3RS2_methyl-22tritylamino-2-/2-£ghenyImethy12-2^ "H-tetrazol-5-yl/-amino_gentanoate^ The operation is done as indicated at stage d) of the preparation following example 1, starting with 14 g of the cis product obtained at stage c) of the preparation following example 8. 19.87 g of the expected product is obtained, m.p. ~ 140°C, Rf = 0.17 (eluent : hexane-ethyl acetate, 7-3). 52-i253x2552«2-tritylamino:3-/2-£ghenylmethyl2-2-H-tetrazol^S-yV-amino gentanoic acid.

By operating as indicated at stage c) of the preparation following example 1, starting with 19.8 g of the product obtained in the preceding stage, and 4.4 g of the expected product is obtained, m.p. 2f2O5eC, Rf=0.27, (eluent : ethyl acetate-hexane 7-3).

E2_i2§5i45§2-4z€£!}Yiz1z2?z£E!}EEZii?£5GZi2z2z!iz£®££552iz5z z^i/.z2zS£itYtamino-23azetidinone1 The operation is done as at stage f) of the preparation following example 1, utilizing 4.75 g of the acid prepared as above. 1.82 g of the expected product is obtained. Rf = 0.4, (eluent : methylene chloride-isopropyl ether 95-5). 52-£2§3λ2§η2 3"an,iDoz4"eii}Ziziz23z£Ei}®DZiT-i!}Zi2z3z5z tet razo 1 -5-y 1 /-2-aze t i di£2E2-22X 5£2£5i°£i5® r By operating as at stage g) of the preparation following example 1, starting with 1.8 g of the product obtained above, 1.08 g of the expected product is obtained.

Rfs0.66 (eluent : ethyl acetate-ethanol-water 7-2-1). - 68 EXAMPLE 10 : (3SR,4RS_) 5-/3-//2-(2-aminothiazol-4-yl)-2-methoxyimino acetyl/-amino/-4-methyl-2-oxo-l-azetidiny1/-2-H-tetrazol-2-acetic acid.

A. _(3SR,4RS) 5-/3-//2-( 22arninothiazol-4-^O-2-methox^imino 5 a2S£Zi^"25!ino/z4zi!!2£!}yiz2z2i2ziz252£i2i2yiZziztiz£S££azolz z2z2ceta£2.2£.£S££52£Xi At 50eC 2.27 g of (3SR.4RS) 3-//2-(2-tritylamino)-thiazol3 -4-yl)-2-azetidinone is dissolved in 35 cm of dimethylformamide, the solution is allowed to return to ambient temperature and 170 mg of sodium hydride at 55% in oil is added, with agitation for 15 minutes, followed by adding 1 cm of tert-butyl bromoacetate and leaving for 16 hours under agitation. The reactional mixture is poured into 250 cm of an aqueous solution of 0.1M monosodium phosphate, and extracted with ether. The extract is washed with water, dried and concentrated to dryness under reduced’ pressure. The residue is chromatographed on silica (eluent : methylene chlorideacetone 9-1), and 1.3 g of the expected product is obtained,.-with 130 mg of the corresponding derivative substituted at position 1. §i-i223i4522_5zZ2zZZ2zi2zai!!i2oti}iaz2iz5zyi2z2zT®£!}2iy~ £5!i22_a2e£yi/aii!i222ziz!!!®£!}yi*2-oxozl-aze£idinyl/-2-H-tetrazol-2-acetic acid. 960 mg of the product obtained at stage A is*agitated for minutes in 3 cm of trifluoroacetic acid. After concentrating to dryness under reduced pressure, the residue is taken up by 6 cm of 66% formic acid, heated for 15 minutes at 50eC then allowed to return to ambient temperature. The insoluble matter is separated, the filtrate is concentrated under reduced pressure until it crystallizes; water is added with agitation for 30 minutes, followed by separating, washing with water and drying under reduced pressure. After re-Crystallizing from ethanol, the expected product is recovered. m.p. t* 240°C. Rf=0.14 (eluent : ethyl acetate-ethanol-water 7-2-1). - 69 NMR Spectrum (DMSO) 1.38 - 1.44 ppm : CH^CH 3.89 ppm : OCH^ 4.55 ppm : CH^-CH .55 ppm : H3 .67 ppm : N-CH2-C00H 6.83 ppm : of the thiazole 9,41 - 9.51 ppm : NH-CO EXAMPLE 11 : (3SR.4SR) 3-//2-(2-amlnothlazol-4-yl)-2-methoxyimino acetyl/-amino/- 4-(fluoromethyl)-1-(1-H-tetrazol-5-y1)-2-azetldinone.

A. (3SR.4SR) 3-tritylamino-4-f luo rome thyl-^azetidinone. 2.22 g of (3SR,4SR) 3-amino-4-fluoromethyl-2-azetidinone hydrochloride, prepared as in Belgian patent 894,785, is agitated for 3 hours at ambient temperature in 60 cm of methylene chloride, 4.2 cm of triethylamine and 4.1 g 3 of trityl chloride. 100 cm of methylene chloride is added, followed by washing with water, drying and concentrating to dryness under reduced pressure. The crystals are taken up in isopropyl ether, separated, washed with isopropyl ether, then with pentane, dried under reduced pressure at 50°C, and 4.36 g of the expected product is obtained, m.p. 200° - 202°C (with decomposition).

B. £3SR24SR)^l2(1-benzyltetrazol-5-y12^3-tri.tylamino-4z£i22£2!!2£!}Ziz2za52£i2iG2n£ 3.6 g of the product obtained in the preceding stage is 3 dissolved at 50®C in 60 cm of tetrahydrofuran, then the 3 solution is cooled to -40°C. Over 3 minutes, 15 cm of a 0.66M solution of sodium bis-trimethylsily1 amide in tetrahydrofuran is added, the mixture is agitated for 5 minutes at -30°C, then cooled to -60eC, and a suspension is obtained which is poured slowly into a solution of 2 g of 5-fluoro-l-benzyltetrazole in 900 cm of toluene.

After agitating for 30 minutes at ambient temperature, adding 50 cm of a 1M aqueous solution of monosodium phosphate, decanting, drying and concentrating to dryness under reduced pressure, a residue is obtained which is - 70 chromatographed on silica (eluent : benzene-ethyl acetate 97-3). 2.6 g of crude product is isolated which is crystallized from ether. 2.18 g of the expected product is obtained. Rf = 0.4 (eluent : benzene-ethyl acetate 95-5). £±-ί223±4§32-1ζί1ζ5®2Ξϊ2£®ί£2Ξ2ΐζ5ζΖ22ζ2ζ2ί?222ζ4ζ£222£2ζ methyl-2-azetidinone hydrochloride. —" —————————————— 3 2.18 g of the preceding product in 60 cm of methylene chloride and 1.3 cm of a 5M solution of hydrochloric acid is agitated for 30 minutes at ambient temperature in a methanol-water solution (97-3). The precipitate is separated, washed with methylene chloride and then with ether, dried, and 1.17 g of the expected product Is obtained, m.p. 180 - 200®C (with decomposition).

D^_(3SR,4SR) 3-amino-4-fluoromethyl^iz^l-H-tetrazol-5zZi2z3z252£i5i222S-!}Z5£22!}i2£i5®’ A mixture of 1.17 g of the hydrochloride obtained at the 3 preceding stage in 50 cm of methanol, with 160 mg of palladium at 18% on carbon is hydrogenated for 30 minutes at 40eC. After filtering and concentrating the filtrate to dryness under reduced pressure, 836 mg of the expected product is obtained. Rf=0.1 (eluent : ethyl acetate-ethanol water 7-2-1).

Ei_£253i4§52-2zZZ2zZ££i£yi2Si22zi£!ii252iz2zZi2zSzS2£i}2iXz 25 i5?i22Zz52®£iiZz2!Di22Zz2"f3’uo£2!B2£!2Xizi^ l-H-tetrazol-5ζΖ22ζ2ζ25®£ί5ί222®· 102 mg of the product obtained at the preceding stage is 3 3 dissolved in 3 cm of acetonitrile and 0.2 cm of triethylamine; this solution is poured slowly into a suspension of mixed paratoluene sulphonic and 2-(2-tritylaminothiazol-4-yl)-2-methoxy acetic (syn isomer) anhydride prepared as at stage b) of example 1, starting with 203 mg of 2-(2-tritylaminothiazol-4-yl)-2-methoxyimino acetic acid, syn isomer, and 88 mg of paratoluene sulphonyl chloride. After agitating for 30 minutes, 0.05 cm of acetic acid is added; the mixture is then concentrated to 2 cm under reduced pressure, taken up with ethyl acetate, washed with water, dried and concentrated to dryness. The residue is taken up again by ethyl acetate, cooled, separated and the - 71 crystals are dried. 186 mg of the expected product is obtained, m.p. « 200°C. 3^_£353Λ453ΐ-2ζ£Ζ2ζ£2ζ2"ϊϊ22£3ΐ352ΐζ4ζΣϋΣ2ζ!5®£ί}2ϊϊ1ΐ!ϊϊ22 acetyl/-aminoZ-4-( fluoromethyl )γ1-;( l-H-tetrazol-5-yl)-2-azetidinone. 202 mg of the product obtained as previously is heated for minutes at 50°C ln 4 cm of 66% formic acid. This is then cooled, separated, and the filtrate is concentrated under reduced pressure. After taking up by water, the crystals are separated and washed with water, with acetone, and then with ether. 88 mg of the expected product is isolated, m.p. * 250°C. Rf~0.2 (eluent : ethyl acetateethanol-water 7-2-1).

NMR Spectrum (DMSO) 3.86 ppm : OCH^ from 5.60 to 5.74 ppm : 6.78 ppm : of the thiazole 7.22 ppm : NHg 9.44 - 9.53 ppm ; NH-CO The 5-fluoro-l-benzyltetrazole utilized at the start of example 11 was prepared as follows: s£!?i-£arbadize 9.7 cm^ of hydrazine hydrate in 50 cm3 of tetrahydrofuran 3 and 50 cm of ether is cooled to -5®C +2° under an inert " 3 atmosphere, and 26.6 g of benzyl Isocyanate in 100 cm of ether is added. The mixture is agitated for 16 hours while allowing the temperature to return to ambient; the precipitate is separated, washed with ether, taken up by 250 cm of methanol and heated to reflux. After 3 filtering and concentrating the filtrate to 50 cm under reduced pressure, ethyl acetate is added and the methanol is eliminated by distilling. The remainder is concentrated to 100 cm , then cooled, the crystals are separated, washed with ethyl acetate and dried under reduced pressure. 25.56 g of the expected product is obtained, m.p.«115*0. - 72 of Εϊϊ£ΩΣΐΕΕ£-ϊ22-carbamic_acid. 8.19 g of sodium nitrite is added to a solution of 19.5 g of the amide obtained in the preceding stage in 3 331.5 cm of water and 58.5 cm of 2N hydrochloric acid, maintained at a temperature lower than 25°C. After * agitating, for 1 hour, the precipitate is separated, washed with water and dried and 18.9 g of the expected product is obtained, m.p. 85°C. - 22-5z25i2£2zlz5SD2:Xi£2£E£22i®· A solution of 23.5 g of phosphorus pentachloride in 250 cm of trichloroethylene is added slowly under agitation to a suspension of 15.8 g of the product obtained in the 3 preceding stage in 150 cm of trichloroethylene. After heating for 1 hour at reflux, the solution is cooled and poured into an aqueous solution of sodium bicarbonate, then decanted and extracted by methylene chloride. The extract is washed with an aqueous solution of sodium chloride, dried and concentrated to dryness under reduced pressure. The residue is chromatographed on silica (eluent: hexane-ethyl acetate 7-3) and 6.85 g of the expected product is obtained. 32_5z£i22£2zizb225Ki£2££222i2 g of 18-6 crown ether and 20 g of potassium fluoride 3 are mixed in 3 litres of acetonitrile. 500 cm of the solvent is distilled off under a current of argon and 7.9 g of the product obtained as in the preceding stage is added. This is heated to reflux for 65 hours, then filtered and concentrated to dryness under reduced pressure. The residue is taken up in benzene, concentrated to dryness, the new residue is chromatographed on silica (eluent: hexane-ethyl acetate 7-3) and 5.73 g of the expected product is obtained. Rf=0.23 (eluent : hexane-ethyl acetate 7-3).

* EXAMPLE 12 : (35) 3-//2-(2-aminothiazol-4-yl)-2-methoxy35 iminoacety1/-amino/-!-(3-trifluoromethyl-lH-1,2,4-trlazol-5-yl)-2-azetidlnone. - 73 The operation is done as at stage a) of example 3, starting with (3S) 3-amino-l-(l-H-l,2,4-triazol-5-yl)-2-azetldinone hydrochloride and mixed paratoluene sulphonic and 2-(2-tritylaminothiazol-4-yl)-2-methoxy5 imino acetic (syn isomer) anhydride, prepared as at stage b) of example 3. The synthesis is continued as in stage b) of example 3, and the expected product ls obtained. Rf=0.15 0.2 (eluent: methylene chloride-acetone-methanol, 75-17-8). NMR Spectrum (DMSO) 3.85 ppm : (s) OCH^ 3.75 to 4.33 ppm : (m) - 5.19 ppm : (m) H3 6.78 ppm : (s) of the thiazole 7.22 ppm : (s) NH2 9.31 ppm : (d) NH-CO IR Spectrum (nujol) 1780-1663 cm1 : -C«0 1530 cm1 : secondary amide 1588 cm’1 : conjugated system 1150-1200:cm1 : CF- : -1 J 1025 and 1045 cm : oxime The (3S) 3-amino-l-(l-H-l,2,4-triazol-5-yl)-2-azetidinone hydrochloride utilized at the start of example 12 has been prepared as follows: 22_ib£22Zl *3z2Tin2z5z££i£i22£2Hi££!}ZlzI±2ifz££i252l£ g of 2-phenylmethyl-hydrazine carboximidamide is . 3 agitated at ambient temperature in 100 cm of methanol with 2.7 g of sodium methylate, then 6 cm of ethyl trifluoroacetate is added, with agitation for 1 hour, followed by concentration to dryness under reduced pressure. The residue is taken up with ether, chromatographed on silica, eluting with ether, and 7.1 g of crude product ls obtained, which is triturated in isopropyl ether, then separated and dried. 6.25 g of the expected product is obtained, m.p. = 126°C„ f z££i222 Iz5-yl2x2-aze t idlnone hydrochloride. - 74 The operation is done as in stages a), b), c), d) and e) of the preparation after example 3, starting with the product obtained in the preceding stage and N-trityl-L-serine lactone.

EXAMPLE 13 : (3S) 3-//2-(2-aminothiazoi-4-yi)-2-methoxyimino acetyl/-amino/-l-(4-nitro-3-trifluoromethy1-1H-pyrazol-5-yl)-2-azetldinone. * ¢:-(2§2_2z te££E2£25Z-£2£E2Gii2Ti22zizZizZ2ziE322Xi t3i22z -ethyl/^3-trifluoromethyl-4-ηίtropyrazol^S^yi/;210 azetidinone. 925 mg of 3-tertbutoxycarbonylamino-2-azetidinone, prepared according to the French patent 2,509,299 is cooled to -35°C 3 in 20 cm of tetrahydrofuran, and 6.25 cm of an 0.8M solution of sodium bis trimethylsilyl amide in tetra15 hydrofuran. After agitating for 15 minutes at -35°C, 2.2 g of l-^-(phenylthio)ethyl/-3-trifluoromethyl-4-nitro-5-fluoropyrazole is added. The mixture is allowed to return to ambient temperature, then poured Into 100 cm of a IM aqueous solution of monosodium phosphate and extracted with ether. The organic phase is dried, then concentrated, and the residue is chromatographed on silica (eluent: hexane-ethyl acetate 75-25), and 1.65 g of the expected product is isolated. Rf=0.22 (eluent, hexaneethyl acetate, 8-2). lj_i352-2zi®££5y£2iX2a£222Zi25?iE2z2zZizZ2ziEi32£?Z22222t?22Zi2 ££3ziZz3z££i£i22£2TS£!3Ziz5zGi££2EZ£22Olz2zZiZz2z -azetidinone. 400 mg of m-chloroperbenzoic acid in a solution of 1.05 g of the product obtained in the preceding stage is added under agitation and in two lots with an interval of 5 minutes to 10 cm of methylene chloride. After leaving under agitation for 30 minutes at ambient temperature,4 cm of methylene chloride is added. The organic phase * is washed with an aqueous solution of potassium acid carbonate, then dried and concentrated to dryness. 1.05 g of the expected product is isolated, Rf=0.45 (eluent: * methylene chloride-ethyl acetate 9-1). - 75 0^.^(3§2_3-tertbutoxycarbonylaminozl2Zziz£i££2z2z££iz fluorome thylgyrazol-5-y1/~2-azetidinone. 2.4 cm of 1.45M solution of potassium tertbutylate in tetrahydrofuran is added to 1.60 g of the product prepared as in stage B) above in 80 cm of ether.

After agitating for 15 minutes, 3.3 cm of N hydrochloric 3 acid and then 20 cm of water are added, followed by decanting, extracting with ether, drying the organic phase and concentrating it to dryness under reduced pressure. After chromatographing on silica (eluent: methylene chloride-methanol 96-4), 580 mg of crude product is isolatedwhichis re-crystallized from a mixture of isopropyl and ethyl ethers, 5-3. 503 mg of the expected product is obtained, m.p. ** 2OO-21O°C (with decomposition) Rf = 0.3 (eluent : methylene chloride-methanol 9-1) .^3-amlno-l-/4-nitro-3-trifluoromethylgyrazol75zZiZz2z£S££i5i£2G2_££i£l22£2£2££2££· 452 mg of the product obtained In the preceding stage C is agitated for 15 minutes at ambient temperature in 5 cm of trifluoroacetic .acid, then concentrated to dryness. • * 3 The residue is taken up by 15 cm of acetonitrile and concentrated. This operation is repeated four times, then the solvent is evaporated under reduced pressure and 476 mg of the expected product is recovered. Rf=0.2 (eluent: methylene chloride-methanol 8-2).

E._£3s2_3-//2-£2-t£ityiaminothiazoi-4.--yi2-2-methoxy imino ac®£yiZza5!i£2Zz1zi5"ni£ro*2z££i£i22£2T2t!3Z1‘*1!i*2Zra£oLZ5* "Zi2z2-azetidinone.

A solution of 475 mg of the product previously obtained in 3 cm of acetonitrile and 0.35 cm of triethylamine is added to a suspension of mixed paratoluene sulphonic and 2-(2-tritylaminothiazol-4-yl)-2-methoxyimino acetic (syn isomer) anhydride, prepared as in stage b) of example 1, starting with 600 mg of acid and 256 mg of paratoluene sulphonyl chloride. After agitating for 1 hour at ambient temperature, the mixture is concentrated; the residue is taken up by methylene chloride, washed with a IM aqueous - 76 solution of monosodium phosphate and 0.1N hydrochloric acid; the organic phase is dried and concentrated to dryness. After chromatographing the residue on silica (eluent: methylene chloride-methanol 94-6), 657 mg of the product sought is isolated. Rf*0.4 (eluent: methylene chloride-methanol 9-1). ΕΛ^ί222-2ζΖΖ2ζί2ζ25ΐ22£ϊ}ΐ2522ζ4ζΧΐ2ζ3ζ22£!ϊ25Σΐ5ΐ22_2£££ΧΐΖζ z£!?i22Zzizi2z2i£E2z2z£Ei£i22E2!S££!2Zizi3z2ZEaz2iz5zXi2z2" azetidinone· By operating as in stage b) of example 3, starting with 610 mg of the product obtained in the preceding stage E, 257 mg of the expected product is obtained, m.p. * 200210eC. Rfs0.45 (eluent: ethyl acetate-ethanol-water 85-10-5).

NMR Spectrum (DMSO) 3.87 ppm : N-OCH^ 4.11 to 4.42 ppm : H4 5.18 ppm : H3 6.77 ppm : of the thiazole 7.22 ppm :. NH^ 9.36 - 9.44 ppm : NH-CO IR Spectrum (nujol) 1790 (inflexion) 1763 (max) 1750-1680-1655 cm-1 : C=0 1603-1585-1537-1528 cm-1 : aromatic The l-/2-phenylthio)-ethyl/-3-trifluoromethyl-4-nitro-5-fluoropyrazole utilized at the start of example 13 was prepared as follows: a2_3z5E2moziznitE2~5-t£ifluoromethylpyrazole, g of 3-bromo-5-trifluoromethylpyrazole is heated to 80°C in 100 cm of pure sulphuric acid and, over 15 minutes, lOg of potassium nitrate is added. After agitating for 45 minutes at 80°C, cooling, pouring on ice, extracting with methylene, drying the organic phase and concentrating it to dryness under reduced pressure at 50°C, 16.9 g of the expected product is obtained, m.p. = 50-60eC. - 77 52_lx/22£Ehenylthlo22®£byl/;3-trifluorornethyl-4-nitro-5-bromo gyrazole. l. 95 g of sodium at 55% in oil Is added to 10.4 g of the product obtained at the preceding stage in 100 cm of dimethyl formamide. After 15 minutes of agitation at ambient temperature, 10 g of 2-phenylthio-l-bromoethane # is added and the mixture is taken to 80°C for 16 hours.

It is then cooled, poured into 600 cm of water and extracted with ether, the organic phase is dried and * concentrated under reduced pressure. The residue is taken up with hexane, cooled, the crystals are separated, washed with hexane and with isopropyl ether, then again with hexane. After recrystallizing from isopropyl ether, 6.2 g of the expected product is isolated. After chromatographing the mother liquors on silica (eluent: hexane-ethyl acetate 8-2), a second lot of 6.1 g of identical product is recovered, that is, 12.3 g of the expected product. m. p. 66-68°C. 22-.izZ3ziEi}£DZi££‘io2z££!}Z1,Zz2z££i£222£2iD££!}Ziz5z0ii£ozSz -fluorogyrazole. g of 18-6 crown ether, 1200 cm3 of acetonitrile and 7 g of potassium fluoride are taken to reflux under inert 3 atmosphere, then 200 cm of the solvent is distilled off and 6.2 g of the product obtained in the preceding stage is added. After heating for 2 hours at reflux, filtering and concentrating to dryness, taking up the residue with benzene and concentrating this under reduced pressure, 4.8 g of the expected product is obtained.

EXAMPLE 14 : (3SR.4SR) 3-//2-(2-aminothiazol-4-yl)-2-/(1-carboxy--- -l-methylethoxy) iminoZ-acetyl·/-amino/-4-(fluoromethyl)-1-(tetrazol-5-yl)-2-azetidinone trifluoroacetate.

By operating as in example 7, stages E and F, starting ’ with (3SR.4SR) 3-amino-4-fluoromethyl-l-(l-H-tetrazol-5-yl)-2-azetidinone hydrochloride prepared as in stage D of - 78 example 11 and mixed paratoiuene sulphonic and 2-(2-tritylaminothiazol-4-yl)-2-/-(1-carboxy-l-methylethoxy)imino/-acetic anhydride prepared as in example 7, the expected product is obtained.

NMR : Spectrum (DMSO) 1.64 ppm (s) : gem-dimethyl 4.69 to 5.06 ppm (m) : H4 + CHgF 5.66 ppm (m) : H3 6.75 ppm (s) : of the thiazole 7.36 ppm (m) : NH-CO 12.65 ppm : CFg-COgH IR Spectrum (nuj ο1) 1780-1675 cm1 : amide and trifluoroacetate 1640 cm'1 : NH., 1590 cm-1 : CO, θ 1550 cm : conjugated system 1200-1143 cm'1 : CF3 EXAMPLE 15: (3SR.4RS) 3-//2-(2-amlnothiazol-4-yl)-2-methoxyimino acetyl/-amlno/-4-rf luoromethyl-l-C tetrazol-5-yl)20 -2-azetidino_ne.

By operating as Ln example 11, stages A and E, starting wi th (3SR,4RS) 3-amino-4-fluoromethy1-2-azet idinone hydrochloride, the expected product is obtained. Rf=0.2 (eluent: ethyl acetate-ethanol-water 7-2-1)..

NMR Spectrum (DMSO) 3.86 ppm (s) : O-CH^ 4.56 to 5.22 ppm (m) : CH2-F + H3 +H4 7.24 ppm (s) : NHn 9.42 ppm (d) : NH-CO IR Spectrum (nujol) 1770-1675 cm1 : C=0 1528 cm1 : secondary amide 1640 cm1 (deformation) : NH? -l 1611-1592-1528 cm : conjugated system 1032 cm*1 : oxime - 79 The (3SR.4RS) 3-amino-4-fluoromethyl-2-azetidinone hydrochloride utilized at the start of example 15 has been prepared as follows: 22_i25§i43l2.12332_2z25ii22z5z£i22£2T2£!}ZizizilzE322Zi2£!}Zi2z -2-azetidinone. 8.6 g of hydrazine hydrate in 50 cm of methanol Is added over 3 minutes to a solution of 61 g of .(3RS,4RS,1ISR) 3-phthalimido-4-fluoro-l-(1-phenylethyl)-2-azetidinone in 600 cm of dioxan. After agitating for 1 hour at ambient temperature 175 cm of N hydrochloric acid ls added. The dioxan is evaporated, 400 cm of methanol is added, with agitation for 2 hours at 40°C. After filtering, the filtrate is concentrated to dryness under reduced pressure, the residue is taken up with 300 cm of water and the insoluble matter is eliminated by filtering. The filtrate is washed with methylene chloride, 87 cm of 2N sodium hydroxide is added.to the aqueous phase, which is then extracted with methylene chloride. The organic phase is dried,.concentrated .to dryness, and 34.3 g of the expected product is obtained. Rf=0.4 (eluent: methylene chloride-methanol-ammonia 95-5-0.5). 52.( ’ 3^2 3"/£Phenylmethylene^aminE/^-fluoromethyl-l-(1-phenylethyl)-2-azetidinone. 34.3 g of the product obtained in the preceding stage is agitated for 15 minutes at ambient temperature under an 3 inert atmosphere in 500 cm of methylene chloride with 16.6 g of benzaldehyde and 40 g of magnesium sulphate.

By filtering and concentrating the filtrate to dryness under reduced pressure, 48 g of the expected product is obtained. 22.£2§3i43§±iiSR2_3-amino242fluoromethyl-l-^l^gheny1ethyI2z2-azetidinone. 47.7 g of the product obtained in the preceding stage is 3 cooled to -50®C in 500 cm of tetrahydrofuran and 185 cm of a 0.83M solution of sodium bistrimethylsilyl amide ln tetrahydrofuran. After agitating for 15 minutes at -50°C, the solution is poured into 500 cm of N hydrochloric acid. - 80 After agitating for a further 15 minutes, decantation the aqueous phase is washed with ether then with methylene 3 chloride. 20 g of ammonium chloride and then 25 cm of concentrated ammonia are added to the aqueous phase.

After extraction with methylene chloride, the organic phase is separated, dried and concentrated to dryness under reduced pressure. After chromatographing on silica (eluent: methylene chloride-methanol-ammonia 97-3-0.5), 19.5 g of the expected product (trans isomer) is Isolated, with Rf =» 0.3 (eluent: methylene chloride-methanol-ammonia 95-5-0.5) and 5 g of the corresponding cis isomer. d2_£3SRA 4RSi12rSR2_3-ghthalimido24-f luorome thyl-l^H; 19.3 g of the product obtained in the preceding stage is taken to reflux for 5 hours in 500 cm of tetrahydrofuran 3 with 20 g of N-ethoxycarbonyl phthalimide and 16 cm of triethylamine. After concentrating to dryness, the residue is taken up with ethanol, cooled, and the crystals are separated,a washed with ethanol, then with ether. 19 g of product is recovered, then a further 6.5 g after chromatography of the mother liquors on silica (eluent: benzeneacetone 9-1). Rf. = 0.3. e)_3-£hthalimido-4-fluororneth£l-2-azetidinone. g of the product obtained in the preceding stage in 3 3 400 cm of acetonitrile and 240 cm of water is taken to reflux, then 40 g of ammonium persulphate in 100 cm of water is added over 15 minutes. Reflux is maintained for 2 hours 30 minutes, then, after cooling and saturating with sodiumchloride and decanting, the aqueous phase is extracted with ethyl acetate. The organic phases are dried and concentrated to dryness. After chromatographing the residue on silica (eluent: methylene chloride-ethyl acetate 75-25) and then allowing to crystallize from ether, 7.15 g of the expected product is obtained, m.p.175-178°C. - 81 £L.i253,L4532._2z§K!i22z4z£i22£2T2£!!Xlz2z2£2£i£i2222 hydrochloride. - .l. 43 g of hydrazine hydrate in 10 cm of methanol is added over 5 minutes to a solution of 7.1 g of the product obtained in the preceding stage ln 150 cm of dioxan. This ls agitated for 30 minutes at ambient 3 temperature, then 29 cm of N hydrochloric acid is added, and the whole is concentrated under reduced pressure. The residue is taken up by 200 cm of methanol and heated for l hour at 40°C. The methanol is evaporated and the • 3 remainder ls taken up by 200 cm of water, then filtered, and the filtrate is concentrated under reduced pressure 3 until a volume of 100 cm is obtained, which ls again filtered and the filtrate is concentrated to dryness under reduced pressure. The residue is taken up with methanol, the crystals are separated, washed with methanol and then with ether, and 3.59 g of the expected product is obtained. m. p. * 200°C (decomposition) Rf=0.2 (eluent: methylene chloride-methanol-ammonia 9-1-0.1).

EXAMPLE 16 : A preparation for injection has been made up with the formula: - (3SR,4RS) 3-//2-(2-aminothiazol-4-yl)-2-methoxyimino acetyl/-amino/-4-methyl-l-( lH-tetrazol-5-yl) -2-azetidinone, syn isomer...............;....... 500 mg - aqueous excipient ................................ 5 cm^ EXAMPLE 17 :Capsules have been made up with the formula: - (3SR.4RS) 3-//2-(2-aminothiazol-4-yl)-2/-(carboxymethoxy)-imino/-acetyl/-amino/-4-methy1-1-(lH-tetrazol-5-yl)-2-azetidinone, syn isomer....................................... 250 mg - excipient q.s. for a capsule finished 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 each of which the same quantity of a sterile nutritive medium is distributed. In each tube, increasing quantities of the product under study * are distributed, then each tube is inoculated with a - 82 bacterial strain. After incubation for twenty-four or forty-eight hours in an oven at 37eC, the inhibition to the growth is evaluated by trans-illumination, which enables the minimum inhibiting concentrations (M.l.C.) to be determined, expressed in fg/cm .

The following results were obtained: STRAINS Prod. ex. 1 Prod. ex. 2 Frod« . ex.3 24 H 48 H 24 H 48 H 24 H 48 E Pseudomonas aeruginosa 1771 m <5 <5 <5 ¢5 5 10 Escherichia Coli 1894 0,08 0,08 0,3 * 0,3 0,15 0,15 ii > ¢72 0,3 0,3 0,6 0,6 0,3 0,3 «» « TS'I 0,6 1,2 10 10 10 1C » 1507 E 0,3 0,3 0,6 0,6 0,6 0,6 *’ DCO 1,2 1,2 O C *- 9 wf 2,5 0,61 ? *- .ι .ι [£2 0,6 0,6 0,6 1,2 0,6 0,6 Salmonella typhimurium MZ 11 1,2 1,2 1,2 2,5 0,3 0,3 Klebsiella pneumonae 52145 . 1,2 2,5 2,5 2,5 1,2 1,2 Aeruginosa 1522 E 1,2 1,2 0,5 0,6 0,3 0,3 Ehtercbacter cloacae 1321 E 0,6 0,6 1,2 1,2 0,3 0,3 Serratia marcesceus 2532 20 20 20 >40 2.5 5 Proteus mirabilis A 235 0,15 0,15 0,6 1,2 0,6 0,6 Proteus vulgaris A 232 0,3 0,3 1,2. 2,5 0,5 0,3 Providencia DU 48 0,6 0,6 1,2 1,2 0,3 0,6 STRAINS ?rod. ex. 4 Prod. ex. 6 Prod. ex.7 24 H 48 H 24 H 48 H 24 H 48 E Pseudomonas aeruginosa 1771 m 2.5 5 . 0,6 0.6 Escherichia Coll 1894 £0.04 <0,04 0.6 0.6 0,6 0,6 ». »078 0.3 0.3 0.3 0,3 0.3 0.6 h u TE4 0,6 1.2 0,6 0,6 1.2 1,2 ·· 1507 E 0,15 0.15 0.6 0.6 1,2 1/2H *’ DCO 1.2 1.2 0,6 0.6 0.6 1.2 " DC2 £0.04 <0.04 0.3 0.3 0.6 0.6 Salmonella typhinurium MZ 11 1,2 1,2 0,6 0.6 0.6 0,6 Klebsiella pneumonae 52145 5 5 2.5 2.5 2,5 2.5 " Aeruginosa 1522 E 1.2 1.2 0.6 0.6 1.2 1.2 Ehterobacter cloacae 1321 E 1,2 1.2 0,3 0.6 2.5 2,5 Serratia marcesceus 2532 20 20 2.5 5 1.2 1,2 Proteus mirabilis A 235 0.3 0.3 0,15 0.15 0.15 0.15 Proteus vulgaris A 232 0,3 0,3 0,08 0.15 0,08 0,08 Providencia DU 48 2.5 2,5 0.6 0.6 0,6 0.6 STRAINS . Prod. ex. 11 24 H 48 H Pseudomonas aeruginosa 1771 m Escherichia Coli 1894 (0.04 <0.04 .. .1 0.15 0,15 »» tem 0.6 0.6 1507 E 0,08 0,08 *' 000 0,6 0,6 » , DC2 0,15 0.15 Salmonella typhimuriun NE ll 0,3 0.3 Klebsiella pneumonae 52145 1.2 1,2 " Aeruginosa 1522 E 0.6 0,6 Enterobacter cloacae 1321 E 0.3 0.3 Serratia marcesceus 2532 10 10 Proteus mirabilis A 235 0,15 0,15 Proteus vulgaris Λ 232 0,15 0,15 Providencia CU 48 1.2 1.2

Claims (22)

1. Products of general formula (I): (I) in which R represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from carboxy radicals, optionally sal ified 20 or esterified; amino, methylamino, dimethylamino and diethylamino radicals; the phenyl radical optionally substituted by one or more radicals chosen from the following radicals: hydroxy, methyl, methoxy, chloro, bromo, fluoro; fluoro, chloro, bromo or iodo radicals; nitrile, CONH,, or CONH S0 2 R“ radicals in which R represents an 25 alkyl radical having from 1 to 4 carbon atoms; a phenyl radical, an amino, methyl or dimethylamino radical; a heterocyclic amino radical chosen from plperidino, morpholino, piperazino or 4-ethyl-2,3-dioxo-l-piperazino radicals; - a cycloalkyl radical having from 3 to 8 carbon atoms or a 30 radical: - 85 salified or esterified, in which nc represents a whole number from 0 to 5. - one of the following radicals: acetyl,, propionyl or benzoyl, carbamoyl, dimethylamino carbonyl, phenyl or benzyl optionally substituted by alkyl, alkoxy or halogen; Rj represents a hydrogen atom, an alkyl, alkenyl, alkynyl or thioalkyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from azido or alkylthio radicals having from 1 to 4 carbon atoms or a phenylthio radical, optionally salified or esterified carboxy radicals, amino, methylamino, dimethylamino or diethylamino radicals, the phenyl radical, optionally substituted by one or more radicals chosen from hydroxy, halogeno, trifluoromethyl, amino, alkyl or alkoxy radicals having from 1 to 4 carbon atoms; fluoro, chloro, bromo or iodo radicals, nitrile, CONH^ or CONH SO^R radicals in which R represents an alkyl radical having from 1 to 4 carbon atoms, a phenyl radical, an amino, methyl or dimethylamino radical, a heterocyclic amino radical chosen from piperidino, morpholino, piperazino or 4-ethyl-2,3-dioxo-l-piperazino radicals; a heterocyclic aryl radical chosen from the following radicals: thienyl, furyl, pyrannyl, thiazolyl, thiadizolyl, oxazolyl, oxadiazolyl, pyridinyl or pyrimidinyl; and the following radicals: acetoxy, propionyloxy, benzoyloxy, acetylamino, benzylcarbonyl, carbamoyloxy, methylaminocarbonyloxy or dimethylaminocarbonyloxy, acetyl, propionyl, and benzoyl, - a free, esterified or salified carboxy radical, - a phenyl radical optionally substituted by one of the following radicals; alkyl, trifluoromethyl, alkoxy, alkylthio, halogen, hydroxyl, amino or hydroxyalkyl, a heterocyclic radical chosen from the following radicals: thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyi, imidazolinyl, imidazolyl, triazolyl, tetrazolyl, thladiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl optionally substituted by an alkyl, carboxy, carboxy alkyl, aminoalkyl or dialkylaminoalkyl radical, - an acetyl, propionyl, n-butyryl or benzoyl radical, optionally substituted by alkoxy or hydroxy, - a carbamoyl, methyl or dimethylcarbamoyl radical, - a azido radical, - 86 Rg represents a nitrogen-containing heterocycle optionally substituted by one or more of the radicals chosen from the group formed by the following radicals: nitro, carboxy, CFp nitrile, halogen, sulpho, alkylsulpho, (CH^NHSO^, 5 (CHgJ^jSOgNHg, (CHg^COgH, in which n represents a whole number from I to 4 and containing at least one acid hydrogen, χ represents a CH radical or a nitrogen atom, the wavy lines indicate that the OR radical can exist in cis or trans form or in the form of a cis-trans mixture, the products of formula (I) being in racemic or 10 optionally active form, as well as the salts of the products of formula (l) with bases and acids.

2. The products according to Claim 1 of general formula (Γ ): in which R* represents a hydrogen atom or a linear or branched alkyl 25 radical having from 1 to 5 carbon atoms, optionally substituted by one or more of the radicals chosen from the group formed by the following radicals: free, esterified or sal ified carboxy radical, amino, monoor dimethylamino, phenyl, halogen, nitrile, CCNHSO^R 1 ' in which R represents an alkyl radical having 1 to 4 carbon atoms, phenyl or 30 amino, mono- or dimethylamino, or R 1 represents an acetyl, propionyl or phenyl carbonyl radical or a phenyl radical, or R' represents a cycloalkyl radical having 3 to 8 carbon atoms or a radical: - 87 salified or esterified, in which nc represents a whole number from 0 to 5, R'^ represents a hydrogen atom or an alkyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from the group formed by the following radicals: halogen, azido, hydroxyl, mercapto, phenyl, amino, nitrile, alkylthio having 1 to 4 carbon atoms or optionally oxidized phenylthio, acetyl, propionyl, benzoyl, acetoxy, propionyloxy, benzoyloxy, acetylamino, y benzylcarbonyl, carbamoyloxy, methyl or dimethyl carbamoyloxy; or R'l represents an alkenyl or alkynyl radical having at the most 12 carbon atoms, optionally substituted by a phenyl radical or by one or t> more halogen atoms, or R'^ represents a thioalkyl radical optionally substituted by carbamoyl; or R'^ represents a phenyl radical optionally substituted by halogen, a CFj, amino, hydroxy, alkyl or alkoxy radical; or R'^ represents an esterified carboxy radical, a carbamoyl radical or an azido radical; R' 2 represents one of the following radicals: tetrazolyl, triazolyl, imidazolyl, purazolyl or pyrroiyl, optionally substituted by one or more of the radicals chosen from the group formed by the following radicals: nitro, carboxy, CFp nitrile, halogen, sulpho, alkylsulpho, (CH 2 ) n SQ 3 H, (CH 2 ) n NH$O 3 H, (CH 2 ) n S0 2 NH ? or (CH 2 ) n C0 2 H, in which n represents a whole number from 1 to 4, the products having syn isomerism; the wavy line indicates that the products can exist in cis or trans form, or in the form of a cis-trans mixture, the products of formula (Γ) being in racemic or optically active form, as well as the salts of t’ne products of formula (Γ) with bases and acids,

3. The products of general formula (Γ) as defined in Claim 2 in which R* represents a hydrogen atom, one of the following radicals: methyl, phenyl, difluoromethyl, 1-methyl-i-carboxy ethyl, cyano methyl, carboxy methyl (methyl sulphonyl), carbamoyl methyl or a radical: - 88 salified or esterified, in which nc represents a whole number from 0 to 5; R' x represents a hydrogen atom, a methyl, fluoromethyl, trifluoromethyl, ethoxycarbonyl or carbamoyl radical; 5 R' 2 represents a lH-tetrazol-5-yl radical, or l,3,4-triazol-2-yl radical, optionally substituted by a trifluoromethyl or carboxymethyl radical.

4. The products of general formula (I 1 ) as defined in Claim 2 in 10 which R 1 represents a radical: ri salified or esterified, in which nc represents a whole number from 0 to 5.

5. Any one of the products of formula (I) of which the names follow: -cis or trans, syn isomer, racemic or optically active 3-[[2-(2-aminothiazol-4-yl)2-methoxyim1no acetyl]amino]4-methyl 25 l-(lH-tetrazol-5-yl)2-azetidinone; -cis or trans, syn isomer, racemic or optically active 3-[[2-(2-aminothiazol-4-yl)2-carboxymethoxy imino acetyl]amino]4-methyl l-(lH-tetrazol-5-yl)2-azetidinone; -cis or trans, syn isomer, racemic or optically active 30 3-[[2-(2-aminothiazol-4-yl )2-(l-carboxy-l-methyl) ethoxyimino acetyl ]amino]4-methyl l-(lH-tetrazol-5-yl)2-azetidinone; -cis or trans, syn isomer, racemic or optically active 3-[[2-(2-annnothiazol-4-yl)2-methoxyimino acetyl]amino]4-fluoromethyl 1-(1H-tetrazo1-5-yl)2-azet i d i none; 35 -cis or trans, syn isomer, racemic or optically active 3-[[2-(2-aminothiazol-4-yl )2-fluoromethoxy- iminoacetyl ]4-methyl 1-(1H-tetrazo1-5-yl)2-azet i d i none. - 89

6. Preparation process for products of general formula (I) as defined in Claim 1, characterized in that a product of formula (II): (II) cis or trans, racemic or optically active, in which formula either RjP represents Rp R* having the significance indicated in Claim 1, or R^p represents the substituent Rj in which the reactive functions are protected and either Rgp represents Rg, Rg having the significance indicated in Claim 1, or R?p represents the substituent Rg in which the reactive functions are protected, is treated by a product of formula (III): (HI) syn or anti, in which Rb represents a hydrogen atom or a protector group of the amino radical, and Rp represents a protector group of the hydroxyl radical, or Rp represents R, R having the significance indicated in Claim 1, or Rp represents a radical R in which the reactive functions are protected so as to obtain a product of formula (IV): - 90 NHRb (IV) Ι ί < 10 30. syn or anti, racemic or optically active, in which X, Rp, RjP, R?P and Rb have the previous significance, which product is submitted, if necessary and if desired, to any one of the following reactions, in any order: a) cleavage by hydrolysis, hydrogenolysis or by the action of the thiourea of the protector group or groups which can be represented by Rb and Rp or which can be contained in Rp, R^p and R?p; b) esterification or salification of the carboxyl or sulpho radicals which can be contained in the radicals Rp, R^p and R^p; c) salification by an acid of the amino radical or radicals; d) resolution of the molecule so as to obtain an optically active product.

7. Process according to Claim 6, for the preparation of products of formula (I) as defined in Claim 1, characterized in that, for the operation of the process, a product of formula (II) is used in which R^p represents a hydrogen atom, a methyl, fluoromethyl, trifluoromethyl, ethoxycarbonyl or carbamoyl radical, and R?p represents a lH-tetrazol-5-yl or l,3,4-triazol-2-yl radical optionally substituted by a trifluoromethyl or carboxymethyl radical, and product of formula (III) in which Rb represents a protector group of the amino radical and Rp represents a protector radical of the hydroxyl radical, or one of the following radicals: methyl, phenyl, difluoromethyl, 1-methyl, 1-carboxy ethyl, cyanomethyl, carboxymethyl or methylsulphonyl carbamoylmethyl. - 91 8. Process according to Claim 6 for the preparation of products of formula (1), characterized in that the products of formula (II): (Π) are prepared by reacting a product of formula (V): (V) in which R|P and Rgp have the significance indicated in Claim 6, in the presence of a strong base, with a product of formula (VI): Rap. (VI) R'ap/ B 0 in which Ap represents a hydrogen atom or an ester group, Rap and R’ap are such that either Rap and R'ap each represents a hydrogen atom, or one represents a hydrogen atom and the other represents a protector group of the amino radical, or Rap and R'ap together form a divalent protector radical of the amino radical, so as to obtain a product of formula (VII): (VII)

8. 10 in which Ap, R^p, R 2 P, Rap and R’ap keep the previous significance and the wavy line indicates that the substituent R^p can exist in alpha or beta position, which product of formula (VII) is submitted, if desired, to one or other of the following reactions, in any order: a) separation of the two isomers; 15 b) protection of the NH 2 radical when Rap and R'ap each represents a hydrogen atom, which product of formula (VII), in the form of a single isomer or a mixture of isomers, is submitted, when Ap represents an ester group, to a saponification agent, then to a beta-lactamization agent, so as to obtain a product of formula (VIII): 30 which product is submitted, if necessary and if desired, to any one of the following reactions, in any order: a) separation of the isomers; b) cleavage by hydrolysis, hydrogenolysis or by the action of the thiourea of one of the radicals Rap and R'ap or of these two 35 radicals when one represents a protector group or both represent together a protector group, so as to obtain an expected product of formula (II)· - 93 9. Process according to Claim 6 for the preparation of products of formula (I), characterized in that the products of formula (II): (Π) are prepared by reacting a beta-lactone of formula (IX): in which R^p, Rap and R'ap have the significance indicated in Claim 8, with a product of fonnula (A): H 2 N-R 2 p (A) in which R 2 p has the significance indicated in Claim 8, so as to obtain a product of formula (X): Rap R'ap R,p (X) 0 R jP y which product of formula (X) is, if desired, submitted to one or other * - 94 of the following reactions, in any order: a) separation of the isomers when R^p does not represent a hydrogen atom; b) protection of the NH 2 radical when Rap and R'ap each represents a hydrogen atom or modification of the protector group represented by one or other of Rap and R'ap or which is formed by Rap and R'ap together, and which product of formula (X), in the form of an isomer or of a mixture of isomers, is submitted to a cyclization reagent so as to obtain a product of formula (VIII): Rap, R,p (VIII) f IU which product of formula (VIII) can be separated into its isomers and which is submitted, when Rap or R'ap represents a protector group of the amino radical or when Rap and R'ap together represent a divalent, protector radical of the amino radical, to the action of a cleavage reagent by hydrolysis or hydrogenolysis, or to the action of the thiourea so as to obtain an expected product of formula (II). 10. Process according to Claim 9, characterized in that in order to prepare a product of formula (II) in which the substituent RjP represents a hydrogen atom or a methyl radical, the process described in Claim 8 is put into operation, starting with a product of formula (IX) in which Rjp represents a hydrogen atom or a methyl radical.

9. 11. Process according to Claim 6 for the preparation of products of formula (I), characterized in that the products of formula (II): |P (II) - 95 are prepared by reacting a product of formula: F 1) in which R|P, Rap and R'ap are defined as previously, with a product of formula: Y-R 2 p (XII) in which R 2 p is defined as previously and Y represents a nucleofugal group in the presence of a base, so as to obtain a product of formula (VIII) as defined previously, which can be separated into its isomers and which is submitted, when either Rap or R'ap represents a protector group of the amino radical or when Rap and R'ap together represent a divalent protector radical of the amino radical, to the action of a cleavage reagent by hydrolysis or hydrogenolysis or to the action of the thiourea, so as to obtain an expected product of formula (II).

10. 12. Process according to Claim 11, characterized in that the products of fonnula (XI) of trans configuration, are prepared by reacting a base on a product of formula (XIp: N R'ap Z \ (Xip - 96 of cis configuration, in which R^p, Rap and R'ap are defined as previously and Rc represents a hydrogen atom or a protector group, so as to obtain a product of formula (XI 2 ); of trans configuration, in which R^p, Rap, R'ap and Rc are defined as 15 previously, which is submitted, if appropriate, to the action of a cleavage agent of the Rc protector group.

11. 13. As medicaments, the products corresponding to the formula (I) as defined in Claim 1 and their pharmaceutically acceptable salts.

12. 14. As medicaments, the products corresponding to the formula (I*) as defined in Claims 2 to 4 and their pharmaceutically acceptable salts.

13. 15. As medicaments, the products defined in Claim 5. . 25

14. 16. Pharmaceutical compositions containing, as active principle, at least one medicament according to one of Claims 13 to 15.

15. 17. As new industrial products, the products of general formula 30 (II): H> ,R,P (Π) R,p in which Rjp and R 2 p have the significance indicated in Claim 6. X - 97

16. 18. As new industrial products, the products of general formula (II) as defined in Claim 17 in which R 3 p represents a hydrogen atom or an alkyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from the group formed by the following radicals: halogen, azido, hydroxyl, mercapto, phenyl, amino, nitrile, alkylthio having from 1 to 4 carbon atoms or optionally oxidized phenylthio; acetyl, propionyl, benzoyl, acetoxy, A propionyloxy, benzoyloxy, acetylamino, benzylcarbonyl, carbamoyloxy, methyl or dimethylcarbamoyloxy, and R 2 p represents an optionally protected tetrazolyl radical.

17. 19. As new industrial products, the products of general formula (II) as defined in Claim 17 in which RjP represents a fluoromethyl radical and R^p represents an optionally protected tetrazolyl radical.

18. 20. A product according to Claim 1, substantially as described herein by way of Example.

19. 21. As a medicament, a product according to Claim 20.

20. 22. A pharmaceutical composition comprising a product according to Claim 20.

21. 23. A process for preparing products according to Claim 1, substantially as described herein by way of Example.

22. 24. Products prepared by the process of Claim 23.