MXPA01001927A - Azetidine derivatives, preparation and medicines containing them - Google Patents

Abstract

The invention concerns compounds of formula (1) wherein:R represents an chain (A) or (B);R1 is methyl or ethyl;R2 is either an optionally substituted aromatic or an optionally substituted heteroaromatic;R3 and R4, identical or different, are either an optionally substituted aromatic or an optionally substituted heteroaromatic;R'represents a hydrogen atom or a -CO-alk radical, their optical isomers, their salts, their preparation and medicines containing them.

Description

DERIVATIVES OF AZE, TIDTNA, ITS PREPARATION AND THE MEDICINES THAT CONTAIN THEM Description of the invention The present invention relates to the azetidine derivatives of the formula: FU its optical isomers, its salts, its preparation and the medicines that contain them. In the formula (I), R represents a chain Ri represents a methyl or ethyl radical, Ref: 127188 R2 represents either an aromatic radical chosen from phenyl, naphthyl, or indenyl, these aromatic radicals being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, -CO-alk, hydroxyl, -COOR5, formyl, trifluoromethyl, trifluoromethylsulfañyl, trifluoromethoxy, nitro, -NR6R7, -CO-NH-NR6R7, -N (al) COOR8, cyano, -CONHR9, -CO-NR16RL7, alkylsul phenyl, hydroxyalkyl, -0-alk-NR? 2Ri3 or alkylthio -alkyl or a heteroaromatic radical selected from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, indolinyl, indolyl, isochromanyl, isoquinolyl, pyridyl, quinolyl, 1, 2 rings. 3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl, thienyl, these heteroaromatic radicals being unsubstituted or substituted by a halogen, alkyl, alkoxy, -COOR 5, trifluoromethyl, trifluoromethylsulfañyl, trifluoromethoxy, nitro, -NR6R7, -CO-NH-NR6R7, cyano, -CONHRg, alkylsulfañilo, hydroxyalkyl or alkyl thioalkyl, R3 and R, identical or different, represent either an aromatic radical chosen from phenyl, naphthyl or indenyl, these aromatic radicals may not be substituted or substituted with one or more halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOR5, -CONR10R11, -CO-NH-NR6, R7, alkylsulphanyl, hydroxyalkyl groups, alk-NR6R7 or alkylthioalkyl; or a heteroaromatic radical chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, isochromanyl, isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl rings. , thiazolyl, thienyl, these heteroaryl groups being unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOR5, -CO-NH-NR6R7, -CONR10R11, -alk-NR6R7 , alkyl sulphanyl, hydroxyalkyl or alkylthioalkyl, R5 is an alkyl or phenyl radical optionally substituted by one or more halogen atoms, R6 and R ?, identical or different represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, - alk-0-alk, hydroxyalkyl or R6 and R7 form together with the nitrogen atom to which they are attached, a saturated or unsaturated mono or bicyclic heterocycle having from 3 to 10 members, containing other heteroatom chosen from oxygen, sulfur and nitrogen, and which is optionally substituted with one or several alkyl radicals, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR? 4R 5, oxo , hydroxyalkyl, -alk-O-alk, -CO-NH2, R8 represents an alkyl radical, Rg represents a hydrogen atom or an alkyl or alkyl radical substituted with dialkylamino, phenyl, cycloalkyl (optionally substituted with -COOalk) or a saturated or unsaturated monocyclic or bicyclic heterocycle having from 3 to 10 members, optionally containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl radicals, Rio and Rn, identical or different, represent a hydrogen atom or an alkyl radical or Rio and Rn form together with the nitrogen atom to which they are attached, a saturated mono or bicyclic heterocycle having from 3 to 10 members, optionally containing another heteroatom chosen between oxygen, sulfur and nitrogen, and which is optionally substituted with an alkyl radical, R12 and i3 / identical or different, represent a hydrogen atom or an alkyl radical, cycloalkyl or R12. and Ri3 together with the nitrogen atom to which they are attached are a saturated mono or bicyclic heterocycle having from 3 to 10 members, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen, and which is optionally substituted with an alkyl radical , -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR14Ri5 or a saturated mono or bicyclic heterocycle having from 3 to 10 members and containing a heteroatom selected from oxygen, sulfur and nitrogen, 14 and Ris, identical or different, represent a hydrogen atom or an alkyl radical or -COOalk, Rie and RL form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having from 3 to 10 members, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen, Rr represents a hydrogen atom or a radical -CO-alk, alk represents an alkyl or alkylene radical. In the preceding definitions and those which follow, unless otherwise mentioned, the radicals and alkyl and alkylene portions and the radicals and alkoxy portions are straight or branched chain and contain from 1 to 6 carbon atoms. Among the alkyl radicals there may be mentioned methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl tert-butyl, pentyl, hexyl radicals. The alkoxy radicals include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy sec-butoxy, tert-butoxy, pentyloxy radicals. The term halogen comprises chlorine, fluorine, bromine and iodine. When R and / or R 3 and / or R 4 independently represent a substituted phenyl, it is preferably mono, di or trisubstituted. When Re and 7 together with the nitrogen atom to which a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 members are attached, it is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl, imidazolyl, thiomorpholinyl or furyl, these cycles being optionally substituted by an alkyl, hydroxyalkyl, alk-O-alk, -CONH2, -COalk, -COOalk, oxo, -CSNHalk, -CONHalk, or -CO-alk-NR? 4Ri5 and, in particular, with a methyl, ethyl, propyl, isobutyl, acetyl, N, N-dimethylamino-methylcarbonyl, ethyloxycarbonyl, methylcarbamoyl, methylthiocarbamoyl, N-methylamino-methylcarbonyl, N-methyl-N-terbutoxycarbonylaminomethylcarbonyl, oxo, -CSNHCH3, - radical CONHCH3. When Rio and R 11 together with the nitrogen atom to which they are attached form a saturated mono- or bicyclic heteroscycle having 3 to 10 members, this is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl cycle, these being cycles optionally substituted with an alkyl. When R.sup.1 Z and R.sup.13 together with the nitrogen atom to which they are attached form a saturated or mono- or bicyclic heterocycle having 3 to 10 members, this is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl ring. , these cycles being optionally substituted with an alkyl radical, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR? Ri5 or a saturated mono or bicyclic heterocycle having from 3 to 10 members, and containing a heteroatom chosen from oxygen, sulfur and nitrogen and, in particular with a thiomorpholinyl radical. When R 6 and R 17 together form the nitrogen atom to which they are attached, a saturated mono or bicyclic heterocycle having from 3 to 10 members, this is preferably a piperidyl ring. When Rg represents an alkyl radical substituted with a saturated or unsaturated mono or bicyclic heterocycle, having from 3 to 10 members, optionally containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen, the latter is preferably a pyrrolidinyl ring , tetrahydrofuryl, morpholinyl, pyrrolyl, these cycles being optionally substituted with one or more alkyl radicals. The compounds of the formula (I) can be present in the form of enantiomers and diastereoisomers. These optical isomers and their mixtures form part of the invention. The compounds of the formula (I) for which R represents a chain of the formula (A) can be prepared by dehydration of a corresponding compound of the formula (la): FU FU wherein Ri, R2, R3 and R4 have the same meanings as in formula (I) and R "represents a hydroxyl, methanesulphonyloxy or acetyloxy radical This dehydration is carried out by any method known to the person skilled in the art which allows to dehydrate an alcohol or a derivative thereof to obtain the corresponding alkene Preferably, derivatives are used for which R "is a methanesulfonyloxy or acetyloxy radical, obtained from a corresponding derivative for which R" is a hydroxyl radical, by action of methanesulfonyl chloride or acetyl chloride, in an inert solvent such as pyridine, tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane, chloroform for example), at a temperature between 5 ° C and 20 ° C and then treated with a base such as an alkali metal hydroxide (soda for example), an alkali metal carbonate (sodium carbonate) or of potassium for example), an amine such as trialkylamine (triethylamine for example), 4-dimethylaminopyridine, diaza-1,8-bicyclo [5.4.0] undec-7-ene, at a temperature comprised between 0 ° C and the boiling temperature of the reaction medium. The methansul phyloxy and the acetyloxy can be isolated or not. The compounds of the formula (I) for which R represents a chain (B) in which R 'is a hydrogen atom, can be prepared by the action of a derivative R S02CH2R2 (II) for which Ri and 2 have the same meanings as in the formula (I) on an azetidinone of the formula: N- (III) wherein R3 and R4 have the same meanings as in formula (I). The process is generally carried out in an inert solvent such as an ether (tetrahydrofuran, for example), in the presence of a strong base such as lithium diisopropylamide, potassium tert-butylate or n-butyllithium, temperature between -70 ° C and -15 ° C. The derivatives of the formula (II) can be obtained by application or adaptation of the methods described in the examples. It is mainly operated according to the following reaction schemes: Ft CrtrSOjrR, (II) in these formula Hal represents a halogen atom and, preferably, chlorine, bromine or iodine, Ri and R2 have the same meanings as in the formula (I) The reaction (a) is generally carried out in an inert solvent such as dimethylformamide or an aliphatic alcohol of 1 to 4 carbon atoms, at a temperature comprised between 20 and 30 ° C. Reaction (b) is carried out by any known methods that allow to oxidize a sulfur derivative without touching the rest of the molecule, such as those described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, it is operated by the action of an organic peroxyacid or a salt of such peroxyacid (peroxycarboxylic acids or peroxysulfonic acids, mainly peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, peroxyformic acid, monoperoxyphthalic acid) or mineral peracids or a salt of such acid (for example periodic or persulphuric acid), in an inert solvent such as a chlorinated solvent (chloroform, dichloromethane for example), to a temperature between 0 and 25 ° C. It is also possible to use hydrogen peroxide or a periodate (sodium periodate, for example), in an inert solvent such as an aliphatic alcohol of 1 to 4 carbon atoms (methanol, ethanol, for example), water or a mixture of these solvents, at a temperature between 0 and 20 ° C. It is also possible to operate by means of tert-butylhydroperoxide in the presence of titanium tetraisopropylate in an aliphatic alcohol of 1 to 4 carbon atoms (methanol, ethanol for example) or a water-alcohol mixture, at a temperature close to 25 ° C or by means of oxoneR (potassium peroxymonosulfate), in an aliphatic alcohol of 1 to 4 carbon atoms (methanol, ethanol for example), in the presence of water, acetic acid or sulfuric acid at a temperature close to 20 ° C. The reaction (c) is preferably carried out in an inert solvent such as an aliphatic alcohol having 1 to 4 carbon atoms (methanol, ethanol, for example), at a temperature between 20 ° C and the boiling point of the reaction medium. The derivatives of the formula (IV) are marketed or can be obtained by application or adaptation of methods described in the examples. In particular, the methylated derivative or the corresponding alcohol is halogen by means of a halogenating agent such as hydrobromic acid, in acetic acid, at a temperature close to 20 ° C or N-bromo- or N-chlorosuccinimide in the presence of benzoyl peroxide, in an inert solvent such as tetrachloromethane, at the boiling point of the reaction medium. The methylated derivatives or the corresponding alcohols are marketed or can be obtained according to the methods described by BRINE G. A. et al., J. Heterocyl. Chem, 26, 677 (1989) and NAGARATHNAM D., Synthesis, 8, 743 (1992) and in the examples. The azetidinones of formula (III) can be obtained by application or adaptation of the methods described by KATRITZKY A. R. et al., J. Heterocycl. Chem., 271 (1994), or DAVE P. R., J. Org. Chem., 61, 5453 (1996) and in the examples. It is generally operated according to the following reaction scheme: B in these formulas, R3 and R4 have the same meanings as in the formula (I) and X represents a chlorine or bromine atom. In step A, it is preferably carried out in an inert solvent such as an aliphatic alcohol of 1 to 4 carbon atoms (ethanol, methanol, for example), optionally in the presence of an alkali metal hydroxide, at a temperature of boiling the reaction medium. In step B, the reduction is generally carried out by means of lithium aluminum hydride, 4 within the tetrahydrofuran at the boiling temperature of the reaction medium. In step C, it is preferably operated in an inert solvent such as an aliphatic alcohol of 1 to 4 carbon atoms (ethanol, methanol, for example) in the presence of sodium acid carbonate, at a temperature of between ° C and the boiling temperature of the reaction medium. In step D, it is preferably oxidized in DMSO, by means of the sulfur trioxide-pyridine complex, at a temperature close to 20 ° C or by means of dimethyl sulfoxide, in the presence of oxalyl chloride and triethylamine, at a temperature between -70 ° and -50 ° C. In step E, it is operated according to the method described by GRISAR M. and collaborators in J. Med. Chem. 885 (1973). The magnesia of the brominated derivative is formed and after the nitrile is reacted, in an ether such as ethyl ether, at a temperature comprised between 0 ° C and the boiling temperature of the reaction medium. After hydrolysis with alcohol, the intermediate imine is reduced if it is with sodium borohydride at a temperature between 0 ° C and the boiling temperature of the reaction medium. The R3-CO-R4 derivatives are marketed or can be obtained by application or adaptation of the methods described by KUNDER N. G. et al., J. Chem. Soc. Perkin Trans 1, 2815 (1997); MORENO-MARRAS M., Eur. J. Med. Chem., 2J3 (5) 477 (1988); SKLNNER et al., J. Med. Chem., 14 6) 546 (1971); HURN N. K. Tet. Lett., 3_6 (52) 9453 (1995); MEDICI A. and collaborators, Tet. Lett., 24 (28) 2901 (1983); RIECKE R. D. et al., J. Org. Chem. 52_ (20) 6921 (1997); KNABE J. et al., Arch. Pharm., 306 (9) 648 (1973); CONSONNI R. et al., J. Chem. Soc. Perkin Trans 1, 1809 (1996); FR-96-2481 and JP-94-261393. The R3Br derivatives are marketed or can be obtained by application or adaptation of the methods described by BRANDSMA L. and collaborators Synth. Comm., 2_0 (11) 1967 and 3153 (1990); LEMAIRE M. and collaborators, Synth. Comm., 24 (1) 95 (1994); GODA H. et al., Synthesis, 9_ 849 (1992); BAEUERLE P. et al., J. Chem. Soc. Perkin Trans 2, 489 (1993). The R4CN derivatives are marketed or can be obtained by application or adaptation of the methods described by BOUYSSOU P. et al., J. Het. Chem. 2_9 (4) 895 (1992); SUZUKI N. et al., J. Chem. Soc. Comm. 1523 (1984); MARBURG S. et al., J. Het. Chem. 11_ 1333 (1980); PERCEC V. et al., J. Org. Chem. 6j0 (21) 6895 (1995). The compounds of the formula (I) for which R represents a chain (B) in which R 'is a hydrogen atom, can also be prepared by the action of a derivative R3CH (Br) R4 (VI) for which R3 and R4 have the same meanings as in the formula (I) on a derivative of the formula: in which Ri and R? they have the same meanings as in formula (I). This reaction is generally carried out in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), in an inert solvent such as acetonitrile, at the boiling temperature of the reaction medium. The derivatives of the formula (VI) are marketed or can be obtained by application or adaptation of the method described by BACHMANN. E., J. Am. Chem. Soc. 2135 (1993). In general, the corresponding alcohol R3CHOHR4 is brominated by means of hydrobromic acid, in acetic acid, at a temperature between 0 ° C and the boiling temperature of the reaction medium. The corresponding alcohols R3CHOHR4 are marketed or can be obtained by application or adaptation of methods described by PLASZ A. C. et al., J. Chem. Soc. Chem. Comm. 527 (1972). The derivatives of the formula (VII) can be obtained by hydrolysis of a derivative of the formula: SOjjR,: vni) in which R and R2 have the same meanings as in the formula (I). This reaction is generally carried out by means of hydrochloric acid, in an inert solvent such as an ether (for example dioxane), at a temperature close to 20 ° C. The derivatives of the formula (VIII) are obtained by the action of. vinyl chloroformate on a corresponding compound of formula (I) for R representing a chain of formula (B), R 'represents a hydroxyl radical, R3 and R4 are phenyl radicals, in an inert solvent such as a solvent chlorinated (dichloromethane, chloroform for example), at a temperature comprised between 0 ° C and the boiling temperature of the reaction mixture. The compounds of the formula (I) for which R is a chain (B) in which R 'is a radical -CO-alk can be prepared by the action of a halide Hal-CO-alk in which Hal represents an atom of halogen and, preferably, a chlorine atom and alk represents an alkyl radical on a corresponding compound of the formula (I) for which R is a chain (B) in which R 'is a hydrogen atom.

This reaction is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane, chloroform for example), at a temperature between -50 ° C and 20 ° C, in the presence of n-butyllithium. The compounds of the formula (I) for which R 2 represents an aromatic radical or a heteroaromatic radical substituted with -NR 6 R? wherein Re and R7 each represent a hydrogen atom, can also be prepared by the reduction of a corresponding compound of the formula (I), for which R2 represents an aromatic radical or a heteroaromatic radical substituted with nitro. This reaction is carried out by any known method that allows reducing a nitro to amino, without touching the rest of the molecule. Preferably, iron is used in the presence of hydrochloric acid in an aliphatic alcohol of 1 to 4 carbon atoms such as ethanol, at the boiling temperature of the reaction medium. The compounds of the formula (I), for which R 2 represents an aromatic or heteroaromatic radical substituted with -CONHR 9 and / or R 3 and / or R 4 represent an aromatic radical or a heteroatomatic radical substituted with -CONR QRH, can also be prepared by the action of a corresponding compound of the formula (I) for which R2 and / or R3 and / or R4 represent an aromatic or heteroatomatic radical substituted with -COOR & for which R5 is alkyl or phenyl optionally substituted with halogens, respectively with an amine H2NR9 or HNR10R11 for which R9, Rio and R11 have the same meanings as in the formula (I). This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane, chloroform, for example) or an aliphatic alcohol of 1 to 4 carbon atoms (methanol, ethanol, for example), at a temperature comprised between 0 ° C and the boiling temperature of the reaction mixture. The compounds of the formula (I) for which R 2 represents an aromatic radical substituted with hydroxyl and / or R 3 and / or R 4 represent an aromatic or heteroatomatic radical substituted with hydroxyl, can also be prepared by hydrolysis of a compound of the formula ( I) corresponding to which R 2 represents an aromatic radical substituted by alkoxy and / or R 3 and / or R 4 represent an aromatic or heteroaromatic radical substituted by alkoxy. This reaction is carried out by any method of hydrolysis of an alkoxy in hydroxyl without touching the rest of the molecule. Preferably, it is hydrolysed by means of boron tribromide, in a chlorinated solvent such as dichloromethane, at a temperature close to 20 ° C. The compounds of the formula (I) for which R 2 represents an aromatic radical substituted with -NR 6 R 7 for which R 6 represents an alkyl radical and R 7 represents a hydrogen atomcan also be prepared by deprotection of a corresponding compound of the formula (I) for which R2 represents an aromatic radical substituted by an -N (alk) COORs in which R8 represents a terbutyl radical. This reaction is generally carried out by means of hydrochloric acid, in a solvent such as dioxane, at a temperature close to 20 ° C. The compounds of the formula (I) for which R2 and / or R3 and / or R4 represent an aromatic or heteroatomatic radical substituted with -C00R5, can also be prepared by esterification of a derivative of the formula: for which R represents a chain C = C (S02R?) R '2 or C (OR') CH (S02R?) R'2, Ri, R'2, R '3 and R' 4 have the same meanings as the substituents Ri, R2, R3 and R4 of the formula (I), provided that at least one of the substituents R'2, R'3, R '4 represents an aromatic or heteroaromatic radical substituted with carboxyl, by means of a derivative of the formula R5OH for which R is alkyl or phenyl optionally substituted with one or more halogen radicals. When R 5 is alkyl, this reaction is generally carried out in the presence of a mineral acid (sulfuric acid for example), at a temperature between 20 ° C and the boiling temperature of the reaction medium. When R 5 is optionally substituted phenyl, this reaction is preferably carried out in the presence of a carbodiimide (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, N, N '-dicyclohexylcarbodiimide, for example), in an inert solvent such as a amide (dimethylformamide) or a chlorinated solvent (methylene chloride, dichloro-1,2-ethane, chloroform for example), at a temperature between 0 ° C and the boiling temperature of the reaction mixture. The derivatives of the formula (IX) for which R represents a chain C = C (S02R?) R '2 or C (OR') CH (S02R?) R'2, R ', Ri, R'2, R '3 and R' has the same meanings as the substituents R ', Rx, R2, R3, and R4 of the formula (I), provided that at least one of the substituents R' 2, R'3, R ' 4 represents an aromatic or heteroatomatic radical substituted with carboxyl, can be obtained according to the methods described above for the preparation of the compounds of the formula (I), from the corresponding intermediates and mainly according to the method described in the example 29. The compounds of the formula (I) for which R.sup.2 and / or R.sup.3 and / or R.sup.4 represent an aromatic or heteroaromatic radical substituted with alkylthioalkyl, can also be prepared by the action of a derivative of the formula (IX) for the which R represents a chain C = C (S02R) R 'z C (OR') CH (S02R?) R'2, R ', Rlf R'2, R' 3 and R '4 have the same meaning than the substituents R ', Ri, R2, R and R4 of the formula (I), provided that at least one of the substituents R'2 / R'3 and R' 4 represents an aromatic or heteroaromatic radical substituted with haloalkyl on a sodium alkylthiolate. This reaction is generally carried out in an inert solvent such as an amide (dimethylformamide for example), at a temperature close to 20 ° C. The derivatives of the formula (IX) for which R represents a chain C = C (S02R?) R '2 or C (OR') CH (S02R?) R '2, R', Ri, R'2, R '3 and R' 4 have the same meanings as the substituents R ', Ri, R2, Ra and R4 of the formula (I), provided that at least one of the substituents R'2, R' 3 and R ' 4 represents an aromatic or heteroaromatic radical substituted with halogenalkyl, can be obtained by the action of a phosphorus trihalogenide (preferably phosphorus tribromide) on a corresponding compound of formula (I) for which R 2 and / or R 3 and / or R 4 represent an aromatic or heteroaromatic radical substituted with hydroxyalkyl, in an inert solvent such as a solvent chlorinated (carbon tetrachloride, chloroform for example), at a temperature close to 20 ° C. The compounds of the formula (I), for which R.sup.2 and / or R.sup.3 and / or R.sup.4 represent an aromatic radical substituted with hydroxyalkyl in which the alkyl contains a carbon atom, can also be prepared by reduction of a compound of the formula (I) for which at least one of the substituents R2, R3, R4 represents an aromatic radical substituted with formyl. This reaction is generally carried out by means of sodium borohydride, in an aliphatic alcohol of 1 to 4 carbon atoms (methanol, ethanol, for example), at a temperature close to 0 ° C. The compounds of the formula (I) for which R3 and / or R4 represent an aromatic radical substituted by -alk-NR6R7, for which alk is an alkyl containing a carbon atom, can also be prepared by the action of a compound of the formula (I) for which at least one of the substituents R, R4 represents an aromatic radical substituted with formyl on an amine HNR6R7 in which Re and R7 have the same meanings as in the formula (I). This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloroethane for example), at a temperature close to 20 ° C in the presence of sodium triacetoxyborohydride or sodium cyanoborohydride. The compounds of the formula (I) for which R2 represents an aromatic or heteroaromatic radical substituted with -CONHRg and / or R3 and / or R4, represents an aromatic or heteroaromatic radical substituted with -CO-NR10R11, can also be prepared by the action of a derivative of the formula (IX) for which R represents a chain C = C (S02R?) R'2 or C (OR ') CH (S02R?) R' 2, R ', Rlf R'2, R '3 and R 'have the same meanings as the substituents R', Ri, R2, R3 and R4 of the formula (I), provided that at least one of the substituents R'2, R'3 and R'4 represents a radical aromatic or heteroaromatic substituted with carboxyl respectively on an amine H2NR9 or HNR10Ru in which R9 / R and Rn have the same meanings as in the formula (I). This reaction is preferably carried out either in the presence of a condensation agent used in peptide chemistry such as a carbodiimide (for example l- (3-dimethylaminopropyl) -3-ethylcarbodiimide, N, N'-dicyclohexylcarbodii ida) or N, N'-diimidazolecarbonyl, in an inert solvent such as an ether (tetrahydrofuran, dioxane for example), an amide (dimethylformamide) or a chlorinated solvent (methylene chloride, 1,2-dichloroethane, chloroform for example), a temperature between 0 ° C and the boiling temperature of the reaction mixture, or after pre-binding of the acid on a TFP-type resin of the formula. wherein S represents an aminopolystyrene resin, in an inert solvent such as dimethylformamide, in the presence of 4-3Q dimethylaminopyridine, at a temperature close to 20 ° C. The bond on the resin is generally carried out in dimethylformamide, in the presence of 4-dimethylaminopyridine and 1,3-diisopropylcarbodiimide, at a temperature close to 20 ° C. The compounds of the formula (I) for which R 2 and / or R 3 and / or R 4 represent an aromatic or heteroaromatic radical substituted with -CO-NH-NR 6 R 7 can also be prepared by the action of a compound of the formula (I) corresponding for which R2 and / or R3 and / or R4 represent an aromatic or heteroaromatic radical substituted with -COOR5, and R5 represents an alkyl or phenyl radical optionally substituted with halogens, on a hydrazine H2N-NReR7 for which R6 and R7 have the same meanings as in the formula (I). This reaction is generally carried out in an inert solvent such as dimethylformamide, at a temperature close to 20 ° C. The compounds of the formula (I) for which R2 represents an aromatic or heteroaromatic radical substituted with -C0-NHR9 in which Rg represents a hydrogen atom and / or R3 and / or R4 represent an aromatic or heteroaromatic radical substituted with - CO-NR10R11 in which Ri0 and Rp are hydrogen atoms, can also be prepared by the hydrolysis of a corresponding compound of the formula (I) for which R2 and / or R3 and / or R4 represent an aromatic or substituted heteroaromatic radical with cyano. This reaction is carried out by any known method that allows to pass a nitrile to the corresponding carbamoyl without touching the rest of the molecule. Preferably, it operates by means of hydrochloric acid, in acetic acid, at a temperature close to 20 ° C. The compounds of the formula (I) for which R 2 represents an aromatic radical substituted with -0-alkNR 12 R 3 can also be prepared by the action of a derivative of the formula (IX) for which R represents a C = C chain (S02R ?) R '2 or C (OR') CH (S02R) R '2, R' / R ?, R'2, R'3 and R '4 have the same meanings as the substituents R', RL, R2, R3 and R4 of the formula (I), with the proviso that at least one of the substituents R'2, R'3 and R '4 represents an aromatic radical substituted with -O-alk-Hal in which alk represents a radical alkyl and Hal represents a halogen atom and, preferably, a chlorine or bromine atom, on an HNR 2 R 3 amine in which Ri 2 and R 13 have the same meanings as in the formula (I). This reaction is generally carried out in an inert solvent such as acetonitrile, in the presence of an alkali metal carbonate. (potassium carbonate for example), at a temperature close to 20 ° C. The derivatives of the formula (IX) for which R represents a chain C = C (S02R) R '2 or C (OR') CH (S02R?) R '2 R' Ri '2 / R'3 and R' 4 have the same meanings as the substituents R ', Ri, R2, R3 and R4 of the formula (I), with the proviso that at least one of the substituents '2 / R'3 and R' 4 represents an aromatic radical substituted with -O-alk-Hal in which Hal represents an alkyl radical and Hal represents a halogen atom which can be obtained by the action of a corresponding compound of the formula (I) for which R 2 represents an aromatic radical substituted by hydroxyl, with a Hal-alk-Hal derivative in which Hal represents a halogen. This reaction is generally carried out in an inert solvent such as a ketone (methyl ethyl ketone for example), in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), at the boiling temperature of the medium of reaction. The compounds of the formula (I) for which R3 and / or R4 represent an aromatic radical substituted by -alk-NR6R7, can also be prepared by the action of a derivative of the formula (IX) for which R represents the chain C = C (S02R?) R'2 or C (OR ') CH (S02R?) R'2 / R', R? # R'2, R'3 Y R 'have the same meanings as the substituents R', Ri, R2, R3 and R4 of the formula (I), provided that at least one of the substituents R 'R' represents an aromatic radical substituted by -alk-Cl wherein alkyl represents an alkyl radical on an amine HNR6R in which Re and R7 have the same meanings as in the formula (I). This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), optionally in the presence of a nitrogenous base such as dimethylaminopyridine, diisopropylethylamine, at a temperature comprised between 5 and 25 ° C. The derivatives of the formula (IX) for which R represents the chain C = C (S02R) R '2 or C (OR') CH (S02R?) R'2, R ', RL, R'2, R' 3 and R '4 have the same meanings as the substituents R', Ri, R2, R3 and R of the formula (I), provided that at least one of the substituents R'3, R'4 represents an aromatic substituted radical with -alk-Cl, they can be obtained by the action of thionyl chloride on a corresponding compound of the formula (I) for which at least one of the substituents R3, R4 represents an aromatic radical substituted by one or several hydroxyalkyl radicals. This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), at a temperature comprised between 10 and 30 ° C. The compounds of the formula (I) for which R represents a B chain, R 'represents a hydrogen atom and R and / or R4 represents an aromatic radical substituted by hydroxyalkyl in which the alkyl residue contains a carbon atom, can also be prepared by the action of diisobutylaluminum hydride on a corresponding compound of the formula (I), for which R represents a B chain, R 'represents a hydrogen atom and R3 and / or R represents an aromatic radical substituted with one or several radicals -COOR5 in which R5 is an alkyl radical. This reaction is generally carried out in toluene, at a temperature between -30 ° C and 0 ° C. The compounds of the formula (I) for which Rz represents a phenyl radical substituted with -NR6R7, represent a 1-piperazinyl ring substituted at the 4-position with an alkyl radical which can also be prepared by the action of a corresponding compound of the formula (I), for which R2 represents a phenyl radical substituted with a radical -NR6R7 representing a 1-piperazinyl ring on an alk-CHO derivative in which alk represents a straight or branched chain alkyl radical containing from 1 to 5 carbon atoms. This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloroethane, chloroform for example) in the presence of NaBH (0C0CH3) 3, at a temperature close to 20 ° C. The compounds of the formula (I) for which R 2 represents a phenyl radical substituted with -NR 6 R 7 represent a 1-piperazinyl ring substituted at the 4-position with a -COOalk radical which can also be prepared by the action of a compound of the formula (I) corresponding to which R2 represents a phenyl radical substituted with a radical -NR6R7, which represents a 1-piperazinyl ring on a derivative of the formula Hal-COOalk in which alk represents an alkyl radical and Hal represents a halogen atom and, preferably, a chlorine atom. This reaction is generally carried out in the pyridine, at a temperature close to 20 ° C. The compounds of the formula (I) for which R 2 represents a phenyl radical substituted with -NR 6 R 7 represent a 1-piperazinyl ring substituted in the 4-position with a radical -CO-NHalk or -CS-NHalk can also be prepared by the action of a corresponding compound of formula (I) for which R 2 represents a phenyl radical substituted with -NR 5 R 7 representing a 1-piperazinyl ring, on a derivative of the formula Y = C = Nalk in which alk represents an alkyl radical of straight or branched chain containing 1 to 6 carbon atoms and Y represents a sulfur or oxygen atom.

This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), at a temperature close to 20 ° C. The compounds of the formula (I) for which R 2 represents a phenyl radical substituted with a radical -NR 6 R 7 representing a 1-piperazinyl ring substituted at the 4-position with a radical -CO-alk-NR 4 R 5 can also be prepared by the action of a corresponding compound of formula (I) for which R 2 represents a phenyl radical substituted with a radical -NR 6 R 7 representing a 1-piperazinyl ring, with an acid of the formula Ris R 4 N -alk-COOH in which alk represents an alkyl radical and R14 and R15 have the same meanings as in formula (I) followed optionally by a deprotection of the product for which R? 4 is a tert-butoxycarbonyl radical, to obtain the compounds for which Ri4 It is a hydrogen atom. This reaction is generally carried out in an inert solvent such as a chlorinated solvent (eg dichloroethane), at a temperature close to 20 ° C. The deprotection is carried out by means of formic acid at a temperature close to 20 ° C. The compounds of the formula (I) for which R 2 represents a phenyl radical substituted with a radical -NR 6 R 7 represent a 1-piperazinyl ring substituted in the 4-position with a radical -CO-alk in which alk represents a methyl radical, can also be prepared by the action of a corresponding compound of the formula (I) for which R2 represents a phenyl radical substituted with a radical -NR6R7 representing a 1-piperazinyl cyclo, with acetic anhydride. This reaction is carried out in general in the presence of pyridine, at a temperature close to 20 ° C. It is understood by the person skilled in the art that, for the operation of the processes according to the invention described above, it may be necessary to introduce protective groups of the amino, hydroxyl and carboxyl functional groups in order to avoid secondary reactions. These groups are those that allow to be eliminated without touching the rest of the molecule. Examples of protecting groups of the amino functional group include terbutyl or methyl carbamates, which can be regenerated by means of iodotrimethylsilane or allyl by means of palladium catalysts. Examples of protecting groups of the hydroxyl functional group include triethylsilyl, tert-butyldimethylsilyl groups which can be regenerated by means of tetrabutylammonium fluoride or the dissymmetric acetals (methoxymethyl, tetrahydropyranyl, for example) with regeneration by means of hydrochloric acid. . As protective groups of the carboxyl functional groups, mention may be made of esters (allyl, benzyl, for example), oxazoles and 2-alky1,13-oxazolines. Other usable protective groups are described by GREENE T. W. et al., Protecting Groups in Organic Synthesis, second edition 1991, Jonh Wiley & Sons. The compounds of the formula (I) can be purified by commonly known methods, for example by crystallization, chromatography or extraction. The enantiomers of the compounds of the formula (I) can be obtained by cleavage of the racemic mixtures for example by chromatography on a chiral column according to PIRCKLE W. H. et al., Asymmetric synthesis, vol. 1, Academic Press (1983) or by formation of salts or by synthesis from chiral precursors. The diastereoisomers can be prepared according to the known classical methods (crystallization, chromatography or from chiral precursors). The compounds of the formula (I) can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. These salts also form part of the invention. As examples of pharmaceutically acceptable salts, the following salts may be mentioned: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene-bis-β-oxinaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophylline acetate and p-toluenesulfonate. The compounds of the formula (I) have interesting pharmacological properties. These compounds possess a strong affinity for cannabinoid receptors and particularly those of the CB1 type. These are antagonists of the CB1 receptor and are therefore useful in the treatment and prevention of disorders that affect the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system, the gastrointestinal tract and reproductive disorders (Hollister , Pharm. Rev. 38, 1986, 1-20, Reny and Sinha, Prog. Drug Res., 36, 71-114 (1991), Consroe and Sandyk, in Marijuana / Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds, CRC Press, 1992), bacterial, viral and parasitic infections. Thus, these compounds can be used for the treatment or prevention of psychosis, including schizophrenia, disorders of anxiety, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, disorders of cognition , cranial trauma, panic attacks, peripheral neuropathies, glaucoas, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, compulsive-obsessive disorder, senile dementia, thymus disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancers, movement disorders induced by drugs, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunological diseases, sclerosis in plaques, vomiting, asthma, appetite disorders, (bulimia, anorexia), obesity , memory disorders, in the suppression of chronic treatments and alcohol abuse om edicamentos (opioids, barbi túricos, cannabis, cocaine, amphetamine, fencíclido, hallucinogens, benzodiazepinas for example), like analgesic or potentiali zadores of the analgesic activity of the narcotic and not narcotic medicines. These can also be used for the treatment or prevention of intestinal transit disorders, such as antibacterial, antiviral and antiparasitic. The affinity of the compounds of the formula (I) for the cannabis receptors has been determined according to the method described by KUSTER J.E., STEVENSON J.I., WARD S.J., D'AMBRA T.E. HAYCOCK D.A. in J. Pharmacol. Exp. Ther., 264 1352-1363 (1993). In this test, the IC 50 of the compounds of the formula (I) is less than or equal to 100 nM.

Its antagonistic activity has been shown by the model of hypothermia induced by a cannabis receptor agonist (CP-55940) in the mouse, according to the method described by Pertwee RG Dan Marijuana, Harvey DJ eds, 84 Oxford IRL Press, 263-277 (1985). In this test, the ED 50 of the compounds of the formula (I) is less than or equal to 50 mg / kg. The compounds of the formula (I) have a weak toxicity. Its LD50 is greater than 40 mg / kg subcutaneously in the mouse. Preferred compounds of formula (I) are those for which: R represents a chain (A) or (B) and R 'represents a hydrogen atom or a radical -COalk, R represents a methyl or ethyl radical, R2 represents either an aromatic radical chosen from phenyl and naphthyl, these aromatic radicals being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, hydroxyl, -COOR 5 / trifluoromethyl, trifluoromethylsulfañyl, trifluoromethoxy, -NR 6 R 7, -CO-NH- radicals NR6R7, cyano, -CONHRg, alkylsulfonyl, hydroxyalkyl, nitro, -CO-NR? 6Ri7, -0-alkNR? 2R? 3 or alkylthioalkyl or a heteroaromatic selected from isoquinolyl, pyridyl, quinolyl, 1,2,3,4 -tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thienyl, these heteroaromatics being unsubstituted or substituted by a halogen, alkyl, alkoxy, -COOR 5, trifluoromethyl, trifluoromethylsulfañyl, trifluoromethoxy, -NR 6 R 7, -CO-NH-NR 6 R 7, cyano , -CONHRg, alkylsulphanyl, hydroxyalkyl, nitro or alkylthioalkyl, R3 and R4, identical or different, represent either an aromatic radical chosen from phenyl or naphthyl, these aromatic radicals being unsubstituted or substituted by one or more halogen groups, alkoxy alkyl, trifluoromethyl, trifluoromethoxy, -CONR10R11, -alk -NR6R7, hydroxyalkyl, formyl, -COOR5, or a heteroaromatic radical selected from the thiazolyl or thienyl rings, these aromatics being unsubstituted or substituted with a halogen, alkyl, alkoxy, -CONRioRn, -alk-NR6R7, hydroxyalkyl or -COOR5 R5 is alkyl or phenyl optionally substituted with one or more halogens, R6 and R, identical or different represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl or R6 and R7 together with the nitrogen atom to which they are attached are a saturated or unsaturated mono or bicyclic heterocycle having 3 to 10 members, optionally containing another hetero atom chosen from oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl radicals, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -C0-alk-NR? 4Ri5, oxo, hydroxyalkyl, -alk-0-alk, -CO-NH2, Rg represents a hydrogen atom or an alkyl or alkyl radical substituted with dialkylamino, phenyl, cycloalkyl (optionally substituted with -COOalk) or a saturated or unsaturated monocyclic or bicyclic heterocycle to 10 members, optionally containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen, and optionally substituted by one or more identical or different alkyl radicals, Rio and Rn, represent a hydrogen atom or an alkyl radical, or Rio and Rn together with the nitrogen atom to which they are attached are a saturated mono or bicyclic heterocycle, having 3 to 10 members, which optionally contains another heteroatom selected from oxygen, sulfur and nitrogen and which is optionally substituted with an alkyl radical, R12 and 13 identical or different, represent a hydrogen atom or an alkyl radical, cycloalkyl or Ri2 and R13 together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 members, which optionally contains another heteroatom chosen from oxygen, sulfur, and nitrogen, and which is optionally substituted with an alkyl radical, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR ? 4R? 5 or a saturated mono or bicyclic heterocycle, having 3 to 10 members, and containing a heteroatom chosen from oxygen, sulfur and nitrogen, R14 and R15 identical or different, represent a hydrogen atom or an alkyl radical, or -COOalk, R1 and R17 together with the nitrogen atom to which they are attached are a saturated mono or bicyclic heterocycle having from 3 to 10 members optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen, alk represents an alkyl or alkylene radical, its isomers optics and their salts with a mineral or organic acid.

Particularly preferred compounds of the formula (I) are those for which: R represents a chain (A) or (B), R 'represents a hydrogen atom or a radical -COalk, Ri represents a methyl or ethyl radical, R2 represents either an aromatic radical chosen from naphthyl or phenyl, phenyl substituted with one or more halogen, alkyl, alkoxy, hydroxyl, -COOR 5 groups (in which Rs represents an alkyl or phenyl radical optionally substituted with several halogens), trifluoromethyl, trifluoromethyl fañilo, trifluoromethoxy, -NR6R7, (in which R6 and R identical or different, represent a hydrogen atom or an alkyl radical or -COOalk, or R6 and R7 together with the nitrogen atom to which they are attached, "a heterocycle chosen from pyrrolidinyl, piperidyl, piperazinyl or piperazinyl substituted with one or more alkyl radicals, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR? 4R 5 in which R14 and Ris, identical or different, re present a hydrogen atom or an alkyl radical), -CO-NH-NR6R7 (R <Y> R <7>, identical or different, represent a hydrogen atom or an alkyl radical, or R6 and R7 together form the nitrogen atom to which are attached, a heterocycle selected from piperidyl, piperazinyl, or piperazyl substituted with one or more alkyl radicals), cyano, -CONHRg (in which Rg represents a hydrogen atom or an alkyl or alkyl radical substituted with dialkylamino, phenyl, cycloalkyl ( optionally substituted with -COOalk) or a heterocycle selected from pyrrolidinyl (optionally substituted by alkyl), tetrahydrofuryl, morpholinyl or pyrrolyl), alkylsulfañyl, hydroxyalkyl, nitro, -CO-NR? 6Ri7 (in which R 6 and R 7 together form with the nitrogen atom to which they are attached, a piperidyl), -0-alkNR? 2R 3 (in which Rí2 and R13 form together with the nitrogen atom to which a morpholino cycle is attached) or alkylthioalk ilo, or a heteroaromatic radical chosen from: isoquinolyl, pyridyl, quinolyl, 1,2, 3-4-tetrahydroisoquinolyl, 1, 2, 3, -tetrahydroquinolyl, thienyl, or thienyl substituted with a -CQ0R5 (in which R5 represents an alkyl radical) or -CONHRg, (in which Rg represents an alkyl radical), R3 and R4, identical or different, represent either an aromatic radical chosen from: phenyl or phenyl substituted with one or more halogen, alkyl, alkoxy groups , trifluoromethyl, trifluoromethoxy, hydroxyalkyl, formyl, -COOR5 (in which R5 is an alkyl radical), -CONR 0Rn (in which R and Rn, identical or different, represent a hydrogen atom or an alkyl radical), -alk -NR6R7 (in which Re and R7, identical or different represent a hydrogen atom or an alkyl radical, cycloalkyl, -alk-O-alk, hydroxyalkyl, or R6 and R7 together with the nitrogen atom to which they are attached , a heterocyclic selected from piperidyl (optionally substituted with oxo alkyl), pyrrolidinyl (optionally substituted by alkyl, hydroxyalkyl, -alk-O-alk, -C0-NH2), thiomorpholinyl, morpholinyl, pyrrolyl, piperazinyl optionally substituted by oxo, alkyl, hydroxyalkyl, -COOR5 (in which R5 is an alkyl radical), or a heteroaromatic radical chosen from: thiazolyl or thienyl, alk represents an alkyl or alkylene radical, its optical isomers and its salts with a mineral or organic acid. Preferably, when R2 is a substituted phenyl radical, the latter is monosubstituted and, in particular, in the 3-position or disubstituted and, in particular, in the 3, 5-positions; 2.5, or 2, 3. Preferably, when R3 is a substituted phenyl radicalthe latter is monosubstituted and, in particular, in the 4 or disubstituted position and, in particular, in the 2,4 positions. Preferably, when R 4 is a substituted phenyl radical, the latter is monosubstituted and, in particular, in the 4 or disubstituted position and, in particular in the 2,4-positions. Among the preferred compounds, mention may be made of the following compounds: l-benzhydryl-3- [(methylsul fonyl) (phenyl) -met ilen] azetidine, l-benzhydryl-3 - [(3-methylphenyl) (methylsul-fonyl) methylene] -zetidine , l-benzhydryl-3 - [(3-chlorophenyl) - (ethyl-sulfonyl) methylene-benzetidine, l-benzhydryl-3 - [(3,5-dichlorophenyl) - (methylsulfonyl) melened] azetidine, l-benzhydryl-3- [(2,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, l-benzhydryl-3- [(2,3-dichlorophenyl) (methyl-sulphonyl) methylene] azetidine, l-benzhydryl-3- [(3-fluorophenyl) ) (Methylsulonyl) methylenazetidine, l-benzhydryl-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, l-benzhydryl-3- [(3-romophenyl) (methylsulfonyl) methylazeketidine, l-benzhydryl- 3- [(3-iodophenyl) (methyl-sulphonyl) methylene] azetidine, l-benzhydryl-3- [(methylsulfonyl) (3-trifluorornetoxy phenyl) methylene] azetidine, l-benzhydryl-3- [(methylsulfonyl) (3 -trifluoromethylphenyl) methylene] azetidine, l-benzhydril-3-. { [3, 5-bis (trifluoromethyl) (phenyl] (methylsulfonyl) methylene.} - azetidine, l-benzhydryl-3- [(3,5-dibromophenyl) (methyl-sulphonyl) methylene] azetidine, l-benzhydryl- 3- [(3-methoxycarbonylphenyl) - (methylsulfonyl) methylene] azetidine, l-benzhydryl-3- [(3-cyanophenyl) (methylsulfonyl) ethylene] azeti ina, l-benzhydryl-3- [(3-carbamoylphenyl) ) (methylsulfonyl) methylene] azetidine, l-benzhydryl-3- [(methylsul fonyl) (naphth-1-yl) (methylsul fonyl) methylene] azetidine, l- [bis (4-chlorophenyl) methyl] -3- [ (3,5-difluorophenyl) (methylsulfonyl) methylene] azet idine, l- [bis (4-methoxy phenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) met ilenjazetidine, l- [bis (4 -methyl phenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -3- [(3,5-difluorophenyl) (methyl-sulfonyl) methylene] -l- [( 4-methoxyphenyl) (phenyl) methyl)] -azetidine, (R) -3- [(3,5-difluorophenyl) (methyl-sulfonyl) methylene] -l- [(4-methoxyphenyl) (phenyl) methyl] -azetidine , (S) -3- [(3,5-difluorophenyl) methylsul fonyl) methylene] -l- [(4-methoxyphenyl) (phenyl) methyl] -azetidine, l- [bis (4-trifluoromethoxy phenyl) methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methylazeketidine, l- [bis (4-trifluoromethylphenyl) ethyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) ethylene] azetidine, l- [bis (4-chlorophenyl) methyl] 3-. { [3,5-bis- (trifluoromethyl) phenyl] methylsulfonylmethylene], azetidine, (RS) -l- [(4-chlorophenyl) (2,4-dichlorophenyl) -methyl] -3 - [(3, 5-difluorophenyl) (methylsulfonyl) methylene] -zetidine, (R) -l- [(4-chlorophenyl) (2,4-di chlorophenyl) -methyl] -3- [(3,5-difluorophenyl) methylsulfonyl) methylene] -azetidine, (S) -l- [(4-chlorophenyl) (2,4-di chlorophenyl) -methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] -zetidine, (RS) -1 -. { (4-chlorophenyl) [4- (hydroxymethyl) -phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) -methylene-benzetidine, (R) -1-. { (4-chlorophenyl) [4- (hydroxymethyl) -phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) -methylene] azet i ina, (S) -l-. { (4-chlorophenyl) [4-hydroxymethyl) -phenyl] met il} -3- [(3,5-difluorophenyl) (methylsulfonyl) -methylene] azetidine, (RS) -1-. { (4-chloro phenyl) [4- (pyrrolidylmethyl) phenyl] methyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) -methylene] azetidine, (R) -1- t (4-chlorophenyl) [4- (pyrrolidylmethyl) -phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) -methylene] azetidine, (S) -1-. { (4-chlorophenyl) [4- (pyrrolidylmethyl) -phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) -methylene] azetidine, 1-. { (RS) - (4-chlorophenyl) [4- (3, 3-dimet i 1-piperidin-1-yl-methyl) phenyl] methyl} -3- [(3, 5-difluorophenyl) methylsulfonyl) ethylene] azetidine, l-. { (R) - (4-chlorophenyl) [4- (3, 3-dimet i 1-piperidin-1-yl-methyl) phenylmethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, l-. { (S) - (4-chlorophenyl) [4- (3, 3-dimethyl-1-piperidin-1-yl-methyl) phenylmethyl} -3- [(3, 5-difluorophenyl) (methylsul fonyl) met ilen] azetidine, 1-. { (RS) - (4-chlorophenyl) [4- (t -omorpholin-4-yl-methyl) phenyl] methyl} -3 - [(3, 5-difluorophenyl) (methylsul fonyl) methylene] azetidine, l-. { (R) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} -3- [(3, 5-difluorophenyl) methyl-sulfonyl) ethylene] azetidine, 1-. { (S) - (4-chloro-phenyl) [4- (thiomorpholin-4-yl-methyl) -phenyl] -methyl} -3- [(3, 5-difluorophenyl) (methyl-sulfonyl) ethylene] azetidine, l-. { (RS) - (4-chloro-phenyl) [4- (N-ethyl-N-cyclohexyl-aminomethyl) -hexylmethyl} -3- [(3, 5-difluorophenyl) (methylsul fonyl) methylene] azetidine, l-. { (R) - (4-chlorophenyl) [4- (N-ethyl-N-cyclohexyl-aminomethyl) phenyl] methyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-. { (S) - (4-chlorophenyl) [4- (N-ethyl-N-cyclohexyl-aminomethyl) phenyljraethyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-. { . { (RS) - (4-chlorophenyl). { 4- [(4-ethoxycarbonyl-piperazinyl) methyljphenyl} methyl } } -3 - [(3,5-difluoro-phenyl) (methylsulfonyl) ethylene] azetidine, 1-. { . { (R) - (4-chlorophenyl). { 4- [(4-ethoxycarbonyl-piperazinyl) methyljphenyl} ethyl} } -3 - [(3, 5-difluoro-phenyl) (methylsulfonyl) methylenazetidine, l-. { . { (S) - (4-chlorophenyl) (4 - [(4-ethoxycarbonyl-piperazinyl) ethyl] phenyl] methyl]} -.]. 3 - [(3,5-difluoro-phenyl) (methylsulfonyl. Methylenazetidine, 1- { (RS) - (4-chlorophenyl) [4- (N-cyclopropyl-N-propyl-aminomethyl) phenyl] methyl.}. -3 - [(3,5-difluoro-phenyl). (methylsulphonyl) methylenazetidine, l- { (R) - (4-chlorophenyl) [4- (N-cyclopropyl-N-propyl-aminomethyl) phenylmethyl] -3- [(3,5-difluoro-phenyl)] (Methylsulonyl) methylenediazetidine, L- { (S) - (4-chlorophenyl). [4- (N-cyclopropyl-N-propyl-aminomethyl) phenylmethyl] -3 - [(3,5-difluoro) -phenyl) (methylsul fonyl.) methylenediazetidine, 1- { (RS) - (4-chlorophenyl) [4- (diisopropylamino-methyl) phenylmethyl} -3- [(3,5-difluorophenyl) (methyl) -sulfonyl) methylenediazetidine, 1- { (R) - (4-chloro phenyl) [4- (di i sopropi 1 aminomethyl) phenyljmethyl.} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyleneJazetidine, l- { (S) - (4-chlorophenyl) [4- (di isopropylaminomethyl) phenylmethyl] -3- [(3,5-di fluoro phenyl) (e til-sulfonyl) methylenejazetidine, l-. { . { (RS) - (4-chloro phenyl). { 4 - [bis- (2-methoxy-ethyl) aminomethyl 1J phenyl} methyl } } -3- [(3,5-di fluoro phenyl) - (methylsul fonyl) methylene] azetidine, 1-. { . { (R) - (-chloro phenyl). { 4 - [bis- (2-methoxy-ethyl) aminomethyl] phenyl} methyl } } -3 - [(3, 5-difluoro phenyl) - (methylsulfonyl) methylenejazetidine, l-. { . { (S) - (4-chloro phenyl). { 4- [bis- (2-methoxy-ethyl) aminomethyljphenyl} ethyl} } -3 - [(3,5-di fluoro-phenyl) - (methylsulfonyl) methylene-benzetidine, 1-. { (RS) - (4-chlorophenyl) [4- (di-n-propylaminomethyl) phenylmethyl} -3- [(3,5-di-fluorophenyl) (methylsul-fonyl) methylene-benzetidine, 1-. { (R) - (4-chlorophenyl) [4- (di-n-propylaminomethyl) phenylmethyl} -3 - [(3, 5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, l-. { (S) - (4-chlorophenyl) [4- (di-n-propylamino-methyl) phenylmethyl} -3- [(3, 5-difluorophenyl) - (methylsulfonyl) methyleneJazetidine, l-. { (RS) - (4-Chloro phenyl) [4- (piperidin-1-yl-methyl) phenylmethyl} -3- [(3, 5-difluorophenyl) - (methylsulfoni 1) methylenejazetidine, l-. { (R) - (4-chlorophenyl) [4- (piperidin-1-yl-methyl) phenylmethyl} -3- [(3, 5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, 1-. { (S) - (4-chlorophenyl) [4- (piperidin-1-yl-ethyl) phenylmethyl} -3- [(3,5-di-fluorophenyl) - (methylsulfonyl) methylene-benzetidine, 1-. { (RS) - (4-chlorophenyl) [4- (4-methyl-piperazin-1-yl-methyl) phenyl-1-methyl} -3- [(3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, 1-. { (R) - (4-chlorophenyl) [4- (4-methyl-piperazin-1-yl-methyl) phenyl] ethyl} -3- [(3, 5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, l-. { (S) - (4-chlorophenyl) [4- (4-methyl-piperazin-1-yl-methyl) phenylmethyl} -3 - [(3, 5-difluorophenyl) - (methylsulfonyl) methylene-benzetidine, 1-. { (RS) - (4-chlorophenyl) [4- (4-morpholin-4-yl-methyl) phenylmethyl} -3- [(3, 5-difluorophenyl) - (methylsulfonyl) met ilenjazetidine, l-. { (R) - (-chloro phenyl) [4- (morpholin-4-yl-methyl) phenylmethyl} -3- [(3, 5-difluorophenyl) - (methylsul fonyl) methylenejazetidine, l-. { (S) - (4-chlorophenyl) [4- (morpholin-4-yl-ethyl) phenylmethyl} -3 - [(3, 5-difluorophenyl) - (methylsulfonyl) ethylenejazetidine, 1 -. { (RS) - (4-chlorophenyl) [4- (diethyl-inomethyl) -phenyl-methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) -methylene-benzetidine, 1--. { (R) - (4-chlorophenyl) [4- (diethylaminomethyl) -phenylmethyl} -3 - [(3, 5-difluorophenyl) (methylsulfonyl) -ethylenjazetidine, 1- (S) - (4-chlorophenyl) [4- (diethylaminomethyl) -phenylmethyl} -3- [(3, 5-difluorophenyl) (me tilsul fonil) -metilenjazet idina, l-. { (RS) - (4-chlorophenyl) [4- (piperazin-2-one-4-yl-methyl) phenylmethyl} -3- [(3,5-difluorophenyl) - (methylsulfonyl) ethylenejazetidine, 1 -. { (R) - (4-chloro-phenyl) [4- (piperazin-2-one-4-yl-methyl) phenyl-methyl} -3 - [(3, 5-difluorophenyl) - (methylsulfonyl) methylene-benzetidine, 1-. { (S) - (4-chlorophenyl) [4- (piperazin-2-one-4-yl-methyl) phenylmethyl} -3- [(3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, l-. { (RS) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenylmethyl} -3 - [(3, 5-difluorophenyl) - (methylsulfonyl) ethylene] azetidine, l-. { (R) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenylmethyl} -3- [(3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, l-. { (S) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) fe ilj ethyl} -3- [(3, 5-difluorophenyl) - (methylsul fonyl) eti lenjazetidine, (RS) -l-. { (4-chlorophenyl) [4- (N, N-dimethyl-1-carbamoyl) phenylmethyl} -3- [(3,5-difluorophenyl) - (methylsulfonyl) methylene-benzetidine, (R) -1-. { (4-chlorophenyl) [4- (N, N-dimetucarbamoi 1) phenylmethyl} -3- [(3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, (S) -l-. { (4-chlorophenyl) [4- (N, N-dimethyl-1-carbamoyl) phenylmethyl} -3 - [(3, 5-difluorophenyl) - (methylsulfonyl) methyleaxazetidine, (RS) -l-. { (4-chlorophenyl) [4- (N-ethyl-carbamoyl) phenylmethyl} -3- [(3, 5-difluorophenyl) - (methylsulfonyl) ethylenejazetidine, (R) -l-. { (4-chlorophenyl) [4- (N-ethylcarbamoyl) -phenylmethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) -methylene-benzet idine, (S) -1-. { (4-chlorophenyl) [4- (N-ethylcarbamoyl) - 'phenyl] ethyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) -methylene-benzetidine, (RS) -l- [(4-carbamoyl-phenyl) (4-chlorophenyl) -methyl] -3- [(3,5-difluorophenyl) ( methylsulfonyl) -methylene-benzethidine, (R) -l- [(4-carbamoylphenyl) (4-chlorophenyl) -methyl-3- [(3,5-difluorophenyl) (methylsulfonyl) ethylenediazetidine, (S) -l- [(4 -carbamoyl phenyl) (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) -methylene-benzetidine, l- [bis (4-chlorophenyl) methyl] -3 - [(3,5-dichloro -phenyl) (methylenesulfonyl) methylene-benzethidine, l-benzhydryl-3- [(3-methylsulfanyl-phenyl) - (methylsulfonyl) methylene-benzetidine, l-benzhydryl-3 - [(3-methylsulfanylmethyl) - (phenyl) J (methylsulfonyl) methylene-benzetidine , l- [bis (4-chlorophenyl) methyl] -3- [(3-cyano-phenyl) (methylsulfonyl) ethylene-benzetidine, l- [bis (4-chloro-phenyl) -methyl] -3- [(3-carbamoyl-phenyl) (methylsulfonyl methylenediazetidine, l- [bis (4-chlorophenyl) -meiJ-3 - [(3-methoxy-phenyl) (methylsulfonyl.) ethylenediazetidine, l- [bis (4-chlorophenyl) methyl] -3- [(3-) hydroxyphenyl) (m eti-lysulfonyl) methylenediazetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsul fonyl) (3-pyrrolidinylphenyl) methylenazetidine, 1- [bis (4-chloro phenyl) methyl] -3 - [(3- hydroxymethylphenyl) (methylsulfonyl) ethylenejazetidine, l- [bis (4-chlorophenyl) methylj3-. { (methyl-sulfonyl) [3- (N-piperidi-1-carbamoyl) -phenyl-methylene} -zetidine, l- [bis (4-chlorophenyl) ethylJ-3- [(methylsulfonyl) (3-trifluoromethyl) phenylsulfanyl) - (methylsulfonyl) methylene-benzetidine, l- [bis (4-fluorophenyl) methyl] 3- [(3, 5-difluoro-phenyl) (methylsulfonyl) methylene-benzetidine, l- [bis (2-fluorophenyl) methyl] -3 - [(3,5-di-fluoro-phenyl) (methylsulfonyl) methylene] -zetidine, l- [bis (3-fluorophenyl) methyl] -3- [(3,5-difluoro-phenyl) (methylsulfonyl) ethylenaszetidine, (RS) -l- [(4-chloro-phenyl) (thiazol-2-yl) methyl] -3- [(methylsulfonyl) (phenyl)] methylenazetidine, (R) -l - [(4-chloro-phenyl) (thiazol-2-yl) methyl-J-3- [(methylsulfonyl) (phenyl) methylene] -zetidine, (S) -l - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(methylsul fonyl) (phenyl) methylenazetidine, (RS) -l- [(4-chlorophenyl) (tien- 2-yl) methyl] -3 - [(3, 5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, (R) -l- [(4-chlorophenyl) (thien-2-yl) methyl-3- [(3, 5 -di fluorophenyl) (methylsulfonyl) ethylenejazetine, (S) -l- [(4-chlorophenyl) (thien-2-yl) ethyl J-3 - [(3,5-difluorophenyl) (methylsulfonyl) ethylene-benzetidine, l-benzhydryl-3- [(ethylsulfonyl) (phenyl) - methylenazetidine, l- [bis (4-chlorophenyl) methylJ-3-. { . { 3- [N- (4-methyl-piperazinyl) carbamoyl] phenyl} (methylsulfonyl) ethylene} -azetidine, l- [bis (4-chlorophenyl) methyl] -3-. { . { 3- (2,2-dimethylcarbohydrazido) phenylj (methylsul fonyl) ethylene} azetidine, l- [bis (thien-2-yl) methyl] -3- [(3,5-difluoro-phenyl) (methylsul-fonyl) ethylene-azetidine, l- [bis (p-tolyl) methyl] -3- [ (methylsulfonyl) - (phenyl) methylenazetidine, l - [(4-chlorophenyl) (4-hydroxymethylphenyl) -methylJ-3- [(3,5-di-fluorophenyl) (methylsul-fonyl) -methylene-benzetidine, l- [bis (4- chlorophenyl) methyl] -3 - [(3-methylamino-phenyl) (methylsul-fonyl) methylene-benzetidine, (RS) -l - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3, 5 -difluorophenyl) (methylsulphonyl) methylenazetidine, (R) -l - [(4-Chlorophenyl) (thiazol-2-yl) methylJ-3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -l- [(4-chlorophenyl) (thiazole -2-yl) methylJ-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, l- [bis (4-chlorophenyl) methyl] -3- [(methylsulfonyl) (2-methoxycarbonylthien-5-yl) ethylene-azetidine] , l- [bis (4-chlorophenyl) methyl] -3-hydroxy-3- [(methylsulfonyl) (2-methoxycarbonyl-thien-5-yl) ethyl] -azetidine- (RS), l- [bis (4- chlorophenyl) methyl] -3 - [(2-isobutyl-aminocarbonylthien-5-yl) (methylsulfonyl) methylene-azetidine, l- [bis (4-chlorophenyl) methyl] -3- [(3-methoxycarbonylphenyl) (methylsulfonyl) methyl] - (RS)] azetidin-3-ol, l- [bis (4-chlorophenyl) methyl] -3- [(methyl-sulfonyl) (pyridin-4-yl) methyl- (RS)] azetidin-3-ol , l- [bis (4-chlorophenyl) methyl] -3- [(ethyl-sulfonyl) (pyridin-3-yl) methyl- (RS) Jazetidin-3-ol, 3- (. {1 l- [bis] (4-chlorophenyl) methylJazetidin-3-ylidene.} - methanesul fonyl-met il) N- (3-morpholin-4-yl-propyl) benzamide, 3- (. {1 - l- [bis (4-chlorophenyl} metilJazeti din-S-iliden} -metanesulfonyl-methyl) N- (3-dimethylamino-propyl) benzamide, 3- (. {1 l- [bis (4-chlorophenyl) methyl] azeti-3-ylidene} - methanesulfonyl-methyl) - (2 -pyrrolidin-1-yl-ethyl) benzamide, 3- (. {1 l- [bis (4-chlorophenyl) methyl-Jazetidin-3-ylidene} -metansul-fonyl-methyl) N- (2-dimethylamino-1-methyl) ethyl) benzamide, 3- ( { 1 - [bis (4-chlorophenyl) methylJazetidin-3-ylidene] -metanesulfonyl-methyl) N-piperidin-1-yl-benza ida, 3- ( { l- [bis (4-chlorophenyl) methylJazetidin-3-ylidene] -metanesulfonyl-methyl) N-isobutyl-benzamide, 3- (. {1 l- [bis (4-chlorophenyl) methylJazetidin-3-ylidene}. -metansul fonyl-methyl) N- (3-imidazol-1-yl-propyl) benzamide, 3- (. {1-l- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} -metansul fonyl -methyl) N- (2-dimethylamino-ethyl.) benzamide, N '-methyl-hydrazide of 3- (. {1 - l- [bis (4-chlorophenyl) ethyl] -Jazetidin-3-ylidene} - methanesulfonyl- methyl) benzoic acid, 3- ( { 1 - [bis (4-chlorophenyl) ethyl] -Jazetidin-3-ylidene} - methanesulfonylmethyl) - (2-methyl) -morpholin-4-yl-ethyl) benzamide, 3- (. { l- [bis (4-chlorophenyl) methylJazetidin-3-ylidene} -metanesulfonyl-methyl) N- (l-ethyl-pyrrolidin-2-ylmethyl) benzamide, 3- (. {1-l- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} -metanesulfonyl-ethyl) N- (2,2-dimethyl-propyl) -benzamide, 3- (. {1 l- [bis (4-chlorophenyl) methylJazetidin-3-ylidene} - methanesulfonyl-methyl) N-cyclohexylmethyl-benzamide, 3- ( { l- [bis (4-chlorophenyl) methylJazetidin-3-ylidene.} - methanesulfonyl-methyl) N-cyclopropylmethyl-benzamide, 3- (. {1 l- [bis (4-chlorophenyl) methylJazetidin- 3-ylidene.} - methanesulfonyl-methyl) N- (2-methyl-butyl) -benzamide, 3- (. {1 l- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene}. methanesulfonylmethyl) N- (2-phenyl-propyl) -benzamide, 3- (. {1-l- [bis (4-chlorophenyl) methylazetidin-3-ylidene} -metansul foni 1 -methyl) N- ( tetrahydro-furan-2-ylmethyl) benzamide, 3- (. {1 L- [bis (4-chlorophenyl) met ilJazetidin-3-ylidene} -metansul fonyl-methyl) N- (2, 2, -diphenyl- ethyl) -benzamide, 3- ( { 1 - [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} - methanesulfonyl-methyl) N- (2-et. il-butyl) benzamide, methyl ester of 4-acid. { [3- ( { 1 - [bis (4-chlorophenyl) methyl] azetidin-3-ylidene] - methanesulfonylmethyl) benzoylaminojmethyl} -cyclohexanecarboxylic, 2 -amino- 1-. { 4- [3- (. {L- [bis- (4-chlorophenyl) -methyl] azetidin-3-ylidene} - methanesulfonyl-methyl) phenyl-piperazin-1-yl} -etanone, (2- {4- [3- ( { 1 - [bis- (4-chlorophenyl) methylJazetidin-3-ylidene} -metanesulfonyl-methyl) phenyl] piperazine-1-tert-butyl ester. -yl.} -2-oxo-ethyl) carbamic, l-. { 4- [3- ( { 1 - [bis- (4-chlorophenyl) met i 1J-azetidin-3-ylidene} - methanesulfonyl-methyl) phenyl-piperazin-1-yl} -2-methyl lamino-ethanone, tert-butyl ester of (2- {4- [3- (. {1- [bis- (4-chlorophenyl) methylJazetidin-3-ylidene} -metanesulfonyl-methyl} Phenylpiperazin-1-yl.} -2-oxo-ethyl) N-methylcarbamic acid, N-methylamide of 4- [3- (. {I-l- [bis- (4-chlorophenyl) methylJazetidin-3-ylidene}. .-methanesulfonyl-methyl) phenyljpiperazine-1-carbothioic acid, 4- [3- (. {1-l- [bis- (4-chlorophenyl) methyl-Jazetidin-3-ylidene} - methanesulfonyl-methyl) -N-methylamide. l-piperazine-1-carboxylic acid, 4- [3- (. {1-l- [Bis- (4-chlorophenyl) methyl-Jiazididin-3-ylidene} - methanesulfonyl-methyl) phenyl-Jpiperazin-1-carboxylic acid methyl ester, - - l- [3- ( { l- [bis- (4-chlorophenyl) methylJazetidin-3-ylidene} - methanesulfonylmethyl) phenylJ-4-isobutyl-piperazine, 1- [3- ( { l- [bis- (4-chlorophenyl) methyl-Jazetidin-3-ylidene} - methanesulfonyl-methyl) phenyl] -4-ethyl-piperazine, 4-acetyl- [3- (. {l- [bis] - (4-chlorophenyl) methyl] azetidin-3-ylidene.} - methanesulfon il-methyl) phenyljpiperazine, 1-. { 4- [3- ( { 1-bis- (4-chlorophenyl) methy1J-azetidin-3-ylidene} - methanesulfonyl-methyl) phenyl-J-piperazin-1-yl} -2-dimet i lamino-ethanone, l- [3- ( { L- [bis- (4-chlorophenyl) methylJazetidin-3-ylidene} -meta-s-phenyl-methyl) phenyl-Jpiperazine, tert-butyl ester of the acid 4- [3- ( { L- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} - methanesulfonylmethyl) phenyljpiperazine-1-carboxylic acid, l- [bis- (4- methoxycarbonylphenyl) methylJ-3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, 3-acetoxy-l- [bis (4-methoxycarbonyl-phenyl) -methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methyl] - (RS) Jazetidine, (RS) -4- [4- ((4-chlorophenyl) { 3- [(3,5-di-fluoro-phenyl) -methansulfoni-1-methylene-benzethidin-1-yl} -methyl) benzylmorpholine, 4- (4-. {3- [(1-benzhydryl-azetidin-3-ylidene) -methanesulfonyl-methylene] -phenoxy] butyl) orpholine, 4- (4-. {3 - [(1-benzhydryl azetidin-3-ylidene) -metansul foni 1-methyl] phenoxy] propyl) morpholine, their optical isomers and their salts. Among these compounds, the following compounds are particularly preferred: l- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluoro-phenyl) (methylsul fonyl) methylbenzoetidine, 1- [bis (4-chlorophenyl)] methyl] -3- [(3,5-difluoro-phenyl) (methylsulfonyl.) ethyl- (RS) Jazetidin-3-ol, 3-acetoxy-l- [bis- (4-chlorophenyl) methyl] -3- [(3, 5-di fluorophenyl) (methylsul fonyl) methyl) -methylsulfonylmethyl- (RS) -azetidine, its optical isomers and its salts with a mineral or organic acid.

The following examples illustrate the invention without limiting it.

Example 1 To a solution of 1 g of l-benzhydryl-3- [(methylsulfonyl) (phenyl) methyl- (RS) Jazetidin-3-ol in 10 ml of pyridine, cooled to 5 ° C, 0.3 ml of methanesulfonyl chloride are added . Stir 2 hours at 5 ° C, then add 1 g of 4-dimethylaminopyridine in 10 ml of dichloromethane at 5 ° C. The solution is stirred 15 hours at room temperature and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is subjected to chromatography on a column of silica gel (granulometry at 0.04-0.06 mm, diameter 3 cm, height 25 cm), eluting under a pressure of 0.5 bar of nitrogen with dichloromethane and collecting fractions of 80 ml. Fractions 17 to 20 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 10 ml of ethyl ether. 0.14 g of l-benzhydryl-3- [(methylsulfonyl) (phenyl) methylenejazetidine is obtained which melts at 210 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH aro.), 7.30 ( 4H, t, J = 7Hz, 4CH aroi.), Between 7.40 and 7.60 (9H, m, 9 CH arom.) J. L-benzhydryl-3- [(methylsulfonyl) (phenyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: to a solution of 1.4 ml of diisopropylamine in 10 ml of tetrahydrofuran, under an argon atmosphere , cooled to 0 ° C, add 6.25 ml of n-butyllithium 1.6 N in solution in hexane, then cool to -70 ° C. A mixture of 1.7 g of benzylmethylsulfone in 30 ml of tetrahydrofurane is then added and the stirring is maintained at -70 ° C for 45 minutes. 2.4 g of l-benzhydrilazetidin-3-one are added and then stirred for 20 minutes allowing the mixture to reach room temperature. The reaction mixture is filtered, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up with 50 ml of ethyl acetate, 30 ml of water and 20 ml of normal hydrochloric acid. The precipitate is filtered, washed with 30 ml of distilled water, drained and dried. 2 g of 1-benzhydryl-3- [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol are obtained which melts at 260 ° C.

The l-benzhydrilazetidin-3-one can be prepared according to the mode of operation described by KATRITZKY A.R. and collaborators in J. Heterocycl. Chem, 271 (1994).

Example 2 Operating according to the mode of operation of example 1 from 1.9 g of l-benzhydryl-3- [(3-methylphenyl) (methylsulfonyl) ethyl- (RS) Jazet idin-3-ol, of 0.52 ml of methanesulfonyl chloride and 1.7 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 17 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane and then a mixture of dichloromethane and ethanol (98.5 / 1.5 in volumes) as eluents and collecting 100 ml fractions. Fractions 5 and 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 2 ml of dichloromethane and 20 ml of diisopropyl oxide. 0.9 g of l-benzhydryl-3- [(3-methyl phenyl) (methylsulfonyl) -methylene-benzetidine is obtained which melts at 180 ° C [NMR spectrum in DMSO-d6, 'T = 300K, d in ppm (300 MHz) : 2.35 (3H, s, PhCH3), 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.20 (5H, m, SCH aro ..}., 7.30 (5H, t, J = 7Hz, 5CH arom.), 7.50 (4H, d, J = 7Hz, 4 CH arom.)]. The l-benzhydril-3- [( 3-methylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of example 1 from 2.8 g of methyl (3-methylbenzyl) sulfone and 3.6 g of 1-benzhydrilazetidin-3-one, is obtained after purification on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (98.5 / 1.5 by volume) as eluent, 2.6 g of a solid. This is collected with 25 ml of diisopropyl oxide. After filtration, drying and drying, 1.9 g of l-benzhydryl-3- [(3-methylphenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol is obtained which melts at 170 ° C. Methyl (3-methylbenzyl) sulfone can be prepared in the following manner: to a solution of 30 ml of water, 30 ml of acetic acid and 15 ml of 36 N sulfuric acid, 10.5 g of water are added at room temperature. oxone® and then 2.6 g of methyl (3-methylbenzyl) sulfide and 30 ml of ethanol. The mixture is stirred 48 hours at room temperature and then taken up with 100 ml of water and 100 ml of ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium bicarbonate, decanted, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 2.8 g of methyl (3-methylbenzyl) sulfone are obtained in the form of a gum. The methyl (3-meth ylbenzyl) sulfide can be prepared in the following manner: to a solution of 3.7 g of 3-methylbenzyl bromide in 25 ml of dimethylformamide, it is added, keeping the temperature below 30 ° C, 1.7 g of sodium methylthiolate The mixture is stirred for 2 hours at a temperature close to 20 ° C and then taken up in 50 ml of ethyl acetate.The organic phase is washed with 3 portions of 100 ml of water, dried over sodium sulfate, magnesium and concentrated to dryness under reduced pressure (2.7 kPa) 2.6 g of methyl (3-methylbenzyl) sulfide are obtained in the form of an oil.

Example 3 To a solution of 3.3 g of l-benzhydryl-3- [(4-methylphenyl) (methylsulfonyl) ethyl- (RS) Jazetidin-3-ol in 10 ml of pyridine, cooled to 5 ° C, 0.3 ml of chloride are added of methanesulfonyl. Stir 2 hours at 5 ° C and then add 1 g of 4-dimethylaminopyridine in 10 ml of dichloromethane at 5 ° C. The solution is stirred 15 hours at room temperature and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is subjected to chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 25 cm), eluting under a pressure of 0.5 bar of nitrogen with dichloromethane and collecting fractions of 80 ml. Fractions 17 through 20 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 30 ml of acetonitrile. 0.14 g of l-benzhydryl-3- obtained [(4-methylphenyl) (methylsulfonyl) etilenjazetidina melting at 210 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.30 ( 3H, s, PhCH3), 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, S, NCH), 7.20 (4H, m, 4CH arom.), 7.30 (6H, t, J = 7Hz, 6CH arom.), 7.45 (4H, d, J = 7Hz, 4 CH arom.)]. L-benzhydryl-3- [(4-methylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of example 1 from 4 g of Methyl (4-methylbenzyl) sulfone and 5.1 g of 1-benzhydrylazetidin-3-one give 3 g of 1-benzhydryl-3 - [(4-methylphenyl) (methylsul fonyl) methyl- (RS)] azetidine- 3-ol melting at 226 ° C. Methyl (4-methylbenzyl) sulfone can be prepared as follows: operating according to the mode of operation of Example 2 from 3.5 g of methyl (4-methylbenzyl) sulfide and 12.3 g of oxoneR 3.5 g of met il (4-methylbenzyl) sulfone are obtained in the form of a solid Methyl (4-meth i lbenzyl) sul furo * can be prepared as follows: operating according to the mode of operation of the Example 2: from 5.6 g of 4-methylbenzyl bromide and 2.3 g of sodium methylthiolate, 4.7 g of methyl (4-methylbenzyl) sulfide are obtained in the form of a solid.

Example 4 To a solution of 3.3 g of l-benzhydryl-3- [(2-methyl phenyl) (methylsulfoyl) methyl- (RS) Jazetidin-3-ol in 50 ml of dichloromethane, at room temperature, 0.7 ml of chloride are added of methanesulfonyl and then 3.8 g of dimethylaminopyridine. The solution is stirred for 3 hours under reflux and then collected with 2 50 ml portions of water. The organic phase is decanted, dried and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a column of silica gel (0.04-0.06 mm granulometrí to, diameter 3 cm, height 25 cm), eluting under a pressure of 0.5 bara nitrogen with dichloromethane and then with a mixture of dichloromethane and ethanol (mixture 99/1 by volume) and collecting 100 ml fractions. Fractions 6 to 17 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 50 ml of ethyl ether. 2.6 g of l-benzhydryl-3- [(2-methylphenyl) (methylsulfonyl) methylenazetidine are obtained in the form of a foam [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.30 ( 3H, s, PhCH3), 2.95 (3H, s, SCH3), 3.50 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.70 (1H, s, NCH), between 7.10 and 7.35 (10H, 10CH arom.), 7.45 (4H, m, 4CH arom)]. L-benzhydryl-3- [(2-methylphenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 from 3.4 g of methyl (2-meth yl-benzyl) sulfone and 4.3 g of 1-benzhydrylazetidin-3-one, 3.4 g of 1-benzhydryl-3- [(2-methylphenyl) (methylsulfonyl) ethyl (RS)] azetidin-3-ol are obtained that melts at 218 ° C. The methyl (2-methylbenzyl) sulfone can be prepared in the following manner: by operating according to the mode of operation of example 2 from 4.5 g of methyl (2-methylbenzyl) sulfide and 16.2 g of oxoneR, 3.4 g of methyl are obtained (2-methylbenzyl) sulfone in the form of a solid. The methyl (2-methyl and Ibenzyl) sulfide can be prepared in the following manner: by operating according to the mode of operation of Example 2 starting from 5.6 g of 2-methylbenzyl bromide and 2.1 g of sodium methylthiolate, 4.5 g are obtained. of methyl (2-methylbenzyl) sulfide in the form of a solid.

Example 5 Operating according to the mode of operation of example 4 from 2.1 g of l-benzhydryl-3- [(2-chlorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol, of 0.55 ml methanesulfonyl chloride and 2.3 g of 4-dimethylaminopyridine, the obtained residue is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 25 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting fractions of 100 ml. Fractions 12 through 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 3 ml of dichloromethane and 40 ml of ethyl ether. 1.1 g of 1-benzhydryl-3- [(2-chlorophenyl) (methylsulfonyl) ethylenjazetidine is obtained which melts at 204 ° C [NMR spectrum in DMSO-d6, T-300K, d in ppm (300 MHz): 2.95 ( 3H, s, SCH3), 3.60 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.70 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.45 (7H, m, 7CH arom.), 7.55 (1H, d, J = 7Hz, CH arom.)]. L-benzhydryl-3 - [(2-chlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol is 1 9 can be prepared as follows: operating according to the mode of operation of example 1 from 4 g of (2-chlorobenzyl) ethylsulfone and 4.6 g of 1-benzhydrilazetidin-3-one, the residue obtained is taken up with 50 ml of acetate of ethyl, filtered and dried. 2.4 g of l-benzhydryl-3- [(2-chlorophenyl) (methylsulfonyl) ethyl- (RS) Jazetidin-3-ol are obtained in the form of a white solid. The (2-chlorobenzyl) methylsulfone can be prepared in the following manner: by operating according to the mode of operation of example 2 from 3.4 g of (2-chlorobenzyl) methylsulfide and 12 g of oxoneR, 4 g of (2-chlorobenzyl) ethylsulfone are obtained in the form of an oil which crystallizes. The (2-chlorobenzyl) ethylsulfide can be prepared in the following manner: by operating according to the mode of operation of example 2 from 4 g of 2-chlorobenzyl bromide and 1.5 g of sodium methylthiolate, 3.4 g of -chlorobenzyl) methylsulfide in the form of an oil.

Example 6 Operating according to the mode of operation of example 4 from 3 g of l-benzhydryl-3- [(3-chlorophenyl) (methylsulfonyl) ethyl- (RS) Jazetidin-3-ol, of 0.79 ml of methanesulfonyl chloride and 3.3 g of 4-dimethylaminopyridine, the obtained residue is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 25 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting fractions of 100 ml. Fractions 2 through 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 40 ml of ethyl ether. 1.7 g of l-benzhydryl-3- [(3-chlorophenyl) (methylsulfonyl) .methylenejazetidine is obtained which melts at 205 ° C [NMR spectrum in DMS0-d6, T-300K, d in ppm (300 MHz) : 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH3), 4.70 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.45 (8H, m, 8CH arom.)]. The l-benzhydryl-3 - [(3-chlorophenyl) (methylsulfonyl) ethyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of example 1 from 3.1 g of (3-chlorobenzyl) methylsulphone and 3.4 g of 1-benzhydrylazetidin-3-one , 3.4 g of 1-benzhydryl-3- [(3-chlorophenyl) (methylsulfonyl) et il- (RS) Jazetidin-3-one are obtained in the form of a white solid.The (3-chlorobenzyl) ethylsulfone can be prepared as follows: operating according to the mode of operation of example 2 from 3.2 g of (3-chlorobenzyl) methylsulfide and 12 g of oxoneR, 3.2 g of (3-chlorobenzyl) sulfone are obtained in the form of a white solid. The (3-chlorobenzyl) methylsulfide can be prepared in the following manner: by operating according to the mode of operation of example 2 from 4 g of 3-chlorobenzyl bromide and 1.5 g of sodium methylthiolate, 3.2 g of 3-chlorobenzylmethylsulfide in the form of an oil.

Example 7 • Operating according to the mode of operation of Example 4 from 3.3 g of l-benzhydryl-3- [(4-chlorophenyl) (methylsul foni 1) ethyl- (RS) Jazetidin-3-ol, 0.87 ml of chloride of methanesulfonyl and 3.6 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 25 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting fractions of 100 ml. Fractions 8 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 3 ml of 30 ml of ethyl ether. 0.5 g of l-benzhydryl-3- [(4-chlorophenyl) (methylsulfonyl.) Et ilenjazetidine is obtained which melts at 192 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz ): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.70 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), between 7.40 and 7.55 (8H, m, 8CH arom.)]. l-benzhydryl-3- [(4-chlorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of example 1 from 2.8 g of (4-chlorobenzyl) methylsulfone and 3.24 g of 1-benzhydrilazetidin-3-one , after crystallization in 80 ml, 3.4 g of l-benzhydryl-3- [(4-chlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol is obtained in the form of a white solid. 4-chlorobenzyl) methylsulfone can be prepared in the following manner: by operating according to the mode of operation of example 2 from 3.5 g of (4-chlorobenzyl) methylsulfide and 12.3 g of oxoneR, 3.5 g of (4-chlorobenzyl) methylsulfone are obtained in the form of a solid.

Example 8 Operating according to the mode of operation of Example 4 from 3.1 g of l-benzhydryl-3- [(3,5-dichlorophenyl). (Methylsulfonyl.) Ethyl- (RS) Jazetidin-3-ol, 0.75 ml of methanesulfonyl chloride and 3.1 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 25 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 100 ml fractions Fractions 6 through 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa) The solid obtained is crystallized from a mixture of 2 ml of dichloromethane and 30 ml of ethyl ether. 0.8 g of 1-benzhydryl-3- [(3,5-dichlorophenyl) (methylsulfonyl) -methylene-benzetidine is obtained which melts at 204 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz)] : 2.95 (3H, s, SCH3), 3.85 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom ..}. , 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.45 (6H, m, 6CH arom.), 7.70 (1H, s, CH arom.)]. L-benzhydryl-3- [(3,5-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 starting from 4 g of (3, 5-dichlorobenzyl) ethylsulfone and 4 g of 1-benzhydrilazetidin-3-one, 3.2 g of 1-benzhydryl-3- [(3,5-dichlorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin are obtained -3-ol in the form of a white solid. The (3, 5-dichlorobenzyl) methylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 from 5.3 g of (3, 5-dichlorobenzyl) ethyl sulfur and 17 g of oxone R, 5 g of (3,5-dichlorobenzyl) methylsulphide are obtained in the form of a white solid. The (3, 5-dichlorobenzyl) ethylsulfide can be prepared in the following manner: by operating according to the mode of operation of example 2 from 5 g of 3,5-dichlorobenzyl chloride and 2 g of sodium methylthiolate, 5.3 are obtained g of (3,5-dichlorobenzyl) met ilsulfide in the form of an oil.

Example 9 Operating according to the mode of operation of example 4 from 5 g of l-benzhydryl-3- [(3,4-dichlorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol, 1.2 ml of methanesulfonyl chloride and 3.8 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 4 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (70/30 in volume) as eluent collecting 35 ml fractions. Fractions 30 to 55 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 50 ml of ethyl ether. 1.5 g of l-benzhydryl-3- [(3,4-dichlorophenyl) (methylsulfonyl) methylenazetidine is obtained which melts at 170 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.70 (1H, s, NCH), 7.20 (2H, t, J = 7Hz, 2CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), Between 7.35 and 7.50 (5H, m, 5CH arom.), 7. 65 (2H, m, 2CH arom.)] L-Benzhydryl-3- [(3,4-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained as follows: operating according to the operation mode of example 1 from 4.5 g of (3,4-dichlorobenzyl) methylsulphone and 4.3 g 1-benzhydrilazetidin-3-one, 5 g of 1-benzhydryl-3- [(3, 4- dichlorophenyl) (methylsulfonyl) ethyl- (RS) Jazetidin-3-ol in the form of a white solid. The (3,4-dichlorobenzyl) methylsulphone can be prepared in the following manner: by operating according to the mode of operation of Example 2 from 4.3 g of (3, 4-dichlorobenzyl) methylsulfide and 13 g of oxoneR, 4.7 g of (3, -dichlorobenzyl) methylsulfone are obtained in the form of a white solid. The (3,4-dichlorobenzyl) ethyl sulfur can be prepared in the following manner: by operating according to the mode of operation of Example 2 starting from 2.8 ml of 3,4-dichlorobenzyl chloride and 1.5 g of sodium ethyl acetate, they obtain 4.3 g of (3,4-dichlorobenzyl) et ilsulfide in the form of an oil.

Example 10 Operating according to the mode of operation of Example 4 from 1.8 g of l-benzhydryl-3- [(2,5-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol of 0.4 ml of sodium chloride methanesulfonyl and 1.8 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 25 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting fractions of 100 ml. Fractions 8 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 2 ml of dichloromethane and 30 ml of ethyl ether. 1.2 g of 1-benzhydryl-3- [(2,5-dichlorophenyl) (methylsulfonyl) -methylene-benzetidine is obtained which melts at 202 ° C [Spectrum of 'NMR in DMSO-d6, T = 300K, d in ppm (250 MHz ): 3.00 (3H, s, SCH3), 3.70 (2H,, NCH2), 4.25 (2H, s, NCH2), 4.70 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom .), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.45 (4H, d, J = 7Hz 4CH arom.}., Between 7.55 and 7.70 (3H,, 3CH arom.) J The l- Benzhydril-3 - [(2,5-dichlorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 from 1.2 g of (2) , 5-dichlorobenzyl}, methylsulfone and 1.2 g of l-benzhydrilazetidin-3-one, 1.8 g of 1-benzhydryl-3- [(2,5-dichlorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3 are obtained. -ol in the form of a solid, (2, 5-dichlorobenzyl) methylsulfone can be prepared as follows: 1.9 g of sodium methansulphinate is added at room temperature to a solution of 2.7 g of 2-chloride. 5-dichlorobenzyl in 30 ml of ethanol. The mixture is refluxed for 5 hours, cooled to room temperature and then taken up in 50 ml of water and 50 ml of ethyl acetate. The organic phase is decanted, washed with 20 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 1.2 g of (2,5-dichlorobenzyl) methanesulphone are obtained in the form of a white solid.

Example 11 Operating according to the mode of operation of Example 4 from 9.1 g of l-benzhydryl-3- [(2,4-dichlorophenyl) (methylsulfonyl.) Ethyl- (RS) Jazetidin-3-ol, 2.2 ml of chloride of methanesulfonyl and 7 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 5.5 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 40 ml fractions Fractions 27 through 39 are combined and concentrated to dryness under reduced pressure (2.7 kPa) The solid obtained is crystallized from 20 ml of ethyl ether to obtain 1.5 g of l-benzhydril-3. -[ ( 2, 4-dichlorophenyl) (methylsulfonyl) methylenjazet idine that melts at 165 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz): 3.00 (3H, s, SCH3), 3.65 (2H, m, NCH2), 4.25 (2H,, NCH2), 4.75 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom ..}., 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.45 (6H, 6CH arom.), 7.80 (1H, s, CH arom.) J L-benzhydryl-3 - [(2,4-dichlorophenyl) (methylsulfonyl) methyl- ( RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 starting from 4.8 g of (2,4-dichlorobenzyl) methylsulfone and 4.7 g of l-benzhydryl Jazetidin-3-one, 9.1 g of 1-benzhydryl-3- [(2,4-dichlorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol are obtained in the form of a brown foam. (2,4-Dichlorobenzyl) ethylsulfone is it can be prepared in the following manner: by operating according to the mode of operation of example 2 from 4 g of (2,4-dichlorobenzyl) methylsulfide and 13 g of oxone R, 4.8 g of (2,4-dichlorobenzyl) methyl are obtained sulfone in the form of a solid that melts at 111 ° C. The (2,4-dichlorobenzyl) methylsulfide can be prepared in the following manner: by operating according to the mode of operation of Example 2 starting from 2.8 ml of 2,4-chlorobenzyl chloride and 1.5 g of sodium methylthiolate, 4 are obtained. g of (2,4-dichlorobenzyl) methylsulfide in the form of an oil.

Example 12 Operating according to the mode of operation of Example 4 from 3 g of l-benzhydryl-3- [(2,3-dichlorophenyl) (methylsulfonyl) met il- (RS) Jazet idin-3-ol, of 1.1 g of chloride of methanesulfonyl and 3 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry at 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane and Ethanol (98/2 by volume) as eluent and collecting 100 ml fractions. Fractions 10 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 40 ml of ethyl ether. 1.6 g of l-benzhydryl-3 - [(2,3-dichloropheni-1) (methylsulfonyl) methylenazetidine is obtained which melts at 201 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz)] : 3.00 (3H, s, SCH3), 3.60 (2H, m, NCH2), 4.20 (2H, m, NCH2), 4.70 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.45 (6H, 6CH arom.), 7.70 (1H, J = 8 and 2Hz, CH arom.)] The l-benzhydril- 3- [(2,3-dichlorophenyl) (methylsulfonyl) ethyl- (RS) Jazetidin-3-ol can be prepared in the following manner: by operating according to the mode of operation of Example 1 from 3.6 g of (2, 3 -dichlorobenzyl) methylsulfone and 3.6 g of l-benzhydrilazetidin-3-one 5.4 g of 1-benzhydryl-3- [(2,3-dichlorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol are obtained in the form of a white solid. The (2,3-dichlorobenzyl) methylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 10 starting from 3 g of 2,3-dichlorobenzyl chloride and 2.4 g of sodium methansulphonate, 3.6 g of (2,3-dichlorobenzyl) methylsulfone in the form of a white solid.

Example 13 Operating according to the mode of operation of example 4 from 2.5 g of l-benzhydryl-3- [(3-fluorophenyl) (methylsul fonyl) methyl- (RS) Jazetidin-3-ol, of 0.72 ml of methanesulfonyl chloride and 2.9 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 25 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting fractions of 100 ml. Fractions 2 through 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 40 ml of ethyl ether. 1.5 g of l-benzhydryl-3- [(3-fluorophenyl) (methylsulfonyl.) Methylenazetidine is obtained which melts at 210 ° C [NMR spectrum in DMS0-d6, T = 300K, d in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.70 (1H, s, NCH), between 7.10 and 7.30 (9H, m, 9CH arom.), 7.45 (5H, m, 5CH arom.)] L-benzhydryl-3 - [(3-fluorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: operating in the mode of operation of example 1 from 2. 6 g of 3-fluorobenzylmethelsulfone and 3.3 g of 1-benzhydrylazet idin-3-one, 2.9 g of 1-benzhydryl-3- [(3-fluorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol are obtained. in the form of a white solid that melts at 200 ° C. The 3-fluorobenzylmethylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 from 3.1 g of 3-fluorobenzyl methyl sulfide and 13 g of oxone R, 2.7 g of 3-fluorobenzyl methyl sulfone are obtained in the form of a solid. White. The 3-fluorobenzylmethyl sulfide can be prepared in the following manner: by operating according to the mode of operation of Example 2 from 2.6 ml of 3-fluorobenzyl bromide and 1.6 g of sodium methylthiolate, 3.1 g of 3-fluorobenzylmethylsulfur are obtained under the shape of an oil.

Example 14 Operating according to the mode of operation of Example 4 from 4.3 g of l-benzhydryl-3- [(2-fluorophenyl) (methylsul fonyl) methyl- (RS) Jazet idin-3-ol, 1.2 ml of methanesulfonyl chloride and 3.7 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (granulometry 0.04-0.06 mm, diameter 4.5 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting fractions of 30 ml. Fractions 28 to 58 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 100 ml of ethyl ether. 2.3 g of l-benzhydryl-3- [(2-fluorophenyl) (methylsulfonyl) methylazetidine is obtained which melts at 188 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz ): 3.00 (3H, s, SCH3), 3.65 (2H, m, NCH2), 4.20 (2H, m, NCH2), 4.75 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom.), 7.30 (6H, m, 6CH arom.), 7.50 (6H, m, 6CH arom.)]. L-benzhydryl-3- [(2-fluorophenyl) (methylsulfonyl) ethyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 from 3.4 g of 2 -fluorobenzylmethylsulfone and 4.2 g of 1-benzhydrilazetidin-3-one 4.3 g of 1-benzhydryl-3 - [(3-fluoro-phenyl) (methylsulfonyl) methyl (RS) Jazetidin-3-ol are obtained in the form of a white solid . The 2-fluorobenzylmethylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 from 3 g of 2-fluorobenzyl methyl sulfide and 13 g of oxone R, 3.6 g of 3-fluorobenzyl methyl sulfone are obtained in the form of a solid. White. The 2-fluorobenzylmethylsulfide can be prepared in the following manner: by operating according to the mode of operation of Example 2 starting from 2.4 ml of 2-fluorobenzyl bromide and 1.5 g of sodium methylthiolate, 3 g of 2-fluorobenzymethyl sulfide are obtained under the shape of an oil.Example 15 Operating according to the mode of operation of example 4 from 1 g of l-benzhydryl-3- [(4-fluorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol, of 0.3 ml of methanesulfonyl chloride and 0.6 g of 4-dimethylaminopyridine, the obtained residue is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting fractions of 30 ml. Fractions 20 through 35 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 50 ml of ethyl ether. 0.4 g of l-benzhydryl-3- [(4-fluorophenyl) (methylsulfonyl) methylene] azetidine is obtained which melts at 186 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, m, NCH2), 4.20 (2H, m, NCH2), 4.75 (1H, s, NCH), between 7.15 and 7.35 (8H,, 8CH arom.) 7.45 (6H, m, 6CH arom.) J. L-benzhydryl-3 - [(4-fluorophenyl) (methylsulfonyl) met il- (RS)] azetidin-3-ol can be obtained in the following manner: operating according to the mode of operation of Example 1 from 2.8 g of 4-fluorobenzylmethylsulfone and 3.6 g of 1-benzhydrylazetidin-3-one, 1 g of 1-benzhydryl-3 - [(4-fluorophenyl) (methylsulfonyl) ethyl- (RS) Jazetidin-3-ol is obtained in the form of a white solid. The 4-fluorobenzylmethylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 from 3 g of 4-fluorobenzylmethylsulfide and 13 g of oxone ", 3 g of 4-fluorobenzylmethylsulfone are obtained in the form of a white solid that melts at 110 ° C. The 4-fluorobenzylmethylsulfide can be prepared as follows: operating according to the mode of operation of example 2 from 2.5 ml of 4-fluorobenzyl chloride and 1.5 g of sodium methylthiolate, they obtain 3 g of 4-fluorobenzylmethylsulfide in the form of an oil.

Example 16 Operating according to the mode of operation of Example 4 from 3.8 g of l-benzhydryl-3- [(3, 5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, of 1 ml of methanesulfonyl and 4.2 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting fractions of 100 ml. Fractions 5 to 10 are concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 30 ml of ethyl ether. 0.8 g of l-benzhydryl-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylenazetidine is obtained which melts at 172 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz): 3.00 (3H, s, SCH3), 3.85 (2H,, NCH2), 4.20 (2H,, NCH2), 4.75 (1H, s, NCH), between 7.10 and 7.40 (9H, m, 9CH arom.), 7.50 (4H, d J = 7Hz, 4CH, arom.)] L-Benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonyl) ethyl- (RS)] azetidin-3-ol can be obtained from the following The following example shows that 3.9 g of 1-benzhydryl-3 - [(3, 5) is obtained by operating according to the mode of operation of Example 1 from 3.2 g of 3,5-difluorobenzylmethyl sulfone and 3.7 g of 1-benzhydrylazetidin-3-one. -di fluorophenyl) (methylsul fonyl) -methyl- (RS) Jazetidin-3-ol in the form of a white solid.

The 3,5-difluorobenzylmethylsulfone can be prepared in the following manner: by operating according to the mode of operation of example 2 from 4.2 g of 3,5-difluorobenzylmethylsulfide and 16 g of oxoneR, 3.3 g of 3,5-di is obtained. fluorobenzylmethylsulfone in the form of a white solid. The 3,5-difluorobenzylmethylsulfide can be prepared in the following way: by operating according to the mode of operation of Example 2 starting from 5 g of 3,5-difluorobenzyl bromide and 2 g of sodium methylthiolate, 4.9 g of 3 are obtained. , 5-difluorobenzylmethylsulfide in the form of an oil.

Example 17 Operating according to the mode of operation of example 4 from 5.2 g of l-benzhydryl-3 - ['(2,3-difluorophenyl) (methylsul fonyl) methyl- (RS) azetidin-3-ol of 2.3 ml of chloride of methanesulfonyl and 7.3 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 6 cm, height 40 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and methanol (98/2 by volume ) as eluent and collecting 50 ml fractions. Fractions 65 through 87 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 75 ml of ethyl ether. They are obtained 2. 5 g of l-benzhydryl-3- [(2,3-difluorofenyl) (methylsulfonyl) methylenazetidine which melts at 208 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (400 MHz)] : 3.05 (3H, s, SCH3), 3.70 (2H, s, NCH2), 4.25 (2H, s, NCH2), 4.75 (1H, s, NCH), between 7. 15 and 7.55 (13H, m, 13CH arom.)]. L-Benzhydryl-3 - [(2,3-difluorofenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 starting from 4 g of (2,3-difluorobenzyl) ethylsulfone and 4.8 g of 1-benzhydrylazetidin-3-one give 5.5 g of 1-benzhydryl-3- [(2,3-difluorofenyl) (methylsulfonyl) - methyl- (RS)] azetidin-3-ol in the form of a beige solid. (2,3-difluorobenzyl) ethylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 10 from 4.1 g of 2,3-difluorobenzyl bromide and 4.1 g of sodium methansulfonate. , 4 g of (2,3-difluorobenzyl) methylsulfone are obtained in the form of a white solid.

Example 18 Operating according to the mode of operation of Example 4 from 5.2 g of l-benzhydryl-3- [(2,5-difluorophenyl) (methylsulfonyl) ethyl- (RS) Jazetidin-3-ol, 2.3 ml of methanesulfonyl chloride and 7.3 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 6 cm, height 40 cm) under a pressure of 0.5 bar of nitrogen with a dichloromethane mixture. and ethanol (98/2 by volume) as eluent and collecting 50 ml fractions. Fractions 73 through 90 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 75 ml of ethyl ether. 2.6 g of l-benzhydryl-3- [(2,5-difluorophenyl) (methylsulfonyl) met ilenjazetidine are obtained which melts at 176 ° C. L-benzhydryl-3- [(2,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 starting from 4 g of (2,5-difluorobenzyl) ethylsulfone and 4.8 g of l-benzhydrylazetidin-3-one give 5.9 g of 1-benzhydryl-3 - [(2,5-difluorophenyl). (methylsulfonyl) -methyl. - (RS)] azetidin-3-ol in the form of a cream white solid The (2,5-difluorobenzyl) methylsulfone can be prepared as follows: operating according to the mode of operation of example 10 from 4.1 g of 2, 5-difluorobenzyl bromide and 4.1 g of sodium meta-sulphinate, 4.8 g of (2,5-difluorobenzyl) methylsulfone are obtained in the form of a white solid which melts at 95 ° C.

Example 19 Operating according to the mode of operation of Example 4 starting from 7.7 g of l-benzhydryl-3- [(3-bromophenyl) (me tilsul fonil) et il- (RS) Jazetidin-3-ol, of 1.8 ml methanesulfonyl chloride and 5.8 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 35 cm), under a pressure of 0.5 bar of nitrogen with dichloromethane and then a mixture of licor methane and ethanol (99.5 / 0.5 by volume) as eluents and collecting fractions of 100 ml. Fractions 17 through 28 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 5 ml of dichloromethane and 50 ml of ethyl ether. 3.5 g of l-benzhydryl-3- [(3-bromophenyl) (methylsulfonyl) et ilenjazetidine is obtained which melts at 200 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom.) , 7.30 (4H, t, J = 7Hz, 4CH arom.), Between 7.35 and 7.55 (6H, m, 6CH arom.), 7.65 (2H, m, 2CH arom.)] L-Benzhydril-3- [( 3-bromophenyl) (met ilsul foni 1) ethyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of example 1 starting from 8 g of 3-bromobenzylmethylsulfuna and 7.6 g of 1-benzhydrilazet idin-3-one, 8 g of 1-benzhydryl-3- [(3-bromopheni 1) (methylsul fonyl) methyl- (RS) Jazetidin-3 are obtained. ol in the form of a white solid. The 3-bromobenzylmethylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 from 9 g of 3-bromobenzyl methyl sulfide and 27 g of oxone R, 8.2 g of 3-bromobenzyl methyl sulfone are obtained in the form of a solid. White.

The 3-bromobenzylmethylsulfide can be prepared in the following manner: by operating according to the mode of operation of Example 2 from 10 g of 3-bromobenzyl bromide and 3.1 g of sodium methylthiolate, 9 g of low 3-bromobenzylmethylsulphur are obtained the shape of an oil.

Example 20 Operating according to the mode of operation of example 4 from 1.5 g of l-benzhydryl-3- [(3-iodophenyl) (methylsulfonyl) ethyl- (RS) Jazetidin-3-ol, of 0.3 ml of methanesulfonyl chloride and 1.4 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane and then with a mixture of dichloromethane and ethanol (99.7 / 0.3 by volume) as eluents and collecting 100 ml fractions. Fractions 16 to 24 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 1.5 ml of dichloromethane and 25 ml of ethyl ether. 0.5 g of l-benzhydryl-3- [(3-iodophenyl) (methylsul fonyl) met ilenjazetidine is obtained which melts at 198 ° C [NMR spectrum in DMS0-d6, T = 300K, d in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), between 7.10 and 7.30 (7H, m, 7CH arom.), 7.45 (5H, m, 5CH arom.), 7.80 (2H, m, 2CH arom.)]. L-benzhydryl-3- [(3-iodophenyl) (methylsulfonyl) ethyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 starting from 3. 7 g of 3-iodobenzylmethylsulfone and 3 g of 1-benzhydrylazetidin-3-one give 1.5 g of 1-benzhydryl-3- [(3-iodo phenyl) (methylsul fonyl) ethyl- (RS) Jazetidin-3-ol in the form of a white solid. The 3-iodobenzylmethylsulfone can be prepared in the following manner: by operating according to the mode of operation of example 2 from 3.6 g of 3-iodobenzylmet ilsulfuro and 10.3 g of oxoneR, 3.7 g of 3-iodobenzylmethylsulfone are obtained in the form of a white solid. The 3-iodobenzylmet ilsulfuro can be prepared in the following manner: by operating according to the mode of operation of example 2 from 5 g of 3-iodobenzyl bromide and 1.3 g of sodium methylthiolate, 4 g of 3-iodobenzymethyl sulfide are obtained in the form of an oil.

Example 21 Operating according to the mode of operation of example 4 from 2.4 g of l-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethoxy phenyl) ethyl- (RS)] azetidin-3-ol, 0.6 ml of sodium chloride methanesulfonyl and 2.3 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane and then with a mixture of dichloromethane and ethanol (99.7 / 0.3 by volume) as eluents and collecting 100 ml fractions. Fractions 12 through 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 2 ml of dichloromethane and 30 ml of ethyl ether. 0.7 g of 1-benzhydryl-3- [(methylsulonyl) (3-trifluoromethoxyphenyl) et ilenjazetidine is obtained which melts at 162 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz): 3.00 (3H, s, SCH3), 3.80 (2H, m, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), between 7.15 and 7.40 (6H,, 6CH arom.), Between 7.45 and 7.55 (7H, m, 7CH arom.), 7.60 (1H, t, J = 7 Hz, CH arom.)]. L-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethoxyphenyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 from 2.4 g of Methyl (3-trifluoromethoxybenzyl) sulfone and 2.2 g of l-benzhydrilazetidin-3-one give 2.4 g of l-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethoxyphenyl) methyl- (RS) Jazetidin-3-ol under the shape of a white solid. The methyl (3-trifluoromethoxybenzyl) sulphone can be prepared in the following manner: by operating according to the mode of operation of example 2 starting from 2.6 g of methyl (3- trifluoromethoxybenzyl) sulphide and 7.2 g of oxoneR, 2.4 g of methyl (3-trifluoromethoxybenzyl) sulphone are obtained in the form of a white solid. The methyl (3-trifluoromethoxybenzyl) sulfide can be prepared in the following manner: by operating according to the mode of operation of example 2 from 3 g of 3-trifluoromethoxybenzyl bromide and 1 g of sodium methylthiolate, 3.3 g of methyl are obtained (3-trifluoromethoxybenzyl) sulfide in the form of an oil.

Example 22 Operating according to the mode of operation of Example 4 from 4.1 g of l-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethoxyphenyl) ethyl- (RS) J-azetidin-3-ol, of 1 ml of methanesulfonyl chloride and 4.2 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 100 ml fractions. Fractions 10 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 2 ml dichloromethane and 30 ml ethyl ether. 1.2 g of l-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethylphenyl) methylenejazetidine is obtained which melts at 178 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.00 ( 3H, s, SCH3), 3.80 (2H, s, NCH2), 4.15 (2H, s, NCH2), 4.70 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, "2CH arom.) , 7.30 (4H, t J = 7Hz, 4CH arom.), 7.45 (4H, m, J = 7Hz, 4CH arom.), Between 7.60 and 7.80 (4H, m, 4CH arom.).] The l-benzhydril- 3- [(Methylsulfonyl) (3-trifluoromethylphenyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 starting from 3.4 g of methyl (3-trifluoromethylbenzyl. sulfone and 3.4 g 1-benzhydrilazetidin-3-one, 4.2 g of 1-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethylphenyl) -methyl- (RS) Jazetidin-3-ol are obtained in the form of a White solid Methyl (3-trifluoromethylbenzyl) sulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 starting from 3.3 g of met il ( 3- tri fluorometylbenzene) sulfide and 10 g of oxone ", 3.4 g of methyl (3-trifluoromethylbenzyl) sulfone are obtained in the form of a white solid. The methyl (3-trifluoromethylbenzyl) sulfide can be prepared in the following manner: by operating according to the mode of operation of Example 2 starting from 3. 9 g of 3-trifluoromethylbenzyl bromide and 1.4 g of sodium methylthiolate give 3.3 g of methyl (3-trifluoromethylbenzyl) sulfide in the form of an oil.

Example 23 Operating according to the mode of operation of Example 4 from 2.7 g of l-benzhydril-3-. { [3,5-bis (trifluoromethyl) phenyl] (methylsulfonyl) methyl- (RS)} azetidin-3-ol of 0.6 ml of methanesulfonyl chloride and 2.4 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry at 0.04-0.06 mm, diameter 6 cm, height 40 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 100 ml fractions. Fractions 7 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 10 ml of ethyl ether. 1 g of l-benzhydril-3- is obtained. { [3,5-bis (trifluoromethyl) phenyl] (methylsulfonyl) methylene} -azetidine that melts at 192 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.00 (3H, s, SCH3), 3.85 (2H, s, NCH2), 4.15 (2H , s, NCH2), 4.70 (1H, s, NCH), 7.15 (2H, t, J = 7 Hz, 2CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.40 (4H, d, J = 7Hz, 4CH arom.), 8.05 (2H, s, 2CH arom.), 8.15 (1H, s, CH arom)].

The l-benzhydril-3-. { [3,5-bis (trifluoromethyl) phenyl (methylsul fonyl) methylene} azetidin-3-ol can be obtained as follows: operating according to the mode of operation of example 1 from 3.1 g of methyl [3,5-bis (trifluoromethyl) benzyl sulfone and 2.4 g of 1-benzhydril-3- ona, 2.8 g of 1-benzhydril-3- are obtained. { [3,5-bis (trifluoromethyl) phenyl] (methylsulfonyl) -methylene} azetidin-3-ol in the form of a white solid. The methyl [3,5-bis (trifluoromethyl) benzyl sulfone can be prepared in the following manner: by operating according to the mode of operation of Example 10 from 3 g of 3,5-bis (tri fluoromethyl) benzyl chloride and 2 g of sodium methansulfinate, 3.1 g of methyl [3,5-bis (tri fluoromethyl) benzyl sulfone are obtained in the form of a white solid which melts at 132 ° C.

Example 24 Operating according to the mode of operation of Example 4 starting from 10.7 g of l-benzhydryl-3- [(3,5-dibromo phenyl) (methylsulfonyl) ethyl- (RS)] azetidin-3-ol, of 2.2 ml of chloride of methanesulfonyl and 7 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 5.5 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 35 ml fractions. Fractions 40 to 58 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 50 ml of ethyl ether. 1.5 g of l-benzhydryl-3- [(3,5-dibromophenyl) (methylsulfonyl.) Methylenejazetidine is obtained which melts at 209 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz ): 3.00 (3H, s, SCH3), 3.88 (2H, s, NCH2), 4.22 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.22 (2H, t, J = 7 Hz, 2CH ring), 7.33 (4H, t, J = 7Hz, 4CH arom.), 7.48 (4H, d, J = 7Hz, 4CH arom.), 7.68 (2H, s, 2CH arom.), 7.95 (1H, s , CH arom.).] L-benzhydryl-3- [(3,5-dibromophenyl) (methylsul fonyl) ethyl- (RS)] azetidin-3-ol can be obtained as follows: operating according to the mode of operation of Example 1 from 6.2 g of (3,5-dibromobenzyl) methylsulfone and 4.5 g of l-benzhydrilazetidin-3-one, 10.7 g of 1-benzhydril-3- [(3,5-dibromo phenyl) are obtained. (methylsul fonyl) methyl- (RS) Jazetidin-3-ol in the form of a foam.

The (3, 5-dibromobenzyl) methylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 starting from 5.8 g of (3,5-dibromobenzyl) ethylsulfide and 13 g of oxone R, 6.2 g are obtained. of (3,5-dibromobenzyl) methylsulfone in the form of a white solid. The (3, 5-dibromobenzyl) methylsulfide can be prepared in the following manner: by operating according to the mode of operation of Example 2 starting from 6.6 g of 3,5-dibromobenzyl bromide and 1.5 g of sodium methylthiolate, 5.8 are obtained g of (3,5-dibromobenzyl) methylsulfide in the form of an oil.

Example 25 Operating according to the mode of operation of Example 4 from 4.2 g of l-benzhydryl-3 - [(methylsulfonyl) (3-nitro phenyl) ethyl- (RS) Jazetidin-3-ol, of 1.1 g of methanesulfonyl chloride and 2.5 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry at 0.04-0.06 mm, diameter 4 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) as eluents and collecting 400 ml fractions. Fractions 17 through 33 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from 15 ml of ethyl acetate. 0.6 g of 1-benzhydri l-3- [(methylsulfonyl) (3-nitrophenyl) methylenazetidine is obtained which melts at 184 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.00 (3H, s, SCH3), 3.85 (2H, s, NCH2), 4.25 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7. 45 (4H, d, J = 7Hz, 4CH arom.), 7.75 (1H, t, J = 7Hz, CH arom.), 7.85 (1H, d, J = 7Hz, CH arom), 8.25 (2H,, 2CH arom) .J. L-benzhydryl-3- [(methylsulfonyl) (3-nitrophenyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 from 3.9 g of methyl (3-nitrobenzyl) sulfone and 4.2 g of 1-benzhydrilazetidin-3-one, 4.2 g of 1-benzhydryl-3- [(methylsulfonyl) (3-nitrophenyl) methyl- (RS) Jazetidin-3-ol are obtained under the shape of a foam. The methyl (3-nitrobenzyl) sulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 starting from 18.1 g of methyl (3-nitrobenzyl) sulfide and 68 g of oxone ", 13.9 g of methyl (3-nitrobenzyl) sulfone in the form of a foam Methyl (3-nitrobenzyl) sulfide can be prepared as follows: operating according to the mode of operation of example 2 from 17.2 g of benzyl chloride and 7.7 g of sodium methylthiolate, 18.2 g of methyl (3-nitrobenzyl) sulfide are obtained in the form of an oil.

Example 26 A mixture of 0.34 g of l-benzhydryl-3- [(methylsulfonyl) (3-nitrophenyl) methylenejazetidine, 16 ml of 1 N hydrochloric acid in 8 ml of ethanol and 16 ml of tetrahydrofuran is heated to reflux. 0.17 g of powdered iron are added and the reflux is maintained for 3 hours. The mixture is then cooled to room temperature, and the insoluble material is filtered. The solution is taken up with 10 ml of 1 N sodium hydroxide and 50 ml of a saturated aqueous solution of sodium chloride. The aqueous phase is extracted with 3 40 ml portions of dichloromethane, the extracts are combined, dried over sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) as eluent and collecting fractions of 20 ml. Fractions 13 through 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 15 ml of ethyl ether. 0.17 g of 3 - [(3-aminophenyl) (methylsulfonyl) met ilenj-1-benzhydril-azetidine is obtained which melts at 197 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz) : 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 5.25 (2H, s, NH2), 6.55 (3H, , 3CH arom.), 7.05 (1H, t, J = 7Hz, CH arom.), 7.20 (2H, t, J = 7Hz, 2CH arom.), 7.30 (4H, t, J = 7Hz, 4CH, arom. ), 7.45 (4H, d, J = 7Hz, 4CH arom.)] Example 27 Operating according to the mode of operation of example 4 from 1.2 g of l-benzhydryl-3- [(3-methoxycarbonyl phenyl) (methylsul fonyl) methyl- (RS) Jazet idin-3-ol, of 0.3 ml of methanesulfonyl and 1.3 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane and then a mixture of dichloromethane and ethyl acetate (99.5 / 0.5 by volume) as eluents and collecting 100 ml fractions. Fraction 18 is concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is precipitated in 5 ml of ethyl ether. 0.13 g of l-benzhydryl-3- [(3-ethoxycarbonyl phenyl) (methylsulfonyl) ethylenaszetidine are obtained in the form of a foamy solid [NMR spectrum in DMS0-d6, T = 300K, d in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom. ), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.45 (4H, d, J = 7Hz, 4CH arom.), 7.60 (1H, t, J = 7Hz ', CH arom.), 7.70 ( 1H, d, J = 7Hz, CH arom), 8.00 (2H, m, 2CH arom.) J. L-benzhydryl-3- [(3-methoxycarbonyl phenyl) (methylsulfonyl) ethyl- (RS) J-azetidin-3-ol can be prepared in the following manner: by operating according to the mode of operation of example 1 from 3 g of (3-methoxycarbonylbenzyl) methylsulfone and 3.6 g of 1-benzhydrilazetidin-3-one, is obtained, after purification by chromatography on silica gel column (granulometry at 0.04-0.06 mm, diameter 3 cm, height 30 cm ) under a pressure of 0.5 bar of nitrogen with dichloromethane and then a mixture of dichloromethane and ethanol (99/1 by volume) as eluents, 1.2 g of l-benzhydryl-3- [(3-methoxycarbonyl) (methylsulfonyl) methyl - (RS)] -azetidin-3-ol in the form of a foam. The (3-methoxycarbonylbenzyl) methylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 starting from 4.3 g of (3-methoxycarbonylbenzyl) methylsulfide and 13.4 g of oxone ", 3.4 g of (3-methoxycarbonylbenzyl) sulfone in the form of a white solid The (3-methoxycarbonylbenzyl) methylsulfide can be prepared in the following manner: by operating according to the mode of operation of example 2 from 5 g of 3-methoxycarbonylbenzyl bromide and 1.7 g of sodium methylthiolate, 4.3 g of (3-methoxycarbonylbenzyl) methylsulfide are obtained in the form of an oil.

Example 28 Operating according to the mode of operation of example 4 from 6.2 g of l-benzhydryl-3- [(3-cyanophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol, of 1.6 ml of methanesulfonyl chloride and 6.8 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane and then with a mixture of dichloromethane and ethyl acetate (99.5 / 0.5 by volume) as eluents and collecting fractions of 250 ml. Fractions 10 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 5 ml of dichloromethane and 70 ml of ethyl ether. 2.9 g of l-benzhydryl-3- [(3-cyanophenyl) (methylsulfonyl) methylenazetidine is obtained which melts at 152 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.00 ( 3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.45 (4H, d, J = 7Hz, 4CH arom.), 7.65 (1H, t, J = 7Hz, CH arom.}., 7.75 (1H, d, J = 7Hz, CH arom. ), 7.90 (2H, m, 2CH arom.)]. El-benzhydryl-3- [(3-cyanophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol can be prepared as follows: according to the mode of operation of example 1 from 3.9 g of (3-cyanobenzyl) methylsulfone and 4.7 g of 1-benzhydrilazetidin-3-one, 6.2 g of 1-benzhydryl-3- [(3-cyanophenyl)) are obtained ( methylsulfonyl) methyl- (RS) Jazetidin-3-ol in the form of a white solid The (3-cyanobenzyl) ethylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 from 6.7 g of (3-cyanobenzyl) methylsulphide and 27.6 g of oxone ", 3.9 g of (3-cyanobenzyl) methylsulfone are obtained in the form of a white solid The (3-cyanobenzyl) methylsulfide can be prepared as follows: the operation mode of Example 2 from 8 g of 3-cyanobenzyl bromide and 3.1 g of sodium methylthiolate, 6.8 g of (3-cyanobenzyl) methylsulfide are obtained in the form of an oil.

Example 29 A mixture of 3 g of 1-benzhydryl-3- [(3-carboxyphenyl) (methylsulfonyl) -methylene-benzetidine hydrochloride, 1.3 g of pentafluorophenol, 1.4 g of 1- (3-dimethylaminopropyl) hydrochloride is stirred at room temperature for 15 hours. ) -3-ethylcarbodiimide in 30 ml of dimethylformamide. The mixture is taken up with 100 ml of water and 100 ml of a saturated aqueous solution of sodium chloride, and 50 ml of ethyl acetate. The organic phase is decanted, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane then a mixture of dichloromethane and ethanol (99.4 / 0.6 by volume). ) as eluents and collecting 100 ml fractions. Fractions 13 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 10 ml of ethyl ether. 0.6 g of l-benzhydryl-3- [(methylsulfonyl) (3-pentafluorophenoxycarbonyl phenyl) -methylene-benzetidine is obtained which melts at 182 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (400 MHz): 3.00 (3H, s, SCH3), 3.85 (2H, s, NCH2), 4.25 (2H, m, NCH2), 4.75 (1H, s, NCH), 7.20 (2H, t, J = 7 Hz, 2CH arom. ), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.45 (4H, d, J = 7Hz, 4CH arom.), 7.70 (1H, t, J = 7Hz, CH arom.), 8.20 (2H , m, 2CH arom.) J. The l-benzhydryl-3- [(3-carboxyphenyl) (methylsulfonyl) ethylenazetidine hydrochloride can be prepared as follows: a mixture of 10 g of 1-benzhydryl-3- [(at 10 ° C for 7 days is heated. 3-cyanophenyl) (methylsul-fonyl) methylene-benzetidine in 40 ml of acetic acid and 40 ml of concentrated hydrochloric acid (d = 1.18). The reaction mixture it is cooled in a water bath with ice and the precipitate formed is filtered on sintered ice. The solid is washed with 20 ml of a mixture of acetic acid and concentrated hydrochloric acid (50-50 by volume) and then with 3 portions of 20 ml of water and finally with 20 ml of ethanol. The white solid obtained is reduced under pressure (2.7 kPa) at 45 ° C and 2.5 g of l-benzhydryl-3- [(3-carboxyphenyl) (methylsulfonyl) methylenazetidine hydrochloride in the form of a white solid are obtained.

Example 30 A solution of 0.65 g of l-benzhydryl-3- [(methylsulfonyl) (3-pentafluorophenoxycarbonylphenyl) -methylenebenzetidine in 25 ml of 6.2 N ammoniacal ethanol is stirred at room temperature. The mixture is concentrated to dryness under reduced pressure ( 2.7 kPa) and then the residue is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (99/1 in volume) then with a mixture of dichloromethane and ethanol (98/2 by volume) as eluents and collecting 60 ml fractions. Fractions 18 through 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.2 g of l-benzhydryl-3- [(3-carbamoylphenyl) (methylsulfonyl) methylenazetidine is obtained which melts at 140 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.00 ( 3H, s, SCH3), 3.80 (2H, s, NCH2), 4.25 (2H, m, NCH2), 4.75 (1H, s, NCH), 7.25 (2H, t, J = 7 Hz, 2CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), Between 7.45 and 7.65 (7H, 6CH arom and CONH2), 7.95 (2H,, 2CH arom.), 8.10 (1H, s, CONH2).

Example 31 Operating according to the mode of operation of example 4 from 4.6 g of l-benzhydryl-3- [(3-methoxyphenyl) (methylsul fonyl) met il- (RS)] azetidin-3-ol, of 1.2 ml of chloride of methanesulfonyl and 3.8 g of 4-dimethylaminopyridine are obtained after recrystallization from 150 ml of acetonitrile 2.6 g of l-benzhydryl-3- [(3-methoxy phenyl) (methylsulfonyl) -methylene-benzetidine which melts at 179 ° C. NMR in DMSO-d6, T = 300K, d in ppm (250 MHz): 2.95 (3H, s, SCH3), 3.75 (2H, s, OCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.00 (3H, m, 3 CH arom.), between 7.20 and 7.12 (11H,, 10H phenyls and 1 CH arom.) J. The l-benzhydril-3 - [(3-methoxyphenyl) (methylsulfonyl) methyl- (RS) Jazet idin-3-ol can be obtained in the following manner: by operating according to the mode of operation of example 1 from 3.4 g of (3-methoxybenzyl} methylsulfone and 4 g of 1-benzhydrilazetidin-3-one, 4.6 g of 1-benzhydryl-3- [(3-methoxy phenyl) (methylsulfonyl) methyl- (RS) are obtained. Jazetidin-3-ol in the form of a white solid. The (3-methoxybenzyl) methylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 starting from 3.4 g of (3-methoxybenzyl) methylsulfide and 13 g of oxone ", 4 g of (3-methoxybenzyl) methylsulfone are obtained in the form of a white solid which melts at 71 ° C. The (3-methoxybenzyl) methylsulfide can be prepared from the following manner: by operating according to the mode of operation of Example 2 from 3.1 g of 3-methoxybenzyl bromide and 1.5 g of sodium methylthiolate, 3.4 g of (3-methoxybenzyl) ethyl sulfur are obtained in the form of an oil.

Example 32 ml of a 1 M solution of boron tribromide in dichloromethane are added with stirring to a solution of 1.3 g of l-benzhydryl-3- [3-methoxyphenyl) (methylsulfonyl) methylene-benzetidine in 100 ml of dichloromethane. Stirring is maintained 16 hours at room temperature. The reaction medium is taken up in 100 ml of ice water. The organic phase is washed with 3 portions of 50 ml water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is precipitated in 150 ml of isopropyl ether and then dissolved in 50 ml of dichloromethane. The organic phase is washed with 3 portions of 30 ml of a saturated aqueous solution of sodium bicarbonate, decanted, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is precipitated in 80 ml of ethyl ether. 0.36 g of l-benzhydryl-3- [(3-hydroxyphenyl) (methylsul fonyl) ethylenjazetidine are obtained from a solid that melts at 248 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 6.85 (3H, m, 3CH arom.), 7.25 (3H,, 3CH arom), 7.35 (4H, t, J = 7Hz, 4CH arom.), 7.50 (4H, d, J = 7Hz, 4CH arom.}., 9.50 (1H, s, OH)] .

Example 33 Operating according to the mode of operation of example 32 from 1.4 g of l-benzhydryl-3- [(4-methoxyphenyl) (methylsul fonyl) met ilenjazetidine, 10 ml of a 1 M solution of boron tribromide and 100 ml of dichloromethane, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3.5 cm, height 24 cm) under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50 / 50 in volume) as eluents and collecting fractions of 25 ml. Fractions 21 through 37 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 30 ml of ethyl ether. 0.6 g of l-benzhydryl-3- [(4-hydroxyphenyl) (methylsulfonyl) ethylenjazetidine is obtained which melts at 211 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.90 ( 3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 6.80 (2H, d, J = 7 Hz, 2CH arom.), between 7.10 and 7.35 (8H, 8CH arom), 7.48 (4H, d, J = 7Hz, 4CH arom.), 9.80 (1H, s, OH arom.) J. L-benzhydryl-3- [(4-methoxyphenyl) (methylsul fonyl) met ilenjazetidine can be obtained in the following manner: by operating according to the mode of operation of example 4 from 3.5 g of l-benzhydril-3- [ (4-methoxy phenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol, 0.9 ml of methanesulfonyl chloride and 2.9 g of 4-dimethylaminopyridine, the residue obtained is purified by recrystallization from 100 ml of acetonitrile. 1 g of l-benzhydryl-3- [(4-methoxyphenyl) (methylsulfonyl) methylenazetidine is obtained which melts at 181 ° C. L-benzhydryl-3 - [(4-methoxy phenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of example 1 from 3.5 g of (4-methoxybenzyl) methylsulfone and 4 g of 1-benzhydrilazetidin-3-one, 3.6 g of 1-benzhydryl-3- [(4-methoxy phenyl). (Methylsulfonyl) methyl-) RS are obtained. Jazet idin-3- ol in the form of a white solid. The (4-methoxybenzyl) methylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 starting from 3.4 g of (4-methoxybenzyl) methylsulfide and 13 g of oxone ", 3.5 g of (3-methoxybenzyl) methylsulfone are obtained in the form of a white solid which melts at 113 ° C. The (4-methoxybenzyl) methylsulfide can be prepared from as follows: operating according to the mode of operation of Example 2 from 3.1 g of 4-methoxybenzyl chloride and 1.5 g of sodium methylthiolate, 3.4 g of (4-methoxybenzyl) ethylsulfide are obtained in the form of an oil.

Example 34 Operating according to the mode of operation of example 32 from 1.4 g of l-benzhydryl-3- [(2-methoxyphenyl) (methylsulfonyl) methylene-benzetidine, 10 ml of a 1 M solution of boron tribromide and 100 ml of dichloromethane, the residue obtained is purified by chromatography on a silica gel column (granulometry 0.04-0.06 mm, diameter 4 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 40 ml fractions. Fractions 15 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 40 ml of ethyl ether. 0.7 g of l-benzhydryl-3- [(2-hydroxyphenyl) (methylsulfonyl) methylenazetidine is obtained which melts at 196 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.00 ( 3H, s, SCH3), 3.60 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 6.85 (1H, t, J = 7Hz, CH arom.), 6.90 (1H, d, J = 7Hz, CH arom.), 7.20 (4H, m, 4CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.48 (4H, d, J = 7Hz, 4CH arom.), 9.90 (1H, s, OH)]. L-benzhydryl-3- [(2-methoxyphenyl) (methylsulfonyl) methylenejazetidine can be obtained in the following manner: by operating according to the mode of operation of Example 4 from 4.2 g of l-benzhydryl-3- [(2- methoxy phenyl] - (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 1.1 ml of methanesulfonyl chloride and 3.5 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (granule etria 0.04-0.06 mm, diameter 4 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane and ethyl acetate (50/50 by volume ) as eluents and collecting 40 ml fractions. The fractions 23 to 54 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 40 ml of ethyl ether. 1.9 g of l-benzhydryl-3- [(2-methoxyphenyl) (methylsul fonyl) methylene] azetidine are obtained which melts at 204 ° C. L-Benzhydryl-3 - [(2-methoxy phenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 from 4 g of (2-methoxybenzyl) ethylsulfone and 4.5 g of 1-benzhydrylazetidin-3-one, 4.3 g of 1-benzhydryl-3- [(2-methoxyphenyl) (methylsulfonyl) ethyl- (RS) Jazetidin-3-ol are obtained shape of a brown foam. The (2-methoxybenzyl) ethylsulfone can be prepared in the following manner: by operating according to the mode of operation of example 10 from 3.1 g of 2-methoxybenzyl chloride and 4.1 g of sodium methylsulfinate, 4 g of (2-ethoxybenzyl) methylsulfone in the form of a white solid.

Example 35 Operating according to the mode of operation of example 4 from 2.1 g of l-benzhydryl-3- [(methylsulfonyl). (Naphth-2-yl) methyl- (RS) Jazetidin-3-ol, 0.5 ml of chloride of methanesulfonyl and 2.2 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granule etria 0.04-0.06 mm, diameter 4 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 100 ml fractions Fractions 6 through 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa) The solid obtained is crystallized from 20 ml of ethyl ether to obtain 0.6 g of 1-benzhydryl. 3- [(methylsulfonyl) (naphth-2-yl) methylene] azetidine which melts at 178 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.00 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.20 (4H, m, 4CH arom.), 7.30 (4H, t, J = 7 Hz 4CH aro .}., 7.45 (4H, d, J = 7Hz, 4CH arom.), 7.52 (3H, m, 3CH arom.), 7.90 (4H, m, 4CH arom. ) J. L-benzhydryl-3- [(methylsulfonyl) (naph-2-yl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 starting from 3.5 g of methyl (naphth-2-ylmethyl) sulfone and 3.8 g of 1-benzhydrilazetidin-3-one give 2.2 g of 1-benzhydryl-3- [(methylsul-fonyl) (naphth-2-yl) methyl- (RS) J-azetidin-3-ol in the form of a white solid that melts at 196 ° C. Methyl (naphth-2-ylmethyl) sulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 from 4.2 g of methyl (naphth-2-ylmethyl) sulfide and 13.7 g of oxone ", obtain 3.6 g of methyl (naphth-2-ylmethyl) sulfone in the form of a cream-colored solid.

The methyl (naphth-2-ylmethyl) sulfide can be prepared in the following manner: by operating according to the mode of operation of example 2 from 5 g of 2-bromomethylnaphthalene and 1.8 g of sodium methylthiolate, 4.2 g of methyl are obtained (naphth-2-ylmethyl) sulfide in the form of an oil.

Example 36 Operating according to the mode of operation of Example 4 from 4.3 g of l-benzhydryl-3 - [(methylsulfonyl) (naphth-1-yl) methyl- (RS) Jazetidin-3-ol, of 1.1 ml of methanesulfonyl chloride 4.6 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 4 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting fractions of 100 ml. Fractions 6 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 30 ml of ethyl ether. 2.5 g of l-benzhydryl-3- [(methylsul onyl) (naphth-1-yl) methylenejazetidine is obtained which melts at 196 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz) : 3.00 (3H, s, SCH3), 3.35 and 3.50 (1H, each, dd, J = 16 and 3Hz, NCH2), 4.35 (2H, m, NCH2), 4.75 (1H, s, NCH), between 7.10 and 7.70 (14H, m, 14CH arom.), 8.00 (3H, m, 3CH arom.)] _. L-benzhydryl-3- [(methylsulfonyl) (naphth-1-yl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 from 4.1 g of methyl (naphth-1-ylmethyl) sulfone and 4.4 g of 1-benzhydrilazetidin-3-one 4.3 g of 1-benzhydryl-3- [(methylsulfonyl) (1-naphthyl) ethyl- (RS) J- are obtained. azetidin-3-ol in the form of a solid Methyl (naphth-1-ylmethyl) sulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 from 4.3 g of methyl (naphth-1) -ylmethyl) sulfide and 13.9 g of oxone ", 4.1 g of methyl (naphth-1-ylmethyl) sulfone are obtained in the form of a white solid.Methyl (naphth-1-ylmethyl) sulfide can be prepared as follows : operating according to the mode of operation of example 2 from 4 g of 1-chloromethylnaphthalene chloride and 1.8 g of sodium methylthiolate, 4.5 g of methyl (naphth-1-ylmethyl) sulfide are obtained in the form of an oil.

Example 37 Operating according to the mode of operation of example 4 from 0.6 g of l-benzhydryl-3- [(methylsulfonyl) (3-pyrrolidinophenyl) methyl- (RS) J-azetidin-3-ol, of 0.15 ml of methanesulfonyl chloride and 0.6 g of 4-dimethylaminopyridine, the residue obtained is purified by column chromatography on silica gel (granulometry 0.04-0.06 mm, diameter 2 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and methanol (98/2 by volume) as eluents and collecting fractions of 20 ml. Fractions 8 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 8 ml of ethyl ether. 0.36 g of l-benzhydryl-3- [(methylsulfonyl) (3-pyrrolidinophenyl) ethylenejazetidine is obtained which melts at 153 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz): 1.95 ( 4H, m, SCH3), 2.95 (3H, s, NCH2), 3.20 (4H, m, 2 NCH2), 3.80 (2H, s, NCH), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 6.60 (3H, m, 3CH arom.), 7.20 (3H, m, 3CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.48 (4H, d, J = 7Hz, 4CH CH arom.)].

L-benzhydryl-3- [(methylsulfonyl) (3-pyrrolidinophenyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 from 0.77 g of 3 -pyrrolidinobenzylmethylsulfone and 0.76 g of 1-benzhydrilazetidin-3-one, 0.6 g of 1-benzhydryl-3- [(3-methylsulfonyl) (3-pyrrolidinophenyl) - (ethyl) - (RS) Jazetidin-3-ol are obtained under the shape of a solid. The methyl (3-pyrrolidinobenzyl) sulfone can be prepared in the following manner: by operating according to the mode of operation of example 2 from 1 g of methyl (3-pyrrolidinobenzyl) sulfide and 3.3 g of oxone ", 0.8 g of Methyl (3-pyrrolidinobenzyl) sulfone in the form of a solid Methyl (3-pyrrolidinobenzyl) sulfide can be prepared in the following manner: a mixture of 2 g of water is heated at reflux under a stream of nitrogen for 3 hours. (3-iodobenzyl) methylsulfide, 1.3 ml of pyrrolidine, 1.1 g of sodium terbutylate, 0.28 g of 1,1-bis (diphenylphosphino) ferrocenylpalladium chloride, 0.63 g of 1,1-bis (diphenylphosphino) ferrocene and 60 ml The reaction medium is cooled to room temperature and filtered on sintered glass, the precipitate is washed with 20 ml of tetrahydrofuran and 10 ml of dichloromethane, and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is collected with 30 ml of ac ethyl acetate and 30 ml of hydrochloric acid. 3 N The aqueous phase is decanted, neutralized (pH = 7.8) with 35 ml of 3 N sodium oxide and taken up in 50 ml of ethyl acetate. The organic phase is extracted; 4 g of silica are added and then the mixture is concentrated to dryness under reduced pressure (2.7 kPa). The powder obtained is eluted on sintered glass containing 20 g of silica, with a mixture of cyclohexane and ethyl acetate (90/90 by volume). The filtrate is concentrated to dryness under reduced pressure (2.7 kPa). 1.2 g of methyl (3-pyrrolidinobenzyl) sulfide are obtained in the form of an oil. The 1,1-bis (diphenylphosphino) ferrocenyl palladium chloride can be prepared according to Hayashi T. et al., J. Am. Chem. Soc., 106, 158 (1984). Example 38 Method 1 To a solution of 2.94 g of l- [bis (4-chlorophenyl) methylJ-3- [(3,5-difluorophenyl) (methylsul fonyl) methyl- (RS) azetidin-3-ol in 250 ml of dichloromethane at 22 ° C, 0.65 ml of methanesulfonyl chloride is added and then, in small portions in 15 minutes, 2.42 g of 4-dimethylaminopyridine; The orange solution is stirred 2 hours at room temperature. The reaction mixture is washed 3 times with 150 ml of distilled water and once with 150 ml of a saturated solution of sodium chloride, then dried with magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). ). The residue obtained is subjected to chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 5.5 cm, height 15 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (1/9 in volume) as eluents and collecting 70 ml fractions. Fractions 15 to 36 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.86 g of a white foam is obtained which is crystallized from isopropyl ether to obtain a solid that melts at 190 ° C. Recrystallization from 145 ml of ethanol leads to 1.08 g of l- [bis (4-chlorophenyl) methylJ-3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine which melts at 206 ° C [NMR spectrum in DMS0- d6, T = 300K, d in ppm (300 MHz): 3.00 (3HA s, SCH), 3.87 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.15 (2H, d, J = 8Hz, 2CH arom.), 7.30 (5H,, SCH arom.), 7.45 (4H, d, J = 7Hz, 4CH arom.) J.

Method 2 To a solution of 2.2 g of 3-acetoxy-l- [bis (4-chlorophenyl) methylJ-3 - [(3,5-difluorophenyl) - (methylsulfonyl) methyl- (RS) Jazetidine in 25 ml of dioxane at room temperature , 0.80 g of crushed soda are added. After 16 hours at room temperature, 50 ml of water and 100 ml of ethyl acetate are added. The mixture is decantedThe organic phase is taken up in 100 ml of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). A white foam is obtained which crystallizes from isopropyl ether to obtain 0.85 g of a solid that melts at 190 ° C. Recrystallization from 20 ml of ethanol leads to 0.70 g of l- [bis (4-chlorophenyl) methylJ-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine which melts at 205 ° C.

Example 39 To a solution of 6.8 g of bis (4-chlorophenyl) bromomethane in 300 ml of acetonitrile, 6.75 g of 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3 hydrochloride are added. Then 2.97 g of potassium carbonate. The reaction mixture is heated at reflux for 1 hour, cooled to room temperature, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is subjected to chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 8.5 cm, height 22 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 in volume) as eluents and collecting fractions of 250 ml. Fractions 11 to 48 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 5.3 g of l- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methyl-sulfonyl) methyl- (RS)] azetidin-3-ol [1H-NMR spectrum (300 MHz), (CD3) 2SO dβ, d in ppm): 2.00 (s: 3H); 2.94 (s: 3H); 3.25 (mt: 2H); 3.48 (d, J = 9 Hz: 1H); 3.80 (d, J = 9 Hz: 1H); 4.54 (s: 1H9 5.34 (s: 1H), 7.15 (d, J = 8.5 Hz: 2H), 7.20 to 7.40 (mt: 8H), 7.50 (broad t, J = 9Hz: 1H) J. 4-chlorophenyl) romomethane can be prepared according to the mode of operation described by BACHMANN WE, J. Am. Chem. Soc, 2135 (1933). - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl hydrochloride] (RS) Jazetidin-3-ol can be obtained as follows: to a solution of 37 g of 3 - [(3,5-di fluorophenyl) (methylsulfonyl) methyl- (RS) Jl- (vinyloxycarbonyl) azetidin -3-ol in 160 ml of dioxane is added 160 ml of a 6.2 N solution of hydrochloric acid in dioxane.After 16 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 320 ml of ethanol, heated at reflux for 1 hour and cooled in an ice water bath The solid that appears is filtered, washed with ethyl ether and dried at 40 ° C under reduced pressure (2.7 g. kPa), 29.85 g of crystal are obtained s whites whose melting temperature is higher than 260 ° C. 3 - [(3,5-difluoro phenyl) (methylsulfonyl) ethyl- (RS) Jl- (vinyloxycarbonyl) azetidin-3-ol can be obtained in the following manner: to a solution of 60.18 g of l-benzhydril-3 - [(3,5-difluorophenyl) (methylsulfonyl) -methyl- (RS) Jazetidin-3-ol in 1000 ml of dichloromethane is added at 5 ° C a solution of 14.0 ml of vinyl chloroformate in 35 ml of dichloromethane. After 20 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is subjected to chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 11 cm, height 32 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (3/7 in volume) as eluents and collecting fractions of 1000 ml. Fractions 8 through 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 37 g of 3 - [(3,5-difluorophenyl) (methylsul fonyl) methyl- (RS)] - 1- (vinyloxycarbonyl) azetidin-3-ol are obtained in the form of white crystals melting at 195 ° C.

Example 40 To a solution of A. 11 g of (3,5-difluorobenzyl) ethylsulfone in 70 ml of tetrahydrofuran under an argon atmosphere are added at -70 ° C, 14 ml of a 1.6 N solution of n-butyllithium in hexane. After 1 hour at -70 ° C, a solution of 6.8 g of l- [bis (4-chlorophenyl) methylJazetidin-3-one in 30 ml of tetrahydrofuran is added and then, after 1 hour, a solution of 2 ^. 3 m_ of acetyl chloride in 20 ml of tetrahydrofuran and the temperature of the reaction mixture is brought to 20 ° C for 1 hour. 50 ml of water and 200 ml of ethyl acetate are added. The mixture is decanted, the organic phase is washed with 100 ml of water, 100 ml of a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 14.4 g of 3-acetoxy-l- [bis- (4-chlorophenyl) methylJ-3 - [(3,5-difluorophenyl) (methylsul fonyl) methyl) methylsul fonylmethyl- (RS) Jazetidine are obtained in the form of a yellow oil [NMR spectrum aH (400 MHz, CDC13 d in ppm) 2.79 (s: 3H); 3.04 (AB, J = 9 Hz: 2H), 3.27 (d, J = 9Hz: ÍH); 3.45 (s: 1H); 3.81 (d, J-9 Hz: 1H); 4. 32 (s, 1H); 4.49 (s: 1H) 6.88 (tt, J = 9 and 2.5 Hz: 1H); from 7.20 to 7.35 (mt: 10H) J. The l- [bis (4-chlorophenyl) methylazetidin-3-one can be prepared according to the following procedure: to a solution of 5.0 ml of oxalyl chloride in 73 ml of dichloromethane cooled to -78 ° C, it is added a solution of 8.1 ml of dimethyl sulfoxide in 17.6 ml of dichloromethane. After 0.5 hours at -78 ° C, a solution of 16.0 g of l- [bis (4-chlorophenyl) methylazetidin-3-ol dissolved in 50 ml of dichloromethane is poured. After 5 hours at -78 ° C, 26.6 ml of triethylamine are added dropwise, and the reaction mixture is allowed to reach room temperature. After 16 hours, the reaction mixture is washed with 4 portions of 200 ml of water and then with 200 ml of a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. (2.7 kPa). The residue obtained is subjected to chromatography on a silica column (granulometry 0.04-0.06 mm, diameter 9.2 cm, height 21 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (40/60 cm). volume) as eluents and collecting 200 ml fractions. Fractions 15 to 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 8.9 g of l- [bis (4-chlorophenyl) methyljazetidin-3-one are obtained in the form of pale yellow crystals that melt at 111 ° C. The l- [bis (4-chlorophenyl) met ilJazetidin-3-ol can be prepared according to the mode of operation described by KATRITZKY A. R. et al., J. Heterocycl. Chem., (1994), 271 starting from 35.5 g of [bis (4-chlorophenyl) methyljamine hydrochloride and 11 ml of epichlorohydrin. 9 g of l- [bis (4-chlorophenyl) ethylJazetidin-3-ol are isolated. The [bis (4-chlorophenyl) methyl amine hydrochloride can be prepared according to the method described by GRISAR M. et al., J. Med. Chem. 885 (1973).

Example 41 Operating according to the mode of operation of example 38 (method 1), starting from 0.72 g of 1- [bis (4-methoxy phenyl) methylJ-3- [(3, 5-difluorophenyl) - (methylsulfonyl) ethyl- (RS) Jazetidin-3-ol and after chromatography on a silica gel column (granulometry 0.04-0.06 mm, diameter 4.0 cm, height 16.5 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 40 ml fractions, 0.10 g of a white foam is obtained. After crystallization from a mixture of ethyl acetate and cyclohexane, 60 mg of l- [bis (4-methoxy-phenyl) -methyl-3- [(3,5-difluorophenyl) - (methylsulfonyl) methylenazetidine in the form of a solid that melts at 180 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz): 3.00 (3H, s, SCH3), 3.70 (6H, s, OCH3), 3.80 (2H, s, NCH2), 4.15 (2H, s, NCH2), 4.58 (1H, s, NCH), 6.85 (4H, d, J = 7Hz, 4CH arom.), 7.15 (2H, d, J = 8Hz, 2CH arom. .), 7.30 (5H, m, 5CH arom.). The l- [bis (4-methoxyphenyl) methylJ-3- [(3,5-difluorophenyl) (methylsul fonyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: operating according to the mode of Example 39 operation from 1.2 g of bis (4-methoxyphenyl) bromomethane and 1.2 g of 3 - [(3,5-difluorophenyl) (methylsul fonyl) methyl- (RS)] azetidin-3-ol hydrochloride and after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height 18 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 by volume) as eluent and collecting 50 ml fractions, fractions 9 through 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) 0.55 g of l- [bis (4-methoxyphenyl) methyl J-3 are obtained. [(3, 5-difluorophenyl) - (ethylsulfonyl) methyl- (RS) Jazetidin-3-ol The bis (4-methoxyphenyl) bromomethane can be prepared according to the mode of operation described by BACHMANN, EJ Am. Chem. Soc, 213 5 (1933).

Example 42 Operating according to example 38 (method 1), from 0.47 g of l- [bis (4-methyl phenyl) methylJ-3- [(3,5-difluorophenyl) (methylsul fonyl) methyl- (RS) J-azetidin-3-ol and after chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 3.2 cm, height 18.5 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (1/9 by volume) as eluents and collecting fractions of 35 ml, 0.30 g of a white solid are obtained. After crystallisation from diisopropyl oxide, 0.20 g of l- [bis (4-methylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine in the form of white needles which melt at 200 ° are obtained. C. L- [bis (4-methyl-1-phenyl) -methyl] -3- [(3,5-difluorophenyl) - (methylsulfonyl) methyl- (RS) Jazetidin-3-ol can be obtained in the following manner: by operating as example 39 from 0.7 g of bis (4-methylphenyl) bromomethane and 0.8 g of 3 - [(3,5-difluorophenyl) methylsulfonyl) methyl- (RS)] -azetidin-3-ol hydrochloride and after chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 4 cm, height 19 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 40 ml fractions, fractions 35 to 40 are combined and concentrated to dryness under reduced pressure (2.7 kPa.) 0.47 g of l- [bis (4-methylphenyl) methyl] -3- [( 3, 5-difluorophenyl) - (methylsulfonyl.) Methyl- (RS) Jazetidin-3-ol The bis (4-methylphenyl) bromomethane can be prepared according to the mode of operation described by BACHMANN .EJ Am. Chem. Soc, 2135 (1933).

Example 43 Operating according to example 38 (method 1), from 1.42 g of 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] - 1 - [(4-methoxyphenyl) (phenyl) ethyl- ( RS)] azetidin-3-ol, mixture of two diastereoisomers, and after chromatography on a silica gel column (granulometry 0.04-0.06 mm, diameter 4 cm, height 21 cm) under a pressure of 0.5 bar of argon with a Mixing ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 40 ml fractions, give 0.10 g of a white solid. After crystallisation from diisopropyl oxide, 50 mg of (RS) -3 - [(3,5-difluorophenyl) (methylsul foni 1) methylene] -1- (4-methoxyphenyl) (phenyl) methyljazetidine are obtained in the form of a white solid [NMR spectrum in DMSO-d6, 'T = 300K, d in ppm (300 MHz): 2.23 (6H, s, 2 PhCH3), 3.00 (3H, s, NCH3), 3.80 (2H, s, NCH2 ), 4.12 (2H, s, NCH2), 4.58 (1H, S, NCH), 7.08 (4H, t, J = 7Hz, 4CH arom.), 7.15 (2H, d, J = 8Hz, 2CH arom.), 7.25 (5H, m, 5CH arom.)]. The mixture of diastereomers 3 - [(3,5-difluorophenyl) (methylsul fonyl) methyl- (RS) J- [(4-methoxyphenyl). { phenyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to example 39 from 2.52 g of (RS) -bromo (4-methoxyphenyl) (phenyl) methane and 2.85 g of 3- [(3, 5-difluorophenyl). (methylsulfonyl) methyl- (RS) J-azetidin-3-ol hydrochloride and after chromatography on a silica gel column (granulometry 0.04-0.06 mm, diameter 5.6 cm , height 19 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 by volume) as eluent and collecting fractions of 100 ml, fractions 11 to 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) 1.16 g of the diastereomer mixture 3 - [(3,5-difluorophenyl) (methylsul fonyl) methyl- (RS)] - 1 - [(4-methoxy phenyl) ( Phenyl) methyl- (RS)] azetidin-3-ol The (RS) -bromo (4-methoxyphenyl) (phenyl) methane can be prepared according to the mode of operation described by BACHMANN WE, J. Am. Chem. Soc. , 2135 (1933).

Example 44 Operating as in example 38 (method 1), starting from 0.47 g of l- [bis (4-trifluoromethoxy-phenyl) -methylJ-3 - [(3,5-difluorophenyl) - (methylsulfonyl) methyl- (RS) Jazetidin -3-ol and after chromatography on silica gel column (granulometry 0.04-0.06 mm, diameter 4.2 cm, height 14 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting fractions of 25 ml, 0.28 g of l- [bis (4-trifluoromethoxyphenyl) are obtained. methylJ-3- [(3, 5-difluorophenyl) - (methylsulfonyl) methylene-benzetidine in the form of a solid [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.05 (3H, s, SCH3), 3.95 (2H, s, NCH2), 4.25 (2H, s, NCH2), 4.90 (1H, s, NCH), 7.20 (2H, t, J = 8Hz, 2CH arom.), 7.32 (5H, m, 5CH arom.), 7.60 (4H, d, J = 7Hz, 4CH arom.) J. The l- [bis (4-trifluoromethoxyphenyl) methylJ-3- [(3,5-di fluorophenyl) (methylsulfonyl) methyl- (RS)] -azetidin-3-ol can be obtained in the following manner: by operating as in example 39 from 1.59 g of bis (4-trifluoromethoxyphenyl) bromomethane and 1.2 g of 3 - [(3,5-di fluorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol hydrochloride and after chromatography on a column of silica gel (granularity 0.04-0.06 mm, diameter 4.8 cm, height 17 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 by volume) as eluent and collecting fractions of 50 ml, fractions 15 to 23 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.49 g of l- [bis (4-trifluoromethoxyphenyl) methylJ-3- [(3,5-difluorophenyl) (methylsulfonyl.) Methyl- (RS) Jazetidin-3-ol is obtained. Bis (4-trifluoromethoxyphenyl) ) Bromomethane can be prepared according to the mode of operation described by BACHMANN, E., J. Am. Chem. Soc, 2135 (1933), starting from 1.39 g of bis (4-trifluoramethoxyphenyl) methane, 3 ml of hydrobromic acid at 33 ° C. % in acetic acid and 0.6 ml of acetyl bromide 1.59 g of bis (4-trifluoromethoxyphenyl) bromomethane is obtained in the form of a brown oil, Bis (4-trifluoromethoxyphenyl) methanol is prepared according to PAVÍA MR et al. J. Med. Chem. 4238 (1992).

Example 45 Operating as in example 38 (method 1), from 0.25 g of l- [bis (4-trifluoromethylphenyl) methylJ-3- [(3, 5-difluorophenyl) - (methylsulfonyl) methyl- (RS)] azetidin- 3-ol and after chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 2.4 cm, height 14 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (2/8 in volume) as an eluent and collecting fractions of 20 ml, 0.12 g of l- [bis (4-trifluoromethylphenyl) methylJ-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine in the form of a white solid are obtained [ NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.05 (3H, s, SCH3), 3.95 (2H, s, NCH2), 4.25 (2H, s, NCH2), 4.90 (1H , s, NCH), 7.20 (2H, t, J = 8Hz, 2CH arom.), 7.32 (5H, m, 5CH arom.), 7.6Q (4H, d, J = 7Hz, 4CH arom.) J. L- [bis (4-trifluoromethylphenyl) methyl] -3 - [(3,5-difluoro-phenyl) (methylsulfonyl) methyl- (RS) J-azetidin-3-ol can be obtained in the following manner: by operating as in Example 39 from 1.46 g of bis (4-tri fluoromethylphenyl) bromomethane and 1.2 g of 3 - [(3,5-di fluorophenyl) methylsulfonyl) methyl- (RS)] azetidin-3-ol hydrochloride and after chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 4.8 cm, height 17 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (30/70 by volume) as eluent and collecting 50 ml fractions, fractions 9 through 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.25 g of l- [bis (4-trifluoromethylphenyl) ethylJ-3- [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol are obtained. The bis (4-trifluoromethylphenyl) bromomethane can be prepared according to the mode of operation described by BACHMANN W.E. J. Am. Chem. Soc., 2135 (1993), starting with 2.5 g of bis (4-trifluoromethylphenyl) ethanol, 6 ml of 33% hydrobromic acid in acetic acid and 1.2 ml of acetyl bromide. 2.9 g of bis (4-trifluoromethylphenyl) bromomethane are obtained in the form of a brown oil. The bis (4-trifluoromethylphenyl) methanol is prepared according to PAVÍA M.R. and collaborators J. Med. Chem. 4238 (1992).

Example 46 Operating according to example 38 (method 2), starting from 3.16 g of 3-acetoxy-l- [bis (4-chlorophenyl) methyl 1-3-. { [3,5-bis (trifluoromethyl) phenyl] - (methylsulfonyl) methyl- (RS)} azetidine and 0.96 g of ground soda, after 16 hours at room temperature, a yellow foam is obtained which is subjected to chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 4.8 cm, height 14 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting 40 ml fractions. 1.49 g of l- [bis (4-chlorophenyl) methylJ-3- are thus obtained. { [3,5-bis (trifluoromethyl) phenyl] (methylsulfonyl) methylene} -azetidine in the form of a white foam [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.05 (3H, s, SCH3), 3.90 (2H, s, NCH2), 4.30 ( 2H, s, NCH2), 4.80 (1H, s, NCH), 7.40 (2H, t, J = 7Hz, 2CH arom.), 7.50 (2H, d, J = 7Hz, 2CH arom.), 8.10 (2H, s, 6CH arom.), 8.20 (1H, s, CH arom.)]. 3-Acetoxy-l- [bis (4-chlorophenyl) methylJ-3-. { [3,5-bis (trifluoromethyl) phenyl] - (methylsulfonyl) methyl- (RS)} azetidine can be obtained as follows: operating as in example 40 from 2. 0 g of [3,5-bis (trifluoromethyl) benzylmethyl sulfone, 4. 1 ml of a 1.6 N solution of n-butyllithium in hexane, 2.0 g of l- [bis (4-chlorophenyl) methyljazetidin-3-one and 0.77 ml of acetyl chloride in 20 ml of anhydrous diisopropyl oxide, they are obtained, after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 5.6 cm, height 16 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (1/9 in volume) as eluent and collecting 100 ml fractions, 3.56 g of 3-acetoxy-l- [bis (4-chlorophenyl) methylJ-3- [[3,5-bis (trifluoromethyl) phenylj-? methylsulfonyl) methyl- (RS )} azetidine in the form of a white foam. [3,5-Bis (trifluoromethyl) benzyl methylsulfone is prepared in the following manner: by operating according to Example 10 from 1.8 g of 3,5-bis (trifluoromethyl) benzyl chloride and 1.22 g of sodium methansulfinate, they obtain 1.86 g of [3,5-bis (trifluoromethyl) benzylmethyl sulfone in the form of a white solid.

Example 47 Operating as in example 38 (method 1) from 0.27 g of a mixture of the two diastereoisomers l- [(4-chlorophenyl) (2,4-dichlorophenyl) methyl- (RS)] - 3 - [(3, 5-difluorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol and after chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 2.4 cm, height 7.5 cm) under a pressure of 0.5 bar Argon with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting fractions of 20 ml give 0.10 g of (RS) -l- [(4-chlorophenyl) (2,4-dichlorophenyl)) methyl] -3- [(3,5-difluorophenyl). (methylsul fonyl) methylene-benzetidine in the form of a white solid [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz): 3.02 ( 3H, s, SCH3), 3.82 (1H, dd, J = 3 and 16Hz, NCH), 4.04 (1H, dd, J = 3 and 16Hz, NCHH), 4.10 (1H, dd, J = 3 and 16Hz, NCHH ), 4.35 (1H, dd, J = 3 and 16Hz, NCHH), 5.12 (1H, s, NCH), 7.18 (2H, d, J = 8Hz, arom.), 7.32 (1H, t, J = 8Hz, CH arom.), 7.38 (2H, d, J = 7Hz, 2CH arom.), 7.45 (2H, d, J = 7Hz, 2CH arom.), 7.48 (1H, dd, J = 2 and 7Hz, CH arom.), 7.58 (1H, d, J = 2Hz, CH arom.), 7.80 (1H, d, J = 7Hz, CH arom.)]. The mixture of the two diastereoisomers 1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl- (RS)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3 -ol can be obtained in the following manner: by operating according to example 39 starting from 0.56 g of (RS) -bromo (4-chlorophenyl) (2,4-dichlorophenyl) methane and 0.50 g of hydrochloride of 3 - [(3 , 5-difluorophenyl) (methylsulfonyl.) Methyl- (RS) Jazetidin-3-ol and after chromatography on a silica gel column (granulometry 0.04-0.06 mm, diameter 4.0 cm, height 13 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent and collecting fractions of 40 ml, fractions 9 to 14 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.27 g of the mixture of the two diastereoisomers l - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl- (RS)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS azetidin-3-ol The (RS) -bromo (4-chloro) phenyl) (2,4-dichlorophenyl) methane can be prepared according to the mode of operation described by BACHMANN. E. J. Am. Chem. Soc., 2135 (1993) starting from 4.05 g of (RS) - (4-chlorophenyl). (2, -dichlorophenyl) methanol, 10 ml of 33% hydrobromic acid in acetic acid and 2.1 ml of bromide of acetyl 4.6 g of (RS) -bromo (4-chlorophenyl) (2,4-dichlorophenyl) methane are obtained in the form of a greenish oil.

The (RS) - (4-chlorophenyl) (2,4-dichlorophenyl) methanol is prepared according to PAVÍA M.R. et al., J. Med. Chem. 4238 (1992).

Example 48 To a solution of 18.9 g of l-. { (4-chloro-phenyl) [4- (1, 3-dioxolan-2-yl) fe-iljmethyl- (RS)} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine in 80 ml of tetrahydrofuran, add 75.6 ml of 5 N hydrochloric acid. After 3 hours at room temperature, the mixture is taken up with dichloromethane and distilled water and then it is brought to pH 14 by the addition of 30% sodium hydroxide and decanted. The organic phase is washed twice with 100 ml of water and then with 100 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 16 g of (RS) -l- [(4-chlorophenyl) (4-formylphenyl) methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methylenazetidine in the form of a white foam are obtained [NMR Spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.06 (3H, s, SCH3), 3.95 (2H, m, NCH2), 4.26 (2H, m, NCH2), 4.91 (1H, s, NCH), 7.20 (2H, d, J = 8Hz, 2CH arom.), 7.36 (1H, t, J = 8Hz, 1CH arom.), 7.40 and 7.52 (4H, 2d, J = 7.5Hz, 4CH arom.) , 7.70 and 7.88 (4H, 2d, J = 7.5Hz, 4CH arom ..}., 9.97 (1H, s, aldehyde CH)]. The l- { [(4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl] methyl- (RS) 1J-3-E (3, 5-difluorophenyl) (methylsulfonyl) methylenejazetidine can be prepared according to the following method: to a solution of 34.45 g of the mixture of two diastereoisomers 3-acetoxy-l- { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl} phenylJmethyl- (RS)} -3- [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] -azetidine in 400 ml of tetrahydrofuran under argon atmosphere at 0 ° C, 13.0 ml 1,8-diazabicyclo [5] are added dropwise. -4-0] undec-7-ene and after the usual treatment and after chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 10.2 cm, height 23 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting fractions of 250 ml give 16.6 g of l-. { [(4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyljmethyl- (RS)} ] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylenediazetidine in the form of a white solid.

The mixture of the two diastereoisomers 3-acetoxy-1-. { [(4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) -phenylmethyl- (RS)} J-3- [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS) Jazetidine can be obtained in the following manner: by operating according to Example 40 from 11.6 g of (3,5-difluorobenzyl) methylsulfone, 35.1 ml of a 1.6 N solution of n-butyl lithium in hexane, 19.3 g of l-. { [(4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyljmethyl- (RS)} Jazetidin-3-one and 8.8 ml of acetyl chloride in 500 ml of tetrahydrofuran give 37.8 g of the mixture of the two diastereomers 3-acetoxy-1 -. { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenylJmeti 1- (RS)} -3 - [(3, 5-difluorophenyl). (Methylsulfonyl) methyl- (RS) Jazetidine in the form of a white foam: 1- ({(4-chlorophenyl) [4- (1,3-dioxolan -2-yl) phenylmethyl- (RS).} Azetidin-3-one can be prepared as follows: to a solution of 28.32 g of l-. {(4-chlorophenyl) [4- (1, 3 -dioxolan-2-yl) phenylJmeti1- (RS).}. azetidin-3-ol in 200 ml of dimethyl sulfoxide, 46 ml of triethylamine are added at room temperature and then a solution of 34 g of methanol is added dropwise. complex sulfur trioxide-pyridine in 100 ml of dimethyl sulfoxide After 0.25 hours at room temperature, the reaction mixture is poured onto ice, extracted with ethyl acetate, washed with 3 portions of 400 ml of water and then with 400 ml of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) .The residue obtained is chromatographed on a silica gel column. (granulometry 0.04-0.06 mm, diameter 9.2 cm, height 21 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent and collecting fractions of 250 ml. Fractions 9 through 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 20.4 g of 1- (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyljmethyl- (RS) are obtained} azetidin-3-one in the form of a yellow oil. The l-. { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyljmethyl- (RS)} azetidin-3-ol can be prepared according to the mode of operation described by KATRITZKY A. R. et al., J. Heterocycl. Chem. 271 (1994) starting from 35.0 g of 1-. { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenylmethyl} amine, 8.3 g of epibromohydrin, 5.1 g of sodium acid carbonate and 400 ml of ethanol. 30.3 g of l- are isolated. { (4-chlorophenyl) [4- (1, 3-dioxol n-2-yl) phenylJmeti1- (RS)} azetidin-3-ol. The hydrochloride of. { . (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyljmethyl- (RS)} Amine can be prepared according to the method described by GRISAR M. et al., J. Med. Chem. 885 (1973) from 67.2 g of 4- (1,3-dioxolan-2-yl) benzonitrile, 88.2 g of -bromo-4-chlorobenzene, 11 g of magnesium and 600 ml of ethyl ether. 42.3 g of. { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenylmethyl- (RS)} -amine in the form of a yellow oil.

Example 49 To a solution of 0.50 g of (RS) -l-. { (4-chlorophenyl) (-formyl phenyl) methyl} -3- [(3,5-difluorophenyl) methylsulfonyl) methylenazetidine in 15 ml of methanol at 0 ° C, 0.020 g of sodium borohydride are added. After 1 hour at 0 ° C, 40 ml of water are added and the product is extracted with 100 ml of dichloromethane. The organic phase is washed twice with 40 ml of water and then with 40 ml of a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is subjected to chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3.2 cm, height 14 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (30/70 in volume) as eluent and collecting fractions of 20 ml. Fractions 20 through 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.29 g of (RS) -1- are obtained. { (4-chlorophenyl) [4- (hydroxymethyl) phenylmethyl} -3- [(3,5-difluorophenyl) - (methylsulfonyl) methylene-benzetidine in the form of a white foam [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz): 3.02 (3H, s, SCH3), 3.90 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.42 (2H, d, J = 5Hz, OCH2), 4.75 (1H, s, NCH), 5.10 (1H, t, J = 5Hz, OH), between 7.10 and 7.50 (11H, m, 11CH arom.)].

Example 50 To a solution of 0.10 g of pyrrolidine in ml of 1,2-dichloroethane, 0.75 g of (RS) -l- are added. { (4-chlorophenyl) (4-formylphenyl) ethyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylenazetidine and then 0.68 g of sodium triacetoxyborohydride. After 20 hours at room temperature, 2 ml of 1 N sodium hydroxide are added, the product is extracted with 1QQ ml of dichloromethane, the organic phase is washed twice with 50 ml of water and then 50 ml of a saturated solution of Sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is subjected to chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 4.1 cm, height 13 cm) under a pressure of 0.5 bar of argon with ethyl acetate as eluent and collecting 20 ml fractions. Fractions 10 through 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.39 g of (RS) -l- are obtained. { (4-chlorophenyl) [4- (pyrrolidylmethyl) phenylmethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine in the form of a white foam [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 1.65 (4H, m, 2CH2 ), 2.40 (4H, m, 2NCH2), 3.02 (3H, s, SCH3), 3.50 (2H, s, NCH2Ph), 3.85 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H , s, NCH), between 7.15 and 7.40 (9H, m, 9CH arom.), 7.48 (2H, d, J = 7Hz, 2CH arom.)].

Example 51 Operating as in example 50, from 0.93 ml of a solution of 2 M dimethylamine in methanol, 30 ml of 1,2-dichloroethane, 0.75 g of (RS) -l-. { (4-chloro phenyl) (4-formyl phenyl) methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) ethylenaszetidine and then 0.9 g of sodium triacetoxyborohydride, is obtained after chromatography on a silica gel column (granulometry 0.04-0.06 mm, diameter 4 cm, height 17.5 cm ) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (30/70 by volume) as eluent and collecting fractions of 40 ml, 0.46 g of (RS) -l-. { (4-chlorophenyl) (4-dimethylaminomethyl) methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azet idine in the form of a white solid [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.12 (6H, s, N (CH2) 2), 3.02 (3H, s, SCH3), 3.32 (2H, s, NCH2Ph), 3.90 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.18 (2H, d, J = 8Hz, 2CH arom.), 7.22 (2H, d, J = 8Hz, 2CH arom.), 7.35 (1H, t, J = 8Hz, CH arom.), 7.39 (4H, m, 4CH arom), 7.48 (4H, d, J = 7Hz, 4CH arom.)].

Example 52 A solution of 0.5 g of (RS) -l- is stirred. { (4-carboxyphenyl) (4-chlorophenyl) methylJ-3- [(3,5-difluorophenyl) - (methylsul-fonyl) methylenediazetidine in 10 ml of dichloromethane at 0 ° C with 0.5 ml of a (2M) solution of dimethylamine in Ethanol: 13 ml of hydroxybenzotriazole, 0.2 g of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride and 0.18 ml of diisopropylethylamine are added, and after 20 hours at room temperature, the reaction mixture is diluted with dichloromethane, washed with water and dried. With 80 ml of water and then 80 ml of a saturated sodium chloride solution, it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) .The residue obtained is subjected to column chromatography. of silica gel (granulometry 0.04-0.06 mm, diameter 4.1 cm, height 13 cm) under a pressure of 0.5 bar of argon with a mixture of dichloromethane / acetonitrile / methanol (98/1/1 by volume) as eluent and collecting fractions of 15 ml, fractions 13 to 15 meet and then concentrated to dryness under reduced pressure (2.7 kPa). 0.16 g of a cream colored solid is obtained which, after being taken up with isopropyl ether and dried, leads to 0.11 g of (RS) -l-. { (4-chlorophenyl) [4- (N, N-dimethylaminocarbonyl) phenylmethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) ethylene] -zetidine in the form of a solid [NMR spectrum in DMS0-d6, T = 300K, d in ppm (300 MHz): 2.85 (3H, s, broad NCH3 ..}. , 2.95 (3H, s, broad NCH3), 3.00 (3H, s, SCH3), 3.90 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), 7.15 (2H , d, J = 8Hz, 2CH arom.), 7.30 (1H, t, J = 8Hz, CH arom.), 7.35 (4H, m, 4CH arom.), 7.50 (4H, d, J = 7Hz, 4CH arom. ..}.]. The (RS) -1- { (4-carboxyphenyl) (4-chlorophenyl) methylJ-3- [(3,5-di-fluorophenyl) (methylsulfonyl) methylene-benzetidine can be prepared as follows : to a solution of 0.50 g of (RS) -l- { (4-cyclophenyl) (4-formyl phenyl) methyl.}. -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine in 10 ml. of acetone at 0 ° C, 1.0 ml of Jones's reagent is added.After 5 hours, the reaction mixture is poured into distilled water, the product is extracted with 50 ml of ethyl acetate, the organic phase is washed twice with 50 ml of water and then with 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). stalize in a mixture of ethyl acetate-cyclohexane, filter and dry. 0.50 g of (RS) -1- are obtained. { (4-carboxyphenyl) (4-chlorophenyl) ethyl- (RS) J-3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine in the form of a white solid.

Example 53 It can be operated as in example 52, from 1 g of (RS) -1-. { (4-carboxyphenyl) (4-chlorophenyl) methylJ-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylenazetidine, 0.38 g of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, 22 mg of hydroxybenzotriazole hydrate, ml of dichloromethane, and 0.83 g of a 2M solution of ethylamine in tetrahydrofuran, subjecting to column chromatography on silica gel (granulometry 0.04-0.06 mm, diameter 4.1 cm, height 15 cm) under a pressure of 0.5 bar of argon with a Mix ethyl acetate and cyclohexane (45/55 by volume) as eluent and collect 30 ml fractions. Fractions 22 to 32 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.29 g of (RS) -l- are obtained. { (4-chlorophenyl) [4- (N-ethylcarbamoyl) phenylmethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine in the form of a white solid [NMR spectrum in DMS0-d6, T = 300K, d in ppm (300 MHz): 1.07 (3H, t, J - 6Hz, CH3), 3.00 (3H, s, SCH3), 3.35 (2H, m, NCH2), 3.90 (2H, s, NCH2.), 4.20 (2H, s.NCH2), 4.80 (1H, s, NCH), 7.15 (2H, d, J = 8Hz, 2CH arom.), 7.30 (1H, t, J = .8Hz ^ CH arorn ..), 7.35 (2H, d, J = 7Hz, 2CH arom.), 7.48 (4H, m, 4CH arom.), 7.74 (2H, d, J = 7Hz, 2CH arom.), 8.37 (1H, t, CONH)].

Example 54 The operation is carried out according to example 52, starting from 1 g of (RS) -1-. { (4-carboxy phenyl) (4-chlorophenyl) methyl} -3- [(3, 5-difluorophenyl) (methylsul-fonyl) methylene-benzetidine, 0. 38 g of 1,3-dimethylaminopropyl-3-ethylcarbodyl hydrochloride, 22 mg of hydroxybenzotriazole hydrate, 40 ml of dichloromethane and 0.24 ml of a 7 N solution of ammonia in methanol and chromatographing on a column of silica gel ( granulometry 0.04-0.06 mm, diameter 4.1 cm, height 15 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (60/40 by volume) as eluent and collecting fractions of 35 ml. Fractions 38 through 48 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.29 g of a solid are obtained which, after being taken up with isopropyl ether and dried, yields 0.22 g of (RS) -l- [(4-carbamoyl phenyl) (4-chlorophenyl) methyl- (RS)] -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylenediazetidine in the form of a white solid [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.00 (3H, s, SCH3), 3.90 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.82 (1H, s, NCH), 7.17 (2H, d, J = 8Hz, 2CH arom.), 7.30 (1H, t, J = 8Hz, CH arom.), 7.38 (2H, d, J = 7Hz, 2CH arom.), 7.50 (5H, m, 4CH arom. And ^ CONH2), 7.80 (2H, d, J = 7Hz, 2CH aro.}., 7.90 (1H, s, * í CONH2)].

Example 55 The operation is carried out according to the mode of operation of Example 4 starting from 1.7 g of l- [bis (4-chlorophenyl) methyl] -3- [3,5-dichlorophenyl] (methylsulfonyl) methyl- (RS) Jazetidine-3-ol , of 0.35 ml of methanesulfonyl chloride and 1.5 g of 4-dimethylaminopyridine. The residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (99.5 / 0.5 by volume) as an eluent and collecting 100 ml fractions. Fractions 7 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The solid is crystallized from 15 ml of ethyl ether. 0.2 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-dichlorophenyl) (methylsulfonyl) methylenazetidine is obtained which melts at 200 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.00 (3H, s ^ SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.35 (4H, d, J = 7Hz, 4CH arom ..}. 7.45 (6H, m, 6CH arom.), 7.67 (1H, s, CH arom.) J. L- [bis (4-chlorophenyl) methylJ-3- [(3,5-dichlorophenyl) (methylsulfonyl) methyl] - (RS) Jazetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of example 39 from 4 g of bis (4-chlorophenyl) bromomethane and 3 g of hydrochloride of 3 - [(3, 5-dichlorophenyl) methylsulfonyl} methyl- (RS) Jazetidin-3-ol, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 25 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane and then a mixture of dichloromethane and ethanol (99/1 by volume) as eluent and collecting 100 ml fractions. Fractions 15 to 19 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.7 g of l- [bis (4-chlorophenyl) methylJ-3- [(3,5-dichlorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol are obtained in the form of a foam. The bis (4-chlorophenyl) bromomethane can be prepared according to the mode of operation described by BACHMANN W. E. J. A. Chem. Soc., 2135 (1933). 3 - [(3,5-Dichlorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol hydrochloride can be obtained in the following manner: by operating according to the mode of operation of example 39 from 5.6 g of 3 - [(3,5-dichlorophenyl) - (methylsulfonyl) methyl- (RS) Jl- (vinyloxycarbonyl) -azetidin-3-ol and 56 ml of a 6.2 N hydrochloric dioxane solution in 56 ml of dioxane give 5.1 g of 3 - [(3,5-dichlorophenyl) - (methylsulfonyl) methyl- (RS)] azetidin-3-ol in the form of a foam, 3- [(3,5-dichlorophenyl) (methylsulfonyl)] -methyl- (RS)] -l- (vinyloxycarbonyl) azetidin-3-ol can be prepared in the following manner: by operating according to the mode of operation of example 39 from 7.4 g of l-benzhydryl-3- [(3 , 5-dichlorophenyl) (methylsulfonyl) methyl- (RS) Jazetidin-3-ol and 1.6 ml of vinyl chloroformate in 75 ml of dichloromethane, the residue is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 40 cm) under a pressure of 0.5 bar of nitrogen with a mixture of ethyl acetate and cyclohexane (30/70 by volume) as eluent and collecting 100 ml fractions. Fractions 4 through 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 5.6 g of 3 - [(3,5-dichlorophenyl) (methylsulfonyl) methyl- (RS) J-1- (vinyloxycarbonyl) azetidin-3-ol are obtained in the form of a foam.

Example 56 Operating according to the mode of operation of the Example 4 from 0.5 g of l-benzhydryl-3- [(3-dimethylamino phenyl) (methylsulfonyl) methyl- (RS) 1 azetidin-3-ol, of 0.1 ml of methanesulfonyl chloride and 0.5 g of 4 -dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 2 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (98 / 2 in volumes) as eluent and collecting the 20 ml fractions. Fractions 8 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 8 ml of ethyl ether. 0.3 g of l-benzhydryl-3- [(3-dimethylaminophenyl) (methylsulfonyl) methylene] azetidine is obtained which melts at 176 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz): 2.90 (6H, s, N (CH3) 2), 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 6.70 (3H, m, 3CH arom.), 7.20 (3H,, 3CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.48 (4H, d, J = 7Hz, 4CH arom.)] . L-benzhydryl-3- [(3-dimethylamino phenyl) (methylsulfonyl) met il- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 a Starting with 0.4 g of (3-dimethylaminobenzyl) methylsulphone, 0.4 g of 1-benzhydryl-azet idin-3-one and 1.2 ml of a 1.6 M solution of n-butyllithium in hexane, 0.5 g of the -benzhydryl-3- [(3-dimethylamino phenyl) (methylsulfonyl) methyl- (RS)] azet idin-3-ol in the form of a solid that melts at 185 ° C. The (3-dimethylaminobenzyl) methylsulfone can be prepared in the following manner: by operating according to the mode of operation of Example 2 from 1.4 g of (3-dimethylaminobenzyl) methylsulfide and 5.1 g of oxone ", 1.1 g is obtained. of (3-dimethylaminobenzyl) ethylsulphone in the form of a white solid that melts at 195 ° C. The (3-dimethylaminobenzyl) methylsulfide can be prepared as follows: operating according to the mode of operation of Example 37 from of 4 g of (3-iodobenzyl) methylsulphide, 1.4 g of dimethylamine in solution in 5 ml of tetrahydrofuran, 2.9 g of sodium terbutylate, 0.56 g of 1,1'-bis (diphenylphosphino) ferrocenyl chloride Palladium and 1.3 g of 1,1-bis (diphenylphosphino) ferrocene in 35 ml of tetrahydrofuran, 0.9 g of (3-dimethylaminobenzyl) ethylsulfide are obtained in the form of an oil.

Example 57 By operating according to the mode of operation of Example 4 from 1.3 g of l-benzhydryl-3- [(3-methylsulfanylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, of 0.3 ml of methanesulfonyl chloride and 1.4 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 2 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a dichloromethane mixture. and ethanol (98/2 in volumes) as eluent and collecting the 20 ml fractions. Fractions 11 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 15 ml of ethyl ether. 0.6 g of l-benzhydryl-3- [(3-methylsulfanylphenyl) (methylsulfonyl) methylene] azetidine is obtained which melts at 146 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.45 (3H, s, PhSCH3), 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), between 7.10 and 7.50 ( 14H, m, 14CH arom.)]. L-benzhydryl-3- [(3-methylsulfanylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 from 1.1 g of methyl (3-methylsulfanylbenzyl) sulfone, 1.2 g of 1-benzhydryl azetidin-3-one, 1.3 g of 1-benzhydryl-3- [(3-methylsulfanylphenyl) (methylsulfonyl) methyl- (RS)] azetidine is obtained -3-ol in the form of a solid. Methyl (3-methylsulfonylbenzyl) sulfone can be prepared as follows: it is heated to a temperature close to 100 ° C, under a stream of argon, for 1 hour a mixture of 5 g of (3-iodobenzyl) met ilsulphone and 1 g of tetrakistriphenylphosphine palladium in 250 ml of dimethyl sulfoxide. 2.5 g of sodium methylthiolate are added and then heating to 100 ° C is maintained for 18 hours. The reaction medium is cooled to room temperature, taken up in 700 ml of ethyl acetate and 500 ml of water. The organic phase is decanted, washed with 10 portions of 500 ml of water, 500 ml of a saturated aqueous solution of sodium chloride, filtered on sintered glass and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (70/30 then 60/40 then 50/50 in volumes) as eluent and receiving the 30 ml fractions. Fractions 26 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.2 g of methyl (3-methylsulfanylbenzyl) et ilsulfone are obtained in the form of an oil.

Example 58 To a solution cooled to 5 ° C of 1.1 g of 1-benzhydril-3-. { [3- (tert-butyldimethylsilyloxymethyl] -1-phenyl] (methylsulfonyl) methylene} azetidine in 10 ml of tetrahydrofuran, add 4 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. The mixture is stirred for 3 hours at a temperature close to 20 ° C and then it is taken up with 100 ml of ethyl acetate and 2 50 ml portions of water. The organic phase is decanted, extracted, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The obtained residue is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 2 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (95/5 by volume) as an eluent and receiving fractions of 60 ml. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.5 g of l-benzhydryl-3- [(3-hydroxymethylphenyl) (methylsul fonyl) methylene] azetidine are obtained in the form of a white solid which melts at 152 ° C.

[NMR spectrum in DMS0-d6, T = 300K, d in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, S, NCH2), 4.20 (2H, s, NCH2), 4.50 (2H, d, J = 5Hz, OCH2), 4.75 (1H, s, NCH), 5.25 (1H, T, J = 5Hz, OH), 7.20 (2H, t, J = 7Hz, 2CH arom.), 7.30 (8H, 8CH arom.), 7.45 (4H, d, J = 7Hz, 4 CH arom.)]. The l-benzihydril-3-. { [3- (tert-butyldimethylsilyloxymethyl) phenyl] (methylsulfonyl) -methylene} azetidine can be prepared in the following manner: by operating according to the mode of operation of Example 4 from 1.6 g of l-benzhydryl-3-. { [3- (tert-butyldimethyl if lyoxymethyl) phenyl] - (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 0.3 ml of mentansulfonyl chloride and 1.4 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and receiving fractions of 60 ml. Fractions 15 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.1 g of 1-benzhydril-3- is obtained. { [3- (tert-Butyldimethylsilyloxymethyl) phenyl] - (methylsulfonyl) methylene] azetidine in the form of a white solid which melts at 148 ° C. The • l-benzhydril-3-. { [3- (tert-butyldimethylsiloxymethyl) phenyl] (methylsul fonyl) met il- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 from 2 g of [3- (tert-butyldimethylsilyloxymethyl) benzyl] methylsulfone and 1.5 g of l-benzhydryl-azetidin-3-one, 1.6 g of l-benzhydryl-3- is obtained. { [3- (tert-Butyldimethylsilyloxymethyl) phenyl] (methylsulfonyl) methyl- (RS)] azetidin-3-ol in the form of a white solid that melts at 175 ° C. The [3- (tert-butyldimethylsilyloxymethyl) benzyl] methylsulfone can be prepared in the following manner: a mixture of 13.4 g of (3-hydroxymethylbenzyl) methylsulfone, 11 g of imidazole and 18 g of the mixture is stirred at a temperature of about 20 [deg.] C. for 18 hours. 12 g of tert-butyldimethylsilane chloride. The solution is concentrated to dryness under reduced pressure (2.7 kPa), the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 5 cm, height 50 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and receiving 100 ml fractions. Fractions 7 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 5.7 g of [3- (tert-butyldimethylsilyloxymethyl) benzyl] methylsulfone are obtained under the form of a white solid which melts at 80 ° C. The (3-hydroxymethylbenzyl) methylsulfone can be prepared in the following manner: a mixture of 26 g of 3- (methylsulphenylmethyl) benzoic acid and 4.6 g of lithium hydride is stirred for 18 hours at a temperature close to 20 ° C. of aluminum in 600 ml of tetrahydrofuran. The solution is cooled to 0 ° C and then 15 ml of ethyl acetate are added successively, 5 ml of water, 5 ml of a 15% aqueous solution of soda and finally 30 ml of water. The mixture is filtered on celite, the filtrate is taken up with 600 ml of ethyl acetate. The organic phase is taken up with 500 ml of water and then 200 ml of an aqueous solution saturated with sodium chloride, decanted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 10.4 g of (3-hydroxymethylbenzyl) methylsulfone are obtained in the form of a gum. The 3- (methylsulfonylmethyl) benzoic acid can be prepared in the following manner: by operating according to the mode of operation of Example 10 from 23.3 g of 3-chloromethylbenzoic acid and 23.3 g of sodium methansulfin, 26 g of acid are obtained 3- (Methylsulfonylmethyl) benzoic acid in the form of a white solid that melts at 210 ° C.

Example 59 To a solution of 0.8 g of l-benzhydryl-3 - [(3-bromomethyl phenyl) (methylsulfonyl) methylene] azetidine in 8 ml of dimethylformamide, 0.13 g of methylthiolate of methylthiolate is added, maintaining the temperature below 30 ° C. sodium. The mixture is stirred 18 hours at a temperature close to 20 ° C and then it is taken up with 30 ml of ethyl acetate and 50 ml of water. The organic phase is decanted, extracted and washed with 3 portions of 50 ml of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a column of silica gel (granularity 0.04-0.06 mm, diameter 2 cm, height 28 cm.) Under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (90 / 10 in volumes) as eluent and receiving 50 ml fractions Fractions 8 a 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.3 g of 1-benzhydril-3- are obtained. { [3- (Methylsulphonylmethyl) phenyl] - (methylsulfonyl) methylene} azetidine in the form of a white solid that melts at 150 ° C [NMR spectrum in DMS0-d6, T = 300K, d in ppm (300 MHz): 1.95 (3H, s, SCH3), 2.95 (3H, s, SCH3), 3.75 (2H, s, SCH2), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7. 20 (2H, t, J = 7Hz, CH arom.), 7.30 (8H, d, J = 7Hz, 8CH arom.), 7.45 (4H, d, J = 7Hz, 4 CH arom.)]. L-benzhydryl-3- [(3-bromomethyl phenyl) (methylsulfonyl) methylene] azetidine can be prepared as follows: to a mixture of 1 g of l-benzhydryl-3- [(3-hydroxymethylphenyl) (methylsulfonyl) methylene] azetidine in 10 ml of dichloromethane, 0.23 ml of phosphorus tribromide plus one drop of pyridine is added at a temperature close to 20 ° C. The stirring is maintained 18 hours at the same temperature. The reaction medium is taken up in 20 ml of water and 10 ml of an aqueous solution saturated with sodium chloride. The organic phase is decanted, extracted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 1 g of l-benzhydryl-3- [(3-bromomethyl phenyl) (methylsulfonyl) methylene] azetidine is obtained in the form of a foam used in the crude state in the subsequent syntheses.

Example 60 Operating according to the mode of operation of Example 4 starting from 6.6 g of l-benzhydryl-3- [(methylsulfonyl) (quinol-8-yl) methyl- (RS)] azetidin-3-ol, of 1.7 ml of methanesulfonyl and 5.2 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (particle size 0.04-0.06 mm, diameter 6.5 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with a dichloromethane mixture and methanol (95/5 in volumes) as eluent and receiving 40 ml fractions. Fractions 7 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 100 ml of ethyl ether. 4.4 g of l-benzhydryl-3- [(methylsulfonyl) (quinol-8-yl) methylene] azetidine is obtained which melts at 212 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz ): 3.15 (3H, s, SCH3), 3.55 (2H, broad s, NCH2), 4.30 (2H, s, NCH), 4.70 (1H, s, NCH), 7.18 (2H, t, J = 7Hz, 2CH arom.), 7.25 (4H, t, J = 7Hz, 4CH arom.), 7.43 (4H, d, J = 7Hz, 4 arom. CH), 7.62 (2H, m, 2CH quinoline), 7.75 (1H, dd, J = 2 and 7Hz, CH quinoline), 8.05 (1H, dd, J = 2 and 7Hz, CH quinolein), 8.43 (1H, dd, J = 2 and 8Hz, CH quinoline), 9.00 (1H, dd, J = 2 and 5Hz, CH quinoline)]. L-benzhydryl-3- [(methylsulfonyl) (quinol-8-yl) methyl- (RS)] azet idin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 starting from 5.5 g of methyl (quinol-8-ylmethyl) sulfone, 5.9 g of 1-benzhydril-azetidin-3-one and 18.8 ml of a 1.6 M solution of n-butyl lithium in hexane, give 6.6 g of -benzhydryl-3- [(methylsulfonyl) (quinol-8-yl) methyl- (RS)] azetidin-3-ol in the form of a beige solid. Methyl (quinol-8-ylmethyl) sulfone can be prepared in the following manner: by operating according to the mode of operation of Example 10 from 4.5 g of 8-chloromethylquinoline and 4.4 g of sodium meta-sulphinate., 5.7 g of methyl (quinol-8-ylmethyl) sulfone are obtained in the form of a beige solid. 8-Chloromethylquinoline can be prepared as follows: To a mixture of 7.1 g of 8-methylquinoline in 250 ml of carbon tetrachloride, 6.7 g of N-chlorosuccinimide is added at a temperature close to 20 ° C and then 250 g. mg of benzoyl peroxide. The reaction mixture is heated to reflux of the solvent for 36 hours and then cooled to 20 ° C. The mixture is filtered on sintered glass, the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The obtained residue is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 5.5 cm, height 32 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and receiving 40 ml fractions. Fractions 21 to 40 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 4.5 g of 8-chloromethylquinoline are obtained in the form of a brown oil used in the crude state in the subsequent syntheses.

Example 61 Operating according to the mode of operation of Example 4 from 6.2 g of l- [bis (4-chlorophenyl) methyl] -3- [(3-cyanophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol , of 1.4 ml of methanesulfonyl chloride and 6.1 g of 4-di and ylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 4 cm, height 60 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and receiving fractions of 100 ml. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 25 ml of ethyl ether. 0.7 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine are obtained in the form of a solid that melts at 178 ° C [NMR spectrum in DMS0- d6, T = 300K, d in ppm (300 MHz): 3.00 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, laa NCH2), 4.75 (1H, s, NCH), 7.30 (4H, d, J = 7Hz, 4CH arom.), 7.40 (4H, d, J = 7Hz, 4CH arom.), 7.60 (1H, t, J = 7Hz, arom. CH), 7.70 (1H, d, J = 7Hz, CH arom.), 7.85 (2H, m, 2CH arom.}.]. 1- [bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsul fonyl) ethyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 from 5.5 g of (3-cyanophenyl) methylsulfone, of 6.1 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one and 13.8 ml of a 1.6 M solution of n-butyllithium in hexane, affords 6.3 g of 1- [bis (4 chloro-phenyl) methyl] -3- [(3-cyanophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol in the form of a foam.

Example 62 A mixture of 4.5 g of 1- [bis (4-chlorophenyl) ethyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine in 50 ml of acetic acid and 50 ml is heated at 50 ° C for 20 hours. of concentrated hydrochloric acid (d = 1.18). The reaction mixture is cooled to room temperature and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is taken up in 100 ml of ethanol and then the solution is concentrated to dryness under reduced pressure (2.7 Kpa). The residue is precipitated in 60 ml of ethyl ether. The solid obtained is purified by chromatography on a column of silica gel (granularity 0.04-0.06 mm, diameter 25 cm, height 40 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane plus a mixture of dichloromethane and ethanol (99.5 / 0.5 in. volumes) as eluent and receiving fractions of 30 ml. Fractions 35 to 46 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 15 ml of ethyl ether. 0.2 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3-carbamoylphenyl) (methylsulfonyl) methylene] azetidine are obtained in the form of a solid which melts at 192 ° C.

NMR in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.95 (3H, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4. 80 (1H, s, NCH), 7.35 (4H, d, J = 7Hz, 4CH arom.), 7. 45 (5H, d, J = 7Hz, 4 arom. CH and * s C0NH2), 7.50 (2H, m, 2CH arom.), 7.85 (2H, m, 2CH arom.)].

Example 63 Operating according to the mode of operation of Example 1 from 0.8 g of l-benzhydril-3-. { [3- (N-tert-butyloxycarbonyl 1-N-methylamino) phenylj (methylsulfanyl) methyl- (RS)} azetidin-3-ol, 0.2 ml of methanesulfonyl chloride and 0.7 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.0-0.06 mm, diameter 2 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (98/2 in volumes) as eluent receiving fractions of 20 ml. Fractions 4 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from 10 ml of ethyl acetate. 0.5 g of 1-benzhydril-3- are obtained. { [3- (N-tert-butyloxycarbonyl-N-methylamino) phenyl] (methylsulfonyl) methylene} azetidine in the form of a solid that melts at 161 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 1.30 (9H, s, (CH3) 3), 2.95 (3H, s, SCH3), 3.15 (3H, s, NCH3), 3.75 (2H, s, SCH2), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), between 7.15 and 7.50 (14H , m, 14CH arom.)]. The l-benzhydril-3-. { [3- (N-tert-butyloxycarbonyl-N-methylamino) phenyl] (methylsulfonyl) -methyl- (RS)} azet idin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 starting from 1.6 g of [3- (N-tert-butyloxycarbonyl-N-methylamino) benzyl] methylsulfone, of 1.3 g of 1-benzhydrilazetidin-3-one and 3.8 ml of a 1.6 M solution of n-butyllithium in hexane, 0.8 g of l-benzhydryl-3- are obtained. { [3- (N-tert-butyloxycarbonyl-N-methylamino) phenyl] (methylsulfonyl) methyl- (RS)} azetidin-3-ol in the form of a white solid. [3- (N-tert-Butyloxycarbonyl-N-methylamino) benzyl] methylsulfone can be prepared as follows: To a solution cooled to 0 ° C of methyl (3-methylaminobenzyl) sulfone in 30 ml of dioxane are added 2.5 g of di-tert-butyl dicarbonate in 40 ml of dioxane. Stirring is maintained 18 hours at room temperature. The reaction mixture is taken up in 75 ml of dichloromethane; the organic phase is washed with 75 ml of water and then with 75 ml of an aqueous solution saturated with sodium chloride. The organic phase is decanted, extracted, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 2 cm, height 35 cm) under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 in volumes) as eluent receiving fractions of 20 ml. Fractions 5 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.8 g of [3- (N-tert-butyloxycarbonyl-N-methylamino) benzyl] methylsulfone is obtained in the form of a colorless oil. Methyl (3-methylaminobenzyl) sulphone can be prepared as follows: a mixture of 9.7 ml of formic acid (d = 1.22) and 19.6 ml of acetic anhydride is heated for 3 hours at 50 ° C. (d = 1.08) and then the solution is allowed to reach room temperature. 40 ml of tetrahydrofuran are added and cooled to -20 ° C. 14.8 g of (3-aminobenzyl) methylsulfone are added and 200 ml of tetrahydrofuran. Stirring is maintained 2 hours at -20 ° C and then 48 hours at room temperature. The mixture is filtered on sintered glass, the precipitate is washed with 3 portions of 50 ml of diisopropyl oxide and then dried. The filtrate is concentrated to half the volume (2.7 kPa), the precipitate obtained is filtered on sintered glass and washed with 3 30 ml portions of diisopropyl oxide and then dried. The two precipitates are combined and dissolved in 375 ml of tetrahydrofuran. The solution is cooled to 0 ° C; 100 ml of a 2 M solution of borane dimethylsulfide in tetrahydrofuran are added, and then refluxed for 3 hours. The mixture is cooled to 5 ° C and then 60 ml of methanol are added in 20 minutes. Stirring is maintained 1 hour at room temperature. A stream of hydrogen chloride is bubbled into the solution for 5 minutes. The reaction medium is then heated at reflux for 1 hour, cooled to room temperature and collected with 300 ml of water. The solution is made alkaline by the addition of 3 N sodium hydroxide and then with a saturated aqueous solution of sodium bicarbonate. The organic phase is extracted with 2 portions of 250 ml of ethyl acetate, washed with 300 ml of a saturated aqueous solution of sodium bicarbonate and 2 portions of 300 ml. This is concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is taken up in 100 ml of 4 N hydrochloric acid, then in 100 ml of ethyl acetate. The aqueous phase is made alkaline with 120 ml of 3 N sodium hydroxide, then with an aqueous solution of sodium bicarbonate. The organic phase is extracted with 2 portions of 75 ml of ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. (2.7 kPa). 9 g of methyl (3-methylaminobenzyl) sulfone are obtained in the form of a pink solid. The (3-aminobenzyl) ethylsulfone can be prepared in the following manner: a mixture of 23.7 g of methyl (3-nitrobenzyl) sulfone, 65 ml of hydrochloric acid (d = 1.18) and 150 ml of methanol is heated at reflux for 15 minutes. . 18.5 g of iron are added in 10 minutes and refluxed for 4 hours and then 18 hours at room temperature. The reaction mixture is made alkaline with an aqueous solution of ammonia and then with an aqueous solution of sodium bicarbonate. The organic phase is extracted with 3 portions of 250 ml of ethyl acetate, dried over magnesium sulfate, filtered on sintered glass and concentrated to dryness under reduced pressure (2.7 kPa). 14.9 g of (3-aminobenzyl) methylsulfone are obtained in the form of a beige solid used in the crude state in the subsequent syntheses.

Example 64 A mixture of 0.3 g of l-benzhydril-3- is stirred for 18 hours at room temperature. { [3- (N-tert-butyloxycarbonyl-N-methylamino) phenyl] (methylsulfonyl) methylene} azetidine, 4 ml of a 4.7 N solution of hydrochloric dioxane and 4 ml of dioxane. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up with 100 ml of water and 20 ml of diethyl oxide. The aqueous phase is made alkaline with 30 ml of an aqueous solution of sodium bicarbonate. The organic phase is extracted with 2 40 ml portions of ethyl acetate, washed with 2 30 ml portions of water, decanted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 20 ml of diethyl oxide. 0.16 g of l-benzhydryl-3- [(3-methylaminophenyl) (methylsulfonyl) methylene] azetidine are obtained in the form of a solid that melts at 161 ° C.

[NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz): 2.65 (3H, d, J = 5Hz, NCH3), 2.95 (3H, s, SCH3), 3. 80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 5.80 (1H, q, J = 5Hz, NH), 6.60 (3H, m, 3CH arom.) , 7.15 (1H, t, J = 7Hz, CH arom.), 7.22 (2H, t, J = 7Hz, 2CH arom.), 7.30 (4H, t, J = 7Hz, 4CH arom.), 7.48 (4H, d, J = 7Hz, 4 CH arom.)].

Example 65 Operating according to the mode of operation of Example 4 from 11.3 g of l- [bis (4-chlorophenyl) methyl] -3 - [(3-methoxyphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 2.6 ml of methanesulfonyl chloride and 10.9 g of 4-dimethylaminopyridine are obtained after recrystallization from 20 ml of diethyl oxide, 5 g of l- [bis (4-chlorophenyl) methyl] -3- [(3-methoxyphenyl) ) (methylsulfonyl) ethylene] azetidine which melts at 181 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.77 (3H, s, 0CH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), '4.80 (1H, s, NCH), 6.95 (3H, m, 3CH arom.), 7.35 (5H, m, 5 CH arom.), 7.45 (4H, d, J = 7Hz, 4 CH arom.)]. 1- [Bis (4-dichlorophenyl) methyl] -3 - [(3-methoxy phenyl) (methylsulfonyl) ethyl- (RS) azetidin-3-ol can be obtained in the following manner: operating according to the mode of operation of the Example 1 from 6.6 g of (3-methoxybenzyl) methylsulphone, 10 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one and 23 ml of a 1.6 N solution of n-butyllithium in hexane, 11.4 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3-methoxyphenyl) (methylsulfonyl) methyl- (RS) azetidin-3-ol are obtained in the form of a white solid which melts at 130 ° C.

Example 66 Operating according to the mode of operation of Example 32 from 4.8 g of l- [bis (4-chlorophenyl) methyl] -3 - [(3-methoxyphenyl) (methylsulfonyl) methylene] azetidine, 32 ml of a 1 M solution of boron tribromide in dichloromethane, the residue obtained was purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol as eluent (98/2 in volumes) and collecting fractions of 20 ml. Fractions 16 and 17 are concentrated to dryness under reduced pressure (2.7 kPa), after crystallization from 5 ml of diethyl oxide, 0.1 g of l- [bis (4-chlorophenyl) methyl] -3 - [(3-hydroxyphenyl) (methylsulphyl) methylene] azetidine is obtained form of a solid that melts at 114 ° C [NMR spectrum in DMS0-d6, T = 300K, d in ppm (250 MHz): 2.92 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, 's, NCH), 6.80 (3H, m, 3CH arom.), 7.20 (1H, t, J = 7Hz, CH arom.), 7.37 (4H, t, J = 7Hz, 4CH arom.), 7.47 (4H, d, J = 7Hz, 4 CH arom.)].

Example 67 Operating according to the mode of operation of the Example 4 from 0.6 g of l- [bis (4-chlorophenyl) methyl} -3- [(methylsulfoni 1) (3-pyrrolidinylphenyl) ethyl- (RS)] azetidin-3-ol, 0.1 ml of methanesulfonyl chloride and 0.5 g of 4-dimethylaminopyridine, the residue obtained was purified by chromatography on a gel column of silica (granulometry 0.04-0.06 mm, diameter 2 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol as eluent (98.5 / 1.5 in volumes) and collecting fractions of 10 ml. Fraction 4 is concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization, 5 ml of diethyl oxide, 0.5 g of l- [bis (4-chlorophenyl) 'methyl] -3- [(methylsulfonyl) (3-pyrrolidinylphenyl) methylene] azetidine are obtained in the form of a solid which melt at 133 ° C [NMR spectrum in DMS0-d6, T = 300K, d in ppm (400 MHz): 2.00 (4H, m, 2 CH2), 2.95 (3H, s, SCH3), 3.20 (4H, m , 2 NCH2), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), 6.50 (1H, s, CH arom.), 6.6 (1H, d, J = 7Hz, CH arom.), 6.65 (1H, d, J = 7Hz, CH arom.), 7.30 (1H, t, J = 7Hz, CH arom.), 7.40 (4H, d, J = 7Hz, 4 CH arom.), 7.50 (4H, d, J = 7Hz, 4 CH arom.)]. 1- [Bis (4-chlorophenyl) ethyl] -3- [(methylsulfonyl) (3-pyrrolidinylphenyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: by operating according to the mode of operation of the Example 1 from 0.5 g of methyl (3-pyrrolidinylbenzyl) sulfone, 0.6 g of l- [bis (4-chlorophenyl) methyl] azet idin-3-one and 1.4 ml of a 1.6 N solution of n-butyllithium in hexane, 0.6 g of 1- [bis (4-chlorophenyl) methyl] -3- [(methylsulfonyl) (3-pyrrolidinylphenyl) methyl- (RS)] azetidin-3-ol are obtained in the form of a cream-colored solid .

Example 68 Operating according to the mode of operation of Example 58 from 5.1 g of l- [bis (4-chlorophenyl) methyl] -3-. { [3- (tert-butyldimethylsilyl-loxi-methyl) phenyl] (methylsulfonyl) methylene} azetidine and 17 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran, the residue obtained was purified by chromatography on a silica gel column (granulometry 0.04-0.06 mm, diameter 2 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (97/3 in volumes) as eluent and collecting 100 ml fractions. Fractions 10 to 14 are combined, concentrated to dryness under reduced pressure (2.7 kPa). The yellow solid obtained is taken up in 2 ml of dichloromethane and 10 ml of ethyl acetate, and then filtered on sintered glass and washed with 2 ml of ethyl acetate. 1.6 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3-hydroxymethylphenyl) (methylsulfonyl) methylene] -zetidine are obtained in the form of a white solid which melts at 214 ° C [NMR spectrum] in DMSO-d6, T = 300K, d in ppm (400 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.50 (2H, d, J = 5Hz, OCH2), 4.80 (1H, s, NCR), 5.25 (IR, t, J = 5Hz, OH), 7.30 (1H, d, J = 7Hz, CH arom.), Between 7.35 and 7.45 (7H , m, 7CH arom.), 7.50 (4H, d, J = 7Hz, 4CH arom.)]. 1- [bis (4-chlorophenyl) methyl] -3-. { [3- (tert-butyldimethylsilyl-QX-methyl) phenyl] (methylsulfonyl) -methylene} azetidine can be prepared in the following manner: by operating according to the mode of operation of Example 4 starting from 10.8 g of l- [bis (4-chlorophenyl) methyl] -3-. { [- (tert-butyldimethylsilyloxy-methyl) phenyl] (methylsulfonyl) methyl- (RS)} azetidin-3-ol, 2 ml of methanesulfonyl chloride and 8.5 g of 4-dimethylamino inopyridine, the residue obtained is purified by chromatography on a silica gel column (granulometry 0.04-0.06 mm, diameter 4 cm, height 40 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 100 ml fractions. Fractions 12 to 29 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 5.2 g of 1- [bis (4-chlorophenyl) methyl] -3- are obtained. { [3- (tert-butyldimethyl-1-silyloxymethyl) phenyl] (methylsulfonyl) methylene} azetidine in the form of a gum. 1- [bis (4-chloro-phenyl) methyl] -3-. { [3- (tert-butyldimethylsilyloxymethyl) phenyl] (methylsulfonyl) -methyl- (RS)} azet idin-3-ol can be obtained in the following manner: by operating according to the mode of operation of Example 1 starting from 5.8 g of [3- (tert-butylsilyloxymethyl) benzyl] methylsulfone and 5.6 g of 1- [bis ( 4-chlorophenyl) methyl] azetidin-3-one, 10.8 g of 1- [bis (4-chlorophenyl) methyl] -3- are obtained. { [3- (tert-butyldimethylsilyloxymethyl) phenyl] (methylsulfonyl) ethyl- (RS)} Azetidin-3-ol in the form of a rubber.

Example 69 A mixture of 0.45 g of l- [bis (4-chlorophenyl) methyl] -3- is stirred for 18 hours at room temperature. { [methylsul fonyl] [3- (pentafluorophenoxycarbonyl) phenyl] methylene} azetidine, 0. 07 ml of 1-aminopiperidine in 4 ml of dimethylformamide. The mixture is taken up in 30 ml of ethyl acetate. The organic phase is washed with 3 portions of 50 ml of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 0.2 g of 1- [bis (4-chlorophenyl) methyl] -3- are obtained. { (methylsulfonyl) [3- (N-piperidylcarbamoyl) phenyl] methylene} azetidine melting at 175 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (400 MHz): 1.40 (2H, m, CH2), 1.60 (4H, m, 2CH2), 2.85 (4H, m, 2NCH2), 3.00 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), between 7.45 and 7.60 (10H, m, 10CH arom.), 7.75 (2H, m, 2CH arom.), 9.45 (1H, s, NH)]. 1- [bis (4-chlorophenyl) methyl] -3-. { (methylsulfonyl) [3- (pentafluorophenoxycarbonyl) phenyl] methylene} azetidine can be prepared in the following manner: by operating according to the mode of operation of Example 29 from 2.6 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3-carboxyphenyl) (methylsulfonyl) hydrochloride) methylene] azetidine, 0.9 g of pentafluorophenol, 0.9 g of l- (3-dimethylaminopropyl) -3-ylcarbodiimide hydrochloride in 25 ml of dimethylformamide, the residue obtained is purified by chromatography on a silica gel column (granulometry 0.04-0.06 mm, diameter 2 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (99/1 in volumes) as eluent and collecting fractions of 30 ml. Fractions 7 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.9 g of l- [bis (4-chlorophenyl) met il] -3- are obtained. { (methylsulfonyl) [3- (pentafluorophenoxycarbonyl) phenyl] methylene} azetidine in the form of a foam.

L- [bis (4-chlorophenyl) methyl] -3 - [(3-carboxyphenyl) (methylsulfonyl) methylene] azetidine can be prepared as follows: to a mixture of 0.5 g of 1- [bis (4-chlorophenyl) ) methyl] -3- [(3-hydroxymethylphenyl) (methylsulfonyl) methylene] azetidine in 9 ml of acetone, cooled to 5 ° C, add 2 ml of Jones's reagent. The stirring is maintained 2 hours at this temperature and then 50 ml of a mixture of water and ice and 50 ml of ethyl acetate are added. The organic phase is decanted, washed with 50 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. (2.7 kPa). The obtained residue is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 25 cm) under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol as eluent and collecting fractions of 60 g. ml. Fractions 12 to 14 are combined, concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 10 ml of ethyl ether. 32 mg of 1- [bis (4-chlorophenyl) methyl] -3 - [(3-carboxyphenyl) (methylsulfonyl) methylene] azetidine are obtained in the form of a solid that melts at 205 ° C [NMR spectrum in DMSO -d6, T = 300K, d in ppm (400 MHz): 2.90 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH) , 7.33 (4H, d, J = 7Hz, 4CH arom.), 7.39 (1H, d, J = 7Hz, CH arom.), 7.42 (4H, d, J = 7Hz, 4CH arom.), 7.49 (1H, t, J = 7Hz, CH arom.), 7.57 (1H, d, J = 7Hz, CH arom.), 7.90 (2H, s, CH arom., and NH +)].

Example 70 Operating according to the mode of operation of Example 4 from 0.8 g of l- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-trifluoromethylsulfanylphenyl) methyl- (RS)] azetidin-3-ol, 0.24 g of methanesulfonyl chloride and 0.7 g of 4-dimethylaminopyridine, the residue obtained was purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 2 cm, height 18 cm) under a pressure of 0.5 bar nitrogen with dichloromethane as eluent and collecting 50 ml fractions. Fractions 12 to 17 meet, they are concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is again purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 2 cm, height 20 cm) under a pressure of 0.5 bar of nitrogen with dichloromethane as eluent and collecting 30 ml fractions. Fractions 15 to 28 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 0.25 g of 1- [bis (4-chlorophenyl) ethyl] -3- [(methylsulfonyl) (3-trifluoromethylsulfanylphenyl) -methylene] azetidine is obtained which melts at 70 ° C [NMR spectrum in DMSO-d6 + CD3C02D , T = 300K, d in ppm (300 MHz): 3.00 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), 7.35 (4H, d, J = 7Hz, 4CH arom.), 7.45 (4H, d, J = 7Hz, 4CH arom.), 7.60 (2H, m, 2CH arom.), 7.75 (2H, m, 2CH arom.) The 1- [bis (4-chlorophenyl) methyl] -3- [(methylsulfonyl) (3-trifluoromethylsulfanyl phenyl) -methyl- (RS)] azet idin-3-ol can be obtained in the following manner: according to the mode of operation of Example 1 from 2 g of methyl (3-trifluoromethylsulfanylbenzyl) sulfone, 2.3 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one and 5.5 ml of a solution of - 1.6 M butyl lithium in hexane, 0.9 g of l-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethylsulfanylphenyl) methyl- (RS)] azetidino-3-ol are obtained in the form of a white solid.

The methyl (3-trifluoromethylsulfanylbenzyl) sulfone can be prepared in the following manner: by operating according to the mode of operation of Example 10 from 5 g of 3-trifluoromethylsulfanylbenzyl chloride and 3.2 g of sodium methansulfinate, 5.2 g of methyl are obtained (3-trifluoromet ilsulfanylbenzyl) sulfone in the form of a white solid that melts at 125 ° C.

Example 71 Operating as in Example 38 (Method 1), from 0.72 g of 1- [bis (4-fluorophenyl) methyl] -3- [(3, 5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin- 3-ol, of 0.18 ml of methanesulfonyl chloride and 0.66 g of 4-dimethylaminopyridine, is obtained after chromatography on a silica gel column (granulometry 0.04-0.06 mm, diameter 2.5 cm, height 15 cm) under a pressure of 1 bar of argon with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting fractions of 25 ml, 0.42 g of l- [bis (4-fluorophenyl) methyl] -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine in the form of a white foam [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz): 3.05 (3H, s, SCH3), 3.90 (2H , s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), 7.15 (6H, m, 6CH arom.), 7.35 (1H, t, J = 8Hz, CH arom.), 7.50 (4H, dd, J = 6 and 8Hz, 4CH arom.)]. 1- [Bis (4-fluorophenyl) methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) ethyl- (RS)] azetidin-3-ol can be obtained in the following manner: Example 39 from 2.25 g of bis (4-fluorophenyl) bromomethane, 1.1 g of potassium carbonate, and 2.5 g of 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin hydrochloride. -3-ol. After chromatography on a silica gel column (granularity 0.04-0.06 mm, diameter 4.4 cm, height 25 cm) under a pressure of 0.9 bar of argon with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 60 ml fractions, fractions '23 to 39 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.72 g of 1- [bis (4-fluorophenyl) methyl] -3- [(3,5-difluorophenyl) (methylsul fonyl) methyl- (RS)] azetidin-3-ol are obtained in the form of a solid White. Bis (4-fluorophenyl) bromomethane can be prepared according to the mode of operation described by BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933) from 4 g of 4,4'-difluorobenzidrol, 2.70 ml of acetyl bromide and 14 ml of a solution of 33% hydrobromic acid in acetic acid.

Example 72 Operating as in example 38 (Method 1), starting from 1.22 g of 1- [bis (2-fluorophenyl) methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin- 3-ol, of 0.29 ml of methanesulfonyl chloride and 1.1 g of 4-dimethylaminopyridine, is obtained after chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 23 cm) under a pressure of 1 bar of argon with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting 60 ml fractions, 0.177 g of l- [bis (2-fluorophenyl) ethyl] -3- [(3, 5-difluorophenyl) (methyl-sulfonyl) methylene] azetidine in the form of a white foam [NMR spectrum in DMS0-d6, T = 300K, d in ppm (300 MHz): 3.05 (3H, s, SCH3), 3.95 (2H, s, NCH2), 4.25 (2H, s, NCH2), 5.35 (1H, s, NCH), 7.20 (6H, m, 6CH arom.), 7.35 (3H, m, 3CH arom.), 7.55 (2H, m, 2CH arom.)]. 1- [Bis (2-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be obtained in the following manner: Example 39 from 2 g of bis (2-fluorophenyl) bromomethane, 1.0 g of potassium carbonate and 2.22 g of 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidine hydrochloride 3-ol. After chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 17 cm) under a pressure of 1 bar of argon with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as an eluent and collecting 60 ml fractions, fractions 6 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.22 g of 1- [bis (2-fluorophenyl) ethyl] -3- [(3,5-difluorophenyl) (methylsul fonyl) methyl- (RS)] azetidin-3-ol are obtained in the form of an off-white solid . The bis (2-fluororenyl) bromomethane can be prepared according to the mode of operation described by BACHMANN. E. , J. Am. Chem. Soc, 2135 (1933), from 1.80 g of 2, 2 'di f luorobenzhydrol, of 1.22 ml of acetyl bromide and 6.5 ml of a solution of 33% hydrobromic acid in acetic acid.

The 2, 2'-difluorobenzidrol can be prepared according to the following method: to a solution cooled to -70 ° C under an argon atmosphere of 8.8 g of 2-bromofluorobenzene in 100 ml of tetrahydrofuran, 32 ml of anhydride are drained off dropwise. -butyl lithium in 1.6 M solution in hexane. After stirring for 10 minutes at -70 ° C, 2.1 ml of ethyl formate are slowly added and then the mixture is stirred at -70 ° C for 30 minutes. The reaction medium is then brought to 0 ° C, and then 50 ml of ethyl acetate and 100 ml of saturated ammonium chloride solution are added. After stirring, the organic phase is separated, dried over magnesium sulfate, concentrated to dryness at 55 ° C, under reduced pressure (2.7 kPa). 3.63 g of 2,2'-difluorobenzidrol are obtained, in the form of a yellow oil.

Example 73 Operating as in Example 38 (Method 1), from 1.15 g of 1- [bis (3-fluorophenyl) methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin- 3-ol, of 0.264 ml of methanesulfonyl chloride, and 0.98 g of 4-dimethylaminopyridine, are obtained after chromatography on a silica gel column (granulometry 0.06-0.200 mm, diameter 2.8 cm, height 25 cm), under a pressure of 1 bar of argon with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting 60 ml fractions, 0.55 g of 1- [bis (3-fluorophenyl) methyl] -3- [( 3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine in the form of a white solid that melts at 178 ° C [NMR spectrum in DMS0-d6, T = 300K, d in ppm (250 MHz): 3.05 (3H, s, SCH3), 3.95 (2H, s, NCH2), 4.25 (2H, s, NCH2), 4.80 (1H, s, NCH), 7.10 (2H, m, 2CH arom.), 7.20 (2H,, 2CH arom.), Between 7.30 and 7.50 (7H, m, 7CH arom.)]. 1- [Bis (3-fluorophenyl) methyl] -3- [(3,5-difluorophenyl) (methylsul fonyl) ethyl- (RS)] azetidin-3-ol can be prepared in the following manner: by operating according to Example 1 from 1.2 g of (3, 5-difluorobenzyl) methylsulfone and 1.5 g of 1- [bis (3-fluorophenyl) methyl] azetidin-3-one, is obtained after purification on a silica gel column (granulometry 0.06-0.200 mm, diameter 3.2 cm, height 30 cm), under a pressure of 1 bar of argon with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting fractions of 60 ml, 1.95 g of l- [bis (3- fluorophenyl.} ethyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS) lazetidin-3-ol, in the form of a white solid, which melts at 170 ° C (decomposition). 1- [bis (3-fluorophenyl) methyl] azetidin-3-one can be prepared by operating in a manner identical to the mode of operation described by KATRITZKY AR et al., J. Heterocycl. Chem. 271 (1994), starting from of 4.9 g of [bis (3-fluorophenyl) methyl] amine and 1.78 ml of epichlorohydrin The [bis (3-fluorophenyl) methyl] amine can be prepared as follows: a suspension of 1.27 g of lithium hydride and from aluminum in 80 ml of tetrahydrofuran, a solution of 5.17 g of the 3,3 '-difluorobenzophenone oxime in 30 ml of tetrahydrofuran is drained off under an argon atmosphere in 30 minutes. After 5 hours of stirring at reflux, 1.3 ml of water, 1.3 ml of 4 N sodium hydroxide, 2.6 ml of water and then 50 ml of ethyl acetate are added successively. After drying over magnesium sulfate and concentration to dryness under reduced pressure (2.7 kPa), 4.9 g of [bis (3-fluorophenyl) ethyl are obtained} amine, in the form of a yellow oil. 2ÍS The oxime of 3, 3'-difluorobenzophenone can be prepared according to the following procedure: in a solution of 5.0 g of 3,3 '-difluorobenzophenone in 10 ml of ethanol, a solution of 1.6 g of water is dropped off dropwise. Hydroxylamine hydrochloride in 8 ml of water, and then 1.2 g of sodium hydroxide in pellets is added in small fractions. The reaction mixture, brought to reflux for 10 minutes, is cooled to 20 ° C and then acidified with 7.5 ml of 4 N hydrochloric acid. The oily precipitate obtained, once crushed, becomes a white solid which is filtered, washed with water and then dried at 35 ° C under reduced pressure (2.7 kPa). 5.17 g of the oxime of 3,3'-difluorobenzophenone are obtained in the form of a white solid.

Example 74 Operating as in Example 1, starting from 1. 30 g of a mixture of two diastereoisomers l - [(4-chlorophenyl) (thiaz.o1-2-yl) methyl- (RS)] - 3 - [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3 -ol, of 0.35 ml of methanesulfonyl chloride and 1.22 g of 4-dimethylaminopyridine, is obtained after chromatography on a silica gel column (granulometry 0.06-0.200 mm, diameter 2.4 cm, height 25 cm) under pressure from 1 bar of argon with a mixture of ethyl acetate and cyclohexane (1/1 by volume) as eluent and collecting fractions of 30 ml, 0.7 g of (RS) -l - [(4-chlorophenyl) (thiazole-2 il) methyl] -3- [(methylsulfonyl) (phenyl) methylene] azetidine, in the form of a pink solid [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.95 (2H, m, NCH2), 4.35 (2H, m, NCH2), 5.25 (1H, s, NCH), 7.45 (9H, m, 9CH arom.), 7.65 (1H, d, J = 2Hz, thiazole CH), 7.70 (1H, d, J = 2Hz, thiazole CH.).] The mixture of two diastereoisomers l - [(4-chlorophenyl) (thiazol-2-yl) methyl- (RS)] -3- [(methylsulfonyl ) (phenyl) methyl- (RS)] azetidin-3-ol, can be obtained in the following manner: by operating as in Example 39 from 4.47 g of (RS) -bromo (4-chlorophenyl) (thiazole-2) -il) methane and 4.31 g of 3- [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol hydrochloride and after chromatography on a silica gel column (granulometry 0.06-0.200 mm, diameter 5.6 cm, height 40 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 in Volumes) up to fraction 35, and then with pure ethyl acetate as eluent and collecting fractions of 60 ml, fractions 38 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.3 g of the mixture of two diastereoisomers l- [(4-chlorophenyl). (Thiazol-2-yl) methyl- (RS) J-3- [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin are obtained. -3-ol, in the form of a whitish solid The (RS) -bromo (4-chlorophenyl) (thiazol-2-yl) methane can be prepared according to the mode of operation described by BACHMANN., E. Am. Chem. Soc., 2135 (1933), from 3.5 g of (RS) - (4-chlorophenyl) (2-thiazolyl) methanol, 3.81 g of acetyl bromide and 12.0 ml of a solution of hydrobromic acid 33% in acetic acid The (RS) - (4-chlorophenyl) (thiazol-2-yl) methanol can be prepared according to the mode of operation described by G. EVAN BOSWELL et al., J. Heterocyclic Chem., 32, 1801 (1995), from 4.22 g of 4-chlorobenzaldehyde and 4.92 g of 2-bromothiazole.

Example 75 Operating as in Example 1, from 0.52 g of a mixture of two diastereoisomers l - [(4-chlorophenyl) (thien-2-11.} Ethyl- (RS)] -3- [(3, 5- difluorophenyl) (methylsulfonyl) ethyl- (RS)] azetidin-3-ol, 0.14 ml of methanesuflonyl chloride and 0.49 g of 4-dimethylaminopyridine, is obtained after chromatography on a silica gel column (granulometry 0.06-0.200 mm , diameter 2.4 cm, height 20 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent and collecting fractions of 30 ml, 0.32 g of (RS) -l - [(4-chlorophenyl) (thien-2-yl) methyl] -3- [(3,5-difluorophenyl) (methylsul fonyl) et ilen)] azetidine, in the form of a white solid, which melts at 176 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.98 (3H, s, SCH3), 3.90 (2H, m, NCH2), 4.20 (2H, s, NCH2), 5.03 (1H, s, NCH), 6.85 (1H, dd, J = 3 and 5Hz, CH thiophene), 7.08 (3H,, 2CH arom. And 1CH thiophene), 7.22 (1H, t, J = 8Hz, CH arom. ), 7.32 (3H, m, 2CH arom. and 1CH thiophene} , 7.40 (2H, d, J = 7Hz, 2CH arom.)].

The mixture of two diastereoisomers l - [(4-chlorophenyl) (thien-2-11.} Ethyl- (RS)] - 3 - [(3,5-difluorophenyl) (methylsul fonyl) methyl- (RS)] azetidin -3-ol can be prepared as follows: operating as in Example 1 from 1.60 ml of n-butyl-lithium 1.6 N in solution in hexane, of 0.83 g of (3, 5-difluorobenzyl) methylsulfone and 1.06 g of 1- [(4-chlorophenyl) (thien-2-yl) ethyl- (RS)] azetidin-3-one, it is obtained after purification on a column of silica gel (granulometry 0.06-0.200 mm, diameter 2.8 cm, height 30 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 in volumes) as eluent and collecting fractions of A 0 ml, 0.55 g of the diastereomer mixture l - [(4-chlorophenyl) (thien-2-yl) ethyl- (RS)] -3- [(3,5-difluorophenyl) ) (methylsulfonyl) ethyl- (RS)] azetidin-3-ol, in the form of a broken white solid. 1- [(4-chlorophenyl) (thien-2-yl) methyl- (RS)] azetidin-3-one can be prepared by operating as follows: to a solution cooled to -70 ° C of 1.83 ml of chloride of oxalyl in 20 ml of dichloromethane under an argon atmosphere, 3.04 ml of dimethyl sulfoxide is emptied in 10 minutes. After 30 minutes of stirring at -60 ° C, a solution of 5.2 g of l - [(4-chlorophenyl) (thien-2-yl) methyl (RS)] azetidin-3-ol in 20 minutes is emptied in 20 minutes. ml of dichloromethane, the mixture is stirred for 3 hours at a temperature between -60 ° C and -70 ° C, then 9.12 ml of triethylamine is added. The mixture is then allowed to come to room temperature, then diluted with water. The organic phase is separated, dried over magnesium sulfate, then concentrated under reduced pressure to dryness. The residue is subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 4 cm, height 36 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (1/9 in volumes) as eluent and collecting 60 ml fractions. 3.3 g of 1- [(4-chlorophenyl) (thien-2-yl) methyl- (RS)] azetidin-3-one are obtained in the form of a yellow oil which crystallizes at ordinary temperature. 1- [(4-chlorophenyl). (Thien-2-yl) methyl- (RS)] azetidin-3-ol can be prepared as follows: to a solution of 11.0 g of [(4-chlorophenyl) (thien-2-yl) ethyl- (RS)] amine in 80 ml of ethanol is added 4.12 g of sodium bicarbonate.The mixture is heated to 65 ° C and then 4.03 ml of epibromohydrin are added. stirring at 65 ° C, the cooled mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 3.6 cm , height 32 cm), under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 by volume) as eluent and collecting 60 ml fractions to obtain 6.3 g of 1- [(4- chlorophenyl) (thien-2-yl) methyl- (RS)] azetidin-3-ol, in the form of a pale yellow oil.The [(4-chlorophenyl) (thien-2-yl) methyl- (RS)] Amine can be prepared as follows To a suspension cooled to 10 [deg.] C. of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of 4-bromochlorobenzene and 2.43 g of magnesium) in 120 ml of anhydrous ethyl ether, a solution of 10.92 g of 2% is slowly -thiophenecarbonitrile in 80 ml of ethyl ether. After one hour of reflux, the mixture is cooled to 10 ° C, 40 ml of methanol are slowly added and then filtered over supercel. 4.54 g of sodium borohydride are added under an argon atmosphere and in small fractions, in 15 minutes and then the reaction mixture is stirred for 20 hours at 20 ° C. The mixture obtained is diluted with ethyl acetate, then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue is subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 5 cm, height 42 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (4/6 in volumes) as eluent and collecting 100 ml fractions. The fractions 6 to 12 are concentrated to dryness corresponding to 13 g of i in the form of a yellow oil which is taken up in 100 ml of methanol. The obtained solution is added with 2.4 g of sodium borohydride, and is stirred for one hour at 5 ° C. The mixture obtained is diluted with ethyl acetate, then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue is subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 3.2 cm, height 40 cm) under a pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (4/6 in volumes) as eluent and 60 ml fractions are collected. 11.0 g of [(4-chlorophenyl) (thien-2-yl.) Methyl- (RS)] amine are obtained in the form of a yellow oil.

Example 76 Operating as described in Example 75, from 1.66 g of the mixture of two chiral diastereomers 1- [(4-chlorophenyl) (thien-2-yl) methyl- (R *)] -3- [(3, 5-difluorophenyl) (methylsulfonyl) methyl- (R *)] azetidin-3-ol and l - [(4-chlorophenyl) (thien-2-yl) methyl- (R *)] -3- [(3.5 -difluorophenyl) (methylsulfonyl) methyl- (S *)] azetidin-3-ol, 50 ml of dichloromethane, 0.45 ml of methanesulfonyl chloride, and 1.64 g of 4-dimethylaminopyridine, 0.6 g of (+) -1- are obtained [(4-chlorophenyl) (thien-2-yl) methyl-3- [(3,5-difluorophenyl) (methylsulfonyl) -methylene] azetidine, in the form of white crystals melting at 136 ° C, [a] 20D = 3.2 ° (c = 0.5% in dichloromethane). The mixture of two chiral diastereomers 1- [(4-chlorophenyl) (thien-2-yl) methyl- (R *)] -3- [(3, 5-difluorophenyl) (methylsul fonyl) methyl- (R *)] azetidin-3-ol and 1- [(4-chlorophenyl) (thien-2-yl) methyl- (R *)] -3- [(3 , 5-difluorophenyl) (methylsulfonyl) methyl- (S *)] azetidin-3-ol can be prepared as described in Example 75, from 1.06 g of (+) - 1 - [(4-chlorophenyl) ( thien-2-yl) methyl] azetidin-3-one, 0.82 g of (3, 5-difluorobenzyl) methylsulfone, 2.5 ml of n-butyllithium solution 1.6 N in hexane, and 25 ml of tetrahydrofuran. Obtained after purification by chromatography, 1.7 g of the mixture of two chiral diastereomers l - [(4-chlorophenyl) (thien-2-yl) methyl- (R *)] -3- [(3,5-difluorophenyl) ) (methylsulfonyl) methyl- (R *)] azetidin-3-ol and 1- [(4-chlorophenyl) (thien-2-yl) methyl- (R *)] -3- [(3,5-difluorophenyl) (methylsul fonyl) methyl- (S *)] azetidin-3-ol, in the form of a white solid. The (+) -1- [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-one can be prepared as described in Example 75 from 12.4 g of (+) -1- [ (4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-ol, 220 ml of dichloromethane, 7.1 ml of dimethyl sulfoxide, 4.4 ml of oxalyl chloride and 21.5 ml of triethylamine. 9.2 g of (+) -! - [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-one are obtained in the form of a pale yellow oil which crystallizes at 20 ° C.

The (+) -1- [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-ol can be prepared as described in Example 75, from 16.1 g of (+) - [(4-chlorophenyl) (thien-2-yl) methyl] amine, 130 ml of ethanol, 5.9 ml of epibro hydrin, and 6.05 g of sodium bicarbonate. They are obtained after purification by chromatography, 11.5 g of (+) - 1 - [(4-chlorophenyl) - (thien-2-yl) methyl] azetidin-3-ol, in the form of a cream-colored oil, (+.) -4- [( chlorophenyl) (thien-2-yl) methyl] amine can be prepared in the following manner: to a solution of 109 g of [(4-chlorophenyl) (thien-2-yl) methyl (RS)] amine in 500 ml of Methanol, 73 g of D- (-.} - tartaric acid are added The mixture is concentrated to dryness under reduced pressure (2.7 kPa) The obtained foam is collected with 2.05 liters of an ethanol-water 90/10 mixture in volumes After 20 hours of slow stirring at 20 ° C, the crystalline suspension obtained is filtered, the crystals are washed with the minimum of the same mixture of solvents, and then dried, a new recrystallization is carried out under the same conditions with 1.5 liters of the same solvent mixture, 44.9 g of acid tartrate crystals are obtained from the amine [a] 20D = + 10.3 ° (c = 0.5% in dimethylformamide.) This compound is recrystallized in 600 ml of a mix 80/20 ethanol-water in volumes (the crystals are filtered and washed with 2 30 ml portions of the same solvent mixture and then drained), then recrystallized under the same conditions with 400 ml of a mixture of ethanol-water 78/22. 28.2 g of D- (-) -tartrate acid of (+) - [(4-chlorophenyl) (thien-2-yl) methyl] amine are obtained, in the form of white crystals [a] 20D = + 10.8 ° ( c = 0.5% in dimethylformamide). This salt is taken up with 400 ml of an aqueous solution of 1 N sodium hydroxide and with 100 ml of ethyl acetate. The organic phase is separated, washed with 100 ml of water, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa). 16.1 g of (+.) - [(4-chlorophenyl) (t-ene-2-yl) methyl] amine are obtained, in the form of an oil which crystallizes at 20 ° C. [A] 0D = + 32.7 ° (c = 0.5% in dichloromethane).

Example 77 Operating as described in Example 75, from 1.30 g of the mixture of two chiral diastereomers 1- [(4-chlorophenyl) (thien-2-yl) methyl- (S *)] - 3 - [(3, 5-di fluorophenyl) (methylsulfonyl) methyl- (R *) lazetidin-3-ol and l - [(4-chlorophenyl) (thien-2-yl) methyl- (S *)] -3- [(3.5 -difluoro-phenyl) (methylsulfonyl) methyl- (S *)] azetidin-3-ol, 40 ml of dichloromethane, 0.35 ml of methanesulfonyl chloride and 1.28 g of 4-dimethylaminopyridine, 0.97 g of (-) - are obtained 1- [(4-chlorophenyl) (thien-2-yl) methyl] -3- [(3,5-difluorophenyl) methylsulfonyl) -methylene] azetidine, in the form of white crystals melting at 135 ° C, [a ] 20 D = -3.4 ° (c = 0.5% in dichloromethane). The mixture of two chiral diastereomers 1- [(4-chlorophenyl) (thien-2-yl) methyl- (S *)] -3- [(3,5-difluorophenyl) (methylsulfonyl) methyl- (R *)] azetidin -3-ol and 1- [(4-chlorophenyl) (thien-2-yl) methyl- (S *)] -3- [(3,5-difluorophenyl) (methylsulfonyl) methyl- (S *)] -azetidin -3-ol can be prepared as described in Example 75, starting from 1.06 g of (-) - 1 - [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-one, 0.82 g of (3, 5-difluorobenzyl) ethylsulfone, 2.5 ml of n-butyllithium solution 1.6 N in hexane, and 25 ml of tetrahydrofuran. Obtained after purification by chromatography, 1.3 g of the mixture of two chiral diastereomers l - [(4-chlorophenyl) (thien-2-yl) methyl- (S *)] -3- [(3, 5-difluorophenyl) ) (methylsulfonyl) methyl- (R *)] azetidin-3-ol and 1- [(4-chlorophenyl) (thien-2-yl) methyl- (S *)] - 3 - [(3,5-difluorophenyl} (methylsulfonyl) ethyl- (S *)] azetidin-3-ol, in the form of a white solid, (-) -1- [(4-chlorophenyl) (thien-2-yl) methyl] azetidin- 3-one can be prepared as described in Example 75, starting from 11.4 g of (-) -1- [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-ol, 200 ml of di chloromethane, 4.0 ml of dimethyl sulfoxide, 4.0 ml of oxalyl chloride, and 19.5 ml of triethylamine. 8.3 g of (-) - 1 - [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-one are obtained in the form of a pale yellow oil which crystallizes at 20 ° C. The (-) -1- [(4-clsphenyl) (thien-2-yl) methyl] azetidin-3-ol can be prepared as described in Example 75, from 15.4 g of (-) - [( chloro-phenyl] - (thien-2-yl) methyl] amine, 120 ml of ethanol, 5.8 ml of epibromohydrin, and 5.8 g of sodium bicarbonate are obtained after purification by chromatography, 10.7 g of (-) - 1- [(4-chlorophenyl) (thien-2-yl) methyl] azetidin-3-ol, in the form of a cream-colored oil.

The (-) - [(4-chlorophenyl) (thien-2-yl) ethyl] amine can be prepared in the following manner: to a solution of 43 g of [(4-chlorophenyl) (thien-2-yl) methyl] - (RS) Laminate in 200 ml of methanol, add 29 g of L- (+) - tartaric acid. The obtained mixture crystallizes in 2 hours at room temperature. The crystals are filtered, washed with 2 portions of 10 ml of S e e_Lect metal. a, a recrystallization with 500 ml of an 80/20 ethanol-water mixture in iaa. crystals are filtered, washed with 2 30 ml portions of the same solvent mixture, then dried under vacuum at 45 ° C. A final recrystallization is carried out with 350 ml of a mixture of ethanol-water 78/22 in volumes, leaving stirring 20 hours at 20 ° C. The crystals obtained are drained, dried under reduced pressure (2.7 kPa). 26 g of (-) - [(4-chlorophenyl) (thien-2-yl) methylamine L- (+) - tartrate acid are obtained. [OI120D = -10.7 ° (c = 0.5% in dimethylformamide). This salt is taken up with 400 ml of an aqueous solution of 1 N sodium hydroxide and with 100 ml of ethyl acetate. The organic phase is separated, washed with 100 ml of water, dried over magnesium sulfate, concentrated to dryness under reduced pressure (2.7 kPa). 15.4 g of (-) - [(4-chlorophenyl) (thien-2-yl) methyl-sheet are obtained, in the form of an oil which crystallizes at 20 ° C. [α] 20 D = -31.7 ° (c = 0.5% in dichloromethane).

Example 78 Operating according to the mode of operation of Example 1 from 3.4 g of l-benzhydryl-3- [(ethylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol, of 0.72 ml of methanesulfonyl chloride and 3.8 g of 4-dimethylaminopyridine are obtained, after recrystallization from 40 ml of acetonitrile, 1.9 g of l-benzhydryl-3- [(ethylsulphone) (phenyl) methylene] -zetidine in the form of crystals melting at 210 ° C [ NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 1.15 (3H, t, J = 6Hz, CH3), 2.92 (2H, q, J = 6Hz, CH2), 3.83 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), between 7.20 and 7.50 (15H, m, 3 phenyls)]. L-benzh.ydril-3-f (ethylsulfonyl) (phenyl) -methyl- (RS)] azetidin-3-ol can be obtained by operating according to the mode of operation described in Example 1 from 2.4 g of benzylethylsulfone, 2.2 ml of diisopropylamine, 10 ml of n-butyllithium 1.6 N in solution in hexane, 65 ml of tetrahydrofuran and 3.1 g of l-benzhydril-azetidin-3-one. They are obtained after recrystallization from 30 ml of acetonitrile, 3.6 g of l-benzhydryl-3- [(ethylsulfonyl) (phenyl). Methyl- (RS)] azetidin-3-ol in the form of white crystals which melt 222 ° C. The benzylethylsulfone can be prepared by operating according to the mode of operation of Example 2 from 6.3 g of benzylethylsulfide, 50 ml of acetic acid, 50 ml of water, 25 ml of sulfuric acid 36 N and 24.8 g of oxane. 3.2 g of benzylethylalone are obtained, by recrystallization from 20 ml of ethyl ether, in the form of a solid which melts at 86 ° C. The benzylethylsulphide can be prepared in the following manner: to a solution of 5 g of benzyl mercaptan in 50 ml. ml of dimethylformamide under an argon atmosphere, 1.2 g of sodium hydride are added in small portions and then 3.36 ml of ethyl iodide are emptied, maintaining a temperature below 45 ° C. The mixture is stirred for 2 hours and then collected with 200 ml of ethyl ether.The organic phase is washed a with 200 ml of water and then with 3 portions of 100 ml of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 6.3 g of benzylethyl sulfide are obtained in the form of a pale yellow liquid.

Example 79 To a solution of 0.45 g of l- [bis (4-chlorophenyl) methyl] -3-. { (methylsulfonyl) [3- (pentafluorophenoxycarbonyl] phenyl] methylene] azetidine in 5 ml of dimethylformamide, add 0.083 g of l-amino-4-methylpiperazine, stir 20 hours at room temperature and then add 40 ml of acetate The organic phase is washed with 4 portions of 20 ml of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) .The residue is triturated with 10 ml of ethyl ether, filter, and then dry. 0.2 g of 1- [bis (4-chlorophenyl) ethyl] -3- are obtained. { (methylsulfonyl) (. N-4-methylpiperazinylcarbamoyl) -phenyl] methylene} azetidine in the form of a yellow solid, melting at 162 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.20 (3H, -s, NCH3), 2.40 (4H, m, 2 NCH2), 2.90 (4H, m, 2 NCH2), 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH ..}., 7.40 (4H, d, J = 7Hz, 4CH arom.), 7.50 (4H, d, J = 7Hz, 4CH arom.), 7.55 (2H,, 2CH arom.), 7.80 (2H,, 2CH arom.), 9.50 (1H, s, CONH)]. 1- [Bis (4-chlorophenyl) methyl] -3- ({(methylsul onyl) [3- (pentafluorophenoxycarbonyl) -phenyl] methylene] azetidine is can be prepared as follows: to a solution of 2.9 g of 1- [bis (4-chlorophenyl) ethyl] -3- [(3-carboxyphenyl) (methylsulfonyl) methylene] azetidine in 25 ml of dimethylformamide, 0.94 is added g of N- (3-dimethylaminopropyl) N'-ethylcabodiimide hydrochloride and 0.89 g of pentafluorophenol, stir for 20 hours at room temperature and then collect with 50 ml of ethyl acetate.The organic phase is washed with 100 ml of water , 200 ml of a solution saturated aqueous sodium bicarbonate and then with two 50 ml portions of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is subjected to chromatography on a column of silica gel (granulometry 0.04-0.006 mm, diameter 2 cm) eluting with a mixture of dichloromethane and ethanol (99/1 by volume). 0.92 g of 1- [bis (4-chlorophenyl) methyl] -3- are obtained. { (methylsulfonyl) [3- (pentafluorophenoxycarbonyl) -phenyl] methylene] azetidine, in the form of a white foam. 1- [Bis (4-chlorophenyl) methyl] -3- [(3-carboxyphenyl) (methylsulfonyl) methylene] azetidine can be prepared in the following manner: to a solution of 3.8 g of 1- [bis (4-chlorophenyl) ) methyl] -3- [(3-cyanophenyl) (methylsul fonyl) methylene] azetidine in 5 ml of acetic acid is added a solution of 36% hydrochloric acid at a temperature of 50 ° C. The heating is continued 48 hours and then the mixture is evaporated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 30 ml of ethanol and evaporated to dryness again. The residue is triturated in 35 ml of ethyl ether. 3.8 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3-carboxyphenyl) (methylsulfonyl) methylene] azetidine are obtained in the form of a beige solid. 1- [bis (4-chlorophenyl) methyl] -3- [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine can be prepared according to the mode of operation of example 4, from 11 g of 1- [ bis (4-chlorophenyl) methyl] -3- [(3-cyanophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 150 ml of dichloromethane, 2.54 ml of methanesulfonyl chloride and 10.7 g of 4 -dimethylaminopyridine, at room temperature for 3 hours The residue obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 4.5 cm) and eluted with dichloromethane and then with a mixture of dichloromethane and ethanol (99.6 /0.4 volumes) The fractions are evaporated to dryness under reduced pressure (2.7 kPa) 3.8 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methylene are obtained ] azetidine, in the form of a white foam, 1- [bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be prepared from l as follows: to a solution of 17.6 ml of 1.6 M n-butyllithium in hexane, in 30 ml of tetrahydrofuran under an argon atmosphere, and cooled to -70 ° C, a solution of 5 g of 3-cyanobenzylmethylsulfone is added in 500 ml of tetrahydrofuran in 15 minutes. The mixture is stirred for 1 hour 30 minutes. Then a solution of 7.8 g of l- [bis (4-chlorophenyl) methyl] azetidin-3-ana in 80 ml of tetrahydrofuran is drained in 10 minutes. After stirring for 1 hour 30 minutes, 60 ml of a saturated aqueous solution of ammonium chloride are emptied, and then it is allowed to reach room temperature. The mixture is collected with 300 ml of ethyl acetateThe organic phase is washed with 200 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and evaporated under reduced pressure (2.7 kPa). 11 g of l- [bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) -methyl- (RS)] azetidin-3-ol are obtained in the form of a foam. The (3-cyanobenzyl) methylsulfone can be prepared in the following manner: from a solution of 20.2 g of 3-chloromethylbenzonitrile in 200 ml of ethanol, 17.4 g of 85% sodium methansulfinate are added. The mixture is stirred at reflux for 20 hours, then it is taken up with 500 ml of ethyl acetate and 500 ml of water. The insoluble material is filtered, the organic phase in the filtrate is dried over magnesium sulphate and evaporated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated with 100 ml of ethyl ether. After filtration and drying of the solid, 21 g of (3-cyanobenzyl) methylsulfone are obtained in the form of white crystals melting at 165 ° C. The 3-chloromethylbenzonitrile can be prepared in the following manner: for 3 hours, 32 g of 3-chloromethylbenzoamide in 200 ml of phosphorus oxychloride is heated at 95 ° C, then 1 liter of ice is charged, stirred for 1 hour, extracted Mix with 500 ml of dichloromethane. The organic phase is washed with 200 ml of water, dried over magnesium sulphate and evaporated to dryness under reduced pressure (2.7 kPa). 20.2 g of 3-chloromethylbenzonitrile are obtained in the form of a white solid. The 3-chloromethylbenzoamide can be prepared in the following manner: to a solution of 50 g of 3-chloromethylb-enzoyl chloride in 150 ml of ethyl ether, 150 ml of ammonia solution (d = 0.90) is drained, cooled , stirred for 1 hour, filtered and washed with 2 200 ml portions of ethyl ether. 32 g of 3-chloromethylbenzoamide are obtained in the form of white crystals.

Example 80 Operating according to the mode of operation of Example 79 starting from 0.5 g of l- [bis (4-chlorophenyl) methyl] -3-. { (methylsulfonyl) [3- (pentafluorophenoxycarbonyl) phenyl] methylene} azetidine, 0.06 ml, 1, 1-dimethylhydrazine and 5 ml of dimethylformamide, 0.125 g of l- [bis (4-chlorophenyl) methyl] -3- is obtained. { [3- (2, 2-dimethylcarbohydrazido) -phenyl] (methylsulfonyl.) Ethylenejazetidine, in the form of a white solid, which melts at 134 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.60 (6H, s, N (CH3) 2), 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, S , NCH), 7.35 (4H, d, J = 7Hz, 4CH arom.), 7.45 (4H, d, J = 7Hz, 4CH arom.), 7.50 (2H, m, 2CH arom.), 7.80 (2H, m , 2CH arom.), 9.50 (1H, s, CONH)].

Example 81 Operating according to the mode of operation described in Example 1 starting from 2.2 g of 1- [bis (thien-2-yl) methyl] -3- [(3,5-difluoraf nyl) (methylsulfonyl) -methyl- (RS )] azetidin-3-ol, 0.64 ml of methanesulfonyl chloride, 2.3 g of 4-dimethylaminopyridine and 75 ml of dichloromethane, after purification by chromatography and crystallisation in diisopropyl oxide, 1.3 g of 1- [ bis (thien-2-yl) ethyl] -3- [(3 ^ 5-difluorophenyl) (methylsulfonyl) -methylene] azetidine, in the form of white crystals melting at 165 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.00 (3H, s, SCH3), 3.92 (2H, s, NCH2), 4.28 (2H, s, NCH2), 5.40 (1H, s, NCH), 6.95 ( 2H, dd, J = 5 y.2Hz, 2CH uncle), 7.15 (2H, 23 d, J = 2Hz, 2CH thio.), 7.20 (2H, m, 2CH arom.), 7.35 (1H, t, J = 8Hz, CH arom.}., 7.50 (2H, d, J = 5Hz, 2CH thio.)]. l- [Bis (thien-2-yl) methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) ethyl- (RS)] azetidin-3-ol can be obtained in the same way as of operation described in Example 1, from 1.5 g of 1- [bis (thien-2-yl) m.etiilaz.etidin-3-one, 4 ml of n-butyllithium 1.6 N in hexane, 1- 3 g of (3,5-difluorobenzyl) methylsulfone and 40 ml of tetrahydrofuran are obtained after purification by chromatography, 2.2 g of 1- [bis (thien-2-yl) methyl] -3- [(3 , 5-di fluorophenyl) (methylsulfanyl) methyl- (RS)] azetidin-3-ol, in the form of white crystals melting at 145 ° C. 1- [bis-thien-2-yl) methyl] azetidine- 3-one can be prepared by working as described in Example 75, starting with 4 g of 1- [bis (thien-2-yl) methyl] azetidin-3-ol, 2.6 ml of dimethyl sulfoxide, 7.7 ml of triethylamine, 7.7 ml of oxalyl chloride, and 100 ml of dichloromethane. chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 30 cm) with a mixture of cyclohexane and ethyl acetate (1/1 by volume). The obtained fractions are evaporated to dryness under reduced pressure (2.7 kPa). 3.2 g of 1- [bis (thien-2-yl) ethyl] azetidin-3-one are obtained in the form of cream-colored crystals melting at 70 ° C. 1- [Bis (thien-2-yl) methyl] azetidin-3-ol can be prepared by operating as described in Example 75, from 6 g of 1- [bis (thien-2-yl) methyl] amine, 2.5 ml of epibromohydrin, 2.6 g of sodium bicarbonate and 50 ml of ethanol. 4 g of 1- [bis (thien-2-yl) methyl] azetidin-3-ol are obtained in the form of beige crystals melting at 115 ° C. 1- [bis (thien-2-yl) methyl] amine can be prepared in the following manner: to a suspension cooled under an argon atmosphere at 10 ° C of thien-2-ylmagnesia bromide (prepared from 1.29 g. of magnesium and 3.22 ml of 2-bromothiophene in 75 ml of diethyl oxide), a solution of 5 ml of thien-2-ylcarbonitrile in 50 ml of diethyl oxide is drained off dropwise. After 1 hour and 30 minutes of reflux, the reaction medium is cooled to 5 ° C and then 20 ml of methanol are added dropwise, the suspension is filtered, the solid is washed with methanol. The filtrate obtained is a brown solution. 2.45 g of sodium borohydride, in several portions, is added to this solution under an argon atmosphere. The mixture is stirred at room temperature for 16 hours, then diluted with ethyl acetate and water is added slowlyThe organic phase is extracted, washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure (2.7 kPa) at 55 ° C. A brown oil is obtained which is subjected to chromatography on a column of silica gel (granulometry 0.2-0.063 mm, diameter 8 cm, height 25 cm) and eluted with a mixture of cyclohexane and ethyl acetate (90/10 then 85/15 in volumes). Fractions 21 to 30 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 11 g of 1- [bis (thien-2-yl) ethyl] amine are obtained in the form of a crystallized solid.

Example 82 Operating according to the mode of operation described in Example 1 from 0.47 g of 4-dimethylaminopyridine, 0.13 ml of methanesulfonyl chloride, 25 ml of dichloromethane and 0.48 g of 1- (bis-p-tolylmethyl) -3- [( methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol, after purification by chromatography and crystallization from diisopropyl oxide, 0.25 g of l- (bis-p-tolylmethyl) -3- [( Methylsul fonyl) (phenyl) methylene] -zetidine, in the form of a white solid [NMR spectrum in DMSO-d6, T = 300K, d in ppm (250 MHz): 2.23 (6H, s, 2 Ph-CH3) , 2.98 (3H, s, SCH3), 3.76 (2H, s, NCH2), 4.20 (2H, s, NCH2), 5.55 (1H, s, NCH), 7.10 (4H, d, J = 7Hz, 4 CH arom. .), 7.32 (4H, d, J = 7Hz, 4 CH arom.), 7.43 (5H, s, phenyl.}.]. 1- (bis-p-tolylmethyl) -3- [(methylsulfonyl) (phenyl) ) methyl- (RS)] azetidin-3-ol can be prepared according to the mode of operation described in Example 39, from 0.59 g of bromine (bis-p-tolyl) methane, 20 ml of acetonitrile, 0.3 g of carbonat or of potassium and 0.6 g of 3- [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol hydrochloride. The residue obtained is subjected to chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 4 cm, height 16 cm) with a mixture of cyclohexane / ethyl acetate (7/3 by volume). The fractions are concentrated to dryness under reduced pressure (2.7 kPa). 0.48 g of 1- (bis-p-tolylmethyl) -3- [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol are obtained in the form of a white solid. Bromine (di-p-tolyl) methane can be prepared according to the mode of operation described by BACHMANN W.E., J. Am. Chem. Soc, 2135, (1933). 3- [(Methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol hydrochloride can be prepared according to the mode of operation described in Example 39 from 7 g of 3- [(methylsulfonyl) (phenyl Methyl- (RS)] -1- (vinyloxycarbonyl) azetidin-3-ol, 35 ml of dioxane, 35 ml of a 6.2 N solution of hydrochloric acid in dioxane gave 5 g of 3- [-] hydrochloride. (methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol, in the form of a white solid, 3- [(Methylsulfonyl) (phenyl) methyl- (RS)] -1- (inyloxycarbonyl) azetidine- 3-ol can be prepared according to the mode of operation described in Example 38 (Method 1), starting from 10 g of l-benzhydryl-3- [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-. ol, 600 ml of dichloromethane and 2.52 ml of vinyl chloroformate The residue was subjected to chromatography on a column of silica gel (granulometry 0.06-0.2 mm, diameter 5.2 cm, height 36 cm) with a mixture of cyclohexane and ethyl acetate. ethyl (7/3 by volume) co Eluent The fractions are evaporated to dryness under reduced pressure (2.7 kPa). 7 g of 3- [(methylsulfonyl) (f niD.me.thyl- (RS)] - 1 - (inyloxycarbonyl) azetidin-3-ol in the form of a white solid.

To a solution of 0.77 g of (-) -! - [(4-chlorophenyl) (4-formylphenyl) methyl] -3- [(3,5-difluorophenyl). (Methylsulfonyl methylene.) Azetidine in 20 ml of Methanol at 0 ° C under argon, a solution of 30 mg of sodium borohydride in 2 ml of methanol is poured in. After stirring for 4 hours at 0 ° C, water is added and then extracted with dichloromethane. it is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, evaporated to dryness under reduced pressure (2.7 kPa) The white foam obtained is purified on a column of silica gel (granulometry 0.04-0.06 mm , diameter 3.2 cm, height 17 cm) with a mixture of cyclohexane and ethyl acetate (60/40 by volume) as eluent, after 1.5 ml absolute ethanol, 0.1 g of (+) -1- [ (4-chlorophenyl) (4-hydroxymethyl phenyl) methyl] -3- [(3,5-difluorophenyl) -24S (methylsulfonyl) methylene] azetidine, in the form of white crystals melting at 190 ° C, [a] 20D = + 4.2 ° (c = 0.5% in methanol.}. [NMR spectrum in DMSO-d6, T = 300K , d in ppm (300 MHz): 3.05 (3H, s, SCH3), 3.95 (2H, s, NCH2} , 4.22 (2H, s, NCH2), 4.48 (2H, d, J = 6Hz, CH20), 4.75 (1H, s, NCH), 5.15 (1H, t, J = 6Hz, OH), 7.20 (2H, m , 2CH arom.), 7.28 (2H, d, J = 7Hz, 2CH arom.), 7.40 (5H, m, 5 CH arom.), 7.50 (2H, d, J = 7Hz, 2CH aram ..)]. The (-) -1- [(4-chlorophenyl) (4-formylphenyl) methyl] -3- [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine can be prepared in the following manner: to a solution of 0.83 g of ( +) -! -. { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine in 5 ml of tetrahydrofuran, 3.32 ml of a 5 N hydrochloric acid solution are emptied, and then left stirring for 20 hours. Dichloromethane and water are added to the reaction medium and then an aqueous solution of 30% sodium hydroxide until a pH of 14 is obtained. The aqueous phase is extracted with dichloromethane, the organic phase is washed successively with water, with an aqueous solution Saturated with sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). 0.8 g of (-) -! - [(4-chlorophenyl) (4-formylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl}. Methylene] -zetidine are obtained in the form of a white foam The (+) -! - { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl] ethyl.}. -3- [(3,5-difluorophenyl) ( methylsulfonyl) methylene] azetidine can be obtained in the following manner: to a solution of 2.42 g of the mixture of two diastereomers 3-acetoxy-l-. {(4-chlorophenyl) [4- (1,3-dioxolan-2 -yl) phenyl] ethyl- (R *).} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (R *)] azetidine and 3-acetoxy-1 - (4-chlorophenyl) ) [4- (1, 3-dioxolan-2-yl) phenyl] methyl- (R *).} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl (S *)] azetidine in 25 ml of tetrahydrofuran under an argon atmosphere at 0 ° C, 0.93 g of 1,8-diazabicyclo [5-4-0] undec-7-ene is dropped dropwise After stirring for 1 hour and 30 minutes at 0 ° C, the reaction medium is diluted with ethyl acetate, washed with water and with a water solution It is saturated with sodium chloride. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The crude product is purified on a column of silica gel (granulometry 0.04-0.06 mm, diameter 4.8 cm, height 17.5 cm) with a mixture of cyclohexane and ethyl acetate (80/20 by volume) as eluent. 1.21 g of (+) -! - are obtained. { (4-chloro-phenyl). [4- (L "3-dioxolan-2-yl) phenyl] -methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) -methylene] azetidine, low The form of a yellow foam The mixture of do-s diastereoisomers 3-acetoxy-l-. {(4-chlorophenyl) [4- (1,3-dioxolan-2-yl) -phenyl] methyl- (R * ) 1-3- [(3, 5-difluorophenyl). (Methylsulfonyl) methyl- (R *)] azetidine and 3-acetoxy-l- { (4-chlorophenyl) [4- (1,3-dioxlan .2-yl) phenyl] methyl- (R *).} - 3 - [(3,5-di-fluorophenyl) (methylsulfonyl) ethyl- (S *)] -azetidine can be prepared as follows: a a solution of 1.08 g of 3,5-difluorobenzylmethylsulfone under an argon atmosphere cooled to -70 ° C, 3.27 ml of n-butyllithium is emptied dropwise, stirring for 1 hour at -70 ° C and then emptying dropwise a solution of 1.80 g of (+) -! - { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl.}. phenyl.} - methyl.} azetidine 3-one in 10 ml of tetrahydrofuran After stirring 3 hours at -70 ° C and 1 hour at -20 ° C, a solution of 0.74 ml of acetyl chloride in 10 ml of anhydrous diethyl dioxide at -20 ° C and stir 2 hours at -20 ° C. The reaction mixture is poured into water, the mixture is extracted with ethyl acetate, the organic phase is washed with water and with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness under reduced pressure. (2.7 kPa). 2.42 g of a mixture of two diastereoisomers of 3-acetoxy-1- are obtained. { (4-chlorophenyl) [- (? 3-dioxolan-2-yl) phenyl] methyl- (R *.}.]. 3 - [(3,5-difluorophenyl) (methylsulfonyl) ethyl (R *) ] azetidine and 3-acetoxy-l- { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl] methyl- (R *).} -3- [(3, 5-difluorophenyl) - (methylsulfonyl) methyl- (S *)] azetidine, in the form of a yellow oil. The (- * -.}. -! - { (4-chloro nyl) [4- (1, 3-dioxolan-2-yl) phenyl] ethyl.} Azetidin-3-one can be prepared from the The following is a solution of 1.38 g of (+) - 1 - {(4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl] methyl.} azetidin-3-ol in 20 ml of anhydrous dimethyl sulfoxide under an argon atmosphere, 2.24 ml of triethylamine are then emptied and then 1.65 g of a solution of the sulfur-trioxide-pyridine complex in 20 ml of anhydrous dimethyl sulfoxide are added dropwise after 1 hour. 15 minutes of stirring at room temperature, the reaction medium is poured onto ice, extracted with ethyl acetate, the organic phase is washed with water, with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, it is filtered and concentrated to dryness under reduced pressure (2.7 kPa) The oily residue obtained (1.31 g) is combined with another batch of the same crude compound (1.21 g) and purified together on a column of gel. lice (granulometry 0.04-0.06 mm, diameter 4.8 cm, height 18 cm) with a mixture of cyclohexane and ethyl acetate (80/20 by volume) as eluent. 1.87 g of (+) -! - are obtained. { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl] methyl} -azetidin-3-one, in the form of a yellow oil. [a] 20 365 nm = + 5.9 ° (c = 0.5; methanol } . The (+) -l-. { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl] methyl} azetidin-3-ol can be described according to the mode of operation described in Example 75, starting from 4.43 g of (+) -. { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl] methyl} amine, 40 ml of absolute ethanol, 1.25 ml of epibromohydrin, and 1.28 g of sodium bicarbonate. 1.66 g of (+) - 1 - are obtained. { (4-chlorophenyl) [4- (1, 3-diaxolan-2-yl) phenyl] methyl} azetidin-3-ol, in the form of a yellow oil. 25Q The (+) -. { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl] methyl} chiral amine, can be obtained as follows: to a suspension of 18.16 g of chiral (R *) - [(4-chlorophenyl) (4-formylphenyl) methyl] amine hydrochloride, in 1000 ml of toluene, 3.95 g. ml of ethylene glycol and 0.82 g of paratoluensulfonic acid monohydrate is added. After stirring for 20 hours at reflux temperature, the reaction medium is cooled, washed with a saturated aqueous solution of sodium bicarbonate, with water and with a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The obtained residue is purified on a column of silica gel (granulometry 0.04-0.06 mm, diameter 8.4 cm, height 21.5 cm) with a mixture of cyclohexane and ethyl acetate (30/70 by volume) as eluent, collecting fractions of 250 ml, fractions 23 to 30 are concentrated to dryness under reduced pressure (2.7 kPa). You get 1.39 g of (+) -. { (4-chlorophenyl) [4- (1, 3-dioxolan-2-yl) phenyl] -methyl} chiral amine, in the form of a yellow oil.

The chiral (R *) - [(4-chlorophenyl) (4-ylphenyl) methylmethylamine hydrochloride can be prepared in the following manner: to a solution of 51.4 g of diastereoisomer N-. { (4-chlorophenyl) [4- (diethoxymethyl) phenyl] ethyl- (R *)} - (R) -2-phenyl-glycinol in 660 ml of anhydrous dicylanum, empty 330 ml of methanol, cool the mixture with an ice bath, add 60.96 g of lead tetraacetate, stir for 5 minutes and then 1 liter of a pH 7 phosphate buffer is poured in. After stirring for 30 minutes at room temperature, the mixture is filtered, the aqueous phase is extracted with dichloromethane. The organic phase is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up with 1 liter of diethyl oxide and 1 liter of an aqueous 3 N hydrochloric acid solution is added, the mixture is stirred for 15 minutes at room temperature, the aqueous phase is separated, washed with ethyl acetate, then it is concentrated to dryness under reduced pressure (2.7 kPa). 18.16 g of chiral (R *) - [(4-chlorophenyl) (4-formylphenyl) -methyl] amine hydrochloride are obtained in the form of a white solid, N-. {(4-chlorophenyl) [ 4- (diethoxymethyl) phenyl] methyl- (R *).} - (R) -2-phenylglycinol can be prepared as follows: to a solution cooled to -70 ° C, under an argon atmosphere, of 87.7 g of 4-bromochlorobenzene, 286 ml of 1.6 M n-butyllithium in hexane are added dropwise and the mixture is stirred for 15 minutes at -70 [deg.] C. This solution is then added dropwise to the solution cooled to 0 [deg.] C. following: 30 g of (R) -N- [4- (diethoxymethyl) benzylidene] -2-phenylglycinol in 300 ml of diethyl oxide The mixture is stirred for 2 hours at 0 ° C and then poured into water. The organic material is washed with water, then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 71.5 g of a reddish oil are obtained which is purify on a c silica gel olumna (granulometry 0.04-0.06 mm, diameter 11 cm, height 45 cm) with a mixture of cyclohexane and ethyl acetate (85/15 by volume, then 80/20 and 75/25) as eluent, collecting fractions of 1 liter. Fractions 11 to 17 are concentrated to dryness under reduced pressure (2.7 Kpa). 39.85 g of a single diastereoisomer N { (4-chlorophenyl) [4- (diethoxymethyl) phenyl] methyl- (R *)} - (R) -2-phenylglycinol, in the form of a reddish-orange oil.

The (R) -N- [4- (diethoxymethyl) benzylidene] -2-phenylglycinol can be prepared in the following manner: to a white suspension of 24.7 g of (R) - (-) -2-phenylglycinol in 500 ml of toluene are poured 35.9 ml of 4- (diethoxymethyl) benzaldehyde. The cloudy yellow solution is heated to reflux for 6 hours 30 minutes, then it is stirred at room temperature for 20 hours. After concentration to dryness of the reaction medium under reduced pressure (2.7 kPa), 61.6 g of (R) -N- [4- (diethoxymethyl) benzylidene] -2-phenylglycinol are obtained, in the form of an oil yellow.

Example 84 Operating according to the mode of operation of Example 1, starting from 5.6 g of l- [bis (4-chlorophenyl) methyl] -3-. { [3- (N-tert-butyloxycarbonyl-1-N-methylamino) phenyl] (methylsul fonyl) methyl- (RS)} azetidin-3-ol, 100 ml of dichloromethane, 1.59 g of methanesulfonyl chloride and 4.5 g of 4-dimethylaminopridine. They are allowed to stir 3 hours at room temperature. The crude product obtained is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 4 cm and weight on silica of 250 g), eluting under a pressure of 0.5 bar of nitrogen with a mixture of ethyl acetate. Cyclohexane (30/70 by volume) and collecting 100 ml fractions. Fractions 12 to 18 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 3.2 g of l- [bis (4-chlorophenyl) methyl] -3- are obtained. { [3- (N-tert-butyloxycarbonyl-1-N-methylamino) phenyl] (methylsulfonyl) methylene} azetidine in the form of a white foam [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 1.30 (9H, s, OC (CH3) 3), 2.65 (3H, s, J = 6Hz, NCH3), 2.85 (3H, s, SCH3), 3.50 (2H, s, NCH2), 3.90 (2H, s, NCH2), 4.45 (1H, s, NCH), between 6.85 and 7.05 (8H, m, 8 CH arom.), 7.10 (4H, d, J = 7Hz, 4 CH arom.)]. 1- [bis (4-chlorophenyl) methyl] -3-. { [3- (N-tert-Butyloxycarbonyl-N-methylamino) phenyl] (methylsulfonyl) methyl- (RS)} azetidin-3-ol can be prepared according to the mode of operation described in Example 1 from 3.8 g of [3- (N-tert-butyloxycarbonyl-N-methylamino) benzylmethylsulfone, 50 ml of tetrahydrofuran, 9.5 ml of a solution of -butyl lithium 1.6 N in hexane, 3.82 g of l- [bis (4-chlorophenyl) methyl] azetidin-3-one. The crude product is purified by chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 4 c, weight on silica 250 g), eluting under a pressure of 0.5 bar of nitrogen with dichloromethane and then with a dichloromethane mixture. and ethanol (99/1 by volume) and collecting 500 ml fractions. Fractions 10 to 16 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 5.6 g of 1- [bis (4-chloropheni1) methyl] -3- are obtained. { [3- (N-tert-Butyloxycarbonyl-N-methylamino) phenyl] (methylsulfonyl) methyl- (RS)} azetidin-3-ol, in the form of a foam.

Example 85 2.7 g of 1- [bis (4-chlorophenyl) methyl] -3- are stirred for 20 hours. { [3- (N-tert-butyloxycarbonyl-N-methylamino) phenyl] (methylsul fonyl) methylene} -zetidine in 30 ml of dioxane and 30 ml of a 4.7 N hydrochloric dioxane solution. The reaction medium is evaporated to dryness under reduced pressure (2.7 kPa), taken up in 50 ml of water and 50 ml of ethyl acetate, it is stirred and neutralized with caution with a saturated aqueous solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulfate, treated with animal black and then concentrated under reduced pressure (2.7 kPa) to a volume of about 25 ml, then filtered, concentrated to dryness under reduced pressure. 1.3 g of 1- [bis (4-chlorophenyl) ethyl] -3 - [(3-methylaminophenyl) (ethylsulfonyl) ethylene] azetidine are obtained, in the form of white crystals which melt at 228 ° C [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 2.65 (3H, s, J = 6Hz, NCH3), 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), 5.85 (1H, q, J = 6Hz, NH), 6.55 (3H, m, 3 CH arom.), 7.15 (1H, t, J = 7Hz, CH arom.), 7.40 (4H, d, J = 7Hz, 4CH arom.), 7.50 (4H, m, 4CH arom.)].

Example 86 The procedure is as in Example 1, starting from 0.40 g of a mixture of two diastereoisomers l - [(4-chlorophenyl). (Thiazol-2-yl) ethyl- (RS)] -3- [(3, 5 -difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 0.10 ml of methanesulfonyl chloride and 0.37 g of 4-dimethylaminopyridine, is obtained after chromatography on a column of silica gel (granulometry 0.06- 0.200 mm, diameter 1.2 cm, height 20 cm), under a pressure of 1 bar of argon with a mixture of ethyl acetate and cyclohexane (40/60 by volume) as eluent and 20 ml fractions are collected0.13 g of (RS) -l - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3- [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine in the form of a pink solid [NMR spectrum in DMSO-d6, T = 300K, d in ppm (300 MHz): 3.05 (3H, s, SCH3), 4.05 (2H, s, NCH2), 4.35 (2H, m, NCH2 ), 5.25 (1H, s, NCH), 7.20 (2H, d, J = 8Hz, 2CH arom.), 7.35 (1H, T, J = 8Hz, CH arom.), 7.45 (2H, d, J = 7Hz , 2CH arom.), 7.50 (2H, d, J = 7Hz, 2CH arom.), 7.70 (1H, d, J = 2Hz, CH thiazole.), 7.75 (1H, d, J = 2Hz, CH thiazole) The mixture of two diastereoisomers l - [(4-chlorophenyl) (thiazol-2-yl) methyl- (RS)] - 3 - [(3,5-difluorophenyl) - (ethyl sulfonyl) ethyl- (RS)] azetidin-3-ol, can be prepared as follows: operating as in Example 72, starting from 1.01 g of (RS) -bromo (4-chlorophenyl) thiazol-2-ylmethane and 0.55 g of hydrochloride of (RS) ) -3- [(3, 5-difluorophenyl) (methylsulfonyl) methyl] azetidin-3-ol and after chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diam. etro 4.4 cm, height 38 cm), under a pressure of 0.5 bar of argon eluting with a mixture of ethyl acetate and cyclohexane (30/70 by volume then 40/60 from fraction 16) and collecting fractions of 60 ml, the fractions 21 to 35 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.40 g of the mixture of two diastereoisomers 1- [(4-chlorophenyl) (thiazol-2-yl) ethyl- (RS)] -3- [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS) are obtained. ] azetidin-3-ol, in the form of a whitish solid.

Example 87 To a solution of 0.32 g of l-. { (R *.} - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl.} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A and 5 mg of Sodium iodide in 10 ml of dichloromethane, 50 mm3 of pyrrolidine are added.After 20 hours of stirring at 20 ° C, 50 mm3 of pyrrolidine is added to the mixture, stirred for 8 hours and then 50 mm3 of pyrrolidine and stirred for 20 hours at 20 ° C. The reaction mixture is washed with water and then the organic phase is dried over magnesium sulfate, concentrated to dryness under vacuum (2.7 kPa) .The residue obtained is subjected to chromatography on a 2sa column of silica gel (granulometry 0.06-0.200 mm, diameter 1.2 cm, height 30 cm.) under a pressure of 0.1 baria of argon eluting with dichloromethane and then with a mixture of dichloromethane and methanol (97.5 / 2.5 by volume) and collecting fractions of 3 ml Fractions 12 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) 0.18 g of l-. {(R *) - (4-chlorophenyl) [A- (pyrrolidinylmethyl) phenyl] methyl.} - 3 - [(3,5-difluorofyl) - (methylsulfonyl) ethylene] -zetidine, form A isomer, in the form of a glanquecine foam [a] 20365 nm = -22.5 ° +/- 0.7 (c = 0.5%, dichloromethane) [2 H NMR spectrum (300 MHz, CDC13, d in ppm): 1.78 (mt: 4H) 2.51 (mt: 4H),; 2.81 (s: 3H); 3.58 (s: 2H); 3.84 (mt: 2H); 4.33 (mt: 2H); 4.50 (s: 1H); 6.84 (tt, J = 9 and 2.5 Hz: 1H); 6.98 (mt: 2H); from 7.20 to 7.40 (mt: 8H)]. The l-. { (R *.}. - [(4-chloromethyl) phenyl] (4-chlorophenyl) methyl.} - 3 - [(3,5-di fluorophenyl) - (methylsulfonyl) ethylene] zetidine, isomer form A, can be Prepare by operating in the following manner: to a solution of 28.0 g of the mixture of 2 diastereoisomers (forms A) l-. {(R *) - [(4-chloromethyl) phenyl] - (-chlorophenyl) methyl.}. -3- [(R) - (3, 5-difluorophenyl) (methylsulfonyl) methyl] azetidin-3-ol, and l- { (R *) - [(4-chloromethyl) phenyl] - (4-chlorophenyl) ) methyl.}. -3- [(S) - (3,5-difluorophen-ll (ethylsulfonyl) ethyl)] -azetidin-3-ol, 32 g of 4-dimethylaminopyridine, in 500 ml of dichloromethane, 12.4 are added ml of methanesulfonyl chloride After one hour of stirring at 10 ° C, and then one hour at 20 ° C, the reaction mixture was washed with 500 ml of water, the organic phase was dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) The residue was subjected to chromatography on a column of silica gel (granulometry 0.06-0 .200 mm, diameter 6 cm, height 30 cm) under a pressure of 0.2 bar of argon eluting with dichloromethane and collecting fractions of 250 ml. Fractions 9 to 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 6.3 g of l- are obtained. { (R *) - [4- (chloromethyl) phenyl} - (4-chlorophenyl) methyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, in the form of a white foam. The mixture of 2 diastereoisomers (forms A) l-. { (R *) - [4- (chloromethyl) phenyl] (-chlorophenyl) methyl]. 3 - [(R) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] -azetidin-3 -ol, and 1- { (R *) - [- (chloromethyl) phenyl] (4-chlorophenyl.) methyl.}. -3- [(S) - (3,5-difluorophenyl) (methylsulfonyl) ethyl.}.] azetidin-3-ol, can be prepared by operating as follows: to a solution of 0.20 g of a mixture of 2 diastereoisomers (forms A) l- { (R *) - (4-chlorophenyl) ) [4- (hydroxymethyl) phenyl] methyl.} - 3 - [(R) - (3,5-difluorophenyl) - (m-t-sulphonyl) methyl] azetidin-3-ol, and l-. {(R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl.} - 3 - [(S) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol, in 10 ml of dichloromethane, 60 mm.sup.3 of thionyl chloride are added.After 20 hours of stirring at 20 ° C, 5 ml of a saturated aqueous solution of sodium hydrogen carbonate is added to the reaction mixture, then it is stirred for 15 minutes. The mixture is decanted, the organic phase is washed with water, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is subjected to chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 1.0 cm, height 20 cm), under a pressure of 0.2 bar of argon eluting with a mixture of cyclohexane and ethyl acetate (75/25 by volume) and collecting fractions of 20 ml. Fractions 4 to 7 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.17 g of a mixture of 2 diastereoisomers (forms A) 1- are obtained. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(R) - (3, 5-difluorophenyl) (methylsulfonyl) ethyl)] azetidin-3-ol, and l-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(S) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol, in the form of a white foam. The mixture of 2 diastereoisomers (Forms A) 1 { (R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 [(R) - (3,5-di-fluorophenyl) (methylsulfonyl) ethyl)] -azetidin-3-ol and 1-. { (R *) - (4-chlorophenyl) [4- (hydroxymethyl). Phenol ethyl] -3 - [(S) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol, it can be prepared by operating in the following manner: to a solution maintained under an argon atmosphere and cooled to -30 ° C of 0.58 g of the mixture of 2 diastereomers (forms A) 3-acetoxy-1-. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3- [(R) - (3, 5-difluorophenyl) (methylsul fonyl) methyl)] azetidine and 3-acetoxy-1-. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(S) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidine, in 10 ml of anhydrous toluene, add 1.6 ml of a 1.5 M solution in toluene, of diisobutylaluminum hydride. After 15 minutes of stirring at -30 ° C, 1.0 ml of this same hydride solution is added again, then the mixture is allowed to reach 0 ° C. After 30 minutes of stirring, the stirred mixture is added with 3 ml of water and 6 ml of 1 N sodium hydroxide and then extracted with 25 ml of dichloromethane. The organic phase is washed with 5 ml of water, 5 ml of brine, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 1.2 cm, height 30 cm) under a pressure of 0.1 bar of argon eluting with a mixture of cyclohexane and ethyl acetate (50/50 in volume) and collecting fractions of 30 ml. Fractions 4 to 12 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.42 g of the mixture of 2 diastereoisomers are obtained (forms A) 1-. { (R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3- [(R) - (3, 5-difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol, and l-. { (R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3- [(S) - (3,5-difluorophenyl) (methylsul fonyl) methyl)] -azetidin-3-ol, in the form of a white lacquer.

The mixture of 2 diastereoisomers (forms A) 3-acetoxy-1-. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) -phenyl] methyl} -3- [(R) - (3,5-diplusphenyl) (methylsulfonyl) methyl)} azetidine, and 3-acetoxy-l-. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3- [(S) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidine can be prepared by operating as described in Example 40, starting with 1.0 g of (3,5-difluorobenzyl) methylsulfone, ml of tetrahydrofuran, 3 ml of a 1.6 N solution of n-butyl lithium in hexane, of 1.45 g of l-. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomer form A, and 0.43 ml acetyl chloride. 1.28 g of the mixture of 2 diastereoisomers (forms A) 3-acetoxy-1- is obtained. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3- [(R) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidine and 3-acetoxy-1-. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) -phenyl] methyl} -3- [(S) - (3,5-difluoro-phenyl) (methyl-sulfonyl) methyl)] azetidine, in the form of a beige foam. 1- [(R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomer form A, can be prepared by operating as described in Example 40, from 0.55 ml of oxalyl chloride, of 25 ml of dichloromethane, of 0.90 ml of dimethyl sulfoxide, of 1.75 g of l-. { (4-chlorophenyl) [4- (methoxycarbanyl) phenylmethyl} azetidin-3-ol and 2.70 ml of triethylamine. You get 1.45 g of the l-. { (R *) - (-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomer form A, in the form of a yellow foam. The l-. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl Jmethyl} azetidin-3-ol, isomer form A, can be prepared by operating according to the mode of operation described by KATRITZKY A.R. and collaborators, in J. Heterocycl. Chem. (1994), 271 from 2.0 g of methyl (+) -4- [(R *) -amino- (4-chlorophenyl) methyl] benzoate, of 30 ml of ethanol, 0.60 g of acid carbonate of sodium, and 0.60 ml of epibromohydrin. 1.76 g of 1- are obtained. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -azetidin-3-ol, isomer form A, in the form of a pasty solid. The methyl (+) -4- [(R *) -amino- (4-chlorophenyl) ethyl] benzoate can be prepared by operating in the following manner: to a solution of 9.2 g of 4- [(RS) -amino- Methyl (4-chlorophenyl) methyl] benzoate in 10 ml of methanol, 2.51 g of D- (-) - tartaric acid are added.

The solution is concentrated to dryness under reduced pressure (2.7 kPa). The cream colored foam obtained is dissolved in 50 ml of ethanol containing 5% water and the resulting solution is allowed to crystallize for 20 hours at 20 ° C. the crystals are filtered, washed with ethanol with 5% water, drained, then dried under reduced pressure (2.7 kPa). 3.4 g of white crystals are obtained which are referred to as "A crystals" [and which are preserved for the further preparation of the second (-) - 4- [(R *) -amino- (-chlorophenyl) methyl] benzoate enantiomer of methyl)]. The mother liquors are concentrated to dryness, and a white foam (8.1 g) is obtained, which is dissolved in 100 ml of ethyl acetate. To the obtained solution is added 50 ml of 1 N sodium hydroxide, stirred and decanted. The organic phase is washed with 50 ml of water, then dried over magnesium sulfate, and concentrated to dryness under reduced pressure (2.7 kPa). A yellow solid is obtained, which is dissolved in 100 ml of methanol. To the obtained solution is added 1.85 g of L- (+) - tartaric acid and the resulting solution is concentrated to dryness under reduced pressure (2.7 kPa). A creamy foam is obtained which, once dissolved in 27 ml of 4% ethanol of water, it is allowed to crystallize for 20 hours at 20 ° C. The crystals are filtered, washed with 4% ethanol of water, drained, then dried under reduced pressure (2.7 kPa). 3.4 g of methyl (+) -4- [(R *) -amino- (4-chlorophenyl) ethyl] benzoate L- (+) - tartrate crystals are obtained, which are recrystallized in 60 ml of ethanol with 5 ml of methanol. % of water. After drying, after drying, 2.78 g of white crystals are obtained, which are dissolved in 50 ml of ethyl acetate. The solution obtained is added with 100 ml of 1 N sodium hydroxide, stirred, decanted. The organic phase is washed with 50 ml of water, then dried over magnesium sulfate, and concentrated to dryness under reduced pressure (2.7 kPa). 2.1 g of methyl (+) -4- [(R *) -amino- (4-chlorophenyl) methyl] benzoate are obtained, in the form of a white solid. 4- [(RS) -amino- (4-chlorophenyl) methyl] benzoate d-methyl can be prepared by operating as follows: a suspension of 1.63 g of 4- [(RS) -phthalide- (4- methyl chlorofenyl) methyl] benzoate in 200 ml of methanol, 3.9 ml of hydrazine hydrate are added. After 5 hours of stirring at reflux temperature and then 20 hours at 20 ° C, the reaction mixture is filtered, the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is taken up with a mixture of 200 ml of water and 200 ml of ethyl acetate. After 15 minutes of stirring, the resulting suspension is filtered, the filtrate is decanted in a separating funnel, and the organic phase is washed with 50 ml of water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. (2.7 kPa). 8.4 g of methyl 4- [(RS) -amino- (4-chlorophenyl) methyl] benzoate are obtained, in the form of a pale yellow oil. The 4- [(RS) -phthalide- (4-chlorophenyl) methyl] benzoate methyl, can be prepared by operating as follows: to a solution of 11.6 g of 4- [(RS) -bromo- (4- methyl chlorofenyl) methyl] benzoate, in 70 ml of dimethylformamide, 12.6 g of potassium phthalimide are added. After 3 hours of stirring at reflux temperature, the reaction mixture is cooled to 20 ° C then 300 ml of ethyl acetate and 30 ml of water are added. After stirring, the mixture is decanted, the aqueous phase is extracted with 2 100 ml portions of ethyl acetate, the combined organic phases are washed with 2 portions of 400 ml of water, then dried over magnesium sulfate, and they are concentrated to dryness under reduced pressure (2.7 kPa). 16.3 g of methyl 4- [(RS) -phthalimido- (4-chlorophenyl) methyl] benzoate are obtained in the form of a yellow solid in paste form. Methyl 4- [(RS) -bromo- (4-chlorophenyl) methyl] benzoate can be prepared by operating as follows: to a solution of 17.4 g of 4 - [(RS) - (4-chlorophenyl) ( methyl hydroxy) methyl] benzoate in 200 ml of acetonitrile, 10.18 g of N, N'-carbonyldiimidazole, and 54.3 ml of allyl bromide are added. After 30 minutes of stirring at 20 ° C, the reaction mixture is brought to reflux for 2 hours, stirred for 20 hours at 20 ° C and concentrated almost to dryness under reduced pressure (2.7 kPa). The mixture, taken up with dichloromethane, was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 7 cm, height 30 cm) under a pressure of 0.5 bar of argon eluting with dichloromethane, and collecting fractions of 500 ml. The fractions 3 to 6 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 11.6 g of methyl 4- [(RS) -bromo- (4-chlorophenyl) methyl] benzoate are obtained, in the form of an oil which will be used as such in the next step. Methyl 4- [(RS) - (4-chlorophenyl) (hydroxy) methyl] benzoate can be prepared by operating as follows: a suspension of 2.75 g of methyl 4- (4-crolobenzoyl) benzoate, in 200 ml of methanol at 20 ° C, small fractions are slowly added (medium heating up to 50 ° C), 1.21 g of sodium borohydride. After stirring for 20 hours at 20 ° C, the reaction mixture is concentrated to a reduced volume and then 150 ml of dichloromethane are added and 100 ml of 0.5 N hydrochloric acid are stirred. After decanting, the organic phase is dried over sulphate of magnesium, concentrated to dryness under reduced pressure (2.7 kPa). 2.5 g of methyl 4- (RS) - (4-chlorophenyl) (hydroxy) methyl] benzoate are obtained, in the form of a colorless oil which crystallizes slowly at 20 ° C, and which will be used as it is in the next step . Methyl 4- (4-chlorobenzoyl) benzoate can be prepared by operating as follows: To a solution cooled to -22 ° C of 19.3 g of terephthalic acid chloride as monomethyl ester in 200 ml of tetrahydrofuran are added under Argon atmosphere 27.4 ml of tri-n-butylphosphine. After stirring for 20 minutes at -22 ° C, a solution of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of bromo-4-chlorobenzene, 2.43 g of magnesium and a glass of magnesium) is poured, maintaining this temperature. iodine in 100 ml of diethyl oxide at reflux). After stirring for 30 minutes at -22 ° C, 150 ml of 1 N hydrochloric acid are added slowly, the mixture is allowed to reach 20 ° C and then the medium is diluted with 200 ml of diethyl oxide. The white suspension obtained is filtered, the solid is washed with 2 portions of 50 ml of water, then with 2 portions of 50 ml of diethyl oxide. After draining and drying under reduced pressure (2.7 kPa), 16.2 g of methyl 4- (4-chlorobenzoyl) benzoate are obtained, in the form of a white solid melting at 170 ° C.

Example 88 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (methyl-sulfonyl) methylene] azetidine, isomer form A, 1.0 ml of dichloromethane, and 0.025 g of 3,3-dimethylpiperidine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm) eluting with 80 ml of dichloromethane then eluting with a mixture of dichloromethane and methanol (95/5 by volume) ), collecting fractions of 2.5 ml from the use of this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.040 g of 1- are obtained. { (R *.} - (4-chlorophenyl) [4- (3, 3-dimethyl-piperidin-1-yl-methyl) phenyl] methyl.} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, in the form of a white foam [XH NMR spectrum (300 MHZ, CDC13, d in ppm): 0.94 (s: 6H), 1.2 (mt: 2H), from 1.50 to 1.65 ( mt: 2H), 1.99 (s broad: 2H), 2.27 (mf: 2H), 2.81 (s: 3H), 3.36 (s, 2H), 3.85 (mt: 2H), 4.33 (mt: 2H), 4.49 ( s: 1H), 6.84 (tt, J = 8.5 and 2.5 Hz: 1H), 6.98 (mt: 2H), from 7.20 to 7.40 (mt: 8H)].

Example 89 The procedure is as described in Example 87, starting from 0.05 g of -. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3, 5-difluorophenyl). { methylsulfonyl) methylene] azetidine, isomer form A, methylsulfonylmethyl, 1.0 ml dichloromethane, and 0.025 g thiomorpholine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm) eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume) ), collecting fractions of 2.5 ml from the use of this eluent mixture. The fractions 3 to 8 are then concentrated to dryness under reduced pressure (2.7 kPa). 0.038 g of - are obtained. { (R *) - [(4-chlorophenyl)} - [-thiomorpholin-4-yl-methyl) phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene} azetidine, isomer form A, in the form of a white foam [XH NMR spectrum (300 MHz, CDC13, d in ppm.): from 2.60 to 2.75 (mt: 8H), 2.80 (s: 3H), 3.44 ( s: 2H), 3.84 (mt: 2H), 4.33 (mt: 2H), 4.50 (s: 1H), 6.83 (tt, J = 8.5 and 2.5 Hz: 1H), 6.97 (mt: 2H), 7.20 a 7.40 (mt: 8H)].

Example 90 The procedure is as described in Example 87, starting with 0.05 g of the -. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) ethyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 ml of dichloromethane and 0.025 g of N-cyclohexyl-N-ethyl-amine The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane , then with a mixture of dichloromethane and methanol (95/5 by volume), collecting fractions of 2.5 ml from the use of this eluent mixture.Fractions 5 to 8 are combined and then concentrated to dryness or reduced pressure ( 2.7 kPa), 0.022 g of. (R *.) - (4-chlorophenyl). [4- (N-ethyl-N-cyclohexyl-aminomethyl) phenyl] methyl] are obtained. -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, in the form of a white foam [XH NMR spectrum (300 MHz, CDC13 with addition of a few drops of CD3COOD d4, d in ppm): from 1.15 to 1.25 (mt: 2H); 1 .29 (t, J = 7.5 Hz: 3H); from 1.45 to 1.65 (mt: AE); 1.88 (mt: 2H); 2.17 (mt: 2H); 2.81 (s: 3H); 3.05 (q, J = 7.5 Hz: 2H); 3.27 (mt: 1H); 3.95 (mt: 2H); 4.18 (s: 2H); 4.40 (mt: 2H); 4.66 (s: 1H); 6. 82 (tt, J = 8.5 and 2.5 Hz: 1H); 7.00 (mt: 2H); from 7. 20 to 7.40 (mt: 4H); 7.41 (d, J = 8 Hz: 2H); 7.53 (d, J = 8 Hz: 2H)].

Example 91 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) ethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 ml of dichloromethane and 0.032 g of 4- (ethoxycarbonyl) piperazine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm) eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting fractions of 2.5 ml from the use of this eluent mixture. Fractions 2 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.021 g of 1- are obtained. { (R *.} - (4-chlorophenyl) - {3- [3- (4-ethoxycarbonylpiperazinyl) methyl] phenyl} methyl}.}.} -. 3 - [(3,5-difluorophenyl) (methylsulfonyl methylene] -azetidine, isomer form A, in the form of a white foam [1 H-NMR spectrum (400 MHz, CDC13,? in ppm): 1.25 (t, J = 7 Hz: 3H); 2.36 (mt: 4H); 2.80 (s: 3H); 3.44 (s: 2H); 3.46 (mt: 4H); 3.85 (mt: 2H); 4. 13 (q.J = 7 Hz: 2H); 4.34 (mt: 2H); 4.50 (s: 1H); 6. 83 (tt, J = 9 and 2.5 Hz: 1H); 6.98 (mt: 2H); from 7.20 to 7.40 (mt: 8H)].

Example 92 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl.} Methylene] azetidine, isomer form A, 1.0 ml dichloromethane, and 0.023 g of N-cyclopropyl-N-propyl-amine The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting fractions of 2.5 ml from the use of this eluent mixture Fractions 3 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 0.026 g of 1- (R *) - (4-chlorophenyl) [4-N-cyclopropyl-N-propyl-aminomethyl) phenyl] methyl} -3- [(3,5-di-fluoro-phenyl) (methylsulfonylmethylene-lazetidine, isomer form A, in the form of a white foam [XH-NMR spectrum (400 MHz, CDC13 with the addition of a few drops of CDaCOOD d4, d in ppm ): 0.34 (mt: 2H), 0.70 (mt: 2H), 0.91 (t, J = 7Hz: 3H), 1.08 mt: 1H); 1.76 (mt: 2H); 2.82 (s: 3H); 2.92 (d, J = 7hZ: 2H); 3.00 (mt: 2H); 3.90 (mt: 2H); 4.25 (s: 2H); 4.37 (mt: 2H); 4.59 (s: 1H); 6.83 (tt, J = 9 and 2.5 Hz: 1H); 7.00 (mt: 2H); from 7.20 to 7.45 (mt: 8H)]. Example 93 The procedure is as described in Example 87, but stirring the reaction mixture for 6 days at 20 ° C, starting with 0.05 g of l-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 ml of dichloromethane, 5 mg of sodium iodide and 0.02 g of diisopropylamine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume) collecting fractions of 2.5 ml from the use of this eluent mixture. Fractions 2 through 8 meet and 2-7-a then they are concentrated to dryness under reduced pressure (2.7 kPa.) 0.028 g of 1- ({(R *) - (4-chlorophenyl) [4- (diisopropylaminomethyl) phenyl] -methyl} -3 are obtained. - [(3, 5-di-lucomene) (methylsulfonyl) -methylene-benzetidine, isomer form A, in the form of a white foam [1 H-NMR spectrum (300 MHz, CDC13, d in ppm): 1.00 (mf: 12H); 2.80 (s: 3H), from 2.90 to 3.10 (mf: 2H), 3.58 (mt: 2H), 3.84 (mt: 2H), 4.33 (mt: 2H), 4.48 (s: 1H), 6.82 (tt, J = 8.5 and 2.5 Hz: 1H), 6.97 (mt: 2H), from 7.20 to 7.40 (mt: 8H)].

Example 94 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [- (chloromethyl) phenyl] - (4-chlorophenyl) ethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 ml dichloromethane and 0.027 g bis- (2-methoxyethyl) amine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 3 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.014 g of 1- are obtained. { (R *.} - (-chlorophenyl). {4- [bis- (2-methoxyethyl) aminomethyl] phenyl} methyl.}.].]. 3 - [(3,5-difluorophenyl) (methylsulfonyl methylene] azetidine, isomer form A, in the form of a white foam [NMR spectrum? E (300 MHz, CDC13, d in ppm): 2.70 (broad t, J = 5.5 Hz: 4H.); 2.81 ( s: 3H), 3.29 (s: 6H), 3.46 (broad t, J = 5.5 Hz: 4H), 3.65 (broad s: 2H), 3.85 (mt: 2H), 4.33 (mt: 2H), 4.49 (s) : 1H), 6.84 (tt, J = 9 and 2.5 Hz: 1H), 6.98 (mt: 2H), from 7.20 to 7.40 (mt: 8H)].

Example 95 The procedure is as described in Example 87, from 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) ethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 ml of dichloromethane and 0.020 g of di-n-propylamine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.025 g of l- are obtained. { (R *) - (4-chlorophenyl) [4- (di-n-propylaminomethyl). Phenylethyl 1-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, in the form of a white foam [XH NMR spectrum (400 MHz, CDC13, d in ppm): 0.85 (t, J = 7.5 Hz: 6H.).; 1.45 (mt: 4H); 2.34 (t, J = 7.5 Hz: 4H); 2.80 (s: 3H); 3.48 (s: 2H); 3.84 (mt: 2H); 4.33 (mt: 2H); 4.50 (s: 1H); 6.83 (tt, J = 9 and 2.5 Hz: 1H); 6.98 (mt: 2H) / from 7.20 to 7.40 (mt: 8H)].

Example 96 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (ethyl-sulfonyl) methylene] azetidine, isomer form A, 1.0 ml dichloromethane and 0.017 g piperidine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 5 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.035 g of 1- are obtained. { (R *) - (4-chlorophenyl) [4- (piperidin-1-yl-methyl) phenyl J ethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, in the form of a white foam [NMR spectrum 1E (300 MHz, CDC13, d in ppm): from 1.35 to 1.65 ( mt: 6H); 2.35 (mf: 4H); 2.80 (s: 3H); 3.41 (broad s: 2H); 3.84 (mt: 2H); 4.33 (mt: 2H); 4.50 (s: 1H); 6.84 (tt, J = 8.5 and 2.5 Hz: 1H); 6.98 (mt: 2H); from 7.20 to 7.40 (mt: 8H)].

Example 97 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 ml of dichloromethane and 0.020 g of N-methylpiperazine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 3 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.025 g of 1- are obtained. { (R *) - (4-chlorophenyl) [4- (4-methyl-piperazin-1-yl-methyl) phenyl] methyl} } -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, in the form of a white foam [1 H-NMR spectrum (300 MHz, CDC13, d in ppm): 2.28 (s: 3H ); from 2.30 to 2.60 (mf: 8H); 2.80 (s: 3H); 3.45 (s: 2H); 3.84 (mt: 2H); 4.33 (mt: 2H); 4.50 (s: 1H); 6.84 (tt, J = 8.5 and 2.5 Hz: 1H); 6.98 (mt: 2H); from 7.20 to 7.40 (mt: 8H)].

Example 98 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) ethylene] azetidine, isomer form A, 1.0 ml dichloromethane and 0.018 g morpholine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.022 g of l- are obtained. { (R *) - (4-chlorophenyl) [4- (morpholin-4-yl-methyl) phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, in the form of a white foam [1 H-NMR spectrum (300 MHz, CDC13, d in ppm): 2.41 (t, J = 5 Hz: 4H); 2.80 (s: 3H); 3.43 (s 2H); 3.69 (t, J = 5 Hz: 4H); 3.85 (mt: 2H); 4.33 (mt: 2H.);; 4.50 (s: 1H); 6.84 (tt, J = 8.5 and 2.5 Hz: 1H); 6.98 (mt: 2H); from 7.20 to 7.40 (mt: 8H)].

Example 99 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-di fluorophenyl) (methylsulfonyl) ethylene] azetidine, isomer form A, 1.0 ml dichloromethane and 0.020 ml D-prolinol. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.025 g of l- are obtained. { (R *.} - (4-chlorophenyl). [4- ((2R) -hydroxymethyl-pyrrolidin-1-yl-methyl-yl) -phenyl] -methyl] -3- [(3, 5-difluoro- phenyl.}. (methylsulfonyl) methylene] azetidine, isomer form A, in the form of a white foam [X-NMR spectrum (300 MHz, (CD3) 2SO d6 with the addition of a few drops of CD3COOD d4, d in ppm) : from 1.60 to 2.15 (mt: 4H); from 2.90 to 3.05 (mt: 1H); 2.98 (s: 3H); 3.13 (mt: 1H); 3.38 (mt: 1H); from 3.50 to 3.60 (mt: 1H); 3.56 (d, J = 5 Hz: 2H); 3.90 (mt: 2H); 4.04 (d, J = 13.5 Hz: 2H); 4.21 (mt: 2H); 4.40 (d, J = 13.5 Hz: 2H); 4.78 (s: 1H); 7.14 (mt: 2H); 7.27 (tt, J = 9 and 2.5 Hz: 1H); from 7.30 to 7.55 (mt: 8H)].

Example 100 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl-3 - [(.3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 ml of dichloromethane and 0.015 g of diethylamine. The crude product was subjected to chromatography on a column of silica gel (gravity 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. The fractions 4 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.025 g of l- are obtained. { (R *) - (4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl} -3- [(3,5-difluoro-phenyl) (methylsulfonyl) methylene] azetidine, isomer form A, in the form of a white foam [XH NMR spectrum (400 MHz, CDC13, d in ppm): 1.03 (t , J = 7 Hz: 6H); 2.50 (q, J = 7 Hz: 4H); 2.81 (s: 3H); 3.50 (s: 2H); 3.85 (mt: 2H); 4.34 (mt: 2H); 4.49 (s: 1H); 6.84 (tt, J = 9 and 2.5 Hz: 1H); 6.99 (mt: 2H); from 7.20 to 7.40 (mt: 8H)].

Example 101 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) etyl-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 ml of dichloromethane and 0.026 g of N- (hydroxyethyl) piperazine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 3 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.032 g of l- are obtained. { . { (R *) - (4-chlorophenyl). { 4- [4- (hydroxyethyl) -piperazin-1-yl-methyl] phenyl} methyl } } -3 - [(3,5-difluorophenyl) (methyl-sulfonyl) methylene] azetidine, isomer form A, in the form of a white foam [1E-NMR spectrum (300 MHz, CDC13, d in ppm): from 2.40 to 2.60 (mt: 8H); t, J = 5.5 Hz: 2H); 2.80 (s: 3H); 3.44 (s: 2H); 3.60 (t, J = 5.5 Hz: 2H); 3.84 (mt: 2H); 4.33 (mt: 2H); 4.50 (s: 1H); 6.84 (tt, J = 9 and 2.5 Hz: 1H); 6.98 (mt 2H); from 7.20 to 7.40 (mt: 8H)].

Example 102 The procedure is as described in Example 87, but stirring the reaction mixture for 4 days at 20 ° C, starting with 0.05 g of l-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (methylsulfanyl) methylene] azetidine, isomer form A, 1.0 ml of dichloromethane and 0.023 g of 2 (RS), 6 (RS) -dimethylpiperidine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 2 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.024 g of 1- are obtained. { (R *) - (4-chlorophenyl) [4- (2 (RS), 6 (RS) -dimethylpiperidin-1-yl-methyl) phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, mixture of isomers, form A, in the form of a white foam [1 H NMR spectrum (400 MHz, CDC13 with the addition of a few drops of CD3C00D d4, at a temperature of 353 ° K, d in ppm): from 1.20 to 1.45 (mt: 2H); 1.60 (d, J = 7 Hz: 6H); from 1.80 to 2.10 (mt: 4H); 2.80 (s: 3H); 3.17 (mt: 2H); 3.90 (mt: 2H); 4.34 (broad d, J = 16 Hz: 1H); 4.40 (mt: 2H); 4.43 (broad d, J = 16 Hz: 1H); 4.62 (s: 1H); 6.82 (tt, J = 9 and 2.5 Hz: 1H) 6.98 (mt: 2H); from 7.20 to 7.50 (mt: 8H)].

Example 103 The procedure is as described in Example 87, but stirring the reaction mixture for 4 days at 20 ° C, starting with 0.05 g of l-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 ml dichloromethane and 0.024 g piperazin-2-one. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.022 g of 1- are obtained. { (R *) - (4-chlorophenyl) [4- (piperazin-2-one-4-yl-methyl) phenyl] ethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, in the form of a white foam [NMR spectrum? K (400 MHz, CDC13, d in ppm): 2.62 (t, J = 5.5 Hz: 2H); 2.80 (s: 3H); 3.11 (s: 2H); 3.34 (mt: 2H); 3.51 (s: 2H); 3.85 (mt: 2H); 4.34 (mt: 2H); 4.51 (s: 1H); 5.76. (mf: 1H); 6.84 (broad t, JHF = 9 Hz: 1H); 6.98 (mt: 2H); from 7.20 to 7.40 (mt: 8H)]. Example 104 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) ethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 ml of dichloromethane and 0.020 g of L-prolinol. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 m, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.028 g of l- are obtained. { t CR *) - (4-chlorophenyl). { 4- [(2S) - (hydroxymethyl) pyrrolidin-1-yl-methyl] phenyl} methyl } } -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] -zetidine, isomer form A, in the form of a white foam [XH NMR spectrum (300 MHz, CDC13, d in ppm): 1.50 to 2.00 (mt: 4H); 2.24 (mt: 1H); 2.71 (mt: 1H); 2.80 (s: 3H); 2.93 (mt: 1H); 3.28 (d, J = 13.5 Hz: 1H); 3.45 (mt: 1H); 3.65 (d, J = 11 and 4 Hz: 1H); 3.84 (mt: 2H); 3.91 (d, J = 13.4 Hz: 1H); 4.33 (mt: 2H.);; 4.50 (s: 1H); 6.83 (tt, J = 8.5 and 2.5 Hz: 1H); 6.98 (mt: 2H); from 7.20 to 7.40 (mt: 8H)].

Example 105 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (methyl-sulfonyl) methylene] azetidine, isomer form A, 1.0 ml dichloromethane and 0.023 g (2S) - (methoxymethyl) pyrrolidine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume) f collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 2 to 6 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.037 g of 1- are obtained. { . { (R *) - (4-chlorophenyl). { 4- [(2S) - (methoxymethyl) pyrrolidin-1-yl-methyl] phenyl} methyl } } -3- [(3,5-difluorophenyl) - (methylsulfonyl) methylene] -zetidine, isomer form A, in the form of a white foam [XE NMR spectrum (300 MHz, CDC13, d in ppm): 1.66 ( mt: 2H), 1.90 (mt: 1H), 2.16 (mt: 1H), 2.68 (mt: 1H), 2.80 (s: 3H), 2.89 (mt: 1H), from 3.25 to 3.45 (mt: 4H); 3.31 (s: 3H), 3.84 (mt: 2H), 4.04 (d, J = 13.5 Hz: 1H), 4.33 (mt: 2H), 4.50 (s: 1H), 6.84 (tt, J = 8.5, and 2.5 Hz : 1H), 6.98 (mt: 2H), from 7.20 to 7.40 (mt: 8H)].

Example 106 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 ml of dichloromethane and 0.020 g of 2 (RS), 5 (RS) -dimethylpyrrolidine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. The fractions 3 to 6 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.024 g of 1- are obtained. { (R *) - (4-chlorophenyl) [4- (2 (RS), 5 (RS) -dimethylpyrrolidin-1-yl-methyl) phenyl] -methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl.}. -methylene] azetidine, mixture of isomers, form A, in the form of a white foam [1 H-NMR spectrum (400 MHz, CDC13 with the addition of some drops of CD3COOD d4, d in ppm): 1.68 (d, J = 7 Hz: 6H), from 2.00 to 2.15 (mt: 4H), 2.82 (s: 3H), 3.22 (mt: 2H), 3.92 (mt: 2H), 4.30 (s: 2H), 4.33 (mt: 1H), 4.45 (d, J = 16.5 and 3 Hz: 1H), 4.63 (s: 1H), 6.84 (tt, J = 8.5 and 2.5 Hz: 1H); ), 7.00 (mt: 2H), from 7.20 to 7.55 (mt: 8H)].

Example 107 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [(4-chloromethyl) phenyl] -4- (chlorophenyl) methyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, 1.0 ml of dichloromethane and 0.023 g of L-prolinamide. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 2 to 5 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.028 g of l- are obtained. { (R *) - (4-chlorophenyl) [4- ((2S) -carbamoylpyrrolidin-1-yl-methyl) phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl.} Methylene] azetidine, isomer form A, in the form of a white foam [H NMR spectrum (400 MHz, CDC13, d in ppm): 1.65 to 1.85 (mt: 2H); 1.92 (mt: 1H); from 2.15 to 2.35 (mt: 2H); 2.80 (s: 3H); 3.00 (mt: 1H); 3.16 (dd, J = 10 and 5.5 Hz: 1H); 3.41 (d, J = 13.5 Hz: 1H); 3.86 (mt: 2H); 3.89 (d, J = 13.5 Hz: 1H); 4.33 (mt: 2H); 4.51 (s: 1H); 5.23 (mt: IR "), 6.84 (tt, J = 9 and 2.5 Hz: 1H), 6.98 (mt: 2H), 7.17 (mf: 1H), 7.20 to 7.40 (mt: 8H)].

Example 108 The procedure is as described in Example 87, but stirring the reaction mixture for 4 days at 20 ° C, starting with 0.05 g of l-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (methylsulfanyl.} Ethylene] azetidine, isomer form A, 1.0 ml of dichloromethane and 0.021 g of diethanolamine The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting the 2.5 ml fractions from the use of this eluent mixture. Fractions 2 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.004 g of 1- are obtained. { (R *) - (4-chlorophenyl) [4- (dihydroxyethylamino) phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form A, in the form of a white foam [XH NMR spectrum (300 MHz, CDC13, d in ppm): 2.69 (t, J = 5.5 Hz: 4H); 2.80 (s: 3H); 3.61 (t, J = 5.5 Hz: 4H); 3.65 (s, 2H); 3.84 (mt: 2H); 4.33 (mt: 2H); 4. 50 (s: 1H); 6.83 (tt, J = 9 and 2.5 Hz: 1H); 6.98 (mt: 2H); from 7.20 to 7.40 (mt: 8H)].

Example 109 To a solution of 0.24 g of l-. { (R *) - [4- (chloromethyl] phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (tiisulfonyl) methylene] azetidine, isomer form A , in 5 ml of dicloromethane, 0.055 g of imidazole is added, After 3 hours of reflux, 5 mg of sodium iodide are added to the mixture, After 20 hours of stirring under reflux, the reaction mixture cool to 20 ° C, then chromatograph on a column of silica gel (granulometry 0.06-0.200 mm, diameter 1.0 cm, height 20 cm), eluting with 120 ml of unfractionated dichloromethane, and then with a dichloromethane mixture and methanol (98/2 and then 96/4 by volume), collecting 4 ml fractions Fractions 12 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa) 0.039 g of 1-. { (R *) - (4-chlorophenyl) [4- (imidazol-1-yl-methyl) phenyl] methyl.} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer A, in the form of a white foam.

Example 110 The procedure is as described in Example 87, starting with 0.05 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) m-ethyl-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, form B-5 -omer, 5 mg of sodium iodide, ml of dichloromethane and 0.190 g of pyrrolidine. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 1.5 cm, height 20 cm), under a pressure of 0.1 baria of argon eluting with dichloromethane, and then with a mixture of dichloromethane and methanol (95/5 by volume), and collecting the 25 ml fractions. Fractions 20 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.28 g of 1- are obtained. { (R *) - (4-chlorophenyl) [4- (pyrrolidin-1-yl-methyl) phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form B, in the form of a white foam. [a] 20365 nm = + 26.8 ° +/- Q.8 (c = 0.5%; dichloromethane.) [XH NMR spectrum (300 MHz, CDC13, d in ppm): 1.78 (mt: 4H); 2.50 ( mt: 4H), 2.80 (s: 3H), 3.57 (s: 2H), 3.84 (mt: 2H), 4.34 (mt: 2H), 4.50 (s: 1H), 6.84 (tt, J = 9, and 2.5 Hz : 1H), 6.98 (mt: 2H), 7.20 to 7.40 (mt: 8H)]. The l- { (R *) - [4- (chloromethyl.} Phenyl] - (4-chlorophenyl) methyl .3. [3, 5-difluorophenyl] - (methyl-sulfonyl.) Methylene] azetidine., Isomer form B, can be prepared by operating as described in Example 87, from 7.3 g of The mixture of 2 diastereoisomers (B-forms) l-. {(R *.} - [4- (chloromethyl) pheni 1-t.-clar.Q-phenyl}. methyl.}. -3 - [(R} - (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol and 1- { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl}. -3- [(S) - (3, 5-difluorophenyl) (methylsulfonyl.] Methyl)] -azetidin-3-ol, 8.2 g of 4-dimethylaminopyridine, 150 ml of dichloromethane, and 3.2 ml of methanesulfonyl chloride. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.2 bar of argon eluting with dichloromethane and collecting 100 ml fractions. Fractions 15 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 2.50 g of l- are obtained. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form B, in the form of a white foam.

The mixture of 2 diastereomers l-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(R) - (3, 5-difluorophenyl)} (methylsulfonyl.] Methyl)] azetidin-3-ol, and l-. {(R *) - [4- (chloromethyl). phenyl] - (4-chlorophenyl) methyl.} - 3 - [(S) - (3 5-di fluorophenyl) (methylsulfonyl) methyl) 3-azetidin-3-ol, can be prepared as described in Example 87, from 11.0 g of the mixture of 2 diastereoisomers l-. {(R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] ethyl] -3 - [(R) - (3, 5-difluoro-phenyl) (methylsulfonyl) methyl)] azetidin-3-ol and 1-. {(R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl.} - 3- [(S) - (3, 5-difluorophenyl) (methylsulfonyl) methyl].] Azetidin-3-ol, 250 ml of dichloromethane, and 3.1 ml of thionyl chloride The crude product was subjected to chromatography on a column of silica gel (granulometry 0.04-0.06 mm, diameter 3 cm, height 30 cm) under a pressure of 0.2 bar of argon eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting fractions of 50 ml The fractions 9 a 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 7.3 g of the mixture of 2 diastereoisomers (forms B) l- are obtained. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(R) - (3, 5-difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol, and l-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(S) - (3, 5-difluorophenyl) (mathylsulfonyl.] Methyl)] -azetidin-3-ol, in the form of a white foam. Mix. of 2 diastereoisomers (forms B) l-. { (R *) - (4-chlorophenyl) [4- (hydroxymethyl.] Phenyl] methyl.} - 3 - [(R) - (3,5-difluarophenyl) - (methylsulfonyl) ethyl)] - azetidin-3-ol, and 1- { (R *.}. - (4-chlorophenyl) [4- (hydroxymethyl) phenylmethyl] -3- [(R) - (3,5-difluorophenyl) ( methylsulfonyl) ethyl)] azetidin-3-ol, can be prepared as described in Example 87, from 18.0 g of the mixture of 2 diastereomers (B-forms) 3-acetoxy-1 - (R *} - (4-chlorophenyl). [4- (methoxycarbonyl) phenyl] methyl.}. -3- [(R) - (3,5-difluoro-phenyl) (methylsulfonyl) methyl)] azetidine and 3-acetoxy -l- { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] ethyl.}. -3- [(S) - (3,5-difluoraphenyl) (methylsul fonyl) methyl)] -azetidine, 150 ml of anhydrous toluene, and 100 ml of a 20% solution in toluene, of diisobutylaluminum hydride The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 3 cm, height 30 cm) under pressure of 0.1 bar of argon eluting with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 50 ml fractions. Fractions 15 to 30 meet and then go to Concentrate to dryness under reduced pressure (2.7 kPa). 11.0 g of the mixture of 2 diastereoisomers (forms B) l- are obtained. { (R *) - (4-chlorophenyl) [4- (hydroxymethyl) enyl] ethyl} -3- [(R) - (3, 5-difluorophenyl) (methylsulfonyl) methyl] azetidin-3-ol, and 1-. { (R *.} - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl.} - 3 - [(S) - (3,5-difluorophenyl) - (methylsulfonyl) methyl.} - 1 azetidine -3-ol, in the form of a white foam The mixture of 2 diastereomers (forms B) 3-acetoxy-l-. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) -phenyl] methyl} -3- [(R) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidine, and 3-acetoxy-1-. { (R *) - (4-chlorophenyl) [4- (pLetaxycarbonyl) phenyl] methyl} -3- [(R) - (3, 5-difluorophenyl) (methylsulfonyl) methyl)] azetidine, can be prepared as described in Example 40, from 11.2 g of (3,5-difluorobenzyl) methylsulfone, 350 ml of tetrahydrofuran, 34 ml of a 1.6 N solution of n-butyl lithium in hexane, of 11.2 g of l-. { (R *.} - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl.} Azetidin-3-one, isomer form B, and 5.5 ml of acetyl chloride The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 4 cm, height 40 cm), eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting fractions of 100 ml. The samples are combined and then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 21 g of an impure cream-colored foam that is subjected to chromatography on a silica gel column (granulometry 0.06-0.200 mm)., diameter 4 cm, height 40 cm), eluting with dichloromethane and collecting fractions of 100 ml, The fractions 11 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 20.0 g of the mixture of 2 diastereoisomers (B-forms) 3-acetoxy-1- are obtained. { (R *) - (4-chloro nyl). [4- (methoxycarbonyl) -phenyl] methyl.}. -3- [(R) - (3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine and 3- acetoxy-l- { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl.}. -3- [(S) - (3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine , in the form of a white foam, L-. {(R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl.} azetidin-3-one, isomer form B, can be prepared operating as described in Example 40, from 8.7 ml of oxalyl chloride, 350 ml of dichloromethane, 14.2 ml of dimethyl sulfoxide, 29.0 g of l-. {(R *) - (4-chlorophenyl) [ 4-'C.methoxycarb.Qnil): phenyl] methyl} azetidin-3-ol, isomer B, and 43 ml of triethylamine. The crude product is subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 4 cm, height 40 cm), eluting with dichloromethane and collecting fractions of 250 ml. Fractions 7 to 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 15.5 g of l- are obtained. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -azetidin-3-one, isomer form B, in the form of an orange oil. The l-. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-ol, isomer form B, can be prepared according to the mode of operation described by KATRITZKY A.R. and collaborators, in J. Heterocycl. Chem., (1994), 271, from 25.5 g of methyl (-) -4- [1- (R *) -amino-1- (4-chlorophenyl) methylbenzoate, 250 ml of ethanol, 7.9 g of sodium hydrogen carbonate, and 7.7 ml of epibromohydrin. 29 g of l- are obtained. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-ol, isomer form B, in the form of a yellow oil.

The methyl (-) -4- [(R *) -amino- (4-chlorophenyl) methyl] benzoate can be prepared by carrying out two successive recrystallizations 9 of white crystals (3.4 g) called "crystals A" of Example 87, in 68 ml of ethanol with 5% refluxing water The crystals obtained are filtered, drained and then dried under reduced pressure (2.7 kPa) to obtain 2.2 g of D - (-) - tartrate (- ) -4- [(R *) -amino- (4-chlorophenyl) methyl] benzoate methyl, in the form of white crystals, dissolved in 50 ml of ethyl acetate, 50 ml of hydroxide are added to the obtained solution of sodium 1 N, stirred and then decanted The organic phase is washed with 50 ml of water, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). -) -4- [(R *) -amino- (4-chlorophenyl) ethyl] benzoate methyl, in the form of a white solid. [A] 20 ° C, 365 nm = 58.1 ° +/- 1 (c = 0.5%).

Example 111 The procedure is as described in Example 110, but stirring the reaction mixture for 48 hours at 20 ° C, from 0.05 g of l-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) ethyl} -3- [(3, 5-difluorophenyl) (methylsulium-11-methylene] azetidine, isomer form B, 1.0 ml of dichloromethane and 0.030 ml of N-methylpiperazine The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-). 0.200 mm, diameter 8 mm, height 5 cm), eluting with 50 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting the 3 ml fractions from the use of this eluent mixture. fractions 4 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 0.025 g of 1- (R *) - (4-chlorophenyl) [4- (4-methyl-piperazine- 1-yl-methyl) phenyl] methyl.}. -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form B, in the form of a cream-colored foam [NMR spectrum? E (300 MHz, CDC13, d in ppm): 2.28 (s: 3H), 2.44 (mf: 8H), 2.80 (s: 3H), 3.45 (s: 2H), 3.85 (mt: 2H), 4.34 (mt: 2H); 4.50 (s: 1H); 6.84 (tt, J = 9 and 2.5 Hz: 1H); 6. 99 (mt: 2H); from 7.20 to 7.40 (mt: 8H)].

Example 112 The procedure is as described in Example 110, but stirring the reaction mixture for 48 hours at 20 ° C, from 0.05 g of l-. { (R *.} - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl] -3- [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, isomer form B 1.0 ml of dichloromethane and 0.030 ml of L-propinol The crude product was subjected to chromatography on a silica gel column. (granulometry 0.06-0.200 mm, diameter 8 mm, height cm), eluting with 50 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting the 3 ml fractions from the use of this eluent mixture. The fractions 2 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.025 g of l- are obtained. { . { (R *) - (4-chlorophenyl). { 4- [(2S) - (hydroxymethyl) pyrrolidin-1-yl-methyl] phenyl} methyl } } -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -azetidine, isomer form B, in the form of a cream-colored foam [1 H-NMR spectrum (300 MHz, CDC13, d in ppm): from 1.80 to 2.00 (mt: 1H); 2.72 (mt: IR "), 2.80 (s: 3H), 2.94 (mt: 1H), 3.28 (d, J = 13.5 Hz: 1H), 3.45 (mt: 1H), 3.65 (d, J = 10.5 and 3.5) Hz: 1H), 3.85 (mt: 2E), 3.92, C * J = 13.5 Hz: 1H), 4.34 (mt: 2H), 4.50 (s: 1H), 6.84 (tt, J = 8.5 and 2.5 Hz: 1H ), 6.98 (mt: 2H), from 7.15 to 7.40 (mt: 8H.}.].

Example 113 The procedure is as described in Example 110, but stirring the reaction mixture for 48 hours at 20 ° C, from 0.05 g of l-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl] -3- [(3,5-di fluorophenyl) - (methylsulfonyl) ethylene] azetidine, isomer form B, 1.0 ml of dichloromethane and 0.030 g of D-prolinol The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 5 cm), eluting with 50 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting the 3 ml fractions from the use of this eluent mixture. Fractions 2 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.029 g of l- are obtained. { . { (R *) - (4-chlorophenyl). { 4- [(2R) - (hydroxymethyl) pyrrolidin-1-yl-methyl] phenyl} methyl } } -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] -zetidine, isomer form B, in the form of a cream-colored foam [1 H-NMR spectrum (300 MHz, CDC13, d in ppm.): 1.50 to 2.00 (mt: 4H); 2.24 (mt: 1H); 2.71 (mt: IR "), 2.81 (s: 3H), 2.93 (mt: 1H), 3.28 (d, J = 13.5 Hz: 1H), 3.44 (t: unfolded, J = 10.5 and 2.5 Hz: IR"); 3.66 (dd, J = 10.5 and 3.5 Hz: 1H); 3.85 (mt: 2H); 3.92 (d, J = 13.5 Hz: IR "), 4.33 (mt: 2H), 4.50 (s: 1H), 6.84 (tt, J = 9 and 2.5 Hz: 1H), 6.98 (mt: 2H), 7.15 at 7.40 (mt: 8H)].

Example 114 The procedure is as described in Example 110, but stirring the reaction mixture for 48 hours at 20 ° C, from 0.05 g of l-. { (R *.}. - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl.} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form B, 1.0 ml dichloromethane and 0.030 ml morpholine The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height 5 cm.), eluting with 50 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting the 3 ml fractions from the use of this eluent mixture.Fractions 2 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.047 g of 1- { (R *) - (4-chlorophenyl) [4- (morpholin-1-yl-methyl) phenyl] methyl.}. -3- [(3,5-difluorophenyl). methylsulfonyl) methylene] azetidine, isomer form B, in the form of a white foam [1 H NMR spectrum (300 MHz, CDC13, d in ppm.): 2.40 (mt: 8H), 2.81 (s: 3H), 3.43 (s: 2H), 3.69 (mt: 4H), 3.84 (mt: 2H), 4.34 (mt: 2H), 4. 50 (s: 1H); 6.84 (tt, J = 8.5 and 2.5 Hz: 1H); 6.99 (mt: 2H); from 7.20 to 7.40 (mt: 8H)].

Example 115 The procedure is as described in Example 110, but stirring the reaction mixture for 48 hours at 20 ° C, from 0.05 g of l-. { (R *) - [4- (chloromethyl) phenyl] - (4-chloro phenyl) methyl} -3- [(3,5-difluorophenyl) - (methylsuifonyl) methylene] azetidine, isomer form B, 1.0 ml of dichloromethane and 0.030 ml of thiomorpholine The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 8 mm, height cm), eluting with 50 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting the 3 ml fractions from the use of this eluent mixture. Fractions 2 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa.) 0.047 g of 1- (R *) - (4-chlorophenyl) [4- (thiomorpholine-4 -yl-methyl) phenyl.} methyl.}. 3 - [(3,5-di fluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form B, in the form of a white foam [NMR spectrum 1H (300 MHz, CDC13, d in ppm.:.: From 2.60 to 2.75 (mt: 8H); 2.81 (s: 3H); 3.44 (s: 2H); 3.85 (mt: 2H); 4.34 (mt: 2H); 4.50 (s: 1H); 6.84 (tt, J = 8.5 and 2.5 Hz: 1H); 6.98 (mt: 2H); from 7.15 to 7.40 (mt: 8H)].

Example 116 The procedure is as described in Example 110, but stirring the reaction mixture for 48 hours at 20 ° C, starting with 0.200 g of l-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form B, 5.0 ml of dichloromethane and 0.120 g of piperazin-2-one. The crude product was subjected to chromatography on a column of silica gel (granulometry 0.06-0.200 mm, diameter 1.0 cm, height 10 cm), eluting with 50 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 in volume), collecting the 5 ml fractions from the use of this eluent mixture. Fractions 3 to 13 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.090 g of 1- are obtained. { (R *) - (4-chlorophenyl) [4- (piperazin-2-on-4-yl-methyl) phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl.} Methylene] azetidine, isomer form B, in the form of a white powder.

Example 117 The procedure is as described in Example 110, starting with 0.200 g of l-. { (R *) - [4- (chloromethyl) f nyl- (4-chlorophenyl) methyl.} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomer form B, 5.0 ml dichloromethane and 0.120 g of 3,3-dimethylpiperidine The crude product was subjected to chromatography on a silica gel column (granulometry 0.06-0.200 mm, diameter 1.0 mm, height 10 cm), eluting with 50 ml of dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume), collecting the 5 ml fractions from the use of this eluent mixture.Fractions 4 to 11 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). obtain 0.120 g of 1- {(R *) - (4-chlorophenyl) [4- (3, 3-dimethylpiperidinyl-methyl) -phenyl] methyl} -3- [(3,5-difluorophenyl) ( methylsulfonyl) -methylene] azetidine, isomer form B, in the form of a white powder.

Example 118 The procedure is as described in Example 110, stirring for 72 hours at 20 ° C, starting with 0.200 g of 1-. { (R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene-azetidine, isomer form B, 5.0 ml of dichloromethane and 0.080 g of imidazole. The reaction mixture was subjected directly to chromatography on a column of silica gel (granulometry 0.06-0.200 mu, diameter 1.0 cm, height 10 cm), eluting with 100 ml of unfractionated dichloromethane, then with a mixture of dichloromethane and methanol ( 98/2 and then 96/4 in volume), collecting the 5 ml fractions. Fractions 5 to 12 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.035 g of 1- are obtained. { (R *) - (4-chlorophenyl) [4- (imidazol-1-yl-methyl) phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] -azetidine, isomer form B, in the form of. a white powder, [aKuD -6.7 (c 0.5% dichloromethane) Example 119 To a suspension of 6.12 g of l- [bis (4-chlorophenyl) methyl] azetidin-3-one and 5.15 g of methyl 5- (methylsulfonylmethyl) thiophene-2-carboxylate in 200 ml of tetrahydrofuran, under an argon atmosphere, cooled to -70 ° C, 2.47 g of potassium tert-butylate are added. The mixture is stirred for 1 hour 30 minutes at a temperature close to -70 ° C, then 1.7 ml of methanesulfonyl chloride in solution in 8 ml of ethyl ether is added. After 1 hour of stirring at a temperature close to -70 ° C the mixture is allowed to reach room temperature, and then 80 ml of distilled water are added. The mixture is concentrated in a rotary evaporator to one third of its initial volume, and then extracted with 500 ml of dichloromethane. The organic phase is washed with 3 portions of 80 ml of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained was subjected to chromatography on a column of silica gel (granulometry 0.02-0.04 mm, diameter 7.5 cm, height 35 cm) eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (70 / 30 in volume) and collecting fractions of 40 ml. Fractions 19 to 29 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.6 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (2-methoxycarbonylthien-5-yl) ethylene] azetidine is obtained in the form of a cream colored foam [NMR spectrum 1H (400 MHz, CDC13, d in ppm): 2.91 (s: 3H); 3.88 (s: 3H); 4.08 (mt: 2H); 4.37 (mt: 2H); 4.53 (s: 1H); from 7.25 to 7.45 (mt: 9H); 7.71 (d, J = 3.5 Hz: 1H)]. Fractions 34 to 48 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 2.6 g of l- [bis (4-chlorophenyl) methyl] -3-hydroxy-3- [(methylsulfonyl) (2-methoxycarbonylthien-5-yl) methyl] azetidine- (RS) are obtained in the form of a colored powder cream [2H NMR Spectrum (400 MHz, CDC13, d in ppm): 2.87 (s: 3H); 2.89 (d, J = 8 Hz: IR "), 2.96 (d, J = 8 Hz: 1H), 3.21 (d, J = 8 Hz: 1H), 3.76 (d, J = 8 Hz: 1H), 3.82 (s: 3H), 4.55 (s: 1H), 4.86 (s: 1H), 6.86 (s: IR "); from 7.35 to 7.45 (mt: 9H); 7.73 (d, J = 4 Hz: 1H)]. The methyl 5- (methylsulfonylmethyl) thiophene-2-carboxylate can be prepared as follows: to a solution of 16 g of methyl 5-bromomethyl-thiophene-2-carboxylate in 150 ml of tetrahydrofuran are added, at room temperature , 6.94 g of sodium methansulfinate. The suspension is stirred at reflux for 2 hours and 30 minutes, and after stirring again with 50 ml of ethanol, it is stirred again for 3 hours at reflux. The mixture is concentrated to dryness under reduced pressure (2.7 kPa) and 150 ml of distilled water are added to the obtained residue, and then it is extracted with 2 portions of 300 ml of ethyl acetate.The organic phase is washed successively with 100 ml of distilled water and 2 portions of 50 ml of saturated aqueous sodium chloride solution, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). (Methylsulfonylmethyl) thiophene-2-carboxylic acid methyl ester in the form of a yellow solid that melts at 133 ° C [NMR spectrum? E (400 MHz, (CD3) 2SO d6, at a temperature of 373K, d in ppm): 3.05 (s: 3H); 4.22 (mt: 2H); 4.40 (mt: 2H); 4.98 (broad s: 1H); 7.30 (d, J = 3.5 Hz: 1H); 7.39 (d, J = 8 Hz: 4H); 7.50 (d, J = 8 Hz: 4H); 7.66 (d, J = 3.5 Hz: 1H)]. Methyl 5-bromomethyl-thiophene-2-carboxylate can be prepared according to Curtin M. L., Davidsen, S.K., Heyman H.R., Garland R.B., Sheppard G.S., J. Med. Chem .; 1998, 41 (1), 74-95.

Example 120 To a solution of 163.5 mg of 1- [bis (4-chlorophenyl) methyl] -3- [(methylsulfonyl) (2-hydroxycarbonylthien-5-illmetilej?] Azetidine hydrochloride in 3 ml of dichloromethane, at room temperature, add 47 μl of N, N'-diisopropylcarbodiimide, 3.66 mg of 4-dimethylaminopyridine and 60 μl of isobutylamine The mixture was stirred for 18 hours at room temperature, and then subjected to chromatography on a silica gel column (0.04 granulometry). -0.06 mm), eluting with a mixture of dichloromethane and ethyl acetate (90/10 by volume) This gives 60 mg of 1- [bis (4-chlorophenyl) methyl] -3- [(2-isobutylaminoca -rbonylthien-S -yl) (methylsulfonyl) -methylene] azetidine in the form of a colorless lacquer [H NMR spectrum (400 MHz, CDC13, d in ppm): 0.97 (d, J = 7 Hz: 6H); 1.88 (mt: 1H), 2.90 (s: 3H), 3.25 (t, J = 7 Hz: 2H), 4.08 (mt: 2H), 4.36 (mt: 2H), 4.52 (s: 1H), 4.56 (broad t , J = 7 Hz: 1H), from 7.20 to 7.40 (mt: 10H)].

The l- [bis (4-chlorophenyl) methyl] -3- [(methylsulfonyl) (2-hydroxy-carbonylthien-5-yl.) Methylene-azetidine hydrochloride can be prepared in the following manner: g of 1- [bis (4-chlorophenyl) methyl] -3- [(methylsulfonyl) (2-methoxycarbonylthien-5-yl) methylene] -zetidine in 250 ml of acetic acid, at room temperature, 250 ml are added The mixture is stirred for 38 hours at a temperature of 50 ° C, and then it is concentrated to dryness under reduced pressure (2.7 kPa). To the residue is added three times 250 ml of toluene and concentrated to dryness under reduced pressure (2.7 kPa) After trituration of the residue in 400 ml of ethyl ether, 14.2 g of 1- [bis (4-chloro-phenyl) methyl] -3- [(methylsulfonyl) (2- hydroxycarbonylthien-5-yl) -methylene] azetidine in the form of a beige powder.

Example 121 To a solution of 0.92 g of l- [bis (4-chlorophenyl) methyl] -azetidin-3-one and 0.75 g of [(3-methoxycarbonylphenyl) methyl] methylsulfone in 30 ml of tetrahydrofuran, under an argon atmosphere, cooled to -70 ° C, 0.37 g of potassium tert-butylate was added and stirred for 2 hours at -70 ° C. 10 ml of a 0.1 N hydrochloric acid solution are added immediately and the mixture is allowed to reach room temperature. After adding 50 ml of ethyl acetate, the reaction mixture is decanted, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is subjected to chromatography on a column of silica gel (granulometry 0.02-0.06 mm, diameter 3 cm, height 50 cm) eluting under a pressure of 0.8 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (70/30 in volume) and collecting fractions of 120 ml, Fractions 11 to 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 10 ml of isopropyl ether and 30 ml of pentane. 0.30 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3-methoxycarbonyl phenyl) - (methylsulfonyl) methyl- (RS) 1 azet idin-3-ol are thus obtained in the form of a white solid [XE NMR spectrum (400 MHz, CDC13, d in ppm): 2.73 (s: 3H); 3.05 (AB, J - 9 Hz: 2H); 3.27 (d, J = 9 Hz: 1H); 3.63 (s: 1H); 3.79 (d, J = 9 Hz: 1H); 3.95 (s: 3H); 4.32 (s: 1H); 4.59 (s: 1H); from 7.15 to 7.35 (mt: 8H); 7.51 (t, J = 8 Hz: 1H); 7.94 (broad d, J = 8 Hz: IR "), 8.10 (broad d, J = 8 Hz: 1H), 8.32 (broad s: 1H)].

Example 122 By operating according to the mode of operation of Example 1 starting from 0.66 g of methyl- (pyridin-4-yl-methyl) sulfone and 1.18 g of l- [bis (4-chlorophenyl) methyl] -azetidin-3-one, obtained after purification on a column of silica gel (particle size 0.20-0.06 mm, diameter 3 cm, height 50 cm) under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (70/30 by volume) as eluent and collecting 120 ml fractions, 0.20 g of a white solid. This is collected with 20 ml of diisopropyl oxide. After filtration, drying and drying, 0.16 g of 1- [bis (4-chlorophenyl) methyl] -3- [(methylsul fonyl) (pyridin-4-yl) methyl- (RS)] -azetidin-3 are obtained. -ol [XH NMR spectrum (400 MHz, CDC13, d in ppm): 2.76 (s: 3H); 3.03 (AB, J = 9 Hz: 2H); 3.27 (d, J = 9 Hz: 1H); 3.53 (s: 1H); 3.83 (d, J = 9 Hz: 1H); 4.32 (s: 1H); 4.51 (s: 1E); from 7.20 to 7.30 (mt: 8H); 7.63 (d, J = 6 Hz: 2H); 8.68 (d, j = 6 Hz: 2H)].

Methyl- (pyridin-4-yl-methyl) sulfone can be prepared according to the reference JP43002711.

Example 123 By operating according to the mode of operation of Example 1 starting from 0.47 g of methyl (pyridin-3-yl-methyl) sulfone and 0.83 g of l- [bis (4-chlorophenyl) methyl] -azetidin-3-one, after purification on a column of silica gel (particle size 0.20-0.06 mm, diameter 3 cm, height 50 cm) under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (70/30 by volume) as eluent and collecting fractions of 120 ml, 0.50 g of a white solid. This is collected with 30 ml of diisopropyl oxide. After filtration, drying and drying, 0.40 g of 1- [bis (4-chlorophenyl) ethyl] -3 - [(methylsulfonyl) (pyridin-3-yl) methyl- (RS)] -azetidin-3 are obtained. ol [1E NMR spectrum (300 MHz, CDC13, d in ppm): 2.77 (s: 3H); 3.03 (AB, J = 9 Hz: 2H); 3.28 (d, J = 9 Hz: 1H); 3.66 (s: 1H); 3.83 (d, J = 9 Hz: 1H); 4.33 (s: 1H); 4.55 (s: 1H); from 7.20 to 7.30 (mt: 8H); 7.37 (dd, J = 8 and 5 Hz: 1H); 8.16 (dt, J = 8 and 2 Hz: 1H); 8.68 (dd, J = 5 and 1.5 Hz: 1H); 8.83 (d, J = 2 Hz: 1H)]. Methyl- (pyridin-3-yl-methyl) sulfone can be prepared according to the reference JP43002711.

Example 124 To a suspension of 150 mg of 3- (. {L- [bis (4-chlorophenyl) methyl] -azetidin-3-ylidene} -metanesulfonyl-methyl) enzoic acid activated on TFP resin (165 μM) in 3 ml of dichloromethane, pre-watered 90 minutes at a temperature close to 20 ° C, 0.0388 ml of N- (3-aminopropyl) orfoline is added at the same temperature. The suspension is stirred at a temperature close to 20 ° C for 22 hours, then filtered on sintered glass. The solid residue is collected with 2 1.5 ml portions of dichloromethane. The filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. 60 mg of 3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidi-3-ylidene} - methanesulfonylmethyl) N- (3-morpholin-4-yl-propyl) are thus obtained. ) benzamide in the form of a pale yellow foam.

The 3- [. { l- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} -metanesulfonyl-methyl) N- (3-morpholin-4-yl-propyl) benzamide can also be prepared in the following manner: to a solution of 300 mg of 3- (. {1- [bis- (4- chlorofenyl) methyl] -azetidin-3-ylidene.} - methanesulfonyl-methyl) benzoic acid in 10 ml of anhydrous dichloromethane (on calcium chloride) and 5 ml of dimethylformamide, under an inert atmosphere of nitrogen, at a temperature close to 20 ° C C, 0.083 ml of N- (3-a-inopropyl) morpholine, 110 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 5 mg of 4-dimethylaminopyridine are successively added. The solution obtained is stirred at a temperature close to 20 ° C for approximately 22 hours, then it is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. The solid residue is taken up in 25 ml of dichloromethane, washed with 2 portions of 20 ml of a saturated aqueous solution of sodium bicarbonate. After decanting, the organic phase is dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. 400 mg of a yellow oil is obtained in this way, which is purified by chromatography under nitrogen pressure (0.8 bar) on 60 ml of silica (0.040-0.63 mm) contained in a 2.2 cm diameter column eluting with a methanol mixture -dichloromethane (2-98 in volume). The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. 130 mg of 3- (. {1-l- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene}. Methanesulfonyl-methyl) N- (3-morpholin-4-yl) are thus obtained. -propyl) -benzamide in the form of a white crystalline powder [1 H-NMR spectrum (300 MHz, (CD3) 2 SO d6, d in ppm): 1.68 (mt: 2H); from 2.25 to 2.40 (mt: 6H); 2.97 (s, 3H); from 3.20 to 3.35 (mt: 2H); 3.57 (t, J = 4.5 Hz: 4H); 3.81 (mt: 2H); 4.22 (mt: 2H); 4.79 (s: IR "), 7.36 (d, J = 8.5 Hz: 4H), 7.46 (d, J = 8.5 Hz: 4H), 7.50 to 7.60 (mt: 2H), 7.83 (s broad: 1H); 7.86 (broad d, J = 8 Hz: 1H), 8.53 (t, J = 5.5 Hz: 1H)].

Example 125 The operation is carried out under the conditions described in Example 124 starting from 150 mg of 3- (. {1-l- [bis- (4-chlorophenyl) methyl] -zetidin-3-ylidene} -metan-sulfonylmethyl) benzoic acid activated on TFP resin (165 μM) and 0.033 ml of N, N-dimethyl-1,3-propanediamine. Thus, 52 mg of 3- (. {1- [bis- (4-cyclophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) N- (3-dimethylamino-propyl) - are obtained. benzamide in the form of a white powder [1 H-NMR spectrum (400 MHz, (CD3) 2 SO d6, d in ppm): 1.65 (mt: 2H); 2.18 (s: 6H); from 2.20 to 2.35 (mt: 2H); 2.98 (.s: 3H); from 3.25 to 3.45 (mt: 2H); 3.82 (mt: 2H); 4.23 (mt: 2H); 4.80 (s: 1H); 7.36 (d, J = 8.5 Hz: 4H); 7.46 (d, J = 8.5 Hz: 4H); from 7.50 to 7.60 (mt: 2H); 7.83 (broad s: 1H); 7.86 (broad d, J = 8 Hz: 1H); 8.57 (t, J = 5.5 Hz: 1H)].

Example 126 The operation is carried out under the conditions described in Example 124 starting from 150 mg of 3- (. {1-l- [Bis- (4-chlorophenyl) methyl] -zetidin-3-ylidene} -metan-sulfonylmethyl) benzoic acid activated on TFP resin (165 μM) and 0.0333 ml of 1- (aminoethyl) pyrrolidine. 39 mg of 3- (. {1- [bis- (4-chloro-phenyl) methyl] -azetidin-3-ylidene} - methanesulfonylmethyl) N- (2-pyrrolidin-1-yl) are thus obtained. ethyl) benzamide in the form of a pale yellow powder [1 H NMR spectrum (300 MHz, (CD3) 2 SO d6 with the addition of a few drops of CD4COOD d4, d in ppm): 1.80 to 2.00 (mt: 4H); 2.97 (s: 3H); 3.20 (mt: 6H); 3.57 (t, J = 6.5 Hz: 2H); 3.80 (mt: 2H); 4.23 (mt: 2H); 4.77 (s: 1H); 7.35 (d, J = 8.5 Hz: 4H); 7.45 (d, J = 8.5 Hz: 4H); from 7.50 to 7.65 (mt: 2H); 7.87 (broad s: 1H); 7.90 (broad d, J = 7.5 Hz: 1H)].

Example 127 The operation is carried out under the conditions described in Example 124 starting from 150 mg of activated 3- (. {L- [bis- (-chlorophenyl) methyl] -azetidin-3-ylidene} -metansul-phenylmethyl) -benzoic acid TFP resin (165 μM) and 0.033 ml of 1- (dimethylamino) 2-propylamine. 49 mg of 3- (. {1- [bis- (4-chloro-phenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) N- (2-dimethylamino-1-) are thus obtained. methyl-ethyl) benzamide in the form of a white powder [NMR spectrum aH (400 MHz, (CD3) 2SO d6, d in ppm): 1.13 (d, J = 6.5 Hz: 3H); from 2.10 to 2.25 (mt: 1H); 2.15 (s: 6H); 2.38 (dd, J = 13 and 8 Hz: 1H); 2.98 (s: 3H); 3.80 (mt: 2H); 4.14 (mt: 1H); 4.23 (mt: 2H); 4.79 (s: 1H); 7.36 (d, J = 8 Hz: 4H); from 7.45 to 7.60 (mt: 2H); 7.46 (d, J = 8 Hz: 4H); 7.83 (broad s: 1H); 7.87 (broad d, J = 8 Hz: 1H); 8.16 (broad d, J = 8 Hz: 1H)].

Example 128 The operation is carried out under the conditions described in Example 124 starting from 150 mg of 3- (. {1-l- [Bis- (4-chlorophenyl) methyl] -6-azetidin-3-ylidene.} - methanesulfonylmethyl) benzoic acid activated on TFP resin (165 μM) and 0.026 ml of piperidine. In this way, 56 mg of 3- (. {- 1- (bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} -metanesulfonyl-methyl) N-piperidin-1-yl-benzamide is obtained. the shape of a white powder [NMR spectrum? E (400 MHz, (CD3) SO d6, d in ppm): from 1.45 to 1.70 (mt: 6H); from 2.90 to 3.05 (mt: 2H); 2.98 (s: 3H); 3.19 (mf: 1H); 3.57 (mf: 1H); 3.85 (mt: 2H); 4.23 (mt: 2H); 4.80 (s: 1H); from 7.30 to 7.55 (mt: 12H)].

Example 129 The operation is carried out under the conditions described in Example 124 starting from 150 mg of 3- (. {1 - [bis- (4-chloro-phenyl) -methyl] -zetidin-3-ylidene} -metanesulfonyl-methyl) Activated benzoic on TFP resin (165 μM) and 0.0265 ml of diisobutylamine. 46 mg of 3- (. {1- [bis- (-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonylmethyl) N-isobutyl-benzamide is obtained in the form of a white powder [ 1 H NMR spectrum (400 MHz, (CD3) 2 SO d6, d in ppm): 0.89 (d, J = 7 Hz: 6H); 1.85 (mt: 1H); 2.98 (s: 3H); 3.09 (t, J = 6.5 Hz: 2H); 3.82 (mt: 2H); 4.23 (mt: 2H); 4.79 (s: 1H); 7.36 (d, J = 8.5 Hz: 4H); 7.46 (d, J = 8.5 Hz: 4H); from 7.50 to 7.60 (mt: 2H); 7.84 (broad s: 1H); 7.88 (broad d, J = 8 Hz: 1H); 8.51 (t, J = 6 Hz: 1H)].

Example 130 It operates under the conditions described in Example 124 from 150 mg of 3- (. {L- [bis- (4-chlorophenyl) ethyl] -azetidin-3-ylidene} -metanesulfonyl-methyl) benzoic acid activated on resin TFP (165 μM) and 0.0316 ml of N- (3-aminopropyl) imidazole. Thus, 54 mg of 3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) N- (3-imidazol-1-yl) are obtained. -propyl) benzamide in the form of a yellow foam [XH NMR spectrum (400 MHz, (CD3) 2 SO d6, d in ppm): 1.97 (mt: 2H); 2.98 (s: 3H); 3.25 (mt: 2H); 3.81 (mt: 2H); 4.02 (t, J = 7 Hz: 2H); 4.23 (mt: 2H); 4.79 (s: 1H); from 6.85 to 6.95 (mt: 2H); 7.36 (d, J = 8.5 Hz: 4H); 7.46 (d, J = 8.5 Hz: 4H); from 7.50 to 7.60 (mt: 2H); 7.84 (broad s: IR "), 7.88 (broad d, J = 8 Hz: 1H), 8.56 (t, J = 5.5 Hz: 1H)].

Example 131 The operation is carried out under the conditions described in Example 124 starting from 150 mg of 3- (. {1-l- [Bis- (4-chlorophenyl) methyl] -zetidin-3-ylidene} -metanesulfonyl-methyl) benzoic acid activated on TFP resin (165 μM) and 0.030 ml of N, N- (dimethyl) ethylenediamine. Thus, 53 mg of 3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) N- (2-dimethyl-amino-ethyl) are obtained. ) benzamide in the form of an ocher foam [XH NMR spectrum (400 MHz, (CD3) 2S0 d6, d in ppm): 2.18 (2s: 6H); from 2.35 to 2.45 (mt: 2H); 2.98 (s: 3H); from 3.25 to 3.50 (mt: 2H); 3.81 (mt: 2H); 4.23 (mt: 2H); 4.79 (s: 1H); 7.36 (d, J = 8 Hz: 4H); 7.46 (d, J = 8 Hz: 4H); from 7.45 to 7.60 (mt: 2H); 7.83 (broad s: 1H); 7.86 (broad d, J = 8 Hz: 1H); 8.43 (t, J = 6.5 Hz: 1H)].

Example 132 The operation is carried out under the conditions described in Example 124 starting from 150 mg of 3- (. {1-l- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) benzoic acid activated on TFP resin (165 μM) and 0.0141 ml of ethyl hydrazine. 42 mg of N '-methyl-hydrazide of 3- (. {1- [bis- (-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) benzoic acid are thus obtained under the form of a pale yellow foam [XE NMR spectrum (400 MHz, (CD3) 2S0 d6, d in ppm): 2.96 (s: 3H); 3.18 (broad s: 3H); 3.83 (mt: 2H); 4.22 (mt: 2H); 4.80 (s broad: 2H); from 7.35 to 7.65 (mt: 12H)].

Example 133 The operation is carried out under the conditions described in Example 124 starting from 150 mg of 3- (. {1-l- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) benzoic acid activated on TFP resin (165 μM) and 0.0345 ml of N- (2-aminoethyl) morpholine. 62 mg of 3- (. {1-l- [Bis- (4-chlorophenyl) ethyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) N- (2-morpholin-4-yl) are thus obtained. ethyl) benzamide in the form of an ocher foam [XH NMR spectrum (400 MHz, (CD3) 2 SO d6, d in ppm): from 2.30 to 2.45 (mt: 4H); 2.46 (t, J = 7.5 Hz: 2H); 2.98 (s: 3H); 3.38 (mt: 2H); from 3.50 to 3.65 (mt: 4H); 3.82 (mt: 2H); 4.24 (mt: 2H); 4.79 (s: 1H); 7.36 (d, J = 8.5 Hz: 4H); 7.46 (d, J = 8.5 Hz: 4H); from 7.50 to 7.60 (mt: 2H); 7.83 (broad s: 1H); 7.85 (dd, J = 8 and 2 Hz: 1H); 8.45 (t, J = 6.5 Hz: 1H)].

Example 134 The operation is carried out under the conditions described in Example 124 starting from 150 mg of 3- (. {1 - [bis- (4-chloro-phenyl) -methyl] -zetidin-3-ylidene} -metanesulfonyl-methyl) activated benzoic on TFP resin (165 μM) and 0.0396 ml of 2- (aminomethyl) N-ethylpyrrolidine. 58 mg of 3- (. {1-l- [bis- (-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) N- (1-ethyl-pyrrolidin-2-yl are thus obtained. ilmethyl) benzamide in the form of an ocher foam. The 3- ( { 1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene) -methanesulfonyl-methyl) N- (1-ethyl-pyrrolidin-2-ylmethyl) benzamide can also be prepared in the conditions described in Example 126 from 700 mg of the 3- acid. { ( { 1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} -metanesulfonylmethyl) benzoic acid activated on TFP resin (770 μM), 0.324 ml of triethylamine and 0.25 ml of 2- (aminomethyl) ) N-ethyl-pyrrolidine. In this way 370 mg of a solid is obtained, which is purified by chromatography under nitrogen pressure (0.7 bar) on 100 ml of silica (0.040-0.063 mm) contained in a 2.5 cm diameter column eluting with a methanol-dichloromethane mixture (15-85 by volume). Fractions containing no more than the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. In this way 160 mg of 3- (. {1- [bis- (4-chloro-phenyl) methyl] -zetidin-3-ylidene} - methanesulfonyl-methyl) N- (1-ethyl-pyrrolidin- 2-ylmethyl) benzamide in the form of a pale yellow powder [H NMR spectrum (400 MHz, (CD3) 2SO d6, d in ppm): 1.04 (t, J = 7 Hz: 3H); from 1.50 to 1.70 (mt: 3H); 1.78 (mt: 1H); 2.14 (mt: 1H); 2.28 (mt: 1H); 2.59 (mt: 1H); 2.83 (mt: 1H); 2.98 (s: 3H); from 3.00 to 3.15 (mt: 2H); from 3.30 to 3.45 (mt: 1H); 3.82 (mt: 2H); 4.23 (mt: 2H); 4.79 (s: 1H); 7.36 (d, J = 8.5 Hz: 4H); 7.46 (d, J = 8.5 Hz: 4H); from 7.50 to 7.60 (mt: 2H); 7.86 (broad s: 1H); 7.85 (broad d, J = 8 Hz: 1H); 8.41 (t, J = 6 Hz: 1H)].

Example 135 The operation is carried out under the conditions described in Example 124 starting from 110 mg of the acid 3- (. {1-l- [Bis- (4-chlorophenyl) methyl.} - azetidin-3-ylidene.} - methansulfonyl. methyl) benzoic activated on TFP resin (121 μM) and 0.023 ml of neo-pentylamine. 69 mg of 3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl.idene.] - methanesulfonylmethyl) N- (2,2-dimethyl) are thus obtained. -propi 1) benzamide in the form of a pale yellow powder [1 H NMR spectrum (400 MHz, (CD3) 2SO d6, d in ppm): 0.90 (s: 9H); 2.98 (s: 3H); 3.11 (d, J = 6.5 Hz: 2H); 3.82 (mt: 2H); 4.23 (mt: 2H); 4.79 (s: 1H); 7.36 (d, J = 8 Hz: 4H); 7.46 (d, J = 8 Hz: 4H); from 7.45 to 7.60 (mt: 2H); 7.83 (broad s: 1H); 7.86 (broad d, J = 8 Hz: 1H); 8.37 (t, J = 6.5 Hz: 1H)].

Example 136 It operates under the conditions described in Example 124 from 110 mg of 3- (. {L- [bis- (4-chlorophenyl) ethyl] -azetidin-3-ylidene} -metanesulfonyl-methyl) benzoic acid activated on resin TFP (121 μM) and 0.025 ml of amino-methyl-cyclohexane. 44 mg of 3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonylmethyl] -N-cyclohexylmethyl} benzamide are obtained in this way form of a pale yellow powder whose characteristics are the following [1 H NMR spectrum (400 MHz, (CD3) 2S0 d6, d in ppm): 1.17 (mt: 4H), from 1.45 to 1.80 (mt: 5H) 2.97 (s: 3H); 3.10 (d, J = 6 Hz: 2H); 3.80 (mt: 2H) 4.23 (mt: 2H); 4.79 (s: 1H); 7.36 (d, J = 8 Hz: 4H) 7.46 (d, J = 8 Hz: 4H); from 7.45 to 7.60 (mt: 2H) 7.83 (broad s: 1H); 7.86 (broad d J = 8 Hz: 1H) 8.47 (t, J = 6 Hz: 1H))].

Example 137 It operates under the conditions described in Example 124 from 110 mg of 3- (. {L- [bis- (4-chlorophenyl) ethyl] -zetidin-3-ylidene} -metanesulfonyl-methyl) -benzoic acid activated on resin TFP (121 μM), 0.026 ml of triethylamine and 21 mg of amino-methyl-cyclopropane hydrochloride. 68 mg of 3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl) N-cyclopropylmethyl-benzamide are obtained in the form of a foam yellow [NMR spectrum ^? (400 MHz, (CD3) 2SO d6, d in ppm): 0.24 (mt: 2H); 0.44 (mt: 2H); 1.03 (mt: 1H); 2.98 (s: 3H); 3.15 (t, J = 6 Hz: 2H); 3.82 (mt: 2H); 4.23 (mt: 2H); 4.79 (s: 1H); 7.36 (d, J = 8.5 Hz: 4H); 7.46 (d, J = 8.5 Hz: 4H); from 7.50 to 7.60 (mt: 2H); 7.86 (broad s: 1H); 7.89 (broad d, J = 8 Hz: 1H); 8.64 (t, J = 6 Hz: 1H)].

Example 138 The operation is carried out under the conditions described in Example 124 starting from 110 mg of 3- (. {1-l- [Bis- (4-chlorophenyl) methyl] -zetidin-3-ylidene} - methanesulfonyl-methyl) benzoic acid activated on TFP resin (121 μM) and 0.023 ml of 2-methyl-butylamine. 49 mg of 3- (. {1- [bis- (4-chlorophenyl) ethyl} - azetidin-3-ylidene} - methanesulfonylmethyl) N- (2-methyl-butyl) benzamide are thus obtained. [NMR spectrum - "- H (400 MHz, (CD3) 2SO d6, d in ppm): 0.80 to 0.95 (mt: 6H), from 1.05 to 1.20 (mt: 1H), 1.41 (mt: 1H), 1.64 (mt: 1H); 2.98 (s: 3H); 3.06 (mt: 1H); 3.19 (mt: 1H); 3.81 (mt: 2H); 4.23 (mt: 2H); 4.79 (s: 1H); 7.36 (mt: 1H); d, J = 8 Hz: 4H), 7.46 (d, J = 8 Hz: 4H), 7.35 to 7.60 (mt: 2H), 7.84 (broad s: 1H), 7.87 (broad d, J = 8 Hz: 1H); 8.49 (t, J = 5.5 Hz: 1H)].

Example 139 The operation is carried out under the conditions described in Example 124 starting from 110 mg of 3- (. {1-l- [Bis- (4-chlorophenyl) methyl] -zetidin-3-ylidene} - methanesulfonyl-methyl) benzoic acid activated on TFP resin (121 μM) and 0.028 ml of 2-methyl-phenethylamine. In this way, 42 mg of 3- (. {1- [bis- (4-chlorophenyl) methyl-11-azetidin-3-ylidene} - methanesulfonylmethyl) N- (2-phenyl-propyl) benzamide is obtained. in the form of a yellow paste [1 H NMR spectrum (400 MHz, (CD3) 2SO d6, d in ppm): 1.24 (d, J = 7 Hz: 3H); 2.97 (s: 3H); 3.07 (mt: 1H); from 3.20 to 3.50 (mt: 2H); 3. 80 (mt: 2H); 4.23 (mt: 2H); 4.80 (s: 1H); from 7.10 to 7.40 (mt: 5H); 7.38 (d, J = 8 Hz: 4H); 7.47 (d, J = 8 Hz: 4H); from 7.50 to 7.60 (mt: 2H); 7.77 (broad s: 1H); 7.79 (broad d, J = 8 Hz: 1H); 8.55 (t, J = 6 Hz: 1H)].

Example 140 The operation is carried out under the conditions described in Example 124 starting from 110 mg of 3- (. {1-l- [bis- (-chloro-phenyl) -methyl] -zetidin-3-ylidene} -metanesulfonyl-methyl) benzoic acid activated on TFP resin (121 μM) and 0.020 ml of tetrahydrofurfurylmethylamine. 42 mg of 3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) N- (tetrahydrofuran-2-ylmethyl) benzamide are thus obtained in the form of a yellow paste [1 H NMR spectrum (400 MHz, (CD3) 2S0 d6, d in ppm): 1.58 (mt: 1H); from 1.75 to 2.00 (mt: 3H); s: 3H); from 3.20 to 3.40 (mt: 2H); 3.63 (mt: 1H); 3.77 (mt: 1H); 3.82 (mt: 2H); 3.98 (mt: 1H); 4.23 (mt: 2H); 4.79 (s: 1H); 7.36 (d, J = 8 Hz: 4H); 7.46 (d, J = 8 Hz: 4H); from 7.50 to 7.60 (mt: 2H); 7.84 (broad s: 1H); 7.88 (broad d, J = 8 Hz: 1H); 8.60 (t, J = 6 Hz: 1H)].

Example 141 The operation is carried out under the conditions described in Example 124 starting from 110 mg of 3- (. {1-l- [Bis- (4-chlorophenyl) methyl.} - azetidin-3-ylidene.} - methanesulfonyl-methyl ) activated benzoic on TFP resin (121 μM) and 39 mg of 2,2-di phenylethylamine. 39 mg of 3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonylmethyl) N- (2, 2-diphenyl-ethyl) benzamide are thus obtained in the form of a yellow paste [1 H NMR spectrum (400 MHz, (CD3) 2S0 d6, d in ppm): 2.95 (s: 3H); 3.77 (mt: 2H); 3. 90 (dd, J = 8 and 6.5 Hz: 2H); 4.22 (mt: 2H); 4.42 (t, J = 8 Hz: 1H); 4.79 (s: 1H); from 7.10 to 7.40 (mt: 10H); 7.38 (d, J = 8.5 Hz: 4H); from 7.45 to 7.60 (mt: 2H); 7.48 (d, J = 8.5 Hz: 4H); 7.70 (mt: 2H); 8.56 (t, J = 6.5 Hz: 1H)].

Example 142 It operates under the conditions described in Example 124 from 110 mg of 3- (. {L- [bis- (4-chlorophenyl) methyl] -zetidin-3-ylidene} -metanesulfonyl-methyl) -benzoic acid activated on resin TFP (121 μM) and 19 mg of 2-ethyl-butylamine. 47 mg of 3- (. {1- [bis- (4-chlorophenyl) methyl] -zetidin-3-ylidene} -metanesul-phenylmethyl) N- (2-ethyl-butyl) -benzamide are thus obtained the shape of a pale yellow powder [1 H NMR spectrum (400 MHz, (CD3) 2 SO d6, d in ppm): 0.86 (t, J = 7 Hz: 6H); from 1.20 to 1.40 (mt: 4H); 1.50 (mt: 1H); 2.98 (s: 3H); 3. 19 (t, J = 6 Hz: 2H); 3.82 (mt: 2H); 4.24 (mt: 2H); 4.79 (s: 1H); 7.36 (d, J = 8.5 Hz: 4H); 7.46 (d, J = 8.5 Hz: 4H); from 7.45 to 7.60 (mt: 2H); 7.83 (s broad: 1H); 7.86 (broad d, J = 8 Hz: 1H); 8.42 (t, J = 6 Hz: 1H)].

Example 143 The operation is carried out under the conditions described in Example 124 starting from 110 mg of 3- (. {1-l- [bis- (4-chlorophenyl) ethyl] -azetidin-3-ylidene} - methanesulfonylmethyl) benzoic acid activated on TFP resin (121 μM), 0.026 ml of triethylamine and 39 mg of 4-a-methyl-cyclohexanecarboxylic acid methyl ester hydrochloride. 47 mg of the methyl ester of 4-acid are thus obtained. { [3- ( { 1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonylmethyl) benzoylamino] -methyl} -cyclohexanecarboxylic acid in the form of a pale yellow paste [NMR spectrum - "- H (400 MHz, (CD3) 2SO d6, d in ppm): from 0.90 to 1.05 (mt: 2H), from 1.20 to 1.40 (mt) : 2H), 1.52 (mt: 1H), from 1.70 to 2.00 (mt: 4H), 2.27 (mt: 1H), 2.98 (s: 3H), 3.12 (t, J = 6.5 Hz: 2H), 3.60 (s) : 3H), 3.80 (mt: 2H), 4.23 (mt: 2H), 4.79 (s: 1H), 7.36 (d, J = 8 Hz: 4H), 7.46 (d, J = 8 Hz: 4H); 7.45 to 7.60 (mt: 2H), 7.83 (s broad: 1H), 7.87 (broad d, J = 8 Hz: 1H), 8.50 (t, J = 6 Hz: 1H).] The acid 3- (. { 1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene] -metanesulfonyl-methyl-benzoic acid activated on TFP resin can be prepared under the following conditions: a suspension of 1.07 g of fresh TFP ( free phenol functional group, 1.1 mmol / g, or 1.17 mM) in 15 ml of anhydrous dimethylformamide, pre-agitated for 10 minutes at a temperature close to 20 ° C, is added, at the same temperature, 1.18 g of the acid 3- (. {1 - [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonylmethyl) benzoic acid. After 10 minutes of stirring at a temperature close to 20 ° C, 14 mg of 4-dimethylaminopyridine are added, then after 10 minutes of stirring at the same temperature, 0.185 ml of 1,3-diisopropylcarbodiimide. After 23 hours of stirring at a temperature close to 20 ° C, the suspension is filtered, the resin is washed with 45 ml of dimethylformamide, 45 ml of tetrahydrofuran, 45 ml of dichloromethane, and then dried in vacuo to constant weight. 1.5 g of 3- (. {L- [bis- (4-chlorophenyl) methyl] -zetidin-3-ylidene} -metanesulfonyl-methyl) -benzoic acid activated on TFP resin in the form of a pale yellow resin. The TFP resin (the structure shown below) can be prepared as follows: To a suspension of 2 g of commercial aminomethyl polystyrene resin (0.39 mmol / g, 0.78 mmol) in 15 ml of dimethylformamide, pre-treated for 5 minutes at a temperature close to 20 ° C, 492 mg of diisopropylcarbodiimide, 819.3 mg of the acid are successively added. 2, 3, 5, 6-tetrafluoro-4-hydroxy-benzoic acid and 50 mg of 4-dimethylaminopyridine. After about 20 hours of stirring, at a temperature close to 20 ° C, the suspension is filtered, and the resin is rinsed with 3 portions of 20 ml of dimethylformamide, 3 portions of 20 ml of tetrahydrofuran and 3 portions of 20 ml of dichloromethane. The resin obtained is dried under reduced pressure at a temperature close to 40 ° C. The resin obtained is then stirred, at a temperature close to 20 ° C, for about 20 hours, in suspension in a mixture of piperidine / dimethylformamide (10/90 by volume). The suspension is filtered, and the resin is rinsed with 3 portions of 20 ml of dimethylformamide, 3 portions of 20 ml of tetrahydrofuran and 3 portions of 20 ml of dichloromethane. The resin obtained is dried under reduced pressure at a temperature close to 40 ° C and is used as such.

Example 144 A solution of 76 mg of (2- {4- [3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} -metanesulfonyl tert-butyl ester. -methyl) phenyl] -piperazin-1-yl.} -2-oxo-ethylcarbamic acid in 2.5 ml of formic acid is stirred for 1 hour at a temperature close to 45 ° C. The reaction medium is concentrated to dryness under reduced pressure (5 kPa) at a temperature close to 30 ° C, taken up in 10 ml of ethyl acetate and made alkaline with 10 ml of a saturated aqueous solution of sodium bicarbonate. After decanting, the organic phase is washed with 10 ml of water, dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. 51 mg of 2-amino-1- are thus obtained. { 4- [3- ( { 1 - [bis- (4-chlorophenyl) ethyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) phenyl] -piperazin-1-yl} -etanone in the form of a beige lacquer [XH NMR spectrum (400 MHz, CDC13, d in ppm): from 1.95 to 2.25 (extended mf: 2H); 2.77 (s: 3H); from 3.10 to 3.30 (mt: 4H); from 3.50 to 3.60 (t: 2H); 3.56 (broad s: 2H); from 3.75 to 3.90 (mt: 4H); 4.34 (mt: 2H); 4.50 (s: 1H); 6.84 (broad d, J = 8 Hz: 1H); 6.91 (dd, J = 8 and 2 Hz: 1H); 7.01 (mt: 1H); from 7.20 to 7.40 (mt: 9H)].

E emplo 145 108.5 mg of 1- [3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonylmethyl) phenyl] -piperazine are added successively at a temperature close to 20 ° C, 1.02 g of supported EDCI (5 M), 44 mg of N-Boc-glycine and then 10 ml of dichloromethane. After 20 hours of stirring, at a temperature close to 20 ° C, the reaction mixture is filtered on sintered glass. The resin is rinsed with 3 5 ml portions of dichloromethane. The combined filtrates are washed with 20 ml of water, dried over magnesium sulfate, filtered on sintered glass, and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. 143 mg of the (2- {4- [3- (. {L- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} -butyl ester are obtained in this manner. -metanesulfonyl-methyl) phenyl] -piperazin-1-yl.} -2-oxo-ethyl) carbamic acid in the form of a cream-colored lacquer [XH NMR spectrum (400 MHz, (CD3) 2S0 d6, d in ppm ): 1.40 (s: 9H); 2.93 (s: 3H); from 3.05 to 3.20 (mt: 4H); 3.57 (mt: 4H); 3.80 (mt: 2H); 3.84 (d, J = 6 Hz: 2H); 4.19 (mt: 2H); 4.78 (s: 1H); 6.79 (t, J = 6 Hz: 1H); 6.82 (d, J = 8 Hz: 1H); 6.93 (broad s: 1H); 6.99 (dd, J = 8 and 2.5 Hz: 1H); 7.27 (t, J = 8 Hz: 1H); 7.36 (d, J = 8 Hz: 4H); 7.46 (d, J = 8 Hz: 4H)]. The supported EDCI reagent is commercial, and can also be prepared according to the following reference: M. Desai, L. Stramiello, Tetrahedron Le ters, 34, 48, 7685-7688 (1993).

Example 146 A. 81 mg solution of the tert-butyl ester of the acid. { 2- . { 4- [3- ( { 1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene) -methanesulfonyl-methyl) phenyl] -piperazin-1-yl} -2-oxo-ethyl) N-methylcarbamic acid in 2.5 ml of formic acid is stirred for 1 hour at a temperature close to 45 ° C. The reaction medium is concentrated to dryness under reduced pressure (5 kPa) at a temperature close to 30 ° C., it is taken up with 10 ml of ethyl acetate and made alkaline with 10 ml of a saturated aqueous solution in sodium bicarbonate. After decanting, the organic phase is washed with 10 ml of water, dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. 58 mg of l- are thus obtained. { 4- [3- ( { 1 - [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) phenyl] -piperazin-1-yl} -2-methylaminoethanone in the form of a beige lacquer [1H-NMR spectrum (400 MHz, CDC13, d in ppm): from 1.95 to 2.15 (extended mf: 1H); 2.51 (broad s: 3H); 2.77 (s: 3H); from 3.10 to 3.30 (mt: 4H); 3.49 (broad s: 2H); 3.58 (mt: 2H); from 3.75 to 3.90 (mt: 4H); 4.33 (mt: 2H); 4.49 (s: 1H); 6.83 (broad d, J = 8 Hz: 1H); 6.90 (dd, J = 8 and 2 Hz: 1H); 7.00 (mt: 1H); from 7.20 to 7.40 (mt: 9H)].

Example 147 A 108.5 mg of 1- [3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene) -methanesulfonylmethyl) phenyl] -piperazine are added successively, at a temperature close to 20 °. C, 1.02 g of supported EDCI (5 mM), 47.3 mg of N-Boc-sarcosine and then 10 ml of dichloromethane. After 20 hours of stirring, at a temperature close to 20 ° C, the reaction mixture is filtered on sintered glass. The resin is rinsed with 3 5 ml portions of dichloromethane. The combined filtrates are washed with 20 ml of water, dried over magnesium sulfate, filtered on sintered glass, and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. 143 mg of the (2- {4- [3- (. {L- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} -butyl ester are obtained in this manner. -metanesulfonyl-methyl) phenyl] -piperazin-1-yl.} -2-oxo-ethyl) N-methyl-carbamic acid in the form of a cream-colored lacquer [XH NMR spectrum (400 MHz, (CD3) 2SO d6 , d in ppm). A mixture of rotamers was observed at room temperature; 1.31 and 1.41 (2s: 9H in total); 2.78 and 2.81 (2s: 3H in total); 2.93 (2s: 3H); from 3.10 to 3.25 (mf: 4H); from 3.45 to 3.65 (mt: 4H); 3.80 (mt: 2H); 4.06 and 4.09 (2s: 2H in total); 4.19 (mt: 2H); 4.78 (s: 1H); 6.83 (broad d, J = 8 Hz: 1H); 6.93 (broad s: 1H); 7.00 (dd, J = 8 and 2.5 Hz: 1H); 7.27 (t, J = 8 Hz: 1H); 7.36 (d, J = 8 Hz: 4H); 7.46 (d, J = 8 Hz: 4H)].

Example 148 A 54.25 mg of 1- [3- ( { 1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) phenyl] -piperazine are added successively, at a temperature close to 20 ° C, 2 ml of dichloromethane and then 11 mg of methyl isothiocyanate. After 6 hours of stirring, at a temperature close to 20 ° C, 0.05 ml of water are added to the reaction mixture. After 15 minutes of stirring at the same temperature, the reaction medium is dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. 61 mg of 4- [3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene-methanesulfonyl-methyl) phenyl] - N-methylamide are obtained in this way piperazine-1-carbothioic in the form of a beige lacquer [NMR spectrum aH (400 MHz, CDC13, d in ppm): 2.77 (s: 3H); 3.20 (d, J = 5 Hz: 3H); 3.32 (t, J = 5.5 Hz: 4H); 3.81 (mt: 2H); 4.00 (t, J = 5.5 Hz: 4H); 4.33 (mt: 2H); 4.49 (s: 1H); 5.63 (broad q, J = 5 Hz: 1H); 6.80 (d, J = 8 Hz: 1H); 6.85 (dd, J = 8 and 2.5 Hz: 1H); 6.94 (broad s: 1H); from 7.20 to 7.30 (mt: 5H); 7.32 (d, J = 8 Hz: 4H)].

Example 149 A 54.25 mg of 1- [3- ( { 1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) phenyl] -piperazine are added successively, at a temperature close to 20 ° C, 2 ml of dichloromethane and then 11.5 mg of methyl isocyanate. After stirring for 4 hours, at a temperature close to 20 ° C, 0.05 ml of water are added to the reaction mixture. After 15 minutes of stirring at the same temperature, the reaction medium is dried over magnesium sulfate, filtered on paper, and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. Thus, 66 mg of 4- [3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} -metanesulfonylmethyl) phenyl] -piperazm is obtained. - 1-carboxylic acid in the form of a beige lacquer [1 H-NMR spectrum (400 MHz, CDC13, d in ppm): 2.75 (s: 3H); 2.85 (d, J = 5 Hz: 3H); 3.19 (broad t, J = 5.5 Hz: 4H); 3.52 (broad t, J = 5.5 Hz: 4H); 3.80 (mt: 2H); 4.33 (mt: 2H); 4.45 (broad q, J = 5 Hz: 1H); 4.49 (s: 1H); 6.81 (d, J = 8 Hz: 1H); 6.89 (dd, J = 8 and 2.5 Hz: 1H); 6.98 (broad s: 1H); from 7.20 to 7.30 (mt: 5H); 7.32 (d, J = 8 Hz: 4H)].

Example 150 A 54.25 mg of 1- [3- ( { 1- [bis- (4-chlorophenyl) methyl] -a zetidin-3-ylidene} - methanesulfonylmethyl) phenyl] -piperazine are added successively, at a temperature close to at 20 ° C, 2 ml of pyridine and then 10.4 mg of methyl chloroformate. After 6 hours of stirring at a nearby temperature! at 20 ° C, the reaction medium is concentrated under reduced pressure (5 kPa) at a temperature close to 30 ° C. The residue obtained is taken up in 5 ml of ethyl acetate and 5 ml of water. After decanting, the organic phase is washed with 2 ml of water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (1 kPa) at a temperature close to 40 ° C. This gives 62 mg of 4- [3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl iden.} - methanesulfonylmethyl) phenyl] -piperazine methyl ester. -1-carboxylic acid in the form of a beige lacquer [NMR spectrum aH (400 MHz, CDC13, d in ppm): 2.75 (s: 3H); 3.15 (broad s, J = 5.5 Hz: 4H); 3.62 (mt: 4H); 3.74 (s: 3H); 3.80 (mt: 2H); 4.32 (mt: 2H); 4.49 (s: 1H); 6.81 (d, J = 8 Hz 1H); 6.90 (dd, J = 8 and 2.5 Hz: IR "), 6.99 (broad s: 1H), 7.20 to 7.40 (mt: 9H)].

E p 151 To a solution of 54.25 mg of 1- [3- ( { 1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) phenyl} -piperazine in 2 ml of 1,2-dichloroethane are added successively, at a temperature close to 20 ° C, 32 mg of sodium acetoxyborohydride and then 22 mg of isobutyraldehyde. After 4 hours of stirring at a temperature close to 20 ° C, 3 ml of dichloromethane and 2 ml of a saturated aqueous solution of sodium bicarbonate are added to the reaction medium. After decanting, the organic phase is dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. 63 mg of 1- [3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene}. -metansul-fonyl-methyl) phenyl] -4-isobutyl are thus obtained. -piperazine in the form of a beige lacquer [NMR spectrum? E (400 MHz, CDC13, d in ppm): 0.92 (d, J = 7 Hz: 6H); 1.82 (mt: 1H); 2.14 (d, J = 8. Hz: 2H); 2.54 (t, J = 5.5 Hz: 4H); 2.75 (s: 3H); 3.18 (t, J = 5.5 Hz: 4H); 3.81 (mt: 2H); 4.32 (mt: 2H); 4.49 (s: 1H); 6.78 (d, J = 8 Hz: 1H); 6.89 (dd, J = 8 and 2.5 Hz: 1H); 6.97 (broad s: 1H); from 7.15 to 7.30 (mt: 5H); 7.32 (d, J = 8 Hz: 4H)].

Example 152 To a solution of 54 mg of 1- [3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} -metanesulfonylmethyl) phenyl] -piperazine in 2 ml of 1, 2-dichloroethane is added successively, at a temperature close to 20 ° C, 32 mg of sodium acetoxyborohydride and then 13 mg of acetaldehyde. After stirring for 21 hours at a temperature close to 20 ° C, 2 ml of a saturated aqueous solution of sodium bicarbonate are added to the reaction mixture. After decanting, the aqueous phase is again extracted with 2 ml of dichloromethane. The organic phases are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 20 ° C. 60 mg of a solid residue are thus obtained, which is collected with 2 ml of methanol and 0.5 ml of dichloromethane. The obtained solution is deposited on a silica cartridge (500 mg of SCX phase).

The cartridge is washed with 50 ml of methanol, then the expected product is eluted with 5 ml of ammoniacal methanol (2 N) and then 5 ml of supplemental methanol. The filtrate is concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 30 ° C. 42 mg of 1- [3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) phenyl] -4-ethyl are thus obtained -piperazine in the form of a colorless lacquer [1K NMR spectrum (300 MHz, CDC13, d in ppm): 1.14 (5, J = 7.5 Hz: 3H); 2.48 (q, J = 7.5 Hz: 2H); 2.60 (broad t, J = 5 Hz: 4H); 2.77 (s: 3H); 3.22 (broad t, J = 5 Hz: 4H); 3.82 (mt: 2H); 4.33 (mt: 2H); 4. 49 (s: 1H); 6.79 (broad d, J = 8 Hz: 1H); 6.91 (dd, J = 8 and 2 Hz: 1H); 6.98 (mt: 1H); from 7.20 a 7. 40 (mt: 9H)].

Example 153 A 54 mg of 1- [3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene}. -metanesulfonylmethyl) phenyl] -piperazine are added successively, at a temperature close to 20 ° C, 2 ml of pyridine and then 11.5 mg of acetic anhydride. After 23 hours of agitation, at a temperature close to ° C, the reaction medium is concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 30 ° C. The residue obtained is taken up in 5 ml of ethyl acetate and 2 ml of water.

After decanting, the organic phase is washed with 2 ml of water, dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. Thus, 52 mg of 4-acetyl-l- [3- (. {L- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonylmethyl) phenyl] are obtained. piperazine in the form of a beige foam [1 H-NMR spectrum (400 MHz, CDC13, d in ppm): 2.16 (s: 3H); 2.77 (s: 3H); from 3. 10 to 3.25 (mt: 4H); 3.63 (broad t, J = 5.5 Hz: 2H); 3.78 (broad t, J = 5.5 Hz: 2H); 3.82 (mt: 2H); 4. 34 (mt: 2H); 4.50 (s: 1H); 6.84 (broad d, J = 8 Hz: 1H); 6.92 (dd, J = 8 and 2 Hz: 1H); 7.02 (mt: 1H); from 7.20 to 7.40 (mt: 9H)].

Example 154 A 54 mg of 1- [3- (. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) phenyl] -piperazine are added successively, at a temperature close to 20 ° C, 511 mg of supported EDCI (2.5 mM), 11.5 mg of N, N-dimethylglycine and then 5 ml of dichloromethane. After 24 hours of stirring, at a temperature close to 20 ° C, 35 mg of N, N-dimethylglycine are added. After 96 hours of stirring, at a temperature close to 20 ° C, the reaction mixture is filtered on sintered glass. The resin is rinsed with 3 portions of 2.5 ml of dichloromethane. The combined filtrates are washed with 10 ml of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa) at a temperature close to 20 ° C. 53 mg of 1- are obtained in this way. { - [3- ( { 1- [bis- (-chlorophenyl) methyl] -azetidin-3-ylidene} - methanesulfonyl-methyl) phenyl] -piperazin-1-yl} -2-dimethylamino-ethanone in the form of a beige foam [1 H NMR spectrum (400 MHz, (CD3) 2 SO d6, d in ppm): 2.20 (s: 6H); 2.94 (s: 3H); 3.12 (s: 2H); 3.16 (mt: 4H); 3.58 (mt: 2H); 3.68 (mt: 2H); 3.80 (mt: 2H); 4.19 (mt: 2H); 4.78 (s: 1H); 6.81 (broad d, J = 8 Hz: 1H); 6.93 (broad s: 1H); 6.99 (dd, J = 8 and 2.5 Hz: 1H); 7.26 (t, J = 8 Hz: 1H); 7.36 (d, J = 8 Hz: 4H); 7.46 (d, J = 8 Hz: 4H)].

Example 155 A solution of 320 mg of the 4- [3- (. {1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylden.} Methanesulfonylmethyl) phenyl ester} piperazine-l-carboxylic acid in 5 ml of formic acid is stirred for 5 hours at a temperature close to 20 ° C, then 1 hour at a temperature close to 45 ° C. The reaction medium is concentrated to dryness under reduced pressure (5 kPa) at a temperature close to 30 ° C, taken up in 20 ml of ethyl acetate and made alkaline with 10 ml of a saturated aqueous solution of sodium bicarbonate. After decanting, the organic phase is washed with 3 portions of 10 ml of water, dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. The obtained residue is purified by depositing in solution in a minimum of dichloromethane on silica gel deposited on a plate [(gel 0.5 mm thick, 5 plates 20 x 20 cm, eluent: dichloromethane-methanol (80-20 by volume) The area corresponding to the desired adsorbed product, located with UV rays, is scraped off and the collected silica is washed with sintered glass with a dichloromethane-methanol mixture (75-25 by volume) .The filtrates are combined and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 30 ° C. 180 mg of 1- [3- (. {1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylide is thus obtained .} metansul fonylmethyl) phenyl] piperazine in the form of a white powder [H NMR spectrum (400 MHz, CDC13, d in ppm): 2.77 (s: 3H), 3.05 (mt: 4H), 3.16 (mt: 4H), 3.81 (mt: 2H), 4.33 (mt: 2H), 4.49 (s: 1H), 6.79 (broad d, J = 8 Hz: 1H), 6.90 (dd, J = 8, and 2.5 Hz. 6.98 (mt: 1H), from 7.20 to 7.40 (mt: 9H)]. The ter-butyl ester of 4- [3- (. { l- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} -metanesulfonylmethyl) phenylpiperzine-1-carboxylic acid can be prepared in the following manner: by operating according to the mode of operation of Example 4 starting from 1. 32 g of 4- [3- (. {L- [bis- (4-chlorophenyl) methyl] -3-hydroxy-azetidin-3-yl] methanesulfonyl-methyl) phenyl-tert-butyl ester} piperazine-1-carboxylic acid, 0.232 ml of methanesulfonyl chloride and 0.733 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a column of silica gel (granulometry 0.063-0.200 mm, diameter 2 cm, height 25 c) at atmospheric pressure with a mixture of dichloromethane-methanol (99.5-0.5 by volume) as eluent and collecting fractions of 15 ml. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (5 kPa.) At a temperature close to 30 ° C. 0.86 g of the 4- [3- (4- (3-tert-butyl) ester are obtained in this way {1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonyl-methyl) phenyl] piperazine-1-carboxylic acid in the form of a white foam [1 H NMR spectrum (400 MHz, CDC13, d in ppm): 1.50 (s: 9H); 2.77 (s: 3H); 3.14 (t, J = 5 Hz: 4H); 3.57 (t, J = 5 Hz: 4H); 3.81 (mt: 2H); 4.34 (mt: 2H); 4.49 (s: 1H); 6.81 (d, J = 8 Hz: 1H); 6.90 (dd, J = 8 and 2.5 Hz: 1H); 6.99 (broad s: 1H); from 7.20 to 7.30 (mt: 5H); 7.32 (d, J = 8 Hz: 4H)]. 4- [3- (. {L- [bis- (4-chlorophenyl) methyl] -3-hydroxy-azetidin-3-yl} methanesulfonyl-methyl) phenyl] piperazine-1-tert-butyl ester -carboxylic acid can be prepared as follows: operating according to the mode of operation of Example 1 from 0.886 g of the 4- (3-methanesulfonylmethyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester of 0.765 g of - [bis (4-chlorophenyl) methylazetidin-3-one and 1.72 ml of a 1.6 M solution of n-butyllithium in hexane give 1.37 g of the 4- [3- (1- (1-tert-butyl ester [bis- (4-chlorophenyl) methyl] -3-hydroxy-azetidin-3-yl.} - methanesulfonyl-methyl) phenyl] piperazine-1-carboxylic acid in the form of a beige powder. 4- (3-methanesulfonylmethylphenyl) piperazine-1-carboxylic acid can be prepared according to the following manner: by operating according to the mode of operation of Example 10 starting from 1.55 g of the 4- (3-chloromethylphenyl) piperazine- tert-butyl ester. 1-carboxylic and 0.766 g of sodium methansulfinate, 0.9 g of the 4- (3-methanesulfonylmethylphenyl) iperazine-1-carboxylic acid tert-butyl ester in the form of a beige powder are obtained. The 4- (3-chloromethylphenyl) piperazine-1-carboxylic acid tert-butyl ester can be prepared as follows: by the reaction of 16.4 g of the 4- (3-hydroxymethylphenyl) piperazine-tert-butyl ester 1-carboxylic acid in 150 ml of di, chloromethane, at a temperature close to 20 ° C, with 29 ml of diisopropylethylamine and 8.7 ml of methanesulfonyl chloride, are obtained after purification on a chromatography column (silica 0.063-0.200 mm, diameter 6 cm, height 45 cm, fractions of 100 ml) eluting with dichloromethane, 15 g of the 4- (3-chloromethylphenyl) piperazine-1-carboxylic acid tert-butyl ester in the form of a beige powder. The 4- (3-hydroxymethylphenyl) piperazine-1-carboxylic acid tert-butyl ester can be prepared in the following manner: by reaction of 15.8 g of a mixture of 4- (3-ethoxycarbonylphenyl) tert-butyl esters of 4- (3-ethoxycarbonylphenyl) acids) piperazine-1-carboxylic acid and 4- (3-n-butyloxycarbonyl phenyl) piperazine-1-carboxylic acid in solution in 500 ml of anhydrous THF, at a temperature close to -10 ° C, and 102 ml of diisobutylaluminum hydride in solution in toluene (20% by weight), 12.8 g of the 4- (3-hydroxymethylphenyl) piperazine-1-carboxylic acid tert-butyl ester are obtained in the form of a beige oil. The mixture of tert-butyl esters of 4- (3-ethoxycarbonylphenyl) piperazine-1-carboxylic acid and 4- (3-n-butyloxycarbonylphenyl) piperazine-1-carboxylic ester can be prepared according to the method described in WO 9726250.

Example 156 Operating according to Example 38 (Method 2), from 0.3 g of 3-acetoxy-l- [bis (4-methoxycarbonylphenyl) methyl] -3- [(3,5-difluorophenyl) - (methylsulfonyl) methyl- (RS ) azetidine and 105 mg of lithium hydroxide m-hydrate in 10 ml of acetonitrile, at a temperature close to 70 ° C, give 0.24 g of l- [bis (4-methoxycarbonyl phenyl) methyl] -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine in the form of an orange foam [NMR spectrum "? (400 MHz, CDC13, d in ppm): 2.81 (s: 3H); from 3.85 to 3.95 (mt: 2H); 3.89 (s: 6H); 4.37 (mt: 2H); 4.67 (s: 1H); 6.84 (tt, J = 9 and 2.5 Hz: 1H); 6.99 (mt: 2H); 7.50 (d, J = 8 Hz: 4H); 7.97 (d, J = 8 Hz: 4H)].

Example 157 Operating according to the mode of operation of the Example 40 from 4.45 g of (3,5-difluorobenzyl) methylsulfone, 6.36 g of l- [bis (4-methoxycarbonylphenyl) methyl] azetidin-3-one, 2.18 ml of acetyl chloride and 17 ml of a 1.6 solution. M of n-butyl lithium in hexane, 10.8 g of 3-acetoxy-1- [bis (4-methoxycarbonylphenyl) methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] are obtained. azetidine in the form of a pale yellow foam [XH NMR spectrum (400 MHz, (CD3) 2S0 d6, d in ppm): 2.03 (s: 3H); 2.96 (s: 3H); from 3.25 to 3.40 (mt: 2H); 3. 52 (broad d, J = 8 Hz: 1H); from 3.75 to 3.90 (mt: 1 HOUR); 3.52 (s: 3H); 3.83 (s: 3H); 4.72 (s: 1H); 5.36 (s: 1H); 7.27 (d, J = 8 Hz: 2H); from 7.35 to 7.45 (mt: 2H); 7.43 (d, J = 8 Hz: 2H); 7.54 (tt, J = 9.5 and 2.5 Hz: 1H); 7.81 (d, J = 8 Hz: 2H); 7.88 (d, J = 8 Hz: 2H)]. L- [bis (4-methoxycarbonylphenyl) methyl] azetidin-3-one can be prepared in the same manner as l-. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-one (Example 110) from l- [bis (4-methoxycarbonyl phenyl) methyl] azetidin-3-ol. L- [Bis (4-methoxycarbonylphenyl) methyl] azetidin-3-ol can be prepared in the same manner as l-. { (R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-ol (Example 110) from bis (4-ethoxycarbonyl phenyl) methylamine. Bis (4-methoxycarbonyl phenyl) methylamine can be prepared in the same manner as methyl 4 - [(RS) -amino- (4-chlorophenyl) methyl] benzoate (Example 87) from the 4,4 '- dimethoxycarbonyl-benzophenone.

Example 158 Operating according to the mode of operation of Example 110, starting from 40 mg of (RS) -l-. { [4- (chloromethyl) phenyl] (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methyl) methylsulfonyl-methylene] azetidine, 0.25 ml of dichloromethane and 0.0196 ml of morpholine give 35.8 mg of (RS) -4- [4- ((4- chlorophenyl). {3- [3,5-di-fluorophenyl] methanesulfonyl-methylene] azetidin-1-yl} -methyl) benzyl] morpholine in the form of a white foam [1 H-NMR spectrum (400 MHz, CDC13, d in ppm): 2.41 (mt: 4H); 2.80 (s: 3H); 3.42 (s: 2H); 3.69 (t, J = 4.5 Hz: 4H); 3.84 (mt: 2H); 4.33 (mt: 2H); 4.50 (s: 1H); 6.83 (tt, J = 9 and 2.5 Hz: 1H); 6.98 (mt: 2H); from 7.20 to 7.40 (mt: 8H)]. The (RS) -l-. { [4- (chloromethyl) phenyl] (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) - (methylsulfonyl) ethyl) ethylsulfonylmethylene} azetidine can be prepared in the following manner: by operating according to Example 87, starting from 415 mg of (RS.) - l- dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. The residue obtained is purified by depositing in a minimum of dichloromethane on chrography on silica gel deposited on a plate [(gel 0.5 mm thick, 2 plates 20 x 20 cm, eluent: dichloromethane-methanol (92.5-7.5 in volume)] The zone corresponding to the desired product adsorbed, located with UV rays, is scraped and the collected silica is washed on sintered glass with a mixture of dichloromethane-methanol (80-20 by volume) .The filtrates are combined and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. 25.2 mg of A - (4-. {3- [(1-benzhydryl-azetidin-3-ylidene) methanesulfonyl- methyl.}. phenoxy] -butyl) orpholine in the form of a pale yellow foam [X-ray NMR spectrum (400 MHz, CDC13, d in ppm): 1.66 (mt: 2H); 1.81 (mt: 2H); 2.40 t, J = 7.5 Hz: 2H); 2.46 (mt: 4H); 2.77 (s: 3H); 3.72 (t, J = 5 Hz: 4H); 3.84 (mt: 2H); 3.96 (t, J = 6.5 Hz: 2H); 4.36 (mt: 2H); 4.53 (s: 1H); 6.87 (dd, J = 8 and 2 Hz: 1H); 6.93 (d, J = 8 Hz: 1H); 6.96 (d, J = 2 Hz: 1H); from 7.10 to 7.35 (mt: 7H); 7.42 (d, J = 8 Hz: 4H)]. dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. The residue obtained is purified by depositing in a minimum of dichloromethane on chrography on silica gel deposited on a plate [(gel 0.5 mm thick, 2 plates 20 x 20 cm, eluent: dichloromethane-methanol (92.5-7.5 in volume)] The zone corresponding to the desired product adsorbed, located with UV rays, is scraped and the collected silica is washed on sintered glass with a mixture of dichloromethane-methanol (80-20 by volume) .The filtrates are combined and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. 25.2 mg of 4- (4-. {3- [(1-benzhydryl-azetidin-3-ylidene) methanesulfonyl- methyl] phenoxy] -butyl) morpholine in the form of a pale yellow foam [NMR spectrum aH (400 MHz, CDC13, d in ppm): 1.66 (mt: 2H); 1.81 (mt: 2H); 2.40 t, J = 7.5 Hz: 2H); 2.46 (mt: 4H); 2.77 (s: 3H); 3.72 (t, J = 5 Hz: 4H); 3. 84 (mt: 2H); 3.96 (t, J = 6.5 Hz: 2H); 4.36 (mt: 2H); 4.53 (s: 1H); 6.87 (dd, J = 8 and 2 Hz: 1H); 6.93 (d, J = 8 Hz: 1H); 6.96 (d, J = 2 Hz: 1H); from 7.10 to 7.35 (mt: 7H); 7.42 (d, J = 8 Hz: 4H)].

The l-benzhydril-3-. { [3- (4-bromo-butoxy) phenyl] methanesulfonyl-methylene} -zetidine can be prepared as follows: To a solution of 500 mg of l-benzhydryl-3- [(3-hydroxyphenyl) (methylsul fonyl) methylene] azetidine in 10 ml of methyl ethyl ketone, add successively at a temperature close to 20 ° C, under an inert atmosphere of argon, 0.586 ml of 1, -dibromobutane and 255 mg of potassium carbonate. The reaction mixture is brought to reflux of the solvent, under an inert argon atmosphere, for 7 hours, then it is left at a temperature close to 20 ° C for about 4 days. The reaction mixture is filtered on sintered glass filled with celite. The solid residue is rinsed with ethyl acetate, then the filtrate is concentrated to dryness under reduced pressure (10 kPa) at a temperature close to 40 ° C. The brown oil obtained is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.200 mm) contained in a 3 cm diameter column eluting with a methanol-dichloromethane mixture (0.5-99.5 by volume). The fractions (10 ml) containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. 408.4 mg of l-benzhydryl-3 are thus obtained. { [3- (4-bromo-butoxy) phenyl] methanesulfonyl-methylene} -acetidine in the form of a brown foam.

Example 160 To a solution of 45 mg of l-benzhydril-3-. { [3- (4-bromo-propyloxy) phenyl J-methanesulfonyl-methylene} -zetidine in 3.5 ml of anhydrous acetonitrile, are added successively, at a temperature close to 20 ° C, under an inert argon atmosphere, 0.110 ml of morpholine and then 35 mg of potassium carbonate. After stirring for 20 hours at a temperature close to 20 ° C, the reaction medium is diluted with 40 ml of ethyl acetate and 10 ml of water. The separated organic phase is washed with 10 ml of water, then 2 portions of 10 ml of a saturated aqueous solution in sodium chloride, dried over magnesium sulfate, filtered on sintered glass, then concentrated to dryness under pressure. reduced (9 kPa) at a temperature close to 40 ° C. The yellow lacquer obtained is purified by deposit in a minimum of dichloromethane on chromatography on silica gel on a plate [(gel 0.5 mm thick, 2 plates 20 x 20 cm, eluent: dichloromethane-methanol (97.5-2.5 in volume).] The zone corresponding to the desired product adsorbed, located with UV rays, is scraped off and the received silica is washed on sintered glass with a dichloromethane-methanol mixture (85-15 by volume). Concentrate to dryness under reduced pressure (1 kPa) at a temperature close to 40 ° C. 33 mg of 4- (4-. {3- [(1-benzhydryl azetidin-3-ylidene) ethanesulfonyl are thus obtained. -methyl] phenoxy.}. -propyl) morpholine in the form of a white foam [H NMR spectrum (400 MHz, (CD3) 2S0 d6, d in ppm): 1.87 (mt: 2H); 2.37 (mt: 4H ), 2.42 (t, J = 7.5 Hz: 2H), 2.94 (s: 3H), 3.58 (mt: 4H), 3.80 (mt: 2H), 4.02 (t, J = 7 Hz: 2H), 4.20 (mt), : 2H); 4.74 (s: 1H); 6.97 (mt: 3 H); 7.22 (t, J = 7.5 Hz: 2H); from 7.25 to 7.40 (mt: 1H); 7.32 (t, J = 7.5 Hz: 4H); 7.48 (d, J = 7.5 Hz: 4H)]. The l-benzhydril-3-. { (3- (4-bromo-propyloxy) phenyl] methanesulfonyl-methylene.} -azetidine can be prepared as follows: to a solution of 500 mg of l-benzhydryl-3- [(3-hydroxyphenyl) (methylsulfonyl) ethylene] azetidine in 10 ml of methyl ethyl ketone, 0.5 ml of 1,3-dibromopropane and 255 mg of potassium carbonate are successively added at a temperature close to 20 ° C under an inert argon atmosphere. leads to solvent reflux, under an inert argon atmosphere, for 7 hours, then left at a temperature near 20 ° C for about 4 days. The reaction mixture is filtered on sintered glass filled with celite. The solid residue is rinsed with ethyl acetate, then the filtrate is concentrated to dryness under reduced pressure (10 kPa) at a temperature close to 40 ° C. The brown oil obtained is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.200 mm) contained in a 3 cm diameter column eluting with a methanol-dichloromethane mixture (0.5-99.5 by volume). The fractions (10 ml) containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. 511.1 mg of l-benzhydryl-3 are thus obtained. { [3- (4-bromo-propyloxy) phenyl] methansul fonyl-methylene} -azetidine in the form of a brown foam. The medicaments according to the invention are constituted by a compound of the formula (I) or an isomer or a salt of such a compound, in the pure state or in the form of a composition in which it is associated with any other product. Physically compatible, which can be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically. As solid compositions for oral administration, tablets, capsules, powders (gelatin capsules, sacks) or granules can be used. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compounds can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish. As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing the inert diluents such as water, ethanol, S68 may be used. glycerol, vegetable oils or paraffin oil. These compositions may comprise substances other than diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers. Sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As a solvent or. vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents may be employed. These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. The sterilization can be done in various ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. These can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols. Compositions for topical administration can be for example creams, lotions, eye drops, mouthwash, nasal drops or aerosols. In human therapy, the compounds according to the invention are particularly useful for the treatment and / or prevention of psychoses, including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, disorders. cerebellar and spinocerebellar, from cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucomas, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors or tremors, compulsive-obsessive disorder, senile dementia, thymic disorders, Tourette syndrome, tardive dyskinesia, bipolar disorders, cancers, movement disorders induced by drugs, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunological diseases, plaque sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, intestinal transit disorders, in suspension or abstinence from chronic treatments and abuse of alcohol or drugs (opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclide, hallucinogens, benzodiazepines, for example), as analgesics or potentiators of the analgesic activity of narcotic and non-narcotic medications, such as antibacterial, antiviral and antiparasitic drugs. The doses depend on the effect sought, the duration of the treatment and the route of administration used; These are generally between 5 mg and 1000 mg per day orally for an adult, with unit doses ranging from 1 mg to 250 mg of active substance. In general, the doctor will determine the appropriate dosage according to age, weight and all other factors specific to the subject to be treated. The following examples illustrate the compositions according to the invention: Example A • Capsules dosed at 50 mg of active product having the following composition are prepared according to the usual technique: Compound of the formula (I) 50 mg Cellulose 18 mg Lactose 55 mg Colloidal silica 1 mg Carboxymethylstarch sodium 10 mg Talc 10 mg Magnesium stearate 1 mg EXAMPLE B Compressed tablets dosed at 50 mg of active compound having the following composition are prepared according to the usual technique: Compound of the formula (I) 50 mg - Lactose 104 mg - Cellulose 40 mg - Polividone 10 mg - Carboxymethylstarch sodium 22 mg - Talc 10 mg - Magnesium stearate 2 mg - Colloidal silica 2 mg - Mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3.5-24.5) as long as 1 tablet with finished film at 245 mg EXAMPLE C An injectable solution containing 10 mg of active compound having the following composition is prepared: Compound of the formula (I) 10 mg - Benzoic acid 80 mg - Benzyl alcohol 0.06 ml - Sodium benzoate 80 mg - 95% ethanol 0.4 ml - Sodium hydroxide 24 mg - Propylene glycol 1.6 ml - Water as much as 4 ml It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (34)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. The compounds of the formula: characterized because R represents a chain Ri represents a methyl or ethyl radical, R 2 represents either an aromatic radical chosen from phenyl, naphthyl, or indenyl, these aromatic radicals being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, -CO-alk, hydroxyl groups, -COOR5, formyl, trifluoromethyl, trifluoromethylsulfañyl, trifluoromethoxy, nitro, -NR6R7, -CO-NH-NR6R7, - (alk) COOR8, cyano, -CONHR9 -CO-NR16Ri7, alkylsulfañilo, hydroxyalkyl, -0-alk-NR12R? 3 or alkylthioalkyl or a heteroaromatic radical selected from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, indolinyl, indolyl, isochoryl, isoquinolyl, pyridyl, quinolyl, 1 cycles. 2,3-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl, thienyl, these heteroaromatic radicals being unsubstituted or substituted with a halogen, alkyl, alkoxy, -COOR 5, trifluoromethyl, trifluoromethylsulfañyl, trifluoromethyl radical xi, nitro, -NR6R7, -C0-NH-NR6R7, cyano, -CONHRg, alkylsul phenyl, hydroxyalkyl or alkylthioalkyl, R3 and R4, identical or different, represent either an aromatic radical chosen from phenyl, naphthyl or indenyl, and may be these aromatic radicals unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoro ethoxy, -CO-alk, cyano, -COORs, -CONR10R11, -CO-NH-NR6, R7, alkylsulfañyl groups , hydroxyalkyl, -alk-NReR-r or alkylthioalkyl; or a heteroaromatic radical selected from the benzofuryl, benzothiazol, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenz.Qthienyl, furyl, isochromanyl, isoquinolyl, pyrrolyl, quinolyl, 1,2,3 cyclohexane cycles. , 4-tetrahydroisoquinolyl, thiazolyl, thienyl, these heteroaromatic groups may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOR5, -CO-NH-NR6R7, -CQNR10R11, -alk-NR6R7 , alkylsulphanyl, hydroxyalkyl or alkylthioalkyl, Rs is an alkyl or phenyl radical optionally substituted with one or more halogen atoms, Re and R7, identical or different represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl or either Re and R7 together with the nitrogen atom to which they are attached form a saturated or unsaturated mono or bicyclic heterocycle having from 3 to 10 members, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen, and which is optionally substituted with one or several alkyl radicals, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR14R15, oxo, hydroxyalkyl, -alk-O-alk, -CO-NH2, R8 represents a radical alkyl, R9 represents a hydrogen atom or an alkyl or alkyl radical substituted with dialkylamino, phenyl, cycloalkyl (optionally substituted with -CQOalk) or a saturated or unsaturated mono or bicyclic heterocycle having from 3 to 10 members, optionally containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl radicals, Rio and Ria, which are identical or different, represent a hydrogen atom or an alkyl radical or Rio and Rn form together with the atom of nitrogen to which they are attached, a saturated mono or bicyclic heterocycle having from 3 to 10 members, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen, and which is optionally substituted with an alkyl radical, R12 and Ri3, identical or different, represent a hydrogen atom or an alkyl radical, cycloalkyl or Ri2 and R13 together with the nitrogen atom to which they are attached are a saturated mono or bicyclic heterocycle having from 3 to 10 members, which optionally contains another heteroatom chosen from oxygen, sulfur and nitrogen, and which is optionally substituted with an alkyl radical, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CQ-alk-NRi4Ri5 or a heterocycle mono or bicyclic saturated having from 3 to 10 members and containing a heteroatom chosen from oxygen, sulfur and nitrogen, R14 and R15, identical or different, represent a hydrogen atom or an alkyl radical or -COOalk, ie and R17, form together with the nitrogen atom to which are attached a saturated mono or bicyclic heterocycle having from 3 to 10 members, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen, R 'represents a hydrogen atom or a radical -CO- alk, alk represents an alkyl or alkylene radical, it being understood that the radicals and alkyl and alkylene portions and the radicals and alkoxy portions are straight or branched chain and contain 1 to 6 carbon atoms, their isomers s opticals and their salts with a mineral or organic acid.

2. The compounds of the formula (I) according to claim 1, characterized in that R6 and R7 together with the nitrogen atom to which they are attached are a mono or bicyclic, saturated or unsaturated heterocycle having from 3 to 10 members, this is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl, imidazolyl, thiomorpholinyl or furyl cycle, these cycles being optionally substituted by an alkyl, hydroxyalkyl, alk-O-alk, -CONH2, -COalk, -COOalk, oxo, - CSNHalk, -CONHalk, or -CO-alk-NR? DR15 in which alk, R14 and R15 have the same meanings as in claim 1, their optical isomers and their salts with a mineral or organic acid.

3. The compounds of the formula (I) according to any of claims 1 or 2 characterized in that when R? 0 and Rn form together with the nitrogen atom to which they are attached, a mono or bicyclic saturated heterocycle and having 3 to 10 members, this is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl cycle, these cycles being optionally substituted with an alkyl, their optical isomers and their salts with a mineral or organic acid.

4. The compounds of the formula (I) according to any of claims 1 to 3, characterized in that when R 2 and 13 together form the nitrogen atom to which a saturated mono or bicyclic heterocycle is attached and which has 3 to 10 members, this is an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl cycle, these cycles being optionally substituted by an alkyl radical, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk- NRi4.Ra5 Q a saturated mono- or bicyclic heterocycle having from 3 to 10 members and containing a heteroatom chosen from oxygen, sulfur and nitrogen, and, in particular, by a thiomorpholinyl radical, alk, R14 and R15 having the same meanings as in claim 1, their optical isomers and their salts with a mineral or organic acid.

5. The compounds of the formula (I) according to any of claims 1 to 4, characterized in that when R? e and p form together with the nitrogen atom to which a saturated mono- or bicyclic heterocycle is attached and having from 3 to 10 members, this is a piperidyl ring, its optical isomers and its salts with a mineral or organic acid.

6. The compounds of the formula (I) according to any of claims 1 to 5, characterized in that R9 represents an alkyl radical substituted with a saturated or unsaturated mono- or bicyclic heterocycle having from 3 to 10 members, optionally containing one or several heteroatoms chosen from oxygen, sulfur and nitrogen, the latter being a pyrrolidinyl, tetrahydrofuryl, morpholinyl, pyrrolyl cycle and these cycles being optionally substituted with one or more alkyl radicals, their optical isomers and their salts with a mineral or organic acid.

7. The compounds of the formula (I) according to claim 1, characterized in that: R represents a chain (A) or (B), R 'represents a hydrogen atom or a radical -COalk, Rx represents a methyl or ethyl radical , R2 represents either an aromatic radical chosen from phenyl and naphthyl, these aromatic radicals being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, hydroxy radicals, -CQQRs, trifluoromethyl, trifluoromethylsulfañil, trifluoromethoxy, -NR6R7, -CO -NH-NR6R7, cyano, -CONHR9, alkylsulfañilo, hydroxyalkyl, nitro, -CO-NR16R17, -0-alkNR12Ri3 or alkylthioalkyl or a heteroaromatic chosen from isoquinolinyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1, 2,3,4-tetrahydroquinolyl, thienyl, these heteroaromatics being unsubstituted or substituted with a halogen, alkyl, alkoxy, -COOR 5, trifluoromethyl, trifluoromethylsulfañyl, trifluoromethoxy, -NR6R7, -CO-NH-NRgR?, cyano, -CONHR9, alkylsulfañilo, hydroxyalkyl, nitro or alkylthioalkyl, R3 and R4, identical or different, represent either an aromatic radical chosen from phenyl or naphthyl, these aromatic radicals being unsubstituted or substituted by one or more halogen groups, alkoxy alkyl, trifluoromethyl, trifluoromethoxy, -CONRioRn, -alk-NR6R7, hydroxyalkyl, formyl, -COOR5, or a heteroaromatic radical chosen from the thiazolyl or thienyl rings, these aromatics being unsubstituted or substituted by a halogen, alkyl, alkoxy, -CONR10R11, -alk-NR6R7, hydroxyalkyl or -C00R5, Rs is alkyl or phenyl optionally substituted with one or more halogens, R6 and R7, identical or different represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl or R6 and R7 together with the nitrogen atom to which a saturated or unsaturated mono or bicyclic heterocycle is attached in 3 to 10 members, which optionally contains another heteroatom chosen from oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl radicals, -Coalk, -COOalk, -CO-NHalk, -CS-NHalk, -C0- alk-NR? 4Ri5, oxo, hydroxyalkyl, -alk-O-alk, -C0-NH2, Rg represents a hydrogen atom or an alkyl or alkyl radical substituted with dialkylamino, phenyl, cycloalkyl (optionally substituted with -COOalk) or a saturated or unsaturated monocyclic or bicyclic heterocycle having 3 to 10 members, optionally containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen, and optionally substituted with one or more alkyl, Rio and Rj radicals? identical or different, represent a hydrogen atom or an alkyl radical, or Ri0 and Rn together with the nitrogen atom to which they are attached are a saturated mono or bicyclic heterocycle, having 3 to 10 members, optionally containing another heteroatom selected between oxygen, sulfur and nitrogen and which is optionally substituted with an alkyl radical, R 12 and 13 identical or different, represent a hydrogen atom or an alkyl, cycloalkyl radical or Ri 2 and R 3 together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen, and which is optionally substituted with an alkyl radical, -COalk, -COOalk, -CO-NHalk, is attached; CS-NHalk, -C0-alk-NR? 4Ri5 or a saturated mono or bicyclic heterocycle, having 3 to 10 members, and containing a heteroatom chosen from oxygen, sulfur and nitr geno, R14 and R15 identical or different, represent a hydrogen atom or an alkyl radical, or -COOalk, Rie and Ri7 together with the nitrogen atom to which they are attached are a saturated mono or bicyclic heterocycle having from 3 to 10 members which optionally contains another heteroatom chosen from oxygen, sulfur and nitrogen, alk represents an alkyl or alkylene radical, it being understood that the radicals and alkyl and alkylene portions and the radicals and alkoxy portions are straight or branched chain and contain from 1 to 6 carbon atoms. carbon, its optical isomers and its salts with a mineral or organic acid. 3 £ 5-

8. The compounds of the formula (I) according to claim 1, characterized in that R represents a chain (A) or (B), R 'represents a hydrogen atom or a radical -COalk, Ri represents a methyl or ethyl radical, R 2 represents either an aromatic radical chosen from naphthyl, phenyl, phenyl substituted with one or more halogen, alkyl, alkoxy, hydroxyl, -COOR 5 groups (in which R 5 represents an alkyl or phenyl radical optionally substituted with several halogens), trifluoromethyl , trifluoromethylsulfanyl, trifluoromethoxy, -NR6R7, (in which R6 and R7 identical or different, represent a hydrogen atom or an alkyl radical or -COOalk, or R6 and R7 together with the nitrogen atom to which they are attached, constitute a heterocycle chosen from pyrrolidinyl, piperidyl, piperazinyl or piperazinyl substituted with one or more alkyl radicals, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR14R? 5, in which R14 and R15, identical or different , represent a hydrogen atom or an alkyl radical), -CO-NH-NR6R7 (Re and R, identical or different, represent a hydrogen atom or an alkyl radical, or R $ and R together with the nitrogen atom to which they are attached, a heterocycle selected from piperidyl, piperazinyl, or piperazyl substituted with one or more alkyl radicals), cyano, -CONHRg (in which Rg represents a hydrogen atom or an alkyl or alkyl radical substituted with dialkylamino, phenyl, cycloalkyl (optionally substituted with -COOalk} or a heterocycle selected from pyrrolidinyl (optionally substituted with alkyl), tetrahydrofuryl, morpholinyl), alkylsulfañilo, hydroxyalkyl, nitro, -CO-NR? 6R? 7 (in which Ri6 and n form together with the nitrogen atom to which they are attached , a piperidyl), -O-alkNR ^ Ria (in which R12 and R13 form together with the nitrogen atom to which a morpholino cycle is attached) or alkylthioalkyl, or a heteroaromatic radical selected from: isoquinolyl, pyridyl, quinolyl , 1,2, 3-4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thienyl, or thienyl substituted with a -COOR 5 (in which R 5 represents an alkyl radical) or -CONHR 9, (in which g represents an alkyl radical), R3 and R < , identical or different, represent either an aromatic radical chosen from: phenyl or phenyl substituted with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, hydroxyalkyl, formyl, -COOR 5 groups (in which R 5 is an alkyl radical), -CONRioRn (in which Rio and R3.1, identical or different, represent a hydrogen atom or an alkyl radical), -alk-NReR? (in which Re and R7, identical or different represent a • hydrogen atom or an alkyl radical, cycloalkyl, -alk-O-alk, hydroxyalkyl, or Re and R7 form, together with the nitrogen atom to which they are attached, a heterocycle selected from piperidyl (optionally substituted with alkyl oxo), pyrrolidinyl (optionally substituted with alkyl, hydroxyalkyl, -alk-O-alk, -CO-NH2), thiomorpholinyl, morpholinyl, pyrrolyl, piperazinyl optionally substituted by oxo, alkyl, hydroxyalkyl, -COOR5 (in which R5 is an alkyl radical) or a heteroaromatic radical chosen from: thiazolyl or thienyl, alk represents an alkyl or alkylene radical, it being understood that the radicals and alkyl and alkylene portions and the radicals and alkoxy portions are straight or branched chain and contain from 1 to 6 carbon atoms. carbon, its optical isomers and its salts with a mineral or organic acid.

9. The compounds, characterized in that they are chosen from: l-benzhydryl-3- [(methylsulfonyl) (phenyl) -methylene-benzethidine, l-benzhydryl-3- [(3-methyl phenyl) (methylsulfonyl) methylene] -zetidine, l-benzhydryl-3- ( 3-chlorophenyl) - (methylsulfonyl) methylene-benzethidine, l-benzhydryl-3- [(3,5-dichlorophenyl) - (methylsulfonyl) methylene-benzetidine, l-benzhydryl-3 - [(2,5-dichlorophenyl) (methyl-sulphonyl) methylene-benzetidine, l-benzhydryl-3- [(2,3-dichlorophenyl) (methylsulfonyl) methylene] -zetidine, l-benzhydryl-3- [(3-fluorophenyl) (methylsulfonyl) methylene] -zetidine, l-benzhydryl-3- [(3,5-difluorophenyl) ) (methylsulfonyl) methylene-benzethidine, 1-benzhydryl-3- [(3-bromophenyl) (methylsulfonyl) methylene-benzethidine, 1-benzhydryl-3- [(3-iodophenyl) (methylsulfonyl) methylene-benzethidine, 1-benzhydryl-3- [(methylsulfonyl)] (3-trifluoromethoxy-phenyl) methylene-benzethidine, l-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethyl-phenyl) -methylene-benzethidine, l-benzhydryl-3-. { [3, 5-bis (trifluoromethyl). (Phenyl) (methylsul fonyl) methylene.) -azetidine, l-benzhydryl-3- [(3,5-dibromophenyl) (methylsulfonyl) methylene-benzetidine, l-benzhydryl-3- [ (3-methoxycarbonyl-phenyl) - (methylsulfonyl) methylene-benzethidine, 1-benzhydryl-3- [(3-cyano-phenyl) (methylsulfonyl) methylene-benzethidine, 1-benzhydryl-3- [(3-carbamoyl-phenyl) (methylsulfonyl) methylene-benzetidine, 1-benzhydryl -3- [(methylsulfonyl) (naphth-1-yl) (methylsulphonyl) methylene-benzetidine, l- [bis (4-chlorophenyl) methyl] -3- [(3,5-difluorophenyl) (i-ylsulfsyl) methylenazetidine, l- [ bis (-methoxy-phenyl) -methyl-3- [(3,5-difluorophenyl) (methylsulfonyl) -methylene-benzetidine, l- [bis (4-methylphenyl) methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] -zetidine , (RS) -3- [3, 5-difluorophenyl) (methylsul fonyl) methyl in J-l- [(4-methoxy phenyl) (phenyl) methyl) J-azetidine, (R) -3- [(3, 5 -difluorophenyl) (methylsul fonyl) methylene] -l- [. {4-methoxy phenyl) (phenyl) methylj-azetldlna, (S) -3 - [(3,5-difluorophenyl) methylsulfoni l) methylene J-1 - [(4-methoxyphenyl) (phenyl) methyl-J-azetidine, l-bis (4-trifluorometide ifenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsul fonyl) methylene] -zetidine, l- [ bis (4-trifluoromethylphenyl) ethylJ-3- [(3,5-difluoro-phenyl) (methylsul-fonyl) -methylene-benzetidine, 1- [bis (4-chlorophenyl) methyl] -3-. { [3,5-bis- (trifluoromethyl) phenylethylsulfonylmethylene} azetidine, (RS) -l- [(-chloro phenyl) (2, -dichlorophenyl) -methylJ-3- [(3,5-di fluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -l- [(4-chlorophenyl) ( 2, -dichlorophenyl) -methyl J-3- [(3,5-difluorophenyl) methylsulfonyl) ethylene-benzetidine, (S) -l - [(4-chlorophenyl) (2,4-dichlorophenyl) -methyl-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, (RS) -1- i (4-chlorophenyl) [4- (hydroxymethyl) -phenylmethyl} -3- [3,5-difluorophenyl) (methylsulfonyl) -methylene-benzetidine, (R) -1-. { (4-chlorophenyl) [4- (hydroxymethyl) -phenylmethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) -methylene-benzetidine, (S) -1-. { (4-chlorophenyl) [4-hydroxymethyl) -phenylmethyl} -3 - [(3, 5- ifluorophenyl) (methylsulfonyl) -methylene-benzetidine, (RS) -l-. { (4-chlorophenyl) [4- (pyrrolidylmethyl) -phenylmethyl} -3- [(3,5-difluorophenyl) (methylsul-fonyl) -methylene-benzetidine, (R) -l- (4-chlorophenyl) [4- (pyrrolidylmethyl) -phenyl] -methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) -methylene-benzetidine, (S) -1-. { (4-chlorophenyl) [4- (pyrrolidylmethyl) -phenylmethyl} -3- [(3, 5-di fluorophenyl) (ethylsulfonyl) -methylene-benzetidine, l-. { (RS) - (4-chlorophenyl) [4- (3, 3-dimethyl-piperidin-1-yl-methyl) phenylmethyl} -3-JJ (3, 5-difluorophenyl) ethylsulfonyl) methylenejazetidine, l-. { (R) - (4-chlorophenyl) [4- (3, 3-dimethyl-piperidin-1-yl-methyl.}. Phenylmethyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, - { (S) - (4-chlorophenyl) [4- (3, 3-dimethyl-piperidin-1-yl-methyl) phenylmethyl} -3- | (3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine , l- { (RS) - (4-chlorophenyl) [4- (thiomorpholin-4-yl-methyl) phenylmethyl} -3- [(3 £ 5-difluorophenyl) (methylsul-fonyl) methylene-benzetidine, 1- {(R) - (4-chlorophenyl)} [4- (thiomorpholin-4-ylmethyl) phenylmethyl} - 3 - [(3,5-difluorophenyl) ethyl-sulphonyl) methylenediazetidine, 1-. (S) - (4-chlorophenyl) [4 - {thiomorpholinyl-methylmethyl] phenylmethyl] -3- [(3,5-di fluorophenyl) (methylsulfonyl) methylene] azetidine, 1- (RS) - (4-chlorophenyl) [4- (N-ethyl-N-cyclohexyl-aminomethyl) phenylmethyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, 1-. {(R) - (4 -chlorophenyl) [4- (N-ethyl-N-cyclohexyl-aminomethyl) phenylmethyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine , l-. { (S) - (4-chlorophenyl) [4- (N-ethyl-N-cyclohexyl-aminomethyl) phenylmethyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, 1-. { . { (RS) - (4-chlorophenyl). { - [(4-ethoxycarbonyl-piperazinyl) methyljphenyl} .metil} } -3- [(3, 5-difluorophenyl) (methylsulfonyl.) Methylenazetidine, l- { { (R) - (4-chlorophenyl). {4 - [(4-ethocarbaryl-piperazinyl) ethyl) phenyl Methyl.}.]. 3 - [(3, 5-difluorophenyl) (methylsulfonyl) methylenazetidine, l- { { (S) - (4-chlorophenyl) { 4- [( 4-ethoxycarbonyl-piperazinyl) methyl phenyl} methyl, 3, 3-difluorophenyl) (methylsulfonyl) -Rethylenazetidine, 1- (RS) - (4-chlorophenyl) [4 - (N-cyclopropyl-N-propyl-aminomethyl) phenylmethyl} -3- [(3,5-difluoro-phenyl) (methylsulfonyl) methylene-benzetidine, l- { (R) - (4-chlorophenyl) [A - (N-cyclopropyl-N-propy1-aminomethyl) phenylmethyl} -3 - [(3,5-difluorophenyl) (methylsulphonyl) ethylenejazetidine, l- { (S) - (4-chlorophenyl) f4- (N -cyclopropyl-N-propyl-aminomethyl.} phenylmethyl] -3-f (3,5-difluorophenyl) (methylsulfonyl) -Rethylene-Jazetidine, l- { (RS) - (4-chlorophenyl) [4- (di isopropy 1aminomethyl) phenylmethyl.} - 3 - [(3,5-difluorophenyl). (methylsulfonyl) methylenejazetidine. 1- . { (R) - (4-chlorophenyl) [4- (diisopropylaminomethyl) phenylmethyl} -3-f (3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, 1-. { (S) - (4-chlorophenyl) [4- (diisopropylamino-methyl) phenylmethyl} -3-f (3, 5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, 1-. { . { (RS) - (4-chlorophenyl). { 4- [bis- (2-methoxy-ethyl) aminomethyl-phenyl} methyl } } -3 - [(3, 5-di fluorophenyl) - (methylsulfonyl) methylenejazetidine, l-. { . { (R) - (4-chlorophenyl). { 4- [bis- (2-methoxy-ethyl) aminomethyl-phenyl} methyl } } -3- [(3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, l-. { ((S) - (4-chlorophenyl). { 4- [bis- (2-methoxy-ethyl) aminomethyl-phenyl} methyl } } -3-[. { 3, 5-difluorophenyl) • (methylsulfonyl) methylene-benzetidine, 1-. { (RS) - (-chlorophenyl) [4- (di-n-propylaminomethyl) phenylmethyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, l-. { (R) - (4-chlorophenyl) [4- (di-n-propylamino-methyl) phenylmethyl} -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene-benzetidine, 1-. { (S) - (4-chlorophenyl) [4- (di-n-propylaminomethyl) phenylmethyl} -3- [(3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, l-. { (RS) - (4-chlorophenyl) [4- (piperidin-1-yl-methyl) phenylmethyl} -3- [(3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, 1-. { (R) - (4-chlorophenyl) [4- (piperidin-1-yl-methyl) phenylmethyl} -3- [(3, 5-di fluorophenyl) - (methylsulfonyl) methylenejazetidine, l-. { (S) - (4-chlorophenyl) [4- (piperidin-1-yl-methyl) phenylmethyl} -3-f (3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, 1-. { (RS) - (4-chlorophenyl) [4- (4-methyl-piperazin-1-yl-methyl) phenylmethyl} -3- [(3,5-difluorophenyl) - (methylsulfonyl) ethylenjazetidine, 1-. { (R) - (4-chlorophenyl) [4- (4-methyl-iperazin-1-yl-methyl) phenylmethyl} -3-f (3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, 1-. { (S) - (4-chlorophenyl) [4- (4-methyl-piperazin-1-yl-methyl) phenylmethyl} -3-f (3, 5-di fluorophenyl) - (methylsul fonyl) methylene-benzetidine, 1-. { (RS) - (4-chlorophenyl) [4- (4-morpholin-4-ylmethyl) phenylmethyl} -3- [(3,5-di-fluorophenyl) - (methylsulfonyl) methylene-benzetidine, 1-. { (R) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenylmethyl} -3- [(3, 5-difluorophenyl) -. { methylsulfonyl) methylene-azetidine, 1-. { (S) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenylmethyl} -3-f (3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, 1-. { (RS) - (4-chlorophenyl) [4- (diethylaminomethyl) • phenylmethyl} -3-f (3, 5-difluorophenyl) (methylsulfonyl) -methylene-benzetidine, 1-. { (R) - (4-chlorophenyl) [4- (diethylaminomethyl) -phenylmethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) -methylene-benzetidine, 1-. { (S) - (4-chlorophenyl) [A - (diethylaminomethyl) -phenylmethyl} -3- [(3,5-di-fluorophenyl) (methylsulfonyl) -methylene-benzetidine, 1-. { (RS) - (4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenylmethyl} -3-f (3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, 1-. { (R) - (4-Chloro-phenyl) [4- (piperazin-2-one-4-yl-methyl) -phenyl-methyl)} -3-f (3, 5-difluorophenyl) - (methylsulphonyl) methylenazetidi a, 1-. { (S) - (4-chlorophenyl) [4- (piperazin-2-one-4-yl-methyl) phenylmethyl} -3-f (3,5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, 1-. { (RS) - (4-chlorophenyl) f4- (imidazol-1-yl-methyl) phenylmethyl} -3-f (3, 5-di fluorophenyl) - (methylsulfonyl) methylenejazetidine, l-. { (R) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenylmethyl} -3-f (3, 5-difluorophenyl) -. { methylsulfonyl) methylene-azetidine, 1-. { (S) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenylmethyl} -3-f (3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, (RS) -1-((4-chloro phenyl) f4- (N, N-dimetucarbamoi 1) phenylmethyl} -3-f (3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, (R) -l-. { (4-chlorophenyl) f4- (N, N-dimethyl-carbamoi 1) phenylmethyl} -3- [(3, 5-difluorophenyl) -. { methylsulfonyl) methylenejazetidine, (S) -l-. { (-chloro phenyl) [4- (N, N-dimethyl-carbamoyl) phenylmethyl} -3-f (3, 5-di fluorophenyl) -. { methylsulfonyl) methylene-benzetidine, (RS) -1-((4-chlorophenyl) [4- (N-ethylcarbamoyl) phenylmethyl} -3-f (3, 5-difluorophenyl) - (methylsulfonyl) methylenejazetidine, (R) -l-. { (4-chlorophenyl) [4- (N-ethylcarbamoyl) phenylmethyl} -3-f (3, 5-difluorophenyl) (methylsulfonyl) methylenejazetidine, (S) -l-. { (4-chlorophenyl) [4- (N-ethylcarbamoyl) phenylmethyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, (RS) -1-f (4-carbamoyl-phenyl) (4-chlorophenyl) -methyl-3-f (3,5-difluorophenyl) (methylsulfonyl) -methylene-benzetidine, (R) -1-f (4-carbamoyl phenyl) (4-chlorophenyl) -methyl-3-f (3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, (S) -1-f (4-carbamoyl) phenyl) (4-chlorophenyl) -methyl-3-f (3,5-difluorophenyl) (methylsulfonyl) -methylene-benzetidine, l-fbis (4-chlorophenyl) methyl-3- [(3,5-dichloro-phenyl) (methylene sulfonyl) Methylenazetidine, l-benzhydryl-3-f (3-methylsulphenylphenyl) - (methylsulfonyl) methylenazetidine, l-benzhydryl-3- [(3-methylsulfanylmethyl) - (phenyl) J (methylsulfonyl) methylenediazetidine, l- [bis (4-chlorophenyl) methyl] J-3-f (3-cyanophenyl) (methylsulfonyl) ethylenejazetidine, 1-fbis (4-chlorophenyl) methylJ-3-f (3-carbamoyl-phenyl) (methylsulphonyl) methylene-benzetidine, 1-fbis (4-chlorophenyl) methylJ-3-f (3-methoxy-phenyl) (methylsul-fonyl) methylene-benzetidine, 1-fbis (4-chlorophenyl) methy1J-3-f (3-hydroxy-phenyl) (methyl sulfonyl) methylenazetidine, 1-fbis (4-chlorophenyl) met i 1J-3-f (methyl-sulfonyl) (3- pyrrolidinylphenyl) methylenazetidine, 1-fbis (4-chlorophenyl) methylJ-3-f (3-hydroxy-methyl phenyl) (methylsulfonyl) methylene-benzetidine, 1-fbis (4-chlorophenyl) methylj3-. { (methyl-sulfonyl) [3- (N-piperidylcarbamoyl) phenyl-methylene} azetidine, 1-fbis (4-chlorophenyl) methylJ-3-f (methylsulfonyl) (3-trifluoromethylsulfanylphenyl) - (methylsulfonyl) methyleneprazetidine, 1-fbis (4-fluorophenyl) methylJ-3-. { (3, 5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, 1-fbis (2-fluorophenyl) methylJ-3-f (3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, 1-fbis (3-fluorophenyl) methyl] -3- f (3, 5-difluorophenyl) (methylsulphonyl) methylene-benzetidine, (RS) -1-f (4-chlorophenyl) (thiazol-2-yl) methylJ-3- [(methylsulfonyl) (phenyl) methylene] azetidine, (R) - 1-f (4-chlorophenyl) (thiazol-2-yl) methylJ-3- [(methylsulfonyl) (phenyl) methylene] azetidine, (S) -1-f (4-chlorophenyl) (thiazol-2-yl) methylJ-3 - [(methylsulfonyl) (phenyl) methylene-benzetidine, (RS) -1-f (4-chlorophenyl) (thien-2-yl) methylJ-3 - [(3,5-di-fluorophenyl) (methylsulfonyl) methylene-benzetidine, (R) -1-f (4-chlorophenyl) (thien-2-yl) methylJ-3- [(3, 5-difluorophenyl). (Methylsulfonyl) methylene-benzetidine, (S) -1-f (-chlorophenyl). (thien-2-yl) methyl] -3-f (3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, l-benzhydryl-3- [(ethylsulfonyl) (phenyl) -methylene-benzetidine, 1-fbis (4-chlorophenyl) methyl J-3- { { 3- [N- (4-methyl-piperazinyl) carbamoyl-phenyl] - (methylsulfonyl) methylene.} - azetidine, 1-fbis (4-chlorophenyl) methyl J-3-. { 3- (2,2-dimethylcarbohydrazido) phenylj (methylsulfonyl) methylene.} - azetidine, 1-fbis (thien-2-yl) methylJ-3-f (3,5-difluoro-phenyl) (methyl) sulphile) methylenazetidine, 1-fbis (p-tolyl) methylJ-3- [(methylsul fonyl) -. {phenyl) methylenazetidine, 1-f (4-chlorophenyl) (4-hydroxymethylphenyl) -methyl-3-f ( 3, 5-difluorophenyl) (methylsul fonyl) -methylene-benzetidine, 1-fbis (4-chlorophenyl) methylJ-3-f (3-methylamino-phenyl) (methylsulfonyl) methylene-azetidine, (RS) -1-f (4-chlorophenyl) (thiazol-2-yl) methyl] -3-f (3,5-difluorophenyl) (methylsulf onil) methylenejazetidine, (R) -1-f (4-chlorophenyl) (thiazol-2-yl) methylJ-3-f (3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, (S) -l - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3-f (3,5-difluorophenyl) (methylsulfonyl) methylene-benzetidine, 1-fbis (4-chlorophenyl) methyl J-3- [ (methylsul fonyl) (2-methoxycarbonylthien-5-yl) methylene-benzetidine, 1-fbis (4-chlorophenyl) methyl] -3-hydroxy-3- [(methylsulfonyl) (2-ethoxycarbonyl-thien-5-yl) methyl-azetidin - (RS), 1-fbis (4-chlorophenyl) methylj-3-f (2-isobutyl-aminocarbonylthien-5-yl) (methylsulfonyl) methylene-benzetidine, 1-fbis (4-chlorophenyl) methyl J-3-f (3- methoxycarbonylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 1-fbis (4-chlorophenyl) methyl-3-f (methyl-sulfonyl) (pyridin-4-yl) methyl- (RS) Jazetidin-3 -ol, 1-fbis (4-chlorophenyl) methyl] -3-f (methylsulfonyl) (pyridin-3-yl) methyl- (RS) Jazetidin-3-ol, 3- (. {1-fbis (4- chlorophenyl) methylJazetidin-3-ylidene.} - methanesulfonyl-methyl) N- (3-morpholin-4-yl-propyl) benzamide, 3- (. {1-fbis (4-chlorophenyl) methyl] azetidin-3- yliden.} - methanesulfonyl-methyl) N- (3-dimethylamino-propyl) benzamide, 3- (. {1-fbis (4-chlorophenyl) me tilJazetidin-3-iliden} -metanesulfonyl-methyl) N- (2-pyrrolidin-1-yl-ethyl) -benzamide, 3- (. {1-fbis (4-chlorophenyl) methyl-Jazetidin-3-ylidene} -metanesulfonyl-methyl) - (2-pyrrolidin-1-yl-ethyl) -benzamide, -dimethylamino-1-methyl-ethyl) benzamide, 3- (. {1-fbis (4-chlorophenyl) methylJazetidin-3-ylidene} - methanesulfonyl-methyl) N-piperidin-1-yl-benzamide, 3- ( { 1-fbis (4-chloro-phenyl) -methyl-benzethidin-3-ylidene} -metanesulfonyl-methyl) -N-isobutyl-1-benzamide, 3- (. {1-fbis (4-chlorophenyl) methyl-Jaszetidin-3- ylidene.} - methanesulfonyl-methyl) N- (3-imidazol-1-yl-propyl) benzamide, 3- (. {1-fbis (4-chlorophenyl) methyl-Jazetidin-3-ylidene} -metanesulfonyl-methyl N- (2-dimethylamino-ethyl) benzamide, 3- (. {1-fbis (4-chlorophenyl) methylJazetidin-3-ylidene} -metanesulfonylmethyl) benzoic acid N '-methyl hydrazide, 3- ( {.1-fbis (4-chlorophenyl) methylJazetidin-3-ylidene} -metanesulfonyl-methyl) N- (2-morpholin-4-yl-ethyl) benzamide, 3- (. {1-fbis (4 -chlorophenyl) methylJazetidin-3-ylidene.} - methanesulfonyl-methyl) N- (1-ethyl-pyrrolidin-2-ylmethyl) benzamide, 3-. { . { L-fbis (4-chlorophenyl) methylJazetidin-3-ylidene} -metanesulfonyl-methyl} N- (2,2-dimethyl-propyl) benzamide, 3- (. {1-fbis (4-chlorophenyl) ethylJazetidin-3-ylidene} - methanesulfonyl-methyl) N-cyclohexylmethyl-benzamide, 3- ( {1-fbis (4-chlorophenyl) methylJazetidin-3-ylidene}. -metansul fonyl-methyl) N-cyclopropylmethyl-benzamide, 3- (. {L-fbis (4-chlorophenyl) methyl] azetidin-3- ylidene) -metansul fonyl-methyl) N- (2-methyl-butyl) -benzamide, 3- (. {1-fbis (4-chlorophenyl) methyl-Jazetidin-3-ylidene}. -metanesulfonyl-methyl) N - (2-phenyl-propyl) -benzamide, 3- (. {1-fbis (4-chloro-phenyl) -methyl-Jazetidin-3-ylidene} -metanesulfonyl-methyl) N- (tetrahydro-furan-2-ylmethyl) benzamide, 3- ( { 1-fbis (4-chlorophenyl) methylJazetidin-3-ylidene.} - methanesulfonyl-methyl) N- (2, 2, -di phenyl-ethyl) -benzamide, 3- (. { 1-fbis (-chlorophenyl) methylJazetidin-3-ylidene} -metansul foni 1-methyl) N- (2-ethyl-butyl) benzamide, methyl ester of 4-acid. { [3- ( { 1-fbis (4-chlorophenyl) ethylJazetidin-3-ylidene] -metanesulfonylmethyl) benzoylaminojmethyl} -cyclohexanecarboxylic, 2-amino-l-. { 4-. { 3- ( { 1-fbis- (4-chlorophenyl) -methylJazetidin-3-ylidene} - methanesulfonyl-methyl) phenyl-piperazin-1-yl} ethanone, (2- {4- [3- (. {1-fbis- (4-chlorophenyl) methylJazetidin-3-ylidene} -metanesulfonyl-methyl) phenyljpiperazin-1-yl ester} -2-oxo-ethyl) carbamic, l-. { 4- [3- ( { 1-fbis- (4-chlorophenyl) methy1-azetidin-3-ylidene} -metansul-fonyl-methyl) -phenyl-piperazin-1-yl} -2-methylamino-ethanone, (2- {4-f3- ( { 1- [bis- (-chlorophenyl) methyl-3-ylidene} -methylene-methyl) phenyl} piperazine. -l-yl.} -2-oxoethyl) N-methylcarbamic acid, N-methylamide of 4- [3-. { . { l- [bis- (4-chlorophenyl) methylJazetidin-3-ylidene} methanesulfonylmethyl) phenyljpiperazine-1-carbothioic acid, 4- [3- (. {1-fbis- (4-chlorophenyl) methylJazetidin-3-ylidene} -metanesulfonylmethyl) phenylpiperidine-1-carboxylic acid N-methylamide , 4- [3- (. {1-fbis- (4-chlorophenyl) methylJazetidin-3-ylidene} -metanesulfonylmethyl) phenylpiperidine-1-carboxylic acid methyl ester, 1- [3- (. {1 -fbis- (4-chlorophenyl) methylJazetidin-3-ylidene.} - methanesulfonylmethyl] phenylJ-4-isobutyl-piperazine, 1- [3- (. {1-fbis- (4-chlorophenyl) methylJazetidin -3-ylidene.} - methanesulfonyl-methyl) phenyl J-4-ethyl-piperazine, 4-acetyl l- [3- ( { 1-fbis- (4-chlorophenyl) methylJazetidin-3-ylidene} - methanesulfonylmethyl) phenyljpiperazine, 1-. { 4- [3- ( { 1-bis- (4-chlorophenyl) methy1-azetidin-3-ylidene} - methanesulfonyl-methyl) phenyl-piperazin-1-yl} -2-dimethylamino-ethanone, l- [3- ( { 1-fbis- (4-chlorophenyl) methylJazetidin-3-ylidene} -metanesulfonyl-methyl) phenyljpiperazine, terbutyl ester of 4-f3- ( {1-fbis- (4-chlorophenyl) methyl-Jazetidin-3-ylidene} -metanesulfonylmethyl) phenyljpiperazine-l-carboxylic acid,? - [bis- (4-methoxycarbonylphenyl) methyl] -3-f (3,5-difluorophenyl) (methylsulfonyl) methylene-azetidine, 3-acetoxy-1-fbis (4-methoxycarbonyl-phenyl) -methyl-3-f (3, 5-difluorophenyl) (methylsulfonyl) methyl- (RS) Jazetidine, (RS) -4-f - (( 4-chlorophenyl). {3-f (3,5-difluoro-phenyl) -methanesulfonyl-methylene-1-yl-ididin-1-yl} -methyl) -benzyl-morpholine, 4- (4-. {3- (l-benzhydryl-azetidin -3-ylidene) -metanesulfonyl-methyl-phenoxy.} Butyl) morpholine, 4- (4-. {3-f (l-benzhydryl-azetidin-3-ylidene) -metansul-fonyl-methyl-phenoxy} -propyl) -morpholine, its optical isomers and its salts with a mineral or organic acid.

10. The following compounds: l- [bis (4-chlorophenyl) methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 3-acetoxy-l- [bis- (4-chlorophenyl) methyl] -3 - [(3, 5 -difluorophenyl) (methyl-sulphonyl) methyl) methylsulfonylmethyl- (RS) Jazetidine its optical isomers and its salts with a mineral or organic acid.

11. The process for preparing the compounds of the formula (I) according to claim 1, for which R represents a chain of the formula (A) characterized in that a corresponding compound of the formula (a) is dehydrated: wherein Ri, R2, R3 and R4 have the same meanings as in claim 1 and R "represents a hydroxyl, methanesulphonyloxy or acetyloxy radical, the product is isolated and optionally transformed into a salt with a mineral or organic acid.

12. The process for the preparation of the compounds of the formula (I) according to claim 1, for which R represents a chain (B) in which R 'is a hydrogen atom, characterized in the process in that a derivative is reacted R? S02CH2 2 (II) for which Ri and R2 have the same meanings as in claim 1, on an azetidinone of the formula: wherein R3 and R4 have the same meanings as in claim 1, the product is isolated and optionally transformed into a salt with a mineral or organic acid.

13. The process for the preparation of the compounds of the formula (I) according to claim 1, for which R represents a chain (B) in which R 'is a hydrogen atom, characterized in the process in that a derivative is reacted R3CH (Br) R4 for which R3 and R4 have the same meanings as in claim 1, on a derivative of the formula: in which Ri and R2 have the same meanings as in claim 1, the product is isolated and optionally transformed into salt with a mineral or organic acid.

14. The process for preparing the compounds of the formula (I) according to claim 1, for which R is a chain (B) in which R 'is a -CO-alk radical, characterized in that the process is reacted a Hal-CO-alk halide in which Hal represents a hydrogen atom and alk represents a straight or branched chain alkyl radical containing 1 to 6 carbon atoms, on a corresponding compound of the formula (I) for which R is a chain (B) in which R 'is a hydrogen atom, the product is isolated and eventually transformed into a salt with a mineral or organic acid.

15. The process for preparing the compounds of the formula (I) according to claim 1, for which R 2 represents a radical. aromatic or a heteroaromatic radical substituted with -NR6R in which Re and R? each represents a hydrogen atom characterized in the process because a corresponding compound of formula (I) is reduced for which R2 represents an aromatic radical or a heteroaromatic radical substituted with nitro, the product is isolated and optionally converted into a salt with a mineral or organic acid.

16. The process for the preparation of the compounds of the formula (I) according to claim 1, for which R 2 represents an aromatic or heteroaromatic radical substituted by -CONHRg and / or R 3 and / or R 4 represents an aromatic radical or a heteroaromatic radical substituted with -CONRIO n characterized the process because a corresponding compound of formula (I) is reacted for which R2 and / or R3 and / or R4 represents an aromatic radical or a heteroaromatic radical substituted with -C00R5 for which R5 is alkyl or phenyl optionally substituted with halogens, respectively with an amine H2NRg or HNR10Rn for which R3, Rio and R11 have the same meanings as in claim 1, the product is isolated and optionally transformed into salt with a mineral or organic acid .

17. The process for the preparation of the compounds of the formula (I) according to claim 1, for which R 2 represents an aromatic radical substituted by hydroxyl and / or R 3 and / or R 4 represents an aromatic radical or a heteroaromatic radical substituted by hydroxyl The process is characterized in that a compound of the corresponding formula (I) is hydrolyzed for which R 2 represents an aromatic radical substituted with alkoxy and / or R 3 and / or R 4 represents an aromatic radical or a heteroaromatic radical substituted with alkoxy, the product and is eventually transformed into salt with a mineral or organic acid.

18. The process for preparing the compounds of the formula (I) according to claim 1, for which R 2 represents an aromatic radical substituted with -NReR 7 for which Re represents an alkyl radical and R 7 represents a hydrogen atom, characterized in The process is that a corresponding compound of formula (I) is deprotected for which R2 represents an aromatic radical substituted with an -N (alk) COOR8 in which Rβ represents a terbutyl radical, the product is isolated and optionally converted to salt with a mineral or organic acid.

19. The process for the preparation of the compounds of the formula (I) according to claim 1, for which R 2 and / or R 3 and / or R 4 represent an aromatic radical or a heteroaromatic radical substituted with -COOR 5, characterized in that the process is esterified a derivative of the formula: FU for which R represents a chain C = C (S02R?) R '2 or C (OR') CH (S02R?) R'2, i, R'2, '3 and R' "have the same meanings as substituents Ri, R2, R3 and R4 of claim 1, subject to the proviso that at least one of the substituents R'2, R'3, R '4 represents an aromatic radical or a substituted heteroaromatic radical. with carboxyl, by means of a derivative of the formula R5OH for which R5 is alkyl or phenyl optionally substituted with one or more halogen radicals, the product is isolated and optionally converted into a salt with a mineral or organic acid.

20. The process for preparing the compounds of the formula (I) according to claim 1, for which R.sub.2 and / or R.sub.3 and / or R.sub.4 represents an aromatic radical or a heteroaromatic radical substituted with alkylthioalkyl, characterized in that the procedure is carried out react a derivative of the formula: for which R represents a chain C = C (SO2R1) R '2 or C (OR') CH (S02R?) R'2, R ', Ri, 2', s 'and 4' have the same meanings as substituents R ', Ri, R2, R3 and R4 of claim 1, with the proviso that at least one of the substituents R2', R3 ', R4' represent an aromatic radical or a heteroaromatic radical substituted with haloalkyl on a sodium alkylthiolate for which the alkyl part has a straight or branched chain and contains 1 to 6 carbon atoms, the product is isolated and optionally converted into a salt with a mineral or organic acid.

21. The process for preparing the compounds of the formula (I) according to claim 1, for which R 2 and / or R 3 and / or R 4 represent an aromatic radical substituted by hydroxyalkyl in which the alkyl contains a carbon atom, The process is characterized in that a compound of the formula (I) is reduced for which at least one of the substituents R.sup.2, R.sup.3, R.sup.4 represents an aromatic radical substituted with formyl, the product is isolated and optionally converted into a salt with an acid. mineral or organic.

22. The process for the preparation of the compounds of the formula (I) according to claim 1, for which R3 and / or R4 represent an aromatic radical substituted with -alk-NReR7 for which alk is an alkyl containing an carbon, the process characterized in that a compound of the formula (I) is reacted for which at least one of the substituents R3, R represents an aromatic radical substituted with formyl on an amine HNR6R7 in which Re and 7 have the same meanings that in the formula (I), the product is isolated and eventually transformed into salt with a mineral or organic acid.

23. The process for preparing the compounds of the formula (I) according to claim 1, for which R 2 represents an aromatic radical or a heteroaromatic radical substituted with -CONHR 9 and / or R 3 and / or R 4 represents an aromatic radical or a heteroaromatic radical substituted with -C0-NR? 0Rn, wherein the process is characterized in that a derivative of the formula is reacted: for which R represents a chain C = C (SO2 1) R '2 or C (OR') CH (S02R?) R'2, R ', Ri, R'2, R'3 and R' 4 have the same as the substituents R ', Ri, R2, R3 and R4 of claim 1, provided that at least one of the substituents R'2, R'3, R' 4 represents an aromatic radical or a substituted heteroaromatic radical with carboxyl respectively on an amine H2NR9 or HNR10R11 in which R9, Rio and R ?? they have the same meanings as in the formula (I), the product is isolated and eventually transformed into salt with a mineral or organic acid.

24. The process for the preparation of the compounds of the formula (I) according to claim 1, for which R2 and / or R3 and / or R4 represent an aromatic radical or a heteroaromatic radical substituted with -C0-NH-NR6R7, characterized the process in that a corresponding compound of formula (I) is reacted for which R 2 and / or R 3 and / or R 4 represent an aromatic radical or a heteroaromatic radical substituted with -COOR 5 and R 5 represents an alkyl or phenyl radical optionally substituted with the halogens, on a hydrazine H2N-NR6R7 for which R and R? they have the same meanings as in the formula (I), the product is isolated and eventually transformed into salt with a mineral or organic acid.

25. The process for preparing the compounds of the formula (I) according to claim 1, for which R 2 represents an aromatic radical or a heteroaromatic radical substituted with -CO-NHRg in which R 9 represents a hydrogen atom and / or R3 and / or R4 represent an aromatic radical or a heteroaromatic radical substituted with -CO-NR10R11 in which Ro and Rn are hydrogen atoms, characterized in that a corresponding compound of the formula (I) is hydrolysed for which R2 and R3 and / or R4 represent an aromatic radical or a heteroaromatic radical substituted with cyano, the product is isolated and optionally converted into a salt with a mineral or organic acid.

26. The process for the preparation of the compounds of the formula (I) according to claim 1, for which R2 represents an aromatic radical substituted by -0-alk-NR? 2Ri3, characterized in that a derivative of the formula is reacted : for which R represents a chain C = C (SO2R1) R '2 or C (OR') CH (SO2R1) R'2, R ', Ri, R'2, R'3 and R'4 have the same meanings than the substituents R ', Ri, R2, R3 and R4 of claim 1 with the proviso that at least one of the substituents R'2, R'3, R'4 represents an aromatic radical substituted with -O-alk-Hal in which alk represents a straight or branched chain alkyl radical and containing 1 to 6 carbon atoms, and Hal represents a halogen atom on an amine HNR12R13 in which R12R13 has the same meanings as in claim 1, isolates the product and is eventually transformed into salt with a mineral or organic acid.

27. The process for preparing the compounds of the formula (I) according to claim 1, for which R3 and / or R4 represent an aromatic radical substituted by -alk-NRgR7, characterized in that a derivative of the compound is reacted formula:

R, for which R represents a chain C = C (SO2R1) R '2 or C (OR') CH (S02R?) R'2, R ', Ri, R'2, R'3 and R' 4 have the same means that the substituents R ', Ri, R2, R3 and R4 of claim 1, subject to the proviso that at least one of the substituents R'3, R'4 represents an aromatic radical substituted with -alk-Cl in which represents an alkyl radical containing from 1 to 6 carbon atoms straight or branched chain on an amine HNR6R7 in which ReR7 has the same meanings in claim 1, isolates the product and is eventually transformed into salt with a mineral acid or organic 28. The process for preparing the compounds of the formula (I) according to claim 1, for which R represents a B chain, R 'represents a hydrogen atom and R3 and / or R4 represent an aromatic radical substituted with hydroxyalkyl in which the alkyl residue contains 1 carbon atom, characterized in that the diisobutyl aluminum hydride is reacted over a corresponding compound of the formula (I) for which R represents a B chain, R 'represents an hydrogen and R3 and / or R4 represent an aromatic radical substituted by one or more radicals -COOR5 in which R5 is an alkyl radical, the product is isolated and optionally converted into a salt with a mineral or organic acid.

29. The process for preparing the compounds of the formula (I) according to claim 1, for which R2 represents a phenyl radical substituted with -NReR? representing a 1-piperazinyl ring substituted at the 4-position with an alkyl radical, the process characterized in that a corresponding compound of the formula (I) is reacted for which R 2 represents a phenyl radical substituted with a radical -NR 6 R 7 representing a 1-piperazinyl cycle on an alk-CHO derivative in which alk represents a straight or branched chain alkyl radical containing 1 to 5 carbon atoms, the product is isolated and optionally converted into a salt with a mineral or organic acid.

30. The process for the preparation of the compounds of the formula (I) according to claim 1, for which R2 represents a phenyl radical substituted with -NReR7 representing a 1-piperazinyl ring substituted at the 4-position with a -COOalk radical, The process is characterized in that a compound of the corresponding formula (I) is reacted for which R 2 represents a phenyl radical substituted with a radical -NR 6 R 7 representing a 1-piperazinyl ring on a derivative of the formula Hal-COOalk in which represents a straight or branched chain alkyl radical containing 1 to 6 carbon atoms and Hal represents a halogen atom, the product is isolated and is optionally converted to a salt with a mineral or organic acid.

31. The process for preparing the compounds of the formula (I) according to claim 1, for which R 2 represents a phenyl radical substituted with -NR 6 R 7 representing a 1-piperazinyl ring substituted at the 4-position with a radical -CO- NHalk or -CS-Nhalk, characterized in that the process is carried out by reacting a corresponding compound of the formula (I) for which R 2 represents a phenyl radical substituted with -NR 6 R representing a 1-piperazinyl ring on a derivative of the formula Y = C = Nalk in which alk represents a straight or branched chain alkyl radical containing 1 to 6 carbon atoms and Y represents a sulfur or oxygen atom, the product is isolated and optionally converted into a salt with a mineral acid or organic

32. The process for preparing the compounds of the formula (I) according to claim 1, for which R2 represents a phenyl radical substituted with a radical -NR6R7 representing a 1-piperazinyl ring substituted at the 4-position with a -CO-alk-NR? 4Ri5 radical, characterized in that a compound of the invention is reacted corresponding formula (I) for which R2 represents a phenyl radical substituted with a radical -NR6R7 represents a 1-piperazinyl ring with an acid of the formula R? 5Ri4N-alk-COOH in which alk represents a straight-chain alkyl radical or branched containing 1 to 6 carbon atoms and R14 and R15 have the same meanings as in claim 1, optionally followed by a deprotection of the product for which R14 is a tert-butoxycarbonyl radical to obtain the compounds for which R14 is a hydrogen atom, the product is isolated and eventually transformed into salt with a mineral or organic acid.

• 33. The process for preparing the compounds of the formula (I) according to claim 1, for which R 2 represents a phenyl radical substituted with a radical -NR 6 R 7 represents a 1-piperazinyl ring substituted at the 4-position with a radical -CO-alk in which alk represents a methyl radical, wherein the process is characterized in that a compound of the corresponding formula (I) is reacted for which R 2 represents a phenyl radical substituted with a radical -NR 6 R 7 represents a 1-piperazinyl ring With acetic anhydride, the product is isolated and eventually converted to salt with a mineral or organic acid.

34. The pharmaceutical compositions, characterized in that they contain as an active ingredient at least one compound of the formula (I) according to any of claims 1 to 10.