NO324505B1 - Acetidine derivatives, their preparation and pharmaceutical compositions containing the compounds - Google Patents

Description

The present invention relates to compounds with the formula:

their salts, their preparation and pharmaceutical preparations containing the compounds.

In formula (I) means:

R a residue CRiR2, C=C(R5)SO2R6 or C=C(R7)SO2alk,

Ri either a hydrogen atom and R2 means a residue -C(R8)(R9)(Rio), -C(R8)(Rn)(Ri2),

-CO-NR13R14, -CH2-CO-NR13R14, -CH2-CO-R6, -CO-Re, -CO-cycloalkyl, -SO-Re,

-SO2-R6, -C(OH)(R12)(R6), -C(OH)(R6)(alkyl), -C(=NOalk)R6, ,.

-C(=NO-CH2-CH=CH2)R6, -CH2-CH(R6)NR3iR32, -CH2-C(=NOalk)R6,

-CH(R6)NR3iR32, -CH(R6)NHSO2alk, -CH(R6)NHCONAlk or -CH(R6)NHCOalk,

or

Ri an alkyl residue, NH-R15, cyano, -S-alk-NRi6Ri7, -CH2-NR18Ri9 or -NR20R2i and R2

means a residue -C(R8)(Rn)(R,2),

R3 and R4 are phenyl optionally substituted with one or more halogen, -COOalk,

hydroxyalkyl or -alk-NR24R2s; or a heteroaromatic selected from pyridyl, pyrimidinyl or thienyl, as these heteroaromatics may optionally be substituted with one or more halogens,

R5 a hydrogen atom,

R6 Scar or Hot,

R7 cycloalkyl, heterocycloalkyl or heterocyclenyl, optionally substituted with a -CSO-phenyl radical,

R.8 a hydrogen atom or an alkyl residue,

R9 a residue -CO-NR26R27, -COOH, -COOalk, -CH2OH, -NH-CO-NH-alk,

-CH2-NHR28 or -NHCOOalk,

or Rg and R9 together form a carbon-bound morpholine, pyrrolidine or piperazine ring, which may optionally be substituted with alkanoyl,

Rio a rest Ar or Het,

Rn a residue -SO2-alk, -SO2-Ar, -SO2-Het,

Ri2 a hydrogen atom or a residue Ar or Het,

Ro a hydrogen atom or an alkyl residue,

R14 a residue Ar, Het, -alk-Ar or -alk-Het,

R15 a residual alkyl, cycloalkyl or -alk-NR29R3o,

Ri6 and R17 are the same or different and mean a hydrogen atom or an alkyl residue, or Ri6 and Rn together with the nitrogen atom to which they are attached form a piperazine ring optionally substituted with one or more alkyl residues,

Ri 8 is a hydrogen atom or an alkyl residue,

R19 a hydrogen atom or a residue alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO2alk, -CO-NHalk or -COOalk,

-NR2oR2i an imidazole ring,

R24 and R25 are the same or different and mean a hydrogen atom or an alkyl residue,

R28 a residue -CH2-alk, benzyl, -SO2alk, -CONHalk, -COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, -CO-(CH2)„OH,

ner equal to 1, 2 or 3,

R29 and R30 together with the nitrogen atom to which they are bound form a pyrrolidine ring,

R31 and R32 are the same or different and mean a hydrogen atom or an alkyl residue, Ar or

-alk-Ar,

alk means an alkyl or alkylene residue,

Ar means a phenyl radical which is optionally substituted with one or more selected substituents

among halogen, alkyl, -alk-NR24R25, -NR24R25, CF3, pyrrolyl, azetidinyl, hydroxyalkyl or (alkoxycarbonyl)(alkyl)amino,

Het means a heterocycle selected from thienyl, pyridyl, tetrahydrofuryl, morpholinyl,

pyrrolidinyl or piperidinyl, where the heterocycle is optionally substituted with one or more halogen, alkoxycarbonyl or oxo,

where alkyl and alkylene residues and parts and alkoxy acid residues and parts are in straight or branched chain ag contains 1 to 6 carbon atoms and the cycloalkyl residues contain 3 to 10

carbon atoms,

their optical isomers and their salts with mineral or organic acids.

In the definitions above and in those that follow, unless otherwise stated, alkyl and

alkyl moieties and residues and alkoxy moieties and residues straight or branched chain with 1 to 6 carbon atoms, and the cycloalkyl residue contains 3 to 10 carbon atoms.

Among alkyl radicals, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-

butyl, tert-butyl, pentyl, hexyl. Among the carboxylic acid residues can be mentioned methoxy, ethoxy,

n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyl-

oxy.

Cycloalkyl residues include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term halogen includes chlorine, fluorine, bromine and iodine.

When R3 and/or R4 independently means substituted phenyl, this is preferably mono-, di-

or trisubstituted.

Preferably means:

R a residue CRiR2,

Ri either a hydrogen atom and R2 a residue -C(R8)(Rn)(Rn) or -C(R8)(R9)(Rio), or Ri an alkyl residue and R2 a residue -C(R8)(Rn)( Ri2),

R3 and R4 are phenyl which is optionally substituted with one or more halogen, hydroxyalkyl or -alk-NR24R2s; or a heteroaromatic selected from pyridyl, pyrimidinyl or thienyl, as these may optionally be substituted with one or more halogen,

R8 is a hydrogen atom,

R9 is a residue -CO-NR26R27, -COOalk, -CH2OH, -NH-CO-NH-alk, -CH2-NHR28 or

-NHCOOalk,

Rio is a remnant of Ar or Het,

Rn is a residue -SO2-alk, -SO2-Ar, -SO2-Het,

Ri2 is a hydrogen atom or a residue Ar or Het,

R24 and R25 are the same or different and mean a hydrogen atom or an alkyl residue,

Ar is a phenyl radical, optionally substituted with one or two substituents selected from halogen, alkyl, -alk-NR24R25, -NR24R25 or CF3,

It is a pyridyl or thienyl,

their optical isomers and their salts with a mineral or organic acid.

The compounds of formula (I) can exist in the form of enantiomers and diastereoisomers. These optical isomers and their mixtures form part of the invention. The present invention further provides a method for preparing compounds of formula (I), where R means a residue CR1R2, where Ri means a hydrogen atom and R2 a residue C(R8)(Rn)(Ri2), where R8 means a hydrogen atom, Rn means a residue -SO2-Ar, -SO2-Het or -SO2alk and Ri2 means a hydrogen atom or a residue Ar or Het, characterized by reducing a compound of formula:

Ra means an alkyl residue, Het or Ar and Rb means a hydrogen atom or a residue Ar or

Het, alkyl, Ar and Het have the same meaning as in claim 1, isolates the product and

optionally converting it to a salt with a mineral or organic acid.

The present invention further provides a method for preparing v compounds of formula (I), where R means a residue CRiR2, where Ri means a hydrogen atom and R2 means a residue C(R8)(Rii)(Ri2), where R8 means a hydrogen atom , Rn means a residue -S02-

Ar, -SO2-Het or -SO2alk and Ri2 means a hydrogen atom or an Ar or Het,

characterized by reacting a compound R3CH(Br)R4 with a compound of the formula:

where Ra means an alkyl residue, Het or Ar and Rb means a hydrogen atom or a residue Ar or Het, alkyl, Ar and Het have the same meaning as in claim 1, isolates the product and optionally converts it to a salt with a mineral or organic acid.

The present invention further provides a method for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH(R6)NR3iR32, R31 is a hydrogen atom and R32 is an alkyl residue, characterized by reacting a corresponding compound of formula (I) where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CO-R6 with an amine NHR3iR32, where R31 is a hydrogen atom and R32 a alkyl residue, isolates the product and optionally converts it into a salt with a mineral or organic acid.

The compounds of formula (I) where R means a residue CRiR2, where Ri means a hydrogen atom and R2 means a residue C(Rg)(Rn)(Ri2), where Rg means a hydrogen atom, Rn means a residue

-S02-Ar, -S02-Het or -SC^alk and Ri2 means a hydrogen atom or a residue Ar or Het, and the compounds of formula (I) where R means a C=C(Rs)SO2R6 or C=C(R7 )SC>2alk, is produced according to the following reaction scheme:

where, in the formulas, either Ra means an alkyl residue, Het or Ar and Rb means a hydrogen atom or a residue Ar or Het, or Ra means a residue Ar or Het and Rb means a hydrogen

atom or an alkyl residue, or Ra means an alkyl residue and Rb means a cycloalkyl, heterocycloalkyl or heterocyclenyl residue, optionally substituted with a -CSO-phenyl residue, Rc means a hydrogen atom or an acetyl residue, R3, R4, Ar and Het have the same meaning as under formula (I).

The reactions d and e can only be used when Rb is a hydrogen atom.

The reaction is generally carried out in an inert solvent, for example an ether such as tetrahydrofuran, in the presence of a strong base such as tert-butyllithium, n-butyllithium, lithium diisopropylamide or potassium tert-butylate at a temperature between -75°C and -15°C .

The dehydration reaction b generally occurs by any dehydration method well known to those skilled in the art which allows an alcohol to be dehydrated to obtain the corresponding alkene. Preferably, the acetyloxy derivative is prepared by the action of acetyl chloride in an inert solvent such as pyridine, tetrahydrofuran or dioxane, a chlorinated solvent such as dichloromethane or chloroform, at a temperature between 5°C and 20°C, after which the whole is treated with a base such as an alkali metal hydroxide such as NaOH , an alkali metal carbonate such as sodium or potassium carbonate, an amine, for example a trialkylamine such as triethylamine, 4-dimethylaminopyridine, diaza-1,8-bicyclo-[5.4.]undecene-7-, at a temperature between 0°C and the boiling temperature of the reaction medium . The acetyloxy intermediate can optionally be isolated. The acetyl oxide compound can also be produced directly in the reaction medium from reaction a.

Reduction c generally takes place in an inert solvent, for example an aliphatic C1.4 alcohol such as methanol, a chlorinated solvent such as chloroform or dichloromethane or a mixture of these solvents, in the presence of NaBHi, at a temperature between 0°C and the boiling point of the reaction medium .

Reaction d is carried out by the action of trimethylsilyl chloride in an inert solvent, for example an ether such as tetrahydrofuran, in the presence of n-butyllithium at a temperature of -70°C.

Reaction e likewise takes place in an inert solvent, for example an ether such as tetrahydrofuran, in the presence of a strong base such as tert-butyllithium, n-butyllithium or lithium diisopropylamide, potassium tert-butylate, at a temperature between -70°C and -15 °C. Reaction f generally takes place in a chlorinated solvent, for example dichloromethane or chloroform, at a temperature between 0°C and the boiling temperature of the reaction medium.

The hydrolysis g takes place in an inert solvent, for example an ether such as dioxane, using hydrochloric acid at a temperature close to 20°C.

The reactions h and j preferably take place in an inert solvent such as acetonitrile in the presence of an acid such as an alkali metal carbonate, for example potassium carbonate, at the boiling temperature of the reaction medium.

The reaction in takes place under a hydrogen atmosphere in the presence of a catalyst such as palladium or a derivative thereof, in an inert solvent such as methanol or ethanol, at a temperature between 15°C and 60°C.

The reaction k takes place in an inert solvent, for example a chlorinated solvent such as dichloromethane or chloroform, at a temperature between 0°C and the boiling temperature of the reaction mixture.

The compounds R3CH(Br)R4 are commercially available or can be obtained by applying or adapting the method described by W.E. Bachmann in "J. Am. Chem. Soc", 2135 (1933). In general, the corresponding alcohol R3CHOHR4 is brominated using hydrobromic acid in acetic acid at a temperature between 0°c and the boiling temperature of the reaction mixture.

The corresponding alcohols R3CHOHR4 are commercially available or can be obtained by applying or adapting the methods described by A.C. Plasz et al. in "J. Chem. Soc. Chem. Comm.", 527 (1972).

The intermediate products of formula 2 can be obtained by applying or adapting the methods described in the examples. In particular, one works according to the following reaction schemes:

where Hal means a halogen atom and preferably chlorine, bromine or iodine and Ra and Rb have the same meaning as mentioned earlier for compound (2).

Reaction a generally takes place in an inert solvent such as dimethylformamide or an aliphatic Ci-4 alcohol, at a temperature between 20°C and 30°C.

The reactions b and e take place by any known method which allows to oxidize a sulfur derivative without touching the rest of the molecule as described for example by M. Hudlicky in "Oxidations in Organic Chemistry", ACS Monograph, 186, 252-263

(1990). For example, one works by the action of an organic peracid or a salt of such a peracid (peroxycarboxylic or peroxysulfonic acid, especially peroxybenzoic, 3-chloroperoxybenzoic, 4-nitroperoxybenzoic, peroxyacetic, trifluoroperoxyacetic, peroxyformic or monoperoxyphthalic acid) or mineral peracids or a salt of such an acid (such as periodic or persulfuric acid) in an inert solvent, for example a chlorinated solvent such as chloroform or dichloromethane, at a temperature between 0°C and 25°C. It is also possible to use hydrogen peroxide, optionally in the presence of a metal oxide such as sodium tungstate or a periodate such as sodium periodate, in an inert solvent, for example an aliphatic C 14 alcohol such as methanol or ethanol, acetic acid, water or a mixture of these solvents, by a temperature between 0°C and 60°C. It is likewise possible to work in tert-butyl hydroperoxide in the presence of titanium tetraisopropyl in an aliphatic Ci-4 alcohol such as methanol or ethanol, or a water-alcohol mixture, at a temperature close to 25°C or with the help of Oxone® ( potassium peroxymonosulfate), in an aliphatic C 14 alcohol such as methanol or ethanol, in the presence of water, acetic acid or sulfuric acid, at a temperature close to 20°C.

Reaction c preferably takes place in an inert solvent, for example an aliphatic Ci.4 alcohol such as methanol or ethanol, at a temperature between 20°C and the boiling temperature of the reaction medium.

Reaction d takes place under an inert atmosphere such as argon and at a temperature between 50°C and the boiling temperature of the reaction mixture.

The reaction f generally takes place in an inert solvent such as tetrahydrofuran or an aliphatic ether such as ethyl ether, at a temperature close to -70°C.

Reaction g generally takes place in an inert solvent such as dimethylformamide, an aliphatic ether such as ethyl ether or an aliphatic C1-4 alcohol in the presence of a base such as sodium hydride and at a temperature between 0°C and 60°C.

The derivatives of formula Rb-CEk-Hal are commercially available or can be obtained by applying or adapting the methods described in the examples. In particular, the methyl derivative or the corresponding alcohol is halogenated using 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 and at the boiling temperature of the reaction medium. The methylated derivatives or the corresponding alcohols are commercially available and can be obtained according to the methods described by G.A. Brine et al. in "J. Heterocycl. Chem.", 26,677 (1989) and by D. Nagarathnam in "Synthesis" 8,743 (1992) as well as in the Examples.

The azeridinones of formula 3 can be obtained using the addition methods described by A.R. Katritzky et al. in "J. Heterocycl. Chem.", 271 (1994) or P.R. Dave in "J. Org. Chem.", 61, 5453 (1996) and the examples. One generally works according to the following reaction scheme:

where R3 and R4 in these formulas have the same meaning as formula (I) and Hal means a chlorine or bromine atom.

In step A, one preferably works in an inert solvent, for example an aliphatic Ci-4 alcohol such as ethanol or methanol, possibly in the presence of an alkali metal hydroxide, at the boiling temperature of the reaction medium.

In step B, the reduction is generally carried out using lithium aluminum hydride in tetrahydrofuran at the boiling temperature of the reaction medium.

In step C, one preferably works in an inert solvent, preferably an aliphatic Ci-4 alcohol such as ethanol or methanol in the presence of sodium bicarbonate and at a temperature between 20°C and the boiling temperature of the reaction medium.

In step D, oxidation is preferably carried out in DMSO by means of a sulphur-pyridine trioxide complex at a temperature close to 20°C or by means of dimethylsulfoxide in the presence of oxalyl chloride and triethylamine at a temperature between -70 and -50°C.

In step E, one works according to the method described by M. Grisat et al. in "J. Med. Chm:", 885 (1973). The magnesium compound is formed from the brominated derivative and then reacted with the nitrile in an ether such as ethyl ether at a temperature between 0°C and the boiling temperature of the medium. After hydrolysis with an alcohol, the imide intermediate is reduced in situ with sodium borohydride at a temperature between 0°C and the boiling temperature of the reaction medium.

The derivatives R3-CO-R4 are commercially available or can be obtained by applying or adapting the methods described by N.G. Customers et al. in "J. Chem. Soc. Perkin Trans", 1, 2815 (1997); M. Moreno-Marras in "Eur. J. Med. Chem.", 23 (5) 477 (1988); Skinner et al. in "J. Med. Chem.", 14 (6) 546 (1971); N.K. Hum in "Tet. Lett.", 36 (52) 9453 (1995); A. Medici et al. in "Tet. Lett.", 24 (28) 2901 (1983); R. D. Riecke et al. in "J. Org. Chem.", 62 (20) 6921 (1997); J. Knabe et al. in "Arch. Pharm.", 306 (9) 648 (1973); R. Consonni et al. in "J. Chem. Soc. Perkin Trans.", 1, 1809 (1996); FR-96-2481 and JP-94-261393.

The R3Br derivatives are commercially available or can be obtained by applying or adapting the methods described by L. Brandsma et al. in "Synth. Comm.", 20 (11) 1697 and 3153 (1990); M. Lemaire et al. in "Synth. Comm.", 24 (1) 95 (1994); H. Goda et al. in "Synthesis", 9, 849 (1992); and P. Baeuerle et al. in "J. Chem. Soc. Perkin Trans.", 2,489 (1993).

The derivatives R4CN are commercially available or can be obtained by applying or adapting the methods described by P. Bouyssou et al. in "J. Het. Chem.", 29 (4) 895 (1992); N. Suzuki et al. in "J. Chem. Soc. Chem. Comm.", 1523 (1984); S. Marburg et al. in "J. Het. Chem.", 17 1333 (1980); and V. Percec et al. in "J. Org. Chem.", 60 (21) 6895 (1995).

The compounds of formula (I) where R means a CRiR2 residue, where Ri means a hydrogen atom and R2 a residue C(R8)(R9)(Ri0), wherein R8 means a hydrogen atom, R9 a residue -CO-NR26R27,

-COOH, -COOalk, -CH2OH, -NHCOOalk or -NH-CO-NH-alk and R]0 an Ar or Het residue are prepared according to the following reaction scheme:

wherein R 3 , R 4 , R 10 , R 26 and R 27 have the same meaning as in formula (I) and alk means an alkyl residue.

The compounds of formula 4 are commercially available or can be obtained by esterification of the corresponding compounds, possibly in activated form as acid chloride. The acids are commercially available or can be obtained from the corresponding methylene derivatives according to the method described by J.P. Hansen et al. in "J. Heterocycl.", 10,711

(1973).

Reaction a generally occurs in an inert solvent, for example an ether such as tetrahydrofuran, in the presence of a strong base such as tert-butyllithium, n-butyllithium, lithium diisopropylamide, potassium tert-butylate, at a temperature between -70°C and -15 °C.

The reaction b generally takes place by any dehydration method well known to the person skilled in the art and which allows an alcohol to be dehydrated to obtain a corresponding alkene and in particular the methods described above.

The reduction c generally takes place in an inert solvent, for example an aliphatic Ci-4 alcohol, a chlorinated solvent such as chloroform, dichloromethane or a mixture of such solvents, in the presence of NaBH*, at a temperature between 0°C and the boiling temperature of the reaction medium.

Reaction d takes place by any method known to those skilled in the art to transfer an ester to the corresponding acid touching the rest of the molecule. One preferably works in an inert solvent such as dioxane in the presence of hydrochloric acid at the boiling temperature of the reaction medium.

Reaction e takes place by any method known to those skilled in the art to transfer an acid or a reactive derivative thereof to a carboxamide without touching the rest of the molecule. When using an acid, one preferably works in the presence of a condensation agent used in peptide chemistry as a carbodiimide, for example N,N'-dicyclohexylcarbodiimide or N,N'-diimidazolecarbonyl, in an inert solvent, for example a ether such as tetrahydrofuran or dioxane, an amide such as dimethylformamide or a chlorinated solvent such as methylene chloride, 1,2-dichloroethane or chloroform, at a temperature between 0°C and the reflux temperature of the reaction mixture. When using a reactive acid derivative, it is possible to react the anhydride, a mixed anhydride or an ester (which can be chosen from optionally activated esters of the acid); one works either in an organic medium, possibly in the presence of an acid acceptor, for example an organic nitrogen base such as trialkylamine, pyridine, diaza-1,8-bicyclo[5.4.0]undecene-7 or diaza-1,5-bicyclo[4.3 .0] nonene-5 in a solvent as indicated above or a mixture of such solvents, at a temperature between 0°C and the reflux temperature of the reaction mixture, or one works in a biphasic hydroorganic medium in the presence of an alkali metal or alkaline earth metal base (sodium or potassium) or a carbonate or bicarbonate of an alkali or alkaline earth metal at a temperature between 0 and 40°C.

Reaction f occurs by CURTIUS rearrangement, in the presence of diphenyl phosphorazide and triethylamine, in toluene, at a temperature close to 50°C.

For reactions g and h, you work directly in the reaction medium from step g at a temperature close to 20°C.

The compounds of formula (I) where R means a residue CR1R2, where Ri means a hydrogen atom and R2 means a residue -C(R8)(R9)(Rio), where Rg means a hydrogen atom, R9 a residue -CH2-NHR28 and Rio means an Ar or Het residue, can be prepared according to the following reaction scheme:

is R3, R4 and Rio have the same meaning as in formula (I), Rd means an alkyl or phenyl residue, Re means an alkyl residue, Rf means an alkyl residue, Rg means an alkyl residue, cycloalkylalkyl, cycloalkyl, -(CH2)nOH , n is equal to 1, 2 or 3.

Step a is generally carried out in an inert solvent, for example an aliphatic C 1 -alcohol such as methanol, a chlorinated solvent such as dichloromethane or dichloroethane or tetrahydrofuran, in the presence of a base such as NaBH(OCOCH 3 ) 3 at a temperature close to 20°C.

Step b is generally carried out in an inert solvent, for example a halogen solvent such as dichloromethane, in the presence of an organic base such as triethylamine or dimethylaminopyridine, at a temperature between 0°C and the boiling temperature of the reaction medium.

Step c is generally carried out in an inert solvent such as tetrahydrofuran and dimethylformamide, a chlorinated solvent such as chloroform or 1,2-dichloroethane, an aromatic solvent such as benzene or toluene, at a temperature between 10°C and the boiling temperature of the reaction medium.

Step d takes place by any method known to the person skilled in the art which allows an acid or a reactive derivative thereof to be transferred to a carboxamide without affecting the rest of the molecule, and in particular the methods indicated as preferred above.

The derivatives 6 can be obtained according to the following reaction scheme:

where R 3 , R 4 and R 10 have the same meaning as in formula (I) and Ms is a methylsulfonyloxy acid residue.

Step a is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of triethylamine, at a temperature between 10 and 20°C.

Step b is generally carried out with liquid ammonia in methanol, in an autoclave, at a temperature close to 60°C.

The compounds of formula (I) where R means a residue C R1R2, where Ri is a hydrogen atom and R2 is a residue -CONR13R14 can be prepared according to the following reaction scheme:

where R 3 , R 4 , R 13 and R 14 have the same meaning as in formula (I), Ms means a methylsulfonyloxy acid residue and Et means ethyl.

Step a is carried out in the presence of triethylamine in an inert solvent, for example an ether such as tetrahydrofuran, at a temperature close to 0°C.

Step b is generally carried out in an inert solvent such as a mixture of water and dimethylformamide at a temperature between 30 and 75°C.

Step c is carried out by any method known to those skilled in the art which allows a cyanide to be transferred to acid without touching the rest of the molecule. Preferably, calcium hydroxide is used in an aliphatic Ci-4 alcohol such as ethanol or in an aqueous medium at the boiling temperature of the reaction medium.

Step d is carried out by any method known to the person skilled in the art which allows an acid or a reactive derivative of this acid to be transferred to a carboxamide without touching the rest of the molecule, and in particular the methods described above are preferred.

The compounds of formula (I) where R means a residue CR1R2, where Ri is a hydrogen atom and R2 a residue -CH2-CONR13R14 can be prepared according to the following reaction scheme:

where R 3 , R 4 , R 13 and R 14 have the same meaning under formula (I) and Et means an ethyl residue.

Reaction a is generally carried out in an inert solvent such as tetrahydrofuran in the presence of a base such as sodium hydride or an alkali metal carbonate such as potassium carbonate, at a temperature between 20°C and the boiling temperature of the reaction medium.

Reaction b is generally carried out using NaBHt in ethanol at a temperature close to 0°C.

Reaction c takes place by any method known to those skilled in the art to transfer an ester to the corresponding acid without touching the rest of the molecule. One preferably works in an inert solvent such as dioxane in the presence of hydrochloric acid, at the boiling temperature of the reaction medium.

Reaction d is carried out by any method known to the person skilled in the art to transfer an acid or a reactive derivative thereof to a carboxamide without touching the rest of the molecule and in particular by the methods indicated as preferred.

The intermediates 7 can also be obtained by a malonic acid synthesis according to the following reaction scheme:

where Ms means a methylsulfonyloxyacid residue and R3 and R4 have the same meaning as stated in formula (I).

Reaction a generally occurs by the action of diethyl malonate in an inert solvent such as tetrahydrofuran in the presence of freshly prepared sodium ethylate and at the boiling temperature of the reaction medium.

Reaction b generally takes place in an aqueous hydrochloric acid solution at the reaction medium's boiling temperature.

The compounds In can also be obtained according to the following reaction scheme:

where R3, R4, R13 and R14 have the same meaning as under formula (I).

Step a is carried out by any method known to the person skilled in the art which allows an acid or a reactive derivative of this acid to be transferred to a carboxamide without affecting

• w ~

the rest of the molecule and in particular by the methods previously indicated as preferred.

Step b generally occurs in an inert solvent such as tetrahydrofuran in the presence of a base such as sodium hydride or potassium carbonate at a temperature between 20°C and the boiling point of the reaction mixture.

The reduction in step c generally takes place using NaBFLt in ethanol at a temperature close to 20°C.

The compounds of formula (I) where R means a residue CR1R2, where R1 is a hydrogen atom and R2 means a residue -SOR6 or -SO2R6 can be prepared according to the following scheme:

where R3, R4 and R6 have the same meaning as in formula (I) and Ms is a methylsulfonyloxy acid residue.

Step a is generally carried out in an inert solvent such as tetrahydrofuran in the presence of a mineral base such as sodium hydride and at a temperature between 0°C and the boiling temperature of the reaction medium.

Step b generally occurs by any method known to those skilled in the art for oxidation of a sulfur derivative as described by M. Hudlicky in "Oxidations in Organic Chemistry", ACS Monograph, 186, 252-263 (1990). For example, one works by the action of an organic peroxyacid or a salt of such a peroxyacid (peroxycarboxylic or peroxysulfonic acid and especially peroxybenzo, 3-chloroperoxybenzo, 4-nitroperoxybenzo, peroxyacetic, trifluoroperoxyacetic, peroxyformic or monoperoxyphthalic acid) or mineral peroxyacids or a salt of such an acid (for example periodic or persulphuric acid), in an inert solvent, for example a chlorinated solvent such as chloroform or dichloromethane, at a temperature between 0 and 25°C or also by means of oxone in a water-alcohol mixture (methanol, ethanol).

Step c is generally carried out by any method known to those skilled in the art for oxidizing a sulfinyl derivative. Preferably, one works by the action of an organic peroxy acid or a salt of such a peroxy acid (peroxycarboxylic or peroxysulphonyl acid and especially peroxybenzo, 3-chloroperoxybenzo, 4-nitroperoxybenzo, peroxyacetic, trifluoroperoxyacetic, peroxyformic or monoperoxyphthalic acid) or also by using oxone in a water-alcohol mixture (methanol, ethanol).

The compounds of formula (I) where R means a residue CR1R2, where R1 is a hydrogen atom and R2 means a residue -COR6 or -CO-cycloalkyl, can be prepared according to the following reaction scheme:

where R 3 and R 4 have the same meaning as in formula (I) and Rh has the same meaning as R 6 or means a C 3-10 cycloalkyl radical.

Step a is carried out by any method known in the art which allows an acid or a reactive derivative thereof to be transferred to a carboxamide without affecting the rest of the molecule and in particular the methods indicated above as preferred.

Step b is generally carried out in an inert solvent, for example an ether such as tetrahydrofuran, at a temperature close to 0°C. The organomagnesium compounds are prepared according to methods known to those skilled in the art such as those described in the examples.

The compounds of formula (I) where R 1 is a hydrogen atom and R 2 is a residue

-C(OH)(R6)(Ri2), -C(OH)(R6)(alkyl), -C(=NO-CH2-CH=CH2)R6 or -C(=NOalk)R6 can be prepared according to the following reaction scheme:

where R 3 , R 4 and Re have the same meaning as formula (I), Ri has the same meaning as R 12 or means a C 1-6 alkyl residue in a straight or branched chain and Rj means a C 1-6 alkyl residue in a straight or branched chain or -CH 2 -CHMDH 2 .

Step a is generally carried out in an inert solvent, for example an aliphatic alcohol such as ethanol, in the presence of sodium acetate, at a temperature between 20°C and the boiling temperature of the reaction medium.

Step b is generally carried out in an inert solvent, for example an ether such as tetrahydrofuran, at a temperature close to 0°C. The organomagnesium compounds are prepared according to methods known to those skilled in the art such as those described in the examples.

The compounds of formula (I) where R means a residue CR1R2, where R] is a hydrogen atom and R2 means a residue -CH(R6)NR3iR32, where R31 and R32 are hydrogen atoms,

-CH(R6)NHS02alk, -CH(R6)NHCONAlk or -CH(R6)NHCO Alk, can be prepared according to the following reaction scheme:

where R 3 , R 4 , R 6 and R 31 have the same meanings as in formula (I), Ms means a methylsulfonyloxy acid residue and alk means an alkyl residue.

Reaction a is generally carried out using NaBIL; in an ethanol at a temperature close to 20°C.

Step b is carried out in the presence of triethylamine in an inert solvent, for example an ether such as tetrahydrofuran, at a temperature close to 0°C.

Step c is carried out using liquid ammonia in methanol, in an autoclave at a temperature close to 60°C.

Step d is generally carried out in an inert solvent, for example a halogenated solvent such as dichloromethane, or tetrahydrofuran, in the presence of an organic base such as triethylamine or dimethylaminepyridine, at a temperature close to 20°C.

Step e is carried out by any method known per se to the person skilled in the art which allows an acid or a reactive derivative thereof to be transferred to a carboxamide without affecting the rest of the molecule and in particular the preferred methods as described above.

Step f is generally carried out in an inert solvent such as tetrahydrofuran, dimethylformamide, a chlorinated solvent such as chloroform or dichloroethane, an aromatic solvent such as benzene or toluene, at a temperature between 10°C and the boiling temperature of the reaction medium.

The compounds of formula (I) where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH(Rg)NR3iR32, where R31 is a hydrogen atom and R32 is an alkyl residue, Ar or -alk-Ar, can be prepared by the action of a halide HalR3i on a compound of formula (I) where R means a radical CR1R2, in which Ri is a hydrogen atom and R2 a radical

-CH(R6)NR3iR32, and R31 and R32 are hydrogen atoms.

This reaction is carried out in an inert, polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide in the presence of an organic or a mineral base such as metal potassium carbonate (for example sodium or potassium), trialkyl (triethylamine or dimethylaminopyridine), at a temperature between 0°C and the boiling point of the solvent , optionally in the presence of palladium or a salt or complex thereof.

The compounds of formula (I) where R means a residue CRiR2, where Ri is a hydrogen atom and R2 means a residue -CH(Re)NR3iR32, R31 is a hydrogen atom and R32 an alkyl residue, can likewise be prepared by the action of a corresponding compound of formula (I) where R means a residue CR1R2, where R1 is a hydrogen atom and R2 means -CO-R6 on an amine HNR3iR32, where R31 is a hydrogen atom and R32 an alkyl residue.

This reaction is generally carried out in an inert solvent, for example a chlorinated solvent such as dichloromethane or dichloroethane, in the presence of a reducing agent such as sodium triacetoxyborohydride at a temperature between 0 and 70°C.

The compounds of formula (I) where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH(R6)NR3iR32, and R31 and R32 are alkyl residues, Ar or -alk-Ar, can be prepared by the action of a halide HalR32 on a compound of formula (I) where R means a residue CRiR2, where Ri is a hydrogen atom and R2 means a -CH(R<s)NR3iR32, where R3i is a hydrogen atom and R32 is an alkyl residue, Ar or -alk -Year.

This reaction takes place in an inert, polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or mineral base such as metal potassium carbonate (for example sodium or potassium) trialkylamine (for example triethylamine or dimethylaminopyridine), at a temperature between 0°C and the boiling temperature of the solvent, optionally in the presence of palladium or a salt thereof or a complex thereof.

The compounds of formula (I) where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH(R6)NR3iR32, where R31 is a hydrogen atom and R32 is a C2-6-alkyl residue or C2-6-alk -Ar residue can be prepared by the action of an aldehyde RaCHO, where Ra is alkyl or -alk-Ar on a compound of formula (I) where R means CR1R2, where Ri is a hydrogen atom and R2 means -CH(R6)NR3iR32, where R31 and R32 are hydrogen atoms.

This reaction takes place in an inert solvent such as dichloromethane, dichloroethane, toluene or tetrahydrofuran, at a temperature between 0 and 50°C in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.

The compounds of formula (I) where R means CR1R2, where Ri is a hydrogen atom and R2 means -CH(R<s)NR3iR32, where R31 is alkyl, Ar or -alk-Ar and R32 is C2-6-alkyl or Ar- C2-6 -alk-Ar can be prepared by the action of an aldehyde RaCHO, where Ra is an alkyl residue or -alk-Ar residue on a compound of formula (I) where R means CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH(R6)NR3iR32, where R3i is a hydrogen atom and

R 32 is alkyl, Ar or -alk-Ar.

This reaction takes place in an inert solvent such as dichloromethane, dichloroethane, toluene or tetrahydrofuran, at a temperature between 0 and 50°C in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride. The compounds of formula (I) where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH2-COR6, -CH2-CH(R6)-NR3iR32, -CH2-C(=NOalk)R6 can be prepared in according to the following reaction scheme:

where R3, R4, Rg, R3i and R32 have the same meaning as formula (I) and alk means an alkyl residue.

Step a is generally carried out in a solvent such as tetrahydrofuran, at a temperature between 20°C and the boiling temperature of the reaction medium.

Step b is generally carried out in an inert solvent, for example an aliphatic alcohol such as methanol, a chlorinated solvent such as chloroform or dichloromethane, or a mixture of such solvents, in the presence of a reducing agent such as NaBH4, at a temperature between 0°C and the boiling point of the reaction medium .

Step c takes place by any method known to the person skilled in the art which allows an acid or a reactive derivative thereof to be transferred to a carboxamide without touching the rest of the molecule, and in particular the preferred methods described above.

Step d generally occurs in an inert solvent, for example an ether such as tetrahydrofuran, at a temperature close to 0°C. The organomagnesium compounds are prepared according to methods known to the person skilled in the art as described in the examples.

Step e is generally carried out in an inert solvent, for example an aliphatic Ci-4 alcohol such as methanol, in the presence of sodium acetate, at a temperature between 20°C and the boiling temperature of the reaction medium.

Step f takes place in an inert solvent, for example a chlorinated solvent such as dichloromethane or dichloroethane, in the presence of a reducing agent such as sodium triacetoxyborohydride, at a temperature between 0 and 70°C.

The compounds of formula (I) where R means CR1R2, where R1 means a residue cyano, -S-alk-NRieRn, -NHR15, alkyl or -NR20R21 and R2 means a residue -C(R8)(Rn)(Ri2), where R8 is a hydrogen atom, can be prepared according to the following reaction scheme:

where R3, R4, Rn, Ri2, R15, R16 and Rn have the same meaning as in formula (I), alk means an alkyl residue, Hal means a halogen atom and M means a metal and preferably copper.

Step a is preferably carried out in a polar solvent such as dimethylsulfoxide, at a temperature between 20 and 50°C.

Step b preferably takes place in an inert solvent such as dimethylsulfoxide, tetrahydrofuran, acetonitrile, in the presence of a base, for example an alkali metal carbonate such as potassium carbonate or ammonium hydroxide, at a temperature between 20°C and the boiling temperature of the reaction medium.

Step c preferably takes place in an inert solvent such as dimethylsulfoxide, tetrahydrofuran, acetonitrile in the presence of a base, for example an alkali metal carbonate such as potassium carbonate, or ammonium hydroxide, at a temperature between 20°C and the boiling temperature of the reaction medium.

Step d preferably takes place in an inert solvent, for example an ether such as ethyl ether, or tetrahydrofuran, at a temperature between -78°C and +20°C.

Step e preferably takes place in an inert solvent such as dimethylsulfoxide, tetrahydrofuran, acetonitrile, dichloromethane or dichloroethane, in the presence of a base, for example an alkali metal carbonate such as potassium carbonate or ammonium hydroxide, at a temperature between 20°C and the boiling temperature of the reaction medium.

The compounds of formula (I) where R means CR1R2, where Ri is a residue -alk-NRi8Ri9, where Ri8 and R19 mean a hydrogen atom can be prepared by reduction of the corresponding compound of formula (I) where R means a residue CR1R2, where Ri is a cyano residue.

This reaction generally takes place in an inert solvent such as tetrahydrofuran, ethyl ether or toluene at a temperature between 0°C and the boiling temperature of the reaction medium, in the presence of a reducing agent such as aluminum hydride.

The compounds of formula (I) where R means a residue CR1R2, where Ri means a residue -alk-N-RisRi9, where Rig means a hydrogen atom and R19 a residue alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO2alk, -CO-NHalk or -COOalk can be prepared by the action of a halide HalRig, where Hal means a halogen atom, on a compound of formula (I) where R means CR1R2, where Ri is -alk-NRigRig, where Rig and R19 means a hydrogen atom.

This reaction takes place in an inert, polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or mineral base (such as metal-alkali metal carbonate such as sodium or potassium, trialkylamine such as triethylamine or dimethylaminopyridine, at a temperature between 0°C and the boiling point of the solvent, optionally in the presence of palladium or a salt or complex thereof.

The compounds of formula (I) where R means a residue CR1R2, where Ri means a residue -alk-N-RigRi9, where Rig means an alkyl residue and R19 means alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO2alk, -CO-NHalk or - COOalk can be prepared by reacting an alkyl halide with a compound of formula (I) where R means CR1R2, where Ri means -alk-NRigRi9, where Rig means a hydrogen atom and R19 means alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonate, -SO2alk, -CO -NHalk or -COOalk.

This reaction takes place in an inert, polar solvent such as acetonitrile, tetrahydro-

furan or dimethylformamide in the presence of an organic or mineral base (such as alkali metal carbonate such as sodium or potassium, trialkylamine such as triethylamine or dimethylaminopyridine, at a temperature between 0°C and the boiling temperature of the solvent, optionally in the presence of palladium or a salt or complex thereof.

The compounds of formula (I) where R means a residue CR1R2, where Ri means a hydrogen atom

and R2 a residue -C(R8)(R9)(Rio) or -C(R8)(Rn)(Ri2), and either R1 means alkyl, NH-R15, cyano, -S-alk-NRi6Ri7, -alk- N-RigRi9 or -NR2oR2i and R2 means a residue

-C(Rg)(Rn)(Ri2) and Rg means an alkyl residue, can be produced by alkylation of a to-

corresponding compound with formula (1) where R8 is a hydrogen atom.

This reaction preferably takes place with the aid of a base, for example an alkali metal hydride such as sodium hydride, an alkali metal amide such as sodium amide, or an organometallic derivative, in an inert solvent, for example an ether such as ethyl ether, or tetrahydrofuran, at a temperature between -78 °C and +30°C, using an alkylating agent such as an alkyl halide or an alkyl sulfonate.

The compounds of formula (I) where R means C=C(R7)SO2 can also be prepared according to the following reaction scheme:

where R 3 , R 4 and R 7 have the same meaning as under formula (I), alk means an alkyl residue and Hal means a halogen atom. Reaction A takes place in an inert solvent, for example an ether such as ethyl ether, in the presence of a strong base such as tert-butyllithium or n-butyllithium, at a temperature between -70°C and -50°C by adding sulfur and then a alkyl halide such as an -iodide or -bromide).

Reaction B is generally carried out in an inert solvent, for example an ether such as tetrahydrofuran, in the presence of a strong base such as tert-butyllithium or n-butyllithium, at a temperature between -70°C and -50°C and then addition of azetidine- 3-one and returning to ambient temperature by hydrolysis.

Reaction C takes place by any method known to the person skilled in the art which allows a sulfur derivative to be oxidized without touching the rest of the molecule as described earlier.

It is clear to the person skilled in the art that in order to be able to carry out the methods according to the invention as described above, it may be necessary to introduce protective groups for the amino, hydroxy and carboxy functions in order to avoid secondary reactions. These groups are those that can later be eliminated without affecting the rest of the molecule. Examples of protective groups for the amino function include tert-butyl or methylcarbamates which can be regenerated using iodotrimethylsilane or allyl using palladium catalysts. Examples of protective groups for the hydroxy function include triethylsilyl, tert-butyldimethylsilyl which can be regenerated using tetrabutylammonium fluoride or also asymmetric acetals such as methoxymethyl or tetrahydropyranyl with regeneration using hydrochloric acid. Mention may be made of esters such as allyl or benzyl, oxazoles and 2-alkyl-1,3-oxazolines as protective groups for the carboxy function. Other protecting groups which may be used are described by T.W. Green et al. in "Protecting Groups in Organic Synthesis", 2nd edition, 1991, John Wiley & Sons.

The compounds of formula (I) can be purified by known, common methods such as crystallization, chromatography or extraction.

The enantiomers of the compounds of formula (I) can be obtained by resolution of the racemates, for example by chromatography on a chiral column according to W.H. Pirkle et al. in "Asymmetric synthesis", vol. 1, Academip Press (1983) or by formation of salts or by synthesis from chiral precursors. The diastereoisomers can be prepared according to known, classic methods such as crystallization, chromatography or from chiral precursors.

The compounds of 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, for example alcohol, ketone, an ether or a chlorinated solvent. These salts also form part of the invention.

As examples of pharmaceutically acceptable salts, the following can be mentioned: benzenesulfonate, bromine hydrate, chlorohydrate, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene-bis-p-oxynaphthoate, nitrate, oxalate, pamoate, phosphate , salicylate, succinate, sulfate, tartrate, theophylline acetate and p-toluenesulfonate.

The present invention further provides a pharmaceutical preparation, characterized in that it contains as active ingredient at least one compound of formula (I) according to the invention.

The compounds of formula (I) exhibit interesting pharmacological properties. The compounds have a strong affinity for cannabioid receptors and especially those of the CB1 type. They are antagonists of the CB1 receptor and are thus useful in the therapy and prevention of disorders affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system, the gastrointestinal tract or reproductive disorders (see, for example, Hollister, "Pharm. Ree", 38 ,1986,1-20, Reny and Sinha, "Prog. Drug. Res.", 36,71-114 (1991), Consroe and Sandyk in "Marijuana/Cannabinoids, Neurobiology and Neurophysiology", 459, L. Murphy and A . Barthe, ed. CRC Press, 1992).

Thus, the compounds can be used for the therapy or prevention of psychoses, including schizophrenia, anxiety problems, depression and epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, compulsive-obsessional disorders, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancer, movement disorders induced by drugs, dystonias, endotoxemic shocks, hemorrhagic shocks, hypertension, insomnia, immunological diseases, plauque sclerosis, nausea, asthma, appetite problems such as bulemia or anorexia, obesity, memory difficulties, withdrawal after chronic treatments or alcohol or drug abuse (opioids, bartiturates, cannabis, cocaine, amphetamines, phencyclide, hallucinogens or benzodiazepines, as analgesics or potentiators for the analgesic activity of narcotic or non-narcotic drugs. They can also be used for therapy or prevention of intestinal transit.

The affinity of the compounds of formula (I) for cannabis receptors is determined according to the method described by J.E. Kuster, J.I. Stevenson, S.J. Ward, T.E. D'Ambra as well as D.A. Haycock in "J. Pharmacol. Exp. Ther.", 264, 1352-1363 (1993).

In this test, the CI 50 value of the compounds of formula (I) is equal to or less than 1000 nM.

Their antagonistic activity has been shown by means of the hypotermin part, induced by an agonist for cannabis receptors (CP-55940) in mice according to the method described by R.G. Pertwee in "Marijuana," D.J. Harvey, ed., 84 Oxford IRL Press, 263-277 (1985).

In this test, the DE50 value for the compounds of formula (I) is equal to less than 50 mg/kg.

The compounds of formula (I) show a low toxicity and the DL50 value is above 40 mg/kg subcutaneously in mice.

The preferred compounds of formula (I) are the following: (RS)-1-(4-chlorophenyl)methyl]-3-[(3,5-mfluorophenyl)(methylsulfonyl)methyl]-azetim (R)- 1 - [bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]-azetidine, (S)-1-[bis(4-chlorophenyl)methyl]-3-[( 3,5-difluorophenyl)(methylsulfonyl)methyl]-azetidine, (RS)-1-[bis(4-chlorophenyl)methyl]-3-[(pyrid-3-yl)(methylsulfonyl)methyl]-azetidine, (R )-1-[bis(4-chlorophenyl)methyl]-3-[(pyrid-3-yl)(methylsulfonyl)methyl]-azetidine, (S)-1-|T5is(4-chlorophenyl)methyl]-3- [(pyrid-3-yl)(methylsulfonyl)methyl]-azetidine, (RS)-1-I>is(3-fluorophenyl)methyl]-3-[(3,5-aUfluorophenyl)(methylsulfonyl)methyl]-azetidi^ ( R)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]-azetidine, (S)-1-[>is(3-fluorophenyl)methyl]- 3-[(3,5-difl^ 1 -[bis(4-chlorophenyl)methyl]-3-(RS)- {[3-azetidin-1 -yl-phenyl]methylsulfonylmethyl} azetidine, l-[bis(4 -chlorophenyl)methyl]-3-(R)-{[3-azetidin-1-yl-phenyl]methylsulfonylmethyl}azetidine, 1 -[bis(4-chlorophenyl)methyl]-3-(S)- {[3- azetidin-1-yl-phenyl]methylsulfone ylmethyl} azetidine,

(RS)-1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]-pyrrolidine,

(R)-1-[3-({1-|^is-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]pyrrolic,

(S)-1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]pyrrolidine,

(RS)-N-[3-({1-|>is-(4-chlorophenyl)methyl]azetimn-3-yl}methylsulfonylmethyl^ methylamine,

(R)-N-[3-({l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl] amine,

(S)-N-[3-({1-[>is-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]-N-methylarnine,

(RS)-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-bis-trifluoromethylphenyl)methylsulfonyl-methyl]-azetidine,

(R)-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-bis-trifluoromethylphenyl)methylsulfonyl-methyl]-azetidine,

(S)-1-[13is-(4-chlorophenyl)methyl]-3-[(3,5-bis-trifluoromethylphenyl)methylsulfonyl-methyl]-azetidine, 1 - [bis-(4-chlorophenyl)methyl] -3 -(phenylsulfonylmethyl)-azetidine,

(RS)-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethyl]-3-methyl-azetidine,

(R)-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethyl]-3-methyl-

azetidine,

(S)-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethyl]-3-methyl-

azetidine,

(RS)-2- {1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexyl-acetamide,

(R)-2-{1-|>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexyl-acetamide,

(S)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexyl-acetamide,

(RS)-2-{1-I>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-mfluorophenyl)-3 acetamide,

(R)-2-{1-[bis-(4-chlorophenyl)methyl]-azetimn-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide,

(S)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutyl-acetamide,

(RS)-2- {1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropyl-methylacetamide,

(R)-2-{1-[bis-(4-dorphenyl)methyl]-azetimn-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropyl-methylacetamide,

(S)-2-{1-[bis-(4-Worphenyl)methyl]-azetimn-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropyl-methylacetamide,

(RS)-2- {1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropyl-acetamide,

(R)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropyl-acetamide,

(S)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropyl-acetamide,

(RS)-1-[bis-(4-chlorophenyl)-methyl]-3-[ 1 -(3,5-difluorophenyl)-1-methylsulfonyl-ethyl]-azetidine,

(R)-1-Is-(4-chlorophenyl)-methyl]-3-[1-(3,5-difluorophenyl)-1-methylsulfonyl-ethyl]-azetidine,

(S)-1-[bis-(4-chlorophenyl)-methyl]-3-[1-(3,5-difluorophenyl)-1-methylsulfonyl-ethyl]-azetidine,

(RS)-1-[bis-(4-fluorophenyl)-methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine,

(R)-1-[bis-(4-fluorophenyl)-methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine,

(S)-1-[bis-(4-fluorophenyl)-methyl]-3-[(3,5-mfluorophenyl)-methylsulfony

(RS)-{1-[(3-pyridyl)-(4-kHorphenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfone^azetidine,

(SS)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine,

(RR)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methine azetidine,

(SR)- {1 -[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine,

(RS)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine,

(SS)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine,

(RR)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine,

(SR)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine,

(RS)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-1-yl}-methyl)-pyrimidine,

(SR)-5-((4-chlorophenyl)- {3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-1 -yl}-methyl)-pyrimidine,

(RR)-5-((4-chlorophenyl)- {3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-1 -yl}-methyl)-pyrimidine,

(SS)-5-((4-chlorophenyl)-{ 3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetdin-1-yl}-methyl)-pyrimidine,

(SS)-{1-[(2-Fluoro-pyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methyl^methyl]azetidine,

(RR)-{1-[(2-chloro-pyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]azetidine,

(RS)-{1-[(2-Chloro-pyrid-5-yl)-(4-Worphenyl)methyl]-3-[(3,5-mfluorophenyl)-methylsulfonyl-methyl]azetidine,

(SR)-{1-[(2-chloro-pyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]azetidine,

their optical isomers and their pharmaceutically acceptable salts.

Example 1

(RS)-l-| )methyl]-3-[(3,5-difluorophenyl)methylsulfonyl)-methylene]-azetidine in 40 cm<3> of methanol, to which 96 mg of sodium hydroboride has been added and the whole is stirred for 3 hours at 20°C. After addition of 100 cm3 of dichloromethane, the reaction mixture is washed twice with 50 cm<3> of water, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The crude product is chromatographed on a silica gel column with granulometry 0.063-0.200 mm, height 6 cm and diameter 3 cm and it is eluted under an argon pressure of 0.8 bar with dichloromethane and then with dichloromethane + 1% methanol and fractions of 80 cm are recovered<3> . Fractions 13 to 15 are combined and concentrated to dryness at 2.7 kPa. .55 g of a white solid is obtained which is taken up in 50 cm 3 of isopropyl ether, filtered and dried to give 0.47 g of (RS)-1-[bis(4-chlorophenyl)-methyl]-3-[(3, 5-Difluorophenyl)(methylsulfonyl)methyl]-azetidine as a white solid.

<*>H-NMR (400 MHz, (CD3)2SO d6 with the addition of a few drops of CD3COOD d4, at a temperature of 353K, 8 in ppm): 2.46 (t, J = 7.5 Hz, 1H), 2.77 (s, 3H), 3.15 (mt, 2H), 3.40 (mt, 1H), 3.49 (t large, J = 7.5 Hz, 1H), 4.46 (s, 1H), 4.81 (d, J = 9 Hz, 1H), from 7.05 to 7.20 (mt, 3H), from 7.15 to 7.45 (mt, 8H). 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine can be prepared according to two methods:

Method 1

To a solution of 2.94 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]-(RS)]azetidin-3-ol in 250 cm3 of dichloromethane is added at 22°C 0.65 cm<3 >methylsulfonyl chloride and then, in small portions over 15 minutes, 2.42 g of 4-dimethylaminopyridine, after which the orange colored solution is stirred for 2 hours at ambient temperature. The reaction mixture is washed three times with 150 cm 3 of distilled water and once with 150 cm 3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The obtained residue is chromatographed over a silica gel column with granulometry 0.04-0.06 mm,

diameter 5.5 cm and height 15 cm, under an argon pressure of 0.5 bar and with ethyl acetate:cyclohexane in the volume ratio 1:9 as eluent and the fraction is recovered

tions of 70 cm<3>. Fractions 15 to 36 are combined and concentrated to dryness at 2.7

kPa. 1.86 g of white meringue mass is obtained which is crystallized from isopropyl ether to obtain a solid which melts at 190°C. A recrystallization from 45 cm3 of ethanol yields 1.08 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine with a melting point of 206°C.

^-NMR spectrum in DMSO-d6, T=300 K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH3),

3.87 (2H, s, NCH2), 4.20 (2H, s, NCH2) 4.75 (1H, s NCH), 7.15 (2H, d, J

= 8 Hz, 2CH arom.), 7.30 (5H, m, 5CH arom.), 7.45 (4H, d, J = 7 Hz,

4CH arom.).

To a solution of 6.8 g of bis-(4-chlorophenyl)bromomethane in 300 cm3 of acetonitrile is added 6.75

g of 2-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol hydrochloride and then 2.97 g of potassium carbonate. The reaction mixture is heated to reflux for 1 hour, cooled to ambient temperature, filtered and concentrated to dryness at 2.7 kPa. The obtained residue is chromatographed on a silica gel column with granulometry 0.04-0.06 mm, diameter 8.5 cm and height 22 cm, under an argon pressure of 0.5 bar and with ethyl acetate cyclohexane in the volume ratio 25:75 as eluent, recovering fractions of 150 cm<3>. Fractions 11 to 48 are combined and concentrated to dryness at 2.7 kPa. 5.3 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]-(RS)]azetidin-3-ol are obtained.

<!>H-NMR (300 MHz, (CD3)2SO d6, 8 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, 1H), 5.34 (s, 1H), 7.15 ( d, J = 8.5 Hz, 2H), from 7.20 to 7.40 (mt, 8H), 7.50 (t large, J = 9 Hz, 1H).

bis-(4-chlorophenyl)bromomethane can be prepared according to the procedure described by W.E. Bachmann in "J. Am. Chem. Soc", 2135 (1933).

3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol hydrochloride can be obtained in the following way: To a solution of 37 g of 3-[(3,5-difluorophenyl)(methylsulfonyl) )methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol in 160 cm<3> of dioxane is added to 160 cm<3> of a 6.2N hydrochloric acid solution in dioxane. After 16 hours at ambient temperature, the reaction mixture is concentrated to a dry state at 2.7 kPa. The obtained residue is taken up in 320 cm<3 >ethanol, heated to reflux for 1 hour and cooled in an ice water bath. The solid obtained is filtered, washed with ethyl ether and dried at 40°C and 2.7 kPa. 29.85 g of white crystals with a melting temperature of 260°C are obtained.

3-[(3,5-d^fluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol can be obtained in the following way: To a solution of 60.18 g of 1-benzhydryl- 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol in 1000 cm<3> dichloromethane is placed at 5°C a solution of 14 cm<3> vinyl chloroformate in 35 cm<3 > dichloromethane. After 20 hours at ambient temperature, the reaction mixture is concentrated to a dry state at 2.7 kPa. The residue obtained is chromatographed on a silica gel column with granulometry 0.04-0.06 mm, diameter 11 cm and height 32 cm, under an argon pressure of 0.5 bar and with ethyl acetate:cyclohexane in the volume ratio 3:7 as eluent, recovering fractions of 1000 cm<3>. Fractions 8 to 18 are combined and concentrated to dryness at 2.7 kPa. 37 g of 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol are obtained in the form of white crystals which melt at 195°C.

1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol can be obtained as follows: To a solution of 6.73 cm<3> of diisopropylamine in 110 cm< 3> tetrahydrofuran is placed under a nitrogen atmosphere and while cooling to -70°C, 29.5 cm<3>1.6N n-butyllithium in solution in hexane. After 30 minutes, a mixture of 8.7 g of 3,5-difluorobenzylmethylsulfone in 200 cm<3> of tetrahydrofuran is then added and the stirring is maintained for 45 minutes at -70°C. 10 g of 2-benzhydryl-azetidin-3-one, dissolved in 60 cm<3> of tetrahydrofuran, are added and then stirred for 20 minutes before allowing the mixture to return to ambient temperature. The reaction mixture is hydrolyzed with 400 cm<3> of a saturated ammonium chloride solution, extracted with dichloromethane, washed 3 times with 500 cm<3> of water and then with a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The 19 g residue is taken up in isopropyl ether, from which it crystallizes. After filtration and drying, 15.35 g of 1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of white crystals. l-benzhydryl-azetidin-3-one can be prepared according to the procedure described from benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, the heterocycle being optionally substituted with one or more alkyl, alkoxy, vinyl, halogen, oxo, hydroxy, OCF3 or CF3.

3,5-difluorobenzylmethylsulfone can be prepared in the following way: From 33.46 g of 3,5-difluorobenzylmethylsulfide in 318 cm<3> water, 318 cm<3> acetic acid and 318 cm<3> ethanol are placed at 5°C 129.9 g oxone®. After 16 hours at ambient temperature, the reaction mixture is diluted with dichloromethane, washed with water and with a saturated sodium chloride solution, dried, filtered and concentrated to dryness at 2.7 kPa. 35.57 g of 3,5-difluorobenzylmethylsulfone is obtained in the form of white crystals with a melting point of 135°C.

3,5-difluorobenzylmethylsulfide can be prepared in the following way: From 40 g of 3,5-difluorobenzyl bromide and 16.25 g of sodium methylthiolate in DMF, after treatment, 33.46 g of 3,5-difluorobenzylmethylsulfide is obtained in the form of a yellow oil.

Method 2

To a solution of 2.2 g of 3-acetoxy-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidine in 25 cm< 3> dioxane is placed at ambient temperature in 0.80 g of ground sodium hydroxide. After 16 hours at ambient temperature, 50 cm<3> of water and 100 cm<3> of ethyl acetate are added. The mixture is decanted and the organic phase is washed again with 100 cm<3> of water, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. A white meringue mass is obtained which is crystallized from isopropyl ether to obtain 0.85 g of a solid which melts at 190°C. A recrystallization from 20 cm<3> ethanol leads to 0.70 g of 1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine with melting point 205°C.

To a solution of 4.77 g of (3,5-difluorobenzyl)methylsulfone in 70 cm<3> of tetrahydrofuran is added under an argon atmosphere and at -70°C, 14 cm<3> of a 1.6N n-butyllithium solution in hexane. After 1 hour at -70°C, 6.8 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-one in 30 cm<3> tetrahydrofuran are added and then, 1 hour later, a solution of 2.34 cm<3 >acetyl chloride in 20 cm3 tetrahydrofuran, after which the temperature in the reaction mixture is raised to 20°C for 1 hour. 50 cm3 of water and 200 cm3 of ethyl acetate are added. The mixture is decanted, the organic phase is washed with 100 cm 3 of water and 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. 14.4 g of 3-acetoxy-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl)methyl-sulfonylmethyl-(RS)]azetidine are obtained in the form of a yellow oil.

<!>H-NMR (400 MHz, CDCl 3 , 5 in ppm): 2.79 (s, 3H), 3.04 (AB, J = 9 Hz, 2H), 3.27 (d, J

= 9 Hz, 1H), 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).

l-[bis(4-chlorophenyl)methyl]azetidin-3-one can be prepared in the following way: To a solution of 5.0 cm3 of oxalyl chloride in 73 cm3 of dichloromethane, cooled to -78°C, is added a solution of 8 .1 cm3 of dimethylsulfoxide in 17.6 cm3 of dichloromethane. After 0.5 hours by

-78°C a solution of 16.0 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol in 50 cm<3 >dichloromethane is poured. After 5 hours at -78°C, 26.6 cm 3 of triethylamine is added dropwise, and the reaction mixture is allowed to return to ambient temperature. After 16 hours, the reaction mixture is washed with 4 x 200 cm3 of water and then 200 cm3 of a saturated sodium chloride solution, after which the mixture is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The obtained residue is chromatographed on a silica gel column with granulometry 0.04-0.06 mm, diameter 9.2 cm and height 21 cm, under an argon pressure of 0.5 bar with ethyl acetate:cyclohexane in the volume ratio 40:60 as eluents, fractions of 200 cm<3> are recovered. Fractions 15 to 25 are combined and concentrated to dryness at 2.7 kPa. 8.9 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one is obtained in the form of pale yellow crystals which melt at 111°C. 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol can be prepared according to the procedure described by A.R. Katritzky et al. in "J. Heterocycl. Chem.", (1994), 271, starting from 35.5 of [bis-(4-chlorophenyl)methyl]amine hydrochloride and 11.0 cm<3> of epichlorohydrin. 9.0 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol are isolated. [bis-(4-chlorophenyl)methyl]amine hydrochloride can be prepared according to the method described by M. Grisar et al. in "J. Med. Chem.", 885 (1973). Example 2 (-)-1-[>is-(4-chlorophenyl)methyl]-3-[(3,5-& and (+)-1-[bis-(4-chlorophenyl)methyl]-3-[ (3,5-difluorophenyl)(methylsulfonyl)methyl]azetidine can be prepared by HPLC separation on a chiral CHIRALPAK AS column with granulometry 20 [µm, height 23 cm and diameter 6 cm) of 0.52 g of racemate as prepared in Example 1. Elution with heptane:ethanol in the volume ratio 90:10 at a speed of 80 cm<3>/min. and after concentrating the combined fractions to a dry state at 2.7 kPa, 110 mg of (-)-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl) is obtained -methyl]azetidine with [ aD - -6.3° (C = 0.5M in methanol) in the form of a white solid with melting point 178°C and 134 mg (+)-1-[bis-(4-chlorophenyl) methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl]azetidine with [ αD = +5.8° (C = 0.5M in methanol) in the form of a white solid with melting point 178°C.

The mixture of the two diastereoisomeric forms A l-[4-[(R<*>)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methyl-(R)] azetidine-1 - yl}methyl]benzyl]pyrrolidine and 1-[4-[(R<*>)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methyl-(S)]azetidine-1 -yl}-methyl]benzyl]pyrrolidine can be prepared as follows: To a solution of 60 mg of 1-(R<*>)-[4-(4-chlorophenyl)-{3-[(3,5-difluorophenyl) methylsulfonyl-methylene]azetdin-l-yl}-methyl)benzyl]pyrrolidine, isomeric form A, in 2 cm<3> of ethanol and 2 cm<3> of dichloromethane, add 20 mg of sodium borohydride. After stirring for 20 hours at 20°C, 0.25 cm<3> of water, 20 cm3 of dichloromethane are added, after which the whole is stirred and the mixture is dried over magnesium sulfate and then filtered and concentrated to a dry state at 2.7 kPa. The residue is chromatographed over a silica gel column with granulometry 0.063-0.200 mm, height 7 cm and diameter limb, eluting under argon pressure of 0.1 bar and with dichloromethane and then dichloromethane:methanol in the volume ratio 95:5, recovering fractions of 5 cm <3.> Fractions 13 to 18 are combined and concentrated to dryness at 2.7 kPa. 38 mg of the mixture of the two diastereoisomeric forms A 1-[4-[(R<*>)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methyl-(R) ] azetidin-1 -yl} methyl]benzyl]pyrrolidine and 1 - [4-[(R<*>)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methyl-(S )]azetidin-1-yl}-methyl]benzyl]pyrrolidine in the form of a white meringue mass.

1H-NMR (400 MHz, CDCl 3 , 8 in ppm): 1.77 (mt, 4H), from 2.40 to 2.60 (mt, 5H), 2.67 (s,

3H), from 3.10 to 3.25 (mt, 2H), 3.38 (mt, 1H), from 3.50 to 3.70 (mt, 3H), 4.24 (s, 1H), 4 .25 (d, J = 11 Hz, 1H), 6.83 (t large, J = 9 Hz, 1H), 6.94 (mt, 2H), from 7.10 to 7.35 (mt, 8H) .

1 -(R*)- [4-(4-chlorophenyl)- {3- [(3,5-difluorophenyl)-methylsulfonyl-methylene] azetidin-1 -yl}-methyl]benzyl]pyrrolidine, isonier form A, can is prepared by working in the following way: To a solution of 0.32 g of l-{(R<*>)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5 -difluorophenyl)-methylsulfonyl-methylene] azetidine, isomeric form A and 5 mg of sodium iodide in 10

cm<3> dichloromethane, add 50 mm3 pyrrolidine. After stirring for 20 hours at 20°C, 50 mm3 of pyrrolidine is added, after which the whole is stirred for 8 hours and then once again 50

mm<3> pyrrolidine with after stirring for 20 hours at 20°C. The reaction mixture is washed with water and the organic phase is then dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. The obtained residue is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 1.2 cm and height 30 cm, under an argon pressure of

0.1 bar and eluted with dichloromethane and then with dichloromethane:methanol in the volume ratio 97.5:2.5, whereby fractions of 3 cm<3> are recovered. Fractions 12 to 40 are combined and then concentrated to dryness at 2.7 kPa. 0.18 g of 1-(R<*>)-[4-(4-chloro-phenyl)-{3-[(3,5-difluorophenyl)methylsulfonyl-methylene]azetidin-1-yl}methyl]benzyl is obtained ]-

pyrrolidine, isomeric form A, in the form of a white meringue mass.

[ a™ 365nm= -22.5° ± 0.7 (c = 0.5%; dichloromethane)

1H NMR (300 MHz, CDCl 3.8 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).

1- {(R*)-[(4-chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)-methylsulfonyl-methylene] azetidine, isomeric form A, can be prepared by the following method: To a solution of 28.0 g of the mixture of the 2 diastereoisomers (form A) 1-{(R<*>)-[(4-chloromethyl)-phenyl]-(4-Morphenyl)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)-methylsulfonyl-methyl]azetidin-3-ol and 32 g of 4-dimethylaminopyridine in 500 cm3 of dichloromethane are added to 12.4 cm3 of methylsulfonyl chloride. After stirring for 1 hour at 10°C and then 1 hour at 20°C, the reaction mixture is washed with 500 cm3 of water, after which the organic phase is dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. The residue is chromatographed over a silica gel column with granulometry 0.06-0.200 mm, diameter 6 cm and height 30 cm, under an argon pressure of 0.2 bar and the whole is eluted with dichloromethane and fractions of 250 cm<3> are recovered. Fractions 9 to 25 are combined and concentrated at 2.7

kPa. 6.3 g of 1-{(R<*>)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)-methylsulfonyl-methylene]azetidine is obtained, isomeric form A, in the form of a white meringue mass.

The mixture of the two diastereoisomers (form A) 1-{(R<*>)-[4-(chloromethyl)phenyl]-(4-chloro-phenyl)methyl}-3-[(R)-(3,5- difluorophenyl)methylsulfonyl-methyl]azetidin-3-olog 1-{(R<*>)-[4-(thiofluoromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(S>^ azetidin-3-ol , can be prepared by working in the following way: To a solution of 0.20 g of the mixture of the two diastereoisomers (form A) l-{(R<*>)-(4-chlorophenyl)-[4-(hycoxymethyl) phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ol and l-{(R*)-(4-chlorophenyl]-[4-hydroxymethyl)phenyl]methyl} -3-[(S)-(3,5-difluorophenyl)-methylsulfonyl-methyl]azetidin-3-ol in 10 cm3 of dichloromethane is added 6 cm3 of thionyl chloride. After stirring for 20 hours at 20°C, 5 cm<3> of a saturated aqueous sodium hydrogen carbonate solution and then it is stirred for 15 minutes. The mixture is decanted and the organic phase is washed with water, dried over magnesium sulfate and then concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with a granulometry of 0.04-0 .06 mm, dia meter 1.0 cm and height 20 cm, under an argon pressure of 0.5 bar while eluting with cyclohexane:ethyl acetate in the volume ratio 75:25 and recovering fractions of 20 cm<3>. Fractions 4 to 7 are combined and concentrated to dryness at 2.7 kPa. 0.17 g of a mixture of the two diastereoisomers (form A) 1-{(R<*>)-[4-(chloromethyl)-phenyl]-(4-Worphenyl)methyl}-3-[(R)- (3,5-a^fluorophenyl)-methylsulfonyl-methyl]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 meringue mass.

The mixture of the two diastereoisomers (form A) 1-{(R<*>)-(4-chlorophenyl)-[4-(hydroxy-methyl)phenyl] methyl}-[(R)-(3,5-difluorophenyl) methylsulfonyl-methyl]azetidin-3-ol and l-{(R<*>)-(4-chlorophenyl)-[4-(hydroxymethyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl) )methylsulfonyl-methyl]azetidin-3-ol can be prepared by working as follows: To a solution kept under argon and cooled to -30°C of 0.58 g of a mixture of the two diastereoisomers (form A) 3-acetoxy- 1-{(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-difluorophenyl)methylsulfonyl-methyl]azetidine in 10 cm< 3> anhydrous toluene is placed 1.6 cm<3> of a 1.5M solution in toluene of diisobutylaluminum hydride. After stirring for 15 minutes at -30°C, 1.0 cm<3> of the same hydride solution is added again and then the mixture is allowed to return to 0°C. After stirring for 30 minutes, 3 cm3 of water and 6 cm<3> IN of sodium hydroxide are added and the whole is then extracted with 25 cm3 of dichloromethane. The organic phase is washed with 5 cm<3>, 5 cm<3> of saline, then dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 1.2 cm and height 30 cm, under an argon pressure of 0.1 bar, eluting with cyclohexane:ethyl acetate in the volume ratio 50:50 and fractions of 30 cm<3>. Fractions 4 to 12 are combined and then concentrated to dryness at 2.7

kPa. 0.42 g of a mixture of the two diastereoisomers (form A) 1-{(R<*>)-(4-chloro-phenyl)-[4-(hydroxymethyl)phenyl]methyl}-3-[(R) -(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-ol and 1-{(R*)-(4-chlorophenyl)-[4-(hydroxymethyl)phenyl]methyl} -[(S)-( 3,5-difluorophenyl)methylsulfonyl-methyl]azetidin-3-ol in the form of a white lacquer.

The mixture of the two diastereomers (form A) 3-acetoxy-1-{(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 -difluorophenyl)methylsulfonyl-methyl] azetidine can be prepared as follows: To a solution cooled to -60°C of 1.0 g of (3,5-difluorobenzyl)methylsulfone in 30 cm<3> tetra-

hydrofuran, and cooled under argon for 5 minutes, 3 cm3 of a 1.6N n-butyllithium-

solution in hexane. After 1 hour of stirring to -60°C and then 30 minutes at -30°C

a solution previously cooled to -60°C of 1.45 g of 1-[(R<*>)-(4-chlorophenyl)-[4-(methoxycarbonyl)phenyl] methyl }azetidin-3-one is added dropwise , isomeric form A, in 15 cm3 of tetrahydrofuran. After stirring for 30 minutes at -60°C and then 30 minutes at -30°C, Q.43 cm3 of acetyl chloride is added and then the whole is allowed to return to 0°C. 40 cm3 of water and 40 cm<3> of dichloromethane are then added with stirring and it is then allowed to return to ambient temperature, after which the reaction mixture is decanted. The organic phase is washed with 20 cm3 of water and then dried over magnesium sulfate, filtered and concentrated

is dried to a dry state at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.040-0.063 mm, diameter 3 cm and height 30 cm, eluting under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in the volume ratio 75:25 and the re-

fractions of 30 cm<3> are obtained. Fractions 21 to 35 are combined and then concentrated to dryness at 2.7 kPa. 1.28 g of the mixture of the two diastereoisomers (form A) 3-acetoxy-1-{(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-difluorophenyl)methylsulfonyl-methyl]azetidine in the form of a cream-coloured meringue mass.

l-[(R<*>)-(4-chlorophenyl)-[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, isomeric form A,

can be prepared by working in the following way: To a solution of 0.55 cm3 of oxalyl chloride in 5 cm<3> of dichloromethane cooled to -60°C, 0.90 cm<3> of dimethylsulfoxide is poured over the course of 10 minutes. After stirring for 30 minutes at -60°C, a solution of 1.75 g of 1-[(R<*>)-(4-chlorophenyl)-[4-(methoxycarbonyl)phenyl]methyl}- is added within 15 minutes

azetidin-3-ol, isomeric form A, in 20 cm<3> dichloromethane. After 3 hours of stirring at -60°C

2.70 cm<3> of triethylamine is poured into the mixture and it is then allowed to return to 0°C. 20 cm<3> of water is then added, stirred and decanted. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness at 50°C and a pressure of 2.7 kPa. The obtained orange colored oil is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 2 cm and height 30 cm, under an argon pressure of 0.5 bar, eluting with cyclohexane:ethyl acetate in the volume ratio 75:25 and recovering fractions of 30 cm<3>. Fractions 2 to 15 are combined and concentrated to dryness at 2.7 kPa. 1.45 g of 1-{(R<*>)-(4-chlorophenyl)-[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, isomeric form A, is obtained in the form of a yellow meringue mass.

l-{(R<*>)-(4-chlorophenyl)-[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol, isomeric form A, can be prepared as follows: To a suspension of 2.0 g methyl-(+)-4-[(R<*>)-amino-(4-chlorophenyl)methyl]benzoate in 30 cm<3> of ethanol add 0.605 g of sodium hydrogen carbonate and then 0.60 cm of ethanol add 0.605 g of sodium hydrogen carbonate and then 0.60 cm

epibromohydrin. After 20 hours of stirring at 60°C, the reaction mixture is concentrated to a dry state at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 3 cm and height 35 cm, eluting under an argon pressure of 0.5 bar and with cyclohexane:ethyl acetate in the volume ratio 70:30 for fractions 6 to 10, then 60:40 for fractions 18 to 27 and then 50:50, recovering fractions of 60 cm<3.> Fractions 15 to 40 are combined and then concentrated to dryness at 2.7 kPa. The residue is taken up in 30 cm<3> of ethanol, after which 0.20 g of sodium bicarbonate and 0.2 cm<3> of epibromohydrin are added. After stirring for 48 hours at 20°C and 24 hours at 35°C, the mixture was filtered and the filtrate was concentrated to dryness at 60°C and 2.7 kPa. 1.76 g of 1-{(R<*>)-(4-chlorophenyl)-[4-(methoxycarbonyl)phenyl]methyl}azetidine-3-01, isomeric form A, is obtained in the form of a pasty solid.

Methyl-(+)-4-[(R<*>)-amino-(4-chlorophenyl)methyl]benzoate can be prepared by working as follows: To a solution of 9.2 g of methyl-4-[(RS )-amino-(4-chlorophenyl)methyl]-benzoate in 10 cm<3> of methanol is added to 2.51 g of D-(-)-tartaric acid. The solution is concentrated to dryness at 2.7 kPa. Dissolve the resulting cream-colored meringue mass in 50 cm<3 >ethanol containing 5% water and allow the resulting solution to crystallize for 20 hours at 20°C. The crystals are filtered and washed with 5% ethanol in water, poured off and dried at 2.7 kPa. 3.4 g of white crystals are obtained which are called "crystal A" [and which are kept for later preparation of the second enantiomer methyl-(-)-4-[(R<*>)-amino-(4-chlorophenyl)methyl ]benzoate)]. The mother liquor is concentrated to a dry state and 8.1 g of white meringue mass is obtained which is dissolved in 100 cm<3> of ethyl acetate. The solution obtained is placed in 50°C IN sodium hydroxide, stirred and decanted. The organic phase is washed with 50 cm<3> of water and then dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. A yellow solid is obtained which dissolves in 100 cm<3>

methanol. To the obtained solution is added 1.85 g of L-(+)-tartaric acid and the resulting solution is concentrated to dryness at 2.7 kPa. A cream-coloured meringue mass is obtained which, when dissolved in 27 cm<3> of 4% ethanol in water, is allowed to crystallize for 20 hours at 20°C. 3.4 g of crystals of L-(+)-tartrate of methyl-(+)-4-[(R<*>)-amino-(4-chlorophenyl)methyl]benzoate are obtained, which are recrystallized from 60 cm<3> 5% ethanol in water. After decanting and drying, 2.78 g of white crystals are obtained, which are dissolved in 50 cm<3> of ethyl

acetate. The solution obtained is added to 100 cm<3> IN sodium hydroxide, stirred and decanted. The organic phase is washed with 50 cm<3> of water and dried over magnesium

sulfate, and then concentrated to dryness at 2.7 kPa. 2.1 g of methyl-(+)-4-[(R<*>)-amino-(4-chlorophenyl)methyl]benzoate is obtained in the form of a white solid.

Methyl 4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate can be prepared as follows: To

a suspension of 16.3 g of methyl-4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate in 200 cm<3 >methanol is added 3.9 cm<3> hydrazine hydrate. After 5 hours of stirring at reflux temp.

rature and then 20 hours at 20°C, the reaction mixture is filtered and the filtrate is concentrated to dryness at 2.7 kPa. The obtained residue is taken up in a mixture of 200 cm<3> of water and 200 cm<3> of ethyl acetate. After stirring for 15 minutes, the resulting suspension is filtered, the filtrate is decanted into a separating funnel and the organic phase is washed with 50 cm<3> of water, dried over magnesium sulfate and concentrated to dryness at 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.

Methyl 4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate can be prepared by working as follows: To a solution of 11.6 g of methyl-4-[(RS)-bromo-(4- chlorophenyl)methyl]-benzoate in 70 cm<3> N,N-dimethylformamide, 12.6 g of chidium phthalimide are added. After 3 hours of stirring at reflux temperature, the reaction mixture is cooled to 20°C and then 300 cm<3> of ethyl acetate and 300 cm<3> of water are added. After stirring, the mixture is decanted, after which the aqueous phase is extracted with 2 x 100 cm<3> ethyl acetate and the combined organic phases are washed with 2 x 400 cm<3> water and dried over magnesium sulfate and then concentrated to dryness at 2.7 kPa . 16.3 g of methyl-4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate are obtained in the form of a pasty, yellow solid.

Methyl 4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate can be prepared as follows: To

a solution of 17.4 g of methyl-4-[(RS)-(4-chlorophenyl)(hydroxy)methyl]benzoate in 200 cm<3 >acetonitrile is added 10.18 g of N,N'-carbonyldiimidazole and 54.3 cm <3> allyl bromide. After stirring for 30 minutes at 20°C, the reaction mixture is refluxed for 2 hours,

stirred for 20 hours at 20°C and then concentrated almost to dryness at 2.7 kPa. The mixture, taken up in dichloromethane, is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 7 cm and height 30 cm, under an argon pressure of 0.5 bar, eluting with dichloromethane and recovering fractions of 500 cm<3. > Fractions 3 to 6 are combined and concentrated to a dry state at 2.7 kPa. 11.6 g of methyl-4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate are obtained in the form of an oil which is used as such in the following steps.

Methyl 4-[(RS)-(4-chlorophenyl)(hydroxy)methyl]benzoate can be prepared as follows: To a suspension of 2.75 g of methyl-4-(4-chlorobenzoyl)benzoate in 200 cm<3> methanol is added at 20°C, slowly in small portions (a heating of the reaction medium to 50°C is formed), 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 cm<3> of dichloromethane are added, and with stirring 100 cm<3> of 0.5N hydrochloric acid. After decanting, the organic phase is dried over magnesium sulfate and concentrated to a dry state at 2.7 kPa. 2.5 g of methyl-4-[(RS)-(4-chlorophenyl)(hydroxy)methyl]benzoate is obtained in the form of a colorless oil which slowly crystallizes at 20°C and which is used as such in the subsequent step.

Methyl 4-(4-chlorobenzoyl)benzoate can be prepared as follows: To a solution cooled to -22°C of 19.3 g of terephthalic acid monomethyl ester chloride in 200 cm<3> of tetrahydrofuran is placed under argon 27.4 cm<3> tri -n-butylphosphine. After stirring for 20 minutes at 22°C, while maintaining this temperature, a solution of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of 4-bromochlorobenzene, 2.43 g of magnesium and a crystal iodine in 100 cm<3> diethyl oxide during backflow). After stirring for 30 minutes at -22°C, slowly add 150 cm<3> IN hydrochloric acid, after which the mixture is allowed to return to 20°C and the medium is diluted with 200 cm<3> diethyl oxide. The white suspension obtained is filtered and the solid is washed with 2 x 50 cm<3> of water and then 2 x 50 cm<3> of diethyl oxide. After decanting and drying under a pressure of 2.7 kPa, 16.2 g of methyl-4-(4-chloro-benzoyl)benzoate are obtained in the form of a white solid which melts at 170°C.

Example 4

Mixture of the two diastereoisomeric forms B 1-[4-[(R<*>)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methyl-(R)] azeitdin-1 - yl} methyl]benzyl]pyrrolidine and 1 - [4- [(R*)-(4-chlorophenyl)- {3-[(3,5-difluorophenyl)-methylsulfonyl-methyl-(S)]azetidin-1-yl } methyl benzyl]-pyrrolidine can be prepared by working as described in Example 3, from 50 mg of (+)-1-[4-(R*)-(4-chlorophenyl)- {3 - [(3,5-difluorophenyl) methyl-sulfonylmethylene] azetidin-1 -yl} methyl)-benzyljpyrrolidine, isomeric form B, 1.5 cm<3> ethanol, 1.5 cm<3> dichloromethane and 18 mg of sodium borohydride with stirring for 8 hours at 50°C and then for 48 hours at 20°C. 50 mg of the mixture of the two diastereoisomeric forms B 1-[4-[(R<*>)-(4-chloro-phenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methyl-( R)]azetidin-1-yl}methyl]benzyl]pyrrolidine and 1-[4-[(R<*>)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methyl -(S)] azetidin-1-yl }methyl]benzyl]pyrrolidine in the form of a white meringue mass.

1 H-NMR spectrum (300 MHz, CDCl3.8 in ppm). A mixture of the diastereomers in the ratio 60:40 is observed: <*>1.79 (mt, 4H), from 2.45 to 2.60 (mt, 5H), 2.67 (s, 3H), from 3, 10 to 3.30 mt, 2H), 3.40 (mt, 1H), 3.57 and 3.60 (2s, together 2H), 3.65 (t large, J = 7.5 Hz, 1H) , 4.26 and 4.30 (2s, together 2H), 6.84 (tt, J = 9 and 2 Hz : 1H); 6.96 (mt, 2H), from 7.25 to 7.40 (mt, 8H).

(+)-1-[4-(R<*>)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonyl-methylene]azetidin-1-yl}methyl]benzyl]pyrrolidine, isomer form B, can be prepared by working as described in example 3 from 0.50 g of l-{(R<*>)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3 ,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, isomeric form B, 5 mg sodium iodide, 15 cm<3> dichloromethane and 0.190 g pyrrolidine. The crude product is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 1.5 cm and height 20 cm, under an argon pressure of 0.1 bar, eluting with dichloromethane and then dichloromethane: methanol in the volume ratio 95:5 and the fractions of 25 cm<3> are recovered. Fractions 20 to 40 are combined and then concentrated to dryness at 2.7 kPa. 0.28 g of (+)-1-[4-(R<*>)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methylene] azetidin-1-yl} is obtained methyl] - benzyljpyrrolidine, isomeric form B, in the form of a white meringue mass with [a]<20>365 nm= +26.8 ± 0.8 (c = 0.5%; dichloromethane).

1H NMR (300 MHz, CDCl 3 , 8 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), from 7.20 to 7.40 (mt: 8H).

1-{(R<*>)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)-methylene]azetidine, isomeric form B, can be prepared by working as described in example 3 from 7.3 g of the mixture of the two diastereomers, form B, 1-{(R<*>)-[4-(chloro-methyl)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)-(methylsulfonyl)-methyl]azetdin-3-ol, 8.2 g of 4-dimethylaminopyridine, 150 cm<3 >dichloromethane and 3 .2 cm3 methylsulfonyl chloride. The crude product is chromatographed on a silica gel column with granulometry 0.04-0.06 mm, diameter 3 cm and height 30 cm, under an argon pressure of 0.2 bar and elution with dichloromethane and recovery of fractions of 100 cm<3>. Fractions 15 to 30 are combined and concentrated to dryness at 2.7 kPa. 2.50 g of 1-{(R<*>)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl-methylsulfonyl)-methylene]azetidine is obtained, isomeric form B, in the form of a white meringue mass.

The mixture of the two diastereoisomeric forms B, 1-{(R<*>)-[4-(chloromethyl)phenyl]-(4-chloro-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, can be prepared by working as described in example 3 from 11.0 g of the mixture of the two diastereoisomeric forms B, l-{(R<*>)-(4 -chlorophenyl)-[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-olog l-{(R*)-(4- chlorophenyl)-[4-(hydroxymethyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)-(methylsulfonyl)methyl]azetidin-3-ol, 250 cc of dichloromethane and 3.1 cc of thionyl chloride. The crude product is chromatographed on a silica gel column with granulometry 0.04-0.06 mm, diameter 3 cm and height 30 cm, under an argon pressure of 0.2 bar and elution with cyclohexane:ethyl acetate in the volume ratio 70:305 and recovery of fractions of 50 cm<3>. Fractions 9 to 25 are combined and then concentrated to dryness at 2.7 kPa. 7.3 g of a mixture of the two diastereoisomeric forms B is obtained, 1-{(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)(methylsulfonyl)methyl]azetidin-3-ol in the form of a white meringue mass.

The mixture of the two diastereoisomeric forms B l-{(R<*>)-(4-chlorophenyl)-[4-(hydroxy-methyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl) (methylsulfonyl)-methyl]azetidin-3-ol and l-{(R<*>)-(4-chlorophenyl)-[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5 -difluorophenyl)(methylsulfonyl)-methyl]azetidin-3-ol can be prepared as described in example 3 from 18.0 g of the mixture of the two diastereoisomeric forms B 3-acetoxy-1-{(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-difluorophenyl)(methylsulfonyl)methyl] azetidine, 150 cm3 of anhydrous toluene and 100 cm3 of a 20% -ig solution of diisobutylaluminum hydride in toluene. The raw product is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 3 cm and height

30 cm, under an argon pressure of 0.1 bar, and elution with cyclohexane:ethyl acetate in the volume ratio 50:50 and recovery of fractions of 50 cm<3>. Fractions 15 to 30 are combined and then concentrated to dryness at 2.7 kPa. One obtains 11.0 g of a mixture of the two diastereoisomeric forms B l-{(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}-[ (SH^ in the form of a white meringue mass. The mixture of the two diastereomeric forms B 3-acetoxy-1-{(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-[ (R)-(3,5-Difluorophenyl)(methylsulfonyl)-methyl]azetidine can be prepared by working as described in Example 3 from 11.2 g of (3,5-difluorobenzyl)methylsulfone, 350 cm3 of tetrahydrofuran, 34 cm<3 >of a 1.6N n-butyllithium solution in hexane, 11.2 g of 1-[(R<*>)-(4-chlorophenyl)-[4-(methoxy-carbonyl)phenyl]methyl}azetidin-3-one, isomeric form B and 5.5 cm3 of acetyl chloride. The crude product is chromatographed over a silica gel column with granulometry 0.06-0.200 mm, diameter 4 cm and height 40 cm, and elution with cyclohexane:ethyl acetate in the volume ratio 70:30 and recovery of fractions of 100 cm <3> Fractions 10 to 30 are combined and conc is entered into a dry state at 2.7 kPa. 21 g of a cream-colored meringue mass is obtained which is still impure and which is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 4 cm and height 40, and eluted with dichloromethane, recovering fractions of 100 cm<3>. Fractions 11 to 30 are combined and concentrated to dryness at 2.7 kPa. 20.0 g of a mixture of the two diastereoisomeric forms B is obtained 3-acetoxy-1-{(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-difluorophenyl)(methylsulfonyl)-methyl]-azetidine in the form of a white meringue mass. l-[(R<*>)-(4-chlorophenyl)-[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, isomeric form B, can be prepared by working as described in Example 3 from 8.7 cm3 oxalyl chloride, 350 cm<3> dichloromethane, 14.2 cm<3> dimethyl sulfoxide, 29.0 g l-[(R<*>)-(4-chlorophenyl)-[4-(methoxy-carbonyl)phenyl]methyl }azetidin-3-ol, isomeric form B, and 43 cm3 of triethylamine. The crude product is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 4 cm and height 40 cm, eluting with dichloromethane and recovering fractions of 250 cm<3>. Fractions 7 to 25 are combined and then concentrated to dryness at 2.7 kPa. 15.5 g of 1-{(R<*>)-(4-chlorophenyl)-[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, isomeric form B, is obtained in the form of an orange-coloured oil. l-{(R<*>)-(4-chlorophenyl)-[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol, isomeric form B, can be prepared as described in example 3 from 25.5 g of methyl- (-)-4-[l-(R<*>)-amino-l-(4-chlorophenyl)methyl]benzoate, 250 cc of ethanol, 7.9 g of sodium bicarbonate and 7.7 cc of epibromohydrin. 29 g of 1-{(R<*>)-(4-chlorophenyl)-[4-(methoxycarbonyl)phenyl]-methyl}azetidin-3-ol, isomeric form B, is obtained in the form of a yellow oil.

Methyl-(-)-4-[(R<*>)-amino-(4-chlorophenyl)methyl]benzoate can be prepared by carrying out

two successive recrystallizations of 3.4 g of the white crystals, called "crystal A" in Example 3, in 68 cm<3> of 5% ethanol in water under reflux. The crystals obtained are filtered, poured off and dried at 2.7 kPa. 2.2 g of the D-(-)-tartrate of methyl-(-)-4-[(R<*>)-amino-(4-chlorophenyl)methyl]benzoate are obtained in the form of white crystals which are dissolved in 50 cm<3> ethyl acetate. To the solution obtained is added 50 cm<3> IN sodium hydroxide,

after which it is all stirred and drained. The organic phase is washed with 50 cm3 of water,

dried over magnesium sulfate and then concentrated to dryness at 2.7 kPa. One up-

when 1.9 g of methyl-(-)-4-[(R<*>)-amino-(4-chlorophenyl)methyl]benzoate in the form of a white solid with (a)20365 nm = -58.1° ± 1 (c = 0.5%).

Example 5

l-[bis-(thien-2-yl)-methyl]-3-[(RS)-(3,5-difluorophenyl)methylsulfonyl-methyl]azetidine can be prepared by working as described in example 3 from 0.10 g l-[bis-(thien-2-yl)-methylJ-3^[(3,5-difluorophenyl)methylsulfonyl-methylene]azetidine, 2 cm<3> methanol, 2 cm<3>

dichloromethane and 25 mg of sodium borohydride with stirring for 3 hours at 20°C. Raw-

the product is chromatographed on a silica gel column with granulometry 0.063-0.200 mm,

height 7 cm and diameter 1 cm, eluting under an argon pressure of 0.1 bar with dichloromethane and recovering fractions of 4 cm<3>. Fractions 2 to 5 are combined and concen-

is dried to a dry state at 2.7 kPa. 83 mg of 1-[bis-(thien-2-yl)-methyl]-3-[(RS)-(3,5-difluorophenyl)methylsulfonyl-methyl]azetidine is obtained in the form of a white solid.

1H-NMR (400 MHz, CDCl 3 , 6 in ppm): from 2.60 to 2.70 (mt, 1H), 2.66 (s, 3H), 3.31 (mt,

2H), 3.40 (mt, 1H), 3.73 (t large, J = 7.5 Hz, 1H), 4.27 (d, J = 11 Hz, 1H),

4.92 (s, 1H), 6.83 (tt, J = 9 and 2.5 Hz, 1H), from 6.85 to 7.00 (mt, 6H), 7.21

(mt, 2H).

1 -[bis-(thien-2-yl)-methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methylene]azetidine can produce

is prepared by working according to the working method described in example 6 from 2.2 g of l-[bis-(thien-2-yl)-methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl (RS) ]azetidine-3-

ol, 0.64 cm3 of methylsulfonyl chloride, 2.3 g of 4-dimethylaminopyridine and 75 cm<3> of dichloromethane and is obtained after purification by chromatography and crystallization from diisopropyl oxide,

1.3 g of 1-|T3is-(thien-2-yl)-methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methylene]azetidine in

form of white crystals melting at 165°C.

1-[bis-(iten-2-yl)-methyl]-3-[(3,5-mfl can be prepared by working as follows: To a solution cooled to -60°C of 1.3 g (3 ,5-difluorobenzyl)methylsulfone in 20 cm<3> of tetrahydrofuran is placed under argon and during 10 minutes 4 cm<3> of 1,6N n-butyllithium in hexane. After 45 minutes of stirring at

-70°C, it is poured over 10 minutes into a solution of 1.5 g of 1-[bis-(thien-2-yl)methyl]-azetidin-3-one in 20 cm<3> of tetrahydrofuran. After stirring for 3 hours at -70°C, the reaction mixture is allowed to return to normal temperature and 10 cm3 of a saturated, aqueous ammonium chloride solution is added. The mixture is decanted, the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa. The residue is taken up with 20 cm<3> cyclohexane:ethyl acetate in the volume ratio 60:40, after which the obtained suspension is filtered, the solid is poured off and dried in air. 2.2 g of 1-[bis-(iten-2-yl)-methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl (RS)]azetidin-3-ol are obtained in the form of white crystals which melt at 145°C. l-[bis-(iten-2-yl)methyl]azetidin-3-one can be prepared by working as described in example 1 (method 2) from 4 g of l-[bis-(iten-2-yl)-methyl ]azetidin-3-ol, 2.6 cm<3> of dimethylsulfoxide, 7.7 cm3 of triethylamine, 7.7 cm3 of oxalyl chloride and 100 cm<3> of dichloromethane. The obtained residue is purified by chromatography on a silica gel column with granulometry 0.04-0.06 mm, diameter 3 cm and height 30 cm, where it is eluted with cyclohexane:ethyl acetate in the volume ratio 1:1. The fractions obtained are evaporated to dryness at 2.7 kPa. 3.2 g of 1-[bis-(iten-2-yl)methyl]azetdin-3-one is obtained in the form of cream-coloured crystals which melt at 70°C. 1-[bis-(iten-2-yl)-methyl]azetdin-3-ol can be prepared by working as described in example 3 from 6 g of 1-[bis-(thien-2-yl)-methyl]amine, 2.5 cm3 of epibromohydrin, 2.6 g of sodium bicarbonate and 50 cm3 of ethanol. 4 g of 1-[bis-(thien-2-yl)-methyl]azetidin-3-ol are obtained in the form of beige-coloured crystals which melt at 115°C. l-[bis-(thien-2-yl)-methyl]amine can be prepared as follows: To a suspension cooled to 10°C under argon of thien-2-yl-magnesium bromide (prepared from 1.29 g of magnesium and 3.22 cm3 of 2-bromothiophene in 75 cm3 of diethyl oxide) a solution of 5 cm3 of thiophen-2-ylcarbonitrile in 50 cm3 of ethyl oxide is poured dropwise. After 1 hour and 30 minutes under reflux, the reaction medium is cooled to 5°C and 20 cm3 of methanol is poured dropwise, the suspension is filtered, the solid is washed with methanol. The filtrate obtained is a chestnut colored solution. Under argon, 2.45 g of sodium borohydride are added to this solution in several portions. The mixture is stirred at ambient temperature for 16 hours and then diluted with ethyl acetate and water is added slowly. The organic phase is extracted, washed with water, dried over magnesium sulfate and evaporated to dryness.

stand at 2.7 kPa and 55°C. A chestnut-coloured oil is obtained which is chromatographed on

a silica gel column with granulometry 0.2-0.063 mm, diameter 8 cm and height 25 cm,

and eluted with cyclohexane:ethyl acetate in the volume ratio 90:10 —> 85:15. Fractions 21 to 30 are combined and evaporated to dryness at 2.7 kPa. 11 g of 1-[bis-(thien-2-yl)-methyl]amine are obtained in the form of a crystallized solid.

Example 6

l-[bis-(p-tolyl)methyl]-3-[(RS)-methylsulfonyl-phenyl-methyl]azetidine can be prepared by working as described in Example 3 from 0.10 g of l-[bis-(p- tolyl)methyl]-3-(methylsulfonyl-phenyl-methylene)azetidine, 2 cm 3 of methanol, 2 cm 3 of dichloromethane and 25 mg of sodium borohydride. The crude product is chromatographed on a column of silica gel with granulometry 0.063-0.200 mm, height 7 cm and diameter 1 cm, being eluted under an argon pressure of 0.1 bar with dichloromethane and fractions of 4 cm<3> are recovered. Fractions 5 to 10 are combined and concentrated to dryness at 2.7 kPa. 35 mg of 1-[bis-(p-tolyl)methyl]-3-[(RS)-methylsulfonyl-phenyl-methyl]azetidine is obtained in the form of a white solid. 1H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.24 (s, 3H), 2.27 (s, 3H), 2.53 (t, J = 7.5 Hz, 1H), 2.58 (s, 3H), 3.19 (mt, 2H), 3.49 (mt, 1H), 3.69 (t large, J = 7.5 Hz, 1H), 4.22 (s, 1H), 4.28 (d, J = 11.5 Hz, 1H), from 6.95 to 7.45 (mts, 13H). l-[bis-(p-tolyl)methyl]-3-(methylsulfonyl-phenyl-methylene)azetidine can be prepared by working as follows: To a solution of 0.48 g of l-[bis-(p-tolyl) methyl]-3-[methylsulfonyl-phenyl-methyl-(RS)]azetidin-3-ol in 24 cm3 of anhydrous dichloromethane is added 0.125 cm<3 >methylsulfonyl chloride and then in small portions 0.465 g of 4-dimethylaminopyridine. After stirring for 20 hours at 20°C, the reaction mixture is washed with 2 x 80 cm 3 of water, 80 cm 3 of saline solution, dried over magnesium sulfate and then concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.040-0.063 mm, height 17 cm and diameter 3.2 cm and is eluted under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in the volume ratio 80:20 and fractions of 40 cm<3 are recovered. >Fractions 5 to 8 are combined and concentrated to dryness at 2.7 kPa. The residue is stirred with diisopropyl oxide, after which the solid is filtered, poured off and dried at 2.7 kPa.

0.25 g of 1-[bis-(p-tolyl)methyl]-3-(methylsulfonyl-phenyl-methylene)azetidine is obtained in

form of a white solid.

NMR spectrum in DMS0-d6, T=300K, δ 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 = 7 Hz, 4 CH arom.), 7.32 (4H, d, J = 7 Hz, 4 CH arom.), 7.43 (5H, s, phenyl). 1 -[bis-(p-tolyl)methyl]-3-[methylsulfonyl-phenyl-methyl-(RS)]azetidin-3-ol can be prepared by working as follows: To a solution of 0.59 g of bromine ( bis-p-tolyl)methane in 20 cm<3> acetonitrile is added 0.6 g of 3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol hydrochloride and then 0.3 g of potassium carbonate . After 1 hour and 15 minutes of heating to reflux temperature, the reaction mixture is cooled to 20°C and filtered. The filtrate is concentrated to dryness at 2.7 kPa and the residue is chromatographed on a silica gel column with granulometry 0.04-0.06 mm, diameter 4 cm and height 16 cm, eluting with cyclohexane:ethyl acetate in the volume ratio 70:30 and recovering fractions of 50 cm<3>. Fractions 8 to 13 are concentrated to dryness at 2.7 kPa. 0.48 g of 1-[bis-(p-tolyl)methyl]-3-[methylsulfonyl-phenyl-methyl-(RS)]azetidin-3-ol is obtained in the form of a white solid.

Bromo(bis-p-tolyl)methane can be prepared as described by W.E. Bachmann in "J. Am. Chem. Soc", 2135 (1933).

3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol hydrochloride can be prepared as follows: To a solution of 2.62 g of 3-[(methylsulfonyl)(phenyl)methyl-(RS) ]-1-(vinyloxycarbonyl)azetidin-3-ol in 12.6 cm<3> dioxane, 12.6 cm<3> 6.2N hydrochloric acid solution in dioxane is added. After stirring for 20 hours at 20°C, the reaction mixture is concentrated to a dry state at 50°C and 2.7 kPa. The residue is taken up in 25 cm<3> of ethanol and brought to reflux for 1 hour and then allowed to return to 20°C for filtration. The solid is rinsed with diethyl oxide and poured off and dried at a pressure of 2.7 kPa. 1.89 g of 3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol hydrochloride is obtained in the form of white crystals.

3-[(methylsulfonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol can be prepared as follows: To a mixture, cooled to +5°C, of 3.92 g l- benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol in 500 cm<3> anhydrous dichloromethane is poured dropwise a solution of 0.99 cm<3> vinyl chloroformate in 4 cm<3> anhydrous dichloromethane. After stirring for 48 hours at 20°C, the reaction mixture is concentrated to a dry state at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.04-0.06 mm, diameter 5.6 cm and height 15.5 cm, eluting with cyclohexane:ethyl acetate in the volume ratio 70:30 and fractions of 50 cm<3> are recovered. Fractions 17 to 36 are concentrated

to dry state at 2.7 kPa. 0.9 g of 3-[(methylsulfonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol is obtained in the form of a white solid. 1-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol can be prepared by working as described in example 1 (method 1) starting from 47 cm3 of diisopropylamine, 205.6 cm<3>1.6M n-butyllithium solution in hexane, 2.21 tetrahydrofuran, 50 g benzyl methyl sulfone and 69.6 g 1-benzhydryl-azetidin-3-one. 94.3 g of 1-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol are obtained in the form of white crystals. Example 7 1-|>is-(3-iluorophenyl)methyl]-3-(RS)-[(3,5-d^fluorophenyl)methylsulfonylmethyl]azetidine can be prepared by working as described in example 3 starting from 0 .10 g of 1-[bis-(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methylene]azetidine, 2 cm3 of methanol, 2 cm3 of dichloromethane and 20 mg of sodium borohydride with stirring for 48 hours at 20 °C. The crude product is chromatographed on a silica gel column with granulometry 0.063-0.200 mm, height 7 cm, diameter 1 cm, and it is eluted with an argon pressure of 0.1 bar with dichloromethane, recovering fractions of 4 cm<3>. Fractions 3 to 7 are combined and concentrated to dryness at 2.7 kPa. 95 mg of 1-[bis-(3-fluorophenyl)methyl]-3-(RS)-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine is obtained in the form of white crystals. 3-NMR (400 MHz, CDCl 3.8 in ppm): 2.57 (t, J = 7.5 Hz, 1H); 2.66 (s, 3H), from 3.15 to 3.30 (mt, 2H), from 3.30 to 3.50 (mt, 1H), 3.66 (t large, J = 7.5 Hz , 1H), 4.27 (d, J = 11.5 Hz, 1H), 4.28 (s, 1H), from 6.75 to 7.35 (mt, 11H). 1-[bis-(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methylene]azetidine can be prepared by working as described in Example 6 from 1.15 g of 1-[bis-(3 -fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)azetidin-3-ol, 30 cm 3 of dichloromethane, 0.264 cm 3 of methylsulfonyl chloride and 0.98 g of 4-dimethylaminopyridine. After chromatography on a silica gel column with granulometry 0.06-0.200 mm, diameter 2.8 cm and height 25 cm, and elution under an argon pressure of 1 bar with ethyl acetate:cyclohexane in the volume ratio 15:85 and with recovery of fractions of 60 cm<3 >, 0.55 g of 1-[bis-(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methylene]azetidine is obtained in the form of a white solid which melts at 178°C. l-[bis-(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)azetidin-3-ol can be prepared by working as follows: To a mixture cooled to -60°C of diisopropylamine and 10 cm<3> tetrahydrofuran is poured over the course of 10 minutes into 3.65 cm3 of a 1.6M solution of n-butyllithium in hexane and it is stirred for 10 minutes at -30°C and then cooled to -70°C. A solution of 1.2 g of (3,5-difluorobenzyl)methylsulfone in 30 cm<3> of tetrahydrofuran is then added over the course of 20 minutes. After stirring for 30 minutes at -70°C, a solution of 1.5 g of 1-[bis-(3-fluoro-phenyl)methyl]azetidin-3-one in 10 cm<3> of tetrahydrofuran is added over the course of 30 minutes . After stirring for 2 hours at -70°C, the reaction mixture is brought to normal temperature and 20 cm<3> of a saturated, aqueous ammonium chloride solution and 100 cm<3> of dichloromethane are added. The mixture is decanted, after which the organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 3.2 cm and height 30 cm, and elution under an argon pressure of lbar with ethyl acetate cyclohexane in the volume ratio 20:80 while recovering fractions of 60 cm<3>. Fractions 9 to 20 are combined and concentrated to dryness at 2.7 kPa. 1.95 g of 1-[bis-(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)azetidin-3-ol are obtained in the form of a white solid which melts at 170°C during decomposition. l-[bis-(3-fluorophenyl)methyl]azetidin-3-one can be prepared by working as described in Example 1 (Method 2) from 0.7 cm<3> oxalyl chloride, 16 cm<3> dichloromethane, 1, 12 cm<3> of dimethyl sulfoxide, 2 g of 1-[bis-(3-fluorophenyl)methyl]azetidin-3-ol and 3.7 cm<3> of triethylamine. 1.55 g of 1-[bis-(3-fluorophenyl)methyl]azetidin-3-one is obtained in the form of an oil which crystallizes at 20°C. 1-[bis-(3-fluorophenyl)methyl]azetdin-3-ol can be prepared by working as described by A.R. Katritsky in "J. Heterocycl. Chem.", 31, 271 (1994) from 4.9 g of [bis-(3-fluorophenyl)-methylamine and 1.78 cm<3> epichlorohydrin.

[bis-(3-fluorophenyl)methyl]amine can be prepared as follows: To a suspension of 1.27 g of lithium aluminum hydride in 80 cm<3> tetrahydrofuran is poured under an argon atmosphere and over the course of 30 minutes a solution of 5.17 g 3,3'-difluorobenzophenoxime in 30 cm<3 >tetrahydrofuran. After 5 hours of stirring under reflux, 1.3 cm<3> of water, 1.3 cm3 of 4N NaOH, 2.6 cm<3> of water and then 50 cm<3> of acetyl acetate are successively added. After drying over magnesium sulfate and concentration to a dry state at 2.7 kPa, 4.9 g of [bis-(3-fluorophenyl)methyl]amine are obtained in the form of a yellow oil.

3,3'-difluorobenzophenone oxime can be prepared according to the following procedure: To a solution of 5.0 g of 3,3'-difluorobenzophenone in 10 cm<3> of ethanol, a solution of 1.6 g of hydroxylamine hydrochloride in 8 cm<3> of water and then added, in small portions

parts, 1.2 g of sodium hydroxide in lozenge form. The reaction mixture is refluxed for 10 minutes and cooled to 20°C and then acidified with 7.5 cm<3> 4N hydrochloric acid. The oily precipitate is first triturated and turns into a white solid which is filtered and washed with water and dried at 35°C and 2.7 kPa. 5.17 g of 3,3'-difluorobenzophenoxime is obtained in the form of a white solid.

Example 8

1-[bis-(4-chlorophenyl)methyl]-3-(RS)-{[3-azetidin-1-yl-phenyl]methylsulfonyl-methyl} azetidine can be prepared by working as described in example 3, from 0, 10 g of 1-[bis-(4-chloro-phenyl)methyl]-3-[(azetidin-1-yl-phenyl)-methylsulfonyl-methylene]azetidine, 2 cm3 methanol, 2 cm<3> dichloromethane and 30 mg sodium borohydride with stirring for 24 hours at 20°C. The crude product is chromatographed on a silica gel column with granulometry 0.063-0.200 mm, height 7 cm and diameter 1 cm, and is eluted under an argon pressure of 0.1 bar with dichloromethane as eluent and fractions of 4 cm<3> are recovered. Fractions 5 to 10 are combined and concentrated to dryness at 2.7 kPa. 20 mg of 1-[bis-(4-chloro-phenyl)methyl]-3-(RS)-{ [3-azetidin-1-yl-phenyl]methylsulfonyl-methyl} azetidine is obtained in the form of a whitish varnish. <]>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.39 (mt, 2H), from 2.50 to 2.65 (mt, 1H), 2.60 (s, 3H), 3.20 (mt, 2H), 3.47 (mt, 1H), 3.66 (t large, J = 7 Hz, 1H), 3.89 (t large, J = 7.5 Hz, 4H), 4.20 (d, J = 11 Hz, 1H), 4.26 (s, 1H), from 6.35 to 6.50 (mt, 2H), 6.67 (d large, J = 7 .5 Hz, 1H), from 7.10 to 7.40 (mt, 9H). l-[>is-(4-chlorophenyl)methyl]-3-[(azetidin-1-yl-phenyl)-methylsulfonyl-methylene]azetidine can be prepared by working as described in Example 6 from 0.83 g of l-[bis -(4-chlorophenyl)-methyl]-3-[(azetidin-1-yl-phenyl)-methylsulfonyl-methyl-(RS)]azetidin-3-ol, 20 cm<3> dichloromethane, 0.18 cm3 methylsulfonyl chloride and 0.75 g of 4-dimethylaminopyridine. 0.40 g of 1-[bis-(4-chlorophenyl)methyl]-3-[(azetidin-1-yl-phenyl)-methylsulfonyl-methylene]-azetidine is obtained in the form of a white meringue mass. l-[bis-(4-chlorophenyl)methyl]-3-[(azetidin-1-yl-phenyl)-methylsulfonyl-methyl-(RS)]azetidin-3-ol can be prepared by working as described in Example 5 from 1.55 g of l-(3-methyl-sulfonylmethyl-phenyl)azetidine, 5.2 cm<3>1.6M n-butyl lithium solution in hexane, 30 cm<3 >tetrahydrofuran and 2.11 g of l-[bis-( 4-chlorophenyl)methyl]azetidin-3-one. 0.83 g of 1-[bis-(4-chlorophenyl)methyl]-3-[(azetidin-1-yl-phenyl)-methylsulfonyl-methyl-(RS)]azetidin-3-ol is obtained in the form of an ocher solid which melts at 172°C. l-(3-methylsulfonylmethyl-phenyl)azetidine can be prepared by working as follows: To a mixture cooled to 0°C of 10 cm<3> water, 5 cm<3> acetic acid, 1.5 cm<3> 36N sulfuric acid and 6.15 g of oxone are added to a solution of 1.9 g of 1-(3-methylsulfanylmethyl-phenyl)azetidine in 10 cm<3> of ethanol. After stirring for 20 hours at 20°C, 100 cm<3> of water, 100 cm<3> of ethyl acetate are added to the reaction mixture and it is then neutralized while stirring with sodium bicarbonate. The resulting mixture is decanted and the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa. 1.55 g of 1-[3-(methylsulfonylmethyl)-phenyl]azetidine is obtained in the form of a clear brown gum. l-[3-(methylsulfanylmethyl)-phenyl]azetidine can be prepared by working in the following way: To a solution of 4.6 g of l-iodo-3-(methylsulfanylmethyl)-benzene in 60 cm<3> tetrahydrofuran is placed under argon 2.57 g of potassium tert-butylate, 0.64 g of l,r-bis-(diphenyl-phosphino)ferrocenyl.palladium chloride, 1.49 g of l,r-bis-(diphenylphosphino)ferrocene, 0.12 g of copper iodide and 2, 0 g azetidine. After heating to reflux temperature for 3 hours, the reaction mixture is cooled to ordinary temperature, filtered over Celite and washed with 150 cm<3> of ethyl acetate. The filtrate and washing liquid are combined and acidified with 120 cm<3> IN hydrochloric acid and decanted. The aqueous phase is added with 60 cm<3> of ethyl acetate and then made alkaline with sodium bicarbonate, after which the mixture is decanted. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 3.5 cm and height 50 cm, being eluted under an argon pressure of 0.5 bar, with ethyl acetate:cyclohexane in the volume ratio 20:80 and fractions of 100 are recovered cm<3>. Fractions 1 to 3 are combined and concentrated to dryness at 2.7 kPa. 1.9 g of 1-[3-(methylsulfanylmethyl)-phenyl]azetidine is obtained in the form of an oil.

1,r-bis-(diphenylphosphino)ferrocenylpalladium chloride can be prepared by working according to T. Hayashi et al. in "J. Am. Chem. Soc", 106, 158 (1984).

1-iodo-3-(methylsulfanylmethyl)-benzene can be prepared by working in the following manner: 6.4 g of sodium methylthiolate is added to a solution of 25 g of 3-iodobenzyl bromide in 80 cm<3> N,N-dimethylformamide. After stirring for 20 hours at 20°C, 250 cm<3> of water, 200 cm<3> of ethyl acetate are added to the reaction mixture and stirred and decanted. The organic phase is washed with 4 x 200 cm<3> of water, dried over magnesium sulfate, filtered and concentrated to dryness at 50°C and 2.7 kPa. 22 g of 1-iodo-3-(methylsulfanylmethyl)benzene are obtained in the form of a gum.

Example 9

A mixture of the two diastereoisomers forms A l-(R<*>)-{4-[(4-chlorophenyl)-(3-[(3,5-difluorophenyl)-methylsulfonyl-methyl-(R)] -3- imidazolyl-azetidin-1 -yl}methyl]benzyl}-1H-imidazole and l-(R*)-{4-[(4-chlorophenyl)-(3-[(3,5-difluorophenyl)-methylsulfonyl-methyl- (S)}-3-imidazolyl-azetidin-l-yl}methyl]benzyl}-lH-imidazole can be prepared by working as follows: To a solution of 50 mg of l-{(R<*>)-[4 -(chloromethyl)phenyl]-(4-chlorophenyl)-methyl}-3-[(3,5-difluorophenyl)methylsulfonyl-methylene]azetidine, isomeric form A, in 1 cm<3 >dichloromethane, add 13.6 mg of imidazole After stirring for 20 hours at 20°C, the reaction mixture is chromatographed directly on a silica gel column with granulometry 0.063-0.200 mm, height 7 cm and diameter 1 cm, eluting under an argon pressure of 0.1 bar with dichloromethane:methanol in the volume ratio 98:2 , recovering fractions of 4 cm<3>. Fractions 4 to 9 are combined and concentrated to dryness at 2.7 kPa. 20 mg of a mixture of the two diastereoisomeric forms A l-(R<* >)-{4-[(4-chlorophenyl)-(3-[(3,5-difluorophenyl)-methylsulfonyl-methyl-(R)]-3-imidazolyl-azetidin-1-yl}methyl]-benzyl}- 1H-imidazole and 1-(R*)-{4-[(4-chlorophenyl)-(3-[(3,5-difluorophenyl)-methylsulfonyl-methyl-(S)]-3-imidazolyl-azetidine-1- yl}methyl]benzyl}-1H-irnidazole in the form of a white lacquer.

'H-NMR (300 MHz, CDCl3.8 in ppm): A mixture of diastereoisomers is observed, <*>2.64 (s, 3H), 3.42 (d, J = 8 Hz, 1H), 3, 50 (d, J = 8 Hz, 1H), 3.75 (mt, 1H), 4.31 (d large, J = 8 Hz, 1H); 4.40 (s, 1H); 4.54 and 4.55 (2s, 2H combined), 4.72 (s, 1H), 6.84 (mt, 2H), 6.87 (s, 1H), 6.95 (mt, 1H) , 7.11 (s, 1H), from 7.20 to 7.40 (mt, 12H).

Example 10

(1-benzhydryl-azetidin-3-yl)-phenyl-methanone-0-methyloxime, mixture of the two isomers Z and E, can be prepared by working in the following manner: To a suspension of 0.80 g of 1-benzhydryl- 0.286 g of O-methylhydroxylamine hydrochloride and 0.32 g of sodium acetate are added to 3-benzoylazetidine in 30 cm<3> of ethanol. After 24 hours of stirring at reflux temperature, the reaction mixture is allowed to cool to room temperature and filtered. The filtrate is concentrated to dryness at 50°C and 2.7 kPa. The residue is taken up in 100 cm3 of dichloromethane and the solution is added to 20 cm<3> of water and 1N hydrochloric acid and with stirring to an acidic pH value. The organic phase is decanted, dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.064-0.200 mm, height 36 cm and diameter 3.8 cm, eluting under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in the volume ratio 95:5 -» 92:8 80:20 during recovery of fractions of 30 cm<3>. Fractions 8 to 14 are united and

concentrated to dryness at 2.7 kPa. 0.20 g of (1-benzhydryl-azetidin-3-yl)-phenyl-methanone-0-methyloxime, a mixture of two isomers Z and E, is obtained in the form of a white solid.

'H-NMR (250 MHz, (CD3)2SO d6, 8 in ppm): An isomer mixture 65:35 is observed,

<*>2.68-3.02 and from 3.25 to 3.90 (mts, 5H together); 3.76 and 3.80 (2s, 3H combined); 4.26 and 4.38 (2s, 1H combined), from 7.10 to 7.50 (mt, 15H). l-Benzhydryl-3-benzoylazetidine can be prepared by working as follows: To a solution cooled to 0°C of 11.5 g of (l-benzhydryl-azetidin-3-yl)carboxylic acid-N-methoxy-N-methylamide in 350 cm<3> of tetrahydrofuran is added dropwise and under argon 112 cm<3> of an IM solution of phenylmagnesium bromide in tetrahydrofuran and then the mixture is allowed to return to normal temperature. After stirring for 20 hours at 20°C, 400 cm<3> of a saturated, aqueous ammonium chloride solution and then 250 cm<3> of ethyl acetate are added to the reaction mixture. After stirring, the mixture is decanted and the aqueous phase is re-extracted with 250 cm<3> of ethyl acetate, after which the two organic phases are combined and washed with 2x. 250 cm<3> of water, dried over magnesium sulfate, filtered and concentrated to dryness at 50°C and 2.7 kPa. The residue is stirred with 50 cm<3> of diisopropyl oxide, after which the suspension is filtered, the solid is poured off and dried at 2.7 kPa. 9.76 g of 1-benzhydryl-3-benzoylazetidine is obtained in the form of a solid cream.

(1-Benzhydryl-azetidin-3-yl)carboxylic acid-N-methoxy-N-methylamide can be prepared by working as follows: To a suspension of 4.0 g of N,0-dimethylhydroxylamine hydrochloride in 250 cm< 3> dichloromethane, 13.35 g of (1-benzhydryl-azetidin-3-yl)carboxylic acid and 1.0 g of hydroxybenzotyrazole hydrate are placed under stirring. To this mixture under argon and cooled to +5°C are added 6.92 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 8.8 cm<3> of N,N-diisopropylethylamine. After 3 hours of stirring

+5°C and then 20 hours at 20°C, 200 cm<3> of water are added to the reaction mixture and decanted. The organic phase is washed with 300 cm<3> of water, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue is stirred with 100 cm<3> of diisopropyl oxide, after which the suspension is filtered and the solid is poured off and dried at 2.7 kPa. 10.76 g of (1-benzhydryl-azeti^n-3-yl)carbox<y>ls<y>re-N-methoxy<y>-N-meth<y>larnide is obtained in the form of a solid cream.

(l-Benzhydryl-azetidin-3-yl)carboxylic acid can be prepared by working as follows: To a suspension cooled to +5°C of 14 g of (l-benzhydryl-azetidin-3-yl)carbonitrile

into 140 cm<3> of 2-ethoxyethanol, a solution of 11 g of potassium hydroxide in 9 cm<3> of water is poured dropwise, after which the mixture is heated to 95°C. After 16 hours of stirring at this temperature, the reaction mixture is slowly poured with stirring onto ice and kept at 0°C for 68 hours and then concentrated to dryness at 50°C and 2.7 kPa. The residue is taken up in 400 cm<3> of water, after which the solution is acidified to pH 4 with 6N hydrochloric acid and 400 cm<3> of ethyl acetate is added. The resulting suspension is filtered, the solid is poured off and dried at 50°C and 2.7 kPa. 13.55 g of (1-benzhydryl-azetidin-3-yl)carboxylic acid is obtained in the form of a solid cream.

(1-Benzhydryl-azetidin-3-yl)carbonitrile can be prepared by working in the following way: To a solution of 40 g of 1-benzhydryl-azetidin-3-yl-methylsulfonate with 350 cm<3> of N,N-dimethylformamide is added dropwise a solution of 18.54 g of sodium cyanide in 25 cm<3>

water, after which the mixture is heated to 65°C. After 24 hours of stirring at 65°C, the reaction mixture, after it has returned to normal temperature, is once again completely stirred in a mixture of 550 cm<3> of water and 300 g of ice. The obtained suspension is filtered and the solid is washed with 3x110 cm<3> of water and then dissolved in 350 cm<3> of dichloromethane. The solution is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue is stirred in 200 cm<3> of diisopropyl oxide, after which the suspension is filtered and the solid is poured off and dried at 2.7 kPa. 28.4 g of (1-benzhydryl-azetidin-3-yl)carbonitrile is obtained in the form of a pink, cream-coloured solid.

l-Benzhydryl-azetidin-3-yl-methylsulfonate can be prepared by working from 100 g of l-benzhydryl-azetidin-3-ol, 800 cm<3> dichloromethane, 31 cm<3> methylsulfonyl chloride and 35 cm<3 >pyridine. The crude product obtained is chromatographed over a silica gel column with granulometry 0.063-0.200 mm, height 50 cm and diameter 11 cm, and is eluted under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate 80:20 -» 75:25 -» 70:30 - » 60:40 on a volume basis and fractions of 1 liter are recovered. Fractions 12 to 31 are combined and concentrated to dryness at 2.7 kPa. 66 g of 1-benzhydryl-azetidin-3-yl-methylsulfonate are obtained in the form of a yellowish-white solid. 1-Benzhydryl-azetidin-3-ol can be prepared by working as described by Alan R. Katritzky et al. in "J. Heterocyclic Chem.", 31, 271 (1994). Example 11 l-[3-({l-[bis-(4-Worphenyl)methyl]azetidin-3-yl}methylsulfonyl-methyl)phenyl]pyrrolidine-(RS) can be prepared by working as described in example 3 from 0 .10 g l-[3-({ l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonyl-methylene)phenyl]pyrrolidine, 1.5 cm<3 >anhydrous methanol, 1.5 cm3 anhydrous dichloromethane and 30 mg of sodium borohydride with stirring for 3 hours at 20°C and 8 hours at 50°C. The crude product is chromatographed over a silica gel column with granulometry 0.040-0.063 mm, height 8 cm and diameter 1 cm, and it is eluted under an argon pressure of 0.8 bar with cyclohexamethyl acetate in a volume ratio of 80:20 and fractions of 5 cm are recovered<3>. Fractions 22 to 28 are combined and concentrated to dryness at 2.7 kPa, after which the residue is stirred with 5 cm 3 pentane, the solid is filtered, poured off and dried. 18 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}methylsulfonyl-methyl)phenyl]pyrrolidine-(RS) is obtained in the form of a white powder. 1H NMR (300 MHz, CDCl 3 , 8 in ppm): 2.01 (mt, 4H), 2.59 (mt, 1H), 2.61 (s, 3H), from 3.10 to 3.25 (mt, 2H), 3.27 (mt, 4H), from 3.40 to 3.55 (mt, 1H), 3.66 (mt, 1H), 4.20 (d, J = 12 Hz, 1H ), 4.25 (s, 1H), from 6.45 to 6.65 (mt, 3H), from 7.10 to 7.35 (mt:9H). l-[3-({l-[bis-(4-ldorphenyl)methyl]azetidin-3-yl}methylsulfonyl-methylene)phenyl]pyrrolidine can be prepared by working as described in Example 6 from 0.6 g of l-[ bis-(4-chlorophenyl)-methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3-ol, 0.1 cm<3> methylsulfonyl chloride and 0.5 g of 4-dimethylaminopyridine , after which the obtained residue is chromatographed on a silica gel column with granulometry 0.04-0.06 mm, diameter 2 cm and height 30 cm, and eluted under a nitrogen pressure of 0.5 bar with dichloromethane:ethanol in the volume ratio 98.5:1, 5 and fractions of 10 cm<3> are recovered. Fraction 4 is concentrated to a dry state at 2.7 kPa. After recrystallization from 5 cm<3> diethyl oxide, 0.5 g of 1-[3-({ 1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonyl-methylene)phenyl]-pyrrolidine is obtained in the form of a solid that melts at 133°C. 1-[>is-(4-ldorphenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3-ol can be obtained by working according to Example 5 from 0.5 g l-[3-(methylsulfonyl-methyl)phenyl]pyrrolidine, 0.6 g l-[bis-[4-chlorophenyl)methyl]azetidin-3-one, 15 cm3 tetrahydrofuran and 1.4 cm<3> of a 1.6N solution of n-butyllithium in hexane. 0.6 g of 1-[bis-(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)methyl-(RS)]-azetidin-3-ol is obtained in the form of a cream-colored solid. l-[3-(methylsulfonylmethyl)phenyl]pyrrolidine can be prepared by working as described in example 8 from 6 cm<3> water, 6 cm<3> 100% acetic acid, 3.5 cm3 36N sulfuric acid, 3.11 g oxone, 0.96 g of 1-[3-(methylsulfanylmethyl)phenyl]pyrrolidine and 6 cm 3 of ethanol. 0.478 g of 1-[3-(methylsulfonylmethyl)phenyl]pyrrolidine is obtained in the form of a clear, brown gum. 1-[3-(rmethylsulfanylmethyl)phenyl]pyrrolidine can be prepared by working as described in Example 8 from 4.0 g of 1-iodo-3-(methylsulfanylmethyl)-benzene, 120 cm<3> tetrahydrofuran, 2.2 g of sodium -tert-butylate, 0.556 g of 1,r-bis-(diphenylphosphino)ferrocenyl palladium chloride, 1.26 g of 1,r-bis-(diphenylphosphino)ferrocene and 2.6 g of pyrrolidine. 1.9 g of 1-[3-(methyl-sulfanylmethyl)phenyl]pyrrolidine is obtained in the form of an oil.

Example 12

N-(RS)-[3-({l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonyl-methyl)phenyl]-N-methyl-carbamic acid tert-butyl ester can be prepared by working as described in example 3 from 0.10 g of N-[3-({l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonyl-methylene)phenyl]-N-methyl-carbamic acid-tert- butyl ester, 1.5 cm<3> of anhydrous methanol, 1.5 cm<3> of anhydrous dichloromethane and 30 mg of sodium borohydride with stirring for 3 hours at 20°C. The crude product is stirred with 10 cm<3> diisopropyl oxide, after which the solid is filtered, poured off and dried at 2.7 kPa. 94 mg of N-(RS)-[3-({1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}methylsulfonyl-methyl)phenyl]-N-methyl-carbarinic acid tert-butyl ester are obtained in the form of a white powder.

<!>H-NMR (300 MHz, (CD3)2SO d6, 8 in ppm): 1.36 (s, 9 H), 2.46 (t, J = 7.5 Hz, 1H), 2.75

(s, 3H), from 3.00 to 3.55 (mt, 4H), 3.17 (s, 3H), 4.45 (s, 1H), 4.78 (d, J = 11 Hz, 1H ), from 7.20 to 7.50 (mt, 12H).

N- [3-( {1 - [bis-(4-chlorophenyl)methyl] azetidin-3-yl} methylsulfonyl-methylene)phenyl] -N-methyl-carbamic acid tert-butyl ester can be prepared by working as described in Example 6 from 5.6 g of l-bis-(4-chlorophenyl)methyl]-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)-phenyl]methylsulfonyl-methyl-(RS)}azetidine-3- ol, 100 cm<3> dichloromethane, 1.59 g methylsulfonyl chloride and 4.5 g 4-dimethylaminopyridine. The crude product obtained is purified by chromatography over a silica gel column with granulometry 0.04-0.06 mm, diameter 4 cm and 250 g of silicon dioxide, eluting under a nitrogen pressure of 0.5 bar with ethyl acetate cyclohexane in the volume ratio 30:70 and recovering fractions of 100 cm<3>. Fractions 12 to 18 are combined, concentrated to dryness at 2.7 kPa. 3.2 g of tert-butyl ester of N-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonyl-methylene)phenyl]-N-methylcarbamic acid is obtained in the form of white meringue mass.

l-[bis-(4-chlorophenyl)methyl]-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl]-methylsulfonyl-methyl-(RS)}azetidin-3-ol can be prepared by work as described in Example 5 from 3.8 g N-[3-(methylsulfonylmethyl)-phenyl]-N-methyl-carbamic acid tert-butyl ester, 50 cm<3> tetrahydrofuran, 9.5 cm<3> of a 1 .6N n-butyllithium solution in hexane and 3.82 g of 1-bis-(4-Worfen<y>l)rmethyl]azetidin-3-one. The crude product is purified by chromatography over a silica gel column with granulometry 0.04-0.06 mm, diameter 4 cm and 250 g of silicon dioxide, eluting under a nitrogen pressure of 0.5 bar with dichloromethane and then with dichloromethane:ethanol in the volume ratio 99:1 and fractions of 500 cm<3> are recovered. Fractions 10 to 16 are combined and concentrated to dryness at 2.7 kPa. 5.6 g of 1-[bis-(4-chlorophenyl)methyl]-3-{[3-(N-tert-butyloxycarbonyl-N-methyl-amino)phenyl]methylsulfonyl-methyl-(RS)}azetidine- 3-ol in the form of a meringue mass.

N-[3-(methylsulfonylmethyl)-phenyl]-N-methyl-carbarinic acid tert-butyl ester can be prepared in the following way: To a solution of 3 g in 80 cm<3> dichloromethane is added 3.7 g of di-tert-butyl- dicarbonate. After stirring for 20 hours at 20°C, 100 cm<3> of water is added to the reaction mixture and then decanted. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue is chromatographed over a silica gel column with granulometry 0.04-0.06 mm, diameter 4 cm and 300 g of silicon dioxide, eluting with a nitrogen pressure of 0.5 bar with ethyl acetate:cyclohexane in the volume ratio 45:55 and recovering fractions of 100 cm<3>. Fractions 11 to 16 are combined and concentrated to dryness at 2.7 kPa. 3.8 g of N-[3-(methylsulfonyl-methyl)-phenyl]-N-methyl-carbamic acid tert-butyl ester are obtained in the form of a gum which crystallizes.

N-[3-(methylsulfonylmethyl)-phenyl]-N-methylamine can be obtained in the following way: To 50°C and for 3 hours under argon, a mixture of 19.63 cm<3> formic acid and 19.63 cm<3 is heated >acetic anhydride which is then allowed to return to ambient temperature. Pour into 40 cm<3> of tetrahydrofuran and cool the whole to -20°C. After stirring for 2 hours at -20°C, it is poured into a solution of 14.8 g of 3-(methylsulfonylmethyl)-phenylamine, while the temperature is maintained. After stirring for 2 hours at -20°C and then 48 hours at 20°C, the mixture is filtered, the solid is poured off and then washed with 3 x 50 cm<3> diisopropyl oxide and dried at 2.7 kPa. A solid A is obtained. The filtrate is concentrated to half the volume and the resulting suspension is filtered, after which the solid is poured off, washed with diisopropyl oxide and dried. A solid B is obtained. The two solids A and B are combined and taken up in 375 cm<3> of tetrahydrofuran, after which the mixture, cooled to 0°C, is added within 20 minutes of 80 cm<3> of a 2M solution of the dimethyl sulphide borane complex in tetrahydrofuran , after which the temperature is brought to reflux for 3 hours. The reaction mixture, cooled to +5°C, is added over 20 minutes to 60 cm<3> of methanol, stirred for 1 hour at ambient temperature and then gaseous hydrochloric acid is added to pH 1. The mixture is refluxed for 1 hour and 300 cm<3 is added > water and a 3N sodium hydroxide solution to pH 8. The resulting mixture is extracted with 500 cm<3> ethyl acetate, after which the organic phase is successively washed with a saturated, aqueous sodium bicarbonate solution, and with brine and dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. The residue is taken up in 100 cm<3> of 4N sulfuric acid and the resulting solution is washed with 100 cm<3> of ethyl acetate and then made alkaline to pH 8 with 3N sodium hydroxide and a saturated aqueous sodium carbonate solution and then extracted with 2 x 75 cm<3> ethyl acetate. The combined extracts are dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. 8.98 g of N-[3-(methylsulfonylmethyl)-phenyl]-N-methylamine are obtained in the form of a pink solid.

3-(Methylsulfonylmethyl)-phenylamine can be prepared by working in the following manner: A suspension of 23.7 g of 1-(methylsulfonylmethyl)-3-nitrobenzene in 150 cm<3> methanol and 65 cm<3> 36% is heated to reflux -ig hydrochloric acid, then add carefully, during 10 minutes and in small portions, 18.5 g. After 4 hours of reflux and then 20 hours of stirring at normal temperature, 5 g of iron are added to the reaction mixture and heated again to reflux for 1 hour and then for 20 hours to normal temperature. The mixture is then made alkaline to pH 9 with ammonia and with sodium bicarbonate, extracted with 3 x 250 cm<3> ethyl acetate, dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. 14.9 g of 3-(methylsulfonylmethyl)-phenylamine is obtained in the form of a beige-coloured powder. 1-(Methylsulfonylmethyl)-3-nitrobenzene can be prepared by heating to reflux 23.8 g of 3-nitrobenzyl chloride, 20 g of sodium methyl sulfinate and 250 cm<3> of absolute ethanol. 23.74 g of 1-(methylsulfonylmethyl)-3-nitrobenzene is obtained in the form of a white powder.

Example 13

N-[3-({1-bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonyl-methyl)phenyl]-N-methylamine-(RS) can be prepared by working as described in Example 3 from 0 .10 g of N-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl} methylsulfonyl-methylene)phenyl]-N-methyl-amine in 1.5 cm<3> anhydrous methanol , 1.5 cm<3> of anhydrous dichloromethane and 45 mg of sodium borohydride while stirring for 20 hours at 20°C and then for 5 hours at 50°C. The crude product is chromatographed on a silica gel column with granulometry 0.040-0.063 mm, height 10 cm and diameter 1 cm, being eluted under an argon pressure of 0.8 bar with cyclohexane:ethyl acetate in the volume ratio 80:20 —»60:40 and with recovery of fractions of 5 cm<3>. Fractions 20 to 26 are combined and concentrated to dryness at 2.7 kPa, after which the residue is stirred with 5 cm<3> pentane and the solid is filtered, poured off and dried. 20 mg of N-[3-({ 1-bis-(4-ldorphenyl)methyl]azetidin-3-yl}methylsulfonyl-methyl)phenyl]-N-methyl-arnine-(RS) is obtained in the form of a white powder .

<]>H-NMR (300 MHz, CDCl 3 , 8 in ppm): from 2.50 to 2.65 (mt, 1H), 2.60 (s, 3H), .2.82 (d, J

= 5 Hz, 3H), 3.18 (mt, 2H), from 3.35 to 3.50 (mt, 1H), 3.64 (t large, J = 7.5 Hz, 1H), 3.80 (mt, 1H), 4.18 (d, J = 11.5 Hz, 1H), 4.24 (s, 1H), from 6.50 to 6.70 (mt, 3H), from 7.10 to 7.35 (mt, 9H).

N- [3-( {1 - [bis-(4-chlorophenyl)methyl] azetidin-3-yl} methylsulfonyl-methylene)phenyl] -N-methylamine can be prepared by working in the following way: 120 hours stirring 2.7 g l-[bis-(4-chlorophenyl)methyl]-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl]methylsulfonyl-methylene} azetidine in 30 cm<3> dioxane and 30 cm<3 > 4.7N hydrochloric acid dioxane solution. The reaction medium is evaporated to dryness at 2.7 kPa, taken up in 50 cm<3> water and 50 cm<3 >ethyl acetate, stirred and carefully neutralized with a saturated aqueous sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate, treated with animal soot and then concentrated at 2.7 kPa to a volume of around 25 cm<3>, filtered and concentrated to dryness under reduced pressure. 1.3 g of N-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonyl-methylene)phenyl]-N-methyl-amine are obtained in the form of white crystals which melt at 228°C.

Example 14

l-I^is-(4-fluorophenyl)methyl]-3-[(3,5-bis-Mfluoromethylphenyl)methylsulfonyl-methyl]azeti (RS) can be prepared by working as described in Example 3 from 0.10 g of l-[ bis-(4-Worphenyl)methyl]-3-[(3,5-bis-trifluoromethylphenyl)methylsulfonyl-methylene]azetidine, 1.5 cm<3 >anhydrous methanol, 1.5 cm<3> anhydrous dichloromethane and 15 mg sodium borohydride with stirring for 3 hours at 20°C. The crude product is stirred with 5 cm<3> pentane, after which the solid is filtered, poured off and dried. 82 mg of 1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-bis-trifluoromethylphenyl)methylsulfonyl-methyl]azetidine-(RS) is obtained in the form of a white powder. ^-NMR (400 MHz, (CD3)2SO d6, 8 in ppm): 2.84 (s, 3H), 3.08 (mt, 2H), from 3.25 to 3.40 (mt, 1H), from 3.45 to 3.65 (mt, 2H), 4.45 (s, 1H), 5.13 (d, J = 10.5 Hz, 1H), from 7.25 to 7.50 (mt, 8H), 8.11 (s large, 2H), 8.15 (s large, 1H). l-[bis-(4-ldorphenyl)methyl]-3-[(3,5-bis-trifluoromethylphenyl)methylsulfonyl-methylene]-azetidine can be prepared by working as follows: To a solution of 3.16 g of 3- acetoxy-1-[bis-(4-ldorphenyl)methyl]-3-{[3,5-bis(trifluoromethyl)phenyl]methylsulfonyl-methyl-(RS)} azetidine in 40 cm<3> dioxane is added in proportions 0, 96 g ground sodium hydroxide. After stirring for 1 hour at normal temperature, 200 cm<3 >ethyl acetate, 200 cm<3> water are added to the reaction mixture and then decanted. The organic phase is washed with 2 x 80 cm<3> water and then with 80 cm3 of brine, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue is chromatographed over a silica gel column with granulometry 0.040-0.063 mm, height 14.5 cm and diameter 4.8 cm, eluting under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in the volume ratio 85:15 and fractions of 40 cm are recovered <3>. Fractions 8 to 15 are combined and concentrated to dryness at 2.7 kPa and 1.49 g of 1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-bis-trifluoromethylphenyl)methylsulfonyl-methylene is obtained ] azetidine in the form of a white meringue mass.

3-acetoxy-1-[>is-(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluonethyl)phenyl]methylsulfonyl-methyl-(RS)} azetidine can be prepared by working as follows: To a resolution

cooled to -78°C of 2.0 g of [3,5-bis(trifluoromethyl)benzyl]methylsulfone in 35 cm3 of tetrahydrofuran, is poured dropwise under argon, 4.1 cm<3>1.6N n-butyllithium solution in hexane. After stirring for 1 hour at -70°C, a solution of 2.0 g of 1-[bis-(4-chloro-phenyl)methyl]azetidin-3-one in 35 cm<3> of tetrahydrofuran is added dropwise. After stirring for 2 hours at -78°C, a solution of 0.7 cm3 of acetyl chloride is poured into 5 cm3 of anhydrous diethyl oxide and the mixture is then allowed to return to normal temperature. After 2 hours and 30 minutes of stirring, 100 cm3 of water is added to the reaction mixture and decanted. The organic phase is washed with 100 cm3 of water and then with 100 cm3 of saline solution and dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. The residue is chromatographed over a silica gel column with granulometry 0.04-0.06 mm, diameter 5.6 cm and height 16 cm, eluting under an argon pressure of 0.5 bar with ethyl acetate:cyclohexane in the volume ratio 10:19 and then 40: 60 and during recovery of fractions of 100 cm<3>. Fractions 37 to 52 are combined and concentrated to dryness at 2.7 kPa. 3.56 g of 3-acetoxy-1-[bis-(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)phenyl]methylsulfonyl-methyl-(RS)} azetidine are obtained in the form of a white meringue mass.

[3,5-bis(trifluoromethyl)benzyl]methylsulfone can be prepared by heating to reflux 1.8 g of 3,5-bis(trifluoromethyl)benzyl chloride, 50 cm<3> absolute ethanol and 1.22 g sodium methyl sulfinate. 1.86 g of [3,5-bis(trifluoromethyl)benzyl]methylsulfone is obtained in the form of a white solid.

Example 15

N-[4-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonyl-methyl-(RS)]azetidine-1-}methyl-(RS))-benzyl]-N,N -dimethyl-amine, mixture of the two diastereoisomers, can be prepared by working as described in example 3 from 0.10 g of N-[4-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonyl -methylene]azetidin-1-yl}-methyl-(RS))-benzyl]-N,N-dimethylamine, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 45 mg of sodium borohydride under heating for 16 hours at 20°C and then 16 hours at 50°C. The crude product is chromatographed over a silica gel column with granulometry 0.040-0.063 mm, height 22 cm and diameter 1 cm and it is eluted under an argon pressure of 0.8 bar with ethyl acetate:methanol in the volume ratio 97:3, recovering fractions of 20 cm<3> . Fractions 17 to 25 are combined and concentrated to dryness at 2.7 kPa and the residue is stirred with 5 cm<3 >pentane, after which the solid is filtered, poured off and dried. 6 mg of N-[4-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonyl-methyl-(RS)]azetidine-1-}-methyl-(RS))-benzyl] are obtained -N,N-dimethylamine, mixture of the two diastereoisomers, in the form of a white powder.

1H-NMR (300 MHz, CDCl 3 , § in ppm): 2.20 (s, 6H), 2.53 (t, J = 7 Hz, 1H), 2.65 (s, 3H),

from 3.10 to 3.25 (mt, 2H), from 3.30 to 3.45 (mt, 1H), 3.35 (s large, 2H), 3.63 (t large, J = 7 Hz, 1H), 4.24 (s, 1H), 4.25 (d, J = 11 Hz, 1H), 6.82 (tt, J = 9 and 2 Hz, 1H), 6.94 (mt, 2H) , from 7.15 to 7.35 (mt, 8H).

N- [4-((4-chlorophenyl)- {3 -[(3,5-difluorophenyl)methylsulfonyl-methylene] azetidin-1 -yl}-methyl-(RS))-benzyl]-N,N-dimethyl- amine can be prepared by working as follows: To a solution of 0.93 cm<3> of a 2M dimethylamine solution in methanol in 30 cm<3> of anhydrous 1,2-dichloroethane anhydride, put under argon 1.0 g (RS) -4-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methylene] azetidin-1-yl }methyl)-benzaldehyde. After stirring for 30 minutes at normal temperature, 0.9 g of sodium triacetoxyborohydride is added in small portions. After stirring for 48 hours, 2.65 cm<3> IN of sodium hydroxide, 100 cm3 of water and 100 cm3 of dichloromethane are added to the reaction mixture and decanted. The organic phase is washed with 2 x 80 cm<3> of water, and with 80 cm3 of salt solution, dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. The residue is chromatographed over a silica gel column with granulometry 0.04-0.06 mm, diameter 4 cm and height 17.5 cm, eluting under an argon pressure of 0.5 bar with ethyl acetate cyclohexane in the volume ratio 30:70 and fractions of 40 cm are recovered <3>. Fractions 48 to 53 are combined and concentrated to dryness at 2.7 kPa. 0.46 g of N-[4-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonyl-methylene] azetidin-1-yl}-methyl-(RS))-benzyl] - N,N-dimethylamine as a white solid.

(RS)-4-((4-chlorophenyl)-{3-[(3,5-difluoro-phenyl)-methylsulfonyl-methylene]azetidih-1-yl}-methyl)-benzaldehyde can be prepared by working as follows : To a solution of 18.9 g of 1-[(4-chlorophenyl)-(4-[1,3]dioxolan-2-yl-phenyl)methyl]-(RS)-3-[(3,5-difluorophenyl )methylsulfonyl-methylene]azetidine in 80 cm3 of tetrahydrofuran, add 75.6 cm3 of 5N hydrochloric acid. After 3 hours at ambient temperature, the mixture is taken up in dichloromethane and

distilled water and then the pH value is brought to 14 by adding 30% sodium hydroxide and the whole is decanted. The organic phase is washed with 2 x 100 cm<3> of water and then 100 cm3 of a saturated, aqueous sodium chloride solution, dried over magnesium sulfate,

filtered and concentrated to dryness at 2.7 kPa. Man 16 g of (RS)-4-((4-chlorophenyl)-{3-[(3,5-difluoro-phenyl)-methylsulfonyl-methylene]azetidin-1-yl}methyl)-benzaldehyde in the form of a white meringue mass .

1-[(4-chlorophenyl)-(4-[1,3]dioxolan-2-yl-phenyl)methyl]-(RS)-3-[(3,5-difluorophenyl)methylsulfonyl-methylene]azetidine can be prepared as follows: To a solution of 34.45 g of the mixture of the two diastereoisomers 1-[(4-chlorophenyl)-(4-[1,3]-dioxolan-2-yl-phenyl)-methyl-(RS)]- 3-[(3,5-difluorophenyl)methylsulfonyl-methyl-(RS)]azetidin-3-yl-acetati400

cm<3> tetrahydrofuran under argon at 0°C is added dropwise 13.0 cm<3>1,8-diazabicyclo-[5.4.0]undec-7-ene and after usual treatment the product is chromatographed on a silica gel

column with granulometry 0.04-0.06 mm, diameter 10.2 cm and height 23 cm, and elution under an argon pressure of 0.5 bar with ethyl acetate:cyclohexane in the volume ratio 20:80 and recovery of fractions of 250 cm<3 >, whereby 16.6 g of 1-[(4-chloro-phenyl)-(4-[1,3]dioxolan-2-yl-phenyl)methyl]-(RS)-3-[(3,5 -difluorophenyl)methylsulfonyl-methylene]azetidine as a white solid.

The mixture of the two diastereoisomers 1-[(4-chlorophenyl)-(4-[1,3]dioxolan-2-yl-phenyl)-methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulfonyl -methyl-(RS)]azetidin-3-yl acetate can be prepared as follows: By working according to example 1 (method 2) from 11.6

g (3,5-difluorobenzyl)methylsulfone, 35.1 cm<3>1.6N n-butyllithium solution in hexane, 19.3

g l-{(4-chlorophenyl)-[4-([l,3]-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-one and 8.8 cm<3 >acetyl chloride in 500 cm3 of tetrahydrofuran, 37.8 g of a mixture of the two diastereoisomers 1-[(4-chlorophenyl)-(4-[1,3]-dioxolan-2-yl-phenyl)methyl-(RS)]-3-[( 3,5-difluorophenyl)methylsulfonyl-methyl-(RS)]azetidin-3-yl-acetate in the form of a white meringue mass.

1 -{(4-Chlorophenyl)-[4-([ 1,3]-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-one can be

is set up in the following way: To a solution of 28.32 g of 1-{(4-chlorophenyl)[4-([1,3]dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-ol in 200 cm3 of dimethylsulfoxide is placed at ambient temperature 46 cm<3> of triethylamine and then a solution of 34 g of sulfur pyridine trioxide complex in 100 cm<3> of dimethylsulfoxide is added dropwise. After 0.25 hours at ambient temperature, the reaction mixture is poured into ice, extracted with ethyl acetate,

washed with 3 x 400 cm3 of water and then 400 cm3 of a saturated sodium chloride solution

ning, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa.

The obtained residue is chromatographed over a silica gel column with a granulometry of 0.04-

0.06 mm, diameter 9.2 cm and height 21 cm, and is eluted under an argon pressure of 0.5 bar with ethyl acetate:cyclohexane in the volume ratio 20:80 and fractions of 250 cm<3> are recovered. Fractions 9 to 18 are combined and concentrated to dryness at 2.7 kPa. 20.4 g of 1-{(4-chlorophenyl)-[4-([1,3]-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-one are obtained in the form of a yellow oil . 1-{(4-chlorophenyl)[4-([ 1,3]-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-ol can be prepared as described in example 3, starting from 35.0 g {(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine, 8.3 g epibromohydrin, 5.1 g sodium bicarbonate and 400 cm<3 >ethanol. 30.3 g of 1-{(4-chlorophenyl)[4-([1,3]-dioxolan-2-yl)phenyl]methyl-(RS)}-azetidin-3-ol are isolated.

{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine hydrochloride can be prepared according to the method described by M. Grisar et al. in "J. Med. Chem.", 885

(1973) from 67.2 g of 4-([,3]-dioxolan-2-yl)benzonitrile, 88.2 g of 1-bromo-4-chlorobenzene, 11 g of magnesium and 600 cm 3 of ethyl ether. 42.3 g of {(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine are obtained in the form of a yellow oil.

Example 16

1-[(4-chlorophenyl)-(thien-2-yl)-methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl-(RS)] azetidine, mixture of the two diastereoisomers, can be prepared by working as described in Example 3, from 0.10 g of 1-[(4-chlorophenyl)-(thien-2-yl)-methyl-(RS)]-3-[(3,5- difluorophenyl)methylsulfonylmethylene] azetidine, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 45 mg of sodium borohydride, stirring for 16 hours at 20°C and then for 16 hours at 50°C. The crude product is chromatographed on a silica gel column with granulometry 0.040-0.063 mm, height 25 cm and diameter 1 cm, and it is eluted under an argon pressure of 1 bar with cyclohexane:ethyl acetate in a volume ratio of 90:10 and fractions of 20 cm<3> are recovered. Fractions 37 to 42 are combined and concentrated to dryness at 2.7 kPa and the residue is stirred with 5 cm 3 of pentane, after which the solid is filtered, decanted and dried. 8 mg of 1-[(4-chlorophenyl)-(thien-2-yl)-methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl-(RS)]azetidine is obtained, mixture of the two diastereoisomers, in the form of a white powder. <!>H-NMR (300 MHz, CDCl 3.8 in ppm). One observes a mixture of diastereo isomers, from 2.50 to 2.70 (mt, 1H), 2.66 and 2.68 (2s, 3H combined), from 3.15 to 3.80 (mt, 4H), from 4.20 to 4.30 (mt, 1H), 4.31 and 4.57 (2s, 1H together), from 6.80 to 7.00 and from 7.10 to 7.40 (mts, 10H together). l-[(4-chlorophenyl)-(thien-2-yl)-m^azetidine can be prepared by working as described in Example 6 from 0.52 g of a mixture of the two diastereoisomers, l-[(4 -chlorophenyl)-(thien-2-yl)-methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl-(RS)]azetidin-3-ol, 0.14 cm3 of methylsulfonyl chloride and 0 .49 g of 4-dimethylaminopyridine. It is obtained after chromatography on a silica gel column with granulometry 0.06-0.200 mm, diameter 2.4 cm and height 20 cm, and by eluting under an argon pressure of 0.5 bar with ethyl acetate:cyclohexane in the volume ratio 20:80 and recovery of fractions of 30 cm<3>, 0.32 g (RS)-1-[(4-chlorophenyl)-(thien-2-yl)-methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methylene ]azetidine in the form of a white solid melting at 176°C. The mixture of the two diastereoisomers 1-[(4-chlorophenyl)-(thien-2-yl)-methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl-(RS)]azetidine-3 -ol can be prepared by working as described in Example O from 1.60 cm<3>1.6N n-butyllithium in solution in hexane, 0.83 g of (3,5-difluorobenzyl)methylsulfone and 1.06 g 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-azetidin-3-one. After purification on a silica gel column with granulometry 0.06-0.200 mm, diameter 3.6 cm and height 32 cm, and elution under an argon pressure of 0.5 bar with ethyl acetate: cyclohexane in the volume ratio 25:75 and recovery of fractions of 40 cm3 , 0.55 g of a mixture of the diastereoisomers 1-[(4-chlorophenyl)-(thien-2-yl)-methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl-(RS) is obtained ]azetidin-3-ol as an off-white solid. l-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-one can be prepared by working as described in Example 1 (method 2) starting from 1.83 cm< 3> oxalyl chloride, 20 cm3 of dichloromethane, 3.04 cm3 of dimethyl sulfoxide, 5.2 g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-ol, 80 cm3 of dichloromethane and 9 .12 cm3 of triethylamine. 3.3 g of 1-[(4-chlorophenyl)-(thien-2-yl)methyl-(RS)]azetidin-3-one is obtained in the form of a yellow oil which crystallizes at ordinary temperature. l-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-ol can be prepared by working as follows: To a solution of 11.0 g of [(4-chlorophenyl)( thien-2-yl)methyl-(RS)]amine in 80 cm3 of ethanol, add 4.12 g of sodium bicarbonate. To the mixture, heated to 65°C, is added 4.03 cm 3 of epibromohydrin. After stirring for 20 hours at 65°C, the cooled mixture is filtered and the filtrate is concentrated to dryness at 2.7 kPa. The residue is chromatographed over a silica gel column with granulometry 0.06-0.200 mm, diameter 3.6 cm and height 32

cm, eluting under an argon pressure of 0.5 bar with ethyl acetate cyclohexane in volume

ratio 25:75 and recovery of fractions of 60 cm<3>. 6.3 g of 1-[(4-chloro-phenyl)(thien-2-yl)methyl-(RS)]azetidin-3-ol are obtained in the form of a pale yellow oil.

[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]amine can be prepared as follows: To a suspension, cooled to 10°C, of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of 4-bromochlorobenzene and 2.43 g of magnesium) in 120 cm<3> of anhydrous ethyl ether is slowly poured into a solution of 10.92 g of 2-thiophenecarbonitrile in 80 cm<3> of diethyl oxide. After one hour under reflux, the mixture is cooled to 10°C and 40 cm<3> of methanol is slowly added, after which the whole is filtered over supercel. Under argon and in small portions, 4.54 g of sodium borohydride are added over the course of 15 minutes and the reaction medium is then stirred for 20 hours at 20°C. The resulting mixture is diluted with ethyl acetate and then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at 50°C at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 5 cm and height 42 cm, eluting under an argon pressure of 0.5 bar with ethyl acetate:cyclohexane in the volume ratio 4:6 and fractions of 100 cm< 3>. Fractions 6 to 12 are concentrated to a dry product corresponding to 13 g of imine in the form of a yellow oil which is taken up in 100 cm<3> of methanol. 2.4 g of sodium borohydride are added to the solution obtained and stirred for 1 hour at 5°C. The resulting mixture is diluted with ethyl acetate and then washed with water. The organic phase is dried over magnesium sulfate and concentrated to dryness at 50°C and 2.7 kPa. The residue is chromatographed over a silica gel column with granulometry 0.06-0.200 mm, diameter 3.2 cm and height 40 cm, eluting under an argon pressure of 0.5 bar with ethyl acetate cyclohexane in the volume ratio 4:6 and fractions of 60 cm< 3>. 11.0 g of [(4-chlorophenyl)-(thien-2-yl)methyl-(RS)]amine are obtained in the form of a yellow oil.

Example 17

[3-( {1 - [bis-(4-chlorophenyl)methyl] azetidin-3-yl} methylsulfonyl-methyl)phenyl] methanol-(RS) can be prepared by working as described in Example 3, from 0.050 g [3-({ l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonyl-methylene)phenyl]methanol, 1.0 cm<3> anhydrous methanol, 1.0 cm<3> anhydrous dichloromethane and 20 mg of sodium borohydride with stirring for 3 hours at 20°C. The crude product is chromatographed on a silica gel column with granulometry 0.040-0.063 mm, height 20 cm and diameter 1 cm and is eluted under an argon pressure of 0.8 bar with cyclohexane:ethyl acetate in the volume ratio 90:10 and fractions of 10 cm are recovered<3>. Fractions 30 to 38 are combined and concentrated to dryness at 2.7 kPa,

after which the residue is stirred with 5 cm<3> of pentane, the solid is filtered, decanted and dried. 13 mg of [3-({1-bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonyl-methyl)phenyl]-methanol-(RS) is obtained in the form of a white powder.

<*>H-NMR (300 MHz, CDCl3.8 in ppm): 1.75 (t, J = 6 Hz, 1H), 2.52 (t, J = 7.5 Hz, 1H), 2.59 (s, 3H), 3.17 (t large, J = 7.5 Hz, 2H), 3.48 (mt, 1H), 3.65 (mt, 1H), 4.23 (s, 1H), 4.28 (d, J = 11.5 Hz, 1H), 4.70 (d, J = 6 Hz, 2H), from 7.15 to 7.40 (mt, 12 H).

[3 -({1 - [bis-(4-chlorophenyl)methyl] azetidine-3 -1} methylsulfonyl-methylene)phenyl]methanol can be prepared by working as follows: To a solution cooled to +5°C of 5 .1 g of 1-[bis-(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl]methylsulfonyl-methylene} azetidine in 51 cm<3> tetrahydrofuran is poured into 17 cm3 of an IM solution of tetrabutylammonium fluoride in tetrahydrofuran. After 20 minutes of stirring in the cold and 3 hours at 20°C, the reaction mixture is poured into a mixture of 200 cm<3> of water and 100 cm<3> of ethyl acetate and decanted. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The obtained residue is purified by chromatography over a silica gel column with granulometry 0.04-0.06 mm, diameter 2 cm and height 30 cm, and elution under an argon pressure of 0.5 bar with dichloromethane:ethanol in the volume ratio 97:3 and recovery of fractions of 1.00 cm<3>. Fractions 10 to 14 are combined and concentrated to dryness at 2.7 kPa. The yellow solid obtained is taken up in 2 cm<3> dichloromethane and 10 cm<3> ethyl acetate and then filtered on a glass frit and washed with 2 cm<3> ethyl acetate. 1.6 g of [3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonyl-methylene)phenyl]methanol is obtained in the form of a white solid which melts at 214°C.

l-[bis-(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl]methylsulfonyl-methylene} azetidine can be prepared by working in the same way as in example 1, from 10.8 g l -[bis-(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl]methylsulfonyl-methyl-(RS)}azetidin-3-ol, 2 cm3 of methylsulfonyl chloride and 8.5 g of 4-dimethylamino -pyridine, after which the obtained residue is purified by chromatography on a silica gel column with granulometry 0.04-0.06 mm, diameter 4 cm and height 40 cm, under a nitrogen pressure of 0.5 bar and elution with dichloromethane as eluent and recovery of fractions of 100 cm<3>. Fractions 12 to 29 are combined and concentrated to dryness at 2.7 kPa. 5.2 g of 1-[bis-(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl]methylsulfonyl-methylene} azetidine is obtained in the form of a gum. 1-[bis-(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl]methylsulfonyl-methyl-(RS)}azetidin-3-ol can be prepared by working as in example 5 from 5 .8 g of tert-butyl-(3-methylsulfonylmethyl-benzyloxy)dimethyl-silane and 5.6 g of l-[bis-(4-chlorophenyl)-methyl]azetidin-3-one and 10.8 g of l-[ bis-(4-chlorophenyl)methyl]-3-{[3-(tert-butyl-dimethylsilyloxymethyl)phenyl]methylsulfonyl-methyl-(RS)}azetidin-3-ol in the form of a compound.

Tert-butyl-(3-methylsulfonylmethyl-benzyloxy)dimethyl-silane can be prepared by working as follows: To a solution of 5.73 g of (3-methylsulfonylmethyl-phenyl)-methanol in 50 cm<3> N,N- dimethylformamide, 4.87 g of imidazole and then 10.3 cm<3> of tert-butylchlorodimethylsilane are added. After stirring for 20 hours at room temperature, the reaction mixture is concentrated to a dry state at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.06-0.200 mm, diameter 3.5 cm and with 100 g of silicon dioxide, eluting under a nitrogen pressure of 0.5 bar with dichloromethane and recovering fractions of 100 cm<3>. Fractions 2 to 7 are combined and concentrated to dryness at 2.7 kPa. 5.8 g of an oil which crystallizes at normal temperature and with a melting point of 75°C is obtained.

(3-methylsulfonylmethyl-phenyl)methanol can be prepared in the following way: 118 hours and at a temperature close to 20°C, a mixture of 26 g of 3-(methylsulfonylmethyl)benzoic acid and 4.6 g of lithium duminium hydride is stirred in 600 cm<3> tetrahydrofuran. The solution is cooled to 0°C and then poured successively into 15 cm<3> of ethyl acetate, 5 cm<3> of water, 5 cm<3> of a 15

% aqueous sodium hydroxide solution and finally 30 cm<3> of water. The mixture is filtered over Celite and the filtrate is taken up with 600 cm<3> of ethyl acetate. The organic phase is taken up with 500 cm<3> of water and then 200 cm<3> of a saturated aqueous sodium chloride solution, decanted and dried over anhydrous magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. 10.4 g of (3-methylsulfonylmethyl-phenyl)methanol is obtained in the form of a gum.

3-(Methylsulfonylmethyl)benzoic acid can be prepared in the following way: By working as in example 14 from 23.3 g of 3-chloromethylbenzoic acid and 23.3 g of sodium methanesulfinate, 26 g of 3-(methylsulfonylmethyl)benzoic acid is obtained in the form of a white solid which melts at 210°C.

Example 18

l-[bis-(4-chlorophenyl)methyl]-3-(phenylsulfonylmethyl)-azetidine can be prepared by working as follows: To a solution of 0.15 g of l-[bis-(4-chlorophenyl)methyl)]- 3-(phenylsulfonyl-methylene)-azetidine in 3 cm<3> of anhydrous ethanol and 3.5 cm<3> of anhydrous dichloromethane are placed under argon 13 mg of sodium borohydride. After 1 hour and 45 minutes of stirring, 14 mg of sodium borohydride are added again and the whole is allowed to stir for 20 hours at 20°C. The reaction mixture is then heated to 50°C and 9.5 mg of sodium borohydride is added and the whole is then stirred for 2 hours and 30 minutes at 50°C and cooled to room temperature. 0.5 cm<3> of water, 10 cm3 of dichloromethane and 50 mg of magnesium sulphate are then added and the whole is filtered and evaporated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.063-0.200 mm, height 15 cm and diameter 1 cm, eluting under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in the volume ratio 80:20 and fractions of 5 cm are recovered<3> . Fractions 12 to 19 are combined and concentrated to dryness at 2.7 kPa. 29 mg of 1-[bis-(4-chlorophenyl)methyl]-3-(phenylsulfonylmethyl)-azetidine is obtained in the form of a white solid.

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): from 2.75 to 8.90 (mt, 3H), 3.32 (mt, 2H), 3.37 (d,

J = 7 Hz, 2H), 4.22 (s, 1H), from 7.20 to 7.30 (mt, 8H), 7.57 (t large, J = 7.5 Hz, 2H), 7, 67 (tt, J = 7.5 and 1.5 Hz, 1H), 7.88 (d large, J = 7.5 Hz, 2H).

Example 19

l-[bis-(4-chlorophenyl)methyl)]-3-(phenylsulfonylmethylene)-azetidine can be prepared by working as follows: To a solution cooled to -70°C and under argon of 4.34 g (phenylsulfonylmethyl) trimethylsilane in 40 cm3 of dimethyl ether, 12 cm3 of a 1.6M n-butyllithium solution in hexane is poured over the course of 5 minutes. After stirring the mixture for 30 minutes at -60°C, it is poured over the course of 10 minutes into a solution of l-[bis-(4-chlorophenyl)methyl]azetidin-3-one in 30 cm3 of dimethyl ether [prepared in the form of base and prepared by treating 7.35 g of l-| ethyl acetate, subsequent drying and concentration to dryness at 2.7 kPa]. After stirring for 45 minutes at -70°C and then 2 hours at 20°C, 12 cm3 of a saturated, aqueous ammonium chloride solution is added to the mixture, then 20 cm3 of water and the whole is then extracted with 2 x 40 cm3 of ethyl acetate. The combined organic phases are washed with 40 cm 3 of water, dried over magnesium sulfate and then concentrated to dryness at 2.7 kPa. The obtained oil is chromatographed on a silica gel column with granulometry 0.063-0.200 mm, height 40 cm and diameter 5 cm, and is eluted under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in the volume ratio 90:10 — > 85:15 and fractions are recovered of 100 cm<3>. Fractions 10 to 16 are combined and concentrated to dryness at 2.7 kPa. The oil obtained is triturated in 10 cm 3 of diethyl oxide and the suspension is filtered, after which the solid is dried. 1.17 g of 1-[bis-(4-chlorophenyl)methyl)]-3-(phenylsulfonylmethylene)-azetidine is obtained in the form of a white solid.

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): 3.88 (mt, 2H), 4.29 (mt, 2H), 4.50 (s, 1H), 6.17

(mt, 1H), from 7.20 to 7.40 (mt, 8H), 7.56 (t large, J = 7.5 Hz, 2H), 7.64 (tt, J = 7-5 and 1 .5 Hz, 1H), 7.87 (d large, J = 7.5 Hz, 2H).

(Phenylsulfonylmethyl)trimethylsilane can be prepared by working as follows: To a solution cooled to -70°C of 3 g of methylphenylsulfone in 40 cm<3> of anhydrous tetrahydrofuran, pour under stirring and under argon during 20 minutes 13 cm<3 >1.6M n-butyllithium solution in hexane. After stirring for 30 minutes at -70°C, 2.66 cm<3> of trimethylchlorosilane is added and the heating is stopped. After stirring for 4 hours at normal temperature, 30 cm3 of water is added to the reaction mixture and extracted with 30 cm<3> of ethyl acetate. The organic phase is washed with 30 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa. 4.34 g of (phenylsulfonylmethyl)-trimethylsilane is obtained in the form of a yellow liquid.

Example 20

2-{l-|l3is-(4-ldorphenyl)methyl]-azetidin-3-ylmethylsulfonyl}pyridine can be prepared by working as follows: To a solution of 0.25 g of 2-{l-[bis-(4- chlorophenyl)methyl]-azetidin-3-ylidenemethylsulfonyl}pyridine in 20 cm<3> of dichloromethane:methanol in the ratio 50:50 is added 0.125 g of sodium borohydride. After stirring for 1 hour at 50°C, the reaction mixture is cooled to 20°C, 20 cm<3> of dichloromethane, 1 cm<3> of water and 0.1 g of magnesium sulfate are added. The mixture is filtered and the filtrate is concentrated at 50°C and 2.7 kPa. The residue is chromatographed over a silica gel column with granulometry 0.040-0.063 mm, height 15 cm and diameter 1 cm, eluting under an argon pressure of 0.5 bar with cyclohexamethyl-

acetate in the volume ratio 40:60 and fractions of 10 cm<3> are recovered. Fractions 5 to 10 are combined and concentrated to dryness at 2.7 kPa. 0.18 g of 2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-ylmethylsulfonyl}pyridine is obtained in the form of a white powder.

<!>H-NMR (300 MHz, CDCl3.8 in ppm): from 2.80 to 3.00 (mt, 3H), 3.34 (mt, 2H), 3.70 (d,

J = 7 Hz, 2H), 4.25 (s, 1H), from 7.20 to 7.40 (mt, 8H), 7.57 (ddd, J = 8.5

and 1 Hz, 1H), 7.97 (t slotted, J = 8 and 1.5 Hz, 1H), 8.07 (d large, J = 8 Hz, 1H), 8.75 (d large, J = 5 Hz, 1H).

2-{l-| )methyl]-3-(pyrid-2-yl-sulfonylmethyl)azetidin-3-ol in 50 cm<3> dichloromethane is added 0.25 cm<3> methyl-sulfonyl chloride, after which the whole is stirred for 15 minutes and then 0.9 g of 4-dimethylaminopyridine is added. After stirring for 3 hours at 20°C, 30 cm3 of water and 30 cm3 of dichloromethane are added, after which the organic phase is decanted, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue is chromatographed over a silica gel column with granulometry 0.04-0.063 mm, height 25 cm and diameter 2 cm, and

it is eluted under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in the volume ratio 40:60 and fractions of 20 cm<3> are recovered. Fractions 4 to 8 are combined and concentrated to dryness at 2.7 kPa. 0.50 g of 2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-ylidenemethylsulfonyl}pyridine is obtained in the form of a yellow powder. l-[bis-(4-chlorophenyl)methyl]-3-(pyrid-2-yl-sulfonylmethyl)azetidin-3-ol can be prepared by working as follows: To a solution, cooled to -78°C and under argon , of 2.92 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-one in 50 cm<3> tetrahydrofuran, 2.13 g of potassium tert-butylate are added. After stirring for 3 hours at -78°C, the reaction mixture is allowed to return to 0°C and then 50 cm<3> of diethyl oxide, 10 cm<3> of water and 10 cm<3> of saturated, aqueous ammonium chloride solution are added. The organic phase is decanted, dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa. The residue is chromatographed over a silica gel column with granulometry 0.063-0.200 mm, height 30 cm and diameter 3 cm, and it is eluted under an argon pressure of 0.5 bar first with dichloromethane and then with dichloromethane:methanol in the volume ratio 97:3 and fractions of 20 cm<3>. Fractions 8 to 15 are combined and concentrated to dryness at 2.7 kPa. A brown oil is obtained which is still impure and which is chromatographed on a silica gel column with granulometry 0.04-0.063 mm, height 20 cm and diameter 2 cm, and which is eluted under an argon pressure of 0.5 bar first with dichloromethane, then with dichloromethane :methanol in the volume ratio 97:3 and fractions of 20 cm<3> are recovered. Fractions 5 to 25 are combined and concentrated to dryness and the residue obtained is chromatographed again on the same column and under the same conditions, but with elution with dichloromethane. Fractions 12 to 20 are combined and concentrated to dryness at 2.7 kPa. 0.3 g of 1-[bis-(4-chlorophenyl)methyl]-3-(pyrid-2-yl-sulfonylmethyl)azetidin-3-ol is obtained in the form of a white meringue mass.

2-methylsulfonylpyridine can be prepared by working in the following way: To a solution of 20 g of sodium tungstate dihydrate in 10 cm<3> of water, while stirring under argon, add 0.25 cm<3> of 100% acetic acid and then 7.0 g of 2-methylsulfanylpyridine. The mixture is heated to 65°C and poured slowly over 15 minutes into 10 cm<3> of 30% oxygenated water, after which it is stirred once more at 85°C for 30 minutes, after which the mixture is cooled to +10°C . To the medium is added 1.0 cm<3> of 32% ammonia, 5.0 cm<3> of a 37.5% aqueous sodium hydrogen sulphite solution and then 10 cm<3> of water and 50 cm<3> of dichloromethane. The mixture is decanted and the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa. The f heirless oil is treated with 50 cm<3> of petroleum ether and the insoluble gum is filtered and taken up in 30 cm<3> of dichloro-

methane. The obtained solution is concentrated to dryness at 50°C and 2.7 kPa.

3.5 g of 2-methylsulfonylpyridine is obtained in the form of a colorless oil.

2- methylsulfanyl-pyridine can be prepared by working in the following way: To a solvent

of 11.0 g of 2-mercaptopyridine in 105 cm<3> IN sodium hydroxide is slowly added 6.2

cm<3> methyl iodide. The reaction mixture whose temperature rises to 30°C is cooled to room temperature. After stirring for 2 hours, the mixture is extracted with 100 cm<3> of dichloromethane and the organic phase is dried over magnesium sulfate and concentrated to a dry state at 50°C and 2.7 kPa. The obtained oil is purified by distillation under reduced pressure. 9.0 g of 2-methylsulfanylpyridine is obtained in the form of a colorless liquid with pE = 84°C/45

mm Hg.

Example 21

3-{l-[bis-(4-ldorphenyl)methyl]-a2ethidin-3-ylmethylsulfonyl}pyridine can be prepared by

work as described in example 20 from 0.15 g of 3-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-ylidenemethylsulfonyl}pyridine, 20 cm3 of dichloromethane:ethanol 50:50 and 80 mg of sodium boron-

hydride. 0.11 g of 3-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-ylmethylsulfonyl}pyridine is obtained in the form of a white powder.

1 H-NMR (300 MHz, CDCl3.8 in ppm): from 2.75 to 2.95 (mt, 3H), 3.35 (mt, 2H), 3.43 (d,

J = 6.5 Hz, 2H), 4.25 (s, 1H), from 7.20 to 7.40 (mt, 8H), 7.54 (ddd, J = 8-5

and 1 Hz, 1H), 8.18 (ddd, J =8-2.5 and 1.5 Hz, 1H), 8.90 (dd, J = 5 and 1.5

Hz, 1H), 9.11 (dd, J = 2.5 and 1 Hz, 1H).

3-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-ylidenemethylsulfonyl}pyridine can be prepared by working as described in Example 20 from 0.8 g of l-[bis-(4-chlorophenyl)methyl] -3-(pyrid-3-ylsulfonylmethyl)azetidin-3-ol, 50 cc of dichloromethane, 0.22 cc of methylsulfonyl chloride and 0.8 g of 4-dimethylaminopyridine. 0.50 g of 3-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-ylidenemethylsulfonyl}pyridine is obtained in the form of a cream-coloured powder.

1-[bis-(4-chlorophenyl)methyl]-3-(pyrid-3-ylsulfonylmethyl)azetidin-3-ol can be prepared by

to work as described in Example 20 from 3.3 g of 1-[bis-(4-chlorophenyl)methyl]-

azetidin-3-one, 50 cm 3 of tetrahydrofuran, 3.5 g of 3-methylsulfonyl-pyridine and 2.4 g of potassium tert-butylate. 1.4 g of 1-[bis-(4-chlorophenyl)methyl]-3-(pyrid-3-ylsulfonylmethyl)-azetidin-3-ol is obtained in the form of a white powder.

3-methylsulfonyl-pyridine can be prepared by working as described in example 20 from 33 g sodium tungstate, 10 cm3 water, 0.25 cm<3>100% acetic acid and 9.5 cm<3>3-methylsulfanylpyridine, 15 cm<3> of 30% H2O2 and then 2 cm3 of 32% ammonia and 2 cm<3> of aqueous sodium hydrogen sulphite solution. The crude oil obtained is crystallized from 20 cm<3 >diisopropyl oxide and the crystals are filtered, poured off and dried at 2.7 kPa. 4.5 g of 3-methylsulfonylpyridine is obtained in the form of white crystals with a melting point of 58°C.

3-Methylsulfanyl-pyridine can be prepared by working as follows: To a mixture, heated to 80°C and under argon, of 9.4 g of 3-aminopyridine and 100 cm<3> of dimethyl sulphide, 20 cm3 of isoamyl nitrite is added. After stirring for 2 hours at 90°C, the reaction mixture is cooled to 20°C and then purified by fractional distillation under reduced pressure. 8.4 g of 3-methylsulfanylpyridine is obtained in the form of a yellow, pale liquid with an evaporation expression PE = 90°C/30 mm Hg.

Example 22

4-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-ylmethylsulfonyl}pyridine can be prepared by working as described in Example 20 from 0.15 g of 4-{l-[bis-(4-chlorophenyl) )methyl]-azetidin-3-ylidenemethylsulfonyl}pyridine, 20 cm3 of dichloromethane:ethanol in the ratio 50:50 and 80 mg of sodium borohydride. 0.13 g of 4-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl-methylsulfonylpyridine is obtained in the form of a white powder.

1H-NMR (300 MHz, CDCl 3 , 5 in ppm): from 2.75 to 2.90 (mt, 1H), 2.88 (t, J = 7 Hz, 2H),

3.36 (t, J = 7 Hz, 2H), 3.42 (d, J = 7 Hz, 2H), 4.25 (s, 1H), from 7.20 to 7.35 (mt, 8H) , 7.75 (d large, J = 6 Hz, 2H), 8.93 (d large, J = 6 Hz, 2H).

4-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-ylidenemethylsulfonyl}pyridine can be prepared by working as described in Example 20 from 0.8 g of l-[bis-(4-chlorophenyl)methyl) ]-3-(pyrid-4-yl-sulfonylmethyl)azetidin-3-ol, 50 cm<3> dichloromethane, 0.22 cm<3> methylsulfonyl chloride and 0.8 g of 4-dimethylaminopyridine. The crude product is purified by chromatography over a silica gel column with granulometry 0.04-0.063 mm, height 20 cm and diameter 2 cm, being eluted under a pressure of 0.5 bar argon with cyclohexane:ethyl acetate in the volume ratio 40:60 and recovery of fractions of 20 cm<3>. Fractions 5 to 10 are combined and concentrated to dryness at 2.7 kPa. 0.42 g of 4-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-ylidenemethylsulfonyl}pyridine is obtained in the form of a white, crystalline powder.

l-|>is-(4-]dorphenyl)methyl)]-3-(-pyrid-4-yl-sulfonylmethyl)azetidin-3-olcane is prepared by working as described in Example 20 from 2.5 g of l-[ bis-(4-chlorophenyl)methyl)]azetidin-3-one, 50 cm<3> tetrahydrofuran, 2.6 g of 4-methylsulfonyl-pyridine and 1.8 g of potassium tert-butylate. The crude product obtained is purified by chromatography over a silica gel column with granulometry 0.04-0.063 mm, height 30 cm and diameter 3 cm, eluting under an argon pressure of 0.5 bar with dichloromethane and then dichloromethane:methanol in the volume ratio 98:2, whereby fractions of 20 cm<3> are recovered. Fractions 8 to 27 are combined and concentrated to dryness at 2.7 kPa. A cream-colored powder is obtained which is recrystallized from 5 cm<3> of acetonitrile. The crystals are filtered, poured off and dried at 2.7 kPa. 1.4 g of 1-[bis-(4-chlorophenyl)methyl)]-3-(-pyrid-4-yl-sulfonylmethyl)azetidin-3-ol is obtained in the form of white crystals with a melting point of 130°C.

4-methylsulfonyl-pyridine can be prepared by working as described in example 20 from 14 g of sodium tungstate, 4 cm<3> of water, 0.05 cm<3> of 100% acetic acid, 3.3 g of 4-methylsulfanyl-pyridine, 6.5 cm<3> 30% hydrogen peroxide and then 0.25 cm<3> 32% ammonia and 1 cm<3> aqueous 37.5% sodium hydrogen sulphite solution. The crude oil obtained is crystallized from 10 cm<3> diisopropyl oxide, the crystals are filtered, poured off and dried at 2.7 kPa. 2.6 g of 4-methylsulfonylpyridine is obtained in the form of white crystals.

4-Methylsulfanylpyridine can be prepared by working as described in Example 20 from 11.0 4-mercaptopyridine, 105 cm<3> IN sodium hydroxide and 6.2 cm<3> methyl iodide. The impure oil obtained is purified by distillation under reduced pressure. 4.0 g of 4-methylsulfanylpyridine is obtained in the form of a white paste with an evaporation pressure of pEb = 120°C/45 mm Hg.

Example 23

1-[bis-(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)sulfonylmethyl]azetidine can be prepared by working as follows: To a solution of 0.50 g of l-[bis-( 4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)sulfonylmethylene]azetidine dissolved in 25 cm<3> of anhydrous methanol and 25 cm<3> of anhydrous dichloromethane is placed under argon with 78 mg of sodium borohydride. After stirring for 24 hours, 80 cm<3> of water and 50 cm<3> of dichloromethane are added, the whole is decanted, washed with 80 cm<3> of water and then 80 cm<3> of a saturated, aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness at 2.7 kPa. The residue is chromatographed over a silica gel column with granulometry 0.02-0.04 mm, height 20 cm and diameter 14 cm, eluting under a pressure of 0.5 bar argon with cyclohexane:ethyl acetate in the volume ratio 90:10 and fractions of 5 cm<3. >Fractions 60 to 82 are combined and concentrated to dryness at 2.7 kPa. 0.29 g of 1-[bis-(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)su^ is obtained in the form of a white solid.

1H-NMR (300 MHz, CDCl3.8 in ppm): from 2.75 to 2.95 (mt, 1H), 2.88 (t, J = 7 Hz, 2H),

3.36 (t, J = 7 Hz, 2H), 3.41 (d, J = 7 Hz, 2H), 4.26 (s, 1H), 7.13 (tt, J = 9 and 2.5 Hz, 1H), from 7.20 to 7.35 (mt, 8H), 7.44 (mt, 2H).

Example 24

l-[bis-(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)sulfonylmethylene]azetidine can be prepared by working as follows: To 18.8 g of l-[bis-(4-chlorophenyl )methyl)]-3-[(3,5-difluorophenyl)sulfonylmethyl]azetidin-3-ol dissolved in 800 cm<3> of dichloromethane at ambient temperature, 4.3 cm3 of methylsulfonyl chloride are added and then, in small portions, 16 g of 4-dimethylaminopyridine . After 22 hours, the reaction mixture is washed with 3 x 700 cm 3 of water and then 700 cm 3 of a saturated, aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness at 2.7 kPa. The residue (25 g) is chromatographed over a silica gel column with granulometry 0.02-0.04 mm, height 36 cm and diameter 8.5 cm, eluting under an argon pressure of 0.7 bar with cyclohexane:ethyl acetate in a volume ratio of 90 :10 and fractions of 250 cm<3> are recovered. Fractions 2 to 148 are combined and concentrated to dryness at 2.7 kPa. 2.79 g of 1-[bis-(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)sulfonylmethylene]azetidine is obtained in the form of a white solid.

<!>H-NMR (300 MHz, CDCl3.8 in ppm): 3.91 (mt, 2H), 4.28 (mt, 2H), 4.51 (s, 1H), 6.15

(mt, 1H), 7.08 (tt, J = 9 and 2.5 Hz, 1H), from 7.25 to 7.40 (mt, 8H), 7.40 (mt, 2H).

1-[bis-(4-ldorphenyl)methyl)]-3-[(3,5-dlfluorophenyl)sulfonylmethyl]azetidin-3-ol can be prepared by working as follows: To a solution of 13.2 g (3 ,5-difluorophenyl)-methylsulfone in 800 cm<3> of tetrahydrofuran is added dropwise 42.9 cm<3> of 1.6 M butyllithium in hexane. After 0.5 hours at -70°C and one hour at -30°C, add dropwise and at

-70°C 14 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-one, dissolved in 150 cm<3> tetrahydrofuran. After 3 hours at -70°C, the reaction mixture is poured into a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed twice with 400 cm<3>

water and 400 cm<3> of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness at 2.7 kPa. The residues (25.14 g) are chromatographed on a silica gel column with granulometry 0.06-0.04 mm, height 31 cm and diameter 7.5 cm, eluting under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in

the volume ratio 85:15 and fractions of 200 cm<3> are recovered. Fractions 13 to 16 are combined and concentrated to dryness at 2.7 kPa. After crystallization from ethyl ether, filtration and drying, 4.5 g of 1-[bis-(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)-sulfonylmethyl]azetidin-3-ol are obtained in the form of a white solid.

(3,5-difluorophenyl)methylsulfone can be prepared by working as follows: To a solution of 13.3 g of (3,5-difluorophenyl)methylsulfide dissolved in 450 cm3 of methanol, add 225 cm<3> of water and, in small portions at 5°C, 56.3 g Oxone®. After 20 hours at ambient temperature, the reaction mixture is diluted with dichloromethane and water and decanted. The organic phase is washed twice with 700 cm 3 of water and 700 cm 3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated to dryness at 2.7 kPa. 13.2 g of (3,5-difluorophenyl)methylsulfone is obtained in the form of a white solid.

(3,5-difluorophenyl)methyl sulphide can be prepared by working as follows: To 11.8 cm<3> of l-bromo-3,5-difluorobenzene, diluted in 200 cm<3> of ethyl ether, is added dropwise at -70° C 64 cm<3> 1.6M n-butyllithium in hexane. After 52 hours at -?0°C, 14.2 g of S-methyl-methylthiosulfonate, dissolved in 60 cm3 of tetrahydrofuran, are added dropwise and at -70°C. After 3 hours at -70°C and then 18 hours at ambient temperature, the reaction mixture is poured into a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed twice with 300 cm 3 of water and then 300 cm 3 of a saturated, aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated to dryness at 2.7 kPa. 13.3 g of (3,5-difluorophenyl)methyl sulphide is obtained in the form of a yellow oil.

Example 25

To a solution of 0.40 g of 1-[bis-(4-chlorophenyl)-methyl]-3-(phenylsulfanyl)-azetidine in 20 cm 3 of dichloromethane, 0.25 g of metachloroperbenzoic acid is added at ambient temperature. After stirring for 3 hours at ambient temperature, the reaction mixture is washed with 30 cm3 of saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. After chromatography over a silica gel column with granulometry 0.06-0.200 mm, height 25 cm and diameter 2 cm, and elution under an argon pressure of 0.8 bar with ethyl acetate cyclohexane in the volume ratio 20:80 and recovery of fractions of 60 cm<3>, fractions 9 to 16 are recovered and concentrated to dryness at 2.7 kPa, taken up in heptane to isolate 100 mg of 1-[bis-(4-chlorophenyl)methyl]-3-[(RS)-phenylsulfinyl]-azetidine in the form of a white solid.

<*>H-NMR (300 MHz, CDC13, 8 in ppm): 3.01 (t large, J = 7.5 Hz, 1H), 3.32 (t large, J = 7.5 Hz, 1H) , 3.45 (t large, J = 7.5 Hz, 2H), 3.59 (mt, 1H), 4.45 (s large, 1H), from 7.15 to 7.65 (mts, 13H) .

Example 26

To a solution of 0.80 g of 1-[bis-(4-chlorophenyl)-methyl]-3-(phenylsulfanyl)-azetidine in 3.4 cm<3> of water, 3.4 cm<3> of acetic acid, 3, 4 cm<3> of ethanol and 1.7 cm<3> of sulfuric acid are added in several portions to 1.2 g of Oxone®. After stirring for 20 hours at ambient temperature, the reaction mixture is diluted with 100 cm<3> of dichloromethane, washed with 3 x 100 cm<3> of water, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. After chromatography over a silica gel column with granulometry 0.06-0.200 mm, height 40 cm and diameter 2 cm, and elution under an argon pressure of 0.8 bar with ethyl acetate:cyclohexane in the volume ratio 20:80 and with recovery of fractions of 60 cm<3>, fractions 9 to 15 are combined and concentrated to dryness at 2.7 kPa and taken up in heptane, the solid is filtered and dried to isolate 0.23 g of 1-[bis-(4-chlorophenyl)methyl]- 3-(phenyl-sulfonyl)-azetidine as a white solid.

'H-NMR (300 MHz, CDcf3, 8 in ppm): from 3.35 to 3.50 (mt, 4H), 3.96 (mt, 1H), 4.44 (s,

1H), from 7.20 to 7.35 (mt, 8H), 7.57 (t large, J = 7.5 Hz, 2H), 7.68 (tt, J = 7.5 and 1.5 Hz , 1H), 7.88 (d large, J = 7.5 Hz, 2H).

Example 27

To a solution of 0.6 g of methyl 5-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methylsulfonyl-methyl)-thien-2-ylcarboxylate in 70 cm<3 > methanol cooled to close to 0°C, 43.5 mg of sodium borohydride are added. The reaction medium is stirred for 15 minutes at this temperature and then for 5 hours at 20°C before cooling again to close to 0°C and adding 8.7 mg of sodium borohydride. After 18 hours at ambient temperature, the reaction mixture is concentrated to a dry state at 2.7 kPa. The obtained residue is added to 100 cm<3> of dichloromethane and 20 cm<3> of distilled water. The mixture is decanted, the organic phase is washed with 2 x 20 cm<3> of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The obtained residue is purified by flash chromatography over silica gel and eluted with cyclohexane:ethyl acetate in the volume ratio 70:30. 0.18 g of methyl-(RS)-5-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonyl-methyl)-thien-2-ylcarboxylate is obtained in the form of a white powder.

1H-NMR (400 MHz, (CD3)2SO d6.8 in ppm): 2.60 (t, J = 7.5 Hz, 1H), 2.86 (s, 3H), 3.14

(mt, 2H), from 3.20 to 3.35 (mt, 1H), 3.45 (t large, J = 7.5 Hz, 1H), 3.82 (s, 3H), 4.47 ( s, 1H), 5.27 (d, J = 11 Hz, 1H), 7.28 (d, J = 4 Hz, 1H), from 7.30 to 7.50 (mt, 8 H), 7, 72 (d, J = 4 Hz, 1H).

Methyl 5-.({l.-[>is-(4-Morphenyl)methyl]azeu^in-3-ylidene}-methylsulfonyl-methylcarboxylate can be obtained in the following way: To a solution of 6.12 g l- [bis-(4-chloro-phenyl)methyl]azetidin-3-one in 200 cm<3> tetrahydrofuran is placed, under argon and at ambient temperature, 5.15 g of methyl 5-(methylsulfonylmethyl)thien-2-yl carboxylate , after which the resulting suspension is cooled to -70° C. 2.47 g of potassium tert-butylate is successively added and then, after lYz hour at this temperature, a solution of 1.7 cm<3 >methylsulfonyl chloride in 8 cm<3> ethyl ether over 2 minutes. The reaction mixture is kept for 1 hour at -70°C and then allowed to return to 20°C before pouring in 80 cm<3> of distilled water. The tetrahydrofuran is driven off under reduced pressure and the aqueous residue obtained extracted with 500 cm<3> of dichloromethane. The mixture is decanted and the organic phase is washed with 3 x 80 cm<3> of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue obtained r determined by flash chromatography over silica gel and elution with cyclohexane:ethyl acetate in the volume ratio 70:30. 1.6 g of methyl-5-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methylsulfonyl-methyl)-thien-2-ylcarboxylate is obtained in the form of a cream-colored meringue mass.

Methyl 5-(methylsulfonylmethyl)thien-2-yl carboxylate in the following way: To a solution of 73 g of methyl 5-(bromomethyl)thien-2-yl carboxylate in 150 cm<3> of ethanol, add 31.7 g sodium methylsulfinate and the resulting suspension is heated to reflux for 7 hours. The reaction medium is then concentrated to dryness at 2.7 kPa. The residue is extracted with 4 x 500 cm<3> of ethyl acetate and the combined organic phases are washed successively with 250 cm<3> of distilled water and 250 cm<3> of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated incompletely under reduced pressure. The solid obtained is isolated by filtration, rinsed with 3 x 25 cm<3> of ice-cold ethyl acetate and gives

21.4 g of methyl 5-(methylsulfonylmethyl)thien-2-yl carboxylate in the form of a cream-coloured powder.

Methyl 5-(bromomethyl)thien-2-yl carboxylate can be prepared according to the method described by J. Wityak et al. in "Bioorg. Med. Chem. Lett.", (1995), 5(18), 2097-100.

Example 28

(RS)-1-[bis-(4-Morphenyl)methyl]-3-[(3,5-difluorophenyl-cyclopropyl-amine) can be prepared in the following way: To a solution of 3 g of 1-[bis-( 4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)-methylene]-azetidine in 30 cm<3 >dichloromethane is placed, at a temperature close to 24°C and under an inert argon atmosphere, 2 .52 cm3 of cyclopropylamine. After 39 hours at a temperature close to 24° C., the reaction medium is concentrated at 3 mbar and a temperature close to 40° C. In this way, 3.26 g of a pale yellow meringue mass is obtained, which is taken up in 30 cm3 of dichloromethane and 2.52 cm<3> cyclopropylamine. The resulting solution is stirred at a temperature close to 21°C under an inert argon atmosphere for 87 hours and then concentrated under 3 mbar and a temperature close to 40°C. In this way 3.64 g is obtained (RS)-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl-cyclopropyl-amine in the form of a pale yellow meringue mass.

1H NMR (300 MHz, CDCl 3 , 5 in ppm): 0.29 (mt, 1H), from 0.40 to 0.75 (mt, 3H), 2.50

(mt, 1H), 2.73 (s, 3H), 2.90 (mf, 1H), from 3.45 to 3.70 (mt, 3H), 4.36 (s large, 1H), from 4 .60 to 4.80 (mf split, 1H), 6.87 (tt, J = 9 and 2.5 Hz, 1H), from 7.20 to 7.40 (mt, 10H).

Example 29

(RS)-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}(2-pyrrolidin-1-yl-ethyl )-amine can be prepared as follows: To a solution of 50 mg of 1-[bis-(4-ldorphenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methylene]-azetidine in 0.5 cm3 of dichloromethane is placed at a temperature near 21°C and an inert argon atmosphere, 0.076 cm<3> l-(2-aminoethyl)pyrrolidine. The obtained solution is stirred at a temperature close to 21°C under argon for 22 hours, concentrated under an air stream at a temperature close to 42°C, after which the obtained impure residue is dried at around 3 mbar and a temperature close to 40°C. (RS)-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-3-yl}(2-pyrrolidin-1- yl-ethyl)-amine in the form of an ochre-coloured meringue mass.

<*>H-NMR (300 MHz, CDCl 3 , 8 in ppm): from 1.75 to 1.95 (mt, 4H), from 2.55 to 2.85 (mt, 6H), 2.79 (s , 3H), 2.91 (t, J = 6.5 Hz, 2H), 3.06 (d, J = 8.5 Hz, 1H), 3.17 (d, J = 8.5 Hz, 1H ), 3.32 (d, J = 8.5 Hz, 1H), 3.41 (d, J = 8.5 Hz, 1H), 4.31 (s, 1H), 4.56 (s, 1H ), 6.88 (tt, J = 8.5 and 2.5 Hz, 1H), 7.22 (s, 4H), 7.25 (s, 4H), 7.34 (mt, 2H).

Example 30

(RS)-{l-[bis-(4-ildorphenyl)methyl]-3-[(3,5-difluorophenyl)methyl}-methyl-amine can be prepared according to Example 29 from 50 mg of l-[bis -(4-Chlorophenyl)-methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methylene]-azetidine, 0.5 cm3 of dichloromethane and 0.3 cm<3> of a 2M methylamine solution in tetrahydrofuran. (RS)-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}-methyl-amine is obtained in the form of a yellow rubber.

1H NMR (400 MHz, CDCl 3 , 8 in ppm): from 2.00 to 2.20 (mf split, 1H), 2.62 (s, 3H),

2.76 (s, 3H), 3.04 (d, J= 9 Hz, 1H), 3.18 (d, J = 9 Hz, 1H), 3.37 (AB, J = 9 Hz, 2H) , 4.31 (s, 1H), 4.55 (s, 1H), 6.89 (tt, J = 9 and 2.5 Hz, 1H), 7.22 (s, 4H), 7.24 ( s, 4H), 7.32 (mt, 2H).

Example 31

(RS)-{l-[bis-(4-Morphenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}isobutylamine can be prepared according to Example 29 from 50 mg of 1-[bis-(4-chloro-phenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)-methylene]-azetidine, 0.5 cm3 of dichloromethane and 0.0596 cm3 of isobutylamine. (RS)-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}-isobutylamine is obtained in the form of a white meringue mass.

1H NMR (300 MHz, CDCl 3 , 8 in ppm): 1.01 (2d, J = 7 Hz, 6H), from 1.70 to 2.15 (mt cleaved, 1H), 1.76 (mt, 1H), 2.51 (dd, J = 10.5 and 7 Hz, 1H), 2.76 (s, 3H), 2.80 (dd, J = 10.5 and 6 Hz, 1H), 3, 01 (d, J = 8.5 Hz, 1H), 3.14 (d, J = 8.5 Hz, 1H), 3.32 (d, J = 8.5 Hz, 1H), 3.44 ( d, J = 8.5 Hz, 1H), 4.31 (s, 1H), 4.58 (s, 1H), 6.88 (tt, J = 8.5 and 2.5 Hz, 1H), from 7.15 to 7.30 (mt, 8H), 7.35 (mt, 2H).

Example 32

(RS)-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}-ethylamine can be prepared according to Example 29 from 50 mg of 1-[bis-(4-chlorophenyl)-methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methylene]-azetidine, 0.5 cm3 of dichloromethane and 0.30 cm3 of a 2M ethylamine solution in tetrahydrofuran . One obtains (RS)-{1-[bis-(4-fluorophenyl)methyl]-3-[(3,5-(fluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}-ethylamine form of a yellow rubber.

<!>H-NMR (300 MHz, CDCl3, 8 in ppm): 1.22 (t, J = 7 Hz, 3H), from 2.70 to 2.85 (mt, 2H),

2.77 (s, 3H), from 2.95 to 3.10 (mf, 1H), 3.05 (d, J = 8.5 Hz, 1H), 3.17 (d, J = 8.5 Hz, 1H), 3.33 (d, J = 8.5 Hz, 1H), 3.40 (d, J = 8.5 Hz, 1H), 4.30 (s, 1H), 4.54 ( s, 1H), 6.89 (tt, J = 9 and 2.5 Hz, 1H), from 7.15 to 7.30 (mt, 8H), 7.34 (mt, 2H).

Example 33

(RS)-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}-N',N-dimethyl-ethan-1 ,2-diamine can be prepared according to Example 29 from 50 mg of 1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)-methylene]-azetidine, 0.5 cm3 of dichloromethane and 0.0659 cm3 of N,N-dimethylethylenediamine. (RS)-{1-[bis-(4-ldorphenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}-N',N-dimethylethane is obtained -1,2-diamine in the form of a white meringue mass.

^-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.32 (s, 6H), 2.53 (t, J = 6 Hz, 2H), 2.79 (s, 3H),

2.94 (t, J = 6 Hz, 2H), 3.06 (d, J = 8.5 Hz, 1H), 3.16 (d, J = 8.5 Hz, 1H), 3.30 ( d, J = 8.5 Hz, 1H), 3.41 (d, J = 8.5 Hz, 1H), 4.30 (s, 1H), 4.55 (s, 1H), 6.88 ( tt, J = 9 and 2.5 Hz, 1H), 7.21 (s, 4H), 7.24 (s, 4H), 7.34 (mt, 2H).

Example 34

(RS)-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methane-sulfonyl-methyl]-3-methyl-azetidine can be prepared as follows: For a suspension of 400 mg of magnesium shavings in 2.5 cm3 of anhydrous diethyl ether, put under argon and at a temperature close to 24°C a few drops of methyl iodide and then 1 cm3 of methyl iodide in solution in 22.5 cm<3> of diethyl ether. The resulting suspension is stirred for 30 minutes at a temperature close to 24°C and then cooled to a temperature close to 0°C with an ice/water mixture. 1.65 g of complex CuBr.Me2S are then added at a temperature close to 0°C, after which the reaction mixture is stirred for 15 minutes at a temperature close to 0°C. At a temperature close to 0°C, a solution of 0.5 g of 1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)-methylene is added to the obtained yellow suspension ]-azetidine in a mixture of 1 cm3 of tetrahydrofuran and 1 cm3 of diethyl ether. The obtained suspension is stirred for 4 hours at a temperature close to 0°C, and then at a temperature close to 25°C for 16 hours. The black suspension obtained is diluted with 100 cm3 of ethyl acetate and 15 cm3 of a saturated aqueous ammonium chloride solution. The reaction mixture is filtered over a glass frit with Celite and the solid residue is rinsed with ethyl acetate and then with water. After decanting the filtrate, the organic phase is separated, washed with 10 cm3 of water, 10 cm3 of saturated sodium chloride solution, dried

over magnesium sulfate and filtered over a glass frit and concentrated at 20 mbar and a temperature close to 43°C. In this way, 550 mg of an orange-coloured meringue mass is obtained which is purified by preparative thin-layer chromatography on silicon dioxide (14 preparative Merck Kieselgel 60F254 plates, 20 cm x 20 cm; thickness 0.5 mm; depot in solution in dichloromethane) while eluting with methanol:dichloromethane in the volume ratio 0.5:99.5. After elution of the zone corresponding to the desired product with methanol:dichloromethane in the volume ratio 15:85 and filtration on a glass frit with subsequent evaporation of the solvent at reduced pressure and a temperature close to 40°C, 290 mg of a white meringue mass is obtained which dissolves in 15 cm3 of anhydrous dichloromethane and reacted with 500 mg of thiophenol resin (supplier Argonaut, 1.45 mmol/g) and 1 g of ethylenediamine resin (0.8 mmol/g) for 38 hours at a temperature close to 20°C. The suspension is filtered on a glass frit and the resin is rinsed with dichloromethane, after which the filtrate is concentrated at 5 mbar and a temperature close to 43°C. 272.8 mg of a white meringue mass is obtained, which is dissolved in 2 cm3 of dichloromethane and reacted with 1 cm3 of ethylenediamine for 72 hours at a temperature close to 24°C. The impure residue obtained is taken up in 50 cm<3> of ethyl acetate and 10 cm3 of water. After decantation, the organic phase is washed with 10 cm3 of an aqueous, IN hydrochloric acid solution, 10 cm<3> of a saturated, aqueous sodium bicarbonate solution, 10 cm<3> of water, 10 cm<3> of a saturated sodium chloride solution and dried over magnesium sulfate, filtered on a glass frit and concentrated at 8 mbar and a temperature close to 42°C. 263.4 mg of a pale yellow meringue mass is obtained, which is purified by preparative thin-layer chromatography on silicon dioxide (7 preparative Merck Kieselgel 60F254 plates,

20 cm x 20 cm; thickness 0.5 mm; depot in solution in dichloromethane), as it is eluted

with methanol:dichloromethane in the volume ratio 0.5:99.5. After elution of the zone corresponding to the desired product with methane-dichloromethane in a volume ratio of 15:85, filtration over a glass frit and evaporation of the solvents under reduced pressure at a temperature close to 40°C, 191.4 mg of (RS)-{ l-[bis -(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-3-methyl-azetidine in the form of a white meringue mass.

'H-NMR (300 MHz, CDCl3, 8 in ppm): 1.75 (s, 3H), 2.67 (s, 3H), 2.74 (d large, J = 7.5

Hz, 1H), 2.93 (d, J = 7.5 Hz, 1H), 3.21 (d large, J = 7.5 Hz, 1H), 3.46 (d, J = 7.5 Hz , 1H), 4.33 (s large, 2H), 6.87 (tt, J = 9 and 2.5 Hz, 1H), 7.12 (mt, 2H), from 7.15 to 7.35 ( mt, 8H).

Example 35

(RS)-1-(2-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl-sulfanyl}-ethyl)- 4-Methyl-piperazine can be prepared in the following way: To a solution of 99 mg of 1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)-

methylene]-azetidine in 2 cm3 of dichloromethane, 128 mg of 1-(ethanethiol-2-yl)-4-methyl-piperazine are placed at a temperature close to 20°C. After overnight stirring at a temperature close to 20°C, 706 mg of Merrifield resin (1.7 mmol/g) are added. After overnight stirring at a temperature close to 20°C, the suspension is filtered and the resin is rinsed with 2x1 cm3 of dichloromethane. The filtrate is concentrated under reduced pressure. 125 mg of a white oil is obtained in this way, which is purified by chromatography on silica (13 cm 3 of silica 0.06-0.2 mm), and it is eluted with methane-dichloromethane in a volume ratio of 0:100 to 5:95. The fractions containing nothing but the desired product are combined and concentrated to a dry state at reduced pressure. 62 mg of (RS)-1-(2-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl is obtained in this way -sulfanyl}-ethyl)-4-methyl-piperazine in the form of white crystals.

'H-NMR (300 MHz, (CD3)2SO d6, 8 in ppm): 2.15 (s, 3H9, 2.30 and 2.41 (2mfs, 8H),

2.55 (mt, 2H), 2.85 (s, 3H), 3.02 (mt, 2H), 3.09 (d, J = 8.5, 1H), 3.38 (d, J = 8.5 Hz, 1H), 3.42 (d, J = 8.5 Hz, 1H), 3.79 (d, J = 8.5 Hz, 1H), 4.68 (s, 1H), 5 .37 (s, 1H), from 7.30 to 7.50 (mt, 11H).

Example 36

(RS)-(2-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-3-ylsulfanyl}-ethyl)-dimethylamine can be prepared by working as in Example 35, from 99 mg of 1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)-methylene]-azetidine, 2 cm3 of dichloromethane, 84 mg of 2-(dimethylamino)-ethanethiol and 706 mg of Merrifield resin (1.7 mmol/g). 36 mg of (RS)-(2-{l-[bis-(4-chlorophenyl)-methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-3-ylsulfanyl are obtained in this way }-ethyl)-dimethylamine in the form of a whitish powder.

Example 37

(RS)-{1-[[4-(Wormethyl)phenyl]-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-3-yl}-ethyl- amine can be prepared as follows: To a solution of 40 mg of (RS)-{1-[[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl -methylene]-azetidine in 0.1125 cm3 of ethylamine in 2M solution in tetrahydrofuran, containing a grain of sodium iodide, is stirred at a temperature near 20°C for 2 hours and then diluted with 20 cm3 of ethyl acetate and 5 cm<3> of a saturated, aqueous sodium hydrogen carbonate solution. The separated organic phase is washed with 5 cm 3 of water, 5 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered over a glass frit and concentrated at 15 mbar and a temperature close to 40°C. The yellow oil obtained is purified by preparative thin-layer chromatography on silicon dioxide (2 preparative

Merck Kieselgel 60F254 plates, 20 cm x 20 cm; thickness 0.5 mm, depot in solution in dichloromethane) and it is eluted with methanol:dichloromethane in the volume ratio 3:97. After elution of the zone corresponding to the desired product with methane-dichloromethane in a volume ratio of 15:85, filtration on a glass frit and subsequent evaporation of the solvent under reduced pressure at a temperature close to 40°C, 17 mg of (RS)-{ l-[[ 4-(Wonnetyl)phenyl]-(4-ildorphenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-3-yl}-ethylamine as a white solid.

<!>H-NMR (400 MHz, (CD3)2SO d6, 8 in ppm): 1.11 (t, J = 7 Hz, 3H), from 2.10 to 3.55 (mt,

8H), 2.95 (s, 3H), 4.44 (s, 1H), 5.09 (s, 1H), from 7.10 to 7.55 (mt, 11H).

(RS)-{1-[[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methylene]-azetidine can be prepared as follows: To a solution of 590 mg of (RS)-[4-((4-chlorophenyl]-{3-[(3,5-difluorophenyl)-methylsulfonyl-methylene]-azetidin-1-yl}-methyl)-phenyl]methanol in 5 cm<3> of anhydrous dichloromethane, at a temperature close to 21°C, add 0.525 cm<3> of N,N-diisopropyl-ethylamine and then 0.19 cm<3> of methanesulfonyl chloride. After 1 hour at a temperature close to 21°C , 2 cm<3> of methane and dichloromethane are added in the volume ratio of 2.5:97.5 and then from 5 minutes, the reaction mixture is concentrated at 20 mbar and a temperature close to 40° C. The yellow meringue mass obtained is purified by chromatography over silicon dioxide, (50 g silicon dioxide 0.06-0.2 mm contained in a column with a diameter of 3 cm), and the whole is eluted with methaneohdichloromethane in the volume ratio 0:100 and then 1:99 and fractions of 10 cm<3 are recovered.> The fractions which do not contains other than the desired product are united and concentrated to a dry state by reduced pressure. In this way, 421.2 mg of (RS)-{1-[[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methylene]- azetidine in the form of a yellow meringue mass.

(RS)-[4-((4-chlorophenyl]-{3-[(3,5-difluorophenyl)-methylsulfonyl-methylene]-azetidin-1-yl}-methyl)-phenyl]methanol can be prepared as follows: To a solution of 420 mg of (RS)-4-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methylene]azetidin-1-yl}-ethyl)benzaldehyde in 7 cm<3 > methanol, cooled to a temperature close to 0°C (ice + water) 49 mg of sodium tetraborohydride are added in portions. After 2 hours at a temperature close to 0°C, the reaction mixture is concentrated at 15 mbar and a temperature close to 35°C. The residue obtained is purified by chromatography over silica (40 g of silica 0.06-0.2 mm, contained in a column with a diameter of 3 cm), and it is eluted with methaneohdichloromethane in the volume ratio 1:99 and then 2.5:97.5, fractions of 10 cm are recovered<3. >The fractions that do not contain the desired product are combined and concentrated

in dry condition at reduced pressure. 418 mg of (RS)-[4-((4-

chlorophenyl]- {3-[(3,5-difluorophenyl)-methylsulfonyl-methylene]-azetidin-1-yl}-methyl)-phenyl]-methanol in the form of a white meringue mass.

Example 38

(RS)-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-bis-trifluoromethyl-phenyl)-methylsulfonyl-methyl]-azetidin-3-yl}-isobutylamine can be prepared according to Example 29 from 50 mg of 1-[bis-(4-ldorphenyl)methyl]-3-[(3,5-bis-trifluoromethyl-phenyl)-(methylsulfonyl)-methylene]-azetidine, 0.5 cm< 3> dichloromethane and 0.05 cm3 of isobutylamine. 57 mg of (RS)-{1-[bis-(4-ldorphenyl)methyl]-3-[(3,5-bis-trifluoromethyl-phenyl)-methylsulfonyl-methyl]-azetidin-3-yl}-isobutyl are obtained -amine in the form of a pale yellow meringue mass.

1H NMR (300 MHz, CDCl 3 , 8 in ppm): 1.01 (d, J = 7.5 Hz, 6H), 1.76 (mt, 1H), 2.47 (dd,

J = 10.5 and 7.5 Hz, 1H), from 2.75 to 2.85 (mt, 1H), 2.79 (s, 3H), 2.82 (dd, J = 10.5 and 5 .5 Hz, 1H), 3.00 (d, J = 9 Hz, 1H), 3.10 (d, J = 9 Hz, 1H), 3.31 (d, J = 9 Hz, 1H), 3 .40 (d, J = 9 Hz, 1H), 4.30 (s, 1H), 4.74 (s, 1H), 7.13 (d, J = 8.5 Hz, 2H), from 7, 15 to 7.25 (mt, 6H), 7.96 (s large, 1H), 8.31 (s large, 2H).

Example 39

(RS)-1-[bis-(4-chlorophenyl)methyl]-3-cyano-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine can be prepared as follows: To a solution of 9 mg l -[bis-(4-chloro-phenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)-methylene]-azetidine in 2.5 cm3 of dimethylsulfoxide, put at a temperature close to 20°C 17 mg potassium cyanide. The resulting yellow and later chestnut colored solution is heated for 15 minutes to a temperature close to 40°C and then cooled to a temperature close to 20°C. The reaction mixture is concentrated under reduced pressure and then taken up in 10 cm dichloromethane, washed with 3x5 cm 3 water. The organic phase obtained is dried over magnesium sulphate, filtered and concentrated under reduced pressure. In this way, 100 mg of a yellow paste is obtained which is purified by chromatography over silica (10 cm 3 of silica 0.06-0.2 mm, contained in a column with a diameter of 1 cm) and it is eluted with dichloromethane. Fractions that contain nothing but the desired product are combined and concentrated to a dry state at reduced pressure. In this way, 60 mg of (RS)-1-[bis-(4-chlorophenyl)methyl]-3-cyano-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine is obtained in the form of a pale yellow paste .

'H-NMR (300 MHz, (CD3)2SO d6, 8 in ppm): 2.94 (s, 3H), 3.07 (d, J = 7.5 Hz, 1H), from 3.20 to 3 .40 (mt, 1H), 3.61 (d large, J = 7.5 Hz, 1H), 3.68 (d large, J = 7.5 Hz, 1H), 4.64 (s, 1H) , 5.51 (s, 1H), from 7.25 to 7.50 (mt, 11H).

Example 40

(RS)-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenylmethyl}-1-cyclopropyl-ethyl)arnine can be prepared as follows: To a solution of 53 mg ( RS)-C-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}methylamine in 2 cm<3>1,2 -dichloroethane, 0.003 cm3 of cyclopropyl methyl ketone, 0.006 cm3 of acetic acid and then 32 mg of sodium triacetoxyborohydride are added successively at a temperature close to 20°C. The obtained solution is stirred at a temperature close to 20°C for 18 hours, after which 2 cm 3 of saturated, aqueous sodium bicarbonate solution are added. After decantation, the organic phase is concentrated under reduced pressure. In this way, 60 mg of yellow, viscous oil is obtained, which is triturated with isopropyl oxide and petroleum ether. After drying under a pressure of 0.1 mbar, 55 mg of a residue is obtained which is purified by chromatography on silica (4 cm<3> silica 0.06-0.2 mm, contained a column with a diameter of 1.2 cm), eluting with methane-dichloromethane in the volume ratio 0:100 and then 5:95. The fractions containing nothing but the desired product are concentrated to dryness under reduced pressure and purified again by chromatography on silica (4 cm3 silica 0.04-0.063 mm, contained a column of diameter 1.2 cm), and it is eluted with methane, dichloromethane in the volume ratio 0:100 and then 1:99. The fractions containing nothing but the desired product are combined and concentrated to a dry state. 20 mg of (RS)-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-ylmethyl}-1-cyclopropyl is obtained in this way -ethyl)amine.

^-NMR (300 MHz, CDCl3, 8 in ppm): A mixture of diastereoisomers is observed,

<*>from 0.00 to 0.30 and from 0.40 to 0.80 (mts, 5H), 1.09 and 1.17 (2d, J = 6.5 Hz, 3H together), 1, 87 (mt, 1H), from 2.55 to 2.75, from 2.75 to 2.95 and from 3.25 to 3.55 (mts, 4H), 2.68 (s, 3H), 3, 12 (d, J = 8.5 Hz, 1H), from 3.80 to 3.90 (mt, 1H), 4.42 and 4.43 (2s, 1H together), 4.79 and 4.84 (2s, 1H combined), 6.89 (tt, J = 9 and 2.5 Hz, 1H), 7.16 (mt, 2H), from 7.15 to 7.35 (mt, 8H).

(RS)-C- {1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}methylamine can be prepared in the following way: To a solution of 250 mg of (RS)-1-|>is-(4-chlorophenyl)methyl]-3-cyano-3-[(3,5-difl^ in 10 cm<3> anhydrous tetrahydrofuran, cooled to a temperature near 0°C, 1.27 cm3 of a 1.5M diisobutylaluminum hydride solution in tetrahydrofuran is added dropwise.After 30 minutes at a temperature close to 0°C, and then 4 hours at a temperature close to 20°C, cool

the solution again to a temperature close to 0°C. 6.35 cm<3> of water and 1.0 cm<3> of 12N aqueous hydrochloric acid are successively added. After decantation, the aqueous phase is extracted with 3 x 10 cm<3> ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. In this way, 0.42 g of a yellowish oil is obtained, which is purified by chromatography over silica (40 cm<3> silica 0.063-0.2 mm, containing a column with a diameter of 2.7), eluting with methane and dichloromethane in the volume ratio 0:100 and then 5:95. The fractions containing nothing but the desired product are combined and concentrated to dryness under reduced pressure. 110 mg of (RS)-C-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-3-yl}methylamine is obtained in this way .

Example 41

(RS)-N-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-ylmethyl}-isobutyramide can be prepared in the following way: To a solution of 53 mg of (RS)-C-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}methylamine in 2 cm <3> anhydrous dichloromethane, it is set at a temperature close to 20°C

successively 0.0187 cm<3> of isobutyric acid, 0.032 cm<3> of 1,3-diisopropylcarbodiimide and 2.5 mg of 4-dimethylaminepyridine. After stirring for 72 hours, 2 cm<3> of water is added at a temperature close to 20°C, the whole is decanted and then the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The obtained residue is purified by preparative thin-layer chromatography on silica (1 preparative Merck Kieselgel 60F254 plate; 20 cm x 20 cm; thickness 1 mm), eluting with ethyl acetate:dichloromethane in the volume ratio 5:95. After elution of the zone corresponding to the desired product, filtration on a glass frit and subsequent evaporation of the solvents under reduced pressure at a temperature close to 40°C, 16 mg of (RS)-N-{1-[bis-(4-chlorophenyl) are obtained )methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl-methyl}-isobutyramide in the form of a pale yellow powder.

<J>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 1.22 (d, J = 7 Hz, 6H), 2.46 (mt, 1H), 2.69 (s,

3H), 2.99 (d, J = 8.5 Hz, 1H), 3.23 (AB, J = 8.5 Hz, 2H), 3.40 (d, J = 8.5 Hz, 1H) , 3.57 (dd, J = 14 and 4.5 Hz, 1H), 4.09 (dd, J = 14 and 7.5 Hz, 1H), 4.34 (s, 1H), 4.35 ( s, 1H), 6.71 (dd, J = 7.5 and 4.5 Hz, 1H), 6.95 (tt, J = 9 and 2.5 Hz, 1H), from 7.10 to 7, 35 (mt, 10H).

Example 42

(RS)-N- {1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-ylmethyl}-cyclopropanecarboxamide can be prepared in a manner similar to the example 39 from 53 mg of (RS)-C-{1-[>is-(4-Worphenyl)methyl]-3-[(3,5-difluorophenyl)methanesulfonyl-methyl]-azetidin-3-yl}methylamine, 2 cm<3> of anhydrous dichloromethane, 0.0167 cm<3> of cyclopropane carboxylic acid, 0.032 cm<3> of 1,3-diisopropylcarbodiimide and 2.5 mg of 4-dimethylamino-pyridine. 28 mg of (RS)-N-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-3-ylmethyl}-cyclopropanecarboxamide is obtained in the form of a beige colored powder.

<J>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 0.81 (mt, 2H), 1.01 (mt, 2H), from 1.35 to 1.55

(mt, 1H), 2.70 (s, 3H), 3.02 (d, J = 8.5 Hz, 1H), 3.21 (AB limited, J = 8 Hz, 2H), 3.45 (d, J = 8.5 Hz, 1H), 3.62 (dd, J = 14 and 4.5 Hz, 1H), 4.10

(dd, J = 14 and 7.5 Hz, 1H), 4.31 (s, 1H), 4.36 (s, 1H), 6.75 (dd, J = 7.5 and 4.5 Hz, 1H), 6.95 (tt, J = 9 and 2 Hz, 1H), from 7.15 to 7.35 (mt, 10H).

Example 43

(RS)-N-{1-|>is-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-ylmethyl}-diethylamine can be prepared on manner corresponding to example 40 from 53 mg of (RS)-C-{1-[bis-(4-ldorphenyl)methyl]-3-[(3,5-mfluorophenyl)methylsulfonyl-methyl]-azeudin-3-yl}methylamine, 2 cm<3> 1,2-dichloroethane, 0.017 cm<3> acetaldehyde, 0.006 cm<3> acetic acid and 32 mg sodium triacetoxyborohydride. 12 mg of (RS)-N-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-ylmethyl}-diethyl are obtained in this way -amine in the form of a whitish powder.

<!>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 1.00 (t, J = 7 Hz, 6H), 2.49 (q, J = 7 Hz, 4H),

2.54 (d, J = 13.5 Hz, 1H), 2.69 (s, 3H), 2.76 (d large, J = 7.5 Hz, 1H), 3.07 (d large, J = 7.5,1H), 3.15 (d, J = 13.5 Hz, 1H), 3.24 (d large, J = 7.5 Hz, 1H), 4.06 (d large, J = 7.5 Hz, 1H), 4.35 (s, 1H), 5.02 (s, 1H), 6.91 (mt, 1H), from 7.15 to 7.40 (mt, 10H).

Example 44

(RS)-N-{l-| To a solution of 53 mg of (RS)-C-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}methylamine in 2 cm<3> ethyl acetate, it is set at a temperature close to 20°C 150

mg anhydrous IRA-68 resin and then 0.012 cm<3> methylsulfonyl chloride. After stirring overnight at a temperature close to 20°C, 0.001 cm<3> of water is added and then 150 mg of anhydrous IRA-68 resin. After stirring for 1 hour at a temperature close to 20°C, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. In this way, 81 is achieved

mg of a yellow paste which is purified by preparative thin-layer chromatography on silica (1 preparative Merck Kieselgel 60F254 plate; 20 cm x 20 cm; thickness 1 mm), eluting with ethyl acetate:dichloromethane in the volume ratio 5:95. After elution of the zone corresponding to the desired product and filtration on a glass frit with subsequent evaporation of the solvents under reduced pressure at a temperature close to 40°C, 25 mg of (RS)-N-{l-[bis-(4-chlorophenyl) are obtained methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-ylmethyl}-methanesulfonamide in the form of a pale yellow powder.

<*>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.70 (s, 3H), from 2.95 to 3.10 (mt, 2H), 3.05 (s, 3H), 3 .22 (d large, J = 8 Hz, 1H), 3.52 (d, J = 8 Hz, 1H), 3.74 (dd, J = 13.5 and 8 Hz, 1H), 3.90 ( dd, J = 13.5 and 5.5 Hz, 1H), 4.23 (s, 1H), 4.46 (s, 1H), 5.54 (mt, 1H), 7.00 (tt, J = 9 and 2 Hz, 1H), from 7.05 to 7.35 (mt, 10H).

Example 45

(RS)-1-{1-|bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-ylmethyl}-3-isopropyl-urea can be prepared on the following way: To a solution of 53 mg of (RS)-C-{1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl} methylamine in 2 cm3 of dichloromethane, 0.0197 cm3 of isopropyl isocyanate is added at a temperature close to 20°C. After stirring overnight at a temperature close to 20°C, 0.05 cm3 of water is added and after 15 minutes of stirring at a temperature close to 20°C, the reaction mixture is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue (75 mg) is purified by preparative thin-layer chromatography on silica (1 preparative Merck Kieselgel 60F254 plate; 20 cm x 20 cm, thickness 1 mm), eluting with ethyl acetate:dichloromethane in the volume ratio 5:95.

After elution of the zone corresponding to the desired product, filtration over a glass frit and subsequent evaporation of the solvent under reduced pressure at a temperature close to 40°C, 16 mg of (RS)-l-{l-[bis-(4-chlorophenyl)methyl are obtained ]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-ylmethyl}-3-isopropyl-urea in the form of a pale yellow powder.

'H-NMR (300 MHz, CDCl3.8 in ppm): 1.17 (d, J = 7 Hz, 6H), 2.68 (s, 3H), 3.00 (d large,

J = 8.5 Hz, 1H), 3.11 (d, J = 8.5 Hz, 1H), 3.17 (d, J = 8.5 Hz, 1H), 3.46 (d large, J = 8.5 Hz, 1H), 4.15 (d, J = 8 Hz, 1H), 4.29 (s, 1H), 4.43 (s, 1H), 5.11 (mt, 1H), 6.94 (tt, J = 9 and 2 Hz, 1H), from 7.10 to 7.30 (mt, 10H).

Example 46

(RS)-{1-[yts-(4-chlorophenyl)methyl]-3-[(^ylmethyl}-carbarinic acid isobutyl ester can be prepared in the following way: To a solution of 53 mg of (RS)-C-{ 1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}methylamine in 2 cm3 of pyridine is placed at a temperature close to 20°C, 0.016 cm<3> isobutylchloroformate. After stirring overnight at a temperature close to 20°C, the reaction mixture is concentrated under reduced pressure. In this way, 68 mg of a yellow paste is obtained which is purified by preparative thin-layer chromatography on silicon dioxide (1 preparative Merck Kieselgel 60F254 plate; 20 cm x 20 cm; thickness 1 mm), eluting with ethyl acetate:dichloromethane in the volume ratio 5:95. After elution of the zone

corresponding to the desired product, filtration over a glass frit and subsequent evaporation of the solvents under reduced pressure at a temperature close to 40°C, 14 mg of (RS)-{l-[bis-(4-Uorphenyl)methyl]-3-[( 3,5-(Ulfluorophenyl)methylsulfonyl-methyl]-azetidin-3-ylmethyl}-carbamic acid isobutyl ester in the form of a whitish powder.

<*>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 0.96 (d, J = 7 Hz, 6H), 1.95 (mt, 1H), 2.68 (s, 3H), 3 .04 (d, J = 8.5 Hz, 1H), 3.19 (s, 2H), 3.51 (d, J = 8 Hz, 1H), 3.75 (dd, J = 14 and 5 Hz , 1H), from 3.80 to 4.00 (mt, 3H), 4.30 (s, 1H), 4.34 (s, 1H), 5.63 (mf, 1H), 6.95 (tt , J = 9 and 2 Hz, 1H), from 7.10 to 7.30 (mt, 10H).

Example 47

(RS)-{l-[bis-(4-ldorphenyl)methyl]-3-[(3,5-mfluorophenyl)methylsulfonyl-methyl]-azetidin-3-ylmethyl}-dimethyl-amine can be prepared in the following way: To a solution of 52 mg of (RS)-C-{1-|>is-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-yl}methylamine in 2 cm3 of acetonitrile is placed at a temperature close to 20°C, 138 mg of potassium carbonate and then 0.0075 cm3 of methyl iodide. After stirring overnight at a temperature close to 20°C, the reaction medium is filtered on a glass frit, after which the solid is rinsed with dichloromethane and the filtrate is concentrated under reduced pressure. The impure residue obtained (90 mg) is purified by preparative thin-layer chromatography on silica (1 preparative Merck Kieselgel 60F254 plate, 20 cm x 20 cm; thickness 1 mm), and it is eluted with ethyl acetate:dichloromethane in the volume ratio 5:95. After elution of the zone corresponding to the desired product, filtration on a glass frit and evaporation of the solvents under reduced pressure, at a temperature close to 40°c, 11 mg of (RS)-{l-[bis-(4-chloro-phenyl) are obtained methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-3-ylmethyl}-dimethylamine.

1H-NMR (300 MHz, CDCl3.8 in ppm): 2.18 (s, 6H), 2.30 (d, J = 13 Hz, 1H), from 4.65 to 4.78 (mt, 1H ), 2.70 (s, 3H), 2.98 (d, J = 13 Hz, 1H), 3.09 (d, J = 8 Hz, 1H), 3.32 (d, J = 7.5 Hz, 1H), 4.11 (d, J = 8 Hz, 1H), 4.35 (s, 1H), 4.94 (s, 1H), 6.92 (mt, 1H), from 7.10 to 7.40 (mt, 10H).

Example 48

(RS)-1-[bis-(4-chlorophenyl)methyl]-3-[(4-methoxyphenyl)methylsulfonyl-methyl]-azetidine can be prepared as follows: To a solution of 400 mg of l-[bis-(4- chlorophenyl)methyl]-3-[(4-methoxyphenyl)methylsulfonyl-methylene]-azetidine in 4.5 cm<3> ethanol is placed under a

argon atmosphere and at a temperature close to 20°C, 25.5 mg of sodium tetrahydroboride. After stirring for 16 hours at a temperature close to 20°C, 26 mg of sodium tetrahydroboride are added. The reaction medium is stirred at a temperature close to 20°C for 1 hour and then at a temperature close to 50°C for 3 hours. After cooling to a temperature close to 20°C, the reaction medium is concentrated under reduced pressure. The white deposit obtained is taken up in 2 cm<3> of water and 2 cm<3> of dichloromethane. After decantation, the organic phase is concentrated under reduced pressure and the resulting yellow meringue mass is purified by preparative thin-layer chromatography (2 preparative Merck Kieselgel 60F254 plates, 20 cm x 20 cm; thickness 0.5 mm), eluting with methane-dichloromethane in a volume ratio of 1:99 . After elution of the zone corresponding to the desired product with methane-dichloromethane in a volume ratio of 10:90, filtration on a glass frit and then evaporation of the solvents under reduced pressure at a temperature close to 40°C, 14 mg of (RS)-l-[bis-( 4-chloro-phenyl)methyl]-3-[(4-methoxyphenyl)methylsulfonyl-methyl]-azetidine in the form of a white meringue mass.

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.56 (mt, 1H), 2.58 (s, 3H), 3.20 (mt, 2H), from 3.35 to 3.55 (mt, 1H), 3.66 (t large, J = 7.5 Hz, 1H), 3.81 (s, 3H), 4.21 (d, J = 4.5 Hz, 1H), 4, 26 (s large, 1H), 6.90 (d, J = 8.5 Hz, 2H), from 7.15 to 7.40 (mt, 10H).

l-[bis-(4-chlorophenyl)methyl]-3-[(4-methoxyphenyl)methylsulfonyl-methylene]-azetidine can be prepared by working as described in Example 1 from 1 g of (RS)-l-[bis-(4 -chlorophenyl)-methyl]-3-[methylsulfonyl-(4-methoxyphenyl)-methyl]-azetidin-3-ol, 20 cm<3> dichloromethane, 0.229 cm<3> methylsulfonyl chloride and 722 mg of 4-dimethylamino-pyridine. After purification by chromatography on silica under atmospheric pressure (100 g of silica, granulometry 0.063-0.2 mm in a column with a diameter of 3 cm) and subsequent elution with dichloromethane, the fractions containing nothing but the desired product are combined to a dry state under reduced pressure. 650 mg of l-[bis-

(4-chlorophenyl)methyl]-3-[(4-methoxyphenyl)methylsulfonyl-methylene in the form of a yellow gum.

(RS)-1-[>is-(4-chlorophenyl)methyl]-3-[methylsulfonyl-(4-methoxyphenyl)-methyl]-azetidin-3-ol can be prepared by working as described in Example 1 from 19.6 cm<3>1.6N n-butyllithium solution in hexane, 5.7 g of 4-methoxybenzyl-methyl-sulfone and 8.71 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-one in 450 cm<3> tetrahydrofuran. In this way, 8.3 g of (RS)-1-[bis-(4-chlorophenyl)methyl]-3-[methylsulfonyl-(4-methoxyphenyl)-methyl]-azetidin-3-ol are obtained in the form of a beige solid.

4-Methoxybenzyl-methyl-sulfone can be prepared by working as described in example 27 from 13.6 cm 3 of 4-methoxybenzyl chloride, 30 mg of sodium iodide, 14.4 g of sodium methyl sulfinate in 125 cm<3> of ethanol. In this way, 5.75 g of 4-methoxybenzyl-methyl-sulfone is obtained in the form of a white powder.

Example 49

(RS)-2-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetylmorpholine can be prepared as follows: To 37 mg ( RS)-{ 1-[bis-(4-chlorophenyl)methyl]azetidin-3yl}(3,5-difluorophenyl)acetic acid.hydrochloride, at a temperature close to 20°C, 252 mg of supported EDC1 (2, 3 equivalents, the supported EDCl reactant is commercial, but can also be prepared according to the following reference: M. Desai, L. Stramiello, "Tetrahedron Letters", 34, 48, 7685-7688 (1993)), 2 cm<3> anhydrous dichloromethane, 0.006 cm<3> morpholine and then 0.010 cm<3> triethylamine. After stirring for 12 hours at a temperature close to 20°C, the reaction mixture is filtered on a glass frit. The filtrate is washed with 2 cm<3> of water, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa and a temperature close to 20°C. 15 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetylmorpholine is obtained in this way in the form of a beige-colored meringue mass.

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): from 2.60 to 3.80 (mt, 13H), 3.93 (d, J = 10 Hz,

1H), 4.27 (s, 1H), from 6.65 to 6.85 (mt, 3H), from 7.20 to 7.40 (mt, 8H).

Example 50

(RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexyl-acetamide can be prepared as follows: To a solution of 250 mg of (RS)-{1-[bis-(4-chlorophenyl)methyl]azetid^n-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 10 cm<3 >anhydrous dichloromethane is placed that, at a temperature close to 20°C, successively 0.070 cm<3> cyclo-

Hexylamine, 144 mg 1-(3-d4methylaminopropyl)-3-ethylcarbocuimid.hydrochloride, 0.141

cm<3> triethylamine and then 4 mg of hydroxybenzotriazole.hydrate. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is deposited on a Varian column (25 cm<3>) equipped with 12 g of fine silicon dioxide (0.040-0.063 mm), condi-

ion and then eluted with dichloromethane:petroleum ether in the volume ratio 80:20 using a Duramat pump, recovering fractions of 1.5 cm<3>. Fractions 11 to 17 for

combine and concentrate to dryness at 2.7 kPa and 40°C. 169 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide are obtained in this way in form of a white meringue mass.

<!>H-NMR (300 MHz, CDCl 3 , 6 in ppm): from 0.90 to 1.45 (mt, 6H), from 1.50 to 1.90 (mt,

4H), 2.66 (mt, 1H), 2.90 (mt, 1H), from 3.00 to 3.15 (mt, 2H), 3.42 (t large,

J = 7.5 Hz, 1H), 3.52 (d, J = 10.5 Hz, 1H), from 3.60 to 3.80 (mt, 1H), 4.27

(s, 1H), 5.25 (d large, J = 8 Hz, 1H), 6.90 (tt, J = 9 and 2.5 Hz, 1H), 6.82

(mt, 2H), from 7.20 to 7.35 (mt, 8H).

Example 51

(RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetyl-

Piperidine can be prepared as follows: To a solution of 50 mg of (RS)-{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm<3> anhydrous dichloromethane, it is placed successively at a temperature close to 20°C, 0.012 cm<3> piperidine, 29

mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 0.028 cm<3> of triethylamine and 1.5 g of hydroxybenzotriazole hydrate. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is deposited on a Varian column (6 cm<3>) equipped with 3 g of fine silica (0.040-0.063 mm), eluting with dichloromethane using a Duramat pump. The fractions between 8 and 15 cm<3> are combined and concentrated to a dry state at 2.7 kPa and 40°C. In this way, 14 mg of (RS)-2-{1-[bis-(4-chloro-phenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetylpiperidine are obtained in form of a crystal

linsk, white powder.

^-NMR (300 MHz, CDCl3.8 in ppm): from 0.95 to 1.15 and from 1.30 to 1.50 (2mts, 6H combined), 2.74 (mt, 2H), from 3 .00 to 3.15 (mt, 2H), from 3.30 to 3.45 (mt,

4H), from 3.55 to 3.70 (mt, 1H), 3.95 (d, J = 10 Hz, 1H), 4.26 (s, 1H), 6.68

(tt, J = 9 and 2.5 Hz, 1H), 6.80 (mt, 2H), from 7.20 to 7.35 (mt, 8H).

Example 52

(RS)-2-{l-| )-{ 1-[bis-(4-chloro-phenyl)methyl]azetdin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm<3> of anhydrous dichloromethane, it is placed at a temperature near 20°C, successively 0.010 cm3 of pyrrolidine, 0.023 cm<3> of diisopropylcarbodiimide, 0.028 cm<3> of triethylamine and 1.5 mg of hydroxybenzotriazole.hydrate. The obtained solution is stirred at a temperature close to 20°C for about 12 hours. The reaction medium deposited on a Varian column (6 cm<3>) with 3 g of fine silica (0.040-0.063 mm), eluting with dichloromethane using a Duramat pump. The fractions between 11 and 19 are combined and concentrated to dryness at 2.7 kPa and 40° C. 29 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}(3,5-difluorophenyl) are obtained in this way -N-acetylpyrrolidine in the form of a white meringue mass.

1H-NMR (300 MHz, CDCl3.8 in ppm): from 1.75 to 2.00 (mt, 4H), 2.74 (mt, 2H), from 3.00

to 3.30 (mt, 3H), from 3.35 to 3.60 (mt, 4H), 3.80 (d, J = 10.5 Hz, 1H), 4.25 (s, 1H), 6 .68 (tt, J = 9 and 2.5 Hz, 1H), 6.84 (mt, 2H), from 7.20 to 7.40 (mt, 8H).

Example 53

(RS)-2- {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropyl-acetamide can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm3 of anhydrous dichloromethane is placed at a temperature close to 20° C successively 0.009 cm3 of cyclopropylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotyrazole hydrate. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is deposited on a Varian column (6 cm<3>) with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane using a Duramat pump, recovering fractions of 2 cm<3> . Fractions 2 to 6 are combined and concentrated to dryness at 2.7 kPa and 40°C. 29 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylacetamide is obtained in this way in the form of a white meringue mass.

1H-NMR (300 MHz, CDCl3.8 in ppm): 0.40 (mt, 2H), 0.74 (mt, 2H), 2.64 (mt, 2H), 2.89

(dd, J = 7.5 and 5 Hz, 1H), 3.08 (mt, 2H), 3.42 (t large, J = 7.5 Hz, 1H), 3.51 (d, J = 10 .5 Hz, 1H), 4.25 (s, 1H), 5.50 (mf, 1H), 6.70 (tt, J = 9 and 2.5 Hz, 1H), 6.81 (mt, 2H ), from 7.15 to 7.35 (mt, 8H).

Example 54

(RS)-2-{1-[>is-(4-Morphenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl^N-methylacetamide can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-Morphenyl)methyl]azeu^in-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm3 of anhydrous dichloromethane is placed at a temperature near 20°C successively 0.016 cm3 of N-methylcyclohexylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature close to 20° C for 12 hours. The reaction medium is deposited on a Varian column (6 cm<3>) with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane using a Duramat pump, recovering fractions of 2 cm<3.> Fractions 4 to 6 are combined and concentrated to dryness at 2.7 kPa and 40° C. In this way 17 mg of (RS)-2-{l-[bis-(4-chlorophenyl) -methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyldohexyl-N-methylacetamide in the form of a white meringue ass.

'H-NMR (250 MHz, (CD3)2SO d6, at a temperature of 373K, 8 in ppm): from 0.98 to 1.85 mt, 10H), from 2.60 to 3.05 (mt, 8 H), 3.26 (t large, J = 7.5 Hz, w .... 1H), 4.25 (d large, J = 9 Hz, 1H), 4.45 (s, 1H), 7 .00 (mt, 3H), from 7.25 to 7.45 (mt, 8H).

Example 55

(RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(tetrahydrofuran-2-ylmethyl)-acetamide can be prepared in the following manner: To a resolution of 50

mg (RS)- {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm3 of anhydrous dichloromethane is placed successively at a temperature close to 20 °C, 0.013 cm3 tetrahydrofurfurylamine, 29 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 triethylamine and 1.5 mg hydroxybenzotriazole hydrate. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is deposited on a Varian column (6 cm<3>) equipped with 3 g of fine silica (0.040-0.063 mm), conditioned and eluted with dichloromethane using a Duramat pump, recovering fractions of 2 cm<3. > Fractions 3 to 8 are combined and concentrated to dryness at 2.7 kPa and 40°C. 27 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(tetrahydrofuran-2-ylmethyl) are obtained -acetamide in the form of a white solid.

1H-NMR (300 MHz, CDCl3.8 in ppm): from 1.65 to 1.95 (mt, 4H), 2.64 (mt, 1H), 2.89

(dd, J = 7.5 and 5.5 Hz, 1H), from 3.00 to 3.20 (mt, 3H), from 3.30 to 3.60 (mt, 2H), 3.58 (d , J = 10.5 Hz, 1H), from 3.65 to 3.95 (mt, 3H), 4.25 (s, 1H), 5.81 (mr, 1H), 6.68 (tt, J = 9 and 2.5 Hz, 1H), 6.82 (mt, 2H), from 7.15 to 7.35 (mt, 8H).

Example 56

(RS)-2-{1-|>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(2-morpholin-4-yl-ethyl) )-acetamide can be prepared in the following way: To a solution of 50 mg of (RS)-{1-|>is-(4-chlorophenyl)methyl]azetdin-3-yl}(3,5-difluorophenyl)-acetic acid. hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature close to 20°C, 0.016 cm3 of aminoethylmorpholine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are added. . The obtained solution is stirred at a temperature close to 20°C for 12 hours. The reaction medium is deposited on a Varian column (6 cm<3>) and it is successively eluted with dichloromethane:ethyl acetate in the volume ratio 70:30, recovering fractions of 2 cm3 for fractions 1 to 12 and then with dichloromethane:methanol in the volume ratio 98: 2, recovering fractions of 2 cm 3 for fractions 12 to 27. Fractions 13 to 27 are combined and concentrated to dryness at 2.7 kPa at 40°C. 34 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(2-morpholine) are obtained in this way -4-yl-ethyl)-acetamide in the form of a white meringue mass.

<X>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.33 (t large, J = 5 Hz, 4H), 2.38 (t, J = 7 Hz, 2H),

2.65 (mt, 1H), from 2.85 to 3.20 (mt, 3H), 3.25 (q large, J = 7 Hz, 2H), 3.43 (mt, 1H), 3.57 (t, J = 5 Hz, 4H), 3.61 (d, J = 10.5 Hz, 1H), 4.26 (s, 1H), 5.98 (mf, 1H), 6.70 (tt , J = 9 and 2.5 Hz, 1H), 6.83 (mt, 2H), from 7.15 to 7.35 (mt, 8H).

Example 57

(RS)-2- {1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(1-ethylpyrro-lidin-2-ylmethyl) -acetamide can be prepared in the following way: To a solution of 50 mg of (RS)-{1-|13is-(4-chlorophenyl)methyl]azeti(hn-3-yl)(3,5-difluorophenyl)-acetic acid. hydrocl in 2 cm3 of anhydrous dichloromethane, at a temperature close to 20°C, successively 0.018

cm3 of aminomethylethylpyrrolidine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is deposited on a Varian column (diameter 12 mm) with 4 g of silica (0.060-

0.200 mm), is conditioned against dichloromethane using vacuum equipment, where

after all, elute with dichloromethane between 0 and 6 cm3 and then with dichloromethane:methanol in the volume ratio 95:5. The fractions containing the desired product are combined and concentrated to dryness at 2.7 kPa and 40°C for 2 hours. The yellow paste thus obtained is taken up in 2 cm3 of ethyl acetate and with 2 cm3 of distilled water. After stirring, the mixture is frozen and the organic phase is concentrated to a dry state at 2.7 kPa and 40°C.

The obtained residue is taken up in 2 cm3 of diisopropyl oxide and then concentrated to dryness

at 2.7 kPa and 40°C. 38 mg of (RS)-{1-[bis-(4-chlorophenyl)-methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(1-ethylpyrrolidine-2) are obtained in this way -ylmethyl)-acetamide in the form of a white meringue mass.

'H-NMR (300 MHz, CDC13, with the addition of a few drops of CD3COOD d4, 8 in ppm):

0.96 and 1.17 (2t, J = 7.5 Hz, 3H combined), from 1.60 to 2.00 (mt, 4H),

from 2.50 to 2.95 and from 3.10 to 3.85 (mts, 11H), from 3.95 to 4.10 (mt, 1H), 4.10 and 4.14 (2d, J = 10 .5 Hz, 1H together), 5.18 and 5.25 (2s large, 1H

combined), 6.66 (mt, 1H), from 6.80 to 7.00 (mt, 2H), from 7.14 to 7.45

(mt, 8H).

Example 58

(RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutyl)-acetamide can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm3 of anhydrous dichloromethane is placed at a temperature close to 20°C successively 0.012 cm<3> of isobutylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbo(himide.hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotyrazole.hydrate. The obtained solution is stirred at a temperature near 20° C. for about 12 hours. The reaction medium is deposited on a Varian column (diameter 12 mm) with 5 cm3 of silica (0.0600-0.200 mm) conditioned against dichloromethane by means of a vacuum apparatus, and the whole is eluted with dichloromethane between 0 and 6 cm3 and then with dichlorometamethyl acetate in the volume ratio 95:5.

the ions containing nothing but the desired product are combined and concentrated to dryness at 2.7 kPa and 40°C. 40 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide is obtained in this way in the form of a white meringue mass.

1H-NMR (300 MHz, (CD3)2SO d6, 8 in ppm): 0.75 (d, J = 7.5 Hz, 6H), 1.62 (mt, 1H),

2.61 (mt, 1H), from 2.70 to 2.95 (mt, 3H), 3.03 (mt, 2H), 3.22 (t large, J = 7 Hz, 1H), 3.83 (d, J = 10.5 Hz, 1H), 4.45 (s, 1H), 7.00 (mt, 2H), 7.08 (tt, J = 9 and 2.5 Hz, 1H), from 7.25 to 7.45 (mt, 8H), 8.11 (t, J = 6 Hz, 1H).

Example 59

(RS)-2-{1-rbis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N,N-dimethylacetamide can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm<3> of anhydrous dichloromethane is placed at a temperature close to 20°C successively 0.060 cm<3> of dimethylamine in 2M solution in tetrahydrofuran, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloride, 0.028 cm<3> of triethylamine and 1.5 mg hydroxybenzotriazole.hydrate. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is deposited on a Varian column (diameter 12 mm) with 4.4 cm<3> silicon dioxide (0.0600-0.200 mm), conditioned against dichloromethane using a vacuum apparatus, after which elution is carried out with dichloromethane between 0 and 6 cm <3> and then with dichloromethane:ethyl acetate in the volume ratio 95:5. The fractions containing nothing but the intended product are combined and concentrated to dryness at 2.7 kPa and 40°C. In this way, 13 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N,N-dimethylacetamide are obtained in form of a white powder.

1H-NMR (300 MHz, CDCl3.8 in ppm): from 2.70 to 2.80 (mt, 2H), 2.92 (s, 3H), 2.95 (s,

3H), from 3.00 to 3.15 (mt, 2H), 3.38 (t large, J = 7.5 Hz, 1H), 3.96 (d, J = 10 Hz, 1H), 4, 26 (s, 1H), 6.69 (tt, J = 9 and 2.5 Hz, 1H), 6.81 (mt, 2H), from 2.70 to 7.35 (mt, 8H).

Example 60

(RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-benzylacet-amide can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm<3> of anhydrous dichloromethane, it is added at a temperature near 20°C, successively 0.013 cm<3> of benzylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloride, 0.028 cm<3> of triethylamine and 1.5 mg of hydroxybenzotriazole.hydrate. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is deposited on a Varian column (diameter 12 mm) with 4.4 cm<3> silica (0.0600-0.200 mm), conditioned against dichloromethane using a vacuum apparatus, and eluted with dichloromethane between 0 and 6 cm<3 > and then with dichloromethane: ethyl acetate in the volume ratio 95:5. from

the ions containing nothing but the desired product are combined and concentrated to dryness at 2.7 kPa and 40°C. 37 mg of (RS)-2-{1-[bis-(4-ldorphenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-benzylacetamide is obtained in this way in the form of white crystals.

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.67 (mt, 1H), 2.93 (mt, 1H), 3.11 (mt, 2H), 3.43

(t large, J = 7.5 Hz, 1H), 3.62 (d, J = 10.5 Hz, 1H), 4.26 (s, 1H), 4.38 (mt, 2H), 5, 71 (mt, 1H), 6.71 (t large, J = 9 Hz, 1H), 6.83 (mt, 2H), from 7.10 to 7.40 (mt, 13H).

Example 61

(RS)-2- {1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexyl-methylacetamide can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-ldorphenyl)methyl]azetidin-3-yl}(3,5-dlfluorophenyl)-acetic acid.hydrochloride in 2 cm<3 >anhydrous dichloromethane, it is placed at a temperature near 20°C, successively 0.016 cm<3 >aminomethylcyclohexane, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm<3> triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is deposited on a Varian column (6 cm<3>) with 3 g of fine silica (0.040-0.063 mm), conditioned and eluted with dichloromethane using a Duramat pump, recovering fractions of 2 cm<3>. Fractions 2 to 3 are combined and concentrated to dryness at 2.7 kPa and 40°C. 49 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylmethylacetamide are obtained in this way in the form of a white meringue mass.

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): from 0.75 to 1.75 (mt, 11H), 2.65 (mt, 1H), from 2.85 to 3.15 (mt, 5H ), 3.42 (t large, J = 7.5 Hz, 1H), 3.57 (d, J = 10.5 Hz, 1H), 4.27 (s, 1H), 5.40 (mt, 1H), 6.71 (t large, J = 9 Hz, 1H), 6.83 (mt, 2H), from 7.15 to 7.40 (mt, 8H).

Example 62

(RS)-2-{1-|>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-[3-(2-oxo-pyrrolidine- 1-yl)-propyl]-acetamide can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5- difluorophenyl)-acetic acid.hydrochloride in 2 cm<3> of anhydrous dichloromethane, it is placed at a temperature near 20°C, successively 0.017 cm<3> aminopropylpyrrolidinone, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloride, 0.028 cm<3> triethylamine and 1.5 mg of hydroxybenzo-

triazole hydrate. The obtained solution is stirred at a temperature close to 20°C for approx. 12 hours. The reaction medium is deposited on a Varian column (6 cm<3>) with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane using a Duramat pump, recovering fractions of 2 cm<3> . Fractions 4 to 12 are combined and concentrated to dryness at 2.7 kPa and 40°C. 35 mg of (RS)-2-{1-|>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-[3- (2-oxopyrrolidin-1-yl)-propyl]-acetamide in the form of a white meringue mass.

1 H-NMR (300 MHz, CDCl 3.8 in ppm): from 1.50 to 1.65 (mt, 2H), 2.04 (mt, 2H), 2.43 (t,

J = 8 Hz, 2H), 2.64 (mt, 1H), 2.88 (dd, J = 7.5 and 5.5 Hz, 1H); from 3.00 to 3.30 (mt, 6H, from 3.30 to 3.45 (mt, 3H), 3.64 (d, J = 10.5 Hz, 1H), 4.27 (s, 1H ), 6.67 (tt, J = 9 and 2.5 Hz, 1H), 6.90 (mt, 2H), 7.15 (t, J = 6 Hz, 1H), from 7.20 to 7, 35 (mt, 8H).

Example 63

(RS)-2-{1-[>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetyl-(4-methylpiperazine) can be prepared on the following way: To a solution of 50 mg of (RS)-{ 1-|>is-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm<3 >anhydrous dichloromethane, it is placed at a temperature close to 20°C, successively 0.013 cm<3 >N-methylpiperazine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimid.hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole. hydrate. The obtained solution is stirred at a temperature close to 20°C for approx. 12 hours. The reaction medium is deposited on a Varian column (6 cm<3>) with 3 g of fine silica (0.040-0.063 mm), conditioned to dichloromethane using a Duramat pump, and eluted with dichloromethane:ethanol in the volume ratio 98:2, fractions of 2 cm<3> are recovered. Fractions 10 to 24 are combined and concentrated to dryness at 2.7 kPa and 40°C. 39 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetyl-(4 -methylpiperazine) in the form of a white meringue mass.

1H NMR (300 MHz, CDCl3.8 in ppm): 1.83 (mt, 1H), from 2.10 to 2.45 (mt, 3H), 2.21 (s,

3H), 2.74 (mt, 2H), from 2.95 to 3.15 (mt, 2H), from 3.30 to 3.55 (mt, 4H), 3.73 (mt, 1H), 3 .93 (d, J = 10 Hz, 1H), 4.25 (s, 1H), 6.69 (tt, J = 9 and 2.5 Hz, 1H); 6.78 (mt, 2H), from 7.15 to 7.35 (mt, 8H).

Example 64

(RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(2,2-dimethyl-propyl)-acetamide can be prepared as follows: To a solution of 50 mg (RS)-

{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid^ in 2 cm<3> of anhydrous dichloromethane, it is placed at a temperature close to 20°C, successively 0.014 cm<3>

neopentylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm<3> triethylamine and 1.5 mg of hydroxybenzotyrazole hydrate. The obtained solution is stirred at a temperature close to 20°C for approx. 12 hours. The reaction medium is deposited on a Varian column (6 cm3) with 3 g of fine silica (0.040-0.063 mm), conditioned to dichloromethane using a Duramat pump, and eluted with dichloromethane:petroleum in the volume ratio 80:20, recovering fractions of 1.5 cm<3>. Fractions 4 to 8 are combined and concentrated to dryness at 2.7 kPa and 40°C. 40 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(2,2 -dimethyl-propyl)-acetamide in the form of a white meringue mass.

<J>H-NMR (300 MHz, CDCl3.8 in ppm): 0.81 (s, 9H), 2.66 (mt, 1H), from 2.90 to 3.20 (mt,

5H), 3.44 (t large, J = 7.5 Hz, 1H), 3.61 (d, J = 10.5 Hz, 1H), 4.28 (s, 1H), 5.40 (mt , 1H), 6.72 (tt, J = 9 and 2.5 Hz, 1H), 6.85 (mt, 2H), from 7.20 to 7.35 (mt, 8H).

Example 65

(RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(2-pyrrolidin-1-yl-ethyl) -acetamide can be prepared as follows: To a solution of 50 mg of (RS)-{l-|>is-(4-ldorphenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid hydrochloride in 2 cm<3> of anhydrous dichloromethane, it is placed at a temperature close to 20°C, successively 0.015 cm<3 >aminoethylpyrrolidine, 29 mg of 1-(3-dimethylanunopropyl)-3-ethylcarbo(iiirnide.hydrochloride, 0.028 cm<3> triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The obtained solution is stirred at a temperature close to 20° C. for about 12 hours. The reaction medium is deposited on a Varian column (6 cm<3>) with 3 g of fine silica (0.040- 0.063 mm), conditioned to dichloromethane using a Duramat pump, and eluted with dichloromethane:ethanol in the volume ratio 98:4, recovering fractions of 1.5 cm<3>. Fractions 13 to 20 are combined and concentrated to dryness at 2.7 kPa and 40° C. 33 mg of (RS)-2-{1-|T3is-(4-chlorophenyl)methyl]-azetidine is obtained in this way -3-yl}-2-(3,5-difluorophenyl)-N-(2-pyrrolidin-1-yl-ethyl)-acetamide in the form of a white meringue mass.

<*>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 1.78 (mt, 4H), from 2.50 to 2.70 (mt, 3H), 2.54 (mt, 4H), 2 .91 (dd, J = 7.5 and 5 Hz, 1H), 3.10 (mt, 2H), from 3.20 to 3.45 (mt, 3H), 3.64 (d, J = 10, 5 Hz, 1H), 4.27 (s, 1H), 6.67 (tt, J = 9 and 2.5 Hz, 1H), 6.86 (mt, 2H), from 7.15 to 7.35 (mt, 8H).

Example 66

(RS)-2-{1-[>is-(4-chlorophenyl)methyl]-azetimn-3-yl}-2-(3,5-mfluorophenmethylacetamide can be prepared as follows: To a solution of 50 mg (RS)-{ 1-[bis-(4-chlorophenyl)methyl]azetidln-3-yl}(3,5-difluorophenyl)-acetic acid.hy(cochloride in 2 cm<3 >anhydrous dichloromethane, it is successively added at a temperature near 20°C, 0.011 cm<3> cyclopropanemethylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiirinide hydrochloride, 0.028 cm<3> triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. It obtained solution is stirred at a temperature close to 20° C. for 12 hours. The reaction medium is deposited on a

Varian column (6 cm<3>) with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane:petroleum ether in the volume ratio 80:20, using a Duramat pump, recovering fractions of 1, 5 cm<3>. Fractions 3 to 8 are combined and concentrated to dryness at 2.7 kPa and 40°C. 37 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylmethyl-acetamide are obtained in this way in form of a white meringue mass.

<*>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 0.13 (mt, 2H), 0.45 (mt, 2H), 0.86 (mt, 1H), 2.65 (mt, 1H), 2.91 (dd, J = 7.5 and 5 Hz, 1H), from 3.00 to 3.15 (mt, 4H), 3.41 (t large, J = 7.5 Hz, 1H ), 3.57 (d, J = 10.5 Hz, 1H), 4.25 (s, 1H), 5.50 (mt, 1H), 6.70 (tt, J = 9 and 2.5 Hz , 1H), 6.84 (mt, 2H), from 7.15 to 7.35 (mt, 8H).

Example 67

(RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-propyl-acetamide can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm<3> of anhydrous dichloromethane, it is added successively, at a temperature near 20°C, 0.015 cm<3> propylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm<3> triethylamine and 1.5 mg of hydroxybenzotyrazole hydrate. The obtained solution is stirred at a temperature close to 20°C for 12 hours. The reaction medium is deposited on a Varian column (6 cm<3>)

with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane using a Duramat pump. The fractions containing nothing but the desired product are combined and concentrated to dryness at 2.7 kPa and 40°C. In this way, 21 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-propyl-acetamide are obtained in form of a white solid.

1H-NMR (300 MHz, CDCl3.6 in ppm): 0.84 (t, J = 7.5 Hz, 3H), 1.45 (mt, 2H), 2.65 (mt,

1H), 2.92 (dd, J = 7.5 and 5.5 Hz, 1H), from 3.00 to 3.20 (mt, 2H), 3.15 (q, J = 7 Hz, 2H) , 4.43 (t large, J = 7.5 Hz, 1H), 3.56 (d, J = 10.5 Hz, 1H), 4.26 (s, 1H), 5.39 (mt, 1H ), 6.70 (tt, J = 9 and 2.5 Hz, 1H), 6.83 (mt, 2H), from 7.15 to 7.35 (mt, 8H).

Example 68

(RS)-2-{l-[bis-(4-chlorophenyl)methyl]-azeitmn-3-yl}-2-(3,5-(ulfluorophenyl)-N-methylac can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-chloro-phenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm<3> of anhydrous dichloromethane, is placed successively at a temperature close to 20°C, 0.050 cm<3> of a 2M methylamine solution in tetrahydrofuran, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimid.hydrochloride, 0.028 cm<3> of triethylamine and 1.5 mg of hydroxybenzotriazole.hydrate. The resulting solution is stirred at a temperature close to 20°C for 12 hours. The reaction medium is deposited on a Varian column (6 cm<3>) with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane using a Duramat pump. The fractions containing nothing but the desired product are combined and concentrated to dryness at 2.7 kPa and 40° C. 19 mg of (RS)-2-{ 1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-methylacetamide in the form of a white solid.

<!>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.66 (mt, 1H), 2.76 (d, J = 5 Hz, 3H), 2.93 (mt,

1H), 3.10 (mt, 2H), 3.44 (t large, J = 7.5 Hz, 1H), 3.59 (d, J = 10.5 Hz, 1H), 4.28 (s , 1H), 5.41 (mf, 1H), 6.71 (tt, J = 9 and 2.5 Hz, 1H), 6.83 (mt, 2H), from 2.70 to 7.35 (mt , 8H).

Example 69

(RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropyl-acetamide can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm<3> of anhydrous dichloromethane, it is added successively at a temperature near 20°C, 0.011 cm<3> of isopropylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiirinide.hydrochloride, 0.028 cm<3 >triethylamine and 1.5 mg of hydroxybenzotriazole.hydrate. The obtained solution is stirred at a temperature close to 20°C for 12 hours. The reaction medium is deposited on a Varian column (6 cm<3>) with 3 g of fine silica (0.040-0.063 mm), conditioned and eluted with dichloromethane using a Duramat pump, recovering fractions of 1.5 cm<3> . Fractions 6 to 14 are combined and concentrated to dryness at 2.7 kPa and 40°C. Mon

thus obtaining 21 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropyl-acetamide in the form of a white meringue mass.

1H NMR (300 MHz, CDCl3.8 in ppm): 1.05 (d, J = 7 Hz, 3H), 1.10 (d, J = 7 Hz, 3H),

2.65 (mt, 1H), 2.90 (dd, J = 7.5 and 5.5 Hz, 1H), from 3.00 to 3.15 (mt, 2H), 3.42 (t large, J = 7.5 Hz, 1H), 3.51 (d J = 10.5 Hz, 1H), 4.00 (mt, 1H), 4.26 (s, 1H), 5.19 (d large, J = 7.5 Hz, 1H), 6.70 (tt, J = 9 and 2.5 Hz, 1H), 6.82 (mt, 2H), from 7.20 to 7.40 (mt, 8H) .

Example 70

(RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetimn-3-yl}-2-(3,5-difluorophenyl)-N-piperidin-1-yl-acetamide can be prepared as follows method: To a solution of 50 mg of (RS)-{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm<3> anhydrous dichloromethane, it is placed at a temperature close to 20°C, successively 0.013 cm<3> amino-piperidine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiirinide hydrochloride, 0.028 cm<3>

triethylamine and 1.5 mg hydroxybenzotriazole hydrate. The obtained solution is stirred at a temperature close to 20°C for 12 hours. The reaction medium is deposited on a Varian column (6 cm3} with 3 g fine silica (0.040-0.063 mm), conditioned to dichloromethane, using a Duramat pump and eluted with dichloromethane:methanol in the volume ratio 98:2, recovering fractions of 2 cm<3>. Fractions 7 to 12 are combined and concentrated to dryness at 2.7 kPa and 40° C. 33 mg of (RS)-2-{1-[bis-(4-ldorphenyl) is obtained in this way )methyl]-azetdin-3-yl}-2-(3,5-difluorophenyl)-N-piperidin-1-yl-acetamide form as a white solid.

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): from 0.95 to 1.85-2.05 and 2.29 (mts, 10H), from 2.60

to 2.80 (mt, 2H), from 3.00 to 3.20 (mt, 2H), 3.39 (t large, J = 7.5 Hz, 1H), 4.26 (s, 1H), 4.32 (d, J = 10.5 Hz, 1H), 6.00 (s, 1H), 6.65 (tt, J = 9 and 2.5 Hz, 1H), 6.85 (mt, 2H ), from 7.15 to 7.35 (mt, 8H).

Example 71

(RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cycloheptyl-acetamide can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm<3> of anhydrous dichloromethane, it is added successively at a temperature near 20°C, 0.015 cm<3> cycloheptylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiirinide.hydrochloride, 0.028 cm<3>triethylamine and 1.5 mg of hydroxybenzotyrazole.hydrate. The obtained solution is stirred at a temperature close to 20°C for 12 hours. The reaction medium is deposited on a Varian column (6

cm<3>) with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane, using a Duramat pump, recovering fractions of 2 cm<3. >Fractions 3 to 6 are combined and concentrated to dryness at 2.7 kPa and 40°C. 24 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cycloheptyl-acetamide are obtained in this way in form of a white meringue mass.

1H-NMR (300 MHz, CDCl3.8 in ppm): from 1.20 to 1.95 (mt, 12H), 2.65 (mt, 1H), 2.90

(dd, J = 7.5 and 5.5 Hz, 1H), from 3.00 to 3.15 (mt, 2H), 3.42 (t large, J = 7.5 Hz, 1H), 3, 52 (d, J = 10.5 Hz, 1H), 3.86 (mt, 1H), 4.26 (s, 1H), 5.31 (d large, J = 7.5 Hz, 1H), 6 .70 (tt, J = 9 and 2.5 Hz, 1H), 6.82 (mt, 2H), from 7.20 to 7.35 (mt, 8H).

Example 72

(RS)-2-{1-[>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-acetamide can be prepared as follows: To a solution of 98 mg (RS)-{1-[bis-(4-chlorophenyl)-methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 4 cm<3> of anhydrous dichloroethane, it is placed at a temperature close to 20°C, successively 60 mg of 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride and 3 mg of hydroxybenzotriazole hydrate and ammonia is allowed to bubble through the solution for 2 hours with stirring at a temperature close to 20°C. The reaction medium is washed with water and deposited on a Varian column (6 cm<3>) with 3 g of fine silica (0.040-0.063 mm), conditioned and eluted with dichloromethane:ethyl acetate in the volume ratio 9:1, using a Duramat pump . The fractions between 36 and 80 ml are combined and concentrated to dryness at 2.7 kPa and 40°C. 32 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-acetamide are obtained in this way in the form of an amorphous powder.

'H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.66 (mt, 1H), 2.95 (dd, J = 7 and 5 Hz, 1H), from 2.95 to 31.5 (mt , 2H), 3.45 (t large, J = 7 Hz, 1H), 3.67 (d, J = 10.5 Hz, 1H), 4.27 (s, 1H), from 5.20 to 5 .40 (mf, 2H), 6.72 (tt, J = 9 and 2.5 Hz, 1H), 6.84 (mt, 2H), from 7.20 to 7.35 (mt, 8H).

Example 73

Methyl-(RS)-2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetyl-aminoacetate can be prepared as follows: To a solution of 200 mg of (RS)-{1-Ibis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 8 cm<3>dichloroethane is added at a temperature close to 20°C, successively 100 mg of glycine methyl ester hydrochloride, 115 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 6 mg of hydroxybenzotriazole hydrate. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is washed with water, dried, filtered and then concentrated to dryness at 2.7 kPa and 40°C. The residue thus obtained is taken up in 1 cm<3 >dichloromethane, and it is then deposited on an IST PlashPack column with reference SIL-020-005, conditioned and eluted with dichloromethane:ethyl acetate in the volume ratio 95:5 using a Duramat pump. The fractions between 18 and 42 ml are combined and concentrated to dryness at 2.7 kPa and 40°C. In this way, 68 mg of methyl-(RS)-2-{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetylaminoacetate are obtained in the form of cottony white crystals.

<!>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.67 (mt, 1H), 2.93 (dd large, J = 7.5 and 5 Hz,

1H), from 3.00 to 3.15 (mt, 2H), 3.41 (t large, J = 7.5 Hz, 1H), 3.68 (d, J = 10.5 Hz, 1H), 3.74 (s, 3H), 3.93 (dd, J = 18 and 5 Hz, 1H), 4.03 (dd, J = 18 and 5 Hz, 1H), 4.27 (s, 1H), 5.96 (mt, 1H), 6.71 (tt, J = 9 and 2 Hz, 1H), 6.85 (mt, 2H), from 7.20 to 7.35 (mt, 8H).

Example 74

(RS)-2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(3-dimethylamino-propyl)-acetamide can be prepared on the following way: To a solution of 5 mg of (RS)-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm<3> dichloromethane, it is placed at a temperature close to 20°C, successively 0.15 cm<3> N,N-dimethylpropane-1,3-diamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloride, 0.028 cm<3> triethylamine and 1.5 mg hydroxybenzotriazole.hydrate. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is deposited on a Varian column (12 diameter) with 4 cm<3> silica (0.060-0.200 mm), conditioned to dichloromethane using a vacuum apparatus and eluted with dichloromethane between 0 and 6 cm<3> and then with dichloromethane :methanol in the volume ratio 95:5. The fractions containing nothing but the desired product are combined and concentrated to dryness at 2.7 kPa and 40°C. 33 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(3-dimethylamino) are obtained in this way -propyl)-acetamide in the form of white crystals.

<*>H-NMR (300 MHz, CDCl3, with the addition of a few drops of CD3COOD d4.8 in ppm): 1.91 (mt, 2H), 2.71 (s, 6H), 2.95 (mt, 2H ), from 3.15 to 3.40 (mt, 2H), from 3.40 to 3.60 (mt, 1H), from 3.60 to 3.80 (mt, 2H), 4.00 (mt, 2H), 4.28 (d, J = 10.5 Hz, 1H), 5.22 (s, 1H), 6.68 (tt, J = 9 and 2.5 Hz, 1H), 6.90 ( mt, 2H), 7.33 (mt, 4H), 7.46 (d, J = 8 Hz, 4H).

Example 75

(RS)-2-{1-[bis-(4-Morphenyl)methyl-ethyl)-acetamide can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-chlorophenyl) methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 2 cm<3 >dichloromethane, it is placed at a temperature close to 20°C, successively 0.024 cm3 ethanolamine, 29 mg l-(3- dimethylaminopropyl)-3-ethylcarbodiirinide hydrochloride, 0.028 cm3 triethylamine

and 1.5 mg of hydroxybenzotriazole hydrate. The obtained solution is stirred at a temperature close to 20°C. The reaction medium is washed with 2 cm3 of saturated sodium bicarbonate solution, dried over magnesium sulfate and then deposited on an IST FlashPack column with reference SIL-016-002, conditioned in dichloromethane and eluted with dichloromethane:ethyl acetate in the volume ratio 95:5 using a Duramat pump. The fractions between 25 and 60 cm3 are combined and concentrated to a dry state at 2.7 kPa and 40°C. The obtained residue is chromatographed again on an IST FlashPack column with reference SIL-016-002, conditioned to dichloromethane and eluted with dichloromethane:ethyl acetate in the volume ratio 95:5 using a Duramat pump. The fractions between 25 and 35 cm3 are combined and concentrated to a dry state at 2.7 kPa and 40°C. 14 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(2-hydroxy -ethyl)-acetamide as a white solid.

1H NMR (300 MHz, CDCl 3 , 8 in ppm): 2.65 (mt, 1H), 2.91 (mt, 1H), from 3.00 to 3.15

(mt, 2H), from 3.30 to 3.50 (mt, 3H), 3.60 (d, J = 10.5 Hz, 1H), 3.66 (t, J = 5.5 Hz, 2H ), 4.26 (s, 1H), 5.88 (mt, 1H), 6.71 (tt, J = 9 and 2 Hz, 1H), 6.84 (mt, 2H), from 7.20 to 7.35 (mt, 8H).

Example 76

(RS)-1-[{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)methyl]-3-propyl-urea can be prepared as follows: To a solution of 50 mg of (RS)-{1-[bis-(4-chloro-phenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid hydrochloride in 3 cm3 of anhydrous toluene, is added that at a temperature close to 20°C and under argon, successively 0.056 cm<3>

triethylamine and 0.064 cc of diphenylphosphonazide. The obtained solution is stirred at a temperature close to 50°C for around 1 hour. 0.016 cm<3> propylamine is added, after which stirring is continued at a temperature close to 20°C for around 12 hours. The reaction medium

concentrated to a dry state at 2.7 kPa and a temperature close to 40°C. The rest is taken up in 1

in cm3 of dichloromethane and then deposited on a Varian column (6 cm<3>) with 3g of fine silica,

conditioned and eluted with dichloromethane:ethyl acetate in the volume ratio 95:5 using a Duramat pump. The fractions between 12 and 16 cm3 are combined and concentrated to dryness

condition at 2.7 kPa and 40°C. 13 mg of (RS)-1-[{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)methyl]-3-propylurea is obtained in this way in in the form of a beige solid.

1H-NMR (400 MHz, CDCl 3 , 8 in ppm): 0.92 (t, J = 7.5 Hz, 3H), 1.53 (mt, 2H), from 2.55

to 2.75 (mt, 1H), from 2.80 to 3.25 (mt, 6H), 4.26 (t, J = 5.5 Hz, 1H), 4.29 (s, 1H), 4 .92 (t, J = 7 Hz, 1H), 5.31 (d, J = 5.5 Hz, 1H), 6.66 (tt, J = 9 and 2.5 Hz, 1H), 6.79 (mt, 2H), from 7.15 to 7.40 (mt, 8H).

Example 77

(RS)-{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride can be prepared as follows: To a solution of 0.44 g ( RS)-{1-[bis-(4-chloro-phenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.ethyl ester in 7 cm3 dioxane is added 3 cm<3> 6N hydrochloric acid. The obtained solution is stirred at reflux for around 2 hours and then left at a temperature close to 20°C for around 12 hours. The precipitate formed is filtered on a glass frit No. 3, washed with 10 cm 3 of diisopropyl oxide and then dried at 0.27 kPa and a temperature close to 40°C. 0.185 g of (RS)-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid hydrochloride is thus obtained in the form of a white powder.

^-NMR (400 MHz, (CD3)2SO d6, at a temperature of 363K, 8 in ppm): 2.87 (dd, J = 14 and 4 Hz, 1H), 2.95 (mt, 1H), 3 .18 (mt, 1H), 3.96 (d, J = 10.5 Hz, 1H),

4.18 (t, J = 9 Hz, 1H), 4.72 (t, J = 9 Hz, 1H), 5.26 (mf, 1H), 7.00 (mt, 2H), 7.06 ( tt, J = 9.5 and 2.5 Hz, 1H), from 7.30 to 7.60 (mt, 8H).

Example 78

(RS)-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)-acetic acid ethyl ester can be prepared as follows: To a suspension of 0.78 g ( RS)-{ l-[bis-(4-chloro-phenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)-acetic acid.ethyl ester in 20 cm3 of methanol is added 121 mg of sodium borohydride at a temperature close to 0° C. The resulting suspension is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is poured into 200 cm3 of distilled water and then extracted with 3 x 40 cm3 of ethyl acetate. The organic phase is washed

successively with 3 x 40 cm3 of distilled water and then 40 cm3 of saturated sodium chloride solution. After decantation, the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa and a temperature close to 40°C. The obtained residue is chromatographed on a column with 75 cm3 of fine silica (0.040-0.063 mm) under a pressure of 0.7 bar with dichlorometamethyl acetate (the percentage of ethyl acetate varies from 0 — >

10%), as fractions of 15 cm<3> are recovered. Fractions 4 to 11 are combined and concentrated to dryness at 2.7 kPa and 40°C. In this way, 0.46 g of (RS)-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid ethyl ester is obtained in the form of a yellow varnish .

^-NMR (300 MHz, CDC13.8 in ppm): 1.19 (t, J = 7 Hz, 3H), 2.62 (t large, J = 6 Hz, 1H),

2.87 (dd, J = 7.5 and 6 Hz, 1H), from 2.95 to 3.15 (mt, 2H), 3.39 (t large, J = 7.5 Hz, 1H), 3 .78 (d, J = 10.5 Hz, 1H), 4.10 (mt, 2H), 4.25 (s, 1H), 6.69 (tt, J = 9 and 2.5 Hz, 1H) , 6.80 (mt, 2H), from 7.20 to 7.35 (mt, 8H).

Fractions 16 to 26 from the preceding chromatography are combined and concentrated to dryness at 2.7 kPa and 40°C. In this way, 0.24 g of (RS)-{1-[bis-(4-chloro-phenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-ethanol is obtained in the form of a yellow meringue mass.

1H NMR (300 MHz, CDCl 3.8 in ppm): 1.98 (mt, 1H), 2.69 (mt, 1H), from 2.70 to 2.85

(mt, 1H), from 2.90 to 3.10 (mt, 2H), 3.18 (mt, 1H), 3.44 (mt, 1H), from 3.65 to 3.85 (mt, 2H ), 4.28 (s, 1H), from 6.60 to 6.80 (mt, 3H), from 7.20 to 7.35 (mt, 8H).

{1-[bis-(4-Uorphen<y>l)meth<y>l]azetidin-3-ylidene}(3,5-difluorophen<y>l)-acetic<y>re.et<y> ester can be prepared as follows: To a solution of 9.1 g of {1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-azetidin-3-yl}(3,5-difluorophenyl)-acetic acid. ethyl ester in 200 cm<3> of dichloromethane, 6.6 g of 4-dimethylaminopyridine and 2.1 cm3 of methylsulfonyl chloride are added. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction mixture is washed three times with 250 cm<3> of distilled water and then dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa and a temperature close to 40°C. The obtained residue is taken up in heat in 50 cm3 of isopropyl oxide and then left at room temperature for around 12 hours. The white suspension obtained is filtered on a glass frit and washed with 20 cm 3 of petroleum ether and then dried at 0.27 kPa and a temperature close to 40°C for 2 hours. In this way, 7.9 g of {1-bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)-acetic acid ethyl ester are obtained in the form of a cream-coloured powder.

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): 1.25 (t, J = 7 Hz, 3H), 3.85 (mt, 2H), 4.12 (AB, J

= 7.5 Hz, 2H), 4.23 (mt, 2H), 4.51 (s, 1H), from 6.65 to 6.80 (mt, 3H, from 7.20 to 7.40 (mt , 8H).

{1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-azetidin-3-yl}(3,5-diflu ester can be prepared as follows: To a solution of 7.73 cm<3> diisopropylamine in 125 cm<3> of anhydrous tetrahydrofuran, under an inert nitrogen atmosphere and at a temperature close to -70°C, 34.54 cm<3> of a 1.6M butyllithium solution in hexane is added dropwise over the course of 15 minutes. Stirring is maintained at this temperature for 45 minutes and a solution of 11.01 g of ethyl-3,5-difluorophenylacetate in 85 cm<3> of anhydrous tetrahydrofuran is then added over the course of 15 minutes, after which stirring is continued for 1 hour at -78°C and then 16.84 g of 1-[bis-(4-chlorophenyl)methyl]-azetidin-3-one in 90 cm<3> of anhydrous tetrahydrofuran are added, after which the stirring is once again continued for 1 hour at -70°C and then at 0°C under vigorous stirring, 300 cm<3> of saturated ammonium chloride solution are added over the course of 30 minutes, after which the reaction mixture is decanted after 12 hours, the organic phase is washed three times with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The obtained residue is chromatographed on a column with a diameter of 70 mm with 2000 cm<3> fine silica (0.040-0.063 mm) under a pressure of 0.7 bar with dichloromethane:ethyl acetate in the volume ratio 99:1 as eluent. The fractions containing nothing but the desired product are combined and concentrated to dryness at 2.7 kPa and 40°C for 2 hours. In this way, 9.1 g of {1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-azetidin-3-yl}(3,5-difluorophenyl)-acetic acid ethyl ester is obtained in the form of a solid cream.

<!>H-NMR (300 MHz, CDCl3, 8 in ppm): 1.25 (t, J = 7 Hz, 3H), 2.87 (d, J = 8 Hz, 1H),

3.07 (d, J = 8 Hz, 1H), 3.13 (d large, J = 8 Hz, 1H), 3.28 (d large, J = 8 Hz, 1H), 4.12 (s, -2H), 4.21 (mt, 2H), 4.36 (s, 1H), 6.78 (tt, J = 9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H).

Ethyl-3,5-difluorophenylacetate can be prepared in the following way: To a solution of 12 cm<3> of ethanol in 300 cm<3> of anhydrous dichloromethane, at a temperature close to 20°C, successively 20.4 cm<3> of triethylamine is added and then 27.6 g of 3,5-difluorophenylacetic acid chloride in solution in 60 cm<3> of dichloromethane. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction mixture is washed successively with 2 x 150 cm<3> deci-normal hydrochloric acid and then with 2 x 150 cm<3> saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulphate, filtered and concentrated to a dry state at 2.7 kPa and a temperature close to 40°C. 29 g of ethyl 3,5-difluoro-phenylacetate are obtained in this way in the form of a yellow oil.

3,5-difluorophenylacetic acid chloride can be prepared in the following way: To a solution of 25 g of 3,5-difluorophenylacetic acid in 350 cm<3> 1,2-dichloroethane is added at a temperature close to

20°C, successively 19.3 cm3 of oxalyl chloride and then a few drops of dimethylformamide, after which, after 3 hours of stirring at a temperature close to 20°C, 30 cm<3> of oxalyl chloride and then a few drops of dimethylformamide are again added. The reaction medium is concentrated to a dry state at 2.7 kPa and a temperature close to 40°C. In this way, 27.6 g of 3,5-difluorophenylacetic acid chloride is obtained in the form of a yellow oil.

Example 79

(RS)-1-[bis-(4-chlorophenyl)methyl]-3-[1-(3,5-difluorophenyl)-1-methylsulfonyl-ethyl]azetidine is obtained as follows: To a solution of 0.5 g (RS)-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)-methyl]azetidine in 10 cm3 of tetrahydrofuran, cooled to -78°C and kept under a inert atmosphere, place 0.5 cm<3> of a 2M lithium diisopropylamide solution. The temperature is allowed to rise to -20°C and then 0.06 cm3 of iodomethane is added. The temperature is allowed to rise to 0°C over the course of 2 hours, then 20 cm3 of saturated, aqueous ammonium chloride solution is added. The reaction medium is decanted and the aqueous phases are extracted with 2 x 20 cm3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and evaporated to dryness at 40°C under 2.7 kPa, which gives 550 mg of a cream-colored residue. The residue is chromatographed on a silica column (Dynamax, reference 83-121-C, size 21.4 mm x 250 mm, precolumn 21.4 mm x 50 mm, reference R00083121G, silica 8[i, porosity 60 Angstrom; Rainin Instrument Co. Inc ., Mac Road, Woburn, MA 01801, USA), being eluted with heptane:isopropanol in the volume ratio 99:1 at 15 cm 3 per minute (detection 254 nm, fractions of 10 cm<3>). The fractions containing the compound with Rf=32/77 (cyclohexane:ethyl acetate 70:30,254 nm, silica plates reference 1.05719, Merck KGaA, 64271 Darmstadt, Federal Republic of Germany) are combined and evaporated at 40°C under 2.7 kPa, giving 80 mg 1-[bis-(4-chlorophenyl)methyl]-3-[1-(3,5-difluorophenyl)-1-methylsulfonyl-ethyl]azetidine in the form of an amorphous white powder.

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.05 (s, 3H), 2.54 (s, 3H), 2.63 (t, J = 7.5 Hz,

1H), 3.17 (t large, J = 8 Hz, 1H), 3.32 (mt, 1H), 3.44 (t large, J = 8 Hz, 1H), 3.71 (mt, 1H) , 4.27 (s, 1H), 6.83 (tt, J = 9 and 2.5 Hz, 1H), 7.15 (mt, 2H), from 7.20 to 7.40 (mt, 8H) .

Example 80

(RS)-1 -[bis-(4-fluorophenyl)-methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl] azetidine can be prepared as follows: To a suspension of 0.191 cm<3> bis- (4-fluorophenyl)-chloromethane, 300 mg of (RS)-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine hydrochloride and 167 mg of potassium carbonate in 5 cm3 of acetonitrile are placed at a temperature close to 20°C for some

grain potassium iodide. After 48 hours at a temperature close to 20°C, the reaction medium is filtered on a glass frit and the solid is rinsed with acetonitrile, after which the filtrate is purified by preparative thin-layer chromatography on silica (3 preparative Merck Kieselgel 60F254 plates; 20 cm x 20 cm; thickness 1 mm), while it is eluted with methane-dichloromethane in a volume ratio of 1:99. After elution of the zone corresponding to the desired product with methane-dichloromethane in a volume ratio of 10:90, filtration over a glass frit and evaporation of the solvents under reduced pressure and at a temperature close to 40°C, 39 mg of (RS)-l-[bis-( 4-fluorophenyl)-methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl] azetidine in the form of a yellow meringue mass.

'H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.54 (t large, J = 7 Hz, 1H), 2.66 (s, 3H), 3.18 (mt,

2H), from 3.20 to 3.45 (mt, 1H), 3.63 (t large, J = 7 Hz, 1H), 4.27 (s, 1H), 4.28 (d, J = 11 Hz, 1H), 6.83 (tt, J = 9 and 2 Hz, 1H), from 6.90 to 7.05 (mt, 6H), from 7.25 to 7.40 (mt, 4H).

(RS)-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine hydrochloride can be prepared as follows: A suspension of 8.5 g of 1-benzhydryl-3-[(3,5-difluorophenyl)methylsulfonyl -methylene]-azetidine and 1.3 g palladium hydroxide (20% by weight palladium) in 600 cm<3> methanol, 20 cm<3> 1N hydrochloric acid and 4 cm<3> acetic acid, are stirred at a temperature close to 20°C under a hydrogen pressure of 1.5 bar until total absorption of a volume of 2.1 liters of hydrogen. The reaction medium is then filtered on a glass frit with soot. The filtrate is concentrated to dryness under reduced pressure, after which the residue obtained is taken up in ethanol. The white, crystallized product is filtered and dried. In this way, 5.4 g of (RS)-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine hydrochloride is obtained in the form of white crystals.

1-benzhydryl-3-[(3,5-difluorophenyl)-(methylsulfonyl)-methylene]-azetidine can be prepared as follows: A mixture of 18.8 g of 3-acetoxy-1-benzhydryl-3-[(3, 5-difluorophenyl)-(methylsulfonyl)-methyl]-azetidine and 3.9 g of lithium hydroxide monohydrate in 120 cm<3> of acetonitrile are brought to a temperature close to 70°C for 3 hours. After cooling to a temperature close to 2°C, 120 cm<3> of tert-butyl methyl ether, 80 cm<3> of distilled water and then slowly 5 cm<3> of acetic acid are added successively. After decantation, the organic phase is washed with 80 cm<3> of a saturated, aqueous sodium bicarbonate solution, 80 cm<3> of distilled water, 80 cm<3> of a saturated, aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduce pressure. The obtained residue is taken up with ethanol. After one night at a temperature close to 20°C, the obtained mixture is filtered on a glass frit, after which the white crystals obtained are rinsed with ethanol, diisopropyl oxide and dried under reduced pressure at a temperature close to 45°C. This is achieved in this way

14.6 g of 1-benzhydryl-3-[(3,5-difluorophenyl)-(methylsulfony) in the form of white crystals. 3-acetoxy-1-benzhydryl-3-[(3,5-difluorophenyl)-(methylsulfonyl)-methyl]-azetidine can be prepared as follows: To a suspension of 12.37 g of 3,5-difluorobenzyl-methyl-sulfone in 200 cm3 of tetrahydrofuran is added dropwise under an inert nitrogen atmosphere and at a temperature close to -30°C and within 25 minutes, approx. 47.1 cm<3>1.6N n-butyllithium solution in hexane. The cloudy, yellow solution is stirred at a temperature close to -30°C for 2 hours and then added dropwise to a solution of 11.87 g of 1-benzhydryl-azetidin-3-one in 75 cm 3 of dichloromethane. The reaction mixture is stirred for 4 hours at a temperature close to -30°C, after which 6.07 cm<3> of acetyl chloride is added, after which the whole is allowed to return to a temperature close to -10°C for around 30 minutes. 200 cm3 of water and 100 cm3 of dichloromethane are added. After vigorous stirring for 30 minutes and decanting, the organic phase is washed with 3 x 150 cm3 saturated aqueous sodium bicarbonate solution, 150 cm<3> saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The obtained residue is taken up in 50 cm<3> of boiling ethanol. The resulting white suspension is left overnight at a temperature close to 20°C, after which the solid obtained is poured onto a glass frit, rinsed with diisopropyl ether and dried under reduced pressure at a temperature close to 50°C. 19.5 g of 3-acetoxy-1-benzhydryl-3-[(3,5-difluorophenyl)-(methylsulfonyl)-methyl]-azetidine are obtained in this way in the form of white crystals. 1-benzhydryl-azetidin-3-one can be prepared according to the procedure described by A.R. Katritzky et al. in "J. Heterocycl. Chem.", 271 (1994).

3,5-difluorobenzyl-methyl-sulfone can be prepared in the following way: To a mixture of 66.69 cm3 of 3,5-difluorobenzyl bromide, 71.97 g of the sodium salt of methanesulfinic acid and 150 mg of sodium iodide in 625 cm3 of ethanol are refluxed under argon in 16 hours. After cooling to a temperature close to 20°C, the reaction medium is diluted with 3 liters of ethyl acetate, washed with 500 cm3 of water, 500 cm3 of saturated, aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated at 50 mbar and a temperature close to 40 °C. The obtained residue is taken up in 300 cm3 of ethyl ether, after which the solid is filtered on a glass frit, rinsed with 200 cm3 of ethyl ether and dried under reduced pressure at a temperature close to 20°C. This gives 86.9 g of 3,5-difluorobenzyl-methyl-sulfone in the form of a white powder.

Example 81

(RS)-{l-[(3-pyridyl)-(4-fluorophenyl)methyl]-3-[(3,5-mfluorophenyl)methylsu azetidine can be prepared as follows: A mixture of 47 mg of (3-pyridyl) -(4-chloro-phenyl)-bromomethane, 50 mg of (RS)-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine hydrochloride and 58 mg of potassium carbonate in 2 cm3 of acetonitrile are stirred for 2 hours at a temperature .near 20°C, 2 hours with solvent reflux, about 16 hours at a temperature near 20°C and then 1.5 hours at solvent reflux. A few grains of potassium iodide are then added and the reaction mixture is kept for around 2 hours under reflux of the solvent. After cooling to a temperature close to 20°C, the reaction medium is purified by preparative thin-layer chromatography on silica (2 preparative Merck Kieselgel 60F254 plants; 20 cm x 20 cm; thickness 0.5 mm), eluting with methane-dichloromethane in a volume ratio of 2.5: 97.5. After elution of the zone corresponding to the desired product methane/dichloromethane in the volume ratio 10:90, filtration on a glass frit and subsequent evaporation of the solvent under reduced pressure at a temperature close to 40°C, 11 mg of (RS)-{ l-[(3-pyridyl )-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]azetidine in the form of a colorless varnish.

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.59 (mt, 1H), 2.66 (s, 3H), 3.21 (mt, 2H), from 3.30 to 3.50 (mt, 1H), 3.67 (mt, 1H), 4.28 (d large, J = 11 Hz, 1H), 4.32 (s large, 1H), 6.84 (tt, J = 9 and 2 Hz, 1H), 6.95 (mt, 2H), 7.19 (dd large, J = 8 and 5 Hz, 1H), from 7.20 to 7.40 (mt, 4H), 7.64 ( d large, J = 8 Hz, 1H), 8.45 (mt, 1H), 8.59 (s very large, 1H).

(3-pyridyl)-(4-chlorophenyl)-bromomethane can be prepared as follows: A mixture of 150 mg of (3-pyridyl)-(4-chlorophenyl)-methanol in 0.356 cm<3> 33% hydrobromic acid in acetic acid and 0.101 cm3 of acetyl bromide are refluxed for 1 hour and then placed at a temperature close to 20°C for 2 hours, before concentration under reduced pressure and co-evaporation of a few cm3 of toluene. 234 mg of (3-pyridyl)-(4-chlorophenyl)-bromomethane is obtained in this way in the form of a gummy, beige solid.

(3-pyridyl)-(4-chlorophenyl)-methanol can be prepared in the following way: To a solution of 5.83 cm3 of 4-chlorophenylmagnesium bromide in IM solution in ethyl ether, in 5 cm3 of tetrahydrofuran, under an inert argon atmosphere and slowly, 0 .5 cm3 of 3-pyridinecarboxaldehyde. After approx. After 3 hours, 3 cm<3> of a saturated, aqueous ammonium chloride solution and 100 cm3 of water are added. After stirring for 5 minutes at a temperature close to 20°C, the reaction medium is acidified to a pH value of around 2 with an aqueous IN hydrochloric acid solution. The aqueous phase is extracted with 3 x 15 cm 3 of dichloromethane. The re-

remaining aqueous phase treated with 10 cm 3 of an aqueous 1N sodium hydroxide solution and extracted once more with 3x15 cm 3 ethyl acetate. The organic phases containing ethyl acetate are combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. 466 mg of (3-pyridyl)-(4-chlorophenyl)-methanol is obtained in this way in the form of a clear, yellow solid.

Example 82

(RS)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine can be prepared as follows: A mixture of 160 mg ( 4-pyridyl)-(4-chloro-phenyl)-bromomethane, 169 mg of (RS)-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine hydrochloride and 94 mg of potassium carbonate in 5 cm3 of acetonitrile, stirred in around 17 hours at a temperature close to 20°C. A few grains of sodium iodide are then added and, after stirring for 2 hours at a temperature close to 20°C, the reaction mixture is kept below the solvent's reflux temperature for around 16 hours. After cooling to a temperature close to 20°C, the reaction medium is purified by preparative thin-layer chromatography on silica (4 preparative Merck Kieselgel 60F254 plates, 20 cm x 20 cm, thickness 0.5 mm), eluting with methane-dichloromethane in a volume ratio of 2.5: 97.5. After elution of the zone corresponding to the desired products with methane-dichloromethane in the volume ratio 10:90, filtration over a glass frit and subsequent evaporation of the solvent under reduced pressure at a temperature close to 40°C, a first mixture of diastereoisomers is obtained, i.e. 24 mg ( RS)-{ 1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine in the form of a yellow varnish and a second mixture of diastereoisomers, namely 31 mg of (RS)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine in the form of a yellow meringue mass.

The first mixture of diastereoisomers has the following characteristics:

<!>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.62 (t, J = 7 Hz, 1H), 2.67 (s, 3H), 3.21 (t large, J

= 7 Hz, 2H), 3.42 (mt, 1H), 3.70 (t large, J = 7 Hz, 1H), 4.28 (s, 1H), 4.28 (d, J = 11 Hz , 1H), 6.85 (tt, J = 9 and 2.5 Hz, 1H), 6.97 (mt, 2H), from 7.20 to 7.35 (mt, 6H), 8.52 (dd , J = 4.5 and 1.5 Hz, 2H).

The second mixture of diastereoisomers has the following characteristics:

1H-NMR (300 MHz, CDCl3.8 in ppm): 2.59 (t, J = 7 Hz, 1H), 2.67 (s, 3H), 3.26 (mt,

2H), from 3.35 to 3.50 (mt, 1H), 3.63 (t large, J = 7 Hz, 1H), 4.28 (s, 1H), 4.28 (d, J = 11 Hz, 1H), 6.85 (tt, J = 9 and 2 Hz, 1H), 6.97 (mt, 2H), from 7.20 to 7.40 (mt, 6H), 8.50 (dd, J = 4.5 and 1.5 Hz, 2H).

(4-pyridyl)-(4-chlorophenyl)-bromomethane can be prepared in the following way: A solution of 100 mg of (4-pyridyl-(4-chlorophenyl)methanol in 0.24 cm3 of 33% hydrobromic acid in acetic acid is refluxed for 1 hour and then set aside at a temperature close to 20° C. 0.675 cm3 of acetyl bromide is then added and the reaction mixture is brought to reflux for 42 hours, after which it is allowed to return to a temperature close to 20° C, before being concentrated under reduced pressure 163 mg of (4-pyridyl)-(4-chloro-phenyl)-bromomethane is obtained in this way in the form of a beige-like meringue-gum mass.

(4-pyridyl-(4-chlorophenyl)methanol can be prepared in the following way: 348 mg of sodium tetrahydroboride is added to a solution of 2 g of 4-(4-chlorobenzoyl)-pyridine in 160 cm3 of ethanol at a temperature close to 20°C. After stirring for 2 hours at a temperature close to 20°C, 90 mg of tetrahydroboride is added. After about Wi hour at the same temperature, the reaction medium is diluted with 200 cm3 of dichloromethane and 200 cm3 of water. The pH value of the aqueous phase is adjusted to a value of around 5 at addition of 13 cm<3> IN aqueous hydrochloric acid solution. After decantation, the aqueous phase is extracted with 3 x 100 cm3 of dichloromethane. The organic phases are combined and dried over magnesium sulfate, filtered and concentrated under reduced pressure. In this way, 2 g are obtained (4-pyridyl-(4-chlorophenyl)methanol in the form of a white powder.

Example 83

(RS)-{1-[(2-chloro-pyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine can be prepared as follows: A mixture of 300 mg of (2-chloro-pyrid-5-yl)-(4-chlorophenyl)-bromomethane, 225 mg of (RS)-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine hydrochloride, 125 mg of potassium iodide and 521 mg of potassium carbonate in 5 cm3 of acetonitrile are heated for about 2 hours until the solvent refluxes. After cooling to a temperature close to 20°C, the reaction medium is filtered on a glass frit. The obtained residue is rinsed

with dichloromethane and the filtrates are evaporated under reduced pressure. In this way, 402 mg of chocolate-coloured meringue mass is obtained, which is purified by preparative thin-layer chromatography on silicon dioxide with 4 preparative Merck Kieselgel 60F254 plants, 20 cm x 20 cm, thickness 0.5 mm, eluting with methane-dichloromethane in a volume ratio of 2.5:97 ,5. After elution of the zone corresponding to the desired product with methane-dichloromethane in the volume ratio 10:90, filtration over a glass frit and after-

following evaporation of the solvent under reduced pressure at a temperature close to 40°C, a first mixture of diastereoisomers is obtained, namely 14 mg of (RS)-{l-[(2-chloro-pyrid-5-yl)-(4-chlorophenyl) methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine, in the form of a chestnut colored meringue mass, and a second mixture of diastereoisomers, namely 10 mg of (RS)-{ l-[(2-chloro- pyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine in the form of a beige colored meringue mass.

The first mixture of diastereoisomers has the following characteristics:

1H-NMR (300 MHz, CDCl3.6 in ppm): 2.57 (t, J = 7.5 Hz, 1H), 2.65 (s, 3H), from 3.15 to 3.30 (mt , 2H), 3.40 (mt, 1H), 3.63 (t large, J = 7.5 Hz, 1H), 4.27 (d, J = 11 Hz, 1H), 4.31 (s, 1H), 6.84 (tt, J = 9 and 2 Hz, 1H), 6.95 (mt, 2H), from 7.20 to 7.35 (mt, 5H), 7.63 (dd, J = 8 and 2.5 Hz, 1H), 8.38 (d, J = 2.5 Hz, 1H).

The second mixture of diastereoisomers has the following characteristics:

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.57 (t, J = 7.5 Hz, 1H)* 2.64 (s, 3H), 3.18 (t, large, J = 7.5 Hz, 2H), 3.38 (mt, 1H), 3.63 (t large, J = 7.5 Hz, 1H), 4.24 (d, J = 11.5 Hz , 1H), 4.29 (s, 1H), 6.83 (tt, J = 9 and 2 Hz, 1H), 6.94 (mt, 2H), 7.20 (d, J = 8 Hz, 1H ), from 7.20 to 7.35 (mt, 4H), 7.59 (dd, J = 8 and 2.5 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H). (2-chloro-pyrid-5-yl)-(4-chlorophenyl)-bromomethane can be prepared as follows: To a solution of 100 mg of (2-chloro-pyrid-5-yl)-(4-chlorophenyl)-methanol in 2 cm3 of carbon tetrachloride, under an inert argon atmosphere and at a temperature close to 0°C, 0.153 cm<3> of thionyl bromide is placed. After 3V2 hours at a temperature close to 0°C, the reaction mixture is concentrated under reduced pressure and coevaporated with a few cm3 of toluene. 1.3 g of brown liquid is obtained in this way, which is taken up in dichloromethane, water and sodium dithionite are added. After decantation, the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 0.33 g of (2-chloro-pyrid-5-yl)-(4-chlorophenyl)-bromomethane is thus obtained in the form of a brown oil. (2-Chloro-pyrid-5-yl)-(4-chlorophenyl)-methanol can be prepared by working in a manner similar to Example 84 from 22.5 cm<3> IM 4-chlorophenylmagnesium bromide solution in ethyl ether, in 30 cm3 of tetrahydrofuran, under argon, and 2.9 g of 2-chloro-pyridine-5-carboxaldehyde in 30 cm 3 of tetrahydrofuran. In this way, 3.42 g of (2-chloro-pyrid-5-yl)-(4-chloro-phenyl)-methanol is obtained in the form of a pale green powder. 2-Chloro-pyridine-5-carboxaldehyde can be prepared according to G. Pandey, T.D. Bagul, A.K. Sahoo in "J. Org. Chem.", 1998, 63,760-768. Example 84 (RS)-5-((4-Morphenyl)-{3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-1-yl}-methyl)-pyrimidine can be prepared in the following way: A mixture of 50 mg 5-[bromo-(4-chloro-phenyl)-methyl]-pyrimidine, 52.6 mg (RS)-3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidine hydrochloride, 44 mg potassium iodide and 73 mg of potassium carbonate in 2 cm<3> of acetonitrile are heated for about 5 hours until the solvent refluxes. After cooling to a temperature close to 20°C, the reaction medium is purified by direct deposition on preparative thin-layer chromatography on silica (2 preparative Merck Kieselgel 60F254 plates; 20 cm x 20 cm, thickness 0.5 mm), eluting with methane-dichloromethane in the volume ratio of 2 ,5:97,5. After elution of the zone corresponding to the desired product with methane-dichloromethane in the volume ratio 10:90, filtration on a glass frit and subsequent evaporation of the solvents under reduced pressure at a temperature close to 40°C, a first mixture of diastereoisomers is obtained, namely 8 mg of (RS)- 5-((4-Chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azeti(hn-1-yl}-methyl)-pyririniin in the form of a yellow meringue mass and a second mixture of diastereoisomers , namely 6 mg of RS)-5-((4-chloro-phenyl)-{3-[(3,5-difluorophenyl)methylsulfonyl-methyl]-azetidin-1-yl}-methyl)-pyrimidine in the form of a yellow meringue mass.

The first mixture of diastereoisomers has the following characteristics:

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.60 (t large, J = 7 Hz, 1H), 2.66 (s, 3H), 3.24 (t large, J = 7 Hz, 2H), 3.41 (mt, 1H), 3.66 (t large, J = 7 Hz, 1H), 4.28 (d, J = 11.5 Hz, 1H), 4.33 (s large, 1H), 6.84 (t large, J = 9 Hz, 1H), 6.95 (mt, 2H), from 7.25 to 7.35 (mt, 4H), 8, 71 (s large, 2H), 9.08 (s large, 1H).

The second mixture of diastereoisomers has the following characteristics:

'H-NMR (300 MHz, CDCl3.8 in ppm): 2.61 (t large, J = 7 Hz, 1H), 2.66 (s, 3H), 3.24 (t large, J = 7 Hz, 2H), 3.43 (mt, 1H), 3.65 (t large, J = 7 Hz, 1H), 4.28 (d, J = 11.5 Hz, 1H), 4.33 (s large, 1H), 6.85 (tt, J = 9 and 2 Hz, 1H), 6.96 (mt, 2H), from 7.25 to 7.35 (mt, 4H), 8 .69 (s, 2H), 9.06 (s, 1H). 5-|>rom-(4-chlorophenyl)-methyl]-pyrimidine can be prepared in the following way: To a solution of 205 mg of (4-chlorophenyl)-pyrimidin-5-yl-methanol in 1 cm3 of carbon tetrachloride and 1 cm3 dichloromethane is placed, under an inert argon atmosphere and at a temperature close to 0°C, 0.36 cm3 of thionyl bromide. After 21 hours at a temperature close to 0°C, the reaction mixture is brought to a temperature close to 20°C, concentrated under reduced pressure and coevaporated with a few cm 3 of toluene. The brown liquid obtained is taken up in 10 cm3 of dichloromethane, washed with 5 cm<3> of saturated, aqueous sodium dithionite solution and then with water. After decantation, the organic phase is dried over magnesium sulphate, filtered and concentrated to a dry state at 2.7 kPa. 227 mg of a viscous beige liquid is obtained in this way, which is taken up with a minimum of dichloromethane and purified by preparative thin-layer chromatography on silicon dioxide (2 preparative Merck Kieselgel 60F254 plates, 20 cm x 20 cm; thickness 0.5 mm), it is eluted with methane-dichloromethane in the volume ratio 2.5:97.5. After elution with the zone corresponding to the desired product with methane-dichloromethane in the volume ratio 10:90, filtration on a glass frit and subsequent evaporation of the solvents under reduced pressure at a temperature close to 40°C, 51 mg of 5-[bromo-(4-chlorophenyl) is obtained -methyl]-pyrimidine in the form of a yellow meringue mass.

(4-chlorophenyl)-pyrimidin-5-yl-methanol can be prepared by working in a manner similar to example 83: A solution of 636 mg of 5-bromopyrimidine in 10 cm3 of tetrahydrofuran is placed under an inert argon atmosphere and at a temperature close to -78 °C, dropwise, 2.5 cm<3>1.6M n-butyllithium solution in hexane. After 10 minutes at a temperature close to -78°C, a solution of 562 mg of 4-chlorobenzaldehyde in 1 cm3 of tetrahydrofuran is added dropwise. After stirring for 30 minutes at a temperature close to -78°C, the mixture is allowed to return slowly to a temperature close to 20°C and 15 cm<3> of saturated, aqueous ammonium chloride solution, 60 cm3 of ethyl acetate and 10 cm3 of water are successively added. The aqueous phase is extracted with 15 cm3 of ethyl acetate, after which the organic phases are combined, dried over magnesium sulphate, filtered on a glass frit and concentrated at 20 mbar and a temperature close to 44°C. Most of the orange colored oil obtained (1.09 g) is purified by chromatography on a column with a diameter of 30 mm and with 60 g of average silicon dioxide (0.063-0.200 mm) under atmospheric pressure, eluting with a gradient of methane and dichloromethane in the volume ratio 0:100 - > 7:93. The fractions containing nothing but the desired product are combined and concentrated to dryness under reduced pressure. 293 mg of (4-chlorophenyl)-pyrimidin-5-yl-methanol is obtained in this way in the form of a yellow oil.

Example 85

The phenolic ester of 4-({1-[bis-(4-fluorophenyl)methyl]azetidin-3-ylidene}-methylsulfonyl-methyl)-3,6-dihydro-2H-pyridine-1-carbothionic acid can be prepared as follows : To a solution of 0.23 g of phenolic ester of 4-({1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-azetidin-3-yl}-methylsulfonyl-methyl)-3,6-chhyd ^o-2H-pyridin-l-carbothionic acid is added to 5 cm<3 >dichloromethane of 0.140 g of 4-dimethylamino-pyridine and then 0.042 cm<3> of methanesulfonyl chloride. The reaction mixture is stirred for 20 hours at 20°C and then diluted with 10 cm<3> of water. After decantation, the organic phase is washed successively with 100 cm<3> of water and 100 cm<3> of a saturated, aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness at 40°C under 2.7 kPa. The oil obtained is triturated for 45 minutes in 50 cm<3> of diisopropyl ether. The solid formed is filtered and gives 120 mg of phenolic ester 4-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methylsulfonyl-methyl)-3,6-dihydro-2H-pyridine-1- carbothionic acid in the form of a beige solid which melts at 184°C.

1H NMR (400 MHz, CDCl 3 , 8 in ppm): 2.53 (mf, 2H), 2.95 (s, 3H), 3.90 (mf, 2H), 4.04

(t, J = 5.5 Hz, 1H), 4.24 (mt, 3H), 4.49 (mf, 2H), 4.60 (mt, 1H), 5.90 (mf, 1H), from 7.05 to 7.50 (mt, 13H).

4-({1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-azetidin-3-yl}-methylsulfonyl-methyl)-3,6-dihydro-2H-pyridine-1-carbothionic acid phenol ester is prepared on following method: To a mixture of 0.72 g of 4-methylsulfonylmethyl-3,6-dihydro-2H-pyridine-l-carbothionic acid phenol ester and 0.708 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-one in 15 cm<3> of dry tetrahydrofuran is cooled under an inert atmosphere to -78°C, after which 0.52 g of potassium tert-butylate is added. The reaction mixture is stirred at -78°C for 4 hours and then 0.354 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-one is added. After 2 hours at -78°C, everything is allowed to return to 20°C. The reaction mixture is diluted in 100 cm<3> of water and then the tetrahydrofuran is evaporated at 2.7 kPa and 40°C. The aqueous phase is extracted with 2 x 100 cm<3 >ethyl acetate. The organic extracts are combined and dried over magnesium sulfate and concentrated at 2.7 kPa and 40°C. The residue, obtained by chromatography on silica (200 g silica, Amicon, 20-45 [im porosity 60 Angstrom, column diameter 5 cm), eluting with cyclohexane:ethyl acetate in the volume ratio 6:4. The fractions with Rf=1 1/64 (cyclohexane:ethyl acetate 6:4, silica plate, Merck reference 1.05719, Merck KGaA, 64271 Darmstadt, Federal Republic of Germany) are combined and concentrated at 2.7 kPa and 40°C to give 240 mg of 4 -({1-[bis-(4-chloro-phenyl)methyl]-3-hydroxy-azeti(Un-3-yl}-methylsulfonyl-methyl)-3,6-dihydro-2H-pyridine-1-carbothionic acid- phenol ester.

The phenol ester of 4-methylsulfonylmethyl-3,6-dihydro-2H-pyridine-1-carbothionic acid can be prepared as follows: To a solution of 1 g of 1-benzyl-4-methylsulfonylmethyl-1,2,3,6-tetrahydro-pyridine in 10 cm<3> of dichloromethane, 0.778 cm<3> of phenyl-thiochloroformate is placed under argon. The solution immediately becomes very distinctly amber colored. The reaction mixture is stirred for 4 hours at 21°C and then diluted in 100 cm<3> of dichloromethane. The organic medium is washed with 2 x 50 cm3 of water, dried over magnesium sulphate and evaporated to dryness at 40°C under 2.7 kPa. The residue obtained is purified by chromatography on a silica column (reference SIL-020-005, FlashPack, Jones Chromatography Limited, New Road, Hengoed, Mid Glamorgan, CF82 8AU, United Kingdom), eluting with cyclohexane:ethyl acetate in the volume ratio of 6: 4 at a rate of 10 cm<3>/min. and fractions of 5 cm<3> are recovered. The fractions with Rf=12/74 (cyclohexane:ethyl acetate 1:1, silica plate, Merck reference 1.05719, Merck KGaA, 64271 Darmstadt, Federal Republic of Germany) are combined and concentrated at 2.7 kPa and 40°C, yielding 700 mg of 4-methylsulfonylmethyl -3,6-dihydro-2H-pyridine-1-carbothionic acid phenolic ester. 1-benzyl-4-methylsulfonylmethyl-1,2,3,6-tetrahydro-pyridine can be prepared as follows: To a solution of 17.6 g of 1-benzyl-4-methylsulfonylmethyl-pyridinium bromide in 700 cm3 of water, cooled to 5 °C, a solution of 5.14 g of sodium borohydride and 25 g of sodium carbonate in 700 cm3 of water is added dropwise over the course of 1 hour, while not exceeding a temperature of 5°C in the reaction medium. The reaction mixture is stirred for 4 hours at 0°C, after which it is allowed to return to ambient temperature overnight. The yellow solid formed is isolated by filtration and dried under 2.7 kPa, which gives 9.6 g of 1-benzyl-4-methylsulfonylmethyl-1,2,3,6-tetrahydro-pyridine with an Rf equal to 44/81 ( dichloromethane:methanol in the volume ratio 95:5, silicon dioxide plate, Merck reference 1.05719, Merck KGaA, 62471 Darmstadt, Federal Republic of Germany). 1-Benzyl-4-methylsulfonylmethyl-pyridinium bromide can be prepared in the following way: To a solution of 10 g of 4-methylsulfonylmethylpyridine in 200 cm3 of acetonitrile is added 14 cm<3 >benzyl bromide, after which it is heated to reflux for 3 hours and then the whole is allowed to invert back to ambient temperature overnight. The solid formed is filtered, dried at 2.7 kPa and 17.6 g of 1-benzyl-4-methylsulfonylmethyl-pyridinium bromide is obtained.

4-Methylsulfonylmethylpyridine can be prepared in the following way: To a solution of 57.4 g of 4-chloromethylpyridine hydrochloride, 700 cm3 of ethanol, slowly add 14 g of sodium hydroxide pastilles and then 35.7 g of sodium methanesulfinate. After the addition, the tempe-

raw temperature 28°C. The reaction mixture is heated to reflux for 2 hours and then allowed to return to ambient temperature overnight. The reaction medium is brought to 50°C and filtered hot on paper. The filtrate is evaporated to dryness at 40°C and 2.7 kPa. The residue is recrystallized from 300 cm<3> of isopropanol, which gives 29.6 g of 4-methylsulfonylmethylpyridine.

Example 86

(RS)-1-[2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-[(3,5-difluorophenyl)-ethyl]-3-propyl-urea can be prepared by working in the following manner: To a solution of 90 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-(sulfurophenyl)- ethylamine in 5 cm<3>tetrahydrofuran is added 0.052 cm<3> n-propyl isocyanate. After about 72 hours of stirring at a temperature near 20°C, the reaction mixture is filtered and concentrated to dryness under reduced pressure, and then taken up with diisopropyl ether. the resulting reaction mixture is filtered and concentrated to a dry state under reduced pressure. In this way, 80g of a pale yellow solid is obtained which is dissolved in 5 cm<3> of tetrahydrofuran and to which 80 mg of trapping resin is added. After around 18 hours of stirring at a temperature near 20° C., the reaction mixture is filtered and concentrated to dryness under reduced pressure, thus obtaining 36 mg of a pasty solid which is purified by chromatography under pressure on a silica column, as it is eluted with cyclohexane:ethyl acetate in the volume ratio 50:50. Fractions 16 to 20 are combined and concentrated to dryness under reduced pressure. 6 mg of (RS)-1-[2-{1-[bis-(4-chlorophenyl)ethyl]-zetidin-3-yl}-2-[(3,5-difluorophenyl)-ethyl]-3- propyl urea in the form of an oil.

<!>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 0.88 (t, J = 7.5 Hz, 3H), from 1.35 to 1.60 (mt,

2H), from 2.25 to 2.55 and from 2.65 to 3.05 (2 series of mts, 6H together), 3.04 (mt, 2H), 3.22 (mt, 1H), 3 .38 (mt, 1H), 4.07 (mt, 1H), from 4.10 to 4.20 (mt, 1H), 4.17 (s, 1H), 6.62 (tt, J = 9 and 2.5 Hz, 1H), 6.82 (mt, 2H), from 7.20 to 7.45 (mt, 8H).

(RS)-2-{1-1>is-(4-chlorophenyl)methyl]azetimn-3-yl}-2-(3,5-mfluorophenyl)-ethylamine can be prepared by working as follows: To an autoclave, cooled with 1.2 g of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)methanesulfonic acid ethyl ester are introduced into an acetone-CC>2 ice bath in solution in 10 cm<3> methanol and then a solution of 30 cm<3> ammonia in 30 cm<3> methanol. The closed autoclave is stirred and brought to a temperature close to 60°C for 24 hours. After cooling to a temperature close to 20°C, the remaining solution is concentrated to dryness under reduced pressure. In this way, a rubber is obtained which is triturated with ethyl ether at a temperature close to 20°C for around 16 hours. The insoluble material is filtered, dried in a desiccator for 3 hours. 830 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-ethylamine is obtained in this way in the form of a whitish solid .

(RS)-2-{l-| To a solution of 1.9 g of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-[(3,5-difluorophenyl)-ethanol in 20 cm< 3 >dichloromethane, it is placed at a temperature close to 20°C, 0.34 cm<3> methanesulfonyl chloride. After cooling the reaction mixture to a temperature close to 10°C, 0.89 cm 3 of triethylamine is added. After stirring the solution for 20 hours at a temperature close to 20°C, 100 cm 3 of water and then 150 cm 3 of dichloromethane are added dropwise. The organic phase is decanted and separated and then washed with 2 x 50 cm3 of water, 50 cm3 of a saturated aqueous sodium chloride solution, 50 cm3 of water and then dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The yellow meringue mass that is obtained (2 g) is purified on a silicon dioxide column with a granulometry of 0.020-0.045 mm, under a pressure of 0.4 bar and eluted with cyclohexane:ethyl acetate in the volume ratio 80:20. Fractions 49 to 111 are combined and concentrated to dryness under reduced pressure. 1.2 g of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)methanesulfonic acid ethyl ester is obtained in the form of a white meringue mass.

Example 87

(RS)-N-[2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-ethyl]-cyclopropanecarboxamide can be prepared by working in the following manner: To a solution of 90 mg of (RS)-[2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-ethylamine in 5 cm<3> tetrahydrofuran, at a temperature close to 20°C, 0.018 cm<3> of diisopropylcarbodiimide, 10 mg of cyclopropanecarboxylic acid, 16 mg of hydroxybenzotriazole hydrate and then 0.4 g of morpholine supported on polystyrene are added successively. The obtained suspension is stirred at a temperature close to 20°C for 20 hours. The reaction medium is filtered and concentrated to dryness under reduced pressure. 80 mg of paste-like product is thus obtained, which is purified by transfer to an SPE column (SCX phase, 1 g phase). In this way, 76 mg of residue is obtained, which is purified by chromatography under pressure on a silicon dioxide column and is eluted with cyclohexane:ethyl acetate in the volume ratio 70:30. Fractions 9 to 19 are combined and concentrated to dryness under reduced pressure. 12 mg of (RS)-N-[2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-ethyl]-cyclopropanecarboxamide is obtained in the form of a colorless oil.

1H-NMR (300 MHz, CDCl3.8 in ppm): 0.70 (mt, 1H), from 0.80 to 1.00 (mt, 2H), from 1.15

to 1.35 (mt, 1H), from 2.35 to 2.55 and from 2.70 to 3.10 (2 series of mts, 7H

combined), 3.26 (mt, 1H), 3.47 (mt, 1H), 4.19 (s, 1H), 5.63 (mt, 1H),

6.62 (tt, J = 9 and 2.5 Hz, 1H), 6.81 (mt, 2H), from 7.20 to 7.45 (mt, 8H).

Example 88

(RS)-N-[2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-ethyl]-3-methyl-butyramide can be prepared by to work in the following way: To a solution of 45 mg of (RS)-2-{l-| 114 mg of HATU, 30.6 mg of isovaleric acid and then 0.2 g of morpholine supported on polystyrene are placed in 5 cm<3 >tetrahydrofuran at a temperature close to 20°C. The resulting suspension is stirred at a temperature close to 20°C for 20 hours. The reaction medium is filtered and concen-

is spun to a dry state under reduced pressure. In this way, 46 mg of an orange-coloured oil is obtained, which is purified by chromatography under pressure on a column with 5 g of silicon dioxide, eluting with cyclohexane:ethyl acetate in a volume ratio of 70:30. The fractions containing nothing but the desired product are combined and concentrated to dryness under reduced pressure. 6 mg of (RS)-N-[2-{1-[bis-(4-chlorophenyl)-methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-ethyl]-3-methyl are obtained -butyramide in the form of a colorless oil.

<!>H-NMR (400 MHz, CDCl 3 , 8 in ppm): 0.88 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H),

from 1.85 to 2.10 (mt, 3H), from 2.30 to 2.55 and from 2.70 to 3.10 (2 series of mts, 6H together), 3.37 (tm, 2H) , 4.19 (s, 1H), 5.45 (mt, 1H), 6.65 (tt,

J = 9 and 2.5 Hz, 1H); 6.82 (mt, 2H), from 7.20 to 7.45 (mt, 8H).

Example 89

(RS)-N-[2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-ethyl]-isobutyramide can be prepared by working in a manner similar to the previous example 3: From 45 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-ethyl] -amine, 5 cm3 of tetrahydrofuran, 114 mg of HATU, 26 mg of isobutyric acid and 0.2 g of morpholine supported on polystyrene, 10 mg of (RS)-N-[2-{l-[bis-(4-chlorophenyl)methyl]azetidine is obtained -3-yl}-2-(3,5-difluorophenyl)-ethyl]-isobutyramide in the form of an opaque oil.

<J>H-NMR (400 MHz, (CD3)2SO d6, 8 in ppm): 0.87 (d, J = 7 Hz, 3H), 0.93 (d, J = 7 Hz,

3H), from 2.15 to 2.85 (mt, 7H), from 3.00 to 3.25 (mt, 2H), 4.40 (s, 1H), from 7.00 to 7.20 (mt , 3H), 7.38 (mt, 4H), 7.52 (mt, 4H), 7.77 (mt, 1H).

Example 90

{l-[bis-(4-Urophenyl)methyl]azeu^n-3-yl}(3,4-difluorophenyl)-methane^ can be prepared by working in the following manner: To a solution of 128 mg of l-[ bis-(4-chlorophenyl)-methyl]azetidine-3-carboxylic acid.N-methoxy-N-methylamide in 3 cm3 tetrahydrofuran, cooled in an acetone/dry ice bath, add 3 cm3 solution of 0.5N 3,4-difluoro-phenyl- magnesium bromide in tetrahydrofuran. After stirring for 20 hours at a temperature close to 0°C, 10 cm3 of water is added, after which the reaction medium is stirred for 1 hour at a temperature close to 20°C. The decanted, aqueous phase is extracted with 20 cm 3 of ethyl acetate. The organic phases are combined and washed with 2x15 cm<3> of water, dried over magnesium sulfate and

concentrated to dryness under reduced pressure. In this way, 123 mg of a residue is obtained which is purified by chromatography under pressure on a column with 20 g of silicon dioxide, eluting with dichloromethane (stabilized on amyl). 47 mg of {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,4-difluorophenyl)-methanone is obtained in this way in the form of a white powder.

1H NMR (300 MHz, CDCl 3 , 5 in ppm): 3.34 (t, J = 7.5 Hz, 2H), 3.56 (t, J = 8 Hz, 2H),

4.05 (mt, 1H), 4.35 (s, 1H), from 7.15 to 7.40 (mt, 9H), 7.58 (dmt, J = 9 Hz, 1H), 7.70 ( ddd, J = 9/7.5 and 2.5 Hz, 1H). l-[bis-(4-chlorophenyl)methyl]azetidine-3-carboxylic acid.N-methoxy-N-methylamide can be prepared by working as follows: To a suspension of 2.03 g of N,0-dimethylhydroxylamine hydrochloride in 40 cm3 of dichloromethane, cooled to a temperature close to 0°C in an ice bath, add 2.65 cm<3>1-methylpiperidine. The obtained yellow solution, solution A, is preserved at a temperature close to 0°C. To a suspension of 7 g of 1-[bis-(4-chlorophenyl)methyl]-azetidine-3-carboxylic acid in 300 cc of dichloromethane and 40 cc of tetrahydrofuran, cooled to a temperature near -8°C in an ice/isopropanol bath , successively add 2.65 cm<3>1-methylpiperidine and then 1.6 cm3 of methyl chloroformate. After about 5 minutes of stirring at a temperature close to -8°C, the previously prepared solution A is added dropwise. After 10 minutes of stirring at a temperature close to -8°C, the cooling bath is removed and the reaction mixture is stirred at a temperature close to 20°C for about 20 hours and then washed with 3 x 150 cm<3> of water and concentrated to dryness under reduced pressure. In this way, 8.19 g of a residue is obtained which is purified under pressure on 500 g of Amicon silicon dioxide (particle diameter 20-45 ?m), eluting with ethyl acetate:dichloromethane in the volume ratio 8:92. In this way, 6.6 g of 1-[bis-(4-chlorophenyl)methyl]azetidine-3-carboxylic acid, N-methoxy-N-methylamide are obtained in the form of a pale yellow oil. 1-[bis-(4-chlorophenyl)methyl]azetidine-3-carboxylic acid can be prepared in a manner similar to that described by A.G. Anderson and R. Lok in "J. Org. Chem.", 37, 3953-3955

(1972) from l-benzhydrylazetidin-3-ol, using l-[bis-(4-chlorophenyl)methyl]azetidin-3-ol as starting material.

Example 91

{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methanone can be prepared by working as for {l-[bis-(4-chlorophenyl)methyl]azetidine -3-yl}(3,4-difluorophenyl)-methanone from 1.1 g of 1-[bis-(4-chlorophenyl)methyl]azetidine-3-carboxylic acid.N-methoxy-N-methylamide, 1.5 cm <3> l-bromo-3,5-difluorobenzene and 316 mg of magnesium shavings. 880 mg of {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methanone is obtained in this way in the form of a pale yellow, viscous oil.

1H-NMR (300 MHz, CDCl3.8 in ppm): 3.34 (t, J = 7.5 Hz, 2H), 3.55 (t, J = 8 Hz, 2H),

4.03 (mt, 1H), 4.44 (s, 1H), 7.01 (tt, J = 9 and 2.5 Hz, 1H), from 7.20 to 7.40 (mt, 10H).

Example 92

{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-cyclohexyl-methanone can be prepared by working as for {l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}- (3,4-difluorophenyl)-methanone from 284 mg of 1-[bis-(4-chlorophenyl)methyl]azetidine-3-carboxylic acid.N-methoxy-N-methylamide and 1.68 cm<3> 2N cyclohexylmagnesium chloride in THF. 116 mg of {1-bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methanone is obtained in this way in the form of a yellow, viscous oil.

'H-NMR (400 MHz, CDCl3.8 in ppm): from 1.10 to 1.35 and from 1.55 to 1.85 (2 series of mt, 10H combined), 2.30 (mt, 1H ), 3.14 (t, J = 8 Hz, 2H), 3.36 (t, J = 8 Hz, 2H), 3.56 (mt, 1H), 4.31 (s, 1H), from 7 .20 to 7.35 (mt, 8H).

Example 93

{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-phenyl-methanone can be prepared by working as for {l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}- (3,4-difluorophenyl)-methanone from 258 mg of 1-| . 208 mg of {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-phenyl-methanone is obtained in this way in the form of a yellow, viscous oil.

<!>H-NMR (300 MHz, CDC13.8 in ppm): 3.35 (t, J = 8 Hz, 2H), 3.57 (t, J = 8 Hz, 2H),

4.13 (mt, 1H), 4.35 (s, 1H), 7.25 (dmt, J = 8 Hz, 4H), 7.34 (dmt, J = 8 Hz, 4H), 7.45 ( t large, J = 8 Hz, 2H), 7.56 (tt, J = 8 and 1.5 Hz, 1H), 7.84 (dmt, J = 8 Hz, 2H).

Example 94

(RS)-1-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-ethanol can be prepared by working as follows: To a solution of 100 mg of {1-[bis-(4-chloro-phenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methanone in 4 cm3 of tetrahydrofuran, cooled to a temperature below -40°C, is placed 0.167 cm3 of a 3N methylmagnesium bromide solution. After stirring for 20 hours at a temperature close to 0°C, 5 cm3 of water is added, after which the aqueous phase is decanted and extracted with 5 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure. In this way, 91 mg of a residue is obtained which is purified by chromatography under pressure on a column with 10 g of silicon dioxide, eluting with ethyl acetate:cyclohexane in a volume ratio of 1:9. 74 mg of (RS)-1-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-ethanol is thus obtained in the form of a colorless oil.

<!>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 1.46 (s, 3H), 2.71 (mt, 1H), 2.82 (mt, 1H), 2.98

(t, J = 7.5 Hz, 1H, 3.24 (t, J = 7.5 Hz, 1H), 3.34 (mt, 1H), 4.31 (s, 1H), 4.33 ( mf, 1H), 6.67 (tt, J = 9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.25 to 7.35 (mt, 8H).

Example 95

O-allyl oxime of {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methanone can be prepared by working as follows: A solution of 100 mg { 1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methanone and 101 mg of O-allyl-hydroxylamine hydrochloride in 5 cm3 of pyridine are stirred at a temperature close to 20°C for 20 hours. 5 cm<3> of water is added and the reaction mixture is extracted with 2x5 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure. In this way, 111 mg of a yellow oil is obtained, which is purified by chromatography under pressure on a column with 20 g of silicon dioxide (particle diameter 0.04 to 0.063 mm), eluting with ethyl acetate:cyclohexane in a volume ratio of 2:98. 68 mg of {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methanone-0-allyloxime is obtained in this way in the form of a colorless viscous oil.

<!>H-NMR (300 MHz, CDCl 3.8 in ppm). A mixture of the two isomers Z is observed

and E in approximate proportions of 65:35 or vice versa; 2.84 and 3.11 (21 large, respectively J = 8 Hz and J = 7.5 Hz, 2H together), 3.44 and 3.66 (21 large, respectively J = 7.5 Hz and J = 8 Hz, 2H in total); 3.58 and 3.81 (2 mts, 1H together), 4.16 and 4.30 (2s, 1H together), 4.59 (mt, 2H), 5.22

(dmt, J = 11 Hz, 1H), 5.27 (dmt, J = 18 Hz, 1H), 5.96 (mt, 1H), 6.80 (tt, J

= 9 and 2.5 Hz, 1H), 6.91 (mt, 2H), from 7.20 to 7.35 (mt, 8H).

Example 96

{1-[bis-(4-ldorphenyl)methyl]azetdin-3-yl}(3,5-difluorophenyl)-methanone-O-ethyl oxime can be prepared by proceeding as described for the preparation of the O-allyl oxime of {l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methanone: From 100 mg of {l-[bis-(4-chlorophenyl)methyl]azetidin-3 -yl}(3,5-difluorophenyl)-methanone and 90 mg of O-ethyl-hydroxyl-amine hydrochloride, 83 mg of {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl} are obtained in this way -(3,5-difluorophenyl)-methanone-0-ethyl-oxime in the form of a colorless, viscous oil.

1 H-NMR (300 MHz, CDCl3.8 in ppm). A mixture of the two isomers Z is observed

and E in approximate proportions of 65:35 or vice versa; 1.25 and 1.27 (21, J = 7 Hz, 3H together), 2.82 and 3.12 (21 large, respectively J = 8 Hz and J =

7.5 Hz, 2H total), 3.45 and 3.66 (21 large, respectively J = 7.5 Hz and J = 8 Hz, 2H total); 3.58 and 3.78 (2 mts, 1H together), from 4.05 to 4.20 (mt, 2H), 4.16 and 4.30 (2 s, 1H together), 6.80 ( tt, J = 9 and 2.5 Hz, 1H), 6.91 (mt, 2H), from 7.20 to 7.35 (mt, 8H).

Example 97

(RS)-1-[ {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)-methyl]-3-methylurea can be prepared as follows: To a solution of 300 mg of {1-[bis-(4-chlorophenyl)-methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 15 cm<3> of anhydrous toluene is placed successively, under an inert hydrogen atmosphere and at a temperature near 20°C, 0.336 cm<3> of triethylamine and 0.384 cm<3> of diphenylphosphonazide. The obtained solution is stirred at a temperature close to 60°C for around 90 minutes. 2.6 cm<3> of a 2M methylamine solution in tetrahydrofuran is added and stirring is continued at a temperature close to 20°C for around 12 hours, after which the reaction mixture is concentrated to dryness at

2.7 kPa and a temperature close to 40°C. The residue is taken up in 1 cm<3> methanol and deposited on a Bond-Elut SCX Varian 5 g column with the reference 1225-6027, conditioned against methanol. The column is washed with methanol and eluted with 2N ammoniacal methanol. The ammoniacal fractions are combined and concentrated to dryness at 2.7 kPa and a temperature

close to 40°C. In this way, 250 mg of a clear oil is obtained, which is taken up in 1 cm<3> of dichloromethane and then deposited on a column with a diameter of 16 mm, filled with 5 g of silicon dioxide with a granulometry of 0.015-0.035 mm, conditioned and eluted with dichloromethane between 0 and 40 cm<3> and then eluted with dichloromethane:ethyl acetate in the volume ratio 80:20 using a pump system. The fractions between 50 and 80 cm<3> are combined and concentrated to a dry state at 2.7 kPa and 40°C. In this way, 140 mg of (RS)-1-[{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methyl]-3-methylurea is obtained in the form of a meringue mass.

1H-NMR (400 MHz, CDCl3.8 in ppm): 2.66 (mt, 1H), 2.82 (d, J = 5 Hz, 3H), 2.95 (mt,

1H), 3.03 (mt, 1H), 3.18 (mt, 2H), 4.24 (mt, 1H), 4.30 (s, 1H, 4.92 (t, J = 7 Hz, 1H ), 5.36 (d large, J = 7 Hz, 1H), 6.67 (tt, J = 9 and 2.5 Hz, 1H), 6.80 (mt, 2H), from 7.20 to 7 .30 (mt, 8H).

Preparation of {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-acetic acid hydrochloride is described in WO 99/67228, Example 77".

Example 98

(RS)-1-[{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methyl]-3-iso-propylurea can be prepared as follows: To a solution of 17 (il of isopropylamine in 1 cm<3> of anhydrous toluene is placed under an inert nitrogen atmosphere and at a temperature close to 20°C, 3 cm<3>, i.e. 0.1 mM of a freshly prepared solution of (RS )-1-[bis-(4-chloro-phenyl)methyl]-3-[(3,5-difluorophenyl)isocyanato-methyl]-azetidine The obtained solution is stirred at a temperature close to 20°C for about 12 hours. The reaction medium is concentrated at 2.7 kPa and a temperature close to 40° C. The solid residue is taken up in 1 cm<3> methanol and then deposited on a Bond-Elut SCX Varian 500 mg column with reference 1210-2040, conditioned against methanol . The column is washed with methanol and eluted with 2N ammoniacal methanol. The ammoniacal fractions are combined and concentrated to dryness at 2.7 kPa and a temperature close to 40° C. The solid residue thus obtained is taken up in 1 cm of dichloromethane and then deposited on a IST FlashPack column with reference SIL 016-0 02, filled with 2 g of silica (0.065-0.090 mm), conditioned against dichloromethane and eluted with dichloromethane:ethyl acetate in the volume ratio 90:10 using a pump system. The fractions between 20 and 38 cm<3> are combined and concentrated to a dry state at 2.7 kPa and 40°C. In this way, 14 mg of (RS)-1-[{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methyl]-3-isopropylurea is obtained in the form of a white meringue mass.

*H-NMR (400 MHz, CDCl3, 8 in ppm): 1.14 (d, J = 6.5 Hz, 3H), 1.15 (d, J = 6.5 Hz, 3H), 2.66 (mt, 1H), 2.92 (dd large, J = 8 and 5.5 Hz, 1H), 3.01 (dd large, J = 8 and 5.5 Hz, 1H), 3.16 (t, J = 8 Hz, 1H), 3.20 (t, J = 8 Hz, 1H), 3.85 (mt, 1H, 4.06 (d, J = 8 Hz, 1H), 4.29 (s, 1H), 4 .91 (t, J = 7 Hz, 1H), 5.17 (d, J = 6.5 Hz, 1H), 6.66 (tt, J = 9 and 2 Hz, 1H), 6.78 (mt , 2H), from 7.20 to 7.35 (mt, 8H).

(RS)-l-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)isocyanato-methyl]-azetidine can be prepared as follows: To a solution of 150 mg {l-[bis- (4-chlorophenyl)methyl]-azetidin-3-yl}(3,5-difluorophenyl)-acetic acid.hydrochloride in 9 cm<3> of anhydrous toluene is placed under an inert nitrogen atmosphere and at a temperature close to 20°C, 0.126 cm<3> triethylamine and 0.195 cm<3> diphenylphosphonazide. The obtained solution is stirred at a temperature close to 50°C for around 1 hour. The whole is allowed to cool and in this way (RS)-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)isocyanato-methyl]-azetidine is obtained in solution in toluene, which is used later in this form.

Example 99

(RS)-1-[ {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)-methyl]-3-iso-butylurea can be prepared as follows: To a solution of 20 ul of isobutylamine in 1 cm<3> of anhydrous toluene is placed under an inert nitrogen atmosphere and at a temperature close to 20°C, 3 cm<3>, i.e. 0.1 mM of a solution of freshly prepared (RS)-l -[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)isocyanatomethyl]-azetidine. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is then concentrated to a dry state at 2.7 kPa and a temperature close to 40°C. The solid residue is taken up in 1 cm<3 >methanol and then deposited on a Bond-Elut SCX Varian column with 500 mg and reference 1210-2040, conditioned to the methanol. The column is washed with methanol and then eluted with 2N ammoniacal methanol. The ammoniacal fractions are combined and concentrated to dryness at 2.7 kPa and a temperature close to 40°C. The residue thus obtained is taken up in 1 cm<3> of dichloromethane and deposited on an IST FlashPack column with reference SIL 016-002, filled with 2 g of silicon dioxide (0.065-0.090 mm), conditioned in dichloromethane and eluted with dichloromethane:ethyl acetate in the volume ratio 90:10 using a pump system. The fractions between 0 and 15 cm<3> are combined and concentrated to a dry state at 2.7 kPa and 40°C. In this way, 14 mg of (RS)-1-[{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methyl]-3-isobutylurea is obtained in the form of a white meringue mass.

<!>H-NMR (400 MHz, CDC13.5 in ppm): 0.89 (d, J = 6.5 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H),

1.74 (mt, 1H), 2.66 (mt, 1H), from 2.90 to 3.25 (mt, 6H), 4.29 (s and mt, 2H

together), 4.90 (t, J = 7 Hz, 1H), 5.34 (d large, J = 6.5 Hz, 1H), 6.66 (tt,

J = 9 and 2 Hz, 1H), 6.80 (mt, 2H), from 7.20 to 7.35 (mt, 8H).

Example 100

N-methyl-N-phenyl-1-[^is-(4-chlorophenyl)methyl]azetidine-3-carboxamide can be prepared on

the following way: To a solution of 100 mg of l-[bis-(4-chlorophenyl)methyl]azetidine-3-

carboxylic acid in 2 cm3 of anhydrous dichloromethane, 0.039 cm3 of N-methylaniline, 87 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiirinide hydrochloride, 0.063 cm3 of triethylamine and then 4 mg of hydroxybenzotriazole hydrate are added successively, at a temperature close to 20°C. . The up-

solution reached is stirred at a temperature close to 20°C for 12 hours. The reaction medium is deposited on an IST FlashPack column with reference SIL 016-005, filled with 5 g of silicon

dioxide (0.065-0.090 mm), conditioned to dichloromethane and eluted with dichloromethane:ethyl acetate in a gradient where the percentage of ethyl acetate goes from 0 to 5 volumes, using a pump system, recovering fractions of 1.5 cm<3.> The fractions 3 to 15 are combined and concentrated to dryness at 2.7 kPa and 50°C. In this way, 954 mg of 1-[2-is-(4-chlorophenyl)methyl]azetidine-N-methyl-N-phenyl-3-carboxarnide is obtained in the form of a cream-colored meringue mass.

<J>H-NMR (400 MHz, CDCl 3 , 8 in ppm): 3.08 (mt, 2H), 3.21 (mt, 3H), 3.27 (s, 3H), 4.35

(s, 1H), 7.06 (d, J = 7.5 Hz, 2H), from 7.15 to 7.45 (mt, 11H).

Example 101

l-[bis-(4-chlorophenyl)methyl]azetidine-N-benzyl-N-methyl-3-carboxamide can be prepared on

following way: To a suspension of 150 mg of l-[bis-(4-chlorophenyl)methyl]azetidine-3-

carboxylic acid, activated on 165 µM TFP in 2 cm<3> dichloromethane, is added 0.0213 cm<3 >N-benzylmethylamine. The suspension is stirred at a temperature close to 20°C for 22 hours and

then filtered over a frit. The solid residue is washed again with 2x1 cm<3> of dichloromethane.

The filtrates are combined and concentrated to dryness at 2.7 kPa and a temperature close to

40°C. 38 mg of 1-[bis-(4-chlorophenyl)methyl]azetidine-N-benzyl-N-methyl-3-carboxamide is obtained in this way in the form of a colorless gum.

1H-NMR (300 MHz, CDCl3.8 in ppm): 2.78 (s, 3H), from 3.25 to 3.55 (mt, 5H), 4.38 (mt,

2H), 4.57 (s, 1H), from 7.15 to 7.40 (mt, 13H).

1-|^is-(4-chlorophenyl)methyl]a2ethidine-3-carboxylic acid, activated on TFP resin, can be prepared as follows: To a suspension of 2.7 g of TFP resin (free phenol function, 1, 1 mmol/g, corresponding to 2.975 mM) in 40 cm3 of anhydrous dimethylformamide add: 2 g of l-[bis-(4-chlorophenyl)methyl]azetidine-3-carboxylic acid, 75 mg of 4-dimethylaminopyridine, 0.927 cm<3 >1.3 -diisopropylcarbodiimide. After 19 hours of stirring at a temperature close to 20°C

the suspension is filtered, after which the resin is washed with 40 cm3 of dimethylformamide, 40 cm3 of tetrahydrofuran, 40 cm3 of dichloromethane, and dried under reduced pressure to constant weight. In this way, 3.6 g of 1-[bis-(4-chlorophenyl)methyl]azetidine-3-carboxylic acid, activated on TFP resin, is obtained. 1-[bis-(4-chlorophenyl)methyl]azetidine-3-carboxylic acid can be prepared in a manner similar to that described by A.G. Anderson and R. Lok in "J. Org. Chem.", 37, 3953-3955 (1972) from l-benzhydrylazetidin-3-ol, using l-[bis-(4-chlorophenyl)methyl] azetidine as starting material -3-ol.

The TFP resin (free phenolic function) can be prepared according to the method described in WO9967228.

Example 102

(RS)-[{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methyl]-methylamine can be prepared as follows: To a solution of 108 mg { l-[bis-(4-chlorophenyl)-methyl]azetidin-3-yl}(3,5-difluorophenyl)-methanone in 2 cm3 of anhydrous 1,2-dichloroethane is added 0.099 cm<3> methylamine and then successively 84 mg sodium triacetoxyborohydride and 0.014 cm3 of acetic acid. After stirring for 12 hours at a temperature close to 20°C, 0.992 cm3 of methylamine, 85 mg of sodium triacetoxyborohydride and then 0.143 cm3 of acetic acid are again successively added. The obtained solution is stirred at a temperature close to 20°C for 24 hours and then washed with 4 cm<3> of saturated sodium bicarbonate solution. The organic phase is decanted and dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue thus obtained is purified on an IST FlashPack column with reference SIL 016-002, filled with 2 g of silica (0.065-0.090 mm), conditioned to dichloromethane and eluted with a dichloromethane:methanol gradient where the percentage of methanol varies from 0 to 6 volumes using a pump system, recovering fractions of 1 cm<3>. Fractions 8 to 18 are combined and concentrated to dryness at 2.7 kPa and 50°C. In this way, 66 mg of [{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methyl]-methylamine is obtained in the form of a colorless honey.

1H-NMR (300 MHz, CDCl3.8 in ppm): 2.25 (s, 3H), 2.60 (mt, 1H), 2.68 (t, J = 7 Hz,

1H), 2.94 (t, J = 7 Hz, 1H), 3.02 (t large, J = 7 Hz, 1H), 3.34 (t large, J = 7 Hz, 1H), 3.58 (d, J = 9 Hz, 1H), 4.25 (s, 1H), 6.67 (tt, J = 9 and 2.5 Hz, 1H), 6.80 (mt, 2H), from 7, 20 to 7.35 (mt, 8H).

Example 103

(RS)-[{l-[bis-(4-ldorphenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methyl]-isobutylamine can be prepared as follows: To a solution of 109 mg { l-[bis-(4-chlorophenyl)-methyl]azetidin-3-yl}(3,5-difluorophenyl)-methanone in 2 cm<3> anhydrous 1,2-dichloroethane is added 0.028 cm<3> isobutylamine and then successively 85 mg of sodium triacetoxyborohydride and 0.015 cm3 of acetic acid. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is deposited on a column filled with 5 g of silicon dioxide, conditioned to dichloromethane and eluted with a dichloromethane:ethyl acetate gradient where the percentage of ethyl acetate varies from 0 to 10 volumes, using a pump system. The fractions containing the desired product are combined and concentrated to dryness at 2.7 kPa and 40°C. 8 mg of (RS)-[{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-(3,5-difluorophenyl)-methyl]-isobutylamine is obtained in this way.

1H NMR (300 MHz, CDCl 3 , 8 in ppm): 0.85 (d, J = 7 Hz, 3H), 0.87 (d, J = 7 Hz, 3H),

1.63 (mt, 1H), 2.15 (dd, J = 11 and 7.5 Hz, 1H), 2.25 (dd, J = 11 and 7 Hz, 1H), 2.57 (mt, 1H ), 2.70 (t, J = 7 Hz, 1H), 2.92 (t, J = 7 Hz, 1H), 3.01 (t large, J = 7.5 Hz, 1H), 3.33 (t large, J = 7.5 Hz, 1H), 3.66 (d, J = 9 Hz, 1H), 4.25 (s, 1H), 6.66 (tt, J = 9 and 2.5 Hz, 1H), 6.81 (mt, 2H), from 7.20 to 7.35 (mt, 8H).

Example 104

(RS)-[{l-|>is-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)methyl]butylamine can be prepared as follows: To a solution of 108 mg { l-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-3,5-difluorophenyl)-methanone in 2 cm3 of anhydrous 1,2-dichloroethane is added 0.0265 cm3 of n-butylamine and then successively 95 mg sodium triacetoxyborohydride, and 0.0143 cm<3 >acetic acid. After around 16 hours of stirring at a temperature close to 20°C, 0.0265 cm 3 of n-butylamine, 85 mg of sodium triacetoxyborohydride and then 0.143 cm 3 of acetic acid are again successively added. The obtained solution is stirred at a temperature close to 20°C for about 24 hours and then washed with 4 cm 3 of saturated sodium bicarbonate solution. The organic phase is decanted and then dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa. The residue thus obtained is purified on an IST FlashPack column with reference SUL 016-002, filled with 2 g of silicon dioxide (0.065-0.090 mm) conditioned to

dichloromethane and eluted with a dichloromethane:methanol gradient, where the percentage of methanol varies from 0 to 6 volumes, using a pump system, recovering fractions of 1 cm<3>. Fractions 25 to 30 are combined and concentrated to dryness at 2.7 kPa and 50°C. 37 mg of (RS)-[{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}(3,5-difluorophenyl)-methyl]butylamine is obtained in this way in the form of a colorless honey .

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): 0.85 (t, J = 7.5 Hz, 3H), from 1.20 to 1.50 (mt,

4H), 2.37 (t large, J = 7 Hz, 2H), 2.56 (mt, 1H), 2.67 (t, J = 7 Hz, 1H), 2.89 (t, J = 7 Hz, 1H), 2.99 (t large, J = 7 Hz, 1H), 3.32 (t large, J = 7 Hz, 1H), 3.67 (d, J = 9 Hz, 1H), 4 .24 (s, 1H), 6.65 (tt, J = 9 and 2.5 Hz, 1H), 6.80 (mt, 2H), from 7.20 to 7.35 (mt, 8H).

Example 105

(RS)-N-[{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)-methyl]-3-methyl-butyramide can be prepared as follows: To a solution of 0.017 cm3 of isovaleric acid in 2 cm3 of anhydrous dichloromethane is placed successively, at a temperature close to 20°C, 0.025 cm<3> of N,N'-diisopropylcarbodiimide, 10 mg of hydroxybenzotriazole hydrate and 30 mg of (RS)-C- {1-|^is-(4-chlorophenyl)methyl]azetidin-3-yl}-C-(3,5-difluorophenyl)methylamine. The obtained solution is stirred at a temperature close to 20°C for around 12 hours. The reaction medium is deposited on a Bond-Elut SCX Varian 500 mg column with reference 1210-2040 and conditioned against methanol. The column is washed with methanol and eluted with 2N ammoniacal methanol. The ammoniacal fractions are combined and concentrated to dryness at 2.7 kPa and a temperature close to 40°C. 35 mg of (RS)-N-[{ 1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)-methyl]-3-methyl-butyramide is obtained in this way in the form of a yellow honey.

1H-NMR (300 MHz, CDCl 3 , 8 in ppm): 0.98 (d, J = 5 Hz, 6H), from 2.05 to 2.25 (mt, 3H),

2.71 (mt, 1H), 2.90 (mt, 1H), 3.00 (mt, 1H), 3.20 (mt, 2H), 4.30 (s, 1H), 5.14 (t , J = 7.5 Hz, 1H), 6.48 (d large, J = 7.5 Hz, 1H), 6.67 (tt, J = 9 and 2.5 Hz, 1H), 6.75 ( mt, 2H), from 7.20 to 7.40 (mt, 8H).

(RS)-C- {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-C-(3,5-difluorophenyl)-methylamine can be prepared as follows: To a solution of 216 mg ( RS)-{ l-[bis-(4-chlorophenyl)-methyl]azetidin-3-yl}(3,5-difluorophenyl)-methanone in 10 cm3 of methanol is placed ? and then successively 385 mg of ammonium acetate and 29 mg of sodium cyanoborohydride. The obtained solution is stirred at a temperature close to 20°C for around 12 hours and then heated to 45°C for 6 hours. 29 mg of sodium cyanoborohydride are added to this solution. The stirring

is continued at a temperature close to 20°C for 72 hours. The reaction medium is poured into a mixture of 30 cm<3> ice water with 5 cm<3> 4N aqueous sodium hydroxide solution and then extracted with 2 x 30 cm<3> ethyl acetate, the organic phase is then extracted with 2 x 30 cm<3> IN hydrochloric acid and the aqueous phase thus obtained is made alkaline with an aqueous normal sodium hydroxide solution and then extracted with 3 x 20 cm<3> ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa and 40°C. 35 mg of (RS)-C-{1-[bis-(4-chlorophenyl)-methyl]azetidin-3-yl}-C-(3,5-difluorophenyl)-methylamine are obtained in this way in the form of a yellow honey.

The medicines according to the invention consist of a compound of formula (I) or an isomer or a salt of such a compound, in pure form or in the form of a preparation in which the compound is associated with any other pharmaceutically compatible product, inert or possibly physiological actively. The medicines according to the invention can be used orally, parenterally, rectally or topically.

Tablets, pills, powders (gelatin capsules, bags) or granules can be used as solid preparations for oral administration. In these preparations, the active ingredient according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silicon dioxide, under an argon stream. The preparations may also include substances other than the diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragés) or a varnish.

As liquid preparations for oral administration, one can use pharmaceutically acceptable solutions, suspensions, emulsions, syrups or elixirs containing inert diluents, water, ethanol, glycerol, vegetable oils or paraffin oil. The preparations may include substances other than the diluents, for example wetting agents, colourants, thickeners, flavoring substances or stabilisers.

Sterile preparations for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. Water, propylene glycol, a polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters such as ethyl oleate or other suitable organic solvents can be used as solvent or carrier. These preparations may also contain additives, particularly wetting agents, isotonizing agents, emulsifiers, dispersants and stabilisers. Sterilization can take place in many ways, for example by aseptic filtration, by incorporating sterilizing agents into the preparation or by radiation or heating. They can likewise be produced in the form of sterile, solid preparations that can be dissolved at the time of use in sterile water or any other sterile, injectable medium.

The preparations for rectal administration are rectal suppositories or capsules which, in addition to the active ingredient, contain emollients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Preparations for topical administration can be, for example, creams, lotions, eye drops, colloquials, nasal drops or aerosols.

In the human therapeutic area, the compounds according to the invention are particularly useful for the therapy or prevention of psychoses, including schizophrenia, anxiety problems, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucoma, migraines . hypotension, insomnia, immunological diseases, plaque sclerosis, nausea, asthma, appetite problems (bulemia, anorexia), obesity, memory impairment, intestinal transit problems, problems in connection with chronic treatment or abuse of alcohol or drugs (opioids, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallocinogen er, benzodiazepines and others), as analgesics or potentiators for the analgesic activity of narcotic or non-narcotic drugs.

The doses depend on the intended effect, the duration of the treatment and the route of administration used and are generally between 5 mg and 1000 mg per day orally for an adult with unit doses from 1 mg to 250 mg of active ingredient.

Generally speaking, the doctor determines the appropriate dosage as a function of age, weight and all other factors of importance for the individual being treated.

The following examples shall illustrate the preparations according to the invention:

EXAMPLE A

Gel pills with doses of 50 mg of active ingredient and with the following composition are prepared in a manner known per se:

EXAMPLE B

In a manner known per se, tablets are prepared with doses of 50 mg of active ingredient and with the following composition:

EXAMPLE C

An injectable solution is prepared containing 10 mg of active ingredient and with the following composition:

Claims (49)

1. Compound, characterized by the formula: there R means a residue CRiR2, C=C(R5)SO2R6 or C=C(R7)SO2alk, Ri means either a hydrogen atom and R2 means a residue -C(Rg)(R9)(Rio), -C(R8)(Rn)(Ri2), -CO-NR,3Ri4, -CH2-CO-NR13Ri4, -CH2 -CO-R6, -CO-Re, -CO-cycloalkyl, -SO-Re, -SO2-R6, -C(OH)(R12)(R6), -C(OH)(R6)(alkyl), - C(=NOalk)R6, -C(=NO-CH2-CH=CH2)R6, -CH2-CH(R6)NR3iR32, -CH2-C(=NOalk)R6, -CH(R6)NR3,R32, - CH(R6)NHSO2alk, -CH(R6)NHCONAlk or -CH(R6)NHCOalk, or Ri means an alkyl residue, NH-Ri5, cyano, -S-alk-NRi6Ri7, -CH2-NRi8Ri9 or -NR20R2i and R2 means a residue-C(R8)(Rii)(Ri2), R 3 and R 4 are phenyl optionally substituted with one or more halogen, -COOalk, hydroxyalkyl or -alk-NR^^; or a heteroaromatic selected from pyridyl, pyrimidinyl or thienyl, as these heteroaromatics may optionally be substituted with one or more halogens, R5 means a hydrogen atom, R$ means Ar or Het, R7 means cycloalkyl, heterocycloalkyl or heterocyclenyl, optionally substituted with a -CSO-phenyl radical, Rg means a hydrogen atom or an alkyl residue, R9 means a residue -CO-NR26R27, -COOH, -COOalk, -CH2OH, -NH-CO-NH-alk, -CH2-NHR28 or -NHCOOalk, or Rg and R9 together form a carbon-bound morpholine, pyrrolidine or piperazine ring, which may optionally be substituted with alkanoyl, Rio means a residue Ar or Het, Ri 1 means a residue -SO2-alk, -SO2-Ar, -SO2-Het, Ri2 means a hydrogen atom or a residue Ar or Het, Ri 3 means a hydrogen atom or an alkyl residue, Ru means a residue Ar, Het, -alk-Ar or -alk-Het, Rice means a residue alkyl, cycloalkyl or -alk-NR29R3o, Ri6 and Rn are the same or different and mean a hydrogen atom or an alkyl residue, or Ri6 and Rn together with the nitrogen atom to which they are attached form a piperazine ring optionally substituted with one or more alkyl residues, Rig means a hydrogen atom or an alkyl residue, R19 means a hydrogen atom or an alkyl residue, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO2alk, -CO-NHalk or -COOalk, -NR2oR2i means an imidazole ring, R^ and R25 are the same or different and mean a hydrogen atom or an alkyl residue, R28 means a residue -CH2-alk, benzyl, -SO2alk, -CONHalk, -COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, -CO-(CH2)nOH, n is equal to 1,2 or 3, R29 and R30 together with the nitrogen atom to which they are attached form a pyrrolidine ring, R31 and R32 are the same or different and mean a hydrogen atom or an alkyl residue, Ar or -alk-Ar, alk means an alkyl or alkylene residue, Ar means a phenyl radical which is optionally substituted with one or more substituents selected from halogen, alkyl, -alk-NR24R25, -NR24R25, CF3, pyrrolyl, azetidinyl, hydroxyalkyl or (alkoxycarbonyl)(alkyl)amino, Het means a heterocycle chosen from thienyl, pyridyl, tetrahydrofuryl, morpholinyl, pyrrolidinyl or piperidinyl, where the heterocycle is optionally substituted with one or more halogen, alkoxycarbonyl or oxo, there. alkyl and alkylene residues and moieties and olefin residues and moieties are straight or branched chain and contain 1 to 6 carbon atoms and the cycloalkyl residues contain 3 to 10 carbon atoms, their optical isomers and their salts with mineral or organic acids. 2. Compound according to claim 1, characterized in that Het is selected from piperidyl, pyridyl or thienyl. 3. Compound with formula (I) according to claim 1, characterized in that Ri 6 and Rn, together with the nitrogen atom to which they are attached, form a piperazinyl cycle. 4. Compound with formula (I) according to claim 1, characterized by R means a residue CRiR2, Ri means either a hydrogen atom and R2 a residue -C(R8)(Rn)(Ri i) or -C(Rg)(R9)(Rio), or R 1 means an alkyl residue and R 2 a residue -C(R 8 )(R n )(Ri 2 ). R3 and R4 are phenyl which is optionally substituted with one or more halogen, hydroxyalkyl or -alk-NR24R25; or a heteroaromatic selected from pyridyl, pyrimidinyl or thienyl, as these may optionally be substituted with one or more halogen, R8 is a hydrogen atom, R9 is a residue -CO-NR26R27, -COOalk, -CH2OH, -NH-CO-NH-alk, -CH2-NHR28 or -NHCOOalk, Rio is a remnant of Ar or Het, Rn is a residue -SO2-alk, -SO2-Ar, -SO2-Het, Ri2 is a hydrogen atom or a residue Ar or Het, Rm and R25 are the same or different and mean a hydrogen atom or an alkyl residue, Ar is a phenyl radical, optionally substituted with one or two substituents selected from halogen, alkyl, -alk-NR^Rw, -NR24R25 or CF3, It is a pyridyl or thienyl, their optical isomers and their salts with a mineral or organic acid. 5. Compound, characterized in that it is selected from the following compounds: (RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]-azetidine, (R) -1 - [bis(4-chlorophenyl)methyl] -3- [(3,5-difluorophenyl)(methylsulfonyl)methyl] -azetidine, (S)-1-[bis(4-chlorophenyl)methyl]-3-[ (3,5-difluorophenyl)(methylsulfonyl)methyl (RS)-1-[>is(4-chlorophenyl)methyl]-3-[(pyrid-3-yl)(methylsulfonyl)methyl]-azetidine, (R) -l-[>is(4-chlorophenyl)methyl]-3-[(pyrid-3-yl)(methylsulfonyl)methyl]-azetidine, (S)-1-[bis(4-chlorophenyl)methyl]-3- [(pyrid-3-yl)(methylsulfonyl)methyl]-azetidine, (RS)-l-[bis(3-fluorophenyl)methyl]-3-[(3,5-diflu^^ (R)-l-[ >is(3-fluorophenyl)methyl]-3-[(3,5-difluoro (S)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluoro l-|>is( 4-chlorophenyl)methyl]-3-(RS)-{[3-azetidin-1-yl-phenyl]methylsulfonylmethine 1 -[bis(4-chlorophenyl)methyl]-3-(R)- {[3-azetidin- 1 -yl-phenyl]methylsulfonylmethyl} azetidine, 1 -[bis(4-chlorophenyl)methyl]-3-(S)- {[3-azetidin-1 -yl-phenyl]methylsulfonylmethyl} azetidine, (RS)-1 - [3-( {1 -[bis-(4-Chlorophenyl)methyl]azetidine-3 -yl}methylsulfonylmethyl)phenyl]pyrrolidine, (R)-1 -[3-( {1 -[bis-(4-chlorophenyl)methyl]azetidin-3-yl} methylsulfonylmethyl)phenyl]pyrrolidine, (S)-1 -[3-( {1 -[bis-(4-chlorophenyl)methyl]azetidin-3-yl} methylsulfonylmethyl)phenyl]pyrrolidine, (RS)-N-[3-( {1 -[bis -(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]-N-methylamine, (R)-N-[3-({l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]-N-methylamine, (S)-N-[3-( {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl} methylsulfonylmethyl)phenyl]-N-methylamine, (RS)-1-(4-chlorophenyl)methyl]-3-[(3,5-bis-trifluoromethylphenyl)mazetidine, (R)-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-bis-trifluoromethylphenyl)methylsulfonyl-mazetidine, (S)-l-[bis-(4-fluorophenyl)methyl]-3-[(3,5-bis-trifluoromethylphenyl)methylsulfonyl-methyl]^ azetidine, l-[bis-(4-fluorophenyl)methyl]-3 -(phenylsulfonylmethyl)-azetidine, (RS)-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethyl]-3-m azetidine, (R)-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethyl]-3-methyl-azetidine, (S)-1-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethyl]-3-methyl-azetidine, (RS)-2-{1-|>is-(4-fluorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyU acetamide, (R)-2-{1-|>is-(4-thiophenyl)methyl]-azetimn-3-yn^ acetamide, (S)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexyl-acetamide, (RS)-2- {1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutyl-acetamide, (R)-2-{1-|>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutyl-acetamide, (S)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutyl-acetamide, (RS)-2-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropyl-methylacetamide, (R)-2- {1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropyl-methylacetamide, (S)-2- {1-[bis-(4-chlorophenyl)meryl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropyl-methylacetamide, (RS)-2- {1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropyl-acetamide, (R)-2- {1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropyl-acetamide, (S)-2- {1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropyl-acetamide, (RS)-1-[bis-(4-chlorophenyl)-methyl]-3-[ 1 -(3,5-difluorophenyl)-1-methylsulfonyl-ethyl]-azetidine, (R)-1-[bis-(4-chlorophenyl)-methyl]-3-[ 1 -(3,5-difluorophenyl)-1-methylsulfonyl-ethyl]-azetidine, (S)-1 -[bis-(4-chlorophenyl)-methyl]-3-[ 1 -(3,5-difluorophenyl)-1-methylsulfonyl-ethyl]-azetidine, (RS)-1-|>is- (4-fluorophenyl)-methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine, (R)-1-[bis-(4-fluorophenyl)-methyl]-3-[(3 ,5-difluorophenyl)-methylsulfonyl-methyl]-a2eudine, (S)-1-[is-(4-fluorophenyl)-methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine, (RS)- {1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine, (SS)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine, (RR)-{1-[(3-pyridyl)-(4-chlorphrenyl)me azetidine, (SR)- {1 -[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine, (RS)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine, (SS)- {1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine, (RR)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine, (SR)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidine, (RS)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-1-yl}-methyl)-pyrimidine, (SR)-5-((4-chlorophenyl)- {3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-1 -yl}-methyl)-pyrimidine, (RR)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-1-yl}-methyl)-pyrimidine, (SS)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonyl-methyl]-azetidin-1-yl}-methyl)-pyrimidine, (SS)- {1 -[(2-chloro-pyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl] azetidine, (RR)- {1 -[(2-chloro-pyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluophrenyl)-methylsulfonyl-methyl]azetidine, (RS)-{1-[(2-Chloro-pyrid-5-yl)-(4-N-methyl]azetidine, (SR)-{1-[(2-Wor-pyrid-5-yl)-(4-Morphenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonyl-methyl] azetidine, their optical isomers and their pharmaceutically acceptable salts with a mineral or organic acid. 6. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri means a hydrogen atom and R2 a residue C(R8)(Rn)(Ri2), where Rg means a hydrogen atom, R\ \ means a residue -SCVAr, -SCVHet or -SO2alk and R12 means a hydrogen atom or a residue Ar or Het, characterized by reducing a compound with formula: Ra means an alkyl residue, Het or Ar and Rb means a hydrogen atom or a residue Ar or Het, alkyl, Ar and Het have the same meaning as in claim 1, isolates the product and optionally converts it to a salt with a mineral or organic acid . 7. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri means a hydrogen atom and R2 means a residue C(Rg)(Rn)(Ri2)" where Ra means a hydrogen atom, Rn means a residue -SCVAr, -SO2-Het or -SC^alk and Ri 2 means a hydrogen atom or an Ar or Het, characterized by reacting a compound R3CH(Br)R4 with a compound of the formula: where Ra means an alkyl residue, Het or Ar and Rb means a hydrogen atom or a residue Ar or Het, alkyl, Ar and Het have the same meaning as in claim 1, isolates the product and optionally converts it to a salt with a mineral or organic acid. 8. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue C=C(R5)SO2R6 or C=C(R7)SO2alk, characterized by dehydrating a compound of the formula: where either Ra means a residue Ar or Het and Rb means a hydrogen atom or an alkyl residue, or Ra means an alkyl residue and Rb means a cycloalkyl, heterocycloalkyl or heterocyclenyl residue, optionally substituted with a -CSO-phenyl residue, Rc means a hydrogen atom or a acetyl residue, R3, R4, Ar and Het have the same meaning as in claim 1, isolates the product and optionally converts it to a salt with a mineral or organic acid. 9. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue C=C(R5)SO2R6 or C=C(R7)SO2alk, characterized by reacting R3CH(Br)R4 with a compound of the formula : where either Ra means a residue Ar or Het and Rb means a hydrogen atom or an alkyl residue, or Ra means an alkyl residue and Rb means a cycloalkyl-,, heterocycloalkyl or hetero-cyclenyl residue, optionally substituted with a residue -CSO-phenyl, Rc means a hydrogen atom or an acetyl residue, R3, R4, Ar and Het have the same meaning as in claim 1, isolates the product and optionally converts it to a salt with a mineral or organic acid. 10. Process for the preparation of compounds of formula (1) according to claim 1, where R means a residue CR1R2, where Ri means a hydrogen atom and R2 means a residue C(Rg)(R9)(Rio), where Rg means a hydrogen atom, R9 means a residue -CO-NR26R27 and Rio means a residue Ar or Het, characterized by reacting an amine HNR26R27, where R26 and R27 have the same meaning as in claim 1, with an acid with the formula: where R3, R4 and Rio have the same meaning as in claim 1, isolates the product and optionally converts it into a salt with a mineral or organic acid. 11. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CRiR2, where Ri means a hydrogen atom and R2 means a residue C(Rg)(R9)(Rio), where R8 means a hydrogen atom, R9 means a residue -COOH and Rio means a residue Ar or Het, characterized by hydrolyzing the corresponding ester with the formula: where R 3 , R 4 and R 10 have the same meaning as in claim 1 and alk means a straight or branched C 1-6 alkyl residue, isolates the product and optionally converts it to a salt with a mineral or organic acid. 12. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri means a hydrogen atom and R2 means a residue C(Rg)(R9)(Rio), where Rg means a hydrogen atom, R9 means a residue -COOalk or -CH2OH and Rio means a residue Ar or Het, characterized by reducing a compound with the formula: where R 3 , R 4 and R 10 have the same meaning as in claim 1 and alk means a straight or branched C 1-6 alkyl residue, isolates the product and optionally converts it to a salt with a mineral or organic acid. 13. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CRiR2, where Ri means a hydrogen atom and R2 means a residue C(R8)(R9)(Rio), where R8 means a hydrogen atom, R9 means a residue -NHCOOalk and Rio means a residue Ar or Het, characterized by converting an alcohol alkOH, where alk means a straight or branched Ci_6 alkyl residue with a compound of the formula: where R3, R4 and Rio have the same meaning as in claim 1, isolates the product and optionally converts it into a salt with a mineral or organic acid. 14. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri means a hydrogen atom and R2 means a residue C(Rg)(R9)(Rio), where Rg means a hydrogen atom, R9 means a residue -NH-CO-NH-alk and Rio means a residue Ar or Het, characterized by reacting an amine-alkNH2, where alk means a straight or branched Ci-6 alkyl residue, with a compound of the formula: where R 3 , R 4 and R 10 have the same meaning as in formula (I), isolates the product and optionally converts it to a salt with a mineral or organic acid. 15. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri means a hydrogen atom and R2 means a residue C(Rg)(R9)(Rio), where Rg means a hydrogen atom, R9 means a residue -CH2-NHR2g, R2g a residue -CH2-alk or benzyl and Rio means a residue Ar or Het, characterized by reacting a compound with the formula: where R3, R4 and R10 have the same meaning as in claim 1, with an aldehyde RdCHO where Rd means a residue -CH2-alk or benzyl and alk means a straight or branched C1-6 alkyl residue, isolates the product and optionally converts it to a salt with a mineral or organic acid. 16. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CRiR2, where Ri means a hydrogen atom and R2 means a residue C(R8)(R9)(Rio), where R8 means a hydrogen atom, R9 is a residue -CH2-NHR28, R28 is a residue SO2alk and Rio is a residue Ar or Het, characterized by reacting an amine with the formula: where R3, R4 and R10 have the same meaning as in claim 1, with a compound ClSO2Re, where Re means a straight or branched C1_6 alkyl residue, isolates the product and optionally converts it into a salt with a mineral or organic acid. 17. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CRiR2, where Ri means a hydrogen atom and R2 means a residue C(Rg)(R9)(Rio), R8 is a hydrogen atom, R9 is a residue -CH2-NHR2g, R28 is a residue -CO-NHalk and Rio is a residue Ar or Het, characterized by reacting a compound with the formula: where R3, R4 and R10 have the same meaning as in claim 1, with a compound RfNCO where Rf means a straight or branched C1-6 alkyl residue, isolates the product and optionally converts it to a salt with a mineral or organic acid. 18. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue C(R8)(R9)(Rio), Rs is a hydrogen atom, R9 is a residue -CH2-NHR28, R28 is a residue -COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, -CO-(CH2)nOH and Rio is a residue Ar or Het, characterized by reacting a compound with the formula: where R3, R4 and R10 have the same meaning as in claim 1, with an acid HOOCRg where Rg means a straight or branched C1-6 alkyl residue, C3.10-cycloalkyl (straight or branched) C1-6-alkyl, C3-io- cycloalkyl, -(CH2)nOH and n is equal to 1,2 or 3, isolates the product and optionally converts it to a salt with a mineral or organic acid. 19. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CONR13R14, characterized by reacting an amine NHR13R14, where Ri 3 and R]4 has the same meaning as in claim 1, with a connection with the formula: where R3 and R4 have the same meaning as in formula (I), isolates product and optionally converts it to a salt with a mineral or organic acid. 20. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 is a residue -CH2-CONR13R14, characterized by reacting a compound HNR13R14, where R13 and Ru have the same meaning as in claim 1, with a connection with the formula: where R3 and R4 have the same meaning as in claim 1, isolates the product and optionally converts it to a salt with a mineral or organic acid. 21. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 is a residue -CH2-CONR13R14, characterized by reducing a compound with the formula: where R3, R4, R13 and Ru have the same meaning as in claim 1, isolates the product and optionally converts it to a salt with a mineral or organic acid. 22. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where R1 is a hydrogen atom and R2 is a residue -SOR6, characterized by oxidizing a compound of the formula: where R3, R4 and R<s have the same meaning as in claim 1, isolates the product and optionally converts it to a salt with a mineral or organic acid. 23. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CRiR2, where R1 is a hydrogen atom and R2 means a residue -SO2R6, characterized in that a compound of the formula is oxidized: where R3, R4, and Ré have the same meaning as in claim 1, isolates the product and optionally converts it into a salt with a mineral or organic acid. 24. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CRiR2, where Ri is a hydrogen atom and R2 means a residue -COR6 or -CO-cycloalkyl, characterized by reacting a compound with the formula: where R3 and R4 have the same meaning as in claim 1, with a compound RhMgBr, where Rh has the same meaning as R$ in claim 1, or also means a C3-io-cycloalkyl residue, isolates the product and optionally converts it into a salt with a mineral or organic acid. 25. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 is a residue -C(OH)(Re)(Ri2) or - C(OH)(R6) )(alkyl), characterized by reacting a compound with the formula: where R3, R4 and Re have the same meaning as in claim 1, with a compound RiMgBr, where Ri has the same meaning as R]2 in claim 1 or also means a straight or branched C1-6 alkyl residue, isolates the product and optionally converts it to a salt with a mineral-ener organic acid. 26. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -C(=NOalk)R6 or -C(=NO-CH2-CH=CH2 )R6, characterized by atman reacts a compound with the formula: where R3, R4 and R6 have the same meaning as in claim 1, with a compound RjONH2, where Rj means a straight or branched C1-6 alkyl residue or -CH2-CH=CH2, isolates the product and optionally converts it into a salt with a mineral or organic acid. 27. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CRiR2, where Ri is a hydrogen atom and R2 means a residue -CH(R6>NR3iR32, where R31 and R32 mean hydrogen atoms, characterized by reacting ammonia with a compound of the formula: where R3, R4 and Re have the same meaning as in claim 1 and Ms means a methylsulfonyloxy acid residue, isolates the product <p>g optionally converts it to a salt with a mineral or organic acid. 28. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where R] is a hydrogen atom and R2 means a residue -CH(R6)NR3iR32, where R31 is a hydrogen atom and R32 is an alkyl residue, Ar or -alk-Ar, characterized by reacting a halide HalR3i with a corresponding compound of formula (I), where R means a CR1R2, where R1 is a hydrogen atom and R2 means a residue -CH(R<5)NR3iR32 , R31 and R32 are hydrogen atoms, isolate the product and optionally convert it into a salt with a mineral or organic acid. 29. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH(R6)NR3iR32, R31 and R32 are residues alkyl, Ar or -alk- Ar, characterized by reacting a halide HalR32 with a corresponding compound of formula (I), where R means a residue CR1R2, where Ri is a hydrogen atom and R2 is a residue -CH(R6)NR3iR32, R31 is a hydrogen atom and R32 is a residual alkyl, Ar or -alk-Ar, isolates the product and optionally converts it to a salt with a mineral or organic acid. 30. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH(R6)NR3iR32, R31 is a hydrogen atom and R32 is a residue C2-6 -alkyl or (C2.6-alk)-Ar, characterized by reacting an aldehyde RaCHO, where Ra is an alkyl residue or -alk-Ar, with a corresponding compound of formula (I), where R means a residue CR1R2 , where Ri is a hydrogen atom and R2 is a residue -CH(Re)NR3iR32, R31 and R32 are hydrogen atoms, isolates the product and optionally converts it to a salt with a mineral or organic acid. 31. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CRiR2, where R! is a hydrogen atom and R2 means a residue -CH(R6)NR3iR32, R31 is a residue alkyl, Ar or -alk-Ar and R32 is a residue C2-6-alkyl or (C2-6-alk)-Ar, characterized by that one reacts an aldehyde RaCHO, where Ra is an alkyl residue or -alk-Ar with a corresponding compound of formula (I), where R means a residue CR1R2, where Ri is a hydrogen atom and R2 is a residue -CH(R6) NR3iR32, R31 is a hydrogen atom and R32 is an alkyl residue, Ar or -alk-Ar, isolates the product and optionally converts it to a salt with a mineral or organic acid. 32. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH(R6)NHS02alk, characterized by reacting a compound with the formula: where R3, R4 and R6 have the same meaning as in claim 1, with a compound ClSC«2alk, where -alk means a straight or branched C1-6 alkyl residue, isolates the product and optionally converts it into a salt with a mineral or organic acid. 33. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH(R6)NHCONHalk, characterized in that reacts a compound with the formula: where R3, R4 and R6 have the same meaning as in claim 1, with a compound alkNCO, where alk means a straight or branched C1-6 alkyl residue, isolates the product and optionally converts it into a salt with a mineral or organic acid. 34. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH(R6)NHCOalk, characterized by reacting a compound with the formula:.. .. where R3, R4 and R6 have the same meaning as in claim 1, with a compound alkCOOH where R31 has the same meaning as in claim 1, isolates the product and optionally converts it to a salt with a mineral or organic acid. 35. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH2-COR6, characterized by reacting a compound with the formula: where R3 and R4 have the same meaning as in claim 1, with a compound of the formula ReMgBr, where R6 has the same meaning as in claim 1, isolates the product and optionally converts it to a salt with a mineral or organic acid. 36. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH2-CH(R6)-NR31R32, characterized by reacting a compound with the formula : where R3 and R4 have the same meaning as in claim 1, with a compound of the formula HNR31R32, where R31 and R32 have the same meaning as in claim 1, isolates the product and optionally converts it to a matter with a mineral or organic acid. 37. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CRiR2, where Ri is a hydrogen atom and R2 means a residue -CH2-C(=NOalk)R6, characterized by reacting a compound with the formula : where R3 and R4 have the same meaning as in claim 1, with a compound of the formula alkONH2, where alk means a straight or branched C1-6 alkyl residue, isolates the product and optionally converts it into a salt with a mineral or organic acid. 38. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri means a cyano residue and R2 means a residue -C(R8)(Rn)(Ri2), where R8 is a hydrogen atom, characterized by atman reacts a compound with the formula: where R3, R4, Rn and R12 have the same meaning as in claim 1, with sodium cyanide, isolates the product and optionally converts it to a salt with a mineral or organic acid. 39. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri means a -S-alk-NRi6Rn and R2 means a residue -C(R8)(Rn)(Ri2), where Ra is a hydrogen atom, characterized by reacting a compound with the formula: where R3, R4, Rn and Ri2 have the same meaning as in claim 1, with a compound of the formula HS-alk-NRieRn, where alk means a straight or branched C1-6 alkyl residue and R16 and R17 have the same meaning as in claim 1, isolates the product and optionally converts it to a salt with a mineral or organic acid. 40. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri means a residue -NHR15 and R2 means a residue -C(Rg)(Rii)(Ri2), where R8 is a hydrogen atom , characterized by atman reacts a compound with the formula: where R3, R4, R11 and Ri 2 have the same meaning as in claim 1, with a compound, H2NR15, where R15 has the same meaning as in claim 1, isolates the product and optionally converts it into a salt with a mineral or organic acid. 41. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CRiR2, where Ri means an alkyl residue and R2 means a residue -C(Rg)(Rn)(Ri2), where R8 is a hydrogen atom, characterized by atman reacts a compound with the formula: where R3, R4, Rn and R12 have the same meaning as in claim 1, with a compound alkMHal2, where alk means a straight or branched C1_6 alkyl residue and M means a metal, isolate the product and optionally convert it into a salt with a mineral - or organic acid. 42. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where R] means a residue -NR20R21 and R2 means a residue -QRgXRnXRu), where Rg is a hydrogen atom, characterized by atman reacting a compound with the formula: where R3, R4, Rn and R12 have the same meaning as in claim 1, with a compound HNR20R21, where NR20R21 has the same meaning as in claim 1, isolates the product and optionally converts it to a salt with a mineral or organic acid. 43. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where R] means a residue -alk-NRigRu, Ris and R19 means hydrogen atoms, characterized by reducing a corresponding compound of formula (I ) where Ri means a cyano residue, isolates the product and optionally converts it to a salt with a mineral or organic acid. 44. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri means a residue -alk-NRi8Ri9, Ri8 means is a hydrogen atom and R19 means a residue alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SCtøalk , -CO-NHalk or -COOalk, characterized by atman converting a halide HalRi9, where Hal means a halogen atom with a corresponding compound of formula (I) where R means a residue CRiR2, where R] means a residue -alk-NRi8Ri9, Ri 8 and R19 means a hydrogen atom, isolates the product and optionally converts it into a salt with a mineral or organic acid. 45. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CRiR2, where Ri is a residue -alk-NRi8Ri9, Ris means an alkyl residue and R19 means a residue alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO2alk , -CO-NHalk or -COOalk, characterized by reacting an alkyl halide with a corresponding compound of formula (I), reducing a corresponding compound of formula (I) where R means a residue CR1R2, where Ri means a residue -alk- NRi8Ri9, Rig means a hydrogen and R19 means a residue alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO2alk, -CO-NHalk or -COOalk, isolates the product and optionally converts it to a salt with a mineral or organic acid. 46. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where either Ri means a hydrogen atom and R2 means a residue -C(R8)(R9)(Rio) or -C(R8)( Rn)(Ri2) or R] means an alkyl residue, NH-R,5, cyano, -S-alk-NRi6Ri7 and R2 a residue-C(R8)(Rii)(Ri2) and R8 means an alkyl residue, characterized in that one alkylates a corresponding compound of formula (I), where Rg is a hydrogen atom, isolates the product and optionally converts it to a salt with a mineral or organic acid. 47. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue C=C(R7)SO2alk, characterized by oxidizing a compound of the formula: where R3, R4 and R7 have the same meaning as in claim 1, and alk means a straight or branched C1-6 alkyl residue, isolates the product and optionally converts it to a salt with a mineral or organic acid. 48. Process for the preparation of compounds of formula (I) according to claim 1, where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CH(Re)NR3iR32, R31 is a hydrogen atom and R32 is an alkyl residue, characterized by that one reacts a corresponding compound of formula (I) where R means a residue CR1R2, where Ri is a hydrogen atom and R2 means a residue -CO-R^ with an amine NHR31R32, where R31 is a hydrogen atom and R32 an alkyl residue, isolates the product and optionally converts it to a salt with a mineral or organic acid. 49. Pharmaceutical preparation, characterized in that it contains as active ingredient at least one compound of formula (I) according to one of claims 1 to 5.