AU5523299A - Azetidine derivatives, preparation and medicines containing them - Google Patents

Description

WO 00/15609 1 PCT/FR99/02147 AZETIDINE DERIVATIVES, THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM The present invention relates to azetidine 5 derivatives of formula:

R

3

R

4 N () R their optical isomers, their salts, their preparation and medicaments containing them. In formula (I), 10 R represents a chain

SO

2 R, OR' S0 2 R, C=CH\ or C-CH\ (A) 2 (B) 2 R, represents a methyl or ethyl radical,

R

2 represents either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being nonsubstituted or substituted with one or more 15 halogens, alkyl, alkoxy, -CO-alk, hydroxyl, -COOR 5 , formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NR 6

R

7 , -CO-NH-NR 6

R

7 , -N(alk) COOR 8 , cyano, -CONHR 9 , -CO-NR 16

R

17 , alkylsulfanyl, hydroxyalkyl, -O-alk-NR 12

R

13 or alkylthioalkyl or a 20 heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, 2 indolinyl, isochromanyl, isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl, or thienyl rings, it being possible for these heteroaromatics to 5 be nonsubstituted or substituted with a halogen, alkyl, alkoxy, -COOR., trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro,

-NR

6

R

7 , -CO-NH-NR 6

R

7 , cyano, -CONHR 9 , alkylsulfanyl, hydroxyalkyl or alkylthioalkyl, 10 R 3 and R 4 , which are identical or different, represent either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being nonsubstituted or substituted with one or more halogens, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, 15 -CO-alk, cyano, -COOR, -CONRR 11 , -CO-NH-NR 6 R, alkylsulfanyl, hydroxyalkyl, -alk-NR 6

R

7 or alkylthioalkyl; or a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 20 2,3-dihydrobenzothienyl, furyl, isochromanyl, isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl or thienyl rings, it being possible for these heteroaromatics to be nonsubstituted or substituted with a halogen, alkyl, 25 alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOR 5 , -CO-NH-NRR,, -CONR 10

R,

11 -alk-NR 6

R

7 , alkylsulfanyl, hydroxyalkyl or alkylthioalkyl; 3 R 5 is an alkyl or phenyl radical which is optionally substituted with one or more halogen atoms,

R

6 and R 7 , which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, 5 alkylcycloalkyl, -alk-0-alk or hydroxyalkyl radical or alternatively R 6 and R, together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from 10 oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NRR 14

R

15 oxo, hydroxyalkyl, -alk-O-alk or -CO-NH 2 radicals,

R

8 represents an alkyl radical, 15 R 9 represents a hydrogen atom or an alkyl radical or an alkyl radical substituted with a dialkylamino, phenyl, cycloalkyl (optionally substituted with -COOalk) or a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing one or more 20 heteroatoms chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, Rio and Rii, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Rio 25 and R 1 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono or bicyclic heterocycle optionally containing another 4 heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl radical,

R

12 and R, 13 which are identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical or 5 alternatively R 12 and R 13 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted 10 with an alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk or -CO-alk-NR,R 1 radical or a 3- to 10-membered saturated mono- or bicyclic heterocycle containing a heteroatom chosen from oxygen, sulfur and nitrogen,

R

4 and R, 5 , which are identical or different, represent 15 a hydrogen atom or an alkyl or -COOalk radical, Ri1 and R 17 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen, 20 R' represents a hydrogen atom or a -CO-alk radical, alk represents an alkyl or alkylene radical. In the preceding definitions and in those which follow, unless otherwise stated, the alkyl and alkylene radicals and portions and the alkoxy radicals 25 and portions are in the form of a straight or branched chain and contain 1 to 6 carbon atoms. Among the alkyl radicals, there may be 5 mentioned methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl radicals. Among the alkoxy radicals, there may be mentioned methoxy, ethoxy, n-propoxy, iso-propoxy, 5 n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and pentyloxy radicals. The term halogen comprises chlorine, fluorine, bromine and iodine. When R 2 and/or R 3 and/or R, represent 10 independently a substituted phenyl, the latter is preferably mono-, di- or trisubstituted. When R 6 and R 7 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, 15 the latter is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl, imidazolyl, thiomorpholinyl or furyl ring, these rings being optionally substituted with an alkyl, hydroxyalkyl, -alk-O-alk, -CONH 2 , -COalk, -COOalk, oxo, -CSNHalk, 20 -CONHalk or -CO-alk-NRR 5 radical and, in particular, with a methyl, ethyl, propyl, isobutyl, acetyl, N,N dimethylaminomethylcarbonyl, methyloxycarbonyl, methylcarbamoyl, methylthiocarbamoyl, N-methylaminomethylcarbonyl, N-methyl 25 N-tertbutoxycarbonylaminomethylcarbonyl, oxo, -CSNHCH 3 or -CONHCH 3 radical. When Rio and R 11 together form with the 6 nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl 5 ring, these rings being optionally substituted with an alkyl. When R 12 and R 13 form together with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, 10 the latter is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl ring, these rings being optionally substituted with an alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk or -CO-alk-NR 14

R

15 radical or a 3- to 10-membered saturated 15 mono- or bicyclic heterocycle containing a heteroatom chosen from oxygen, sulfur and nitrogen, and, in particular, with a thiomorpholinyl radical. When R 6 and R 17 together form with the nitrogen atom to which they are attached a 3- to 20 10-membered saturated mono- or bicyclic heterocycle, the latter is preferably a piperidyl ring. When R 9 represents an alkyl radical substituted with a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally 25 containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen, the latter is preferably a pyrrolidinyl, tetrahydrofuryl, morpholinyl or pyrrolyl 7 ring, these rings being optionally substituted with one or more alkyl radicals. The compounds of formula (I) may be provided in the form of enantiomers and diastereoisomers. These 5 optical isomers and mixtures thereof form part of the invention. The compounds of formula (I) for which R represents a chain of formula (A) may be prepared by dehydration of a corresponding compound of formula (Ia)

R

3 R4 N (Ia) s 2 R, 10 R 2 in which R., R 2 , R 3 and R 4 have the same meanings as in formula (I) and R" represents a hydroxyl, methanesulfonyloxy or acetyloxy radical. This dehydration is carried out by any method 15 known to persons skilled in the art which makes it possible to dehydrate an alcohol or one of its derivatives in order to obtain the corresponding alkene. Preferably, derivatives are used for which R" is a methanesulfonyloxy or acetyloxy radical obtained 20 from the corresponding derivative for which R" is a hydroxyl radical by the action of methanesulfonyl chloride or acetyl chloride, in an inert solvent such as pyridine, tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane or chloroform for example), at 8 a temperature of between 5*C and 20'C and then the medium is treated with a base such as an alkali metal hydroxide (sodium hydroxide for example), an alkali metal carbonate (sodium or potassium carbonate for 5 example), an amine such as a trialkylamine (triethylamine for example), 4-dimethylaminopyridine, diaza-1,8-bicyclo[5.4.0]undec-7-ene, at a temperature of between 0 0 C and the boiling temperature of the reaction mixture. The methanesulfonyloxy and the 10 acetyloxy may be isolated or otherwise. The compounds of formula (I) for which R represents a chain (B) in which R' is a hydrogen atom may be prepared by reacting the derivative RISO 2

CH

2

R

2 (II) for which R and R 2 have the same meanings as in 15 formula (I) with an azetidinone of formula:

R

3 in which R 3 and R 4 have the same meanings as in formula

(I)

The procedure is generally carried out in an 20 inert solvent such as an ether (tetrahydrofuran for example), in the presence of a strong base such as lithium diisopropylamide, potassium tert-butoxide or n-butyllithium, at a temperature of between -70 0 C and -15 0 C. 25 The derivatives of formula (II) may be I 9 obtained by application or adaptation of the methods described in the examples. In particular, the procedure is carried out according to the following reaction schemes:

R

1 SNa

R

2

-CH

2 -Hal ,.-~ R 2

-CH

2 -S-R, (IV) (a) M

R

1 -S 2 Na ()(b) oidation

R

2

-CH

2

-SO

2 R, 5 In these formulae Hal represents a halogen atom and, preferably, chlorine, bromine or iodine, R. and R 2 have the same meanings as in formula (I). The reaction (a) is generally carried out in 10 an inert solvent such as dimethylformamide or a 1-4C aliphatic alcohol, at a temperature of between 20 and 300C. The reaction (b) is carried out by any known method which makes it possible to oxidize a sulfur 15 containing derivative without affecting the rest of the molecule such as the methods described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, the procedure is carried out by the action of an organic peroxy acid or a salt 20 of such a peroxy acid (peroxycarboxylic or peroxysulfonic acids, especially peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, peroxyformic acid or monoperoxyphthalic acid) or in I 10 organic peracids or a salt of such an acid (for example periodic or persulfuric acid), in an inert solvent such as a chlorinated solvent (chloroform or dichloromethane for example), at a temperature of between 0 and 25 0 C. 5 It is also possible to use hydrogen peroxide or a periodate (sodium periodate for example), in an inert solvent such as 1-4C aliphatic alcohol (methanol or ethanol for example), water or a mixture of these solvents, at a temperature of between 0 and 20'C. It is 10 also possible to carry out the procedure using tert butyl hydroperoxide in the presence of titanium tetraisopropoxide in a 1-4C aliphatic alcohol (methanol or ethanol for example) or a water-alcohol mixture, at a temperature close to 25 0 C or using oxoneR(potassium 15 peroxymonosulfate), in a 1-4C aliphatic alcohol (methanol or ethanol for example), in the presence of water, acetic acid or sulfuric acid, at a temperature close to 20'C. The reaction (c) is preferably carried out in 20 an inert solvent such as a 1-4C aliphatic alcohol (methanol or ethanol for example), at a temperature of between 200C and the boiling temperature of the reaction medium. The derivatives of formula (IV) are 25 commercially available or may be obtained by application or adaptation of the methods described in the examples. In particular, the methylated derivative 11 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 chlorosuccinimide in the presence of benzoyl peroxide, 5 in an inert solvent such as tetrachloromethane, at the boiling temperature of the reaction medium. The methylated derivatives or the corresponding alcohols are commercially available or may be obtained according to the methods described by BRINE G.A. et al., J. 10 Heterocycl. Chem., 26, 677 (1989) and NAGARATHNAM D., Synthesis, 8, 743 (1992) and in the examples. The azetidinones of formula (III) may be obtained by application or adaptation of the methods described by KATRITZKY A.R. et al., J. Heterocycl. 15 Chem., 271 (1994) or DAVE P.R.,J. Org. Chem., 61, 5453 (1996) and in the examples. The procedure is generally carried out according to the following reaction scheme: 0 A N.OH 3 R4 HYDROXYLAMINE R I R4 B Br N NH R R E 3 4 R3 R4 C X OH N D< (R3K R 4 (I I I)R 12 In these formulae, R 3 and R 4 have the same meanings as in formula (I) and X represents a chlorine or bromine atom. In step A, the procedure is preferably 5 carried out in an inert solvent such as a 1-4C aliphatic alcohol (ethanol or methanol for example), optionally in the presence of an alkali metal hydroxide, at the boiling temperature of the reaction medium. 10 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, the procedure is preferably carried out in an inert solvent such as a 1-4C 15 aliphatic alcohol (ethanol or methanol for example) in the presence of sodium hydrogen carbonate, at a temperature of between 20'C and the boiling temperature of the reaction medium. In step D, the oxidation is preferably 20 carried out in DMSO, using the sulfurtrioxide-pyridine complex, at a temperature close to 20'C or using dimethyl sulfoxide, in the presence of oxalyl chloride and triethylamine, at a temperature of between -70 and -50 0 C. 25 In step E, the procedure is carried out according to the method described by GRISAR M. et al., in J. Med. Chem., 885 (1973). The magnesium compound of 13 the brominated derivative is formed and then the nitrile is reacted, in an ether such as ethyl ether, at a temperature of between 0 0 C and the boiling temperature of the reaction medium. After hydrolysis 5 with an alcohol, the intermediate imine is reduced in situ with sodium borohydride at a temperature of between 0 0 C and the boiling temperature of the reaction medium. The R,-CO-R. derivatives are commercially 10 available or may be obtained by application or adaptation of the methods described by KUNDER N.G. et al. J. Chem. Soc. Perkin Trans 1, 2815 (1997); MORENO MARRAS M., Eur. J. Med. Chem., 23 (5) 477 (1988); SKINNER et al., J. Med. Chem., 14 (6) 546 (1971); HURN 15 N.K., Tet. Lett., 36 (52) 9453 (1995); MEDICI A. et al., Tet. Lett., 24 (28) 2901 (1983); RIECKE R.D. et al., J. Org. Chem., 62 (20) 6921 (1997); KNABE J. et al., Arch. Pharm., 306 (9) 648 (1973); CONSONNI R. et al., J. Chem. Soc. Perkin Trans 1, 1809 (1996); 20 FR-96-2481 and JP-94-261393. The R 3 Br derivatives are commercially available or may be obtained by application or adaptation of the methods described by BRANDSMA L. et al., Synth. Comm., 20 (11) 1697 and 3153 (1990); 25 LEMAIRE M. et al., Synth. Comm., 24 (1) 95 (1994); GODA H. et al., Synthesis, 9 849 (1992); BAEUERLE P. et al., J. Chem. Soc. Perkin Trans 2, 489 (1993).

14 The R 4 CN derivatives are commercially available or may be obtained by application or adaptation of the methods described by BOUYSSOU P. et al., J. Het. Chem., 29 (4) 895 (1992); SUZUKI N. et 5 al., J. Chem. Soc. Chem. Comm., 1523 (1984); MARBURG S. et al., J. Het. Chem., 17 1333 (1980); PERCEC V. et al., J. Org. Chem. 60 (21) 6895 (1995). The compounds of formula (I) for which R represents a chain (B) in which R' is a hydrogen atom 10 may also be prepared by action of a derivative

R

3 CH(Br)R, (VI) for which R 3 and R, have the same meanings as in formula (I) with a derivative of formula: HN L lOH S2,(V1I)

S

2 R, R 2 15 in which R and R 2 have the same meanings as in formula (I). This reaction is generally carried out in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), in an inert solvent 20 such as acetonitrile, at the boiling temperature of the reaction medium. The derivatives of formula (VI) are commercially available or may be obtained by application or adaptation of the method described by 25 BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933).

15 Generally, the corresponding alcohol R 3

CHOHR

4 is brominated using hydrobromic acid, in acetic acid, at a temperature of between 0*C and the boiling temperature of the reaction medium. 5 The corresponding R 3

CHOHR

4 alcohols are commercially available or may be obtained by application or adaptation of the methods described by PLASZ A.C. et al., J. Chem. Soc. Chem. Comm., 527 (1972). 10 The derivatives of formula (VII) may be obtained by hydrolysis of a derivative of formula:

H

2 C=HCOOC-N OH (Vill)

SO

2

R

1 - R2 in which R 1 and R 2 have the same meanings as in formula 15 (I). This reaction is generally carried out using hydrochloric acid, in an inert solvent such as an ether (dioxane for example), at a temperature close to 20*C. The derivatives of formula (VIII) are 20 obtained by reacting vinyl chloroformate with a corresponding compound of formula (I) for [lacuna] R represents a chain of formula (B), R' represents a hydroxyl radical, R 3 and R 4 are phenyl radicals, in an inert solvent such as a chlorinated solvent 25 (dichloromethane or chloroform for example), at a 16 temperature of between 0 0 C and the boiling temperature of the reaction mixture. The compounds of formula (I) for which R is a chain (B) in which R' is a -CO-alk radical may be 5 prepared by reacting a halide Hal-CO-alk in which Hal represents a halogen atom and, preferably, a chlorine atom and alk represents an alkyl radical with a corresponding compound of formula (I) for which R is a chain (B) in which R' is a hydrogen atom. 10 This reaction is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane or chloroform for example), at a temperature of between -50'C and 20'C, in the presence of n-butyllithium. 15 The compounds of formula (I) for which R 2 represents an aromatic or a heteroaromatic substituted with -NR 6 R, in which R 6 and R, each represent a hydrogen atom may also be prepared by reducing a corresponding compound of formula (I) for which R 2 represents an 20 aromatic or a heteroaromatic substituted with nitro. This reaction is carried out by any known method which makes it possible to reduce a nitro to an amino without affecting the rest of the molecule. Preferably, iron is used in the presence of 25 hydrochloric acid in a 1-4C aliphatic alcohol such as ethanol, at the boiling temperature of the reaction medium.

17 The compounds of formula (I) for which R 2 represents an aromatic or heteroaromatic substituted with -COHNR 9 and/or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with -CONR 0

R

11 may also be 5 prepared by reacting a corresponding compound of formula (I) for which R 2 and/or R, and/or R, represent an aromatic or a heteroaromatic substituted with -COOR 5 for which R 5 is alkyl or phenyl optionally substituted with halogens with respectively an amine H 2

NR

9 or HNR,R,, for 10 which R 9 , RIO and R 11 have the same meanings as in formula (I). This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane or chloroform for example) or a 1-4C 15 aliphatic alcohol (methanol or ethanol for example), at a temperature of between 0 0 C and the boiling temperature of the reaction mixture. The compounds of formula (I) for which R 2 represents an aromatic substituted with hydroxyl and/or 20 R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with hydroxyl may also be prepared by hydrolysis of a corresponding compound of formula (I) for which R 2 represents an aromatic substituted with alkoxy and/or R 3 and/or R 4 represent an aromatic or a 25 heteroaromatic substituted with alkoxy. This reaction is carried out by any method of hydrolyzing an alkoxy to a hydroxyl without affecting 18 the rest of the molecule. Preferably, the hydrolysis is carried out using boron tribromide, in a chlorinated solvent such as dichloromethane, at a temperature close to 20 0 C. 5 The compounds of formula (I) for which R 2 represents an aromatic substituted with -NRR, for which

R

6 represents an alkyl radical and R, represents a hydrogen atom may also be prepared by deprotecting a corresponding compound of formula (I) for which R 2 10 represents an aromatic substituted with an -N(alk)COOR, in which R 8 represents a tert-butyl radical. This reaction is generally carried out using hydrochloric acid, in a solvent such as dioxane at a temperature close to 20 0 C. 15 The compounds of formula (I) for which R 2 and/or R 3 and/or R. represent an aromatic substituted with -COOR 5 may also be prepared by esterification of a derivative of formula:

R

3 ' R4 N (IX) R 20 for which R represents a chain C=C(SO 2

R,)R'

2 or

C(OR')CH(SO

2

R)R'

2 , R,, R' 2 , R', and R', have the same meanings as the substituents RI, R 2 , R 3 and R, of formula (I) with the proviso that at least one of the substituents R'2, R'3 and R', represents an aromatic or a 25 heteroaromatic substituted with carboxyl, using a 19 derivative of formula R 5 OH for which R 5 is alkyl or phenyl optionally substituted with one or more halogens. When R 5 is alkyl, this reaction is generally 5 carried out in the presence of an inorganic acid (sulfuric acid for example), at a temperature of between 20'C and the boiling temperature of the reaction medium. When R 5 is optionally substituted phenyl, this reaction is preferably carried out in the 10 presence of a carbodiimide (1-(3-dimethylaminopropyl) 3-ethylcarbodiimide or N,N'-dicyclohexylcarbodiimide for example), in an inert solvent such as an imide (dimethylformamide) or a chlorinated solvent (methylene chloride, 1,2-dichloroethane or chloroform for 15 example), at a temperature of between 0 0 C and the boiling temperature of the reaction mixture. The derivatives of formula (IX) for which R represents a chain C=C (S0 2

R

1 ) R' 2 or C(OR')CH(SO 2

R

1 ) R' 2' R', Ri, R' 2 , R' 3 and R', have the same meanings as the 20 substituents R', R, R 2 , R 3 and R 4 of the formula (I) with the proviso that at least one of the substituents

R'

2 , R' 3 and R', represents an aromatic or a heteroaromatic substituted with carboxyl may be obtained according to the methods described above for 25 the preparation of the compounds of formula (I) from the corresponding intermediates and in particular according to the method described in Example 29.

20 The compounds of formula (I) for which R 2 and/or R 3 and/or R. represent an aromatic or a heteroaromatic substituted with alkylthioalkyl may also be prepared by reaction of a derivative of formula (IX) 5 for which R represents a chain C=C(SOR)R' 2 or

C(OR')CH(S

2

R,)R'

2 , R', R,, R' 2 , R' 3 and R' 4 have the same meanings as the substituents R', R,, R 2 , R, and R, of the formula (I) with the proviso that at least one of the substituents R' 2 , R' and R' 4 represents an aromatic or a 10 heteroaromatic substituted with haloalkyl with sodium alkylthiolate. This reaction is generally carried out in an inert solvent such as an amide (dimethylformamide for example), at a temperature close to 20'C. 15 The derivatives of formula (IX) for which R represents a chain C=C (S0 2

R,)R'

2 or C(OR')CH(SO 2 R,) R' 2 R', Ri, R' 2 , R' 3 and R' 4 have the same meanings as the substituents R', Ri, R 2 , R 3 and R. of the formula (I) with the proviso that at least one of the substituents 20 R' 2 , R' 3 and R' 4 represents an aromatic or a heteroaromatic substituted with haloalkyl may be obtained by reacting a phosphorus trihalide (preferably phosphorus tribromide) with a corresponding compound of formula (I) for which R 2 and/or R 3 and/or R 4 represent an 25 aromatic or a heteroaromatic substituted with hydroxyalkyl, in an inert solvent such as a chlorinated solvent (carbon tetrachloride or chloroform for 21 example), at a temperature close to 20 0 C. The compounds of formula (I) for which R 2 and/or R 3 and/or R. represent an aromatic substituted with hydroxyalkyl in which the alkyl contains one 5 carbon atom may also be prepared by reducing a compound of formula (I) for which at least one of the substituents R 2 , R 3 and R. represents an aromatic substituted with formyl. This reaction is generally carried out using 10 sodium borohydride, in a 1-4C aliphatic alcohol (methanol or ethanol for example), at a temperature close to O'C. The compounds of formula (I) for which R, and/or R. represents an aromatic substituted with 15 -alk-NRR 7 for which alk is an alkyl containing one carbon atom may also be prepared by reacting a compound of formula (I) for which at least one of the substituents R 3 and R. represents an aromatic substituted with formyl with an amine HNR 6 R, in which R 20 and R 7 have the same meanings as in formula (I). This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloroethane for example), at a temperature close to 20'C in the presence of sodium triacetoxyborohydride or 25 sodium cyanobord'hydride. The compounds of formula (I) for which R 2 represents an aromatic or a heteroaromatic substituted 22 with -CONHR and/or R 3 and/or R. represents an aromatic or heteroaromatic substituted with -CO-NRR 11 may also be prepared by reacting a derivative of formula (IX) for which R represents a chain C=C(SO 2 R,)R'2 or 5 C(OR')CH(SO 2

R,)R'

2 , R' , R 1 , R' 2 , R' 3 and R' 4 have the same meanings as the substituents R', R 1 , R 2 , R, and R, of the formula (I) with the proviso that at least one of the substituents R' 2 , R' 3 and R', represents an aromatic or a heteroaromatic substituted with carboxyl with 10 respectively an amine H 2 NR, or HNR,R 1 in which R,, Rio and

R

1 have the same meanings as in formula (I). This reaction is preferably carried out in the presence of a condensing agent which is used in peptide chemistry such as a carbodiimide (for example 15 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or N,N' dicyclohexylcarbodiimide) or N,N'-carbonyldiimidazole, in an inert solvent such as an ether (tetrahydrofuran or dioxane for example), an amide (dimethylformamide) or a chlorinated solvent (methylene chloride, 1,2 20 dichloroethane or chloroform for example) at a temperature of between 0 0 C and the boiling temperature of the reaction mixture, or after prior binding of the acid to a resin of the TFP type of formula: F F OH -N F O F 25 in which S represents an aminopolystyrene resin, in an 23 inert solvent such as dimethylformamide, in the presence of 4-dimethylaminopyridine, at a temperature close to 20'C. The binding to the resin is generally carried out-in dimethylformamide, in the presence of 5 4-dimethylaminopyridine and 1,3-diisopropyl carbodiimide, at a temperature close to 20 0 C. The compounds of formula (I) for which R 2 and/or R 3 and/or R. represent an aromatic or a heteroaromatic substituted with -CO-NH-NR 6 R, may also be 10 prepared by reacting a corresponding compound of formula (I) for which R 2 and/or R 3 and/or R, represent an aromatic or a heteroaromatic substituted with -COOR 5 and

R

5 represents an alkyl or phenyl radical optionally substituted with halogens, with a hydrazine H 2 N-NR A for 15 which R 6 and R, have the same meanings as in formula (I). This reaction is generally carried out in an inert solvent such as dimethylformamide, at a temperature close to 20 0 C. 20 The compounds of formula (I) for which R 2 represents an aromatic or a heteroaromatic substituted with -CO-NHR 9 in which R 9 represents a hydrogen atom and/or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with -CO-NR 0

R

1 in which Rio 25 and R 1 are hydrogen atoms may also be prepared by hydrolysis of a corresponding compound of formula (I) for which R 2 and/or R 3 and/or R. represent an aromatic or 24 a heteroaromatic substituted with cyano. This reaction is carried out by any known method which makes it possible to pass from a nitrile to the corresponding carbamoyl without affecting the 5 rest of the molecule. Preferably, the procedure is carried out using hydrochloric acid, in acetic acid, at a temperature close to 20'C. The compounds of formula (I) for which R 2 represents an aromatic substituted with -O-alk-NR 12

R

13 10 may also be prepared by reacting a derivative of formula (IX) for which R represents a chain C=C(SOR 1

)

R'2 or C(OR' )CH(SO 2

RI)R'

2 1 RN, RI, R ,2 R 3 ' and R,' have the same meanings as the substituents R', R,, R 2 , R, and R, of the formula (I) with the proviso that at least one 15 of the substituents R2', R,' or R,' -represents an aromatic substituted with -0-alk-Hal in which alk represents an alkyl radical and Hal represents a halogen atom and, preferably, a chlorine or bromine atom, with an amine HNR 12

R

13 in which R 12

R

13 have the same 20 meanings as in formula (I). This reaction is generally carried out in an inert solvent such as acetonitrile, in the presence of an alkali metal carbonate (potassium carbonate for example), at a temperature close to 20'C. 25 The derivatives of formula (IX) for which R represents a chain C=C(SO 2

R)R'

2 or C(OR')CH(S 2

R

1

)R'

2 , R', R 1 , R 2 ', R 3 ' and R' 4 have the same meanings as the 25 substituents R', R, R 2 , R 3 and R 4 of the formula (I) with the proviso that at least one of the substituents

R

2 ', R 3 ' or R 4 ' represents an aromatic substituted with -0-alk-Hal in which alk represents an alkyl radical and 5 Hal represents a halogen atom may be obtained by reacting a corresponding compound of formula (I) for which R 2 represents an aromatic substituted with hydroxide with a Hal-alk-Hal derivative in which Hal represents a halogen. 10 This reaction is generally carried out in an inert solvent such as a ketone (methyl ethyl ketone for example), in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), at the boiling temperature of the reaction medium. 15 The compounds of formula (I) for which R 3 and/or R. represents an aromatic substituted with -alk-NR 6 R7 may also be prepared by reacting a derivative of formula (IX) for which R represents a chain C=C(S0 2

RO)R'

2 or C(OR')CH(SO 2

R

1

)R'

2 , R', R,, R2', R 3 ' and 20 R 4 ' have the same meanings as the substituents R', R,,

R

2 , R 3 and R 4 of the formula (I) with the proviso that at least one of the substituents R ' or R 4 ' represents a substituted aromatic -alk-Cl in which alk represents an alkyl radical with an amine HNR 6

R

7 in which R 6 R, have the 25 same meanings as in formula (I). This reaction is generally carried out in an inert solvent such as a chlorinated solvent 26 (dichloromethane for example), optionally in the presence of a nitrogen base such as dimethylaminopyridine, diisopropylethylamine, at a temperature of between 5 and 25*C. 5 The derivatives of formula (IX) in which R represents a chain C=C(SOA)RR' 2 or C(OR')CH(S0 2

R,)R

2 , R, Ri, R 2 1 , R 3 ' and R 4 ' have the same meanings as the substituents R', R,, R 2 , R 3 and Rd of the formula (I) with the proviso that at least one of the substituents 10 R 3 ' or R ' represents an aromatic substituted with -alk-Cl may be obtained by reacting thionyl chloride with a corresponding compound of formula (I) for which at least one of the substituents R 3 or R 4 represents an aromatic substituted with one or more hydroxyalkyl 15 radicals. This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), at a temperature of between 10 and 30'C. 20 The compounds of formula (I) for which R represents a chain B, R' represents a hydrogen atom and

R

3 and/or R 4 represents an aromatic substituted with hydroxyalkyl in which the alkyl residue contains one carbon atom may also be prepared by reacting 25 diisobutylaluminum hydride with a corresponding compound of formula (I) for which R represents a chain B, R' represents a hydrogen atom and R 3 and/or R, 27 represents an aromatic substituted with one or more

-COOR

5 radicals, in which R. is an alkyl radical. This reaction is generally carried out in toluene, at a temperature of between -30 0 C and 0 0 C. 5 The compounds of formula (I) for which R 2 represents a phenyl radical substituted with -NR 6 R, representing a 1-piperazinyl ring substituted at the 4 position with an alkyl radical may also be prepared by reacting a corresponding compound of formula (I) for 10 which R 2 represents a phenyl radical substituted with a radical -NR 6 R7 representing a 1-piperazinyl ring with an alk-CHO derivative in which alk represents a straight or branched-chain alkyl radical containing 1 to 5 carbon atoms. 15 This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloroethane or chloroform for example), in the presence of NaBH(OCOCH 3

)

3 , at a temperature close to 20 0 C. 20 The compounds of formula (I) for which R 2 represents a phenyl radical substituted with -NR 6

R

7 representing a 1-piperazinyl ring substituted at the 4 position with a radical -COOalk may also be prepared by reacting a corresponding compound of formula (I) for 25 which R 2 represents a phenyl radical substituted with a radical -NR 6

R

7 representing a 1-piperazinyl ring with a derivative of formula Hal-COOalk in which alk 28 represents an alkyl radical and Hal represents a halogen atom and, preferably, a chlorine atom. This reaction is generally carried out in pyridine, at a temperature close to 20'C. 5 The compounds of formula (I) for which R 2 represents a phenyl radical substituted with -NR 6

R

7 representing a 1-piperazinyl ring substituted at the 4 position with a radical -CO-NHalk or -CS-NHalk may also be prepared by reacting a corresponding compound of 10 formula (I) for which R 2 represents a phenyl radical substituted with -NR 6

R

7 representing a 1-piperazinyl ring with a derivative of formula Y=C=Nalk in which alk represents a straight- or branched-chain alkyl radical containing 1 to 6 carbon atoms and Y represents a 15 sulfur or oxygen atom. This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), at a temperature close to 20 0 C. 20 The compounds of formula (I) for which R 2 represents a phenyl radical substituted with a radical

-NR

6

R

1 representing a 1-piperazinyl ring substituted at the 4 position with a radical -CO-alk-NRR 15 may also be prepared by reacting a corresponding compound of 25 formula (I) for which R 2 represents a phenyl radical substituted with a radical -NR 6 R, representing a 1-piperazinyl ring with an acid of formula 29

R

15

R

14 N-alk-COOH in which alk represents an alkyl radical and R 4 and R 15 have the same meanings as in formula (I), optionally followed by deprotection of the product for which R 4 is a tert-butoxycarbonyl radical in order to 5 obtain the compounds for which R 14 is a hydrogen atom. This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloroethane for example), at a temperature close to 20*C. The deprotection is carried out using formic acid 10 at a temperature close to 20 0 C. The compounds of formula (I) for which R 2 represents a phenyl radical substituted with a radical

-NR

6

R

7 representing a 1-piperazinyl ring substituted at the 4 position with a radical -CO-alk in which alk 15 represents a methyl radical may also be prepared by reacting a corresponding compound of formula (I) for which R 2 represents a phenyl radical substituted with a radical -NR 6

R

7 representing a 1-piperazinyl ring with acetic anhydride. 20 This reaction is generally carried out in the presence of pyridine, at a temperature close to 20 0 C. It is understood for persons skilled in the art that, to carry out the processes according to the invention which are described above, it may be 25 necessary to introduce groups protecting amino, hydroxyl and carboxyl functions in order to avoid side reactions. These groups are those which allow removal 30 without affecting the rest of the molecule. As examples of groups protecting the amino function, there may be mentioned tert-butyl or methylcarbamates which may be regenerated using iodotrimethylsilane or allyl using 5 palladium catalysts. As examples of groups protecting the hydroxyl function, there may be mentioned triethylsilyl and tert-butyldimethylsilyl which may be regenerated using tetrabutylammonium fluoride or alternatively asymmetric acetals (methoxymethyl or 10 tetrahydropyranyl for example) with regeneration using hydrochloric acid. As groups protecting carboxyl functions, there may be mentioned esters (allyl or benzyl for example), oxazoles and 2-alkyl-1,3 oxazolines. Other protecting groups which can be used 15 are described by GREENE T.W. et al., Protecting Groups in Organic Synthesis, second edition, 1991, John Wiley & Sons. The compounds of formula (I) may be purified by the customary known methods, for example by 20 crystallization, chromatography or extraction. The enantiomers of the compounds of formula (I) may be obtained by resolution of the racemates for example by chromatography on a chiral column according to PIRCKLE W.H. et al., Asymmetric synthesis, Vol. 1, 25 Academic Press (1983) or by formation of salts or by synthesis from chiral precursors. The diastereoisomers may be prepared according to known conventional methods 31 (crystallization, chromatography or from chiral precursors). The compounds of formula (I) may be optionally converted to addition salts with an 5 inorganic or organic acid by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. These salts also form part of the invention. As examples of pharmaceutically acceptable 10 salts, the following salts may be mentioned: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methane sulfonate, methylene-bis 9-oxynaphtoate, nitrate, oxalate, pamoate, phosphate, 15 salicylate, succinate, sulfate, tartrate, theophyllineacetate and p-toluenesulfonate. The compounds of formula (I) exhibit advantageous pharmacological properties. These compounds possess a high affinity for the cannabinoid 20 receptors and particularly those of the CBl type. They are CBI receptor antagonists and are therefore useful in the treatment and prevention of disorders affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory 25 system, the gastrointestinal apparatus and reproductive disorders (Hollister, Pharm. Rev.; 38, 1986, 1-20, Reny and Sinha, Prog. Drug Res., 36, 71-114 (1991), Consroe 32 and Sandyk, in Marijuana/Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds, CRC Press, 1992) of bacterial, viral and parasitic infections. 5 Accordingly, these compounds may be used for the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, cranial trauma, panic 10 attacks, peripheral neuropathies, glaucomas, migraine, Parkinson's disease, Alzeimer's disease, Huntington's chorea, Raynaud's syndrome, tremor, obsessive compulsive disorder, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar 15 disorders, cancers, movement disorders induced by medicaments, dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory 20 disorders, in weaning from chronic treatments and alcohol or drug abuse (opiods, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines for example), as analgesics or potentiators of the analgesic activity of the narcotic 25 and nonnarcotic drugs. They may also be used for the treatment or prevention of intestinal transit disorders, as antibacterial, antiviral and 33 antiparasitic agents. The affinity of the compounds of formula (I) for the cannabis receptors has been determined according to the method described by KUSTER J.E., 5 STEVENSON J.I., WARD S.J., D'AMBRA T.E., HAYCOCK D.A. in J. Pharmacol. Exp. Ther., 264 1352-1363 (1993). In this test, the IC,, of the compounds of formula (I) is less than or equal to 100 nM. Their antagonist activity has been shown by 10 means of the model of hypothermia induced by an agonist of the cannabis receptors (CP-55940) in mice, according to the method described by Pertwee R.G. in Marijuana, Harvey D.J. eds, 84 Oxford IRL Press, 263-277 (1985). In this text the ED50 of the compounds of 15 formula (I) is less than or equal to 50 mg/kg. The compounds of formula (I) exhibit low toxicity. Their LD 50 is greater than 40 mg/kg by the subcutaneous route in mice. The preferred compounds of formula (I) are 20 those for which R represents a chain (A) or (B) and R' represents a hydrogen atom or a -COalk radical, R represents a methyl or ethyl radical,

R

2 represents either an aromatic chosen from phenyl and 25 naphthyl, these aromatics being nonsubstituted or substituted with one or more halogens, alkyl, alkoxy, hydroxyl, -COOR., trifluoromethyl, trifluoromethyl- 34 sulfanyl, trifluoromethoxy, -NRR,, -CO-NH-NRR,, cyano,

-CONHR

9 , alkylsulfanyl, hydroxyalkyl, nitro, -CO-NR 16 Rl, -O-alkNR 12

R

13 or alkylthioalkyl or a heteroaromatic chosen from isoquinolyl, pyridyl, quinolyl, 5 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl and thienyl, these heteroaromatics being unsubstituted or substituted with a halogen, alkyl, alkoxy, -COOR,, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, -NR 6 R, 10 -CO-NH-NR 6

R

7 , cyano, -CONHR 9 , alkylsulfanyl, hydroxyalkyl, nitro or alkylthioalkyl,

R

3 and R 4 , which are identical or different, represent either an aromatic chosen from phenyl or naphthyl, these aromatics being nonsubstituted or substituted 15 with one or more halogens, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CONR 0

R

1 , -alk-NRR 7 , hydroxyalkyl, formyl or -COOR,, or a heteroaromatic chosen from thiazolyl or thienyl rings, these heteroaromatics being unsubstituted or substituted with 20 a halogen, alkyl, alkoxy, -CONRR, 1 , -alk-NRR

,

, hydroxyalkyl or -COOR .

R

5 is alkyl or phenyl which is optionally substituted with one or more halogens,

R

6 and R 7 , which are identical or different, represent a 25 hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl,-alk-O-alk or hydroxyalkyl radical or alternatively R 6 and R 7 together form with the nitrogen 35 atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally 5 substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR 14

R,

15 oxo, hydroxyalkyl, alk-0-alk or -CO-NH 2 radicals,

R

9 represents a hydrogen atom or an alkyl radical or an alkyl radical substituted with dialkylamino, phenyl, 10 cycloalkyl (optionally substituted with -COOalk) or a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl 15 radicals, Rio and R 1 , which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Rio and R 11 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono 20 or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl radical,

R

12 and R, 13 which are identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical or 25 alternatively R 12 and R 13 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle optionally 36 containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk or -CO-alk-NRR 15 radical or a 3- to 10-membered saturated 5 mono- or bicyclic heterocycle containing a heteroatom chosen from oxygen, sulfur and nitrogen,

R

14 and R, 5 , which are identical or different, represent a hydrogen atom or an alkyl or -COOalk radical,

R

16 and R.

7 together form with the nitrogen atom to which 10 they are attached a 3- to 10-membered saturated mono or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen, alk represents an alkyl or alkylene radical, their optical isomers and their salts with an inorganic 15 or organic acid. The compounds of formula (I) which are particularly preferred are those for which R represents a chain (A) or (B), R' representing a hydrogen atom or a radical -COalk, 20 R. represents a methyl or ethyl radical,

R

2 represents either an aromatic chosen from naphthyl, phenyl, phenyl substituted with one or more halogen, alkyl, 25 alkoxy, hydroxyl, -COOR, (in which R. represents an alkyl or phenyl radical optionally substituted with several halogens) trifluoromethyl, trifluoromethyl- 37 sulfanyl, trifluoromethoxy, -NR 6

R

7 (in which R, and R,, which are identical or different, represent a hydrogen atom or an alkyl or -COOalk radical or alternatively R 6 and R 7 together form with the nitrogen atom to which 5 they are attached a heterocycle chosen from pyrrolidinyl, piperidyl, piperazinyl or piperazinyl substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk or -CO-alk-NRR 15 radicals, in which R 4 and R 5 , which are identical or different, 10 represent a hydrogen atom or an alkyl radical),

-CO-NH-NR

6 R, (R 6 and R 7 , which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R 6 and R 7 together form with the nitrogen atom to which they are attached a 15 heterocycle chosen from piperidyl, piperazinyl or piperazyl substituted with one or more alkyl radicals), cyano, -CONHR, (in which R, represents a hydrogen atom or an alkyl radical or an alkyl radical substituted with dialkylamino, phenyl, cycloalkyl (optionally 20 substituted with -COOalk) or a heterocycle chosen from pyrrolidinyl (optionally substituted with alkyl), tetrahydrofuryl, or morpholinyl), alkylsulfanyl, hydroxyalkyl, nitro, -CO-NR 16

R

17 , (in which R 16 and R 17 together form with the nitrogen atom to which they are 25 attached a piperidyl ring), -O-alkNR 12 RI, (in which R 12 and R 13 together form with the nitrogen atom to which they are attached a morpholino ring) or alkylthioalkyl, 38 or a heteroaromatic chosen from isoquinolyl, pyridyl, quinolyl, 5 1, 2, 3, 4-tetrahydroisoquinolyl, 1,2, 3, 4-tetrahydroquinolyl, thienyl, or thienyl substituted with a -COOR, (in which R, represents an alkyl radical) or -CONHR,, (in which R, 10 represents an alkyl radical),

R

3 and R 4 , which are identical or different, represent either an aromatic chosen from phenyl or phenyl substituted with one or more halogen, alkyl, 15 alkoxy, trifluoromethyl, trifluoromethoxy, hydroxyalkyl, formyl, -COOR, (in which R, is an alkyl radical), -CONR,R 1 (in which R 1 , and R,,, which are identical or different, represent a hydrogen atom or an alkyl radical), -alk-NR 6 R, (in which R, and R,, which are 20 identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, -alk-0-alk or hydroxyalkyl radical or alternatively R 6 and R, together form with the nitrogen atom to which they are attached a heterocycle chosen from piperidyl (optionally substituted with 25 alkyl or oxo), pyrrolidinyl (optionally substituted with alkyl, hydroxyalkyl, -alk-0-alk or -CO-NH 2 ), thiomorpholinyl, morpholinyl, pyrrolyl, piperazinyl 39 optionally substituted with oxo, alkyl, hydroxyalkyl, -COOR, (in which R, is an alkyl radical), or a heteroaromatic chosen from thiazolyl or 5 thienyl, alk represents an alkyl or alkylene radical, their optical isomers and their salts with an inorganic or organic acid. Preferably, R 2 is a substituted phenyl 10 radical, the latter is monosubstituted and, in particular, at the 3-position or alternatively disubstituted and, in particular at the 3,5, 2,5 or 2, 3-positions. Preferably, when R 3 is a substituted phenyl 15 radical, the latter is monosubstituted and, in particular, at the 4-position or disubstituted and, in particular, at the 2,4-positions. Preferably, when R 4 is a substituted phenyl radical, the latter is monosubstituted and, in 20 particular, at the 4-position or disubstituted and, in particular, at the 2,4-positions. The following compounds may be mentioned among the preferred compounds: 25 1-benzhydryl-3- [ (methylsulfonyl) (phenyl)methylene] azetidine, 1-benzhydryl-3- 40 [(3-methyiphenyl) (methylsulfonyl)methylene] azetidine, 1-benzhydryl-3- [(3-chiorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3, 5-dichiorophenyl) (methylsulfonyl) 5 methylene] azetidine, 1-benzhydryl-3- [(2, 5-dichiorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(2, 3-dichiorophenyl) (methylsulfonyl) methylene] azetidine, 10 1-benzhydryl-3- [(3-f luorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3-bromophenyl) (methylsulfonyl) 15 methylene] azetidine, 1-benzhydryl-3- [(3-iodophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethoxy phenyl) methylene] azetidine, 20 1-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethyl phenyl) methylene] azetidine, 1-benzhydryl-3-{ [3, 5-bis (trifluoromethyl)phenyl] (methylsulfonyl )methylene} azetidine, 1-benzhydryl-3- [(3, 5-dibromophenyl) (methylsulfonyl) 25 methylene] azetidine, 1-benzhydryl-3- [(3-methoxycarbonyiphenyl) (methylsulfonyl )methylene] azetidine, 41 1-benzhydryl-3- II(3-cyanophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine, 5 1-benzhydryl-3- II(3-carbamoyiphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3-[I(methylsulfonyl) (naphth-1-yl) (methylsulfonyl)methylene] azetidine, 1- [bis (4-chlorophenyl)methyl] -3- [(3, 5-difluorophenyl) 10 (methylsulfonyl)methylene] azetidine, 1-[bis(4-methoxyphenyl)methyl]-3-[ (3,5-difluorophenyl) (rethylsulfonyl)methylene] azetidine, 1- [bis (4-methylphenyl)methyl] -3- [(3, 5-difluorophenyl) (methylsul fonyl) methylene] azetidine, 15 (RS)-3- [(3, 5-difluorophenyl) (methylsulfonyl)methylene] 1-1 (4-methoxyphenyl) (phenyl)methyl) ]azetidine, (R) -3- [(3,5-difluorophenyl) (methylsulfonyl)methylene] 1- [(4-methoxyphenyl) (phenyl)methyl) ]azetidine, (S)-3-[ (3, 5-difluorophenyl) (methylsulfonyl)methylene] 20 1- [(4-rethoxyphenyl) (phenyl)methyl) ]azetidine, 1- [bis(4-trifluoromethoxyphenyl)methyl]-3-[ (3,5 difluorophenyl (methylsulfonyl)methylene] azetidine, 1- [bis (4-trifluoromethylphenyl)methyl] -3-[(3,5 difluorophenyl (methylsulfonyl) methylene] azetidine, 25 1-[bis(4-chlorophenyl)methyl]-3-{[(3,5-bis (trifluoromethyl)phenyl] methylsulfonylmethylene} azetidine, 42 (RS) -1- [(4-chiorophenyl) (2, 4-dichlorophenyl)methyl] 3- [(3, 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (R)-1- [(4-chiorophenyl) (2,4-dichlorophenyl)methyl] 5 3- [(3, 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (S)-1- [(4-chiorophenyl) (2,4-dichlorophenyl)methyl] 3- [(3, 5-difluorophenyl) (methylsulforiyl)methylene] azetidine, 10 (RS) -1-{(4-chiorophenyl) [4-hydroxyrnethyl)phenyl] methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R)-l-{ (4-chiorophenyl) [4- (hydroxymethyl)phenyl] methyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) 15 methylene] azetidine, (S)-1--{ (4-chiorophenyl) [4- (hydroxymethyl)phenyl] methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS)-1-{ (4-chiorophenyl) [4- (pyrrolidylmethyl) 20 phenyl]rnethyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R)-1-{ (4-chiorophenyl) [4- (pyrrolidylmethyl)phenyl] methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 25 (S)-1-{ (4-chiorophenyl) [4- (pyrrolidylrnethyl)phenyl] methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylenel azetidine, 43 1-{ (RS)- (4-chiorophenyl) [4- (3,3-dimethylpiperidin-1-yl methyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl)methylenel azetidine, 1-{ (R)-(4--chlorophenyl) [4- (3,3-dimethylpiperidin-1-yl 5 methyl)phenyllrnethyl}-3- [(3, 5-difluorophenyl) (methyl sulfonyl) methylene] azetidine, 1-{ (S) -(4-chiorophenyl) [4- (3,3-dimethylpiperidin-l-yl methyl)phenyllmethyl}-3- [(3, 5-difibuorophenyl) (methylsulfonyl) methylene] azetidine, 10 l-{ (RS)-(4-chlorophenyl) [4-(thiomorpholin-4 ylmethyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, l-{ (R) -(4-chiorophenyl) [4- (thiomorpholin-4 ylmethyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) 15 (methylsulfonyl)methylenelazetidine, l-{ (S)- (4-chiorophenyl) [4-(thiomorpholin-4 ylmethyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl )methylene] azetidine, 1-{ (RS) -(4-chiorophenyl) [4- (N-ethyl-N 20 cyclohexylaminomethyl)phenyllmethyl}-3- [(3,5 difluorophenyl) (methylsulfonyl)methylene] azetidine, l-{ (R)-(4-chlorophenyl) [4- (N-ethyl-N cyclohexylaminomethyl)phenyllrnethyl}-3- [(3,5 difluorophenyl) (methylsulfonyl)methylene] azetidine, 25 1-{ (S)- (4-chiorophenyl) [4- (N-ethyl-N cyclohexylaminomethyl) phenyllmethyl} -3- [(3,5 difluorophenyl) (methylsulfonyl)methylene] azetidine, 44 1-{ {(RS) -(4-chiorophenyl) {4- [(4-ethoxycarbonyl piperazinyl)rnethyl]phenyl}methyl}}-3- [(3,5 difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-{ {(R) -(4-chiorophenyl) {4- [(4-ethoxycarbonyl 5 piperazinyl)methylpheyllmfethy.}}-3- [(3,5 difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-{{ (S)-(4-chlorophenyl) {4-[ (4-ethoxycarbonyl piperazinyl)methyllphenyl}methyl}}-3-[ (3,5 difluorophenyl) (methylsulfonyJ~methylene] azetidine, 10 1-{ (RS)- (4-chiorophenyl) [4- (N-cyclopropyl-N-propyl aminomethyl) phenyllmethyl} -3- [(3, 5-difluorophenyl) (rethylsulfonyl)methylene] azetidine, 1-{ (R)- (4-chiorophenyl) [4- (N-cyclopropyl-N-propyl aminomethyl) phenyl ]methyl} -3- [(3, 5-difluorophenyl) 15 (methylsulfonyl)methylene]azetidine, 1-{ (S)- (4-chiorophenyl) [4- (N-cyclopropyl-N-propyl aminomethyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-{ (RS) -(4-chiorophenyl) [4- (diisopropylaminomethyl) 20 phenyllmethyl}-3- [(3,5-difluorophenyl) (methyl sulfonyl)methylenel azetidine, 1-{ (R) -(4-chiorophenyl) [4- (diisopropylaminomethyl) phenyllmethyl}-3- [(3, 5-difluorophenyl) (methyl sulfonyl) methylene] azetidine, 25 1-{ (S) -(4-chiorophenyl) [4- (diisopropylaminomethyl) phenyllmethyl}-3- (3, 5-difluorophenyl) (methyl sulfonyl) methylene] azetidine, 45 1-{{ (RS)- (4-chiorophenyl) {4-[bis-(2-methoxyethyl)amino methyllphenylimethyl} 1-3- [(3, 5-difluorophenyl) (methylsulfonyl)methylenelazetidine, 1-{{ (R)-(4-chlorophenyl) {4-[bis-(2-methoxyethyl)amino 5 methyllphenyl}methyl}}-3-[ (3,5-difluorophenyl) (methylsulfonyl)methylenelazetidine, 1- {{ (S) -(4-chiorophenyl) {4- [bis- (2-methoxyethyb) amino methyl]phenyllmethyl} 1-3-11(3, 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 10 1-{ (RS) -(4-chiorophenyl) [4- (di-n-propylamino methyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-{ (R) -(4-chiorophenyl) [4- (di-n-propylamino rethyl)phenyllmethyll-3- [(3, 5-difluorophenyl) 15 (methylsulfonyl)methylenelazetidine, 1-{ (S) -(4-chiorophenyl)[14- (di-n-propylamino methyl)phenyllmethyl}-3-[1(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-{ (RS)- (4-chiorophenyl) [4- (piperidin-1-ylmethyl) 20 phenyllmethyl}-3-[1(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-{ (R) -(4-chiorophenyl) [4- (piperidin-1-ylmethyl) phenyllmethyl}-3-[1(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine., 25 1-{ (S)- (4-chiorophenyl) [4- (piperidin-1-ylmethyl) phenyllmethyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 46 1-{ (RS) -(4-chiorophenyl) [4- (4-methylpiperazin-1-yl methyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) (methyl sulfonyl )methylene] azetidine, 1-{ (R)-(4-chlorophenyl) [4-(4-methylpiperazin-1-yl 5 methyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) (methyl sulfonyl )methyibene] azetidine, 1-{ (S)- (4-chiorophenyl) [4- (4-methylpiperazin-1-yl methyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) (methyl sulfonyl )methylene] azetidine, 10 1-{ (RS)-(4-chlorophenyl) [4- (morpholin-4-yl methyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-{ (R) -(4-chiorophenyl) [4- (morpholin-4-yl methyl)pheriyllmethyl}-3- [(3, 5-difluorophenyl) 15 (methylsulfonyl)rnethylene] azetidine, 1-{ (S)-(4-chlorophenyl) [4- (morpholin-4-yl methyl)phenyllmethyl}-3- [(3,5-difluorophenyl) (xethylsulfonyl)methylene] azetidine, 1-{ (RS) -(4-chiorophenyl) [4- (diethylaminomethyl) 20 phenyllmethyl}-3-[ (3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, l-{ (R) -(4-chiorophenyl) [4- (diethylaminomethyl) phenyllmethyl}-3-[ (3,5-difluorophenyl) (methylsulfonyl)methylenel azetidine, 25 1-{ (S)- (4-chiorophenyl) [4- (diethylaminomethyl) phenyllmethyl}-3- [(3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 47 1-{ (RS)-(4-chlorophenyl) [4-(piperazin--2-on-4-yl methyl)phenyllmethyll-3- [3, 5-difluorophenyl) (methyl sulfonyl)methylene] azetidine, 1-{ (R)-(4-chlorophenyl) [4- (piperazin-2-on-4-yl 5 methyl)phenyllmethyl}-3-[ (3,5-difluorophenyl) (methyl sulfonyl) methylene] azetidine, 1-{ (S)-(4-chlorophenyl) [4- (piperazin-2-on-4-yb methyl)phenyllmethyl}-3- [3, 5-difluorophenyl) (methyl sulfonyl)methylene] azetidine, 10 1-{(RS)-(4-chlorophenyl) [4-(imidazol-1-yl methyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) (methyl sulfonyl)methylene] azetidine, 1-{ (R)-(4-chloropheayl) [4-(imidazol-l-yl methyl)phenyl]methyl}-3-[ (3,5-difluorophenyl) (methyl 15 sulfonyl)methylene] azetidine, 1-{ CS) -(4-chiorophenyl) [4- (imidazol-l-yl methyl)pheriyllmethyl}-3- [(3, 5-difluorophenyl) (methyl sulfonyl) methylenel azetidine, (RS) -1-{(4-chiorophenyl) [4- (N,N-dimethylcarbamoyl) 20 phenyllmethyl}-3- [(3,5-difluorophenyl) (rethylsulfonyl) methylene] azetidine, CR) -1-{(4-chiorophenyl) [4- (N,N-dimethylcarbamoyl) phenyllmethyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 25 (S)-l-{ (4-chiorophenyl) [4- (N,N-dimethylcarbamoyl) phenyllmethyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 48 (RS)-1-{ (4-chiorophenyl) [4- (N-ethylcarbamoyl)phenyl] methyl}-3- [(3, 5-difluorophenyl)(methylsulfonyl) methylene] azetidine, (R) -1-{ (4-chiorophenyl) [4- (N-ethylcarbamoyl)phenyl] 5 methyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S)-l-{ (4-chiorophenyl) [4- (N-ethylcarbamoyl)phenyl] methyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 10 (RS) -1-[ (4-carbamayiphenyl) (4-chlorophenyl)methyl] 3- [(3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (R) -1-[ (4-carbamayiphenyl) (4-chlorophenyl)methyl] 3- [(3,5-difluorophenyl) (methylsulfonyl)methylene] 15 azetidine, (S) -1-f(4-carbamoylphenyl) (4-chlorophenyl)methyl] 3- [(3, 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[ (3,5-dichiorophenyl) 20 (methylsulfonyl)methylene] azetidine, 1-benzhydryl-3- [(3-methylsulfanyiphenyl) (methylsulfonyl)methylene] azetidine, 1-benzhydryl-3- [(3-methylsulfanylmethyl)phenyl) 1 (methylsulfonyl) methylene] azetidine, 25 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl) (methylsulfonyl)methylene] azetidine, 1- [bis (4-chlorophenyl)methyl] -3- [(3-carbamoylphenyl) - 49 (methylsulfonyl)methylelel azetidine, 1- [bis (4-chlorophenyl)methyl] -3-f (3-methoxyphenyl) (methylsulfonyl )methylene] azetidine, 1-f bis(4-chlorophenyl)mfethyl]-3-[(3-hydroxyphenyl) 5 (methylsulfonyl)nethylelazetidine, 1- [bis (4-chlorophenyl)methyll -3- [(3-methylsulfonyl) (3 -pyrrolidinyiphenyl )methylenel azetidine, 1- [bis (4-chlorophenyl)methyll -3-f (3-hydroxymethyl phenyl) (methylsulfonyl)methylene] azetidine, 10 1-[bis(4-chlorophenyl)methyl]3-{ (methylsulfonyl) [3-(N piperidylcarbamoyl )phenyl ]methylene }azetidine, 1- [bis (4-chlorophenyl)methyl] -3-f (methylsulfonyl) (3-trifluoromethylsulfanylphelyl) (rethyibsulfonyl) methylene] azetidine, 15 1-[bis(4-fluoropheny1)methy1]-3-[(3,%-dif1uorophel) (methylsulfonyl) methylene] azetidine, 1- [bis (2-fluorophenyl)methyl] -3- [(3, 5-difluorophenyl) (methylsulfonyl)methylele] azetidine, 1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophelyl) 20 (methylsulfonyl)methylene] azetidine, (RS)-1-f (4-chiorophenyl) (thiazol-2-yl)methyl] 3-f (methylsulfonyl) (phenyl)methylene] azetidine, (R)-1- [(4-chiorophenyl) (thiazol-2-yl)methyl] 3-f (methylsulfonyl) (phenyl)inethylene] azetidine, 25 (S)-1-f (4-chiorophenyl) (thiazol-2-yl)rnethyl] 3-f (methylsulfonyl) (phenyl)methylene]azetidine, (RS)-1-[(4-chlorophenyl) (thien-2-y1)methyl]-3-[(3,5- 50 difluorophenyl) (methylsulfonyl)methylene] azetidine, (R)-l-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene] azetidine, (S)-1-[(4-chlorophenyl) (thien-2-yl)methyll-3-[(3,5 5 difluorophenyl) (rethylsulfonyl)methylene] azetidine, 1-benzhydryl-3- [(ethylsulfonyl) (phenyl)methylene] azetidine, 1- [bis (4-chlorophenyl)methyl] -3-{ {3- [N- (4 methylpiperazinyl) carbamoyllphenyl} (methylsulfonyl) 10 methylene] azetidine, 1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2 dimethylcarbohydrazido)phenyl] (methylsulfonyl) methylene Iazetidine, 1- [bis (thien-2-yl)methyl] -3- [3, 5-difluorophenyl) 15 (methylsulfonyl)methylene] azetidine, 1-[bis(p-tolyl)methyl]-3-[ (methylsulfonyl) (phenyl) methylene] azetidine, 1- [4-chiorophenyl) (4-hydroxymethyiphenyl )methyl] 3- [(3,5-difluorophenyl) (methylsulfonyl)methylene] 20 azetidine, 1- [bis (4-chlorophenyl)methyll -3- [(3-methylaminophenyl) (rethylsulfonyl)methylenel azetidine, (RS)-1-[(4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)rnethylene] azetidine, 25 (R)-1-[(4-chlorophenyl) (thiazol-2-yl)methyll-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene] azetidine, (S)-l-[(4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5- 51 difluorophenyl) (methylsulfonyl)methylenelazetidine, 1- [bis(4-chlorophenyl)methyl]-3-[ (methylsulfonyl) (2 methoxycarbonylthien-5-y)methylene] azetidine, -1- Ibis (4-chlorophenyl)methyl] -3-hydroxy-3- [(methyl 5 sulfonyl) (2-methoxycarbonylthien-5-yl)methyl] azetidine (RS), 1- [bis (4-chlorophenyl)methyl] -3-I (2-isobutyl aminocarbonylthien-5-yl) (methylsulfonyl) methylene] azetidine, 10 1- Ibis (4-chlorophenyl)methyl] -3-[l(3-methoxycarbonyl phenyl) (methylsulfonyl)methyl- (RS) azetidin-3-ol, 1- [bis (4-chlorophenyl)methyl] -3-[l(methylsulfonyl) (pyridin-4-y1)methyl- (RS)azetidin-3-ol, 1- Ibis (4-chlorophenyl)methyl] -3-[l(methyilsulfonyl) 15 (pyridin-3-y1)methyl- (RS)azetidira-3-o1, 3- ({1-[bis(4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N- (3-morpholin-4-yl propyl) benzamide, 3- ({1-[bis (4-chlorophenyl)methyl] azetidin-3-ylidene} 20 methanesulfonylmethyl) -N- (3-dimethylaminopropyl) benzamide, 3- ({1-[bis(4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N- (2-pyrrolidin-1-ylethyl) benzarnide, 25 3- ({1-[bis(4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N- (2-dimethylamino-1 methylethyl )benzamide, 52 3- ({l-Ibis(4-chlorophenyl)methyliazetidin-3-ylidene} methanesulfonylmethyl) -N-piperidin-1-ylbenzamide, 3- ({1-[bis(4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N-isobutylbenzamide, 5 3- ({1-[bis(4-chlorophenyl)methyllazetidi-3-ylidele} methanesulfonylmethyl) -N-(3-imidazol-1-ylpropyl) benzamide, 3- ((1-[bis (4-chlorophenyl)methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (2 -dimethylaminoethyl) 10 benzamide, 3- ({1-[bis- (4-chlorophenyl)methyllazetidin-3 ylidene}methanesulfonylmethyl)benzoic acid N' methyihydrazide, 3- ({1-[bis- (4-chlorophenyl)methyl] azetidin-3-ylidene} 15 methanesulfonylmethyl) -N- (2-morpholin-4-ylethyl) benzamide, 3- ({1-[bis- (4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N- (1-ethylpyrrolidin-2 ylmethyl) benzamide, 20 3-({1-[bis- (4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N- (2, 2-dimethyipropyl )benzamide, 3-({l-[bis-(4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N-cyclohexylmethylbenzamide, 3- ({1-[bis- (4-chlorophenyl)methyllazetidin-3-ylidene} 25 methanesulfonylmethyl) -N-cyclopropylmethylbenzamide, 3- ({1-[bis- (4-chlorophenyl)methyl]azetidin-3-ylidene} methanesul fonylmethyl) -N- (2 -methylbutyl) benzamide, 53 3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene} methanesulfonylmethyl)-N-(2-phenylpropyl)benzamide, 3-({1-[bis-(4-chlorophenyl)methyljazetidin-3-ylidene} methanesulfonylmethyl)-N-(tetrahydrofuran-2 5 ylmethyl)benzamide, 3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene} methanesulfonylmethyl)-N-(2,2-diphenylethyl)benzamide, 3-({l-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene} methanesulfonylmethyl)-N-(2-ethylbutyl)benzamide, 10 4-{,[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl)benzoylamino]methyl}cyclo hexanecarboxylic acid methyl ester, 2-amino-l-{4-[3-({1-[bis-(4-chlorophenylimethyl] azetidin-3-ylidene}methanesulfonyl 15 methyl)phenyllpiperazin-1-yl}ethanone, (2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2 oxoethyl)carbamic acid tert-butyl ester, 1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3 20 ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2 methylaminoethanone, (2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2 oxoethyl)-N-methylcarbamic acid tert-butyl ester, 25 4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl)phenyl]piperazine-1 carbothioic acid N-methylamide, 54 4-[3-({l-[bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl)phenyl]piperazine-1 carboxylic acid N-methylamide, 4-[3-({l-[bis(4-chlorophenyl)methyl]azetidin-3 5 ylidene}methanesulfonylmethyl)phenyl]piperazine-1 carboxylic acid methyl ester, 1-[3-({1-[bis(4-chlorophenyl)methyllazetidin-3 ylidene}methanesulfonylmethyl)phenyl]-4 isobutylpiperazine, 10 1-[3-({l-[bis(4-chlorophenyl)methyllazetidin-3 ylidene}methanesulfonylmethyl)phenyl]-4 ethylpiperazine, 4-acetyl 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin 3-ylidene}methanesulfonylmethyl)phenyl piperazine, 15 1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2 dimethylaminoethanone, 1-[3-({1-[bis(4-chlorophenyl)methyliazetidin-3 ylidene}methanesulfonylmethyl)phenyl]piperazine, 20 4-[3-({1-[bis(4-chlorophenyl)methyllazetidin-3 ylidene}methanesulfonylmethyl)phenyl]piperazine-1 carboxylic acid tert-butyl ester, 1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene]azetidine, 25 3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3 [(3,5-difluorophenyl) (methylsulfonyl)methyl (RS)azetidine, 55 (RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluorophenyl) methanesulfonylmethylene]azetidin-1-yl}methyl) benzyl]morpholine, 4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methane 5 sulfonylmethyl]phenoxy}butyl)morpholine, 4-(4-{3-[(l-benzhydrylazetidin-3-ylidene)methane sulfonylmethyl]phenoxy}propyl)morpholine, their optical isomers and their esters. Among these compounds, the following 10 compounds are particularly preferred; 1-[bis(4-chlorophenyl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluoro phenyl) (methylsulfonyl)methylene(RS)]azetidin-3-ol, 15 3-acetoxy-l-[bis(4-chlorophenyl)methyl]-3-[(3,5 difluorophenyl)(methylsulfonyl)methyl)methyl sulfonylmethyl(RS)]azetidine their optical isomers and their salts with an inorganic or organic acid. 20 The following examples illustrate the invention without limiting it. Example 1 25 0.3 cm 3 of methanesulfonyl chloride is added to a solution of 1 g of 1-benzhydryl 3-[(methylsulfonyl) (phenyl)methyl-(RS)]azetidin-3-ol in 56 10 cm 3 of pyridine, cooled to 5'C. The mixture is stirred for 2 hours at 5*C and then 1 g of 4-dimethylaminopyridine is added in 10 cm 3 of dichloromethane at 5 0 C. The solution is stirred for 5 15 hours at room temperature and then concentrated to a dryness under reduced pressure (2.7 kPa). The residue obtained is chomatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm), eluting at a nitrogen pressure of 0.5 bar with 10 dichloromethane and collecting 80 cm fractions. Fractions 17 to 20 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 10 cm of ethyl ether. 0.14 g of 1-benzhydryl 15 3-[(methylsulfonyl) (phenyl)methylene]azetidine is obtained melting at 210'C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 2.95 (3H, s, SCH 3 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH 20 arom.), between 7.40 and 7.60 (9H, m, 9 CH arom.)]. 1-Benzhydryl-3-[(methylsulfonyl) (phenyl) methyl-(RS)]azetidin-3-ol may be obtained in the following manner: 6.25 cm' of 1.6 N n-butyllithium in solution in hexane are added to a solution of 1.4 cm 3 of 25 diisopropylamine in 10 cm of tetrahydrofuran, under an argon atmosphere, cooled to OC, and then the mixture is cooled to -70'C. A mixture of 1.7 g of benzyl methyl 57 sulfone in 30 cm 3 of tetrahydrofuran are then added and the stirring is maintained for 45 minutes at -70 0 C. 2.4 g of 1-benzhydrylazetidin-3-one are added and then the mixture is stirred for 20 minutes while allowing the 5 mixture to return to room temperature. The reaction mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 50 cm 3 of ethyl acetate, 30 cm 3 of water and 20 cm 3 of normal hydrochloric acid. The precipitate is 10 filtered, washed with 30 cm 3 of distilled water, drained and dried. 2 g of 1-benzhydryl 3-[(methylsulfonyl) (phenyl)methyl-(RS)]azetidin-3-ol are obtained melting at 260 0 C. 1-Benzhydrylazetidin-3-one may be prepared 15 according to the procedure described by KATRITZKY A.R. et al. in J. Heterocycl. Chem., 271 (1994). Example 2 20 On carrying out the operation according to the procedure of Example 1 starting with 1.9 g of 1-benzhydryl-3-[(3-methylphenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol, 0.52 cm 3 of methanesulfonyl chloride and 1.7 g of 4-dimethylaminopyridine, the residue 25 obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 17 cm) at a nitrogen pressure of 0.5 bar with 58 dichloromethane and then a dichloromethane and ethanol mixture (98.5/1.5 by volume) as eluents and collecting 100 cm' fractions. Fractions 5 and 6 are combined and concentrated to dryness under reduced pressure (2.7 5 kPa). The solid obtained is crystallized from 2 cm of dichloromethane and 20 cm of diisopropyl ether. 0.9 g of 1-benzhydryl-3-[(3-methylphenyl) (methylsulfonyl) methylene]azetidine is obtained melting at 180'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.35 10 (3H, s, PhCH,), 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 7.20 (5H, m, 5CH arom.), 7.30 (5H, t, J=7Hz, 5CH arom.), 7.50 (4H, d, J=7Hz, 4 CH arom.)]. 1-Benzhydryl-3-[(3-methylphenyl) 15 (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 2.8 g of methyl(3-methylbenzyl)sulfone and 3.6 g of 1-benzhydrylazetidin-3-one, 2.6 g of a 20 solid are obtained after purification on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar with a dichloromethane and ethanol mixture (98.5/1.5 by volume) as eluent. The solid is taken up in 25 cm 3 of 25 diisopropyl ether. After filtration, draining and drying, 1.9 g of 1-benzhydryl-3-[(3-methylphenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained 59 melting at 170'C. Methyl(3-methylbenzyl)sulfone may be prepared in the following manner: 10.5 g of oxoneR and then 2.6 g of methyl(3-methylbenzyl)sulfide and 30 cm' of ethanol 5 are added, at room temperature, to a solution of 30 cm of water, 30 cm' of acetic acid and 15 cm of 36 N sulfuric acid. The mixture is stirred for 48 hours at room temperature and then taken up in 100 cm of water and 100 cm 3 of ethyl acetate. The organic phase is 10 washed with a saturated aqueous sodium bicarbonate solution, decanted off, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 2.8 g of methyl(3-methylbenzyl)sulfone are obtained in the form of a gum. 15 Methyl(3-methylbenzyl)sulfide may be prepared in the following manner: 1.7 g of sodium methylthiolate are added, while the temperature is kept below 30'C, to a solution of 3.7 g of 3-methylbenzyl bromide in 25 cm of dimethylformamide. The mixture is stirred for 20 2 hours at a temperature close to 20'C and then taken up in 50 cm 3 of ethyl acetate. The organic phase is washed with 3 times 100 cm' of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 2.6 g of methyl(3-methyl 25 benzyl)sulfide are obtained in the form of an oil.

60 Example 3 0.3 cm 3 of methanesulfonyl chloride is added to a solution of 3.3 g of 1-benzhydryl-3-[(4 5 methylphenyl) (methylsulfonyl)methyl-(RS) Iazetidin-3-ol in 10 cm 3 of pyridine, cooled to 50C. The mixture is stirred for 2 hours at 5OC and then 1 g of 4-dimethylaminopyridine is added in 10 cm 3 of dichloromethane at 5*C. The solution is stirred for 10 15 hours at room temperature and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm), eluting at a nitrogen pressure of 0.5 bar with 15 dichloromethane and collecting 80 cm 3 fractions. Fractions 17 to 20 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 30 cm 3 of acetonitrile. 0.14 g of 1-benzhydryl-3-[(4-methylphenyl) 20 (methylsulfonyl)methylenelazetidine is obtained melting at 2100C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.30 (3H, s, PhCH 3 ), 2.95 (3H, s, SCH 3 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ) , 4.75 (1H, s, NCH), 7.20 (4H, m, 4CH arom.), 7.30 (6H, t, J=7Hz, 6CH arom.), 25 7.45 (4H, d, J=7Hz, 4 CH arom.)]. 1-Benzhydryl-3-[(4-methylphenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be 61 obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 4 g of methyl(4-methylbenzyl)sulfone and 5.1 g of 1-benzhydrylazetidin-3-one, 3 g of 5 l-benzhydryl-3- [ (4-methylphenyl) (methylsulfonyl) methyl (RS)]azetidin-3-ol are obtained melting at 226'C. Methyl(4-methylbenzyl)sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 10 3.5 g of methyl(4-methylbenzyl)sulfide and 12.3 g of oxoneR, 3.5 g of methyl(4-methylbenzyl)sulfone are obtained in the form of a solid. Methyl(4-methylbenzyl)sulfide may be prepared in the following manner: on carrying out the operation 15 according to the procedure of Example 2 starting with 5.6 g of 4-methylbenzyl bromide and 2.3 g of sodium methylthiolate, 4.7 g of methyl(4-methylbenzyl)sulfide are obtained in the form of a solid. 20 Example 4 0.7 cm' of methanesulfonyl chloride and then 3.8 g of 4-dimethylaminopyridine are added to a solution of 3.3 g of 1-benzhydryl-3-[(2-methylphenyl) 25 (methylsulfonyl)methyl-(RS)]azetidin-3-ol in 50 cm 3 of dichloromethane, at room temperature. The solution is stirred for 3 hours under reflux and then taken up in 62 twice 50 cm 3 of water. The organic phase is decanted off, dried and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 5 0.04-0.06 mm, diameter 3 cm, height 25 cm), eluting at a nitrogen pressure of 0.5 bar with dichloromethane and then with a dichloromethane and ethanol mixture (99/1 by volume mixture) and collecting 100 cm 3 fractions. Fractions 6 to 17 are combined and then concentrated to 10 dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 50 cm 3 of ethyl ether. 2.6 g of 1-benzhydryl-3-[(2-methylphenyl) (methylsulfonyl)methylene]azetidine are obtained in the form of a foam [NMR spectrum in DMSO-d6, T=300K, 8 in 15 ppm (300 MHz): 2.30 (3H, s, PhCH 3 ), 2.95 (3H, s, SCH 3 ), 3.50 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.70 (1H, s, NCH) between 7.10 and 7.35 (10H, m, 10CH arom.), 7.45 (4H, m, 4CH arom.)]. 1-Benzhydryl-3-[(2-methylphenyl) 20 (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 3.4 g of methyl(2-methylbenzyl)sulfone and 4.3 g of 1-benzhydrylazetidin-3-one, 3.4 g of 25 1-benzhydryl-3-[(2-methylphenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol are obtained melting at 218'C. Methyl(2-methylbenzyl)sulfone may be prepared 63 in the following manner: by carrying out the operation according to the procedure of Exa ple 2 starting with 4.5 g of methyl(2-methylbenzyl)sulfide and 16.2 g of oxoneR, 3.4 g of methyl(2-methylbenzyl)sulfone are 5 obtained in the form of a solid. Methyl(2-methylbenzyl)sulfide may be prepared in the following manner: on carry:.ng out the operation according to the procedure of Example 2 but starting with 5.6 g of 2-methylbenzyl bromide and 2.1 g of 10 sodium methylthiolate, 4.5 g of methyl(2-methylbenzyl) sulfide are obtained in the form of a solid. Example 5 15 On carrying out the operation according to the procedure of Example 4 but starting with 2.1 g of 1-benzhydryl-3-[(2-chlorophenyl) (nethylsulfonyl)methyl (RS)]azetidin-3-ol, 0.55 cm 3 of methanesulfonyl chloride and 2.3 g of 4-dimethylaminopyrid:.ne, the residue 20 obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 n, diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 100 cm 3 fractions. Fractions 12 to 18 are combined and 25 concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 3 cm 3 of dichloromethane and 40 cm of ethyl 64 ether. 1.1 g of 1-benzhydryl-3-[( -chlorophenyl) (methylsulfonyl)methyleneazetidine are obtained melting at 204 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.60 (2H, s, NCH 2 ), 5 4.20 (2H, s, NCH 2 ), 4.70 (iH, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J 7Hz, 4CH arom.), 7.45 (7H, m, 7CH arom.), 7.55 (lH, d, J=7Hz, CH arom.)]. 1-Benzhydryl-3-[(2-chlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be 10 obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 4 g of (2-chlorobenzyl)methylsulfone and 4.6 g of 1-benzhydrylazetidin-3-one, the residue obtained is taken up in 50 cm of ethyl acetate, 15 filtered and dried. 2.4 g of 1-benzhydryl-3-[(2 chlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid. (2-Chlorobenzyl)methylsulfone may be prepared in the following manner: on carrying out the operation 20 according to the procedure of Example 2 starting with 3.4 g of (2-chlorobenzyl)methylsulfide and 12 g of oxone , 4 g of (2-chlorobenzyl)methylsulfone are obtained in the form of an oil which crystallizes. (2-Chlorobenzyl)methylsulfide may be prepared 25 in the following manner: on carrying out the operation according to the procedure of Example 2 but starting with 4 g of 2-chlorobenzyl bromide and 1.5 g of sodium 65 methylthiolate, 3.4 g of (2-chlorobenzyl)methylsulfide are obtained in the form of an oil. Example 6 5 On carrying out the operation according to the procedure of Example 4 starting with 3 g of 1-benzhydryl-3-[(3-chlorophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol, 0.79 cm 3 of methanesulfonyl chloride and 3.3 g of 4-dimethylaminopyridine, the residue 10 obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 100 cm 3 fractions. Fractions 2 to 5 are combined and 15 concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 40 cm 3 of ethyl ether. 1.7 g of 1-benzhydryl-3-[(3 chlorophenyl) (methylsulfonyl)methylene]azetidine are obtained melting at 205 0 C [NMR spectrum in DMSO-d6, 20 T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.70 (lH, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 (8H, m, 8CH arom.)]. 1-benzhydryl-3-[(3-chlorophenyl) 25 (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 66 starting with 3.1 g of (3-chlorobenzyl)methylsulfone and 3.4 g of 1-benzhydrylazetidin-3-one, 3.4 g of 1-benzhydryl-3-[(3-chlorophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol are obtained in the form of a white 5 solid. (3-Chlorobenzyl)methylsulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 3.2 g of (3-chlorobenzyl)methylsulfide and 12 g of 10 oxoneR, 3.2 g of (3-chlorobenzyl)methylsulfone are obtained in the form of a white solid. (3-Chlorobenzyl)methylsulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 15 4 g of 3-chlorobenzyl bromide and 1.5 g of sodium methylthiolate, 3.2 g of 3-chlorobenzylmethylsulfide are obtained in the form of an oil. Example 7 20 On carrying out the operation according to the procedure of Example 4 starting with 3.3 g of 1-benzhydryl-3-[(4-chlorophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol, 0.87 cm 3 of methanesulfonyl chloride 25 and 3.6 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, 67 height 25 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 100 cm' fractions. Fractions 8 to 12 are combined and concentrated to dryness under reduced pressure 5 (2.7 kPa). The solid obtained is crystallized from a mixture of 3 cm 3 and 30 cm 3 of ethyl ether. 0.5 g of 1-benzhydryl-3-[(4-chlorophenyl) (methylsulfonyl) methylene]azetidine is obtained melting at 192'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 10 (3H, s, SCH2), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), between 7.40 and 7.55 (8H, m, 8CH arom.)]. 1-Benzhydryl-3-[(4-chlorophenyl) 15 (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 2.8 g of (4-chlorobenzyl)methylsulfone and 3.24 g of 1-benzhydrylazetidin-3-one, 3.4 g of 20 1-benzhydryl-3-[(4-chlorophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol are obtained in the form of a white solid after crystallization from 80 cm 3 . (4-Chlorobenzyl)methylsulfone may be prepared in the following manner: on carrying out the operation 25 according to the procedure of Example 2 starting with 3.5 g of (4-chlorobenzyl)methylsulfide and 12.3 g of oxone , 3.5 g of (4-chlorobenzyl)methylsulfone are 68 obtained in the form of a solid. Example 8 5 On carrying out the operation according to the procedure of Example 4 starting with 3.1 g of l-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl) methyl-(RS)]azetidin-3-ol, 0.75 cm 3 of methanesulfonyl chloride and 3.1 g of 4-dimethylaminopyridine, the 10 residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 100 cm 3 fractions. Fractions 6 to 10 are combined and 15 concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 2 cm 3 of dichloromethane and 30 cm 3 of ethyl ether. 0.8 g of l-benzhydryl-3-[(3,5-dichlorophenyl) (methylsulfonyl)methylene]azetidine is obtained melting 20 at 204 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 2.95 (3H, s, SCH 3 ), 3.85 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 (6H, m, 6CH arom.), 7.70 (l.H, s, CH arom.)]. 25 1-Benzhydryl-3-[(3,5-dichlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the 69 operation according to the procedure of Example 1 starting with 4 g of (3,5-dichlorobenzyl)methylsulfone and 4 g of 1-benzhydrylazetidin-3-one, 3.2 g of 1-benzhydryl-3- [(3, 5-dichlorophenyl) (methylsulfonyl) 5 methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid. (3, 5-Dichlorobenzyl)methylsulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 10 starting with 5.3 g of (3,5-dichlorobenzyl) methylsulfide and 17 g of oxoneR, 5 g of (3,5 dichlorobenzyl)methylsulfone are obtained in the form of a white solid. (3,5-Dichlorobenzyl)methylsulfide may be 15 prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 5 g of 3,5-dichlorobenzyl chloride and 2 g of sodium methylthiolate, 5.3 g of (3,5 dichlorobenzyl)methylsulfide are obtained in the form 20 of an oil. Example 9 On carrying out the operation according to 25 the procedure of Example 4 starting with 5 g of 1-benzhydryl-3-[(3,4-dichlorophenyl)(methylsulfonyl) methyl-(RS)]azetidin-3-ol, 1.2 cm 3 of methanesulfonyl 70 chloride and 3.8 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 35 cm) at a nitrogen pressure of 0.5 bar 5 with a mixture of cyclohexane and ethyl acetate (70/30 by volume) as eluent and collecting 35 cm 3 fractions. Fractions 30 to 55 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 50 cm 3 of ethyl ether. 1.5 10 g of l-benzhydryl-3-[(3,4-dichlorophenyl) (methylsulfonyl)methylene]azetidine are obtained melting at 170 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH 3 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.70 (lH, s, NCH), 7.20 (2H, t, 15 J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), between 7.35 and 7.50 (5H, m, 5CH arom.), 7.65 (2H, m, 2CH arom.)]. 1-Benzhydryl-3-[(3,4-dichlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be 20 obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 4.5 g of (3,4-dichlorobenzyl) methylsulfone and 4.3 g of l-benzhydrylazetidin-3-one, 5 g of 1-benzhydryl-3-[(3,4-dichlorophenyl) 25 (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid. (3,4-Dichlorobenzyl)methylsulfone may be 71 prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 4.3 g of (3,4-dichlorobenzyl) methylsulfide and 13 g of oxone", 4.7 g of (3,4 5 dichlorobenzyl)methylsulfone are obtained in the form of a white solid. (3,4-Dichlorobenzyl)methylsulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 10 starting with 2.8 cm 3 of 3,4-dichlorobenzyl chloride and 1.5 g of sodium methylthiolate, 4.3 g of (3,4 dichlorobenzyl)methylsulfide are obtained in the form of an oil. 15 Example 10 On carrying out the operation according to the procedure of Example 4 starting with 1.8 g of 1-benzhydryl-3-[(2,5-dichlorophenyl) (methylsulfonyl) 20 methyl-(RS)]azetidin-3-ol, 0.4 cm 3 of methanesulfonyl chloride and 1.8 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar 25 with dichloromethane as eluent and collecting 100 cm 3 fractions. Fractions 8 to 14 are combined and concentrated to dryness under reduced pressure 72 (2.7 kPa). The solid obtained is crystallized from a mixture of 2 cm 3 of dichloromethane and 30 cm 3 of ethyl ether. 1.2 g of 1-benzhydryl-3-[(2,5-dichlorophenyl) (methylsulfonyl)methylenelazetidine are obtained 5 melting at 202'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 3.00 (3H, s, SCH,), 3.70 (2H, m, NCH 2 ), 4.25 (2H, m, NCH 2 ), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 (4H, d, J=7Hz, 4CH arom.), between 7.55 and 7.70 (3H, 10 m, 3CH arom.)]. 1-Benzhydryl-3-[(2,5-dichlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 15 starting with 1.2 g of (2,5-dichlorobenzyl) methylsulfone and 1.2 g of 1-benzhydrylazetidin-3-one, 1.8 g of 1-benzhydryl-3-[(2,5-dichlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid. 20 (2,5-Dichlorobenzyl)methylsulfone may be prepared in the following manner: 1.9 g of sodium methanesulfinate are added, at room temperature, to a solution of 2.7 g of 2,5-dichlorobenzyl chloride in 30 cm 3 of ethanol. The mixture is heated under reflux 25 for 5 hours, cooled to room temperature and then taken up in 50 cm 3 of water and 50 cm 3 of ethyl acetate. The organic phase is decanted off, washed with 20 cm 3 of a 73 saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 1.2 g of (2,5 dichlorobenzyl)methylsulfone are obtained in the form 5 of a white solid. Example 11 On carrying out the operation according to 10 the procedure of Example 4 starting with 9.1 g of 1-benzhydryl-3-[(2,4-dichlorophenyl) (methylsulfonyl) methyl-(RS)]azetidin-3-ol, 2.2 cm of methanesulfonyl chloride and 7 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a 15 silica gel column (particle size 0.04-0.06 mm, diameter 5.5 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 40 cm 3 fractions. Fractions 27 to 39 are combined and concentrated to dryness under reduced pressure 20 (2.7 kPa). The solid obtained is crystallized from 20 cm 3 of ethyl ether. 1.5 g of 1-benzhydryl-3-[(2,4 dichlorophenyl) (methylsulfonyl)methylene]azetidine are obtained melting at 165'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 3.00 (3H, s, SCH 3 ), 3.65 25 (2H, m, NCH 2 ), 4.25 (2H, m, NCH 2 ), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 (6H, m, 6CH arom.), 7.80 (1H, s, CH 74 arom.)]. 1-Benzhydryl-3-[(2,4-dichlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the 5 operation according to the procedure of Example 1 starting with 4.8 g of (2,4-dichlorobenzyl) methylsulfone and 4.7 g of 1-benzhydrylazetidin-3-one, 9.1 g of 1-benzhydryl-3-[(2,4-dichlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained 10 in the form of a brown foam. (2,4-Dichlorobenzyl)methylsulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 4 g of (2,4-dichlorobenzyl)methylsulfide 15 and 13 g of oxoneR, 4.8 g of (2,4-dichlorobenzyl) methylsulfone are obtained in the form of a white solid melting at 111 0 C. (2,4-Dichlorobenzyl)methylsulfide may be prepared in the following manner: on carrying out the 20 operation according to the procedure of Example 2 starting with 2.8 cm 3 of 2,4-dichlorobenzyl chloride and 1.5 g of sodium methylthiolate, 4 g of (2,4 dichlorobenzyl)methylsulfide are obtained in the form of an oil. 25 Example 12 75 On carrying out the operation according to the procedure of Example 4 starting with 3 g of 1-benzhydryl-3-[(2,3-dichlorophenyl) (methylsulfonyl) methyl-(RS)]azetidin-3-ol, 1.1 g of methanesulfonyl 5 chloride and 3 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane and ethanol (98/2 by 10 volume) as eluent and collecting 100 cm 3 fractions. Fractions 10 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 40 cm of ethyl ether. 1.6 g of 1-benzhydryl-3-[(2,3-dichlorophenyl) 15 (methylsulfonyl)methylene]azetidine are obtained melting at 201'C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 3.00 (3H, s, SCH 3 ) , 3.60 (2H, m, NCH 2 ) 4.20 (2H, m, NCH 2 ), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 20 (6H, m, 6CH arom.), 7.70 (1H, dd, J=8 and 2Hz, CH arom.)]. 1-Benzhydryl-3-[(2,3-dichlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the 25 operation according to the procedure of Example 1 starting with 3.6 g of (2,3-dichlorobenzyl) methylsulfone and 3.6 g of 1-benzhydrylazetidin-3-one, 76 5.4 g of 1-benzhydryl-3-[(2,3-dichlorophenyl) (methylsulfonyl)methyl- (RS) ]azetidin-3-ol are obtained in the form of a white solid. (2, 3-Dichlorobenzyl)methylsulfone may be 5 prepared in the following manner: on carrying out the operation according to the procedure of Example 10 starting with 3 g of 2,3-dichlorobenzyl chloride and 2.4 g of sodium methanesulfinate, 3.6 g of (2,3 dichlorobenzyl)methylsulfonate are obtained in the form 10 of a white solid. Example 13 On carrying out the operation according to 15 the procedure of Example 4 starting with 2.5 g of 1-benzhydryl-3-[(3-fluorophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol, 0.72 cm of methanesulfonyl chloride and 2.9 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel 20 column (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting 100 cm 3 fractions. Fractions 2 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid 25 obtained is crystallized from 40 cm' of ethyl ether. 1.5 g of 1-benzhydryl-3- [(3-fluorophenyl) (methylsulfonyl) methylenelazetidine are obtained melting at 210 0 C [NMR 77 spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH 3 ), 3.80 (2H, m, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.70 (1H, s, NCH), between 7.10 and 7.30 (9H, m, 9CH arom.), 7.45 (5H, m, 5CH arom.)]. 5 1-Benzhydryl-3-[(3-fluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 2.6 g of 3-fluorobenzyl methyl sulfone 10 and 3.3 g of 1-benzhydrylazetidin-3-one, 2.9 g of 1-benzhydryl-3-[(3-fluorophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol are obtained in the form of a white solid melting at 200'C. (3-Fluorobenzyl) methyl sulfone may be 15 prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 3.1 g of 3-fluorobenzyl methyl sulfide and 13 g of oxone , 2.7 g of 3-fluorobenzyl methyl sulfone are obtained in the form of a white solid. 20 (3-Fluorobenzyl) methyl sulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 2.6 cm 3 of 3-fluorobenzyl bromide and 1.6 g of sodium methylthiolate, 3.1 g of 3-fluorobenzyl 25 methyl sulfide are obtained in the form of an oil. Example 14 78 On carrying out the operation according to the procedure of Example 4 starting with 4.3 g of 1-benzhydryl-3- [(2-f luorophenyl) (methylsulfonyl)methyl 5 (RS)]azetidin-3-ol, 1.2 cm of methanesulfonyl chloride and 3.7 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4.5 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with 10 dichloromethane as eluent and collecting 30 cm 3 fractions. Fractions 28 to 58 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . The solid obtained is crystallized from 100 cm 3 of ethyl ether. 2.3 g of 1-benzhydryl-3-[(2-fluorophenyl) 15 (methylsulfonyl)methylene]azetidine are obtained melting at 188'C [NMR spectrum in DMSO-d6, T=300K, S in ppm (300 MHz): 3.00 (3H, s, SCH 3 ), 3.65 (2H, m, NCH 2 ), 4.20 (2H, m, NCH 2 ) , 4.75 (lH, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (6H, m, 6CH arom.), 7.50 (6H, 20 m, 6CH arom.)]. 1-Benzhydryl-3-[(2-fluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 25 starting with 3.4 g of 2-fluorobenzyl methyl sulfone and 4.2 g of 1-benzhydrylazetidin-3-one, 4.3 g of 1-benzhydryl-3- [(3-f luorophenyl) (methylsulfonyl)methyl- 79 (RS)]azetidin-3-ol are obtained in the form of a white solid. (2-Fluorobenzyl) methyl sulfone may be prepared in the following manner: on carrying out the 5 operation according to the procedure of Example 2 starting with 3 g of 2-fluorobenzyl methyl sulfide and 13 g of oxoneR, 3.6 g of 3-fluorobenzyl methyl sulfone are obtained in the form of a white solid. (2-Fluorobenzyl) methyl sulfide may be 10 prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 2.4 cm 3 of 2-fluorobenzyl bromide and 1.5 g of sodium methylthiolate, 3 g of 2-fluorobenzyl methyl sulfide are obtained in the form of an oil. 15 Example 15 On carrying out the operation according to the procedure of Example 4 starting with 1 g of 20 1-benzhydryl-3-[(4-fluorophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol, 0.3 cm of methanesulfonyl chloride and 0.9 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, 25 height 35 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 30 cm 3 fractions. Fractions 20 to 35 are combined and 80 concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 50 cm 3 of ethyl ether. 0.4 g of 1-benzhydryl-3-[(4 fluorophenyl) (methylsulfonyl)methylene]azetidine are 5 obtained melting at 186 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.80 (2H, m, NCH 2 ), 4.20 (2H, m, NCH 2 ), 4.75 (1H, s, NCH), between 7.15 and 7.35 (8H, m, 8CH arom.), 7.45 (6H, m, 6CH arom.)]. 10 1-Benzhydryl-3-[(4-fluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 2.8 g of 4-fluorobenzyl methyl sulfone 15 and 3.6 g of 1-benzhydrylazetidin-3-one, 1 g of l-benzhydryl-3-[(4-fluorophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol is obtained in the form of a white solid. (4-Fluorobenzyl) methyl sulfone may be 20 prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 3 g of 4-fluorobenzyl methyl sulfide and 13 g of oxone , 3 g of 4-fluorobenzyl methyl sulfone are obtained in the form of a white solid melting at 110'C. 25 (4-Fluorobenzyl) methyl sulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 81 starting with 2.5 cm 3 of 4-fluorobenzyl chloride and 1.5 g of sodium methylthiolate, 3 g of 4-fluorobenzyl methyl sulfide are obtained in the form of an oil. 5 Example 16 On carrying out the operation according to the procedure of Example 4 starting with 3.8 g of 1-benzhydryl-3-[(3,5-difluorophenyl) (methylsulfonyl) 10 methyl-(RS)]azetidin-3-ol, 1 cm 3 of methanesulfonyl chloride and 4.2 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar 15 with dichloromethane as eluent, collecting 100 cm fractions. Fractions 5 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 30 cm 3 of ethyl ether. 0.8 g of 1-benzhydryl-3-[(3,5 20 difluorophenyl) (methylsulfonyl)methylene]azetidine are obtained melting at 172 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 3.00 (3H, s, SCH2), 3.85 (2H, m, NCH 2 ), 4.20 (2H, m, NCH 2 ), 4.75 (1H, s, NCH), between 7.10 and 7.40 (9H, m, 9CH arom.), 7.50 (4H, d, 25 J=7Hz, 4CH arom.)]. 1-Benzhydryl-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be 82 obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 3.2 g of 3,5-difluorobenzyl methyl sulfone and 3.7 g of 1-benzhydrylazetidin-3-one, 3.9 g 5 of 1-benzhydryl-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid. (3,5-Difluorobenzyl) methyl sulfone may be prepared in the following manner: on carrying out the 10 operation according to the procedure of Example 2 starting with 4.2 g of 3,5-difluorobenzyl methyl sulfide and 16 g of oxoneR, 3.3 g of 3,5-difluorobenzyl methyl sulfone are obtained in the form of a white solid. 15 (3,5-Difluorobenzyl) methyl sulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 5 g of 3,5-difluorobenzyl bromide and 2 g of sodium methylthiolate, 4.9 g of 3,5-difluorobenzyl 20 methyl sulfide are obtained in the form of an oil. Example 17 On carrying out the operation according to 25 the procedure of Example 4 starting with 5.2 g of 1-benzhydryl-3-[(2,3-difluorophenyl) (methylsulfonyl) methyl-(RS)]azetidin-3-ol, 2.3 cm' of methanesulfonyl 83 chloride and 7.3 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 6 cm, height 40 cm) at a nitrogen pressure of 0.5 bar 5 with a mixture of dichloromethane and methanol (98/2 by volume) as eluent and collecting 50 cm 3 fractions. Fractions 65 to 87 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 75 cm 3 of ethyl ether. 2.5 10 g of 1-benzhydryl-3-[(2,3-difluorophenyl) (methylsulfonyl)methylene]azetidine are obtained melting at 208 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (400 MHz): 3.05 (3H, s, SCH 3 ), 3.70 (2H, s, NCH 2 ), 4.25 (2H, s, NCH 2 ), 4.75 (lH, s, NCH), between 7.15 and 15 7.55 (13H, m, 13CH arom.)]. 1-Benzhydryl-3-[(2,3-difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 20 starting with 4 g of (2,3-difluorobenzyl) methyl sulfone and 4.8 g of 1-benzhydrylazetidin-3-one, 5.5 g of 1-benzhydryl-3-[(2,3-difluorophenyl) (methyl sulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a beige solid. 25 (2,3-Difluorobenzyl) methyl sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 10 84 starting with 4.1 g of 2,3-difluorobenzyl bromide and 4.1 g of sodium methanesulfinate, 4 g of (2,3-difluoro benzyl) methyl sulfone are obtained in the form of a white solid. 5 Example 18 On carrying out the operation according to the procedure of Example 4 starting with 5.2 g of 10 1-benzhydryl-3-[(2,5-difluorophenyl) (methylsulfonyl) methyl-(RS)]azetidin-3-ol, 2.3 cm 3 of methanesulfonyl chloride and 7.3 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 15 6 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane and methanol (98/2 by volume) as eluent and collecting 50 cm 3 fractions. Fractions 73 to 90 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid 20 obtained is crystallized from 75 cm 3 of ethyl ether. 2.6 g of 1-benzhydryl-3-[(2,5-difluorophenyl) (methylsulfonyl)methylene]azetidine are obtained melting at 176'C. 1-Benzhydryl-3-[(2,5-difluorophenyl) 25 (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 85 starting with 4 g of (2,5-difluorobenzyl) methyl sulfone and 4.8 g of 1-benzhydrylazetidin-3-one, 5.9 g of 1-benzhydryl-3-[(2,5-difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained 5 in the form of a cream-colored solid. (2,5-Difluorobenzyl) methyl sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 10 starting with 4.1 g of 2,5-difluorobenzyl bromide and 10 4.1 g of sodium methanesulfinate, 4.8 g of (2,5 difluorobenzyl) methyl sulfone are obtained in the form of a white solid melting at 95'C. Example 19 15 On carrying out the operation according to the procedure of Example 4 starting with 7.7 g of 1-benzhydryl-3-[(3-bromophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol, 1.8 cm 3 of methanesulfonyl chloride 20 and 5.8 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then a dichloromethane and ethanol 25 mixture (99.5/0.5 by volume) as eluents and collecting 100 cm 3 fractions. Fractions 17 to 28 are combined and concentrated to dryness under reduced pressure (2.7 86 kPa). The solid obtained is crystallized from a mixture of 5 cm 3 of dichloromethane and 50 cm 3 of ethyl ether. 3.5 g of l-benzhydryl-3-[(3-bromophenyl) (methylsulfonyl)methylene]azetidine are obtained 5 melting at 200'C [NMR spectrum in DMSO-d6, T=300K, S in ppm (300 MHz): 2.95 (3H, s, SCH 3 ), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH 2 ), 4.75 (lH, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), between 7.35 and 7.55 (6H, m, 6CH arom.), 7.65 (2H, m, 10 2CH arom.)]. 1-Benzhydryl-3-[(3-bromophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 15 starting with 8 g of 3-bromobenzyl methyl sulfone and 7.6 g of l-benzhydrylazetidin-3-one, 8 g of 1-benzhydryl-3-[(3-bromophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol are obtained in the form of a white solid. 20 3-Bromobenzyl methyl sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 9 g of 3-bromobenzyl methyl sulfide and 27 g of oxone, 8.2 g of 3-bromobenzyl methyl sulfone are obtained in 25 the form of a white solid. 3-Bromobenzyl methyl sulfide may be prepared in the following manner: on carrying out the operation 87 according to the procedure of Example 2 starting with 10 g of 3-bromobenzyl bromide and 3.1 g of sodium methylthiolate, 9 g of 3-bromobenzyl methyl sulfide are obtained in the form of an oil. 5 Example 20 On carrying out the operation according to the procedure of Example 4 starting with 1.5 g of 10 1-benzhydryl-3-[(3-iodophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol, 0.3 cm of methanesulfonyl chloride and 1.4 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, 15 height 35 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane and ethanol (99.7/0.3 by volume) as eluents and collecting 100 cm fractions. Fractions 16 to 24 are combined and concentrated to dryness under reduced 20 pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 1.5 cm of dichloromethane and 25 cm 3 of ethyl ether. 0.5 g of 1-benzhydryl-3-[(3 iodophenyl)(methylsulfonyl)methylene]azetidine is obtained melting at 198 0 C [NMR spectrum in DMSO-d6, 25 T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), between 7.10 and 7.30 (7H, m, 7CH arom.), 7.45 (5H, m, 88 5CH arom.), 7.80 (2H, m, 2CH arom.)]. 1-Benzhydryl-3- [ (3-iodophenyl) (methylsulfonyl)methyl-(RS)Iazetidin-3-ol may be obtained in the following manner: on carrying out the 5 operation according to the procedure of Example 1 starting with 3.7 g of 3-iodobenzyl methyl sulfone and 3 g of 1-benzhydrylazetidin-3-one, 1.5 g of 1-benzhydryl-3- [ (3-iodophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol are obtained in the form of a white 10 solid. 3-Iodobenzyl methyl sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 3.6 g of 3-iodobenzyl methyl sulfide and 10.3 g of 15 oxoneR, 3.7 g of 3-iodobenzyl methyl sulf one are obtained in the form of a white solid. 3-Iodobenzyl methyl sulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 20 5 g of 3-iodobenzyl bromide and 1.3 g of sodium methylthiolate, 4 g of 3-iodobenzyl methyl sulfide are obtained in the form of an oil. Example 21 25 On carrying out the operation according to the procedure of Example 4 starting with 2.4 g of 89 1-benzhydryl-3-[(methylsulfonyl) (3-trifluoro methoxyphenyl)methyl-(RS)]azetidin-3-ol, 0.6 cm 3 of methanesulfonyl chloride and 2.3 g of 4-dimethylamino pyridine, the residue obtained is purified by 5 chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane and ethanol (99.7/0.3 by volume) as eluents and collecting 100 cm 3 fractions. 10 Fractions 12 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 2 cm of dichloromethane and 30 cm 3 of ethyl ether. 0.7 g of 1-benzhydryl-3-[(methylsulfonyl) (3-trifluoro 15 methoxyphenyl)methylene]azetidine -is obtained melting at 1620C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (250 MHz): 3.00 (3H, s, SCH,), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), between 7.15 and 7.40 (6H, m, 6CH arom.), between 7.45 and 7.55 (7H, m, 7CH 20 arom.), 7.60 (lH, t, J=7Hz, CH arom.)]. 1-Benzhydryl-3-[(methylsulfonyl) (3-trifluoro methoxyphenyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 25 2.4 g of methyl(3-trifluoromethoxybenzyl)sulfone and 2.2 g of 1-benzhydrylazetidin-3-one, 2.4 g of 1-benzhydryl-3-[(methylsulfonyl) (3-trifluoro- 90 methoxyphenyl)methyl- (RS) Jazetidin-3-ol are obtained in the form of a white solid. Methyl (3-f luoromethoxybenzyl) sulf one may be prepared in the following manner: on carrying out the 5 operation according to the procedure of Example 2 starting with 2.6 g of methyl(3-trifluoromethoxy benzyl)sulfide and 7.2 g of oxoneR, 2.4 g of methyl (3-trifluoromethoxybenzyl)sulfone are obtained in the form of a white solid. 10 Methyl (3-trifluoromethoxybenzyl) sulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 3 g of 3-trifluoromethoxybenzyl bromide and 1 g of sodium methylthiolate, 3.3 g of methyl 15 (3-trifluoromethoxybenzyl)sulfide are obtained in the form of an oil. Example 22 20 On carrying out the operation according to the procedure of Example 4 starting with 4.1 g of 1-benzhydryl-3- [ (methylsulfonyl) (3-trifluoro methylphenyl)methyl-(RS)]azetidin-3-ol, 1 cm' of methanesulfonyl chloride and 4.2 g of 4-dimethylamino 25 pyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm) at a 91 nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting 100 cm 3 fractions. Fractions 10 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized 5 from a mixture of 2 cm of dichloromethane and 30 cm 3 of ethyl ether. 1.2 g of 1-benzhydryl-3 [(methylsulfonyl) (3-trifluoromethylphenyl)methylene) azetidine are obtained melting at 178'C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 3.00 (3H, s, 10 SCH 3 ), 3.80 (2H, s, NCH 2 ), 4.15 (2H, s, NCH 2 ), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 (4H, d, J=7Hz, 4CH arom.), between 7.60 and 7.80 (4H, m, 4CH arom.)]. 1-Benzhydryl-3- [ (methylsulfonyl) (3-trifluoro 15 methylphenyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 3.4 g of methyl(3-trifluoromethylbenzyl)sulfone and 3.4 g of 1-benzhydrylazetidin-3-one, 4.2 g of 20 1-benzhydryl-3- [ (methylsulfonyl) (3-trifluoromethyl phenyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid. Methyl (3-trifluoromethylbenzyl) sulf one may be prepared in the following manner: on carrying out the 25 operation according to the procedure of Example 2 starting with 3.3 g of methyl(3-trifluoromethylbenzyl)sulfide and 10 g of 92 oxone , 3.4 g of methyl(3-trifluoromethylbenzyl)sulfone are obtained in the form of a white solid. Methyl(3-trifluoromethylbenzyl)sulfide may be prepared in the following manner: on carrying out the 5 operation according to the procedure of Example 2 starting with 3.9 g of 3-trifluoromethylbenzyl bromide and 1.4 g of sodium methylthiolate, 3.3 g of methyl (3-trifluoromethylbenzyl)sulfide are obtained in the form of an oil. 10 Example 23 On carrying out the operation according to the procedure of Example 4 starting with 2.7 g of 1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl] 15 (methylsulfonyl)methyl-(RS)}azetidin-3-ol, 0.6 cm of methanesulfonyl chloride and 2.4 g of 4-dimethylamino pyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 6 cm, height 40 cm) at a 20 nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting 100 cm fractions. Fractions 7 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 10 cm of ethyl ether. 1 g of 1-benzhydryl 25 3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl) methylene}azetidine is obtained melting at 192'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.00 93 (3H, s, SCH 3 ), 3.85 (2H, s, NCH 2 ), 4.15 (2H, s, NCH 2 ), 4.70 (1H, s, NCH), 7.15 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.40 (4H, d, J=7Hz, 4CH arom.), 8.05 (2H, s, 2CH arom.), 8.15 (1H, s, CH 5 arom.)]. 1-Benzhydryl-3-{ [3, 5-bis (trifluoromethyl) phenyl](methylsulfonyl)methylene}azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 10 starting with 3.1 g of methyl[3,5-bis(trifluoromethyl) benzyl]sulfone and 2.4 g of 1-benzhydrylazetidin-3-one, 2.8 g of 1-benzhydryl-3-{[(3,5-bis(trifluoromethyl) phenyl](methylsulfonyl)methylene}azetidin-3-ol are obtained in the form of a white solid. 15 Methyl[3,5-bis(trifluoromethyl)benzylsulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 10 starting with 3 g of 3,5-bis(trifluoromethyl)benzyl chloride and 2 g of sodium methanesulfinate, 3.1 g of 20 methyl[3,5-bis(trifluoromethyl)benzyl]sulfone are obtained in the form of a white solid melting at 132'C. Example 24 25 On carrying out the operation according to the procedure of Example 4 starting with 10.7 g of 1-benzhydryl-3- [(3, 5-dibromophenyl) (methylsulfonyl) - 94 methyl-(RS)]azetidin-3-ol, 2.2 cm of methanesulfonyl chloride and 7 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 5 5.5 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 35 cm fractions. Fractions 40 to 58 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 50 10 cm 3 of ethyl ether. 1.5 g of l-benzhydryl-3-[3,5 dibromophenyl) (methylsulfonyl)methylene]azetidine are obtained melting at 209 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 3.00 (3H, s, SCH 3 ), 3.88 (2H, s, NCH 2 ), 4.22 (2H, s, NCH 2 ), 4.75 (lH, s, NCH), 15 7.22 (2H, t, J=7Hz, 2CH arom.), 7.33 (4H, t, J=7Hz, 4CH arom.), 7.48 (4H, d, J=7Hz, 4CH arom.), 7.68 (2H, s, 2CH arom.), 7.95 (1H, s, CH arom.)]. 1-Benzhydryl-3-[(3,5-dibromophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be 20 obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 6.2 g of (3,5-dibromobenzyl)methylsulfone and 4.5 g of 1-benzhydrylazetidin-3-one, 10.7 g of 1-benzhydryl-3-[3,5-dibromophenyl) (methylsulfonyl) 25 methyl-(RS)]azetidin-3-ol are obtained in the form of a foam. (3,5-Dibromobenzyl)methylsulfone may be 95 prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 5.8 g of (3,5-dibromobenzyl)methylsulfide and 13 g of oxoneR, 6.2 g of (3,5-dibromobenzyl) 5 methylsulfone are obtained in the form of a white solid. (3,5-Dibromobenzyl)methylsulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 10 starting with 6.6 g of 3,5-dibromobenzyl bromide and 1.5 g of sodium methylthiolate, 5.8 g of (3,5 dibromobenzyl)methylsulfide are obtained in the form of an oil. 15 Example 25 On carrying out the operation according to the procedure of Example 4 starting with 4.2 g of 1-benzhydryl-3-[(methylsulfonyl) (3-nitrophenyl)methyl 20 (RS)]azetidin-3-ol, 1.1 cm 3 of methanesulfonyl chloride and 2.5 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with a 25 mixture of cyclohexane and ethyl acetate (50/50 by volume) as eluents, collecting 400 cm fractions. Fractions 17 to 33 are combined and concentrated to 96 dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from 15 cm 3 of ethyl acetate. 0.6 g of 1-benzhydryl-3-[(methylsulfonyl) (3-nitrophenyl)methylene]azetidine is obtained melting 5 at 184 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH 3 ), 3.85 (2H, s, NCH 2 ), 4.25 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 (4H, d, J=7Hz, 4CH arom.), 7.75 (1H, t, J=7Hz, CH arom.), 7.85 10 (1H, d, J=7Hz, CH arom.), 8.25 (2H, m, 2CH arom.)]. 1-Benzhydryl-3-[(methylsulfonyl) (3-nitrophenyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 15 starting with 3.9 g of methyl(3-nitrobenzyl)sulfone and 4.2 g of 1-benzhydrylazetidin-3-one, 4.2 g of 1-benzhydryl-3-[(methylsulfonyl) (3-nitrophenyl)methyl (RS)]azetidin-3-ol are obtained in the form of a foam. Methyl(3-nitrobenzyl)sulfone may be prepared 20 in the following manner: on carrying out the operation according to the procedure of Example 2 but starting with 18.1 g of methyl(3-nitrobenzyl)sulfide and 68 g of oxone , 13.9 g of methyl(3-nitrobenzyl)sulfone are obtained in the form of a foam. 25 Methyl(3-nitrobenzyl)sulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 97 17.2 g of 3-nitrobenzyl chloride and 7.7 g of sodium methylthiolate, 18.2 g of methyl(3-nitrobenzyl)sulfide are obtained in the form of an oil. 5 Example 26 A mixture of 0.34 g of 1-benzhydryl 3-[(methylsulfonyl) (3-nitrophenyl)methylene]azetidine, 16 cm 3 of 1 N hydrochloric acid in 8 cm' of ethanol and 10 16 cm of tetrahydrofuran is heated under reflux. 0.17 g of iron powder is added and the reflux is maintained for 3 hours. The mixture is then cooled to room temperature and the insoluble matter is filtered off. The solution is taken up in 10 cm of 1 N sodium 15 hydroxide and 50 cm of a saturated aqueous sodium chloride solution. The aqueous phase is extracted with 3 times 40 cm' of dichloromethane, the extracts are combined, dried over sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue 20 is purified on a silica gel column (particle size 0.04 0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) as eluent, collecting 20 cm fractions. Fractions 13 to 31 are combined and 25 concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 15 cm 3 of ethyl ether. 0.17 g of 3-[(3-aminophenyl)- 98 (methylsulfonyl)methylene]-1-benzhydrylazetidine is obtained melting at 197 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (250 MHz): 2.95 (3H, s, SCH 3 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 5 5.25 (2H, s, NH 2 ), 6.55 (3H, m, 3CH arom.), 7.05 (1H, t, J=7Hz, CH arom.), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 (4H, d, J=7Hz, 4CH arom.)]. 10 Example 27 On carrying out the operation according to the procedure of Example 4 starting with 1.2 g of 1-benzhydryl-3- [ (3-methoxycarbonylphenyl) 15 (methylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.3 cm 3 of methanesulfonyl chloride and 1.3 g of 4-dimethylamino pyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a 20 nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane and ethyl acetate (99.5/0.5 by volume) as eluents and collecting 100 cm 3 fractions. Fraction 18 is concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is 25 precipitated in 5 cm 3 of ethyl ether. 0.13 g of 1-benzhydryl-3- [ (3-methoxycarbonylphenyl) (methylsulfonyl)methylene]azetidine is obtained in the 99 form of a foamy solid [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.80 (2H, s,

NCH

2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 5 7.45 (4H, d, J=7Hz, 4CH arom.), 7.60 (1H, t, J=7Hz, CH arom.), 7.70 (1H, d, J=7Hz, CH arom.), 8.00 (2H, m, 2CH arom.)]. 1-Benzhydryl-3-[(3-methoxycarbonylphenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be 10 obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 3 g of (3-methoxycarbonylbenzyl) methylsulfone and 3.6 g of 1-benzhydrylazetidin-3-one, 1.2 g of 1-benzhydryl-3-[(3-methoxycarbonylphenyl) 15 (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a foam after purification by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and 20 then a dichloromethane and ethanol mixture (99/1 by volume) as eluents. (3-Methoxycarbonylbenzyl)methylsulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 25 starting with 4.3 g of (3-methoxycarbonylbenzyl) methylsulfide and 13.4 g of oxoneR, 3.4 g of (3-methoxy carbonylbenzyl)methylsulfone are obtained in the form 100 of a white solid. (3-Methoxycarbonylbenzyl)methylsulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 5 starting with 5 g of 3-methoxycarbonylbenzyl bromide and 1.7 g of sodium methylthiolate, 4.3 g of (3-methoxycarbonylbenzyl)methylsulfide are obtained in the form of an oil. 10 Example 28 On carrying out the operation according to the procedure of Example 4 starting with 6.2 g of 1-benzhydryl-3- [ (3-cyanophenyl) (methylsulfonyl)methyl 15 (RS)]azetidin-3-ol, 1.6 cm 3 of methanesulfonyl chloride and 6.8 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with 20 dichloromethane and then a dichloromethane and ethyl acetate mixture (99.5/0.5 by volume) as eluents and collecting 250 cm fractions. Fractions 10 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized 25 from a mixture of 5 cm 3 of dichloromethane and 70 cm 3 of ethyl ether. 2.9 g of 1-benzhydryl-3-[(3-cyanophenyl) (methylsulfonyl)methylene]azetidine are obtained 101 melting at 152 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 5 (4H, d, J=7Hz, 4CH arom.), 7.65 (1H, t, J=7Hz, CH arom.), 7.75 (1H, d, J=7Hz, CH arom.), 7.90 (2H, m, 2CH arom.)]. 1-Benzhydryl-3-[(3-cyanophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be 10 obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 3.9 g of (3-cyanobenzyl)methylsulfone and 4.7 g of 1-benzhydrylazetidin-3-one, 6.2 g of 1-benzhydryl-3-[(3-cyanophenyl) (methylsulfonyl)methyl 15 (RS)]azetidin-3-ol are obtained in the form of a white solid. (3-Cyanobenzyl)methylsulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 20 6.7 g of (3-cyanobenzyl)methylsulfide and 27.6 g of oxoneR, 3.9 g of (3-cyanobenzyl)methylsulfone are obtained in the form of a white solid. (3-Cyanobenzyl)methylsulfide may be prepared in the following manner: on carrying out the operation 25 according to the procedure of Example 2 starting with 8 g of 3-cyanobenzyl bromide and 3.1 g of sodium methylthiolate, 6.8 g of (3-cyanobenzyl)methylsulfide 102 are obtained in the form of an oil. Example 29 5 A mixture of 3 g of 1-benzhydryl-3-[(3 carboxyphenyl) (methylsulfonyl)methylene]azetidine hydrochloride, 1.3 g of pentafluorophenol, 1.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 30 cm 3 of dimethylformamide is stirred at room temperature for 10 15 hours. The mixture is taken up in 100 cm 3 of water and 100 cm 3 of a saturated aqueous sodium chloride solution and 50 cm 3 of ethyl acetate. The organic phase is decanted off, dried over magnesium sulfate and concentrated to dryness under reduced pressure 15 (2.7 kPa). The residue is purified-by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then a dichloromethane and methanol mixture (99.4/0.6 by volume) as eluents 20 and collecting 100 cm 3 fractions. Fractions 13 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 10 cm 3 of ethyl ether. 0.6 g of 1-benzhydryl 3-[(methylsulfonyl) (3-pentafluorophenoxy 25 carbonylphenyl)methylene]azetidine is obtained melting at 182'C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (400 MHz): 3.00 (3H, s, SCH 3 ), 3.85 (2H, s, NCH 2 ), 4.25 (2H, 103 s, NCH 2 ), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 (4H, d, J=7Hz, 4CH arom.), 7.70 (1H, t, J=7Hz, CH arom.), 8.20 (2H, m, 2CH arom.)]. 5 1-Benzhydryl-3- [ (3-carboxyphenyl) (methyl sulfonyl)methylene]azetidine hydrochloride may be prepared in the following manner: a mixture of 10 g of 1-benzhydryl-3- [ (3-cyanophenyl) (methylsulfonyl) methylene]azetidine in 40 cm 3 of acetic acid and 40 cm 3 10 of concentrated hydrochloric acid (d=1.18) is heated at 45'C for 7 days. The reaction medium is cooled on an ice-cold water bath and the precipitate formed is filtered on sintered glass. The solid is washed with 20 cm 3 of a mixture of acetic acid and concentrated 15 hydrochloric acid (50-50 by volume) and then with 3 times 20 cm 3 of water and finally with 20 cm 3 of ethanol. The white solid obtained is under reduced pressure (2.7 kPa) at 45 0 C and 2.5 g of 1-benzhydryl 3-[ (3-carboxyphenyl) (methylsulfonyl)methylene]azetidine 20 hydrochloride are obtained in the form of a white solid. Example 30 25 A solution of 0.65 g of 1-benzhydryl 3-[(methylsulfonyl) (3-pentafluorophenoxycarbonylphenyl) methylene]azetidine in 25 cm 3 of 6.2 N ammoniacal 104 ethanol is stirred for 4 hours at room temperature. The mixture is concentrated to dryness under reduced pressure (2.7 kPa) and then the residue is purified by chromatography on a silica gel column (particle size 5 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a dichloromethane and ethanol mixture (99/1 by volume) and then a dichloromethane and ethanol mixture (98/2 by volume) as eluents and collecting 60 cm 3 fractions. Fractions 18 to 10 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.2 g of 1-benzhydryl 3-[(3-carbamoylphenyl) (methylsulfonyl)methylene] azetidine is obtained melting at 140'C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 3.00 (3H, s, SCH), 15 3.80 (2H, s, NCH 2 ), 4.25 (2H, s, NCH 2 ), 4.75 (lH, s, NCH), 7.25 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), between 7.45 and 7.65 (7H, m, 6CH arom. and 1/2 CONH 2 ), 7.95 (2H, m, 2CH arom.), 8.10 (1H, s,

CONH

2 ). 20 Example 31 On carrying out the operation according to the procedure of Example 4 starting with 4.6 g of 25 1-benzhydryl-3-[(3-methoxyphenyl) (methylsulfonyl) methyl-(RS)]azetidin-3-ol, 1.2 cm 3 of methanesulfonyl chloride and 3.8 g of 4-dimethylaminopyridine, 2.6 g of 105 1-benzhydryl-3-[(3-methoxyphenyl) (methylsulfonyl) methylenelazetidine are obtained, after recrystallization from 150 cm 3 of acetonitrile, melting at 179 0 C [NMR spectrum in DMSO-d6, T=300K, S in ppm (250 5 MHz): 2.95 (3H, s, SCH,), 3.75 (3H, s, OCH 3 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ) , 4.75 (1H, s, NCH), 7.00 (3H, m, 3 CH arom.), between 7.20 and 7.12 (11H, m, 10H phenyls and 1 CH arom.)]. 1-Benzhydryl-3-[(3-methoxyphenyl) 10 (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 3.4 g of (3-methoxybenzyl)methylsulfone and 4 g of 1-benzhydrylazetidin-3-one, 4.6 g of 15 1-benzhydryl-3-[(3-methoxyphenyl) (methylsulfonyl) methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid. (3-Methoxybenzyl)methylsulfone may be prepared in the following manner: on carrying out the 20 operation according to the procedure of Example 2 starting with 3.4 g of (3-methoxybenzyl)methylsulfide and 13 g of oxone , 4 g of (3-methoxybenzyl) methylsulfone are obtained in the form of a white solid melting at 71 0 C. 25 (3-Methoxybenzyl)methylsulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 106 starting with 3.1 g of 3-methoxybenzyl bromide and 1.5 g of sodium methylthiolate, 3.4 g of (3-methoxybenzyl)methylsulfide are obtained in the form of an oil. 5 Example 32 10 cm 3 of a 1 M solution of boron tetrabromide in dichloromethane are added, with stirring, to a 10 solution of 1.3 g of 1-benzhydryl-3-[(3-methoxyphenyl) (methylsulfonyl)methylene]azetidine in 100 cm 3 of dichloromethane. The stirring is maintained for 16 hours at room temperature. The reaction medium is taken up in 100 cm 3 of ice-cold water. The organic phase is 15 washed with 3 times 50 cm' of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is precipitated in 150 cm 3 of isopropyl ether and then dissolved in 50 cm 3 of dichloromethane. The organic phase is washed 20 with 3 times 30 cm 3 of a saturated aqueous solution of sodium bicarbonate, decanted off, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is precipitated in 80 cm 3 of ethyl ether. 0.36 g of 1-benzhydryl-3-[(3 25 hydroxyphenyl) (methylsulfonyl)methylene]azetidine is obtained from a solid melting at 248 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 2.95 (3H, s, SCH 3 ) , 107 3.80 (2H, s, NCH 2 ) , 4.20 (2H, s, NCH 2 ) , 4.75 (1H, s, NCH), 6.85 (3H, m, 3 CH arom.), 7.25 (3H, m, 3 CH arom.), 7.35 (4H, t, J=7Hz, 4CH arom.), 7.50 (4H, d, J=7Hz, 4CH arom.), 9.50 (1H, s, OH)]. 5 Example 33 On carrying out the operation according to the procedure of Example 32 starting with 1.4 g of 10 1-benzhydryl-3- [ (4-methoxyphenyl) (methylsulfonyl) methylene]azetidine, 10 cm 3 of a 1 M boron tribromide solution and 100 cm 3 of dichloromethane, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3.5 cm, 15 height 24 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) as eluents and collecting 25 cm fractions. Fractions 21 to 37 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . The solid 20 obtained is crystallized from a mixture of 30 cm 3 of ethyl ether. 0.6 g of 1-benzhydryl-3-[(4 hydroxyphenyl) (methylsulfonyl)methylene]azetidine is obtained melting at 211 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.90 (3H, s, SCH), 3.80 25 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 6.80 (2H, d, J=7Hz, 2CH arom.), between 7.10 and 7.35 (8H, m, 8CH arom.), 7.48 (4H, d, J=7Hz, 4CH arom.), 108 9.80 (1H, s, OH)]. 1-Benzhydryl-3-[(4-methoxyphenyl) (methylsulfonyl)methylene]azetidine may be obtained in the following manner: on carrying out the operation 5 according to the procedure of Example 4 starting with 3.5 g of 1-benzhydryl-3-[(4-methoxyphenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.9 cm 3 of methanesulfonyl chloride and 2.9 g of 4-dimethylaminopyridine, the residue obtained is 10 purified by recrystallization from 100 cm 3 of acetonitrile. 1 g of 1-benzhydryl-3-[(4 methoxyphenyl) (methylsulfonyl)methylene]azetidine is obtained melting at 181'C. 1-Benzhydryl-3-[(4-methoxyphenyl) (methyl 15 sulfonyl)methyl-(RS)]azetidin-3-ol- may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 3.5 g of (4-methoxybenzyl)methylsulfone and 4 g of 1-benzhydrylazetidin-3-one, 3.6 g of 1-benzhydryl 20 3-[(4-methoxyphenyl) (methylsulfonyl)methyl-(RS)] azetidin-3-ol are obtained in the form of a white solid. (4-Methoxybenzyl)methylsulfone may be prepared in the following manner: on carrying out the 25 operation according to the procedure of Example 2 starting with 3.4 g of (4-methoxybenzyl)methylsulfide and 13 g of oxoneR, 3.5 g of (3-methoxybenzyl)- 109 methylsulfone are obtained in the form of a white solid melting at 113'C. (4-Methoxybenzyl)methylsulfide may be prepared in the following manner: on carrying out the 5 operation according to the procedure of Example 2 starting with 3.1 g of 4-methoxybenzyl chloride and 1.5 g of sodium methylthiolate, 3.4 g of (4-methoxy benzyl)methylsulfide are obtained in the form of an oil. 10 Example 34 On carrying out the operation according to the procedure of Example 32 starting with 1.4 g of 15 1-benzhydryl-3-[(2-methoxyphenyl) (methylsulfonyl) methylene]azetidine, 10 cm 3 of a 1 M solution of boron tribromide and 100 cm 3 of dichloromethane, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, 20 height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 40 cm 3 fractions. Fractions 15 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 25 40 cm 3 of ethyl ether. 0.7 g of 1-benzhydryl-3-[(2 hydroxyphenyl) (methylsulfonyl)methylene]azetidine is obtained melting at 196 0 C [NVR spectrum in DMSO-d6, 110 T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.60 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 6.85 (1H, t, J=7Hz, CH arom.), 6.90 (1H, d, J=7Hz, CH arom.), 7.20 (4H, m, 4CH arom.), 7.30 (4H, t, J=7Hz, 5 4CH arom.), 7.48 (4H, d, J=7Hz, 4CH arom.), 9.90 (1H, s, OH)]. 1-Benzhydryl-3-[(2-methoxyphenyl) (methyl sulfonyl)methylene]azetidine may be obtained in the following manner: on carrying out the operation 10 according to the procedure of Example 4 starting with 4.2 g of 1-benzhydryl-3-[(2-methoxyphenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol, 1.1 cm 3 of methanesulfonyl chloride and 3.5 g of 4-dimethylamino pyridine, the residue obtained is purified by 15 chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane and ethyl acetate (50/50 by volume) as eluents and collecting 40 cm 3 fractions. Fractions 23 to 20 54 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 40 cm 3 of ethyl ether. 1.9 g of 1-benzhydryl-3-[(2-methoxyphenyl) (methylsulfonyl) methylene]azetidine are obtained melting at 204'C. 25 1-Benzhydryl-3-[(2-methoxyphenyl) (methyl sulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation 111 according to the procedure of Example 1 starting with 4 g of (2-methoxybenzyl)methylsulfone and 4.5 g of 1-benzhydrylazetidin-3-one, 4.3 g of 1-benzhydryl 3-[(2-methoxyphenyl)(methylsulfonyl)methyl-(RS)] 5 azetidin-3-ol are obtained in the form of a brown foam. (2-Methoxybenzyl)methylsulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 10 starting with 3.1 g of (2-methoxybenzyl) chloride and 10 4.1 g of sodium methanesulfinate, 4 g of (2-methoxy benzyl)methylsulfone are obtained in the form of a white solid. Example 35 15 On carrying out the operation according to the procedure of Example 4 starting with 2.1 g of 1-benzhydryl-3-[(methylsulfonyl) (naphth-2-yl)methyl (RS)]azetidin-3-ol, 0.5 cm of methanesulfonyl chloride and 2.2 g of 4-dimethylaminopyridine, the residue 20 obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 100 cm fractions. Fractions 6 to 10 are combined and 25 concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 20 cm 3 of ethyl ether. 0.6 g of 1-benzhydryl-3-[(methyl- 112 sulfonyl) (naphth-2-yl)methylene]azetidine is obtained melting at 178'C [NMR spectrum in DMSO-d6, T=300K, 3 in ppm (300 MHz): 3.00 (3H, s, SCH), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 7.20 (4H, m, 4CH 5 arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 (4H, d, J=7Hz, 4CH arom.), 7.52 (3H, m, 3CH arom.), 7.90 (4H, m, 4CH arom.)]. 1-Benzhydryl-3- [ (methylsulfonyl) (naphth 2-yl)methyl-(RS)]azetidin-3-ol may be obtained in the 10 following manner: on carrying out the operation according to the procedure of Example 1 starting with 3.5 g of methyl(naphth-2-ylmethyl)sulfone and 3.8 g of 1-benzhydrylazetidin-3-one, 2.2 g of 1-benzhydryl 3-[(methylsulfonyl) (naphth-2-yl)methyl-(RS)]azetidin 15 3-ol are obtained in the form of a white solid melting at 196 0 C. Methyl(naphth-2-ylmethyl)sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 20 starting with 4.2 g of methyl(naphth-2-ylmethyl)sulfide and 13.7 g of oxoneR, 3.6 g of methyl(naphth 2-ylmethyl)sulfone are obtained in the form of a cream colored solid. Methyl(naphth-2-ylmethyl)sulfide may be 25 prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 5 g of (2-bromomethyl)naphthalene and 113 1.8 g of sodium methylthiolate, 4.2 g of methyl(naphth 2-ylmethyl)sulfide are obtained in the. form of an oil. Example 36 5 On carrying out the operation according to the procedure of Example 4 starting with 4.3 g of 1-benzhydryl-3-[(methylsulfonyl) (naphth-1-yl)methyl (RS)]azetidin-3-ol, 1.1 cm 3 of methanesulfonyl chloride 10 and 4.6 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 100 cm 3 15 fractions. Fractions 6 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 30 cm 3 of ethyl ether. 2.5 g of 1-benzhydryl-3-[(methyl sulfonyl) (naphth-1-yl)methylene] azetidine are obtained 20 melting at 196'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH 3 ), 3.35 and 3.50 (1H each, dd, J=16 and 3 Hz, NCH 2 ), 4.35 (2H, m, NCH 2 ), 4.75 (1H, s, NCH), between 7.10 and 7.70 (14H, m, 14CH arom.), 8.00 (3H, m, 3CH arom.)]. 25 1-Benzhydryl-3-[(methylsulfonyl) (naphth 1-yl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation 114 according to the procedure of Example 1 starting with 4.1 g of methyl(naphth-1-ylmethyl)sulfone and 4.4 g of 1-benzhydrylazetidin-3-one, 4.3 g of 1-benzhydryl 3-[(methylsulfonyl) (naphth-1-yl)methyl-(RS)]azetidin 5 3-ol are obtained in the form of a solid. Methyl(naphth-1-ylmethyl)sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 4.3 g of methyl(naphth-1-ylmethyl)sulfide 10 and 13.9 g of oxoneR, 4.1 g of methyl(naphth-1-yl methyl)sulfone are obtained in the form of a white solid. Methyl(naphth-1-ylmethyl)sulfide may be prepared in the following manner: on carrying out the 15 operation according to the procedure of Example 2 starting with 4 g of 1-chloromethylnaphthalene chloride and 1.8 g of sodium methylthiolate, 4.5 g of methyl(naphth-1-ylmethyl)sulfide are obtained in the form of an oil. 20 Example 37 On carrying out the operation according to the procedure of Example 4 starting with 0.6 g of 25 1-benzhydryl-3-[(methylsulfonyl) (3-pyrrolidinophenyl) methyl-(RS)]azetidin-3-ol, 0.15 cm 3 of methanesulfonyl chloride and 0.6 g of 4-dimethylaminopyridine, the 115 residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a dichloromethane and methanol mixture (98/2 by 5 volume) as eluents and collecting 20 cm fractions. Fractions 8 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 8 cm 3 of ethyl ether. 0.36 g of 1-benzhydryl-3-[(methylsulfonyl) (3-pyrrolidino 10 phenyl)methylene]azetidine is obtained melting at 153'C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (250 MHz): 1.95 (4H, m, 2 CH 2 ), 2.95 (3H, s, SCH 3 ), 3.20 (4H, m, 2

NCH

2 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 6.60 (3H, m, 3CH arom.), 7.20 (3H, m, 3CH 15 arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.48 (4H, d, J=7Hz, 4CH arom.)]. 1-Benzhydryl-3-[(methylsulfonyl) (3-pyrrolidinophenyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the 20 operation according to the procedure of Example 1 starting with 0.77 g of 3-pyrrolidinobenzyl methyl sulfone and 0.76 g of 1-benzhydrylazetidin-3-one, 0.6 g of 1-benzhydryl-3-[(methylsulfonyl) (3-pyrrolidino phenyl)methyl-(RS)]azetidin-3-ol is obtained in the 25 form of a solid. Methyl(3-pyrrolidinobenzyl)sulfone may be prepared in the following manner: on carrying out the 116 operation according to the procedure of Example 2 starting with 1 g of methyl(3-pyrrolidinobenzyl)sulfide and 3.3 g of oxoneR, 0.8 g of methyl(3-pyrrolidino benzyl)sulfone is obtained in the form of a solid. 5 Methyl(3-pyrrolidinobenzyl)sulfide may be prepared in the following manner: a mixture of 2 g of (3-iodobenzyl)methylsulfide, 1.3 cm 3 of pyrrolidine, 1.1 g of sodium tert-butoxide, 0.28 g of 1,1'-bis(diphenyl phosphino)ferrocenyl palladium chloride, 0.63 g of 10 1,1'-bis(diphenylphosphino)ferrocene and 60 cm 3 of tetrahydrofuran is heated under reflux, under a nitrogen stream, for 3 hours. The reaction medium is cooled to room temperature and filtered on sintered glass. The precipitate is washed with 20 cm' of 15 tetrahydrofuran and 10 cm 3 of dichloromethane and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up with 30 cm 3 of ethyl acetate and 30 cm 3 of 3 N hydrochloric acid. The aqueous phase is decanted off, neutralized 20 (pH = 7-8) with 35 cm 3 of 3 N sodium hydroxide and taken up in 50 cm 3 of ethyl acetate. The organic phase is extracted; 4 g of silica are added and then the mixture is concentrated to dryness under reduced pressure (2.5 kPa). The powder obtained is eluted on sintered glass 25 containing 20 g of silica with a mixture of cyclohexane and ethyl acetate (90/10 by volume). The filtrate is concentrated to dryness under reduced pressure (2.7 117 kPa). 1.2 g of methyl(3-pyrrolidinobenzyl)sulfide are obtained in the form of an oil. 1,1'-Bis(diphenylphosphino)ferrocenyl palladium chloride may be prepared according to Hayashi 5 T. et al., J. Am. Chem. Soc., 106, 158 (1984). Example 38 Method 1 10 0.65 cm 3 of methanesulfonyl chloride is added 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 cm 3 of dichloromethane at 15 22'C, followed, in small portions over 15 minutes, by 2.42 g of 4-dimethylaminopyridine; the orange-colored solution is stirred for 2 hours at room temperature. The reaction mixture is washed 3 times with 150 cm 3 of distilled water and once with 150 cm 3 of a saturated 20 sodium chloride solution and then dried with magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 5.5 cm, height 15 cm), at an 25 argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (1/9 by volume) as eluents and collecting 70 cm 3 fractions. Fractions 15 to 36 are 118 combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.86 g of white foam are obtained, which foam is crystallized from isopropyl ether in order to obtain a solid melting at 1900C. A 5 recrystallization from 145 cm of ethanol gives 1.08 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluoro phenyl) (methylsulfonyl)methylene]azetidine melting at 2060C [NMR spectrum in DMSO-d6, T=300K, 3 in ppm (300 MHz): 3.00 (3H,s, SCH), 3.87 (2H, s, NCH 2 ), 4.20 (2H, 10 s, NCH 2 ), 4.75 (1H, s, NCH), 7.15 (2H, d, J=8Hz, 2CH arom.), 7.30 (5H, m, 5CH arom.), 7.45 (4H, d, J=7Hz, 4CH arom.)]. Method 2 15 0.80 g of ground sodium hydroxide is added 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 of 20 dioxane at room temperature. After 16 hours at room temperature, 50 cm of water and 100 cm 3 of ethyl acetate are added. The mixture is separated after settling out, the organic phase rewashed with 100 cm of water, dried over magnesium sulfate, filtered and 25 concentrated to dryness under reduced pressure (2.7 kPa). A white foam is obtained which is crystallized from isopropyl ether in order to obtain 119 0.85 g of a solid melting at 190 0 C. Recrystallization from 20 cm of ethanol gives 0.70 g of 1-[bis (4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]azetidine melting at 205'C. 5 Example 39 6.75 g of 3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol hydrochloride 10 and then 2.97 g of potassium carbonate are added to a solution of 6.8 g of bis(4-chlorophenyl)bromomethane in 300 cm 3 of acetonitrile. The reaction mixture is heated for 1 hour under reflux, cooled to room temperature, filtered and concentrated to dryness under reduced 15 pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 8.5 cm, height 22 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 by volume) as eluents 20 and collecting 250 cm 3 fractions. Fractions 11 to 48 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 5.3 g of 1-[bis(4-chlorophenyl) methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl) methyl (RS)]azetidin-3-ol are obtained. [ 1 H NMR spectrum 25 (300 MHz, (CD,) 2 SO-d6, 8 in ppm): 2.00 (s, 3H), 2.94 (s, 3H), 3.25 (mt, 2H), 3.48 (d, J=9Hz, 1H), 3.80 (d, J=9Hz, 1H), 4.54 (s, 1H), 5.34 (s, 1H), 7.15 (d, 120 J=8.5Hz, 2H), from 7.20 to 7.40 (mt, 8H), 7.50 (broad t, J=9Hz, 1H)]. Bis (4-chlorophenyl)bromomethane may be prepared according to the procedure described by 5 BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933). 3-[ (3,5-Difluorophenyl) (methylsulfonyl) methyl-(RS)]azetidin-3-ol hydrochloride may be obtained in the following manner: 160 cm 3 of a 6.2 N hydrochloric acid solution in dioxane are added to a solution of 10 37 g of 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl (RS) ]-1- (vinyloxycarbonyl)azetidin-3-ol in 160 cm of dioxane. After 16 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) . The residue obtained is 15 taken up in 320 cm 3 of ethanol, heated for 1 hour under reflux and cooled in an ice-cold water bath. The solid which appears is filtered, washed with ethyl ether and dried at 40'C under reduced pressure (2.7 kPa). 29.85 g of white crystals are obtained whose melting point is 20 greater than 260'C. 3- [(3, 5-Difluorophenyl) (methylsulfonyl) methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol may be obtained in the following manner: a solution of 14.0 cm 3 of vinyl chloroformate in 35 cm of dichloromethane is 25 added at 5*C to a solution of 60.18 g of 1-benzhydryl 3- [(3, 5-difluorophenyl) (methylsulfonyl)methyl- (RS) ] azetidin-3-ol in 1000 cm 3 of dichloromethane. After 20 121 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 5 11 cm, height 32 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (3/7 by volume) as eluents and collecting 1000 cm 3 fractions. Fractions 8 to 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 37 g of 10 3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)] 1-(vinyloxycarbonyl)azetidin-3-ol are obtained in the form of white crystals melting at 195'C. Example 40 15 14 cm 3 of a 1.6 N n-butyllithium solution in hexane are added at -70'C to a solution of 4.77 g of (3,5-difluorobenzyl)methylsulfone in 70 cm 3 of tetrahydrofuran under an argon atmosphere. After 1 hour 20 at -70'C, a solution of 6.8 g of 1-[bis(4 chlorophenyl)methyl]azetidin-3-one in 30 cm of tetrahydrofuran is added and then, 1 hour later, a solution of 2.34 cm 3 of acetyl chloride in 20 cm of tetrahydrofuran and the temperature of the reaction 25 mixture is raised to 20'C for 1 hour. 50 cm 3 of water and 200 cm 3 of ethyl acetate are added. The mixture is separated after settling out, the organic phase washed 122 with 100 cm 3 of water, 100 cm 3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 14.4 g of 3-acetoxy-1-[bis(4 5 chlorophenyl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl)methylsulfonyl methyl-(RS)]azetidine are obtained in the form of a yellow oil [1H NMR spectrum (400 MHz, CDC1 3 , in ppm): 2.79 (s, 3H), 3.04 (AB, J=9Hz, 2H), 3.27 (d, J=9Hz, 10 1H), 3.45 (s, 1H), 3.81 (d, J=9Hz, 1H), 4.32 (s, 1H), 4.49 (s, 1H), 6.88 (tt, J=9 and 2.5Hz, 1H), from 7.20 to 7.35 (mt, 1OH)]. 1-[Bis(4-chlorophenyl)methyllazetidin-3-one may be prepared according to the following procedure: a 15 solution of 8.1 cm 3 of dimethyl sulfoxide in 17.6 cm of dichloromethane is added to a solution of 5.0 cm 3 of oxalyl chloride in 73 cm 3 of dichloromethane cooled to -78 0 C. After 0.5 hour at -78'C, a solution of 16.0 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol dissolved in 20 50 cm 3 of dichloromethane is poured in. After 5 hours at -78'C, 26.6 cm 3 of triethylamine are added dropwise and the reaction mixture is allowed to return to room temperature. After 16 hours, the reaction mixture is washed with 4 times 200 cm 3 of water and then with 25 200 cm 3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue 123 obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 9.2 cm, height 21 cm) at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (40/60 by volume) as 5 eluents and collecting 200 cm fractions. Fractions 15 to 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 8.9 g of 1-[bis(4 chlorophenyl)methyl]azetidin-3-one are obtained in the form of pale yellow crystals melting at 111 0 C. 10 1-[Bis(4-chlorophenyl)methyl]azetidin-3-ol may be prepared according to the procedure described by KATRITZKY A.R. et al., J. Heterocycl. Chem., (1994), 271 starting with 35.5 g of [bis(4-chlorophenyl) methyl]amine hydrochloride and 11.0 cm of 15 epichlorohydrin. 9.0 g of 1-[bis(4-chlorophenyl) methyl]azetidin-3-ol are isolated. [Bis(4-chlorophenyl)methyl]amine hydrochloride may be prepared according to the method described by GRISAR M. et al., J. Med. Chem., 885 20 (1973). Example 41 On carrying out the operation according to 25 the procedure of Example 38 (Method 1), starting with 0.72 g of 1-[bis(4-methoxyphenyl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl-(RS)Iazetidin- 124 3-ol and after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4.0 cm, height 16.5 cm) at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as 5 eluent and collecting 40 cm fractions, 0.10 g of a white foam is obtained. After crystallization from a mixture of ethyl acetate and cyclohexane, 60 mg of 1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]azetidine are obtained in the 10 form of a solid melting at 180'C [NMR spectrum in DMSO d6, T=300K, 8 in ppm (250 MHz): 3.00 (3H, s, SCH,), 3.70 (6H, s, 2 OCH,), 3.80 (2H, s, NCH 2 ), 4.15 (2H, s, NCH 2 ), 4.58 (1H, s, NCH), 6.85 (4H, d, J=7Hz, 4CH arom.), 7.15 (2H, d, J=8Hz, 2CH arom.), 7.30 (5H, m, 5CH arom.)]. 15 1-[Bis(4-methoxyphenyl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin 3-ol may be obtained in the following manner: on carrying out the operation according to Example 39 starting with 1.2 g of bis(4-methoxyphenyl)bromomethane 20 and 1.2 g of 3-[(3,5-difluorophenyl)(methylsulfonyl) methyl-(RS)]azetidin-3-ol hydrochloride and after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height 18 cm), at an argon pressure of 0.5 bar with a mixture of ethyl 25 acetate and cyclohexane (25/75 by volume) as eluent and collecting 50 cm 3 fractions, fractions 9 to 18 are combined and then concentrated to dryness under reduced 125 pressure (2.7 kPa). 0.55 g of 1-[bis(4-methoxyphenyl) methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol is obtained. Bis(4-methoxyphenyl)bromomethane may be 5 prepared according to the procedure described by BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933). Example 42 10 On carrying out the operation according to Example 38 (Method 1), starting with 0.47 g of 1-[bis (4-methylphenyl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol and after chromatography on a silica gel column (particle size 15 0.04-0.06 mm, diameter 3.2 cm, height 18.5 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (1/9 by volume) as eluent and collecting 35 cm 3 fractions, 0.30 g of a white solid is obtained. After crystallization from diisopropyl ether, 20 0.20 g of 1-[bis(4-methylphenyl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene]azetidine is obtained in the form of white needles melting at 200'C. 1-[Bis(4-methylphenyl)methyll-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin 25 3-ol may be obtained in the following manner: on carrying out the operation as in Example 39 starting with 0.7 g of bis(4-methylphenyl)bromomethane and 0.8 g 126 of 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)] azetidin-3-ol hydrochloride and after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4.0 cm, height 19 cm), at an argon pressure of 5 0.5 bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 40 cm fractions, fractions 35 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.47 g of 1-[bis(4-methylphenyl)methyl]-3-[(3,5 10 difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin 3-ol is obtained. Bis (4-methylphenyl) bromomethane may be prepared according to the procedure described by BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933). 15 Example 43 On carrying out the operation according to Example 38 (Method 1), starting with 1.42 g of 3-[(3,5 20 difluorophenyl) (methylsulfonyl)methyl- (RS) ]-l-[ (4 methoxyphenyl) (phenyl)methyl- (RS) ]azetidin-3-ol, a mixture of the two diastereoisomers, and after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4.0 cm, height 21 m), at an 25 argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 40 cm 3 fractions, 0.10 g of a white solid is 127 obtained. After crystallization from diisopropyl ether, 50 mg of (RS)-3-[(3,5-difluorophenyl) (methylsulfonyl) methylene]-1-(4-methoxyphenyl)(phenyl)methyl]azetidine are obtained in the form of a white solid [NMR spectrum 5 in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.23 (6H,s, 2 PhCH,), 3.00 (3H,s, SCH 3 ), 3.80 (2H, s, NCH 2 ), 4.12 (2H, s, NCH 2 ), 4.58 (1H, s, NCH), 7.08 (4H, d, J=7Hz, 4CH arom.), 7.15 (2H, d, J=8Hz, 2CH arom.), 7.25 (5H, m, 5CH arom.)] 10 The mixture of diastereoisomers 3-[(3,5 difluorophenyl) (methylsulfonyl)methyl-(RS)]-1-[(4 methoxyphenyl) (phenyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to Example 39 starting with 2.52 g 15 (RS)-bromo(4-methoxyphenyl) (phenyl)methane and 2.85 g of 3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)] azetidin-3-ol hydrochloride and after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 5.6 cm, height 19 cm), at an argon pressure of 20 0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 by volume) as eluent and collecting 100 cm 3 fractions, fractions 11 to 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.16 g of the mixture of diastereoisomers 25 3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)] 1-[(4-methoxyphenyl) (phenyl)methyl-(RS)]azetidin-3-ol are obtained.

128 (RS) -bromo (4-methoxyphenyl) (phenyl ) methane may be prepared according to the procedure described by BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933). 5 Example 44 On carrying out the operation as in Example 38 (Method 1), starting with 0.47 g of 1-[bis (4-trifluoromethoxyphenyl)methyl]-3-[ (3, 5-difluoro 10 phenyl) (methylsulfonyl)methyl- (RS) ]azetidin-3-ol, and after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4.2 cm, height 14 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and 15 collecting 25 cm 3 fractions, 0.28 g of 1-[bis (4-trifluoromethoxyphenyl)methyl]-3- [(3, 5-difluoro phenyl) (methylsulfonyl)methylenelazetidine is obtained in the form of a solid [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.05 (3H, s, SCH 3 ), 3.95 20 (2H, s, NCH 2 ), 4.25 (2H, s, NCH 2 ), 4.90 (lH, s, NCH), 7.20 (2H, d, J=8Hz, 2CH arom.), 7.32 (5H, m, 5CH arom.), 7.60 (4H, d, J=7Hz, 4CH arom.)]. 1- [Bis (4-trifluoromethoxyphenyl)methyl] 3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)] 25 azetidin-3-ol may be obtained in the following manner: on carrying out the operation as in Example 39 starting with 1.59 g of bis(4-trifluoromethoxyphenyl)- 129 bromomethane and 1.2 g of 3-[(3,5-difluorophenyl) (methylsulfonyl)methyl- (RS) ] azetidin-3-ol hydrochloride and after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height 17 5 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 by volume) as eluent and collecting 50 cm fractions, fractions 15 to 23 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.49 g of 1-[bis 10 (4-trifluoromethoxyphenyl)methyl]-3- [(3, 5-difluoro phenyl) (methylsulfonyl)methyl]azetidin-3-ol is obtained. Bis (4-trifluoromethoxyphenyl)bromomethane may be prepared according to the procedure described by 15 BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933), starting with 1.39 g of bis(4-trifluoromethoxyphenyl)methanol, 3 cm 3 of 33% hydrobromic acid in acetic acid and 0.6 cm of acetyl bromide. 1.59 g of bis(4-trifluoromethoxy phenyl)bromomethane are obtained in the form of a brown 20 oil. Bis (4-trifluoromethoxyphenyl)methanol is prepared according to PAVIA M.R. et al., J. Med. Chem., 4238 (1992). 25 Example 45 On carrying out the operation as in Example 130 38 (Method 1), starting with 0.25 g of 1-[bis (4-trifluoromethylphenyl)methyl]-3-[(3,5-difluoro phenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol, and after chromatography on a silica gel column (particle 5 size 0.04-0.06 mm, diameter 2.4 cm, height 14 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 20 cm 3 fractions, 0.12 g of 1-[bis (4-trifluoromethylphenyl)methyl]-3-[(3,5-difluoro 10 phenyl) (methylsulfonyl)methylene]azetidine is obtained in the form of a white solid [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.05 (3H, s, SCH 3 ), 3.95 (2H, s, NCH 2 ), 4.25 (2H, s, NCH 2 ), 4.90 (lH, s, NCH), 7.20 (2H, d, J=8Hz, 2CH arom.), 7.32 (5H, m, 5CH 15 arom.), 7.60 (4H, d, J=7Hz, 4CH arom.)]. 1-[Bis(4-trifluoromethylphenyl)methyl] 3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)] azetidin-3-ol may be obtained in the following manner: on carrying out the operation as in Example 39 starting 20 with 1.46 g of bis(4-trifluoromethylphenyl)bromomethane and 1.2 g of 3-[(3,5-difluorophenyl) (methylsulfonyl) methyl-(RS)]azetidin-3-ol hydrochloride and after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height 17 cm), at an 25 argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (30/70 by volume) as eluent and collecting 50 cm 3 fractions, fractions 9 to 14 are 131 combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.25 g of 1-[bis (4-trifluoromethylphenyl)methyl]-3-[ (3,5-difluoro phenyl) (methylsulfonyl)methyl- (RS) ]azetidin-3-ol is 5 obtained. Bis (4-trifluoromethylphenyl)bromomethane may be prepared according to the procedure described by BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933), starting with 2.5 g of bis(4-trifluoromethylphenyl)methanol, 10 6 cm 3 of 33% hydrobromic acid in acetic acid and 1.2 cm 3 of acetyl bromide. 2.9 g of bis(4-trifluoromethyl phenyl)bromomethane are obtained in the form of a brown oil. Bis(4-trifluoromethylphenyl)methanol is 15 prepared according to PAVIA M.R. et al., J. Med. Chem., 4238 (1992). Example 46 20 On carrying out the operation according to Example 38 (Method 2), starting with 3.16 g of 3-acetoxy-l-[bis(4-chlorophenyl)methyll-3-{[3,5 bis (trifluoromethyl)phenyl] (methylsulfonyl)methyl (RS)}azetidine and 0.96 g of ground sodium hydroxide, a 25 yellow foam is obtained, after 16 hours at room temperature, which is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, 132 height 14 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting 40 cm' fractions. 1.49 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis 5 (trifluoromethyl)phenyl](methylsulfonyl)methylene} azetidine are thus obtained in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 3.05 (3H,s, SCH,), 3.90 (2H, s, NCH 2 ), 4.30 (2H, s,

NCH

2 ), 4.80 (1H, s, NCH), 7.40 (2H, d, J=7Hz, 2CH 10 arom.), 7.50 (2H, d, J=7Hz, 2CH arom.), 8.10 (2H, s, 2CH arom.), 8.20 (1H, s, CH arom.)]. 3-Acetoxy-l-[bis(4-chlorophenyl)methyl] 3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl) methyl-(RS)}azetidine may be obtained in the following 15 manner: on carrying out the operation as in Example 40 starting with 2.0 g of [3,5-bis(trifluoro methyl)benzyl]methylsulfone, 4.1 cm 3 of a 1.6 N solution of n-butyllithium in hexane, 2.0 g of 1-[bis(4-chloro phenyl)methyllazetidin-3-one and 0.77 cm 3 of acetyl 20 chloride in 20 cm 3 of anhydrous diisopropyl ether, 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 foam after chromatography on a silica gel column (particle 25 size 0.04-0.06 mm, diameter 5.6 cm, height 16 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (1/9 by volume) as eluent and 133 collecting 100 cm 3 fractions. [3,5-Bis(trifluoromethyl)benzyl]methylsulfone is prepared in the following manner: on carrying out the operation according to Example 10 starting with 5 1.8 g of 3,5-bis(trifluoromethyl)benzyl chloride and 1.22 g of sodium methanesulfinate, 1.86 g of [3,5-bis (trifluoromethyl)benzyl]methylsulfone are obtained in the form of a white solid. 10 Example 47 On carrying out the operation as in Example 38 (Method 1), starting with 0.27 g of the mixture of the two diastereoisomers 1-[(4-chlorophenyl) (2,4 15 dichlorophenyl)methyl-(RS)]-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol and after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 7.5 cm), at an argon pressure of 0.5 bar with a mixture of ethyl 20 acetate and cyclohexane (15/85 by volume) as eluent and collecting 20 cm 3 fractions, 0.10 g of (RS) 1-[(4-chlorophenyl) (2,4-dichlorophenyl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene]azetidine is obtained in the form of a white solid [NMR spectrum in 25 DMSO-d6, T=300K, 8 in ppm (250 MHz): 3.02 (3H, s, SCH), 3.82 (1H, dd, J=3 and 16Hz, NCHH), 4.04 (1H, dd, J=3 and 16Hz, NCHH), 4.10 (1H, dd, J=3 and 16Hz, NCHH), 134 4.35 (1H, dd, J=3 and 16Hz, NCHH), 5.12 (1H, s, NCH), 7.18 (2H, d, J=8Hz, 2CH arom.), 7.32 (1H, t, J=8Hz, CH arom.), 7.38 (2H, d, J=7Hz, 2CH arom.), 7.45 (2H, d, J=7Hz, 2CH arom.), 7.48 (1H, dd, J=2 and 7Hz, CH 5 arom.), 7.58 (1H, d, J=2Hz, CH arom.), 7.80 (1H, d, J=7Hz, CH arom.)]. The mixture of the two diastereoisomers 1-[(4-chlorophenyl) (2,4-dichlorophenyl)methyl-(RS)) 3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)] 10 azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to Example 39 starting with 0.56 g of (RS)-bromo(4-chlorophenyl) (2,4 dichlorophenyl)methane and 0.50 g of 3-[(3,5-difluoro phenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol 15 hydrochloride and after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4.0 cm, height 13 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent and collecting 40 cMr fractions, 20 fractions 9 to 14 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.27 g of the mixture of the two diastereoisomers 1-[(4 chlorophenyl) (2,4-dichlorophenyl)methyl-(RS)]-3-[(3,5 difluoro-phenyl) (methylsulfonyl)methyl-(RS)]azetidin 25 3-ol is obtained. (RS)-bromo(4-chlorophenyl) (2,4-dichloro phenyl)methane may be prepared according to the 135 procedure described by BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933) starting with 4.05 g of (RS) (4-chlorophenyl) (2, 4-dichlorophenyl)methanol, 10 cm 3 of 33% hydrobromic acid in acetic acid and 2.1 cm 3 of 5 acetyl bromide. 4.6 g of (RS)-bromo(4-chlorophenyl) (2,4-dichlorophenyl)methane are obtained in the form of a greenish oil. (RS)-(4-chlorophenyl) (2,4-dichlorophenyl) methanol is prepared according to PAVIA M.R. et al., J. 10 Med. Chem., 4238 (1992). Example 48 75.6 cm 3 of 5 N hydrochloric acid are added to 15 a solution of 18.9 g of 1-{(4-chlorophenyl)[4-(1,3 dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluoro phenyl) (methylsulfonyl)methylenelazetidine in 80 cm 3 of tetrahydrofuran. After 3 hours at room temperature, the mixture is taken up in dichloromethane and distilled 20 water and then adjusted to pH 14 by addition of 30% sodium hydroxide and separated after settling out. The organic phase is washed twice with 100 cm 3 of water and then 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and 25 concentrated to dryness under reduced pressure (2.7 kPa). 16 g of (RS)-l-[(4-chlorophenyl) (4-f ormylphenyl)methyl] -3- [ (3,5-difluorophenyl)- 136 (methylsulfonyl)methylene]azetidine are obtained in the form of a white foam [Spectrum in DMSO-d6, T=300K, S in ppm (300 MHz): 3.06 (3H, s, SCH,), 3.95 (2H, m, NCH 2 ), 4.26 (2H, m, NCH 2 ), 4.91 (1H, s, NCH), 7.20 (2H, d, 5 J=8Hz, 2CH arom.), 7.36 (1H, t, J=8 Hz, 1CH arom.), 7.40 and 7.52 (4H, 2d, J=7.5Hz, 4CH arom.), 7.70 and 7.88 (4H, 2d, J=7.5Hz, 4CH arom.), 9.97 (lH, s, CH aldehydic)]. 1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl) 10 phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methyl sulfonyl)methylene]azetidine may be prepared according to the following method: 13.0 cm of 1,8 diazabicyclo[5.4.0]undec-7-ene are added dropwise to a solution of 34.45 g of the mixture of the two 15 diastereoisomers 3-acetoxy-1-{(4-chlorophenyl) [4-(1,3 dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl-(RS)]-azetidine in 400 cm 3 of tetrahydrofuran under argon at 00C, and after customary treatment, 16.6 g of 1-{(4 20 chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)} 3-[(3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine are obtained in the form of a white solid after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 10.2 cm, height 23 cm), at 25 an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 250 cm 3 fractions.

137 The mixture of the two diastereoisomers 3-acetoxy-l-{(4-chlorophenyl) [4-(1,3-dioxolan 2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidine may be obtained 5 in the following manner: on carrying out the operation according to Example 40, starting with 11.6 g of (3,5 difluorobenzyl)methylsulfone, 35.1 cm of a 1.6 N solution of n-butyllithium in hexane, 19.3 g of 1-{(4 chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl 10 (RS)}azetidin-3-one and 8.8 cm of acetyl chloride in 500 cm 3 of tetrahydrofuran, 37.8 g of the mixture of the two diastereoisomers 3-acetoxy-l-{(4-chlorophenyl) [4-(1,3-dioxolan-2-yl)phenyllmethyl-(RS)}-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidine 15 are obtained in the form of a white foam. 1-{(4-Chlorophenyl) [4-(1,3-dioxolan-2-yl) phenyl]methyl-(RS)}azetidin-3-one may be prepared in the following manner: 46 cm 3 of triethylamine are added at room temperature to a solution of 28.32 g of 1-{(4 20 chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl (RS)}azetidin-3-ol in 200 cm 3 of dimethyl sulfoxide, and then a solution of 34 g of sulfur trioxide-pyridine complex in 100 cm 3 of dimethyl sulfoxide are added dropwise. After 0.25 hour at room temperature, the 25 reaction mixture is poured over ice, extracted with ethyl acetate, washed with 3 times 400 cm of water and then with 400 cm 3 of a saturated sodium chloride 138 solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 5 9.2 cm, height 21 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent and collecting 250 cm 3 fractions. Fractions 9 to 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 20.4 g of 10 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 may be prepared 15 according to the procedure described by KATRITZKY A.R. et al., J. Heterocycl. Chem., 271 (1994) starting with 35.0 g of {(4-chlorophenyl)[4-(1,3-dioxolan-2-yl) phenyl]methyl}amine, 8.3 g of epibromohydrin, 5.1 g of sodium hydrogen carbonate and 400 cm 3 of ethanol. 30.3 g 20 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-(RS)}amine hydrochloride may be prepared according to the method described by GRISAR M. et al., 25 J. Med. Chem., 885 (1973) starting with 67.2 g of 4-(1,3-dioxolan-2-yl)benzonitrile, 88.2 g of 1-bromo 4-chlorobenzene, 11 g of magnesium and 600 cm 3 of ethyl 139 ether. 42.3 g of {(4-chlorophenyl)[4-(1,3-dioxolan 2-yl)phenyllmethyl-(RS)}amine are obtained in the form of a yellow oil. 5 Example 49 0.020 g of sodium borohydride is added to a solution of 0.50 g of (RS)-l-{(4-chlorophenyl) (4-formylphenyl)methyl}-3-[(3,5-difluorophenyl) (methyl 10 sulfonyl)methylene]azetidine in 15 cm 3 of methanol at 0*C. After 1 hour at 0 0 C, 40 cm of water are added and the product extracted with 100 cm 3 of dichloromethane. The organic phase is washed twice with 40 cm of water and then 40 cm 3 of a saturated sodium chloride solution, 15 dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 14 cm), at an argon pressure of 0.5 bar with a 20 mixture of ethyl acetate and cyclohexane (30/70 by volume) and collecting 20 cm 3 fractions. Fractions 20 to 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.29 g of (RS)-l-{(4-chlorophenyl) [4-(hydroxymethyl)phenyl] 25 methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl) methylene]azetidine is obtained in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, 8 in ppm 140 (250 MHz): 3.02 (3H, S, SCH,), 3.90 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.42 (2H, d, J=5Hz, OCH 2 ), 4.75 (1H, s, NCH), 5.10 (1H, t, J=5Hz, OH), between 7.10 and 7.50 (11H, m, 11CH arom.)]. 5 Example 50 0.75 g of (RS)-1-{(4-chlorophenyl) (4-formyl phenyl)methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl) 10 methylenelazetidine and then 0.68 g of sodium triacetoxyborohydride are added to a solution of 0.10 g of pyrrolidine in 20 cm 3 of 1,2-dichloroethane. After 20 hours at room temperature, 2 cm 3 of 1 N sodium hydroxide are added, the product is extracted with 100 cm 3 of 15 dichloromethane, the organic phase is washed twice with 50 cm 3 of water and then 50 cm 3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is 20 chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4.1 cm, height 13 cm), at an argon pressure of 0.5 bar with acetate as eluent and collecting 20 cm 3 fractions. Fractions 10 to 18 are combined and then concentrated to dryness under reduced 25 pressure (2.7 kPa). 0.39 g of (RS)-l-{(4-chlorophenyl) [4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluoro phenyl) (methylsulfonyl)methylene]azetidine is obtained 141 in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 1.65 (4H, m, 2CH 2 ), 2.40 (4H,m, 2NCH 2 ), 3.02 (3H,s, SCH 3 ), 3.50 (2H, s, NCH 2 Ph), 3.85 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, 5 NCH), between 7.15 and 7.40 (9H, m, 9CH arom.), 7.48 (2H, d, J=7Hz, 2CH arom.)]. Example 51 10 On carrying out the operation as in Example 50 starting with 0.93 cm 3 of a 2 M solution of dimethylamine in methanol, 30 cm 3 of 1,2-dichloroethane, 0.75 g of (RS)-l-{(4-chlorophenyl) (4-formylphenyl) methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl) 15 methylene]azetidine and then 0.9 g of sodium triacetoxyborohydride, there is obtained after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 17.5 cm), at an argon pressure of 0.5 bar with a mixture of ethyl 20 acetate and cyclohexane (30/70 by volume) as eluent and collecting 40 cm 3 fractions, 0.46 g of (RS)-1-[(4-chlorophenyl) (4-dimethylaminomethyl)methyl] 3-[(3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine in the form of a white solid [NMR spectrum in 25 DMSO-d6, T=300K, 6 in ppm (300 MHz): 2.12 (6H, s,

N(CH,)

2 ), 3.02 (3H,s, SCH,), 3.32 (2H, s, NCH 2 Ph), 3.90 (2H,s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 142 7.18 (2H, d, J=8Hz, 2CH arom.), 7.22 (2H, d, J=8Hz, 2CH arom.), 7.35 (1H, t, J=8Hz, CH arom.), 7.39 (4H, m, 4CH arom.), 7.48 (4H, d, J=7Hz, 4CH arom.)]. 5 Example 52 A solution of 0.5 g of (RS)-1-{(4-carboxy phenyl) (4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]azetidine in 10 cm of 10 dichloromethane at O'C is stirred with 0.5 cm' of a solution (2 M) of dimethylamine in ethanol. 13 mg of hydroxybenzotriazole, 0.2 g of 1,3-dimethylaminopropyl 3-ethylcarbodiimide hydrochloride and 0.18 cm 3 of diisopropylethylamine are then added. After 20 hours at 15 room temperature, the reaction mixture is diluted with dichloromethane, washed twice with 80 cm 3 of water and then 80 cm 3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The 20 residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4.1 cm, height 13 cm), at an argon pressure of 0.5 bar with a dichloromethane/acetonitrile/methanol (98/1/1 by volume) mixture as eluent and collecting 15 cm 3 25 fractions. Fractions 13 to 15 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.16 g of a cream-colored solid is obtained 143 which, after taking up in isopropyl ether and drying, gives 0.11 g of (RS)-1-{(4-chlorophenyl)[4-N,N dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluoro phenyl) (methylsulfonyl)methylene]azetidine in the form 5 of a solid [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 2.85 (3H, broad s, NCH,), 2.95 (3H,broad s,

NCH

3 ), 3.00 (3H, s, SCH 3 ), 3.90 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.80 (1H, s, NCH), 7.15 (2H, d, J=8Hz, 2CH arom.), 7.30 (lH, t, J=8Hz, CH arom.), 7.35 (4H, m, 4CH 10 arom.), 7.50 (4H, d, J=7Hz, 4CH arom.)]. (RS)-1-{(4-carboxyphenyl) (4-chlorophenyl) methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl) methylenelazetidine may be prepared in the following manner: 1.0 cm 3 of Jones reagent is added to a solution 15 of 0.50 g of (RS)-l-{(4-chlorophenyl) (4-formylphenyl) methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl) methylene]azetidine in 10 cm 3 acetone at 0 0 C. After 5 hours, the reaction mixture is poured into distilled water, the product is extracted with 50 cm 3 of ethyl 20 acetate, the organic phase is washed twice with 50 cm 3 of water and then 50 cm 3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from an 25 ethyl acetate-cyclohexane mixture, filtered and dried. 0.50 g of (RS)-l-{(4-carboxyphenyl) (4-chlorophenyl) methyl-(RS)]-3-[(3,5-difluorophenyl) (methylsulfonyl)- 144 methylene]azetidine is obtained in the form of a white solid. Example 53 5 The operation is carried out as in Example 52, starting with 1 g of (RS)-l-{(4-carboxyphenyl) (4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl) (methyl sulfonyl)methylene]azetidine, 0.38 g of 1,3-dimethyl 10 aminopropyl-3-ethylcarbodiimide hydrochloride, 22 mg of hydroxybenzotriazole hydrate, 30 cm 3 of dichloromethane and 0.83 cm 3 of a 2 M ethylamine solution in THF, chromatographing on a silica gel column (particle size 0.04-0.06 mm, diameter 4.1 cm, height 15 cm), at an 15 argon pressure of 0.5 bar with a m-ixture of ethyl acetate and cyclohexane (45/55 by volume) as eluent and collecting 30 cm 3 fractions. Fractions 22 to 32 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.29 g of (RS)-l-{(4-chloro 20 phenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene]azetidine is obtained in the form of a white solid [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 1.07 (3H, t, J=6Hz, CH,), 3.00 (3H, s, SCH,), 3.35 (2H, m, NCH 2 ), 3.90 25 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.80 (lH, s, NCH), 7.15 (2H, d, J=8Hz, 2CH aroma) , 7.30 (lH, t, J=8Hz, CH arom.), 7.35 (2H, d, J=7Hz, 2CH arom.), 7.48 (4H, m, 145 4CH arom.), 7.74 (2H, d, J=7Hz, 2CH arom.), 8.37 (lH, t, CONH)]. Example 54 5 The operation is carried out as in Example 52, starting with 1 g of (RS)-1-{(4-carboxyphenyl) (4-chlorophenyl)methyl] -3- [(3, 5-difluorophenyl) (methyl sulfonyl)methylene]azetidine, 0.38 g of 1,3 10 dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, 22 mg of hydroxybenzotriazole hydrate, 40 cm 3 of dichloromethane and 0.24 cm of a 7 N solution of ammonium hydroxide in methanol and chromatographing on a silica gel column (particle size 0.04-0.06 mm, 15 diameter 4.1 cm, height 15 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (60/40 by volume) as eluent and collecting 35 cm 3 fractions. Fractions 38 to 48 are combined and then concentrated to dryness under reduced pressure 20 (2.7 kPa). 0.29 g of a solid is obtained which, after taking up in isopropyl ether and drying, gives 0.22 g of (RS)-1-[(4-carbamoylphenyl) (4-chlorophenyl)methyl (RS)]-3-[(3,5-difluorophenyl) (methylsulfonyl) methylene]azetidine in the form of a white solid [NMR 25 spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH 3 , 3.90 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ) , 4.82 (1H, s, NCH), 7.17 (2H, d, J=8Hz, 2CH arom.), 7.30 146 (1H, t, J=8Hz, CH arom.), 7.38 (2H, d, J=7Hz, 2CH arom.), 7.50 (5H, m, 4CH arom. and CONH 2 ), 7.80 (2H, d, J=7Hz, 2CH arom.), 7.90 (1H, s, CONH 2

)

5 Example 55 The operation is carried out according to the procedure of Example 4 starting with 1.7 g of 1-[bis (4-chlorophenyl)methyll-3-[(3,5-difluorophenyl) 10 (methylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.35 cm of methanesulfonyl chloride and 1.5 g of 4-dimethylamino pyridine. The residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm), at a 15 nitrogen pressure of 0.5 bar with a mixture of dichloromethane and ethanol (99.5/0.5 by volume) as eluent and collecting 100 cm 3 fractions. Fractions 7 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The solid is crystallized 20 from 15 cm 3 of ethyl ether. 0.2 g of 1-[bis(4-chloro phenyl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl) methylene]azetidine is obtained melting at 200'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 25 4.75 (1H, s, NCH), 7.35 (4H, d, J=7Hz, 4CH arom.), 7.45 (6H, m, 6CH arom.), 7.67 (1H, s, CH arom.)]. 1-[Bis(4-chlorophenyl)methyl]-3-[(3,5- 147 dichlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin 3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 39 starting with 4 g of bis(4-chloro 5 phenyl)bromomethane and 3 g of 3-[(3,5-dichlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol hydrochloride, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 40 cm), at a 10 nitrogen pressure of 0.5 bar with dichloromethane and then a mixture of dichloromethane and ethanol (99/1 by volume) as eluent and collecting 100 cm 3 fractions. Fractions 15 to 19 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.7 g of 15 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a foam. Bis(4-chlorophenyl)bromomethane may be prepared according to the procedure described by 20 BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933). 3-[(3,5-Dichlorophenyl) (methylsulfonyl) methyl-(RS)]azetidin-3-ol hydrochloride may be obtained in the following manner: on carrying out the operation according to the procedure of Example 39 starting with 25 5.6 g of 3-[(3,5-dichlorophenyl) (methylsulfonyl)methyl (RS)]-1-(vinyloxycarbonyl)azetidin-3-ol and 56 cm 3 of a 6.2 N solution of hydrochloric dioxane in 56 cm 3 of 148 dioxane, 5.1 g of 3-[(3,5-dichlorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol hydrochloride are obtained in the form of a foam. 3-[(3,5-Dichlorophenyl) (methylsulfonyl) 5 methyl-(RS)]-l-(vinyloxycarbonyl)azetidin-3-ol may be prepared in the following manner: on carrying out the operation according to the procedure of Example 39 starting with 7.4 g of 1-benzhydryl-3-[(3,5-dichloro phenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol and 10 1.6 cm 3 of vinyl chloroformate in 75 cm of dichloromethane, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 40 cm), at a nitrogen pressure of 0.5 bar with a mixture of ethyl 15 acetate and cyclohexane (30/70 by volume) as eluent and collecting 100 cm 3 fractions. Fractions 4 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 5.6 g of 3-[(3,5-dichlorophenyl) (methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl) 20 azetidin-3-ol are obtained in the form of a foam. Example 56 On carrying out the operation according to the procedure of Example 4 starting with 0.5 g of 25 1-benzhydryl-3-[(3-dimethylaminophenyl) (methyl sulfonyl)methyl-(RS)]azetidin-3-ol, 0.1 cm 3 of methanesulfonyl chloride and 0.5 g of 4-dimethyl- 149 aminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with a mixture of 5 dichloromethane and ethanol (98/2 by volume) as eluent and collecting 20 cm fractions. Fractions 8 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 8 cm of ethyl ether. 0.3 g of 1-benzhydryl-3-[(3 10 dimethylaminophenyl) (methylsulfonyl)methylene]azetidine is obtained melting at 176 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 2.90 (6H, s, N(CHI) 2 ), 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 6.70 (3H, m, 3CH arom.), 7.20 (3H, 15 m, 3CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.48 (4H, d, J=7Hz, 4CH arom.)]. 1-Benzhydryl-3-[(3-dimethylaminophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the 20 operation according to the procedure of Example 1 starting with 0.4 g of (3-dimethylaminobenzyl) methylsulfone, 0.4 g of 1-benzhydrylazetidin-3-one and 1.2 cm of a 1.6 M solution of n-butyllithium in hexane, 0.5 g of 1-benzhydryl-3-[(3-dimethylaminophenyl) 25 (methylsulfonyl)methyl-(RS)]azetidin-3-ol is obtained in the form of a solid melting at 185 0 C. (3-Dimethylaminobenzyl)methylsulfone may be 150 prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 1.4 g of (3-dimethylaminobenzyl) methylsulfide and 5.1 g of oxone , 1.1 g of 5 (3-dimethylaminobenzyl)methylsulfone are obtained in the form of a white solid melting at 195'C. (3-Dimethylaminobenzyl)methylsulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 37 10 starting with 4 g of (3-iodobenzyl)methylsulfide, 1.4 g of dimethylamine in solution in 5 cm 3 of tetrahydrofuran, 2.9 g of sodium tert-butoxide, 0.56 g of 1,1-bis(diphenylphosphino)ferrocenylpalladium chloride and 1.3 g of 1,1'-bis(diphenylphosphino) 15 ferrocene in 35 cm of tetrahydrofuran, 0.9 g of (3-dimethylaminobenzyl)methylsulfide is obtained in the form of an oil. Example 57 20 On carrying out the operation according to the procedure of Example 4 starting with 1.3 g of 1-benzhydryl-3-[(3-methylsulfanylphenyl) (methyl sulfonyl)methyl-(RS)]azetidin-3-ol, 0.3 cm 3 of 25 methanesulfonyl chloride and 1.4 g of 4-dimethylamino pyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 151 0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane and ethanol (98/2 by volume) as eluent and collecting 20 cm 3 fractions. Fractions 11 to 13 are 5 combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 15 cm 3 of ethyl ether. 0.6 g of 1-benzhydryl-3-[(3 methylsulfanylphenyl)(methylsulfonyl)methylene] azetidine is obtained melting at 146 0 C [NMR spectrum in 10 DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.45 (3H, s, PhSCH,), 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), between 7.10 and 7.50 (14H, m, 14CH arom.)]. 1-Benzhydryl-3-[(3-methylsulfanylphenyl) 15 (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 1.1 g of methyl(3-methylsulfanylbenzyl) sulfone, 1.2 g of 1-benzhydrylazetidin-3-one, 1.3 g of 20 1-benzhydryl-3-[(3-methylsulfanylphenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a solid. Methyl(3-methylsulfanylbenzyl)sulfone may be prepared in the following manner: a mixture of 5 g of 25 (3-iodobenzyl)methylsulfone and 1 g of tetrakis triphenylphosphinepalladium in 250 cm 3 of dimethyl sulfoxide is heated at a temperature close to 100'C, 152 under a nitrogen stream, for 1 hour. 2.5 g of sodium methylthiolate are added and then the heating at 100 0 C is maintained for 18 hours. The reaction medium is cooled to room temperature and taken up in 700 cm 3 of 5 ethyl acetate and 500 cm of water. The organic phase is decanted off, washed with 10 times 500 cm of water, 500 cm 3 of a saturated aqueous sodium chloride solution, filtered on sintered glass and concentrated to dryness under reduced pressure (2.7 kPa) . The residue obtained 10 is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 and then 60/40 and then 50/50 by volume) as eluent and collecting 15 30 cm 3 fractions. Fractions 26 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.2 g of methyl(3-methylsulfanyl benzyl)methylsulfone are obtained in the form of an oil. 20 Example 58 4 cm of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to a solution, 25 cooled to 5 0 C, of 1.1 g 1-benzhydryl-3-{[3-(tert-butyl dimethylsiloxymethyl) phenyl] (methylsulfonyl)methylene} azetidine in 10 cm 3 of tetrahydrofuran. The mixture is 153 stirred for 3 hours at a temperature close to 20*C and then taken up in 100 cm of ethyl acetate and twice 50 cm 3 of water. The organic phase is decanted off, extracted, dried over anhydrous magnesium sulfate and 5 concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with a mixture of 10 dichloromethane and ethanol (95/5 by volume) as eluent and collecting 60 cm 3 fractions. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.5 g of 1-benzhydryl-3-[(3 hydroxymethylphenyl) (methylsulfonyl)methylene]azetidine 15 is obtained in the form of a white solid melting at 152 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 2.95 (3H, s, SCH 3 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.50 (2H, d, J=5Hz, OCH 2 ), 4.75 (1H, s, NCH), 5.25 (1H, t, J=5Hz, OH), 7.20 (2H, t, J=7Hz, 2CH 20 arom.), 7.30 (8H, m. 8CH arom.), 7.45 (4H, d, J=7Hz, 4 CH arom.)]. 1-Benzhydryl-3-{[3-(tert-butyldimethyl silyloxymethyl)phenyl](methylsulfonyl)methylene} azetidine may be prepared in the following manner: on 25 carrying out the operation according to the procedure of Example 4 starting with 1.6 g of 1-benzhydryl-3-{[3 (tert-butyldimethylsiloxymethyl)phenyl](methyl- 154 sulfonyl)methyl-(RS)]azetidin-3-ol, 0.3 cm of methanesulfonyl chloride and 1.4 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column 5 (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 60 cm 3 fractions. Fractions 15 to 30 are combined and concentrated to dryness under reduced pressure 10 (2.7 kPa). 1.1 g of 1-benzhydryl-3-{[3-(tert-butyl dimethylsiloxymethyl)phenyl](methylsulfonyl)methylene} azetidine are obtained in the form of a white solid melting at 148'C. 1-Benzhydryl-3-{[3-(tert-butyldimethyl 15 silyloxymethyl)phenyl](methylsulfonyl)methyl-(RS)] azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 2 g of [3-(tert butyldimethylsilyloxymethyl)benzyl]methylsulfone and 20 1.5 g of 1-benzhydrylazetidin-3-one, 1.6 g of 1-benzhydryl-3-{[3-(tert-butyldimethylsilyloxymethyl) phenyl](methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid melting at 175 0 C. [(3-(Tert-butyldimethylsilyloxy 25 methyl)benzyl]methylsulfone may be prepared in the following manner: a mixture of 13.4 g of (3-hydroxymethylbenzyl)methylsulfone, 11 g of imidazole 155 and 12 g of tert-butyldimethylsilane chloride is stirred for 18 hours at a temperature close to 20'C. The solution is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by 5 chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 5 cm, height 50 cm), at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 100 cm 3 fractions. Fractions 7 to 14 are combined and concentrated to dryness under 10 reduced pressure (2.7 kPa). 5.7 g of [3-(tert-butyl dimethylsilyloxymethyl)benzyl]methylsulfone are obtained in the form of a white solid melting at 80 0 C. (3-Hydroxymethylbenzyl)methylsulfone may be prepared in the following manner: a mixture of 26 g of 15 3-(methylsulfonylmethyl)benzoic acid and 4.6 g of lithium aluminium hydride in 600 cm 3 of tetrahydrofuran is stirred for 18 hours at a temperature close to 20 0 C. The solution is cooled to OC and then 15 cm 3 of ethyl acetate, 5 cm 3 of water, 5 cm 3 of a 15% aqueous solution 20 of sodium hydroxide and finally 30 cm 3 of water are added successively. The mixture is filtered on celite, the filtrate taken up in 600 cm 3 of ethyl acetate. The organic phase is taken up in 500 cm 3 of water and then 200 cm 3 of a saturated aqueous sodium chloride solution, 25 decanted off, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 10.4 g of (3-hydroxymethyl- 156 benzyl)methylsulfone are obtained in the form of a gum. 3-(Methylsulfonylmethyl)benzoic acid may be prepared in the following manner: on carrying out the operation according to the procedure of Example 10 5 starting with 23.3 g of 3-chloromethylbenzoic acid and 23.3 g of sodium methanesulfinate, 26 g of 3-(methyl sulfonylmethyl)benzoic acid are obtained in the form of a white solid melting at 210 0 C. 10 Example 59 0.13 g of sodium methylthiolate is added, while the temperature is maintained below 30'C, to a solution of 0.8 g of 1-benzhydryl-3-[(3-bromomethyl 15 phenyl) (methylsulfonyl)methylene]azetidine in 8 cm 3 of dimethylformamide. The mixture is stirred for 18 hours at a temperature close to 20'C and then taken up in 30 cm 3 of ethyl acetate and 50 cm 3 of water. The organic phase is decanted off, extracted and washed with 3 20 times 50 cm 3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 28 cm) at a 25 nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90/10 by volume) as eluent and collecting 50 cm 3 fractions. Fractions 8 to 157 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.3 g of 1-benzhydryl 3-{[3-(methylsulfanylmethyl)phenyll(methylsulfonyl) methylene]}azetidine is obtained in the form of a white 5 solid melting at 150'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 1.95 (3H, s, SCH,), 2.95 (3H, s, SCH,), 3.75 (2H, s, SCH 2 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7Hz, CH arom.), 7.30 (8H, d, J=7Hz, 8CH arom.), 7.45 10 (4H, d, J=7Hz, 4 CH arom.)]. 1-Benzhydryl-3-[(3-bromomethylphenyl) (methyl sulfonyl)methylenelazetidine may be prepared in the following manner: 0.23 cm 3 of phosphorus tribromide and then a drop of pyridine are added, at a temperature 15 close to 20 0 C, to a mixture of 1 g of 1-benzhydryl 3-[(3-hydroxymethylphenyl) (methylsulfonyl)methylene] azetidine in 10 cm of dichloromethane. The stirring is maintained for 18 hours at the same temperature. The reaction medium is taken up in 20 cm of water and 20 10 cm 3 of a saturated aqueous sodium chloride solution. The organic phase is decanted off, extracted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 1 g of 1-benzhydryl-3-[(3-bromomethyl 25 phenyl) (methylsulfonyl)methylene]azetidine is obtained in the form of a foam used in the crude state in subsequent syntheses.

158 Example 60 On carrying out the operation according to 5 the procedure of Example 4 starting with 6.6 g of 1-benzhydryl-3-[(methylsulfonyl) (quinol-8-yl)methyl (RS)]azetidin-3-ol, 1.7 cm of methanesulfonyl chloride and 5.2 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel 10 column (particle size 0.04-0.06 mm, diameter 6.5 cm, height 35 cm), at a nitrogen pressure of 0.5 bar with a dichloromethane and methanol mixture (95/5 by volume) as eluent and collecting 40 cm 3 fractions. Fractions 7 to 15 are combined and concentrated to dryness under 15 reduced pressure (2.7 kPa). The solid obtained is crystallized from 100 cm 3 of ethyl ether. 4.4 g of 1-benzhydryl-3-[(methylsulfonyl) (quinol-8-yl) methylenelazetidine are obtained melting at 212'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 3.15 20 (3H, s, SCH 3 ), 3.55 (2H, broad s, NCH 2 ), 4.30 (2H, s,

NCH

2 ), 4.70 (1H, s, NCH), 7.18 (2H, t, J=7Hz, 2CH arom.), 7.25 (4H, t, J=7Hz, 4CH arom.), 7.43 (4H, d, J=7Hz, 4 CH arom.), 7.62 (2H, m, 2CH quinoline), 7.75 (lH, dd, J=2 and 7Hz, CH quinoline), 8.05 (1H, dd, J=2 25 and 7Hz, CH quinoline), 8.43 (1H, dd, J=2 and 8Hz, CH quinoline), 9.00 (1H, dd, J=2 and 5Hz, CH quinoline)]. 1-Benzhydryl-3-[(methylsulfonyl) (quinol- 159 8-yl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 5.5 g of methyl(quinol-8-ylmethyl)sulfone, 5.9 g of 5 1-benzhydrylazetidin-3-one and 18.8 cm 3 of a 1.6 M solution of n-butyllithium in hexane, 6.6 g of 1-benzhydryl-3-[(methylsulfonyl) (quinol-8-yl)methyl (RS)]azetidin-3-ol are obtained in the form of a beige solid. 10 Methyl(quinol-8-ylmethyl)sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 10 starting with 4.5 g of 8-chloromethylquinoline and 4.4 g of sodium methanesulfinate, 5.7 g of 15 methyl(quinol-8-ylmethyl)sulfone are obtained in the form of a beige solid. 8-Chloromethyl quinoline may be prepared in the following manner: 6.7 g of N-chlorosuccinimide and then 250 mg of benzoyl peroxide are added, at a 20 temperature close to 20 0 C, to a mixture of 7.1 g of 8-methylquinoline in 250 cm 3 of carbon tetrachloride. The reaction medium is heated at the reflux temperature of the solvent for 36 hours and then cooled to 20 0 C. The mixture is filtered on sintered glass and the 25 filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a silica gel column (particle size 160 0.04-0.06 mm, diameter 5.5 cm, height 32 cm), at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 40 cm 3 fractions. Fractions 21 to 40 are combined and concentrated to dryness under 5 reduced pressure (2.7 kPa). 4.5 g of 8-chloromethyl quinoline are obtained in the form of a brown oil which is used in the crude state in subsequent syntheses. Example 61 10 On carrying out the operation according to the procedure of Example 4 starting with 6.2 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol, 1.4 cm of 15 methanesulfonyl chloride and 6.1 g of 4-dimethylamino pyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 60 cm), at a nitrogen pressure of 0.5 bar with dichloromethane as 20 eluent and collecting 100 cm 3 fractions. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 25 cm of ethyl ether. 0.7 g of 1- [bis (4-chlorophenyl)methyl] -3- [ (3-cyanophenyl) 25 (methylsulfonyl)methylene]azetidine is obtained in the form of a solid melting at 178 0 C [NMR spectrum in DMSO d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH 3 ), 3.80 161 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), 7.30 (4H, d, J=7Hz, 4CH arom.), 7.40 (4H, d, J=7Hz, 4CH arom.), 7.60 (1H, t, J=7Hz, CH arom.), 7.70 (1H, d, J=7Hz, CH arom.), 7.85 (2H, m, 2CH arom.)]. 5 1-[Bis(4-chlorophenyl)methyl]-3-[(3 cyanophenyl) (methylsulfonyl)methyl- (RS) ]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 5.5 g of (3-cyanophenyl) 10 methylsulfone, 6.1 g of 1-[bis(4-chlorophenyl) methyllazetidin-3-one and 13.8 cm 3 of a 1.6 M solution of n-butyllithium in hexane, 6.3 g of 1-[bis (4-chlorophenyl)methyl]-3-[(3-cyanophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained 15 in the form of a foam. Example 62 A mixture of 4.5 g of 1-[bis(4-chlorophenyl) 20 methyl] -3-[ (3-cyanophenyl) (methylsulfonyl)methylene) azetidine in 50 cm 3 of acetic acid and 50 cm of concentrated hydrochloric acid (d=1.18) is heated at 50'C for 20 hours. The reaction medium is cooled to room temperature and concentrated to dryness under 25 reduced pressure (2.7 kPa). The oil obtained is taken up in 100 cm of ethanol and then the solution is concentrated to dryness under reduced pressure 162 (2.7 kPa). The residue is precipitated in 60 cm 3 of ethyl ether. The solid obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 25 cm, height 40 cm) at a 5 nitrogen pressure of 0.5 bar with dichloromethane and then a dichloromethane and ethanol mixture (99.5/0.5 by volume) as eluent and collecting 30 cm 3 fractions. Fractions 35 to 46 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid 10 obtained is crystallized from 15 cm 3 of ethyl ether. 0.2 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3 carbamoylphenyl) (methylsulfonyl)methylene]azetidine is obtained in the form of a solid melting at 192'C [NNR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 15 (3H, s, SCH ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.80 (lH, s, NCH), 7.35 (4H, d, J=7Hz, 4CH arom.), 7.45 (5H, d, J=7Hz, 4CH arom. and 1/2 CONH 2 ), 7.50 (2H, m, 2CH arom.), 7.85 (2H, m, 2CH arom.)]. 20 Example 63 On carrying out the operation according to the procedure of Example 1 starting with 0.8 g of 1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methyl 25 amino)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-ol, 0.2 cm 3 of methanesulfonyl chloride and 0.7 g of 4-dimethylaminopyridine, the residue obtained is 163 purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with a dichloromethane and ethanol mixture (98/2 by volume) as 5 eluent, collecting 20 cm 3 fractions. Fractions 4 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from 10 cm 3 of ethyl acetate. 0.5 g of 1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl 10 N-methylamino)phenyl](methylsulfonyl)methylene} azetidine is obtained in the form of a solid melting at 161'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 1.30 (9H, s, (CH,),), 2.95 (3H, s, SCH,), 3.15 (3H, s, NCH,), 3.75 (2H, s, SCH2), 3.80 (2H, s, NCH 2 ), 4.20 15 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), between 7.15 and 7.50 (14H, m, 14CH arom.)]. 1-Benzhydryl-3-{[3-(N-tert-butyloxycarbonyl N-methylamino)phenyl](methylsulfonyl)methyl-(RS)} azetidin-3-ol may be obtained in the following manner: 20 on carrying out the operation according to the procedure of Example 1 starting with 1.6 g of [3-(N tert-butyloxycarbonyl-N-methylamino)benzyl]methyl sulfone, 1.3 g of 1-benzhydrylazetidin-3-one and 3.8 cm' of a 1.6 M solution of n-butyllithium in hexane, 0.8 g 25 of 1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl N-methylamino)phenyl](methylsulfonyl)methyl-(RS)} azetidin-3-ol is obtained in the form of a white solid.

164 [3- (N-tert-butyloxycarbonyl-N-methylamino) benzyl]methylsulfone may be prepared in the following manner: 2.5 g of di-tert-butyl dicarbonate in 40 cm of dioxane are added to a solution, cooled to OC of 5 methyl(3-methylaminobenzyl)sulfone in 30 cm of dioxane. The stirring is maintained for 18 hours at room temperature. The reaction medium is taken up in 75 cm of dichloromethane; the organic phase is washed with 75 cm 3 of water and then with 75 cm 3 of a saturated 10 aqueous sodium chloride solution. The organic phase is decanted off, extracted, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a silica gel column 15 (particle size 0.04-0.06 mm, diameter 2 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (50/50 by volume) as eluent, collecting 20 cm 3 fractions. Fractions 5 to 10 are combined and concentrated to dryness under 20 reduced pressure (2.7 kPa). 1.8 g of [3-(N-tert butyloxycarbonyl-N-methylamino) benzyl] methyl sulf one are obtained in the form of a colorless oil. Methyl(3-methylaminobenzyl)sulfone may be prepared in the following manner: a mixture of 9.7 cm 3 25 of formic acid (d=1.22) and 19.6 cm 3 of acetic anhydride (d=1.08) is heated for 3 hours at 50'C and then the solution is allowed to return to room temperature.

165 40 cm 3 of tetrahydrofuran are added and the mixture is cooled to -20*C. 14.8 g of (3-aminobenzyl)methylsulfone and 200 cm of tetrahydrofuran are then added. The stirring is maintained for 2 hours at -20'C and then 48 5 hours at room temperature. The mixture is filtered on sintered glass, the precipitate is washed with 3 times 50 cm 3 of diisopropyl ether and then dried. The filtrate is concentrated to half its volume (2.7 kPa), the precipitate obtained is filtered on sintered glass and 10 washed with 3 times 30 cm 3 of diisopropyl ether and then dried. The two precipitates are combined and dissolved in 375 cm 3 of tetrahydrofuran. The solution is cooled to OC; 100 cm 3 of a 2 M solution of borane dimethyl sulfide in tetrahydrofuran added and then heated under 15 reflux for 3 hours. The mixture is cooled to 5oC and then 60 cm 3 of methanol are added over 20 minutes. The stirring is maintained for 1 hour at room temperature. A stream of hydrogen chloride is bubbled in the solution for 5 minutes. The reaction medium is then 20 heated under reflux for 1 hour, cooled to room temperature and taken up in 300 cm 3 of water. The solution is alkalinized with 3N sodium hydroxide and then with a saturated aqueous sodium bicarbonate solution. The organic phase is extracted with twice 33 25 250 cm of ethyl acetate, washed with 300 cm 3 of a saturated aqueous sodium bicarbonate solution and twice 300 cm 3 . It is concentrated to dryness under reduced 166 pressure (2.7 kPa). The oil obtained is taken up in 100 cm 3 of 4 N hydrochloric acid and then with 100 cm of ethyl acetate. The aqueous phase is alkalinized with 120 cm' of 3 N sodium hydroxide, and then with an 5 aqueous sodium bicarbonate solution. The organic phase is extracted with twice 75 cm 3 of ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 9 g of methyl(3-methylaminobenzyl)sulfone 10 are obtained in the form of a pink solid. (3-Aminobenzyl)methylsulfone may be prepared in the following manner: a mixture of 23.7 g of methyl (3-nitrobenzyl)sulfone, 65 cm 3 of hydrochloric acid (d=1.18) and 150 cm 3 of methanol is heated under reflux 15 for 15 minutes. 18.5 g of iron are added over 10 minutes and the reflux is maintained for 4 hours and then 18 hours at room temperature. The reaction medium is alkalinized with an aqueous solution of ammonium hydroxide and then with an aqueous sodium bicarbonate 20 solution. The organic phase is extracted with 3 times 250 cm 3 of ethyl acetate, dried over magnesium sulfate, filtered on sintered glass and concentrated to dryness under reduced pressure (2.7 kPa). 14.9 g of (3-aminobenzyl)methylsulfone are obtained in the form 25 of a beige solid which is used in the crude state in subsequent syntheses.

167 Example 64 A mixture of 0.3 g of 1-benzhydryl-3-{[3-(N tert-butyloxycarbonyl-N-methylamino)phenyl](methyl 5 sulfonyl)methylene}azetidine, 4 cm of a 4.7 N solution of hydrochloric dioxane and 4 cm 3 of dioxane is stirred for 18 hours at room temperature. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 100 cm' of water 10 and 20 cm 3 of diethyl ether. The aqueous phase is alkalinized with 30 cm 3 of an aqueous sodium bicarbonate solution. The organic phase is extracted with twice 40 cm 3 of ethyl acetate, washed with twice 30 cm of water, decanted off, dried over anhydrous magnesium 15 sulfate, filtered and concentrated -to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 20 cm 3 of diethyl ether. 0.16 g of 1-benzhydryl 3-[(3-methylaminophenyl) (methylsulfonyl)methylene] azetidine is obtained in the form of a solid melting at 20 161'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 2.65 (3H, d, J=5Hz, NCH,), 2.95 (3H, s, SCH), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (lH, s, NCH), 5.80 (1H, q, J=5Hz, NH), 6.60 (3H, m, 3CH arom.), 7.15 (1H, t, J=7Hz, CH arom.), 7.22 (2H, t, J=7Hz, 2CH 25 arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.48 (4H, d, J=7Hz, 4 CH arom.)].

168 Example 65 On carrying out the operation according to the procedure of Example 4 starting with 11.3 g of 5 1-[bis(4-chlorophenyl)methyll-3-[(3-methoxyphenyl) (methylsulfonyl)methyl-(RS)Jazetidin-3-ol, 2.6 cm 3 of methanesulfonyl chloride and 10.9 g of 4-dimethylamino pyridine, 5 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3 methoxyphenyl) (methylsulfonyl)methyleneazetidine are 10 obtained after recrystallization from 20 cm 3 of diethyl ether, melting at 181 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH 3 ), 3.77 (3H, s, OCH ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.80 (lH, s, NCH), 6.95 (3H, m, 3CH arom.), 7.35 (5H, 15 m, 5CH arom.), 7.45 (4H, d, J=7Hz, 4CH arom.)]. 1-[Bis(4-chlorophenyl)methyl]-3-[(3-methoxy phenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 20 starting with 6.6 g of (3-methoxybenzyl)methylsulfone, 10 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 23 cm of a 1.6 N solution of n-butyllithium in hexane, 11.4 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxy phenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are 25 obtained in the form of a white solid melting at 130'C. Example 66 169 On carrying out the operation according to the procedure of Example 32 starting with 4.8 g of 1- [bis (4-chlorophenyl)methyl] -3- [ (3-methoxyphenyl) 5 (methylsulfonyl)methylene]azetidine, 32 cm 3 of a 1 M solution of boron tribromide in dichloromethane, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), at a nitrogen pressure of 0.5 bar 10 with a mixture of dichloromethane and ethanol (98/2 by volume) as eluent and collecting 20 cm 3 fractions. Fractions 16 to 17 are concentrated to dryness under reduced pressure (2.7 kPa). 0.1 g 1-[bis(4-chloro phenyl)methyl] -3- [ (3-hydroxyphenyl) (methylsulfonyl) 15 methylene]azetidine is obtained, after recrystallization from 5 cm 3 of diethyl ether, in the form of a solid melting at 114'C [NMR spectrum in DMSO d6, T=300K, 8 in ppm (250 MHz): 2.92 (3H, s, SCH 3 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.80 (1H, s, NCH), 20 6.80 (3H, m, 3CH arom.), 7.20 (1H, t, J=7Hz, CH arom.), 7.37 (4H, t, J=7Hz, 4CH arom.), 7.47 (4H, d, J=7Hz, 4 CH arom.)]. Example 67 25 On carrying out the operation according to the procedure of Example 4 starting with 0.6 g of 170 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl) (3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3-ol, 0.1 cm of methanesulfonyl chloride and 0.5 g of 4-dimethyl aminopyridine, the residue obtained is purified by 5 chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a dichloromethane and ethanol mixture as eluent (98.5/1.5 by volume) and collecting 10 cm 3 fractions. Fraction 4 is concentrated 10 to dryness under reduced pressure (2.7 kPa). 0.5 g 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl) (3-pyrrolidinylphenyl)methylene]azetidine is obtained, after recrystallization from 5 cm of diethyl ether, in the form of a solid melting at 133'C [NMR spectrum in 15 DMSO-d6, T=300K, 8 in ppm (400 MHz): 2.00 (4H, m, 2

CH

2 ), 2.95 (3H, s, SCH,), 3.20 (4H, m, 2 NCH 2 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.80 (lH, s, NCH), 6.50 (lH, s, CH arom.), 6.60 (lH, d, J=7Hz, CH arom.), 6.65 (lH, d, J=7Hz, CH arom), 7.20 (lH, t, J=7Hz, CH arom.), 20 7.40 (4H, d, J=7Hz, 4 CH arom.), 7.50 (4H, d, J=7Hz, 4 CH arom.)]. 1-[Bis(4-chlorophenyl)methyll-3-[(methyl sulfonyl) (3-pyrrolidinylphenyl)methyl-(RS)]azetidin 3-ol may be obtained in the following manner: on 25 carrying out the operation according to the procedure of Example 1 starting with 0.5 g of methyl (3-pyrrolidinylbenzyl)sulfone, 0.6 g of 1-[bis- 171 (4-chlorophenyl)methyl]azetidin-3-one and 1.4 cm 3 of a 1.6 N solution of n-butyllithium in hexane, 0.6 g of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl) (3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3-ol is 5 obtained in the form of a cream-colored solid. Example 68 On carrying out the operation according to 10 the procedure of Example 58 starting with 5.1 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyl dimethylsilyloxymethyl)phenyl](methylsulfonyl) methylene}azetidine and 17 cm 3 of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran, the 15 residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with a dichloromethane and ethanol mixture (97/3 by volume) as eluent and collecting 100 cm 3 fractions. 20 Fractions 10 to 14 are combined, concentrated to dryness under reduced pressure (2.7 kPa). The yellow solid obtained is taken up in 2 cm 3 of dichloromethane and 10 cm 3 of ethyl acetate and then filtered on sintered glass and washed with 2 cm 3 of ethyl acetate. 25 1.6 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxy methylphenyl) (methylsulfonyl)methylene]azetidine are obtained in the form of a white solid melting at 214'C 172 [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (400 MHz): 2.95 (3H, s, SCH), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s,

NCH

2 ), 4.50 (2H, d, J=5Hz, OCH 2 ), 4.80 (lH, s, NCH), 5.25 (lH, t, J=5Hz, OH), 7.30 (1H, d, J=7Hz, CH arom.), 5 between 7.35 and 7.45 (7H, m, 7CH arom.), 7.50 (4H, d, J=7Hz, 4CH arom.)]. 1-[Bis(4-chlorophenyl)methyll-3-{[3-(tert butyldimethylsilyloxymethyl)phenyl](methylsulfonyl) methylene}azetidine may be prepared in the following 10 manner: on carrying out the operation according to the procedure of Example 4 starting with 10.8 g of 1-[bis (4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyl oxymethyl)phenyl](methylsulfonyl)methyl-(RS)}azetidin 3-ol, 2 cm 3 of methanesulfonyl chloride and 8.5 g of 15 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 100 cm 3 20 fractions. Fractions 12 to 29 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 5.2 g of 1-[bis(4-chlorophenyl)methyll 3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methyl sulfonyl)methylene}azetidine are obtained in the form 25 of a gum. 1-[Bis(4-chlorophenyl)methyll-3-{[3-(tert butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)- 173 methyl-(RS)}azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 5.8 g of [3-(tert-butylsilyloxymethyl)benzyl]methyl 5 sulfone and 5.6 g of 1-[bis(4-chlorophenyl)methyl] azetidin-3-one, 10.8 g of 1-[bis(4-chlorophenyl) methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl) phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-ol are obtained in the form of a gum. 10 Example 69 A mixture of 0.45 g of 1-[bis(4-chloro phenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluoro phenoxycarbonyl)phenyl]methylene}azetidine, 0.07 cm 3 of 15 1-aminopiperidine in 4 cm 3 of dimethylformamide is stirred for 18 hours at room temperature. The mixture is taken up in 30 cm 3 of ethyl acetate. The organic phase is washed with 3 times 50 cm 3 of water, dried over magnesium sulfate, filtered and concentrated to dryness 20 under reduced pressure (2.7 kPa). 0.2 g of 1-[bis (4-chlorophenyl)methyl]-3-{(methylsulfonyl) [3-(N piperidylcarbamoyl)phenyl]methylene}azetidine is obtained melting at 175 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (400 MHz): 1.40 (2H, m, CH 2 ), 1.60 (4H, 25 m, 2CH 2 ), 2.85 (4H, m, 2NCH 2 ), 3.00 (3H, s, SCH 3 ), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH 2 ), 4.80 (1H, s, NCH), between 7.45 and 7.60 (10H, m, 10CH arom.), 7.75 (2H, 174 m, 2CH arom.), 9.45 (lH, s, NH)]. 1-[bis(4-chlorophenyl)methyl]-3-{(methyl sulfonyl) [3-(pentafluorophenoxycarbonyl)phenyl] methylene}azetidine may be prepared in the following 5 manner: on carrying out the operation according to the procedure of Example 29 starting with 2.6 g of 1-[bis (4-chlorophenyl)methyll-3-[(3-carboxyphenyl) (methyl sulfonyl)methylene]azetidine hydrochloride, 0.9 g of pentafluorophenol, 0.9 g of 1-(3-dimethylaminopropyl) 10 3-ethylcarbodiimide hydrochloride in 25 cm 3 of dimethyl formamide, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with a mixture of 15 dichloromethane and ethanol (99/1 by volume) as eluent and collecting 30 cm 3 fractions. Fractions 7 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.9 g of 1-[bis(4-chlorophenyl) methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxy 20 carbonyl)phenyl]methylene}azetidine is obtained in the form of a foam. 1-[Bis(4-chlorophenyl)methyl]-3-[(3 carboxyphenyl) (methylsulfonyl)methylene]azetidine may be prepared in the following manner: 2 cm 3 of Jones 25 reagent are added to a mixture of 0.5 g of 1-[bis (4-chlorophenyl)methyl]-3-[(3-hydroxymethylphenyl) (methylsulfonyl)methylene]azetidine in 9 cm 3 of acetone, 175 cooled to 5'C. This stirring is maintained for 2 hours at this temperature and then 50 cm 3 of a mixture of water and ice and 50 cm of ethyl acetate are added. The organic phase is decanted off, washed with 50 cm 3 of a 5 saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 25 10 cm), at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane and ethanol as eluent and collecting 60 cm 3 fractions. Fractions 12 to 14 are combined, concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 15 10 cm 3 of ethyl ether. 32 mg of 1-[bis(4-chlorophenyl) methyl]-3-[(3-carboxyphenyl) (methylsulfonyl)methylene] azetidine are obtained in the form of a solid melting at 2050C [NMR spectrum in DMSO-d6, T=300K, S in ppm (400 MHz): 2.90 (3H, s, SCH 3 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, 20 s, NCH 2 ), 4.80 (1H, s, NCH), 7.33 (4H, d, J=7Hz, 4CH arom.), 7.39 (1H, d, J=7Hz, CH arom.), 7.42 (4H, d, J=7Hz, 4CH arom.), 7.49 (1H, t, J=7Hz, CH arom.), 7.57 (1H, d, J=7Hz, CH arom.), 7.90 (2H, s, CH arom. and NH-)]. 25 Example 70 176 On carrying out the operation according to the procedure for Example 4 starting with 0.8 g of 1- [bis (4-chlorophenyl)methyl] -3- [ (methylsulfonyl) 5 (3-trifluoromethylsulfanylphenyl)methyl (RS) ]azetidin 3-ol, 0.24 g of methanesulfonyl chloride and 0.7 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 10 18 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 50 cm fractions. Fractions 12 to 17 are combined, concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is again purified by 15 chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 20 cm), at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 30 cm 3 fractions. Fractions 15 to 28 are combined, concentrated to dryness under reduced 20 pressure (2.7 kPa). 0.25 g of 1-[bis(4-chlorophenyl) methyl] -3- [ (methylsulfonyl) (3-trifluoromethylsulfanyl phenyl)methylene]azetidine is obtained melting at 70'C [NMR spectrum in DMSO-d6 + CDCO 2 D, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH), 3.80 (2H, s, NCH 2 ), 4.20 25 (2H, s, NCH 2 ), 4.80 (lH, s, NCH), 7.35 (4H, d, J=7Hz, 4CH arom.), 7.45 (4H, d, J=7Hz, 4 CH arom.), 7.60 (2H, m, 2CH arom), 7.75 (2H, m, 2CH arom.)].

177 1-[Bis(4-chlorophenyl)methyl]-3-[(methyl sulfonyl)(3-trifluoromethylsulfanylphenyl)methyl-(RS)] azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the 5 procedure of Example 1 starting with 2 g of methyl (3-trifluoromethylsulfanylbenzyl)sulfone, 2.3 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 5.5 cm 3 of a 1.6 M solution of n-butyllithium in hexane, 0.9 g of 1-benzhydryl-3-[(methylsulfonyl) (3-trifluoromethyl 10 sulfanylphenyl)methyl-(RS)]azetidin-3-ol is obtained in the form of a white solid. Methyl(3-trifluoromethylsulfanylbenzyl) sulfone may be prepared in the following manner: on carrying out the operation according to the procedure 15 of Example 10 starting with 5 g of 3-trifluoromethyl sulfanylbenzyl chloride and 3.2 g of sodium methane sulfinate, 5.2 g of methyl(3-trifluoromethylsulfanyl benzyl)sulfone are obtained in the form of a white solid melting at 125'C. 20 Example 71 On carrying out the operation as in Example 38 (Method 1), starting with 0.72 g of 1-[bis(4-fluoro 25 phenyl)methyll-3-[(3,5-difluorophenyl) (methylsulfonyl) methyl-(RS)]azetidin-3-ol, 0.18 cm 3 of methanesulfonyl chloride and 0.66 g of 4-dimethylaminopyridine, 0.42 g 178 of 1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluoro phenyl) (methylsulfonyl)methylene]azetidine is obtained, after chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2.5 cm, height 15 cm), at 5 an argon pressure of 1 bar with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting 25 cm 3 fractions, in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 3.05 (3H, s, SCH,), 3.90 (2H, s, NCH 2 ), 4.20 (2H, s, 10 NCH 2 ), 4.80 (1H, s, NCH), 7.15 (6H, m, 6CH arom.), 7.35 (1H, t, J=8Hz, CH arom.), 7.50 (4H, dd, J=6 and 8Hz, 4CH arom.)]. 1-[Bis(4-fluorophenyl)methyll-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl-(RS)Iazetidin 15 3-ol may be obtained in the following manner: the operation is carried out as in Example 39 starting with 2.25 g of bis(4-fluorophenyl)bromomethane, 1.1 g of potassium carbonate and 2.5 g of 3-[(3,5-difluoro phenyl) (methylsulfonyl)methyl-(RS)Iazetidin-3-ol 20 hydrochloride. After chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4.4 cm, height 25 cm), at an argon pressure of 0.9 bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 60 cm 3 fractions, 25 fractions 23 to 39 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.72 g of 1-[bis(4-fluorophenyl)methyl)-3-[(3,5-difluorophenyl)- 179 (methylsulfonyl)methyl- (RS) ]azetidin-3-ol is obtained in the form of a white solid. Bis(4-fluorophenyl)bromomethane may be prepared according to the procedure described by 5 BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933) starting with 4 g of 4,4'-difluorobenzydrol, 2.70 cm 3 of acetal bromide and 14 cm of a 33% hydrobromic acid solution in acetic acid. 10 Example 72 On carrying out the operation as in Example 38 (Method 1), starting with 1.22 g of 1-[bis(2-fluoro phenyl)methyl] -3- [(3, 5-difluorophenyl) (methylsulfonyl) 15 methyl-(RS)]azetidin-3-ol, 0.29 cm 3 of methanesulfonyl chloride and 1.1 g of 4-dimethylaminopyridine, 0.177 g of 1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluoro phenyl) (methylsulfonyl)methylenelazetidine is obtained, after chromatography on a silica gel column (particle 20 size 0.04-0.06 mm, diameter 3 cm, height 23 cm), at an argon pressure of 1 bar with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting 60 cm 3 fractions, in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 25 3.05 (3H, s, SCH 3 ), 3.95 (2H, s, NCH 2 ), 4.25 (2H, s,

NCH

2 ), 5.35 (1H, s, NCH), 7.20 (6H, m, 6CH arom.), 7.35 (3H, m, 3CH arom.), 7.55 (2H, m, 2CH arom.)].

180 1-[Bis(2-fluorophenyl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin 3-ol may be obtained in the following manner: the operation is carried out as in Example 39 starting with 5 2 g of bis(2-fluorophenyl)bromomethane, 1.0 g of potassium carbonate and 2.22 g of 3-[(3,5-difluoro phenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol hydrochloride. After chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, 10 height 17 cm), at an argon pressure of 1 bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 60 cm fractions, fractions 6 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.22 g of 15 1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a whitish solid. Bis(2-fluorophenyl)bromomethane may be prepared according to the procedure described by 20 BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933), starting with 1.80 g of 2,2'-difluorobenzydrol, 1.22 cm 3 of acetyl bromide and 6.5 cm 3 of a 33% solution of hydrobromic acid in acetic acid. 2,2'-difluorobenzydrol may be prepared 25 according to the following method: 32 cm 3 of a 1.6 M solution of n-butyllithium in hexane are poured dropwise into a solution, cooled to -70'C under argon, 181 of 8.8 g of 2-bromofluorobenzene in 100 cm of tetrahydrofuran. After stirring for 10 minutes at -70 0 C, 2.1 cm' of ethyl formate are added slowly and then the mixture is stirred at -70'C for 30 minutes. 5 The reaction medium is then brought to 0*C and then supplemented with 50 cm' of ethyl acetate and 100 cm 3 of saturated ammonium chloride solution. After stirring, the organic phase is separated, dried over magnesium sulfate, concentrated to dryness at 55'C, under reduced 10 pressure (2.7 Kpa). 3.63 g of 2,2'-difluorobenzydrol are obtained in the form of a yellow oil. Example 73 15 On carrying out the operation as in Example 38 (Method 1), starting with 1.15 g of 1-[bis (3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methyl sulfonyl)methyl-(RS)]azetidin-3-ol, 0.264 cm' of methanesulfonyl chloride, and 0.98 g of 20 4-dimethylaminopyridine, 0.55 g of 1-[bis(3-fluoro phenyl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl) methylene]azetidine is obtained, after chromatography on a silica gel column (particle size 0.06-0.200 mm, diameter 2.8 cm, height 25 cm), at an argon pressure of 25 1 bar with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting 60 cm fractions, in the form of a white solid melting at 182 1780C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 3.05 (3H, s, SCH,), 3.95 (2H, s, NCH 2 ), 4.25 (2H, s, NCH 2 ), 4.80 (1H, s, NCH), 7.10 (2H, m, 2CH arom.), 7.20 (2H, m, 2CH arom.), between 7.30 and 7.50 (7H, m, 5 7CH arom.)]. 1-[Bis(3-fluorophenyl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin 3-ol may be prepared in the following manner: on carrying out the operation according to Example 1 10 starting with 1.2 g of (3,5-difluorobenzyl)methyl sulfone and 1.5 g of 1-[bis(3-fluorophenyl)methyl] azetidin-3-one, 1.95 g of 1-[bis(3-fluorophenyl) methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl (RS)]azetidin-3-ol are obtained, after purification on 15 a silica gel column (particle size 0.06-0.200 mm, diameter 3.2 cm, height 30 cm), at an argon pressure of 1 bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent and collecting 60 cm fractions, in the form of a white solid melting at 20 170'C (decomposition). 1-[Bis(3-fluorophenyl)methyl]azetidin-3-one may be prepared by carrying out the operation in a manner identical to the procedure described by KATRITZKY A.R. et al., J. Heterocycl. Chem., 271 25 (1994), starting with 4.9 g of [bis(3-fluorophenyl) methyl]amine and 1.78 cm of epichlorohydrin. [Bis(3-fluorophenyl)methyl]amine may be 183 prepared in the following manner: a solution of 5.17 g of 3,3'-difluorobenzophenone oxime in 30 cm 3 of tetrahydrofuran is poured, under an argon atmosphere over 30 minutes, into a suspension of 1.27 g of lithium 5 aluminum hydride in 80 cm 3 of tetrahydrofuran. After stirring for 5 hours under reflux, 1.3 cm 3 of water, 1.3 cm 3 of 4 N sodium hydroxide, 2.6 cm of water and then 50 cm 3 of ethyl acetate are added successively. After drying over magnesium sulfate and concentrating 10 to dryness under reduced pressure (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 may be prepared according to the following procedure: a 15 solution of 1.6 g of hydroxylamine hydrochloride in 8 cm 3 of water is poured dropwise into a solution of 5.0 g of 3,3'-difluorobenzophenone in 10 cm 3 of ethanol, and then 1.2 g of sodium hydroxide pellets are added in small fractions. The reaction mixture, heated under 20 reflux for 10 minutes, is cooled to 20'C and then acidified with 7.5 cm of 4 N hydrochloric acid. Once triturated, the oily precipitate obtained becomes a white solid which is filtered, washed with water and then dried at 35'C under reduced pressure (2.7 kPa). 25 5.17g of 3,3'-difluorobenzophenone oxime are obtained in the form of a white solid.

184 Example 74 On carrying out the operation as in Example 1, starting with 1.30 g of a mixture of two 5 diastereoisomers 1-[(4-chlorophenyl) (thiazol-2-yl) methyl-(RS)1-3-[(methylsulfonyl) (phenyl)methyl (RS)]azetidin-3-ol, 0.35 cm 3 of methanesulfonyl chloride and 1.22 g of 4-dimethylaminopyridine, 0.7 g of (RS) 1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methyl 10 sulfonyl) (phenyl)methylenelazetidine is obtained, after chromatography on a silica gel column (particle size 0.06-0.200 mm, diameter 2.4 cm, height 25 cm), at an argon pressure of 1 bar with a mixture of ethyl acetate and cyclohexane (1/1 by volume) as eluent and 15 collecting 30 cm 3 fractions, in the form of a pinkish solid [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.95 (2H, m, NCH 2 ), 4.35 (2H, m, NCH 2 ), 5.25 (lH, s, NCH), 7.45 (9H, m, 9CH arom.), 7.65 (lH, d, J=2Hz, CH thiazole), 7.70 (lH, d, J=2Hz, 20 CH thiazole)]. The mixture of the two diastereoisomers 1-[(4-chlorophenyl) (thiazol-2-yl)methyl-(RS)] 3-[(methylsulfonyl) (phenyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying 25 out the operation as in Example 39 starting with 4.47 g of (RS)-bromo(4-chlorophenyl) (thiazol-2-yl)methane and 4.31 g of 3-[(methylsulfonyl) (phenyl)methyl- 185 (RS)]azetidin-3-ol hydrochloride and after chromatography on a silica gel column (particle size 0.06-0.200 mm, diameter 5.6 cm, height 40 cm), at an argon pressure of 0.5 bar with a mixture of ethyl 5 acetate and cyclohexane (25/75 by volume) up to fraction 35 and then with pure ethyl acetate as eluent and collecting 60 cm 3 fractions, fractions 38 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.3 g of the mixture of the two 10 diastereoisomers 1-[(4-chlorophenyl)(thiazol-2-yl) methyl-(RS)]-3-[(methylsulfonyl) (phenyl)methyl (RS)]azetidin-3-ol are obtained in the form of a whitish solid. (RS)-bromo(4-chlorophenyl) (thiazol 15 2-yl)methane may be prepared according to the procedure described by BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933), starting with 3.5 g of (RS)-(4-chlorophenyl) (2-thiazolyl)methanol, 3.81 g of acetyl bromide and 12.0 cm 3 of a 33% solution of hydrobromic acid in acetic 20 acid. (RS)-(4-chlorophenyl) (thiazol-2-yl)methanol may be prepared according to the procedure described by G. EVAN BOSWELL et al., J. Heterocyclic Chem., 32, 1801 (1995), starting with 4.22 g of 4-chlorobenzaldehyde 25 and 4.92 g of 2-bromothiazole. Example 75 186 On carrying out the operation as in Example 1, starting with 0.52 g of a mixture of the two diastereoisomers 1-[(4-chlorophenyl) (thien-2-yl)methyl 5 (RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl (RS)]azetidin-3-ol, 0.14 cm 3 of methanesulfonyl chloride and 0.49 g of 4-dimethylaminopyridine, 0.32 g of (RS) 1-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene]azetidine is 10 obtained, after chromatography on a silica gel column (particle size 0.06-0.200 mm, diameter 2.4 cm, height 20 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent and collecting 30 cm 3 fractions, in the form of a 15 white solid melting at 176'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.98 (3H, s, SCH,), 3.90 (2H, m, NCH 2 ), 4.20 (2H, s, NCH 2 ), 5.03 (1H, s, NCH), 6.85 (1H, dd, J=3 and 5Hz, CH thiophene), 7.08 (3H, m, 2CH arom. and 1CH thiophene), 7.22 (1H, t, J=8Hz, CH 20 arom.),7.32 (3H, m, 2CH arom. and 1CH thiophene), 7.40 (2H, d, J=7Hz, 2CH arom.)]. The mixture of the two diastereoisomers 1-[(4-chlorophenyl) (thien-2-yl)methyl-(RS)]-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin 25 3-ol may be prepared in the following manner: on carrying out the operation as in Example 1 starting with 1.60 cm of 1.6 N n-butyllithium in solution in 187 hexane, 0.83 g of (3,5-difluorobenzyl)methylsulfone and 1.06 g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)] azetidin-3-one, 0.55 g of the mixture of diastereo isomers 1-[4-chlorophenyl)(thien-2-yl)methyl-(RS)] 5 3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)] azetidin-3-ol is obtained, after purification on a silica gel column (particle size 0.06-0.200 mm, diameter 2.8 cm, height 30 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane 10 (25/75 by volume) as eluent and collecting 40 cm 3 fractions, in the form of an off-white solid. 1-[(4-Chlorophenyl) (thien-2-yl)methyl-(RS)] azetidin-3-one may be prepared by carrying out the operation in the following manner: 3.04 cm 3 of dimethyl 15 sulfoxide are poured over 10 minutes into a solution, cooled to -70'C, of 1.83 cm 3 of oxalyl chloride in 20 cm 3 of dichloromethane under argon. After stirring for 30 minutes at -60'C, a solution of 5.2 g of 1-[(4-chlorophenyl) (thien-2-yl)methyl-(RS)]azetidin 20 3-ol in 80 cm 3 of dichloromethane is poured in over 20 minutes, the mixture is stirred for 3 hours at a temperature of between -60' and -70'C and then 9.12 cm 3 of triethylamine are added. The mixture is then allowed to return to room temperature and then diluted with 25 water. The organic phase is separated, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residue is chromatographed 188 on a silica gel column (particle size 0.06-0.200 mm, diameter 4 cm, height 36 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (1/9 by volume) as eluent and collecting 60 cm 3 5 fractions. 3.3 g of 1-[(4-chlorophenyl)(thien-2-yl) methyl-(RS)]zetidin-3-one are obtained in the form of a yellow oil which crystallizes at room temperature. 1-[(4-Chlorophenyl) (thien-2-yl)methyl-(RS)] azetidin-3-ol may be prepared in the following manner: 10 4.12 g of sodium bicarbonate are added to a solution of 11.0 g of [(4-chlorophenyl) (thien-2-yl)methyl-(RS)] amine in 80 cm 3 of ethanol. The mixture is heated at 65'C and supplemented with 4.03 cm 3 of epibromohydrin. After stirring for 20 hours at 65 0 C, the cooled mixture 15 is filtered and the filtrate concentrated to dryness under reduced pressure (2.7 Kpa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3.6 cm, height 32 cm), at an argon pressure of 0.5 bar with a mixture of ethyl 20 acetate and cyclohexane (25/75 by volume) as eluent and collecting 60 cm 3 fractions. 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)] 25 amine may be prepared in the following manner: a solution of 10.92 g of 2-thiophenecarbonitrile in 80 cm of ethyl ether is poured slowly into a suspension, 189 cooled to 10 0 C, of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of 4-bromochlorobenzene and 2.43 g of magnesium) in 120 cm of anhydrous ethyl ether. After refluxing for one hour, the mixture is cooled to 5 10 0 C, supplemented slowly with 40 cm of methanol and then filtered on supercel. 4.54 g of sodium borohydride are added under argon and in small fractions over 15 minutes and then the reaction medium is stirred for 20 hours at 20'C. The mixture obtained is diluted with 10 ethyl acetate and then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at 50 0 C under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 5 cm, height 42 15 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (4/6 by volume) as eluent and collecting 100 cm 3 fractions. Fractions 6 to 12, concentrated to dryness, correspond to 13 g of imine in the form of a yellow oil which is taken up in 100 cm 3 of 20 methanol. The solution obtained is supplemented with 2.4 g of sodium borohydride and stirred for one hour at 5 0 C. The mixture obtained is diluted with ethyl acetate and then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at 50 0 C 25 under reduced pressure (2.7 Kpa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3.2 cm, height 40 cm), at an 190 argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (4/6 by volume) as eluent and collecting 60 cm fractions. 11.0 g of [(4-chloro phenyl) (thien-2-yl)methyl-(RS)]amine are obtained in 5 the form of a yellow oil. Example 76 On carrying out the operation as described in 10 Example 75, starting with 1.66 g of the mixture of the two chiral diastereoisomers 1-[(4-chlorophenyl) (thien 2-yl)methyl-(R*)1-3-[(3,5-difluorophenyl) (methyl sulfonyl)methyl-(R*)]azetidin-3-ol and 1-[(4-chloro phenyl) (thien-2-yl)methyl-(R*)-3-[(3,5-difluoro 15 phenyl)(methylsulfonyl)methyl-(S*)]azetidin-3-ol, 50 cm' of dichloromethane, 0.45 cm of methanesulfonyl chloride, and 1.64 g of 4-dimethylaminopyridine, 0.6 g of (+)-l-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methylenelazetidine is 20 obtained in the form of white crystals melting at 136"C, [a] 20" = +3.20 (c = 0.5% in dichloromethane). The mixture of the two chiral diastereo isomers 1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)] 3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(R*)] 25 azetidin-3-ol and 1-[(4-chlorophenyl) (thien-2-yl) methyl-(R*)1-3-[(3,5-difluorophenyl) (methylsulfonyl) methyl-(S*)]azetidin-3-ol may be prepared as described 191 in Example 75, starting with 1.06 g of (+)-l [(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-one, 0.82 g of (3,5-difluorobenzyl)methylsulfone, 2.5 cm of 1.6 N solution of n-butyllithium in hexane, and 25 cm 3 5 of tetrahydrofuran. 1.7 g of the mixture of the two chiral diastereoisomers 1-[(4-chlorophenyl) (thien 2-yl)methyl-(R*)-3-[(3,5-difluorophenyl) (methyl sulfonyl)methyl-(R*)]azetidin-3-ol and 1-[(4-chloro phenyl) (thien-2-yl)methyl-(R*)]-3-[(3,5-difluoro 10 phenyl) (methylsulfonyl)methyl-(S*)]azetidin-3-ol are obtained, after purification by chromatography, in the form of a white solid. (+)-l-[(4-Chlorophenyl) (thien-2-yl) methyl]azetidin-3-one may be prepared as described in 15 Example 75, starting with 12.4 g of (+)-l-[(4-chloro phenyl) (thien-2-yl)methyl]azetidin-3-ol, 220 cm 3 of dichloromethane, 7.1 cm 3 of dimethyl sulfoxide, 4.4 cm of oxalyl chloride and 21.5 cm 3 of triethylamine. 9.2 g of (+)-l-[(4-chlorophenyl) (thien-2-yl)methyl]azetidin 20 3-one are obtained in the form of a pale yellow oil crystallizing at 20'C. (+)-l-[(4-Chlorophenyl) (thien-2-yl)methyll azetidin-3-ol may be prepared as described in Example 75, starting with 16.1 g of (+)-[(4-chloro 25 phenyl) (thien-2-yl)methyl]amine, 130 cm' of ethanol, 5.9 cm 3 of epibromohydrin and 6.05 g of sodium bicarbonate. 11.5 g of (+)-l-[(4-chlorophenyl) (thien- 192 2-yl)methyl]azetidin-3-ol are obtained, after purification by chromatography, in the form of a cream colored oil. (+)-4-[(Chlorophenyl) (thien-2-yl)methyl]amine 5 may be prepared in the following manner: 73 g of D-(-) tartaric acid are added to a solution of 109 cr of [(4-chlorophenyl) (thien-2-yl)methyl-(RS)]aminE in 500 cm 3 of methanol. The mixture is concentrated to dryness under reduced pressure (2.7 kPa). The foam 10 obtained is taken up in 2.05 liters of an ethanol-water 90/10 by volume mixture. After stirring slowly for 20 hours at 20'C, the crystalline suspension obtained is filtered, the crystals washed with a minimum amount of the same mixture of solvents, and then dried. Another 15 recrystallization is carried out under the sane conditions with 1.5 liters of the same mixturE of solvents. 44.9 g of crystals of the acid tartrate of the amine are obtained. [a]" = +10.30 (c = 0.5% in dimethylformamide). This compound is recrysta:lized 20 from 600 cm 3 of an ethanol-water 80/20 by volume mixture (the crystals are filtered and washed with tw:ce 30 cm 3 of the same mixture of solvents and then drained) and then recrystallized under the same conditions with 400 cm 3 of an ethanol-water 78/22 mixture. 28.2 g of 25 acid D-(-)-tartrate of (+)-[(4-chlorophenyl)thien 2-yl)methyl]amine are obtained in the form of white crystals [a] 20 = +10.80 (c = 0.5% in dimethylf rmamide).

193 This salt is taken up in 400 cm of a 1 N aqueous solution of sodium hydroxide and with 100 cm 3 of ethyl acetate. The organic phase is separated, washed with 100 cm of water, dried over magnesium sulfate and 5 then concentrated to dryness under reduced pressure (2.7 kPa). 16.1 g of (+)-[(4-chlorophenyl)-(thien 2-yl)methyllamine are obtained in the form of an oil which crystallizes at 20 0 C. [a] 200 = +32.70 (c = 0.5% in dichloromethane). 10 Example 77 On carrying out the operation as described in Example 75, starting with 1.30 g of the mixture of the 15 two chiral diastereoisomers 1-[(4-chlorophenyl)(thien 2-yl)methyl-(S*)-3-[(3,5-difluorophenyl) (methyl sulfonyl)methyl-(R*)]azetidin-3-ol and 1-[(4-chloro phenyl) (thien-2-yl)methyl-(S*)-3-[(3,5-difluoro phenyl) (methylsulfonyl)methyl-(S*)]azetidin-3-ol, 40 cm 3 20 of dichloromethane, 0.35 cm 3 of methanesulfonyl chloride and 1.28 g of 4-dimethylaminopyridine, 0.97 g of (-)-l [(4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5-difluoro phenyl) (methylsulfonyl)methylene]zetidine is obtained in the form of white crystals melting at 135 0 C, [a] 20 t 25 -3.40 (c = 0.5% in dichloromethane). The mixture of the two chiral diastereo isomers 1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]- 194 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)] azetidin-3-ol and 1-[(4-chlorophenyl) (thien-2-yl) methyl-(S*)]-3-[(3,5-difluorophenyl) (methylsulfonyl) methyl-(S*)]azetidin-3-ol may be prepared as described 5 in Example 75, starting with 1.06 g of (-)-1 [(4-chlorophenyl) (thien-2-yl)methyllazetidin-3-one, 0.82 g of (3,5-difluorobenzyl)methylsulfone, 2.5 cm 3 of 1.6 N solution of n-butyllithium in hexane, and 25 cm 3 of tetrahydrofuran. 1.3 g of the mixture of the two 10 chiral diastereoisomers 1-[(4-chlorophenyl) (thien 2-yl)methyl-(S*)-3-[(3,5-difluorophenyl) (methyl sulfonyl)methyl-(R*)]azetidin-3-ol and 1-[(4-chloro phenyl) (thien-2-yl)methyl-(S*)-3-[(3,5-difluoro phenyl) (methylsulfonyl)methyl-(S*)]azetidin-3-ol are 15 obtained after purification by chromatography in the form of a white solid. (-)-l-[(4-Chlorophenyl) (thien-2-yl) methyl]azetidin-3-one may be prepared as described in Example 75, starting with 11.4 g of (-)-l-[(4-chloro 20 phenyl) (thien-2-yl)methyl]azetidin-3-ol, 200 cm 3 of dichloromethane, 4.0 cm 3 of dimethyl sulfoxide, 4.0 cm 3 of oxalyl chloride and 19.5 cm 3 of triethylamine. 8.3 g of (-)-l-[(4-chlorophenyl) (thien-2-yl)methyl]azetidin 3-one are obtained in the form of a pale yellow oil 25 crystallizing at 20'C. (-)-1-[(4-Chlorophenyl) (thien-2-yl) methyl]azetidin-3-ol may be prepared as described in 195 Example 75, starting with 15.4 g of (-)-[(4-chloro phenyl) (thien-2-yl)methyl]amine, 120 cm 3 of ethanol, 5.8 cm 3 of epibromohydrin and 5.8 g of sodium bicarbonate. 10.7 g of (-)-l-[ (4-chlorophenyl) (thien 5 2-yl)methyl]azetidin-3-ol are obtained, after purification by chromatography, in the form of a cream colored oil. (-) - [ (4-Chlorophenyl) (thien-2-yl)methyl]amine may be prepared in the following manner: 29 g of L-(+) 10 tartaric acid are added to a solution of 43 g of [(4-chlorophenyl) (thien-2-yl)methyl-(RS)]amine in 200 cm 3 of methanol. The mixture obtained crystallizes in 2 hours at room temperature. The crystals are filtered, washed with twice 10 cm 3 of methanol. 15 Recrystallization is carried out with 500 cm 3 of an ethanol-water 80/20 by volume mixture, the crystals are filtered, washed with twice 30 cm 3 of the same mixture of solvents and then dried under vacuum at 45*C. A final recrystallization is carried out with 350 cm 3 of 20 an ethanol-water 78/22 by volume mixture, allowing the mixture to be stirred for 20 hours at 20'C. The crystals obtained are drained, dried under reduced pressure (2.7 kPa). 26 g of acid L-(+)-tartrate of (-)-[(4-chlorophenyl) (thien-2-yl)methyl]amine are 25 obtained. [a] 20 = -10.7' (c = 0.5% in dimethylformamide). This salt is taken up in 400 cm of a 1 N 196 aqueous sodium hydroxide solution and with 100 cm 3 of ethyl acetate. The organic phase is separated, washed with 100 cm 3 of water, dried over magnesium sulfate and then concentrated to dryness under reduced pressure 5 (2.7 kPa). 15.4 g of (-)-[(4-chlorophenyl)(thien-2-yl) methyl]amine are obtained in the form of an oil which crystallizes at 20 0 C. [a] 20 = -31.7' (c = 0.5% in dichloromethane). 10 Example 78 On carrying out the operation according to the procedure of Example 1 starting with 3.4 g of 1-benzhydryl-3-[(ethylsulfonyl) (phenyl)methyl-(RS)] 15 azetidin-3-ol, 0.72 cm 3 of methanesulfonyl chloride and 3.8 g of 4-dimethylaminopyridine, 1.9 g of 1-benzhydryl-3- [ (ethylsulfonyl) (phenyl)methylene] azetidine are obtained, after recrystallization from 40 cm 3 of acetonitrile, in the form of crystals melting 20 at 210 0 C [[NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 1.15 (3H, t, J=6Hz, CH 3 ), 2.92 (2H, q, J=6Hz,

CH

2 ), 3.83 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.75 (1H, s, NCH), between 7.20 and 7.50 (15H, m, 3 phenyls)]. 1-Benzhydryl-3-[(ethylsulfonyl)(phenyl) 25 methyl-(RS)]azetidin-3-ol may be obtained by carrying out the operation according to the procedure described in Example 1 starting with 2.4 g of benzylethylsulfone, 197 2.2 cm 3 of diisopropylamine, 10 cm of 1.6 N n-butyllithium in solution in hexane, 65 cm 3 of tetrahydrofuran and 3.1 g of 1-benzhydrylazetidin 3-one. 3.6 g of 1-benzhydryl-3-[(ethylsulfonyl) 5 (phenyl)methyl-(RS)]azetidin-3-ol are obtained, after recrystallization from 30 cm 3 of acetonitrile, in the form of white crystals melting at 222'C. Benzylethylsulfone may be prepared by carrying out the operation according to the procedure 10 of Example 2 starting with 6.3 g of benzylethylsulfide, 50 cm 3 of acetic acid, 50 cm 3 of water, 25 cm 3 of 36 N sulfuric acid and 24.8 g of oxoneR. 3.2 g of benzylethylsulfone are obtained, by recrystallization from 20 cm 3 of ethyl ether, in the form of a solid 15 melting at 86'C. Benzylethylsulfide may be prepared in the following manner: 1.2 g of sodium hydride are added in small portions to a solution of 5 g of benzylmercaptan in 50 cm 3 of dimethylformamide under argon, and then 20 3.36 cm 3 of ethyl iodide are poured in, while the temperature is maintained below 45'C. The mixture is stirred for 2 hours and then taken up in 200 cm 3 of ethyl ether. The organic phase is washed with 200 cm 3 of water and then with 3 times 100 cm 3 of water, dried over 25 magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 6.3 g of benzylethylsulfide are obtained in the form of a pale yellow liquid.

198 Example 79 0.083 g of 1-amino-4-methylpiperazine is 5 added to a solution of 0.45 g of 1-[bis(4-chloro phenyl)methyl]- 3 -{(methylsulfonyl) [3-(pentafluoro phenoxycarbonyl)phenyl]methylene]azetidine in 5 cm 3 of dimethylformamide. The mixture is stirred for 20 hours at room temperature and then 40 cm' of ethyl acetate are 10 added. The organic phase is washed with 4 times 20 cm 3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated with 10 cm 3 of ethyl ether, filtered and then dried. 0.2 g of 1-[bis(4-chloro 15 phenyl)methyl]-3-{(methylsulfonyl)[(N-4 methylpiperazinylcarbamoyl)phenyl methylene}azetidine is obtained in the form of a yellow solid melting at 162'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.20 (3H, s, NCH), 2.40 (4H, m, 2 NCH 2 ), 20 2.90 (4H, m, 2 NCH 2 ), 2.95 (3H, s, SCH,), 3.80 (2H, s,

NCH

2 ), 4.20 (2H, s, NCH 2 ), 4.80 (lH, s, NCH), 7.40 (4H, d, J=7Hz, 4CH arom.), 7.50 (4H, d, J=7Hz, 4CH arom.), 7.55 (2H, m, 2CH arom.), 7.80 (2H, m, 2CH arom.), 9.50 (1H, s, CONH)]. 25 1-[Bis(4-chlorophenyl)methyll-3-{(methyl sulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl] methylene]azetidine may be prepared in the following 199 manner: 0.94 g of N-(3-dimethylaminopropyl) N'-ethylcarbodiimide hydrochloride and 0.89 g of pentafluorophenol are added to a solution of 2.9 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl) 5 (methylsulfonyl)methylene]azetidine in 25 cm' of dimethylformamide. The mixture is stirred for 20 hours at room temperature and then taken up in 50 cm 3 of ethyl acetate. The organic phase is washed with 100 cm 3 of water, 200 cm 3 of a saturated aqueous sodium bicarbonate 10 solution and then with twice 50 cm 3 of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kpa). The residue is chromatographed on a silica column (particle size 0.04-0.006 mm, diameter 2 cm), eluting with a mixture 15 of dichloromethane and ethanol (99/1 by volume). 0.92 g of 1-[bis(4-chlorophenyl)methyll-3-{(methylsulfonyl) [3-(pentafluorophenoxycarbonyl)phenyl]methylene] azetidine is obtained in the form of a white foam. 1-[Bis(4-chlorophenyl)methyl]-3-[(3-carboxy 20 phenyl)(methylsulfonyl)methylene]azetidine may be prepared in the following manner: a 36% solution of hydrochloric acid at a temperature of 50'C is added to a solution of 3.8 g of 1-[bis(4-chlorophenyl)methyl] 3-[(3-cyanophenyl) (methylsulfonyl)methylene]azetidine 25 in 5 cm 3 of acetic acid. The heating is continued for 48 hours and then the mixture is evaporated to dryness under reduced pressure (2.7 Kpa). The residue is taken 200 up in 30 cm 3 of ethanol and again evaporated to dryness. The residue is triturated in 35 cm 3 of ethyl ether. 3.8 g of 1-[bis (4-chlorophenyl)methyll 3-[ (3-carboxyphenyl) (methylsulfonyl)methylene) ] 5 azetidine are obtained in the form of a beige solid. 1- [Bis (4-chlorophenyl)methyl] -3-[(3 cyanophenyl) (methylsulfonyl)methylene]azetidine may be prepared according to the procedure of Example 4, starting with 11 g of l-[bis(4-chlorophenyl)methyl] 10 3-[ (3-cyanophenyl) (methylsulfonyl)methyl- (RS) ]azetidin 3-ol, 150 cm 3 of dichloromethane, 2.54 cm of methanesulfonyl chloride and 10.7 g of 4-dimethylamino pyridine, at room temperature for 3 hours. The residue obtained is purified by chromatography on a silica gel 15 column (particle size 0.04-0.06 mm, diameter 4.5 cm) and eluted with dichloromethane and then with a mixture of dichloromethane and ethanol (99.6/0.4 by volume). The fractions are evaporated to dryness under reduced pressure (2.7 Kpa). 3.8 g of 1-[bis(4-chlorophenyl) 20 methyl] -3-[ (3-cyanophenyl) (methylsulfonyl)methylene] azetidine are obtained in the form of a white foam. 1- [Bis (4-chlorophenyl)methyl] -3- [(3 cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol may be prepared in the following manner: a solution of 25 5 g of 3-cyanobenzyl methyl sulfone in 500 cm 3 of tetrahydrofuran is added over 15 minutes to a solution of 17.6 cm 3 of 1.6 M n-butyllithium in hexane, in 30 cm' 201 of tetrahydrofuran under argon, and cooled to -70*C. The mixture is stirred for 1 hour 30 minutes. Next, a solution of 7.8 g of 1-[bis(4-chlorophenyl)methyl] azetidin-3-one in 80 cm 3 of tetrahydrofuran is poured in 5 over 10 minutes. After stirring for 1 hour 30 minutes, 60 cm 3 of a saturated aqueous ammonium chloride solution are poured in and then the mixture is allowed to return to room temperature. The mixture is taken up in 300 cm 3 of ethyl acetate, the organic phase washed with 200 cm 3 10 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure (2.7 Kpa). 11 g of 1-[bis(4-chlorophenyl) methyl]-3-[(3-cyanophenyl) (methylsulfonyl)methyl-(RS)] azetidin-3-ol are obtained in the form of a foam. 15 (3-Cyanobenzyl)methylsulfone may be prepared in the following manner: starting with a solution of 20.2 g of 3-chloromethylbenzonitrile in 200 cm 3 of ethanol, 17.4 g of 85% sodium methanesulfinate are added. The mixture is stirred for 20 hours under reflux 20 and then taken up in 500 cm 3 of ethyl acetate and 500 cm 3 of water. The insoluble matter is filtered off, the organic phase in the filtrate is dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 Kpa). The solid obtained is 25 triturated with 100 cm 3 of ethyl ether. After filtration and drying of the solid, 21 g of (3-cyanobenzyl) methylsulfone are obtained in the form of white 202 crystals melting at 165 0 C. 3-Chloromethylbenzonitrile may be prepared in the following manner: 32 g of 3-chloromethylbenzoamide in 200 cm 3 of phosphorus oxychloride are heated at 95 0 C 5 for 3 hours, and then 1 liter of ice is loaded, the mixture stirred for 1 hour and extracted with 500 cm 3 of dichloromethane. The organic phase is washed with 200 cm 3 of water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.7 Kpa). 10 20.2 g of 3-chloromethylbenzonitrile are obtained in the form of a white solid. 3-Chloromethylbenzoamide may be prepared in the following manner: 150 cm 3 of a solution of ammonium hydroxide (d=0.90) are poured into a solution of 50 g 15 of 3-chloromethylbenzoyl chloride -in 150 cm 3 of ethyl ether, the mixture is cooled, stirred for 1 hour, filtered and washed with twice 200 cm 3 of ethyl ether. 32 g of 3-chloromethylbenzoamide are obtained in the form of white crystals. 20 Example 80 On carrying out the operation according to the procedure of Example 79 starting with 0.5 g of 25 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl) [3-(pentafluorophenoxycarbonyl)phenyl]methylene} azetidine, 0.06 cm 3 , 1,1-dimethylhydrazine and 5 cm 3 of 203 dimethylformamide, 0.125 g of 1-[bis(4-chlorophenyl) methyll-3-{(3-(2,2-dimethylcarbohydrazido)phenyl] (methylsulfonyl)methylene}azetidine is obtained in the form of a white solid melting at 134'C [NMR spectrum in 5 DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.60 (6H, s,

N(CH

3

)

2 ), 2.95 (3H, s, SCH 3 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.80 (1H, s, NCH), 7.35 (4H, d, J=7Hz, 4CH arom.), 7.45 (4H, d, J=7Hz, 4CH arom.), 7.50 (2H, m, 2CH arom.), 7.80 (2H, m, 2CH arom.), 9.50 (1H, s, 10 CONH)]. Example 81 On carrying out the operation according to 15 the procedure described in Example 1 starting with 2.2 g of 1-[bis(thien-2-yl)methyl]-3-[(3,5-difluoro phenyl) (methylsulfonyl)methyl- (RS) Jazetidin-3-ol, 0.64 cm 3 of methanesulfonyl chloride, 2.3 g of 4-dimethylaminopyridine and 75 cm 3 of dichloromethane, 20 1.3 g of 1-[bis(thien-2-yl)methyl]-3-[(3,5-difluoro phenyl) (methylsulfonyl)methylene] azetidine are obtained, after purification by chromatography and crystallization from diisopropyl ether, in the form of white crystals melting at 165'C [NMR spectrum in DMSO 25 d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.92 (2H, s, NCH 2 ), 4.28 (2H, s, NCH 2 ), 5.40 (1H, s, NCH), 6.95 (2H, dd, J=5 and 2Hz, 2CH thio.), 7.15 (2H, d, 204 J=2Hz, 2CH thio.), 7.20 (2H, m, 2CH arom.), 7.35 (1H, t, J=8Hz, CH arom.), 7.50 (2H, d, J=5Hz, 2CH thio.)]. 1-[Bis(thien-2-yl)methyl]-3-[(3,5-difluoro phenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be 5 obtained according to the procedure described in Example 1, starting with 1.5 g of 1-[bis(thien 2-yl)methyl]azetidin-3-one, 4 cm 3 of 1.6 N n-butyl lithium in hexane, 1.3 g of (3,5-dichlorobenzyl) methylsulfone and 40 cm 3 of tetrahydrofuran. 2.2 g of 10 1-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained, after purification by chromatography, in the form of white crystals melting at 145 0 C. 1-[Bis-thien-2-yl)methyl]azetidin-3-one may 15 be prepared by carrying out the operation as described in Example 73, starting with 4 g of 1-[bis(thien 2-yl)methyl]azetidin-3-ol, 2.6 cm 3 of dimethyl sulfoxide, 7.7 cm 3 of triethylamine, 7.7 cm 3 of oxalyl chloride, and 100 cm 3 of dichloromethane. The residue 20 obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) with, as eluent, a mixture of cyclohexane/ethyl acetate (1/1 by volume). The fractions obtained are evaporated to dryness under 25 reduced pressure (2.7 Kpa). 3.2 g of 1-[bis(thien 2-yl)methyllazetidin-3-one are obtained in the form of cream-colored crystals melting at 70*C.

205 1-[Bis(thien-2-yl)methyl]azetidin-3-ol may be prepared by carrying out the operation as described in Example 73, starting with 6 g of 1-[bis(thien 2-yl)methyl]amine, 2.5 cm of epibromohydrin, 2.6 g of 5 sodium bicarbonate and 50 cm 3 of ethanol. 4 g of 1-[bis(thien-2-yl)methyl]azetidin-3-ol are obtained in the form of beige crystals melting at 115*C. 1-[Bis(thien-2-yl)methyl]amine may be prepared in the following manner: a solution of 5 cm 3 of 10 thien-2-ylcarbonitrile in 50 cm of diethyl ether is poured dropwise into a suspension, cooled under argon to 10'C, of thien-2-ylmagnesium bromide (prepared from 1.29 g of magnesium and 3.22 cm 3 2-bromothiophene in 75 cm 3 of diethyl ether). After refluxing for 1 hour and 15 30 minutes, the reaction medium is cooled to 5oC and then 20 cm 3 of methanol are poured in dropwise, the suspension filtered and the solid washed with methanol. The filtrate obtained a brown solution. 2.45 g of sodium borohydride are added to this solution, under 20 argon, in several portions. The mixture is stirred at room temperature for 16 hours and then diluted with ethyl acetate and supplemented with water slowly. The organic phase is extracted, washed with water, dried over magnesium sulfate and evaporated to dryness under 25 reduced pressure (2.7 kpa) at 55 0 C. A brown oil is obtained which is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 8 cm, 206 height 25 cm) and eluted with a mixture of cyclohexane/ethyl acetate (90/10 and then 85/15 by volume) . Fractions 21 to 30 are combined and evaporated to dryness under reduced pressure (2.7 kpa) . 11 g of 5 1-[bis(thien-2-yl)methyl]amine are obtained in the form of a crystallized solid. Example 82 10 On carrying out the operation according to the procedure described in Example 1 starting with 0.47 g of 4-dimethylaminopyridine, 0.13 cm 3 of methane sulfonyl chloride, 25 cm 3 of dichloromethane and 0.48 g of 1-(bis-p-tolylmethyl)-3-[(methylsulfonyl) (phenyl) 15 methyl-(RS)]azetidin-3-ol, 0.25 g of 1-(bis-p-tolyl methyl) -3- [ (methylsulfonyl) (phenyl)methylene]azetidine is obtained, after purification by chromatography and crystallization from diisopropyl ether, in the form of a white solid [NMR spectrum in DMSO-d6, T=300K, 6 in 20 ppm (250 MHz): 2.23 (6H, s, 2 PhCH,), 2.98 (3H, s, SCH,), 3.76 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 5.55 (1H, s, NCH), 7.10 (4H, d, J=7Hz, 4 CH arom.), 7.32 (4H, d, J=7Hz, 4 CH arom.), 7.43 (5H, s, phenyl)]. 1-(Bis-p-tolylmethyl)-3-[(methylsulfonyl) 25 (phenyl)methyl-(RS)]azetidin-3-ol may be prepared according to the procedure described in Example 39, starting with 0.59 g of bromo(bis-p-tolyl)methane, 207 20 cm 3 of acetonitrile, 0.3 g of potassium carbonate and 0.6 g of 3-[(methylsulfonyl)(phenyl)methyl (RS)]azetidin-3-ol hydrochloride. The residue obtained is chromatographed on a silica gel column (particle 5 size 0.04-0.06 mm, diameter 4 cm, height 16 cm) with, as eluent, a cyclohexane/ethyl acetate (7/3 by volume) mixture. The fractions are concentrated to dryness under reduced pressure (2.7 Kpa). 0.48 g of l-(bis p-tolylmethyl)-3-[(methylsulfonyl) (phenyl)methyl 10 (RS)]azetidin-3-ol is obtained in the form of a white solid. Bromo(di-p-tolyl)methane may be prepared according to the procedure described by BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933). 15 3-[(Methylsulfonyl) (phenyl)methyl (RS)]azetidin-3-ol hydrochloride may be prepared according to the procedure described in Example 39 starting with 7 g of 3-[(methylsulfonyl)(phenyl)methyl (RS)]-1-(vinyloxycarbonyl)azetidin-3-ol, 35 cm 3 of 20 dioxane, 35 cm 3 of a 6.2 N solution of hydrochloric acid in dioxane. 5 g of 3-[(methylsulfonyl) (phenyl)methyl (RS)]azetidin-3-ol hydrochloride are obtained in the form of a white solid. 3-[(Methylsulfonyl) (phenyl)methyl-(RS)] 25 l-(vinyloxycarbonyl)azetidin-3-ol may be prepared according to the procedure described in Example 38 (Method 1), starting with 10 g of 1-benzhydryl- 208 3-[(methylsulfonyl) (phenyl)methyl-(RS)]azetidin-3-ol, 600 cm 3 of dichloromethane and 2.52 cm 3 of vinyl chloroformate. The residue is chromatographed on a silica gel column (particle size 0.06-0.2 mm, diameter 5 5.2 cm, height 36 cm with, as eluent, a cyclohexane/ ethyl acetate (7/3 by volume) mixture. The fractions are evaporated to dryness under reduced pressure (2.7 Kpa). 7 g of 3-[(methylsulfonyl)(phenyl)methyl (RS)]-1-(vinyloxycarbonyl)azetidin-3-ol are obtained in 10 the form of a white solid. Example 83 A solution of 30 mg of sodium borohydride in 2 cm 3 of methanol is poured into a solution of 0.77 g of 15 (-)-l-[(4-chlorophenyl) (4-formylphenyl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene]azetidine in 20 cm 3 of methanol at 0 0 C under argon. After stirring for 4 hours at 0 0 C, water is added and the mixture is then extracted with dichloromethane. The organic phase 20 is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness under reduced pressure (2.7 kpa). The white foam obtained is purified on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, 25 height 17 cm) with, as eluent, a cyclohexane/ethyl acetate (60/40 by volume) mixture. 0.1 g of (+)-l-[(4 chlorophenyl) (4-hydroxymethylphenyl)methyl]-3-[(3,5- 209 difluorophenyl) (methylsulfonyl)methylene]azetidine is obtained, after crystallization from 1.5 cm' of absolute ethanol, in the form of white crystals melting at 190 0 C, [a]2% = +4.20 (c = 0.5% in methanol) [NMR 5 spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.05 (3H, s, SCH 3 ), 3.95 (2H, s, NCH 2 ), 4.22 (2H, s, NCH 2 ), 4.48 (2H, d, J=6Hz, CH 2 0), 4.75 (1H, s, NCH), 5.15 (1H, t, J=6Hz, OH), 7.20 (2H, m, 2CH arom.), 7.28 (2H, d, J=7Hz, 2CH arom.), 7.40(5H, m, 5 CH arom.), 7.50 (2H, 10 d, J=7Hz, 2CH arom.)]. (-)-l-[(4-Chlorophenyl) (4-formylphenyl) methyl]-3-[(3,5-difluorophenyl)methylsulfonyl methylene]azetidine may be prepared in the following manner: 3.32 cm of a 5 N solution of hydrochloric acid 15 are poured into a solution of 0.83 g of (+)-l-{(4 chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl} 3-[(3,5-difluorophenyl) (methylsulfonyl)methylenel azetidine in 5 cm 3 of tetrahydrofuran and then the mixture is kept stirring for 20 hours. Dichloromethane 20 and water are added to the reaction medium followed by a 30% aqueous solution of sodium hydroxide until a pH = 14 is obtained. The aqueous phase is extracted with dichloromethane, the organic phase is washed successively with-water, with a saturated aqueous 25 solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kpa). 0.8 g of (-)-l-[(4-chloro- Ir 210 phenyl) (4-formylphenyl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]azetidine is obtained in the form of a white foam. (+)-l-{(4-Chlorophenyl)[4-(1,3-dioxolan 5 2-yl)phenyl]methyl}- 3 -[(3,5-difluorophenyl) (methyl sulfonyl)methylenelazetidine may be obtained in the following manner: 0.93 g of 1,8-Diazabicyclo[5-4-0] undec-7-ene is poured dropwise into a solution of 2.42 g of the mixture of the two diastereoisomers 10 3-acetoxy-l-{(4-chlorophenyl) [4-(1,3-dioxolan 2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluoro phenyl) (methylsulfonyl)methyl-(R*)]azetidine and 3-acetoxy-l-{(4-chlorophenyl) [4-(1,3-dioxolan 2-yl)phenyl]methyl-(R*)}-3-[(3,5 15 difluorophenyl) (methylsulfonyl)methyl-(S*)]azetidine in 25 cm 3 of tetrahydrofuran under argon at 0 0 C. After stirring for 1 hour and 30 minutes at 0*C, the reaction medium is diluted with ethyl acetate, washed with water and with a saturated aqueous sodium chloride solution. 20 The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The crude product is purified on a silica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height 17.5 cm) with, as eluent, a cyclohexane/ethyl 25 acetate (80/20 by volume) mixture. 1.21 g of (+)-1-{(4 chlorophenyl) [4-(1,3-dioxolan-2-yl)phenyl]methyl} 3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]- 211 azetidine are obtained in the form of a yellow foam. The mixture of the two diastereoisomers 3-acetoxy-1-{(4-chlorophenyl) [4-(1,3-dioxolan 2-yl)phenyl]methyl-(R*)1-3-[(3,5-difluorophenyl) 5 (methylsulfonyl)methyl-(R*)]azetidine and 3-acetoxy 1-{(4-chlorophenyl) [4-(1,3-dioxolan-2-yl)phenyllmethyl (R*)}-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl (S*)]azetidine may be prepared in the following manner: 3.27 cm 3 of n-butyllithium are poured dropwise into a 10 solution of 1.08 g of 3-5-difluorobenzyl methyl sulfone under argon, cooled to -70*C, and then the mixture is kept stirring for 1 hour at -70'C and then a solution of 1.80 g of (+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan 2-yl)phenyllmethyl}azetidin-3-one in 10 cm 3 of 15 tetrahydrofuran is poured in dropwise. After stirring for 3 hours at -70'C and for 1 hour at -20 0 C, a solution of 0.74 cm 3 of acetyl chloride in 10 cm 3 of anhydrous diethyl ether at -20'C is poured in and the mixture is stirred for 2 hours at -20 0 C. The reaction medium is 20 thrown over water, the mixture is extracted with ethyl acetate, the organic phase washed with water and with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kpa). 2.42 g of the mixture of 25 the two diastereoisomers 3-acetoxy-l-{(4-chlorophenyl) [4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl-(R*)]azetidine 212 and 3-acetoxy-l-{(4-chlorophenyl) [4-(1,3-dioxolan 2-yl)phenyl]methyl-(R*)}-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl-(S*)]azetidine are obtained in the form of a yellow oil. 5 (+)-l-{(4-Chlorophenyl)[4-(1,3-dioxolan 2-yl)phenyllmethyl}azetidin-3-one may be prepared in the following manner: 2.24 cm 3 of triethylamine are poured into a solution of 1.38g of (+)-1-{(4-chloro phenyl)[4-(1,3-dioxolan-2-yl)phenyllmethyl~azetidin 10 3-ol in 20 cm 3 of anhydrous dimethyl sulfoxide under argon, followed dropwise by 1.65 g of a solution of sulfur trioxide pyridine complex in 20 cm 3 of anhydrous dimethyl sulfoxide. After stirring for 1 hour and 15 minutes at room temperature, the reaction medium is 15 thrown over ice, extracted with ethyl acetate, the organic phase washed with water, with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kpa). The oily residue obtained 20 (1.31 g), combined with another batch of the same crude compound (1.21 g), are purified together on a silica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height 18 cm), with, as eluent, a cyclohexane/ethyl acetate (80/20 by volume) mixture. 25 1.87 g of (+)-l-{(4-chlorophenyl)[4-(1,3-dioxolan 2-yl)phenyl]methyl}azetidin-3-one are obtained in the form of a yellow oil. [a]"365nm = +5.9 (c = 0.5; 213 methanol). (+)-l-{(4-Chlorophenyl)[4-(1,3-dioxolan 2-yl)phenyl]methyl}azetidin- 3 -ol may be described according to the procedure described in Example 73, 5 starting with 4.43 g of (+)-{(4-chlorophenyl)[4-(1,3 dioxolan-2-yl)phenyl]methyl}amine, 40 cm 3 of absolute ethanol, 1.25 cm 3 of epibromohydrin and 1.28 g of sodium bicarbonate. 1.66 g of (+)-1-{(4-chlorophenyl)[4-(1,3 dioxolan-2-yl)phenyl]methyl}azetidin-3-ol are obtained 10 in the form of a yellow oil. Chiral (+)-{(4-chlorophenyl)[4-(1,3-dioxolan 2-yl)phenyl]methyl}amine may be obtained in the following manner: 3.95 cm 3 of ethylene glycol are poured into a suspension of 18.16 g of chiral (R*)-[(4-chloro 15 phenyl) (4-formylphenyl)methyl]amine hydrochloride, in 1000 cm 3 of toluene, and 0.82 g of para-toluenesulfonic acid monohydrate is added. After stirring for 20 hours at the reflux temperature, the reaction medium is cooled, washed with a saturated aqueous sodium 20 bicarbonate solution, with water and with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue obtained is purified on a silica gel column (particle size 0.04 25 0.06 mm, diameter 8.4 cm, height 21.5 cm) with, as eluent, a cyclohexane/ethyl acetate (30/70 by volume) mixture, collecting 250 cm 3 fractions. Fractions 23 to 214 30 are concentrated to dryness under reduced pressure (2.7 kpa). 1.39 g of chiral (+)-{(4-chlorophenyl) [4-(1,3-dioxolan-2-yl)phenyllmethyl}amine are obtained in the form of a yellow oil. 5 Chiral (R*)-[(4-chlorophenyl) (4-formyl phenyl)methyl]amine hydrochloride may be prepared in the following manner: 330 cm 3 of methanol are poured into a solution of 51.4 g of the diastereoisomer N-{(4 chlorophenyl)[4-(diethoxymethyl)phenyl]methyl-(R*)} 10 (R)-2-phenylglycinol in 660 cm 3 of anhydrous dichloromethane, the mixture cooled with an ice bath, 60.96 g of lead tetraacetate added, the mixture stirred for 5 minutes and then 1 liter of a phosphate buffer solution pH 7 poured in. After stirring for 30 minutes 15 at room temperature, the mixture is filtered and the aqueous phase is extracted with dichloromethane. The organic phase is concentrated to dryness under reduced pressure (2.7 kpa). The residue is taken up in 1 liter of diethyl ether and supplemented with 1 liter of a 3 N 20 aqueous solution of hydrochloric acid, the mixture is stirred for 15 minutes at room temperature, the aqueous phase is separated, washed with ethyl acetate and then concentrated to dryness under reduced pressure (2.7 kpa). 18.16 g of chiral (R*)-[(4-chlorophenyl)(4 25 formylphenyl)methyl]amine hydrochloride are obtained in the form of a white solid. N-{(4-chlorophenyl) [4-(diethoxy- 215 methyl)phenyl]methyl- (R*) }- (R) -2-phenylglycinol may be prepared in the following manner: 286 cm of 1.6 M n-butyllithium in hexane are poured dropwise into a solution, cooled to -70'C, under argon, of 87.7 g of 5 4-bromochlorobenzene and the mixture is stirred for 15 minutes at -70'C. This solution obtained is then added dropwise to the following solution cooled to 0 0 C: 30 g of (R)-N-[4- (diethoxymethyl)benzylidene] 2-phenylglycinol in 300 cm of diethyl ether. The 10 mixture is stirred for 2 hours at 0 0 C and then thrown over water. The organic phase is washed with water and then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kpa). 71.5 g of 15 a reddish oil are obtained, which oil is purified on a silica gel column (particle size 0.04-0.06 mm, diameter 11 cm, height 45 cm), with, as eluent, a cyclohexane/ethyl acetate (85/15 by volume, then 80/20 and 75/25) mixture, collecting 1 liter fractions. 20 Fractions 11 to 17 are concentrated to dryness under reduced pressure (2.7 kpa). 39.85 g of the sole diastereoisomer N-{(4-chlorophenyl) [4- (diethoxymethyl) phenyl]methyl- (R*) } -(R) -2 phenylglycinol are- obtained in the form of an orange 25 red oil. (R) -N- [4- (diethoxymethyl)benzylidene] 2-phenylglycinol may be prepared in the following 216 manner: 35.9 cm of 4-(diethoxymethyl)benzaldehyde are poured into a white suspension of 24.7 g of (R)-(-) 2-phenylglycinol in 500 cm 3 of toluene. The cloudy yellow solution is heated under reflux for 6 hours 5 30 minutes, and is then stirred at room temperature for 20 hours. After concentrating the reaction medium to dryness under reduced pressure (2.7 kpa), 61.6 g of (R)-N-[4-(diethoxymethyl)benzylidenel-2-phenylglycinol are obtained in the form of a yellow oil. 10 Example 84 On carrying out the operation according to the procedure of Example 1, but starting with 5.6 g of 15 1-[bis(4-chlorophenyl)methyll-3-{[3-(N-tertbutyloxy carbonyl-N-methylamino)phenyl](methylsulfonyl)methyl (RS))azetidin-3-ol, 100 cm 3 of dichloromethane, 1.59 g of methanesulfonyl chloride and 4.5 g of 4-dimethyl aminopyridine. The mixture is kept stirring for 3 hours 20 at room temperature. The crude product obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm and weight of silica 250 g), eluting at a nitrogen pressure of 0.5 bar with an ethyl acetate/cyclohexane (30/70 by 25 volume) mixture and collecting 100 cm 3 fractions. Fractions 12 to 18 are combined, concentrated to dryness under reduced pressure (2.7 kpa). 3.2 g of 217 1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxy carbonyl-N-methylamino)phenyl](methylsulfonyl) methylene}azetidine are obtained in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 5 MHz): 1.30 (9H, s, OC(CH,) 3 ), 2.65 (3H, s, J=6Hz, NCH 3 ), 2.85 (3H, s, SCH,), 3.50 (2H, s, NCH 2 ), 3.90 (2H, s,

NCH

2 ), 4.45 (1H, s, NCH) between 6.85 and 7.05 (8H, m, 8 CH arom.), 7.10 (4H, d, J=7Hz, 4 CH arom.)]. 1-[Bis(4-chlorophenyl)methyl]-3-{[3-(N 10 tertbutyloxycarbonyl-N-methylamino)phenyl] (methylsulfonyl)methyl-(RS)}azetidin-3-ol may be prepared according to the procedure described in Example 1 starting with 3.8 g of [3-(N-tertbutyloxy carbonyl-N-methylamino)benzyl]methylsulfone, 50 cm 3 of 15 tetrahydrofuran, 9.5 cm 3 of a 1.6 N solution of n-butyllithium in hexane, 3.82 g of 1-[bis(4-chloro phenyl)methyl]azetidin-3-one. The crude product is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, weight of 20 silica 250 g), eluting at a nitrogen pressure of 0.5 bar with dichloromethane and then with a dichloro methane and ethanol mixture (99/1 by volume) and collecting 500 cm 3 fractions. Fractions 10 to 16 are combined, concentrated to dryness under reduced 25 pressure (2.7 kPa). 5.6 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(N tertbutyloxycarbonyl-N-methylamino)phenyll(methyl- 218 sulfonyl)methyl- (RS) }azetidin-3-ol, are obtained in the form of a foam. Example 85 5 2.7 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3 (N-tertbutyloxycarbonyl-N-methylamino)phenyl](methyl sulfonyl)methylene}azetidine in 30 cm of dioxane and 30 cm 3 of a 4.7 N solution of hydrochloric dioxane are 10 stirred for 20 hours. The reaction medium is evaporated to dryness under reduced pressure (2.7 kpa), taken up in 50 cm 3 of water and 50 cm 3 of ethyl acetate, stirred and neutralized carefully with a saturated aqueous sodium bicarbonate solution. The organic phase is 15 separated, dried over magnesium sulfate, treated with animal charcoal and then concentrated under reduced pressure (2.7 kpa) to a volume of about 25 cm, then filtered, concentrated to dryness under reduced pressure. 1.3 g of 1-[bis(4-chlorophenyl)methyll-3-[(3 20 methylaminophenyl) (methylsulfonyl)methylene]azetidine are obtained in the form of white crystals melting at 228'C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.65 (3H, s, J=6Hz, NCH 3 ), 2.95 (3H, s, SCH 3 ), 3.80 (2H, s, NCH 2 ), 4.20 (2H, s, NCH 2 ), 4.80 (1H, s, 25 NCH), 5.85 (1H, q, J=6Hz, NH), 6.55 (3H, m, 3 CH arom.), 7.15 (1H, t, J=7Hz, CH arom.), 7.40 (4H, d, J=7Hz, 4CH arom.), 7.50 (4H, m, 4CH arom.)].

219 Example 86 On carrying out the operation as in Example 5 1, starting with 0.40 g of a mixture of two diastereoisomers 1-[(4-chlorophenyl) (thiazol 2-yl)methyl-(RS) ]-3-[3,5-difluorophenyl) (methyl sulfonyl)methyl-(RS)]azetidin-3-ol, 0.10 cm' of methanesulfonyl chloride and 0.37 g of 4-dimethylamino 10 pyridine, 0.13 g of (RS)-1-[(4-chlorophenyl)(thiazol 2-yl)methyl]-3-[3, 5-difluorophenyl) (methylsulfonyl) methylene]azetidine is obtained, after chromatography on a silica gel column (particle size 0.06-0.200 mm, diameter 1.2 cm, height 20 cm), at an argon pressure of 15 1 bar with a mixture of ethyl acetate and cyclohexane (40/60 by volume) as eluent and collecting 20 cm 3 fractions, in the form of a pinkish solid [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.05 (3H, s, SCH,) , 4.05 (2H, s, NCH 2 ) , 4.35 (2H, m, NCH 2 ) , 5.25 (1H, 20 s, NCH), 7.20 (2H, d, J=8Hz, 2CH arom.), 7.35 (1H, t, J=8Hz, CH arom.), 7.45 (2H, d, J=7Hz, 2CH arom.), 7.50 (2H, d, J=7Hz, 2CH arom.), 7.70 (1H, d, J=2Hz, CH thiazole), 7.75 (1H, d, J=2Hz, CH thiazole)]. The mixture of the two diastereoisomers 25 1-[(4-chlorophenyl) (thiazol-2-yl)methyl-(RS)]-3-[3,5 difluorophenyl) (methylsulfonyl)methyl- (RS) ]azetidin 3-ol may be obtained in the following manner: on 220 carrying out the operation as in Example 72, starting with 1.01 g of (RS)-bromo(4-chlorophenyl)thiazol 2-ylmethane and 0.55 g of (RS)-3-[3,5-difluorophenyl) (methylsulfonyl)methyl]azetidin-3-ol hydrochloride and 5 after chromatography on a silica gel column (particle size 0.06-0.200 mm, diameter 4.4 cm, height 38 cm), at an argon pressure of 0.5 bar and eluting with a mixture of ethyl acetate and cyclohexane (30/70 by volume and then 40/60 from fraction 16) and collecting 60 cm 10 fractions, fractions 21 to 35 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.40 g of the mixture of the two diastereoisomers 1-[(4-chlorophenyl) (thiazol 2-yl)methyl-(RS)]-3-[3,5-difluorophenyl) (methyl 15 sulfonyl)methyl-(RS)]azetidin-3-ol- which is obtained in the form of a whitish solid.

221 Example 87 50 mm' of pyrrolidine are added to a solution of 0.32 g of 1-{(IR)-[4-(chloromethyl)phenyl] (4-chloro 5 phenyl)methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl) methylene]azetidine, form A isomer, and 5 mg of sodium iodide in 10 cm 3 of dichloromethane. After stirring for 20 hours at 20 0 C, 50 mm 3 of pyrrolidine are added to the mixture, stirred for 8 hours and then 50 mm 3 of 10 pyrrolidine are again added and the mixture is stirred for 20 hours at 20 0 C. The reaction mixture is washed with water and then the organic phase is dried over magnesium sulfate and concentrated to dryness under vacuum (2.7 kPa). The residue obtained is 15 chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), at an argon pressure of 0.1 bar, eluting with dichloromethane and then with a dichloromethane and methanol mixture (97.5/2.5 by volume) and collecting 3 cm 3 fractions. 20 Fractions 12 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of 1-{ (R')-(4-chlorophenyl) [4-pyrrolidinylmethyl)phenyl] methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl eneiazetidine, form A isomer, is obtained in the form 25 of a white foam aa] 20 365nm = -22.50 +/- 0.7 (c = 0.5%; dichloromethane) ['H NMR spectrum (300 MHz, CDCl 3 , 8 in ppm): 1.78 (mt, 4H), 2.51 (mt, 4H), 2.81 (s, 3H), 3.58 221 222 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5Hz, IH), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)]. 1-{ (R) - [(4-chloromethyl) phenyl] (4 5 chlorophenyl)methyl}-3-[(3,5-difluorophenyl) (methyl sulfonyl)methylene]azetidine, form A isomer, may be prepared by carrying out the operation in the following manner: 12.4 cm 3 of methanesulfonyl chloride are added to a solution of 28.0 g of the mixture of the 2 10 diastereoisomers (forms A) 1-{ (R*) - [(4-chloromethyl) phenyl] (4-chlorophenyl)methyl}-3-[(R)-(3,5-difluoro phenyl) (methylsulfonyl)methyl]azetidin-3-ol and 1-{ (R) [(4-chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(S) (3,5-difluorophenyl) (methylsulfonyl)methyl]azetidin-3 15 ol and 32 g of 4-dimethylaminopyridine, in 500 cm 3 of dichloromethane. After stirring for 1 hour at 10 0 C and then 1 hour at 20 0 C, the reaction mixture is washed with 500 cm 3 of water, the organic phase is dried over magnesium sulfate and concentrated to dryness under 20 reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 6 cm, height 30 cm), at an argon pressure of 0.2 bar, eluting with dichloromethane and collecting 250 cm 3 fractions. Fractions 9 to 25 are 25 combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 6.3 g of 1-{(R*)-[4-(chloromethyl) phenyl] (4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl) 222 223 (methylsulfonyl)methylenelazetidine, form A isomer, are obtained in the form of a white foam. The mixture of the 2 diastereoisomers (forms A) 1-{ (R*) -[4-(chloromethyl)phenyl] (4-chlorophenyl) 5 methyl}-3-[(R)-(3,5-difluorophenyl) (methyl sulfonyl)methyl)]azetidin-3-ol, and 1-{ (R) -[(4 chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(S) (3,5-difluorophenyl) (methylsulfonyl)methyl)]azetidin-3 ol, may be prepared by carrying out the operation in 10 the following manner: 60 mm' of thionyl chloride are added to a solution of 0.20 g of the mixture of the 2 diastereoisomers (forms A) 1-{ (R) - [4- (chlorophenyl) [4 (hydroxymethyl)phenyllmethyl}-3-[(R)-(3,5 difluorophenyl) (methylsulfonyl)methyl)]azetidin-3-ol, 15 and 1-((R*)-(4-chlorophenyl) [4 (hydroxymethyl)phenyl]methyl}-3-(S)-(3,5 difluorophenyl) (methylsulfonyl)methyllazetidin-3-ol, in 10 cm 3 of dichloromethane. After stirring for 20 hours at 20 0 C, 5 cm 3 of a saturated aqueous sodium hydrogen 20 carbonate solution are added to the reaction mixture and then the mixture is stirred for 15 minutes. The mixture is separated after settling out, the organic phase is washed with water, dried over magnesium sulfate and then concentrated to dryness under reduced 25 pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 1.0 cm, height 20 cm), at an argon pressure of 0.2 bar, 223 224 eluting with a cyclohexane and ethyl acetate mixture (75/25 by volume) and collecting 20 cm 3 fractions. Fractions 4 to 7 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.17 g of the 5 mixture of the 2 diastereoisomers (forms A) 1-{(R*)-[4 (chloromethyl)phenyll-[4-chlorophenyllmethyl}-3-[(R) (3,5-difluorophenyl) (methylsulfonyl)methyl)]azetidin-3 ol, and 1-{(R*)-[4-(chloromethyl)phenyll (4 chlorophenyl)methyl) -3-[(S) (3,5 10 difluorophenyl) (methylsulfonyl)methyl)]azetidin-3-ol is obtained in the form of a white foam. The mixture of the 2 diastereoisomers (forms A) 1-( (R*)-4- (chlorophenyl)phenyl] [4 (hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5 15 difluorophenyl) (methylsulfonyl)methyl)]azetidin-3-ol, and 1- (R*) - (4-chlorophenyl) [4- (hydroxymethyl)phenyl] methyl}-3-((S)-(3,5-difluorophenyl) (methyl sulfonyl)methyl]azetidin-3-ol, may be prepared by carrying out the operation in the following manner: 1.6 20 cm 3 of a 1.5 M solution of diisobutylaluminum hydride in toluene are added to a solution, maintained under argon and cooled to -30'C, of 0.58 g of the mixture of the 2 diastereoisomers (forms A) 3-acetoxy-1-((R')-(4 chlorophenyl) [4-(methoxycarbonyl)phenyl]methyl}-3-[(R) 25 (3,5-difluorophenyl) (methylsulfonyl)methyl)]azetidine and 3-acetoxy-1-{ (R*) - (4-chlorophenyl) [4- (methoxy carbonyl)phenyl]methyl}-3-[(S)-(3,5-difluoro 224 225 phenyl) (methylsulfonyl)methyllazetidine, in 10 cm 3 of anhydrous toluene. After stirring for 15 minutes at -300C, 1.0 cm 3 of this same hydride solution is again added and then the mixture is allowed to return to OC. 5 After stirring for 30 minutes, the stirred mixture is supplemented with 3 cm 3 of water and 6 cm 3 of 1 N sodium hydroxide and then extracted with 25 cm 3 of dichloromethane. The organic phase is washed with 5 cm of water, 5 cm 3 of brine, and then dried over magnesium 10 sulfate and concentrated to dryness under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm) , at an argon pressure of 0.1 bar, eluting with a cyclohexane and ethyl acetate 15 mixture (50/50 by volume) and collecting 30 cm 3 fractions. Fractions 4 to 12 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.42 g of the mixture of the 2 diastereoisomers (forms A) 1-{ (R*) - (4 -chlorophenyl) [4 20 (hydroxymethyl)phenyllmethyl}-3-[(R) -(3,5-difluoro phenyl) (methylsulfonyl)methyl) lazetidin-3-ol, and 1 (R*) - (4-chlorophenyl) [4- (hydroxymethyl)phenyl]methyl} 3- [(S) (3,5-difluorophenyl) (methylsulfonyl)methyl) ] azetidin-3-ol is obtained in the form of a white 25 lacquer. The mixture of the 2 diastereomers (forms A) 3 -acetoxy-1- { (R*) - (4 -chlorophenyl) [4- (methoxycarbonyl) 225 226 phenyl]methyl}-3-[(R)-(3,5-difluorophenyl) (methyl sulfonyl)methyl) }azetidine and 3-acetoxy-1-{ (R*) - (4 chlorophenyl) [4-(methoxycarbonyl)phenyllmethyl}-3-[(S) (3,5-difluorophenyl) (methylsulfonyl)methyl)}azetidine 5 may be prepared by carrying out the operation as described in Example 40, starting with 1.0 g of (3,5 difluorobenzyl) methylsulfone, 30 cm 3 of tetrahydrofuran, 3 cm 3 of a 1.6 N solution of n-butyl.lithium in hexane, 1.45 g of 1-{(R*)-(4-chlorophenyl) [44-(methoxycarbonyl) 10 phenyl]methyl}azetidin-3-one, form A isomer, and 0.43 cm 3 of acetyl chloride. 1.28 g of the mixture of the 2 diastereoisomers (forms A) 3-acetoxy-1-{(R*)-(4 chlorophenyl) [4-methoxycarbonyl)phenyllmethyl}-3-[(R) (3,5-difluorophenyl) (methylsulfonyl)methyl)]azetidine 15 and 3-acetoxy-1-{ (R*) - (4-chlorophenyl) [4-methoxy carbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl) (methylsulfonyl)methyl)]azetidine are obtained in the form of a beige foam. 1-{ (R*) - [(4-chlorophenyl) [4- (methoxycarbonyl) 20 phenyllmethyl}azetidin-3-one, form A isomer, may be prepared by carrying out the operation as described in Example 40, starting with 0.55 cm 3 of oxalyl chloride, 25 cm 3 of dichloromethane, 0.90 cm 3 of dimethyl sulfoxide, 1.75 g of 1-{(4-chlorophenyl) [4-(methoxy 25 carbonyl)phenyllmethyl}azetidin-3-ol, and 2.70 cm 3 of triethylamine. 1.45 g of 1-{(R*)-(4-chlorophenyl) [4 (methoxycarbonyl)phenyl]methyl}azetidin-3-one, form A 226 227 isomer, are obtained in the form of a yellow foam. 1-{ (R*) (4 -chlorophenyl) [4 - (methoxycarbonyl) phenyl]methyl}azetidin-3-ol, form A isomer, may be prepared by carrying out the operation according to the 5 procedure described by KATRITZKY A.R. et al., in J. Heterocycl. Chem., (1994), 271 from 2.0 g of methyl (+) -4- [ (R*) -amino - (4 -chlorophenyl) methyl] benzoate, 30 cm 3 of ethanol, 0.60 g of sodium hydrogen carbonate and 0.60 cm 3 of epibromhydrin. 1.76 g of 1-{(R*)-(4 10 chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl}azetidin-3-ol, form A isomer, are obtained in the form of a pasty solid. Methyl (+) -4- [(R*) -amino- (4-chlorophenyl) methyl] benzoate may be prepared by carrying out the 15 operation in the following manner: 2.51 g of D-(-) tartaric acid are added to a solution of 9.2 g of methyl (4- [(RS) -amino- (4-chlorophenyl)methyl]benzoate in 10 cm 3 of methanol. The solution is concentrated to dryness under reduced pressure (2.7 kPa) . The cream 20 colored foam obtained is dissolved in 50 cm 3 of ethanol containing 5% water and the resulting solution is allowed to crystallize for 20 hours at 20 0 C. The crystals are filtered, washed with ethanol containing 5% water, drained and then dried under reduced pressure 25 (2.7 kPa) . 3.4 g of white crystals are obtained which are called "A crystals" [and which are stored for the subsequent preparation of the second enantiomer, methyl 227 228 (-) -4 - [ (R*) -amino- (4 -chlorophenyl) methyl] benzoate] . The mother liquors are concentrated to dryness and a white foam (8.1 g) is obtained which is dissolved in 100 cm' of ethyl acetate. The solution obtained is supplemented 5 with 50 cm 3 of 1 N sodium hydroxide, stirred and separated after settling out. The organic phase is washed with 50 cm 3 of water and then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) . A yellow solid is obtained 10 which is dissolved in 100 cm 3 of methanol. The solution obtained is supplemented with 1.85 g of L-(+)-tartaric acid and the resulting solution is concentrated to dryness under reduced pressure (2.7 kPa) . A cream colored foam is obtained which, once dissolved in 27 cm 3 15 of ethanol containing 4% water, is allowed to crystallize for 20 hours at 20 0 C. The crystals are filtered, washed with ethanol containing 4% water, drained and then dried under reduced pressure (2.7 kPa) . 3.4 g of methyl (+) -4- [(R*) -amino-(4 20 chlorophenyl)methyllbenzoate L-(+)-tartrate crystals are obtained which are recrystallized from 60 cm 3 of ethanol containing 5% water. After draining and then drying, 2.78 g of white crystals are obtained which are dissolved in 50 cm 3 of ethyl acetate. The solution 25 obtained is supplemented with 100 cm 3 of 1 N sodium hydroxide, stirred and separated after settling out. The organic phase is washed with 50 cm 3 of water and 228 229 then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) . 2.1 g of methyl (+) -4- [(R*) -amino- (4-chlorophenyl)methyllbenzoate are obtained in the form of a white solid. 5 Methyl 4- [(RS) -amino- (4-chlorophenyl) methyl]benzoate may be prepared by carrying out the operation in the following manner: 3.9 cm 3 of hydrazine hydrate are added to a suspension of 16.3 g of methyl 4-[ (RS) -phthalimido- (4-chlorophenyl)methyll]benzoate in 10 200 cm' of methanol. After stirring for 5 hours at the reflux temperature and then for 20 hours at 20 0 C, the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is taken up in a 15 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 separated after settling out in a separating funnel, and the organic phase is washed with 50 cm 3 of water, dried over 20 magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 8.4 g of methyl 4-[(RS) amino- (4-chlorophenyl)methyl]benzoate are obtained in the form of a pale yellow oil. Methyl 4- [(RS) -phthalimido- (4-chlorophenyl) 25 methyl]benzoate may be prepared by carrying out the operation in the following manner: 12.6 g of potassium phthalimide are added to a solution of 11.6 g of methyl 229 230 4- [(RS) -bromo- (4-chlorophenyl)methyl]benzoate in 70 cm 3 of dimethylformamide. After stirring for 3 hours at the reflux temperature, the reaction mixture is cooled to 20'C and then supplemented with 300 cm 3 of ethyl acetate 5 and 300 cm 3 of water. After stirring, the mixture is separated after settling out, the aqueous phase reextracted with twice 100 cm 3 of ethyl acetate, the combined organic phases are washed with twice 400 cm 3 of water and then dried over magnesium sulfate and 10 concentrated to dryness under reduced pressure (2.7 kPa) . 16.3 g of methyl 4-[(RS)-phthalimido-(4 chlorophenyl)methyl]benzoate are obtained in the form of a pasty yellow solid. Methyl 4- [(RS) -bromo- (4-chlorophenyl) 15 methyl]benzoate may be prepared by carrying out the operation in the following manner: 10.18 g of N,N'-carbonyldiimidazole and 54.3 cm 3 of allyl bromide are added to a solution of 17.4 g of methyl 4-[(RS)-(4 chlorophenyl) (hydroxy)methyl]benzoate in 200 cm 3 of 20 acetonitrile. After stirring for 30 minutes at 200C, the reaction mixture is heated under reflux for 2 hours, stirred for 20 hours at 200C and concentrated to dryness under reduced pressure (2.7 kPa) . The mixture, taken up in dichloromethane, is chromatographed on a 25 silica gel column (particle size 0.06-0.200 mm, diameter 7 cm, height 30 cm) , at an argon pressure of 0.5 bar, eluting with dichloromethane and collecting 230 231 500 cm 3 fractoins. Fractions 3 to 6 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 11.6 g of methyl 4-[(RS)-bromo-(4 chlorophenyl)methyl]benzoate are obtained in the form 5 of an oil which will be used as it is in the next step. Methyl 4- [(RS) - (4-chlorophenyl) (hydroxy) methyl] benzoate may be prepared by carrying out the operation in the following manner: 1.21 g of sodium borohydride are slowly added in small ,fractions to a 10 suspension of 2.75 g of methyl 4-(4-chlorobenzoyl) benzoate in 200 cm 3 of methanol at 20'C (heating of the medium up to 50CC occurs) . After stirring for 20 hours at 20 0 C, the reaction mixture is concentrated to a reduced volume and then supplemented with 150 cm 3 of 15 dichloromethane and, while stirring, with 100 cm 3 of 0.5 N hydrochloric acid. After separating after settling out, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 2.5 g of methyl 4-[(RS)-(4--chlorophenyl) 20 (hydroxy)methyllbenzoate are obtained in the form of a colorless oil which slowly crystallizes at 20'C, and which will be used as it is in the next step. Methyl 4-(4-chlorobenzoyl)benzoate may be prepared by carrying out the operation in the following 25 manner: 27.4 cm' of tri-n-butylphosphine are added, under argon, to a solution, cooled to -22 0 C, of 19.3 g of terephthalic acid chloride monomethyl ester in 231 232 200 cm 3 of tetrahydrofuran. After stirring for 20 minutes at -220C, a solution of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of 4-bromochlorobenzene, 2.43 g of magnesium and an iodine crystal in 100 cm 3 of 5 diethyl ether under reflux) is poured in while this temperature is maintained. After stirring for 30 minutes at -22 0 C, 150 cm3 of 1 N hydrochloric acid are slowly added, the mixture is allowed to return to 20 0 C and then the medium is diluted with 200 cm 3 of diethyl 10 ether. The white suspension obtained is filtered, the solid is washed with twice 50 cm 3 of water and then with twice 50 cm 3 of diethyl ether. 1G.2 g of methyl 4- (4 chlorobenzoyl)benzoate are obtained, after draining and then drying under reduced pressure (2.7 kPa) , in the 15 form of a white solid melting at 1700C. Example 88 The operation is carried out as described in 20 Example 87, starting with 0 .05 g of 1-{ (R*) - [4 (chloromethyl)phenyl] - (4-chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.025 g of 3,3-dimethylpiperidine. The crude product is 25 chromatographed on a silica gel column (particle size 0.O6-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then eluting with a 232 233 dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure 5 (2.7 kPa) . 0.040 g of 1-{ (R*) - (4-chlorophenyl) [4- (3,3 dimethylpiperidin-1-ylmethyl)phenyll]methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl)methylenel azetidine, form A isomer, is obtained in the form of a white foam [H NMR spectrum (300 MHz, CDCl,, 5 in ppm) : 0.94 (s, 10 6H), 1.21 (mt, 2H), from 1.50 to 1.65 (mt, 2H), 1.99 (broad s, 2H), 2.27 (unresolved complex, 2H), 2.81 (s, 3H), 3.36 (s, 2H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.84 (tt, J=8.5 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)]. 15 Example 89 The operation is carried out as described in Example 87, starting with 0.05 g of methylsulfonyl 20 methyl 1- { (R*) - [4 - (chloromethyl) phenyl] (4 chlorophenyl)methyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl)methyleneazetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.025 g of thiomorpholine. The crude product is chromatographed on 25 a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm) , eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and 233 234 methanol mixture (95/S by volume), collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.038 g of 1 5 { (R*) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyllmethyl}-3- [(3,5-difluorophenyl) (methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDC1 3 , 5 in ppm) : from 2.60 to 2.75 (mt, 8H), 10 2.80 (s, 3H), 3.44 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=8.5 and 2.5Hz, 1H), 6.97 (mt, 2H), from 7.20 to 7.40 (mt, 8H)]. Example 90 15 The operation is carried out as described in Example 87, starting with 0. 05 g of 1- {(R*) - [4- (chloro methyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5 difluorophenyl) (methylsulfonyl)methylenel azetidine, 20 form A isomer, 1.0 cm 3 of dichloromethane and 0.025 g of N-cyclohexyl-N-ethylamine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then with a 25 dichloromethane and ethanol mixture (95/5) by volume), collecting 2.5 cm 3 fractions immediately after using this eluent mixture. 0. 022 g of 1- { (R*) - (4 -chloro 234 235 phenyl) [4-(N-ethyl-N-cyclohexylaminomethyl)phenyl] methyl}}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene]azetidine, form A isomer, is obtained in the form of a white foam ["H NMR spectrum (300 MHz, CDC1, 5 with addition of a few drops of CDCOOD-d4, 6 in ppm) from 1.15 to 1.25 (mt, 2H), 1.29 (t, J=7.5Hz, 3H), from 1.45 to 1.65 (mt, 4H), 1.88 (mt, 2H), 2.17 (mt, 2H), 2.81 (s, 3H), 3.05 (q, J=7.5Hz, 2H), 3.27 (mt, 1H), 3.95 (mt, 2H), 4.18 (s, 2H), 4.40 (mt, 2H), 4.66 (s, 10 1H), 6.82 (tt, J=8.5 and 2.5Hz, 1H), 7.00 (mt, 2H), from 7.20 to 7.40 (mt, 4H), 7.41 (d, J=8Hz, 2H), 7.53 (d, J=8Hz, 2H)] . 15 Example 91 The procedure is carried out as described in Example 87, starting with 0. 05 g of 1- { (R*) - [4- (chloro methyl)phenyl] (4- (chlorophenyl)methyl}-3- [(3,5 20 difluorophenyl) (methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.032 g of 4-(ethoxycarbonyl)piperazine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting 25 with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm 3 fractions immediately after using 235 236 this eluent mixture. Fractions 2 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.021 g of 1-{ { (R*) - (4-chlorophenyl) {4- [ (4 ethoxycarbonylpiperazinyl)methyllphenyl}methyl} }-3 5 [(3, 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, form A isomer, is obtained in the form of a white foam [H NMR spectrum (400 MHz, CDC1 3 , 6 in ppm) : 1.25 (t, J=7Hz, 3H), 2.36 (mt, 4H), 2.80 (s, 3H), 3.44 (s, 2H), 3.46 (mt, 4H), 3.85 (mt, 2H), 4.13 (q, J=7Hz, 10 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)]. Example 92 15 The operation is carried out as described in Example 87, starting with 0. 05 g of 1- { (R*) - [4 - (chloro methyl)phenyl] (4-chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.023 g of 20 N-cyclopropyl-N-propylamine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), 25 collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 3 to 9 are combined and then concentrated to dryness under reduced pressure 236 237 (2.7 kPa) . 0.026 g of 1- { (R*) - (4-chlorophenyl) [ (4-N cyclopropyl-N-propylaminomethyl)phenyllmethyl}-3- [(3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, form A isomer, is obtained in the form of a white foam 5 [H NMR spectrum (400 MHz, CDC1 3 with addition of a few drops of CDCOOD-d4, 6 in ppm): 0.34 (mt, 2H), 0.70 (mt, 2H), 0.91 (t, J=7Hz, 3H), 1.08 (mt, 1H), 1.76 (mt, 2H), 2.82 (s, 3H), 2.92 (d, J=7Hz, 2H), 3.00 (mt, 2H), 3.90 (mt, 2H), 4.25 (s, 2H), 4.37 (mt, 2H), 4.59 (s, 1H), 10 6.83 (tt, J=9 and 2.5Hz, 1H), 7.00 (mt, 2H), from 7.20 to 7.45 (mt, 8H)]. Example 93 15 The operation is carried out as described in Example 87, but by stirring the reaction mixture for 6 days at 20 0 C, starting with 0.05 g of 1-{(R*)-[4 (chloromethyl)phenyl] (4- (chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, 20 form A isomer, 1.0 cm 3 of dichloromethane, 5 mg of sodium iodide and 0.020 g of diisopropylamine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm) , eluting with 80 cm 3 of dichloromethane and then 25 with a dichloromethane and methanol mixture (95/5 by volume) , collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 2 to 8 are 237 238 combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.028 g of 1-{ (R*) - (4-chloro phenyl) [4- (diisopropylaminomethyl) phenyli methyl} -3 [(3, 5-difluorophenyl) (methylsulfonyl)methylenel 5 azetidine, form A isomer, is obtained in the form of a white foam ['H NMR spectrum (300 MHz, CDCl 3 , 6 in ppm) 1.00 (unresolved complex, 12H), 2.80 (s, 3H), from 2.90 to 3.10 (unresolved complex, 2H), 3.58 (mt, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.48 (s, 1H), 6.82 (tt, J=8.5 10 and 2.5Hz, 1H), 6.97 (mt, 2H), from 7.20 to 7.40 (mt, 8H) . Example 94 15 The operation is carried out as described in Example 87, starting with 0. 05 g of 1- ( (R*) - [4- (chloro methyl)phenyl] (4- (chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.027 g 20 of bis(2-methoxyethyl)amine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), 25 collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 3 to 10 are combined and then concentrated to dryness under reduced pressure 238 239 (2.7 kPa) . 0 . 014 g of 1-{{ (R*) - (4-chlorophenyl) {4 [bis (2-methoxyethyl) aminomethyll phenyl}methyl} } -3 [(3, 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, form A isomer, is obtained in the form of a 5 white foam ['H NMR spectrum (300 MHz, CDCl 3 , 6 in ppm) 2.70 (broad t, J=5.5Hz, 4H), 2.81 (s, 3H), 3.29 (s, 6H), 3.46 (broad t, J=5.5Hz, 4H) 3.65 (broad s, 2H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 10 (mt, 8H)]. Example 95 The operation is carried out as described in 15 Example 87, starting with 0. 05 g of 1-{ (R*) - [4 - (chloro methyl)phenyl] (4-chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.020 g of di-n-propylamine. The crude product is 20 chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm 3 fractions immediately after using 25 this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.025 g of 1-{ (R*) - (4- (chlorophenyl) [4- (di-n 239 240 propylaminomethyl)phenyl]methyl}-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam ['H NMR spectrum (400 MHz, CDC1 3 , 6 in ppm): 0.85 (t, 5 J=7Hz, 6H) 1.45 (mt, 4H), 2.34 (t, J=7.5Hz, 4H), 2.80 (s, 3H), 3.48 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)]. 10 Example 96 The operation is carried out as described in Example 87, starting with 0.05 g of 1-((R*)-[4-(chloro methyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5 15 difluorophenyl) (methylsulfonyl)methylenelazetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.017 g of piperidine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm) , eluting with 80 cm 3 of 20 dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 5 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.035 g of 1 25 { (R*)-(4-chlorophenyl) [4-(piperidin-1-ylmethyl)phenyl] methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl enelazetidine, form A isomer, is obtained in the form 240 241 of a white foam ['H NMR spectrum (300 MHz, CDCl 3 , 5 in ppm): from 1.35 to 1.65 (mt, 6H) , 2.35 (unresolved complex, 4H), 2.80 (s, 3H), 3.41 (broad s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 5 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H) I. Example 97 10 The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R*)-[4-(chloro methyl)phenyl] (4-chlorophenyl)methyl}-3- [ (3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.020 g 15 of N-methylpiperazine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), 20 collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 3 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.025 g of 1-{ (R*)-(4-chlorophenyl) [4-(4 methylpiperazin-1-ylmethyl)phenylmethyl-3- [(3,5 25 difluorophenyl) (methylsulfonyl)methylenel azetidine, form A isomer, is obtained in the form of a white foam ['H NMR spectrum (300 MHz, CDC1 3 , 5 in ppm) : 2.28 (s, 241 242 3H), from 2.30 to 2.60 (unresolved complex, 8H), 2.80 (s, 3H), 3.45 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)]. 5 Example 98 The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R*)-[4-(chloro 10 methyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.018 g of morpholine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, 15 diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to 20 dryness under reduced pressure (2.7 kPa). 0.022 g of 1 {(R*)-(4-chlorophenyl) [4-(morpholin-4-ylmethyl)phenyl] methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl) methylenelazetidine, form A isomer, is obtained in the form of a white foam ['H NMR spectrum (300 MHz, CDCl 3 , a 25 in ppm): 2.41 (t, J=5Hz, 4H), 2.80 (s, 3H), 3.43 (s, 2H), 3.69 (t, J=5Hz, 4H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5Hz, 1H), 6.98 (mt, 242 243 2H) , from 7.20 to 7.40 (mt, 8H)]. Example 99 5 The operation is carried out as described in Example 87, starting with 0. 05 g of 1- {(R*) - [4- (chloro methyl)phenyl] (4-chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl) methylenel azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.020 cm 3 10 of D-prolinol. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm) , eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm 3 15 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.025 g of 1 (R*) - (4-chlorophenyl) [4- ( (2R) -hydroxymethylpyrrolidin 1-ylmethyl)phenyllmethyl}-3-[(3,5-difluorophenyl) 20 (methylsulfonyl)methylenelazetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, (CD 3

)

2 SO-d6 with addition of a few drops of

CD

3 COOD-d4, 6 in ppm) : from 1.60 to 2.15 (mt, 4H) , from 2.90 to 3.05 (mt, 1H), 2.98 (s, 3H), 3.13 (mt, 1H), 25 3.38 (mt, 1H), from 3.50 to 3.60 (mt, 1H), 3.56 (d, J=5Hz, 2H), 3.90 (mt, 2H), 4.04 (d, J=13.5Hz, 2H), 4.21 (mt, 2H), 4.40 (d, J=13.SHz, 2H), 4.78 (s, 1H), 7.14 243 244 (mt, 2H), 7.27 (tt, J=9 and 2.5Hz, 1H), from 7.30 to 7.55 (mt, 8H)]. Example 100 5 The operation is carried out as described in Example 87, starting with 0.05 g of 1-{ (R*) - [4- (chloro methyl)phenyl] (4-chlorophenyl)methyl}-3- [ (3,5 difluorophenyl) (methylsulfonyl)methylene] azetidine, 10 form A isomer, 1.0 cm 3 of dichloromethane, and 0.015 g of diethylamine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and 15 methanol mixture (95/5 by volume), collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 4 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.025 g of 1 ( (R*) - (4-chlorophenyl) [4- (diethylaminomethyl)phenyl] 20 methyl}-3- [ (3,5-difluorophenyl) (methylsulfonyl) methylene]azetidine, form A isomer, is obtained in the form of a white foam ['H NMR spectrum (400 MHz, CDCl 3 , 5 in ppm): 1.03 (t, J=7Hz, 6H), 2.50 (q, J=7Hz, 4H), 2.81 (s, 3H), 3.50 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 25 4.49 (s, 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.99 (mt, 2H), from 7.20 to 7.40 (mt, 8H)]. 244 245 Example 101 The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R*)-[4-(chloro 5 methyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.026 g of N-(hydroxyethyl)piperazine. The crude product is chromatographed on a silica gel column (particle size 10 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm' fractions immediately after using this eluent mixture. Fractions 3 to 10 are combined and 15 then concentrated to dryness under reduced pressure (2.7 kPa) . 0.032 g of 1-{{(R*)-(4-chlorophenyl) {4-[4 (hydroxyethyl)piperazin-1-ylmethyl]phenyl}methyl}}-3 [(3,5-difluorophenyl) (methylsulfonyl) methylenelazetidine, form A isomer, is obtained in the 20 form of a white foam [H NMR spectrum (300 MHz, CDCl 3 , 5 in ppm): from 2.40 to 2.60 (mt, 8H), 2.54 (t, J=5.5Hz, 2H), 2.80 (s, 3H), 3.44 (s, 2H), 3.60 (t, J=5.5Hz, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 25 (mt, 8H)]. Example 102 245 246 The operation is carried out as described in Example 87 but by stirring the reaction mixture for 4 days at 20'C, starting with 0.05 g of 1-{ (R') - [4 5 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.023 g of 2(RS),6(RS)-dimethylpiperidine. The crude product is chromatographed- on a silica gel column (particle size 10 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 2 to 9 are combined and 15 then concentrated to dryness under reduced pressure (2.7 kPa) . 0.024 g of 1-{ (R*) -(4-chlorophenyl) [4-(2(RS) 6 (RS) dimethyl (piperidin-1-ylmethyl) phenyll methyl} -3 [(3, 5-difluorophenyl) (methylsulfonyl) methylene]azetidine, form A isomer, is obtained in the 20 form of a white foam ['H NMR spectrum (400 MHz, CDCl, with addition of a few drops of CDCOOD-d4, at a temperature of 353K, 5 in ppm): from 1.20 to 1.45 (mt, 2H), 1.60(d,J=7Hz, 6H)), from 1.80 to 2.10 (mt, 4H)), 2.80 (s, 3H), 3.17 (mt, 2H), 3.90 (mt,2H), 4.34 (broad 25 d, J=16Hz, 1H) , 4.40 (mt, 2H), 4.43 (broad d, J=16Hz, 1H), 4.62 (s,1H), 6.82 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.50 (mt,8H)]. 246 247 Example 103 The operation is carried out as described in 5 Example 87, but by stirring the reaction mixture for 4 days at 200C, starting with 0.05 g of 1-{(R*) -[4 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl) methylenel azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.024 g 10 of piperazin-2-one. The crude product is chromato graphed on a silica gel column (particle size 0.06 0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 15 cm 3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.022 g of 1-{ (R*) - (4-chlorophenyl) [4- (piperazin 2-on-4-ylmethyl)phenyllmethyl}-3- [(3,5-difluorophenyl) 20 (methylsulfonyl)methylenelazetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (400 MHz, CDCl 3 , 5 in ppm) : 2.62 (t, J=5.5Hz, 2H) , 2.80 (s, 3H), 3.11 (s, 2H), 3.34 (mt, 2H), 3.51 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.51 (s, 1H), 5.76 25 (unresolved complex, 1H), 6.84 (broad t, JHF=9Hz, 1H), 6.98 (mt, 2H) from 7.20 to 7.40 (mt, 8H)]. 247 248 Example 104 The operation is carried out as described in Example 87, starting with 0.05 g of 1-{ (R*) - [4- (chloro 5 methyl)phenyl] (4- (chlorophenyl)methyl}-3-[(3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.020 g of L-prolinol. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, 10 diameter 8 mm, height 8 cm) , eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to 15 dryness under reduced pressure (2.7 kPa) . 0.028 g of 1 (R*) - (4-chlorophenyl) {4- [ (2S) - (hydroxymethyl) pyrrolidin-1-ylmethyllphenyl}methyl}}-3- [(3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, form A isomer, is obtained in the form of a white foam 20 ['H NMR spectrum (300 MHz, CDCl 3 , 6 in ppm) : from 1.50 to 2.00 (mt, 4H), 2.24 (mt, 1H), 2.71 (mt, 1H), 2.80 (s, 3H), 2.93 (mt, 1H), 3.28 (d, J=13.5Hz, 1H), 3.45 (mt, 1H), 3.65 (d, J=11 and 4Hz, 1H), 3.84 (mt, 2H), 3.91 (d, J=13.5Hz, 1H), 4.33 (mt, 2H), 4.50 (s, 1H), 25 6.83 (tt, J=8.5 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)]. 248 249 Example 105 The operation is carried out as described in Example 87, starting with 0.05 g of 1-((R*)-[4- (chlor 5 methyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5 difluorophenyl) (methylsulfonyl)methylenelazetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.023 g of (2S)-(methoxymethyl)pyrrolidine.-The crude product is chromatographed on a silica gel column (particle size 10 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm' of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 2 to 6 are combined and 15 then concentrated to dryness under reduced pressure (2.7 kPa) . 0.037 g of 1-{{(R*)-(4-chlorophenyl) {4-((2S) (methoxymethyl)pyrrolidin-1-ylmethyllphenyl}methyl}}-3 [(3,5-difluorophenyl) (methylsulfonyl) methylenelazetidine, form A isomer, is obtained in the 20 form of a white foam ['H NMR spectrum (300 MHz, CDCl 3 , in ppm): 1.66 (mt, 2H), 1.90 (mt, 1H), 2.16 (mt, 1H), 2.68 (mt, 1H), 2.80 (s, 3H), 2.89 (mt, 1H), from 3.25 to 3.45 (mt, 4H), 3.31 (s, 3H), 3.84 (mt, 2H), 4.04 (d, J=13.5Hz, 1H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, 25 J=8.5 and 2.5Hz, 1H), 6.98 (mt, 2H) from 7.20 to 7.40 (mt, 8H)]. 249 250 Example 106 The operation is carried out as described in Example 87, starting with 0. 05 g of 1- { (R*) - [4- (chloro 5 methyl)phenyl] (4- (chlorophenyl)methyl}-3-[(3,5 difluorophenyl) (methylsulfonyl) methylenel azetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.020 g of 2 (RS) , 5 (RS) -dimethylpyrrolidine. The crude product is chromatographed on a silica gel column (particle size 10 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 3 to 6 are combined and 15 then concentrated to dryness under reduced pressure (2.7 kPa) . 0.024 g of 1-{ (R*)-(4-chlorophenyl) [4 (2 (RS) , 5 (RS) -dimethylpyrrolidin-1-ylmethyl)phenyll methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylenelazetidine, mixture of isomers, form A, is 20 obtained in the form of a white foam [ 1 H NMR spectrum (400 MHz, CDCl 3 with addition of a few drops of CDCOOD d4, 8 in ppm): 1.68 (d, J=7Hz, 6H) , from 2.00 to 2.15 (mt, 4H), 2.82 (s, 3H), 3.22 (mt, 2H), 3.92 (mt, 2H), 4.30 (s, 2H), 4.33 (mt, 1H), 4.45 (d, J=16.5 and 3Hz, 25 1H), 4.63 (s, 1H), 6.84 (tt, J=8.5 and 2.5Hz, 1H), 7.00 (mt, 2H) , from 7.20 to 7.55 (mt, 8H)]. 250 251 Example 107 The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R*) -[4-(chloro 5 methyl)phenyll-4-(chlorophenyl)methyl}-3-[(3,S difluorophenyl) (methylsulfonyl)methylene] azetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.023 g of L-prolinamide. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, 10 diameter 8 mm, height 8 cm) , eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm 3 fractions immediately after using this eluent mixture. Fractions 2 to 5 are combined and then concentrated to 15 dryness under reduced pressure (2.7 kPa). 0.028 g of 1 (R*) - (4-chlorophenyl) [4- ( (2S) -carbamoylpyrrolidin-1 ylmethyl)phenyllmethyl}-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam ['H NMR spectrum 20 (400 MHz, CDCl, 5 in ppm) : from 1.65 to 1.85 (mt, 2H) 1.92 (mt, 1H), from 2.15 to 2.35 (mt, 2H), 2.80 (s, 3H), -3.00 (mt, 1H), 3.16 (dd, J=10 and 5.5Hz, 1H), 3.41 (d, J=13.5Hz, 1H), 3.86 (mt, 2H), 3.89 (d, J=13.5Hz, 1H), 4.33 (mt, 2H), 4.51 (s, 1H), 5.23 (unresolved 25 complex, 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), 7.17 (unresolved complex, 1H)), from 7.20 to 7.40 (mt, 8H) ]. 251 252 Example 108 The operation is carried out as described in 5 Example 87, but by stirring the reaction mixture for 4 days at 20 C, starting with 0.05 g of 1-{(R*)-[4 (chloromethyl)phenyl] (4- (chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl) methylenel azetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.021 g of 10 diethanolamine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm) , eluting with 80 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume) , collecting 2.5 cm 3 15 fractions immediately after using this eluent mixture. Fractions 2 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.004 g of 1 (R') - (4-chlorophenyl) [4- (dihydroxyethylaminomethyl) phenyl]methyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) 20 methylenelazetidine, form A isomer, is obtained in the form of a white foam ["H NMR spectrum (300 MHz, CDC 3 , in ppm): 2.69 (t, J=5.5Hz, 4H), 2.80 (s, 3H), 3.61 (t, J=5.5Hz, 4H), 3.65 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=9 and 2.5Hz, 1H), 6.98 25 (mt, 2H) , from 7.20 to 7.40 (mt, 8H)1. 252 253 Example 109 0.055 g of imidazole is added to solution of 0 .24 g of 1- { (R*) - [4- (chloromethyl) phenyl] (4 5 chlorophenyl)methyl}-3- [ (3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, form A isomer, in 5 cm 3 of dichloromethane. After heating for 3 hours under reflux, the mixture is supplemented with 5 mg of sodium iodide. After stirring for 20 hours under 10 reflux, the reaction mixture is cooled to 20'C and then chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.0 cm, height 20 cm), eluting with 120 cm 3 of dichloromethane without fractionating, and then with a dichloromethane and methanol mixture 15 (98/2 and then 96/4 by volume) , collecting 4 cm 3 fractions. Fractions 12 to 14 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0. 039 g of 1- { (R*) - (4-chlorophenyl) [4- (imidazol-1 ylmethyl)phenyl]methyl}-3- [(3,5-difluorophenyl) 20 (methylsulfonyl)methylenelazetidine, form A isomer, is obtained in the form of a white foam. Example 110 25 The operation is carried out as described in Example 87, starting with 0. 50 g of 1- { (R*) - [4 - (chloro methyl)phenyl] (4- (chlorophenyl)methyl}-3- [(3,5 253 254 difluorophenyl) (methylsulfonyl) methylenel azetidine, form B isomer, 5 mg of sodium iodide, 15 cm 3 of dichloromethane and 0.0190 g of pyrrolidine. The crude product is chromatographed on a silica gel column 5 (particle size 0.06-6.200 mm, diameter 1.5 cm, height 20 cm), at an argon pressure of 0.1 bar, eluting with dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume) and collecting 25 cm' fractions. Fractions 20 to 40 are combined and then 10 concentrated to dryness under reduced pressure (2.7 kPa) . 0.028 g of 1-{(R*)-(4-chlorophenyl) [4 (pyrrolidin-1-ylmethyl)phenyl]methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl)methylenel azetidine, form B isomer, is obtained in the form of a white foam. 15 [a] 2 0 365nm = +26.8 +/- 0.8 (c = 0.5-, dichloromethane) ['H NMR spectrum (300 MHz, CDC1, 3 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 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 20 to 7.40 (mt, 8H)]. 1-{ (R*) -[4- (chloromethyl)phenyl] (4 (chlorophenyl)methyl}-3-((3,5-difluorophenyl) (methylsulfonyl)methylenelazetidine, form B isomer, may be prepared by carrying out the operation as described 25 in Example 87, starting with 7.3 g of the mixture of the 2 diastereoisomers (B forms) 1-{ (R*) - [4- (chloro methyl)phenyl] (4-chlorophenyl)methyl}-3-[(R)-(3,5 254 255 difluorophenyl) (methylsulfonyl)methylene] azetidin-3-ol and 1- { (R') - [4 - (chloromethyl) phenyl] (4 - chlorophenyl) methyl}-3-[(S)- (3,5-difluorophenyl) (methylsulfonyl) methyl]azetidin-3-ol, 8.2 g of 4-dimethylaminopyridine, 5 150 cm 3 of dichloromethane and 3.2 cm 3 of methanesulfonyl chloride. The crude product is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), at an argon pressure of 0.2 bar, eluting with dichloromethane and 10 collecting 100 cm 3 fractions. Fractions 15 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 2.50 g of 1-{ (R*)-[4 (chloromethyl) phenyl] - (4-chlorophenyl) methyl) -3- { (3,5 difluorophenyl) (methylsulfonyl) methylenel azetidine, 15 form B isomer, are obtained in the form of a white foam. The mixture of the 2 diastereoisomers 1-{(R*) [4- (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- [(R) (3,5-difluorophenyl) (methylsulfonyl)methyl) ] azetidin-3 20 ol and 1- { (R*) - [4- (chloromethyl) phenyl] (4-chlorophenyl) methyl}-3-[(S) -(3,5-difluorophenyl) (methylsulfonyl) methyl)]azetidin-3-ol, may be prepared by carrying out the operation as described in Example 87, starting with 11.0 g of a mixture of the 2 diastereoisomers 1-{(R*) 25 [4-chlorophenyl) [4- (hydroxymethyl)phenyl)methyl}-3 [(R)-(3,5-difluorophenyl) (methylsulfonyl)methyl)] azetidin-3-ol and 1-{ (R*) - [4- (chlorophenyl] (4 255 256 (hydroxymethyl)phenyl)methyl}-3-[(S)-(3,5 difluorophenyl) (methylsulfonyl)methyl)]azetidin-3-ol, 250 cm 3 of dichloromethane and 3.1 cm 3 of thionyl chloride. The crude product is chromatographed on a 5 silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), at an argon pressure of 0.2 bar, eluting with a cyclohexane and ethyl acetate mixture (70/30 by volume) and collecting 50 cm 3 fractions. Fractions 9 to 25 are combined and then concentrated to 10 dryness under reduced pressure (2.7 kPa). 7.3 g of the mixture of the 2 diastereoisomers (B forms) 1-{(R*)-[4 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(R) (3,5-difluorophenyl) (methylsulfonyl)methyl)lazetidin-3 ol and 1-{ (R*)-[4-(chloromethyl)phenyl] (4 15 chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl) (methylsulfonyl)methyl)lazetidin-3-ol are obtained in the form of a white foam. The mixture of the 2 diastereoisomers (B forms) 1-{ (I.)-(4-chlorophenyl) [4-(hydroxymethyl) 20 phenyl]methyl}-3-[(R)-(3;5-difluorophenyl) (methylsulfonyl)methyl)]azetidin-3-ol and 1-{(R*)-(4 chlorophenyl) [4-(hydroxymethyl)phenyl]methyl}-3-[(R) (3,5-difluorophenyl) (methylsulfonyl)methyl)lazetidin-3 ol may be prepared by carrying out the operation as 25 described in Example 87, starting with 18.0 g of the mixture of the 2 diastereoisomers (B form) 3-acetoxy-1 (R*) - (4-chlorophenyl) [4- (methoxycarbonyl) 256 257 phenyl]methyl}-3-[(R)-(3,5-difluorophenyl) (methylsulfonyl)methyllazetidine and 3-acetoxy-1-{(R) (4-chlorophenyl) [4-(methyloxycarbonyl)phenyl]methyl}-3 [(S)-(3,5-difluorophenyl) (methylsulfonyl)methyl)] 5 azetidine, 150 cm 3 of anhydrous toluene and 100 cm 3 of a 20% solution of diisobutylaluminum hydride in toluene. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3 cm, height 30 cm), at an argon pressure of 0.1 bar, eluting 10 with a cyclohexane and ethyl acetate mixture (50/50 by volume) and collecting 50 cm 3 fractions. Fractions 15 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 11.0 g of the mixture of the 2 diastereoisomers (B forms) 1-{(R*)-(4-chloro 15 phenyl) [4-(hydroxymethyl)phenyllmethyl}-3-[(R)-(3,5 difluorophenyl) (methylsulfonyl)methyllazetidin-3-ol and 1-{(R*)-(4-chlorophenyl) [4-(hydroxymethyl) phenyl]methyl}-3-[(S)-(3,5-difluorophenyl) (methylsulfonyl)methylazetidin-3-ol are obtained in 20 the form of white foam. The mixture of the 2 diastereoisomers (B forms) 3-acetoxy-1-( (R*) - (4-chlorophenyl) [4 (methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5 difluorophenyl) (methylsulfonyl)methyl)]azetidine and 3 25 acetoxy-1-{ (R*) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl]methyl}-3-[(R)-(3,5-difluorophenyl) (methylsulfonyl)methyl)]azetidine may be prepared by 257 258 carrying out the operation as described in Example 40, starting with 11.2 g of (3,5-difluorobenzyl) methylsulfone, 350 cm 3 of tetrahydrofuran, 34 cm 3 of a 1.6 N solution of n-butyllithium in hexane, 11.2 g of 5 1-{(R*)-(4-chlorophenyl) [4-(methoxycarbonyl) phenyllmethyl}azetidin-3-one, form B isomer, and 5.5 cm 3 of acetyl chloride. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 4 cm, height 40 cm), eluting 10 with a cyclohexane and ethyl acetate mixture (70/30 by volume) and collecting 100 cm 3 fractions. Fractions 10 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 21 g of a still impure cream-colored foam are obtained, which foam is 15 chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 4 cm, height 40 cm), eluting with dichloromethane and collecting 100 cm 3 fractions. Fractions 11 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 20.0 g of 20 the mixture of the 2 diastereoisomers (B forms) 3 acetoxy-{ (R*) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl]methyl}-3-((R)-(3,5-difluorophenyl) (methylsulfonyl)methyl)]azetidine and 3-acetoxy-{ (R) (4-chlorophenyl) [4-(methoxycarbonyl)phenyl]methyl}-3 25 [(S)-(3,5-difluorophenyl) (methylsulfonyl)methyl)] azetidine are obtained in the form of a white foam. -{ (R*) - (4-chlorophenyl) [4- (methoxycarbonyl) 258 259 phenylimethyl}azetidin-3-one, form B isomer, may be prepared by carrying out the operation as described in Example 40, starting with 8.7 cm 3 of oxalyl chloride, 350 cm 3 of dichloromethane, 14.2 cm 3 of dimethyl 5 sulfoxide, 29.0 g of 1-{ (R*) - (4-chlorophenyl) [4 (methoxycarbonyl)phenyl]methyl}azetidin-3-ole, form B isomer, and 43 cm 3 of triethylamine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 4 cm, height 40 cm), 10 eluting with dichloromethane and collecting 250 cm 3 fractions. Fractions 7 to 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 15.5 g of 1-{ (R*) -(4- [chlorophenyl) [4 (methoxycarbonyl)phenyllmethyl}azetidin-3-one, form B 15 isomer, are obtained in the form of an orange-colored oil. 1-{ (R*) - (4 -chlorophenyl) [4 - (methoxycarbonyl) phenyl]methyl}azetidin-3-ol, form B isomer, may be prepared according to the procedure described by 20 KATRITZKY A.R. et al., in J. Heterocycl. Chem., (1994), 271, starting with 25.5 g of methyl (-) -4- [1-(R*) -amino 1-(4-chlorophenyl)methyl]benzoate, 250 cm 3 of ethanol, 7.9 g of sodium hydrogen carbonate, and 7.7 cm 3 of epibromohydrin. 29 g of 1-{ (R*) - (4-chlorophenyl) [4 25 (methoxycarbonyl)phenyl]methyl}azetidin-3-ol, form B isomer, are obtained in the form of a yellow oil. Methyl (-) -4- [ (R*) amino (4-chlorophenyl) 259 260 methyl]benzoate, may be prepared by carrying out two successive recrystallizations of the white crystals (3.4 g) called "A crystals" of Example 87, from 68 cm 3 of ethanol containing 5% water under reflux. The 5 crystals obtained are filtered, drained and then dried under reduced pressure (2.7 kPa). 2.2 g of methyl (-)-4-[(R*)amino(4-chlorophenyl)methylbenzoate D-(-) tartrate are obtained in the form of white crystals which are dissolved in 50 cm' of ethyl acetate. The 10 solution obtained is supplemented with 50 cm 3 of 1 N sodium hydroxide, stirred and then separated after settling out. The organic phase is washed with 50 cm 3 of water and then dried over magnesium sulfate and concentrated to dryness under reduced pressure 15 (2.7 kPa). 1.9 g of methyl (-)-4-[(R*)amino(4 chlorophenyl)methyllbenzoate are obtained in the form of a white solid [a]20 0 C, 365nm = -58.10 +/- 1 (c 0.5%) 20 Example 111 The operation is carried out as described in Example 110, but by stirring the reaction mixture for 48 hours at 20 0 C, starting with 0.05 g of 1-{(R*)-[4 25 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene)]azetidine, form B isomer, 1.0 cm 3 of dichloromethane and 0.030 cm 3 260 261 of N-methylpiperazine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 5 cm), eluting with 50 cm' of dichloromethane and then with a 5 dichloromethane and methanol mixture (95/5 by volume), collecting 3 cm 3 fractions immediately after using this eluent mixture. Fractions 4 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0 . 025 g of 1-{ (R*) - (4 -chlorophenyl) [4- (4 10 methylpiperazin-1-ylmethyl)phenyl]methyl}-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene) ] azetidine, form B isomer, is obtained in the form of a cream colored foam ['H NMR spectrum (300 MHz, CDC1, 6 in ppm): 2.28 (s, 3H), 2.44 (unresolved complex, 8H), 2.80 15 (s, 3H), 3.45 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.99 (mt, 2H), from 7.20 to 7.40 (mt, 8H)]. Example 112 20 The operation is carried out as described in Example 110, but by stirring the reaction mixture for 48 hours at 200C, starting with 0.05 g of 1-{(R*)-[4 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5 25 difluorophenyl) (methylsulfonyl)methylene) ] azetidine, form B isomer, 1.0 cm 3 of dichloromethane and 0.030 cm 3 of L-Prolinol. The crude product is chromatographed on 261 262 a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 5 cm), eluting with 50 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 3 cm 3 5 fractions immediately after using this eluent mixture. Fractions 2 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.025 g of 1 S(R*) - (4-chlorophenyl) {4- [(2S) - (hydroxymethyl) pyrrolidin-1-ylmethyl]phenyl}methyl} }-3- [(3,5 10 difluorophenyl) (methylsulfonyl)methylene] azetidine, form B isomer, is obtained in the form of a cream colored foam ['H NMR spectrum (300 MHz, CDCl 3 , 6 in ppm): from 1.80 to 2.00 (mt, 4H), 2.24 (mt, 1H), 2.72 (mt, 1H), 2.80 (s, 3H), 2.94 (mt, 1H), 3.28 (d, 15 J=13.5Hz, 1H), 3.45 (mt, 1H), 3.65 (d, J=10.5 and 3.5Hz, 1H), 3.85 (mt, 2H), 3.92 (d, J=13.5Hz, 1H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.15 to 7.40 (mt, 8H)]. 20 Example 113 The operation is carried out as described in Example 110, but by stirring the reaction mixture for 48 hours at 200C, starting with 0.05 g of 1-{ (R*)-[4 25 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl)methylene) ] azetidine, form B isomer, 1.0 cm 3 of dichloromethane and 0.030 cm 3 262 263 of D-Prolinol. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 5 cm) , eluting with 50 cm 3 of dichloromethane and then with a dichloromethane and 5 methanol mixture (95/5 by volume), collecting 3 cm 3 fractions immediately after using this eluent mixture. Fractions 2 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.029 g of 1 {{(R*)-(4-chlorophenyl) {4-(2R)-(hydroxymethyl) 10 pyrrolidin-1-ylmethyllphenyl}methyl}}-3-[(3,5 difluorophenyl) (methylsulfonyl)methylenelazetidine, form B isomer, is obtained in the form of a cream colored foam [-H NMR spectrum (300 MHz, CDCl, 6 in ppm): from 1.50 to 2.00 (mt, 4H), 2.24 (mt, 1H), 2.71 15 (mt, 1H), 2.81 (s, 3H), 2.93 (mt, 1H), 3.28 (d, J=13.5Hz, 1H), 3.44 (split t, J=10.5 and 2.5Hz, 1H), 3.66 (dd, J=10.5 and 3.5Hz, 1H), 3.85 (mt, 2H), 3.92 (d, J=13.5Hz, 1H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.15 to 20 7.40 (mt, 8H)]. Example 114 The operation is carried out as described in 25 Example 110, but by stirring the reaction mixture for 48 hours at 20 0 C, starting with 0.05 g of 1-((R*)-[4 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-((3,5 263 264 difluorophenyl) (methylsulfonyl) methylene) ] azetidine, form B isomer, 1.0 cm 3 of dichloromethane and 0.030 cm 3 of morpholine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, 5 diameter 8 mm, height 5 cm) , eluting with 50 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 3 cm 3 fractions immediately after using this eluent mixture. Fractions 2 to 9 are combined and then concentrated to 10 dryness under reduced pressure (2.7 kPa) . 0.047 g of 1 {(R*) - (4-chlorophenyl) [4- (morpholin-1-ylmethyl) phenyl]methyl}-3- [(3, 5-difluorophenyl) (methyl sulfonyl)methylene]azetidine, form B isomer, is obtained in the form of a white foam ['H NMR spectrum 15 (300 MHz, CDC1 3 , 6 in ppm) : 2.40 (mt, 4H) , 2.81 (s, 3H), 3.43 (s, 2H), 3.69 (mt, 4H), 3.84 (mt, 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5Hz, 1H), 6.99 (mt, 2H), from 7.20 to 7.40 (mt, 8H)]. 20 Example 115 The operation is carried out as described in Example 110, but by stirring the reaction mixture for 48 hours at 20 0 C, starting with 0.05 g of 1-{ (R*)-[4 25 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl) methylene) ] azetidine, form B isomer, 1.0 cm 3 of dichloromethane and 0.030 cm 3 264 265 of thiomorpholine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 5 cm), eluting with 50 cm 3 of dichloromethane and then with a dichloromethane and 5 methanol mixture (95/5 by volume) , collecting 3 cm 3 fractions immediately after using this eluent mixture. Fractions 2 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.047 g of 1 {(R*) - (4- (chlorophenyl) [4- (thiomorpholin-4-ylmethyl) 10 phenyllmethyl}-3-[(3,5-difluorophenyl) (methyl sulfonyl)methylene]azetidine, form B isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl 3 , 5 in ppm) : from 2.60 to 2.75 (mt, 8H) 2.81 (s, 3H), 3.44 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 15 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.15 to 7.40 (mt, 8H)]. Example 116 20 The operation is carried out as described in Example 110, but by stirring the reaction mixture for 48 hours at 200C, starting with 0.200 g of 1-((R*)-[4 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl) methylene) ] azetidine, 25 form B isomer, 5.0 cm 3 of dichloromethane and 0.120 cm 3 of piperazin-2-one. The crude product is chromatographed on a silica gel column (particle size 265 266 0.06-0.200 mm, diameter 1.0 cm, height 10 cm), eluting with 50 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 5 cm 3 fractions immediately after using this 5 eluent mixture. Fractions 3 to 13 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.090 g of 1-i (R*) -(4-(chlorophenyl) [4 (piperazin-2-on-4-ylmethyl)phenyl]methyl}-3-[(3,5 difluorophenyl) (methylsulfonyl)methylene] azetidine, 10 form B isomer, is obtained in the form of a white powder. Example 117 15 The operation is carried out as described in Example 110 starting with 0.200 g of 1- { (R*) - [4 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl)methylene) ] azetidine, form B isomer, 5.0 cm 3 of dichloromethane and 0.120 of 20 3,3-dimethylpiperidine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.0 cm, height 10 cm), eluting with 50 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), 25 collecting 5 cm 3 fractions immediately after using this eluent mixture. Fractions 4 to 11 are combined and then concentrated to dryness under reduced pressure (2.7 266 267 kPa) . 0.120 g of 1- { (R*) - (4-chlorophenyl) [4- (3, 3 dimethylpiperidinylmethyl)phenyl]methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl) methylenel azetidine, form B isomer, is obtained in the form of a white 5 powder. Example 118 The operation is carried out as described in 10 Example 110, by stirring for 72 hours at 20 0 C, starting with 0 . 200 g of 1-{ (R*) - [4 - (chloromethyl) phenyl] (4 chlorophenyl)methyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl)methylene)]azetidine, form B isomer, 5.0 cm 3 of dichloromethane and 0.080 of imidazole. The 15 reaction mixture is directly chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.0 cm, height 10 cm) , eluting with 100 cm 3 of dichloromethane without fractionating, and then with a dichloromethane and methanol mixture (98/2 and then 20 96/4 by volume) , collecting 5 cm 3 fractions. Fractions 5 to 12 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.35 g of 1-{(R*) -(4 chlorophenyl) [4- (imidazol-1-ylmethyl)phenyl]methyl}-3 [(3, 5-difluorophenyl) (methylsulfonyl)methylenel } 25 azetidine, form B isomer, is obtained in the form of a white powder. [a]2 0 D = -6.7" (c = 0.5% dichloromethane) 267 268 Example 119 2.47 g of potassium tert-butoxide are added to a suspension of 6.12 g of 1-[bis(4-chlorophenyl) 5 methyllazetidin-3-one and 5.15 g of methyl 5 (methylsulfonylmethyl) thiophene-2-carboxylate in 200 cm 3 of tetrahydrofuran, under an argon atomosphere, cooled to -700C. The mixture is stirred for 1 hour 30 min at a temperature close to -70 0 C, and then 1.7 cm 3 of 10 methanesulfonyl chloride in solution in 8 cm 3 of ethyl ether is added. After stirring for 1 hour at a temperature close to -700C, the mixture is allowed to return to room temperature and then 80 cm 3 of distilled water are added. The mixture is concentrated in a 15 rotary evaporator to one third of its initial volume, and is then extracted with 500 cm 3 of dichloromethane. The organic phase is washed with three times 80 cm 3 of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure 20 (2.7 kPa) . The residue obtained is chromatographed on a silica gel column (particle size 0.02-0.04 mm, diameter 7.5 cm, height 35 cm), eluting at a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30 by volume) and collecting 40 cm 3 fractions. 25 Fractions 19 to 29 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 1.6 g of 1- [bis (4-chlorophenyl)methyl] -3- [(methylsulfonyl) (2 268 269 methoxycarbonylthien-5-yl)methylene]azetidine are obtained in the form of a cream-colored foam ['H NMR spectrum (400 MHz, CDC1, 6 in ppm): 2.91 (s, 3H), 3.88 (s, 3H), 4.08 (mt, 2H), 4.37 (mt, 2H), 4.53 (s, 1H), 5 from 7.25 to 7.45 (mt, 9H), 7.71 (d, J=3.5Hz, 1H)]. Fractions 34 to 48 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 2.6 g of (RS)-1-[bis(4-chlorophenyl)methyll 3-hydroxy-3-[(methylsulfonyl) (2-methoxycarbonylthien-5 10 yl)methyllazetidine are obtained in the form of cream colored powder [1H NMR spectrum (400 MHz, (CD 3

)

2 SO-dG, S in ppm): 2.87 (s, 3H), 2.89 (d, J=8Hz, 1H), 2.96 (d, J=8Hz, 1H), 3.21 (d, J=8Hz, 1H), 3.76 (d, J=8Hz, 1H), 3.82 (s, 3H), 4.55 (s, 1H), 4.86 (s, 1H), 6.86 (s, 1H), 15 from 7.35 to 7.45 (mt, 9H), 7.73 (d, J=4Hz, 1H)]. Methyl 5-(methylsulfonylmethyl)thiophene-2 carboxylate may be prepared in the following manner: 6.94 g of sodium methanesulfinate are added, at room temperature, to a solution of 16 g of methyl 5 20 bromomethylthiophene-2-carboxylate in 150 cm 3 of tetrahydrofuran. The suspension is stirred for 2 hours 30 min under reflux, and then after addition of 50 cm 3 of ethanol is again stirred for 3 hours under reflux. The mixture is concentrated to dryness under reduced 25 pressure (2.7 kPa) and the residue obtained is supplemented with 150 cm 3 of distilled water and is then extracted with twice 300 cm 3 of ethyl acetate. The 269 270 organic phase is successively washed with 100 cm 3 of distilled water and twice 50 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulfate and concentrated to dryness under reduced 5 pressure (2.7 kPa) . 14 g of methyl 5 (methylsulfonylmethyl) thiophene-2-carboxylate are thus obtained in the form of a yellow solid melting around 133 0 C [H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, at a temperature of 373 K, 6 in ppm): 3.05 (s, 3H), 4.22 10 (mt, 2H), 4.40 (mt, 2H), 4.98 (broad s, 1H), 7.30 (d, J=3.5Hz, 1H), 7.39 (d, J=8Hz, 4H), 7.50 (d, J=8Hz, 4H), 7.66 (d, J=3.5Hz, 1H)]. Methyl 5-bromomethylthiophene-2-carboxylate may be prepared according to Curtin M.L., Davidsen S. 15 K., Heyman H.R., Garland R.B., Sheppard G.S., J. Med. Chem., 1998, 41 (1), 74-95. Example 120 20 47 pl of N,N'-diisopropylcarbodiimide, 3.66 mg of 4-dimethylaminopyridine and 60 pl of isobutylamine are added to a solution of 163.5 mg of 1 [bis(4-chlorophenyl)methyll-3-[(methylsulfonyl) (2 hydroxycarbonylthien-5-yl) methylenel azetidine 25 hydrochloride in 3 cm 3 of dichloromethane, at room temperature. The mixture is stirred for 18 hours at room temperature and then chromatographed on a silica 270 271 gel column (particle size 0.04-0.06 mm), eluting with a dichloromethane and ethyl acetate mixture (90/10 by volume). 60 mg of 1-[bis(4-chlorophenyl)methyl]-3-[2 isobutylaminocarbonylthien-5-yl) (methylsulfonyl) 5 methylene]azetidine are thus obtained in the form of a colorless lacquer ['H NMR spectrum (400 MHz, CDCl 3 , 6 in ppm): 0.97 (d, J=7Hz, 6H), 1.88 (mt, 1H), 2.90 (s, 3H), 3.25 (t, J=7Hz, 2H), 4.08 (mt, 2H), 4.36 (mt, 2H), 4.52 (s, 1H), 4.56 (broad t, J=7Hz, 1H), from 7.20 to 7.40 10 (mt, 10H)] . 1- [bis (4-chlorophenyl)methyl] -3 [(methylsulfonyl) (2-hydroxycarbonylthien-5 yl)methylenelazetidine hydrochloride may be prepared in the following manner: 250 cm 3 of concentrated 15 hydrochloric acid are added to a solution of 14 g of 1 [bis (4-chlorophenyl)methyl] -3- [(methylsulfonyl) (2 methoxycarbonylthien-5-yl)methylene]azetidine in 250 cm 3 of acetic acid, at room temperature. The mixture is stirred for 38 hours at a temperature of 500C and is 20 then concentrated to dryness under reduced pressure (2.7 kPa). Three times, the residue is supplemented with 250 cm 3 of toluene and concentrated to dryness under reduced pressure (2.7 kPa) . After trituration of the residue in 400 cm' of ethyl ether, 14.2 g of 1 25 [bis (4-chlorophenyl)methyl] -3- [(methylsulfonyl) (2 hydroxycarbonylthien-5-yl) methylenel azetidine hydrochloride are obtained in the form of a beige 271 272 powder. Example 121 5 0.37 g of potassium tert-butoxide is added to a solution of 0.92 g of 1-[bis(4-chlorophenyl)methyll azetidin-3-one and 0.75 g of [(3-methoxycarbonyl phenyl)methyl]methylsulfone in 30 cm 3 of tetrahydrofuran, under an argon atmosphere, cooled to 10 -70 0 C, and the mixture is stirred for 2 hours at -700C. 10 cm 3 of a 0.1 N solution of hydrochloric acid are then added and the mixture is allowed to return to room temperature. After addition of 50 cm 3 of ethyl acetate, the reaction mixture is separated after settling out, 15 dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 pKa) . The residue is chromatographed on a silica gel column (particle size 0.20-0.06 mm, diameter 3 cm, height 50 cm) , eluting at a nitrogen pressure of 20 0.8 bar with a cyclohexane and ethyl acetate mixture (70/30 by volume) and collecting 120 cm 3 fractions. Fractions 11 to 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPA) . The residue is crystallized from 10 cm 3 of isopropyl ether 25 and 30 cm 3 of pentane. 0.30 g of 1-[bis(4 chlorophenyl)methyl] -3- [(3 methoxycarbonylphenyl) (methylsulfonyl) methyl 272 273 (RS)]azetidin-3-ol is thus obtained in the form of a white solid ['H NMR spectrum (400 MHz, CDCl 3 , 6 in ppm) 2.73 (s, 3H), 3.05 (AB, J=9Hz, 2H), 3.27 (d, J=9Hz, 1H), 3.63 (s, 1H), 3.79 (d, J=9Hz, 1H), 3.95 (s, 3H), 5 4.32 (s, 1H), 4.59 (s, 1H), from 7.15 to 7.35 (mt, 8H), 7.51 (t, J=8Hz, 1H), 7.94 (broad d, J=8Hz, 1H), 8.10 (broad d, J=8Hz, 1H), 8.32 (broad s, 1H))]. Example 122 10 By carrying out the operation according to the procedure of Example 1, starting with 0.66 g of methyl(pyridin-4-ylmethyl)sulfone and 1.18 g of 1-[bis(4-chlorophenyl)methyllazetidin-3-one, 0.20 g of 15 a white solid is obtained after purification on a silica gel column (particle size 0.20-0.06 mm, diameter 3 cm, height 50 cm), at a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30 by volume) as eluent and collecting 120 cm 3 fractions. The 20 solid is taken up in 20 cm 3 of diisopropyl ether. After filtration, draining and drying, 0.16 g of 1-[bis(4 chlorophenyl)methyll-3-[(methylsulfonyl) (pyridin-4 yl)methyl-(RS)]-azetidin-3-ol is obtained [1H NMR spectrum (400 MHz, CDC1 3 , 8 in ppm): 2.76 (s, 3H), 3.03 25 (AB, J=9Hz, 2H), 3.27 (d, J=9Hz, 1H), 3.53 (s, 1H), 3.83 (d, J=9Hz, 1H), 4.32 (s, 1H), 4.51 (s, 1H), from 7.20 to 7.30 (mt, 8H), 7.63 (d, J=6Hz, 2H), 8.68 (d, 273 274 J=6Hz, 2H)]. Methyl (pyridin-4-ylmethyl) sulfone may be prepared according to the reference JP43002711. 5 Example 123 By carrying out the operation according to the procedure of Example 1, starting with 0.47 g of 10 methyl(pyridin-3-ylmethyl)sulf one and 0.83 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one, 0.50 g of a white solid is obtained after purification on a silica gel column (particle size 0.20-0.06 mm, diameter 3 cm, height 50 cm) , at a nitrogen pressure of 0.5 bar 15 with a cyclohexane and ethyl acetate mixture (70/30 by volume) as eluent and collecting 120 cm 3 fractions. The solid is taken up in 30 cm 3 of diisopropyl ether. After filtration, draining and drying, 0.40 g of 1-[bis(4 chlorophenyl)methyl] -3- [(methylsulfonyl) (pyridin-3 20 yl)methyl-(RS)]-azetidin-3-ol is obtained [H NMR spectrum (300 MHz, CDCl 3 , 5 in ppm) : 2.77 (s, 3H) , 3.03 (AB, J=9Hz, 2H), 3.28 (d, J=9Hz, 1H), 3.66 (s, 1H), 3.83 (d, J=9Hz, 1H), 4.33 (s, 1H), 4.55 (s, 1H), from 7.20 to 7.30 (mt, 8H), 7.37 (dd, J=8 and 5Hz, 1H), 8.16 25 (dt, J=8 and 2Hz, 1H), 8.68 (dd, J=5 and 1.5Hz, 1H), 8.83 (d, J=2Hz, 1H) ] . Methyl (pyridin-3-ylmethyl) sulf one may be 274 275 prepared according to the reference JP43002711. Example 124 0.0388 cm 3 of N-(3-aminopropyl)morpholine is 5 added, at the same temperature, to a suspension of 150 mg of 3-({l- [bis(4-chlorophenyl)methyllazetidin-3 ylidene}methanesulfonylmethyl) benzoic acid activated on TFP resin (165 pM) in 3 cm 3 of dichloromethane, pre stirred for 90 minutes at a temperature close to 20 0 C. 10 The suspension is stirred at a temperature close to 20 0 C for 22 hours and then filtered on sintered glass. The solid residue is rewashed with twice 1.5 cm 3 of dichloromethane. The filtrates are combined and concentrated to dryness under reduced pressure 15 (2.7 kPa) at a temperature close to 40 0 C. 60 mg of 3- ( {1- [bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl) -N- (3-morpholin-4 ylpropyl)benzamide are thus obtained in the form of a pale yellow foam. 20 3-({1- [bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl) -N- (3-morpholin-4 ylpropyl)benzamide may also be prepared in the following manner: 0.083 cm 3 of N-(3-aminopropyl) morpholine, 110 mg of 1-(3-dimethylaminopropyl)-3 25 ethylcarbodiimide and 5 mg of 4-dimethylaminopyridine are successively added to a solution of 300 mg of 3 ({1- [bis (4-chlorophenyl)methyl] azetidin-3 275 276 ylidene}methanesulfonylmethyl)benzoic acid in 10 cm 3 of anhydrous dichloromethane (over calcium chloride) and 5 cm 3 of dimethylformamide, under an inert atmosphere of nitrogen, at a temperature close to 20'C. The solution 5 obtained is stirred at a temperature close to 200C for about 22 hours and then concentrated to dryness under reduced pressure (0.27 kPa) at a temperature close to 400C. The solid residue is taken up in 25 cm 3 of dichloromethane and washed with twice 20 cm 3 of a 10 saturated aqueous sodium bicarbonate solution. After separation after settling out, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 400C. 400 mg of a yellow oil are 15 thus obtained, which oil is purified by chromatography under nitrogen pressure (0.8 bar) on 60 cm 3 of silica (0.040-0.063 mm) contained in a column 2.2 cm in diameter, eluting with a methanol/dichloromethane mixture (2-98 by volume) . The fractions containing only 20 the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 400C for 2 hours. 130 mg of 3- ((1- [bis (4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl) -N- (3 morpholin-4-ylpropyl)benzamide are thus obtained in the 25 form of a white crystalline powder ['H NMR spectrum (300 MHz, (CD 3

)

2 SO-d6, 6 in ppm): 1.68 (mt, 2H) , from 2.25 to 2.40 (mt, 6H), 2.97 (s, 3H), from 3.20 to 3.35 (mt, 276 277 2H), 3.57 (t, J=4..SHz, 4H), 3.81 (mt, 2H), 4.22 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5Hz, 4H), 7.46 (d, J=8.5Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 1H), 8.53 (t, J=5.5Hz, 5 1H)]. Example 125 The operation is carried out under the 10 conditions described in Example 124 starting with 150 mg of activated 3- ({1- [bis(4-chlorophenyl)methyll azetidin-3 -ylidene}methanesulfonylmethyl) benzoic acid on TFP resin (165 pM) and 0.033 cm 3 of N,N-dimethyl-1,3 propanediamine. 52 mg of 3- ({1- [bis (4-chlorophenyl) 15 methyl azetidin-3-ylidene}methanesulfonylmethyl) -N- (3 dimethylaminopropyl)benzamide are thus obtained in the form of a white powder ['H NMR spectrum (400 MHz,

(CD

3

)

2 SO-d6, 5 in ppm) : 1.65 (mt, 2H), 2.18 (s, 6H), from 2.20 to 2.35 (mt, 2H), 2.98 (s, 3H), from 3.25 to 20 3.45 (mt, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.80 (s, 1H), 7.36 (d, J=8.5Hz, 4H), 7.46 (d, J=8.5Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 1H), 8.57 (t, J=5.5Hz, 1H)]. 25 Example 126 The operation is carried out under the 277 278 conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4 chlorophenyl) methyl] azetidin-3-ylidene}methane sulfonylmethyl)benzoic acid on TFP resin (165 pM) and 5 0.0333 cm 3 of 1-(aminoethyl)pyrrolidine. 39 mg of 3-(({1 [bis(4-chlorophenyl)methyl]azetidin-3-ylidene} methanesulfonylmethyl) -N- (2-pyrrolidin-1 ylethyl)benzamide are thus obtained in the form of a pale yelow powder [-H NMR spectrum (300 MHz, (CD 3

)

2 SO-d6 10 with addition of a few drops of CD 3 COOD-d4, 6 in ppm) from 1.80 to 2.00 (mt, 4H), 2.97 (s, 3H), 3.20 (mt, 6H), 3.57 (t, J=6.5Hz, 2H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.77 (s, 1H), 7.35 (d, J=8.5Hz, 4H), 7.45 (d, J=8.5Hz, 4H), from 7.50 to 7.65 (mt, 2H), 7.87 (broad 15 s, 1H), 7.90 (broad d, J=7.5Hz, 1H)]. Example 127 The operation is carried out under the 20 conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 pM) and 0.0333 cm 3 of 1 (dimethylamino)-2-propylamine. 49 mg of 3-({1- [bis(4 25 chlorophenyl)methyl]azetidin-3-ylidene}methane sulfonylmethyl) -N- (2-dimethylamino-1-methylethyl) benzamide are thus obtained in the form of a white 278 279 powder [1H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 6 in ppm): 1.13 (d, J=6.5Hz, 3H), from 2.10 to 2.25 (mt, 1H), 2.15 (s, 6H), 2.38 (dd, J=13 and 8Hz, 1H), 2.98 (s, 3H), 3.80 (mt, 2H), 4.14 (mt, 1H)), 4.23 (mt, 2H), 4.79 (s, 5 1H), 7.36 (d, J=8Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.46 (d, J=8Hz, 4H), 7.83 (broad s, IH)), 7.87 (broad d, J=8Hz, 1H), 8.16 (broad d, J=8Hz, 1H)I. Example 128 10 The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({l-[bis(4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid 15 on TFP resin (165 PM) and 0.026 cm 3 of piperidine. 56 mg of 3-({1-[bis(4-chlorophenyl)methyllazetidin-3 ylidene}methanesulfonylmethyl) -N-piperidin-1 ylbenzamide are thus obtained in the form of a white powder ['H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 6 in ppm) 20 from 1.45 to 1.70 (mt, 6H), from 2.90 to 3.05 (mt, 2H), 2.98 (s, 3H), 3.19 (unresolved complex, 1H), 3.57 (unresolved complex, 1H), 3.85 (mt, 2H), 4.23 (mt, 2H), 4.80 (s, 1H), from 7.30 to 7.55 (mt, 12H)]. 25 Example 129 The operation is carried out under the 279 280 conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl) benzoic acid on TFP resin (165 pM) and 0.0265 cm 3 of isobutylamine. 5 46 mg of 3-({1- [bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl) -N-isobutylbenzamide are thus obtained in the form of a white powder [1H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 3 in ppm) : 0.89 (d, J=7Hz, 6H), 1.85 (mt, 1H), 2.98 (s, 3H), 3.09 (t, 10 J=6.5Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5Hz, 4H), 7.46 (d, J=8.5Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.88 (broad d, J=8Hz, 1H), 8.51 (t, J=6Hz, 1H)]. 15 Example 130 The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-bis(4-chlorophenyl)methyl] 20 azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 pM) and 0.0316 cm 3 of N-(3 aminopropyl)imidazole. 54 mg of 3-({1-[bis(4 chlorophenyl)methyl]azetidin-3-ylidene}methane sulfonylmethyl) -N- (3-imidazol-1-ylpropyl)benzamide are 25 thus obtained in the form of a yellow foam ['H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 6 in ppm): 1.97 (mt, 2H), 2.98 (s, 3H), 3.25 (mt, 2H), 3.81 (mt, 2H), 4.02 280 281 (t, J=7Hz, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), from 6.85 to 6.95 (mt, 2H), 7.36 (d, J = 8.5Hz, 4H), 7.46 (d, J=8.5Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.88 (broad d, J=8Hz, 1H), 8.56 (t, J=5.5Hz, 5 1H)]. Example 131 The operation is carried out under the 10 conditions described in Example 124 starting with 150 mg of activated 3-((1-[bis(4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 pM) and 0.030 cm 3 of N,N (dimethyl)ethylenediamine. 53 mg of 3- ({1- [bis (4 15 chlorophenyl)methyl]azetidin-3-ylidene}methane sulfonylmethyl) -N- (2-dimethylaminoethyl)benzamide are thus obtained in the form of an ochre-colored foam ['H NMR spectrum (400 MHz, (CD3) 2 SO-d6, 5 in ppm) : 2.18 (2s, 6H), from 2.35 to 2.45 (mt, 2H), 2.98 (s, 3H), from 20 3.25 to 3.50 (mt, 2H), 3.81 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8Hz, 4H), 7.46 (d, J=8Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 1H), 8.43 (t, J=6.5Hz, 1H)]. 25 Example 132 The operation is carried out under the 281 282 conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 pM) and 0.0141 cm 3 of methylhydrazine. 5 42 mg of 3-((1-[bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl) benzoic acid N'methylhydrazide are thus obtained in the form of a pale yellow foam ['H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 6 in ppm): 2.96 (s, 3H), 3.18 (broad s, 3H), 3.83 (mt, 10 2H), 4.22 (mt, 2H), 4.80 (broad s, 2H), from 7.35 to 7.65 (mt, 12H)]. Example 133 15 The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3- ({1- [bis (4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 pM) and 0.0345 cm 3 of N-(2 20 aminoethyl)morpholine. 62 mg of 3-({1-[bis(4 chlorophenyl) methyl azetidin-3-ylidene}methane sulfonylmethyl)-N-(2-morpholin-4-ylethyl)benzamide are thus obtained in the form of an ochre-colored foam ['H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 6 in ppm) : from 2.30 25 to 2.45 (mt, 4H), 2.46 (t, J=7.5Hz, 2H), 2.98 (s, 3H), 3.38 (mt, 2H), from 3.50 to 3.65 (mt, 4H), 3.82 (mt, 2H), 4.24 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5Hz, 282 283 4H), 7.46 (d, J=8.5Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.85 (dd, J=8 and 2Hz, 1H), 8.45 (t, J=6.5Hz, 1H)]. 5 Example 134 The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1- [bis(4-chlorophenyl)methyl] 10 azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 pM) and 0.0396 cm 3 of 2-(aminomethyl) N-ethylpyrrolidine. 58 mg of 3-({1-[bis(4 chlorophenyl) methyl] azetidin-3-ylidene}methane sulfonylmethyl) -N- (1-ethylpyrrolidin-2 15 ylmethyl)benzamide are thus obtained in the form of an ochre-colored foam. 3- ({l- [bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl) -N- (1-ethylpyrrolidin-2 ylmethyl)benzamide may also be prepared under the 20 conditions described in Example 126 starting with 700 mg of activated 3-({1- [bis(4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl) benzoic acid on TFP resin (770 pM), 0.324 cm 3 of triethylamine and 0. 25 cm 3 of 2- (aminomethyl) -N-ethylpyrrolidine. 370 mg 25 of a solid are thus obtained, which solid is purified by chromatography under nitrogen pressure (0.7 bar) on 100 cm 3 of silica (0.040-0.063 mm) contained in a column 283 284 2.5 cm in diameter, eluting with a methanol dichloromethane mixture (15-85 by volume). The fractions containing only the desired product are combined and concentrated to dryness under reduced 5 pressure (0.27 kPa) at 400C for 2 hours. 160 mg of 3- ((1- [bis(4-chlorophenyl)methyl]azetidin-3-ylidene} methanesulfonylmethyl) -N- (1-ethylpyrrolidin-2 ylmethyl)benzamide are thus obtained in the form of a pale yellow powder [H NMR spectrum (400 MHz, (CD 3

)

2

SO

10 d6, 6 in ppm): 1.04 (t, J=7Hz, 3H) , from 1.50 to 1.70 (mt, 3H), 1.78 (mt, 1H), 2.14 (mt, 1H), 2.28 (mt, 1H), 2.59 (mt, 1H), 2.83 (mt, 1H), 2.98 (s, 3H), from 3.00 to 3.15 (mt, 2H), from 3.30 to 3.45 (mt, 1H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5Hz, 15 4H), 7.46 (d, J=8.5Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.86 (broad s, 1H), 7.85 (broad d, J=8Hz, 1H), 8.41 (t, J=6Hz, 1H)]. 20 Example 135 The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl] 25 azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 pM) and 0.023 cm 3 of neopentylamine. 69 mg of 3-({1-[bis(4-chlorophenyl)methyllazetidin-3 284 285 ylidene}methanesulfonylmethyl) -N- (2,2 dimethylpropyl)benzamide are thus obtained in the form of a pale yellow powder [ H NMR spectrum (400 MHz, (CD,),SO-d6, 6 in ppm): 0.90 (s, 9H) , 2.98 (s, 3H), 3.11 5 (d, J=6.5Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8Hz, 4H), 7.46 (d, J=8Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 1H), 8.37 (t, J=6.5Hz, 1H)]. 10 Example 136 The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-((1-[bis(4-chlorophenyl)methyl] 15 azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 pM) and 0.025 cm 3 of aminomethylcyclohexane. 44 mg of 3-({1-[bis(4 chlorophenyl) methyl] azetidin-3-ylidene}methane sulfonylmethyl) -N-cyclohexylmethylbenzamide are thus 20 obtained in the form of a pale yellow powder whose characteristics are the following (H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 5 in ppm): 0.92 (mt, 2H), 1.17 (mt, 4H), from 1.45 to 1.80 (mt, 5H), 2.97 (s, 3H), 3.10 (d, J=6Hz, 2H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.79 25 (s, 1H) , 7.36 (d, J=8Hz, 4H) , 7.46 (d, J=8Hz, 4H) , from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 1H), 8.47 (t, J=6Hz, 1H)]. 285 286 Example 137 The operation is carried out under the 5 conditions described in Example 124 starting with 110 mg of activated 3-({1l- [bis(4-chlorophenyl)methyll azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 pM) , 0.026 cm 3 of triethylamine and 21 mg of aminomethylcyclopropane hydrochloride. 68 mg of 10 3- ({1- [bis(4-chlorophenyl)methyl] azetidin-3-ylidene} methanesulfonylmethyl)-N-cyclopropylmethylbenzamide are thus obtained in the form of a yellow foam [1H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 6 in ppm) : 0.24 (mt, 2H), 0.44 (mt, 2H), 1.03 (mt, 1H), 2.98 (s, 3H), 3.15 15 (t, J=6Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5Hz, 4H), 7.46 (d, J=8.5Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.86 (broad s, 1H), 7.89 (broad d, J=8Hz, 1H), 8.64 (t, J=6Hz, 1H)]. 20 Example 138 The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyll 25 azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 pM) and 0.023 cm 3 of 2 methylbutylamine. 49 mg of 3- ({1- [bis(4-chlorophenyl) 286 287 methyllazetidin-3-ylidene}methanesulfonylmethyl)-N-(2 methylbutyl)benzamide are thus obtained ['H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 6 in ppm) : from 0.80 to 0.95 (mt, 6H), from 1.05 to 120 (mt, 1H), 1.41 (mt, 1H), 1.64 5 (mt, 1H), 2.98 (s, 3H), 3.06 (mt, 1H), 3.19 (mt, 1H), 3.81 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8Hz, 4H), 7.46 (d, J=8Hz, 4H), from 7.35 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.87 (broad d, J=8Hz, 1H), 8.49 (t, J=5.5Hz, 1H)]. 10 Example 139 The operation is carried out under the conditions described in Example 124 starting with 15 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyll azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 pM) and 0.028 cm 3 of 2-methyl phenethylamine. 42 mg of 3-((1-[bis(4-chlorophenyl) methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2 20 phenylpropyl)benzamide are thus obtained in the form of a yellow paste [*H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 6 in ppm): 1.24 (d, J=7Hz, 3H), 2.97 (s, 3H), 3.07 (mt, 1H), from 3.20 to 3.50 (mt, 2H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.80 (s, 1H), from 7.10 to 7.40 (mt, 5H), 25 7.38 (d, J=8Hz, 4H), 7.47 (d, J=8Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.77 (broad s, 1H), 7.79 (broad d, J=8Hz, 1H), 8.55 (t, J=6Hz, 1H)]. 287 288 Example 140 The operation is carried out under the 5 conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 pM) and 0.020 cm 3 of tetrahydrofurfurylmethylamine. 42 mg of 3-({1-[bis(4 10 chlorophenyl)methyl]azetidin-3-ylidene}methane sulfonylmethyl) -N- (tetrahydrofuran-2-ylmethyl) benzamide are thus obtained in the form of a yellow paste ['H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 5 in ppm) : 1.58 (mt, 1H), from 1.75 to 2.00 (mt, 3H), 2.98 (s, 3H), from* 15 3.20 to 3.40 (mt, 2H), 3.63 (mt, 1H), 3.77 (mt, 1H), 3.82 (mt, 2H), 3.98 (mt, 1H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8Hz, 4H), 7.46 (d, J=8Hz, 4H), from 7.50 to 7.60 (mt, 2H)), 7.84 (broad s, 1H), 7.88 (broad d, J=8Hz, 1H), 8.60 (t, J=6Hz, 1H)]. 20 Example 141 The operation is carried out under the conditions described in Example 124 starting with 25 110 mg of activated 3-((1-[bis(4-chlorophenyl)methyll azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 pM) and 39 mg of 2,2 288 289 diphenylethylamine. 39 mg of 3-((l-[bis(4 chlorophenyl)methyllazetidin-3-ylidene}methane sulfonylmethyl) -N- (2,2-diphenylethyl)benzamide are thus obtained in the form of a yellow paste [1H NMR spectrum 5 (400 MHz, (CD 3

)

2 SO-d6, 6 in ppm): 2.95 (s, 3H), 3.77 (mt, 2H), 3.90 (dd, J=8 and 6.5Hz, 2H), 4.22 (mt, 2H), 4.42 (t, J=8Hz, 1H), 4.79 (s, 1H), from 7.10 to 7.40 (mt, 10H), 7.38 (d, J=8.5Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.48 (d, J=8.5Hz, 4H), 7.70 (mt, 2H), 8.56 10 (t, J=6.5Hz, 1H)]. Example 142 The operation is carried out under the 15 conditions described in Example 124 starting with 110 mg of activated 3- ({l- [bis (4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 pM) and 19 mg of 2-ethylbutylamine. 47 mg of 3-({1-[bis(4-chlorophenyl)methyllazetidin-3 20 ylidene}methanesulfonylmethyl) -N- (2-ethylbutyl) benzamide are thus obtained in the form of a pale yellow powder ['H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, a in ppm): 0.86 (t, J=7Hz, 6H), from 1.20 to 1.40 (mt, 4H), 1.50 (mt, 1H), 2.98 (s, 3H), 3.19 (t, J=6Hz, 2H), 25 3.82 (mt, 2H), 4.24 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5Hz, 4H), 7.46 (d, J=8.5Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 289 290 1H), 8.42 (t, J=6Hz, 1H)]. Example 143 5 The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-((l-[bis(4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 pM), 0.026 cm 3 of triethylamine and 10 39 mg of 4-aminomethylcyclohexanecarboxylic acid methyl ester hydrochloride. 47 mg of 4-([3-({1-[bis-(4 chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonyl methyl) benzoylamino] methyl}cyclohexanecarboxylic acid methyl ester are thus obtained in the form of a pale 15 yellow paste ['H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 5 in ppm): from 0.90 to 1.05 (mt, 2H), from 1.20 to 1.40 (mt, 2H), 1.52 (mt, 1H), from 1.70 to 2.00 (mt, 4H), 2.27 (mt, 1H), 2.98 (s, 3H), 3.12 (t, J=6.5Hz, 2H), 3.60 (s, 3H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 20 1H), 7.36 (d, J=8Hz, 4H), 7.46 (d, J=8Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.87 (broad d, J=8Hz, 1H), 8.50 (t, J=6Hz, 1H)]. Activated 3- ({1- [bis (4-chlorophenyl)methyl azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid 25 on TFP resin may be prepared under the following conditions: 1.18 g of 3-({1-[bis(4 chlorophenyl) methyl] azetidin-3-ylidene}methane 290 291 sulfonylmethyl)benzoic acid is added, at the same temperature, to a suspension of 1.07 g of TFP resin (free phenol function, 1.1 mmol/g, that is to say 1.17 mM) in 15 cm 3 of anhydrous dimethylformamide, 5 prestirred for 10 minutes at a temperature close to 20 0 C. After stirring for 10 minutes at a temperature close to 20'C, 14 mg of 4-dimethylaminopyridine are added and then after stirring for 10 minutes at the same temperature, 0.185 cm 3 of 1,3-diisopropyl 10 carbodiimide. After stirring for 23 hours at a temperature close to 200C, the suspension is filtered and the resin is washed with 45 cm 3 of dimethylformamide, 45 cm 3 of tetrahydrofuran, 45 cm 3 of dichloromethane, and then dried under vacuum to 15 constant weight. 1.5 g of activated 3-({1-[bis(4 chlorophenyl)methyllazetidin-3-ylidene}methane sulfonylmethyl)benzoic acid on TFP resin are thus obtained in the form of a pale yellow resin. The TFP resin (structure below) may be 20 prepared in the following manner: F F OH HO O F 492 mg of diisopropylcarbodiimide, 819.3 mg of 2,3,5,6 tetrafluoro-4-hydroxybenzoic acid and 50 mg of 4 dimethylaminopyridine are successively added to a 25 suspension of 2 g of commercially available aminomethyl 291 292 polystyrene resin (0.39 mmol/g; 0.78 mmol) in 15 cm 3 of dimethylformamide, prestirred for 5 minutes at a temperature close to 20'C. After stirring for about 20 hours at a temperature close to 200C, the suspension is 5 filtered and the resin is rinsed with three times 20 cm 3 of dimethylformamide, three times 20 cm 3 of tetrahydrofuran and three times 20 cm 3 of dichloromethane. The resin obtained is dried under reduced pressure at a temperature close to 400C. The 10 resin obtained is then stirred, at a temperature close to 200C, for about 20 hours, in suspension in a piperidine/dimethylformamide mixture (10/90 by volume). The suspension is filtered and the resin is rinsed with three times 20 cm 3 of dimethylformamide, three times 15 20 cm 3 of tetrahydrofuran and three times 20 cm 3 of dichloromethane. The resin obtained is dried under reduced pressure at a temperature close to 400C and is used as it is. 20 Example 144 A solution of 76 mg of (2-{4-[3-({1-[bis-(4 chlorophenyl) methyl] azetidin-3-ylidene}methane sulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl) 25 carbamic acid tert-butyl ester in 2.5 cm 3 of formic acid is stirred for 1 hour at a temperature close to 450C. The reaction medium is concentrated to dryness under 292 293 reduced pressure (5 kPa) at a temperature close to 300C, taken up in 10 cm 3 of ethyl acetate and alkalinized with 10 cm 3 of a saturated aqueous sodium bicarbonate solution. After separating after settling 5 out, the organic phase is washed with 10 cm 3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 400C. 51 mg of 2-amino-1-{4-[3 ({l- [bis- (4-chlorophenyl)methyllazetidin-3-ylidene} 10 methanesulfonylmethyl)phenyl]piperazin-1-yl}ethanone are thus obtained in the form of a beige lacquer ['H NMR spectrum (300 MHz, CDCl 3 , 5 in ppm) : from 1.95 to 2.25 (broad unresolved complex, 2H), 2.77 (s, 3H), from 3.10 to 3.30 (mt, 4H), from 3.50 to 3.60 (mt, 2H), 3.56 15 (broad s, 2H), from 3.75 to 3.90 (mt, 4H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (broad d, J=8Hz, 1H), 6.91 (dd, J=8 and 2Hz, 1H), 7.01 (mt, 1H), from 7.20 to 7.40 (mt, 9H)]. 20 Example 145 1.02 g of supported EDCI (5 mM), 44 mg of N-Boc-glycine and then 10 cm 3 of dichloromethane are successively added, at a temperature close to 20'C, to 25 108.5 mg of 1-[3-({1-[bis-(4-chlorophenyl) methyl] azetidin-3-ylidene}methanesulfonylmethyl) phenylipiperazine. After stirring for 20 hours at a 293 294 temperature close to 20 0 C, the reaction mixture is filtered on sintered glass. The resin is rinsed with three times 5 cm 3 of dichloromethane. The combined filtrates are washed with 20 cm 3 of water, dried over 5 magnesium sulfate, filtered on sintered glass and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 400C. 143 mg of (2-{4-'[3-({1 [bis- (4-chlorophenyl)methyl] azetidin-3-ylidene}methane sulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl) 10 carbamic acid tert-butyl ester are thus obtained in the form of a cream-colored lacquer [1H NMR spectrum (400 MHz, (CD 3

)

2 SO-d6, 6 in ppm): 1.40 (s, 9H), 2.93 (s, 3H), from 3.05 to 3.20 (mt, 4H), 3.57 (mt, 4H), 3.80 (mt, 2H), 3.84 (d, J=6Hz, 2H), 4.19 (mt, 2H), 4.78 (s, 15 1H), 6.79 (t, J=6Hz, 1H), 6.82 (d, J=8Hz, 1H), 6.93 (broad s, 1H), 6.99 (dd, J=8 and 2.5Hz, 1H), 7.27 (t, J=8Hz, 1H), 7.36 (d, J=8Hz, 4H), 7.46 (d, J=8Hz, 4H)]. The supported EDCI reagent is commercially available and may also be prepared according to the 20 following reference: M. Desai, L. Stramiello, Tetrahedron Letters, 34, 48, 7685-7688 (1993). Example 146 25 A solution of 81 mg of (2-(4-[3-({1-[bis-(4 chlorophenyl)methyl]azetidin-3-ylidene}methane sulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N 294 295 methylcarbamic acid tert-butyl ester in 2.5 cm 3 of formic acid is stirred for 1 hour at a temperature close to 45 0 C. The reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature 5 close to 30 0 C, taken up in 10 cm 3 of ethyl acetate and alkalinized with 10 cm 3 of a saturated aqueous sodium bicarbonate solution. After separating after settling out, the organic phase is washed with 10 cm 3 of water, dried over magnesium sulfate, filtered and concentrated 10 to dryness under reduced pressure (1 kPa) at a temperature close to 40 0 C. 58 mg of 1-{4-[3-({1-[bis (4-chlorophenyl)methyll azetidin-3-ylidene}methane sulfonylmethyl) phenyl] piperazin-1-yl} -2 methylaminoethanone are thus obtained in the form of a 15 beige lacquer [1H NMR spectrum (300 MHz, CDC 3 ), 6 in ppm): from 1.95 to 2.15 (broad unresolved complex, 1H), 2.51 (broad s, 3H), 2.77 (s, 3H), from 3.10 to 3.30 (mt, 4H), 3.49 (broad s, 2H), 3.58 (mt, 2H), from 3.75 to 3.90 (mt, 4H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.83 20 (broad d, J=8Hz, 1H), 6.90 (dd, J=8 and 2Hz, 1H), 7.00 (mt, 1H), from 7.20 to 7.4-0 (mt, 9H)]. Example 147 25 1.02 g of supported EDCI (5 mM), 47.3 mg of N-Boc-sarcosine and then 10 cm 3 of dichloromethane are successively added, at a temperature close to 20 0 C, to 295 296 108.5 mg of 1-[3-({1-[bis-(4-chlorophenyl) methyll azetidin-3-ylidene}methanesulfonylmethyl) phenylipiperazine. After stirring for 20 hours at a temperature close to 20 0 C, the reaction mixture is 5 filtered on sintered glass. The resin is rinsed with three times 5 cm 3 of dichloromethane. The combined filtrates are washed with 20 cm 3 of water, dried over magnesium sulfate, filtered on sintered glass and concentrated to dryness under reduced pressure (1 kPa) 10 at a temperature close to 40 0 C. 143 mg of (2-{4-[3-({1 [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene}methane sulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N methylcarbamic acid tert-butyl ester are thus obtained in the form of a cream-colored lacquer ['H NMR spectrum 15 (400 MHz, (CD 3

)

2 SO-d6, 6 in ppm) . A mixture of rotamers is observed at room temperature; 1.31 and 1.41 (2s, 9H in total), 2.78 and 2.81 (2s, 3H in total), 2.93 (2s, 3H), from 3.10 to 3.25 (unresolved complex, 4H), from 3.45 to 3.65 (mt, 4H), 3.80 (mt, 2H), 4.06 and 4.09 20 (2s, 2H in total), 4.19 (mt, 2H), 4.78 (s, 1H), 6.83 (broad d, J=8Hz, 1H), 6.93 (broad s, 1H), 7.00 (dd, J=8 and 2.5Hz, 1H), 7.27 (t, J=8Hz, 1H), 7.36 (d, J=8Hz, 4H) , 7.46 (d, J=8Hz, 4H)]. 25 Example 148 2 cm 3 of dichloromethane and then 11 mg of 296 297 methyl isothiocyanate are successively added, at a temperature close to 200C, to 54.25 mg of 1-[3-({1 [bis- (4-chlorophenyl)methyl] azetidin-3-ylidene}methane sulfonylmethyl)phenylpiperazine. After stirring for 6 5 hours at a temperature close to 200C, 0.05 cm 3 of water is added to the reaction mixture. After stirring for 15 minutes at the same temperature, the reaction medium is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a 10 temperature close to 400C. 61 mg of 4-[3-({1-[bis-(4 chlorophenyl)methyl]azetidin-3-ylidene}methane sulfonylmethyl) phenyll piperazine-1-carbothioic acid N methylamide are thus obtained in the form of a beige lacquer ['H NMR spectrum (400 MHz, CDC 3 ) , 5 in ppm) : 15 2.77 (s, 3H), 3.20 (d, J=5Hz, 3H), 3.32 (t, J=5.5Hz, 4H), 3.81 (mt, 2H), 4.00 (t, J=5.5Hz, 4H), 4.33 (mt, 2H), 4.49 (s, 1H), 5.63 (broad q, J=5Hz, 1H), 6.80 (d, J=8Hz, 1H), 6.85 (dd, J=8 and 2.5Hz, 1H), 6.94 (broad s, 1H), from 7.20 to 7.30 (mt, 5H), 7.32 (d, J=8Hz, 20 4H)]. Example 149 2 cm' of dichloromethane and then 11.5 mg of 25 methyl isocyanate are successively added, at a temperature close to 20 0 C, to 54.25 mg of 1-[3-({1 [bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methane 297 298 sulfonylmethyl)phenyljpiperazine. After stirring for 4 hours at a temperature close to 200C, 0.05 cm 3 of water is added to the mixture. After stirring for 15 minutes at the same temperature, the reaction medium is dried 5 over magnesium sulfate, filtered on paper and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 0 C. 66 mg of 4-[3-((l-[bis (4-chlorophenyl)methyllazetidin-3-ylidene}methane sulfonylmethyl)phenyl]piperazine-1-carboxylic acid N 10 methylamide are thus obtained in the form of a beige lacquer [1H NMR spectrum (400 MHz, CDCl 3 ) , 6 in ppm) 2.75 (s, 3H), 2.85 (d, J=SHz, 3H), 3.19 (broad t, J=5.5Hz, 4H), 3.52 (broad t, J=5.5Hz, 4H), 3.80 (mt, 2H), 4.33 (mt, 2H), 4.45 (broad q, J=5Hz, 1H), 4.49 (s, 15 1H), 6.81 (d, J=8Hz, 1H), 6.89 (dd, J=8 and 2.5Hz, lH), 6.98 (broad s, 1H), from 7.20 to 7.30 (mt, 5H), 7.32 (d, J=8Hz, 4H)]. Example 150 20 2 cm 3 of pyridine and then 10.4 mg of methyl chloroformate are successively added, at a temperature close to 20 0 C, to 54.25 mg of 1-[3-((1-[bis-(4 chlorophenyl)methyl]azetidin-3-ylidene}methane 25 sulfonylmethyl)phenyl]piperazine. After stirring for 6 hours at a temperature close to 200C, the reaction medium is concentrated to dryness under reduced 298 299 pressure (5 kPa) at a temperature close to 30 0 C. The residue obtained is taken up in 5 cm 3 of ethyl acetate and 5 cm 3 of water. After separating after settling out, the organic phase is washed with 2 cm 3 of water, dried 5 over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40*C. 62 mg of 4-[3-({1-[bis-(4 chlorophenyl)methyl]azetidin-3-ylidene}methane sulfonylmethyl)phenyllpiperazine-1-carboxylic acid 10 methyl ester are thus obtained in the form of a beige lacquer [IH NMR spectrum (400 MHz, CDCl 3 ) , 6 in ppm) : 2.75 (s, 3H)), 3.15 (broad t, J=5.5Hz, 4H), 3.62 (mt, 4H), 3.74 (s, 3H), 3.80 (mt, 2H), 4.32 (mt, 2H), 4.49 (s, 1H), 6.81 (d, J=8Hz, 1H), 6.90 (dd, J=8 and 2.5Hz, 15 1H), 6.99 (broad s, 1H), from 7.20 to 7.40 (mt, 9H)]. Example 151 32 mg of sodium acetoxyborohydride and then 20 22 mg of isobutyraldehyde are successively added, at a temperature close to 20 0 C, to a solution of 54.25 mg of 1-[3- ({1- [bis- (4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl)phenyl]piperazine in 2cm 3 of 1,2-dichloroethane. After stirring for 4 hours at a 25 temperature close to 20 0 C, 3 cm 3 of dichloromethane and 2 cm 3 of a saturated aqueous sodium bicarbonate solution are added to the reaction medium. After separating 299 300 after settling out, the organic [lacuna] is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 0 C. 63 mg of 1-[3-({1-[bis--(4-chlorophenyl) S methyl]azetidin-3-ylidene}methanesulfonylmethyl) phenyl]-4-isobutylpiperazine are thus obtained in the form of a beige lacquer ['H NMR spectrum (400 MHz, CDCl 3 ), in ppm): 0.92 (d, J=7Hz, 6H), 1.82 (mt, 1H), 2.14 (d, J=8Hz, 2H), 2.54 (t, J=5.5Hz, 4H), 2.75 (s, 10 3H), 3.18 (t, J=5.5Hz, 4H), 3.81 (mt, 2H), 4.32 (mt, 2H), 4.49 (s, 1H), 6.78 (d, J=8Hz, 1H), 6.89 (dd, J=8 and 2.5Hz, 1H), 6.97 (broad s, 1H), from 7.15 to 7.30 (mt, 5H) , 7.32 (d, J=8 Hz, 4H)]. 15 Example 152 32 mg of sodium acetoxyborohydride and then 13 mg of acetaldehyde are successively added, at a temperature close to 20'C, to a solution of 54 mg of 20 1-[3-({1- [bis-(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl)phenylpiperazine in 2 cm 3 of 1,2-dichloroethane. After stirring for 21 hours at a temperature close to 20 0 C, 2 cm 3 of a saturated aqueous sodium bicarbonate solution are added to the reaction 25 medium. After separating after settling out, the aqueous phase is reextracted with 2 cm 3 of dichloromethane. The pooled organic phases are dried 300 301 over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 200C. 60 mg of a solid residue are thus obtained, which residue is taken up in 2 cm 3 of methanol 5 and 0.5 cm 3 of dichloromethane. The solution obtained is deposited on a silica catridge (500 mg of SCX phase). The cartridge is washed with 5 cm 3 of methanol and then the expected product is eluted with 5 cm 3 of ammoniacal methanol (2 N) and then with an additional 5 cm 3 of 10 methanol. The filtrate is concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 300C. 42 mg of 1-[3-({l-[bis-(4-chlorophenyl) methyl] azetidin-3-ylidene}methanesulfonylmethyl) phenyl] -4-ethylpiperazine are thus obtained in the form 15 of a colorless lacquer [ 1 H NMR spectrum (300 MHz, CDCl 3 ) , 5 in ppm): 1.14 (t, J=7.5Hz, 3H) , 2.48 (q, J=7.5Hz, 2H), 2.60 (broad t, J=5Hz, 4H), 2.77 (s, 3H), 3.22 (broad t, J=5Hz, 4H), 3.82 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.79 (broad d, J=8Hz, 1H), 6.91 (dd, 20 J=8 and 2Hz, 1H), 6.98 (mt, 1H), from 7.20 to 7.40 (mt, 9H) . Example 153 25 2 cm 3 of pyridine and then 11.5 mg of acetic anhydride are successively added, at a temperature close to 200C, to 54 mg of 1-[3-({1-[bis-(4 301 302 chlorophenyl)methyl]azetidin-3-ylidene}methane sulfonylmethyl)phenyl]piperazine. After stirring for 23 hours at a temperature close to 200C, the reaction medium is concentrated to dryness under reduced 5 pressure (1kPa) at a temperature close to 30 0 C. The residue obtained is taken up in 5 cm 3 of ethyl acetate and 2 cm 3 of water. After separating after settling out, the organic phase is washed with 2 cm 3 of water, dried over magnesium sulfate, filtered and concentrated to 10 dryness under reduced pressure (1 kPa) at a temperature close to 40- 0 C. 52 mg of 4-acetyl 1-[3-({1-[bis-(4 chlorophenyl)methyl]azetidin-3-ylidene}methane sulfonylmethyl)phenyl]piperazine are thus obtained in the form of a beige foam ['H NMR spectrum (300 MHz, 15 CDCl 3 ), 6 in ppm): 2.16 (s, 3H) , 2.77 (s, 3H), from 3.10 to 3.25 (mt, 4H), 3.63 (broad t, J=5.5Hz, 2H), 3.78 (broad t, J=5.5Hz, 2H), 3.82 (mt, 2H), 4.34 (mt, 2H), 4.50 (s, IH), 6.84 (broad d, J=8Hz, 1H), 6.92 (dd, J=8 and 2Hz, 1H), 7.02 (mt, 1H), from 7.20 to 7.40 (mt, 20 9H)]. Example 154 511 mg of supported EDCI (2.5 mM), 11.5 mg of 25 N, N-dimethylglycine and then 5 cm 3 of dichloromethane are successively added, at a temperature close to 20 0 C, to 54 mg of 1-[3-( {1--[bis-(4-chlorophenyl) 302 303 methyl] azetidin-3-ylidene}methanesulfonylmethyl) phenyllpiperazine. After stirring for 24 hours at a temperature close to 20 0 C, 35 mg of N,N-dimethylglycine are added. After stirring for 96 hours at a temperature 5 close to 20 0 C,the reaction mixture is filtered on sintered glass. The resin is rinsed with three times 2.5 cm 3 of dichloromethane. The combined filtrates are washed with 10 cm 3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under 10 reduced pressure (5 kPa) at a temperature close to 20 0 C. 53 mg of 1-{4-[3-({l-[bis-(4-chlorophenyl) methyl]azetidin-3-ylidene}methanesulfonylmethyl) phenyl]piperazin-1-yl}-2-dimethylaminoethanone are thus obtained in the form of a beige foam [1H NMR spectrum 15 (400 MHz, (CD 3

)

2 So-d6, 6 in ppm): 2.20 (s, 6H), 2.94 (s, 3H), 3.12 (s, 2H), 3.16 (mt, 4H), 3.58 (mt, 2H), 3.68 (mt, 2H), 3.80 (mt, 2H), 4.19 (mt, 2H), 4.78 (s, 1H), 6.81 (broad d, J=8Hz, 1H), 6.93 (broad s, 1H), 6.99 (dd, J=8 and 2.5Hz, 1H) , 7.26 (t, J=8Hz, 1H) , 7.36 (d, 20 J=8Hz, 4H) , 7.46 (d, J=8Hz, 4H)] . Example 155 A solution of 320 mg of 4-[3-({1-[bis-(4 25 chlorophenyl)methyl]azetidin-3-ylidene}methane sulfonylmethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester in 5 cm 3 of formic acid is stirred for 303 304 5 hours at a temperature close to 200C, and then for 1 hour at a temperature close to 450C. The reaction medium is concentrated to dryness under reduced pressure (5 kPa) at a temperature close to 30 0 C, taken 5 up in 20 cm 3 of ethyl acetate and alkalinized with 10 cm 3 of a saturated aqueous sodium bicarbonate solution. After separating after settling out, the organic phase is washed with three times 10 cm 3 of water, dried over magnesium sulfate, filtered and concentrated to dryness 10 under reduced pressure (1 kPa) at a temperature close to 400C. The residue obtained is purified by depositing, in solution in a minimum of dichloromethane, on silica gel deposited on a plate [(gel 0.5 mm thick, 5 plates of 20 x 20 cm, eluent: 15 dichloromethane-methanol (80-20 by volume)]. The zone corresponding to the adsorbed desired product, located with UV rays, is scraped and the silica recovered is washed on sintered glass with a dichloromethane methanol mixture (75-25 by volume) . The filtrates are 20 combined and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 300C. 180 mg of 1- [3- ((1-[bis-(4-chlorophenyl)methyllazetidin-3 ylidene}methanesulfonylmethyl)phenyl]piperazine are thus obtained in the form of a white powder ["H NMR 25 spectrum (300 MHz, CDCl3, 5 in ppm): 2.77 (s, 3H)), 3.05 (mt, 4H), 3.16 (mt, 4H), 3.81 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.79 (broad d, J=8Hz, 1H), 6.90 (dd, J=8 304 305 and 2.5Hz, 1H), 6.98 (mt, 1H), from 7.20 to 7.40 (mt, 9H)] . 4- [3- ( (1- [bis- (4-chlorophenyl)methyll azetidin-3-ylidene}methanesulfonylmethyl) 5 phenyllpiperazine-1-carboxylic acid tert-butyl ester may be prepared in the following manner: on carrying out the operation according to the procedure of Example 4 starting with 1.32 g of 4-[3-((1-[bis-(4 chlorophenyl)methyll -3-hydroxyazetidin-3-yl}methane 10 sulfonylmethyl)phenyl]piperazinel-1-carboxylic acid tert-butyl ester, 0.232 cm 3 of methanesulfonyl chloride and 0.733 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.063-0.200 mm, diameter 2 cm, 15 height 25 cm) at atmospheric pressure with a dichloromethane-methanol mixture (99.5-0.5 by volume) as eluent and collecting 15 cm 3 fractions. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (5 kPa) 20 at a temperature close to 30 0 C. 0.86 g of 4-[3 ((1-[bis-(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl)phenyllpiperazine-1 carboxylic acid tert-butyl ester is thus obtained in the form of a white foam ['H NMR spectrum (400 MHz, 25 CDCl 3 , 6 in ppm) : 1.50 (s, 9H) , 2.77 (s, 3H) , 3.14 (t, J=5Hz, 4H), 3.57 (t, J=5Hz, 4H), 3.81 (mt, 2H), 4.34 (mt, 2H) 4.49 (s, 1H), 6.81 (d, J=8Hz, 1H), 6.90 (dd, 305 306 J=8 and 2.5Hz, 1H), 6.99 (broad s, 1H), from 7.20 to 7.30 (mt, 5H), 7.32 (d, J=8Hz, 4H)]. 4-[3-({1-[bis-(4-chlorophenyl)methyl]-3 hydroxyazetidin-3-yl}methanesulfonylmethyl) 5 phenyl]piperazine-1-carboxylic acid tert-butyl ester may be prepared in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 0.886 g of 4-(3-methane sulfonylmethylphenyl)piperazine-1-carboxylic acid tert 10 butyl ester, 0.765 g of 1-[bis-(4-chlorophenyl)methyl] azetidin-3-one and 1.72 cm 3 of a 1.6 M solution of n butyllithium in hexane, 1.37 g of 4-[3-({1-[bis-(4 chlorophenyl) methyl] -3-hydroxyazetidin-3-yl}methane sulfonylmethyl)phenyllpiperazine-1-carboxylic acid 15 tert-butyl ester are obtained in the form of a beige powder. 4- (3-Methanesulfonylmethylphenyl) piperazine 1-carboxylic acid tert-butyl ester may be prepared in the following manner: on carrying out the operation 20 according to the procedure of Example 10 starting with 1.55 g of 4-(3-chloromethylphenyl)piperazine-1 carboxylic acid tert-butyl ester and 0.766 g of sodium methanesulfinate, 0.9 g of 4-(3-methanesulfonyl methylphenyl)piperazine-l-carboxylic acid tert-butyl 25 ester is obtained in the form of a beige powder. 4- (3 -Chloromethylphenyl) piperazine-1 carboxylic acid tert-butyl ester may be prepared in the 306 307 following manner: by reacting 16.4 g of 4-(3 hydroxymethylphenyl) piperazine-1-carboxylic acid tert butyl ester in 150 cm 3 of dichloromethane, at a temperature close to 20 0 C, with 29 cm 3 of 5 diisopropylethylamine and 8.7 cm 3 of methanesulfonyl chloride, 15 g of 4-(3-chloromethylphenyl)piperazine-1 carboxylic acid tert-butyl ester are obtained in the form of a beige powder after purification on a chromatographic column (silica 0.063-0.200 mm, diameter 10 6 cm, height 45 cm, 100 cm 3 fractions) , eluting with dichloromethane. 4- (3-Hydroxymethylphenyl) piperazine-1 carboxylic acid tert-butyl ester may be prepared in the following manner: by reacting 15.8 g of tert-butyl 15 esters of 4-(3-butoxycarbonylphenyl)piperazine-1 carboxylic and 4- (3 -n-butyloxycarbonylphenyl) piperazine-1-carboxylic acids in solution in 500 cm 3 of anhydrous THF, at a temperature close to -10 0 C, with 102 cm 3 of diisobutylaluminum hydride in solution in 20 toluene (201 by weight), 12.8 g of 4-(3 hydroxymethylphenyl) piperazine-1-carboxylic acid tert butyl ester are obtained in the form of a beige oil. The mixture of tert-butyl esters of 4-(3 ethoxycarbonylphenyl) piperazine-1-carboxylic and 4- (3 25 n-butyloxycarbonylphenyl) piperazine-1-carboxylic acids may be prepared according to the method described in patent WO 9726250. 307 308 Example 156 On carrying out the operation according to 5 Example 38 (method 2) starting with 0.3 g of 3-acetoxy 1- [bis(4-methoxycarbonylphenyl)methyl] -3- [(3,5 difluorophenyl) (methylsulfonyl) methyl (RS) ] azetidine and 105 mg of lithium hydroxide monohydrate in 10 cm 3 of acetonitrile, at a temperature close to 70 0 C, 0.24 g of 10 1- [bis (4-methoxycarbonylphenyl)methyl] -3- [(3, 5 difluorophenyl) (methylsulfonyl)methylene]azetidine is obtained in the form of an orange-colored foam ['H NMR spectrum (300 MHz, CDCl, 8 in ppm) : 2.81 (s, 3H) , from 3.85 to 3.95 (mt, 2H), 3.89 (s, 6H), 4.37 (mt, 2H), 15 4.67 (s, 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.99 (mt, 2H), 7.50 (d, J=8Hz, 4H), 7.97 (d, J=8Hz, 4H)]. Example 157 20 On carrying out the operation according to the procedure of Example 40 starting with 4.45 g of (3,5-difluorobenzyl)methylsulfone, 6.36 g of 1-[bis(4 methoxycarbonylphenyl)methyl]azetidin-3-one, 2.18 cm 3 of acetyl chloride and 17 cm 3 of a 1.6 M solution of n 25 butyllithium in hexane, 10.8 g of 3-acetoxy-l-[bis(4 methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl (RS) I azetidine are obtained in 308 309 the form of a pale yellow foam ['H NMR spectrum (400 MHz, (CD,) 2 SO-d6, 6 in ppm) : 2.03 (s, 3H) , 2.96 (s, 3H), from 3.25 to 3.40 (mt, 2H), 3.52 (broad d, J=8Hz, 1H), from 3.75 to 3.90 (mt, 1H), 3.82 (s, 3H), 3.83 (s, 5 3H), 4.72 (s, 1H), 5.36 (s, 1H), 7.27 (d, J=8Hz, 2H), from 7.35 to 7.45 (mt, 2H), 7.43 (d, J=8Hz, 2H), 7.54 (tt, J=9.5 and 2.5Hz, 1H), 7.81 (d, J=8Hz, 2H), 7.88 (d, J=8Hz, 2H)]. 1- [bis (4-methoxycarbonylphenyl) methyl 10 azetidin-3-one may be prepared in the same manner as 1 {(R*) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl}azetidin-3-one (Example 110) from 1-[bis(4 methoxycarbonylphenyl)methyl]azetidin-3-ol. 1-[bis(4-methoxycarbonylphenyl)methyl] 15 azetidin-3-ol, may be prepared in the same manner as 1-{ (R*) - (4-chlorophenyl) [4- (methoxycarbonyl)phenyl] methyl}azetidin-3-ol (Example 110) from bis(4 methoxycarbonylphenyl) methylamine. Bis(4-methoxycarbonylphenyl)methylamine may 20 be prepared in the same manner as methyl 4-[(RS) -amino (4-chlorophenyl)methyl]benzoate (Example 87) from 4,4' dimethoxycarbonylbenzophenone. Example 158 25 On carrying out the operation according to the procedure of Example 110 starting with 40 mg of 309 310 (RS) -1- ([4- (chloromethyl)phenyl] (4-chlorophenyl) methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl) methyl)methylsulfonylmethylenelazetidine, 0.25 cm 3 of dichloromethane and 0.0196 cm 3 of morpholine, 35.8 mg of 5 (RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluoro phenyl) methanesulfonylmethylene] azetidin-l yl}methyl)benzyl]morpholine are obtained in the form of a white foam ['H NMR spectrum (400 MHz, CDCl 3 , 5 in ppm): 2.41 (mt, 4H), 2.80 (s, 3H), 3.42 (s, 2H), 3.69 10 (t, J=4.5Hz, 4H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)]. (RS)-1- ([4-(chloromethyl)phenyl] (4 chlorophenyl)methyl}-3- [(3,5-difluorophenyl) (methyl 15 sulfonyl)methyl)methylsulfonylmethylene]azetidine may be prepared in the following manner: on carrying out the operation according to Example 87 starting with 415 mg of (RS)-1-{(4-(chlorophenyl) [4-(hydroxymethyl) phenyllmethyl}-3- [(3,5-difluorophenyl) (methyl 20 sulfonyi)methylenelazetidine, 5 cm 3 of dichloromethane, 0.19 cm 3 of methanesulfonyl chloride and 0.53 cm 3 of diisopropylethylamine, 421.2 mg of (RS)-1-{[4 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- [(3,5 difluorophenyl) (methylsulfonyl)methyl)methylsulfonyl 25 methylenelazetidine are obtained in the form of a cream-colored foam. 310 311 Example 159 25 mg of potassium carbonate and then 0.016 cm 3 of morpholine are successively added, at a 5 temperature close to 20 0 C, under an inert atmosphere of argon, to a solution of 33 mg of 1-benzhydryl-3-([3-(4 bromobutoxy)phenyl]methanesulfonylmethylene}azetidine in 2 cm 3 of anhydrous acetonitrile. After stirring for 17 hours at a temperature close to 200C, the reaction 10 medium is diluted with 10 cm 3 of ethyl acetate and 4 cm 3 of water. The separated organic phase is washed with 4 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered on sintered glass and then concentrated to dryness under reduced 15 pressure (1 kPa) at a temperature close to 400C. The residue obtained is purified by depositing, in solution in a minimum of dichloromethane, on chromatography on silica gel deposited on a plate [(gel 0.5 mm thick, 2 plates of 20 x 20 cm, eluent: dichloromethane-methanol 20 (92.5-7.5 by volume)]. The zone corresponding to the desired product adsorbed, located with UV rays, is scraped and the silica recovered is washed on sintered glass with a dichloromethane-methanol mixture (80-20 by volume). The filtrates are combined and concentrated to 25 dryness under reduced pressure (1 kPa) at a temperature close to 40'C. 25.2 mg of 4-(4-{3-[(1 benzhydrylazetidin-3-ylidene)methanesulfonylmethyl] 311 312 phenoxy}butyl)morpholine are obtained in the form of a pale yellow foam ['H NMR spectrum (400 MHz, CDCl 3 , 6 in ppm) : 1.66 (mt, 2H), 1.81 (mt, 2H) , 2.40 (t, J=7.5Hz, 2H), 2.46 (mt, 4H), 2.77 (s, 3H), 3.72 (t, J=5Hz, 4H), 5 3.84 (mt, 2H), 3.96 (t, J=6.5Hz, 2H), 4.36 (mt, 2H), 4.53 (s, 1H), 6.87 (dd, J=8 and 2Hz, 1H), 6.93 (d, J=8Hz, 1H), 6.96 (d, J=2Hz, 1H), from 7.10 to 7.35 (mt, 7H); 7.42 (d, J=8Hz, 4H)]. 1-Benzhydryl-3- { [3- (4-bromobutoxy)phenyl] 10 methanesulfonylmethylene}azetidine may be prepared in the following manner: 0.586 cm 3 of 1,4-dibromobutane and 255 mg of potassium carbonate are successively added at a temperature close to 20'C, under an inert atmosphere of argon, to a solution of 500 mg of 1-benzhydryl-3 15 [(3-hydroxyphenyl) (methylsulfonyl)methylene] azetidine in 10 cm 3 of methylethyl ketone. The reaction mixture is heated at the reflux temperature of the solvent, under an inert atomosphere of argon, for 7 hours and then left at a temperature close to 20 0 C for about 4 days. 20 The reaction mixtue is filtered on sintered glass covered with celite. The solid residue is rinsed with ethyl acetate and then the filtrate is concentrated to dryness under reduced pressure (10 kPa) at a temperature close to 40'C. The brown oil obtained is 25 purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.200 mm) contained in a column 3 cm in diameter, eluting with a methanol-dichloromethane 312 313 mixture (0.5-99.5 by volume). The fractions (10 cm 3 ) containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 400C for 2 hours, 408.4 mg of 1-benzhydryl-3 5 ( [3-(4-bromobutoxy)phenyl] methane sulfonylmethylene}azetidine are thus obtained in the form of a brown foam. Example 160 10 0 .110 cm 3 of morpholine and then 35 mg of potassium carbonate are successively added, at a temperature close to 200C, to a solution of 45 mg of 1-benzhydryl-3-{ [3- (4-bromopropyloxy)phenyl]methane 15 sulfonylmethylene}azetidine in 3.5 cm 3 of anhydrous acetonitrile. After stirring for 20 hours at a temperature close to 20 0 C, the reaction medium is diluted with 40 cm 3 of ethyl acetate and 10 cm 3 of water. The separated organic phase is washed with 10 cm 3 20 of water, and then twice 10 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered on sintered glass and then concentrated to dryness under reduced pressure (9 kPa) at a temperature close to 400C. The yellow lacquer obtained is purified 25 by depositing, in solution in a minimum of dichloromethane, on chromatography on silica gel deposited on a plate [(gel 0.5 mm thick, 2 plates of 20 313 314 x 20 cm, eluent: dichloromethane-methanol (97.5-2.5 by volume) ] . The zone corresponding to the desired product adsorbed, located with UV rays, is scraped and the silica recovered is washed on sintered glass with a 5 dichloromethane-methanol mixture (85-15 by volume) . The filtrates are combined and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 0 C. 33 mg of 4-(4-{3-[(1-benzhydrylazetidin-3 ylidene)methanesulfonylmethyl]phenoxy}propyl)morpholine 10 are thus obtained in the form of a white foam [LH NMR spectrum (300 MHz, (CD 3

)

2 SO-d6, 5 in ppm) : 1.87 (mt, 2H), 2.37 (mt, 4H), 2.42 (t, J=7.5Hz, 2H), 2.94 (s, 3H), 3.58 (mt, 4H), 3.80 (mt, 2H), 4.02 (t, J=7Hz, 2H), 4.20 (mt, 2H), 4.74 (s, 1H), 6.97 (mt, 3H), 7.22 (t, 15 J=7.5Hz, 2H), from 7.25 to 7.40 (mt, 1H), 7.32 (t, J=7.5Hz, 4H), 7.48 (d, J=7.5Hz, 4H)]. 1-Benzhydryl-3- { [3- (4-bromopropyloxy) phenyl]methanesulfonylmethylene}azetidine may be prepared in the following manner: 0.5 cm 3 of 1,3 20 dibromopropane and 255 mg of potassium carbonate are successively added at a temperature close to 20 0 C, under an inert atmosphere of argon, to a solution of 500 mg of 1-benzhydryl-3- [(3-hydroxyphenyl) (methyl sulfonyl)methylene]azetidine in 10 cm 3 of methyl ethyl 25 ketone. The reaction mixture is heated at the reflux temperature of the solvent, under an inert atmosphere of argon, for 7 hours, and then left at a temperature 314 315 close to 20'C for about 4 days. The reaction mixture is filtered on sintered glass covered with celite. The solid residue is rinsed with ethyl acetate and then the filtrate is concentrated to dryness under reduced 5 pressure (10 kPa) at a temperature close to 400C. The brown oil obtained is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.200 mm) contained in a column 3 cm in diameter, eluting with a methanol-dichloromethane mixture (0.5-99.5 by volume). 10 The fractions (10 cm 3 ) containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 0 C for 2 hours. 511.1 mg of benzhydryl-3-{ [3- (4-bromopropyloxy) phenyllmethanesulfonylmethylene}azetidine are thus 15 obtained in the form of a brown foam. The medicaments according to the invention consists of a compound of formula (I) or an isomer or a salt of such a compound, in the pure state or in the form of a composition in which it is combined with any 20 other pharmaceutically compatible product which may be inert or physiologically active. The medicaments according to the invention may be used orally, parenterally, rectally or topically. As solid compositions for oral 25 administration, tablets, pills, powders (gelatine capsules, sachets) or granules may be used. In these compositions, the active ingredient according to the 315 316 invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compositions may also comprise substances other than diluents, for example 5 one or more lubricants such as magnesium stearate or talc, a coloring, a coating (sugar-coated tablet) or a glaze. As liquid compositions for oral administration, there may be used pharmaceutically 10 acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may comprise substances other than diluents, for example wetting, sweetening, thickening, 15 flavoring or stabilizing products. Sterile compositions for parenteral administration may be preferably solutions which are aqueous or nonaqueous, suspensions or emulsions. As solvent or vehicle, there may be used water, propylene 20 glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents. These compositions may also contain adjuvants, in particular wetting, isotonizing, 25 emulsifying, dispersing and stabilizing agents. Sterilization may be carried out in several ways, for example by aseptisizing filtration, by incorporating 316 317 sterilizing agents into the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or any other 5 injectable sterile medium. Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene 10 glycols. Compositions for topical administration may be, for example, creams, lotions, collyria,.collutoria, nasal drops or aerosols. In human therapy, the compounds according to 15 the invention are particularly useful for the treatment and/or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, cranial trauma, panic 20 attacks, peripheral neuropathies, glaucomas, migraine, Parkinson's disease., Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremor, obsessive compulsive disorder, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar 25 disorders, cancers, movement disorders induced by medicaments, dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, 317 318 multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, intestinal transit disorders, in weaning from chronic treatments and alcohol or drug abuse 5 (opiods, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines for example) , as analgesics or potentiators of the analgesic activity of the narcotic and nonnarcotic drugs as antibacterial, antiviral and antiparasitic 10 agents. The doses depend on the desired effect, the duration of the treatment and the route of administration used; they are generally between 5 mg and 1000 mg per day orally for an adult with unit doses 15 ranging from 1 mg to 250 mg of active substance. In general, the doctor will determine the appropriate dosage depending on the age, weight and any other factors specific to the subject to be treated. The following examples illustrate the 20 compositions according to the invention: PXAMPTE A Gelatin capsules containing a dose of 50 mg of active product and having the following composition 25 are prepared according to the usual technique: - Compound of formula (I) ................. 50 mg - Cellulose............................ 318 319 18 mg - Lactose........ 55 mg - Colloidal silica..................... 5 1 mg - Sodium carboxymethylstarch ...........------. 10 mg - Talc................................... 10 mg - Magnesium stearate ..-------................... 1 mg 10 EXAMPT,E R Tablets containing a dose of 50 mg of active product and having the following composition are prepared according to the usual technique: 15 - Compound of formula (I) ------.............. 50 mg - Lactose.............................. 104 mg - Cellulose ............................ 40 mg 20 - Polyvidone ................................. 10 mg - Sodium carboxymethylstarch ........... 22 mg - Talc................................. 10 mg - Magnesium stearate ---------................... 2 mg 25 - Colloidal silica..................... 2 mg - Mixture of hydroxymethylcellulose, glycerin, 319 320 titanium oxide (72-3.5-24.5) qs 1 finished film coated tablet containing 245 mg 'AM PT, C 5 An injectable solution containing 10 mg of active product and having the following composition is prepared: - Compound of formula (I) ................... 10 mg - Benzoic acid ......................... 10 80 mg - Benzyl alcohol....................... 0.06 ml - Sodium benzoate....................... 80 mg 15 - Ethanol, 95% .......................... 0.4 ml - Sodium hydroxide...................... 24 mg - Propylene glycol...................... 20 1.6 ml - Water.................................. qs 4 ml 320

Claims (34)

1. Compounds of formula: R3 R4 R 5 in which R represents a chain S0 2 R 1 OR' S0 2 R 1 C=CH or C-CH\ (A) (B) 2 R. represents a methyl or ethyl radical, R 2 represents either an aromatic chosen from phenyl, 10 naphthyl or indenyl, these aromatics being nonsubstituted or substituted with one or more halogens, alkyl, alkoxy, -CO-alk, hydroxyl, -COOR, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NRR,, -CO-NH-NRR 7 , 15 -N(alk)COOR., cyano, -CONHR,, -CO-NR, 6 R, 7 , alkylsulfanyl, hydroxyalkyl, -O-alk-NR 1 2 R. 3 or alkylthioalkyl or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2, 3 -dihydrobenzofuryl, 2, 3 -dihydrobenzothienyl, 20 indolinyl, indolyl, isochromanyl, isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4 tetrahydroquinolyl, thiazolyl, or thienyl rings, it 322 being possible for these heteroaromatics to be nonsubstituted or substituted with a halogen, alkyl, alkoxy, -COOR, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, 5 -NRR 7 , -CO-NH-NRR,, cyano, -CONHR 9 , alkylsulfanyl, hydroxyalkyl or alkylthioalkyl, R 3 and R 4 , which are identical or different, represent either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being nonsubstituted or 10 substituted with one or more halogens, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOR, -CONR 0 R,,, -CO-NH-NRR, alkylsulfanyl, hydroxyalkyl, -alk-NR6R 7 or alkylthioalkyl; or a heteroaromatic chosen from 15 benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2, 3-dihydrobenzofuryl, 2, 3-dihydrobenzo thienyl, furyl, isochromanyl, isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl or thienyl rings, it being possible for these 20 heteroaromatics to be nonsubstituted or substituted with a halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOR, -CO-NH-NRR 7 , -CONR, 1 R,,, -alk-NRR,, alkylsulfanyl, hydroxyalkyl or alkylthioalkyl; 25 R. is an alkyl or phenyl radical which is optionally substituted with one or more halogen atoms, R, and R, which are identical or different, represent a 322 323 hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively R, and R, together form with the nitrogen atom to which they are attached a 3- to 10-membered 5 saturated or unsaturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR 4 R 5 , oxo, hydroxyalkyl, 10 -alk-O-alk or -CO-NH 2 radicals, R. represents an alkyl radical, R 9 represents a hydrogen atom or an alkyl radical or an alkyl radical substituted with dialkylamino, phenyl, cycloalkyl (optionally substituted with -COOalk) or a 15 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, 20 Rio and R 11 , which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R 0 and RI, together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono or bicyclic heterocycle optionally containing another 25 heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl radical, RP. 2 and R1, which are identical or different, represent 323 324 a hydrogen atom or an alkyl or cycloalkyl radical or alternatively R 12 and R 1 3 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle optionally 5 containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk or -CO-alk-NR 1 4 R radical or a 3- to 10-membered saturated mono- or bicyclic heterocycle containing a heteroatom 10 chosen from oxygen, sulfur and nitrogen, R 14 and Ri., which are identical or different, represent a hydrogen atom or an alkyl or -COOalk radical, R 16 and R 1 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono 15 or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen, R' represents a hydrogen atom or a -CO-alk radical, alk represents an alkyl or alkylene radical, it being understood that the alkyl and alkylene radicals and 20 portions and the alkoxy radicals and portions are in the form of a straight or branched chain and contain 1 to 6 carbon atoms, their optical isomers and their salts with an inorganic or organic acid.

2. Compounds of formula (I) according to 25 claim 1, for which when R. and R, together form with the nitrogen atom to which they are attached a 3- to 10 membered saturated or unsaturated mono- or bicyclic 324 325 heterocycle, the latter is an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl, imidazolyl, thiomorpholinyl or furyl ring, these rings being optionally substituted with an alkyl, hydroxyalkyl, 5 -alk-O-alk, -CONH 2 , -COalk, -COOalk, oxo, -CSNHalk, -CONHalk or -CO-alk-NR 4 R., in which alk, R4 and R1, have the same meanings as in claim 1, their optical isomers and their salts with an inorganic or organic acid. 10

3. Compounds of the formula (I) according to either of claims 1 and 2, for which when R 1 , and RI, together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, the latter is an azetidinyl, 15 pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl ring, these rings being optionally substituted with an alkyl, their optical isomers and their salts with an inorganic or organic acid. 20

4. Compounds of formula (I) according to one of claims 1 to 3, for which when R 12 and R 1 3 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, the latter is an azetidinyl, pyrrolidinyl, 25 piperazinyl, piperidyl, morpholinyl or thiomorpholinyl ring, these rings being optionally substituted with an alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk or 325 326 -CO-alk-NR 1 4 RI, radical or a 3- to 10-membered saturated mono- or bicyclic heterocycle containing a heteroatom chosen from oxygen, sulfur and nitrogen, and, in particular, with a thiomorpholinyl radical, alk, R 1 , and 5 RI, having the same meanings as in claim 1, their optical isomers and their salts with an inorganic or organic acid.

5. Compounds of formula (I) according to one of claims 1 to 4, for which when R,, and R,, together 10 form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, the latter is preferably a piperidyl ring, their optical isomers and their salts with an inorganic or organic acid. 15

6. Compounds of formula (I) according to one of claims 1 to 5 for which R, represents an alkyl radical substituted with a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing one or more heteroatoms chosen from oxygen, 20 sulfur and nitrogen, the latter being a pyrrolidinyl, tetrahydrofuryl, morpholinyl or pyrrolyl ring, these rings being optionally substituted with one or more alkyl radicals, their optical isomers and their salts with an inorganic 25 or organic acid.,

7. Compounds of formula (I) according to claim 1 for which 326 327 R represents a chain (A) or (B), R' representing a hydrogen atom or a -COalk radical, R 1 represents a methyl or ethyl radical, R 2 represents either an aromatic chosen from phenyl and 5 naphthyl, these aromatics being nonsubstituted or substituted with one or more halogens, alkyl, alkoxy, hydroxyl, -COOR,, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, -NRR,, -CO-NH-NRR 7 , cyano, -CONHR,, alkylsulfanyl, 10 hydroxyalkyl, nitro, -CO-NR,,R, -0-alkNR 2 Rl 3 or alkylthioalkyl or a heteroaromatic chosen from isoquinolyl, pyridyl, quinolyl, 1,2,3,4 tetrahydroisoquinolyl, 1,2,3, 4-tetrahydroquinolyl and thienyl, these heteroaromatics being unsubstituted or 15 substituted with a halogen, alkyl, alkoxy, -COOR., trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, -NRR, -CO-NH-NRR 7 , cyano, -CONHR,, alkylsulfanyl, hydroxyalkyl, nitro or alkylthioalkyl, R 3 and R 4 , which are identical or different, represent 20 either an aromatic chosen from phenyl or naphthyl, these aromatics being nonsubstituted or substituted with one or more halogens, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CONRI 0 Ru 1 , -alk-NR6R, hydroxyalkyl, formyl or -COOR., or a heteroaromatic 25 chosen from thiazolyl or thienyl rings, these heteroaromatics being nonsubstituted or substituted by a halogen, alkyl, alkoxy, -CONR,R 11 , -alk-NRR 7 , 327 328 hydroxyalkyl or -COOR, R, is alkyl or phenyl which is optionally substituted with one or more halogens, R 6 and R 7 , which are identical or different, represent a 5 hydrogen atom or an alkyl, -COalk, cycloalkyl, alkylcycloalkyl, alk-0-alk or hydroxyalkyl radical or alternatively R, and R, together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle 10 optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR 1 4 R, 5 , oxo, hydroxyalkyl, alk-0-alk or -CO-NH 2 radicals, 15 R 9 represents a hydrogen atom or an alkyl radical or an alkyl radical substituted with dialkylamino, phenyl, cycloalkyl (optionally substituted with -COOalk) or a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing one or more 20 heteroatoms chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, RI, and R 11 , which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R, 0 25 and R 11 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono or bicyclic heterocycle optionally containing another 328 329 heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl radical, R 2 and R 13 , which are identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical or 5 alternatively R 12 and R1 3 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted 10 with an alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk or -CO-alk-NR 1 4 RI radical or a 3- to 10-membered saturated mono- or bicyclic heterocycle containing a heteroatom chosen from oxygen, sulfur and nitrogen, R1 and R 1 ,, which are identical or different, represent 15 a hydrogen atom or an alkyl or -COOalk radical, R1 and R, together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen, 20 alk represents an alkyl or alkylene radical, it being understood that the alkyl and alkylene radicals and portions and the alkoxy radicals and portions are in the form of a straight or branched chain and contain 1 to 6 carbon atoms, 25 their optical isomers and their salts with an inorganic or organic acid.

8. Compounds of formula (I) according to 329 330 claim 1, for which R represents a chain (A) or (B), R' representing a hydrogen atom or a radical -COalk, Ri represents a methyl or ethyl radical, 5 R 2 represents either an aromatic chosen from naphthyl, phenyl, phenyl substituted with one or more halogen, alkyl, alkoxy, hydroxyl, -COOR, (in which R, represents an 10 alkyl or phenyl radical optionally substituted with several halogens) trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, -NRR, (in which R 6 and R, which are identical or different, represent a hydrogen atom or an alkyl or -COOalk 15 radical or alternatively R 6 and R, together form with the nitrogen atom to which they are attached a heterocycle chosen from pyrrolidinyl, piperidyl, piperazinyl or piperazinyl substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk or 20 -CO-alk-NR 1 4 R. radicals, in which R 14 and RIS, which are identical or different, represent a hydrogen atom or an alkyl radical) , -CO-NH-NRR, (R, and R, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R, and R, together form 25 with the nitrogen atom to which they are attached a heterocycle chosen from piperidyl, pyrrolyl, piperazinyl or piperazyl substituted with one or more 330 331 alkyl radicals) , cyano, -CONHR, (in which R 9 represents a hydrogen atom or an alkyl radical or an alkyl radical substituted with dialkylamino, phenyl, cycloalkyl (optionally substituted with -COOalk) or a heterocycle 5 chosen from pyrrolidinyl (optionally substituted with alkyl), tetrahydrofuryl or morpholinyl), alkylsulfanyl, hydroxyalkyl, nitro, -CO-NR16R7, (in which R., and R. 7 together form with the nitrogen atom to which they are attached a piperidyl ring), -O-alkNR 2 RI 3 (in which R 12 10 and R 13 together form with the nitrogen atom to which they are attached a morpholino ring) or alkylthioalkyl, or a heteroaromatic chosen from isoquinolyl, pyridyl, 15 quinolyl, 1,2,3, 4-tetrahydroisoquinolyl, 1, 2, 3, 4 -tetrahydroquinolyl, thienyl, or thienyl substituted with a -COOR, (in which R, 20 represents an alkyl radical) or -CONHR, (in which R 9 represents an alkyl radical), R 3 and R 4 , which are identical or different, represent either an aromatic chosen from phenyl or 25 phenyl substituted with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, hydroxyalkyl, formyl, -COOR (in which R, is an alkyl 331 332 radical) , -CONRIOR,, (in which R,, and R,,, which are identical or different, represent a hydrogen atom or an alkyl radical) , -alk-NRR, (in which R, and R, which are identical or different, represent a hydrogen atom or an 5 alkyl, cycloalkyl, -alk-0-alk or hydroxyalkyl radical or alternatively R, and R, together form with the nitrogen atom to which they are attached a heterocycle chosen from piperidyl (optionally substituted with alkyl or oxo), pyrrolidinyl (optionally substituted 10 with alkyl, hydroxyalkyl, -alk-0-alk or -CO-NH 2 ) thiomorpholinyl, morpholinyl, pyrrolyl, piperazinyl optionally substituted with oxo, alkyl, hydroxyalkyl, -COOR, (in which R, is an alkyl radical), or a heteroaromatic chosen from 15 thiazolyl or thienyl, alk represents an alkyl or alkylene radical, it being understood that the alkyl and alkylene radicals and portions and the alkoxy radicals and 20 portions are in the form of a straight or branched chain and contain 1 to 6 carbon atoms, their optical isomers and their salts with an inorganic or organic acid.

9. The compounds chosen from: 25 1-benzhydryl-3- [(methylsulfonyl) (phenyl)methylene] azetidine, 1-benzhydryl-3- [(3-methylphenyl) (methylsulfonyl) 332 333 methylene] azetidine, 1-benzhydryl-3- [(3-chiorophenyl) (met-hylsulfonyl) methylenel azetidine, 1-benzhydryl-3-[(3, 5-dichlorophenfl) (rethylsulfonyl) 5 methylenel azetidine, 1-benzhydryl-3- [(2, 5-dichiorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(2,3-dichiorophenyl) (methylsulfonyl) methylenel azetidine, 10 1-benzhydryl-3- [(3-f luorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3,5-difluorophenyl) (rethylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3-bromophenyl) (methylsulfonyl) 15 methylene] azetidine, 1-benzhydryl-3- [(3-iodophenyl) (methylsulfonyl) methylenel azetidine, 1-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethoxy phenyl) methylene] azetidine, 20 1-benzhydryl-3- [(3-methylsulfonyl) (3-trifluoromethyl phenyl) methylene] azetidine, 1-benzhydryl-3-{ [3,5-bis(trifluoromethyl)phenyl] (methylsulfonyl) methylenelazetidine, 1-benzhydryl-3- [(3, 5-dibromophenyl) (methylsulfonyl) 25 methylene] azetidine, 1-benzhydryl-3- [(3-methoxycarbonyiphenyl) (methylsulfonyl) methylene] azetidine, 333 334 1-benzhydryl-3- [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- Ii(3-carbainoyiphenyl) (methy].sulfonyl) methylenel azetidine, 5 1-benzhydryl-3- II(methylsulfonyl) (naphth-1-yl) (methylsulfonyl)mrethylenel azetidine, 1- [bis(4-chlorophenyl)methyll -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-methoxyphenyl)tnethyll -3-[£(3,5-difluorophenyl) 10 (rethylsulfonyl) methylene] azetidine, 1- [bis (4-methylphenyl)methyl] -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -3- [(3,5-difluorophenyl) (methylsulfonyl)methylenel 1- [(4-methoxyphenyl) (phenyl)methyl] azetidine, 15 (R) -3- [(3,5-difluorophenyl) (methylsulfonyl)methylenel 1- [(4-methoxyphenyl) (phenyl)methyl] azetidine, (S)-3- [(3,5-difluorophenyl) (methylsulfonyl)methylenel 1- [(4-iethoxyphenyl) (phenyl)methyl] azetidine, 1- Ibis (4-trifluoromethoxyphenyl) methyl] -3- [(3,5 20 difluorophenyl) (methylsulfonyl)methylenel azetidine, 1- [bis(4-trifluorornethylphenyl)methyl] -3-[(3,5 difluorophenyl) (methylsulfonyl) methylenel azetidine, 1- [bis(4-chlorophenyl)methyl] -3-{ [3,5-bis (trifluorornethyl) phenyl] methylsulfonylmethylene} 25 azetidine, (RS) -1- (4-chiorophenyl) (2,4-dichlorophenyl)methyll 3- [(3, 5-difluoropheny.) (methylsulfonyl)methylene] 334 335 azetidine, (R) -l-Il(4-chiorophenyl) (2,4-dichloropheny-L)methyll 3-[(31 5-difluorophenyl) (methylsulfonyl)methylene] azet idirie, 5 (S) -1-[(4-chiorophenyl) (2,4-dichlorophenyl)methyl] 3- [(3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (RS) -1-{(4-chiorophenyl) [4- (hydroxyrnethyl)phenyl] methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl) 10 methylene] azetidine, (R,) -1-{(4-chiorophenyl) 14- (hydroxynethyl)phenyll methyl}-3- II(3,5-difluorophenyl) (methylsulfonyl) methylenel azetidine, (S) -1-{(4-chiorophenyl) [4- (hydroxymethyl)phenyll 15 methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1-{(4-chiorophenyl) [4- (pyrrolidylmethyl) phenyljrnethyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 20 (R) -1-{(4-chiorophenyl) [4- (pyrrolidylrnethyl)phenyll methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidiie, (S) -l-{(4-chiorophenyl) [4- (pyrrolidylmethyl)phenyll methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) 25 methylene] azetidine, 1-{ (RS)-(4-chlorophenyl) [4- (3,3-dimethylpiperidin-1-yl methyl)phenyllmethyl}-3- [(3,5-difluorophenyl) 335 336 (methylsulfonyl)mrethylenel azetidine, 1-{ (R)-(4-chlorophenyl) 14-(3,3-dimethylpiperidin-1-y1 methyl)phenylllmethyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylenel azetidine, 5 i-{ (S)-(4-chlorophenyl) [4-(3,3-dimethylpiperidin-1-yl methyl)phenylimethyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-{ (RS) -(4-chiorophenyl) [4- (thiomorpholin-4 ylmethyl)phenyllrnethyl}-3- [(3,5-difluorophenyl) 10 (rethylsulfonyl)methylenel azetidine, 1-{ (R) -(4-chiorophenyl) 14- (thiomorpholin-4 ylmethyl) phenyl] methyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylenel azetidine, 1-{ (S) -(4-chiorophenyl) [4- (thiomorpholin-4 15 ylmethyl)phenyllmethyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylenel azetidiie, 1-{ (RS) -(4-chiorophenyl) [4-(N-ethyl-N cyclohexylaminomethyl) phenyl] methyl} -3- [(3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, 20 1- {(R) -(4-chiorophenyl) [4- (N-ethyl-N cyclohexylaminomethyl) phenyl] methyl} -3- [(3,5 difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-{ (S) -(4-chiorophenyl) [4- (N-ethyl-N cyclohexylaminomethyl)PhefllmethylV-3-[(3,5 25 difluorophenyl) (methylsulfonyl)methylene] azetidine, 1- { (RS) -(4-chlorophenyl) {4- [(4-ethoxycarbonyl piperazinyl)methyllphenyllmethyl}}-3-[(3,5 336 337 difluorophenyl) (methylsulfonyl) methylenel azetidine, 1- { {(R) -(4-chlorophenyl) {4-[(4-ethoxycarbonyl piperazinyl)methyllphenylimethyl}}-3- [(3,5 difluorophenyl) (methylsulfonyl)methylene] azetidine, s 1-{{ (S)-(4--chlorophenyl) {4-[(4-ethoxycarbonyl piperazinyl)methyllphenylimethyl} }-3-[(3,S difluorophenyl) (rethylsulfonyl) methylene] azetidine, i-{ (RS) -(4-chiorophenyl) [4- (N-cyclopropyl-N-propyl aminomethyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) 10 (methylsulfonyl)methylene] azetidine, 1-{ (R) -(4-chiorophenyl) [4- (N-cyclopropyl--N-propyl aminomethyl) phenyll methyl} -3- [(3, 5-difluorophenyl) (rethylsulfonyl) methylene] azetidine, i-{ (S) -(4-chiorophenyl) [4- (N-cyclopropyl-N-propyl 15 aminomethyl)phenyllmethyl}-3- [(3,5-difluorophenyl) (rethylsulfonyl) methylenel azetidine, 1- {(RS) -(4-chiorophenyl) [4- (diisopropylaminomethyl) phenyllmethyl}-3- [(3, 5-difluorophenyl) (methyl sulfonyl) methylene] azetidine, 20 l-{ (R) -(4-chiorophenyl) [4- (diisopropylaminomethyl) phenyllmethyl}-3- [(3,5-difluorophenyl) (methyl sulfonyl) methylenel azetidine, l-{ (S) -(4-chiorophenyl) [4- (diisopropylaminomethyl) phenyllmethyl}-3- [(3, 5-difluorophenyl) (methyl 25 sulfonyl)methylenelazetidine, 1- { {(RS) -(4-chiorophenyl) {4- [bis- (2-methoxyethyl) amino methyl] phenylimethyl}}-3- [(3, 5-difluorophenyl) 337 338 (methylsulfonyl) methylenel azetidiie, i-{{ (P) -(4-chiorophenyl) {4- ibis- (2-methoxyethyl) amino methyllphenyllmethyl} }-3-[£(3,5-difluorophenyl) (methylsulfonyl) methylenel azetidine, 5 1-{{ (S) -(4-chiorophenyl) {4- [bis-(2-methoxyethyl)amino methyl] phenylimethyl} }-3- [(3',5-difluorophenyl) (methylsulfonyl) methylene] azetidine, i-{ (RS) -(4-chiorophenyl) [4- (di-ri-propylamiio methyl)phenylllmethyl}-3- [(3, 5-difluorophenyl) 10 (methy2.sulfonyl)mrethylenelazetidine, 1-{ (P) -(4-chiorophenyl) [4- (di-n-propylamino methyl)phenyllmethyl}-3- [(3,5-difluorophenyl) (methylsulfonyl)methylenel azetidine, 1-{ (S) -(4-chiorophenyl) [4- (di-n-propylamino 15 methyl)phenyllmethyl}--3- [(3,5-difluorophenyl) (methylsulfonyl) methylenel azetidine, l-{ (RS) -(4-chiorophenyl) [4- (piperidin-1-ylmethyl) phenyllmethyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 20 i-{ (R) -(4-chiorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylenel azetidine, 1-{ (S)- (4-chiorophenyl) [4- (piperidin-1-ylmethyl) phenyllmethyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) 25 methylenelazetidine, 1-{ (RS) -(4-chiorophenyl) [4- (4-methylpiperazin-1-yl *methyl)phenylllmethyl}-3- [(3,5-difluorophenyl) (methyl 338 339 sulfonyl) methylene] azetidine, 1-{ (R) -(4-chiorophenyl) [4- (4-methylpiperazin-1-yl methyl)phenyllmethyl}-3- [(31 5-difluorophenyl) (methyl sulfornyl)mrethylenel azetidine, 5 1-{ (S) -(4-chiorophenyl) 14-(4-methylpiperazin-1-yl methyl)phenyljtnethyl-3-[(3,5-difluorophenyl) (methyl sulfonyl) methylene] azetidine, i-{ (RS)-(4-chiorophenyl) 14- (morpholin-4-yl methyl)phenylllmethyl}-3- [(3, 5-difluorophenyl) 10 (methylsulforiyl)methylenel azetidine, 1-{ (R)-(4-chlorophenyl) [4- (morpholin-4-yl methyl)phenyllmethyl}-3- Ii(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-{ (S)-(4-chlorophenyl) [4- (morpholin-4-yl 15 methyl)phenyllmethyl}-3-[(3,5-difluorophenyl) (methylsulfonyl) methylenelazetidine, 1-{ (RS) -(4-chiorophenyl) [4- (diethylaminomethyl) phenyl] methyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylenel azetidine, 20 1-{ (R) -(4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl} -3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-{ (S) -(4-chiorophenyl) [4- (diethylaminomethyl) phenyllmethyl}-3-[(3,5-difluorophenyl) 25 (methylsulfonyl) methylenel azetidine, 1-{(RS)-(4-chlorophenyl) [4-(piperazin-2-on-4-yl methyl)phenylljmethyl}-3- [3,5-difluorophenyl) (methyl 339 340 sulfonyl) methylenel azetidine, 1-{ (R) -(4-chiorophenyl) 14-(piperazin-2-on--4-yl methyl)phenylimethyl}-3- [3, 5-difluorophenyl) (methyl sulfonyl) methylenelazetidine, 5 1-{(S)-(4-chlorophenyl) [4- (piperazin-2-on-4-yl methyl)phenyllmethyl}-3- [(3, 3-difluorophenyl) (methyl sulfonyl) methylenelazetidine, 1- {(RS) -(4-chloropheiyl) [4- (imidazol-1-yl methyl)phenyllmethyl}-3- [(3, 5-difluorophenyl) (methyl 10 sulfonyl)rnethylenel azetidine, 1-{ (R)-(4-chlorophenyl) [4-(imidazol-1-yl methyl)phenyllmethyl}-3- [(3,5-difluorophenyl) (methyl sulfonyl) methylene] azetidine, i-{ (S) -(4-chiorophenyl) [4- (imidazol-1-yl 15 methyl)phenylllmethyl}-3- [(3, 5-difluorophenyl) (methyl sulfonyl) methylenel azetidine, (RS) -1-{(4-chiorophenyl) [4- (N,N-dimethylcarbamoyl) phenyllmethyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylenel azetidine, 20 (R) -1-{(4-chiorophenyl) [4- (N,N-dimethylcarbamoyl) phenyllmethyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S)-l-{ (4-chiorophenyl) [4-(N,N-dimethylcarbamoyl) phenyl] methyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) 25 methylenel azetidine, (RS) -l-{(4-chiorophenyl) [4- (N-ethylcarbamoyl)phenyll methyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) 340 341~ methylene] azetidine, (R) -1-{(4-chiorophenyl) [4- (N-ethylcarbamoyl)phenyli methyl}-3- [(3, 5-difluorophenyl) (methylsulfonyl) methylenel azetidine, 5 (S) -l-{(4-chiorophenyl) [4- (N-ethylcarbamoyl2phenyl] methy:l}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1-[(4-carbarnoylphenyl) (4-chlorophenyl)tnethyl] 3- [(3, 5-difluorophenyl) (methylsulforiyl)methylene] 10 azetidine, (R,) -1-[(4-carbamoylphenyl) (4-chlorophenyl)methyl] 3- [(3,5-difluorophenyl) (methylsulfonyl)methylenel azetidine, (S) -1-[(4-carbamoylphenyl) (4-chlorophenyl)methyl] 15 3- [(3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 1- [bis (4-chlorophenyl)methyll -3- [(3, 5-dichiorophenyl) (rethylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3-methylsulfanylphenyl) 20 (methylsulfonyl)methylene] azetidine, 1-benzhydryl-3- [(3-methylsulfanylmethyl)phenyl)] (methylsulfonyl) methylenel azet-idine, 1- [bis (4-chlorophenyl)methyl] -3- [(3-cyanophenyl) (methylsulfonyl) methylenelazetidine, 25 1- Ibis (4-chlorophenyl)methyl] -3- [(3-carbamoylphenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl)methyll -3- [(3-methoxyphenyl) 341 342 (methylsulfonyl) methylenelazetidine, 2.-[bis (4-chlorophenyl)methyll -3-[£(3-hydroxyphenyl) (methylsulfonyl) methylenel azetidine, 1- Ibis (4-chlorophenyl)methyl] -3-LI(rethylsulfonyl) 5 (3 -pyrrolidinyiphenyl) methylene] azetidine, 1- [bis (4-chlorophenyl)methfyl -3- [(3-hydroxymethyl phenyl) (methylsulfonyl) methylenel azetidine, 1- [bis(4-chlorophenyl)methyl] 3- .{(methylsuifonyl) [3- (N piperidylcarbamoyl) phenyl] methylenelazetidine, 10 1- [bis(4-chlorophenyl)methyl] -3- [(methylsulfonyl) (3-trifluoromethylsulfanylphelyl) (methylsulfonyl) methylenel azetidine, 1-L[bis(4-fluorophenyl)mfethyll -3-[(3,5-difluorophenyl) (methylsulfonyl) methylenel azetidine, 15 1- [bis(2-fluoropheny)methylII-3-[3,5-difluorophenyl) (methylsulfonyl) methylenel azetidine, 1- [bis(3-f2.uorophenyl)rnethyll -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS)-l- [(4-chiorophenyl) (thiazol-2--yl)methyl] 20 3- [(methylsulfonyl) (phenyl)methylene] azetidine, (R) -1-[(4-chiorophenyl) (thiazol-2-yl)methyl] 3-LI(methylsulfonyl) (phenyl)methylene] azetidine, (S) -1-[(4-chiorophenyl) (thiazol-2-yl)methyl] 3-LI(methylsulfonyl) (phenyl)methylenel azetidine, 25 (RS)-l-[(4-chlorophenyl) (thien-2-yl)rnethyll-3-[(3,5 difluorophenyl) (methylsulfonyl)methylenel azetidine, (R,)-1-[(4-chlorophenyl) (thien-2-yl)methyl]-3-LI(3,5 342 343 difluoropheiyl) (methylsulfonyl) methylene] azetidine, difluorophenyl) (rethylsulfonyl)rnethylene] azetidine, 1-benzhydryl-3- [(ethylsulfonyl) (phenyl)methylene] 5 azetidine, 1- Ibis(4-chlorophenyl)methyll -3-{{3- iN- (4 methylpiperazinyl) carbamoyll phenyl} (methylsulfonyl) methylene }azetidine, 1- [bis(4-chlorophenyl)methyll -3-{ 13- (2,2 10 dirnethylcarbohydrazido) phenyl] (methylsulfonyl) methylene~azetidine, 1-[Ibis(thien-2-yl)methyl]-3-[3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-tbis(p-tolyl)methylj -3-{(rnethylsulfonyl) (phenyl) 15 methylenel azetidine, 1- (4-chiorophenyl) (4-hydroxymethyiphenyl) methyl] 3-[(3, 5-difluorophenyl) (methylsulfonyl)methylenel azetidine, 1- [bis (4-chlorophenyl)methyl] -3- [(3-rethylaminophenyl) 20 (methylsulfonyl)methylene] azetidine, (RS)-1-[(4-chlorophenyl) (thiazol-2-yl)methyll-3-[(3,5 difluorophenyl) (methylsulfonyl)rnethylene] azetidine, (R)-1-t(4-chlorophenyl) (thiazol-2-yl)methylj-3-[(3,5 difluorophenyl) (methylsulfonyl) methylenel azetidine, 25 (S)-1-[(4-chlorophenyl) (thiazol-2-yl)methyl]-3-{(3,5 difluorophenyl) (methylsulfonyl)methylene] azetidine, 1- [bis(4-chlorophenyl)methyl] -3- [(methylsulfonyl) (2 343 344 methoxycarbonylthiei-5-yl) methylene] azetidine, (RS) -1- bis(4-chlorophenyl)methyl] -3-hydroxy-3 [(methylsulfonyl) (2-methoxycarbonylthien-5 yl) methyl] azetidine, 5 1- [bis(4-chlorophenyl)methyl]-3- [(2-isobutyl aminccarbonylthiei-5-yl) (methylsulfonyl) methylenel azetidine, 1- Ibis (4-chlorophenyl)methyl] -3-[(3-methoxycarbonyl phenyl) (methylsulfonyl)methyl- (RS)'azetidin-3-ol, 10 1- Ibis (4-chiorophenyl) methyl] -3- [(rethylsulfonyl) (pyridin-4-yl)methyl- (RS)azetidin-3-ol, 1- Ibis (4-chlorophenyl)methyl] -3- [(methylsulfonyl) (pyridin-3-yl) methyl- (RS) azetidin-3-ol, 3- ({l- bis (4-chlorophenyl)methyllazetidin-3-ylidene} 15 methanesulfonylmethyl) -N- (3-morpholin-4-yl propyl) benzamide, 3- ({- Ibis (4-chlorophenyl)methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (3- dimethylaminopropyl) benzamide, 20 3- ({i- [bis(4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N- (2-pyrrolidin-1-ylethyl) benzamide, 3-({l- Ibis (4-chlorophenyl)methyll azetidin-3-ylidene} methanesulfonylmethyl) -N- (2-dimethylamino-l 25 methylethyl) benzamide, 3-({1- [bis (4-chiorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmet-hyl) -N-piperidin-1-ylbenzamide, 344 345 3- ({1- bis (4-chlorophenyl)methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- isobuty.benzamide, 3- ({1- bis(4-chlorophenyl)methyllazetidii-3-ylidene} methanesulfonylmethyl) -N- (3-imidazol-1-ylpropyl) 5 berizamide, 3- ({i- tbis(4-chlorophenyl)methyllazetidiri-3-ylidene} methanesulfonylmethyl) -N- (2-dimethylaminoethyl) benzamide, 3- ({1-[bis- (4-chlorophenyl)methyl] azetidir±-3 10 ylideneimethanesulfonylmethyl)benzoic acid Nl methyihydrazide, 3- ({i- bis- (4-chlorophenyl)methyl] azetidin-3-ylidene} methanesulfonyrnethyl) -N- (2-morpholin-4-ylethyl) benzamide, 15 3- ({1-[Ibis- (4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N- (l-ethylpyrrolidin-2 ylrnethyl) benzamide, 3- ({1- bis- (4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N- (2, 2-dimethyipropyl) benzamide, 20 3-({1- [bis-(4-chlorophenyl)methyl]azetidin-3-ylidene} methanesulfonylmethyl) -N-cyclohexylmethylbenzamide, 3- ({1-[bis- (4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N-cyclopropylmethylbenzamide, 3- ({1-[bis- (4-chlorophenyl)rnethyllazetidin-3-ylidene} 25 methanesulfonylmethyl) -N- (2-methylbutyl)benzamide, 3- (1- [bis- (4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N- (2-phenylpropyl) benzamide, 345 346 3- ((1- [bis- (4-chlorophenyl)methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (tetrahydrofuran-2 ylmethyl) benzamide, 3-((1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene} 5 methanesulfonylmethyl)-N-(2,2-diphenylethyl)benzamide, 3-((1-[bis-(4-chlorophenyl)methyllazetidin-3-ylidene} methanesulfonylmethyl) -N- (2-ethylbutyl) benzamide, 4-{ [3-({1- l[bis(4-chlorophenyl)methyllazetidin-3 ylidene}methanesulfonylmethyl) benzoylamino] methyl}cyclo 10 hexanecarboxylic acid methyl ester, 2-amino-1-{4- [3- ({1- [bis- (4-chlorophenyl)methyl] azetidin-3 -ylidene}methanesulfonyl methyl) phenyll piperazin-1-yl } ethanone, (2-{4- [3-({1- [bis(4-chlorophenyl)methyllazetidin-3 15 ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2 oxoethyl)carbamic acid tert-butyl ester, 1-{4-[3-((1-[bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl) phenyl] piperazin-1-yl} -2 methylaminoethanone, 20 (2-{4-[3-({1-bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl)phenyll]piperazin-1-yl}-2 oxoethyl) -N-methylcarbamic acid tert-butyl ester, 4-[3-((1-(bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl) phenyl] piperazine-l 25 carbothioic acid N-methylamide, 4- [3-((1- [bis(4-chlorophenyl)methyl] azetidin-3 ylidene}methanesulfonylmethyl) phenyl] piperazine-1 346 347 carboxylic acid N-methylamide, 4- [3- ({1- [bis(4-chlorophenyl)methyl] azetidin-3 ylidene}methanesulfonylmethyl)phenyl]piperazine-1 carboxylic acid methyl ester, 5 1- [3-({1- [bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl) phenyl] -4 isobutylpiperazine, 1-[3- ((- [bis (4-chlorophenyl)methyl] azetidin-3 ylidene}methanesulfonylmethyl) phenyl] -4 10 ethylpiperazine, 4-acetyl 1-[3-((1-[bis(4-chlorophenyl)methyl]azetidin 3-ylidene}methanesulfonylmethyl)phenylpiperazine, 1-{4-[3-({l-[bis(4-chlorophenyl)methyl]azetidin-3 ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2 15 dimethylaminoethanone, 1- [3- ({1- [bis(4-chlorophenyl)methyllazetidin-3 ylidene}methanesulfonylmethyl)phenyllpiperazine, 4- [3- ({1- [bis (4-chlorophenyl)methyl] azetidin-3 ylidene}methanesulfonylmethyl) phenyl] piperazine-l 20 carboxylic acid tert-butyl ester, 1- [bis (4-methoxycarbonylphenyl)methyl] -3- [(3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, 3-acetoxy-1- [bis (4-methoxycarbonylphenyl)methyl] -3 [(3, 5-difluorophenyl) (methylsulfonyl)methyl 25 (RS)azetidine, (RS) -4- [4- ( (4-chlorophenyl) {3- [(3, 5-difluorophenyl) methanesulfonylmethylene]azetidin-1-yl}methyl) 347 348 benzyl] morpholine, 4- (4-{3- [(1-benzhydrylazetidin-3-ylidene)methane sulfonylmethyl]phenoxy}butyl)morpholine, 4- (4-{3- [ (1-benzhydrylazetidin-3-ylidene)methane 5 sulfonylmethyl]phenoxy}propyl)morpholine, their optical isomers and their salts with an inorganic or organic acid.

10. The following compounds: 1- [bis(4-chlorophenyl)methyl] -3- [(3,5 10 difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[(3,5 difluorophenyl) (methylsulfonyl)methyl- (RS) ] azetidin-3 ol, 3-acetoxy-1- [bis- (4-chlorophenyl)methyl] -3- [(3,5 15 difluorophenyl) (methylulfonyl) methyl) methylsulfonyl methyl- (RS) ] azetidine their optical isomers and their salts with an inorganic or organic acid.

11. Process for the preparation of the 20 compounds of formula (I) according to claim 1 for which R represents a chain of formula (A) , characterized in that a corresponding compound of formula (la): R3 R4 N -- (1a) SOaR 1 R2 348 349 in which R 1 , R 2 , R 3 and R 4 have the same meanings as in claim 1 and R" represents a hydroxyl, methanesulfonyloxy or acetyloxy radical, is dehydrated, the product isolated and optionally converted to a salt 5 with an inorganic or organic acid.

12. Process for the preparation of the compounds of formula (I) according to claim 1 for which R represents a chain (B) in which R' is a hydrogen atom, characterized in that a derivative R 1 SO 2 CH 2 R 2 (I,) 10 for which R 1 and R 2 have the same meanings as in claim 1 is reacted with an azetidinone of formula: R 3 R4 in which R 3 and R 4 have the same meanings as in claim 1, 15 the product isolated and optionally converted to a salt with an inorganic or organic acid.

13. Process for the preparation of the compounds of formula (I) according to claim 1 for which R represents a chain (B) in which R' is a hydrogen 20 atom, characterized in that a derivative R 3 CH(Br)R 4 for which R. and R 4 have the same meanings as in claim 1 is reacted with a derivative of formula: 349 350 HN OH (VII) SO2R R2 in which R. and R 2 have the same meanings as in claim 1, the product isolated and optionally converted to a salt with an inorganic or organic acid. 5

14. Process for the preparation of the compounds of formula (I) according to claim 1 for which R is a chain (B) in which R' is a -CO-alk radical, characterized in that a halide Hal-CO-alk in which Hal represents a hydrogen atom and alk represents a 10 straight- or branched-chain alkyl radical containing 1 to 6 carbon atoms is reacted with a corresponding compound of formula (I) for which- R is a chain (B) in which R' is a hydrogen atom, the product isolated and optionally converted to a salt with an inorganic or 15 organic acid.

15. Process for the preparation of the compounds of formula (1) according to claim 1 for which R 2 represents an aromatic or a heteroaromatic substituted with -NRR, in which R, and R 7 each 20 represent a hydrogen atom, characterized in that a corresponding compound of formula (I) for which R2 represents an aromatic or a heteroaromatic substituted with nitro is reduced, the product isolated and optionally converted to a salt with an inorganic or 25 organic acid. 350 351

16. Process for the preparation of the compounds of formula (I) according to claim 1 for which R 2 represents an aromatic or heteroaromatic substituted with -CONHR 9 or R 3 and/or R 4 represent an aromatic or a 5 heteroaromatic substituted with -CONR 10 R 11 , characterized in that a corresponding compound of formula (I) for which R 2 and/or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with -COOR, for which R. is alkyl or phenyl optionally substituted with halogens is 10 reacted respectively with an amine H 2 NR 9 or HNRORa 1 for which R 9 , Ri. and R 1 have the same meanings as in claim 1, the product isolated and optionally converted to a salt with an inorganic or organic acid..

17. Process for the preparation of the 15 compounds of formula (I) according to claim 1 for which R 2 represents an aromatic substituted by hydroxyl and/or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with hydroxyl, characterized in that a corresponding compound of formula (I) for which R 2 20 represents an aromatic substituted by alkoxy and/or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with alkoxy is hydrolyzed, the product isolated and optionally coverted to a salt with an inorganic or organic acid. 25

18. Process for the preparation of the compounds of formula (I) according to claim 1 for which R 2 represents an aromatic substituted with -NR 6 R 7 for 351 352 which R. represents an alkyl radical and R, represents a hydrogen atom, characterized in that a corresponding compound of formula (I) for which R 2 represents an aromatic substituted with -N(alk)COOR, in which R. 5 represents a tert-butyl radical is deprotected, the product isolated and optionally converted to a salt with an inorganic or organic acid.

19. Process for the preparation of the compounds of formula (I) according to claim 1 for which 10 R 2 and/or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with -COOR., characterized in that a derivative of formula: R 3X RR N (IX) LR 15 for which R represents a chain C=C(SO 2 R,)R' 2 or C(OR')CH(SO 2 R,)R' 2 , R,, R' 2 , R', and R' 4 have the same meanings as the substituents R,, R 2 , R 3 and R 4 of claim 1 with the proviso that at least one of the substituents R' 2R1 and R' 4 represents an aromatic or a 20 heteroaromatic substituted with carboxyl, is esterified using a derivative of formula ROH for which R, is alkyl or phenyl optionally substituted with one or more halogens, the product isolated and optionally converted to a salt with an inorganic or organic acid. 25

20. Process for the preparation of the 352 353 compounds of formula (I) according to claim 1 for which R 2 and/or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with alkylthicalkyl, characterized in that a derivative of formula: 3 R 4 ' N (IX) R 5 for which R represents a chain C=C(S0 2 RI)R' 2 or C(OR')CH(S0 2 R,)R' 2 , R', R 1 , R' 2 , R' 3 and R' 4 have the same meanings as the substituents R', R 1 , R 2 , R 3 and R 4 of 10 claim 1 with the proviso that at least one of the substituents R2', R 3 ' and R 4 ' represents an aromatic or a heteroaromatic substituted with haloalkyl, is reacted with a sodium alkylthiolate for which the alkyl portion is a straight or branched chain and contains 1 to 6 15 carbon atoms, the product isolated and optionally converted to a salt with an inorganic or organic acid.

21. Process for the preparation of the compounds of formula (I) according to claim 1 for which R 2 and/or R 3 and/or R 4 represent an aromatic substituted 20 with hydroxyalkyl in which the alkyl contains a carbon atom, characterized in that a compound of formula (I) for which at least one of the substituents R 2 , R 3 and R 4 represents an aromatic substituted with formyl, is reduced, the product isolated and optionally converted 25 to a salt with an inorganic or organic acid. 353 354

22. Process for the preparation of the compounds of formula (I) according to claim 1 for which R 3 and/or R 4 represents an aromatic substituted with -alk-NRR, for which alk is an alkyl containing a carbon 5 atom, characterized in that a compound of formula (I) for which at least one of the substituents R 3 and R 4 represents an aromatic substituted with formyl is reacted with an amine HNRR, in which R 6 and R, have the same meanings as in formula (I) , the product isolated 10 and optionally converted to a salt with an inorganic or organic acid.

23. Process for the preparation of the compounds of formula (I) according to claim 1 for which R 2 represents an aromatic or a heteroaromatic 15 substituted with -CONHR 9 and/or R 3 and/or R 4 represents an aromatic or a heteroaromatic substituted with -CO NR.R.., characterized in that a derivative of formula: R3 N (IX) R 20 for which R represents a chain C=C(SO 2 R)R' 2 or C(OR')CH(SO2R,)R' 2 , R', R 1 , R' 2 , R' 3 and R'4 have the same meanings as the substituents R' , R 1 , R 2 , R 3 and R 4 of claim 1 with the proviso that at least one of the substituents R'2, R'3 and R' 4 represents an aromatic or 25 a heteroaromatic substituted with carboxyl, is reacted 354 355 respectively with an amine H 2 NR 9 or HNR,,R 1 in which R 9 , RIO and R 1 have the same meanings as in formula (I) , the product isolated and optionally converted to a salt with an inorganic or organic acid. 5

24. Process for the preparation of the compounds of formula (I) according to claim 1 for which R and/or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with -CO-NH-NRsR 7 , characterized in that a corresponding compound of 10 formula (I) for which R 2 and/or R 3 and/or R 4 represents an aromatic or a heteroaromatic substituted with -COOR and R. represents an alkyl or phenyl radical which is optionally substituted by halogens, is reacted with a hydrazine H 2 N-NRR, for which R, and R, have the same 15 meanings as in formula (I), the product isolated and optionally converted to a salt with an inorganic or organic acid.

25. Process for the preparation of the compounds of formula (I) according to claim 1 for which 20 R 2 represents an aromatic or a heteroaromatic substituted with -CO-NHR 9 in which R 9 represents a hydrogen atom and/or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with -CO-NR 10 R. 1 radicals in which Ri. and R, 1 are hydrogen atoms, characterized in 25 that a corresponding compound of formula (I) for which R 2 and/or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with cyano is hydrolyzed, 355 356 the product isolated and optionally converted to a salt with an inorganic or organic acid.

26. Process for the preparation of the compounds of formula (I) according to claim 1 for which 5 R 2 represents an aromatic substituted with -0-alk-. NR 12 R 13 , characterized in that a derivative of formula: R 3 R4' _ N (IX) R for which R represents a chain C=C(SO 2 RI)R' 2 or 10 C(OR')CH(SO 2 R)R 2 , R', R 1 , R 2 ', R 3 ' and R 4 ' have the same meanings as the substituents R' , R 1 , R 2 , R 3 and R 4 of claim 1 with the proviso that at least one of the substituents R 2 ' , R 3 ' , R 4 ' represents an aromatic substituted with -0-alk-Hal in which alk represents a 15 straight- or branched-chain alkyl radical containing 1 to 6 carbon atoms and Hal represents a halogen atom, is reacted with an amine HNR 12 Ra 3 in which R 12 , R 13 have the same meanings as in claim 1, the product isolated and optionally converted to a salt with an inorganic or 20 organic acid.

27. Process for the preparation of the compounds of the formula (I) according to claim 1, for which R 3 and/or R 4 represents an aromatic substituted with -alk-NRR,, characterized in that a derivative of 25 formula: 356 357 R3' R4 N (IX) R for which R represents a chain C=C(SO 2 R,)R' 2 or C(OR') CH(SO 2 RI)R' 2 , R', RI, R 2 ', R 3 ' and R 4 ' have the same 5 meanings as the substituents R' , R 1 , R 2 , R 3 and R 4 of claim 1 with the proviso that at least one of the substituents R 3 1 , R 4 ' represents an aromatic substituted with -alk-Cl in which alk represents a straight- or branched-chain alkyl radical containing 1 to 6 carbon 10 atoms, is reacted with an amine HNR R, in which R., R 7 have the same meanings as in claim 1, the product isolated and optionally converted to a salt with an inorganic or organic acid.

28. Process for the preparation of the 15 compounds of formula (I) according to claim 1 for which R represents a chain B, R' represents a hydrogen atom and R 3 and/or R 4 represents an aromatic substituted with hydroxyalkyl in which the alkyl residue contains one carbon atom, characterized in that diisobutylaluminum 20 hydride is reacted with a corresponding compound of formula (I) for which R represents a chain B, R' represents a hydrogen atom and R 3 and/or R, represents an aromatic substituted with one or more -COOR, radicals, in which R. is an alkyl radical, the product 25 isolated and optionally converted to a salt with an 357 358 inorganic or organic acid.

29. Process for the preparation of the compounds of formula (I) according to claim 1 for which R 2 represents a phenyl radical substituted with -NRR 7 5 representing a 1-piperazinyl ring substituted at the 4 position with an alkyl radical, characterized in that a corresponding compound of formula (I) for which R 2 represents a phenyl radical substituted with a radical -NRR 7 representing a 1-piperazinyl ring is reacted with 10 an alk-CHO derivative in which alk represents a straight- or branched-chain alkyl radical containing 1 to 5 carbon atoms, the product isolated and optionally converted to a salt with an inorganic or organic acid.

30. Process for the preparation of the 15 compounds of formula (I) according to claim 1 for which R 2 represents a phenyl radical substituted with -NR R, representing a 1-piperazinyl ring substituted at the 4 position with a -COOalk radical, characterized in that a corresponding compound of formula (I) for which R 2 20 represents a phenyl radical substituted with a radical -NR 6 R 7 representing a 1-piperazinyl ring is reacted with a derivative of formula Hal-COOalk in which alk represents a straight- or branched-chain alkyl radical containing 1 to 6 carbon atoms and Hal represents a 25 halogen atom, the product isolated and optionally converted to a salt with an inorganic or organic acid.

31. Process for the preparation of the 358 359 compounds of formula (I) according to claim I for which R 2 represents a PhenYl radical SubSt ituted i forwhc representing a i sbsitte with -NRR Position With a -CO-Nalk ring substituted at the 4 5 characterized in that or -CS-NHalk radical, formula (i f ih a corresponding compound of (I) for whic R 2 represents a phenyl radical substituted with -NRR 7 represents a phPiperazinyl ring is reacted with a derivative Of formula YaC-Na k in which alk represents a straight- or branchedchai 10 alkyl radical containing , to 6 carbon atoms and Y represents a sulfur or oxygen atom, the product isolated and optionallyt Wit inorganic or organic c. to a salt with an

32. Process for the 15 compoundspreparation of the R2 represents a phenyl ra according to claim i for which resents a radical substituted with a 7 N representing a I-PiPerazin 1 ring substituted at the 4 position with a -O-alkn radical, characterized in that a correspondingR 20Of formula (1) frwihR acrepnngcompound 20uofsforut witfor which R 2 represents a Phenyl radical sub s itut d wi h a adi c l NN 1-piperaadicalring.,R 7 representing a S~btittedreacted wt IPiperazinyl ring is a with an acid of formula RR 1 4Nalko0aH innwhich al represents a straight- or 25 branchedcha alkyl radical containing i to 6 carbon Sotonl 14 and R have the same meanings as in claim O ptionally followed by action of the product for which R 14 is a tert-butOr oxyarbn~lradical in order 360 to obtain the compounds for which R, is a hydrogen atom, the product isolated and optionally converted to a salt with an inorganic or organic acid.

33. Process for the preparation of the 5 compounds of formula (I) according to claim 1 for [lacuna] R 2 represents a phenyl radical substituted with a radical -NRR, representing a 1-piperazinyl ring substituted at the 4 position with a -CO-alk radical in which alk represents a methyl radical, characterized in 10 that a corresponding compound of formula (I) for which R 2 represents a phenyl radical substituted with a radical -NRR, representing a 1-piperazinyl ring is reacted with acetic anhydride, the product isolated and optionally converted to a salt with an inorganic or 15 organic acid.

34. Pharmaceutical compositions containing, as active ingredient, at least one compound of formula (I) according to one of claims 1 to 10. 360