AU772025B2

AU772025B2 - Azetidine derivatives, preparation and medicines containing them

Info

Publication number: AU772025B2
Application number: AU55232/99A
Authority: AU
Inventors: Daniel Achard; Herve Bouchard; Jean Bouquerel; Marc Capet; Serge Grisoni; Augustin Hittinger; Jean-Luc Malleron; Serge Mignani
Original assignee: Aventis Pharma SA
Current assignee: Aventis Pharma SA
Priority date: 1998-09-11
Filing date: 1999-09-09
Publication date: 2004-04-08
Anticipated expiration: 2019-09-09
Also published as: EP1112251A1; HUP0103341A2; DZ2887A1; CO5150230A1; ZA200102003B; AU5523299A; JP4767413B2; TW530046B; WO2000015609A1; ATE239703T1; CA2342739C; JP2002525267A; CA2342739A1; EP1112251B1; DE69907698D1; DK1112251T3; CZ301446B6; PL198526B1; CZ2001883A3; HUP0103341A3

Description

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

R

3

IRR

their optical isomers, their salts, their preparation and medicaments containing them.

In formula R represents a chain

/SO

2 R, OR' /SOR, C=CH

C-CH

R or R2

R

1 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 halogens, alkyl, alkoxy, -CO-alk, hydroxyl, -COORs, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NR 6

R

7

-CO-NH-NR

6

R

7 -N(alk)COORs, cyano, -CONHR 9 -CO-NRi 6

R

17 alkylsulfanyl, hydroxyalkyl, -O-alk-NR 2

R

13 or alkylthioalkyl or a 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 be nonsubstituted or substituted with a halogen, alkyl, alkoxy, -COOR., trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NR A -CO-NH-NR 6

R

7 cyano, -CONHR 9 alkylsulfanyl, hydroxyalkyl or alkylthioalkyl, R 3 and 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, -CO-alk, cyano, -COOR 5 -C0NR,,R, -CO-NH-NR 6

R

7 alkylsulfanyl, hydroxyalkyl, -alk-NR 6 R, or alkylthioalkyl; or a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2, 3-dihydrobenzofuryl, 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, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOR -CO-NH-NR 6

R

7 ,I -C0NR 0

R

11 -alk-NR 6

R

7 alkylsulfanyl, hydroxyalkyl or alkylthioalkyl;

R

5 is an alkyl or phenyl radical which is optionally substituted with one or more halogen atoms,

R

6 and which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively R 6 and R, together form with the nitrogen atom to which they are attached a 3- to 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 oxo, hydroxyalkyl, -alk-O-alk or -CO-NH, radicals, R, represents an alkyl radical,

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 heteroatoms chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,

R

10 and which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Rio and R, together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated monoor bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl radical, R, and R 13 which are identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical or alternatively R 1 and R 13 together form with the nitrogen atom to which they are attached a 3- to saturated mono- or bicyclic heterocycle optionally 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, 4 radical or a 3- to 10-membered saturated mono- or bicyclic heterocycle containing a heteroatom chosen from oxygen, sulfur and nitrogen,

R

14 and R 1 which are identical or different, represent a hydrogen atom or an alkyl or -COOalk radical, R 6 and R 17 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated monoor 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.

In the preceding definitions and in those which follow, unless otherwise stated, 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.

Among the alkyl radicals, there may be 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, 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, and/or R, represent independently a substituted phenyl, the latter is preferably mono-, di- or trisubstituted.

When R 6 and R, together form with the nitrogen atom to which they are attached a 3- to saturated or unsaturated mono- or bicyclic heterocycle, 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,, -COalk, -COOalk, oxo, -CSNHalk, -CONHalk or -CO-alk-NR 4

,R

15 radical and, in particular, with a methyl, ethyl, propyl, isobutyl, acetyl, N,Ndimethylaminomethylcarbonyl, methyloxycarbonyl, methylcarbamoyl, methylthiocarbamoyl, N-methylaminomethylcarbonyl, N-methyl- N-tertbutoxycarbonylaminomethylcarbonyl, oxo, -CSNHCH, or -CONHCH, radical.

When R 1 i and R 1 together form with the nitrogen atom to which they are attached a 3- to saturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or thiomorpholinyl ring, these rings being optionally substituted with an alkyl.

When R, and R 13 form together with the nitrogen atom to which they are attached a 3- to saturated mono- or bicyclic heterocycle, 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 4

R

5 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.

When R 16 and R 17 together 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.

When R 9 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, sulfur and nitrogen, the latter is preferably a pyrrolidinyl, tetrahydrofuryl, morpholinyl or pyrrolyl ring, these rings being optionally substituted with one or more alkyl radicals.

The compounds of formula may be provided in the form of enantiomers and diastereoisomers. These optical isomers and mixtures thereof form part of the invention.

The compounds of formula for which R represents a chain of formula may be prepared by dehydration of a corresponding compound of formula (Ia)

R

3 N- (la)

SO

2

RI

in which R 1

R

3 and R 4 have the same meanings as in formula and R" represents a hydroxyl, methanesulfonyloxy or acetyloxy radical.

This dehydration is carried out by any method 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 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 a temperature of between 5 0 C and 20 0 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 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°C and the boiling temperature of the reaction mixture. The methanesulfonyloxy and the acetyloxy may be isolated or otherwise.

The compounds of formula for which R represents a chain in which R' is a hydrogen atom may be prepared by reacting the derivative R 1

SOCH

2

R

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

R

3 N- (111) in which R, and R 4 have the same meanings as in formula The procedure is generally carried out in an inert solvent such as an ether (tetrahydrofuran for example), in the presence of a strong base such as lithium diisopropylamide, potassium tert-butoxide or n-butyllithium, at a temperature of between -70 0 C and 0

C.

The derivatives of formula (II) may be 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: RSNa

R

2

-CH

2 -Hal R 2

-CH

2

-S-R,

(IV)

(V)

R-SO

2 Na oxidation

R

2

-CH

2

-SO

2

-R,

1 1 In these formulae Hal represents a halogen atom and, preferably, chlorine, bromine or iodine, R, and R, have the same meanings as in formula The reaction is generally carried out in an inert solvent such as dimethylformamide or a 1-4C aliphatic alcohol, at a temperature of between 20 and 0

C.

The reaction is carried out by any known method which makes it possible to oxidize a sulfurcontaining 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 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 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.

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 0 C. It is also possible to carry out the procedure using tertbutyl 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 oxone"(potassium 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 0

C.

The reaction is preferably carried out in an inert solvent such as a 1-4C aliphatic alcohol (methanol or ethanol for example), at a temperature of between 20°C and the boiling temperature of the reaction medium.

The derivatives of formula (IV) are 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 0 C or N-bromo- or chlorosuccinimide in the presence of benzoyl peroxide, 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.

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.

Chem., 271 (1994) or DAVE Org. Chem., 61, 5453 (1996) and in the examples. The procedure is generally carried out according to the following reaction scheme: SA

N

O H R R4 HYDROXYLAMINE R R4o 3 H Br NH 2 1 IE R< R 4

R

3

R

4 E 4 C X D OH N R3 4

N

(111)

R

(II) R 3 4 In these formulae, R 3 and R 4 have the same meanings as in formula and X represents a chlorine or bromine atom.

In step A, the procedure is preferably 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.

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 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 carried out in DMSO, using the sulfurtrioxide-pyridine complex, at a temperature close to 20 0 C or using dimethyl sulfoxide, in the presence of oxalyl chloride and triethylamine, at a temperature of between -70 and 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 the brominated derivative is formed and then the nitrile is reacted, in an ether such as ethyl ether, at a temperature of between 0°C and the boiling temperature of the reaction medium. After hydrolysis with an alcohol, the intermediate imine is reduced in situ with sodium borohydride at a temperature of between 0°C and the boiling temperature of the reaction medium.

The R 3

-CO-R

4 derivatives are commercially 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 Eur. J. Med. Chem., 23 477 (1988); SKINNER et al., J. Med. Chem., 14 546 (1971); HURN 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., 306 648 (1973); CONSONNI R. et al., J. Chem. Soc. Perkin Trans 1, 1809 (1996); FR-96-2481 and JP-94-261393.

The RBr 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); LEMAIRE M. et al., Synth. Comm., 24 95 (1994); GODA H. et al., Synthesis, 9 849 (1992); BAEUERLE P. et al., J. Chem. Soc. Perkin Trans 2, 489 (1993).

The RCN derivatives are commercially available or may be obtained by application or adaptation of the methods described by BOUYSSOU P. et al., J. Het. Chem., 29 895 (1992); SUZUKI N. et 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 for which R represents a chain in which R' is a hydrogen atom may also be prepared by action of a derivative RCH(Br)R, (VI) for which R, and R, have the same meanings as in formula with a derivative of formula:

HN

OH

(VII)

SO

2

R,

R2 in which R i and R 2 have the same meanings as in formula This reaction is generally carried out in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), in an inert solvent such as acetonitrile, at the boiling temperature of the reaction medium.

The derivatives of formula (VI) are commercially available or may be obtained by application or adaptation of the method described by BACHMANN J. Am. Chem. Soc., 2135 (1933).

Generally, the corresponding alcohol RCHOHR, is brominated using hydrobromic acid, in acetic acid; at a temperature of between 0"C and the boiling temperature of the reaction medium.

The corresponding RCHOHR, 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).

The derivatives of formula (VII) may be obtained by hydrolysis of a derivative of formula:

H

2

C=HCOOC-N-

OH (VIll)

,R,

in which R, and R, have the same meanings as in formula 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 The derivatives of formula (VIII) are 20 obtained by reacting vinyl chloroformate with a corresponding compound of formula for which R represents -a chain of formula R' represents a hydroxyl radical, R, and R 4 are phenyl radicals, in an inert solvent such as a chlorinated solvent (dichloromethane or chloroform for example), at a

S

16 temperature of between 0°C and the boiling temperature of the reaction mixture.

The compounds of formula for which R is a chain in which R' is a -CO-alk radical may be 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 for which R is a chain in which R' is a hydrogen atom.

This reaction is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane or chloroform for example), at a temperature of between -50'C and 20'C, in the presence of n-butyllithium.

The compounds of formula for which R 2 represents an aromatic or a heteroaromatic substituted with -NR 6 R, in which R 6 and R 7 each represent a hydrogen atom may also be prepared by reducing a corresponding compound of formula for which R 2 represents an 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 hydrochloric acid in a 1-4C aliphatic alcohol such as ethanol, at the boiling temperature of the reaction medium.

The compounds of formula for which R, represents an aromatic or heteroaromatic substituted with -COHNR, and/or R, and/or R, represent an aromatic or a heteroaromatic substituted with -CONRioR 1 1 may also be prepared by reacting a corresponding compound of formula for which R, and/or R 3 and/or R, represent an aromatic or a heteroaromatic substituted with -COOR s for which R s is alkyl or phenyl optionally substituted with halogens with respectively an amine H 2

NR

9 or HNR 10

R

1 for which R.

0 and R, have the same meanings as in formula This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane or chloroform for example) or a 1-4C aliphatic alcohol (methanol or ethanol for example), at a temperature of between 0°C and the boiling temperature of the reaction mixture.

The compounds of formula for which R 2 represents an aromatic substituted with hydroxyl and/or R, and/or R, 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, and/or R, represent an aromatic or a 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.

The compounds of formula for which R, represents an aromatic substituted with -NR 6 R 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 for which R, represents an aromatic substituted with an -N(alk)COOR in which R, 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.

The compounds of formula for which R 2 and/or R, and/or R 4 represent an aromatic substituted with -COOR, may also be prepared by esterification of a derivative of formula:

R

3 R4--R N7 (IX) for which R represents a chain C=C(SO, 2 or C(OR')CH(SO2R,)R' 2

R'

2 and R' 4 have the same meanings as the substituents Ri, R 3 and R 4 of formula with the proviso that at least one of the substituents R' 2 and represents an aromatic or a heteroaromatic substituted with carboxyl, using a 19 derivative of formula ROH for which R 5 is alkyl or phenyl optionally substituted with one or more halogens.

When R, is alkyl, this reaction is generally carried out in the presence of an inorganic acid (sulfuric acid for example), at a temperature of between 20 0 C and the boiling temperature of the reaction medium. When R s is optionally substituted phenyl, this reaction is preferably carried out in the presence of a carbodiimide (l-(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 example), at a temperature of between 0°C and the boiling temperature of the reaction mixture.

The derivatives of formula (IX) for which R represents a chain C=C(SO 2 or C(OR')CH(SO 2 R )R' 2

R'

2

R'

3 and have the same meanings as the substituents RI, R 2 R, and R, of the formula (I) with the proviso that at least one of the substituents R' 2 R' and represents an aromatic or a heteroaromatic substituted with carboxyl may be obtained according to the methods described above for the preparation of the compounds of formula from the corresponding intermediates and in particular according to the method described in Example 29.

The compounds of formula for which R, and/or R, and/or R 4 represent an aromatic or a heteroaromatic substituted with alkylthioalkyl may also be prepared by reaction of a derivative of formula (IX) for which R represents a chain C=C(SO, 2

R)R'

2 or C(OR')CH(SOR,)R',, R' R' 3 and have the same meanings as the substituents R 2 R, and R, of the formula with the proviso that at least one of the substituents and represents an aromatic or a 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 0

C.

The derivatives of formula (IX) for which R represents a chain C=C(SO2R)R' 2 or C(OR')CH(SOR,)R' 2

R

1

R'

3 and have the same meanings as the substituents R

I

R

2 R, and R 4 of the formula (I) with the proviso that at least one of the substituents

R'

2 and 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 for which R, and/or R 3 and/or R, represent an aromatic or a heteroaromatic substituted with hydroxyalkyl, in an inert solvent such as a chlorinated solvent (carbon tetrachloride or chloroform for example), at a temperature close to 20 0

C.

The compounds of formula for which R 2 and/or R, and/or R 4 represent an aromatic substituted with hydroxyalkyl in which the alkyl contains one carbon atom may also be prepared by reducing a compound of formula for which at least one of the substituents R 3 and R, represents an aromatic substituted with formyl.

This reaction is generally carried out using sodium borohydride, in a 1-4C aliphatic alcohol (methanol or ethanol for example), at a temperature close to 0°C.

The compounds of formula for which R, and/or R 4 represents an aromatic substituted with -alk-NRR 7 for which alk is an alkyl containing one carbon atom may also be prepared by reacting a compound of formula for which at least one of the substituents R, and R 4 represents an aromatic substituted with formyl with an amine HNR 6 R, in which R 6 and R, have the same meanings as in formula This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloroethane for example), at a temperature close to 0 C in the presence of sodium triacetoxyborohydride or sodium cyanoborohydride.

The compounds of formula for which R, represents an aromatic or a heteroaromatic substituted r 22 with -CONHR, and/or R, and/or R 4 represents an aromatic or heteroaromatic substituted with -CO-NRioR, 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

C(OR')CH(SORI)R'

2

R

1 R' R' 3 and R' 4 have the same meanings as the substituents R, and R, of the formula with the proviso that at least one of the substituents R' and represents an aromatic or a heteroaromatic substituted with carboxyl with respectively an amine H 2

NR

9 or HNRioR 1 in which and Rl have the same meanings as in formula 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 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, 1,2dichloroethane or chloroform for example) at a temperature of between 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: 0 F 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 0 C. The binding to the resin is generally carried out-in dimethylformamide, in the presence of 4-dimethylaminopyridine and 1,3-diisopropylcarbodiimide, at a temperature close to 20 0

C.

The compounds of formula for which R 2 and/or R, and/or R, represent an aromatic or a heteroaromatic substituted with -CO-NH-NR 6 R, may also be prepared by reacting a corresponding compound of formula for which R, and/or R, and/or R 4 represent an aromatic or a heteroaromatic substituted with -COOR, and

R

s represents an alkyl or phenyl radical optionally substituted with halogens, with a hydrazine H 2 N-NRgR, for which R 6 and R 7 have the same meanings as in formula This reaction is generally carried out in an inert solvent such as dimethylformamide, at a temperature close to 20 0

C.

The compounds of formula for which R 2 represents an aromatic or a heteroaromatic substituted with -CO-NHR, in which R 9 represents a hydrogen atom and/or R, and/or R, represent an aromatic or a heteroaromatic substituted with -CO-NR,R. in which R, 0 and RI, are hydrogen atoms may also be prepared by hydrolysis of a corresponding compound of formula (I) for which R 2 and/or R, and/or R 4 represent an aromatic or 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 rest of the molecule. Preferably, the procedure is carried out using hydrochloric acid, in acetic acid, at a temperature close to 20 0

C.

The compounds of formula for which R 2 represents an aromatic substituted with -O-alk-NR 2

R,

may also be prepared by reacting a derivative of formula (IX) for which R represents a chain C=C(SO 2

R'

2 or C(OR')CH(SO 2

R

I

R

2 and have the same meanings as the substituents R 2 R, and

R

4 of the formula with the proviso that at least one of the substituents or R 4 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, in which R 2

R

13 have the same meanings as in formula 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 0

C.

The derivatives of formula (IX) for which R represents a chain C=C(SOR )R' 2 or C(OR')CH(SO 2 R) R' 2

R

1

R

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

R

2 or represents an aromatic substituted with -O-alk-Hal in which alk represents an alkyl radical and Hal represents a halogen atom may be obtained by reacting a corresponding compound of formula for which R 2 represents an aromatic substituted with hydroxide with a Hal-alk-Hal derivative in which Hal represents a halogen.

This reaction is generally carried out in an inert solvent such as a ketone (methyl ethyl ketone for example), in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), at the boiling temperature of the reaction medium.

The compounds of formula for which R, and/or R 4 represents an aromatic substituted with -alk-NR 6

R

7 may also be prepared by reacting a derivative of formula (IX) for which R represents a chain

C=C(SOR,)R'

2 or C(OR')CH(SO 2

R,)R'

2

R

2 and have the same meanings as the substituents RI, R R, and R 4 of the formula with the proviso that at least one of the substituents R 3 or R 4 represents a substituted aromatic -alk-Cl in which alk represents an alkyl radical with an amine HNR 6 R in which R 6

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 26 (dichloromethane for example), optionally in the presence of a nitrogen base such as dimethylaminopyridine, diisopropylethylamine, at a temperature of between 5 and 25 0

C.

The derivatives of formula (IX) in which R represents a chain C=C(SOR) or C(OR')CH(SO,R)R R', Ri, and have the same meanings as the substituents Ri, R 2

R

3 and R 4 of the formula (I) with the proviso that at least one of the substituents or R 4 represents an aromatic substituted with -alk-Cl may be obtained by reacting thionyl chloride with a corresponding compound of formula for which at least one of the substituents R, or R 4 represents an aromatic substituted with one or more hydroxyalkyl 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 0

C.

The compounds of formula 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 diisobutylaluminum hydride with a corresponding compound of formula for which R represents a chain B, R' represents a hydrogen atom and R, and/or R 4 27 represents an aromatic substituted with one or more

-COOR

5 radicals, in which R 5 is an alkyl radical.

This reaction is generally carried out in toluene, at a temperature of between -30 0 C and 0°C.

The compounds of formula for which R, represents a phenyl radical substituted with- -NR6R, 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 for which R 2 represents a phenyl radical substituted with a radical -NR 6

R

7 representing a 1-piperazinyl ring with an alk-CHO derivative in which alk represents a straightor branched-chain alkyl radical containing 1 to carbon atoms.

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 at a temperature close to 0

C.

The compounds of formula 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 for which R, 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 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 0

C.

R,

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 formula for which R 2 represents a phenyl radical substituted with -NR 6 R 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 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.

The compounds of formula for which R 2 represents a phenyl radical substituted with a radical

-NR

6

R

7 representing a 1-piperazinyl ring substituted at the 4 position with a radical -CO-alk-NR,,R, may also be prepared by reacting a corresponding compound of formula 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

R,

1

R,

1 N-alk-COOH in which alk represents an alkyl radical and R 14 and R, have the same meanings as in formula optionally followed by deprotection of the product for which R, 1 is -a tert-butoxycarbonyl radical in order to obtain the compounds for which R 4 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 0 C. The deprotection is carried out using formic acid at a temperature close to 20 0

C.

The compounds of formula for which R, 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 represents a methyl radical may also be prepared by reacting a corresponding compound of formula for which R 2 represents a phenyl radical substituted with a radical -NR 6

R

7 representing a 1-piperazinyl ring with acetic anhydride.

This reaction is generally carried out in the presence of pyridine, at a temperature close to 200C.

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 necessary to introduce groups protecting amino, hydroxyl and carboxyl functions in order to avoid side reactions. These groups are those which allow removal 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 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 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-l,3oxazolines. Other protecting groups which can be used are described by GREENE T.W. et al., Protecting Groups in Organic Synthesis, second edition, 1991, John Wiley Sons.

The compounds of formula may be purified by the customary known methods, for example by crystallization, chromatography or extraction.

The enantiomers of the compounds of formula 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, Academic Press (1983) or by formation of salts or by synthesis from chiral precursors. The diastereoisomers may be prepared according to known conventional methods (crystallization, chromatography or from chiral precursors).

The compounds of formula may be optionally converted to addition salts with an 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 salts, the following salts may be mentioned: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methane sulfonate, methylene-bis- S-oxynaphtoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllineacetate and p-toluenesulfonate.

The compounds of formula exhibit advantageous pharmacological properties. These compounds possess a high affinity for the cannabinoid receptors and particularly those of the CB1 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 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 and Sandyk, in Marijuana/Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds, CRC Press, 1992) of bacterial, viral and parasitic infections.

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 attacks, peripheral neuropathies, glaucomas, migraine, Parkinson's disease, Alzeimer's disease, Huntington's chorea, Raynaud's syndrome, tremor, obsessivecompulsive disorder, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar 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 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 and nonnarcotic drugs. They may also be used for the treatment or prevention of intestinal transit disorders, as antibacterial, antiviral and 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., STEVENSON WARD D'AMBRA HAYCOCK D.A.

in J. Pharmacol. Exp. Ther., 264 1352-1363 (1993).

In this test, the ICs 0 of the compounds of formula is less than or equal to 100 nM.

Their antagonist activity has been shown by 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 formula is less than or equal to 50 mg/kg.

The compounds of formula exhibit low toxicity. Their LD 50 is greater than 40 mg/kg by the subcutaneous route in mice.

The preferred compounds of formula are those for which R represents a chain or 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 naphthyl, these aromatics being nonsubstituted or substituted with one or more halogens, alkyl, alkoxy, hydroxyl, -COOR,, trifluoromethyl, trifluoromethyl- 34 sulfanyl, trifluoromethoxy, -NR 6

-CO-NH-NR

6 cyano, -CONHR,, alkylsulfanyl, hydroxyalkyl, nitro, -CO-NR 6 -O-alkNR 2

R

13 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 substituted with a halogen, alkyl, alkoxy, -COOR,, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, -NRR

-CO-NH-NR

6

R

7 cyano, -CONHR,, alkylsulfanyl, hydroxyalkyl, nitro or alkylthioalkyl, R, and which are identical or different, represent either an aromatic chosen from phenyl or naphthyl, these aromatics being nonsubstituted or substituted with one or more halogens, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CONRIoR -alk-NR 6

R

hydroxyalkyl, formyl or -COOR s or a heteroaromatic chosen from thiazolyl or thienyl rings, these heteroaromatics being unsubstituted or substituted with a halogen, alkyl, alkoxy, -CONR 1 oR,, -alk-NR 6

R

7 hydroxyalkyl or -COOR,.

Rs is alkyl or phenyl which is optionally substituted with one or more halogens, R, and R 7 which are identical or different, represent a 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 atom to which they are attached a 3- to 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-NR4,R 5 oxo, hydroxyalkyl, alk-O-alk or -CO-NH, radicals,

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 heteroatoms chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,

R,

1 and R n which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R, 0 and R 1 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated monoor bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl radical, R, and R which are identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical or alternatively R 12 and R 13 together form with the nitrogen atom to which they are attached a 3- to saturated mono- or bicyclic heterocycle optionally 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 4

R

5 radical or a 3- to 10-membered saturated mono- or bicyclic heterocycle containing a heteroatom chosen from oxygen, sulfur and nitrogen,

R

14 and R 1 s, 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 they are attached a 3- to 10-membered saturated monoor 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 or organic acid.

The compounds of formula which are particularly preferred are those for which R represents a chain or R' representing a hydrogen atom or a radical -COalk, 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, alkoxy, hydroxyl, -COOR s (in which R 5 represents an 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 radical or alternatively R, 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 -CO-alk-NR,R 5 radicals, in which R 1 and Ri 5 which are identical or different, represent a hydrogen atom or an alkyl radical), -CO-NH-NRR, and which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R 6 and R, together form with the nitrogen atom to which they are attached a 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 substituted with -COOalk) or a heterocycle chosen from pyrrolidinyl (optionally substituted with alkyl), tetrahydrofuryl, or morpholinyl), alkylsulfanyl, hydroxyalkyl, nitro, -CO-NR, 6

R

7 (in which R 16 and R 17 together form with the nitrogen atom to which they are attached a piperidyl ring), -O-alkNR 2 (in which R 12 and R, together form with the nitrogen atom to which they are attached a morpholino ring) or alkylthioalkyl, or a heteroaromatic chosen from isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thienyl, or thienyl substituted with a -COOR s (in which R represents an alkyl radical) or -CONHR,, (in which R, represents an alkyl radical), R, and which are identical or different, represent either an aromatic chosen from phenyl or phenyl substituted with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, hydroxyalkyl, formyl, -COOR, (in which R, is an alkyl radical), -CONRiR, (in which R 10 and which are identical or different, represent a hydrogen atom or an alkyl radical), -alk-NRR, (in which R, and which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively R 6 and R 7 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 with alkyl, hydroxyalkyl, -alk-O-alk or -CO-NH,), thiomorpholinyl, morpholinyl, pyrrolyl, piperazinyl 39 optionally substituted with oxo, alkyl, hydroxyalkyl,

-COOR

s (in which R 5 is an alkyl radical), or a heteroaromatic chosen from thiazolyl or thienyl, alk represents an alkyl or alkylene radical-; their optical isomers and their salts with an inorganic or organic acid.

Preferably, R, is a substituted phenyl 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, is a substituted phenyl 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 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: l-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]azetidine, l-benzhydryl-3- [(3-methyiphenyl) (methylsulfonyl)rnethylene] azetidine, 1-benzhydryl-3- [(3-chiorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- 5-dichiorophenyl) (methylsulfonyl) methyleielazetidine, 1-benzhydryl-3- 5-dichiorophenyl) (iethylsulfonyl) methylene] azetidine, 1-benzhydryl-3- 3-dichiorophenyl) (rethylsulfonyl) rnethylene] azetidine, 1-benzhydryl-3- luorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- 5-difluorophenyl) (rethylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3-bromophenyl) (methylsulfonyl) inethylene] azetidine, 1-benzhydryl-3- [(3-iodophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(methylsulfonyl) (3-trifluorornethoxyphenyl)methylene] azetidine, 1-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethylphenyl) methylene] azetidine, 1-benzhydryl-3-{ 5-bis (trifluoromethyl)phenyl] (methylsulfonyl )methylene} azetidine, 1-benzhydryl-3- 5-dibromophenyl) (methylsulfonyl) rnethylene] azetidine, 1-benzhydryl-3- [(3-methoxycarbonyiphenyl) (methylsulfonyl)rnethylene] azetidine, 41 1-benzhydryl-3- [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3-cyanophenyl) (methylsulfonyl) inethylene] a~etidine, 1-benzhydryl-3- [(3-carbamayiphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(methylsulfonyl) (naphth-1-yl) (rethylsulfonyl) methylene] azetidine, 1-[bis(4-chlorophenyl)methyl]-3- (methylsulfonyl)methylenellazetidine, 1- [bis (4-methoxyphenyl)methyl] 5-difluorophenyl) (rethylsul fonyl)mrethylene] azetidine, 1-[bis(4-methylphenyl)methyl]-3- (methylsulfonyl)methylene] azetidine, (3,5-difluorophenyl) (methylsulfonyl)methylenel- 1- [(4-methoxyphenyl) (phenyl)rnethyl) ]azetidine, [(3,5-difluorophenyl) (rethylsulfonyl)rnethylene] 1- [(4-methoxyphenyl) (phenyl)methyl) Iazetidine, (3,5-difluorophenyl) (methylsulfonyl)methylene]- 1- [(4-methoxyphenyl) (phenyl)methyl) ]azetidine, 1-[bis(4-trifluoromethoxy-phenyl)methyl]-3- diE luorophenyl (methylsulfonylL)methylene]azetidine, 1-[bis(4-trifluoromethylphenyl)methyl]-3-[ diE luorophenyl (methylsulfonyl)methylenelazetidine, 1-[bis(4-chlorophenyl)methyl]-3-{ (trifluoromethyl )phenyl] methyl sulfonylrnethylene} azetidine, (RS) -l-Il(4-chiorophenyl) (2,4-dichlorophenyl)methyl]- 3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, [(4-chiorophenyl) (2,4-dichlorophenyl)methyl]- 3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (2,4-dichlorophenyl)methyl]- 3- 5-difluorophenyl) (rethylsulfonyl)rnethylenelazetidine, (4-chiorophenyl) [4-hydroxymethyl)phenyl] methyl}-3- 5-difluorophenyl) (rethylsulfonyl)methylene] azetidine, (4-chiorophenyl) (hydroxymethyl)phenyl]methyil}-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (hydroxyrnethyl)phenyl] methyl}-3- 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) (4-chiorophenyl) (pyrrolidylmethyl)phenyl]rnethyil}73- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (pyrrolidylrnethyl)phenyl]methyl}-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (pyrrolidylmethyl)phenyl]methyl}-3- 5-difluorophenyl) (rethylsulfonyl)methylene] azetidine, (RS)-(4-chlorophenyl) (3,3-dimethylpiperidin-1-ylmethyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl )methylene] azetidine, (R)-(4-chlorophenyl) [4-(3,3-dimethylpiperidin-1-ylmethyl)phenyllmethyl} 5-difluorophenyl) (methylsulfonyl)methylele] azetidine, (S)-(4-chlorophenyl) [4-(3,3-dirnethylpiperidin-1-ylmethyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-{(RS)-(4-chlorophenyl) (thiomorpholin-4ylrethyl)phenyl]methyl}-3- (methylsulfonyl)methylene] azetidine, CR) -(4-chiorophenyl) (thiomorpholin-4ylmethyl)phenyl]methyl}-3- 5-difluorophenyl) (methylsulfonyl)methylenelazetidine, (S)-(4-chlorophenyl) (thiomorpholin-4ylmethyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl)rnethylene] azetidine, (RS)-(4-chlorophenyl) (N-ethyl-Ncyclohexylaminomethyl)phenyllmethyl}-3- difluorophenyl) (methylsulfonyl)methylenelazetidine, CR) -(4-chiorophenyl) (N-ethyl-Ncyclohexylaminomethyl)phenyl]rnethyl}-3- difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-{(S)-(4-chlorophenyl) [4-(N-ethyl-Ncyclohexylaminomethyl)phenyllrethyl}-3- difluorophenyl) (methylsulfonyl)methylene] azetidine, -(4-chiorophenyl) [(4-ethoxycarbonylpiperazinyl)methyllphenyl}methyl)}1-3- difluorophenyl) (methylsulfonyl)methylene]azetidine, -(4-chiorophenyl) [(4-ethoxycarbonylpiperazinyl)methyllphelyl}fethyl}}-3- difluorophenyl) (methylsulfonyl)methylenelazetidine, -(4-chiorophenyl) [(4-ethoxycarbonylpiperazinyl)methyllphenyl}methyl} 1-3- difluorophenyl) (methylsulfonyl)methylene]azetidine, (RS) -(4-chiorophenyl) (N-cyclopropyl-N-propylaminomethyl)phenyllmethyl}-3- 5-difluorophenyl) (rethylsuilfonyl)methylene] azetidine, -(4-chiorophenyl) (N-cyclopropyl-N-propylaminomethyl)phenyllmethyl}-3- 5-difluorophenyl) (rethylsulfonyl)methylenelazetidine, (4-chiorophenyl) (N-cyclopropyl-N-propylaminomethyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (RS) -(4-chiorophenyl) (diisopropylaminomethyl) phenyllrnethyl}-3-[E(3,5-difiluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (diisopropylaminomethyl)phenylLmethyl}-3- 5-difluorophenyl) (methylsulfonyl )methylene] azetidine, -(4-chiorophenyl) (diisopropylaminomethyl) phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chlorophenyl) {4-[bis-(2--methoxyethyl)aminomethyllphenyl}methyl} 1-3-11(3, 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-U (R)-(4-chlorophenyl) {4-[bis-(2-methoxyethyl)aminomethyliiphenyl}methyl}}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylenel azetidine,- (4-chiorophenyl) {4-[bis- (2-methoxyethyl)aminomethyllphenyl}methyl} 1-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (RS) -(4-chiorophenyl) (di-n-propylaminomethyl)phenyl]methyl}-3-[1(3, 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, -(4-chiorophenyl) (di-n-propylarninomethyl)phenyllmethyl}-3- 11(3,5-difluorophenyl)- (methylsulfonyl)inethylene] azetidine, -(4-chiorophenyl) (di-n-propylaminomethyl)phenyllmethyl}-3- 11(3,5-difluorophenyl)- (methylsulfonyl)methylene] azetidine, (RS) -(4-chiorophenyl) (piperidin-1-ylmethyl) phenyllmethyl}-3-[ 5-difluorophenyl) (rethylsulfonyl) methylene] azetidine, -(4-chiorophenyl) (piperidin-1-ylmethyl) phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-{(S)-(4-chlorophenyl) (piperidin-1-ylmethyl)phenyllmethyl}-3- 5-difluorophenyl) (iethylsulfonyl) methylene] azetidine, (4-chloropheiyl) (4-methylpiperazin-1-ylrethyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl )methylene] azetidine, (R)-(4-chlorophenyl) (4-methylpiperazin-l-ylmethyl)pheflyllmethyl}-3-[ (3,5-difluorophenyl) (methylsul fonyl) methylene] azetidine, (4-chiorophenyl) (4-rethylpiperazin-1-ylrethyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl )methylene] azetidine, (RS)-(4-chlorophenyl) (rorpholin-4-ylrethyl)phenyllmethyl}-3- (methylsulfonyl)methylene] azetidine, (R)-(4-chlorophenyl) (morpholin-4-ylmethyl)phenyllmethyl}-3- (rethylsulfonyl)methylene] azetidine, (S)-(4-chlorophenyl) (rorpholin-4-ylmethyl)phenyl]methyl}-3- 5-difluorophenyl) (rethylsulfonyl)methylene] azetidine, (RS) -(4-chiorophenyl) (diethylaminomethyl)phenyllmethyl}-3-[ (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (diethylaminornethyl)phenylllmethyl}-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (diethylaminornethyl)phenyl~methyl}-3- (methylsulfonyl)methylene] azetidine, 47 (RS)-(4-chlorophenyl) (piperazin-2-on-4-ylmethyl~phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl) methylenel azetidine, (R)-(4-chliorophenyl) (piperazin-2-on-4-ylmethyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S)-(4-chlorophenyl) (piperazin-2-on-4-ylmethyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl)mrethylene Iazetidine, l-{(RS)-(4-chlorophenyl) [4-(imidazol-1-ylmethyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, -(4-chiorophenyl) (imidazol-1-ylmethyl)phenyl]methyl}-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, l-{(S)-(4-chlorophenyl) [4-(imidazol-1-ylrethyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (N,N-dimethylcarbamoyl)phenyllmethyl}-3- [(3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (N,N-dirnethylcarbarnoyl)phenyllmethyl}-3- [(3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (N,N-dimethylcarbamoyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 48 (4-chiorophenyl) (N-ethylcarbamoyl)phenyl]rnethyl}-3- 5-difluoropheiyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (N-ethylcarbamoyl)phenyl]methyl}-3-[1(3, 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (N-ethylcarbamoylL)phenyl]methyl}-3- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (RS) [(4-carbamoylphenyl) (4-chlorophenyl)methyl] 3- 5-difluorophenyl) (methylsulfonyl)rnethylene] azetidine, [(4-carbamoylphenyl) (4-chlorophenyl)methylL]- 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, -1-f(4-carbamoylphenyl) (4-chilorophenyl)methyl] 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 1- [bis (4-chlorophenyl)methyl] 5-dichiorophenyl) (methylsulfonyl)methylene] azetidine, 1-benzhydryl-3- [(3-methylsulfanylphenyl) (methylsulfonyl)methylene] azetidine, 1-benzhydryl-3- [(3-methylsulfanylrnethyl)phenyl)] (methylsulfonyl) methylene] azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)- (methylsulfonyl)methylene] azetidine, 1- [bis (4-chlorophenyl)rnethyl] [(3-carbamoylphenyl) (methylsulfonyl)methylene] azetidine, 1- [bis(4-chlorophenyl)methyl] [(3-methoxyphenyl)- (rethylsulfonyl)rnethylene] azetidine, 1- [bis(4-chlorophenyl)methYl] -3-Il(3-hydroxyphenyl)- (methylsulfonyl )methylenel azetidine, 1- [bis (4-chlorophenyl)mfethyl] -3-f (3-rnethylsulfonyl) (3-pyrrolidinylphenyl)methYlelazetidine, 1- [bis (4-chlorophenyl)methyl] -3-f (3-hydroxymethylphenyl) (methylsulfonyl)methylene] azetidine, 1-[bis(4-chlorophenyl)methyl]3-{ (methylsulfonyl) (Npiperidylcarbamoyl) phenyl ]methylenel azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[ (methylsulfonyl)- (3-trifluorornethylsulfanylphenyl) (methylsulfonyl) methylene] azetidine, 1-[bis(4-fluorophenyl)methyll-3-[ (methylsulfonyl)methylene] azetidine, 1- [bis (2-fluorophenyl)methyl] 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 1- [bis (3-f luorophenyl)methyl] 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, [(4-chiorophenyl) (thiazol-2-yl)rnethyl]- 3- [(methylsulfonyl) (phenyl)rnethylenelazetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]- 3-f (methylsulfonyl) (phenyl)methylene]azetidine, (S)-1-[(4-chlorophenyl) (thiazol-2-yl)rnethyl]- 3-f (methylsulfonyl) (phenyl)methylene]azetidine, (RS)-1-[(4-chlorophenyl) (thien-2-yl)rethyl]-3-H(3,5difluorophenyl) (methylsulfonyl)methylene] azetidine, (R)-1-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5difluorophenyl) (rethylsulfonyl)methylene] azetidine, (S)-1-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5difluorophenyl) (methylsulfoiyl)rnethylene] azetidine, 1-benzhydryl-3- [(ethylsulfonyl) (phenyl)methylene] azetidine, 1- [bis (4-chlorophenyl)methyll (4methylpiperazinyl) carbamoyl] phenyll (methylsulfonyl) methylene] azetidine, 1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2dimethylcarbohydrazido)phenyl] (methylsulfonyl) methylene} azetidine, 1- [bis (thien-2-yl)methyl] 5-difluorophenyl) (rethylsulfonyl)methylene] azetidine, 1-[bis(p-tolyl)rnethyl]-3-[ (methylsulfonyl) (phenyl)rnethylene] azetidine, 1- [4-chiorophenyl) (4-hydroxymethylphenyl)methyll 3- 5-difluorophenyl) (rethylsulfonyl)methylene] azetidine, 1- [bis (4-chlorophenyl)rnethyl] [(3-methylaminophenyl) (methylsulfonyl)methylene] azetidine, (RS)-1-[(4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5difluorophenyl) (methylsulfonyl)methylene]azetidine, (R)-1-[(4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5difluorophenyl) (rethylsulfonyl)methylene]azetidine, (S)-l-[(4-chlorophenyl) (thiazol-2-yl)rnethyl]-3-[ difluorophenyl) (rethylsulfonyl)methylene]azetidine, 1-[bis(4-chlorophenyl)methyll-3-[ (methylsulfoayl) (2azetidine, (bis (4-chlorophenyl)methyl] -3-hydroxy-3- [(methylsulfonyl)

(RS),

1- [bis (4-chlorophenyl)methyl] -3-Il(2-isobutyl- (methylsulfonyl) methylene] azetidine, 1- [bis(4-chlorophenyl)methyl]-3-[ (3-methoxycarbonylphenyl) (methylsulfonyl)methyl- (RS)azetidin-3-ol, 1- Ibis (4-chlorophenyl)methyl]-3- [(rethylsulfonyl) (pyridin-4-yl)methyl- (RS) azetidin-3-ol, 1- [bis (4-chlorophenyl)rnethyl] -3-Il(methylsulfonyl) (pyridin-3-yl)methyl- (RS)azetidiri-3-ol, 3- bis (4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl) (3-morpholin-4-ylpropyl) benzamide, 3- ({1-[bis(4-chlorophenyl)methyllazetidin-3-ylidene}methanesulfonylmethyl) (3-dimethylaminopropyl) benzamide, 3- [bis(4-chlorophenyl)methyllazetidin-3-ylidene}methanesulfonylmethyl) (2-pyrrolidin-1-ylethyl) benzamide, 3- ({l-[bis(4-chlorophenyl)methyllazetidin-3-ylidene}methanesulfonylmethyl) (2-dimethylamino-1methylethyl )benzamide, 52 3- ({1-[bis (4-chlorophenyl)methyl] azetidin-3-ylidene} methanesul fonylmethyl) -N-piperidin- 1-ylbenzamide, 3- ({1-[bis (4-chlorophenyl)methyl] azetidin-3-ylideie}methanesulfbnylmethyl) -N-isobutylbenzamide, 3- ({l-[bis(4-chlorophenyl)methyllazetidin-3-ylidene}methanesulfonylmethyl) (3-imidazol-1-ylpropyl) benzamide, 3- ({1-[bis (4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl) (2-dimethylaminoethyl) benzarnide, 3- (4-chlorophenyl)methyllazetidin-3ylidenelmethanesulfonylmethyl)benzoic acid N' methyihydrazide, 3- (4-chlorophenyl)rnethyllazetidin-3-ylidene}iethanesulfonylmethyl) (2-morpholin-4-ylethyl) benzamide, 3- [bis- (4-chlorophenyl)methyllazetidin-3-ylidene}methanesulfonylmethyl) (l-ethylpyrrolidin-2ylmethyl) benzamide, (4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl) 2-dimethyipropyl )benzamide, 3- (4-chlorophenyl)methyllazetidin-3-ylidene}methanesulfonylmethyl) -N-cyclohexylmethylbenzamide, 3- [bis- (4-chlorophenyl)methyllazetidin-3-ylidene}methanesulfonylmethyl) -N-cyclopropylmethylbenzamide, 3- [bis- (4-chlorophenyl)methyllazetidin-3-ylidene}methanesulfonylmethyl) (2-methylbutyl) benzamide, 3- (4-chlorophenyl)methylllazetidin-3-ylidene}methanesulfonylmethyl) (2 -phenyipropyl) benzamide, 3- (4-chlorophenyl)methyl] azetidin-3-ylidene} methanesulfonylmethyl) (tetrahydrofuran-2ylniethyl) benzamide, 3- bis- (4-chlorophenyl)methyllazetidil-3-ylidele}methanesulfonyrnethyl) (2,2 -diphenylethyl )benzamide, 3-({1-[bis-(4-chlorophenyl)rnethyllazetidin-3-ylidene}methanesulfonylmethyl) (2-ethylbutyl) benzamide, 4-{1[3-({1-[bis(4-chlorophenyl)methyllazetidin-3ylidene}methanesulfonylmethyl )benzoylaminolmethyl}cyclo hexanecarboxylic acid methyl ester, 2-amino-l-{4- [bis- (4-chlorophenyllmethyl] azetidin- 3-ylidene }methanesul fonylmethyl)phenyl]piperazin-l-yllethanone, Ibis (4-chlorophenyl)methyl]azetidin-3ylidene}methanesulfonylrnethyl )phenyl] piperazin-l-yl 1-2oxoethyl)carbamic acid tert-butyl ester, Ibis- (4-chlorophenyl)methyl]azetidin-3yliderie}methanesulfonylrethyl)phenyllpiperazin-l-yl}- 2 methylaminoethanone, ((1-[bis (4-chlorophenyl)methyllazetidin-3ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}- 2 oxoethyl)-N-methylcarbamic acid tert-butyl ester, 4-[3-({l-[bis(4-chlorophenyl)methyl]azetidin-3ylidenelmethanesulfonylmethyl )phenyl] piperazine-1carbothioic acid N-methylamide, 4-13- [bis (4-chlorophenyl)methyllazetidin-3ylidene}methanesulfonylmethyl) phenyl] piperazine-1carboxylic acid N-methylamide, 4- ({1-[bis (4-chlorophenyl)methyl]azetidin-3ylidene}methanesulfonylmethyl)phenyllpiperazine-1carboxylic acid methyl ester, 1- [bis (4-chlorophenyl)methyl] azetidin-3ylidene}methanesulfonylmethyl) phenyl] -4i sobutylpiperazime, l-[3-({l-[bis(4-chlorophenyl)methylllazetidin-3ylidene}methanesulfonylmethyl) phenyl] -4ethylpiperazine, 4-acetyl 1-[3-({l-[bis(4-chlorophenyl)methyllazetidin- 3-ylidene}methanesulfonylmethyl )phenyl] piperazine, l-{4-[3-({l-[bis(4-chlorophenyl)methyllazetidin-3ylidene}rnethanesulfonylmethyl)phenyllpiperaziri-l-yl}-2dime thylaminoethanone, 1- [bis (4-chlorophenyl)methyl]azetidin-3ylidene}methanesulfonylmethyl )phenylipiperazine, 4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3ylidenelmethanesulfonylmethyl) phenyllpiperazine-lcarboxylic acid tert-butyl ester, 1- [bis (4-methoxycarbonylphenyl)methyl] -3-1(3,5difluorophenyl) (methylsulfonyl~methylene~azetidine, 3-acetoxy-l-[Ibis (4-methoxycarbonylphenyl)methyl] -3- 5-difluorophenyl) (methylsulfonyl)methyl- (RS) azetidine, (RS) ((4-chlorophenyl) 5-difluorophenyl) methanesulfonylmethylene] azetidin-l-yllmethyl) benzyllImorpho line, 4- I(l-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl] phenoxy}butyl)morpholine, 4- [(l-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl Iphenoxy}propyl )morpho line, their optical isomers and their esters.

Among these compounds, the following compounds are particularly preferred; l-[bis(4-chlorophenyl)methyl]-3-[ difluorophenyl) (methylsulfonyl)methylenelazetidine, 1-[bis(4-chlorophenyl)methyl]-3- phenyl) (methylsulfonyl)methylene(RS) ]azetidin-3-ol, 3-acetoxy-l-[bis(4-chlorophenyl)methyl]-3-[(3,5difluorophenyl) (methylsulfonyl) methyl)methylsulfonylmethyl (RS) ]azetidine their optical isomers and their salts with an inorganic or organic acid.

The following examples illustrate the invention without limiting it.

Example 1 0.3 CM 3 of methanesulfonyl chloride is added to a solution of 1 g of l-benzhydryl- 3- [(methylsulfonyl) (phenyl)methyl- (RS) ]azetidin-3-ol in cm 3 of pyridine, cooled to 5 0 C. The mixture is stirred for 2 hours at 5 0 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 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 cm), eluting at a nitrogen pressure of 0.5 bar with 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 residue is crystallized from 10 cm of ethyl ether.

0.14 g of l-benzhydryl- 3-[(methylsulfonyl)(phenyl)methylene]azetidine is obtained melting at 210 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), between 7.40 and 7.60 (9H, m, 9 CH arom.)].

l-Benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: 6.25 cm 3 of 1.6 N n-butyllithium in solution in hexane are added to a solution of 1.4 cm' of diisopropylamine in 10 cm of tetrahydrofuran, under an argon atmosphere, cooled to 0°C, and then the mixture is cooled to -70 0 C. A mixture of 1.7 g of benzyl methyl 57 sulfone in 30 cm' of tetrahydrofuran are then added and the stirring is maintained for 45 minutes at -70 0 C. 2.4 g of l-benzhydrylazetidin-3-one are added and then the mixture is stirred for 20 minutes while allowing the 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 of ethyl acetate, 30 cm' of water and 20 cm 3 of normal hydrochloric acid. The precipitate is filtered, washed with 30 cm of distilled water, drained and dried. 2 g of l-benzhydryl- 3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol are obtained melting at 260 0

C.

l-Benzhydrylazetidin-3-one may be prepared according to the procedure described by KATRITZKY A.R.

et al. in J. Heterocycl. Chem., 271 (1994).

Example 2 On carrying out the operation according to the procedure of Example 1 starting with 1.9 g of l-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 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 dichloromethane and then a dichloromethane and ethanol mixture (98.5/1.5 by volume) as eluents and collecting 100 cm 3 fractions. Fractions 5 and 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 2 cm 3 of dichloromethane and 20 cm 3 of diisopropyl ether. 0.9 g of l-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methylene]azetidine is obtained melting at 180 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 2.35 (3H, s, PhCH,), 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), 7.20 (5H, m, arom.), 7.30 (5H, t, J=7Hz, 5CH arom.), 7.50 (4H, d, J=7Hz, 4 CH arom.)].

l-Benzhydryl-3-[(3-methylphenyl)- (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 l-benzhydrylazetidin-3-one, 2.6 g of a 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 diisopropyl ether. After filtration, draining and drying, 1.9 g of l-benzhydryl-3-[(3-methylphenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained melting at 170C.

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 3 of ethanol are added, at room temperature, to a solution of 30 cm 3 of water, 30 cm 3 of acetic acid and 15 cm 3 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 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.

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 0 C, to a solution of 3.7 g of 3-methylbenzyl bromide in 25 cm 3 of dimethylformamide. The mixture is stirred for 2 hours at a temperature close to 20 0 C and then taken up in 50 cm 3 of ethyl acetate. The organic phase is washed with 3 times 100 cm 3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 2.6 g of methyl(3-methylbenzyl)sulfide are obtained in the form of an oil.

Example 3 0.3 cm 3 of methanesulfonyl chloride is added to a solution of 3.3 g of l-benzhydryl-3-[(4methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol in 10 cm 3 of pyridine, cooled to 5 0 C. The mixture is stirred for 2 hours at 5 0 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 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 cm), eluting at a nitrogen pressure of 0.5 bar with 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 l-benzhydryl-3-[(4-methylphenyl)- (methylsulfonyl)methylene]azetidine is obtained melting at 210 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.30 (3H, s, PhCH,), 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20- (2H, s, NCH,), 4.75 (1H, s, NCH), 7.20 (4H, m, 4CH arom.), 7.30 (6H, t, J=7Hz, 6CH arom.), 7.45 (4H, d, J=7Hz, 4 CH arom.)].

l-Benzhydryl-3-[(4-methylphenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be 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 l-benzhydrylazetidin-3-one, 3 g of l-benzhydryl-3-[(4-methylphenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol are obtained melting at 226 0

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 3.5 g of methyl(4-methylbenzyl)sulfide and 12.3 g of oxone", 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 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.

Example 4 0.7 cm 3 of methanesulfonyl chloride and then 3.8 g of 4-dimethylaminopyridine are added to a solution of 3.3 g of l-benzhydryl-3-[(2-methylphenyl)- (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 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 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 dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 50 cm 3 of ethyl ether. 2.6 g of l-benzhydryl-3-[(2-methylphenyl)- (methylsulfonyl)methylene]azetidine are obtained in the form of a foam [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 2.30 (3H, s, PhCH,), 2.95 (3H, s, SCH,), 3.50 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.70 (1H, s, NCH) between 7.10 and 7.35 (10H, m, 10CH arom.), 7.45 (4H, m, 4CH arom.)].

l-Benzhydryl-3-[(2-methylphenyl)- (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 l-benzhydrylazetidin-3-one, 3.4 g of l-benzhydryl-3-[(2-methylphenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol are obtained melting at 218 0

C.

Methyl(2-methylbenzyl)sulfone may be prepared in the following manner: by carrying out the operation according to the procedure of Example 2 starting with g of methyl(2-methylbenzyl)sulfide and 16.2 g of oxone", 3.4 g of methyl(2-methylbenzyl)sulfone are obtained in the form of a solid.

Methyl(2-methylbenzyl)sulfide may be prepared in the following manner: on carrying 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 sodium methylthiolate, 4.5 g of methyl(2-methylbenzyl)sulfide are obtained in the form of a solid.

Example On carrying out the operation according to the procedure of Example 4 but starting with 2.1 g of l-benzhydryl-3-[(2-chlorophenyl) (methylsulfonyl)methyl- (RS)]azetidin-3-ol, 0.55 cm of methanesulfonyl chloride and 2.3 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 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 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 3 of ethyl 64 ether. 1.1 g of l-benzhydryl-3-[(2-chlorophenyl)- (methylsulfonyl)methylene]azetidine are obtained melting at 204 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz) 2.95 (3H, s, SCH,), 3.60 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.70 (1H, 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 (1H, d, J=7Hz, CH arom.)].

l-Benzhydryl-3-[(2-chlorophenyl)- (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 4 g of (2-chlorobenzyl)methylsulfone and 4.6 g of l-benzhydrylazetidin-3-one, the residue obtained is taken up in 50 cm 3 of ethyl acetate, filtered and dried. 2.4 g of l-benzhydryl-3-[(2chlorophenyl)(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 according to the procedure of Example 2 starting with 3.4 g of (2-chlorobenzyl)methylsulfide and 12 g of oxoneR, 4 g of (2-chlorobenzyl)methylsulfone are obtained in the form of an oil which crystallizes.

(2-Chlorobenzyl)methylsulfide may be prepared 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 methylthiolate, 3.4 g of (2-chlorobenzyl)methylsulfide are obtained in the form of an oil.

Example 6 On carrying out the operation according to the procedure of Example 4 starting with 3 g of l-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 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 concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from cm 3 of ethyl ether. 1.7 g of l-benzhydryl-3-[(3chlorophenyl)(methylsulfonyl)methylene]azetidine are obtained melting at 205 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz) 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 (8H, m, 8CH arom.)].

l-benzhydryl-3-[(3-chlorophenyl)- (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 3.1 g of (3-chlorobenzyl)methylsulfone and 3.4 g of l-benzhydrylazetidin-3-one, 3.4 g of l-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol are obtained in the form of a white 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 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 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 On carrying out the operation according to the procedure of Example 4 starting with 3.3 g of l-benzhydryl-3-[(4-chlorophenyl)(methysulfonyl)methyl- (RS)]azetidin-3-ol, 0.87 cm of methanesulfonyl chloride 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 3 fractions. Fractions 8 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 3 cm 3 and 30 cm 3 of ethyl ether. 0.5 g of l-benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)methylene]azetidine is obtained melting at 192 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 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.)].

l-Benzhydryl-3-[(4-chlorophenyl)- (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 l-benzhydrylazetidin-3-one, 3.4 g of l-benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol are obtained in the form of a white solid after crystallization from 80 cm.

(4-Chlorobenzyl)methylsulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with g of (4-chlorobenzyl)methylsulfide and 12.3 g of oxoneR, 3.5 g of (4-chlorobenzyl)methylsulfone are obtained in the form of a solid.

Example 8 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 of methanesulfonyl chloride and 3.1 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 with dichloromethane as eluent and collecting 100 cm 3 fractions. Fractions 6 to 10 are combined and 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' of ethyl ether. 0.8 g of l-benzhydryl-3-[(3,5-dichlorophenyl)- (methylsulfonyl)methylene]azetidine is obtained melting at 204 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.85 (2H, s, NCH,), 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 (1H, s, CH arom.)].

l-Benzhydryl-3-[(3,5-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 starting with 4 g of and 4 g of l-benzhydrylazetidin-3-one, 3.2 g of l-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid.

may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 5.3 g of methylsulfide and 17 g of oxone", 5 g of dichlorobenzyl)methylsulfone are obtained in the form of a white solid.

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-dichlorobenzyl chloride and 2 g of sodium methylthiolate, 5.3 g of dichlorobenzyl)methylsulfide are obtained in the form of an oil.

Example 9 On carrying out the operation according to the procedure of Example 4 starting with 5 g of l-benzhydryl-3-[(3,4-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol, 1.2 cm 3 of methanesulfonyl 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 with a mixture of cyclohexane and ethyl acetate (70/30 by volume) as eluent and collecting 35 cm 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. 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, 6 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH 2 4.20 (2H, s, NCH,), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), between 7.35 and 7.50 (5H, m, 5CH arom.), 7.65 (2H, m, 2CH arom.)].

l-Benzhydryl-3-[(3,4-dichlorophenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol may be 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, g of l-benzhydryl-3-[(3,4-dichlorophenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid.

(3,4-Dichlorobenzyl)methylsulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 4.3 g of (3,4-dichlorobenzyl)methylsulfide and 13 g of oxone", 4.7 g of (3,4dichlorobenzyl)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 starting with 2.8 cm 3 of 3,4-dichlorobenzyl chloride and g of sodium methylthiolate, 4.3 g of (3,4dichlorobenzyl)methylsulfide are obtained in the form of an oil.

Example On carrying out the operation according to the procedure of Example 4 starting with 1.8 g of l-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)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 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 l-benzhydryl-3-[(2,5-dichlorophenyl)- (methylsulfonyl)methylene]azetidine are obtained melting at 202 0 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, m, 3CH arom.)].

l-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 starting with 1.2 g of methylsulfone and 1.2 g of l-benzhydrylazetidin-3-one, 1.8 g of l-benzhydryl-3-[(2,5-dichlorophenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid.

(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 cm 3 of ethanol. The mixture is heated under reflux 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 saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 1.2 g of dichlorobenzyl)methylsulfone are obtained in the form of a white solid.

Example 11 On carrying out the operation according to the procedure of Example 4 starting with 9.1 g of l-benzhydryl-3-[(2,4-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol, 2.2 cm 3 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 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 (2.7 kPa). The solid obtained is crystallized from cm 3 of ethyl ether. 1.5 g of l-benzhydryl-3-[(2,4dichlorophenyl)(methylsulfonyl)methylene]azetidine are obtained melting at 165 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 3.00 (3H, s, SCH,), 3.65 (2H, m, NCH,), 4.25 (2H, m, NCH,), 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.)].

l-Benzhydryl-3-[(2,4-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 starting with 4.8 g of (2,4-dichlorobenzyl)methylsulfone and 4.7 g of l-benzhydrylazetidin-3-one, 9.1 g of 1-benzhydryl-3-[(2,4-dichlorophenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained 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 and 13 g of oxone", 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 operation according to the procedure of Example 2 starting with 2.8 cm 3 of 2,4-dichlorobenzyl chloride and g of sodium methylthiolate, 4 g of (2,4dichlorobenzyl)methylsulfide are obtained in the form of an oil.

Example 12 On carrying out the operation according to the procedure of Example 4 starting with 3 g of l-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol, 1.1 g of methanesulfonyl 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 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 3 of ethyl ether. 1.6 g of l-benzhydryl-3-[(2,3-dichlorophenyl)- (methylsulfonyl)methylene]azetidine are obtained melting at 201 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.60 (2H, m, NCH,), 4.20 (2H, m, NCH,), 4.70 (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 (1H, dd, J=8 and 2Hz, CH arom.)].

l-Benzhydryl-3-[(2,3-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 starting with 3.6 g of (2,3-dichlorobenzyl)methylsulfone and 3.6 g of l-benzhydrylazetidin-3-one, 5.4 g of l-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 prepared in the following manner: on carrying out the operation according to the procedure of Example starting with 3 g of 2,3-dichlorobenzyl chloride and 2.4 g of sodium methanesulfinate, 3.6 g of (2,3dichlorobenzyl)methylsulfonate are obtained in the form of a white solid.

Example 13 On carrying out the operation according to the procedure of Example 4 starting with 2.5 g of l-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 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 obtained is crystallized from 40 cm 3 of ethyl ether. g of l-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methylene]azetidine are obtained melting at 210 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.80 (2H, m, NCH,), 4.20 (2H, s, NCH,), 4.70 (1H, s, NCH), between 7.10 and 7.30 (9H, m, 9CH arom.), 7.45 (5H, m, 5CH arom.)].

l-Benzhydryl-3-[(3-fluorophenyl)- (methylsulfonyl)methyl-(RS)]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 and 3.3 g of l-benzhydrylazetidin-3-one, 2.9 g of l-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol are obtained in the form of a white solid melting at 200 0

C.

(3-Fluorobenzyl) methyl sulfone may be 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.

(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 methyl sulfide are obtained in the form of an oil.

Example 14 On carrying out the operation according to the procedure of Example 4 starting with 4.3 g of l-benzhydryl-3-[(2-fluorophenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol, 1.2 cm 3 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 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 l-benzhydryl-3-[(2-fluorophenyl)- (methylsulfonyl)methylene]azetidine are obtained melting at 188 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.65 (2H, m, NCH,), 4.20 (2H, m, NCH 2 4.75 (1H, s, NCH), 7.20 (2H, t, J=7Hz, 2CH arom.), 7.30 (6H, m, 6CH arom.), 7.50 (6H, m, 6CH arom.)].

l-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 starting with 3.4 g of 2-fluorobenzyl methyl sulfone and 4.2 g of l-benzhydrylazetidin-3-one, 4.3 g of l-benzhydryl-3-[(3-fluorophenyl) (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 operation according to the procedure of Example 2 starting with 3 g of 2-fluorobenzyl methyl sulfide and 13 g of oxone", 3.6 g of 3-fluorobenzyl methyl sulfone are obtained in the form of a white solid.

(2-Fluorobenzyl) methyl sulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 2.4 cm 3 of 2-fluorobenzyl bromide and g of sodium methylthiolate, 3 g of 2-fluorobenzyl methyl sulfide are obtained in the form of an oil.

Example On carrying out the operation according to the procedure of Example 4 starting with 1 g of l-benzhydryl-3-[(4-fluorophenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol, 0.3 cm 3 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, 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 concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from cm 3 of ethyl ether. 0.4 g of l-benzhydryl-3-[(4fluorophenyl)(methylsulfonyl)methylene]azetidine are obtained melting at 186 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH 3 3.80 (2H, m, NCH,), 4.20 (2H, m, NCH,), 4.75 (1H, s, NCH), between 7.15 and 7.35 (8H, m, 8CH arom.), 7.45 (6H, m, 6CH arom.)].

l-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 and 3.6 g of l-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 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 0

C.

(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 g of sodium methylthiolate, 3 g of 4-fluorobenzyl methyl sulfide are obtained in the form of an oil.

Example 16 On carrying out the operation according to the procedure of Example 4 starting with 3.8 g of l-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)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 with dichloromethane as eluent, collecting 100 cm 3 fractions. Fractions 5 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from cm 3 of ethyl ether. 0.8 g of l-benzhydryl-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine are obtained melting at 172 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (250 MHz): 3.00 (3H, s, SCH,), 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, J=7Hz, 4CH arom.)].

l-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 l-benzhydrylazetidin-3-one, 3.9 g of l-benzhydryl-3-[(3,5-difluorophenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid.

methyl sulfone may be prepared in the following manner: on carrying out the 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 methyl sulfone are obtained in the form of a white solid.

(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 methyl sulfide are obtained in the form of an oil.

Example 17 On carrying out the operation according to the procedure of Example 4 starting with 5.2 g of l-benzhydryl-3-[(2,3-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 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 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. 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,), 3.70 (2H, s, NCH 2 4.25 (2H, s, NCH 2 4.75 (1H, s, NCH), between 7.15 and 7.55 (13H, m, 13CH arom.)].

l-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 starting with 4 g of (2,3-difluorobenzyl) methyl sulfone and 4.8 g of l-benzhydrylazetidin-3-one, 5.5 g of l-benzhydryl-3-[(2,3-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a beige solid.

(2,3-Difluorobenzyl) methyl sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 84 starting with 4.1 g of 2,3-difluorobenzyl bromide and 4.1 g of sodium methanesulfinate, 4 g of (2,3-difluorobenzyl) methyl sulfone are obtained in the form of a white solid.

Example 18 On carrying out the operation according to the procedure of Example 4 starting with 5.2 g of l-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 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 obtained is crystallized from 75 cm 3 of ethyl ether. 2.6 g of l-benzhydryl-3-[(2,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine are obtained melting at 176 0

C.

l-Benzhydryl-3-[(2,5-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 starting with 4 g of (2,5-difluorobenzyl) methyl sulfone and 4.8 g of l-benzhydrylazetidin-3-one, 5.9 g of l-benzhydryl-3-[(2,5-difluorophenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a cream-colored solid.

methyl sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example starting with 4.1 g of 2,5-difluorobenzyl bromide and 4.1 g of sodium methanesulfinate, 4.8 g of difluorobenzyl) methyl sulfone are obtained in the form of a white solid melting at 95 0

C.

Example 19 On carrying out the operation according to the procedure of Example 4 starting with 7.7 g of l-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol, 1.8 cm of methanesulfonyl chloride 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 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' of ethyl ether.

g of l-benzhydryl-3-[(3-bromophenyl)- (methylsulfonyl)methylene]azetidine are obtained melting at 200 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.75 (1H, 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, 2CH arom.)].

l-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 starting with 8 g of 3-bromobenzyl methyl sulfone and 7.6 g of l-benzhydrylazetidin-3-one, 8 g of l-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol are obtained in the form of a white solid.

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 the form of a white solid.

3-Bromobenzyl methyl sulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 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.

Example On carrying out the operation according to the procedure of Example 4 starting with 1.5 g of l-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol, 0.3 cm 3 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, 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. Fractions 16 to 24 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 1.5 cm 3 of dichloromethane and 25 cm 3 of ethyl ether. 0.5 g of l-benzhydryl-3-[(3iodophenyl)(methylsulfonyl)methylene]azetidine is obtained melting at 198 0 C [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,), 4.75 (1H, s, NCH), between 7.10 and 7.30 (7H, m, 7CH arom.), 7.45 (5H, m, 88 arom.), 7.80 (2H, m, 2CH arom.)].

l-Benzhydryl-3-[(3-iodophenyl)- (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 3.7 g of 3-iodobenzyl methyl sulfone and 3 g of l-benzhydrylazetidin-3-one, 1.5 g of l-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol are obtained in the form of a white 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 oxone", 3.7 g of 3-iodobenzyl methyl sulfone 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 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 On carrying out the operation according to the procedure of Example 4 starting with 2.4 g of 89 l-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methyl-(RS)]azetidin-3-ol, 0.6 cm 3 of methanesulfonyl chloride and 2.3 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 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.

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 3 of dichloromethane and 30 cm 3 of ethyl ether. 0.7 g of l-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methylene]azetidine -is obtained melting at 162°C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (250 MHz): 3.00 (3H, s, SCH 3 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), between 7.15 and 7.40 (6H, m, 6CH arom.), between 7.45 and 7.55 (7H, m, 7CH arom.), 7.60 (1H, t, J=7Hz, CH arom.)].

l-Benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)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 2.4 g of methyl(3-trifluoromethoxybenzyl)sulfone and 2.2 g of l-benzhydrylazetidin-3-one, 2.4 g of l-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid.

Methyl(3-fluoromethoxybenzyl)sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 2.6 g of methyl(3-trifluoromethoxybenzyl)sulfide and 7.2 g of oxoneR, 2.4 g of methyl- (3-trifluoromethoxybenzyl)sulfone are obtained in the form of a white solid.

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- (3-trifluoromethoxybenzyl)sulfide are obtained in the form of an oil.

Example 22 On carrying out the operation according to the procedure of Example 4 starting with 4.1 g of l-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)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 35 cm) at a 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 from a mixture of 2 cm 3 of dichloromethane and 30 cm 3 of ethyl ether. 1.2 g of l-benzhydryl-3- [(methylsulfonyl)(3-trifluoromethylphenyl)methylene]azetidine are obtained melting at 178 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.15 (2H, s, NCH,), 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.)].

l-Benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)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 l-benzhydrylazetidin-3-one, 4.2 g of l-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid.

Methyl(3-trifluoromethylbenzyl)sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 3.3 g of methyl(3-trifluoromethylbenzyl)sulfide and 10 g of oxoneR, 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 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.

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]- (methylsulfonyl)methyl-(RS)}azetidin-3-ol, 0.6 cm 3 of methanesulfonyl chloride and 2.4 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 6 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting 100 cm 3 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- 3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methylene}azetidine is obtained melting at 192C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.85 (2H, s, NCH,), 4.15 (2H, s, NCH,), 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 arom.)].

l-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 starting with 3.1 g of benzyl]sulfone and 2.4 g of l-benzhydrylazetidin-3-one, 2.8 g of l-benzhydryl-3-{[(3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methylene}azetidin-3-ol are obtained in the form of a white solid.

may be prepared in the following manner: on carrying out the operation according to the procedure of Example starting with 3 g of chloride and 2 g of sodium methanesulfinate, 3.1 g of methyl[3,5-bis(trifluoromethyl)benzyl]sulfone are obtained in the form of a white solid melting at 132 0

C.

Example 24 On carrying out the operation according to the procedure of Example 4 starting with 10.7 g of l-benzhydryl-3-[(3,5-dibromophenyl) (methylsulfonyl)- 94 methyl-(RS)]azetidin-3-ol, 2.2 cm 3 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 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 35 cm 3 fractions. Fractions 40 to 58 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from cm 3 of ethyl ether. 1.5 g of l-benzhydryl-3-[3,5dibromophenyl)(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,), 3.88 (2H, s, NCH 2 4.22 (2H, s, NCH 2 4.75 (1H, s, NCH), 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 obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with 6.2 g of and 4.5 g of l-benzhydrylazetidin-3-one, 10.7 g of l-benzhydryl-3-[3,5-dibromophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a foam.

may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 5.8 g of and 13 g of oxone 6.2 g of methylsulfone are obtained in the form of a white solid.

may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 6.6 g of 3,5-dibromobenzyl bromide and g of sodium methylthiolate, 5.8 g of dibromobenzyl)methylsulfide are obtained in the form of an oil.

Example On carrying out the operation according to the procedure of Example 4 starting with 4.2 g of l-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methyl- (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 mixture of cyclohexane and ethyl acetate (50/50 by volume) as eluents, collecting 400 cm 3 fractions.

Fractions 17 to 33 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from 15 cm 3 of ethyl acetate.

0.6 g of l-benzhydryl-3-[(methylsulfonyl)- (3-nitrophenyl)methylene]azetidine is obtained melting at 184 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.85 (2H, s, NCH,), 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 (1H, d, J=7Hz, CH arom.), 8.25 (2H, m, 2CH arom.)].

l-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 starting with 3.9 g of methyl(3-nitrobenzyl)sulfone and 4.2 g of l-benzhydrylazetidin-3-one, 4.2 g of l-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 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 oxoneR, 13.9 g of methyl(3-nitrobenzyl)sulfone are obtained in the form of a foam.

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.

Example 26 A mixture of 0.34 g of l-benzhydryl- 3-[(methylsulfonyl)(3-nitrophenyl)methylene]azetidine, 16 cm 3 of 1 N hydrochloric acid in 8 cm 3 of ethanol and 16 cm 3 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 3 of 1 N sodium hydroxide and 50 cm 3 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 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 cm 3 fractions. Fractions 13 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from cm 3 of ethyl ether. 0.17 g of 3-[(3-aminophenyl)- (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,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), 5.25 (2H, s, 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.)].

Example 27 On carrying out the operation according to the procedure of Example 4 starting with 1.2 g of l-benzhydryl-3-[(3-methoxycarbonylphenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.3 cm 3 of methanesulfonyl chloride and 1.3 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 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 precipitated in 5 cm 3 of ethyl ether. 0.13 g of l-benzhydryl-3-[(3-methoxycarbonylphenyl)- (methylsulfonyl)methylene]azetidine is obtained in the 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,), 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.), 7.60 (1H, t, J=7Hz, CH arom.), 7.70 (1H, d, J=7Hz, CH arom.), 8.00 (2H, m, 2CH arom.)].

l-Benzhydryl-3-[(3-methoxycarbonylphenyl)- (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 g of (3-methoxycarbonylbenzyl)methylsulfone and 3.6 g of l-benzhydrylazetidin-3-one, 1.2 g of l-benzhydryl-3-[(3-methoxycarbonylphenyl)- (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 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 starting with 4.3 g of (3-methoxycarbonylbenzyl)methylsulfide and 13.4 g of oxoneR, 3.4 g of (3-methoxycarbonylbenzyl)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 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.

Example 28 On carrying out the operation according to the procedure of Example 4 starting with 6.2 g of l-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methyl- (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 dichloromethane and then a dichloromethane and ethyl acetate mixture (99.5/0.5 by volume) as eluents and collecting 250 cm 3 fractions. Fractions 10 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 5 cm 3 of dichloromethane and 70 cm 3 of ethyl ether. 2.9 g of l-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,), 4.20 (2H, s, NCH,), 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.), 7.65 (1H, t, J=7Hz, CH arom.), 7.75 (1H, d, J=7Hz, CH arom.), 7.90 (2H, m, 2CH arom.)].

l-Benzhydryl-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 3.9 g of (3-cyanobenzyl)methylsulfone and 4.7 g of l-benzhydrylazetidin-3-one, 6.2 g of l-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methyl- (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 6.7 g of (3-cyanobenzyl)methylsulfide and 27.6 g of oxone 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 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 0 102 are obtained in the form of an oil.

Example 29 A mixture of 3 g of l-benzhydryl-3-[(3carboxyphenyl)(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 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 (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 bar with dichloromethane and then a dichloromethane and methanol mixture (99.4/0.6 by volume) as eluents and collecting .100 cm 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 l-benzhydryl- 3-[(methylsulfonyl)(3-pentafluorophenoxycarbonylphenyl)methylene]azetidine is obtained melting at 182 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (400 MHz): 3.00 (3H, s, SCH,), 3.85 (2H, s, NCH,), 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.)].

l-Benzhydryl-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidine hydrochloride may be prepared in the following manner: a mixture of 10 g of l-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine in 40 cm 3 of acetic acid and 40 cm 3 of concentrated hydrochloric acid (d=1.18) is heated at 0 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 cm 3 of a mixture of acetic acid and concentrated 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 l-benzhydryl- 3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidine hydrochloride are obtained in the form of a white solid.

Example A solution of 0.65 g of l-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 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 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.2 g of l-benzhydryl- 3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine is obtained melting at 140 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 3.00 (3H, s, SCH 3 3.80 (2H, s, NCH,), 4.25 (2H, s, NCH 2 4.75 (1H, 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,), 7.95 (2H, m, 2CH arom.), 8.10 (1H, s, 1/2 CONH 2 Example 31 On carrying out the operation according to the procedure of Example 4 starting with 4.6 g of l-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 l-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine are obtained, after recrystallization from 150 cm 3 of acetonitrile, melting at 179 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (250 MHz): 2.95 (3H, s, SCH,), 3.75 (3H, s, OCH,), 3.80 (2H, s, NCH 2 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), 7.00 (3H, m, 3 CH arom.), between 7.20 and 7.12 (11H, m, phenyls and 1 CH arom.)].

l-Benzhydryl-3-[(3-methoxyphenyl)- (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 l-benzhydrylazetidin-3-one, 4.6 g of l-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 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.

(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 g of sodium methylthiolate, 3.4 g of (3-methoxybenzyl)methylsulfide are obtained in the form of an oil.

Example 32 cm 3 of a 1 M solution of boron tetrabromide in dichloromethane are added, with stirring, to a solution of 1.3 g of l-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 washed with 3 times 50 cm 3 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 cm 3 of dichloromethane. The organic phase is washed 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 cm 3 of ethyl ether. 0.36 g of l-benzhydryl-3-[(3hydroxyphenyl) (methylsulfonyl)methylene]azetidine is obtained from a solid melting at 248 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.95 (3H, s, SCH,), 107 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 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)].

Example 33 On carrying out the operation according to the procedure of Example 32 starting with 1.4 g of l-benzhydryl-3- (4-methoxyphenyl) (methylsulfonyl) methylene]azetidine, 10 cm 3 of a 1 M boron tribromide solution and 100 cm' 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, 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 3 fractions.

Fractions 21 to 37 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of 30 cm 3 of ethyl ether. 0.6 g of l-benzhydryl-3-[(4hydroxyphenyl)(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 (2H, s, NCH,), 4.20 (2H, s, NCH,), 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)].

l-Benzhydryl-3- (4-methoxyphenyl) (methylsulfonyl)methylene]azetidine may be obtained in the following manner: on carrying out the operation according to the procedure of Example 4 starting with g of l-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 purified by recrystallization from 100 cm 3 of acetonitrile. 1 g of l-benzhydryl-3-[(4methoxyphenyl)(methylsulfonyl)methylene] azetidine is obtained melting at 181 0

C.

l-Benzhydryl-3-[(4-methoxyphenyl)(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 g of (4-methoxybenzyl)methylsulfone and 4 g of l-benzhydrylazetidin-3-one, 3.6 g of l-benzhydryl- 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 operation according to the procedure of Example 2 starting with 3.4 g of (4-methoxybenzyl)methylsulfide and 13 g of oxone, 3.5 g of (3-methoxybenzyl)- 109 methylsulfone are obtained in the form of a white solid melting at 113 0

C.

(4-Methoxybenzyl)methylsulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 3.1 g of 4-methoxybenzyl chloride and g of sodium methylthiolate, 3.4 g of (4-methoxybenzyl)methylsulfide are obtained in the form of an oil.

Example 34 On carrying out the operation according to the procedure of Example 32 starting with 1.4 g of l-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, 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 40 cm 3 of ethyl ether. 0.7 g of l-benzhydryl-3-[(2hydroxyphenyl)(methylsulfonyl)methylene]azetidine is obtained melting at 196 0 C [NMR spectrum in DMSO-d6, 110 T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.60 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), 6.85 (1H, t, J=7Hz, CH arom.), 6.90 (1H, d, J=7Hz, CH arom.), 7.20 (4H, m, 4CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.48 (4H, d, J=7Hz, 4CH arom.), 9.90 (1H, s, OH)].

l-Benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methylene]azetidine may be obtained in the following manner: on carrying out the operation according to the procedure of Example 4 starting with 4.2 g of l-benzhydryl-3-[(2-methoxyphenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol, 1.1 cm' of methanesulfonyl chloride and 3.5 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 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 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 l-benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methylene]azetidine are obtained melting at 204 0

C.

l-Benzhydryl-3-[(2-methoxyphenyl)(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 4 g of (2-methoxybenzyl)methylsulfone and 4.5 g of l-benzhydrylazetidin-3-one, 4.3 g of l-benzhydryl- 3-[(2-methoxyphenyl)(methylsulfonyl)methyl-(RS)]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 starting with 3.1 g of (2-methoxybenzyl) chloride and 4.1 g of sodium methanesulfinate, 4 g of (2-methoxybenzyl)methylsulfone are obtained in the form of a white solid.

Example On carrying out the operation according to the procedure of Example 4 starting with 2.1 g of l-benzhydryl-3-[(methylsulfonyl)(naphth-2-yl)methyl- (RS)]azetidin-3-ol, 0.5 cm 3 of methanesulfonyl chloride and 2.2 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 30 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 concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from cm of ethyl ether. 0.6 g of l-benzhydryl-3-[(methyl- 112 sulfonyl)(naphth-2-yl)methylene]azetidine is obtained melting at 178 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH 2 4.75 (1H, s, NCH), 7.20 (4H, m, 4CH 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.)].

l-Benzhydryl-3-[(methylsulfonyl)(naphth- 2-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 g of methyl(naphth-2-ylmethyl)sulfone and 3.8 g of l-benzhydrylazetidin-3-one, 2.2 g of l-benzhydryl- 3-[(methylsulfonyl)(naphth-2-yl)methyl-(RS)]azetidin- 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 starting with 4.2 g of methyl(naphth-2-ylmethyl)sulfide and 13.7 g of oxone", 3.6 g of methyl(naphth- 2-ylmethyl)sulfone are obtained in the form of a creamcolored solid.

Methyl(naphth-2-ylmethyl)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 (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 On carrying out the operation according to the procedure of Example 4 starting with 4.3 g of l-benzhydryl-3-[(methylsulfonyl)(naphth-l-yl)methyl- (RS)]azetidin-3-ol, 1.1 cm 3 of methanesulfonyl chloride 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 fractions. Fractions 6 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from cm 3 of ethyl ether. 2.5 g of l-benzhydryl-3-[(methylsulfonyl)(naphth-l-yl)methylene] azetidine are obtained melting at 196 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 3.00 (3H, s, SCH,), 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.)].

l-Benzhydryl-3-[(methylsulfonyl)(naphthl-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 l-benzhydrylazetidin-3-one, 4.3 g of l-benzhydryl- 3-[(methylsulfonyl)(naphth-1-yl)methyl-(RS)]azetidin- 3-ol are obtained in the form of a solid.

Methyl(naphth-l-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-l-ylmethyl)sulfide and 13.9 g of oxone", 4.1 g of methyl(naphth-1-ylmethyl)sulfone are obtained in the form of a white solid.

Methyl(naphth-l-ylmethyl)sulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 2 starting with 4 g of l-chloromethylnaphthalene chloride and 1.8 g of sodium methylthiolate, 4.5 g of methyl(naphth-l-ylmethyl)sulfide are obtained in the form of an oil.

Example 37 On carrying out the operation according to the procedure of Example 4 starting with 0.6 g of l-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 volume) as eluents and collecting 20 cm 3 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 l-benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinophenyl)methylene]azetidine is obtained melting at 153 0

C

[NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 1.95 (4H, m, 2 CH 2 2.95 (3H, s, SCH,), 3.20 (4H, m, 2 NCH,), 3.80 (2H, s, NCH 2 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), 6.60 (3H, m, 3CH arom.), 7.20 (3H, m, 3CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.48 (4H, d, J=7Hz, 4CH arom.)].

l-Benzhydryl-3-[(methylsulfonyl)- (3-pyrrolidinophenyl)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 0.77 g of 3-pyrrolidinobenzyl methyl sulfone and 0.76 g of l-benzhydrylazetidin-3-one, 0.6 g of l-benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinophenyl)methyl-(RS)]azetidin-3-ol is obtained in the 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 oxone

R

0.8 g of methyl(3-pyrrolidinobenzyl)sulfone is obtained in the form of a solid.

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,l'-bis(diphenylphosphino)ferrocenyl palladium chloride, 0.63 g of l,l'-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 3 of 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 (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 kPa). The powder obtained is eluted on sintered glass 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 T. et al., J. Am. Chem. Soc., 106, 158 (1984).

Example 38 Method 1 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 22 0 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 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 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 190 0 C. A recrystallization from 145 cm 3 of ethanol gives 1.08 g of l-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine melting at 206 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H,s, SCH,), 3.87 (2H, s, NCH,), 4.20 (2H, s, NCH,), 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 0.80 g of ground sodium hydroxide is added to a solution of 2.2 g of 3-acetoxy-l-[bis- (4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)- (methylsulfonyl)methyl-(RS)]azetidine in 25 cm 3 of dioxane at room temperature. After 16 hours at room temperature, 50 cm 3 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 3 of water, dried over magnesium sulfate, filtered and 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 3 of ethanol gives 0.70 g of l-[bis- (4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine melting at 205 0

C.

Example 39 6.75 g of 3-[(3,5-difluorophenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol hydrochloride 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 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 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 l-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl) methyl- (RS)]azetidin-3-ol are obtained. 1 H NMR spectrum (300 MHz, (CD,),SO-d6, 8 in ppm): 2.00 3H), 2.94 (s, 3H), 3.25 (mt, 2H), 3.48 J=9Hz, 1H), 3.80 (d, J=9Hz, 1H), 4.54 1H), 5.34 1H), 7.15 (d, 9 120 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 BACHMANN 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 37 g of 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl- (RS)]-1-(vinyloxycarbonyl)azetidin-3-ol in 160 cm 3 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 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 0 C under reduced pressure (2.7 kPa). 29.85 g of white crystals are obtained whose melting point is greater than 260 0

C.

3-[(3,5-Difluorophenyl)(methylsulfonyl)methyl-(RS)]-l-(vinyloxycarbonyl)azetidin-3-ol may be obtained in the following manner: a solution of 14.0 cm 3 of vinyl chloroformate in 35 cm 3 of dichloromethane is added at 5 0 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 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 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 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]l-(vinyloxycarbonyl)azetidin-3-ol are obtained in the form of white crystals melting at 195 0

C.

Example 14 cm 3 of a 1.6 N n-butyllithium solution in hexane are added at -70 0 C to a solution of 4.77 g of in 70 cm 3 of tetrahydrofuran under an argon atmosphere. After 1 hour at -70 0 C, a solution of 6.8 g of l-[bis(4chlorophenyl)methyl]azetidin-3-one in 30 cm 3 of tetrahydrofuran is added and then, 1 hour later, a solution of 2.34 cm 3 of acetyl chloride in 20 cm 3 of tetrahydrofuran and the temperature of the reaction mixture is raised to 20 0 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-l-[bis(4chlorophenyl)methyl]-3-[(3,5difluorophenyl)(methylsulfonyl)methyl)methylsulfonylmethyl-(RS)]azetidine are obtained in the form of a yellow oil [1H NMR spectrum (400 MHz, CDC1 3 8 in ppm): 2.79 3H), 3.04 (AB, J=9Hz, 2H), 3.27 J=9Hz, 1H), 3.45 1H), 3.81 J=9Hz, 1H), 4.32 1H), 4.49 1H), 6.88 (tt, J=9 and 2.5Hz, 1H), from 7.20 to 7.35 (mt, 1-[Bis(4-chlorophenyl)methyl]azetidin-3-one may be prepared according to the following procedure: a solution of 8.1 cm 3 of dimethyl sulfoxide in 17.6 cm 3 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 0 C, a solution of 16.0 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol dissolved in 50 cm 3 of dichloromethane is poured in. After 5 hours at -78 0 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 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 eluents and collecting 200 cm 3 fractions. Fractions to 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 8.9 g of l-[bis(4chlorophenyl)methyl]azetidin-3-one are obtained in the form of pale yellow crystals melting at 111 0

C.

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 3 of epichlorohydrin. 9.0 g of l-[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 (1973).

Example 41 On carrying out the operation according to the procedure of Example 38 (Method starting with 0.72 g of l-[bis(4-methoxyphenyl)methyl]-3-[(3,5difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin- 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 eluent and collecting 40 cm 3 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] [(3,5-difluorophenyl) (methylsulfonyl)methylene]azetidine are obtained in the form of a solid melting at 180 0 C [NMR spectrum in DMSOd6, T=300K, 8 in ppm (250 MHz): 3.00 (3H, s, SCH,), 3.70 (6H, s, 2 OCH,), 3.80 (2H, s, NCH,), 4.15 (2H, s, NCH,), 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.)].

1-[Bis(4-methoxyphenyl)methyl]-3-[(3,5difluorophenyl) (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 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 acetate and cyclohexane (25/75 by volume) as eluent and collecting 50 cm fractions, fractions 9 to 18 are combined and then concentrated to dryness under reduced 125 pressure (2.7 kPa). 0.55 g of l-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol is obtained.

Bis(4-methoxyphenyl)bromomethane may be prepared according to the procedure described by BACHMANN J. Am. Chem. Soc., 2135 (1933).

Example 42 On carrying out the operation according to Example 38 (Method 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 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, 0.20 g of l-[bis(4-methylphenyl)methyl]-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of white needles melting at 200 0

C.

l-[Bis(4-methylphenyl)methyl]-3-[(3,5difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin- 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

I.

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 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 difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin- 3-ol is obtained.

Bis(4-methylphenyl)bromomethane may be prepared according to the procedure described by BACHMANN J. Am. Chem. Soc., 2135 (1933).

Example 43 On carrying out the operation according to Example 38 (Method starting with 1.42 g of difluorophenyl) (methylsulfonyl)methyl-(RS)]-l-[(4methoxyphenyl)(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 at an 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, 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 in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.23 (6H,s, 2 PhCH,), 3.00 (3H,s, SCH,), 3.80 (2H, s, NCH2), 4.12 (2H, s, NCH 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, arom.)] The mixture of diastereoisomers difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-[(4methoxyphenyl)(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 (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 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 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 J. Am. Chem. Soc., 2135 (1933).

Example 44 On carrying out the operation as in Example 38 (Method starting with 0.47 g of l-[bis- (4-trifluoromethoxyphenyl)methyl]-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 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 collecting 25 cm 3 fractions, 0.28 g of 1-[bis- (4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a solid [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 3.05 (3H, s, SCH,), 3.95 (2H, s, NCH 2 4.25 (2H, s, NCH 2 4.90 (1H, s, NCH), 7.20 (2H, d, J=8Hz, 2CH arom.), 7.32 (5H, m, arom.), 7.60 (4H, d, J=7Hz, 4CH arom.)].

1-[Bis(4-trifluoromethoxyphenyl)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 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 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 3 fractions, fractions 15 to 23 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.49 g of 1-[bis- (4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-ol is obtained.

Bis(4-trifluoromethoxyphenyl)bromomethane may be prepared according to the procedure described by BACHMANN 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-trifluoromethoxyphenyl)bromomethane are obtained in the form of a brown oil.

Bis(4-trifluoromethoxyphenyl)methanol is prepared according to PAVIA M.R. et al., J. Med. Chem., 4238 (1992).

Example On carrying out the operation as in Example 130 38 (Method starting with 0.25 g of 1-[bis- (4-trifluoromethylphenyl)methyl]-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 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 l-[bis- (4-trifluoromethylphenyl)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): 3.05 (3H, s, SCH,), 3.95 (2H, s, NCH,), 4.25 (2H, s, NCH 2 4.90 (1H, s, NCH), 7.20 (2H, d, J=8Hz, 2CH arom.), 7.32 (5H, m, 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 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 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-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol is obtained.

Bis(4-trifluoromethylphenyl)bromomethane may be prepared according to the procedure described by BACHMANN J. Am. Chem. Soc., 2135 (1933), starting with 2.5 g of bis(4-trifluoromethylphenyl)methanol, 6 cm 3 of 33% hydrobromic acid in acetic acid and 1.2 cm 3 of acetyl bromide. 2.9 g of bis(4-trifluoromethylphenyl)bromomethane are obtained in the form of a brown oil.

Bis(4-trifluoromethylphenyl)methanol is prepared according to PAVIA M.R. et al., J. Med. Chem., 4238 (1992).

Example 46 On carrying out the operation according to Example 38 (Method starting with 3.16 g of 3-acetoxy-l-[bis(4-chlorophenyl)methyl]-3-{[3,5bis(trifluoromethyl)phenyl](methylsulfonyl)methyl- (RS)}azetidine and 0.96 g of ground sodium hydroxide, a 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 3 fractions.

1.49 g of l-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis- (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,), 4.30 (2H, s, NCH,), 4.80 (1H, s, NCH), 7.40 (2H, d, J=7Hz, 2CH 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 manner: on carrying out the operation as in Example starting with 2.0 g of 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-chlorophenyl)methyl]azetidin-3-one and 0.77 cm 3 of acetyl chloride in 20 cm 3 of anhydrous diisopropyl ether, 3.56 g of 3-acetoxy-l-[bis(4-chlorophenyl)methyl]-3-{[3,5bis(trifluoromethyl)phenyl](methylsulfonyl)methyl- (RS)}azetidine are obtained in the form of a white foam after chromatography on a silica gel column (particle 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 fractions.

is prepared in the following manner: on carrying out the operation according to Example 10 starting with 1.8 g of 3,5-bis(trifluoromethyl)benzyl chloride and 1.22 g of sodium methanesulfinate, 1.86 g of (trifluoromethyl)benzyl]methylsulfone are obtained in the form of a white solid.

Example 47 On carrying out the operation as in Example 38 (Method starting with 0.27 g of the mixture of the two diastereoisomers 1-[(4-chlorophenyl)(2,4dichlorophenyl)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 acetate and cyclohexane (15/85 by volume) as eluent and collecting 20 cm 3 fractions, 0.10 g of (RS)l-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a white solid [NMR spectrum in DMSO-d6, T=300K, 6 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 arom.), 7.58 (1H, d, J=2Hz, CH arom.), 7.80 (1H, d, J=7Hz, CH arom.)].

The mixture of the two diastereoisomers 1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl-(RS)]- 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol 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)(2,4dichlorophenyl)methane and 0.50 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 4.0 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 cm 3 fractions, 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 chlorophenyl)(2,4-dichlorophenyl)methyl-(RS)]-3-[(3,5difluoro-phenyl)(methylsulfonyl)methyl-(RS)]azetidin- 3-ol is obtained.

(RS)-bromo(4-chlorophenyl)(2,4-dichlorophenyl)methane may be prepared according to the 135 procedure described by BACHMANN 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 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.

Med. Chem., 4238 (1992).

Example 48 75.6 cm 3 of 5 N hydrochloric acid are added to a solution of 18.9 g of 1-{(4-chlorophenyl)[4-(1,3dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine in 80 cm 3 of tetrahydrofuran. After 3 hours at room temperature, the mixture is taken up in dichloromethane and distilled water and then adjusted to pH 14 by addition of 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 concentrated to dryness under reduced pressure (2.7 kPa). 16 g of (RS)-l-[(4-chlorophenyl)- (4-formylphenyl)methyl]-3-[(3,5-difluorophenyl)to 136 (methylsulfonyl)methylene]azetidine are obtained in the form of a white foam [Spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.06 (3H, s, SCH 3 3.95 (2H, m, NCH,), 4.26 (2H, m, NCH,), 4.91 (1H, s, NCH), 7.20 (2H, d, 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 (1H, s, CH aldehydic)].

1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine may be prepared according to the following method: 13.0 cm 3 of 1,8diazabicyclo[5.4.0]undec-7-ene are added dropwise to a solution of 34.45 g of the mixture of the two diastereoisomers 3-acetoxy-l-{(4-chlorophenyl)[4-(1,3dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5difluorophenyl)(methylsulfonyl)methyl-(RS)]-azetidine in 400 cm 3 of tetrahydrofuran under argon at 0°C, and after customary treatment, 16.6 g of 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 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 in the following manner: on carrying out the operation according to Example 40, starting with 11.6 g of difluorobenzyl)methylsulfone, 35.1 cm of a 1.6 N solution of n-butyllithium in hexane, 19.3 g of chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl- (RS)}azetidin-3-one and 8.8 cm 3 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-(l,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidine are obtained in the form of a white foam.

l-{(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 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 reaction mixture is poured over ice, extracted with ethyl acetate, washed with 3 times 400 cm 3 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 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 l-{(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 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 of l-{(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., 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)phenyl]methyl-(RS)}amine are obtained in the form of a yellow oil.

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)(methylsulfonyl)methylene]azetidine in 15 cm 3 of methanol at 0°C. After 1 hour at 0°C, 40 cm 3 of water are added and the product extracted with 100 cm 3 of dichloromethane.

The organic phase is washed twice with 40 cm 3 of water and then 40 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 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 mixture of ethyl acetate and cyclohexane (30/70 by volume) and collecting 20 cm 3 fractions. Fractions 20 to are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.29 g of (RS)-l-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, 6 in ppm 140 (250 MHz): 3.02 (3H, s, SCH,), 3.90 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.42 (2H, d, J=5Hz, OCH,), 4.75 (1H, s, NCH), 5.10 (1H, t, J=5Hz, OH), between 7.10 and 7.50 (11H, m, 11CH arom.)].

Example 0.75 g of (RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine 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 hours at room temperature, 2 cm 3 of 1 N sodium hydroxide are added, the product is extracted with 100 cm 3 of dichloromethane, the organic phase is washed twice with 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 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 pressure (2.7 kPa). 0.39 g of (RS)-l-{(4-chlorophenyl)- [4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 1.65 (4H, m, 2CH,), 2.40 (4H,m, 2NCH 2 3.02 (3H,s, SCH,), 3.50 (2H, s, NCHPh), 3.85 (2H, s, NCH 2 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), between 7.15 and 7.40 (9H, m, 9CH arom.), 7.48 (2H, d, J=7Hz, 2CH arom.)].

Example 51 On carrying out the operation as in Example 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)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)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 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 DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.12 (6H, s, 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.)].

Example 52 A solution of 0.5 g of (RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine in 10 cm 3 of dichloromethane at 0°C is stirred with 0.5 cm 3 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 room temperature, the reaction mixture is diluted with dichloromethane, washed twice with 80 cm' 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 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 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)-l-{(4-chlorophenyl)[4-N,Ndimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine in the form 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,), 3.00 (3H, s, SCH,), 3.90 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.80 (1H, s, NCH), 7.15 (2H, d, J=8Hz, 2CH arom.), 7.30 (1H, t, J=8Hz, CH arom.), 7.35 (4H, m, 4CH arom.), 7.50 (4H, d, J=7Hz, 4CH arom.)].

(RS)-l-{(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine may be prepared in the following manner: 1.0 cm 3 of Jones reagent is added to a solution 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°C. After hours, the reaction mixture is poured into distilled water, the product is extracted with 50 cm 3 of ethyl 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 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 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)(methylsulfonyl)methylene]azetidine, 0.38 g of 1,3-dimethylaminopropyl-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 argon pressure of 0.5 bar with a mixture 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-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5difluorophenyl)(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, 3.00 (3H, s, SCH,), 3.35 (2H, m, NCH 2 3.90 (2H, s, NCH 2 4.20 (2H, s, NCH,), 4.80 (1H, s, NCH), 7.15 (2H, d, J=8Hz, 2CH arom.), 7.30 (1H, 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 (1H, t, CONH)].

Example 54 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)(methylsulfonyl)methylene]azetidine, 0.38 g of 1,3dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, 22 mg of hydroxybenzotriazole hydrate, 40 cm 3 of dichloromethane and 0.24 cm 3 of a 7 N solution of ammonium hydroxide in methanol and chromatographing on a silica gel column (particle size 0.04-0.06 mm, diameter 4.1 cm, height 15 cm), at an argon pressure of 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 (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 spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 3.00 (3H, s, SCH,, 3.90 (2H, s, NCH,), 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 V2 CONH,), 7.80 (2H, d, J=7Hz, 2CH arom.), 7.90 (1H, s, /2 CONH,)].

Example The operation is carried out according to the procedure of Example 4 starting with 1.7 g of 1-[bis- (4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.35 cm' of methanesulfonyl chloride and 1.5 g of 4-dimethylaminopyridine. The residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm), at a 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 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The solid is crystallized from 15 cm 3 of ethyl ether. 0.2 g of l-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained melting at 200 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 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-chlorophenyl)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 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 l-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a foam.

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 5.6 g of 3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl- (RS)]-l-(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)methyl-(RS)]-1-(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 l-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol and 1.6 cm 3 of vinyl chloroformate in 75 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 cm, height 40 cm), at a nitrogen pressure of 0.5 bar with a mixture of ethyl 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)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 l-benzhydryl-3-[(3-dimethylaminophenyl)(methylsulfonyl)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 dichloromethane and ethanol (98/2 by volume) as eluent and collecting 20 cm 3 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. 0.3 g of l-benzhydryl-3-[(3dimethylaminophenyl)(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, 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), 6.70 (3H, m, 3CH arom.), 7.20 (3H, m, 3CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.48 (4H, d, J=7Hz, 4CH arom.)].

l-Benzhydryl-3-[(3-dimethylaminophenyl)- (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 0.4 g of (3-dimethylaminobenzyl)methylsulfone, 0.4 g of l-benzhydrylazetidin-3-one and 1.2 cm 3 of a 1.6 M solution of n-butyllithium in hexane, g of l-benzhydryl-3-[(3-dimethylaminophenyl)- (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 (3-dimethylaminobenzyl)methylsulfone are obtained in the form of a white solid melting at 195 0

C.

(3-Dimethylaminobenzyl)methylsulfide may be prepared in the following manner: on carrying out the operation according to the procedure of Example 37 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 l,l'-bis(diphenylphosphino)ferrocene in 35 cm 3 of tetrahydrofuran, 0.9 g of (3-dimethylaminobenzyl)methylsulfide is obtained in the form of an oil.

Example 57 On carrying out the operation according to the procedure of Example 4 starting with 1.3 g of l-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.3 cm 3 of methanesulfonyl chloride and 1.4 g of 4-dimethylaminopyridine, 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 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 l-benzhydryl-3-[(3methylsulfanylphenyl)(methylsulfonyl)methylene]azetidine is obtained melting at 146 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 2.45 (3H, s, PhSCH,), 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), between 7.10 and 7.50 (14H, m, 14CH arom.)].

l-Benzhydryl-3-[(3-methylsulfanylphenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol 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 l-benzhydrylazetidin-3-one, 1.3 g of l-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 (3-iodobenzyl)methylsulfone and 1 g of tetrakistriphenylphosphinepalladium in 250 cm 3 of dimethyl sulfoxide is heated at a temperature close to 100 0

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 ethyl acetate and 500 cm 3 of water. The organic phase is decanted off, washed with 10 times 500 cm 3 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 is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 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 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-methylsulfanylbenzyl)methylsulfone are obtained in the form of an oil.

Example 58 4 cm 3 of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to a solution, cooled to 5 0 C, of 1.1 g l-benzhydryl-3-{[3-(tert-butyldimethylsiloxymethyl)phenyl](methylsulfonyl)methylene}azetidine in 10 cm 3 of tetrahydrofuran. The mixture is 153 stirred for 3 hours at a temperature close to 20 0 C and then taken up in 100 cm 3 of ethyl acetate and twice cm 3 of water. The organic phase is decanted off, extracted, dried over anhydrous 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 30 cm), at a nitrogen pressure of 0.5 bar with a mixture of 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 l-benzhydryl-3-[(3hydroxymethylphenyl)(methylsulfonyl)methylene]azetidine 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,), 3.80 (2H, s, NCH,), 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 arom.), 7.30 (8H, m. 8CH arom.), 7.45 (4H, d, J=7Hz, 4 CH arom.)].

l-Benzhydryl-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methylene}azetidine may be prepared in the following manner: on carrying out the operation according to the procedure of Example 4 starting with 1.6 g of l-benzhydryl-3-{[3- (tert-butyldimethylsiloxymethyl)phenyl](methyl- 154 sulfonyl)methyl-(RS)]azetidin-3-ol, 0.3 cm 3 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, height 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 (2.7 kPa). 1.1 g of l-benzhydryl-3-{[3-(tert-butyldimethylsiloxymethyl)phenyl](methylsulfonyl)methylene}azetidine are obtained in the form of a white solid melting at 148 0

C.

l-Benzhydryl-3-{[3-(tert-butyldimethylsilyloxymethyl)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-(tertbutyldimethylsilyloxymethyl)benzyl]methylsulfone and 1.5 g of l-benzhydrylazetidin-3-one, 1.6 g of l-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-butyldimethylsilyloxymethyl)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 0

C.

The solution is 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 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 reduced pressure (2.7 kPa). 5.7 g of [3-(tert-butyldimethylsilyloxymethyl)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 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 0°C and then 15 cm 3 of ethyl acetate, 5 cm 3 of water, 5 cm 3 of a 15% aqueous solution of sodium hydroxide and finally 30 cm' 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, 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 starting with 23.3 g of 3-chloromethylbenzoic acid and 23.3 g of sodium methanesulfinate, 26 g of 3-(methylsulfonylmethyl)benzoic acid are obtained in the form of a white solid melting at 210 0

C.

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 l-benzhydryl-3-[(3-bromomethylphenyl) (methylsulfonyl)methylene]azetidine in 8 cm 3 of dimethylformamide. The mixture is stirred for 18 hours at a temperature close to 20 0 C and then taken up in cm 3 of ethyl acetate and 50 cm of water. The organic phase is decanted off, extracted and washed with 3 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 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 l-benzhydryl- 3-{[3-(methylsulfanylmethyl)phenyl](methylsulfonyl)methylene]}azetidine is obtained in the form of a white solid melting at 150 0 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,), 3.80 (2H, s, NCH 2 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7Hz, CH arom.), 7.30 (8H, d, J=7Hz, 8CH arom.), 7.45 (4H, d, J=7Hz, 4 CH arom.)].

l-Benzhydryl-3-[(3-bromomethylphenyl)(methylsulfonyl)methylene]azetidine 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 close to 20 0 C, to a mixture of 1 g of l-benzhydryl- 3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]azetidine in 10 cm 3 of dichloromethane. The stirring is maintained for 18 hours at the same temperature. The reaction medium is taken up in 20 cm 3 of water and 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 l-benzhydryl-3-[(3-bromomethylphenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a foam used in the crude state in subsequent syntheses.

158 Example On carrying out the operation according to the procedure of Example 4 starting with 6.6 g of l-benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methyl- (RS)]azetidin-3-ol, 1.7 cm 3 of methanesulfonyl chloride and 5.2 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 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 reduced pressure (2.7 kPa). The solid obtained is crystallized from 100 cm 3 of ethyl ether. 4.4 g of l-benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methylene]azetidine are obtained melting at 212 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 3.15 (3H, s, SCH,), 3.55 (2H, broad s, NCH,), 4.30 (2H, s, NCH,), 4.70 (1H, s, NCH), 7.18 (2H, t, J=7Hz, 2CH arom.), 7.25 (4H, t, J=7Hz, 4CH arom.), 7.43 (4H, d, J=7Hz, 4 CH arom.), 7.62 (2H, m, 2CH quinoline), 7.75 (1H, dd, J=2 and 7Hz, CH quinoline), 8.05 (1H, dd, J=2 and 7Hz, CH quinoline), 8.43 (1H, dd, J=2 and 8Hz, CH quinoline), 9.00 (1H, dd, J=2 and 5Hz, CH quinoline)].

l-Benzhydryl-3-[(methylsulfonyl)(quinol- 8-yl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying out the operation according to the procedure of Example 1 starting with g of methyl(quinol-8-ylmethyl)sulfone, 5.9 g of l-benzhydrylazetidin-3-one and 18.8 cm 3 of a 1.6 M solution of n-butyllithium in hexane, 6.6 g of l-benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methyl- (RS)]azetidin-3-ol are obtained in the form of a beige solid.

Methyl(quinol-8-ylmethyl)sulfone may be prepared in the following manner: on carrying out the operation according to the procedure of Example starting with 4.5 g of 8-chloromethylquinoline and 4.4 g of sodium methanesulfinate, 5.7 g of 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 temperature close to 200C, 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 200C.

The mixture is filtered on sintered glass and the 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 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 4.5 g of 8-chloromethylquinoline are obtained in the form of a brown oil which is used in the crude state in subsequent syntheses.

Example 61 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 3 of methanesulfonyl chloride and 6.1 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 60 cm), at a nitrogen pressure of 0.5 bar with dichloromethane as 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 3 of ethyl ether. 0.7 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)- (methylsulfonyl)methylene]azetidine is obtained in the form of a solid melting at 178 0 C [NMR spectrum in DMSOd6, T=300K, 8 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.80 161 (2H, s, NCH,), 4.20 (2H, s, NCH,), 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.)].

1-[Bis(4-chlorophenyl)methyl]-3-[(3cyanophenyl)(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)methylsulfone, 6.1 g of l-[bis(4-chlorophenyl)methyl]azetidin-3-one and 13.8 cm 3 of a 1.6 M solution of n-butyllithium in hexane, 6.3 g of l-[bis- (4-chlorophenyl)methyl]-3-[(3-cyanophenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a foam.

Example 62 A mixture of 4.5 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine in 50 cm 3 of acetic acid and 50 cm 3 of concentrated hydrochloric acid (d=1.18) is heated at 0 C for 20 hours. The reaction medium is cooled to room temperature and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is taken up in 100 cm 3 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 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 obtained is crystallized from 15 cm 3 of ethyl ether. 0.2 g of l-[bis(4-chlorophenyl)methyl]-3-[(3carbamoylphenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a solid melting at 192 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH 2 4.80 (1H, s, NCH), 7.35 (4H, d, J=7Hz, 4CH arom.), 7.45 d, J=7Hz, 4CH arom. and /2 CONH 2 7.50 (2H, m, 2CH arom.), 7.85 (2H, m, 2CH arom.)].

Example 63 On carrying out the operation according to the procedure of Example 1 starting with 0.8 g of l-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)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 cm), at a nitrogen pressure of 0.5 bar with a dichloromethane and ethanol mixture (98/2 by volume) as 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 l-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl- N-methylamino)phenyl](methylsulfonyl)methylene}azetidine is obtained in the form of a solid melting at 161 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 1.30 (9H, s, 2.95 (3H, s, SCH,), 3.15 (3H, s, NCH,), 3.75 (2H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), between 7.15 and 7.50 (14H, m, 14CH arom.)].

l-Benzhydryl-3-{[3-(N-tert-butyloxycarbonyl- N-methylamino)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 1.6 g of tert-butyloxycarbonyl-N-methylamino)benzyl]methylsulfone, 1.3 g of l-benzhydrylazetidin-3-one and 3.8 cm 3 of a 1.6 M solution of n-butyllithium in hexane, 0.8 g of l-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 3 of dioxane are added to a solution, cooled to 0°C of methyl(3-methylaminobenzyl)sulfone in 30 cm 3 of dioxane.

The stirring is maintained for 18 hours at room temperature. The reaction medium is taken up in 75 cm 3 of dichloromethane; the organic phase is washed with cm 3 of water and then with 75 cm 3 of a saturated 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 (particle size 0.04-0.06 mm, diameter 2 cm, height 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 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.8 g of [3-(N-tertbutyloxycarbonyl-N-methylamino)benzyl]methylsulfone 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 of formic acid (d=1.22) and 19.6 cm' of acetic anhydride (d=1.08) is heated for 3 hours at 50 0 C and then the solution is allowed to return to room temperature.

165 cm 3 of tetrahydrofuran are added and the mixture is cooled to -20 0 C. 14.8 g of (3-aminobenzyl)methylsulfone and 200 cm 3 of tetrahydrofuran are then added. The stirring is maintained for 2 hours at -20 0 C and then 48 hours at room temperature. The mixture is filtered on sintered glass, the precipitate is washed with 3 times cm 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 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 0°C; 100 cm 3 of a 2 M solution of borane dimethyl sulfide in tetrahydrofuran added and then heated under reflux for 3 hours. The mixture is cooled to 5°C 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 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 250 cm 3 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' of 4 N hydrochloric acid and then with 100 cm' of ethyl acetate. The aqueous phase is alkalinized with 120 cm 3 of 3 -N sodium hydroxide, and then with an 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 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 for 15 minutes. 18.5 g of iron are added over 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 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 of a beige solid which is used in the crude state in subsequent syntheses.

167 Example 64 A mixture of 0.3 g of l-benzhydryl-3-{[3-(Ntert-butyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methylene}azetidine, 4 cm 3 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 3 of water 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 cm 3 of ethyl acetate, washed with twice 30 cm 3 of water, decanted off, dried over anhydrous magnesium 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 161 0 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,), 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), 5.80 (1H, q, J=5Hz, NH), 6.60 (3H, m, 3CH arom.), 7.15 (1H, t, J=7Hz, CH arom.), 7.22 (2H, t, J=7Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.48 (4H, d, J=7Hz, 4 CH arom.)].

168 Example On carrying out the operation according to the procedure of Example 4 starting with 11.3 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)- (methylsulfonyl)methyl-(RS)]azetidin-3-ol, 2.6 cm 3 of methanesulfonyl chloride and 10.9 g of 4-dimethylaminopyridine, 5 g of l-[bis(4-chlorophenyl)methyl]-3-[(3methoxyphenyl)(methylsulfonyl)methylene]azetidine are 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,), 3.77 (3H, s, OCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.80 (1H, s, NCH), 6.95 (3H, m, 3CH arom.), 7.35 m, 5CH arom.), 7.45 (4H, d, J=7Hz, 4CH arom.)].

1-[Bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(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 6.6 g of (3-methoxybenzyl)methylsulfone, g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 23 cm 3 of a 1.6 N solution of n-butyllithium in hexane, 11.4 g of l-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white solid melting at 130 0

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)- (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 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-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine is obtained, after recrystallization from 5 cm 3 of diethyl ether, in the form of a solid melting at 114 0 C [NMR spectrum in DMSOd6, T=300K, 8 in ppm (250 MHz): 2.92 (3H, s, SCH,), 3.80 (2H, s, NCH 2 4.20 (2H, s, NCH 2 4.80 (1H, s, NCH), 6.80 (3H, m, 3CH arom.), 7.20 (1H, t, J=7Hz, CH arom.), 7.37 (4H, t, J=7Hz, 4CH arom.), 7.47 (4H, d, J=7Hz, 4 CH arom.)].

Example 67 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 3 of methanesulfonyl chloride and 0.5 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 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' fractions. Fraction 4 is concentrated 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 3 of diethyl ether, in the form of a solid melting at 133 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (400 MHz): 2.00 (4H, m, 2 2.95 (3H, s, SCH,), 3.20 (4H, m, 2 NCH,), 3.80 (2H, s, NCH 2 4.20 (2H, s, NCH 2 4.80 (1H, s, NCH), 6.50 (1H, s, CH arom.), 6.60 (1H, d, J=7Hz, CH arom.), 6.65 (1H, d, J=7Hz, CH arom), 7.20 (1H, t, J=7Hz, CH arom.), 7.40 (4H, d, J=7Hz, 4 CH arom.), 7.50 (4H, d, J=7Hz, 4 CH arom.)].

1-[Bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)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 0.5 g of methyl- (3-pyrrolidinylbenzyl)sulfone, 0.6 g of l-[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 l-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)- (3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3-ol is obtained in the form of a cream-colored solid.

Example 68 On carrying out the operation according to the procedure of Example 58 starting with 5.1 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methylene}azetidine and 17 cm 3 of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran, 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 dichloromethane and ethanol mixture (97/3 by volume) as eluent and collecting 100 cm 3 fractions.

Fractions 10 to 14 are combined, concentrated to dryness under reduced pressure (2.7 kPa). The yellow solid obtained is taken up in 2 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.

1.6 g of l-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]azetidine are obtained in the form of a white solid melting at 214 0

C

172 [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (400 MHz): 2.95 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s,

NCH

2 4.50 (2H, d, J=5Hz, OCH 2 4.80 (1H, s, NCH), 5.25 (1H, t,-J=5Hz, OH), 7.30 (1H, d, J=7Hz, CH arom.), between 7.35 and 7.45 (7H, m, 7CH arom.), 7.50 (4H, d, J=7Hz, 4CH arom.)].

1-[Bis(4-chlorophenyl)methyl]-3-{[3-(tertbutyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methylene}azetidine may be prepared in the following manner: on carrying out the operation according to the procedure of Example 4 starting with 10.8 g of l-[bis- (4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl] (methylsulfonyl)methyl-(RS)}azetidin- 3-ol, 2 cm 3 of methanesulfonyl chloride and 8.5 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 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 100 cm 3 fractions. Fractions 12 to 29 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 5.2 g of l-[bis(4-chlorophenyl)methyl]- 3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methylene}azetidine are obtained in the form of a gum.

l-[Bis(4-chlorophenyl)methyl]-3-{[3-(tertbutyldimethylsilyloxymethyl)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]methylsulfone 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.

Example 69 A mixture of 0.45 g of l-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine, 0.07 cm of 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' of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 0.2 g of 1-[bis- (4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(Npiperidylcarbamoyl)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, 1.60 (4H, m, 2CH 2 2.85 (4H, m, 2NCH 2 3.00 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.80 (1H, s, NCH), between 7.45 and 7.60 (10H, m, 10CH arom.), 7.75 (2H, 174 m, 2CH arom.), 9.45 (1H, s, NH)].

l-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine may be prepared in the following manner: on carrying out the operation according to the procedure of Example 29 starting with 2.6 g of 1-[bis- (4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidine hydrochloride, 0.9 g of pentafluorophenol, 0.9 g of l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride in 25 cm 3 of dimethylformamide, 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 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 l-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine is obtained in the form of a foam.

1-[Bis(4-chlorophenyl)methyl]-3-[(3carboxyphenyl)(methylsulfonyl)methylene]azetidine may be prepared in the following manner: 2 cm of Jones 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 0 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 3 of ethyl acetate are added. The organic phase is decanted off, washed with 50 cm 3 of a 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 cm), at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane and ethanol as eluent and collecting cm 3 fractions. Fractions 12 to 14 are combined, concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 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 205 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (400 MHz): 2.90 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 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 Example 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)- (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 18 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 50 cm 3 fractions. Fractions 12 to 17 are combined, concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is again purified by 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 pressure (2.7 kPa). 0.25 g of l-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)methylene]azetidine is obtained melting at [NMR spectrum in DMSO-d6 CD 3

CO

2 D, T=300K, 6 in ppm (300 MHz): 3.00 (3H, s, SCH,), 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.80 (1H, 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-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)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 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 l-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)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 of Example 10 starting with 5 g of 3-trifluoromethylsulfanylbenzyl chloride and 3.2 g of sodium methanesulfinate, 5.2 g of methyl(3-trifluoromethylsulfanylbenzyl)sulfone are obtained in the form of a white solid melting at 1250C.

Example 71 On carrying out the operation as in Example 38 (Method starting with 0.72 g of l-[bis(4-fluorophenyl)methyl]-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-difluorophenyl)(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 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, 6 in ppm (250 MHz): 3.05 (3H, s, SCH,), 3.90 (2H, s, NCH,), 4.20 (2H, s, NCH,), 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.)].

l-[Bis(4-fluorophenyl)methyl]-3-[(3,5difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin- 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-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol 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, fractions 23 to 39 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.72 g of l-[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 BACHMANN J. Am. Chem. Soc., 2135 (1933) starting with 4 g of 4,4'-difluorobenzydrol, 2.70 cm of acetal bromide and 14 cm 3 of a 33% hydrobromic acid solution in acetic acid.

Example 72 On carrying out the operation as in Example 38 (Method starting with 1.22 g of l-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.29 cm 3 of methanesulfonyl chloride and 1.1 g of 4-dimethylaminopyridine, 0.177 g of l-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained, after chromatography on a silica gel column (particle 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): 3.05 (3H, s, SCH,), 3.95 (2H, s, NCH 2 4.25 (2H, s, NCH,), 5.35 (1H, s, NCH), 7.20 (6H, m, 6CH arom.), 7.35 (3H, 3CH arom.), 7.55 (2H, m, 2CH arom.)].

180 l-[Bis(2-fluorophenyl)methyl]-3-[(3,5difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin- 3-ol may be obtained in the following manner: the operation is carried out as in Example 39 starting with 2 g of bis(2-fluorophenyl)bromomethane, 1.0 g of potassium carbonate and 2.22 g of 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol hydrochloride. After chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, 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 3 fractions, fractions 6 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.22 g of l-[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 BACHMANN 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 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 0 C under argon, of 8.8 g of 2-bromofluorobenzene in 100 cm 3 of tetrahydrofuran. After stirring for 10 minutes at 0 C, 2.1 cm of ethyl formate are added slowly and then the mixture is stirred at -70 0 C for 30 minutes.

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 0 C, under reduced pressure (2.7 Kpa). 3.63 g of 2,2'-difluorobenzydrol are obtained in the form of a yellow oil.

Example 73 On carrying out the operation as in Example 38 (Method starting with 1.15 g of l-[bis- (3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.264 cm 3 of methanesulfonyl chloride, and 0.98 g of 4-dimethylaminopyridine, 0.55 g of l-[bis(3-fluorophenyl)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 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 solid melting at 182 178 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (250 MHz): 3.05 (3H, s, SCH,), 3.95 (2H, s, NCH,), 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, 7CH arom.)].

l-[Bis(3-fluorophenyl)methyl]-3-[(3,5difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin- 3-ol may be prepared in the following manner: on carrying out the operation according to Example 1 starting with 1.2 g of sulfone and 1.5 g of l-[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 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 3 fractions, in the form of a white solid melting at 170 0 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 (1994), starting with 4.9 g of [bis(3-fluorophenyl)methyl]amine and 1.78 cm 3 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 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 3 of water and then 50 cm 3 of ethyl acetate are added successively.

After drying over magnesium sulfate and concentrating 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 solution of 1.6 g of hydroxylamine hydrochloride in 8 cm 3 of water is poured dropwise into a solution of 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 reflux for 10 minutes, is cooled to 20 0 C and then acidified with 7.5 cm 3 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 0 C under reduced pressure (2.7 kPa).

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 diastereoisomers 1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-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-[(methylsulfonyl)(phenyl)methylene]azetidine 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 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,), 4.35 (2H, m, NCH 2 5.25 (1H, s, NCH), 7.45 (9H, m, 9CH arom.), 7.65 (1H, d, J=2Hz, CH thiazole), 7.70 (1H, d, J=2Hz, CH thiazole)].

The mixture of the two diastereoisomers l-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]- 3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: on carrying 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 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 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- 2-yl)methane may be prepared according to the procedure described by BACHMANN 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 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 and 4.92 g of 2-bromothiazole.

Example 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- (RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl- (RS)]azetidin-3-ol, 0.14 cm of methanesulfonyl chloride and 0.49 g of 4-dimethylaminopyridine, 0.32 g of (RS)l-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained, after chromatography on a silica gel column (particle size 0.06-0.200 mm, diameter 2.4 cm, height 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 white solid melting at 176 0 C [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 2.98 (3H, s, SCH,), 3.90 (2H, m, NCH,), 4.20 (2H, s, NCH,), 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 arom.),7.32 (3H, m, 2CH arom. and 1CH thiophene), 7.40 (2H, d, J=7Hz, 2CH arom.)].

The mixture of the two diastereoisomers l-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin- 3-ol may be prepared in the following manner: on carrying out the operation as in Example 1 starting with 1.60 cm 3 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 diastereoisomers 1-[4-chlorophenyl)(thien-2-yl)methyl-(RS)]- 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 bar with a mixture of ethyl acetate and cyclohexane (25/75 by volume) as eluent and collecting 40 cm 3 fractions, in the form of an off-white solid.

l-[(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 sulfoxide are poured over 10 minutes into a solution, cooled to -70°C, of 1.83 cm 3 of oxalyl chloride in cm 3 of dichloromethane under argon. After stirring for 30 minutes at -60 0 C, a solution of 5.2 g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin- 3-ol in 80 cm 3 of dichloromethane is poured in over 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 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 bar with a mixture of ethyl acetate and cyclohexane (1/9 by volume) as eluent and collecting 60 cm 3 fractions. 3.3 g of l-[(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: 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 0 C and supplemented with 4.03 cm 3 of epibromohydrin.

After stirring for 20 hours at 65 0 C, the cooled mixture 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 acetate and cyclohexane (25/75 by volume) as eluent and collecting 60 cm 3 fractions. 6.3 g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-ol are obtained in the form of a pale yellow oil.

[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]amine may be prepared in the following manner: a solution of 10.92 g of 2-thiophenecarbonitrile in 80 cm 3 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 3 of anhydrous ethyl ether.

After refluxing for one hour, the mixture is cooled to 10 0 C, supplemented slowly with 40 cm 3 of methanol and then filtered on supercel. 4.54 g of sodium borohydride are added under argon and in small fractions over minutes and then the reaction medium is stirred for hours at 20 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 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 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 methanol. The solution obtained is supplemented with 2.4 g of sodium borohydride and stirred for one hour at 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

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 3 fractions. 11.0 g of [(4-chlorophenyl)(thien-2-yl)methyl-(RS)]amine are obtained in the form of a yellow oil.

Example 76 On carrying out the operation as described in Example 75, starting with 1.66 g of the mixture of the two chiral diastereoisomers l-f(4-chlorophenyl) (thien- 2-yl)(methylsulfonyl)methyl-(R*)]azetidin-3-ol and l-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)1-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidin-3-ol, 50 cm of dichloromethane, 0.45 cm 3 of methanesulfonyl chloride, and 1.64 g of 4-dimethylaminopyridine, 0.6 g of (+)-l-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5difluorophenyl) (methylsulfonyl)methylene]azetidine is obtained in the form of white crystals melting at 136 0 C, 20 +3.20 (c 0.5% in dichloromethane).

The mixture of the two chiral diastereoisomers 1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]- 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)] azetidin-3-ol and l-[(4-chlorophenyl) (thien-2-yl)methyl-(R*)1-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(S*)1azetidin-3-ol may be prepared as described 191 in Example 75, starting with 1.06 g of [(4-chiorophenyl)(thien-2-yl)methyl]azetidi-3-oe, 0.82 g of 5-dif luorobenzyl)methylsulffone, 2.5 cm' of 1.6 N solution of n-butyllithium in hexane, and 25 cm 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)(methylsulfonyl)methyl-(R*)]azetidin-3-ol and 1-[(4-chiorophenyl)(thien-2-yl)methyl-(R*)1-3-[(3,5phenyl)(methylsulfonyl)methyl-(S*)Ilazetidin-3-ol are obtained, after purification by chromatography, in the form of a white solid.

(+)-1-[(4-Chiorophenyl)(thien-2-yl)methyl]azetidin-3-one may be prepared as described in Example 75, starting with 12.4 g of (+)-l-[(4-chlorophenyl)(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- 3-one are obtained in the form of a pale yellow oil crystallizing at 20 0

C.

(+)-l-[(4-Chlorophenyl) (thien-2-yl)methyl]azetidin-3-ol may be prepared as described in Example 75, starting with 16.1 g of (+)-[(4-chlorophenyl)(thien-2-yl)methyllamine, 130 cm 3 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 creamcolored oil.

(+)-4-[(Chlorophenyl) (thien-2-yl)methyl]amine may be prepared in the following manner: 73 g of tartaric acid are added to a solution of 109 g 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 obtained is taken up in 2.05 liters of an ethanol-water 90/10 by volume mixture. After stirring slowly for hours at 20 0 C, the crystalline suspension obtained is filtered, the crystals washed with a minimum amount of the same mixture of solvents, and then dried. Another recrystallization is carried out under the same 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] 2 +10.30 (c 0.5% in dimethylformamide). This compound is recrystallized from 600 cm of an ethanol-water 80/20 by volume mixture (the crystals are filtered and washed with twice 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 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 dimethylformamide).

193 This salt is taken up in 400 cm 3 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 3 of water, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa). 16.1 g of (+)-[(4-chlorophenyl)-(thien- 2-yl)methyl]amine are obtained in the form of an oil which crystallizes at 20 0 C. 20 +32.70 (c 0.5% in dichloromethane).

Example 77 On carrying out the operation as described in Example 75, starting with 1.30 g of the mixture of the two chiral diastereoisomers 1-[(4-chlorophenyl)(thien- 2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]azetidin-3-ol and 1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidin-3-ol, 40 cm 3 of dichloromethane, 0.35 cm 3 of methanesulfonyl chloride and 1.28 g of 4-dimethylaminopyridine, 0.97 g of [(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]zetidine is obtained in the form of white crystals melting at 135 0 C, [a]20 -3.40 (c 0.5% in dichloromethane).

The mixture of the two chiral diastereoisomers l-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]- 194 3-[l(3,5-difluorophenyl) (methylsulfonyl)methyl- azetidin-3-ol and (4-chiorophenyl) (thien-2-yl) methyl-(S*) (3,5-difluorophenyl) (methylsulfonyl)methyl-(S*)]azetidin-3-ol may be prepared as described in Example 75, starting with 1.06 g of [(4-chiorophenyl) (thien-2-yl)methyl]azetidin-3-one, 0.82 g of (3,5-difluorobeflzyl)methylsulfone, 2.5 CM 3 of 1.6 N solution of n-butyllithiun in hexane, and 25 cm' of tetrahydrofuran. 1.3 g of the mixture of the two chiral diastereoisomers 1-f (4-chlorophenyl) (thien- 2-yl)methyl-(S*) 1-3-f (3,5-difluorophenyl) (methylsulfonyl)methyl-(R*) ]azetidin-3-ol and 1-f (4-chlorophenyl)(tin2y ehl(*)--(,-iloo phenyl) (methylsulfonyl)methyl- ]azetidin-3-ol are obtained after purification by chromatography in the form of a white solid.

(4-Chiorophenyl) (thien-2-yl)methyllazetidin-3-one may be prepared as described in Example 75, starting with 11.4 g of (-)-l-[(4-chlorophenyl) (thien-2-yl)methyllazetidin-3-ol, 200 CM 3 of dichloromethane, 4.0 CM 3 of dimethyl sulf oxide, 4.0 CM 3 of oxalyl chloride and 19.5 CM 3 Of triethylamine. 8.3 g of (4-chlorophenyl) (thien-2-yl)methyl]azetidin- 3-one are obtained in the form of a pale yellow oil crystallizing at -1-f(4-Chlorophenyl) (thien-2-yl) methyllazetidin-3-ol may be prepared as described in 195 Example 75, starting with 15.4 g of (-)-[(4-chlorophenyl) (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- 2-yl)methyl]azetidin-3-ol are obtained, after purification by chromatography, in the form of a creamcolored oil.

(-)-[(4-Chlorophenyl)(thien-2-yl)methyl]amine may be prepared in the following manner: 29 g of 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.

Recrystallization is carried out with 500 cm 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 0 C. A final recrystallization is carried out with 350 cm of an ethanol-water 78/22 by volume mixture, allowing the mixture to be stirred for 20 hours at 20 0 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 obtained. 20 -10.70 (c 0.5% in dimethylformamide).

This salt is taken up in 400 cm 3 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 (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. 2 -31.70 (c 0.5% in dichloromethane).

Example 78 On carrying out the operation according to the procedure of Example 1 starting with 3.4 g of l-benzhydryl-3-[(ethylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol, 0.72 cm 3 of methanesulfonyl chloride and 3.8 g of 4-dimethylaminopyridine, 1.9 g of l-benzhydryl-3-[(ethylsulfonyl)(phenyl)methylene]azetidine are obtained, after recrystallization from cm 3 of acetonitrile, in the form of crystals melting at 210 0 C [[NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 1.15 (3H, t, J=6Hz, 2.92 (2H, q, J=6Hz, 3.83 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.75 (1H, s, NCH), between 7.20 and 7.50 (15H, m, 3 phenyls)].

l-Benzhydryl-3-[(ethylsulfonyl)(phenyl)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 3 of 1.6 N n-butyllithium in solution in hexane, 65 cm 3 of tetrahydrofuran and 3.1 g of l-benzhydrylazetidin- 3-one. 3.6 g of l-benzhydryl-3-[(ethylsulfonyl)- (phenyl)methyl-(RS)]azetidin-3-ol are obtained, after recrystallization from 30 cm 3 of acetonitrile, in the form of white crystals melting at 2220C.

Benzylethylsulfone may be prepared by carrying out the operation according to the procedure of Example 2 starting with 6.3 g of benzylethylsulfide, cm 3 of acetic acid, 50 cm 3 of water, 25 cm 3 of 36 N sulfuric acid and 24.8 g of oxone". 3.2 g of benzylethylsulfone are obtained, by recrystallization from 20 cm 3 of ethyl ether, in the form of a solid melting at 860C.

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 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 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.

O

198 Example 79 0.083 g of l-amino-4-methylpiperazine is added to a solution of 0.45 g of l-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene]azetidine in 5 cm' of dimethylformamide. The mixture is stirred for 20 hours at room temperature and then 40 cm 3 of ethyl acetate are 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 l-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[(N-4methylpiperazinylcarbamoyl)phenyl]methylene}azetidine is obtained in the form of a yellow solid melting at 162 0 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 2.90 (4H, m, 2 NCH,), 2.95 (3H, s, SCH,), 3.80 (2H, s,

NCH

2 4.20 (2H, s, NCH 2 4.80 (1H, 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)].

1-[Bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[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)- (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 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 of dichloromethane and ethanol (99/1 by volume). 0.92 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)- [3-(pentafluorophenoxycarbonyl)phenyl]methylene]azetidine is obtained in the form of a white foam.

1-[Bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidine may be prepared in the following manner: a 36% solution of hydrochloric acid at a temperature of 50 0 C is added to a solution of 3.8 g of l-[bis(4-chlorophenyl)methyl]- 3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine 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)methyl]- 3-[(3-carboxyphenyl)(methylsulfonyl)methylene)]azetidine are obtained in the form of a beige solid.

1-[Bis(4-chlorophenyl)methyl]-3-[(3cyanophenyl)(methylsulfonyl)methylene]azetidine may be prepared according to the procedure of Example 4, starting with 11 g of 1-[bis(4-chlorophenyl)methyl]- 3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin- 3-ol, 150 cm of dichloromethane, 2.54 cm 3 of methanesulfonyl chloride and 10.7 g of 4-dimethylaminopyridine, at room temperature for 3 hours. The residue obtained is purified by chromatography on a silica gel 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)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine are obtained in the form of a white foam.

1-[Bis(4-chlorophenyl)methyl]-3-[(3cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol may be prepared in the following manner: a solution of 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 3 201 of tetrahydrofuran under argon, and cooled to The mixture is stirred for 1 hour 30 minutes. Next, a solution of 7.8 g of l-[bis(4-chlorophenyl)methyl]azetidin-3-one in 80 cm 3 of tetrahydrofuran is poured in over 10 minutes. After stirring for 1 hour 30 minutes, 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 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure (2.7 Kpa). 11 g of l-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a foam.

(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 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 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 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).

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 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.

Example On carrying out the operation according to the procedure of Example 79 starting with 0.5 g of l-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)- [3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine, 0.06 cm', l,l-dimethylhydrazine and 5 cm 3 of 203 dimethylformamide, 0.125 g of l-Ibis(4-chlorophenyl)methyl] (2,2-dimethylcarbohydrazido)phenyl]- (methylsulfonyl)methylene}azetidine is obtained in the form of a white solid melting at 134*C [NNR spectrum in DMSO-d6, T=300K, 8 in ppm (300 1MHz): 2.60 (6H, s, N(CH 3 I) 2.95 (3H, s, SCH 3 3.80 (2H, s, NCH 2 4.20 (2H, s, NCH,), 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 (2H1, m, 2CH arom.), 9.50 (1H, s,

CONH)].

Example 81 On carrying out the operation according to the procedure described in Example 1 starting with 2.2 g of l-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl- (RS) ]azetidin-3-ol, 0.64 cm' of methanesulfonyl chloride, 2.3 g of 4 -dime thyl aminopyri dine and 75 cm' of dichloromethane, 1.3 g of l-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl) (methylsulfonyl )methylene] azetidine are obtained, after purification by chromatography and crystallization from diisopropyl ether, in the form of white crystals melting at 165 0 C [N14R spectrum in DMSOd6, T=300K, 6in ppm (300 M4Hz) 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-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol may be 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' of 1.6 N n-butyllithium in hexane, 1.3 g of methylsulfone and 40 cm 3 of tetrahydrofuran. 2.2 g of l-[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 be prepared by carrying out the operation as described in Example 73, starting with 4 g of l-[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 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 reduced pressure (2.7 Kpa). 3.2 g of l-[bis(thien- 2-yl)methyl]azetidin-3-one are obtained in the form of cream-colored crystals melting at 70 0

C.

205 l-[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 l-[bis(thien- 2-yl)methyl]amine, 2.5 cm 3 of epibromohydrin, 2.6 g of sodium bicarbonate and 50 cm' 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 0

C.

1-[Bis(thien-2-yl)methyl]amine may be prepared in the following manner: a solution of 5 cm 3 of thien-2-ylcarbonitrile in 50 cm 3 of diethyl ether is poured dropwise into a suspension, cooled under argon to 10 0 C, of thien-2-ylmagnesium bromide (prepared from 1.29 g of magnesium and 3.22 cm 3 2-bromothiophene in cm' of diethyl ether). After refluxing for 1 hour and 30 minutes, the reaction medium is cooled to 5°C 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 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 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 1-[bis(thien-2-yl)methyl]amine are obtained in the form of a crystallized solid.

Example 82 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 methanesulfonyl chloride, 25 cm 3 of dichloromethane and 0.48 g of 1-(bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol, 0.25 g of 1-(bis-p-tolylmethyl)-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 ppm (250 MHz): 2.23 (6H, s, 2 PhCH,), 2.98 (3H, s, SCH,), 3.76 (2H, s, NCH,), 4.20 (2H, s, NCH,), 5.55 (1H, s, NCH), 7.10 (4H, d, J=7Hz, 4 CH arom.), 7.32 (4H, d, J=7Hz, 4 CH arom.), 7.43 (5H, s, phenyl)].

1-(Bis-p-tolylmethyl)-3-[(methylsulfonyl)- (phenyl)methyl-(RS)]azetidin-3-ol may be prepared according to the procedure described in Example 39, starting with 0.59 g of bromo(bis-p-tolyl)methane, 207 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 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-(bisp-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methyl- (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).

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)]-l-(vinyloxycarbonyl)azetidin-3-ol, 35 cm 3 of 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)]l-(vinyloxycarbonyl)azetidin-3-ol may be prepared according to the procedure described in Example 38 (Method starting with 10 g of l-benzhydryl- 208 3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol, 600 cm' 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 5.2 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 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 (-)-l-[(4-chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine in cm 3 of methanol at 0°C under argon. After stirring for 4 hours at 0°C, water is added and the mixture is then extracted with dichloromethane. The organic phase 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, height 17 cm) with, as eluent, a cyclohexane/ethyl acetate (60/40 by volume) mixture. 0.1 g of chlorophenyl)(4-hydroxymethylphenyl)methyl]-3-[(3,5- 209 difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained, after crystallization from 1.5 cm 3 of absolute ethanol, in the form of white crystals melting at 190 0 C, [a]20 +4.20 (c 0.5% in methanol) [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 3.05 (3H, s, SCH,), 3.95 (2H, s, NCH 2 4.22 (2H, s, NCH 2 4.48 (2H, d, J=6Hz, CH 2 4.75 (1H, s, NCH), 5.15 (1H, t, J=6Hz, OH), 7.20 (2H, m, 2CH arom.), 7.28 (2H, d, J=7Hz, 2CH arom.), 7.40(5H, m, 5 CH arom.), 7.50 (2H, d, J=7Hz, 2CH arom.)].

(-)-1-[(4-Chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethylene]azetidine may be prepared in the following manner: 3.32 cm 3 of a 5 N solution of hydrochloric acid are poured into a solution of 0.83 g of chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}- 3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine in 5 cm 3 of tetrahydrofuran and then the mixture is kept stirring for 20 hours. Dichloromethane 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 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- 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- 2-yl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine 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 3-acetoxy-l-{(4-chlorophenyl)[4-(1,3-dioxolan- 2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]azetidine and 3-acetoxy-l-{(4-chlorophenyl)[4-(1,3-dioxolan- 2-yl)phenyl]methyl-(R*)}-3-[(3,5difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidine in cm 3 of tetrahydrofuran under argon at 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.

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 acetate (80/20 by volume) mixture. 1.21 g of chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}- 3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine are obtained in the form of a yellow foam.

The mixture of 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 and 3-acetoxyl-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl- (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 solution of 1.08 g of 3-5-difluorobenzyl methyl sulfone under argon, cooled to -70 0 C, and then the mixture is kept stirring for 1 hour at -70 0 C and then a solution of 1.80 g of (+)-l-{(4-chlorophenyl)[4-(1,3-dioxolan- 2-yl)phenyl]methyl}azetidin-3-one in 10 cm 3 of tetrahydrofuran is poured in dropwise. After stirring for 3 hours at -70 0 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 0 C is poured in and the mixture is stirred for 2 hours at -20 0 C. The reaction medium is 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 the two diastereoisomers 3-acetoxy-l-{(4-chlorophenyl)- [4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5difluorophenyl)(methylsulfonyl)methyl-(R*)]azetidine 212 and 3-acetoxy-l-{(4-chlorophenyl)[4-(1,3-dioxolan- 2-yl)phenyl]methyl-(R*)}-3-[(3,5difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidine are obtained in the form of a yellow oil.

(+)-l-{(4-Chlorophenyl)[4-(1,3-dioxolan- 2-yl)phenyl]methyl}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 (+)-l-{(4-chlorophenyl) [4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin- 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 minutes at room temperature, the reaction medium is 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 (1.31 combined with another batch of the same crude compound (1.21 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.

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] 20 365nm (c 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, starting with 4.43 g of (+)-{(4-chlorophenyl)[4-(1,3dioxolan-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 (+)-l-{(4-chlorophenyl)[4-(1,3dioxolan-2-yl)phenyl]methyl}azetidin-3-ol are obtained 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-chlorophenyl)(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 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- 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 are concentrated to dryness under reduced pressure (2.7 kpa). 1.39 g of chiral (+)-{(4-chlorophenyl)- [4-(1,3-dioxolan-2-yl)phenyl]methyl}amine are obtained in the form of a yellow oil.

Chiral (R*)-[(4-chlorophenyl) (4-formylphenyl)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 chlorophenyl)[4-(diethoxymethyl)phenyl]methyl-(R*)}- (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 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 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)(4formylphenyl)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 4-bromochlorobenzene and the mixture is stirred for minutes at -700C. This solution obtained is then added dropwise to the following solution cooled to 0°C: g of (R)-N-[4-(diethoxymethyl)benzylidene]- 2-phenylglycinol in 300 cm of diethyl ether. The mixture is stirred for 2 hours at 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 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.

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)-2phenylglycinol are obtained in the form of an orange red oil.

(R)-N-[4-(diethoxymethyl)benzylidene]- 2-phenylglycinol may be prepared in the following 216 manner: 35.9 cm 3 of 4-(diethoxymethyl)benzaldehyde are poured into a white suspension of 24.7 g of 2-phenylglycinol in 500 cm 3 of toluene. The cloudy yellow solution is heated under reflux for 6 hours 30 minutes, and is then stirred at room temperature for hours. After concentrating the reaction medium to dryness under reduced pressure (2.7 kpa), 61.6 g of (R)-N-[4-(diethoxymethyl)benzylidene]-2-phenylglycinol are obtained in the form of a yellow oil.

Example 84 On carrying out the operation according to the procedure of Example 1, but starting with 5.6 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxycarbonyl-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-dimethylaminopyridine. The mixture is kept stirring for 3 hours 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 eluting at a nitrogen pressure of bar with an ethyl acetate/cyclohexane (30/70 by 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-tertbutyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methylene}azetidine are obtained in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, 8 in ppm (300 MHz): 1.30 (9H, s, 2.65 (3H, s, J=6Hz, NCH,), 2.85 (3H, s, SCH,), 3.50 (2H, s, NCH,), 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.)].

l-[Bis(4-chlorophenyl)methyl]-3-{[3-(Ntertbutyloxycarbonyl-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-tertbutyloxycarbonyl-N-methylamino)benzyl]methylsulfone, 50 cm of tetrahydrofuran, 9.5 cm 3 of a 1.6 N solution of n-butyllithium in hexane, 3.82 g of l-[bis(4-chlorophenyl)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 silica 250 eluting at a nitrogen pressure of bar with dichloromethane and then with a dichloromethane and ethanol mixture (99/1 by volume) and collecting 500 cm 3 fractions. Fractions 10 to 16 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 5.6 g of l-[bis(4-chlorophenyl)methyl]-3-{[3-(Ntertbutyloxycarbonyl-N-methylamino)phenyl](methyl- 218 sulfonyl)methyl-(RS)}azetidin-3-ol, are obtained in the form of a foam.

Example 2.7 g of l-[bis(4-chlorophenyl)methyl]-3-{[3- (N-tertbutyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methylene}azetidine in 30 cm 3 of dioxane and cm 3 of a 4.7 N solution of hydrochloric dioxane are 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 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 3 then filtered, concentrated to dryness under reduced pressure. 1.3 g of l-[bis(4-chlorophenyl)methyl]-3-[(3methylaminophenyl)(methylsulfonyl)methylene]azetidine are obtained in the form of white crystals melting at 228 0 C [NMR spectrum in DMSO-d6, T=300K, 6 in ppm (300 MHz): 2.65 (3H, s, J=6Hz, NCH,), 2.95 (3H, s, SCH 3 3.80 (2H, s, NCH,), 4.20 (2H, s, NCH,), 4.80 (1H, s, NCH), 5.85 (1H, q, J=6Hz, NH), 6.55 (3H, m, 3 CH arom.), 7.15 (1H, t, J=7Hz, CH arom.), 7.40 (4H, d, J=7Hz, 4CH arom.), 7.50 (4H, m, 4CH arom.)].

219 Example 86 On carrying out the operation as in Example 1, starting with 0.40 g of a mixture of two diastereoisomers 1-[(4-chlorophenyl)(thiazol- 2-yl)methyl-(RS)]-3-[3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.10 cm 3 of methanesulfonyl chloride and 0.37 g of 4-dimethylaminopyridine, 0.13 g of (RS)-l-[(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 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, 6 in ppm (300 MHz): 3.05 (3H, s, SCH,), 4.05 (2H, s, NCH,), 4.35 (2H, m, NCH,), 5.25 (1H, s, NCH), 7.20 (2H, d, J=8Hz, 2CH arom.), 7.35 (lH, 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 1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[3,5difluorophenyl)(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 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 3 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)(methylsulfonyl)methyl-(RS)]azetidin-3-ol- which is obtained in the form of a whitish solid.

221 Example 87 mm' of pyrrolidine are added to a solution of 0.32 g of 1-{(R')-[4-(chloromethyl)phenyl] (4-chlorophenyl)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 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 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 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.

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)methylene]azetidine, form A isomer, is obtained in the form of a white foam [a] 2 °365nm -22.5° 0.7 (c dichloromethane) [H NMR spectrum (300 MHz, CDC13, 5 in ppm): 1.78 (mt, 4H), 2.51 (mt, 4H), 2.81 3H), 3.58 221 222 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)] 1-({(R*)-[(4-chloromethyl)phenyl] (4chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)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 diastereoisomers (forms A) l-{(R')-[(4-chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl) (methylsulfonyl)methyl]azetidin-3-ol and [(4-chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- (3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3ol 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 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 combined and then concentrated to dryness under reduced pressure (2.7 kPa). 6.3 g of (R')-[4-(chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)- 222 223 (methylsulfonyl)methylene]azetidine, form A isomer, are obtained in the form of a white foam.

The mixture of the 2 diastereoisomers (forms A) (R 4-(chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- (R)-(3,5-difluorophenyl) (methylsulfonyl)methyl)]azetidin-3-ol, and chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(S)- (3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3ol, may be prepared by carrying out the operation in the following manner: 60 mm 3 of thionyl chloride are added to a solution of 0.20 g of the mixture of the 2 diastereoisomers (forms A) (R')-[4-(chlorophenyl) [4- (hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5difluorophenyl) (methylsulfonyl)methyl)]azetidin-3-ol, and 1-{(R')-(4-chlorophenyl) [4- (hydroxymethyl)phenyl]methyl}-3-(S)- difluorophenyl)(methylsulfonyl)methyl]azetidin-3-ol, in cm 3 of dichloromethane. After stirring for 20 hours at 20°C, 5 cm 3 of a saturated aqueous sodium hydrogen 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 pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 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' fractions.

Fractions 4 to 7 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) 0.17 g of the mixture of the 2 diastereoisomers (forms A) 1 (chloromethyl)phenyl [4-chlorophenyllmethyl}-3-[I(R) (methylsulfonyl)methyl) lazetidin-3ol, and 1-({(R.)-t4-(chloromethyl)phenyl] (4chlorophenyl)methyl} difluorophenyl) (methylsulfonyl)methyl) ]azetidin-3-ol is obtained in the form of a white foam.

The mixture of the 2 diastereoisomers (forms A) 1-{f 4- (chlorophenyl) phenyl [4 (hydroxymethyl)phenyllmethyl}-3-[(R) difluorophenyl) (methylsulfonyl)methyl) ]azetidin-3-ol, and 1-f -(4-chiorophenyl) (hydroxymethyl)phenyl] methyl}1-3- [(S)-(3,5-difluorophenyl) (methylsulfonyl)methylllazetidin-3-ol, may be prepared by carrying out the operation in the following manner: 1.6 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 0 C, of 0.58 g of the mixture of the 2 diastereoisomers (forms A) 3 -acetoxy- 1-{f 4 chlorophenyl) 14- (methoxycarbonyl)phenyllmethyl}-3- (3,5-difluorophenyl) (methylsulfonyl) methyl) ]azetidine and 3 -acetoxy- 1-{I (4 -chlorophenyl) [4 (methoxy- *carbonyl)phenyllmethyl}-3-[(S)-(3,5-difluoro- 224 225 phenyl) (methylsulfonyl)methyllazetidine, in 10 cm 3 of anhydrous toluene. After stirring for 15 minutes at 0 C, 1.0 cm 3 of this same hydride solution is again added and then the mixture is allowed to return to 0°C.

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 3 of water, 5 cm 3 of brine, and then dried over magnesium 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 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) )-(4-chlorophenyl) [4- (hydroxymethyl)phenyl] methyl}-3- phenyl) (methylsulfonyl)methyl)]azetidin-3-ol, and 1- (4-chlorophenyl) (hydroxymethyl)phenyl]methyl}- (3,5-difluorophenyl) (methylsulfonyl)methyl)]azetidin-3-ol is obtained in the form of a white lacquer.

The mixture of the 2 diastereomers (forms A) 3-acetoxy-l-{ -(4-chlorophenyl) [4-(methoxycarbonyl)- 225 226 phenyljmethyl}-3-[(R)-(3,5-difluorophenyl) (methylsulf onyl) methyl) I}azetidine and 3 -acetoxy-l1-{( chiorophenyl) 14- (methoxycarbonyl) phenyll methyl} l(S) (3.57difluorophenyl) (methylsulfonyl)methyl) }azetidine may be prepared by carrying out the operation as described in Example 40, starting with 1.0 g of dif luorobenzyl) methylsulf one, 30 cm' of tetrahydrofuran, 3 cm' of a 1.6 N solution of n-butyl~lithium in hexane, 1. 45 g of (4 -chlorophenyl) [4 -(methoxycarbonyl) phenyllmethyl~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*)-(4chiorophenyl) t4-methoxycarbonyl)phenyllmethyl} (methylsulfonyl)methyl) ]azetidine and 3-acetoxy-1-1{ -chiorophenyl). [4 -methoxycarbonyl)phenyllmethyl}-3-[l(S) -(3,5-difluorophenyl) (methylsulfonyl)methyl)lazetidine are obtained in the form of a beige foam.

C(4 -chiorophenyl) [4 (methoxycarbonyl) phenyllmethyliazetidin-3-one, form A isomer, may be prepared by carrying out the operation as described in Example 40, starting with 0.55 cm' of oxalyl chloride, cm' of dichioromethane, 0.90 cm 3 of dimethyl sulfoxide, 1.75 g of 1-{(4-chlorophenyl) 14-(methoxycarbonyl)phenyllmethyl~azetidin-3-ol, and 2.70 cm 3 Of t riethylamine. 1. 45 g of 1 -chlorophenyl) [4 (methoxycarbonyl)phenyllmethyllazeti-din-3-one, form A 226 227 isomer, are obtained in the form of a yellow foam.

(4-chlorophenyl) [4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol, form A isomer, may be prepared by carrying out the operation according to the 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, cm 3 of ethanol, 0.60 g of sodium hydrogen carbonate and 0.60 cm 3 of epibromhydrin. 1.76 g of 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 operation in the following manner: 2.51 g of 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 creamcolored 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°C. The crystals are filtered, washed with ethanol containing water, drained and then dried under reduced pressure (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 [(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 3 of ethyl acetate. The solution obtained is supplemented 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 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 creamcolored foam is obtained which, once dissolved in 27 cm 3 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 chlorophenyl)methyl]benzoate 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 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 -amino-(4-chlorophenyl)methyl]benzoate are obtained in the form of a white solid.

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)methyl]benzoate in 200 cm 3 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 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 magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa.). 8.4 g of methyl amino-(4-chlorophenyl)methyl]benzoate are obtained in the form of a pale yellow oil.

Methyl 4-[(RS)-phthalimido-(4-chlorophenyl)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 and then supplemented with 300 cm 3 of ethyl acetate 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 concentrated to dryness under reduced pressure (2.7 kPa). 16.3 g of methyl 4-[(RS)-phthalimido-(4chlorophenyl)methyl]benzoate are obtained in the form of a pasty yellow solid.

Methyl 4-[(RS)-bromo-(4-chlorophenyl)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 chlorophenyl)(hydroxy)methyl]benzoate in 200 cm 3 of 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 silica gel column (particle size 0.06-0.200 mm, diameter 7 cm, height 30 cm), at an argon pressure of 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-(4chlorophenyl)methyl]benzoate are obtained in the form 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 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 500C occurs). After stirring for 20 hours.

at 200C, the reaction mixture is concentrated to a reduced volume and then supplemented with 150 cm 3 of dichloromethane and, while stirring, with 100 cm' of 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)- (hydroxy)methyl]benzoate are obtained in the form of a colorless oil which slowly crystallizes at 200C, 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 manner: 27.4 cm 3 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 minutes at -22 0 C, 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 diethyl ether under reflux) is poured in while this temperature is maintained. After stirring for minutes at -22 0 C, 150 cm 3 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 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. 16.2 g of methyl 4-(4chlorobenzoyl)benzoate are obtained, after draining and then drying under reduced pressure (2.7 kPa), in the form of a white solid melting at 170 0

C.

Example 88 The operation is carried out as described in Example 87, starting with 0.05 g of (chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.025 g of 3,3-dimethylpiperidine. 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 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 (2.7 kPa). 0.040 g of 1-{(R')-(4-chlorophenyl) *dimethylpiperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam NMR spectrum (300 MHz, CDC1, 6 in ppm) 0.94 (s, 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 2H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.49 1H), 6.84 (tt, J=8.5 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

Example 89 The operation is carried out as described in Example 87, starting with 0.05 g of methylsulfonyl methyl l-((R')-[4-(chloromethyl)phenyl] (4chlorophenyl)methyl}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine, form A isomer, cm' of dichloromethane and 0.025 g of thiomorpholine. 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 233 234 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 (2.7 kPa). 0.038 g of 1- (R')-(4-chlorophenyl) [4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam NMR spectrum (300 MHz, CDC13, 6 in ppm) from 2.60 to 2.75 (mt, 8H), 2.80 3H), 3.44 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 1H), 6.83 (tt, J=8.5 and 2.5Hz, 1H), 6.97 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

Example The operation is carried out as described in Example 87, starting with 0.05 g of (R')-[4-(chloromethyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, 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 dichloromethane and ethanol mixture (95/5) by volume), collecting 2.5 cm 3 fractions immediately after using this eluent mixture. 0.022 g of (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 [1H NMR spectrum (300 MHz, CDC13 with addition of a few drops of CD 3 COOD-d4, 6 in ppm): from 1.15 to 1.25 (mt, 2H), 1.29 J=7.5Hz, 3H), from 1.45 to 1.65 (mt, 4H), 1.88 (mt, 2H), 2.17 (mt, 2H), 2.81 3H), 3.05 J=7.5Hz, 2H), 3.27 (mt, 1H), 3.95 (mt, 2H), 4.18 2H), 4.40 (mt, 2H), 4.66 (s, 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 J=8Hz, 2H), 7.53 J=8Hz, 2H)].

Example 91 The procedure is carried out as described in Example 87, starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5difluorophenyl)(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 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 (R')-(4-chlorophenyl){4-[(4ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3azetidine, form A isomer, is obtained in the form of a white foam [tH NMR spectrum (400 MHz, CDC13, 6 in ppm): 1.25 J=7Hz, 3H), 2.36 (mt, 4H), 2.80 3H), 3.44 2H), 3.46 (mt, 4H), 3.85 (mt, 2H), 4.13 J=7Hz, 2H), 4.34 (mt, 2H), 4.50 1H), 6.83 (tt, J=9 and 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

Example 92 The operation is carried out as described in Example 87, starting with 0.05 g of l-((R')-[4-(chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.023 g of 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), 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 (4-chlorophenyl) cyclopropyl-N-propylaminomethyl)phenyl]methyl}-3- difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (400 MHz, CDC1, with addition of a few drops of CD 3 COOD-d4, 6 in ppm) 0.34 (mt, 2H), 0.70 (mt, 2H) 0.91 J=7Hz, 3H), 1.08 (mt, 1H) 1.76 (mt, 2H), 2.82 3H), 2.92 J=7Hz, 2H) 3.00 (mt, 2H), 3.90 (mt, 4.25 2H), 4.37 (mt, 2H), 4.59 1H), 6.83 J=9 and 2.5Hz, 1H), 7.00 (mt, 2H), from 7.20 to 7.45 (mt, 8H)].

Example 93 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 (chloromethyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, 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 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-chlorophenyl) [4-(diisopropylaminomethyl)phenyl]methyl}-3azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDC13, 6 in ppm): 1.00 (unresolved complex, 12H), 2.80 3H), from 2.90 to 3.10 (unresolved complex, 2H), 3.58 (mt, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.48 1H), 6.82 (tt, and 2.5Hz, 1H), 6.97 (mt, 2H), from 7.20 to 7.40 (mt, 8H) Example 94 The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R')-[4-(chloromethyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.027 g 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), 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 -(4-chlorophenyl) {4- [bis(2-methoxyethyl)aminomethyl]phenyl}methyl} -3azetidine, form A isomer, is obtained in the form of a white foam 1 H NMR spectrum (300 MHz, CDC13, 8 in ppm): 2.70 (broad.t, J=5.5Hz, 4H), 2.81 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 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

Example The operation is carried out as described in Example 87, starting with 0.05 g of (R')-[4-(chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.020 g of di-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), 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) 0.025 g of 1-((R*)-(4-(chlorophenyl) [4-(di-n- 239 240 propylaminomethyl)phenyl]methyl}-3- difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam NMR spectrum (400 MHz, CDC1,, 6 in ppm) 0.85 (t, J=7Hz, 6H) 1.45 (mt, 4H), 2.34 J=7.5Hz, 4H), 2.80 3H), 3.48 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 1H), 6.83 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

Example 96 The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R')-[4-(chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- difluorophenyl)(methylsulfonyl)methylene]azetidine, 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 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- (R )-(4-chlorophenyl) [4-(piperidin-1-ylmethyl)phenyl] methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form 240 241 of a white foam [1H NMR spectrum (300 MHz, CDC13, 5 in ppm): from 1.35 to 1.65 (mt, 6H), 2.35 (unresolved complex, 4H), 2.80 3H), 3.41 (broad s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 1H), 6.84 (tt, and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

Example 97 The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R')-[4-(chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.020 g 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), 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 (R')-(4-chlorophenyl) methylpiperazin-1-ylmethyl)phenyl]methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam NMR spectrum (300 MHz, CDC1,, 5 in ppm) 2.28 (s, 241 242 3H), from 2.30 to 2.60 (unresolved complex, 8H), 2.80 3H), 3.45 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 1H), 6.84 (tt, J=8.5 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

Example 98 The operation is carried out as described in Example 87, starting with 0.05 g of [4-(chloromethyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5difluorophenyl)(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, 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 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) methylene]azetidine, form A isomer, is obtained in the form of a white foam NMR spectrum (300 MHz, CDC13, in ppm): 2.41 J=5Hz, 4H), 2.80 3H), 3.43 (s, 2H), 3.69 J=5Hz, 4H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.50 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 The operation is carried out as described in Example 87, starting with 0.05 g of (R')-[4-(chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.020 cm 3 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 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- S(R) (4-chlorophenyl) -hydroxymethylpyrrolidin- 1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam 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 3H), 3.13 (mt, 1H), 3.38 (mt, 1H), from 3.50 to 3.60 (mt, 1H), 3.56 (d, 2H), 3.90 (mt, 2H), 4.04 J=13.5Hz, 2H), 4.21 (mt, 2H), 4.40 J=13.5Hz, 2H), 4.78 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 The operation is carried out as described in Example 87, starting with 0.05 g of 1-((R')-[4-(chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, 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 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]methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene]azetidine, form A isomer, is obtained in the form of a white foam NMR spectrum (400 MHz, CDC1 3 6 in ppm): 1.03 J=7Hz, 6H), 2.50 J=7Hz, 4H), 2.81 3H), 3.50 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.49 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-(chloromethyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5difluorophenyl)(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 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 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) 0.032 g of (R')-(4-chlorophenyl) {4 [4- (hydroxyethyl)piperazin-1-ylmethyl]phenyl}methyl}}-3methylene]azetidine, form A isomer, is obtained in the form of a- white foam [IH NMR spectrum (300 MHz, CDC1 3 in ppm): from 2.40 to 2.60 (mt, 8H), 2.54 2H), 2.80 3H), 3.44 2H), 3.60 J=5.5Hz, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (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 0 C, starting with 0.05 g of (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5difluorophenyl) (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 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 then concentrated to dryness under reduced pressure (2.7 kPa) 0.024 g of 1-{(R')-(4-chlorophenyl) 6(RS)dimethyl(piperidin-l-ylmethyl)phenyl]methyl}-3- (methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [IH NMR spectrum (400 MHz, CDC13 with addition of a few drops of CD 3 COOD-d4, at a temperature of 353K, 6 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 3H), 3.17 (mt, 2H), 3.90 (mt,2H), 4.34 (broad d, J=16Hz, 1H), 4.40 (mt, 2H), 4.43 (broad d, J=16Hz, 1H), 4.62 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 Example 87, but by stirring the reaction mixture for 4 days at 20 0 C, starting with 0.05 g of (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane, and 0.024 g of piperazin-2-one. 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 cm 3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 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 (R')-(4-chlorophenyl) [4-(piperazin- 2-on-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam NMR spectrum (400 MHz, CDC1 3 6 in ppm): 2.62 J=5.5Hz, 2H), 2.80 3H), 3.11 2H), 3.34 (mt, 2H), 3.51 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.51 1H), 5.76 (unresolved complex, 1H), 6.84 (broad t, JH= 9 Hz, 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- (chloromethyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5difluorophenyl)(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, 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 dryness under reduced pressure (2.7 kPa). 0.028 g of 1- ')-(4-chlorophenyl) {4-[(2S)-(hydroxymethyl)pyrrolidin-1-ylmethyl]phenyl}methyl}} difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam NMR spectrum .(300 MHz, CDC1 3 6 in ppm) from 1.50 to 2.00 (mt, 4H), 2.24 (mt, 1H), 2.71 (mt, 1H), 2.80 3H), 2.93 (mt, 1H), 3.28 J=13.5Hz, 1H), 3.45 (mt, 1H), 3.65 J=ll and 4Hz, 1H), 3.84 (mt, 2H), 3.91 J=13.5Hz, 1H), 4.33 (mt, 2H), 4.50 1H), 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 (R')-[4-(chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, 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 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 6 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.037 g of 1-{{(R')-(4-chlorophenyl) (methoxymethyl)pyrrolidin-1-ylmethyl]phenyl}methyl} -3methylene]azetidine, form A isomer, is obtained in the form of a white foam NMR spectrum- (300 MHz, CDC13, in ppm): 1.66 (mt, 2H), 1.90 (mt, 1H), 2.16 (mt, 1H), 2.68 (mt, 1H), .2.80 3H), 2.89 (mt, 1H), from 3.25 to 3.45 (mt, 4H), 3.31 3H), 3.84 (mt, 2H), 4.04 (d, J=13.5Hz, 1H), 4.33 (mt, 2H), 4.50 1H), 6.84 (tt, J=8.5 and 2.5Hz, 1H), 6.98 (mt, 2H) from 7.20 to 7.40 (mt, 249 250 Example 106 The operation is carried out as described in Example 87, starting with 0.05 g of (chloromethyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.020 g of 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 fractions immediately after using this eluent mixture. Fractions 3 to 6 are combined and 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)phenyl]methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl)methylene]azetidine, mixture of isomers, form A, is obtained in the form of a white foam 1 H NMR spectrum (400 MHz, CDC1 3 with addition of a few drops of CD 3

COOD-

d4, 6 in ppm): 1.68 J=7Hz, 6H), from 2.00 to 2.15 (mt, 4H), 2.82 3H), 3.22 (mt, 2H), 3.92 (mt, 2H), 4.30 2H), 4.33 (mt, 1H), 4.45 J=16.5 and 3Hz, 1H), 4.63 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-(chloromethyl)phenyl]-4-(chlorophenyl)methyl}-3-[(3,5difluorophenyl)(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, 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 dryness under reduced pressure (2.7 kPa). 0.028 g of 1- )-(4-chlorophenyl) [4-((2S)-carbamoylpyrrolidin-1ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [lH NMR spectrum (400 MHz, CDC13, 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 J=13.5Hz, 1H), 3.86 (mt, 2H), 3.89 J=13.5Hz, 1H), 4.33 (mt, 2H), 4.51 1H), 5.23 (unresolved 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 Example 87, but by stirring the reaction mixture for 4 days at 20 0 C, starting with 0.05 g of (chloromethyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm 3 of dichloromethane and 0.021 g of 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 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- S(R) (4-chlorophenyl) (dihydroxyethylaminomethyl) phenyl]methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam NMR spectrum (300 MHz, CDC13, in ppm): 2.69 J=5.5Hz, 4H), 2.80 3H), 3.61 (t, 4H), 3.65 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 1H), 6.83 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

252 0 253 Example 109 0.055 g of imidazole is added to solution of 0.24 g of (R')-[4-(chloromethyl)phenyl] (4chlorophenyl)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 reflux, the reaction mixture is cooled to 20 0 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 (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-1ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam.

Example 110 The operation is carried out as described in Example 87, starting with 0.50 g of l-{(R')-[4-(chloromethyl)phenyl] (4-(chlorophenyl)methyl}-3-[(3,5- 253 254 difluorophenyl)(methylsulfonyl)methylene]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 (particle size 0.06-0.200 mm, diameter 1.5 cm, height 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 3 fractions. Fractions 20 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) 0.028 g of (R')-(4-chlorophenyl) [4- (pyrrolidin-l-ylmethyl)phenyl]methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, form B isomer, is obtained in the form of a white foam.

[a] 2 0 365nm +26.80 0.8 (c dichloromethane) [H NMR spectrum (300 MHz, CDC1,, in ppm): 1.78 (mt, 4H), 2.50 (mt, 4H), 2.80 3H), 3.57 2H), 3.84 (mt, 2H), 4.34 (mt, 2H), 4.50 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

[4-(chloromethyl) phenyl] (4- (chlorophenyl)methyl}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine, form B isomer, may be prepared by carrying out the operation as described in Example 87, starting with 7.3 g of the mixture of the 2 diastereoisomers (B forms) 1-{(R')-[4-(chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(R)-(3,5- 254 255 difluorophenyl) (methylsulfonvl)methylenel azetidin-3-ol arnd C (4 (chloromethyl) phenyl]1 (4 -chlorophenyl) methyl}-3-[(S)-(3,5-difluorophenyl) (methylsulfonyl)methyllazetidin-3-ol, 8.2 g of 4-dimethylaminopyridine, 150 cm' of dichioromethane and 3 .2 cm' of methanesulfonyl chloride. The crude product is chromatographed on a silica gel column (particle size 0.04-0.0G mm, diameter 3 cm, height 30 cm), at an argon pressure of 0.2 bar, eluting with dichloromethane and collecting 100 cm' fractions. Fractions 15 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) 2.50 g of (chloromethyl)phenyl (4-chlorophenyl)methyl}-3-{ difluorophenyl) (methylsulfonyl) methylene] azetidine, form 3 isomer, are obtained in the form of a white foam.

The mixture of the 2 diastereoisomers chlor omethyl)phenyl] (4-chlorophenyl)methyl}-3- [CR) 5-difluorophenyl) (methylsulfonyl)methyl) ]azetidin-3-.

ol1 and 1-{I 4- (chlorome thyl) phenyl]1 (4 -chlorophenyl) methyl}-3- [CS) -(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-{CR) [4-chlorophenyl) Chydroxyrethyl)phenyl)methyl}-3- [CR) -(3,5-difluorophenyl) Cmethylsulfonyl)methyl)] azetidin-3 -ol and [4 chlorophenyl] (4 255 256 (hydroxymethyl)phenyl)methyl}-3- 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 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 dryness under reduced pressure (2.7 kPa). 7.3 g of the mixture of the 2 diastereoisomers (B forms) (chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)- (3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3ol and 1- (chloromethyl) phenyl] (4chlorophenyl)methyl}-3-[(S)- (methylsulfonyl)methyl)]azetidin-3-ol are obtained in the form of a white foam.

The mixture of the 2 diastereoisomers (B forms) (R')-(4-chlorophenyl) [4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3;5-difluorophenyl)- (methylsulfonyl)methyl)]azetidin-3-ol and chlorophenyl) [4-(hydroxymethyl)phenyl]methyl}-3-[(R)- (3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3ol may be prepared by carrying out the operation as described in Example 87, starting with 18.0 g of the mixture of the 2 diastereoisomers (B form) 3-acetoxy-l- )-(4-chlorophenyl) (methoxycarbonyl)- 256 257 phenyl]I methyl) 5-difluorophenyl) (methylsulfonyl)methyll azetidine and 3-acetoxy-1-{ (4-chiorophenyl) (methyloxycarbonyl) phenyl] methyl} -3- 5-difluorophenyl) (methylsulfonyl)methyl)] azetidine, 150 cm 3 of anhydrous toluene and 100 cm 3 of a 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 with a cyclohexane and ethyl acetate mixture (50/50 by volume) and collecting 50 cm 3 fractions. Fractions 15 to are combined and then concentrated to dryness under reduced pressure (2.7 kPa) 11.0 g of the mixture of the 2 diastereoisomers (3 forms) 1 -chlorophenyl) (hydroxymethyl)phenyllmethyl}-3-[(R)-(3,5difluorophenyl) (methylsulfonyl) methyl] azetidin-3-ol and 1-f (4-chlorophenyl) (hydroxymethyl) phenyllmethyl}-3- -(3,5-difluorophenyl) (methylsulfonyl)methyl] azetidin-3-ol are obtained in the form of white foam.

The mixture of the 2 diastereoisomers (B forms) 3- ace toxy-1-{f -(4-chlorophenyl) [4- (methoxycarbonyl)phenylllmethyl}-3- difluorophenyl) (methylsulfonyl)methyl) lazetidine and.3- 2 5 acetoxy- 1-{f (4 -chlorophenyl) 4- (methoxycarbonyl) phenyllmethyl}-3- -(3,5-difluorophenyl) (methylsulfonyl)methyl)]azetidine may be prepared by 257 258 carrying out the operation as described in Example starting with 11.2 g of methylsulfone, 350 cm 3 of tetrahydrofuran, 34 cm 3 of a 1.6 N solution of n-butyllithium in hexane, 11.2 g of (R')-(4-chlorophenyl) [4-(methoxycarbonyl)phenyl]methyl}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 with a cyclohexane and ethyl acetate mixture (70/30 by volume) and-collecting 100 cm 3 fractions. Fractions 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 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 the mixture of the 2 diastereoisomers (B forms) 3acetoxy-{ (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- [(S)-(3,5-difluorophenyl) (methylsulfonyl)methyl)]azetidine are obtained in the form of a white foam.

(R')-(4-chlorophenyl) [4-(methoxycarbonyl)- 258 259 phenyl]methyl}azetidin-3-one, form B isomer, may be prepared by carrying out the operation as described in Example 40, starting with 8.7 cm' of oxalyl chloride, 350 cm 3 of dichloromethane, 14.2 cm 3 of dimethyl 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), 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 [chlorophenyl) [4- (methoxycarbonyl)phenyl]methyl}azetidin-3-one, form B 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 KATRITZKY A.R. et al., in J. Heterocycl. Chem., (1994), 271, starting with 25.5 g of methyl 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 (4-chlorophenyl) [4- (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 crystals obtained are filtered, drained and then dried under reduced pressure (2.7 kPa). 2.2 g of methyl (-)-4-[(R*)amino(4-chlorophenyl)methyl]benzoate tartrate are obtained in the form of white crystals which are dissolved in 50 cm 3 of ethyl acetate. The 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 (2.7 kPa) 1.9 g of methyl chlorophenyl)methyl]benzoate are obtained in the form of a white solid [a]20 0 C, 365nm -58.1° 1 (c 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 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5difluorophenyl)(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 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 4 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) 0.025 g of 1-{(R')-(4-chlorophenyl) methylpiperazin-l-ylmethyl)phenyl]methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene) ]azetidine, form B isomer, is obtained in the form of a creamcolored foam NMR spectrum (300 MHz, CDC1 3 in ppm): 2.28 3H), 2.44 (unresolved complex, 8H), 2.80 3H) 3.45 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.50 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.99 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

Example 112 The operation is carried out as described in Example 110, but by stirring the reaction mixture for 48 hours at 20°C, starting with 0.05 g of (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3- 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 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) (2S)-(hydroxymethyl)pyrrolidin-1-ylmethyl]phenyl}methyl}}-3- difluorophenyl)(methylsulfonyl) methylene]azetidine, form B isomer, is obtained in the form of a creamcolored foam NMR spectrum (300 MHz, CDC1 3 in ppm): from 1.80 to 2.00 (mt, 4H), 2.24 (mt, 1H), 2.72 (mt, 1H), 2.80 3H), 2.94 (mt, 1H), 3.28 (d, J=13.5Hz, 1H), 3.45 (mt, 1H), 3.65 J=10.5 and 1H), 3.85 (mt, 2H), 3.92 J=13.5Hz, 1H), 4.34 (mt, 2H), 4.50 1H), 6.84 (tt, J=8.5 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.15 to 7.40 (mt, 8H)].

Example 113 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 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5difluorophenyl)(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 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)pyrrolidin-1-ylmethyl]phenyl}methyl}}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene]azetidine, form B isomer, is obtained in the form of a creamcolored foam [IH NMR spectrum (300 MHz, CDC1 3 in ppm): from 1.50 to 2.00 (mt, 4H), 2.24 (mt, 1H), 2.71 (mt, 1H), 2.81 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 J=13.5Hz, 1H), 4.33 (mt, 2H), 4.50 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.15 to 7.40 (mt, 8H)].

Example 114 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 (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, 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 dryness under reduced pressure (2.7 kPa). 0.047 g of 1- (4-chlorophenyl) [4-(morpholin-1-ylmethyl) phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form B isomer, is obtained in the form of a white foam NMR spectrum (300 MHz, CDC13, 5 in ppm) 2.40 (mt, 4H), 2.81 3H), 3.43 2H), 3.69 (mt, 4H), 3.84 (mt, 2H), 4.34 (mt, 2H), 4.50 1H), 6.84 (tt, J=8.5 and 2.5Hz, 1H), 6.99 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

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 (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5difluorophenyl) (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 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)phenyl]methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]azetidine, form B isomer, is obtained in the form of a white foam NMR spectrum (300 MHz, CDC13, 5 in ppm): from 2.60 to 2.75 (mt, 8H), 2.81 3H), 3.44 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.50 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 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 0.200 g of (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene)]azetidine, 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 eluent mixture. Fractions 3 to 13 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) 0.090 g of 1- (R')-(4-(chlorophenyl) [4- (piperazin-2-on-4-ylmethyl)phenyl]methyl}-3- difluorophenyl)(methylsulfonyl)methylene]azetidine, form B isomer, is obtained in the form of a white powder.

Example 117 The operation is carried out as described in Example 110 starting with 0.200 g of (chloromethyl)phenyl] (4-chlorophenyl)methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)methylene) ]azetidine, form B isomer, 5.0 cm 3 of dichloromethane and 0.120 of 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), 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 (2.7 267 kPa) 0.120 g of (4-chlorophenyl) dimethylpiperidinylmethyl)phenyl]methyl}-3-[(3,5difluorophenyl) (methylsulfonyl)methylene]azetidine, form B isomer, is obtained in the form of a white powder.

Example 118 The operation is carried out as described in Example 110, by stirring for 72 hours at 20 0 C, starting with 0.200 g of [4-(chloromethyl)phenyl] (4chlorophenyl)methyl}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene)]azetidine, form B isomer, cm 3 of dichloromethane and 0.080 of imidazole. The 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 96/4 by volume), collecting 5 cm 3 fractions. Fractions to 12 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) 0.35 g of chlorophenyl) [4-(imidazol-1-ylmethyl)phenyl]methyl}-3- (methylsulfonyl)methylene]}azetidine, form B isomer, is obtained in the form of a white powder. [a] 20 D (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)methyl]azetidin-3-one and 5.15 g of methyl (methylsulfonylmethyl)thipphene-2-carboxylate in 200 cm 3 of tetrahydrofuran, under an argon atomosphere, cooled to -70 0 C. The mixture is stirred for 1 hour 30 min at a temperature close to -70°C, and then 1.7 cm 3 of methanesulfonyl chloride in solution in 8 cm 3 of ethyl ether is added. After stirring for 1 hour at a temperature close to -70 0 C, 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 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 (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.02-0.04 mm, diameter 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.

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 are obtained in the form of a cream-colored foam NMR spectrum (400 MHz, CDC1,,. 6 in ppm): 2.91 3H), 3.88 3H), 4.08 (mt, 2H), 4.37 (mt, 2H), 4.53 1H), from 7.25 to 7.45 (mt, 9H), 7.71 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)methyl]- 3-hydroxy-3-[(methylsulfonyl)(2-methoxycarbonylthien-5yl)methyl]azetidine are obtained in the form of creamcolored powder [1H NMR spectrum (400 MHz, (CD 3 2 SO-d6, 6 in ppm) 2.87 3H), 2.89 J=8Hz, 1H), 2.96 (d, J=8Hz, 1H), 3.21 J=8Hz, 1H), 3.76 J=8Hz, 1H), 3.82 3H), 4.55 1H), 4.86 1H), 6.86 1H), from 7.35 to 7.45 (mt, 9H), 7.73 J=4Hz, 1H)].

Methyl 5-(methylsulfonylmethyl)thiophene-2carboxylate 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 bromomethylthiophene-2-carboxylate in 150 cm 3 of tetrahydrofuran. The suspension is stirred for 2 hours 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 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 pressure (2.7 kPa). 14 g of methyl (methylsulfonylmethyl)thiophene-2-carboxylate are thus obtained in the form of a yellow solid melting around 133 0 C NMR spectrum (400 MHz, (CD 3 2 SO-d6, at a temperature of 373 K, 8 in ppm): 3.05 3H), 4.22 (mt, 2H), 4.40 (mt, 2H), 4.98 (broad s, 1H), 7.30 (d, 1H), 7.39 J=8Hz, 4H), 7.50 J=8Hz, 4H), 7.66 J=3.5Hz, 1H)].

Methyl 5-bromomethylthiophene-2-carboxylate may be prepared according to Curtin Davidsen S.

Heyman Garland Sheppard J. Med.

Chem., 1998, 41 74-95.

Example 120 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)methyl]-3-[(methylsulfonyl) (2hydrochloride 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-[2methylene]azetidine are thus obtained in the form of a colorless lacquer NMR spectrum (400 MHz, CDC1 3 6 in ppm): 0.97 J=7Hz, 6H), 1.88 (mt, 1H), 2.90 3H), 3.25 J=7Hz, 2H), 4.08 (mt, 2H), 4.36 (mt, 2H), 4.52 1H), 4.56 (broad t, J=7Hz, 1H), from 7.20 to 7.40 (mt, 1-[bis(4-chlorophenyl)methyl]-3yl)methylene]azetidine hydrochloride may be prepared in the following manner: 250 cm 3 of concentrated hydrochloric acid are added to a solution of 14 g of 1- [bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl) (2in 250 cm 3 of acetic acid, at room temperature. The mixture is stirred for 38 hours at a temperature of 50 0 C and is 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 3 of ethyl ether, 14.2 g of 1- [bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl) (2hydrochloride are obtained in the form of a beige 271 272 powder.

Example 121.

0.37 g of potassium tert-butoxide is added to a solution of 0.92 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 0.75 g of [(3-methoxycarbonylphenyl)methyl]methylsulfone in 30 cm 3 of tetrahydrofuran, under an argon atmosphere, cooled to -70°C, and the mixture is stirred for 2 hours at -70 0

C.

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, 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 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' of isopropyl ether and 30 cm 3 of pentane. 0.30 g of 1-[bis(4chlorophenyl)methyl]-3- methoxycarbonylphenyl)(methylsulfonyl)methyl- 272 273 (RS)]azetidin-3-ol is thus obtained in the form of a white solid NMR spectrum (400 MHz, CDC1 3 5 in ppm): 2.73 3H), 3.05 (AB, J=9Hz, 2H), 3.27 J=9Hz, 1H), 3.63 1H), 3.79 J=9Hz, 1H), 3.95 3H), 4.32 1H), 4.59 1H), from 7.15 to 7.35 (mt, 8H), 7.51 J=8Hz, 1H), 7.94 (broad d, J=8Hz, 1H), 8.10 (broad d, J=8Hz, 1H), 8.32 (broad s, Example 122 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)methyl]azetidin-3-one, 0.20 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 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 20 cm 3 of diisopropyl ether. After filtration, draining and drying, 0.16 g of 1-[bis(4chlorophenyl)methyl]-3-[(methylsulfonyl) (pyridin-4yl)methyl-(RS)]-azetidin-3-ol is obtained NMR spectrum (400 MHz, CDC1 3 6 in ppm): 2.76 3H), 3.03 (AB, J=9Hz, 2H), 3.27 J=9Hz, 1H), 3.53 1H), 3.83 J=9Hz, 1H), 4.32 1H), 4.51 1H), from 7.20 to 7.30 (mt, 8H), 7.63 J=6Hz, 2H), 8.68 (d, 273 274 J=6Hz, 2H)].

Methyl(pyridin-4-ylmethyl)sulfone may be prepared according to the reference JP43002711.

Example 123 By carrying out the operation according to the procedure of Example 1, starting with 0.47 g of methyl(pyridin-3-ylmethyl)sulfone 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 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(4chlorophenyl)methyl]-3-[(methylsulfonyl) (pyridin-3yl)methyl-(RS)]-azetidin-3-ol is obtained NMR spectrum (300 MHz, CDCI 3 in ppm): 2.77 3H), 3.03 (AB, J=9Hz, 2H), 3.28 J=9Hz, 1H), 3.66 1H), 3.83 J=9Hz, 1H), 4.33 1H), 4.55 1H), from 7.20 to 7.30 (mt, 8H), 7.37 (dd, J=8 and 5Hz, 1H), 8.16 (dt, J=8 and 2Hz, 1H), 8.68 (dd, J=5 and 1.5Hz, 1H), 8.83 J=2Hz, 1H)].

Methyl(pyridin-3-ylmethyl)sulfone may be 274 275 prepared according to the reference JP43002711.

Example 124 0.0388 cm 3 of N-(3-aminopropyl)morpholine is added, at the same temperature, to a suspension of 150 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3ylidene}methanesulfonylmethyl)benzoic acid activated on TFP resin (165 pM) in 3 cm 3 of dichloromethane, prestirred for 90 minutes at a temperature close to 20 0

C.

The suspension is stirred at a temperature close to 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 (2.7 kPa) at a temperature close to 40 0 C. 60 mg of 3-((1-[bis(4-chlorophenyl)methyl]azetidin-3ylidene}methanesulfonylmethyl)-N-(3-morpholin-4ylpropyl)benzamide are thus obtained in the form of a pale yellow foam.

3-({l-[bis(4-chlorophenyl)methyl]azetidin-3ylidene}methanesulfonylmethyl)-N-(3-morpholin-4ylpropyl)benzamide may also be prepared in the following manner: 0.083 cm 3 of N-(3-aminopropyl)morpholine, 110 mg of 1-(3-dimethylaminopropyl)-3ethylcarbodiimide 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 cm 3 of dimethylformamide, under an inert atmosphere of.

nitrogen, at a temperature close to 20 0 C. The solution obtained is stirred at a temperature close to 20 0 C for about 22 hours and then concentrated to dryness under reduced pressure (0.27 kPa) at a temperature close to 0 C. The solid residue is taken up in 25 cm 3 of dichloromethane and washed with twice 20 cm 3 of a 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 40 0 C. 400 mg of a yellow oil are 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 the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 0 C for 2 hours. 130 mg of 3-({l-[bis(4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl)-N-(3morpholin-4-ylpropyl)benzamide are thus obtained in the 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 3H), from 3.20 to 3.35 (mt, 276 277 2H), 3.57 J=4..SHz, 4H), 3.81 (Mt, 2H), 4.22 (mt, 2H), 4. 79 1H-) 7 .36 J=8 .5Hz, 4H) 7'.46 (d, from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 1H), 8.53 1H)].

Example 125 The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[Ibis(4-chlorophenyl)methyl] azetidin-3-ylideneimethanesulfonylnethyl)benzoic acid on TFP resin (165 pM) and 0.033 cm 3 of N,N-dimethyl-1,3propanediamine. 52 mg of 3- bis (4-chlorophenyl) methyl] azetidin-3-ylidene~methanesulfonylnethyl) (3dimethylaminopropyl)benzamide are thus obtained in the form of. a white powder [1H NMR spectrum (400 MHz,

(CD

3 ),S0-dG, 8 in ppm) :1.65 (mt, 2H) 2.18 6H) from 2.20 to 2.35 (mt, 2H), 2.98 3H), from 3.25 to 3.45 (mt, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.80 (s, 1H), 7.36 J=8.5Hz, 4H), 7.46 J=8.5Kz, 4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 1H), 8.57 J=5.5Hz, 1K)].

Example 126 The operation is carried out under the 277 278 conditions described in Example 124 starting with 150 mg of activated 3-({1--tbis(4chlorophenyl)methyl] azetidin-3-ylideneimethanesulfonylmethyl)benzoic acid on TFP resin (165 jiM) and 0.0333 cm' of 1-(aminoethyl)pyrrolidine. 39 mg of ibis (4-chlorophenyl)methyl] azetidin-3-ylidene}methanesulfonylmethyl) (2 -pyrrolidin-1ylethyl)benzamide are thus obtained in the form of a pale yelow powder NMR spectrumn (300 MHz, (CD 3 2 S0-d6 with addition of a few drops of CD 3 COOD-d4, 6 in ppm): from 1.80 to 2.00 2.97 3H), 3.20 (mt, 6H), 3.57 Ct, J=6.5Hz, 2H), 3.80 (rnt, 2H), 4.23 (mt, 2H), 4.77 Cs, 1H) 7.35 J=8.5Hz, 4H) 7.45 (d, 4H), from 7.50 to 7.65 Cmt, 2H), 7.87 (broad s, 1H), 7.90 (broad d, J=7.5Hz, 1H)]- Example 127 The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyll azetidin-3-ylidenelmethanesulfonylmethyl) benzoic acid on TEP resin (165 pM) and 0.0333 cm 3 Of 1- Cdimethylamino)-2-propylamine. 49 mg of [bis (4chiorophenyl) methyl] azetidin-3-ylidenernethanesulfonylmethyl) C2-dimethylamino-1-methylethyl) benzamide are thus obtained in the form of a white 278 279 powder [1H NM?. spectrum (400 MHz, (CD 3 2 S0O-d6, 6 in ppm): 1.13 J=6.5Hz, from 2.10 to 2.25 (mt, 1H), 2.15 6H), 2.38 (dd, J=13 and 8Hz, 1H), 2.98 3H), 3.80 (mt 1 2H), 4.14 (mt, 1K), 4.23 (mt, 2H), 4.79 (s, 7.36 J=8Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.46 J=8Hz, 7.83 (broad s, 1H), 7.87 (broad d, J=8Hz, 1H) 8.16 (broad d, J=8Hz, 1H)].

Example 128 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-ylidenelmethanesulfonylmethyl)benzoic acid on TFP resin (165 PM) and 0.026 cm 3 of piperidine. 56 mg of 3- ({1-.Ibis(4-chlorophenyl)methyllazetidin-3ylidenelmethanesulfonylmethyl) -N-piperidinylbenzamide are thus obtained in the form of a white powder NMR spectrum (400 MHz, (CD 3 SO-d6, 6 in ppm): from 1.45 to 1.70 (mt, from 2.90 to 3.05 (mt, 2K), 2.98 3K), 3.19 (unresolved complex, 1K), 3.57 (unresolved complex, 1K), 3.85 (mt, 2H), 4.23 (mt, 2K), 4.80 1K), from 7.30 to 7.55 (mt, 12K)].

Example 129 The operation is carried out under the 279 280 conditions described in Example 124 starting with 150 mg of activated [bis(4-chlorophenyl)methyl] azetidin-3-ylidenelmethanesulfonylmethyl)benzoic acid on TFP resin (165 hiM) and 0.0265 cm 3 Of isobutylamine.

46 mg of 3-({1-tbis(4-chlorophenyl)methyllazetidin-3ylidenelmethanesulfonylmethyl) -N-isobutylbenzamide are thus obtained in the form of a white powder f'H- NMR spectrum (400 MHz, (CD 3 2 S0-d6, (5 in ppm): 0.89 (d, J=7Hz, 6H), 1.85 (mt, 1H), 2.98 3H), 3.09 (t, J=6.5Hz, 2H), 3.82 (mt, 2H), 4.23 (mt 1 2H), 4.79 (s, 1H), 7.36 J=8.5Hz, 4H), 7.46 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 J=6Hz, 1H)].

Example 130 The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated Ebis(4-chlor ophenyl)methyl] azetidin-3-ylidene~methanesulfonylmethyl)benzoic acid on TFP resin (165 pM) and 0.0316 cm 3 of aminopropyl)imid azole. 54 mg of 3-({1-[bis(4chlorophenyl)methyl] azetidin-3-ylidene~methanesulfonylmethyl) (3-imidazol-1-ylpropyl)benzamide are thus obtained in the form of a y ellow foam NMR spectrum (400 MHz, (CD 3 SO-d6, 6 in ppm): 1.97 (mt, 2H), ,2.98 3H), 3.25 (mt, 21H) 3.81 (mt, 2K), 4.02 280 J=7Hz, 2H) 4.23 (mt, 2H), 4.79 from 6.85 to 6. 95 (mt, 2H) 7 .3 6 J 8 .5Hz, 411), 7. 46 (d, 4H), from 7.50 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.88 (broad d, J=8Hz, 1H), 8.56 iH)1.

Example 132.

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-ylidenelmethanesulfonylmethyl) benzoic acid on TFP resin (165 biM) and 0.030 cm' of N,N- (dimethyl)ethylenediamine. 53 mg of 3- ({1-[bis (4chlorophenyl)methyllazetidin-3-ylidene~methanesulfonylm ethyl) (2-dimethylaminoethyl) benzamide are thus obtained in the form of an ochre-colored foam ['H NMR spectrum (400 MHz, (CD,),S0-d6, 6 in ppm) :2.18 (2s, 6H) from 2.35 to 2.45 (mt, 2H) 2.98 3H) from 3.25 to 3.50 (mt, 2H), 3.81 (mt, 2H), 4.23 (mt, 2H), 4.79 1H) 7.36 J=8Hz, 4H) 7.46 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 J=6.5Hz, 1H)].

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-chlorop henyl)methyl] azetidin-3-ylidene~methanesulfonylmethyl)benzoic acid on TFP resin (165 p.M) and 0.0141 cm' of methyihydrazine.

42 mg of 3-({1-[bis(47chlorophenyl)methyllazetidin-3 ylidene~methanesulfonylmethyl) benzoic acid N'methylhydrazide are thus obtained in the form of a pale yellow foam ['1H NMR spectrum (400 MHz, (CD 3 2 S0-d6,- 6 in ppm): 2.96 3.18 (broad s, 3H) 3.83 (mt,.

2H), 4.22 (mt, 2H), 4.80 (broad s, 2H), from 7.35 to 7.65*.(mt, 12H)1.

Example 133 The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({l-fbis(4-chlorophenyl)methyll azetidin-3-ylidene~methanesulfonylmethyl).benzoic acid on TFP resin (1G5 haM) and 0.0345 cm' of N- (2aminoethyl)morpholine. 62 mg of 3-({l-[bis(4chlorophenyl)methyl] azetidin-3-ylidene~methanesulfonylmethyl) (2-morpholin-4-ylethyl)benzamide are thus obtained in the form of an ochre-colored foam ['H NMR spectrum (400 MHz, (CD 3 2 S0-d6, 6 in ppm) from 2.30 to 2.45 (mt, 4H), 2.46 J=7.5Hz, 2H), 2.98 3H), 3.38 (mt, 2H), from 3.50 to 3.65 (mt, 3.82 (mt, 4.24 (mt, 4.79 1H), 7.36 282 283 4H), 7.46 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 J=6.5Hz, lH)1.

Example 134 The operation is carried out under the conditi ons described in Example 124 starting with 150 mg of activated Ibis(4-chlorophenyl)methyl]azetidin-3-ylideneimethanesulfonylmethyl)benzoic acid on TEP resin (165 pM) and 0.0396 cm 3 of 2-(aminomethyl)- N-ethylpyrrolidine.. 58 mg of 3-({1-[bis(4chiorophenyl) methyl] azetidin-3 -ylidene~methanesulfonyirnethyl) (1-ethylpyrrolidin-2ylmethyl)benzamide are thus obtained in the form of an ochre-colored foam.

[bis(4-chlorophe nyl)methylllazetidin-3ylidenelmethanesulfonylmethyl) (1-ethylpyrrolidin-2ylmethyl)ben zamide may also be prepared under the conditions described in Example 126 starting with 700 mg of activated 3-({1-Cbis(4-chlorophenyl) methyl]azetidin-3-ylideneimethanesulfonylmethyl)benzoic acid on TFP resin (770 pM) 0.324 cm 3 Of triethylamine and 0.25 cm' of 2-(aminomethyl)-N-ethylpyrrolidine. 370 mg 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 cm in diameter, eluting with a methanoldichloromethane mixture (15-85 by volume). The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 0 C for 2 hours. 160 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N- (-ethylpyrrolidin-2ylmethyl)benzamide are thus obtained in the form of a pale yellow powder [H NMR spectrum (400 MHz, (CD 3 2

SO-

d6, 5 in ppm): 1.04 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 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 1H), 7.36 4H), 7.46 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)].

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]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)methyl]azetidin-3- 284 285 ylidene~methanesulfonylmethyl) (2,2dimethylpropyl)benzamide are thus obtained in the form of a pale yellow powder NMR spectrum (400 MHz,

(CD

3 2 S0-d6, 6 in ppm) 0. 90 9H) 2.98 3H), 3. 11 J=6.5Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 1H) 7.36 J=8Hz, 4H) 7.46 J=8Hz, from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 1H) 8.37 J=6.5Hz, 1H)].

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)methyllazetidin-3-ylideneimethanesulfonylmethyl)benzoic acid on TEP resin (121 pM) and 0.025 cm 3 Of aminomethylcyclohexane. 44 mg of 3-({1-[bis(4chlorophenyl)methyl] azetidin-3-yli-denelmethanesulfonylmethyl) -N-cyclohexylmethylbenzamide are thus obtained in the form of a pale yellow powder whose characteristics are the following NMP. spectrum (400 MHz, (CD 3 2 s-d6, 6 in ppm) 92 (mt, 2K) 1. 17 (mt, from 1.45 to 1.80 (mt, 5H), 2.97 3H), 3.10 J=6Hz, 2K), 3.80 (mt, 2K), 4.23 (mt, 2K), 4.79 1H) 7.36 J=8Hz, 4H) 7.46 J=8Hz, 4H) from 7.45 to 7.60 (mt, 2K), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 1K), 8.47 J=6Hz, 1K)].

285 286 Example 137 The operation is carried out under the conditions described in Example 124 starting with .110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidenelmethanesulfonylmethyl)benzoic acid on TEP resin (121 pM), 0..026 cm 3 of triethylamine and 21 mg of aminomethylcyclopropane hydrochloride. 68 mg of 3- bis(4-chlorophenyl)methyllazetidin-3-ylidene}methanesulfonylmethyl) -N-cyci-opropylmethylbenzamide are thus obtained in the' form of a yellow foam [1H NMR spectrum (400 MHz, (CD 3 2 S0-d6, 6 in ppm) :0.24 (mt, 2H), 0.44 (mt, 2H), 1.03 (mt, 1H), 2.98 3H), 3.15 J=6Hz, 2H), 3.82 (tnt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 J=8.5Hz, 4H), 7.46 J=8.5Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.86 (broad s, 1K), 7.89. (broad d, J=8Hz, 1H) 8.64 J=6Hz, IH)].

Example 138 The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3- bis (4-chlorophenyl)methyll azetidin-3-ylidenelmethanesulfonylmethyl)benzoic acid on TFP resin (121 pM) and 0.023 cm 3 of 2T methylbutylamine. 49 mg of 3- [bis(4-chlorophenyl) 286 287 methyl] azetidin-3-ylidenelmethanesulfonylmethyl) (2methylbutyl) benzamide are thus obtained NMR spectrum (400 MHz, CCD 3 ).2SO-d6, 5 in ppm) from 0.80 to 0.95 (mt, from 1.05 to 120 (mt, 1H), 1.41 (tnt, 1H), 1.64 (mt, 1H), 2.98 Cs, 3H), 3.06 (mt, 1H), 3.19 (mt, 1H), 3.81 (mt, 2H), 4.23 (mt, 2H), 4.79 Cs, 1H), 7.36 (d, J=8Hz, 4H), 7.46 J=8H4z, 4H), from 7.35 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.87 (broad d, J=8Hz, 1H), 8.49 J=5.5Hz, lH)].

Example 139 The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-C{1-[bisC4-chlorophenyl)methyljazetidin-3-ylideneimethanesulfonylmethyl)benzoic acid on TEP resin (121 PM) and 0.028 cm 3 of 2-methylphenethylamine. 42 mg of 3- Cl- [bis(4-chlorophenyl) methyl] azetidin-3-ylideneimethanesulfonylmethyl) (2phenylpropyl)benzamide are thus obtained in the form of a yellow paste NMR spectrum (400 MHz, CCD3) 2 SO-dG, in ppm): 1.24 Cd, J=7Hz, 3H), 2.97 Cs, 3H), 3.07 (mt, 1H), from 3.20 to 3.50 (tnt, 2H), 3.80 Cmt, 2H), 4.23 (mt, 2H), 4.80 Cs, 1H), from 7.10 to 7.40 (tnt, 7.38 Cd, J=8Hz, 4H), 7.47 Cd, J=8Hz, 4H), from 7.50 to 7.60 (tnt, 2H) 7.77 (broad s, 1H) 7.79 (broad d, J=8Hz, 1H), 8.55 Ct, J=6Hz, 1K)].

287 288 Example 140 The operation is carried out under the conditions described in Example 124 sta rtin g with 110 mg of activated 3-({1-{bis(4-chlorophenyl)methyl] azetidin-3-ylideneimethanesulfonylmethyl)benzoic acid on TFP resin (121 p2M) and 0.020 cm' of tetrahydrofurfurylmethy~amine. 42 mg of 3-({1-[bis(4chlorophenyl)methyllazetidin-3-ylidenelmethane.

sulfonylmethyl) (tetrahydrofuran-2-ylmethyl) benzamide are thus obtained in the form of a yellow paste 1 H NMR spectrum (400 MHz, (CD 3 2 S0-d6, 5 in ppm) :1.58 (mt, 1H) from 1.75 to 2.00 (mt, 3K), 2.98 3H) from' 3.20 to 3.40 (mt, 2H), 3.63 (mt, 1H), 3.77 (mt, 1H), 3.82 (mt, 2H), 3.98 (mt, 1H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 J=8Kz, 4H) 7.46 J=8Hz, 4H) from 7.50 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.88 (broad d, J=8Hz, 1K) 8.60 J=GKz, 1K) 1 Example 141 The operation is carried out under the conditions described in Example 124 st.arting with 110 mg of a ctivated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidenelmethanesulfonylmethyl)benzoic acid on TFP resin (121 piM) and 39 mg of 2,2- 288 289 diphenylethylamine. 39 mg of 3-({1-[bis(4chlorophenyl)methyl] azetidin-3-ylidene~methanesulfonylmethyl) 2-diphenylethyl)benzamide are thus obtained in the* form of a yellow paste NMR spectrum (4 00 MHz, (CD3) SO-d6, 6 in ppm) 2. 95 Cs, 3H-) 3 .77 (mt, 2H), 3.90 (dd, J=8 and 6.5Hz, -4.22 Cmt, 2H), 4.42 J=8Hz, 1H), 4.79 Cs, 1H), from 7.10 to 7.40 (mt 1 10H), 7.38 Cd, J=8.5Kz, 4H), from 7.45 to 7.60 Cmt, 2K), 7.48 J=8.5Kz, 4H), 7.70 (mt, 2H), 8.56 J=6.5Kz, 1K)].

Example 142 The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-C{1- [bis(4-chlorophenyl)methyl] azetidin-3-ylidenelmethanesulfonylmethyl)benzoic acid on TFP resin (121 hiM) and 19 mg of 2-ethylbutylamine.

47 mg of 3-({1-[bis(4-chlorophenyl)methyllazetidin-3ylidenelmethanesulfonylmethyl) (2-ethylbutyl) benzamide are thus obtained in the form of a pale yellow powder NMR spectrum (400 MHz, (CD 3 ),S0-d6, in ppm) 0.86 Ct, J=7Kz, 6H), from 1.20 to 1.40 Cmt, 4K), 1.50 Cmt, 1H), 2.98 3H), 3.19 Ct, J=6K-z, 2K), 3.82 Cmt, 2K), 4.24 Cmt, 2H); 4.79 Cs, 1K), 7.36 Cd, 4K), 7.46 Cd, J=8.5Kz, 4H), from 7.45 to 7.60 Cmt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 289 290 1H), 8.42 J=GHz, 1H)].

Example 143 The operation is carried out under the 'conditions described in Example 124 starting with 110 mg of activated [bis(4-chlorophenyl)methyll azetidin-3-ylidene~methanesuilforiylmethyl)benzoic acid on TFP resin (121 tiM) 0.026 cm' of triethylamine and 39 mg of 4-aminomethylcyclohexanecarboxylic acid methyl* ester hydrochloride. 47 mug of chlorophenyl)methyl]azetidin-3-ylideneimethanesulfonylmethyl) benzoylamino] methyllcyclohexanecarboxylic acid methyl ester are thus obtained in the form of ,a pale yellow paste NMR spectrum (400 MHz, (CD 3 2 S0-dG, ~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 3H), 3.12 J=6.5Hz, 2H), 3.60 3.80 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 J=8Hz; 4H), 7.46 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 J=GHz, 1H)].

Activated [bis (4-chlorophenyl)methyll azetidin-3-ylidene~methanesulfonylmethyl)benzoic acid on TFP resin may be prepared under the following conditions: 1.18 g of 3-({1-[bis(4chlorophenyl)methyl] azetidin-3-ylideneimethane- 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' of anhydrous dimethylformamide, prestirred for 10 minutes at a temperature close to After stirring for 10 minutes at a temperature close to 200C, 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-diisopropylcarbodiimide. After stirring for 23 hours at a temperature close to. 20C, 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 constant weight. 1.5 g of activated 3-({1-[bis(4chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin are thus obtained in the form of a pale yellow resin.

The TFP resin (structure below) may be prepared in the following manner:

F

(FNH F OH 0 F 492 mg of diisopropylcarbodiimide, 819.3 mg of 2,3,5,6tetrafluoro-4-hydroxybenzoic acid and 50 mg of 4dimethylaminopyridine are successively added to a 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 hours at a temperature close to 200C, the suspension is 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 resin obtained is then stirred, at a temperature close to 20°C, 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 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.

Example 144 A solution of 76 mg of chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)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 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 to dryness under reduced pressure (1 kPa) at a temperature close to 40 0 C. 51 mg of 2-amino-1-{4-[3- ({l-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl] piperazin-1-yl}ethanone are thus obtained in the form of a beige lacquer NMR spectrum (300 MHz, CDC13, 6 in ppm): from 1.95 to 2.25 (broad unresolved complex, 2H), 2.77 3H), from 3.10 to 3.30 (mt, 4H), from 3.50 to 3.60 (mt, 2H), 3.56 (broad s, 2H), from 3.75 to 3.90 (mt, 4H), 4.34 (mt, 2H), 4.50 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)].

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 200C, to 108.5 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 20 hours at a 293 294 temperature close to 20°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 magnesium sulfate, filtered on sintered glass and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 400C. 143 mg of [bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamic acid tert-butyl ester are thus obtained in the form of a cream-colored lacquer NMR spectrum (400 MHz, (CD 3 2 SO-d6, 5 in ppm): 1.40 9H), 2.93 (s, 3H), from 3.05 to 3.20 (mt, 4H), 3.57 (mt, 4H), 3.80 (mt, 2H), 3.84 J=6Hz, 2H), 4.19 (mt, 2H), 4.78 (s, 1H), 6.79 J=6Hz, 1H), 6.82 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 J=8Hz, 4H), 7.46 J=8Hz, 4H)].

The supported EDCI reagent is commercially available and may also be prepared according to the following reference: M. Desai, L. Stramiello, Tetrahedron Letters, 34, 48, 7685-7688 (1993).

Example 146 A solution of 81 mg of chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)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 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 to dryness under reduced pressure (1 kPa) at a temperature close to 40 0 C. 58 mg of (4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2methylaminoethanone are thus obtained in the form of a beige lacquer [1H NMR spectrum (300 MHz, CDC1 3 6 in ppm): from 1.95 to 2.15 (broad unresolved complex, 1H), 2.51 (broad s, 3H), 2.77 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 1H), 6.83 (broad d, J=8Hz, 1H), 6.90 (dd, J=8 and 2Hz, 1H), 7.00 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].

Example 147 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)methyl azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 20 hours at a 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 magnesium sulfate, filtered on sintered glass and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 0 C. 143 mg of [bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-Nmethylcarbamic acid tert-butyl ester are thus obtained in the form of .a cream-colored lacquer NMR spectrum (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 (2s, 2H in total), 4.19 (mt, 2H), 4.78 1H), 6.83 (broad d, J=8Hz, 1H), 6.93 (broad s, 1H), 7.00 (dd, J=8 and 2.5Hz, 1H), 7.27 J=8Hz, 1H), 7.36 J=8Hz, 4H) .7.46 J=8Hz, 4H)] Example 148 2 cm 3 of dichloromethane and then 11 mg of 296 297 methyl isothiocyanate are successively added, at a temperature close to 20 0 C, to 54.25 mg of [bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 6 hours at a temperature close to 20 0 C, 0.05 cm 3 of water is added to the reaction mixture. After stirring for 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 temperature close to 40 0 C. 61 mg of chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-l-carbothioic acid Nmethylamide are thus obtained in the form of a beige lacquer NMR spectrum (400 MHz, CDC1 3 6 in ppm): 2.77 3H), 3.20 J=5Hz, 3H), 3.32 4H), 3.81 (mt, 2H), 4.00 J=5.5Hz, 4H), 4.33 (mt, 2H), 4.49 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 J=8Hz, 4H)].

Example 149 2 cm' of dichloromethane and then 11.5 mg of methyl isocyanate are successively added, at a temperature close to 20 0 C, to 54.25 mg of [bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methane- 297 298 sulfonylmethyl)phenyl]piperazine. After stirring for 4 hours at a temperature close to 20 0 C, 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 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-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-l-carboxylic acid Nmethylamide are thus obtained in the form of a beige lacquer [IH NMR spectrum (400 MHz, CDC1 3 8 in ppm): 2.75 3H), 2.85 J=5Hz, 3H), 3.19 (broad t, 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, 1H), 6.81 J=8Hz, 1H), 6.89 (dd, J=8 and 2.5Hz,.1H), 6.98 (broad s, 1H), from 7.20 to 7.30 (mt, 5H), 7.32 .J=8Hz, 4H)] Example 150 2 cm 3 of pyridine and then 10.4 mg of methyl chloroformate are successively added, at a temperature close to 200C, to 54.25 mg of chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)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 over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40 0 C. 62 mg of chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-l-carboxylic acid methyl ester are thus obtained in the form of a beige lacquer [1H NMR spectrum (400 MHz, CDC1 3 6 in ppm): 2.75 3H), 3.15 (broad t, J=5.5Hz, 4H), 3.62 (mt, 4H), 3.74 3H), 3.80 (mt, 2H), 4.32 (mt, 2H), 4.49 1H), 6.81 J=8Hz, 1H), 6.90 (dd, J=8 and 1H), 6.99 (broad s, 1H), from 7.20 to 7.40 (mt, 9H)].

Example 151 32 mg of sodium acetoxyborohydride and then 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-3ylidene}methanesulfonylmethyl)phenyl]piperazine in 2cm 3 of 1.,2-dichldroethane. After stirring for 4 hours at a 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 phase 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)methyllazetidin-3-ylidene}methanesulfonylmethyl)phenyll -4-isobutylpiperazine are thus obtained in the form of a beige lacquer NMR spectrum (400 MHz, CDC1,), 8 in ppm): 0.92 J=7Hz, 6H), 1.82 (mt, 1H), 2.14 J-8Hz, 2H), 2.54 J=5.5Hz, 4H), 2.75 (s, 3H), 3.18 J=5.5Hz, 4H), 3.81 (mt, 2H), 4.32 (mt, 2H), 4.49 1H), 6.78 J=8Hz, 1H), 6.89 (dd, J=8 and 2.5Hz, 11), 6.97 (broad s, 1H), from 7.15 to 7.30 (mt, 5H), 7.32 J 8 Hz, 4H)].

Example 152 32 mg of sodium acetoxyborohydride and then 13 mg of acetaldehyde are successively added, at a temperature close to 20 0 C, to a solution of 54 mg of 1- 3-(1-[bis-(4-chlorophenyl)methyl])azetidin-3ylidene}methanesulfonylmethyl)phenyl]piperazine in 2 cm of 1,2-dichloroethane. After stirring for 21 hours at a temperature close to 20 0 C, 2 cm' 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 cm3 of dichloromethane. The pooled organic phases are dried 300V over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 20 0 C. 60 mg of a solid residue are thus obtained, which residue is taken up in 2 cm 3 of methanol 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 methanol. The filtrate is concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 0 C. 42 mg of 1-[3-((1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-ethylpiperazine are thus obtained in the form of a colorless lacquer NMR spectrum (300 MHz, CDC1 3 5 in ppm): 1.14 J=7.5Hz, 3H), 2.48 (q, 2H), 2.60 (broad t, J=5Hz, 4H), 2.77 3H), 3.22 (broad t, J=5Hz, 4H), 3.82 (mt, 2H), 4.33 (mt, 2H), 4.49 1H), 6.79 (broad d, J=8Hz, 1H), 6.91 (dd, J=8 and 2Hz, 1H), 6.98 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].

Example 153 2 cm 3 of pyridine and then 11.5 mg of acetic anhydride are successively added, at a temperature close to 20°C, to 54 mg of 301 302 chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 23 hours at a temperature close to 20 0 C, the reaction medium is concentrated to dryness under reduced pressure (IkPa) 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 dryness under reduced pressure (1 kPa) at a temperature close to 40°C. 52 mg of 4-acetyl chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine are thus obtained in the form of a beige foam NMR spectrum (300 MHz, CDCl) 5 in ppm): 2.16 3H), 2.77 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 1H), 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, 9H)].

Example 154 511 mg of supported EDCI (2.5 mM), 11.5 mg of 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)phenyl]piperazine. 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 close to 20 0 C,the reaction mixture is filtered on sintered glass. The resin is rinsed with three times 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 reduced pressure (5 kPa) at a temperature close to 0 C. 53 mg of 1-{4-[3-({l-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-l-yl}-2-dimethylaminoethanone are thus obtained in the form of a beige foam 1 H NMR spectrum (400 MHz, (CD 3 2 SO-d6, 6 in ppm): 2.20 6H), 2.94 (s, 3H), 3.12 2H), 3.16 (mt, 4H), 3.58 (mt, 2H), 3.68 (mt, 2H) 3.80 (mt, 2H), 4.19 (mt, 2H), 4.78 1H), 6.81 (broad d, J=8Hz, 1H), 6.93 (broad s, 1H), 6.99 (dd, J=8 and 2.5Hz, 1H), 7.26 J=8Hz, 1H), 7.36 (d, J=8Hz, 4H), 7.46 J=8Hz, 4H)].

Example 155 A solution of 320 mg of chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-l-carboxylic acid tert-butyl ester in 5 cm 3 of formic acid is stirred for 303 304 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 300C, taken up in 20 cm 3 of ethyl acetate and alkalinized with 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 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: 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 dichloromethanemethanol mixture (75-25 by volume). The filtrates are combined and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 300C. 180 mg of 1-[3-({l-[bis-(4-chlorophenyl)methyl]azetidin-3ylidene}methanesulfonylmethyl)phenyl]piperazine are thus obtained in the form of a white powder NMR spectrum (300 MHz, CDC13, 5 in ppm): 2.77 3H), 3.05 (mt, 4H), 3.16 (mt, 4H), 3.81 (mt, 2H), 4.33 (mt, 2H), 4.49 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)methyl]azetidin-3-ylidene}methanesulfonylmethyl)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 4 starting with 1.32 g of chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methanesulfonylmethyl)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, 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) at a temperature close to 30 0 C. 0.86 g of 4-[3- ({(-[bis-(4-chlorophenyl)methyl]azetidin-3ylidene}methanesulfonylmethyl)phenyl]piperazine-1carboxylic acid tert-butyl ester is thus obtained in the form of a white foam [1H NMR spectrum (400 MHz, CDC13, 8 in ppm): 1.50 9H) 2.77 3H), 3.14 (t, 4H), 3.57 J=5Hz, 4H), 3.81 (mt, 2H), 4.34 (mt, 2H) 4.49 1H), 6.81 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 J=8Hz, 4H)] 4-[3-({1-[bis-(4-chlorophenyl)methyl]-3hydroxyazetidin-3-yl}methanesulfonylmethyl)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-methanesulfonylmethylphenyl)piperazine-1-carboxylic acid tertbutyl 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 nbutyllithium in hexane, 1.37 g of chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methanesulfonylmethyl)phenyl]piperazine-l-carboxylic acid 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 according to the procedure of Example 10 starting with 1.55 g of 4-(3-chloromethylphenyl)piperazine-lcarboxylic acid tert-butyl ester and 0.766 g of sodium methanesulfinate, 0.9 g of 4-(3-methanesulfonylmethylphenyl)piperazine-1-carboxylic acid tert-butyl ester is obtained in the form of a beige powder.

4-(3-Chloromethylphenyl)piperazine-1carboxylic acid tert-butyl ester may be prepared in the 306 307 following manner: by reacting 16.4 g of 4-(3hydroxymethylphenyl)piperazine-l-carboxylic acid tertbutyl ester in 150 cm 3 of dichloromethane, at a temperature close to 20 0 C, with 29 cm 3 of diisopropylethylamine and 8.7 cm 3 of methanesulfonyl chloride, 15 g of 4-(3-chloromethylphenyl)piperazine-lcarboxylic 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 6 cm, height 45 cm, 100 cm 3 fractions), eluting with dichloromethane.

4-(3-Hydroxymethylphenyl)piperazine-1carboxylic acid tert-butyl ester may be prepared in the following manner: by reacting 15.8 g of tert-butyl esters of 4-(3-butoxycarbonylphenyl)piperazine-1carboxylic and 4-(3-n-butyloxycarbonylphenyl)piperazine-l-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 toluene (20% by weight), 12.8 g of 4-(3hydroxymethylphenyl)piperazine-1-carboxylic acid tertbutyl ester are obtained in the form of a beige oil.

The mixture of tert-butyl esters of 4-(3ethoxycarbonylphenyl)piperazine-1-carboxylic and 4-(3n-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 Example 38 (method 2) starting with 0.3 g of 3-acetoxy- 1-[bis(4-methoxycarbonylphenyl)methyl]-3- 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 1-[bis(4-methoxycarbonylphenyl)methyl]-3- difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of an orange-colored foam NMR spectrum (300 MHz, CDCl 3 6 in ppm): 2.81 3H), from 3.85 to 3.95 (mt, 2H), 3.89 6H), 4.37 (mt, 2H), 4.67 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.99 (mt, 2H), 7.50 J=8Hz, 4H), 7.97 J=8Hz, 4H)].

Example 157 On carrying out the operation according to the procedure of Example 40 starting with 4.45 g of 6.36 g of l-[bis(4methoxycarbonylphenyl)methyl]azetidin-3-one, 2.18 cm 3 of acetyl chloride and 17 cm 3 of a 1.6 M solution of nbutyllithium in hexane, 10.8 g of 3-acetoxy-1-[bis(4methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)- (methylsulfonyl)methyl(RS)]azetidine are obtained in 308 309 the form of a pale yellow foam NMR spectrum (400 MHz, (CD 3 ),SO-d6, 8 in ppm) 2.03 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 3H), 3.83 (s, 3H), 4.72 1H), 5.36 1H), 7.27 J=8Hz, 2H), from 7.35 to 7.45 (mt, 2H), 7.43 J=8Hz, 2H), 7.54 (tt, J=9.5 and 2.5Hz, 1H), 7.81 J=8Hz, 2H), 7.88 J=8Hz, 2H)].

1-[bis(4-methoxycarbonylphenyl)methyl]azetidin-3-one may be prepared in the same manner as 1- -(4-chlorophenyl) [4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one (Example 110) from l-[bis(4methoxycarbonylphenyl)methyl]azetidin-3-ol.

1-[bis(4-methoxycarbonylphenyl)methyl]azetidin-3-ol, may be prepared in the same manner as l-{(R*)-(4-chlorophenyl) [4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol (Example 110) from bis(4methoxycarbonylphenyl)methylamine.

Bis(4-methoxycarbonylphenyl)methylamine may be prepared in the same manner as methyl 4-[(RS)-amino- (4-chlorophenyl)methyl]benzoate (Example 87) from 4,4'dimethoxycarbonylbenzophenone.

Example 158 On carrying out the operation according to the procedure of Example 110 starting with 40 mg of 309 310 (RS) (chloromethyl)pheiyl] (4-chiorophenyl) methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methyl)methylsulfonylmethylene] azetidine, 0.25 cm' of dichioromethane and 0.0196 cm' of morpholine, 35.8 mg of (RS)-4-t4-((4-chlorophenyl){3-[(3,5-difluorophenyl) methanesulfonylmethylene] azetidin-lyllmethyl)benzyllmorpholine are obtained in the form of a white foam NMR spectrum (400 MHz, CDC 3 1 6 in ppm): 2.41 (mt, 4H), 2.80 3.42 2H), 3.69 J=4.5Hz, 4H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 1H), 6.83 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

[4-(chloromethyl)phenyl] (4chlorophenyl)methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) 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)-l-{(4-(chlorophenyl) (hydroxymethyl)phenyllmethyl}-3- [(3,5-difluorophenyl) (methylsulfony'l)methylenellazetidine, 5 cm 3 of dichioromethane, 0.19 cm 3 of methanesulfonyl chloride and 0.53 cm 3 Of diisopropylethylamine, 421.2 mg of (RS) (chloromethyl)phenyl] (4-chlorophenyl)methyl} difluorophenyl) (methylsulfonyl)methyl)methylsulfonylmethylenelazetidine are obtained in the form of a cream-colored foam.

310 311 Example 159 mg of potassium carbonate and then 0.016 cm 3 of morpholine are successively added, at a temperature close to 20 0 C, under an inert atmosphere of argon, to a solution of 33 mg of l-benzhydryl-3-{[3-(4bromobutoxy)phenyl]methanesulfonylmethylene}azetidine in 2 cm 3 of anhydrous acetonitrile. After stirring for 17 hours at a temperature close to 20 0 C, the reaction 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 pressure (1 kPa) at a temperature close to 40 0 C. 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 (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 dryness under reduced pressure (1 kPa) at a temperature close to 40C. 25.2 mg of benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]- 311 (0 312 phenoxy}butyl)morpholine are obtained in the form of a pale yellow foam NMR spectrum (400 MHz, CDC1 3 5 in ppm): 1.66 (mt, 2H), 1.81 (mt, 2H), 2.40 2H), 2.46 (mt, 4H), 2.77 3H), 3.72 J=5Hz, 4H), 3.84 (mt, 2H), 3.96 J=6.5Hz, 2H), 4.36 (mt, 2H), 4.53 1H), 6.87 (dd, J=8 and 2Hz, 1H), 6.93 (d, J=8Hz, 1H), 6.96 J=2Hz, 1H), from 7.10 to 7.35 (mt, 7H) 7.42 J=8Hz, 4H) l-Benzhydryl-3-{ [3-(4-bromobutoxy)phenyl]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 0 C, under an inert atmosphere of argon, to a solution of 500 mg of l-benzhydryl-3- [(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.

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 0 C. The brown oil obtained is purified by chromatography at atmospheric pressure on 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') containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 0 C for 2 hours, 408.4 mg of l-benzhydryl-3- ([3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidine are thus obtained in the form of a brown foam.

Example 160 0.110 cm 3 of morpholine and then 35 mg of potassium carbonate are successively added, at a temperature close to 20 0 C, to a solution of 45 mg of l-benzhydryl-3-{[3-(4-bromopropyloxy)phenyl]methanesulfonylmethylene}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 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 40 0 C. The yellow lacquer 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 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 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 400C. 33 mg of 4-(4-{3-[(l-benzhydrylazetidin-3ylidene)methanesulfonylmethyl]phenoxy}propyl)morpholine are thus obtained in the form of a white foam NMR spectrum (300 MHz, (CD 3 2 SO-d6, 6 in ppm) 1.87 (mt, 2H), 2.37 (mt, 4H), 2.42 J=7.5Hz, 2H), 2.94 (s, 3H), 3.58 (mt, 4H), 3.80 (mt, 2H), 4.02 J=7Hz, 2H), 4.20 (mt, 2H), 4.74 1H), 6.97 (mt, 3H), 7.22 (t, J=7.5Hz, 2H), from 7.25 to 7.40 (mt, 1H), 7.32 (t, 4H), 7.48 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 1,3dibromopropane 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)(methylsulfonyl)methylene]azetidine in 10 cm 3 of methyl ethyl 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 0 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 pressure (10 kPa) at a temperature close to 40 0 C. The brown oil obtained is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.200 mm) contained in a column 3 cm in diameter, eluting with a methanol-dichloromethane 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 40 0 C for 2 hours.

511.1 mg of benzhydryl-3- [3-(4-bromopropyloxy)phenyl]methanesulfonylmethylene}azetidine are thus obtained in the form of a brown foam.

The medicaments according to the invention consists of a compound of formula 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 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 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 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 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, 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 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, 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 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 glycols.

Compositions for topical administration may be, for example, creams, lotions, collyria,.collutoria, nasal drops or aerosols.

In human therapy, the compounds according to the invention are particularly useful for the treatment and/or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration' cerebellar and spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucomas, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremor, obsessivecompulsive disorder, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar 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 (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 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 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 compositions according to the invention: EXAMPLE A Gelatin capsules containing a dose of 50 mg of active product and having the following.composition are prepared according to the usual technique: Compound of formula 50 mg Cellulose 318 319 18 mg Lactose mg Colloidal silica.. Sodium carboxymethylstarch............

mg Magnesium 1 mg mg 1 mg FXAMPT, R Tablets containing a dose of 50 mg of active product and having the following composition are prepared according to the usual technique: -Compound of formula 50 mg 104 mg mg 10 mg Sodium carboxymethylstarch............... 22 mg mg Magnesium 2 mg Colloidal 2 mg Mixture of hydroxymethylcellulose, glycerin, 319 320 titanium oxide (72-3.5-24.5) qs 1 finished filmcoated tablet containing 245 mg PXAMPT,E C An injectable solution containing 10 mg of active product and having the following composition is prepared: Compound of formula 10 mg Benzoic acid 80 mg Benzyl alcohol 0.06 ml Sodium mg Ethanol, 0.4 ml Sodium hydroxide 24 mg Propylene glycol 1.6 ml Water qs 4 ml 320 P:\OPERUgc55232-99 claims.doc.09/I04 -320A- The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form or suggestion that that prior art forms part of the common general knowledge in Australia.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

WO 00/15609 321 PCT/FR99/0214 CLAI MS 1. Compounds of formula:

NR(I

R4R in which R represents a chain S0 2

R

1 OR' S02Ri C H R 2 o r H 2

R

Ri 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 halogens, alkyl, alkoxy, -CO-alk, hydroxyl, -COOR 9 formyl, trifluoromethyl, trifluoromethylsulfanyl, trif luoromethoxy, nitro, -NR 6

-CO-NH-NR

6

R,

1S -N(alk)COOR., cyano, -CON'HR9 -CO-NR 16 alkylufnyl, hydroxyalkyl, -O-alk-NR 12 or alkylthioalkyl or a heteroaromatic chosen from the benzofuryl, benzothiazolyl,.benzothienyl, benzoxazolyl, chromanyl, 2,3 -dihydrobenzofuryl, 2, 3-dihydrobenzothienyl, indolinyl, indolyl, isochromanyl, isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4tetrahydroquinolyl, thiazolyl, or thienyl rings, it 7 322 being possible for these heteroaromatics to be nonsubstituted or substituted with a halogen, alkyl, alkoxy, -COOR,, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NRR-, -CO-NH-NR,R, cyano, -CONHR, 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 substituted with one or more halogens, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOR,, -CO-NH-NR,R,, alkylsulfanyl, hydroxyalkyl, -alk-NR,R, or alkylthioalkyl; or a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 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, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOR 5

-CO-NH-NR

6 -C0NR 0

R

11 -alk-NR 6 alkylsulfanyl, hydroxyalkyl or alkylthioalkyl; RS is an alkyl or phenyl radical which is optionally substituted with one or more halogen atoms,

R

6 and 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 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 ,Rs, oxo, hydroxyalkyl, -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 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, Ro and R 1 i, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R, 0 and together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated monoor bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl radical, Ri. and which are identical or different, represent 323 324 a hydrogen atom or an alkyl or cycloalkyl radical or alternatively

R

12 and R 13 together form with the nitrogen atom to which they are attached a 3- to saturated mono- or bicyclic heterocycle optionally 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, 4 R, radical or a 3- to 10-membered saturated mono- or bicyclic heterocycle containing a heteroatom chosen from oxygen, sulfur and nitrogen,

R,

4 and Ri,, which are identical or different, represent a hydrogen atom or an alkyl or -COOalk radical,

R

1 and R 1 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated monoor 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 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 according to claim 1, for which when R, and R, together form with the nitrogen atom to which they are attached a 3- to 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, -alk-O-alk, -CONH,, -COalk, -COOalk, oxo, -CSNHalk, -CONHalk or -CO-alk-NR 4 in which alk, R1 and R,s have the same meanings as in claim 1, their optical isomers and their salts with an inorganic or organic acid.

3. Compounds of the formula according to either of claims 1 and 2, for which when R, 0 and R 11 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, 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.

4. Compounds of formula according to one of claims 1 to 3, for which when and R, 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, 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

R,

1 radical or a 3- to 10-membered saturated mono- or bicyclic heterocycle containing a heteroatom chosen from oxygen, sulfur and nitrogen, and alk, R 14 and R 1 i having the same meanings as in claim 1, their optical isomers and their salts with an inorganic or organic acid.

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

6. Compounds of formula according to one of claims 1 to 5 for which R 9 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.

*o 7. Compounds of formula according to **laim 1 for which claim 1 for which 326 327 R represents a chain or R' representing a hydrogen atom or a -COalk radical, R, represents a methyl or ethyl radical,

R

2 represents either an aromatic chosen from phenyl and naphthyl, these aromatics being nonsubstituted or substituted with one or more halogens, alkyl, alkoxy, hydroxyl, -COOR,, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, -NRR,, -CO-NH-NRgR,, cyano, -CONHR,, alkylsulfanyl, hydroxyalkyl, nitro, -CO-NRiR., -O-alkNR 12

R

13 or alkylthioalkyl or a heteroaromatic chosen from isoquinolyl, pyridyl, quinolyl, 1,2,3,4tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl and thienyl, these heteroaromatics being unsubstituted or substituted with a halogen, alkyl, alkoxy, -COORs, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, -NRR 7 ,-CO-NH-NRR,, cyano, -CONHR, 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 with one or more halogens, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CONR 0 ,Rl, -alk-NRR,, hydroxyalkyl, formyl or -COORs, or a heteroaromatic chosen from thiazolyl or thienyl rings, these heteroaromatics being nonsubstituted or substituted by a halogen, alkyl, alkoxy, -CONR 0 ,Rl, -alk-NRR,, 327 328 hydroxyalkyl or -COORs, R, is alkyl or phenyl which is optionally substituted with one or more halogens, R, and R 7 which are identical or different, represent a 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 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,,R,, oxo, hydroxyalkyl, alk-O-alk or -CO-NH 2 radicals,

R

R,

1 and R 1 i, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R, 0 and R 1 i together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated monoor 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 which are identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical or alternatively R 12 and R, 3 together form with the nitrogen atom to which they are attached a 3- to saturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with an alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHa.lk or -CO-alk-NR, 4 R, 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 15 which are identical or different, represent a hydrogen atom or an alkyl or -COOalk radical, R, and together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated monoor bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen, 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, their optical isomers and their salts with an inorganic or organic acid.

8. Compounds of formula according to 329

Claims

9. The compounds chosen from: 1-benzhydryl-3-[(methylsulfonyl) (phenyl)methylene]- azetidine, 1-benzhydryl-3-[(3-methylphenyl) (methylsulfonyl)- 332 333 methyleie]azetidiie, 1-benzhydryl-3- [(3-chiorophenyl) (methylsulfonyl) rnethylene] azetidine, 1-benzhydryl-3- [(3,5-dichiorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3-[(2, 5-dichiorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(2,3-dichiorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- 1(3-f luorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3-bromopheiyl) (methylsulfonyl) rethylenelazetidine, 1-benzhydryl-3- [(3-iodophenyl) (methylsulfonyl) methylenel azetidine, 1-benzhydryl-3- [(methylsulfonyl) (3-trifluoromethoxy- phenyl) methylene] azetidine, 1-benzhydryl-3- [(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) methylene] azetidine, 1-benzhydryl-3 -[(3-methoxycarbonylphenyl) (methylsulfonyl) methylene] azetidine, 334 1-benzhydryl-3- [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine, i-benzhydryl-3- -carbamoylphenyl) (methylsulfonyl) methylenel azetidine, 1-benzhydryl-3- [(methylsulfonyl) (naphth-1-yl) (methylsulfonyl)mrethylenel azetidine, 1- [bis(4-chlorophenyl)rnethyl] [(3,5-difluorophenyl) (methylsulfonyl).methylene] azetidine, 1- Ibis (4-methoxyphenyl) methyl] II(.3, 5-difluorophenyl) (methylsulfonyl) methylenel azetidine, 1- [bis (4-methylphenyl)methyll 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -3-f (3,5-difluorophenyl) (methylsulfonyl)methylene] 1-f (4-methoxyphenyl) (phenyl)methyl] azetidine, [(3,5-difluorophenyl) (methylsulfonyl)methylene] 1- [(4-methoxyphenyl) (phenyl) methyl] azetidine, [(3,5-difluorophenyl) (methylsulfonyl)methylenel 1-f (4-methoxyphenyl) (phenyl)methyl] azetidine, 1- [bis(4-trifluoromethoxyphenyl)methyl] [13,5- difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-fbis(4-trifluoromethylpheiyl)methyl] difluorophenyl) (methylsulfonyl)methylenel azetidine, 1-[bis(4-chlorophenyl)methyl]-3-{1[3,5-bis- (trifluoromethyl) phenyl] methylsulfonylmethylene} azetidine, (RS) -1-f(4-chiorophenyl) (2,4-dichlorophenyl)methyl] 3-f 5-difluorophenyl) (methylsulfonyl)methylene] 334 335 azetidine, -1--f(4-chiorophenyl) (2,4-dichlorophenyl)methyl] 3- 5-difluorophenyl) (methylsulfonyl)methylenel azetidine, -1-[(4-chiorophenyl) (2,4-dichlorophenyl)methyll 3- [(3,5-difluorophenyl) (methylsulfoiyl)methyleie] azetidine, (RS) -1-{(4-chiorophenyl) (hydroxymethy 1)phenyll methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidiie, (4-chiorophenyl) 14- (hydroxymethyl)phenyll methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, -1-{(4-chiorophenyl) [4-(hydroxymethyl)phenyll methyl}-3-[(3,5--difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1-{(4-chiorophenyl) II4- (pyrrolidylmethyl) phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, -1-{(4-chiorophenyl) [4-(pyrrolidylrnethyl)phenyll methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chioro phenyl) [4-(pyrrolidylmethyl)'phenyll methyl}-3- 1(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -(4-chiorophenyl) [4-(3,3-dirnethylpiperidin-i-yl- methyl)phenyllmethyl}-3- [(3,5-difluorophenyl) 335 (methylsulfoiyl) methylene] azetidine, -(4-chloropheiyl) (3,3-dimethylpiperidin-1-y- methyl)phenyllmethyl}-3-[(3,5-difluorophenyl) (methylsulfonyl)methyleiel azetidine, (S)-(4-chlorophenyl) C3,3-dimethylpiperidin-1-yl- methyl)phenyllmethyl}-3-[I(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, CRS) -(4-chiorophenyl) (thiornorpholin-4- ylrnethyl)phenyllmethyl}-3- [C3,S-difluorophenyl) Ctethylsulfonyl)methylene] azetidine, CR) -(4-chiorophenyl) (thiomorpholin-4- ylmethyl) phenyl] methyl} 5-difluorophenyl) (methylsulfonyl)mrethylenel azetidine, CS) -(4-chloropheiyl) Cthiomorpholin-4- ylmethyl)phenyllmethyl}-3- [(3,5-difluorophenyl) (rethylsulfonyl) methylenel azetidine, CRS) -(4-chiorophenyl) CN-ethyl-N- cyclohexylaminomethyl) phenyl] methyl} difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- R) -(4-chiorophenyl) CN-ethyl-N- cyclohexylaminomethyl) phenyl] methyl} difluorophenyl) (methyisulfonyl)mrethylene] azetidine, CS) -(4-chiorophenyl) (N-ethyl-N- cyclohexylaminomethyl)phenyl] methyl} difluorophenyl) Cmethylsulfonyl)methylene] azetidine, 1-H RS) (4-chioroiohenyl) [C4-ethoxycarbonyl- piperazinyl)methyllphenyllmethyl}}-3- 336 337 difluorophenyl) (methylsulfonyl)methylenel azetidine, 1- -(4-chlorophenyl) Ii(4-ethoxycarbonyl- piperazinyl)methyllphenyllmethyl}}-3- difluorophenyl) (methylsulfonyl)methyleiel azetidine, 1-{{CS)-(4--chlorophenyl) {4-[(4-ethoxycarbonyl- piperazinyl)methyllphenylimethy1}}-3- difluorophenyl) (methylsulfonyljmethylene] azetidine, CRS) -(4-chiorophenyl) CN-cyclopropyl-N-propyl- aminomethyl)phenyllmethyl}-3- 5-difluorophenyl) (rethylsulfonyl)methylenel azetidine, CR) -(4-chiorophenyl) CI'-cyclopropyl-N-propyl- aminomethyl)phenylllmethyl}-3- 5-difluorophenyl) (methylsulfonyl) methylene]l zetidine, CS) (4-chiorophenyl) (N-cyclopropyl-N-propyl- aminomethyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -(4-chiorophenyl) Cdiisopropylaminomethyl) phenyllmethyl}-3- 5-difluorophenyl) (methyl- sulfonyl) methylenel azetidine, CR) 4-chloropheiyl) Cdiisopropylaminomethyl) phenyllmethyl}-3-[(C3,5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, CS) -(4-chiorophenyl) Cdiisopropylaminomethyl) phenyllmethyl}-3- [(3,5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, 1- -(4-chlorophenyl) [bis- C2-methoxyethyl) amino- methyl] phenylimethyl} 5-difluorophenyl) 337 338 (methyl sulfonyl) methylenel azetidine, -(4-chiorophenyl) Ibis- C2-methoxyethyl)amino- methyl] phenyllmethyl} 1(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, CS) -(4-chiorophenyl) {4-(bis-(2-m'ethoxyethyl)amino- methyl] phenyllmethyl} [(3',5-difluorophenyl) (methylsulfonyl) methylenel azetidine, CRS) -(4-chlorophenyl) [4-(di-n.-propylamino- methyl)phenyllmethyl}-3- II(3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, CR) -(4-chiorophenyl) 14- (di-n-propylamino- methyl) phenyl] methyl} -3-1E(3, 5-difluorophenyl) (methyl sulfonyl) methylenel azetidine,. CS) -(4-chiorophenyl) 14- (di-n-propylamino- methyl)phenyllmethyl.-3- 1(3,5-difluorophenyl) Cmethylsulfonyl)methylenel azetidine, CRS) -(4-chiorophenyl) 14- Cpiperidin-J1-ylmethyl) phenyll methyl.}-3- 5-difluorop ,henyl) (methylsulfonyl) methylene] azetidine, CR) -(4-chiorophenyl) 14- Cpiperidin-1-ylmethyl) phenyl] methyl}-3- 3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, CS) -(4-chiorophenyl) Cpiperidin-1-ylmethyl) phenyllmethyl}-3- [C3,5-difluor'ophenyl) (methylsulfonyl) methylene] azetidine, CRS) -(4-chiorophenyl) 14- C4-methylpiperazin-1-yl- methyl)phenyllmethyl}-3- 1(3,5-difluorophenyl) (methyl- 338 339 sulforiyl) methylene] azetidine, CR) 4-chlorophenyl) 14- C4-methylpiperazin-1-yl- methyl)phenyllmethyl}-3- 1(3,5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, CS)- C4-chlorophenyl) C4-methylpiperazin--i-yl- methyl)pheriyllmethyl}-3-[C3,5-difluorophenyl) Cmethyl- sulfonyl) methylenel azetidine, 1-{CRS)-C4-chlorophenyl) 14- Cmorpholiri-4-yl- methyl)pheriyllmethyl}-3- [C3, 5-difluorophenyl) Cmethylsulfonyl) methylene] azetidine, CR)-C4-chlorophenyl) Cmorpholin-4-yl- methyl)phenyllmethyl}-3- [C3,5-difluorophenyl) Cmethylsulfonyl)methylene] azetidine, 1-{CS)-C4-chiorophenyl) Cmorpholin-4-yl- methyl)phenyllmethyl}-3- Cmethylsulfonyl) methylene] azetidine, CRS)- C4-chlorophenyl) Cdiethylaminomethyl) pheriyllmethyl}-3- [C3,5-difluorophenyl) Cmethylsulfonyl) methylenel azetidine, CR)- C4-chlorophenyl) Cdiethylaninornethyl) phenyll methyl} [C3, 5-difluorophenyl) Cmethylsulfonyl) methylene] azetidine, CS)- C4-9hlorophenyl) Cdiethylaminomethyl) phenyllmethyl}-3- [C3,5-difluorophenyl) Cmethylsulfonyl)methylenel azetidine, 1-{CRS)-C4-chlorophenyl) Cpiperazin-2-on-4-yl- methyl)phenyllmethyl}-3- [3,5-difluorophenyl) (methyl- 339 340 sulfonyl) methylene] azetidine, -(4-chiorophenyl) [4-(piperazin-2-on-4-yl- methyl)phenyll methyl}-3- 13, 5-difluorophenyl) (methyl- suJlfonyl) methylenel-azetidine, 1-{(S)-(4-chlorophenyl) [4-(piperazii-2-on-'4-yl- methyl)phenyllmethyl}-3-[(3, 5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, L- -(4-chiorophenyl) (imidazol-1-yl- methyl)phenyilmethyl}-3- [(3,5-difluorophenyl) (methyl- sulfonyl) methylene] azetiidine, -(4-chiorophenyl) [4-(irnidazol-1-yl- methyl)phenyllmethyl}-3- 1(3, 5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, 1-{(S)-(4-chlorophenyl) (imidazol-1-yl- methyl)phenyllrnethyl}-3- [(3,5-difluorophenyl) (methyl- sulfonyl) methylenel azetidine, (RS) -1-{(4-chiorophenyl) (N,N-dimethylcarbamoyl) phenyllmethyl}-3- ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chlorophenyl) (N,N-dimethylcarbamoyl)- phenyllmethyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, {(4-chiorophenyl) (N,N-dimethylcarbamoyl) phenyllmethyl}-3- [(3,5-difluoropheny.) (me thylsulfonyl) methylenel azetidine, (RS) -1-{(4-chiorophenyl) (N-ethylcarbamoyl)phenyl] methyl}-3- 5-difluorophenyl) (methlylsulfonyl) 340 341 methylenel azetidine, -1-{(4-chiorophenyl) (N-ethylcarbamoyl)pheny1] methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylenel azetidine, (4-chiorophenyl) (N-ethylcarbamoyl)phenyl] methyl}-3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1-[(4-carbamoylphenyl) (4-chlorophenyl)methyl] 3- 5-difluorophenyl) (rethylsulfonyljmethylene] azetidine, -1-[(4-carbamoylphenyl) (4-chlorophenyl)methyl] 3- 5-difluoropheiyl) (tethylsulfonyl)methylene] azetidine, -1-[(4-carbamoylphenyl) (4-chlorophenyl)methyl] 3- [(3,5-difluorophenyl) (rethylsulfonyl)methylenel azetidine, 1- [bis (4-chlorophenyl) methyl] 5-dichiorophenyl) (methylsulfoiyl) methylene] azetidine, l-benzhydryl-3.-[(3-methylsulfanylphenyl) (methylsulfonyl)methylene] azetidine, 1-benzhydryl-3- (3-methylsulfanylmethyl)phenyl)] (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl)methyl] [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine, [bis (4-chlorophenyl)methyl] [(3-carbamoylphenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl)methyl] [(3-methoxypheiyl) 341 342 (methylsulfonyl) methylenel azetidine, 1- [bis (4-chloroph-enyl)methyl] -3-f (3-hydroxyphenyl) (methylsulfonyl) methylenel azetidine,, 1- [bis (4-chlorophenyl~methyll [(methylsulfonyl) (3-pyrrolidinylphenyl)methylene] azetidine, 1- Ibis (4-chlorophenyl)methyll -3-f (3-hydroxyrnethyl- phenyl) (methylsulfonyl)methylene] azetidine, 1- [bis (4-chlorophenyl)methyll (methylsulfonyl) (N- piperidylcarbamoyl) phenyl] methylene~azetidine, 1- [bis (4-chlorophenyl)methyl] -3-f (methylsulfonyl) (3-trifluoromethylsulfanylphenyl) (methylsulfonyl) methylene] azetidine, 1 [bis(4-fluorophenyl)methyl] -3-f 5-difluorophenyl) (methylsulfonyl)mrethylene] azetidine, 1- [bis(2-fluorophenyl)methyl] [3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis(3-fluorophenyl)methyl] [(3,5-difluorophenyl) (methyl sulfonyl) methylene] azetidine, (RS) -1-[(4-chiorophenyl) (thiazol-2-yl)methyl] 3-f (methylsulfonyl) (phenyl)methylene] azetidine, (R)-1-f(4-chlorophenyl) (thiazol-2-yl)methyl]- 3-f (methylsulfonyl) (phenyl)methylenel azetidine, -1-[(4-chiorophenyl) (thiazol-2-yl)methyl] 3-f (methylsulfonyl) (phenyl)methylenelazetidine,- (RS)-l-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene] azetidine, (R)-l-[(4-chlorophenyl) (thien-2-yl)methyll-3-[(3,5- 342 343 difluorophenyl) (methylsulfonyl)methylene] azetidine,' (S)-l-t(4-chlorophenyl) (thier-2-yl)methyl]-3-t(3,5- difluorophenyl) (methylsulfonyl)methylene] azetidiie, 1-benzhydryl-3- [(ethylsulfonyl) (phenyl)methylene] azetidine, 1-[bis(4-chlorophenyl)methyll-3-{{3-[.N-(4- methylpiperazinyl) carbamoyll phenyl} (rethylsulfonyl) methylenel}azetidine, 1- [bis(4-chloropheiyl)rnethyl] (2,2- dimethylcarbohydrazido) pheriyl] (methylsulfonyl) methylenelazetidine, 1- [bis(thien-2-yl)methyll (methylsulfonyl)methylenel azetidine, 1-[bis(p-tolyl)methylL]-3-[(rnethylsulfonyl) (phenyl)- methylene] azetidine, 1- [(4-chiorophenyl) (4-hydrox ymethyiphenyl) methyl] 3- I(3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 1- tbis(4-chlorophenyl)methyl] [(3-methylaminophenyl) (methylsulfonyl) methylene] azetidine, (RS)-l-[(4-chlorophenyl) (thiazol-2-yl)methyll-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene] azetidine, (R)-1-[(4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylenel azetidine, (S)-l-[(4-chlorophenyl) (thiazol-2-yl).rethyl]-3-[(3*,5- difluorophenyl) (methylsulfonyl)methylenelazetidine, 1-[bis(4-chlorophenylmethyl] [(methylsulfonyl) (2- 343 344 methoxycarboiylthiei-S-yl) methylene] azetidine, Ibis (4-chlorophenyl)methyl] -3-hydroxy-3- (methylsulfonyl) yl) methyl] azet idine, 1-[bis(4-chlorophenyl)methyl] [(2-isobutyl- (methylsulfonyl) methylene] azetidiie, 1- Ibis (4-chlorophenyl)methyl] [(3-methoxycarbonyl- phenyl) (methylsulfonyl)methyl- (RS)'azetidin-3-ol, 1- Ibis (4-chlorophenyl)methyl] [(methylsulfonyl) (pyridin-4-yl)methyl- (RS) azetidin-3-ol, 1- [bis (4-chlorophenyl)methyll I(methylsulfonyl) (pyridin-3-yl)methyl- (RS)azetidin-3-ol, 3- ({1-[bis (4-chiorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) (3-morpholin-4-yl- propyl) benzamide, Ibis (4-chlorophenyl) me thyl] azetidin-3-ylidene} methanesulfonylmethyl) (3-dimethylaminopropyl) benzamide, 3-({1-.{bis(4-chlorophenyl)methyllazetidin-3-ylidene}- methanesulfonylmethyl) (2-pyrrolidin-1-ylethyl) beuzamide, 3- ({l-[bis (4-chiorophenyl) methyl] azetidin-3-ylidene}- methanesulfonylmethyl) (2-dimethylamino-l- methylethyl) benzamide,- [bis(4-chlorophenyl)methyllazetidin-3-ylidene}- methanesulfonylmethyl) -N-pipEridin-1-ylbenzamide, 344 345 3- ({i-[bis(4-chlorophenyl)methyllazetidin-3-ylideney- methanesulfonylmethyl) -N-isobutylbenzanide, 3- ({i-[bis(4-chlorophenyl)methyllazetidin-3-ylidene}- metharaesulfonylmethyl) (3-imidazol-1-ylpropyl) benzamide, 3- ({1-[bis(4-chlorophenyl)methyllazetidin-3-ylideney- methanesulfonylmethyl) (2-dimethylamincethyl) berizarnide, 3-({1i-[bis-(4--chloropheriyl)methyl]azetidin-3- ylideneimethanesulfonylmethyl)benzoic acid N' methyihydrazide, 3- (4-chlorophenyl)rnethyllazetidin-3-ylidene}- methanesulfonylmethyl) (2-morpholin-4-ylethyl) benzamide, 3- ({1-[bis-(4-chlorophenyl)methyllazetidin-3-ylidene}- methanesulfonylmethyl) (l-ethylpyrrolidin-2- ylmethyl) benzamide, 3- ({1-[bis-(4-chlorophenyl)methyllazetidin-3-ylidene}- methanesulfonylmethyl) (2,2-dimethylpropyl)benzamide, 3 bis-(4-chlorophenyl)methyllazetidin-3-ylidene}- methanesulfonylmethyl) -N-cyclohexylmethylbenzamide, 3- ({1-[bis-(4-chlorophenyl)methyllazetidin-3-ylidene}- methanesulfonylmethyl) -N-cyclopropylrnethylbenzamide, [bis-(4-chlorophenyl)rnethyllazetidin-3-ylidene}- methanesulfonylmethyl) (2-methylbutyl)benzamide, [bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}- methanesulfonylmethyl) (2-phenylpropyl) benzarnide, 345 346 [bis-(4-chloropheriyl)methyl]azetidin-3-ylideie}- methanesulfonylmethyl) (tetrahydrofuran-2- ylmethyl) benzamide, 3-({1-[bis-(4-chlorophenyl)methyllazetidin-3-ylidene}- rethanesulfonyltnethyl) (2,2-diphenylethyl)benzamide, 3- bis- (4-chlorophenyl)methylliazetidiri-3-yl idene}- methariesulfonylmethyl) (2-ethylbutyl) berizamide, 4- Ibis (4-chlorophenyl)methyl] azetidin-3- ylidenelmethanesulfonylmethyl) benzoylarninol methyllcyclo hexanecarboxylic acid methyl ester, 2-amino-l-{4- [bis- (4-chlorophenyl)methyl] azetidin-3 -ylideh'elmethanesulfoiyl- methyl) phenyll piperazin-1-yllethanone, (2-{4-[3-({1-[bis(4-chloropheriyl)methyl]azetidin-3- ylideneimethanesulfonylmethyl)phenyllpiperazin-1-y1}-2- oxoethyl)carbamic acid tert-butyl ester, (4-chlorophenyl) methyll azetidin-3- ylidene~me-thanesulfonylmethyl)phenyllpiperazin-1-yl}-2- methylaminoethanone, (2-{4-[3-({1-[bis(4-chlorophenyl)methyllazetidin-3- ylideneimethanesulfonylmethyl)phenyllpiperazin-1-yl}-2- oxoe thyl) -N-methylcarbamic acid tert-butyl ester, chlorophenyl)methyl] azetidin-3- ylidenelmethanesulfonylmethyl)phenyllpiperazine-l- carbothioic acid N-methylamide, 4- [bis (4-chiorophenyl) methyl] azetidin-3- ylidenelmethanesulfonylmethyl)phenylljpiperazine-l- 346 347 carboxylic acid N-methylamide, 4- L3- ({1-[bis (4-chlorophenyl)methyl] azetidin-3- yliderimethanesulfonylmethyl)phenyllpiperazine-l- carboxylic acid methyl ester, [bis(4-chlorophenyl)methyllazetidii-3- ylidenelmethanesulfonylnethyl) phenyl] -4- isobutylpiperazine, 1-[3-({1l-[bis(4-chlorophenyl)methyl]azetidin-3- ylide neimethanesulfonylmethyl) phenyl] -4- ethylpiperazine, 4-acetyl 1- [bis (4-chlorophenyl)methyllazetidin- 3-ylidene~methanesulfonylmethyl)phenyllpiperazine, 1-{4-[3-C{1-tbis(4-chlorophenyl)methyllazetidin-3- ylideneimethanesulffonylmethyl)phenyllpiperazin-1-yl}-2- dimethylaminoethanone, ({1-[bis(4-chlorophenyl)methyllazetidin-3- ylideneimethanesulfonylmethyl) phenyl] piperazine, 4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylideneimethanesulfonylmethyl)phenyllpiperazine-l- carboxylic acid tert-butyl ester, 1- Ibis (4-methoxycarbonylphenyl)methyll difluorophenyl) (methylsulfonyl) methylene] azetidine, 3-acetoxy-1- [bis (4-methoxycarbonylphenyl)methyl] -3- 5-difluorophenyl) (methylsulfonyl)methyl- (RS)azetidine, (RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluorophenyl)- methanesulfonylmethylene] azetidin-1-yl~methyl) 347 348 benzyl] morpholine, [(l-benzhydrylazetidin3ylidene)thae sulfonylmethyl] phenoxylbutyl) morpholine, 4- ((1-benzhydrylazetidin3ylidene)thae sulfonylmethyl] phenoxy~propyl) morpholine, their optical isomers and their salts with an inorganic or organic acid. The following compounds: 1l[bis(4-chlorophenyl)methyll 3 3 difluorophenyl) (methylsulfonyl)methylenel azetidine, 1- [bis(4-chlorophenyljmethyll- 3 difluorophenyl) (methylsulfonyl)methyl (RS) ]azetidin-3- ol, 3-acetoxy--[bis- 4 -chlorophenyl)methyl] difluorophenyl) (methylulfonyl) methyl) methylsulfonyl. methyl- (RS) Iazetidine their optical isomers and their salts with an inorganic or organic acid.
11. Process for the preparation of the 20 compounds of formula according to claim 1 for which R represents a chain of formula **wherein a corresponding compound of formula (1a): 000** (1a) 0 S0 2 RI 00 R 2 348 349 in which 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 with an inorganic or organic acid.
12. Process for the preparation of the compounds of formula according to claim 1 for which R represents a chain in which R' is a hydrogen atom, wherein a derivative RISO 2 CH 2 R 2 (II) for which RI and R 2 have the same meanings as in claim 1 is reacted with an azetidinone of formula: R 3 N (Ii) in which R, and R 4 have the same meanings as in claim 1, 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 according to claim 1 for which R represents a chain in which R' is a hydrogen atom, wherein a derivative R 3 CH(Br)R 4 for which R 3 and R, have the same meanings as in claim 1 is reacted with a derivative of formula: 4 o S 349 350 HN /OH (VII) SOR, R 2 in which R, and R, have the same meanings as in claim 1, the product isolated and optionally converted to a salt with an inorganic or organic acid.
14. Process for the preparation of the compounds of formula according to claim 1 for which R is a chain in which R' is a -CO-alk radical, wherein a halide Hal-CO-alk in which Hal represents a hydrogen atom and alk represents a straight- or branched-chain alkyl radical containing 1 to 6 carbon atoms is reacted with a corresponding compound of formula for which R is a chain 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 according to claim 1 for which R 2 represents an aromatic or a heteroaromatic substituted with -NRR,, in which R, and R, each represent a hydrogen atom, wherein a ~corresponding compound of formula for which R 2 represents an aromatic or a heteroaromatic substituted S. 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 according to claim 1 for which R 2 represents an aromatic or heteroaromatic substituted with -CONHR, or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with -CONRoRu, wherein a corresponding compound of formula for which R 2 and/or R 3 and/or R, represent an aromatic or a heteroaromatic substituted with -COORs.for which R, is alkyl or phenyl optionally substituted with halogens is reacted respectively with an amine HNR, or HNR,,R n for which Rg, R, 1 and R 11 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 compounds of formula 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, wherein a o corresponding compound of formula 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 Sinorganic or organic acid. 25
18. Process for the preparation of the compounds of formula according to claim 1 for which R 2 represents an aromatic substituted with -NRR, for 351 352 which R, represents an alkyl radical and R, represents a hydrogen atom, wherein a corresponding compound of formula for which R 2 represents an aromatic substituted with -N(alk)COOR, in which R, 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 according to claim 1 for which R 2 and/or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with -COOR,, wherein a derivative of formula: R,' RR N R (IX) for which R represents a chain C=C(SO 2 RI)R' 2 or C(OR')CH(SO 2 R)R' 2 R' 3 and have the same meanings as the substituents R 2 R 3 and R, of claim 1 with the proviso that at least one of the substituents 2R'2, R' 3 and R' 4 represents an aromatic or a heteroaromatic substituted with carboxyl, is esterified using a derivative of formula ROH for which R s 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 according to claim 1 for which R, and/or R 3 and/or R 4 represent an aromatic or a heteroaromatic substituted with alkylthioalkyl, wherein a derivative of formula: R 3 N R (IX) R for which R represents a chain C=C(SOR 1 or C(OR')CH(SOR)R' 2 R, R, R1, R' and R' 4 have the same meanings as the substituents 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 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 carbon atoms, the product isolated and optionally converted to a salt with an inorganic or organic acid. •21. Process for the preparation of the S" compounds of formula according to claim 1 for which R 2 and/or R 3 and/or R 4 represent an aromatic substituted with hydroxyalkyl in which the alkyl contains a carbon atom, wherein a compound of formula (I) for which at least one of the substituents R 2 R, 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 according to claim 1 for which R 3 and/or R 4 represents an aromatic substituted with -alk-NR 6 R 7 for which alk is an alkyl containing a carbon atom, wherein 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 HNR 6 R, in which R 6 and R, have the same meanings as in formula the product isolated and optionally converted to a salt with an inorganic or organic acid.
23. Process for the preparation of the compounds of formula according to claim 1 for which R 2 represents an aromatic or a heteroaromatic substituted with -CONHR, and/or R 3 and/or R, represents an aromatic or a heteroaromatic substituted with -CO- NR 1 oR 11 wherein a derivative of formula: R 3 R *R N: N (IX) R for which R represents a chain C=C(SOR)R', or C(OR')CH(S0 2 R) R' 2 R R' 2 R' and R'4 have the same meanings as the substituents 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, 0 R, 1 in which R,, Ri and R 11 have the same meanings as in formula the product isolated and optionally converted to a salt with an inorganic or organic acid.
24. Process for the preparation of the compounds of formula according to claim 1 for which R 2 and/or R 3 and/or R, represent an aromatic or a heteroaromatic substituted with -CO-NH-NRR 7 wherein a corresponding compound of formula for which R 2 and/or R 3 and/or R 4 represents an aromatic or a heteroaromatic substituted with -COOR s and Rs represents an alkyl or phenyl radical which is optionally substituted by halogens, is reacted with a hydrazine H 2 N-NR,R, for which R 6 and R, have the same meanings as in formula the product isolated and optionally converted to a salt with an inorganic or organic acid.
25. Process for the preparation of the o compounds of formula according to claim 1 for which S* 20 R 2 represents an aromatic or a heteroaromatic substituted with -CO-NHR, in which R, represents a hydrogen atom and/or R 3 and/or R, represent an aromatic or a heteroaromatic substituted with -CO-NR,R l radicals in which R 10 and R 1 are hydrogen atoms, wherein a 25 corresponding compound of formula for which ooo R 2 and/or R 3 and/or R 4 represent an aromatic or a S 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 according to claim 1 for which R 2 represents an aromatic substituted with -0-alk- NR 12 R 13 wherein a derivative of formula: R,' R 4 N (IX) for which R represents a chain C=C(SO 2 R,)R' 2 or C(OR')CH(SO2R)R',, R, R 1 R 2 R'I and R 4 have the same meanings as the substituents RI, R 3 and R, of claim 1 with the proviso that at least one of the substituents R2 R 3 R 4 represents an aromatic substituted with -0-alk-Hal in which alk represents a straight- or branched-chain alkyl radical containing 1 to 6 carbon atoms and Hal represents a halogen atom, is reacted with an amine HNR 2 R 13 in which R 12 R 1 3 have the same meanings as in claim 1, the product isolated and optionally converted to a salt with an inorganic or organic acid.
27. Process for the preparation of the compounds of the formula according to claim 1, for which R 3 and/or R 4 represents an aromatic substituted i with -alk-NR 6 R 7 wherein a derivative of formula: 356 357 R,' (IX) R4R for which R represents a chain C=C(S0 2 or C(OR')CH(SO 2 R 3 and have the same meanings as the substituents R 2 R 3 and R 4 of claim 1 with the proviso that at least one of the substituents R 3 R4' represents an aromatic substituted with -alk-Cl in which alk represents a straight- or branched-chain alkyl radical containing 1 to 6 carbon atoms, is reacted with an amine HNRR 7 in which R, 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 compounds of formula according to claim 1 for which R represents a chain B, R' represents a hydrogen atom and R, and/or R 4 represents an aromatic substituted with hydroxyalkyl in which the alkyl residue contains one carbon atom, wherein diisobutylaluminum hydride is reacted with a corresponding compound of formula 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 according to claim 1 for which R, represents a phenyl radical substituted with -NR 6 R 7 representing a 1-piperazinyl ring substituted at the 4 position with an alkyl radical, wherein a corresponding compound of formula for which R 2 represents a phenyl radical substituted with a radical -NR 6 R 7 representing a l-piperazinyl ring is reacted with 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. Process for the preparation of the compounds of formula according to claim 1 for which R, represents a phenyl radical substituted with -NR 6 R 7 representing a l-piperazinyl ring substituted at the 4 position with a -COOalk radical, wherein S: a corresponding compound of formula for which R 2 20 represents a phenyl radical substituted with a radical -NR 6 R 7 representing a l-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 S358 358 359 compounds of formula according to claim 1 for which R 2 represents a phenyl radical substituted with -NR 6 R 7 representing a l-piperazinyl ring substituted at the 4 position with a -CO-NHalk or -CS-NHalk radical, wherein a corresponding compound of formula for which R, represents a phenyl radical substituted with -NRR, representing a l-piperazinyl ring is reacted 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 sulfur or oxygen atom, the product isolated and optionally converted to a salt with an inorganic or organic acid.
32. Process for the preparation of the compounds of formula according to claim 1 for which R 2 represents a phenyl radical substituted with a radical -NR 6 R representing a l-piperazinyl ring substituted at the 4 position with a -CO-alk-NR 4 R1 radical, wherein a corresponding compound 20 of formula for which R 2 represents a phenyl radical substituted with a radical -NR 6 R 7 representing a l-piperazinyl ring is reacted with an acid of formula R1R,4N-alk-COOH in which alk represents a straight- or branched-chain alkyl radical containing 1 to 6 carbon 25 atoms and R 1 4 and R 1 have the same meanings as in claim 1 optionally followed by deprotection of the product for which R, is a tert-butoxycarbonyl radical in order 359 P:\OPERUgc\55232-99 claim.doc.09/0104 -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 compounds of formula according to claim 1 for which R, represents a phenyl radical substituted with a radical -NR,R representing a 1-piperazinyl ring substituted at the 4 position with a -CO-alk radical in which alk represents a methyl radical, wherein a corresponding compound of formula 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 organic acid.
34.. Pharmaceutical compositions containing, as active ingredient, at least one compound of formula according to one of claims 1 to P:\OPER\Jgc\55232-99 claims.do-09/01/04 -361- A compound according to claim 1 substantially as hereinbefore described with reference to the Examples.
36. A pharmaceutical composition according to claim 34 substantially as hereinbefore described with reference to the Examples.
37. A process according to any one of claims 1 to 33 substantially as hereinbefore described with reference to the Examples.
38. A compound when produced by a process as defined in any one of claims 11 to 33 or 37.
39. Compounds of formula according to claim 4 wherein the 3- to 10-membered saturated mono- or bicyclic heterocycle is a thiomorpholinyl radicle. Compounds of formula according to claim 20 wherein the 3- to 10-membered saturated mono- or bicyclic heterocycle is a piperidyl ring. DATED this 9 th day of January, 2004 Aventis Pharma S.A. by DAVIES COLLISON CAVE **i