SK12452002A3 - Azetidine derivatives, preparation thereof and pharmaceutical compositions containing same - Google Patents

Abstract

The invention concerns a compound of formula (I) wherein R represents a CR1R2 radical, C=C(R5)SO2R6 or C=C(R7)SO2alk, their preparation and pharmaceutical compositions containing them.

Description

Azetidine derivatives, their preparation and pharmaceutical compositions containing them

Technical field

The present invention relates to azetidine derivatives, to a process for their preparation and to pharmaceutical compositions containing them.

SUMMARY OF THE INVENTION

The present invention relates to azetidine derivatives of the general formula:

their salts, processes for their preparation and medicaments containing them.

In the general formula

R is CR ¹ R ² , C = C (R ⁵ ) SO ² R ⁶ or C = C (R ⁷ ) SO 2 alk,

R is H and R is -C (R) (R) (R) -C (R ⁸⁾ (R ¹¹⁾ (R ¹²⁾ -CO-NR ¹³ R ^14, -CH 2 -CO-NR ¹³ R ¹⁴ , -CH 2 -CO-R ⁶ , -CO-R ⁶ ,

-CO-cycloalkyl, -SO-R ^6, -SO 2 R ^6, -C (OH) (R ¹²⁾ (R ^6), -C (OH) (R ⁶⁾ (alkyl), -C (= NOalk) R ⁶ , -C (= NO-CH 2 -CH = CH ₂ ) R ⁶ , -CH 2 -CH (R ⁶ ) NR ³¹ R ³² , -CH 2 -C (= NO-alk) R ⁶ , -CH (R ⁶ ) NR ³¹ R ³² , -CH (R ⁶ ) NHSO 2 alk, -CH (R ⁵ ) NHCONHalk or -CH (R ⁶ ) NHCOalk, or R ¹ represents alkyl, NH-R ¹⁵ , cyano, -S-alk-NR ^is R ¹⁷ , -CH 2 -NR ¹⁸ R ¹⁹ or -NR ²⁰ R ²¹ and R ² is -C (R ³ ) (R ¹¹ ) (R ¹² ),

R ³ and R ⁴ which are the same or different represent either an alkyl or cycloalkyl group or an aromatic group selected from a phenyl, naphthyl or indenyl group, the aromatic groups being unsubstituted or substituted by one or more groups selected from the group consisting of: halogen or alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR ²² R ²³ , -CO-NH-NR ²⁴ R ²⁵ , alkylsulfanyl, alkylsulfinyl , alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR ²⁴ R ²⁵ groups; or a heteroaromatic group selected from benzcfuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl,

1,2,3,4-tetrahydroisoquinolyl, thiazolyl and thienyl rings, wherein the heteroaromatic groups may be unsubstituted or substituted by one or more groups selected from the group consisting of halogen atoms or alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano , -COOH, -COOalk, -CO-NH-NR ²⁴ R ^25, -CONR ²² R ^23, -alk-NR ²⁴ R ^25, alkylsulfonyl phenylsulfanyl, alkylsulfinyl, alkylsulfonyl ", alkylthioalkyl, alkylsulfonyl inylalkyl, alkylsulfonylalkyl or hydroxyalkyl,

R represents a hydrogen atom or an alkyl group,

R ⁶ is Ar or Het,

R ⁷ is cycloalkyl, heterocycloalkyl or heterocyclenyl, optionally substituted with -CSO-phenyl,

R ⁸ represents a hydrogen atom or an alkyl group,

R ⁵ is -CO-NR ²⁶ R ²⁷ , -COOH, -COOalk, -CH ₂ OH, -NH-CO-NH-alk, -CH ₂ -NHR ²⁸ or -NHCOOalk,

R ¹⁰ represents a radical Ar or Het,

R ¹¹ is -SO ₂ -alk, -SO ₂ -Ar or -SO ₂ -Het,

R ¹² represents a hydrogen atom or an Ar or Het group,

R ¹³ represents a hydrogen atom or an alkyl group,

R ¹⁴ is Ar, Het, -alk-Ar or -alk-Het,

R ¹⁵ represents alkyl, cycloalkyl or -alk-NR ²⁹ R ³⁰ ,

R ¹⁶ and R ¹⁷ , which are the same or different, represent a hydrogen atom, an alkyl group or, alternatively, R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle optionally containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups,

R ¹⁸ represents a hydrogen atom or an alkyl group,

R ¹⁹ represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkyialkyl, cycloalkylcarbonyl, -SO ₂ alk, -CO-NHalk or -COOalk group, or alternatively R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached form 3- to 10 a membered unsaturated or saturated mono- or bicyclic heterocycle, optionally containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups,

-NR ²⁰ R ²¹ represents a 3- to 8-membered saturated or unsaturated monocyclic heterocycle, optionally containing another heteroatom selected from oxygen, nitrogen and sulfur,

R ²² and R ²³ , which are the same or different, represent a hydrogen atom or an alkyl group or alternatively R ²² and R ²³ together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing a further heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups,

R ²⁴ and R ²⁵ , which are the same or different, represent a hydrogen atom or an alkyl group, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl or alternatively R ²⁴ and R ²⁵ together with the nitrogen atom to which they form are attached, a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH ₂ radicals,

R ²⁶ and R ²⁷ , which are the same or different, represent a hydrogen atom or an alkyl group, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, -alk-COOalk, -alk-Ar, -alk-Het, Het or -alk-N (alk) ₂ the group R ²⁶ and R ²⁷ may also form together with the nitrogen atom to which they are attached a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or halogen atoms,

O Q

R is -CH ₂ -alk, benzyl, -SO ₂ alk, -CONHalk, -COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl or -CO- (CH ₂ ) _n OH, n is 1, 2 or 3,

R ²⁹ and R ³⁰ , which are the same or different, represent a hydrogen atom or an alkyl group, or alternatively R ²⁹ and R ³⁰ together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing a further heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups,

R ³¹ and R ³² , which are the same or different, represent a hydrogen atom or an alkyl group, Ar or -alk-Ar group or alternatively R ³¹ and R ³² together with the nitrogen atom to which they are attached form a heterocycle selected from the group consisting of: form aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl, alk means alkyl or alkylene,

Ar represents a phenyl or naphthyl group optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR ²² R ²³ , -CO- NH-NR ²⁴ R ²⁵ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, -alk-NR ²⁴ R ²⁵ , -NR ²⁴ R ²⁵ , alkylthioalkyl, formyl, hydroxyl, CF ₃ , OCF ₃ , Het, - O-alk-NH-cycloalkyl or SO ₂ NH ₂ group,

Het means a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocyclic group containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more groups selected from halogen or alkyl, alkoxy, alkoxycarbonyl, -CONR ²² R ²³ , hydroxyl, hydroxylalkyl, oxo or SO ₂ NH ₂ groups.

In the foregoing definitions and the definitions that follow, unless otherwise indicated, alkyl and alkylene groups and portions thereof and alkoxy groups and portions thereof are in the form of a straight or branched chain and contain 1 to 6 carbon atoms, cycloalkyl groups contain 3 to 10 carbon atoms and heterocycloalkyl and heterocyclenyl groups contain 3 to 10 carbon atoms.

Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl groups. Alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and pentyloxy groups.

Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

Heterocycloalkyl groups are cycloalkyl groups in which at least one carbon atom is replaced by a heteroatom selected from nitrogen, sulfur and oxygen. Examples are pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl rings.

Heterocyclenyl groups are cycloalkyl groups in which at least one carbon atom is replaced by a heteroatom selected from oxygen, sulfur and nitrogen and containing at least one carbon-carbon or carbon-nitrogen double bond. Examples of heterocyclenyl groups include 1,2 ', 3,4-tetrahydrohydropyridinyl,

3,6-dihydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl,

1.2.3.6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl,

2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazciinyl,

3,4-dihydro-2H-pyran, dihydrofuranyl and fluorodihydrofuranyl rings. Preferred are 3,6-dihydropyridyl rings.

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

The heterocycles represented by Het include: benzcfuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, indolinyl, indolinyl, isochromanyl, isoquinolyl, piperidyl, pyrolyl, pyridyl, pyrimidinyl, pyrimidinyl 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl and thienyl.

When R ³ and / or R ⁴ represents independently substituted phenyl, the heterocycle is preferably mono-, di- or trisubstituted.

When R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl.

When R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached form a 3 to 10 membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.

The heterocycle formed by NR ²⁰ R ²¹ is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl, piperazinyl or imidazole ring.

When R ²² and R ²³ together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.

When R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.

When R ²⁵ and R ²⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.

When R ²⁹ and R ³⁰ together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.

When R ³¹ and R ³² together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.

Preferably R is CR ¹ and R ² , either R ¹ is hydrogen and R ² is -C (R ⁸ ) (R ¹¹ ) (R ¹² ) or C (R ⁸ ) (R ⁹ ) (R ¹⁰ ) or R ¹ represents an alkyl group and R ² represents a -C (R ⁸ ) (R ¹¹ ) (R ¹² ) group,

R ³ and R ⁴ , which are the same or different, represent either a phenyl group which is unsubstituted or substituted by one or more groups selected from halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ²² R ²³ , hydroxyalkyl or -alk-NR ²⁴ R ²⁵ groups; or a heteroaromatic group selected from pyridyl, pyrimidinyl, thiazolyl and thienyl rings, which heteroaromatic groups may be unsubstituted or substituted by one or more groups selected from the group consisting of halogen atoms, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -CONR ²² R ²³ , -alk-NR ²⁴ R ^25, or hydroxyalkyl groups,

R ³ represents a hydrogen atom,

R ⁹ is -CO-NR ²⁶ R ²⁷ , -COOalk, -CH ₂ OH, -NH-CO-NH-alk, -CH ₂ -NHNR ²⁸ or -NHCOOalk,

^IC R is Ar or Het,

R ¹¹ is -SO ₂ -alk, -SO ₂ -Ar or -SO ₂ -Het,

R ¹² represents a hydrogen atom or an Ar or Het group,

R ²² and R ²³ , which are the same or different, represent a hydrogen atom or an alkyl group, or alternatively R ²² and R ²³ together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing a further heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups,

R ²⁴ and R ²⁵ , which are the same or different, represent a hydrogen atom or an alkyl group, a cycloalkyl, an alkylcycloalkyl, or a hydroxyalkyl group, or alternatively R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached form a 3- to 10-membered an unsaturated or saturated mono- or bicyclic heterocycle, optionally containing an additional heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo or CO- NH ₂ groups,

Ar represents a phenyl or naphthyl group optionally substituted by 1 or 2 substituents selected from the group consisting of halogen or alkyl, alkoxy, -CO-alk, cyano, -COOalk, -CONR ²² R ²³ , alkylsulfonyl, hydroxyalkyl, -alk-NR ²⁴ R ²⁵ , -NR ²⁴ R ²⁵ , hydroxyl, CF ₃ , OCF ₃ , -O-alk-NH-cycloalkyl or SO ₂ NH ₂ ,

Het means benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl ring.

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

Compounds of formula I wherein R is CR ⁴ R ² wherein R ¹ is hydrogen and R ² is C (R ®) (R ¹¹ ) (R ¹² ) wherein R ⁸ is hydrogen, R ¹¹ is - SO ₂ -Ar, -SO ₂ -Het or -SO ₂ alk and R ¹² is hydrogen or Ar or Het, and compounds of formula I wherein R is C = C (R ⁵ ) SO ² R ⁶ or C = C (R ⁷⁾ SO2alk may be prepared according to the following scheme:

Ra-SO ₂ -CH ₂ -Si (CH ₃ ) ₃

In these formulas, either R ^a is alkyl, Het or Ar and R ^b is hydrogen or Ar or Het, or R ^a is Ar or Het and R ^b is hydrogen or alkyl, or R ^a is alkyl and R ^b is cycloalkyl, heterocycloalkyl or heterocyclenyl, optionally substituted with -CSO-phenyl, R ^c is hydrogen or acetyl, R ³ , R ⁴ , Ar and Het are as defined in formula I.

Reaction dae can be used only when R ^b is hydrogen.

The reaction is generally carried out in an inert solvent such as an ether (e.g. tetrahydrofuran) in the presence of a strong base such as tert-butyllithium, n-butyllithium, lithium diisopropylamide or potassium tert-butoxide at a temperature between -70 ° C to

-15. '

The dehydration reaction b is carried out by any method known to the person skilled in the art which allows the dehydration of the alcohol or one of its derivatives to obtain the corresponding alkene. Preferably, the acetyloxy derivative is prepared by treating acetyl chloride in an inert solvent such as pyridine, tetrahydrofuran, dioxane, chlorinated solvents (e.g. dichloromethane or chloroform) at a temperature between 5 ° C and 20 ° C and then treating the obtained solution with a base such as hydroxide an alkali metal (e.g. sodium hydroxide), an alkali metal carbonate (e.g. potassium carbonate), an amine such as a trialkylamine (e.g. triethylamine), 4-dimethylaminopyridine, diaza-1,8-bicyclo [5.4.0] undec-7-ene, at temperature between 0 ° C and the boiling point of the reaction mixture. The acetyloxy intermediate can be isolated. The acetyloxy derivative can also be prepared in the reaction medium of reaction a.

The reduction c is usually carried out in an inert solvent such as a C 1 -C 4 aliphatic alcohol (e.g. methanol), a chlorinated solvent (e.g. chloroform or dichloromethane) or a mixture of these solvents, in the presence of NaBH ₄ , at a temperature between 0 ° C and temperature boiling of the reaction medium.

Reaction d is carried out by treatment with trimethylsilyl chloride, in an inert solvent such as ether (e.g. tetrahydrofuran), in the presence of n-butyllithium, at -70 ° C.

The reaction e is usually carried out in an inert solvent such as ether (e.g. tetrahydrofuran) in the presence of a strong base such as tert-butyllithium, n-butyllithium, lithium diisopropylamide or potassium tert-butoxide at a temperature between -70 ° C and

-15.

The reaction f is usually carried out in a chlorinated solvent (e.g. dichloromethane or chloroform) at a temperature between 0 ° C and the boiling point of the reaction medium.

The hydrolysis of g is carried out in an inert solvent such as ether (e.g. dioxane) by treatment with hydrochloric acid at a temperature of about 20 ° C.

The reactions h and j are preferably carried out in an inert solvent such as acetonitrile in the presence of a base such as an alkali metal carbonate (e.g. potassium carbonate) at the boiling point of the reaction medium.

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

The reaction k is carried out in an inert solvent such as a chlorinated solvent (e.g. dichloromethane or chloroform) at a temperature between 0 ° C and the boiling point of the reaction mixture.

The R ³ CH (Br) R ⁴ derivatives are commercially available or can be prepared using the method described by Bachmann WE, J. Am. Chem. Soc., 2135 (1933). Generally, the corresponding alcohol R ³ CHOHR ⁴ is brominated with hydrobromic acid in acetic acid, at a temperature between 0 DEG C. and the boiling point of the reaction medium.

The corresponding alcohols R ³ CHOHR ⁴ are commercially available or can be prepared using the method described by Plasz AC et al., J. Chem. Soc. Chem. Comm., 527 (1972).

Intermediates of formula 2 can 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:

R b -CH ₂ -Hal

Rasna

R b -CH ₂ -SO ₂ -R

Rash

ICH,

RaNH, isoamytnitrite

MeSSMe d

Rasch,

RaSO ₂ CH ₃ nBuLi

MeSSO ₂ Me

Rahal

In these formulas, Hal is a halogen atom and preferably chlorine, bromine or iodine, R ^a and R ^b have the same meanings as in the above general formula for derivative 2.

Reaction a is generally carried out in an inert solvent such as dimethylformamide or a C 1 -C 4 aliphatic alcohol at a temperature between 20 and 30 ° C.

The reactions of bae are carried out by any known method which allows oxidation of the sulfur-containing derivative without affecting the rest of the molecule, such as those described by M. Hudlicky, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). The process is carried out, for example, by treatment with an organic peroxyacid or salt (such as a peroxycarboxylic or peroxysulfonic acid, in particular peroxybenzoic acid, 3-chloroperbenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, peroxy formic acid or monoperoxyphthalic acid). an acid (such as periodic acid or persulfic acid) in an inert solvent such as a chlorinated solvent (such as chloroform or dichloromethane) at a temperature between 0 and 25 ° C. It is also possible to use hydrogen peroxide, optionally in the presence of a metal oxide (e.g. sodium tungstate) or periodate (e.g. sodium periodate), in an inert solvent such as an aliphatic alcohol having 1 to 4 carbon atoms (e.g. methanol or ethanol), water or a mixture thereof. solvents, at a temperature between 0 and 60 ° C. It is also possible to carry out the process using tert-butyl hydroperoxide in the presence of titanium tetraisopropoxide in a C 1 -C 4 aliphatic alcohol (e.g. methanol or ethanol) or a mixture of water and alcohol at about 25 ° C or using oxone ^R (potassium peroxymonosulfate) , in a C 1 -C 4 aliphatic alcohol (e.g. methanol or ethanol), in the presence of water, acetic acid or sulfuric acid, at a temperature of about 20 ° C.

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

Reaction d is carried out in an inert atmosphere (argon) at a temperature between 50 ° C and the boiling point of the reaction medium.

The reaction is generally carried out in an inert solvent such as tetrahydrofuran or an aliphatic ether (e.g. ethyl ether) at a temperature of about -70 ° C.

Reaction g is generally carried out in an inert solvent such as dimethylformamide, an aliphatic ether (e.g. ethyl ether) or a C 1 -C 4 alcohol, in the presence of a base (e.g. sodium hydride), at a temperature between 0 ° C and 60 ° C.

The derivatives of formula ^Rb -CH2Hal are commercially available or can be prepared using the methods described in the Examples. In particular, the methylated derivative or the corresponding alcohol is halogenated using a halogenating agent such as hydrobromic acid in acetic acid at a temperature of about 20 ° C or N-bromo or N-chlorosuccinimide in the presence of benzoyl peroxide in an inert solvent such as carbon tetrachloride at boiling point. reaction environment. The methylated derivatives or corresponding alcohols are commercially available or can be obtained according to the methods described by Brine GA et al., J. Heterocycl. Chem., 26, 677 (1989) and Nagarathnam D., Synthesis, 8, 743 (1992) and in the Examples.

The azetidinones of formula 3 can be obtained using the methods described by Katritzki A.R. et al., J. Heterocycl. Chem., 271 (1994) or Dave. P.R., J. Org. Chem., 61, 5453 (1996) and in the examples. The procedure is generally carried out according to the following scheme:

R ⁴

A

hydroxylamin

N- ^OH

R r ⁴

I i B Ý

OH

In these formulas, R ³ and R ⁴ have the same meanings as in formula I and Hal represents a chlorine or bromine atom.

In step A, the process is preferably carried out in an inert solvent such as an aliphatic alcohol having 1 to 4 carbon atoms (e.g. ethanol or methanol), optionally in the presence of an alkali metal hydroxide, at the boiling point of the reaction medium.

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

In Step C, the process is preferably carried out in an inert solvent such as a C 1 -C 4 aliphatic alcohol (e.g. methanol or ethanol) in the presence of sodium bicarbonate at a temperature between 20 ° C and the boiling point of the reaction medium.

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

In Step E, the procedure is carried out according to the method of Grisar M. et al., J. Med. Chem., 885 (1973). A magnesium compound of the brominated derivative is prepared and then reacted with a nitrile in an ether such as ethyl ether at a temperature between 0 ° C and the boiling point of the reaction mixture. After hydrolysis with an alcohol, the intermediate imine compound is reduced in situ with sodium borohydride at a temperature between 0 ° C and the boiling point of the reaction medium.

The R ³ -CO-R ⁴ derivatives are commercially available or can be obtained by application or adaptation of the methods described by Kunder NG et al., J. Chem. Soc. Perkin Trans 1, 2815 (1997); Moreno-Marras

M., Eur. J. . Med. Chem., 23 (5), 477 (1988) ; Skinner a al. , J. Med. Chem. 14 (6) 546 (1971); Hurn N. K. . Tet. Lett. 36 (52) 9453 (1995) ; Medici .A. et al., Tet. Lett. 24 (28) 2901 (1983); The R.D. et al., J, Org. Chem (20) 6921 (1997); Knabe J.

et al., Ar. Pharm., 306 (9) 648 (1973); Consonni R. et al., J. Chem. Soc. Perkin Trans 1, 1809 (1996); FR-96-2481 and JP-94-261393.

The R ³ Br derivatives are commercially available or can be obtained by application or adaptation of the methods described by Brandsma L.

et al . , Synth. Comm. 20 mm (11) 1697 a 3153 (1990); Lemaire M. et al . , Synth. Comm. 24 (1) 95 (1994); Goda H. et al., Synthe- sis, 9, 849 (1992); Baeuerle P. et al ., J. Chem. Soc. Perkin trans 2, 489 (1993). R ⁴ CN derivatives are commercially available or can be prepared

application or adaptation of the methods he described Bouyssou P et al., J. Het. Chem. 29 (4) 895 (1992); Suzuki N. et al., J Chem. Soc. Chem. Comm. 1523 (1984) ; Marburg S. a et al., J. Het Chem 1333 ( 1980); Percc V. a et al., J. Org. Chem. 60 ( '21 6895

Compounds of formula I wherein R is CR ³ R ² wherein R is hydrogen and R is C (R) (R ') (R) wherein R ⁸ is hydrogen, R ⁹ is -CO-NR ²⁶ R ¹⁷ , -COOH, -COOalk, -CH ₂ OH, -NHCOOalk or -NH-CO-NH-alk and R ¹⁰ represents an Ar or Het group can be prepared according to the following reaction scheme:

R ³

Γ \

V + R ¹⁰ -CH, NCOOalk

NOH

COOalk R ^{10 4} A

R'4

r ⁴ A

Ny-COOalk 5 R ¹⁰

NR ³

NR ³

A! E ^x Rio

COOH

N = C = O

R ³ h

NHOalk

NH-COOalk

In these formulas, R ³ , R ⁴ , R ¹⁰ , R ²⁰ and R ²⁷ have the same meaning as in formula (I) and alk is alkyl.

The derivatives of formula 4 are commercially available or can be obtained by esterification of the corresponding acids, optionally in an activated form, such as an acid chloride. The acids are commercially available or can be prepared from the corresponding methylated derivatives according to the method described by J. P. Hansen et al.

J. Heterocycl., 10,711 (1973).

The reaction is usually carried out in an inert solvent such as ether (e.g. tetrahydrofuran) in the presence of a strong base such as tert-butyllithium, n-butyllithium, lithium diisopropylamide or potassium tert-butoxide at a temperature between -70 ° C and -15 ° C.

Reaction b is usually carried out by any dehydration method known to those skilled in the art which allows the dehydration of the alcohol to obtain the corresponding alkene, and in particular by the methods described above.

The reduction c is usually carried out in an inert solvent such as an aliphatic alcohol containing 1-4 carbon atoms such as methanol, a chlorinated solvent such as chloroform, dichloromethane or a mixture of these solvents in the presence of NaBH ₄ , at a temperature between 0 ° C and boiling point. reaction environment.

Reaction d is carried out by any method known to those skilled in the art which allows the ester to be converted to the corresponding acid without affecting the rest of the molecule. The process is preferably carried out in an inert solvent such as dioxane in the presence of hydrochloric acid at the boiling point of the reaction medium.

Reaction e is carried out by any method known to the person skilled in the art which makes it possible to convert the acid or its reactive derivative to carboxamide without affecting the rest of the molecule. Preferably, the reaction is carried out in the presence of a condensing agent that is used in peptide chemistry such as carbodiimide (e.g. N, N'-dicyclohexylcarbodiimide) or N, N'-carbonyldiimidazole in an inert solvent such as ether (e.g. tetrahydrofuran or dioxane), amide (dimethylformamide) or chlorinated solvents (e.g. methylene chloride, 1,2-dichloroethane or chloroform) at a temperature between 0 ° C and the reflux temperature of the reaction mixture. When a reactive acid derivative is used, it is possible to react the anhydride, mixed anhydride or ester (which may be selected from activated or non-activated acid esters); the process is then carried out in an organic environment, optionally in the presence of an acid receptor, such as a nitrogen-containing organic base (e.g., trialkylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene or 1,5-diazabicyclo [4.3. 0] non-5-ene), in a solvent as referred to above or a mixture of these solvents, at a temperature between 0 ° C and the reflux temperature of the reaction mixture or a biphasic, aqueous-organic medium in the presence of an alkaline or alkaline earth base ( sodium hydroxide or potassium hydroxide) or an alkali metal or alkaline earth metal carbonate or bicarbonate at a temperature between 0 and 40 ° C.

Reaction f is carried out by Curtius arrangement, in the presence of diphenylphosphorazide azide and triethylamine, in toluene, at a temperature of about 50 ° C.

Reactions g and h are carried out according to the procedure of step g, at a temperature of about 20 ° C.

Compounds of formula I wherein R is CR ¹ R ² , wherein R ¹ is hydrogen and R ² is -C (R ⁸ ) (R ⁹ ) (R ¹⁰ ), wherein R ⁸ is hydrogen, R ⁹ is -CH ₂ NHR ²⁸ and R ¹⁰ represent Ar or Het may be prepared according to the following reaction scheme:

R ⁴ Jk

N

NHCOR

R ³ * 'A

R ³

NHCONHRf

R ¹⁰ Ik

In these formulas, R ³ , R ⁴ and R ^{10 have the} same meaning as in formula I, R ^d is alkyl or phenyl, R ^e is alkyl, R ^f is alkyl, R ⁹ is alkyl, cycloalkylalkyl, cycloalkyl, - (CH 2) _n OH, n - is 1, 2 or

Third

Step a is usually carried out in an inert solvent such as a C 1 -C 4 aliphatic alcohol (e.g. methanol), a chlorinated solvent (e.g. dichloromethane or dichloroethane), or tetrahydrofuran in the presence of a base such as NaBH (OCOCH ₃ ) ₃ , at about 20 ° C.

Step b is generally carried out in an inert solvent such as a halogenated solvent (e.g. dichloromethane) in the presence of an organic base such as triethylamine or dimethylaminopyridine at a temperature between 0 ° C and the boiling point of the reaction medium.

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

Step d is carried out by any method known to the person skilled in the art which allows the acid or its reactive derivative to be converted to carboxamide without affecting the rest of the molecule and in particular according to the preferred methods described above.

Derivatives 6 can be prepared according to the following reaction scheme:

In these formulas, R ³ , R ⁴ and R ^{10 have the} same meanings as in Formula I and M ⁵ is methylsulfonyloxy.

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

Step b is typically carried out with liquid aqueous ammonia in methanol, in an autoclave, at a temperature of about 60 ° C.

Compounds of formula I wherein R is CR ³ R ²

-CONR ¹³ R ¹⁴ can be prepared wherein R ¹ is a hydrogen atom and R ² is a group according to the following reaction scheme:

R ³

R ³ c

EtOCH ₂ CH ₂ OH

R ⁴

N, CONHR ¹³ R ¹⁴ Im

R ¹³ R ¹⁴ NH

R ⁴ _A

N-a

COOH

In these formulas, R ³ , R ⁴ , R ¹³ and R ^{14 have the} same meanings as in formula I, and M ⁵ is methylsulfonyloxy and Et is ethyl.

Step a is carried out in an inert solvent such as ether (e.g. tetrahydrofuran) in the presence of triethylamine at a temperature of about 0 ° C.

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

Step c is carried out by any method known to those skilled in the art which allows the cyanate compound to be converted to the corresponding acid without affecting the rest of the molecule. The process is preferably carried out with potassium hydroxide in an aliphatic alcohol containing 1 to 4 carbon atoms (such as ethanol) or in an aqueous medium at the boiling point of the reaction medium.

Step d is carried out by any method known to those skilled in the art which allows the acid or reactive derivative thereof to be converted to carboxamide without affecting the rest of the molecule and in particular according to the preferred methods described above.

Compounds of formula I for which R is CR ^{1 -} R ² , where R ¹ is hydrogen and R ² is -CH ₂ -CONR ¹³ R ¹⁴ may be prepared according to the following scheme:

COOC ₂ H ₅

NR ¹³ R ¹⁴ NH

NIn \ ^ CONR ¹³ D ¹⁴ d

COOH

In these formulas, R ³ , R ⁴ , R ¹³ and R ¹⁴ have the same meanings as in Formula I and Et is ethyl.

The reaction a is usually carried out in an inert solvent such as tetrahydrofuran in the presence of a base such as sodium hydride or an alkali metal carbonate (e.g. potassium carbonate) at a temperature between 20 ° C and the boiling point of the reaction medium.

Reaction b is usually carried out with NaBH ₄ in ethanol, at a temperature of about 0 ° C.

Reaction c is carried out by any method known to those skilled in the art which allows the ester to be converted to the corresponding acid without affecting the rest of the molecule. The process is preferably carried out in an inert solvent such as dioxane in the presence of hydrochloric acid at the boiling point of the reaction medium.

Reaction d is carried out by any method known to those skilled in the art which allows the acid or its reactive derivative to be converted to carboxamide without affecting the rest of the molecule and in particular according to the preferred methods described above.

Intermediate 7 can also be obtained by malonic synthesis according to the following reaction scheme:

R ⁴

OMs

R ³

N - \ COOH

In these formulas, Ms is methylsulfonyloxy, R ³ and R ⁴ have the same meanings as in formula I.

The reactions are generally carried out by treatment with diethyl malonate in an inert solvent such as tetrahydrofuran in the presence of freshly prepared sodium ethoxide at the boiling point of the reaction medium.

Reaction b is conveniently carried out in aqueous hydrochloric acid at the boiling point of the reaction medium.

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

HNR ¹³ R ”

PO (OC ₂ H ₅ ) _{2 -} CH ₂ COOH - PO (OC ₂ H,) _{2 -} CH ₇ CONR ¹³ R ¹⁴

R ³

R ⁴

NR ³

R ⁴ .

NNIn \ ^ / CONR ¹³ R ¹⁴

13rj 14 \ CONR ¹³ R

In these formulas, R ³ , R ⁴ , R ¹³ and R ^{14 have the} same meanings as in formula I.

Step a is carried out by any method known to the person skilled in the art, which makes it possible to convert the acid or its reactive derivative into carboxamide without affecting the rest of the molecule and in particular by the preferred methods described above.

Step b is usually carried out in an inert solvent such as tetrahydrofuran in the presence of a base such as sodium hydride or potassium carbonate at a temperature between 20 ° C and the boiling point of the reaction medium.

The reduction in step c is usually carried out with NaBH ₄ in ethanol at a temperature of about 20 ° C.

Compounds of formula I wherein R is CR ³ R ² , wherein R ¹ is hydrogen and R ² is -SOR ⁶ or -SO ₂ R ⁶ may be prepared according to the following reaction scheme:

In these formulas, R ³ , R ⁴ and R ^{6 have the} same meaning as in formula I and M ⁵ is methylsulfonyloxy.

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

Step b is usually carried out by any known method that allows the oxidation of the sulfur-containing derivative, such as those described by M. Hudlicky, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, the process is carried out by treatment with an organic peroxyacid or a salt such as a peroxyacid (peroxycarboxylic or peroxy sulfonic acid, in particular peroxybenzoic acid, 3-chloroperoxybenzoic acid,

4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, peroxy formic acid or monoperoxyphthalic acid) or an inorganic peroxyacid or salt of such an acid (such as periodic acid or persulphic acid) in an inert solvent such as a chlorinated solvent (such as chloroform or dichloromethane), a temperature between 0 and 25 ° C or alternatively an oxone in a mixture of water and alcohol (methanol or ethanol).

Step c is usually carried out by any known method which allows oxidation of the sulfinyl derivative. Preferably, the process is carried out by treatment with an organic peroxyacid or salt, such as peroxycarboxylic or persulfonic acid, in particular peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, peroxy formic acid or monoperoxyphthalic acid) alcohol (methanol or ethanol).

The compounds of formula I, wherein R is CR ² R ^T wherein R ¹ is a hydrogen atom and R ² represents a radical -COR ⁶ or -CO-cycloalkyl can be prepared by the following reaction scheme:

R ⁴ rx • Λ

NH CHNOCH.

COOH

R ⁴

In these formulas, R ³ and R ^{4 have the} same

CON _{(CH3) OCH3} RhMgBr lq

CORh as defined in formula I and Rh has the same meaning as R ⁶ or represents a cycloalkyl group containing 3 to 10 carbon atoms.

Step A is carried out by any method known to the person skilled in the art, which allows the acid or its reactive derivative to be converted to the carboxamide without. the remainder of the molecule has been treated and in particular by the preferred methods described above.

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

Compounds of formula I wherein R ¹ is hydrogen and R ² is -C (OH) (R ⁶ ) (R ¹² ), -C (OH) (R ⁶ ) (alkyl), -C (= NO-CH) ? -CH = CH ₂ ) R ⁶ or -C (= NOalk) R ⁶ may be prepared according to the following reaction scheme:

In these formulas, R ³ , R ⁴ and R ^{6 have the} same meanings as in formula I, R ¹ has the same meaning as R ¹² or is a straight or branched chain alkyl group having 1 to 6 carbon atoms and R ^j is an alkyl group having 1 to 6 carbon atoms. Straight or branched chain or group

-ch ₂ -ch = ch ₂ .

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

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

2

Compounds of formula I wherein R is CRR,

9 6 3132 wherein R is hydrogen and R is -CH (R) NR R wherein R ³¹ and R ³² are hydrogen or -CH (R ⁶ ) NHSO ₂ alk, -CH (R ⁶ ) NHCONHalk or - CH (R ⁶ ) NHCOR ³¹ , can be prepared according to the following reaction scheme:

R ⁶

In these formulas, R ³ , R ⁴ , R ⁶ and R ^{31 have the} same meanings as in formula (I ⁾ , M ⁵ is methylsulfonyloxy and alk is alkyl.

Reaction a is usually carried out with NaBH ₄ in ethanol, at a temperature of about 20 ° C.

Step b is carried out in the presence of triethylamine, in an inert solvent such as ether (e.g. tetrahydrofuran) at a temperature of about 0 ° C.

Step c is carried out with liquid aqueous ammonia in methanol, autoclaved at a temperature of about 60 ° C.

Step d is carried out in an inert solvent such as a halogenated solvent (e.g. dichloromethane) or tetrahydrofuran in the presence of an organic base such as triethylamine, dimethylaminopyridine at a temperature of about 20 ° C.

Step e is carried out by any method known to the person skilled in the art which makes it possible to convert the acid or its reactive derivative into carboxamide without affecting the rest of the molecule and in particular by the preferred methods described above.

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

Compounds of formula I wherein R is CR ³ R ² wherein R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³ R ³¹ is hydrogen and R ³² is alkyl, Ar or - an alk-Ar group can be prepared by treating a compound of formula I with HalR ³¹ where R is CR ³ R ² in which R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² wherein R ³¹ and R ³² are hydrogen atoms.

This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide in the presence of an organic or inorganic base (alkali metal carbonate (e.g. sodium or potassium), trialkylamine (e.g. triethylamine or dimethylaminopyridine)) at a temperature between 0 ° C and the boiling point of the solvent, optionally in the presence of palladium or complexes thereof.

Compounds of formula I wherein R is CR ¹ R ² in which R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ is hydrogen and R ³² is alkyl may be prepared by treating a corresponding compound of formula I wherein R is CR ¹ R ² , where R ¹ is hydrogen and R ² is -CO-R ^6, to the amine HNR ³¹ R ³² , wherein R ³¹ is hydrogen and R ³² is alkyl group.

This reaction is usually carried out in an inert solvent such as a chlorinated solvent (e.g. dichloromethane or dichloroethane) in the presence of a reducing agent such as sodium triacetoxyborohydride at a temperature between 0 ° C and 70 ° C.

Compounds of formula I wherein R is CR ³ R ² in which R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ and R ³² are alkyl, Ar or -alk- The Ar group may be prepared by treatment with a HalR ³² halide on a compound of formula I wherein R is CR ³ R ² in which R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ^{3 ±} R ³² wherein R ³¹ is hydrogen and R ³² is alkyl, Ar or -alk-Ar.

This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide in the presence of an organic or inorganic base (alkali metal carbonate (e.g. sodium or potassium), trialkylamine (e.g. triethylamine or dimethylaminopyridine)) at a temperature between 0 ° C and the boiling point of the solvent, optionally in the presence of palladium or complexes thereof.

Compounds of formula I wherein R is CR ³ R ² in which R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ is hydrogen and R ³² is alkyl of 2 to 6 carbon atoms or a (C 2 -C 6) alkylaryl group may be prepared by the action of an aldehyde R ^and CHO where R ^a is alkyl or -alk-Ar for a compound of formula I for which R is CR ^X R ² , wherein R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ and R ³² are hydrogen atoms.

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

Compounds of formula (I) wherein R is CR ^X R ² in which R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ is alkyl, Ar or -alk-Ar and R 2 ³² is an alkyl of 2 to 6 carbon atoms or an alkylaryl group of 2 to 6 carbon atoms in the alkyl moiety, may be prepared by treatment with an aldehyde R ^and CHO where R ^a is alkyl or -alk-Ar for a compound of formula I for which R R ^{@ 1} is CR ^{@ 1} R ^{@ 2} , wherein R ^{@ 1} is hydrogen and R @ ² is --CH (R @ ⁶ ) NR @ ³¹ R @ ³² , R @ ³¹ is hydrogen and R @ ³² is alkyl, Ar or --alk - Ar.

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

Compounds of formula I wherein R is CR ^X R ² in which R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³ 'and R ³² form with the nitrogen to which they are a bonded, heterocycle, selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl, can be prepared by treating a compound of formula I wherein R is CR ^X R ² , where R is a halogen- (2-5C) alk-Hal dihalide ¹ is a hydrogen atom and R ² represents a radical -CH ^(R) NR ³¹ R ³² wherein R ³¹ and R ³² are hydrogen.

This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide in the presence of an organic or inorganic base (alkali metal carbonate (e.g. sodium or potassium), trialkylamine (e.g. triethylamine or dimethylaminopyridine)) at a temperature between 0 ° C and the boiling point of the solvent, optionally in the presence of palladium or complexes thereof.

The compounds of formula I, wherein R ^ is CR ^2, wherein R ¹ is a hydrogen atom and R ² represents a radical -CH 2 -COR ^6, -CH 2 -CH (R ⁶⁾ NR ³¹ R ³² or -CH ₂ C (= NOalk) R ^e can be prepared according to the following reaction scheme:

_r 4 __ \ PO (OC ₂ H ₅ ) ₂ -CH ₂ CON (CH ₃ ) OCH _{3 r}

N 1 -CO-N (CH ₃ ) OCH ₃

N ₀ h ₃ chnoch ₃

involving most

X ^ CO-N _{(CH3) OCH3}

R ⁶ MgBr

R

NalkONH.

R

from

NOalk

R ⁶

NIx R

31 _d 32

HNR R

N> 31

N ', 32 iy

In these formulas, R ³ , R ⁴ , R ⁶ , R ³¹ and R ^{32 have the} same meanings as in formula I and alk is any alkyl group.

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

Step b is usually carried out in an inert medium such as an aliphatic alcohol (e.g. methanol), a chlorinated solvent (chloroform or dichloromethane) or a mixture of these solvents, in the presence of a reducing agent such as NaBH ₄ , at a temperature between 0 ° C and boiling point. environment.

Step c is carried out by any method known to the person skilled in the art which allows the acid or its reactive derivative to be converted to carboxamide without affecting the rest of the molecule and in particular by the suitable methods described above.

Step d is usually carried out in an inert solvent such as an ether such as tetrahydrofuran at a temperature of about 0 ° C. The organomagnesium compounds are prepared according to methods known to those skilled in the art, such as those described in the examples.

Step e is usually carried out in an inert solvent, such as a C 1 -C 4 aliphatic alcohol, in the presence of sodium acetate, at a temperature between 20 ° C and the boiling point of the reaction medium.

Step f is carried out in an inert solvent such as a chlorinated solvent (e.g. dichloromethane or dichloroethane), in the presence of a reducing agent such as. is sodium triacetoxyborohydride, at a temperature between 0 ° C and 70 ° C.

Compounds of formula (I) wherein R is CR R, wherein R ¹ is cyano, -S-alk-NR ¹⁶ R ¹⁷ , -NHR ¹⁵ , alkyl or -NR ' ^C ' R ²¹ and R ² is -C (R ⁸ ) (R ¹¹ ) (R ^X U, where R ⁸ is a hydrogen atom, may be prepared according to the following reaction scheme:

R ³

NR ²⁰ R ^{21 lzd} alk

In these formulas, R ^3, R ^4, R ^u, R ^12, R ^15, R ¹⁶ and R ¹⁷ have the same meanings as in formula I, alk represents an alkyl radical, Hal is a halogen, and M is a metal, preferably copper.

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

Step b is preferably carried out in an inert solvent such as dimethylsulfoxide, tetrahydrofuran or acetonitrile in the presence of a base such as an alkali metal carbonate (e.g. potassium carbonate) or ammonium hydroxide at a temperature between 20 ° C and the boiling point of the reaction medium.

Step c is preferably carried out in an inert solvent such as dimethylsulfoxide, tetrahydrofuran or acetonitrile, in the presence of a base such as an alkali metal carbonate (e.g. potassium carbonate) or ammonium hydroxide, at a temperature between 20 ° C and the boiling point of the reaction medium.

Step d is preferably carried out in an inert solvent such as ether (ethyl ether) or tetrahydrofuran at a temperature between -78 ° C and 20 ° C.

Step e is preferably carried out in an inert solvent such as dimethylsulfoxide, tetrahydrofuran, acetonitrile, dichloromethane or dichloroethane in the presence of a base such as an alkali metal carbonate (e.g. potassium carbonate) or ammonium hydroxide at a temperature between 20 ° C and the boiling temperature of the reaction medium .

Compounds of formula I wherein R is CR ^ ² in which R ^{@ 1} is -alk-NR @ ¹⁸ R @ ¹⁹ , R @ ¹⁸ and R @ ¹⁹ are hydrogen may be prepared by reduction of the corresponding compound of formula I wherein R @ 1 is CR ^X R ² in which R ¹ represents a cyano group.

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

Compounds of formula (I) wherein R is CR ^ ² , wherein R ^{@ 1} is -alk-NR @ ¹⁸ R @ ¹⁹ , R @ ¹⁸ is hydrogen and R @ ¹⁹ is cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, --SC2 alk, A -CO-NHalk or -COOalk group, may be prepared by treating a compound of formula I wherein R 1 is halogenated with HalR ¹⁹ where Hal is a halogen atom

Q is CR R, wherein R is -alk-NR R, where R ¹⁸ and R ¹⁹ are hydrogen.

This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide in the presence of an organic or inorganic base (alkali metal carbonate (e.g. sodium or potassium), trialkylamine (e.g. triethylamine or dimethylaminopyridine)) at a temperature between 0 ° C and the boiling point of the solvent, optionally in the presence of palladium or complexes thereof.

The compounds of formula I, wherein R is CR ^{R 2} wherein R ¹ represents an -alk-NR ^s R ^19, R ¹⁸ is alkyl and R ¹⁹ is a cycloalkyl group, a cykloaikylalkylovú group, cycloalkylcarbonyl, -SO2alk, - A CO-NHalk or -COOalk group may be prepared by treatment of an alkyl halide with a compound of formula (I) wherein R is CR ¹ R ² , wherein R ¹ is -alk-NR ¹⁸ R ¹⁹ , where R ¹⁸ is hydrogen and R ¹⁹ is a cycloalkyl group, a cykloaikylalkylovú group, cycloalkylcarbonyl, -SO2alk, -CO-NHalk or -COOalk radical.

This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide in the presence of an organic or inorganic base (alkali metal carbonate (e.g. sodium or potassium), trialkylamine (e.g. triethylamine or dimethylaminopyridine)) at a temperature between 0 ° C and the boiling point of the solvent, optionally in the presence of palladium or complexes thereof.

Compounds of formula (I) wherein R is CR ^: R ² , wherein R ¹ is hydrogen and R ² is -C (R ⁸ ) (R ⁹ ) (R ¹⁰ ) or -C (R ⁸ ) (R ¹¹⁾ (R ¹² ) or R ¹ is alkyl, NH-R ¹⁵ , cyano, -S-alk-NR ¹⁶ R ¹⁷ , -alk-NR ¹⁸ R ¹⁹ or -NR ²⁰ R ²¹ and R ² is -C (R ⁸⁾ (R ¹¹⁾ (R ¹²⁾ and R ⁸ is alkyl may be prepared by alkylating a corresponding compound of formula I, wherein R ⁸ is a hydrogen atom.

This reaction is preferably carried out with a base such as an alkali metal hydride (e.g. sodium hydride), an alkali metal amide (e.g. sodium amide) or an organometallic derivative in an inert solvent such as an aliphatic ether (ethyl ether) or tetrahydrofuran at a temperature between -78 ° C and 30 ° C, an alkylating agent such as an alkyl halide or an alkyl sulfonate.

Compounds of formula I wherein R is -C =C (R) SO ₂ alk may also be prepared according to the following reaction scheme:

a) n-BuLi

R ⁷ -CH ₂ -PO ₃ Et ₂ ^{—Sfl 1}

c) Hal-alk

A

R ³

In these formulas, R ³ , R ^4, and formula I, alk is a halogen atom.

⁷ have the same meanings as in the alkyl group and Hal represents

Reaction A is usually carried out in an inert solvent such as an ether (e.g. ethyl ether) in the presence of a strong base such as tert-butyllithium or n-butyllithium at a temperature between -70 ° C and -50 ° C and then sulfur addition and then an alkyl halide (e.g. iodide or bromide).

Reaction B is usually carried out in an inert solvent such as ether (e.g. tetrahydrofuran) in the presence of a strong base such as tert-butyllithium or n-butyllithium at a temperature between -70 ° C and -50 ° C, followed by the addition of azetidine- 3-one and adjusting the temperature to room temperature and hydrolysis.

Reaction C is carried out by any known method in which a sulfur-containing derivative is oxidized without affecting the remainder of the molecule as described above.

It will be appreciated that one skilled in the art may need to introduce amino, hydroxyl or carboxyl protecting groups when carrying out the present invention in order to avoid side reactions. These groups are those that can be removed without affecting the rest of the molecule. Examples of such amino-protecting groups are tert-butyl or methylcarbamates which can be regenerated using iodotrimethylsilane or allyl using. of palladium catalysts. Examples of hydroxyl protecting groups include triethylsilyl and tert-butyldimethylsilyl, which can be regenerated using tetrabutylammonium fluoride or alternatively asymmetric acetals (e.g., methoxymethyl or tetrahydropyranyl), which are regenerated using hydrochloric acid. Carboxyl protecting groups include esters (e.g., allyl or benzyl), oxazoles, and the like.

2-alkyl-l, 3-oxazolines. Other protecting groups that may be used are described in Greene T.W. et al., Protective Groups in Organic Synthesis, 2nd Edition, 1991, John Wiley & Sons.

The compounds of the formula I can be purified by methods known per se, for example by crystallization, chromatography or extraction.

The enantiomers of the compounds of formula I may be obtained by resolution of the racemates, for example by chiral column chromatography according to Pirckle W.H. et al., Asymmetry Synthesis, Volume 1, Academic Press (1983) or by salt formation or by synthesis of chiral precursors. Diastereoisomers can be prepared according to known conventional methods (crystallization, chromatography or chiral precursors).

The compounds of formula (I) may optionally be converted to addition salts with an inorganic or organic acid by treatment with 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.

Examples of pharmaceutically acceptable salts include: benzenesulfonate, bromide, chloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene-bis-p-oxynaphthate, nitrate, oxalate, pamoate, phosphate, salicylate succinate, sulfate, tartrate, theophylline acetate and p-toluenesulfonate.

The compounds of formula I exhibit advantageous pharmaceutical properties. These compounds show a high affinity for cannabinoid receptors, in particular of the CB1 type. They are CB1 receptor antagonists and are therefore useful in the treatment and prevention of diseases affecting the central nervous system, immune system, cardiovascular and endocrine system, respiratory system, gastrointestinal organs and reproductive diseases (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. Ed. CRC Press, 1992).

The compounds of the invention can be used for the treatment or prevention of psychoses, including schizophrenia, anxiety, depression, epilepsy, neurodegeneration, cerebral and spinocerebral diseases, cognitive diseases, cranial trauma, panic attack, peripheral neuropathy, glaucoma, Alzheimer, Parkinson's disease. Huntington's chorea, Raynaud's syndrome, tremor, obsessive-compulsive disease, senile dementia, thymus disease, Tourette's syndrome, tardive discinesis, bipolar diseases, cancers, drug-induced movement disorders, dystonia, endotoxic shock, insensitivity, hypotension, haemorrhagia, haemorrhagia multiple sclerosis, vomiting, taste-related diseases (bulimia, anorexia), obesity, memory disorders, drug, alcohol or drug addiction (eg opiates, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogen, benzodiazepine) o analgesics or potentiators of analgesic activity of narcotic and non-narcotic drugs. They can also be used to treat or prevent diseases of the intestinal tract.

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

In this assay, the IC _{50 of the} compounds of Formula I is less than or equal to 1000 nM.

Antagonist activity was shown by a cannabis receptor agonist-induced hypothermia model (CP-55940) in mice according to the method described by Pertwee R.G. in Marijuana, Harvey D.J. ed., 84 Oxford IRL Press, 263-277 (1985).

As used herein, the DE 50 of the compounds of Formula I is less than or equal to 50 mg / kg.

The compounds of formula I exhibit low toxicity. Their LD50 is greater than 40 mg / kg by the subcutaneous route of administration in mice.

Preferred compounds are the following:

Preferred compounds of formula I are as follows:

(RS) -1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) - (methylsulfonyl) methyl] azetidine, (R) -1- [bis (4-chlorophenyl) methyl )] - 3 - [(3,5-difluorophenyl) - (methylsulfonyl) methyl] azetidine, (S) -1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) - ( methylsulfonyl) methyl] azetidine, (RS) -1- [bis (4-chlorophenyl) methyl)] - 3 - [(pyrid-3-yl) - (methylsulfonyl) methyl] azetidine, (R) -1- [bis ( 4-chlorophenyl) methyl)] - 3 - [(pyrid-3-yl) - (methylsulfonyl) methyl] azetidine, (S) -1- [bis (4-chlorophenyl) methyl)] - 3 - [(pyrid-3) -yl) - (methylsulfonyl) methyl] azetidine, (RS) -1- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (R) -1- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (S) -1- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] azetidine,

1- [bis (4-chlorophenyl) methyl] -3- (RS) - ([3-azetetidin-1-yl-phenyl] methylsulfonylmethyl [azetidine,

1- [Bis (4-chlorophenyl) methyl] -3- (R) - {[3-azetidin-l-yl-phenyl] methylsulfonylmethyl} azetidine,

1- [bis (4-chlorophenyl) methyl] -3- (S) - {[3-azetidin-1-ylphenyl] methylsulfonylmethyl} azetidine, (RS) -1- [3 - ((1- [bis (4- Chlorophenyl) methyl] azetidin-3-yl} -methylsulfonylmethyl) phenyl] pyrrolidine, (R) -1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -methylsulfonylmethyl) phenyl (S) -1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] pyrrolidine, (RS) -N- [3 - ((1) - [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] -N-methylamine, (R) -N- [3 - ({1- [bis (4-chlorophenyl) methyl]] azetidin-3-yl} methylsulfonylmethyl) phenyl] -N-methylamine, (S) -N- [3 - ((1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] -N- methylamine, (RS) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-bistrifluoromethylphenyl) methylsulfonylmethyl] azetidine, (R) -1- [bis (4-chlorophenyl) methyl] -3- [(3,5-bistrifluoromethylphenyl) methylsulfonylmethyl] azetidine, (S) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-bistrifluoromethylphenyl) methylsulfonylmethyl] azetidine,

1- [bis (4-chlorophenyl) methyl] -3- (phenylsulfonylmethyl) azetidine, (RS) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] -3 -methyl azetidine, (R) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] -3-methylazetidine, (S) -1- [bis (4-chlorophenyl) methyl] ] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] -3-methylazetidine, (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3, 4-chlorophenyl) methyl] 5-Difluorophenyl) -N-cyclohexylacetamide, (R) -2- {1- [bis (4-chlorophenyl) methyl] azeditin-3-yl} -2- (3,5-difluorophenyl) -N-cyclohexylacetamide, ( S) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluoro-45 phenyl) -N-cyclohexylacetamide, (RS) -2- {1- [bis (4-Chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-isobutylacetamide, (R) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3- yl} -2- (3,5-difluorophenyl) -N-isobutylacetamide, (S) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cycloprop) -N-isobutylacetamide (R) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclopropylmethylacetamide, (S) -2- {1- bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) -N-cyclopropylmethylacetamide, (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3 -yl} -2- (3,5-difluorophenyl) -N-isopropylacetamide, (R) -2- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5- (S) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-isopropylacetamide, (RS) -1- [bis (4-chlorophenyl) methyl] -3- [1- (3,5-difluorophenyl) -1-methylsulfonylethyl] azetidine, (R) -1- [bis (4-chlorophenyl) methyl] -3- [1- (3,5-difluorophenyl) -1-methylsulfonylethyl] azetidine, (S) -1- [bis (4-chlorophenyl) methyl] -3- [1- (3,5-difluorophenyl) -1-methylsulfonylethyl ] azetidine, (RS) -1- [bis (4-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (R) -1- [bis ( 4-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (S) -1- [bis (4-fluorophenyl) methyl] -3 - [(3 (5-difluorophenyl) methylsulfonylmethyl] azetidine, (RS) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (SS) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (RR) - {1 - [(3-pyridyl) - (4-chlorophenyl) (methyl) -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (SR) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (RS) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (SS) - {1 - [(4 -pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (RR) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3- [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (SR) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (RS) ) - 5 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-1-yl} methyl) pyrimidine, (SR) -5 - ((4-chlorophenyl) - {3- [(3,5-difluorophenyl) metylsulfonylme (R) -5 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-1-yl} methyl) pyrimidine;

I (SS) -5 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-1-yl} methyl) pyrimidine, (SS) - {1 - [(2-chloropyrid- 5-yl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (RR) - (1 - [(2-chloropyrid-5-yl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (RS) - {1 - [(2-chloropyrid-5-yl) - (4-chlorophenyl) methyl] -3 - [(3,5 (SR) - (1 - [(2-chloropyrid-5-yl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, their optical isomers and pharmaceutically acceptable salts thereof.

The following examples illustrate the present invention:

DETAILED DESCRIPTION OF THE INVENTION

Example 1 (RS) -1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonylmethyl) azetidine can be prepared from 1.0 g of 1- [bis (4-chlorophenyl) methyl] 1] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine in 40 cm ^{3 of} methanol to which 96 mg of sodium borohydride is added and the mixture is stirred at 20 ° C for 3 hours. 100 cm ^{3 of} dichloromethane are then added, the reaction mixture is washed twice with 50 cm ^{3 of} water and dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The crude product is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 6 cm, diameter 3 cm, eluting under an argon pressure of 0.08 MPa with dichloromethane and then with a mixture of dichloromethane + 1% methanol and 80 cm ³ fractions collected. Combine 13 to 15 and concentrate to dryness under reduced pressure (2.7 kPa) to give 0.55 g of a white solid which is taken up in 50 cm ^{3 of} diisopropyl ether, filtered and dried to give 0.47 g (RS) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine as a white solid pH NMR spectrum (400 MHz, (CD ₃ )) ₂ SO d6 with the addition of a few drops of CD3COOD d4, at a temperature of 353 K, δ in ppm): 2,46 (t, J = 7,5 Hz:

1H); 2.77 (s 3H); 3.15 (mt 2H); 3.40 (mt 1H); 3.49 (broad t, J 7.5 Hz 1H); 4.46 (s 1H); 4.81 (d, J = 9Hz, 1H); from 7.05 to 7.20 (mt 3H); from 7.15 to 7.45 (mt 8H)].

1- [Bis (4-chlorophenyl) methyl]] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine can be prepared according to two methods:

Method 1

0.65 cm ^{3 of} methylsulfonyl chloride is added to the solution of 2.94 g

1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl (RS)] azetidin-3-ol in 250 cm ^{3 of} dichloromethane at 22 ° C and then added 2.42 g of 4-dimethylaminopyridine in small portions over 15 minutes; the orange solution was stirred at room temperature for 2 hours. The reaction mixture is washed three times with 150 cm ^{3 of} distilled water and once with 150 cm ^{3 of} saturated sodium chloride solution, then dried over magnesium sulfate, filtered and 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 5.5 cm, height 15 cm) under argon pressure.

0.05 MPa, with a mixture of ethyl acetate and cyclohexane (1/9, v / v) as eluent, and 70 cm ³ fractions are collected. Fractions 16 to 36 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.86 g of white foam is obtained, which crystallizes from isopropyl ether to give a solid, melting at 190 ° C. Recrystallization from 45 cm ^{3 of} ethanol gives 1.08 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine melting at 206 ° C [NMR spectrum in DMSO-d6, T = 300K, δ in ppm (300 MHz): 3.00 (3H, s, _SCH3), 3.87 (2H, s, _NCH2), 4.20 (2H, s, NCH ₂ ), 4.75 (1H, s, NCH), 7.15 (2H, d, J = 8Hz, 2CH aromatic), 7.30 (5H, m, 5CH aromatic), 7.45 (4H, d) , J = 7Hz, 4CH arom.)].

6.75 g of 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol hydrochloride is added to a solution of 6.8 g of bis (4-chlorophenyl) bromomethane in 300 cm ^{3 of} acetonitrile and then 2.97 g of potassium carbonate are added. The reaction mixture was heated at reflux for 1 hour, cooled to room temperature, filtered and 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 8.5 cm, height 22 cm) under an argon pressure of 0.05 MPa, with a mixture of ethyl acetate and cyclohexane (25/75 by volume) as eluent. and 250 cm ³ fractions are collected. Fractions 11 to 48 are combined and then evaporated to dryness under reduced pressure. 5.3 g are obtained

1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl) methyl (RS)] azetidin-3-ol. ¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 2.00 (s: 3H); 2.94 (s 3H); 3.25 (mt 2H); 3.48 (d, J = 9 Hz 1H); 3.80 (d, J = 9Hz, 1H); 4.54 (s 1H); 5.34 (s 1H); 7.15 '(d, J = 8.5Hz: 2H); from 7.20 to 7.40 (mt 8H);

7.50 (broad t, J 9 Hz 1H)].

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

3 - [(3,5-Difluorophenyl) methylsulfonyl) methyl - (RS)] azetidin-3-ol hydrochloride can be obtained as follows: 160 cm ³

A 6.2 N solution of hydrochloric acid in dioxane is 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 was concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 320 cm ^{3 of} ethanol, the mixture is heated under reflux for 1 hour and cooled in an ice bath. The solid is filtered off, washed with ethyl acetate and dried at 40 ° C under reduced pressure (2.7 kPa). It will be obtained

29.85 g of white crystals having a melting point greater than 260 ° C.

3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] - 1- (vinyloxycarbonyl) azetidin-3-ol can be obtained as follows: a solution of 14 cm ^{3 of} vinyl chloroformate in 35 cm ^{3 of} dichloromethane is added at 5 ° C to a solution of 60.18 g of 1-benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol in 100 cm ^{3 of} dichloromethane. After 20 hours at room temperature, the reaction mixture is 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 11 cm, height 32 cm), under an argon pressure of 0.05 MPa, with a mixture of ethyl acetate and cyclohexane (3/7 by volume) as eluent. and 1000 cm ³ fractions are collected. Fractions 8 to 18 are combined and concentrated under reduced pressure (2.7 kPa). 37 g of 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] - 1- (vinyloxycarbonyl) azetidin-3-ol are obtained in the form of white crystals, melting at 195 ° C.

1-Benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl (RS)] azetidin-3-ol can be obtained as follows: 29 cm < 3 > of N-butyllithium in hexane is added to solution 6 73 cm ^{3 of} diisopropylamine in 110 cm ^{3 of} tetrahydrofuran under argon and the mixture is cooled to -70 ° C. After 30 minutes, a mixture of 8.7 g of 3,5-difluorobenzylmethylsulfone in 200 cm ^{3 of} tetrahydrofuran is added and stirring is maintained at -70 ° C for 45 minutes. 10 g of 1-benzhydrylazetidin-3-one dissolved in 60 cm @ ^{3 of} tetrahydrofuran are then added and the mixture is stirred for 20 minutes while the temperature returns to room temperature. The reaction mixture is hydrolyzed with 400 cm ^{3 of} saturated ammonium chloride solution, extracted with dichloromethane, washed 3 times with 500 cm ^{3 of} water and then with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue (19 g) was taken up in isopropyl ether and allowed to crystallize.

After filtration and drying, 15.35 g of 1-benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol is obtained in the form of white crystals.

1-Benzhydrylazetidin-3-one can be prepared according to the method described by Katritzky A. R. et al. in J. Heterocycl. Chem., 271 (1994).

3.5-Difluorobenzylmethylsulfone may be prepared as follows: starting from 33.46 g of 3,5-difluorobenzylmethylsulfide in 318 cm ^{3 of} water, 318 cm ³ of acetic acid and 318 cm ^{3 of} ethanol and at 5 ° C add 129.9 g of oxone ^R . After 16 hours at room temperature, the reaction mixture is diluted with dichloromethane, washed with water and saturated sodium chloride solution, dried and filtered, and concentrated to dryness under reduced pressure (2.7 kPa) to give

35.57 g of 3,5-difluorobenzylmethylsulfone, as white crystals, m.p. 135 ° C.

3,5-Difluorobenzylmethylsulfide can be prepared as follows: starting from 40 g of 3,5-difluorobenzyl bromide and 16.25 g of sodium methylthiolate in DMF at 60 ° C. 33.46 g of 3,5-difluorobenzylmethylsulfide are obtained in the form of a yellow oil.

Method 2

0.80 g of crushed sodium hydroxide is added to the solution of 2.2 g

3-acetoxy-1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (R)] 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. After settling, the mixture is separated, the organic phase is washed with 100 cm ^{3 of} water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The white foam obtained is crystallized from isopropyl ether to give 0.85 g of a solid, melting at 190 ° C. Crystallization from 20 cm ^{3 of} ethanol gives 0.70 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine melting at 205 ° C.

cm ^{3 of a} 1.6 N solution of n-butyllithium in hexane is added at 70 ° C to a solution of 4.77 g of (3,5-difluorobenzyl) methylsulfone in 70 cm ^{3 of} tetrahydrofuran under argon. After 1 hour at -70 ° C, a solution of 6.8 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one in 30 cm ^{3 of} tetrahydrofuran is added, and after 1 hour a solution of 2.34 cm ^{3 of} acetylchioride in 20 cm ^{3 of} tetrahydrofuran and the temperature of the reaction mixture is raised to 20 ° C for 1 hour. 50 cm ^{3 of} water and 200 cm ^{3 of} ethyl acetate are added. The mixture is separated after settling and the organic phase is washed with 100 cm ^{3 of} water, 100 cm ^{3 of} saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 14.4 g of 3-acetoxy-1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylsulfonylmethyl- (RS)] azetidine are obtained as a yellow oil [ ³ H NMR spectrum (400 MHz, CDCl ₃ , δ in ppm): 2.79 (s: 3H); 3.04 (AB, J = 9Hz, 2H); 3.27 (d, J = 9 Hz: 1H); 3.45 (s: 1H); 3.81 (d, J = 9Hz, 1H); 4.32 (s 1H); 4.49 (s 1H); 6.88 (tt, J 9 and 2.5 Hz); from

7.20 to 7.35 (mt 10H)].

1- [Bis (4-chlorophenyl) methyl] azetidin-3-one can be prepared as follows: 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 75 cm ³ of dichloromethane cooled to -78 ° C. After 0.5 h, a solution of 16.0 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol dissolved in 50 cm ^{3 of} dichloromethane is added at -78 ° C. After 5 hours at -78 ° C, 26.6 cm ^{3 of} triethylamine are added dropwise and the temperature of the reaction mixture returns to room temperature. After 16 hours the reaction mixture is washed 4 times with 200 cm ^{3 of} water and then with 2 to 0 cm ^{3 of} 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 9.2 cm, height 21 cm), eluting under an argon pressure of 0.05 MPa with a mixture of ethyl acetate and cyclohexane (40/60 by volume) as eluent. and 200 cm ³ fractions are collected. Fractions 15 to 25 are combined and concentrated under reduced pressure (2.7 kPa). 8.9 g of 1-bis (4-chlorophenyl) methyl] azetidin-3-one are obtained in the form of yellow crystals melting at 111 ° C.

1- [Bis (4-chlorophenyl) methyl] azetidin-3-ol can be prepared according to the procedure described by Katritzky AR et al., J. Heterocycl. Chem., (1994), 271, starting from 35.5 g of [bis (4-chlorophenyl) methyl] amine hydrochloride and 11.0 cm ^{3 of} epichlorohydrin. 9.0 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol are isolated.

[Bis (4-chlorophenyl) methyl] amine hydrochloride can be prepared according to the method described by Grisar M. et al., J. Med. Chem., 885 (1973).

Example 2 (-) - 1- [Bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine and (+) - 1- [bis (4-chlorophenyl) methyl)] - 3 - [[(3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine · can be prepared by CLHP separation on a Chiralpak AS chiral column (particle size 20 μπι, column height 23 cm, diameter 6 cm) 0, 52 g of the racemate prepared in Example 1. Elution with heptane / ethanol (90/10) at a flow rate of 80 cm ³ / min. and after concentration of the collected fractions to dryness under reduced pressure (2.7 kPa), 110 mg of (-) - 1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) is obtained Methyl] azetidine [α _D ] = 6.3 ° (C = 0.5 M in methanol) as a white solid, melting at 178 ° C and 134 mg of (+) - 1- [bis (4-chlorophenyl) (methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine [α _D ] = + 5.8 ° (C = 0.5 M in methanol) as a white solid, m.p. 178 ° C.

Example 3

A mixture of 2A diastereomeric forms of 1- [4 - [(R *) - (4-chlorophenyl) - {3- [3,5-difluorophenyl) methylsulfonylmethyl- (R)] azetidin-1-yl} methyl] benzyl] pyrrolidine and 1- [4 - [(R *) - (4-Chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (S)] azetidin-1-yl} methyl] benzyl] pyrrolidone can be prepared as follows - 20 mg of sodium borohydride is added to a solution of 60 mg of 1- (R *) - [4- (4-chlorophenyl) - (3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-ylmethyl) benzyl] pyrrolidone, A isomeric form, in 2 cm ^{3 of} ethanol and 2 cm ^{3 of} dichloromethane. The mixture is stirred at 20 ° C for 20 hours, 0.25 cm ^{3 of} water and 20 cm ^{3 of} dichloromethane are added and the mixture is stirred and dried over magnesium sulphate and then filtered and concentrated to dryness under reduced pressure (2.7 kPa). . The residue is chromatographed on a silica gel column (particle size 0.063 0.200 mm, diameter 1 cm, height 7 cm), eluting under an argon pressure of 0.01 MPa, with dichloromethane and then with a mixture of dichloromethane and methanol (95/5, v / v) and collected 5 cm. ³ fractions. Fractions 13-18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 38 mg of a mixture of 2A diesteromeric forms of 1- [4 - [(F *) - (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (F)] azetidin-1-yl} methyl is obtained. benzyl] pyrrolidine and 1- [4 - [(F *) - (4-chlorophenyl) - (3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (S)] azetidin-1-yl} methyl] benzyl] pyrrolidine as a white foam ^[X H-NMR (400 MHz,

CDC1 ₃ , δ v ppm): 1.77 (mt : 4H) ; from 2.40 up to 2.60 (mt 5H); 2 67 (s: 3H); from 3.10 to 3.25 (mt: 2H); 3.38 (mt 1H); from 3, 50 to 3.70 (mt: 3H); 4.24 (s: 1H); 4.25 (d, J = 11Hz: 1H); 6. 83 (wide t, J = 9 Hz 1H); 6, 94 (mt 2H) from 7.10 to 7, 35 (mt

8H)].

1- (F *) - [4- (4-Chlorophenyl) - (3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl) benzyl] pyrrolidine, isomeric form A, can be prepared as follows : 50 mm ^{3 of} pyrrolidine is added to a solution of 0.32 g of 1 - {(F *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl) -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine, isomeric form A, and 5 mg of sodium iodide in 10 cm ^{3 of} dichloromethane. _{It 'The} mixture was stirred for 20 hours at 20 DEG C., 50 mm of pyrrolidine, and the mixture was stirred for 8 hours and was added over 50 mm of pyrrolidine, and the mixture was stirred at 20 ° C for 20 hours. The reaction mixture is washed with water and then the organic phase is dried over magnesium sulphate and concentrated to dryness under vacuum (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), eluting under an argon pressure of 0.01 MPa with dichloromethane and then with a mixture of dichloromethane and methanol (97.5 / 2.5, v / v) and collecting 3 cm ³ fractions. Fractions 12 to 40 are combined and concentrated to dryness under reduced pressure (2.7 kPa). There was obtained 0.18 g of 1- (R *) - [4- (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulphonylmethylene] azetidin-1-yl} methyl) benzyl] pyrrolidine, isomeric form A , in the form of white foam

[A] ²⁰ 365nm = -22,5 ° +/- 0.7 (c = 0.5%; chloride) ^X H NMR spectrum (300 MHz, CDC1 _3, δ v ppm): 1.78 (mt 4H); 2 51 (mt: 4H) ; 2.81 (with 3H); 3.58 (with : 2H); 3.84 (mt : 2H); 4. 33 (mt: 2H) ; 4.50 (2 : 1H); 6.84 (Tt, J = 9 and 2.5 Hz : 1H); 6. 98 (mt: 2H) ; from 7, 20 up to 7.40 (mt 8H) ] ·

1 - {(R *) - [(4-Chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine, isomeric form A, can be prepared as follows: 12 4 cm ^{3 of} methylsulfonyl chloride is added to a solution of 28.0 g of a mixture of two diastereoisomers (Form A) of 1 - ((R *) - [(4-chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(R) 1- (3,5-Difluorophenyl) methylsulfonylmethyl) azetidin-3-ol a

1 - {(R *) - [(4-chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(S) - (3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ol and 32 g of 4 -dimethylaminopyridine in 500 cm ^{3 of} dichloromethane. The mixture is stirred for one hour at 10 ° C and then for one hour at 20 ° C, the reaction mixture is washed with 500 cm ^{3 of} water, the organic phase is dried over magnesium sulphate 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), eluting under argon at 0.02 MPa with dichloromethane and collecting 250 cm ^{3 of} fractions. Fractions 9 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 6.3 g of 1 - {(R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(3,5-difluorophenyl) methylsulphonylmethylene] azetidine, isomeric form A, are obtained. , in the form of white foam.

Mixture of 2 diastereoisomers (Form A) 1 - {(R *) - [4-chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(R) - (3,5-difluorophenyl) methylsulfonylmethyl)] azetidine 3-ol and 1 - {(R *) - [4-chloromethyl) phenyl] (4-chlorophenyl) methyl} -3 - [(S) - (3,5-difluorophenyl) methylsulfonylmethyl)] azetidin-3-ol can be prepared as follows: 6 cm ^{3 of} thionyl chloride is added to a solution of 0.20 g of a mixture of 2 diastereoisomers (Form A) 1 - {(R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(R) - (3,5-difluorophenyl) methylsulfonylmethyl)] azetidin-3-ol and 1 - {(R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [( S) - (3,5-Difluorophenyl) methylsulfonylmethyl)] azetidin-3-ol in 10 cm ^{3 of} dichloromethane. The mixture is stirred at 20 DEG C. for 20 hours, 5 cm @ ^{3 of} saturated aqueous sodium bicarbonate solution are added to the reaction mixture and the mixture is stirred for 15 minutes. The mixture is separated after settling, the organic phase is washed with water, dried over magnesium sulphate and 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 1 cm, height 20 cm), eluting under an argon pressure of 0.02 MPa with a mixture of cyclohexane and ethyl acetate (75/25, v / v), and collected. cm ³ fraction. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.17 g of a mixture of 2 diastereoisomers (Form A) of 1 - {(R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(R) - (3,5- difluorophenyl) methylsulfonylmethyl)] azetidin-3-ol and 1 - {(R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(S) - (3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ol, as a white foam.

Mixture of 2 diastereoisomers (Form A) 1 - {(R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(R) - (3,5-difluorophenyl) methylsulfonylmethyl)] azetidine- 3-ol and 1 - {(R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(S) - (3,5-difluorophenyl) methylsulfonylmethyl)] azetidin-3-ol can be prepared as follows: 1.6 cm ³

A 1.5 M solution of diisobutylaluminium hydride in toluene is added to a solution maintained under argon and cooled to -30 ° C, 0.58 g of a mixture of 2 diastereoisomers (Form A) of 3-acetoxy-1 - {(R *) - (4- chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(R) - (3,5-difluorophenyl) methylsulfonylmethyl)] azetidine and 3-acetoxy-1 - {(R *) - (4-chlorophenyl) [ 4- (methoxycarbonyl) phenyl] methyl} -3 - [(S) - (3,5-difluorophenyl) methylsulfonylmethyl)] -etidine, in 10 cm ^{3 of} anhydrous toluene. After stirring at -30 ° C for 15 minutes, 1.0 cm ^{3 of the} same hydride solution is added again and the temperature returns to 0 ° C. The mixture is stirred for 30 minutes and then 3.0 cm ^{3 of} water and 6 cm ^{3 of} 1 N sodium hydroxide are added and the mixture is extracted with 25 cm ^{3 of} dichloromethane. The organic phase is washed with 5 cm ^{3 of} water, 5 cm ^{3 of} brine and 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), eluting under an argon pressure of 0.01 MPa with a mixture of cyclohexane and ethyl acetate (50/50, v / v) and collected. cm ³ fraction. Fractions 4 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.42 g of a mixture of 2 diastereoisomers (Form A) of 1 - {(R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 [(R) - (3,5-difluorophenyl) is obtained. (methylsulfonylmethyl)] azetidin-3-ol a

1 - ((R *) - (4-chlorophenyl) [4- (hydroxymethylphenyl) methyl} -3 - [(S) - (3,5-difluorophenyl) methylsulfonylmethyl)] azetidin-3-ol, as a white lacquer.

Mixture of 2 diastereoisomers (Form A) of 3-acetoxy-1 - {(R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(R) - (3,5-difluorophenyl) methylsulfonylmethyl] )] toetidine and 3-acetoxy-1 - {(R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(S) - (3,5-difluorophenyl) methylsulfonylmethyl)] toetidine can be prepared as follows: 3 cm ^{3 of a} 1.6 N solution of n-butyllithium in hexane are added over 5 minutes under argon to a solution cooled to -60 ° C, 1.0 g of (3,5-difluorobenzyl) methylsulfone in 30 cm ^{3 of} tetrahydrofuran. The mixture was stirred at -60 ° C for 1 hour and then at -30 ° C for 30 minutes when a solution, pre-cooled to -60 ° C, 1.45 g of 1 - ((R *) - (4-Chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-one, Isomer A, in 15 cm ^{3 of} tetrahydrofuran The mixture is stirred at -60 ° C for 30 minutes and then at -30 ° C for 30 minutes 0.43 cm ^{3 of} acetyl chloride are added to the reaction mixture and the temperature is returned to 0 ° C. 40 cm ^{3 of} water and 40 cm ^{3 of} dichloromethane are then added with stirring and the mixture is returned to room temperature and the mixture is allowed to stand. the phase is washed with 20 cm ^{3 of} water and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) and the residue is chromatographed on a silica gel column (particle size 0.040-0.063 mm, diameter 3 cm, height 30 cm), eluting under a pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (75/25, v / v) and collecting 30 cm ^{3 of the} fraction. it is dried to dryness under reduced pressure (2.7 kPa)

1.25 g of a mixture of 2 diastereoisomers (Form A) of 3-acetoxy-1 - ((R) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl) methyl} -3 - [(R) - (3,5- difluorophenyl) methylsulfonylmethyl) azetidine and 3-acetoxy-1- ({R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(S) - (3,5-difluorophenyl) methylsulfonylmethyl )] azetidine in the form of a cream colored foam.

1 - {(R *) - (4-chlorophenyl) [4-methoxycarbonyl) phenyl] methyl} -azetidin-3-one, isomeric form A, can be prepared according to the following procedure: 0.90 cm ^{3 of} dimethylsulfoxide is added over the course of 10 minutes to a solution of 0.55 cm ^{3 of} oxalyl chloride in 5 cm ^{3 of} dichloromethane cooled to -60 ° C. The mixture was stirred at -60 ° C for 30 minutes and a solution of 1.75 g of 1 - {(R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3 was added over 15 minutes. -olu,. isomeric form A, in 20 cm ^{3 of} dichloromethane. After stirring at -60 ° C for 3 hours, 2.73 cm ^{3 of} triethylamine are added and the temperature of the reaction mixture returns to 0 ° C. 20 cm ^{3 of} water are added and the mixture is stirred and then separated after settling. The organic phase is dried over magnesium sulfate, filtered and. Concentrate to dryness at 50 ° C under reduced pressure (2.7 kPa). The orange-colored oil obtained is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 2 cm, height 30 cm), eluting under a argon pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (75/25 by volume) and collected. 30 cm ³ fractions. Fractions 2 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.45 g of 1- ((R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomeric form A, is obtained in the form of a yellow foam.

1 - {(R *) - (4-chlorophenyl) [4-methoxycarbonyl) phenyl] methyl} azet59-din-3-ol, isomeric form A, can be prepared as follows: 0.605 g of sodium bicarbonate is added to a suspension of 2.0 g of methyl (+) -4 - [(R *) - amino- (4-chlorophenyl) methyl] benzoate in cm ^{3 of} ethanol and then 0.60 cm ^{3 of} epibromohydrin are added. The mixture was stirred at 60 ° C for 20 hours and the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.060-0.200 mm, diameter 3 cm, height 35 cm), eluting under an argon pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (70/30, v / v) for fractions 6-10 and then 60/40 for fractions 18 to 27 and then 50/50) and 60 cm ³ fractions are collected. Fractions 15 to 40 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 30 cm ^{3 of} ethanol and then 0.20 g of sodium hydrogen carbonate and 0.2 cm ^{3 of} epibromohydrin are added. The mixture is stirred at 20 ° C for 48 hours and then at 35 ° C for 24 hours, the mixture is filtered and the filtrate is concentrated to dryness at 60 ° C under reduced pressure (2.7 kPa). 1.76 g are obtained

1 - {(R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-ol, isomeric form A, in paste form.

Methyl (+) -4 - [(R *) - amino- (4-chlorophenyl) methyl] benzoate can be prepared according to the following procedure: 2.51 g of D - (-) - tartaric acid is added to a solution of 9.2 g methyl 4 - [(RS) -amino- (4-chlorophenyl) methyl] benzoate in 10 cm ^{3 of} methanol. The solution is concentrated to dryness under reduced pressure (2.7 kPa). The cream foam is dissolved in 50 cm ^{3 of} ethanol containing 5% water and the solution is left to crystallize at 20 ° C for 20 hours. The crystals are filtered, washed with ethanol containing 5% water, dewatered and dried under reduced pressure (2.7 kPa). 3.4 g of white crystals are obtained, which are designated as A crystals [and which are stored for subsequent preparation of the second enantiomer of methyl (-) - 4 - [(R *) - amino- (4-chlorophenyl) methyl] benzoate]] . The mother liquors are concentrated to dryness and the white foam obtained (8.1 g) is dissolved in 100 cm ^{3 of} ethyl acetate. The solution obtained is made up to 50 cm @ ^{3 with} 1N sodium hydroxide, stirred and, after settling, separated. The organic phase is washed with 50 cm ^{3 of} water and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The yellow solid obtained is dissolved in 100 cm @ ^{3 of} methanol. 1.85 g of L - (+) - tartaric acid are added to the obtained solution, and the resulting solution is concentrated to dryness under reduced pressure (2.7 kPa). The obtained cream colored foam is dissolved in 27 cm ^{3 of} ethanol containing 4% water and allowed to crystallize for 20 hours at 20 ° C. The crystals are filtered off, washed with ethanol containing 4% water, dewatered and then dried under reduced pressure (2.7 kPa). 3.4 g of crystals of methyl (+) - 4 - [(R *) - amino- (4-chlorophenyl) methyl] benzoate of L - (+) - tartrate are obtained, which are recrystallized from 60 cm ^{3 of} ethanol containing 5% water. After removal of water and drying, 2.78 g of white crystals are obtained, which are dissolved in 50 cm @ ^{3 of} ethyl acetate. 100 cm @ ^{3 of} 1N sodium hydroxide are added to the obtained solution, the solution is stirred and separated after settling. The organic phase is washed with 50 cm ^{3 of} water and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). It will be obtained

2.1 g of methyl (+) - 4 - [(R *) - amino- (4-chlorophenyl) methyl] benzoate as a white solid.

Methyl 4 - [(RS) -amino- (4-chlorophenyl) methyl] benzoate can be prepared according to the following procedure: 3.9 cm ^{3 of} hydrazine hydrate is added to a suspension of 16.3 g of methyl 4 - [(RS) -phthalimido- ( 4-chlorophenyl) methyl] benzoate in 200 cm ^{3 of} methanol. The mixture is stirred at reflux for 5 hours and then at 20 ° C for 20 hours, the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in a mixture of 200 cm ^{3 of} water and 200 cm ^{3 of} ethyl acetate. The mixture is stirred for 15 minutes, the resulting suspension is filtered, the filtrate is separated after settling in a separatory funnel and the organic phase is washed with 50 cm ^{3 of} water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 8.4 g of methyl 4 - [(RS) -amino- (4-chlorophenyl) methyl] benzoate are obtained in the form of a pale yellow oil.

Methyl 4 - [(RS) -phthalimido- (4-chlorophenyl) methyl] benzoate can be prepared as follows: 12.6 g of potassium phthalimide is added to a solution of 11.6 g of methyl 4 - [(RS) -bromo- -chlorophenyl) methyl] benzoate in 70 cm ^{3 of} N, N-dimethylformamide. The mixture is stirred at reflux for 3 hours, then cooled to 20 ° C and 300 cm ^{3 of} ethyl acetate and 300 cm ^{3 of} water are added. After stirring, the mixture is separated after settling, the aqueous phase is extracted again with 100 cm ^{3 of} ethyl acetate, the combined organic phases are washed with 400 cm ^{3 of} water and then dried over magnesium sulphate and concentrated to a residue. dryness under reduced pressure (2.7 kPa). 16.3 g of methyl 4 - [(RS) -phthalimido (4-chlorophenyl) methyl] benzoate are obtained in the form of a yellow paste.

Methyl 4 - [(RS) -bromo- (4-chlorophenyl) methyl] benzoate can be prepared by the following procedure: 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

Of 4 - [(RS) - (4-chlorophenyl) (hydroxy) methyl] benzoate in 200 cm ^{3 of} acetonitrile. The mixture was stirred at 20 ° C for 30 minutes, then the reaction mixture was heated at reflux for 2 hours, stirred at 20 ° C for 20 hours, and concentrated to dryness under reduced pressure (2.7 kPa). . The mixture is taken up in dichloromethane and chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 7 cm, height 30 cm) under reduced pressure, eluting under an argon pressure of 0.05 MPa with dichloromethane and collected 500 cm ^3. fractions. Fractions 3-6 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 11.6 g of methyl 4 - [(RS) -bromo- (4-chlorophenyl) methyl] benzoate are obtained in the form of an oil which is used as is in the following stage.

Methyl 4 - [(PS) - (4-chlorophenyl) (hydroxy) methyl] benzoate can be prepared by the following procedure: 1.21 g of sodium borohydride is added slowly in small portions (the medium warms slightly to 50 ° C) to the suspension 2.75 g of methyl 4- (4-chlorobenzoyl) benzoate in 200 ml of methanol at 20 ° C. The mixture is stirred at 20 ° C for 20 minutes, the reaction mixture is concentrated to a reduced volume, and 150 cm ^{3 of} dichloromethane are added and 100 cm ^{3 of} 0.5 N hydrochloric acid are added with stirring. After decantation, the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 2.5 g of 4 - [(PS) - (4-chlorophenyl) (hydroxy) methyl] benzoate are obtained in the form of a colorless oil which slowly crystallizes at 20 ° C and is used alone in the next step.

Methyl 4- (4-chlorobenzoyl) benzoate can be prepared as follows: 27.4 cm ^{3 of} tri-n-butylphosphine are added under argon to 19.3 g of a solution of terephthalic acid monomethyl ester in 200 cm ^{3 of} tetrahydrofuran cooled to -22 ° C. The mixture is stirred for 20 minutes at -22 ° C, and a solution of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of 4-bromochlorobenzene, 2.43 g of magnesium and one iodine crystal in 100 cm ^{3 of} diethyl ether, at reflux) is added. maintains this temperature. After stirring at -22 ° C for 30 minutes, 150 cm ^{3 of} 1 N hydrochloric acid are added slowly, the mixture is returned to 20 ° C and the medium is diluted with 200 cm ^{3 of} diethyl ether. The white suspension obtained is filtered, and the solids are washed twice with 50 cm @ ^{3 of} water and then twice with 50 cm @ ^{3 of} diethyl ether. After removal of water and drying under reduced pressure (2.7 kPa), it is obtained

16.2 g of methyl 4- (4-chlorobenzoyl) benzoate as a white solid, melting at 170 ° C.

Example 4

A mixture of 2 B diastereomeric forms of 1- [4 - [(R *) - (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (R)] azetidin-1-yl] methyl] benzyl] pyrrolidine and 1 - [4 - [(R *) - (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (S)] azetidin-1-yl] methyl] benzylpyrrolidine can be prepared as described in Example 3, starting from 50 mg of (+) - 1- [4- (R *) - (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-ylmethyl) benzyl] pyrrolidine, isomeric form B 1.5 cm ^{3 of} ethanol, 1.5 cm ^{3 of} dichloromethane and 18 mg of borohydride are stirred for 8 hours at 50 ° C and then for 48 hours at 20 ° C. 50 mg of a mixture of 2 diastereomeric forms B, 1- [4 - [(R *) - (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (R)] azetidin-1-yl] methyl] are obtained. benzyl] pyrrolidine and 1- [4 - [(R *) - (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (S)] azetidin-1-ylmethyl] benzylpyrrolidine as a white foam ¹ H NMR spectrum (300 MHz, CDCl 3, δ in ppm). A mixture of diastereoisomers 60/40, * 1.79 (mt 4H) was found; from 2.45 to 2.60 (mt 5H); 2.67 (s 3H); from 3.10 to 3.30 (mt 2H); 3.40 (mt 1H);

3, 57 and 3.60 (2s: 2H pretty); 3, 65 (broad t, J = 7.5 Hz: 1H); 4.26 and 4.30 (2s: 2H pretty); 6, 84 (tt, J = 9 and 2 Hz): 1H); 6.96 (mt: : 2H); from 7.25 to 7.40 (mt : 8H)

(+) - 1- [4- (R *) - (4-Chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl) benzyl] pyrrolidine, isomeric form B, sa can be prepared according to the procedure described in Example 3, starting from 0.50 g of 1 - {(R *) - [4- (chloroethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(3,5- difluorophenyl) (methylsulfonyl) methylene] azetidine, isomeric form B, 5 mg sodium iodide, 15 cm ^{3 of} dichloromethane and 0.190 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 20 cm) under argon under reduced pressure of 0.01 MPa, eluting with dichloromethane and then with a mixture of dichloromethane and methanol (95/5, by volume) and 25 cm ³ fractions are collected. Fractions 20 to 40 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.28 g of (+) -1- [4- (R *) - (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl) benzyl] pyrrolidine is obtained. , isomeric form B in the form of a white foam. [a] ²⁰ 365 = +26.8 nm +/- 0.8 (c = 0.5%, dichloromethane) ^[_1 H NMR (300 MHz, CDC1 _3, δ in ppm):

1.78 (mt 4H); 2.50 (mt 4H) 2.80 (s 3H); 3.57 (s 2H); 3.84 (mt 2H); 4.34 (mt 2H); 4.50 (s 1H); 6.84 (tt, J = 9 and

2.5 Hz: 1H); 6.98 (mt 2H); from 7.20 to 7.40 (mt 8H)].

1 - {(R *) - [4- (Chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomeric form B, may be prepared according to the procedure described in Example 3, starting with 7.3 g of a mixture of 2 B diastereomeric forms, 1 - {(R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(R) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol and 1 - {(R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(S 1- (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol, 8.2 g of 4-dimethylaminopyridine, 150 cm ^{3 of} dichloromethane and 3.2 cm ^{3 of} methylsulfonyl chloride. The crude product is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) under argon pressure.

0.02 MPa, eluting with dichloromethane and collecting 100 cm ^{3 of} fraction.

Fractions 15 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 2.50 g of 1 - ((R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(3,5-difluorophenylmethyisulfonyl) methylene] azetidine, isomeric form B, are obtained. white foam.

Mixture of two diastereomeric forms B, 1 - {(R *) - [4- (chloromethyl) phenyl [4-chlorophenyl) methyl] -3 - [(R) - (3,5-difluorophenyl) (methylsulfonyl) methyl )] azetidin-3-ol and 1 - {(R *) - [4- (chloromethyl) phenyl] (4-chlorophenyl) methyl} -3 - [(S) - (3,5-difluorophenyl) (methylsulfonyl) methyl The] azetidin-3-ol can be prepared according to the procedure described in Example 3, starting from 11.0 g of a mixture of 2 diastereoisomeric forms B, 1 - ((R *) - 4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl } -3 [(R) - (3,5-Difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol and

1 - ((R) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(S) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] 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) under an argon pressure of 0.02 MPa, eluting with a mixture of cyclohexane and ethyl acetate (70/30, v / v) and collected. 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 a mixture of 2 diastereoisomeric forms B, 1 - {(R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(R) - (3,5-difluorophenyl) are obtained. (methylsulfonyl) methyl) azetidin-3-ol and 1 - {(R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(S) - (3,5- difluorophenyl) ^1- (methylsulfonyl) methyl)] azetidin-3-ol as a white foam.

Mixture of two diastereomeric Forms B, 1 - {(R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(R) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol and 1 - {(R *) - [4- (chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(R) -3,5-difluorophenyl) (methylsulfonyl) methyl) The azetidin-3-ol can be prepared according to the procedure described in Example 3, starting from 18.0 g of a mixture of 2 diastereoisomeric forms B, 3-acetoxy-1 - ((R *) - (4-chlorophenyl) [4- (methoxy) carbonyl) phenyl] methyl} -3 - [(R) - (3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine and 3-acetoxy-1 - {(R *) - (4-chlorophenyl) [4- (methyl65) oxycarbonyl) phenyl] methyl} -3 - [(S) - (3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine, 150 cm ^{3 of} anhydrous toluene and 100 cm ^{3 of a} 20% solution of diisobutylaluminium hydride in toluene The crude product is chromatographed on silica gel column (particle size 0.06 0.200 mm, diameter 3 cm, height 30 cm) under an argon pressure of 0.01 MPa, eluting with a mixture of cyclohexane and ethyl acetate (50/50, v / v) and collecting 50 cm ³ Fractions 15 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 11.0 g of a mixture of 2 diastereoisomeric forms B, 1 - {(R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(R) - (3,5-difluorophenyl) are obtained. (methylsulfonyl) methyl] and zetidin-3-ol and 1 - ((R *) - [(4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(S) -3,5-difluorophenyl (methylsulfonyl) methyl] azetidin-3-ol as a white foam.

Mixture of 2 diastereomeric Forms B, 3-acetoxy-1 - {(R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(R) - (3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine and 3-acetoxy-1 - {(R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(S) - (3,5-difluorophenyl) methylsulfonyl) methyl Azetidine can be prepared according to the procedure described in Example 3, starting from 11.2 g of (3,5-difluorobenzyl) methylsulfone, 350 cm ^{3 of} tetrahydrofuran, 34 cm ^{3 of a} 1.6 N solution of n-butyllithium in hexane, 11.2 g. 1 - {(R *) - (4-chlorophenyl): 4- (methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomeric form B '; 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 cm, height 40 cm), eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 100 cm ^{3 of} fractions. Fractions 10 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 21 g of a cream-colored foam are obtained, which still contains impurities. The foam is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 4 cm, height 40 cm), eluting with dichloromethane to give 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 a mixture of 2 diastereoisomeric forms B are obtained,

3-acetoxy-l - {(R) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} 66

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 as a white foam.

1 - {(R *) - (4-Chlorophenyl) [4-methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomeric form B, can be prepared according to the procedure described in Example 3, starting from 8.7 cm ^{3 of} oxalyl chloride , 350 cm ^{3 of} dichloroethane, 14.2 cm ^{3 of} dimethylsulfoxide, 29.0 g of 1 - {(R *) (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-ol, isomeric form B 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 of} fractions. Fractions 7 to 25 are combined and concentrated. under reduced pressure (2.7 kPa). 15.5 g of 1 - {(R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomeric form B, is obtained in the form of an orange-colored oil.

1 - {(R *) - (4-Chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-ol, isomeric form B, can be prepared as described in Example 3, starting from 25.5 g of methyl (-) - 4- [1- (R *) - amino-1- (4-chlorophenyl) methyl] benzoate, 250 cm ^{3 of} ethanol, 7.9 g of sodium bicarbonate and 7.7 g of epibromohydrin. 29 g of 1 - {(R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azeditin-3-ol, isomeric form B, are obtained in the form of a yellow oil.

Methyl (-) - 4 - [(R *) - amino- (4-chlorophenyl) methyl] benzoate can be prepared by carrying out two successive recrystallizations of white crystals (3.4 g) called A crystals, Example 3, from 68 cm ³ ethanol containing 5% of water at reflux. The crystals obtained are filtered, freed from water and then dried under reduced pressure (2.7 kPa). 2.2 g of methyl (-) - 4- [1- (R *) - amino- (4-chlorophenyl) methyl] benzoate D - (-) - tartrate are obtained in the form of white crystals which are dissolved in 50 cm @ ^3. ethyl acetate. To the solution obtained is added 50 cm @ ^{3 of} 1 N sodium hydroxide, then the mixture is stirred and separated after settling. The organic phase is washed with 50 cm @ ^{3 of} water and dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 1.9 g of methyl (-) - 4 - [(R *) - amino- (4-chlorophenyl) methyl] benzoate are obtained in the form of a white solid. [α] 20 ° C, 365 nm = -58.1 ° +/- 1 (c = 0.5%).

Example 5

1- [Bis (thien-2-yl) methyl] -3 - [(RS) - (3,5-difluorophenyl) methylsulfonylmethyl] azetidine can be prepared according to the procedure described in Example 3, starting from 0.10 g of 1- [ bis (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine, 2 cm ^{3 of} methanol, 2 cm ^{3 of} dichloromethane and 25 mg of sodium borohydride, with stirring for 3 hours at 20 ° C. The crude product is chromatographed on a silica gel column (particle size 0.063-0.200 mm, diameter 1 cm, height 7 cm) eluting under an argon pressure of 0.01 MPa with dichloromethane and collecting 4 cm ^{3 of the} fraction. Fractions 2 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). To give 83 mg of 1- [bis (thien-2-yl) methyl] -3 - [[RS) - (3,5-difluorophenyl) methylsulfonylmethyl] azetidine as a white solid: ^[X H-NMR (400 MHz, CDCl 3 δ in ppm): from 2.60 to 2.70 (mt 1H); 2.66 (s 3H); 3.31 (mt 2H); 3.40 (mt 1H); 3.73 (broad t, J 7.5 Hz 1H); 4.27 (d, J = 11Hz: 1H); 4.92 (s 1H); 6.83 (tt, J = 9 and 2.5 Hz); from 6.85 to 7.00 (mt 6H); 7.21 (mt 2H)].

1- [Bis (shadow-2-yl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine can be prepared according to the procedure described in Example 6, starting from 2.2 g of 1- [bis (thien- 2-yl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (PS)] azetidin-3-ol,

0.64 cm ^{3 of} methylsulfonyl chloride, 2.3 g of 4-dimethylaminopyridine and 75 cm ^{3 of} dichloromethane; After purification by chromatography and crystallization from diisopropyl ether, 1.3 g of 1- [bis (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine are obtained in the form of white crystals, m.p. C.

1- [Bis (shadow-2-yl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl68 methyl- (RS)] azetidin-3-ol can be prepared according to the following procedure: 4 cm ³ 1.6 N n-Butyllithium in hexane is added under argon over 10 minutes to a solution cooled to -60 ° C, 1.3 g of (3,5-difluorobenzyl) methylsulfone in 20 cm ^{3 of} tetrahydrofuran. The mixture is stirred at -70 ° C for 45 minutes and a solution of 1.5 g of 1- [bis (thien-2-yl) methyl] azetidin-3-one in 20 cm ^{3 of} tetrahydrofuran is added over 10 minutes. The mixture is stirred at -70 ° C for 3 hours, then the temperature is returned to room temperature and 10 cm ^{3 of} saturated aqueous ammonium chloride solution are added. After settling, the mixture is separated, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 20 cm @ ^{3 of a} mixture of cyclohexane and ethyl acetate (60/40), the suspension obtained is filtered, the solids are dehydrated and air-dried. 2.2 g of 1- [bis (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl (RS)] azetidin-3-ol are obtained in the form of white crystals, m.p. C.

1- [Bis (thien-2-yl) methyl] azetidin-3-one can be prepared according to the procedure described in Example 1 (method 2), starting from 4 g of 1- [bis (thien-2-yl) methyl] azetidin-3-ol, 2,6 cm ^{3 of} dimethylsulfoxide,

7.7 cm ^{3 of} triethylamine, 7.7 cm ^{3 of} oxalyl chloride and 100 cm ^{3 of} dichloromethane. The obtained residue was purified by silica gel column chromatography (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) eluting with a mixture of cyclohexane and ethyl acetate (1/1, v / v). The fractions obtained are evaporated to dryness under reduced pressure (2.7 kPa) to give 3.2 g of 1- [bis (thien-2-yl) methyl] azetidin-3-one as cream-colored crystals, m.p. C.

1- [Bis (thien-2-yl) methyl] azetidin-3-ol can be prepared according to the procedure described in Example 3, starting from 6 g of 1- [bis (thien-2-yl) methyl] amine, 2,5 cm @ 2 of epibromohydrin, 2.6 g of sodium bicarbonate and 50 cm @ ^{3 of} ethanol. 4 g of 1- [bis (thien-2-yl) methyl] azetidin-3-ol are thus obtained in the form of beige crystals, melting at 115 ° C.

1- [Bis (thien-2-yl) methyl] amine can be prepared as follows: a solution of 5 cm ^{3 of} 2-thiophenecarbonitrile in 50 cm ^{3 of} diethyl ether is added dropwise to a solution cooled to 10 ° C with thien-2-ylmagnesium bromide (prepared from 1.29 g magnesium and 3.22 cm ³⁾

2-bromothiophene in 75 cm ^{3 of} diethyl ether). The mixture is refluxed for 1.5 hours, then the reaction medium is cooled to 5 ° C and 20 cm ^{3 of} methanol are added dropwise twice, the suspension is filtered and the solid is washed with methanol. The filtrate [lacuna] obtained is a brown solution. Sodium borohydride (2.45 g) was added in several portions to this solution under argon. The mixture was stirred at room temperature for 16 hours and then diluted with ethyl acetate and water was added slowly. The organic phase is extracted, washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure (2.5 kPa) at 55 ° C. The brown oil obtained is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter cm, height 23 cm) eluting with a mixture of cyclohexane and ethyl acetate (90/10 and then 85/15). 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 as a crystalline solid.

Example 6

1- [Bis (p-tolyl) methyl] -3 - [(RS) methylsulfonylphenylmethyl] azetidine can be prepared according to the procedure described in Example 3, starting from 0.10 g of 1- [bis (p-tolyl) methyl] -3 - (methylsulfonylphenylmethylene) azetidine, 2 cm ^{3 of} methanol, 2 cm ^{3 of} dichloromethane and 25 mg of sodium borohydride. The crude product is chromatographed on a silica gel column (particle size 0.063-0.200 mm, diameter 1 cm, height 7 cm) eluting under an argon pressure of 0.01 MPa with dichloromethane and 4 cm ³ fractions are collected. Fractions 5-10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 35 mg is obtained

1- [bis (p-tolyl) methyl] -3 - [(RS) methylsulfonylphenylmethyl] azetidine as a white solid pH NMR spectrum (300 MHz, CDCl 3, δ in ppm): 2.24 (s: 3H); 2.27 (s 3H); 2.53 (t, J = 7.5Hz: 1H);

2.58 (s 3H); 3.19 (mt 2H); 3.49 (mt 1H); 3.69 (broad t, J 7.5 Hz 1H); 4.22 (s 1H); 4.28 (d, J = 11.5 Hz 1H); from

6.95 to 7.45 (mts: 13H)].

1- [Bis (p-tolyl) methyl] -3- (methylsulfonylphenylmethylene) azetidine can be prepared as follows: 0.125 cm ^@ -1 of methylsulfonyl chloride is added to a solution of 0.48 g of 1- [bis (p-tolyl) methyl] - 3- [methylsulfonylphenylmethyl- (RS)] azetidin-3-ol in 25 cm ^{3 of} anhydrous dichloromethane, and then 0.465 g of 4-dimethylaminopyridine is added in small amounts. The mixture is stirred at 20 ° C for 20 hours, washed twice with 80 cm ^{3 of} water, 80 cm ^{3 of} brine, 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 0.040-0.063 mm, height 17 cm, diameter

3.2 cm), eluting under a pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (80/20, v / v) and collecting 40 cm ^{3 of} fraction. Fractions 5-8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred with diisopropyl ether, the solid is filtered off, dehydrated and then dried under reduced pressure (2.7 kPa). 0.25 g of 1- [bis (p-tolyl) methyl] -3- (methylsulfonylphenylmethylene) azetidine is obtained as a white solid [NMR spectrum in DMSO-d6, T = 300K, δ in ppm (250 MHz): 2 23 (6H, s, 2Ph-CH ₃ ), 2.98 (3H, s, SCH ₃ ), 3.76 (2H, s, NCH ₂ ), 4.20 (2H, s, NCH ₂ ), 5 55 (1H, s, NCH), 7.10 (4H, d, J = 7Hz, 4CH aromatic), 7.32 (4H, d, J = 7Hz, 4CH aromatic), 7.43 (5H) , s, phenyl)].

1- [Bis (p-tolyl) methyl] -3 - [(methylsulfonyl) phenylmethyl (RS)] azetidin-3-ol can be prepared as follows: 0.6 g of 3 - [(methylsulfonyl) (phenyl) hydrochloride methyl (RS)] azetidin-3-ol is added to a solution of 0.59 g of bromo (bis-p-tolyl) methane in 20 cm ^{3 of} acetonitrile and then 0.3 g of potassium carbonate is added. After heating the mixture at reflux for 1.5 h, cool the reaction mixture to 20 ° C and filter. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is chromatographed on silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 16 cm), eluting with a mixture of cyclohexane and ethyl acetate (70/1). 30, by volume) and 50 cm ³ fractions are collected. Fractions 8 to 13 are concentrated to dryness under reduced pressure (2.7 kPa). 0.48 g is obtained

1- [bis (p-tolyl) methyl] -3 - [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol as a white solid.

Bromo (bis-p-tolyl) methane can be prepared according to the procedure described by Bachmann W.E., J. Am. Chem. Soc., 2135, (1933).

3 - [(Methylsulfonyl) phenylmethyl- (RS)] azeditin-3-ol hydrochloride can be prepared as follows: 12.6 cm @ ^{3 of a} 6.2 N solution of hydrochloric acid in dioxane are added to the solution

2.62 g of 3 - [(methylsulfonyl) (phenyl) methyl- (RS)] - 1- (vinyloxycarbonyl) azetidin-3-ol in 12.6 cm @ ^{3 of} dioxane. The mixture was stirred at 20 ° C for 20 hours and then concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue is taken up in 25 cm ^{3 of} ethanol and refluxed for 1 hour, then the mixture is returned to 20 ° C and filtered. The solid is washed with diethyl ether and then freed from water and dried under reduced pressure (2.7 kPa). There was thus obtained 3 - [(methylsulfonyl) phenylmethyl- (RS)] azetidin-3-ol hydrochloride (1.89 g) as white crystals.

3 - [(Methylsulfonyl) (phenyl) methyl (RS)] - 1- (vinyloxycarbonyl) azetidin-3-ol can be prepared as follows: a solution of 0.99 cm ^{3 of} vinyl chloroformate in 4 cm ^{3 of} anhydrous dichloromethane is added dropwise to mixture, cooled to + 5 ° C, 3.92 g of 1-benzhydryl-3 - [(methylsulfonyl) (phenyl) methyl (RS)] azetidin-3-ol in 500 cm ^{3 of} anhydrous dichloromethane. The mixture is stirred at 20 ° C for 48 hours and then the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on. Silica gel (particle size 0.04-0.06 mm, diameter 5.6 cm, height 15.5 cm), eluting with a mixture of cyclohexane and ethyl acetate (70/30, v / v) and collecting 50 cm ³ fractions. Fractions 17 to 36 are concentrated to dryness under reduced pressure (2.7 kPa). 0.9 g of 3 - [(methylsulfonyl) (phenyl) methyl (RS)] - 1- (vinyloxycarbonyl) azetidin-3-ol is obtained as a white solid.

1-Benzhydryl-3 - [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol can be prepared as described in Example 1 (method 1), starting from 47 cm ^{3 of} diisopropylamine, 205.6 cm ³

1.6 M n-butyllithium in hexane, 2.2 L tetrahydrofuran, 50 g benzylmethylsulfone and 69.6 g 1-benzhydrylazetidin-3-one. 94.3 g of 1-benzhydryl-3 - [(methylsulfonyl) (phenyl) methyl- (RS)] azetidin-3-ol are obtained in the form of white crystals.

Example <1

1- [Bis (3-fluorophenyl) methyl] -3- (RS) - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine can be prepared as described in Example 3, starting from 0.10 g of 1- [bis (3-fluorophenyl) methyl] azetidine. -fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine, 2 cm ^{3 of} methanol, 2 cm ^{3 of} dichloromethane and 20 mg of borohydride while stirring at 20 ° C for 48 hours. The crude product is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 7 cm, diameter 1 cm), eluting under argon at 0.01 MPa with dichloromethane and collecting 4 cm ³ fractions. Fractions 3-7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 95 mg of 1- [bis (3-fluorophenyl) methyl] -3- (RS) - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine are obtained as white crystals [ ³ H NMR spectrum (300 MHz, CDCl ₃ , δ) in ppm): 2.57 ' (t, J = 7.5 Hz: 1H);

2.66 (s 3H); from 3.15 to 3.30 (mt 2H); from 3.30 to 3.50 (mt 1H); 3.66 (broad t, J 7.5 Hz 1H); 4.27 (d, J = 11.5 Hz):

1H); 4.28 (s 1H); from 6.75 to 7.35 (mt 11H)].

1- [Bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine can be prepared as described in Example 6, starting from. from 1.15 g of 1- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, cm ^{3 of} dichloromethane, 0.264 cm ^{3 of} methylsulfonyl chloride and 0.98 g

4-dimethylaminopyridine. The residue is chromatographed on silica gel (particle size 0.06-0.200 mm, diameter 2.8 cm, height 25 cm), eluting under an argon pressure of 0.1 MPa with a mixture of ethyl acetate and cyclohexane (15/85, by volume) and collected 60 cm. ³ fractions. 0.55 g of 1- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonylmethylene) azetidine is obtained in the form of a white solid, melting at 178 ° C.

1- [Bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol can be prepared as follows: 3.65 cm ³ 1.6 A solution of n-butyllithium in hexane is added over 10 minutes to a mixture cooled to -60 ° C with diisopropylamine and 10 cm ^{3 of} tetrahydrofuran, stirred for 10 minutes at -30 ° C and then cooled to -70 ° C. A solution of 1.2 g of 3,5-difluorobenzylmethylsulfone in 30 cm ^{3 of} tetrahydrofuran is then added over 20 minutes. The mixture is stirred at -70 ° C for 30 minutes, then a solution of 1.5 g of 1- [bis (3-fluorophenyl) methyl] azetidin-3-one in 10 cm ^{3 of} tetrahydrofuran is added over 30 minutes. The mixture is stirred at -70 ° C for 2 hours, then the temperature is brought to room temperature and 20 cm ^{3 of} saturated aqueous ammonium chloride solution and 100 cm ^{3 of} dichloromethane are added. The mixture is separated after settling, the organic phase is washed with water and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel (particle size 0.06 0.200 mm, diameter 3.2 cm, height 30 cm), eluting under an argon pressure of 0.1 MPa with a mixture of ethyl acetate and cyclohexane (20/80, v / v) and collecting 60 cm ^3. fractions. Fractions 9 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.95 g of 1- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl (RS)] azetidin-3-ol are obtained as a white solid, m.p. at 170 ° C (dec.).

1- [Bis (3-fluorophenyl) methyl] azetidin-3-one can be prepared as described in Example 1 (method 2), starting from 0.7 cm ^{3 of} oxalyl chloride, 16 cm ^{3 of} dichloromethane, 1.12 cm ^{3 of} dimethylsulfoxide, 2 g of 1- [bis (3-fluorophenyl) methyl] azetidin-3-ol and 3.7 cm ^{3 of} triethylamine. 1.55 g of 1- [bis (3-fluorophenyl) methyl] azetidin-3-one are obtained in the form of an oil which crystallizes at 20 ° C.

1- [Bis (3-fluorophenyl) methyl] azetidin-3-ol can be prepared according to the method described by Katritsky AR in J. Heterocycl. Chem., 31, 271 (1994) starting from 4.9 g of [bis (3-fluorophenyl) methyl] amine and 1.78 cm ^{3 of} epichlorohydrin.

Ί 4 [Bis (3-fluorophenyl) methyl] amine can be prepared as follows: a solution of 5.17 g of 3,3'-difluorobenzophenone oxime in 30 cm ^{3 of} tetrahydrofuran is added under argon over 30 minutes to a suspension of 1.27 g of lithium aluminum hydride in 80 cm ^{3 of} tetrahydrofuran. The mixture was stirred at reflux for 5 hours and added gradually

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. After drying over magnesium sulphate and concentration 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 can be prepared by the following procedure: a solution of 1.6 g of hydroxylamine hydrochloride in 8 cm ^{3 of} water is added dropwise to a solution of 5.0 g of 3,3'-difluorobenzophenone in 10 cm ^{3 of} ethanol and in small portions 1.2 g of sodium hydroxide pellets are added. The reaction mixture is heated at reflux for 10 minutes, then cooled to 20 ° C and acidified with 7.5 cm ^{3 of} 4 N hydrochloric acid. The oily precipitate obtained is triturated again, becoming a white solid, which is filtered, washed with water and dried at 35 ° C under reduced pressure (2.7 kPa). 5.17 g of 3,3'-difluorobenzophenone oxime are obtained in the form of a white solid.

Example 8

1- [Bis (4-chlorophenyl) methyl] -3- (RS) - {[3-azetidin-1-ylphenyl] methylsulfonylmethyl} azetidine can be prepared according to the procedure described in Example 3, starting from 0.10 g of 1- [g] bis (4-chlorophenyl) methyl] -3 - [(azetidin-1-ylphenyl) methylsulfonylmethylene] azetidine, 2 cm ^{3 of} methanol, 2 cm ^{3 of} dichloromethane and 30 mg of sodium borohydride while stirring at 20 ° C for 24 h. The crude product is chromatographed on silica gel (particle size 0.063-0.200 mm, diameter 1 cm, height 7 cm), eluting under an argon pressure of 0.01 MPa with dichloromethane and 4 cm ³ fractions are collected. Fractions 5-10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 20 mg of 1- [bis (4-chlorophenyl) methyl] -3- (RS) - {[3-azetidine-17] are obtained.

-ylphenyl] methylsulfonylmethyl] azetidine as an off-white lacquer pH NMR spectrum (300 MHz, CDCl ₃ , δ in ppm)]: 2.39 (mt:

2H); from 2.50 to 2.65 (mt 1H); 2,60 (s 3H); 3.20 (mt 2H); 3, 47 (mt . : 1H); 3.66 (broad t, J = 7 Hz) : 1H); 3.89 (wide t, J = 7.5 Hz: 4H); 4.20 (d, J = 11Hz): 1H); 4.26 (s : 1H); from 6, 35 to 6.50 (mt 2H); 6.67 (broad d, J = 7.5Hz : 1H); from 7.10 to 7.40 (mt 9H)]. I- [ Bis (4-chlorophenyl) methyl] -3 - [(azetidin-l-yl-phenyl) metylsul-

phonylmethylene] azetidine can be prepared as described in Example 6, starting from 0.83 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(azetidin-1-ylphenyl) methylsulfonylmethyl- (RS)] azetidine-3- ol, cm ^{3 of} dichloromethane, 0.18 cm ^{3 of} methylsulfonyl chloride and 0.75 g

4-dimethylaminopyridine. 0.40 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(azetidin-1-ylphenyl) methylsulfonylmethylene] azetidine are obtained in the form of a white foam.

1- [Bis (4-chlorophenyl) methyl] -3 - [(azetidin-1-ylphenyl) methylsulfonylmethyl- (RS)] azetidin-3-ol can be prepared as described in Example 5, starting from 1.55 g of 1- (3-methylsulfonylmethylphenyl) azetidine, 5.2 cm ^{3 of a} 1.6 M solution of n-butyllithium in hexane, 30 cm ^{3 of} tetrahydrofuran and 2.11 g of 1- [bis (4-chlorophenyl) methyl] azetidine-3- one. 0.83 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(azetidin-1-ylphenyl) methylsulfonylmethyl (RS)] azetidin-3-ol is obtained in the form of a ocher-colored solid, m.p. 172 ° C.

1- (3-Methylsulfonylmethylphenyl) azetidine can be prepared by the following procedure: a solution of 1.9 g of 1- (3-methylsulfanylmethylphenyl) azetidine in 10 cm ^{3 of} ethanol is added to the mixture cooled to 0 ° C, 10 cm ^{3 of} water, 5 cm ³ acetic acid, 1.5 cm @ ^{3 of} 36 N sulfuric acid and 6.25 g of oxone. The mixture is stirred for 20 hours at room temperature, 100 cm ^{3 of} water, 100 cm ^{3 of} ethyl acetate are added and then neutralized with stirring with sodium bicarbonate. The resulting mixture is separated after settling, the organic phase is dried over magnesium sulphate and then filtered and concentrated to dryness under reduced pressure (2.7 kPa). 1.55 g of 1- (3-methylsulfonylmethylphenyl) azetidine are obtained in the form of a light brown gum.

1- [3- (Methylsulfonylmethyl) phenyl] azetidine can be prepared as follows: 2.57 g potassium tert-butoxide, 0.64 g 1,1'-bis (diphenylphosphino) ferrocenyl palladium chloride, 1.49 g 1,1'-bis (diphenylphosphino) ferrocene, 0.12 g of copper (I) iodide and 2.0 g of azetidine are added under argon to a solution of 4.6 g of 1-iodo-3- (methylsulfanylmethyl) benzene in 60 cm ^{3 of} tetrahydrofuran. The mixture is heated at reflux for 3 hours, then cooled to room temperature and filtered through celite, and then the celite is washed with 150 cm ^{3 of} ethyl acetate. The combined filtrate and washings were acidified with 120 cm @ ^{3 of} 1N hydrochloric acid and separated after settling. 60 cm ^{3 of} ethyl acetate are added to the aqueous phase, and then the aqueous phase is basified with sodium bicarbonate and the mixture is separated after settling. The organic phase is dried over magnesium sulfate, filtered 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 3.5 cm, height 50 cm), eluting under an argon pressure of 0.05 MPa with a mixture of ethyl acetate and cyclohexane (20/80, v / v) and collecting 100 g. cm ³ fraction. Fractions 1-3 are combined and concentrated to dryness under reduced pressure (2.7 kPa). It will be obtained

1.9 g of 1- [3- (methylsulfonylmethyl) phenyl] azetidine as an oil.

1,1'-Bis (diphenylphosphino) ferrocenyl palladium chloride can be prepared as described by Hayashi T. et al., J. Am. Chem. Soc., 106, 158 (1984).

1-Iodo-3- (methylsulfanylmethyl) benzene can be prepared as follows: 6.4 g of sodium methylthiolate are added to a solution of 25 g of 3-iodobenzyl bromide in 80 cm ^{3 of} N, N-dimethylformamide. The mixture is stirred for 20 hours at 20 DEG C. and then 250 cm @ ^{3 of} water, 200 cm @ ^{3 of} ethyl acetate are added and the mixture is stirred and then separated after settling. The organic phase is washed four times with 200 cm ^{3 of} water, dried over magnesium sulphate, filtered and concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). 22 g of 1-iodo-3- (methylsulfanylmethyl) benzene are obtained in the form of a gum.

Example 9

Mixture of 2 diastereoisomers Form A 1- (R *) - {4 - [(4-chlorophenyl) (3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (R)] - 3-imidazolylazetidin-1-yl} methyl] benzyl } - 1 H -imidazole and 1- (R *) - {4- (4-chlorophenyl) (3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (S))} -3-imidazolyl-azetidin-1-yl} methyl] benzyl] -1H-imidazole can be prepared by the following procedure: 13.6 mg of imidazole is added to a solution of 50 mg of 1 - {(R *) - (4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} - 3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine, isomeric form A, in 1 cm ^{3 of} dichloromethane The mixture is stirred at 20 ° C for 20 hours and then the reaction mixture is directly chromatographed on a silica gel column (particle size). 0.063-0.200 mm, diameter 1 cm, height 7 cm), eluting under a pressure of 0.01 MPa with a mixture of dichloromethane and methanol (98/2, v / v) and collecting 4 cm ³ fractions. to dryness under reduced pressure (2.7 kPa) to give 20 mg of a mixture of 2 diastereoisomers of Form A, 1- (R *). - (4 - [(4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (R)] - 3-imidazolylazetidin-1-yl) methyl] benzyl} -1R-imidazole and 1- ( R *) - {4 - [(4-chlorophenyl) - (3- [3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (S)]} - 3-imidazolyl-azetidin-1-yl} methyl] benzyl] -1 / t-IMI-

carbonyldiimidazole as a white varnish ^[X H NMR ( 300 MHz, CDCl ₃ , δ (ppm): mixture of diastereoisomers observed.  2.64 (s 3H); 3.42 (d, J = 8 Hz: 1H); 3.50 (d, J = 8) Hz: 1H); 3.75 (mt: 1H); 4.31 (broad d, J = 8 Hz: 1H); 4.40 (with : 1H); 4.54 and 4.55 (2s: 2H total); 4.72 (s 1H); 6.84 (mt : 2H) ; 6.87 (s 1H);

6.95 (mt 1H); 7.11 (s 1H); from 7.20 to 7.40 (mt 12)].

Example 10

O-Methyloxime (1-benzhydrylazetidin-3-yl) phenylmethanone and a mixture of 2 isomers 2 and E can be prepared by the following procedure: 0.286 g of O-methylhydroxylamine and 0.32 g of sodium acetate are added to a suspension of 0.80 g of 1-benzhydryl mixture Of 3-benzoylazetidine in 30 cm ^{3 of} ethanol. The mixture was stirred at reflux for 24 hours and then cooled to room temperature and filtered. The filtrate is concentrated to dryness at 50 ° C and concentrated under reduced pressure (2.7 kPa). The residue is taken up in 100 cm ^{3 of} dichloromethane and 20 cm ^{3 of} water and 1 N hydrochloric acid are added to the solution with stirring until an acidic pH is obtained. The organic phase is separated after settling, dried over magnesium sulfate and then filtered and concentrated to dryness under reduced pressure (2.7 kPa).

The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, diameter 3.8 cm, height 36 cm), eluting under an argon pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (95/5, 92/8 then 80/20). , by volume) and 30 cm ³ fractions are collected. Fractions 8 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.20 g of O-methyloxime (1-benzhydrylazetidin-3-yl) phenylmethanone, a mixture of 2 isomers Z and E, is obtained as a white solid. 1 H NMR spectrum (250 MHz, (CD ₃ ) ₂ SO d6, δ v) ppm). A mixture of isomers 65/35, * 2.68-3.02 and from 3.25 to 3.90 (mts: 5H total) was observed; 3.76 and 3.80 (2s: 3H overall); 4.26 and 4.38 (2s: 1H overall); from 7.10 to 7.50 (mt 15H)].

1-Benzhydryl-3-benzoylazetidine can be prepared as follows: 112 cm ^{3 of a} 1 M solution of phenylmagnesium bromide in tetrahydrofuran is added dropwise, under argon, to a solution cooled to 0 ° C, 11.5 g of N-methoxy-N-methylamide ( 1-benzhydrylazetidin-3-yl) carboxylic acid in 350 cm ^{3 of} tetrahydrofuran and the temperature of the mixture returned to room temperature. The mixture is stirred at 20 ° C for 20 hours, then 400 cm ^{3 of} saturated ammonium chloride solution are added to the reaction mixture, followed by 250 cm ^{3 of} ethyl acetate. The mixture is stirred and, after settling, separated, the aqueous phase is extracted again with 250 cm ^{3 of} ethyl acetate and the combined organic phases are washed twice with 250 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue is stirred with 50 cm ^{3 of} diisopropyl ether, the suspension is filtered, the solid is drained and then dried under reduced pressure (2.7 kPa). 1-Benzhydryl-3-benzoylazetidine is obtained as a cream-colored solid.

(1-Benzhydrylazetidin-3-yl) carboxylic acid N-methoxy-N-methylamide can be prepared as follows: 13.35 g of (1-benzhydrylazetidin-3-yl) carboxylic acid and 1.0 g of hydroxybenzotriazole hydrate are added with stirring to a suspension of 4.0 g of N, O-dimethylhydroxyoxylamine hydrochloride in 250 cm ^{3 of} dichloromethane. Then 6.92 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 8.8 cm ^{3 of} N, N-diisopropylethylamine are added to the mixture under argon and the mixture is placed under argon and cooled to + 5 ° C. The mixture is stirred for 3 hours at + 5 ° C and then for 20 hours at 20 ° C, 200 cm ^{3 of} water are added and then separated after settling. The organic phase is washed with 300 cm ^{3 of} water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred with 100 cm @ ^{3 of} diisopropyl ether, the suspension is filtered and the solid is drained of water and dried under reduced pressure (2.7 kPa). 10.76 g of (1-benzhydrylazetidin-3-yl) carboxylic acid N-methoxy-N-methylamide is obtained as a cream-colored solid.

(1-Benzhydrylazetidin-3-yl) carboxylic acid can be prepared as follows: a solution of 11 g of potassium hydroxide in 9 cm ^{3 of} water is added dropwise to the suspension, cooled to + 5 ° C, 14 g of (1-benzhydrylazetidin-3- yl) carbonitrile in 140 cm ^{3 of} 2-ethoxyethanol and then heated to 95 ° C. The mixture is stirred for 16 hours at this temperature and then poured slowly and with stirring on ice and left at 0 ° C for 68 hours and concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue is transferred to, i

400 cm ^{3 of} water, the solution is acidified to pH 4 using 6 N hydrochloric acid and then 400 cm ^{3 of} ethyl acetate are added. The resulting mixture is filtered, the solid is dehydrated and dried at 50 ° C under reduced pressure (2.7 kPa). 13.55 g of (1-benzhydrylazetidin-3-yl) carboxylic acid are obtained in the form of a cream-colored solid.

(1-Benzhydrylazetidin-3-yl) carbonitrile can be prepared as follows: a solution of 18.54 g of sodium cyanide in 25 cm ^{3 of} water is added dropwise to a solution of 40 g of 1-benzhydrylazetidin-3-ylme80 tylsulfonate in 350 cm ³ Ν, Ν-dimethylformamide. The mixture is stirred at 65 ° C for 24 hours, then the reaction mixture is returned to room temperature and poured into a mixture of 550 cm ^{3 of} water and 300 g of ice with stirring. The suspension obtained is filtered, the solid is washed three times with 110 cm @ ^{3 of} water and then dissolved in 350 cm @ ^{3 of} dichloromethane. The solution is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred with 200 cm ^{3 of} diisopropyl ether, the suspension is filtered, the solid is drained and then dried under reduced pressure (2.7 kPa). 28.4 g of (1-benzhydrylazetidin-3-yl) carbonitrile are obtained in the form of a pinkish, cream-colored solid.

1-Benzhydrylazetidin-3-ylmethylsulfonate can be prepared starting from 100 g of 1-benzhydrylazetidin-3-ol, 800 cm ^{3 of} dichloromethane, 31 cm ^{3 of} methylsulfonyl chloride and 35 cm ^{3 of} pyridine. The crude product is chromatographed on a silica gel column (particle size 0.063-0.200 mm, diameter 11 cm, height 50 cm), eluting under an argon pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (80/20, 75/25 and then 70/30 and 60/40, v / v) and 1-liter fractions were collected. Fractions 12 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 66 g of 1-benzhydrylazetidin-3-yl methylsulfonate are obtained as a yellowish solid.

1-Benzhydrylazetidin-3-ol may be present. prepared by the procedure of Alan R. Katritzky et al., in J. Heterocyclic Chem .; 31, 271 (1994).

Example 11 (RS) -1- [3 - ({1-Bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] pyrrolidine can be prepared as described in Example 3, starting from 0.10 g 1 - [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] pyrrolidine,

1.5 cm ^{3 of} anhydrous methanol, 1.5 cm ^{3 of} anhydrous dichloromethane and 300 mg of sodium borohydride. The mixture was stirred at 20 ° C for 3 hours and then at 50 ° C for 8 hours. The crude product is chromatographed on a silica gel column (particle size 0.040-0.063 mm, diameter 1 cm, height 8 cm), eluting under an argon pressure of 0.08 MPa with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 5 cm ^3. fractions. Fractions 22 to 28 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is stirred with 5 cm ^{3 of} pentane, the solid is filtered off, dehydrated and dried. 18 mg of (RS) -1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl [methylsulfonylmethyl) phenyl] pyrrolidine is obtained as a white powder [1 H NMR

spectrum (300 MHz CDC1 ₃ , δ v PF > m): 2.01 (mt: 4H); 2.59 (mt: 1H); 2.61 (with 3H); from 3.10 to 3.25 (mt : 2H); 3.27 (mt: 4H); from 3.40 d o 3, 55 (mt : 1H); 3 , 66 (mt : 1H) ; 4.20 (D, J = 12 Hz: 1H); 4.25 (with 1H); from 6.45 to 6, 65 (mt 3H); from 7 , 10 to 7.35 (mt 9H)] 1 ·

1- [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] pyrrolidine can be prepared according to the procedure described in Example '6, starting from 0.6 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-pyrrolidinylphenyl) methyl- (RS)] azetidin-3-ol, 0.1 cm ^{3 of} methylsulfonyl chloride and 0.5 g of 4-dimethylaminopyridine, the residue obtained is purified silica gel column chromatography (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), eluting under an argon pressure of 0.05 MPa with a mixture of dichloromethane and ethanol as eluent (98.5 / 1.5, v / v) and 10 cm &lt; -1 &gt; fractions were collected. Fraction 4 is concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization from 5 cm ^{3 of} diethyl ether, 0.5 g of 1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] pyrrolidine is obtained as a solid, m.p. 133 ° C.

1- [Bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-pyrrolidinylphenyl) methyl- (RS)] azetidin-3-ol can be obtained according to the procedure described in Example 5, starting from 0.5 g 1- [3- (methylsulfonylmethyl) phenyl] pyrrolidine, 0.6 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one, 15 cm ^{3 of} tetrahydrofuran and 1.4 cm ^{3 of a} 1.6 N solution n -butyllithium in hexane. 0.6 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-pyrrolidinylphenyl) methyl (RS)] azetidin-3-ol is obtained as a cream-colored solid.

1- [3- (Methylsulfonylmethyl) phenyl] pyrrolidine can be prepared as described in Example 8, starting from 6 cm ^{3 of} water, 6 cm ^{3 of} 100% acetic acid, 3.5 cm ^{3 of} 36 N sulfuric acid, 3.11 g of oxone 0.96 g of 1- [3- (methylsulfanylmethyl) phenyl] pyrrolidine and 6 clear ethanol. 0.478 g of 1- [3- (methylsulfonylmethyl) phenyl] pyrrolidine is obtained as a light brown gum.

1- [3- (Methylsulfanylmethyl) phenyl] pyrrolidine can be prepared as described in Example 8, starting from 4.0 g of 1-iodo-3- (methylsulfanylmethyl) benzene, 120 cm ^{3 of} tetrahydrofuran, 2.2 g of potassium tert-butoxide , 0.556 g of 1,1'-bis (diphenylphosphino) ferrocenyl palladium chloride, 1.26 g of 1,1'-bis (diphenylphosphino) ferrocene, and

2.6 g of pyrrolidine. 1.9 g of 1- [3- (methylsulfanylmethyl) phenyl] pyrrolidine are obtained in the form of an oil.

Example 12

N- (RS) - [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] -N-methylcarbamic acid tert-butyl ester can be prepared according to the procedure described in Example 3, starting from from 0.10 g of N- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] -N-methylcarbamic acid tert-butyl ester, 1,5 cm ^{3 of} anhydrous methanol, 1.5 cm ^{3 of} anhydrous dichloromethane and 30 mg of sodium borohydride are stirred at 20 ° C for 3 hours. The crude product is stirred with 10 cm ^{3 of} diisopropyl ether, the solid is filtered off and then dried under reduced pressure (2.7 kPa). 94 mg of N- (RS) - [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl [methylsulfonylmethyl) phenyl] -N-methylcarbamic acid tert-butyl ester is obtained in the form of a white powder [ ^X H NMR (300 MHz, (CD _{3) 2} SO d6, δ in ppm): 1.36 (s: 9H); 2.46 (t, J =

7.5 Hz: 1H); 2.75 (s 3H); from 3.00 to 3.55 (mt 4H); 3.17 (s 3H); 4.45 (s 1H); 4.78 (d, J = 11Hz: 1H); from 7.20 to 7.50 (mt 12H)].

N- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylmethylsulfonylmethylene) phenyl] -N-methylcarbamic acid tert-butyl ester can be prepared by the procedure described in Example 6, starting from 5.6 g. 1- [bis (4-chlorophenyl) methyl] -3 - {[3- (N-tert-butyloxycarbonyl-N-methylamino) phenyl] methylsulfonylmethyl- (RS)} azetidin-3-ol,

100 cm ^{3 of} dichloromethane, 1.59 g of methylsulfonyl chloride and 4.5 g of 4-dimethylaminopyridine. The crude product obtained is purified by silica gel column chromatography (particle size 0.04-0.06 mm, diameter 4 cm and weight of silica gel 250 g), eluting under a nitrogen pressure of 0.05 MPa with a mixture of ethyl acetate and cyclohexane (30/70 by volume) and 100 cm ³ fractions are collected. Fractions 12 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). It will be obtained

3.2 g of N- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] methylsulfonylmethylene) phenyl] -N-methylcarbamic acid tert-butyl ester as a white foam.

1- [Bis (4-chlorophenyl) methyl] -3 - {[3- (N-tert-butyloxycarbonyl-N-methylamino) phenyl] methylsulfonylmethyl- (RS)} azetidin-3-ol can be prepared as described in Example 5 starting with 3,8 g of N- [3- (methylsulfonylmethyl) phenyl] -N-methylcarbamic acid tert-butyl ester, 50 cm ^{3 of} tetrahydrofuran, 9,5 cm ^{3 of a} 1,6 N solution of n-butyllithium in hexane and 3,82 g 1- [Bis (4-chlorophenyl) methyl] azetidin-3-one. The crude product is purified by silica gel column chromatography (particle size 0.04-0.06 mm, diameter 4 cm and silica gel weight 250 g), eluting under a nitrogen pressure of 0.05 MPa with dichloromethane and then with a mixture of dichloromethane and ethanol (99/1 by volume). ) and 500 cm ³ fractions are collected. Fractions 10-16 are combined and concentrated under reduced pressure (2.7 kPa). 5.6 g of 1- [bis (4-chlorophenyl) methyl] -3 - {[3- (N-tert-butyloxycarbonyl-N-methylamino) phenyl] methylsulfonylmethyl (RS)} azetidin-3-ol are obtained in the form of: foam.

N- [3- (methylsulfonylmethyl) phenyl] -N-methylcarbamic acid tert-butyl ester can be prepared by the following procedure: 3.7 g of di-tert-butyl dicarbonate are added to a solution of 3 g of N- [3- (methylsulfonylmethyl) phenyl] N-methylamine in 80 cm ^{3 of} dichloromethane. The mixture is stirred at 20 DEG C. for hours, 100 cm @ ^{3 of} water are added to the reaction mixture and the mixture is separated after standing. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa). The residue was purified by silica gel column chromatography (particle size 0.04-0.06 mm, diameter 4 cm and weight of silica gel 300 g), eluting under a nitrogen pressure of 0.05 MPa with a mixture of ethyl acetate and cyclohexane (45/55 by volume) and collected. 100 cm ³ fractions. Fractions 11-16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 3.8 g of N- [3- (methylsulfonylmethyl) phenyl] -N-methylcarbamic acid tert-butyl ester are obtained in the form of a gum which crystallizes.

N- [3- (Methylsulfonylmethyl) phenyl] N-methylamine can be prepared as follows: a mixture of 9.65 g of formic acid and 19.63 g of acetic anhydride is heated to 50 ° C under argon and then allowed to return the temperature of the reaction solution. to room temperature. 40 cm ^{3 of} tetrahydrofuran are added and the mixture is cooled to -20 ° C. The mixture was stirred at -20 ° C for 2 hours and 14.8 g was added

3- (methylsulfonylmethyl) phenylamine, maintaining the temperature at this value. The mixture is stirred for 2 hours at -20 ° C and then for 48 hours at 20 ° C, then the mixture is filtered, the solid is drained, washed with water and washed three times with 50 cm ^{3 of} diisopropyl ether and dried under reduced pressure (2.7 '). kPa). Solid A was obtained. The filtrate was concentrated to half the volume, the resulting suspension was filtered, the solid was drained, washed with diethyl ether and dried. A solid B is obtained. Both A and B are combined and transferred to 375 cm ^{3 of} tetrahydrofuran and the mixture is cooled to 0 ° C and 80 cm ^{3 of a} 2 M solution of borane-dimethylsulfide complex in tetrahydrofuran are added over 20 minutes. was heated at reflux for 3 hours. The reaction mixture is cooled to + 5 ° C, 60 cm ^{3 of} methanol are added over 20 minutes, the mixture is stirred for 1 hour at room temperature and then gaseous hydrochloric acid is added to pH 1. The mixture is heated under reflux for 1 hour and 300 cm ^{3 of} water, 3 N sodium hydroxide solution are then added until pH 8. The mixture is extracted with 500 cm ^{3 of} ethyl acetate, the organic phase is washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated to dryness. under reduced pressure (2.7 kPa). The residue is taken up in 100 cm ^{3 of} 4 N hydrochloric acid and the solution is washed with 100 cm ^{3 of} ethyl acetate, basified to pH 8 using 3 N sodium hydroxide and saturated aqueous sodium carbonate solution and then extracted twice with 75 cm ^{3 of} ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). There were obtained 8.98 g of N- [3- (methylsulfonylmethyl) phenyl] N-methylamine as a pink solid.

3- (Methylsulfonylmethyl) phenylamine can be prepared by the following procedure: a suspension of 23.7 g of 1- (methylsulfonylmethyl) -3-nitrobenzene in 150 cm ^{3 of} methanol and 65 cm ^{3 of} 36% hydrochloric acid is heated to reflux and then added carefully after 18.5 g of iron in small portions over 10 minutes. The mixture was heated at reflux for 4 hours and then stirred at room temperature for 20 hours, 5 g of iron were added to the reaction mixture and then refluxed for 1 hour and then at room temperature for 20 hours. The mixture is basified to pH 9 with aqueous ammonia and sodium bicarbonate and then extracted three times with 250 cm ^{3 of} ethyl acetate, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 14.9 g of 3- (methylsulfonylmethyl) phenylamine are obtained in the form of a beige powder.

1- (Methylsulfonylmethyl) -3-nitrobenzene can be prepared by refluxing 23.8 g of 3-nitrobenzyl chloride, 20 g of sodium methylsulfinate and 250 cm ^{3 of} absolute ethanol. 23.74 g of 1- (methylsulfonylmethyl) -3-nitrobenzene are obtained in the form of a white powder.

Example 13 (RS) -N- [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl [methylsulfonylmethyl) phenyl] -N-methylamine can be prepared by the procedure described in Example 3, starting from 0.10 g of N- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] -N-methylamine, 1,5 cm ^{3 of} anhydrous methanol, 1,5 cm ³ anhydrous dichloromethane and 45 mg of sodium borohydride while stirring and heating at 20 ° C for 20 hours and then at 50 ° C for 5 hours. The crude product is purified by silica gel column chromatography (particle size 0.040-0.063 mm, diameter 1 cm, height 10 cm), eluting under an argon pressure of 0.08 MPa with a mixture of cyclohexane and ethyl acetate (80/20 and then 60/40 by volume) and 5 cm ³ fractions are collected. Fractions 20 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is stirred with 5 cm ^{3 of} pentane, the solid is filtered off, the water is removed and dried. 20 mg of (RS) -N- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] -N-methylamine is obtained as a white powder [ ³ H NMR spectrum] (300 MHz, CDCl 3, δ in ppm)]: from 2.50 to 2.65 (mt 1H); 2.60 (s 3H); 2.82 (d, J = 5Hz: 3H); 3.18 (mt 2H); from 3.35 to 3.50 (mt 1H); 3.64 (broad t, J = 7.5 Hz: 1H); 3.80 (mt 1H);

4.18 (d, J = 11.5 Hz 1H); 4.24 (s 1H); from 6.50 to 6.70 (mt 3H); from 7.10 to 7.35 (mt 9H).

N- [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] -N-methylamine can be prepared by the following procedure: 2.7 g 1- [bis (4-chlorophenyl) methyl ] -3 - {[3- (N-tert-butyloxycarbonyl-N-methylamino) phenyl] methylsulfonylmethylene} azetidine in 30 cm ^{3 of} dioxane and 30 cm ^{3 of a} 4.7 N hydrogen chloride dioxane solution is stirred for 20 hours. dry under reduced pressure (2.7 kPa), transferred to 50 cm ^{3 of} water and 50 cm ^{3 of} ethyl acetate, stirred and carefully neutralized with a saturated aqueous sodium bicarbonate solution, the organic phase is separated and dried over magnesium sulfate, treated with animal and then concentrated under reduced pressure (2.7 kPa) to a volume of about 25 cm ³ , filtered and concentrated to dryness under reduced pressure to give 1.3 g of N- [3- ({1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] -N-methylamine as white crystals, melting at 228 ° C.

Example 14 (RS) -1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-bis-trifluoromethylphenyl) methylsulfonylmethyl] azetidine can be prepared as described in Example 3, starting from 0.1 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-bis-trifluoromethylphenyl) methylsulfonylmethylene] azetidine, 1.5 cm ^{3 of} anhydrous methanol, 1.5 cm ^{3 of} anhydrous dichloromethane and 15 mg of sodium borohydride, the mixture being Stir and heat to 20 ° C for 3 hours. The crude product is stirred with 5 cm @ ^{3 of} pentane, the solid is filtered off, dehydrated and dried. 82 mg of (RS) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-bis-trifluoromethylphenyl) methylsulfonylmethyl] azetidine are obtained as a white powder [ ³ H NMR spectrum (400 MHz, (CD)] ₃ ) ₂ SO d6, δ in ppm)]: 2.84 (s: 3H); 3.08 (mt 2H); from 3.25 to 3.40 (mt 1H); from 3.45 to 3.65 (mt 2H); 4.45 (s: 1H); 5.13 (d, J = 10.5 Hz: 1H); from 7.25 to 7.50 (mt 8H); 8.11 (broad s: 2H); 8.15 (broad s: IH)] ·.

1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-bis-trifluoromethylphenyl) methylsulfonylmethylene] azetidine can be prepared as follows: 0.96 g of crushed sodium hydroxide is added portionwise to a solution of 3.16 g 3-acetoxy-1- [bis (4-chlorophenyl) methyl] -3 - {[3,5-bis (trifluoromethyl) phenyl] methylsulfonylmethyl- (RS) -azetidine in cm ^{3 of} dioxane. The mixture is stirred at room temperature for 1 hour and 200 cm ^{3 of} ethyl acetate, 200 cm ^{3 of} water are added to the reaction mixture and the mixture is then separated after settling. The organic phase is washed twice with 80 cm ^{3 of} water, then with 80 cm ^{3 of} brine, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The crude product is purified by silica gel column chromatography (particle size 0.040-0.063 mm, diameter

4.8 cm, height 14.5 cm), eluting under a pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (85/15 by volume) and collecting 40 cm ^{3 of} fraction. Fractions 8 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.49 g of 1- [bis (4-chlorophenyl) methyl] -3 - {[(3,5-bis-trifluoromethylphenyl) methylsulfonylmethylene} azetidine are obtained in the form of a white foam.

3-Acetoxy-1- [bis (4-chlorophenyl) methyl] -3 - {[3,5-bis (trifluoromethyl) phenyl] methylsulfonylmethyl- (RS)} azetidine can be prepared by the following procedure: 4.1 cm ³ 1 A 6 N solution of n-butyllithium in hexane is added dropwise and under argon to a solution cooled to -78 ° C, 2.0 g of [3,5-bis (trifluoromethyl) benzyl] methylsulfone in 35 cm ^{3 of} tetrahydrofuran. The mixture is stirred for 1 hour at -70 ° C and 2 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one in 35 cm ^{3 of} tetrahydrofuran are added dropwise. The mixture is stirred at -78 ° C for 2 hours, a solution of 0.7 cm ^{3 of} acetyl chloride in 5 cm ^{3 of} anhydrous diethyl ether is added and the temperature of the mixture is returned to room temperature. The mixture is stirred for 2 hours 30 minutes, 100 cm @ ^{3 of} water are added to the reaction mixture and the mixture is separated after settling. The organic phase is washed with 100 cm ^{3 of} water, then 100 cm ^{3 of} brine and 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 0.04-0.06 mm, diameter 5.6 cm, height 16 cm), eluting under an argon pressure of 0.05 MPa with a mixture of ethyl acetate and cyclohexane (10/90 and then 40/1). 60 vol.) And 100 cm ³ fractions are collected. Fractions 37 to 52 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 3.56 g of 3-acetoxy-1- [bis (4-chlorophenyl) methyl] -3 - {[3,5-bis (trifluoromethyl) phenyl] methylsulfonylmethyl- (RS)} azetidine are obtained in the form of a white foam.

[3,5-Bis (trifluoromethyl) benzyl] methylsulfone can be prepared by heating to reflux, 1.8 g of 3,5-bis (trifluoromethyl) benzyl chloride, 50 cm ^{3 of} absolute ethanol and 1.22 g of sodium methylsulfinate. 1.86 g of [3,5-bis (trifluoromethyl) benzyl] methylsulfone are obtained in the form of a white solid.

Example 15

N- [4 - ((4-chloro-phenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl (RS)] azetidin-1-y1} methyl (RS)) benzyl] -N, N-dimethylamine, a mixture of two diastereoisomers can be prepared as described in Example 3, starting from 0.10 g of N- [4 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl - (RS) -benzyl] -N, N-dimethylamine, 1.5 cm ^{3 of} anhydrous methanol, 1.5 cm ^{3 of} anhydrous dichloromethane and 45 mg of sodium borohydride, the mixture is stirred for 16 hours at 20 ° C and then for 16 hours hours at 50 DEG C. The crude product is chromatographed on a silica gel column (particle size 0.040-0.063 mm, diameter 1 cm, height 22 cm), eluting under an argon pressure of 0.08 MPa with a mixture of ethyl acetate and methanol (97/3 by volume) and collecting 20 cm ³ fractions. fractions 17-25 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue was stirred with 5 cm ³ of pentane, the solid was filtered, freed of water and dried. obtained 6 mg of N- [4 - ((4-chloroph enyl) - (3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (RS)] azetidin-1-yl} methyl (RS) benzyl] -N, N-dimethylamine, a mixture of two diastereoisomers

mérov vo in the form of a white powder pH NN IR spectrum (300 MHz) c DC1 ₃ , δ in ppm)] : 2.20 (s: 6H); 2.53 (T, J = 7 Hz: 1H); 2.65 (with 3H); from 3.10 to 3.25 (mt 2H); from 3 30 up to 3,4 5 (mt: 1H) ; 3.35 (br s: 2H); 3.63 (wide t, J - 7 Hz: 1H); 4.24 (with : 1H); 4.25 (d, J = 11 Hz: 1H); 6.82 (t t, J = 9 and 2 Hz: 1H);  6. 94 (mt

: 2H); from 7.15 to 7.35 (mt 8H)].

N- [4 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl- (RS)) benzyl] -N, N-dimethylamine can be prepared as follows : 1.0 .. (RS) -4 - ((4-Chlorophenyl) - (3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl) benzaldehyde is added, under argon, to solution 0 93 cm @ ^{3 of a} 2 M solution of dimethylamine in methanol in 30 cm @ ^{3 of} anhydrous 1,2-dichloroethane was stirred at room temperature for 30 minutes and 0.9 g of sodium triacetoxyborohydride was added in small portions. a mixture of 2.65 cm "1 N sodium hydroxide solution, 100 cm ³ of water and 100 cm ³ of dichloromethane and the mixture is separated after settling. the organic phase was washed twice with 80 ^cc of water and 80 cm ³ of brine, then dried over magnesium sulfate and concentrated The residue is chromatographed on a silica gel column (particle size 0.04 0.06 mm, diameter 4 cm, height 17.5 cm), eluting under an argon pressure of 0.05 MPa. ethyl acetate / cyclohexane (30/70 by volume) and 40 cm ³ fractions are collected. Fractions 48-53 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.46 g of N- [4 - ((4-chlorophenyl) - {3 - [(- 3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl (RS)) benzyl] -N, N is obtained. -dimethylamine as a white solid.

(RS) -4 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl) benzaldehyde can be prepared as follows: 75.6 cm ^{3 of} 5 N hydrochloric acid 18.9 g of 1 - [(4-chlorophenyl) - (4- [1,3] dioxolan-2-ylphenyl) methyl] - (RS) -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] was added to the solution. azetidine in 80 cm ^{3 of} tetrahydrofuran. After 3 hours at room temperature, the mixture is taken up in dichloromethane and distilled water and the pH of the mixture is adjusted to 14 with 30% sodium hydroxide and the mixture is separated after settling. The organic phase is washed twice with 100 cm ^{3 of} water and then with 100 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 16 g of (RS) -4 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl) benzaldehyde are obtained in the form of a white foam.

1 - [(4-Chlorophenyl) - (4- [1,3] dioxolan-2-ylphenyl) methyl] - (PS) -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine can be prepared as follows: 13 0 cm ^{3 of} 1,8-diazabicyclo [5-4-O] undec-7-ene is added dropwise to a solution of 34.65 g of a mixture of two diastereoisomers, 1 - [(4-chlorophenyl) - (4- [1, 2-chlorophenyl)] 3] dioxolan-2-ylphenyl) methyl (PS)] - 3 - [(3,5-difluorophenyl) methylsulfonylmethyl (RS)] azetidin-3-yl acetate in 400 cm ^{3 of} tetrahydrofuran under argon at 0 ° C and after by conventional work-up, the product is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter

10.2 cm, height 23 cm), eluting under an argon pressure of 0.05 MPa with a mixture of ethyl acetate and cyclohexane (20/80 by volume) and collecting 250 cm ³ fractions. 16.6 g of 1 - [(4-chlorophenyl) - (4- [1,3] dioxolan-2-ylphenyl) methyl] - (RS) -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine are obtained in in the form of a white solid.

Mixture of two diastereoisomers 1 - [(4-chlorophenyl) - (4- [1,3] dioxolan-2-ylphenyl) methyl- (RS)] - 3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (RS)] azetidine -3-Ylacetate can be obtained as follows: proceed as in Example 1 (Method 2), starting from

11.6 g of (3,5-difluorobenzyl) methylsulfone, 35.1 cm ^{3 of a} 1.6 N solution of n-butyllithium in hexane, 19.3 g of 1 - {(4-chlorophenyl) [4 - ([1,3] dioxolan-2-yl) phenyl] methyl- (RS)} azetidin-3-one and 8.8 cm ^{3 of} acetyl chloride in 500 cm ^{3 of} tetrahydrofuran to give a mixture of two 1 - [(4-chlorophenyl) - (4- [1] 3] dioxolan-2-ylphenyl) methyl (RS)] - 3 - [(3,5-difluorophenyl) methylsulfonylmethyl (RS)] azetidin-3-yl acetate diastereoisomers as a white foam.

1 - {(4-Chlorophenyl) [4 - ([1,3] dioxolan-2-yl) phenyl] methyl- (RS)} azetidin-3-one can be prepared as follows: 46 cm ^{3 of} triethylamine are added at temperature to a solution of 28.32 g of 1 - {(4-chlorophenyl) [4 - ([1,3] dioxolan-2-yl) phenyl] methyl (RS) Jazetidin-3-ol in 200 cm ^{3 of} dimethylsulfoxide, then a solution of 34 g of sulfur trioxide-pyridine complex in 100 cm ^{3 of} dimethylsulfoxide is added dropwise. After 0.25 hours at room temperature, the reaction mixture is poured onto ice, extracted with ethyl acetate, washed three times with 400 cm ^{3 of} water and then with 400 cm ^{3 of} saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness. reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 9.2 cm, height 21 cm), under an argon pressure of 0.05 MPa with a mixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent. and 250 cm ³ fractions are collected. Fractions 9 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 20.4 g of 1 - ((4-chlorophenyl) [4 - ((1,3) dioxolan-2-yl) phenyl) methyl (RS) Jazetidin-3-one are obtained in the form of a yellow oil.

1 - {(4-Chlorophenyl) [4 - ([1,3] dioxolan-2-yl) phenyl] methyl- (RS)} azetidin-3-ol can be prepared as described in Example 3, starting from 35, 0 g of {(4-chlorophenyl) [4- (1,3-dioxolan-2-yl) phenyl] methyl] amine, 8.3 g of epibromohydrin, 5.1 g of sodium bicarbonate and 400 cm ^{3 of} ethanol. 30.3 g of 1 - {(4-chlorophenyl) [492] are obtained

- ([1,3] dioxolan-2-yl) phenyl] methyl- (RS)} azetidin-3-ol.

{(4-chlorophenyl) [4 - ([1,3] -dioxolan-2-yl) phenyl] methyl- (RS)} amine hydrochloride can be prepared according to the method described by Grisar M. et al., J. Med. Chem., 885 (1973) starting from 67.2 g

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 ether. 42.3 g of {(4-chlorophenyl) [4- ([1,3] -dioxolan-2-yl) phenyl] methyl- (RS) -aminine are obtained as a yellow oil.

Example 16

1 - [(4-Chlorophenyl) (thien-2-yl) methyl- (RS)] - 3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (RS)] azetidine, a mixture of two diastereoisomers, may be prepared as described in Example 3, starting from 0.10 g of 1 - [(4-chlorophenyl) (thien-2-yl) methyl- (RS)] - 3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine, 1.5 cm ³ anhydrous methanol, 1.5 cm ^{3 of} anhydrous dichloromethane and 45 mg of sodium borohydride, the mixture is stirred at 20 ° C for 16 hours and at 50 ° C for 16 hours. The crude product is chromatographed on a silica gel column (particle size 0.040-0.063 mm, diameter 1 cm, height 25 cm), eluting under an argon pressure of 100 bar with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 20 cm ^{3 of} fractions. Fractions 37 to 42 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is stirred with 5 cm ^{3 of} pentane, the solid is filtered off and dried. 8 mg of 1 - [(4-chlorophenyl) (thien-2-yl) methyl- (RS)] - 3 - [(3,5-difluorophenyl) methylsulfonylmethyl (RS)] azetidine are obtained, a mixture of the two diastereoisomers as white. powder ^[X H NMR (300 MHz, CDCl3, δ in ppm). A mixture of two diastereoisomers was found, from 2.50 to 2.70 (mt 1H); 2.66 and 2.68 (2s: 3H overall); from 3.15 to 3.80 (mt 4H); from 4.20 to 4.30 (mt 1H);

4.31 and 4.57 (2s: 1H overall); from 6.80 to 7.00 and from 7.10 to 7.40 (mts: 10H total)].

1 - [(4-Chlorophenyl) (thien-2-yl) methyl- (RS)] - 3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine can be prepared as described in Example 6, starting from 0.52 g mixtures of two 1 - [(4-chlorophenyl) (thien-2-yl) methyl (RS)] - 3 - [(3,5-difluorophenyl) methylsulfonylmethyl (RS)] azetidin-3-ol diastereoisomers,

0.14 cm @ ^{3 of} methylsulfonyl chloride and 0.49 g of 4-dimethylaminopyridine. After chromatography on a silica gel column (particle size 0.06 0.200 mm, diameter 2.4 cm, height 20 cm), eluting under an argon pressure of 0.05 MPa with a mixture of ethyl acetate and cyclohexane (20/80 by volume) and collecting 30 cm ^{3 of} fractions, 0.32 g of (RS) -1 - [(4-chlorophenyl (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine is obtained in the form of a white solid, m.p. C.

A mixture of two diastereoisomers of 1 - [(4-chlorophenyl) (thien-2-yl) methyl- (RS)] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl- (RS)] azetidin-3-ol can be prepared by as described in Example O, starting from 1.60 cm @ ^{3 of} 1.6 N n-butyllithium in hexane, 0.83 g of (3,5-difluorobenzylmethylsulfone) and 1.6 g of 1 - [(4-chlorophenyl) (thien- 2-yl) methyl- (RS)] azetidin-3-one After purification on a silica gel column (particle size 0.06-0.200 mm, diameter 2.8 cm, height 30 cm), eluting under an argon pressure of 0.05 MPa ethyl acetate / cyclohexane (25/75 by volume) and collecting 40 cm ³ fractions gave 0.55 g of a mixture of diastereoisomers of 1 - [(4-chlorophenyl) (thien-2-yl) methyl (RS)] -3 - [( 3,5-difluorophenyl) methylsulfonylmethyl- (RS)] azetidin-3-ol as an off-white solid.

1 - [(4-Chlorophenyl) (thien-2-yl) methyl- (RS)] azetidin-3-one can be prepared as described in Example 1 (method 2), starting from 1.83 cm @ ^{3 of} oxalyl chloride; cm ^{3 of} dichloromethane, 3.04 cm ^{3 of} dimethylsulfoxide, 5.2 g of 1 - [(4-chlorophenyl) (thien-2-yl) methyl (RS)] azetidin-3-ol, 80 cm ^{3 of} dichloromethane and 9.12 cm 3 ³ triethylamine to give 3.3 g of 1 - [(4-chlorophenyl) (thien-2-yl) methyl (RS)] azetidin-3-one as a yellow oil which crystallizes at room temperature.

1 - [(4-Chlorophenyl) (thien-2-yl) methyl- (RS)] azetidin-3-ol can be prepared as follows: 4.12 g of sodium bicarbonate is 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 to 65 ° C and 4.03 cm ^{3 of} epibromohydrin are added. The mixture is stirred at 65 ° C for 20 hours, the crude mixture is filtered and the filtrate is concentrated 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) eluting under an argon pressure of 0.05 MPa with a 25/75 by volume mixture of ethyl acetate and cyclohexane 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 can be prepared as follows: a solution of 10.92 g of 2-thiophenecarbonitrile in 80 cm ^{3 of} diethyl ether is added slowly to the suspension cooled to 10 ° C 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. The mixture is heated under reflux for 1 hour, cooled to 10 ° C and 40 cm ^{3 of} methanol are slowly added and then the mixture is filtered through supercel. 4.54 g of sodium borohydride are then added in small portions under argon over 15 minutes and the reaction mixture is stirred at 20 ° C for 20 hours. The resulting mixture was diluted with ethyl acetate and washed with water. The organic phase is dried over magnesium sulphate and concentrated to dryness at 50 ° 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) eluting under an argon pressure of 0.05 MPa with a mixture of ethyl acetate and cyclohexane (4/6 by volume) and collecting 100 cm ³ fractions. . Fractions 6 to 12 are concentrated to dryness, corresponding to 13 g of imine as a yellow oil which is taken up in 100 cm ^{3 of} methanol. 2.4 g of sodium borohydride were added to the obtained solution, and the mixture was stirred at 5 ° C for 1 hour. The resulting mixture was diluted with ethyl acetate and then washed with water. The organic phase is dried over magnesium sulphate 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 3.2 cm, height 40 cm) eluting under a pressure of 0.05 MPa with a mixture of ethyl acetate and cyclohexane (4/6 by volume) and collecting 60% of the residue. cm ³ fraction. 11.0 g of [(4-chlorophenyl) (thien-2-yl) methyl- (RS)] amine are obtained in the form of a yellow oil.

Example 17 (RS) - [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] methanol can be prepared by the procedure described in Example 3, starting from 0.050 g of [3- ( {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] methanol, 1.0 cm ^{3 of} anhydrous methanol, 1.0 cm ^{3 of} anhydrous dichloromethane and 20 mg of sodium borohydride while stirring the mixture 3 hours at 20 ° C. The crude product is chromatographed on a silica gel column (particle size 0.040-0.063 mm, diameter 1 cm, height 20 cm) eluting under an argon pressure of 0.08 MPa with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 10 cm ³ fractions. Fractions 30 to 38 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred with 5 cm ^{3 of} pentane, the solid is filtered off and dried. 13 mg of (RS) - [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl [methylsulfonylmethyl) phenyl] methanol is obtained as a white powder.

¹ H NMR spectrum (300 MHz); MHz, CDCl ₃ , δ v ppm) 1.75 (t, J = 6) Hz: 1H); 2.52 (t, J = 7.5) Hz: 1H); 2.59 (with : 3H); 3.17 (broad t, J = 7.5 Hz: 2H); 3.48 (mt 1H); 3.65 (mt : 1H); 4.23 (s: 1H); 4.28 (d, J = 11.5 Hz) : 1H); 4.70 (d, J = 6 Hz: 2H); from 7.15 to

7.40 (mt 12H)].

[3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] methanol can be prepared as follows: 17 cm ^{3 of a} 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran is added to a solution cooled to + 5 ° C, 5.1 g of 1- [bis (4-chlorophenyl) methyl] -3 - {[3- (tert-butyldimethylsilyloxymethyl) phenyl] methylsulfonylmethylenesetidine in 51 cm ^{3 of} tetrahydrofuran. The mixture is stirred for 20 minutes cold and then at 20 ° C for 3 hours, the reaction mixture is poured into a mixture of 200 cm ^{3 of} water and 100 cm ^{3 of} ethyl acetate and then separated after settling. The organic phase is washed with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.06 mm, diameter 2 cm, height cm) eluting with a mixture of dichloromethane and ethanol (97/3 by volume) under a nitrogen pressure of 0.05 MPa and collecting 100 cm ^{3 of} fraction. Fractions 10-14 are combined and 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 a frit and washed with 2 cm ^{3 of} ethyl acetate. 1.6 g of [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] methanol are obtained in the form of a white foam, melting at 214 ° C.

1- [Bis (4-chlorophenyl) methyl] -3 - {[3- (tert-butyldimethylsilyloxymethyl) phenyl] methylsulfonylmethylene} azetidine can be prepared as described in Example 1, starting from 10.8 g of 1- [bis (4- chlorophenyl) methyl] -3 - {[3- (tert-butyldimethylsilyloxymethyl) phenyl] methylsulfonylmethyl- (RS)} azetidin-3-ol, 2 cm ^{3 of} methylsulfonyl chloride and 8.5 g of 4-dimethylaminopyridine. The residue obtained is purified by silica gel column chromatography (particle size 0.06 0.06 mm, diameter 4 cm, height 40 cm) eluting under argon with 0.05 MPa with dichloromethane and collecting 100 cm ^{3 of} fractions. Fractions 12 to 29 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 5.2 g of 1- [bis (4-chlorophenyl) methyl] -3 - {[3- (tert-butyldimethylsilyloxymethyl) phenyl] methylsulfonylmethylene} azetidine are obtained in the form of a gum.

1- [Bis (4-chlorophenyl) methyl] -3 - {[3- (tert-butyldimethylsilyloxymethyl) phenyl] methylsulfonylmethyl- (RS)} azetidin-3-ol may be prepared as described in Example 5, starting from 5.8 g of tert-butyl- (3-methylsulfonylmethylbenzyloxy) dimethylsilane and 5.6 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one gave 10.8 g of 1- [bis (4-chlorophenyl) methyl] -3 - {[3- (tert-Butyldimethylsilyloxymethyl) phenyl] methylsulfonylmethyl- (RS)} azetidin-3-ol as a gum.

Tert-butyl- (3-methylsulfonylmethylbenzyloxy) dimethylsilane can be prepared as follows: 4.87 g of imidazole are added to a solution of 5.73 g of (3-methylsulfonylmethylphenyl) methanol in 50 cm ³

N, N-dimethylformamide and then 10.3 cm ^{3 of} tert-butylchlorodimethylsilane are added. After stirring at room temperature for 20 hours, the reaction mixture was 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 3.5 cm, silica gel weight 100 g) eluting under a nitrogen pressure of 0.05 MPa with dichloromethane and collecting 100 cm ^{3 of} fraction. Fractions 2 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 5.8 g of an oil are obtained, which crystallizes at room temperature (mp = 75 ° C).

(3-Methylsulfonylmethylphenyl) methanol can be prepared as follows: a mixture of 26 g of 3- (methylsulfonylmethyl) benzoic acid and 4.6 g of lithium aluminum hydride in 600 cm ^{3 of} tetrahydrofuran is stirred at about 20 ° C for 18 hours. The solution is cooled to 0 ° C and then 15 cm ^{3 of} ethyl acetate, 30 cm ^{3 of} water, 5 cm ^{3 of} 15% aqueous sodium hydroxide solution and finally 30 cm ^{3 of} water are successively added. The mixture is filtered through diatomaceous earth and the filtrate is taken up in 60 cm ^{3 of} ethyl acetate. The organic phase is taken up in 500 cm ^{3 of} water and then 200 cm ^{3 of} saturated aqueous sodium chloride solution, separated after settling, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 10.4 g of (3-methylsulfonylmethylphenyl) methanol are obtained in the form of a gum.

3- (Methylsulfonylmethyl) benzoic acid can be prepared by the following procedure: the reaction is carried out according to the procedure of Example 14, starting from 23.3 g of 3-chloromethylbenzoic acid,

23.3 g of sodium methanesulfinate gave 26 g of 3- (methylsulfonylmethyl) benzoic acid as an off-white solid, melting at 210 ° C.

Example 18

1- [Bis (4-chlorophenyl) methyl] -3- (phenylsulfonylmethyl) azetidine can be prepared as follows: 13 mg of sodium borohydride is added under argon to a solution of 0.15 g of 1- [bis (4-chlorophenyl) methyl] methyl) -3- (phenylsulfonylmethylene) azetidine in 3 cm ^{3 of} anhydrous ethanol and 3.5 cm ^{3 of} anhydrous dichloromethane. The mixture was stirred for 1 hour and 45 minutes, 14 mg of sodium borohydride was added again, and the mixture was stirred at 20 ° C for 20 hours. The reaction mixture was then heated to 50 ° C, 9.5 mg of sodium borohydride was added and stirred at 50 ° C for 2 hours 30 minutes and then cooled to room temperature. It is then added to a mixture of 0.5 cm ^{3 of} water, 10 cm ^{3 of} dichloromethane and 50 mg of magnesium sulfate, the mixture is filtered and evaporated 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 cm, height 15 cm) eluting under an argon pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 5 cm ³ fractions. . Fractions 12 to 19 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 29 mg of 1- [bis (4-chlorophenyl) methyl)] - 3- (phenylsulfonylmethyl) azetidine are obtained as a white solid.

substances [ ³ Η NMR spectrum (300 MHz, CDCl ₃ , δ v ppm): from 2,75 to 8,90 (mt: 3H) ; 3.32 (mt : 2H) ; 3.37 (d, J = 7 Hz: 2H); 4.22 (s : 1H); from 7.20 to 7.30 (mt: 8H); 7.57 (wide t, J = 7,5 Hz: 2H); 7.67 (Tt, J = 7.5 and 1.5 Hz: 1H); 7.88 (br d. J = 7.5

Hz: 2H)].

Example 19

1- [Bis (4-chlorophenyl) methyl)] -3- (phenylsulfonylmethylene) azetidine can be prepared as follows: 12 cm ^{3 of a} 1.6 M solution of n-butyllithium in hexane are added over 5 minutes under argon to the cooled solution. to -70 ° C, 4.34 g of (phenylsulfonylmethyl) trimethylsilane in 40 cm ^{3 of} dimethyl ether. The reaction mixture is stirred for 30 minutes at -60 [deg.] C. and a solution of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one in 30 cm &lt; 3 ^{&gt; of} dimethyl ether [obtained as base prepared by treatment 7, 35 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one hydrobromide dissolved in 30 cm ^{3 of} water with 25 cm ^{3 of} 1 N sodium hydroxide and extraction of the base obtained with 30 cm ^{3 of} diethyl ether and then drying and concentration to dryness pressure (2.7 kPa)]. The mixture was stirred at -70 ° C for 45 minutes and then at 20 ° C for 2 hours. To the reaction mixture is added 12 cm ^{3 of} saturated aqueous ammonium chloride solution, 20 cm ^{3 of} water, and then extracted with 40 cm ^{3 of} ethyl acetate. The combined organic phases are [lacuna] with 40 cm ^{3 of} water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 40 cm, diameter 5 cm) eluting under an argon pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (90/10 and then 85/15 by volume) and collecting 100 g. cm ³ fraction. Fractions 10-16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is triturated with 10 cm @ ^{3 of} diethyl ether, the suspension is filtered and the solid is dried. 1.17 g of 1- [bis (4-chlorophenyl) methyl)] -3- (phenylsulfonylmethylene) aze-

tidine as a white solid [H NMR Spectrum (300MHz, CDCl _{3 (} δ in ppm): 3.88 (mt 2H); 4.29 (mt : 2H); 4.50 (s 1H); 6.17 (mt 1H); from 7.20 to 7.4 0 (mt 8 H); 7.56 (wide t, J = 7.5Hz: 2H) ; 7.64 (tt, J = 7.5 and 1.5 Hz: 1H); 7 87 (wide d, J = 7.5 Hz: 2H)].

(Phenylsulfonylmethyl) trimethylsilane can be prepared as follows: 13 cm ^{3 of a} 1.6 M solution of n-butyllithium in hexane are added under stirring under argon over 20 minutes to a solution cooled to -70 ° C, 3 g of methylphenylsulfone in 40 cm ^{3 of} anhydrous tetrahydrofuran. The mixture is stirred for 30 minutes at -70 ° C, 2.66 cm ^{3 of} trimethylchlorosilane are added to the mixture, and cooling is stopped. The mixture is stirred for 4 hours at room temperature, 30 cm ^{3 of} water are added to the reaction mixture and the mixture is extracted with 30 cm ^{3 of} ethyl acetate. The organic phase is washed with 30 cm ^{3 of} water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 4.34 g of (phenylsulfonylmethyl) trimethylsilane are obtained in the form of a yellow liquid.

Example 20

2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylmethylsulfonyl} pyridine can be prepared as follows: 0.125 g of sodium borohydride is added to a solution of 0.25 g of 2- {1- [bis (4- chlorophenyl) methyl) azetidin-3-ylidenemethylsulfonyl} pyridine in 20 cm ^{3 of a} 50/50 mixture of dichloromethane and ethanol. The mixture is stirred at 50 DEG C. for 1 hour, then the reaction mixture is cooled to 20 DEG C. and 20 cm @ ^{3 of} dichloromethane, 1 cm @ ^{3 of} water and 0.1 g of magnesium sulfate are added. The mixture was filtered and the filtrate was concentrated at 50 ° C under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, height 15 cm, diameter 1 cm) eluting under a argon pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (40/60 by volume) and collecting 10 cm ³ fractions. Fractions 5-10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of 2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-ylmethylsulfonyl [pyridine] is obtained in the form of a white powder. ¹ H NMR spectrum (300 MHz, CDCl 3, δ in ppm): from 2.80 to 3.00 (mt 3H);

3.34 (mt 2H); 3.70 (d, J = 7Hz, 2H); 4.25 (s 1H); from 7.20 to 7.40 (mt 8H); 7.57 (ddd, J = 8-5 and 1 Hz 1H); 7.97 (split t, J = 8 and 1.5 Hz 1H); 8.07 (broad d, J = 8 Hz: 1H); 8.75 (broad d, J = 5 Hz 1H)].

2- (1- [Bis (4-chlorophenyl) methyl)] azetidin-3-ylidenemethylsulfonyl] pyridine can be prepared as follows: 0.25 cm ^{3 of} methylsulfonyl chloride is added to a solution of 0.9 g of 1- [bis (4-chlorophenyl) methyl )] - 3- (pyrid-2-ylsulfonylmethyl) azetidin-3-ol in 50 cm ³ of dichloromethane. The mixture was stirred for 15 minutes and 0.9 g of 4-dimethylaminopyridine was added. The mixture is then stirred for 3 hours at 20 ° C, 30 cm ^{3 of} water and 30 cm ^{3 of} dichloromethane are added and the organic phase is separated after settling, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04 0.063 mm, height 25 cm, diameter 2 cm) eluting under a pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (40/60 by volume) and collecting 20 cm ^{3 of} fractions. Fractions 4 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.50 g is obtained

2- {1- [bis (4-chlorophenyl) methyl)] azetidin-3-ylidenemethylsulfonyl} pyridine as a yellow powder.

101

1- [Bis (4-chlorophenyl) methyl]] - 3- (pyrid-2-ylsulfonylmethyl) azetidin-3-ol can be prepared as follows: 2.13 g of potassium tert-butoxide are added under argon to a solution cooled to 50 ° C. -78 ° C, 2.92 g of 1- [bis (4-chlorophenyl) methyl)] azetidin-3-one and 3 g of 2-methylsulfonylpyridine in 50 cm ^{2 of} tetrahydrofuran. The mixture is stirred for 3 hours at -78 ° C, then the reaction mixture is returned to 0 ° C and 50 cm ^{3 of} diethyl ether, 10 cm ^{3 of} water and 10 cm ^{3 of} saturated aqueous ammonium chloride solution are added. The organic phase is separated after settling, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 30 cm, diameter 3 cm) eluting under an argon pressure of 0.05 MPa first with dichloromethane and then with a dichloromethane / methanol (97/3 by volume) mixture and collecting 20 cm ^3. fractions. Fractions 8 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The brown oil obtained still contains impurities and is chromatographed on a silica gel column (particle size 0.04-0.63 mm, height 20 cm, diameter 2 cm) eluting under an argon pressure of 0.05 MPa first with dichloromethane and then with a mixture of dichloromethane and methanol (97). (3, v / v) and 20 cm ³ fractions are collected. Fractions 5 to 25 are combined and concentrated to dryness and the residue is re-chromatographed on the same column under the same conditions but eluted with dichloromethane. Fractions 12 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.3 g of 1- [bis (4-chlorophenyl) methyl)] - 3- (pyrid-2-ylsulfonylmethyl) azetidin-3-ol is obtained in the form of a white foam.

2-Methylsulfonylpyridine can be prepared as follows: 0.25 cm @ ^{3 of} 100% acetic acid are added with stirring and under argon to a solution of 20 g of sodium tungstate dihydrate in 10 cm @ ^{3 of} water and then 7.0 g of 2-methylsulfanylpyridine. The mixture is heated to 65 ° C, then 10 cm ^{3 of} 30% hydrogen peroxide are slowly added over 15 minutes and the mixture is stirred at 85 ° C for 30 minutes and then cooled to + 10 ° C. To the reaction mixture were added 1.0 cm @ ^{3 of} 32% aqueous ammonia and 5.0 cm @ ^{3 of a} 37.5% aqueous solution of sodium hydrogen sulfite, 10 cm @ ^{3 of} water and 50 cm @ ^{3 of} dichloromethane. After settling, the mixture is separated, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The colorless oil obtained is disintegrated with 50 cm ^{3 of} petroleum ether and the insoluble gum is filtered and taken up in 30 cm ^{3 of} dichloromethane. The resulting solution is concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). 3.5 g of 2-methylsulfonylpyridine are obtained in the form of a colorless oil.

2-Methylsulfanylpyridine can be prepared as follows: 6.2 cm ^{3 of} methyl iodide are added slowly to a solution of 11.0 g of 2-mercaptopyridine in 105 cm ^{3 of} 1 N sodium hydroxide. The reaction mixture whose temperature was raised to 30 ° C was cooled to room temperature. The mixture is stirred for 2 hours, then extracted with 100 cm ^{3 of} dichloromethane, the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is purified by distillation under reduced pressure. 9.0 g are obtained

2-methylsulfanylpyridine as a colorless liquid, boiling point 84 ° C / 45 mmHg.

Example 21

3- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylmethylsulfonyl} pyridine can be prepared according to the procedure described in Example 20, starting from 0.15 g of 3- {1- [bis (4-chlorophenyl) methyl] Azetidin-3-ylidenemethylsulfonylpyridine, 20 cm @ ^{3 of a} 50/50 mixture of dichloromethane and ethanol and 80 mg of sodium borohydride. 0.11 g of 3- {1- [bis (4-chlorophenyl) methyl] azetidin-3-ylmethylsulfonyl] pyridine is obtained as a white powder [ ³ H NMR spectrum (300 MHz, CDCl 3, δ in ppm): from 2.75 up to 2.95 (mt 3H); 3.35 (mt 2H); 3.43 (d, J = 6.5 Hz, 2H); 4.25 (s 1H); from 7.20 to 7.40 (mt 8H); 7.54 (ddd, J = 85 and 1 Hz: 1H) / 8.18 (ddd, J = 8-2.5 and 1.5 Hz: 1H); 8.90 (dd, J = 5 and 1.5 Hz 1H); 9.11 (dd, J = 2.5 and 1 Hz: 1H)].

3- {1- [Bis (4-chlorophenyl) methyl)] azetidin-3-ylidenemethylsulfonyl] pyridine can be prepared as described in Example 20,

103 starting from 0.8 g of 1- [bis (4-chlorophenyl) methyl)] - 3- (pyrid-3-ylsulfonylmethyl) azetidin-3-ol, 50 cm ^{3 of 4} dichloromethane, 0.22 cm ^{3 of} methylsulfonyl chloride and 0 , 8 g of 4-dimethylaminopyridine. 0.50 g of 3- {1- [bis (4-chlorophenyl) methyl)] azetidin-3-ylidenemethylsulfonyl] pyridine are obtained in the form of a cream-colored powder.

1- [Bis (4-chlorophenyl) methyl)] - 3- (pyrid-3-ylsulfonylmethyl) azetidin-3-ol can be prepared according to the procedure described in Example 20, starting from 3.3 g of 1- [bis (4- chlorophenyl) methyl) azetidin-3-one, 50 cm ^{3 of} tetrahydrofuran, 3.5 g of 3-methylsulfonylpyridine and 2.4 g of potassium tert-butoxide. 1.4 g of 1- [bis (4-chlorophenyl) methyl)] - 3- (pyrid-3-ylsulfonylmethyl) azetidin-3-ol are obtained in the form of a white powder.

3-Methylsulfonylpyridine can be prepared as described in Example 20 starting from 33 g of sodium tungstate, 10 cm ^{3 of} water, 0.25 cm ^{3 of} 100% acetic acid, 9.5 g of 3-methylsulfanylpyridine, 15 cm ^{3 of} 30% hydrogen peroxide and 2 cm ^{3 of} 32% aqueous ammonia and 2 cm ^{3 of} aqueous sodium bisulfite solution. The crude oil obtained is crystallized with 20 cm @ ^{3 of} diisopropyl ether, the crystals are filtered, freed from water and dried under reduced pressure (2.7 kPa). 4.5 g of 3-methylsulfonylpyridine are obtained in the form of white crystals (mp = 58 ° C).

3-Methylsulfanylpyridine can be prepared as follows: 20 cm ^{3 of} isoamyl nitrite are added to a mixture heated to 80 ° C under argon, 9.4 g of 3-aminopyridine and 100 cm ^{3 of} dimethylsulfide. The mixture was stirred at 90 ° C for 2 hours, cooled to 20 ° C and then purified by fractional distillation under reduced pressure. 8.4 g of 3-methylsulfanylpyridine are obtained in the form of a pale yellow liquid, mp = 90 ° C / 30 mm Hg.

Example 22

4- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylmethylsulfonyl} pyridine can be prepared according to the procedure described in Example 20, starting from 0.15 g of 4- {1- [bis (4-chlorophenyl) methyl] )] azetidin-3104

-ylidenemethylsulfonyl} pyridine, 20 cm ^{3 of} 50/50 mixture of dichloromethane and ethanol and 80 mg of sodium borohydride. 0.13 g is obtained

4- {1- [bis (4-chlorophenyl) methyl] azetidin-3-ylmethylsulfonyl} pyridine as a white powder. [ ³ H NMR spectrum (300 MHz, CDCl ₃ , δ in ppm): from 2.75 to 2.90 (mt 1H); 2.88 (t, J = 7Hz: 2H); 3.36 (t, J = 7Hz, 2H); 3.42 (d, J = 7Hz, 2H); 4.25 (s 1H); from

7.20 to 7.35 (mt 8H); 7.75 (broad d, J = 6 Hz: 2H); 8.93 (broad d, J = 6 Hz: 2H)].

4- {1- [Bis (4-chlorophenyl) methyl)] azetidin-3-ylidenemethylsulfonyl [pyridine can be prepared according to the procedure described in Example 20, starting from 0.8 g of 1- [bis (4-chlorophenyl) methyl]] -3- (pyrid-4-ylsulfonylmethyl) azetidin-3-ol, 50 cm ^{3 of} dichloromethane, 0.22 cm ^{3 of} methylsulfonyl chloride and 0.8 g of 4-dimethylaminopyridine. The crude product is purified by silica gel column chromatography (particle size 0.04-0.063 mm, height 20 cm, diameter 2 cm) eluting under an argon pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (40/60 by volume) and collecting 20 cm ^3. fractions. Fractions 5-10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.42 g of 4- {1- [bis (4-chlorophenyl) methyl)] azetidin-3-ylidenemethylsulfonyl} pyridine is obtained in the form of a white crystalline powder.

1- [Bis (4-chlorophenyl) methyl]] - 3- (pyrid-4-ylsulfonylmethyl) azetidin-3-ol can be prepared according to the procedure described in Example 20, starting from 2.5 g of 1- [bis (4- chlorophenyl) methyl) azetidin-3-one, 50 cm ^{3 of} tetrahydrofuran, 2.6 g of 4-methylsulfonylpyridine and

1.8 g of potassium tert-butoxide. The crude product obtained is purified by silica gel column chromatography (particle size 0.04 0.063 mm, height 30 cm, diameter 3 cm) eluting under an argon pressure of 0.05 MPa with dichloromethane and then with a mixture of dichloromethane and methanol (98/2 by volume) and collected. 20 cm ³ fractions. Fractions 8 to 27 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The cream-colored powder obtained is recrystallized from 5 cm @ ^{3 of} acetonitrile. The crystals are filtered, freed from water and dried under reduced pressure (2.7 kPa). 1.4 g of 1- [bis (4-chlorophenyl) methyl)] - 3- (pyrid-4-ylsulfonylmethyl) azetidin-3-ol are obtained in the form of white solids.

105 crystals, m.p. = 130 ° C.

4-Methylsulfonylpyridine can be prepared as described in Example 20 starting from 14 g of sodium tungstate, 4 cm ^{3 of} water, 0.05 cm ^{3 of} 100% acetic acid, 3.3 g of 4-methylsulfanylpyridine, 6.5 cm ^{3 of} hydrogen peroxide and then 25 cm ^{3 of} 32% aqueous ammonia and 1 cm ^{3 of} 37.5% aqueous sodium bisulfite solution. The crude product obtained is crystallized with 10 cm @ ^{3 of} diisopropyl ether, the crystals are filtered, freed from water and dried under reduced pressure (2.7 kPa). 2.6 g of 4-methylsulfonylpyridine are obtained in the form of white crystals.

4-Methylsulfanylpyridine can be prepared as described in Example 20, starting from 11.0 g of 4-mercaptopyridine, 105 cm ^{3 of} 1 N sodium hydroxide and 6.2 cm ^{3 of} methyl iodide. The crude oil obtained is purified by distillation under reduced pressure. 4.0 g of 4-methylsulfanylpyridine are obtained in the form of a white paste, boiling point 120 ° C / 45 mm Hg.

Example 23

1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) sulfonylmethyl] azetidine can be prepared as follows: 78 mg of sodium borohydride is added under argon to a solution of 0.50 g of 1- [bis ( 4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) sulfonylmethylene] azetidine dissolved in 25 cm ^{3 of} anhydrous methanol and 25 cm ^{3 of} anhydrous dichloroethane. After stirring for 24 hours 80 cm ^{3 of} water and 50 cm ^{3 of} dichloromethane are added, the mixture is separated after settling, washed with 80 cm ^{3 of} water and then with 80 cm ^{3 of} saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is chromatographed on a silica gel column (particle size 0.02-0.04 mm, height 20 cm, diameter 14 cm) eluting under argon at 0.07 MPa with a mixture of cyclohexane and ethyl acetate (90/100 by volume) and collecting 5 cm ^3. fractions. Fractions 60-82 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.29 g of 1- [bis (4-chlorophenyl) 106 methyl] -3 - [(3,5-difluorophenyl) sulfonylmethyl] azetidine is obtained as a white solid. ^[X H NMR (300 MHz, CDCl3, δ in ppm): from 2.75 to 2.95 (mt: 1H); 2.88 (t, J = 7Hz: 2H); 3.36 (t, J = 2H: 2H); 3.41 (d, J = 7Hz, 2H); 4.26 (s 1H); 7.13 (tt, J = 9 and 2.5 Hz 1H); from 7.20 to 7.35 (mt 8H); 7.44 (mt 2H)].

Example 24

1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) sulfonylmethylene] azetidine can be prepared as follows: 4.3 cm ^{3 of} methylsulfonyl chloride are added at room temperature to 18.8 g of 1- [ bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) sulfonylmethyl] azetidin-3-ol dissolved in 800 cm ^{3 of} dichloromethane. 16 g of dimethylaminopyridine are then added in small portions. After 22 hours, the reaction mixture is washed three times with 700 cm @ ^{3 of} water and then with 700 cm @ ^{3 of} saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.02-0.04 mm, height 36 cm, diameter

8.5 cm) eluting with a mixture of cyclohexane and ethyl acetate (90/10 by volume) under an argon pressure of 0.07 MPa and collecting 250 cm ^{3 of} fraction. Fractions 2 to 148 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2.79 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) sulfonylmethylene] azetidine are obtained as a white solid [ ³ H NMR spectrum (300 MHz, CDCl ₃ , δ v) ppm): 3.91 (mt 2H); 4.28 (mt 2H); 4.51 (s 1H); 6.25 (mt 1H); 7.08 (tt, J 9 and 2.5 Hz 1H); from 7.25 to 7.40 (mt 8H); 7.40 '(mt 2H)].

1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) sulfonylmethyl] azetidin-3-ol can be prepared as follows:

42.9 cm @ ^{3 of} 1.6 M butyllithium in hexane are added dropwise to the solution

13.2 g of (3,5-difluorophenyl) methylsulfone in 800 cm @ ^{3 of} tetrahydrofuran. After 0.5 hour at -70 ° C and 0.5 hour at -30 ° C, 14 g of 1- [bis (4-chlorophenyl) methyl] azetidine-3- is added dropwise at -70 ° C. of ions dissolved in 150 cm ^{3 of} tetrahydrofuran.

107

After 3 hours at -70 ° C, the reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed twice with 400 cm ^{3 of} water and then with 400 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue (25.14 g) is chromatographed on a silica gel column (particle size 0.06-0.04 mm, height 31 cm, diameter 7.5 cm) eluting under a argon pressure of 0.05 MPa with a mixture of cyclohexane and ethyl acetate (85/15). , by volume) and 200 cm ³ fractions are collected. Fractions 13-16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After crystallization from ethyl ether, filtration and drying, 4.5 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) sulfonylmethyl] azetidin-3-ol is obtained as a white solid.

(3,5-Difluorophenyl) methylsulfone can be prepared as follows: 225 cm ^{3 of} water and 56.3 g of oxone® are added in small portions at 5 ° C to a solution of 13.3 g of (3,5-difluorophenyl) methylsulfide dissolved in 450 cm ^{3 of} methanol. After 20 hours at room temperature, the reaction mixture was diluted with dichloromethane and water and separated after settling. The organic phase is washed twice with 700 cm @ ^{3 of} water and then with 700 cm @ ^{3 of a} saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under reduced pressure (2.7 kPa). 13.2 g of (3,5-difluorophenyl) methylsulfone are obtained in the form of a white solid.

(3,5-Difluorophenyl) methylsulfide can be prepared as follows: 64 cm ^{3 of} 1,6 M n-butyllithium in hexane are added dropwise at -70 ° C to 11.8 cm ^{3 of} 1-bromo-3,5- of difluorobenzene diluted in 200 cm ^{3 of} ethyl ether. After 0.5 h, 14.2 g of S-methyl methylthiosulfonate dissolved in 60 cm ^{3 of} tetrahydrofuran is added dropwise at -70 ° C. After 3 hours at -70 ° C and 18 hours at room temperature, the reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed twice with 200 cm ^{3 of} water and then with 300 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). 13.7 g of (3,5-difluorophenyl) methylsulfide are obtained in the form of a yellow oil.

Example 25

0.25 g of meta-chloroperbenzoic acid is added at room temperature to a solution of 0.40 g of 1- [bis (4-chlorophenyl) methyl] -3- (phenylsulfanyl) azetidine in 20 cm ^{3 of} dichloromethane. After stirring for 3 hours at room temperature, the reaction mixture is washed with 30 cm ^{3 of} saturated sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). After chromatography on a silica gel column (particle size 0.06-0.200 mm, height 25 cm, diameter 2 cm) eluting under an argon pressure of 0.08 MPa with ethyl acetate / cyclohexane 20/80 (v / v) and a vintage of 60 cm ³ fractions, fraction 9 to 16 joints and concentrated to dryness under reduced pressure (2.7 kPa), transferred to heptane and isolated 100 mg of 1- [bis (4-chlorophenyl) methyl] -3 - [(RS) -phenylsulfinyl] azetidine as a white solid [1 H NMR (300 MHz, CDCl 3, δ in ppm): 3.01 (broad t, J = 7.5 Hz: 1H); 3.32 (broad t, J 7.5 Hz 1H); 3.45 (broad t, J 7.5 Hz 2H); 3.59 (mt 1H); 4.45 (broad s, 1H); from 7.15 to 7.65 (mts: 13H)].

Example 26

Add 1.2 g of oxone ^R in several portions to a solution of 0.80 g of 1- [bis (4-chlorophenyl) methyl] -3- (phenylsulfanyl) azetidine in 3.4 cm ^{3 of} water, 3.4 cm ³ of acetic acid 3.4 cm ^{3 of} ethanol and 1.7 cm ³ of sulfuric acid. The reaction mixture is stirred for 20 hours at room temperature, then diluted with 100 cm ^{3 of} dichloromethane, washed three times with 100 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). After chromatography on a silica gel column (particle size 0.06-0.200 mm, height 40 cm, diameter 2 cm) eluting under an argon pressure of 0.08 MPa with a 20/80 (v / v) ethyl acetate / cyclohexane mixture and a 60 cm ³ fraction vintage, fraction 9 to 15 joints and concentrate to dryness under reduced pressure

Transferred to heptane, the solid was filtered off and after drying 0.23 g of 1- [bis (4-chlorophenyl) methyl] -3- (phenylsulfonyl) azetidine was isolated as a white solid. ^[X H NMR (300 MHz, CDCl3, δ in ppm): from 3.35 to 3.50 (mt: 4H);

3.96 (mt 1H); 4.44 (s 1H); from 7.20 to 7.35 (mt 8H); 7.57 (broad t, J 7.5 Hz 2H); 7.68 (tt, J = 7.5 and 1.5 Hz: 1H);

7.88 (broad d, J = 7.5 Hz: 2H)].

Example 27

43.5 mg of sodium borohydride is added to the solution of 0.6 g of methyl

5 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methylsulfonylmethyl) thien-2-ylcarboxylate in 70 cm ^{3 of} methanol cooled to about 0 ° C. The reaction mixture was stirred at this temperature for 15 minutes and then at 20 ° C for 5 hours, re-cooled to about 0 ° C and 8.7 mg of sodium borohydride was added. After 18 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). 100 cm @ ^{3 of} dichloromethane and 20 cm @ ^{3 of} distilled water are added to the residue. After settling, the mixture is separated, the organic phase is washed twice with 20 cm @ ^{3 of} distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: cyclohexane / ethyl acetate (70/30 by volume)]. 0.18 g of methyl (RS) -5 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl [methylsulfonylmethyl) thien-2-ylcarboxylate] is obtained as a white powder [ ³ H NMR spectrum (400 MHz) MHz, (CD 3) ₂ SO d6, δ in ppm): 2.60 (t, J = 7.5 Hz: 1H); 2.86 (s 3H); 3.14 (mt 2H); from 3.20 to 3.35 (mt 1H); 3.45 (broad t, J 7.5 Hz 1H); 3.82 (s 3H); 4.47 (s 1H); 5.27 (d, J = 11Hz: 1H); 7.28 (d, J = 4Hz, 1H); from 7.30 to 7.50 (mt 8H); 7.72 (d, J = 4Hz: 1H)].

Methyl 5 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methylsulfonylmethyl) thien-2-ylcarboxylate can be obtained as follows: 5.15 g methyl 5- (methylsulfonylmethyl) thien-2-ylcarboxylate 6.12 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one in 200 cm ^{3 of} tetrahydrofuran are added at room temperature under an argon atmosphere and then the suspension obtained is cooled to -70 ° C. Thereafter, 2.47 g of potassium tert-butoxide are added successively, and after an hour and 30 minutes a solution of 1.7 cm @ ^{3 of} methylsulfonyl chloride in 8 cm @ ^{3 of} ethyl ether is added at this temperature over minutes.

The reaction mixture is kept at -70 ° C for 1 hour and then the temperature is raised to 20 ° C and the mixture is poured into 80 cm ^{3 of} distilled water. The tetrahydrofuran is removed under reduced pressure and the aqueous residue obtained is extracted with 500 cm @ ^{3 of} dichloromethane. After settling, the mixture is separated, the organic phase is washed three times with 80 cm ^{3 of} distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: cyclohexane / ethyl acetate (70/30 by volume)]. 1.6 g of methyl are obtained

5 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methylsulfonylmethyl) thien-2-ylcarboxylate as a cream colored foam.

Methyl 5- (methylsulfonylmethyl) thien-2-ylcarboxylate can be obtained as follows: 31.7 g of sodium methylsulfinate is added to a solution of 73 g of methyl 5- (bromomethyl) thien-2-ylcarboxylate in 150 cm ^{3 of} ethanol and the suspension obtained is heated. at reflux for 7 hours. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa). The residue is extracted four times with 500 cm @ ^{3 of} ethyl acetate, the combined organic phases are washed successively with 250 cm @ ^{3 of} distilled water and 250 cm @ ^{3 of} saturated sodium chloride solution, dried over magnesium sulfate and concentrated incompletely under reduced pressure. The solid is isolated by filtration, washed three times with 25 cm ^{3 of} ice-cold ethyl acetate to give 21.4 g of methyl

5- (methylsulfonylmethyl) thien-2-ylcarboxylate as a cream colored powder.

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

Example 28

111 (RS) -1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylcyclopropylamine can be prepared as follows: 2.52 cm ^{3 of} cyclopropylamine are added to the solution 3 g of 1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine in 30 cm ^{3 of} dichloroethane, at a temperature of about 24 ° C, under an inert argon atmosphere. After 39 hours at about 24 ° C, the reaction mixture is concentrated under reduced pressure (3 kPa) at about 40 ° C. 3.26 g of a light yellow foam are obtained, which is taken up in 30 cm @ ^{3 of} dichloromethane and 2.52 cm @ ^{3 of} cyclopropylamine. The resulting solution is stirred at about 21 ° C under an inert argon atmosphere and then concentrated at 3 kPa at about 40 ° C. 3.64 g of (RS) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylcyclopropylamine are obtained in the form of a pale yellow foam. pH NMR spectrum (300 MHz, CDCl 3, δ in ppm): 0.29 (mt 1H); from 0.40 to 0.75 (mt 3H); 2.50 (mt 1H); 2.73 (s 3H); 2.90 (uncleaved complex: 1H); from

3.45 to 3.70 (mt 3H); 4.36 (broad s 1H); from 4.60 to 4.80 (broad uncleaved complex: 1H); 6.87 (tt, J 9 and 2.5 Hz 1H); from 7.20 to 7.40 (mt 10H)].

Example 29 (RS) - {1- [Bis (4-Chloro-phenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -azetidin-3-yl} - (2-pyrrolidin-1-ylethyl) -amine can be prepared as follows: 0.076 cm ^{3 of} 1- (2-aminoethyl) pyrrolidine is added to a solution of 50 mg of 1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine in 0.5 cm ^{3 of} dichloroethane, at a temperature of about 21 ° C, under an inert argon atmosphere. The resulting solution was stirred at room temperature about 21 ° C under argon for 22 hours, concentrated under a stream of air at 42 ° C, and then the residue obtained was dried under reduced pressure (about 3 kPa) at about 40 ° C. There was thus obtained (RS) - {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl} - (2-pyrrolidin-1-ylethyl) amine in the form of ocher colored foam. @ ¹ H NMR spectrum (300 MHz, CDCl3, .delta

112 ppm); from 1.75 to 1.95 (mt 4H); from 2.55 to 2.85 (mt 6H); 2.79 (s 3H); 2.91 (t, J = 6.5 Hz: 2H); 3.06 (d, J = 8.5Hz, 1H); 3.17 (d, J = 8.5 Hz: 1H); 3.32 (d, J = 8.5 Hz: 1H); 3.41 (d, J = 8.5 Hz: 1H); 4.31 (s 1H); 4.56 (s 1H); 6.88 (tt, J = 8.5 and 2.5 Hz 1H); 7.22 (s: 4H); 7.25 (s 4H); 7.34 (mt 2H)].

Example 30 (RS) - {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methanesulfonylmethyl] azetidin-3-yl [methylamine] can be prepared according to Example 29, starting from 50 mg 1 - [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 0.5 cm ^{3 of} dichloromethane and 0.3 cm ^{3 of a} solution of methylamine in tetrahydrofuran (2 M solution) . There was thus obtained (RS) - {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl] methylamine as a yellow gum. [ ³ H NMR spectrum (400 MHz, CDCl ₃ δ in ppm): from 2.00 to 2.20 (broad uncleaved complex: 1H); 2.62 (s 3H); 2.76 (s 3H); 3.04 (d, J = 9Hz, 1H); 3.18 (d, J = 9Hz, 1H); 3.37 (AB, J = 9Hz, 2H); 4.31 (s 1H); 4.55 (s 1H); 6.89 (tr, J = 9 and 2.5 Hz 1H); 7.22 (s: 4H); 7.24 (s: 4H); 7.32 (mt 2H)].

Example 31 (RS) - {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl} isobutylamine can be prepared according to Example 29, starting from 50 mg of 1 - [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 0.5 cm ^{3 of} dichloromethane and 0.0596 cm ^{3 of} isobutylamine. This afforded (RS) - {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl} isobutylamine as a white foam. [ ^! 1 H NMR spectrum (300 MHz, CDCl ₃ δ in ppm): 1.01 (2d, J = 7 Hz: 6H); from 1,70 to

2.15 (broad uncleaved complex: 1H); 1.76 (mt 1H); 2.51 (dd, J = 10.5 and 7 Hz: 1H); 2.76 (s 3H); 2.80 (dd, J = 10.5 and 6 Hz: 1H); 3.01 (d, J = 8.5 Hz: 1H); 3.14 (d, J = 8.5 Hz: 1H); 3.32 (d, J = 8.5 Hz: 1H); 3.44 (d, J = 8.5 Hz: 1H); 4.31 (s 1H); 4.58 (s 1H); 6.88 (tt, J = 8.5 and 2.5 Hz 1H); from

113

7.15 to 7.30 (mt 8H); 7.35 (mt 2H)].

T

Example 32 (RS) - {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl} ethylamine can be prepared according to Example 29, starting from 50 mg 1 - [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 0.5 cm ^{3 of} dichloroethane and 0.3 cm ^{3 of} ethylamine in tetrahydrofuran (2 M solution). There was thus obtained (RS) - {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl} ethylamine as a yellow gum.

[ ¹ H NMR spectrum (300 MHz, CDCl ₃ δ in ppm) : 1,22 ( t, J = 7Hz : 3 H); from 2.70 to 2.85 (mt 2H); 2 77 (p 3H); from 2.95 to 3.10 (uncleaved complex: 1H); 3.05 (D, J = 8.5 Hz : 1H); 3, 17 (D, J = 8.5 Hz: 1H); 3.33 (d, J) = 8.5 Hz: 1H ); 3.40 (d, J = 8.5 Hz: 1H); 4.30 (s 1H); 4.54 (with : 1H); 6, d 39 (tt, J 9 a 2.5 Hz: 1H); from 7.15 to 7.30 (mt: 8H); 7, 34 (mt 2H)].

Example 33 (RS) -N- {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl] -N ', N'-dimethylethane-1 2-diamine can be prepared according to example 29, starting from 50 mg of 1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 0.5 cm ³ of dichloromethane and 0.0659 cm &lt; ³ &gt; of N, N-dimethylethylenediamine. (RS) -N- {1-Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl} -N ', N'-di-

methylethane-1,2-diamine in the form white peny [ ¹ H NMR Spectrum (300 MHz, CDCl3 δ in ppm): 2.32 (with 6H); : 2,53 (t, J = 6Hz): 2H); 2.79 (s 3H); 2.94 (t, J) = 6 Hz: 2H); 3 06 (d, J = 8.5) Hz: 1H); 3.16 (d, J = 8.5 Hz: 1H) ; 3.30 (d, J = 8.5 Hz: 1H); 3.41 (d, J = 8.5Hz) : 1H); 4.30 (with : 1H); 4.55 ( s: 1H); 6.88 (tt, J) = 9 and 2.5 Hz : 1H); 7.21 (with 4H); 7.24 ( s: 4H); 7.34 (mt:

2H)].

Example 34

114 (RS) -1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methanesulfonylmethyl] -3-methylazetidine can be prepared as follows: a few drops of pure methyl iodide are added under argon at temperature about 24 ° C to a suspension of 400 mg magnesium turnings in 2.5 cm ^{3 of} anhydrous diethyl ether, and then 1 cm ^{3 of} methyl iodide in a solution of 22.5 cm ^{3 of} diethyl ether is added. The resulting suspension was stirred at about 24 ° C for 30 minutes and then cooled to about 0 ° C in an ice / water mixture. Add at 0 ° C

1.65 g of CuBr.Me ₂ S complex and the reaction mixture was stirred at 0 ° C for 15 min. The resulting yellow suspension is added at a temperature of about 0 ° C to a solution of 0.5 g of 1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) methylsulfonyl) methylene] azetidine in a mixture of 1 cm ³ tetrahydrofuran and 1 cm ^{3 of} diethyl ether. The resulting suspension was stirred at about 0 ° C for 4 hours and then at about 25 ° C for 16 hours. The black suspension obtained is diluted with 100 cm ^{3 of} ethyl acetate and 15 cm ^{3 of} saturated aqueous ammonium chloride solution. The reaction mixture is filtered on a frit covered with diatomaceous earth, the solid residue is washed with ethyl acetate and then with water. After decanting the filtrate, the organic phase is separated, washed with 10 cm ^{3 of} water, 10 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered on a glass frit and concentrated to dryness under reduced pressure (20 kPa) at a temperature of about 43 ° C. 550 mg of an orange-colored foam are obtained, which is purified by preparative thin layer chromatography on silica gel [14 Merck Kieselgel 60F254 preparative plates; 20 x 20 cm; thickness 0,5 mm; coating in dichloromethane solution], eluting with a mixture of methanol and dichloromethane (0.5-99.5 by volume). Elution of the zone corresponding to the desired product with a mixture of methanol and dichloromethane (15/85 by volume), filtration on a frit and then evaporation of the solvents under reduced pressure at about 40 ° C gave 290 mg of a white foam which was dissolved in 15 cm ^{3 of} anhydrous dichloromethane. reacted with 500 mg of thiophenol resin (supplied by Argonaut,

1.45 mMol / g) and 1 g of ethylenediamine resin (0.8 mMol / g) for 38 hours at about 20 ° C. The suspension is filtered through a frit, then the resin is washed with dichloromethane and the filtrate is concentrated

115 under reduced pressure (5 kPa) at a temperature of about 43 ° C. It will be obtained

272.8 mg of a white foam which is dissolved in 2 cm @ ^{3 of} dichloromethane and treated with 1 cm @ ^{3 of} ethylenediamine for 72 hours at a temperature of about 24 ° C. The crude residue obtained is taken up in 50 cm ^{3 of} ethyl acetate and 10 cm ^{3 of} water. After decantation, the organic phase is washed with 10 cm ^{3 of} aqueous 1 N hydrochloric acid solution, 10 cm ^{3 of} saturated aqueous sodium hydrogen carbonate solution, 10 cm ^{3 of} water, 10 cm ^{3 of} aqueous sodium chloride solution, dried over magnesium sulfate, filtered on a glass frit and concentrate to dryness under reduced pressure (8 kPa) at a temperature of about 42 ° C. 263.4 mg of a light yellow foam is obtained, which is purified by preparative thin layer chromatography on silica gel [7 Merck Kieselgel 60F254 preparative plates; 20 x 20 cm; thickness 0,5 mm; coating in dichloromethane], eluting with methanol / dichloromethane (0.5 / 99.5 by volume). After eluting the zone corresponding to the desired product with a mixture of methanol and dichloromethane (15/85 by volume), filtering on a frit and then evaporating the solvents under reduced pressure at about 40 ° C, 191.4 mg of (RS) -1- [bis (4- chlorophenyl) methyl] -3 - [([3,5-difluorophenyl) methylsulfonylmethyl] -3-methylazetidine as a white foam.

[ ^ς] NMR spectrum (300 MHz, CDCl 3, δ in ppm): 1.75 (s: 3H);

2.67 (s 3H); 2.74 (broad d, J 7.5 Hz 1H); 2.93 (d, J =

7.5 Hz: 1H); 3.21 (broad d, J = 7.5 Hz: 1H); 3.46 (d,

J = 7.5Hz: 1H); 4.33 (broad s 2H); 6.87 (tt, J 9 and 2.5 Hz 1H); 7.12 (mt 2H) from 7.15 to 7.35 (mt 8H).

Example 35 (RS) -1- (2- {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylsulfanyl} ethyl) -4-methylpiperazine prepared as follows: 128 mg of 1- (ethanthiol-2-yl) -4-methylpiperazine was added at about 20 ° C to a solution of 99 mg of 1- [bis (4-chlorophenyl) methyl]] - 3 - [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine in 2 cm ^{3 of} dichloromethane. The mixture was stirred overnight at room temperature at about 20 ° C and added

116

706 mg of Merrifield resin (1.7 mMol / g). After stirring overnight at about 20 ° C, the suspension is filtered and the resin is washed twice with 1 cm ^{3 of} dichloromethane. The filtrate was concentrated under reduced pressure. 125 mg of a white oil are obtained, which is purified by chromatography on silica gel (13 cm ³ 0.06-0.2 mm silica gel), eluting with a mixture of methanol and dichloromethane (0/100 and then 5/95 by volume). Fractions containing only the desired product were combined and concentrated to dryness under reduced pressure. 62 mg of (RS) -1- (2- (1- [bis (4-chlorophenyl) methyl) -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylsulfanyl} ethyl) -4-methylpiperazine are obtained. [ ³ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm):

2.15 (s 3H); 2.30 and 2.41 (2 mfs: 8H); 2.55 (mt 2H); 2.85 (s 3H); 3.02 (mt 2H); 3.09 (d, J = 8.5 Hz: 1H); 3.38 (d, J =

8.5 Hz: 1H); 3.42 (d, J = 8.5 Hz: 1H); 3.79 (d, J = 8.5 Hz: 1H); 4.68 (s 1H); 5.37 (s 1H); from 7.30 to 7.50 (mt 11H)].

Example 36 (FS) - (2- {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylsulfanyl} ethyl) dimethylamine can be prepared according to the procedure described in Example 35, starting from 99 mg of 1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 2 cm ^{3 of} dichloromethane, 84 mg of 2- (dimethylamino) ethanethiol and 706 mg of Merrifield resin (1.7 mMol / g). 36 mg of (RS) - (2- {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylsulfanyl} ethyl) dimethylamine are obtained as an off-white solid. powder.

Example 37 (RS) - {1 - [[4- (Chloromethyl) phenyl] - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl} ethylamine can be prepared as follows: solution of 40 mg of (RS) - {1 - [[4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine in 0.1125 cm ^{3 of} ethylamine (2) M solution in tetrahydrofuran) containing a sodium iodide grain is stirred at

The mixture is diluted with 20 cm @ ^{3 of} ethyl acetate and 5 cm @ ^{3 of a} saturated aqueous solution of sodium bicarbonate. The separated organic phase is washed with 5 cm ^{3 of} water, 5 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered on a glass frit and concentrated to dryness under reduced pressure (15 kPa) at a temperature of about 40 ° C. The yellow oil obtained is purified by preparative thin layer chromatography on silica gel [2 Merck Kieselgel 60F254 preparative plates; 20 x 20 cm; thickness 0,5 mm; coating in dichloromethane solution], eluting with methanol / dichloromethane (3/97 by volume). After eluting the zone corresponding to the desired product with a mixture of methanol and dichloromethane (15/85 by volume), filtering on a frit and then evaporating the solvents under reduced pressure at about 40 ° C, 17 mg of (RS) - {1 - [[4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl} ethylamine as a white solid. ^[T H NMR (400 MHz, (CD _{3) 2} SO d6, δ in ppm): 1.11 (t, J = 7 Hz: 3H); from 2.10 to 3.55 (mt 8H); 2.95 (s 3H); 4.44 (s 1H); 5.09 (s 1H); from 7.10 to 7.55 (mt 11H)].

(RS) - {1 - [[4- (Chloromethyl) phenyl] - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine can be prepared as follows: 0.525 cm ^{3 of} N, N-diisopropylethylamine is added at a temperature of about 21 ° C to a solution of 590 mg of (RS) - [4 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl) phenyl] methanol in 5 cm ^{3 of} anhydrous dichloromethane and then 0.19 cm ^{3 of} methanesulfonyl chloride. After 1 hour at about 21 ° C, 2 cm ³ of methanol / dichloromethane (2.5 / 97.5 by volume) are added and after 5 minutes the reaction mixture is concentrated under reduced pressure (20 kPa) at about 40 ° C. The resulting yellow foam is purified by chromatography on silica gel (50 g 0.6-0.2 mm silica gel in a 3 cm diameter column), eluting with methanol / dichloromethane (0/100 and then 1/99 by volume) and collected 10 cm ^3. fractions. Fractions containing only the desired product were combined and concentrated to dryness under reduced pressure. 421.2 mg of (RS) - {1 - [[4- (chloro-118 ethyl) phenyl] - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine is obtained as a yellow foam.

(RS) - [4 - ((4-Chlorophenyl) - (3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl) phenyl] methanol can be prepared as follows: 49 mg of sodium tetraborohydride is added in portions to a solution of 420 mg of (RS) - [4 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl) benzaldehyde in 7 cm ^{3 of} methanol cooled to temperature about 0 ° C (ice + water) After 2 hours at about 0 ° C, the reaction mixture is concentrated under reduced pressure (15 kPa) at about 35 ° C. The residue obtained is purified by silica gel chromatography (40 g 0.06). - 0.2 mm silica gel in a column of 3 cm diameter, eluting with methanol / dichloromethane (1/99 and then 2,5 / 97,5 by volume) and collecting 10 cm ^{3 of the} fractions. concentrated to dryness under reduced pressure to give 418 mg of (RS) - [4 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonyimethylene] azetidin-1-ylmethyl) phenyl] methanol as the form white foam.

Example 38 (RS) - (1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-bistrifluoromethylphenyl) methylsulfonylmethyl] azetidin-3-yl} isobutylamine can be prepared according to Example 29, starting from 50 mg 1 - [bis (4-chlorophenyl) methyl)] -3 - [(3,5-bistrifluoromethylphenyl) (methylsulfonylmecylene) azetidine, 0.5 cm ^{3 of} dichloromethane and 0.05 cm ^{3 of} isobutyl amine to give 57 mg (RS) - { 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-bis-trifluoromethylphenyl) methylsulfonylmethyl] azetidin-3-yl} izobutyiamínu as a light yellow foam. pH-NMR (300 MHz, CDC1 _3, δ in

ppm) : 1.01 (d, J = 7.5 l · Iz: 6H); 1.76 (mt 1H); 2.4 7 (dd, J = 10.5 and 7.5 Hz: 1H); from 2.75 up to 2.85 (mt 1H); 2.79 (s: 3H); 2.82 (dd, J = 10.5 and 5.5 Hz: 1H); 3.00 (d, J = 9 Hz 1H); 3.10 (D, J = 9 Hz 1H); 3.31 (D, J = 9Hz: 1H); 3.40 (d, J = 9) Hz: 1H); 4.30 (s 1H); 4.74 (with : 1H); 7.13 (d, J = 8.5Hz: 2H) ; from 7.15 to 7.25 (mt 6H); 7.96 (wide p : 1H); 8.31 (broad with :

2H)].

119

Example 39 {RS) -1- [Bis (4-chlorophenyl) methyl] -3-cyano-3 - [(3,5-difluorophenylmethylsulfonylmethyl) azetidine can be prepared as follows: 17 mg of potassium cyanide is added to a solution of 99 mg

1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine in 2.5 cm ^{3 of} dimethyl sulfoxide at about 20 ° C. The resulting yellow and then brown solution was heated at about 40 ° C for 15 minutes and then cooled to about 20 ° C. The reaction mixture is concentrated under reduced pressure and then taken up in 10 cm ^{3 of} dichloromethane and washed three times with 5 cm ^{3 of} water. The obtained organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. 100 mg of a yellow paste is obtained which is purified by chromatography on silica gel (10 cm ³ 0.06 0.02 mm silica gel in a 1 cm diameter column) eluting with dichloromethane. Fractions containing only the desired product were combined and concentrated to dryness under reduced pressure. 60 mg of (RS) -1- [bis (4-chlorophenyl) methyl] -3-cyano-3 - [(3,5-difluórfenylmetylsulfonylmetyl] azetidine as a yellow paste. ^{[; H} NMR (300 MHz, ( CD ₃ ) ₂ SO, d 6, δ in ppm): 2.94 '(s: 3H), 3.07 (d, J = 7.5 Hz: 1H), from 3.20 to 3.40 (mt: 1H), 3.61 (broad d, J =

7.5 Hz: 1H); 3.68 (broad d, J = 7.5 Hz: 1H); 4.64 (s 1H); 5.51 (s 1H); from 7.25 to 7.50 (mt 11H)].

Example 40 (RS) - {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl} - (1-cyclopropylethyl) amine can be prepared as follows: 0.03 cm ^{3 of} cyclopropylmethyl ketone, 0.006 cm ³ of acetic acid and then 32 mg of sodium triacetoxyborohydride are gradually added to a solution of 53 mg of (RS) -C- [1- [bis (4-chlorophenyl) methyl] -3 - [(3, 5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethylamine in 2 cm ^{3 of} 1,2-dichloroethane at a temperature of about 20 ° C. The solution obtained is stirred at a temperature in the region of 20 DEG C. for 18 hours and then 2 cm @ ^{3 of a} saturated aqueous sodium hydrogen carbonate solution are added. After decantation, the organic phase is concentrated

120 under reduced pressure. 60 mg of a viscous oil are obtained, which is triturated with isopropyl ether and petroleum ether. After drying at 0.01 MPa, 55 mg of residue is obtained, which is purified by chromatography on silica gel (4 cm ³ 0.06-0.2 mm silica gel in a diameter column).

1.2 cm) eluting with methanol / dichloromethane (0/100 then 5/95, v / v). Fractions containing only the desired product were combined and concentrated to dryness under reduced pressure and purified again by silica gel chromatography (4 cm ³ 0.04-0.063 mm silica gel in a 1.2 cm diameter column) eluting with methanol / dichloromethane (0/0). 100 and then 5/95, by volume). Fractions containing only the desired product are combined and concentrated to dryness. 20 mg of (RS) - [1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl} - (1-cyclopropylethylamine) are obtained. [ ³ H NMR spectrum (300 MHz, CDCl ₃ , δ in ppm): mixture of diastereoisomers observed, from 0.00 to 0.30 and from 0.40 to 0.80 (mts: 5H); 1.09 and 1.17 (2d, J = 6.5 Hz: 3H total) 1.87 (mt 1H), from 2.55 to 2.75, from 2.75 to 2.95 and from 3.25 to 3.55 (mts: 4H) 2.68 (s: 3H); 3.12 (d, J = 8.5 Hz: 1H); from 3.80 to

3.90 (mt 1H); 4.42 and 4.43 (2s: 1H total); 4.79 and 4.84 (2s: 1H total); 6.89 (tt, J 9 and 2.5 Hz 1H); 7.16 (mt 21); from

7.15 to 7.35 (mt 8H).

{RS) -C- (1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl [methylamine] can be prepared as follows: 1, 27 cm ^{3 of a} 1.5 M solution of diisobutylaluminum hydride in tetrahydrofuran is added dropwise to a solution of 250 mg of (RS) -1- [bis (4-chlorophenyl) methyl] -3-cyano-3 - [(3,5-difluorophenyl) methylsulfonylmethyl] of azetidine in 10 cm ^{3 of} anhydrous tetrahydrofuran cooled to about 0 ° C. After 30 minutes at about 0 ° C and then 4 hours at about 20 ° C, the solution obtained is cooled again to 0 ° C. 6.35 cm ^{3 of} water and 1.06 cm ^{3 of} aqueous hydrochloric acid (12 N) are added, after decanting, the aqueous phase is extracted three times with 10 cm ^{3 of} ethyl acetate, the organic phases are combined, dried over magnesium sulfate, filtered and concentrated to a residue. Dry under reduced pressure to give 0.42 g

121 dark yellow oil, which is purified by chromatography on silica gel (40 cm ³ silica gel 0.063-0.2 mm in a 2.7 cm column), eluting with methanol / dichloromethane (0/100 then 5/95, v / v). Fractions containing only the desired product were combined and concentrated to dryness under reduced pressure. 110 mg of (RS) -C- {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl] methylamine are obtained.

Example 41 (RS) -N- {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl} isobutyramide can be prepared as follows: 0.0187 cm ³ of isobutanoic acid, 0.032 cm ^{3 of} 1,3-diisopropylcarbodiimide and 2.5 mg of 4-dimethylaminopyridine are added successively to a solution of 53 mg of (RS) -C- {1- [bis (4-chlorophenyl) methyl] -3- [ (3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethylamine in 2 cm ^{3 of} anhydrous dichloromethane at about 20 ° C. The mixture is stirred at about 20 DEG C. for 72 hours, 2 cm @ ^{3 of} water are added, then the mixture is separated after settling and the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by preparative silica gel chromatography [1 Merck Kieselgel 60F254 preparative plate; 20 x 20 cm; 1 mm thick], eluting with ethyl acetate-dichloromethane (5-95, v / v). After elution of the zone corresponding to the desired product, filtration through a frit and then evaporation of the solvent under reduced pressure at about 40 ° C, 16 mg of (RS) -N- {1- [bis (4-chlorophenyl) methyl] -3- [ (3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl} isobutyramide as a pale yellow powder. ^[X H NMR (300 MHz, CDCl3, δ in ppm):

1.22 (d, J = 7Hz: 6H); 2.46 (mt 1H); 2.69 (s 3H); 2.99 (d, J = 8.5 Hz: 1H); 3.23 (AB, J = 8.5 Hz: 2H); 3.40 (d, J =

8.5 Hz: 1H); 3.57 (dd, J = 14 and 4.5 Hz: 1H); 4.09 (dd, J = 14 and 7.5 Hz 1H); 4.34 (s: 1H); 4.35 (s: 1H); 6.71 (dd, J = 7.5 and 4.5 Hz: 1H); 6.95 (tt, J = 9 and 2.5 Hz 1H); from 7.10 to 7.35 (mt 10H)].

122

Example 42 (RS) -N- {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl} cyclopropanecarboxamide can be prepared in a similar manner to Example 39, starting from 53 mg of (RS) -C- {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methanesulfonylmethyl] azetidin-3-yl] methylamine, 2 cm ^{3 of} anhydrous dichloromethane, 0.0167 cm ^{3 of} cyclopropanecarboxylic acid, 0.032 cm ^{3 of} 1,3-diisopropylcarbodiimide and 2.5 mg of 4-dimethylaminopyridine. 28 mg of (RS) -N- {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl} cyclopropanecarboxamide are obtained as a beige powder. ¹ H NMR spectrum

(300 MHz CDCl ₃ , δ in ppm) : 0,81 (mt : 2H); 1.01 (mt: 2H); from 1, 35 to 1 , 55 (mt: 1H); 2.70 ( with : 3H); 3.02 (d, J = 8.5 Hz: 1H); 3.21 '(AB restriction, J = 8 Hz: 2H); 3.45 (d, J = 8.5 Hz: 1H); 3, 62 (dd, J = 14 and 4.5 Hz: : 1H); 4.10 (dd, J = 14 a 7.5 Hz); 4.31 (s : 1H); 4.36 (with : 1H); 6.75 (dd, J) = 7.5 a 4.5 Hz:: 1H); 6.95 (tt, J = 9 a 2 Hz : 1H); from 7.15 to 7.35 (mt

: 10H)].

Example 43 (RS) - {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl] Diethylamine can be prepared by a similar procedure to that in Example 40, starting from 53 mg (RS) -C- {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl} methylamine, 2 cm ³ 1,2-dichloroethane, 0.017 cm ^{3 of} acetaldehyde, 0.006 cm ³ of acetic acid and 32 mg of sodium triacetoxyborohydride. 12 mg of (RS) - {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl} diethylamine is obtained as an off-white powder. ^[X H NMR

spectrum 300 MHz, CDCI3, δ v ppm): 1.00 (t, J = 7 Hz: 6H); 2.49 (g, J = 7) Hz: 4H ); 2.54 (d, J = 13.5 Hz: 1H) ; 2.69 (s: 3H); 2.76 (broad d, J = 7.5 Hz: 1H); 3.07 (br d, J = 7.5 Hz: 1H); 3.15 (d, J = 13,5 Hz: 1H); 3.24 (br d, J = 7.5 Hz: 1H); 4.06 (br d, J = 7.5 Hz: 1H): 4.35 (s : 1H); 5.02 (with :

123

1Η); 6.91 (mt 1H); from 7.15 to 7.40 (mt 10H)].

Example 44 {RS} -N- {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl [methanesulfonamide] can be prepared by the following procedure: 150 mg anhydrous resin IRA-68 is added to a solution of 53 mg of (RS) -C- {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl} methylamine in 2 cm ^Of ethyl acetate at a temperature of about 20 ° C, and then 0.012 cm ^{3 of} methylsulfonyl chloride are added. The mixture is stirred overnight at about 20 ° C, 0.001 cm ^{3 of} water are added followed by 150 mg of anhydrous IRA-68 resin. The mixture was stirred at about 20 ° C for 1 hour, then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. 81 mg of a yellow paste are obtained, which is purified by preparative silica gel chromatography [Merck Kieselgel 60F254 preparative plate; 20 x 20 cm; thickness 1 mm], eluting with ethyl acetate-dichloromethane (5-95, v / v). After elution of the zone corresponding to the desired product, filtration through a frit and then evaporation of the solvent under reduced pressure at about 40 ° C, 25 mg of {RS} -N- {1- [bis (4-chlorophenyl) methyl] -3 - [( 3,5-difluorophenyl 1) methylsulfonylmethyl] azetidin-3-ylmethylmethanesulfonamide as a pale yellow powder. @ ¹ H NMR spectrum (300 MHz, CDCl3, .delta

ppm): 2.70 (s 3H); C > d 2.95 to 3.10 (mt 2H); 3, 05 (with : 3H); 3.22 (wide d, J = 8 Hz: 1H); 3.52 (d, J = 8) Hz: 1H); 3.74 (Dd, J = 13.5 and 8 Hz: 1H); 3,9i 0 (dd, J = 13.5 and 5.5 Hz: 1H); 4.23 (s 1H); 4.46 (s : 1H); 5 54 (mt : 1H); 7 00 (tt , J = 9 a 2 Hz : 1H); from 7.05 to 7.35 (mt: 10H)]

Example 45 (RS) -1- {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl} -3-isopropylurea can be prepared as follows: 0 0.197 cm ^{3 of} isopropyl isocyanate is added at a temperature of about 20 ° C to a solution of 53 mg of (RS) -C- {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] aze124 tidin 3-ylmethylamine in 2 cm ^{3 of} dichloromethane. The mixture is stirred overnight at about 20 ° C, 0.05 cm ^{3 of} water are added and then stirred for 15 minutes at about 20 ° C, the reaction mixture is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by preparative silica gel chromatography [Merck Kieselgel 60F254 preparative plate; 20 x 20 cm; 1 mm thick], eluting with ethyl acetate-dichloromethane (5-95, v / v). After eluting the zone corresponding to the desired product, filtering through a frit and then evaporating the solvent under reduced pressure at about 40 ° C, 16 mg of (RS) -1- (1- [bis (4-chlorophenyl) methyl] -3- [( 3,5-difluoro-phenyl) methylsulfonylamino onylmethyl] azetidin-3-ylmethyl} -3-isopropylisourea as a light yellow powder. ^{[; H} NMR (300 MHz, CDC1 _3, δ in ppm): 1.17 (d , J =

7 Hz 6H); 2.68 (s: 3H) ; 3.00 (wide d, J = 8, 5 Hz: 1H); 3.11 (d, J = 8.5 Hz: 1H); 3.17 (d, J = 8.5 Hz: 1H); 3.46 (br d, J = 8.5Hz : 1H); 3.64 (dd, J) = 14 a 5 Hz: 1H); 3.86 (mt 1H); .3.96 (dd, J = 14 and 7.5 Hz: 1H); 4 .15 (d, J = 8 Hz : 1H); 4.29 (s 1H); 4.43 (s 1H); 5 11 (mt : 1H); 6.94 (Tt, J = 9 a 2 Hz: 1H); from 7.10 to 7.30 (mt: 10H)].

Example 46

(RS) - {1- [Bis (4-Chloro-phenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -azetidin-3-ylmethyl} -carbamic acid isobutyl ester can be prepared by the following procedure: 0.016 cm ^{3 of} isobutyl-chloroformate to a solution of 53 mg of (RS) -C- {1- [bis (4-chlorophenyl) methyl] -3- [(3,5-difluorophenylmethylsulfonylmethyl) azetidin-3-yl} methylamine in 2 cm ^{3 of} pyridine at a temperature of about 20 The mixture was stirred overnight at about 20 ° C and then concentrated under reduced pressure to give 68 mg of a paste which was purified by preparative thin layer chromatography on silica gel [1 Merck Kieselgel 60F254 preparative plate; 20 x 20 cm] , thickness 1 mm] eluting with ethyl acetate-dichloromethane (5-95, v / v) After eluting the zone corresponding to the desired product, filtering through a frit and then evaporating the solvent under reduced pressure at

125 [deg.] C. to about 14 mg of (RS) - {1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl} carbamic acid isobutyl ester not completely white powder. pH NMR spectrum (300 MHz, CDCl ₃ , δ in ppm): 0.96 (d, J =

7 Hz 6H) ; 1.95 (mt 1H); 2.68 (with : 3H); 3.04 (d, J = 8.5) Hz: 1H); 3 19 (s:, 2K); 3.51 (d, J = 8 Hz : 1H); 3.75 (dd, J = 14 a 5 Hz 1H) ; from 3.80 to 4.00 (mt : 3H) ; 4.30 (s 1H); 4.34 (with : 1H); 5 63 (uncleaved complex: 1H); 6.95 (tt, J = 9 and 2) Hz: 1H); from 7 10 to 7.30 (mt 10H)].

Example 47 (RS) - {1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl} dimethylamine can be prepared as follows: 138 mg of potassium carbonate is added at a temperature of about 20 ° C to a solution of 52 mg of (RS) -C- (1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl] methylamine in 2 cm ³ of acetonitrile, followed by addition of methyl iodide ^J 0.0075 cm. the mixture was stirred overnight at about 20 DEG C., the mixture is filtered on sintered glass and the solid is washed with dichloromethane and concentrated to dryness under reduced pressure. the crude The residue (90 mg) is purified by thin layer chromatography on silica gel [1 Merck Kieselgel 60F254 preparative plate; 20 x cm; 1 mm thickness], eluting with ethyl acetate-dichloromethane (5-95, v / v). filtration through a frit and then evaporation of the solvent under reduced pressure at about 40 ° C afforded 11 mg (RS) - {1 - [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl [dimethylamine. [ ³ Η NMR spectrum (300 MHz,

CDCl ₃ , δ in ppm): 2.18 (s: 6H); 2.30 (d, J = 13 Hz 1H); from 4.65 to 4.78 (mt 1H); 2.70 (s 3H); 2.98 (d, J = 13 Hz 1H); 3.09 (d, J = 8Hz, 1H); 3.32 (d, J = 7.5Hz, 1H); 4.11 (d, J = 8Hz: 1H); 4.35 (s 1H); 4.94 (s 1H); 6.92 (mt 1H); from 7.10 to

7.40 (mt 10H)].

126

Example 48 (RS) -1- [Bis (4-chlorophenyl) methyl] -3 - [(4-methoxyphenyl) methylsulfonylmethyl] azetidine can be prepared as follows:

Add 25.5 mg of sodium tetraborohydride to the solution of 400 mg

1- [bis (4-chlorophenyl) methyl] -3 - [(4-methoxyphenyl) methylsulfonylmethylene] azetidine in 4.5 cm ^{3 of} ethanol under argon at about 20 ° C. The mixture was stirred at about 26 ° C for 16 hours and 26 mg of sodium tetraborohydride was added. The reaction mixture is stirred at about 20 ° C for 4 hours and then at about 50 ° C for 3 hours. After cooling to about 20 ° C, the reaction mixture was concentrated under reduced pressure. The white precipitate obtained is taken up in 2 cm ^{3 of} water and 2 cm ^{3 of} dichloromethane. After decantation, the organic phase is concentrated under reduced pressure and the resulting yellow foam is purified by preparative thin layer chromatography on silica gel [2 preparative plates Merck Kieselgel 60F254; 20 x 20 cm; thickness mm], eluting with methanol-dichloromethane (1-99, v / v). Elution of the zone corresponding to the desired product with methanol-dichloromethane (10-90, v / v), filtration through a frit and then evaporation of the solvents under reduced pressure at about 40 ° C afforded 14 mg of (RS) -1- [bis (4-chlorophenyl) methyl] -3 - [(4-methoxyphenyl) methylsulfonylmethyl] azetidine as a white foam. ¹ H NMR spectrum (300 MHz, CDCl 3, δ in ppm): 2.56 (mt 1H); 2.58 (s 3H);

3.20 (mt 2H); from 3.35 to 3.55 (mt 1H); 3.66 (broad t, J =

7.5 Hz 1H); 3.81 (s 3H); 4.21 (d, J = 4.5 Hz: 1H; 4.26 (broad s 1H); 6.90 (d, J = 8.5 Hz: 2H); from 7.15 to 7.40 (mt 10H)].

1- [Bis (4-chlorophenyl) methyl] -3 - [(4-methoxyphenyl) methylsulfonylmethylene] azetidine can be prepared according to the procedure described in Example 1 starting from 1 g of (RS) -1- [bis (4-chlorophenyl) methyl] -3- [methylsulfonyl- (4-methoxyphenyl) methyl] azetidin-3-ol, 20 cm ^{3 of} dichloromethane, 0.229 cm ^{3 of} methylsulfonyl chloride and 722 mg of 4-dimethylaminopyridine. After purification by chromatography on silica gel at atmospheric pressure (100 g silica gel, particle size 0.063 0.2 mm, column diameter 3 cm, eluting with dichloromethane),

127 containing only the desired product combined and concentrated to dryness under reduced pressure. 650 mg of 1- [bis (4-chlorophenyl) methyl] -3 - [(4-methoxyphenyl) methylsulfonylmethylene] toetidine are obtained in the form of a yellow gum.

(RS) -1- [Bis (4-chlorophenyl) methyl] -3- [methylsulfonyl- (4-methoxyphenyl) methyl] azetidin-3-ol can be prepared as described in Example 1, starting from 19.6 cm ³ 1 6 N of n-butyllithium in hexane, 5.7 g of 4-methoxybenzylmethylsulfone and 8.71 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one in 450 cm ^{3 of} tetrahydrofuran. 8.3 g of (RS) -1- [bis (4-chlorophenyl) methyl] -3- [methylsulfonyl- (4-methoxyphenyl) methyl] azetidin-3-ol are obtained as a beige solid.

4-Methoxybenzylmethylsulfone can be prepared as described in Example 27, starting from 13.6 cm ^{3 of} 4-methoxybenzyl chloride, 30 mg of sodium iodide, 14.4 g of sodium methylsulfinate in 125 cm ^{3 of} ethanol. 5.75 g of 4-methoxybenzylmethylsulfone are obtained in the form of a white powder.

T

Example 49 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-acetylmorpholine can be prepared as follows: 252 mg EDCI per carriers (2.3 equivalents, EDCI carrier is commercially available or can be prepared according to the following reference: M. Desai, L. Stramiello, Tetrahedron Letters, 34, 48,

7685-7688 (1993)), 2 cm ^{3 of} anhydrous dichloroethane, 0.006 cm ^{3 of} morpholine and then 0.010 cm ^{3 of} triethylamine are added gradually, at a temperature of about 20 ° C, to 37 mg of hydrochloride (RS) - {1- [bis (4- chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid. The mixture was stirred at about 20 ° C for 12 hours and then filtered through a frit. The filtrate is washed with 2 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 20 ° C. 15 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-acetylmorpholine are obtained as a beige foam. pH NMR spectrum (300 MHz,

128

CDCl 3, δ in ppm): from 2.60 to 3.80 (mt: 13H); 3.93 (d, J = 10Hz: 1H); 4.27 (s: 1H) from 6.65 to 6.85 (mt: 3H) from 7.20 to 7.40 (mt: 8H)].

Example 50 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclohexylacetamide can be prepared as follows: 0.070 cm ^{3 of} cyclohexylamine , 144 mg of hydrochloride

Of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.141 cm ^{3 of} triethylamine and then 4 mg of hydroxybenzotriazole hydrate are gradually added at about 20 ° C to a solution of 250 mg of (RS) - {1- [bis (4-chlorophenyl) hydrochloride methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 10 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (25 cm ³ ) filled with 12 g of fine silica gel (0.040-0.063 mm), treated and then eluted with dichloromethane-petroleum ether (80-20, v / v) and then collected using a Duramat pump. 5 cm ³ fractions. Fractions 11 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 169 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclohexylacetamide are obtained as a white foam. [ ³ H NMR spectrum (300 MHz, CDCl ₃ , δ in ppm)

6H); from 1.50 to 1.90 (mt 4H); 2.66 (mt (mt from 0.90 to 1.45 1H); 2.90 (mt:

1H); from 3.00 to 3.15 (mt ih:

(with

3.52 (d, J = 10.5 Hz)

2H); 3.42 (broad t, J = 7.5 Hz):

1H); from 3.60 to 3.80 (mt 1H); 4,27 ih:

5.25 (broad d, J = 8 Hz: 1H); 6.90 (tt, J = 9)

2.5 Hz: 1H); 6.82 (mt 2H); from 7.20 to 7.35 (mt 8H).

Example 51 (RS) -2- (1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) -N-acetylpiperidine can be prepared as follows: 0.012 cm ^{3 of} piperidine 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm @ ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are added sequentially at a temperature of ca.

129

20 ° C to a solution of 50 mg of (RS) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,5-difluorophenyl) acetic acid hydrochloride in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution is stirred at about 20 ° C for about 12 hours. The reaction mixture was then allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm) and eluted with dichloromethane using a Duramat pump. Fractions between 8 and 15 cm ³ are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 14 mg of (RS) -2- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-acetylpiperidine are obtained as a white crystalline solid.

powder. [ ³ Η NMR Spectrum (300 MHz CDCl 3, δ in ppm): from 0,95 to 1.15 and from 1.30 to 1.50 (2mts : 6H pretty); 2.74 (mt 2H); from 3.00 to 3.15 (mt 2H) of 3, 30 to 3.45 (mt 4H); from 3,55 do 3.70 (mt 1H); 3.95 (d, J = 10 Hz : 1H) ; 4.26 (s: 1H); 6.68 (tt, J = 9 and 2.5 Hz 1H); 6.80 (mt : 2H); from 7.20 to 7 35 (mt:

8H)].

Example 52 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-acetylpyrrolidine can be prepared as follows: 0.010 cm ^{3 of} pyrrolidine and 0.023 cm ^{3 of} diisopropylcarbodiimide, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3) hydrochloride. 5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloroethane at about 20 ° C. The resulting solution is stirred at about 20 ° C for about 12 hours. The reaction mixture was then allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm) and eluted with dichloromethane using a Duramat pump. Fractions between 11 and 19 cm ³ are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 29 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-acetylpyrrolidine are obtained as a white foam. f ¹ ?! Nuclear Magnetic Resonance Spectrum (300 MHz, CDCl ₃ , δ in ppm): from 1.75 to 2.00 (mt: 4H); 2.74 (mt 2H); from

130

3.00 up to 3.30 (mt 3H); from 3.35 do 3,60 (mt: 4H); 3.80 (d, J = 10.5 Hz: 1H); 4.25 (s 1H); 6, 68 (Tt, J = 9 and 2.5 Hz : 1H); 6.84 (mt 2H); from 7.20 to 7.40 (mt: 8H) ] ·

Example 53 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) -N-cyclopropylacetamide can be prepared as follows: 0.009 cm ³ cyclopropylamine, 29 mg of hydrochloride

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm @ ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS) - {1- [bis (4-chlorophenyl) methyl] azetidine-3 hydrochloride. -yl} - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane at a temperature of about 20 ° C. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is then allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm), treated and then eluted with dichloromethane using a Duramat pump and 2 cm ^{3 of} fractions are collected. Fractions 2-6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 29 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) -N-cyclopropylacetamide are obtained as a white foam. ^[X H NMR (300 MHz, CDC1 _3, δ in ppm): 0.40 (mt: 2H); 0.74 (mt 2H); 2.64 (mt 2H); 2.89 (dd, J = 7.5 and 5 Hz: 1H); 3.08 (mt 2H); 3.42 (broad t, J 7.5 Hz 1H); 3.51 (d, J = 10.5 Hz: 1H); 4.25 (s 1H); 5.50 (uncleaved complex: 1H); 6.70 (tt, J = 9 ' a)

2.5 Hz: 1H); 6.81 (mt 2H) from 7.15 to 7.35 (mt 8H)].

Example 54 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclohexyl-N-methylacetamide can be prepared as follows 0.016 cm ^{3 of} N-methylcyclohexylamine, 29 mg of 1- (3-dimethylaminophyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added at about 20 ° C to a solution of 50 mg of hydrochloride

131 (RS) - {1- [Bis (4-Chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) -acetic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is then allowed to settle in a Varian column (6 cm ³ ) packed with 3 g of fine silica gel (0.040-0.063 mm), treated and eluted with dichloromethane using a Duramat pump, and 2 cm ^{3 of} fractions are collected. Fractions 4-6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 17 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluoro-) are obtained.

phenyl) -N-cyclohexyl-N-methylacetamide in the form of white foam. ¹ H NMR spectrum (250 MHz (CD ₃ ) ₂ SO d6, at 373K, δ v ppm): from 0.98 to 1.85 (mt: 10H); from 2.60 to 3.05 (mt: 8H); (broad t, J = 7.5Hz : 1H) ; 4.25 (wide d, J = 9 Hz): 1H); 4.45 (s 1H); 7.00 (mt : 3H) ; from 7.25 to 7.45 (mt 8H)].

Example 55 (RS) -2- [1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (tetrahydrofuran-2-ylmethyl) acetamide can be prepared as follows: 0.013 cm ^{3 of} tetrahydrofurylamine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added at about 20 ° C to 50 mg of hydrochloride (RS). - {1-bis (4-chlorophenyl) methyl] azetidin-3-yl] - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is then allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm), treated and then eluted with dichloromethane using a Duramat pump and 2 cm ^{3 of} fractions are collected. Fractions 3-8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 27 mg of 2 (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (tetrahydrofuran-2-ylmethyl) acetamide are obtained. as a white solid. ^[X H NMR (300 MHz, CDCl3, δ in ppm): from 1.65 to 1.95 (mt: 4H); 2.64 (mt 1H); 2.89 (dd, J =

132

7.5 and 5.5 Hz: 1H); from 3,00 do 3.20 (mt 3H); from 3.30 to 3, 60 (mt : 2H) ; 3.58 (d, J = 10.5 Hz: 1H); from 3.65 to 3, 95 (mt: 3H); 4.25 (with : 1H); 5 81 (mt: 1H); 6, 68 (tt, J = 9 and 2.5 Hz: 1H); 6.82 (mt: 2H); from 7,15 do 7.35 (mt: 8H)].

Example 56 (RS) -2- {1- [Bis (4-chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) -N- (2-morpholin-4-ylethyl) -acetamide can be prepared as follows: 0.016 cm ^{3 of} aminoethylmorpholine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added at about 20 ° C to a solution of 50 mg of hydrochloride (RS) - {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution is stirred at about 20 ° C for 12 hours. The reaction mixture was then allowed to settle in a Varian Cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm) treated with dichloromethane using a Duramat pump and eluted sequentially with dichloromethane-ethyl acetate (70-30, v / v), collected. 2 cm ³ fractions for fractions 1 to 12 and then with dichloromethane-methanol (98-2, v / v) and collect 2 cm ³ fractions for fractions 12 to 27. Fractions 13 to 27 are combined and concentrated to dryness under reduced pressure ( 2.7 kPa). 34 mg of (RS) -2- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -2- (3,5-difluorophenyl) -N- (2-morpholin-4-ylethyl) was obtained. acetamide in the form of a white foam. ¹ H NMR spectrum

(300 MHz, CDCl ₃ , δ in ppm): 2.33 (wide t, J = 5 Hz: ; 4H); 2.38 (T, J = 7Hz: 2H) ; 2.65 (mt: 1H); from · 2, 85 to 3.20 (mt: 3H); 3.25 (wide q, J = 7 Hz : 2H) ; 3.43 (mt 1H); 3 57 (t, J = 5 Hz 4H); 3.61 (d, J = 10.5 Hz: 1H); 4. , 26 (s: 1H); 5, 98 (ner cleaved complex: 1H); 6. 70 (tt, J = 9 and 2.5 Hz: 1H); 6, 83 (mt 2H); from 7,15 do 7.35 (mt 8H)].

Example 57 (RS) -2- {1- [Bis (4-chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5-di-1,3-fluoro-phenyl) -N- (1-ethyl-pyrrolidin-2-ylmethyl) -acetamide can be prepared as follows: 0.018 cm ^{3 of} aminomethylethylpyrrolidine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are gradually added to a solution of 50 mg at about 20 ° C. (RS) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid hydrochloride in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (12 mm diameter) packed with 4 cm ^{3 of} silica gel (0.060-0.200 mm), treated with dichloromethane using a vacuum apparatus, eluting with dichloromethane between 0 and 6 · cm ³ and then with dichloromethane-methanol mixture. (95-5, v / v). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C for 2 hours. The yellow paste thus obtained is taken up with 2 cm ^{3 of} ethyl acetate and then with 2 cm ^{3 of} distilled water. After stirring, the mixture is frozen and the organic phase is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The residue is taken up in 2 cm diizopropyiéteru ^J, and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 ° C. 38 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (1-ethylpyrrolidin-2-ylmethyl) is obtained. acetamide in the form of a white foam. ^[X H NMR (300 MHz, CDCl3 with a few drops of CD3 COOD d4, δ in ppm): 0.96 and 1.17 (2t, J = 7.5 Hz: 3H in total); from 1.60 to 2.00 (mt 4H); from 2.50 to 2.95-from 3.10 to

3.85 (mts: 11H); from 3.95 to 4.10 (mt 1H); 4.10 and 4.14 (2d, J = 10.5 Hz: 1H total); 5.18 and 5.25 (2 broad s: 1H total);

6.66 (mt 1H); from 6.80 to 7.00 (mt 2H); from 7.15 to 7.45 (mt 8H)].

Example 58 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-isobutylacetamide can be prepared as follows: 0.012 cm ^{3 of} isobutylamine 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine, and

1.5 mg of hydroxybenzotriazole hydrate is gradually added at about 20 ° C to a solution of 50 mg of (RS) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) hydrochloride of acetic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (12 mm in diameter) filled with 5 cm ^{3 of} silica gel (0.060-0.200 mm), treated with dichloromethane using a vacuum apparatus, eluting with dichloromethane between 0 and 6 cm ³ and then with dichloromethane-methanol ( 95-5, v / v). Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C for 2 hours. 40 mg of (RS) -2- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-isobutylacetamide are obtained in the form of a white solid. [ ^X H

Nuclear Magnetic Resonance Spectrum (300 MHz, (CD ₃ ) ₂ SO d6) δ in ppm): 0.75 (D, J = 7.5 Hz 6H); 1.62 (mt: 1H); 2.61 (mt 1H); from 2.70 to 2.95 (mt 3H); 3.03 (mt 2H) ; 3.22 (broad t, J = 7Hz: 1H); 3.83 (d, J = 10.5 Hz: 1H); 4. 45 (s 1H); 7 00 (mt 2H); 7.08 (tt, J 9 and 2.5 Hz: 1H); from 7.25 to 7.45 i (mt 8H); 8.11 (T, J = 6Hz

1H)].

Example 59 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N, N-dimethylacetamide can be prepared as follows: 06 cm ^{3 of} dimethylamine in a 2 M solution in tetrahydrofuran, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are gradually added to a solution of 50 mg at about 20 ° C. (RS) - (1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid hydrochloride in 2 cm ^{3 of} anhydrous dichloromethane The solution obtained is stirred at about 20 ° C. The reaction mixture is allowed to settle in a Varian cartridge (12 mm in diameter) filled with 5 cm ^{3 of} silica gel (0.060-0.200 mm), treated with dichloromethane using a vacuum apparatus, eluting with dichloromethane.

135 in the range of 0 and 6 cm ³ and then dichloromethane-methanol (95-5, v / v). Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 13 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N, N-dimethylacetamide are obtained in the form of a white powder. ¹ H NMR spectrum (300 MHz, CDCl ₃ , δ in ppm): from

2.70 to 2.80 (mt 2H); 2.92 (s 3H); 2.95 (s 3H); from 3.00 to

3.15 (mt 2H); 3.38 (broad t, J 7.5 Hz 1H); 3.96 (d, J = 10Hz: 1H); 4.26 (s 1H); 6.69 (tt, J 9 and 2.5 Hz 1H); 6.81 (mt 2H); from 7.20 to 7.35 (mt 8H)].

Example 60 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-benzylacetamide can be prepared as follows: 0.013 cm ^{3 of} benzylamine 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm @ ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are added successively at about 20 DEG C. to 50 mg of (RS) - {1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (12 mm in diameter), packed with 4.4 cm ^{3 of} silica gel (0.060 0.200 mm), treated with dichloromethane using a vacuum apparatus, eluting with dichloromethane between 0 and 6 cm ³ and then with dichloromethane- methanol (95-5, v / v). Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 37 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) -N-benzylacetamide are obtained in the form of white crystals. pH NMR spectrum (300 MHz, CDCl 3, δ in ppm): 2.67 (mt 1H); 2.93 (mt:

1H): 3.11 (mt 2H); 3.43 (broad t, J 7.5 Hz 1H); 3.62 (d,

J = 10.5 Hz: 1H); 4.26 (s 1H); 4.38 (mt 2H); 5.71 (mt:

1H); 6.71 (broad t, J 9 Hz 1H); 6.83 (mt 2H); from 7.10 to

7.40 (mt 13H)].

136

Example 61 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclohexylmethylacetamide can be prepared by the following procedure: 0.016 cm ³ aminomethylcyclohexane 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm @ ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are added successively at about 20 DEG C. to a solution of 50 mg of hydrochloride [1- [bis (4-) - chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (6 cm ³ ) filled with 5 g of fine silica gel (0.040-0.063 mm), treated and then eluted with dichloromethane using a Duramat pump and 2 cm ^{3 of} fractions are collected. Fractions 2-3 are combined and concentrated to dryness under reduced pressure (2 > 7 kPa) at 40 ° C. 49 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) -N-cyclohexylmethylacetamide are obtained as a white foam. ¹ H NMR spectrum (300 MHz, CDCl 3, δ in ppm): from 0.75 to 1.75 (mt 11H); 2.65 (mt 1H); from 2.85 to 3.15 (mt 5H); 3.42 (broad t, J 7.5 Hz 1H); 3.57 (d, J = 10.5 Hz: 1H); 4.27 (s 1H); 5.40 (mt 1H);

6.71 (broad t, J 9 Hz 1H); 6.83 (mt 2H); from 7.15 to 7.40 (mt 8H)].

Example 62 (RS) -2- [1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- [3- (2-oxopyrrolidin-1-yl) propyl] acetamide can be prepared as follows: 0.017 cm ^{3 of} aminopropylpyrrolidinone, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added at about 20 ° C to a solution of 50 mg of (RS) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid hydrochloride in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (6 cm ³ ) with a 1337 g fine silica gel (0.040-0.063 mm) cartridge, treated and then eluted with dichloromethane using a Duramat pump and collecting 2 cm ³ fractions. Fractions 4 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 35 mg of (RS) -2- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- [3- (2-oxopyrrolidin-1)] are obtained. [ ³ H-NMR (300 MHz, CDCl ₃ , δ in ppm): from 1.50 to 1.65 (mt: 2H); 2.04 (mt: 2H) 2.43 (t, J = 8Hz, 2H);

2.64 (mt 1H); 2.88 (dd, J = 7.5 and 5.5 Hz: 1H); from 3.00 to 3.30 (mt 6H); from 3.30 to 3.45 (mt 3H); 3.64 (d, J = 10.5 Hz: 1H); 4.27 (s 1H); 6.67 (tt, J 9 and 2.5 Hz 1H); 6.90 (mt 2H); 7.15 (t, J = 6Hz, 1H); from 7.20 to 7.35 (mt 8H)].

Example 63 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-acetyl (4-methylpiperazine) can be prepared as follows 0.013 cm ^{3 of} N-methylpiperazine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added at about 20 ° C to a solution of 50 mg of hydrochloride (RS). 1 - {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm), treated with dichloromethane with the aid of

Duramat pump, eluting with dichloromethane-ethanol (98-02, v / v) and collecting 2 cm ³ fractions. Fractions 10 to 24 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 39 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-acetyl (4-methylpiperidine) are obtained.

-piperazine) in shape white foam. ¹ H NMR spectrum (300 MHz CDCI3, δ v ppm): 1.83 (mt : 1H); from 2 , 10 to 2, 45 (mt: 3H); 2.21 (with : 3H); 2.74 (mt 2H); from 2, 95 to 3.15 (mt : 2H); from 3.30 to 3.55 (mt: 4H); 3.73 (mt : 1H); 3.93 (d, J = 10 Hz: 1H); 4.25 (with : 1H);

138

6.69 (tt, J 9 and 2.5 Hz 1H); 6.78 (mt 2H); from 7.15 to 7.35 (mt 8H)].

Example 64 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (2,2-dimethylpropyl) acetamide can be prepared as follows: 0.014 cm ^{3 of} neopentylamine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added at about 20 ° C to a solution of 50 mg of hydrochloride (RS). 1 - {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel. (0.040-0.063 mm), treated with dichloromethane at. help

Duramat pump, eluting with dichloromethane-petroleum ether (80-20, v / v) and collecting 1.5 cm ³ fractions. Fractions 4 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 40 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) -N- (2,2-dimethylpropyl) - are obtained.

acetamide in the form of white foam. [H NMR spectrum (300 MHz, CDCl 3) δ v ppm): 0.81 (s 9H); 2.66 (mt : 1H); from 2.90 to 3.20 (mt 5H); 3, 44 (wide t, J = 7.5 Hz: 1H); 3.61 (d, J = 10.5Hz) 1H) : 4,28 (s 1H); 5.40 (mt: 1H) ; 6.72 (tt, J = 9.5 and 2.5 Hz) 1H); 6, 85 (mt 2H); from 7.20 to 7.35 (mt 8H)].

Example 65 (RS) -2- {1- [Bis (4-Chloro-phenyl) -methyl] -azetidin-3-yl) -2- (3,5-difluoro-phenyl) -N- (2-pyrrolidin-1-yl-ethyl) -acetamide can be prepared as follows: 0.015 cm ^{3 of} aminoethylpyrrolidine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added at about 20 ° C to a solution of 50 mg of hydrochloride (RS) - (1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane The solution obtained is stirred at about 20 ° C. The reaction mixture is allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm) treated with dichloromethane using a Duramat pump, eluting with dichloromethane / ethanol (98-04, v / v) and collected. 1.5 cm ³ fractions. fractions 13-20 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. to give 33 mg of (RS) -2- {1- [bis (4 -c chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (2-pyrrolidin-1-ylethyl) acetamide as a white foam. pH NMR spectrum

(300 MHz, CDCl 3, δ in ppm): 1.78 (mt: 4H); from 2.50 to 2.70 (mt: 3H); 2.54 (mt 4H); 2.91 (dd, J = 7, 5 and 5 Hz: 1H); 3,10 (mt: 2H); from 3.20 to 3.45 (mt 3H) ; 3.64 (d, J = 10.5 Hz): : 1H); 4.27 (with : 1H); 6.67 (tt, J = 9 a 2.5 Hz : 1H); 6.86 (mt : 2H); from

7.15 to 7.35 (mt 8H)].

Example 66 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclopropylmethylacetamide can be prepared as follows: 0.011 cm ^{3 of} cyclopropanemethylamine 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm @ ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are added successively at about 20 DEG C. to a solution of 50 mg of hydrochloride (RS) - {1- [bis] (4-chlorophenyl) methyl] azetidin-3-yl) - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloroethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm), treated and then eluted with dichloromethane-petroleum ether (80-20, v / v) using a Duramat pump and collected 1, 5 cm ³ fractions. Fractions 3-8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 37 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) -N-cyclopropylmethylacetamide are obtained as a white foam. [ ³ H NMR spectrum (300 MHz, CDCl 3, δ in ppm):

140

0.13 (mt (2H): 0.45 (mt: 2H); 0.86 2.91 (Dd, J = 7.5 and 5 Hz: 1H); from 3, (wide t J = 7.5 Hz : 1H), ; 3.57 (d, : 1H) ; 5 50 (mt 1H); 6.70 (tt, J : 2H) ; from 7.15 to 7.35 (mt: 8H)].

1Η); 2.65 (mt 1H);

3.15 (mt 4H); 3.41), 5 Hz: 1H); 4.25 (s 5 Hz 1H); 6, 84 (mt

Example 67 (KS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-propylacetamide can be prepared as follows: 0.015 cm ^{3 of} propylamine 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are added gradually to a solution of 50 mg of (RS) - (1- [bis ( 4-Chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane The solution obtained is stirred at about 20 ° C for 12 hours and the reaction mixture is allowed to settle in Varianova. cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm), treated and eluted with dichloromethane using a Duramat pump The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at temperature 40 ° C. 21 mg of (RS) -2- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-propyl acetamide is obtained in the form of a white p. pH NMR spectrum (300 MHz, CDCl ₃ , δ in ppm): 0.84 (t, J = 7.5

7.5 Hz

3H)

1.45 (mt

2H)

2.65 (mt

1 H?

2.92 (dd,

a 5, 5 Hz: 1H) ; from 3.00 to 3.20 (mt : 2H) ; 3 15 (q, J = 7) Hz 2H); 4.43 (wide t, J = 7.5 Hz: 1H); 3 , 56 (D, J = 10.5 Hz 1H); 4.26 (with : ´ IH) 5.39 (mt 1H); 6.70 (Tt, J = 9 and 2.5 Hz 1H); 6.83 (mt : 2H); from 7.15 to 7.35 (mt: 8H].

Example 68 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-propyl acetamide can be prepared as follows: 0.050 cm ³ 2 M solution of methylamine in tetrahydrofuran, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride,

141

0.028 cm @ ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are added at a temperature of about 20 DEG C. to a solution of 50 mg of (RS) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3, Of 5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm), treated and eluted with dichloromethane using a Duramat pump. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 19 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-methylacetamide are obtained as a white foam. pH NMR spectrum (300 MHz, CDCl 3, δ in ppm): 2.66 (mt 1H); 2.76 (d, J = 5Hz, 3H); 2.93 (mt 1H); 3.10 (mt 2H); 3.44 (broad t, J 7.5 Hz 1H); 3.59 (d, J = 10.5 Hz: 1H); 4.28 (s 1H); 5.41 (uncleaved complex: 1H); 6.71 (tt, J = 9 and 2.5 Hz 1H); 6.83 (mt 2H); from 7.20 to 7.35 (mt 8H)].

Example 69 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-isopropylacetamide can be prepared as follows: 0.011 cm ^{3 of} isopropylamine 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine, and

1.5 mg of hydroxybenzotriazole hydrate is gradually added at about 20 ° C to a solution of 50 mg of (R'S) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) hydrochloride of acetic acid in 2 cm ^{3 of} anhydrous dichloroethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040 0.063 mm), treated and then eluted with dichloromethane using a Duramat pump, and 1.5 cm ^{3 of} fractions are collected. Fractions 6 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 21 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-isopropylpylacetamide are obtained in the form of a white foam. [ ³ H NMR spectrum (300 MHz, CDCl 3, δ in ppm): 1.05 (d, J = 7 Hz: 3H); 1.10 (d, J = 7Hz: 3H); 2.65 (mt 1H); 2.90 (dd, J = 7.5 and 5.5 Hz: 1H); from 3.00 to 3.15 (mt 2H); 3.42 (broad t, J 7.5 Hz 1H); 3.51 (d, J = 10.5 Hz: 1H); 4.00 (mt 1H); 4.26. (s 1H); 5.19 (broad d, J 7.5 Hz 1H); 6.70 (tt, J = 9 and 2.5 Hz 1H); 6.82 (mt:

2H); from 7.20 to 7.40 (mt 8H)].

Example 70 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-piperidin-1-ylacetamide can be prepared as follows: 0.013 cm ^{3 of} aminopiperidine, 2.9 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are added successively at a temperature of about 20 ° C to a solution of 50 mg of hydrochloride (RS) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm) treated with dichloromethane using a Duramat pump. elute with dichloromethane-ethanol (98-02, v / v) and collect 2 cm ^{3 of} fraction. Fractions 7 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 33 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-piperidin-1-ylacetamide is obtained as a residue. white solid. ¹ H NMR spectrum (300 MHz, CDCl 3, δ in ppm): from 0.95 to 1.85-2.05 and 2.29 (mts: 10H); from 2.60 to 2.80 (mt 2H); from 3.00 to 3.20 (mt 2H); 3.39 (broad t, J 7.5 Hz 1H); 4.26 (s 1H); 4.32 (d, J = 10.5 Hz: 1H); 6.00 (s 1H);

6.65 (tt, J 9 and 2.5 Hz 1H); 6.85 (mt 2H); from 7.15 to 7.35 (mt 8H)].

Example 71 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-di-14-fluorophenyl) -N-cycloheptylacetamide can be prepared as follows: 0.015 cm ³ cycloheptylamine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are added successively at about 20 ° C to a solution of 50 mg of hydrochloride (RS) - {1- [ bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm), treated and eluted with dichloromethane using a Duramat pump, collecting 2 cm ^{3 of} fractions. Fractions 3-6 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 24 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclo-

heptylacetamide in the form of a white foam. [ ^X H NMR Spectrum (300 MHz CDCl3, δ in ppm): from 1.20 to 1.95 (mt: 12H) ; 2.65 (mt: 1H); 2.90 (dd, J = 7.5 and 5.5 Hz: 1H); from 3.00 to 3.15 (mt: 2H); 3.42 (broad t, J = 7.5 Hz: 1H); 3.52 (d, J = 10.5 Hz: 1H); 3.86 (mt 1H); 4.26 (s 1H); 5.31 (broad d. J = 7.5Hz: 1H); 6, 70

(tt, J = 9 and 2.5 Hz 1H); 6.82 (mt 2H); from 7.20 to 7.35 (mt 8H)].

Example 72 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) acetamide may be used. prepared as follows: 60 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 3 mg of hydroxybenzotriazole hydrate are successively added at about 20 ° C to a solution of 98 mg of (RS) - {1- [bis (4-chlorophenyl) hydrochloride (methyl) azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 4 cm ^{3 of} anhydrous dichloroethane. Ammonia was then bubbled through the mixture with stirring at about 20 ° C. The reaction mixture is washed with water and then allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.063 mm), treated and eluted with dichloromethane-ethyl acetate (9-1, v / v) using a Duramat pump. Fractions. Combine in the 36 and 80 ml range and concentrate to dryness under reduced pressure (2.7 kPa) at 40 ° C. 32 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) acetamide are obtained as an amorphous powder. 300 MHz, CDCl 3, δ in ppm): 2.66 (mt 1H); 2.95 (dd, J = 7 and 5 Hz 1H); from 2.95 to

3.15 (mt 2H); 3.45 (broad t, J 7 Hz 1H); 3.67 (d, J 10.5 Hz: 1H); 4.27 (s 1H); from 5.20 to 5.40 (uncleaved complex: 2H); 6.72 (tt, J 9 and 2.5 Hz 1H); 6.84 (mt 2H); from 7.20 to 7.35 (mt 8H)].

Example 73

Methyl (RS) -2- (1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-acetylaminoacetate can be prepared as follows: 100 mg methyl ester hydrochloride glycine, 115 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and 6 mg of hydroxybenzotriazole hydrate are added gradually to a solution of 200 mg of (RS) - {1- [bis (4-chlorophenyl) methyl] hydrochloride at about 20 ° C. ] Azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 8 cm ^{3 of} dichloroethane The solution obtained is stirred at about 20 ° C for 12 hours, the reaction mixture is washed with water, dried, filtered and concentrated The resulting residue is taken up in 1 cm ^{3 of} dichloromethane and then allowed to settle in an IST FlashPack cartridge with reference number SIL-020-005 treated and eluted with dichloromethane. ethyl acetate (95-05, v / v) using a Duramat pump Fractions between 18 and 42 mL were combined and concentrated to dryness to afford a solid. pressure (2.7 kPa) at 40 DEG C. 68 mg of methyl (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5) are obtained. -difluorophenyl) -N-acetylamine acetate in the form of white crystals overgrown with feathers. ¹ H NMR spectrum (300 MHz, CDCl 3, δ in ppm): 2.67 (mt 1H); 2.93 (broad dd, J = 7.5 and 5 Hz: 1H); from

3.00 to 3.15 (mt 2H); 3.41 (broad t, J 7.5 Hz 1H); 3.68 (d, J = 10.5 Hz: 1H); 3.74 (s 3H); 3.93 (dd, J = 18 and 5 Hz):

145

1H); 4.03 (dd, J = 18 and 5 Hz): : 1H); 4.27 (s: : 1H); 5, 96 (mt: 1H); 6.71 (tt, J = 9 and 2 Hz): 1H); 6.85 (mt: : 2H); from 7, 20 to 7.35 (mt: 8H)]. Example 74

(RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (3-dimethylaminopropyl) acetamide can be prepared as follows: 0.015 cm ^{3 of} N, N-dimethylpropane-1,3-diamine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added at about 20 ° C to A solution of 50 mg of (RS) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid hydrochloride in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is allowed to settle in a Varian cartridge (12 mm diameter) filled with 4 cm ^{3 of} fine silica gel (0.060-0.200 mm) treated with dichloromethane using a vacuum apparatus, eluting with dichloromethane between 0 and 6 cm ³ and then with dichloromethane-ethanol ( 95-05, v / v). Fractions containing only the desired product were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 33 mg of [lacuna] (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (3-dimethylaminopropyl) acetamide are obtained. in the form of white crystals. ¹ H NMR spectrum (300 MHz, CDCl 3, with the addition of a few drops of CD 3 COOD d 4, δ in ppm): 1.91 (mt: 2H); 2.71 (s 6H); 2.95 (mt 2H); from 3.15 to

3.40 (mt 2H); from 3.40 to 3.60 (mt 1H); from 3.60 to 3.80 (mt 2H); 4.00 (mt 2H); 4.28 (d, J = 10.5 Hz: 1H); 5.22 (s 1H);

6.68 (tt, J 9 and 2.5 Hz 1H); 6.90 (mt 2H); 7.33 (mt 4H);

7.46 (d, J = 8Hz: 4H)].

Example 75 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (2-hydroxyethyl) acetamide can be prepared as follows : 0.024 cm ^{3 of} ethanolamine, 29 mg of hydrochloride

146

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm ^{3 of} triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are added successively at a temperature of about 20 ° C to a solution of 50 mg of (RS) - {1- [bis (4-chlorophenyl) hydrochloride (methyl) azetidin-3-yl) - (3,5-difluorophenyl) acetic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution is stirred at a temperature of about 20 ° C. The reaction mixture is washed with 2 cm ^{3 of} saturated sodium bicarbonate solution, dried over sodium sulfate and then allowed to settle in an IST FlashPack cartridge with reference number SIL-020-005 treated with dichloromethane and eluted with dichloromethane-ethyl acetate (95-05, v / v) to using a Duramat pump. Fractions between 25 and 60 cm ³ are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The residue is chromatographed again on an IST FlashPack cartridge with reference number SIL-020-005 treated with dichloromethane and eluted with dichloromethane-ethyl acetate (95-05, v / v) using a Duramat pump. Fractions between 25 and 35 cm ³ are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 14 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (2-hydroxyethyl) acetamide are obtained in the form of a white solid. solid. ^[X H NMR (300 MHz, CDC1 _3, δ in

ppm): 2 65 (mt: IH); 2.91 (mt: IH); from 3.00 to 3.15 (mt : 2H); from 3.30 to 3.50 (mt 3H); 3.60 (d, J = 10.5Hz) : IH) ; 3 66 (t, J = 5.5 Hz : 2H) ; 4.26 (s: IH); 5.88 (mp 1H); 6.71 (Tt, J = 9 and 2 Hz: IH ); 6. 84 (mt 2H); ); from 7.20 to 7.35 (mt : 8H) ]

Example 76 (RS) -1 - [{1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methyl] -3-propylurea can be prepared as follows: 0.056 cm ³ triethylamine and 0.064 cm ^{3 of} diphenylphosphonoazide are gradually added under an inert argon atmosphere at 20 ° C to a solution of 50 mg of (RS) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3, Of 5-difluorophenyl) acetic acid in 3 cm ^{3 of} anhydrous toluene. The resulting solution is stirred at about 50 ° C for about 1 hour. Propylamine (0.016 cm ³⁾ is added and the mixture is stirred at about 20 ° C for 12 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 ° C. The residue is taken up in 1 cm ^{3 of} dichloromethane and then allowed to settle in a Varian cartridge (6 cm ³ ) filled with 3 g of fine silica gel (0.040-0.63 mm), treated and eluted with dichloromethane-ethanol (95-05 by volume) to using a Duramat pump. Fractions between 12 and 16 cm ³ are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 13 mg of (RS) -1 - [{1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) methyl] -3-propylurea was obtained as a beige solid. . ^[X H-NMR (400 MHz, CDC1 _3, δ in ppm): 0.92 (t, J =

7 5 Hz: 3H); 1.53 (mt: 2H); from 2.55 to 2.75 (mt IH) ; from 2.80 to 3.25 (mt 6H); 4.26 (T, J = 5.5 Hz : IH ); 4.29 (s: 1H); 4. 92 (t, J = 7 Hz: IH); 5.31 (d, J = 5 5 Hz: : IH); 6. 66 (tt, J = 9 and 2, 5 Hz : IH); 6.79 (mt: 2H); from 7 15 to 7.40 (mt : 8H)].

Example 77 ·

(RS) - {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl) - (3,5-difluorophenyl) acetic acid hydrochloride may be prepared as follows: 3 cm ^{3 of} 6 N hydrochloric acid are added to the solution ethyl ester 0.44 g of (RS) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid in 7 cm ^{3 of} dioxane. The resulting solution is stirred at reflux for about 2 hours and the porous is left at about 20 ° C for about 12 hours. The resulting precipitate is filtered on frit no. 3, washed with 10 cm ^{3 of} diisopropyl ether and then dried under reduced pressure (0.27 kPa) at a temperature of about 40 ° C. 0.185 g of (RS) - {1- [bi's (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid hydrochloride is obtained in the form of a white powder. ^[X H-NMR (400 MHz, (CD ₃₎ 2 SO d6, at 363K, δ in ppm): 2.87 (dd, J = 14 and 4 Hz: 1H); 2.95 (mt 1H), 3.18 (mt 1H); 3.96 (d, J = 10.5 Hz: 1H); 4.18 (r, J = 9 Hz: 1H); 4.72 (t, J = 9 Hz: 1H); 5.26 (uncleaved complex: 1H); 7.00 (mt 2H); 7.06 (tt, J = 9.5 and 2.5 Hz: 1H); from 7.30 to 7.60 (mt 8H)].

148

Example 78

(RS) {1- [Bis (4-Chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) -acetic acid ethyl ester can be prepared as follows: 121 mg of sodium borohydride is added at about 0 ° C to a suspension of 0.78 g of (RS) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene] - (3,5-difluorophenyl) acetic acid ethyl ester in 20 cm ^{3 of} ethanol. The resulting suspension is stirred at about 20 ° C for 12 hours. The reaction mixture is poured into 200 cm ^{3 of} distilled water and extracted three times with 40 cm ^{3 of} ethyl acetate. The organic phase is washed successively with three times 40 cm @ ^{3 of} distilled water and then 40 cm @ ^{3 of} saturated sodium chloride solution. After decanting, the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 ° C. The residue obtained is chromatographed on a column of silica gel packed with 75 cm ^{3 of} fine silica gel (0.040-0.063 mm) under reduced pressure of 0.07 MPa and eluted with dichloromethane-ethyl acetate (the percentage of ethyl acetate varies from 0 to 10%) and collected 15 cm ^3. fractions. Fractions 4-11 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.46 g of (RS) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) - (3,5-difluorophenyl) acetic acid ethyl ester is obtained in the form of a yellow lacquer. ^[X H NMR (300 MHz, CDC1 _3, δ in ppm): 1.19 (t, J = 7 Hz: 3H); 2.62 (broad t, J 6 Hz 1H); 2.87 (dd, J = 7.5 and 6 Hz: 1H); from 2.95 to

3.15 (mt 2H); 3.39 (broad t, J 7.5 Hz 1H); 3.78 (d, J = 10.5 Hz: 1H); 4.10 (mt 2H); 4.25 (s 1H); 6.69 (tt, J 9 and 2.5 Hz 1H); 6.80 (mt 2H); from 7.20 to 7.35 (mt 8H)].

Fractions 16 to 26 from the above chromatography were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.24 g of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) ethanol is obtained as a yellow foam.

^[X H NMR spectrum (300 MHz CDCl3, δ in ppm): 1.98 (unresolved complex : 1H); 2.69 (mt: 1H); from 2 70 to 2.85 (mt: 1H); from 2,90 to 3.10 (mt 2H) ); 3 18 (mt: 1H) ; 3,4 4 (mt : 1H); from 3.65

149 to 3.85 (mt 2H); 4.28 (s 1H); from 6.60 to 6.80 (mt 3H); from

7.20 to 7.35 (mt 8H)].

{1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene} (3,5-difluorophenyl) acetic acid ethyl ester can be prepared by the following procedure: 6.6 g of 4-dimethylaminopyridine and 2.1 cm ^{3 of} methylsulfonyl chloride are added. to a solution of 9.1 g of (1- [bis-4-chlorophenyl) methyl] -3-hydroxyazetidin-3-yl} - (3,5-difluorophenyl) acetic acid ethyl ester in 200 cm ^{3 of} dichloromethane. The resulting solution is stirred at about 20 ° C for about 12 hours. The reaction mixture is washed three times with 250 cm @ ^{3 of} distilled water and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 ° C. The residue is taken up hot with 50 cm ^{3 of} isopropyl ether and then left at about 20 ° C for about 12 hours. The white suspension obtained is filtered through a frit, washed with 20 cm @ ^{3 of} petroleum ether and then dried under reduced pressure (0.27 kPa) at about 40 DEG C. for 2 hours. 7.9 g of {1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} - (3,5-difluorophenyl) acetic acid ethyl ester are obtained in the form of a cream-colored powder. ^{[Χ Η} NMR (300 MHz, CDCl3, δ in ppm):

1.25 (t, J = 7Hz: 3H); 3.85 (mt 2H); 4.12 (AB, J = 7.5Hz, 2H); 4.23 (mt 2H); 4.51 (s 1H); from 6.65 to 6.80 (mt 3H); from 7.20 to 7.40 (mt 8H)].

{1- [Bis (4-Chloro-phenyl) -methyl] -3-hydroxy-azetidin-3-yl} - (3,5-difluoro-phenyl) -acetic acid ethyl ester can be prepared as follows: 34.54 cm @ -1 of a 1.6 M solution of butyllithium in hexane are added dropwise over 15 minutes to a solution of 7.73 cm ^{3 of} diisopropylamine in 125 cm ^{3 of} anhydrous tetrahydrofuran under an inert nitrogen atmosphere at a temperature of about 70 ° C. The mixture was stirred at this temperature for 45 minutes and a solution was added over 15 minutes

II, 01 g of ethyl 3,5-difluorophenylacetate in 85 cm ^{3 of} anhydrous tetrahydrofuran. Stirring is continued for 1 hour at -78 ° C, 16.84 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one in 90 cm ^{3 of} anhydrous tetrahydrofuran is added, stirring is continued at -70 ° C for 1 hour. 300 cm @ ^{3 of} saturated ammonium chloride solution are added at 0 DEG C. under vigorous stirring for 30 minutes, the reaction mixture is separated after 12 hours by settling, the organic phase is washed with saturated sodium bicarbonate solution, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a 70 mm diameter column packed with 2000 cm ^{3 of} fine silica gel (0.040-0.063 mm) under reduced pressure of 0.07 MPa with dichloromethane-ethyl acetate (99-01, v / v). Product-only fractions were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C for 2 hours. 9.1 g of {1- [bis (4-chlorophenyl) methyl] -3-hydroxyazetidin-3-yl} - (3,5-difluorophenyl) acetic acid ethyl ester are obtained in the form of a cream-colored solid. ¹ H NMR spectrum (300 MHz, CDCl ₃ , δ in ppm): 1.25 (t, J = 7 Hz: 3H); 2.87 (d, J = 8Hz: 1H); 3.07 (d, J = 8Hz, 1H); (broad d, J = 8 Hz 1H); 3.28 (broad d, J = 8 Hz 1H); 4.12 (s 2H); 4.21 (mt 2H); 4.36 (s 1H); 6.78 (tt, J = 9 and

2.5 Hz: 1H); 6.98 (mt 2H); from 7.20 to 7.40 (mt 8H)].

Ethyl 3,5-difluorophenylacetate can be prepared as follows: 20.4 cm ^{3 of} triethylamine and then 27.6 g of 3,5-difluorophenylacetic acid chloride in solution in 60 cm ^{3 of} dichloromethane are gradually added to a solution of 12 cm ^{3 of} ethanol in 300 cm 3 ^{3 of} anhydrous dichloromethane at about 20 ° C. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is washed successively with 150 cm @ ^{3 of a} decinormal hydrochloric acid solution and then with 150 cm @ ^{3 of a} saturated solution of sodium bicarbonate. The organic phase was dried with magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 ° C. 29 g of ethyl 3,5-difluorophenyl acetate are obtained in the form of a yellow oil.

3,5-Difluorophenylacetic acid chloride can be prepared as follows: 19.3 cm ^{3 of} oxalyl chloride and then a few drops of dimethylformamide are gradually added to a solution of 25 g

3,5-difluorophenylacetic acid in 350 cm ^{3 of} 1,2-dichloroethane at a temperature of about 20 ° C. The mixture is stirred at about 20 ° C for 3 hours,

151 cm &lt; ^{3 &gt; of} oxalyl chloride are added successively and then again a few drops of dimethylformamide. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 ° C. It will be obtained

27.6 g of 3,5-difluorophenylacetic acid chloride as a yellow oil.

Example 79 (RS) -1- [Bis (4-chlorophenyl) methyl] -3- [1- (3,5-difluorophenyl) -1-methylsulfonylethyl] azetidine was obtained as follows: 0.5 cm ^{3 of a} 2 M lithium diisopropylamide solution is added to a solution of 0,5 g of (RS) -1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine in 10 cm ^{3 of} tetrahydrofuran cooled to - 78 ° C and maintained under an inert atmosphere. The temperature of the mixture is raised to -20 ° C and then 0.06 cm ^{3 of} iodomethane are added. The temperature is raised to 0 ° C over 2 hours and then a solution of 20 cm ^{3 of} saturated aqueous ammonium chloride is added. After settling, the reaction mixture is separated and the aqueous phase is extracted twice with 20 cm ^{3 of} ethyl acetate. The organic extracts are combined, dried over magnesium sulphate and evaporated to dryness at 40 ° C under reduced pressure (2.7 kPa) to give 550 mg of a cream colored residue. The residue is chromatographed on a silica gel column (Dynamax, reference 83-121-C, size 21.4 mm x 250 mm, precolumn 21.4 mm x 50 mm, reference R00083121G, 8 µ silica gel, porosity 60 Angstroem; Rainin Instrument Co. Inc. , Mac Road, Woburn, MA 01801, USA), eluting with heptane: isopropanol (99: 1, v / v) at 15 cm ³ per minute (detection 254 nM, 10 cm ³ fraction). The fractions containing the compound with Rf = 32/77 (cyclohexane: ethyl acetate 70:30, 254 nm, silica gel reference plates 1.05719, Merck KGaA, 64271 Darmstadt, Germany) were combined and evaporated at 40 ° C under a pressure of 2.7 kPa to give 80 mg of 1- [bis (4-chlorophenyl) methyl] -3- [1- (3,5-difluorophenyl) -1-methylsulfonylethyl] azetidine as a white amorphous powder. ^[H NMR (300 MHz, CDCl3, δ in ppm): 2.05 (s: 3H); 2.54 (s 3H);

2.63 (t, J = 7.5Hz: 1H); 3.17 (broad t, J 8 Hz 1H); 3.32 (mt 1H); 3.44 (broad t, J 8 Hz 1H); 3.71 (mt 1H); 4.27

152 (s: 1H); 6.83 (tt, J 9 and 2.5 Hz 1H); 7.15 (mt 2H); from

7.20 to 7.40 (mt 8H)].

Example 80 (RS) -1- [Bis (4-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine can be prepared as follows: several potassium iodide granules are added to a suspension of 0.191 cm ³ bis (4-fluorophenyl) chloroethane, 300 mg of (RS) -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine and 167 mg of potassium carbonate in 5 cm ^{3 of} acetonitrile, at a temperature of about 20 ° C. After 48 hours at about 20 ° C, the reaction mixture is filtered on a frit, the solid washed with acetonitrile and the filtrate purified by preparative thin layer chromatography on silica gel [3 preparative plates Merck Kieselgel 60F254; 20 x 20 cm; thickness 1 mm], eluting with methanol / dichloromethane (1/99 by volume). Elution of the zone corresponding to the desired product with methanol / dichloromethane (10/90 by volume), filtration on a frit and then evaporation of the solvents under reduced pressure at about 40 ° C afforded 39 mg of (RS) -1- [bis (4-fluorophen)]. enyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine as a yellow foam. ^[X H NMR

(300 MHz CDC1 ₃ , δ v ppm): 2.54 (wide t, J = 7Hz: IH); 2.66 (with : 3H); 3, 18 (mt : 2H); from 3.20 to 3.45 (mt: IH); 3, 63 (wide t, J = 7 Hz : IH); 4.27 (s: 1H); 4.28 (d, J) = 11 Hz: IH); 6.83 (tt, J = 9 and 2 Hz: IH) ; from 6.90 to 7.05 (mt : 6H) ; from

7.25 to 7.40 (mt 4H)].

(RS) -3 - [(3,5-Difluorophenyl) methylsulfonylmethyl] azetidine hydrochloride can be prepared as follows: suspension

8.5 g of 1-benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonylmethylene)] azetidine and 1.3 g of palladium hydroxide (20% by weight of palladium) in 600 cm @ ^{3 of} methanol, 20 cm @ -1 of N hydrochloric acid, and 4 cm @ ³ of acetic acid are stirred at about 20 DEG C. under a hydrogen atmosphere until the volume of 2.1 liters of hydrogen is completely absorbed. The reaction mixture is then filtered on a charcoal frit. The filtrate is concentrated to dryness under reduced pressure and then the residue is taken up in ethanol. The crystalline product is filtered off and dried. 5.4 g of (RS) -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine hydrochloride are obtained in the form of white crystals.

1-Benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine can be prepared as follows: a mixture of 18.8 g

3-Acetoxy-1-benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine and 3.9 g of lithium hydroxide monohydrate in 120 cm ^{3 of} acetonitrile are heated at about 70 ° C for 3 hours. . After cooling to about 2 ° C, 120 cm ^{3 of} tert-butyl methyl ether and 80 cm ^{3 of} distilled water are added successively, and then 5 cm ³ of acetic acid are slowly added. After decanting, the organic phase is washed with 80 cm ^{3 of} saturated aqueous sodium bicarbonate solution, 80 cm ^{3 of} distilled water, 80 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is taken up in ethanol. The mixture is left overnight at a temperature of about 20 ° C, then filtered through a frit, the white crystals are washed with ethanol, diisopropyl ether and dried under reduced pressure at a temperature of about 45 ° C. 14.6 g of 1-benzhydryl-3 - [(3,5-difluorophenyl) methylsulfonyl) methylene] azetidine are obtained in the form of white crystals.

3-Acethoxy-1-benzhydryl-3 - [(3,5-difluorophenyl) methylsulfonyl) methyl] azetidine can be prepared as follows: 47.1 cm ³

1.6 N n-butyllithium in hexane solution is added dropwise over 25 minutes to a suspension of 12.37 g of 3,5-difluorobenzylmethylsulfone in 200 cm ^{3 of} tetrahydrofuran under an inert atmosphere of nitrogen, at a temperature of about -30 ° C. The cloudy yellow solution was stirred at about -30 ° C for 2 hours and then added dropwise

II, 87 g of 1-benzhydrylazetidin-3-one in 75 cm @ ^{3 of} dichloromethane. ¹ The mixture is stirred for 1.5 hours at a temperature of about -30 DEG C. before adding 6.07 cm ³ of acetyl chloride and the reaction temperature was adjusted to about 10 ° C for 30 minutes. 200 cm ^{3 of} water and 100 cm ^{3 of} dichloromethane are added. After vigorous stirring and decantation, the organic phase is washed three times with 150 cm ^{3 of a} saturated aqueous solution.

154 of sodium bicarbonate, 150 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crystalline residue obtained is taken up in 50 cm @ ^{3 of} boiling ethanol. The resulting white suspension was allowed to stand overnight at about 20 ° C and then a solid was obtained, drained of water through a frit, washed with diisopropyl ether, and dried under reduced pressure at about 50 ° C. 19.5 g of 3-acetoxy-1-benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine are obtained in the form of white crystals.

1-Benzhydrylazetidin-3-one can be prepared according to the procedure described by Katritzky A.R. et al. in J. Heterocycl. Chem., 271 (1994).

3,5-Difluorobenzylmethylsulfone can be prepared as follows: 66.69 cm @ ^{3 of} 3,5-difluorobenzyl bromide, 71.97 g of sodium methanesulfonic acid salt and 150 mg of sodium iodide in 625 cm @ ^{3 of} ethanol are heated to reflux under argon for about 16 hours. After cooling to about 20 ° C, the reaction mixture is diluted with 3 l of ethyl acetate, washed with 500 cm ^{3 of} water, 500 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (50 kPa) at temperature of about 40 ° C. The residue is taken up in 300 cm ^{3 of} ethyl ether, the solid is filtered off on a frit, washed with 200 cm ^{3 of} ethyl ether, dried under reduced pressure at a temperature of about 20 ° C. 86 g are obtained

3,5-difluorobenzylmethylsulfone as a white powder.

Example 81 (RS) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine can be prepared as follows: a mixture of 47 mg of 3- ( pyridyl) - (4-chlorophenyl) bromomethane, 50 mg of (RS) -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine hydrochloride and 58 mg of potassium carbonate in 2 cm ³ are stirred at about 20 ° C for about 3 hours. for 2 hours at the reflux temperature of the solvent, then for 16 hours at a temperature of about 20 ° C and then for 1.5 hours at reflux temperature of the solvent. A few granules of potassium iodide are then added and the reaction mixture is maintained at the reflux temperature of the solvent for about 2 hours. After cooling to about 20 ° C, the reaction mixture is purified by preparative thin layer chromatography on silica gel [2 Merck Kieselgel 60F254 preparative plates; 20 x 20 cm; thickness 0.5 mm], eluting with methanol-dichloromethane (2.5-97.5, v / v). After eluting the zone corresponding to the desired product with methanol-dichloromethane (10-90, v / v), filtering through a frit, and evaporating the solvent under reduced pressure at about 40 ° C, 11 mg of (RS) - (1 - [(3-pyridyl)) is obtained. - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine as a colorless lacquer [ ³ H NMR spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.59 (mt: 1H); 2.66 (s: 3H); 3.21 (mt: 2H); from 3.30 to 3.50 (mt: 1H); 3.67 (mt: 1H); 4.28 (broad d) J = 11 Hz: 1H); 4.32 (broad s: 1H); 6.84 (tt, J = 9 and 2 Hz: 1H); 6.95 (mt: 2H); 7.19 (broad dd) J = 8 and 5 Hz: 1H); from 7.20 to 7.40 (mt: 4H); 7.64 (broad d, J = 8 Hz: 1H); 8.45 (mt: 1H); 59 (very broad with 1H).

(3-Pyridyl) - (4-chlorophenyl) bromomethane can be prepared as follows: a mixture of 150 mg of (3-pyridyl) - (4-chlorophenyl) methanol in 0.356 cm ³ of hydrobromic acid (33% in acetic acid) and 0.101 cm ^The acetyl bromide ( ³⁾ is heated at reflux for 1 hour and then left at about 20 ° C for 2 hours and concentrated under reduced pressure and re-evaporated with a few cm ^{3 of} toluene. 234 mg of (3-pyridyl) (4-chlorophenyl) bromomethane are obtained as a gummy beige solid.

(3-Pyridyl) - (4-chlorophenyl) methanol can be prepared as follows: 0.5 cm ^{3 of} 3-pyridinecarboxaldehyde is slowly added under an inert argon atmosphere to a solution of 5.83 cm ^{3 of} 4-chlorophenylmagnesium bromide (1 M solution in ether) in 5 cm ^{3 of} tetrahydrofuran. After about 3 hours, 3 cm ^{3 of} saturated aqueous ammonium chloride solution and 10 cm ^{3 of} water are added to the reaction mixture. The mixture is stirred at about 20 ° C for 5 minutes, then the mixture is acidified to about pH 2 with a 1N hydrochloric acid solution. The aqueous phase is extracted

156 three times 15 cm ^{3 of} dichloromethane. The remaining aqueous phase is treated with 10 cm @ ^{3 of a} 1N aqueous sodium hydroxide solution and extracted again three times with 15 cm @ ^{3 of} ethyl acetate. Combine the organic phases containing ethyl acetate, dry over magnesium sulfate, filter and concentrate to dryness. 466 mg of (3-pyridyl) -4- (4-chlorophenyl) methanol is obtained as a shiny yellow solid.

Example 82 (RS) - {1 - [(4-Pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine can be prepared as follows: a mixture of 160 mg (4- ( pyridyl) - (4-chlorophenyl) bromomethane.

169 mg of (RS) -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine hydrochloride and 94 mg of potassium carbonate in 5 cm ^{3 of} acetonitrile are stirred at about 20 ° C for about 17 hours. A few granules of sodium iodide are added, the mixture is stirred at about 20 ° C for 2 hours and then the reaction mixture is maintained at the reflux temperature of the solvent for 1.5 hours. After cooling to about 20 ° C, the reaction mixture is purified by preparative thin layer chromatography on silica gel [4 preparative plates Merck Kieselgel 60F254; 20 x 20 cm; thickness 0.5 mm], eluting with methanol-dichloromethane (2.5-97.5, v / v). After eluting the zone corresponding to the desired product with methanol-dichloromethane (10-90, v / v), filtering through a frit and evaporating the solvent under reduced pressure at about 40 ° C, a first mixture of diastereoisomers, i.e. 24 mg (RS) - {1- [ (4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] -etidine in the form of a yellow lacquer and a second mixture of diastereoisomers, i.e. 31 mg (RS) - {1 - [(4- pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] -etidine as a yellow foam. The first mixture of diastereoisomers has the following characteristics. [ ³ H NMR spectrum (300 MHz, CDCl 3,

δ in ppm): 2, 62 (t, J = 7) Hz: 1H); 2.67 (s 3H); 3.21 (broad t, J = 7 Hz: 2H); 3.42 (mt: 1H); 3.70 (broad t J = 7 Hz: 1H); 4.28 (with : 1H); 4.28 (d, J = 11) Hz: 1H); 6.85 (tt, J = 9 and 2.5 Hz: 1H); 6, 97 (mt: 2H); from 7 , 20 to 7.35 (mt 6H); 8.52

157 (dd, J = 4.5 and 1.5 Hz: 2H).

The second mixture of diastereoisomers has the following characteristics

^[X H NMR (300 MHz, CDCl3, δ in ppm) 2.59 (t, J = 7 Hz: 1H); 2.67 (s 3H); 3.26 (mt 2H); from 3, 35 to 3.50 (mt: 1H); 3.63 (broad t, J 7 Hz 1H); 4.28 (s 1H); 4.28 (D, J = 11 Hz: 1H); 6.85 (tt, J 9 and 2 Hz): 1H); 6.97 (mt: 2H); from 7.20 to 7.40 (mt 6H); 8.50 (dd, J = 4) 5 and 1.5 Hz 2H).

(4-Pyridyl) - (4-chlorophenyl) bromomethane can be prepared as follows: a solution of 100 mg of (4-pyridyl) - (4-chlorophenyl) methanol in 0.24 cm ³ of hydrobromic acid (33% in acetic acid) is heated at reflux for 1 hour and then return to about 20 ° C. Acetyl bromide (0.675 cm ³⁾ is added and the reaction mixture is heated under reflux for 1.5 hours and then the reaction mixture is returned to about 20 ° C and the mixture is concentrated under reduced pressure. 163 mg of (4-pyridyl) - (4-chlorophenyl) bromomethane are obtained in the form of a beige foam rubber.

(4-Pyridyl) - (4-chlorophenyl) methanol can be prepared as follows: 348 mg of sodium tetraborohydride is added at a temperature of about 20 ° C to a solution of 2 g of 4- (4-chlorobenzoyl) pyridine in 160 cm ^{3 of} ethanol. The mixture was stirred at about 20 ° C for 2 hours and 90 mg of sodium tetraborohydride was added. After about 1.5 hours at the same temperature, the reaction mixture is diluted with 200 cm ^{3 of} dichloromethane and 200 cm ^{3 of} water. The pH of the aqueous phase is then adjusted to about 5 by adding about 13 cm ^{3 of} an aqueous solution of 1 N hydrochloric acid. After decantation, the aqueous phase is extracted three times with 100 cm @ ^{3 of} dichloromethane. The organic phase was combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. 2 g of (4-pyridyl) - (4-chlorophenyl) methanol are thus obtained in the form of a white powder.

Example 83 (RS) - {1 - [(2-Chloropyrid-5-yl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine can be prepared at 158 as follows: mixture 300 mg (2-chloropyrid-5-yl) - (4-chlorophenyl) bromomethane, 225 mg of (RS) -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine hydrochloride, 125 mg of potassium iodide and 521 mg of potassium carbonate in 5 cm ^{3 of} acetonitrile is heated at the reflux temperature of the solvent for 2 hours. After cooling to about 20 ° C, the reaction mixture is filtered through a frit. The solid residue was washed with dichloromethane and the filtrate was evaporated under reduced pressure. 402 mg of chocolate foam is obtained, which is purified by preparative thin layer chromatography on silica gel [4 preparative plates Merck Kieselgel 60F254; 20 x 20 cm; thickness

0.5 mm], eluting with methanol-dichloromethane (2.5-97.5, v / v). After eluting the zone corresponding to the desired product with methanol-dichloromethane (10-90, v / v), filtration, sintering and evaporating the solvent under reduced pressure at about 40 ° C, a first mixture of diastereoisomers, i.e. 14 mg (RS) - {1- - [(2-chloropyrid-5-yl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine as a brown foam and a second mixture of diastereoisomers, i.e. 10 mg (RS) - { 1 - [(2-chloropyrid-5-yl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine as a beige foam.

The first mixture of diastereomers with the following characteristics: ^[X H NMR (300 MHz, CDC1 _3, δ in ppm): 2.57 (t, J = 7.5 Hz: 1H); 2.65 (s 3H); from 3.15 to 3.30 (mt 2H); 3.40 (mt 1H);

3.63 (broad t, J 7.5 Hz 1H); 4.27 (d, J = 11Hz: 1H); 4.31 (s 1H); 6.84 (tt, J 9 and 2 Hz 1H); 6.95 (mt 2H); from 7.20 to 7.35 (mt 5H); 7.63 (dd, J = 8 and 2.5 Hz 1H); 8.38 (d, J =

2.5 Hz: 1H).

The second mixture of diastereoisomers has the following characteristics:

[ ^X H NMR sp &lt; + &gt; sktrum (300 MHz, CDCl ₃ , δ in ppm): 2, 57 (T, J = 7.5 Hz 1H) ; 2.64 (s: 3H) ; 3 , 18 (wide t, J = 7.5 H from : 2H) ; 3.38 (mt 1H) ; 3.63 (br t, J = 7.5Hz: 1H); 4.24 (d , J = 11.5 Hz 1H) ; 4.29 (s: 1H ); 6.83 (tt, J =) - 9 and 2 Hz 1H); 6, 94 (mt 2H) ; 7.20 (d, J = 8 Hz: 1H); from 7.20 to 7, 35 (mt 4H); 7

159 (dd, J = 8 and 2.5 Hz 1H); 8.34 (d, J = 2.5 Hz: 1H).

2- (Chloropyrid-5-yl) - (4-chlorophenyl) bromomethane can be prepared as follows: 0.153 cm ^{3 of} thionyl bromide are added under an inert argon atmosphere at a temperature of about 0 ° C to a solution of 100 mg of (2-chloropyrid-5-). yl) - (4-chlorophenyl) methanol in 2 cm ^{3 of} chlorine ₍ 1 du carbon). After 3.5 hours at about 0 ° C, the reaction mixture is concentrated under reduced pressure and evaporated with a few cm ^{3 of} toluene to give 1. 3 g of brown liquid, which is taken up in dichloromethane, water and sodium dithionite are added, after decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure to give 0.33 g.

2- (chloropyrid-5-yl) - (4-chlorophenyl) bromomethane as a brown oil.

2- (Chloropyrid-5-yl) - (4-chlorophenyl) bromomethane can be prepared by a procedure similar to Example 84, starting from

22.5 cm ^{3 of} 4-chlorophenylmagnesium bromide (1 M solution in ethyl ether) in 30 cm ^{3 of} tetrahydrofuran, under an inert argon atmosphere and 2.9 g

Of 2-chloropyridine-5-carboxaldehyde in 30 cm ^{3 of} tetrahydrofuran. 3.42 g of 2- (chloropyrid-5-yl) - (4-chlorophenyl) methanol are obtained in the form of a light green powder.

2-Chloropyridine-5-carboxaldehyde can be prepared as described in the following reference: G. Pandey, T. D. Bagul, A.K. Sahoo, J. Org. Chem., 1998, 63, 760-768.

Example 84 (RS) -5- ((4-Chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-1-yl} methyl) pyrimidine can be prepared as follows: a mixture of 50 mg of 5- [bromo] - (4-chlorophenyl) methyl] pyrimidine,

52.6 mg of (RS) -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine hydrochloride, 44 mg of potassium iodide and 73 mg of potassium carbonate in 2 cm ^{3 of} acetonitrile are heated at the reflux temperature of the solvent for about 5 hours. After cooling to about 20 ° C, the reaction mixture is purified by preparative thin-layer chromatography

160 layers on silica gel [2 Merck Kieselgel 60F254 preparative plates; 20 x 20 cm; thickness 0.5 mm], eluting with methanol-dichloromethane (2.5-97.5, v / v). After eluting the zone corresponding to the desired product with methanol-dichloromethane (10-90, v / v), filtering through a frit and evaporating the solvent under reduced pressure at about 40 ° C, a first mixture of diastereoisomers, i.e. 8 mg (RS) -5- (( 4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-1-ylmethyl) pyrimidine as a yellow foam and a second mixture of diastereoisomers, i.e. 6 mg (RS) -5 - ((4-chlorophenyl)) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-1-yl} methyl) pyrimidine as a yellow foam.

The first mixture of diastereoisomers has the following characteristics: ¹ H NMR spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.60 (broad t, J = 7 Hz: 1H); 2.66 (s 3H); 3.24 (broad t, J 7 Hz 2H); 3.41 (mt 1H); 3.66 (broad t, J 7 Hz 1H); 4.28 (d, J = 11.5 Hz 1H); 4.33 (broad s 1H); 6.84 (broad t, J 9 Hz 1H); 6.95 (mt 2H); from 7.25 to 7.35 (mt 4H); 8.71 (broad s 2H); 9.08 (broad s 1H).

The second mixture of diastereoisomers has the following characteristics: ¹ H NMR spectrum (300 MHz, CDCl 3, δ in ppm): 2.61 (t, J = 7 Hz: 1H); 2.66 (s 3H); 3.24 (broad t, J 7 Hz 2H); 3.43 (mt 1H); 3.65 (broad t, J 7 Hz 1H); 4.28 (d, J = 11.5 Hz 1H); 4.33 (s 1H); 6.85 (tt, J 9 and 2 Hz 1H); 6.96 (mt 2H); from

7.25 to 7.35 (mt 4H); 8.69 (s 2H); 9.06 (s 1H).

5- [Bromo- (4-chlorophenyl) methyl] pyrimidine can be prepared by the following procedure: 0.36 cm ^{3 of} thionyl bromide is added to a solution of 205 mg of (4-chlorophenyl) pyrimidin-5-ylmethanol in 1 cm ³ of carbon tetrachloride and 1 cm ³ dichloromethane under an inert argon atmosphere at about 0 ° C. After 2.5 hours at about 0 ° C, the reaction mixture is brought to about 20 ° C, concentrated under reduced pressure and evaporated with a few cm ^{3 of} toluene. The brown liquid obtained is taken up in 10 cm ^{3 of} dichloromethane, washed with 5 cm ^{3 of} aqueous sodium dithionite solution and then with water. After decanting, the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 227 mg of beige viscous liquid are obtained, which is taken up with a minimum amount of dichloromethane and purified by preparative thin layer chromatography on silica gel [2 preparative plates Merck Kieselgel 60F254; 20 x 20 cm; thickness 0.5 mm], eluting with methanol-dichloromethane (2.5-97.5, v / v). After eluting the zone corresponding to the desired product with methanol-dichloromethane (10-90, v / v), filtering through a frit, and evaporating the solvent under reduced pressure at about 40 ° C, 51 mg are obtained.

Of 5- [bromo- (4-chlorophenyl) methyl] pyrimidine as a yellow foam.

4- (Chlorophenyl) pyrimidin-5-ylmethanol can be prepared by a procedure similar to Example 83, 2.5 cm ^{3 of} n-butyllithium (1.6 M solution in hexane) are added dropwise to a solution of 636 mg of 5-bromopyridine in 10 cm ^{3 of} tetrahydrofuran under argon atmosphere at about -78 ° C. After 10 minutes at about -78 ° C, a solution of 562 mg of 4-chlorobenzaldehyde in 1 cm ^{3 of} tetrahydrofuran is added dropwise. The mixture is stirred for 30 minutes at about -78 ° C, then the temperature of the reaction mixture is slowly raised to about 20 ° C and 15 cm ^{3 of} saturated aqueous ammonium chloride solution, 60 cm ^{3 of} ethyl acetate and 10 cm ^{3 of} water are gradually added. The aqueous phase is extracted with 15 cm ^{3 of} ethyl acetate, the organic phases are combined, dried over magnesium sulphate and filtered through a frit and concentrated under reduced pressure (20 kPa) at a temperature of about 44 ° C. The orange-colored oil obtained (1.09 g) is purified by chromatography on a 30 mn column packed with 60 g of medium size silica (0.063 0.200 mm) at atmospheric pressure, eluting with a gradient of methanol / dichloromethane (0/100 to 7/93, volume). Fractions containing only the desired product were combined and concentrated to dryness under reduced pressure. 293 mg of 4- (chlorophenyl) pyrimidin-5-yl) methanol are obtained as a yellow oil.

Example 85

4 - ({1- [Bis (4-chlorophenyl) methyl] azetidine-3162 phenol ester)

-ylidene} methylsulfonylmethyl) -3,6-dihydro-2H-pyridine-1-carbothioic acid can be prepared as follows: 0.140 g of 4-dimethylaminopyridine and then 0.042 cm ^{3 of} methanesulfonyl chloride are added to a solution of 0.23 g of phenol 4 - ({1-bis (4-chlorophenyl) methyl] -3-hydroxyazetidin-3-yl [methylsulfonylmethyl) -3,6-dihydro-2H-pyridine-1-carbothioic acid ester in 5 cm ^{3 of} dichloromethane. The reaction mixture is stirred at 20 ° C for 20 hours and then diluted with 10 cm ^{3 of} water. After decanting, the organic phase is washed successively with 100 cm ^{3 of} water and 100 cm ^{3 of} saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness at 40 ° C and 2.7 kPa. The oil obtained is triturated in 50 cm @ ^{3 of} diisopropyl ether for 45 minutes. The resulting solid was filtered to give 120 mg of 4 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene [methylsulfonylmethyl) -3,6-dihydro-2H-pyridine-1-carbothioic acid phenolic ester as a beige solid, melting at 184 ° C. ^[X H-NMR (400 MHz, CDCl3, δ in ppm): 2.53 (unresolved complex: 2H); 2.95 (s 3H); 3.90 (uncleaved complex: 2H); 4.04 (t, J = 5.5Hz, 1H); 4.24 (mt 3H); 4.49 (uncleaved complex: 2H); 4.60 (mt 1H); 5.90 (uncleaved complex: 1H); from 7.05 to 7.50 (mt 13H)].

4 - ({1- [Bis (4-Chloro-phenyl) -methyl] -3-hydroxy-azetidin-3-yl [methylsulfonylmethyl) -3,6-dihydro-2H-pyridine-1-carbothioic acid phenol ester was prepared as follows: 52 g of potassium tert-butoxide are added to a mixture of 0.72 g of phenolic ester, 4-methylsulfonylmethyl-3,6-dihydro-2H-pyridine-1-carbothioic acid and 0.708 g of 1- [bis (4-chlorophenyl) methyl] azetidine -3-one in 15 cm ^{3 of} dry tetrahydrofuran cooled in an inert atmosphere to -78 ° C. The reaction mixture was stirred at -78 ° C for 4 hours and then 0.354 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one was added. After 2 hours at -78 ° C, the temperature returns to 20 ° C. The reaction mixture is diluted with 100 cm @ ^{3 of} water and the tetrahydrofuran is evaporated off at a pressure of 2.7 kPa and a temperature of 40 ° C. The aqueous phase is extracted twice with 100 cm ^{3 of} ethyl acetate. The organic extracts are combined and dried over magnesium sulphate and concentrated at 2.7 kPa

163 and at 40 ° C. The residue obtained is chromatographed on silica gel (200 g silica gel, Amicon, 20-45 μπι, porosity 60 Angstroem, column diameter 5 cm), eluting with cyclohexane: ethyl acetate (6: 4, v / v). Fractions with Rf = 11/64 (cyclohexane: ethyl acetate)

6: 4, Merck silica gel plate (1.05719, Merck KGaA, 64721 Darmstadt, Germany) were combined and concentrated at 2.7 kPa and 40 ° C to give 240 mg of phenol ester

4 - ((1- [bis (4-chlorophenyl) methyl) -3-hydroxyazetidin-3-yl [methylsulfonylmethyl) -3,6-dihydro-2H-pyridine-1-carbothioic acid.

4-Methylsulfonylmethyl-3,6-dihydro-2H-pyridine-1-carbothioic acid phenol ester can be prepared as follows: 0.778 cm ^{3 of} phenylthio chloroformate is added to a solution of 1 g of 1-benzyl-4-methylsulfonylmethyl-1,2,3 6-tetrahydropyridine in 10 cm ^{3 of} dichloromethane under argon. The solution is immediately colored to a very dark amber color. The reaction mixture is stirred at 21 DEG C. for 4 hours and then diluted with 100 cm @ ^{3 of} dichloromethane. The organic phase is washed twice with 50 cm ^{3 of} water, dried over magnesium sulphate and evaporated to dryness at 40 ° C and 2.7 kPa. The residue obtained is purified by chromatography on a silicone cartridge (Reference SIL-020-005, FlashPack, Jones Chromatcgraphy Limited, New Road, Hengoed, Mid Glamorgan, CF82 8AU, UK), eluting with cyclohexane: ethyl acetate 6: 4 '(10 cm -1 / min, cm ³ fractions). Fractions with Rf = 12/74 (cyclohexane: ethyl acetate 1: 1, silica gel plate, Merck reference 1.05719, Merck KGaA, 64271 Darmstatd, Germany) were combined and concentrated at 2.7 kPa at 40 ° C and 700 mg of 4-methylsulfonylmethyl-3,6-dihydro-2H-pyridine-1-carbothioic acid phenolic ester is obtained.

1-Benzyl-4-methylsulfonylmethyl-1,2,3,6-tetrahydropyridine can be prepared as follows: a solution of 5.14 g of sodium borohydride and 25 g of sodium carbonate in 700 cm ^{3 of} water is added dropwise over 1 hour, without to a solution of 17.6 g of 1-benzyl-4-methylsulfonylmethylpyridinium bromide in 700 cm ^{3 of} water cooled to 5 ° C. The reaction mixture was stirred at 0 ° C for 4 hours and then at the temperature of the mixture

164 returns to room temperature overnight. The yellow solid obtained is isolated by filtration and dried at 2.7 kPa to give 9.6 g of 1-benzyl-4-methylsulfonylmethyl-1,2,3,6-tetrahydropyridine having Rf 44/81 (dichloromethane: methanol, 95: 5 by volume, silica gel plate, Merck reference 1.05719, Merck KGaA, 64271 Darmstatd, Germany). 1-Benzyl-4-methylsulfonylmethylpyridinium bromide can be prepared as follows: 14 cm ^{3 of} benzyl bromide are added to a solution of 10 g of 4-methylsulfonylmethylpyridine in 200 cm ^{3 of} acetonitrile and then the mixture is heated under reflux for 3 hours. room temperature. The resulting solid is filtered, dried under vacuum at 2.7 kPa to give

17.6 g of 1-benzyl-4-methylsulfonylmethylpyridinium bromide.

4-Methylsulfonylmethylpyridine can be prepared as follows: 14 g of sodium hydroxide pellets and then 35.7 g of sodium methanesulfinate are added slowly to a solution of 57.4 g of hydrochloride

Of 4-chloromethylpyridine in 700 cm ^{3 of} ethanol. After addition, the temperature of the mixture was 28 ° C. The reaction mixture was refluxed for two hours and then returned to room temperature overnight. Heat the reaction mixture to 50 ° C and filter while hot through filter paper. The filtrate is evaporated to dryness at 40 ° C and 2.7 kP, a. The residue is recrystallized from 300 cm @ ^{3 of} isopropanol and recovered

29.6 g of 4-methylsulfonylmethylpyridine.

Example 86 (RS) -1- [2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) ethyl] -3-propylurea can be prepared by the following procedure: 0.552 g of n-propyl isocyanate is added to a solution of 90 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) ethylamine in 5 cm ³ tetrahydrofuran. The mixture is stirred for about 72 hours at about 20 ° C, the reaction mixture is filtered and concentrated to dryness under reduced pressure and taken up with diisopropyl ether. The resulting mixture was filtered and concentrated to dryness

165 under reduced pressure. 80 mg of a light yellow solid are obtained, which is dissolved in 5 cm @ ^{3 of} tetrahydrofuran and 80 mg of carrier resin are added to the mixture. After stirring for about 18 hours at about 20 ° C, the reaction mixture is filtered and then concentrated to dryness under reduced pressure. 36 mg of a pasty solid are obtained, which is purified by chromatography under reduced pressure on a silica gel cartridge, eluting with a mixture of cyclohexane and ethyl acetate (50/50 by volume). Fractions 16 to 20 are combined and concentrated to dryness under reduced pressure. 6 mg of (RS) -1- [2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) ethyl] -3-propylurea was obtained as an oil. . [ ³ H NMR spectrum (300 MHz, CDCl ₃ , δ in ppm):

0.88 (t, J = 7.5 Hz: 3H); from 1.35 to 1, 60 (mt: 2H); from 2.25 to 2.55 and from 2.65 to 3 .05 (2 series mts : 6H tot om); 3.04 (mt: 2H); 3.22 (mt 1H); 3.38 (mt 1H); 4.07 (Mt: 1H); from 4.10 to 4.20 (mt: 1H); 4.17 (s 1H); 6.62 (tt, J = 9 a 2, 5 Hz: 1H); 6, 82 (mt: 2H); from 7, 20 to 7.45 (mt: 8H].

(RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl] -2- (3,5-difluorophenyl) ethylamine can be prepared as follows:

1.2 g of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) methanesulfonic acid ethyl ester in cm ^{3 of} methanol and then 30 cm ^{3 of} ammonia in 30 cm ^{3 of} methanol are charged into an autoclave cooled with a mixture of acetone and dry ice. The sealed autoclave was shaken and heated to about 60 ° C for 24 hours. After cooling to about 20 ° C, ammonia is evaporated in air at about 20 ° C and the remaining solution is concentrated to dryness under reduced pressure. The resulting gum was triturated with ethyl ether at about 20 ° C for 16 hours. The insoluble material was filtered off and dried in a desiccator for 3 hours. 830 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) ethylamine is obtained as a white solid.

(RS) -2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) methanesulfonic acid ethyl ester can be prepared as follows: 0.34 cm ^{3 of} methanesulfonyl chloride add 1.9 g of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidine-3166 to the solution

-yl} -2- (3,5-difluorophenyl) ethanol in 20 cm ^{3 of} dichloromethane, at a temperature of about 20 ° C. After cooling the reaction mixture to about 10 ° C, 0.89 cm ^{3 of} triethylamine are added. The solution is stirred at a temperature in the region of 20 DEG C. for 20 hours, 100 cm @ ^{3 of} water are added dropwise, followed by 150 cm @ ^{3 of} dichloromethane. After settling, the organic phase is separated, washed twice with 50 cm ^{3 of} water, 50 cm ^{3 of} saturated aqueous sodium chloride solution, 50 cm ^{3 of} water and dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The resulting yellow foam (2 g) is purified on a silica gel column (particle size 0.0209-0.045 mm) at a pressure of 0.04 MPa and eluted with a mixture of cyclohexane and ethyl acetate (80/20 by volume). Fractions 49 to 111 are combined and concentrated to dryness under reduced pressure. 1.2 g of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) methanesulfonic acid diethyl ester is obtained as a white foam.

Example 87 (RS) -N- [2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) ethyl] cyclopropanecarboxamide can be prepared as follows: 0.018 cm ³ diisopropylcarbodiimide, 10 mg of cyclopropanecarboxylic acid, 16 mg of hydroxybenzotriazole hydrate and then 0.4 g of morpholine carried on polystyrene are gradually added to a solution of 90 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidine-3 -yl} -2- (3,5-difluorophenyl) ethylamine in 5 cm ^{3 of} tetrahydrofuran at about 20 ° C. The resulting suspension is stirred at about 20 ° C for 20 hours. The reaction mixture was filtered and concentrated to dryness under reduced pressure. 80 mg of a pasty product are obtained, which is purified through an SPE cartridge (SCX phase, 1 g phase). The 76 mg residue thus obtained is purified by chromatography on a silica gel cartridge, eluting with a cyclohexane / ethyl acetate mixture (70/30, v / v). Fractions 9 to 19 are combined and concentrated to dryness under reduced pressure. 12 mg of (RS) -N- [2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) ethyl] cyclopropanecarboxamide is obtained as a colorless oil. ¹ H NMR spectrum (300 MHz, CDCl 3, δ in ppm): 0.70 (mt 1H); from 0.80 to 1.00 (mt:

167

2H); from 1.15 up to 1.35 (mt : IH) ; from 2.35 do 2,55 and from 2.70 to 3, 10 (2 series mts: 7H total); 3.26 (mt : IH); 3 47 (mt 1H); 4.19 (with : IH) ; 5.63 (mt: IH); 6, 62 (Tt, J = 9 a 2.5 Hz: 1H); 6.81 (mt : 2H) ; from 7.20 to 7.45 (mt: 8H)] •

Example 88 (RS) -N- [2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) ethyl] -3-methylbutyramide can be prepared as follows : 114 mg of HATU, 30.6 mg of isovaleric acid and then 0.2 g of morpholine carried on polystyrene are added to a solution of 45 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } -2- (3,5-difluorophenyl) ethylamine in 5 cm ^{3 of} tetrahydrofuran at about 20 ° C. The resulting suspension is stirred at about 20 ° C for 20 hours. The reaction mixture was filtered and concentrated to dryness under reduced pressure. 46 mg of an orange-colored oil are obtained, which is purified by chromatography on a silica gel cartridge, eluting with a cyclohexane / ethyl acetate mixture (70/30, v / v). Fractions containing only the desired product were combined and concentrated to dryness under reduced pressure. 6 mg is obtained. (RS) -N- [2- [1- [Bis- (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) ethyl] -3-methylbutyramide as a colorless oil. ^[X H-NMR (400 MHz, CDC1 _3, δ ppm) "0.88 (d, J = 6.5 Hz: 3H); 0.91 (d, J = 6.5Hz, 3H); from 1.85 to 2.10 (mt 3H); from 2.30 to 2.55 and from 2.70 to 3.10 (2 series mts: 6H total); 3.37 (mt 2H); 4.19 (br: 1H); 5.45 (mt 1H); 6.65 (tt, J = 9 and 2.5 Hz 1H); 6.82 (mt 2H); from 7.20 to 7.45 (mt 8H)].

Example 89 (RS) -N- [2- {1- [Bis (4-chlorophenyl) methylazetidin-3-yl) -2- (3,5-difluorophenyl) ethyl] isobutyramide may be prepared by a method similar to Example 3 starting with 45 mg of (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) ethylamine, cm ^{3 of} tetrahydrofuran, 114 mg of HATU, 26 mg of isobutanoic acid and 0.2 g of morpholine carried on polystyrene to give 10 mg

168 (RS) -N- [2- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) ethyl] isobutyramide as an opaque oil. [ ³ H NMR spectrum (400 MHz, (CD ₃ ) 2 SO d6, δ in ppm): 0.87 (d, J = 7)

Hz: 3H); 0.93 (d, J = 7Hz, 3H); from 2.15 to 2.85 (mt 7H); from

3.00 to 3.25 (mt 2H); 4.40 (s 1H); from 7,00 to 7,20 (mt:

3H); 7.38 (mt 4H); 7.25 (mt 4H); 7.77 (mt 1H)].

Example 90 [1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,4-difluorophenyl) methanone can be prepared as follows: 3 cm ^{3 of a} 0.5 N solution of 3,4-difluorophenylmagnesium bromide in tetrahydrofuran is added to a solution of 128 mg of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid N-methoxy-N-methylamide in 3 cm ^{3 of} tetrahydrofuran, cooled in an acetone / dry ice bath. The mixture is stirred at about 0 ° C for 20 hours, 10 cm ^{3 of} water are added and the reaction mixture is stirred at about 20 ° C for 1 hour. The aqueous phase separated by settling is extracted with 20 cm ^{3 of} ethyl acetate. The combined organic phases are washed twice with 15 cm ^{3 of} water, dried over magnesium sulphate and concentrated to dryness under reduced pressure. 123 mg of residue are obtained, which is purified by chromatography under reduced pressure on a cartridge of 20 g of silica gel, eluting with dichloromethane (stabilized on amylene). 47 mg of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-difluorophenyl) methanone are obtained in the form of a white powder. ¹ H NMR spectrum (300 MHz, CDCl 3, δ in ppm): 3.34 (t, J = 7.5 Hz: 2H); 3.56 (t, J = 8Hz, 2H); 4.05 (mt 1H); 4.35 (s 1H); from

7.15 to 7.40 (mt 9H); 7.58 (dmt, J = 9Hz, 1H); 7.70 (ddd, J = 9 / 7.5 and 2.5 Hz: 1H).

1- [Bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid N-methoxy-N-methylamide can be prepared as follows:

2.65 cm @ ^{3 of} 1-methylpiperidine are added to a suspension of 2.03 g of N, O-dimethylhydroxylamine hydrochloride in 40 cm @ ^{3 of} dichloromethane, cooled to about 0 DEG C. in a cold water bath. The resulting yellow solution (solution A) is stored at about 0 ° C. Then it is added gradually to a suspension of 7 g of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid in 300 cm ^{3 of} dichloromethane and 40 cm ^{3 of} tetrahydrofuran, cooled to about -8 ° C in an ice-isopropanol bath.

2.65 cm @ ^{3 of} 1-methylpiperidine and then 1.6 cm @ ^{3 of} methyl chloroformate. The mixture was stirred at about -8 ° C for 5 minutes and solution A prepared above was added dropwise. The mixture is stirred for 10 minutes at about -8 ° C, the cooling bath is removed and the reaction mixture is stirred at about 20 ° C for 20 hours and then washed three times with 150 cm ^{3 of} water and concentrated to dryness under reduced pressure. 8.19 g of a residue are obtained, which is purified under pressure on 500 g of Amicon silica gel (particle diameter 20-45 [mu] m), eluting with a mixture of ethyl acetate / dichloromethane (8-92, v / v). 6.6 g of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid N-methoxy-N-methylamide are obtained in the form of a pale yellow oil.

1- [Bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid can be prepared according to the procedure described by Anderson A.G. and Lok R.J., Org. Chem., 37, 3953-3955 (1972) from 1-benzhydrylazetidin-3-ol, using as raw material, 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol.

Example 91 [1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methanone can be prepared as in the case of {1- [bis (4-chlorophenyl) methyl] azetidin-3 -yl} - (3,4-difluorophenyl) methanone, starting from 1.1 g of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid N-methoxy-N-methylamide, 1,5 cm ³ 1-bromo-3,5-difluorobenzene and 316 mg of magnesium shavings. 880 mg of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methanone are obtained as a light yellow viscous oil. [ ³ H NMR spectrum (300 MHz, CDCl 3,

3.55 (t, J = 8Hz)

2H) δ ppm: 3.34 (t, J = 7.5 Hz)

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

Example 92

170 {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -cyclohexylmethanone can be prepared as in the case of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,4 -difluorophenyl) methanone, starting from 284 mg of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid N-methoxy-N-methylamide and 1.68 cm ^{3 of} 2 N cyclohexylmagnesium chloride in THF. 116 mg of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -cyclohexylmethanone are thus obtained in the form of a viscous oil. [ ¹ H NMR spectrum (400 MHz, CDCl ₃ , δ in ppm): from 1.10 to 1.35 and from 1.55 to

1.85 (2 mt series: 10H total); 2.30 (mt 1H); 3.14 (t, J = 8Hz: 2H); 3.36 (t, J = 8Hz, 2H); 3.56 (mt 1H); 4.31 (s 1H); from 7.20 to 7.35 (mt 8H)].

Example 93 {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} phenylmethanone can be prepared as in the case of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,4 -difluorophenyl) methanone, starting from 258 mg of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid N-methoxy-N-methylamide and 1.02 cm ^{3 of} 3 N phenylmagnesium bromide in THF. 208 mg of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} phenylmethanone are obtained in the form of a yellow viscous oil [ ³ H NMR spectrum (300 MHz, CDCl 3, δ in ppm): 3.35 ( t, J = 8Hz: 2H); 3.57 (t, J = 8Hz, 2H); 4.13 (mt 1H); 4.35 (s 1H); 7.25 (dmt, J = 8Hz: 4H);

7.34 (dmt, J = 8Hz: 4H); 7.45 (broad t, J 8 Hz 2H); 7.56 (tt, J = 8 and 1.5 Hz 1H); 7.84 (dmt, J = 8Hz: 2H)].

Example 94 (RS) -1- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -1- (3,5-difluorophenyl) ethanol can be prepared as follows: 0.167 cm ³ 3 N of methylmagnesium bromide solution is added to a solution of 100 mg of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methanone in 4 cm ^{3 of} tetrahydrofuran, cooled to below -40 ° C. The mixture is stirred for 20 hours at 0 DEG C., 5 cm @ ^{3 of} water are added and then the aqueous phase separated by settling is extracted with 5 cm @ ^{3 of} ethyl acetate. The combined organic phases are dried over magnesium sulfate

171 and concentrated to dryness under reduced pressure. 91 mg of a residue are obtained which is purified by chromatography under reduced pressure on a 10 g silica gel cartridge, eluting with ethyl acetate / cyclohexane (1/9, v / v). 74 mg of (FS) -1- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1- (3,5-difluorophenyl) ethanol are thus obtained in the form of a colorless oil. pH-NMR (300 MHz, CDC1 _3, δ in ppm):

1.46 (s: 3H); 2.71 (mt: 1H); 2.82 i (mt 1H); 2.98 ( t, J Hz: 1H); 3.24 (t, J = 7, 5 Hz: 1H); 3.34 (mt 1H); 4.31 1H); 4.33 (mf: 1H); 6, 67 (tt, J 9) and 2.5 Hz: 1H); 6, 98 2H); from 7.25 to 7.35 (mt: 8H)].

Example 95

{1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methanone O-allyloxime can be prepared as follows: 100 mg solution of {1- [bis (4-chlorophenyl) methyl] Azetidin-3-yl} - (3,5-difluorophenyl) methanone and 101 mg of O-allylhydroxylamine hydrochloride in 5 cm ^{3 of} pyridine are stirred at about 20 ° C for 20 hours. 5 cm ^{3 of} water are then added and the reaction mixture is extracted twice with 5 cm ^{3 of} ethyl acetate. The combined organic phases were dried over magnesium sulfate and then concentrated to dryness under reduced pressure. 111 mg of a yellow oil are obtained, which is purified by chromatography under reduced pressure on a 20 g silica gel cartridge (particle diameter 0.04 to 0.063 mm), eluting with ethyl acetate / cyclohexane (2/98, v / v). 68 mg of O-allyloxime {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methanone are thus obtained as a colorless viscous oil. pH NMR (300 MHz, CDCl ₃ , δ in ppm). The mixture of 2 Z and E isomers is in an approximate 65/35 ratio or vice versa; 2.84 and 3.11 (2 broad t, respectively J = 8 Hz and J = 7.5 Hz: 2H total); 3.44 and 3.66 (2 broad t, each mts 1H 1H); 5.22

J = 7.5 Hz and J = 8 Hz 2H pretty) ; 3.58 and 3.81 pretty); 4.16 and 4.30 (2 s: 1H total); 4.59 (mt (dmt, J = 11) Hz : 1H); 5.27 (dmt, J = 18 Hz: 1H); 1H); 6.80 (tt, J = 9 and 2.5 Hz : 1H); 6.91 (mt 2H);

7.35 (mt 8H).

172

Example 96

{1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl) - (3,5-difluorophenyl) methanone O-ethyloxime can be prepared by a procedure as described for the preparation of O-allyloxime {1- [bis (4 -chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methanone, starting from 100 mg (1 [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) of methanol and 90 mg of O-ethylhydroxylamine hydrochloride to give 83 mg of O-ethyloxime {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methanone as a colorless viscous oil. ^[X H NMR (300 MHz, CDCl3, δ in ppm). a mixture of 2 isomers Z and E located in the approximate ratio of 65/35, or vice versa;

1.25 and 1.27 (2t, J = 7Hz: 3H total); 2.82 and 3.12 (2 broad t, respectively J = 8 Hz and J = 7.5 Hz: 2H total); 3.45 and 3.66 (2 broad t, respectively J = 7.5 Hz and J = 8 Hz: 2H total); 3.58 a

3.78 (2 mts: 1H total); from 4.05 to 4.20 (mt 2H); 4.16 and 4.30 (2 s: 1H total); 6.80 (tt, J = 9 and 2.5 Hz 1H); 6.91 (mt:

2H); from 7.20 to 7.35 (mt 8H)].

Example 97 (RS) -1 - [{1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methyl] -3-methylurea can be prepared as follows: 0.336 cm ³ triethylamine and 0.384 cm ^{3 of} diphenylphosphonoazide are added in an inert nitrogen atmosphere at about 20 ° C gradually to a solution of 300 mg of (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) - (3,5-diphenyl) hydrochloride of trifluoromethyl) acetic acid in 15 cm @ ^{3 of} anhydrous toluene The solution obtained is stirred at about 60 DEG C. for about 90 minutes, then 2.6 cm @ ^{3 of a} 2 M solution of metalamine in tetrahydrofuran are added, stirring is maintained at about 20 DEG. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 DEG C. The residue is taken up in 1 cm @ ^{3 of} methanol and then applied to a Bond-Elut SCX Varian 5 cartridge. g with reference 1225-6027 treated methanol The cartridge is washed with methanol and eluted with 2 N ammonia methanol. centered on

173 dryness under reduced pressure at about 40 ° C. To give 250 mg of a light oil which is taken up in 1 ^cm3 of dichloromethane and then loaded to the cartridge 16 nm in diameter, packed with 5 g silica gel of particle size from 0.015 to 0.035 mm, conditioned and eluted with dichloromethane between 0 and 40 cm ³ and elute with dichloromethane-ethyl acetate (80-20, v / v) using a pumping system. Fractions between 50 and 80 cm ³ are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 140 mg of (RS) -1 - [{1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methyl] -3-methylurea are obtained as a foam. 1 H NMR spectrum (400 MHz, CDCl 3, δ in ppm): 2.66 (mt 1H); 2.82 (d, J = 5Hz: 3H); 2.95 (mt 1H); 3.03 (mt 1H); 3.18 (mt 2H); 4.24 (mt 1H); 4.30 (s: 1H); 4.92 (t, J = 7 Hz: 1H); 5.36 (broad d, J = 7 Hz: 1H); 6.67 (tt, J = 9 and 2.5 Hz 1H); 6.80 (mt 2H); from 7.20 to 7.30 (mt 8H)].

The preparation of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid hydrochloride is described in the patent containing carbon derivatives, Example 77.

Example 98 (RS) -1 - [{1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methyl] -3-isopropylurea can be prepared as follows: 3 cm ³ i.e., 0.1 mM of a freshly prepared solution of (RS) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) isocyanatomethyl] azetidine is added under an inert nitrogen atmosphere at about 20 ° C. ° C to a solution of 17 μΐ of isopropylamine in 1 cm ^{3 of} anhydrous toluene. The resulting solution is stirred at about 20 ° C for about 12 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 ° C. The solid residue is taken up with 1 cm ^{3 of} methanol and then loaded onto a Bond-Elut SCX Varian 500 mg cartridge with reference 1225-6027 treated methanol. The cartridge is washed with methanol and eluted with 2 N ammonia methanol. The ammoniacal fractions were combined and concentrated to dryness under reduced pressure at about 40 ° C. The residue is collected

174 cm ^{3 of} dichloromethane and then loaded onto an IST FlashPack with reference SIL 016-002, filled with 2 g of silica gel (0.065 0.090 mm), treated with dichloromethane and eluted with dichloromethane-ethyl acetate (90-10 by volume) using a vacuum pump. Fractions between 20 and 38 cm ³ are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 14 mg of (RS) -1 - [(1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) - (3,5-difluorophenyl) methyl] -3-isopropylurea was obtained as a white foam. ^Χ NMR Spectrum (400 MHz, CDCl 3, δ in ppm): 1.14 (d, J = 6.5 Hz: 3H);

1.15 (D, J = 6.5 Hz: 3H); 2.66 (mt: 1H) ; 2.92 (wide dd, J - 8 a 5.5 Hz 1H); 3.01 (broad dd, J = 8 and 5.5 Hz: 1H); 3.16 (T, J = 8 Hz : 1H); 3.20 (t, J) = 8 Hz: 1H); 3.85 (mt 1H); 4.06 (D, J = 8 Hz: 1H); 4.29 (s : 1H) ; 4. 91 (t, J = -7 Hz 1H); 5, 17 (D, J - 6.5 Hz: 1H); 6.66 (Tt, j = 9 and 2 Hz: 1H); 6.78 (mt : 2H) r from 7.20 to 7.35 (mt: 8H)].

(RS) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) isocyanatomethyl] azetidine can be prepared as follows: 0.126 cm ^{3 of} triethylamine and 0.195 cm ^{3 of} diphenylphosphonoazide are gradually added under an inert atmosphere to a solution of 150 mg of [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) acetic acid hydrochloride in 9 cm ^{3 of} anhydrous toluene. The resulting solution was stirred at about 50 ° C for 1 hour. The mixture was cooled to give (RS) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) isocyanatomethyl] azetidine in toluene which was subsequently used in this form.

Example 99 (RS) -1 - [(1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methyl] -3-isobutylurea can be prepared as follows: 3 cm ³ i.e. 0.1 mM freshly prepared solution of (RS) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) isocyanatomethyl] azetidine is added under an inert nitrogen atmosphere at a temperature of about 20 ° C. ° C to a solution of 20 μΐ of isopropylamine in 1 cm ^{3 of} anhydrous toluene The solution obtained is stirred at a temperature of about 20 ° C for about

175 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 ° C. The solid residue is taken up with 1 cm ^{3 of} methanol and then loaded onto a Bond-Elut SCX Varian 500 mg cartridge with reference 1225-6027 treated methanol. The cartridge is washed with methanol and eluted with 2 N ammonia methanol. The ammoniacal fractions were combined and concentrated to dryness under reduced pressure at about 40 ° C. The residue obtained is taken up with 1 cm ^{3 of} dichloromethane and then loaded onto an IST FlashPack cartridge, with reference SIL 016-002, filled with 2 g of silica gel (0.065-0.090 mm), treated with dichloromethane and eluted with dichloromethane-ethyl acetate (90-10 by volume). using a vacuum pump. Fractions between 0 and 15 cm ³ are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 14 mg of (RS) -1 - [{1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methyl] -3- is obtained.

iso! butylurea .y in the forum me white foam. ^[X H NMR spectrum (400 MHz, CDC1 _3, δ in ppm): 0.89 (d, J) = 6.5 Hz: 3H); 0.90 (d, J) = 6, 5 Hz: 3H); 1.74 (mt: 1H); 2.66 (mt: 1H); From 2, 90 to 3.25 (mt 6H); 4.29 (s and mt: 2H total) ; 4.90 (t, J = 7) Hz: 1H); 5, 34 (wide d, J = 6.5 Hz : 1H); 6, e > 6 (tt, J = 9 and 2 Hz: 1H); 6, 80 (mt 2H); from 7.20 to 7.35 (mt: 8H)].

Example 100

N-Methyl-N-phenyl-1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxamide can be prepared as follows: 0.039 cm ^{2 of} N-methylaniline, 87 mg of 1- (3-dimethylaminopropyl) -3- Ethylcarbodiimide, 0.063 cm ^{3 of} triethylamine and then 4 mg of hydroxybenzotriazole hydrate are gradually added at about 20 ° C to a solution of 100 mg of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid in 2 cm ^{3 of} anhydrous dichloromethane. The resulting solution is stirred at about 20 ° C for about 12 hours. The reaction mixture is loaded onto an IST FlashPack cartridge, with reference SIL 016-005, filled with 5 g silica gel (0.065-0.090 mm), treated with dichloromethane and eluted with a gradient of dichloromethane-ethyl acetate (percentages of ethyl acetate vary from 0 to 5, v / v). help pump

176 and 1.5 cm ³ fractions are collected. Fractions 3 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. 95 mg of 1- [bis (4-chlorophenyl) methyl] azetidine-N-methyl-N-phenyl-3-carboxamide are thus obtained in the form of a cream colored foam.

PH NMR Spectrum (400 MHz CDCl ₃ , δ in ppm) : 3.08 (mt : 2H); 3.21 (mt 3H); 3.27 (with : 3H); 4.35 (s : 1H); 7.06 (d, J) = 7.5 Hz: 2H) ; from 7.15 to 7.45 (mt: HH)]. ¹ -

Example 101

1- [Bis (4-chlorophenyl) methyl] azetidine-N-benzyl-N-methyl-3-carboxamide can be prepared as follows: 0.0213 cm ^{3 of} N-benzylmethylamine is added to a suspension of 150 mg of 1- [bis (4 (chlorophenyl) methyl] azetidine-3-carboxylic acid activated on TFP resin (165 μΜ) in 2 cm ^{3 of} dichloromethane. The suspension is stirred at about 20 ° C for 22 hours and then filtered on a frit. The solid residue obtained is washed twice with 1 cm @ ^{3 of} dichloromethane. The filtrates were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 38 mg of 1- [bis (4-chlorophenyl) methyl] azetidine-N-benzyl-N-methyl-3-carboxamide are thus obtained in the form of a colorless gum. pH NMR spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.78 (s: 3H); from

3.25 to 3.55 (mt 5H); 4.38 (mt 2H); 4.57 (s 1H); from 7.15 to 7.40 (mt 13H).

1- [Bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid activated on THP resin can be prepared as follows: 2 g 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid, 73 mg 4 -dimethylaminopyridine, 0.927 cm @ ^{3 of} 1,3-diisopropylcarbodiimide is added to a suspension of 2.7 g of TFP resin (free phenol function, 1.1 mmol / g, i.e. 2.975 mM) in 40 cm @ ^{3 of} anhydrous dimethylformamide. After stirring for 19 hours at about 20 ° C, the suspension is filtered, the resin washed with 40 cm ^{3 of} dimethylformamide, 40 cm ^{3 of} tetrahydrofuran, 40 cm ^{3 of} dichloromethane and then dried under vacuum to constant weight. 3.6 g of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid activated on THP resin are thus obtained.

1- [Bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid can be prepared in a manner similar to that described by Anderson A.G.

and Lok R., J. Org. Chem., 37, 3953-3955 (1972) from 1-benzhydrylazetidin-3-ol, using the raw material 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol.

TFP resin (free phenol functional group) can be prepared according to the procedure described in WO 9967228.

Example 102 (RS) - [{1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methyl] methylamine can be prepared as follows: 0.099 cm ^{3 of} methylamine is added to the solution 108 mg of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methanone in 2 cm ^{3 of} anhydrous 1,2-dichloroethane, then 84 mg of sodium triacetoxyborohydride and 0.014 are added successively cm ³ of acetic acid. The mixture is stirred for 12 hours at a temperature in the region of 20 DEG C. and 0.992 cm @ ^{3 of} methylamine, 85 mg of sodium triacetoxyborohydride and then 0.143 g of acetic acid are gradually added. The solution obtained is stirred at a temperature of about 20 DEG C. for about 24 hours and then washed with 4 cm @ ^{3 of} saturated sodium bicarbonate solution. The organic phase is separated by settling and then dried over magnesium sulphate, filtered and concentrated under reduced pressure (2.7 kPa). The residue obtained is purified on an IST FlashPack cartridge, with reference SIL 016-002, filled with 2 g of silica gel (0.065-0.090 mm), treated with dichloromethane and eluted with a gradient of dichloromethane-methanol (methanol percentages vary from 0 to 6, v / v). by means of a vacuum pump and 1 cm ³ fractions are collected. Fractions 8 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. 66 mg of [{1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methyl] methylamine are thus obtained as colorless honey [ ³ H NMR spectrum (300 MHz, CDCl 3) δ in ppm): 2.25 (s: 3H); 2.60 (mt 1H); 2.68 (t, J = 7Hz: 1H); 2.94 (t, J 7 Hz 1H);

178

3.02 (broad t, J 7 Hz 1H); 3.34 (broad t, J 7 Hz 1H);

3.58 (d, J = 9Hz, 1H); 4.25 (s 1H); 6.67 (tt, J 9 and 2.5 Hz 1H); 6.80 (mt 2H); from 7.20 to 7.35 (mt 8H)].

Example 103 (RS) - [{1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl] - (3,5-difluorophenyl) methyl] isobutylamine can be prepared as follows: 0.028 cm ^{3 of} isobutylamine is added to the solution 109 mg of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methanone in 2 cm ^{3 of} anhydrous 1,2-dichloroethane, then 85 mg of sodium triacetoxyborohydride and 0.015 are added successively cm ³ of acetic acid. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is loaded onto a cartridge filled with 5 g of silica gel, treated with dichloromethane and eluted with a gradient of dichloromethane-ethyl acetate (percent ethyl acetate varies from 0 to 10, by volume) using a vacuum pump. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. To obtain 8 mg of (RS) - [{1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3, 5-difluorophenyl) methyl] isobutylamine ^[X H NMR (300 MHz, CDC1 ₃ , δ in ppm): 0.85 (d, J =

Hz: 3H); 0.87 (d, J = 7Hz: 3H); 1.63 (mt 1H); 2.15 (dd, J = 11 and 7.5 Hz 1H); 2.25 (dd, J = 11 and 7 Hz 1H); 2.57 (mt 1H); 2.70 (t, J 7 Hz 1H); 2.92 (t, J = 7Hz: 1H); 3.01 (broad t, J 7.5 Hz 1H); 3.33 (broad t, J 7.5 Hz 1H);

3.66 (d, J = 9Hz, 1H); 4.25 (s 1H); 6.66 (tt, J 9 and 2.5 Hz 1H); 6.81 (mt 2H); from 7.20 to 7.35 (mt 8H)].

Example 104 (RS) - [(1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methyl] butylamine can be prepared as follows: 0.0265 cm ^{3 of} n-butylamine is added to a solution of 108 mg of (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methanone in cm ^{3 of} colorless 1,2-dichloroethane, followed by the stepwise addition of 95 mg of sodium triacetoxyborohydride and 0.0143 cm @ ³ of acetic acid, the mixture is stirred for about 16 hours at about 20 DEG C., 0.0265 cm @ ^{3 of} n-butylamine, 85 mg of sodium triacetoxyborohydride and then 0.143 cm @ ³ of acetic acid are gradually added. The solution is stirred at about 20 DEG C. for 24 hours and then washed with 4 cm @ ^{3 of} saturated sodium bicarbonate solution.The organic phase is separated by settling and then dried over magnesium sulphate, filtered and concentrated under reduced pressure (2.7 kPa). The residue obtained is purified on an IST FlashPack cartridge, with reference SIL 016-002, filled with 2 g of silica gel (0.065). 0.090 mm), treated with dichloromethane and eluted with a gradient of dichloromethane-methanol (methanol percentage varies from 0 to 6, by volume) by means of a vacuum pump and collecting 1 cm ^{3 of} fraction. Fractions 25 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. There was thus obtained (RS) - [{1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methyl] butylamine as a colorless honey. ¹ H NMR spectrum (300 MHz, CDCl 3, δ in ppm): 0.85 (t, J = 7.5 Hz: 3H); from 1.20 to 1.50 (mt 4H); 2.37 (broad t, J 7 Hz 2H); 2.56 (mt 1H); 2.67 (t, J = 7Hz: 1H); 2.89 (t, J = 7Hz: 1H); 2.99 (broad t, J 7 Hz 1H);

3.32 (broad t, J 7 Hz 1H); 3.67 (d, J = 9Hz, 1H); 4.24 (s 1H); 6.65 (tt, J 9 and 2.5 Hz 1H); 6.80 (mt 2H); from 7.20 to 7.35 (mt 8H)].

Example 105 (RS) -N - [{1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methyl] -3-methylbutyramide can be prepared as follows: 0.025 cm ³ N, N'-diisopropylcarbodiimide, 10 mg hydroxybenzotriazole hydrate, 30 mg (RS) -C- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -C- (3,5-difluorophenyl) methylamine added successively to a solution of 0.017 cm @ 3 of isovaleric acid in 2 cm @ ^{3 of} anhydrous dichloromethane, at a temperature of about 20 ° C. The resulting solution was stirred at about 20 ° C for 12 hours. The reaction mixture is loaded onto a 500 mg Bond-Elut SCX Varian cartridge with reference 1210-2040, treated with methanol. The cartridge is washed with methanol and eluted with 2 N

180 with ammonia methanol. The ammoniacal fractions were combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40 ° C. 35 mg of (RS) -N - [{1- (bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methyl] -3-methylbutyramide are thus obtained in the form of:

of yellow honey • ΓΗ Nuclear Magnetic Resonance Spectrum (300 MHz, CDCl 3, δ in ppm): 0.98 (d, J = 5 Hz: 6H); from 2 .05 to 2.25 (mt 3H); 2.71 (mt: 1H); 2.90 (mt: 1H); 3.00 (mt : 1H); 3.20 (mt : 2H); 4.30 (s: 1H); 5.14 (t, J = 7, 5 Hz : 1H ); 6.48 (broad d, J = 7.5 Hz: 1H); 6.67 (tt, J = 9 and 2.5 Hz: : 1H); 6.75 (mt: 2H); from 7.20 to 7.40 (mt:

8H)].

(RS) - C- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl) -C- (3,5-difluorophenyl) methylamine can be prepared as follows: to a solution of 216 mg of (RS) - { 1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) methanone in 10 cm ^{3 of} methanol was sequentially added 385 mg of ammonium acetate and 29 mg of cyanoborohydride. The resulting solution is stirred at about 20 ° C for about 12 hours and then gently heated to 45 ° C for 6 hours. To the solution was added 29 mg of sodium cyanoborohydride. Stirring is continued at about 20 ° C for 72 hours. The reaction mixture is poured into a mixture of 30 cm ^{3 of} ice-cold water with 5 cm ^{3 of} 4 N aqueous sodium hydroxide solution and then extracted twice with 30 cm ^{3 of} ethyl acetate, the organic phase is extracted twice with 30 cm ^{3 of 3} N hydrochloric acid. aqueous sodium hydroxide solution and then extracted three times with 20 cm ^{3 of} ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. There was thus obtained (RS) -C- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -C- (3,5-difluorophenyl) methylamine as a yellow honey.

The pharmaceutical compositions of the present invention comprise a compound of formula I or an isomer or salt of such a compound in pure form or in the form of a composition in which it is combined with any other pharmaceutical product which is inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or

181 local.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, sachets) or granules may be used. In these compositions, the active ingredient of the invention is mixed under a stream of argon with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica gel. The compositions may also contain substances other than diluents, for example lubricants such as magnesium stearate or talc, colorants, coatings (sugar coated tablets) or glaze.

As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil may be used. The compositions may contain other substances, such as diluents, for example wetting, sweetening, thickening, flavoring or stabilizing agents.

The sterile compositions for parenteral administration may preferably be solutions which are aqueous or non-aqueous, suspensions or emulsions. As the solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. These compositions may contain adjuvants, in particular wetting, isotonic, emulsifying, dispersing and stabilizing agents. Sterilization can be accomplished in several ways, for example by sterile filtration, incorporation of sterilizing agents into the composition, irradiation, or heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or other injectable medium.

Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active ingredient, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

182

Compositions for topical administration can be, for example, in the form of creams, liquid formulations for external use, eye drops, rinsing agents, nasal drops or aerosols.

The compounds of the invention can be used in human therapy for the treatment or prevention of psychoses, including schizophrenia, anxiety, depression, epilepsy, neurodegeneration, cerebral and spinocerebral diseases, cognitive diseases, cranial trauma, panic attack, peripheral neuropathy, migraine, glaucoma Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremor, obsessive-compulsive disease, senile dementia, thymus disease, Tourette's syndrome, tardive discinesis, bipolar diseases, cancers, drug-induced movement disorders, dystonia, shine, endotoxic, endotoxic, endotoxic, endotoxic, endotoxic immunological diseases, multiple sclerosis, vomiting, asthma, taste-related diseases (bulimia, anorexia), obesity, memory disorders, drug, alcohol or drug addiction (e.g. opiates, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinog new, benzodiazepines), as analgesics or potentiator analgesic activity of narcotic and non-narcotic drugs.

The doses depend on the desired effect, duration of treatment and route of administration; they are generally between 5 mg and 1000 mg per day for oral administration in adults, with a unit dose containing 1 mg to 250 mg of the active ingredient.

In general, the physician may determine the appropriate dose depending on the age, weight and other factors specific to the subject being treated.

The following examples illustrate the compositions of the present invention:

Example A

183

Gelatin capsules containing a dose of 50 mg of the active ingredient and having the following composition are prepared using conventional techniques:

- Compound of formula I 50 mg - Cellulose 18 mg - Lactose 55 mg - Colloidal silica 1 mg - Carboxymethylated sodium starch 10 mg - Talc 10 mg - Magnesium stearate 1 mg

Example B

Tablets containing a dose of 50 mg of active compound and having the following composition are prepared using conventional techniques.

- Compound of formula I 50 mg - Lactose 104 mg - Cellulose 40 mg - Polyvidone 10 mg - Carboxymethylated sodium starch 22 mg - Talc 10 mg - Magnesium stearate 2 mg - Colloidal silica 2 mg Mixture of hydroxymethylcellulose, gly tin, oxide and titanium (72-3.5-24.5) qs 1 s used on

coating the tablet containing 245 mg.

Example C

Prepare an injectable solution containing 10 mg of the active ingredient:

Compound of Formula I mg

184

- Benzoic acid 80 mg - Benzyl alcohol 0.06 ml - Sodium benzoate 80 mg - Ethanol, 95% 0.4 ml - Sodium hydroxide 2 4 mg - Propylene glycol 1.6 ml

- Water qs 4 ml

Claims (56)

A compound of the general formula wherein R is CR ³ R ² , C = C (R ⁵ ) SO ² R ⁶ or C = C (R ⁷ ) SO 2 alk, R ¹ is H and R ² is -C (R ⁸⁾ (R ⁹⁾ (R ¹⁰⁾ -C (R ⁸⁾ (R ¹¹⁾ (R ¹²⁾ -CO-NR ¹³ R ^14, -CH 2 -CO-NR ¹³ R ¹⁴ , -CH 2 -CO-R ⁶ , -CO-R ⁶ , -CO-cycloalkyl, -SO ² -R ⁶ , -SO ² R ⁶ , -C (OH) (R ¹² ) (R ⁶ ), -C (OH) (R ⁶ ) (alkyl), -C (= NOalk) ) R ⁶ , -C (= NO-CH 2 -CH-CH ₂ ) R ⁶ , -CH 2 -CH (R ⁶ ) NR ³¹ R ³² , -CH 2 -C (= NO-alk) R ⁶ , -CH (R 6) ⁶ ) NR ³¹ R ³² , -CH (R ⁶ ) NHSO ₂ alk, -CH (R ⁶ ) NHCONHalk or -CH (R ⁶ ) NHCOalk, or R ¹ represents alkyl, NH-R ¹⁵ , cyano, -S-alk -NR ¹⁶ R ¹⁷ , -CH ₂ -NR ¹⁸ R ¹⁹ or -NR ²⁰ R ²¹ and R ² is -C (R ⁸ ) (R ¹¹ ) (R ¹² ), R ³ and R ⁴ which are the same or different represent either an alkyl or cycloalkyl group or an aromatic group selected from a phenyl group, a naphthyl group or an indenyl group, the aromatic groups being unsubstituted or substituted by one or more groups selected from the group consisting of halogen atoms, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR ²² R ²³ , -CO-NH-NR ²⁴ R ²⁵ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl , alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR ²⁴ R ²⁵ groups; or a heteroaromatic group selected from the group consisting of benzofuryl, 186 benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl and thienyl ring, these heteroaromatic groups may be unsubstituted groups or substituted with one or more groups selected from the group consisting of halogen atoms, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR ²⁴ R ²⁵ , -CONR ²² R ²³ , alk-NR ²⁴ R ^25, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R ⁵ represents a hydrogen atom or an alkyl group, R ⁶ is Ar or Het, R ⁷ is cycloalkyl, heterocycloalkyl or heterocyclenyl optionally substituted with -CSO-phenyl, R ⁸ represents a hydrogen atom or an alkyl group, R ⁹ is -CO-NR ²⁶ R ²⁷ , -COOH, -COOalk, -CH ₂ OH, -NH-CO-NH-alk, -CH ₂ -NHR ²⁸ or -NHCOOalk, R ¹⁰ represents a radical Ar or Het, R ¹¹ represents a radical -SO ₂ -alk, -SO ₂ -Ar or -SO ₂ -Het, · ' R ¹² represents a hydrogen atom or an Ar or Het group, R ¹³ represents a hydrogen atom or an alkyl group, R ¹⁴ represents an Ar, Het, -alk-Ar or -alk-Het group R is alkyl, cycloalkyl or -alk-NRR, 187 R ¹⁶ and R ¹⁷ , which are the same or different, represent a hydrogen atom or an alkyl group or alternatively R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle optionally containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups, R ¹⁸ represents a hydrogen atom or an alkyl group, R ¹⁹ represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO ₂ alk, -CO-NHalk or -COOalk group, or alternatively R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached form 3- to 10 a membered unsaturated or saturated mono- or bicyclic heterocycle, optionally containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups, -NR ²⁰ R ²¹ represents a 3- to 8-membered saturated or unsaturated monocyclic heterocycle, optionally containing another heteroatom selected from oxygen, nitrogen and sulfur, R ²² and R ²³ , which are the same or different, represent a hydrogen atom or an alkyl group or alternatively R ²² and R ²³ together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups, R ²⁴ and R ²⁵ , which are the same or different, represent a hydrogen atom or an alkyl group, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl or alternatively R ²⁴ and R ²⁵ together with the nitrogen atom to which they form are bound, a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups, -COalk, -COOalk, -CO-NHalk , -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH ₂ groups, R ²⁶ and R ²⁷ , which are the same or different, represent a hydrogen atom or an alkyl group, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, -alk-COOalk, -alk-Ar, -alk-Het, Het or -alk-N (alk) ₂ the group R and R may also form together with the nitrogen atom to which they are attached a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle, optionally containing a further heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or a plurality of alkyl, alkoxy or halogen atoms, R ²⁸ represents -CH ₂ -alk, benzyl, -SO ₂ alk, -CONHalk, -COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, -CO- (CH ₂ ) _n OH group, n is 1, 2 or 3, R ²⁹ and R ³⁰ , which are the same or different, represent a hydrogen atom or an alkyl group, or alternatively R ²⁹ and R ³⁰ together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing a further heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups, R ³¹ and R ³² , which are the same or different, represent a hydrogen atom or an alkyl group, Ar or -alk-Ar group or alternatively R ³¹ and R ³² together with the nitrogen atom to which they are attached form a heterocycle selected from the group consisting of: form aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl, alk means alkyl or alkylene, Ar represents a phenyl group or a naphthyl group optionally 189 substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR ²² R ²³ , -CO-NH-NR ²⁴ R ²⁵ , alkylsulfanyl , alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, -alk-NR ²⁴ R ^25, -NR ²⁴ R ^25, alkylthioalkyl, formyl, hydroxyl, CF _3, OCF _3, Het, -O-alk-NH-cycloalkyl or SO2NH2 group, Het means a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocyclic group containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkoxy, alkoxycarbonyl, -CONR ²² R ²³ , hydroxyl, hydroxylalkyl, oxo or. SO ₂ NH ₂ groups, alkyl and alkylene groups and portions thereof, and alkoxy groups and portions thereof are in the form of a straight or branched chain and contain 1 to 6 carbon atoms, cycloalkyl groups contain 3 to 10 carbon atoms, and heterocycloalkyl and heterocyclenyl groups contain 3 to 10 carbon atoms, their optical isomers and their salts with inorganic or organic acids. A compound according to claim 1, for which Het is selected from the group consisting of benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, indolinyl, indolyl, isochromanyl, isoquinolyl, piperidyl , pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl, thienyl. A compound of formula I according to claim 1, wherein when R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 3 to 10 membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is azetidinyl, pyrrolidinyl, piperidinyl , a morpholinyl, thiamorph190 linyl or piperazinyl ring. A compound of formula I according to claim 1, wherein when R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached form a 3 to 10 membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is azetidinyl, I a pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. A compound of formula I according to claim 1, wherein the heterocycle formed by NR ²⁰ R ²¹ is an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl, piperazinyl or imidazole ring. A compound of formula I according to claim 1, wherein when R ²² and R ²³ together with the nitrogen atom to which they are attached form a 3 to 10 membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is azetidinyl, pyrrolidinyl, piperidinyl , morpholinyl, thiamorpholinyl or piperazinyl ring. A compound of formula I according to claim 1, wherein when R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached form a 3 to 10 membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is azetidinyl, pyrrolidinyl, piperidinyl , morpholinyl, thiamorpholinyl or piperazinyl ring. A compound of formula I according to claim 1, wherein when R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a 3 to 10 membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is azetidinyl, pyrrolidinyl, piperidinyl , morpholinyl, thiamorpholinyl or piperazinyl ring. 191 A compound of formula I according to claim 1, wherein when R ²⁹ and R ³⁰ together with the nitrogen atom to which they are attached form a 3 to 10-membered saturated or unsaturated monocyclic or bicyclic heterocycle, the heterocycle is azetidinyl, pyrrolidinyl, piperidinyl , morpholinyl, thiamorpholinyl or piperazinyl ring. A compound of formula I according to claim 1, wherein: R is CR ³ R ^2, either R ¹ is H and R ² is -C (R ⁸⁾ (R ^s) (R ¹²⁾ or -C (R ⁸⁾ (R ⁹⁾ (R ^10), or R ¹ is alkyl and R ² is -C (R ⁸⁾ (R ¹¹⁾ (R ^12), R ³ and R ⁴ , which are the same or different, represent either a phenyl group which is unsubstituted or substituted by one or more groups selected from halogen atoms, alkyl, alkoxy, t, fluoromethyl, trifluoromethoxy, cyano, -CONR ²² R ²³ , hydroxyalkyl or -alk-NR ²⁴ R ²⁵ groups; or a heteroaromatic group selected from pyridyl, pyrimidinyl, thiazolyl and thienyl rings, which heteroaromatic groups may be unsubstituted or substituted by one or more groups selected from the group consisting of halogen atoms, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano , » -CONR ²² R ²³ , -alk-NR ²⁴ R ^25, or hydroxyalkyl groups, R ⁸ represents a hydrogen atom, R ³ is -CO-NR ²⁶ R ²⁷ , -COOalk, -CK ₂ OH, -NH-CO-NH-alk, -CH ₂ -NHNR ²⁸ or -NHCOOalk group, R ¹⁰ represents a radical Ar or Het, 192 R is ^the radical -SO ₂ -alk, -SO ₂ -Ar or -SO ₂ -Het, R ¹² represents a hydrogen atom or an Ar or Het group, R ²² and R ²³ , which are the same or different, represent a hydrogen atom or an alkyl group, or alternatively R ²² and R ²³ together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing a further heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups, R ²⁴ and R ²⁵ , which are the same or different, represent a hydrogen atom or an alkyl group, a cycloalkyl, an alkylcycloalkyl, or a hydroxyalkyl group, or alternatively, R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached form a 3- to 10-membered a saturated or unsaturated mono- or bicyclic heterocycle, optionally containing a further heteroatom selected from oxygen, sulfur. and nitrogen and optionally substituted with one or more alkyl groups, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo or -CO-NH ₂ groups, Ar is phenyl or naphthyl, optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, alkyl, alkoxy, -CO-alk, cyano, -COOalk, -CONR ²² R ²³ , alkylsulfonyl, hydroxyalkyl, -alk -NR ²⁴ R ²⁵ , -NR ²⁴ R ²⁵ , hydroxyl, CF ₃ , OCF 3, -O-alk-NH-cycloalkyl or SO ₂ NH ₂ group, Het means benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl ring, its optical isomers and salts thereof with an inorganic or organic acid. 193 11. A compound selected from the group consisting of the following compounds: (RS) -1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) - (methylsulfonyl) methyl] azetidine, (R) -1- [bis (4-chlorophenyl) methyl] )] - 3 - [(3,5-difluorophenyl) - (methylsulfonyl) methyl] azetidine, (S) -1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) - ( methylsulfonyl) methyl] azetidine, (RS) -1- [bis (4-chlorophenyl) methyl)] - 3 - [(pyrid-3-yl) - (methylsulfonyl) methyl] azetidine, (R) -1- [bis ( 4-chlorophenyl) methyl)] - 3 - [(pyrid-3-yl) - (methylsulfonyl) methyl] azetidine, (S) -1- [bis (4-chlorophenyl) methyl)] - 3 - [(pyrid-3) (R) -1- [bis (3-fluorophenyl) methyl] -3- [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (R) -yl) - (methylsulfonyl) methyl] azetidine, (R) ) -1- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (S) -1- [bis (3-fluorophenyl) methyl] -3 - [(3) 5-difluorophenyl) methylsulfonylmethyl] azetidine, 1- [bis (4-chlorophenyl) methyl] -3- (RS) - {[3-azetidin-1-yl-phenyl] methylsulfonylmethyl} azetidine, 1- [bis (4-chlorophenyl) methyl] -3- (R) - {[3-azetidin-1-ylphenyl] methylsulfonylmethyl} azetidine, 194 1- [bis (4-chlorophenyl) methyl] -3- (S) - {[3-azetidin-1-ylphenyl] methylsulfonylmethyl} azetidine, (RS) -1- [3 - ({1- [bis (4 (chlorophenyl) methyl] azetidin-3-yl} -methylsulfonylmethyl) phenyl] pyrrolidine, (K) -1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] pyrrolidine, (S) -1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] pyrrolidine, (FS) -N- [3- ( {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] -N-methylamine, (F) -N- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidine] -3-yl) methylsulfonylmethyl) phenyl] -N-methylamine, (S) -N- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] -N-methylamine (FS) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-bistrifluoromethylphenyl) methylsulfonylmethyl] azetidine, (F) -1- [bis (4-chlorophenyl) methyl] -3- [ (3,5-bistrifluoromethylphenyl) methylsulfonylmethyl] azetidine, (S) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-bistrifluoromethylphenyl) methylsulfonylmethyl] azetidine, 1- [bis (4-chlorophenyl) methyl] -3- (phenylsulfonylmethyl) azetidine, (FS) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] -3 -methylazetidine, (F) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl] methyl] -3-methylazetidine, (S) -1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] -3-methylazetidine, (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3) (5-difluorophenyl) -N-cyclohexylacetamide, (R) -2- {1- [bis (4-chlorophenyl) methyl] azeditin-3-yl} -2- (3,5-difluorophenyl) -N- cyclohexylacetamide, (S) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) -N-cyclohexylacetamide, (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) -N-isobutylacetamide, (R) -2- {1- [bis (4-chlorophenyl) methyl] azetidine -3-yl} -2- (3,5-difluorophenyl) -N-isobutylacetamide, (S) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3, 4-chlorophenyl) methyl 5-Difluorophenyl) -N-isobutylacetamide, (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) -N -cyclopropylmethylacetamide, (R) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclopropylmethylacetamide, (S) -2- {1 -bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclopropylmethylacetamide, (RS) -2- {1- [bis (4-chlorophenyl) methyl] azetidine -3-yl) -2- (3,5-difluorophenyl) -N-isopropylacetamide, (R) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3 (S) -2- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -2- (3,5-difluorophenyl) -N-isopropylacetamide, 5-difluoro (phenyl) -N-isopropylacetamide, (RS) -1- [bis (4-chlorophenyl) methyl] -3- [1- (3,5-difluorophenyl) -1-methylsulfonylethyl] azetidine, (R) -1- [bis (4-chlorophenyl) methyl] ] -3- [1- (3,5-difluorophenyl) -1-methylsulfonylethyl] azetidine, (S) -1- [bis (4-chlorophenyl) methyl] -3- [1- (3,5-difluorophenyl)] -1-methylsulfonylethyl] azetidine, (RS) -1- [bis (4-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (R) -1- [bis (4-fluorophenyl) (methyl) -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (S) -1- [bis (4-fluorophenyl) methyl] -3 - [(3,5-d) (fluorophenyl) methylsulfonylmethyl] azetidine, (RS) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (SS) - {1- [ (3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (RR) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] - 3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (SR) - (1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (RS) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, 197 (SS) - {1 - [(4-Pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (RR) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (SR) - (1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3 (5-difluorophenyl) methylsulfonylmethyl] azetidine, (RS) -5 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-1-yl} methyl) pyrimidine, (SR) -5 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-1-yl} methyl) pyrimidine, (RR) -5 - ((4-chlorophenyl) - {3 - [(3 (5-difluorophenyl) methylsulfonylmethyl] azetidin-1-yl} methyl) pyrimidine, (SS) -5 - ((4-chlorophenyl) - (3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-1-yl) methyl (pyrrolidine), (SS) - {1 - [(2-chloropyrid-5-yl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (RR) - {1- [(2-chloropyrid-5-yl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (RS) - {1 - [(2-chloropyrid-5-yl)] - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) metylsulfonylm ethyl] azetidine, (SR) - {1 - [(2-chloropyrid-5-yl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, their optical isomers and their pharmaceuticals acceptable salts with inorganic or organic acid. 198 A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ^X R ² , wherein R ¹ is hydrogen and R ² is C (R ⁸ ) (R ¹¹ ) (R ¹² ), wherein R ⁸ R ¹¹ is -SO ₂ -Ar, -SO ₂ -Het or -SO ₂ alk and R ¹² is hydrogen or Ar or Het, wherein the derivative of formula: wherein R ^a is alkyl, Het or Ar and R ^b is hydrogen or Ar or Het, alkyl, Ar and Het have the same meanings as in claim 1, is reduced, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ³ R ² wherein R ¹ is hydrogen and R ² is C (R ⁸ ) (R ¹¹ ) (R ¹² ) wherein R ⁸ is H, R ¹¹ represents a radical -SO ₂ -Ar, -SO ₂ -Het or -SO ₂ alk and R ¹² represents a hydrogen atom or a radical Ar or Het, characterized in that a derivative R ³ CH (Br) R ⁴ reacts with a derivative of the general formula: wherein R ^a is alkyl, Het or Ar and R ^b is hydrogen or Ar or Het, alkyl, Ar and Het have the same meanings as in claim 1, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1 1, wherein R is C = C (R ⁵ ) SO ² R ⁶ or C = C (R ⁷ ) SO 2 alk, wherein the derivative of the general formula: wherein either R ^a is Ar or Het and R ^b is hydrogen or alkyl, or R ^a is alkyl and R ^b is cycloalkyl, heterocycloalkyl or heterocyclenyl optionally substituted with -CSO-phenyl, R ^c is hydrogen or the acetyl group, R ³ , R ⁴ , Ar and Het are as defined in claim 1, dehydrated, the product isolated and, optionally, converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is C = C (R ⁵ ) SO ² R ⁶ or C = C (R ⁷ ) SO 2 alk, wherein R ³ CH (Br) R ⁴ is reacted with derivative of the general formula: wherein either R ^a is Ar or Het and R ^b is hydrogen or alkyl, or R ^a is alkyl and R ^b is cycloalkyl, heterocycloalkyl or heterocyclenyl optionally substituted with -CSO-phenyl, R ^c 200 is H or acetyl, R ^3, R ^4, Ar and Het are as defined in Claim 1, the product isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ^X R ² , wherein R ¹ is hydrogen and R ² is C (R ⁸ ) (R ⁹ ) (R ¹⁰ ), wherein R ⁸ is H, R ⁹ represents a radical -CO-NR ²⁶ R ^27, and R ¹⁰ represents a radical Ar or Het, characterized in that an amine HNR ²⁶ R ²⁷ wherein R ²⁶ and R ²⁷ are as defined in claim 1, is reacted with acid of general formula: R ³ A N-L · COOH R ¹⁰ wherein R ^3, R ⁴ and R ¹⁰ have the same meanings as in Claim 1, the product isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ^X R ² , wherein R ¹ is hydrogen and R ² is C (R ⁸ ) (R ⁹ ) (R ¹⁰ ), wherein R ⁸ is H, R ⁹ is -COOH and R ¹⁰ represents a radical Ar or Het, characterized in that the corresponding ester of formula: R ¹⁰ COOalk wherein R ³ , R ⁴ and R ¹⁰ have the same meanings as in claim 1 and alk represents a C 1 -C 6 alkyl group, straight chain or branched, is hydrolyzed, the product is isolated and optionally converted to an inorganic salt or an organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ¹ R ² , wherein R ¹ is hydrogen and R ² is C (R ⁸ ) (R ⁹ ) (R ¹⁰ ), wherein R ⁸ is hydrogen, R ⁹ is -COOalk or -CH ₂ OH and R ¹⁰ is Ar or Het, characterized in that the compound of formula: R ³ R ⁴ A wherein R ³ , R ⁴ and R ¹⁰ have the same meanings as in claim 1 and alk represents a C 1 -C 6 alkyl group, straight or branched, reduced, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ² , wherein R ¹ is hydrogen and R ² is C (R ⁸ ) (R ⁹ ) (R ¹⁰ ), wherein R ⁸ is hydrogen, R ⁹ is -NHCOOalk, and R ¹⁰ is Ar or Het, characterized in that the alcohol alkOH, where alk is a C 1 -C 6 alkyl group, is reacted with a straight or branched chain derivative with a derivative of the general formula of formula: 202 wherein R ³ , R ⁴ and R ¹⁰ have the same meanings as in claim 1, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ³ R ² , wherein R ¹ is hydrogen and R ² is C (R ⁸ ) (R ⁹ ) (R ¹⁰ ), wherein R ⁸ is hydrogen, R ⁹ is -NHCONHalk, and R ¹⁰ is Ar or Het, wherein the amine alkNH ₂ , wherein alk is a straight or branched chain alkyl group having 1 to 6 carbon atoms, is reacted with a derivative of the general formula: wherein R ³ , R ⁴ and R ¹⁰ have the same meanings as in claim 1, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ¹ R ² , wherein R ¹ is hydrogen and R ² is C (R ⁸ ) (R ⁹ ) (R ¹⁰ ), wherein R ⁸ is hydrogen, R ⁹ is -CH 2 -NR ²⁸ , R ²⁸ is -CH 2 -alk or 203 benzyl group and R ¹⁰ represents a radical Ar or Het, characterized in that reacting a compound of the formula: wherein R ³ , R ⁴ and R ¹⁰ have the same meanings as in claim 1, with an aldehyde of the general formula R ^d CHO, wherein R ^d represents a -CH ₂ -alk or benzyl group and alk represents an alkyl group having 1 to 6 carbon atoms, The product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ² , wherein R ¹ is hydrogen and R ² is C (R ⁸ ) (R ⁹ ) (R ¹⁰ ), wherein R ⁸ is hydrogen. is H, R ⁹ is -CH 2 NHR ^28, R ²⁸ represents a radical -SO 2 alk and R ¹⁰ represents a radical Ar or Het, characterized in reacting an amine of the formula: R ³ wherein R ³ , R ⁴ and R ¹⁰ have the same meanings as in claim 1, with a derivative of the general formula ClSO ₂ R ^e , where R ® represents a C 1 -C 6 alkyl group, straight or branched, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ³ R ² , wherein R ¹ is hydrogen and R ² is C (R ⁸ ) (R ⁹ ) (R ¹⁰ ) wherein R ⁸ is hydrogen, R ⁹ is -CH ₂ -NHR ²⁸ , R ²⁸ is -CO-NHalk, and R ¹⁰ is Ar or Het, characterized in that a derivative of the general formula: R ³ R ⁴ A wherein R ³ , R ⁴ and R ¹⁰ have the same meanings as in claim 1, with the derivative R ^f NCO, wherein R ^f represents a C 1 -C 6 alkyl group, straight or branched, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ^X R ² , wherein R ¹ is hydrogen and R ² is C (R ⁸ ) (R ⁹ ) (R ¹⁰ ) wherein R ⁸ is hydrogen, R ⁹ is -CH 2 -NR ²⁸ , R ²⁸ is -CO-alk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl or -CO- (CH 2) _n OH, and R ¹⁰ is Ar or Het, by reacting a derivative of the general formula: 205 wherein R ^3, R ⁴ and R ¹⁰ have the same meanings as in Claim 1, with an acid HOOCR ⁹ wherein R ^g is an alkyl group having 1 to 6 carbon atoms, straight or branched chain, a cycloalkylalkyl group having 3 to 10 carbon atoms in the cycloalkyl moiety and 1 to 6 carbon atoms in the alkyl moiety, wherein the alkyl moiety is a straight or branched chain, a cycloalkyl group containing 3 to 10 carbon atoms, or a - (CH ₂ ) _n OH n group equal to 1, 2 or 3; is isolated and optionally converted with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ^X R ² , wherein R ¹ is hydrogen and R ² is -CONR ¹³ R ¹⁴ , characterized in that an amine of the formula HNR is reacted ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ have the same meanings as in claim 1, with a derivative of the general formula: R ³ N-, \ COOH where R ³ and R ⁴ have the same meanings as in formula I, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for preparing compounds of formula I according to claim 1 206 1, wherein R is CR * R ² , wherein R ¹ is hydrogen and R ² is -CH ₂ -CONR ¹³ R ¹⁴ , wherein the amine of formula HNR ¹³ R ¹⁴ , wherein R ¹³ and R ^{13 14} have the same meanings as in claim 1, react with a derivative of the general formula: R ³ NCOOH wherein R ³ and R ⁴ have the same meanings as in claim 1, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ³ R ² , wherein R ¹ is hydrogen and R ² is -CH ₂ -CONR ¹³ R ¹⁴ , wherein the derivative of the formula : R ³ N \ ^ / CONR ¹³ R ¹⁴ wherein R ^3, R ^4, R ¹³ and R ¹⁴ have the same meanings as in Claim 1, is reduced, the product isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ² , wherein R ¹ is hydrogen and R ² is -SOR ⁶ , wherein the derivative of the formula: 207 R ³ wherein R ³ , R ⁴ and R ⁶ have the same meanings as in claim 1, oxidize, isolate the product and optionally convert it into an inorganic or organic acid salt. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ³ R ² , wherein R ¹ is hydrogen and R ² is -SO ₂ R ⁶ , wherein the derivative of the formula: R ³ SOR ⁶ wherein R ³ , R ⁴ and R ⁶ have the same meanings as in claim 1, oxidize, isolate the product and optionally convert it into a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ⁴ R ² , wherein R ¹ is hydrogen and R ² is -COR ⁶ or -CO-cycloalkyl, characterized in that: the derivative of the general formula: R ³ \ CON _{(CH3) OCH3} 208 wherein R ³ and R ⁴ have the same meanings as in claim 1, react with a derivative of the general formula R ^h MgBr, wherein R ^h has the same meaning as R ⁶ in claim 1 or still represents a C 3 -C 10 cycloalkyl group, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ⁴ R ² , wherein R ¹ is hydrogen and R ² is -C (OH) (R ⁶ ) (R ¹² ) or -C (OH) (R ⁶ ) (alkyl) characterized in that the derivative of the general formula: R ³ COR ⁶ wherein R ³ , R ⁴ and R ⁶ have the same meanings as in claim 1, react with a derivative of the general formula R 1 'MgBr, wherein R ¹ has the same meaning as R ¹² in claim 1, or still represents an alkyl group of 1 The product is isolated and optionally converted to a salt with an inorganic or oganoic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ³ R ² , wherein R ¹ is hydrogen and R ² is -C (= NOalk) R ⁶ or -C (= NO-CH ₂ - CH = CH 2) R °, characterized in that the derivative of the general formula: R ³ where R ³ , R ⁴ and R ⁶ have the same meanings as in claim 1, reacts with a derivative of the general formula R ^j ONH 2, where R ^j represents a straight or branched chain alkyl group having 1 to 6 carbon atoms, or -CH 2 -CH = CH 2, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ¹ R ² , wherein R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ and R ³² is an atom hydrogen, characterized in that aqueous ammonia is reacted with a derivative of the general formula: R ³ R ⁶ wherein R ³ , R ⁴ and R ⁶ have the same meanings as in claim 1 and M ⁵ represents a methylsulfonyloxy group, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ² , wherein R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ is hydrogen and R ³² represents an alkyl group, an Ar group or an -alk-Ar group, characterized by reacting a halide HalR ³¹ with the corresponding compound of the formula I, wherein R is CR ³ R ² , where R ¹ is a hydrogen atom and R ² is a group -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ and R ³² represent a hydrogen atom, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ¹ R ² , wherein R ¹ is hydrogen and R ² 210 is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ and R ³² are alkyl, Ar or -alk-Ar, characterized in that HalR ³² is reacted with the corresponding compound of formula I, wherein: R is CR ¹ R ² where R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ is hydrogen and R ³² is alkyl, Ar or -alk-Ar, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for preparing compounds of formula I according to claim 1 1, wherein R ^ is CR ^2, wherein R ¹ is H and R ² represents a radical -CH (R ⁶⁾ NR ³¹ R ^32, R ³¹ is H and R ³² is an alkyl group having 2 to 6 carbon atoms, or a (C 2 -C 6) alkylaryl group comprising reacting an aldehyde of formula R ^and CHO, where R ^a is an alkyl or -alk-Ar group, with the corresponding compound of formula I wherein R is CR ² , where R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ and R ³² are hydrogen, the product is isolated and optionally converted to a salt with an inorganic or organic acid . A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ² , wherein R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ is alkyl, Ar or -alk-Ar and R ³² is C 2 -C 6 alkyl or C 2 -C 6 alkylaryl in the alkyl moiety which is reacted with an aldehyde of formula R ^and CHO, wherein R ^a is alkyl or -alk-Ar, with the corresponding compound of formula I, wherein R is CR ^X R ² , wherein R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ represents a hydrogen atom and R ³² represents an alkyl group, an Ar group or an -alk-Ar group, the product is isolated and optionally converted to an inorganic or organic salt 211 acid. A process for the preparation of compounds of formula I according to claim 1 1, wherein R is CR ^X R ² , wherein R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ and R ³² form, with the nitrogen atom to which they are attached, a heterocycle, selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl, characterized in that a dihalide of formula Hal- (2-5C) alk-Hal is reacted with a corresponding compound of formula I, wherein R is CR R, wherein R ¹ is H and R ² represents a radical -CH (R ⁶⁾ NR ³¹ R ^32, R ³¹ and R ³² represent a hydrogen atom, the product isolated and optionally converted to a salt with an inorganic or organic acid. A process for preparing compounds of formula I according to claim 1 1, wherein R is CR ^ ² , where R ¹ is hydrogen, and R ² is -CH (R ⁶ ) NHSO ₂ alk, wherein the derivative of the general formula: R ³ wherein R ^3, R ⁴ and R ⁶ have the same meanings as in claim 1, is rea ^J-dumping with a derivative of the formula CISO ₂ alk wherein alk is alkyl of 1 to 6 carbon atoms, straight or branched chain, the product was is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ¹ R ² , wherein R ¹ is hydrogen and R ² is -CH (R ⁶ ) NHCONHalk, characterized in that the derivative of the general formula: 212 R ³ wherein R ³ , R ⁴ and R ⁶ have the same meanings as in claim 1, reacted with a derivative of the formula alkNCO, wherein alk represents a straight or branched chain alkyl group having 1 to 6 carbon atoms, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ^X R ² , wherein R ¹ is hydrogen and R ² is -CH (R ⁶ ) NHCOR ³¹ , wherein the derivative of the formula : R ³ wherein R ³ , R ⁴ and R ⁶ have the same meanings as in claim 1, react with a derivative of the general formula R ³¹ COOH, wherein R ³¹ has the same meaning as in claim 1, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ³ R ² , wherein R ¹ is hydrogen and R ² is -CH ₂ COR ⁶ , wherein the derivative of the formula: 213 N 1 CO-N (CH ₃ ) OCH ₃ wherein R ³ and R ⁴ have the same meanings as in claim 1, react with a derivative of the general formula R ⁶ MgBr, wherein R ⁶ has the same meaning as in claim 1, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ² , wherein R ¹ is hydrogen and R ² is -CH ₂ CH (R ⁶ ) -NR ³¹ R ³² , characterized in that: the derivative of the general formula: R ³ wherein R ³ and R ⁴ have the same meanings as in claim 1, react with a derivative of the general formula HNR ³¹ R ³² , wherein R ³¹ and R ³² have the same meanings as in claim 1, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ³ R ² , wherein R ¹ is hydrogen and R ² is -CH ₂ -C (= NOalk) R ⁶ , characterized in that: derivative of general formula: 214 wherein R ³ and R ⁴ have the same meanings as in claim 1, reacted with a derivative of the formula alkONH ₂ , wherein alk is a straight or branched chain alkyl group having 1 to 6 carbon atoms, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ² , wherein R ¹ is cyano and R ² is -C (R ⁸ ) (R ¹¹ ) (R ¹² ), wherein R ⁸ is an atom hydrogen, characterized in that the derivative of the general formula: R ³ wherein R ³ , R ⁴ , R ¹¹ and R ¹² have the same meanings as in claim 1, are reacted with sodium cyanide, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ¹ R ² , wherein R ¹ is -S-alk-NR ¹⁶ R ¹⁷ and R ² is -C (R ⁸ ) (R ¹¹ ) (R ¹² ), wherein R ⁸ represents a hydrogen atom, characterized in that the derivative of the general formula: 215 wherein R ³ , R ⁴ , R ¹¹ and R ¹² have the same meanings as in claim 1, reacted with a derivative of the general formula HS-alk-NR ¹⁶ R ¹⁷ , wherein alk represents an alkyl group having 1 to 6 carbon atoms directly or and R ¹⁶ and R ¹⁷ have the same meanings as in claim 1, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ^X R ² , wherein R ¹ is -NHR ^15, and R ² is -C (R ⁸ ) (R ¹¹ ) (R ¹² ), wherein R ⁸ represents a hydrogen atom, characterized in that the derivative of the general formula: R ³ R A wherein R ^3, R ^4, R ¹¹ and R ¹² have the same meanings as in Claim 1, with a derivative H ₂ NR ¹⁵ wherein R ¹⁵ is as defined in the claims, the product isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ^X R ² , wherein R ¹ is an alkyl group and R ² is -C (R ⁸ ) (R ¹¹ ) (R ¹² ), wherein R ⁸ means a hydrogen atom, 216, wherein the derivative of the general formula: ^{R3 R} Y wherein R ^3, R ^4, R ¹¹ and R ¹² have the same meanings as in Claim 1, with a derivative of formula alkMHal wherein alk is alkyl of 1 to 6 carbon atoms, straight or branched, M is a metal, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ² , wherein R ¹ is -NR ²⁰ R ²¹ and R ² is -C (R ⁸ ) (R ¹¹ ) (R ¹² ) wherein R ⁸ is a hydrogen atom, characterized in that the derivative of the general formula: R ³ R ⁴ A wherein R ³ , R ⁴ , R ¹¹ and R ¹² have the same meanings as in claim 1, react with a derivative of HNR ²⁰ R ²¹ , wherein NR ²⁰ R ²¹ have the same meanings as in claim 1, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1 217 1, wherein R is CR- ² , wherein R ¹ is -alkNR ^18, R ¹⁹ , R ¹⁸ and R ¹⁹ are hydrogen, characterized in that the corresponding compound of formula I wherein R ¹ is cyano is reduced, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ¹ R ² , wherein R ¹ is -alkNR ¹⁸ R ¹⁹ , R ¹⁸ is hydrogen and R ¹⁹ is alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO ₂ alk, -CO-NHalk or -COOalk, characterized in that the halide of formula HalR ¹⁹ , where Hal is halogen, is reacted with the corresponding compound of formula I, wherein R is CR ² , wherein R ¹ is -alkR ¹⁸ R ¹⁹ , where R ¹⁸ and R ¹⁹ are hydrogen, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CRR, wherein R is -alkNR R, R ¹⁸ is alkyl and R ¹⁹ is alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO 2 alk, -CO -NHalk or -COOalk, characterized in that the alkyl halide is reacted with the corresponding compound of formula I wherein R is CR ¹ R ² , where R ¹ is alk NR ¹⁸ R ¹⁹ , where R ¹⁸ is hydrogen and R ¹⁹ is alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO2alk, -CO-NHalk or -COOalk, the product is isolated and optionally converted to a salt with an inorganic or organic acid. A process for the preparation of compounds of formula I according to claim 1, wherein R is CR ¹ R ² , wherein either R ¹ is hydrogen and R ² is -C (R ⁸ ) (R ⁹ ) (R ¹⁰ ) or -C (R ⁸⁾ (R ¹¹⁾ (R ^12), or R ¹ is alkyl, NHR ^15, cyano, -S-alk-NR ¹⁶ R ^17, -alk-NR ¹⁸ R ¹⁹ or -NR ²⁰ R ²¹ and R ² is a group 218 -C (R ⁸ ) (R ¹¹ ) (R ¹² ) and R ⁸ represent an alkyl group, characterized in that the corresponding compound of formula I wherein R ⁸ represents a hydrogen atom is alkylated, the product is isolated and optionally converted to a salt with an inorganic or organic acid. I 54. A process for the preparation of compounds of formula I according to claim 1, wherein R is -C = C (R ⁷⁾ SC ^ alk which comprises contacting said Cisa characterized in that a derivative of formula: R ³ wherein R ³ , R ⁴ and R ⁷ have the same meanings as in claim 1 and alk represents a straight or branched chain C 1 -C 6 alkyl group and the product is isolated and optionally converted to an inorganic or organic acid salt . A process for the preparation of compounds of formula I according to claim 1 1, wherein R is CR ³ R ² , wherein R ¹ is hydrogen and R ² is -CH (R ⁶ ) NR ³¹ R ³² , R ³¹ is hydrogen and R ³² is alkyl, wherein: the corresponding compound of formula I wherein R is CR ³ R ² , where R ¹ is hydrogen and R ² is CO-R ⁶ , is reacted with an amine of formula HNR ³¹ R ³² , where R ³¹ is hydrogen; and R ³² is an alkyl group, the product isolated and optionally converted to a salt with an inorganic or organic acid. 56. A pharmaceutical composition comprising as an active ingredient at least one compound 219 of the formula I as claimed in claims 1 to 11