BG107056A - Azetidine derivativs, preparation thereof and pharmaceutical compositions contaning same - Google Patents

Abstract

The invention concerns a compound of formula wherein R represents a CR1R2 radical, C=C(R5)SO2R6 or C=C(R7)SO2alk, their preparation and pharmaceutical compositions containing them. 56 claims

Description

The present invention relates to derivatives of the formula:

(I) their salts, their preparation and the medicines containing them.

In formula (I),

R represents the radical CR] R ₂ , C = C (R ₅ ) SO ₂ R ₆ or C = C (R ₇ ) SO ₂ alk, where R _x represents a hydrogen atom and R ₂ represents the radical -C (R ₈ ) (R ₉ ) (R ₁₀ ), -C (R ₈ ) (R _u ) (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) (P _b ) (alkyl), -C (= NOaAk) R ₆ , -C (= NO-CH ₂ -CH = CH ₂ ) R ₆ , -CH ₂ -CH (R ₆ ) NR ₃₁ R ₃₂ , -CH ₂ -C (= NOaAk) R ₆ , -CH (R ₆ ) NR ₃₁ R ₃₂ ,

-CH (R ₆ ) NHSO ₂ aAk, -CH (R ₆ ) NHCONHaAk or -CH (R ₆ ) NHCOaAk, wherein R 1 represents an alkyl radical, NH-R ₁₅ , cyano, -S-aAk-NR ₁₆ R ₁₇ ,

-CH ₂ -NR ₁₈ R ₁₉ , or -NR ₂₀ R _{21 in} R ₂ represents a radical

-C (R ₈ ) (R _n ) (R ₁₂ ),

R ₃ and R ₄ , the same or different, represent an alkyl radical or cycloalkyl, an aromatic radical selected from phenyl, naphthyl or indenyl, these aromatic radicals being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalkyl, -CONR ₂₂ R _23, -CO-NH-NR ₂₄ R _25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -aAk-NR ₂₄ R25; such as heteroaromatic radical is selected from the rings benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3ς * dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolin, isoquinolin , thiazolyl, thienyl, these heteroaromatic radicals may be unsubstituted or substituted by one or more halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR ₂₄ R ₂₅ , -CONR ^ R ^, -aAk-NR ₂₄ R _25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, and kilsulfanilalkil, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxy

R ₅ represents a hydrogen atom or an alkyl radical,

R ₆ represents the radical Ar or Het,

R ₇ represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical optionally substituted by the radical -CSOphenyl,

R ₈ represents a hydrogen atom or an alkyl radical,

R ₉ represents the radical -CO-NR ₂₆ R ₂₇ , -COOH, -COOalk, -CH ₂ OH, -NH-CO-NH-alkyl, -CH ₂ -NHR ₂₈ or -NHCOOalk,

R ₁₀ represents the radical Ar or Het,

R 11 represents the radical -SO ₂ -alk, -SO ₂ -Ar, -SO ₂ -Het,

R ₁₂ represents a hydrogen atom or the radical Ar or Het,

R ₁₃ represents a hydrogen atom or an alkyl radical

R ₁₄ represents the radical Ar, Het, -alk-Ar or -alk-Het,

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

R ₁₆ and R ₁₇ , the same or different, represent a hydrogen atom or an alkyl radical, or else R ₁₆ and R ₁₇ form together with the nitrogen atom to which a mono or bicyclic unsaturated or saturated heterocycle having 3 to 10 chains and optionally containing one or more other heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals,

R ₁₈ represents a hydrogen atom or an alkyl radical,

R ₁₉ represents a hydrogen atom or an alkyl radical, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO ₂ alk, -CO-NHalk or COOalk, or R ₁₈ and R ₁₉ form a single atom or a bicyclic unsaturated or saturated heterocycle attached to the basket. having 3 to 10 chain units and optionally containing one or more other heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals,

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

R ₂₂ and, identical or different, represent a hydrogen atom or an alkyl radical or else R ₂₂ and R ₂₃ form together with the nitrogen atom to which a mono or bicyclic saturated heterocycle having 3 to 10 chain units is attached, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals,

R ₂₄ and R 4, the same or different, represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl, or else R ₂₄ and R ₂₅ form together with the nitrogen atom to which one is attached a mono or bicyclic saturated or unsaturated heterocycle having 3 to 10 chain units, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk, -CO-NH ₂ ,

R ₂₆ and R ₂₇ , the same or different, represent a hydrogen atom or an alkyl radical, hydroxyalkyl, cycloalkylalkyl, -alk-COOalk, -alk-Ar-, alk-Het, Het, -alk-N (alk) ₂ , R ₂₆ and R ₂₇ may also form it with the nitrogen atom to which are attached a mono or bicyclic saturated or unsaturated heterocycle having 3 to 10 chain units and optionally containing one or more other heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, alkoxy, halogen,

R ₂₈ represents a radical such as -CH ₂ -alk, benzyl, -SO ₂ alk, -CONHalk, -COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, -CO- (CH ₂ ) _n OH, n is equal to 1, 2 or 3,

R _{29 and} R ₃₀ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₂₉ and R ₃₀ form together with the nitrogen atom to which a mono or bicyclic saturated heterocycle having 3 to 10 chain units is optionally attached, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals,

R ₃₁ and R ₃₂ , identical or different, represent a hydrogen atom or an alkyl radical, Ar or -alk-Ar, or else R ₃₁ and R ₃₂ form together with the nitrogen atom to which a heterocycle selected from aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl is attached , alk represents an alkyl radical or alkylene,

Ar represents a phenyl or naphthyl radical optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR ^ R ^,

-CO-NH-NR ^ R ^ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, -aAk-NR ^ R ^, -NR ₂₄ R ₂ 5 ₅ alkylthioalkyl, formyl, hydroxyl, CF _3, OCF ₃ , Het, -O-alkyl-1H-cycloalkyl or SO ₂ NH ₂ ,

Het is a mono or bicyclic unsaturated or saturated heterocycle having 3 to 10 chain units and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted by one or more halogen, alkyl, alkoxy, alkoxycarbonyl, -CONR ₂₂ R ₂₃ , hydroxy, hydroxyalkyl, oxo or SO ₂ NH ₂ .

In the foregoing definitions and those which follow, unless otherwise noted, the alkyl and alkylene radicals and moieties and alkoxy radicals and moieties are straight or branched and contain from 1 to 6 carbon atoms, cycloalkyl radicals contain from 3 to 10 carbon atoms and heterocycloalkyl and heterocyclenyl radicals contain 3 to 10 carbon atoms.

Among the alkyl radicals are the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tertiary-butyl, pentyl, hexyl radicals. Among the alkoxy radicals may be cited the radicals methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tertiarybutoxy, pentyloxy.

Among the cycloalkyl radicals may be mentioned the radicals cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

Heterocycloalkyl radicals are cycloalkyl radicals whose at least one of the carbon atoms is substituted by a heteroatom selected from nitrogen, sulfur and oxygen. Among them may be cited pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl rings.

Heterocyclenyl radicals are cycloalkyl radicals whose at least one carbon atom is substituted by one heteroatom selected from oxygen, sulfur and nitrogen, and which contain at least one double carbon-carbon or carbon-nitrogen bond. Rings may be cited between heterocyclenyl radicals

1,2,3,4-tetrahydro-pyridinyl, 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-pyrazolinyl, 3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl. 3,6-dihydropyridyl rings are preferred.

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

Among the Het heterocycles represented, the following heterocycles may be cited: benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3dihydrobenzothienyl, furyl, indolinyl, indolyl, isochromol, pyrrolidine, pyrrolidinyl, isochromidine, quinolyl, 1,2,3,4tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl, thienyl.

When R ₃ and / or R ₄ represent independently substituted phenyl, it is preferably mono, di or trisubstituted.

When R ₁₆ and R ₁₇ form together with the nitrogen atom to which a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 chain units is attached, it is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring .

When R ₁₈ and R ₁₉ form together with the nitrogen atom to which a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 chain units is attached, it 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 imidazolyl ring.

When R ₂₂ and R ₂₃ form together with the nitrogen atom to which a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 chain units is attached, it is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring .

When R ₂₄ and together with the nitrogen atom to which are attached a mono or bicyclic, saturated or unsaturated heterocycle having from 3 to 10 chain units is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.

When R ₂₆ and R ₂₇ form together with the nitrogen atom to which a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 chain units is attached, it is preferably to be azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring .

When R ₂₉ and R ₃₀ form together with the nitrogen atom to which a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 chain units is attached, it is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring .

When R ₃₁ and R ₃₂ form together with the nitrogen atom to which a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 chain units is attached, it is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring .

In a preferred way,

R represents the radical CR, R ₂ , wherein R _t represents a hydrogen atom and R ₂ represents the radical C -C (R ₈ ) (R ') (R ₁₂ ) or -C (R ₈ ) (R ₉ ) (R ₁₀ ) _; where R ₁ represents an alkyl radical and R 1 represents the radical -C (R ₈ ) (R _n ) (R ₁₂ ),

R ₃ and R ₄ , identical or different, represent phenyl, unsubstituted or substituted by one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ₂₂ R ₂₃ , hydroxyalkyl or -aivk-NR 4 R 4; the heteroaromatic radical being selected from the ring pyridyl, pyrimidine / ι, thiazolyl, thienyl, these heteroaromatic radicals may be unsubstituted or substituted by one or more halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethoxy

-CONR22R23, -aAk-NR ₂₄ R ₂₅ , or hydroxyalkyl,

R ₈ represents a hydrogen atom,

R ₉ represents the radical -CO-NR _2ft R ₂₇ , -COOalk, -CH ₂ OH, -NH-CO-NH-alk, -CH ₂ -NHR ₂₈ or -NHCOOalk,

R _lo represents the radical Ar or Het,

R _n represents the radical -SO ₂ -alk, -SO ₂ -Ar, -SO ₂ -Het,

R ₁₂ represents a hydrogen atom or a radical Ar or Het

R ₂₂ and R ₂₃ , the same or different, represent a hydrogen atom or an alkyl radical, or else R ₂₂ and R 23 form together with the nitrogen atom to which a mono or bicyclic saturated heterocycle having 3 to 10 units of Chains is attached, optionally containing another a heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals,

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

Ar represents a phenyl or naphthyl radical optionally substituted by 1 or 2 substituents selected from halogen, alkyl, alkoxy, -COalk, cyano, -COOalk, -CONR ^ R ^, alkylsulfonyl, hydroxyalkyl, -alkNR ₂₄ R25, -NR ^ R ^, hydroxy, CF ₃ , OCF ₃ , -O-alkyl-NH-cycloalkyl or are ₂ nh ₂ ,

Het represents 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 presented in the form of enantiomers and diastereomers. These optical isomers and mixtures thereof are part of the invention.

Compounds of formula (I) for which R represents the radical CR ₁ R ₂ in which R 1 represents a hydrogen atom and R ₂ represents a radical C (R ₈ ) (R _n ) (R ₁₂ ) in which R ₈ represents a hydrogen atom, R _n represents the radical -SO ₂ -Ar, -SO ₂ -Het or -SO ₂ alk and R ₁₂ represents a hydrogen atom or the radical Ar or Het and the compounds of formula (I) for which R represents the radical C = C (R _s ) SO ₂ R ₆ or C = C (R ₇ ) SO ₂ alk, may be prepared according to the following reaction scheme:

Ra-SO, CH ₂ Rb +

Ra-SO ₂ -CH, -Si (CH ₃ ),

Mr Rücker

COOCH = CH \

in these formulas, Ra represents an alkyl radical, Het or Ar and Rb represents a hydrogen atom or a radical Ar or Het, Ra represents a radical Ar or Het and Rb represents a hydrogen atom or an alkyl radical, Ra represents an alkyl radical and Rb represents a cycloalkyl, heterocycloalkyl radical, or heterocyclenyl optionally substituted by the radical -CSO-phenyl, Rc represents a hydrogen atom or an acetyl radical, R ₃ , R ₄ , Ar and Het have the same meanings as in formula (I).

Reactions d and e cannot be used when R b is a hydrogen atom.

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

The dehydration reaction b is generally carried out by all the dehydration methods known to one of skill in the art, allowing an alcohol dehydrator to obtain the corresponding alkene. Preferably, the acetyloxy derivative is obtained by treatment with acetyl chloride in the presence of an inert solvent such as pyridine, tetrahydrofuran, dioxane, a chlorinated solvent (eg dichloromethane, chloroform), at a temperature included between 5 ° C and 20 ° C, and then treated with a base such as an alkali metal hydroxide (e.g. sodium), an alkali metal carbonate (e.g. sodium or potassium carbonate), an amine such as trialkylamine (e.g. triethylamine), 4-dimethylaminopyridine, diazo-1,8-bicyclo [5.4.0] undecene- 7, at a temperature switched on between

U ° C u the boiling point of the reaction medium. The acetyloxy intermediate may be isolated or uninsulated. The acetyloxy intermediate can also be prepared directly in the reaction medium of reaction a.

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

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

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

The reaction f is usually carried out in the presence of a chlorinated solvent (e.g. dichloromethane, chloroform) at a temperature of 0 ° C to the reflux temperature of the reaction medium.

Hydrolysis g is carried out in the presence of an inert solvent such as ether (eg dioxane), via hydrochloric acid, at a temperature close to 20 ° C.

Reactions h and j are carried out in the presence of an inert solvent such as acetonitrile, in the presence of an alkaline substance such as an alkali metal carbonate (e.g. potassium carbonate), at the reflux temperature of the reaction medium.

Reaction i is carried out under an atmosphere of hydrogen, in the presence of a catalyst such as palladium or its derivatives, in the presence of an inert solvent such as methanol or ethanol, at a temperature between 15 ° C and 60 ° C.

Reaction k is carried out in the presence of an inert solvent such as a chlorinated solvent (e.g. dichloromethane, chloroform) at a temperature included between 0 ° C and the reflux temperature of the reaction mixture.

The R ₃ CH (Br) R ₄ derivatives are commercialized or can be obtained by applying or adapting the method described by BACHMANN WE, J. Am. Chem. Soc., 2135 (1933). Typically, alcohol corresponding to R ₃ CHOHR ₄ is brominated via hydrobromic acid, in the presence of acetic acid, at a temperature included between 0 ° C and the reflux temperature of the reaction medium.

The alcohols corresponding to R ₃ CHOHR ₄ are commercialized or can be obtained by applying or adapting the method described by PLASZ AC. et al., J. Chem. Soc. Chem. Comm., 527 (1972).

The intermediates of formula 2 can be prepared by applying or adapting the methods described in the examples. Namely, it works according to the following reaction schemes:

Rb-CH ₂ -Hal RaSNa __________ Rb-CH ₂ -S-Ra a ✓ Ra-SOjNa ⁴ yoxydation Rb-CH ₂ -SO ₂ -Ra 2

RaSH

RaNH ₂ isoamyinitrite MeSSMe d

g! CH.

RaSCH, __θ_ r “cBuLi ^T MeSSO-Me

4.

RaSO, CH,

RaHal in these formulas Hal represents a halogen atom and preferably chlorine, bromine or iodine, Ra and Rb having the same designations as previously mentioned for by-product 2.

Reaction a is typically carried out in the presence of an inert solvent such as dimethylformamide or aliphatic alcohol 14C, at a temperature included between 20 ° C and 30 ° C.

Reactions b and e were performed by all known methods allowing the oxidation of a sulfur derivative without, however, affecting the molecule, such as those described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, it is carried out by the action of an organic peroxy acid or a salt of such peroxy acid (peroxycarboxylic or peroxisulfonic acids, namely peroxybenzoic acid, 3chloperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyline, trifluoroperoxyacetic acid, trifluoroperoxyphenyl) a salt of such an acid (for example periodic or persulfuric acid) in the presence of an inert solvent such as a chlorinated solvent (e.g., x chloroform, dichloromethane) at a temperature of between 0 and 25 ° C. Hydrogen peroxide may also be used, optionally in the presence of metal oxide (sodium tungstate) or periodate (e.g., sodium periodate), in the presence of an inert solvent such as aliphatic alcohol 1-4C (e.g., methanol, ethanol) acetic acid, water or a mixture of these solvents at a temperature between 0 and 60 ° C. It is also possible to operate by tertiobutylhydrocress in the presence of titanium tetraisopropylate in the presence of aliphatic alcohol 1-4C (e.g. methanol, ethanol) or a mixture of water-alcohol at a temperature close to 25 ° C or by oxone ^K (potassium peroxymonosulfate), in the presence of aliphatic alcohol 1-4C (eg, methanol, ethanol), in the presence of water, acetic acid or sulfuric acid, at a temperature close to 20 ° C.

The reaction c is carried out in the presence of an inert solvent such as aliphatic alcohol 1-4C (e.g. methanol, ethanol) at a temperature included between 20 ° C and the reflux temperature of the reaction medium.

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

The reaction f is usually carried out in the presence of an inert solvent such as tetrahydrofuran or aliphatic ether (eg, ethyl ether) at a temperature close to -70 ° C.

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

The derivatives of formula Rb-CH ₂ -Hal are commercialized or can be obtained by applying or adapting the methods described in the examples. In particular, the methylated derivative or the corresponding alcohol is halogenated by means of a halogenating substance, such as hydrobromic acid, in the presence of acetic acid, at a spray temperature of up to 20 ° C, or N-bromo or N-chlorosuccinimide in the presence of benzoyl peroxide, in the presence of an inert solvent such as tetrachloromethane at the reflux temperature of the reaction medium. The methylated derivatives or the corresponding alcohols are commercialized or can be prepared according to the methods described by BRINE GA et al., J.

SS Heterocyl. Chem. 26, 677 (1989) and NAGARATHNAM D., Synthesis, 8, 743 (1992) and in the Examples.

The azetidinones of formula 3 can be prepared by the application or adaptation of the methods described by KATRTTZKY A. R. et al., J. Heterocyl. Chem., 271 (1994), or DAVE P.R., J. Org. Chem., 61, 5453 (1996) and in the Examples. Usually the following reaction scheme is used:

A —--------------->.

HYDROXYLAMINE

c i

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, it is preferable to operate in the presence of an inert solvent such as an aliphatic alcohol 1-4C (e.g. ethanol, methanol), optionally in the presence of an alkali metal hydroxide at the reflux temperature of the reaction medium.

In step B, the reduction is usually effected, by means of lithium and aluminum hydride, in the presence of tetrahydrofuran at the reflux temperature of the reaction medium.

In eman C, preferably 8 is the presence of an inert solvent such as aliphatic alcohol 1-4C (e.g. ethanol, methanol), in the presence of sodium hydrogen carbonate, at a temperature included between 20 ° C and the reflux temperature of the reaction medium.

In step D, it is oxidized, preferably in the presence of DMSO, by the sulfur pyridine complex at a temperature close to 20 ° C or by dimethyl sulfoxide in the presence of oxalyl chloride and triethylamine at a temperature between -70 and -50 °. S.

In step E, work is done according to the method described by GRISAR M. et ifll. in

J. Med. Chem., 885 (1973). A magnesium brominated derivative is formed and then reacted with nitrile in the presence of an ether such as ethyl ether at a temperature between 0 ° C and the reflux temperature of the reaction medium. After hydrolysis with alcohol, the intermediate imine is reduced in sieve with sodium borohydride at a temperature between 0 ° C and the reflux temperature of the reaction medium.

The R ₃ -CO-R ₄ derivatives are commercialized or can be obtained by applying or adapting the methods described by KUNDER NG et coll. J. Chem. Soc. Perkin Trans 1, 2815 (1997); MORENO-MARRAS M., Eur. J. Med. Chem. 23 (5) 477 (1988); SKINNER et al., J. Med. Chem., 14 (6) 546 (1971); HURN NK, Tet. Lett., 36 (52) 9453 (1995); MEDICI A et coll., Tet. Lett., 24 (28) 2901 (1983); RIECKE RD et al., J. Org Chem., 62 (20) 6921 (1997); KNABE J. et coll., Arch. Pharm., 306 (9) 648 (1973); CONSONNI R. et coll., J. Chem. Soc. Perkin Trans 1,1809 (1996); FR-96-2481 et JP-94-261393.

The R ₃ Br derivatives are commercialized or can be obtained by applying or adapting the methods described by BRANDSMA L. et coll., Synth. Comm., 20 (11) 1697 et 3153 (1990); LEMAIRE M. et coll., Synth. Comm., 24 (1) 95 (1994); H. et al., Synthesis, 9 849 (1992); BAEUERLE P. et al., J. Chem. Soc. Perkin Trans 2, 489 (1993).

The R ₄ CN derivatives are commercialized or can be obtained by applying or adapting the methods described by BOUYSSOU P. et coll., J. Het. Chem., 29 (4) 895 (1992); SUZUKI N. et al., J. Chem. Soc. Chem. comm., 1523 (1984); MARBURG S. et al., J. Het. Chem., 17 1333 (1980); PERCEC V. et coll, J. Org. Chem., 60 (21) 6895 (1995).

The compounds of formula (I) for which R represents the radical CR ₁ R ₂ in which R _t represents a hydrogen atom and R ₂ represents the radical C (R ₈ ) (R ₉ ) (R ₁₀ ) in which R ₈ represents a hydrogen atom, R ₉ represents the radical -CO-NR ₂₆ R ₂₇ , -COOH, -COOalk, -CH ₂ OH, -NHCOOalk or -NH-CO-NH-alk, and R ₁₀ represents the radical Ar or Het can be prepared according to the following reaction scheme:

+ R, _o —CH ₂ --COOalk

R.

R, 0

N

COOH

akNH

HOalk

NH-COOa! K \ ^ NH-CO \ ig ^Ri 2

R-10 lh in these formulas R ₃ , R 4, R m, R ₂₆ and R 27 have the same meanings as in formula (I) and alkyl represents an alkyl radical.

The derivatives of formula 4 are commercialized or can be obtained by esterification of the corresponding acids, optionally in an active form such as acid chloride. The acids are commercialized or can be obtained starting from the corresponding methylated derivatives according to the method described by JP. HANSEN et al., J. HeteocycL, 10, 711 (1973).

Reaction a is usually carried out in the presence of an inert solvent such as ether (e.g. tetrahydrofuran), in the presence of a strong base such as tert-butyl spy, n-butyllithium, lithium diisopropylamide, potassium tert-butylate, at a temperature included between -70 ° C and -4 ° C.

Reaction b is generally carried out by all the dehydration methods known to one of skill in the art, allowing alcohol as the dehydrator to obtain the corresponding alkene, namely the methods described previously.

The reduction with is usually carried out in the presence of an inert solvent such as aliphatic alcohol (1-4C) 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 included between 0 ° C and reflux temperature. of the reaction medium.

Reaction d is carried out by any method known to one of skill in the art, allowing the acid ester to pass accordingly without affecting the molecule. Preferably, it is carried out in the presence of an inert solvent such as dioxane, in the presence of hydrochloric acid, at the reflux temperature of the reaction medium.

The reaction is carried out by any method known to one of skill in the art, allowing the passage of an acid or a reactive derivative of that acid with carboxamide without interfering with the molecule. Preferably, when acid is employed, it is operated in the presence of a condensing agent used in peptide chemistry, such as carbodiimide (e.g., Ν, Ν'-dicyclohexylcarbodiimide) or Ν, Νdiimidazole carbonyl, in an inert solvent such as ether (e.g. tetrahydrofuran). dioxane), amide (dimethylformamide) or chlorinated solvent (eg methylene chloride, dichloro-1,2 ethane, chloroform) at a temperature included between 0 ° C and the reflux temperature of the reaction mixture. When an acid derivative is used, it may be possible to react with an anhydride, anhydride mixture or an ester (which may be selected from activated esters or may not be acid); then working in an organic medium, optionally in the presence of an acid acceptor such as a nitrous organic base (e.g., trialkylamine, pyridine, diaz-1,8 bicyclo [5.4.0] undecene-7 or diaz-1,5 bicyclo [43.0] nonene -5), in a solvent such as that cited above, or a mixture of these solvents, at a temperature included between 0 ° C and the reflux temperature of the reaction mixture, in biphasic organic medium in the presence of an alkaline or alkaline earth base (soda, potash ) or alkaline or alkaline earth metal carbonate or bicarbonate at a temperature of incl ene between 0 and 40 ° C.

Reaction f was carried out by regrouping CURTIUS in the presence of diphenylphosphorazide and triethylamine in the presence of toluene at a temperature close to 50 ° C.

For the reactions g and h, direct β is the presence of the reaction medium from step g at a temperature close to 20 ° C.

The compounds of formula (I), for which R represents a radical CR ^ in which R ₃ is a hydrogen atom and R ₂ represents a radical -C (R ₈₎ (R ₉₎ (R ₁₀₎ in which R ₈ is a hydrogen atom, Rg is the radical -CH ₂ -NHR ₂₈ , and R ₁₀ represents the radical Ar or Het, can be prepared according to the following reaction scheme:

fl * ·

--- N HOHL Rd ^ 10 Ii

In these formulas, R ₃ , R ₄ and R ₁₀ have the same meanings as in formula (I), Rd represents an alkyl or phenyl radical, R e represents an alkyl radical, R f represents an alkyl radical, R g represents an alkyl radical, cycloalkylalkyl, cycloalkyl, - ( CH ₂ ) _n OH, n is equal to 1,2,3.

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

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

The step c is usually carried out in the presence of an inert solvent such as tetrahydrofuran, dimethylformamide, chlorinated solvent (eg chloroform, dichloro-1,2 ethane), an aromatic solvent (eg benzene, toluene) at a temperature of between 10 ° C and a reflux temperature. the reaction medium.

Step d is performed by all methods known to one of skill in the art, allowing the passage of an acid or a reactive derivative of that acid with carboxamide without interfering with the molecule, and most preferably the methods described previously.

Derivatives 6 can be prepared by the following reaction scheme:

In these formulas, R ₃ , R 4 and R ₁₀ have the same meanings as in formula (I) and Ms is a methylsulfonyloxy radical.

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

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

Compounds of formula (I) in which R represents the radical CR 1 in which R x is a hydrogen atom and R ₂ is a radical -CONR ₁₃ R ₁₄ can be obtained by the following reaction scheme:

r * 28

Im

CONHRi ₃ R ₁₄ ^R 13 ^R 14 ^NH d

c

EtOCH ₂ CH ₂ OH

N- \ COOH

In these formulas, R ₃ , R 4, R ₁₃ and R ₁₄ have the same meanings as in formula (I) and Ms represents a methylsulfonyloxy radical and Et represents ethyl.

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

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

The step c is carried out by all methods known to one of skill in the art, allowing cyanic acid to pass through without affecting the molecule. Preferably, it is run by potash in the presence of aliphatic alcohol (1-4C) (eg ethanol) or in an aqueous medium at the reflux temperature of the reaction medium.

Eman dee performs all methods known to one of ordinary skill in the art, allowing the passage of an acid or a reactive derivative of that acid with carboxamide without affecting the molecule, and in particular the preferred methods described previously.

Compounds of formula (I) for which R represents the radical CR 1 R ₂ in which R 1 is a hydrogen atom and R ₂ is a radical -CH ₂ -CONR ₁₃ R ₁₄ can be prepared by the following reaction scheme:

R. r ₄

R.

r ₄

EtOOC-PO (OEt) ₂

R,

r ₄

N--

X ^ CoD

R ₁₃ R. ₄ NH ^R 3

R.

r ₄

with coos ₂ n ₅

- \ / CONR ₁₃ R ₁₄

In

UNC

In these formulas, R ₃ , R ₄ , R ₁₃ and R ₁₄ have the same meanings as in formula (I) and Et represents an ethyl radical.

Reaction a is generally carried out in the presence of an inert solvent such as tetrahydrofuran, in the presence of an alkaline substance such as sodium hydride or an alkali metal carbonate (e.g., potassium carbonate), at a temperature included between 20 ° C and the reflux temperature of the reaction medium.

Reaction b is usually carried out by NaBH ₄ , in the presence of ethanol, at a temperature close to 0 ° C.

The reaction with is carried out by all methods known to one skilled in the art, allowing it to pass through an acid ester accordingly without affecting the molecule. It is preferably operated in the presence of an inert solvent such as dioxane, in the presence of hydrochloric acid, at the reflux temperature of the reaction medium.

. **> Reaction d is performed by all methods known to the skilled person

Ng from the range allowing it to pass through an acid or a reactive derivative of that acid with carboxamide without affecting the molecule, and it is the preferred methods described previously.

Intermediates 7 can also be prepared by malone synthesis according to the following reaction scheme:

R.

OMs

R.

* 4

R.

cooc ₂ h _e r ₄

Coon

COOC ₂ H ₅

In these formulas, Ms represents a methylsulfonyloxy radical, R ₃ and R ₄ having the same meanings as in formula (I).

Reaction a is generally carried out by treatment with diethylmalonate in the presence of an inert solvent such as tetrahydrofuran, in the presence of freshly prepared sodium ethylate, at the reflux temperature of the reaction medium.

Reaction b is typically carried out in aqueous hydrochloric acid at the reflux temperature of the reaction medium.

The In compounds can also be prepared by the following reaction scheme:

hnr, ₃ r ₁₄

PO (OC ₂ H ₅ ) ₂ -CH ₂ COOH ------ ► PO (OC ₂ H ₅ ) ₂ -CH ₂ CONR ₁₃ R "

\ ^ conr _{) 3} r ₁₄ --- 4 ^ CONR, ₃ R, ₄

In

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 one of skill in the art, permitting it to pass through an acid or a reactive derivative of that acid with carboxamide without affecting the molecule, namely the preferred methods described previously.

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

The reduction in step c is usually carried out by NaBH ₄ in the presence of ethanol at a temperature close to 20 ° C.

Compounds of formula (I) for which R represents the radical CR _X R ₂ in which R ₃ is a hydrogen atom and R ₂ is a radical -SOR 6 or -SO ₂ R ₆ can be prepared by the following reaction scheme:

1o

In these formulas, R ₃ , R ₄ , and R ₆ have the same meanings as in formula (I) and Ms is a methylsulfonyloxy radical.

Step a is typically carried out in an inert solvent such as tetrahydrofuran in the presence of an inorganic alkaline substance such as sodium hydride, at a temperature of between 0 ° C and the reflux temperature of the reaction medium.

Step b was performed by All methods for oxidizing a sulfur derivative by a person skilled in the art, such as those described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252263 (1990). For example, it works by acting with an organic peroxy acid or a salt of such peroxy acid (peroxycarboxylic or peroxysulfonic acids, namely peroxybenzoic acid, 3chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, trifluoroperoxyacetic acid, trifluoroperoxyacetic acid a salt of such an acid (for example periodic or persulfuric acid), in the presence of an inert solvent such as a chlorinated solvent (e.g., x chloroform, dichloromethane), at a temperature of between 0 and 25 ° C, or by oxone In the presence of a water-alcohol mixture (methanol, ethanol).

The step c is typically carried out by any method of oxidizing a sulfinyl derivative by one of ordinary skill in the art. Preferably, it is operated by Exposure to an organic peroxy acid or salt of such peroxy acid (peroxycarboxylic or peroxysulfonic acids, namely peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroacetic acid, trifluoroacetic acid, trifluoroacetic acid or by oxone in the presence of a mixture of water and alcohol (methanol, ethanol).

Compounds of formula (I) for which R represents the radical CR 1 in which R _x is a hydrogen atom and R ₂ is a radical -COR ₆ or -CO-cycloalkyl can be prepared by the following reaction scheme:

R,

R. L HXHNOCI-L —_____ Ν

I

And soon!

I \

CON (CH ₃ ) OCH ₃

fq

CORh

In these formulas, R ₃ and R ₄ have the same meanings as in formula (I) and Rh has the same meanings as R ₆ or represents a cycloalkyl radical (3 to 10 carbon atoms).

Step a is performed by all methods known to one of skill in the art, allowing the passage of an acid or a reactive derivative of that acid with carboxamide, without prejudice to the molecule, and in particular the preferred methods described previously.

Step b is typically carried out in the presence of an inert solvent such as an ether such as tetrahydrofuran at a temperature close to 0 ° C. Organomagnesium substances are prepared by methods known to one skilled in the art, such as those described in the examples.

Compounds of formula (I) for which R 1 is a hydrogen atom and R ₂ is a radical -C (OH) (R 6) (R ₁₂ ), -C (OH) ( _1-6 ) (alkyl), -C (= NO-CH ₂ -CH = CH ₂ ) R ₆ or -C (= NOalk) R ₆ can be prepared by 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 meanings as R ₁₂ or represents an alkyl radical (1 to 6 straight or branched chain carbon atoms) and R 1 represents an alkyl radical (1 to 6 straight or branched chain carbon atoms) or -CH ₂ -CH = CH ₂ .

Step a is usually carried out in the presence of an inert solvent such as an aliphatic alcohol (eg ethanol), in the presence of sodium acetate, at a temperature included between 20 ° C and the reflux temperature of the reaction medium.

Step b is typically carried out in the presence of an inert solvent such as an ether such as tetrahydrofuran at a temperature close to 0 ° C. Organomagnesium substances are prepared by methods known to one skilled in the art, such as those described in the examples.

Compounds of formula (I) for which R represents the radical CR [R ₂ in which R 1 is a hydrogen atom and R ₂ represents a radical -CH (R ₆ ) NR ₃₁ R ₃₂ in which R ₃₁ and R ₃₂ are hydrogen atoms, -CH (R ₆ ) NHSO ₂ alk, -CH (R ₆ ) NHCONHaIk or -CH (R ₆ ) NHCOR ₃₁ can be prepared by the following reaction scheme:

Λ **

ν.

H-CO-P ^

lu

Iv

NH-SO ₂ alk

NH-CO-NHalk

In these formulas, R ₃ , R ₄ , R ₆ and R ₃₁ have the same meanings as in formula (I), Ms represents a methylsulfonyloxy radical, alk represents an alkyl radical.

Reaction a is typically carried out by NaBH4, in the presence of ethanol, at a temperature close to 20 ° C.

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

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

Step d is usually carried out in the presence of an inert solvent such as a halogenated solvent (eg dichloromethane) or tetrahydrofuran, in the presence of an organic alkali substance such as triethylamine, dimethylaminopyridine, at a temperature close to 20 ° C.

The step is carried out by any method known to one of skill in the art, permitting it to pass through an acid or a reactive derivative of that acid with carboxamide, without prejudice to the molecule and precisely the preferred methods described previously.

Step f is usually carried out in the presence of an inert solvent such as tetrahydrofuran, dimethylformamide, a chlorinated solvent (eg chloroform, dichloroethane), an aromatic solvent (eg benzene, toluene) at a temperature included between 10 ° C and the reflux temperature of the reaction medium.

The compounds of formula (I) for which R represents the radical CR 1 R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical

-CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ is a hydrogen atom and R ₃₂ is an alkyl radical, Ar or -alk-Ar can be obtained by the action of the halide HalR ₃₁ on a compound of formula (I), for which R represents the radical CR ₂ , in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , 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 alkaline substance (alkali metal carbonate (e.g., sodium, potassium), trialkylamine (e.g., triethylamine, dimethylaminopyridine), between 0 ° C and the boiling point of the solvent, optionally in the presence of palladium or its salts or complexes.

Compounds of formula (I) for which R represents the radical CR) R ₂ in which R 1 is a hydrogen atom and R ₂ represents a radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ is a hydrogen atom R ₃₂ is an alkyl radical can also be obtained by the action of a compound of formula (I), respectively, for which R represents the radical CR ₍ R ₂ , wherein R 1 is a hydrogen atom and R ₂ represents the radical -CO-R ₆ on the amine HNR ₃₁ R ₃₂ for which R ₃₁ is a hydrogen atom and R ₃₂ is an alkyl radical.

This reaction is usually carried out in the presence of an inert solvent such as a chlorinated solvent (e.g. dichloromethane, 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) for which R represents the radical CR, R ₂ in which R 1 is a hydrogen atom and R ₂ represents a radical

-CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ and R ₃₂ are alkyl radicals, Ar or -alk-Ar can be obtained by the action of the halide HalR ₃₂ on a compound of formula (I), for which R represents the radical CR ] R ₂ in which R _t is a hydrogen atom and R ₂ represents a radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ is a hydrogen atom and R ₃₂ is an alkyl radical, 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 alkaline substance (alkali metal carbonate (e.g., sodium, potassium), trialkylamine (e.g., triethylamine, dimethylaminopyridine), between 0 ° C and the boiling point of the solvent, optionally in the presence of palladium or its salts or complexes.

Compounds of formula (I) for which R represents the radical CR ₁ R ₂ in which R _t is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃ i is a hydrogen atom and R ₃₂ is an alkyl radical, (26C) or -alk (2-6C) -Ar can be prepared by the action of the aldehyde RaCHO for which Ra is an alkyl radical or -alk-Ar on a compound of formula (I) for which R represents the radical CR ₁ R ₂ , in which R is a hydrogen atom and R ₂ represents a radical

-CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ and R ₃₂ are hydrogen atoms.

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

Compounds of formula (I) for which R represents the radical CR _L R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ is an alkyl radical, Ar or -alk-Ar and R ₃₂ is an alkyl radical (2-6C) or -alk (2-6C) -Ar can be prepared by the action of the aldehyde RaCHO for which Ra is an alkyl radical or -alk-Ar on a compound of formula (I) for which R represents the radical CR ₁ R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ is a hydrogen atom and R ₃₂ is an alkyl radical, Ar or -alk-Ar.

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

The compounds of formula (I) for which R represents the radical CR 1 R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ and R ₃₂ form with the nitrogen atom to which they are an attached heterocycle selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl may be prepared by the action of the halalkyl (2-5C) -Hal dihalide on a compound of formula (I) for which R represents the radical CR _t R ₂ , in which Rj is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ and

R ₃₂ is 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 alkaline substance (alkali metal carbonate (e.g., sodium, potassium), trialkylamine (e.g., triethylamine, dimethylaminopyridine), between 0 ° C and the boiling point of the solvent, optionally in the presence of palladium or its salts or complexes.

Compounds of formula (I) for which R represents the radical CR ₂ R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH ₂ COR ₆ , -CH ₂ -CH (R ₆ ) -NR ₃₁ R ₃₂ , -CH ₂ -C (= NOalk) R ₆ can be prepared by the following reaction scheme:

/ · '

Thu * '

H ₃ CHNOCH ₃

alkONH ₂

PO (OC ₂ H _s ) ₂ -CH.CON (CHj) OCH ₃

'^< 4 ^ -CO-N (CH ₃ ) OCH ₃

X ^ CO-N (CH ₃ ) OCH ₃

R ₆ MgBr

T

lx R ₆ ^{f HNR} 3, ^R 3;

In the formulas R ₃ , R ₄ , R ₆ , R ₃₁ , R ₃₂ have the same meanings as in formula (I) and alk represents an alkyl radical.

Eman a is typically carried out in the presence of a solvent such as tetrahydrofuran, at a temperature between 20 ° C and the reflux temperature of the reaction medium.

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

The step c is carried out by any method known to one of skill in the art, permitting it to pass through an acid or a reactive derivative of that acid with carboxamide, without prejudice to the molecule and precisely the preferred methods described previously.

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

The step is usually carried out in the presence of an inert solvent such as aliphatic alcohol 1-4C, such as methanol, in the presence of sodium acetate, at a temperature included between 20 ° C and the reflux temperature of the reaction medium.

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

The compounds of formula (I) for which R represents the radical CRfRj in which Rj represents a cyano radical, -S-alkyl-NR ₁₆ R ₁₇ , -NHR ₁₅ , alkyl or -NR ₂₀ R ₂₁ and R ₂ represents the radical

-C (R ₈ ) (R _n ) (R ₃₂ ) in which R ₈ is a hydrogen atom can be prepared by the following reaction scheme:

In these formulas, R ₃ , R ₄ , R _n , R ₁₂ , R _{t 5} , R ₁₆ and R ₁₇ have the same meanings as in formula (I), alk represents an alkyl radical, Hal represents a halogen atom, and M represents a metal, preferably copper .

Step a is carried out in the presence of a polar solvent such as dimethyl sulfoxide at a temperature between 20 and 50 ° C.

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

The step c is preferably carried out in the presence of an inert solvent such as dimethyl sulfoxide, tetrahydrofuran, acetonitrile, in the presence of an alkaline substance such as an alkali metal carbonate (eg potassium carbonate) or ammonium hydroxide, at a temperature included between 20 ° C and the boiling point. environment.

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

The step is preferably carried out in the presence of an inert solvent such as dimethylsulfoxide, tetrahydrofuran, acetonitrile, dichloromethane, dichloroethane, in the presence of an alkaline substance such as an alkali metal carbonate (eg potassium carbonate) or ammonium hydroxide, at a temperature of C at 40 ° C. of boiling the reaction medium.

The compounds of formula (I) for which R represents the radical CR 1 R ₂ in which R ₃ represents the radical, -alk-NR ₁₈ R ₁₉ ,

R ₁₈ and R ₁₉ represent a hydrogen atom, can be obtained by reduction of a compound of formula (I), respectively, wherein R represents the radical CR ₁ R ₂ in which R 1 represents a cyano radical.

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

The compounds of formula (I) for which R represents the radical CR 1 R ₂ in which R 1 represents the radical, -alk-NR ₁₈ R ₁₉ ,

R ₁₈ represents a hydrogen atom and R ₁₉ represents a radical alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO ₂ alk, -CO-NHalk or -COOalk, can be prepared by the action of the halide HalR ₁₉ , in which Hal represents halogen, on a compound of formula (I) for which R represents the radical CR _r R ₂ in which R 1 represents the radical -alk-NR ₁₈ R ₁₉ , wherein

R _J8 u R ₁₉ represent a hydrogen atom.

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

The compounds of formula (I) for which R represents the radical CR ₁ R ₂ in which R 1 represents the radical, -alk-NR ₁₈ R ₁₉ ,

R ₁₈ represents an alkyl radical and R ₁₉ represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO ₂ alkyl, -CO-NHalk or -COOalk radical, may be prepared by the action of an alkyl halide on a compound of formula (I) for which R? <*. represents the radical CR 1 R ₂ in which R 1 represents the radical

-alk-NR ₁₈ R ₁₉ where R ₁₈ represents a hydrogen atom and R ₁₉ represents a radical alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO ₂ alk, -CO-NHalk or -COOalk.

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

The compounds of formula (I) for which R represents the radical CR _t R ₂ in which R 1 represents a hydrogen atom and R ₂ represents the radical -C (R ₈ ) (R ₉ ) (R ₁₀ ) or -C (R ₈ ) (R _n ) (R ₁₂ ), let R _x be an alkyl radical, NH-R ₁₅ , cyano, -S-alkyl-NR ₁₆ R ₁₇ , -alk-NR ₁₈ R ₁₉ , or -NR ₂₀ R ₂₁ and R ₂ represent the radical -C (R ₈ ) (R _n ) (R ₁₂ ) and R ₈ represents an alkyl radical can be prepared by alkylating a compound of formula (I), respectively, for which R ₈ is a hydrogen atom.

This reaction is preferably carried out using an alkaline Substance such as an alkali metal hydride (e.g., sodium hydride), an alkali metal amide (e.g. sodium amide) or an organometallic derivative, in the presence of an inert solvent such as aliphatic ether (ethyl ether) or tetrahydro ether, or tetrahydro ether. at a temperature included between -78 ° C and 30 ° C by an alkylating agent such as alkyl halide or alkyl sulfonate.

Compounds of formula (I) for which R represents the radical C = C (R ₇ ) SO ₂ alk can also be prepared by the following reaction scheme:

β, -α-ι, -ρο ^

a) n-BuLi

b) S ₈

c) Hal-alk

A

'' W ''

In these formulas, R ₃ , R ₄ and R ₇ have the same meanings as in formula (I), alk represents an alkyl radical and Hal represents a halogen atom.

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

Reaction B is usually carried out in the presence of an inert solvent such as ether (e.g. tetrahydrofuran), in the presence of a strong base such as tertiary-butyllithium or n-butyllithium, at a temperature included between -70 ° C and -50 ° C, then azetidine is added -3-on, return to room temperature and hydrolyze.

Reaction C is carried out by all known methods, allowing the oxidation of a sulfur derivative without affecting the molecule, such as those described previously.

It is understood by one of ordinary skill in the art that, for the application of the methods of the invention previously described, protecting groups of amino, hydroxy and carboxy functions may be introduced if necessary to avoid secondary reactions. These groups are those which are intended to be removed without affecting the rest of the molecule. Examples of protecting groups of amino function may be cited tert-butyl or methyl carbamates which can be reduced by iodotrimethylsilane or allyl by palladium catalysts. Examples of hydroxy function protecting groups may be cited triethylsilyl, tert, butyldimethylsilyl, which can be reduced by tetrabutylammonium fluoride or asymmetric acetals (e.g. methoxymethyl, tetrahydropyranyl) by hydrochloric acid regeneration. As protecting groups for carboxy functions, esters (e.g., allyl, benzyl), oxazoles and 2-alkyl-1,3-oxazolines may be cited. Other usable protecting groups are described by GREENE T. W. et al., Protecting Groups in Organic Synthesis, second edition, 1991, Jonh Wiley & Sons.

The compounds of formula (I) can be purified by known conventional methods, for example crystallization, chromatography or extraction.

The enantiomers of the compounds of formula (I) may be obtained by cleavage of racemates, for example by chromatography on a chiral column according to PIRCKLE W. H. et al., Asymmetric synthesis, vol. 1, Academic Press (1983), either by salt formation or by synthesis starting from chiraux precursors. The diastereoisomers can be prepared according to known classical methods (crystallization, chromatography or starting from chiraux precursors).

The compounds of formula (I) may optionally be transformed into salts by the addition of inorganic or organic acid by the action of such an acid in the presence of an organic solvent such as an alcohol, ketone, ether or chlorinated solvent. These salts are also part of the invention.

Examples of pharmaceutically acceptable salts include the following salts: benzenesulfonate, bromohydrate, chlorhydrate, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene bis-p-oxynate, phosphate, salicylate, succinate, sulfate, tartrate, theophylline acetate and p-toluenesulfonate.

The compounds of formula (I) have interesting pharmacological properties. These compounds have a strong affinity for cannabinoid receptors and especially those of type CB1. These are CB1 receptor antagonists and are therefore useful in treating and preventing diseases related to the central nervous system, immune system, cardiovascular or endocrine system, respiratory system, gastrointestinal system, and reproductive disorders (Hollister , Pharm. Rev .; 38, 1986, 1-20, Reny et Sinha, Prog. Drug Res., 36, 71 -114 (1991), Consroe et Sandyk, in Marijuana / Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L and Barthe A. Eds, CRC Press, 1992).

Also, these compounds can be used to treat or prevent psychosis including schizophrenia, anxiety, depression, epilepsy, neurodegeneration, brain and spinal cord diseases, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucoma, disease , Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, involuntary-nightmares, elderly dizziness, thymic diseases, Tourette's syndrome, late dyskinesia, bipolar diseases, cancers diseases, diseases induced by medicines, gucmoHuu, endotoxD / cervical contractions, hemorrhagic shocks, hypotension, insomnia, immunological diseases, sclerotic plaques, vomiting, asthma, appetite disorders (bulemia, anemia) such as drug addiction and alcohol or drug abuse (e.g., opiates, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines), as painkillers or analgesic drugs nal and non-narcotic drugs. They can also be used to treat or prevent it by passing it through the gut.

The affinity of the compounds of formula (I) for cannabis receptors was determined according to the method described by KUSTER J. E., STEVENSON J. I., WARD S. J., D'AMBRA Τ. E., HAYCOCK D. A. in J. Pharmacol. Exp. Ther., 264 1352-1363 (1993).

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

Their antagonistic activity was demonstrated by a hypothermic model induced by a V cannabis receptor agonist (CP-55940) in a mouse according to the method described by Pertwee R.

G. in Marijuana, Harvey D.J. eds, 84 Oxford IRL Press, 263-277 (1985).

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

The compounds of formula (I) have low toxicity. Their DL ₅ o is at most 40 mg / kg by the subcutaneous route in mice.

Preferred compounds of formula (I) are the following:

(R) -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, (R8) -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, (R) -1- [bis (3-fluorophenyl) methyl] -3- [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (R) -1- [bis (3-fluoroph) enyl) 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- (K5) - {[Zazetidin-1-yl-

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

1- [bis (4-chlorophenyl) methyl] -3- (S) - {[3-azetidin-1-yl-phenyl] methylsulfonyl-methyl} azetidine, (K8) -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] pyrrolidine, (8) 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-methyl-amine,

N) - N- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] 4-methyl-amine, (S) -N- [3 - ({1 - [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] -N-methyl-amine, (R8) -1- [bis- (4-chlorophenyl) methyl] -3 - [(3 , 5-Bis-trifluoromethylphenyl) methylsulfonyl-methyl] azetidine, (R) -1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5-bis-trifluoromethylphenyl) methylsulfonyl-methyl] azepschine, (8 ) -1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5-bis-trifluoromethylphenyl) methylsulfonylmethyl] azetidine,

1- [bis- (4-chlorophenyl) methyl] 3- (phenylsulfonylmethyl) -azetidine, (R8) -1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl ] -3-methyl-azetidine, (N) N- [bis- (4-chlorophenyl) -megpyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -3-methyl-azetidine, (8) 4- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl-3-methyl-azetidine, (R) -2- {1- [6is- (4-chlorophenyl) methyl] -azetidine -3-yl} -2- (3,5-difluorophenyl) -N-cyclohexylacetamide, (N) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5- difluorophenyl), N-cyclohexylacetamide, (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluoro) Nyl) N-cyclohexylacetamide, (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-isobutylacetamide, (K) -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) N-isobutylacetamide, (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl } -2- (3,5-difluorophenyl) -N-cyclopropylmethyl acetamide, (N) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) ) N-cyclopropylmethyl acetamide, (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) N-cyclopropylmethyl acetamide, (And 8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-isopropylacetamide, (I) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) N-isopropylacetamide,

N, (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) N-isopropylacetamide, (K8) -1- [bis- (4-chlorophenyl) -methyl] -3- [1- (3,5-difluorophenyl) -1methylsulfonyl-ethyl] -azetidine, (R) -1- [bis- (4-chlorophenyl) -methyl] -3- [ 1- (3,5-difluorophenyl) -1methylsulfonyl-ethyl] -azetidine, (S) - 1- [bis- (4-chlorophenyl) -methyl] -3- [1- (3,5-difluorophenyl) -1methylsulfonyl- ethylfazetidine, (R8) -1- [bis- (4-fluoro-phenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (R) -1- [bis- (4 -fluoro-phenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (S) -1- [bis- (4-fluoro-phenyl) -methyl] -3 - [( 3,5-difluorophenyl) -methylsulf onylmethyl] -azetidine, (K8) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (88) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (II) - {1 - [(3-pyridyl) - (4- chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (SR) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] 3 - [(3,5 -difluorophenyl) methylsulfonyl-methylfazetidine, (K8) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (88) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (RR) - {1 - [(4-pyri Dil) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (S) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (K8) -5 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidine-1 -yl} -methyl) -pyrimidine, (8R) -5 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] »azetidin-1-yl} -methyl) -pyrimidine , (R) -5 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl} azetidin-1-yl} -methyl) -pyrimidine, (88) -5 - (( 4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidin-1-yl} -methyl) -pyrimidine, (88) - {1 - [(2-chloro-pyrid- 5-yl) - (4-chlorophenyl) methyl-3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (II) - {1 - [(2-chloro-pyrid-5-yl) - ( 4-chlorophenyl) methyl-3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (R) - {1 - [(2-chloro-pyrid-5-yl) - (4-chlorophenyl) methyl- 3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (S) - {1 - [(2-chloro-pyrid-5-yl) - (4-chlorophenyl) methyl-3 - [(3, 5-difluorophenyl) methylsulfonyl-methyl] -azetidine, their optical isomers and their pharmaceutically acceptable salts.

The following examples illustrate the invention.

Example 1 (S) -1- [bis (4-chlorophenyl) methyl)] -3 - [(3,5-difluorophenyl) (methylsulfonylmethyl] -azetidine, can be obtained starting from 1.0 g

1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -azetidine, in 40 cm methanol, 96 mg of sodium hydroboride are added and stirred for 3 hours at 20 ° C. After 100 cm ^{3 of} dichloromethane was added, the reaction mixture was washed twice with 50 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The crude material is chromatographed on a silica gel column (particle size 0,063 - 0,200 mm, height 6 cm, diameter 3 cm) eluting under pressure of 0.8 bar from argon with dichloromethane then with a mixture of dichloromethane + 1% methanol and collecting fractions of 80 Article ³ . Fractions 13 to 15 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.55 g of a white solid are obtained, which is recovered with 50 cm ^{3 of} isopropyl ether, filtered and dried to give 0.47 g (RS) -1- [6uc (4chlorophenyl) methyl)] - 3- [(3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine as a white solid [RMN 1 H spectrum (400 MHz, (CD ₃ ) ₂ SO d6 with a few drops of CD ₃ COOD d4, at 353 K , δ at ppm): 2.46 (t, J = 7.5 Hz: 1H); 2.77 (s: 3H);

3.15 (mt: 2H); 3.40 (mt: 1H); 3.49 (t width, J = 7.5 Hz: 1H); 4.46 (s: 1H);

4.81 (d, J = 9 Hz: 1H); om 7.05 go 7.20 (mt: 3H); om 7.15 to 7.45 (mt: 8H)].

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

Method 1

To a solution of 2.94 g of 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methyl- (S)] azetidin-3-ol in 250 cm dichloromethane at 22 ° C. 0.65 cm ^{3 of} methylsulfonyl chloride are then added, then in small portions for 15 minutes, 2.42 g of 4-dimethylamino pyridine; The orange solution was stirred for 2 hours at room temperature. The reaction mixture was washed 3 times with 150 cm ^{3 of} distilled water and once with 150 cm ^{3 of} saturated sodium chloride solution, then dried with magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue was chromatographed on a silica gel column (particle size 0.04 - 0.06 mm, height 15 cm, diameter 5.5 cm) under pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (1/9 in volumes ), eluting with fractions of 70 cm ³ . Fractions 15 to 36 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 1.86 g of product are obtained in the form of a white kiss which crystallizes in isopropyl ether to give a solid melting at 190 ° C. Crystallization in 45 cm ^{3 of} ethanol gave 1.08 g of 1- [bis (4-chlorophenyl) methyl)] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] -azetidine melting at 206 ° C. [RMN spectrum in DMSO-d6, T = 300 K, δ in ppm (300 MHz): 3.00 (3H, s, SCH ₃ ), 3.87 (2H, s, NCH ₂ ), 4.20 (2H , s, NCH ₂ ), 4.75 (1H, s, NCH), 7.15 (2H, d, J = 8 Hz, 2CH aromatic), 7.30 (5H, m, 5CH aromatic), 7.45 (4H, d, J = 7 Hz, 4CH aromatic)].

To a solution of 6.8 g of bis (4-chlorophenyl) bromomethane 6 300 cm of acetonitrile, 6.75 g of 3 - ((3,5 difluorophenyl) (methylsulfonyl) methyl- (K8)] azetidin-3-ol are added. then 2.97 g of potassium carbonate The reaction mixture is heated to reflux for 1 hour, cooled to room temperature, filtered and concentrated to dryness under reduced pressure (2.7 kPa) .The resulting residue is chromatographed on a silica gel column. (granulometry 0.04 - 0.06 mm, height 22 cm, diameter 8.5 cm), pressurized 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 in volumes), eluting and fractions of 250 ppm were collected. Fractions 11 to 48 were combined, then concentrated to dryness under reduced pressure (2.7 kPa) to give 5.3 g of 1- [bis (4chlorophenyl) methyl] -3 - [( 3,5-difluorophenyl) (methylsulfonyl) methyl (RS)] 3emuguH-3-OA [RMN 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 = 9 Hz: 1H); 4.54 (s: 1H); 5.34 (s: 1H); 7.15 (d, J = 8.5 Hz: 2H); om 7.20 to 7.40 (mt: 8H); 7.50 (t width, J = 9 Hz: 1H)].

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

The hydrochloride of 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl (RS)] a3emuguH-3-OA can be obtained as follows: to a solution of 37 g of 3 - [(3,5-difluorophenyl) (methylsulfonyl) ) methyl- (1S)] -1 (vinyloxy-carbonyl) azetidin-3-ol in 160 cm ³ dioxane add 160 cm ^{3 of} 6.2N hydrochloric acid solution in dioxane. After 16 hours at room temperature, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue was extracted with 320 cm ^{3 of} ethanol, refluxed for 1 hour and cooled in an ice-water bath. The solid was filtered off, washed with ethyl ether and dried at 40 ° C under reduced pressure (2.7 kPa). 29.85 g of white crystals having a melting point above 260 ° C are obtained.

3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (S)] - 1- (vinyloxycarbonyl) azetidin-3-ol can be obtained as follows: to a solution of 60.18 g of 1-benzhydryl-3 - [(3,5difluorophenyl) (methylsulfonyl) methyl- (K8)] azetidin-3-ol in 1000 cm dichloromethane was added at 5 ° C a solution of 14 cm ³ vinyl chloroformate in 35 cm ³ dichloromethane. After 20 hours at room temperature, the reaction mixture was 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, height 32 cm, diameter 11 cm), under pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (3/7 in volumes). eluting and collecting fractions of 1000 cm ³ . fractions 8 to 18 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 37 g of 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (S)] -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)] 3emuguH-3-OA can be prepared as follows: to a solution of 6.73 cm diisopropylamine in 110 cm tetrahydrofuran, under atmosphere of argon, at cooling to -70 ° C, 29.5 cm ³ was added

1.6 N solution of p-butyllithium in hexane. After 30 minutes, a mixture of 8.7 g of 3,5-difluorobenzyl methyl sulfone in 200 cm те of tetrahydrofuran was added and stirring was maintained for 45 minutes at -70 ° C. 10 g of 1-benzhydryl azetidin-3-one dissolved in 60 cm @ 3 of tetrahydrofuran were added, then stirred for 20 minutes, allowing the mixture to return to room temperature. The reaction mixture was hydrolyzed with 400 cm ^{3 of} saturated ammonium chloride solution, extracted with dichloromethane, washed 3 times with 500 cm 3 of water, then with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). The residue (19 g) was recovered with isopropyl ether in which it crystallized. Filtration and drying afforded 15.35 g of 1-benzhydryl-3 - [(3,5difluorophenyl) (methylsulfonyl) methyl- (II.5)] azetidin-3-ol as white crystals.

1-Benzhydryl azetidin-3-one can be prepared according to the method of operation described by KATRITZKY A.R. et coll, dans J. Heterocycl. Chem., 271 (1994).

3,5-difluorobenzyl methyl sulfone can be prepared as follows: starting from 33.46 g of 3,5-difluorobenzyl methyl sulfide in 318 cm 3 of water, 318 cm of acetic acid and 318 cm of ethanol, at 5 C 129 were added. 9 g of oxon ^K. After 16 hours at room temperature, the reaction mixture was diluted with dichloromethane, washed with water and saturated sodium chloride solution, dried, filtered and concentrated to dryness under reduced pressure (2.7 kPa). They are obtained

35.57 g of 3,5-difluorobenzyl methyl sulfone as white crystals, PF = 135 ° C.

3,5-difluorobenzyl methyl sulfide can be prepared as follows: starting from 40 g of 3,5-difluorobenzyl bromide and 16.25 g of sodium methyl thiolate in DMF at 60 ° C, after treatment 33.46 g are obtained 3,5-difluorobenzyl methyl sulfide as a yellow oil.

Method 2

To a solution of 2.2 g of 3-acetoxy-1- [bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methyl- (S)] azetidine in 25 cm ³ dioxane at room temperature, add 0.80 g of soda ash. After 16 hours at room temperature, 50 cc water and 100 cc ethyl acetate were added. The mixture was decanted, the organic phase was washed again with 100 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). A white kiss product was obtained which crystallized in isopropyl ether to give 0.85 g of solid melting at 190 ° C. Recrystallization in 20 cm ³ ethanol gave 0.70 g of 1 [bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine melting at 205 ° C.

To a solution of 4.77 g (3,5-difluorobenzyl) methylsulfone in 70 cm 3 of tetrahydrofuran under argon atmosphere was added at -70 ° C, 14 cm ^{3 a} 1.6 N solution of n butyllithium in hexane. 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 was added, after 1 hour a solution of 2.34 cm ^{3 of} acetyl chloride in 20 cm ³ tetrahydrofuran and the temperature of the reaction mixture was raised to 20 ° C for 1 hour. 50 cm ^{3 of} water and 200 cm ^{3 of} ethyl acetate were added. The mixture was decanted, the organic phase was 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). They are obtained

14.4 g of 3-acetoxy-1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-

(RS)] a3emuguH as a yellow oil. [RMN 1 H 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 = 9 Hz: 1H); 4.32 (s: 1H);

4.49 (s: 1H); 6.88 (tt, J = 9 at 2.5 Hz: 1H); om 7.20 go 7.35 (mt: 10H) J.

1- [bis (4-chlorophenyl) methyl] azetidin-3-one can be prepared by the following working method: to a solution of 5.0 cm ³ oxalyl chloride in 73 cm ³ dichloromethane cooled to -78 ° C, is added a solution of 8.1 cm ³ dimethyl sulfoxide in 17.6 cm ³ dichloromethane. After 0.5 hours at -78 ° C, a solution of 16.0 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol dissolved in 50 cm ^{3 of} dichloromethane was poured. After 5 hours at -78 ° C, 26.6 cm ^{3 of} triethylamine was added dropwise and the reaction mixture was allowed to return to room temperature. After 16 hours, the reaction mixture was washed 4 times with 200 cm ^{3 of} water, then with 200 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 column of w silica gel (particle size 0,04 - 0,06 mm, height 21 cm, diameter 9,2 cm), under pressure of 0,5 bar of argon, with a mixture of ethyl acetate and cyclohexane (40 / 60 in volumes) eluting and collecting 200 cm ³ fractions. fractions 15 to 25 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). They are obtained

8.9 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one as pale yellow crystals, melting at 11 ° C.

1- [bis (4-chlorophenyl) methyl] azetidin-3-ol can be prepared according to the method of operation described by KATRITZKY AR et al., J. Heterocycl. Chem., (1994), 271 starting from 35,5 g of hydrochloride [bis (4-chlorophenyl) methyl] amine i11,0st ³ epichlorhydrin. 9.0 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol were isolated.

The hydrochloride of [bis (4-chlorophenyl) methyl] amine can be prepared by the method described by GR1SAR 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 - [(3,5difluorophenyl) (methylsulfonyl) methyl] -azetidine can be obtained by separating CLHP into a CHIRALPAKAS chiral column (20 µm high, 23 cm high, diameter bst) at 0.52 g of racemate obtained in Example 1. Eluted with a heptane / ethanol mixture (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 (-) - 1- [bis (4-chlorophenyl) methyl)] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl] -azetidine [a _D ] = -6.3 ° ( C = 0.5M in methanol) as a white solid, melting at 178 ° C and 134 mg (+) - 1- [bis (4-chlorophenyl) methyl)] - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl] -azetidine [a _D ] = + 5.8 ° (C = 0.5M in methanol) as a white solid, melting at 178 ° C.

Example 3

Mixture of 2 diastereoisomeric forms A 1- [4 - [N *) - (4-chlorophenyl) - {3 [(3,5-difluorophenyl) -methylsulfonyl-methyl- (R)] azetidin-1-yl} methyl] benzyl] pyrrolidine and 1- [4 - [(N *) - (4-chlorophenyl) - {3 - [(3,5difluorophenyl) -methylsulfonyl-methyl- (5)] azetidin-1-yl} methyl] benzyl] pyrrolidine may be prepared by the following procedure: To a solution of 60 mg 1- (N *) - [4- (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonyl-methylene] azetidin-1-yl} methyl) benzyl] pyrrolidine, isomeric form A in 2 cm ³ ethanol and 2 cm ³ dichloromethane, was added 20 mg of sodium hydroboride. After stirring at 20 ° C for 20 hours, 0.25 cm ^{3 of} water, 20 cm ^{3 of} dichloromethane were added, stirred, and the mixture was dried over magnesium sulfate, then filtered and concentrated to dryness under reduced pressure (2.7 kPa ). The residue was chromatographed on a silica gel column (particle size 0,0630,200 mt, height 7 cm, diameter 1 cm), eluting under pressure of 0.1 bar of argon, with dichloromethane, then with a mixture of dichloromethane and methanol (95 / 5 in volumes) and 5 cm ³ fractions were collected. fractions 13 to 18 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 38 mg of a mixture of 2 diastereoisomeric forms A is obtained 1- [4 - [(N *) - (4-chlorophenyl) - {3 - [(3,5difluorophenyl) -methylsulfonyl-methyl- (R)] azetidin-1-yl } methyl] benzyl] pyrrolidine and 1- [4 - [(N *) - (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonyl-methyl- (8)] azetidin-1-yl} methyl ] benzyl] pyrrolidine in the form of a white kiss. [Spectrum RMN ^d H (400 MHz, CDCl ₃ , δ in ppm): 1.77 (mt: .4H); from 2.40 to 2.60 (mt: 5H); 2.67 (s: 3H); from 3.10 to

3.25 (mt: 2H); 3.38 (mt: 1H); from 3.50 to 3.70 (mt: 3H); 4.24 (s: 1H);

4.25 (d, J = 11 Hz: 1H); 6.83 (t width, J = 9 Hz: 1H); 6.94 (mt: 2H); om 7.10 go 7.35 (mt: 8H) J.

1- (N *) - [4- (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-1-yl} methyl) benzyl] pyrrolidine, isomeric form A, can be obtained as proceed as follows: To a solution of 0.32 g 1 - {(1 *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -

3 - [(3,5-difluorophenyl) methylsulfonyl-methylene] azetidine, isomeric form A and 5 mg of sodium iodide in 10 cm ^{3 of} dichloromethane were added 50 m ^{3 of} pyrrolidine. After stirring for 20 hours at 20 ° C, to the mixture was added 50 mm ³ pyrrolidine, stirred for 8 hours, then was added again 50 mm ³ pyrrolidine and stirred for 20 hours at 20 ° C. The reaction mixture was washed with water, then the organic phase was dried over magnesium sulfate, concentrated to dryness in vacuo (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0,063 - 0,200 mm, height 30 cm, diameter

1.2 cm3), pressurized with 0.1 bar of argon, eluting with dichloromethane, then with a mixture of dichloromethane and methanol (97.5 / 2.5 in volumes) and collecting fractions of Zet ³ . Fractions 12 to 40 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of 1- (N *) - [4- (4-chlorophenyl) - {3 [(3,5-difluorophenyl) methylsulfonyl-methylene] azetidin-1-yl} methyl) benzyl] pyrrolidine isomeric form A is obtained , in the form of a white O kiss, [a] ²⁰ 365 pt = -22.5 ° +/- 0.7 (c = 0.5%; dichloromethane).

RMN ^! H (300 MHz, CDCl ₃ , δ in ppm): 1.78 (mt: 4H); 2.51 (mt: 4H); 2.81 (s: 3H); 3.58 (s: 2H); 3.84 (mt: 2H); 4.33 (mt: 2H); 4.50 (s: 1H); 6.84 (tt, J = 9 and 2.5 Hz: 1H); 6.98 (mt: 2H); om 7.20 to 7.40 (mt: 8H)].

1 - {(R *) - [(4-chloromethyl) phenyl] (4-chlorophenyl) methyl} -3 - [(3,5-difluorophenyl) methyl-sulfonyl-methylene] azetidine, isomeric form A, can be obtained by works as follows: to a solution of 28.0 g of a mixture of 2 diastereoisomers (Forms A) 1 - {(R *) - [(4chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(I) - (3,5-difluorophenyl) methylsulfonyl-methyl)] azetidin-3-ol, and 1 - {(k *) - [(4-chloromethyl) phenyl] (4-chlorophenyl) methyl} -3 - [(8) - (3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ol, 32 g 4-dimethylaminopyridine, 500 ml of dichloromethane, 12.4 cm ^{3 of} methylsulfonyl chloride are added. After stirring at 10 ° C for 1 hour, then at 20 ° C for 1 hour, the reaction mixture was washed with 500 cm ^{3 of} water, the organic phase was dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.06 0.200 mm, height 30 cm, diameter 6 cm), pressurized 0.2 bar of argon, eluting with dichloromethane and collecting fractions of 250 cm ³ . fractions 9 to 25 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 6.3 g of 1 - {(R *) [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(3,5 difluorophenyl) methylsulfonyl-methylene] azetidine, isomeric form A, are obtained in the form on a white kiss.

Mixture of 2 diastereoisomers (Forms A) N {N *) - [4- (chloromethyl) phenyl] (4-chlorophenyl) methyl} -3 - [(R) - (3,5-difluorophenyl) methylsulfonylmethyl)] azetidine -3-ol, and l - {(R *) - [4- (xaphenylmethyl) phenyl] (4-chlorophenyl) methyl} -3 - [(S) - (3,5-difluorophenyl) methyl-sulfonylmethyl)] azetidin-3 -ol, can be obtained by working as follows: To a solution of 0.20 g of a mixture of 2 diastereoisomers (Forms A) 1 - {(1H) - (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) - (3,5difluorophenyl) methylsulfonyl-methyl)] azetidin-3- ol, in 10 cm dichloromethane, 6 cm thionyl chloride are added. After stirring at 20 ° C for 20 hours, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, then stirred for 15 minutes. The mixture was decanted, the organic phase was washed with water, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0,04 - 0,06 mm, height 20 cm, diameter 1,0 cm) under pressure of 0.2 bar of argon, eluting with a mixture of cyclohexane and ethyl acetate (75 / 25 in volumes) and fractions of 20 cm ³ were collected, fractions 4 to 7 were pooled, then concentrated to dryness under reduced pressure (2.7 kPa). 0.17 g of a mixture of 2 diastereoisomers (Forms A) 1 - {(1H) - [4- (chloromethyl) phenyl] (4chlorophenyl) megpyl} -3 - [(K.) - (3,5-difluorophenyl) is obtained ) megpilsulfonylmethyl)] azetidin-3-ol, and 1 - {(N *) - [4- (chloromethyl) phenyl] (4-chlorophenyl) methyl} -3 - [(S) - (3,5-difluorophenyl) methyl-sulfonylmethyl )] azetidin-3-ol, in the form of a white kiss.

Mixture of 2 diastereoisomers (Forms A) 1 - {(N *) - (4- (chlorophenyl) [4 (hydroxymethyl) phenyl] methyl} -3 - [(N) - (3,5-difluorophenyl) methylsulfonylmethyl)] azetidine -3-ol, and 1 - {(N *) - [4- (chlorophenyl) [4 (hydroxymethyl) phenyl] methyl} -3 - [(S) - (3,5-difluorophenyl) methylsulfonylmethyl)] azetidine- 3-ol can be obtained by working as follows: To a solution maintained under argon and cooled to -30 ° C on 0.58 g of a mixture of 2 diastereoisomers (Forms A) 3-acetoxy-1 - {(I * ) (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(R) - (3,5difluorophenyl) methylsulfonyl-methyl)] azetidine, and 3-acetoxy-1 - {(R *) (4 -chlorophenyl) [4- (methoxycar onyl) phenyl] methyl} -3 - [(8) - (3,5-difluorophenyl) methylsulfonyl-methyl)] azetidine, in a 10 cm of anhydrous toluene was added 1,6 cm 1.5M solution of diisobutylaluminum hydride in toluene. After stirring at -30 ° C for 15 minutes, 1.0 cm ³ of this same hydride solution was added again, then the mixture was allowed to return to 0 ° C. After stirring for 30 minutes, the stirred mixture was added to 3 cm 3 of water and 6 cm 2 of sodium hydroxide 1N, then extracted with 25 cm ^{3 of} dichloromethane. The organic phase was washed with 5 cm ^{3 of} water, 5 cm ^{3 of} brine, then dried over magnesium sulfate, and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0,06-0,200 mm, height 30 cm, diameter 1.2 cm), pressurized with 0.1 bar of argon, eluting with a mixture of cyclohexane and ethyl acetate (50/50 in volumes) and were collected with fractions of 30 cm ³ . fractions 4 to 12 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 0.42 g of a mixture of 2 diastereoisomers (Forms A) * 1 - {(R *) - [4 (chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(1 H) - (3,5difluorophenyl) are obtained ) methylsulfonyl-methyl)] azetidin-3-ol, and l - {(R *) - [4 (chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(S) - (3,5difluorophenyl) methylsulfonyl -methyl)] azetidin-3-ol, in the form of a white lacquer.

Mixture of 2 diastereoisomers (Form A), 3-agemokcu-1 - {(R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(R) - (3,5W difluorophenyl) methylsulfonyl- methyl)] azetidine, and 3-auemoccu-1 - {(R *) (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(S) - (3,5difluorophenyl) methylsulfonyl-methyl)] azetidine can be prepared by working as follows: To a solution cooled to -60 ° C on 1.0 g (3,5-difluorobenzyl) methylsulfone in 30 cm ³ tetrahydrofuran is poured under argon for 5 minutes, 3 cm ³ 1,6N solution of p-butyl lithium in hexane. After stirring at -60 ° C for 1 hour, then at -30 ° C for 30 minutes, a solution, pre-cooled to 73, was added dropwise to this mixture.

60 ° C, at 1.45 g of 1 - {(K *) - (4-chlorophenyl) [4 (methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomeric form AB 15 cm ³ tetrahydrofuran. After stirring at -60 ° C for 30 minutes, then 0.43 cm ^{3 of} acetyl chloride was added for 30 minutes at -30 ° C, then allowed to return to 0 ° C. Then, 40 cm ^{3 of} water and 40 cm ^{3 of} dichloromethane are added to the medium with stirring, then allowed to return to normal temperature and decanted. The organic phase was washed with 20 cm3 of water, 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 0,040,063 mm, height 30 cm, diameter 3 cm), eluting under pressure of 0.5 bar of argon, with a mixture of cyclohexane and ethyl acetate (75/25 in volumes) and collecting fractions from 30 Art. ³ . Fractions 21 to 35 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 1.28 g of a mixture of 2 diastereoisomers (Forms A) of 3-acetoxy-1 - {(N- (4-chlorophenyl) [4 (methoxycarbonyl) phenyl] methyl} -3 - [(1) - (3.5) are obtained -difluorophenyl) methylsulfonyl-methyl)] azetidine, and 3-acetoxy-1 - {(1 H) - (4-chlorophenyl) [4 (methoxycarbonyl) phenyl] methyl} -3 - [(8) - (3,5- difluorophenyl) methylsulfonylmethyl] azetidine, in the form of a cream kiss.

Chig

1 - {(R) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomeric form A, can be prepared by working as follows: To a solution cooled to -60 ° C of 0.55 cm ^{3 of} oxalyl chloride in 5 cm ^{3 of} dichloromethane was poured out for 10 minutes 0.90 cm ^{3 of} dimethyl sulfoxide. After stirring at -60 ° C for 30 minutes, a solution of 1.75 g of 1 - {(K *) - (4-chlorophenyl) [4 (methoxycarbonyl) phenyl] methyl} azetidine-3 was added to the mixture for 15 minutes. -ol, isomeric form A, B cm ³ dichloromethane. After stirring for 3 hours at -60 ° C, they were poured

2.70 cm ^{3 of} triethylamine, then allowed to return to 0 ° C. Then 20 cm ^{3 of} water was added, stirred, then decanted. The organic phase was dried over magnesium sulfate, filtered, then concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The resulting orange oil was chromatographed on a silica gel column (particle size 0.06 0.200 mm, height 30 cm, diameter 2 cm), pressurized with 0.5 bar of argon, eluting with a mixture of cyclohexane and ethyl acetate (75/25 in volumes ) and fractions of 30 cm ³ were collected. fractions 2 to 15 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 1.45 g of 1 - {(k *) - (4-chlorophenyl) [4 (methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomeric form A, is obtained as a yellow kiss.

1 - {(R) - (4-chlorophenyl) [4- (methoxycarbopyl) phenyl] methyl} azetidin-3-ol, isomeric form A, can be prepared by working as follows: To a suspension of 2.0 g Methyl (+) - 4 - [(N *) - amino- (4-chlorophenyl) methyl] benzoate, in 30 cm ethanol, 0.605 g sodium hydrogen carbonate was added, then 0.60 cm ³ epibromhydrin. After stirring at 60 ° C for 20 hours, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0,060,200 mt, height 35 cm, diameter 3 cm), eluting under pressure of 0.5 bar of argon, with a mixture of cyclohexane and ethyl acetate (70/30 in volumes for fractions 6 to 10 , then 60/40 for fractions 18 to 27, then 50/50) and fractions of 60 cm are collected. Fractions 15 to 40 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). The residue was extracted with 30 cm ^{3 of} ethanol, then 0.20 g of sodium bicarbonate and 0.2 cm ^{3 of} epibromhydrin were added. After stirring for 48 hours at 20 ° C, then at 35 ° C for 24 hours, the mixture was filtered and the filtrate concentrated to dryness at 60 ° C under reduced pressure (2.7 kPa). 1.76 g of 1 - {(N *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidine-3-olisomer Form A are obtained as a sticky solid.

Methyl (+) - 4 - [(N *) - amino- (4-chlorophenyl) methyl] benzoate can be obtained by working as follows: To a solution of 9.2 g of methyl 4 - [(1 <8 ) -amino- (4-chlorophenyl) methyl] benzoate in 10 cm ^{3 of} methanol, 2.51 g of D - (-) - mapamoxy acid are added. The solution was concentrated to dryness under reduced pressure (2.7 kPa). The resulting cream kiss was dissolved in 50 cm3 ethanol containing 5% water and the resulting solution was allowed to crystallize for 20 hours at 20 ° C. The crystals were filtered off, washed with ethanol with 5% water, drained, then dried under reduced pressure (2.7 kPa). 3.4 g of white crystals are obtained which are referred to as "crystals A" [which are subsequently stored for the preparation of the two enantiomers of methyl (-) - 4- (N *) - amino- (4chlorophenyl) methyl] benzoate)] . The liquid basic structural components were concentrated to dryness to give a white kiss (a) (8.1 g) which was dissolved in 100 cm3 ethyl acetate. The resulting solution was added to 50 cm 3 of sodium hydroxide 1N, stirred, and decanted. The organic phase was washed with 50 cm ^{3 of} water, then dried over magnesium sulfate, and concentrated to dryness under reduced pressure (2.7 kPa). A yellow solid was obtained which dissolved in 100 cm ^{3 of} methanol. The resulting solution was added to 1.85 g of L - (+) - mapmapamoBa acid and the resulting solution concentrated to dryness under reduced pressure (2.7 kPa). A creamy kiss is obtained which is dissolved in 27 cm ^{3 of} ethanol at one time with 4% water, allowed to crystallize for 20 hours at 20 ° C. The crystals were filtered off, washed with ethanol with 4% water, drained, then dried under reduced pressure (2.7 kPa). 3.4 g of L - (+) - mapamapam crystals of methyl (+) - 4 - [(R *) amino- (4-chlorophenyl) methyl] benzoate are obtained, which is recrystallized in 60 cm3 ethanol with 5% water. After draining, then drying, they are obtained

2.78 g of white crystals which were dissolved in 50 cm ^{3 of} ethyl acetate. The resulting solution was added to 100 cm 3 of sodium hydroxide 1N, stirred and decanted. The organic phase was washed with 50 cm ^{3 of} water, then dried over magnesium sulfate, and concentrated to dryness under reduced pressure (2.7 kPa). 2.1 g of methyl (+) -4 - [(R *) - amino- (4-chlorophenyl) methyl] benzoate are obtained as a white solid.

Methyl 4- [N, S] -amino- (4-chlorophenyl) methyl] benzoate can be obtained by working as follows: To a suspension of 16.3 g of methyl 4 - [(S) -phthalimido- (4-chlorophenyl) methyl] benzoate, in 200 cm ^{3 of} methanol, was added 3.9 cm hydrazine hydrate. After stirring at reflux temperature for 5 hours, then at 20 ° C for 20 hours, the reaction mixture was filtered, the filtrate was concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue was extracted with a mixture of 200 cc water and 200 cc ethyl acetate. After stirring for 15 minutes, the resulting suspension was filtered, the filtrate was decanted into a decanter ampoule, and the organic phase was washed with 50 cm3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). They are obtained

8.4 g of methyl 4 - [(S) -amino- (4-chlorophenyl) methyl] benzoate, as a pale yellow oil.

W ' Methyl 4 - [(1 S) -phthalimido- (4-chlorophenyl) methyl] benzoate can be prepared by working as follows: to a solution of 11.6 g of 2 methyl 4 - [(R 8) -bromo- ( 4-chlorophenyl) methyl] benzoate, in 70 cmΝ, dimethylformamide, 12.6 g of potassium phthalimide were added. After stirring at reflux temperature for 3 hours, the reaction mixture was cooled to 20 ° C, then 300 cm ^{3 of} ethyl acetate and 300 cm ^{3 of} water were added. After stirring, the mixture was decanted, the aqueous phase was re-extracted twice with 100 cm @ ^{3 of} ethyl acetate, the combined organic phases washed twice with 400 cm @ ^{3 of} water, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (27 kPa). 16.3 g of methyl 4 - [(RS) phthalimido- (4-chlorophenyl) methyl] benzoate are obtained as a yellow sticky solid. Methyl 4- [N, S] -bromo- (4-chlorophenyl) methyl] benzoate can be obtained by working as follows: to a solution of 17.4 g of methyl 4f (R8) - (4-chlorophenyl) (hydroxy) ) methyl] benzoic acid in 200 cm ^{3 of} acetonitrile, 10.18 g of NN'-carbonyldiimidazole are added, and 54.3 cm of allyl bromide. After stirring at 20 ° C for 30 minutes, the reaction mixture was refluxed for 2 hours, stirred for 20 hours at 20 ° C and concentrated to near dryness under reduced pressure (27 kPa). The mixture was extracted with dichloromethane, chromatographed on a silica gel column (granulometry 0,06-0,200 mm, height 30 cm, diameter 7 cm), pressurized with 0.5 bar of argon, eluting with dichloromethane, and fractions were collected 500 Art ³ . fractions 3 to 6 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 11.6 g of methyl 4 - [(1 S) -bromo- (4-chlorophenyl) methyl] benzoate are obtained, in the form of an oil, which will be used as is, in the next step.

Methyl 4 - [(1 S) - (4-chlorophenyl) (hydroxy) methyl] benzoate can be prepared by working as follows: to a suspension of 2.75 g of methyl 4- (4-chlorobenzoyl) benzoate, in 200 cm. ³ methanol at 20 ° C, slowly added in small fractions (produced by heating the medium to 50 ° C) 1.21 g of sodium borohydride. After stirring for 20 hours at 20 ° C, the reaction mixture was concentrated by reducing the volume then added to 150 cm ^{3 of} dichloromethane and stirring to 100 cm ^{3 of} hydrochloric acid 0.5 N. After decanting, the organic phase was dried over magnesium sulfate, concentrated to dryness under reduced pressure (2.7 kPa). 2.5 g of methyl 4 - [(RS) - (4 chlorophenyl) (hydroxy) methyl] benzoate are obtained in the form of a colorless oil which crystallizes slowly at 20 ° C and will be used as is, in the next step .

Methyl 4- (4-chlorobenzoyl) benzoate can be prepared by working as follows: to a solution cooled to -22 ° C, 19.3 g of terephthalic acid monomethyl ester in 200 cm ^{3 of} tetrahydrofuran is added under argon 27.4 cm ³ tri-p-butylphosphine. After stirring at -22 ° C for 20 minutes, a solution of 4-chlorophenylmagnesium bromide (obtained starting from 19.15 g of bromo-4-chlorobenzene, 2.43 g of magnesium and crystalline iodine in 100) was poured out at this temperature. cm ³ diethyl oxide at reflux). After stirring at -22 ° C for 30 minutes, 150 cm ^{3 of} hydrochloric acid 1 N was slowly added, the mixture was allowed to return to 20 ° C, then the medium was diluted with 200 cm ^{3 of} diethyl oxide. The resulting white suspension was filtered, the solid was washed twice with 50 cm ^{3 of} water, then twice with 50 cm ^{3 of} diethyl oxide. After drying, then drying under reduced pressure (2.7 kPa), 16.2 g of methyl 4- (4-chlorobenzoyl) benzoate is obtained, as a white solid, melting at 170 ° C.

Example 4

Mixture of 2 diastereoisomeric forms B 1- [4 - [(N *) - (4-chlorophenyl) - {3 [(3,5-difluorophenyl) -methylsulfonyl-methyl- (N)] azetidin-1-yl} methyl] benzyl] pyrrolidine and 1- [4 - [(N *) - (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl- (S)] azetidin-1-yl} methyl] benzyl] pyrrolidine can be prepared by working as described in Example 3 starting from 50 mg (+) - 1- [4- (N *) - (4-chlorophenyl) - {3 - [(3,5difluorophenyl) methyl- sulfonylmethylene] azetidin-1-yl} methyl) benzyl] pyrrolidine, isomeric form B, 1.5 cm ³ ethanol, 1.5 cm ³ dichloromethane, and 18 mg sodium hydroboride while stirring for 8 hours at 50 ° C, then 48 hours at 20 ° C. 50 mg of a mixture of 2 diastereoisomeric forms of 1- [4 - [(1 *) - (4-chlorophenyl) - {3 [(3,5-difluorophenyl) -methylsulfonyl-methyl- (1)] azetidin-1yl} is obtained methyl] benzyl] pyrrolidine and 1- [4 - [(N *) - (4-chlorophenyl) - {3 - [(3,5difluorophenyl) -methylsulfonyl-methyl- (8)] azetidin-1-yl} methyl] benzyl ] pyrrolidine, in the form of a white kiss. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm). A mixture of diastereomer 60/40, * 1.79 (mt: 4H) was observed; 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 completely); 3.65 (t width, J = 7.5 Hz: 1H); 4.26 and 4.30 (2s: 2H completely); 6.84 (tt, J = 9 and 2 Hz: 1H); 6.96 (mt: 2H); from 7.25 to 7.40 (mt: 8H).

(+) - 1- [4- (B *) - (4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl} methyl) benzyl] pyrrolidine, isomeric form B may was obtained by working as described in Example 3, starting from 0.50 g of 1 - {(1 H) - [4- (chloromethyl) phenyl] - (4 chlorophenyl) methyl} -3 - [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomeric form B, 5 mg sodium iodide, cm ³ dichloromethane and 0.190 g pyrrolidine. The crude material obtained is chromatographed on a silica gel column (particle size 0.06 0.200 mm, height 20 cm, diameter 1.5 cm), pressurized with 0.1 bar of argon, eluting with dichloromethane, then with a mixture of dichloromethane and methanol (95/5 by volume) and fractions of 25 cm ³ were collected. Fractions 20 to 40 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 0.28 g (+) - 1- [4- (N *) - (4-chlorophenyl) - {3 - [(3,5 difluorophenyl) methylsulfonyl-methylene] azetidin-1-yl} methyl) benzyl] pyrrolidine is obtained , isomeric form B, in the form of a white kiss, [a] ²⁰ 365 pt = + 26.8 ° +/- 0.8 (c = 0.5%; dichloromethane) [RMN spectrum ² H (300 MHz, CDQ 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 at 2.5 Hz: 1H); 6.98 (mt: 2H); om 7.20 go 7.40 (mt: 8H) J.

1 - {(N *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, isomeric form B, can be obtained working as described in Example 3 starting from 7.3 g of a mixture of 2 diastereoisomeric forms B 1 {(R *) - [4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [(I) - (3,5difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol, and l - {(R *) - [4 (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3- [ (S) - (3,5-difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol, 8.2 g 4-dimethylaminopyridine, 150 cm ³ dichloromethane, 3.2 cm ³ methylsulfonyl chloride. The crude material is chromatographed on a silica gel column (particle size 0,04 - 0,06 mm, height 30 cm, diameter 3 cm), pressurized with 0.2 bar of argon, eluting with dichloromethane and collecting fractions of 100 cm ³ . The fractions 15 to 30 were combined, then concentrated to dryness under reduced pressure (2.7 kPa).

2.50 g of 1 - {(1 *) - [4- (chloromethyl) phenyl] - (4chlorophenyl) methyl} -3 - ((3,5-difluorophenylmethylsulfonyl) methylene] azetidine, isomeric form B, are obtained in the form of white kiss.

Mixture of 2 diastereoisomeric forms B 1 - {(B *) - [4- (chloromethyl) phenyl] (4-chloro phenyl) methyl} -3 - [(B) - (3,5difluorophenyl) (methylsulfonyl) methyl)] azetidine -3-ol, and l - {(R *) - [4 (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(S) - (3,5difluorophenyl) (methylsulfonyl) methyl)] azetidine- 3-ol can be obtained by working as described in Example 3, starting from 11.0 g of a mixture of 2 diasomeric forms B 1 - {(R *) - (4-chlorophenyl) [4- ( hydroxymethyl) phenyl] methyl} -3 - [(R) - (3,5difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol and l - {(R *) - (4chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(S) - (3,5difluorophenyl) (methylsulfonyl) methyl )] azetidin-3-ol, 250 cm ³ of dichloromethane, and 3,1 cm thionyl chloride. The crude material obtained is chromatographed on a silica gel column (particle size 0,04-0,06 mm, height 30 cm, diameter 3 cm) under pressure of 0.2 bar of argon, eluting with a mixture of cylohexane and ethyl acetate (70 / 30 in volumes) and fractions of 50 cm ³ were collected, fractions 9 to 25 were collected

W pools, then concentrated to dryness under reduced pressure (2.7 kPa). 7.3 g of a mixture of 2 diastereoisomeric forms B, 1 - {(1H) - [4- (chloromethyl) phenyl] - (4-chloro phenyl) methyl} -3 - [(B) (3.5- difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol, and l - {(R *) - [4 (chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 - [(8) - (3,5difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol as a white kiss.

Mixture of 2 diastereoisomeric forms B 1 - {(N *) - (4-chlorophenyl) [4 (hydroxymethyl) phenyl] methyl} -3 - [(B) - (3,5difluorophenyl) (methylsulfonyl) methyl)] azetidin-3 -ol and l - {(R *) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(R) - (3,5difluorophenyl) (methylsulfonyl) methyl)] azetidin-3-ol, may was prepared by working as described in Example 3, starting from 18.0 g of a mixture of 2 diastereoisomeric forms B 3 acetoxy-1 - {(B *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl } -3 [(R) - (3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine, and 3-acetoxy1 - {(R) - (4-chlorophenyl) [4- (methyloxycarbonyl) phenyl] methyl} -3 - [(8) - (3,5d fluorophenyl) (methylsulfonyl) methyl] azetidine, 150 cm @ ³ of anhydrous toluene and 100 cm @ ³ of 20% solution in toluene diizobutilaluminiy hydride. The crude material obtained is chromatographed on a silica gel column (particle size 0,06-0,200 mm, height 30 cm, diameter 3 cm) under pressure of 0.1 bar of argon, eluting with a mixture of cylohexane and ethyl acetate (50/50 in volumes) and fractions of 50 cm ³ were collected. Fractions 15 to 30 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 11.0 g of a mixture of 2 diastereoisomeric forms of B 1 - {(B *) - (4-chlorophenyl) [4 (hydroxymethyl) phenyl] methyl} -3 - [(N) - (3,5difluorophenyl) (methylsulfonyl) are obtained methyl] azetidin-3-ol and l - {(R *) - (4chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(S) - (3,5difluorophenyl) (methylsulfonyl) methyl] azetidine -3-ol in the form of a white kiss.

Mixture of 2 diastereoisomeric forms B 3-acetoxy-1 - {(N *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(B) - (3,5difluorophenyl) (methylsulfonyl) methyl] azetidine and 3-anemocec-1 - {(R *) - (4chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(B) - (3,5difluorophenyl) (methylsulfonyl) methyl] azetidine, can be obtained working as described in Example 3, starting from 11.2 g (3,5-difluorobenzyl) methylsulfone, 350 cm ³ tetrahydrofuran, 34 cm ³

1.6 N solution of n-butyllithium in hexane, 11.2 g l - {(R *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomeric form B, and 5, 5 cm ³ acetyl chloride. The crude material obtained is chromatographed on a silica gel column (particle size 0,060,200 mt, height 40 cm, diameter 4 cm), eluting with a mixture of cyclohexane and ethyl acetate (70/30 in volumes) and collecting fractions of 100 cm ³ . The fractions 10 to 30 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 21 g of a creamy impurity is obtained, which is chromatographed on a silica gel column (granulometry 0,06-0,200 mm, height 40 cm, diameter 4 cm), eluting with dichloromethane and collecting fractions of 100 cm ³ . fractions 11 to 30 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 20.0 g of a mixture of 2 diastereoisomeric forms of B-3-anemoccu-1 - {(R *) - (4chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(K) - (3,5difluorophenyl) are obtained (methylsulfonyl) methyl)] azetidine, and 3-auemokcu - {(R *) - (4chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} -3 - [(S) - (3,5difluorophenyl) (methylsulfonyl) methyl] azetidine, in the form of a white kiss.

1 - {(B *) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomeric form B, can be prepared by working as described in Example 3, starting from from 8.7 cm ³ oxalyl chloride, 350 cm ³ dichloromethane, 14.2 cm ³ dimethyl sulfoxide, 29.0 g l - {(R *) - (4 chlorophenyl) [4- (methoxycarbonyl) phenyl] methyl} azetidine-3- ol, isomeric form B, and 43 cm triethylamine. The crude material obtained is chromatographed on a silica gel column (particle size 0.06 0.200 mm, height 40 cm, diameter 4 cm), eluting with dichloromethane and collecting fractions of 250 cm ³ . fractions 7 to 25 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 15.5 g of 1 - {(N *) - (4-chlorophenyl) [4 (methoxycarbonyl) phenyl] methyl} azetidin-3-one, isomeric form B, are obtained in the form of an orange oil.

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

Methyl (-) - 4- [1- (R *) - amino-1- (4-chlorophenyl) methyl] benzoate can be obtained by performing two successive recrystallizations of white crystals (3.4 g) designated as " crystals A &apos; in Example 3, in 68 cm &lt; ^{3 &gt; of} ethanol with 5% water at reflux. The resulting crystals are filtered off, then dried under reduced pressure (2.7 kPa). 2.2 g of D - (-) - mapmapam of methyl (-) - 4 - [(B *) - amino- (4-chlorophenyl) methyl] benzoate are obtained in the form «2 of white crystals which are dissolved in 50 cm3 ethyl acetate. The resulting solution was added to 50 cm 3 of sodium hydroxide 1Ν, stirred, then decanted. The organic phase was washed with 50 cm ^{3 of} water, then dried over magnesium sulfate, and concentrated to dryness under reduced pressure (2.7 kPa). They are obtained

1.9 g of methyl (-) - 4- [1- (N *) - amino- (4-chlorophenyl) methyl] benzoate, as a white solid. [a] 20 ° C, 365 nm = -58.1 ° +/- 1 (c = 0.5%).

Example 5

1- [bis- (thien-2-yl) -methyl] -3 - [(R 8) - (3,5-difluorophenyl) methylsulfonylmethyl] azetidine can be prepared by working as described in Example 3, starting from from 0.10 g of 1- [bis- (thien-2-yl) methyl] -3- [(3,5-difluorophenyl) methylsulfonyl-methylene] azetidine, 2 cm methanol, 2 cm dichloromethane, and 25 mg sodium hydroboride, stirring for 3 hours at 20 ° C. The crude material obtained is chromatographed on a silica gel column (particle size 0,063 - 0,200 mm, height 7 cm, diameter 1 cm), eluting under pressure of 0.1 bar from argon with dichloromethane and collecting fractions of 4 cm ³ . fractions 2 to 5 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 83 mg of 1- [6uc- (mueH-2-UA) -MemA] -3 - [(RS) - (3,5difluorophenyl) methylsulfonylmethyl] azetidine are obtained as a white solid. [RMN * H spectrum (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); 5.73 (t width, J = 7.5 Hz: 1H); 4.27 (d, J = 11Hz: 1H); 4.92 (s: 1H); 6.83 (mt, J = 9 at 2.5 Hz: 1H); om6.85 to 7.00 (mt: 6H); 7.21 (mt: 2H)].

1- [bis- (thien-2-yl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine can be prepared by working as described in Example 6, starting from 2.2 g 1- [bis- (thien-2-yl) methyl] -3- [(3,5-difluorophenyl) methylsulfonyl-methyl- (P8)] azetidin-3-ol, 0.64 cm ³ methylsulfonyl chloride, 2, 3 g of 4-dimethylaminopyridine and 75 cm ^{3 of} dichloromethane are obtained after purification by chromatography and crystallization in diisopropyl oxide, 1.3 g of 1- [bis- (thien-2-yl) -methyl] -3 [(3,5 -difluorophenyl) methylsulfonylmethylene] azetidine in the form of white crystals melting at 165 ° C.

1- [bis- (thien-2-yl) -methyl] -3- [(3,5-difluorophenyl) methylsulfonyl-methyl (RS)] -3emuguH-3-OA can be prepared by working as follows: to a solution cooled to -60 ° C on 1.3 g (3,5difluorobenzyl) methylsulfone in 20 cm ³ tetrahydrofuran was added under argon for 10 minutes 4 cm ³ n-butyl lithium 1.6 N in hexane. After stirring at -70 ° C for 45 minutes, a solution of 1.5 g of 1- [bis- (thien-2-yl) methyl] azetidin-3-one in 20 cm ^{3 of} tetrahydrofuran was poured over 10 minutes. After stirring at -70 ° C for 3 hours, the reaction mixture was allowed to return to normal temperature, then 10 cm ^{3 of} saturated aqueous ammonium chloride was added. The mixture was decanted, the organic phase was dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). The residue was extracted with a 20 cm ³ mixture of cyclohexane and ethyl acetate (60/40 in volumes), the resulting suspension filtered, the solid drained, then air-dried. 2.2 g of 1- [bis- (thien-2-yl) methyl] -3- [(3,5-difluorophenyl) methylsulfonyl-methyl-N-8)] azetidin-3-ol are obtained in the form of white melting crystals at 145 ° C.

1- [bis- (thien-2-yl) -methyl] azetidin-3-one can be prepared by working as described in Example 1 (method 2) starting from 4 g of 1- [bis- ( thien-2-yl) methyl] azetidin-3-ol, 2.6 cm ³ dimethylsulfoxide, 7.7 * 1 cm triethylamine, 7.7 cm oxalyl chloride, and 100 cm dichloromethane. The resulting residue was purified by chromatography on a silica gel column (granulometry 0.04-0.06 mm, height 30 cm, diameter 3 cm), eluting with a mixture of cyclohexane and ethyl acetate (1/1 in volumes). The resulting fractions were evaporated to dryness under reduced pressure (2.7 kPa). 3.2 g of 1- [bis- (thien-2-yl) methyl] azetidin-3-one are obtained in the form of cream crystals melting at 70 ° C.

1- [bis- (thien-2-yl) -methyl] azetidin-3-ol can be prepared by working as described in Example 3, starting from 6 g of 1- [bis (thien-2-yl) ) -methyl] amine, 2.5 cm ³ epibromhydrin, 2.6 g sodium bicarbonate and 50 cm ³ ethanol. 4 g of 1- [bis- (thien-2-yl) methyl] azetidin-3-ol are obtained in the form of beige crystals melting at 115 ° C.

1- [Bis- (thien-2-yl) -methyl] amine can be prepared as follows: to a suspension, cooled under argon to 10 ° C, of thien-2-yl-magnesium bromide (obtained from starting from 1.29 g of magnesium and 3.22 cm 2 of bromothiophene in 75 cm ^{3 of} diethyl oxide) are poured dropwise into a solution of 5 cm ^{3 of} thiophene-2-yl-carbonitrile in 50 cm ^{3 of} diethyl oxide. After refluxing for 1 hour and 30 minutes, the reaction medium was cooled to 5 ° C, then 20 cm ^{3 of} methanol was dropwise poured, the suspension was filtered, and the solid was washed with ethanol. The filtrate was obtained as a brown solution. Under argon, 2.45 g of sodium borohydride were added several times to this solution. The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate and slowly added water. The organic phase was extracted, washed with water, dried over magnesium sulfate and evaporated to dryness under O under reduced pressure (2.7 kPa) at 55 ° C. A brown oil was obtained, which was chromatographed on a silica gel column (granulometry 0.2 - 0.063 mm, height 25 cm, diameter 8 cm) and eluted with a mixture of cyclohexane and ethyl acetate (90/10, then 85/15 in volumes), fractions 21 to 30 were combined and evaporated to dryness under reduced pressure (2.7 kPa). 11 g of 1- [bis- (thien-2-yl) methyl] amine are obtained in the form of a crystallized solid.

Example 6

1- [bis- (p-tolyl) methyl] -3 - [(P8) -methylsulfonyl-phenyl-methyl] azetidine can be prepared by working as described in Example 3, starting from 0.10 g 1 - [bis- (p-tolyl) methyl] -3 - (- methylsulfonylphenyl-methylene) azetidine, 2 cm methanol, 2 cm dichloromethane, and 25 mg sodium hydroboride. The crude product obtained is chromatographed on a silica gel column (particle size 0,0630,200 mm, height 7 cm, diameter 1 cm), eluting under pressure of 0.1 bar from argon with dichloromethane and collecting fractions of 4 cm ³ . Fractions 5 to 10 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 35 mg of 1- [bis- (ptholyl) methyl] -3 - [(1 S) -methylsulfonyl-phenyl-methyl] azetidine are obtained as a white solid. [RMN ³ H spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.24 (s: 3H); 2.27 (s: 3H); 2.53 (t, J = 7.5 Hz: 1H);

2.58 (s: 3H); 3.19 (mt: 2H); 3.49 (mt: 1H); 3.69 (t width, J = 7.5 Hz: 1H); 4.22 (s: 1H); 4.28 (d, J = 11.5 Hz: 1H); om 6.95 go 7.45 (mts: 13H) J.

1- [bis- (p-tolyl) methyl] -3 - (- methylsulfonyl-phenyl-methylene) azetidine can be prepared by working as follows: to a solution of 0.48 g of 1- [bis- (p- tolyl) methyl] -3 - (- methylsulfonyl-phenyl-methyl (RS)] a3emuguH-3-oA in 25 cm ³ anhydrous dichloromethane, 0.125 cm ³ methylsulfonyl chloride is added, then in small fractions 0.465 g

4-dimethylaminopyridine. After stirring at 20 ° C for 20 hours, the reaction mixture was washed twice with 80 cm 3 of water, with 80 cm 2 of brine, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0,040,063 mt, height 17 cm, diameter 3.2 cm), eluting under pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (80/20 in volumes) and collect fractions of 40 cm ³ . fractions 5 to 8 were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was stirred with diisopropyl oxide, the solid filtered, filtered and then dried under reduced pressure (2.7 kPa) to give 0.25 g of 1- [bis- (phtolyl) methyl] -3 - (- methylsulfonyl-phenyl-methylene) azetidine, in the form of a white solid. [RMN spectrum in DMSO-d6, T = 300K, δ in ppm (250 Mhz): 2.23 (6H, s, 2 Ph-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 = 7 Hz, 4CH aromatic), 7.43 (5H, s, phenyl)].

1- [bis- (p-tolyl) methyl] -3 - [(methylsulfonyl) -phenyl-methyl- (S)] azetidin-3ol can be obtained as follows: to a solution of 0.59 g of bromo (bis- p-tolyl) methane, in 20 cm ^{3 of} acetonitrile, 0.6 g of 3 - [(methylsulfonyl) (phenyl) methyl (III)] azetidin-3-ol, then 0.3 g of potassium carbonate are added. After 1 hour and 15 minutes of heating at reflux temperature, the reaction mixture was cooled to 20 ° C and filtered. The filtrate was concentrated to dryness under reduced pressure (2.7 kPa) and the residue was chromatographed on a silica gel column (particle size 0.04-0.06 mm, height 16 cm, diameter 4 cm), eluting with a mixture of cyclohexane and ethyl acetate (70/30 in volumes) and fractions of 50 cm ³ were collected. Fractions 8 to 13 were concentrated to dryness under reduced pressure (2.7 kPa). 0.48 g of 1- [bis- (p-tolyl) methyl] -3 [(methylsulfonyl) (phenyl) methyl- (S)] azetidin-3-ol are obtained as a white solid.

Bromo (bis-p-gopolyl) methane can be obtained as described by BACHMANN W.E., J. Am. Chem. Soc., 2135, (1933).

Chlorhydrate of 3 - [(methylsulfonyl) phenyl-methyl- (K8)] azetidin-3-ol can be obtained by working as follows: to a solution of 2.62 g of 3 - [(methylsulfonyl) (phenyl) methyl- (1S)] -1 (vinyloxycarbonyl) azetidin-3-ol in 12.6 cm-2 dioxane, a 12.6 cm ³ 6.2N hydrochloric acid solution in dioxane was added. After stirring at 20 ° C for 20 hours, the mixture was concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue was extracted with 25 cm ^{3 of} ethanol, refluxed for 1 hour, then allowed to return to 20 ° C and filtered. The solid was washed with diethyl oxide, then drained and dried under reduced pressure (2.7 kPa). 1.89 g of 3 - [(methylsulfonyl) phenyl-methyl- (K8)] azetidin-3-ol hydrochloride are obtained as white crystals.

3 - [(methylsulfonyl) (phenyl) methyl- (S)] - 1- (vinyloxycarbonyl) azetidin-3ol can be obtained by working as follows: to a mixture cooled to +5 ° C at 3.92 g 1-Benzhydryl-3 [(methylsulfonyl) (phenyl) methyl- (K8)] azetidin-3-ol in 500 cm ³ anhydrous dichloromethane, a solution of 0.99 cm vinyl chloroformate in 4 cm ³ anhydrous dichloromethane was added dropwise. After stirring at 20 ° C for 48 hours, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.04 - 0.06 mm, height 15.5 cm, diameter 5.6 cm), eluting with a mixture of cyclohexane and ethyl acetate (70/30 in volumes) and collect fractions of 50 cm ³ . Fractions 17 to 36 were concentrated to dryness under reduced pressure (2.7 kPa). 0.9 g of 3 - [(methylsulfonyl) (phenyl) methyl- (S)] - 1- (vinyloxycarbonyl) azetidin-3-ol, the white solid form, are obtained.

1-Benzhydryl-3 - [(methylsulfonyl) (phenyl) methyl- (S)] azepidin-3-ol can be prepared by working as described in Example 1 (method 1) starting from 47 cm diisopropylamine, 205.6 cm solution of p-butyllithium 1.6M in hexane, 2.2 liters of tetrahydrofuran 50 g of benzylmethylsulfone and 69.6 g of 1-benzhydryl-azetidin-3-one. 94.3 g of 1-benzhydryl-3 - [(methylsulfonyl) (phenyl) methyl- (K8)] azetidin-3-ol are obtained as white crystals.

Example 7

1- [bis- (3-fluorophenyl) methyl] -3- (K8) - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine can be prepared by working as described in Example 3, starting from 0 , 10 g of 1- [bis- (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine, 2 cm ^{3 of} methanol, 2 cm ^{3 of} dichloromethane, and 20 mg of sodium hydroboride while stirring over 48 hours at 20 ° C. The crude material is chromatographed on a silica gel column (particle size 0,063 - 0,200 mm, height 7 cm, diameter 1 O cm), eluting under pressure of 0,01 bar from argon with dichloromethane and collecting fractions of 4 cm, fractions 3 to 7 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 95 mg of 1- [bis- (3-fluorophenyl) methyl] -3- (K8) - [(3,5difluorophenyl) methylsulfonyl-methyl] azetidine are obtained in the form of white crystals [RMN spectrum ^X H (300 MHz, CDCl ₃₎ , δ in ppm): 2.57 (t: J = 7.5Hz: 1H); 2.66 (s: 3H); from 3.15 to 3.3O (mt: 2H); from 3.30 to 3.50 (mt: 1H); 3.66 (t width, J = 7.5 Hz: 1H); 4.27 (d, J = 11.1, 5 Hz: 1H); 4.28 (s: 1H); om 6.75 to 7.35 (mt: 11H)].

1- [bis- (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine can be obtained by working as described in Example 6, starting from 1.15 g 1- [bis (3fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl (RS)] 3emuguH-3-oA, 30 cm dichloromethane, 0.264 cm methylsulfonyl chloride, and 0.98 g 4- dimethylaminopyridine. Obtained, after chromatography on a silica gel column (particle size 0,06 0,200 mm, height 25 cm, diameter 2.8 cm), under pressure of 1 bar of argon, eluting with a mixture of ethyl acetate and cyclohexane (15/85 in volumes ) and fractions of 60 cm ³ were collected, 0.55 g of 1- [bis- (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine as a white solid, melting at 178 ° S.

1- [bis (3-fluorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methyl- (S)] azetidin-3-ol can be obtained by working as follows: to a mixture cooled to -60 ° C of diisopropylamine and 10 cm ³ tetrahydrofuran, poured out for 10 minutes a 3.65 cm ³ 1.6 M solution of n-butyllithium in hexane, stirred for 10 minutes at -30 ° C, after this is cooled to -70 ° C. After 20 minutes, a solution of 1.2 g (3,5-difluorobenzyl) methylsulfone in 30 cm ^{3 of} tetrahydrofuran was added. After stirring at -70 ° C for 30 minutes, the mixture was added over 30 minutes to a solution of 1.5 g of 1- [bis (3-fluorophenyl) methyl] azetidine-

3-it in 10 st ³ tetrahydrofuran. After stirring at -70 ° C for 2 hours, the reaction mixture was brought to ambient temperature, then 20 cm ^{3 of} saturated aqueous ammonium chloride and 100 cm ^{3 of} dichloromethane were added. The mixture was decanted, the organic phase was washed with water, then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0,06-0,200 mm, height 30 cm, diameter 3.2 cm), eluting under pressure of 1 bar of argon with a mixture of ethyl acetate and cyclohexane (20/80 in volumes). and fractions of 60 cm ³ were collected. fractions 9 to 20 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.95 g of 1- [bis (3fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl (RS)] is obtained. ° C (decomposition).

1- [bis (3-fluorophenyl) methyl] azetidin-3-one can be prepared by working as described in Example 1 (method 2), starting from 0.7 cm ³ oxalyl chloride, 16 cm ³ dichloromethane, 1.12 cm ³ dimethyl sulfoxide, 2 g 1- [bis (3-fluorophenyl) methyl] azetidin-3-ol and 3.7 cm ³ triethylamine. 1.55 g of 1- [bis (3fluorophenyl) 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 by working as described by KATRITSKY AR in J. Heterocycl. Chem., 31, 271 (1994), starting from 4.9 g of [bis (3fluorophenyl) methyl] amine and 1.78 cm ^{3 of} epichlorohydrin.

[Bis (3-fluorophenyl) methyl] amine can be prepared as follows: to a suspension of 1.27 g of lithium and aluminum hydride in 80 cm ^{3 of} tetrahydrofuran is poured under an atmosphere of argon for 30 minutes a solution of 5 , 17 g of 3,3-difluorobenzophenone oxime in 30 cm ³ tetrahydrofuran. After 5 hours stirring

3 phlegmas, 1.3 cm 3 of water, 1.3 cm of soda 4N are added sequentially,

2.6 cm3 of water then 50 cm3 of ethyl acetate. After drying on magnesium sulfate and concentrating to dryness under reduced pressure (2.7 kPa), 4.9 g of [bis (3-fluorophenyl) methyl] amine are obtained as a yellow oil.

3-3'-difluorobenzophenone oxime can be prepared according to the following procedure: in a solution of 5.0 g of 3,3-difluorobenzophenone in 10 cm ethanol, a solution of 1.6 g of hydroxylamine hydrochloride in 8 cm is poured dropwise ³ water, then small fractions of 1.2 g of baking soda are added. The reaction mixture was refluxed for 10 minutes and cooled to 20 ° C, then acidified with 7.5 cm ^{3 of} hydrochloric acid 4N. The resulting oily precipitate was triturated to become a white solid, which was filtered, washed with water, then dried at 35 ° C under reduced pressure (2.7 kPa). 5.17 g of 3,3-difluorobenzophenone oxime are obtained as a white solid.

Example 8

1- [bis- (4-chlorophenyl) methyl] -3- (1 S) - {[3-azetidin-1-yl-phenyl] methylsulfonylmethyl} azetidine can be prepared by working as described in Example 3, starting from 0.10 g of 1- [bis- (4-chlorophenyl) methyl] -3 - [(azetidin-1-yl-phenyl) -methylsulfonylmethylene] azetidine, 2 cm ³ dichloromethane, and 30 mg of sodium hydroboride, stirred in for 24 hours at 20 ° C. The crude product was chromatographed on a silica gel column (particle size 0,063 - 0,200 mm, height 7 cm, diameter 1 cm), eluting under pressure of 0.1 bar from argon with dichloromethane and collecting fractions of cm ³ . The fractions 5 to 10 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 20 mg of 1- [bis- (4-chlorophenyl) methyl] -3- (S) - {[3-azetidin-1-yl-phenyl] methyl-sulfonylmethyl} azetidine are obtained in the form of broken white lacquer. [RMN spectrum ^] H (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 (t width, J = 7Hz: 1H); 3.89 (t width, J = 7.5 Hz: 4H); 4.20 (d, J = 11 Hz: 1H); 4.26 (s: 1H); om 6.35 to 6.50 (mt: 2H); 6.67 (d width, J = 7.5 Hz: 1H); om 7.10 go

7.40 (mt: 9H)].

1- [bis- (4-chlorophenyl) methyl] -3 - [(azetidin-1-yl-phenyl) -methylsulfonylmethylene] azetidine can be prepared by working as described in Example 6, starting from 0, 83 g of 1- [bis- (4-chlorophenyl) methyl] -3 - [(azetidin-1-yl-phenyl) -methylsulfonyl-methyl (RS)] 3emuguH-3-OA, 20 cm ³ dichloromethane, 0.18 cm ³ methylsulfonyl chloride, and 0.75 g of 4-dimethylaminopyridine. 0.40 g of 1- [bis- (4-chlorophenyl) methyl] -3 - [(azetidin-1-yl-phenyl) -methylsulfonylmethylene] azetidine are obtained in the form of a white kiss.

1- [bis- (4-chlorophenyl) methyl] -3 - [(azetidin-1-yl-phenyl) -methylsulfonylmethyl- (K8)] azetidin-3-ol can be prepared by working as described in Example 5, starting from 1.55 g of 1- (3-methylsulfonylmethyl-phenyl) azetidine, 5.2 cm -1 of 1.6 M solution of butyl lithium in hexane, 30 cm ^{3 of} tetrahydrofuran and 2.11 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-one. 0.83 g of 1- [bis- (4-chlorophenyl) methyl] -3 - [(azetidin-1-yl-phenyl) -methylsulfonyl-methyl (1 S)] azetidin-3-ol are obtained as a color solid of ocher melting at 172 ° C.

1- (3-Methylsulfonylmethyl-phenyl) azetidine can be prepared by working as follows: to a mixture cooled to 0 ° C at 10 cm ³ Water, 5 cm ³ acetic acid, 1.5 cm ³ sulfuric acid 36 N , and 6.15 g of oxon, a solution of 1.9 g of 1- (3-methylsulfanylmethylphenyl) azetidine in 10 cm ^{3 of} ethanol was added. After stirring for 20 hours at 20 ° C,

The reaction mixture was supplemented with 100 ml of water, 100 ml of ethyl acetate, then neutralized by stirring with sodium bicarbonate. The resulting mixture was decanted, the organic phase was dried over magnesium sulfate, then filtered and concentrated to dryness under reduced pressure (2.7 kPa). They are obtained

1.55 g of 1- [3- (methylsulfonylmethyl) -phenyl] azetidine, in the form of a light brown wood resin.

1- [3- (methylsulfonylmethyl) -phenyl] azetidine can be prepared by working as follows: to a solution of 4.6 g of 1-iodo-3 (methylsulfanylmethyl) -benzene in 60 cm ^{3 of} tetrahydrofuran are added under argon 2.57 g potassium tert-butylate, 0.64 g Ι, Ι-bis (diphenylphosphino) ferrocenyl palladium chloride, 1.49 g Ι, Γ-bis (diphenylphosphino) ferrocene, 0.12 g copper iodide, and 2, 0 g azetidine. After heating at reflux temperature for 3 hours, the reaction mixture was cooled to normal temperature, filtered on celite, then washed with 150 cm ^{3 of} ethyl acetate. The filtrate and washing liquid were combined and acidified with 120 cm ^{3 of} hydrochloric acid 1N, then decanted. The aqueous phase was added to 60 cm ^{3 of} ethyl acetate, then basified with sodium bicarbonate and the mixture was decanted. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.06

0,200 mm, height 50 cm, diameter 3,5 cm), eluting under pressure of 0,5 bar from argon with a mixture of ethyl acetate and cyclohexane (20/80 in volumes) and collecting fractions of 100 cm ³ . fractions 1 to were combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.9 g of 1- [3- (methylsulfanylmethyl) -phenyl] azetidine are obtained in the form of an oil.

1,1-Bis- (diphenylphosphino) ferrocenyl palladium chloride, can be prepared by working according to Hayashi T. et al., In J. Am. Chem. Soc., 106, 158 (1984).

F ⁴

1-iodo-3- (methylsulfanylmethyl) -benzene can be prepared by the following procedure: 6.4 g of sodium methyl thiolate are added to a solution of 25 g of 3-iodobenzyl bromide in 80 cm ст, N-dimethylformamide. After stirring at 20 ° C for 20 hours, the reaction mixture was supplemented with 250 cm ^{3 of} water, 200 cm ^{3 of} ethyl acetate and stirred and then decanted. The organic phase was washed twice with 200 cm ^{3 of} water, dried over magnesium sulfate, filtered, then 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 vegetable resin.

Example 9

Mixture of 2 diastereoisomeric forms A 1- (N *) - {4 - [(4-chlorophenyl) - {3 [(3,5-difluorophenyl) -methylsulfonyl-methyl- (R)] - 3-imidazolyl-azetidin-1-yl } methyl] benzyl} -1H-imidazole and 1- (N *) - {4 - [(4-chlorophenyl) - {3 [(3,5-difluorophenyl) -methylsulfonyl-methyl- (S)} -3-imidazolyl -azetidine98

1-yl} methyl] benzyl] -1H-imidazole, can be prepared by working as follows: to a solution of 50 mg of l - {(R *) - [4chloromethyl) phenyl] - (4-chlorophenyl) methyl} -3 [(3,5-difluorophenyl) methylsulfonylmethylene] azetidine, isomeric form A, in 1 cm ³ dichloromethane, 13.6 mg of imidazole are added. After stirring at 20 ° C for 20 h, the reaction mixture was directly chromatographed on a silica gel column (0.063-0.200 mm granularity, 7 cm in height, 1 cm in diameter), eluting under pressure of 0.1 bar of argon with a mixture of dichloromethane and methanol (98/2 by volume) and 4 cm ³ fractions were collected. Fractions 4 to 9 were combined and concentrated to dryness under reduced pressure (2.7 kPa). A 20 mg mixture of 2 diastereoisomeric forms N, N *) - {4 - [(4-chlorophenyl) - {3- [(3,5-difluorophenyl) -methylsulfonyl-methyl (1H) -3-imidazolyl-azetidine is obtained -1-yl} megpyl] benzyl] -1H-imidazole and 1- (R *) - {4 [(4-chlorophenyl) - {3- [(3,5-difluorophenyl) -methylsulfonyl-methyl- (8)} -3-imidazolyl-azetidin-1-yl} methyl] benzyl] -1H-imidazole, in the form of a white lacquer. [RMN '11 spectrum (300 MHz, CDCl ₃ , δ in ppm): diastereoisomer mixture observed, * 2.64 (s: 3H); 3.42 (d, J = 8 Hz: 1H); 3.50 (d, J = 8 Hz: 1H); 3.75 (mt: 1H); 4.31 (d width, J = 8 Hz: 1H); 4.40 (s: 1H); 4.54 in 4.55 (2s: 2H in full); 4.72 (s: 1H); 6.84 (mt: 2H); 6.87 (s: 1H); 6.95 (mt: 1H); 7.11 (s: 1H); om 7.20 go 7.40 (mt: 12H) J.

Example 10 (1-Benzhydryl-azetidin-3-yl) -phenyl-methanone O-methyl oxime, a mixture of 2 isomers Z and E, can be prepared by working as follows: to a suspension of 0.80 g 1- benzhydryl 3-benzoyl azetidine in 30 cm ethanol, 0.286 g of O-methylhydroxylamine hydrochloride, 0.32 g of sodium acetate were added. After stirring at reflux temperature for 24 hours, the reaction mixture was allowed to cool to ambient temperature and filtered. The filtrate was concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue was extracted with 100 cm @ ^{3 of} dichloromethane, and the solution was added to 20 cm @ 3 of water and 1N hydrochloric acid, stirring to acidic pH. The organic phase was decanted, dried over magnesium sulfate, then filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 36 cm, diameter 3.8 cm) eluting under pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (95/5, 92/8 then 80/20 8 volumes) and fractions of 30 cm ³ were collected. fractions 8 to 14 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.20 g of (1-benzhydryl-azetidin-3-yl) -phenyl-methanone O-methyl oxime, a mixture of 2 isomers Z and E, are obtained as a white solid. [RMN spectrum ^! And (250 MHz, (CD ₃ ) ₂ SO d6, d in ppm). An isomeric mixture of 65/35, * 2.68-3.02 and from 3.25 to 3.90 (mts: 5H in full) is observed; 3.76 and 3.80 (2s: 3H completely); 4.26 and 4.38 (2s: 1H completely); from 7.10 to

7.50 (mt: 15H)].

1-Benzhydryl 3-benzoyl azetidine can be prepared by working as follows: to a solution cooled to 0 ° C at 11.5 g (1benzhydryl-azetidin-3-yl) carboxyl-N-methoxy-N-methylamide acid in 350 cm ³ tetrahydrofuran, poured dropwise, under argon, 112 cm ³ 1M solution of phenylmagnesium bromide in tetrahydrofuran, then allowed to return to normal temperature. After stirring at 20 ° C for 20 hours, the reaction mixture was supplemented with 400 cm ^{3 of} saturated aqueous ammonium chloride, then with 250 cm ^{3 of} ethyl acetate. After stirring,

The 100 mixture was decanted, the aqueous phase was re-extracted with 250 cm ^{3 of} ethyl acetate, and the two organic phases were combined and washed twice with 250 cm 3 of water, dried over magnesium sulfate, then filtered and concentrated to dryness at 50 ° C at reduced pressure (2.7 kPa). The residue was stirred with 50 cm <RTI ID = 0.0> diisopropyl </RTI> oxide, the suspension filtered, the solid drained, then dried under reduced pressure (2.7 kPa). 9.76 g of 1-benzhydryl 3-benzoyl azetidine are obtained as a cream solid.

(1-Benzhydryl-azetidin-3-yl) carboxylic-L} -methoxy-N-methylamidic acid can be prepared by working as follows: to a suspension of 4.0 g of N, N-dimethylhydroxylamine hydrochloride in 250 cm ³ dichloromethane, 13.35 g (1-benzhydrylazetidin-3-yl) carboxylic acid, and 1.0 g hydroxybenzotriazole hydrate are added with stirring. To this mixture, placed under argon and cooled to + 5 ° C, was added 6.92 g of 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide chlorhydrate and 8.8 cm ^{3 of} N, N-diisopropylethylamine. After stirring for 3 hours at + 5 ° C, then 20 hours at 20 ° C, the reaction mixture was added to 200 cm3 of water, then decanted. The organic phase was washed with 300 cm ^{3 of} water, dried over magnesium sulfate, filtered, then concentrated to dryness * 2 under reduced pressure (2.7 kPa). The residue was stirred with 100 cm of diisopropyl oxide, the suspension filtered, and the solid was drained, then dried under reduced pressure (2.7 kPa). 10.76 g of (1-benzhydryl-azetidin-3-yl) carboxylic-N-methyl-N-methylamidic acid are obtained as a cream solid.

101 (1-Benzhydryl-azetidin-3-yl) carboxylic acid can be prepared by working as follows: to a suspension cooled to + 5 ° C on 14 g (1-benzhydryl-azetidin-3-yl) carbonitrile In 140 century ³

2-Ethoxyethanol was poured dropwise into a solution of 11 g of potassium hydroxide in 9 cm ^{3 of} water, then the mixture was heated to 95 ° C. After stirring at this temperature for 16 hours, the reaction mixture was slowly poured over ice-stirring, left at 0 ° C for 68 hours, then concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue is taken up with 400 cm @ ^{3 of} water, the solution was acidified to pH 4 with hydrochloric acid 6 N, then «h are added 400 cm of ethyl acetate. The resulting suspension was filtered, the solid was drained, then dried at 50 ° C under reduced pressure (2.7 kPa). 13.55 g of (1-benzhydryl-azetidin-3-yl) carboxylic acid are obtained as a cream solid.

(1-Benzhydryl-azetidin-3-yl) carbonitrile can be prepared by the following procedure: To a solution of 40 g of methyl-sulfonate of 1-benzhydryl-azetidin-3-yl in 350 cm ст, N-dimethylformamide is added solution of 18.54 g of sodium cyanide in 25 cm ^{3 of} water was added dropwise, then the mixture was heated to 65 ° C. After stirring at 65 ° C for 24 hours, the reaction mixture was allowed to return to normal temperature, then poured with stirring into a mixture of 550 cm of water and 300 g of ice. The resulting suspension was filtered, the solid was washed 3 times with 110 cm ^{3 of} water, then dissolved in 350 cm ^{3 of} dichloromethane. The solution was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue was stirred with 200 cm ^{3 of} diisopropyl oxide, the suspension filtered, the solid drained, then dried under reduced pressure (2.7 kPa). 28.4 g (1102 benzhydryl-azetidin-3-yl) carbonitrile are obtained as a creamy pink solid.

1-Benzhydryl-azetidin-3-yl methyl sulfonate can be prepared by working from 100 g of 1-benzhydryl-azetidin-3-ol, 800 'I * 2 * 2 cm dichloromethane, 31 cm methylsulfonyl chloride and 35 cm pyridine . The crude product obtained is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 50 cm, diameter 11 cm), eluting under pressure of 0.5 bar from argon with a mixture of cyclohexane and ethyl acetate (80/20, 75 / 25 then 70/30 and 60/40 in volumes) and fractions of 1 liter were collected. Fractions 12 to 31 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 66 g of 1-benzhydryl-azetidin-3-yl are obtained 66 g as a pale yellow solid.

1-Benzhydryl-azetidin-3-ol can be prepared by working as described by Alan R. KATRITZKY et al., In J. Heterocyclic Chem .; 31, 271 (1994).

Example 11

1- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] pyrrolidine- (P8) can be prepared by working as described in Example 3 by from 0.10 g of 1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] pyrrolidine, 1.5 cm ³ anhydrous methanol, 1.5 cm ³ anhydrous dichloromethane, and 30 mg of sodium hydroboride, was stirred for 3 hours at 20 ° C, then for 8 hours at 50 ° C. The crude product is chromatographed on a silica gel column (particle size 0,040 - 0,063 mm, height 8 cm, diameter 1 cm),

103 eluting a 0.8 bar argon pressure with a mixture of cyclohexane and ethyl acetate (80/20 in volumes) and collecting 5 cm ³ fractions. fractions 22 to 28 were combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue was stirred with 5 cm ³ pentane, the solid was filtered, drained and dried. 18 mg of 1- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3yl} methylsulfonyl-methyl) phenyl] pyrrolidine- (K8) is obtained as a white powder. [Spectrum RMN ^J H (300 MHz, CDCI _3, δ in ppm). 2.01 (mt: 4H);

2.59 (mt: 1H); 2.61 (s: 3H); om 3.10 go 3.25 (mt: 2H); 3.27 (mt: 4H); om 3.40 to 3.55 (mt: 1H); 3.66 (mt: 1H); 4.20 (d, J = 12 Hz: 1H);

4.25 (s: 1H); om 6.45 to 6.65 (mt: 3H); om 7.10 go 7.35 (mt: 9H)].

1- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] pyrrolidine can be prepared by working as described in Example 6, starting from 0, 6 g of 1- [bis- (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-pyrrolidinylphenyl) methyl (RS)] a3emuguH-3-OA, 0.1 cm ^{3 of} methylsulfonyl chloride and 0.5 g of ^4- dimethylaminopyridine, obtained The residue was purified by chromatography on a silica gel column (particle size 0,040-0,06 mm, height 30 cm, diameter 2 cm), eluting under pressure of 0.5 bar of nitrogen, eluting with a mixture of dichloromethane and ethanol (98, 5 / 1.5 in volumes) and collect fractions tions from the 10th century ³ . fraction 4 was concentrated to dryness under reduced pressure (2.7 kPa). Recrystallization from 5 cm ³ diethyl oxide yields 0.5 g of 1- [3 - ({1 [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] pyrrolidine as a melting solid at 133 ° C.

104

1- [bis- (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-pyrrolidinylphenyl) methyl- (S)] azetidin-3-ol can be prepared according to the procedure of Example 5, starting from 0.5 g of 1- [3- (methylsulfonyl-methyl) phenyl] pyrrolidine, 0.6 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-one B 15 cm ³ tetrahydrofuran and 1.4 cm 1.6N solution of n butyllithium B hexane. 0.6 g of 1- [bis- (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-pyrrolidinylphenyl) methyl- (S)] azetidin-3-ol are obtained in the form of a cream solid.

1- [3- (methylsulfonylmethyl) phenyl] pyrrolidine can be prepared by working as described in Example 8, starting from 6 cm ^{3 of} water, 6 cm ^{3 of} acetic acid 100%, 3,5 cm ^{3 of} sulfuric acid 36N , 3.11 g of oxon, 0.96 g of 1- [3- (methylsulfanylmethyl) phenyl] pyrrolidine and 6 cm @ ^{3 of} ethanol. 0.488 g of 1- [3 (methylsulfonylmethyl) phenyl] pyrrolidine are obtained in the form of a light brown gum.

1- [3- (methylsulfanylmethyl) phenyl] pyrrolidine can be prepared by working as described in Example 8, starting from 4.0 g of 1-iodo-3- (methylsulfanylmethyl) -benzene, 120 cm ³ tetrahydrofuran,

2.2 g of sodium tert-butylate, 0.556 g of Ι, Γ-bis (diphenylphosphino) ferrocenyl palladium chloride, 1.26 g Ι, Γ-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} methylsulfonyl-methyl) phenyl] -NH-methyl105 carbamic acid tertiary-butyl ester can be obtained by obtaining worked as described in Example 3 starting from 0.10 g of tertiary-butyl ester of N- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonyl-methylene) phenyl] -Nmethyl-carbamic acid, 1.5 cm ³ anhydrous methanol, 1.5 cm ³ anhydrous dichloromethane, and 30 mg sodium hydroboride, stirring for 3 hours at 20 ° C. The crude product was stirred with 10 cm ^{3 of} diisopropyl oxide, the solid filtered, drained, then dried under reduced pressure (2.7 kPa). 94 mg of N- (RS) - [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonyl-methyl) phenyl] -H-methyl-carbamic acid tertiary-butyl ester is obtained under white powder form. [RMN spectrum ^] H (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); om 3.00 to 3.55 (mt: 4H); 3.17 (s: 3H); 4.45 (s: 1H); 4.78 (d, J = 11 Hz: 1H); om 7.20 to 7.50 (mt: 12H)].

N- [3 - ({1- [6uc- (4chlorophenyl) methyl] azetidin-3-yl} methylsulfonyl-methylene) phenyl] -Methyl-carbamic acid tertiary-butyl ester can be prepared by working as described in Example 6 starting from 5.6 g of 1- [bis- (4-chlorophenyl) methyl] -3 - {[3- (1-tert-butyloxycarbonyl-N-methylamino) phenyl] methylsulfonyl-methyl- [S]} 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 was purified by chromatography on a silica gel column (particle size 0,040-0,06 mt, diameter 4 cm and weight of silica 250 g), eluting under pressure of 0.5 bar of nitrogen with a mixture of ethyl acetate and cyclohexane (30/70 in volumes) and fractions of 100 cm ³ were collected. Fractions 12 to 18 were combined, concentrated to dryness at

106 reduced pressure (2.7 kPa). 3.2 g of tertiary butyl ester of L- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonyl-methylene) phenyl] -H-methyl-carbamic acid are obtained in the form of a white kiss.

1- [bis- (4-chlorophenyl) methyl] -3 - {[3- (N-tert-butyloxycarbonyl-N-methylamino) phenyl] methylsulfonyl-methyl- (S)} azetidin-3-ol can be prepared by working as follows is described in Example 5, starting from 3.8 g of N- [3 (methylsulfonylmethyl) -phenyl] -1H-methyl-carbamic acid tertiary butyl ester, 50 cm ³ tetrahydrofuran, 9.5 cm ³ 1,6N solution of n-butyl lithium in hexane, and 3.82 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one. The crude product was purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, weight of silica 250 g), eluting under pressure of 0.5 bar of nitrogen with dichloromethane, then with a mixture of dichloromethane and ethanol (99/1 in volumes) and collect fractions of 500 cm ³ . fractions 10 to 16 were combined, concentrated to dryness under reduced pressure (2.7 kPa). 5.6 g of 1- [bis- (4-chlorophenyl) methyl] -3 - {[3- (tert-butyloxycarbonyl-N-methylamino) phenyl] methylsulfonyl-methyl (RS)} a3emuguH-3-OA are obtained in the form of a kiss .

N- [3- (methylsulfonylmethyl) -phenyl] -14methyl-carbamic acid tertiary butyl ester can be prepared by working as follows: to a solution of 3 g of N- [3- (methylsulfonylmethyl) phenyl] -N-methylamine in 80 cm dichloromethane, 3.7 g of diethyl-butyl di-carbonate are added. After stirring for 20 hours at 20 ° C, the reaction mixture was added to 100 cm ^{3 of} water, then decanted. The organic phase is dried over magnesium sulphate, filtered then concentrated to dryness under reduced pressure.

107 pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm and weight of silica 300 g), eluting under pressure of 0.5 bar of nitrogen with a mixture of ethyl acetate and cyclohexane (45 / 55 in volumes) and fractions of 100 cm ³ were collected. fractions 11 to 16 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 3.8 Gmepnuepen butyl ester of L- [3- (methylsulfonylmethyl) phenyl] -1H-methyl-carbamic acid is obtained in the form of a crystallizing resin.

N- [3- (methylsulfonylmethyl) -phenyl] -N-methylamine can be prepared by working as follows: heated at 50 ° C for 3 hours, under argon, a mixture of 9.65 cm ³ formic acid and 19.63% acetic anhydride, then the resulting solution was allowed to return to normal temperature. Pour 40 cm ^{3 of} tetrahydrofuran and cool the medium to -20 ° C. After stirring at -20 ° C for 2 hours, a solution of 14.8 g of 3 (methylsulfonylmethyl) -phenylamine was poured while maintaining the temperature. After stirring at -20 ° C for 2 hours, then at 20 ° C for 48 hours, the mixture was filtered, the solid was drained, then washed 3 times with 50 cm ^{3 of} diisopropyl oxide and dried under reduced pressure (2.7 kPa). A solid is obtained. The filtrate is concentrated to half volume, the resulting suspension is filtered, the solid is drained, washed with diisopropyl oxide, and dried. Solids B are obtained. The two solids A and B are combined and recovered with 375 cm ^{3 of} tetrahydrofuran and the mixture cooled to 0 ° C and a 80 cm 2M solution of the borane dimethyl sulfide complex in tetrahydrofuran is added over a period of 20 minutes. this set the reflux temperature for 3 hours. The reaction

108 a mixture cooled to +5 ° C was added over 60 minutes to 60 cm ³ methanol, stirred for one hour at room temperature, then gaseous hydrochloric acid was added to pH

1. The mixture is refluxed for one hour, then 300 cm ^{3 of} water and 3N sodium hydroxide solution are added, at pH 8. The resulting mixture is extracted with 500 cm ^{3 of} ethyl acetate, the organic phase is washed subsequently with saturated aqueous sodium hydrogen carbonate solution and brine, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue was extracted with 100 cm ^{3 of} sulfuric acid 4N, the resulting solution was washed with 100 cm ^{3 of} ethyl acetate, then basified to pH 8 with 3N sodium hydroxide and with saturated aqueous sodium carbonate solution, then extracted twice with 75 cm ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 8.98 g of N- [3- (methylsulfonylmethyl) -phenyl] -1H-methylamine are obtained as a pink solid.

3- (methylsulfonylmethyl) -phenylamine can be prepared by working as follows: heated to reflux a suspension of

23.7 g of 1- (methylsulfonylmethyl) -3-nitrobenzene in 150 cm of methanol and 65 cm ^{3 of} hydrochloric acid 36% are then added cautiously for 10 minutes, in small fractions, 18.5 g of iron. After 4 hours of refluxing, then stirring at ambient temperature for 20 hours, the reaction mixture is supplemented with 5g of iron, then refluxing for 1 hour, then 20 hours at ambient temperature. The mixture was then basified to pH 9 with ammonia and sodium bicarbonate, then extracted 3 times with 250

109 ο

cm3 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 obtained 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 as a white powder.

Example 13

N- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] -N-methyl-amine (I8) can be prepared by working as described in Example 3, starting from 0.10gN- [3 ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] -1H-methyl-amine, 1.5 cm ³ anhydrous methanol, 1.5 cm ³ anhydrous dichloromethane, and 45 mg sodium hydroboride, stirred for 20 hours at 20 ° C, then for 5 hours at 50 ° C. The crude product was chromatographed on a silica gel column (particle size 0,04 - 0,063 mm, height 10 cm, diameter 1 O cm), eluting under pressure of 0.8 bar from argon with a mixture of cyclohexane and ethyl acetate (80/20, after this 60/40 in volumes) and 5 cm ³ fractions were collected. Fractions 20 to 26 were combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue was stirred with 5 cm ³ pentane, the solid was filtered, filtered and dried. 20 mg of N- [3 - ({1- [6uc- (4chlorophenyl) methyl] azetidin-3-yl} methylsulfonyl-methyl) phenyl] -N-methylMUH- (RS) are obtained in the form of a white powder. [RMN '11 spectrum (300 MHz, no

CDCI ₃ , δ in ppm): om 2.50 to 2.65 (mt: 1H); 2.60 (s: 3H); 2.82 (d, J = 5 Hz: 3H); 3.18 (mt: 2H); om 3.35 to 3.50 (mt: 1H); 3.64 (t width, J = 7.5 Hz: 1H); 3.80 (mt: 1H); 4.18 (d, J = 11.5 Hz: 1H); 4.24 (s: 1H); om

6.50 to 6.70 (mt: 3H); om 7.10 go 7.35 (mt: 9H)].

N- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] -N-methyl-amine can be prepared by working as follows: for 20 stirred 2.7 g of 1 [bis (4-chlorophenyl) methyl] -3 - {[3- (N-methylphenylmethylamino) phenyl] methylsulfonyl-methylene} azetidine in 30 cm ³ dioxane Cu 30 cm ³ 4 hours. 7 N solution of hydrogen chloride dioxane. The reaction mixture was evaporated to dryness under reduced pressure (2.7 kPa), extracted with 50 cm ^{3 of} water and 50 cm ^{3 of} ethyl acetate, stirred and neutralized cautiously with saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate, treated to coarse black, then concentrated under reduced pressure (2.7 kPa) to a volume of about 25 cm ³ , then filtered, concentrated to dryness under reduced pressure. 1.3 gN- [3 - ({1- [bucc- (4-chlorophenyl) memul] azemugun-3-yl} memulcylphonylmethylene) phenyl] -1H-methyl-amine is obtained as white crystals melting at 228 ° C.

l ** ·

Example 14

1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-bis-trifluoromethylphenyl) methylsulfonylmethyl] azetidine- (I8) can be prepared by working as described in Example 3, starting from from 1- [bis (4chlorophenyl) methyl] -3 - [(3,5-bis-trifluoromethylphenyl) methylsulfonylmethylene] azetidine, 1.5 cm anhydrous methanol, 1.5 cm anhydrous

Ill dichloromethane, and 15 mg sodium hydroboride were stirred for 3 hours at 20 ° C. The crude product was stirred with 5 cm ³ pentane, the solid filtered, filtered and dried. 82 mg of 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-bistrifluoromethylphenyl) methylsulfonylmethyl] azetidine- (1 < 8 &gt;) are obtained as a white powder. [RMN H 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); by

3.45 to 3.65 (mt: 2H); 4.45 (s: 1H); 5.13 (d, J = 10.5 Hz: 1H); om 7.25 to 7.50 (mt: 8H); 8.11 (s broad: 2H); 8.15 (s broad: 1H)].

1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-bis-trifluoromethylphenyl) methylsulfonyl-methylene] azetidine can be prepared by working as follows: to a solution of 3.16 g 3- acetoxy-1- [bis (4chlorophenyl) methyl] -3 - {[3,5-bis (trifluoromethyl) phenyl] methylsulfonylMemuA- (RS)} a3emuguH in 40 cm ³ dioxane, 0.96 g of triturated soda was added to the fractions. After stirring at ambient temperature for 1 hour, the reaction mixture was made up with 200 cm ^{3 of} ethyl acetate, 200 cm ^{3 of} water, then decanted. The organic phase was washed 3 × times with 80 cm3 of water, then with 80 cm3 of brine, dried over magnesium sulfate, then 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

14.5 cm, 4.8 cm in diameter), eluting under pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (85/15 in volumes) and collecting fractions of 40 cm ³ . fractions 8 to 15 were combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.49 g of 1- [bis (4-chlorophenyl) methyl] -3 - {[3,5bis (trifluoromethyl) phenyl ] methylsulfonyl-methylene} azetidine in the form of a white kiss.

112

3-acetoxy-1- [bis (4-chlorophenyl) methyl] -3 - {[3,5-bis (trifluoromethyl) phenyl] methylsulfonyl-methyl- (RS)} ethidine can be prepared by working on as follows: to a solution cooled to -78 ° C, 2.0 g of [3.5bis (trifluoromethyl) benzyl] methylsulfone in 35 cm tetrahydrofuran, poured dropwise, under argon, 4.1 cm ³ 1.6 N solution of butyl lithium in hexane. After stirring at -70 ° C for 1 hour, a solution of 2.0 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3one in 35 cm ³ tetrahydrofuran was added dropwise. After stirring at -78 ° C for 2 hours, a solution of 0.7 cm ^{3 of} acetyl chloride in 5 cm ^{3 of} anhydrous diethyl oxide was poured, then the mixture was allowed to return to normal temperature. After 2 hours and 30 minutes of stirring, the reaction mixture was added to 100 ml of water and decanted. The organic phase was washed with 100 cm ^{3 of} water, then with 100 cm ^{3 of} brine, then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0,04-0,06 mt, height 16 cm, diameter 5,6 cm), eluting under pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane and (10 / 90, then 40/60 in volumes) and 100 cm ³ fractions were collected. fractions 37 to 52 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 3.56 g of 3-acetoxy-1- [bis (4chlorophenyl) methyl] -3 - {[3,5-bis (trifluoromethyl) phenyl] methylsulfonylMemuA- (RS)} a3emuguH are obtained as a white kiss.

[3,5-Bis (trifluoromethyl) benzyl] methylsulfone can be obtained by refluxing 1.8 g of 3.5-bis 12 (trifluoromethyl) benzyl chloride, 50 cm absolute ethanol and 1.22 g

113 Sodium methylsulfinate. 1.86 g of [3,5bis (trifluoromethyl) benzyl] methylsulfone are obtained as a white solid.

Example 15

N- [4 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonyl-methyl (RS)] a3emuguH-1-uA} MemuA- (RS)) - 6eH3UA] -N, N- guMemuA-aMiiH, a mixture of two diastereoisomers can be prepared by working as described in Example 3, starting from 0.10 g of N 4 - [4 - ((4-chlorophenyl) - {3 [(3,5 -difluorophenyl) methylsulfonyl-methylene] azetidin-1-yl} -methyl (RS)) - 6eH3UA] -N, N-guMemuA-aMUH, 1.5 cm ³ anhydrous methanol, 1.5 cm ³ anhydrous dichloromethane, and 45 mg sodium hydrogen chloride, stirred for 16 hours at 20 ° C, then stirred for 16 hours at 50 ° C. The crude product was chromatographed on a silica gel column (particle size 0.040 - 0.063 mm, height 22 cm, diameter 1 cm), eluting under pressure of 0.8 bar from argon with a mixture of ethyl acetate and methanol and (97/3 in volumes) and 20 cm ³ fractions were collected. fractions 17 to 25 were combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue was stirred with 5 cm ³ pentane, the solid was filtered, filtered and dried. 6 mg of N- [4 - ((4-chlorophenyl) - {3 - [(3,5difluorophenyl) methylsulfonyl-methyl-N8)] azetidin-1-yl} methyl- (L8) 6ei3UA] -N, N is obtained -guMemuA-aMUH, a mixture of two diastereoisomers, in the form of a white powder. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.20 (s: 6H); 2.53 (t, J = 7 Hz: 1H); 2.65 (s: 3H); om 3.10 go

3.25 (mt: 2H); om 3.30 to 3.45 (mt: 1H); 3.35 (s width: 2H); 3.63 (t width, J = 7 Hz: 1H); 4.24 (s: 1H); 4.25 (d, J = 11 Hz: 1H); 6.82 (tt, J = 9 at 2 Hz: 1H); 6.94 (mt: 2H); om 7.15 to 7.35 (mt: 8H)].

114

B1- [4 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-1-yl} methyl-N (8)) -benzyl] -N, N-dimethyl-amine may is obtained by working as follows: to a solution of 0.93 * 2 cm 2M solution of dimethylamine in methanol in 30 cm anhydrous 1,2 dichloroethane is added under argon 1,0 g (1 <5) -4 - (( 4-chlorophenyl) - {3 - [(3,5difluorophenyl) methylsulfonylmethyl] azetidin-1-yl} methyl) benzaldehyde. After stirring at ambient temperature for 30 minutes, 0.9 g of sodium triacetoxy borohydride were added in small fractions. After stirring for 48 hours, 2.65 cm ^{3 of} sodium hydroxide 1 N, 100 cm ^{3 of} water and 100 cm ^{3 of} dichloromethane were added to the reaction mixture, then decanted. The organic phase was washed twice with 80 cm ^{3 of} water and with 80 cm ^{3 of} brine, then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.04-0.06 mm, height 17.5 cm, diameter 4 cm) eluting under pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane and (30 / 70 in volumes) and fractions of 40 cm ³ were collected. fractions 48 to 53 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.46 g of N- [4 - ((4-chlorophenyl) - {3 - [(3,5difluorophenyl) methylsulfonyl-methylene] azetidin-1-yl} methyl-N- (8) are obtained. -aMUH as a white solid.

(R 8) -4 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] azetidin-1-yl} methyl) -benzaldehyde can be prepared by working as follows: to a solution of 18.9 g of 1 - [(4-chlorophenyl) (4- [1,3] dioxolan-2-yl-phenyl) methyl] - (R 8) -3 - ((3,5-difluorophenyl) methylsulfonyl-methylene] azetidine in 80 cm < 2 &gt; tetrahydrofuran, 75.6 cm &lt; 5 &gt; of hydrochloric acid were added, After 3 hours at room temperature, the mixture was extracted with dichloromethane

115 distilled water, then the pH was adjusted to 14 by the addition of 30% soda and decanted. The organic phase was washed twice with 100 cm ^{3 of} water, then with 100 cm ^{3 of} saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 16 g (K8) -4 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonylmethylene] azetidin-1-yl} methyl) -benzaldehyde are obtained in the form of a white kiss.

1 - [(4-chlorophenyl) - (4- [1,3] dioxolan-2-yl-phenyl) methyl] - (R 8) -3 - [(3,5-difluorophenyl) methylsulfonyl-methylene] azetidine can be prepared by the following method: to a solution of 34.45 g of a mixture of two diastereoisomeric acetates of 1 - [(4-chlorophenyl) - (4- [1,3] dioxolan-2-ylphenyl) methyl] - (1 S) -3 - [( 3,5-difluorophenyl) -methylsulfonyl-methyl (RS)] a3emuguH-3-UA in 400 cm ³ tetrahydrofuran under argon at 0 ° C, 13.0 cm ³ 1,8-diazabicyclo [5-4 are added dropwise -0] undec-7-ene and after the usual treatment the product is chromatographed on a silica gel column (particle size 0,04-0,06 mm, height 23 cm, diameter 10,2 cm), k then eluting under pressure 0,5 bar of argon with a mixture of ethyl acetate and cyclohexane (20/80 by volume) and collecting fractions of 250 cm ^3, yielding 16,6 g 1 - [(4-chlorophenyl) - (4- [1,3] dioxolan-2-yl-phenyl) methyl] - (R 8) -3 - [(3,5-difluorophenyl) methylsulfonyl-methylene] azetidine as a white solid.

A mixture of two diastereoisomeric acetates of 1 - [(4-chlorophenyl) - (4 [1,3] dioxolan-2-yl-phenyl) methyl] - (1 S) -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl - (1S)] azetidin 3-yl can be prepared as follows: proceeding according to example 1 (method 2) starting from 11.6 g (3,5-difluorobenzyl) methylsulfone, 35.1 cm 1, 6N

116 solution of η butyl alcohol in hexane, 19.3 g of 1 - {(4-chlorophenyl) [4 - ([1,3] dioxolan-2-yl) phenyl] methyl- (1 < 8 &gt;) azetidin-3-one and 8.8 cm ³ acetyl chloride in 500 cm ³ tetrahydrofuran yielded 37.8 g of a mixture of two diastereoisomeric acetates of 1 - [(4-chlorophenyl) - (4- [1,3] dioxolan-2-ylphenyl) methyl ] - (K8) -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl (K8)] azetidin-3-yl as a white kiss.

1 - {(4-chlorophenyl) [4 - ([1,3] -dioxolan-2-yl) phenyl] methyl- (R 8)} azetidin-3-one can be prepared as follows: to a solution of 28, 32 g of 1 - {(4-chlorophenyl) [4 - ([1,3] -dioxolan-2-yl) phenyl] methyl- (P8)} azetidin-3-ol in 200 cm ³ dimethyl sulfoxide were added at room temperature 46 cm ³ triethylamine, then a solution of 34 g of the sulfur-pyridine trioxide complex in 100 cm ^{3 of} dimethyl sulfoxide was added dropwise. After 0.25 hours at room temperature, the reaction mixture was poured onto ice, extracted with ethyl acetate, washed 3 times with 400 cm ^{3 of} water, then with 400 cm ^{3 of} saturated sodium chloride solution, dried over magnesium sulfate, Filter and concentrate to dryness under reduced pressure (2.7 kPa). The resulting residue was chromatographed on a silica gel column (particle size 0.04-0.06 mm, height 21 cm, diameter 9.2 cm), pressurized with 0.5 bar of argon, eluting with a mixture of ethyl acetate and cyclohexane and (20 / 80 in volumes) and fractions of 250 centimeters were collected. fractions 9 to 18 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 20.4 g of 1 - {(4-chlorophenyl) [4 - ([[1,3] -dioxolan-2-yl) phenyl] methyl- (P8)} azetidin-3-one are obtained as a yellow oil.

1 - {(4-chlorophenyl) [4 - ([1,3] -dioxolan-2-yl) phenyl] methyl-N- (8)} azetidin-3-ol can be prepared as described in Example 3, such as starting from 35.0 g {(4-chlorophenyl) [4- (1,3-dioxolan-2-yl) phenyl] methyl} amine, 8.3 g

117 epibromhydrin, 5.1 g of sodium bicarbonate and 400 cm ^{3 of} ethanol. 30.3 g of 1 - {(4-chlorophenyl) [4 - ([1,3] -dioxolan-2yl) phenyl] methyl- (S)} azetidin-3-ol are isolated.

Chlorhydrate of {(4-chlorophenyl) [4 - ([1,3] -dioxolan-2-yl) phenyl] methyl (RS)} aMUH can be obtained by the method described by GRISAR M. et al., J.Med . Chem., 885 (1973) starting from 67.2 g of 4 - ([1,3-dioxolan-2-yl) benzonitrile, 88.2 g of 1-bromo-4-chlorobenzene, 11 g of magnesium and 600 cm ^{3 of} ethyl ether . 42.3 g of {(4-chlorophenyl) [4 - ([1,3] dioxolan-2-yl) phenyl] methyl- (K 8)} amine are obtained as a yellow oil.

Example 16

1 - [(4-chlorophenyl) - (thien-2-yl) -methyl- (P8)] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl- (S)] azetidine, a mixture of two diastereoisomers, may was prepared by working as described in Example 3, starting from 0.10 g of 1 - [(4-chlorophenyl) - (thien-2-yl) -methyl- (K 8)] -3 - [( 3,5difluorophenyl) methylsulfonylmethylene] azetidine, 1.5 cm anhydrous methanol, 1.5 cm anhydrous dichloromethane, and 45 mg sodium hydroboride, stirred for 16 hours at 20 ° C, then for 16 hours hours at 50 ° C. The crude product was chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 25 cm, diameter 1 cm), eluting under a pressure of 1 bar of argon with a mixture of cyclohexane and ethyl acetate (90/10 in volumes) and collected fractions of 20 cm ³ . Fractions 37 to 42 were combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue was stirred with 5 cm ³ pentane, the solid was filtered, filtered and dried. 8 mg of 1 - [(4-chlorophenyl) - (thien-2-yl) -methyl- (S)] - 3 - [(3,5-difluorophenyl) methylsulfonyl-methyl- (K8)] azetidine, a mixture of two diastereoisomers, are obtained under

118 white powder form. [RMN H spectrum (300 MHz, CDCl ₃ , δ B ppm). A mixture of diastereoisomers from 2.50 to 2.70 (mt: 1H) was observed; 2.66 and 2.68 (2s: 3H completely); from 3.15 to 3.80 (mt: 4H); from 4.20 to 4.30 (mt: 1H); 4.31 and 4.57 (2s: 1H completely); from 6.80 to 7.00 and from

7.10 to 7.40 (mts: 10H in full)].

1 - [(4-chlorophenyl) - (thien-2-yl) -methyl- (R 8)] -3 - [(3,5-difluorophenyl) methylsulfonyl-methylene] azetidine can be prepared by working as described in example 6, starting from 0.52 g of a mixture of two diastereoisomers 1 - [(4-chlorophenyl) (thien-2-yl) -methyl-N 8)] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl ( RS)] a3emuguH-3-OA, 0.14 cm methylsulfonyl chloride and 0.49 g 4 dimethylaminopyridine. After chromatography on a silica gel column (granulometry 0.06-0.200 mm, height 20 cm, diameter 2.4 cm), eluting under pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (20/80 in volumes) and fractions of 30 cm ³ were collected, 0.32 g of N 8) -1 - [(4-chlorophenyl) - (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl- methylene] azetidine as a white solid, melting at 176 ° C.

Mixture of two diastereoisomers 1 - [(4-chlorophenyl) - (thien-2-yl) -methyl (N)] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl- (1 S)] azetidin-3- ol, can be prepared by working as described in Example O, starting from a 1.60 cm ³ n-butyllithium 1,6N solution in hexane, 0.83 g (3,5-difluorobenzyl) methylsulfone and 1, 06 g of 1 - [(4-chlorophenyl) (thien-2-yl) methyl- (K 8)] azetid-3-one. After purification on a silica gel column (granulometry 0,06-0,200 mm, height 30 cm, diameter 2.8 cm), eluting under pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 in volumes ) and se

119 collected fractions of 40 cm ³ , 0.55 g of a mixture of diastereoisomers 1 - [(4-chlorophenyl) - (thien-2-yl) -methyl- N - 8)] - 3 - [(3,5 difluorophenyl) - methylsulfonyl-methyl- (S)] azetidin-3-ol, in the form of a brittle white solid.

1 - [(4-chlorophenyl) (thien-2-yl) methyl- (1 S)] azetid-3-one can be prepared by working as described in example 1 (method 2), starting from 1, 83 cm ³ oxalyl chloride, 20 cm ³ dichloromethane, 3.04 cm dimethylsulfoxide, 5.2 g 1 - [(4-chlorophenyl) (thien-2-yl) methyl (RS)] a3emugu-3-OA, 80 cm ³ dichloromethane, and 9.12 cm ^{3 of} triethylamine. 3.3 g of 1 - [(4-chlorophenyl) (thien-2-yl) methyl- (1 S)] azetidin-3one are obtained in the form of a yellow oil which crystallizes at ordinary temperature.

1 - [(4-chlorophenyl) (thien-2-yl) methyl-N- (8)] azetid-3-ol can be prepared by working as follows: to a solution of 11.0 g [(4-chlorophenyl) ) (Thien-2-yl) megpyl- (S)] amine in 80 cm ethanol was added 4.12 g of sodium bicarbonate. The mixture was heated to 65 ° C by the addition of 4.03 cm ³ epibromhydrin. After stirring at 65 ° C for 20 hours, the mixture was cooled and filtered and the filtrate was concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0,060,200 mt, height 32 cm, diameter 3.6 cm), eluting under pressure of 0.5 bar of argon with a mixture of ethyl acetate and cyclohexane (25/75 in volumes) and collect fractions of 60 cm ³ . They are obtained

6.3 g of 1 - [(4-chlorophenyl) (thien-2-yl) methyl- (S)] azetid-3-ol, as a pale yellow oil.

[(4-Chlorophenyl) (thien-2-yl) methyl- (K8)] amine can be prepared as follows: to a slurry cooled to 10 ° C to 4120 chlorophenylmagnesium bromide (obtained from 19,15 g of 4bromochlorobenzene and 2.43 g of magnesium) in 120 cm ^{3 of} anhydrous ethyl ether, a slow solution of 10.92 g of 2-thiophenecarbonitrile in 80 cm ^{3 of} diethyl oxide was poured. After one hour at reflux, the mixture was cooled to 10 ° C, 40 cm ^{3 of} methanol was slowly added and then filtered on supercell. 4.54 g of sodium borohydride are added under argon and in small fractions for 15 minutes, then the reaction medium is stirred for 20 hours at 20 ° C. The resulting mixture was diluted with ethyl acetate, then washed with water. The organic phase was dried over magnesium sulfate, concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0,06-0,200 mm, height 42 cm, diameter 5 cm), eluting under pressure of 0.5 bar from argon with a mixture of ethyl acetate and cyclohexane (4/6 in volumes). and 100 cm ³ fractions were collected. fractions 6 to 12 were concentrated to dryness, respectively, to 13 g of imine as a yellow oil, which was taken back in 100 cm ^{3 of} methanol. The resulting solution was added to 2.4 g of sodium borohydride, and stirred for one hour at 5 ° C. The resulting mixture was diluted with ethyl acetate, then washed with water. The organic phase was dried over magnesium sulfate, 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, height 40cm, diameter 3,2cm), eluting under pressure of 0,5 bar from argon with a mixture of ethyl acetate and cyclohexane (4/6 in volumes). and fractions of 60 cm were collected. 11, g of [(4-chlorophenyl) (thien-2-yl) methyl- (S)] amine are obtained as a yellow oil.

Example 17

121 [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] methanol- (I8) can be prepared by working as described in Example 3, starting from of 0.050 g [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] methanol, 1.0 cm ³ anhydrous methanol, 1.0 cm ³ anhydrous dichloromethane, and 20 mg sodium hydroboride, stirred for 3 hours at 20 ° C. The crude product was chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 20 cm, diameter 1 cm), eluting under pressure of 0.8 bar from argon with a mixture of cyclohexane and ethyl acetate (90/10 in volumes) and fractions of 10 cm ³ were collected. fractions 30 to 38 were combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue was stirred with 5 cm ³ pentane, the solid was filtered, drained and dried. 13 mg of [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] methanol (RS) are obtained in the form of a white powder. [RMN spectrum ^] H (300 MHz, CDCl ₃ , δ in ppm): 1.75 (t, J = 6 Hz: 1H); 2.52 (t, J = 7.5 Hz: 1H); 2.59 (s: 3H); 3.17 (t width, J = 7.5 Hz: 2H); 3.48 (mt: 1H); 3.65 (mt: 1H); 4.23 (s: 1H); 4.28 (d, J = 11.1, 5 Hz: 1H); 4.70 (d, J = 6 Hz: 2H); om 7.15 go 7.40 (mt: 12H)].

[3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] methanol can be obtained by working as follows: to a solution cooled to + 5 ° C, at 5.1 g of 1- [bis- (4-chlorophenyl) methyl] -3 - {[3- (tertiarybutyldimethylsilyloxymethyl) phenyl] methyl-sulfonyl-methylene} azetidine in 51 cm ³ tetrahydrofuran, pour 17 cm ^{3 of a} 1M solution of tetrabutylammonium fluorine tetrahydrofuran. After stirring for 20 minutes, it was then cooled for 3 hours at 20 ° C, the reaction

The mixture was poured into a mixture of 200 cm ^{3 of} water and 100 cm ^{3 of} ethyl acetate, then decanted. The organic phase was washed with water, dried over magnesium sulfate, then filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue was purified by chromatography on a silica gel column (particle size 0,04-0,06 mm, height 30 cm, diameter 2 cm), eluting under pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and ethanol (97 / 3 in volumes) and fractions of 100 cm ³ were collected. fractions 10 to 14 were combined, concentrated to dryness under reduced pressure (2.7 kPa). The yellow solid obtained was extracted with ² cm ^{3 of} dichloromethane and 10 cm ^{3 of} ethyl acetate, then filtered on a glass frit and washed with 2 cm ^{3 of} ethyl acetate. They are obtained

1.6 g of [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethylene) phenyl] methanol as a white solid, melting at 214 ° C.

1- [bis- (4-chlorophenyl) methyl] -3 - {[3- (tertiarybutyldimethylsilyloxymethyl) phenyl] methylsulfonylmethyl} azetidine can be prepared by working the procedure of Example 1 starting from 10, 8 g of 1- [bis (4-chloro-phenyl) methyl] -3 - {[3- (tertiarybutyldimethylsilyloxymethyl) phenyl] methylsulfonyl-methyl (S)} azetidin-3-ol, 2 cm ³ methylsulfonyl chloride and 8.5 g 4Dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0,04-0,06 mt, height 40 cm, diameter 4 cm), pressurized with 0.5 bar of nitrogen, eluting with dichloromethane and collecting fr. 100 st shares ³ . Fractions 12 to 29 were combined, concentrated to dryness under reduced pressure (2.7 kPa). 5.2 g of 1- [bis- (4-chlorophenyl) methyl] -3 - {[3- (tertiarybutyldimethylsilyloxymethyl) phenyl] methyl-sulfonyl-methylene} azetidine are obtained

123 nog resin form.

- [bis (4-chloro-phenyl) methyl] -3 - {[3- (tertiarybutyldimethylsilyloxymethyl) phenyl] methylsulfonyl-methyl (RS)} a3emuguH-3-OA can be prepared by the method of Example 5, such as starting from 5.8 g of tertiary-butyl- (3-methylsulfonylmethyl-benzyloxy) dimethyl-silane and 5.6 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one, 10.8 g of 1- [ bis (4-chlorophenyl) methyl] -3 - {[3- (tertiarybutyldimethylsilyloxymethyl) phenyl] methylsulfonylmethyl (RS)} a3emuguH-3-oA in the form of a resin.

Tertiary-butyl- (3-methylsulfonylmethyl-benzyloxy) dimethyl-silane can be prepared by working as follows: to a solution of 5.73 g (3-methylsulfonylmethyl-phenyl) methanol in 50 cm @ ³ , N-dimethylformamide, 4.87 g of imidazole are added followed by 10.3 cm ^{3 of} tertiary-butyl chlorodimethylsilane. After stirring at ambient temperature for 20 hours, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.06-0.200 mt, 3.5 cm diameter, weight of silica 100 g), eluted under pressure of 0.5 bar of nitrogen with dichloromethane, and fractions of 100 were collected. Article ³ . Fractions 2 to 7 were combined, concentrated to dryness under reduced pressure (2.7 kPa). 5.8 g of an oil are obtained which crystallizes at ordinary temperature. PF = 75 ° C.

(3-Methylsulfonylmethyl-phenyl) methanol can be obtained by working as follows: stirring for 18 hours at a temperature close to 20 ° C with a mixture of 26 g of 3- (methylsulfonylmethyl) benzoic acid and 4.6 g of lithium hydride and aluminum in the 600's ³

124 tetrahydrofuran. The solution was cooled to 0 ° C, then 15 cm ^{3 of} ethyl acetate, 5 cm ^{3 of} water, 5 cm ^{3 of} 15% aqueous soda solution were added successively, and finally 30 cm ^{3 of} water. The mixture was filtered over celite, the filtrate was extracted with 600 cm ^{3 of} ethyl acetate. The organic phase was extracted with 500 cm ^{3 of} water, then with 200 cm 3 of saturated aqueous sodium chloride solution, decanted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). They are obtained

10.4 g (3-methylsulfonylmethyl-phenyl) methanol, in the form of a resin.

3- (methylsulfonylmethyl) benzoic acid can be prepared as follows: proceeding from Example 14 starting from

23.3 g of 3-chloromethylbenzoic acid and 23.3 g of sodium methanesulfinate give 26 g of 3- (methylsulfonylmethyl) benzoic acid as a white solid, melting at 210 ° C.

Example 18

1- [bis- (4-chlorophenyl) methyl] -3- (phenylsulfonylmethyl) -azetidine can be prepared by working as follows: to a solution of 0.15 g of 1- [bis- (4-chlorophenyl) methyl) ] -3- (Phenylsulfonylmethylene) -azetidine in 3 cm anhydrous ethanol and 3.5 cm anhydrous dichloromethane were added under argon 13 mg sodium borohydride. After 1 hour and 45 minutes of stirring, 14 mg of sodium borohydride was added again, then allowed to stir for 20 hours at 20 ° C. The reaction mixture was then heated to 50 ° C, 9.5 mg of sodium hydroboride was added and allowed to stir for 2 hours and 30 minutes at 50 ° C, then cooled to normal temperature. Then a mixture of 0.5 cm ^{3 of} water, 10 cm ^{3 was added}

125 dichloromethane, then 50 mg magnesium sulfate, and filtered, then evaporated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0,063-0,200 mm, height 15 cm, diameter 1 cm), eluted under pressure of 0.5 bar from argon with a mixture of cyclohexane and ethyl acetate (80/20 in volumes) and collected. fractions of 5 cm ³ . fractions 12 to 19 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 29 mg of 1- [bis- (4-chlorophenyl) methyl] -3 (phenylsulfonylmethyl) -azetidine are obtained in the form of a white solid. [RMN spectrum ^X H (300 MHz, CDCl ₃ , δ in ppm): 2.75 to 8.90 (mt: 3H); 3.32 (mt: 2H); 3.37 (d, J = 7 Hz: 2H); 4.22 (s: 1H); om 7.20 to 7.30 (mt: 8H); 7.57 (t width, J = 7.5 Hz: 2H); 7.67 (mt, J = 7.5 in 1.5 Hz: 1H); 7.88 (d width, 1 = 7.5 Hz: 2H)].

Example 19

1- [bis- (4-chlorophenyl) methyl)] - 3- (phenylsulfonylmethylene) -azetidine can be prepared by working as follows: to a solution cooled to -70 ° C, under argon, at 4.34 g (phenylsulfonylmethyl) trimethylsilane in 40 cm ³ dimethyl ether, poured out for 5 minutes a 12 cm 1,6 m solution of n-butyllithium in hexane. After 30 minutes of stirring the mixture at -60 ° C, a solution of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-one in 30 cm dimethyl ether was poured over 10 minutes [produced in the form of a base obtained by treatment with 7.35 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-one dissolved in 30 cm ^{3 of} water, 25 cm ^{3 of} sodium hydroxide 1N and extraction of the resulting base with 30 cm ^{3 of} diethyl oxide, after this is dried and concentrated to dryness under reduced pressure (2.7 kPa). After 45

After stirring at -70 ° C for 126 minutes, then at 20 ° C for 2 hours, the reaction mixture was added to 12 cm ^{3 of} saturated aqueous ammonium chloride solution, 20 cm 3 of water, then extracted twice with 40 cm 2 of ethyl acetate. The organic phases were combined with 40 cm3 of water, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa). The resulting oil was chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 40 cm, diameter 5 cm), eluted under pressure of 0.5 bar from argon with a mixture of cyclohexane and ethyl acetate (90/10, then 85 / 15 in volumes) and fractions of 100 cm ³ were collected. Fractions 10 to 16 were combined and concentrated to dryness under reduced pressure (2.7 kPa). The resulting oil was crushed into 10 cm ^{3 of} diethyl oxide, the suspension filtered, and the solid dried. 1.17 g of 1- [bis- (4-chlorophenyl) methyl)] -3 (phenylsulfonylmethylene) -azetidine are obtained as a white solid. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm): 3.88 (mt: 2H); 4.29 (mt: 2H); 4.50 (s: 1H); 6.17 (mt: 1H);

om 7.20 to 7.40 (mt: 8H); 7.56 (t width, J = 7.5 Hz: 2H); 7.64 (mt, J = 7.5 in 1.5 Hz: 1H); 7.87 (d width, J = 7.5 Hz: 2H)].

(phenylsulfonylmethyl) trimethylsilane can be obtained by working as follows: to a solution cooled to -70 ° C, of 3g methyl phenyl sulfone in 40 cm ³ anhydrous tetrahydrofuran, poured under argon for 20 minutes 13 cm ³ 1.6M solution of p-butyllithium in hexane. After stirring at -70 ° C for 30 minutes, 2.66 cm @ ^{3 of} trimethylchlorosilane were added to the mixture and heating was stopped. After stirring at ordinary temperature for 4 hours, the reaction mixture was added to 30 cm 3 of water and extracted with 30 cm ^{3 of} ethyl acetate. The organic phase is washed with 30

127 cm ³ Water, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). They are obtained

4.34 g (phenylsulfonylmethyl) trimethylsilane, as a yellow liquid.

Example 20

2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylmethylsulfonyl} pyridine can be prepared by working as follows: to a solution of 0.25 g 2- {1- [bis- ( 4-chlorophenyl) methyl] -azetidin-3- <3-ylidenemethylsulfonyl} pyridine in a 20 cm mixture of 50/50 dichloromethane and ethanol, 0.125 g of sodium hydroboride are added. After stirring at 50 ° C for 1 hour, the reaction mixture was cooled to 20 ° C, 20 cm-3 of dichloromethane, 1 cm of water and 0.1 g of magnesium sulfate were added. The mixture was filtered, and the filtrate was concentrated at 50 ° C under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (granulometry 0.040-0.063 mm, height 15 cm, diameter 1 cm), eluting under pressure of 0.5 bar from argon with a mixture of cyclohexane and ethyl acetate (40/60 in volumes) and fractions of 10 cm ³ were collected. fractions 5 to 10 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of 2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3ylmethylsulfonyl} pyridine are obtained in the form of a white powder. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.80 to 3.00 (mt: 3H); 3.34 (mt: 2H); 3.70 (d, J = 7 Hz: 2H); 4.25 (s: 1H); from 7.20 to 7.40 (mt: 8H); 7.57 (ddd, J = 8-5 and 1 Hz; 1H); 7.97 (t split, J = 8 in 1.5 Hz: 1H); 8.07 (d width, J = 8 Hz: 1H); 8.75 (d width, J = 5 Hz: 1H)].

128

2- {1- [bis- (4-chlorophenyl) methyl)] - azetidin-3-ylidenemethylsulfonyl} pyridine can be prepared by working as follows: to a solution of 0.9 g of 1- [bis- (4-chlorophenyl) methyl)] - 3 (-pyrid-2-yl-sulfonylmethyl) azetidin-3-ol in 50 cm ^{3 of} dichloromethane, 0.25 cm ^{3 of} methylsulfonyl chloride were added, stirred for 15 minutes and 0.9 g of 4-dimethylaminopyridine was added . After stirring at 20 ° C for 3 hours, 30 cm ^{3 of} water was added to the mixture and 30 cm ^{3 of} dichloromethane, then the organic phase was decanted, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2, 7 kPa). The residue was chromatographed on a silica gel column (particle size 0,04-0,063 mm, height 25 cm, diameter 2 cm), eluting under pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (40/60 in volumes ) and fractions of 20 cm ³ were collected. Fractions 4 to 8 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.50 g of 2- {1- [bis- (4-chlorophenyl) methyl)] - azetidin-3-ylidenemethylsulfonyl} pyridine are obtained as a yellow powder.

1- [bis- (4-chlorophenyl) methyl)] -3- (- pyrid-2-yl-sulfonylmethyl) azetidin-3-ol can be prepared by working as follows: to a solution cooled to -78 ° C, under argon, to 2.92 g of 1- [bis- (4-chlorophenyl) methyl)] azetidin-3-one and 3 g of 2-methylsulfonyl-pyridine in 50 cm ³ tetrahydrofuran, 2.13 g of potassium tertiary butylate were added. After stirring at -78 ° C for 3 hours, the reaction mixture was allowed to return to 0 ° C, then 50 cm ^{3 of} diethyloxide, 10 cm ^{3 of} water and 10 cm ^{3 of} saturated aqueous ammonium chloride were added. The organic phase was decanted, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0,063 - 0,200

129 mm, height 30 cm, diameter 3 cm), eluting under pressure of 0.5 bar of argon with dichloromethane, then with a mixture of dichloromethane and methanol (97/3 in volumes) and collecting fractions of 20 cm ³ . fractions 8 to 15 were combined and concentrated to dryness under reduced pressure (2.7 kPa). A brown oil, which was still unclean, was obtained, which was chromatographed on a silica gel column (particle size 0,04 - 0,063 mm, height 20 cm, diameter 2 cm), eluting under pressure of 0.5 bar of argon, first with dichloromethane, then with a mixture of dichloromethane and methanol (97/3 in volumes) and 20 cm ³ fractions were collected. fractions 8 to 25 were combined and concentrated to dryness and the resulting residue was again chromatographed in the same column and under the same conditions but eluted with dichloromethane. fractions 12 to 20 were combined and concentrated to dryness and under reduced pressure (2.7 kPa). 0.3 g of 1- [bis- (4-chlorophenyl) methyl)] -3 - (- pyrid-2-yl-sulfonylmethyl) azetidin-3-ol are obtained in the form of a white kiss.

2-methylsulfonyl-pyridine can be prepared by the following procedure: to a solution of 20 g of tungstate of sodium dihydrate, in 10 cm ^{3 of} water, are added with stirring under argon 0.25 cm ^{3 of} acetic acid 100%, then 7.0 g of 2-methylsulfanylpyridine. This mixture was heated to 65 ° C, poured slowly for 15 minutes 10 cm of oxygen water 30%, then stirred at 85 ° C for 30 minutes, then cooled to + 10 ° C. To the mixture was added 1.0 cm ^{3 of} ammonia 32%, 5.0 cm ^{3 of an} aqueous solution of 37.5% sodium hydrogen sulfite, then 10 cm 3 of water and 50 cm dichloromethane. The mixture was decanted, the organic phase was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The colorless oil obtained is diluted with 50

130 cm ^{3 of} petroleum ether and the insoluble resin was filtered and extracted with 30 cm ^{3 of} dichloromethane. The resulting solution was concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). 3.5 g were obtained

2-methylsulfonyl-pyridine, in the form of a colorless oil.

2-Methylsulfanyl-pyridine can be prepared by the following procedure: To a solution of 11.0 g of 2-mercaptopropyridine in 105 cm ^{3 of} sodium hydroxide 1N, 6.2 cm ^{3 of} methyl iodide are slowly added. The reaction mixture, whose temperature rises to 30 ° C, is cooled to ordinary temperature. After stirring for 2 hours, the mixture was extracted with 100 cm 2 of dichloromethane, the organic phase was dried over magnesium sulfate, and concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The resulting oil is purified by distillation under reduced pressure. 9.0 g of 2-methylsulfanyl-pyridine are obtained as a colorless liquid, pE = 84 ° C / 45 mmHg.

Example 21

3- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylmethylsulfonyl} pyridine can be prepared by working as described in Example 20, starting from 0.15 g 3- {1- [bis- (4-chlorophenyl) methyl)] - azetidin-3-ylidenemethylsulfonyl} pyridine, a 20 cm 50/50 mixture of dichloromethane and ethanol, and 80 mg of sodium hydroboride. 0.11 g of 3- {1- [bis (4-chlorophenyl) methyl] -azetidin-3-ylmethylsulfonyl} pyridine are obtained in the form of a white powder. [RMN ³ H spectrum (300 MHz, CDCI ₃ , δ in ppm): 2.75 to 2.95 (mt: 3H); 3.35 (mt: 2H); 3.43 (d, J = 6.5 Hz: 2H); 4.25 (s: 1H); from 7.20 to 7.40 (mt: 8H); 7.54 (ddd, J = 8-5 and 1 Hz

131: W); 8.18 (ddd, J = 8 - 2.5 in 1.5 Hz: 1H); 8.90 (dd, J = 5 in 1.5 Hz: 1H); 9.11 (dd, J = 2.5 in 1 Hz: 1H) J.

3- {1- [bis- (4-chlorophenyl) methyl)] - azetidin-3-ylidenemethylsulfonyl} pyridine can be prepared by working as described in Example 20, starting from 0.8 g of 1- [bis- ( 4-chlorophenyl) methyl) -3- (- pyrid-3-yl-sulfonylmethyl) azetidin-3-ol, 50 cm ³ dichloromethane, 0.22 cm ³ methylsulfonyl chloride and 0.8 g ⁴ dimethylaminopyridine. 0.50 g of 3- {1- [bis- (4-chlorophenyl) methyl)] - azetidin-3-ylidenemethylsulfonyl} pyridine are obtained as a cream powder.

1- [bis- (4-chlorophenyl) methyl)] -3- (- pyrid-3-yl-sulfonylmethyl) azetidin-sol, can be prepared by working as 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-methylsulfonyl-pyridine, and 2.4 g of potassium tertiary butylate. 1.4 g of 1- [bis- (4-chlorophenyl) methyl)] -3- (- pyrid-3-yl-sulfonylmethyl) azetidin-3-ol are obtained in the form of a white powder.

3-Methylsulfonyl-pyridine can be prepared by working as described in Example 20, starting from 33 g of sodium tungstate, 10 cm ^{3 of} water, 0.25 cm ^{3 of} acetic acid 100%, 9.5 g of 3-methylsulfanyl-pyridine , 15 cm of oxygen water 30% then 2 cm ^{3 of} ammonia 32% and 2 cm ³ aqueous solution of 37.5% sodium hydrogen sulphite. The brown oil obtained was crystallized with 20 cm @ ^{3 of} diisopropyl oxide, the crystals were filtered off, drained, and dried under reduced pressure (2.7 kPa). 4.5 g of 3-methylsulfonyl-pyridine are obtained as white crystals, PF = 58 ° C.

132

3-methylsulfanyl-pyridine can be prepared by working as follows: to a mixture heated to 80 ° C, under argon, to 9.4 g of 3aminopyridine and 100 cm of dimethyl disulfide, 20 cm of isoamyl nitrite is added. After stirring at 90 ° C for 2 hours, the reaction mixture was cooled to 20 ° C, then purified by fractional distillation under reduced pressure. 8.4 g of 3-methylsulfanyl-pyridine are obtained in the form of a pale yellow liquid, PE = 90 ° C / 30 ml of mercury.

Example 22

4- {1- [Bis- (4-chlorophenyl) methyl] -azetidin-3-ylmethylsulfonyl} pyridine can be prepared by working as described in Example 20, starting from 0.15 g 4- {1 - [bis- (4-chlorophenyl) methyl)] - azetidin-3-ylidenemethylsulfonyl} pyridine, 20 cm. 0.13 g of 4- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylmethylsulfonyl} pyridine are obtained in the form of a white powder. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm): 2.75 to 2.90 (mt: 1H); 2.88 (t, J = 7Hz: 2H); 3.36 (t, J = 7 Hz: 2H);

3.42 (d, J = 7Hz: 2H); 4.25 (s: 1H); om 7.20 to 7.35 (mt: 8H); 7.75 (d width, J = 6 Hz: 2H); 8.93 (d width, J = 6 Hz: 2H)].

4- {1- [bis- (4-chlorophenyl) methyl)] - azetidin-3-ylidenemethylsulfonyl} pyridine can be prepared by working as described in Example 20, starting from 0.8 g of 1- [bis- (4-chlorophenyl) methyl) -3- (- pyrid-4-yl-sulfonylmethyl) azetidin-3-ol, 50 cm dichloromethane, 0.22 cm methylsulfonyl chloride, and 0.8 g 4 dimethylaminopyridine. The crude product was purified by chromatography on a silica gel column (particle size 0,04 - 0,063 mm,

133, height 20 cm, diameter 2 cm), eluting under pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (40/60 in volumes) and collecting 20 cm ³ fractions. fractions 5 to 10 were 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 are obtained as a white crystalline powder.

1- [bis- (4-chlorophenyl) methyl)] -3- (- pyrid-4-yl-sulfonylmethyl) azetidin-3-ol can be prepared by working as 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-methylsulfonyl-pyridine, and 1.8 g of potassium tertiary butylate. The crude product obtained is purified by chromatography on a silica gel column (granulometry 0.04 - 0.063 mm, height 30 cm, diameter 3 cm), eluting under pressure of 0.5 bar from argon with dichloromethane, then with a mixture of dichloromethane and methanol (98/2 by volume) and 20 cm ³ fractions were collected. Fractions 8 to 27 were combined and concentrated to dryness under reduced pressure (2.7 kPa). A cream powder was obtained which was recrystallized from 5 cm ^{3 of} acetonitrile. The crystals were filtered, drained, and dried under reduced pressure (2.7 kPa). 1.4 g of 1- [bis- (4-chlorophenyl) methyl)] -3 - (- pyrid-4-yl-sulfonylmethyl) azetidin-3-ol are obtained in the form of white crystals PF = 130 ° C.

4-Methylsulfonyl-pyridine can be prepared by working as described in Example 20, starting from 14 g of sodium tungstate, 4 cm ^{3 of} water, 0.05 cm ^{3 of} acetic acid 100%, 3.3 g of 4-methylsulfanyl- pyridine, 6.5 cm 3 of oxygen water 30% then 0.25 cm ^{3 of} ammonia 32% and 1 cm ³ aqueous solution of 37.5% sodium hydrogen sulfide. The brown oil obtained was crystallized with 10 cm ³ diisopropyloxide, the crystals were filtered off, drained, and

134 was dried under reduced pressure (2.7 kPa). 2.6 g of 4-methylsulfonyl-pyridine are obtained as white crystals.

4-Methylsulfanyl-pyridine can be prepared by working as described in Example 20 starting from 11.0 g of 4 mercaptopyridine, 105 cm ^{3 of} sodium hydroxide 1 N, and 6.2 cm ^{3 of} methyl iodide. The brown oil obtained is purified by distillation under reduced pressure. 4.0 g of 4-methylsulfanyl-pyridine are obtained in the form of a white paste, pEb = 120 ° C / 45 mt mercury.

Example 23

1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) sulfonylmethyl] azetidine can be obtained by working as follows: to a solution of 0.50 g of 1- [bis (4chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) sulfonylmethylene] azetidine dissolved in 25 cm ³ anhydrous methanol and 25 cm ³ anhydrous dichloromethane, 78 mg of sodium borohydride are added under argon. After stirring for 1 <2 hours, 80 cc of water and 50 cc of dichloromethane were added, decanted, washed with 80 cc of water, then with 80 cc of saturated aqueous sodium chloride solution. The organic phase was dried with magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.02-0.04 mm, height 20 cm, diameter 14 cm), eluting under a pressure of 0.7 bar of argon, with a mixture of cyclohexane and ethyl acetate (90 / 10 in volumes) and fractions of 5 cm ³ were collected. fractions 60 to 82 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.29 g of 1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) sulfonylmethyl] azetidine are obtained as a white solid.

135

Substance. [RMN * H spectrum (300 MHz, CDCI ₃ , δ in ppm): from 2.75 to 2.95 (mt: 1H); 2.88 (t, J = 7Hz: 2H); 3.36 (t, J = 7 Hz: 2H); 3.41 (d, J = 7 Hz: 2H); 4.26 (s: 1H); 7.13 (mt, J-9 at 2.5 Hz: 1H); om 7.20 go

7.35 (mt: 8H); 7.44 (mt: 2H)].

Example 24

1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) sulfonylmethylene] azetidine can be prepared by working as follows: 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 at room temperature, 4.3 cm ^{3 of} methylsulfonyl chloride are then added, in small portions, 16 g of 4 dimethylamino pyridine . After 22 hours, the reaction mixture was washed 3 times with 700 cm 3 of water, then with 700 cm 3 of saturated aqueous sodium chloride solution. The organic phase was dried with magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2.7 kPa). The residue (25 g) was chromatographed on a silica gel column (particle size 0.02 - 0.04 mm, height 36 cm, diameter

8.5 cm), eluting under pressure 0,7 bar of argon with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting fractions of £ 250 cm ^3. Fractions 2 to 148 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 2.79 g of 1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) sulfonylmethylene] azetidine are obtained as a white solid. [RMN 1 H spectrum (300 MHz, CDO ₃ , δ in ppm): 3.91 (mt: 2H); 4.28 (mt: 2H); 4.51 (s: 1H); 6.15 (mt: 1H); 7.08 (tt,: J = 9 at 2.5 Hz: 1H); om 7.25 to 7.40 (mt: 8H); 7.40 (mt: 2H)].

136

1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) sulfonylmethyl] azetidin-3-ol can be obtained by the following procedure: to a solution of 13.2 g (3.5difluorophenyl) methylsulfone in 800 cm ³ tetrahydrofuran, 42.9 cm ³ butyllithium 1.6M in hexane was added dropwise. After 0.5 hours at -70 ° C and 0.5 hours at -30 ° C, 14 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one are added dropwise at -70 ° C. dissolved in 150 cm ^{3 of} tetrahydrofuran. After 3 hours at -70 ° C, the reaction mixture was poured onto saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed twice with 400 cm ^{3 of} water, then with 400 cm ^{3 of} saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2.7 kPa). The residue (25.14 g) was chromatographed on a silica gel column (particle size 0.06 - 0.04 mm, height 31 cm, diameter 7.5 cm), eluting under pressure of 0.5 bar of argon, with a mixture of cyclohexane and ethyl acetate (85/15 in volumes) and 200 cm ³ fractions were collected. fractions 13 to 16 were combined and concentrated to dryness under reduced pressure (2.7 kPa). Crystallization from ethyl ether, filtration and drying afforded 4.5 g of 1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) sulfonylmethyl] azetidin-3-ol as a white solid. .

(3,5-difluorophenyl) methylsulfone can be prepared by the following procedure: to a solution of 13.3 g (3,5difluorophenyl) methylsulfide dissolved in 450 cm ^{3 of} methanol, 225 cm ^{3 of} water are added and, in small quantities at 5 ° C, 56.3 g of oxon ^K. After 20 hours at room temperature, the reaction mixture was diluted with dichloromethane and water and decanted. The organic phase was washed twice with 700 cm ^{3 of} water, then with 700 cm ^{3 of} saturated aqueous solution

137 of sodium chloride, dried with magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2.7 kPa). 13.2 g (3,5-difluorophenyl) methylsulfone are obtained as a white solid.

(3,5-difluorophenyl) methylsulfide can be obtained by working as follows: To 11.8 cm 1-bromo-3,5-difluorobenzene diluted in 200 cm ³ ethyl ether, dropwise at -70 ° C 64 cm ³ butyl lithium 1.6 M in hexane. After 0.5 hours at -70 ° C, 14.2 g of methyl methyl thiosulfonate dissolved in 60 cm ^{3 of} THF are added dropwise at -70 ° C. After 3 hours at -70 ° C, then 18 hours at room temperature, the reaction mixture was poured onto saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed twice with 300 cm ^{3 of} water, then with 300 cm ^{3 of} saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2.7 kPa). 13.3 g (3,5-difluorophenyl) methylsulfide are obtained as a yellow oil.

Example 25

To a solution of 0.40 g of 1- [bis- (4-chlorophenyl) -methyl] -3- (phenylsulfanyl) azetidine in 20 cm &lt; ³ &gt; After stirring at room temperature for 3 hours, the reaction mixture was washed with 30 cm ^{3 of} saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). After chromatography on a silica gel column (granulometry 0.06-0.200 mm, height 25 cm, diameter 2 cm), elute under pressure 0.8 bar of argon, with a mixture of ethyl

138 acetate / cyclohexane 20/80 volumes and fractions of 60 cm ³ were collected, fractions 9 to 16 were combined and concentrated to dryness under reduced pressure (2.7 kPa), extracted into heptane to isolate 100 mg 1- [ bis- (4-chlorophenyl) -methyl] -3 - [(R 8) -phenylsulfinyl] -azetidine as a white solid. [Spectrum RMN * H (300 MHz, CDCl ₃ , δ in ppm): 3.01 (t width, J = 7.5 Hz: 1H); 3.32 (t width, J = 7.5 Hz: 1H); 3.45 (t width, J = 7.5 Hz: 2H); 3.59 (mt: 1H); 4.45 (s width: 1H); om 7.15 to 7.65 (mts: 13H)].

Example 26

To a solution of 0.80 g of 1- [bis- (4-chlorophenyl) -methyl] -3- (phenylsulfanyl) azetidine in 3.4 cm ^{3 of} water, 3.4 cm ^{3 of} acetic acid, 3.4 cm ^{3 of} ethanol and

1.7 cm ³ sulfuric acid, 1.2 g of oxon ^K were added several times.

After stirring at room temperature for 20 hours, the reaction mixture was diluted with 100 cm 3 of dichloromethane, washed 3 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 (granulometry 0.06-0.200 mm, height 40 cm, diameter 2 cm), pressure was eluted under pressure of 0.8 bar of argon with ethyl acetate / cyclohexane 20/80 volumes and fractions of 60 were collected. ³ , fractions 9 to 15 were combined and concentrated to dryness under reduced pressure (2.7 kPa), extracted into heptane, the solid filtered and dried to isolate 0.23 g 1- [bis- (4- chlorophenyl) methyl] -3- (phenylsulfinyl) azetidine as a white solid. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm): 3.35 to 3.50 (mt: 4H); 3.96 (mt: 1H); 3.44 (s: 1H); from 7.20 to 7.35 (mt: 8H); 7.57 (t width, J = 7.5 Hz: 2H);

7.68 (tt, J = 7.5 and 1.5 Hz: 1H); 7.88 (d width, J = 7.5 Hz: 2H)].

139

Example 27

To a solution of 0.6 g methyl 5 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} -methylsulfonyl-methyl) -thiene-2-yl-carboxylate in 70 cm methanol cooled at 0 ° C , 43.5 mg of sodium borohydride was added. The reaction mixture was stirred for 15 minutes at this temperature, then 5 hours at 20 ° C before cooling to about 0 ° C and 8.7 mg of sodium borohydride added. After 18 hours at room temperature, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue was added to 100 > 2 < 2 cm &lt; 2 &gt; of dichloromethane and 20 cm of distilled water. The mixture was decanted, the organic phase was washed twice with 20 cm ^{3 of} distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue was purified by flash chromatography on silica gel [eluent: cyclohexane / ethyl acetate (70/30 in volumes)]. 0.18 g of methyl (RS) -5 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonyl-methyl) -thien-2-yl-carboxylate is obtained as a white powder. [RMN * H spectrum (400 MHz, (CD ₃ ) ₂ SO d6, δ B ppm): 3.60 (t, J = 7.5 Hz: 1H); 2.86 (s: 3H); 3.14 (mt: 2H); om 3.20 to 3.35 (mt: 1H); 3.45 (t width, J = 7.5 Hz: 1H); 3.82 (s: 3H); 4.47 (s: 1H); 5.27 (d, J = 11 Hz: 1H); 7.28 (d, J = 4 Hz: 1H); om 7.30 to 7.50 (mt: 8H); 7.72 (d, J = 4 Hz: 1H)].

Methyl 5- ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methylsulfonyl-methyl) -thien-2-yl-carboxylate can be prepared as follows: to a solution of 6.12 g 1 - [Bis (4chlorophenyl) methyl] azetidin-3-one in 200 cm ³ tetrahydrofuran is added at room temperature under an argon atmosphere, 5.15 g

140 methyl 5- (methylsulfonylmethyl) thien-2-yl-carboxylate, then the resulting suspension was cooled to -70 ° C. 2.47 g of potassium tertiary butylate are added sequentially, after 1 hour and 30 minutes at this temperature, a solution of 1.7 cm ^{3 of} methylsulfonyl chloride in 8 cm ^{3 of} ethyl ether for 2 minutes. The reaction medium is maintained for 1 hour at -70 ° C, then allowed to rise to about 20 ° C before 80 cm ^{3 of} distilled water is poured. The THF is removed under reduced pressure and the resulting aqueous residue is extracted with 500 cm ^{3 of} dichloromethane. The mixture was decanted, the organic phase was washed 3 times with 80 cm @ ^{3 of} distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue was purified by flash chromatography on silica gel [eluent: cyclohexane / ethyl acetate (70/30 in volumes)]. They are obtained

1.6 g methyl 5 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methylsulfonyl-methyl) -thien-2-yl-carboxylate in the form of a cream-colored kiss.

Methyl 5- (methylsulfonylmethyl) thien-2-yl-carboxylate can be prepared as follows: 31.7 g of sodium methyl sulfinate are added to a solution of 73 g of methyl 5 (bromomethyl) thien-2-yl-carboxylate in 150 cm ethanol and the resulting suspension was refluxed for 7 hours. The reaction medium was then concentrated to dryness under reduced pressure (2.7 kPa). The residue was extracted four times with 500 cm ^{3 of} ethyl acetate, the combined organic phases were washed sequentially with 250 cm ^{3 of} distilled water and 250 cm ^{3 of} saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The selected solid was <5 isolated by filtration, washed three times with 25 cm3 of ice ethyl

141 acetate to give 21.4 g of methyl 5- (methylsulfonylmethyl) -thiene-

2-yl-carboxylate in powder form with a cream color.

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

Example 28 (S) -1- [Bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -azetidin-3-yl-cyclopropyl-amine can be prepared as follows : to a solution of 3 g of 1- [bis- (4-chlorophenyl) -methyl)] - 3 [(3,5-difluorophenyl) - (methylsulfonyl) -methylene] -azetidine in 30 cm dichloromethane at a temperature close to 24 ° C, under an inert argon atmosphere, 2.52 cm cyclopropylamine was added. After 39 hours at a temperature close to 24 ° C, the reaction medium was concentrated under reduced pressure (3 mbar) at a temperature near 40 ° C. This gives 3.26 g of a pale yellow kiss, which is extracted with 30 cm 2 of dichloromethane and 2.52 cm cyclopropylamine. The resulting solution was stirred at a temperature near 21 ° C, under an inert argon atmosphere for 87 hours, then concentrated at 3 mbar at a temperature near 40 ° C. 3.64 g of (S) -1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] -azetidin-3-yl-cyclopropyl-amine are thus obtained in the form of a pale yellow kiss. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 0.29 (mt: 1H); om 0.40 to 0.75 (mt: 3H);

2.50 (mt: 1H); 2.73 (s: 3H); 2.90 (mf: 1H); om3.45 go 3.70 (mt: 3H);

4.36 (s width: 1H); om 4.60 to 4.80 (mf expanded: 1H); 6.87 (mt, J = 9 at 2.5 Hz: 1H); om 7.20 to 7.40 (mt: 10H)].

142

Example 29 (1 S) - {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-yl} - (2-pyrrolidin-1- yl-ethyl) -amine can be prepared as follows: to a solution of 50 mg of 1 [bis (4-chlorophenyl) -methyl)] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] -azetidine in 0,5 cm ^{3 of} dichloromethane, at a temperature close to 21 ° C under an inert atmosphere of argon, 0.76 cm ^{3 of} 1- (2aminoethyl) pyrrolidine is added. The resulting solution was stirred at a temperature near 21 ° C, under an argon atmosphere for 22 hours, concentrated under air at a temperature near 42 ° C, then the crude residue obtained was dried under reduced pressure (about 3 mbar ) at a temperature close to 40 ° C. (I8) - {1- [Bis- (4-chlorophenyl) -methyl] -3 [(3,5-difluorophenyl) -methylsulfonyl-methyl] -azetidin-3-yl} - (2-pyrrolidin-1-yl) is obtained ethyl) -amine in the form of an ocher-colored kiss. [RMN ³ H spectrum (300 MHz, CDCl ₃ , δ in ppm): 1.75 to 1.95 (mt: 4H); from 2.55 to 2.85 (mt: 6H); 2.79 (s: 3H); 2.91 (t, J = 6.5 Hz: 2H); 3.06 (d, J = 8.5 Hz: 1H); 3.17 (d, J = 8.5 Hz: 1H); 3.32 (d, J = 8.5 Hz: 1H); 3.41 (d, J = 8.5 Hz: 1H); 4.31 (s: 1H); 4.56 (s: 1H); 6.88 (mp, J =

8.5 at 2.5 Hz: 1H); 7.22 (s: 4H); 7.25 (s: 4H); 7.34 (mt: 2H)].

Example 30 N - (1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methanesulfonyl-methyl] -azetidin-3-yl} -methyl-amine may 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 dichloromethane , and a 0.3 cm ³ solution of methylamine in

143 tetrahydrofuran (2M solution). (RS) - {1- [6uc- (4chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidin-3-yl} -methyl-amine is obtained as a yellow gum. [RMN ³ H spectrum (400 MHz, CDCl ₃ , δ in ppm): from 2.00 to 2.20 (mf expanded: 1H); 2.62 (s: 3H); 2.76 (s: 3H); 3.04 (d, J = 9 Hz: 1H); 3.18 (d, J = 9 Hz: 1H); 3.37 (AB, J = 9 Hz: 2H); 4.31 (s: 1H); 4.55 (s: 1H); 6.89 (tt, J = 9 at 2.5 Hz: 1H); 7.22 (s: 4H); 7.24 (s: 4H); 7.32 (mt: 2H) J.

Example 31 (K8) - {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-yl} -isobutyl-amine can be obtained , 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 isobutylamine. (B8) - {1- [Bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-yl} -isobutyl-amine is obtained as a white kiss. [RMN ^X H spectrum (300 MHz, CDCl ₃ , δ in ppm): 1.01 (2d, J = 7Hz: 6H); om 1.70 to 2.15 (mf expanded: 1H); 1.76 (mt: 1H);

2.51 (dd, J = 10.5 at 7 Hz: 1 H); 2.76 (s: 3H); 2.80 (dd, J = 10.5 at 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 (mp, J =

8.5 at 2.5 Hz: 1H); om 7.15 to 7.30 (mt: 8H); 7.35 (mt: 2H) J.

Example 32 (B8) - {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-yl} -ethyl-amine can be obtained ,

144 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 dichloromethane, and a 0.3 cm ³ solution of ethylamine in tetrahydrofuran (2M solution). (RS) - {1- [6uc- (4chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidin-3-yl} -ethyl amine is obtained in the form of a yellow gum. [RMN spectrum Ή (300 MHz, CDCl ₃ , δ in ppm): 1.22 (t, J = 7Hz: 3H); om 2.70 to 2.85 (mt: 2H); 2.77 (s: 3H); om 2.95 go 3.10 (mf: 1H); 3.05 (d, J =

8.5 Hz: 1H); 3.17 (d, J = 8.5 Hz: 1H); 3.33 (d, J = 8.5 Hz: 1H); 3.40 (d, J = 8.5 Hz: 1H); 4.30 (s: 1H); 4.54 (s: 1H); 6.89 (tt, J = 9 at 2.5 Hz: 1H); om 7.15 to 7.30 (mt: 8H); 7.34 (mt: 2H) J.

Example 33 (E8) -1H- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-yl} -N, N'- dimethyl-ethane-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 dichloromethane, and 0.0659 cm ³ Ν, dimethylethylenediamine. This gives (K8) -N- {1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] -azetidin-3-yl} -N ', N- dimethyl-ethane-1,2-diamine as a white kiss. [RMN * H spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.32 (s: 6H); 2.53 (t, J = 6 Hz: 2H); 2.79 (s: 3H); 2.94 (t, J = 6 Hz: 2 H); 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 (s: 1H); 4.55 (s: 1H); 6.88 (tt, J = 9 at 2.5 Hz: 1H); 7.21 (s: 4H);

7.24 (s: 4H); 7.34 (mt: 2H).

Example 34

145 (K8) -1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methane-sulfonylmethyl] -3-methyl-azetidine can be prepared as follows: to suspension of 400 mg magnesium scrap in 2.5 cm anhydrous diethyl ether, add, under argon atmosphere, at a temperature close to 24 ° C, a few drops of pure methyl iodide, then a 1 cm solution of methyl iodide in 22.5 cm. diethyl ether. The resulting suspension was stirred for 30 minutes at a temperature close to 24 ° C, then cooled to a temperature close to 0 ° C with a mixture of ice + water. They are added at a temperature close to 0 ° C,

1.65 g of CuBr.Me ₂ S complex, then the reaction mixture was stirred for 15 minutes at a temperature close to 0 ° C. To the resulting yellow suspension was added, at a temperature close to 0 ° C, a solution of 0.5 g of 1- [bis- (4-chlorophenyl) -methyl)] -3 - [(3,5-difluorophenyl) - N (methylsulfonyl) ) -methylene] -azetidine in a mixture of 1 cm tetrahydrofuran and 1 cm diethyl ether. The resulting suspension was stirred for 4 hours at a temperature close to 0 ° C, then at a temperature close to 25 ° C for 16 hours. The resulting black suspension was diluted with 100 cc ethyl acetate and 15 cc saturated aqueous ammonium chloride solution. The reaction mixture was filtered on celite glass frit, the solid residue was washed with ethyl acetate, then with water. After decanting the filtrate, the organic phase was separated, washed with 10 cm ^{3 of} water, 10 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered on a glass frit, and concentrated under reduced pressure (20 mbar). at a temperature close to 43 ° C. This gave 550 mg of an orange kiss which was purified by preparative chromatography on a thin layer of silica [14 Merck Kieselgel Preparation Plates 60F254; 20 x 20 cm; thickness 0.5 mm; stored in dichloromethane solution], eluting with a methanol-dichloromethane mixture (0,5146

99.5 In volumes). Elution of the corresponding area of the desired product with a methanol-dichloromethane mixture (15-85 in volumes), filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C yields 290 mg of a white kiss, which was dissolved in 15 cm ^{3 of} anhydrous dichloromethane and reacted with 500 mg thiophenol resin (Argonaut supplier, 1.45 mMol / g) and 1 g ethylene diamine resin (0.8 mMol / g) for 38 hours at temperature close to 20 ° C. The suspension was filtered on a glass frit, the resins were washed with dichloromethane, and the filtrate was concentrated under reduced pressure (5 mbar) at a temperature close to 43 ° C. 272.8 g of a white kiss are obtained which is dissolved in 2 cm ^{3 of} dichloromethane and reacted with 1 cm ^{3 of} diethylenediamine for 72 hours at a temperature close to 24 ° C. The crude residue obtained is extracted with 50 cm ^{3 of} ethyl acetate and 10 cm ^{3 of} water. After decanting, the organic phase is washed with 10 cm ³ aqueous hydrochloric acid 1N, 10 cm ³ saturated aqueous sodium bicarbonate, 10 cm ³ water, 10 cm ³ saturated aqueous sodium chloride, dried over magnesium sulfate, filtered is concentrated on a glass frit, and concentrated under reduced pressure (8 mbar) at a temperature close to 42 ° C. They are obtained

263.4 mg pale yellow kiss which is purified by preparative chromatography on a thin layer of silica [7 Merck Kieselgel Preparation Plates 60F254; 20 x 20 cm; thickness 0.5 mm; stored in a solution of dichloromethane], eluting with a methanol-dichloromethane mixture (0.5-99.5 in volumes). Elution of the corresponding area of the desired product with a methanol dichloromethane mixture (15-85 in volumes), filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C yields 191,4 mg (RS) - 1- [6uc- (4-

147 chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] -3methyl azetidine as a white kiss. [RMN * H spectrum (300 MHz, CDCl ₃ , δ in ppm): 1.75 (s: 3H); 2.67 (s: 3H); 2.74 (d width, J = 7.5 Hz: 1H); 2.93 (d, J = 7.5 Hz: 1H); 3.21 (d width, J = 7.5 Hz: 1H); 3.46 (d, J = 7.5 Hz: 1H); 4.33 (s width: 2H); 6.87 (mt, J = 9 at 2.5 Hz: 1H); 7.12 (mt: 2H); om 7.15 to 7.35 (mt: 8H).

Example 35 (K8) -1- (2- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylsulfanyl} -ethyl) -4-methyl-piperazine can be prepared as follows: 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, at a temperature near 20 ° C, 128 mg of 1- (ethanethiol-2-yl) -4-methyl-piperazine was added. After stirring overnight at a temperature near 20 ° C, 706 mg of Merrifield resin (1.7 mMol / g) was added. After stirring overnight at a temperature close to 20 ° C, the suspension was filtered and the resin was washed twice with 1 cm ^{3 of} dichloromethane. The filtrate was concentrated under reduced pressure. 125 mg of a white oil are thus obtained, which is purified by chromatography on silica (13 cm ³ silica 0.06-2.2 mmol), eluting with a methanol dichloromethane mixture (0-100 then 5-95 volumes), The fractions containing no desired product were combined and concentrated to dryness under reduced pressure. 62 mg (RS) -1- (2- {1 [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -azetidin-3-ylsulfanyl} -ethyl are thus obtained ) -4-methyl-piperazine in the form of white crystals. [RMN * H spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 2.15 (s: 3H); 2.30 and 2.41 (2mfs: 8H); 2.55 (mt: 2H); 2.85 (with:

148

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); om 7.30 to 7.50 (mt: 11H)].

Example 36 (K8) - (2- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylsulfanyl} -ethyl) -dimethyl -amine may be prepared by working as β Example 35 starting from 99 mg of 1- [bis (4-chlorophenyl) -methyl)] -3 - [(3,5-difluorophenyl) (methylsulfonyl) -methylene] -azetidine, 2 cm ³ dichloromethane, 84 mg 2 (dimethylamino) -ethanethiol, and 706 mg Merrifield resin (1.7 mMol / g). 36 mg (RS) - (2- {1- (bis- (4-chlorophenyl) -methyl] -3 - ((3,5-difluorophenyl) -methylsulfonyl-methyl] -azetidin-3-ylsulfanyl-ethyl) are thus obtained dimethyl amine as a white powder.

Example 37 (RS) - {1 - [[4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl] -3 - ((3,5difluorophenyl) -methylsulfonyl-methyl] -azetidin-3-yl} -ethyl- an amine can be prepared as follows: solution of 40 mg (RS) - {1 - [[4 (chloromethyl) phenyl] - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylene ] -azetidine in 0.1125 cc ethylamine (2M solution in tetrahydrofuran) containing sodium iodide grains was stirred at a temperature close to 20 ° C for 2 hours, then diluted with 20 cc ³ ethyl acetate and 5 cc ³ saturated aqueous sodium bicarbonate solution washed with 5 cm ^{3 of} water, 5 cm ^{3 of} saturated aqueous sodium chloride, dried over magnesium sulphate, filtered on a glass frit and concentrated under reduced pressure (15 mbar) at

149 the temperature is close to 40 ° C. The yellow oil obtained was purified by preparative chromatography on a thin layer of silica [2 Merck Kieselgel Preparation Plates 60F254; 20 x 20 cm; thickness 0.5 mm; stored in a solution of dichloromethane], eluting with a methanol-dichloromethane mixture (3-97 in volumes). Elution of the corresponding area of the desired product with a methanol-dichloromethane mixture (15-85% by volume), filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C yields 17 mg (I8) - {1 - [[4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) -methylsulfonyl-methyl] -azetidin-3-yl} -ethyl-amine as a white solid substance. [RMN spectrum H (400 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 1.11 (t, J = 7Hz: 3H); om2.10 go 3.55 (mt: 8H); 2.95 (s: 3H); 4.44 (s: 1H); 5.09 (s: 1H); om 7.10 go 7.55 (mt: 11H)].

(S) - {1 - [[4- (chloromethyl) phenyl] - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methylene] -azetidine can be obtained as follows: to a solution of 590 mg (RS) - [4 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonyl-methylene] -azetidin-1-yl} -methyl) -phenyl] -methanol in 5 cm ³ anhydrous dichloromethane , at a temperature close to 21 ° C, 0.525 cm ³ Ν, Ν-diisopropylethylamine, then 0.19 cm ³ methane sulfonyl chloride are added. After 1 hour at a temperature near 21 ° C, 2 cm ^{3 of} methanol / dichloromethane (2.5 / 97.5 in volumes) were added, after 5 minutes the reaction mixture was concentrated under reduced pressure (20mbar) at a temperature of up to 40 ° C. The resulting yellow kiss was purified by chromatography on silica (50 g silica 0.06 - 0.2 mt contained in a 3 cm diameter column) as

150 was eluted with a methanol-dichloromethane mixture (0-100 then 1-99 volumes) to collect fractions of 10 cm ³ . The fractions containing no desired product were combined and concentrated to dryness under reduced pressure. 421.2 mg (RS) - {1 - [[4 (chloromethyl) phenyl] - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methylene] -azetidine are thus obtained in the form of yellow kiss.

(H8) - [4 - ((4- (chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -azetidin-1-yl} -methyl) -phenyl] -methanol can be obtained by the following method: to a solution of 420 mg ^ 8) -4 - ((4-chlorophenyl) - {3 [(3,5-difluorophenyl) -methylsulfonyl-methylene] azetidin-1-yl} -methyl) 3 o benzaldehyde in 7 cm methanol cooled to a temperature close to 0 C (ice + water) was added in portions 49 mg of sodium tetrahydroboride. After 2 hours at a temperature close to 0 ° C, the reaction medium was concentrated under reduced pressure (15 mbar) at a temperature near 35 ° C. The resulting residue was purified by chromatography on silica (40 g silica 0.06 0.2 mt contained in a 3 cm diameter column), eluting with a methanol-dichloromethane mixture (1/99 then 2.5 / 97.5 volumes) fractions of 10 cm ³ were collected. The fractions containing no desired product were combined and concentrated to dryness under reduced pressure. Thus, 418 mg of (E8) - [4 - ((4- (chlorophenyl) - {3 - [(3,5difluorophenyl) -methylsulfonyl-methylene] -azetidin-1-yl} -methyl) -phenyl] methanol are obtained in the form on a white kiss.

Example 38 (1S) - {1- [bis- (4-chlorophenyl) -methyl] -3 - ((3,5-bis-trifluoromethyl-phenyl) methylsulfonyl-methyl] -azetidin-3-yl} -isobutyl-amine can be prepared according to Example 29 starting from 50 mg of 1- [bis (4151 chlorophenyl) -methyl)] -3 - [(3,5-bis-trifluoromethyl-phenyl) (methylsulfonyl) -methylene] -azetidine, O , 5 cm dichloromethane, and 0.05 cm isobutylamine. 57 mg (RS) - {1- [bis- (4-chlorophenyl) -methyl] 3 - [(3,5-bis-trifluoromethyl-phenyl) -methylsulfonyl-methyl] -azetidin-3-yl} -isobutyl-amine are obtained in the form of a pale yellow kiss. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm): 1.01 (d, J = 7.5 Hz; 6Η); 1.76 (mt: 1H); 2.47 (dd, J = 10.5 in 7.5 Hz: 1H); om 2.75 to 2.85 (mt: 1H);

2.79 (s: 3H); 2.82 (dd, J = 10.5 in 5.5 Hz: 1H); 3.00 (d, J = 9 Hz: 1H); 3.10 (d, J = 9 Hz: 1H); 3.31 (d, J = 9 Hz: 1H); 3.40 (d, J = 9 Hz: 1H); 4.30 (s: 1H); 4.74 (s: 1H); 7.13 (d, J = 8.5 Hz: 2H); om 7.15 to 7.25 (mt: 6H); 7.96 (s width: 1H); 8.31 (s broad: 2H)].

Example 39 (S) -1- [bis- (4-chlorophenyl) -methyl] -3-cyano-3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine can be prepared as follows: to a solution of 99 mg of 1- [bis (4-chlorophenyl) -methyl)] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) -methylene] -azetidine in 2.5 cm dimethylsulfoxide, at a temperature close to 20 ° C 17 mg potassium cyanide. The resulting yellow solution, then auburn, was heated for 15 minutes at a temperature close to 40 ° C, then cooled to a temperature near 20 ° C. The reaction medium was concentrated under reduced pressure, then extracted with 10 cm dichloromethane, washed 3 times with 5 cm ³ water. The resultant organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gives 100 mg of a yellow fine mass which is purified by chromatography on silica (10 cm ³ silica 0.06-0.2 mt, contained in a 1 cm diameter column) eluting with dichloromethane.

152

The fractions containing no desired product were combined and concentrated to dryness under reduced pressure. 60 mg of (S) -1- [bis- (4-chlorophenyl) -methyl] -3-cyano-3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine are obtained in the form of a yellow fine mass. [RMN spectrum ^! H (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 2.94 (s: 3H); 3.07 (d, J = 7.5 Hz: 1H); om 3.20 to 3.40 (mt: 1H); 3.61 (d width, J = 7.5 Hz: 1H); 3.68 (d width, J = 7.5 Hz: 1H); 4.64 (s: 1H); 5.51 (s: 1H); om 7.25 to 7.50 (mt: 11H)].

Example 40

Q ^ 8) - {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylmethyl} - (1-cyclopropyl-ethyl) - an amine can be prepared as follows: to a solution of 53 mg (RS) of C- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -azetidine- 3-yl} -methylamine in 2 cm ³ 1,2-dichloroethane, at a temperature close to 20 ° C, 0.03 cm ^{3 of} cyclopropyl methyl ketone, 0.006 cm ^{3 of} acetic acid, then 32 mg of sodium triacetoxyborohydride are added sequentially. The resulting solution was stirred at a temperature close to 20 ° C for 18 hours, then brownish, then a 2 cm ³ saturated aqueous solution of NaOH was added. After decanting, the organic phase was concentrated under reduced pressure. This gives 60 mg of a yellow viscous oil which is triturated with isopropyl oxide, petroleum ether. After drying below 0.1 mbar, 55 mg of residue was obtained, which was purified by chromatography on silica (4 cm ³ silica 0.06 - 0.2 mt contained in a column with a diameter of 1.2 cm) as eluted with methanol / dichloromethane mixture (0/100 then 5/95 in volumes), the fractions not containing the desired product are

153 were combined, concentrated to dryness under reduced pressure, and purified again by chromatography on silica (4 cm silica 0,04-0,063 mt contained in a column with a diameter of 1.2 cm), eluting with a mixture methanol / dichloromethane (0/100 then 1/99 in volumes), the fractions not containing the desired product were combined and concentrated to dryness. 20 mg of (S) - {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylmethyl} - (1-cyclopropyl) are thus obtained -ethyl) -amine. [RMN * H spectrum (300 MHz, CDCl ₃ , δ in ppm): A mixture of diastereoisomers, 0.00 to 0.30 and 0.40 to 0.80 (mts: 5H), was observed; 1.09 and 1.17 (2d, J = 6.5 Hz: 3H completely); 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 completely);

4.79 and 4.84 (2s: 1H completely); 6.89 (tt, J = 9 and 2.5Hz: 1H); 7.16 (mt: 2H);

from 7.15 to 7.35 (mt: 8H) J.

(R8) -C- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-yl} -methylamine can be obtained by the following method: to a solution of 250 mg (RS) -1- [6uc- (4chlorophenyl) -methyl] -3-cyano-3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -azetidine in 10 cm ³ anhydrous tetrahydrofuran, cooled to a temperature close to 0 ° C, a solution of diisobutylaluminum hydride 1.5 M in tetrahydrofuran was added dropwise 1.27 cm ³ . After 30 minutes at a temperature close to 0 ° C, then 4 hours at a temperature close to 20 ° C, the solution was again cooled to a temperature of 0 ° C. 6.35 cm ^{3 of} water are then added followed by 1.06 cm ^{3 of} aqueous hydrochloric acid (12 N). After decantation, the aqueous phase was extracted 3 times with 10 cm @ ^{3 of} ethyl acetate. The organic phases are combined, dried over magnesium

154 sulfate, filtered and concentrated under reduced pressure. This gives 0.42 g of a dark yellow oil which is purified by chromatography on silica (40 cm ³ silica 0,063 - 0,2 mt contained in a column with a diameter of 2.7 cm), eluting with a mixture of methanol / dichloromethane (0/100 then 5/95 in volumes), the fractions not containing the desired product were combined and concentrated to dryness under reduced pressure. Thus, 110 mg of (K8) -C- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-yl} -methylamine are obtained.

Example 41 (I.8) -HH- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylmethyl} -isobutyramide can be prepared by as follows: to a solution of 53 mg (RS) -C- {1- [6uc (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidin-3-yl} - methylamine in 2 cm ³ anhydrous dichloromethane, at a temperature close to 20 ° C, 0.0187 cm ³ isobutyrylic acid, 0.032 cm ³ 1,3-diisopropylcarbodiimide and 2.5 mg were successively added.

4-dimethylaminopyridine. After stirring for 72 hours at a temperature near 20 ° C, 2 cm ^{3 of} water was added, decanted, then the organic phase was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue obtained was purified by preparative chromatography on a thin layer of silica [1 Merck Kieselgel 60F254 preparation plates; 20 x 20 cm; 1 m thick], eluting with ethyl acetate-dichloromethane (5-95 vol.). Elution of the desired product area, filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C yielded 16 mg (RS) -N- {1- [bis- (4-

155 chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl} isobutyramide as a pale yellow powder. [Spectrum RMN ¹ H (300 MHz, CDCl ₃ , δ B ppm): 1.22 (d, J = 7 Hz: 6H);

2.46 (mt: 1H); 2.69 (s: 3H); 2.99 (d, J = 8.5 Hz: 1H); 3.23 (AB, J = 8.5 Hz: 2H); 3.40 (d, J = 8.5 Hz: 1H); 3.57 (dd, J = 14 at 4.5 Hz: 1H); 4.09 (dd, J = 14 at 7.5 Hz: 1H); 4.34 (s: 1H); 4.35 (s: 1H); 6.71 (dd, J = 7.5 in 4.5 Hz: 1H); 6.95 (ft, J = 9 at 2.5 Hz: 1H); om 7.10 go 7.35 (mt: 10H) J.

Example 42 (RS) -N- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylmethyl} -cyclopropanecarboxamide may be prepared in a manner similar to Example 39 starting from 53 mg of (K8) -C- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methanesulfonyl-methyl] -azetidin-3-yl} -methylamine, 2 cm anhydrous dichloromethane, 0,0167 cm cyclopropanecarboxylic acid, 0,032 cm

1,3-diisopropylcarbodiimide and 2.5 mg 4-dimethylaminopyridine. 28 mg of (K8) -N- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] -azetidin-3-ylmethyl} cyclopropanecarboxamide are obtained dust. [RMN spectrum ^X H (300 MHz, CDCl ₃ , δ in ppm): 0.81 (mt: 2H); 1.01 (mt: 2H); by

C, 1.35 to 1.55 (mt: 1H); 2.70 (s: 3H); 3.02 (d, J = 8.5 Hz: 1H); 3.21 (AB limit, J = 8 Hz: 2H); 3.45 (d, J = 8.5 Hz: 1H); 3.62 (dd, J = 14 at 4.5 Hz: 1H); 4.10 (dd, J = 14 at 7.5 Hz: 1H); 4.31 (s: 1H); 4.36 (s: 1H); 6.75 (dd, J =

7.5 in 4.5 Hz: 1H); 6.95 (mt, J = 9u2Hz: 1H); om 7.15 to 7.35 (mt: 10H)].

Example 43

156 (H8) - {N [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylmethyl} -diethyl-amine can be prepared by similar to Example 40 starting from 53 mg of (1 S) -C- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine-3- yl} -methylamine, 2 cm 2 dichloroethane, 0,017 cm acetaldehyde, 0,006 cm 3 acetic acid and 32 mg sodium triacetoxyborohydride. 12 mg (RS) {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -azetidin-3-ylmethyl} -diethyl-amine are thus obtained in the form of powdered white powder. [RMN * H spectrum (300 MHz, CDCl ₃ , δ in ppm): 1.00 (t, J = 7 Hz: 6H); 2.49 (q, J = 7 Hz: 4H); 2.54 (d, J = 13.5 Hz: 1H); 2.69 (s: 3H); 2.76 (d width, J = 7.5 Hz: 1H); 3.07 (d width, J = 7.5 Hz: 1H); 3.15 (d, J = 13.5 Hz: 1H); 3.24 (d width, J = 7.5 Hz: 1H); 4.06 (d width, J = 7.5 Hz: 1H);

4.35 (s: 1H); 5.02 (s: 1H); 6.91 (mt: 1H); om 7.15 go 7.40 (mt: 10H)].

Example 44 N- (R) -N- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylmethyl} -methanesulfonamide as follows: to a solution of 53 mg (RS) -C- {1- [6uc (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidin-3-yl} -methylamine in 2 cm ethyl acetate, at a temperature near 20 ° C, 150 mg of anhydrous IRA-68 resin, then 0.012 cm ^{3 of} methylsulfonyl chloride are added. After stirring overnight at a temperature near 20 ° C, 0.01 cm ^{3 of} water was added, then 150 mg of anhydrous IRA-68 resin. After 1 hour stirring at a temperature near 20 ° C, the reaction mixture was filtered and the filtrate filtered concentrates under reduced pressure. This gives 81 mg of a yellow fine dispersive mass which is purified by preparative

157

thin layer chromatography [1 Merck Kieselgel Preparative Plate 60F254; 20 x 20 cm; 1 m thick], eluting with ethyl acetate-dichloromethane (5-95 by volume). Elution of the corresponding product range, filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C yielded 25 mg of (1 S) -N- {1- [bis- (4-chlorophenyl) ) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylmethyl} -methanesulfonamide as a pale yellow powder. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm): 2.70 (s: 3H); from 2.95 to 3.10 (mt: 2H); 3.05 (s: 3H); 3.22 (d width, J = 8Hz: 1H); 3.52 (d, J = 8 Hz: 1H); 3.74 (dd, J = 13.5 in 8 Hz: 1H);

3.90 (dd, J = 13.5 in 5.5 Hz: 1H); 4.23 (s: 1H); 4.46 (s: 1H); 5.54 (mt: 1H); 7.00 (mp, J = 9 at 2 Hz: 1H); om 7.05 to 7.35 (mt: 10H)].

Example 45

N-) -1- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylmethyl} -3-isopropyl-urea may be prepared as follows: to a solution of 53 mg (RS) -C- {1 [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -azetidin-3-yl} -methylamine in 2 cm ³ dichloromethane, at a temperature close to 20 ° C, 0.0197 cm ³ diisopropyl isocyanate is added. After stirring overnight at a temperature near 20 ° C, 0.05 cm ^{3 of} water was added, after 15 minutes of stirring at a temperature near 20 ° C, the reaction mixture was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue (75 mg) was purified by preparative chromatography on a thin layer of silica [1 Merck Kieselgel Preparation Plate 60F254; 20x20 cm; thickness 1

158 mm] eluting with ethyl acetate-dichloromethane (5-95 6 volumes). Elution of the desired product area, filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C gave 16 mg (K8) -1- {1- [bis- (4-chlorophenyl) ) -methyl] -3 - [(3,5difluorophenyl) -methylsulfonyl-methyl] -azetidin-3-ylmethyl} -3-isopropyl-urea in the form of a pale yellow powder. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 1.17 (d, J = 7 Hz: 6H); 2.68 (s: 3H); 3.00 (d width, J = 8.5 Hz: 1H); 3.11 (d, J = 8.5Hz: 1H); 3.17 (d, J = 8.5 Hz: 1H); 3.46 (d width, J = 8.5 Hz: 1H); 3.64 (dd, J = 14 at 5 Hz: 1H); 3.86 (mt: 1H); 3.96 (dd, J = 14 at 7.5Hz: 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 at 2 Hz: 1H); om

7.10 to 7.30 (mt: 10H)].

Example 46

(R8) - {N [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] -azetidin-3-ylmethyl} -carboxylic acid isobutyl ester can be obtained by the following method: to a solution of 53 mg (RS) -C- {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-yl} - methylamine in 2 cm ³ pyridine at a temperature close to 20 ° C, 0.016 cm ³ isobutyl chloroformate is added. After stirring overnight at a temperature near 20 ° C, 0.05 cm ^{3 of} water was added, after 15 minutes of stirring at a temperature near 20 ° C, the reaction mixture was concentrated under reduced pressure. This gives 68 mg of a yellow fine particulate matter which is purified by preparative chromatography on a thin layer of silica [1 Merck Kieselgel Preparation Plate 60F254; 20x20 cm; 1 m thick], eluting with a mixture of ethyl

159 acetate-dichloromethane (5-95 vol.). Elution of the corresponding product area, filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C yielded 14 mg of (RS) -l- {1- [bis- ( 4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylmethyl} -carboxylic acid in the form of a triturated white powder. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm): 0.96 (d, J = 7 Hz: 6H); 1.95 (mt: 1H); 2.68 (s: 3H); 3.04 (d, J = 8.5Hz: 1H); 3.19 (s: 2H); 3.51 (d, J = 8 Hz: 1H); 3.75 (dd, J = 14 at 5 Hz: 1H); om 3.80 to 4.00 (mt: 3H); 4.30 (s: 1H); 4.34 (s: 1H); 5.63 (mt: 1H);

_ 6.95 (tt, J = 9 in 2 Hz: 1H); om 7.10 go 7.30 (mt: 10H)].

W

Example 47 (k8) - {1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylmethyl} -dimethyl-amine can be obtained as follows: to a solution of 52 mg (RS) -C- {1- [6uc (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidin-3-yl} -methylamine in 2 cm ³ acetonitrile, at a temperature close to 20 ° C, 138 mg of potassium carbonate is added, then 0.0075 cm ^{3 of} methyl iodide. After stirring overnight at a temperature near 20 ° C, the reaction mixture was filtered on a glass frit, the solid was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The resulting crude residue (90 mg) was purified by preparative chromatography on a thin layer of silica [1 Merck Kieselgel Preparation Plate 60F254; 20 x 20 cm; 1 mm thick], eluting with ethyl acetate-dichloromethane (5-95 by volume). After elution of the corresponding area of the desired product, filtration

160

Glass evaporation, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C, gave 11 mg (1 S) - {1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5 -difluorophenyl) methylsulfonyl-methyl] -azetidin-3-ylmethyl} -dimethyl-amine. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.18 (s: 6H); 2.30 (d, J = 13 Hz: 1H); om 4.65 to 4.78 (mt: 1H); 2.70 (s: 3H); 2.98 (d, J = 13 Hz: 1H); 3.09 (d, J = 8 Hz: 1H); 3.32 (d, J = 7.5 Hz: 1H); 4.11 (d, J = 8 Hz: 1H);

4.35 (s: 1H); 4.94 (s: 1H); 6.92 (mt: 1H); om 7.10 go 7.40 (mt: 10H)].

Example 48 N- (8) -1- [bis- (4-chlorophenyl) methyl] -3 - [(4-methoxyphenyl) methylsulfonylmethyl] azetidine can be prepared as follows: to a solution of 400 mg of 1- [bis- (4 -chlorophenyl) methyl] -3 - [(4-methoxyphenyl) methyl-sulfonyl-methylene] azetidine in 4.5 cm ³ ethanol, under an argon atmosphere at a temperature close to 20 ° C, 25.5 mg of sodium tetrahydroboride is added. After stirring for 16 hours at a temperature close to 20 ° C, 26 mg of sodium tetrahydroboride was added. The reaction medium was stirred at a temperature near 20 ° C for 4.5 hours, then at a temperature near 50 ° C for 3 hours. After cooling to a temperature close to 20 ° C, the reaction medium was concentrated under reduced pressure. The resulting white precipitate was extracted with 2 cm ^{3 of} water and 2 cm ^{3 of} dichloromethane. After decanting, the organic phase was concentrated under reduced pressure and the resulting yellow kiss was purified by preparative chromatography on a thin layer of silica [2 Merck Kieselgel Preparation Plates 60F254; 20 x 20 cm; 0.5 m thick], eluting with a methanol-dichloromethane mixture (1-99 in volumes). After elution

161 of the corresponding area of the desired product with a mixture of methanol dichloromethane (10-90 in volumes), filtered on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C yields 14 mg (RS) -1- [ 6uc- (4-chlorophenyl) methyl] -3 - [(4-methoxyphenyl) methylsulfonyl-methyl] azetidine as a white kiss. [RMN * H 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 (t width, J = 7.5 Hz: 1H); 3.81 (s: 3H); 4.21 (d, J =

4.5 Hz: 1H); 4.26 (s broad: 1H); 6.90 (d, J = 8.5 Hz: 2H); om 7.15 go

7.40 (mt: 10H) J.

1- [bis- (4-chlorophenyl) methyl] -3 - [(4-methoxyphenyl) methylsulfonylmethylene] azetidine can be prepared by working as described in Example 1 starting from 1 g (K8) -1- [ bis- (4-chlorophenyl) methyl] -3- [methylsulfonyl- (4-methoxy-phenyl) -methyl] -azetidin-3-ol, 20 cm ³ dichloromethane, 0.229 cm ³ methylsulfonyl chloride and 722 mg ⁴ dimethylamino-pyridine. After purification by chromatography on silica at atmospheric pressure (100 g of silica, particle size 0,063 - 0,2 mt contained in a column of 3 cm diameter), eluting with dichloromethane, the fractions containing no desired product were combined and concentrated to dry under CL under reduced pressure to give 650 mg of 1- [bis- (4-chlorophenyl) methyl] -3 - [(4-methoxyphenyl) methylsulfonylmethylene] azetidine as a yellow gum.

(E8) -T [bis- (4-chlorophenyl) -methyl] -3- [methylsulfonyl- (4-methoxy-phenyl) methyl] -azetidin-3-ol can be prepared by working as described in example 1 starting from a 19.6 cm 1.6 N solution of butyllithium in hexane, 5.7 g of 4-methoxybenzyl methyl sulfone and 8.71 g of 1162 [bis- (4-chlorophenyl) -methyl] -azetidine-3- it is in 450 cm ³ tetrahydrofuran. 8.3 g of (S) 4 - [bis- (4-chlorophenyl) -methyl] -3 [methylsulfonyl- (4-methoxy-phenyl) -methyl] -azetidin-3-ol are thus obtained as a beige solid .

4-Methoxybenzyl-methyl-sulfone can be prepared by working as described in Example 27 starting from 13.6 cm ^{3 4} methoxybenzyl chloride, 30 mg sodium iodide, 14.4 g sodium methyl sulfinate in 125 cm ³ ethanol. 5.75 g of 4-methoxybenzyl-methyl-sulfone are thus obtained as a white powder.

Example 49 (RS) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -L (-acetyl-morpholine can be obtained as follows : to a solution of 37 mg of N- (8) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid was added sequentially at a temperature close to to 20 ° C, 252 mg EDCI (2.3 equivalents, EDCI reagent is commercially available and can also be prepared according to the following publication: M. Desai, L. Stramiello, Tetrahedron Letters, 34, 48, 7685- 7688 (1993)), 2 cm ³ anhydrous dichloromethane, 0,006 cm ³ morpholine, then 0,010 cm ³ triethylamine. After stirring for 12 hours at a temperature close to 20 ° C, the reaction mixture was filtered on a glass frit. The filtrate was 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 close to 20 ° C. 15 mg of (K8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2 (3,5-difluoro-phenyl) -L-acetyl-morpholine are thus obtained in the form of beige

163 kiss. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.60

3.80 (mt: 13H); 3.93 (d, J = 10 Hz: 1H); 4.27 (s: 1H); om 6.65 to 6.85 (mt: 3H); om 7.20 to 7.40 (mt: 8H)].

Example 50 N- (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclohexylacetamide can be prepared as follows: to a solution of 250 mg of (RS) - {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 10 cm ³ anhydrous dichloromethane, at a temperature close to 0.070 cm cyclohexylamine, 144 mg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.141 cm ³ triethylamine, then 4 mg hydroxybenzotriazole hydrate are added successively to 20 ° C, 2. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium is loaded into a Varian cartridge (25 cm ³ ) together with 12 g of fine silica (0.040-0.063 mt), provided it is then eluted with a dichloromethane-petroleum ether mixture (80-20 by volume) with using a Duramat pump, collecting fractions of 1.5 cm ³ , fractions 11 to 17 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus, 169 mg of (RS) -2- {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) -cyclohexylacetamide are obtained as a white kiss. [RMN spectrum 300 (300 MHz, CDCl ₃ , δ in ppm): 0.90 to 1.45 (mt: 6H); from 1.50 to

1.90 (m: 4H); 2.66 (mt: 1H); 2.90 (mt: 1H); from 3.00 to 3.15 (mt: 2H);

3.42 (t width, J = 7.5 Hz: 1H); 3.52 (d, J = 10.5 Hz: 1H); from 3.60 to

3.80 (mt: 1H); 4.27 (s: 1H); 5.25 (d width, J = 8 Hz: 1H); 6.90 (tt, J = 9 at 2.5 Hz: 1H); 6.82 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

164

Example 51 (P8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-acetylpiperidine can be prepared as follows: to a solution of 50 mg of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 2 cm anhydrous dichloromethane, at a temperature of close to 20 ° C, 0.012 cm ^{3 of} piperidine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm ^{3 of} triethylamine, and 1.5 mg of hydroxybenzotriazole hydrate are added sequentially. The resulting solution was stirred at a temperature close to 20 ° C for about an hour. Place the reaction medium in a Varian cartridge (6 cm ³ ) together with 3 g fine silica (0.040-0.063 mt), eluting with dichloromethane using a Duramat pump. The fractions included between 8 and 15 cm ³ were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 14 mg of (K8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5difluorophenyl) -1H-acetylpiperidine are thus obtained in the form of a white crystalline powder. [RMN ¹ H spectrum (300 MHz, CDCl ₃ , δ in ppm): 0.95 to

1.15 and 1.30 to 1.50 (2mts: 6H in full); 2.74 (mt: 2H); from 3.00 to

3.15 (mt: 2H); from 3.30 to 3.45 (mt: 4H); from 3.55 to 3.70 (mt: 1H);

C, 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); om 7.20 to 7.35 (mt: 8H)].

Example 52 (P8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-acetylpyrrolidine can be prepared as follows: to a solution of 50 mg hydrochloride of (K8) - {1- [bis- (4-chlorophenyl)

165 β methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid in 2 cm anhydrous dichloromethane, at a temperature close to 20 ° C, were added sequentially, 0.010 cm pyrrolidine, 0.023 cm diisopropylcarbodiimide, 0.028 cm ³ triethylamine, and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. Place the reaction medium in a Varian cartridge (6 cm ³ ) together with 3 g fine silica (0.040-0.063 mt), eluting with dichloromethane using a Duramat pump. The fractions included between 11 to 19 cm ³ were pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gives 29 mg of (1-8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) -N4-acetylpyrrolidine as a white kiss . [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm): 1.75 to 2.00 (mt: 4H); 2.74 (mt: 2H); from 3.00 to 3.30 (mt: 3H); from 3.35 to 3.60 (mt: 4H); 3.80 (d, J = 10.5 Hz: 1H); 4.25 (s: 1H); 6.68 (tt, J = 9 and 2.5 Hz: 1H); 6.84 (mt: 2H); om 7.20 to 7.40 (mt: 8H)].

Example 53 N- (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclopropylacetamide can be prepared as follows: to a solution of 50 mg of (RS) - {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 2 cm ³ anhydrous dichloromethane, at a temperature close to to 20 ° C, 0.009 cm ^{3 of} cyclopropylamine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm ^{3 of} triethylamine, and 1.5 mg of hydroxybenzotriazole hydrate are added sequentially. The resulting solution was stirred at a temperature near 20 ° C

166 for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mt), provided it was then eluted with dichloromethane using a Duramat pump, collecting 2 cm ³ fractions. Fractions 2 to 6 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 29 mg (RS) -2- {1- [6uc (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclopropyl acetamide are obtained in the form of a white kiss.

[RMN spectrum ^] H (300 MHz, CDCl ₃ , δ in ppm): 0.40 (mt: 2H); 0.74 (mt: 2H); 2.64 (mt: 2H); 2.89 (dd, J = 7.5 in 5 Hz: 1H); 3.08 (mt: 2H);

3.42 (t width, J = 7.5 Hz: 1H); 3.51 (d, J = 10.5 Hz: 1H); 4.25 (s: 1H);

5.50 (mf: 1H); 6.70 (mt, J = 9 at 2.5 Hz: 1H); 6.81 (mt: 2H); om 7.15 go

7.35 (mt: 8H)].

Example 54 (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclohexyl-14-methylacetamide can be obtained as follows: to a solution of 50 mg of (RS) - {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 2 cm ³ anhydrous dichloromethane , at a temperature near 20 ° C, 0.016 cm @ 3 of N-methylcyclohexylamine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm of triethylamine, and 1.5 mg of hydroxybenzotriazole hydrate are added sequentially. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mt), provided it was then eluted with dichloromethane using a Duramat pump, collecting 2 cm ³ fractions. fractions

167 to 6 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gives 17 mg (RS) -2- {1- [6uc (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -1Hcyclohexyl-N-methylacetamide as a white kiss.

[RMN 1 H spectrum (250 MHz, (CD ₃ ) ₂ SO d6, at 373K δ in ppm): from 0.98 to 1.85 (mt: 10H); om 2.60 to 3.05 (mt: 8H); 3.26 (t width, J = 7.5 Hz: 1H); 4.25 (d width, J = 9 Hz: 1H); 4.45 (s: 1H); 7.00 (mt: 3H); om 7.25 go 7.45 (mt: 8H) J.

Example 55

N-) -2- {T [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -18- (tegrahydrofuran-2-ylmethyl) -acetamide can be obtained as follows: to a solution of 50 mg of (RS) {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 2 cm ³ anhydrous dichloromethane, at a temperature close to 20 ° C, 0.013 cm @ ^{3 of} tetrahydrofurfurylamine, 29 mg of 1- (3 dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm @ 3 of triethylamine are added sequentially, and

1.5 mg hydroxybenzotriazole hydrate. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm) together with 3 g of fine silica (0.040-0.063 mt), provided it was then eluted with dichloromethane using a Duramat pump pomide, collecting 2 cm ³ fractions. fractions 3 to 8 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 27 mg of 2 (RS) -2- {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N (tetrahydrofuran-2-ylmethyl) - is thus obtained acetamide in the form of a white solid

168 substance. [RMN H spectrum (300 MHz, CDCl ₃ , δ in ppm): from 1.65 to 1.95 (mt: 4H); 2.64 (mt: 1H); 2.89 (dd, J = 7.5 in 5.5 Hz: 1H); om 3.00 to 3.20 (mt: 3H); om 3.30 to 3.60 (mt: 2H); 3.58 (d, J = 10.5 Hz: 1H); om 3.65 to 3.95 (mt: 3H); 4.25 (s: 1H); 5.81 (mt: 1H); 6.68 (tt, J = 9 at 2.5 Hz: 1H); 6.82 (mt: 2H); om 7.15 to 7.35 (mt: 8H)].

Example 56 (R) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (2-morpholin-4-yl- ethyl) -acetamide can be prepared as follows: to a solution of (RS) - {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid 50 mgxApupugam acid in 2 cm ³ anhydrous dichloromethane, at a temperature close to 20 ° C, 0.016 cm ³ aminoethylmorpholine, 29 mg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cmt triethylamine, and 1.5 mg were added sequentially. hydroxybenzotriazole hydrate. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mt), eluting under dichloromethane using a Duramat pump, eluting sequentially with a dichloromethane-ethyl acetate mixture (70-30 in volumes) and collect fractions of 2 cm ³ for fractions 1 to 12, then with dichloromethane-methanol (98-2 in volumes) and collect fractions of 2 cm ³ for fractions 12 to 27. Fractions 13 to 27 are combined and concentrate to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus 34 mg (RS) -2- {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) -N- (2-morpholine-

4-yl-ethyl) -acetamide as a white kiss. [RMN spectrum ¹ H (300 MHz, CDCl ₃ , δ in ppm): 2.33 (t width, J = 5 Hz: 4H); 2.38 (t,

169

J = 7 Hz: 2H); 2.65 (mt: 1H); om 2.85 go 3.20 (mt: 3H); 3.25 (q width, J = 7 Hz: 2H); 3.43 (mt: 1H); 3.57 (t, J = 5 Hz: 4H); 3.61 (d, J = 10.5 Hz: 1H); 4.26 (s: 1H); 5.98 (mf: 1H); 6.70 (mt, J = 9 at 2.5 Hz: 1H); 6.83 (mt: 2H); om 7.15 to 7.35 (mt: 8H)].

Example 57 (R8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (1-ethylpyrrolidin-2-ylmethyl) -acetamide can be prepared as follows: to a solution of (RS) - {1- [6uc (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid 50 mgxApoxugpam in 2 cm ³ anhydrous dichloromethane at a temperature close to 20 ° C, 0.018 cm aminomethylethylpyrrolidine, 29 mg 1- (3 dimethylaminopropyl) -3-ethylcarbodiimide chloride, 0.028 cm ³ triethylamine are added sequentially, and

1.5 mg hydroxybenzotriazole hydrate. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium is placed in a Varian cartridge (12 mt iuaMembp) together with 4 cm ³ silica (0.060-0.200 mt), under dichloromethane using a vacuum apparatus, eluting with dichloromethane between 0 and 6 cm, then with the dichloromethane-methanol mixture (95-5 in volumes), the fractions containing the desired product were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C for 2 hours. The yellow fine dispersion thus obtained is recovered with 2 cm 3 ethyl acetate, then with 2 cm ³ distilled water. After stirring, the mixture was solidified, the organic phase was concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. the resulting residue was extracted with 2 cm ^{3 of} di-isopropyl oxide, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gives 38 mg

170 (R) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (1-ethylpyrrolidin-2-ylmethyl) - acetamide in the form of a white kiss. [RMN spectrum ^! H (300 MHz, CDCl ₃ with a few drops of CD ₃ COOD d4, δ in ppm): 0.96 and 1.17 (2t, J = 7.5 Hz: 3H in full); from 1.60 to 2.00 (mt: 4H); from 2.50 to 2.95 - from 3.10 to 3.85 (mts: 11H); om 3.95 to 4.10 (mt: 1H); 4.10 in 4.14 (2d, J = 10.5 Hz: 2H in full); 5.18 u 5.25 (2s wide: W full); 6.66 (mt: 1H); om 6.80 to 7.00 (mt: 2H); om 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: to a solution of 50 mg of (I8) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 2 cm ³ anhydrous dichloromethane, at temperatures close to 20 ° C, 0.012 cm @ ^{3 of} isobutylamine, 29 mg of chlorhydrate <2 of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm of triethylamine, and 1.5 mg of hydroxybenzotriazole hydrate are added sequentially. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium is placed in a Varian cartridge (12 mt diameter) together with 5 cm3 of silica (0.060-0.200 mt), eluting with dichloromethane between 0 and 6 cm ³ under dichloromethane using a vacuum apparatus, then with a mixture of dichloromethane-ethyl acetate (95-5 in volumes), the fractions containing no desired product were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus, 40 mg of (P8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-isobutylacetamide are obtained as a white kiss.

171 [RMN * H spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ 6 ppm): 0.75 (d, J =

7.5 Hz: 6H); 1.62 (mt: 1H); 2.61 (mt: 1H); om 2.70 to 2.95 (mt: 3H); 3.03 (mt: 2H); 3.22 (t width, J = 7 Hz: 1H); 3.83 (d, J = 10.5 Hz: 1H);

4.45 (s: 1H); 7.00 (mt: 2H); 7.08 (tt, J = 9 at 2.5 Hz: 1H); om 7.25 go

7.45 (mt: 8H); 8.11 (t, J = 6 Hz: 1H) J.

Example 59 (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N, N-dimethylacetamide can be obtained as follows way:

A solution of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid solution in 50 mgxAopxugpam in 2 cm anhydrous dichloromethane, at a temperature close to to 20 [deg.] C., sequentially, 0.060 cm &lt; ^{3 &gt; of a} 2M solution of dimethylamine in tetrahydrofuran, 29 mg of 1- (3-dimethylaminopropyl) -3ethylcarbodiimide, 0.028 cm @ ^{3 of} triethylamine, and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium is placed in a Varian cartridge (12 mm diameter) together with 4.4 cm ³ silica (0.060-0.200 mm), and under conditions of dichloromethane using a vacuum apparatus, elution is carried out Q, with dichloromethane between 0 and 6 ³ , then with a mixture of dichloromethane ethyl acetate (95-5 v / v), the fractions containing no desired product were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 13 mg of (RS) -2- {1- [6uc (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -1 H, N-dimethylacetamide are obtained in the form of a white powder. [RMN spectrum ^X H (300 MHz, CDCl ₃ , δ in ppm): 2.70 to 2.80 (mt: 2H); 2.92 (s: 3H); 2.95 (s: 3H); from 3.00 to 3.15 (mt: 2H); 3.38 (t width, J = 7.5 Hz: 1H);

172

3.96 (d, J = 10 Hz: 1H); 4.26 (s: 1H); 6.69 (tt, J = 9 at 2.5 Hz: 1H); 6.81 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

Example 60 (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-benzylacetamide can be prepared as follows: to a solution of 50 mg of (RS) - {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 2 cm ³ anhydrous dichloromethane, at a temperature of close to 20 ° C, 0.013 cm @ ^{3 of} benzylamine, 29 mg of 1- (3 dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm @ 3 of triethylamine were added sequentially, and

1.5 mg hydroxybenzotriazole hydrate. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (12 mt diameter) together with 4.4 cm3 of silica (0.060-0.200 mt), eluting with dichloromethane between 0 and 6 cm ³ under dichloromethane using a vacuum apparatus. then, with the dichloromethane-ethyl acetate mixture (95-5 V by volume), the fractions containing no desired product were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gives 37 mg (RS) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl-1-benzylacetamide as white crystals. [Spectrum RMN Ή (300 MHz, CDCl ₃ , δ in ppm): 2.67 (mt: 1H); 2.93 (mt: 1H); 3.11 (mt: 2H); 3.43 (t width, J = 7. 5 Hz: 1H); 3.62 (d, J = 10.5 Hz: 1H); 4.26 (s: 1H); 4.38 (mt: 2H); 5.71 (mt: 1H); 6 , 71 (t width, J = 9 Hz: 1H); 6.83 (mt: 2H); om 7.10 to 7.40 (mt: 13H)].

Example 61

173 (RS) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclohexylmethylacetamide can be prepared as follows: to solution of 50 mg of {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 2 cm anhydrous dichloromethane at a temperature close to 20 ° C , 0.016 cm aminomethylcyclohexane, 29 mg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm ³ triethylamine, and 1.5 mg hydroxybenzotriazole hydrate are added sequentially. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium is placed in the cartridge Varian (6 cm ^3), together with 3 g of fine silica (0.040-0.063 mm), with the proviso that then eluted with dichloromethane with the help of a pump Duramat collecting fractions of 2st ^3. fractions 2 to 3e were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus, 49 mg of N, S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin3-yl} -2- (3,5-difluoro-phenyl) -L-cyclohexylmethylacetamide is obtained in the form of a white kiss . [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 0.75 to 1.75 (mt: IN); 2.65 (mt: 1H); from 2.85 to 3.15 (mt: 5H); 3.42 (t width, J = 7.5 Hz: 1H); 3.57 (d, J = 10.5 Hz: 1H); 4.27 (s: 1H); 5.40 (mt: 1H); 6.71 (t width, J = 9 Hz: 1H); 6.83 (mt: 2H); om 7.15 go 7.40 (mt: 8H)].

Example 62 N- (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N- [3- (2-oxo-pyrrolidine) -1-yl) -propyl] -acetamide can be prepared as follows: to a solution of 50 mg of (RS) {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - ( 3,5-difluorophenyl) -acetic acid in 2 cm ³ anhydrous dichloromethane at a temperature close to

174 ° C, 0.017 cm ³ aminopropylpyrrolidone, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide chloride, 0.028 cm ³ triethylamine, and 1.5 mg hydroxybenzotriazole hydrate were added sequentially. The resulting solution was stirred at a temperature near 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (6cm) together with 3g of fine silica (0.040-0.063 mt), provided it was then eluted with dichloromethane using a Duramat pump, collecting 2m ³ fractions. fractions 4 to 12 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus, 35 mg (RS) -2- {1- [6uc- (4L * chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N- [3- (2 -oxopyrrolidin-1-yl) -propyl] -acetamide as a white kiss.

[RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 1.50 to 1.65 (mt: 2H); 2.04 (mt: 2H); 2.43 (t, J = 8 Hz: 2H); 2.64 (mt: 1H); 2.88 (dd, J = 7.5 in 5.5 Hz: 1H); om 3.00 go 3, 30 (mt: 6H); om 3.30 to 3.45 (mt: 3H); 3.64 (d, J = 10.5 Hz: 1H); 4.27 (s: 1H); 6.67 (mt, J = 9 at 2.5 Hz: 1H);

6.90 (mt: 2H); 7.15 (t, J = 6 Hz: 1H); om 7.20 go 7.35 (mt: 8H) J.

Example 63 (R) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-acetyl (4-methylpiperazine) may be prepared as follows: to a solution of 50 mg of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 2 cm ³ anhydrous dichloromethane, at a temperature near 20 ° C, were added sequentially, 0.013 cm ^{3 of} N-methylpiperazine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide chloride, 0.028 cm of triethylamine, and 1.5 mg of hydroxybenzotriazole hydrate.

The resulting solution was stirred at a temperature close to 20 ° C

175 for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mt), eluted with a dichloromethane-ethanol mixture (98-02 in volumes) under dichloromethane using a Duramat pump. by collecting fractions of 2 cm ³ , fractions 10 to 24 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gives 39 mg of (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidine-

3-yl} -2- (3,5-difluorophenyl) -N-acetyl (4-methylpiperazine) as a white kiss. [RMN H spectrum (300 MHz, CDCl ₃ , δ in ppm):

1.83 (mt: 1H); om 2.10 go 2.45 (mt: 3H); 2.21 (s: 3H); 2.74 (mt: 2H); om 2.95 to 3.15 (mt: 2H); om 3.30 to 3.55 (mt: 4H); 3.73 (mt: 1H); 3.93 (d, J = 10 Hz: 1H); 4.25 (s: 1H); 6.69 (tt, J = 9 at 2.5 Hz: 1H);

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

Example 64 (P8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (2,2-dimethyl-propyl) -acetamide can be prepared as follows: to a solution of 50 mg of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl) - (3,5-difluorophenyl) -acetic acid solution in 2 cm ³ anhydrous dichloromethane at a temperature close to 20 ° C, 0.014 cm ³ neopentylamine, 29 mg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm triethylamine, and 1.5 mg hydrate are added sequentially of hydroxybenzotriazole.

The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mm), under dichloromethane using a Duramat pump, eluted with a dichloromethane-petroleum ether mixture (80-20 v / v). )

176 collecting fractions of 1.5 cm ³ . fractions 4 to 8 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus, 40 mg (RS) -2- {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) -N- (2,2-dimethylpropyl) is obtained ) -acetamide in the form of a white kiss. [RMN spectrum

* H (300 MHz, CDCl ₃ , δ in ppm): 0.81 (s: 9H); 2.66 (mt: 1H); from 2.90 to

3.20 (mt: 5H); 3.44 (t width, J = 7.5 Hz: 1H); 3.61 (d, J = 10.5 Hz: 1H);

4.28 (s: 1H); 5.40 (mt: 1H); 6.72 (mt, J = 9 at 2.5 Hz: 1H); 6.85 (mt: 2H); om

7.20 to 7.35 (mt: 8H)].

Example 65 (K8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (2-pyrrolidin-1-yl- ethyl) -acetamide can be prepared as follows: to a solution of 50 mg of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) - acetic acid In 2 cm ³ anhydrous dichloromethane, at a temperature close to 20 ° C, 0.015 cm ³ aminoethylpyrrolidine, 29 mg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm triethylamine, and 1.5 were added sequentially mg hydroxybenzotriazole hydrate. The resulting solution was stirred at a temperature near 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mt), eluting with a dichloromethane-ethanol mixture (98-04 in volumes) under dichloromethane using a Duramat pump. collecting fractions of 1.5 cm ³ . fractions 13 to 20 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus 33 mg (RS) -2- {1- [6uc- (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (2-pyrrolidin-1- yl-ethyl) 177 acetamide as a white kiss. [RMN spectrum ^! H (300 MHz, CDCI ₃ , δ B ppm): 1.78 (mt: 4H); from 2.50 to 2.70 (mt: 3H); 2.54 (mt: 4H); 2.91 (dd, J = 7.5 in 5 Hz: 1H); 3.10 (mt: 2H); om 3.20 to 3.45 (mt: 3H); 3.64 (d, J = 10.5 Hz; 1H); 4.27 (s: 1H); 6.67 (mt, J = 9 at 2.5 Hz: 1H);

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

Example 66 (P8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclopropylmethyl acetamide can be prepared as follows method: 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 anhydrous dichloromethane, at temperatures close to 20 ° C, 0.011 cm cyclopropane methylamine, 29 mg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm triethylamine, and 1.5 mg hydroxybenzotriazole hydrate are added sequentially. The resulting solution was stirred at a temperature near 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mt), provided it was then eluted with a dichloromethane-petroleum ether mixture (8020 by volume) using a Duramat pump. collecting fractions of 1.5 centimeters. fractions 3 to 8 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 37 mg (RS) -2- {1- [6uc- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclopropylmethyl acetamide are thus obtained in the form of a white kiss. [RMN spectrum ^X H (300 MHz, CDCI ₃ , δ in ppm): 0.13 (mt: 2H); 0.45 (mt: 2H); 0.86 (mt: 1H); 2.65 (mt: 1H); 2.91 (dd, J = 7.5 in 5 Hz: 1H); om 3.00 to 3.15 (mt: 4H); 3.41 (t width, J = 7.5 Hz: 1H); 3.57 (d,

178

J = 10.5 Hz: 1H); 4.25 (s: 1H); 5.50 (mt: 1H); 6.70 (mt, J = 9 at 2.5 Hz: 1H);

6.84 (mt: 1H); om 7.15 go 7.35 (mt: 8H) J.

Example 67

(R8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -P4-propylacetamide can be prepared as follows: to solution of 50 mg of (RS) - {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 2 cm ³ anhydrous dichloromethane, at a temperature close to 20 ° C, 0.015 cm ^{3 of} propylamine, 29 mg of 1- (3 dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm ^{3 of} triethylamine are added sequentially, and

1.5 mg hydroxybenzotriazole hydrate. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mm) provided it was eluted with dichloromethane using a Duramat pump. The fractions containing no desired product were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 21 mg of (RS) -2- {1- [6uc- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5difluorophenyl) -14-propylacetamide are thus obtained as a white solid. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 0.84 (t, J = 7.5 Hz: 3H); 1.45 (mt: 2H); 2.65 (mt: 1H); 2.92 (dd, J = 7.5 in 5.5 Hz: 1H); om 3.00 to 3.20 (mt: 2H); 3.15 (q, J = 7 Hz: 2H); 4.43 (t width, J = 7.5 Hz: 1H); 3.56 (d, J = 10.5 Hz: 1H); 4.26 (s: 1H); 5.39 (mt: 1H); 6.70 (mt, J = 9 at 2.5 Hz: 1H); 6.83 (mt: 2H); om 7.15 go 7.35 (mt: 8H) J.

Example 68 \ 9

(RS) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-methylacetamide can be prepared as follows: to solution of (RS) - <1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid in 2 cm ³ anhydrous dichloromethane at 50 mgxAopxugpam at a temperature close to 20 ° C, sequentially, 0.050 cm 2M solution of methylamine in tetrahydrofuran, 29 mg of 1- (3-dimethylaminopropyl) -3ethylcarbodiimide hydrochloride, 0.028 cm ^{3 of} triethylamine, and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution was stirred at a temperature near 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mm) provided it was eluted with dichloromethane using a Duramat pump. The fractions containing no desired product were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 19 mg of (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-methylacetamide are obtained in the form of a white solid. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm): 2.66 (mt: 1H); 2.76 (d, J = 5 Hz: 3H); 2.93 (mt: 1H); 3.10 (mt: 2H); 3.44 (t width, J = 7.5 Hz: 1H); 3.59 (d, J = 10.5 Hz: 1H); 4.28 (s: 1H); 5.41 (mf: 1H); 6.71 (tt, J = 9 at 2.5 Hz: 1H); 6.83 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

Example 69 (R8) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-isopropylacetamide can be prepared as follows: to (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid solution in 50 mg x Apoxugpam in 2 cm ³

180 anhydrous dichloromethane, at a temperature near 20 ° C, were added sequentially, 0.011 cm ^{3 of} isopropylamine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide chloride, 0.028 cm of triethylamine, and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mm), provided that it was then eluted with dichloromethane using a Duramat pump and 1.5 cm fractions were collected. ³ . fractions 6 to 14 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 21 mg of (RS) -2- {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -isopropylacetamide are thus obtained in the form of a white kiss. [RMN * H spectrum (300 MHz, CDCl ₃ , δ in ppm): 1.05 (d, J = 7 Hz: 3H); 1.10 (d, J = 7 Hz: 3H); 2.65 (mt: 1H); 2.90 (dd, J = 7.5 in 5.5 Hz: 1H); om 3.00 go

3.15 (mt: 2H); 3.42 (t width, J = 7.5 Hz: 1H); 3.51 (d, J = 10.5 Hz: 1H); 4.00 (mt: 1H); 4.26 (s: 1H); 5.19 (d width, J = 7.5 Hz: 1H); 6.70 (mt, J = 9 at 2.5 Hz; 1H); 6.82 (mt: 2H); om 7.20 to 7.40 (mt: 8H)].

Example 70 (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -piperidin-1-yl-acetamide may be prepared as follows: to a solution of 50 mg of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 2 cm ³ anhydrous dichloromethane, at a temperature close to 20 ° C, 0.013 cm ^{3 of} aminopiperidine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm ³ were added sequentially

181 triethylamine, and 1.5 mg hydrate of hydroxybenzotriazole. The resulting solution was stirred at a temperature near 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mm), provided that it was eluted with dichloromethane-ethanol (98-02 in volumes) by collecting 2 cm ³ fractions. fractions 7 to 12 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 33 mg of (K8) -2- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluoro-phenyl) -N-piperidin-1-yl are thus obtained -acetamide as a white solid. [RMN * H spectrum (300 MHz, CDCl ₃ , δ in ppm): 0.95 to 1.85-2.05 and 2.29 (mts: 10H); from 2.60 to

2.80 (mt: 2H); from 3.00 to 3.20 (mt: 2H); 3.39 (t width, 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 at 2.5 Hz: 1H); 6.85 (mt: 2H); om 7.15 go 7.35 (mt: 8H) J.

Example 71 (P5) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cycloheptylacetamide can be prepared as follows: to a solution of 50 mgxAopxugpam of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid in 2 cm ³ anhydrous dichloromethane, at a temperature close to 20 ° C, 0.015 cm ^{3 of} cycloheptylamine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.028 cm ^{3 of} triethylamine, and 1.5 mg of hydroxybenzotriazole hydrate are added sequentially. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium was placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mm) at

182 condition that it is then eluted with dichloromethane using a Duramat pump, collecting 2 cm ³ fractions. fractions 3 to 6 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 24 mg of (RS) -2- {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N4cycloheptylacetamide are thus obtained in the form of a white kiss. [RMN spectrum 300 (300 MHz, CDCl ₃ , δ in ppm): 1.20 to 1.95 (mt: 12H);

2.65 (mt: ΙΗ); 2.90 (dd, J = 7.5 in 5.5 Hz: 1H); om 3.00 to 3.15 (mt: 2H);

3.42 (t width J = 7.5 Hz: 1H); 3.52 (d, J = 10.5 Hz: 1H); 3.86 (mt: 1H); 4.26 (s: 1H); 5.31 (d width, J = 7.5 Hz: 1H); 6.70 (mt, J = 9 at 2.5 Hz: 1H); 6.82 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

Example 72 (S) -2- {T [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -acetamide can be prepared as follows: to a solution of 98 mg of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 4 cm anhydrous dichloroethane at a temperature close to 20 ° C , 60 mg of 1- (3-dimethylaminopropyl) -3ethylcarbodiimide hydrochloride, and 3 mg of hydroxybenzotriazole hydrate are added sequentially, allowing ammonia to pass for 2 hours with stirring at a temperature close to 20 ° C. The reaction medium was washed with water, then placed in a Varian cartridge (6 cm ³ ) together with 3 g of fine silica (0.040-0.063 mt), provided it was eluted with a dichloromethane-ethyl acetate mixture (9 -1 in volumes). ) using a Duramat pump. The fractions included between 36 and 80 ml were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 32 mg of (P8) -2- {1- [bis- (4-chlorophenyl) methyl] 183 azetidin-3-yl} -2- (3,5-difluorophenyl) -acetamide are thus obtained in the form of an amorphous powder. [RMN spectrum ^X H (300 MHz, CDCl ₃ , δ B ppm): 2.66 (mt: 1H); 2.95 (dd, J = 7 at 5 Hz: 1H); om 2.95 to 3.15 (mt: 2H); 3.45 (t width J = 7 Hz: 1H); 3.67 (d, J = 10.5 Hz: 1H); 4.27 (s: 1H); om 5.20 to 5.4O (mf: 2H); 6.72 (mt, J = 9 at 2.5 Hz: 1H); 6.84 (mt: 2H); om 7.20 go

7.35 (mt: 8H)].

Example 73

Methyl (RS) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) -N-acetylamino acetate can be obtained by the following method: to a solution of 200 mg of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 8 cm ³ dichloroethane, at a temperature of near 20 [deg.] C., 100 mg of hydrochloride of glycine methyl ester, 115 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, and 6 mg of hydroxybenzotriazole hydrate are added sequentially. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium was washed with water, dried, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The residue thus obtained is recovered with 1 cm ^{3 of} dichloromethane, V · then placed in a 1ST FlashPack cartridge, SIL-020-005 reference, provided it is eluted with a mixture of dichloromethane-ethyl acetate (95-05 by volume) using Duramat pump. The fractions included between 18 and 42 ml were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 68 mg of methyl (RS) -2 {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -Macetylamino acetate are thus obtained in the form of porous white crystals .

[RMN spectrum Ή (300 MHz, CDCl ₃ , δ in ppm): 2.67 (mt: 1H); 2.93

184 (dd width, J = 7.5 and 5 Hz: 1H); om 3.00 to 3.15 (mt: 2H); 3.41 (t width J = 7.5 Hz: 1H); 3.68 (d, J = 10.5 Hz: 1H); 3.74 (s: 3H); 3.93 (dd, J = 18 at 5 Hz: 1H); 4.03 (dd, J = 18 at 5 Hz: 1H); 4.27 (s: 1H); 5.96 (mt: 1H);

6.71 (mt, J = 9 at 2 Hz: 1H); 6.85 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

Example 74 (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (3-dimethylamino-propyl) -acetamide can be prepared as follows: to a solution of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid 50 mgxAopxugpam solution in 2 cm ³ anhydrous dichloromethane, at a temperature close to 20 ° C, was added successively, 0.015 cm ³ H, N-dimethylpropane-1,3-diamine, 29 mg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide chloride, 0.028 cm ³ triethylamine and 1.5 mg hydrate of hydroxybenzotriazole. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium is placed in a Varian cartridge (12t diameter) together with 4 cm ^{3 of} silica (0.060-0.200 mm) and under dichloromethane using a vacuum apparatus eluting with dichloromethane between 0 and 6 cm ³ , then with dichloromethane-methanol mixture (95-5 in volumes). The fractions containing no desired product were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gives 33 mg ^ 8) -2- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (3-dimethylamino-propyl) acetamide in the form of white crystals. [RMN ^X H spectrum (300 MHz, CDC1 ₃ with a few drops of CD ₃ COOD d4, δ in ppm):

1.91 (mt: 2H); 2.71 (s: 6H); 2.95 (mt: 2H); from 3.15 to 3.40 (mt: 2H); by

3.40 to 3.60 (mt: 1H); from 3.60 to 3.80 (mt: 2H); 4.00 (mt: 2H); 4.28

185 (d, J = 10.5 Hz: 1H); 5.22 (s: 1H); 6.68 (tt, J = 9 at 2.5 Hz: 1H); 6.90 (mt: 2H); 7.33 (mt: 4H); 7.46 (d, J = 8 Hz: 4H)].

Example 75

N-) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N- (2-hydroxy-ethyl) -acetamide may be prepared as follows: to a solution of 50 mg of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid hydrochloride in 2 cm ³ anhydrous dichloromethane, at a temperature near 20 ° C, were added sequentially, 0.024 cm ^{3 of} ethanolamine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide chloride, 0.28 cm ^{3 of} triethylamine and

1.5 mg hydroxybenzotriazole hydrate. The resulting solution was stirred at a temperature close to 20 ° C. The reaction medium is washed with 2 cm ³ saturated sodium bicarbonate solution, dried over magnesium sulfate, then placed in a 1ST FlashPack cartridge, SIL-016-002 reference under dichloromethane and eluted with a dichloromethane-ethyl acetate mixture (95- 05 in volumes) using a Duramat pump. The fractions included between 25 and 60 cm ³ were pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting residue was again chromatographed on a 1ST FlashPack cartridge, SIL-016-002 reference under dichloromethane, and eluted with a dichloromethane-ethyl acetate mixture (95-05 by volume) using a Duramat pump. The fractions included between 25 and 355 ³ were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 14 mg (RS) -2- {1- [6uc (4-chlorophenyl) methyl] -azeppidin-3-yl} -2- (3,5-difluorophenyl) -1H- (2-hydroxy-ethyl) -acetamide are thus obtained in the form of a white solid. [Spectrum RMN ² H (300 MHz, CDCI ₃ , δ in ppm): 2.65 (mt: 1H); 2.91

186 (mt: 1H); om 3.00 to 3.15 (mt: 2H); om 3.30 to 3.50 (mt: 3H); 3.60 (d, J = 10.5 Hz: 1H); 3.66 (t, J = 5.5 Hz: 2H); 4.26 (s: 1H); 5.88 (mt: 1H);

6.71 (mt, J = 9 at 2 Hz: 1H); 6.84 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

Example 76 (S) -1 - [{1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) methyl] -3-propylurea can be prepared as follows : to a solution of 50 mgxAopxugpam of (RS) - {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid in 3 cm ³ anhydrous toluene, under inert argon atmosphere at temperatures near 20 ° C, 0.056 cm @ ^{3 of} triethylamine and 0.064 cm of diphenylphosphonoazide are added sequentially. The resulting solution was stirred at a temperature close to 50 ° C for about 1 hour. 0.016 cm ³ propylamine was added and stirring was maintained at a temperature close to 20 ° C for about 12 hours. The reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. The residue was extracted with 1 cm ^{3 of} dichloromethane, then placed in a Varian cartridge (6 cm ³ ) together with 3 cm ^{3 of} fine silica (0.040-0.063 mm), provided it was eluted with a mixture of dichloromethane-ethyl acetate (95- 5 in volumes) with the help of a Duramat pump. The fractions included between 12 and 16 cm ³ were pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 13 mg (RS) -1 - [{1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -methyl] -3-propylurea are thus obtained in the form of a beige solid.

[RMN 1 H spectrum (400 MHz, CDCl ₃ , δ in ppm): 0.92 (t, J = 7.5 Hz: 3H); 1.53 (mt: 2H); om 2.55 go 2.75 (mt: 1H); om 2.80 go 3.25 (mt:

187

6H); 4.26 (t, J = 5.5 Hz: 1H); 4.29 (s: 1H); 4.92 (t, J = 7 Hz: 1H); 5.31 (d, J =

5.5 Hz: 1H); 6.66 (tt, J = 9 at 2.5 Hz: 1H); 6.79 (mt 2H); om 7.15 go

7.40 (mt: 8H)].

Example 77

Chlorhydrate of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5difluorophenyl) -acetic acid can be obtained as follows: to a solution of 0.44 g (RS) - {1- [Bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid ethyl ester in 7 cm dioxane, again 3 cm hydrochloric acid 6N is added.

The resulting solution was stirred at reflux for about 2 hours, then left at a temperature close to 20 ° C for about 12 hours. The precipitate formed was filtered on glass frit No 3, washed with 10 cm ³ diisopropyl oxide, then dried under reduced pressure (0.27 kPa) at a temperature close to 40 ° C. Thus, 0.185 g of (RS) - {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5difluorophenyl) -acetic acid hydrochloride is obtained as a white powder. [RMN 1 H spectrum (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 (t, J = 9 Hz: 1H); 4.72 (t, J = 9 Hz: 1H); 5.26 (mf: 1H); 7.00 (mt: 2H); 7.06 (mt, J = 9.5 in 2.5 Hz: 1H); om 7.30 to 7.60 (mt: 8H)].

Example 78

(RS) {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5 difluorophenyl) -acetic acid ethyl ester can be prepared as follows: to a suspension of 0.78 (RS) - {1- [bis- (4188 chlorophenyl) methyl] -azetidin-3-ylidene} - (3,5-difluorophenyl) -acetic acid ethyl ester in 20 cm ³ ethanol, 121 mg of sodium is added again borohydride at a temperature close to 0 ° C. The resulting suspension was stirred at a temperature near 20 ° C for about 12 hours. The reaction medium was poured onto 200 cm @ ^{3 of} distilled water, then extracted 3 times with 40 cm @ ^{3 of} ethyl acetate. The organic phase was washed successively 3 times with 40 cm ^{3 of} distilled water, then with 40 cm ^{3 of} saturated sodium chloride solution. After decanting, the organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness under reduced C pressure (2.7 kPa) at a temperature close to 40 ° C. The resulting residue was chromatographed on a column equipped with 75 cm ^{3 of} fine silica (0.040-0.063 mm) under pressure of 0.7 bar with a mixture of dichloromethane-ethyl acetate (the percentage of ethyl acetate ranged from 0 to 10%), collecting fractions of 15 Article ³ . Fractions 4 to 11 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. Thus, 0.46 g of (RS) {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} - (3,5difluorophenyl) -acetic acid ethyl ester is obtained as a yellow vegetable resin. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 1.19 (t, J = 7 Hz: 3H); 2.62 (t width, J = 6 Hz: 1H); 2.87 (dd, J = 7.5 in 6 Hz: 1H);

^{O om 2,95 go 3,15 (mt:} 2H); 3.39 (t width, 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 = 9.5 in 2.5 Hz: 1H);

6.80 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

The fractions 16 to 26 of the previous chromatography were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gives 0.24 g of (S) -2- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) -ethanol as a yellow

189 kiss. [Spectrum RMN ^d H (300 MHz, CDCl ₃ , δ in ppm): 1.98 (mf: 1H); 2.69 (mt: 1H); from 2.70 to 2.85 (mt: 1H); om 2.90 to 3.10 (mt: 2H); 3.18 (mt: 1H); 3.44 (mt: III); om 3.65 to 3.85 (mt: 2H); 4.28 (s: 1H); om 6.60 to 6.80 (mt: 3H); om 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 as follows: to a solution of 9.1 g of ethyl ester of {1- [Bis- (4-chlorophenyl) methyl] -3-hydroxy-azetidin-3-yl} - (3,5-difluorophenyl) <2 acetic acid in 200 cm dichloromethane, 6.6 g again added

4-dimethylaminopyridine, 2.1 cm ³ methylsulfonyl chloride. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction mixture was washed 3 times <2 with 250 cm3 of distilled water, then dried with magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. The resulting residue was extracted hot with 50 cm ^{3 of} isopropyl oxide, then left at a temperature close to 20 ° C for about 12 hours. The resulting white suspension was filtered on a glass frit, washed with 20 cm 3 of petroleum ether, then dried under vacuum under reduced pressure (0.27 kPa) at a temperature close to 40 ° C for 2 hours. 7.9 g of {1 [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene) - (3,5-difluorophenyl) acetic acid ethyl ester is obtained in the form of a cream powder. [RMN spectrum ^X H (300 MHz, CDCl ₃ , δ in ppm): 1.25 (t, J = 7Hz: 3H); 3.85 (mt: 2H); 4.12 (AB, J = 7.5 Hz; 2H); 4.23 (mt: 2H); 4.51 (s: 1H); om 6.65 to 6.80 (mt: 3H); om 7.20 to 7.40 (mt: 8H)].

190

{1- [Bis- (4-chlorophenyl) methyl] -3-hydroxy-azetidin-3-yl} - (3,5-difluorophenyl) -acetic acid ethyl ester can be prepared as follows: to a solution of 7.73 cm diisopropylamine in 125 cm anhydrous tetrahydrofuran, under an inert nitrogen atmosphere at a temperature close to -70 ° C, a 34.54 cm 1.6 M solution of butyllithium in hexane is added dropwise over 15 minutes, stirring is maintained. at this temperature for 45 minutes, a solution of 11.01 g of ethyl 3,5-difluorophenyl acetate in 85 cm ^{3 of} anhydrous tetrahydrofur is added over 15 minutes en, stirring was continued for 1 hour at -78 ° C, 16.84 g of 1- [bis- (4-chlorophenyl) methyl] -azetidin-3-one in 90 cm ³ anhydrous tetrahydrofuran was added, stirring continued for 1 hour at -70 ° C, added at 0 ° C with vigorous stirring of 300 cm ³ saturated ammonium chloride solution for 30 minutes, the reaction mixture was decanted after 12 hours, the organic phase was washed 3 times with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a column of 70 mt diameter, equipped with 2000 cm fine fine silica (0.040-0.063 mt) under a pressure of 0.7 bar with a mixture of dichloromethane-ethyl acetate (99-01 in volumes), the fractions not containing the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C for 2 hours. Thus, 9.1 g of {1- [bis- (4-chlorophenyl) methyl] -3-hydroxy-azetidin-3-yl} - (3,5-difluorophenyl) acetic acid ethyl ester was obtained as a cream solid. [RMN spectrum Ή (300 MHz, CDCl ₃ , δ in ppm): 1.25 (t, J = 7 Hz: 3H); 2.87 (d, J = 8 Hz: 1H); 3.07 (d, J = 8 Hz: 1H); 3.13 (d width, J = 8 Hz: 1H); 3.28 (d width, J = 8Hz: 1H); 4.12 (s: 2H); 4.21 (mt: 2H); 4.36 (s: 1H); 6.78

191 (tt, J = 9 in 2.5 Hz: 1H); 6.98 (mt: 2H); om 7.20 to 7.40 (mt: 8H)].

Ethyl 3,5-difluorophenyl acetate can be prepared as follows: to a solution of 12 cm ³ ethanol in 300 cm ³ anhydrous dichloromethane, at a temperature close to 20 ° C 20.4 cm triethylamine is added successively, then 27.6 g 3,5difluorophenylacetic acid chloride in a solution of 60 cm ³ dichloromethane. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction mixture was washed successively 2 times with 150 cm ^{3 of} decinormal hydrochloric acid solution, then twice with 150 cm ^{3 of} saturated sodium bicarbonate solution. The organic phase was dried with magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. This gives 29 g of ethyl 3,5-difluorophenyl acetate as a yellow oil.

Chloride of 3,5-difluorophenylacetic acid can be prepared in the following way: to a solution of 25 g 3,5difluorofenilotsetna acid in 350 cm @ ³ of 1,2-dichloroethane, at a temperature close to 20 ° C, were successively added 19.3 cm ³ oxalyl chloride, then a few drops of dimethylformamide, after 3 hours of stirring at a temperature close to 20 ° C, 30 cm ^{3 of} oxalyl chloride are again successively added, then a few drops of dimethylformamide. The reaction medium was concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. 27.6 g of 3,5-difluorophenylacetic acid chloride are thus obtained as a yellow oil.

Example 79

192 (K8) -1- [bis- (4-chlorophenyl) methyl] -3- [1- (3,5-difluorophenyl) -1methylsulfonyl-ethyl] -azetidine is obtained in the following way: to a solution of 0.5 g ( 8) -1- [bis- (4-chlorophenyl) methyl] -3- [1- (3,5difluorophenyl) (methylsulfonyl) methyl] -azetidine in 10 cm cooled tetrahydrofuran to -78 ° C and maintained under an inert atmosphere. added 0.5 cm ³ 2M solution of lithium diisopropylamide. The temperature was allowed to rise again to -20 ° C, then 0.06 cm ^{3 of} iodomethane was added. The temperature was allowed to rise again to 0 ° C for a period of 2 hours, then a 20 cm ³ saturated aqueous ammonium chloride solution was added. The reaction medium was decanted and the aqueous phases were extracted twice with 20 cm @ ^{3 of} ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and evaporated to dryness at 40 ° C below 2.7 kPa to give 550 mg of a cream-colored residue. The residue was chromatographed on a silica column (Dynamax, reference 83121-C size 21.4 mm x 250 mm, pre-column 21.4 mm x 50 mm, reference R00083121G, silica 8µ porosity 60 Amgstroem; Rainin Instrument Co. Inc., Mac Road, Wobum, MA 01801, USA) eluting with a heptane: isopropanol (99: 1 v / v) mixture at 15 ppm (detection 254 pt, 10 cm fractions). fractions contained compound with Rf = 32/77 (cyclohexane: ethyl acetate 70: 30, 254 pt, silica plates, reference 1.05719, Merck KGaA, 64271 Darmstatd, Allemagne) were combined and evaporated at 40 ° C under 2.7 kPa to give 80 mg of 1- [bis- (4-chlorophenyl) methyl] -3- [1- (3,5-difluorophenyl) -1-methylsulfonyl-ethyl] azetidine as a white amorphous powder. [Spectrum RMN ¹ H (300 MHz, CDCl ₃ , δ in ppm): 2.05 (s: 3H); 2.54 (s: 3H); 2.63 (t, J = 7.5 Hz: 1H); 3.17 (t width, J = 8 Hz: 1H); 3.32 (mt: 1H); 3.44 (t width, J = 8 Hz:

193

1H); 3.71 (mt: 1H); 4.27 (s: 1H); 6.83 (mt, J = 9 at 2.5 Hz: 1H); 7.15 (mt: 2H); om 7.20 to 7.40 (mt: 8H)].

Example 80 (K8) -1- [bis- (4-chloro-phenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -azetidine can be prepared as follows: to a suspension of 0.191 cm. ³ bis- (4-fluoro-phenyl) -chloromethane, 300 mg of (K8) -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidine hydrochloride and 167 mg of potassium carbonate in 5 cm ³ acetonitrile, at a temperature of close to 20 ° C, a few granules of potassium iodide are added. After 48 hours at a temperature near 20 ° C, the reaction medium was filtered on a glass frit, the solid was washed with acetonitrile, and the filtrate was purified by preparative chromatography on a thin layer of silica [3 Merck Kieselgel Preparation Plates 60F254; 20x20 cm ³ ; 1 mm thick], eluting with a methanol-dichloromethane mixture (1-99 in volumes). Elution of the corresponding area of the desired product with a methanol-dichloromethane mixture (10-90% by volume), filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C yields 39 mg (I8) - 1- [bis- (4-chloro-phenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine as a yellow kiss. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.54 (t width, J = 7 Hz: 1H); 2.66 (s: 3H); 3.18 (mt: 2H); om 3.20 to 3.45 (mt: 1H); 3.63 (t width, J = 7 Hz: 1H); 4.27 (s: 1H); 4.28 (d, J = 11 Hz: 1H); 6.83 (mt, J = 9 at 2 Hz: 1H); om 6.90 go 7.05 (mt: 6H); om 7.25 to 7.40 (mt: 4H)].

194

Chlorhydrate of (S) -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidine can be prepared as follows: suspension of 8.5 g of 1-benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonyl methylene] -azetidine and

1.3 g of palladium hydroxide (20% by weight per palladium), in 600 cm 3 of methanol, 20 cm ^{3 of} hydrochloric acid 1N and 4 cm ^{3 of} acetic acid, were stirred at a temperature close to 20 ° C under an atmosphere of hydrogen (1.5 bars ) to fully absorb 2.1 liters of hydrogen. The reaction medium is then filtered on a glass frit, black-coated, the filtrate is concentrated to dryness under reduced pressure, then the resulting residue is taken up with ethanol. The white crystallized product was filtered off and dried. 5.4 g of (KB) -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine hydrochloride are thus obtained in the form of white crystals.

1-Benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -azetidine can be prepared as follows: a mixture of 18.8 g of 3-acetoxy-1-benzhydryl-3 - [(3,5-difluorophenyl) ) (methylsulfonyl) methyl] -azetidine and 3.9 g of lithium hydroxide monohydrate in 120 cm ^{3 of} acetonitrile were placed at a temperature close to 70 ° C for 3 hours. After cooling to a temperature near 2 ° C, 120 cm ^{3 of} tert-butyl and methyl ether, 80 cm ^{3 of} distilled water, then slowly 5 cm ^{3 of} acetic acid were added sequentially. 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, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was extracted with ethanol. After overnight at a temperature near 20 ° C, the resulting mixture was filtered on a glass frit, the white crystals obtained were washed with ethanol, diisopropyl oxide and dried under reduced pressure at a temperature close to

195 ° C. 14.6 g of 1-benzhydryl-3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine are thus obtained in the form of white crystals.

3-acetoxy-1-benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl] azetidine can be prepared as follows: to a suspension of 12.37 g of 3,5-difluorobenzyl-methyl-sulfone in 200 cm ³ tetrahydrofuran, under an inert nitrogen atmosphere at a temperature close to -30 ° C, was added dropwise over a period of about 25 minutes a 47.1 cm ³ solution of n-butyllithium 1,6N in hexane. The cloudy yellow solution was stirred at -30 ° C for 2 hours, then a solution of 11.87 g of 1-benzhydryl azetidin-3-one in 75 cm ^{3 of} dichloromethane was added dropwise. The reaction mixture was stirred for 1.5 hours at a temperature close to -30 ° C, then 6.07 cm ^{3 of} acetyl chloride was added, and the medium temperature was allowed to return to a temperature close to -10 ° C for about 30 minutes . 200 cm ^{3 of} water and 100 cm ^{3 of} dichloromethane are added. After vigorous stirring for 30 minutes and decanting, the organic phase was washed 3 times with 150 cm ^{3 of} saturated aqueous sodium hydrogen carbonate solution, 150 cm ^{3 of} saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated to dry under reduced pressure. The resulting crystalline residue was extracted with 50 cm ^{3 of} boiling ethanol. The resulting white suspension was allowed to stand overnight at a temperature close to 20 ° C, then the resulting solid residue was drained on a glass frit, washed with diisopropyl ether, and dried under reduced pressure at a temperature close to 50 ° C. 19.5 g of 3-acetoxy-1-benzhydryl-3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl] -azetidine are thus obtained in the form of white crystals.

196

1-Benzhydryl azetidin-3-one can be prepared according to the method described by KATRITZKY A. R. et al. In J. Heterocycl. Chem., 271 (1994).

3,5-difluorobenzyl-methyl-sulfone can be prepared as follows: mixture of 66,69 cm ³ 3,5-difluorobenzyl bromide, 71,97 g methanesulfonic acid sodium salt and 150 mg sodium iodide in 625 cm ³ ethanol heated to reflux under an argon atmosphere for about 16 hours. After cooling to a temperature near 20 ° C, the reaction medium is diluted with 3 liters of ethyl acetate, washed with 500 cm ^{3 of} water, 500 cm ^{3 of} saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated reduced pressure (50 mbar) at a temperature close to 40 ° C. The resulting residue was extracted with 300 cm ^{3 of} ethyl ether and the solid filtered on a glass frit, washed with 200 cm ^{3 of} ethyl ether, dried under reduced pressure at a temperature close to 20 ° C. 86.9 g of 3,5-difluorobenzyl-methyl-sulfone are thus obtained as a white powder.

Example 81 (R) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine can be prepared as follows: 47 mg (3-pyridyl) - (4-chlorophenyl) -bromomethane, 50 mg (k8) -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidine hydrochloride and 58 mg potassium carbonate in 2 cm ³ acetonitrile , stirred for about 3 hours at a temperature near 20 ° C, sprayed with solvent for 2 hours, about 16 hours at a temperature near 20 ° C, then sprayed with solvent for 1.5 hours. Then a few granules of potassium iodide are added, and the reaction mixture is maintained for about 2 hours under solvent dew. Next

197 cooling to a temperature near 20 ° C, the reaction medium was purified by preparative chromatography on a thin layer of silica [2 Merck Kieselgel Preparation Plates 60F254; 20 x 20 cm; 0.5 m thick], eluting with a mixture of methanol dichloromethane (2.5 - 97.5% by volume). Elution of the corresponding area of the desired product with a methanol-dichloromethane mixture (10-90 in volumes), filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C yields 11 mg (I8) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 [(3,5-difluorophenyl) -methylsulfonyl-methyl] -azetidine as a colorless gum. [Spectrum RMN ^d H (300 MHz, CDCl ₃ , δ in ppm): ^V 2.59 (mt: 1H); 2.66 (s: 3H); 3.21 (mt: 2H); om 3.30 to 3.50 (mt: 1H);

3.67 (mt: 1H); 4.28 (d width, J = 11 Hz: 1H); 4.32 (s width: 1H); 6.84 (mt, J = 9 at 2 Hz: 1H); 6.95 (mt: 2H); 7.19 (dd width, J = 8 at 5 Hz: 1H); om 7.20 to 7.40 (mt: 4H); 7.64 (d width, J = 8 Hz: 1H); 8.45 (mt: 1H);

8.59 (too broad: 1H)].

(3-Pyridyl) - (4-chlorophenyl) -bromomethane can be prepared as follows: a mixture of 150 mg (3-pyridyl) - (4-chlorophenyl) -methanol in 0.356 cm hydrobromic acid (33% in acetic acid) and 0.101 cm ^{3 of} acetyl bromide was refluxed for 1 hour, then left at a temperature close to 20 C for 2 hours before concentrating under reduced pressure and co-evaporated with several cm ^{3 of} toluene. 234 mg of (3-pyridyl) - (4-chlorophenyl) -bromomethane are thus obtained in the form of a birch-free solid.

(3-Pyridyl) - (4-chlorophenyl) -methanol can be prepared as follows: to a solution of 5.83 cm ³ 4-chlorophenylmagnesium bromide (1M

198 solution in ethyl ether) in 5 cm ³ tetrahydrofuran, under an inert atmosphere of argon, slowly add 0,5 cm ³ 3-pyridinecarboxaldehyde. After about 3 hours, 3 cm ³ saturated aqueous ammonium chloride solution and 10 cm ³ water were added to the reaction mixture. After stirring for 5 minutes at a temperature close to 20 ° C, the reaction medium was acidified to pH about 2 with aqueous hydrochloric acid 1N. The aqueous phase was extracted 3 times with 15 cm ^{3 of} dichloromethane. The remaining aqueous phase was treated with 10 cm ³ aqueous soda solution 1 N and re-extracted 3 times with 15 cm ³ ethyl acetate. The organic phases containing ethyl acetate were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gives 466 mg of (3-pyridyl) - (4-chlorophenyl) -methanol as a bright yellow solid.

Example 82 (K8) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl} -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine can be prepared as follows: 160 mg of (4-pyridyl) - (4-chlorophenyl) -bromomethane, 169 mg of (S) -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidine hydrochloride and 94 mg of potassium carbonate in 5 cm ³ acetonitrile , stirred for about 17 hours at a temperature near 20 C. Then a few granules of sodium iodide were added, and after 2 hours stirring at a temperature near 20 ° C, the reaction mixture was maintained for about 1.5 hours under reflux with solvent. . After cooling to a temperature near 20 ° C, the reaction medium is purified by preparative chromatography on a thin layer of silica [4 Merck Kieselgel Preparation Plates 60F254; 20 x 20 cm; 0.5 mm thick], eluting with a mixture of methanol dichloromethane (2.5-97.5 by volume). After eluting the corresponding

199 zone of the required products with methanol-dichloromethane mixture (1090 volumes), filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C, gives the first mixture of diastereoisomers, 24 mg (RS) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 [(3,5-difluorophenyl) -methylsulfonyl-methyl] -azetidine as a yellow gum, and a second mixture of diastereoisomers, 31 mg (RS ) - {1 - ((4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -azetidine as a yellow kiss. The first mixture of diastereoisomers e.g. has the following characteristics: [RMN ² H spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.62 (t, J = 7 Hz: 1H); 2.67 (s: 3H); 3.21 (t width) , J = 7 Hz: 2H); 3.42 (mt: 1H); 3.70 (t width, J = 7Hz: 1H); 4.28 (s: 1H); 4.28 (d, J = 11 Hz: 1H); 6.85 (tt, J = 9 at 2.5 Hz: 1H); 6.97 (mt: 2H); 7.20 to 7.35 (mt: 6H); 8.52 ( dd, J = 4.5 in 1.5Hz: 2H).

The second mixture of diastereoisomers has the following characteristics: [RMN spectrum 300 (300 MHz, CDC1 ₃ , δ β ppm):

2.59 (t, J = 7 Hz: 1H); 2.67 (s: 3H); 3.26 (mt: 2H); om 3.35 to 3.50 (mt: 1H); 3.63 (t width, J = 7Hz: 1H); 4.28 (s: 1H); 4.28 (d, J = 11 Hz: 1H); 6.85 (mt, J = 9 at 2 Hz: 1H); 6.97 (mt: 2H); om 7.20 to 7.40 (mt: 6H); 8.50 (dd, J = 4.5 at 1.5Hz: 2H).

w (4-Pyridyl) - (4-chlorophenyl) -bromomethane can be prepared as follows: solution of 100 mg (4-pyridyl) - (4-chlorophenyl) -methanol in 0.24 cm ³ hydrobromic acid (33% 8 Acetic acid) is heated at reflux for 1 hour, then allowed to return to a temperature close to 20 ° C. Then 0.675 cm @ ^{3 of} acetyl bromide are added and the reaction mixture is refluxed for 1.5 hours, then allowed to boil.

200 was returned to a temperature close to 20 ° C before concentrating under reduced pressure. 163 mg of (4-pyridyl) - (4 ~ chlorophenyl) -bromomethane are thus obtained in the form of a beige resinous kiss.

(4-Pyridyl) - (4-chlorophenyl) -methanol can be prepared as follows: to a solution of 2 g of 4- (4-chlorobenzoyl) -pyridine in 160 cm ³ ethanol are added at a temperature close to 20 ° With 348 mg of sodium tetrahydroboride. After stirring for 2 hours at a temperature close to 20 ° C, 90 mg of sodium tetrahydroboride was added.

After about 1.5 hours at the same temperature, the reaction medium was diluted with 200 cm ^{3 of} dichloromethane and 200 cm ^{3 of} water. The pH of the aqueous phase was adjusted to a value of about 5 by the addition of about 13 cm ³ aqueous hydrochloric acid 1N. After decantation, the aqueous phase was extracted 3 times with 100 cm @ 2 of dichloromethane. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gives 2g (4-pyridyl) - (4-chlorophenyl) -methanol as a white powder.

Example 83 (S) - {1 - [(2-chloro-pyrid-5-yl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] -azetidine can be prepared by as follows: mixture of 300 mg (2-chloro-pyrid-5-yl) - (4-chlorophenyl) bromomethane, 225 mg of (S) -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine hydrochloride , 125 mg of potassium iodide and 521 mg of potassium carbonate in 5 cm ^{3 of} acetonitrile, is heated at reflux with solvent for about 2 hours. After cooling to a temperature near 20 ° C, the reaction medium was filtered on a glass frit. The solid residue was washed with dichloromethane, and

The 201 filtrates were evaporated under reduced pressure. This gives 402 mg of a chocolate kiss, which is purified by preparative chromatography on a thin layer of silica [4 Merck Kieselgel Preparation Plates 60F254; 20 x 20 cm; 0.5 mm thick], eluting with a methanol-dichloromethane mixture (2.5-97.5 in volumes). Elution of the corresponding area of the desired product with a methanol-dichloromethane mixture (10-90 in volumes), filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C, yielded the first mixture of diastereoisomers, 14 mg (RS) - {1 - [(2-XAopo-nupug-5-yA) - (4Chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidine in the form of a brown kiss, and second mixture of diastereoisomers, 10 mg (RS) - {1 - [(2-XApo-nupug-5-yl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidine in the form of beige kiss.

The first mixture of diastereoisomers has the following characteristics: [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm):

2.57 (t, J = 7.5 Hz: 1H); 2.65 (s: 3H); om 3.15 to 3.30 (mt: 2H); 3.40 (mt: 1H); 3.63 (t width, J = 7.5Hz: 1H); 4.27 (d, J = 11 Hz: 1H); 4.31 (s: 1H); 6.84 (mt, J = 9 at 2 Hz: 1H); 6.95 (mt: 2H); om 7.20 to 7.35 (mt: 5H);

C, 7.63 (dd, J = 8 at 2, 5 Hz: 1H); 8.38 (d, J = 2.5 Hz: 1H).

The second mixture of diastereoisomers has the following characteristics: [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm):

2.57 (t, J = 7.5 Hz: 1H); 2.64 (s: 3H); 3.18 (t width, J = 7.5 Hz: 2H); 3.38 (mt: 1H); 3.63 (t width, J = 7.5Hz: 1H); 4.24 (d, J = 11.5Hz: 1H);

4.29 (s: 1H); 6.83 (mt, J = 9 at 2 Hz: 1H); 6.94 (mt: 2H); 7.20 (d, J = 8 Hz

202: 1H); om 7.20 to 7.35 (mt: 4H); 7.59 (dd, J = 8 at 2, 5 Hz: 1H); 8.34 (d, J = 2.5 Hz: 1H).

(2-Chloro-pyrid-5-yl) - (4-chlorophenyl) -bromomethane can be prepared as follows: to a solution of 100 mg (2-chloro-pyrid-5-yl) - (4-chlorophenyl) -methanol in 2 cm ³ tetrachloromethane, under an inert atmosphere of argon, at a temperature close to 0 ° C 0.153 cm ³ thionyl bromide is added. After 3.5 hours at a temperature close to 0 ° C, the reaction medium was concentrated under reduced pressure and evaporated with several cm ^{3 of} toluene. This gives 1.3 g of a brown liquid which is extracted with dichloromethane, water and sodium dithionite are added. After decanting, the organic phase was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 0.33 g of (2-chloro-pyrid-5-yl) - (4-chlorophenyl) -bromomethane are thus obtained in the form of a brown oil.

(2-Chloro-pyrid-5-yl) - (4-chlorophenyl) -methanol can be prepared in a manner similar to Example 84 starting from 22.5 cm 4 chlorophenylmagnesium bromide (1M solution in ethyl ether) in 30 cm ³ tetrahydrofuran, under an inert atmosphere of argon, and 2.9 g 2-chloropyridine-5-carboxaldehyde in 30 cm ³ tetrahydrofuran. 3.42 g (2-chloro-pyrid-5-yl) - (4-chlorophenyl) -methanol are thus obtained as a pale green powder.

2-Chloro-pyridine-5-carboxaldehyde can be prepared according to the following publication: G. Pandey, T. D. Bagul, A. K. Sahoo, J. Org. Chem., 1998, 63, 760-768.

Example 84

203 (R) -5 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidin-1-yl} methyl) -pyrimidine can be prepared as follows: 50 mg of 5- [bromo- (4-chlorophenyl) -methyl] -pyrimidine, 52.6 mg of (K8) -3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidine, 44 mg of potassium iodide and 73 mg of potassium carbonate in 2 cm ³ acetonitrile was refluxed with solvent for about 5 hours. After cooling to a temperature near 20 ° C, the reaction medium was purified from the precipitate directly by preparative chromatography on a thin layer of silica [2 Merck Kieselgel Preparation Plates 60F254; 20 x 20 cm; 0.5 mm thick], eluting with a methanol-dichloromethane mixture (2.5-97.5 by volume). After elution of the corresponding area of the desired product with a methanol-dichloromethane mixture (10-90 in volumes), filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C, a first mixture of diastereoisomers is obtained, 8 mg (1S) -5 - ((4-chlorophenyl) - {3 - [(3,5difluorophenyl) -methylsulfonyl-methyl] -azetidin-1-yl} -methyl) -pyrimidine as a yellow kiss, and a second mixture of diastereoisomers, 6 mg (K8) -5 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -azetidin-1-yl} -methyl) -pyrimidine as a yellow kiss.

The first mixture of diastereoisomers has the following characteristics: [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm):

2.60 (t width, J = 7 Hz: 1H); 2.66 (s: 3H); 3.24 (t width, J = 7 Hz: 2H); 3.41 (mt: 1H); 3.66 (t width, J = 7Hz: 1H); 4.28 (d, J = 11.5 Hz: 1H); 4.33 (s width: 1H); 6.84 (t width: 1H); 6.95 (mt: 2H); om 7.25 to 7.35 (mt: 4H); 8.71 (s width: 2H); 9.08 (s width: 1H).

204

The second mixture of diastereoisomers has the following characteristics: [RMN * H spectrum (300 MHz, CDCl ₃ , δ in ppm):

2.61 (t, J = 7 Hz: 1H); 2.66 (s: 3H); 3.24 (t width, J = 7 Hz: 2H);

3.43 (mt: 1H); 3.65 (t width, J = 7Hz: 1H); 4.28 (d, J = 11.5 Hz: 1H); 4.33 (s: 1H); 6.85 (mt, J = 9 at 2 Hz: 1H); 6.96 (mt: 2H); om 7.25 to 7.35 (mt: 4H); 8.69 (s: 2H); 9.06 (s: 1H).

5- [Bromo- (4-chlorophenyl) -methyl] -pyrimidine can be prepared as follows: to a solution of 205 mg (4-chlorophenyl) -pyrimidin-5-ylmethanol in 1 cm ³ tetrachloromethane and 1 cm ³ dichloromethane, under C inert atmosphere of argon, at a temperature close to 0 ° C, 0.36 cm ^{3 of} thionyl bromide is added. After 2.5 hours at a temperature close to 0 ° C, the reaction medium was brought to a temperature near 20 ° C, concentrated under reduced pressure, and evaporated with several cm of toluene. The resulting brown liquid was extracted with 10 cm ^{3 of} dichloromethane, washed with 5 cm ^{3 of} saturated aqueous sodium dithionite, then with water. After decanting, the organic phase was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. This gives 227 mg of beige viscous liquid, which is extracted with a minimum of dichloromethane and purified by preparative chromatography on a thin layer of silica [2 Merck Kieselgel Preparation Plates 60F254; 20 x 20 cm; 0.5 mm thick], eluting with a methanol-dichloromethane mixture (2.5-97.5 by volume). Elution of the corresponding area of the desired product with a methanol dichloromethane mixture (10-90 by volume), filtration on a glass frit, then evaporation of the solvents under reduced pressure at a temperature close to 40 ° C yielded 51 mg of 5-bromo- (4chlorophenyl). ) -methyl] -pyrimidine in the form of a yellow kiss.

205 (4-chlorophenyl) -pyrimidin-5-yl-methanol can be prepared by working in a similar manner to Example 83: to a solution of 636 mg 5bromopyrimidine in 10 cm ³ tetrahydrofuran, under an inert atmosphere of argon, at a temperature close to -78 ° C, dropwise 2.5 cm ³ p. butyl lithium (1.6 M solution in hexane). After 10 minutes at a temperature near - 78 ° C, a solution of 562 mg of 4-chlorobenzaldehyde in 1 cm ³ tetrahydrofuran was added dropwise. After stirring for 30 minutes at a temperature close to -78 ° C, the temperature of the reaction medium was allowed to slowly rise again to a temperature close to 20 ° C, and a 15 cm ³ saturated aqueous ammonium chloride solution, 60 cm ethyl acetate was added in succession. and 10 3 3 cm water. The aqueous phase was extracted with 15 cm3 ethyl acetate, the organic phases were combined, dried over magnesium sulfate, filtered on a glass frit and concentrated under reduced pressure (20 mbar) at a temperature close to 44 ° C. The resulting orange oil (1.09 g) was essentially purified by column chromatography with a diameter of 30 m along with 60 g of silica, average dimensions (0.063-0.200 m) at atmospheric pressure, eluting with a methanol / dichloromethane gradient (0 / 100 to 7/93 In volumes), the fractions not containing the desired product were combined and concentrated to dryness under reduced pressure. There was thus obtained 293 mg (4-chlorophenyl) -pyrimidin-5-yl-methanol as a yellow oil.

Example 85 4 - ({1- [Bis- (4-chlorophenyl) -methyl] -azetidin-3-ylidene} methylsulfonyl-methyl) -3,6-dihydro-2H-pyridine-1-thiocarboxylic acid phenolic ester may is prepared as follows: to a solution of 0.23 g of phenol ester of 4 - ({1- [bis- (4-chlorophenyl) -methyl] -3-hydroxy-azetidine206

3-yl} -methylsulfonyl-methyl) -3,6-dihydro-2H-pyridine-1-thiocarboxylic acid in 5 cm ^{3 of} dichloromethane add 0.140 g of 4-dimethylaminopyridine, then 0.042 cm ^{3 of} methane sulfonyl chloride, the reaction mixture was stirred. 20 hours at 20 ° C, then diluted with 10 cm ^{3 of} water. After decanting, the organic phase was washed successively <% <2 with 100 cm <3> of water and 100 cm <3> of saturated NaCl solution, dried over magnesium sulfate and concentrated to dryness at 40 ° C below 2.7 kPa. The resulting oil was triturated for 45 minutes in 50 cm ^{3 of} diisopropyl ether. The solid formed was filtered to give 120 mg of phenol ester of 4 - ({1- [bis- (4-chlorophenyl) methyl] -azetidin-3-ylidene} -methylsulfonyl-methyl) -3,6-dihydro-2Hpyridine- 1-Thiocarboxylic acid as a beige solid, melting at 184 ° C. [RMN * H spectrum (400 MHz, CDCl ₃ , δ in ppm): 2.53 (mf: 2H); 2.95 (s: 3H); 3.90 (mf: 2H); 4.04 (t, J = 5.5 Hz: 1H); 4.24 (mt: 3H); 4.49 (mf: 2H); 4.60 (mt: 1H); 5.90 (mf: 1H); om 7.05 go 7.50 (mt: 13H) J.

4 - ({1- [bis- (4-chlorophenyl) -methyl] -3-hydroxy-azetidine- phenolic ester-

3-yl} -methylsulfonyl-methyl) -3,6-dihydro-2H-pyridine-1-thiocarboxylic acid is prepared as follows: to a mixture of 0.72 g of 4-methylsulfonylmethyl-3,6-dihydro- 2H-Pyridine-1-thiocarboxylic acid acid and 0.708 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one in 15 cm dry tetrahydrofuran, cooled under inert atmosphere at -78 ° C, 0.52 g are added potassium tertiarybutylate. The reaction mixture was stirred at -78 ° C for 4 hours, then 0.354 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one was added. After 2 hours at 78 ° C, the temperature was allowed to rise to 20 ° C. The reaction mixture was diluted in 100 cm ^{3 of} water, then the tetrahydrofuran was evaporated below 2.7 kPa at 40 ° C. The aqueous phase was extracted 2 times

207 with 100 cm &lt; ³ & gt ^{; of} ethyl acetate. The organic extracts were combined and dried over magnesium sulfate, concentrated at 2.7 kPa at 40 ° C. The resulting residue was chromatographed on silica (200 g silica, Amicon, 20-45 μπι with 60 Angstroem porosity, column 5 cm in diameter), eluting with cyclohexane: ethyl acetate (6: 4 v / v), fractions with Rf = 11/64 (cyclohexane: ethyl acetate 6: 4, silica plate, Merck standard 1.05719, Merck KGaA, 64271 Darmstatd, Allemagne) were combined and concentrated below 2.7 kPa at 40 ° C to obtain 240 mg 4 - ({1- [Bis- (4-chlorophenyl) -methyl] -3-hydroxyazetidin-3-yl} -methylsulfonyl-methyl) -3,6-dihydro-2H-pyridine-1-thiocarboxylic acid phenolic ester.

4-Methylsulfonylmethyl-3,6-dihydro-2H-pyridine-1-thiocarboxylic acid phenolic ester can be prepared as follows: to a solution of 1 g of 1-benzyl-4-methylsulfonylmethyl-1,2,3,6-tetrahydropyridine in 10 cm ³ , under an argon atmosphere at, 0.778 cm ³ phenyl thiochloroformate is added. The solution takes on an instantly solid dark amber color. The reaction mixture was stirred at 21 ° C for 4 hours, then diluted in 100 cm ^{3 of} dichloromethane. The organic medium was washed twice with 50 cm ^{3 of} water, dried over magnesium sulfate and evaporated to dryness at 40 ° C below

2.7 kPa. The resulting residue was purified by chromatography on a silica cartridge (standard SIL-020-005, FlashPack, Jones Chromatography Limited, New Road, Hendoed, Mid Glamorgan, CF82 8AU, Royaume Uni), eluting with a mixture of cyclohexane: ethyl acetate 6 : 4 (10 cm ³ / min, fractions of 5 cm ³ ). The fractions with Rf = 12/74 (cyclohexane: ethyl acetate 1: 1, silica plate, Merck standard 1.05719, Merck KGaA, 64271 Darmstatd, Allemagne)

208 were combined and concentrated below 2.7 kPa at 40 ° C to afford 700 mg of 4-methylsulfonylmethyl-3,6-dihydro-2Hpyridine-1-thiocarboxylic acid phenolic ester.

1-Benzyl-4-methylsulfonylmethyl-1,2,3,6-tetrahydro-pyridine can be prepared as follows: to a solution of 17.6 g of 1-benzyl-4methylsulfonylmethyl-pyridine bromide in 700 cm ^{3 of} water, cooled to 5 ° C, a solution of 5.14 g of sodium borohydride and 25 g of sodium carbonate in 700 cm ^{3 of} water was added dropwise over an hour in a reaction medium not exceeding 5 ° C. The reaction medium was stirred C for four hours at 0 ° C, then allowed to rise to room temperature overnight. The yellow solid formed was isolated by filtration and dried under 2.7 kPa to give 9.6 g of 1-benzyl-4methylsulfonylmethyl-1,2,3,6-tetrahydro-pyridine having Rf 44/81 ( dichloromethane: methanol, 95: 5 by volume, silica plaque, Merck standard 1.05719, Merck KGaA, 64271 Darmstatd, Allemagne).

1-Benzyl-4-methylsulfonylmethyl-pyridine bromide can be prepared as follows: To a solution of 10 g of 4-methylsulfonylmethyl-pyridine in 200 cm ст of acetonitrile 14 cm бен of benzyl bromide are added, then heated to reflux for 3 hours, then allowed to return to room temperature overnight. The solid formed was filtered off, dried in a vacuum of 2.7 kPa to give 17.6 g of 1-benzyl-4methylsulfonylmethyl-pyridine bromide.

4-methylsulfonylmethyl-pyridine can be prepared as follows: 14 g of sodium hydroxide granules are slowly added to a solution of 57.4 g of 4-chloromethyl pyridine hydrochloride in 700 cm ^{3 of} ethanol,

209 then 35.7 g of sodium methanesulfinate. After the addition, the temperature was 28 ° C. The reaction mixture was refluxed for 2 hours, then allowed to return to room temperature overnight. The reaction medium was adjusted to 50 ° C, then filtered hot on paper. The filtrate was evaporated to dryness at 40 ° C below 2.7 kPa. The residue was recrystallized from 300 cm ^{3 of} isopropanol to give 29.6 g of 4-methylsulfonylmethyl-pyridine.

Example 86 (S) -1- [2- {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -ethyl] -3- propyl urea can be prepared by the following procedure: to a solution of 90 mg (RS) -2- {1- [bis- (4-chloro-phenyl) methyl] -azetidin-3-yl} -2- (3,5-difluoro * phenyl) -ethylamine in 5 cm ³ tetrahydrofuran, 0.052 cm ³ n was added. propyl isocyanate. After stirring for about 72 hours at a temperature close to 20 ° C, the reaction mixture was filtered, concentrated to dryness under reduced pressure, extracted with diisopropyl ether. The resulting mixture was filtered and concentrated to dryness under reduced pressure. This gives 80 mg of a pale yellow solid, which is dissolved in 5 cm ^{3 of} tetrahydrofuran, and 80 mg of scavemger resin is added to it. After stirring for about 18 hours at a temperature close to 20 ° C, the reaction mixture was filtered, then concentrated to dryness under reduced pressure. This gives 36 mg of a sticky solid, which is purified by chromatography under pressure on a silica cartridge, eluting with a mixture of cyclohexane and ethyl acetate (50/50 in volumes), fractions 16 to 20 are combined and concentrated to dryness under reduced pressure. 6 mg (RS) -1- [2- {1- [6uc- (4-XApo210 phenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) -ethyl] is obtained -3-Propylurea in the form of an oil. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm): 0.88 (t, J = 7.5 Hz: 3H); om 1.35 go 1.60 (mt: 2H); om 2.25 go 2.55 u om 2.65 go 3.05 (2 mts series: 6H completely); 3.04 (mt: 2H); 3.22 (mt: 1H); 3.38 (mt: 1H); 4.07 (mt: 1H); om 4.10 go 4.20 (mt: 1H); 4.17 (s: 1H); 6.62 (tt, J = 9 at 2.5 Hz: 1H); 6.82 (mt: 2H); om 7.20 go

7.45 (mt: 8H) J.

(RS) -2- {1- [Bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -ethylamine can be prepared by the following Method: 1.2 g of methanesulfonic acid ethyl ester (RS) -2- {l [bis- (4-chloro-phenyl) -methyl] -azetidine-3- are introduced into an autoclave cooled by an acetone bath and carbolide. yl} -2- (3,5-difluoro-phenyl) in a solution of 10 cm methanol, then a solution of 30 cm ammonia in 30 cm methanol. The autoclave was closed, stirred and brought to a temperature close to 60 ° C for 24 hours. After cooling to a temperature near 20 ° C, the ammonia was allowed to evaporate in the air at a temperature close to 20 ° C, then the remaining solution was concentrated to dryness under reduced pressure. This gives a resin which is triturated with ethyl ether at a temperature close to 20 ° C for about 18 hours. The resulting insoluble product was filtered, dried in a desiccator for 3 hours. Thus, 830 mg of (RS) -2- {1- [6uc- (4chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) -ethylamine are obtained in the form of an off-white solid.

Methanesulfonic acid ethyl ester (RS) -2- {1- [6uc- (4-XAOPophenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) may be

211 obtained as follows: to a solution of 1.9 g (RS) -2- {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) - of ethanol in 20 cm ^{3 of} dichloromethane, at a temperature close to 20 ° C, 0.34 cm ^{3 of} methane sulfonyl chloride was added. After cooling the reaction mixture to a temperature close to 10 ° C, 0.89 cm 3 of triethylamine was added. After stirring the solution for 20 hours at a temperature close to 20 ° C, 100 cm ^{3 of} water, then 150 cm ^{3 of} dichloromethane are added dropwise. The organic phase was decanted and dried, washed twice with 50 cm ^{3 of} water, 50 cm ³ <1 of saturated aqueous sodium chloride solution, 50 cm 3 of water, then dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. The yellow kiss (2g) thus obtained was purified on a silica column (particle size 0.020-0.045 mt) at a pressure of 0.4 bar, eluting with a mixture of cyclohexane and ethyl acetate (80/20 in volumes). Fractions 49 to 111 were combined and concentrated to dryness under reduced pressure. 1.2 g of methanesulfonic acid ethyl ester (RS) -2- {1- [6uc- (4-xopophenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) are obtained in the form of a white kiss.

Example 87 (S) -1H- [2- {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -ethyl] -cyclopropanecarboxamide may to be prepared by the following procedure: to a solution of 90 mg (RS) -2- {1- [6uc- (4chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5- Difluoro-phenyl) -ethylamine in 5 cm ³ tetrahydrofuran, at a temperature close to 20 ° C, 0.018 cm ³ diisopropylcarbodiimide, 10 mg cyclopropanecarboxylic acid, 16 mg hydroxybenzotriazole hydrate are then added in succession, then 0.4 g of morpholine applied to polystyrene. Received

The 212 suspension was stirred at a temperature near 20 ° C for 20 hours. The reaction medium was filtered and concentrated to dryness under reduced pressure. This gives 80 mg of a viscous product which is purified by passing through a SPE cartridge (SCX phase, 1 g phase). This gives 76 mg of a residue which is purified by flash chromatography on a silica cartridge, eluting with a mixture of cyclohexane and ethyl acetate (70/30 in volumes), fractions 9 to 19 are combined and concentrated to dryness under reduced pressure. . 12 mg of (K8) -N- [2- {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -ethyl] is obtained cyclopropanecarboxamide as a colorless oil. [RMN * H spectrum (300 MHz, CDCl ₃ , δ in ppm): 0.70 (mt: 1H); om 0.80 go 1.00 (mt: 2H); om 1.15 to 1.35 (mt: 1H); om 2.35 go

2.55 u om 2.70 go 3.10 (2 mts series: 7H completely); 3.26 (mt: 1H); 3.47 (mt: 1H); 4.19 (s: 1H); 5.63 (mt: 1H); 6.62 (tt, J = 9 at 2.5 Hz: 1H); 6.81 (mt: 2H); om 7.20 to 7.45 (mt: 8H)].

Example 88 (S) -N- [2- {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -ethyl] -3- methyl-butyramide can be prepared by the following procedure: to a solution of 45 mg (RS) -2- {1- [6uc- (4chloro-phenyl) -methyl] -azetidin-3-yl} -2- ( 3,5-Difluoro-phenyl) -ethylamine in 5 cm ³ tetrahydrofuran, at a temperature close to 20 ° C, 114 mg of HATU, 30.6 mg of isovaleric acid are added, then 0.2 g of morpholine applied to polystyrene. The resulting suspension was stirred at a temperature near 20 ° C for 20 hours. The reaction medium was filtered and concentrated to dryness under reduced pressure. This gives 46 mg of orange oil which

213 was purified by flash chromatography on a cartridge with 5 g of silica eluting with a mixture of cyclohexane and ethyl acetate (70/30 in volumes), the fractions containing no desired product were combined and concentrated to dryness under reduced pressure. 6 mg of (S) -N- [2- {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) -ethyl] is obtained 3-methyl-butyramide as a colorless oil. [RMN spectrum ^! H (400 MHz, CDCl ₃ , δ in ppm): 0.88 (d, J = 6.5 Hz: 3H); 0.91 (d, J = 6.5 Hz: 3H); om 1.85 go 2.10 (mt: 3H); om 2.30 go 2.55 u om 2.70 go 3.10 (2 mts series: 6H completely); 3.37 (mt: 2H); 4.19 (s: 1H); 5.45 (mt: 1H); 6.65 (tt, J = 9 at 2.5 Hz: 1H);

C6.82 (mt: 2H); om 7.20 to 7.45 (mt: 8H)].

Example 89 (S) -L- [2- {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -ethyl] -isobutyramide may to be prepared by working in a manner similar to the preceding Example 3: starting from 45 mg (RS) -2 {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) ethylamine, 5 cm ³ tetrahydrofuran, 114 mg HATU, 26 mg isobutyric acid, and 0.2 g of morpholine applied to polystyrene to give 10 mg (RS) -N- [2- {1 - [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -2- (3,5-difluoro-phenyl) -ethyl] -isobutyramide in the form of an opaque oil. [RMN 1 H spectrum (400 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 0.87 (d, J = 7 Hz: 3H); 0.93 (d, J = 7 Hz: 3H); om 2.15 to 2.85 (mt: 7H); om 3.00 to 3.25 (mt: 2H); 4.40 (s: 1H); om 7.00 to 7.20 (mt: 3H); 7.38 (mt: 4H); 7.52 (mt: 4H); 7.77 (mt: 1H)].

Example 90

214 {1- [Bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,4-difluoro-phenyl) methanone can be prepared by working as follows: to a solution of 128 mg of 1- [bis- (4-chloro-phenyl) -methyl] -azetidine-3-carboxylic acid N-Memokcu-N-methyl amide in 3 cm tetrahydrofuran cooled in an acetone bath and carboled, 3 cm ³ solution of 3,4-difluoro-phenylmagnesium bromide 0.5N in tetrahydrofuran. After stirring for 20 hours at a temperature close to 0 ° C, 10 cm ^{3 of} water was added, then the reaction mixture was stirred for 1 hour at a temperature close to 20 ° C. The decanted aqueous phase was extracted with 20 cm ^{3 of} ethyl acetate. The combined organic phases were washed twice with 15 cm3 of water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. This gives 123 mg of a residue which is purified by flash chromatography over a cartridge of 20 g of silica eluting with dichloromethane (stabilized on amylene). 47 mg of {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,4-difluoro-phenyl) -methanone are obtained in the form of a white powder. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm): 3.34 (t, J = 7.5 Hz: 2H); 3.56 (t, J = 8 Hz: 2H); 4.05 (mt: 7H); 4.35 (s: 1H); om 7.15 to 7.40 (mt: 9H); 7.58 (dmt, J = 9 Hz: 1H); 7.70 (ddd, J = 9 / 7.5 in 2.5 Hz: 1H)].

1- [Bis- (4-Chloro-phenyl) -methyl] -azetidine-3-carboxylic acid N-Memokcu-N-methyl amide can be prepared by working as follows: to a suspension of 2.03 g of hydrochloride at Ν , Dimethylhydroxyamine in 40 cm ^{3 of} dichloromethane, cooled to a temperature close to 0 ° C by an ice water bath, are added

2.65 cm ^{3 of} 1-methylpiperidine. The resulting yellow solution (solution A) is stored at a temperature close to 0 ° C. To a suspension of 7 g

215 β 1- [Bis- (chloro-phenyl) -methyl] -azetidine-3-carboxylic acid in 300 cm dichloromethane and 40 cm ³ tetrahydrofuran cooled to -8 ° C by ice bath and isopropanol are added sequentially 2.65 cm @ 1 of methylpiperidine, then 1.6 cm @ 1 methyl chloroformate. After about 5 minutes of stirring at a temperature close to -8 ° C, the resulting pre-solution A was added dropwise. After 10 minutes of stirring at a temperature near -8 ° C, the cooling bath was removed and the reaction mixture was stirred at a temperature close to to 20 ° C for about 20 hours, then washed 3 times with 150 cm ^{3 of} water, and concentrated to dryness under reduced pressure. This gives 8.19 g of a residue which is purified under pressure on 500 g of Amicon silica (particle diameter: 20-45 µm), eluting with ethyl acetate / dichloromethane (8-92 in volumes). Thus, 6.6 g of 1- [bis- (4-chloro-phenyl) methyl] -azetidine-3-carboxylic acid N-Memokcu-N-methyl amide are obtained in the form of a pale yellow oil.

1- [bis- (4-Chloro-phenyl) -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) starting from 1-benzhydrylazetidin-3-ol, using as a starting material 1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-ol.

Example 91 {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) methanone can be prepared by working as for {1- [bis - (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,4-difluoro-phenyl) -methanone, starting from 1.1 g of N-Memokcu-N-methyl amide of 1- [bis - (4-Chloro-phenyl) 216 methyl] -azetidine-3-carboxylic acid, 1.5 cm ^{3 of} 1-bromo-3,5 difluorobenzene, and 316 mg of magnesium chips. Thus, 880 mg of {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -methanone is obtained in the form of a pale yellow viscous oil [RMN * H spectrum] (300 MHz, CDCl ₃ , δ in ppm): 3.34 (t, J = 7.5 Hz: 2H); 3.55 (t, J = 8 Hz: 2H); 4.03 (mt: 1H); 4.44 (s: 1H); 7.01 (mt, J = 9 at 2.5 Hz: 1H); om 7.20 to 7.40 (mt: 10H)].

Example 92

C {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -cyclohexyl-methanone can be prepared by working as for {1- [bis- (4-chlorophenyl) -methyl ] -azetidin-3-yl} - (3,4-difluoro-phenyl) -methanone, starting from 284 g of N-Memokcu-N-methyl amide of 1- [bis- (4-chloro-phenyl) methyl] -azetidine-3-carboxylic acid, and 1.68 cm cyclohexylmagnesium chloride 2N in THF. 116 mg of {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -cyclohexyl-methanone are obtained in the form of a yellow viscous oil. RMN H spectrum (400 MHz, CDCl ₃ , δ in ppm): 1.10 to 1.35 and 1.55 to 1.85 (2 series mt: 10H in full); 2.30 (mt: 1H); 3.14 (t, J = 8 Hz: 2H); 3.36 (t, J = 8 Hz: 2H); 3.56 (mt: 1H); 4.31 (s: 1H); om 7.20 to 7.35 (mt: 8H)].

Example 93 {1- [Bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -phenyl-methanone can be prepared by working as for {1- [bis- (4-chloro-phenyl) ) * methyl] azetidin-3-yl} - (3,4-difluoro-phenyl) -methanone, starting from 258 mg of 1- [bis- (4-chloro-phenyl) N-Memokcu-N-methyl amide -methyl] azetidine-3-carboxylic acid, and 1.02 cm ³ phenylmagnesium bromide

217

3N 8 THF. 208 mg of {1- [bis- (4-chloro-phenyl) -methyl] azetidin-3-yl} -phenyl-methanone are thus obtained in the form of a yellow Viscous oil. RMN ^X H spectrum (300 MHz, CDCl ₃ , δ Β ppm): 3.35 (t, J = 8 Hz: 2H);

3.57 (t, J = 8 Hz: 2H); 4.13 (mt: 1H); 4.35 (s: 1H); 7.25 (dmt, J = 8 Hz: 4H); 7.34 (dmt, J = 8 Hz: 4H); 7.45 (t width, J = 8 Hz: 2H); 7.56 (mp, J = 8 at 1.5 Hz: 1H); 7.84 (dmt, J = 8 Hz: 2H)].

Example 94 S-1- {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -1- (3,5-difluorophenyl) -ethanol can be prepared by working as follows: to a solution of 100 mg {1- [bis- (4-chloro-phenyl) -methyl] azetidin-3-yl} - (3,5-difluoro-phenyl) -methanone 6 4 cm ³ tetrahydrofuran, cooled to a temperature lower than -40 ° C, a 0.167 cm solution of methylmagnesium bromide 3N is added. After stirring for 20 hours at a temperature close to 0 ° C, 5 cm ^{3 of} water was added, then the aqueous phase was decanted and extracted with 5 cm ^{3 of} ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated to dryness under reduced pressure. This gives 91 mg of a residue which is purified by flash chromatography on a cartridge of 10 g of silica eluting with ethyl acetate / cyclohexane (1/9 in volumes). 74 mg (RS) of 1- {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -1- (3,5-difluoro-phenyl) ethanol are thus obtained as a colorless butter. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 1.46 (s: 3H); 2.71 (mt: 1H); 2.82 (mt: 1H);

2.98 (t, J = 7.5 Hz: 1H); 3.24 (t, J = 7.5 Hz: 1H); 3.34 (mt; 1H); 4.31 (s: 1H); 4.33 (mf: 1H); 6.67 (mt, J = 9 at 2.5 Hz: 1H); 6.98 (mt: 2H); om

7.25 to 7.35 (mt: 8H)].

218

Example 95

{1- [Bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -1- (3,5-difluoro-phenyl) -methanone O-allyl oxime can be prepared by working on the following method: solution of 100 mg {1- [bis- (4-chloro-phenyl) -methyl] azetidin-3-yl} - (3,5-difluoro-phenyl) -methanone and 101 mg of O-allyl-hydroxylamine hydrochloride in 5 cm ^{3 the} pyridine was stirred at a temperature close to 20 ° C for 20 hours. Then 5 cm ^{3 of} water was added, and the reaction mixture was extracted twice with 5 cm ^{3 of} ethyl acetate. The combined organic phases were dried over magnesium sulfate, then concentrated to dryness under reduced pressure. This gives 111 mg of a yellow oil which is purified by flash chromatography over a cartridge of 20 g of silica (particle diameter from 0.04 to 0.063 mm), eluting with ethyl acetate / cyclohexane (2/98 in volumes). . 68 mg of {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -1 (3,5-difluoro-phenyl) -methanone are obtained in the form of 68 mg colorless viscous oil. [RMN spectrum ^] H (300 MHz, CDCl ₃ , δ in ppm). A mixture of 2 isomers Z and E is observed in a ratio of approximately 65/35 or vice versa; 2.84 and 3.11 (2t widths, respectively J = 8 Hz and J = 7.5 Hz: 2H in full); 3.44 and 3.66 (21 widths, respectively J = 7.5 Hz and J = 8 Hz: 2H in full); 3.58 and 3.81 (2mts: 1H population); 4.16 and 4.30 (2s: 1H completely); 4.59 (mt: 2H); 5.22 (dmt, J = 11 Hz: 1H); 5.27 (dmt, J = 18 Hz: 1H); 5.96 (mt: 1H); 6.80 (mt, J = 9 at 2.5 Hz: 1H); 6.91 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

Example 96

219

{1- [Bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) -methanone O-emu-ocuM can be prepared by working as described for the preparation of {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) -methanone O-allyl oxime: starting from 100 mg {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) -methanone and 90 mg of O-allyl hydroxylamine hydrochloride, 83 mg of O-ethyl-oxime are obtained. {1- [Bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) -methanone as a colorless viscous oil. [RMN ³ H spectrum (300 MHz, CDCl ₃ , δ in ppm). A mixture of 2 isomers Z and E is observed in a ratio of approximately 65/35 or vice versa; 1.25 and 1.27 (21, J = 7 Hz: 3H completely); 2.82 and 3.12 (2t widths, J = 8 Hz and J =, respectively)

7.5 Hz: 2H completely); 3.45 and 3.66 (2t widths, J = 7.5 Hz and J = 8 Hz: 2H overall); 3.58 and 3.78 (2mts: 1H population); from 4.05 to

4.20 (mt: 2H); 4.16 and 4.30 (2s: 1H completely); 6.80 (tt, J = 9 and 2.5 Hz: 1H); 6.91 (mt: 2H); from 7.20 to 7.35 (mt: 8H)].

Example 97 (E8) -1 - [{1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -methyl] -3-methylurea may be prepared as follows: to a solution of {1- [bis- (4-chloro-phenyl) methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) -acetic acid 300 mg hydrochloride ³ anhydrous toluene, under an inert nitrogen atmosphere at a temperature near 20 ° C, was added sequentially, 0,336 cm ³ triethylamine and 0,384 cm ³ diphenylphosphonoazide. The resulting solution was stirred at a temperature close to 60 ° C for about 90 minutes. A 2.6 cm ³ solution of methylamine 2M in tetrahydrofuran was added and stirring was maintained at a temperature close to 20 ° C in

220 for about 12 hours, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. The residue was extracted with 1 cm ^{3 of} methanol, then placed in a BOND-ELUT SCX VARIAN 5g cartridge standard 1225-6027 under methanol conditions. The cartridge was washed with methanol, then eluted with ammonia solution of methanol 2N. The ammonia fractions were combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. This gives 250 mg of a light oil which is recovered with 1 cm ^{3 of} dichloromethane, then placed in a cartridge 16 mm in diameter filled with 5 g of silica of 0.015 - 0.035 mm, dried and eluted with dichloromethane between 0 and 40 cm, then eluted with a mixture of dichloromethane-ethyl acetate (80-20 by volume) using a pump system. The fractions included between 50 and 80 cm ³ were pooled and concentrated under reduced pressure (2.7 kPa) at 40 ° C. 140 mg N, 8 - -1 - [{1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} (3,5-difluoro-phenyl) -methyl] -3-methylurea are thus obtained in the form of a kiss. [RMN spectrum ^! H (400 MHz, CDCI ₃ , δ Β ppm). 2.66 (mt: 1H); 2.82 (d, J = 5 Hz: 3H); 2.95 (mt: 1H); 3.03 (mt: 1H); 3.18 (mt: 2H); 4.24 (mt: 1H); 4.30 (s: 1H); 4.92 (t, J = 7 Hz: 1H); 5.36 (d width, J = 7 Hz: 1H); 6.67 (mt, J = 9 at 2.5 Hz: 1H); 6.80 (mt: 2H); om 7.20 go C 7.30 (mt: 8H)].

The preparation of {1- [bis- (4-chloro-phenyl) -methyl] azetidin-3-yl} - (3,5-difluoro-phenyl) -acetic acid hydrochloride is described in the patent "carbon derivatives", Example ΊΊ .

Example 98

221 (RS) -1- ({1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -methyl] -3-isopropylurea can be obtained as follows: to a solution of 17 μΐ isopropylamine in 1 cm anhydrous toluene, under an inert atmosphere of nitrogen, at a temperature close to 20 ° C, 3 cm ³ 0.1 mM freshly prepared solution of (RS) -l- [ 6uc (4-chloro-phenyl) -methyl] -3 - [(3,5-difluoro-phenyl) -isocyanato-methyl] azetidine The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. the medium was concentrated to dryness under reduced pressure (2.7 kPa) at temperature tail region of 40 ° C. The solid residue is taken up with 1 cm @ ³ of methanol, then placed in a cartridge BOND-ELUT SCX VARIAN 500 mg benchmark from 1210 to 2040 in terms of methanol. The cartridge was washed with methanol then eluted with ammonia solution of methanol 2 N. The ammonia fractions were combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. The thus obtained solid residue was extracted with 1 cm ³ dichloromethane, then placed in a cartridge 1ST FlashPack standard SIL 016-002 filled with 2 g silica (0.065 - 0.090 mm), conditioned with dichloromethane and eluted with with dichloromethane ethyl acetate (90-10 in volumes) by means of a pumping system, the fractions included between 20 and 38 cm ³ were combined and concentrated under reduced pressure (2.7 kPa) at 40 ° C. 14 mg of (S) -1 - [{1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} (3,5-difluoro-phenyl) -methyl] -3- are thus obtained isopropylurea in the form of a white kiss. [RMN spectrum ^! H (400 MHz, CDCI 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 (dd width, J = 8 at 5.5 Hz: 1H); 3.01 (dd width, J = 8 at 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 (t, J = 6.5 Hz:

222

1H); 6.66 (tt, J = 9 at 2 Hz: 1H); 6.78 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

(K8) -1- [bis- (4-chloro-phenyl) -methyl] -3 - [(3,5-difluoro-phenyl) -isocyanatomethyl] -azetidine can be obtained as follows: to a solution of 150 mg {1- [Bis- (4-chloro-phenyl) -methyl] azetidin-3-yl} - (3,5-difluoro-phenyl) -acetic acid chloride in 9 cm anhydrous toluene, under an inert nitrogen atmosphere, at temperatures close to 20 ° C, the following are added successively: 0.126 cm ^{3 of} triethylamine and 0.195 cm ^{3 of} diphenylphosphinoazide. The resulting solution was stirred at a temperature close to 50 ° C for about 1 hour. It is allowed to cool to give (S) -N [bis- (4-chloro-phenyl) -methyl] -

3 - [(3,5-difluoro-phenyl) -isocyanato-methyl] -azetidine as a solution in toluene to be used later in this form.

Example 99 (1 S) -1 - [{1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -methyl] -3-isobutylurea may be prepared as follows: to a solution of 20 μΐ isobutylamine in 1 cm ³ anhydrous toluene, under an inert nitrogen atmosphere at a temperature close to 20 ° C, 3 cm ³ 0.1 mM freshly prepared solution of (RS) -l is added - [6uc (4-chloro-phenyl) -methyl] -3 - [(3,5-difluoro-phenyl) -isocyanato-methyl] azetidine. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium was concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. The solid residue was extracted with 1 cm ^{3 of} methanol, then placed in a BOND-ELUT SCX VARIAN 500 mg standard 1210-2040 cartridge under methanol conditions. The cartridge is

223 was washed with methanol, then eluted with methanol 2N ammonia solution. The ammonia fractions were combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. The solid residue thus obtained is recovered with 1 cm ^{3 of} dichloromethane, then placed in a cartridge of 1ST Flashpack standard SIL 016-002 filled with 2 g of silica (0.065 - 0.090 mm), conditioned with dichloromethane and eluted with a mixture of dichloromethane acetate (90-10 in volumes) with the help of a pump system. The fractions included between 0 and 15 cm ³ were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 14 mg of (K5) -1 - [{1- [bis- (4-chloro-phenyl) -methyl] azetidin-3-yl} - (3,5-difluoro-phenyl) -methyl] -3- are thus obtained isobutylurea in the form of a white kiss. [RMN ² H spectrum (400 MHz, CDCl 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); om 2.90 to 3.25 (mt: 6H); 4.29 (su mt: 2H completely); 4.90 (t, J = 7 Hz: 1H); 5.34 (d width, J = 6.5 Hz: 1H); 6.66 (tt, J = 9 at 2Hz: 1H); 6.80 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

Example 100

N-methyl-N-phenyl-1- [bis- (4-chloro-phenyl) -methyl] -azetidine-3-carboxamide can be prepared as follows: to a solution of 100 mg 1 [bis- (4-chloro -phenyl) -methyl] -azetidine-3-carboxylic acid in 2 cm anhydrous dichloromethane, at a temperature close to 20 ° C, was added successively: 0.039 cm ³ N-methylaniline, 87 mg 1- (3 dimethylaminopropyl) -3- ethylcarbodiimide, 0.063 cm ^{3 of} triethylamine, then 4 mg of hydroxybenzotriazole hydrate. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium is loaded into a 1ST FlashPack cartridge

224 standard SIL 016-005, filled with 5 g of silica (0.065 - 0.090 mm), conditioned with dichloromethane and eluted with a dichloromethane-ethyl acetate gradient mixture (percentage of ethyl acetate varying from 0 to 5 volumes) by pump system by collecting fractions of 1.5 cm ³ . fractions 3 to 15 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. 95 mg of 1- [bis- (4-chloro-phenyl) -methyl] -azetidine-N-methyl-N-phenyl-3-carboxamide are thus obtained in the form of a cream kiss. [RMN * H spectrum (400 MHz, CDCl ₃ , δ in ppm): 3.08 (mt: 2H); 3.21 (mt: 3H); 3.27 (s: 3H); 4.35 (s: 1H); 7.06 (d, J = 7.5 Hz: 2H); om

7.15 to 7.45 (mt: 11H)].

Example 101

1- [bis- (4-chloro-phenyl) -methyl] -azetidine-N-benzyl-N-methyl-3-carboxamide can be prepared as follows: to a suspension of 150 mg 1- [bis- (4- chloro-phenyl) -methyl] -azetidine-3-carboxylic acid activated on TFP resin (165 μΜ) in 2 cm ³ dichloromethane add 0.0213 cm ³ N-benzylmethylamine. The suspension was stirred at a temperature near 20 ° C for 22 hours, then filtered on a frit. The solid residue was washed again twice with 1 cm ^{3 of} dichloromethane. The filtrates were combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. This gave 38 mg of 1- [bis- (4-chloro-phenyl) -methyl] -azetidine-N-benzyl-N-methyl-3-carboxamide in the form of a colorless gum. [Spectrum RMN * H (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)].

225

1- [bis- (4-Chloro-phenyl) -methyl] -azetidine-3-carboxylic acid activated on TFP resin can be prepared as follows: to a suspension of 2.7 g of TFP resin (functionally free phenol, 1, 1 mmole / g, 2.975 mM) in 40 cm ^{3 of} anhydrous dimethylformamide were added: 2g of 1- [bis- (4-chloro-phenyl) -methyl] -azetidine-3-carboxylic acid, 73 mg of 4-dimethylaminopyridine, 0.927 1,3diisopropylcarbodiimide. After stirring for 19 hours at a temperature close to 20 ° C, the suspension was filtered, the resin was washed with 40 cm ³ dimethylformamide, 40 cm ³ tetrahydrofuran, 40 cm ³ dichloromethane, then dried under vacuum to constant weight. 3.6 g of 1- [bis- (4-chloro-phenyl) -methyl] -azetidine-3-carboxylic acid activated on TFP resin are thus obtained.

1- [bis- (4-Chloro-phenyl) -methyl] -azetidine-3-carboxylic acid can be prepared in a manner similar to that described by ANDERSON A.

G. et LOK R. J. Org. Chem., 37, 3953-3955 (1972) starting from 1-benzhydrylazetidin-3-ol, using as the first substance 1 [bis- (4-chloro-phenyl) -methyl] -azetidin-3-ol.

The TFP (functionally free phenol) resin can be prepared according to the method of operation described in patent WO9967228.

Example 102 N- (5) - [{1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) methyl] -methylamine can be obtained by the following Method: To a solution of 108 mg {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) -methanone in 2 cm anhydrous dichloro-1,2- ethane was added: 0.099 cm <3> of methylamine, then successively 84 mg <2 of sodium triacetoxyborohydride, 0.014 cm of acetic acid. Next

For 226 hours stirring at a temperature near 20 ° C, 0.992 cm @ 3 of methylamine, 85 mg of sodium triacetoxyborohydride, then 0.0143 cm @ ^{3 of} acetic acid are added successively again. The resulting solution was stirred at a temperature near 20 ° C for <2 hours for about 24 hours, then washed with 4 cm saturated sodium bicarbonate solution. The organic phase was decanted, then dried over magnesium sulfate, filtered, then concentrated under reduced pressure (2.7 kPa). The residue thus obtained was purified on a 1ST FlashPack cartridge 1 SIL 016-002 filled with 2 g silica. dioxide (0.065 - 0.090 mt), conditioned

It is inoculated with dichloromethane and eluted with a gradient mixture of dichloromethane-methanol (the percentage of methanol varies from 0 to 6 volumes) by means of a pumping system, collecting fractions of 1 cm ³ . Fractions 8 to 18 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. 66 mg of {{1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) methyl] -methylamine are thus obtained in the form of colorless copper. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm). 2.25 (s: 3H); 2.60 (mt: 1H); 2.68 (t, J = 7 Hz: 1H); 2.94 (t, J = 7 Hz: 1H); 3.02 (t width, J = 7 Hz: 1H); 3.34 (t width, J = 7 Hz: 1H); 3.58 (d, J = 9 Hz: 1H); 4.25 (s: 1H); 6.67 (mt, J = 9 at 2.5 Hz: 1H); 6.80 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

Example 103

N 5) - [{1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) methyl] -isobutylamine can be prepared as follows: to solution of 109 mg {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-2 difluoro-phenyl) -methanone in 2 cm anhydrous dichloro-1,2- ethane, 0.028 cm ^{3 of} isobutylamine are added, then successively: 85 mg

227 sodium triacetoxyborohydride, 0.015 cm ³ acetic acid. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours. The reaction medium is placed in a cartridge filled with 5 g of silica, conditioned with dichloromethane and eluted with a gradient mixture of dichloromethane-ethyl acetate (percentage of ethyl acetate varies from 0 to 10 volumes) using a pump system, fractions containing the desired the product was combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 8 mg (RS) - [{1- [6uc- (4chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) -methyl] isobutylamine are thus obtained. [Spectrum RMN11 (300 MHz, CDCl ₃ , δ in ppm). 0.85 (d, J = 7 Hz: 3H); 0.87 (d, J = 7 Hz: 3H); 1.63 (mt: 1H); 2.15 (dd, J = 11 at 7.5 Hz: 1H); 2.25 (dd, J = 11 at 7 Hz: 1H); 2.57 (mt: 1H); 2.70 (t, J = 7 Hz: 1H); 2.92 (t, J = 7 Hz: 1H); 3.01 (t width, J = 7.5 Hz: 1H); 3.33 (t width, J = 7.5 Hz: 1H); 3.66 (d, J = 9 Hz: 1H); 4.25 (s: 1H); 6.66 (tt, J = 9 at 2.5 Hz: 1H); 6.81 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

Example 104 N- (8) - [{1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) methyl] -butylamine can be obtained by the following Method: To a solution of 108 mg {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) -methanone in 2 cm anhydrous dichloro-1,2- ethane, 0.0265 cm ^{3 of} n-butylamine, then 95 mg of sodium triacetoxyborohydride, 0.0143 cm ^{3 of} acetic acid are added sequentially. After stirring for about 16 hours at a temperature near 20 ° C, 0.0265 cm @ 3 of butylamine, 85 mg of sodium triacetoxyborohydride, then 0.143 cm ^{3 of} acetic acid were added again. The resulting solution was stirred at a temperature close to

228 to 20 ° C for about 24 hours, then washed with 4 cm ³ saturated sodium bicarbonate solution. The organic phase was decanted, then dried over magnesium sulphate, filtered, then concentrated under reduced pressure (2.7 kPa). The residue thus obtained was purified on a 1ST FlashPack cartridge SIL 016-002 filled with 2 g silica. dioxide (0.065 - 0.090 mt), conditioned with dichloromethane and eluted with a dichloromethane-methanol gradient mixture (methanol percentages varying from 0 to 6 volumes) using a pump system collecting fractions of 1 cm ³ . fractions 25 to 30 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. 37 mg (K8) - [{1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) methyl] -butylamine are thus obtained in the form of colorless honey. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm). 0.85 (d, J = 7.5 Hz: 3H); om 1.20 go

1.50 (mt: 4H); 2.37 (t width, J = 7 Hz: 2H); 2.56 (mt: 1H); 2.67 (t, J = 7 Hz: 1H); 2.89 (t, J = 7 Hz: 1H); 2.99 (t width, J = 7 Hz: 1H); 3.32 (t width, J = 7 Hz: 1H); 3.67 (d, J = 9 Hz: 1H); 4.24 (s: 1H); 6.65 (mp, J = 9 at 2.5 Hz: 1H); 6.80 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

Example 105 (1 S) -N - [{1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluorophenyl) -methyl] -3-methyl-butyramide may To be prepared as follows: To a solution of 0.017 cm isovaleric acid in 2 cm anhydrous dichloromethane at a temperature close to 20 ° C, the following is added sequentially: 0.025 cm ³ Ν, Ν-diisopropylcarbodiimide, 10 mg hydroxybenzotriazole hydrate, 30 mg ( N8) -C- {1- [bis- (4-chloro-phenyl) -methyl] azetidin-3-yl} -C- (3,5-difluoro-phenyl) -methylamine. The resulting solution was stirred at a temperature close to 20 ° C for

229 about 12 hours. The reaction medium is placed in a BOND-ELUT SCX VARIAN 500 mg cartridge standard 1210-2040 conditioned with methanol. The cartridge was washed with methanol, then eluted with methanol 2N ammonia solution. The ammonia fractions were combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. This gives 35 mg (RS) -N - [{1 [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} - (3,5-difluoro-phenyl) -methyl] -

3-methyl-butyramide in the form of yellow copper. [RMN * H spectrum (300 MHz, CDCl ₃ , δ in ppm). 0.98 (d, J = 5 Hz: 6H); om 2.05 go 2.25 (mt: 3H); 2.71 (mt: 1H); 2.90 (mt: 1H); 3.00 (mt: 1H); 3.20 (mt: 2H); 4.30 (s: 1H); 5.14 (t, J = 7.5 Hz: 1H); 6.48 (d width, J = 7.5 Hz: 1H); 6.67 (tt, J = 9 at 2.5 Hz: 1H); 6.75 (mt: 2H); om 7.20 go 7.40 (mt: 8H) J.

(K8) -C - [{1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -C- (3,5-difluorophenyl) -methylamine can be prepared as follows: to a solution of 216 mg (1 S) - {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} (3,5-difluoro-phenyl) -methanone in 10 cm ³ methanol, after 385 mg of ammonium acetate and 29 mg of sodium cyanoborohydride were added sequentially. The resulting solution was stirred at a temperature close to 20 ° C for about 12 hours, then cooled to 45 ° C for 6 hours. 29 mg of sodium cyanoborohydride are again added to this solution. Stirring is continued at a temperature close to 20 ° C for 72 hours. The reaction medium was poured into a mixture of 30 cm ³ ice water with 5 cm ³ aqueous sodium hydroxide solution 4N, then extracted twice with 30 cm 3 ethyl acetate, the organic phase extracted twice with 30 cm 3 hydrochloric acid N, thus obtained the aqueous phase was basified with aqueous sodium hydroxide solution, normal, then extracted three times with 20 cm ³

230 ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 35 mg of (S) -C - [{1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -C- (3,5-difluorophenyl) -methylamine are thus obtained in the form of yellow honey.

The medicaments of the invention are composed of a compound of formula (I) or an isomer or salt thereof, in pure form or in a form in which it is bound to another pharmaceutically acceptable substance which may be inert or physiologically active. The medicaments of the invention may be administered orally, parenterally, rectally or topically.

Tablets, pills, powders (gelatin capsules, pills) or granules may be used as solid compositions for oral administration. In these compositions, the major active ingredient according to the invention is mixed with one or more inert diluents, such as amidone, cellulose, sucrose, lactose or silica under an argon stream. These compositions may also contain other substances such as diluents, for example one or more lubricants, such as magnesium stearate or talc, colorant, coating (dragee) or glaze.

As liquid compositions for oral administration, solutions, suspensions, emulsions, syrups and other pharmaceutically acceptable elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil may be used. These compositions may contain other substances

231 as diluents, for example, wetting, sweetening, curing, flavoring or stabilizing agents.

Sterile compositions for parenteral use may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents, may be used as the solvent or carrier. These compositions may also contain additives, in particular wetting, isotonic, emulsifying, dispersing and stabilizing agents. Sterilization can be done in several ways, for example by aseptic filtration, by introducing sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of solid sterile compositions that can be dissolved at the time of use in sterile water or other injectable sterile medium.

Formulations for rectal administration are suppositories or rectal capsules which contain, in addition to the active substance, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions for topical administration may be, for example, creams, lotions, externally applied liquid medicines for eye diseases, gums and mucous membranes of the mouth, nasal drops or aerosols.

232

In human therapy, the compounds of the invention are particularly useful for the treatment and / or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, brain and spinal cord diseases, cranial trauma, panic attacks, peripheral neuropathies, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, fears, illness associated with an obsessive inability to perform an action due to a source of anxiety and guilt, old-fashioned fatigue dementia, thymic diseases, Tourette syndrome, slow dyskinesia, bipolar diseases, tumors, changes in drug administration, dystonias, endotoxochemical shocks, hemorrhagic shocks, low blood pressure, insomnia, immunological diseases, sclerosis, sclerosis appetite (bowelia, anorexia), obesity, memory disorders, bowel disorders, chronic illness and alcohol or drug abuse (eg opiates, barbiturates, catabis, cocaine, amphetamine, phenic id, halutsinogeni, benzodiazepines), and pain relievers drugs or reinforcing substances on the activity of pain-relieving drugs in narcotic and non-narcotic medicaments.

.laai

The doses depend on the effect sought, the duration of treatment and the route of administration used; they typically include between 5 mg and 1000 mg per day of oral route for an adult with unitary doses ranging from 1 mg to 250 mg of active substance.

Generally, the physician determines the appropriate posology as a function of age, weight and all other factors inherent in the subject.

233

The following examples illustrate the compositions of the invention:

Example A

According to conventional techniques, capsule doses of 50 mg of active substance are obtained, having the following composition:

Compound of Formula (I) mg

- Cellulose 18 mg -Lactose 55 mg -Colloidal silica 1 mg - Sodium carboxymethylamidone 10 mg -Talk 10 mg -Magnesium stearate 1 mg

Example B

According to conventional techniques, doses of 50 mg tablets with the following composition are obtained:

Compound of Formula (I) 50 mg -Lactose 104 mg - Cellulose 40 mg -Colloidal silica 1 mg -Polividone 10 mg - Sodium carboxymethylamidone 22 mg -Talk 10 mg -Magnesium stearate 2 mg -Colloidal silica 2 mg

-A mixture of hydroxymethylcellulose, glycerin,

234 Titanium Oxide (72-3.5-24.5) q.s.p. 1 finished thin-coated tablet 245 mg

Example C.

An injectable solution containing 10 mg of active substance is obtained, which has the following composition:

Claims (56)

A compound of formula (I) wherein R represents the radical CR ₁ R ₂ , C = C (R ₅ ) SO ₂ R ₆ or C = C (R ₇ ) SO ₂ alk, where R 1 represents a hydrogen atom and R ₂ represents the radical -C (R ₈ ) (R ₉ ) ( R ₁₀ ), -C (R _s ) (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 ₁ , -C (OH) (R ₁₂ ) (R ₆ ), -C (OH) (R ₆ ) (aAkuA), -C (= NOaAk) R ₆ , -C (= NO-CH ₂ -CH = CH ₂ ) R ₆ , -CH ₂ -CH (R ₆ ) NR ₃₁ R ₃₂ , -CH ₂ -C (= NOaAk) R ₆ , -CH (R ₆ ) NR ₃₁ R ₃₂ , -CH (R ₆ ) NHSO ₂ aAk, -CH (R ₆ ) NHCONHa _A k or -CH (R ₆ ) NHCOaAk, wherein R 1 represents an alkyl radical, NH-R ₁₅ , cyano, -S-axk-NR ₁₆ R ₁₇ , -CH ₂ -NR ₁₈ R ₁₉ , or -NR ₂₀ R _{21 in} R ₂ represents a radical -C (R ₈ ) (R _n ) (R ₁₂ ), R ₃ and R ₄ , the same or different, represent an alkyl radical or cycloalkyl, an aromatic radical selected from phenyl, naphthyl or indenyl, these aromatic radicals being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, 236 -COOalkyl, -CONR22R23, -CO-NH-NR24R25 , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or iuk-NR ₂₄ R25; such as the heteroaromatic radical is selected from the rings benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolidinyl , thiazolyl, thienyl, these heteroaromatic radicals may be unsubstituted or substituted by one or more halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, C trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR24R25, -CONR ₂₂ R23> -aAk-NR ₂₄ R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R _s represents a hydrogen atom or an alkyl radical, R ₆ represents the radical Ar or Het, R ₇ represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical optionally substituted by the radical -CSOphenyl, R ₈ represents a hydrogen atom or an alkyl radical, R ₉ represents the radical -CO-NR ₂₆ R ₂₇ , -COOH, -COOalk, -CH ₂ OH, -NH-CO-NH-alk, -CH ₂ -NHR ₂₈ or -NHCOOalk, R ₁₀ represents the radical Ar or Het, 237 R _n represents the radical -SO ₂ -alk, -SO ₂ -Ar, -SO ₂ -Het, R ₁₂ represents a hydrogen atom or the radical Ar or Het, R ₁₃ represents a hydrogen atom or an alkyl radical R ₁₄ represents the radical Ar, Het, -alk-Ar or -alk-Het, R ₁₅ represents an alkyl radical, a cycloalkyl radical, or -alk-NR ₂₉ R ₃₀ , R ₁₆ and R ₁₇ , the same or different, represent a hydrogen atom or an alkyl radical, or else R ₁₆ and R ₁₇ form together with the nitrogen atom to which a mono or bicyclic unsaturated or saturated heterocycle having 3 to 10 chains and optionally containing one or more other heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R ₁₈ represents a hydrogen atom or an alkyl radical, R ₁₉ represents a hydrogen atom or an alkyl radical, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO ₂ alk, -CO-NHalk or COOalk, or R ₁₈ and R ₁₉ form a nitrogen atom to which a mono or bicyclic unsaturated or saturated heterocycle is attached. having from 3 to 10 chain units and optionally containing one or more other heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, 238 -NR ₂₀ R2i represents a saturated or unsaturated monocyclic heterocycle having 3 to 8 chain units and optionally containing another heteroatom selected from oxygen, sulfur and nitrogen. R ₂₂ and R 2, the same or different, represent a hydrogen atom or an alkyl radical or else R ₂₂ and R 2 form together with the nitrogen atom to which a mono or bicyclic saturated heterocycle is attached, having 3 to 10 chain units, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R ₂₄ and R 4, the same or different, represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl, or else R ₂₄ and together with the nitrogen atom to which are attached a mono or a bicyclic saturated or unsaturated heterocycle having 3 to 10 chain units optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, -COalk, -COOalk, -CO-NHalk, -CS -NHalk, oxo, hydroxyalkyl, -alk-O-alk, -CO-NH ₂ , R ₂₆ and R ₂₇ , the same or different, represent a hydrogen atom or an alkyl radical, hydroxyalkyl, cycloalkylalkyl, -alk-COOalk, -alk-Ar-, alk-Het, Het, -alk-N (alk) ₂ , R ₂₆ and R ₂₇ may also form with a nitrogen atom to which are attached a mono or bicyclic saturated or unsaturated heterocycle having 3 to 10 chain units and optionally containing one or more other heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, alkoxy, halogen, 239 R ₂₈ represents a radical such as -CH ₂ -alk, benzyl, -SO ₂ alk, -CONHalk, -COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, -CO- (CH ₂ ) _II OH, η is equal to 1, 2 or 3, R _{29 and} R ₃₀ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₂₉ and R ₃₀ form together with the nitrogen atom to which a mono or bicyclic saturated heterocycle is attached, having 3 to 10 chain units, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R _{31 and} R ₃₂ , the same or different, represent a hydrogen atom or an alkyl radical, Ar or -alk-Ar, or else R ₃₁ and R ₃₂ form together with the nitrogen atom to which a heterocycle selected from aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl is attached. alk represents an alkyl radical or alkylene, Ar represents a phenyl or naphthyl radical optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR ^ R ^, -CO-NH-NR ₂₄ R ₂₅ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, -aAk-NR ^ R ^, -NR ^ R ^, alkylthioalkyl, formyl, hydroxyl, CF _3, OCF _3, Het, -O-alk-NH-cycloalkyl or SO ₂ NH ₂ , Het is a mono or bicyclic unsaturated or saturated heterocycle having 3 to 10 chain units and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, and 240 optionally substituted by one or more halogen, alkyl, alkoxy, alkoxycarbonyl, -CONR ₂₂ R ₂₃ , hydroxy, hydroxyalkyl, oxo or SO ₂ NH ₂ , alkyl and alkylene radicals, and straight and branched alkoxy radicals and moieties, and contain 1 to 6 carbon atoms, cycloalkyl radicals contain 3 to 10 carbon atoms and heterocycloalkyl and heterocyclenyl radicals contain 3 to 10 carbon atoms, their optical isomers and their salts with inorganic or organic acids. / · * A compound according to claim 1 wherein Het is selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, indolinyl, indolyl, isochromanyl, isoquinolylpyrrolidinyl, piperidinyl, piperidinyl, 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 form together with the nitrogen atom to which a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 chain units is azetidinyl, pyrrolidinyl , piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. A compound of formula (I) according to claim 1 wherein when R ₁₈ and R ₁₉ form together with the nitrogen atom to which are attached a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 chain units is azetidinyl, 241 pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. A compound of formula (I) according to claim 1 wherein the heterocycle formed with NR ₂₀ R ₂₁ is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl, piperazinyl or imidazolyl ring. The compound of formula (I) according to claim 1, wherein when R ₂₂ and R 23 form together with the nitrogen atom to which a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 chain units is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. A compound of formula (I) according to claim 1, wherein when R24 and R25 form together with the nitrogen atom to which a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 chain units 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 form together with the nitrogen atom to which a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 chain units is azetidinyl, pyrrolidinyl , piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. A compound of formula (I) according to claim 1 wherein when 242 R ₂₉ and R ₃₀ together with the nitrogen atom to which are attached a mono or bicyclic, saturated or unsaturated heterocycle having 3 to 10 chain units is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. A compound of formula (I) according to claim 1 for which R represents a radical CR ₃ R _2, R, represents a hydrogen atom and R ₂ represents a radical -C (R ₈₎ (R _n) (R ₁₂₎ or -C (R ₈₎ (R ₉₎ (R _1O), as R) represents an alkyl radical and R ₂ represents the radical -C (R ₈ ) (R ₁₁ ) (R ₁₂ ), R ₃ and R ₄ , identical or different, represent phenyl, unsubstituted or substituted by one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR 2 R 4, hydroxyalkyl or -aAk-NR ₂₄ R ₂₅ ; the heteroaromatic radical being selected from the ring pyridyl, pyrimidinyl, thiazolyl, thienyl, these heteroaromatic radicals may be unsubstituted or substituted by one or more halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -CONRnR ^, -aAk-NR ₂₄ R25, or hydroxyalkyl, R ₈ represents a hydrogen atom, R ₉ represents the radical -CO-NR ₂₆ R ₂₇ , -COOalk, -CH ₂ OH, -NH-CO-NH-alkyl, -CH ₂ -NHR ₂₈ or -NHCOOalk, 243 _{R) 0} represents a radical Ar or Het, R _n represents the radical -SO ₂ -alk, -SO ₂ -Ar, -SO ₂ -Het, R ₁₂ represents a hydrogen atom or the radical Ar or Het R ₂₂ and R ₂₃ , the same or different, represent a hydrogen atom or an alkyl radical or m »kR ₂₂ and R ₂₃ form together with the nitrogen atom to which a mono or bicyclic saturated heterocycle having 3 to 10 chain units containing optionally another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R ₂₄ and R 4, the same or different, represent a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, or else R ₂₄ and R 4 form together with the nitrogen atom to which a mono or bicyclic saturated or unsaturated heterocycle is attached which has 3 to 10 chain units containing optionally another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, okco, -CO- NH ₂ , Ar represents a phenyl or naphthyl radical optionally substituted by 1 or 2 substituents selected from halogen, alkyl, alkoxy, -COalk, cyano, -COOalk, -CONR ₂₂ R ₂₃ , alkylsulfonyl, hydroxyalkyl, -alkNR ^ R ^, -NR ^ R ^ , hydroxy, CF ₃ , OCF ₃ , -O-alkyl-NH-cycloalkyl or SO ₂ NH ₂ , 244 Het represents benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl ring, and their optical isomers, and their optical isomers salts with inorganic or organic acid. 11. Compound selected from the following compounds: (R) -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, (S) -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, (S) -1- [bis (4-chlorophenyl) methyl] -3 - [(pyrid-3-yl) (methylsulfonyl) methyl ] -azetidine, (K8) -1- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, 245 (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- (1 S) - {[3-azetidin-1-ylphenyl] methylsulfonyl-methyl} azetidine, 1- [6is (4-chlorophenyl) methyl] -3- (N) - {[3-azetidin-1-yl-phenyl] methylsulfonylmethyl} azetidine, 1- [bis (4-chlorophenyl) methyl] -3- (S) - {[3-azetidin-1-yl-phenyl] methylsulfonylmethyl} azetidine, (S) -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] pyrrolidine, (S) -1- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] pyrrolidine, (S) -H- [3 - ({ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] 4H-methyl-amine, (R) -N- [3- ({1- [bis- (4-chlorophenyl) methyl] ] azetidin-3-yl} methylsulfonylmethyl) phenyl] 4H-methyl-amine, 246 (S) -N- [3 - ({1- [bis- (4-chlorophenyl) megpyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] -N-methyl-amine, (R8) -1- [bis- ( 4-chlorophenyl) methyl] -3 - [(3,5-bis-trifluoromethylphenyl) methylsulfonyl-methyl] azetidine, (R) -1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5- bis-trifluoromethylphenyl) methylsulfonyl-methyl] azetidine, (S) -1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5-bis-trifluoromethylphenyl) methylsulfonyl-methyl] azetidine, 1- [bis- (4-chlorophenyl) methyl] -3- (phenylsulfonylmethyl) -azetidine, (S) -1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) - methylsulfonyl · methyl] -3-methyl-azetidine, (N) -1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -3-methyl-azetidine, ( 8) -1- [bis- (4-chlorophenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonylmethyl] -3-methyl-azetidine, (RS) -2- {1- [bis- ( 4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-cyclohexylacetamide, N- - 2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) N-cyclohexylacetamide, (S) -2- {1- [bis - (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) 247 N-cyclohexylacetamide, (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) -N-isobutylacetamide, (K) -2- { N- [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) N-isobutylacetamide, (RS) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2 - (3,5difluorophenyl) -N-cyclopropylmethyl acetamide, (k) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) N- cyclopropylmethyl acetamide, (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -2- (3,5-difluorophenyl) N-cyclopropylmethyl acetamide, (K5) - 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-difluorophenyl) N-isopropylacetamide, (S) -2- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl } -2- (3,5-difluorophenyl) N-isopropylacetamide, 248 (S) -1- [bis- (4-chlorophenyl) -methyl] -3- [1- (3,5-difluorophenyl) -1methylsulfonyl-ethyl] -azetidine, (R) -1- [bis- (4 -chlorophenyl) -methyl] -3- [1- (3,5-difluorophenyl) -1methylsulfonyl-ethyl] -azetidine, (S) -1- [bis- (4-chlorophenyl) -methyl] -3- [1- (3,5-difluorophenyl) -1methylsulfonyl-ethyl] -azetidine, (S) -1- [bis- (4-fluoro-phenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] - azetidine, w (R) -1- [bis- (4-fluoro-phenyl) -methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (8) -1- [bis- (4-fluoro) -phenyl) -methyl] -3 - [(3,5-difluorophenyl) -methylsulfonyl methyl] -azetidine, (S) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 - [( 3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (SS) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] - azetidine, (KK) - {1 - [(3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (S) - {1 - [( 3-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, 249 (R 8) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methylfazetidine, (88) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonylmethylfazetidine, (IR) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3 , 5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (S) - {1 - [(4-pyridyl) - (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine , (S) -5 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonyl-11-methyl] azetidin-1-yl} -methyl) -pyrimidine, (8K) -5 - (( 4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidin-1-yl} -methyl) -pyrimidine, (II) -5 - ((4-chlorophenyl) - {3 - [(3,5-difluorophenyl) -methylsulfonyl-methyl] azetidin-1-yl} -methyl) -pyrimidine, (88) -5 - ((4-chlorophenyl) - {3 - [(3,5- difluorophenyl) -methylsulfonyl-methyl] azetidin-1-yl} -methyl) -pyrimidine, (88) - {1 - [(2-chloro-pyrid-5-yl) - (4-chlorophenyl) methyl-3 - [( 3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (IR) - {1 - [(2-chloro-pyrid-5-yl) - (4-chlorophenyl) methyl-3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, 250 (K8) - {1 - [(2-chloro-pyrid-5-yl) - (4-chlorophenyl) methyl-3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, (8I) - { 1 - [(2-chloro-pyrid-5-yl) - (4-chlorophenyl) methyl-3 - [(3,5-difluorophenyl) methylsulfonyl-methyl] -azetidine, their optical isomers and their pharmaceutically acceptable salts with inorganic or organic acid. A method for preparing compounds of formula (I) according to claim 1 wherein R represents the radical CR _X R ₂ in which R 1 represents a hydrogen atom and R ₂ represents a radical C (R ₈ ) (R _n ) (R ₁₂ ), in which R ₈ represents a hydrogen atom, R _n 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 it is reduced by a derivative of the formula : in which Ra represents an alkyl radical, Het or Ar and Rb represents a hydrogen atom or the radical Ar or Het, alkyl, Ar and Het have the same meanings as in claim 1, the product is isolated and optionally transformed into a salt with an inorganic or organic acid. 251 A process for the preparation of compounds of formula (I) according to claim 1 wherein R represents the radical CR ₁ R ₂ in which R ₁ represents a hydrogen atom and R ₂ represents the radical C (R ₈ ) (R _n ) (R ₁₂ ) in which R ₈ represents a hydrogen atom, R _n represents a radical -SO ₂ -Ar, -SO ₂ -Het or -SO ₂ alk, and R ₁₂ represents a hydrogen atom or the radical Ar or Het, characterized in that a derivative of the formula R ₃ CH (Br) R4 is reacted with a derivative of the formula: in which Ra represents an alkyl radical, Het or Ar and Rb represents a hydrogen atom or the radical Ar or Het, alkyl, Ar and Het have the same meanings as in claim 1, the product is isolated and optionally transformed into a salt with an inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1 for which R represents the radical C = C (R ₅ ) SO ₂ R 6 or C = C (R ₇ ) SO ₂ alk, characterized in that it is dehydrated derivative of the formula: 252 in which Ra represents the radical Ar or Het and Rb represents a hydrogen atom or an alkyl radical, wherein Ra represents an alkyl radical and Rb represents a cycloalkyl radical, heterocycloalkyl or heterocyclenyl optionally substituted by the radical -CSO-phenyl, Rc represents a hydrogen atom or acetyl, ₃ , R ₄ , Ar and Het have the same meanings as in claim 1, isolate the product and optionally transform it into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to I * ⁴ claim 1 for which R represents the radical C = C (R ₅ ) SO ₂ R ₆ or C = C (R ₇ ) SO ₂ alk, characterized in that R ₃ CH (Br) R 4 is reacted with a derivative of the formula: in which Ra represents a radical Ar or Het and Rb represents a hydrogen atom or an alkyl radical, Ra represents an alkyl radical and Rb represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical optionally substituted by a -CSO-phenyl, Rc represents a hydrogen atom or an acetyl radical, R ₃ , R ₄ , Ar and Het have the same meanings as in claim 1, isolate the product and optionally transform it into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1 for which R represents the radical CR ₃ R ₂ in which R ₃ 253 represents the hydrogen atom u R ₂ represents the radical C (R ₈ ) (R ₉ ) (R ₁₀ ) in which R ₈ represents the hydrogen atom, Rg represents the radical -CO-NR ₂₆ R ₂₇ and R ₁₀ represents the radical Ar or Het, characterized by wherein the amine HNR ₂₆ R ₂₇ in which R ₂₆ and R ₂₇ have the same meanings as in claim 1 is reacted with an acid of formula: in which, R ₃ , R ₄ , R ₁₀ have the same meanings as in claim 1, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, wherein R represents the radical CR ₁ R ₂ in which R 1 represents a hydrogen atom and R ₂ represents the radical C (R ₈ ) (R ₉ ) (R ₁ ) in which R ₈ represents a hydrogen atom, Rg represents a -COOH radical and R ₁₀ represents an Ar or Het radical, characterized in that an ester corresponding to the formula is hydrolyzed: 254 in which, R ₃ , R 4, R ₁₀ have the same meanings as in claim 1, and alk represents an alkyl radical (1-6C straight or branched chain), isolated the product and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR _X R ₂ in which R 1 represents a hydrogen atom and R ₂ represents the radical C (R ₈ ) (R ₉ ) (R ₁₀ ) in wherein R ₈ represents a hydrogen atom, R ₉ represents a radical -COOalk or -CH ₂ OH and R _lo represents a radical Ar or Het, characterized in that the reducing compound of the formula: R. y-COOalk ^ 10 in which, R ₃ , R ₄ , R ₁₀ have the same meanings as in claim 1, and alk represents an alkyl radical (1-6C straight or branched chain), the product is isolated and optionally transformed into salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, wherein R represents the radical CR ₁ R ₂ in which R 1 represents a hydrogen atom and R ₂ represents the radical C (R ₈ ) (R ₉ ) (R ₁₀ ) in which R ₈ represents a hydrogen atom, R ₉ represents a radical -NHCOOalk and R ₁₀ represents a radical Ar or Het, characterized in that the alcohol is alkOH for which alk 255 represents an alkyl radical (1-6C straight or branched chain) reacted with a derivative of the formula: in which, R ₃ , R ₄ , R ₁₀ have the same meanings as in claim 1, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, wherein R represents the radical CR ₃ R ₂ in which R ₃ represents a hydrogen atom and R ₂ represents the radical C (R ₈ ) (R ₉ ) (R ₁₀ ) in which R ₈ represents a hydrogen atom, R ₉ represents the radical -NH-CO-NH-alk and R ₁₀ represents the radical Ar or Het, characterized in that the amine is alkNH ₂ , for which alk represents an alkyl radical (1-6C with straight or branched chain) reacts with a derivative of the formula: \ ^ / N = C = O in which, R ₃ , R ₄ , R ₁₀ have the same meanings as in formula (I), 256 the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R ₁ is a hydrogen atom and R ₂ represents the radical -C (R ₈ ) (R ₉ ) (R ₁₀ ), R ₈ is a hydrogen atom, R ₉ is the radical -CH 2 NHR 4 and R ₂₈ represents the radical -CH ₂ -alk or benzyl and R ₁₀ represents the radical Ar or Het, characterized by the derivative of the formula: wherein R ₃ , R ₄ , R ₁₀ have the same meanings as in claim 1, reacted with the aldehyde RdCHO for which Rd represents the radical -CH ₂ alk or benzyl and alk represents the alkyl radical (1-6C with straight or branched) chain), isolate the product and optionally transform it into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -C (R ₈ ) (R ₉ ) (R ₁₀ ), R ₈ ^{is a} hydrogen atom, R ₉ is a -CH ₂ -NHR ₂₈ radical, and R ₂₈ is a -SO ₂ alk radical and R ₁₀ is an Ar or Het radical, wherein the amine of formula: 257 In which, R ₃ , R 4, R ₁₀ have the same meanings as in claim 1, react with a ClSO ₂ Re derivative for which Re represents an alkyl radical (1-6C straight or branched chain), isolate the product and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR; R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -C (R ₈ ) (R ₉ ) (R ₁₀ ) , Rg is a hydrogen atom, R ₉ is a radical -CH ₂ -NHR ₂₈ , and R _2g is a radical-CO-NHalk and R ₁₀ is a radical Ar or Het, characterized in that a derivative of the formula: in which R ₃ , R 4, R ₁₀ have the same meanings as in claim 1, react with a derivative RfNCO, for which Rf is an alkyl radical (1-6C straight or branched chain), the product is isolated and 258 is optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, wherein R represents the radical CR ₃ R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -C (R ₈ ) (R 9) (R ₁₀ ). R 5 is a hydrogen atom, R ₉ is -CH ₂ -NHR ₂ radical, and R ₂₈ represents -COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, -CO- (CH ₂ ) _n OH, and R ₁₀ represents Ar or Het radical, characterized in that that derivative of the formula: R. nh ₂ in which, R ₃ , R 4, R ₁₀ have the same meanings as in claim 1, is reacted with the acid HOOCRg, for which Rg represents an alkyl radical (1-6C straight or branched chain), cycloalkyl (310C) alkyl ( 1-6C straight or branched chain), cycloalkyl (3-C 5), - (CH ₂ ) _n OH and n is equal to 1, 2, 3, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, wherein R represents the radical CR ₃ R ₂ in which R ₃ is a hydrogen atom and R ₂ is a radical -CONR ₁₃ R ₁₄ characterized by 259 that amine NHR ₁₃ R ₁₄ in which R ₁₃ and R ₁₄ have the same meanings as in claim 1 is reacted with a derivative of the formula: \ UNC In which R ₃ and R ₄ have the same meanings as in Formula (I), the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ In which R 1 is a hydrogen atom and R ₂ is a radical -CH ₂ -CONR ₁₃ R ₁₄ , characterized in that amine NHR ₁₃ R ₁₄ in which R ₁₃ and R ₁₄ have the same meanings as in claim 1 is reacted with a derivative of the formula: UNC In which R ₃ and R 4 have the same meanings as in claim 1, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CRxR ₂ in which R 1 260 is a hydrogen atom and R ₂ is a radical -CH ₂ -CONR ₁₃ R ₁₄ , characterized in that it is reduced by a derivative of the formula: N-V ' ^CONR 13 ^R ' in which R ₃ , R ₄ , R ₁₃ and R ₁₄ have the same meanings as in claim 1, isolate the product and optionally transform it into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R 1 is a hydrogen atom and R ₂ is a -SOR g radical characterized in that it is oxidized by a derivative of formula : wherein R ₃ , R ₄ and R ₆ have the same meanings as in claim 1, the product is isolated and optionally transformed into a salt with inorganic or organic acid. 261 A process for the preparation of compounds of formula (I) according to claim 1, wherein R represents the radical CR ₁ R ₂ in which R ₃ is a hydrogen atom and R ₂ represents the radical -SO ₂ R ₆ characterized in that it is oxidized by a derivative with the formula: \ SOR ₆ in which R ₃ , R ₄ and R ₆ have the same meanings as in claim 1, isolate the product and optionally transform it into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -COR 6 or -CO 2 cycloalkyl, characterized in that formula: --- \ CON (CH ₃ ) OCH ₃ in which R ₃ , R ₄ have the same meanings as in claim 1, reacts with a RhMgBr derivative for which Rh has the same meanings as R ₆ in claim 1 or represents a cycloalkyl radical (3-C 5), isolated The product is transformed into a salt with inorganic or organic acid. 262 A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₃ R ₂ in which R ₃ is a hydrogen atom and R ₂ represents the radical -C (OH) (Re) (R ₁₂ ) or -C (OH) (R ₆ ) (alkyl), characterized in that the derivative of the formula: in which R ₃ , R ₄ and R ₆ have the same meanings as in claim 1, react with a derivative RiMgBr, for which R 1 has the same meanings as R ₁₂ in claim 1 or represents an alkyl radical (1-6C straight or branched chain) , the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₃ R ₂ in which R ₃ is a hydrogen atom and R ₂ represents the radical -C (= NOalk) R ₆ or -C (= NO-CH ₂ -CH = CH ₂ ) R ₆ , characterized in that the derivative of the formula: 263 COR ₆ in which R ₃ , R ₄ and R ₆ have the same meanings as in claim 1, reacted with a derivative R ₁ OH ₂ , for which R 1 represents an alkyl radical (1-6C straight or branched chain) or -CH ₂ -CH = CH ₂ , isolate the product and optionally transform it into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR _X R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ and R ₃₂ represents hydrogen atoms, characterized in that the ammonia is reacted with a derivative of the formula: R. wherein R ₃ , R ₄ and R ₆ have the same meanings as in claim 1, and Ms is a methylsulfonyloxy radical, the product is isolated and optionally transformed into an inorganic or organic acid salt. 264 A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R _x is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ is hydrogen atom and R ₃₂ is an alkyl radical, Ar or -alk-Ar, characterized in that the halide HalR _{31 is} reacted with a compound of formula (I), respectively, wherein R represents the radical CR ₁ R ₂ in which R _t is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ and R ₃₂ are hydrogen atoms, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃ i and R ₃₂ are alkyl radicals, Ar or -alk-Ar, characterized in that the halide HalR _{32 is} reacted with a compound of formula (I), respectively, wherein R represents a radical CR ₁ R ₂ in which R 1 is a hydrogen atom and R ₂ represents a radical - CH (R ₆ ) NR ₃ and R ₃₂ , R _3i is a hydrogen atom and R ₃₂ is an alkyl radical, Ar or -alk-Ar, the product is isolated and optionally transformed into a salt with inorganic or organic oxygen spruce. A process for the preparation of compounds of formula (I) according to claim 1, wherein R represents the radical CR _X R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ is a hydrogen atom and R ₃₂ is an alkyl radical (2-6C) or -alk (2-6C) -Ar, characterized in that the aldehyde RaCHO for which Ra is an alkyl radical or -alk-Ar is reacted with a compound of formula (I ) respectively, wherein R represents the radical CR ₁ R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃ and R ₃₂ , R ₃₁ 265 u R ₃₂ are hydrogen atoms, 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, for which R represents the radical Cl ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ is alkyl a radical, Ar or -alk-Ar and R ₃₂ is an alkyl radical (2-6C) or -alk (2-6C) -Ar, characterized in that the aldehyde RaCHO for which Ra is an alkyl radical or -alk-Ar reacts with a compound of formula (I) respectively wherein R represents the radical CR ₁ R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ is a hydrogen atom and R ₃₂ is an alkyl radical, Ar or -alk-Ar, isolate the product and f entualno transformed into a salt with an inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ and R ₃₂ form with the nitrogen atom to which a heterocycle is selected, selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, characterized in that the halalkyl (2-5C) halide reacts with a compound of formula (I), respectively, wherein R represents the radical CR _t R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NR ₃₁ R ₃₂ , R ₃₁ and R ₃₂ are hydrogen atoms, the product is soluble and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NHSO ₂ alk, 266 characterized in that the derivative of the formula: NH ₂ in which R ₃ , R ₄ and R ₆ have the same meanings as in claim 1 is reacted with the derivative ClSO ₂ alk, for which the alk represents an alkyl radical (1-6C straight or branched chain), the product is isolated and optionally is transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NHCONHalk, characterized in that the derivative having the formula: wherein R ₃ , R ₄ and R ₆ have the same meanings as in claim 1, reacted with the alkNCO derivative, for which the alk represents an alkyl radical (1-6C straight or branched chain), the product is isolated and optionally transformed into a salt with inorganic or organic acid. 267 A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR _X R ₂ in which R _x is a hydrogen atom and R ₂ represents the radical -CH (R ₆ ) NHCOR ₃₁ , characterized in that derivative of the formula: nh ₂ in which R ₃ , R ₄ and R ₆ have the same meanings as in claim 1 is reacted with the derivative R ₃₁ COOH, for which R ₃₁ has the same meanings as in claim 1, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₃ R ₂ in which R 1 is a hydrogen atom and R ₂ represents the radical -CH ₂ -COR ₆ , characterized in that the derivative with the formula: CO-N (CH ₃ ) OCH ₃ in which R ₃ and R ₄ have the same meanings as in claim 1 is reacted with a derivative of formula R ₆ MgBr, for which R ₆ has the same 268 meanings as β claim 1, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CRxR ₂ in which Ry is a hydrogen atom and R ₂ represents the radical -CH ₂ -CH (R ₆ ) -NR ₃₁ R ₃₂ , characterized in that a derivative of the formula: wherein R ₃ and R ₄ have the same meanings as in claim 1, reacted with a derivative of formula HNR ₃₁ R ₃₂ for which R ₃₁ and R ₃₂ have the same meanings as in claim 1, the product is isolated and optionally transformed into salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, wherein R represents the radical CR _X R ₂ in which R ₃ is a hydrogen atom and R ₂ represents the radical -CH ₂ -C (= NOalk) R 6, characterized by with the derivative of the formula: ^R 6 269 in which R ₃ and R ₄ have the same meanings as in claim 1, reacted with a derivative of the formula alkONH ₂ , for which alk represents an alkyl radical and (1-6C straight or branched chain), the product is isolated and optionally transformed in salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, wherein R represents the radical CR ₁ R ₂ in which R 1! represents a cyano radical and R ₂ represents a radical -C (R ₈ ) (R _n ) (R ₁₂ ), wherein R ₈ is a hydrogen atom, characterized in that the derivative of the formula: N - and wherein R ₃ , R ₄ , R _n and R ₁₂ have the same meanings as in claim 1, reacted with sodium cyanide, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R 1 represents the radical -S-alkyl-NR _{1 6} R ₁₇ and R ₂ represents the radical -C (R ₈ ) (R _n ) (R ₁₂ ), wherein R ₈ is a hydrogen atom, characterized in that the derivative of the formula: 270 In which R ₃ , R ₄ , R _n uR ₁₂ uMam have the same meanings as in claim 1, reacted with the derivative HS-alk-NR ₁₆ R ₁₇ , for which the alk represents an alkyl radical (1-6C straight or branched chain) and R ₁₆ and R ₁₇ have the same meanings as in claim 1, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR 1 R ₂ in which R ₃ represents the radical -NHR ₁₅ and R ₂ represents the radical -C (R ₈ ) (R _n ) ( R ₁₂ ) wherein R ₈ is a hydrogen atom, characterized in that the derivative of the formula: in which R ₃ , R ₄ , R _n and R ₁₂ have the same meanings as in claim 1, reacts with the derivative H ₂ NR ₁₅ for which R ₁₅ has the same 271 meanings as in claim 1, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R _x represents alkyl radicals R ₂ represents the radical -C (R ₈ ) (R _n ) (R ₁₂ ), wherein R ₈ is a hydrogen atom, characterized in that the derivative of the formula: in which R ₃ , R ₄ , R _n and R ₁₂ have the same meanings as in claim 1, reacted with the derivative alkMHal, for which alk represents an alkyl radical (1-6C straight or branched chain) and M represents a metal, the product is Isolated and optionally transformed into a salt with inorganic or organic acid. V- A method for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₃ R ₂ in which Rx represents the radical -NR ₂₀ R ₂₁ and R ₂ represents the radical -C (R ₈ ) (R ₁₁ ) (R ₁₂ ) in which R ₈ is a hydrogen atom, characterized in that the derivative of the formula: 272 In which R ₃ , R ₄ , R _h uR ₁₂ uMam have the same meanings as in claim 1, reacted with the derivative HNR ^ ji, for which NR20R21 has the same meanings as in claim 1, the product is isolated and optionally transformed into an inorganic salt or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR 1 R ₂ in which R 1 represents the radical -alk-NR ₁₈ R ₁₉ , R ₁₈ and R ₁₉ represent hydrogen atoms, characterized by with the reduction of a compound of formula (I), respectively, wherein R &lt; 1 &gt; is a cyano radical, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₃ R ₂ in which R ₃ represents the radical -alk-NR ₁₈ R ₁₉ , R ₁₈ represents a hydrogen atom and R ₁₉ represents an alkyl radical , cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO ₂ alk, -CO-NHalk or -COOalk, characterized in that the halide HalR ₁₉ , wherein Hal represents halogen, is reacted with a compound of formula (I), respectively, wherein R represents the radical CR ₃ R ₂ in which R ₃ represents the radical -alk-NR _{1 8} R ₁₉ , wherein R ₁₈ and R ₁₉ represent 273 Hydrogen atom, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R 1 represents the radical -alk-NR ₁₈ R ₁₉ , R ₁₈ represents an alkyl radical and R ₁₉ represents an alkyl radical, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SO ₂ alk, -CO-NHalk or -COOalk, wherein the alkyl halide is reacted with a compound of formula (I), respectively, wherein R represents the radical CR 1 in which R 1 represents the radical -alk- NRi ₈ R ₁₉ , wherein R ₁₈ represents a hydrogen atom and R ₁₉ represents an alkyl radical, cycloalkyl, cycloal kylalkyl, cycloalkylcarbonyl, -SO ₂ alk, -CO-NHalk or -COOalk, the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents the radical CR ₁ R ₂ in which R 1 represents a hydrogen atom and R ₂ represents the radical -C (R ₈ ) (R ₉ ) (Rio) or -C (R ₈ ) (R _n ) (R ₁₂ ), wherein I 1 represents an alkyl radical, NH-R ₁₅ , cyano, -S-alkyl-NR ₁₆ R ₁₇ , -alk-NR ₁₈ R ₁₉ , or -NR ₂₀ R ₂₁ and R ₂ represents the radical -C (R ₈ ) (R _n ) (R ₁₂ ), and R ₈ represents an alkyl radical, characterized in that the alkyl of a compound of formula (I), respectively, for which R ₈ is a hydrogen atom, is the product is isolated and optionally transformed into a salt with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 1, for which R represents a radical C = C (R ₇ ) SO ₂ aIk, characterized in that it is oxidized by a derivative of the formula: 274 In which R ₃ , R ₄ and R ₇ have the same meanings as in claim 1 and alk represents an alkyl radical (1-6C straight or branched chain), the product is isolated and optionally transformed into a salt with an inorganic or organic acid. 55. Process for the preparation of compounds of formula (I), according to claim 1 for which R represents a radical CR _X R ₂ in which R _x is a hydrogen atom and R ₂ represents a radical -CH / R ^) NR _3X R _32, wherein R ₃₁ is a hydrogen atom and R ₃₂ is an alkyl radical, characterized in that a compound of formula (I), respectively, for which R represents the radical CR _X R ₂ , in which R _x is a hydrogen atom and R ₂ represents a radical - CO-R _6, is reacted with an amine HNR ₃₁ R ₃₂ for which R ₃₁ is a hydrogen atom and R ₃₂ is an alkyl radical, the product isolated and W transforming optionally in salt with an inorganic or organic acid a. A pharmaceutical composition comprising as active ingredient in principle at least one compound of formula (I) according to any one of claims 1 to 11.