BG107058A - Pharmaceutical compositions containing azetidine derivatives, novel azetidine derivatives and preparation thereof - Google Patents

Abstract

The invention concerns pharmaceutical compositions containing as active principle a compound of formula wherein: R1 represents a -N(R4)R5, -N(R4)-Co-R5, -N(R4)-SO2R6 radical or one of its pharmaceutically acceptable salts, the novel derivatives of the given formula, their pharmaceutically acceptable salts and their preparation. 21 claims

Description

Pharmaceutical compositions containing azetidine derivatives, novel azetidine derivatives and their preparation

The present invention relates to pharmaceutical compositions containing, as a general rule, at least one compound of the formula as active ingredient:

(I) or its pharmaceutically acceptable salts, novel derivatives of formula (I), their pharmaceutically acceptable salts and their preparation.

A compound of formula (I) for which R ₂ and R ₃ represent phenyl radicals, Rx represents a radical -N (R ₄ ) SO ₂ R ₆ , R ₄ represents a phenyl radical and R ₆ represents a methyl radical is described as intermediate in the synthesis of the patent WO99 / 01451. The other compounds and their pharmaceutically acceptable salts are novel and as such form part of the invention.

In formula (I)

R 1 represents the radical -N (R ₄ ) R ₅ , -N (R ₄ ) -CO-R 5, -N (R ₄ ) -SO ₂ -R ₆ ,

R ₂ and R ₃ , the same or different, represent aromatic radicals selected from phenyl, naphthyl and indenyl, these aromatic radicals being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-a1k , cyano, -COOH, COOalk, -CONR ₇ R _8, -CO-NH-NR ₉ R _10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR ₇ R _8; the heteroaromatic radical is selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl,

2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, fluoroquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, triazolyl and thienyl rings, these heteroaromatic unsaturated radicals, may alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOalk, -CO-NH-NR ₉ R ₁₀ ,

-CONR ₇ R ₈ , -alk-NR ₉ R ₁₀ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl,

R ₄ represents the radical -C (R _n ) (R ₁₂ ) -Het, -Het, - (CR _n ) (R ₁₂ ) -Ar, Ar, cycloalkyl or norbornyl,

R ₅ represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens,

R 8 represents a hydroxyalkyl, -alk-COOalk, -alk-CONR ₇ R ₈ radical, alk-NR ₇ R ₈ , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens,

R ₇ and R ₈ , being the same or different, represent a hydrogen atom or an alkyl radical, or else R ₇ and R ₈ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly another is attached a heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals,

R ₉ and R ₁₀ , identical or different, represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl, or else R ₉ and R ₁₀ form together with the nitrogen atom to which one is attached a saturated or unsaturated mono or bicyclic 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, -COalk, -COOalk, -CO-NHalk, - CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH ₂ ,

R _n represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxyalkyl, Ar, Het, -CH ₂ Ar, CH ₂ Het or alkyl optionally substituted by one or more halogens,

R ₁₂ represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxyalkyl or alkyl optionally substituted by one or more halogens, or else R _n and R ₁₂ form together with carbon an atom to which is attached a saturated mono or bicyclic ring 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,

Ar represents a phenyl, naphthyl or indenyl radical, these various radicals being optionally substituted by one or more halogens, alkyl, alkoxy, -CO-alk, cyano, * COOH, COOalk,

-CONR ₁₃ R ₁₄ , -CO-NH-NR ₁₅ R ₁₆ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, -alk-NR ₁₅ R ₁₆ , -NR ₁₅ R ₁₆ , alkylthioalkyl, formyl, CF ₃ , OCF ₃ , Het, -O-alk-NH-cycloalkyl, SO ₂ NH ₂ , hydroxy, hydroxyalkyl, -NHCOalk, NHCOOalk or at 2 adjacent carbon atoms with dioxymethylene,

Het is a saturated or unsaturated mono or bicyclic 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 alkyl radicals, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy , nitrogen heterocycles are optionally in their N-oxide form,

R ₁₃ and R ₁₄ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₃ and R ₁₄ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals,

R ₁₅ and R ₁₆ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₅ and R ₁₆ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, alk represents an alkyl or alkylene radical.

In the foregoing definitions, and the following, except to the contrary, the alkyl and alkylene radicals and moieties and alkoxy radicals and moieties are straight or branched and contain from 1 to 6 carbon atoms and cycloalkyl radicals contain from 3 to 10 carbon atoms.

Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl may be mentioned among the alkyl radicals. Alkoxy radicals may be cited as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy.

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

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

Among the heterocycles represented as Het, the following heterocycles may be cited: benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinolin, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazolin, indolin, indolinyl, indole , piperazine, triazole, furan, tetrahydroisoquinoline, tetrahydroquinoline, these heterocycles are optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ radicals.

The compounds of formula (I) may be presented in the form of enantiomers and diastereomers. These isomers and mixtures thereof are also part of the invention.

Preferably, the compounds of formula (I) are those for which

R 1 represents the radical -N (R ₄ ) R ₅ , -N (R ₄ ) -SO ₂ -R ₆ ,

R ₂ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR ₇ R ₈ , hydroxyalkyl or -alk-NR ₇ R ₈ ; the heteroaromatic radical is selected from pyridyl , pyrimidyl, thiazolyl and thienyl rings, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R ₈ , -alk-NR ₉ R ₁₀ , alkylsulfanylalkylsulfanylalkylsulfanyl; or hydroxyalkyl,

R ₃ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR ₇ R ₈ , hydroxyalkyl or -alk-NR ₇ R ₈ ; the heteroaromatic radical is selected from pyridyl , pyrimidyl, thiazolyl and thienyl rings, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R ₈ , -alk-NR ₉ R ₁₀ , alkylsulfanylalkylsulfanylalkylsulfanyl; or hydroxyalkyl,

R ₄ represents the radical -C (R ₁₁ ) (R ₁₂ ) -Het, -Het, -C (R _n ) (R ₁₂ ) -Ar, Ar or norbornyl,

R ₅ represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxy, -CH ₂ Ar, -CH ₂ Het or alkyl,

R ₆ represents the radical hydroxyalkyl, -alk-COOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxy, -CH ₂ Ar, -CH ₂ Het or alkyl,

R ₇ and R ₈ , the same or different, represent a hydrogen atom or an alkyl radical, or else R ₇ and R ₈ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 chain units, optionally other, is attached a heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals,

R ₉ and R ₁₀ , identical or different, represent a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl, or else R ₉ and R ₁₀ form together with the nitrogen atom to which a saturated or unsaturated mono is attached or a W bicyclic 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, -COalk, -COOalk, -CO-NHalk, oxo, hydroxyalkyl, or -CO-NH ₂ ,

R _n represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxyalkyl, Ar, Het,

-CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens,

R ₁₂ represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R _g , -alk-NR ₇ R ₈ , alkoxyalkyl or alkyl optionally substituted by one or more halogens, or else R _n and R ₁₂ form together with carbon an atom to which is attached a saturated mono or bicyclic ring 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,

Ar represents a phenyl or naphthyl radical, these various radicals being optionally substituted by one or more halogens, alkyl, alkoxy, -CO-alk, cyano, -CONR ₁₃ R ₁₄ , alkylsulfonyl, -alk-NR ₁₅ R ₁₆ , -NR ₁₅ R ₁₆ , CF ₃ , OCF ₃ , SO ₂ NH ₂ , hydroxy, hydroxyalkyl, or at 2 adjacent carbon atoms with dioxymethylene,

Het is a saturated or unsaturated mono or bicyclic heterocycle having 3 to 10 chain units and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted by one or more alkyl radicals, alkoxy, halogen, oxo, hydroxy, nitrogen heterocycles are optionally in their N-oxide form, and in particular Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiol iazole, furan, tetrahydroisoquinoline, tetrahydroquinoline, these heterocycles are optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ radicals.

R ₁ and R ₁₄ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₃ and R ₁₄ form together with the nitrogen atom to which a saturated mono or bicyclic 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 ₁₅ and R ₁₆ , the same or different, represent a hydrogen atom or an alkyl radical, or R _{1 S} and R ₁₆ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing optionally attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals,

Even more preferably, the compounds of formula (I) are selected from the following compounds:

R 1 represents the radical -N (R ₄ ) -SO ₂ R ₆ ,

R ₂ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, CONR ₇ R ₈ , hydroxyalkyl or -alk-NR ₇ R ₈ ; the heteroaromatic radical is selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R ₈ hydroxyalkyl

R ₃ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, CONR ₇ R ₈ , hydroxyalkyl or -alk-NR ₇ R ₈ ; the heteroaromatic radical is chosen from pyridyl, pyrimidyl, thiazolyl and thienyl rings, these heteroaromatics radicals may be unsubstituted or substituted with halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R ₈ or hydroxyalkyl,

R ₄ represents -Het or Ar,

R ₆ represents a hydroxyalkyl or alkyl radical,

R ₇ and R ₈ , the same or different, represent a hydrogen atom or an alkyl radical, or else R ₇ and R ₈ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly another is attached a heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals,

Ar represents a phenyl or naphthyl radical, these different radicals being optionally substituted with one or more halogen, alkyl, alkoxy, -CO-alk, cyano, -CONR ₁₃ R _14, -alk-NRi ₅ R _16, -NR ₁₅ Ri ₆ CF ₃ , OCF ₃ , SO ₂ NH ₂ , hydroxy or hydroxyalkyl,

4 ", Het represents a saturated or unsaturated mono or bicyclic heterocycle having 3 to 10 chain units and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted by one or more alkyl radicals, alkoxy, halogen, oxo, hydroxy , and in particular Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazoline, furanthioline, furan and are optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxyl, OCF ₃ or CF ₃ radicals,

R ₁₃ and R ₁₄ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₃ and R ₁₄ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals,

R ₁₅ and R ₁₆ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₅ and R ₁₆ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals.

Among the preferred compounds, the following compounds may be cited:

No. {1- [Bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -14- (6-chloropyrid-2-yl) 0 * ·

V methyl sulfonamide,

N- {R [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -L- (6-ethylpyrid-2-yl) methyl-sulfonamide, No. {1- [bis- (4-chlorophenyl) methyl ] -Azetidin-3-yl} -1H-quinol-6-yl-methylsulfonamide,

N- {1- [bis- (4-chlorophenyl) mesyl] -azetidin-3-yl} -N-xuH0A-5-yl-methyl-sulfonamide,

N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -1H-isoquinol-5-yl-methylsulfonamide,

N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N-pyrid-3-yl-methylsulfonamide, and- {1- [bis- (4-chlorophenyl) methyl] -azetidine -3-yl} -N- (1-oxide-pyrid-3-yl) methylsulfonamide,

N- (1R, 2S, 4S) -6unucco [2,2,1] xenine-2-UA-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -methylsulfonamide,

N- (1R, 2R, 4S) -6uuukAo [2,2,1] xenin-2-UA-N- {1- [6uc- (4-xAopo <]> eHUA) MemuA] azetidin-3-yl} - methylsulfonamide,

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, # ** ·

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (thiazol-2-yl) -methylsulfonamide,

N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N- (3-methoxyphenyl) methylsulfonamide, No. {1- [bis- (4-chlorophenyl) -methyl] azetidin-3 -yl} -1H- (3-hydroxyphenyl) methylsulfonamide,

N- {1- [6uc- (4-XAOpo4> eHUA) -MemuA] a3emuguH-3-UA} -N- (3-methylphenyl) -methylsulfonamide,

N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -1H- (methylsulfonyl) -3-aminobenzoate ethyl,

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) -methylsulfonamide,

6-6βΗ3ΐΐΛ-Ν- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} amine,

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) amine,

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1'- (3,5-difluorobenzyl) methylsulfonamide,

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (pyrid-3-yl-methyl) methylsulfonamide,

N- {1- [bis- (4-fluoro-phenyl) -methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4- chlorophenyl) -pyrid-3-yl-methyl] -azetidin-3-yl} -L- (3,5-difluorophenyl) -methylsulfonamide,

N) - N- {1 - [(4-chlorophenyl) -pyrid-3-yl-methyl] -azetidin-3-yl} -L- (3,5-difluorophenyl) -methylsulfonamide, (S) -N- {1- [(4-chlorophenyl) -pyrid-3-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, (RS) -N- {1 - [(4-xAOp <^ eHUA ) -Nupug-4-uA-MemuA] -a3emuguH-3-uA} -N- (3,5difluorophenyl) -methylsulfonamide, (N) -N- {1 - [(4-chlorophenyl) -pyrid-4-yl- methyl] -azetidin-3-yl} -N- (3,5difluorophenyl) -methylsulfonamide, (S) -N {1 - [(4-chlorophenyl) -pyrid-4-yl-methyl] -azetidin-3-yl} -N (3,5difluorophenyl) -methylsulfonamide, (RS) -N- {1 - [(4-XAopc ^ eHUA) -nupui-gim-5-uA-MemuA] -a3emuguH-3-UA} -N- (3 , 5-difluorophenyl) -methylsulfonamide, (N) -X- {1 - [(4-chlorophenyl) -pyrimidin-5-yl-methyl] -azetidin-3-yl} -N- (3,5dif fluorophenyl) -methylsulfonamide, (S) -N {1 - [(4-chlorophenyl) -pyridin-5-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, No. {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) benzylsulfonamide, their optical isomers and their pharmaceutically acceptable salts.

Compounds of formula (I) for which R ₃ represents the radical -N (R ₄ ) R ₅ in which R ₅ is a hydrogen atom, -N (R ₄ ) -CO-R ₅ , -N (R ₄ ) -SO ₂ R <5, R ₄ is the radical -C (R _n ) (R ₁₂ ) -Ar or -C (R _n ) (R ₁₂ ) -Het and R ₁₂ is a hydrogen atom, can be prepared according to the following reaction scheme:

In these formulas R ₂ , R ₃ , R ₆ and R _n have the same meanings as in Formula (I), Rb represents the radical Ar or Het, Ar and Het have the same meanings as in Formula (I) and Hal represents a halogen atom and for preferably chlorine or bromine.

Step a is typically carried out in an inert solvent such as tetrahydrofuran, dioxane, chlorinated solvent (e.g. dichloromethane, chloroform) at a temperature included between 15 and 30 ° C in the presence of an alkaline substance such as trialkylamine (e.g. triethylamine, dipropylethylamine or dipropylethylamine) in pyridine medium at a temperature between 0 and 30 ° C.

Step b is carried out in the presence of a methanol medium in an autoclave at a temperature between 50 and 70 ° C.

The step is usually carried out in an inert solvent medium, such as a chlorinated solvent (eg dichloromethane), in the presence of sodium triacetoxyborohydride and acetic acid, at a temperature close to 20 ° C.

Step d is typically carried out in an inert solvent such as tetrahydrofuran, dioxane, chlorinated solvent (e.g. dichloromethane, chloroform), in the presence of an amine such as trialkylamine (e.g. triethylamine), at a temperature included between 5 ° C and 20 ° C.

The Rb-COR _n derivatives are commercialized or can be obtained according to the methods described, for example, by R. C. LAROCK, Coprehensive Organic Transformations, VCH editor.

The Hal-SO ₃ R ₆ derivatives are commercialized or can be obtained by halogenating the corresponding sulfonic acids, namely in situ in the presence of chlorosulfonylisocyanate and alcohol, in a halogenated solvent medium (eg dichloromethane, chloroform).

The Hal-COR ₅ derivatives are commercialized or can be obtained by halogenating the corresponding carboxylic acids, namely in situ in the presence of thionyl chloride, in a medium of halogenated solvent (e.g. dichloromethane, chloroform).

Azetidines 1 can be prepared by the application or adaptation of the methods described by KATRITZKY A. R. et coll, J. Heterocycl. Chem., 271 (1994) or DAVE P. R., J. Org. Chem., 61, 5453 (1996) and in the Examples. It is usually operated according to the following reaction scheme:

A

HYDROXYLAMINE

P

Y

In these formulas, R ₂ and R ₃ 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 an inert solvent medium such as aliphatic alcohol 1-4C (eg 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 lithium and aluminum hydride, in tetrahydrofuran medium at the reflux temperature of the reaction medium.

In step C, it is operated in the presence of an inert solvent medium 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, the method described by GRISAR M. et coll, dans J. Med. Chem., 885 (1973). A magnesium brominated derivative is formed, then reacted with nitrile in an ether medium 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 situ with sodium borohydride at a temperature between 0 ° C and the reflux temperature of the reaction medium.

The R ₂ -CO-R ₃ 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 coll .. J. Med. Chem .. 14 (6) 546 (1971); HURN Ν. K .. Tet. Lett .. 36 (52) 9453 (1995); MEDICES A. et coll .. Tet. Lett .. 24 (28) 2901 (1983); RIECKE R. D. 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 I. 1809 (1996); FR-96-2481 et JP-94261393.

The R ₃ Brca derivatives are commercialized or can be obtained by applying or adapting the methods described by BRANDSMA L. et coll., Synth. Comm., 20 (11) 1967 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 ₂ 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 al., J. Org. Chem., 60 (21) 6895 (1995).

The compounds of formula (I) for which R represents the radical -N (R4) R ₅ can be prepared according to the following reaction scheme

R ₅ (R ₄ ) NH

In these formulas, R ₂ , R ₃ , R ₄ and R ₅ have the same meanings as in formula (I).

This reaction is usually carried out in an inert solvent medium such as a chlorinated solvent (eg dichloromethane), in the presence of sodium triacetoxyborohydride and acetic acid, at a temperature close to 20 ° C.

The HN (R ₄ ) R ₅ compounds are commercialized or can be prepared by conventional methods known to one of ordinary skill in the art or by application or adaptation of the methods described by Park K.K. et al., J. Org. Chem., 60 (19) 6202 (1995); Kalir A. et al., J. Med. Chem., 12 (3) 473 (1969); Sarges R., J. Org. Chem., 40 (9) 1216 (1975); Zaugg Η. E., J. Org. Chem., 33 (5) 2167 (1968); Med. Chem., 10 128 (1967); J. Am. Chem. Soc., 2244 (1955); Chem. Ber., 106,2890 (1973); Chem. Pharm. Bull., 16 (10) 1953 (1968); Bull. Soc. Chim. Fr., 835 (1962).

The azetidines 2 can be prepared by oxidizing the corresponding azetidinols, preferably in dimethyl sulfoxide medium, by means of the sulfur pyridine trioxide 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 ° C is -50 ° C.

Compounds of formula (I) for which R _t represents the radical -N (R ₄ ) COR ₅ or -N (R ₄ ) SO ₂ R ₆ can be prepared by the following reaction scheme:

Hal-SO.R.

Ο

In these formulas, R ₂ , R ₃ , R ₄ , R ₅ and R ₆ have the same meanings as in formula (I) and Hal represents a halogen atom, preferably chlorine.

Steps a and b are typically carried out in an inert solvent such as tetrahydrofuran, dioxane, chlorinated solvent (eg dichloromethane, chloroform) in the presence of an amine such as trialkylamine (eg triethylamine) at a temperature between 5 ° C and 20 ° C.

The compounds of formula (I) for which R 1 represents the radical -N (R ₄ ) -SO ₂ -R ₆ for which R ₄ is the Het or Ar radical can be prepared by the following reaction scheme:

FL

N- \ ms

In these formulas, R ₂ , R ₃ and R ₆ have the same meanings as in formula (I), Rd represents the radical Ar or Het (Het and Ar have the same meanings as in formula (I)) and Ms represents the methylsulfonyloxy radical.

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

Step b is typically carried out in an inert solvent such as tetrahydrofuran, dioxane, chlorinated solvent (e.g. dichloromethane, chloroform) at a temperature included between 15 ° C and 30 ° C, in the presence of an alkaline substance such as trialkylamine (e.g. triethylamine, dipropylethylamine) medium of pyridine, at a temperature between 0 ° C and 30 ° C.

The step is preferably carried out in an inert solvent such as dioxane, in the presence of CsCO ₅ , under reflux of the reaction mixture.

Derivatives for which Rd represents a nitrided N-oxide heterocycle may be non-oxidized reduced compounds according to the method described by SANGHANEL E. et coll, Synthesis 1375 (1996).

The Rd-NH-SO ₂ R <5 derivatives can be obtained by the following reaction scheme:

Hal-SO ₂ -R ₆

Rd-NH ₂ ---------- ► Rd-NH-SO <R _r

In these formulas Hal represents a halogen atom and Rd represents the radical Het or Ar. The reaction is carried out in an inert solvent such as tetrahydrofuran, dioxane, chlorinated solvent (eg dichloromethane, chloroform) at a temperature included between 15 ° C and 30 ° C in the presence of an alkaline substance such as trialkylamine (eg triethylamine, dipropylethylamine) in a medium of pyridine, at a temperature of between 0 ° C and 30 ° C.

Derivatives for which Rd represents a nitrous N-oxide heterocycle can be obtained by the method described by RHIE R., Heterocycles, 41 (2) 323 (1995).

The compounds of formula (I) can also be prepared by the following reaction scheme:

R.-CO-R.

R _? Sr + R.-CHO

R.-CHOH-R.

^r ₂ —CHBr - R ₃

In these formulas, R _x , R ₂ and R ₃ have the same meanings as in formula (I) and Ph represents phenyl.

Step a is typically carried out in an alcoholic medium such as methanol in the presence of sodium borohydride at a temperature close to 20 ° C.

In step b, a magnesium brominated derivative is obtained by reaction, in an inert solvent such as ethyl ether or tetrahydrofuran, at a temperature included between 0 ° C and the reflux temperature of the reaction mixture.

The step c is carried out by means of a halogenating agent such as hydrobromic acid, thionyl bromide, thionyl chloride, a mixture of triphenylphosphine and tetrabromide or tetrachloromethane, in acetic acid medium or an inert solvent such as dichloromethane, chloroform, tetrachloromethane, temperature tetrachloromethane and the reflux temperature of the reaction medium.

Step d is carried out by hydrogen, in the presence of palladium carbide, in an alcohol medium such as methanol at a temperature close to 20 ° C.

The step is carried out in an inert solvent medium such as acetonitrile, in the presence of an alkali metal carbonate (e.g. potassium carbonate) and potassium iodide, at a temperature included between 20 ° C and the reflux temperature of the reaction medium.

The R ₃ Br derivatives and the R ₂ -CHO derivatives are commercialized or can be obtained by the methods described, for example, by R. C. LAROCK, Comprehensive Organic Transformations, VCH editor.

The compounds of formula (I) for which R _t represents the radical

Jim ..

w * · -N (R ₄ ) -SO ₂ -R ₆ for which R ₄ is a piperid-4-yl radical optionally substituted on nitrogen by an alkyl radical may also be prepared by the following reaction scheme:

In these formulas, R ₂ , R ₃ and R ₆ have the same meanings as in formula (I) and alk represents an alkyl radical and Re represents a tert-butylcarbonyloxy radical.

Step a is carried out in an inert solvent medium such as a chlorinated solvent (e.g. dichloromethane), in the presence of a hydride such as sodium triacetoxyborohydride and acetic acid, at a temperature included between 0 ° C and the reflux temperature of the reaction medium.

Step b is usually carried out in an inert solvent such as tetrahydrofuran, dioxane, chlorinated solvent (eg dichloromethane, chloroform) in the presence of an amine such as trialkylamine (eg triethylamine) at a temperature between 5 ° C and 20 ° C.

The step c is carried out by hydrochloric acid in a dioxane medium at a temperature between 0 ° C and the reflux temperature of the reaction medium.

Step d is carried out by anyone known to one of skill in the art to alkylate an amine without affecting the rest of the molecule. For example, an alkyl halide may be used in the presence of an organic base such as triethylamine, an alkali metal hydroxide (e.g. soda, potash), optionally in the presence of tetrabutylammonium bromide, in an inert solvent such as dimethylsulfoxide, dimethylformamide or pyridine, including pyridine 20 and 50 ° C.

Compounds of formula (I) for which R _x represents the radical -N (R ₄ ) -SO ₂ -R ₆ for which R ₄ is a phenyl radical substituted with the pyrrolid-1-yl radical can also be prepared by action of pyrrolidine on a compound of formula (I), respectively, for which Rx represents the radical -N (R ₄ ) SO ₂ R ₆ for which R ₄ is a phenyl radical substituted by a halogen atom.

This reaction is preferably carried out in dimethyl sulfoxide at a temperature between 50 and 95 ° C.

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. Tertbutyl or methyl carbamates, which can be reduced by iodotrimethylsilane or allyl by palladium catalysts, may be cited as examples of amino function protecting groups. 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) with hydrochloric acid regeneration. Esters (for example allyl, benzyl), oxazoles and 2-alkyl-1,3-oxazolines may be cited as protecting groups of carboxy functions. Other usable protecting groups are described by GREEN 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) can be obtained by cleavage of racemates, for example, by chromatography on a herbal column according to PIRCKLE W.H. et coll., asymmetric synthesis, vol. 1, academic Press (1983), either by the formation of salts or by synthesis starting from chiraux precursors. 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 and by irradiation with such acid in an organic solvent medium such as alcohol, ketone, ether or chlorinated solvent. These salts are also part of the invention.

The following salts may be cited as examples of pharmaceutically acceptable salts: benzenesulfonate, bromhydrate, chlorhydrate, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene bis-L-oxinafatoate, , 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 the CB1 species. 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, and Marijuana / Cannabinoids, Neurobiology and Neurophsiology, 459, Murphy L. and Barth 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 diseases, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucoma, disease , Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, involuntary-nightmares, elderly illness, thymic diseases, Tourette's syndrome, late-onset screening, bipolar diseases, cancer and diseases, diseases induced by medications, dystonias, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, sclerotic plaques, vomiting, asthma, appetite disorders (bulemia, anorexia), disorders, catastrophic diseases, disorders drug addiction and abuse of alcohol or drugs (eg, opiates, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines) as anti-narcotic drugs or agents that enhance the analgesic activity of narcotics neoplastic 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 T. E., HAYCOCK D.A. dans 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 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 ₅₀ is a maximum of 40 mg / kg subcutaneously in a mouse.

The following examples illustrate the invention.

Example 1

N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N- (6-chloropyrid-2-yl) methylsulfonamide can be prepared by working as follows: to a solution of 1 , 54 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3ol and 1.22 g of N- (6-chloropyrid-2-yl) methylsulfonamide in 120 cm ^{3 of} anhydrous tetrahydrofuran were added under argon 2,4 cm ³ ethyl azodicarboxylate and 1.44 g triphenylphosphine. After stirring for 20 hours at 20 ° C, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 30 cm, diameter

4.5 cm 3), eluted under pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (80/20 in volumes) and fractions of 60 cm ³ were collected. Fractions 6 to 9 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.75 g of N- {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} -N- (6-chloropyrid-2-yl) methylsulfonamide are obtained as a white kiss. [RMN spectrum Ή (300 MHz, CDCl ₃ , δ in ppm): 2.85 to 3.00 (mt: 2H); 2.91 (s: 3H); 3.57 (t split, J = 7 and 2 Hz: 2H); 4.25 (s: 1H); 4.64 (mt: 1H); om 7.20 to 7.35 (mt: 9H); 7.36 (dd, J = 8 and 1 Hz: 1H);

7.71 (t, J = 8 Hz: 1H)].

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

Chlorhydrate of [bis- (4-chlorophenyl) methyl] amine can be obtained by the method described by GRISAR M. et al., J. Med. Chem., 885 (1973).

B1- (6-chloropyrid-2-yl) methylsulfonamide can be prepared by working as follows: to a solution cooled to +5 ° C of 2-amino-

6-chloropyridine in 12.5 cm ³ pyridine, 7.8 cm ³ methylsulfonyl chloride was poured dropwise over 1 hour. After returning to normal temperature and stirring for 20 hours, the black reaction mixture was added to 140 cm ^{3 of} water and extracted with 200 cm ^{3 of} dichloromethane. The organic phase was decanted, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is chromatographed on a silica gel column (0.063-0.200 mm granularity, 30 cm high, 4 cm diameter), eluted under pressure of 0.5 bar from argon with a mixture of cyclohexane and ethyl acetate (70/30 in volumes) and collected. fractions of 60 cm ³ . fractions 5 to 11 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 17 g of N- (6-chloropyrid-2-yl) methylsulfonamide are obtained as a yellow oil.

Example 2

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (6-ethylpyrid-2-yl) methylsulfonamide can be prepared by working as described in Example 1, starting from from 0.61 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol, 0.40 g of N- (6-fluoro-2-yl) methylsulfonamide, 50 cm ^{3 of} anhydrous tetrahydrofuran, 0.96 cm ^{3 of} ethyl azodicarboxylate and 0.557 g of triphenylphosphine. The crude product was chromatographed on a silica gel column (particle size 0,040-0,063 mm, height 20 cm, diameter 2 cm), eluted under pressure of 0.5 bar from argon with a mixture of cyclohexane and ethyl acetate (70/30 in volumes) and collected. fractions of 30 cm ³ . Fractions 6 to 9 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.3 g of an oil are obtained which is converted into a powder in a mixture of 5 cm ^{3 of} diethyl oxide and 5 cm ^{3 of} diisopropyl oxide. The suspension was filtered, the solid was drained, then dried under reduced pressure (2.7 kPa). 0.11 g of N- {1- [6uc- (4chlorophenyl) methyl] -azetidin-3-yl} -N4- (6-ethylpyrid-2-yl) methylsulfonamide are obtained as a white solid. [RMN spectrum Ή (300 MHz, CDCl ₃ , δ in ppm): 1.26 (t, J = 7.5 Hz: 3H); 2.76 (q, J = 7.5 Hz: 2H); om 2.85 to 2.95 (mt: 2H); 2.90 (s: 3H); 3.53 (t split, J = 7 in 2 Hz: 2H); 4.22 (s: 1H); 4.69 (mt: 1H); 7.07 (d, J = 7.5 Hz: 1H); om 7.15 to 7.30 (mt: 9H); 7.64 (t, J = 7.5 Hz: 1H)].

N- (6-ethylpyrid-2-yl) methylsulfonamide can be prepared by working as follows: to a solution cooled to +5 ° C at 2.50 g

2-amino-6-ethylpyridine in 2.50 cm ³ pyridine, drop by drop

1.56 cm ³ methylsulfonyl chloride. After stirring for 20 hours at 20 ° C, the reaction mixture was added to 8 cm ^{3 of} water and filtered. The filtrate was concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0,040-0,063 mm, height 30 cm, diameter 4 cm), eluted under pressure of 0.5 bar from argon with 1.5 liters of dichloromethane then with a mixture of dichloromethane and methanol (98/2 V volumes) and fractions of 60 cm ³ were collected. fractions 8 to 12 were combined and concentrated to dryness under reduced pressure (2.7 kPa). They are obtained

2.8 g of N- (6-ethylpyrid-2-yl) methylsulfonamide, as a yellow oil.

Example 3

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinolyl-6-ylmethylsulfonamide can be prepared by working as follows: to a solution of 0.50 g of N-quinolyl -6-yl-methylsulfonamide in 50 cm ^{3 of} anhydrous tetrahydrofuran, 0.70 g of 1- [bis-4-chlorophenyl) methyl] azetidin-3-ol, 0.597 g of triphenylphosphine are then added under argon then 0.40 cm ^{3 of} diethyl azodicarboxylate are poured . After stirring at 20 ° C for 20 hours, the reaction mixture was heated to reflux temperature for 4 hours, then 2.98 g of triphenylphosphine and 2.0 cm ^{3 of} diethyl azodicarboxylate were added. After stirring for 48 hours at 20 ° C, the mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was taken up in 30 cm ^{3 of} diethyl oxide, the resulting suspension filtered, the filtrate concentrated to dryness. One fraction of the residue obtained (0.90 g) was purified on a Bond Elut column with a sulfonic acid SCX cation exchange resin (0.054 mt, 4 cm in height, 3 cm in diameter), eluting first with methanol then with ammonia 2M solution in methanol to elute the expected product, 5 cm ³ fractions were collected. fractions 16 to 19 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.33 g of an oil is obtained which is stirred in 10 cm ^{3 of} diisopropyl oxide. The resulting suspension was filtered. The filtrate is filtered again, it is recommended that after 15 minutes the solid be dried at C under reduced pressure (2.7 kPa). 83 mg of N- {1- [6uc (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinolyl-6-yl-methylsulfonamide are obtained as a white solid. [Spectrum RMN * H (300 MHz, CDCl ₃ , δ in ppm): 2.87 (s: 3H); 2.89 (mt: 2H); 3.55 (t split, J = 7 and 1 Hz: 2H); 4.18 (s: 1H); 4.69 (mt: 1H); om 7.15 to 7.30 (mt: 8H); 7.47 (dd, J = 8.5 at 4 Hz: 1H); 7.58 (dd, J = 9 at 2.5 Hz: 1H);

7.73 (d, J 2.5 Hz: 1H); 8.10 to 8.20 (mt: 2H); 8.97 (dd, J = 4 at 1.5 Hz: 1H)].

N-quinolyl-6-yl-methylsulfonamide can be prepared by working as follows: to a solution cooled to +3 ° C at 1.98 g

6-aminoquinolein in 1.75 cm of pyridine was poured dropwise over 1 hour 1.1 cm ^{3 of} methylsulfonyl chloride. After stirring at 20 ° C for 20 hours, the reaction mixture was added to 10 cm ^{3 of} water and 50 cm ^{3 of} dichloromethane, then filtered. The filtrate was decanted, the organic phase was dried over magnesium sulfate, then filtered and concentrated to dryness under reduced pressure (2.7 kPa). 1.15 g of N-quinolyl-6-yl-methylsulfonamide are obtained as a creamy yellow solid.

Example 4 No. {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} 4H-quinolyl-5-ylmethylsulfonamide can be prepared by working as follows: to a solution of 0.50 g of # quinolyl- 5-yl-methylsulfonamide in 70 cm ^{3 of} anhydrous tetrahydrofuran, 0.70 g of 1- [bis-4-chlorophenyl) methyl] azetidin-3-ol, 0.597 g of triphenylphosphine were then added under argon then 0.40 cm ^{3 of} diethyl azodicarboxylate were poured and 0.45 g of 1,2-bis (diphenylphosphine) ethane. After stirring for 20 hours at 20 ° C, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was extracted with 70 cm ^{3 of} ethyl acetate, the resulting solution washed with 30 cm ^{3 of} brine, dried over magnesium sulfate, filtered, then concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The resulting violet oil was purified by chromatography on a silica gel column (particle size 0,063-0,200 mm, height 35 cm, diameter 3.9 cm), eluted under pressure of 0.5 bar from argon with a mixture of cyclohexane and ethyl acetate (40/60 then 30/70 and 20/80 in volumes) and 50 cm ³ fractions were collected. fractions 6 to 12 were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was extracted with 15 cm 3 of methanol, the resulting white suspension filtered, the solid drained, then dried at 50 ° C under reduced pressure (2.7 kPa). 0.35 g of N- {1- [6uc- (4chlorophenyl) methyl] azetidin-3-yl} -N-quinolyl-5-yl-methylsulfonamide are obtained as a white solid. [Spectrum RMN ^d H (300 MHz, CDCl ₃ , δ in ppm): 2.60 (t, J = 7 Hz: 1H); 2.84 (t, J = 7 Hz: 1H); 2.99 (s: 3H); 3.36 (t split, J = 7 in 2.5 Hz: 1H); 3.56 (t split, J = 7 in 2.5 Hz: 1H); 4.01 (s: 1H); 4.85 (mt: 1H); om 7.10 go 7.25 (mt: 8H); 7.40 (dd, J = 7.5 and 1 Hz: 1H); 7.54 (dd, J = 8.5 in 4 Hz: 1H); 7.74 (dd, J = 8 at 7.5 Hz: 1H); 8.20 (d width, J = 8 Hz: 1H); 8.54 (d broad, J = 9Hz: 1H); 8.99 (dd, J = 4 at 1.5 Hz: 1H)].

4- (quinol-5-yl) methylsulfonamide can be prepared by working as described in Example 3, starting from 2.0 g of 5 aminoquinolein, 3.0 cm ³ pyridine, 1.1 cm ³ methylsulfonyl chloride. 2.47 g of N- (quinol-5-yl) methylsulfonamide are obtained as a yellow brown solid.

Example 5

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -H-isoquinol-5-ylmethylsulfonamide can be prepared by working as described in Example 4 starting from 0.497 g D4- (isoquinol-5-yl) methylsulfonamide, 70 cm ³ anhydrous tetrahydrofuran, 0.712 g 1- [bis-

4-chlorophenyl) methyl] azetidin-3-ol, 0.597 g of triphenylphosphine, 0.40 cm ^{3 of} diethyl azodicarboxylate and 0.45 g of 1,2-bis- (diphenylphosphine) ethane. The crude brown oil obtained was purified by chromatography on a silica gel column (particle size 0,063-0,200 mm, height 38 cm, diameter 3 cm), eluted with a mixture of cyclohexane and ethyl acetate (30/70 in volumes) and fractions of 40 were collected Article ³ . fractions 8 to 23 were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was stirred in 15 cm ³ diethyloxide, the suspension filtered, the insoluble matter was chromatographed on a SCX resin column (height 4 cm, diameter 3 cm), washed first with a mixture of methanol and dichloromethane (50/50 in volumes). , then eluted with 2M ammonia solution in methanol, and 20 cm ³ fractions were collected. fractions 1 to 6 were combined and the undissolved white substance which appeared filtered, the solid was drained, then dried at 50 ° C under reduced pressure (2.7 kPa). 0.169 g of N- {1- [6uc- (4chlorophenyl) methyl] azetidin-3-yl} -1H-isoquinol-5-yl-methylsulfonamide is obtained as a white solid. [RMN spectrum ^] H (300 MHz, CDCl ₃ , δ in ppm): 2.64 (t, J = 7 Hz: 1H); 2.81 (t, J = 7 Hz: 1H); 2.98 (s: 3H); 3.36 (t split, J = 7 in 2 Hz: 1H); 3.55 (t split, J = 7 in 2 Hz: 1H); 4.02 (s: 1H); 4.86 (mt: 1H); om 7.10 go 7.25 (mt: 8H); 7.60 (dd, J = 8 and 1 Hz: 1H); 7.66 (t, J = 8 Hz: 1H);

7.93 (d broad, J = 6 Hz: 1H); 8.06 (d broad, J = 8 Hz: 1H);

8.66 (d, J = 6Hz: 1H); 9.32 (broad: 1H)].

N- (isoquinol-5-yl) methylsulfonamide can be prepared by working as described in Example 4, starting from 2.0 g of 5 amino aminoquinoline, 3.0 cm ³ pyridine, 1.1 cm ³ methylsulfonyl chloride. 2.3 g of N- (isoquinol-5-yl) methylsulfonamide are obtained as a beige solid.

Example 6

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-pyrid-3-ylmethylsulfonamide can be prepared by working as follows: to a solution of 0.144 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidine-

3-yl} -N4- (1-oxide-pyrid-3-yl) -methylsulfonamide in 5 cm chloroform, poured 0.042 cm ³ phosphorus trichloride, then the mixture was heated to reflux temperature. After 1 hour and 30 minutes of stirring, the reaction mixture was allowed to return to normal temperature, then 5 cm of hydrochloric acid 0.1 N was added, then stirred and decanted. The organic phase was diluted with 20 cm ^{3 of} chloroform, dried over magnesium sulfate, filtered, then 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 9 cm, diameter 1.8 cm), eluted under pressure of 0.1 bar from argon with a mixture of dichloromethane and methanol (95/5 in volumes) and collect fractions of 15 cm ³ . fractions 2 to 4 were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was stirred with 15 cm 3 of diethyl oxide, the suspension filtered, the solid drained, then dried under reduced pressure (2.7 kPa). 35 mg of N- {1 [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L-pyrid-3-yl-methylsulfonamide are obtained as a cream solid. [RMN spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.80 to 2.95 (mt: 2H); 2.87 (s: 3H); 3.51 (t split, J = 7 and 1.5 Hz: 2H); 4.18 (s: 1H); 4.65 (mt: 1H); by

7.15 to 7.35 (mt: 8H); 7.37 (dd broad, J = 8 and 5 Hz: 1H); 7.64 (d demultiplicated, J = 8 Hz: 1H); 8.52 (d broad, J = 2 Hz: 1H); 8.61 (d broad, J = 5 Hz: 1H)].

Example 7

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (1-oxide-pyrid-3-yl) methylsulfonamide can be prepared by working as follows: to a solution of 0.265 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3ol and 0.162 g of N- (1-oxide-pyrid-3-yl) methylsulfonamide in 25 cm ^{3 of} anhydrous tetrahydrofuran were added under argon of 0.16 cm. ³ diethyl azodicarboxylate and 0.226 g triphenylphosphine. After stirring for 20 hours at 20 ° C, then for 24 hours at reflux temperature, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 20 cm, diameter 1.5 ** cm), eluted under pressure of 0.5 bar from argon with a mixture of dichloromethane and methanol (98/2 v volumes) and 40 cm ³ fractions were collected. fractions 26 to 64 were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was stirred in 10 cm ^{3 of} diethyl oxide, the suspension filtered, the insoluble matter drained, then dried under reduced pressure (2.7 kPa). 0.10 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -14 (1-oxide-pyridin-3-yl) -methylsulfonamide are obtained as a white solid. [RMN spectrum ^] H (400 MHz, (CD ₃ ) ₂ SO d6, δ in ppm):

2.78 (t, J = 7 Hz: 2H); 3.06 (s: 3H); 3.37 (t, J = 7 Hz: 2H); 4.45 (s: 1H); 4.71 (mt: 1H); om 7.30 to 7.50 (mt: 10H); 8.21 (broad d, J = 6.5 Hz: 1H); 8.27 (broad: 1H) J.

B [- (1'-Oxide-pyrid-3-yl) methylsulfonamide can be prepared by working as follows: to a solution of 1.81 g of N-nupug -3-ylmethylsulfonamide, in 71 cm ^{3 of} N, N-dimethylformamide and 3 cm ³ methanol, 7.1 g of 3-chloroperoxybenzoic acid 50-55%, then 0.56 cm ^{3 of} hydrofluoric acid 40% are added in portions. After stirring at 20 ° C for 1 hour, the reaction mixture was poured into 500 g of ice, stirred, then filtered. The filtrate was concentrated to dryness at 60 ° C under reduced pressure (2.7 kPa). The residue was extracted with a 50 cm ³ mixture of dichloromethane and methanol (98/2 in volumes), then filtered. The filtrate was chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 27 cm, diameter 4 cm), eluted under pressure of 0.5 bar from argon with a mixture of dichloromethane and methanol (98/2, 97/3 after 50/50 in volumes) and fractions of 60 cm ³ were collected, fraction 62 was concentrated to dryness under reduced pressure (2.7 kPa). 0.96 g of N- (1-oxugpyrid-3-yl) methylsulfonamide are obtained as a yellowish solid.

N-Pyrid-3-yl-methylsulfonamide can be prepared by working as described in Example 1, starting from 2 g of 3-aminopyridine, 5.0 cm ^{3 of} pyridine and 1.8 cm ^{3 of} methyl sulfonyl chloride. The crude product obtained was stirred in 40 cm &lt; ^{3 &gt; of} diethyl oxide, the suspension filtered, then the solid was drained and dried under reduced pressure (2.7 kPa). 2.47 g of N-nupug-3-ylmethylsulfonamide are obtained as a tan solid.

Example 8

N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -L-cyclohexylmethylsulfonamide can be prepared by working as follows: to a solution of 1.8 g of N- {1- [ bis- (4-chlorophenyl) methyl] azetidine-3UA-N-cyclohexylamine, and 0.7 cm ³ triethylamine and 20 mg 4 dimethylaminopyridine in 25 cm ³ dichloromethane were added with stirring 0.4 cm ³ methylsulfonyl chloride. After stirring for 48 hours at 20 ° C, 20 cm ^{3 of} dichloromethane, 20 cm ^{3 of} water were added to the reaction mixture and stirred and decanted. The organic phase was dried over magnesium sulfate and concentrated at 50 ° C under reduced pressure (2.7 kPa). The brown oily residue was chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 20 cm, diameter 2.0 cm), eluted under pressure of 0.1 bar from argon with a mixture of dichloromethane and methanol (96/4 in volumes) and fractions of 10 cm ³ were collected. fractions 2 to 4 and 5 to 10 were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 1.5 cm), eluted under pressure of 0.1 bar from argon with a mixture of cyclohexane and ethyl acetate (70/30 in volumes ) and fractions of 5 cm are collected. Fractions 7 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.10 g of N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -1H-cyclohexyl-methylsulfonamide are obtained in the form of a cream kiss. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm): 0.80 to 1.90 (mt: 10 H); 2.82 (s: 3H); 3.36 (t broad, J = 7.5 Hz: 2H); 3.46 (broad t, J = 7.5 Hz: 2H); 3.59 (mt: 1H); 4.08 (mt: 1H); 4.42 (s: 1H); om 7.20 to 7.40 (mt: 8H)].

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -H-cyclohexylamine can be prepared by working as follows: to a solution of 1.5 g of 1- [bis- ( 4-chlorophenyl) methyl] azetidin-3-one in 25 cm dichloro-1,2 ethane, add 0.5 g cyclohexylamine, 1 g sodium triacetoxyborohydride and 0.3 cm acetic acid 100%. After stirring at 20 ° C for 20 hours, 20 cm ^{3 of} dichloromethane and 10 cm ^{3 of} water were then added to the reaction mixture with stirring, then neutralized to pH 7 to 8 with aqueous sodium hydroxide 1N. The mixture was decanted, the organic phase was dried over magnesium sulfate and concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). 1.8 g of L1- {1- [bis- (4-chlorophenyl) methyl] azetidine-

3-yl} -14-cyclohexylamine, in the form of a cream paste, which is used as it is in the next step.

1- [Bis- (4-chlorophenyl) methyl] azetidin-3-one can be prepared as follows: To a solution of 5.0 cm 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 2 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 silica gel column (granulometry)

0,04-0,06 mm, height 21 cm, diameter 9,2 cm), nog pressure 0,5 bar of argon eluting with a mixture of ethyl acetate and cyclohexane (40/60 in volumes) and collecting fractions of 200 Art ³ . Fractions 15 to 25 were combined, then concentrated to dryness under reduced pressure (2.7 kPa). 8.9 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-one are obtained in the form of pale yellow crystals melting at 111 ° C.

Example 9

N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -1H-cyclopropylmethylsulfonamide can be prepared by working as described in Example 8, starting from 1.6 g of N- {1- [6uc- (4q chlorophenyl) methyl] azetidin-3-yl} -N-cyclopropylamine, 25 cm dichloromethane, 0.7 cm ³ triethylamine, 20 mg 4-dimethylaminopyridine and 0.4 cm ³ methylsulfonyl chloride as a mixture was stirred for 20 hours at 20 ° C. The crude product was chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluted under pressure of 0.1 bar from argon with a mixture of dichloromethane and methanol (97/3 in volumes ) and fractions of 10 cm ³ were collected. fractions 6 to 9 and 10 to 20 se

W was combined and concentrated to dryness under reduced pressure (2.7 kPa).

The resulting residue was chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 2 cm), eluted under pressure of 0.1 bar from argon with a mixture of cyclohexane and ethyl acetate (70/30 in volumes). and fractions of 10 cm ³ were collected. Fractions 6 to 11 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.14 g of N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N4-cyclopropyl-methylsulfonamide are obtained in the form of a cream kiss. [RMN * H spectrum (300 MHz,

CDCl ₃ , δ in ppm): 0.79 (mt: 2H); 0.95 (mt: 2H); 2.11 (mt: 1H);

2.84 (s: 3H); 3.17 (t broad, J = 7 Hz: 2H); 3.50 (mt: 2H); 4.18 (mt: 1H); 4.29 (s: 1H); om 7.20 to 7.40 (mt: 8H)].

No. {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -1H-cyclopropylamine can be prepared by working as described in Example 8 starting from 1.5 g of 1- [bis - (4-chlorophenyl) methyl] azetidin-3-one 25 cm ³ dichloro-1,2-ethane, 0.37 cm ³ cyclopropylamine, 1 g sodium triacetoxyborohydride and 0.3 cm acetic acid 100%. 1.6 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -cyclopropylamine are obtained in the form of a brown oil, which is used as is in the next step.

Example 10

N- (1R, 2S, 4S) -6Muo [2,2,1] xenin-2-yA-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -methylsulfonamide may be obtained by working as described in Example 8, starting from 2 gN (1R, 2S, 4S) -6unukAo [2,2,1] xenm-2-uA-N- {1- [bis- (4chlorophenyl) methyl] azetidin-3-yl} amine, 25 cm dichloromethane, 0.7 cm triethylamine, 20 mg 4-dimethylaminopyridine and 0.4 cm ³ methylsulfonyl chloride, stirring for 20 hours. The brown oily residue was chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluted under pressure of 0.1 bar from argon with a mixture of dichloromethane and methanol (97/3 in volumes) and fractions of 10 cm ³ were collected. fractions 6 to 18 were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 2 cm), eluting with a pressure of 0.1 bar om argon with a mixture of cyclohexane and ethyl acetate (70/30 in volumes) and fractions of 10 cm ³ were collected. Fractions 8 to 14 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.70 g of N- (1R, 2S, 4S) bicyclo [2,2,1] xenin-2-yl-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl are obtained } methylsulfonamide, in the form of a cream kiss. [RMN spectrum Ή (300 MHz, CDCl ₃ , δ in ppm): from 1.20 to 1.75 (mt: 7 H);

1.84 (t broad, J = 12.5 Hz: 1H); 2.29 (mt: 1H); 2.35 (mt: 1H);

2.82 (s: 3H); om 3.35 to 3.55 (mt: 3H); 3.66 (mt: 1H); om 3.90 to 4.05 (mt: 2H); 4.51 (s: 1H); om 7.20 to 7.45 (mt: 8H)].

N- (1R, 2S, 4S) -6-methyl [2,2,1] xenin-2-UA-N- {1- [6uc- (4-chlorophenyl) methyl] azetidin-3-yl} amine, can be prepared as was run as described in Example 8, starting from 1.5 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one, 25 cm dichloro-1,2-ethane, 1.5 g (lR , 2S, 4S) -6uuukAo [2,2,1] xenmuA-2-aMUH, 1 g sodium triacetoxyborohydride and 0.3 cm ³ acetic acid 100%. 2 g of N- (1R, 2S, 4S) -6u4ukAo [2,2,1] xenin-2 - {- N- {1- [6uc- (4chlorophenyl) methyl] azetidin-3-yl} amine are obtained, under the form of brown oil that is used as it is in the next step.

w Example 11

N- (1R, 2S, 4S) -6-methyl [2,2,1] xenin-2-yl-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -methylsulfonamide may be obtained by working as described in Example 8, starting from 1.8 gN (1R, 2S, 4S) -6uuukAo [2,2, 1] xenm-2-UA-N- {1- [6uc- ( 4 <2 chlorophenyl) methyl] azetidin-3-yl} amine, 25 cm dichloromethane, 0.7 cm triethylamine, 20 mg 4-dimethylaminopyridine and 0.4 cm ³ methylsulfonyl chloride, and stirred for 20 hours. The brown oily residue was chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluted under pressure of 0.1 bar from argon with a mixture of cyclohexane and ethyl acetate (60/40 in volumes) and fractions of 10 cm ³ were collected. fractions 3 to 12 were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 2 cm), eluted under pressure of 0.1 bar from argon with a mixture of cyclohexane and ethyl acetate (70/30 in volumes) and fractions of 10 cm ³ were collected. Fractions 4 to 10 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.10 g of N- (1R, 2S, 4S) bicyclo [2,2,1] xenin-2-yl-N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl are obtained } methylsulfonamide, in the form of a yellow kiss. [RMN spectrum ^g H (300 MHz, CDCl ₃ , δ in ppm): 1.00 to 1.85 (mt: 8 H); 2.14 (mt: 1H); 2.33 (mt: 1H); 2.82 (s: 3H); from 3.40 to 3.60 (mt: 4H); 3.71 (dd broad, J = 8 and 6 Hz: 1H); 4.10 (mt: 1H); 4.47 (s: 1H); from 7.20 to 7.40 (mt: 8H)].

N- (1R, 2R, 4S) -6-methyl [2,2,1] hept-2-yl-1 N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} amine, can be prepared as was run as described in Example 8, starting from 1.5 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one, 25 cm dichloro-1,2-ethane, 0.6 g (lR , 2R, 4S) -6uuukAo [2,2,1] xenmuA-2-aMUH, 1 g of sodium triacetoxyborohydride and 0.3 cm ^{3 of} acetic acid 100%. 1.8 gN- (1R, 2R, 4S) -6u4ukAo [2,2,1] xenin-2-UA-N- {1- [6uc- (4chlorophenyl) methyl] azetidin-3-yl} amine is obtained. in the form of a cream paste that is used as it is in the next step.

Example 12

N - [(1-benzhydryl) azetidin-3-yl] -N-phenyl-methylsulfonamide can be prepared by the following procedure: pour into a solution of 2 g of 1-benzhydryl 3-anilino azetidine in 40 cm ^{3 of} dichloromethane 0.7 cm ^{3 of} methylsulfonyl chloride, then 1.34 cm ^{3 of} triethylamine are added. After stirring at 20 ° C for 4 hours and 15 minutes, the reaction mixture was washed twice with 20 cm3 of water, the organic phase was dried over magnesium sulfate, then concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The resulting brown oil was chromatographed on a silica gel column. The resulting chestnut oil was chromatographed on a silica gel column (0.063-0.2 mm in height, 26 cm in height, 3.6 cm in diameter), eluted under pressure of 0.5 bar of argon with a mixture. of cyclohexane and ethyl acetate (70/30 in volumes) and 50 cm ³ fractions were collected. Fractions 10 to 15 were combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue triturated with diethyl oxide, the suspension filtered, the solid drained, then dried under reduced pressure (2.7 kPa) ). 35 mg of N - [(1-benzhydryl) azetidin-3-yl] -1H-phenyl-methylsulfonamide are obtained as a white solid. [RMN ^X H spectrum (300 MHz, (CD ₃ ) ₂ SO d6 with the addition of a few drops of CD ₃ COOD d4, δ in ppm):

2.72 (mt: 2H); 2.92 (s: 3H); 3.36 (mt: 2H); 4.32 (s: 1H); 4.73 (mt: 1H); om 7.10 go 7.45 (mt: 15H)].

1-Benzhydryl 3-anilino azetidine can be prepared by working as described in Example 8, starting from 5 g of 1-benzhydryl azetidin-3-one, 1.92 cm ³ aniline, 74 cm ³ dichloro-1,2- ethane,

6.3 g of sodium triacetoxyborohydride and 1.2 cm ^{3 of} acetic acid 100

%. 8.81 g of 1-benzhydryl 3-anilino azetidine are obtained in the form of a brown gum, which is used as is in the next step.

Example 13

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide can be obtained by working as follows: to a mixture of 1.23 g 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl methylsulfonate and 0.66 g] N- (3,5-difluorophenyl) methylsulfonamide, in 25 cm ³ dioxane, 1.0 g of cesium carbonate is added. After stirring for 5 hours at reflux temperature, after 20 hours at 20 ° C, the reaction mixture was added to 50 cm ^{3 of} diethyl oxide and 30 cm ^{3 of} brine, then stirred and 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 0.040-0.063 mm, height 25 cm, diameter 2 cm), eluted under pressure of 0.5 bar from argon with a mixture of cyclohexane and ethyl acetate (65/35 in volumes) and fractions of 10 centimeters are collected. Fractions 6 to 10 were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 15 cm, diameter 1.0 cm), eluted under pressure of 0.5 bar from argon with a mixture of cyclohexane and ethyl acetate (65/35 in volumes) and fractions of 5 cm ³ were collected. concentrate Ί to dryness under reduced pressure (2.7 kPa). 0.11 g of N- {1- [6uc- (4chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide are obtained as a white powder. [RMN spectrum ^X H (300 MHz, CDCl ₃ , δ in ppm): 2.82 (s: 3H); 2.85 (mt: 2H); 3.52 (t split, J = 7 in 2 Hz: 2H); 4.22 (s: 1H); 4.47 (mt: 1H); om 6.75 to 6.90 (mt: 3H); om 7.20 to 7.35 (mt: 8H)].

Memog 2

To a solution of 1.41 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol and 0.95 g of N- (3,5-difluorophenyl) methylsulfonamide β 100 cm ³ anhydrous tetrahydrofuran were added under argon 0.78 cm ^{3 of} diethyl azodicarboxylate, and 1.31 g of triphenylphosphine. After stirring at 20 ° C for 16 hours, 300 cm ^{3 of} ethyl acetate were added, <2 the reaction mixture was washed twice with 100 cm 3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue was chromatographed on a silica gel column (granulometry 0.020-0.063 mm, height 50 cm, diameter 4 cm), eluted under a pressure of 0.6 bar of argon with a mixture of cyclohexane and ethyl acetate (75/25 in volumes) and collected. 125 cm ³ fractions. fractions 6 to 12 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.8 g of a solid are obtained which is dissolved in a mixture of ethyl acetate / diisopropyl ether (15/2 in volumes), cooled, diluted with 100 cm ^{3 of} pentane to initiate crystallization. Filtration and drying afforded 1.0 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -14- (3,5-difluorophenyl) methylsulfonamide in the form of white melting crystals at 154 ° C.

N- (3,5-difluorophenyl) methylsulfonamide can be prepared by working as follows: to a solution of 3.5 g of 3,5-difluoroaniline in 75 cm ³ dichloromethane, slowly add 2 cm ³ methylsulfonyl chloride, 3 , 8 cm &lt; ^{3 &gt; of} triethylamine and 20 mg of 4-dimethylaminopyridine. After stirring for 20 hours at 20 ° C, 20 cm ^{3 of} dichloromethane and 20 cm ^{3 of} water were added to the reaction mixture, then stirring was then decanted. The organic phase was dried over magnesium sulfate, filtered, then 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 20 cm, diameter 2.0 cm), eluted under pressure of 0.1 bar from argon with dichloromethane and 25 cm ³ fractions were collected. fractions 14 to 20 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.66 g of N- (3,5-diphenylphenyl) memylcylphonamide is obtained as a white powder.

1- [bis (4-chlorophenyl) methyl] azetidin-3-yl methylsulfonate can be prepared by working as follows: to a solution of 12 g of 1 [bis (4-chlorophenyl) methyl] azetidin-3-ol in 200 cm @ 3 of dichloromethane were added under argon for 10 minutes 3.5 cm @ ^{3 of} methylsulfonyl chloride, then cooled to +5 DEG C. and 3.8 cm of pyridine were poured over 10 minutes. After stirring at +5 ° C for 30 minutes, then at 20 ° C for 20 hours, the reaction mixture was diluted with 100 cm ^{3 of} water and 100 cm ^{3 of} dichloromethane. The mixture is first filtered and then 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 resulting oil was chromatographed on a silica gel column (particle size 0,063-0,200 mm, height 40 cm, diameter 3.0 cm), eluted under pressure of 0.5 bar from argon with a mixture of cyclohexane and ethyl acetate (70/30 in volumes). and fractions of 100 cm ³ were collected. fractions 4 to 15 were combined and concentrated to dryness under reduced pressure (2.7 kPa). They are obtained

6.8 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl methylsulfonate, the yellow oil form.

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

Chlorhydrate of [bis (4-chlorophenyl) methyl] amine can be obtained by the method described by GRISAR M. et al., J. Med. Chem., 885 (1973).

Example 14

X- {1- [bis- (4-chlorophenyl) megpyl] azetidin-3-yl} -1H- (4,6-dimethylpyrimid-2-yl) -methylsulfonamide can be prepared by working as described in Example 13 (method 2) starting from 0.20 g of N- (4,6 dimethylpyrimid-2-yl) -methylsulfonamide and 0.308 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol. After chromatography on a silica gel column (granulometry 0.06-0.04 mt, height 50 cm, diameter 2m), pressure was eluted with 0.6 bar of argon with dichloromethane, then with a mixture of dichloromethane + 1% methanol, after this with a mixture of • 2 dichloromethane + 2% methanol and 200 cm fractions were collected, fractions 4 to 7 were combined and concentrated to dryness under reduced pressure (2.7 kPa). Crystallization from diisopropyl ether, filtration and drying afforded 0.20 g of N- {1- [6uc- (4chlorophenyl) methyl] azetidin-3-yl} -N- (4,6-dimethylpyrimid-2-yl) methylsulfonamide in the form of a white solid. [Spectrum RMN 1 H (300 MHz, CDCl ₃ , δ in ppm): 2.39 (s: 6H); 2.89 (t broad, J = 7.5 Hz: 2H); 3.51 (s: 3H); 3.77 (mt: 2H); 4.27 (s: 1H); 4.77 (mt: 1H); 6.73 (s .: 1H); om 7.20 to 7.35 (mt: 8H)].

N- (4,6-dimethylpyrimid-2-yl) -methylsulfonamide can be prepared by working as follows: to a mixture of 1.23 g of 2-amino-4,6 dimethylpyrimidine, 0,77 cm ^{3 of} methylsulfonyl chloride and 50 mg of 4 dimethylaminopyridine dissolved in 50 cm ^{3 of} dichloromethane are added

1.4 cm ^{3 of} triethylamine at 0 ° C. After 16 hours at room temperature, the reaction mixture was washed twice with 100 cm <^{3> of} water, dried over magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2.7 kPa). 1.0 g of a yellow powder are obtained, which is treated with 15 cm ^{3 of} soda 10% at 100 ° C for 1 hour. After cooling, the reaction mixture was extracted twice with 50 cm &lt; ³ &gt; of dichloromethane. The aqueous phase was acidified to pH = 1 with 5 cm ^{3 of} hydrochloric acid 10N and extracted twice with 50 cm ^{3 of} dichloromethane. The resultant organic phases were combined, washed with 50 cm ^{3 of} water, dried over magnesium sulfate, filtered and concentrated. 0.20 g of N- (4,6-dimethylpyrimid-2-yl) -methylsulfonamide are obtained as a yellow powder.

Example 15 No. {1- [Bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L &apos;-( 1,3,4-thiadiazol-2-yl) methylsulfonamide can be prepared by working as described in Example 13 (method 2) starting from 0.10 g of N- (1,3,4 thiadiazol-2-yl) -methylsulfonamide and 0.215 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol. After chromatography on a silica gel column (granulometry 0.06-0.04 mm, height 25 cm, diameter 1 cm), pressure was eluted under pressure of 0.8 bar from argon with ethyl acetate / cyclohexane 20/80, then 40 / 60 in volumes and fractions of 60 cm ³ were collected, fractions 26 to 31 were combined and concentrated to dryness under reduced pressure (2.7 kPa). Crystallization in diisopropyl ether, filtration and drying afforded 40 mg of N- {1 [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1,3,4-thiadiazol-2-yl) methylsulfonamide in the form of a white solid. [RMN spectrum Ή (300 MHz, CDCl ₃ , δ in ppm): 3.01 (s: 3H); 3.09 (t split, J = 7 and 1.5 Hz: 2H); 3.70 (t split, J = 7 in 1.5 Hz: 2H); 4.28 (s: 1H); 4.76 (mt: 1H); om 7.20 to 7.35 (mt: 8H); 9.01 (s: 1H)].

B1- (1,3,4-thiadiazol-2-11l) -methylsulfonamide can be prepared by working as follows: to a mixture of 2.02 g of 2-amino-1,3,4thiadiazole in 10 cm ^{3 of} pyridine , 1.5 cm ^{3 of} methylsulfonyl chloride are added. After 2 hours at room temperature, 60 cm ^{3 of} water was added and the reaction mixture filtered. The combined aqueous phase was acidified to pH = 2 with hydrochloric acid 1N, extracted 2 times with 50 cm ^{3 of} ethyl acetate, the organic phase washed twice with 50 cm ^{3 of} water, dried over magnesium sulfate, filtered then evaporated to dry under reduced pressure (2.7 kPa). 0.1 g of a yellow powder are obtained.

Example 16

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (thiazol-2-yl) methylsulfonamide can be prepared by working as described in Example 15 starting from 0 , 50 g of N- (thiazol-2-yl) methylsulfonamide and 0.5 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol. After chromatography on a silica gel column (granulometry 0.06-0.04 mm, height 60 cm, diameter 2 cm), elute under pressure

0.9 bar om argon with a mixture of ethyl acetate / cyclohexane 20/80, then 40/60 In volumes and fractions of 30 cm ³ were collected, fractions 9 to 12 were combined and concentrated to dryness under reduced pressure (2.7 kPa). Crystallization from diisopropyl ether, filtration and drying, yielded 0.21 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3yl} -N (thiazol-2-yl) -methylsulfonamide as a white solid. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm): 2.95 to 3.10 (mt: 2H); 3.00 (s: 3H); 3.59 (mt: 2H); 4.22 (broad s: 1H); 4.69 (mt: 1H); from 7.20 to 7.35 (mt: 9H); 7.60 (mt: 1H)].

N (thiazol-2-yl) -methylsulfonamide can be prepared by working as follows: To a mixture of 1.0 g 2-aminothiazole in 5 cm ³ pyridine, 1.15 g methylsulfonyl chloride is added. After 2 hours at room temperature, 20 cm3 of water was added, the reaction medium filtered and the solid collected (0.35 g). The combined aqueous phase was acidified to pH = 2 with hydrochloric acid 1N, extracted 2 times with 40 cm @ ^{3 of} ethyl acetate, the organic phase washed twice with 30 cm @ ^{3 of} water, dried over magnesium sulfate, filtered then evaporated to dry under reduced pressure (2.7 kPa). 0.15 g of a white solid having spectral characteristics close to the filtered solid are obtained corresponding to a mixture of N- (thiazol-2-yl) -methylsulfonamide and N (thiazol-2-yl) -di (methylsulfonyl) imide used. as it is for the next stage.

Example 17

N- {1- [bis- (4-chlorophenyl) -methyl] -azetidin-3-yl} -N- (3-hydroxyphenyl) methylsulfonamide can be obtained by working as follows: to a mixture of 0.5 g No. {1- [Bis- (4-chlorophenyl) -methyl] -azetidin-3-yl} -N- (3-methoxyphenyl) -methylsulfonamide 6 20 cm ³ dichloromethane, dropwise added at 2 ° C 7,63 cm ³ 1M boron tribromide solution. After 20 hours at room temperature, the reaction medium was poured onto ice and extracted with 60 cm ^{3 of} dichloromethane. The organic phase was washed 3 times with 80 cm ^{3 of} water, then twice with 80 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered then evaporated to dryness under reduced pressure (2.7 kPa) . 0.33 g of a white kiss is obtained which is taken up in acetonitrile, filtered and dried to give 0.20 g of a white solid. [Spectrum RMN ^d H (300 MHz, CDCl ₃ , δ in ppm): 2.81 (s: 3H); 2.86 (t broad, J = 7.5 Hz: 2H); 3.50 (broad t, J = 7.5 Hz: 2H); 4.20 (s: 1H); 4.53 (mt: 1H);

5.36 (mf: 1H); om 6.70 to 6.85 (mt: 3H); om 7.15 to 7.35 (mt: 9H)].

Example 18

N- {1- [bis- (4-chlorophenyl) -methyl] -azetidin-3-yl} -NH-methoxyphenyl) methylsulfonamide can be prepared by working as described in Example 15, starting from 1.58 g N- (3-methoxyphenyl) methylsulfonamide and 2.0 g 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol. After chromatography on a silica gel column (particle size 0,060,04 mt, height 24 cm, diameter 7,8 cm), elute under pressure 0,7 bar of argon with ethyl acetate / cyclohexane 50/50, then 40/60 in volumes and 100 cm ³ fractions were collected, fractions 7 to 10 were combined and concentrated to dryness under reduced pressure (2.7 kPa) (2.05 g). Crystallization from diisopropyl ether, filtration and drying afforded 0.21 g of N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -L- (3-methoxyphenyl) -methylsulfonamide.

N- (3-methoxyphenyl) -methylsulfonamide can be prepared by working as follows: to a mixture of 5.0 g of 3-methoxyaniline in 150 cm ^{3 of} pyridine are added at 3 ° C, 3.14 cm ^{3 of} methyl sulfonyl chloride . After 20 hours at room temperature, 200 cm 3 of water and 400 cm ^{3 of} ethyl acetate were added and the reaction medium was decanted. The organic phase was washed 3 times with 400 cm 3 of water and 400 cm 3 of saturated sodium chloride solution, dried over magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2.7 kPa). After chromatography on a silica gel column (granulometry 0.06-0.04 mm, height 23 cm, diameter 7.8 cm), pressure eluted 0.7 bar of argon with ethyl acetate / cyclohexane 25/75 in volumes and 100 cm fractions were collected, fractions 24 to 36 were combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 6.21 g of N- (3methoxyphenyl) methylsulfonamide as an orange oil.

Example 19 No. {1- [bis- (4-chlorophenyl) -methyl] -azetidin-3-yl} -N- (3-hydroxymethylphenyl) -methylsulfonamide can be prepared by working as follows: to a mixture of 0, 5 g of ethyl N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N- (methylsulfonyl) -3-aminobenzoate in 20 cm ^{3 of} toluene were added dropwise at -50 ° C, 1.46 cm ³ toluene solution of 20% diisopropyl aluminum hydride. After 1.5 hours at 0 ° C and 1.5 hours at 10 ° C, the reaction mixture was cooled to 0 ° C and 20 cm ^{3 of} water was slowly added. After filtering the precipitate and extracting with ethyl acetate, the organic phase is washed twice with 80 cm ^{3 of} water, then with 80 cm ³ saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). 0.46 g of an oil is obtained, which is chromatographed on a silica gel column (granulometry 0.06-0.04 mm, height 16 cm, diameter 4 cm), eluted under pressure of 0.7 bar from argon with ethyl acetate / mixture. cyclohexane 40/60 in volumes and 20 cm ³ fractions were collected, fractions 72 to 76 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.20 g of N- {1- [6uc- (4chlorophenyl) -methyl] -azetidin-3-yl} -N- (3-hydroxymethyl-phenyl) methylsulfonamide are obtained as a white solid. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 1.80 (mt: 1H); 2.83 (s: 3H);

2.87 (mt: 2H); 3.52 (mt: 2H); 4.21 (broad s: 1H); 4.60 (mt: 1H); 4.74 (d broad, J = 4Hz: 2H); om 7.10 go 7.45 (mt: 12H)].

Example 20

Ethyl N- {1- [bis- (4-chlorophenyl) -methyl] -azetidin-3-yl} -N (methylsulfonyl) -3-aminobenzoate can be prepared by working as described in Example 15, starting from from 1.58 g of Ethyl b1- (methylsulfonyl) -3-aminobenzoate and 2.0 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol. After chromatography on a silica gel column (particle size 0,06-0,04 mm, height 24 cm, diameter

7.8 cm), eluting under pressure 0,7 bar of argon with a mixture of ethyl acetate / cyclohexane 50/50 and then 40/60 by volume and fractions of 100 cm @ ³ fractions 7 through 10 were combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 2.0 g of a yellow oil.

Ethyl b1- (methylsulfonyl) -3-aminobenzoate can be prepared by working as follows: to a mixture of 5.0 g of ethyl 3-aminobenzoate in 150 cm ³ pyridine are added at 3 ° C, 2.35 cm ³ methylsulfonyl chloride. After 20 hours at room temperature, 200 cm ^{3 of} water and 400 cm ^{3 of} ethyl acetate were added and the reaction medium was decanted. The organic phase was washed 3 times with 400 cm ^{3 of} water and 400 cm ^{3 of} saturated sodium chloride solution, dried over magnesium sulfate, filtered then evaporated to dryness under reduced pressure (2.7 kPa). After chromatography on a silica gel column (granulometry 0.06-0.04 mm, height 25 cm, diameter 7.8 cm), pressure eluted 0.7 bar of argon with ethyl acetate / cyclohexane 25/75 in volumes and 100 cm ³ fractions were collected, fractions 27 to 36 were combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 5.24 g of ethyl N (methylsulfonyl) -3-aminobenzoate as an orange oil.

Example 21

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) -methylsulfonamide can be prepared as follows: to a solution of 0 , 47 g of N- {1- [6uc- (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (piperid-4-yl) -methylsulfonamide in 20 cm ³ dichloromethane, 0.11 cm ³ isobutyraldehyde added, 0.057 cm ³ acetic acid 100% and 320 mg sodium triacetoxyborohydride. After stirring at 20 ° C for 20 hours, 50 cmA of saturated aqueous sodium bicarbonate solution was added to the reaction mixture and decanted. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by chromatography on a silica gel column (particle size 0,063-0,200 mm, height 20 cm, diameter 2 cm), eluted under pressure of 0.5 bar from argon with a mixture of cyclohexane and ethyl acetate (40/60 in volumes) and collect fractions of 30 cm ³ . fractions 3 to 15 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.22 g of N- {1- [6uc- (4chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) methylsulfonamide are obtained as a white kiss. [RMN spectrum Ή (300 MHz, CDCl ₃ , δ in ppm): 0.87 (d, J = 7 Hz: 6H); om 1.60 go 1.90 (mt: 5H); 1.93 (t broad, J = 11.5 Hz: 2H); 2.03 (d, J = 7.5 Hz: 2H);

2.84 (s: 3H); 2.89 (d broad, J = 11.5 Hz: 2H); 3.38 (t broad, J = 7 Hz: 2H); 3.47 (t broad, J = 7 Hz: 2H); 3.62 (mt: 1H); 4.08 (mt: 1H); 4.43 (s: 1H); om 7.20 to 7.40 (mt: 8H)].

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (nunepug-4-UA) methylsulfonamide can be prepared by working as follows: to a solution of 19 g K- {1- [Bis- (4-chlorophenyl) methyl] azetidin-3-yl} -1H- (1-tert-butoxycarbonyl piperid-4-yl) -methylsulfonamide in 100 cm ³ dioxane, slowly pour 50 cm ³ hydrochloric acid solution 6 N in dioxane. After stirring for 20 hours at 20 ° C, the reaction mixture was concentrated at 50 ° C under reduced pressure (2.7 kPa). The residue was extracted with 200 cm ^{3 of} ethyl acetate and 200 cm ^{3 of} water. The aqueous phase was basified with aqueous 4N sodium hydroxide solution, then extracted with 200 cm ^{3 of} ethyl acetate. This organic phase was dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). 15.5 g of N- {1- [6uc (4-chlorophenyl) methyl] azetidin-3-yl} -N- (piperid-4-yl) -methylsulfonamide are obtained in the form of a cream kiss.

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (1-hyperbutoxycarbonylpiperid-4-yl) -methylsulfonamide can be prepared by working as follows: to a solution of 14.7 g 4- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylamino} - (1-tert-butoxycarbonyl) piperidine in 250 cm ³ dichloromethane, 4.60 cm ³ • 5 methylsulfonyl chloride slowly added , then 4.60 cm 3 of triethylamine and 100 mg of 4 dimethylaminopyridine. After stirring at 20 ° C for 20 hours, 200 cm ^{3 of} saturated aqueous sodium bicarbonate solution was added to the reaction mixture, then stirred for 30 minutes and decanted. The organic phase was dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). The resulting kiss was extracted with 250 cm ^{3 of} dichloromethane, again slowly added 4.60 cm ^{3 of} methylsulfonyl chloride, then 4.60 cm ^{3 of} triethylamine and 100 mg of 4 dimethylaminopyridine. After stirring at 20 ° C for 20 hours, 200 cm ^{3 of} saturated aqueous sodium bicarbonate solution was added to the reaction mixture, then stirred for 30 minutes and decanted. The organic phase was dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by chromatography on a silica gel column (particle size 0,063-0,200 mm, height 35 cm, diameter 5 cm), eluted under pressure of 0.5 bar from argon with a mixture of cyclohexane and ethyl acetate (70/30 in volumes) and collect fractions of 250 cm ³ . Fractions 4 to 18 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 19 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -1H- (1-tert-butoxycarbonylpiperid-4-yl) -methylsulfonamide are obtained in the form of a cream kiss, which is used as is is in the next stage.

4- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylamino} - (1-tert-butoxycarbonyl) -piperidine, can be prepared by working as follows: to a solution of 9.22 g 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylamine in 300 cm ^{3 of} dichloromethane, 6.58 g of 1-tert-butoxycarbonyl-piperidin-4-one are added. 9.54 g of sodium triacetoxyborohydride are added in two parts to the mixture cooled to + 5 °, then 1.72 cm ³ acetic acid is poured 100%. After stirring at 20 ° C for 20 hours, 500 cm ^{3 of} saturated aqueous sodium bicarbonate solution was slowly added to the reaction mixture, then stirred well and decanted. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). 15 g of 4- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylamino} - (1-tert-butoxycarbonyl) piperidine are obtained in the form of a cream kiss, which is used as is in the next step.

Example 22

N-6eH3UA-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} amine: to a solution of 369 mg of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylamine in cm ³ dichloromethane was added, at room temperature under an argon atmosphere, 0.134 cm ³ benzaldehyde. The mixture was cooled to about 0 ° C before the gradual addition of 382 mg of sodium triacetoxyborohydride, then 70 ml of acetic acid. After stirring at room temperature, the mixture was poured onto 50 cm ^{3 of} saturated aqueous sodium bicarbonate solution, then extracted twice with 25 cm 3 of dichloromethane. mix well and decant. The organic phase was combined and 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: dichloromethane / methanol (95/5 by volume)]. 0.29 g of N-benzyl N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} amine is obtained in the form of a colorless oil. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm):

2.71 (t broad, J = 7 Hz: 2H); 3.42 (mt: 2H); 3.49 (mt: 1H); 3.70 (s: 2H); 4.25 (s: 1H); om 7.20 to 7.40 (mt: 13H)].

1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl-amine can be prepared as follows: to 27 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl methyl sulfonate contained autoclave pre-cooled to about -60 ° C, add 400 cm ³ mixture of methanol and liquid ammonia (50/50 in volumes). The reaction mixture was then stirred at 60 ° C for 24 hours, then left free to air to allow ammonia to evaporate and finally concentrated under reduced pressure (2.7 kPa). The residue was taken up with 500 cm ^{3 of} aqueous 0.37N sodium hydroxide solution and extracted <4 times with 500 cm 3 of ethyl ether. The combined β organic phases were washed sequentially twice with 100 cm <2 of distilled water and with 100 cm 3 of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa). The resulting residue was purified by flash chromatography on silica gel [eluent: dichloromethane / methanol (95/5 by volume)]. 14.2 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl-amine are obtained in the form of an oil which is thickened to a creamy solid.

Example 23

N-benzyl-T4- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonamide: to a solution of 120 mg of N-6eH3UA-N- {1- [6uc- (4? 2 chlorophenyl) methyl] azetidin-3-yl} amine in 5 cm dichloromethane are added, at room temperature under an argon atmosphere, 104 mm ³ triethylamine. The mixture was cooled to about 0 ° C before 46.4 mm ^{3 of} methylsulfonyl chloride was added, then stirred at room temperature for 16 hours. The reaction mixture was diluted with 20 cm ^{3 of} dichloromethane, then washed twice with 15 cm ^{3 of} distilled water. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a resin which crystallized by trituration in methanol. 42 mg of N-benzyl-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonamide are thus obtained in the form of a cream powder melting at 171 ° C.

Example 24

B1- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) amine can be prepared as in Example 22, but using 188 mg of 3,5-difluorobenzaldehyde and 369 mg of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl-amine and 382 mg of sodium triacetoxyborohydride, without purification by flash chromatography. 0.48 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N (3,5-difluorobenzyl) amine are obtained in the form of a colorless oil. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.73 (mt: 2H); by

3.40 to 3.55 (mt: 3H); 3.70 (s: 2H); 4.26 (s: 1H); 6.69 (tt, J = 9 and 2 Hz: 1H); 6.83 (mt: 2H); om 7.20 to 7.35 (mt: 8H)].

Example 25

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) methylsulfonamide

To a solution of 433 mg of {{1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} N- (3,5-difluorobenzyl) amine in 30 cm ³ dichloromethane was added at room temperature under an argon atmosphere. , 347 tm ³ triethylamine. The mixture was cooled to about 0 ° C before a solution of 46.4 mm ³ methylsulfonyl chloride in 5 cm ³ dichloromethane was added, then stirred at room temperature for 1 hour. The reaction mixture was diluted with 20 cm ^{3 of} dichloromethane, then washed twice with 20 cm ^{3 of} distilled water. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue was introduced, in the form of methanol solution, into a Bond Elut® SCX cartridge (10g), eluting sequentially with methanol and 1M ammonia in methanol solution. The ammonia fractions were collected and concentrated to dryness under reduced pressure (2.7 kPa). 0.44 g of {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -1H- (3,5difluorobenzyl) methylsulfonamide are thus obtained in the form of a cream-colored kiss. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.81 (s: 3H); 3.02 (t broad, J = 7.5 Hz: 2H); 3.38 (t broad, J = 7.5 Hz: 2H);

4.23 (s: 1H); 4.40 (mt: 1H); 4.54 (s: 2H); 6.75 (mt, J = 9 at 2 Hz: 1H); 6.95 (mt: 2H); 7.25 (mt: 8H) J.

Example 26

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) acetamide

To a solution of 2 g of N- {1 ~ [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N (3,5-difluorobenzyl) amine in 75 cm ^{3 of} dichloromethane was added at room temperature under an atmosphere of argon, 1.6 cm ^{3 of} triethylamine.

The mixture was cooled to about 0 ° C before 0.66 cm ^{3 of} acetyl chloride was added dropwise, then stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 cm ^{3 of} dichloromethane, then washed twice with 20 cm3 of distilled water. The organic phase was 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: dichloromethane / methanol (98/2 by volume)]. 1.2 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidine-

3-yl} -N- (3,5-difluorobenzyl) acetamide as a colorless oil. [RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm). A mixture of rotamers is observed. * 2.06 and 2.14 (2s: 3H completely); 2.97 (mt: 2H);

3.43 (mt: 2H); 4.20 and 4.25 (2s: 1H completely); 4.54 and 4.75 to 4.80 (mt: 1H completely); 4.68 and 4.78 (2s broad: 2H full); 6.70 (mt: 3H); 7.24 (broad s: 8H)].

Example 27

B1- {1- [bis- (4-chlorophenyl) megpyl] azetidin-3-yl} -N- (pyrid-4-yl-methyl) methylsulfonamide

To a solution of 398 mg of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} β

N- (pyrid-4-ylmethyl) amine in 8 cm dichloromethane was added, at room temperature, under an argon atmosphere, 346 ml of triethylamine. The mixture was cooled to about 0 ° C before 155 mt ³ methylsulfonyl chloride was added, then stirred at room temperature for 3 hours. The reaction mixture was diluted with 35 cm 3 of dichloromethane, then washed twice with 20 cm ^{3 of} distilled water. The organic phase was 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: dichloromethane / methanol (97/3 in volumes)]. 288 mg of N- {1- [6uc- (4chlorophenyl) methyl] azesidin-3-yl} -N- (pyrid-4-yl-methyl) methylsulfonamide are obtained in the form of a cream-colored kiss. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm). 2.83 (s: 3H); 3.02 (t broad, J = 7.5 Hz: 2H); 3.40 (broad t, J = 7.5 Hz: 2H);

4.23 (s: 1H); 4.43 (mt: 1H); 4.57 (s: 2H); om 7.20 to 7.35 (mt: 8H); 7.32 (d broad, J = 5.5 Hz: 2H); 8.60 (d broad, J = 5.5 Hz: 2H)].

Example 28

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-4-yl-methyl) -amine can be prepared as follows: to a solution of 369 mg 1 [ bis- (4-chlorophenyl) methyl] azetidin-3-ylamine in 15 cm ^{3 of} dichloromethane was added, at room temperature under an argon atmosphere, 0.126 cm ^{3 of} pyrid-4-yl-carboxaldehyde. The mixture was cooled to about 0 ° C before the gradual addition of 382 mg of sodium triacetoxyborohydride, followed by 70 ml of acetic acid. After stirring at room temperature for 72 hours, the mixture was poured onto 100 cm ^{3 of} saturated aqueous sodium bicarbonate solution, then extracted twice with 100 cm dichloromethane. The combined organic phases were washed with 50 cm ^{3 of} distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue was introduced, in the form of a solution of 5 cm ³ methanol, into a Bond Elut® SCX cartridge (10g), eluting sequentially with 50 cm ³ methanol and 60 cm ³ solution of 1M ammonia in methanol. The ammonia fractions were collected and concentrated to dryness under reduced pressure (2.7 kPa). 0.48 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-4-yl-methyl) amine is thus obtained in the form of a colorless oil.

Example 29

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-3-yl-methyl) methylsulfonamide

It was performed according to the operating method of Example 27 but proceeded from 380 mg of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (pyrid-3-ylmethyl) amine to give 319 mg N- {1- [6uc- (4-chlorophenyl) methyl] azetidin-3-yl} -14- (pyrid-3-yl-methyl) methylsulfonamide as a cream-colored kiss.

[RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm). 2.80 (s: 3H); 3.02 (t split, J = 7 and 1.5 Hz: 2H); 3.38 (t split, J = 7 in 1.5 Hz: 2H); 4.22 (s: 1H); 4.35 (mt: 1H); 4.56 (s: 2H); 7.23 (broad s: 8H); 7.31 (dd, J = 8 at 5 Hz: 1H); 7.80 (d broad, J = 8 Hz: 1H); 8.57 (dd, J = 5 in 1.5 Hz: 1H); 8.63 (d broad, J = 1.5 Hz: 1H)].

Example 30

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (pyrid-3-yl-methyl) -amine may be prepared as in Example 28 but starting from 0.124 cm ³ pyrid-3-yl-carboxyaldehyde, 0.36 g of 1- [bis- (4-chlorophenyl) methyl] azetidine-

3-yl-amine and 0.38 g of sodium triacetoxyborohydride. 0.44 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -1 N (pyrid-3-yl-methyl) -amine is thus obtained in the form of a colorless oil.

Example 31

N- {1- [bis- (4-chlorophenyl) methyl] azepidin-3-yl} -1H- (1,1-dioxo-1H-1H ⁶ benzo [s] isothiazol-3-yl) -amine

To 386 mg of 1- [bis- (4-chlorophenyl) methyl] azetidin-3yl methylmethanesulfonate in the form of a solution of 10 cm ³ dimethylformamide was added 182 mg of 1,2-benzisothiazole-3-amine and 326 mg of cesium carbonate. The reaction medium was then stirred at 100 ° C for 9 hours, then concentrated under reduced <5 pressure (2.7 kPa). The residue was washed four times with 5 cc of boiling distilled water, disaggregated by stirring in 5 cc of distilled water at room temperature, then combined by filtration and purified by flash chromatography on silica gel [eluent: dichloromethane / methanol (98/2 in volumes)]. 53 mg of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -H- (1,1-dioxo-1H1L ^6- benzo [6] isothiazol-3-yl) -amine are obtained in the form of a viscous product. [RMN spectrum 300 (300 MHz, CDCl ₃ , δ in ppm). 3.17 (mt: 2H); 3.61 (t broad, J = 7.5 Hz: 2H); 4.37 (s: 1H); 4.75 (mt: 1H); om 6.30 to 6.40 (mf: 1H); om 7.20 to 7.35 (mt: 8H); 7.62 (d broad, J =

7.5 Hz: 1H); 7.69 (broad t, J = 7.5 Hz: 1H); 7.76 (t broad, J =

7.5 Hz: 1H); 7.93 (d broad, J = 7.5 Hz: 1H)].

1,2-Benzisothiazole-3-amine 1,1-dioxide can be prepared by the method described by Stoss, P. et al., Chem. Ber. (1975), 108 (12), 3855-63.

Example 32

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) -tertz-butyloxycarbonylsulfamide can be prepared as follows: to a solution of 0.095 cm ³ tert-butyl alcohol in 2 cm ³ anhydrous dichloromethane, 0.048 cm ³ chlorosulfonyl isocyanate are added, after 2 minutes stirring, 0.21 gN-1 [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -amine c

1.25 cm ³ anhydrous dichloromethane, then 0.084 cm ³ triethylamine. After stirring for 1 hour at a temperature close to 20 ° C, 2 cm ^{3 of} saturated sodium bicarbonate solution were added with vigorous stirring. The reaction medium was decanted, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue was chromatographed on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mt), provided it was then eluted with a petroleum ether-ethyl acetate mixture with Duramat pump pomace, collecting fractions of 2 cm3, fractions 6 to 17 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C for 2 hours. This gives 61 mg of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) -tert-butyloxycarbonylsulfamide as a white kiss. [RMN * H spectrum (400 MHz, CDCl ₃ , δ in ppm). 1.47 (s: 9H); 2.77 (t broad, J = 8 Hz: 2H); 3.52 (mt: 2H); 4.19 (s: 1H); 5.06 (mt: 1H); om 6.75 to 6.90 (mt: 3H); om 7.15 to 7.35 (mt: 8H)].

Example 33 (1 S) -L 1- {1 - [(4-chlorophenyl) -pyridin-3-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide can be prepared as follows : to a mixture of 0.2 g 3- [bromo- (4-chlorophenyl) -methyl] -pyridine and

0.22 g of H-azetidin-3-yl-N- (3,5-difluorophenyl) methylsulfonamide hydrochloride In 10 cm ^{3 of} acetonitrile 0.2 g of potassium carbonate and 23 mg of potassium iodide are then added, then the mixture is heated to reflux. refrigerate for 3 hours. Then 0.2 g of potassium carbonate is added again and further refluxed for 15 hours. After cooling to 21 ° C, the insoluble matter was removed by filtration, then concentrated to dryness at 40 ° C below 2.7 kPa. 170 mg of a colorless gum were obtained which was purified by chromatography on a silica cartridge (standard 811 ^ 020-005, FlashPack, Jones Chromatography Limited, New Road, Hengoed, Mid Glamorgan, CF82 8AU, Royaume Uni) eluting with a cyclohexane mixture : ethyl acetate 1: 1 (6 cm ³ / min, fractions of 5 cm 3), fractions with Rf = 5/57 (cyclohexane: ethyl acetate 1: 1, silica plaque, Merck standard 1.05719, Merck KGaA, 64271 Darmstatd, Allemagne) were combined and concentrated below 2.7 kPa at 40 ° C to afford 100 mg of (K8) -N {1 - [(4-chlorophenyl) -pyridin-3-yl-methyl] -azetidin-3-yl } (3,5-difluorophenyl) -methylsulfonamide melting at 110 ° C. [RMN spectrum ^X H (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm). 2.77 (mt: 2H); 2.98 (s: 3H); 3.38 (mt: 2H); 4.50 (s: 1H); 4.70 (mt: 1H);

7.11 (mt: 2H); om 7.20 to 7.40 (mt: 2H); 7.34 (d, J = 8 Hz: 2H);

7.41 (d, J = 8 Hz: 2H); 7.72 (d broad, J = 8 Hz: 1H); 8.40 (dd, J = 5 in 1.5 Hz: 1H); 8.58 (d, J = 1.5 Hz: 1H)].

The two isomers of (P8) -N- {1 - [(4-chloro-phenyl) -pyridin-3-yl-methyl] azetidin-3-yl} -N- (3,5-difluoro-phenyl) -methylsulfonamide may be separated into the chiral stationary phase of CHIRACEL OD.

First isomer: spectrum RMN ^] H (300 MHz, CDCl ₃ , δ in ppm): 2.82 (s: 3H); 2.87 (mt: 2H); 3.53 (mt: 2H); 4.29 (s: ΙΗ); 4.47 (mt:

W); 6.80 (mt: 3H); 7.19 (dd, J = 8 at 5 Hz: 1H);

om 7.20 to 7.35 (mt: 4H); 7.62 (d broad, J = 8 Hz: 1H);

8.45 (d broad, J = 5 Hz: 1H); 8.59 (broad: W).

Second isomer: spectrum RMN Η (300 MHz, CDCl ₃ , δ in ppm): 2.82 (s: 3H); 2.87 (mt: 2H); 3.54 (mt: 2H); 4.29 (s: 1H); 4.48 (mt:

1H); 6.80 (mt: 3H); 7.19 (dd broad, J = 8 at 5 Hz: 1H); om 7.25 to 7.35 (mt: 4H); 7.62 (dt, J = 8 at 2 Hz: 1H);

8.46 (dd, J = 5 at 2 Hz: 1H); 8.59 (d broad, J = 2 Hz: 1H).

H-azetidin-3-yl-N- (3,5-difluorophenyl) methylsulfonamide chloride is obtained as follows: in a 500 cm ³ hydrogenerator, a solution of 1 g of N- (1-benzhydryl-azetidin-3-yl) -N- (3,5difluorophenyl) -methylsulfonamide in a mixture of 2.5 cm ³ hydrochloric acid 1 M and 0.41 cm ³ acetic acid hydrogenates in the presence of 0.161 g of palladium hydroxide under 30 bars of hydrogen for 4 hours. The catalyst was removed by filtration on a layer of celite, then the filtrate was concentrated to dryness at 40 ° C below

2.7 kPa to give 630 mg of N-α3emuguH-3-UA-N- (3,5difluorophenyl) -methylsulfonamide, melting at 216 ° C.

N1-benzhydryl-azetidin-3-yl) -N- (3,5-difluorophenyl) -methylsulfonamide can be prepared by working as in Example 13 (method 2) as follows: to a solution of 2g 1-benzhydryl-azetidine -3-ol in 100 cm ^{3 of} tetrahydrofuran was added successively 0.86 g of N- (3,5 difluorophenyl) methylsulfonamide, 3.28 g of triphenyl phosphine, then 2 ml of diethyl azodicarboxylate. An increase in temperature was observed, which changed from 22 ° C to 29 ° C, so that a precipitate formed finally with the addition of diethyl azodicarboxylate. After 20 hours at 22 ° C, the precipitate was removed by filtration, then the filtrate was concentrated to dryness at 40 ° C below 2.7 kPa. The residue was triturated with 5 cm ³ methanol for 20 minutes at 21 ° C to afford 1.07 g N- (1-benzhydrylazetidin-3-yl) -N- (3,5-difluorophenyl) methylsulfonamide in the form of a white amorphous solid.

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

3- [Bromo- (4-chlorophenyl) -methyl] -pyridine is prepared as follows:

To 3.5 g (4-chlorophenyl) -pyridin-3-yl-methanol, 3.5 cm 3 solution of hydrobromic acid 48% in acetic acid and 1 cm ³ acetyl bromide are added. The resulting amber mixture was heated to reflux for 4 hours, then cooled to 20 ° C, concentrated to dryness at 40 ° C at 2.7kPa, resulting in 1.53 g of 3- [bromo] - (4-chlorophenyl) -methyl] -pyridine (Rf = 75/90, 254 pt, silica plates, standard 1.05719, Merk KGaA, 64271 Darmstatd, Allemagne).

c (4-Chlorophenyl) -pyridin-3-yl-methanol was prepared as follows: To a solution of 3 g of pyridine-3-carboxaldehyde in tetrahydrofuran at 5 ° C, a 20 cm ³ molar solution of 4-chlorophenyl magnesium bromide was added. in ethyl ether. After reheating to 20 ° C, it was allowed to react for 15 hours with stirring. Then 20 cm ^{3 of} saturated ammonium chloride solution was added, followed by 20 cm ^{3 of} ethyl acetate. The mixture was decanted and the organic phases extracted with 20 cm @ ^{3 of} ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, then concentrated to dryness at 40 ° C at 2.7 kPa. The resulting residue was chromatographed on silica (Amicon, 20-45 µm, 500 g silica, column 5 cm in diameter) eluting with a mixture of cyclohexane: ethyl acetate from 80: 20 to 50: 50 under argon pressure of 0.4 bar. fractions containing the compound with Rf = 13/53 (Merk silica plates, standard 1.05719, Merk KGaA, 64271 Darmstatd, Allemagne) were combined and evaporated to dryness at 40 ° C at 2.7 kPa to obtain 2.53 g (4-Chlorophenyl) -pyridin-3-ylmethanol.

Example 34

N- {1- [bis- (4-fluoro-phenyl) -methyl] -azetidin-3-yl) -N- (3,5-difluorophenyl) methylsulfonamide was obtained as follows: to a mixture of 0.2 g

4,4-difluorobenzhydryl chloride and 0.26 g of N-azetidine-Zyl-N- (3,5-difluorophenyl) -methylsulfonamide in 10 cm ³ acetonitrile were added 0.36 g of potassium carbonate and 27 mg of potassium iodide, after this mixture was refluxed for 3 hours. After cooling to 21 ° C, the insoluble matter is removed by filtration, then concentrated to dryness at 40 ° C at

2.7 kPa. The residue was triturated with 30 cm ^{3 of} ethyl acetate, then the solid was removed by filtration, the filtrate was concentrated to dryness at 40 ° C at 2.7 kPa to give 90 mg of a pale yellow solid, which was purified by chromatography on BondElut SCX cartridge containing 2 g silica (standard 1225-6019, Varian Associates, Inc. 24201 Frampton Avenue, Harbor City, CA90710, USA) eluting with methanolic 2M ammonia solution, fractions with Rf = 16/82 (cyclohexane ethyl acetate 7/3), silica plates, standard 1.05719, Merk KGaA, 64271 Darmstatd, Allemagne) were combined and concentrated to dryness at 2.7 kPa at 40 ° C to give 243 mg of N- {1- [bis- (4-fluoro-phenyl) -methyl] -azetidin-3-yl) -N- (3,5-difluorophenyl) methylsulfonamide melting at 98 ° C. [RMN spectrum ¹ H (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 2.74 (t broad, J = 7 Hz: 2H); 3.00 (s: 3H); 3.37 (t broad, J = 7 Hz: 2H); 4.43 (s: 1H); 4.69 (mt:

1H); om 7.05 go 7.20 (mt: 6H); 7.28 (tt, J = 9 at 2.5 Hz: 1H);

7.40 (mt: 4H)].

ζ ^. Example 35 N- (S) -N- {1 - [(4-chlorophenyl) -pyridin-4-yl-methyl] -azetidin-3-yl) -L- (3,5-difluorophenyl) -methylsulfonamide was prepared as follows: mixture of about 100 mg (4-pyridyl) - (4-chlorophenyl) -chloromethane, 143 mg of N-azetidin-3-yl-N- (3,5-difluorophenyl) -methylsulfonamide, 17 g of potassium iodide and 200 mg of potassium carbonate in 5 cm ³ acetonitrile, stirred for about 18 hours at a temperature close to 20 ° C. The reaction mixture was then heated at reflux β for 3 hours, 17 mg of potassium iodide added and allowed to reflux for 2 hours. After cooling to a temperature near 20 ° C, the reaction mixture was filtered on a glass frit. The solid was washed with acetonitrile then 2 times with 3 cm ³ ethyl acetate. The filtrates were concentrated to dryness under reduced pressure. 230 mg of a pale yellow solid are obtained, which is purified by preparative chromatography on a thin layer of silica [4 Merck Kieselgel Preparation Plates 60F254; 20x20 cm; 0.5 m thick], eluting with a methanol-dichloromethane mixture (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 12 mg of (1 S) -H- {1 - [(4-chlorophenyl) - pyridin-4-yl-methyl] -azetidin-3-yl) -N (3,5-difluorophenyl) -methylsulfonamide. [RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm). 2.82 (s: 3H); 2.96 (mf: 2H); from 3.50 to 3.80 (mt: 2H); 4.33 (mf: 1H); 4.54 (mt: 1H); 6.82 (mt: 3H); om 7.20 go

7.45 (mt: 6H); 8.53 (d broad, J = 5.5 Hz: 2H)].

The two isomers of (S) -N- {1 - [(4-chloro-phenyl) -pyridin-4-yl-methyl] azetidin-3-yl} -N- (3,5-difluoro-phenyl) -methanesulfonamide can be separated into the chiral stationary phase of CHIRACEL OJ.

First isomer: RMN 1 H spectrum (300 MHz, CDCl ₃ , δ in ppm). 2.83 (s: 3H); 2.87 (t broad, J = 7.5 Hz: 2H); 3.51 (mt: 1H); 3.60 (mt: 1H); 4.24 (s: 1H); 4.50 (mt: 1H); 6.82 (mt: 3H); om 7.20 go

7.35 (mt: 6H); 8.50 (d broad, J = 5.5 Hz; 2H).

Second isomer: RMN spectrum ^! H (300 MHz, CDCl ₃ , δ in ppm). 2.83 (s: 3H); 2.88 (t, J = 7.5 Hz: 2H); 3.51 (mt: 1H); 3.61 (mt:

1H); 4.25 (s: 1H); 4.51 (mt: 1H); 6.81 (mt: 3H); om 7.20 to 7.35 (mt: 6H); 8.50 (d broad, J = 5.5 Hz: 2H).

(4-Pyridyl) - (4-chlorophenyl) -chloromethane can be prepared as follows: to a suspension of 100 mg (4-pyridyl) - (4-chlorophenyl) methanol in 2 cm ³ toluene, cooled to a temperature close to 0 0 C, 0.0559 cm ^{3 of} thionyl chloride are added. After 2 hours at a temperature close to 0 ° C and 1 hour at a temperature close to 20 ° C, the reaction medium was concentrated under reduced pressure.

About 100 mg of (4-pyridyl) - (4-chlorophenyl) -chloromethane are obtained as a white solid.

(4-Pyridyl) - (4-chlorophenyl) -methanol can be prepared as follows <2: To a solution of 2 g of 4- (4-chlorobenzoyl) -pyridine in 160 cm ethanol are added at a temperature close to 20 ° C, 348 mg of sodium tetrahydroboride. After stirring for 2 hours at a temperature close to 20 ° C, 90 mg of sodium tetrahydroboride is 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 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 @ ^{3 of} dichloromethane. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gives 2 g of (4-pyridyl) - (4-chlorophenyl) -methanol as a white powder.

Example 36

To a solution of 330 mg of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} (3,5difluorobenzyl) amine in 25 cm ³ tetrahydrofuran was added, at room temperature under an argon atmosphere, 24.4 mg dispersion of sodium hydride 75% in mineral oil. The mixture was stirred at room temperature for 1 hour before 59 ml of ³ methyl chloroformate was added, then stirring was maintained for 18 hours under the same conditions. 0.3 cm ^{3 of} distilled water was added to the reaction mixture and the tetrahydrofuran was steam distilled. The resulting residue was extracted with dichloromethane, the organic phase was 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: dichloromethane / methanol (97.5 / 2.5 by volume)]. 328 mg of methyl {1- [bis (4-chlorophenyl) methyl] azetidin-3yl} - (3,5-difluorobenzyl) carbamate are obtained in the form of a colorless oil. [RMN spectrum 300 (300 MHz, CDCl ₃ , δ in ppm). 2.97 (mt: 2H); 3.39 (mt: 2H); 3.71 (s: 3H); 4.24 (broad s: 1H); 4.45 (mf:

1H); 4.57 (s: 2H); om6.65 go 6.80 (mt: 3H); om 7.15 go 7.30 (mt: 2H).

EXAMPLE 37 (RS) -N- {1 - [(4-Xanoophenyl) -NupuMuguH-5-ylmethyl] -3emuguH-3-yl} -N- (3,5-difluoro-phenyl) -methylsulfonamide may be obtained by working as in Example 33, starting from 0.16 g of N- (S) -5- [bromo- (4-chloro-phenyl) -methyl] -pyrimidine bromide, 0.131 g of N-azetidine-3 chlorohydrate -yl-N [- (3,5-difluorophenyl) -methanesulfonamide in 5 cm &lt; ³ & gt ^{; of} acetonitrile, 303 mg of potassium carbonate and 95 mg of potassium iodide, give 26 mg (P8) -N- {1 - [(4-chloro- phenyl) -pyrimidin-5-yl-methyl] azetidin-3-yl} -N- (3,5-difluoro-phenyl) -methylsulfonamide as a yellow kiss. [RMN spectrum (400 MHz, CDC1 ₃ , δ in ppm):

2.83 (s: 3H); 2.91 (mt: 2H); 3.57 (mt: 2H); 4.31 (s: 1H);

4.50 (mt: 1H); om 6.75 to 6.90 (mt: 3H); 7.29 (s: 4H); 8.71 (s: 2H); 9.08 (s: 1H)].

The medicaments of the invention are composed of at least one compound of formula (I) or an isomer or salt of this compound, in the pure state or in the form of a composition 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 main active ingredient according to the invention is mixed with one or more inert diluents, such as amidone, cellulose, sucrose, lactose or silica, under a stream of argon. 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 such 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 co-spores 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.

In human therapy, the compounds of the invention are particularly useful for treating and / or preventing psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, brain and spinal diseases, cognitive disorders, traumatic trauma, panic attacks, peripathy, peripathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, involuntary-nightmare disease, senile illness, thymic diseases, Tourette's syndrome, late disc zia, bipolar diseases, cancers, diseases induced by drugs, dystonias, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, sclerotic plaques, vomiting, asthma, appetite disorders, appetite disorders, disorders of appetite, memory, intestinal disorders, weaning in chronic illnesses such as drug addiction and alcohol or drug abuse (e.g., opiates, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines), such as pain spokoyavashti drugs or agents enhancing the analgesic activity of narcotic and non-narcotic drugs.

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.

The following examples illustrate compositions according to 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) 50 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 active substance tablets are obtained, having the following composition:

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

- Mixture of hydroxymethylcellulose, glycerin, 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:

Compound of Formula (I) 10 mg -Benzoic acid 80 mg -Benzyl alcohol 0,06 ml -Sodium benzoate 80 mg -Ethanol 95% 0,4 ml - Sodium hydroxide 24 mg Propylene glycol 1.6 ml - Water q.s.p. 4 ml

S2

Claims (21)

Patent Claims Is a pharmaceutical composition comprising as active ingredient at least one compound of the formula: (I) in which R 1 represents the radical -N (R ₄ ) R ₅ , -N (R ₄ ) -CO-R ₅ , -N (R ₄ ) -SO ₂ -R ₆ , R ₂ and R ₃ , the same or different, represent aromatic radicals selected from phenyl, naphthyl and indenyl, these aromatic radicals being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-a1k , cyano, -COOH, COOalk, -CONR ₇ R _8, -CO-NH-NR ₉ R _10, alkylsulfanyl, W · alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR ₇ R _8; the heteroaromatic radical is selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-Dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3,4tetrahydroisoquinolyl, thiazolyl and thienyl rings, these heteroaromatic radicals may be substituted by alkylene, butalkylene, alkali, or alkaloxy, , hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOalk, -CO-NH-NR ₉ R ₁₀ , -CONR ₇ R ₈ , -alk-NR ₉ R ₁₀ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R ₄ represents the radical -C (R _n ) (R ₁₂ ) -Het, -Het, -C (R _u ) (R 12) -Ar, Ar, cycloalkyl or norbornyl, R ₅ represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens, R ₆ represents a hydroxyalkyl radical, -alk-COOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens, R ₇ and R ₈ , the same or different, represent a hydrogen atom or an alkyl radical or m> kR ₇ and R ₈ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing optionally attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R ₉ and R ₁₀ , the same or different, represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl, or else R ₉ and R ₁₀ form together with the nitrogen atom to which one is attached a saturated or unsaturated mono or bicyclic 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, -COalk, -COOalk, -CO-NHalk, - CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH ₂ , R _n represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxyalkyl, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens, R ₁₂ represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxyalkyl or alkyl optionally substituted by one or more halogens, or else R _n and R ₁₂ form together with carbon an atom to which is attached a saturated mono or bicyclic ring 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, Ar represents a phenyl, naphthyl or indenyl radical, these various radicals being optionally substituted by one or more halogens, alkyl, alkoxy, -CO-alk, cyano, -COOH, COOalk, -CONR ₁₃ R ₁₄ , -CO-NH-NR ₁₅ R ₁₆ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR ₁₅ R ₁₆ , -NR ₁₅ R ₁₆ , alkylthioalkyl, formyl, CF ₃ , OCF ₃ , Het, -O -alk-NH-cycloalkyl, SO ₂ NH ₂ , hydroxy, hydroxyalkyl, -NHCOalk, NHCOOalk or at 2 adjacent carbon atoms with dioxymethylene, Het is a saturated or unsaturated mono or bicyclic 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 alkyl radicals, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy , nitrogen heterocycles are optionally in their N-oxide form, R ₁₃ and R ₁₄ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₃ and R ₁₄ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R ₁₅ and R ₁₆ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₅ and R ₁₆ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, alk represents an alkyl or alkylene radical, alkyl and alkylene radicals and moieties and alkoxy radicals and moieties having a straight or branched chain and containing 1 to 6 carbon atoms and c kloalkilovite radicals contain 3 to 10 carbon atoms, the optical isomers of these compounds and their pharmaceutically acceptable salts with an inorganic or organic acid. A pharmaceutical composition according to claim 1, wherein in formula (I) Het is selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, quinoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazoline, indole, isoquinoline, isoquinoline, isoquinoline , thiazole, thiadiazole, piperidine, piperazine, triazole, furan, tetrahydroisoquinoline, tetrahydroquinoline, these heterocycles are optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ rad. A pharmaceutical composition according to claim 1, wherein in the compound of formula (I) R _x represents the radical -N (R ₄ ) R ₅ , -N (R ₄ ) -SO ₂ -R ₆ , R ₂ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR ₇ R ₈ , hydroxyalkyl or -alk-NR ₇ R ₈ ; the heteroaromatic radical is selected from pyridyl , pyrimidyl, thiazolyl and thienyl rings, these heteroaromatics radicals may be unsubstituted or substituted with halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R _8, -alk-NR9R _10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl, R ₃ represents unsubstituted or substituted one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR ₇ R ₈ , hydroxyalkyl or -alk-NR ₇ R ₈ ; the heteroaromatic radical is selected from pyridyl, pyrimidyl, pyridyl , thiazolyl and thienyl rings, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R ₈ , -alk-NR ₉ R ₁₀ , alkylsulfanyl, alkylsulfanyl, alkylsulfanyl, alkylsulfanyl , R ₄ represents the radical -C (R _n ) (R ₁₂ ) -Het, -Het, -C (R _n ) (R ₁₂ ) -Ar, Ar or norbornyl, R _s represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxy, -CH ₂ Ar, -CH ₂ Het or alkyl, R ₆ represents the radical hydroxyalkyl, -alk-COOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxy, -CH ₂ Ar, -CH ₂ Het or alkyl, R ₇ and R ₈ , the same or different, represent a hydrogen atom or an alkyl radical, or else R ₇ and R ₈ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R _g and R ₁₀ , the same or different, represent a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl or nbkR ₉ and R ₁₀ form together with the nitrogen atom to which a saturated or unsaturated mono or a bicyclic 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, oxo, hydroxyalkyl, or - CO-NH ₂ , R _n represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxyalkyl, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens, R ₁₂ represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxyalkyl or alkyl optionally substituted by one or more halogens, or nbkR _u and R ₁₂ form together with the carbon atom to which are attached a saturated mono or bicyclic cycle 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, Ar represents a phenyl or naphthyl radical, these various radicals being optionally substituted by one or more halogens, alkyl, alkoxy, -CO-alk, cyano, -CONR ₁₃ R ₁₄ , alkylsulfonyl, -alk-NR ₁₅ R ₁₆ , -NR ₁₅ R ₁₆ , CF ₃ , OCF ₃ , SO ₂ NH ₂ , hydroxy, hydroxyalkyl, or at 2 adjacent carbon atoms with dioxymethylene, Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazolidine, furanthiol, tetrahydroquinoline, furan or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ radicals, R ₁₃ and R ₁₄ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₃ and R ₁₄ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R ₁₅ and R ₁₆ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₅ and R ₁₆ form together with the nitrogen atom to which are attached a saturated mono or bicyclic 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, the optical isomers of these compounds, and their pharmaceutically acceptable salts with inorganic or organic acid. A pharmaceutical composition according to claim 1 for which in the compound of formula (I) R 1 represents the radical -N (R ₄ ) -SO ₂ R ₆ , R ₂ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ₇ R ₈ , hydroxyalkyl or -alk-NR ₇ R ₈ ; the heteroaromatic radical is selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R ₈ hydroxyalkyl R ₃ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ₇ R ₈ , hydroxyalkyl or -alk-NR ₇ R ₈ ; the heteroaromatic radical is selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R ₈ hydroxyalkyl R ₄ represents -Het or Ar, Rg represents a hydroxyalkyl or alkyl radical, R ₇ and R ₈ , the same or different, represent a hydrogen atom or an alkyl radical, or else R ₇ and R ₈ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly another is attached a heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, Ar represents a phenyl or naphthyl radical, these different radicals being optionally substituted by one or more halogens, alkyl, alkoxy, -CO-alk, cyano, -CONR ₁₃ R ₁₄ , -alk-NR ₁₅ R ₁₆ , -NR _{1 S} R ₁₆ , CF ₃ , OCF ₃ , SO ₂ NH ₂ , hydroxy or hydroxyalkyl, Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazole, furan, tetrahydroetinyltetrohydroline and tetrahydro tetrahydro tetrahydroethanol or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ radicals, R _{13 and} R ₁₄ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₃ and R ₁₄ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly another is attached a heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R ₁₅ and R ₁₆ , being the same or different, represent a hydrogen atom or an alkyl radical, or R _{1 S} and R ₁₆ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals. the optical isomers of these compounds and their pharmaceutically acceptable salts with inorganic or organic acid. A composition according to claim 1 wherein the compound of formula (I) is selected from the following compounds: No. {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -1H- (6-chloropyrid-2-yl) methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N4- (6-ethylpyrid-2-yl) methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide, B1- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -L1-quinol-5-yl-methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -14-isoquinol-5-yl-methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N-pyrid-3-yl-methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -14- (1-oxide-pyrid-3-yl) methylsulfonamide, N- (1R, 2S, 4S) -6uuukAo [2,2J] xenin-2-uA-N- {1- [6uc- (4-XAopc> 4> eHUA) MemuA] azetidin-3-yl} -methylsulfonamide, N- (1R, 2R, 4S) -6-methyl [2,2,1] xenin-2-yl-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -1H- (3,5-difluorophenyl) methylsulfonamide, 14- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (thiazol-2-yl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -1H- (3-methoxyphenyl) methylsulfonamide, N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N- (3-hydroxyphenyl) methylsulfonamide, T4- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N- (3-hydroxymethylphenyl) -methylsulfonamide, T4- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N- (methylsulfonyl) -3-aminobenzoate ethyl, N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) -methylsulfonamide, N-6eH3UA-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} amine, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) amine, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-3-yl-methyl) methylsulfonamide, N- {1- [bis- (4-fluoro-phenyl) -methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4- chlorophenyl) -pyrid-3-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, (R) -N {1 - [(4-chlorophenyl) -pyrid-3-yl- methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrid-3-yl-methyl] -azetidin-3-yl } -N- (3,5difluorophenyl) -methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) -pyrid-4-yl-methyl] -azetidin-3-yl} -N- (3,5difluorophenyl) ) -methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) -pyrid-4-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, ad (S) -N- {I - [(4-chlorophenyl) -pyrid-4- l-methyl] -azetidin-3-yl} -N - (3,5-difluoro-xenyl) -methylsulfonamide, (RS) -N- {l - [(4-xAop <x |> eHUA) -nupuMuguH- 5-uA-MemuA] -a3emuguH-3-iiA} -N- (3,5-difluorophenyl) -methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-yl-methyl] -azetidine -3-yl} -1H- (3,5difluorophenyl) -methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-yl-methyl] -azetidin-3-yl} -H- (3,5difluorophenyl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -1H- (3,5-difluorophenyl) benzylsulfonamide, their optical isomers and their pharmaceutically acceptable salts with inorganic or organic acid. 6. Compound of formula: * 2 * 4 (I) in which R 1 represents the radical -N (R ₄ ) R ₅ , -N (R ₄ ) -CO-R ₃ , -N (R ₄ ) -SO ₂ -R 4, R ₂ and R ₃ , identical or different, represent aromatic radicals selected from phenyl, naphthyl and indenyl, these aromatic radicals being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-a1k , cyano, -COOH, COOalk, -CONR ₇ R _8, -CO-NH-NR ₉ R _10, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR ₇ R _8; the heteroaromatic radical is selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-Dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3,4tetrahydroisoquinolyl, thiazolyl and thienyl rings, these heteroaromatic radicals may be substituted by alkylene, butalkylene, alkali, or alkaloxy, , hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOalk, -CO-NH-NR ₉ R ₁₀ , -CONR ₇ R ₈ , -alk-NR ₉ R ₁₀ , alkylsulfinyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R ₄ represents the radical -C (R _n ) (R ₁₂ ) -Het, -Het, -C (R _n ) (R ₁₂ ) -Ar, Ar, cycloalkyl or norbornyl, R ₅ represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens, R ₆ represents a hydroxyalkyl radical, -alk-COOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens, R ₇ and R ₈ , the same or different, represent a hydrogen atom or an alkyl radical, or else R ₇ and R ₈ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 chain units, optionally other, is attached a heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R ₉ and R ₁₀ , identical or different, represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl, or else R ₉ and R ₁₀ form together with the nitrogen atom to which one is attached a saturated or unsaturated mono or bicyclic 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, -COalk, -COOalk, -CO-NHalk, - CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH ₂ , R _n represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxyalkyl, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens, R ₁₂ represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxyalkyl or alkyl optionally substituted by one or more halogens, or HbkR _n and R ₁₂ form together with the carbon atom to which are attached a saturated mono or bicyclic cycle 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, Ar represents a phenyl, naphthyl or indenyl radical, these various radicals being optionally substituted by one or more halogens, alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR ₁₃ R ₁₄ , -CO-NH-NR ₁₅ R ₁₆ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR ₁₅ R ₁₆ , -NR ₁₅ R ₁₆ , alkylthioalkyl, formyl, CF ₃ , OCF ₃ , Het, -O -alk-NH-cycloalkyl, SO ₂ NH ₂ , hydroxy, hydroxyalkyl, -NHCOalk, NHCOOalk, or at 2 adjacent carbon atoms with dioxymethylene, Het is a saturated or unsaturated mono or bicyclic 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 alkyl radicals, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy , nitrogen heterocycles are optionally in their N-oxide form, R ₁₃ and R ₁₄ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₃ and R ₁₄ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R ₁₅ and R ₁₆ , the same or different, represent a hydrogen atom or an alkyl radical, or m> kR ₁₅ and R ₁₆ form together with the nitrogen atom to which a saturated mono or bicyclic 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, alk represents an alkyl or alkylene radical, alkyl and alkylene radicals and moieties and alkoxy radicals and moieties having a straight or branched chain and containing 1 to 6 carbon atoms and zinc oalkilovite radicals contain 3 to 10 carbon atoms, the optical isomers of these compounds and their pharmaceutically acceptable salts with an inorganic or organic acid, with the exception of the compound for which R ₂ and R ₃ represent phenyl radicals, R ₃ represents a radical -N (R ₄₎ SO ₂ R (5 for which R ₄ represents a phenyl radical and R ₆ represents a methyl radical. A compound of formula (I) according to claim 6 for which Het is selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinolin, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyridine , thiadiazole, piperidine, piperazine, triazole, furan, tetrahydroisoquinoline, tetrahydroquinoline, these heterocycles are optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ radicals. A compound of formula (I) according to claim 6 for which Rx represents the radical -N (R ₄ ) R ₅ , -N (R ₄ ) -SO ₂ R ₆ , R ₂ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR ₇ R ₈ , hydroxyalkyl or -alk-NR ₇ R ₈ ; the heteroaromatic radical is selected from pyridyl , pyrimidyl, thiazolylB and thienyl rings, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R ₈ , -alk-NR ₉ R ₁₀ , alkylsulfonylsulfonylsulfanyl hydroxyalkyl, R ₃ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR ₇ R ₈ , hydroxyalkyl or -alk-NR ₇ R ₈ ; the heteroaromatic radical is selected from pyridyl , pyrimidyl, thiazolyl and thienyl rings, these heteroaromatics radicals may be unsubstituted or substituted with halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R _8, -aIk-NR ₉ R _10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, or hydroxyalkyl, R ₄ represents the radical -C (R _n ) (R ₁₂ ) -Het, -Het, -C (R _n ) (R ₁₂ ) -Ar, Ar or norbornyl, R ₅ represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxy, -CH ₂ Ar, -CH ₂ Het or alkyl, R ₆ represents the radical hydroxyalkyl, -alk-COOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxy, -CH ₂ Ar, -CH ₂ Het or alkyl, R ₇ and R ₈ , the same or different, represent a hydrogen atom or an alkyl radical, or else R ₇ and R ₈ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 chain units, optionally other, is attached a heteroatom selected from oxygen, sulfur and nitrogen; and 100 is optionally substituted by one or more alkyl radicals, R ₉ and R ₁₀ , the same or different, represent a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl or else ₉ and R ₁₀ form together with the nitrogen atom to which a saturated or unsaturated mono or a bicyclic 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, oxo, hydroxyalkyl, or - CO-NH ₂ , R _u represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxyalkyl, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens, R ₁₂ represents a hydrogen atom or a radical hydroxyalkyl, -alkCOOalk, -alk-CONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxyalkyl or alkyl optionally substituted by one or more halogens, or itbkRu and R ₁₂ form together with the carbon atom to which are attached to a saturated mono or bicyclic cycle 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, Ar represents a phenyl or naphthyl radical, these various radicals being optionally substituted by one or more halogens, alkyl, alkoxy, -CO-alkyl, cyano, -CONR ₁₃ R ₁₄ , alkylsulfonyl, -alk-NR ₁₅ R ₁₆ , -NR ₁₅ R ₁₆ , CF ₃ , OCF ₃ , SO ₂ NH ₂ , hydroxy, hydroxyalkyl, or at 2 101 adjacent carbon atoms with dioxymethylene, Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazolidine, furanthiolate, furanotinol, furanthiolate, furan one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ radicals, R ₁₃ and R ₁₄ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₃ and R ₁₄ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R ₁₅ and R ₁₆ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₅ and R ₁₆ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom chosen from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, the optical isomers of these compounds and their pharmaceutically acceptable salts with an inorganic or organic acid, with the exception of the compound for which R ₂ and R ₃ represent phenyl Addict, Ri represents a radical -N (R4) SO ₂ R ₆ for which R4 represents a phenyl radical and R ₆ represents a methyl radical 102 A compound of formula (I) according to claim 6 wherein R _t represents the radical -N ^ R ^ j-SO ^ R.,. R _; represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl. trifluoromethoxy, cyano, -CONR ₇ R ₈ , hydroxyalkyl or -alk-NR ₇ R _s ; the heteroaromatic radical is selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings; hydroxy, (X trifluoromethyl, trifluoromethoxy, -CONR ₇ R ₈ , or hydroxyalkyl, R ₃ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ₇ R ₈ , hydroxyalkyl or -alk-NR ₇ R ₈ ; thienyl rings, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R ₈ , or hydroxyalkyl, R ₄ represents the radical -Het or Ar, R ₆ represents a hydroxyalkyl or alkyl radical, R ₇ and R ₈ , the same or different, represent a hydrogen atom or an alkyl radical or else ₇ and R ₈ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 chain units containing possibly another heteroatom are attached selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, 10? .Ag represents a phenyl or naphthyl radical, these different radicals being optionally substituted is one or more halogens. alkyl. alkoxy-CO-alk. cyano, -CONR _l3 R _14, -alk-NR ₁₅ R _lf>. -NR ₁₅ R ₁₀ . CF-. OCF ₃ , SO _; NH ₂ . hydroxy or hydroxyalkyl. Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazole, furan, tetrahydro, tetrahydro-tetrahydro-tetrahydro-tetrahydro-tetrahydroethanol more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ radicals, R ₁₃ and R ₁₄ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₃ and R ₁₄ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R ₁₅ and R ₁₆ , the same or different, represent a hydrogen atom or an alkyl radical, or R ₁₅ and R ₁₆ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 moieties containing possibly attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, the optical isomers of these compounds and their pharmaceutically acceptable salts with inorganic or organic acid, except for the compound of which R _; and R _; are phenyl radicals, R represents the radical -N (R ₄ ) SO _; R ₀ for which R ₄ represents a phenyl radical and R 1 represents a methyl radical A compound of formula (I) according to claim 6 selected from the following compounds: N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -L- (6-chloropyrid-2-yl) methyl-sulfonamide, B1- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -B1- (6-ethylpyrid-2-yl) methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azeppidin-3-yl} -N-quinol-6-yl-methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N-quinol-5-yl-methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azeggshidin-3-yl} -N-isoquinol-5-yl-methylsulfonamide, N- {1- [Bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -1H-pyrid-3-yl-megpilsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N- (1-oxide-pyrid-3-yl) methylsulfonamide, N- (1R, 2S, 4S) -6-amino [2,2,1] xenin-2-UA-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -methylsulfonamide, 105 N- (1R.2R.4S) -6-methyl-2,2-yl] -phenyl-2-UA-N- {1- [bis- (4-chlorophenyl) megpyl] azetidin-3-yl} -methylsulfonamide. N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (3,5-difluorophenyl) methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (thiazol-2-yl) -megpylsulfonamide, N- {1- [bis- (4-chloro (x {) enyl) -methyl] azetidin-3-yl} -N- (3-methoxyphenyl) methylsulfonamide, N- {1- [bis- (4-chlorophenyl) -methyl] azeppidin-3-yl} -1H- (3-hydroxyphenyl) methylsulfonamide, N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -1H- (3-hydroxymethyl-phenyl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N- (methylsulfonyl) -3-aminobenzoate ethyl, N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) -methylsulfonamide, N-6β-3-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} amine, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N4- (3,5-difluorobenzyl) amine, N- {1- [bis (4-chloro-phenyl) megpyl] azetidin-3-yl} -CH3, 510o difluorobenzyl) methylsulfonamide, N- {1- [bis (4-oxo-xenyl) methyl] azetidin-3-yl} -L1- (pyrid-3-yl-methyl) methylsulfonamide, N- {1- [bis- (4-fluoro-phenyl) -methyl] -azetidin-3-yl} -L- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4- chlorophenyl) -pyrid-3-yl-methyl] -azeppidin-3-yl} -1H- (3,5-difluorophenyl) -methylsulfonamide, N) - N- {1 - [(4-chlorophenyl) -pyrid-3-yl-methyl] -azetidin-3-yl} -1H- (3,5-difluorophenyl) -methylsulfonamide, (8) -H- {1- [(4-chlorophenyl) -pyrid-3-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, N, 8) -N- {1 - [(4-chlorophenyl) -pyrid -4-yl-methyl] -azepidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, N) - N- {1 - [(4-chlorophenyl) -pyrid-4-yl-methyl] -azetidin-3-yl} -L- (3,5-difluorophenyl) -methylsulfonamide, (S) -H- {1- [(4-chlorophenyl) -pyrid-4-yl-methyl] -azetidin-3-yl} -1H- (3,5difluorophenyl) -methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrimidine -5-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, 107 (R) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, (S) -N- { 1 - [(4-chlorophenyl) -pyrimidin-5-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) benzylsulfonamide, their optical isomers and their pharmaceutically acceptable salts with inorganic or organic acid. 11. N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, its optical isomers and its pharmaceutically acceptable salts with inorganic or organic acid. A process for the preparation of compounds of formula (I) according to claim 6, wherein R 1 represents the radical -N (R ₄ ) R ₅ in which R ₅ is a hydrogen atom, R ₄ is a radical -CR _n R ₁₂ -Ar or -CR _U R ₁₂ -Het and R ₁₂ is a hydrogen atom, characterized in that the Rb-COR _U derivative for which R _n has the same meanings as in claim 6 reacts with a derivative of the formula: R. GHH ₂ as Rb represents the radical Ar or Het, R ₂ , R ₃ , R _n , Ar and Het IOS have the same meaning as in claim 6, the product is isolated and optionally transformed into a pharmaceutically acceptable salt. A method for preparing compounds is the formula (I) according to claim 6, wherein R 1 represents the radical -N (R 4) -CO-R ₅ in which R ₄ is a radical -C (R _lt ) (R ₁₂ ) -Het or -C (R _H ) (R ₁₂ ) -Ar and R _n is a hydrogen atom, characterized in that the Hal-COR 1 derivative reacts with a derivative of the formula: as Hal represents a halogen atom, Rb represents the radical Ar or Het, and R ₂ , R ₃ , R ₅ , R _n , Ar and Het have the same meanings as in claim 6, the product is isolated and optionally transformed into a pharmaceutically acceptable salt. A process for the preparation of compounds of formula (I) according to claim 6, wherein R 1 represents the radical -N (R ₄ ) -SO ₂ R ₆ in which R ₄ is a radical -C (R _n ) (R ₁₂ ) -Ar or -C (R _n ) (R ₁₂ ) -Het and R ₁₂ is a hydrogen atom, characterized in that the HaI-SO ₂ R ₆ derivative reacts with a derivative of the formula: R b k> 0 as R _; , R _3, Rn, R ₅ have the same meanings as in Claim 6. Hal represents a halogen atom and Rb represents a radical Ar and Het, the product is isolated and optionally converted into a pharmaceutically acceptable salt thereof. A process for the preparation of compounds of formula (I) according to claim 6, wherein R _t represents the radical -N (R 4) R ₅ wherein R ₅ (R ₄ ) NH is reacted with a derivative of formula: with R ₂ , R ₃ , R ₄ , R ₅ having the same meanings as in claim 6, the product is isolated and optionally transformed into a pharmaceutically acceptable salt. A process for the preparation of compounds of formula (I) according to claim 6, for which R _x represents the radical -N (R ₄ ) SO ₂ R ₆ characterized in that the Hal-SO ₂ R ₆ derivative reacts with a derivative with formula: NH I R4 110 as R ;, R ;. R 4 and u have the same meanings as β claim 6, and Hal represents a halogen atom, the product is isolated and optionally transformed into a pharmaceutically acceptable salt. A process for the preparation of compounds of formula (I) according to claim 6, wherein R represents a radical characterized in that the Hal-COR * derivative is reacted with a derivative of the formula: R 4 as R ₂ , R ₃ , R ₄ and R ₅ have the same meanings as in claim 6, and Hal represents a halogen atom, the product is isolated and optionally transformed into a pharmaceutically acceptable salt. A process for the preparation of compounds of formula (I) according to claim 6, wherein R 1 represents the radical -N (R ₄ ) SO ₂ -R ₆ , R ₄ is a radical Het or Ar, characterized in that the derivative Rd -NH-SO ₂ -R ₆ reacts with a derivative of the formula: or N N as Rd represents the radical Ar or Het, R _; . R _; and R4 have the same meanings as in claim 6. and Ms represents the methylsulfonyloxy radical. the product is isolated and optionally transformed into a pharmaceutically acceptable salt. 19. A process for the preparation of compounds of formula (I) according to claim 6, characterized by! with that derivative R _; -CHBr-R ₃ reacts with a derivative of the formula: HN as R 1, R ₂ and R ₃ have the same meanings as in claim 6, the product being isolated and optionally transformed into a pharmaceutically acceptable salt. A process for the preparation of compounds of formula (I) according to claim 6, wherein R _t represents the radical -N (R ₄ ) -SO ₂ -R 6 for which R ₄ is a piperid-4-yl radical substituted with alkyl by alkyl a radical characterized in that the compound of formula (I) is alkylated, for which R 1 represents the radical -N (R ₄ ) SO ₂ - R ₆ for which R ₄ is a piperid-4-yl radical, the product is isolated and transformed optionally in a pharmaceutically acceptable salt. A process for the preparation of compounds of formula (I) according to claim 6, wherein R 1 represents the radical-N (R ₄ ) -SO ₂ -R ₆ for which R ₄ is a phenyl radical substituted with the pyrrolid-1-yl radical characterized in that the pyrrolidine is reacted with a compound of formula (I), for which R1 represents a radical 112 -N (RJSCbR * for the group is a phenyl radical substituted by a halogen atom, the product is isolated and optionally transformed into a pharmaceutically acceptable salt.