BG66001B1 - Pharmaceutical compositions containing azetidine derivatives, novel azetidine derivatives and preparation thereof - Google Patents

Abstract

The invention relates to pharmaceutical compositions comprising as active ingredient at least one compound of the formula wherein R1 represents a radical -N (R4) R5, -N (R4) -CO-R5, -N (R4) -SO2R6, or one of its pharmaceutically acceptable salts, to novel derivatives of the above formula, to their pharmaceutically acceptable salts and to their preparation.

Description

Technical field

The invention relates to pharmaceutical compositions containing as active ingredient at least one compound of formula:

A

or pharmaceutically acceptable salts thereof, novel derivatives of formula (I), their pharmaceutically acceptable salts and their preparation. The compounds of formula (I) are useful in the treatment and prevention of diseases of the central nervous system, immune system, cardiovascular or endocrine system, respiratory system, gastrointestinal tract and reproductive disorders.

SUMMARY OF THE INVENTION

A compound of formula (I), for which R 1 and R ₃ represent phenyl radicals, R represents a radical -N 1 R ₄ SO 4, R ₄ represents a phenyl radical and R ₆ represents a methyl radical is described as intermediate in the synthesis of WO 1999/001451 . 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 , -NCR 4 -CO-R 2, -N (R ₄ ) -SO ₂ -R ₆ ,

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- alk, cyano, -COOH, COOalk, -CONR ₇ R ₈ , -CO-NH-NR ₉ R ₁₀ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, or hydroxyalkyl; the hetero hetero radical is selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanil, 2,3-dihydrobenzofuril, 2,3 dihydrobenzothienyl, furyl, imidazolyl, isochromanil, isoquinol, pyrrolidyl, 1, 2, 3 and thienyl ring, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOalk, -CHOH-NR ₉ R _{10 O} , -CONR 2, -alk-NR ₉ R ₁₀ , alkylsulfanyl, alkylsulfinyl, alkyl sulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl,

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

R ₅ represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONR ₇ R ₈ , -alk-NR ₁ R 1, alkoxy, Ar, Het, -CH, Ar, CH ₂ Het or alkyl optionally substituted by one or more halogens,

R ₆ represents the radical hydroxyalkyl, -alk-COOalk, -alk-CONR 6, -alk-NR 4, 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 and R 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 1 and R ₁₀ , the same or different, represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-Oalk, hydroxyalkyl, or else R 1 and R ₁₀ form together with the nitrogen atom to which they are 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,

66001 B1 hydroxyalkyl, -alk-O-alk or -CO-NH ₂ ,

R _n represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONR ₇ R ₈ , -alk-NR _? 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, -alk-COOalk, -alkCONRjRg, -alk-NRjRg, alkoxyalkyl or alkyl optionally substituted by one or more halogens, or else R _H and R ₁₂ form together with the carbon atom to which they 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 _{] 3} 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-alkylNH-cycloalkyl, SO ₂ NH ₂ , hydroxy, hydroxyalkyl, -NHCOalk, NHCOOalk or at 2 adjacent carbon atoms with dioxymethylene,

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

In the foregoing definitions, and those which follow, except to the contrary mention, 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, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 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, quinoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazolin, indole, indole, indole 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.

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 2 -SO, - ^,

R ₂ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR 1 R 8, hydroxyalkyl or

66001 Bl

-alk-NR ₇ R _g ; the heteroaromatic radical is chosen from pyridyl, pyrimidyl, thiazolyl and thienyl ring, these heteroaromatic radicals can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R _8, -alkNR ₉ R _10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, or hydroxyalkyl,

R ₃ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -COalk, cyano, -CONR 4, hydroxyalkyl or -alkNR _? R ₈ ; the heteroaromatic radical is chosen from pyridyl, pyrimidyl, thiazolyl and thienyl ring, these heteroaromatic radicals can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R _8, -alk-NR ^ R ^, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, or hydroxyalkyl,

R ₄ represents the radical -C (R ₁ ) (R 3 Het, -Het, -C (R _H ) (R _{1 2} ) -Ar, Ar or norbornyl,

R ₅ represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONR ₇ R ₈ , -alk-NR ₁ R 1, alkoxy, -CH ₂ Ar, -CH ₂ Het or alkyl,

R ₆ represents a radical hydroxyalkyl, -alk-COOalk, -alk-CONR ₇ R _8, -alk-NR ₇ R _s, alkoxy, -CHyAr, -CHjHet or alkyl,

R ₇ and R ₈ , the same or different, represent a hydrogen atom or an alkyl radical, or else R, and R _g 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 ₉ and R ₁₀ , the same or different, represent a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl, -alk-Oalk or hydroxyalkyl or else R 1 and R ₁₀ form together with the nitrogen atom to which a saturated or unsaturated atom is attached. a 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, oxo, hydroxyalkyl, or -CO-NH ₂ ,

R _H represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONR 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, -alk-COOalk, -alkCONR ₇ R ₈ , -alk-NR ₇ R ₈ , alkoxyalkyl or alkyl optionally substituted by one or more halogens, or else R _H and R _{1 2} form together with the carbon atom to which a saturated mono or bicyclic ring is attached, having 3 to 10 chain units, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals,

Ar represents a phenyl or naphthyl radical, these various radicals being optionally substituted by one or more halogens, alkyl, alkoxy, -CO-alkyl, cyano, -CONR _{] 3} R ₁₄ , alkylsulfonyl, -alk-NR ₁₅ R ₁₆ , -NR _1S R _{] 6} , 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, the nitrogen heterocycles are optionally in their N-oxide form, and in particular Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxalin, quinoline, pyrrole, pyridine, imidazine, imidazine, imidazine, imidazine, imidazine , you diazole, furan, tetrahydroisoquinoline, tetrahydroquinoline, these heterocycles being optionally substituted with 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 chain units is attached optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by

66001 Bl one or more alkyl radicals,

R ₅ and R ₁₆ , the same or different, represent a hydrogen atom or an alkyl radical, or else R ₁₅ and R ₁₆ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 units of chains containing optionally 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 4 R 4 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 ring, these heteroaromatic radicals can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R _g or hydroxyalkyl,

R ^, represent an unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, CONR ₇ R _8, hydroxyalkyl or -alk-NR ₇ R _g; the heteroaromatic radical is selected from a pyridyl, pyrimidyl, thiazolyl and thienyl ring, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR1, or hydroxy,

R ₄ represents -Het or Ar,

R ₆ represents a hydroxyalkyl or alkyl radical,

R1 and Rg, the same or different, represent a hydrogen atom or an alkyl radical, or else R1 and R4 form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 chain moieties containing optionally attached 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 _{] 3} R ₁₄ , -alkNR ₁₅ R ₁₆ , -NR _{) 5} R ₁₆ , CF ₃ , OCF ₃ , SO ₂ NH ₂ , hydroxy or hydroxyalkyl,

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, and in particular Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazolidine, furanthioline, furan are optionally substituted with 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 else 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 is attached optionally containing 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 else R ₁₅ and R ₁₆ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 chain units is attached optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals.

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

N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N- (6-chloropyrid-2-yl) -methylsulfonamide,

N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -L- (6-ethylpyrid-2-yl) -methylsulfonamide,

N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N-quinol-6-yl-methyl-sulfonamide,

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

N- {1- [bis- (4-chlorophenyl) methyl] -azetes

66001 Blah din-3-yl} -N-isoquinol-5-yl-methyl-sulfonamide,

N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -T4-pyrid-3-yl-methyl-sulfonamide,

N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -T4- (1-oxide-pyrid-3-yl) -methylsulfonamide,

N- (1R, 2S, 4S) -6hl [hexo [2,2,1] hept-2-yl-N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} methylsulfonamide,

N- (1R, 2R, 4S) -6huhuio [2,2,1] xenT-2-yl-N {1- [bis- (4-chlorophenyl) methyl] -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,

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

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

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

B1- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) methylsulfonamide,

N-6eH3Hn-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} amine,

N- {1- [bis (4-chlorophenyl) methyl] azetidin3-yl} -L- (3,5-difluorobenzyl) amine,

N- {1- [bis (4-chlorophenyl) methyl] azetidin3-yl} -N- (3,5-difluorobenzyl) methylsulfonamide,

N- {1- [bis (4-chlorophenyl) methyl] azetidin3-yl} -N- (pyrid-3-yl-methyl) -methylsulfonamide,

14- {1- [bis- (4-fluoro-phenyl) -methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, (RS) -N- {1 - [(4- chlorophenyl) -pyrid-3-ylmethyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) -pyrid-3-ylmethyl] -azetidin-3-yl} -L [- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrid-3-ylmethyl] -azetidin-3-yl} - N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) -pyrid-4-ylmethyl] -azetidin-3-yl} -L [- (3,5-difluorophenyl) ) methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) -pyrid-4-ylmethyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrid-4-yl] til] -azetidin-3-yl} -L [- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-yl-methyl] -azetidin-3-yl } -N- (3,5-difluorophenyl) -methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-yl-methyl] -azetidin-3-yl} -N- (3,5 -difluorophenyl) -methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-ylmethyl] -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.

The compounds of formula (I), for which Rj represents a radical -N / R ^ Rj, where R ₅ is a hydrogen atom, -N (R ₄₎ -CO-R _5, -N (R ₄₎ -SO ₂ R ₆ , 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:

66001 Bl

In these formulas, R ₃ , R ₆ and R _n have the same meanings as in formula (I), R b represents j 5 radicals Ar or Het, Ar and Het have the same meanings as in formula (I) and Hal represents a halogen atom and preferably chlorine or bromine.

Step a is typically carried out in an inert solvent medium 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 trial-45 kilamine (e.g. triethylamine , dipropylethylamine) or 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 and 20 ° C.

The Rb-COR _U derivatives are commercialized or can be prepared according to methods described, for example, by R. C. Larock,

66001 Bl

Coprehensive Organic Transformations, VCH editor.

The Hal-SO ₂ 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 al., 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

«3 Rj

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.

ON A

N

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 bicarbonate, 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,

66001 B1 intermediate imine is reduced in situ with sodium borohydride at a temperature between 0 ° C and the reflux temperature of the reaction medium.

The derivatives R ^ CO-Rj are commercialized or can be obtained by applying or adapting the methods described by Kunder NG et al. J. Chem. Soc. Perkin Trans 1, 2815 (1997); Moreno-Marras M., Eur. J. Med. Chem., 23 (5) 477 (1988); Skinner et al., J. Med. Chem., 10 14 (6) 546 (1971): Hum Ν. K., Tet. Lett., 36 (52) 9453 (1995); Medici A. et coll., Tet. Lett., 24 (28) 2901 (1983); Riecke R. D. et al., J. Org. Chem., 62 (20) 6921 (1997); Knabe J. et al., Arch. Pharm., 306 (9) 648 (1973); Consonni R. et coll. J. 15 Chem. Soc. Perkin Trans 1, 1809 (1996); FR-962481 et JP-94-261393.

The R ₃ Br derivatives are commercialized or can be obtained by applying or adapting the methods described by Brandsma L. et coll., Synth. Comm., 20 (11) 1967 et 3153 (1990); Lemaire M. et coll., Synth. Comm., 24 (1) 95 (1994); Goda H. et al., Synthesis, 9849 (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 al., J. Het. Chem., 29 (4) 895 (1992); Suzuki N, et al., J. Chem. Soc. Chem. Comm., 1523 (1984); Marburg S. et coll., J. Het. Chem., 17 1333 (1980); Percec V. et al., J. Oig. Chem., 60 (21) 6895 (1995).

The compounds of formula (I) for which R 1 represents the radical -N (R ₄ ) R ₅ can be prepared according to the following reaction scheme:

N-- * with R ^ RJNH N—, L a 1 ----- L.R5 2 θ 1 1s N 1 R4

In these formulas 1 ', R 1, 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 (e.g. 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, as reported by one of ordinary skill in the art, or by the 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, via the sulfapyridine trioxide complex, at a temperature close to 20 ° C or by dimethyl sulfoxide, in the presence of oxalyl chloride and triethylamine, at a temperature included between -70 ° C and -50 ° C.

The 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:

66001 Bl

Hal-SO, R. .

-

In these formulas, R _; . 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 (e.g. dichloromethane, chloroform), in the presence of an amine such as trialkylamine (e.g. 20 triethylamine), at a temperature included between 5 ° C and 20 ° C. .

The compounds of formula (I) for which R _t represents the radical -N (R ₄ ) -SO ₂ -R ₆ for which R ₄ is the radical Het or Ar can be obtained 25 by the following reaction scheme:

R.

In these formulas, R 1, 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.

Stage b usually takes place in

66001 Bl inert solvent medium 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 5 trialkylamine (eg triethylamine, dipropylethylamine) in pyridine medium , 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 ₃ , at reflux of the reaction mixture.

Derivatives for which Rd represents a nitrided N-oxide heterocycle may be non-oxidized reduced compounds according to the 15 method described by Sanghanel E. et al., Synthesis 1375 (1996).

The Rd-NH-SO ₂ R ₆ derivatives can be prepared by the following reaction scheme:

Hal-SO ₂ -R ₆

Rd-NH ₂ ------------- Rd-NH-SO ₂ -R ₆

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 medium 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. pyridine at a temperature of between 0 ° C and 30 ° C.

Derivatives for which Rd is a nitrided N-oxide heterocycle can be prepared 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-Br + R, -CHO

R-rCHOH-R.

66001 Bl

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

Step a is usually 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 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.

Compounds c formula (I), where R ^ represents a radical -N (R ₄₎ -SO ₂ -R ₆ for which R ₄ is a radical piperid-4-yl optionally substituted on the nitrogen with an alkyl radical can also be prepared by the following reaction scheme:

66001 Bl

In these formulas, R ₂ , GC 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 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 step c is carried out by hydrochloric acid, under dioxane at a temperature between 0 ° C and the boiling point 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.

The compounds of formula (I) for which R 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 obtained by treatment with pyrrolidine on a compound of formula (I), respectively, for which R 1 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 described previously, protecting groups of amino, hydroxy and carboxy functions may be introduced if necessary, u to avoid secondary reactions. These groups are those which are intended to be removed without affecting the rest of the molecule. Tert-butyl 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 threatened by Green T. W. et al., Protecting Groups in Organic Synthesis, second edition, 1991, John 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 in a herbal column according to Pirckle W. H. et al., Asymmetric synthesis, vol. 1, academic Press (1983), either by salt formation or by synthesis, starting from chiraux precursors. 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 treatment with such acid in an organic solvent medium such as an 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 the like

66001 Bl 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 tract 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 Neurophysiology 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 cord diseases, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucoma, glaucoma, Parkinson's, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, involuntary-nightmares, elderly dizziness, 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 (e.g., opiates, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines) as analgesic drugs or agents that enhance the analgesic activity of rkotic 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 CI ₅₀ of the compounds of formula (I) is less than or equal to 1000 nM.

Their antagonistic activity is 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.

Examples of carrying out the invention

Example 1

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N (6-chloropyrid-2-yl) methylsulfonamide can be prepared by the following procedure. To a solution of 1.54 g

- [bis- (4-chlorophenyl) methyl] azetidin-3-ol and 1.22 g of N- (6-chloropyrid-2-yl) methylsulfonamide, in 120 cm ³ anhydrous tetrahydrofuran, were added under argon 2.4 cm ³ ethyl azodicarboxylate and 1.44 g of triphenylphosphine. After stirring at 20 ° C for 20 h, 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), eluted under pressure of 0,5 bar from argon with a mixture of cyclohexane and ethyl acetate (80/20 in volumes) and collect fractions of 60 cm ³ . Fractions 6 to 9 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.75 g of N- {1- [6hc- (4chlorophenyl) methyl] -azetidin-3-yl} -H- (6chloropyrid-2-yl) -methylsulfonamide are obtained as a white kiss. [Spectrum R. Μ. Ν. Ή (300 MHz, CDCl ₃ , delta in ppm): 2.85 to 3.00 (mt: 2H); 2.91 (s: 3H); 3.57 (t doubled, J = 7 and

Hz: 2H); 4.25 (s: 1H); 4.64 (mt: 1H); from 7.20 to 7.35 (mt: 9H); 7.36 (dd, J = 8 and 1 Hz: 1H); 7.71 (t, J = 8 Hz: 1H)].

- [bis- (4-chlorophenyl) methyl] azetidin-3 ol can be prepared according to the method of

66001 B1, described by Katritzky A. R. et al., 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: pour dropwise dropwise to a solution cooled to + 5 ° C of 2-amino6-chloropyridine in 12.5 cm ³ pyridine. 7.8 cm < ^{3 > of} methylsulfonyl chloride for 1 h. After returning to normal temperature and stirring for 20 h, 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 (particle size 0,063-0,200 mm, height 30 cm, diameter 4 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 60 cm ³ . Fractions 5 to 11 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 17 g of L1- (6-chloropyrid-2-yl) methylsulfonamide are obtained as a yellow oil.

Example 2

N- {1- [bis- (4-chlorophenyl) methyl] azetidin3-yl} -L- (6-ethyl pyrid-2-yl) -methylsulfonamide can be prepared by working as described in Example 1, such as from 0.61 g of 1 [bis- (4-chlorophenyl) methyl] azetidin-3-ol, 0.40 g of N- (6-ethylpyrid-2-yl) methylsulfonamide, 50 cm ^{3 of} anhydrous tetrahydrofuran, 0.96 cm ^{3 of} ethyl azodicarboxylate and 0.577 g of triphenylphosphine. The crude product is 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- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N- (6-ethylpyrid-2-yl) -methylsulfonamide are obtained as a white solid. [RMN Ή spectrum (300 MHz, CDCl ₃ , delta in ppm): 1.26 (t, J = 7.5 Hz: 3H); 2.76 (q, J = 7.5 Hz: 2H); from 2.85 to 2.95 (mt: 2H); 2.90 (s: 3H); 3.53 (t split, J = 7 and 2 Hz: 2H); 4.22 (s: 1H); 4.69 (mt: 1H); 7.07 (d, J = 7.5 Hz: 1H); from 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 of 2-amino-6-ethylpyridine in 2.50 cm ³ pyridine , 1.56 cm ^{3 of} methylsulfonyl chloride was poured dropwise. After stirring at 20 ° C for 20 h, 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 is 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 1 dichloromethane, then with a mixture of dichloromethane and methanol (98 / 2 in 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). 2.8 g of L1- (6-ethylpyrid-2-yl) methylsulfonamide are obtained as a yellow oil.

Example 3

B1- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L1-quinolyl-6-yl-methylsulfonamide can be prepared by working as follows: to a solution of 0.50 g of N -quinolyl-6-ylmethylsulfonamide in 50 cm < ³ & gt ^{; 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 azodicarboxyl. After stirring at 20 ° C for 20 h, the reaction mixture was heated to reflux temperature for 4 h, then 2.98 g of triphenylphosphine and 2.0 cm ^{3 of} diethyl azodicarboxylate were added. After stirring at 20 ° C for 48 h, the mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was taken up with 30 cm ^{3 of} diethyloxide, the resulting suspension filtered, the filtrate concentrated to dryness. One fraction of the residue obtained (0.90 g) was purified on a column

66001 Bl

Bond Elut with SCX cation exchange resin Sulfonic Acid (0,054 mm granulometry, height 4 cm, diameter 3 cm), eluted first with methanol then with 2M ammonia solution in methanol to elute the expected product, 5 cm fractions were collected ³ . 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 min the solid be dried at 50 ° C under reduced pressure (2.7 kPa). 83 mg of N- (1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinolyl-6-ylmethylsulfonamide are obtained as a white solid. [Spectrum RMN Ή (300 MHz, CDCI) ₃ , delta 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); 7.15 to 7.30 (mt: 8H); 7.47 (dd, J =

8.5 and 4 Hz: 1H); 7.58 (dd, J = 9 and 2.5 Hz: 1H); 7.73 (d, J = 2.5 Hz: 1H); 8.10 to 8.20 (mt: 2H); 8.97 (dd, J = 4 and 1.5 Hz: 1H) J.

N-quinolyl-6-yl-methylsulfonamide can be prepared by the following procedure: pour a solution dropwise to + 3 ° C at 1.98 g 6aminoquinoline in 1.75 cm ³ pyridine. 1 h 1,1 cm ³ methylsulfonyl chloride. After stirring at 20 ° C for 20 h, 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 quinolyl-6-yl-methylsulfonamide are obtained as a creamy yellow solid.

Example 4

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L-quinolyl-5-yl-methylsulfonamide can be prepared by working as follows: to a solution of 0.50 g b1 -quinolyl-5-ylmethylsulfonamide in 70 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 azodicarboxyl are poured 0.45 g of 1,2-bis (diphenylphosphine) ethane. After stirring at 20 ° C for 20 h, the reaction mixture was concentrated 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 dry 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 fractions of 50 cm ³ 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 [deg.] C. under reduced pressure (2.7 kPa). 0.35 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinolyl-5-yl-methylsulfonamide are obtained as a white solid. [RMN spectrum Ή (300 MHz, CDCl ₃ , delta 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 and 2.5 Hz: 1H); 3.56 (t split, J = 7 and 2.5 Hz: 1H); 4.01 (s: 1H); 4.85 (mt: 1H); from 7.10 to 7.25 (mt: 8H); 7.40 (dd, J = 7.5 and 1 Hz: 1H); 7.54 (dd, J = 8.5 and 4 Hz: 1H); 7.74 (dd, J = 8 and 7.5 Hz: 1H); 8.20 (d width, J = 8 Hz: 1H); 8.54 (d width, J = 9 Hz: 1H); 8.99 (dd, J = 4 and 1.5 Hrz: 1H)].

14- (quinol-5-yl) methylsulfonamide can be prepared by working as described in Example 3, starting from 2.0 g of 5-aminoquinoline, 3.0 cm ³ pyridine, 1.1 cm ³ methylsulfonyl chloride . 2.47 g of b1- (quinol-5yl) methylsulfonamide are obtained as a yellow brown solid.

Example 5

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-isoquinol-5-yl-methylsulfonamide can be prepared by working as described in Example 4, starting from 0.497 g b1- (isoquinol-5-yl) -methylsulfonamide, 70 cm ³ anhydrous tetrahydrofuran, 0.712 g 1- [bis-4-chlorophenyl) methyl] azetidin-3-ol, 0,597 g triphenylphosphine, 0,40 cm ³ 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), eluting with a mixture of

66001 B1 cyclohexane and ethyl acetate (30/70 in volumes) and fractions of 40 cm ³ were collected. Fractions 8 to 23 were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was stirred in 15 cm < ^{3 > of} diethyloxide, the suspension was 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 fractions of 20 cm ³ 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- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -T9-isoquinol-5-yl-methylsulfonamide are obtained as a white solid. [RMN spectrum Ή (300 MHz, CDCl ₃ , delta 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 and 2 Hz: 1H); 3.55 (t split, J = 7 and 2 Hz: 1H); 4.02 (s: 1H); 4.86 (mt: 1H); from 7.10 to 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 = 6 Hz: 1H); 9.32 (s 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 aminoquinolein, 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] azetidin3-yl} -N-pyrid-3-yl-methylsulfonamide can be prepared by working as follows: to a solution of 0.144 g of H- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-oxide-pyrid3-yl) -methylsulfonamide in 5 cm < ³ & gt ^; chloroform, poured 0.042 cm < ^{3 > of} phosphorus trichloride, then the mixture was heated to reflux temperature. After stirring for 1 h and 30 min, the reaction mixture was allowed to return to normal temperature, then 5 cm ³ hydrochloric acid 0.1 N was added, then stirred and decanted. The organic phase was diluted with 20 cm < ³ & gt ^{; 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} diethyloxide, the suspension filtered, the solid drained, then dried under reduced pressure (2.7 kPa). 35 mg of L1- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-pyrid-3-ylmethylsulfonamide are obtained in the form of a cream solid. [RMN spectrum 300 (300 MHz, CDCl ₃ , delta 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); from 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} -T4- (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-3-ol and 0.162 g of N- (1-oxide-pyrid-3-yl) methylsulfonamide in 25 cm ^{3 of} anhydrous tetrahydrofuran are added under argon 0 , 16 cm ^{3 of} diethyl azodicarboxylate and 0.226 g of triphenylphosphine. After stirring at 20 ° C for 20 h, then refluxing for 24 h, the reaction mixture was concentrated under reduced pressure (2.7 kPa). The residue is 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 in volumes). and fractions of 40 cm ³ 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- [6hc (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-oxide-pyridin-3-yl) -methylsulfonamide are obtained.

66001 Bl as a white solid. [RMN spectrum Ή (400 MHz, (CD ₃ ) ₂ SOd ₆ , delta 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); from 7.30 to 7.50 (mt: 10H); 8.21 (d broad, J = 6.5 Hz: 1H); 8.27 (broad: 1H)].

N- (1-oxide-pyrid-3-yl) methylsulfonamide can be prepared by working as follows: to a solution of 1.81 g of N-pyrid-3-ylmethylsulfonamide, in 71 cm ³ Ν, Ν-dimethylformamide and 3 cm ^{3 of} 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 h, 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 0,0630,2 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 this 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-oxide-pyrid-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 resulting crude product was stirred in 40 cm < ^{3 > of} diethyloxide, the suspension filtered, then the solid was drained and dried under reduced pressure (2.7 kPa). 2.47 g of N-pyrid-3-yl-methylsulfonamide are obtained as a pink solid.

Example 8

N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} N -cyclohexyl-methylsulfonamide can be prepared by working as follows: to a solution of 1.8 g of N- {1- [6hc- (4-chlorophenyl) methyl] azetidin-3-yl-N-cyclohexylamine, and 0.7 cm ^{3 of} triethylamine and 20 mg of 4-dimethylaminopyridine in 25 cm ^{3 of} dichloromethane were added with stirring 0.4 cm ^{3 of} methylsulfonyl chloride. After stirring at 20 ° C for 48 h, 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 (0.063-0.2 mm granulometry, 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 ³ were collected. Fractions 7 to 10 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.10 g of N- {1- [6hc- (4chlorophenyl) -methyl] azetidin-3-yl} N-cyclohexyl-methylsulfonamide are obtained as a cream kiss. [RMN spectrum 300 (300 MHz, CDCl ₃ , delta in ppm): 0.80 to 1.90 (mt: 10 H); 2.82 (s: 3H); 3.36 (broad t, 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); from 7.20 to 7.40 (mt: 8H)].

No. {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -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 ^{3 of} dichloro-1,2-ethane, 0.5 g of cyclohexylamine, 1 g of sodium triacetoxyborohydride and 0.3 cm ^{3 of} acetic acid 100% are added. After stirring at 20 ° C for 20 h, 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 dry at 50 ° C under reduced pressure (2.7 kPa). 1.8 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} N -cyclohexylamine are obtained in the form of a cream paste which is used as is in the next step.

1- [bis- (4-chlorophenyl) methyl] azetidin-3one can be prepared as follows:

66001 Bl Work: To a solution of 5.0 cm ³ oxalyl chloride in 73 cm ³ dichloromethane cooled to -78 ° C, a solution of 8.1 cm ³ dimethyl sulfoxide in 17.6 cm ³ dichloromethane was added. After 0.5 h at -78 ° C, pour a solution of 16.0 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol dissolved in 50 cm ^{3 of} dichloromethane. After 5 h at-78 ° C, 26.6 cm ^{3 of} triethylamine was added dropwise and the reaction was allowed to return to room temperature. After 16 h, 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 resulting residue was chromatographed on a silica gel column (particle size 0,04-0,06 mm, height 21 cm, diameter 9,2 cm), pressurized with 0,5 bar of argon, eluting with a mixture of ethyl acetate and cyclohexane (40 / 60 in volumes) and fractions of 200 cm ³ were collected. 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] azetidin3-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} -L-cyclopropyl-methylsulfonamide can be prepared by working as described in Example 8, starting from 1.6 g N {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -Ncyclopropylamine, 25 cm ³ dichloromethane, 0.7 cm ³ triethylamine, 20 mg 4-dimethylaminopyridine and 0.4 cm ³ methylsulfonyl chloride, such as the mixture was stirred for 20 h 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 were 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} -L-cyclopropylmethylsulfonamide are obtained in the form of a cream kiss. [RMN spectrum (300 MHz, CDCl ₃ , delta) 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); from 7.20 to 7.40 (mt: 8H)].

B [- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl) -N-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 @ ³ acetic acid 100%. 1.6 g of N {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} N-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) -6hiuhoio [2,2,1] hept-2-yl-N {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonamide may be obtained by working as described in Example 8, starting from 2 g of N- (1R, 2S, 4S) -6huhkho [2,2,1] hept-

2- roi-N- {1- [bis- (4-chlorophenyl) methyl] azetidine-

3-yl} amine, 25 cm < ³ > of dichloromethane, 0.7 cm < ^{3 > of} triethylamine, 20 mg of 4-dimethylaminopyridine and 0.4 cm < ^{3 > of} methylsulfonyl chloride, stirring for 20 h. The brown oily residue was chromatographed on a silica gel column (0.063-0.2 mm granulometry, height 30 cm, 2.0 cm diameter), 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 is 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 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] hept-2-yl-b1- {1- [bis- (4chlorophenyl) -methyl] azetidin-3-yl} methylsulfonamide are obtained , in the form of cream

66001 Bl kiss. [RMN spectrum 300 (300 MHz, CDCl ₃ , delta in ppm): 1.20 to 1.75 (mt: 7H); 1.84 (t broad, J = 12.5 Hz: 1H); 2.29 (mt 1H); 2.35 (mt: 1H); 2.82 (s: 3H); from 3.35 to 3.55 (mt: 3H); 3.66 (mt: 1H); from 3.90 to 4.05 (mt: 2H); 4.51 (s: 1H); from 7.20 to 7.45 (mt: 8H)].

N- (1R, 2S, 4S) -6huhioio [2,2,1] hept-2-yl-N {1- [bis- (4-chlorophenyl) methyl] azetidin-3yl} amine, can be prepared as is operated as described in Example 8, starting from

1.5 g 1- [bis- (4-chlorophenyl) methyl] azetidin-3one, 25 cm ³ dichloro-1,2-ethane, 1.5 g (1R, 2S, 4S) bicyclo [2,2,1] heptyl-2-amine, 1 g sodium triacetoxyborohydride and 0.3 cm ³ acetic acid 100%. 2 g of N- (1R, 2S, 4S) bicyclo [2,2,1] hept-2-yl-N- {1- [bis- (4chlorophenyl) methyl] azetidin-3-yl} amine are obtained in the form of brown oil that is used as it is in the next step.

Example 11

N- (1 R, 2S, 4S) -6-chloro [2,2, 1] hept-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) -6mjHwio [2,2,1] xenT-

2-yl-L1- {1- [bis- (4-chlorophenyl) methyl] azetidine-

3-yl} amine, 25 cm ³ dichloromethane, 0.7 cm ³ triethylamine, 20 mg 4-dimethylaminopyridine and 0.4 cm ³ methylsulfonyl chloride, and stirred for 20 h. 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 0,0630,2 mm, height 30 cm, diameter 2 cm), eluted under pressure of 0.1 bar of 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) -6huhoxy [2,2,1] xenT-2-wi-N- {1 [bis- (4-chlorophenyl) methyl] azetidine-3- are obtained or methylsulfonamide, in the form of a yellow kiss. [RMN spectrum 300 (300 MHz, CDCl ₃ , delta in ppm): 1.00 to 1.85 (mt: 8H); 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) -6hichiolo [2,2, 1] hept-2-yl-b1 {1- [bis- (4-chlorophenyl) methyl] azetidin-3yl} amine, can be prepared as is operated as described in Example 8, starting from

1.5 g 1- [bis- (4-chlorophenyl) methyl] azetidin-3one, 25 cm ³ dichloro-1,2-ethane, 0.6 g (1R, 2R, 4S) bicyclo [2,2,1] heptyl-2-amine, 1 g sodium triacetoxyborohydride and 0.3 cm ³ acetic acid 100%. 1.8 g of N (1R, 2R, 4S) -6huiolo [2,2,1] xenT-2-wi-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} are obtained amine, in the form of a cream paste, which is used as it is in the next step.

Example 12

B1 - [(1-benzhydryl) azetidin-3-yl] -N-phenyl-methylsulfonamide can be prepared by proceeding in the following way: to a solution of 2 g of 1-benzhydryl 3-anilino azetidine in 40 cm ³ of dichloromethane, are poured 0.7 cm ^{3 of} methylsulfonyl chloride, then 1.34 cm ^{3 of} triethylamine are added. After stirring at 20 ° C for 4 h and 15 min, the reaction mixture was washed twice with 20 cm ^{3 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 (particle size 0.0630.2 mm, height 26 cm, diameter 3.6 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 50 cm ³ 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 N, N - [(1-benzhydryl) azetidin3-yl] -1H-phenyl-methylsulfonamide, is obtained as a white solid. [RMN spectrum 300 (300 MHz, (CD ₃ ) ₂ SOd ₆ with a few drops of CD ₃ COOD d4, delta in ppm): 2.72 (mt: 2H); 2.92 (s: 3H); 3.36 (mt: 2H); 4.32 (s: 1H); 4.73 (mt: 1H); from 7.10 to 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

66001 B1 azetidin-3-one, 1.92 cm ³ aniline, 74 cm ³ dichloro 1,2-ethane, 6.3 g sodium triacetoxyborohydride and 1.2 cm ³ 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] azetidin3-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 of b1- (3,5-difluorophenyl) methylsulfonamide in 25 cm ³ dioxane were added 1.0 g of cesium carbonate. After stirring at reflux temperature for 5 h, after 20 h 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 cm ³ were 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 of argon with a mixture of cyclohexane and ethyl acetate (65/35 in volumes) and fractions of 5 cm ³ were collected. Fraction 7 was concentrated to dryness under reduced pressure (2.7 kPa). 0.11 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3yl} -N- (3,5-difluorophenyl) -methylsulfonamide are obtained in the form of a white powder. [RMN spectrum Ή (300 MHz, CDCl ₃ , delta in ppm): 2.82 (s: 3H); 2.85 (mt: 2H); 3.52 (t split, J = 7 and 2 Hz: 2H); 4.22 (s: 1H); 4.47 (mt: 1H); from 6.75 to 6.90 (mt: 3H); from 7.20 to 7.35 (mt: 8H)].

Method 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 in 100 cm ^{3 of} anhydrous tetrahydrofuran were added under argon 0.78 cm ^{3 of} diethyl azodicarboxylate, and 1.31 g of triphenylphosphine. After 16 h stirring at

At 300 DEG C., 300 cm @ ^{3 of} ethyl acetate was added, the reaction mixture was washed twice with 100 cm @ ^{3 of} water, dried over magnesium sulfate and concentrated in dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0,020-0,063 mm, height 50 cm, diameter 4 cm), eluted under pressure of 0,6 bar from argon with a mixture of cyclohexane and ethyl acetate (75/25 in volumes) and collected. fractions of 125 cm ³ . 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 by volume), 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} -N (3,5-difluorophenyl) -methylsulfonamide in the form of white melting crystals at 154 ° C.

B1- (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 of} dichloromethane, slowly add 2 cm ^{3 of} methyl sulfonyl chloride, 3,8 cm ^{3 of} triethylamine and 20 mg of 4-dimethylaminopyridine. After stirring at 20 ° C for 20 h, 20 cm ^{3 of} dichloromethane and 20 cm ^{3 of} water were added to the reaction mixture, stirred and 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 B1- (3,5-difluorophenyl) methylsulfonamide are obtained as a white powder.

1- [bis (4-chlorophenyl) methyl] azetidin-3yl or 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 dichloromethane, added under argon for 10 min 3.5 cm ³ methylsulfonyl chloride, then cooled to + 5 ° C and poured 3.8 cm ³ pyridine for 10 min. After 30 min stirring at + 5 ° C,

66001 B1 then 20 h at 20 ° C, 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 100 cm ³ fractions were collected. Fractions 4 to 15 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 6.8 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl methylsulfonate are obtained in the form of a yellow oil.

- [bis (4-chlorophenyl) methyl] azetidin-3 ol can be prepared according to the method described in Katritzky A. R. et al., 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] azetidin3-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

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (4,6-dimethylpyrimid-2-yl) methylsulfonamide can be prepared by working as described in Example 13 (method 2) starting from 0.20 g of H- (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 mm, height 50 cm, diameter 2 cm), pressure was eluted with 0.6 bar of argon with dichloromethane, then with a mixture of dichloromethane +1% methanol, then with a mixture of dichloromethane + 2% methanol and 200 cm ³ fractions were collected, fractions 4 to 7 were combined and concentrated to dryness under reduced pressure (2.7 kPa). Crystallization in diisopropyl ether, filtration and drying afforded 0.20 g of L1- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (4,6-dimethylpyrimid-2yl) - methylsulfonamide as a white solid. [RMN Spectrum 300 (300 MHz, CDCl ₃ , delta 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); from 7.20 to 7.35 (mt: 8H) J.

N- (4,6-dimethylpyrimid-2-yl) -methylsulfonamide can be prepared by working as follows: to a mixture of 1.23 g of 2-amino4,6-dimethylpyrimidine, 0.77 cm ^{3 of} methylsulfonyl chloride and 50 mg of 4-dimethylaminopyridine dissolved in 50 cm ^{3 of} dichloromethane add 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 < ³ > 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

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (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-2yl) -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-2yl) -methylsulfonamide in the form of a white solid. [RMN spectrum 300 (300 MHz, CDCl ₃ , delta in ppm): 3.01 (s: 3H); 3.09 (t

66001 B1 fork, J = 7 and 1.5 Hz: 2H); 3.70 (t split, J = 7 and 1.5 Hz: 2H); 4.28 (s: 1H); 4.76 (mt: 1H); from 7.20 to 7.35 (mt: 8H); 9.01 (s: 1H)].

N- (1,3,4-thiadiazol-2-yl) -methylsulfonamide can be prepared by working as follows: to a mixture of 2.02 g of 2-amino-1,3,4-thiadiazole in 10 cm ^{3 of} pyridine 1.5 cm ^{3 of} methylsulfonyl chloride are added. After 2 h at room temperature, 60 cm ^{3 of} water was added and the reaction mixture was filtered. The combined aqueous phase was acidified to pH = 2 with hydrochloric acid 1N, extracted twice with 50 cm ³ ethyl acetate, the organic phase washed twice with 50 cm ³ 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] azetidin3-yl} -N- (thiazol-2-yl) -methylsulfonamide can be prepared by working as described in Example 15, starting from 0.50 g L-thiazole-

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), pressure eluted 0.9 bar of argon with 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 in diisopropyl ether, filtration and drying afforded 0.21 g of N- {1 [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N (thiazol-2-yl) -methylsulfonamide in the form of white solid. [RMN Ή spectrum (300 MHz, CDCl ₃ , delta 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)].

B1- (Thiazol-2-yl) -methylsulfonamide can be prepared by the following procedure: To a mixture of 1.0 g 2-aminothiazole in 5 cm ³ pyridine, 1.15 g methylsulfonyl chloride is added. After 2 h at room temperature, 20 cm ^{3 of} water was added, the reaction medium was filtered and the solid collected (0.35 g). The combined aqueous phase was acidified to pH = 2 with hydrochloric acid 1N, extracted twice with 40 cm ³ ethyl acetate, the organic phase washed twice with 30 cm ³ water, dried over magnesium sulfate, filtered then evaporated to dry under reduced pressure (2.7 kPa). 0.15 g of a white solid are obtained with spectral characteristics close to the filtered solid corresponding to a mixture of L-thiazole-

2-yl) -methylsulfonamide and b1- (thiazol-2-yl) di (methylsulfonyl) imide, which is used as it is for the next step.

Example 17

N- {1- [bis- (4-chlorophenyl) -methyl] -azetidin-3-yl} -N- (3-hydroxyphenyl) -methylsulfonamide can be prepared by working as follows: to a mixture of 0.5 g N- {1- [6hc- (4-chlorophenyl) -methyl] -azetidin-3-yl} -B [- (3-methoxyphenyl) -methylsulfonamide in 20 cm < ³ > ³ a 1M solution of boron tribromide. After 20 h 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 recovered in acetonitrile, filtered and dried to give 0.20 g of a white solid. [RMN spectrum Ή (300 MHz, CDCl ₃ , delta 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 (mt: 1H); from 6.70 to 6.85 (mt: 3H); from 7.15 to 7.35 (mt: 9H) J.

Example 18

N- {1- [bis- (4-chlorophenyl) -methyl] -azetidin-3-yl} -N- (3-methoxyphenyl) -methyl sulfonamide can be prepared by working as described in Example 15, such as is obtained from 1.58 g of N- (3-methoxyphenyl) -methylsulfonamide and 2.0 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3ol. After chromatography on a silica gel column (particle size 0,06-0,04 mm, 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 fractions of 100 cm ³ 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, yielded 0.21 g of N

66001 B1 {1- [Bis- (4-chlorophenyl) -methyl] -azetidin-3-yl} T4- (3-methoxyphenyl) -methylsulfonamide.

N- (3-methoxyphenyl) methylsulfonamide can be prepared by proceeding in the following way: to a mixture of 5,0 g 3-methoxyaniline in 150 magazine ³ of pyridine are added at 3 ° C, 3,14 cm ³ methylsulfonyl chloride . After 20 h 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 ³ 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 L1- (3-methoxyphenyl) methylsulfonamide as an orange oil.

Example 19

N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N- (3-hydroxymethyl-phenyl) methylsulfonamide can be prepared by working as follows: to a mixture of 0.5 g ethyl b1- (1- [bis- (4-chlorophenyl) -methyl] -azetidin-3-yl} -B1- (methylsulfonyl) -3-aminobenzoate in 20 cm ^{3 of} toluene, dropwise added at -50 ° C. 1.46 cm ³ toluene solution of 20% diisopropylaluminum hydride After 1.5 h at 0 ° C and 1.5 h at 10 ° C, the reaction mixture was cooled to 0 ° C and 20 cm ^{3 of} water was slowly added. filtering the precipitate and extraction with ethyl acetate, the organic phase was washed 2 times 80 cm @ ^{3 of} water and then 80 cm ^{3 of} n saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2.7 kPa) to give 0.46 g of oil, 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 of argon with ethyl acetate / cyclohexane 40/60 mixture in volumes and fractions of 20 cm ³ were collected, fractions 72 to The 76 were combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.20 g of N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N- (3-hydroxymethylphenyl) -methylsulfonamide are obtained as a white solid. [RMN spectrum Ή (300 MHz, CDCl ₃ , delta in ppm): 1.80 (mt: 1H); 2.83 (s: 3H); 2.87 (mt: 2H); 3.52 (mt: 2H); 4.21 (s broad: 1H); 4.60 (mt: 1H); 4.74 (d broad, J = 4 Hz: 2H); from 7.10 to 7.45 (mt: 12H) J.

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 1.58 g ethyl b1- (methylsulfonyl) -3aminobenzoate and 2.0 g 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), elute under pressure 0,7 bar of argon with ethyl acetate / cyclohexane 50/50, then 40/60 in volumes and fractions of 100 cm ³ were collected, fractions 7 to 10 were combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 2.0 g of a yellow oil.

Ethyl 1- (methylsulfonyl) -3-aminobenzoate can be prepared by the following procedure: to a mixture of 5.0 g of ethyl 3-aminobenzoate in 150 cm ^{3 of} pyridine are added at 3 ° C, 2.35 cm ^{3 of} methyl sulfonyl chloride. After 20 h at room temperature, 200 cm ^{3 of} water were added and 400 cm ^{3 of} ethyl acetate 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 (particle size 0,06-0,04 mm, height 25 cm, diameter 7,8 cm), elute under pressure 0,7 bar of argon with ethyl acetate / cyclohexane 25/75 in volumes and fractions of 100 cm ³ 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 b1- (methylsulfonyl) -3-aminobenzoate as an orange oil .

Example 21

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L- (1-isobutyl-piperid-4-yl) methylsulfonamide can be prepared by working as follows: to a solution of 0.47 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3

66001 Byl} -> 1- (piperid-4-yl) -methyl sulfonamide in 20 cm ³ dichloromethane, 0.11 cm ³ isobutyraldehyde, 0.057 cm ³ acetic acid 100% and 320 mg sodium triacetoxyborohydride are added. After stirring at 20 ° C for 20 h, 50 cm ^{3 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 L1- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) -methylsulfonamide are obtained in the form of a white kiss. [RMN spectrum 300 (300 MHz, CDCl ₃ , delta in ppm): 0.87 (d, J = 7 Hz: 6H); from 1.60 to 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); from 7.20 to 7.40 (mt: 8H)].

N- {1- [bis- (4-chlorophenyl) methyl] azetidine-

3-yl} -Spiperid-4-yl) -methylsulfonamide can be prepared by working as follows: to a solution of 19 g of b1- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} - N- (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 at 20 ° C for 20 h, 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 sodium hydroxide 4N, 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- [bis- (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] azetidine-

3-yl} -N- (1-tert-butoxycarbonylpiperid-4yl) -methylsulfonamide can be prepared by working as follows: to a solution of 14.7 g of 4- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylamino} - (1-tert-butoxycarbonyl) -piperidine in 250 cm ³ dichloromethane, 4.60 cm ³ methylsulfonyl chloride was slowly added, then 4.60 cm ³ triethylamine and 100 mg 4-dimethylaminopyridine. After stirring at 20 ° C for 20 h, 200 cm ^{3 of} saturated aqueous sodium bicarbonate solution was added to the reaction mixture, then stirred for 30 min 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 h, 200 cm ^{3 of} saturated aqueous sodium bicarbonate solution was added to the reaction mixture, then stirred for 30 min 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} -L- (1-tert-butoxycarbonylpiperid-4-yl) -methylsulfonamide are obtained in the form of a cream kiss, which is used as is in the next step.

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 were added to the mixture cooled to + 5 ° in two portions, then 1.72 cm ^{3 of} acetic acid was poured 100%. Next

66001 Bl h stirring at 20 ° C, 500 cm ^{3 of} saturated aqueous sodium bicarbonate 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-3ylamino} - (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-benzyl-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 15 cm ^{3 of} dichloromethane are added, at room temperature under an argon atmosphere, 0.134 cm ^{3 of} benzaldehyde. The mixture was cooled to about 0 ° C before the gradual addition of 382 mg of sodium triacetoxyborohydride, then 70 mm ^{3 of} acetic acid. After stirring at room temperature for 16 h, the mixture was poured onto 50 cm ^{3 of} saturated aqueous sodium bicarbonate solution, then extracted twice with 25 cm ^{3 of} dichloromethane, stirred well and decanted. The organic phase was combined and dried over magnesium sulfate, filtered, 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 as a colorless oil. [RMN Ή spectrum (300 MHz, CDCl ₃ , delta 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); from 7.20 to 7.40 (mt: 13H)].

1- [bis- (4-chlorophenyl) methyl] azetidin-3yl-amine can be prepared as follows: to 27 g of 1- [bis- (4-chlorophenyl) methyl] azetidine-

3-yl methylsulfonate, contained in an autoclave pre-cooled to about -60 ° C, was added 400 cm ^{3 of a} mixture of methanol and liquid ammonia (50/50 in volumes). The reaction mixture was then stirred at 60 ° C for 24 h, then left free to air to allow ammonia to evaporate and finally concentrated under reduced pressure (2.7 kPa). The residue is recovered with 500 cm ³ aqueous solution

0,3 7N sodium hydroxide and extracted four times with 500 cm @ ^{3 of} ethyl ether. The combined organic phases were washed twice successively with 100 cm ^{3 of} distilled water and 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-6eH3nn-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -methylsulfonamide: to a solution of 120 mg of N-6eH3Hn-N- {1- [6nc- (4chlorophenyl) methyl] azetidin-3-yl} amine in 5 cm < 3 > dichloromethane was 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 h. 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

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) amine can be obtained as in Example 22, but using 188 mg of 3.5 difluorobenzaldehyde and 369 mg of 1- [bis- (4-chlorophenyl) methyl] azetidin3-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. [Spectrum R.M.N. Ή (300 MHz, CDCl3, δ in ppm): 2.73 (mt: 2H); from 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); from 7.20 to 7.35 (mt: 8H)].

66001 Bl

Example 25

N- {1- [bis- (4-chlorophenyl) methyl] azetidin3-yl} -N- (3,5-difluorobenzyl) methylsulfonamide

To a solution of 433 mg of N- {1- [6hc- (4chlorophenyl) methyl] azetidin-3-yl} -N- (3,5difluorobenzyl) amine in 30 cm ³ dichloromethane was added at room temperature under an argon atmosphere, 347 mm 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 h. 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 taken up in methanol solution in a Bond Elut® SCX cartridge (10 g), 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 N {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N (3,5-difluorobenzyl) methylsulfonamide are thus obtained in the form of a cream-colored kiss. [RMN spectrum Ή (300 MHz, CDCl ₃ , delta 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 (tt, J = 9 and 2 Hz: 1H); 6.95 (mt: 2H); 7.25 (mt: 8H) J.

Example 26

N- {1- [bis- (4-chlorophenyl) methyl] azetidin3-yl} -N- (3,5-difluorobenzyl) acetamide

To a solution of 2 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (3,5-difluorobenzyl) amine in 75 cm ^{3 of} dichloromethane were added at room temperature under an atmosphere of argon, 1.6 cm ³ 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 h. The reaction mixture was diluted with 50 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 (98/2 by volume)]. 1.2 g of N- {1- [6hc (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5difluorobenzyl) acetamide are obtained in the form of a colorless oil. [RMN spectrum 300 (300 MHz, CDC1 ₃ , delta 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

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

To a solution of 398 mg of N- {1- [6hc- (4chlorophenyl) methyl] azetidin-3-yl} -14- (pyrid-4ylmethyl) amine in 8 cm ³ dichloromethane was added at room temperature under an argon atmosphere, 346 mm ³ triethylamine. The mixture was cooled to about 0 ° C before 155 mm ^{3 of} 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- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-4-yl-methyl) -methylsulfonamide are obtained in the form of a cream-colored kiss. [RMN Ή spectrum (300 MHz, CDCl ₃ , delta 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); from 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, then 70 mm ^{3 of} acetic acid. After 72 h stirring at room

66001 B1 the mixture was poured onto 100 cm ^{3 of} saturated aqueous sodium bicarbonate solution, then extracted twice with 100 cm ^{3 of} 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 (10 g), 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- [6hc (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (pyrid-

4-yl-methyl) amine 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 operated according to the operating method of Example 27, but proceeded from 380 mg of N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -14- (pyrid3-yl-methyl) amine to afford 319 mg of N {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} N- (pyrid-3-yl-methyl) -methylsulfonamide are obtained in the form of a cream-colored kiss. [RMN spectrum Ή (300 MHz, CDCl ₃ , delta in ppm): 2.80 (s: 3H); 3.02 (t split, J = 7 and 1.5 Hz: 2H); 3.38 (t split, J = 7 and 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 and 5 Hz: 1H); 7.80 (d broad, J = 8 Hz: 1H); 8.57 (dd, J = 5 and 1.5 Hz: 1H); 8.63 (d broad, J = 1.5 Hz: 1H)].

Example 30

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

Example 31

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1,1-dioxo-1-lambda ^6- benzo [b] isothiazol-3-yl) -amine

To 386 mg of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl methane sulfonate in the form of a solution of 10 cm ³ dimethylformamide was added 182 mg 1,1-dioxide of 1,2-benzisothiazole-3-amine and 326 mg of cesium carbonate. The reaction medium was then stirred at 100 ° C for 9 h, then concentrated under reduced pressure (2.7 kPa). The residue was washed four times with 5 cm ^{3 of} boiling distilled water, disaggregated by stirring in 5 cm ^{3 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} -N- (1,1-dioxo-1H-lambda ^6- benzo [6] isothiazol-3-yl) -amine are obtained in the form of a viscous product. [RMN spectrum Ή (300 MHz, CDCl ₃ , delta in ppm): 3.17 (mt: 2H); 3.61 (t broad, J = 7.5 Hz: 2H); 4.37 (s: 1H); 4.75 (mt: 1H); from 6.30 to 6.40 (mt: 1H); from 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} -L- (3,5-difluorophenyl) -N'-tert-butyloxycarbonylsulfamide can be obtained as follows: to a solution of 0,095 cm ³ tertsbutilov alcohol in 2 cm @ ³ of anhydrous dichloromethane was added 0,048 cm ³ chlorosulfonylisocyanate after 2 min stirring was added sequentially, 0,21 g Y1-1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - N- (3,5-difluorophenyl) -amine in 1.25 cm ^{3 of} anhydrous dichloromethane, then 0.084 cm ^{3 of} triethylamine. After stirring for 1 hour at a temperature close to 20 ° C, 2 cm ^{3 of} saturated sodium bicarbonate solution was 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 cm ³ ) filled with 3 g of fine silica (0.040-0.063 mm), provided it was then eluted with a petroleum ether-ethyl acetate mixture using a pump.

66001 Bl

Duramat, collecting fractions of 2 cm ³ . Fractions 6 to 17 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C for 2 h. 61 mg of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorophenyl) -N-tert-butyloxycarbonylsulfamide are thus obtained in the form of a white kiss. [RMN spectrum Ή (400 MHz, CDCl ₃ , delta 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); from 6.75 to 6.90 (mt: 3H); from 7.15 to 7.35 (mt: 8H)].

Example 33 (RS) -N- {1 - [(4-chlorophenyl) -pyridin-3-ylmethyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide can be prepared as follows: to a mixture of 0.2 g of 3- [bromo- (4-chlorophenyl) -methyl] -pyridine and 0.22 g of hydrochloride of N-azetidin-3-yl-N- (3,5-difluorophenyl) methylsulfonamide in 10 cm ^{3 of} acetonitrile 0.2 g of potassium carbonate and 23 mg of potassium iodide are added, then the mixture is refluxed for 3 h. Then 0.2 g of potassium carbonate was added again, further refluxing for 15 h. 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 was obtained, which was purified by chromatography on a silica cartridge (standard SIL-020-005, FlashPack, Jones Chromatography Limited, New Road, Hengoed, Mid Glamorgan, CF82 8AU, Royaume Uni) eluting with a mixture cyclohexane: ethyl acetate 1: 1 (6 cm ³ / min, fractions of 5 cm ³ ). The fractions with Rf-5/57 (cyclohexane: ethyl acetate 1: 1, silica plate, Merck standard 1.05719, Merck KGaA, 64271 Darmstatd, Allemagne) were combined and concentrated below 2.7 kPa at 40 ° C. yield 100 mg of (P8) N - {1 - [(4-chlorophenyl) pyridin-3-yl-methyl] -azetidin-3-yl} -N (3,5difluorophenyl) -methylsulfonamide, melting at 110 ° C. [RMN spectrum Ή (300 MHz, (CD ₃ ) ₂ SO d6, delta 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); from 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 and 1.5 Hz: 1H); 8.58 (d, J = 1.5 Hz: 1H)].

The two isomers of (RS) -N- {1 - [(4-fluorophenyl) -pyridin-3-yl-methyl] -azetidin-3-yl} -N (3,5-difluorophenyl) -methylsulfonamide can be separated on chiral stationary phase Chiracel OD.

First isomer: RMN spectrum 300 (300 MHz, CDCl ₃ , delta ppm). 2.82 (s: 3H); 2.87 (mt: 2H); 3.53 (mt: 2H); 4.29 (s: 1H); 4.47 (mt: 1H); 6.80 (mt: 3H); 7.19 (dd, J = 8 and 5 Hz: 1H); from 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: 1H).

Second isomer: Spectrum RMN Ή (300 MHz, CDC1 _3, delta 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 and 5 Hz: 1H); from 7.25 to 7.35 (mt: 4H); 7.62 (dt, J = 8 and 2 Hz: 1H); 8.46 (dd, J = 5 and 2 Hz: 1H); 8.59 (d broad, J = 2 Hz: 1H).

Azetidin-3-yl-N- (3,5difluorophenyl) -methylsulfonamide hydrochloride is obtained as follows: in a 500 cm ³ hydrogenerator, a solution of 1 gN- (1-6eH3ximpHn-a3eTimHH-3-Hn) No. (3 , 5-Difluorophenyl) -methylsulfonamide in a mixture of 2.5 cm ³ hydrochloric acid 1M and 0.41 cm ³ acetic acid was hydrogenated in the presence of 0.161 g of palladium hydroxide below 30 bar of hydrogen for 4 h. 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-azetidin-3-yl-N (3,5-difluorophenyl) methylsulfonamide, melting at 216 ° C.

N- (1-benzhydryl-azetidin-3-yl) -N (3,5difluorophenyl) -methylsulfonamide can be prepared by working as in Example 13 (method 2) as follows: to a solution of 2 g of 1-benzhydryl- azetidin-3-ol in 100 cm ^{3 of} tetrahydrofuran was added successively 0.86 g of N (3,5-difluorophenyl) methylsulfonamide, 3.28 g of triphenylphosphine, then 2 ml of diethylazodicarboxylate. 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 h 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 min at 21 ° C to give 1.07 g of (1-benzhydryl)

66001 B1 azetidin-3-yl) -N- (3,5-difluorophenyl) -methylsulfonamide as a white amorphous solid.

-benzhydryl-azetidin-3-ol can be prepared according to the method described in Katritzky A. R. et al., J. Heterocycl. Chem., 271 (1994).

3- [Bromo- (4-chlorophenyl) -methyl] -pyridine was prepared as follows: To a 1.5 g (4-chlorophenyl) -pyridin-3-yl-methanol solution was added 3.5 cm ³ hydrochloric acid solution 48% in acetic acid and 1 cm ^{3 of} acetyl bromide. The resulting amber mixture was heated to reflux for 4 h, then cooled to 20 ° C, concentrated to dryness at 40 ° C at 2.7 kPa, resulting in 1.53 g of 3 [bromo - (4-chlorophenyl) -methyl] -pyridine (Rf = 75/90, 254 nm, silica plates, standard 1.05719, Merck KGaA, 64271 Darmstatd, Allemagne).

(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 was added.

4-chlorophenyl magnesium bromide in ethyl ether. After reheating to 20 ° C, it was allowed to react for 15 h 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 microm, 500 g silica, 5 cm diameter column), eluting with a cyclohexane: ethyl acetate mixture from 80:20 to 50:50 under argon pressure 0, 4 bar. The fractions containing the compound of Rf-13/53 (Merck silica plates, standard 1.05719, Merck KGaA, 64271 Darmstatd, Allemagne) were combined and evaporated to dryness at 40 ° C at 2.7 kPa to give 2, 53 g (4-chlorophenyl) -pyridin-3-yl-methanol.

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 HaN-azetidin-3-yl chloride

B1- (3,5-difluorophenyl) -methylsulfonamide in 10 cm ³ acetonitrile was added 0.36 g of potassium carbonate and 27 mg of potassium iodide, then the mixture was refluxed for 3 h. After cooling to 21 ° C, the insoluble matter was removed by filtration, then concentrated to dryness at 40 ° C at 2.7 kPa. The residue was triturated with 30 cm &lt; ³ & gt ^{; 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 a BondElut SCX cartridge containing 2 g of silica (standard 1225-6019, Varian Associates, Inc.). 24201 Frampton Avenue, Harbor City, CA90710, USA) eluting with methanolic 2M ammonia solution. The fractions with Rf = 16/82 (cyclohexanetyl acetate 7/3), silica plates, standard 1.05719, Merck KGaA, 64271 Darmstatd, Allemagne) were combined and concentrated to dryness at 2.7 kPa at 40 ° C. 243 mg of N- {1- [bis- (4-fluoro-phenyl) -methyl] -azetidin-3-yl) -L1- (3,5-difluorophenyl) -methylsulfonamide, melting at 98 ° C, were obtained. [RMN spectrum, Ή (300 MHz, (CD ₃ ) ₂ SO d6, delta in ppm): 2.74 (t broad, J = 7 Hz: 2H); 3.00 (s: 3H); 3.37 (t broad, J = Ί Hz: 2H); 4.43 (s: 1H); 4.69 (mt: 1H); from 7.05 to

7.20 (mt: 6H); 7.28 (tt, J = 9 and 2.5 Hz: 1H); 7.40 (mt: 4H)].

Example 35 (RS) -N- {1 - [(4-chlorophenyl) -pyridin-4-yl-methyl] -azetidin-3-yl) -L- (3,5-difluorophenyl) -methylsulfonamide was prepared as follows: a mixture of ca. 100 mg (4-pyridyl) - (4-chlorophenyl) -chloromethane, 143 mg of L1-azetidin-3-yl-L1- (3,5difluorophenyl) -methylsulfonamide, 17 g of potassium iodide and 200 mg of potassium carbonate in 5 cm ³ acetone , stirred for about 18 h at a temperature close to 20 ° C. The reaction mixture was then refluxed for 3 h, 17 mg of potassium iodide were added and the mixture was further refluxed for 2 h. After cooling to a temperature near 20 ° C, the reaction mixture was filtered on a glass frit. The solid was washed with acetonitrile, then twice with 3 cm &lt; ³ & gt ^{; of} ethyl acetate. The filtrates were concentrated to dryness under reduced pressure.

66001 Bl

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; 20 x 20 cm; 0.5 mm 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) A- {1 - [(4-chlorophenyl) pyridine -4-yl-methyl] -azetidin-3-yl) -L- (3,5-difluorophenyl) -methylsulfonamide. [RMN spectrum Ή (300 MHz, CDCl ₃ , delta in ppm): 2.82 (s: 3H); 2.96 (mt: 2H); from 3.50 to 3.80 (mt: 2H); 4.33 (mt: 1H); 4.54 (mt: 1H); 6.82 (mt: 3H); by

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

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

First isomer: RMN spectrum 300 (300 MHz, CDCl ₃ , delta 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); from 7.20 to 7.35 (mt: 6H); 8.50 (d broad, J = 5.5 Hz: 2H).

Second isomer: RMN spectrum 300 (300 MHz, CDCI ₃ , delta 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); by

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 of} toluene, cooled to a temperature close to 0 ° C, 0.0559 cm ^{3 of} thionyl chloride are added. After 2 h at a temperature close to 0 ° C and 1 h at a temperature close to 20 ° C, the reaction medium was concentrated under reduced pressure.

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

(4-Pyridyl) - (4-chlorophenyl) -methanol can be prepared as follows: to a solution of 2 g of 4- (4-chlorobenzoyl) -pyridine in 160 cm ³ ethanol are added at a temperature close to 20 ° C, 348 mg of sodium tetrahydroboride. After stirring for 2 hours at a temperature close to 20 ° C, 90 mg of sodium tetrahydroboride was added. After about 1.5 hours at the same temperature, the reaction medium was diluted with 200 cm ^{3 of} dichloromethane and 200 cm ^{3 of} water. The pH of the aqueous phase was adjusted to about 5 by adding about 13 cm &lt; ^{3 &gt; of} aqueous 1N hydrochloric acid solution. After decanting, the aqueous phase was extracted 3 times with 100 cm &lt; ³ &gt; of dichloromethane. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gives 2 g (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) (3,5-difluorobenzyl) amine in 25 cm @ ^{3 of} 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 h before adding 59 mm ³ methyl chloroformate, then stirring was maintained for 18 h 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 in volumes)]. 328 mg of methyl {1- [bis (4chlorophenyl) methyl] azetidin-3-yl} - (3,5difluorobenzyl) carbamate are obtained in the form of a colorless oil. [RMN spectrum 300 (300 MHz, CDC1 ₃ , delta in ppm). 2.97 (mt: 2H); 3.39 (mt: 2H); 3.71 (s: 3H); 4.24 (broad s: 1H); 4.45 (mt: 1H); 4.57 (s: 2H); from 6.65 to 6.80 (mt: 3H); from 7.15 to 7.30 (mt: 2H).

Example 37 (RS) -N- {1 - [(4-chloro-phenyl) -pyrimidine-

5-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide can be obtained by working as in Example 33, starting from 0.16 g of bromohydrate of (RS) -5- [6poMO- (4

66001 B1 chloro-phenyl) -methyl] -pyrimidine, 0.131 g of L1-azetidin-3-yl-N- (3,5difluorophenyl) -methanesulfonamide in 5 cm ³ acetonitrile, 303 mg of potassium carbonate and 95 mg of potassium iodide, 0.131 g give 26 mg (RS) -N- {1 [(4-chloro-phenyl) -pyrimidin-5-yl-methyl] azetidin-3-yl} -N- (3,5-difluoro-phenyl) methylsulfonamide in the form of yellow kiss. [RMN Ή spectrum (400 MHz, CDCl ₃ , delta in ppm): 2.83 (s: 3H); 2.91 (mt: 2H); 3.57 (mt: 2H); 4.31 (s: 1H); 4.50 (mt: 1H); from 6.75 to 6.90 (mt: 3H); 7.29 (s: 4H); 8.71 (s: 2H); 9.08 (s: 1H) J.

The medicaments of the invention are composed of at least one compound of formula (I) or an isomer or salt thereof, 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. As solvent or carrier, 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. These compositions may also contain additives, in particular wetting, isotonic, emulsifying, dispersing and stabilizing agents.

Sterilization can be done in several ways, for example by aseptic filtration, by introducing sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of solid sterile compositions that can be dissolved at the time of use in sterile water or other injectable sterile medium.

Formulations for rectal administration are suppositories or rectal capsules containing; 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 the treatment and / or prevention of psychoses, including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, brain and spinal diseases, cognitive disorders, cranial trauma, panic attacks, petropia , glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, involuntary-nightmares, elderly dizziness, thymic diseases, Tourette's syndrome, late disc izia, 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 conditions such as drug addiction and alcohol or drug abuse (e.g., opiates, barbiturates, cannabis, cocaine, amphetamine,

66001 Bl phencyclide, hallucinogens, benzodiazepines) as painkillers or agents that enhance 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 usually include between 5 and 1000 mg per day orally for an adult with unitary doses ranging from 1 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 of treatment.

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 Talc 10 mg Magnesium stearate 1 mg Example B Obtained according to conventional wisdom technique, tablet doses with 50 mg active a substance having the following composition: Compound of Formula (I) 50 mg Lactose 104 mg Cellulose 40 mg Polyvidone 10 mg Sodium carboxymethylamidone 22 mg Talc 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

Claims

Claims (21)

Claims A pharmaceutical composition comprising, as an active ingredient, at least one compound of the formula: R in which R 1 represents the radical -N (R ₄ ) R ₅ , N (R ₄ ) -CO-R ₅ , -N 4 -SO, -R ₆ , R1 and R1, 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-alk , cyano, -COOH, COOalk, -CONR ₇ R ₈ , -CO-NHNR ₉ R ₁₀ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, -hydroxyalkyl _? R ₈ ; the heteroaromatic radical is selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolidine , thiazolyl and thienyl ring, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOalk, -CO-NH-NR ₉ R ₁₀ , -CONR 2, - alk-NR ₉ R ₁₀ , alkylsulfanyl, alkylsulfinyl, alkyls ulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R ₄ represents the radical 66001 Bl -C (R _n ) (R _{| 2} ) -Het, -Het, -C (R ') (R ₁₂ ) -Ar, Ar, cycloalkyl or norbornyl, R ₅ represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONR ₇ R ₈ , -alk-NR _? R _g , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens, R ₆ represents the hydroxyalkyl radical, -alk-COOalk, -alk-CONR _? R ₈ , -alk-NR ₇ R _g , 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 _? and R ₈ together with the nitrogen atom to which are attached 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 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 they are attached a saturated or unsaturated 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, -COalk, -COOalk, -CO- NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH ₂ , R _H represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONRjRg, -alk-NR, N, alkoxyalkyl, Ar, Het, CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens, R ₂ represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONR-R 8, -alk-NR 1 R 1, alkoxyalkyl or alkyl optionally substituted by one or more halogens, or else R _H and R _{1 2} 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 _{] 4} , -CO-NH-NR ₁₅ R ₁₆ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR ₁₅ R ₁₆ , -NR _{] 5} R ₁₆ , alkylthioalkyl, formyl, CF ₃ , OCF ₃ , Het, -O-alkyl-NH-cycloalkyl, SO ₂ NH ₂ , hydroxy, hydroxyalkyl, -NHCOalk, NHCOOalk or at 2 adjacent carbon atoms with dioxymethylene, 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 and optionally substituted by one or more alkyl radicals, alkoxy, halogen, alkoxycarbonyl, oxo , hydroxy, nitrogen heterocycles are optionally in their oxide form, R ₁₃ and R ₁₄ , the same or different, represent a hydrogen atom or an alkyl radical, or else 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 is attached optionally containing 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 chain units is attached, optionally containing 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 up to 6 carbon atoms and cycloalkyl radicals contain 3 to 10 carbon atoms, the optical isomers of these compounds, and their pharmaceutically acceptable salts with inorganic or organic acid. The pharmaceutical composition of claim 1, wherein in formula (I) Het is selected from benzimidazole, benzoxazole, 66001 Bl benzothiazole, benzothiophene, cinnoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, triazotrochinol, fumaric acid, triazoline substituted with one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ radicals. The pharmaceutical composition of claim 1, wherein in the compound of formula (I) R 1 represents the radical -N (R ₄ ) R ₅ , -N (R ₄ ) -SO ₂ -R ₆ , It 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 chosen from pyridyl, pyrimidyl, thiazolyl and thienyl ring, these heteroaromatic radicals can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ₇ R _8, -alk-NR _{9 R] 0} , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl 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 chosen from pyridyl, pyrimidyl, thiazolyl and thienyl ring, these heteroaromatic radicals can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONRjRg, -alkNR ₉ R _10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, , or hydroxyalkyl, R ₄ represents the radical -C (R 1)) (R ₂ ) -Het, -Het, -C (R _n ) (R ₁₂ ) -Ar, Ar or norbornyl, R ₅ represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONR ₇ R ₈ , -alk-NR 4 R 6, alkoxy, -CH ₂ Ar, -CH ₂ Het or alkyl, R ₆ represents the radical hydroxyalkyl, -alk-COOalk, -alk-CONR 4, -alk-NR 4, alkoxy, -CH ₂ Ar, -CH, Het or alkyl, R ₇ and R _g , the same or different, represent a hydrogen atom or an alkyl radical, or else R 7 _? and R ₈ together with the nitrogen atom to which are attached 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 ₉ and R ₁₀ , identical or different, represent a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl, -alk-Oalk or hydroxyalkyl or else R 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 containing optionally another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, -COalk, -COOalk, -CONHalk, oxo, hydroxyalkyl, or - CO-NH ₂ , R _H represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONR _? R ₈ , -alk-NR 1 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, -alk-COOalk, -alkCONR ₇ R _g , -alk-NR _? R ₈ , alkoxyalkyl or alkyl optionally substituted by one or more halogens, or R ₁₃ and R ₁₂ form together with the carbon atom to which a saturated mono or bicyclic ring 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 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, thiadithrothinol, fuetrothiol, tetrahydrothiol one or more alkyl, 66001 B1 alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ radicals, R ₁₃ and R ₄ , the same or different, represent a hydrogen atom or an alkyl radical, or else R ₁₃ and R ₁₄ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 chain links is attached optionally containing 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 chain units is attached, 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. The pharmaceutical composition of claim 1, wherein in the compound of formula (I) R 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 -alkNR ₇ R ₈ ; the heteroaromatic radical is selected from a pyridyl, pyrimidyl, thiazolyl and thienyl ring, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR1, or hydroxy, R ₃ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ₇ R ₈ , hydroxyalkyl or -alkNR _? R _g ; the heteroaromatic radical is selected from a pyridyl, pyrimidyl, thiazolyl and thienyl ring, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR 1-4 alkyl or hydroxyalkyl; R ₄ represents -Het or Ar, R ₆ represents a hydroxyalkyl or alkyl radical, R ₇ and R ₈ , identical 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 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 _{] 3} R ₁₄ , -alkNR _iS R ₁₆ , -NR ₁₅ 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, tetrahydroetinyltetroquinol, tetrahydro tetrahydro, tetrahydro tetrahydroethanol 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 else 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 is attached optionally containing 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 chain units is attached, 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. The composition of claim 1, wherein the compound of formula (I) is selected from 66001 Bl the following compounds: N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N- (6-chloropyrid-2-yl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -1H- (6-ethylpyrid-2-yl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -L4-quinol-6-yl-methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -L-quinol-5-yl-methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N-isoquinol-5-yl-methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -L-pyrid-3-yl-methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N- (1-oxide-pyrid-3-yl) -methylsulfonamide, N- (1R, 2S, 4S) -6hichocto [2,2,1] xenT-2-wi-N {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} methylsulfonamide, N- (1R, 2R, 4S) -6huhoo [2,2,1] hept-2-yl-14 {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] azetidin3-yl} -L1- (3,5-difluorophenyl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] azetidin3-yl} -N- (thiazol-2-yl) -methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N- (3-methoxyphenyl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N- (3-hydroxyphenyl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N- (3-hydroxymethyl-phenyl) methylsulfonamide, N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -L1- (methylsulfonyl) -3-aminobenzoate ethyl, N- {1- [bis- (4-chlorophenyl) methyl] azetidin3-yl} -N- (1-isobutyl-piperid-4-yl) -methylsulfonamide, N-benzyl-> 1- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} amine, N- {1- [bis (4-chlorophenyl) methyl] azetidine- 3-yl} -N- (3,5-difluorobenzyl) amine, N- {1- [bis (4-chlorophenyl) methyl] azetidin3-yl} -N- (3,5-difluorobenzyl) methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin3-yl} -N- (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-ylmethyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) -pyrid-3-ylmethyl] -azetidin-3-yl} -N4- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrid-3-ylmethyl] -azetidin-3-yl} -N - (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) -pyrid-4-ylmethyl] -azetidin-3-yl} -L- (3,5-difluorophenyl) methylsulfonamide , (R) -N- {1 - [(4-chlorophenyl) -pyrid-4-ylmethyl] -azetidin-3-yl} -L- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - {(4-chlorophenyl) -pyrid-4-yl lmethyl] -azetidin-3-yl} -L- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) -pyrimidin5-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-yl-methyl] -azetidin-3-yl} -N- (3,5- difluorophenyl) -methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-ylmethyl] -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. 6. Compound of formula: R in which 66001 Bl R 1 represents the radical -N (R 1) R _t , N (R ₄ ) -CO-R ₅ , -N (R ₄ ) -SO ₂ -R ₆ , 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- alk, cyano, -COOH, COOalk, -CONR ^ Rg, CO -NH-NR ₉ R _{| 0,} alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR ₇ R _g; the heteroaromatic radical is selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolidine, 4-pyrrolidine, 4-pyridyl -tetrahidroizohinolilov, thiazolyl and thienyl ring, these heteroaromatic radicals can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOalk, -CO-NHNR _{9 R] 0,} -CONR ^, -alk-NR ₉ R _{10 O} , alkylsulfanyl, alkylsulfinyl, alkyls ulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R ₄ represents the radical -C (N)) (R ₁₂ ) -Het, -Het, -C (R _H ) (R ₁₂ ) -Ar, Ar, cycloalkyl or norbornyl, R ₅ represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONR 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, -alk-COOalk, -alk-CONR 16, -alk-NR ₇ R ₈ radical, alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted by one or more halogens, R ₇ and R _s , the same or different, represent a hydrogen atom or an alkyl radical or else R ₇ and Rg form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 chain moieties containing optionally attached another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R 1 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 they are attached to a saturated or unsaturated 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, -COalk, -COOalk, -CO -NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH ₂ , R _H represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONR ₇ R _g , -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, -alk-COOalk, -alkCONR 2, -alk-NR 1 R 8, alkoxyalkyl or alkyl optionally substituted by one or more halogens, or else R _H and R ₁₂ form together with the carbon atom to which they are attached to 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 different radicals being optionally substituted by one or more halogens, alkyl, alkoxy, -CO-alk, cyano, COOH, -COOalk, -CONR _{) 3} 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-alkyl-NH-cycloalkyl, SO ₂ NH ₂ , hydroxy, hydroxyalkyl, -NHCOalk, NHCOOalk or at 2 adjacent carbon atoms with dioxymethylene, 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 and optionally substituted by one or more alkyl radicals, alkoxy, halogen, alkoxycarbonyl, oxo , hydroxy, nitrogen heterocycles are optionally in their oxide form, R ₁₃ and R ₁₄ , the same or different, represent a hydrogen atom or an alkyl 66 001 Bl radical, or _{R] 3} and R ₁₄ together with the nitrogen atom to which they are attached a saturated mono or bicyclic heterocycle having 3 to 10 units of the chain, which may contain another heteroatom selected from oxygen, sulfur and nitrogen and is optionally substituted by one or more alkyl radicals, R _l5 and R _16, identical or different, represent a hydrogen atom or an alkyl radical, or _{R] 5} and R ₁₆ together with the nitrogen atom to which they are attached a saturated mono or bicyclic heterocycle having 3 to 10 units of the chains optionally containing 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 cycloalkyl radicals contain from 3 to 10 carbon atoms, the optical isomers of these compounds and their pharmaceutically acceptable salts with inorganic or organic acids except the compound for which R ₂ and R ₃ represent a phenyl radical, R 1 represents the radical -N (R ₄ ) SO ₂ R ₆ 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, quinoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, 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 radicals. A compound of formula (I) according to claim 6 for which R _t represents the radical -N (R ₄ ) R ₅ , N (R ₄ ) -SO ₂ R ₆ , represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR _? R ₈ , hydroxyalkyl or -alkNR ₇ R ₈ ; the heteroaromatic radical is chosen from pyridyl, pyrimidyl, thiazolyl and thienyl ring, these heteroaromatic radicals can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ^, -alk-NR ₉ R _10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl 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 chosen from pyridyl, pyrimidyl, thiazolyl and thienyl ring, these heteroaromatic radicals can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ^, -alk-NR _{9 R] 0,} alkylsulfanyl , alkylsulfinyl, alkylsulfonyl, or hydroxyalkyl, R ₄ represents the radical -C (R _H ) (R _{] 2} ) Het, -Het, -C (R _1] ) (R _{] 2} ) -Ar, Ar or norbornyl, R ₅ represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONR 4, -alk-NR 4 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 * 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 ₉ and R _jo , the same or different, represent a hydrogen atom or an alkyl radical, cycloalkyl, alkylcycloalkyl, -alk-Oalk or hydroxyalkyl or else R ₉ and R form together with the nitrogen atom to which a saturated or unsaturated mono or bicyclic moiety is attached. 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, -CO40 66001 Bl NHalk, oxo, hydroxyalkyl, or -CO-NH ₂ , R 1] represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alkCONR ₇ R ₈ , -alk-NR _? 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, -alk-COOalk, -alkCONI-R 8, -alk-NR 1 R 8, alkoxyalkyl or alkyl optionally substituted by one or more halogens, or else R _H and R ₁₂ form together with the carbon atom to which are attached to 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-alkyl, cyano, -CONR _{] 3} R ₁₄ , alkylsulfonyl, -alk-NR _{] 5} R ₁₆ , -NR _{] 5} R _{] 6} , 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, hshuxalin, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadithroitinol with 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 units of moiety is attached. chains 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 else R ₁₅ and R ₁₆ form together with the nitrogen atom to which a saturated mono or bicyclic heterocycle having 3 to 10 chain units is attached optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, the optical isomers of these compounds and their pharmaceutically acceptable salts with inorganic or organic acid, with the exception of the compound of which R ₂ and R ₃ represents phenyl and radicals, R represents the radical -N (R ₄ ) SO ₂ R ₆ for which R ₄ represents a phenyl radical and R ₆ represents a methyl radical. A compound of formula (I) according to claim 6, wherein R _t 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 -alkNR ₇ R ₈ ; the heteroaromatic radical is selected from a pyridyl, pyrimidyl, thiazolyl and thienyl ring, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR4, or hydroxy, R ₃ represents unsubstituted or substituted phenyl with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ₇ R ₈ , hydroxyalkyl or -alkNR ₇ R ₈ ; the heteroaromatic radical is selected from a pyridyl, pyrimidyl, thiazolyl and thienyl ring, these heteroaromatic radicals may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR4, or hydroxy, R ₄ represents the radical -Het or Ar, R ₆ represents a hydroxyalkyl or alkyl radical, R ₇ and R _g , identical or different, represent a hydrogen atom or an alkyl radical, or else R ₇ and R _g 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, Ar represents a phenyl or naphthyl radical, these various radicals being optionally 66001 B1 substituted with one or more halogens, alkyl, alkoxy, -CO-alkyl, cyano, -CONR ₃ R ₁₄ , -alkNR ₅ R ₁₆ , -NR ₁₅ 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, tetrahydroetinyltetroquinol, tetrahydro tetrahydro, tetrahydro tetrahydroethanol more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ radicals, R ₁₃ and R _u , identical or different, represent a hydrogen atom or an alkyl radical, or else 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 is attached, optionally containing 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 units of chains containing optionally 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, with the exception of the compound for which R. and R ₃ represents phenyl radicals, Rj represents a radical -N (R ₄₎ SO ₂ R ₆ for which R ₄ represents a phenyl radical and R ₆ 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, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -L- (6-ethylpyrid-2-yl) -methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N-quinol-6-yl-methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N-quinol-5-yl-methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -L1-isoquinol-5-yl-methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N-pyrid-3-yl-methyl-sulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} -N- (1-oxide-pyrid-3-yl) -methylsulfonamide, N- (1R, 2S, 4S) -6hichioio [2,2,1] hept-2-yl-N {1- [bis- (4-chlorophenyl) methyl] -azetidin-3-yl} methylsulfonamide, N- (1R, 2R, 4S) -6huhkho [2.2. 1] hept-2-yl-N- {1- [bis- (4-chlorophenyl) methyl] -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} -L1- (thiazol-2-yl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N- (3-methoxyphenyl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N- (3-hydroxyphenyl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) -methyl] azetidin-3-yl} -N- (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} -L- (1-isobutyl-piperid-4-yl) -methylsulfonamide, N-benzyl-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} amine, N- {1- [bis (4-chlorophenyl) methyl] azetidin3-yl} -N- (3,5-difluorobenzyl) amine, N- {1- [bis (4-chlorophenyl) methyl] azetidin3-yl} -L1- (3,5-difluorobenzyl) methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin3-yl} -T4- (pyrid-3-yl-methyl) -methylsulfonamide, B1- {1- [bis- (4-fluorophenyl) -methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) - pyrid-3-ylmethyl] -azetidin-3-yl} -1H- (3,5-difluorophenyl) methylsulfonamide, 66001 B1 (R) -N- {1 - [(4-chlorophenyl) -pyrid-3-ylmethyl] -azetidin-3-yl} -B1- (3,5-difluorophenyl) methylsulfonamide, (S) -N- { 1 - [(4-chlorophenyl) -pyrid-3-ylmethyl] -azetidin-3-yl} -T4- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) - pyrid-4-ylmethyl] -azetidin-3-yl} -L- (3,5-difluorophenyl) methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) -pyrid-4-ylmethyl] -azetidine- 3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrid-4-ylmethyl] -azetidin-3-yl} -L- (3 , 5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-ylmethyl] -azetidin-3-yl} -L- (3,5-difluorophenyl) -methylsulfonamide, ( R) -N- {1 - [(4-x orophenyl) -pyrimidin-5-yl-methyl] -azetidin-3-yl} -14- (3,5-difluorophenyl) -methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-yl-methyl ] -azetidin-3-yl} -L1- (3,5-difluorophenyl) -methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -L- (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, for which R ₃ represents the radical -N (R ₄ ) R ₅ in which R ₁ is a hydrogen atom, R ₄ is a radical -CR _n R ₁₂ -Ar or CR _n R _{1 2} -Het and R ₁₂ is a hydrogen atom, characterized in that the derivative Rb-COR _n , for which R _H has the same meanings as in claim 6, is reacted with a derivative of the formula: where Rb represents the radical Ar or Het, R ₂ , R ₃ , 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 represents the radical -N (R ₄ ) -CO-R ₅ in which R ₄ is the radical -C (R _U ) (R ₁₂ ) -Het or -C (R _H ) (R ₁₂ ) -Ar and R ₁₂ is a hydrogen atom, characterized in that the Hal-COR ₅ derivative reacts with a derivative of the formula: wherein 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 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 1 represents the radical -N (R ₄ ) -SO ₂ R ₆ in which R ₄ is a radical -C (R _n ) (R _{] 2} ) -Ar or -C (R _n ) (R ₁₂ ) -Het and R ₁₂ is a hydrogen atom, characterized in that the Hal-SO ₂ R ₆ derivative reacts with a derivative of the formula: where R ^ R ₃ , R _n , R ₅ have the same meanings as in claim 6, Hal represents a halogen atom and Rb represents the radicals Ar and Het, the product is isolated and optionally transformed into a pharmaceutically acceptable salt. 15. Method for the preparation of compounds with 66001 B1 formula (I) according to claim 6, for which R1 represents the radical -NCRJRj, characterized in that the derivative R ₅ (R ₄ ) NH reacts with a derivative of the formula: as Rj, R ,, R _4, R ₅ have the same meanings as in Claim 6, 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 1 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 R ₄ , R 1, R ₄ , R ₄ and R ₆ 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, for which R _f represents the radical -NCRJCOR, wherein the Hal-COR ₆ derivative is reacted with a derivative of the formula: NH I R 4 as R ₂ , R 1, 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 the radical Het or Ar, characterized in that the derivative Rd -NH-SO ₂ -R ₆ reacts with a derivative of the formula: wherein Rd represents the radical Ar or Het, R ₂ , R ₃ and R ₆ have the same meanings as in claim 6, and Ms represents the methylsulfonyloxy radical, 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, characterized in that the derivative R ₂ -CHBr-R _{3 is} reacted with a derivative of the formula: HN-- as Rj, R ₂ and R ₃ have the same meanings as in Claim 6, 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 1 represents the radical -N (R ₄ ) -SO ₂ -R ₆ , for which R ₄ is a piperid-4-yl radical substituted with nitrogen by an alkyl radical, wherein 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 being isolate and possibly transform 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 1 R ₄ -SO 2 -R 4 for which R ₄ is a phenyl radical substituted by the radical 66001 B1 pyrrolid-1-yl, wherein the pyrrolidine is reacted with a compound of formula (I), respectively, for which R represents the radical -N (R ₄ ) SO ₁ R ₆ for which R ₄ is a phenyl radical substituted by halogen atom, the product is isolated and optionally transformed into a pharmaceutically acceptable salt. Publication of the Patent Office of the Republic of Bulgaria 1797 Sofia, 52-B Dr. GM Dimitrov Blvd. Expert: A. Koleva Cf. № 66060 Circulation: 40 CP