OA12222A - Pharmaceutical compositions containing azetidine derivatives, the new azetidine derivatives and their preparation. - Google Patents

Abstract

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

Description

1 012222

The present invention relates to pharmaceutical compositions containing as active ingredient at least one compound of formula: R, or a pharmaceutically acceptable salt thereof, the novel derivatives of formula (I), their pharmaceutically acceptable salts and their preparation.

The compound of formula (I) for which R 2 and R 3 represent phenyl radicals, R 1 represents a radical -N (R 4) SO 2 R e, R 4 represents a phenyl radical and R 6 represents a methyl radical is described as a synthetic intermediate in patent WO 99/01451. The other compounds and their pharmaceutically acceptable salts are novel and as such form part of the invention. In formula (I) R, represents a radical -N (R4) R5, -N (R4) -CO-R5, -N (R4) -SO2R6, R2 and R3, which may be identical or different, represent either a chosen aromatic phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, COOalk, -CONR7R8, -CO-NH -NRgR10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulphinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR7R8; is a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromannyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromannyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3 rings , 4-tetrahydroisoquinolyl, thiazolyl and thienyl, these heteroaromatic compounds being unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOalk, -CO-NH-NR9R10, -CONR7R8, -alk- NR 9 R 10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl or hydroxyalkyl, R4 represents a radical -C (R11) (R12) -Het, -Het, - (CR1XR1J-Ar, Ar, cycloalkyl or norbornyl, R5 represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxy, Ar, Het, -CH2Ar, -CH2Het oralkyl optionally substituted by one or more halogen,

Re represents a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxy, Ar, Het, -CH1R, -CH2Het or alkyl optionally substituted with 1 or more halogen,. R7 and R8, which may be identical or different, represent a hydrogen atom or a unradical alkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a saturated mono or bicyclic heterocycle having 3 to 10 chaines, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyls, R9 and R10, which may be identical or different, represent a hydrogen atom or a radical alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl; or Rg and R10 together with the nitrogen atom to which they are attached form a saturated or unsaturated mono- or bicyclic heterocycle having 3 to 10 chaines, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH2,

Rn represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxyalkyl, Ar, Het, -CH2Ar, -CH2Het or alkyl optionally substituted by one or more halogen, R12 represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -a! k-NR7R8, alkoxyalkyl or alkyl optionally substituted with one or more halogen, or Rn and R12 together with the carbon atom to which they are attached a mono or bicyclic saturated ring having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl,

Ar represents a phenyl, naphthyl or indenyl radical, these different radicals being optionally substituted by one or more halogen, alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR13R14, -CO-NH-NR15R16, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR15R16, -NR15R16, alkylthioalkyl, formyl, CF3, OCF3, Het, -O-alk-NH-cycloalkyl, SOZNH2, hydroxy, hydroxyalkyl, -NHCOalk, NHCOOalk or on 2 adjacent carboxane atoms by dioxymethylene,

Het represents an unsaturated or saturated mono- or bicyclic heterocycle having 3 to 10 members and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen optionally substituted with one or more alkyls, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, where the nitrogenous heterocycles are optionally in their N-oxidized form, R 13 and R 39, which are identical or different, represent a hydrogen or unradical alkyl atom, or R 13 and R 14 form together with the nitrogen atom that they are attached a saturated mono or bicyclic heterocycle; having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyls, R 1 S and R 16, which may be identical or different, represent a hydrogen atom or a radical alkyl, or R 15 and R 16 together with the nitrogen atom they are attached to a mono or bicyclic saturated heterocycle having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl, alk represents an alkyl or alkylene radical.

In the preceding definitions and those which follow, unless otherwise stated, the radicals and alkyl and alkylene portions and the radicals and alkoxy moieties are straight or branched chain and contain 1 to 6 carbon atoms and the cycloalkyl radicals contain 3 to 10 carbon atoms.

Among the alkyl radicals, mention may be made of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl radicals. Alkoxy radicals include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy.

Among the cycloalkyl radicals, mention may be made of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals.

The term halogen includes chlorine, fluorine, bromine and iodine. 012222

Among the heterocycles represented by Het, there may be mentioned heterocycluccessers: benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine , piperazine, triazole, furan, tetrahydroisoquinoline, tetrahydroquinoline, these heterocycles being optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF3 or CF3.

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

Preferably, the compounds of formula (I) are those for which 1 represents a radical -N (R4) R5, -N (R4) -SO2Re, R2 represents either a phenyl which is unsubstituted or substituted by one or more halogen, alkyl alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR7R8, hydroxyalkyl or -alk-NR7R8; or a heteroaromatic chosen from pyridyl, pyrimidyl, thiazolyl and thienyl, these heteroaromatic rings being unsubstituted or substituted by unhalogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR7R8, -alk-NR9R10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl, R3 represents either phenyl unsubstituted or substituted by one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR7R8, hydroxyalkyl or -alk-NR7R8; or a heteroaromatic chosen from pyridyl, pyrimidyl, thiazolyl and thienyl, these heteroaromatic rings being unsubstituted or substituted by unhalogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR7R8i -alk-NR9R10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl, R4 represents a radical -C1R1XR1Het, -Het, -C (R11) (R12) -Ar, Ar or nornbornyl, R5 represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxy, -CH2Ar, -CH2Het or alkyl, R6 represents hydroxyalkyl, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxy, -CHzAr, -CH2Het or alkyl, R7 and Rs, identical or different, represent a hydrogen atom or unradical alkyl or R7 and R8 form together with the nitrogen atom to which they are attached a mono or bicyclic saturated heterocycle having 3 to 10chainons, optionally containing another heteroatom chosen bymioxygen, sulfurand N and being optionally substituted with one or more alkyls, R 9 and R 10, which may be identical or different, represent a hydrogen atom or a radical alkyl, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl, or R 9 and R 10 together with the atom nitrogen to which they are attached a saturated or unsaturated mono- or bicyclic heterocycle having 3 to 10 chaines, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, oxo, hydroxyalkyl or -CO-NH2,

Rn represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxyalkyl, Ar, Het, -CH1Ar, -CH2Het or alkyl optionally substituted by one or more halogen, R12 represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxyalkyl or alkyl optionally substituted with one or more halogen, or Rn and R12 together with the carbon atom to which they are attached a mono or bicyclic saturated ring having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl,

Ar represents a phenyl or naphthyl radical, these different radicals are optionally substituted by one or more halogen, alkyl, alkoxy, -CO-alk, cyano, -CONR13R14, alkylsulfonyl, -alk-NR16R16, -NR15R16, CF3, OCF3, SO2NH2i hydroxy , hydroxyalkyl or on 2 adjacent carbon atoms <by dioxymethylene,

Het represents an unsaturated or saturated mono or bicyclic heterocycle having 3 to 10 members and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen optionally substituted by one or more alkyl, alkoxy, halogen, oxo, hydroxy, the nitrogenous heterocycles being optionally in their form N-oxidized and, more particularly, Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF3 or CF3. R13 and R14, which may be identical or different, represent a hydrogen atom or an alkyl radical, or else R13 and R14 together with the nitrogen atom to which they are attached form a saturated mono- or bicyclic heterocycle having 3 to 10 ring members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyls, R15 and R16, which may be identical or different, represent a hydrogen atom or an unadical alkyl or else R15 and R16 together with the atom form of nitrogen, to which are attached a saturated mono- or bicyclic heterocycle having 3 to 10 members, optionally containing another heteroatom selected from methoxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl,

Even more preferably, the compounds of formula (I) are chosen from the following compounds: represents a radical -N (R4) -SO2Rg, R2 represents either a phenyl which is unsubstituted or substituted by one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR7R8, hydroxyalkyl or -alk-NR7R8; or a heteroaromatic member selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings, which heteroaromatic groups may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR7R8 or hydroxyalkyl, R3 represents either unsubstituted or substituted phenyl one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR7R8, hydroxyalkyl or -alk-NR7R8; or a heteroaromatic member selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings, which heteroaromatic groups may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR7R8 or hydroxyalkyl, R4 represents -Het or Ar,

R 8 represents a hydroxyalkyl or alkyl radical, R 7 and R 8, which may be identical or different, represent a hydrogen atom or an alkyl radical, or R 7 and R 8 together with the nitrogen atom to which they are attached form a saturated mono or bicyclic heterocycle; having 3 to 10 chaines, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl,

Ar represents a phenyl or naphthyl radical, these different radicals are optionally substituted by one or more halogen, alkyl, alkoxy, -CO-alk, cyano, -CONR13R14, -alk-NR15R16, -NR1SR16, CF3, OCF3, SO2NH2, hydroxy or hydroxyalkyl ,

Het represents an unsaturated or saturated mono or bicyclic heterocycle having 3 to 10 members and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen optionally substituted by one or more alkyl, alkoxy, halogen, oxo, hydroxy and more particularly, Het represents a chosen heterocycle among benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles are optionally substituted with one or more alkyl, alkoxy, halogen alkoxycarbonyl, oxo, hydroxy, OCF3 or CF3, R13 and R14, which may be identical or different, represent a hydrogen atom or an unstituted alkyl radical, or else R13 and R14 together with the nitrogen atom form a mono or bicyclic heterocycle; saturated having 3 to 10 links, possibly containing a a heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyls, R15 and R16, which may be identical or different, represent a hydrogen atom or an unadical alkyl or else R15 and R16 form together with the nitrogen atom, which they are attached to a mono or bicyclic saturated heterocycle having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyls.

Among the preferred compounds, there may be mentioned 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} -N- (6-ethylpyrid-2-yl) methylsulfonamide, N- {1- [bis- (4 chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol 5-yl-methyl-15-sulfonamide, N41- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-isoquinol-5-yl-methylsulfonamide, N- {1- [bis- (4 chlorophenyl) methyl] azetidin-3-yl} -N-pyrid-3-ylmethylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- ( 1-oxide-pyrid-3-yl) -methylsulfonamide, N- (1 R, 2S, 4S) -bicyclo [2,2,1] hept-2-yl-N- {1 - [bis (4-chlorophenyl) ) methyl] azetidin-3-yl) methylsulfonamide, N- (1R, 2R, 4S) -bicyclo [2,2,13hept-2-yl-N- {1- [bis- (4-chlorophenyl) methyl] 11 012222 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- [bs- (4-chlorophenyl) -methyl] azetidine; 3-yl) -N- (3-hydroxyphenyl) methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3-hydroxymethylphenyl) - methylsulfonamide, ethyl N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (methylsulfonyl) -3-aminobenzoate, N- {1- [bis (4- chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) -5-methylsulfonamide, N-benzyl-N- {1- [bins (4-chlorophenyl) methyl] azetidin-3 N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) amine, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-3-ylmethyl) ) -methylsulfonamide, N- {1- [bis- (4-fluorophenyl) 1) -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- N- (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} -N- (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-ylmethyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, (RS) -N- {1- [(4-Chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl) -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl)} pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) pyrimidine) idin-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 pharmaceutically acceptable salts thereof.

The compounds of formula (I) for which R 1 represents a radical -NiRJRg in which R 5 is a hydrogen atom, -N (R 4) -CO-R 5> -N (R 4) -SO 2 R 6, R 4 is a radical - CfR ^ XR ^ -Ar or -C (R11XR12) -Het and R12 is a hydrogen atom may be prepared according to the following reaction scheme:

COR.sup.5

In these formulas R2, R3, R6 and Rn have the same meanings as in formula (I), Rb represents radical Ar or Het, Ar and Het having the same meanings as in formula (I) and Hal represents a halogen atom and preferably chlorine or bromine. The step is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane, chloroform).

chloroform for example), at a temperature between 15 and 30 ° C, in the presence of a base such as a trialkylamine (triethylamine, dipropylethylamine for example) or in the pyridine, at a temperature between 0 and 30 ° C Step b is preferably carried out in methanol, in an autoclave, at a temperature between 50 and 70 ° C.

Stage c is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), in the presence of sodium triacetoxyborohydride and acetic acid, at a temperature in the region of 20 ° C.

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

The Rb-COR 2 derivatives are commercially available or may be obtained according to the methods described for example by R. C. LAROCK, Coprehensive Organic Transformations, VCH editor.

Hal-SCRg derivatives are commercially available or can be obtained by halogenation of the corresponding sulfonic acids, especially in situ in the presence of chlorosulfonyl isocyanate and alcohol, in a halogenated solvent (dichloromethane, chloroform, for example).

Hal-COR5 derivatives are commercially available or can be prepared by halogenation of the corresponding carboxylic acids, especially in situ in the presence of thionyl chloride in a halogenated solvent (dichloromethane, chloroform, for example).

Azetidinols 1 can be obtained by application or adaptation of the methods described by KATRITZKY A.R et al., J. Heterocycl. Chem., 271, 012222 (1994) or DAVE P.R., J. Org. Chem., 61, 5453 (1996) and in the examples.On generally operates according to the following reaction scheme:

AT

HYDROXYLAMINE

N-OH

B ''

Br R. -

D fs *

2

In these formulas R2 and R3 have the same meanings as in formula (I) and Hal represents a chlorine or bromine atom.

In step A, it is preferably carried out in an inert solvent such as a 1-4C aliphatic alcohol (ethanol, methanol for example), optionally in the presence of an alkali metal hydroxide, at the boiling point of the middle reaction. In step B, the reduction is generally carried out using lithium aluminum hydride in the tetrahydrofuran at the boiling temperature of the reaction medium. 16 012222

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

In step D, the procedure described by GRISAR M. et al. In J. Med. Chem., 885 (1973). The magnesium of the brominated derivative is formed, and the nitrile is reacted in an ether such as ethyl ether at a temperature of between 0.degree. C. and the boiling point of the reactional reactor. After hydrolysis with an alcohol, the intermediate imine is reduced in situ by sodium borohydride at a temperature between 0 ° C and the boiling temperature of the reaction medium.

The R2-CO-R3 derivatives are commercially available or can be obtained by application or adaptation of the methods described by KUNDER N.G. et al. J. Chem. Soc. Perkin Trans 1, 2815 (1997); MORENO-MARRAS M., Eur. J.Med. Chem., 23 (5) 477 (1988); SKINNER et al., J. Med. Chem., 14 (6) 546 (1971); HURN N.K., Tet. Lett., 36 (52) 9453 (1995); MEDICI A. et al., Tet.Lett., 24 (28) 2901 (1983); 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 al., J. Chem. Soc. Perkin Trans 1, 1809 (1996); FR-96-2481 and JP-94-261393.

The R3Br derivatives are commercially available or can be obtained by application or adaptation of the methods described by BRANDSMA L. et al., Synth. Comm., 20 (11) 1697 and 3153 (1990); LEMAIRE M. et al., Synth.Comm., 24 (1) 95 (1994); GODA, H. et al., Synthesis, 849 (1992), BAEUERLE P. et al., J. Chem. Soc. Perkin Trans 2, 489 (1993).

The R2CN derivatives are commercially available or can be obtained by application or adaptation of the methods described by BOUYSSOU P. et al., J. 012222 J. Het. Chem., 29 (4) 895 (1992); SUZUKI N. et al., J. Chem. Soc. Chem. Com., 1523 (1984); MARBURG S. et al., J. Het. Chem., 1333 (1980), PERCEC V. et al., J. Org. Chem., 60 (21) 6895 (1995).

The compounds of formula (I) for which R 1 represents a radical -NiRJRg5 may be prepared according to the following reaction scheme:

In these formulas R2, R3, R4 and R5 have the same meanings as in formula (I).

This reaction is generally carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), in the presence of sodium triacetoxyborohydride and acetic acid, at a temperature of 20 ° C.

The compounds HN (R4) R5 are commercially available or can be prepared according to conventional methods known to those skilled in the art or by application or adaptation of the methods described by Park K.K. et al., J. Org. Chem., 60 (19) 6202 (1995); Kalir A. et al., J. Med. Chem., 12 (3) 473 (1969); Sarges R., J. Org. Chem., 40 (9) 1216 (1975); Zaugg H.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. 20 Soc. Chim. Fr., 835 (1962).

The azetidinones 2 may be obtained by oxidation of the corresponding azetidinols, preferably in dimethylsulfoxide, by means of the sulfur trioxide-pyridine complex, at a temperature in the region of 20 ° C. or by means of dimethylsulfoxide, in the presence of oxalyl chloride. and triethylamine at a temperature between -70 ° C and -50 ° C.

The compounds of formula (I) for which Rn represents a radical -N (R4) COR5 or -N (R4) SO2R6 may be prepared according to the following reaction scheme:

In these formulas, R2, R3, R4, R5 and R6 have the same meanings as in formula (I) and Hal represents a halogen atom and preferably chlorine. Steps a and b are generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane, chloroform for example), in the presence of an amine such as a trialkylamine (triethylamine for example) ), at a temperature between 5 ° C and 20 ° C.

The compounds of formula (I) for which R 1 represents a radical -N (R 4) -SO 2 -R 6 for which R 4 is a radical Het or Ar can be prepared according to the following reaction scheme: ## STR2 ##

R, Ν ·

If

'N ^ S ° 2-R6

Rd

Rd-NH-SO2-Rg N · T> M <

In these formulas R2, R3 and R6 have the same meanings as in formula (I), Rd represents an Ar or Het radical (Het and Ar having the same meaning as in formula (I)) and Ms represents a methylsulfonyloxy radical. The step is generally carried out in an inert solvent such as letetahydrofuran, in the presence of triphenylphosphine and dediethylazodicarboxylate, at a temperature between 0 ° C and the boiling temperature of the reaction medium. Step b is generally carried out in an inert solvent such as letetahydrofuran, dioxane, a chlorinated solvent (dichloromethane, chloroform for example), at a temperature of between 15 ° C. and 30 ° C., in the presence of a base such as trialkylamine (triethylamine, dipropylethylamine for example) or pyridine at a temperature between 0 ° C and 30 ° C. Step c is preferably carried out in an inert solvent such as ledioxane, in the presence of CsCO3, under reflux of the reaction mixture. 012222

The derivatives for which Rd represents a N-oxidized nitrogen heterocycle may be reduced unoxidized compound according to the method described by SANGHANEL E. et al., Synthesis 1375 (1996).

Derivatives Rd-NH-SOjRe can be obtained according to the following reaction scheme5:

Hal-SO2-R6

Rd-NH2 - »- Rd-NH-SO2-R6

In these formulas Hal represents a halogen atom and Rd represents a radical Het or Ar. The reaction is carried out in an inert solvent such as letetahydrofuran, dioxane, a chlorinated solvent (dichloromethane, chloroform, for example), a temperature of between 15 ° C. and 30 ° C., in the presence of a base such as trialkyamine (triethylamine, dipropylethylamine for example) or in pyridine, at a temperature of between 0 ° C. and 30 ° C.

The derivatives for which Rd represents a N-oxidized nitrogen heterocycle can be obtained according to the method described by RHIE R., Heterocycles, 41 (2) 323 (1995).

The compounds of formula (I) may also be prepared according to the following reaction scheme: ## STR2 ##

R3Br + R2-CHO

In these formulas R 2 R 2 and R 3 have the same meanings as in formula (I) and Ph represents a phenyl. The step is generally carried out in an alcohol such as methanol, in the presence of sodium borohydride, at a temperature in the region of 20 ° C.

In step b, the magnesium derivative of the brominated derivative is prepared and reacted with an inert solvent such as ethyl ether or tetrahydrofuran at a temperature between 0 ° C. and the boiling point of the reaction medium. Step c is carried out using a halogenating agent such as hydrobromic acid, thionyl bromide, thionyl chloride, a mixture of triphenylphosphine and tetrabromide or carbon tetrachloride, in the case of acetic acid. or an inert solvent such as dichloromethane, chloroform, carbon tetrachloride or toluene, at a temperature between 0 ° C and the boiling temperature of the reaction medium. Step d is carried out using hydrogen in the presence of palladium on carbon, in an alcohol such as methanol, at a temperature of 20 ° C. Step e is carried out in an inert solvent such as acetonitrile, in the presence of an alkali metal carbonate (potassium carbonate for example) and potassium iodide, at a temperature of between 20 ° C. the boiling temperature of the reaction medium.

The R3Br derivatives and the R2-CHO derivatives are commercially available or may be obtained according to the methods described for example by R. C. LAROCK,

Comprehensive Organic Transformations, VCH editor.

The compounds of formula (I) for which R 1 represents a radical-N (R 4) -SO 2 -R 6 for which R 4 is a piperid-4-yl radical optionally substituted on the nitrogen by an alkyl radical may also be prepared according to the following reaction scheme: 012222

In these formulas R2, R3 and R6 have the same meanings as in formula (I), alk represents an alkyl radical and Re represents a tert-butylcarbonyloxy radical. The step is carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), in the presence of a hydride such as sodium letriacetoxyborohydride and acetic acid, at a temperature of between 0.degree. C and the boiling temperature of the reaction medium. Step b is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane, chloroform for example), in the presence of an amine such as a trialkylamine (triethylamine for example) ), at a temperature between 5 ° C and 20 ° C. Step c is carried out by means of hydrochloric acid in the dioxane at a temperature of between 0 ° C. and the boiling point of the reaction medium. Step d is carried out by any means known to those skilled 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 (sodium hydroxide, potassium hydroxide for example), optionally in the presence of tetrabutylammonium bromide, or an inert solvent such as dimethylsulfoxide, dimethylformamide or lapyridine at a temperature of between 20 and 50 ° C.

The compounds of formula (I) for which R 1 represents a radical -N (R 4) -SO 2 -R 6 for which R 4 is a phenyl radical substituted by a 1-pyrrolido radical may also be prepared by the action of pyrrolidine on a compound of formula ( I) corresponding for which R! represents unradical -N (R4) SO2Re for which R4 is a phenyl radical substituted by a halogen atom.

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

It is understood by those skilled in the art that, for the implementation of the processes according to the invention described above, it may be necessary to introduce protective groups of the amino, hydroxy and carboxyafin functions to avoid side reactions. These groups are those that allow to be eliminated without touching the rest of the molecule. Examples of protective groups of the amino function include tert-butyte or methyl carbamates which can be regenerated by means of iodotrimethylsilane or allyl by means of palladium catalysts. Examples of hydroxy protecting groups are The triethylsilyl, tert-butyldimethylsilyl can be regenerated by means of tetrabutylammonium fluoride or the asymmetric acetals (methoxymethyl, tetrahydropyranyie, for example) with regeneration by means of hydrochloric acid. As carboxy protecting groups, there may be mentioned esters (allyl, benzyl for example), oxazoles and 2-alkyl-1,3-oxazolines. Other useful protecting groups are described by GREENE T.W. et al., Protecting Groups in Organic Synthesis, Second Edition, 1991, Jonh Wiley & amp .; Sounds.

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

The enantiomers of the compounds of formula (I) can be obtained by duplicating the racemic compounds, for example by column chromatography according to PIRCKLE W.H. et al., Asymmetric synthesis, vol. 1, AcademiePress (1983) or by salt formation or synthesis from chiral precursors. The diastereoisomers can be prepared according to known conventional methods (crystallization, chromatography or from chiral precursors).

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

Examples of pharmaceutically acceptable salts are the following salts: benzenesulphonate, hydrobromide, hydrochloride, citrate, ethanesulphonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulphonate, methylene-bis-b-oxynaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllinacetate and p-toluenesulfonate. 01 222 26

The compounds of formula (I) have interesting pharmacological properties. These compounds have a high affinity for cannabinoid receptors and particularly those of CB1 type. They are antagonists of the CB1 receptor and are therefore useful in the treatment and prevention of disorders affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system, the gastrointestinal tract and reproductive disorders (Hollister , Pharm Rev. 38, 1986, 1-20, Reny and Sinha, Prog Drug Res., 36, 71-114 (1991), Consroe and Sandyk, in Marijuana / Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds, CRC Press, 1992). Thus these compounds can be used for the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, trauma headache, panic attacks, peripheral neuropathies, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's lachorea, Raynaud's syndrome, tremor, compulso-obsessional disorder, senile dementia, disordering, Tourette's syndrome, tardive dyskinesia, bipolar disorder, cancer, drug-induced movement disorders, dystonia, endotoxemic shock, shock-shock, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia) xie), obesity, memory disorders, withdrawal from chronic treatment and abuse of alcohol or drugs (opioids, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines, for example), aschaemia or potentiating the analgesic activity of narcotic and non-narcotic drugs. They can also be used for treatment or prevention of intestinal transit. 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., AMBRA T.E., HAYCOCK D.A. in J. Pharmacol. Exp. Ther., 264, 1352-1363 (1993).

In this test, the IC50 of the compounds of formula (I) is less than or equal to 1000 nM.

Their antagonistic activity has been shown by the model of cannabis-receptor agonist-induced hypothermia (CP-55940) in the mouse, according to the method described by Pertwee RG in Marijuana, Harvey DJ Eds, 84 Oxford IRL Press, 263- 277 (1985).

In this test, the ED50 of the compounds of formula (I) is less than or equal to 50 mg / kg. The compounds of formula (I) have low toxicity. Their LD50 is above 40 mg / kg subcutaneously in mice.

The following examples illustrate the invention.

Example 1

N- {1-tbis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (6-chloropyrid-2-yl) -20-methylsulfonamide can be prepared by operating as follows: 1.54 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol and 1.22 g of N- (6-chloropyrid-2-yl) methylsulfonamide in anhydrous 120 cm3 of anhydrous tetrahydrofuran are added. argon 2.4 cc of diethyl azodicarboxylate and 1.44 g of triphenylphosphine. After stirring for 20 hours at 20 ° C, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.040-0.063 mm, height 30 cm, diameter 4.5 cm), eluting under a pressure of 0.5 bar of argon with a mixture of cyclohexane and dichloroacetate. ethyl (80/20 by volume) and collecting fractions of 60 cm3. Fractions 6 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.75 g of N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (6-chloropyrid-2-yl) methylsulfonamide are obtained in the form of a white glass. [1 H NMR spectrum (300 MHz, CDCl 3, δ in ppm): 2.85 to 3.00 (mt: 2H); 2.91 (s: 3H); 3.57 (t split, J = 7 and 2 Hz: 2H); 4.25 (s: 1H); 4.64 (mt: 1H); from 7.20 to 7.35 (mt: 9H); 7.36 (dd, J = 8 and 1 Hz: 1H); 7.71 (t, J = 8 Hz: 1H)].

1- [Bis (4-chlorophenyl) methyl] azetidin-3-ol can be prepared according to the procedure described by KATRITZKY A.R. et al., J. Heterocycl. Chem., 271 (1994), starting from 35.5 g of [bis (4-chlorophenyl) methyl] amine hydrochloride and 11.0 cm3 of epichlorohydrin. Oit isolates 9.0 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol.

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

N- (6-chloropyrid-2-yl) methylsulphonamide can be prepared by operating as follows: To a cooled solution at + 5 ° C of 2-amino-6-chloropyridine in 12.5 cm3 of pyridine, is poured dropwise. dropwise in 1 hour 7.8 cm3 of methylsulfonyl chloride. After returning to room temperature and stirring for 20 hours, the black reaction mixture is treated with 140 cm 3 of water and extracted with dichloromethane (200 cc). The organic phase is decanted, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is chromatographed on a column of silica gel (particle size 0.063-0.200 mm, height 30 cm, diameter 4 cm), eluting under a pressure of 0.5 bar of argon with a mixture of cyclohexane and titanium. ethyl acetate (70/30 by volume) and containing 60 cm3 fractions. Fractions 5 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 17 g of N- (6-chloropyrid-2-yl) methylsulfonamide are obtained in the form of a yellow oil. Example 2

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (6-ethylpyrid-2-yl) methylsulfonamide can be prepared by operating as described in Example 1, from 0.61 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol, 0.40 g of N- (6-ethylpyrid-2-yl) methylsulfonamide, 50 cm3 of tetrahydrofuran anhydrous, 0.96 cc of diethyl azodicarboxylate and 0.577 g of triphenylphosphine. The crude product is chromatographed on a column of silica gel (particle size 0.040-0.063 mm, height 20 cm, diameter 2 cm), eluting under a pressure of 0.5 bar of argon with a mixture of cyclohexane and acetate of ethyl (70/30 by volume) and collecting 30 cm3 fractions. Fractions 6 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.3 g of an oil is obtained which is triturated in a mixture of 5 cm 3 of diethyl ether and 5 cm 3 of diisopropyl ether. The suspension is filtered, the solid filtered off and 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 in the form of a white solid [1 H NMR spectrum (300 MHz, CDCl 3, δ enppm): 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 = 7.5HzHz: 1H);

N- (6-ethylpyrid-2-yl) methylsulfonamide can be prepared by operating as follows: To a solution cooled to +5 ° C. of 2.50 g of 2-amino-6-ethylpyridine in 2.50 cm 3 1.56 cm3 of methylsulfonyl chloride are added dropwise to pyridine. After stirring for 20 hours at 20 ° C., the reaction mixture is treated with 8 cm3 of water and filtered. The filtrate is concentrated at 50 ° C. under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.040-0.063 mm, height 30 cm, diameter 4 cm), eluting at a pressure of 0.5 bar of argon with 1.5 liters of dichloromethane and then with a mixture of dichloromethane and methanol (98/2 by volume) and collecting 60 cm3 fractions. Fractions 8 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2.8 g of N- (6-ethylpyrid-2-yl) methylsulfonamide are obtained in the form of a yellow oil.

Example 3

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide can be prepared by operating as follows: A solution of 0.50 g of N-quinol-6-yl-methylsulfonamide in 50 cm3 of anhydrous anhydrofuran, 0.70 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol, 0.597 g of triphenylphosphine are added under argon and then 40 cm3 of diethyl azodicarboxylate. After stirring for 20 hours at 20 ° C., the reaction mixture is heated at reflux temperature for 4 hours and then 2.98 g of triphenylphosphine and 2.0 cm3 of diethylazodicarboxylate are added. After stirring for 48 hours at 20 ° C., the mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up with 30 cm3 of diethyl ether, the suspension obtained is filtered and the filtrate is concentrated to dryness. A fraction of the residue obtained (0.90 g) is purified on a Bond Elut SCX resin sulfonic acid exchange cation column, (particle size 0.054 mm, height 4 cm, diameter 3 cm), eluting first with methanol and then with a solution. 2M ammonia in ethanol to elute the expected product, collecting 5 cm3 fractions. Fractions 16 to 19 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.33 g of an oil is obtained which is stirred in 10 cm3 of diisopropyl ether. The resulting suspension is filtered. The filtered filtrate gives again, after 15 minutes, a solid which is dried at 50 ° C. under reduced pressure (2.7 kPa). 83 mg of chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-yl-methylsulfonamide are obtained in the form of a white solid (1 H NMR spectrum (300 MHz, CDCl 3, δ in ppm) : 2.87 (s: 3H); 2.89 (mt: 2H); 3.55 (t split, J = 7 and 1 Hz: 2H); 4.18 (s: 1H); 4.69 (mt: 1H); from 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)] N-Quinol-6-yl-methylsulfonamide can be prepared by operating as follows: To a cooled solution at + 3 ° C of 1, 98 g of 6-aminoquinoline in 1.75 cm3 of pyridine is poured dropwise over 1 hour 1.1 cm3 of methylsulfonyl chloride. After stirring for 20 hours at 20.degree. C., the reaction mixture is treated with 10 cm.sup.3 of water and 50 cm.sup.3 of dichloromethane, and then filtered. The filtrate is decanted, the organic phase is dried over magnesium sulfate, then filtered and concentrated to dryness under reduced pressure (2.7 kPa). 1.15 g of N-quinol-6-yl-methylsulfonamide are obtained in the form a creamy yellow solid.

Example 4 N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-5-ylmethylsulfonamide can be prepared by operating as follows: At 0.50 g solution of N- (quinol-5-yl) methylsulphonamide in anhydrous 70 cm3 of anhydrousetetrahydrofuran, 0.70 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol, 0.597 g of triphenylphosphine are added under argon and then 40 cm3 of diethyl azodicarboxylate and 0.45 g of 1,2-bis (diphenylphosphine) ethane. After stirring for 20 hours at 20 ° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 70 cm3 of ethyl acetate, the resulting solution is washed with brine, dried over magnesium sulphate, filtered and then concentrated at 50 ° C. under reduced pressure (2.7 kPa). . The violet oil obtained is purified by chromatography on a column of silica gel (particle size 0.063-0.200 mm, height 35 cm, diameter 3.9 cm), eluting under a pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (40/60 then 30/70 and 20/80 by volume) and collecting fractions of 50 cm3. Fractions 6 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 15 cm3 of methanol, the resulting white suspension is filtered, the solid filtered off and then dried at 50 ° C. under reduced pressure (2.7 kPa). 0.35 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-5-yl-methylsulfonamide are obtained in the form of a white solid [NMR spectrum]. 1H (300 MHz, CDCl3, δ in ppm): 2.60 (t, J = 7 Hz: 1H); 2.84 (t, J = 7 Hz: 1H); 2.99 (s: 3H); 3.36 (t split, J = 7 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, J = 8Hz: 1H); 8.54 (broad d, J = 9 Hz: 1H); 8.99 (dd, J = 4 and 1.5 Hz: 1H)].

N- (quinol-5-yl) methylsulfonamide can be prepared by operating as described in Example 3, starting with 2.0 g of 5-aminoquinoline, 3.0 cm 3 of pyridine, 1.1 cm 3 of methylsulfonyl. 2.47 g of N- (quinol-5-yl) methylsulfonamide are obtained in the form of a yellow-brown solid.

Example 5

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-isoquinol-5-ylmethylsulfonamide can be prepared by operating as described in Example 4, starting from 0.497. g of N- (isoquinol-5-yl) methylsulfonamide, 70 cm3 of anhydrous tetrahydrofuran, 0.712 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol, 0.597 g of triphenylphosphine, 0.40 cm3d Diethyl azodicarboxylate and 0.45 g of 1,2-bis (diphenylphosphine) ethane. The crude brown oil obtained is purified by chromatography on a column of silica gel (particle size 0.063-0.200 mm, height 38 cm, diameter 3 cm), eluting with a cyclohexane / ethyl acetate mixture (30/70 with volumes) and collecting 40 cc fractions. Fractions 8 to 23 are combined and concentrated under reduced pressure (2.7 kPa). The residue is stirred in 15 cm3 of diethyl ether, the suspension is filtered and the insoluble material is chromatographed on a SCX resin column (height 4 cm, diameter 3 cm), washing first with a mixture of methanol and dichloromethane ( 50/50 by volume) and then eluting with 2M ammonia solution in methanol and collecting 20 cc fractions. Fractions 1 to 6 are combined and the white insoluble which appears is filtered, the solid is drained and then dried at 50 ° C under reduced pressure (2.7 kPa). 0.169 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-isoquinol-5-yl-methylsulfonamide are obtained in the form of a white solid [NMR spectrum]. 1H (300 MHz, CDCl3, δ enppm): 2.64 (t, J = 7 Hz: 1H); 2.81 (t, J = 7 Hz: 1H); 2.98 (s: 3H); 3.36 (t = double, 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 (broad d, J = 6 Hz: 1H); 8.06 (broad d, J = 8 Hz: 1H); 8.66 (d, J = 6 Hz: 1H); 9.32 (s wide: 1H)].

N- (isoquinol-5-yl) methylsulfonamide can be prepared by operating as described in Example 4, starting from 2.0 g of 5-aminoisoquinoline, 3.0 cm 3 of pyridine and 1.1 cm 3 of methylsulfonyl chloride. 2.3 g of N- (isoquinol-5-yl) methylsulfonamide are obtained in the form of a beige solid. Example 6

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-pyrid-3-ylmethylsulfonamide can be prepared by operating as follows: To a solution of 0.144 g of N - {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-oxide-pyrid-3-yl) -methylsulfonamide in 5 cm3 of chloroform, run042 cm3 of phosphorus trichloride, and then heat the mixture at reflux temperature. After stirring for 1 hour and 30 minutes, the reaction mixture is allowed to return to room temperature, followed by addition of 5 cm 3 of 0.1 N hydrochloric acid, followed by stirring and decanting. The organic phase is diluted with 20 cm3 of chloroform, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.063-0.200 mm, height 9 cm, diameter 1.8 cm), eluting under a pressure of 0.1 bar argon with a mixture of dichloromethane and methanol ( 95/5 volume) and collecting 15 cm3 fractions. Fractions 2 to 4 are collected and concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred with 15 cm3 of diethyl ether, the suspension is filtered, the solid is filtered off and then dried under reduced pressure (2.7 kPa). 35 mg of N- {1 -

[Bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-pyrid-3-ylmethylsulfonamide as a cream solid [NMR Spectrum]. 1H (300 MHz, CDCl3, δ in ppm): from 2.80 to 2.95 (mt: 2H); 2.87 (s: 3H); 3.51 (t split, J = 7 and 1.5Hz: 2H); 4.18 (s: 1H); 4.65 (mt: 1H); from 7.15 to 7.35 (mt: 8H); 7.37 (ddlarge, J = 8 and 5 Hz: 1H); 7.64 (d multiplied, J = 8 Hz: 1H); 8.52 (broad, J = 2 Hz: 1H); 8.61 (broad d, J = 5 Hz: 1H)].

Example 7

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-oxide-pyrid-3-yl) -methylsulfonamide can be prepared by operating as follows: 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 cm3 of anhydrous tetrahydrofuran, 0.14 cm3 of diethyl azodicarboxylate and 0.226 g of triphenylphosphine are added under argon. After stirring for 20 hours at 20 ° C., then 24 hours at reflux temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.063-0.2 mm, height 20 cm, diameter 1.5 cm), eluting under a pressure of 0.5 bar of argon with a mixture of dichloromethane and methanol ( 98Z2) and collecting 40 cm3 fractions. Fractions 26 to 64 are sonicated and concentrated to dryness under reduced pressure (2.7 kPa). the residue is stirred in 10 cm3 of diethyl ether, the suspension is filtered, the insoluble material is extracted and then dried under reduced pressure (2.7 kPa). 0.10 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-oxide-pyridin-3-yl) -methylsulphonylamide are obtained in the form of a white solid [1H NMR spectrum (400 MHz, (CD3) 2SO d6, δ in ppm): 2.78 (t, J = 7 Hz: 2H); 3.06 (s: 3H); 3.37 (t, J = 7 Hz: 2H); 4.45 (s: 1H); 4.71 (mt: 1H); from 7.30 to 7.50 (mt: 10H); 8.21 (broad d, J = 6.5 Hz: 1H); 8.27 (s wide: 1H)].

N- (1-Oxide-pyrid-3-yl) methylsulfonamide can be prepared by proceeding as follows: To a solution of 1.81 g of N-pyrid-3-yl-methylsulfonamide in 71 cm3 of Ν, Ν- dimethylformamide and 3 cm3 of ethanol, 7.1 g of 50-55% 3-chloroperoxybenzoic acid and then 0.56 cm3 of 40% hydrofluoric acid are added in portions. After stirring for 1 hour at 20 ° C., the reaction mixture is poured into 500 g of ice, stirred and filtered. The filtrate is concentrated to dryness at 60 ° C. under deduced pressure (2.7 kPa). Lerésidu is taken up in 50 cm3 of a mixture of dichloromethane and methanol (98/2 by volume) and then filtered. The filtrate is chromatographed on a column of silica gel (particle size 0.063-0.2 mm, height 27 cm, diameter 4 cm), eluting under a pressure of 0.5 bar of argon with a mixture of dichloromethane and methanol (98 / 2, 97/3 then 50/50 by volume) and recording fractions of 60 cm3. Fraction 62 is concentrated to dryness under reduced pressure (2.7 kPa). 0.96 g of N- (1-oxide-pyrid-3-yl) methylsulfonamide are obtained in the form of a yellowish solid. 012222 36

The N-pyrid-3-yl-methylsulfonamide can be prepared by operating as described in Example 1, starting from 2 g of 3-aminopyridine, 5 cm 3 of pyridine and 1.8 cm 3 of methylsulfonyl chloride. The crude product obtained is stirred in ethyldehyde diethyl ether, the suspension is filtered and the solid is stripped and dried under reduced pressure (2.7 kPa). 2.47 g of N-pyrid-3-yl-methylsulfonamide are obtained in the form of a pinkish solid.

Example 8

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-cyclohexylmethylsulfonamide can be prepared by operating as follows: A solution of 1.8 g of N- { 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-cyclohexylamine, 0.7 cm3 of triethylamine and 20 mg of 4-dimethylaminopyridine in 25 cm3 of dichloromethane, 0.4 sub-agitation is added. cm3 of methylsulfonyl chloride. After stirring for 48 hours at 20 ° C., 20 cm3 of dichloromethane, 20 cm3 of water are added to the reaction mixture and the mixture is stirred and decanted. The organic phase is dried over magnesium sulphate and concentrated at 50 ° C. under reduced pressure (2.7 kPa). The brown oil residue is chromatographed on a column of silica gel (particle size 0.063-0.2 mm, height 20 cm, diameter 2.0 cm), eluting under a pressure of 0.1 bar of argon with a mixture of dichloromethane and methanol (96/4 by volume) and collecting 10 cm3 fractions. Fractions 2 to 4 and 5 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a desilice gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 1.5 cm), eluting under a pressure of 0.1 bar of argon with a cyclohexane / acetate mixture. of ethyl (70/30 by volume) and collecting 37 fractions of 5 cm3. Fractions 7 to 10 are combined and concentrated under reduced pressure (2.7 kPa). 0.10 g of N- {1- [bis- (4-chlorophenyl) methyl] azetdin-3-yl} -N-cyclohexylmethylsulfonamide are obtained as a cream meringue (M.M.N. 1H (300 MHz, CDCl3, δ in 5 ppm): from 0.80 to 1.90 (mt: 10H); 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) j.

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-cyclohexylamine can be prepared by proceeding as follows: To a solution of 1.5 g of 1-bis [bis- (4-chlorophenyl) methyl] azetidin-3-one in 25 cm3 of 1,2-dichloroethane is added 0.5 g of cyclohexylamine, 1 g of triacetoxyborohydride desodium and 0.3 cm3 of 100% acetic acid. . After stirring for 20 hours at 20 ° C., 20 cm 3 of dichloromethane and 10 cm 3 of water are added to the reaction mixture and the mixture is then neutralized to pH 7 to 8 with a 1N aqueous sodium hydroxide solution. The mixture is decanted, the organic phase is dried over magnesium sulphate and concentrated to dryness 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 will be used as it is in the next step. . The 1- [bis (4-chlorophenyl) methyl] azetidin-3-one may be prepared according to the following operating method: to a solution of 5.0 cm3 of oxalyl chloride in 73 cm3 of dichloromethane cooled to -78 ° C, a solution of 8.1 cm3 of dimethylsulfoxide in 17.6 cm3 of dichloromethane is added. After 0.5 hours at -78 ° C., a solution of 16.0 g of 1- [bis (4-chlorophenyl) methyl is poured in ] After 5 hours at -78 ° C., 26.6 cm 3 of triethylamine are added dropwise and the reaction mixture is allowed to return to ambient temperature. After 16 hours, the reaction mixture is washed with 4 times 200 cm3 of water and then with 200 cm3 of a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 9.2 cm, height 21 cm), at a pressure of 0.5 bar of argon with a mixture of acetate of d ethyl and cyclohexane (40/60 by volume) as eluents and collecting 200 cc fractions. Fractions 15 to 25 are combined and then concentrated under reduced pressure (2.7 kPa). 8.9 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one are obtained as pale yellow crystals melting at 11 ° C.

Example 9

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-cyclopropylmethylsulfonamide can be prepared by operating as described in Example 8, starting from 1.6 g. N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-cyclopropylamine, 25 cm3 of dichloromethane, 0.7 cm3 of triethylamine, 20 mg of 4-dimethylaminopyridine and 0 4 cm3 of methylsulfonyl chloride, stirring the mixture for 20 hours at 20 ° C. The crude product is chromatographed on a column of silica gel (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under a pressure of 0.1 bar of argon with a mixture of dichloromethane and methanol (97/3 by volume) and collecting 10 cm3 fractions. Fractions 6 to 9 and 10 to 20 are combined and concentrated to dryness under reduced pressure (2.7 Kpa). The residue obtained is chromatographed on a column of silica gel (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under a pressure of 0.1 bar of argon with a mixture of cyclohexane and titanium dioxide. ethyl acetate (70/30 by volume) and containing fractions of 10 cm3. Fractions 6 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.14 g of N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-cyclopropylmethylsulfonamide is obtained in the form of a cream meringue (1H NMR spectrum ( 300 MHz, CDCl3, δ in ppm): 0.79 (mt: 2H); 0.95 (mt: 2H); 2.11 (mt: 1H); 2.84 (s: 3H); 3.17 (t 5 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)].

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-cyclopropylamine may be prepared by operating as described in Example 8, starting from 1.5 g of 1- [ bis- (4-chlorophenyl) methyl] azetidin-3-one, 25 cm3 of 1,2-dichloroethane, 0.37 cm3 of cyclopropylamine, 1 g of triacetoxyborohydride desodium and 0.3 cm3 of 100% acetic acid. 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 will be used as it is. 'next step.

Example 10 N- (1R, 2S, 4S) -bicyclo [2,2,1] hept-2-yl-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} - methylsulfonamide, can be prepared by operating as described in Example 8, starting from 2.0 g of N- (1R, 2S, 4S) -bicyclo [2,2,13hept-2-yl-N- {1 [bis- (4-chlorophenyl) methyl] azetidin-3-yl} amine, 25 cm3 of dichloromethane, 0.7 cm3 of triethylamine, 20 mg of 4-dimethylaminopyridine and 0.4 cm3 of methylsulfonyl, with stirring for 20 hours. The oily brown residue is chromatographed on a column of silica gel (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under a pressure of 0.1 bar of argon with a mixture of dichloromethane and of methanol (97/3 in 25 volumes) and collecting 10 cm3 fractions. Fractions 6 to 18 were separated and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under a pressure of 0.1 40 012222 bar of argon with a mixture of cyclohexane and of ethyl acetate (70/30 volumes) and collecting 10 cm3 fractions. Fractions 8 to 14 are collected 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-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3 are obtained. 1H NMR spectrum (300 MHz, CDCl3, δ in ppm): from 1.20 to 1.75 (mt: 7H); 1.84 (tmax) .beta.-1-methylsulfonamide, in the form of a cream meringue. , 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) -bicyclo [2,2,1] hept-2-yl-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} amine can be prepared operating as described in Example 8, starting from 1.5 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-one, 25 cm3 of 1,2-dichloroethane, 1.5 g of (1R, 2S, 4S) -bicyclo [2,2,1] heptyl-2-amine, 1 g of sodium triacetoxyborohydride and 0.3 cm3 of 100% acetic acid. 2 g of N- (1R, 2S, 4S) -bicyclo [2,2,1] hept-2-yl-N- {1 - [bis- (4-chlorophenyl) methyl] azetidin-3-yl} are obtained. amine, in the form of a brown oil which will be used as it is at the next step.

Example 11

N- (1 R, 2R, 4S) -bicyclo [2,2,1] hept-2-yl-N- {1 - [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -methylsulfonamide can be prepared by operating as described in Example 8, starting from 1.8 g of N- (1R, 2R, 4S) -bicyclo [2,2,1] hept-2-yl-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} amine, 25 cm3 of dichloromethane, 0.7 cm3 of triethylamine, 20 mg of 4-dimethylaminopyridine and 0.4 cm3 of methylsulfonyl chloride, for 20 hours. The oily brown residue is chromatographed on a column of silica gel (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under a pressure of 0.1 bar of argon with a 012222 mixture. cyclohexane and ethyl acetate (60Z40 by volume) and collecting fractions of 10 cm3. Fractions 3 to 12 are combined and concentrated to dryness under reduced pressure (2.7 Kpa). The residue is chromatographed on a column of silica gel (particle size 0.063-0.2 5 mm, height 30 cm, diameter 2.0 cm), eluting at a pressure of 0.1 bar of argon with a mixture of cyclohexane and titanium. ethyl acetate (70/30 volumes) and collecting 10 cm3 fractions. Fractions 4 to 10 are sonicated and concentrated to dryness under reduced pressure (2.7 kPa). 0.1 g of N- (1R, 2R, 4S) -bicyclo [2,2,1] hept-2-yl-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3 are obtained. yl} methylsulfonamide, in the form of a yellow meringue [1H NMR spectrum (300 MHz, CDCl3, δ 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 (broad, J = 8 and 6 Hz: 1H); 4.10 (mt: 1H); 4.47 (s: 1H); from 7.20 to 7.40 (mt: 8H)]. N- (1 R, 2R, 4S) -bicyclo [2,2,1] hept-2-yl-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} amine can be prepared by operating as described in Example 8, starting with 1.5 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-one, 25 cm3 of 1,2-dichloroethane , 0.6 g of (1R, 2R, 4S) -bicyclo [2,2,1] heptyl-2-amine, 1.0 g of sodium triacetoxyborohydride and 0.3 cm 3 of acetic acid with 100%. 1.8 g of N- (1R, 2R, 4S) -bicyclo [2,2,1] hept-2-yl-N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3 are obtained. yl} amine, in the form of a cream paste which will be used as it is at the next step.

Example 12 N - [(1-Benzhydryl) azetidin-3-yl] -N-phenylmethylsulfonamide can be prepared by operating as follows: To a solution of 2 g of 1-benzhydryl-3-anilino azetidine, in 40 cm3 of dichloromethane, poured 0.7 cm3 of methylsulfonyl chloride and then add 1.34 cm3 of triethylamine. 42 012222

After stirring for 4 hours and 15 minutes at 20 ° C., the reaction mixture is washed with twice 20 cm3 of water, the organic phase is dried over magnesium sulphate and then concentrated to dryness at 50 ° C. under reduced pressure (2 ° C.). 7 kPa). The brownish oil obtained is chromatographed on a column of silica gel (particle size 0.063-0.2 mm, height 26 cm, diameter 3.6 cm), eluant under a pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 50 cm3 fractions. Fractions 10 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is triturated in diethyl ether, the suspension is filtered, the solid is drained and then dried under reduced pressure (2.7 kPa). . 35 mg of N - [(1-benzhydryl) azetidin-3-yl] -N-phenylmethylsulfonamide are obtained in the form of a white solid (M.M.N. 1H (300 MHz, (CD3) 2SO d6 with addition of a few drops of CD3COOD d4, δ 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) j.

1-Benzhydryl-3-anilino azetidine can be prepared by operating as described in Example 8, starting from 5 g of 1-benzhydryl azetidin-3-one, 1.92 cm3 of aniline, 74 cm3 of dichloro -1,2-ethane, 6.3 g of sodium triacetoxyborohydride and 1.2 cm3 of 100% acetic acid. 8.81 g of 1-benzhydryl-3-anilino azetidine are obtained in the form of a brown gum which will be used as it is in the next step.

Example 13

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide can be prepared by operating as follows: At a mixture of 1.23 1 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl methylsulphonate and 0.66 g of N- (3,5-difluorophenyl) methylsulphonamide in 25 cm 3 of dioxane are added. cesium carbonate. After stirring for 5 hours at reflux temperature and then 20 hours at 20 ° C., 50 cm3 of diethyloxide and 30 cm3 of brine are added to the reaction mixture and the mixture is then stirred and decanted. Organic Laphase is dried over magnesium sulfate, filtered and concentrated to dryness at 50 ° C. under reduced pressure (2.7 kPa). The orange oil obtained is chromatographed on a column of silica gel (particle size 0.040-0.063 mm, height 25 cm, diameter 2.0 cm), eluting under a pressure of 0.5 bar of argon with a mixture of cyclohexane and ethyl acetate (65/35 by volume) and collecting 10 cm3 fractions. Fractions 6 to 10 are combined and concentrated to dryness under reduced pressure (2.7 Kpa). The residue is chromatographed on a column of silica gel (particle size 0.040-0.063 mm, height 15 cm, diameter 1.0 cm), eluting under a pressure of 0.5 bar of argon with a mixture of cyclohexane and silica gel. ethyl acetate (65/35 by volume) and collecting 5 cm3 fractions. Fraction 7 is concentrated to dryness under reduced pressure (2.7 kPa). 0.11 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide is obtained in the form of a powder-white powder [ 1H NMR Spectrum (300 MHz, CDCl3, δ 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 cm3 of anhydrous deetrahydrofuran 0.78 cm3 of diethyl azodicarboxylate and 1.31 g of triphenylphosphine are added under argon. After stirring for 16 hours at 20.degree. C., 300 cm.sup.3 of ethyl acetate are added, the reaction mixture is washed twice with 100 cm.sup.3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 g). , 7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.20-0.063 mm, height 50 cm, diameter 4 cm), eluting under a pressure of 0.6 bar of argon with a mixture of cyclohexane and silica gel. ethyl acetate (75/25 by volume) and recording fractions of 125 cm3. Fractions 6 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.8 g of unsolide are obtained which is dissolved under heat in an ethyl acetate / diisopropyl ether mixture (15/2 by volume), cooled, diluted with 100 cm3 of pentane to initiate crystallization. After filtration and drying, 1.0 g of N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamides are obtained in the form of white crystals. at 154 ° C.

N- (3,5-difluorophenyl) methylsulfonamide can be prepared by proceeding as follows: To a solution of 3.5 g of 3,5-difluoroaniline in 75 cm3 of dichloromethane is slowly added 2.0 cm3 of demethylsulfonyl chloride 3.8 cc of triethylamine and 20 mg of 4-dimethylaminopyridine. After stirring for 20 hours at 20 ° C., the reaction mixture, supplemented with 20 cm.sup.3 of dichloromethane and 20 cm.sup.3 of water, is stirred and then decanted. The organic phase is dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.063-0.200 mm, height 20 cm, diameter 2.0 cm), eluting under a pressure of 0.1 bar of argon with dichloromethane and collecting fractions of 25.degree. cm3. Fractions 14 to 20 are combined and concentrated under reduced pressure (2.7 kPa). 0.66 g of N- (3,5-difluorophenyl) methylsulfonamide is obtained in the form of a white powder.

1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl methylsulfonate can be prepared by proceeding as follows: To a solution of 12 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3 -ol in 200 cm3 of dichloromethane is added under argon in 10 minutes 3.5 cm3 of methylsulfonyl chloride, then cold to + 5 ° C and flows in 10 minutes 3.8 cm3 of pyridine. After stirring for 30 minutes at + 5 ° C. and 20 hours at 20 ° C., the reaction mixture is diluted with 100 cm 3 of water and 100 cm 3 of dichloromethane. The mixture, first filtered, is decanted. The organic phase is washed with water, then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a column of silica gel (particle size 0.063-0.200 mm, height 40 cm, diameter 3.0 cm), eluting under a pressure of 0.5 bar of argon with a mixture of cyclohexane and titanium dioxide. ethyl acetate (70/30 by volume) and collecting fractions of 100 cm3. Fractions 4 to 15 are combined and concentrated under reduced pressure (2.7 kPa). 6.8 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl methylsulphonate are obtained in the form of a yellow oil.

1- [Bis (4-chlorophenyl) methyl] azetidin-3-ol can be prepared according to the procedure described by KATRITZKY A.R. et al., J. Heterocycl. Chem., 271 (1994), starting from 35.5 g of [bis (4-chlorophenyl) methyl] amine hydrochloride and 11.0 cm3 of epichlorohydrin. 9.0 g of 1 - [bis (4-chlorophenyl) methyl] azetidin-3-ol are isolated.

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

Example 14

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (4,6-dimethylpyrimid-2-yl) methylsulfonamide can be prepared by operating as described in US Pat. Example 13 (method 2), starting from 0.20 g of N- (4,6-dimethylpyrimid-2-yl) methylsulfonamide and 0.308 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3 ol.After chromatography on a column of silica gel (particle size 0.06-0.04 mm, height 50 cm, diameter 2 cm), eluting under a pressure of 0.6 bar argon with dichloromethane then a mixture of dichloromethane + 1% of methanol and then a mixture of dichloromethane + 2% of methanol and collecting fractions of 200 cm3, fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After crystallization from diisopropyl ether, filtration and drying, 0.20 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (4,6-dimethylpyrimid-2) is obtained. -yl) - methylsulfonamide in the form of a white solid [NMR spectrum] 1H (300 MHz, CDCl3, δ in ppm): 2.39 (s: 6H); 2.89 (broad t, 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)].

N- (4,6-dimethylpyrimid-2-yl) -methylsulfonamide can be prepared by operating as follows: To a mixture of 1.23 g of 2-amino-4,6-dimethylpyrimidine, 0.77 cm3 of chloride of methylsulfonyl and 50 mg of 4-dimethylaminopyridine dissolved in 50 cm3 of dichloromethane, 1.4 cm3 of triethylamine are added at 0 ° C. After 16 hours at room temperature, the reaction medium is washed with twice 100 cm3 of water, dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). 1.0 g of a yellow powder is obtained which is treated with 15 cm3 of 10% sodium hydroxide at 100 ° C. for 1 hour. After cooling, the reaction mixture is extracted with 2 times 50 cm3 of dichloromethane. The aqueous phase is acidified to pH -1 with 5 cm3 of 10N hydrochloric acid and extracted with 2 times 50 cm3 of dichloromethane. The organic phases obtained are combined, washed with 50 cm3 of water, dried over magnesium sulfate, filtered and concentrated. 0.20 g of N- (4,6-dimethylpyrimid-2-yl) methylsulfonamide is obtained in the form of 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 operating as described in Example 13 (method 2), starting from 0.10 g of N- (1,3,4-thiadiazol-2-yl) -methylsulfonamide and 0.215 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3 After chromatography on a column of silica gel (0.06-0.022 mm 0.04 mm, height 25 cm, diameter 1 cm), eluting under a pressure of 0.8 bar of argon with an acetate mixture. of ethyl / cyclohexane 20/80 then 40/60 by volume and collecting fractions of 60 cm3, fractions 26 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After crystallization from diisopropyl ether, filtration and drying, 40 mg of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1,3,4-thiadiazole) are obtained. 2-yl) -methylsulfonamide as a white solid [1 H NMR Spectrum (300 MHz, CDCl3, δ in ppm): 3.01 (s: 3H); 3.09 (t split, J = 7 and 1.5Hz: 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 operating as follows: to a mixture of 2.02 g of 2-amino-1,3,4-thiadiazole in 10 cm3 of pyridine is added 1.5 cm3 of methylsulfonyl chloride.After 2 hours at room temperature, 60 cm3 of water are added, the reaction medium is filtered. The aqueous phase collected is acidified to pH = 2 with 1N hydrochloric acid, extracted with 2 times 50 cm3 of ethyl acetate, the organic phase washed with 2 times 50 cm3 of water, dried over magnesium sulphate, filtered and then evaporated. to dryness under reduced pressure (2.7 kPa). 0.1 g of a yellow powder is obtained. Example 16

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (thiazol-2-yl) methylsulfonamide can be prepared by operating as described in Example 15, from 0.50 g of N- (thiazol-2-yl) methylsulfonamide and 0.5 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol. After chromatography on a column of silica gel (particle size 0.06-0.04 mm, height 60 cm, diameter 2 cm), eluting under a pressure of 0.9 bar of argon with an ethyl acetate / cyclohexane mixture 20/80 then 40/60 by volume and collecting fractions of 30 cm3, fractions 9 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After crystallization from diisopropyl ether, filtration and drying, 0.21 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (thiazol-2-yl) are obtained. methylsulfonamide in the form of a white solid [NMR spectrum] 1H (300 MHz, CDCl3, δ in ppm): from 2.95 to 3.10 (mt: 2H); 3.00 (s: 3H); 3.59 (mt: 2H); 4.22 (brs: 1H); 4.69 (mt: 1H); from 7.20 to 7.35 (mt: 9H); 7.60 (mt: 1H)].

N- (Thiazol-2-yl) -methylsulfonamide can be prepared by operating as follows: to a mixture of 1.0 g of 2-aminothiazole in 5 cm3 depyridine is added 1.15 g of methylsulfonyl chloride. After 2 hours at room temperature, 20 cm3 of water are added, the reaction mixture is filtered and the solid collected (0.35 g). The collected aqueous phase is acidified to pH = 2 with 1N hydrochloric acid, extracted with 2 times 40 cm3 of ethyl acetate, the organic phase washed with 2 times 30 cm3 of water, dried over magnesium sulfate, filtered and filtered. evaporated to dryness under reduced pressure (2.7 kPa). 0.15 g of a white solid is obtained with the spectral characteristics close to the filtered solid corresponding to a mixture of N- (thiazol-2-yl) -methylsulfonamide and N- (thiazol-2-yl) -di (methylsulfonyl) imide, which it is used as is for the next step.

Example 17

N- {1- [bis- (4-Chlorophenyl) methyl] azetidin-3-yl} -N- (3-hydroxyphenyl) methylsulfonamide can be prepared by operating as follows: at a mixture of 0 5 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3-methoxyphenyl) methylsulfonamide in 20 cm3 of dichloromethane are added dropwise at 2 °. C 7.63 cc of a 1M solution of debribromide. After 20 hours at room temperature, the reaction mixture is poured onto ice and extracted with dichloromethane (60 cc). The organic phase washed with 3 times 80 cm3 of water and then twice with 80 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). 0.33 g of a white meringue is obtained which is taken up in acetonitrile, filtered and dried in order to obtain 0.20 g of a white solid (NMR Spectrum). 1H (300 MHz, CDCl3, δ in ppm): 2.81 (s: 3H); 2.86 (broad t, J = 7.5 Hz: 2H); 3.50 (broad t, J = 7.5 Hz: 2H); 4.20 (s: 1H); 4.53 (mt: 1H); 5.36 (mf: 1H); from 6.70 to 6.85 (mt: 3H); from 7.15 to 7.35 (mt: 9H)].

Example 18

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3-methoxyphenyl) methylsulfonamide can be prepared by operating as described in Example 15, from 1.58 g of N- (3-methoxyphenyl) methylsulfonamide and 2.0 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol after chromatography on a column of silica gel (particle size 0.06-0, 04 mm, height 24 cm, diameter 7.8 cm), eluting under a pressure of 0.7 bar of argon with an ethyl acetate / cyclohexane mixture 50/50 then 40/60 by volume and containing fractions of 100 cm 3, fractions 7 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa) (2.05 g). After crystallization from diisopropyl ether, filtration and drying, 0.21 g of N- {1H-bis (4-chlorophenyl) methyl] azetidin-3-yl) -N- (3-methoxyphenyl) methylsulfonamide are obtained.

N- (3-methoxypheryl) methylsulphonamide can be prepared by proceeding as follows: to a mixture of 5.0 g of 3-methoxyaniline in 150 cm3 of pyridine is added at 3 ° C, 3.14 cm3 of methylsulfonyl chloride . After 20 hours at room temperature, 200 cm3 of water and 400 cm3 of ethyl acetate are added and the reaction medium decanted. The organic phase is washed with water (400 cc) and saturated sodium chloride (400 cc), dried over magnesium sulphate, filtered and then evaporated under reduced pressure (2.7 kPa). After chromatography on a column of silica gel (particle size 0.06-0.04 mm, height 23 cm, diameter 7.8 50 012222 cm), eluting under a pressure of 0.7 bar of argon with a mixture of acetonitrile. ethyl / cyclohexane 25/75 by volume and collecting fractions of 100 cm3, fractions 24 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa), 6.21 g of N- (3-methoxyphenyl) is obtained. methylsulfonamide in the form of an orange oil.

Example 19

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3-hydroxymethyl-phenyl) -methylsulfonamide can be prepared by operating as follows: 5 g of ethyl N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (methylsulfonyl) -3-aminobenzoate in 20 cm3 of toluene are added dropwise. at -50 ° C., 1.46 cm 3 of a toluene solution containing 20% of diisopropyl aluminum hydride. After 1.5 hours at 0 ° C. and 1.5 hours at 10 ° C., the reaction medium is cooled to 0 ° C. and 20 cm3 of water are slowly added. After filtration of the precipitate and extraction with ethyl acetate, the organic phase washed with 2 times 80 cm 3 of water and then 80 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). 0.46 g of an oil is obtained, which is chromatographed on a column of silica gel (particle size 0.06-0.04 mm, height 16 cm, diameter 4 cm), eluting under a pressure of 0.7 bar. With Argon with a 40/60 volume ethyl acetate / cyclohexane mixture and collecting 20 cc fractions, fractions 72-76 are combined and concentrated under reduced pressure (2.7 kPa). 0.20 g of N- {1- [bis- (4-chlorophenyl) -methyl] -azetidin-3-yl} -N- (3-hydroxymethyl-phenyl) -methylsulfonamide is obtained in the form of a white solid. [NMR spectrum 1H (300 MHz, CDCl3, δ in ppm): 1.80 (mt: 1H); 2.83 (s: 3H); 2.87 (mt: 2H); 3.52 (mt: 2H); 4.21 (brs: 1H); 4.60 (mt: 1H); 4.74 (broad d, J - 4 Hz: 2H); from 7.10 to 7.45 (mt: 12H)]. 51 012222

Example 20

Ethyl N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (methylsulfonyl) -3-aminobenzoate can be prepared by operating as described in the example 15, from 1.58 g of ethyl N- (methylsulfonyl) -3-aminobenzoate and 2.0 g of 1- [bis- (4-chlorophenyl) methyl] azetidin-3-ol. Afterchromatography on a column of silica gel (particle size 0.06-0.04 mm, height 24 cm, diameter 7.8 cm), eluting under a pressure of 0.7 bar of argon with a mixture of ethyl acetate / cyclohexane 50/50 then 40/60 by volume and collecting 100 cm3 fractions, fractions 7 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to obtain 2.0 g of a yellow oil.

The ethyl N- (methylsulfonyl) -3-aminobenzoate can be prepared by operating as follows: to a mixture of 5.0 g of ethyl 3-aminobenzoate in 150 cm3 of pyridine is added at 3 ° C, 2 35 cm3 of methylsulfonyl chloride. After 20 hours at room temperature, 200 cm3 of water and 400 cm3 of ethyl acetate are added and the reaction medium is decanted. The organic phase is washed with water (400 cc) and 400 cm 3 of a solution saturated with chloride. of sodium, dried over magnesium sulphate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). After chromatography on a column of silica gel (particle size 0.06-0.04 mm, height 25 cm, diameter 7.8 cm), eluting under a pressure of 0.7 bar of argon with an acetate mixture of The fractions 27 to 36 are dissolved in water and concentrated to dryness under reduced pressure (2.7 kPa) to give 5.24 g of N- (methylsulphonyl) -substituted phenyl / cyclohexane. Ethyl 3-aminobenzoate in the form of an orange oil.

Example 21 52 012222

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) -methylsulfonamide can be prepared by operating as follows: 0.47 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl) -N- (piperid-4-yl) -methylsulfonamide in 20 cm3 of dichloromethane is added 0.11 cm3. isobutyraldehyde, 0.057cm3 of 100% acetic acid and 320 mg of sodium triacetoxyborohydride. After stirring for 20 hours at 20 ° C., the reaction mixture is treated with 50 cm.sup.3 of a saturated aqueous solution of sodium hydrogencarbonate and decanted. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on a column of silica gel (particle size 0.063-0.200 mm, height 20 cm, diameter 2 cm), eluting under a pressure of 0.5 bar of argon with a cyclohexane / acetate mixture. ethyl (40/60 by volume) and collecting fractions of 30 cm3. Fractions 3 to 15 are combined and concentrated under reduced pressure (2.7 kPa). 0.22 g of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) -methylsulfonamide are obtained in the form of a white meringue [1 H NMR spectrum (300 MHz, CDCl3, δ in ppm): 0.87 (d, J = 7 Hz: 6H); from 1.60 to 1.90 (mt: 5H); 1.93 (broad t, J = 11.5 Hz: 2H); 2.03 (d, J = 7.5 Hz: 2H); 2.84 (s: 3H); 2.89 (broad d, J = 11.5 Hz: 2H); 3.38 (broad t, J = 7 Hz: 2H); 3.47 (broad t, 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] azetidin-3-yl} -N- (piperid-4-yl) methylsulfonamide can be prepared by operating as follows: A solution of 19 g of N- {1- [bis- (4-chlorophenyl) methyl) azetidin-3-yl} -N- (1-tert-butoxycarbonylpiperid-4-yl) methylsulfonylamide in 100 cm3 of dioxane, 50 cm3 of 6N hydrochloric acid solution in ledioxane. After stirring for 20 hours at 20 ° C., the reaction mixture is concentrated at 50 ° C. under reduced pressure (2.7 kPa). The residue is taken up in 200 cm3 of ethyl acetate and 200 cm3 of water. The aqueous phase is alkaline with 4N aqueous sodium hydroxide solution per 200 cm 3 of ethyl acetate. This organic phase is dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). 15.5 g of N- {1- [bs- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (piperidin-4-yl) methylsulfonamide are obtained in the form of a meringuecream.

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-tert-butoxycarbonylpiperid-4-yl) methylsulfonylamide may be prepared by operating as follows: solution of 14.7 g of 4- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylamino} - (1-tert-butoxycarbonyl) -piperidine in 250 cm3 of dichloromethane is slowly added 4.60 cm3 of methylsulfonyl chloride then 4.60 cm3 of triethylamine and 100 mg of 4-dimethylaminopyridine. After stirring for 20 hours at 20 ° C., the reaction mixture is treated with 200 cm.sup.3 of a saturated aqueous solution of sodium hydrogencarbonate and then stirred for 30 minutes and decanted.The organic phase is dried over magnesium sulphate, filtered and concentrated at room temperature. dry under reduced pressure (2.7 kPa). The meringue obtained by 250 cm3 of dichloromethane is again added simultaneously with 4.60 cm 3 of methylsulfonyl chloride and then with 4.60 cm 3 of triethylamine and 100 mg of 4-dimethylaminopyridine. After stirring for 20 hours at 20 ° C., the mixture is treated with 200 cm.sup.3 of a saturated aqueous solution of sodium hydrogencarbonate and then stirred for 30 minutes and decanted. The organic phase is dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on a column of silica gel (particle size 0.063-0.200 mm, height 35 cm, diameter 5 cm), eluting under a pressure of 0.5 bar of argon with a mixture of cyclohexane and dichloroacetate. ethyl (70/30 by volume) and collecting 250 cc fractions. Fractions 4 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 19 g of N- {1- (bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-tert-butoxycarbonylpiperid-4-yl) methylsulfonylamide are obtained in the form of a cream meringue. , which will be used as it is in the next step.

4- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylamino} - (1-tert-butoxycarbonyl) -piperidine can be prepared by operating as follows: To a solution of 9.22 g of [bis (4-chlorophenyl) methyl] azetidin-3-ylamine, in dichloromethane (300 cc) was added 6.58 g 1-tert-butoxycarbonyl-piperidin-4-one. To the mixture, cooled to + 5 ° C., 9.54 g of sodium triacetoxyborohydride are added in two portions and then 1.72 cm3 of 100% acetic acid are run. After stirring for 20 hours at 20 ° C., the reaction mixture is slowly added with 500 cm 3 of a saturated aqueous solution of sodium hydrogencarbonate, then stirred well and decanted. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 50 ° C. under reduced pressure (2.7 kPa). 15 g of 4- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylamino} - (1 "tert-butoxycarbonyl) -piperidines are obtained in the form of a cream meringue which will be used as it is. '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 cm3 of dichloromethane is added, at room temperature under argon atmosphere, 0.134 cm 3 of benzaldehyde. The mixture is cooled to 0 ° C, before gradually adding 382 mg of sodium triacetoxyborohydride, then 70 mm3 of acetic acid. After stirring for 16 hours at room temperature, the mixture is poured into 50 cm 3 of a saturated aqueous solution of sodium hydrogen carbonate and then extracted with twice 25 cm 3 of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane / methanol (95/5 by volume)]. 0.29 g of N-benzyl-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} amine is obtained in the form of a colorless oil (NMR Spectrum). 1H (300 MHz, CDCl3, δ in ppm): 2.71 (tlarge, 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-3-yl amine can be obtained in the following manner: To 27 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl methylsulfonate contained in an autoclave pre-cooled to -60 ° C is added 400 cm3 of a mixture of

SP methanol and liquid ammonia (50/50 by volume). The reaction medium is then stirred at 60 ° C. for 24 hours, then left in the open air to allow evaporation of the ammonia and finally concentrated under reduced pressure (2.7 kPa). The residue is taken up in 500 cm3 of a 0.37N aqueous solution of sodium hydroxide and extracted with four times 500 cm3 of ether-ethyl ether. The combined organic phases are washed successively with two times 100 cm3 of distilled water and 100 cm3 of a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa). The residue obtained is 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 crystallized into a cream-colored solid.

Example 23 N-Benzyl-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonamide: A solution of 120 mg of N-benzyl-N- {1- [bis (4-chlorophenyl)} methyl] azetidin-3-yl} amine in 5 cm3 of dichloromethane is added at room temperature under argon, 104 mm3 of triethylamine. The mixture is cooled to 0 ° C., before adding 46.4 mm 3 of methylsulfonyl chloride, and then it is stirred at room temperature for 16 hours. The reaction mixture is diluted with 20 cm 3 of dichloromethane and then washed with twice 15 cm 3 distilled water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), providing a lacquer which is crystallized by trituration in ethanol. There is thus obtained 42 mg of N-benzyl-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonamide, 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 prepared as in Example 22 but using 188 mg of difluorobenzaldehyde and 369 mg of 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl-amine and 382 mg of sodium triacetoxyborohydride, without purification by flash chromatography. 0.48 g of N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) amine (100 ml) was obtained as a colorless oil (M.M.N. 1H (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)].

Example 25 N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) methylsulfonamide To a solution of 433 mg of N- {1- [bis (4- chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) amine in 30 cm3 of dichloromethane is added at room temperature under argon, 347 mm 3 of triethylamine. 57 012222

The mixture is cooled to 0 ° C, before adding a solution of 46.4 mm3 of methylsulfonyl chloride in 5 cm3 of dichloromethane, and it is stirred at room temperature for 1 hour. The reaction mixture is diluted with 20 cm3 of dichloromethane and then washed with twice 20 cm3 of distilled water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is introduced into solution in methanol on a Bond Elut® SCX cartridge (10 g), eluting successively with methanol and with a 1M solution of ammonia in methanol. The ammonia fractions are concentrated 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 meringue [Spectrum of NMR 1H (300 MHz, CDCl3, δ in ppm): 2.81 (s: 3H), 3.02 (broad t, J = 7.5 Hz: 2H); 3.38 (broad t, 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] azetidin-3-yl} -N- (3,5-difluorobenzyl) acetamide To a solution of 2 g N- {1- [bis (4-chlorophenyl) methyl) ] Azetidin-3-yl} -N- (3,5-difluorobenzyl) amine in 75 cm3 of dichloromethane is added at room temperature under argon, 1.6 cm3 of triethylamine. The mixture is cooled to 0 ° C before 0.66 cm3 of acetyl chloride is added thereto dropwise, followed by stirring at room temperature for 16 hours. The reaction mixture is diluted with 50 cm3 of dichloromethane and is then washed with twice 20 cm3 of distilled water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane / methanol (98/2 by volume)]. 1.2 g of N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) acetamide are obtained in the form of a colorless oil [1 H NMR spectrum (300 MHz , CDCl3, δ in ppm). A mixture of rotamers is observed. * 2.06 and 2.14 (2s: 3H in total); 2.97 (mt: 2H); 3.43 (mt: 2H); 4.20 and 4.25 (2s: 1H in total); 4.54 and 4.75 to 4.80 (mt: 1H in total); 4.68 and 4.78 (2s wide: 2H in total); 6.70 (mt: 3H); 7.24 (s wide: 8H)].

Example 27 N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-4-ylmethyl) -methylsulfonamide To a solution of 398 mg of N- {1- [ bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-4-ylmethyl) amine in 8 cm3 of dichloromethane is added at room temperature under argon, 346 mm 3 of triethylamine.The mixture is cooled to 0 ° C, before adding 155 mm3 of methylsulfonyl chloride, and then it is stirred at room temperature for 3 hours.The reaction mixture is diluted with 35 cm3 of dichloromethane, and then is washed with twice 20 cm3 of water distilled. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane / methanol (97/3 by volume)]. 288 mg of N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-4-ylmethyl) methylsulfonamide are obtained in the form of a cream-colored meringue [Spectrede NMR 1H (300 MHz, CDCl3, δ in ppm): 2.83 (s: 3H); 3.02 (broad t, 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 (broad d, J = 5.5 Hz: 2H); 8.60 (broad, J = 5.5 Hz: 2H)].

Example 28 59 012222

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-4-ylmethyl) amine can be prepared as follows: To a solution of 369 mg of [bis (4-chlorophenyl) methyl] azetidin-3-ylamine in 15 cm3 of dichloromethane is added at room temperature under argon, 0.126 cm3 of pyrid-4-yl-carboxaldehyde. The mixture is cooled to -0 ° C, before gradually adding 382 mg of triacetoxyborohydride desodium, then 70 mm3 of acetic acid. After stirring for 72 hours at room temperature, the mixture is poured into 100 cm 3 of a saturated aqueous solution of sodium hydrogencarbonate and then extracted with twice 100 cm 3 of dichloromethane. The combined organic phases are washed with 50 cm3 of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is introduced in 5 ml of methanol on a Bond Elut® SCX cartridge (10 g), eluting successively with 50 cm3 of methanol and with 60 cm3 of a 1M solution of ammonia in methanol. The ammonia fractions are combined and concentrated to dryness under reduced pressure (2.7 kPa). There is thus obtained 0.48 g of N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-4-ylmethyl) amine as a colorless oil.

Example 29 N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-3-ylmethyl) methylsulfonamide

By operating according to the procedure of Example 27 but starting from 380 mg of N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-3-yl-methyl) amine 319 mg of N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-3-ylmethyl) methylsulfonamide are obtained in the form of a cream-colored meringue. NMR Ή (300 MHz, CDCl 3, δ in ppm): 2.80 (s: 3H), 3.02 (t divided, 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 (brs: 8H), 7.31 (s: 1H), dd, J = 8 and 60 012222

Hz: 1H); 7.80 (broad d, J = 8 Hz: 1H); 8, 57 (dd, J = 5 and 1.5 Hz: 1H); 8.63 (broad d, J = 1.5 Hz: 1H)].

Example 30

N- {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-3-ylmethyl) amine can be prepared as in Example 28 but from 0.124 cm3 of pyridine. 3-yl-carboxaldehyde, 0.36 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl-amine 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 are thus obtained in the form of a colorless oil.

Example 31 N- {1 - [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1,1-dioxo-1H-1H6-benzo [d] isothiazol-3-yl) -amine To 386 mg of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ylmethyl methylsulfonate solution in 10 cm3 of dimethylformamide is added 182 mg of 1,1-dioxydet1,2-benzisothiazol-3-amine and 326 mg. of cesium carbonate. The reaction mixture is then stirred at 100 ° C. for 9 hours, and concentrated under reduced pressure (2.7 kPa). The residue is washed four times with 5 cm3 of boiling distilled water, disrupted by stirring in 5 cm3 of distilled water at ambient temperature, then collected 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-1 X 6 -benzo [d] isothiazol-3-yl are obtained. ) -amine in the form of a pasty product [[NMR spectrum] 1H (300 MHz, CDCl3, δ in ppm): 3.17 (mt: 2H); 3.61 (broad t, J = 7.5 Hz: 2H); 4.37 (s: 1H); 4.75 (mt: 1H); from 6.30 to 6.40 (mf: 1H); from 7.20 to 7.35 (mt: 8H); 7.62 (broad, J = 7.5 Hz: 1H); 7.69 (broad t, J = 7.5 Hz: 1H); 7.76 (t broad, J = 7.5Hz: 1H); 7.93 (broad, J = 7.5 Hz: 1H)]. 61 012222

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

Example 32

N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) -N'-tert-butyloxycarbonylsulfamide can be prepared in the following manner: A solution of 0.095 cm3 of alcohol, tert. butyl in 2 cm3 of anhydrous dichloromethane is added 0.048 cm 3 of chlorosulfonyl isocyanate, after 2 minutes of stirring are added successively, 0.21 g N-1- [bis- (4-chlorophenyl) methyl] azetidin -3-yl} -N- (3,5-difluorophenyl) -amine in anhydrous dichloromethane (1.25 cc), followed by triethylamine (0.084 cc). After stirring for 1 hour at a temperature in the region of 20 ° C., 2 cm 3 of a saturated solution of sodium bicarbonate is added under stirring. The reaction is decanted, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a Varian cartridge (6 cm3) packed with 3 g of Siiicefine (0.040-0.063 mm), packaged and then eluted with a mixture of petroleum ether-ethyl acetate using a Duramat pump. collecting 2 cm3 fractions. Fractions 6 to 17 are combined and concentrated under reduced pressure (2.7 kPa) at 40 ° C for 2 hours. 61 mg of N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) -N'-tert-butyloxycarbonylsulfamide are thus obtained in the form of a meringue. white [1H NMR spectra (400 MHz, CDCl3, δ in ppm): 1.47 (s: 9H); 2.77 (broad t, J = 8Hz: 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: 8Hd)

Example 33 62 012222

(RS) -N- {1 - [(4-chlorophenyl) -pyridin-3-ylmethyl] -aetinin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide can be obtained in the manner following: A mixture of 0.2 g of 3- [bromo- (4-chlorophenyl) methyl] pyridine and 0.22 g of bkazetidin-3-yl-N- (3,5-difluorophenyl) methylsulfonamide hydrochloride. in 10 cm3 of acetonitrile are added 0.2 g of potassium carbonate and 23 mg of potassium iodide and the mixture is then refluxed for 3 hours. After adding 0.2 g of potassium carbonate refluxed for another 15 hours. After cooling to 21 ° C, the insoluble matter is removed by filtration and then concentrated to dryness at 40 ° C at 2.7 kPa. 170 mg of a lacquer are obtained which is purified by chromatography on a silica cartridge (reference SIL-020-005, FlashPack, Jones Chromatography Limited, NewRoad, Hengoed, Mid Glamorgan, CF82 8AU, United Kingdom), eluting with a mixture cyclohexane; ethyl acetate 1: 1 (6 cm3 / min, fractions of 5 cm3). The fractions of Rf = 5/57 (ethyl cyclohexaneracetate 1: 1, silica plate, Merck reference 1.05719, Merck KGaA, 64271 Darmstatd, Germany) are pooled and concentrated at 2.7 kPa at 40 ° C to yield 100 mg of (RS) -N- {1 - [(4-chlorophenyl) -pyridin-3-ylmethyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide melting at 110 ° C [Specter 1H NMR * (300 MHz, (CD3) 2SO d6, δ in ppm): 2.77 (mt: 2H); 2.98 (s: 3H); 3.38 (mt: 2H); 4.50 (s: 1H); 4.70 (mt: 1H); 7.11 (mt: 2H); from 7.20 to 7.40 (mt: 2H); 7.34 (d, J = 8 Hz: 2H); 7.41 (d, J = 8 Hz: 2H); 7.72 (broad d, 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-chloro-phenyl) -pyridin-3-yl-methyl] -azetidin-3-yl} -N- (3,5-difluoro-phenyl) - methanesulfonamide can be separated on CHIRACEL OD chiral stationary phase.

First isomer: spectrum of R.M.N. 1H (300 MHz, CDCl3, δ in ppm): 2.82 (s: 3H); 2.87 (mt: 2H); 3.53 (mt: 2H); 4.29 (s: 1H); 4.47 (mt: 1H); 6.80 (mt: 63.012222 3H); 7.19 (dd, J = 8 and 5 Hz: 1H); from 7.20 to 7.35 (mt: 4H); 7.62 (broad d, J = 8 Hz: 1H); 8.45 (broad d, J = 5 Hz: 1H); 8.59 (s wide: 1H).

Second isomer: spectrum of R.M.N. 1H (300 MHz, CDCl3, δ in ppm): 2.82 (s: 3H); 2.87 (mt: 2H); 3.54 (mt: 2H); 4.29 (s: 1H); 4.48 (mt: 1H); 6.80 (mt: 5H); 7.19 (broad dd, 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 (broad d, J = 2 Hz: 1H).

N-Azetidin-3-yl-N- (3,5-difluorophenyl) -methylsulfonamide hydrochloride is obtained in the following manner: In a 500 cm3 hydrogenator, a solution of 1 g of N- (1-benzhydryl-azetidin-3) In a mixture of 2.5 cm 3 of 1M hydrochloric acid and 0.41 cm 3 of acetic acid is hydrogenated in the presence of 0.161 g of palladium hydroxide under 30 bars of hydrogen for 4 hours. The catalyst is removed by filtration on a bed of celite and the filtrate is concentrated to dryness at 40 ° C. under 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- (3,5-difluorophenyl) -methylsulfonamide can be obtained by operating as in Example 13 (Method 2) in the following manner: To a solution of 2 g of 1-benzhydryl-azetidin-3-ol in 100 cm3 of tetrahydrofuran, 0.86 g of N- (3,5-difluorophenyl) methylsulfonamide, 3.28 g of triphenyl phosphine and then 2 ml of ethyl azodicarboxylate are added successively. An increase in temperature from 22 ° C. to 29 ° C. is observed, as well as the formation of a precipitate at the end of the addition of the diethyl azodicarboxylate. After 20 h at 22 ° C., the precipitate is removed by filtration and the filtrate is then concentrated to dryness at 40 ° C. under 2.7 kPa. The residue is triturated with 5 cm3 of methanol for 20 minutes at 21 ° C providing 1.07 g of N- (1-benzhydryl-azetidin-3-yl) -N- (3,5-difluorophenyl) -methylsulfonamide in the form of a white amorphous solid. 64 012222

1-Benzhydryl-azetidin-3-ol can be prepared according to the procedure described by KATRIT2KY A.R., et al., J. Heterocycl. Chem., 271 (1994).

3- [bromo- (4-chlorophenyl) -methyl] -pyridine is obtained in the following manner: To 1.5 g of (4-chlorophenyl) -pyridin-3-yl-methanol is added 3.5 cm3 of a solution of 48% hydrobromic acid in acetic acid and 1 cm3 of acetyl bromide. The amber color mixture thus obtained is refluxed for 4 hours and then cooled to 20 ° C., concentrated to dryness at 40 ° C. under 2.7 kPa, giving 1.53 g of 3- [bromo- (4-chlorophenyl) methyl-pyridine (Rf = 75/90, 254 nm, Silica Plates, reference 1.05719, Merck KGaA, 64271Darmstatd, Germany).

(4-Chlorophenyl) -pyridin-3-yl-methanol is obtained in the following way: To a solution of 3 g of pyridine-3-carboxaldehyde in tetrahydrofuran at 5 ° C., 20 cm3 of a molar solution of bromide are added. of 4-chlorophenylmagnesium in ethyl ether. After warming to 20 ° C, it is allowed to react for 15 hours with stirring. 20 cm3 of saturated solution of ammonium chloride and 20 cm3 of ethyl acetate are then added. The mixture is decanted and the organic phases are extracted with an additional 20 cm3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulphate and then concentrated to dryness at 40 ° C. under 2.7 kPa. The residue obtained is chromatographed on silica (Amicon, 20-45 μm, 500 g silica, column diameter 5 cm), eluting with a cyclohexane / ethyl acetate mixture of 80:20 to 50:50 under a argon pressure. 0.4 bar. The fractions containing the compound of Rf = 13/53 (Merck Silica Plates, reference 1.05719, Merck KGaA, 64271 Darmstatd, Germany) are combined and evaporated to dryness at 40 ° C. under 2.7 kPa to give 2.53 g of ^ h'orophé! ') -Pyridin-3-yl ~ methanol. 65 012222

Example 34

N- {1- [bis- (4-fluoro-phenyl) -methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide is obtained in the following manner: A mixture of 0 2 g of 4,4'-difluorobenzhydryl chloride and 0.26 g of N-azetidin-3-yl-N- (3,5-difluorophenyl) methylsulfonamide hydrochloride in 10 cm3 of acetonitrile are added with 0.36 g of potassium carbonate and 27 mg of potassium iodide, and the mixture was refluxed for 3 hours. After cooling to 21 ° C, the insoluble matter is removed by filtration and then concentrated to dryness at 40 ° C at 2.7 kPa. The residue is triturated with 30 cm3 of ethyl acetate and then the solid is removed by filtration. The filtrate was concentrated to dryness at 40 ° C at 2.7 kPa to give 90 mg of pale yellow solid which was purified by BondElut SCX cartridge chromatography containing 2 g of grafted silica (Reference 1225-6019, Varian Associates, Inc. 24201). Frampton Avenue, Harbor City, CA90710, USA) eluting with 2M methanolic ammonia solution. The fractions of Rf = 16/82 (cyclohexane-ethyl acetate 7/3), silica plate, reference 1.05719, Merck KGaA, 64271 Darmstatd, Germany) are combined and concentrated under 2.7 kPa at 40 ° C. to yield 243 mg of N- {1- [bis- (4-fluoro-phenyl) -methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide melting at 98 ° C. [NMR Spectrum] 1H (300 MHz, (CD3) 2SO d6, δ in ppm): 2.74 (broad t, J = 7 Hz, 2H), 3.00 (s: 3H); 3.37 (broad t, J = 7 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-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide can be obtained in the manner next :

A mixture of about 100 mg of (4-pyridyl) - (4-chlorophenyl) -chloromethane, 143 mg of N-azetidin-3-yl-N- (3,5-difluorophenyl) methylsulfonamide hydrochloride, 17 mg of potassium iodide and 200 mg of potassium carbonate in 5 cm3 of acetonitrile is stirred for approximately 18 hours at a temperature of 20 ° C. The reaction mixture is then refluxed for 3 hours, supplemented with 17 mg of potassium iodide and refluxed for a further 2 hours. After cooling to a temperature of about 20 ° C, the reaction medium is filtered on a sintered glass. The solid is rinsed with acetonitrile and then twice 3 cm3 of ethyl acetate. The filtrates are concentrated to dryness under reduced pressure. 230 mg of a pale yellow paste is obtained which is purified by preparative chromatography on silica gelcoat [4 preparatory plates Merck Kieselgel 60F254; 20x20 cm, thickness 0.5 mm], eluting with a methanol-dichloromethane mixture (5-95 by volume). After elution of the area corresponding to the product researched, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature of 40 ° C, 12 mg of (RS) -N- {1 - [(4-chlorophenyl) - pyridin-4-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide [NMR Spectrum] 1H (300 MHz, CDCl3, δ in ppm): 2.82 (s: 3H); 2.96 (mf: 2H); from 3.50 to 3.80 (mt: 2H); 4.33 (mf: 1H); 4.54 (mt; 1H); 6.82 (mt: 3H); from 7.20 to 7.45 (mt: 6H); 8.53 (broad, J = 5.5 Hz: 2H)].

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

First isomer: spectrum of R.M.N. 1H (300 MHz, CDCl3, δ in ppm): 2.83 (s: 3H); 2.87 (broad t, 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 (broad, J = 5.5 Hz: 2H).

Second isomer: spectrum of R.M.N. 1H (300 MHz, CDCl3, δ in ppm); 2.83 (012222 (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); from 7.20 to 7.35 (mt: 6H); 8.50 (broad, J = 5.5 Hz: 2H).

(4-Pyridyl) - (4-chlorophenyl) -chloromethane can be prepared in the following manner: To a suspension of 100 mg of (4-pyridyl) - (4-chlorophenyl) methanol in 2 cm3 of toluene, cooled to a temperature of With a temperature of 0 ° C, 0.0598 cm3 of thionyl chloride was added. After 2 hours at a temperature in the region of 0 ° C. and 1 hour at a temperature in the region of 20 ° C., the reaction medium is concentrated under reduced pressure. Approximately 100 mg of (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 cm3 of ethanol is added at a similar temperature. of 20 ° C, 348 mg of sodium tetrahydroboride. After stirring for 2 hours at a temperature of 20 ° C., 90 mg of sodium tetrahydroboride are added. After about 1.5 hours at the same temperature, the reaction medium is diluted with 200 cm 3 of dichloromethane and 200 cm 3 of water. The pH of the aqueous phase is adjusted to about 5 by adding about 13 cm 3 of a 1N hydrochloric acid solution. After decantation, the aqueous phase is extracted with 3 times 100 cm3 of dichloromethane. The organic phases sontrassemblées, dried over magnesium sulfate, filtered and concentrated under reduced pressure. 2 g of (4-pyridyl) - (4-chlorophenyl) methanols are thus obtained in the form of a white powder.

Example 36 To a solution of 330 mg of {1-ibis (4-chlorophenyl) methyl] azetidin-3-yl} (3,5-difluorobenzyl) amine in 25 cm3 of tetrahydrofuran was added at 68 ° C under ambient temperature under argon. 24.4 mg of a dispersion of 75% sodium hydride in mineral oil. The mixture is stirred at room temperature for 1 hour before adding 59 mm 3 of methyl chloroformate, and the stirring is maintained for 18 hours under the same conditions. The reaction mixture is treated with 0.3 cm3 of water and the tetrahydrofuran is rotavapor-driven. The residue obtained is extracted with dichloromethane, the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane / methanol (97.5 / 2.5 by volume)]. 328 mg of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3,5-difluorobenzyl) carbamate are obtained in the form of a colorless oil (M.M.N. 1H (300 MHz, CDCl3, δ in ppm): 2.97 (mt: 2H); 3.39 (mt: 2H); 3.71 (s: 3H); 4.24 (brs: 1H); 4.45 (mf: 1H); 4.57 (s: 2H); from 6.65 to 6.80 (mt: 3H); from 7.15 to 7.30 (mt: 8H)].

Example 37

(RS) -N- {1 - [(4-Chloro-phenyl) -pyrimidin-5-yl-methyl] -azetidin-3-yl} -N- (3,5-difluoro-phenyl) -methylsulfonamide can be obtained Operating as in Example 33, starting from 0.16 g of (RS) -5- [bromo- (4-chloro-phenyl) -methyl] -pyrimidine hydrobromide, 0.131 g of N-azetidin hydrochloride. 3-yl-N- (3,5-difluorophenyl) -methanesulfonamide in 5 cm3 of acetonitrile, 303 mg of potassium carbonate and 95 mg of potassium iodide, thus obtaining 26 mg of (RS) -N- {1 1- (4-Chloro-phenyl) -pyrimidin-5-ylmethyl] -azetidin-3-yl} -N- (3,5-difluoro-phenyl) -methylsulfonamide as yellow meringue [1H NMR Spectrum] (400 MHz, CDCl3, δ in ppm): 2.83 (s: 3H), 2.91 (mt: 2H), 3.57 (mt: 2H), 4.31 (s: 1H); (mt: 1H), 6.75 to 6.90 (mt: 3H), 7.29 (s: 4H), 8.71 (s: 2H), 9.08 (s: 1H)].

The medicaments according to the invention consist of at least one compound of formula (I) or an isomer or a salt of such a compound, in the pure state or in the form of a composition in which it is combined with any other pharmaceutically compatible product which can be inert or physiologically active. The medicaments according to the invention can be used by the oral, parenteral, rectal or topical route.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as starch. , cellulose, sucrose, lactose or silica, under an argon stream. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or alcohols, a dye, a coating (dragees) or a varnish.

As liquid compositions for oral administration, it is possible to use pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil. of paraffin. These compositions may include substances other than diluents, for example wetting agents, sweeteners, thickeners, flavorings or stabilizers.

Sterile compositions for parenteral administration may be preferably aqueous or nonaqueous solutions, suspensions or emulsions. As a solvent or vehicle, 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 adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be effected in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared as sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

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

The compositions for topical administration may be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

In human therapy, the compounds according to the invention are: particularly useful for the treatment and / or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and pinocerebellar disorders, cognitive disorders, head trauma, panic attacks, peripheral neuropathies, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremor, obsessive-obsessive disorder, senile dementia, thymic disorders , Tourette's syndrome, tardive dyskinesia, bipolar disorders, descancers, drug-induced movement disorders, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, intestinal transit disorders, withdrawal from chronic treatment and abuse of alcohol or drugs (opioids, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines, for example), analgesic agents or potentiators the analgesic activity of narcotic and non-narcotic drugs ,.

The doses depend on the desired effect, the duration of the treatment and the administration route used; they are generally between 5 mget 1000 mg per day orally for an adult with unit doses ranging from 1 mg to 250 mg of active substance. In general, the doctor will determine the appropriate dosage depending on age, weight and all other factors specific to the subject to be treated.

The following examples illustrate compositions according to the invention:

EXAMPLE A

The capsules are prepared, according to the usual technique, at 50 mg of active product having the following composition: - Compound of formula (I) ...................... ............................... 50 mg -Cellulose ............... .................................................. .......... 18 mg - Lactose .................................... ......................................... 55 mg - Colloidal silica .... .................................................. ........... 1 mg - Sodium carboxymethyl starch .................................. .... 10 mg -Talc .......................................... ......................................... 10 mg - magnesium stearate ... ............................................... 1 mg

EXAMPLES

Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique: - Compound of formula (I) ....................... ............................. 50 mg 72 012222 - Lactose ............... .................................................. ............ 104 mg - Cellulose .................................. ........................................ 40 mg -Polyvidone ...... .................................................. ............... 10 mg - Sodium carboxymethyl starch .............................. .......... 22 mg 5 -Talc ................................... ................................................ 10 mg - magnesium stearate .............................................. ...... 2 mg - Colloidal silica ....................................... .......................... 2 mg - Mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3,5-24,5 ) qs 1 film-coated tablet, 245 mg

EXAMPLE C

An injectable solution containing 10 mg of active product having the following composition is prepared: - Compound of formula (I) ............................ ........................ 10 mg - Benzoic acid ..................... ......................................... 80 mg 15 '- Benzyl alcohol .. .................................................. .......... 0.06 ml - Sodium Benzoate ................................ ......................... 80 mg - 95% Ethanol .................. ................................................ 0, 4 ml - Sodium hydroxide ............................................ ........... 24 mg - Propylene glycol .................................. .............................. 1.6 ml 20 - Water ............. .................................................. ........... qs 4 ml

Claims (21)

73 012222 CLAIMS 1 - Pharmaceutical composition containing as active ingredient at least one compound of formula: R. (O R. in which R, represents a radical -N (R4) R5, -N (R4) -CO-R5, -N (R4 ) -SO 2 R 6, R 2 and R 3, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk cyano, -COOH, COOalk, -CONR7R8, -CO-NH-NRgRn), alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinyl, alkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR7R8; or a heteroaromatic selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazoly, chromannyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromannyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3 , 4-tetrahydroisoquinolyl, thiazolyl and thienyl, these heteroaromatic compounds being unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOalk, -CO-NH-NR9R10, -CONR7R8, -alk- NR 9 R 10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulphonylalkyl or hydroxyalkyl, R4 represents a radical -QR 1 XR1H-Het, -Het, -C (R11) (R12) -Ar, Ar, cycloalkyl or norbornyl, R5 represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxy, Ar, Het, -CH1Ar, -CH2Het oralkyl optionally substituted by one or more halogen, Re represents a hydroxy radical alkyl, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxy, Ar, Het, -CH1R, -CH2Het or alkyl optionally substituted with 1 or more halogen, R7 and Ra, the same or different, represent an atom of hydrogen or unradical alkyl or R7 and R8 together with the nitrogen atom to which they are attached a saturated mono- or bicyclic heterocycle having 3 to 10 chaines, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyls, Rg and R10, which may be identical or different, represent a hydrogen atom or a radical alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl or else R9 and R10 form together with the nitrogen atom to which they are attached a saturated or unsaturated mono- or bicyclic heterocycle having 3 to 10 chaines, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH2, Rn represents a hydrogen atom or a hydroxyalkyl radical, -alk -COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxyalkyl, Ar, Het, -CHgAr, -CH2Het or alkyl optionally substituted with one or more halogen, R12 represents a hydrogen atom or a hydroxyalkyl radical, -alk -COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxyalkyl or alkyl optionally substituted with one or more halogen, or Rn and R12 together with the carbon atom to which they are attached a saturated mono- or bicyclic ring having 3 to 10 members , optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl, Ar represents a phenyl, naphthyl or indenyl radical, these different radicals being optionally substituted by one or more halogen, alkyl, alkoxy, -CO- alk, cyano, -COOH, -COOa lk, -CONR13R14, -CO-NH-NR15R16, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR15R16, -NR15R16, alkylthioalkyl, formyl, CF3, OCF3, Het, -O-alk-NH-cycloalkyl, SO2NH2, hydroxy, hydroxyalkyl , -NHCOalk, NHCOOalk or on 2 adjacent carbocyclic atoms by dioxymethylene, Het represents an unsaturated or saturated mono- or bicyclic heterocycle having 3 to 10 members and containing one or more heteroatoms selected from methoxygen, sulfur and nitrogen optionally substituted with one or more alkyl or alkoxy , halogen, alkoxycarbonyl, oxo, hydroxy, the nitrogenous heterocycles optionally being in their N-oxidized form, R13 and R14, which may be identical or different, represent a hydrogen or unradical alkyl atom or else R13 and R14 together with the atom form to which they are attached a mono or bicyclic saturated heterocycle having 3 to 10 members, optionally containing another heteroatom selected from methoxygen, sulfur and nitrogen and optionally being In one or more alkyl groups, R 15 and R 16, which may be identical or different, represent a hydrogen atom or an alkyl radical or R 15 and R 16 together with the nitrogen atom to which they are attached form a saturated mono or bicyclic heterocycle having 3- to 10-membered, optionally containing another heteroatom selected from methoxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, alk represents an alkyl or alkylene radical, radicals and alkyl and alkylene moieties and radicals and alkoxy moieties are straight or branched chain and contain 1 to 6 carbon atoms and the cycloalkyl radicals contain 3 to 10 carbon atoms, the optical isomers of these compounds and their salts with a pharmaceutically acceptable inorganic or organic acid. 2 - Pharmaceutical composition according to claim 1 wherein in formula (I) Het is selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine , thiazole, thiadiazole, piperidine, piperazine, triazole, furan, tetrahydroisoquinoline, tetrahydroquinoline, these heterocycles are optionally substituted with one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF3 or CF3. 3 - Pharmaceutical composition according to claim 1 wherein in the compound of formula (I) R1 represents a radical -N (R4) R5, -N (R4> SO2R6, R2 represents either a phenyl unsubstituted or substituted by one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR7R8, hydroxyalkyl or -alk-NR7R8, or a heteroaromatic selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings, these heteroaromatic compounds being unsubstituted or substituted by a Halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR7R8, -alk-NRgR10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl, R3 represents either a phenyl which is unsubstituted or substituted by one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy; , -CO-alk, cyano, -CONR7R8, hydroxyalkyl or -alk-NR7R8, or a heteroaromatic chosen from pyridyl, pyrimidyl, thiazolyl and thienyl rings, these can be unsubstituted or substituted by unhalogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR7R8, -alk-NRgR10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl, R4 is -C (RnXR12) -Het, -Het, -C (Rn) (R, 2) -Ar, Ar or norbornyl, R5 represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxy, -CHgAr, -CH2Het or alkyl, R6 represents a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxy, -CH1R, -CH2Het or alkyl, R7 and R8, identical or different, represent a hydrogen atom or unradical alkyl or R7 and R8 together with the nitrogen atom to which they are attached form a saturated mono- or bicyclic heterocycle having 3 to 10 chaines, optionally containing another heteroatom selected from methoxygen, sulfur and nitrogen and being optionally substituted by one or more alkyls; , Rg and R10, identical or different a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical, or Rg and R10 together with the nitrogen atom to which they are attached form a saturated mono- or bicyclic heterocycle; unsaturated compound having 3 to 10 chaines, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, oxo, hydroxyalkyl or -CO-NH 2, Rn represents an atom; of hydrogen or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxyalkyl, Ar, Het, -CH2Ar, -CH2Het or alkyl optionally substituted with one or more halogen, R12 represents an atom of hydrogen or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxyalkyl or alkyl optionally substituted with one or more halogen, or R "and R12 together with the carbon atom to which they are attached a ring mono or b saturated icyclic ring having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl, Ar represents a phenyl or naphthyl radical, these different radicals are optionally substituted by one or more halogen, alkyl, alkoxy, -CO-alk, cyano, -CONR13R14, alkylsulfonyl, -alk-NR15R16, -NR15R16, CF3, OCF3, SO2NH2, hydroxy, hydroxyalkyl or on 2 adjacent carbon atomsby dioxymethylene, Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl , oxo, hydroxy, OCF3 or CF3, R12 and R14, identical or different , represent a hydrogen atom or unradical alkyl or R13 and R14 form together with the nitrogen atom that they are attached a mono or bicyclic saturated heterocycle having 3 to 10 members, optionally containing another heteroatom selected bymioxygen, sulfur and nitrogen and optionally being substituted by one or more alkyls, R15 and R16, which may be identical or different, represent a hydrogen atom or a unradical alkyl atom or R15 and R16 together with the nitrogen atom which they are attached to form a saturated mono- or bicyclic heterocycle having 3 10-membered, optionally containing another heteroatom selected from methoxygen, sulfur and nitrogen and being optionally substituted with one or more alkyls, the optical isomers thereof. compounds and their salts with a pharmaceutically acceptable inorganic or organic acid. 4 - Pharmaceutical composition according to claim 1 whereininthe compound of formula (I) R1 represents a radical -N (R4) -SO2Re, R2 represents either a phenyl unsubstituted or substituted by one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy cyano, -CONR7R8, hydroxyalkyl or -alk-NR7R8; or a heteroaromatic member selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings, which heteroaromatic groups may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR7R8 or hydroxyalkyl, R3 represents either unsubstituted or substituted phenyl one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR7R8, hydroxyalkyl or -a! k-NR7R8; or a heteroaromatic member selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings, which heteroaromatic groups may be unsubstituted or substituted with halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR7R8 or hydroxyalkyl, R4 represents -Het or Ar, R6 represents a hydroxyalkyl or alkyl radical, R7 and R8, which may be identical or different, represent a hydrogen atom or a unradical alkyl atom, or R7 and R8 together with the nitrogen atom to which they are attached form a saturated mono- or bicyclic heterocycle having 3 with 10 chains, optionally containing another heteroatom selected from methoxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl, Ar represents a phenyl or naphthyl radical, these different radicals are optionally substituted with one or more halogen, alkyl, alkoxy, -CO-alk , cyano, -CONR13R14, -alk-NR15R16, -NR15R16, CF3, OCF3, SO2NH2, hydroxy or hydro xyalkyl, Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted by one or more alkyls, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF3 or CF3, R13 and R14, which may be identical or different, represent a hydrogen atom or a unradical alkyl or else R13 and R14 together with the atom form wherein they are attached to a saturated mono- or bicyclic heterocycle having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyls, R1S and R16, which may be identical or different, represent an atom of hydrogen or unradical alkyl or R1S and R16 together with to the nitrogen atom to which they are attached a mono or bicyclic saturated heterocycle having 3 to 10 members, optionally containing another heteroatom selected from methoxygen, sulfur and nitrogen and being optionally substituted by one or more alkyls, the optical isomers of these compounds and their salts with a pharmaceutically acceptable mineral or organic acid. 5 - Composition according to claim 1 for which the compound of formula (I) is chosen from 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} -N- (6-ethylpyrid-2-yl) methylsulfonamide, N- {B- (4-Chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide N- {1- [bis (4-chlorophenyl) methyl] azetidin-3 N- {1 - [[N- (4-chlorophenyl) methyl] azetidin-3-yl} -N-isoquinol-5-ylmethylsulfonamide; N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-pyrid-3-ylmethylsulfonamide N- {1- [bis- (4-chlorophenyl) methyl) ] azetidin-3-yl} -N- (1-oxide-pyrid-3-yl) -methylsulfonamide, "► N- (1R, 2S, 4S) -bicyclo [2,2,1] hept-2-yl- N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl] methylsulfonamide, N- (1R, 2R, 4S) -bicyclo [2,2,1] hept-2-yl-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-YLJ 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-methoxyphenyl) -methylsulfonamide) chlorophenyl) methyl] azetidin-3-yl} -N- (3-hydroxymethyl-phenyl) methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N N - {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) -methylsulfonamide, ethyl (methylsulfonyl) -3-aminobenzoate N -benzyl-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} amine, N- {1- [bis (4-chlorophenyl) methyl] azetdin-3-yl} -N- 5-difluorobenzyl) amine, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-dithluorobenzyl) methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl]; 4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyri d-3-yl-methyl) -methylsulfonamide, N- {1- [bis- (4-fluoro-phenyl) -methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -5-methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) -pyrid-3-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N- {1-K4-Chlorophenyl) -pyrid-3-ylmethyl} -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, (S) -N4H (4-chlorophenyl) -pyrid- 3-yl-methyl-3-azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) -pyrid-4-ylmethyl] - azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) -pyrid-4-ylmethyl] azetin-3-one N- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrid-4-ylmethyl] azetidin-3-yl} -N- (3,5-Difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) ) -methylsulfonamide, 20 (R) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophen) 1H-methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrimidin-5-ylmethyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) -methylbenzylsulfonamide, 012222 N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) benzylsulfonamide, their optical isomers and their salts with an inorganic or organic-pharmaceutically acceptable acid. 6 - A compound of formula: R. (I) in which R, represents a radical -NiRJRg, -N (R4) -CO-R5, -N (R4) -SO2R6 (R2 and R3, identical or different, represent either a aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, COOalk, -CONR7R8, -CO -NH-NRgR10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR7R8, or a heteroaromatic selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromannyl, 2,3-dihydrobenzofuryl, 2, 3-dihydrobenzothienyl, furyl, imidazolyl, isochromannyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl and thienyl, these heteroaromatic compounds being unsubstituted or halogen substituted, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOalk, -CO-NH-NRgR10, -CONR7R8, -alk-NRgR10, alkylsulfanyl, alkylsulphinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R4 represents a ## STR5 ## wherein R 5 is hydrogen or hydroxyalkyl, -alk-COOalk, -alk-CONR 7 R 8, - R 5, -Het, -Het, -CCR, R, R, Ar, Ar, cycloalkyl or norbornyl; alk-NR7R8, alkoxy, Ar, Het, -CH2Ar, -CH2Het oralkyl optionally substituted with one or more halogen, R6 represents a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxy, Ar, Het , -CH 1 Ar, -CH 2 Het or alkyl optionally substituted with 1 or more halogen, R 7 and R 8, which may be identical or different, represent a hydrogen atom or a radical alkyl, or R 7 and R 8 together with the nitrogen atom to which they are attached a saturated mono- or bicyclic heterocycle having 3 to 10 chaines containing vent another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyls, Rg and R10, which may be identical or different, represent a hydrogen atom or a radical alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O R 1 and R 10 together with the nitrogen atom to which they are attached form a saturated or unsaturated mono- or bicyclic heterocycle having 3 to 10 chaines, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted. by one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH2, Rn represents a hydrogen atom or a hydroxyalkyl radical; , -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxyalkyl, Ar, Het, -CHaAr, -CH2Het or alkyl optionally substituted by one or more halogen, R12 represents a hydrogen atom or a hydroxyalkyl radical, -alk-CO Oalk, -alk-CONR7R8, -alk-NR7R8, alkoxyalkyl or alkyl optionally substituted by one or more halogen, or Rn and R12 together with the carbon atom to which they are attached a saturated mono or bicyclic ring having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl, Ar represents a phenyl, naphthyl or indenyl radical, these different radicals being optionally substituted by one or more halogen, alkyl, alkoxy, -CO -alk, cyano, -COOH, -COOalk, -CONR13R14, -CO-NH-NR15R16, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR15R16, 7 - Compound of formula (I) according to claim 6 for which Het is chosenbenzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole , thiadiazole, piperidine, piperazine, triazole, furan, tetrahydroisoquinoline, tetrahydroquinoline, these heterocycles being optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF3 or CF3. 8 - Compound of formula (I) according to claim 6, for which R represents R 1, R 4, R 4, R 4, R 2, R 2 represents either a phenyl which is unsubstituted or substituted by one or more halogen. alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR7R8, hydroxyalkyl or -alk-NR7R8; or a heteroaromatic chosen from pyridyl, pyrimidyl, thiazolyl and thienyl rings, these heteroaromatic groups being unsubstituted or substituted by unhalogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR7R8, -alk-NRgR10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl, R3 is either phenyl unsubstituted or substituted by one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR7R8, hydroxyalkyl or -alk-NR7R8; or a heteroaromatic chosen from pyridyl, pyrimidyl, thiazolyl and thienyl, these heteroaromatic rings being unsubstituted or substituted by unhalogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR7R8, -alk-NR9R10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl, R4 represents a radical --CiR ^ XR ^ J -Het, -Het, -C (Rn) (R12) -Ar, Ar or norbornyl, R5 represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8 , -alk-NR7R8, alkoxy, -CH1Ar, -CH2Het or alkyl, Re represents a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxy, -CH1R, -CH2Het or alkyl , R7 and R8, which may be identical or different, represent a hydrogen atom or an unstituted alkyl group, or else R7 and R8 together with the nitrogen atom to which they are attached form a saturated mono- or bicyclic heterocycle having 3 to 10 8 922 22 2 members, containing optionally another heteroatom selected bymioxygen, sulfur and N and being optionally substituted with one or more alkyls, Rg and R10, which may be identical or different, represent a hydrogen atom or a radical alkyl, cycloalkyl, alkylcycloalkyl, -a, kO-alk or hydroxyalkyl, orb together Rg and R10 together with the atom nitrogen to which they are attached a saturated or unsaturated mono- or bicyclic heterocycle having 3 to 10 chaines, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, oxo, hydroxyalkyl or -CO-NH2, Rn represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxyalkyl, Ar, Het, -CHsAr, -CH2Het or optionally alkyl substituted by one or more halogen, R12 represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR7R8, -alk-NR7R8, alkoxyalkyl or alkyl optionally substituted with one or more halogen, or Rn and R12 together with the carbon atom to which they are attached form a saturated mono or bicyclic ring having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl, Ar represents a phenyl or naphthyl radical, these different radicals are optionally substituted by one or more halogen, alkyl, alkoxy, -CO-alk, cyano, -CONR13R14, alkylsulfonyl, -alk-NR15R16, -NR15R16, CF3, OCF3, SO2NH2, hydroxy, hydroxyalkyl or on 2 adjacent carbon atoms by dioxymethylene, Het represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazolin, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, furan , tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted by one or more alkyls the, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF3 or CF3, R13 and Ru, identical or different, represent a hydrogen atom or unradical alkyl or R13 and R14 together with the nitrogen atom they are attached a saturated mono- or bicyclic heterocycle having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyls, R15 and R16, which may be identical or different, represent a hydrogen or an alkyl radical or else R 1 S and R 16 form together with the nitrogen atom that they are attached a saturated mono or bicyclic heterocycle having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyls, the optical isomers of these compounds and their salts with a pharmaceutically acceptable inorganic or organic acid, except for the compound for which R2 and R3 represent phenyl radicals, R1 represents a radical -N (R4) SO2R6 for which R4 represents unradical phenyl and R6 represents a methyl radical. 9 - Compound of formula (I) according to claim 6 wherein R! represents a radical -N (R4) -SO2Re, R2 represents either a phenyl which is unsubstituted or substituted by one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR7R8ihydroxyalkyl or -alk-NR7R8; or a heteroaromatic member selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings, which heteroaromatic groups may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR7R8 or hydroxyalkyl, R3 represents either unsubstituted or substituted phenyl one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR7R8, hydroxyalkyl or -alk-NR7R8; or a heteroaromatic member selected from pyridyl, pyrimidyl, thiazolyl and thienyl rings, which heteroaromatic groups may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR7R8 or hydroxyalkyl, R4 represents -Het or Ar, R6 represents a hydroxyalkyl or alkyl radical, R7 and R8, which may be identical or different, represent a hydrogen atom or an alkyl radical or R7 and R8 together with the nitrogen atom to which they are attached form a saturated mono- or bicyclic heterocycle having 3 to 10 chaines, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl, Ar represents a phenyl or naphthyl radical, these different radicals are optionally substituted by one or more halogen, alkyl, alkoxy, -CO-alk, cyano, -CONR13R14, -alk-NR15R16, -NR15R16, CF3, OCF3, SO2NH2, hydroxy or hydroxyalkyl, He t represents a heterocycle selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted; by one or more alkyls, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF3 or CF3, R13 and R14, which may be identical or different, represent a hydrogen atom or a unradical alkyl or else R13 and R14 together with the atom form wherein they are attached to a saturated mono- or bicyclic heterocycle having 3 to 10 members, optionally containing another heteroatom selected from methoxygen, sulfur and nitrogen and being optionally substituted with one or more alkyls, R15 and R16, which may be identical or different, represent a hydrogen atom or unradical alkyl or else R15 and R16 together form with the atom of nitrogen, which are attached to a saturated mono- or bicyclic heterocycle having 3 to 10 members, optionally containing another heteroatom selected from methoxygen, sulfur and nitrogen and being optionally substituted with one or more alkyls, the optical isomers of these compounds and their salts with a mineral acid or pharmaceutically acceptable organic compounds, with the exception of the compound for which R2 and R3 represent phenyl radicals; represents a radical -N (R4) SO2R, for which R4 represents unradical phenyl and R6 represents a methyl radical. ·· 10 - Compound of formula (I) according to claim 6 selected from 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} -N- (6-ethylpyrid-2-yl) methylsulfonamide, N- {1} [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmethylsulfonamide, N- {1 - [bis- (4-chlorophenyl) methyl] azetidin-3-yl ) -N-Quinol-5-yl-methylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-isoquinol-5-ylmethylsulfonamide, N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N-pyrid-3-ylmethylsulfonamide, N- {1- [bis- (4 "chlorophenyl) methyl] azetidin-3 N-(1-oxide-pyrid-3-yl) -methylsulfonamide, N- (1R, 2S, 4S) -bicyclo [2,2,1] hept-2-yl-N- {1- [N] - bis- (4-chlorophenyl) methyl] azetidin-3-yl} -methylsulfonamide, N- (1 R, 2R, 4S) -bicyclo [2,2,1] hept-2-yl-N- {1 - [bis (4-chlorophenyl) methylazetidin-3-yl] methylsulfonamide, N- {1-bis- (4-chlorophenyl) methyl] az tidin-3-yl} -N- (3,5-difluorophenyl) methylsutfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-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-hydroxyphenyl) methylsulfonamide 1-hydroxy-phenyl) methylsulfonamide, N- {1-Bis (4-chlorophenyl) methyl] -azetidin-3-yl} -N- (methylsulfonyl) -3-aminobenzoate, [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) -methylsulfonamide, N-benzyl-N- {1- [bis (4-chlorophenyl) methyl) ] azetidin-3-yl} amine, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) amine, N- {1- [bis (4 chlorophenyl) methyl] azetidin-3-yl} -N- (3,8-difluorobenzyl) methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyridinol) 3-yl-methyl) -methylsulfonamide, N- {1- [bis - (4-Fluoro-phenyl) -methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) -pyrid) 3-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) -pyrid-3-yl-methyl] -azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) -pyrid-3-ylmethyl] azetidin-3-yl N - (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) -pyrid-4-ylmethyl] azetidin-3-yl} -N- ( 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-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS ) -N- {1 - [(4-Ch, orophenyl) -pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N - {1 - [(4-Chlorophenyl) -pyrimidin-5-ylmethyl] 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 salts with an inorganic or organic-pharmaceutically acceptable acid. N- {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, its optical isomers and its salts with an inorganic or organic acid pharmaceutically acceptable. 12 - Process for the preparation of the compounds of formula (I) according to claim 6 for which R1 represents a radical -N (R4) R5 in whichR5 is a hydrogen atom, R4 is a radical -CRMR12 -Ar or -CR ^ R ^ -Het 20 and R12 is a hydrogen atom characterized in that a Rb-CORn derivative is reacted for which Rn has the same meanings as in claim 6 with a derivative of the formula: ## STR2 ## R 2 represents radical Ar or Het, R 2, R 3, R 1 Ar and Het have the same meanings as in claim 6, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 13 - Process for the preparation of the compounds of formula (I) according to claim 6 wherein R, represents a radical -N (R4) -CO-R5 in which R4 is a radical -CiR ^ XR ^ J-Het or -CiR ^ XR And R 12 is a hydrogen atom characterized in that a Hal-COR 5 derivative is reacted with a derivative of the formula: Hal represents a halogen atom Rb represents a radical Ar or Het and R2> R3. R5. R11, Ar and Het have the same meanings as in claim 6, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 14 - Process for the preparation of the compounds of formula (I) according to claim 6 wherein R, represents a radical -N (R4) -SO2R6 in which R4 is a -CIR ^ XR ^ J-Ar or -CfR ^ XR ^ Het radical and R12 is a hydrogen atom characterized in that a Hal-SOjRe derivative is reacted with a derivative of the formula: 97 '012222 N RbH R2, R3. Rn, R5 have the same meanings as in claim 6, Hal represents a halogen atom and Rb represents an Ar and Het radical, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 15 - Process for the preparation of the compounds of formula (I) according to claim 6 for which R1 represents a radical -N (R4) R5, characterized in that a derivative R5 (R4) NH is reacted with a derivative of formula: R. R 2, R 3, R 4) R 5 have the same meanings as in claim 6, isolates the product and optionally converts it into a pharmaceutically acceptable salt. -NR15R16, alkylthioalkyl, formyl, CF3, OCF3, Het, -O-alk-NH-cycloalkyl, SO2NH2, hydroxy, hydroxyalkyl, -NHCOalk, NHCOOalk or on 2 adjacent carbocyclic atoms by dioxymethylene, Het represents an unsaturated mono or bicyclic heterocycle or saturated, having 3 to 10 members and containing one or more heteroatoms selected from 20. oxygen, sulfur and nitrogen optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, the nitrogenous heterocycles optionally being in their N-oxidized form, R13 and R14, identical or different, represent a hydrogen atom or unradical or R13 and R14 together with the nitrogen atom to which they are attached form a mono or bicyclic saturated heterocycle having 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted by one or more alkyls, R15 and R16, which may be identical or different, represent a hydrogen atom or an alkyl radical, or R1S and R16 form together with the nitrogen atom that they are attached a mono or bicyclic saturated heterocycle having 3 to 10 members, containing optionally another heteroatom selected bymioxygen, sulfur and nitrogen and being optionally substituted by one or more alkyl, alk represents an alkyl or alkylene radical, the radicals and alkyl and alkylene moieties and the radicals and alkoxy moieties are straight or branched chain and contain 1 to 6 carbon atoms and the cycloalkyl radicals contain 3 to 10 carbon atoms, the optical isomers of these compounds and their salts with a pharmaceutically acceptable inorganic or organic acid with the exception of the compound for which R2 and R3 represent phenyl radicals, R1 represents a radical -N (R4) SO2R6 for which R4 represents unradical phenyl and R6 represents a methyl radical. 16 - Process for the preparation of the compounds of formula (I) according to claim 6 for which R! represents a radical -N (R4) SO2R6, characterized in that a Hal-SC1R6 derivative is reacted with a derivative of formula: ## STR2 ## R 1, R 2, R 3, R 4 and R 6 have the same meanings as in claim 6 and Hal represents a halogen atom, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 17 - Process for the preparation of the compounds of formula (I) according to claim 6 wherein R, represents a radical -N (R4) COR5characterized in that a Hal-CORg derivative is reacted with a derivative of formula: R 2, R 3, R 4 and R 5 have the same meanings as in claim 6 and Hal represents a halogen atom, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 18 - Process for the preparation of the compounds of formula (I) according to claim 6 wherein R1 represents a radical -N (R4) -SO2-R6, R4 is a radical Het or Ar characterized in that one reacts a derivative Rd-NH-SO2-R6 with a derivative of formula: ## STR2 ## Rd represents an Ar or Het radical, Rz, R3 and Rg have the same meaningsque in claim 6 and Ms represents a methylsulfonyloxy radical, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 19 - Process for the preparation of the compounds of formula (I) according to claim 6 characterized in that a R2-CHBr-R3 derivative is reacted with a derivative of formula: HN- R 2 and R 3 have the same meanings as in claim 6, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 20 - Process for the preparation of the compounds of formula (I) according to claim 6, for which R, represents a radical -N (R4) -SO2-R6 for which R4 is a piperid-4-yl radical substituted on nitrogen by a alkyl radicalcharacterized in that a corresponding compound of formula (I) is alkylated for which R, represents a radical -N (R4) -SO2-R6 for which R4 is unradical piperid-4-yl, isolates the product and optionally converts it in pharmaceutically acceptable salt. 21 - Process for the preparation of the compounds of formula (I) according to claim 6 wherein R, represents a radical -N (R4) -SO2-R6 for which R4 is a phenyl radical substituted by a pyrrolid-1-ylevcharacterized radical in that the pyrrolidine is reacted with a corresponding compound of formula (I) wherein R, represents a radical -N (R4) SO2R6 for which R4 is a phenyl radical substituted by a halogen atom, isolates the product and optionally converts it into a pharmaceutically acceptable salt.