SK287445B6 - Pharmaceutical compositions containing azetidine derivatives, azetidine derivatives and preparation thereof - 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 invention also relates to derivates of formula (I), their pharmaceutically acceptable salts and their preparation.

Description

The present invention relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the general formula (I)

or a pharmaceutically acceptable salt thereof, a novel derivative of formula (I), a pharmaceutically acceptable salt thereof, and a preparation thereof.

BACKGROUND OF THE INVENTION

A compound of formula (I) wherein R ² and R ³ are phenyl, R ¹ is -N (R ⁴ ) SO ₂ R ⁶ , R ⁴ is phenyl and R ⁶ is methyl is reported as a synthesis product in WO99 / 01451. The other compounds and their pharmaceutically acceptable salts are novel and form an object of the invention per se.

SUMMARY OF THE INVENTION

Within the scope of the invention of formula (I)

R ¹ is -N (R ⁴⁾ R ^5, -N (R ⁴⁾ -CO-R ⁵ or -N (R ⁴⁾ -SO ₂ R ^6,

R ² and R ³ , which are the same or different, represent or an aromatic group consisting of a group comprising a phenyl group, a naphthyl group and an indenyl group, the aromatic groups being unsubstituted or substituted by one or more substituents selected from the group consisting of an atom halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR ⁷ R ⁸ , -CO-NH-NR ⁹ R ¹⁰ , alkylsulfanyl , alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, hydroxyalkyl, and -alk-NR ⁷ R ⁸ , or a heteroaromatic group selected from benzofuryl, benzothiazolyl, benzothienyl, benzothienyl, benzothienyl, 2,3-dihy petro-furyl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl and thiazolyl and thiazolyl groups; wherein the heteroaromatic groups may be unsubstituted or substituted by substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR ⁹ R ¹⁰ , -CONR ⁷ R ⁸ , -alk-NR ⁹ R ¹⁰ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl,

R ⁴ is -C (R ^s) (R ¹²⁾ -Het, -Het, -C (R ^s) (R ¹²⁾ -Ar, Ar, cycloalkyl or norbornyl radical,

R ⁵ represents a hydrogen atom, a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or an alkyl group, optionally substituted with one or more halogen atoms,

R ⁶ represents hydroxyalkyl, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or an alkyl group optionally substituted with one or a few halogen atoms,

R ⁷ and R ⁸ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with one or more alkyl groups,

R ⁹ and R ¹⁰ , which are the same or different, represent a hydrogen atom, an alkyl group, a -COOalk group, a cycloalkyl group, an alkylcycloalkyl group, an -alk-O-alk group, a hydroxyalkyl group, or R ⁹ and R ¹⁰ together with a nitrogen atom to which they are attached form a mono- or bicyclic, saturated or unsaturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or two or more a number of substituents selected from the group consisting of alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, alk-O-alk or -CO-NH ₂ ,

R ¹¹ represents a hydrogen atom, a hydroxyalkyl group, -alk-COO-alk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxyalkyl, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl a group optionally substituted with one or more halogen atoms,

R ¹² represents a hydrogen atom, a hydroxyalkyl group, -alk-COO-alk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , an alkoxyalkyl group or an alkyl group optionally substituted with one or more halogen atoms, or also R ¹¹ and R ¹² , taken together with the carbon atom to which they are attached, form a mono- or bicyclic saturated 3- to 10-membered cyclic group which optionally contains another heteroatom from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with one or a plurality of alkyl groups, Ar represents a phenyl group, a naphthyl group or an indenyl group, the various groups being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, -CO-alk, cyano, - COOH, -COOalk, -CONR ¹³ R ¹⁴ , -CO-NH-NR ¹⁵ R ¹⁶ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -al k-NR ¹⁵ R ¹⁶ , -NR ¹⁵ R ¹⁶ , alkylthioalkyl, formyl, CF ₃ , OCF ₃ , Het, -O-alk-NHcycloalkyl, SO ₂ NH ₂ , hydroxy, hydroxyalkyl, -NHCOalk and NHCOOalk, or are substituted on two adjacent carbon atoms with a dioxymethylene group,

Het means a mono- or bicyclic unsaturated or saturated 3- to 10-membered heterocyclic group which optionally contains one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more substituents selected from the group which includes an alkyl group, an alkoxy group, a halogen atom, an alkoxycarbonyl group, an oxo group and a hydroxy group, wherein the nitrogen heterocycles are optionally in their N-oxide form,

R ¹³ and R ¹⁴ , which are the same or different, represent a hydrogen atom or an alkyl group or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group which optionally comprises an additional heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups,

R ¹⁵ and R ¹⁶ , which are the same or different, represent a hydrogen atom or an alkyl group or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group which optionally containing another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with one or more alkyl groups, and alk is an alkyl or alkylene group.

In the definitions set forth above and in the definitions below, unless otherwise noted, alkyl and alkylene groups and moieties and alkoxy and moieties have a straight or branched chain and contain 1 to 6 carbon atoms, and cycloalkyl groups contain 3- to 10- carbon atoms.

Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl. As alkoxy, mention may be made of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, tert-butoxy and pentyloxy.

Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term halogen atom includes a chlorine atom, a fluorine atom, a bromine atom and an iodine atom.

Among the heterocyclic groups Het, the following heterocyclic groups may be mentioned: benzimidazole, benzoxal, benzothiazole, benzothiophene, cinoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imide an indole group, an isoquinoline group, a pyrimidine group, a thiazole group, a thiadiazole group, a piperidine group, a piperazine group, a triazole group, a furan group, a tetrahydroisoquinoline group and a tetrahydroquinoline group, the heterocycles optionally substituted with one or more substituents selected from which includes alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ and CF ₃ .

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

Preferred compounds are those compounds of formula (I) wherein:

R ¹ is -N (R ⁴⁾ R ⁵ or -N (R ⁴⁾ -SO ₂ R ^6,

R ² is or phenyl unsubstituted or substituted with one or more substituents from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR ⁷ R ^8, hydroxyalkyl, alk and -NR ⁷ R ⁸ or a heteroaromatic group selected from the group consisting of pyridyl, pyrimidyl, thiazolyl and thienyl, wherein the heteroaromatic groups may be unsubstituted or substituted with substituents selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl trifluoromethoxy, -CONR ⁷ R ⁸ , -alk-NR ⁹ R ¹⁰ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl and hydroxyalkyl,

R ³ is or a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR ⁷ R ⁸ , hydroxyalkyl, and - alk-NR ⁷ R ^8, or a heteroaromatic group selected from the group consisting of pyridyl, pyrimidyl, thiazolyl and thienyl, these heteroaromatics to be unsubstituted or substituted by substituents selected from the group consisting of halogen, alkyl, alkoxy , hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ⁷ R ^8, -alk-NR ⁹ R ^10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl group and a hydroxyalkyl group,

R ⁴ is -C (R ^s) (R ¹²⁾ -Het, -Het, -C (R ^V) (R ¹²⁾ -Ar, Ar or norbornyl radical,

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

R ⁶ is hydroxyalkyl, -alk-COOalk, -alk-CONR ⁷ R ⁸ , alk-NR ⁷ R ⁸ , alkoxy, -CH ₂ Ar, -CH ₂ Het or an alkyl group,

R ⁷ and R ⁸ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with one or more alkyl groups, R ⁹ and R ¹⁰ , which are the same or different, are hydrogen, alkyl, cycloalkyl R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated or unsaturated 3- to 10-membered heterocyclic group which optionally it comprises an additional heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with one or more radicals from the series consisting of alkyl, -COalk, -COOalk, -CO-NHalk, oxo, hydroxyalkyl, and -CO-NH _2,

R ¹¹ represents a hydrogen atom, a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxyalkyl, Ar, Het, -CH ₂ Ar, -CH ₂ Het or an alkyl group, which is optionally substituted with one or more halogen atoms,

R ¹² represents a hydrogen atom, a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , an alkoxyalkyl group or an alkyl group optionally substituted with one or more halogen atoms, or also R ¹¹ and R 8 ¹² , together with the carbon atom to which they are attached, form a mono- or bicyclic saturated 3- to 10-membered cyclic group which optionally contains another heteroatom from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with one or more alkyl, Ar is phenyl or naphthyl radical, these different radicals being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, -CO-alk, cyano, -CONR ¹⁴ R ^I3, alkylsulfonyl, -alk-NR ¹⁶ R ^l5, -NR ^I5 R ^16, CF _3, OCF _3, SO ₂ NH _2, hydroxyl, and hydroxyalkyl, or the subs substituted on two adjacent carbon atoms with a dioxymethylene group,

Het means a mono- or bicyclic unsaturated or saturated 3- to 10-membered heterocyclic group which optionally contains one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more substituents selected from the group which includes an alkyl group, an alkoxy group, a halogen atom, an oxo group and a hydroxy group, wherein the nitrogen-containing heterocyclic groups are optionally present in their N-oxide form, Het means in particular a heterocyclic group selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene a thiophene group, a quinazoline group, a quinoxaline group, a quinoline group, a pyrrole group, a pyridine group, an imidazole group, an indole group, an isoquinoline group, a pyrimidine group, a thiazole group, a thiadiazole group, a furan group, a tetrahydroisoquinoline group and a tetrahydroquinoline group, the heterocyclic groups being optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ and CF ₃ ,

R ¹³ and R ¹⁴ , which are the same or different, represent a hydrogen atom or an alkyl group or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group which optionally comprises an additional heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups,

R ¹⁵ and R ¹⁶ , which are the same or different, represent a hydrogen atom or an alkyl group or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group which optionally comprising an additional heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups.

Even more preferred compounds are those compounds of formula (I) wherein:

R ¹ is -N (R ⁴⁾ -SO ₂ R ^6,

R ² represents or phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ⁷ R ⁸ , hydroxyalkyl and -alk-NR ⁷ R ⁸ or a heteroaromatic group selected from the group consisting of pyridyl, pyrimidyl, thiazolyl and thienyl, wherein the heteroaromatic groups may be unsubstituted or substituted with substituents selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy CONR ⁷ R ⁸ and hydroxyalkyl,

R ³ represents or phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ⁷ R ^8, hydroxyalkyl, and -alk-NR ⁷ R ^8, or a heteroaromatic group selected from the group consisting of pyridyl, pyrimidyl, thiazolyl and thienyl, these heteroaromatics to be unsubstituted or substituted by substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, CF , trifluoromethoxy, -CONR ⁷ R ^8, and hydroxyalkyl,

R ⁴ is a radical Het or Ar,

R ⁶ represents a hydroxyalkyl group or an alkyl group,

R ⁷ and R ⁸ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl groups, Ar represents a phenyl group or a naphthyl group, the various groups being optionally substituted with one or more substituents from the series consisting of halogen, alkyl, alkoxy, -CO-alk, cyano, -CONR ¹³ R ^14, -alk-NR ¹⁵ R ^ls, -NR ¹⁵ R ^16, CF _3, OCF _3, SO ₂ NH ₂ , hydroxy and hydroxyalkyl,

Het means a mono- or bicyclic unsaturated or saturated 3- to 10-membered heterocyclic group which optionally contains one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more substituents selected from the group which includes an alkyl group, an alkoxy group, a halogen atom, an oxo group and a hydroxy group, wherein Het is in particular a heterocyclic group selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoxaline , a pyrrole group, a pyridine group, an imidazole group, an indole group, an isoquinoline group, a thiazole group, a thiadiazole group, a furan group, a tetrahydroisoquinoline group, and a tetrahydroquinoline group, the heterocyclic groups being the groups are optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF _3, and CF ₃ ,

R ¹³ and R ¹⁴ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with one or more alkyl groups,

R ¹⁵ and R ¹⁶ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl groups.

Among the preferred compounds of the invention include: 7V- [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] ^-N - (6-chloropyrid-2-yl) methyl sulfonamide, 7V- [l- [ bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (6-ethylpyrid-2-yl) methylsulfonamide, N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -A ^, quinolinyl-6-ylmetylsulfónamid, 7V- [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N-quinolin-5-ylmetylsulfónamid,

7V- [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - <W-isoquinolin-5-yl-methyl sulfonamide.

N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N-pyrid-3-ylmethylsulfonamide, N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - 7V- (l-oxidpyrid-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-yl] - methylsulfonamide, N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide,

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

N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (3-hydroxyphenyl) methylsulfonamide, N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N - (3-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-isobutylpiperid-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- (3,5-difluorobenzyl) methylsulfonamide, N- [1- [bis (4-chlorophenyl) methyl] azetidin-3- yl] -7V- (pyridin-3-ylmethyl) methylsulfonamide,

N- [1- [bis (4-fluorophenyl) methyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, [eta] &lt; 5 &gt; -A- [1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl] - N - (3,5-difluorophenyl) methylsulfonamide, (R) - N - [1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl] -A- (3,5-Difluorophenyl) methylsulfonamide, (S) -N- [1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, (7) S) -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-Chloro-phenyl) -pyrid-4-ylmethyl] -azetidin-3-yl] -N- (3,5-difluoro-phenyl) -methylsulfonamide, (7 S) -A- [1 - [ (4-Chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, N, N-N- [1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl] -N ^/ - (3,5-difluorophenyl) methylsulfonamide, (S i N- [l - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl] -N- (3 , 5-difluorophenyl) methylsulfonamide,

N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (3,5-difluorophenyl) benzylsulfonamide, their optical isomers, and their pharmaceutically acceptable salts.

Compounds of formula (I) wherein R ¹ is -N (R ⁴ ) R ⁵ wherein R ⁵ is hydrogen, -N (R ⁴ ) -CO-R ⁵ , -N (R ⁴ ) -SO ₂ R ^6, R ⁴ is -C (R ^H) (R ¹²⁾ -Ar or -C (R ^s) (R ¹²⁾ -Het and R ¹² is H, may be prepared by the following reaction scheme:

In the above formulas, R ² , R ³ , R ⁶ and R ¹¹ have the same meanings as those given for formula (I), R b is Ar or Het, with Ar and Het having the same meanings as those mentioned above and Hal represents a halogen atom, preferably a chlorine or bromine atom.

Step a is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (such as dichloromethane or chloroform) at a temperature of 15 to 30 ° C in the presence of a base such as a trialkylamine (such as triethylamine or dipropylethylamine) or pyridine at 0 to 30 ° C.

Step b is preferably carried out in methanol in an autoclave at a temperature of 50 to 70 ° C.

Step c is generally carried out in an inert solvent such as a chlorinated solvent (e.g. dichloromethane) in the presence of sodium triacetoxyborohydride and acetic acid at a temperature near 20 ° C.

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

Rb-COR ¹¹ derivatives are commercially available or can be obtained by procedures as described, for example, in RCLarock, Coprehensive Organic Transformations, VCH editor.

Hal-SO ₂ R ⁶ derivatives are commercially available or can be obtained by halogenating the corresponding sulfonic acids, especially in situ in the presence of chlorosulfonyl isocyanate and alcohol, in a halogenated solvent environment (e.g. dichloromethane or chloroform).

Hal-COR ⁵ derivatives are commercially available or can be prepared by halogenating the corresponding carboxylic acids, especially in situ in the presence of thionyl chloride in a halogenated solvent (e.g. dichloromethane or chloroform).

Azetidinols 1 can be obtained using the optionally modified procedures described in Katritzky A.R. et al., J. Heterocycl. Chem., 271 (1994) or in Dave P.R., J. Org. Chem., 61, 5453 (1996) and in the examples. In general, the following reaction scheme is followed:

A

hydroxylamin

N .OH

B

br

N l | l

R ²

ABOUT

in the above formulas, R ² and R ³ have the same meanings as those given in relation to the general formula (I) and Hal represents a chlorine atom or a bromine atom.

Step A is preferably operated in an inert solvent such as an aliphatic alcohol containing 1 to 4 carbon atoms (e.g. ethanol or methanol), optionally in the presence of an alkali metal hydroxide at the boiling point of the reaction mixture.

In step B, the reduction is generally carried out with lithium aluminum hydride in tetrahydrofuran at the boiling point of the reaction mixture.

Step C is preferably carried out in an inert solvent such as an aliphatic alcohol containing 1 to 4 carbon atoms (e.g. ethanol or methanol) in the presence of sodium bicarbonate at 20 ° C to the boiling point of the reaction mixture.

Step D follows the method described by Grisar M. et al., J. Med. Chem., 885 (1973). A magnesium analog of the brominated derivative is formed, which is then reacted with the nitrile in an ether such as diethyl ether at a temperature ranging from 0 ° C to the boiling point of the reaction mixture. After alcohol hydrolysis, the imine intermediate is reduced in situ with sodium borohydride at a temperature between 0 ° C to the boiling point of the reaction mixture.

The R ² -CO-R ³ derivatives are commercially available or can be obtained using the optionally adapted methods described in Kunder NG et al., J. Chem.Soc. Perkin Trans 1, 2815 (1997); Moreno-Marras M., Eur. J. Med. Chem., 23 (5) 477 (1988); Skinner et al., J. Med. Chem., 14 (6) 546 (1971); Hum NK, Tet. Lett., 36 (52) 9453 (1995); Medici A. et al., Tet. Lett., 24 (28) 2901 (1983); Rieke RD 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 R ³ Br derivatives are commercially available or can be obtained using the optionally adapted methods described in Brandsma K. et al., Synth.Comm., 20 (11) 1697 and 3153 (1991); Lemaire M. et al., Synth. Comm., 1994, 24 (1) 95; Goda H. et al., Synthesis, 9,849 (1992); Baeurle P. et al., J. Chem.Soc. Perkin Trans 2,489 (1993).

The compound R ² CN are commercially available or may be obtained by application or adapting methods described in Bouyssou P. et al., J.HetChem, 29 (4) 895 (1992); Suzuki N. et al., J. Chem. Chem. Comm., 1523 (1984); Marburg S. et al., J. Het. Chem., 17, 1333 (1980); Percec V. et al., J. Org. Chem., 60 (21) 6895 (1995).

Compounds of formula (I) wherein R ¹ is -N (R ⁴ ) R ⁵ may be prepared according to the following reaction scheme:

In the above formulas, R ² , R ³ , R ⁴ and R ⁵ have the same meanings as given in connection with the general formula (I).

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

The compounds HN (R ⁴ ) R ⁵ are commercially available or can be prepared according to classical known methods or using the optionally modified methods described in Park KK et al., J. Org. Chem., 60 (19) 6202 (195); Kalir A. et al., J. Med. Chem., 12 (3) 473 (1969); Sarges R., J. Org. Chem., 40 (9) 1216 (1975); Zaugg HE, J. Org. Chem., 33 (5), 2167 (1968); Chem., 10, 128 (1967); J. Am. Soc., 2244 (1955); Chem. Ber., 106, 2890 (1973); Pharm. Bull., 16 (10), 1953 (1968); Bull. Soc. Chim. Fr, 835 (1962).

Azetidinones 2 can be obtained by oxidation of the corresponding azetidinols, preferably in dimethylsulfoxide, using sulfur trioxide pyridine complex at about 20 ° C or using dimethylsulfoxide in the presence of oxalyl chloride and triethylamine at a temperature between -70 ° C and -50 ° C.

Compounds of formula (I) wherein R ¹ is -N (R ⁴ ) COR ⁵ or -N (R ⁴ ) SO ₂ R ⁶ may be prepared according to the following reaction scheme:

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

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

Compounds of formula (I) wherein R ¹ is -N (R ⁴ ) SO ₂ R ⁶ , where R ⁴ is Het or Ar, can be prepared according to the following reaction scheme:

In the above formulas, R ² , R ³ and R ⁶ have the same meanings as given for formula (I), Rd stands for Ar or Het, with Het and Ar having the same meanings as given for formula (I), and Ms is methylsulfonyloxy.

Step a is generally carried out in an inert solvent such as tetrahydrofuran in the presence of triphenylphosphine and diethyl azodicarboxylate at 0 ° C to the boiling point of the reaction mixture.

Step b is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (e.g. dichloromethane and chloroform) at 15 to 30 ° C in the presence of a base such as a trialkylamine (e.g. triethylamine or dipropylethylamine) or pyridine at ambient temperature. 0 ° C to 30 ° C.

Step c is preferably carried out in an inert solvent such as dioxane in the presence of CsCO ₃ at the reflux temperature of the reaction mixture.

Derivatives in which Rd represents an N-oxide nitrogen heterocyclic group can be obtained from the corresponding non-oxide compounds by the method described in Sanghanel E. et al., Synthesis 1375 (1996).

Rd-NHSO ₂ R ⁶ derivatives can be obtained according to the following scheme:

Hal-SO ₂ -R ⁶

Rd-NH ₂ ------------ Rd-NH-SO ₂ -R ⁶

In the above formulas, Hal is a halogen atom and Rd is an Ar or Het group. The reaction is carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (such as dichloromethane or chloroform) at 15 to 30 ° C in the presence of a base such as a trialkylamine (such as triethylamine or dipropylethylamine) or pyridine at a temperature 0 to 30 ° C.

Derivatives in which Rd represents an N-oxide nitrogen heterocyclic group can be obtained by the method described in Rhie R., Heterocycles, 41 (2) 323 (1995).

Compounds of formula (I) may be prepared according to the following reaction scheme:

In the above formulas, R ¹ , R ² and R ³ have the same meanings as given in connection with the general formula (I), and Ph represents a phenyl group.

Step a is generally carried out in an alcohol such as methanol in the presence of sodium borohydride at a temperature of about 20 ° C.

In step b, a magnesium analog of the brominated compound is prepared, which is then reacted in an inert solvent such as diethyl ether or tetrahydrofuran at a temperature between 0 ° C and the boiling point of the reaction mixture.

Step c is carried out using a halogenating agent such as hydrobromic acid, thionyl bromide, thionyl chloride, a mixture of triphenylphosphine and tetrabromo- or carbon tetrachloride, in acetic acid or an inert solvent such as dichloromethane, chloroform, carbon tetrachloride or toluene at a temperature between 0 ° C and the boiling point of the reaction mixture.

Step d is carried out using hydrogen in the presence of palladium on carbon in an alcohol such as methanol at a temperature of about 20 ° C.

Step e is carried out in an inert solvent such as acetonitrile in the presence of an alkali metal carbonate (e.g. potassium carbonate) and potassium iodide at a temperature between 20 ° C and the boiling point of the reaction mixture.

The R ³ -Br derivatives and the R ² -CHO derivatives are commercially available or can be obtained by methods described, for example, in RCLarock, Comprehensive Organic Transformations, VCH editor.

Compounds of formula (I) wherein R ¹ is -N (R ⁴ ) -SO ₂ R ⁶ wherein R ⁴ is piperid-4-yl optionally substituted on nitrogen with an alkyl group may also be prepared according to the following reaction scheme :

If

In the above formulas, R ² , R ³ and R ⁶ have the same meanings as given in connection with the general formula (I), and alk represents an alkyl group and R 6 represents a tert-butylcarbonyloxy group.

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

Step b is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (e.g. dichloromethane or chloroform) in the presence of an amine such as a trialkylamine (e.g. triethylamine) at a temperature of 5 to 20 ° C.

Step c is carried out using hydrochloric acid, in dioxane, at a temperature between 0 ° C and the boiling point of the reaction mixture.

Step d is performed using any known reagent used to alkylate the amine without affecting the rest of the molecule. For example, an alkyl halide may be used in the presence of an organic base such as triethylamine, an alkali metal hydroxide (e.g. sodium or potassium hydroxide), optionally in the presence of tetrabutylammonium bromide, in an inert solvent such as dimethylsulfoxide, dimethylformamide or pyridine at 20 to 50 °. C.

Compounds of formula (I) wherein R ¹ is -N (R ⁴ ) -SO ² R ⁶ wherein R ⁴ is phenyl optionally substituted with pyrrolidin-1-yl may also be prepared by treatment of the corresponding compound of formula (I) with pyrrolidine I) wherein R ¹ is -N (R ⁴ ) -SO ² R ⁶ , wherein R ⁴ is phenyl substituted with a halogen atom.

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

It will be appreciated by those skilled in the art that, when carrying out the methods mentioned above, it is necessary to introduce a protecting group on the amino, hydroxyl and carboxyl functional groups in order to avoid side reactions. These protecting groups are groups that can then be removed without adversely affecting the rest of the molecule of the compound. Examples of amino protecting groups include tert-butyl carbamate or methyl carbamate, which can be removed with iodotrimethylsilane or allylsilane, or with a palladium catalyst. Examples of hydroxyl protecting groups include triethylsilyl and tert-butyldimethylsilyl, which can be eliminated using tetrabutylammonium fluoride or asymmetric acetals (e.g., methoxymethyl or tetrahydropyranyl) in regeneration with hydrochloric acid. As protecting groups for the carboxyl function, mention may be made of ester groups (for example allyl or benzyl), oxazole and 2-alkyl-1,3-oxazoline. Other useful protecting groups are described in Greene T.W. et al., Protecting Groups in Organic Synthesis, 2nd Ed., 1991, John Wiley & Sons.

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

The enantiomers of the compounds of formula (I) may be obtained by resolution of the racemates, for example by chromatography on a chiral column as described in Pirckle W.H. et al., Asymmetry Synthesis, vol.1, Academic Press (1983), or by salt formation or synthesis from chiral precursors. Diastereoisomers can be prepared by known classical methods (crystallization or synthesis using chiral precursors).

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

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

The compounds of formula (I) have interesting pharmacological properties. These compounds have a strong affinity for cannabinoid receptors and especially for their CB1 type. They are CB1 receptor antagonists and are also useful for the treatment and prevention of disorders that affect the central nervous system, immune system, cardiovascular and endocrine system, respiratory system and gastrointestinal system, and reproductive disorders (Hollister, Pharm.Rev .; 38, 1986, 1-. 20, Reny and Sinha, Prog.Drug.Res., 36, 71-114 (1991), Vonsroe and Sandyk, Marijuana / Cannabinoids, Neurology and Neurophysiology, 459, Murphy L. and Barthe A. Eds, CRC Press, 1992) .

Said compounds may be used for the treatment or prevention of psychoses including schizophrenia, anxiety, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, skull injuries, panic attacks, peripheral neuropathy, Alzheimer's disease, migraine, migraine, glaucoma, diseases, Raynaud's syndrome, chills, obsessive-compulsive disorders, senile dementia, gland disorders, Tourette's syndrome, delayed dyskinesia, bipolar disorders, cancer, movement disorders caused by drugs, immunological disorders, dystonia, hypothalamus, endotoxicity, endotoxicity, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, chronic types of alcohol or drug withdrawal treatment (e.g., opiates, barbiturates, cannabis, cocaine, amphetamine, pencyk) folk, hallucinogens and benzodiazepines), as analgesics or potentiators of the analgesic effect of narcotic and non-narcotic drugs. The compounds may also be used to treat or prevent bowel patency.

The affinity of the compounds of formula (I) for cannabinoid receptors was determined using the method described by Kuster JE, Stevenson JI, Ward SJ, D'Ambra TE, Haycock DA, J. Pharmacol.Exp.Ther., 264 1352-1363 (1993) .

In this assay, the IC 50 value of the compounds of formula (I) was determined to be less than or equal to 1000 nM.

Their antagonistic efficacy was determined using a cannabinoid receptor agonist induced hypothermia model in mice (CP-55940) and the method described in Pertwee R.G., Marijuana, Harwey D.J. eds., 84 Oxford IRL Press, 263-277 (1985).

In this test, the DE ₅₀ value of the compounds of formula (I) was determined to be less than or equal to mg / kg.

The compounds of formula (I) have low toxicity. The value DL ₅₀ is above 40 mg / kg by subcutaneous administration in mice.

In the following, the invention will be explained in more detail by means of specific embodiments thereof, these examples being illustrative only and not limiting the scope of the invention, which is clearly defined by the terms of the claims and the content of the described section.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

N - [1- [Bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N- (6-chloropyrid-2-yl) methylsulfonamide can be prepared as follows:

To a solution of 1.54 g of [1- [bis (4-chlorophenyl) methyl] azetidin-3-ol and 1.22 g of N- (6-chloropyrid-2-yl) methylsulfonamide in 120 cm ^{3 of} anhydrous tetrahydrofuran was added under an argon atmosphere. 2.4 cm ^{3 of} diethyl azodicarboxylate and 1.44 g of triphenylphosphine are added. After stirring at 20 ° C for 20 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.040-0.063 mm, column height 30 cm, column diameter 4.5 cm) under a pressure of 0.05 MPa argon using a cyclohexane / ethyl acetate mixture (80:20; v / v) as the eluent. collecting 60 cm ³ fractions. Fractions 6 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa). It will be obtained

1.75 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (6-chloropyrid-2-yl) methylsulfonamide as a white, brittle product.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.85-3.00 (mt: 2H), 2.91 (s: 3H), 3.57 (t doubled, 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 as described in Katritzky A.R. et al.,

J. Heterocycl. Chem., 271 (1994), starting from 35.5 g 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 by the method described by Grisar M. et al., J. Med. Chem., 885 (1973).

N - (6-Chloropyrid-2-yl) methylsulfonamide can be prepared as follows:

To a solution of 2-amino-6-chloropyridine in 12.5 cm ^{3 of} pyridine cooled to 5 ° C was added dropwise over one hour 7.8 cm ^{3 of} methylsulfonyl chloride. After warming to ambient temperature and stirring for 20 hours, 140 cm ^{3 of} water are added to the black reaction mixture and extracted with 200 cm ^{3 of} dichloromethane. The organic phase is decanted, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is chromatographed on a silica gel column (0.063-0.200 mm, 30 cm column height, 4 cm column diameter) under argon pressure using a 70/30 cyclohexane / ethyl acetate mixture, eluting with a fraction. with a volume of 60 cm ³ . Fractions 5-11 are combined, evaporated to dryness under reduced pressure (2.7 kPa). 17 g A ^f - (6-chloropyrid-2-yl) methanesulfonamide as a yellow oil.

Example 2 N- [1- [Bis- (4-Chlorophenyl) methyl] azetidin-3-yl] -N- (6-ethylpyrid-2-yl) methylsulfonamide can be prepared by the procedure described in Example 1, wherein: Starting from 0,61 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol, 0.40 g of N- (6-ethylpyrid-2-yl) methylsulfonamide, 50 cm ^{3 of} anhydrous tetrahydrofuran, 0.96 cm ³ diethylazodicarboxylate and 0.577 g triphenylphosphine. The crude product obtained is chromatographed on a silica gel column (0.040-0.063 mm, column height 20 cm, column diameter 2 cm) under a pressure of 0.05 MPa of argon, eluting with a cyclohexane / ethyl acetate mixture (70/30; v / v). collecting 30 cm ³ fractions. Fractions 6-9 are combined, evaporated 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 oxide and 5 cm @ ^{3 of} diisopropyl oxide. The suspension is filtered, the solid is centrifuged and then dried under reduced pressure (2.7 kPa). To give 0.11 g of N- [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N ^{& apos} - (6-ethyl-pyridin-2-yl) methanesulfonamide as a white solid.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 1.26 (t, J = 7.5 Hz: 3H), 2.76 (q, J = 7.5 Hz: 2H) from the 2.85 to 2.95 (mt 2H), 2.90 (s: 3H) 3.53 (t doubled, J = 7 and 2 Hz: 2H) 4.22 (s: 1H), 4.69 (s: 1H); mt: 1H), 7.07 (d, J = 7.5 Hz: 1H), from 7.15 to 7.30 (mt: 9H), 7.64 (t, J = 7.5 Hz: 1H).

N - (6-Ethylpyrid-2-yl) methylsulfonamide can be prepared as follows:

To a solution of 2-amino-6-ethylpyridine in 2.50 cm ^{3 of} pyridine cooled to 5 ° C was added dropwise

1.56 cm @ ^{3 of} methylsulfonyl chloride. After stirring at 20 DEG C. for 20 hours, 8 cm @ ^{3 of} water are added to the reaction mixture and the mixture is filtered. The filtrate is concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.040-0.063 mm, column height 30 cm, column diameter 4 cm) under an argon pressure of 0.05 MPa using initially 1.5 liters of dichloromethane as eluent and then eluting with a dichloromethane mixture. and methanol in a 98: 2 by volume ratio, collecting 60 cm ³ fractions. Fractions 8 to 12 are combined and evaporated 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 as follows:

To a solution of 0.50 g of N-quinol-6-ylmethylsulfonamide in 50 cm ^{3 of} anhydrous tetrahydrofuran is added 0.70 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol, 0.597 g of triphenylphosphine under argon, and then 0.40 cm @ ^{3 of} diethyl azodicarboxylate are added. After stirring at 20 ° C for 20 hours, the reaction mixture is heated to reflux for 4 hours, then 2.98 g of triphenylphosphine and 2.0 cm ^{3 of} diethyl azodicarboxylate are added. After stirring at 20 ° C for 48 hours, the mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is washed with 30 cm ^{3 of} diethyl ether, the suspension obtained is filtered, and the filtrate is concentrated to dryness. The fractions of the product obtained (0.90 g) are purified on a Bond Elut column containing a SCX cation exchange resin (0.054 mm granulometry, 4 cm column height, 3 cm column diameter), eluting first with methanol and then with 2 ml. M solution of ammonia in methanol and 5 cm ³ fractions are collected. Fractions 16 to 19 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 0.33 g of an oil is obtained, which is mixed with 10 cm @ ^{3 of} diisopropyl oxide. The suspension obtained is filtered. The re-filtered filtrate gave a solid after 15 minutes which was dried at 50 ° C under reduced pressure (2.7 kPa). 83 mg of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N-quinol-6-ylmethylsulfonamide are obtained in the form of a white solid.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.87 (s: 3H), 2.89 (mt: 2H), 3.55 (t doubled, J = 7 and 1 Hz): 2H), 4.18 (s: 1H), 4.69 (mt: 1H), 7.15 to 7.30 (mt: 8H), 4.47 (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-ylmethylsulfonamide can be prepared as follows:

To a solution of 1.98 g of 6-aminoquinoline in 1.75 cm ^{3 of} pyridine cooled to 3 ° C was added dropwise over 1 hour 1.1 cm ^{3 of} methylsulfonyl chloride. After stirring at 20 ° C for 20 hours, 10 cm ^{3 of} water and 50 cm ^{3 of} dichloromethane are added to the reaction mixture, then the mixture is filtered. The filtrate is decanted, the organic phase is dried over magnesium sulphate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa). 1.15 g of N-quinol-6-ylmethylsulfonamide is obtained in the form of a cream-yellow solid.

Example 4 N- [1- [Bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N-quinol-5-ylmethylsulfonamide can be prepared as follows:

To a solution of 0.50 g of N-quinol-5-ylmethylsulfonamide in 70 cm ^{3 of} anhydrous tetrahydrofuran was added 0.70 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol, 0.597 g of triphenylphosphine, under argon, and then 0.40 cm @ ^{3 of} diethyl azodicarboxylate and 0.45 g of 1,2-bis (diphenylphosphine) ethane are added. After stirring at 20 ° C for 20 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is washed with 70 cm ^{3 of} ethyl acetate, washed with 30 cm ^{3 of} brine, dried over magnesium sulfate, filtered and then concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The violet oil obtained is purified by chromatography on a silica gel column (granulometry 0.063-0.200 mm, column height 35 cm, column diameter)

3.9 cm) under an argon pressure of 0.05 MPa, eluting with a mixture of cyclohexane and ethyl acetate in a volume ratio of 40:60, then 30:70 and lastly 20:80, eluting with a 50 cm @ ³ fraction. Fractions 6 to 12 are combined and evaporated to dryness under reduced pressure. The residue is washed with 15 cm @ ^{3 of} methanol, then the suspension obtained is filtered, the solid is centrifuged and dried at 50 DEG C. under reduced pressure (2.7 kPa). 0.35 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N-quinol-5-ylmethylsulfonamide is obtained in the form of a white solid.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.60 (t, J = 7 Hz: 1H), 2.84 (t, J = 7 Hz: 1H), 2.99 ( s: 1H), 3.36 (t doubled, J = 7 and 2.5 Hz: 1H), 3.56 (t doubled, J = 7 and 2.5 Hz: 1H), 4.01 (s: 1H) ), 4.85 (mt: 1H), 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 broad, J = 8 Hz: 1H), 8.54 (d broad, J = 9 Hz: 1H), 8.99 (dd, J = 4 and 1, 5 Hz: 1H).

N-quinol-5-ylmethylsulfonamide can be prepared as described in Example 2, starting from 2.0 g of 5-aminoquinoline, 3.0 cm ^{3 of} pyridine and 1.1 cm ^{3 of} methylsulfonyl chloride. 2.47 g of N-quinol-6-ylmethylsulfonamide are obtained in the form of a brown-yellow solid.

Example 5

N - [1- [Bis (4-Chlorophenyl) methyl] azetidin-3-yl] - N -isoquinol-5-ylmethylsulfonamide can be prepared as described in Example 4, starting from 0.497 g of Misoquinol-5. -ylmethylsulfonamide, 70 cm ^{3 of} anhydrous tetrahydrofuran, 0.712 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol, 0.597 g of triphenylphosphine, 0.40 cm ^{3 of} diethyl azodicarboxylate and 0.45 g of 2-bis- (diphenylphosphine) ) ethane. The crude brown oil obtained is purified by chromatography on a silica gel column (0.063-0.200 mm granulometry, 38 cm column height, 3 cm column diameter), eluting with a cyclohexane / ethyl acetate (30:70) mixture, collecting 40 fractions. cm ³ . Fractions 8 to 23 are combined and evaporated to dryness under reduced pressure. The residue is washed with 15 cm ^{3 of} diethyl ether, then the suspension obtained is filtered and the insoluble material is chromatographed on a SCX resin column (4 cm column height, 3 cm column diameter), eluting with methanol / dichloromethane (50% by volume). 50:50 and then a 2M solution of ammonia in methanol and 20 cm ³ fractions are collected. Fractions 1 to 6 are combined and the resulting white solid is filtered off and then centrifuged and dried at 50 ° C under reduced pressure (2.7 kPa). There was obtained 0.169 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N-isoquinol-5-ylmethylsulfonamide as a white solid.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.64 (t, J = 7 Hz: 1H), 2.81 (t, J = 7 Hz: 1H), 2.98 ( s: 3H), 3.36 (t doubled, J = 7 and 2 Hz: 1H), 3.55 (t doubled, J = 7 and 2 Hz: 1H), 4.02 (s: 1H), 4, 86 (mt: 1H), 7.10 to 7.25 (mt: 8H), 7.60 (dd, J = 8 and 1 Hz: 1H), 7.66 (t, J = 8 Hz: 1H), 7.93 (d broad, J = 6 Hz: 1H), 8.06 (d broad, J = 8 Hz: 1H), 8.66 (d, J = 6 Hz: 1H), 9.32 (s broad) : 1H).

The quinolol-5-ylmethylsulfonamide can be prepared 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-ylmethylsulfonamide are obtained in the form of a beige-colored solid.

Example 6

^L - [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - / V-pyridin-3-ylmetylsulfónamid may be prepared as follows:

To a solution of 0.144 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (1-oxidopyrid-3-yl) methylsulfonamide in 5 cm ^{3 of} chloroform is added 0.042 cm ³ of phosphorus trichloride , then the mixture is heated to reflux. After stirring for 1 hour and 30 minutes, the reaction mixture is allowed to cool to ambient temperature, 5 cm ^{3 of} 0.1 N hydrochloric acid are added and the mixture is stirred and then decanted. The organic phase is diluted with 20 cm ^{3 of} chloroform, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.063-0.200 mm, column height 9 cm, column diameter 1.8 cm) under an argon pressure of 100 bar using a 95: 5 mixture of dichloromethane and methanol, collecting fractions. with a capacity of 15 cm ³ . Fractions 2-4 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is stirred with 15 cm ^{3 of} diethyl ether, the suspension is filtered, the solid is centrifuged and then dried under reduced pressure (2.7 kPa). To give 35 mg of N- [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N ^{& apos} pyrid-3-ylmetylsulfónamidu as a cream solid.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.80 to 2.95 (m: 2H), 2.87 (s: 3H), 3.51 (t doubled, J = 7) and 1.5 Hz: 2H), 4.18 (s: 1H), 4.65 (mt: 1H), 7.15 to 7.35 (mt: 8H), 7.37 (dd broad, J = 8) and 5 Hz: 1H), 7.64 (d broad, J = 8 Hz: 1H), 8.52 (d broad, J = 2 Hz: 1H), 8.61 (d broad, J = 5 Hz: 1H) ).

Example 7 N - [1- [Bis (4-Chlorophenyl) methyl] azetidin-3-yl] - N - (1-oxidopyrid-3-yl) methylsulfonamide can be prepared as follows:

To a solution of 0.265 g of [1- [bis (4-chlorophenyl) methyl] azetidin-3-ol and 0.162 g of N - (1-oxidopyrid-3-yl) methylsulfonamide in 25 cm ^{3 of} anhydrous tetrahydrofuran is added 0.16 g under argon. cm ^{3 of} diethyl azodicarboxylate and 0.226 g of triphenylphosphine. After stirring at reflux for 20 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.063-0.200 mm, column height 20 cm, column diameter 1.5 cm) under an argon pressure of 0.05 MPa, eluting with a dichloromethane / methanol (98/2 by volume) mixture. collecting 40 cm ³ fractions. Fractions 26 to 64 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is stirred with 10 cm @ ^{3 of} diethyl ether, the suspension is filtered, the insoluble matter is drained and then dried under reduced pressure (2.7 kPa). 0.10 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (1-oxidopyrid-3-yl) methylsulfonamide is obtained in the form of a white solid. 1 H-NMR (400 MHz, (CD ₃ ) ₂ SO d ₆ , 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), 7.30 to 7.50 (mt: 10H), 8.21 (d broad, J = 6.5 Hz: 1H)

8.27 (s broad Hz: 1H).

N- (1-Oxidopyrid-3-yl) methylsulfonamide can be prepared as follows:

To a solution of 1.81 g of N-pyrid-3-ylmethylsulfonamide in 71 cm ^{3 of} N, N-dimethylformamide and 3 cm ^{3 of} methanol is added portionwise 7.1 g of 50 to 55% 3-chloroperoxybenzoic acid followed by 0.56 cm ^3. 40% hydrofluoric acid. After stirring at 20 ° C for 1 hour, the reaction mixture is poured into 500 g of ice, stirred and then filtered. The filtrate is concentrated to dryness at 60 ° C and under reduced pressure (2.7 kPa). The residue is washed with 50 cm @ ^{3 of} a dichloromethane / methanol (98/2 by volume ⁾ mixture and then filtered. The filtrate is then chromatographed on a silica gel column (0.063-0.200 mm, column height 27 cm, column diameter 4 cm) under an argon pressure of 0.05 MPa using a 98: 2, then 97: 3, dichloromethane: methanol mixture and finally 50:50, collecting 60 cm ³ fractions. Fraction 62 is concentrated to dryness under reduced pressure (2.7 kPa). 0.96 g of N- [1-oxidopyrid-3-yl) methylsulfonamide is obtained as a yellowish solid.

N-Pyrid-3-ylmethylsulfonamide can be prepared 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 40 cm @ ^{3 of} diethyl ether, the suspension is filtered and the solid is centrifuged and then dried under reduced pressure (2.7 kPa). 2.47 g of N-pyrid-3-ylmethylsulfonamide 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 as follows:

To a solution of 1.8 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N-cyclohexylamine, 0.7 cm @ ^{3 of} triethylamine and 20 mg of 4-dimethylaminopyridine in 25 cm @ ^{3 of} dichloromethane are added. with stirring, 0.4 cm @ ^{3 of} methylsulfonyl chloride are added. After stirring at 20 ° C for 48 hours, 20 cm ^{3 of} dichloromethane, 20 cm ^{3 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 oily brown residue is chromatographed on a silica gel column (0.063-0.200 mm granulometry, 20 cm column height, 2.0 cm column diameter) under an argon pressure of 0.01 MPa, eluting with a 96: 4 mixture of dichloromethane and methanol, 10 cm ³ fractions are collected. Fractions 2 to 4 and 5 to 10 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, column height 30 cm, column diameter 1.5 cm) under an argon pressure of 0.01 MPa, eluting with a cyclohexane / ethyl acetate mixture (70/30 by volume). Fractions of 5 cm ³ are collected. Fractions 7 to 10 are combined and evaporated to dryness under reduced pressure (2.7 kPa). There was obtained 0.10 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N-cyclohexylmethylsulfonamide as a cream colored brittle solid.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): from 0.80 to 1.90 (mt: 10H), 2.82 (s: 3H), 3.36 (t broad, J = 7.5 Hz: 2H), 3.46 (t broad, 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).

N- [1- [bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N-cyclohexylamine can be prepared as follows:

To a solution of 1.5 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one in 25 cm ^{3 of} 1,2-dichloroethane is added 0.5 g of cyclohexylamine, 1 g of sodium triacetoxyborohydride and 0.3 cm ^{3 of} 100 % acetic acid. After stirring at 20 ° C for 20 hours, 20 cm ^{3 of} dichloromethane and 10 cm ^{3 of} water are added to the reaction mixture while stirring, and the mixture is neutralized to pH 7-8 with 1 N aqueous sodium hydroxide solution. The reaction 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-colored paste which is used as it is in the following step.

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

To a solution of 5.0 cm ^{3 of} oxalyl chloride in 73 cm ^{3 of} dichloromethane cooled to -78 ° C is added a solution of

8.1 cm ^{3 of} dimethylsulfoxide in 17.6 cm ^{3 of} dichloromethane. After 0.5 h at -78 ° C, a solution of 16.0 g of 1- [bis (4-chlorophenyl) methylazetidin-3-ol in 50 cm ^{3 of} dichloromethane is added to the reaction mixture. After 5 hours at -78 ° C, 26.6 cm ^{3 of} triethylamine are added dropwise and the reaction mixture is allowed to warm to ambient temperature. After 16 hours, the reaction mixture is washed 4 times with 200 cm @ ^{3 of} water, then with 200 cm @ ^{3 of} saturated sodium chloride solution, then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.06 mm granulometry, 21 cm column height, 9.2 cm column diameter) under an argon pressure of 0.05 MPa, eluting with a 60/60 cyclohexane / ethyl acetate mixture. The fractions of 200 cm ³ are collected. Fractions 15 to 25 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 8.9 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-one are obtained in the form of pale yellow crystals having a melting point of 111 ° C.

Example 9

^A, - [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N-cyklopropylmetylsulfónamid may be prepared as described in Example 8, starting from 1.6 g of A / - [l- [ bis (4-chlorophenyl) methyl] azetidin-3-yl] - _J V-cyclopropylamine in 25 cm ³ of dichloromethane, 0.7 cm ³ of triethylamine, 20 mg of 4-dimethylaminopyridine and 0.4 ^cm3 of methylsulfonyl chloride, the reaction was stirred 20 hours at 20 ° C. The crude product is chromatographed on a silica gel column (particle size 0.063-0.2 mm, column height 30 cm, column diameter 2.0 cm) under an argon pressure of 0.01 MPa, eluting with a 97: 3 mixture of dichloromethane and methanol. collecting 10 cm ³ fractions. Fractions 6-9 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.062-0.2 mm, column height 30 cm, column diameter 2.0 cm) under an argon pressure of 0.01 MPa, eluting with a cyclohexane / ethyl acetate mixture (70/30 by volume). collecting 10 cm ³ fractions. Fractions 6 to 11 are combined and evaporated 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 colored brittle product.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 0.79 (mt: 2H), 0.95 (mt: 2H),

2.11 (mt: 1H), 2.84 (s: 3H), 3.17 (t broad, J = 7 Hz: 2H), 3.50 (mt: 2H), 4.18 (mt: 1H) 4.29 (s 1H), from 7.20 to

7.40 (mt 8H).

A ^from - [1- [bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N-cyclopropylamine can be prepared as described in Example 8, starting from 1.5 g of [1- [bis (4- chlorophenyl) methyl] azetidin-3-one in 25 cm ^{3 of} 1,2-dichloroethane, 0.37 cm ^{3 of} cyclopropylamine, 1 g of sodium triacetoxyborohydride and 0.3 cm ^{3 of} 100% acetic acid. It will be obtained

1.6 g of N '- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N-cyclopropylamine as a brown oil, which can be used in the next step.

Example 10

N - [1 R, 25,45) -Bicyclo [2.2.1] hept-2-yl-N- [1-bis (4-chlorophenyl) methyl] azetidin-3-yl] methylsulfonamide can be prepared as described above. of Example 8, starting with 2.0 g A ^s - [17?, 2o ', 4 ° ") - bicyclo [2,2, l] hept-2-yl-N- [l-bis (4-chlorophenyl 1-methyl] azetidin-3-yl] amine, 25 cm ^{3 of} dichloromethane, 0.7 cm ^{3 of} triethylamine, 20 mg

Of 4-dimethylaminopyridine and 0.4 cm ^{3 of} methylsulfonyl chloride with stirring for 20 hours. The oily brown residue is chromatographed on a silica gel column (particle size 0.063-0.2 mm, column height 30 cm, column diameter 2.0 cm) under an argon pressure of 0.01 MPa, eluting with a dichloromethane / methanol (97: v / v) mixture. 3, fractions of 10 cm ³ being collected. Fractions 6 to 18 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.2 mm, column height 30 cm, column diameter 2.0 cm) under an argon pressure of 0.01 MPa, eluting with a cyclohexane / ethyl acetate mixture (70/30 by volume). collecting 10 cm ³ fractions. Fractions 8 to 14 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 0.70 g of A ^/ - [R, 25 ', 45j-bicyclo [2,2, l] hept-2-yl / -N [l-bis (4-chlorophenyl) methyl] azetidin-3-yl ] methylsulfonamide in the form of a cream colored brittle product.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): from 1.20 to 1.75 (mt: 7H), 1.84 (t broad, J = 12.5 Hz: 1H), 2 29 (mt: 1H); 2.35 (mt: 1H); 2.82 (s: 3H); from 3.35 to 3.55 (mt: 3H); 3.66 (mt: 1H);

3.90 to 4.05 (mt 2H), 4.51 (s: 1H), from 7.20 to 7.45 (mt 8H).

ÝV- [l R _J, 25,4S) bicyclo [2,2, l] hept-2-yl-7V- [l-bis (4-chlorophenyl) methyl] azetidin-3-yl] amine may be prepared in as described in Example 8, starting from 1.5 g of [1- [bis (4-chlorophenyl) methyl] azetidin-3-one in 25 cm ^{3 of} 1,2-dichloroethane, 1.5 g (17β, 2S, 4, S ') - bicyclo [2.2.1] heptyl-2-amine, 1 g of sodium triacetoxyborohydride and 0.3 cm ^{3 of} 100% acetic acid. 2 g of (17 R, 25,4S) -bicyclo [2.2.1] heptyl-2-yl-N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -amine is obtained in in the form of a brown oil, which may be used in the next step.

Example 11

N- [17 R, 27 R, 45) -Bicyclo [2.2.1] hept-2-yl-N- [1-bis (4-chloro-phenyl) -methyl] -azetidin-3-yl] -methylsulfonamide can be prepared by of Example 8, starting from 1.8 g of N ^f - [17, 2R, 45) bicyclo [2,2, l] ^{hept-2-yl-I '-} [l-bis (4-chlorophenyl (methyl) azetidin-3-yl] amine, 25 cm ^{3 of} dichloromethane, 0.7 cm ^{3 of} triethylamine, 20 mg of 4-dimethylaminopyridine and 0.4 cm ^{3 of} methylsulfonyl chloride are stirred for 20 hours. The oily brown residue is chromatographed on a silica gel column (particle size 0.063-0.2 mm, column height 30 cm, column diameter 2.0 cm) under an argon pressure of 0.01 MPa, eluting with a mixture of cyclohexane and ethyl acetate (60 by volume): 40, 10 cm ³ fractions being collected. Fractions 3 to 12 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.2 mm, column height 30 cm, column diameter 2.0 cm) under an argon pressure of 0.01 MPa, eluting with a cyclohexane / ethyl acetate mixture (70/30 by volume). collecting 10 cm ³ fractions. Fractions 4 to 10 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 0.10 g of N- [1, 2, 4S] -bicyclo [2.2.1] hept-2-yl-N- [1-bis (4-chlorophenyl) methyl] azetidin-3-yl] is obtained. methylsulfonamide as a yellow brittle product.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): from 1.00 to 1.85 (mt: 8H), 2.14 (mt: 1H), 2.33 (mt: 1H), 2.82 (s: 3H), from 3.40 to 3.60 (mt: 4H), 3.71 (dd broad, J = 8 and 6 Hz: 1H), 4.10 (mt: 1H),

4.47 (s: 1H), from 7.20 to 7.40 (mt 8H).

/ V- [l / ?, 2 / ?, 4S) - bicyclo [2,2, l] hept-2-yl / -N [l-bis (4-chlorophenyl) methyl] azetidin-3-yl] The amine can be prepared as described in Example 8, starting from 1.5 g of [1- [bis (4-chlorophenyl) methyl] azetidin-3-one in 25 cm ^{3 of} 1,2-dichloroethane, 0.6 g ( 12β, 27β, 4S) -bicyclo [2.2.1] heptyl-2-amine, 1 g sodium triacetoxyborohydride and 0.3 cm ^{3 of} 100% acetic acid. 1.8 g of (1R, 2R, 45) -bicyclo [2.2.1] heptyl-2-yl-N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -amine are obtained. in the form of a cream-colored paste, which is used in the next step.

Example 12

N - (1-Benzhydryl) azetidin-3-yl] - N -phenylmethylsulfonamide can be prepared as follows:

To a solution of 2 g of 1-benzhydryl-3-anilinoazetidine in 40 cm @ ^{3 of} dichloromethane is added 0.7 cm @ ^{3 of} methylsulfonyl chloride followed by 1.34 cm @ ^{3 of} triethylamine. After stirring at 20 ° C for 4 and 15 minutes, the reaction mixture is washed twice with 20 cm ^{3 of} water, the organic phase is dried over magnesium sulphate and then concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The chestnut brown oil obtained is chromatographed on a silica gel column (particle size 0.063-0.2 mm, column height 26 cm, column diameter 3.6 cm) under an argon pressure of 0.05 MPa, eluting with a mixture of cyclohexane and ethyl acetate (70% by volume). : 30, fractions of 50 cm ³ being collected. Fractions 10 to 15 are combined and evaporated to dryness under reduced pressure (2.7 kPa), the residue is triturated with diethyl ether, the suspension is filtered, the solid is centrifuged 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.

1 H-nuclear magnetic resonance spectrum (300 MHz, (CD ₃ ) ₂ SO d ₆ with addition of CD ₃ COOD d ₄ , 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).

1-Benzhydryl-3-anilinoazetidine can be prepared as described in Example 8, starting from 5 g of 1-benzhydrylazetidin-3-one, 1.92 cm ^{3 of} aniline, 74 cm ^{3 of} 1,2-dichloroethane, 6.3 g sodium triacetoxyborohydride and 1.2 cm ^{3 of} 100% acetic acid. 8.81 g of 1-benzhydryl-3-anilinoazetidine are obtained in the form of a chestnut-brown gum which is used as is in the following stage.

Example 13 N- [1- [Bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide can be prepared as follows:

To a mixture of 1.23 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ylmethylsulfonate and 0.66 g of N- (3,5-difluorophenyl) methylsulfonamide in 25 cm ^{3 of} dioxane is added 1.0 g of cesium carbonate . After stirring at the reflux temperature of the reaction mixture for 5 hours and for a further 20 hours at 20 ° C, 50 cm ^{3 of} diethyl ether and 30 cm ^{3 of} brine are added to the reaction mixture, which is stirred and decanted. The organic phase is dried over magnesium sulphate, filtered and then concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The orange oil obtained is chromatographed on a silica gel column (0.040-0.063 mm, 25 cm column height, 2.0 cm column diameter) under an argon pressure of 0.05 MPa using a 65:35 cyclohexane / ethyl acetate mixture, 10 cm ³ fractions are collected. Fractions 6 to 10 are combined and evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.040-0.063 mm, column height 15 cm, column diameter 1.0 cm) under an argon pressure of 0.05 MPa, eluting with a cyclohexane / ethyl acetate mixture (65:35; v / v). collecting fractions of 5 cm ³ . 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 white powder.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.82 (s: 3H), 2.85 (m, 2H), 3.52 (t doubled, J = 7 and 2 Hz): 2H), 4.22 (s: 1H), 4.47 (mt: 1H), from 6.67 to 6.90 (mt: 3H), from 7.20 to 7.35 (mt: 8H).

Method 2

To a solution of 1.41 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol and 0.95 g of N - (3,5-difluorophenyl) methylsulfonamide in 100 cm ^{3 of} anhydrous tetrahydrofuran is added under argon atmosphere 0, 78 cm ^{3 of} diethyl azodicarboxylate and 1.31 g of triphenylphosphine. After stirring at 20 DEG C. for 16 hours, 300 cm @ ^{3 of} ethyl acetate are added and the reaction mixture is washed twice with 100 cm @ ^{3 of} water, dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.20-0.063 mm granulometry, 50 cm column height, 4.0 cm column diameter) under an argon pressure of 0.06 MPa using a 75:25 cyclohexane / ethyl acetate mixture, 125 cm ³ fractions are collected. Fractions 6 to 12 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 1.8 g of solid product are obtained, which is dissolved in a 15: 2 by volume mixture of ethyl acetate and diisopropyl ether in the heat, cooled and diluted with 100 cm @ ³ to initiate crystallization. After filtration and drying, 1.0 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide is obtained in the form of white crystals, m.p. is 154 ° C.

N-YS-Difluorophenyl] methylsulfonamide can be prepared as follows:

To a solution of 3.5 g of 3,5-difluoroaniline in 75 cm ^{3 of} dichloromethane are added successively 2.0 cm ^{3 of} methylsulfonyl chloride, 3.8 cm ^{3 of} triethylamine and 20 mg of 4-dimethylaminopyridine. After stirring at 20 ° C for 20 hours, 20 cm ^{3 of} dichloromethane and 20 cm ^{3 of} water are added to the reaction mixture, which is stirred and then decanted. The organic phase is dried over magnesium sulphate, filtered and then concentrated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.063-0.200 mm, column height 20 cm, column diameter 2.0 cm) under an argon pressure of 0.01 MPa, eluting with dichloromethane, collecting 25 cm ³ fractions. Fractions 14 to 20 are combined and evaporated to dryness 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-ylmethylsulfonate can be prepared as follows:

To a solution of 12 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol in 200 cm ^{3 of} dichloromethane under argon was added 3.5 cm ^{3 of} methylsulfonyl chloride over 10 minutes, followed by cooling to 5 ° C. and 3.8 cm ^{3 of} pyridine are added over 10 minutes. After stirring at 5 ° C for 30 minutes and then at 20 ° C for 20 hours, the reaction mixture is diluted with 100 cm ^{3 of} water and 100 cm ^{3 of} dichloromethane. The mixture is first filtered and decanted. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (particle size 0.063-0.200 mm, column height 40 cm, column diameter 3.0 cm) under an argon pressure of 0.05 MPa using cyclohexane and ethyl acetate (70/30 by volume), collecting fractions with volume 100 cm ³ . Fractions 4 to 15 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 6.8 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ylmethylsulfonate are obtained in the form of a yellow oil.

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

[bis (4-Chlorophenyl) methyl] amine can be prepared as described in Grisar M. et al., J. Med. Chem., 885 (1973).

Example 14

N- [1- [bis (4-Chlorophenyl) methyl] azetidin-3-yl] -X- (4,6-dimethylpyrimid-2-yl) methylsulfonamide can be prepared as described in Example 13 (Method 2). starting from 0.20 g of N- (4,6-dimethylpyrimid-2-yl) methylsulfonamide and 0.308 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol. After chromatography on a silica gel column (0.06-0.04 mm granulometry, 50 cm column height, 2.0 cm column diameter) under an argon pressure of 0.06 MPa using dichloromethane as the eluent followed by a dichloromethane / dichloromethane mixture. % methanol and then a mixture of dichloromethane and 2% methanol, collecting 200 cm ³ fractions. Fractions 4 to 7 are combined and evaporated to dryness under reduced pressure (2.7 kPa). Crystallization in diisopropyl ether, filtration and drying gave 0.20 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N - (4,6-dimethylpyrimid-2-yl) methylsulfonamide as a white solid.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.39 (s: 6H), 2.89 (t broad, J = 7.5 Hz: 2H), 3.51 (s 3H), 3.77 (mt 2H), 4.27 (s: 1H), 4.77 (mt: 1H), 6.73 (s: 1H), from 7.20 to 7.35 (mt) 8H).

N - (4,6-Dimethylpyrimid-2-yl) methylsulfonamide can be prepared as follows:

To a mixture of 1.23 g of 2-amino-4,6-dimethylpyrimidine, 0.77 cm ^{3 of} methylsulfonyl chloride and 50 mg of 4-dimethylaminopyridine dissolved in 50 cm ^{3 of} dichloromethane is added at 0 ° C 1.4 cm ^{3 of} triethylamine. After 16 hours at ambient temperature, the reaction mixture is washed twice with 100 cm @ ^{3 of} water, dried over magnesium sulphate, filtered and then evaporated under reduced pressure (2.7 kPa). 1.0 g of a yellow powder is obtained, to which 15 cm @ ^{3 of} 10% sodium hydroxide are added and the mixture is heated at 100 DEG C. for 1 hour. After cooling, the reaction mixture is extracted twice with 50 cm @ ^{3 of} dichloromethane. The aqueous phase is acidified to pH = 1 by the addition of 5 cm @ ^{3 of} 10 N hydrochloric acid and extracted twice with 50 cm @ ^{3 of} dichloromethane. The organic phases obtained are combined, washed with 50 cm @ ^{3 of} water, dried over magnesium sulphate, 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 as described in Example 13 (method 2), starting from 0.10 g of N- (1,3,4-thiadiazol-2-yl) methylsulfonamide and 0.215 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol. After chromatography on a silica gel column (0.06-0.04 mm granulometry, 25 cm column height, 1.0 cm column diameter) under an argon pressure of 0.08 MPa, eluting with a 20:80 mixture of ethyl acetate and cyclohexane. followed by a 40:80 mixture of ethyl acetate and cyclohexane, collecting 60 cm ³ fractions. Fractions 26 to 31 are combined and evaporated to dryness under reduced pressure (2.7 kPa). Crystallization in diisopropyl ether, filtration and drying gave 40 mg of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (1,3,4-thiadiazol-2-yl) methylsulfonamide. as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ , δ in ppm): 3.01 (s: 3H), 3.09 (t doubled, J = 7 and 1.5 Hz: 2H), 3.70 ( t doubled, 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: H).

N - (1,3,4-Thiadiazol-2-yl) methylsulfonamide can be prepared as follows:

To a mixture of 2.02 g of 2-amino-1,3,4-thiadiazole in 10 cm @ ^{3 of} pyridine is added 1.5 cm @ ^{3 of} methylsulfonyl chloride. After 2 hours at ambient temperature, 60 cm ^{3 of} water are added and the reaction mixture is filtered. The aqueous phase is separated and acidified to pH = 2 with the addition of 1 N hydrochloric acid, then extracted twice with 50 cm ^{3 of} ethyl acetate. The organic phase is washed twice with 50 cm @ ^{3 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 as described in Example 15, starting from 0.50 g of N - (thiazol-2-yl) methylsulfonamide and 0.5 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ol. After chromatography on a silica gel column (0.06-0.04 mm granulometry, 60 cm column height, 2.0 cm column diameter) under an argon pressure of 0.09 MPa, eluting with a 20:80 mixture of ethyl acetate and cyclohexane. and then 40:60, in which 30 cm ³ fractions were collected. Fractions 9 to 12 are combined and evaporated to dryness under reduced pressure (2.7 kPa). Crystallization in diisopropyl ether, filtration and drying gave 0.21 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (thiazol-2-yl) methylsulfonamide as a white solid. .

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): from 2.95 to 3.10 (mt: 2H), 3.00 (s: 3H), 3.59 (mt: 2H), 4.22 (s broad: 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 as follows:

To a mixture of 1.0 g of 2-aminothiazole in 5 cm ^{3 of} pyridine is added 1.15 cm ^{3 of} methylsulfonyl chloride. After 2 hours at ambient temperature, 20 cm ^{3 of} water are added and the reaction mixture is filtered and the solid is collected. The aqueous phase is acidified to pH = 2 with the addition of 1 N hydrochloric acid, then extracted twice with 40 cm ^{3 of} ethyl acetate. The organic phase is washed twice with 30 cm @ ^{3 of} water, dried over magnesium sulphate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). 0.15 g of a white solid is obtained, which has spectral characteristics close to the filtered product, which corresponds to a mixture of N - (thiazol-2-yl) methylsulfonamide and N- (thiazol-2-yl) di (methylsulfonyl) imide. The product obtained is used as such in the next step.

Example 17

N- [1- [bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N- (3-hydroxyphenyl) methylsulfonamide can be prepared as follows:

To a mixture of 0.5 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (3-methoxyphenyl) methylsulfonamide in 20 cm ^{3 of} dichloromethane is added dropwise at 2 ° C. 7.63 cm @ ^{3 of a} 1 M boron tribromide solution. After 20 hours at ambient temperature, the reaction mixture is poured onto ice and extracted with 60 cm ^{3 of} dichloromethane. The organic phase is washed three times with 80 cm ^{3 of} water and then twice with 80 cm ^{3 of} saturated sodium chloride solution, dried over magnesium sulphate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). 0.33 g of a white, brittle product is obtained, which is washed with acetonitrile, filtered and dried to give 0.20 g of a white solid.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.81 (s: 3H), 2.86 (t broad, J = 7.5 Hz: 2H), 3.50 (t broad J = 7.5 Hz: 2H), 4.20 (s: 1H), 4.53 (mt: 1H), 5.36 (mt: 1H), from 6.70 to 6.85 (mt: 3H) from 7.15 to 7.35 (mt 9H).

Example 18

N- [1- [bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N- (3-methoxyphenyl) methylsulfonamide can be prepared according to the procedure described in Example 15, starting from 1.58 g. - (3-methoxyphenyl) methylsulfonamide and 2.0 g of [1- [bis (4-chlorophenyl) methyl] azetidin-3-ol. After chromatography on a silica gel (granulometry) column (0.06-0.04 mm, column height 24 cm, column diameter 7.8 cm) under an argon pressure of 0.07 MPa, eluting with a mixture of ethyl acetate and cyclohexane in a volume ratio of 50 : 50 and then 40:60, in which 100 cm ³ fractions are collected. Fractions 7 to 10 are combined and evaporated to dryness under reduced pressure (2.7 kPa) (2.05 g). After crystallization in diisopropyl ether, filtration and drying, 0.21 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (3-methoxyphenyl) methylsulfonamide is obtained.

N - (3-Methoxyphenyl) methylsulfonamide can be obtained as follows:

To a mixture of 5.0 g of 3-methoxyaniline in 150 cm ^{3 of} pyridine is added 3.14 cm ^{3 of} methylsulfonyl chloride at 3 ° C. After 20 hours at ambient temperature, 200 cm ^{3 of} water and 400 cm ^{3 of} ethyl acetate are added and the reaction mixture is decanted. The organic phase is washed three times with 400 cm ^{3 of} water and 400 cm ^{3 of} saturated sodium chloride solution, dried over magnesium sulphate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). After chromatography on a silica gel column (0.06-0.94 mm granulometry, 23 cm column height, 7.8 cm column diameter) under an argon pressure of 0.07 MPa, eluting with a mixture of ethyl acetate and cyclohexane (25:75 by volume). 100 cm ³ fractions are collected. Fractions 24 to 36 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 6.21 g of N- (3-methoxyphenyl) methylsulfonamide as an orange oil.

Example 19

N - [1- [Bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N ^' - (3-hydroxymethylsulfonamide) can be prepared as follows:

To 0.5 g of ^ethyl-A, - [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - <N (methylsulfonyl) -3-aminobenzoate in 20 cm ³ of toluene is added dropwise at room -50 ° C 1.46 cm ^{3 of} 20% toluene solution of diisopropylaluminum hydride. After 1.5 hours at 0 ° C and 1.5 hours at 10 ° C, the reaction mixture is cooled to 0 ° C, then 20 cm ^{3 of} water are added successively. After filtering off the precipitate and extracting with ethyl acetate, the organic phase is washed twice with 80 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). 0.46 g of an oil is obtained, which is chromatographed on a silica gel column (0.06-0.04 mm granulometry, 16 cm column height, 4 cm column diameter) under an argon pressure of 0.07 MPa, eluting with a mixture of ethyl acetate and cyclohexane at a volume ratio of 40:60 at the earliest, at which 20 cm ³ fractions are collected. Fractions 72 to 76 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 0.20 g of N - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N - (3-hydroxymethylphenyl) methylsulfonamide is obtained in the form of a white solid.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 1.80 (mt: 1H), 2.83 (s: 3H), 2.87 (mt: 2H), 3.52 (mt 4.21 (s broad: 1H), 4.60 (mt: 1H), 4.74 (d broad, J = 4 Hz: 2H), from 7.10 to 7.45 (mt: 12H); ).

Example 20

Ethyl N - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N - (methylsulfonyl) -3-aminobenzoate can be prepared as described in Example 15, starting from 1, 58 g of ethyl-a ^/ - (methylsulfonyl) -3-aminobenzoate and 2.0 g of l- [bis (4-chlorophenyl) methyl] azetidin-3-ol. After chromatography on a silica gel column (0.06-0.04 mm granulometry, 24 cm column height, 7.8 cm column diameter) under an argon pressure of 0.07 MPa, eluting with a mixture of ethyl acetate and cyclohexane of at least 50: 50 and then in a volume ratio of 40:60 in which 100 cm ³ fractions were collected. Fractions 7 to 10 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 2.0 g of a yellow oil.

Ethyl N - (methylsulfonyl) -3-aminobenzoate can be prepared as follows:

To a mixture of 5.0 g of ethyl 3-aminobenzoate in 150 cm ^{3 of} pyridine is added 2.35 cm ^{3 of} methylsulfonyl chloride at 3 ° C. After 20 hours at ambient temperature, 200 cm ^{3 of} water and 400 cm ^{3 of} ethyl acetate are added and the reaction mixture is decanted. The organic phase is washed three times with 400 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and then evaporated under reduced pressure (2.7 kPa). After chromatography on a silica gel column (0.06-0.04 mm granulometry, 25 cm column height, 7.8 cm column diameter) under an argon pressure of 0.07 MPa, eluting with a mixture of ethyl acetate and cyclohexane of at least 25: 75, in which 100 cm ³ fractions are collected. Fractions 27 to 36 are combined and evaporated to dryness under reduced pressure (2.7 kPa) to give 5.24 g of ethyl N- (methylsulfonyl) -3-aminobenzoate as an orange oil.

Example 21

N - [1- [Bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N- (1-isobutylpiperid-4-yl) methylsulfonamide can be prepared as follows:

To a solution of 0.47 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (piperid-4-yl) methylsulfonamide in 20 cm ^{3 of} dichloromethane is added 0.11 cm ^{3 of} isobutyraldehyde , 0.057 cm @ ^{3 of} 100% acetic acid and 320 mg of sodium triacetoxyborohydride. After stirring at 20 DEG C. for 20 hours, 50 cm @ ^{3 of} saturated aqueous sodium hydrogen carbonate solution are added to the reaction mixture and the mixture is decanted. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The residue was purified by chromatography on a silica gel column (0.063-0.200 mm, column height 20 cm, column diameter 2 cm) under an argon pressure of 0.05 MPa, eluting with a 40:60 mixture of ethyl acetate and cyclohexane. 30 cm ³ fractions are collected. Fractions 3 to 15 are combined and evaporated to dryness under reduced pressure (2.7 kPa). 0.22 g of M [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (1-isobutylpiperid-4-yl) methylsulfonamide is obtained in the form of a white, brittle product.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 0.87 (d, J = 7 Hz: 6H), from 1.60 to

1.90 (mt: 5H), 1.93 (t broad, J = 11.5 Hz: 2H), 2.03 (d, J = 7.5 Hz: 2H), 2.84 (s: 3H) 2.89 (d broad, J = 11.5 Hz: 2H), 3.38 (t broad, J = 7 Hz: 2H), 3.47 (t broad, J = 7 Hz: 2H), 3, 62 (mt 1H), 4.08 (mt 1H), 4.43 (s 1H),

7.20 to 7.40 (mt 8H).

N - [1- [Bis (4-Chlorophenyl) methyl] azetidin-3-yl] - N - (piperid-4-yl) methylsulfonamide can be prepared as follows:

To a solution of 19 g of N ^' - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (1-tert-butoxycarbonylpiperid-4-yl) methylsulfonamide in 100 cm ^{3 of} dioxane is gradually added 50 cm ³ 6 N hydrochloric acid in dioxane. After stirring at 20 ° C for 20 hours, the reaction mixture is concentrated under reduced pressure (2.7 kPa). The residue is stirred in 200 cm ^{3 of} ethyl acetate and 200 cm ^{3 of} water. The aqueous phase is made alkaline with a 4N aqueous sodium hydroxide solution and then extracted with 200 cm &lt; ^{3 &gt; of} ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). 15.5 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (piperid-4-yl) methylsulfonamide are obtained in the form of a cream-colored, brittle product.

N- [1- [Bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N- (1-tert-butoxycarbonylpiperid-4-yl) methylsulfonamide can be prepared as follows:

To a solution of 14.7 g of 4- [1- [bis (4-chlorophenyl) methyl] azetidin-3-ylamino] - (1-tert-butoxycarbonyl) piperidine in 250 cm ^{3 of} dichloromethane is gradually added 4.60 cm ^{3 of} methylsulfonyl chloride and then 4.60 cm ^{3 of} triethylamine and 100 mg of 4-dimethylaminopyridine. After stirring at 20 DEG C. for 20 hours, 200 cm @ ^{3 of} saturated aqueous sodium hydrogen carbonate solution are added to the reaction mixture, which is left stirring for 30 minutes and then decanted. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on a silica gel column (particle size 0.063-0.200 mm, column height 35 cm, column diameter 5 cm) under an argon pressure of 0.05 MPa, eluting with a cyclohexane / ethyl acetate mixture (70/30; v / v). collecting fractions of 250 cm ³ . Fractions 4 to 18 are combined and concentrated 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 colored brittle product, which is it can itself be used in the next step.

4- [1- [bis (4-Chlorophenyl) methyl] azetidin-3-ylamino)] - (1-tert-butoxycarbonylpiperidine) can be prepared as follows:

To a solution of 9.22 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ylamine in 300 cm ^{3 of} dichloromethane is added 6.58 g of 1- tert -butoxycarbonylpiperidin-4-one. To the mixture cooled to 5 ° C, 9.54 g of sodium triacetoxyborohydride are added in two portions, followed by 1.72 cm ^{3 of} 100% acetic acid. After stirring at 20 DEG C. for 20 hours, 500 cm @ ^{3 of} saturated aqueous sodium hydrogen carbonate solution are gradually added to the reaction mixture, and the mixture is stirred vigorously and decanted. The organic phase is dried over magnesium sulphate, filtered and evaporated 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 -butoxycarbonylpiperidine) are obtained in the form of a cream-colored, brittle product which can be used as such in the next step.

Example 22

7V-Benzyl / N [l-bis (4-chlorophenyl) methyl] azetidin-3-yl] -amine:

To a solution of 369 mg of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ylamine in 15 cm ^{3 of} dichloromethane was added benzaldehyde (0.134 cm ³⁾ at ambient temperature under an argon atmosphere. The mixture is cooled to 0 ° C before 382 mg of sodium triacetoxyborohydride and then 70 mm ³ of acetic acid are added. After stirring at ambient temperature for 16 hours, the mixture is poured into 50 cm @ ^{3 of a} saturated aqueous sodium bicarbonate solution, then extracted twice with 25 cm @ ^{3 of} dichloromethane. The organic phases are combined and dried over magnesium sulphate, filtered and evaporated to dryness at 50 ° C under reduced pressure (2.7 kPa). The residue is purified by flash column chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol, to give 0.29 g of Mbenzyl- N - [1-bis (4-chlorophenyl) methyl] azetidin-3. -yl] amine in the form of a colorless oil.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.71 (t broad, J = 7 Hz: 2H), 3.42 (mt: 2H), 3.49 (mt: 1H) 3.70 (s: 2H), 4.25 (s: 1H), from 7.20 to 7.40 (mt: 13H).

1- [Bis (4-Chlorophenyl) methyl] azetidin-3-ylamine can be prepared as follows:

To 27 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ylmethylsulphonate pre-cooled in an autoclave to about -60 ° C is added 400 cm ^{3 of a} 50:50 methanol / liquid ammonia mixture. The reaction mixture is then stirred at 60 ° C for 24 hours, then allowed to stand in air to evaporate the ammonia and finally concentrated under reduced pressure (2.7 kPa). The residue is dissolved in 500 cm @ ^{3 of} 0.37 N aqueous sodium hydroxide solution and extracted four times with 500 cm @ ^{3 of} ethyl ether. The organic compounds are washed successively twice with 100 cm ^{3 of} saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography using a 95: 5 mixture of dichloromethane and methanol to give 14.2 g of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ylamine as an oil which gradually solidifies to give a cream colored solid.

Example 23

7V-benzyl-N- [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] methyl sulfonamide:

To a solution of 120 mg of N-benzyl-N - ([1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] amine in 5 cm ^{3 of} dichloromethane is added triethylamine at ambient temperature and 104 mm ³ under an argon atmosphere. was cooled to about 0 DEG C. and treated with a 46.4 mm ³ of methylsulfonyl chloride and the mixture was stirred at room temperature for 16 hours. the reaction mixture is diluted with 20 cm ³ of distilled water. the organic phase is dried over magnesium sulfate. filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a lacquer which is crystallized by dissolving in methanol to give 42 mg of N-benzyl-N- [1- [bis ( 4-Chloro-phenyl) -methyl] -azetidin-3-yl] -methylsulfonamide as a cream colored powder, m.p. 171 ° C.

Example 24 N- [1- [Bis (4-Chlorophenyl) methyl] azetidin-3-yl] -X- (3,5-difluorobenzyl) amine can be prepared by the procedure described in Example 22 using 188 mg of 3,5-difluorobenzaldehyde and 369 mg of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ylamine and 382 mg of sodium triacetoxyborohydride. The product was obtained without flash chromatography. 0.48 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (3,5-difluorobenzyl) amine is obtained in the form of a colorless oil.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.73 (m: 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 cm ^{3 of} dichloromethane was added at room temperature under an argon atmosphere of 347. mm ^{3 of} triethylamine. The mixture is then cooled to about 0 ° C and a solution of 46.4 mm ^{3 of} methylsulfonyl chloride in 5 cm ^{3 of} dichloromethane is added and the mixture is stirred at ambient temperature for 1 hour. The reaction mixture is diluted with 20 cm ^{3 of} dichloromethane and then washed twice with 20 cm ^{3 of} distilled water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue was applied as a metallic solution to a Bond Elut SCX column (10 g) and eluted sequentially with methanol followed by a 1 M solution of ammonia in methanol. The ammoniacal fractions are combined and concentrated under reduced pressure (2.7 kPa). There was thus obtained N - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N - (3,5-difluorobenzyl) methylsulfonamide (0.44 g) as a cream colored brittle product.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.81 (s: 3H), 3.02 (t broad, J = 7.5 Hz: 2H), 3.38 (t broad J = 7.5 Hz: 2H), 4.23 (s: 1H), 4.40 (mt1H), 4.54 (s: 2H), 6.75 (tt, J = 9 and 2 Hz: 1H) )

6.95 (mt 2H), 7.25 (mt 8H).

Example 26

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

To a solution of 2 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (3,5-difluorobenzyl) amine in 75 cm ^{3 of} dichloromethane is added at ambient temperature under an argon atmosphere of 1. 6 cm ^{3 of} triethylamine. The mixture is then cooled to about 0 ° C and 0.66 cm ^{3 of} acetyl chloride are added dropwise and the mixture is stirred at ambient temperature for 16 hours. The reaction mixture is diluted with 50 cm ^{3 of} dichloromethane and then washed twice with 20 cm ^{3 of} distilled water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash column chromatography on silica gel, eluting with a dichloromethane / methanol (98/2; v / v) mixture to give 1.2 g of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl]. N - (3,5-difluorobenzyl) -acetamide as a colorless oil. 1 H-Nuclear Magnetic Resonance Spectrum (300 MHz, CDCl ₃ , δ in ppm): A mixture of rotamers can be observed.

2.06 and 2.14 (2s: 3H total), 2.97 (mt: 2H), 3.43 (mt: 2H), 4.20 and 4.25 (2s: 1H total), 4.54 and from 4.75 to 4.80 (mt: 1H total), 4.68 and 4.78 (2 broad: 2H total), 6.57 (tt, J = 9 and 2 Hz: 1H), 6.70 ( mt: 3H), 7.24 (s broad: 8H).

Example 27 N- [1- [Bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N- (pyrid-4-ylmethyl) methylsulfonate

To a solution of 398 mg of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (pyrid-4-ylmethyl) amine in 8 cm ^{3 of} dichloromethane is added at ambient temperature and under an argon atmosphere. 346 mm ^{3 of} triethylamine. The mixture is then cooled to about 0 ° C and a solution of 155 mm ^{3 of} methylsulfonyl chloride is added and the mixture is stirred at ambient temperature for 3 hours. The reaction mixture is diluted with 35 cm ^{3 of} dichloromethane and then washed twice with 20 cm ^{3 of} distilled water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash column chromatography on silica gel, eluting with a dichloromethane / methanol (97/3 by volume) mixture to give 288 mg / N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N - (pyrid-4-ylmethyl) methylsulfonamide as a cream colored brittle product.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.83 (s: 3H), 3.02 (t broad, J = 7.5 Hz: 2H), 3.40 (t broad J = 7.5 Hz: 2H), 4.23 (s: 1H), 4.43 (mt, 1H), 4.57 (s: 2H), from 7.20 to 7.35 (mt: 8H) )

7.32 (d broad, J = 5.5 Hz: 2H), 8.60 (d broad, J = 5.5 Hz: 2H).

Example 28 N- [1- [Bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N- (pyrid-4-ylmethyl) amine

To a solution of 369 mg of 7V- [l- [bis (4-chlorophenyl) methyl] azetidin-3-ylamine in 15 cm ³ of dichloromethane are added at room temperature and under argon, 0.126 mm ³ pyridin-4-yl-carboxaldehyde. The mixture was cooled to about 0 ° C and 382 mg of sodium triacetoxyborohydride was added, followed by 70 mm ³ of acetic acid. After stirring at ambient temperature for 72 hours, the mixture is poured into 100 cm @ ^{3 of} saturated sodium bicarbonate solution and extracted twice with 100 cm @ ^{3 of} dichloromethane. The organic phases are combined, washed with 50 cm ^{3 of} distilled water and dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The residue is taken up in a solution with 5 cm ^{3 of} methanol and applied to a Bond Elut SCX column (10 g) and eluted successively with 50 cm ^{3 of} methanol and then with 60 cm ^{3 of a} 1 M solution of ammonia in methanol. The ammoniacal fractions are combined and concentrated under reduced pressure (2.7 kPa). There was thus obtained N - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N - (pyrid-4-ylmethyl) amine (0.48 g) as a colorless oil.

Example 29

N- [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (pyridin-3-ylmethyl) methylsulfonamide

The procedure was as in Example 27, but starting from 380 mg of N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (pyrid-3-ylmethyl) to give 319 mg of V- [1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (pyrid-3-ylmethyl) methylsulfonamide as a cream colored brittle product.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.80 (s: 3H), 3.02 (t doubled, J = 7 and 1.5 Hz: 2H), 3.38 ( t doubled, J = 7 and 1.5 Hz: 2H), 4.22 (s: 1H), 4.35 (mt: 1H), 4.56 (s: 2H), 7.23 (s broad: 8H) 7.31 (dd, J = 8 and 5 Hz: 1H), 7.80 (dd broad, J = 8 Hz: 1H), 8.63 (d broad, J = 1.5 Hz: 1H).

Example 30

N - [1- [bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N- (pyrid-3-ylmethyl) amine can be prepared as described in Example 28, starting from 0.124 cm ³ pyrid-3-ylcarboxaldehyde, 0.36 g 1- [bis (4-chlorophenyl) methyl] azetidin-3-ylamine and 0.38 g sodium triacetoxyborohydride. There was thus obtained N - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N - (pyrid-3-ylmethyl) amine (0.44 g) as a colorless oil.

Example 31

7V- [1 - [bis (4-chlorophenyl) methyl] azetidin-3-yl] - / V- (1,1-dioxo-1H-1>. ⁶ -benzo [d] isothiazol-3-yl) -amine

To 386 mg of 1- [bis (4-chlorophenyl) methyl] azetidin-3-ylmethylsulfonate in a solution of 10 cm ^{3 of} dimethylformamide was added 182 mg of 1,2-benzisothiazol-3-amine dioxide and 326 mg of cesium carbonate. The reaction mixture is then stirred at 100 ° C for 9 hours, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is washed four times with 5 cm @ ^{3 of} boiling distilled water at ambient temperature and then isolated by filtration and purified by flash chromatography on silica gel, eluting with a dichloromethane / methanol (98/2; v / v) mixture mixture. [bis (4-chlorophenyl) methyl] azetidin-3-yl] -7V- (l, l-dioxo-lH-p ⁶ -benzo [i7] isothiazol-3-yl) -amine as a paste.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 3.17 (mt: 2H), 3.61 (t broad, J = 7.5 Hz: 2H), 4.37 (s: 1H), 4.75 (mt: 1H), from 6.30 to 6.40 (mt: 1H), from 7.20 to 7.35 (mt: 8H), 7.62 (d broad, J = 7) 1.5 Hz: 1H), 7.69 (t broad, J = 7.5 Hz: 1H), 7.76 (t broad, J = 7.5 Hz: 1H), 7.93 (d broad, J = 0.7 Hz) 7.5 Hz: 1H).

1,2-Benzisothiazol-3-amine-1,1-dioxide can be prepared as described by Stoss P. et al.,

Chem., 1975, 108 (12), 3855-63.

Example 32

N- [1- [bis (4-Chlorophenyl) methyl] azetidin-3-yl] -N- (3,5-difluorophenyl) - N, N-tert-butyloxycarbonylsulfamide can be prepared as follows:

To a solution of 0.095 cm ^{3 of} tert-butyl alcohol in 2 cm ^{3 of} anhydrous dichloromethane is added 0.048 cm ^{3 of} chlorosulfonyl isocyanate, then, after stirring for 2 minutes, 0.21 g / N '- [1- [bis (4-chlorophenyl) methyl] azetidine -3-yl] - N - (3,5-difluorophenyl) amine in 1.25 cm ^{3 of} anhydrous dichloromethane and then 0.084 cm ^{3 of} triethylamine. After stirring for one hour at a temperature of about 20 ° C, 2 cm ^{3 of} saturated sodium bicarbonate solution are added with vigorous stirring. The reaction mixture is decanted, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Varian (6 cm ³ ) column packed with fine silica gel (0.040-0.063 mm granulometry), eluting with a mixture of petroleum ether and ethyl acetate and a Duramat pump, collecting 2 cm ³ fractions. Fractions 7 to 17 are combined and evaporated to dryness 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 white, brittle product.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 1.47 (s: 9H), 2.77 (t broad, J = 8 Hz: 2H), 3.52 (mt: 2H) 4.19 (s: 1H), 5.06 (mt: 1H), from 6.75 to 6.90 (mt: 3H), from 7.15 to 7.35 (mt: 8H).

Example 33 (7R-N- [1- (4-Chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide can be prepared as follows:

To a mixture of 0.2 g of 3- [bromo- (4-chlorophenyl) methyl] pyridine and 0.22 g of N-azetidin-3-yl- N - (3,5-difluorophenyl) methylsulfonamide in 10 cm ^{3 of} acetonitrile is added 0.2 g of potassium carbonate and 23 mg of potassium are removed, and the mixture is heated to reflux for 3 hours. After the addition of 0.2 g of potassium carbonate, the mixture was heated at reflux for a further 15 hours. After cooling to 21 ° C, the undissolved portion is collected by filtration and then concentrated to dryness at 40 ° C under reduced pressure (2.7 kPa). 170 mg of a colorless lacquer are obtained, which is purified by chromatography on a silica gel column (SIL-020-005, Flash Pack, Jones Chromatography Limited, New Road, Hengoed, Mid Glamorgan, CF82 8 AU, Royaume Uni). cyclohexane and ethyl acetate in a 1: 1 by volume ratio (cm ³ / min., 5 cm ³ fractions are collected). The fractions with RF = 5/57 (cyclohexane: ethyl acetate 1: 1, silica plate, Merck 1.05719, Merck KGaA, 64271 Darmstadt, Germany) were combined and evaporated to dryness at 40 ° C under reduced pressure of 2.7 kPa to give 100 mg of (7S) -N- [1- (4-chlorophenyl) pyridin-3-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, m.p. 110 C.

1 H-NMR (300 MHz, (CD ₃ ) ₂ SO d ₆ , 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 (d broad, J = 8 Hz: 1H), 8.40 (dd, J = 5 and 1.5 Hz): 1H), 8.58 (d, J = 1.5 Hz: 1H).

The two isomers of (7S) -N- [1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methanesulfonamide can be separated into the stationary chiral phase of Chiracel OD.

First isomer: 1 H-nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ , 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: 3H), 7.19 (dd, J = 8 and 5 Hz: 1H), from 7.20 to 7.35 ( mt: 4H), 7.62 (d broad, J = 8 Hz: 1H), 8.45 (d broad, J = 5 Hz: 1H), 8.59 (s broad: 1H).

Second isomer: 1 H-nuclear magnetic resonance spectrum (300 MHz, CDCl ₃ , δ in ppm): 2.82 (s: 3H), 2.87 (mt: 2H), 3.54 (mt: 2H), 4, 29 (s: 1H), 4.48 (mt: 1H), 6.80 (mt: 3H), 7.19 (dd broad, J = 8 and 5 Hz, 1H), from 7.25 to 7.35 (mt: 4H), 7.62 (dt, J = 8 and 2 Hz: 1H), 8.46 (dd, J = 5 and 2 Hz: 1H), 8.59 (d broad, J = 2 Hz): H).

N-Azetidin-3-yl-N- (3,5-difluorophenyl) methanesulfonamide hydrochloride can be obtained as follows:

In a 500 cm ³ hydrogenation apparatus, a solution of 1 g of N- (1-benzhydrylazetidin-3-yl) -N- (3,5-difluorophenyl) methylsulfonamide in a mixture of 2.5 cm ^{3 of} 1 M hydrochloric acid and 0.41 is hydrogenated. cm ³ of acetic acid in the presence of 0.161 g of palladium hydroxide at a hydrogen pressure of 30 bar for 4 hours. The hydrogenation catalyst was removed by filtration through a pad of Celite and the filtrate was concentrated to dryness under reduced pressure (2.7 kPa) to give 630 mg of N'-azetidin-3-yl- N - (3,5-difluorophenyl) methylsulfonamide, m.p. 216 [deg.] C.

N - (1-Benzhydrylazetidin-3-yl- N - (3,5-difluorophenyl) methylsulfonamide can be obtained by the procedure used in Example 13 (method 2) as follows:

To a solution of 2 g of 1-benzhydrylazetidin-3-ol in 100 cm ^{3 of} tetrahydrofuran was added successively 0.86 g of N- (3,5-difluorophenyl) methylsulfonamide, 3.28 g of triphenylphosphine and then 2 ml of diethyl azodicarboxylate. An increase in temperature from 22 ° C to 29 ° C can be observed as well as precipitate formation upon completion of the diethyl azodicarboxylate addition. After 20 hours at 22 ° C, the precipitate is removed by filtration and the filtrate is concentrated to dryness at 40 ° C and 2.7 kPa. The residue is triturated with 5 cm ^{3 of} methanol for 20 minutes at 21 ° C to give 1.07 g of N ¹ - (1-benzhydrylazetidin-3-yl) - ^N - (3,5-difluorophenyl) methylsulfonamide as a white solid. amorphous solid product.

1-Benzhydrylazetidin-3-ol may be prepared as described in Katritzky A.R. et al., J. Heterocycl. Chem., 271 (1994).

3- [Bromo- (4-chlorophenyl) methyl] pyridine can be obtained as follows:

To 1.5 g of (4-chlorophenyl) methyl] pyrid-3-ylmethanol is added 3.5 cm @ ^{3 of a} 48% solution of hydrobromic acid in acetic acid and 1 cm @ ^{3 of} acetyl bromide. The amber mixture thus obtained is heated under reflux for 4 hours, then cooled to 20 ° C, concentrated to dryness at 40 ° C and 2.7 kPa to give 1.53 g of 3- [Bromo- (4-chlorophenyl) methyl] pyridine (Rf = 75/90, 254 nm, Plaques de Silice, 1.05719, Merc KGaA, 64271 Daemstadt, Federal Republic of Germany).

(4-Chlorophenyl) pyrid-3-ylmethanol can be obtained as follows:

To a solution of 3 g of pyridine-3-carboxaldehyde in tetrahydrofuran at 5 ° C is added 20 cm ^{3 of a} 1M solution of 4-chlorophenyl magnesium bromide in diethyl ether. After warming to 20 ° C, the mixture was allowed to react with stirring for 15 hours. 20 cm @ ^{3 of} saturated ammonium chloride solution are then added, followed by 20 cm @ ^{3 of} ethyl acetate. The mixture is decanted and the organic phase is extracted with an additional 20 cm ^{3 of} ethyl acetate. The organic extracts are combined, dried over magnesium sulphate and then evaporated to dryness at 40 ° C and 2.7 kPa. The residue is chromatographed on a silica gel column (Amicon, 20 to 45 microns, 500 g silica gel, 5 cm column diameter), eluting with a mixture of cyclohexane and ethyl acetate varying in volume from 80: 20 to 50: 50 under pressure argon 0.04 MPa. The fractions containing the compound with Rf = 13/53 (Plaques de Silice Merck, 1.05719, Merck KGaA, 64271 Darmstadt, Federal Republic of Germany) were combined and evaporated to dryness at 40 ^° C and 2.7 kPa to afford 2.53 g of (4-chlorophenyl) pyrid-3-ylmethanol.

Example 34

N- [1- [bis (4-Fluorophenyl) methyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide was obtained as follows:

To a mixture of 0.2 g of 4,4'-difluorobenzhydryl chloride and 0.26 g of ^R and azetidin-3-yl-7V- (3,5-difluorophenyl) methanesulfonamide in 10 cm ³ of acetonitrile is added 0.36 g of potassium carbonate and 27 mg of potassium iodide, the mixture heated at reflux for 3 hours. After cooling to 21 ° C, the undissolved portion is collected by filtration and the filtrate is concentrated to dryness at 40 ° C and under pressure.

2.7 kPa. The residue is stirred in 30 cm ^{3 of} ethyl acetate and the solid is removed by filtration. The filtrate is concentrated to dryness at 40 ° C and 2.7 kPa to give 90 mg of a pale yellow solid which is purified by Bond Elut SCX column chromatography containing 2 g of cleaved silica gel (125-6019, Varian Associates). , Inc.24201 Frampton Avenue, Harbor City, CA90710, USA) using a 2 M methanolic ammonia solution. Fractions with Rf = 16/82 (cyclohexane / ethyl acetate 7: 3, silica gel plate, 1.05719, Merck KGaA, 64271 Darmstadt, Federal Republic of Germany) were combined and evaporated to dryness at 2.7 kPa at 40 ° C, to give 243 mg of N - [[bis (4-fluorophenyl) methyl] azetidin-3-yl] -N ^f - (3,5-difluorophenyl) methanesulfonamide, m.p. 98 ° C.

1 H-NMR (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm): 2.74 (t broad, J = 7 Hz: 2H), 3.00 (s: 3H), 3.37 (t broad, J = 7 Hz: 2H), 4.43 (s: 1H), 4.69 (mt: 1H), 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) pyrid-4-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide was obtained as follows:

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 carbonate potassium acetate in 5 cm ^{3 of} acetonitrile is stirred for about 18 hours at about 20 ° C. The reaction mixture was then heated to reflux for 3 hours. After cooling to about 20 ° C, the reaction mixture is filtered through a sintered glass. The solid is washed with acetonitrile, then twice with 3 cm ^{3 of} ethyl acetate. The filtrates are concentrated under reduced pressure. 230 mg of a pale yellow paste are obtained, which is then purified by preparative thin layer chromatography on silica gel (4 Merck Kieselgel 60F254 preparative plates, 20 x 20 cm, 0.5 mm layer thickness), eluting with a 5: 5 mixture of methanol and dichloromethane. : 95.

Elution of the zone corresponding to the desired product, filtration through a sintered glass filter and removal of the solvents under reduced pressure at about 40 ° C gave 12 mg of (R) -N- [1 - [(4-chlorophenyl) pyrid-4-ylmethyl] ] azetidin-3-yl] -N- (3,5-difluorophenyl) methanesulfonamide.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.82 (s: 3H), 2.96 (mf 2H),

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 (d broad, J = 5.5 Hz: 2H).

The two isomers of (R, S) - N - [1 - [(4-chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl] - N - (3,5-difluorophenyl) methylsulfonamide can be separated into stationary chiral phase Chiracel OJ.

First isomer:

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.83 (s: 3H), 2.87 (t broad, J = 7.5 Hz: 2H), 3.51 (mt: 1H), 3.60 (mt: 1H), 4.24 (s: 1H), 4.50 (mt: 1H), 6.82 (mt: 3H), from 7.20 to 7.35 (mt: 6H).

8.50 (d broad, J = 5.5 Hz: 2H).

Second isomer:

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.83 (s: 3H), 2.88 (t, J = 7.5 Hz: 2H), 3.51 (mt: 1H) ), 3.61 (mt: 1H), 4.25 (s: 1H), 4.51 (mt: 1H), 6.81 (mt: 3H), from 7.20 to 7.35 (mt: 6H) ), 8.50 (d broad, J = 5.5 Hz: 2H).

(4-Pyridyl) - (4-chlorophenyl) chloromethane can be prepared as follows:

To a suspension of 100 mg of (4-pyridyl) - (4-chlorophenyl) methanol in 2 cm ^{3 of} toluene cooled to about 0 ° C is added 0.0598 cm ^{3 of} thionyl chloride. After two hours at about 0 ° C and one hour at about 20 ° C, the reaction mixture is concentrated under reduced pressure. About 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 cm ^{3 of} ethanol is added 348 mg of sodium tetrahydroboride at about 20 ° C. After stirring at about 20 ° C for two hours, 90 mg of sodium borohydride are added. After about 1.5 hours at the same temperature, the reaction mixture is diluted with 200 cm ^{3 of} dichloromethane and 200 cm ^{3 of} water. The pH of the aqueous phase is adjusted to about 5 by adding about 13 cm ^{3 of a} 1N aqueous hydrochloric acid solution. After decantation, the aqueous phase is extracted three times with 100 cm @ ^{3 of} dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. 2 g of (4-pyridyl) - (4-chlorophenyl) methanol are thus obtained in the form of a white powder.

Example 36

To a solution of 330 mg of [1- [bis (4-chlorophenyl) methyl] azetidin] -3-yl] - (3,5-difluorobenzyl) amine in 25 cm ^{3 of} tetrahydrofuran was added 24.4 mg at ambient temperature and under an argon atmosphere. dispersions of sodium hydride in mineral oil. The mixture is stirred at ambient temperature for one hour, then 59 mm ^{3 of} methyl chloroformate are added thereto, and the mixture is stirred for an additional 18 hours under the same conditions. 0.3 cm ^{3 of} distilled water are added to the reaction mixture and the tetrahydrofuran is removed by rotary evaporation. The residue 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 is purified by flash chromatography on silica gel, eluting with a dichloromethane / methanol (97.5: 2.5) mixture. 328 mg of methyl [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) - (3,5-difluorobenzyl) carbamate are obtained as a colorless oil. 1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.97 (mt: 2H), 3.39 (m: 2H), 3.71 (s: 3H), 4.24 (s broad: 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 (7S) -N- [1 - [(4-Chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide can be obtained as described in of Example 33, starting from 0.16 g of (7S) -5- [bromo- (4-chlorophenyl) methyl] pyrimidine, 0.131 g of N-azetidin-3-yl-N- (3,5-difluorophenyl) hydrochloride methanesulfonamide in 5 cm ^{3 of} acetonitrile, 303 mg of potassium carbonate and 95 mg of potassium iodide to give 26 mg of (R) -N- [1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3 -yl] - N - (3,5-difluorophenyl) methylsulfonamide as a yellow brittle product.

1 H-NMR (300 MHz, CDCl ₃ , δ in ppm): 2.83 (s: 3H), 2.91 (mt: 2H), 3.57 (mt: 2H), 4.31 (s 4.50 (mt: 1H), from 6.75 to 6.90 (mt: 3H), 7.29 (s: 4H), 8.71 (s: 2H), 9.08 (s): : H).

The medicaments according to the invention form a compound of formula (I) or an isomer, or a salt thereof, in pure form or in the form of a composition wherein said compound or isomer or salt thereof is combined with another pharmaceutically acceptable product which may be inert or physiologically effective. The medicaments of the invention may be administered orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powder (in gelatin capsules or sachets) or granules may be used. In these compositions, the active compound of the invention is mixed under argon with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica gel. The compositions may also contain substances other than diluents, for example, one or more lubricants such as magnesium stearate or talc, colorants, coating agents (dragees) or lacquers.

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

Sterile compositions for parenteral administration may be aqueous or non-aqueous solutions, suspensions, or emulsions. As the solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate and other suitable solvents can be used. These compositions may also contain additives, in particular wetting agents, isotonizing agents, emulsifying agents, dispersing agents and stabilizing agents. Sterilization can be accomplished in a variety of ways, for example, by aseptic filtration, incorporation of sterilizing agents into the composition, irradiation, or heating. These compositions can also be prepared in the form of sterile solid compositions, which can be dissolved, immediately prior to use, in sterile water or any other sterile injectable medium.

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

Compositions for topical administration are, for example, creams, lotions, patches, oral disinfectants, nasal drops or aerosols.

In human therapy, the compounds of the invention are particularly useful for the treatment and / or prevention of psychoses, including schizophrenia, anxiety, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, skull injuries, panic attacks, migraine peripheral neuropathy, peripheral neuropathy Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, Raynaud's Syndrome, Chills, Obsessive Compulsive Disorders, Senile Dementia, Infant Gland Disorders, Tourette's Syndrome, Late Dyskinesia, Bipolar Disorders, Cancer, Musculoskeletal Disorders, Drugs, Movement Disorders hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, chronic types of alcohol or drug dependence cessation (e.g. opiates, barbiturates, cannabis, k occaine, amphetamine, phencyclide, hallucinogens and benzodiazepines) as analgesics or potentiators of the analgesic effect of narcotic and non-narcotic drugs.

The doses employed depend on the desired effect, the time of treatment and the route of administration used; these doses generally range between 5 and 1000 mg per day when administered orally to an adult using unit dosage forms ranging between 1 and 250 mg of the active ingredient.

In general, it will be the attending physician who will determine the appropriate dosage based on the age, body weight and other personal factors of the patient being treated.

Specific examples of the pharmaceutical compositions of the invention will be described in the following.

Example A

Gelatin capsules are prepared in a conventional manner, each containing 50 mg of active ingredient, the capsules having the following composition:

Compound of Formula (I) 50 mg

Cellulose18 mg

Lactose 55mg

Colloidal silica 1mg

Carboxymethyl starch sodium 10 mg Talc 10mg

Magnesium stearate 1mg

Example B

Tablets are prepared in a conventional manner, each containing 50 mg of active ingredient, each tablet having the following composition:

Compound of Formula (I) 50mg

Lactose 104 mg

Cellulose40 mg

Polyvidone10 mg

Carboxymethyl starch sodium 22 mg talc 10 mg Magnesium stearate 2 mg Colloidal silica 2 mg

A 72: 3.5: 24.5 mixture of hydroxymethylcellulose, glycerin and titanium dioxide in an amount sufficient to provide 1 coated tablet having a final weight of 245 mg.

Example C

An injectable solution is prepared which contains 10 mg of active ingredient and has the following composition: Compound of Formula (I) 10 mg

Benzoic acid80 mg

Benzyl alcohol 0,06ml

Sodium benzoate 80 mg

95% Ethanol 0.4 ml

Sodium hydroxide24 mg

Propylene glycol 1.6 ml

Water sufficient to achieve a volume of 4 ml.

PATENT CLAIMS

Claims (21)

Pharmaceutical composition, characterized in that it contains, as active ingredient, a compound of the general formula (I) in which: R ¹ is -N (R ⁴⁾ R ^5, -N (R ⁴⁾ -CO-R ⁵ or -N (R ⁴⁾ -SO ₂ R ^6, R ² and R ³ , which are the same or different, represent or an aromatic group selected from the group consisting of phenyl, naphthyl and indenyl, these aromatic groups being unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR ⁷ R ⁸ , -CO-NH-NR ⁹ R ¹⁰ , alkylsulfanyl; , alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl group, an alkylsulphinyl, alkylsulphonyl, hydroxyalkyl, and -alk-NR ⁷ R ^8, or a heteroaromatic group selected from the group consisting of benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl 2,3-dihydrobenzofury mono, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl and thienyl groups wherein the heteroaromatic groups may be unsubstituted or substituted with substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR ⁹ R ¹⁰ , -CONR ⁷ R ^S, -alk-NR ⁹ R ^10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl group, an alkylsulphinyl, alkylsulphonyl, and hydroxyalkyl, R ⁴ is -C (R ^H) (R ¹²⁾ -Het, -Het, -C (R ^s) (R ¹²⁾ -Ar, Ar, cycloalkyl or norbornyl radical, R ⁵ is hydrogen, hydroxyalkyl, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR R ⁸ , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or alkyl optionally substituted one or more halogen atoms, R ⁶ is hydroxyalkyl, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het, or an alkyl group optionally substituted with one or more halogen atoms, R ⁷ and R ⁸ , which are the same or different, represent a hydrogen atom or an alkyl group or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group which optionally containing another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl groups, R ⁹ and R ¹⁰ , which are the same or different, are hydrogen, alkyl, -COOalk , cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl, or else R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated or unsaturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more I substituents selected from the group consisting of alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, an oxo group, a hydroxyalkyl, -alk-O-alk or -CO-NH _2, R ¹¹ represents a hydrogen atom, a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxyalkyl, Ar, Het, -CH ₂ Ar, -CH ₂ Het or an alkyl group optionally substituted with one or more halogen atoms, R ¹² represents a hydrogen atom, a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , an alkoxyalkyl group or an alkyl group optionally substituted with one or more halogen atoms, or also R ¹¹ and R 8 ¹² , together with the carbon atom to which they are attached, form a mono- or bicyclic saturated 3- to 10-membered cyclic group which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more carbon atoms; several alkyl groups, Ar is phenyl, naphthyl or indenyl, the various groups being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR ' ³ R ¹⁴ , -CO-NH-NR ¹⁵ R ¹⁶ , alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, -alk-NR ¹⁵ R ¹⁶ , -NR ¹⁵ R ¹⁶ , alkylthioalkyl, formyl, CF ₃ , OCF ₃ , Het, -O-alk-NH-cycloalkyl, SO ₂ NH ₂ , hydroxy, hydroxyalkyl, -NHCO-alk and NHCOOalk, or are substituted on two adjacent carbon atoms with a dioxymethylene group, Het means a mono- or bicyclic unsaturated or saturated 3- to 10-membered heterocyclic group optionally containing one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more substituents selected from the group which includes an alkyl group, an alkoxy group, a halogen atom, an alkoxycarbonyl group, an oxo group and a hydroxy group, wherein the nitrogen heterocycles are optionally in their N-oxide form, R ¹³ and R ¹⁴ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with one or more alkyl groups, R ¹⁵ and R ¹⁶ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl groups, alk means an alkyl or alkylene group, wherein the alkyl and alkylene groups and residues thereof and the alkoxy groups and residues thereof are linear or branched and contain 1 to 6 carbon atoms, and cycloalkyl groups contain 3 to 10 carbon atoms, and optical isomers of the compound and its salts with pharmaceutically acceptable mineral or organic acids. Pharmaceutical composition according to claim 1, characterized in that in the general formula (I), Het represents a benzimidazole group, a benzoxazole group, a benzothiazole group, a benzothiophene group, a cinoline group, a thiophene group, a quinazoline group, a quinoxaline group, a quinoline group, a pyrazole group. , a pyrrole group, a pyridine group, an imidazole group, an indole group, an isoquinoline group, a pyrimidine group, a thiazole group, a thiadiazole group, a piperidine group, a piperazine group, a triazole group, a furan group, a tetrahydroisoquinoline group and a tetrahydroquinoline group optionally substituted; or a plurality of substituents selected from the group consisting of alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF _3, and CF ₃ . Pharmaceutical composition according to claim 1, characterized in that in the compound of formula (I) R ¹ is -N (R ⁴⁾ R ⁵ or -N (R ⁴⁾ -SO ₂ R ^6, R ² is or phenyl unsubstituted or substituted with one or more substituents from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR ⁷ R ^8, hydroxyalkyl, alk and -NR ⁷ R ⁸ , or a heteroaromatic group selected from the group consisting of pyridyl, pyrimidyl, thiazolyl and thienyl, these heteroaromatic groups may be unsubstituted or substituted with substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ⁷ R ⁸ , -alk-NR ⁹ R ¹⁰ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl and hydroxyalkyl, R ³ is or a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR ⁷ R ⁸ , hydroxyalkyl, and - alk-NR ⁷ R ^8, or a heteroaromatic group selected from the group consisting of pyridyl, pyrimidyl, thiazolyl and thienyl, these heteroaromatics being unsubstituted or substituted by substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ⁷ R ⁸ , -alk-NR ⁹ R ¹⁰ , alkylsulfanyl, alkylsulfonyl, alkylsulfonyl or hydroxyalkyl, R ⁴ is -C (R ^{1 I)} (R ¹²⁾ -Het, -Het, - (CR ⁿ⁾ (R ¹²⁾ -Ar, Ar or norbornyl radical, R ⁵ represents a hydrogen atom, a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxy, -CH ₂ Ar, -CH ₂ Het or an alkyl group, R ⁶ is hydroxyalkyl, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxy, -CH ₂ Ar, -CH ₂ Het or an alkyl group, R ⁷ and R ⁸ , which are the same or different, represent a hydrogen atom or an alkyl group or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group which optionally contains an additional heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and optionally substituted with one or more alkyl groups, R ⁹ and R ¹⁰ , which are the same or different, represent a hydrogen atom, an alkyl group, a cycloalkyl group, an alkylcycloalkyl group, an -alk-O-alk or hydroxyalkyl group, or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated or unsaturated 3- to 10-membered heterocyclic group which optionally contains another heteroatom selected from oxygen, sulfur and nitrogen and which is optionally substituted with one or more substituents selected from the group, consisting of alkyl, -COalk, -COOalk, -CO-NHalk, oxo group, a hydroxyalkyl group, and a -CO-NH _2, R ¹¹ represents a hydrogen atom, a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxyalkyl, Ar, Het, -CH ₂ Ar, -CH ₂ Het or an alkyl group, which is optionally substituted with one or more halogen atoms, R ¹² represents a hydrogen atom, a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , an alkoxyalkyl group or an alkyl group optionally substituted with one or more halogen atoms, or also R ¹¹ and R 8 ¹² , together with the carbon atom to which they are attached, form a mono- or bicyclic saturated 3- to 10-membered cyclic group which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more carbon atoms; several alkyl groups, Ar is phenyl or naphthyl, the various groups being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, -CO-alk, cyano, -CONR ¹³ R ¹⁴ , alkylsulfonyl, -alk-NR ¹⁵ R ¹⁶ , -NR ¹⁵ R ¹⁶ , CF ₃ , OCF ₃ , SO ₂ NH ₂ , hydroxy and hydroxyalkyl, or are substituted on two adjacent carbon atoms with a dioxymethylene group, Het means a heterocyclic group selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, pyrimidine, isole, thiazole, thiadiazole, furan, tetrahydroisoquinoline, and tetrahydroquinoline, said heterocyclic groups being optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, and hydroxy; OCF ₃ and CF ₃ , R ¹³ and R ¹⁴ , which are the same or different, represent a hydrogen atom or an alkyl group, or R and R together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with one or more alkyl groups, R ¹⁵ and R ¹⁶ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group which optionally comprises an additional heteroatom selected from oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl groups, including optical isomers of said compound and its salts with pharmaceutically acceptable mineral or organic acids. Pharmaceutical composition according to claim 1, characterized in that in the compound of formula (I) R ¹ is -N (R ⁴⁾ -SO ₂ R ^6, R ² is or phenyl unsubstituted or substituted with one or more substituents from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ⁷ R ^8, hydroxyalkyl or -alk-NR ⁷ R ⁸ or a heteroaromatic group selected from the group consisting of pyridyl, pyrimidyl, thiazolyl and thienyl, which heteroaromatic groups may be unsubstituted or substituted with substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, trifluoromethyl , trifluoromethoxy, -CONR ⁷ R ^8, or hydroxyalkyl, R ³ represents or phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ⁷ R ⁸ , hydroxyalkyl and -alk-NR ⁷ R ^8, or a heteroaromatic group selected from the group consisting of pyridyl, pyrimidyl, thiazolyl and thienyl, these heteroaromatics being unsubstituted or substituted by substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ⁷ R ^8, and hydroxyalkyl, R ⁴ is a radical Het or Ar, R ⁶ represents a hydroxyalkyl group or an alkyl group, R ⁷ and R ⁸ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl groups, Ar is phenyl or naphthyl, the various groups being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, -CO-alk, cyano, -CONR ¹³ R ¹⁴ , -alk- NR ¹⁵ R ¹⁶ , -NR ¹⁵ R ¹⁶ , CF ₃ , OCF ₃ , SO ₂ NH ₂ , hydroxy or hydroxyalkyl, Het represents a heterocyclic group selected from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, thiazole, isool, isool, group, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxyl, OCF _3, and CF ₃ , R ¹³ and R ¹⁴ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with one or more alkyl groups, R ¹⁵ and R ¹⁶ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group which optionally comprises an additional heteroatom selected from oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl groups, including optical isomers of said compound and its salts with pharmaceutically acceptable mineral or organic acids. A pharmaceutical composition according to claim 1, wherein the compound of formula (I) is selected from the group consisting of: N - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -7- (6-chloropyrid-2-yl) methylsulfonamide, N - [1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl] - N - (6-ethylpyrid-2-yl) methylsulfonamide, N - [bis- (4-chlorophenyl) methyl] azetidin-3-yl] -N ^/ quinolinyl-6-ylmetylsulfónamid, ^A, - [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N ^/ -chinol- 5-ylmethylsulfonamide N - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N -isoquinol-5-ylmethylsulfonamide, 7V- [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N-pyridin-3-ylmetylsulfónamid, N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (1-oxidopyrid-3-yl) methylsulfonamide, N - (17 R, 25,45) -bicyclo [2.2.1] hept-2-yl-N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] methylsulfonamide, N - ( 17β, 27β, 45) -bicyclo [2.2.1] hept-2-yl-N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] methylsulfonamide, 7 '- [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) methyl sulfonamide, 7V- [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -7V- (3-methoxyphenyl) methyl sulfonamide, ^N - [l- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl] ^-N, - (3-hydroxyphenyl) methylsulfonamide, 7V- [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (3-hydroxymethylphenyl Ethyl N - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (methylsulfonyl) -3-aminobenzoate, N - [1- [bis (4-chlorophenyl) methyl] azetidine] methylsulfonamide -3-yl] -N- (1-isobutylpiperid-4-yl) methylsulfonamide, N-benzyl-N 1 -bis (4-chlorophenyl) methyl] azetidin-3-yl] amine, N - [1- [bis] (4-chlorophenyl) methyl] azetidin-3-yl] - / V- (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 N- [1- [bis (4-fluorophenyl) methyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, (R) -yl] -N- (pyrid-3-ylmethyl) methylsulfonamide; - N - [1- (4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl] - N '- (3,5-difluorophenyl) methylsulphonamide, (R) -7 H - [1 - [ (4-Chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, (S) -7- [1 - [(4-chlorophenyl) pyrid-3- (methyl) azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- [1 - [(4-chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl] -7] - (3,5-difluorophenyl) methylsulfonamide, (7?) - / V- [l - [(4-chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl] ^-N - (3,5-difluorophenyl) (S) -4- [1 - [(4-chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl] -7 H- (3,5-difluorophenyl) methylsulfonamide, (7 S) -7] - (1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N- [1 - [(4-chlorophenyl) pyr imidin-5-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, (S) -7- (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, wherein: optical isomers of these compounds and salts thereof with pharmaceutically acceptable mineral or organic acids are also included. A compound of formula (I) wherein: R ¹ is -N (R ⁴⁾ R ^5, -N (R ⁴⁾ -CO-R ⁵ or -N (R ⁴⁾ -SO ₂ R ^6, R ² and R ³ , which are the same or different, represent or an aromatic group selected from the group consisting of phenyl, naphthyl and indenyl, these aromatic groups being unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR ⁷ R ⁸ , -CO-NH-NR ⁹ R ¹⁰ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfanylalkyl, hydroxyalkyl and -alk-NR ⁷ R ⁸ , or a heteroaromatic group selected from the group consisting of benzopharyl, benzothiazolyl, benzothienyl, benzothienyl, 2,3-dihydrobenzopharyl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl and thienyl groups, the following: heteroaromatic groups may be unsubstituted or substituted with substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR ⁹ R ¹⁰ , -CONR ⁷ R ⁸ , -alk-NR ⁹ R ¹⁰ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfanylalkyl and hydroxyalkyl, R ⁴ is -C (R ¹¹ ) (R ¹² ) -Het, -Het, -C (R '') (R ' ² ) -Ar, Ar, cycloalkyl or norbomyl, R ⁵ represents a hydrogen atom, a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or an alkyl group optionally substituted one or more halogen atoms, R ⁶ represents hydroxyalkyl, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxy, Ar, Het, -CH ₂ Ar, -CH ₂ Het or an alkyl group optionally substituted by one or more halogen atoms, R ⁷ and R ⁸ , which are the same or different, represent a hydrogen atom or an alkyl group or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group which optionally contains an additional heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and optionally substituted with one or more alkyl groups, R ⁹ and R ¹⁰ , which are the same or different, represent a hydrogen atom or an alkyl group, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl or also R ⁹ and R ¹⁰ together with the nitrogen atom on which bind, form a mono- or bicyclic saturated or unsaturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more substituents selected from the group consisting of alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH _2, R ¹¹ represents a hydrogen atom, a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxyalkyl, Ar, Het, -CH ₂ Ar, -CH ₂ Het or an alkyl group optionally substituted with one or more halogen atoms, R ¹² represents a hydrogen atom, a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , an alkoxyalkyl group or an alkyl group optionally substituted with one or more halogen atoms, or also R ¹¹ and R 8 ¹² , together with the carbon atom to which they are attached, form a mono- or bicyclic saturated 3- to 10-membered cyclic group which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more carbon atoms; several alkyl groups, Ar is phenyl, naphthyl or indenyl, the various groups being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, CONR ¹³ R ^14, -CO-NH-NR ¹⁵ R ^16, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR ¹⁶ R ^ls, -NR ^I5 R ^16, alkylthioalkyl, formyl, CF _3, OCF ₃ , Het, -O-alk-NH-cycloalkyl, SO ₂ NH ₂ , hydroxy, hydroxyalkyl, -NHCO-alk and NHCOOalk, or are substituted on two adjacent carbon atoms with a dioxymethylene group, Het means a mono- or bicyclic unsaturated or saturated 3- to 10-membered heterocyclic group optionally containing one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more substituents selected from the group which includes an alkyl group, an alkoxy group, a halogen atom, an alkoxycarbonyl group, an oxo group and a hydroxy group, the nitrogen heterocycles optionally being in their N-oxide form, R ¹³ and R ¹⁴ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl groups, R ¹⁵ and R ¹⁶ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl groups, alk means an alkyl or alkylene group, wherein the alkyl and alkylene groups and residues and the alkoxy and residues groups have straight or branched chain and contain 1 to 6 carbon atoms and cycloalkyl groups contain 3 to 10 carbon atoms, and the optical isomers of the compound and its salts with pharmaceutically acceptable mineral or organic acids, with the exception of the compound of formula (I) wherein R ² and R ³ is phenyl, R ¹ is N (R ⁴ ) SO ₂ R ⁶ , wherein R ⁴ represents a phenyl group and R ⁶ represents a methyl group. Compound of formula (I) according to claim 6, in which Het is benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, triazole, furan, tetrahydroisoquinoline and tetrahydroquinoline groups, the heterocycles being optionally substituted with one or more selected groups from the group consisting of alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ and CF ₃ . A compound of formula (I) according to claim 6, wherein: R ¹ is -N (R ⁴⁾ R ⁵ or -N (R ⁴⁾ -SO ₂ R ^6, R ² is or phenyl unsubstituted or substituted with one or more substituents from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR ⁷ R ^8, hydroxyalkyl, alk and -NR ⁷ R ⁸ , or a heteroaromatic group selected from the group consisting of pyridyl, pyrimidyl, thiazolyl, and thienyl, which heteroaromatic groups may be unsubstituted or substituted with substituents selected from the group consisting of halogen, alkyl, alkoxy , hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ⁷ R ⁸ , -alk-NR ⁹ R ¹⁰ , alkylsulfanyl, alkylsulfonyl, alkylsulfonyl and hydroxyalkyl, R ³ is or a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR ⁷ R ⁸ , hydroxyalkyl, and - alk-NR ⁷ R ^8, or a heteroaromatic group selected from the group consisting of pyridyl, pyrimidyl, thiazolyl and thienyl, these heteroaromatics being unsubstituted or substituted by substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, -CONR ⁷ R ⁸ , alk-NR ⁹ R ¹⁰ , alkylsulfanyl, alkylsulfonyl, alkylsulfonyl and hydroxyalkyl, R ⁴ is -C (R) (R ¹² ) -Het, -Het, -C (R ^H ) (R ¹² ) -Ar, Ar, or norbomyl, R ⁵ represents a hydrogen atom or a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxy, -CH ₂ Ar, -CH ₂ Het or an alkyl group, R ⁶ is hydroxyalkyl, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxy, -CH ₂ Ar, -CH ₂ Het or an alkyl group, R ⁷ and R ⁸ , which are the same or different, represent a hydrogen atom or an alkyl group or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group which optionally contains an additional heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and optionally substituted with one or more alkyl groups, R ⁹ and R ¹⁰ , which are the same or different, represent a hydrogen atom, an alkyl group, a cycloalkyl group, an alkylcycloalkyl group, -alk-O-alk, a hydroxyalkyl group or also R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated or unsaturated 3- to 10-membered heterocyclic group which optionally contains another heteroatom selected from oxygen, sulfur and nitrogen and which is optionally substituted with one or more substituents selected from the group, which includes alkyl, -COalk, -COOalk, -CO-NHalk, oxo, hydroxyalkyl, and -CO-NH ₂ , R ¹¹ represents a hydrogen atom or a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxyalkyl, Ar, Het, -CH ₂ Ar, -CH ₂ Het or an alkyl group optionally substituted with one or more halogen atoms, R ¹² represents a hydrogen atom or a hydroxyalkyl group, -alk-COOalk, -alk-CONR ⁷ R ⁸ , -alk-NR ⁷ R ⁸ , alkoxyalkyl or alkyl optionally substituted with one or more halogen atoms, or also R ¹¹ and R 8 ¹² , together with the carbon atom to which they are attached, form a mono- or bicyclic saturated 3- to 10-membered cyclic group which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more carbon atoms; several alkyl groups, Ar is phenyl or naphthyl, the various groups being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, -CO-alk, cyano, -CONR ¹³ R ¹⁴ , alkylsulfonyl, - alk-NR ¹⁵ R ¹⁶ , -NR ¹⁵ R ¹⁶ , CF ₃ , OCF ₃ , SO ₂ NH ₂ , hydroxy and hydroxyalkyl or are substituted on two adjacent carbon atoms with a dioxymethylene group, Het means a heterocyclic group which includes benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, pyrimidine, isoquinoline group, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxyl, OCF _3, and CF3. R ¹³ and R ¹⁴ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with one or more alkyl groups, R ¹⁵ and R ¹⁶ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, optionally containing an additional heteroatom selected from oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl groups, and the optical isomers of the compound and its salts with a pharmaceutically acceptable mineral with organic or organic acids, with the exception of the compound of formula (I) wherein R ² and R ³ are phenyl and R ¹ is -N (R ⁴ ) -SO ₂ R ⁶ , where R ⁴ is phenyl and R ⁶ represents a methyl group. A compound of formula (I) according to claim 6, wherein: R ¹ is -N (R ⁴⁾ -SO ₂ R ^6, R ² is or phenyl unsubstituted or substituted with one or more substituents from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ⁷ R ^8, hydroxyalkyl or -alk-NR ⁷ R ⁸ or a heteroaromatic group selected from the group consisting of pyridyl, pyrimidyl, thiazolyl and thienyl, which heteroaromatic groups may be unsubstituted or substituted with substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, trifluoromethyl , trifluoromethoxy, -CONR ⁷ R ^8, or hydroxyalkyl, R ³ represents or phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR ⁷ R ⁸ , hydroxyalkyl or -alk-NR ⁷ R 8 ⁸ , or a heteroaromatic group selected from the group consisting of pyridyl, pyrimidyl, thiazolyl and thienyl, said heteroaromatic groups being unsubstituted or substituted with substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, trifluoromethyl , trifluoromethoxy, -CONR ⁷ R ^8, and hydroxyalkyl, R ⁴ is a radical Het or Ar, R ⁶ represents a hydroxyalkyl group or an alkyl group, R ⁷ and R ⁸ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl groups, Ar represents a phenyl group or a naphthyl group, the various groups being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, -CO-alk, cyano, -CONR ¹³ R ¹⁴ , -alk-NR ¹⁵ R ¹⁶ , -NR ¹⁵ R ¹⁶ , CF ₃ , OCF ₃ , SO ₂ NH ₂ , hydroxy and hydroxyalkyl, Het means a heterocyclic group which includes benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, thiazole, thiazole, thiazole group, furan, tetrahydroisoquinoline and tetrahydroquinoline, said heterocyclic groups being optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ and CF ₃ . R ¹³ and R ¹⁴ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group, which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with one or more alkyl groups, R ¹⁵ and R ¹⁶ , which are the same or different, represent a hydrogen atom or an alkyl group or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached form a mono- or bicyclic saturated 3- to 10-membered heterocyclic group which optionally contains another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and which is optionally substituted with one or more alkyl groups, and the optical isomers of the compound and its salts with a pharmaceutically acceptable mineral yearly macroeconomic dialogue or organic acids, except the compounds of formula (I), wherein R ² and R ³ represent phenyl radicals, and R ¹ is -N (R ⁴⁾ -SO ₂ R ^6, wherein R ⁴ is phenyl and R ⁶ represents a methyl group. A compound of formula (I) according to claim 6 selected from the group consisting of: N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (6-chloropyrid-2-yl) N - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N - (6-ethylpyrid-2-yl) methylsulfonamide, N- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N-chi-6-nol ylmetylsulfónamid, ^N - [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - / N - [1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl] - N -isoquinol-5-ylmethylsulfonamide, N- [1- [bis (4-chlorophenyl) methyl] N-quinol-5-ylmethylsulfonamide azetidin-3-yl] -N-pyrid-3-ylmethylsulfonamide, N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (1-oxidopyrid-3-yl) methylsulfonamide, N - [17 R, 2 S, 4 S) -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-yl] methylsulfonamide, AL [1- [bis] (4-Chlorophenyl) methyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, X- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (thiazol-2) N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N- (3-methoxyphenyl) methylsulfonamide, N- [1- [bis (4-chlorophenyl) methyl] azetidine] -yl) methylsulfonamide; -3-yl] - N - (3-hydroxymethylphenyl) methylsulfonamide, N - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N - (3-yl) N - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N - (methylsulfonyl) -3-aminobenzoate, N - [1- (bis (4-chlorophenyl) methyl] -hydroxymethylphenyl) methylsulfonamide azetidin-3-yl] -N- (1-isobutylpiperid-4-yl) methylsulfonamide, N-benzyl-N- [1-bis (4-chlorophenyl) methyl] azetidin-3-yl] amine, M [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 [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N ^/ - (pyridin-3-ylmethyl) methylsulfonamide 7V- [1 - [bis (4- Fluorophenyl) methyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, (R) -5- [1- (4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3- yl] - N - (3,5-difluorophenyl) methylsulfonamide, ( ^R ) - N - [1 - [(4-chlorophenyl) pyrid-3-yl] azetidin-3-yl] -A ^z - (3, 4-chlorophenyl) pyridin-3-yl] (5) -N- [1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- (5-difluorophenyl) methylsulfonamide; [l - [(4-chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl] -7V- (3,5-difluorophenyl) methyl sulfone id. - [(4-chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulphonamide, (S) -N- [1 - [(4-chlorophenyl) pyrid-4- (methyl) azetidin-3-yl] - N - (3,5-difluorophenyl) methylsulfonamide, (R) -N- [1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl] - N ^{1 -} - (3,5-difluorophenyl) methylsulfonamide, (R) -N- [1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl] -N- (3,5-difluorophenyl) methylsulfonamide, ( 5 - 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 and the optical isomers of these compounds and their salts with pharmaceutically acceptable mineral or organic acids. Compound of formula (I) according to claim 6 or 10, which is N - [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] - N - (3,5-difluorophenyl) methylsulfonamide, its optical isomers and salts thereof with pharmaceutically acceptable mineral or organic acids. A process for the preparation of compounds of formula (I) according to claim 6, wherein R ¹ is -N (R ⁴ ) R ⁵ , wherein R ⁵ is hydrogen and R ⁴ is -CR ^H R ¹² -Ar or -CR ^the R ¹² -Het and R ¹² is H, characterized by reacting a derivative Rb-COR ¹¹ for which R ¹¹ is as defined in claim 6, with a derivative of formula: Rb represents a radical Ar or Het and R ² , R ³ , R ¹¹ , Ar and Het have the same meanings as in claim 6, and the product is isolated and optionally converted to a pharmaceutically acceptable salt. A process for the preparation of compounds of formula (I) according to claim 6, wherein R ¹ is -N (R ⁴ ) -CO-R ⁵ , wherein R ⁴ is -C (R ^H ) (R ¹² ) -Ar or -C (R ^s) (R ^l2) Het, and R ¹² is H, characterized by reacting a derivative Hal-COR ⁵ with a derivative of formula wherein Hal is a halogen atom, Rb represents a radical Ar or Het and R ² , R ³ , R ⁵ , R ¹¹ , Ar and Het have the same meanings as in claim 6, and the product is isolated and optionally converted to a pharmaceutically acceptable salt. 14. A process for the preparation of compounds of formula (I) according to claim 6, wherein R ¹ is -N (R ⁴⁾ -SO 2 R ^6, wherein R ⁴ is -C (R ^s) (R ¹²⁾ -Ar or -C (R ^s) (R ¹²⁾ -Het and R ¹² is H, characterized by reacting a derivative Hal-SO 2 R ⁶ with a derivative of formula: R ^2, R ^3, R ^11, R ⁵ have the meanings as in claim 6, Hal is a halogen atom and Rb is Ar or Het, and the product is isolated and optionally converted to a pharmaceutically acceptable salt. A process for the preparation of compounds of formula (I) according to claim 6, wherein R ¹ is -N (R ⁴ ) R ⁵ , characterized in that a derivative of R ⁵ (R ⁴ ) NH is reacted with a derivative of the formula R ² , R ³ , R ⁴ , R ⁵ have the same meanings as in claim 6, wherein the product is isolated and optionally converted into a pharmaceutically acceptable salt. A process for the preparation of compounds of formula (I) according to claim 6, wherein R ¹ is -N (R ⁴ ) SO ² R ⁶ , characterized in that a Hal-SO 2 -R ⁶ derivative is reacted with a derivative of the general formula wherein R ² , R ³ , R ⁴ and R ⁶ have the same meanings as in claim 6 and Hal represents a halogen atom, and the product is isolated and optionally converted to a pharmaceutically acceptable salt. A process for the preparation of compounds of formula (I) according to claim 6, wherein R ¹ is -N (R ⁴ ) COR ⁵ , characterized in that a Hal-CO-R ⁶ derivative is reacted with a derivative of the general formula wherein: R ^2, R ^3, R ⁴ and R ⁵ have the same meanings as in claim 6 and Hal represents a halogen atom, and the product isolated and optionally converted to a pharmaceutically acceptable salt thereof. A process for the preparation of compounds of formula (I) according to claim 6, wherein R ¹ is -N (R ⁴ ) SO ² R ⁶ , R ⁴ is Het or Ar, characterized in that the Rd-NH derivative is reacted -SO 2 -R ⁶ with a derivative of the formula wherein R d is Ar or Het, R ² , R ³ and R ⁶ have the same meanings as in claim 6, and Ms is methylsulfonyloxy, and the product is isolated and optionally converted to a pharmaceutically acceptable salt . 19. A process for the preparation of compounds of formula (I) according to claim 6, characterized in reacting a derivative R ² -CHBr-R ³ with a derivative of formula HN-V wherein R ¹ , R ² and R ³ have the same meanings as in claim 6, and the product is isolated and optionally converted to a pharmaceutically acceptable salt. A process for the preparation of compounds of formula (I) according to claim 6, wherein R ¹ is -N (R ⁴ ) SO ² R ⁶ , wherein R ⁴ is piperid-4-yl substituted on nitrogen by an alkyl group, characterized in that to alkylate the corresponding compound of formula (I) wherein R ¹ is -N (R ⁴ ) -SO 2 -R ⁶ wherein R ⁴ is piperid-4-yl, whereby the product is isolated and optionally converted to a pharmaceutically acceptable salt. A process for the preparation of compounds of formula (I) according to claim 6, wherein R ¹ is -N (R ⁴ ) SO ² R ⁶ , wherein R ⁴ is a phenyl group substituted by a pyrrolid-1-yl group, characterized in that it is reacting a pyrrolidine with a corresponding compound of formula (I) wherein R ¹ is -N (R ⁴ ) SO ² R ⁶ , wherein R ⁴ is a phenyl group substituted with a halogen atom, whereby the product is isolated and optionally converted to a pharmaceutically acceptable salt.