SK4032003A3 - Association of the CB1 receptor antagonist and sibutramin, for treating obesity - Google Patents

Abstract

The invention concerns the association of the CB1 receptor antagonist and a sibutramin, pharmaceutical compositions containing same and use thereof for treating obesity.

Description

Combination of CB1 receptor antagonist and sibutramine, pharmaceutical composition containing it, and its use in the treatment of obesity

Technical field

The present invention relates to a combination of a CB1 receptor antagonist and sibutramine, pharmaceutical compositions containing it, and its use in the treatment of obesity.

BACKGROUND OF THE INVENTION

CB1 receptor antagonists are known for their effect on food intake and their use as anorexigenic agents (G. Colombo et al., Life Sciences, 63 (8), 113-117 (1998); J. Siamand et al., Behavioral Pharmacol. 9: 179-181 (1998)).

Sibutramine (BTS 54524; N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine; Meridia®, Reductil®), its hydrate and its pharmaceutically acceptable salts, and in particular its hydrochloride , decreases food intake and is used in the treatment of obesity (WO 90/061110; DH Ryan et al., Obesity Research, 3 (4), 553 (1995); HC Jackson et al., British Journal of Pharmacology, 121, 1758 ( G. Fanghanel et al., Inter J. Obes., 24 (2), 144 (2000); GA Bray et al., Obes. Res., 7 (2), 189 (1999)).

SUMMARY OF THE INVENTION

It has now been found that the combination of sibutramine, its hydrate and its pharmaceutically acceptable salts and a CB1 receptor antagonist has a synergistic effect in reducing food intake and is therefore used in the treatment of obesity.

The combination may also contain several receptor antagonists

CB1.

Among the CB1 antagonists, in particular, the azetidine derivatives disclosed in WO 00/15609, WO 01/64633 and WO 01/64634 of general formula (I) may be used.

R (I) wherein each R is A or B

C = CH with ₂ r ';

I

C-CH

R ¹

R ²

R ¹

R ² represents a methyl or ethyl radical, means either an aromatic group selected from phenyl, naphthyl and indenyl, these aromatic groups may be unsubstituted or substituted by one or more halogen, alkyl, alkoxy, -CO-alk, hydroxyl groups, -COOR ⁵ groups, formyl groups, trifluoromethyl groups, trifluoromethylsulfanyl groups, trifluoromethoxy groups, nitro groups, -WR ⁶ R ⁷ groups, -CO-NH-NR ⁶ R ⁷ groups, -N (alk) COOR ^C groups, cyano groups, -CONHR ⁹ groups, -CO-NR ¹⁶ R ¹⁷ groups, alkylsulfanyl groups, hydroxyalkyl groups, -O-alk-NR ¹² R ¹³ groups or alkylthioalkyl groups, or a heteroaromatic group selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl 2,3-dihydroxybenzofuryl j, 2,3-dihydrobenzothienyl, 3-isofuryl, 2,3-dihydrobenzothienyl, indolinyl, indolyl, isochromanyl, isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl, wherein the heteroaromatic groups may be unsubstituted or substituted by a halogen atom, an alkyl group, an alkoxy group, -COOR ⁵ , a trifluoromethyl group, a trifluoromethylsulfanyl group, a trifluoromethoxy group, a nitro group, a nitro group, a nitro group, -NR ⁶ R ⁷ , -CO-NH-NR ⁵ R ⁷ , cyano, -CONHR ⁹ , alkylsulfanyl, hydroxyalkyl or alkylthioalkyl,

R ³ and R ⁴ which are the same or different represent either an aromatic group selected from phenyl, naphthyl or indenyl, which aromatic groups may be unsubstituted or substituted by one or more halogen atoms, alkyl groups, alkoxy groups, formyl groups, hydroxyl groups groups, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOR ^5, -CONR ¹⁰ R ^n, -CO-NH-NR ⁶ R ^7, alkylmercapto, hydroxyalkyl, -alk-NR ⁶ R ⁷ or alkylthioalkyl, or a heteroaromatic group selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, isoquinromyl, pyrrolyl, ch inolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl or thienyl, wherein the heteroaromatic groups may be unsubstituted or substituted by one or more halogen atoms, alkyl groups, alkoxy groups, hydroxy groups, trifluoromethyl groups, trifluoromethoxy groups, trifluoromethoxy groups, trifluoromethoxy groups , -COOR ⁵ group, a -CO-NH-NR ⁶ R ^7, -CONR ¹⁰ R ^U, -alk-NR ⁶ R ^7, alkylmercapto, hydroxyalkyl or alkylthioalkyl,

R ³ is an alkyl or phenyl optionally substituted with one or more halogen atoms,

R ⁶ and R ⁷ , 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 or a hydroxyalkyl group, or R ⁶ and R ⁷ together with a nitrogen atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted by one or more alkyl, -CO-alk, -COOalk groups, -CONHalk groups, -CSNHalk groups, -CO-alk-NR ¹⁴ R ¹³ groups, oxo groups, hydroxyalkyl groups, -alk-O-alk groups, or -CO-NH ₂ groups,

R ⁸ represents an alkyl group,

R ⁹ represents a hydrogen atom, an alkyl group or an alkyl group substituted with a dialkylaminoalkyl group, a phenyl group, a cycloalkyl group (optionally substituted with -COOalk group) or a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 3 to 10 members, optionally containing one or more heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and optionally substituted by one or more alkyl groups,

R ¹⁰ and R ¹¹ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups,

R ¹² and R ¹³ , which are the same or different, represent a hydrogen atom, an alkyl group or a cycloalkyl group, or R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 members , optionally containing a further heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with alkyl, -CO-alk, -COOalk, -CONHalk, -CSNHalk, -CO-alk-NR ¹⁴ R ¹⁵ or a saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 members and containing a heteroatom selected from oxygen, sulfur and nitrogen,

R ¹⁴ and R ¹⁵ , which are the same or different, represent a hydrogen atom, an alkyl group or a -COOalk group,

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing further heteroatoms selected from oxygen, sulfur and nitrogen,

R 'is H or -CO-alk, or R represents a CHR ¹⁸ radical, and

R ¹⁸ represents a radical -NHCOR ¹⁹ or -N (R ²⁰⁾ -YR ^21,

Y is CO or SO ₂ ,

R ⁴ and R ³ , which are the same or different, represent either an aromatic group selected from phenyl, naphthyl or indenyl, which aromatic groups may be unsubstituted or substituted by one or more halogen atoms, alkyl groups, alkoxy groups, formyl groups, hydroxyl groups, trifluoromethyl groups, trifluoromethoxy groups, -CO-alk groups, cyano groups, -COOH groups, -COOalk groups, -CONR ²² R ²³ groups, -CO-NH-NR ²⁴ R ²⁵ groups, alkylsulfanyl groups, alkylsulfinyl groups, alkylsulfonyl groups , alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR ²² R ²³ groups, or a heteroaromatic group selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3- dihydroxybenzofuryl, 2,3-dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl wherein the heteroaromatic groups may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR ²⁴ R ²⁵ , -CONR ²² R ^23, the group-alk-NR ²⁴ R ^25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyiovou group, alkylsulfinylakylovou group, alkylsulfonylalkyl or hydroxyalkyl,

R ¹⁹ represents an -alk-SO 2 R ^26, -alk-SO 2 -CH = CH-R ^26, Het ¹ is substituted by -SO 2 R ²⁶ or phenyl substituted by -SO 2 R ²⁶ or -alk-SO 2 R ²⁶ ,

R ²⁰ represents a hydrogen atom or an alkyl group,

R ²¹ represents a phenylalkyl group, a Het ¹ group or a group

Ar ¹ ,

R ²² and R ²³ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ²² and R ²³ together with the nitrogen atom to which they are attached form a saturated monocyclic or bicyclic group containing 3 to 10 members, optionally containing further a heteroatom selected from oxygen, sulfur and nitrogen, and optionally substituted with one or more alkyl groups,

R ²⁴ and R ²⁵ , 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 or a hydroxyalkyl group, or R ²⁴ and R ²⁵ together with a carbon atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted by one or more alkyl, -CO-alk, -COOalk groups, -CONHalk groups, -CSNHalk groups, oxo groups, hydroxyalkyl groups, -alk-O-alk groups or -CO-NH ₂ groups,

R ²⁵ represents an alkyl group, an Ar ¹ group or a Het ¹ group,

Ar ¹ is phenyl, naphthyl or indenyl, these groups being optionally substituted by one or more halogen atoms, alkyl groups, alkoxy groups, cyano groups, -CO-alk groups, -COOH groups, -COOalk groups, -CONR ²⁷ R groups ²⁸ , -CO-NH-NR ²⁹ R ³⁰ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR ²⁹ R ³⁰ , -NR ²⁹ R ³⁰ , alkylthioalkyl, formyl, hydroxyl, hydroxyalkyl, Het groups, -O-alk-NH-cycloalkyl groups, trifluoromethoxy groups, trifluoromethyl groups, -NH-CO-alk groups, -SO ₂ NH ₂ groups, -NH-COCH 3 groups, -NH-COOalk groups, Het groups or two more adjacent groups may form a dioxymethylene group,

Het ¹ means an unsaturated or saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 ring members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted by one or more alkyl, alkoxy, vinyl, vinyl halogen, alkoxycarbonyl, oxo, hydroxyl, trifluoromethoxy or trifluoromethyl groups, the nitrogen atoms of the heterocycles optionally being in the N-oxidized form,

R ²⁷ and R ²⁸ , which are the same or different, represent a hydrogen atom, an alkyl group, or R ²⁷ and R ²⁸ together with the carbon atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted with one or more alkyl groups,

R ²⁹ and R ³⁰ , 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 or a hydroxyalkyl group, or R ²⁹ and R ³⁰ together with a carbon atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted by one or more alkyl, -CO-alk, -COOalk groups, -CONHalk groups, -CSNHalk groups, oxo groups, hydroxyalkyl groups, -alk-O-alk groups or -CO-NH ₂ groups, or R represents CHR ³¹ , and

R ³¹ represents -NR ³² R ³³ , -NR ³² -CO-R ^33, or -NR ³² -SO ₂ R ^3, R ⁴ and R ³ , which may be the same or different, represent either an aromatic group selected from a phenyl group , naphthyl or indenyl, which aromatic groups may be unsubstituted or substituted by one or more halogen atoms, alkyl groups, alkoxy groups, formyl groups, hydroxyl groups, trifluoromethyl groups, trifluoromethoxy groups, -CO-alk groups, cyano groups, -COOH groups, -COOalk groups, -CONR ²² R ²³ groups, -CO-NH-NR ²⁴ R ²⁵ groups, alkylsulfanyl groups, alkyisulfinyl groups, alkylsulfonyl groups, alkylsulfanylalkyl groups, alkyisulfinylalkyl groups, alkyisulfonylalkyl groups, hydroxyalkyl groups or -alk-NR ⁷ groups ⁸ , or a heteroaromatic group selected from benzofuryl, benzothiazolylo benzothenyl, benzoxazolyl, chromanyl, 2,3-dihydroxybenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidinolyl , 1,2,3,4-tetrahydroisoquinolyl, thiazolyl or thienyl, wherein the heteroaromatic groups may be unsubstituted or substituted by a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a -COOH group, -COOalk, -CO-NH-NR ²⁴ R ²⁵ , -CONR ²² R ²³ , -alk-NR ²⁴ R ²⁵ , alkyisulfanyl, alkyisulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkyisulfinylalkyl, alkyisulfonylalkyl, or hydroxy 10 an alkyl group u.

R ³² is -C (R ³⁵ ) (R ³⁶ ) -Het ² , -Het ² , -C (R ³⁵ ) (R ³⁶ ) -Ar ² , Ar ² , cycloalkyl or norbornyl,

R ³³ is hydrogen, hydroxyalkyl, -alk-COOalk, -alk-CONR ²² R ²³ , -alk-NR ²² R ²³ , alkoxy, Ar ² , Het ² , -CH ² Ar ² , - CH ² Het ² or an alkyl group optionally substituted by one or more halogen atoms,

R ³⁴ represents a hydroxyalkyl, -alk-COOalk, -alk-CONR ²² R ^23, -alk-NR ²² R ^23, alkoxy, Ar ^2, Het ^2, -CH 2 Ar ² group, or a group -CH2Het ² an alkyl group optionally substituted by one or more halogen atoms,

R ³⁵ is hydrogen, hydroxyalkyl, -alk-COOalk, -alk-CONR ²² R ²³ , -alk-NR ²² R ²³ , alkoxyalkyl, Ar ² , Het ² , -CH ² Ar ² , -CH ² Het ² or an alkyl group optionally substituted by one or more halogen atoms,

R ³⁶ is hydrogen, hydroxyalkyl, -alk-COOalk, -alk-CONR ²² R ²³ , -alk-NR ²² R ²³ , alkoxyalkyl or alkyl optionally substituted by one or more halogen atoms, or R ³⁵ and R ³⁶ together with the carbon atom to which they are attached form a saturated monocyclic or bicyclic ring containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups,

Ar ² represents a phenyl group, a naphthyl group or an indenyl group, these groups being optionally substituted by one or more halogen atoms, alkyl groups, alkoxy groups, cyano groups, -CO-alk groups, -COOH groups, -COOalk groups, -CONR ³⁷ groups R ³⁸ , -CO-NH-NR ³⁹ R ⁴⁰ groups, alkylsulfanyl groups, alkylsulfinyl groups, alkylsulfonyl groups, -alk-NR ³⁹ R ⁴⁰ groups, -NR ³⁹ R ⁴⁰ groups, alkylthioalkyl groups, formyl groups, trifluoromethyl groups, trifluoromethoxy groups, Het groups, -O-alk-NH-cycloalkyl groups, -SO2NH2 groups, hydroxyl groups, hydroxyalkyl groups, -NHCOalk groups, -NH-COOalk groups or two adjacent carbon atoms with a dioxymethylene group,

Het ² means an unsaturated or saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 ring members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl groups, oxo or hydroxyl groups, the nitrogen atoms of the heterocycles optionally being in the N-oxidized form,

R ³⁷ and R ³⁸ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ³⁷ and R ³⁸ together with the carbon atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted with one or more alkyl groups,

R ³⁹ and R ⁴⁰ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ³⁹ and R ⁴⁰ together with the carbon atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted by one or more alkyl groups, alk represents an alkyl group or an alkylene group, wherein the alkyl, alkylene and alkoxy groups are straight or branched chain containing 1 to 6 carbon atoms, and cycloalkyl groups contain 3 to 10 carbon atoms, the optical isomers of these compounds, and their pharmaceutically acceptable salts with an inorganic or organic acid.

Preferred azetidine derivatives are the following compounds:

1-benzhydryl-3 - [(methylsulfonyl) (phenyl) methylene] azetidine, 1-benzhydryl-3 - [(3-methylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-chlorophenyl) (methylsulfonyl) ) methylene] azetidine, 1-benzhydryl-3 - [(3,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(2,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1 -benzhydryl-3 - [(2,3-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-fluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-bromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-iodophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethoxyphenyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethylphenyl) methylene] azetidine, 1-benzhydryl-3 - {[3, .5-bis (trifluoromethyl) phenyl] (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3,5-dibromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-mee) 1-benzhydryl-3 - [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine; 1-benzhydryl-3 - [(3-carbamoylphenyl) (methylsulfonyl) methylene] azetidine; 1-benzhydryl-3 - [(3-cyanophenyl) (methylsulfonyl) methylene] benzhydryl-3 - [(methylsulphonyl) (naphth-l-yl) (methylsulfonyl) methylene] azetidine,

1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1- [Bis (4-methoxyphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1- [bis (4-methylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, {RS} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] - 1 - [(4-methoxyphenyl) (phenyl) methyl] azetidine, (R) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1 - [(4-methoxyphenyl) (phenyl) methyl] azetidine (S) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1 - [(4-methoxyphenyl) (phenyl) methyl] azetidine,

1- [bis (4-trifluoromethoxyphenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulphonyl) methylene] azetidine,

1- [bis (4-trifluoromethylphenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine,

1- [bis (4-chlorophenyl) methyl] -3 - {[3,5-bis (trifluoromethyl) phenyl] methylsulfonylmethylene} azetidine, (RS) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3,5-difluoro phenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3) 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine (FS) -1 - {(4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - {( 4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-chlorophenyl) [4- (hydroxymethyl)] phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (FS) -1 - {(4-chlorophenyl) [4- (pyrrolidinylmethyl) phenyl] methyl} -3 - [(3 (5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (F) -1 - {(4-chlorophenyl) [4- (pyrrolidinylmethyl) phenyl] methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 {(4-chloro r phenyl) [4- (pyrrolidinylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1- (RS) - (4-Chlorophenyl) [4- (3,3-dimethylpiperid-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - ((R) - (4-chlorophenyl) [4- (3,3-dimethylpiperid-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ((S) - (4-chlorophenyl) - [4- (3,3-dimethylpiperid-1-ylmethyl) phenyl] 15

methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {(RS) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ((F) - (4- chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (N-ethyl-N) -cyclohexylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ((F) - (4-chlorophenyl) [4- (N-ethyl-N-cyclohexylaminomethyl)) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (N-ethyl-N-cyclohexylaminomethyl) phenyl] - methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {{(FS) - (4-chlorophenyl) {4 - [(4-ethoxycarbonylpiperazinyl) methyl] phenyl] methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - { {(R) - (4-chlorophenyl) (4 - [(4-ethoxycarbonylpiperazinyl) methyl] phenyl] methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ({( S) - (4-chlorophenyl) {4 - [(4-ethoxycarbonylpiperazinyl) methyl] phenyl] methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(FS) - ( 4-chlorophenyl) [4- (N-cyclopropyl-N-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(F) - (4-chlorophenyl) ) [4- (N-Cyclopropyl-N-propylaminomethyl) -phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - ((S) - (4-chlorophenyl) [4- (N-cyclopropyl-N-propylaminomethyl) -phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- {(R) - (4-chlorophenyl) [4- (diisopropylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {(R) - (4-chlorophenyl) - [4- (diisopropylaminomethyl) phenyl] methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4 chlorophenyl) [4- (diisopropylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene) azetidine,

1 - {{(RS) - (4-chlorophenyl) {4- [bis (2-methoxyethyl) aminomethyl] phenyl} methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - ({(R) - (4-chlorophenyl) {4- [bis (2-methoxyethyl) aminomethyl] -phenyl} -methyl]} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {{(S) - (4-chlorophenyl) (4- [bis (2-methoxyethyl) aminomethyl] phenyl} methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-Chlorophenyl) [4- [di-n-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {(R) - (4-chlorophenyl) [4- (di-n-propylaminomethyl) phenyl] methyl) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - ( 4-chlorophenyl) [4- (di-n-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4 - (piperid-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (piperid-1- ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {(S) - (4-Chlorophenyl) [4- (piperid-1-ylmethyl) phenyl] methyl) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - ((RS) - (4-chlorophenyl) [4- (4-methylpiperazin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- { (R) - (4-Chlorophenyl) [4- (4-methylpiperazin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) ) - (4-chlorophenyl) [4- (4-methylpiperazin-l-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {(RS) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(F) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) (4- (diethylaminomethyl)) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl} -3- [ (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {((RS) - (4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene ] azetidine, 1 - ((S) - (4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenyl] methyl 1} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl} -3- [ (3,5,5-Difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {(R) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl} -318

- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl} -3 - [(3, 5-Difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - ((4-chlorophenyl) [4- (N, N-dimethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) ( methylsulfonyl) methylene] azetidine, (R) -1 - ((4-chlorophenyl) [4- (N, N-dimethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-Chlorophenyl) [4- (N, N-dimethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1- {(4-chlorophenyl) [4- (N-ethylcarbamoyl) phenyl] methyl)} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - {(4-chlorophenyl) [ 4- (N-ethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-chlorophenyl) [4- (N-ethylcarbamoyl) phenyl] methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-carbamo ylphenyl) (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3- [ (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-methylsulfanylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-methylsulfanylmethyl) phenyl)] (methylsulfonyl) methylene) azetidine,

1- [Bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine,

1- [Bis (4-chlorophenyl) methyl] -3 - [(3-carbamoyl-phenyl) (methylsulfonyl) methylene] azetidine,

1- [Bis (4-chlorophenyl) methyl] -3 - [(3-methoxyphenyl) (methylsulfonyl) methylene] azetidine,

1- [Bis (4-chlorophenyl) methyl] -3 - [(3-hydroxyphenyl) (methylsulphonyl) methylene] azetidine,

1- [Bis (4-chlorophenyl) methyl] -3 - [(methylsulphonyl) (3-pyrrolidinylphenyl) methylene] azetidine,

1- [bis (4-chlorophenyl) methyl] -3 - [(3-hydroxymethylphenyl) (methylsulfonyl) methylene] azetidine,

1- [Bis (4-chlorophenyl) methyl] -3 - {(methylsulfonyl) [3- (N-piperidylcarbamoyl) phenyl] methylene} azetidine,

1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-trifluoromethylsulfanylphenyl) (methylsulfonyl) methylene] azetidine,

1- [Bis (4-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1- [Bis (2-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl ] -3 - [(methylsulfonyl) - (phenyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(methylsulfonyl) - (phenyl) methylene] Azetidine, (S) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(methylsulfonyl) 20]

- (phenyl) methylene] azetidine, [RS] -1 - [(4-chlorophenyl) (ethylen-2-yl) methyl) -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, (R) ) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(ethylsulfonyl) (phenyl) methylene] azetidine,

1- [Bis (4-chlorophenyl) methyl] -3 - {{3- [N- (4-methylpiperazinyl) carbamoyl] phenyl] (methylsulfonyl) methylene} azetidine,

1- [Bis (4-chlorophenyl) methyl] -3 - {[3- (2,2-dimetylkarbohydrazido) phenyl] (methylsulfonyl) methylene} azetidine,

1- [bis (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1- [bis (p-tolyl) methyl] -3 - [(methylsulfonyl) (phenyl) methylene] azetidine,

1 - [(4-chlorophenyl) (4-hydroxymethylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1- [bis (4-chlorophenyl) methyl] -3 - [(3-methylaminophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine,

1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (2-methoxycarbonylthien-5-yl) methylene] azetidine, (RS) -1 - [[bis (4-chlorophenyl) methyl] -3- hydroxy-3 - [(methylsulfonyl)

- (2-methoxycarbonylthien-5-y1) methyl] azetidine,

1- [bis (4-chlorophenyl) methyl] -3 - [(2-isobutylaminocarbonythien-5-yl) (methylsulfonyl) methylene] azetidine,

1- [bis (4-chlorophenyl) methyl] -3 - [(3-methoxycarbonylphenyl) - (methylsulfonyl) methyl- (PS)] azetidin-3-ol,

1- [Bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (pyrid-4-yl) methyl- (RS)] azetidin-3-ol,

1 - [[Bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (pyrid-3-yl) methyl {RS)] azetidin-3-ol,

3 - ({1- [bis (4-chlorophenyl) methyl] and zetidin-3-ylidene} methanesulfonylmethyl) -N- (3-morpholin-4-ylpropyl) benzamide,

3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene] methanesulfonylmethyl) -N- (3-dimethylaminopropyl) benzamide,

3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (2- (pyrrolidin-1-yl) ethyl) benzamide,

3- ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (2-dimethylamino-1-methylethyl) benzamide,

3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (piperidin-1-yl) benzamide,

3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene] methanesulfonylmethyl) -N-isobutylbenzamide,

3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (3-imidazol-1-ylpropyl) benzamide,

3 - ({1- (bis (4-chlorophenyl) methyl) azetidin-3-ylidene] methanesulfonylmethyl) -N- (2-dimethylaminoethyl) benzamide,

3 '- ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) benzoic acid N'-methylhydrazide,

3 - ({1- [bis (4-chlorophenyl) methyl-azetidin-3-ylidene} methanesulfonylmethyl) -N- (2-morpholin-4-yl-ethyl) -benzamide,

3 - ({1-bis (4-chlorophenyl) methyl] azetidin-3-ylidene [metánsulfonyimetyl) -N- (l-ethyl-pyrrolidin-2-ylmethyl) -benzamide,

3 - ({1- (bis (4-chlorophenyl) methyl] azetidin-3-ylidene (methanesulfonylmethyl) -N- (2,2-dimethylpropyl) benzamide,

3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} metánsulfony1metyl) -N- (cyclohexylmethyl) -benzamide,

3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (cyclopropylmethyl) benzamide,

3 - ((1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (2-methylbutyl) benzamide,

3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) metánsulfony1metyl) -N- (2-phenylpropyl) benzamide,

- ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene [methanesulfonylmethyl) -N- (tetrahydrofuran-2-ylmethyl) benzamide,

3 - ((1- [bis (4-chlorophenyl) methyl) azetidin-3-ylidene [methanesulfonylmethyl) -N- (2,2-diphenylethyl) benzamide,

3 - ((1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) -N- (2-ethylbutyl) benzamide, 4 - {[3 - ((1- [bis (4- chlorophenyl) methyl] azetidin-3-ylidene [methanesulfonylmethyl) -benzoylamino] methyl} cyclohexanecarboxylate,

2-Amino-1- (4- (3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} -methanesulfonylmethyl) phenyl] piperazin-1-yl) ethanone, tert-butyl ester (2) - {4- [3 - ({1- [bis (4-chloro-phenyl) -methyl] -azetidin-3-ylidene) -methanesulfonylmethyl) -phenyl] -piperazin-1-yl) -2-oxo-ethyl) -carbamic acid, 1- {4- [ 3 - ({1- [Bis (4-Chloro-phenyl) -methyl] -azetidin-3-ylidene) -methanesulfonylmethyl) -phenyl] -piperazin-1-yl} -2-methylamino-ethanone, tert-butyl ester (2- {4- [3- ({l- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) phenyl] piperazin-l-yl) -2-oxo-ethyl) -N-butyl ester,

4- [3 - ({[1-Bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethylphenyl] piperazine-1-carbothioic acid N-methylamide,

4- [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethylphenyl] piperazine-1-carboxylic acid N-methylamide, methyl 4- [3 - ({1- [bis] (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) phenyl] piperazine-1-carboxylic acid,

1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene-methanesulfonylmethyl) phenyl] -4-isobutylpiperazine, 1- [3 - ({1- [bis (4-chlorophenyl) methyl] ] azetidin-3-ylidene) methanesulfonylmethyl) phenyl] -4-ethylpiperazine,

4-acetyl-1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} -methanesulfonylmethyl) phenyl] piperazine, 1- {4- [3 - ({1- [bis ( 4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazin-1-yl} -2-dimethylaminoethanone; i

4- [3 - ({1- [Bis (4-chlorophenyl) -1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) phenyl] piperazine, tert -butyl ester ) -methyl] 24

azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazine-l-carboxylic acid,

1- [Bis (4-methoxycarbonylphenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulphonyl) methylene] azetidine,

3-Acetoxy-1- [bis (4-methoxycarbonylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl (RS)] azetidine, (RS) -4- [4- ((4-chlorophenyl) {3 - [(3,5-difluorophenyl) metánsulfony1metylén] azetidin-l-yl} methyl) benzyl] morpholine,

4- (4- {3 - [(1-benzhydrylazetidin-3-ylidene) methanesulfonylmethyl] -phenoxy} butyl) morpholine,

- (4- {3 - [(1-benzhydrylazetidin-3-ylidene) methanesulfonylmethyl] -phenoxy} propyl) morpholine,

N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} thien-2-ylsulfonamide,

N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -4-methoxyphenylsulfonamide,

N- [4- (N- {l- [bis (4-chlorophenyl) methyl] azetidin-3-yl} sulfamoyl) phenyl] acetamide,

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

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

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

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

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

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2,5-dimetoxyfenylsulfónamid,

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

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

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} naphth-l-ylsulfonamide,

N- [1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-difluórfenylsulfónamid,

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1-methyl-1H-imidazol-4-ylsulfonamide,

N- [4- (N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-ylJsulfamoyl) -2-chlorophenyl] acetamide,

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

N- {1- [bis (4-chlorophenylmethyl) azetidin-3-yl} -4-fluorophenylsulfonamide,

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} quinolin-8-ylsulfonamide,

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

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

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

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} pyridin-2-y1sulfónamid,

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3-fluoro-5-pyrrolidin-1-ylphenyl) sulfonamide;

N- {1- [bis (4-chloro-phenyl) -methyl] -azetidin-3-yl} -N-methyl-4-fluoro-26-phenylsulfonamide,

N- {1- [bis [4-chlorophenyl) methyl] azetidin-3-yl} -N-methyl-quinolin-8-ylsulfonamide,

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

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

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

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

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (4-toluene-4-sulfonyl) acetamide, (3-chloro-4-methylsulfonylthiophene-2-carboxy) - {1 - [bis (4-chlorophenyl) methyl] azetidin-3-yl] -amide,

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

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

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4-methanesulfonylbenzamide, (5-methylsulfonylthiophene-2-carboxy) - {1- [bis (4-chlorophenyl) methyl] azetidine- 3-yl} amide, (5-Methylsulfonyl-3-methyl-4-vinylthiophene-2-carboxy) {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} amide, (RS) -N- {1 - [(4-chlorophenyl) pyridin-3-ylmethyl] azetidin-3-yl} -3,5-difluorobenzenesulfonamide, (RS) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidine 3-yl} -3,5'-difluoro-benzenesulfonamide,

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

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

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

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-y1} -N-quinolin-5-y1metylsulfónamid,

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

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

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

N- (1R, 2S, 4S) -bicyclo [2.2.1] hept-2-yl-N- {1- [bis- (4-chloro-phenyl) -methyl-azetidin-3-yl] -methylsulfonamide,

N- (1R, 2R, 4S) - (Bicyclo [2.2.1] hept-2-yl) -N- {1- (bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl) -methylsulfonamide,

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-y1} -N- (3,5-difluorophenyl) methylsulfonamide,

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-y1} -N- (thiazol-2-yl) methylsulphonamide,

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) 28

methylsulphonamide.

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- {l- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (izobutylpiperid-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} -N- (pyrid-3-ylmethyl) methylsulfonamide,

N- {1- [bis (4-fluorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) pyrid-3 -ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (P) -N- {1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl} -N - (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, ( RS) -N- (1 - [(4-chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N- {1 - [(4) (chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) pyrid-4-ylmethyl] azetidine- 3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3 (R) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (S) -, 5-difluorophenyl) methylsulfonamide, (S) - N {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide,

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) benzylsulfonamide, their optical isomers, and their pharmaceutically acceptable salts with an inorganic or organic acid.

And yet particularly preferred are the following azetidine derivatives:

1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol,

3-acetoxy-l- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methyl) methylsulfonylmethyl (RS)] azetidine,

1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, their optical isomers, and their pharmaceutically acceptable salts with an inorganic or organic acid.

Examples of pharmaceutically acceptable salts of azetidine derivatives include: benzenesulfonate, bromide, chloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene-bis-3-oxynaphthate, nitrate, oxalate, pamoate, oxalate, pamoate, oxalate, pamoate salicylate, succinate, sulfate, tartrate, theophylline acetate and p-toluenesulfonate.

Other CB1 antagonists for use in the combinations of the present invention are, for example, the pyrazole derivatives described in EP 576 357, EP 658 546, EP 656 354, WO 97/19063 and WO 00/46209, the benzothiophene and benzofuran derivatives described in WO 96/02248 or sulfonamides described in WO 98/37061. Particular mention is made of the products known under the codes SR141716 and LY320135.

DETAILED DESCRIPTION OF THE INVENTION

The synergistic effect of the combination of sibutramine and CB1 antagonist on food intake was determined according to the following protocol.

The obese Fa / fa Zucker rats at 7 weeks of age from Iffa-Credo, France were used for the study. These rats were placed in individual cages and weighed every day between 8 and 10 pm. At the same time, the amount of food was weighed. This food (M20, Pietrement, France) was changed every day and the rats had free access to food for 24 hours. Rats were treated with vehicle (miglyol 812N and 0.5% methylcellulose / 0.2% polysorbate 80) for 1 week in two consecutive administrations. Rats were treated orally from day 8 with CB1 antagonist (1- [bis (4-dichlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene-ketidine or sibutramine (see table below).

Sibutramine was dissolved in a solution of 0.5% methylcellulose / 0.2% polysorbate 80 and administered at a dose of 3 mg / kg; the CB1 antagonist was dissolved in miglyole 812N (Huls, Allemagne, Germany) at 0.6 mg / kg, and the two products were administered in a volume of 1 ml / kg. Each group consisted of 12-14 animals, the following groups were formed, and the animals were treated every day for 5 days in two consecutive administrations.

Group First submission Second administration 1 "Vehicle group Miglyol 0,5% methylcellulose / 0,2% polysorbate 2 "sibutramínová group Miglyol sibutramine 3 mg / kg 3 antagonist 0,5% methylcellulose / 0,2% "Antagonist group CB1 CB1, 0.6 mg / kg polysorbate 4 'Combination group antagonist CB1, 0.6 mg / kg sibutramine 3 mg / kg

Food consumption of each animal was measured daily. The results are shown as the amount of food consumed during the treatment for 5 days. The results obtained are shown in the following table.

treatment Food consumption within 5 days treatment (g) vehicle 25.52 ± 0.30 Sibutramine 3 mg / kg 24.60 ± 0.32 * CB1 antagonist 0.6 mg / kg 24.00 ± 0.24 ** Sibutramine (3 mg / kg) + CB1 antagonist (0.6 mg / kg) 22.76 ± 0.02 ***

* p <, 0.05 ** p <0.01 *** p <0.001

The results show that in animals receiving sibutramine and CB1 antagonist combinations, the reduction in food consumption is much greater than in animals receiving sibutramine alone or CB1 antagonist alone.

The compounds may be administered orally, parenterally, transdermally, or rectally, either simultaneously, separately or sequentially.

The present invention also relates to pharmaceutical compositions comprising a combination of sibutramine, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and a CB1 receptor antagonist in pure form with one or more compatible diluents and / or excipients and / or in combination with another pharmaceutically acceptable active product. separate or sequential use.

As solid compositions for oral administration, tablets, pills, powders (hard gelatin capsules, sachets) or granules may be used. In these compositions, the active ingredient of the invention is mixed under one stream of argon with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica. These compositions can comprise substances other than diluents, e.g. a lubricant such as _a magnesium stearate or talc, a coloring, a coating (sugar-coated tablets) or a glaze.

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. The compositions may also contain substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing agents.

The sterile compositions for parenteral administration may preferably be solutions which are aqueous or non-aqueous, suspensions or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, can be used as a solvent or vehicle.

Oil, injectable organic esters, for example ethyl oleate, or other organic solvents. These compositions may contain excipients, in particular wetting, isotonic, emulsifying, dispersing and stabilizing agents. Sterilization can be accomplished in several ways, for example by sterile filtration, incorporation of sterilizing agents into the composition, irradiation or heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or other injectable medium.

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

The pharmaceutical compositions usually contain 0.5 to 10 mg sibutramine and 0.1 to 200 mg CB1 antagonist.

The present invention also relates to a method of treating obesity comprising administering to a patient a combination of the invention either simultaneously or separately or in divided doses.

The dose depends on the effect desired, the duration of treatment and the route of administration; in general, 1 to 15 mg sibutramine per day for oral administration and 0.10 to 500 mg CB1 antagonist per day for oral administration are administered to an adult patient.

Generally, the attending physician will determine the appropriate dose according to the age, weight and any other factor specific to the subject to be treated.

Claims (12)

PATENT CLAIMS A combination of a CB1 antagonist and sibutramine, a hydrate thereof, or one of its pharmaceutically acceptable salts. The combination of claim 1, wherein the CB1 antagonist is a compound of formula (I) R ³ where each R is A or B, / ^SO 2 ^{R 1} ? ^r 'so ₂ r' C CH or C-CH R ² R ² (A) (B) R ¹ is methyl or ethyl, R ² represents either an aromatic group selected from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, -CO-alk, hydroxyl, -COOR ⁵ , formyl groups, trifluoromethyl groups, trifluoromethylsulfanyl groups, trifluoromethoxy groups, nitro groups, groups -NR ⁶ R ⁷ , -CO-NH-NR ⁶ R ⁷ groups, -N (alk) COOR ⁸ groups, cyano groups, -CONHR ⁹ groups, -CO-NR ¹⁶ R ¹⁷ groups, alkylsulfanyl groups, hydroxyalkyl groups, groups -O-alk-NR ¹² R ¹³ or alkylthioalkyl groups, or a heteroaromatic group selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydroxybenzofuryl, 2,3-dihydrobenzothienyl, indolinyl , indolyl, isochromanyl, isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl groups, which heteroaromatic groups may be unsubstituted or substituted by halogen, alkyl, alkoxy, -COOR ⁵ , trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NR ⁶ R ⁷ , -CO-NH-NR ⁶ R ⁷ , cyano, -CONHR ⁹ , alkylsulfanyl, hydroxyalkyl or alkylthioalkyl, R ³ and R ⁴ , which are the same or different, represent either an aromatic group selected from a phenyl group, a naphthyl group or an indenyl group, which aromatic groups may be unsubstituted or substituted by one or more halogen atoms, alkyl groups, alkoxy groups, formyl groups, hydroxyl groups, trifluoromethyl groups, trifluoromethoxy groups, -CO-alk groups, cyano groups, -COOR ⁵ groups, -CONR ¹⁰ R ¹¹ groups, -CO-NH-NR ⁶ R ⁷ groups, alkylsulfanyl groups, hydroxyalkyl groups, -alk-NR groups ⁶ R ⁷ or alkylthioalkyl, or a heteroaromatic group selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, J 2,3-dihydrobenzothienyl, furyl, chromanyl, isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquinolinyl, thiazolyl or thienyl groups, these heteroaromatic groups may be unsubstituted or substituted by one or more halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOR ^5, -CO-NH-NR ^C R ^7, -CONR ¹⁰ R ^n, -alk-NR ⁶ R ⁷ , alkylsulfanyl, hydroxyalkyl or alkylthioalkyl groups, R ⁵ is an alkyl or phenyl group optionally substituted with one or more halogen atoms, R ⁶ and R ⁷ , 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 or a hydroxyalkyl group, or R ⁶ and R ⁷ together with a nitrogen atom to which they are attached form a saturated or unsaturated and monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted by one or more alkyl groups, -CO-alk groups , -COOalk groups, groups -CONHalk, -CSNHalk radicals, -CO-alk-NR R, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH _2, R ⁸ represents an alkyl group, R ⁹ represents a hydrogen atom, an alkyl group or an alkyl group substituted with a dialkylaminoalkyl group, a phenyl group, a cycloalkyl group (optionally substituted with -COOalk group) or a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 3 to 10 members, optionally containing one or more heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and optionally substituted by one or more alkyl groups, R ¹⁰ ) and R ¹¹ , which are the same or different, represent a hydrogen atom ¹ or an alkyl group, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 members, optionally containing a further heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups, R ¹² and R ¹³ , which are the same or different, represent a hydrogen atom or an alkyl or cycloalkyl group, or R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 members optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with alkyl, -CO-alk, -COOalk, -CONHalk, CSNHalk, -CO-alk-NR ¹⁴ R ¹⁵ or saturated a 3 to 10 membered monocyclic or bicyclic heterocyclic group containing a heteroatom selected from oxygen, sulfur and nitrogen, R ¹⁴ and R ¹⁵ , which are the same or different, represent a hydrogen atom, an alkyl group or a -COOalk group, R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing further heteroatoms selected from oxygen, sulfur and nitrogen, R 'is H or -CO-alk, or R represents a CHR ¹⁸ radical, and R ¹⁸ - represents a radical -NHCOR ¹⁹ or -N (R ²⁰⁾ -YR ^21, Y ¹ is CO or SO ₂ , R ⁴ and R ³ which are the same or different represent either an aromatic group selected from phenyl, naphthyl or indenyl, which aromatic groups may be unsubstituted or substituted by one or more halogen atoms, alkyl groups, alkoxy groups, formyl groups, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR ²² R ²³ , -CO-NH-NR ²⁴ R ²⁵ , alkylsulfanyl, alkylsulfinyl groups , alkylsulfonyl groups, alkylsulfanylalkyl groups, alkylsulfinylalkyl groups, alkylsulfonylalkyl groups, hydroxyalkyl groups or -alk-NR ²² R ²³ groups, or a heteroaromatic group selected from benzofuryl group, benzothiazolyl group, benzothienyl group, benzothiazolyl group, 2-chromanyl group, chromanyl , 3-dihydroxybenzofuryl, 2,3-diynylbenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl thiazolyl or thienyl, wherein the heteroaromatic groups may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR ²⁴ R ²⁵ , -CONR ²² R ²³ , -alk-NR ²⁴ R ²⁵ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R ¹⁹ represents an -alk-SO 2 R ^26, -alk-SO 2 -CH = CH-R ^26, Het ¹ is substituted by -SO ₂ -R ²⁶ or a phenyl sku39, pin substituted by -SO ₂ -R ²⁶ or - alk-SO ₂ -R ²⁶ R ²⁰ represents a hydrogen atom or an alkyl group, R ²¹ represents a phenylalkyl group, a Het ¹ group or an Ar ¹ group, R ²² and R ²³ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ²² and R ²³ together with the nitrogen atom to which they are attached form a saturated monocyclic or bicyclic group containing 3 to 10 members, optionally containing further a heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups, R ²⁴ and R ²⁵ , 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 or a hydroxyalkyl group, or R ²⁴ and R ²⁵ together with a carbon atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted by one or more alkyl, -CO-alk, -COOalk groups, -CONHalk groups, -CSNHalk groups, oxo groups, hydroxyalkyl groups, -alk-O-alk groups or -CO-NH ₂ groups, R ²⁶ represents an alkyl group, an Ar ¹ group or a Het ¹ group, Ar ¹ is phenyl, naphthyl or indenyl, these groups being optionally substituted by one or more halogen, alkyl, alkoxy, cyano, -CO-alk, -COOH, -COOalk, -COOalk, CONR ²⁷ R ^28, Item ¹ Pina -CO-NH-NR ²⁹ R ^30, alkylsulfanyl, alkyl40 sulfinyl, alkylsulfonyl, -alk-NR ²⁹ R ^30, -NR ²⁹ R ^30, alkylthioalkyl, formyl , hydroxyl groups, hydroxyalkyl groups, Het groups, -O-alk-NH-cycloalkyl groups, trifluoromethoxy groups, trifluoromethyl groups, -NH-CO-alk groups, -SO2NH2 groups, -NH-COCH3 groups, -NH-COOalk groups, Het or two adjacent groups may form a dioxymethylene group, Het ¹ means an unsaturated or saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 ring members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted by one or more alkyl, alkoxy, vinyl, atoms halogen, alkoxycarbonyl, oxo, hydroxyl, trifluoromethoxy or trifluoromethyl groups, the nitrogen atoms of the heterocycles optionally being in the N-oxidized form, R ²⁷ and R ²⁸ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ²⁷ and R ²⁸ together with the carbon atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted with one or more alkyl groups, R ²⁹ and R ³⁰ , 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 or a hydroxyalkyl group, or R ²⁹ and R ³⁰ together with a carbon atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted by one or more alkyl groups, -CO-alk groups , -COOalk groups, groups -CONHalk, -CSNHalk radicals, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH 2 radicals, or R represents a CHR ³¹ radical, and R ³¹ is -NR ³² R ³³ , -NR ³² -CO-R ^33, or -NR ³² -SO ₂ R ^3; R ⁴ and R ³ , which are the same or different, represent either an aromatic group selected from phenyl, naphthyl or indenyl, which aromatic groups may be unsubstituted or substituted by one or more halogen atoms, alkyl groups, alkoxy groups, formyl groups, hydroxyl groups, trifluoromethyl groups, trifluoromethoxy groups, -CO-alk groups, cyano groups, -COOH groups, -COOalk groups, -CONR ²² R ²³ groups, -CO-NH-NR ²⁴ R ²⁵ groups, alkylsulfanyl groups, alkylsulfinyl groups, alkylsulfonyl groups , alkylsulfanylalkyl groups, alkylsulfinylalkyl groups, alkylsulfonylalkyl groups, hydroxyalkyl groups or -alk-NR ⁷ R ⁸ groups, or a heteroaromatic group selected from benzofuryl group, benzothiazolyl group, benzothienyl group, benzoxazolyl group, chromanyl group, 2,3-d ihydroxybenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl or thiazolyl, wherein the heteroaromatic groups may be unsubstituted or substituted by a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a -COOH group, a -COOalk group, a -CO-NH-NR ²⁴ R ^{25 group} , -CONR ²² R ²³ , -alk-NR ²⁴ R ²⁵ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R ³² is -C (R ³⁵ ) (R ³⁶ ) -Het ² , -Het ² , -C (R ³⁵ ) (R ³⁶ ) -Ar ² , Ar ² , cycloalkyl or norbornyl, R ³³ is hydrogen, hydroxyalkyl, -alk-COOalk, -alk-CONR ²² R ²³ , -alk-NR ²² R ²³ , alkoxy, Ar ² , Het ² , -CH ² Ar ² , - CH ² Het ² or an alkyl group optionally substituted by one or more halogen atoms, R ³⁴ represents a hydroxyalkyl, -alk-COOalk, -alk-CONR ²² R ^23, -alk-NR ²² R ^23, alkoxy, Ar ^2, Het ^2, -CH 2 Ar ² group, or a group ^t -CH2Het an alkyl group optionally substituted by one or more halogen atoms, R ³⁵ is hydrogen, hydroxyalkyl, -alk-COOalk, -alk-CONR ²² R ²³ , -alk-NR ²² R ²³ , alkoxyalkyl, Ar ² , Het ² , -CH ² Ar ² , -CH ² Het ² or an alkyl group optionally substituted by one or more halogen atoms, R ³⁵ is hydrogen or hydroxyalkyl, -alk-COOalk, -alk-CONR ²² R ²³ , -alk-NR ²² R ²³ , alkoxyalkyl or alkyl optionally substituted with one or more halogen atoms, or R ³⁵ and R ³⁶ together with the carbon atom to which they are attached form a saturated monocyclic or bicyclic ring containing from 3 to 10 members, optionally containing a further heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups, Ar ² is phenyl, naphthyl or indenyl, these groups being optionally substituted with one or more halogen atoms, alkyl groups, alkoxy groups, cyano groups, -CO-alk groups, -COOH groups, -COOalk groups, -CONR groups ³⁷ R ³⁸ , -CO-NH-NR ³⁹ R ⁴⁰ groups, alkylsulfanyl groups, alkylsulfinyl groups, alkylsulfonyl groups, -alk-NR ³⁹ R ¹⁰ groups, -NR ³⁹ R ⁴⁰ groups, alkylthioalkyl groups, formyl groups, trifluoromethyl groups , trifluoromethoxy, Het, -O-alk-NH-cycloalkyl, -SO ₂ NH ₂ , hydroxyl, hydroxyalkyl, -NHCOalk, -NH-COOalk, or two adjacent carbon atoms with a dioxymethylene group, Het ² means an unsaturated or saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 ring members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl groups, oxo or hydroxyl groups, the nitrogen atoms of the heterocycles optionally being in the N-oxidized form, R ³⁷ and R ³⁸ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ³⁷ and R ³⁸ together with the carbon atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 members; optionally containing a further heteroatom selected from 2 oxygen, sulfur or nitrogen and optionally substituted with one or more alkyl groups, R ³⁹ and R ⁴⁰ , which are the same or different, represent a hydrogen atom or an alkyl group, or R ³⁹ and R ⁴⁰ together with the carbon atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted with one or more alkyl groups, alk represents an alkyl group or an alkylene group, the alkyl, alkylene and alkoxy moieties being straight or branched chain containing 1 to 6 carbon atoms, and cycloalkyl groups containing 3 to 10 carbon atoms, optical isomers of these compounds, and pharmaceutically acceptable salts thereof with an inorganic or organic acid. The combination of claim 2, wherein the compound of the formula is selected from the group consisting of the following compounds: 1-benzhydryl-3 - [(methylsulfonyl) (phenyl) methylene] azetidine, 1-benzhydryl-3 - [(3-methylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-chlorophenyl) (methylsulfonyl) ) methylene] azetidine, 1-benzhydryl-3 - [(3,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(2,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1 -benzhydryl-3 - [(2,3-dichlorophenyl) (methylsulfonyl) methylene] -azetidine, 1-benzhydryl-3 - [(3-fluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-bromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-iodophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethoxyphenyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethylphenyl) methylene] azetidine, 1-benzhydryl-3 - ([3, 5-bis (trifluoromethyl) phenyl] (methylsulfonyl) methylene} azetidine, 1-benzhydryl-3 - [(3,5-dibromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-methoxy) carbonylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-carbamoylphenyl) (methylsulfonyl) methylene] azetidine, 1 benzhydryl-3 - [(methylsulphonyl) (naphth-l-yl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-methoxyphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-methylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] - 1 - [(4-methoxyphenyl) (phenyl) methyl)] azetidine, (R) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1 - [(4-methoxyphenyl) (phenyl) methyl] azetidine (S) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1 - [(4-methoxyphenyl) (phenyl) methyl] azetidine, 1- [bis (4-trifluoromethoxyphenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulphonyl) methylene] azetidine, 1- [Bis (4-trifluoromethylphenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulphonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - {[3,5-bis (trifluoromethyl) phenyl] methylsulfonylmethylene] azetidine, (RS) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3,5-difluoro phenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3,5 -difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, ( RS) -1 - {(4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - {(4-chlorophenyl) ) [4- (hydroxymethyl) phenyl] methyl) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl } -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - {(4-chlorophenyl) [4- (pyrrolidinylmethyl) phenyl] methyl} -3 - [(3,5- difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - {(4-chlorophenyl) [4- (pyrrolidinylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, ( S) -1 - {(4-chlorophenyl) [ 4- (pyrrolidinylmethyl) phenyl] methyl} -347 - [(3, [5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- (RS) - (4-Chlorophenyl) [4- (3,3-dimethylpiperid-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- ((R) - (4-Chlorophenyl) [4- (3,3-dimethylpiperidin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- { (S) - (4-Chlorophenyl) [4- (3,3-dimethylpiperidin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (N- ethyl-N-cyclohexylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (N-ethyl-N-cyclohexylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (N-ethyl-N-cyclohexylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - { ((RS) - (4-chlorophenyl) (4 - [(4-ethoxycarbonylpiperazinyl) methyl] phenylphenyl)} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ({(R ) - (4-chlorophenyl) (4 - [(4-etoxykarbonylpiperazinyl) methyl] phenyl} methyl)}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, I 1 - {{(S) - (4-chlorophenyl) (4 - [(4-etoxykarbonylpiperazinyl) methyl] I -fenylJmetyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (N-cyclopropyl-N-propylaminomethyl) -phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) (4-Chlorophenyl) [4- (N-cyclopropyl-N-propylaminomethyl) -phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4 chlorophenyl) [4- (N-cyclopropyl-N-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (diisopropylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(F) - (4-chlorophenyl) - [4- (diisopropylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (diisopropylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene) azetidine, 1 - {{(RS) - (4-chlorophenyl) (4- [bis (2-methoxyethyl) aminomethyl] phenyl} methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {η (R) - (4-chlorophenyl) {4- [bis (2-methoxyethyl) aminomethyl] phenyl} methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{(S) - (4-chlorophenyl) {4- [bis (2-methoxyethyl) aminomethyl] phenyl} methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(FS) - (4-chlorophenyl) [4- [di-n-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(F) - (4-chlorophenyl) [4- (di-n-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (di-n-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(FS) - (4-Chlorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl} 49 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl} -3 - [(3 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) ( methylsulfonyl) methylene] azetidine, 1 - ((RS) - (4-chlorophenyl) [4- (4-methylpiperazin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene ] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (4-methylpiperazin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (4-methylpiperazin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- {(RS) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - ( 4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4 - (morpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) (4- (diethylaminomethyl) phenyl] methyl) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl) -3 - [(3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ((S) - (4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {((RS) - (4 - chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 11 - ((R) - (4-Chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenyl] methyl) -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ((S) - (4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ((R) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - {(4-chlorophenyl) ) [4- (N, N-dimethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - {(4-chlorophenyl) [4- (N , N-dimethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-chlorophenyl) [4- (N, N-dimethylcarbamoyl) phenyl methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - {(4-chlorophenyl) [4- (N-ethylcarbamoyl) phenyl] methyl)} - 3- [ (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - {(4-chlorophenyl) [4- (N-ethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) ( methylsulfonyl) methylene] azetidine, (S) -1 - {(4-chlorophenyl) [4- (N-ethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) ) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - [(3,5-difluoro) (phenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) - 1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-dichlorophenyl) (methylsulphonyl) methylene] azetidine, 11-benzhydryl-3 - [(3-methylsulfanylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-methylsulfanylmethyl) phenyl)] (methylsulfonyl) methylene) azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (mety1sulfony1) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3-carbamoylphenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3-methoxyphenyl) (methylsulfonyl) methylene] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - [(3-hydroxyphenyl) (methylsulphonyl) methylene] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - [(methylsulphonyl) (3-pyrrolidinylphenyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3-hydroxymethylphenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - ((methylsulfonyl) [3- (N-piperidylcarbamoyl) phenyl] methylene} azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-trifluoromethylsulfanylphenyl) (methylsulfonyl) methylene] azetidine, 1- [Bis (4-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [Bis (2-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl ] -3 - [(methylsulfonyl) - (phenyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(methylsulfonyl) - (phenyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(methylsulfonyl) - (phenyl) methylene] azetidine, (RS) -1 - [(4-chlorophenyl) (Thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (shadow-2-yl) methyl] - 3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(ethylsulfonyl) (phenyl) methylene] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - {{3- [N- (4-methylpiperazinyl) carbamoyl] phenyl] (methylsulfonyl) methylene) azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - {[3- (2,2-dimetylkarbohydrazido) phenyl] (methylsulfonyl) methylene} azetidine, 1- [bis (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (p-tolyl) methyl] -3 - [(methylsulfonyl) (phenyl) methylene] azetidine 1 - [(4-chlorophenyl) (4-hydroxymethylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3-methylaminophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) (methylene) azetidine, (S) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (2-methoxycarbonylthien-5-yl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3-hydroxy-3 - [(methylsulfonyl) (2-methoxycarbonythien-5-yl) methylene] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - [(2-izobutylaminokarbonyltien-5-yl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3-methoxycarbonylphenyl) - (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 1- [Bis (4-chlorophenyl) methyl] -3 - [(methylsulphonyl) (pyridin-4-yl) methyl- (RS)] azetidin-3-ol, 1 - [[Bis (4-chlorophenyl) methyl] -3 - [(methylsulphonyl) (pyridin-3-yl) methyl- (RS)] azetidin-3-ol, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (3-morpholin-4-ylpropyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidénImetánsulfonylmetyl) -N- (3-dimethylaminopropyl) benzamide. 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (2- (pyrrolidin-l-yl) ethyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene [methanesulfonylmethyl) -N- (2-dimethylamino-1-methylethyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (piperidin-l-yl) benzamide, 3 - ({Ϊ- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonyl-54-methyl) -N-isobutylbenzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (3-imidazol-l-yl-propyl) -benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (2-dimethylamino-ethyl) -benzamide, 3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) benzoic acid N'-methylhydrazide, 3 - ({1- [bis (4-chlorophenyl) methylazetidin-3-ylidene} methanesulfonylmethyl) -N- (2-morpholin-4-ylethyl) benzamide, 3- ({1-bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) -N- (1-ethylpyrrolidin-2-ylmethyl) benzamide, 3 - ((1- (bis (4-chlorophenyl) methyl) azetidin-3-ylidene} methanesulfonylmethyl) -N- (2,2-dimethylpropyl) benzamide, 3 - ([1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidénJmetánsulfonylmetyl) -N- (cyclohexylmethyl) -benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) -N- (cyclopropylmethyl) benzamide, 3 - ((1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene] methanesulfonylmethyl) -N- (2-methylbutyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (2-phenylpropyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (tetrahydrofuran-2-ylmethyl) -benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidénJmetánsulfonylmetyl) -N- (2,2-diphenyl-ethyl) -benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene] methanesulfonylmethyl) -N- (2-ethylbutyl) benzamide, methyl 4 - {[3 - ({1- [bis (4- chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -benzoylamino] -methyl} -cyklohexánkarboxyiovej, 2-Amino-1- {4- (3- ({1- [bis (4-chloro-phenyl) -methyl] -azolidin-3-ylidene} -methanesulfonylmethyl) -phenyl] -piperazin-1-yl} -ethanone, tert-butyl ester (2- {4- [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazin-1-yl} -2-oxoethyl) carbamic acid, 1- {4- [3 - ({1- [Bis (4-chloro-phenyl) -methyl] -azetidin-3-ylidene] -methanesulfonylmethyl) -phenyl] -piperazin-1-yl} -2-methylamino-ethanone, 2- (tert-butyl) ester {4- [3 - ((1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazin-1-yl} -2-oxoethyl) -N-methylcarbamic acid, 4- [3 - ({[1-Bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazine-1-carbothioic acid N-methylamide, 4- [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonyl) methylphenyl] piperazine-1-carboxylic acid N-methylamide, methyl 4- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene] methanesulfonylmethyl) phenyl] piperazine-1-carboxylic acid, 1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidénJmetánsulfonylmetyl) phenyl] -4-isobutylpiperazine, 1- [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] -4-ethylpiperazine, I 4-Acetyl-1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} -metánsulfonylmetyl) phenyl] piperazine, 1- {4- [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene [methanesulfonylmethyl) phenyl] piperazin-1-yl} -2-dimethylaminoethanone, 4- [3 - ({1- [Bis (4-Chloro-phenyl) -methyl] -phenyl] -piperazine-1- [3 - ({1- [bis (4-chloro-phenyl) -methyl] -azetidin-3-ylidene] -methanesulfonylmethyl) -phenyl] -piperazine ) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazine-l-carboxylic acid, 1- [Bis (4-methoxycarbonylphenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulphonyl) methylene] azetidine, 3-Acetoxy-1- [bis (4-methoxycarbonylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidine, (RS) -4- [4 - ((4- chlorophenyl) {3 - [(3,5-difluorophenyl) metánsulfonylmetylén] azetidin-l-yl} methyl) benzyl] morpholine, 4- (4- {3 - [(1-benzhydrylazetidin-3-ylidene) methanesulfonylmethyl] phenoxy] butyl) morpholine, 4- (4- {3 - [(1-benzhydryl-azetidin-3-ylidene) methanesulfonylmethyl] phenoxy] propyl) morpholine, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-y1} thien-2-ylsulfonamide, N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -4-methoxyphenylsulfonamide, N- [4- (N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} sulfamoyl) phenyl] acetamide, N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4-metylfeny1sulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-dimetoxyfenylsulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3-fluorophenyl57 sulfonamide, I I N- {N - [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-dichlorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -3-cyanophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2,5-dimetoxyfenylsulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3-trifluórmetylfenylsulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} naphth-2-ylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} naphth-1-ylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-difluórfenylsulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1-methyl-1H-imidazol-4-ylsulphonamide, N- [4- (N- [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl} sulfamoyl) -2- chlorophenyl] acetamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} pyrid-3-ylsulfonamide, N- {1- [bis (4-chlorophenyl methyl] azetidin-3-yl} -4-fluorophenylsulfonamido, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} quinolin-8-ylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} phenylsulfonamide, I N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} (phenylmethyl) I sulfonamide, I N- [1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,5-difluorophenyl58 sulfonamide, N- {1- [bis (4-chloro-phenyl) -methyl] -azetidin-3-yl} -pyrid-2-ylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3-fluoro-5-pyrrolidin-l-yl-phenyl) sulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-methyl-4-fluorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -N-methyl-quinolin-8-ylsulfonamide, N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-methylphenylsulfonamido, N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-methyl (fenyimety1) sulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3-sulfamoylphenylsulfonamide, 2-benzenesulfonyl-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -acetamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (4-toluene-4-sulfonyl) acetamide, (3-chloro-4-methylsulfonylthiophene-2-carboxy) - {1 - [bis (4-chlorophenyl) methyl] azetidin-3-yl] -amide, N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3- (2-fenyletylénsulfonyl) propionamide, N- (l- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -4-methylsulfonyl benzamide ·, N - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4-methanesulfonylbenzamide, (5-methylsulfonylthiophene-2-carboxy) - (1- [bis (4-chlorophenyl) methyl] 59 I azetidin-3-yl} amide, (RS) -N- {1- [1- (5-Methylsulfonyl-3-methyl-4-vinyl-thiophene-2-carboxy) - {1-, [bis (4-chloro-phenyl) -methyl] -azetidin-3-yl} -amide] (4-Chlorophenyl) pyridin-3-ylmethyl] azetidin-3-yl} -3,5-difluorobenzenesulfonamide, (RS) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl } -3,5-difluoro-benzenesulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -N- (6-chloropyrid-2-yl) methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (6-ethyl-pyridin-2-yl) methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -N-quinolin-6-ylmetylsulfónamid, N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-y1} -N-quinolin-5-ylmetylsulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-y1} -N-isoquinolin-5-ylmetylsulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-pyrid-3-ylmetylsulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-1-oxide-3-yl) methylsulfonamide, N- (1F, 2S, 4S) -bicyclo [2.2.1] hept-2-yl-N- {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -methylsulfonamide N- (1H, 2R, 4,5) - (bicyclo [2.2.1] hept-2-yl) -N- {1- (bis- (4-chlorophenyl) methyl) azetidin-3-yl [methyl sulfonamide. I I 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) methylsulphonamide, N- {1- (bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3-methoxyphenyl) methylsulphonamide, 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- (izobutylpiperid-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] -N- (pyridin-3-ylmethyl) methylsulfonamide, N- {1- [bis (4-fluorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) pyridine -3-ylmethyl] azetidin-3-yl) -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl} N- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide (RS) -N- {1 - [(4-chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N- {1- [(4-chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl) -N- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) pyrid-4-ylmethyl] Azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl} -N- ( 3,5-Difluorophenyl) methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (S) N- (1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) benzylsulfonamide, their optical isomers, and their pharmaceutically acceptable salts. The combination of claim 2, wherein the compound of Formula I is selected from the following compounds: 1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 3-acetoxy-l- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methyl) methylsulfonylmethyl (RS)] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) -methylene] azetidine, and their optical isomers and pharmaceutically acceptable salts thereof. The combination of claim 1, wherein the CB1 antagonist is SR141716, hydrates thereof, and pharmaceutically acceptable salts thereof, or LY320135, and pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a CB1 antagonist and sibutramine, a hydrate thereof, or one of its pharmaceutically acceptable salts, in pure form or with one or more compatible and pharmaceutically acceptable diluents and / or excipients and / or optionally in combination with another pharmaceutically compatible and physiologically active product. Pharmaceutical composition according to claim 6, characterized in that the CB1 antagonist is a compound of formula I as defined in claim 2. Pharmaceutical composition according to claim 7, characterized in that the compound of the formula I is selected from the group consisting of the following compounds: 1-benzhydryl-3 - [(methylsulfonyl) (phenyl) methylene] azetidine, 1-benzhydryl-3 - [(3-methylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-chlorophenyl) (methylsulfonyl) ) methylene] azetidine, 1-benzhydryl-3 - [(3,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(2,5-dichlorophenyl) (methylsulfonyl) methylene] - azetidine, 1-benzhydryl-3 - [(2,3-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-fluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [ (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-bromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-iodophenyl) (methylsulfonyl) methylene ] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethoxyphenyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethylphenyl) methylene] azetidine, 1 1-benzhydryl-3 - {[3,5-bis (trifluoromethyl) phenyl] (methylsulfonyl) methylene} azetidine, 1-benzhydryl-3 - [(3,5-dibromophenyl) (methylsulfonyl) methylene] azetidine, 1- benzhydryl-3 - [(3-methoxycarbonylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-carbamoylphenyl) ( methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (naphth-1-yl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [Bis (4-methoxyphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-methylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] - 1 - [(4-methoxyphenyl) (phenyl) methyl)] azetidine, (P) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1 - [(4-methoxyphenyl) (phenyl) methyl] azetidine (S) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1 - [(4-methoxyphenyl) (phenyl) methyl] azetidine, 1- [bis (4-trifluoromethoxyphenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulphonyl) methylene] azetidine, 1- [bis (4-trifluoromethylphenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - {[3,5- bis (trifluoromethyl) phenyl] methylsulfonylmethylene} azetidine, (FS) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine (F) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - [(4- chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (FS) -1 - {(4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl ) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (F) -1 - {(4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl) -3 - [(3,5- (S) -1 - {(4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, ( FS) -1 - {(4-chlorophenyl) [4- (pyrrolidinylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (F) -1 - {(4-chlorophenyl) ) [4- (pyrrolidinylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 {(4-chlorophenyl) [4- (pyrrolidinylmethyl) phenyl] methyl} -3- [ (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- (FS) - (4-Chlorophenyl) [4- (3,3-dimethylpiperidin-1-ylmethyl) 65-phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (3,3-dimethylpiperid-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (3,3-dimethylpiperid-1-ylmethyl) phenyl] -3-methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine 1,1 - {(RS) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - 1 - {(S) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] - (4-chlorophenyl) [4- (N-ethyl-N-cyclohexylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) ^_ (4 -chlorophenyl) [4- (N-ethyl-N-cyclohexylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (N-ethyl-N-cyclohexylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{(RS) - (4-chlorophenyl) (4 - [(4-ethoxycarbonylpiperazinyl) methyl] -phenyl] methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {((R) - (4-chlorophenyl) (4 - [(4-ethoxycarbonylpiperazinyl) methyl] phenyl) methyl) -N-3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{[(S) - (4-Chlorophenyl) {4 - [(4-ethoxycarbonylpiperazinyl) methyl] phenyl] methyl} -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - { (RS) - (4-chlorophenyl) [4- (N-cyclopropyl-N-propylaminomethyl) 66 phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-Chlorophenyl) [4- (N-cyclopropyl-N-propylaminomethyl) -phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- {(S) - (4-chlorophenyl) [4- (N-cyclopropyl-N-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (diisopropylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4- chlorophenyl) - [4- (diisopropylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) (4- (diisopropylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene) azetidine, 1 - {((RS) - (4-chlorophenyl) {4- [bis (2-methoxyethyl) aminomethyl] phenyl} methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {((R) - (4-chlorophenyl) {4- [bis (2-methoxyethyl) aminomethyl] phenyl} methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{(S) - (4-chlorophenyl) {4- [bis (2-methoxyethyl) aminomethyl] phenyl} methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- [di-n-propylaminomethyl) phenyl] methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (di-n-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (di-n-propylaminomethyl) phenyl] ethyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ((R) - (4-chlorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (4-methylpiperazin-1-ylmethyl) phenyl] methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (4-Methylpiperazin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (4-methylpiperazin-1-ylmethyl) phenyl] methyl) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl} · 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) (4- (diethylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4- chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {((RS) - (4-chlorophenyl) [4- (piperazin-2-on-4-ylmethyl) phenyl] methyl ) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenyl] phenyl} -3 - [, (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-Chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl} -3 - [(3 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) ( methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - {(4-chlorophenyl) [4- (N, N-dimethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1- {(4-chlorophenyl) [4- (N, N-dimethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-chlorophenyl) [4- (N, N-dimethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - ((4-chlorophenyl) [4- (N- ethylcarbamoyl) phenyl] methyl)} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - {(4-chlorophenyl) [4- (N-ethylcarbamoyl) phenyl] methyl} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-chlorophenyl) [4- (N-ethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - [(4-carbamoylphenyl) ( 4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - ((3,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-methylsulfanylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-methylsulfanylmethyl) phenyl)] (methylsulfonyl) methylene) azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - [(3-carbamoyl-phenyl) (methylsulfonyl) methylene] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - [(3-methoxyphenyl) (methylsulfonyl) methylene] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - [(3-hydroxyphenyl) (methylsulfonyl) methylene] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-pyrrolidinylphenyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3-hydroxymethylphenyl) (methylsulfonyl) methylene] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - {(methylsulfonyl) [3- (N-piperidylcarbamoyl) phenyl] methylene] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-trifluoromethylsulfanylphenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (2-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) ^! -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(methylsulfonyl) 70] - (phenyl) methylene] azetidine, (F) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(methylsulfonyl) - (phenyl) methylene] azetidine, (S) -1- [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(methylsulfonyl) - (phenyl) methylene] azetidine, (FS) -1 - [(4-chlorophenyl) (thien-2-yl) methyl 3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, (F) -1 - [(4-chlorophenyl) (shadow-2-yl) methyl] -3 - [(3,5- difluorophenyl) - (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, l-benzhydryl-3 - [(ethylsulfonyl) (phenyl) methylene] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - {{3- [N- (4-methylpiperazinyl) carbamoyl] phenyl] (methylsulfonyl) methylene} azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - {[3- (2,2-dimethylcarbohydrazido) phenyl] (methylsulfonyl) methylene} azetidine, 1- [bis (shadow-2-yl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (p-tolyl) methyl] -3 - [(methylsulfonyl) (phenyl) methylene] azetidine, 1 - [(4-chlorophenyl) (4-hydroxymethylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3-methylaminophenyl) (methylsulfonyl) methylene] azetidine, (FS) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] - 3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, (F) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5-difluorophenyl) 71 (S) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, - (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (2-methoxycarbonyl shadow-5-yl) methylene] azetidine, (RS) -1 - [[bis (4-chlorophenyl) methyl] -3 hydroxy-3 - [(methylsulfonyl) - (2-methoxycarbonylthien-5-yl) methyl] azetidine, 1- [Bis (4-chlorophenyl) methyl] -3 - [(2-izobutylaminokarbonyltien-5-yl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3-methoxycarbonylphenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (pyrid-4-yl) methyl (RS)] azetidin-3-ol, 1 - [(bis (4-chlorophenyl) methyl] -3 - [(methylsulphonyl) (pyridin-3-yl) methyl- (RS)] azetidin-3-ol, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (3-morpholin-4-ylpropyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (3-dimethylaminopropyl) benzamide, 3 - ((1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene [methanesulfonylmethyl) -N- (2- (pyrrolidin-1-yl) ethyl) benzamide), 3 - ((1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (2-dimethylamino-1-1methylethyl) benzamide, 3- ({, 1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) -N- (piperidin-1-yl) benzamide, I 3 - ((N - [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N-isobutylbenzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (3-imidazol-1-ylpropyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) -N- (2-dimethylaminoethyl) benzamide, 3 - ({1- [Bis (4-Chloro-phenyl) -methyl] -azetidin-3-ylidene] -methanesulfonylmethyl) -benzoic acid N'-methylhydrazide, 3 - ({1- [bis (4-chlorophenyl) methyl-azetidin-3-ylidénJmetánsulfonylmetyl) -N- (2-morpholin-4-yl-ethyl) -benzamide, 3 - ({1-bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (1-ethyl-pyrrolidin-2-ylmethyl) -benzamide, 3 - ({1- (bis (4-chlorophenyl) methyl) azetidin-3-ylidene) methanesulfonylmethyl) -N- (2,2-dimethylpropyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (cyclohexylmethyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) -N- (cyclopropylmethyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) -N- (2-methylbutyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) -N- (2-phenylpropyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl] -N- (tetrahydrofuran-2-ylmethyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) -N- (2,2-diphenylethyl) benzamide, 3 - ({1- [bis (4-chlorophenyl)) methyl] azetidin-3-ylidene] methanesulfonylmethyl) -N- (2-ethylbutyl) benzamide, 4 - {[3 - ({1- [bis (4- chlorophenyl) methyl] 13 I i azetidin-3-ylidene} methanesulfonylmethyl) -benzoylamino] -methyl} i -cyclohexanecarboxylic 2-Amino-1- {4- (3 - ({1- [bis (4-chlorophenyl)) methyl] and zetidin-3-ylidene} -methanesulfonylmethyl) phenyl] piperazin-1-yl [ethanone, tert-butyl ester (2- {4- [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazin-1-yl} -2-oxoethyl) carbamic acid, 1- {4- [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazin-1-yl} -2-methylaminoethanone, tert-butyl ester (2) - {4- [3 - ({1- [Bis (4-chlorophenyl) mesyl] -azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazin-1-yl} -2-oxoethyl) -N-methylcarbamic acid, 4- [3 - ({[1-Bis (4-chlorophenyl) methyl] azetidin-3-ylidene [methanesulfonylmethyl) phenyl] piperazine-1-carbothioic acid N-methylamide, 4- [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene [methanesulfonyl) methylphenyl] piperazine-1-carboxylic acid N-methylamide, methyl 4- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene [methanesulfonylmethyl) phenyl] piperazine-1-carboxylic acid, 1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene] methanesulfonylmethyl) phenyl] -4-isobutylpiperazine, 1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene [methanesulfonylmethyl) phenyl] -4-ethylpiperazine, I 4-Acetyl-1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} I -methanesulfonylmethyl) phenyl] piperazine I 11- {4, - [3 - ({1- [bis (4-chlorophenyl) methyl] and zolidin-3-ylidene [methan74 sulfonylmethyl) phenyl] piperazin-1-yl] -2-dimethylaminoethanone, 4- [3 - ({1- [bis (4-chlorophenyl)] - tert -butyl ester 1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazine methyl] azetidin-3-methanesulfonylmethyl y1idén}) phenyl] piperazine-1-carboxylic acid, 1- [Bis (4-methoxycarbonylphenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulphonyl) methylene] azetidine, 3-Acetoxy-1- [bis (4-methoxycarbonylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidine, (RS) -4- [4 - ((4- chlorophenyl) {3 - [(3,5-difluorophenyl) metánsulfonylmetylén] azetidin-1-yl) methyl) benzyl] morpholine, 4- (4- {3 - [(1-benzhydrylazetidin-3-ylidene) methanesulfonylmethyl] -phenoxy) butyl) morpholine, 4- (4- {3 - [(l-benzhydryl-azetidin-3-ylidene) methanesulfonylmethyl] phenoxy} propyl) morpholine, N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-y1} thien-2-ylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4-Methoxyphenylsulfonyl-, N- [4- (N- [l- [bis (4-chlorophenyl) methyl] azetidin-3-yl} sulfamoyl) phenyl] acetamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -4-methylphenylsulfonamido, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-dimethoxyphenyl sulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3-fluorophenylsulfonamido, N- {1η [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-dichlorophenyl sulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3-kyanofenylsulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2,5-dimethoxyphenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3-trifiuórmetylfenylsulfónamid, N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} naphth-2-ylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} naphth-1-ylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-difluorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1-methyl-1H-imidazol-4-yisulfónamid, N- [4- (N- {l- [bis (4-chlorophenyl) methyl] azetidin-3-yl} sulfamoyl) -2- chlorophenyl] acetamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} pyrid-3-ylsulfonamide, N- {1- [bis (4-chlórfenyimetyl] azetidin-3-yl} -4-fluorophenylsulfonamido, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} chino1-8-ylsulfonamide, N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) phenylsulfonamide, N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) (phenylmethyl) sulfonamide, I N- {γ [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,5-difluorophenyl sulfonamide, N- {1- [bis (4-chloro-phenyl) -methyl] -azetidin-3-yl} -pyrid-2-ylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3-fluoro-5-pyrrolidin-1-yl-phenyl) sulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-methyl-4-fluorophenyl sulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-mety1chinol-8-y1sulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl] -N-metylfeny1sulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -N-methyl (phenylmethyl) sulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3-sulfamoylphenyisulfonamide, 2-benzenesulfonyl-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -acetamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- [4-toluene-4-sulfonyl) acetamide, (3-chloro-4-methylsulfonylthiophene-2-carboxy) - {1 - [bis (4-chlorophenyl) methyl] azetidin-3-yl] -amide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3- (2-phenylethylenesulfonyl) propionamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4-methylsulfonylbenzamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4-methanesulfonylbenzamide, (5-methylsulfonylthiophene-2-carboxy) - {1- [bis (4-chlorophenyl) methyl] azetidin-3 yl] -amide, I I _η Ί ι (RS) -N- {1 - [(5-Methylsulfonyl-3-methyl-4-vinylthiophene-2-carboxy) - {1 - [[bis (4-chlorophenyl) methyl] azetidin-3-yl} amide] 4-Chlorophenyl) pyridin-3-ylmethyl] azetidin-3-yl} -3,5-difluorobenzenesulfonamide, (RS) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl} -3,5-difluoro-benzenesulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (6-chloropyrid-2-y1) methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (6-ethyl-pyridin-2-yl) methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmetylsulfónamid, N- [1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-5-ylmetylsulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-isoquinolin-5-ylmetylsulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-y1} -N-pyrid-3-ylmetylsulfónamid, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-l-oxide-3-y1) methyl sulfonamide, N- (1R, 2S, 4S) -bicyclo [2.2.1] hept-2-yl-N- {1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -methylsulfonamide, N- (1R, 2R, 4S) - (Bicyclo [2.2.1] hept-2-yl) -N- {1- (bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl} -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, N- {l ¹ - [bis (4-chlorophenyl) methyl] azetidin-3-y1) - N- (thiazol-2-yl) 78 methylsulphonamide. N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3-methoxyphenyl) methylsulphonamide, 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- (izobutylpiperid-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} -N- (pyrid-3-ylmethyl) methylsulfonamide, N- {1- [bis (4-fluorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) pyrid-3 -ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N- {1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl} -N - (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, ( RS) N - {1 - [(4-chlorophenyl) pyrid-4-ylmethyl] and zetidin-3-yl} -NI - (3,5-difluorophenyl) methylsulfonamide, (R) -N- (1 - [(4-chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl) -N- (3,5-difluorophenyl) methylsulfonamide, (S) -N - {1- [ (4-chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] (R) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3) azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide (S) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, 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. Pharmaceutical composition according to claim 7, characterized in that the compound of the formula I is selected from the group consisting of the following compounds: 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol, 3-acetoxy-l- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methyl) methylsulfonylmethyl (RS)] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, Ijoptical isomers and pharmaceutically acceptable salts thereof. I The pharmaceutical composition of claim 6, wherein the CB1 antagonist is SR141716, hydrates thereof, and pharmaceutically acceptable salts thereof, or LY320135, and pharmaceutically acceptable salts thereof. Pharmaceutical composition according to one of claims 6 to 10 for simultaneous, separate or sequential use. Pharmaceutical composition according to one of Claims 6 to 11, characterized in that it contains 0.5 mg of sibutramine and 0.1 to 200 mg of the CB1 antagonist.