BG107739A - Association of the cb1 receptor antagonist and sibutramin, pharmaceutical compositions, containing them and their use for treating obesity - Google Patents

Abstract

The invention concerns the association of the CB1 receptor antagonist and a subutramin, pharmaceutical compositions containing same and use thereof for treating obesity. 12 claims

Description

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

BACKGROUND OF THE INVENTION

CB1 receptor antagonists are known for their effect on food intake and use as anorexigens (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, L-dimethylamine; Meridia®, Reductyl®), its hydrate and its pharmaceutically acceptable salts, and in particular its hydrochloride , reduce food intake and are useful for the treatment of obesity (WO 90/061110; DHRyan et al., Obesity Research, 3 (4), 553 (1995); HCJackson et al., British Journal of

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Pharmacology, 121,1588 (1997); G. Fanghanel et coll., Inter.J.Obes.,

24 (2), 144 (2000); G. A. 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 CB1 receptor antagonist shows a synergistic effect in reducing food consumption and is therefore useful for the treatment of obesity.

The combination may also contain several CB1 receptor antagonists.

Among the CB1 antagonists, the azetidine derivatives described in WO 00/15609 can be used specifically,

WO 01/64633, WO 01/6434 having the general formula:

R

wherein

R represents chain (A), (B) and

^R2 (A) ^R2 (B)

R1 stands for methyl or ethyl radical,

R ₂ denotes an aromatic ring selected from phenyl, naphthyl or indenyl, these aromatic rings being unsubstituted or substituted by one or more halogens, alkyl, alkoxy, -COalk, hydroxy, -CO (H 5, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethyl, trifluoromethoxy) , -NR ₆ R ₇ , -CONH-NR ₆ R ₇ , -N (aiK) COOR ₈ , cyano, -CONHR ₉ , -CO-NR ₁₆ R ₇ ,

03-372-02-PB • · · · • ·

alkylsulfanyl, hydroxyalkyl, -O-anK-NRi2Ri3 or alkylthioalkyl or heteroaromatic ring selected from rings benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanil, 2,3-dihydrobenzofuranyl, 2,3, dihydrobenzofrol, 2, 1,2,3,4-tetrahydroisoquinolyl,

1,2,3,4-tetrahydroquinolyl, thiazolyl, thienyl, these heteroaromatic rings may be unsubstituted or substituted by halogen, alkyl, alkoxy, -COOR ₅ , trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NR 7, -N 7 , cyano, -CONHR9, alkylsulfanyl, hydroxyalkyl or alkylthioalkyl.

R3 and R _4, identical or different, represent aromatic or

ring selected from phenyl, naphthyl or indenyl, these aromatic rings being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOR ₅ , CONR10R11, -CO -NH-NR6R7, alkylsulfanyl, hydroxyalkyl, -alkNR6R7 or alkylthioalkyl; or a heteroaromatic ring selected from the rings benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3dihydrobenzothienyl, furyl, isochromanyl, isoquinolyl, pyrrolyl, quinolyl, 1,2-thironyl, 1,2-thironyl, 1,2,4 these heteroaromatic rings may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOR ₅ , -CO-NH-NR ₆ R ₇ , -CONR10R11, -alkyl-NR6R7, alkylsulfanylsulfonylsulfanyl or alkylthioalkyl,

R ₅ is an alkyl or phenyl radical optionally substituted by one or more halogen atoms,

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R ₆ and R ₇ , identical or different, denote hydrogen

atom or alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl or else R ₆ and R ₇ form together with the nitrogen atom to which they are attached, a heterocycle one or two-ring, saturated or unsaturated, having from 3 to 10 units optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more radicals alkyl, -COalk, -COOalk, -C8-1CHalk, -CO-alk-NR14R ₁ 5, oxo, hydroxyalkyl, -alk-O-alk, -CHOH ₂ ,

Rg stands for an alkyl radical,

R9 represents a hydrogen atom or an alkyl radical or

alkyl substituted with dialkylamine, phenyl, cycloalkyl (optionally substituted with -COOalk) or one or two-ring heterocycle, saturated or unsaturated, having 3 to 10 units containing optionally one or more heteroatoms selected from oxygen, sulfur and nitrogen, and optionally substituted by one or more alkyl radicals,

Rio and Rn, identical or different, denote a hydrogen atom or an alkyl radical, or Rj ₀ and Rn form, together with the nitrogen atom to which they are attached, a mono- or double-ring heterocycle having 3 to 10 units which optionally contains another heteroatom selected between oxygen, sulfur and nitrogen and optionally substituted by an alkyl radical,

Ri ₂ and R13, identical or different, represent a hydrogen atom or an alkyl radical, cycloalkyl or R _i2 and Rj ₃ form together with azoktniya atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members, containing in optionally, another heteroatom selected from oxygen, sulfur and nitrogen

03-372-02-PB ·· · • · • · · • «···· • · ·

and optionally substituted by an alkyl radical, -COalk, -COOalk, CO-alkalk, -SB-Lalk, -CO-anK-NR ^ Ris or a saturated, one or two-ring heterocycle of 3 to 10 units and containing a heteroatom selected from oxygen, sulfur and nitrogen,

R _u and Rig, identical or different, denote a hydrogen atom or an alkyl radical or -COOalk,

Ri ₆ and R ₁₇ form, together with the nitrogen atom to which they are attached, a saturated one or two ring heterocycle of 3 to 10 units, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen,

R 'represents a hydrogen atom or a radical -CO-alk, or R represents a radical CHR) ₈ and

Ri ₈ represents a radical -NHCOR19 or -N (R ₂ o) -Y-R2i,

Y is CO or SO ₂ ,

R4 and R _3, identical or different, represent aromatic or

ring selected from phenyl, naphthyl and indenyl, these aromatic rings being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, COOalk, -CONR ₂₂ R ₂₃ , -CO-NH-NR ₂₄ R ₂₅ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, or alkyl-NR ₂₂ R ₂₃ ; or a heteroaromatic ring selected from the rings benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, pyrrolidine, 1,2-quinolinyl, isoquinolinyl thiazolyl and thienyl, these heteroaromatic rings may be unsubstituted or

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Halogenated, alkyl, alkoxy, trifluoroacetate; hydroxyalkyl,

R 19 denotes a radical -alk-8O ₂ ^ 2b 2 -alk-8O ₂ -CH = CHR26, Heti substituted with -SO2-R26 or phenyl substituted with -SO2-R26 or anK-SO ₂ -R26,

R20 means a hydrogen atom or an alkyl radical,

R21 stands for phenylalkyl radical, Het! or Ar _L R22 and R23, identical or different, represent a hydrogen atom or an alkyl radical or R22 and R ₂ 3 together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members, optionally containing and another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl groups,

R24 and R25, the same or different, denote a hydrogen atom or a radical alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, alk-O-alk or hydroxyalkyl or else R24 and R25 form together with the nitrogen atom to which they are attached, a saturated or unsaturated monohydroxy ether having 3 to 10 units containing, optionally, another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl, -COalk, COOalk, -CO-MHalk, -CS-NHanK, oxo, hydroxyalkyl, -alk-Oalk or -CO-NH2 groups.

R26 denotes an alkyl radical, Arj or Hetj,

Ar! means a phenyl, naphthyl or indenyl radical, optionally substituted by one or more halogens, alkyl, alkoxy, cyano, -CO-alk, -COOH, -COOalk, 03-372-02-PB * · · · · · · · · · · · · · · · · · · · · · · ·

CONR27R28, -CO-NH-NR ₂₉ R ₃ o, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -anK-NR ₂ 9R ₃ o ₅ alkylthioalkyl, formyl, hydroxyl, hydroxyalkyl, Het, -O-alk-YGN-cycloalkyl, OCF _3, CF ₃ , -NH-COalk, -SO ₂ NH ₂ , -NH-COCH ₃ , -NH-COOalk, Het or else on two adjacent carbon atoms by dioxymethylene,

Hetj means a heterocycle, one or two rings,

unsaturated or saturated with 3 to 10 units and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted by one or more alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ groups , the nitrogen heterocycles being in their Oxide form,

R ₂ 7 and R ₂ 8, the same or different, denote hydrogen

an atom or an alkyl radical or else R ₂ 7 and R ₂₈ form together with the nitrogen atom to which they are attached a saturated one or two-ring heterocycle of 3 to 10 units containing, optionally, another heteroatom selected from oxygen, sulfur and nitrogen, and in optionally substituted by one or more alkyl radicals,

R ₂ 9 and R ₃₀ , identical or different, denote a hydrogen atom or a radical alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, alk-O-alk, hydroxyalkyl or else R ₂ 9 and R ₃₀ form together with the nitrogen atom to which they are attached, a saturated or unsaturated mono-or double-ring heterocycle of 3 to 10 units containing, optionally, another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more radicals alkyl, -COalk, -COOalk, -CO-Lalk, SB-INalk, oxo, hydroxyalkyl, -alk-O-alk, -CO-NH ₂ , or R represents CHR ₃ i and

03-372-02-PB • ···· · · ··

R ₃ i means the radical -N (R ₃₂ ) R ₃₃ , -N (R ₃₂ ) -CO-R ₃₃ , N (R ₃₂ ) -SO ₂ R ₃₄ ,

R ₄ and R ₃ , identical or different, denote either an aromatic ring selected from phenyl, naphthyl and indenyl, these aromatic rings being unsubstituted or substituted by one or more halogens, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO -alk, cyano, -COOH, COOalk, -CONR ₂₂ R ₂₃ , -CO-NH-NR ₂₄ R ₂₅ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl; or heteroaromatic ring selected from the rings benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolidyl, pyrrolidyl, pyrrolidinyl 4-tetrahydroisoquinolyl, thiazolyl and thienyl, these heteroaromatic rings may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOalk, -SONH-NR ₂₄ R _25, -CONR ₂₂ R ₂₃ , -aBK-NR ₂₄ R ₂₅ , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanes alkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl,

R ₃₂ represents the radical -C (R ₃₅ ) (R ₃₆ ) -Het ₂ , -Het ₂ , C (R ₃ 5) (R ₃ 6) -Ar ₂ , Ar ₂ , cycloalkyl or norbornyl,

R ₃₃ denotes a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -anK-CONR ₂₂ R ₂₃ , -afl-NR ₂₂ R ₂₃ , alkoxy, Ar ₂ , Het ₂ , -CH ₂ Ar ₂ , -CH ₂ Het ₂ or alkyl optionally substituted by one or more halogens,

R ₃₄ represents hydroxyalkyl radical, -alk-COOalk, alk-CONR ₂ 2R ₂₃ , -anK-NR ₂₂ R ₂₃ , alkoxy, Ar ₂ , Het ₂ , -CH ₂ Ar ₂ , 03-372-02-PB ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

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

R ₃₅ represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, - ^ k-CONR ₂₂ R ₂₃ , -alk-NR ₂₂ R ₂ h, alkoxyalkyl, Ar ₂ , Het ₂ , -CH ₂ Ar ₂ , -CH ₂ Het ₂ or alkyl, optionally substituted by one or more halogens,

R ₃₆ represents a hydrogen atom or hydroxyalkyl

a radical, -alk-COOalk, -afl-CONR ₂₂ R ₂₃ , -alk-NR ₂₂ R ₂ h, alkoxyalkyl or alkyl optionally substituted by one or more halogens, or else R ₃₅ and R ₃₆ form together with the carbon atom with which are linked, a saturated one- or two-ring heterocycle of 3 to 10 units containing, optionally, another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl groups,

Ar ₂ means a phenyl, naphthyl or indenyl radical, such as

these different radicals are optionally substituted by one or more halogens, alkyl, alkoxy, -CO-alk, cyano, -COOH, COOalk, -CONR3 ₇ R ₃₈ , -CO-NH-NR39R40, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, - alκ-NRz9R4o, -NR39R40, alkylthioalkyl, formyl, CF _3, OCF _3, Het, -O-alk-NH-cycloalkyl, SO ₂ NH _2, hydroxy, hydroxyalkyl, -AShSOalk, AShSOOalk or on two sasaedni carbon atoms by dioxymethylene,

Het ₂ means a heterocycle, one or two rings, unsaturated or saturated, with 3 to 10 units and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo , hydroxy, the nitrogen heterocycles optionally in their N-oxide form,

03-372-02-PB • · · ·

- 10 R37 and R ₃₈ , the same or different, denote a hydrogen atom or an alkyl radical, or else R ₃₇ and R ₃₈ form, together with the nitrogen atom to which they are attached, a saturated one or two-ring heterocycle having 3 to 10 units containing in a given case and another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl groups,

R ₃ 9 and R ₄₀ , identical or different, denote a hydrogen atom or an alkyl radical, or else R ₃₉ and R ₄₀ form together with the nitrogen atom to which they are attached a saturated one or two ring heterocycle having 3 to 10 units containing in a given case and another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl groups, alk means an alkyl or alkylene radical, the radicals and the alkyl and alkylene moieties and the alkoxy radicals and moieties are straight or branched and contain 1 to 6 carbon atoms and cycloalkyl radicals vessel hold 3 to 10 carbon atoms,

the optical isomers of these compounds and their pharmaceutically acceptable salts with mineral or organic acid.

Preferred azetidine derivatives are the following: 1-benzhydryl-3 - [(methylsulfonyl) (phenyl) methylene] azetidine, 1-benzhydryl-3 - [(3methylphenyl) (methylsulfonyl) methylene] azetidine,

1-benzhydryl-3 - [(3-chlorophenyl) (methylsulfonyl) methylene] azetidine,

1-benzhydryl-3 - [(3,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine,

03-372-02-PB • 9 · · · · • «

1-benzhydryl-3 - [(2,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine,

-benzhydryl-3 - [(2,3dichlorophenyl) (methylsulfonyl) methylene] azetidine,

1-benzhydryl-3 - [(3fluorophenyl) (methylsulfonyl) methylene] azetidine,

1-benzhydryl-3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

-benzhydryl-3 - [(3bromophenyl) (methylsulfonyl) methylene] azetidine,

-benzhydryl-3 - [(3 iodophenyl) (methylsulfonyl) methylene] azetidine,

1-benzhydryl-3 - [(methylsulfonyl) (3trifluoromethoxyphenyl) methylene] azetidine,

1-benzhydryl-3 - [(methylsulfonyl) (3trifluoromethylphenyl) methylene] azetidine,

-benzhydryl-3- {[(3,5bis (trifluoromethyl) phenyl] (methylsulfonyl) methylene] azetidine,

1-benzhydryl-3 - [(3,5dibromophenyl) (methylsulfonyl) methylene] azetidine,

-benzhydryl-3 - [(3methoxycarbonylphenyl) (methylsulfonyl) methylene] azetidine,

-benzhydryl-3 - [(3cyanophenyl) (methylsulfonyl) methylene] azetidine,

1-benzhydryl-3 - [(3carbamoylphenyl) (methylsulfonyl) methylene] azetidine,

-benzhydryl-3 - [(methylsulfonyl) (naphth-1 yl) (methylsulfonyl) methylene] azetidine,

03-372-02-PB ···· • · · ·

- 12 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

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

1- [bis (4-methylphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (K8) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1- ( (4methoxyphenyl) (phenyl) methyl)] azetidine,

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

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

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

1- (bis (4-chlorophenyl) methyl] -3 - ((((3,5bis (trifluoromethyl) phenyl] methylsulfonylmethylene) azetidine, (1 <8) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (1 <i>) - 1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - ((3,5difluorophenyl) ( methylsulfonyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (1 <8) -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,

03-372-02-PB · 99 · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

(S) -1 - {(4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (K8) -1 - {(4-chlorophenyl) ) [4- (pyrrolidylmethyl) phenyl] methyl} -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (1 H) -1 - {(4-chlorophenyl) [4- (pyrrolidylmethyl) phenyl] methyl } -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-chlorophenyl) [4- (pyrrolidylmethyl) phenyl] methyl} -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {(1-8) - (4-chlorophenyl) [4- (3,3-dimethylpiperidin-1-ylmethyl) phenyl] methyl} -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {(R) - (4-chlorophenyl) [4- (3,3-dimethylpiperidin-1-ylmethyl) phenyl] methyl-3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

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

1 - {(R 8) - (4-chlorophenyl) [4- (thiomorpholin-4-yl-methyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {(j) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

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

1 - {(R 8) - (4-chlorophenyl) [4 - (] N-ethyl-cyclohexylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

03-372-02-PB • · · ·

1 - {(1H) - (4-chlorophenyl) [4- (N-ethyl-cyclohexylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {(S) - (4-chlorophenyl (4- (N-ethyl-cyclohexylaminomethyl) phenyl] methyl) -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

- 14 1 - {{(1 <8) - (4-chlorophenyl) {4- [4 ethoxycarbonylpiperazinyl) methyl] phenyl} methyl}} - 3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

1- {{((1H) - (4-chlorophenyl) {4 - [(4 ethoxycarbonylpiperazinyl) methyl] phenyl} methyl)) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

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

1- (K8) - (4-chlorophenyl) [4- (X-cyclopropyl-N-propylaminomethyl) phenyl] -methyl) -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

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

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

1 - {(1-8) - (4-chlorophenyl) [4 (diisopropylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

03-372-02-PB • · · ·

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

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

1 - {{(1-8) - (4-chlorophenyl) {4- [bis- (2methoxyethyl) aminomethyl] phenyl) methyl)) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

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

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

- {(R 8) - (4-chlorophenyl) [4- (di-propylaminomethyl) phenyl] methyl) -3 - ((3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine,

- {(R) - (4-chlorophenyl) [4- (di-propylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

- {(S) - (4-chlorophenyl) [4- (di-propylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

1 - {(R 8) - (4-chlorophenyl) [4- (piperidin-1-yl) phenyl] methyl} -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

- {(R) - (4-chlorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

03-372-02-PB

- 16 1 - {(S) - (4-chlorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl} -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

- {(R8) - (4-chlorophenyl [4- (4-methylpiperazin-1-ylmethyl) phenyl] methyl} -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

- {(1 <i>) - (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 - {(R 8) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl} -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

- {(R) - (4-chlorophenyl) [4- (morpholin-4ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

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

1 - {(R 8) - (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,

03-372-02-PB • · · · • ·

1 - {(R 8) - (4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,

- {(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 - {(R 8) - (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-xnopc ^ eHHn) [4- (N, N-dimethylcarbamoyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, ( S) -1 - {(4-χποροφβΗΗπ) [4- (Ν, dimethylcarbamoyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, N, 8) -1 - {(4-chlorophenyl) ) [4- (b [-ethylcarbamoyl) phenyl] methyl} -

3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (N) -1 - {(4-chlorophenyl) [4- (N-ethylcarbamoyl) phenyl] methyl} -3 [(3,5-difluorophenyl) ) (methylsulfonyl) methylene] azetidine,

03-372-02-PB ···· ·· · • ·

(S) -1 - {(4-chlorophenyl) [4- (1H-ethylcarbamoyl) phenyl] methyl} -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (1 <8) -1- [ (4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (1 <i>) - 1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

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

1-benzhydryl-3 - [(3methylsulfanylphenyl) (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-carbamoylphenyl) (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 - [(3-methylsulfonyl) (3pyrrolidinylphenyl) methylene] azetidine,

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

1- [bis (4-chlorophenyl) methyl] -3 - {(methylsulfonyl) [3- (Mpiperidylcarbamoyl) phenyl] methylene} azetidine,

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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, (K8) -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, N, 8) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

XR) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (thiene) -2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine,

-benzhydryl-3 - [(ethylsulfonyl) (phenyl) methylene] azetidine,

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

- [bis (4-chlorophenyl) methyl] -3 - {[3- (2,2-dimethylcarbohydrazido) phenyl] (methylsulfonyl) methylene} azetidine

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

03-372-02-PB

- 20 1- [bis (p-tolyl) methyl] -3 (methylsulfonyl) (phenyl) methylene] azetidine,

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

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

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

1- [bis (4-chlorophenyl) methyl] -3-hydroxy-3 [(methylsulfonyl) (2-methoxycarbonylthio-5-yl] azetidin-8), 1- [bis (4-chlorophenyl) methyl] -3- [(2isobutylaminocarbonylthien-5yl) (methylsulfonyl) methylene] azetidine,

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

1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (pyridin-4-yl) methyl- [S]] azetidin-3-ol,

1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (pyridin-3-yl) methyl- [S]] azetidin-3-ol,

3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene-methanesulfonyl-methyl) N- (3-morpholin-4-yl-propyl) benzamide,

03-372-02-PB • · · ·

- 21 • · · ·

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

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

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-ylethyl) benzamide,

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

3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) 14-cyclopropylmethylbenzamide,

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

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

3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) 14- (tetrahydrofuran-2-ylmethyl) benzamide,

3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) L1- (2,2-diphenylethyl) benzamide,

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

2-amino-1- {4- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3ylidene} -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 of ( 2- {4- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazin-1-yl} -2-oxoethyl) L1methylcarbamic acid,

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

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• · • · • · • · • · • • • · • · • • · • · · · • ♦ · • · • · · « • · · • • · · • • · • · • • • · • · • · • »

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

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-3ylidene} -methanesulfonylmethyl) phenyl] piperazine,

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

1- (3 - ((1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) phenyl] piperazine, tert-butyl 4- (3 - ((1- [bis- (4- chlorophenyl) methyl] azetidin-3ylidene} -methanesulfonylmethyl) phenyl] piperazine-1-carboxylate,

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

3- acetoxy-1- [bis (4-methoxycarbonylphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methyl- (KB)] azetidine, (KB) -4- [4 - ((4-chlorophenyl) (3 - ((3,5-difluorophenyl) methanesulfonylmethylene] azetidin-1-yl} methyl) benzyl] morpholine,

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

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

03-372-02-PB ···· ·· ··

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

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

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

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

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

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

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

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

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

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

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-1-Nimidazol-4-ylsulfonamide,

03-372-02-PB • · · · • ·

N- [4- (N- {1- [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} -4fluorophenylsulfonamide,

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

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 difluorophenylsulfonamide,

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

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

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

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

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

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

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

03-372-02-PB • · · · • · • · · ·

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

3-yl} -acetamide,

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (toluene-4-sulfonyl) -acetamide, (3-chloro-4-methylsulfonyl-thiophene-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} -4methylsulfonyl-benzamide,

B1- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4methanesulfonyl-benzamide, (5-methylsulfonylthiophene-2-carboxy) - {1- [bis (4-chlorophenyl) methyl] azetidin-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-yl-methyl] azetidin-3-yl} -3,5-difluorobenzenesulfonamide, (RS) - N- (1 - [(4-chlorophenyl) -pyrimidin-5-yl-methyl ] azetidine-

3-yl} -3,5-difluorobenzenesulfonamide,

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

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

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

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

03-372-02-PB • · ♦ · • · • β · · · · • · · · ·

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

5-ylmethylsulfonamide,

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

N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -14- (1-oxide-pyrid-3-yl) methylsulfonamide,

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

N- (1R, 2R, 4B) -bicyclo [2,2,1] hept-2-yl-N- {1- [6hc (4chlorophenyl) methyl] azetidin-3-yl} -methylsulfonamide,

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

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

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

14- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1H- (3hydroxyphenyl) methylsulfonamide,

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

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

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

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

03-372-02-PB • · · • «····

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-3ylmethyl) -methylsulfonamide,

N- {1- [bis (4-fluorophenyl) -methyl] azetidin-3-yl} -1M- (3,5-difluorophenyl) -methylsulfonamide, (RS) -? - {1 - [(4-chlorophenyl) -pyrid -3-ylmstyl] azstidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, (R) - N- {1 - [(4-chlorophenyl) -pyrid-3-ylmethyl] azetidin-3-yl} -N (3,5-difluorophenyl) -methylsulfonamide, (S) - b1- {1 - [(4-chlorophenyl) -pyrid-3-ylmethyl] azetidin-3-yl} N- (3,5-difluorophenyl) - methylsulfonamide, (RS) 14- {1 - [(4-chlorophenyl) -pyrid-4-ylmethyl] azetidin-3yl} -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) - b [- {1 - [(4-chlorophenyl) -pyrimidin-5-ylmethyl] azetidine-

3-yl} -1H- (3,5-difluorophenyl) -methylsulfonamide, (R) -1H- {1 - [(4-chlorophenyl) -pyrimidin-5-ylmethyl] azetidin-3-yl} -L- (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} -> 1- (3,5-difluorophenyl) benzylsulfonamide, their optical isomers and their pharmaceutically acceptable salts with mineral or organic acid.

03-372-02-PB

In particular, the following azetidine derivatives are preferred:

1- [bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methyl- (1-8)] azetidin-3-ol,

3-acetoxy-1- [bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methyl) methylsulfonylmethyl (K8)] azetidine,

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

Examples of pharmaceutically acceptable salts of azetidine derivatives include the following salts: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene oxynate, methylene-bis pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophylline acetate and p-toluenesulfonate.

Other CB1 antagonists useful for the combinations according to the invention are, for example, the pyrazole derivatives described in EP 576357, EP 658546, EP 656354, WO 97/19063 and WO 00/46209, the benzothiophene and benzofuran derivatives described in WO 96/02248, the arylsulfonamides 98/37061. In particular, products known under the code name SR 141716 and LY 320135 may be mentioned.

The effect of the combination of sibutramine and a CB1 antagonist on food intake is determined according to the following protocol:

03-372-02-PB • ·

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This study used 7-week-old obese Zucker Fa / fa rats obtained from Iffa-Credo, France. The rats were housed in individual cells and weighed daily between 8 and 10 o'clock in the morning. The amount of food is also drawn every morning at the same hour. This food (M20, Pietrement, France) was changed daily and rats had free access to it for 24 hours. All rats were treated with vehicle (migliol 812N and methylcellulose 0.5% polysorbate 80 0 for one week). 2%) on two consecutive applications. Starting at day 8, rats were treated with vehicle, CB1 antagonist (1 - [(bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine) or sibutramine, as appropriate. oral route (see table below).

Sibutramine is dissolved in methylcellulose solution 0.5% polysorbate 80 0.2% and administered at a dose of 3 mg / kg; The CB1 antagonist was dissolved in Migliol 812 N (Hiils, Germany) at a dose of 0.6 mg / kg, both products being administered in a volume of 1 ml / kg. Each group consists of 12 to 14 animals. The respective groups are drawn up and the animals are treated for five days, on two consecutive applications each day.

The group First application Second application carrier group migliol methylcellulose 0.5% polysorbate 0.2% sibutramine group migliol sibutramine 3 mg / kg a CB1 antagonist group CB1 antagonist 0.6 mg / kg methylcellulose 0.5% polysorbate 0.2% group combination CB1 antagonist 0.6 mg / kg sibutramine 3 mg / kg

03-372-02-PB • · ·

Food consumption of each animal is measured daily. The results are expressed as the average amount of food consumed over 5 days of treatment. The results are given in the table below.

Treatment Food consumption over 5 days of treatment (g) Carriers 25.52 ± 0.30 sibutramine 3 mg / kg 24.60 ± 0.32 * CB1 antagonist 0.6 mg / kg 24 ± 0.24 ** sibutramine (3mg / kg) + CB1 antagonist (0.6 mg / kg) 22.76 ± 0.02 ***

* p <0.05 ** p <0.01 *** P <0.0001

The results show that in animals receiving the combination of sibutramine and a CB1 antagonist, the reduction in food consumption is much greater than in animals treated with sibutramine alone or with a CB1 alone antagonist.

The compounds in the combination can be used by oral, parenteral, transdermal or rectal route, either concurrently, individually, or stretched over time.

The present invention also relates to pharmaceutical compositions comprising the combination of sibutramine, its hydrate or any of its pharmaceutically acceptable salts and CB1 receptor antagonist in the pure state or with one or more diluents and / or additives compatible and pharmacologically acceptable and / or optionally in combination with

03-372-02-PB

another pharmaceutically compatible and physiologically active product for use is either concurrent, separate, or stretched over time.

Tablets, pills, powders (gelatin capsules, starch capsules) or granules may be used as solid compositions for oral administration. In these formulations, the active ingredients are mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compositions may also contain other substances such as diluents, for example one or more lubricants such as magnesium stearate or talc, colorant, coating (dragee) or varnish.

As liquid compositions for oral administration, solutions, suspensions, emulsions, syrups and elixirs, pharmaceutically acceptable, containing inert diluents such as water, ethanol, glycerol, vegetable oils or liquid paraffin may be used. These compositions may contain other substances such as diluents, for example wetting agents, sweeteners, sealants, flavoring agents or stabilizers.

Sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. Water, propylene glycol, polyethylene glycol, cooking oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents, may be used as the solvent or carrier. These compositions may also contain additives, in particular wetting agents, isotonizing agents, emulsifiers, dispersing agents and stabilizers. They can be sterilized several times

03-372-02-PB • Methods, for example by aseptic filtration, by incorporating sterilizing agents, by irradiation or by heating. They may also be prepared in the form of solid sterile compositions which may be dissolved at the time of use in sterile water or any other sterile injectable medium.

Formulations for rectal administration are suppositories or rectal capsules containing, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The pharmaceutical compositions generally 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, which consists in administering to a patient a combination according to the invention, either simultaneously, individually, or in a manner stretched over time.

The doses depend on the effect sought, the duration of treatment and the route of administration used; they are generally 1 to 15 mg per day for oral administration to adults, sibutramine and from 0.10 to 500 mg per day for oral administration to adults, by the CB1 antagonist.

Generally, the physician will determine the appropriate daily dosage as a function of age, weight and any other factors inherent in the subject for treatment.

Claims (12)

A combination of a CB1 antagonist and sibutramine, its hydrate or any of its pharmaceutically acceptable salts. A combination according to claim 1, wherein the CB1 antagonist is a compound of general formula (I): wherein R represents chain (A), (B) and / SO ₂ R 1 C = CH c — CH SO2R (A) (B) R1 stands for methyl or ethyl radical, R ₂ denotes an aromatic ring selected from phenyl, naphthyl or indenyl, these aromatic rings being unsubstituted or substituted by one or more halogens, alkyl, alkoxy, -COalk, hydroxy, -COX 5, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethyloxy, trifluoromethylsulfanyl NR ₆ R ₇ , -CONH-NRgRy, N (anK) COORg, cyano, -CONHR9, -CO-NR16R17, alkylsulfanyl, hydroxyalkyl, -O-anK-NR] ₂ Ri3 or an alkylthioalkyl or heteroaromatic ring selected from benzothofol ring , benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,303-372-02-PB dihydrobenzothienyl, indolinyl, indol, isochromanyl, isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl, thienyl, these heteroaromatic rings may be unsubstituted or substituted by halogen, alkyl, alkoxy, -COOR ₅ , trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, R ₇ , -N ₆ , -N ₆ , -N ₆ CHOH-NR6R7, cyano, -CONHR9, alkylsulfanyl, hydroxyalkyl or alkylthioalkyl. 0 ·· »· • 9 • « ·· ·· • • · * • 4 9 • • · • · • · • • «· · ···· • · · • • • 4 • • · • • ··· • • 4 • • » ·· R ₃ and R ₄ , identical or different, denote either an aromatic ring selected from phenyl, naphthyl or indenyl, these aromatic rings being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO -alk, cyano, -COOR5, CONR10R11, -CO-NH-NR6R7, alkylsulfanyl, hydroxyalkyl, -alkNR6R7 or alkylthioalkyl; or a heteroaromatic ring selected from the rings benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3dihydrobenzothienyl, furyl, isochromanyl, isoquinolyl, pyrrolyl, quinolyl, 1,2-thironyl, 1,2-thironyl, 1,2,4 these heteroaromatic rings may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOR ₅ , -CO-NH-NR ₆ R7, -CO-NR10R11-, anK-NR ₆ R ₇ , alkylsulfanyl, hydroxyalkyl or alkylthioalkyl, R ₅ is an alkyl or phenyl radical optionally substituted by one or more halogen atoms, R ₆ and R ₇ , the same or different, denote a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl or else R ₆ and R ₇ form together with the nitrogen atom to which they are attached, heterocycle 03-372-02-PB • ··· one or two-ring, saturated or unsaturated, having 3 to 10 units, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen, and optionally substituted by one or more radicals alkyl, -COalk, -COOalk, -CO-NHanK, -COanK-NRi ₄ R15, oxo, hydroxyalkyl, -alk-O-alk, -CO-NH ₂ , R ₈ represents an alkyl radical, Rq represents a hydrogen atom or an alkyl radical or alkyl substituted with dialkylamine, phenyl, cycloalkyl (optionally substituted with -COOalk) or one or two-ring heterocycle, saturated or unsaturated, having 3 to 10 units, optionally containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, Rio and Rn, equal or different, represent a hydrogen atom or an alkyl radical or else R ₁₀ and Rn together with the nitrogen atom to which they are attached, a mono- or bicyclic heterocycle having 3 to 10 ring members, which optionally contains another heteroatom selected between oxygen, sulfur and nitrogen and optionally substituted by an alkyl radical, R ₂ and R 13, the same or different, denote a hydrogen atom or an alkyl radical, cycloalkyl or else R ₂ and R 13 form, together with the nitrogen atom to which they are attached, a saturated, one- or two-ring heterocycle having from 3 to 10 units containing in a given case another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by an alkyl radical, -COalk, -COOalk, CO-Lalk, -CS-NHanK, -CO-anK-NR] ₄ R ₁₅ or a saturated, one- or a two-ring heterocycle with 3 to 10 units and containing a heteroatom selected from oxygen, sulfur and nitrogen, 03-372-02-PB • ··· • · - 37 -:; ·.:. · · · ·: ·. R14 and R15, the same or different, denote a hydrogen atom or an alkyl radical or -COOalk, R16 and R17 form, together with the nitrogen atom to which they are attached, a saturated one- or two-ring heterocycle of 3 to 10 units, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen, R 'represents a hydrogen atom or a radical -CO-alk, or R represents a radical CHR ₈ and Ris represents the radical -NHCOR19 or -N (R ₂₀ ) -YR ₂ i, Y is CO or SO ₂ , R ₄ and R ₃ , identical or different, denote either an aromatic ring selected from phenyl, naphthyl and indenyl, these aromatic rings being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO alk, cyano, -COOH, COOalk, -CONR ₂₂ R _23, -CO-NH-NR ₂ 4R _25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or aflK-NR ₂₂ R _23; or a heteroaromatic ring selected from the rings benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, pyrrolidine, 1,2-quinolinyl, isoquinolinyl thiazolyl and thienyl, these heteroaromatic rings may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR ₂₄ R ₂₅ , CONR ₂₂ R ₂₃ , -anK-NR ₂₄ R ₂₅ , alkylsulfanyl, alkylsulfinyl, 03-372-02-PB • alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R19 stands for the radical -anK-SO ₂ -R26, -anK-SO ₂ -CH = CHR ₂ 6, Het] substituted by -SO2-R26 or phenyl substituted by -SO2-R26 or anK-SO2-R26, R ₂ o denotes a hydrogen atom or an alkyl radical, R ₂ i denotes a phenylalkyl, Heti or Ari radical, R22 and R _23, identical or different, represent a hydrogen atom or an alkyl radical or else R ₂ 2 and R23 form together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members, optionally containing another a heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl groups, R ₂ 4 and R ₂₅ , the same or different, denote a hydrogen atom or a radical alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, alk-O-alk or hydroxyalkyl or else R ₂₄ and R 25 form together with the nitrogen atom to which they are attached, saturated or an unsaturated one or two-ring heterocycle of 3 to 10 units containing, optionally, another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl, -COalk, COOalk, -CO-INalk, -CS-NHanK, oxo, hydroxyalkyl, -alk-Oalk or -CO-NH2 groups. R26 denotes an alkyl radical, Ari or Heti, Ari means a phenyl, naphthyl or indenyl radical, these radicals being optionally substituted by one or more halogen, alkyl, alkoxy, cyano, -CO-alk, -COOH, COOalk, -CONR ₂₇ R ₂₈ , -CO-NH -NR ₂₉ R 3 _O , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -anK-NR ₂ 9R ₃₀ , -NR ₂₉ R 3 _O , alkylthioalkyl, formyl, hydroxy, hydroxyalkyl, Het, -O-alk 03-372-02-PB · ♦ ·· • · · · · · NH-cycloalkyl, OCF ₃ , CF ₃ , -NH-CO-alk, -SO ₂ NH ₂ , -NH-COCH ₃ , NH-COOalk, Het or else in 2 adjacent carbon atoms by dioxymethylene, Heti means one or two-ring heterocycle, unsaturated or saturated, having 3 to 10 units and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted by one or more alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, OCF ₃ or CF ₃ , the nitrogen heterocycles being optionally in their Oxide form, R ₂₇ and R ₂ 8, the same or different, denote a hydrogen atom or an alkyl radical, or else R ₂₇ and R ₂₈ form together with the nitrogen atom to which they are attached a saturated one or two ring heterocycle of 3 to 10 units, optionally containing and another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl radicals, R ₂ and R ₃ , the same or different, denote a hydrogen atom or a radical alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, alk-O-alk, hydroxyalkyl or else R ₂₉ and R ₃ o form together with the nitrogen atom to which they are attached, a saturated or unsaturated mono-or double-ring heterocycle of 3 to 10 units containing, optionally, another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more radicals alkyl, -COalk, -COOalk, -CO-NHalk, CS-NHanK, oxo, hydroxyalkyl, -alk-O-alk, -CO-NH ₂ , or R is CHR ₃ i and R ₃ i means the radical -N (R ₃₂ ) R ₃₃ , -N (R ₃₂ ) -CO-R ₃₃ , N (R ₃₂ ) -SO ₂ R ₃₄ , 03-372-02-PB ···· - 40 R ₄ and R ₃ , identical or different, denote either an aromatic ring selected from phenyl, naphthyl and indenyl, this ring being selected from phenyl, naphthyl and indenyl, these aromatic rings being unsubstituted or substituted by one or more halogens, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, COOalk, -CONR ₂₂ R ₂ 3, -CO-NH-NR ₂₄ R ₂ 5, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonyl alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or - anK-NRvR5; or heteroaromatic ring selected from the rings benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolidyl, pyrrolidyl, pyrrolidinyl 4tetrahidroizohinolil, thiazolyl, and thienyl, these heteroaromatic rings may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOalk, -CO-NH-NR ₂₄ R ₂ 5, CONR22R23, -anK-NR ₂₄ R ₂ 5, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanyl yl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R ₃₂ represents the radical -C (R ₃₅ ) (R ₃₆ ) -Het ₂ , -Het ₂ , -C (R ₃₅ ) (R ₃₆ ) Ar ₂ , Ar ₂ , cycloalkyl or norbornyl, R ₃₃ represents a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -anK-CONR ₂₂ R 23, -anK-NR ₂₂ R 23 alkoxy, Ar ₂ , Het ₂ , -CH ₂ Ar ₂ , -CH ₂ Het ₂ or alkyl, optionally substituted by one or more halogens, R ₃₄ represents hydroxyalkyl radical, -alk-COOalk, an-K-CONR ₂₂ R ₂₃ , -anK-NR ₂₂ R ₂ 3, alkoxy, Ar ₂ , Het ₂ , -CH ₂ Ar ₂ , 03-372-02-PB ·· · · · · · · · · CH ₂ Het 2 or alkyl optionally substituted by one or more halogens, R35 denotes a hydrogen atom or a radical hydroxyalkyl, -alk-COOalk, -alk-CONR22R2 3, -anK-NR ₂₂ R 23, alkoxyalkyl, Ar ₂ , Het ₂ , -CH ₂ Ar ₂ , -CH ₂ Het ₂ or alkyl, optionally substituted one or more halogens, R ₃₆ represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -anK-CONR ₂₂ R ₂₃ , -alkyl-NR ₂₂ R ₂₃ , alkoxyalkyl or alkyl optionally substituted by one or more halogens, or R ₃₅ and R ₃₆ form together with the carbon atom to which they are attached a saturated one- or two-ring heterocycle of 3 to 10 units containing, optionally, another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl groups, Ar ₂ denotes a phenyl, naphthyl or indenyl radical, these radicals being optionally substituted by one or more halogens, alkyl, alkoxy, -CO-alk, cyano, -COOH, COOalk, -CONR ₃₇ R ₃ 8, -CO -NH-NR ₃₉ R ₄ o, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -aflK-NR ₃₉ R ₄₀ , -NR ₃₉ R ₄₀ , alkylthioalkyl, formyl, CF ₃ , OCF ₃ , Het, -O-alkyl-N-cycloalkyl, SO ₂ NH ₂ , hydroxy, hydroxyalkyl, -SOXOalk, SOXOalk or on two adjacent carbon atoms by dioxymethylene, Het ₂ means a heterocycle, one or two rings, unsaturated or saturated, with 3 to 10 units and containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo , hydroxy, the nitrogen heterocycles optionally in their N-oxide form, 03-372-02-PB ·· ···· · · · · · · · · · · · · · · · · · · · · · · R37 and _R38 , the same or different, denote a hydrogen atom or an alkyl radical or else R37 and R ₃₈ form together with the nitrogen atom to which a saturated one or two ring heterocycle of 3 to 10 units is attached, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl groups, R ₃₉ and R ₄₀ , identical or different, denote a hydrogen atom or an alkyl radical, or else R ₃₉ and R ₄₀ form, together with the nitrogen atom to which they are attached, a saturated one or two-ring heterocycle of 3 to 10 units, optionally containing another heteroatom selected between oxygen, sulfur and nitrogen and optionally substituted by one or more alkyl groups, alk means an alkyl or alkylene radical, the radicals and the alkyl and alkylene moieties and the alkoxy radicals and moieties are straight or branched and contain 1 to 6 carbon atoms and cycloalkyl radicals contains 3 to 10 carbon atoms, the optical isomers of these compounds and their pharmaceutically acceptable salts with mineral or organic acid. Combination according to claim 2, characterized in that the compound of formula (I) is selected from the following compounds: 1-benzhydryl-3 - [(methylsulfonyl) (phenyl) methylene] azetidine, 1-benzhydryl-3 - [(3methylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-chlorophenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB • · · · • · 99 99 · · · · · · · · · · · · · · · · · · · · 1-benzhydryl-3 - [(3,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(2,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(2,3dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3fluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3 bromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3 iodophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (3trifluoromethoxyphenyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (3trifluoromethylphenyl) methylene] azetidine, 1-benzhydryl-3 - {[(3,5bis (trifluoromethyl) phenyl] (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3,5dibromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3methoxycarbonylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3cyanophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3carbamoylphenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB • «· · · t · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 1-benzhydryl-3 - [(methylsulfonyl) (naphth-1 yl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-methoxyphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-methylphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (K8) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1- ( (4methoxyphenyl) (phenyl) methyl)] azetidine, (R) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1 - ((4methoxyphenyl) (phenyl) methyl] azetidine, (8) -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1 - ((4methoxyphenyl) (phenyl) methyl] azetidine, 1- [bis (4-trifluoromethoxyphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-trifluoromethylphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - (((3,5bis (trifluoromethyl) phenyl] methylsulfonylmethylene) azetidine, (1 <8) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (1 <i>) - 1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - ((3,5difluorophenyl) ( methylsulfonyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (K8) -1- ( (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB • (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- (pyrrolidylmethyl) phenyl] methyl) -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - {(4-chlorophenyl) [4- (pyrrolidylmethyl) phenyl] methyl) -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-chlorophenyl) [4- (pyrrolidylmethyl) phenyl] methyl} -3 [(3,5 -difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(E8) - (4-chlorophenyl) [4- (3,3-dimethylpiperidin-1-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- {4) - (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 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- {4- (S) - (4-chlorophenyl) [4- (thiomorpholin-4-yl-methyl) phenyl] methyl) -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {( E) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB • · · · • · · · 1 - {(R 8) - (4-chlorophenyl) [4- (N-ethyl-] cyclohexyl aminomethyl) phenyl] ethyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- {N) - (4-chlorophenyl) [4- (N-ethyl-L-cyclohexylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl (4- (1H-ethyl-cyclohexylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{^ 8) - (4-chlorophenyl) {4- [4ethoxycarbonylpiperazinyl) methyl] phenyl} methyl)) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{^) - (4-chlorophenyl) {4 - [(4ethoxycarbonylpiperazinyl) methyl] phenyl} methyl)) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{(S) - (4-chlorophenyl) {4 - ((4-ethoxycarbonylpiperazinyl) methyl] phenyl) methyl)) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- ^ 8) - ( 4-chlorophenyl) [4- (N-cyclopropyl-] N -propylaminomethyl) phenyl] -methyl) -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- {N) - (4-chlorophenyl) [4- (b [-cyclopropyl-N-propylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) (4-chlorophenyl) [4- (N-cyclopropyl-N-propylaminomethyl) phenyl] methyl) -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB 1 - {(R 8) - (4-chlorophenyl) [4 (diisopropylaminomethyl) phenyl] methyl) -3 - ((3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4 (diisopropylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4 (diisopropylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{((S) - (4-chlorophenyl) (4- (bis- (2-methoxyethyl) aminomethyl] phenyl) methyl}) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{(R) - (4-chlorophenyl) {4- [bis- (2methoxyethyl) aminomethyl] phenyl) methyl)) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{(S) - (4-chlorophenyl) {4- [bis- (2methoxyethyl) aminomethyl] phenyl) methyl)) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (4-chlorophenyl) [4- (di-propylaminomethyl) phenyl] methyl) -3 - ((3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (di-propylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (di-propylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (4-chlorophenyl) [4- (piperidin-1-yl) phenyl] methyl} -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB • · · · · · 1 - {(R) - (4-chlorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 ^- {(S) - (4-chlorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (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 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(1-8) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(1H) - (4-chlorophenyl) [4- (morpholin-4ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 ^- {(S) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl} 3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(1H) - (4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl} 3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB • · · «• · •« · · 1 - {(S) - (4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl) -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (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) -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (4-chlorophenyl) (4- (im idazol-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 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (Κ) -1 - {(4-χποροφεΗΗπ) [4- (Ν , (Dimethylcarbamoyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-χποροφεΗΗπ) [4- (Ν, dimethylcarbamoyl) phenyl] methyl) -3- (((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, N, S) -1 - {(4-chlorophenyl) [4- (L-ethylcarbamoyl) phenyl] methyl} 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB • (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, N, 8) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl (methylsulfonyl) methylene] azetidine, N) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - ((3,5difluorophenyl (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - ((3,5difluorophenyl (methylsulfonyl) methylene) azetidine, 1 - [(bis (4-chlorophenyl) methyl] -3 - ((3,5-difluorophenyl (methylsulfonyl) methylene) azetidine, 1-benzhydryl-3 - [(3methylsulfanylphenyl) (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-carbamoylphenyl) (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 - [(3-methylsulfonyl) (3pyrrolidinylphenyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3-hydroxymethylphenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB • · · ♦ ♦ ·· ♦ · 1- [bis (4-chlorophenyl) methyl] -3 - {(methyl sulfonyl) [3- (Mpiperidylcarbamoyl) phenyl] methylene} azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3trifluoromethylsulfanylphenyl) (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, N, 8) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) ) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfone) il) methylene] azetidine, 1-benzhydryl-3 - [(ethylsulfonyl) (phenyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - {{3- [N- (4methylpiperazinyl) carbamoyl] phenyl} (methylsulfonyl) methylene} azetidine, 1- [bis (4-chlorophenyl) methyl] -3- {[3- (2,2-dimethylcarbohydrazido) phenyl] (methylsulfonyl) methylene} azetidine 03-372-02-PB • · · · • · · • · · · 1- [bis (thien-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (p-tolyl) methyl] -3 (methylsulfonyl) (phenyl) methylene] azetidine, 1 - [(4-chlorophenyl) (4-hydroxymethylphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3methylaminophenyl) (methylsulfonyl) methylene] azetidine, (K8) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3- [ (3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, ( S) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (2methoxycarbonylthien-5-yl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3-hydroxy-3 [(methylsulfonyl) (2-methoxycarbonylthien-5-yl] azetidine- (K8), 1- [bis (4-chlorophenyl) methyl] -3- [(2isobutylaminocarbonylthien-5yl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3methoxycarbonylphenyl) (methylsulfonyl) methyl- (K8)] azetidin-3ol, 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (pyridin-4-yl) methyl- (S)] azetidin-3-ol, 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (pyridin-3-yl) methyl- (R8)] azetidin-3-ol, 03-372-02-PB 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonyl-methyl)] N- (3-morpholin-4-yl-propyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) N- (3-dimethylaminopropyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3 -idylene} 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-ylbenzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) N-isobutyl-benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) L1- (3-imidazol-1-ylpropyl) benzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) T4- (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} sulfonylmethyl) 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-ylidene} methanesulfonylmethyl) N-cyclohexylmethylbenzamide, 3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) L1-cyclopropylmethylbenzamide, 03-372-02-PB • · · · • · · · 3- ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) b [- (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) 1 N- (2-ethylbutyl) benzamide, methyl 4 - {[3 - ({1- [bis- (4- chlorophenyl) methyl] azetidin-3ylidene} -methanesulfonylmethyl) benzoylamino] methyl} cyclohexanecarboxylate, 2-amino-1- {4- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3ylidene} -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 of ( 2- {4- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazin-1-yl} -2-oxoethyl) 1 N [methylcarbamic acid, 4- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazine-1-thiocarboxylic acid N-methylamide, 03-372-02-PB • · · · • · · 4- (3 - ((1- [bis- (4xlophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazine-1-carboxylic acid N-methylamide, methyl 4- [3 - ({1 - [bis - (4-chlorophenyl) methyl] azetidin-3ylidene} -methanesulfonylmethyl) phenyl] piperazine-1-carboxylate, 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-3ylidene} -methanesulfonylmethyl) phenyl] piperazine, 1- {4- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazin-1-yl} -2 dimethylaminoethanone, 1- (3 - ((1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) phenyl] piperazine, tert-butyl 4- (3 - ((1- [bis- (4- chlorophenyl) methyl] azetidin-3ylidene} -methanesulfonylmethyl) phenyl] piperazine-1-carboxylate, 1- [bis (4-methoxycarbonylphenyl) methyl] -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 3- acetoxy-1- [bis (4-methoxycarbonylphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methyl- (S)] azetidine, (1 <8) -4- [4 - ((4- chlorophenyl) (3 - ((3,5difluorophenyl) methanesulfonylmethylene] azetidin-1 yl} methyl) benzyl] morpholine, 4- (4- (3 - ((1-benzhydrylazetidin-3ylidene) methanesulfonylmethyl] phenoxy} butyl) morpholine, 4- (4- (3 - ((1-benzhydrylazetidin-3ylidene) methanesulfonylmethyl] phenoxy} propyl) morpholine, 03-372-02-PB • · · · N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -thien-2-ylsulfonamide, B1- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4-methoxyphenylsulfonamide, B1- [4- (b1- {1- [bis (4-chlorophenyl) methyl] azetidin-3yl} sulfamoyl) phenyl] acetamide, B [- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4methylphenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4 dimethoxyphenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3fluorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-dichlorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3cyanophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2,5 dimethoxyphenyl sulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3trifluoromethylphenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -naphth-2-ylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -naphth-1-ylsulfonamide, B1- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4 difluorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1-methyl-1-Nimidazol-4-ylsulfonamide, 03-372-02-PB • · · · N- [4- (N- {1- [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} -4fluorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -quinol-8ylsulfonamide, 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 difluorophenylsulfonamide, N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -pyrid-2ylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3-fluoro-5-pyrrolidin-1-ylphenyl) sulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-methyl-4fluorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-methylquinol-8-ylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1H-methylphenylsulfonamide, B [- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-methyl (phenylmethyl) sulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3sulfamoylphenylsulfonamide, 03-372-02-PB • · · · 2-benzenesulfonyl-N- {1- [bis (4-chlorophenyl) methyl] azetidin3-yl} -acetamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (toluene-4-sulfonyl) -acetamide, (3-chloro-4-methylsulfonyl-thiophene-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} -4methylsulfonyl-benzamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4methanesulfonyl-benzamide, (5-methylsulfonylthiophene-2-carboxy) - {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } -amide, (5-methylsulfonyl-3-methyl-4-vinylthiophene-2-carboxy) - {1 [bis (4-chlorophenyl) methyl] azetidin-3-yl} -amide, (RS) - 14- {1 - [(4-chlorophenyl) -pyridin-3-yl-methyl] azetidin-3-yl} -3,5-difluorobenzenesulfonamide, (RS) - N- {1 - [(4-chlorophenyl) -pyrimidin-5-yl-methyl ] azetidin3-yl} -3,5-difluorobenzenesulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (6-chloropyrid-2-yl) -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -L1- (6-ethylpyrid-2-yl) -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1M-quinol-6yl) -methylsulfonamide, N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-5-ylmethylsulfonamide, 03-372-02-PB N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1H-isoquinol5-yl-methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl N-pyrid-Sylmethylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-oxide-pyrid-3-yl) methylsulfonamide, N- (1R, 2S, 4S) -6hiihkho [2,2,1] hept-2-yl-N- {1- [6hc (4chlorophenyl) methyl] azetidin-3-yl) -methylsulfonamide, N- (1R, 2R, 48) -bicyclo [2,2,1] hept-2-yl-N- {1- [6hc (4chlorophenyl) methyl] azetidin-3-yl} -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -] N- (thiazol-2yl) -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3methoxyphenyl) -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3-hydroxyphenyl) -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3hydroxymethylphenyl) methylsulfonamide, ethyl N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N (methylsulfonyl) -3-aminobenzoate, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1 isobutyl-piperid-4-yl) -methylsulfonamide, N-benzyl-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3yl} amine, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) amine, 03-372-02-PB • · · · 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-3ylmethyl) -methylsulfonamide, N- {1- [bis (4-fluorophenyl) -methyl] azetidin-3-yl} -L- (3,5-difluorophenyl) -methylsulfonamide, (RS) -1H- {1 - [(4-chlorophenyl) -pyrid- 3-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, (R) -1- N - {1 - [(4-chlorophenyl) -pyrid-3-ylmethyl] azetidin-3-yl } B1- (3,5-difluorophenyl) -methylsulfonamide, (S) - N- {1 - [(4-chlorophenyl) -pyrid-3-ylmethyl] azetidin-3-yl} N- (3,5-difluorophenyl) -methylsulfonamide, (RS) - N- {1 - [(4-chlorophenyl) -pyrid-4-ylmethyl] azetidin-3yl} -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-ilmet l] azetidin-3-yl} Y1- (3,5-difluorophenyl) methylsulfonamide, (RS) - Y1- {1 - [(4-chlorophenyl) -pyrimidine-5-ylmethyl] azetidin 3-yl} -L (- (3,5-difluorophenyl) -methylsulfonamide, (R) - N- {1 - [(4-chlorophenyl) -pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3, 5-difluorophenyl) -methylsulfonamide, (S) -1H- {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. 03-372-02-PB A combination according to claim 2, characterized in that the compound of formula (I) is selected from the following compounds: 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methyl- (S)] azetidin-3-ol, 3-acetoxy-1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methyl) methylsulfonylmethyl (S)] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, their optical isomers and their pharmaceutically acceptable salts. A combination according to claim 1, wherein the CB1 antagonist is SR 141716, its hydrates and its pharmaceutically acceptable salts or LY 320135 and its pharmaceutically acceptable salts. A pharmaceutical composition comprising a CB1 antagonist and sibutramine, a hydrate thereof or any of their pharmaceutically acceptable salts, in the pure state or together with one or more compatible and pharmacologically acceptable diluents and / or additives and / or in a given the case in combination with another pharmaceutically compatible and physiologically active product. Pharmaceutical composition according to claim 6, characterized in that the CB1 antagonist of formula (I) is as defined in claim 2. Pharmaceutical composition according to claim 7, characterized in that the compound of formula (I) is selected from the following compounds: 03-372-02-PB ·· · • · · 1-benzhydryl-3 - [(methylsulfonyl) (phenyl) methylene] azetidine, 1-benzhydryl-3 - [(3methylphenyl) (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 - [(2,3dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3fluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3bromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3 iodophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (3trifluoromethoxyphenyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (3trifluoromethylphenyl) methylene] azetidine, 1-benzhydryl-3- {[3,5bis (trifluoromethyl) phenyl] (methylsulfonyl) methylene} azetidine, 1-benzhydryl-3 - [(3,5dibromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3methoxycarbonylphenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB - 63 - ·: ': :: · ·: · ......: · .. · 1-benzhydryl-3 - [(3cyanophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3carbamoylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (naphth-1 yl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-methoxyphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-methylphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (K8) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1- [ (4methoxyphenyl) (phenyl) methyl)] azetidine, (R) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1 - [(4methoxyphenyl) (phenyl) methyl] azetidine, (8) -3- [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1 - [(4methoxyphenyl) (phenyl) methyl] azetidine, 1- [bis (4-trifluoromethoxyphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-trifluoromethylphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - {[(3,5bis (trifluoromethyl) phenyl] methylsulfonylmethyl} azetidine, (K8) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] - 3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene ] azetidine, 03-372-02-PB • ·· ♦ · ··. - 64 - ·: ...: ::. . ·.: ·: ....... ··: · .. (S) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (1 <8) -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, (K8) -1 - {(4-chlorophenyl) [4- (pyrrolidylmethyl) phenyl] methyl) -3 ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (K) -1 - {(4-chlorophenyl) [4- (pyrrolidylmethyl) phenyl] methyl} -3 [(3,5-di fluorophenyl) (methylsulphonyl) methylene] azetidine, (8) -1 - {(4-chlorophenyl) [4- (pyrrolidinylmethyl) phenyl] methyl) -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (4-chlorophenyl) [4- (3,3-dimethylpiperidin-1-ylmethyl) phenyl] methyl) -3 - ((3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(1H) - (4-chlorophenyl) [4- (3,3-dimethylpiperidin-1-ylmethyl) phenyl] methyl-3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) (4- (3,3-dimethylpiperidin-1-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (4-chlorophenyl) (4- (thiomorpholin-4-yl-methyl) phenyl] methyl) -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {( N) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB ···· - 65 1 ^- {(S) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R8) - (4-chlorophenyl) [4- (1R-ethyl-L [cyclohexylaminomethyl) phenyl] methyl} -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(] <- (4-chlorophenyl) [4- (N-ethyl-cyclohexylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl [4- (N-ethyl-cyclohexylaminomethyl) 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 - {{(R) - (4-chlorophenyl) {4 - [(4ethoxycarbonylpiperazinyl) methyl] phenyl} methyl}} -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{(S) - (4-chlorophenyl) {4 - [(4-ethoxycarbonylpiperazinyl) methyl] phenyl} methyl}} -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- (K8) - ( 4-chlorophenyl) [4- (N-cyclopropyl-L-propylaminomethyl) phenyl] -methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(1 <i>) - (4-chlorophenyl) [4 - (N-cyclopropyl-L-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB - 66 1 - {(S) (4-chlorophenyl) [4- (N-cyclopropyl-N-propylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (4-chlorophenyl) [4 (diisopropylaminomethyl) phenyl] methyl) -3 - ((3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4 (diisopropylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4 (diisopropylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{((S) - (4-chlorophenyl) {4- [bis- (2methoxyethyl) aminomethyl] phenyl) methyl)) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{(1H) - (4-chlorophenyl) {4- [bis- (2methoxyethyl) aminomethyl] phenyl) methyl)) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {{(S) - (4-chlorophenyl) {4- (bis- (2methoxyethyl) aminomethyl] phenyl) methyl)) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (4-chlorophenyl) [4- (di-propyl aminomethyl) phenyl] methyl) -3 - ((3,5 difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (di-propyl aminomethyl) phenyl] methyl) -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, • 4444 • · * • · ♦ • • • 4 • 4 • • 4 • e • 4 • · 4 4 4 4444 • 4 4 · 4 • · 4 • 4 4 • · · 4 444 • ·· 4 • · 4 4 · «44 03-372-02-PB - 67 1 - {(S) - (4-chlorophenyl) [4- (di-propylaminomethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (4-chlorophenyl) (4- (piperidin-1-yl) phenyl] methyl) -3 [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (piperidin-1-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (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 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (4-methylpiperazin-1-ylmethyl) phenyl] methyl) -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R 8) - (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 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 ^- {(S) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB - 68 1 - {(R 8) - (4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(1H) - (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 - {(R 8) - (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) -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(1-8) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (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, (Κ) -1 - {(4-χποροφεΗΗπ) [4- (Ν , Dimethylcarbamoyl) phenyl] methyl) -3 - ((3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 03-372-02-PB (S) -1 - {(4-χποροφβΗΗπ) [4- (Ν, dimethylcarbamoyl) phenyl] methyl} -3 - ((3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - {(4-chlorophenyl) [4- (L-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 - [(3,5difluorophenyl (methylsulfonyl)] methylene] azetidine, (R) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) ethyl] -3 - ((3,5difluorophenyl (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - ((3,5difluorophenyl (methylsulfonyl) methylene) azetidine , 1 - [(bis (4-chlorophenyl) methyl] -3 - ((3,5-difluorophenyl (methylsulfonyl) methylene) azetidine, 1-benzhydryl-3 - [(3methylsulfanylphenyl) (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-carbamoylphenyl) (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, 03-372-02-PB • · · · · · · · · · · · 1- [bis (4-chlorophenyl) methyl] -3 - [(3-methylsulfonyl) (3pyrrolidinylphenyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3-hydroxymethylphenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - {(methylsulfonyl) [3- (Mpiperidylcarbamoyl) phenyl] methylene} azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(methyl sulfonyl) (3trifluoromethylsulfanylphenyl) (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, (S) -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, N, 8) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) ) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5 difluorophenyl) (methylsulfones) l) methylene] azetidine, 1-benzhydryl-3 - [(ethylsulfonyl) (phenyl) methylene] azetidine, 03-372-02-PB • · · · • · • · · · 1- [bis (4-chlorophenyl) methyl] -3- {{3- [N- (4methylpiperazinyl) carbamoyl] phenyl} (methyl sulfonyl) methylene} azetidine, 1- [bis (4-chlorophenyl) methyl] -3- {[3- (2,2-dimethylcarbohydrazido) phenyl] (methylsulfonyl) methylene} azetidine 1- [bis (thien-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (p-tolyl) methyl] -3 (methylsulfonyl) (phenyl) methylene] azetidine, 1 - [(4-chlorophenyl) (4-hydroxymethylphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3methylaminophenyl) (methylsulfonyl) methylene] azetidine, (JB) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3- [ (3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, ( S) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (2methoxycarbonylthien-5-yl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3-hydroxy-3 [(methylsulfonyl) (2-methoxycarbonylthien-5-yl] azetidine- (KB), 1- [bis (4-chlorophenyl) methyl] -3 - [(2-isobutylaminocarbonylthien-5yl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3methoxycarbonylphenyl) (methylsulfonyl) methyl- (KB)] azetidin-3 ol, 03-372-02-PB • ···· ·· · ···· 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (pyridin-4-yl) methyl- (R8)] azetidin-3-ol, 1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (pyridin-3-yl) methyl- (R8)] azetidin-3-ol, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonyl-methyl) N- (3-morpholin-4-yl-propyl) 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-ylbenzamide, 3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) L1-isobutyl-benzamide, 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) 14- (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-ylethyl) benzamide, 3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) L1- (1-ethylpyrrolidin-2-ylmethyl) benzamide, 3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) N- (2,2-dimethylpropyl) benzamide, 03-372-02-PB • · · · ·· · • with ···· 3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) L1-cyclohexylmethylbenzamide, 3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) 14-cyclopropylmethylbenzamide, 3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) b} - (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) T <- (tetrahydrofuran-2-ylmethyl) benzamide, 3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) 14- (2,2-diphenylethyl) benzamide, 3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) 14- (2-ethylbutyl) benzamide, methyl 4 - {[3 - ({1- [bis- (4- chlorophenyl) methyl] azetidin-3ylidene} -methanesulfonylmethyl) benzoylamino] methyl} cyclohexanecarboxylate, 2-amino-1- {4- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3ylidene} -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 of ( 2- {4- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} 03-372-02-PB - 74 · Methanesulfonylmethyl) phenyl] piperazin-1-yl} -2-oxoethyl) methylmethylcarbamic acid, 4- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazine-1-thiocarboxylic acid N-methylamide, 4- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazine-1-carboxylic acid N-methylamide, methyl 4- [3 - ({1- [bis - (4-chlorophenyl) methyl] azetidin-3ylidene} -methanesulfonylmethyl) phenyl] piperazine-1-carboxylate, 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-3ylidene} -methanesulfonylmethyl) phenyl] piperazine, 1- {4- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazin-1-yl} -2 dimethylaminoethanone, 1- [3 - ({1- [bis- (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazine, tert-butyl 4- [3 - ({1- [bis- (4- chlorophenyl) methyl] azetidin-3ylidene} -methanesulfonylmethyl) phenyl] piperazine-1-carboxylate, 1- [bis (4-methoxycarbonylphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 3-acetoxy-1- [bis (4-methoxycarbonylphenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methyl- (1 < 8 &gt;)] azetidine, 03-372-02-PB ···· · · (1 <8) -4- [4 - ((4-chlorophenyl) {3 - ((3,5difluorophenyl) methanesulfonylmethylene] azetidin-1 yl} methyl) benzyl] morpholine, 4- (4- {3 - ((1-benzhydryl azetidin-3ylidene) methanesulfonylmethyl] phenoxy} butyl) morpholine, 4- (4- {3 - ((1-benzhydrylazetidin-3ylidene) methanesulfonylmethyl] phenoxy} propyl) morpholine, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -thien-2-ylsulfonamide, B1- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4-methoxyphenylsulfonamide, X- (4- (N- {1- (bis (4-chlorophenyl) methyl] azetidin-3-yl} sulfamoyl) phenyl] acetamide, B1- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4methylphenylsulfonamide, B [- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4 dimethoxyphenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3fluorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-dichlorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3cyanophenylsulfonamide, N- {1- (bis (4-chlorophenyl) methyl] azetidin-3-yl} -2,5 dimethoxyphenylsulfonamide, X- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3trifluoromethylphenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -naphth-2-ylsulfonamide, 03-372-02-PB ···· • · · · - 76 N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -naphth-1-ylsulfonamide, 14- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4difluorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1-methyl-1-Nimidazol-4-ylsulfonamide, N- [4- (N- {1- [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} -4fluorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -quinol-8ylsulfonamide, 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 difluorophenylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -pyrid-2ylsulfonamide, B1- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3-fluoro-5-pyrrolidin-1-ylphenyl) sulfonamide, B1- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-methyl-4fluorophenylsulfonamide, 14- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-methylquinol-8-ylsulfonamide, 03-372-02-PB • · · · · · · · · · · · N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -] N-methylphenylsulfonamide, X- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-methyl (phenylmethyl) sulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3sulfamoylphenylsulfonamide, 2-benzenesulfonyl-N- {1- [bis (4-chlorophenyl) methyl] azetidine- 3-yl} -acetamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (toluene-4-sulfonyl) -acetamide, (3-chloro-4-methylsulfonyl-thiophene-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} -4methylsulfonyl-benzamide, 14- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4methanesulfonyl-benzamide, (5-methylsulfonylthiophene-2-carboxy) - {1- [bis (4-chlorophenyl) methyl] azetidin-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-yl-methyl] azetidin-3-yl} -3,5-difluorobenzenesulfonamide, (RS) - N- {1 - [(4-chlorophenyl) -pyrimidin-5-yl-methyl ] azetidine- 3-yl} -3,5-difluorobenzenesulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (6-chloropyrid-2-yl) -methylsulfonamide, 03-372-02-PB • · · · · · · · · · · · · · · · · · · · · · · · · · · · N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (6-ethylpyrid-2-yl) -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1H-quinol-6yl-methylsulfonamide, T4- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-5yl-methyl-sulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-isoquinol- 5-ylmethylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-pyrid-3ylmethylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-oxide-pyrid-3-yl) methylsulfonamide, N- (1R, 2S, 4S) -6HijHkno [2,2,1] hept-2-yl- N- {1- [6hc (4chlorophenyl) methyl] azetidin-3-yl} -methylsulfonamide, N- (1R, 2R, 4B) -bicyclo [2,2,1] hept-2-yl-N- {1- [6hc (4chlorophenyl) methyl] azetidin-3-yl} -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -14- (3,5-difluorophenyl) -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (thiazol-2yl) -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3methoxyphenyl) -methylsulfonamide, N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3-hydroxyphenyl) -methylsulfonamide, N- {1- [6hc (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3hydroxymethylphenyl) methylsulfonamide, ethyl b1- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N (methylsulfonyl) -3-aminobenzoate, 03-372-02-PB • ··· • · ...... N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (1-isobutyl-piperid-4-yl) -methylsulfonamide, N-6eH3Hn-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3yl} 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} -1H- (pyrid-3ylmethyl) -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] 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- ilmet l] azetidin-3-yl} 1M- (3,5-difluorophenyl) methylsulfonamide, (RS) - Ν- {1 - [(4-chlorophenyl) -pyrimidine-5-ylmethyl] azetidin 3-yl} -N- (3,5-difluorophenyl) -methylsulfonamide, (R) - N- [1 - [(4-chlorophenyl) -pyrimidin-5-ylmethyl] azetidin-3-yl} -T4- (3,5 -difluorophenyl) -methylsulfonamide, 03-372-02-PB (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 mineral or organic acid. Pharmaceutical composition according to claim 7, characterized in that the compound of formula (I) is selected from the following compounds: 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methyl- (1-8)] azetidin-3-ol, 3-acetoxy-1- [bis- (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methyl) methylsulfonylmethyl (WBCazetidine, 1- [bis (4-chlorophenyl) methyl] -3 - [(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, their optical isomers and their pharmaceutically acceptable salts. A pharmaceutical composition according to claim 6, wherein the CB1 antagonist is SR 141716, its hydrates and its pharmaceutically acceptable salts or LY 320135 and its pharmaceutically acceptable salts. A pharmaceutical composition according to any one of claims 6 to 10, for use simultaneously, individually or over time. A pharmaceutical composition according to any one of claims 6 to 11, characterized in that it contains 0.5 to 10 mg sibutramine and 0.1 to 200 mg CB1 antagonist.