ZA200303015B - Association of the CB1 receptor antagonist and sibutramin, for treating obesity. - Google Patents

Association of the CB1 receptor antagonist and sibutramin, for treating obesity. Download PDF

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ZA200303015B
ZA200303015B ZA200303015A ZA200303015A ZA200303015B ZA 200303015 B ZA200303015 B ZA 200303015B ZA 200303015 A ZA200303015 A ZA 200303015A ZA 200303015 A ZA200303015 A ZA 200303015A ZA 200303015 B ZA200303015 B ZA 200303015B
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Prior art keywords
methyl
chlorophenyl
bis
methylsulfonyl
phenyl
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ZA200303015A
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Odile Piot-Grosjean
Francois Petitet
Philippe Picaut
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Aventis Pharma Sa
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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Description

@ 220 19 ® ~~ B2003/30
COMBINATION OF A CB1 RECEPTOR ANTAGONIST AND OF
SIBUTRAMINE, THE PHARMACEUTICAL COMPOSITIONS COMPRISING
THEM AND THEIR USE IN THE TREATMENT OF OBESITY
The present invention relates to the combination of a CBl receptor antagonist and of sibutramine, to the pharmaceutical compositions comprising them and to their use in the treatment of obesity.
CB1l receptor antagonists are known for their effect on food intake and their use as anorexigenic (G. Colombo et al., Life Sciences, 63 (8), 113-117 (1998); J. Siamand et al., Behavioural Pharmacol., 9, 179-181 (1998)).
Sibutramine (BTS 54524; N-{1-[{1-(4-chloro- phenyl) cyclobutyl]-3-methylbutyl}-N,N-dimethylamine;
MeridiaF, Reductil®), its hydrate and its pharma- ceutically acceptable salts and in particular its hydrochloride reduces food intake and is of use in the treatment of obesity (WO 90/061110; D.H. Ryan et al.,
Obesity Research, 3 (4), 553 (1995); H.C. Jackson et al., British Journal of Pharmacology, 121, 1758 (1997);
G. Fanghanel et al., Inter. J. Obes., 24 (2), 144 (2000); G.A. Bray et al., Obes. Res., 7 (2), 189 (1999)).
It has now been found that the combination of sibutramine, its hydrate and its pharmaceutically acceptable salts and of a CBl receptor antagonist exhibits a synergistic effect in reducing food consumption and is thus of use in the treatment of obesity.
The combination can also comprise several CBI receptor antagonists.
Use may in particular be made, among CBl [lacuna] antagonists, of the azetidine derivatives
® i disclosed in WO 00/15609, WO 01/64633 and WO 01/64634 of formula:
R, + ] (M
R in which either R represents a chain (A) or (B) and
R
SOR, ? SOR,
C=—=CH N or C— RAN
R R
(A) 2 (B) 2
R; represents a methyl or ethyl radical,
R, represents either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, -CO-alk, hydroxyl, -COORs, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NReR;, —-CO-NH-NRgR7, -N (alk) COORg, cyano, -CONHRg, —CO-NRjieR17, alkylsulfanyl, hydroxyalkyl, -0O-alk-NRizRi3 or alkylthicalkyl, or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, indolinyl, indolyl, isochromanyl, isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl rings, it being possible for these heteroaromatics to be o 2003/3015 ® ~ 22003/ unsubstituted or substituted by a halogen, alkyl, alkoxy, —-COORs, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NR¢R7, -CO-NH-NR¢R;, cyano, -CONHRy, alkylsulfanyl, hydroxyalkyl or alkylthioalkyl,
R3; and Rs, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COORs, —-CONRjoRi1, —CO-NH-NRgR7, alkylsulfanyl, hydroxyalkyl, -alk-NRe¢R; or alkylthioalkyl, or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydro- benzothienyl, furyl, isochromanyl, isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl or thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted by a halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COORs, =~CO-NH-NR¢R;, —-CONRigRii, -alk-NR¢R7, alkylsulfanyl, hydroxyalkyl or alkylthioalkyl,
Rs is an alkyl radical or a phenyl radical optionally substituted by one or more halogen atoms,
R¢ and R,, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or else R¢ and Ry; form, together with the nitrogen atom to which they are attached, a saturated or unsaturated and mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being
_ ® 4 substituted by one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NRj4Ris, oxo, hydroxyalkyl, -alk-0O-alk or -CO-NH; radicals,
Rg represents an alkyl radical,
Ry, represents a hydrogen atom or a radical of the type alkyl or alkyl substituted by dialkylamino, phenyl, cycloalkyl (optionally substituted by -COOalk) or a saturated or unsaturated and mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising one or more heteroatoms chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl radicals,
Rio and Ry;, which are identical or different, represent a hydrogen atom or an alkyl radical or else Rio and Rij form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by an alkyl radical,
Rj, and Ri3, which are identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical or else Ry; and Rj; form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by an alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk or -CO- alk-NRjsRi5 radical or a saturated mono- or bicyclic heterocycle having 3 to 10 ring members and comprising a heteroatom chosen from oxygen, sulfur and nitrogen,
C
® 5
Ry; and Ris, which are identical or different, represent a hydrogen atom or an alkyl or -COOalk radical,
R;¢ and Ry; form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen,
R’ represents a hydrogen atom or a -CO-alk radical, or R represents a CHRj;s radical and
Rig represents an —-NHCORig or -N(Rgz) -Y-Ra: radical,
Y is CO or SO,
R, and R;, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -Co0-alk, cyano, -COOH, -COOalk, -CONR32R23, -CO-NH-NR,4Rys5, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NH;zRz3, or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4- tetrahydroisoquinolyl, thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted by a halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, —-CO-NH-NR24R,5, -CONR32Rz3, —-alk-
@ ® 6
NRy4Rz5, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl,
Rig represents an -alk-SO,-Rye¢ radical, an —-alk-SO,-
CH=CH-R,¢ radical, a Het; radical substituted by -S0,-Rys or a phenyl radical substituted by -S0;-Rys or —-alk-SO:-
Rae,
Ryo represents a hydrogen atom or an alkyl radical,
R,; represents a phenylalkyl, Het; or Ar; radical,
R,, and R,3, which are identical or different, represent a hydrogen atom or an alkyl radical or else Ry; and Rj; form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl,
Ros and Rys, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or else R,, and Rys form, together with the nitrogen atom to which they are attached, a saturated or unsaturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or —-CO-NHz,
Rye represents an alkyl, Ar; or Het; radical,
C
®
Ar; represents a phenyl, naphthyl or indenyl radical, these radicals optionally being substituted by one or more halogen, alkyl, alkoxy, cyano, -CO-alk, -COOH, -C0O0Oalk, -CONRjz7Rzg, —-CO-NH-NR,3R3g, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NRzsR3o, —NRz9R30, alkylthioalkyl, formyl, hydroxyl, hydroxyalkyl, Het, -0O-alk-NH-cycloalkyl, OCFj;, CF3, -NH-CO-alk, -SO;NH:, -NH-COCH;, -NH-COOalk or Het or else on 2 adjacent carbon atoms by dioxymethylene,
Het, represents an unsaturated or saturated mono- or bicyclic heterocycle having 3 to 10 ring members and comprising one or more heteroatoms chosen from oxygen, sulfur and nitrogen which is optionally substituted by one or more alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxyl, OCF; or CFs, the nitrogenous heterocycles optionally being in their N- oxidized form,
Ry; and Rpg, which are identical or different, represent a hydrogen atom or an alkyl radical or else Ry; and Rgg form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl radicals,
R,9 and Rizo, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or else R,y and Rj form, together with the nitrogen atom to which they are attached, a saturated or unsaturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being
® ® 8 substituted by one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH, radicals, or R represents CHR3; and
R3; represents an —-N(Rsz)Rs3z, -N(Rj3z) -CO-R33 or -N (R32) =SOsR34 radical,
Ry and Riz, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, —-COOH, COOalk, -CONRz2Rzs3, —-CO-NH-NR24R>5, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR;Rg, or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, gquinolyl, 1,2,3,4-tetra- hydroisoquinolyl, thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted by a halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -CO0alk, -CO-NH-NR;sRzs5, —CONR22Rz3, —-alk-NRz4Rzs, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl,
Ri, represents a -C(Rss) (Rs) ~Hetz, -Hety, -C (R35) (Rig) —Ara,
Ar,, cycloalkyl or norbornyl radical,
® ® 9
R33 represents a hydrogen atom or a hydroxyalkyl, -alk-CO0Oalk, -alk-CONRyzRz3, —-alk-NR:2R3, alkoxy, Ar,
Het,, -CHzAr,, -CHyHet, or alkyl radical, the latter optionally substituted by one or more halogen,
R3s represents a hydroxyalkyl, -alk-COOalk, -alk-CONR;2R3, -alk-NR,;Rz3, alkoxy, Ar,, Het,, -CHyAry, —-CH,Het, or alkyl radical, the latter optionally substituted by one or more halogen,
R3s represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONR,3Rz3, —-alk-NR;;R;3, alkoxyalkyl,
Ar,, Het,, -CH,Ar,, -CHpHet, or alkyl radical, the latter optionally substituted by one or more halogen,
R;¢ represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONRj;R»3, —-alk-NR;3R;3, alkoxyalkyl or alkyl radical, the latter optionally substituted by one or more halogen, or else R35 and Rss form, together with the carbon atom to which they are attached, a saturated mono- or bicyclic ring having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl,
Ar, represents a phenyl, naphthyl or indenyl radical, these various radicals optionally being substituted by one or more halogen, alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR3jR3g, —CO-NH-Rj39Rs, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NRs3gRso, —NR39R40, alkylthioalkyl, formyl, CF;, OCF3, Het, -O-alk-NH- cycloalkyl, SO;NH,, hydroxyl, hydroxyalkyl, -NHCOalk or
NHCOOQalk or on 2 adjacent carbon atoms by dioxymethylene,
_ ¥2003/3013 ® 10
Het, represents an unsaturated or saturated mono- or bicyclic heterocycle having 3 to 10 ring members and comprising one or more heteroatoms chosen from oxygen, sulfur and nitrogen which is optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo or hydroxyl, the nitrogenous heterocycles optionally being in their N-oxidized form,
R37 and Rig, which are identical or different, represent a hydrogen atom or an alkyl radical or else Ray and Rag form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl,
Rss and Ryp, which are identical or different, represent a hydrogen atom or an alkyl radical or else Rig and Rgg form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl, alk represents an alkyl or alkylene radical, the alkyl and alkylene radicals and portions and the alkoxy radicals and portions have straight or branched chains and comprise 1 to 6 carbon atoms and the cycloalkyl radicals comprise 3 to 10 carbon atoms,
® ® 11 the optical isomers of these compounds and their pharmaceutically acceptable salts with an inorganic or organic acid.
The preferred azetidine derivatives are as follows: l-benzhydryl-3-[ (methylsulfonyl) (phenyl) - methylene] azetidine, l-benzhydryl-3-[ (3-methylphenyl) (methylsulfonyl)- methylenelazetidine, 1l-benzhydryl-3-[(3-chlorophenyl) (methylsulfonyl)- methylenelazetidine, l-benzhydryl-3-[(3,5-dichlorophenyl) (methylsulfonyl) - methylenelazetidine, l-benzhydryl-3-[ (2, 5-dichlorophenyl) (methylsulfonyl) - methylene]azetidine, l1-benzhydryl-3-[(2,3-dichlorophenyl) (methylsulfonyl) - methylene]azetidine, l-benzhydryl-3-[ (3-fluorophenyl) (methylsulfonyl) - methylene]azetidine, 1-benzhydryl-3-[(3,5-difluorophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[ (3-bromophenyl) (methylsulfonyl) - methylene]azetidine, l1-benzhydryl-3-[ (3-iodophenyl) (methylsulfonyl) - methylenelazetidine, l-benzhydryl-3-[ (methylsulfonyl) (3-trifluoro- methoxyphenyl)methylene]azetidine, l1-benzhydryl-3-[ (methylsulfonyl) (3-trifluoro- methylphenyl)methylene]azetidine, 1-benzhydryl-3-{[3,5-bis (trifluoromethyl) phenyl]- (methylsulfonyl)methylenelazetidine, 1-benzhydryl-3-[ (3, 5-dibromophenyl) (methylsulfonyl) - methylene]azetidine, 1-benzhydryl-3-[ (3-methoxycarbonylphenyl) - (methylsulfonyl)methylene]azetidine,
® ® , 2200373015 l-benzhydryl-3-[ (3-cyanophenyl) (methylsulfonyl) - - methylene] azetidine, l-benzhydryl-3-[ (3-carbamoylphenyl) (methylsulfonyl) - methylenelazetidine, 1-benzhydryl-3-[(methylsulfonyl) (naphth-1-yl) (methyl-
sulfonyl)methylene]azetidine, 1- [bis (4-chlorophenyl)methyl]-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, 1- [bis (4-methoxyphenyl)methyl]-3-[(3,5-difluoro-
phenyl) (methylsulfonyl)methylene]azetidine, 1- {bis (4-methylphenyl)methyl]-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine, (RS)-3-[(3,5-difluorophenyl) (methylsulfonyl) methylene] - 1-[ (4-methoxyphenyl) (phenyl)methyl) Jazetidine,
(R)-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]- 1-[ (4-methoxyphenyl) (phenyl)methyl]lazetidine, (S)-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]- 1-[ (4-methoxyphenyl) (phenyl)methyllazetidine, 1-[bis (4-trifluoromethoxyphenyl)methyl]-3-[(3,5-di-
fluorophenyl) (methylsulfonyl)methylene]azetidine, 1-[bis (4-trifluoromethylphenyl)methyl]-3-[(3,5-di- fluorophenyl) (methylsulfonyl)methylene]azetidine, 1-[bis (4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoro- methyl) phenyl]lmethylsulfonylmethylene}azetidine,
(RS)-1-[(4-chlorophenyl) (2,4-dichlorophenyl)methyl]-3- [ (3,5-difluorophenyl) (methylsulfonyl)- methylene] azetidine,
(R)-1-[(4-chlorophenyl) (2,4-dichlorophenyl)methyl]-3- [(3,5-difluorophenyl) (methylsulfonyl)-
methylenelazetidine,
(S)-1-[ (4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3- [ (3,5-difluorophenyl) (methylsulfonyl)- methylene]azetidine,
(RS) -1~{ (4-chlorophenyl) [4-
(hydroxymethyl)phenyl]lmethyl}-3-[(3,5-difluoro~ phenyl) (methylsulfonyl)methylene]azetidine,
® ® 13
(R)-1-{ (4-chlorophenyl) [4- (hydroxymethyl) phenyl]lmethyl}-3-[(3, 5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, (S)-1-{ (4-chlorophenyl) [4-
(hydroxymethyl) phenyl]methyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, (RS) -1-{ (4-chlorophenyl) [4- (pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine,
(R)-1-{(4-chlorophenyl) [4- (pyrrolidylmethyl)phenyl]lmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine,
(8)-1-{ (4-chlorophenyl) [4- (pyrrolidylmethyl)phenyllmethyl}-3-[(3,5-difluoro-
phenyl) (methylsulfonyl)methylenelazetidine,
1-{ (RS) - (4-chlorophenyl) [4- (3,3-dimethylpiperidin-1- ylmethyl)phenyllmethyl}-3-[(3,5-difluoro-
phenyl) (methylsulfonyl)methylene]azetidine,
1-{ (R) - (4-chlorophenyl) [4-(3,3-dimethylpiperidin-1-
ylmethyl)phenyllmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine,
1-{ (8) - (4-chlorophenyl) [4-(3,3-dimethylpiperidin-1- ylmethyl)phenyl]methyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine,
1-{(RS)-(4-chlorophenyl) [4-(thiomorpholin-4- ylmethyl)phenyl]lmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine,
1-{ (R) - (4-chlorophenyl) [4- (thiomorpholin-4- ylmethyl)phenyl]lmethyl}-3-[(3,5-difluoro-
phenyl) (methylsulfonyl)methylenelazetidine,
1-{ (S)-(4-chlorophenyl) [4- (thiomorpholin-4- ylmthyl)phenyl]methyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine, 1-{ (RS) -(4-chlorophenyl) [4- (N-ethyl-N-
cyclohexylaminomethyl)phenyllmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine,
@ ® 14 1-{(R)-(4-chlorophenyl) [4- (N-ethyl-N- cyclohexylaminomethyl)phenyl]methyl}-3-[(3, 5- difluorophenyl) (methylsulfonyl)methylenejazetidine, 1-{(S)-(4-chlorophenyl) [4- (N-ethyl-N-
cyclohexylaminomethyl)phenyl]lmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylenejazetidine, 1-{{ (RS) -(4-chlorophenyl) {4-[ (4-ethoxycarbonyl- piperazinyl)methyl]phenyl}methyl}}-3-[(3,5~- difluorophenyl) (methylsulfonyl)methylene]azetidine,
1-{{(R)-(4-chlorophenyl) {4-[ (4-ethoxycarbonyl- piperazinyl)methyl]phenyl}methyl}}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{{(S)-(4-chlorophenyl) {4-[ (4-ethoxycarbonyl- piperazinyl)methyl]phenyl}methyl}}-3-[(3,5-
difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{ (RS) - (4-chlorophenyl) [4- (N-cyclopropyl-N- propylaminomethyl)phenyl]methyl}-3-1[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{ (R)- (4-chlorophenyl) [4- (N-cyclopropyl-N-
propylaminomethyl)phenyl]methyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{(S)-(4-chlorophenyl) [4- (N-cyclopropyl-N- propylaminomethyl)phenyl]lmethyl}-3-[(3,5= difluorophenyl) (methylsulfonyl)methylene]azetidine,
1-{ (RS) - (4-chlorophenyl) [4- (diisopropylamino- methyl) phenyl]lmethyl}-3-[(3,5-difluorophenyl)-
(methylsulfonyl)methylene]azetidine, 1-{ (R) - (4-chlorophenyl) [4- (diisopropylaminomethyl) - phenyl ]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine, 1-{(S)- (4-chlorophenyl) [4- (diisopropylaminomethyl) - phenyllmethyl}-3-[(3,5-difluorophenyl) (methylsulfonyl)- methylenelazetidine, 1-{{ (RS) - (4-chlorophenyl) {4- [bis (2-methoxyethyl) -
aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine,
_ ® 15 1-{{ (R)~-(4-chlorophenyl) {4-[bis (2-methoxyethyl) - aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylenelazetidine, 1-{{(S)-(4-chlorophenyl) {4- [bis (2-methoxyethyl) -
aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylene]azetidine,
1-{ (RS) -(4-chlorophenyl) [4-[di-n~- propylaminomethyl)phenyl]lmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl) [4-(di-n-propylaminomethyl)- phenyl]lmethyl}-3-[ (3, 5-difluorophenyl) (methylsulfonyl) - methylenelazetidine, 1-{(S)-(4-chlorophenyl) [4-(di-n-propylaminomethyl) — phenyl]lmethyl}-3-[(3,5-difluorophenyl) (methyl-
sulfonyl)methylene]azetidine,
1-{ (RS) -(4-chlorophenyl) [4- (piperidin-1-ylmethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine,
1-{ (R)-(4-chlorophenyl) [4- (piperidin-1-ylmethyl) -
phenyl]lmethyl}-3-[(3,5~-difluorophenyl) (methyl- sulfonyl)methylene]azetidine, 1-{(S)-(4-chlorophenyl) [4-(piperidin-1-ylmethyl) - phenyl ]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl) [4-(4-methylpiperazin-1- ylmethyl)phenyl]lmethyl}-3-{(3,5-difluorophenyl)- (methylsulfonyl)methylenelazetidine,
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)phenyllmethyl}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylenelazetidine,
1-{ (RS) -(4-chlorophenyl) [4~ (morpholin-4-
ylmethyl)phenyl]lmethyl}-3-[(3,5-difluorophenyl)-
(methylsulfonyl)methylenelazetidine,
®
® 16 1-{ (R)-(4-chlorophenyl) [4- (morpholin-4-ylmethyl) - phenyl]lmethyl}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylene]azetidine, 1-{(S)-(4-chlorophenyl) [4- (morpholin-4-ylmethyl) -
phenyl]lmethyl}-3-[(3,5-difluorophenyl)-
(methylsulfonyl)methylene]azetidine, 1-{ (RS) -(4-chlorophenyl) [4-(diethylaminomethyl) - phenyl]lmethyl}-3-[(3,5-difluorophenyl) (methyl-~ sulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl) [4-(diethylaminomethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine, 1-{(S)-(4-chlorophenyl) [4- (diethylaminomethyl) - phenyl]lmethyl}-3-[(3,5-difluorophenyl) (methyl-
sulfonyl)methylene]azetidine,
1-{ (RS) - (4-chlorophenyl) [4- (piperazin-2-one-4- ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine,
1-{ (R)- (4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) -
phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine, 1-{(S)-(4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) - phenyl]lmethyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine,
1-{ (RS) -(4-chlorophenyl) [4-(imidazol-1l-ylmethyl)- phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine,
1-{ (R) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) - phenyllmethyl}-3-[(3,5-difluorophenyl) (methyl-
sulfonyl)methylenelazetidine,
1-{(S)- (4-chlorophenyl) [4- (imidazol-1-ylmethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine,
(RS) -1-{ (4-chlorophenyl) [4-(N,N-
dimethylcarbamoyl)phenyl]lmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylenelazetidine,
@ ® 17 (R)=-1-{ (4-chlorophenyl) [4-(N,N- dimethylcarbamoyl)phenyl]lmethyl}-3-[ (3, 5- difluorophenyl) (methylsulfonyl)methylene]azetidine, (S)-1-{ (4-chlorophenyl) [4-(N,N-
dimethylcarbamoyl)phenyl]methyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, : (RS) -1-{ (4-chlorophenyl) [4-(N- ethylcarbamoyl)phenyl]lmethyl) }-3-[(3,5~ difluorophenyl) (methylsulfonyl)methylene]azetidine,
(R)-1-{(4-chlorophenyl) [4-(N- ethylcarbamoyl)phenyl]methyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, (S)-1-{ (4-chlorophenyl) [4- (N= ethylcarbamoyl)phenyl]methyl}-3-[(3,5-
difluorophenyl) (methylsulfonyl)methylene]azetidine, (RS) -1-[ (4-carbamoylphenyl) (4-chlorophenyl)methyl]-3- [(3,5-difluorophenyl) (methylsulfonyl)methylene]- azetidine,
(R) -1-[ (4-carbamoylphenyl) (4-chlorophenyl)methyl]-3-
[ (3,5-difluorophenyl) (methylsulfonyl)methylene]- azetidine,
(S)-1-[ (4-carbamoylphenyl) (4-chlorophenyl)methyl]-3- [(3,5-difluorophenyl) (methylsulfonyl)methylene]- azetidine,
1- [bis (4-chlorophenyl)methyl]-3-[(3,5-dichloro- phenyl) (methylsulfonyl)methylene]azetidine, 1-benzhydryl-3-[ (3-methylsulfanylphenyl) (methyl- sulfonyl)methylenelazetidine, 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)methylenelazetidine,
® 18 1- [bis (4-chlorophenyl)methyl]-3-[ (3-hydroxyphenyl) - (methylsulfonyl)methylene}azetidine, 1- [bis (4-chlorophenyl)methyl]l-3-[ (methylsulfonyl) (3- pyrrolidinylphenyl)methylene]azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[ (3-hydroxy- methylphenyl) (methylsulfonyl)methylene]azetidine, 1- [bis (4-chlorophenyl)methyl]-3-{ (methylsulfonyl) [3-(N- piperidylcarbamoyl)phenyl]lmethylene}azetidine, 1- [bis (4-chlorophenyl)methyl]-3-[ (methylsulfonyl) (3- trifluoromethylsulfanylphenyl) (methylsulfonyl)- methylene]azetidine, 1- [bis (4-fluorophenyl)methyl]-3~[ (3, 5-difluorophenyl) - (methylsulfonyl)methylene]azetidine, 1- [bis (2-fluorophenyl)methyl]}-3-[ (3, 5-difluorophenyl) - (methylsulfonyl)methylenelazetidine, 1- [bis (3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylenelazetidine, (RS) -1-[ (4-chlorophenyl) (thiazol-2-yl)methyl]-3- [ (methylsulfonyl) (phenyl)methylene]azetidine, (R)-1-[ (4-chlorophenyl) (thiazol-2-yl)methyl]-3- [ (methylsulfonyl) (phenyl)methylenelazetidine, (S)-1-[ (4-chlorophenyl) (thiazol-2-yl)methyl]-3- [ (methylsulfonyl) (phenyl)methylene]azetidine, (RS) -1-[ (4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylenelazetidine, (R)-1-[ (4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5~ difluorophenyl) (methylsulfonyl)methylene]azetidine, (S)-1-[ (4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-benzhydryl-3-[(ethylsulfonyl) (phenyl)methylene]- azetidine, 1- [bis (4-chlorophenyl)methyl]-3—-{{3-[N-(4- methylpiperazinyl)carbamoyl]phenyl} (methylsulfonyl)- methylenelazetidine,
@ ® 19 1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2- dimethylcarbohydrazido) phenyl] (methylsulfonyl)- methylene}azetidine, 1-[bis(thien-2-yl)methyl]-3-[(3, 5-difluorophenyl) -
(methylsulfonyl)methylene]azetidine,
1- [bis (p-tolyl)methyl]-3-[ (methylsulfonyl)- (phenyl)methylene]azetidine,
1-[ (4-chlorophenyl) (4-hydroxymethylphenyl)methyl]-3- [ (3,5-difluorophenyl) (methylsulfonyl)methylene]-
azetidine,
1- [bis (4-chlorophenyl)methyl]-3-[(3-methylaminophenyl) - (methylsulfonyl)methylene]azetidine,
(RS) -1-[ (4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5~ difluorophenyl) (methylsulfonyl)methylene]azetidine,
(R)-1-[(4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, (S)-1-[ (4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1- [bis (4-chlorophenyl)methyl]-3-[(methylsulfonyl) (2-
methoxycarbonylthien-5-yl)methylene]azetidine,
(RS) -1- [bis (4-chlorophenyl)methyl]-3-hydroxy-3-
[ (methylsulfonyl) (2-methoxycarbonylthien->5- yl)methyllazetidine,
1- [bis (4-chlorophenyl)methyl]-3-[(2-isobutylamino-
carbonylthien-5-yl) (methylsulfonyl)methylene]azetidine, 1- [bis (4-chlorophenyl) methyl] -3-[(RS)-(3-methoxy- carbonylphenyl) (methylsulfonyl)methyl]azetidin-3-ol, 1- [bis (4-chlorophenyl)methyl]-3-[(RS)~ (methyl- sulfonyl) (pyridin-4-yl)methyl]azetidin-3-ol,
1-[bis(4-chlorophenyl)methyl]-3-[(RS)~- (methylsulfonyl) (pyridin-3-yl)methyljazetidin-3-ol, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-(3~ (morpholin-4- yl)propyl)benzamide,
® e 20 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N- (3- dimethylaminopropyl)benzamide, ’ 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(2-(pyrrolidin-1- yl)ethyl)benzamide, 3-({1l-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N- (2-dimethylamino-1- methylethyl)benzamide, 3-({1l-[bis(4-chlorophenyl)methyl]lazetidin-3- ylidene} (methanesulfonyl)methyl) -N- (piperidin-1- yl)benzamide, 3-({1l-[bis (4-chlorophenyl)methyllazetidin-3- ylidene} (methanesulfonyl)methyl)-N-isobutylbenzamide, 3-({1-[bis(4-chlorophenyl)methyl]lazetidin-3- ylidene)} (methanesulfonyl)methyl) -N-(3- (imidazol-1- yl)propyl)benzamide, 3-({1-[bis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-(2- dimethylaminoethyl)benzamide,
N’-methylhydrazide of 3-({1-[bis (4-chlorophenyl)- methyl)lazetidin-3-ylidene} (methanesulfonyl) - methyl) benzoic acid, 3-({1-[bis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(2- (morpholin-4- yl) ethyl)benzamide, 3-({1-[bis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(l-ethylpyrrolidin- 2-ylmethyl)benzamide, 3-({1-[bis(4-chlorophenyl)methyl]lazetidin-3- ylidene} (methanesulfonyl)methyl) -N- (2, 2- dimethylpropyl)benzamide, 3-({1-[bis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N- (cyclohexylmethyl)benzamide,
@® ® 21 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N- (cyclopropylmethyl)benzamide, 3-({1l-[bis(4-chlorophenyl)methyl]azetidin-3-
vylidene} (methanesulfonyl)methyl) -N-(2- methylbutyl)benzamide, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(2- phenylpropyl)benzamide,
3-({1l-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N- (tetrahydrofuran-2- ylmethyl)benzamide, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N- (2, 2-
diphenylethyl)benzamide, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N- (2- ethylbutyl)benzamide, methyl ester of 4-{[3-({1-[bis(4-chlorophenyl)methyl]-
azetidin-3-ylidene} (methanesulfonyl)methyl)- benzoylaminolmethyl}cyclohexanecarboxylic acid, 2-amino-1-{4-[3-({1-[bis(4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl)phenyl]- piperazin-l-yl}ethanone,
tert-butyl ester of (2-{4-[3-({1-[bis(4-chlorophenyl) - methyl]azetidin-3-ylidene} (methanesulfonyl)methyl) - phenyl]piperazin-l-yl}-2-oxoethyl)carbamic acid, 1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)phenyl]piperazin-1-yl}-
2-(methylamino)ethanone, tert-butyl ester of (2-{4-[3-({1-[bis(4- chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)phenyl]piperazin-1-yl}- 2-oxoethyl) -N-methylcarbamic acid,
@ ® 22
N-methylamide of 4-[3-({1-[bis(4-chlorophenyl)- methyl]azetidin-3-ylidene} (methanesulfonyl)methyl)- phenyl]piperazine-l-carbothioic acid,
N-methylamide of 4-[3-({1-[bis(4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl)phenyl]- piperazine-l-carboxylic acid, methyl ester of 4-[3-({1-[bis(4-chlorophenyl)methyl] - azetidin-3-ylidene} (methanesulfonyl)methyl)- phenyl]piperazine-l-carboxylic acid, 1-[3-({1l-[bis(4-chlorophenyl)methyllazetidin-3- ylidene} (methanesulfonyl)methyl) phenyl] -4- isobutylpiperazine, 1-[3-({1-(bis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) phenyl] -4- ethylpiperazine, 4-acetyl-1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin- 3-ylidene} (methanesulfonyl)methyl)phenyl]piperazine, 1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)phenyl]piperazin-l-yl}- 2-dimethylaminoethanone, 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) phenyl] piperazine, tert-butyl ester of 4-[3-({1- [bis (4—chlorophenyl)- methyllazetidin-3-ylidene} (methanesulfonyl)methyl)- phenyl]lpiperazine-l-carboxylic acid, 1- [bis (4-methoxycarbonylphenyl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylenelazetidine, 3-acetoxy-1-[bis (4-methoxycarbonylphenyl)methyl]-3- [ (RS) -(3,5-difluorophenyl) (methylsulfonyl)methyl]- azetidine, (RS) -4-[4-( (4-chlorophenyl) {3-[(3,5- difluorophenyl) (methanesulfonyl)methylenejazetidin-1- yl}methyl)benzyl]morpholine, 4-(4-{3-[(l-benzhydrylazetidin-3-ylidene) (methane- sulfonyl)methyl]phenoxy}lbutyl)morpholine,
@ ® 23 4-(4-{3-[(l-benzhydrylazetidin-3-ylidene) (methane- sulfonyl)methyl]phenoxy}propyl)morpholine,
N-{1- [bis (4-chlorophenyl)methyl]azetidin-3-yl}thien- 2-ylsulfonamide,
N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 4-methoxyphenylsulfonamide,
N-[4- (N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- sulfamoyl)phenyl] acetamide,
N-{1- [bis (4-chlorophenyl)methyl]azetidin-3-yl}- 4-methylphenylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 3, 4-dimethoxyphenylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 3-fluorophenylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- 3, 4-dichlorophenylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- 3-cyanophenylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- 2,5-dimethoxyphenylsulfonamide,
N-{1-[bis (4-chlorophenyl)methyl]lazetidin-3-yl}- 3-trifluoromethylphenylsulfonamide,
N-{1l-[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}- 1l-methyl-1H-imidazol-4-ylsulfonamide,
N-[4- (N-{1-[bis(4-chlorophenyl)methyl]azetidin- 3-yl}sulfamoyl)-2-chlorophenyl]acetamide,
N-{1-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}pyrid- 3-ylsulfonamide,
N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 4-fluorophenylsulfonamide,
® o 24
N-{1l-[bis (4-chlorophenyl)methyl]azetidin-3-yl}quinol- 8-ylsulfonamide,
N-{1l-[bis (4-chlorophenyl)methyl]azetidin~ 3-yl}phenylsulfonamide,
N-{1l-[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- 2-ylsulfonamide,
N-{1l-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- (3-fluoro-5-pyrrolidin-1l-ylphenyl) sulfonamide,
N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}-
N-methyl-4-fluorophenylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyllazetidin-3-yl}-
N-methylquinol-8-ylsulfonamide,
N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-
N-methylphenylsulfonamide,
N-{1- [bis (4-chlorophenyl)methyllazetidin-3-yl}-
N-methyl (phenylmethyl) sulfonamide,
N-{1-[bis (4-chlorophenyl)methyl]azetidin=-3-yl}- 3-sulfamoylphenylsulfonamide, 2-benzenesulfonyl-N-{1-[bis(4-chlorophenyl)methyl]- azetidin-3-yl}acetamide,
N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 2- (4-toluene-4-sulfonyl)acetamide, (3-chloro-4- (methylsulfonyl)thiophene-2-carboxy) - {1- [bis (4-chlorophenyl)methyllazetidin-3-yl]lamide,
N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- 3-(2-phenylethylenesulfonyl)propionamide,
N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- 4- (methylsulfonyl)benzamide,
N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- 4- (methanesulfonyl)benzamide, (5-(methylsulfonyl)thiophene-2-carboxy) - {1- [bis (4-chlorophenyl)methyllazetidin-3-yl}amide,
® ® . 20 (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]- azetidin-3-yl}-3,5-difluorobenzenesulfonamide,
N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-
N- (6-chloropyrid-2-yl)methylsulfonamide,
N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N- (6-ethylpyrid-2-yl)methylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N- (quinol-6-yl)methylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N-(guinol-5-yl)methylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]jazetidin-3-yl}-
N- (isoguinol-5-yl)methylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N- (pyrid-3-yl)methylsulfonamide,
N-{l-[bis(4-chlorophenyl)methyljazetidin-3-yl}-
N- (pyrid-1-oxide-3-yl)methylsulfonamide,
N- (1R, 2S, 4S) -(bicyclo[2.2.1]hept-2-yl) -N-{1-[bis- (4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonamide,
N- (1R, 2R, 4S) - (bicyclo[2.2.1]hept-2-yl) -N-{1-[bis~- (4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}-
N- (3, 5-difluorophenyl)methylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N-(thiazol-2-yl)methylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N- (3-methoxyphenyl)methylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N- (3-hydroxyphenyl)methylsulfonamide,
N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-
N-(3-(hydroxymethyl)phenyl)methylsulfonamide,
® 26 ethyl N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N- (methylsulfonyl)-3-aminobenzoate,
N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-
N- (isobutylpiperid-4-yl)methylsulfonamide,
N-benzyl-N-{1l-[bis(4-chlorophenyl)methyl]azetidin=- 3-ylltamine,
N-{1l-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-
N- (3, 5-difluorobenzyl) amine,
N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N-(3,5-difluorobenzyl)methylsulfonamide,
N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-
N- (pyrid-3-ylmethyl)methylsulfonamide,
N-{1-[bis (4-fluorophenyl)methyl]lazetidin-3-yl}-
N- (3, 5-difluorophenyl)methylsulfonamide, (RS) -N-{1-[ (4-chlorophenyl) (pyrid-3-yl)methyl}azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (R) -N-{1-[ (4-chlorophenyl) (pyrid=-3-yl)methyl]azetidin- 3-y1l}-N-(3,5-difluorophenyl)methylsulfonamide, (S)-N-{1-[ (4-chlorophenyl) (pyrid-3-yl)methyl]azetidin- 3-y1l}-N-(3,5-difluorophenyl)methylsulfonamide, (RS) -N-{1-[ (4-chlorophenyl) (pyrid-4-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (R)-N-{1-[ (4-chlorophenyl) (pyrid-4-yl)methyl]azetidin- 3-y1l}-N-(3,5-difluorophenyl)methylsulfonamide, (S) -N-{1-[ (4-chlorophenyl) (pyrid-4-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (RS) -N-{1-[ (4-chlorophenyl) (pyrimidin-5-yl)methyl}- azetidin-3-y1l}-N- (3, 5-difluorophenyl)methylsulfonamide, (R) -N-{1-[ (4-chlorophenyl) (pyrimidin-5-yl)methyl]- azetidin-3-yl}-N-(3, 5-difluorophenyl)methylsulfonamide, (S)-N-{1-[ (4-chlorophenyl) (pyrimidin-5-yl)methyl]- azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyllazetidin-3-yl}-N-(3,5- difluorophenyl)benzylsulfonamide, their optical isomers and their pharmaceutically acceptable salts with an inorganic or organic acid. :
® o
And even more particularly preferred are the following azetidine derivatives: 1- [bis (4-chlorophenyl)methyl]-3-[(RS)-(3,5-difluoro- phenyl) (methylsulfonyl)methyljazetidin-3-ol, 3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(RS)- (3,5-difluorophenyl) (methylulphonyl)methyl)methylsulfon ylmethyllazetidine, 1- [bis (4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylenelazetidine, their optical isomers and their pharmaceutically acceptable salts with an inorganic or organic acid.
Mention may be made, as examples of pharmaceutically acceptable salts of the azetidine derivatives, of the following salts: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylenebis-P-oxynaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllinacetate and p- toluenesulfonate.
Other CB1 [lacuna] antagonists of use in the combinations according to the invention are, for example, the pyrazole derivatives disclosed in
EP 576 357, EP 658 546, EP 656 354, WO 97/19063 and
WO 00/46209, the benzothiophene and benzofuran derivatives disclosed in WO 96/02248 or the arylsulfonamides disclosed in WO 98/37061. Mention may in particular be made of the products known under the code SR141716 and LY320135.
The synergistic effect of the combination of sibutramine and of a CB1 [lacuna] antagonist on food intake was determined according to the following protocol:
Obese Fa/fa Zucker rats aged 7 weeks and originating from Iffa-Credo, France, were used in this study. The rats are housed in individual cages and
® weighed every day between 8 and 10 o’clock in the morning. The amount of food is also weighed each morning at the same time. This food (M20, Pietrement,
France) is changed every day and the rats have free access thereto for 24 hours. All the rats are treated for a week with the vehicle (miglyol 812N and 0.5% methylcellulose/0.2% polysorbate 80) in two consecutive administrations. The rats are treated from the 8th day with the vehicle, the CBl [lacuna] antagonist (1- [bis (4-chlorophenyl)methyl]-3-[(3, 5-difluorophenyl) - (methylsulfonyl)methylene]azetidine) or sibutramine by the oral route (see table below).
The sibutramine is dissolved in a 0.5% methylcellulose/0.2% polysorbate 80 solution and administered at a dose of 3 mg/kg; the CBl [lacuna] antagonist is dissolved in miglyol 812N (Hiils, Germany) at a dose of 0.6 mg/kg and the two products are administered under a volume of 1 ml/kg. Each group is composed of 12 to 14 animals. The following groups are formed and the animals are treated for five days at the rate of two consecutive administrations every day.
Ie [ee administration administration “vehicle group” 0.2% polysorbate 2 miglyol sibutramine 3 mg/kg “sibutramine group” 3 CBl1 [lacuna] 0.5% methylcellulose/ “CB1 [lacuna] antagonist 0.2% polysorbate antagonist 0.6 mg/kg group” 4 CB1 [lacuna] sibutramine 3 mg/kg “combination antagonist group” 0.6 mg/kg
® ® 29
The food consumption of each animal is measured every day. The results are expressed as mean amount of food consumed during the 5 days of treatment.
The results obtained are given in the table below. 5 days of treatment (g) 0.6 mg/kg sibutramine (3 mg/kg) + 22.76 £ 0.02***
CBl1 [lacuna] antagonist (0.6 mg/kq) *p<0.05 **p<0,01 ***p<0.0001
The results show that, in the animals receiving the sibutramine and CB1l [lacuna] antagonist combination, the reduction in food consumption is much greater has that of the animals treated either with sibutramine alone or with the CB1l [lacuna] antagonist alone.
The compounds of the combination can be employed orally, parenterally, transdermally or rectally, either simultaneously or separately or spread out over time.
The present invention also relates to the pharmaceutical compositions comprising the combination of sibutramine, its hydrate or one of its pharmaceutically acceptable salts and of a CBl receptor antagonist in the pure state or with one or more compatible and pharmacologically acceptable diluents and/or adjuvants and/or optionally in combination with another pharmaceutically compatible and physiologically
_ @® active product for a use which is either simultaneous or separate or spread out over time.
Use may be made, as solid compositions for oral administration, of tablets, pills, powders (hard gelatin capsules, cachets) or granules. In these compositions, the active principles are mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream.
These compositions can also comprise substances other than the diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragées) or a glaze.
Use may be made, as liquid compositions for oral administration, of pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs comprising inert diluents, such as water, ethanol, glycerol, vegetable oils or liquid paraffin. These compositions can comprise substances other than the diluents, for example wetting, sweetening, thickening, flavouring or stabilizing products.
The sterile compositions for parenteral administration can preferably be solutions in aqueous or nonaqueous form, suspensions or emulsions. Use may be made, as solvent or vehicle, of water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate, or other suitable organic solvents. These compositions can also comprise adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents.
Sterilization can be carried out in several ways, for example by aseptic filtration, by incorporating sterilizing agents in the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at
® the time of use in sterile water or any other injectable sterile medium.
The compositions for rectal administration are suppositories or rectal capsules which comprise, in addition to the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
The pharmaceutical compositions generally comprise 0.5 to 10 mg of sibutramine and 0.1 to 200 mg of the CB1l [lacuna] antagonist.
The present invention also relates to the method for the treatment of obesity which consists in administering, to the patient, a combination according to the invention either simultaneously or separately or spread out over time.
The doses depend on the desired effect, on the duration of treatment and on the administration route used; they are generally from 1 to 15 mg of sibutramine per day by the oral route for an adult and from 0.10 to 500 mg of the CBl [lacuna] antagonist per day by the oral route for an adult.
Generally, the doctor will determine the appropriate dosage according to the age, weight and any other factor specific to the subject to be treated.

Claims (12)

1. A combination of a CBl [lacuna] antagonist and of sibutramine, its hydrate or one of its pharmaceutically acceptable salts.
2. The combination as claimed in claim 1, for which the CB1 [lacuna] antagonist is a compound of formula: R, + ] 0) R in which either R represents a chain (A) or (B) and R SOR, 7 SOR, C=CH{ or C—O R R A) ® (8) ? R: represents a methyl or ethyl radical, R, represents either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, -CO-alk, hydroxyl, -COORs, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NRgR;, —CO-NH-NR¢R7, -N(alk)COORg, cyano, -CONHRg, -CO-NRy¢R17, alkylsulfanyl, hydroxyalkyl, -0O-alk-NRjz;Ri3 or alkylthioalkyl, or a heteroaromatic chosen from the benzofuryl,
® ® benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, indolinyl, indolyl, isochromanyl, isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl,
1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted by a halogen, alkyl, alkoxy, -COORs, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro,
-NRgR;, -CO-NH-NRg¢R;, cyano, -CONHRg, alkylsulfanyl, hydroxyalkyl or alkylthioalkyl, R; and Rs, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COORs, —-CONRioRi11, -CO-NH-NRgR7, alkylsulfanyl, hydroxyalkyl, -alk-NRgR7 or alkylthioalkyl, or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2, 3-dihydrobenzo- thienyl, furyl, isochromanyl, isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl or thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted by a halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COORs, -CO-NH-NRgR7, —CONR:igRi1, -alk-NRgR7, alkylsulfanyl, hydroxyalkyl or alkylthioalkyl,
Rs is an alkyl radical or a phenyl radical optionally substituted by one or more halogen atoms,
Rg and Ry, which are identical or different, represent a hydrogen atom or an alkyl, -CO0alk, cycloalkyl,
® ® 34 alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or else Rg and R; form, together with the nitrogen atom to which they are attached, a saturated or unsaturated and mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NRj4R;s5, oxo, hydroxyalkyl, -alk-0-alk or -CO-NH; radicals,
Rg represents an alkyl radical,
Ry represents a hydrogen atom or a radical of the type alkyl or alkyl substituted by dialkylamino, phenyl,
cycloalkyl (optionally substituted by -COOalk) or a saturated or unsaturated and mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising one or more heteroatoms chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl radicals,
R;; and Rji;, which are identical or different, represent a hydrogen atom or an alkyl radical or else Rj and Rui form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by an alkyl radical,
Ry, and Ris, which are identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical or else Rj, and Ris form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen,
® ® 35 sulfur and nitrogen and optionally being substituted by an alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk or -CO- alk-NR;4R;s radical or a saturated mono- or bicyclic heterocycle having 3 to 10 ring members and comprising a heteroatom chosen from oxygen, sulfur and nitrogen, Ris and R;5, which are identical or different, represent a hydrogen atom or an alkyl or -COOalk radical,
Rj; and Ri; form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen,
R’ represents a hydrogen atom or a -CO-alk radical, or R represents a CHRjg radical and
R;g represents an -NHCOR;g or -N(Rzp)-Y-Rz; radical,
Y is CO or SO, Rs; and R3, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR:2R:3,
-CO-NH-NRy4Rps, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NHzzR2;3, or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,
2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl,
® ® 36 isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4- tetrahydroisoquinolyl, thiazolyl and thienyl rings, it being possible for these hetercaromatics to be unsubstituted or substituted by a halogen, alkyl,
alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NRj4Rzs, —CONRz2Rz3, —alk- NRog4Rz5, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl,
Rig represents an -alk-SO,-Ry¢ radical, an -alk-SO,- CH=CH-R,s radical, a Het; radical substituted by -S0;-Rzs or a phenyl radical substituted by -S0;-Rz¢ or —-alk-SO.- Rae,
Ryo represents a hydrogen atom or an alkyl radical,
R,; represents a phenylalkyl, Het; or Ar; radical,
Ry, and Ry3, which are identical or different, represent a hydrogen atom or an alkyl radical or else Rg; and Ry; form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl,
Ry; and Rys, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or else Ry, and Rys form, together with the nitrogen atom to which they are attached, a saturated or unsaturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being
® ® 37 substituted by one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH;, Rye represents an alkyl, Ar, or Het; radical, Ar; represents a phenyl, naphthyl or indenyl radical, these radicals optionally being substituted by one or more halogen, alkyl, alkoxy, cyano, -CO-alk, -COCH,
-COOalk, -CONRj7Rg, -CO-NH-NRy9R3p, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NRzsR3o, -NR29Rs3o, alkylthioalkyl, formyl, hydroxyl, hydroxyalkyl, Het, -O-alk-NH-cycloalkyl, OCF3, CF3, -NH-CO-alk, -SO;NHz, -NH-COCH;, -NH-COOalk or Het or else on 2 adjacent carbon atoms by dioxymethylene,
Het; represents an unsaturated or saturated mono- or bicyclic heterocycle having 3 to 10 ring members and comprising one or more heteroatoms chosen from oxygen,
sulfur and nitrogen which is optionally substituted by one or more alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxyl, OCF; or CF3, the nitrogenous heterocycles optionally being in their N- oxidized form,
R,; and Rpg, which are identical or different, represent a hydrogen atom or an alkyl radical or else Ry and Rg form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl radicals,
Rpg and R3p, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl,
® ® 38 alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or else Rpg and R3p form, together with the nitrogen atom to which they are attached, a saturated or unsaturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH, radicals,
or R represents CHR3; and R31 represents an —-N(Rs2)Rs3, —N(R32)-CO-R33 or -N (R32) -=SO,R34 radical,
R; and Rj, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy,
formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, COOalk, -CONRgzzRz3, —-CO-NH-NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR;Rg, or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3,4-tetra-
hydroisoquinolyl, thiazolyl and thienyl rings, it being possible for these heterocaromatics to be unsubstituted or substituted by a halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NRy3Rzs5, —CONR2zR23, —alk-NRa4R:zs,
alkylsulfanyl, alkylsulfinyl, alkylsulfonyl,
alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, Rs, represents a —-C(Rss) (Rig) “Hetz, -Hetz, -C(Rss) (Rig) -Ary, Ar,, cycloalkyl or norbornyl radical, R33 represents a hydrogen atom or a hydroxyalkyl, -alk-C0O0Oalk, -alk-CONR22R23, -alk-NR32Rz23, alkoxy, Ar,, Het,, -CH,Ar,, -CH,Het, or alkyl radical, the latter optionally substituted by one or more halogen, R;; represents a hydroxyalkyl, -alk-COOalk, -alk-CONR22R23, -alk-NRssRo3, alkoxy, Ar,, Het,, -CH,Ar,, -CH,Het, or alkyl radical, the latter optionally substituted by one or more halogen, Ri; represents a hydrogen atom or a hydroxyalkyl, -—alk-CO0Oalk, -alk-CONR,,Rz3, —-alk-NRz;Rz3, alkoxyalkyl, Ar,, Het,, -CHyAr,, -CHyHet; or alkyl radical, the latter optionally substituted by one or more halogen, Ris represents a hydrogen atom or a hydroxyalkyl, -alk-CO0Oalk, -alk-CONR2zR23, -alk—-NRy2Rz3, alkoxyalkyl or alkyl radical, the latter optionally substituted by one or more halogen, or else Rj; and Rs¢ form, together with the carbon atom to which they are attached, a saturated mono- or bicyclic ring having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl, Ar, represents a phenyl, naphthyl or indenyl radical, these various radicals optionally being substituted by one or more halogen, alkyl, alkoxy, -CO-alk, cyano,
® 40 -COOH, -COOalk, —-CONR37R3g, —-CO-NH-R3sR40, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR3gRz0, -NR3gRso, alkylthioalkyl, formyl, CF3, OCF3, Het, -O-alk-NH- cycloalkyl, SO,NH,, hydroxyl, hydroxyalkyl, -NHCOalk or
NHCOOalk or on 2 adjacent carbon atoms by dioxymethylene,
Het, represents an unsaturated or saturated mono- or bicyclic heterocycle having 3 to 10 ring members and comprising one or more heteroatoms chosen from oxygen, sulfur and nitrogen which is optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo or hydroxyl, the nitrogenous heterocycles optionally being in their N-oxidized form,
R37; and Rig, which are identical or different, represent a hydrogen atom or an alkyl radical or else Rs; and Rsg form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl,
R39 and Ryo, which are identical or different, represent a hydrogen atom or an alkyl radical or else Ris and Ryo form, together with the nitrogen atom to which they are attached, a saturated mono- or bicyclic heterocycle having 3 to 10 ring members optionally comprising another heteroatom chosen from oxygen, sulfur and nitrogen and optionally being substituted by one or more alkyl, alk represents an alkyl or alkylene radical,
® ® 41 the alkyl and alkylene radicals and portions and the alkoxy radicals and portions have straight or branched chains and comprise 1 to 6 carbon atoms and the cycloalkyl radicals comprise 3 to 10 carbon atoms, the optical isomers of these compounds and their pharmaceutically acceptable salts with an inorganic or organic acid.
3. The combination as claimed in claim 2, for which the compound of formula (I) is chosen from the following compounds: 1-benzhydryl-3-[ (methylsulfonyl) (phenyl) - methylenelazetidine, l-benzhydryl-3-[ (3-methylphenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[ (3-chlorophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[(3,5-dichlorophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[(2,5-dichlorophenyl) (methylsulfonyl)- methylenelazetidine, l-benzhydryl-3-[(2,3-dichlorophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[ (3-fluorophenyl) (methylsulfonyl) - methylenelazetidine, 1-benzhydryl-3-[ (3,5-difluorophenyl) (methylsulfonyl)- methylenelazetidine, 1-benzhydryl-3-[ (3-bromophenyl) (methylsulfonyl) - methylene]azetidine, 1l-benzhydryl-3-[ (3-iodophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[ (methylsulfonyl) (3-trifluoro- methoxyphenyl)methylene]azetidine, l-benzhydryl-3-[ (methylsulfonyl) (3-trifluoro- methylphenyl)methylenelazetidine,
® ® 42 1-benzhydryl-3-{[3, 5-bis (trifluoromethyl) phenyl] - (methylsulfonyl)methylene}azetidine, l1-benzhydryl-3-[ (3, 5-dibromophenyl) (methylsulfonyl) - methylenelazetidine,
1-benzhydryl-3-[(3-methoxycarbonylphenyl)- (methylsulfonyl)methylene]azetidine, 1-benzhydryl-3-[ (3-cyanophenyl) (methylsulfonyl) - methylene] azetidine, 1-benzhydryl-3-[ (3-carbamoylphenyl) (methylsulfonyl) -
methylenelazetidine, 1-benzhydryl-3-[ (methylsulfonyl) (naphth-1-yl) (methyl- sulfonyl)methylene]azetidine,
1- [bis (4-chlorophenyl)methyl]-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine,
1- [bis (4-methoxyphenyl)methyl]-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine,
1- [bis (4-methylphenyl)methyl]-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, (RS) -3-[ (3,5-difluorophenyl) (methylsulfonyl)methylene]-
1-[ (4-methoxyphenyl) (phenyl)methyl)]azetidine,
(R)-3-[ (3, 5-difluorophenyl) (methylsulfonyl)methylene]- 1-[ (4-methoxyphenyl) (phenyl)methyllazetidine, (S)-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]- 1-[ (4-methoxyphenyl) (phenyl)methyl]azetidine,
1-[bis (4-trifluoromethoxyphenyl)methyl]-3-[(3,5-di~ fluorophenyl) (methylsulfonyl)methylene]azetidine, 1-[bis (4-trifluoromethylphenyl)methyl]-3-[(3,5-di- fluorophenyl) (methylsulfonyl)methylene]azetidine, 1-[bis (4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoro-
methyl)phenyl]methylsulfonylmethylene}azetidine,
(RS) -1-[ (4-chlorophenyl) (2, 4-dichlorophenyl)methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl)- methylene]azetidine,
(R)-1-[ (4-chlorophenyl) (2, 4-dichlorophenyl)methyl]-3-
[(3,5-difluorophenyl) (methylsulfonyl)- methylene]azetidine,
® ® 43
(S)-1-[ (4-chlorophenyl) (2, 4-dichlorophenyl)methyl]-3- [ (3,5-difluorophenyl) (methylsulfonyl)- methylene]azetidine, (RS)-1-{ (4-chlorophenyl) [4-
(hydroxymethyl) phenyl]methyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine, (R)-1-{ (4-chlorophenyl) [4- (hydroxymethyl) phenyllmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine,
(S)-1-{(4-chlorophenyl) [4- (hydroxymethyl) phenyl]lmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine, (RS)-1-{ (4-chlorophenyl) [4- (pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluoro-
phenyl) (methylsulfonyl)methylene]azetidine, (R)-1-{ (4-chlorophenyl) [4- (pyrrolidylmethyl)phenyl]lmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine, (S)-1-{ (4-chlorophenyl) [4-
(pyrrolidylmethyl)phenyllmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, 1-{ (RS) - (4-chlorophenyl) [4- (3, 3-dimethylpiperidin-1- ylmethyl)phenyl]methyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine,
1-{(R)=-(4-chlorophenyl) [4-(3,3-dimethylpiperidin-1- ylmethyl)phenyllmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, 1-{ (S)-(4-chlorophenyl) [4- (3, 3-dimethylpiperidin-1- ylmethyl)phenyl]lmethyl}-3-[(3,5-difluoro-
phenyl) (methylsulfonyl)methylenelazetidine, 1-{ (RS) -(4-chlorophenyl) [4- (thiomorpholin-4- ylmethyl)phenyllmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, 1-{ (R)-(4-chlorophenyl) [4- (thiomorpholin-4-
ylmethyl)phenyllmethyl}-3-[(3,5~-difluoro- phenyl) (methylsulfonyl)methylenelazetidine,
®
1-{(S)-(4-chlorophenyl) [4- (thiomorpholin-4- ylmthyl) phenyl]lmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, 1-{ (RS) -(4-chlorophenyl) [4- (N-ethyl-N-
cyclohexylaminomethyl)phenyl]lmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{ (R)-(4-chlorophenyl) [4- (N-ethyl-N- cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl) [4- (N-ethyl-N- cyclohexylaminomethyl)phenyl]lmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{{ (RS) - (4-chlorophenyl) {4-[ (4-ethoxycarbonyl- piperazinyl)methyl]phenyl}methyl}}-3-[(3,5-
difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{{ (R)- (4-chlorophenyl) {4-[ (4-ethoxycarbonyl- piperazinyl)methyllphenyl}methyl}}=-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{{(S)-(4-chlorophenyl) {4-[ (4-ethoxycarbonyl-
piperazinyl)methyl]phenyl}methyl}}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{ (RS) - (4-chlorophenyl) [4- (N-cyclopropyl-N- propylaminomethyl)phenyl]lmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl) [4- (N-cyclopropyl-N- propylaminomethyl)phenyl]lmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{(S)=-(4-chlorophenyl) [4- (N-cyclopropyl-N- propylaminomethyl)phenyl]methyl}-3-[(3,5-
difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{ (RS) - (4-chlorophenyl) [4- (diisopropylamino- methyl) phenyl]lmethyl}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylenelazetidine, 1-{(R)-(4-chlorophenyl) [4- (diisopropylaminomethyl)-
phenyllmethyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine,
® ® 45
1-{ (S)-(4-chlorophenyl) [4- (diisopropylaminomethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl)- methylene]azetidine, 1-{{ (RS) -(4-chlorophenyl) {4- [bis (2-methoxyethyl) -
aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylene]azetidine, 1-{{ (R)-(4-chlorophenyl) {4- [bis (2-methoxyethyl) - aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylene]azetidine,
1-{{(S)-(4-chlorophenyl) {4-[bis (2-methoxyethyl)- aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylene]lazetidine,
1-{ (RS) -(4-chlorophenyl) [4-[di-n- propylaminomethyl)phenyl]methyl}-3-[(3,5-difluoro-
phenyl) (methylsulfonyl)methylene]lazetidine,
1-{ (R)- (4-chlorophenyl) [4- (di-n-propylaminomethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methylsulfonyl)- methylenelazetidine,
1-{ (S)-(4-chlorophenyl) [4- (di-n-propylaminomethyl) -
phenyl]lmethyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine,
1-{ (RS) - (4-chlorophenyl) [4- (piperidin-1-ylmethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine,
1-{ (R) - (4-chlorophenyl) [4-(piperidin-1-ylmethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine,
1-{ (S)-(4-chlorophenyl) [4- (piperidin-1-ylmethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl-
sulfonyl)methylenelazetidine,
1-{ (RS) - (4-chlorophenyl) [4- (4-methylpiperazin-1- ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl) [4- (4-methylpiperazin-1-
ylmethyl)phenyl]lmethyl}-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine,
® ® 46
1-{ (S)-(4-chlorophenyl) [4- (4-methylpiperazin-1- ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl) ~ (methylsulfonyl)methylene]lazetidine, 1-{ (RS) - (4-chlorophenyl) [4- (morpholin-4-
ylmethyl)phenyllmethyl}-3-[(3,5~difluorophenyl)- (methylsulfonyl)methylenelazetidine, 1-{ (R)-(4-chlorophenyl) [4- (morpholin-4-ylmethyl) - phenyl]lmethyl}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylenelazetidine,
1-{(S)-(4-chlorophenyl) [4- (morpholin-4-ylmethyl)- phenyllmethyl}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylenelazetidine,
1-{ (RS) -(4-chlorophenyl) [4- (diethylaminomethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl-
sulfonyl)methylene]azetidine,
1-{ (R) -(4-chlorophenyl) [4- (diethylaminomethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl-
sulfonyl)methylenelazetidine,
1-{(S)- (4-chlorophenyl) [4-(diethylaminomethyl) -
phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine,
1-{ (RS) - (4-chlorophenyl) [4- (piperazin-2-one-4- ylmethyl)phenyllmethyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine,
1-{ (R) - (4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) - phenyl]lmethyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine,
1-{ (S)-(4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl-
sulfonyl)methylenelazetidine,
1-{ (RS) -(4-chlorophenyl) [4-(imidazol-1-ylmethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine,
1-{ (R) = (4-chlorophenyl) [4- (imidazol-1-ylmethyl) -
phenyl]lmethyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine,
® ® 47 1-{(S)-(4-chlorophenyl) [4- (imidazol-1-ylmethyl) - phenyl]lmethyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine, (RS)-1-{(4-chlorophenyl) [4- (N,N-
dimethylcarbamoyl)phenyl]lmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, (R)-1-{ (4-chlorophenyl) [4-(N,N- dimethylcarbamoyl)phenyl]lmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine,
(S)-1-{(4-chlorophenyl) [4-(N,N- dimethylcarbamoyl)phenyl]lmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]lazetidine, (RS)-1-{ (4-chlorophenyl) [4- (N- ethylcarbamoyl)phenyl]methyl) }-3-[(3,5-
difluorophenyl) (methylsulfonyl)methylene]azetidine, (R)-1-{ (4-chlorophenyl) [4- (N- ethylcarbamoyl)phenyl]lmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, (S)-1-{ (4-chlorophenyl) [4-(N-
ethylcarbamoyl)phenyllmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylenelazetidine, (RS) -1-[ (4-carbamoylphenyl) (4-chlorophenyl)methyl]-3- [ (3, 5-difluorophenyl) (methylsulfonyl)methylene]- azetidine,
(R) -1-[ (4-carbamoylphenyl) (4-chlorophenyl)methyl]-3- [(3,5-difluorophenyl) (methylsulfonyl)methylene]- azetidine,
(S)-1-[ (4-carbamoylphenyl) (4-chlorophenyl)methyl]-3- [(3,5-difluorophenyl) (methylsulfonyl)methylene]-
azetidine,
1- [bis (4-chlorophenyl)methyl]-3-[(3,5-dichloro- phenyl) (methylsulfonyl)methylene]azetidine, 1-benzhydryl-3-[ (3-methylsulfanylphenyl) (methyl- sulfonyl)methylene]azetidine,
1-benzhydryl-3-[ (3-methylsulfanylmethyl)phenyl)]- (methylsulfonyl)methylene]azetidine,
® 48 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-[ (methylsulfonyl) (3-
pyrrolidinylphenyl)methylenelazetidine,
1- [bis (4-chlorophenyl)methyl]-3-[ (3-hydroxy- methylphenyl) (methylsulfonyl)methylene]azetidine,
1- [bis (4-chlorophenyl)methyl]-3—-{ (methylsulfonyl) [3-(N- piperidylcarbamoyl)phenyl]lmethylene}azetidine,
1- [bis (4-chlorophenyl)methyl]-3-[ (methylsulfonyl) (3- trifluoromethylsulfanylphenyl) (methylsulfonyl)- methylenelazetidine,
1- [bis (4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylenelazetidine,
1- [bis (2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)-
(methylsulfonyl)methylene]azetidine, 1- [bis (3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine, (RS) -1-[ (4-chlorophenyl) (thiazol-2-yl)methyl]-3- [(methylsulfonyl) (phenyl)methylene]azetidine, (R)-1-[ (4-chlorophenyl) (thiazol-2-yl)methyl]-3- [ (methylsulfonyl) (phenyl)methylene]azetidine, (S)-1-[ (4-chlorophenyl) (thiazol-2-yl)methyl]-3- [ (methylsulfonyl) (phenyl)methylene]azetidine,
(RS) -1-[ (4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5~ difluorophenyl) (methylsulfonyl)methylene]azetidine, (R)-1-[ (4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylenelazetidine, (8)-1-[ (4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5-
difluorophenyl) (methylsulfonyl)methylene]azetidine,
_ ® 49 1-benzhydryl-3-[ (ethylsulfonyl) (phenyl)methylene]- azetidine, 1-[bis(4-chlorophenyl)methyl]-3-{{3-[N-(4- methylpiperazinyl)carbamoyl]phenyl} (methylsulfonyl)-
methylene}azetidine,
1- [bis (4-chlorophenyl)methyl]-3-{[3-(2,2- dimethylcarbohydrazido) phenyl] (methylsulfonyl)- methylenelazetidine, 1-[bis(thien-2-yl)methyl]-3-[ (3, 5-difluorophenyl)-
(methylsulfonyl)methylene]azetidine,
1- [bis (p-tolyl)methyl]-3-[ (methylsulfonyl)- (phenyl)methylenelazetidine,
1-[ (4-chlorophenyl) (4-hydroxymethylphenyl)methyl]-3- [ (3,5-difluorophenyl) (methylsulfonyl)methylene]-
azetidine, 1-[bis (4-chlorophenyl)methyl]-3~[(3-methylaminophenyl) - (methylsulfonyl)methylene]azetidine,
(RS) -1-[ (4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine,
(R)-1-[ (4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5~ difluorophenyl) (methylsulfonyl)methylene]azetidine, (8)-1-[ (4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-[bis (4-chlorophenyl)methyl]-3-[(methylsulfonyl) (2-
methoxycarbonylthien-5-yl)methylene]azetidine,
(RS) -1-[bis (4-chlorophenyl)methyl]-3-hydroxy-3-
[ (methylsulfonyl) (2-methoxycarbonylthien-5- yl)methyllazetidine,
1- [bis (4-chlorophenyl)methyl]-3-[(2~-isobutylamino-
carbonylthien-5-yl) (methylsulfonyl)methylene]azetidine, 1- [bis (4-chlorophenyl)methyl]-3-[(RS)- (3-methoxy- carbonylphenyl) (methylsulfonyl)methyl]azetidin-3-ol, 1- [bis (4-chlorophenyl)methyl]-3-[(RS)- (methyl- sulfonyl) (pyridin-4-yl)methyl]azetidin-3-ol,
1-[bis(4-chlorophenyl)methyl]-3-[(RS)- (methylsulfonyl) (pyridin-3-yl)methyl]azetidin-3-ol,
® ® 50 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-
vylidene} (methanesulfonyl)methyl) -N-(3- dimethylaminopropyl)benzamide, 3-({1l-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-(2-(pyrrolidin-1- yl)ethyl)benzamide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-(2-dimethylamino-1- methylethyl)benzamide, 3-({1l-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(piperidin-1-
vyl)benzamide,
3-({1- [bis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-isobutylbenzamide, 3-({1-[bis (4-chlorophenyl)methyll]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-(3-(imidazol-1-
vyl)propyl)benzamide, 3-({1l-[bis(4-chlorophenyl)methyllazetidin-3- ylidene} (methanesulfonyl)methyl) -N-(2- dimethylaminoethyl)benzamide,
N’ -methylhydrazide of 3-({1-[bis(4-chlorophenyl)-
methyllazetidin-3-ylidene} (methanesulfonyl)- methyl) benzoic acid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-(2-(morpholin-4- yl) ethyl) benzamide,
3-({1l-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(l-ethylpyrrolidin- 2-ylmethyl)benzamide, 3-({1-[bis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(2,2-
dimethylpropyl)benzamide,
® ® 51 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) ~-N- (cyclohexylmethyl)benzamide, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-
vylidene} (methanesulfonyl)methyl) -N- (cyclopropylmethyl)benzamide, 3-({1l-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N- (2- methylbutyl)benzamide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N- (2- phenylpropyl)benzamide, 3-({1l-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-(tetrahydrofuran-2-
ylmethyl)benzamide, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(2, 2- diphenylethyl)benzamide, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-
ylidene} (methanesulfonyl)methyl) -N-(2- ethylbutyl)benzamide, methyl ester of 4-{[3-({1l-[bis(4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl) - benzoylamino]methyl}cyclohexanecarboxylic acid,
2-amino-1-{4-[3-({1-[bis(4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl)phenyl]- piperazin-1-yl}ethanone, tert-butyl ester of (2-{4-[3-({1l-[bis(4-chlorophenyl)- methyl]azetidin-3-ylidene} (methanesulfonyl)methyl)-
phenyllpiperazin-1l-yl}-2-oxoethyl)carbamic acid, 1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)phenyllpiperazin-1-yl}- 2- (methylamino)ethanone, tert-butyl ester of (2-{4-[3-({1-[bis(4-
chlorophenyl)methyl]azetidin-3-
® 52 ylidene} (methanesulfonyl)methyl)phenyl]piperazin-1-yl}- 2-oxoethyl)-N-methylcarbamic acid, N-methylamide of 4-[3-({1-[bis(4-chlorophenyl)- methyl]azetidin-3-ylidene} (methanesulfonyl)methyl) -
phenyl]piperazine-l-carbothioic acid,
N-methylamide of 4-[3-({1-[bis(4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl)phenyl]- piperazine-l-carboxylic acid, methyl ester of 4-[3-({1l-[bis(4-chlorophenyl)methyl]-
azetidin-3-ylidene} (methanesulfonyl)methyl)- phenyl]piperazine-l-carboxylic acid, 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) phenyl] -4- isobutylpiperazine,
1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) phenyl] -4- ethylpiperazine, 4-acetyl-1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin- 3-ylidene} (methanesulfonyl)methyl)phenyl]piperazine,
1-{4-[3-({1-[bis(4-chlorophenyl)methyl]lazetidin-3- ylidene} (methanesulfonyl)methyl)phenyl]piperazin-1-yl}- 2-dimethylaminoethanone, 1-[3-({1-[bis(4-chlorophenyl)methyl ]azetidin-3- ylidene} (methanesulfonyl)methyl)phenyl]lpiperazine,
tert-butyl ester of 4-[3-({1l-[bis(4-chlorophenyl)- methyl]azetidin-3-ylidene} (methanesul fonyl)methyl)- phenyl]piperazine-l-carboxylic acid,
1- [bis (4-methoxycarbonylphenyl)methyl]-3-[ (3, 5- difluorophenyl) (methylsulfonyl)methylenelazetidine,
3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-
[ (RS) -(3,5-difluorophenyl) (methylsulfonyl)methyl]- azetidine, (RS)-4-[4-((4-chlorophenyl) {3-[(3,5- difluorophenyl) (methanesulfonyl)methylene]azetidin-1- vylimethyl)benzyl]morpholine,
® ® 53 4-(4-{3-[(1l-benzhydrylazetidin-3-ylidene) (methane- sulfonyl)methyl]phenoxylbutyl) morpholine, 4-(4-{3-[(l-benzhydrylazetidin-3-ylidene) (methane- sulfonyl)methyl]phenoxy}propyl) morpholine,
N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}thien- 2-ylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 4-methoxyphenylsulfonamide, N-[4-(N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
sulfamoyl)phenyl]acetamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 4-methylphenylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 3,4-dimethoxyphenylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- 3-fluorophenylsul fonamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 3,4-dichlorophenylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
'~ 3-cyanophenylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- 2,5-dimethoxyphenylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 3-trifluoromethylphenylsulfonamide,
N-{l-[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]lazetidin-3-yl}-
3,4-difluorophenylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- l-methyl-1H-imidazol-4-ylsulfonamide, N-[4-(N-{1l-[bis(4-chlorophenyl)methyl]azetidin~ 3-yl}sulfamoyl)-2-chlorophenyl]acetamide,
N-{l-[bis(4-chlorophenyl)methyllazetidin-3-yl}pyrid- 3-ylsulfonamide,
® 54 N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 4-fluorophenylsulfonamide, N-{1l-[bis (4-chlorophenyl)methyl]azetidin-3-yl}quinol- 8-ylsulfonamide,
N-{l-[bis(4-chlorophenyl)methyl]lazetidin- 3-yl}phenylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin- 3-yl} (phenylmethyl) sulfonamide, N-{1l-[bis(4-chlorophenyl)methyllazetidin-3-yl}-
3,5-difluorophenylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}pyrid- 2-ylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- (3-fluoro=-5-pyrrolidin-1-ylphenyl) sulfonamide,
N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N-methyl-4-fluorophenylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- N-methylquinol-8-ylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}-
N-methylphenylsulfonamide,
N-{1l-[bis (4-chlorophenyl)methyl]lazetidin-3-yl}- N-methyl (phenylmethyl) sulfonamide,
N-{1l-[bis (4-chlorophenyl)methyllazetidin-3-yl}- 3-sulfamoylphenylsulfonamide,
2-benzenesulfonyl-N-{1l-[bis(4-chlorophenyl)methyl]- azetidin-3-yl}acetamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 2-(4-toluene-4-sulfonyl)acetamide,
(3-chloro-4- (methylsulfonyl)thiophene-2-carboxy) -
{1l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl]amide, N-{1-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- 3-(2-phenylethylenesulfonyl)propionamide, N-{1l-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-
4- (methylsulfonyl)benzamide,
N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
4- (methanesulfonyl)benzamide,
® 55 (5- (methylsulfonyl) thiophene-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-yllamide, (RS) -N-{1-[ (4-chlorophenyl) (pyridin-3-yl)methyl]- azetidin-3-yl}-3,5-difluorobenzenesulfonamide, (RS) -N-{1-[ (4-chlorophenyl) (pyrimidin-5-yl)methyl] - azetidin-3-yl}-3,5-difluorobenzenesulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N- (6-chloropyrid-2-yl)methylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N- (6-ethylpyrid-2-yl)methylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N-(gquinol-6-yl)methylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N- (quinol-5-yl)methylsulfonamide,
N-{1- [bis (4-chlorophenyl)methyl]azetidin-3-yl}- N-(isoquinol-5-yl)methylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N- (pyrid-3-yl)methylsulfonamide,
N-{1l- [bis (4-chlorophenyl)methyl]azetidin-3-yl}- N- (pyrid-l-oxide-3-yl)methylsulfonamide, N-(1R, 2S,4S)-(bicyclo[2.2.1]hept-2-yl)-N-{1-[bis-
(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonamide, N-(1R, 2R, 4S) - (bicyclo[2.2.1]hept-2-yl)-N-{1-[bis- (4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonamide, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- N-(3,5-difluorophenyl)methylsulfonamide,
N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N-(thiazol-2-yl)methylsulfonamide,
N-{1l- [bis (4-chlorophenyl)methyl]azetidin-3-yl}-
N- (3-methoxyphenyl)methylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyllazetidin-3-yl}- N-(3-hydroxyphenyl)methylsulfonamide,
® 56 ¥2003/3013
N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N- (3- (hydroxymethyl) phenyl)methylsulfonamide, ethyl N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N- (methylsulfonyl)-3-aminobenzoate,
N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N- (isobutylpiperid-4-yl)methylsulfonamide, N-benzyl-N-{1l-[bis(4-chlorophenyl)methyl]azetidin- 3-yl}amine, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N-(3,5-difluorobenzyl) amine, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N-(3,5-difluorobenzyl)methylsul fonamide, N-{1-[bis(4-chlorophenyl)methyl]jazetidin-3-yl}-
N- (pyrid-3-ylmethyl)methylsulfonamide,
N-{1l-[bis(4-fluorophenyl)methyllazetidin-3-yl}- N-(3,5-difluorophenyl)methylsulfonamide,
(RS)-N-{1-[ (4-chlorophenyl) (pyrid-3-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (R)-N-{1-[ (4-chlorophenyl) (pyrid-3-yl)methyl]azetidin-
3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (S)-N-{1-[ (4-chlorophenyl) (pyrid-3-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (RS)-N-{1-[ (4-chlorophenyl) (pyrid-4-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsul fonamide,
(R)-N-{1-[ (4-chlorophenyl) (pyrid-4-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (S)-N-{1-[ (4-chlorophenyl) (pyrid-4-yl)methyl]lazetidin- 3-yl}=N-(3,5-difluorophenyl)methylsul fonamide, (RS)-N-{1-[ (4-chlorophenyl) (pyrimidin-5-yl)methyl] -
azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (R)-N-{1-[ (4-chlorophenyl) (pyrimidin-5-yl)methyl]- azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (S)-N-{1-[ (4-chlorophenyl) (pyrimidin-5-yl)methyl]- azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3, 5- difluorophenyl)benzylsulfonamide,
® ® 57 their optical isomers and their pharmaceutically acceptable salts.
4, The combination as claimed in claim 2, for which the compound of formula (I) is chosen from the following compounds: 1-[bis(4-chlorophenyl)methyl]-3-[(RS)-(3,5- difluorophenyl) (methylsulfonyl)methyl]azetidin-3-ol, 3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(RS)-(3, 5- difluorophenyl) (methylulphonyl)methyl)methylsulfonyl- methylazetidine, 1-[bis(4-chlorophenyl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, their optical isomers and their pharmaceutically acceptable salts.
5. The combination as claimed in claim 1, in which the CB1 [lacuna] antagonist is SR141716, its hydrates and its pharmaceutically acceptable salts or LY320135 and its pharmaceutically acceptable salts.
6. A pharmaceutical composition comprising a CB1l [lacuna] antagonist and sibutramine, its hydrate or one of its pharmaceutically acceptable salts in the pure state or with one or more compatible and pharmacologically acceptable diluents and/or adjuvants and/or optionally in combination with another pharmaceutically compatible and physiologically active product.
7. The pharmaceutical composition as claimed in claim 6, for which the CBl [lacuna] antagonist [lacuna] of formula I as defined in claim 2.
8. The pharmaceutical composition as claimed in claim 7, for which the compound of formula (I) is chosen from the following compounds: l1-benzhydryl-3-[ (methylsulfonyl) (phenyl) - methylene] azetidine, 1-benzhydryl-3-[(3-methylphenyl) (methylsulfonyl)- methylene] azetidine,
° ® 58 1-benzhydryl-3-[(3-chlorophenyl) (methylsulfonyl)- methylene]azetidine, l-benzhydryl-3-[(3,5-dichlorophenyl) (methylsulfonyl) - methylenelazetidine,
1-benzhydryl-3-[(2,5-dichlorophenyl) (methylsulfonyl)- methylene]azetidine, . 1-benzhydryl-3-[(2,3-dichlorophenyl) (methylsulfonyl)- methylenel]azetidine, 1-benzhydryl-3-[ (3-fluorophenyl) (methylsulfonyl) -
methylenelazetidine, 1-benzhydryl-3-[(3,5-difluorophenyl) (methylsulfonyl)- methylenelazetidine, 1-benzhydryl-3-[ (3-bromophenyl) (methylsulfonyl)- methylene]azetidine,
1-benzhydryl-3-[(3-iodophenyl) (methylsulfonyl)- methylenelazetidine, 1-benzhydryl-3-[ (methylsulfonyl) (3-trifluoro- methoxyphenyl)methylene]azetidine, 1-benzhydryl-3-[ (methylsulfonyl) (3-trifluoro-
methylphenyl)methylenelazetidine, l-benzhydryl-3-{[3,5-bis (trifluoromethyl) phenyl]- (methylsulfonyl)methylenelazetidine, l-benzhydryl-3-[ (3, 5-dibromophenyl) (methylsulfonyl) - methylene]azetidine,
1l-benzhydryl-3-[(3-methoxycarbonylphenyl)- (methylsulfonyl)methylene]azetidine, l-benzhydryl-3-[ (3~cyanophenyl) (methylsulfonyl) - methylene]azetidine, l1-benzhydryl-3-[ (3-carbamoylphenyl) (methylsulfonyl)-
methylenelazetidine, l-benzhydryl-3-[ (methylsulfonyl) (naphth-1-yl) (methyl- sulfonyl)methylene]azetidine,
1- [bis (4-chlorophenyl)methyl]-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenel]azetidine,
1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine,
® ® 59 1-[bis (4-methylphenyl)methyl]-3~[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, (RS)=-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]- 1-[ (4-methoxyphenyl) (phenyl)methyl) Jazetidine,
(R)-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]- 1-[ (4-methoxyphenyl) (phenyl)methyl]}azetidine, (S)-3-[(3,5-difluorophenyl) (methylsulfonyl)methylene]- 1-[ (4-methoxyphenyl) (phenyl)methyl] azetidine, 1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-di-
fluorophenyl) (methylsulfonyl)methylene]azetidine, 1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-di- fluorophenyl) (methylsulfonyl)methylene]azetidine, 1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoro- methyl) phenyl]lmethylsulfonylmethylene}azetidine,
(RS)=-1-[(4-chlorophenyl) (2,4-dichlorophenyl)methyl]-3- [(3,5-difluorophenyl) (methylsulfonyl) - methylene]azetidine,
(R)-1-[ (4-chlorophenyl) (2,4-dichlorophenyl)methyl]-3- [(3,5-difluorophenyl) (methylsulfonyl)-
methylenel]azetidine,
(S)-1-[(4-chlorophenyl) (2,4-dichlorophenyl)methyl]-3- [(3,5-difluorophenyl) (methylsulfonyl) - methylenelazetidine,
(RS)=-1-{ (4-chlorophenyl) [4-
(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine, (R)-1-{ (4-chlorophenyl) [4-
(hydroxymethyl) phenyl]lmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine,
(S)-1-{(4-chlorophenyl) [4-
(hydroxymethyl) phenyllmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, (RS)-1-{ (4-chlorophenyl) [4- (pyrrolidylmethyl)phenyllmethyl}—-3-[(3,5~-difluoro-
phenyl) (methylsulfonyl)methylene]azetidine,
° ® 60 (R)-1-{ (4-chlorophenyl) [4- (pyrrolidylmethyl)phenyllmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine, (S)-1-{ (4-chlorophenyl) [4-
(pyrrolidylmethyl)phenyl]lmethyl}-3-[(3,5-difluoro-~ phenyl) (methylsulfonyl)methylene]azetidine,
1-{ (RS) - (4-chlorophenyl) [4-(3,3-dimethylpiperidin-1- ylmethyl)phenyllmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylenelazetidine,
1-{(R)-(4-chlorophenyl) [4-(3,3-dimethylpiperidin-1- ylmethyl)phenyllmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, 1-{(S)-(4-chlorophenyl) [4-(3,3-dimethylpiperidin-1- ylmethyl)phenyllmethyl}-3-[(3,5~-difluoro-
phenyl) (methylsulfonyl)methylene]azetidine,
1-{ (RS) - (4-chlorophenyl) [4- (thiomorpholin-4- ylmethyl)phenyl]lmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, 1-{ (R) -(4-chlorophenyl) [4- (thiomorpholin-4-
vylmethyl)phenyl]lmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine, 1-{(S)-(4-chlorophenyl) [4- (thiomorpholin-4- ylmthyl)phenyl]lmethyl}-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl) [4- (N-ethyl-N- cyclohexylaminomethyl)phenyl]methyl}=-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{ (R)- (4-chlorophenyl) [4- (N-ethyl-N- cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-
difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{(S)-(4-chlorophenyl) [4- (N-ethyl-N- cyclohexylaminomethyl)phenyl]lmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{{ (RS) -(4-chlorophenyl) {4-[ (4—ethoxycarbonyl-
piperazinyl)methyl]phenyl}methyl}}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine,
® 61
1-{{ (R)-(4-chlorophenyl) {4-[ (4-ethoxycarbonyl- piperazinyl)methyl]lphenyl}methyl}}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{{(S)-(4-chlorophenyl) {4~[ (4-ethoxycarbonyl-
piperazinyl)methyl]phenyl}methyl}}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-{ (RS) -(4-chlorophenyl) [4- (N-cyclopropyl-N- propylaminomethyl)phenyl]methyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylenelazetidine,
1-{(R)-(4-chlorophenyl) [4-(N-cyclopropyl-N- propylaminomethyl)phenyl]methyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylenelazetidine, 1-{(S)-(4-chlorophenyl) [4- (N-cyclopropyl-N- propylaminomethyl)phenyl]lmethyl}-3-[(3, 5-
difluorophenyl) (methylsulfonyl)methylenelazetidine, 1-{ (RS) -{(4-chlorophenyl) [4- (diisopropylamino- methyl) phenyl]lmethyl}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylene]azetidine,
1-{ (R) - (4-chlorophenyl) [4- (diisopropylaminomethyl) -
phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine,
1-{ (S)-(4-chlorophenyl) [4- (diisopropylaminomethyl) - phenyl]lmethyl}-3-{(3,5-difluorophenyl) (methylsulfonyl) - methylene]azetidine,
1-{{(RS)-(4-chlorophenyl) {4-[bis (2-methoxyethyl)- aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylenel]azetidine,
1-{{ (R)-(4-chlorophenyl) {4- [bis (2-methoxyethyl) - aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)-
(methylsulfonyl)methylenelazetidine, 1-{{(S)-(4-chlorophenyl) {4- [bis (2-methoxyethyl) - aminomethyl]phenyl}imethyl}}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylene]azetidine,
1-{ (RS) -(4-chlorophenyl) [4-[di-n-
propylaminomethyl)phenyl]lmethyl}-3-[(3,5-difluoro-
phenyl) (methylsulfonyl)methylenelazetidine,
® 62 1-{ (R)-(4-chlorophenyl) [4- (di-n—-propylaminomethyl) - phenyllmethyl}-3-[(3,5-difluorophenyl) (methylsulfonyl)- methylenelazetidine, 1-{(S)-(4-chlorophenyl) [4- (di-n-propylaminomethyl) —
phenyl]lmethyl}-3-[(3,5-difluorophenyl) (methyl-
sulfonyl)methylenel]azetidine, 1-{ (RS) -(4-chlorophenyl) [4- (piperidin-1l-ylmethyl) - phenyl]lmethyl}-3-[ (3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine,
1-{(R)-(4~-chlorophenyl) [4-(piperidin-l-ylmethyl) - phenyl]methyl}-3-[ (3,5-difluorophenyl) (methyl- sulfonyl)methylenel]azetidine, 1-{(S)-(4-chlorophenyl) [4- (piperidin-1-ylmethyl) - phenyl]lmethyl}-3-[ (3,5-difluorophenyl) (methyl-
sulfonyl)methylene]azetidine,
1-{ (RS) -(4-chlorophenyl) [4- (4-methylpiperazin-1- ylmethyl)phenyl]lmethyl}-3-[ (3, 5-difluorophenyl) - (methylsulfonyl)methylene]azetidine, 1-{(R)-(4-chlorophenyl) [4- (4-methylpiperazin-1-
ylmethyl)phenyllmethyl}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylene]azetidine, 1-{(S)-(4-chlorophenyl) [4- (4-methylpiperazin-1- ylmethyl)phenyl]lmethyl}-3-[ (3, 5-difluorophenyl) - (methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl) [4- (morpholin-4- ylmethyl)phenyl]methyl}-3-[ (3, 5-difluorophenyl) - (methylsulfonyl)methylene]azetidine, 1-{(R)-(4-chlorophenyl) [4- (morpholin-4-ylmethyl) - phenyllmethyl}-3-[(3,5-difluorophenyl) -
(methylsulfonyl)methylene]azetidine, 1-{(S)-(4-chlorophenyl) [4- (morpholin-4-ylmethyl) - phenyl]lmethyl}-3-[(3,5-difluorophenyl) - (methylsulfonyl)methylenelazetidine,
1-{ (RS) -(4-chlorophenyl) [4- (diethylaminomethyl) -
phenyl]lmethyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine,
® 63 1-{(R)-(4~-chlorophenyl) [4-(diethylaminomethyl) - phenyllmethyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylenelazetidine, 1-{(S)-(4-chlorophenyl) [4-(diethylaminomethyl) -
phenyl]lmethyl}-3-[(3,5-difluorophenyl) (methyl-
sulfonyl)methylenelazetidine, 1-{ (RS) -(4~-chlorophenyl) [4- (piperazin-2-one-4- ylmethyl)phenyllmethyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl) [4-(piperazin-2-one-4-ylmethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine, 1-{(S)-(4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) - phenyl]methyl}-3-[(3, 5-difluorophenyl) (methyl-
sulfonyl)methylene]azetidine,
1-{ (RS) -(4-chlorophenyl) [4- (imidazol-1-ylmethyl)- phenyl]lmethyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine,
1-{ (R)-(4-chlorophenyl) [4-(imidazol-1-ylmethyl) -
phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine, 1-{(S)-(4-chlorophenyl) [4-(imidazol-1-ylmethyl) - phenyl]methyl}-3-[(3,5-difluorophenyl) (methyl- sulfonyl)methylene]azetidine,
(RS)-1-{(4-chlorophenyl) [4-(N,N- dimethylcarbamoyl) phenyl ]methyl}-3-[(3, 5- difluorophenyl) (methylsulfonyl)methylene]azetidine, (RY=1-{ (4-chlorophenyl) [4- (N,N- dimethylcarbamoyl) phenyl ]methyl}-3-[ (3, 5-
difluorophenyl) (methylsulfonyl)methylene]azetidine, (S)=-1-{ (4-chlorophenyl) [4-(N,N- dimethylcarbamoyl)phenyl]lmethyl}-3-[(3, 5- difluorophenyl) (methylsulfonyl)methylene]azetidine, (RS)-1-{ (4-chlorophenyl) [4- (N-
ethylcarbamoyl)phenyl]lmethyl) }-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine,
® ® 64 (R)-1-{ (4-chlorophenyl) [4- (N- ethylcarbamoyl)phenyl]lmethyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, (S)-1-{ (4-chlorophenyl) [4- (N-
ethylcarbamoyl)phenyl]methyl}-3-[(3,5- difluorophenyl) (methylsulfonyl)methylenelazetidine, (RS)-1-[ (4-carbamoylphenyl) (4-chlorophenyl)methyl]-3- [(3,5-difluorophenyl) (methylsulfonyl)methylene]- azetidine,
(R)-1-[(4-carbamoylphenyl) (4-chlorophenyl)methyl]-3- [(3,5-difluorophenyl) (methylsulfonyl)methylene]- azetidine,
(S)-1-[ (4-carbamoylphenyl) (4-chlorophenyl)methyl]-3- [(3,5-difluorophenyl) (methylsulfonyl)methylene]-
azetidine, 1-[bis(4-chlorophenyl)methyl]-3-{(3,5-dichloro- phenyl) (methylsulfonyl)methylene]azetidine, l-benzhydryl-3-[ (3-methylsulfanylphenyl) (methyl- sulfonyl)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-[(methylsulfonyl) (3- pyrrolidinylphenyl)methylene]azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxy- methylphenyl) (methylsulfonyl)methylene]azetidine, l1-[{bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl) [3~ (N~ piperidylcarbamoyl)phenyl]methylene}azetidine,
® ® 65
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)methylenel]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)methylenelazetidine, (RS)-1-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[(3, 5- difluorophenyl) (methylsulfonyl)methylene]azetidine, (R)-1-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine,
(S)-1-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, l-benzhydryl-3-[ (ethylsulfonyl) (phenyl)methylene]- azetidine, 1-[bis(4-chlorophenyl)methyl]-3—-{{3-[N-(4-
methylpiperazinyl)carbamoyl]phenyl} (methylsulfonyl)- methylene}azetidine, 1-[bis (4-chlorophenyl)methyl]-3-{[3-(2,2- dimethylcarbohydrazido) phenyl] (methylsulfonyl) - methylene}azetidine,
1-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)- (methylsulfonyl)methylene]azetidine, 1-[bis(p-tolyl)methyl]-3-[ (methylsulfonyl)- (phenyl)methylene]azetidine, 1-[(4-chlorophenyl) (4-hydroxymethylphenyl)methyl]-3-
[(3,5-difluorophenyl) (methylsulfonyl)methylene]- azetidine,
® 66 1-[bis(4-chlorophenyl)methyl]-3-[ (3-methylaminophenyl) - (methylsulfonyl)methylene]azetidine, (RS)-1-[(4-chlorophenyl) (thiazol-2-yl)methyl]-3-[ (3, 5- difluorophenyl) (methylsulfonyl)methylenelazetidine,
(R)-1-[(4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylenelazetidine, (S)-1-[(4-chlorophenyl) (thiazol=-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[ (methylsulfonyl) (2-
methoxycarbonylthien-5-yl)methylenelazetidine, (RS)-1-[bis (4-chlorophenyl)methyl] -3-hydroxy-3-
[ (methylsulfonyl) (2-methoxycarbonylthien-5- yl)methyllazetidine, 1- [bis (4-chlorophenyl)methyl]-3-[ (2-isobutylamino-
carbonylthien-5-yl) (methylsulfonyl)methylene]azetidine, 1- [bis (4-chlorophenyl)methyl]-3-[ (RS) - (3-methoxy- carbonylphenyl) (methylsulfonyl)methyllazetidin-3-o0l, 1- [bis (4-chlorophenyl)methyl]-3-[ (RS) - (methyl- sulfonyl) (pyridin-4-yl)methyl]azetidin-3-o0l,
1-[bis(4-chlorophenyl)methyl]-3-[ (RS) - (methylsulfonyl) (pyridin-3-yl)methyl]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} (methanesulfonyl)methyl)-N-(3- dimethylaminopropyl)benzamide, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(2- (pyrrolidin-1-
vyl)ethyl)benzamide, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(2-dimethylamino-1- methylethyl)benzamide, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-
vylidene} (methanesulfonyl)methyl)-N-(piperidin-1- yl)benzamide,
®
® 67 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-isobutylbenzamide, 3-({1l-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-(3-(imidazol-1-
yl)propyl)benzamide,
3-({1-[bis(4-chlorophenyl)methyllazetidin-3- ylidene} (methanesulfonyl)methyl) -N-(2- dimethylaminoethyl)benzamide, N’ -methylhydrazide of 3-({1-[bis(4-chlorophenyl)-
methyllazetidin-3-ylidene} (methanesulfonyl)- methyl)benzoic acid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N- (2- (morpholin-4- yl)ethyl)benzamide,
3-({l-[bis(4~-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(l-ethylpyrrolidin- 2-ylmethyl)benzamide, 3-{({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-(2,2-
dimethylpropyl)benzamide, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N- (cyclohexylmethyl)benzamide, 3-({1-[bis(4-chlorophenyl)methylJ]azetidin-3-
vylidene} (methanesulfonyl)methyl) -N- (cyclopropylmethyl)benzamide, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-(2- methylbutyl)benzamide,
3-({l-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-(2- phenylpropyl)benzamide, 3-({1l-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(tetrahydrofuran-2-
ylmethyl)benzamide,
) ® 68 3-({1-[bis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) -N-(2, 2- diphenylethyl)benzamide, 3-({1-[bis{(4-chlorophenyl)methyl Jazetidin-3- ylidene} (methanesulfonyl)methyl)-N-(2- ethylbutyl)benzamide, methyl ester of 4-{[3-({1l-[bis(4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl) - benzoylamino]methyl}cyclohexanecarboxylic acid,
2-amino-1-{4-[3-({1-[bis(4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl)phenyl]- piperazin-1-yl}ethanone, tert-butyl ester of (2-{4-[3-({1-[bis(4-chlorophenyl)- methyl]azetidin-3-ylidene} (methanesulfonyl)methyl) -
phenyl]piperazin-1-yl}-2-oxoethyl) carbamic acid, 1-{4-[3-({1- [bis (4-chlorophenyl)methyl]lazetidin-3- ylidene} (methanesulfonyl)methyl)phenyl]lpiperazin-1-yl}- 2-(methylamino)ethanone, tert-butyl ester of (2-{4-[3-({1-[bis(4-
chlorophenyl)methyl]lazetidin-3- ylidene} (methanesulfonyl)methyl)phenyl]piperazin-1-yl}- 2-oxoethyl)-N-methylcarbamic acid,
N-methylamide of 4-[3-({1-[bis(4-chlorophenyl) - methyllazetidin-3-ylidene} (methanesulfonyl)methyl) -
phenyl]piperazine-l-carbothioic acid,
N-methylamide of 4-[3-({1-[bis(4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl) phenyl] - piperazine-l-carboxylic acid,
methyl ester of 4-[3-({1-[bis(4-chlorophenyl)methyl]-
azetidin-3-ylidene} (methanesulfonyl)methyl)- phenyl]piperazine-l-carboxylic acid, 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) phenyl} -4- isobutylpiperazine,
® 69 1-[3-({1-[bis(4-chlorophenyl)methyl]lazetidin-3- ylidene} (methanesulfonyl)methyl) phenyl] -4- ethylpiperazine, 4-acetyl-1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin- 3-ylidene} (methanesulfonyl)methyl)phenyllpiperazine, 1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)phenyl]piperazin-1-yl}- 2-dimethylaminoethanone, 1-[3-({1-[bis (4-chlorophenyl)methyl]azetidin-3-
ylidene} (methanesulfonyl)methyl)phenyl]lpiperazine, tert-butyl ester of 4-[3-({1l-[bis(4-chlorophenyl)- methyl]azetidin-3-ylidene} (methanesulfonyl)methyl) - phenyl]piperazine-l-carboxylic acid,
1- [bis (4-methoxycarbonylphenyl)methyl]-3-[(3,5-
difluorophenyl) (methylsulfonyl)methylenelazetidine, 3-acetoxy-1- [bis (4-methoxycarbonylphenyl)methyl]-3-
[ (RS)-(3,5-difluorophenyl) (methylsulfonyl)methyl]- azetidine, (RS)-4-[4-((4-chlorophenyl) {3-[(3,5-
difluorophenyl) (methanesulfonyl)methylene]azetidin-1- yl}methyl)benzyllmorpholine,
4- (4-{3-[ (l-benzhydrylazetidin-3-ylidene) (methane- sulfonyl)methyl]phenoxy}butyl)morpholine, 4-(4-{3-[(1-benzhydrylazetidin-3~ylidene) (methane-
sulfonyl)methyl]phenoxyl}propyl)morpholine, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}thien- 2-ylsulfonamide, N-{1l-[{bis(4-chlorophenyl)methyl]azetidin-3-yl}- 4-methoxyphenylsulfonamide,
N-[4-(N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- sulfamoyl)phenyl]acetamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 4-methylphenylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
3,4-dimethoxyphenylsulfonamide,
@ ® 70 N-{1-[{bis(4-chlorophenyl)methyl]azetidin-3-yl}- 3-fluorophenylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 3,4-dichlorophenylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- 3-cyanophenylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- 2,5-dimethoxyphenylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyllazetidin-3-yl}-
3-trifluoromethylphenylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}naphth-2- ylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}naphth-1- ylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- 3,4-difluorophenylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- l-methyl-1H-imidazol-4-ylsulfonamide, N-[4-(N-{1l-[bis(4-chlorophenyl)methyljazetidin-
3-yl}sulfamoyl)-2-chlorophenyl]acetamide,
N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}pyrid- 3-ylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyllazetidin-3-yl}- 4-fluorophenylsulfonamide,
N=-{l-[bis(4-chlorophenyl)methyllazetidin-3-yl}lquinol- 8-ylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]lazetidin- 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-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}pyrid- 2-ylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyllazetidin-3-yl}- (3-fluoro-5-pyrrolidin-1-ylphenyl) sulfonamide,
® ® 71 N-{1- [bis (4-chlorophenyl)methyl]azetidin-3-yl}- N-methyl-4-fluorophenylsulfonamide, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- N-methylquinol-8-ylsulfonamide,
N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N-methylphenylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N-methyl (phenylmethyl) sulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
3-sulfamoylphenylsulfonamide, 2-benzenesulfonyl-N-{1-[bis (4-chlorophenyl)methyl]- azetidin-3-yl}acetamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 2-(4-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-{1l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}-
4-(methylsulfonyl)benzamide, N-{1l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- 4- (methanesulfonyl)benzamide,
(5- (methylsulfonyl)thiophene-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]- azetidin-3-yl}-3,5-difluorobenzenesulfonamide, N-{1l-[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,
® ® 72
N-{1-[bis(4-chlorophenyl)methyljazetidin-3-yl}- N- (quinol-6-yl)methylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N- (quinol-5-yl)methylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N- (isoquinol-5-yl)methylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N- (pyrid-3-yl)methylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N-(pyrid-l-oxide-3-yl)methylsulfonamide, N-(1R,2S,48)-(bicyclo[2.2.1]hept-2-yl)-N-{1-[bis- (4-chlorophenyl)methyl]lazetidin-3-~yl}methylsulfonamide, N-(1R,2R, 4S) -(bicyclo[2.2.1]hept-2-yl)-N-{1-[bis- (4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N- (3, 5-difluorophenyl)methylsulfonamide, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- N- (thiazol-2-yl)methylsulfonamide,
N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-
N-(3-methoxyphenyl)methylsulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N- (3-hydroxyphenyl)methylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}- N- (3- (hydroxymethyl) phenyl) 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- (isobutylpiperid-4-yl)methylsulfonamide, N-benzyl-N-{1-[bis(4-chlorophenyl)methyl]azetidin-
3-yl}amine, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N-(3,5-difluorobenzyl) amine, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N- (3, 5-difluorobenzyl)methylsul fonamide,
N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-
N- (pyrid-3-ylmethyl)methylsulfonamide,
_ ® 73 N-{1l-[bis (4-fluorophenyl)methyl]azetidin-3-yl}- N-(3,5-difluorophenyl)methylsulfonamide, (RS) -N-{1-[(4-chlorophenyl) (pyrid-3-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (R)-N-{1l-[(4-chlorophenyl) (pyrid-3-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (S)-N-{1-[ (4-chlorophenyl) (pyrid-3-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (RS) -N-{1-[ (4-chlorophenyl) (pyrid-4-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (R)-N-{1-[ (4-chlorophenyl) (pyrid-4-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (S)-N-{1-[(4-chlorophenyl) (pyrid-4-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (RS)-N-{1l-[(4-chlorophenyl) (pyrimidin-5-yl)methyl]- azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (R)-N-{1-[(4-chlorophenyl) (pyrimidin-5-yl)methyl]- azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (S)-N-{1-[ (4-chlorophenyl) (pyrimidin-5-yl)methyl]- azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}-N-(3,5- difluorophenyl)benzylsulfonamide, their optical isomers and their pharmaceutically acceptable salts.
9. The pharmaceutical composition as claimed in claim 7, for which the compound of formula (I) is chosen from the following compounds: l1-[bis(4~chlorophenyl)methyl]-3-[(RS)-(3,5- difluorophenyl) (methylsulfonyl)methyl]azetidin-3-o01, 3-acetoxy-l-[bis(4-chlorophenyl)methyl]-3-[(RS)-(3,5~- difluorophenyl) (methylulphonyl)methyl)methylsulfonyl- methyl]azetidine, 1-[bis(4~-chlorophenyl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene]azetidine, their optical isomers and their pharmaceutically acceptable salts.
® ® 74
10. The pharmaceutical composition as claimed in claim 6, in which the CB1l [lacuna] antagonist is SR141716, its hydrates and its pharmaceutically acceptable salts or LY320135 and its pharmaceutically acceptable salts.
11. The pharmaceutical composition as claimed in one of claims 6 to 10 for a use which is simultaneous, separate or spread out over time.
12. The pharmaceutical composition as claimed in one of claim 6 to 11, comprising 0.5 to 10 mg of sibutramine and 0.1 to 200 mg of the CBl [lacuna] antagonist.
ZA200303015A 2000-10-04 2003-04-16 Association of the CB1 receptor antagonist and sibutramin, for treating obesity. ZA200303015B (en)

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