AU2001293936B2 - 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 PDFInfo
- Publication number
- AU2001293936B2 AU2001293936B2 AU2001293936A AU2001293936A AU2001293936B2 AU 2001293936 B2 AU2001293936 B2 AU 2001293936B2 AU 2001293936 A AU2001293936 A AU 2001293936A AU 2001293936 A AU2001293936 A AU 2001293936A AU 2001293936 B2 AU2001293936 B2 AU 2001293936B2
- Authority
- AU
- Australia
- Prior art keywords
- methyl
- chlorophenyl
- methylsulfonyl
- bis
- methylene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 208000008589 Obesity Diseases 0.000 title claims abstract description 11
- 235000020824 obesity Nutrition 0.000 title claims abstract description 11
- 229940123158 Cannabinoid CB1 receptor antagonist Drugs 0.000 title abstract description 6
- 239000003555 cannabinoid 1 receptor antagonist Substances 0.000 title abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 333
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 320
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 272
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 263
- -1 trifluoromethylsulfanyl Chemical group 0.000 claims description 261
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 205
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 99
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 65
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 60
- 229910052757 nitrogen Inorganic materials 0.000 claims description 50
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 38
- 125000004212 difluorophenyl group Chemical group 0.000 claims description 38
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 32
- 150000003254 radicals Chemical class 0.000 claims description 31
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 30
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 30
- 125000005842 heteroatom Chemical group 0.000 claims description 30
- 229910052760 oxygen Inorganic materials 0.000 claims description 30
- 239000001301 oxygen Substances 0.000 claims description 30
- 239000011593 sulfur Substances 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 28
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 28
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 27
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 claims description 27
- 229940124802 CB1 antagonist Drugs 0.000 claims description 26
- 229960004425 sibutramine Drugs 0.000 claims description 26
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 19
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 18
- 125000004414 alkyl thio group Chemical group 0.000 claims description 16
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 16
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 13
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 12
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 12
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 12
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 12
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 11
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 235000012631 food intake Nutrition 0.000 claims description 10
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 8
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
- 125000004686 alkyl sulfanyl alkyl group Chemical group 0.000 claims description 8
- 125000004687 alkyl sulfinyl alkyl group Chemical group 0.000 claims description 8
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 8
- 150000002390 heteroarenes Chemical class 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 8
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 claims description 8
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 8
- 230000003287 optical effect Effects 0.000 claims description 8
- 125000005493 quinolyl group Chemical group 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 6
- RWRIWBAIICGTTQ-UHFFFAOYSA-N difluoromethane Chemical compound FCF RWRIWBAIICGTTQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 150000004702 methyl esters Chemical class 0.000 claims description 6
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- RAVRTQMDHKJJIW-UHFFFAOYSA-N 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C=1C(F)=CC(F)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 RAVRTQMDHKJJIW-UHFFFAOYSA-N 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 3
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
- 125000006305 3-iodophenyl group Chemical group [H]C1=C([H])C(I)=C([H])C(*)=C1[H] 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 3
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 3
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical group CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 claims description 3
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- LBZUJSQLLVDWDQ-UHFFFAOYSA-N n-[2-(dimethylamino)ethyl]benzamide Chemical compound CN(C)CCNC(=O)C1=CC=CC=C1 LBZUJSQLLVDWDQ-UHFFFAOYSA-N 0.000 claims description 2
- ITNXJLXLFAFOHO-UHFFFAOYSA-N n-piperidin-1-ylbenzamide Chemical compound C=1C=CC=CC=1C(=O)NN1CCCCC1 ITNXJLXLFAFOHO-UHFFFAOYSA-N 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 3
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims 2
- 125000000068 chlorophenyl group Chemical group 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 150000004677 hydrates Chemical class 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- WHWRHLAHKVGQMU-UHFFFAOYSA-N methyl 5-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=CC=C1C(S(C)(=O)=O)=C1CN(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C1 WHWRHLAHKVGQMU-UHFFFAOYSA-N 0.000 claims 2
- WOWBRAWGQVROKX-UHFFFAOYSA-N n-[1-(dimethylamino)propan-2-yl]benzamide Chemical compound CN(C)CC(C)NC(=O)C1=CC=CC=C1 WOWBRAWGQVROKX-UHFFFAOYSA-N 0.000 claims 2
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 claims 2
- 229940124530 sulfonamide Drugs 0.000 claims 2
- CHCDSAYCTJLCPS-UHFFFAOYSA-N 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-3-ol Chemical compound C1N(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)CC1(O)C(S(=O)(=O)C)C1=CC(F)=CC(F)=C1 CHCDSAYCTJLCPS-UHFFFAOYSA-N 0.000 claims 1
- NUBHCVLRJBDQQR-UHFFFAOYSA-N 1-[bis(4-methylphenyl)methyl]-3-[methylsulfonyl(phenyl)methylidene]azetidine Chemical compound C1=CC(C)=CC=C1C(C=1C=CC(C)=CC=1)N(C1)CC1=C(S(C)(=O)=O)C1=CC=CC=C1 NUBHCVLRJBDQQR-UHFFFAOYSA-N 0.000 claims 1
- VGLYSTYECJHDJB-UHFFFAOYSA-N 1-benzhydryl-3-[(3-methylphenyl)-methylsulfonylmethylidene]azetidine Chemical compound CC1=CC=CC(C(=C2CN(C2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)S(C)(=O)=O)=C1 VGLYSTYECJHDJB-UHFFFAOYSA-N 0.000 claims 1
- 125000000579 2,2-diphenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(C1=C([H])C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 claims 1
- REXRDHYTYWTSRD-UHFFFAOYSA-N 2-(oxolan-2-ylmethyl)benzamide Chemical compound NC(=O)C1=CC=CC=C1CC1OCCC1 REXRDHYTYWTSRD-UHFFFAOYSA-N 0.000 claims 1
- VTXYPPVXMJMLCY-UHFFFAOYSA-N 2-piperidin-1-ylbenzamide Chemical compound NC(=O)C1=CC=CC=C1N1CCCCC1 VTXYPPVXMJMLCY-UHFFFAOYSA-N 0.000 claims 1
- MEZNPUULYGXXFL-UHFFFAOYSA-N 3,4-dimethoxybenzenesulfonamide Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1OC MEZNPUULYGXXFL-UHFFFAOYSA-N 0.000 claims 1
- FRTCYRCXRQVABW-UHFFFAOYSA-N 3-[(1-benzhydrylazetidin-3-ylidene)-methylsulfonylmethyl]benzonitrile Chemical compound C=1C=CC(C#N)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 FRTCYRCXRQVABW-UHFFFAOYSA-N 0.000 claims 1
- OHSIVRGAGQXRCH-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]benzamide Chemical compound C=1C=CC(C(N)=O)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 OHSIVRGAGQXRCH-UHFFFAOYSA-N 0.000 claims 1
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- BDJRLRLQKNSDGO-UHFFFAOYSA-N n-(2-phenylpropyl)benzamide Chemical compound C=1C=CC=CC=1C(C)CNC(=O)C1=CC=CC=C1 BDJRLRLQKNSDGO-UHFFFAOYSA-N 0.000 claims 1
- PUWUDJOAVMKLBK-UHFFFAOYSA-N n-(oxolan-2-ylmethyl)benzamide Chemical compound C=1C=CC=CC=1C(=O)NCC1CCCO1 PUWUDJOAVMKLBK-UHFFFAOYSA-N 0.000 claims 1
- IOGYVIDPKHBUOO-UHFFFAOYSA-N n-[(1-ethylpyrrolidin-2-yl)methyl]benzamide Chemical compound CCN1CCCC1CNC(=O)C1=CC=CC=C1 IOGYVIDPKHBUOO-UHFFFAOYSA-N 0.000 claims 1
- UKXSMVIDPJCDAQ-UHFFFAOYSA-N n-[3-(dimethylamino)propyl]benzamide Chemical compound CN(C)CCCNC(=O)C1=CC=CC=C1 UKXSMVIDPJCDAQ-UHFFFAOYSA-N 0.000 claims 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
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- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 3
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- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 description 2
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 description 2
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- STORWMDPIHOSMF-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O STORWMDPIHOSMF-UHFFFAOYSA-N 0.000 description 2
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- 239000000839 emulsion Substances 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- ABOYDMHGKWRPFD-UHFFFAOYSA-N phenylmethanesulfonamide Chemical compound NS(=O)(=O)CC1=CC=CC=C1 ABOYDMHGKWRPFD-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- KFNNPQDSPLWLCX-UHFFFAOYSA-N 1-[1-(4-chlorophenyl)cyclobutyl]-n,n,3-trimethylbutan-1-amine;hydron;chloride;hydrate Chemical compound O.Cl.C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 KFNNPQDSPLWLCX-UHFFFAOYSA-N 0.000 description 1
- RHGZEONZMQWPEO-UHFFFAOYSA-N 1-[3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]phenyl]-4-ethylpiperazine Chemical compound C1CN(CC)CCN1C1=CC=CC(C(=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)S(C)(=O)=O)=C1 RHGZEONZMQWPEO-UHFFFAOYSA-N 0.000 description 1
- LVLGJPPXNPPWIO-UHFFFAOYSA-N 1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)-methylsulfonylmethylidene]azetidine Chemical compound COC1=CC=CC(C(=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)S(C)(=O)=O)=C1 LVLGJPPXNPPWIO-UHFFFAOYSA-N 0.000 description 1
- COEFGPCJQSWIJQ-UHFFFAOYSA-N 1-benzhydryl-3-[(2,3-dichlorophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C=1C=CC(Cl)=C(Cl)C=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 COEFGPCJQSWIJQ-UHFFFAOYSA-N 0.000 description 1
- AOIOEEULBHREII-UHFFFAOYSA-N 1-benzhydryl-3-[(3,5-dibromophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C=1C(Br)=CC(Br)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 AOIOEEULBHREII-UHFFFAOYSA-N 0.000 description 1
- MFOXSVVWCRZNKV-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]-n-methylaniline Chemical compound CNC1=CC=CC(C(=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)S(C)(=O)=O)=C1 MFOXSVVWCRZNKV-UHFFFAOYSA-N 0.000 description 1
- WXVVCNRZPKCKAB-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]benzonitrile Chemical compound C=1C=CC(C#N)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 WXVVCNRZPKCKAB-UHFFFAOYSA-N 0.000 description 1
- ZIMKTAJRBXSZIV-UHFFFAOYSA-N 4-[3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]phenyl]piperazine-1-carboxylic acid Chemical compound C=1C=CC(N2CCN(CC2)C(O)=O)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 ZIMKTAJRBXSZIV-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OPABTIFWXSOYKF-UHFFFAOYSA-N C1CN(CC(C)C)CCC1CN(S(=O)=O)C1CN(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C1 Chemical compound C1CN(CC(C)C)CCC1CN(S(=O)=O)C1CN(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C1 OPABTIFWXSOYKF-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- UVJZGFKZGQSKDV-OUKQBFOZSA-N [(e)-1,3-diphenylprop-2-enyl] acetate Chemical compound C=1C=CC=CC=1C(OC(=O)C)\C=C\C1=CC=CC=C1 UVJZGFKZGQSKDV-OUKQBFOZSA-N 0.000 description 1
- 230000002891 anorexigenic effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 1
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229940045623 meridia Drugs 0.000 description 1
- OEAVTEGCRREXOK-UHFFFAOYSA-N n-(2-ethylbutyl)benzamide Chemical compound CCC(CC)CNC(=O)C1=CC=CC=C1 OEAVTEGCRREXOK-UHFFFAOYSA-N 0.000 description 1
- KGDWBBCCMHGAEW-UHFFFAOYSA-N n-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-4-methoxybenzenesulfonamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)NC1CN(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C1 KGDWBBCCMHGAEW-UHFFFAOYSA-N 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011680 zucker rat Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention concerns the association of the CB1 receptor antagonist and a sibutramin, pharmaceutical compositions containing same and use thereof for treating obesity.
Description
COMBINATION OF 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 CB1 receptor antagonist and of sibutramine, to the pharmaceutical compositions comprising them and to their use in the treatment of obesity.
CB1 receptor antagonists are known for their effect on food intake and their use as anorexigenic Colombo et al., Life Sciences, 63 113-117 (1998); J. Siamand et al., Behavioural Pharmacol., 9, 179-181 (1998)).
Sibutramine (BTS 54524; -(4-chlorophenyl)cyclobutyl]-3methylbutyl}-N,N-dimethylamine; Meridia®, Reductil®), its hydrate and its pharmaceutically 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, 3 553 (1995); H. C. Jackson et al., British Journal of Pharmacology, 121, 1758 (1997); G. Fanghanel et al., Inter. J. Obes., 24 144 (2000); G. A. Bray et al., Obes. Res., 7 189 (1999)).
It has now been found that the combination of sibutramine, its hydrate and its pharmaceutically acceptable salts and of a CB1 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 CB1 receptor antagonists.
Use may in particular be made, among CB1 antagonists, of the azetidine derivatives disclosed in WO 00/15609, WO 01/64633 and WO 01/64634 of formula:
A
3 N
(I
in which either R represents a chain or and 0 2
R
1 T R1S 2
RI
C00H\ or C-CH\ R2 R2 R, represents a methyl or ethyl radical,
R
2 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, -COOR 5 formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NR 6 R-7, -CO-NH-NR 6
R
7 -N (alk) COOR 8 cyano, -CONHR 9
-CO-NR
1 6
R,
7 alkylsulfanyl, hydroxyalkyl, -O-alk-NR 12
R
13 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,
-NR
6
R
7
-CO-NH-NR
6 R7, cyano, -CONHR 9 alkylsulfanyl, hydroxyalkyl or alkylthioalkyl,
R
3 and R 4 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, -CONRioR 11
-CO-NH-NR
6
R
7 alkylsulfanyl, hydroxyalkyl, -alk-NR6R 7 or alkylthioalkyl, or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, 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, -COOR 5
-CO-NH-NR
6
R
7 -CONRioRn, -alk-NR 6
R
7 alkylsulfanyl, hydroxyalkyl or alkylthioalkyl,
R
5 is an alkyl radical or a phenyl radical optionally substituted by one or more halogen atoms,
R
6 and R 7 which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or else R 6 and R 7 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-NR 14
R
15 oxo, hydroxyalkyl, -alk-O-alk or -CO-NH 2 radicals,
R
8 represents an alkyl radical, Rg 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 R1 1 which are identical or different, represent a hydrogen atom or an alkyl radical or else Rio and R 1 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,
R
12 and R 13 which are identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical or else R 12 and R 13 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 -COalk-NR 4
R
15 radical or a saturated mono- or bicyclic heterocycle having 3 to 10 ring members and comprising a heteroatom chosen from oxygen, sulfur and nitrogen,
R
14 and R 15 which are identical or different, represent a hydrogen atom or an alkyl or -COOalk radical,
R
16 and R 17 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 CHR 18 radical and Ri 1 represents an -NHCOR 19 or -N(R 20
)-Y-R
21 radical, Y is CO or SO 2
R
4 and R 3 which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR 22
R
23
-CO-NH-NR
24
R
25 alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NH2 2
R
23 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, 1,2,3,4tetrahydroisoquinolyl, 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-NR 2 4
R
25
-CONR
22
R
2 3 -alk-
NR
24
R
2 5 alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl,
R
1 9 represents an -alk-SO 2
-R
2 6 radical, an -alk-SO 2
CH=CH-R
2 6 radical, a Heti radical substituted by -S0 2
-R
2 6 or a phenyl radical substituted by -S0 2
-R
2 6 or -alk-SO 2
R
2 6
R
20 represents a hydrogen atom or an alkyl radical,
R
21 represents a phenylalkyl, Hetl or Arl radical,
R
22 and R 23 which are identical or different, represent a hydrogen atom or an alkyl radical or else R 2 2 and R 23 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,
R
2 4 and R 2 5 which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or else R 2 4 and R 25 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-NH2,
R
26 represents an alkyl, Arl or Hetl radical, Arl represents a phenyl, naphthyl or indenyl radical, these radicals optionally being substituted by one or more halogen, alkyl, alkoxy, cyano, -CO-alk, -COOH, -COOalk, -CONR 27
R
28
-CO-NH-NR
29
R
3 0 alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR 29
R
30
-NR
29
R
30 alkylthioalkyl, formyl, hydroxyl, hydroxyalkyl, Het, -O-alk-NH-cycloalkyl,
OCF
3
CF
3 -NH-CO-alk, -SO 2
NH
2
-NH-COCH
3 -NH-COOalk or Het or else on 2 adjacent carbon atoms by dioxymethylene, Hetl 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 3 or CF 3 the nitrogenous heterocycles optionally being in their Noxidized form,
R
27 and R 28 which are identical or different, represent a hydrogen atom or an alkyl radical or else R 27 and R 28 form, together with the nitrogen atom to which they are attached, a saturated 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
29 and R 30 which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or else R 29 and R 30 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, -CO~alk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or
-CO-NH
2 radicals, or R represents CHR 3 1 and
R
3 1 represents an -N(R 32
)R
33
-N(R
32
)-CO-R
3 3 or -N (R 32 -S0 2
R
3 4 radical,
R
4 and R 3 which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH-, CO0alk, -C0NR 2 2
R
2 3
-CO-NH-NR
2 4
R
25 alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR 7 RB, 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-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-NR 24
R
2 5 -C0NR 2 2
R
2 3 -al k-NR 24
R
25 alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl,
R
3 2 represents a -C (R 35
(R
3 6 -Het 2 -Het 2 -C (R 35
(R
36 -Ar 2 Ar 2 cycloalkyl or norbornyl radical,
R
33 represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONR 2 2
R
2 3 -alk-NR 22
R
2 3 alkoxy, Ar 2 Het 2
-CH
2 Ar 2
-CH
2 Het 2 or alkyl radical, the latter optionally substituted by one or more halogen,
R
3 4 represents a hydroxyalkyl, -alk-COOalk, -alk-CONR 22
R
2 3 -alk-NR 22
R
2 3 alkoxy, Ar 2 Het 2
-CH
2 Ar 2
-CH
2 Het 2 or alkyl radical, the latter optionally substituted by one or more halogen,
R
35 represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONR 2 2
R
23 -alk-NR 2 2
R
2 3 alkoxyalkyl, Ar 2 Het 2
-CH
2 Ar 2
-CH
2 Het 2 or alkyl radical, the latter optionally substituted by one or more halogen,
R
3 6 represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONRR 2 23, -alk-NR 2 2
R
2 3 alkoxyalkyl or alkyl radical, the latter optionally substituted by one or more halogen, or else R 35 and R 3 6 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 2 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, -CONR 3 7
R
38
-CO-NH-R
3 9
R
4 o, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR 3 9
R
40
-NR
3 9R40, alkylthioalkyl, formyl, CF 3
OCF
3 Het, -O-alk-NHcycloalkyl, SO 2
NH
2 hydroxyl, hydroxyalkyl, -NHCOalk or NHCOOalk or on 2 adjacent carbon atoms by dioxymethylene, Het 2 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 R 38 which are identical or different, represent a hydrogen atom or an alkyl radical or else R 3 7 and R 38 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,
R
39 and R 40 which are identical or different, represent a hydrogen atom or an alkyl radical or else R 39 and R 40 form, together with the nitrogen atom to which they are attached, a saturated 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, the optical isomers of these compounds and their pharmaceutically acceptable salts with an inorganic or organic acid.
The preferred azetidine derivatives are as follows: 1-benzhydryl-3-[ (methylsulfonyl) (phenyl) methylene] azetidine, 1-benzhydryl-3- II(3-methylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3-chiorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- 5-dichlorophenyl) (methylsulfonyl) methylenel azetidine, 1-benzhydryl-3-[ (2,5-dichiorophenyl) (methylsulfonyl)methylene] azetidine, 1-benzhydryl-3-[ (2,3-dichlorophenyl) (methylsulfonyl)methylene] azetidine, 1-benzhydryl-3-[ (3-fluorophenyl) (methylsulfonyl) rnethylene] azetidine, 1-benzhydryl-3- 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3-bromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3-[ (3-iodophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3-[ (methylsulfonyl) (3-trifluoromethoxyphenyl) methylene] azetidine, 1-benzhydryl-3-[ (methylsulfonyl) (3-trifluoromethylphenyl) methylene] azetidine, 1-benzhydryl-3-{ 5-bis (trifluoromethyl)phenyl]- (methylsulfonyl) methylene IIazetidine, 1 -benzhydryl-3-[ (3,5-dibromophenyl) (methylsulfonyl) methylene] azetidine, 1-ben zhydryl-3- [(3-methoxycarbonyiphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- II(3-cyanophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- 3-carbamoylphenyl) (methylsulfonyl) rnethylenel azetidine, 1-benzhydryl-3-[(methylsulfonyl) (naphth-1-yl) (methylsulfonyl) methylene] azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[ phenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-methoxyphenyl)methyl] phenyl) (methylsulfonyl)methylene] azetidine, 1-[bis (4-methylphenyl)methyl]-3-[ phenyl) (methylsulfonyl) methylene] azetidine, (RS) (3,5-difluorophenyl) (methylsulfonyl)methylene]- (4-methoxyphenyl) (phenyl)methyl) ]azetidine, (3,5-difluorophenyl) (methylsulfonyl)methylene]- (4-methoxyphenyl) (phenyl)methyl~azetidine, (3,5-difluorophenyl) (methylsulfonyl)methylene]- 1- [(4-methoxyphenyl) (phenyl)methyl] azetidine, 1- [bis (4-trifluoromethoxyphenyl)rnethyl] fluorophenyl) (methylsulfonyl)methylenelazetidine, 1-Ebis (4-trifluoromethylphenyl)methyl]-3-[ fluorophenyl) (methylsulfonyl)methylene] azetidine, 1-[bis(4-chlorophenyl)methyl]-3-{ 5-bis (trifluoromethyl) phenyll methylsulfonylmethylene }azetidine, (4-chiorophenyl) (2,4-dichlorophenyl)methyl]-3- 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, [(4-chiorophenyl) (2,4-dichlorophenyl)methyl]-3- 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (2,4-dichlorophenyl)methyl]-3- (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) [4- (hydroxymethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) [4- (hydroxymethyl)phenyllmethyl}-3- phenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (4- (hydroxymethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) [4- (pyrrolidylmethyl)phenyllmethylj-3-[ phenyl) (methylsulfonyl) methylene] azetidine, (R)-1-{(4-chlorophenyl) [4- (pyrrolidylmethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl) methylene] azetidine, -1-{(4-chiorophenyl) [4- (pyrrolidylmethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl) methylene] azetidine, (RS) -(4-chiorophenyl) [4-(3,3-dimethylpiperidin-1ylmethyl) phenyl] methyl phenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (3,3-dimethylpiperidin-1ylmethyl)phenyllmethyll-3-[ phenyl) (methylsulfonyl)methylene] azetidine, (S)-(4-chlorophenyl) (3,3-dimethylpipericlin-1ylmethyl) phenyl] methyl 1-3- phenyl) (methylsulfonyl)methylene] azetidine, (RS)-(4-chlorophenyl) [4-(thiomorpholin-4ylmethyl)phenyllmethyll-3-[ phenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (thiomorpholin-4ylmethyl)phenyllmethyl)-3-[ phenyl)(methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (thiomorpholin-4ylmthyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl) methylene] azetidine, (RS) -(4-chiorophenyl) (N-ethyl-Ncyclohexylaminomethyl)phenyllmethyl}-3-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-f -(4-chiorophenyl) (N-ethyl-Ncyclohexylaminomethyl)phenyllmethyll-3-[ difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (N-ethyl-Ncyclohexylaminomethyl)phenyllmethyl}-3-[ difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-f -(4-chiorophenyl) [(4-ethoxycarbonylpiperazinyl)methyllphenyllmethyl} difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-f {(R)-(4-chlorophenyl) (4-ethoxycarbonylpiperazinyl)niethyl]phenyl~methyll difiluorophenyl) (rethylsulfonyl)methylene] azetidine, 1- -(4-chiorophenyl) [(4-ethoxycarbonylpiperazinyl)methyllphenyllmethyl} difluorophenyl) (methylsulfonyl)methylenelazetidine, 1-I (RS) -(4-chiorophenyl) (N-cyclopropyl-Npropylaminomethyl) phenyllmethyll-3- difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (N-cyclopropyl-Npropylaminomethyl)phenyllmethyl)-3-[ difluorophenyl) (rethylsulfonyl)methylene] azetidine, 1-f (4-chiorophenyl) (N-cyclopropyl-Npropylarninomethyl)phenyllmethyl}-3- difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-f (RS)-(4-chlorophenyl) [4-(diisopropylaminomethyl)phenyllmethyl}-3-[ (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (diisopropylaminomethyl) phenyllmethyl}-3-[ 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (diisopropylaminomethyl)phenyllrnethyl}-3-[ 5-difluorophenyl) (methylsulfonyl)inethylene] azetidine, {(RS)-(4-chlorophenyl) {4-[bis (2-methoxyethyl)aminomethyllphenyllmethyl) (methylsulfonyl) methylene] azetidine, -(4-chiorophenyl) [bis (2-methoxyethyl) aminomethyllphenyllmethyll (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, -(4-chiorophenyl) [bis (2-methoxyethyl) aminomethyllphenyl~methyl} 1-3-[l(3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (RS)-(4-chlorophenyl) [4-[di-npropylaminomethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (di-n-propylaminomethyl)phenyllrnethyll-3-[ (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, CS)- (4-chiorophenyl) (di-n-propylaminomethyl)phenyllmethyl}-3-[ (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (piperidin-1-ylmethyl)phenyllrnethyl}-3-[ 5-difluorophenyl) (methylsulfonyl) methylene] azeticline, (R)-(4-chlorophenyl) (piperidin-1-ylmethyl)phenyllmethyll-3-[ 5-difluorophenyl) (methylsulfonyl)methy.ene] azetidine, 1-{(3S)-(4-chlorophenyl) (piperidin-1-ylmethyl)phenyllrnethyll-3-[ 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS)-(4-chlorophenyl) [4-(4-methylpiperazin-lylmethyl)phenyl]methyl}-3-[ (methylsulfonyl) methylene] azetidine, (R)-(4-chlorophenyl) (4-methylpiperazin-lylmethyl)phenyllmethyl)-3-[ (methylsulfonyl)methylene] azetidine, (S)-(4-chlorophenyl) [4-(4-methylpiperazin-1ylmethyl)phenyllmethyl}-3-[ (methylsulfonyl)rnethylene] azetidine, (RS)-(4-chlorophenyl) (morpholin-4ylmethyl)phenyllrnethyl}-3-[ (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (morpholin-4-ylmethyl)phenyllmethyl}-3-[ (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (morpholin-4-ylmethyl)phenyllmethyl}-3-[ (methylsulfonyl) methylene] azeticline, (RS)-(4-chlorophenyl) (diethylaminomethyl)phenyllmethyll-3-[ 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (diethylaminomethyl) phenyl~methyl}-3-[ 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) 14- (diethylaminomethyl) phenyllmethyl}-3-[ 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -(4-chiorophenyl) (piperazin-2-one-4ylmethyl)phenyllmethyl}-3- 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R)-(4-chlorophenyl)[4-(piperazin-2-one-4-ylmethyl)phenyllmethyl)-3-[ 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (piperazin-2-one-4-ylmethyl)phenyllmethyl}-3-[ 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) [4-(imidazol-1-ylmethyl)phenyllmethyl}-3-[ (3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (R)-(4-chlorophenyl) (iricazol-1-ylmethyl)phenyllmethyl)-3-[ 5-difluorophenyl) (methylsulfonyl)rnethylene] azeticline, (S)-(4-chlorophenyl) (imidazol-1-ylmethyl)phenyllmethyl}-3-[ 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) dimethylcarbamoyl)phenyllmethyl}-3-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) cimethylcarbamoyl)phenyllmethyll-3- difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) dimethylcarbamoyl)phenyllmethyl}-3-[ difluorophenyl) (methylsulffonyl)methylene] azetidine, (4-chiorophenyl) ethylcarbamoyl)phenyl]methyl) 1-3-[I(3,5difluorophenyl) (rethylsulfonyl)methylene] azetidine, (4-chiorophenyl) ethylcarbamoyl)phenyllmethyl}-3-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) ethylcarbamoyl)phenyllmethyl}-3- difluorophenyl) (methylsulfonyl)methylene] azetidine, (RS) (4-carbarnoylphenyl) (4-chlorophenyl)methyl]-3- (methylsulfonyl)methylene]azetidine, (4-carbamoylphenyl) (4-chlorophenyl)methyl--3- 5-difluorophenyl) (methylsulfonyl)methylene]azetidine, (4-carbamoylphenyl) (4-chlorophenyl)methyl]-3- (methylsulfonyl)methylene]azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[ phenyl) (methylsulfonyl) methylene] azetidine, 1-benzhyclryl-3- [(3-methylsulfanyiphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3-[ (3-methylsulfanylmethyl)phenyl) (methylsulfonyl) methylene] azetidine, 1-[bis (4-chlorophenyl)methyl]-3- [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine, 1-[bis (4-chlorophenyl)methyll-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) methylenel azeticline, 1-Ibis (4-chlorophenyl)methyl]-3-( (methylsulfonyl) (3pyrrolidinyiphenyl) methylenel azetidine, 1-jibis (4-chlorophenyl)methyl-3-[(3-hydroxymethyiphenyl) (methylsulfonyl)methylene] azetidine, 1-[bis (4-chlorophenyl)methyl]-3-{ (methylsulfonyl) piperidylcarbamoyl) phenyl] methylene Iazetidine, 1-[bis (4-chlorophenyl)methyl]-3-[ (methylsulfonyl) (3trifluoromethylsulfanyiphenyl) (methylsulfonyl) methylene] azetidine, 1-[bis(4-fluorophenyl)methyl]-3-[ (rethylsulfonyl)methylene] azetidine, 1-[bis (2-fluorophenyl)methyl]-3-[ (methylsulfonyl) methylene] azeticline, 1- [bis (3-fluorophenyl)methyl] 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3- [(methylsulfonyl) (phenyl)methylene]azetidine, (4-chiorophenyl) (thiazol-2-yl)rnethyl]-3- [(methylsulfonyl) (phenyl)methylene]azetidine, (4-chiorophenyl) (thiazol-2-yl)methylj-3- [(methylsulfonyl) (phenyl)methylene] azetidine, (4-chiorophenyl) (thien-2-yl)methyl]-3-[ difluorophenyl) (methylsulfonyl)methylenelazetidine, (4-chiorophenyl) (thien-2-yl)methyl]-3-[ cifluorophenyl) (methylsulfonyl)methylene] azetidine, (S)-1-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3-[ (ethylsulfonyl) (phenyl)methylene]azetidine, 1- [bis (4-chlorophenyl)methyl] (4methylpiperazinyl) carbamoyllphenyl} (methylsulfonyl) rnethylenelIazetidine, 1-[bis(4-chlorophenyl)methyll-3-{ dimethylcarbohydrazido) phenyl] (methylsulfonyl) methylene Iazetidine, 1- [bis (thien-2-yl)methyl] 5-difluorophenyl) (methylsulfonyl)methylene] azetidine, 1- [bis (p-tolyl) methyl] [(methylsulfonyl) (phenyl)rnethylene] azetidine, 1- [(4-chiorophenyl) (4-hydroxyrethylphenyl)methyl]-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-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3-[ difluorophenyl) (methylsulfonyl)methylene] azeticline, 1-[bis (4-chlorophenyl)methyl]-3-[ (methyisulfonyl) (2methoxycarbonylthien-5-yl) methylene] azetidine, (RS) -1-[(bis (4-chlorophenyl)methyl]-3-hylroxy-3- [(methylsulfonyl) yl)methyl] azetidine, 1-[bis (4-chlorophenyl)methyl]-3-[ (2-isobutylaminocarbonylthien-5-yl) (methylsulfonyl)methylenelazetidine, 1-[bis (4-chlorophenyl)methyl]-3-[ (RS)-(3-methoxycarbonyiphenyl) (methylsulfonyl)methyl] azetidin-3-ol, 1-[bis(4-chlorophenyl)methyl]-3-E (methylsulfonyl) (pyridin-4-yl)methyl] azetidin-3-ol, 1-[bis(4-chlorophenyl)methyl]-3-[(RS)- (methylsulfonyl) (pyridin-3-yl)methyl] azetidin-3-ol, 3- (4-chlorophenyl)methyl]azetidin-3ylidene} (methanesulfonyl)methyl) (morpholin-4yl) propyl) benzamide, 3- [bis (4-chlorophenyl)methyl] azetidin-3ylidene} (methanesulfonyl)methyl)-N- (3dimethylaminopropyl) benzamide, 3-({1-[bis (4-chlorophenyl)rnethyljazetidin-3ylidene} (methanesulfonyl)methyl)-N- (pyrrolidin-1yl) ethyl) benzamide, 3- ((1-(bis (4-chiorophenyl) methyl] azetidin-3ylidenel (methanesulfonyl)methyl) (2-direthylamino-1methylethyl) benzamide, 3-({l-[bis (4-chlorophenyl)rnethyl]azetidin-3yliclenel (methanesulfonyl)methyl) (piperidin-1yl) benzamide, 3-C Ibis (4-chlorophenyl)methyl] azetidin-3ylidenel (methanesulfonyl)methyl) -N-isobutylbenzamide, 3-({1-ilbis (4-chlorophenyl)methyl]azetilin-3ylidenel (methanesulfonyl)methyl) (imiciazol-lyl) propyl) benzamide, 3-({l-Ilbis (4-chlorophenyl)methyl]azetidin-3ylidenel (methanesulfonyl)methyl) (2dimethylaminoethyl) benzamide, N'-methylhydrazide of 3- [bis (4-chlorophenyl)methyl] azetidin-3-ylidene} (methanesulfonyl) methyl) benzoic acid, 3- ({1-[bis (4-chlorophenyl)methyl]azetidin-3ylidene} (methanesulfonyl)methyl)-N-(2-(morpholin-4yl) ethyl) benzarnide, 3- ({1-[bis (4-chlorophenyl)methyl]azetidin-3ylidene} (methanesulfonyl)methyl) (1-ethylpyrrolidin- 2-ylmethyl) benzamide, 3- [bis (4-chlorophenyl)methyllazetidin-3ylidene} (methanesulfonyl)methyl)-N- (2,2dimethylpropyl) benzamide, 3- C{1-[bis (4-chlorophenyl)methyl]azetidin-3ylidene} (methanesulfonyl)methyl) -N- (cyclohexylmethyl) benzamide, 3- [bis (4-chiorophenyl) methyl] azetidin-3yliclene} (methanesulfonyl)methyl) -N- (cyclopropyirnethyl) benzamide, 3- [bis (4-chiorophenyl) methyl] azetidin-3ylidene} (methanesulfonyl)methyl)-N- (2methylbutyl) benzamide, 3- 1- [bis (4-chiorophenyl) methyl] azetidin-3ylidene} (methanesulfonyl)methyl) (2phenyipropyl) benzamide, 3-({1-[bis (4-chlorophenyl)methyl]azetidin-3ylidene) (methanesulfonyl)methyl) (tetrahydrofuran-2ylmethyl) benzamide, 3-({1-[bis (4-chlorophenyl)methyl]azetidin-3ylidene) (methanesulfonyl)methyl) (2,2diphenylethyl) benzamide, 3- [bis (4-chiorophenyl) methyl] azetidin-3ylidenel (methanesulfonyl)methyl) (2ethylbutyl) benzamide, methyl ester of (4-chiorophenylimethyl]azetidin-3-ylidene} (methanesulfonyl)methyl) benzoylamino]methyl }cyclohexanecarboxylic acid, 2 -amino-l-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene} (methanesulfonyl)methyl)phenyl] piperazin-1-yl lethanone, tert-butyl ester of (2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene} (methanesulfonyl)methyl) phenyllpiperazin-l-yll-2-oxoethyl)carbamic acid, (4-chlorophenyl)methyl~azetidin-3ylidene} (methanesulfonyl)methyl)phenyllpiperazin-1-yl}- 2- (methylamino) ethanone, tert-butyl ester of chiorophenyl) methyl] azetidin-3ylidene} (methanesulfonyl)methyl)phenyllpiperazin-1-yl}- 2-oxoethyl) -N-methylcarbamic acid, N-methylamide of [bis (4-chiorophenyl)methyl] azetidin-3-ylidene I(methanesulfonyl) methyl) phenyllpiperazine-1-carbothioic acid, N-methylamide of 4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene} (methanesulfonyl)methyl)phenyl]piperazine-1-carboxylic acid, methyl ester of 4-113-({1-j(bis (4-chlorophenyl)methyl]azeticlin-3-ylidene} (methanesulfonyl)methyl) phenyllpiperazine-1-carboxylic acid, 1-[3-({1-[bis(4-chlorophenyl)methyllazetidin-3ylidene I(methanesulfonyl) methyl) phenyl] -4isobutylpiperazine, 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3ylidene} (methanesulfonyl)methyl)phenyl] -4ethylpiperazine, 4-acetyl-l- [bis (4-chlorophenyl)methyl] azetidin- 3-ylidenel (methanesulfonyl)methyl)phenyllpiperazine, ({1-[bis (4-chlorophenyl)methyllazetidin-3ylidene} (methanesulfonyl)methyl)phenyllpiperazin-1-yl)- 2-dimethylaminoethanone, 1- [bis (4-chlorophenyl)methyl]azetidin-3ylidene} (methanesulfonyl)methyl)phenyllpiperazine, tert-butyl ester of 4-E3-({1-[bis (4-chlorophenyl)methyl]azetidin-3-ylidene} (methanesulfonyl)methyl) phenyllpiperazine-1-carboxylic acid, 1-[bis (4-methoxycarbonylphenyl)methyl]-3-( difluorophenyl) (methylsulfonyl)methylene] azetidine, 3-acetoxy-1-[bis (4-methoxycarbonylphenyl)methyl] -3- 5-difluorophenyl) (methylsulfonyl)methyl]azetidine, (RS)-4-[4-((4-chlorophenyl) difluorophenyl) (methanesulfonyl)methylene] azetidin-1yl Imethyl) benzyl ]morpholine, 4- (l-benzhydrylazetidin-3-ylidene) (methanesulfonyl)methyllphenoxylbutyl) morpholine, 4- (l-benzhydrylazeticlin-3-ylidene) (methanesulfonyl) methyl] phenoxylpropyl) morpholine, N-f{ [bis (4-chiorophenyl) methyl] azetidin-3-yl Ithien- 2-ylsulfonamide, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- 4-methoxyphenylsulfonamide, N-[4-(N-{l-Ilbis (4-chlorophenyl)methyl]azetidin-3-yl}sulfamoyl) phenyl] acetamide, N- [bis (4 -chiorophenyl) methyl] azetidin-3-yl I- 4-methyiphenylsulfonamide, N-{l-Ilbis (4-chlorophenyl)methyllazetidin-3-yl}- 3, 4-direthoxyphenylsulfonamide, Ibis (4-chlorophenyl)methyl]azetidin-3-yll- 3-f luorophenylsulfonamide, N-{l-[bis(4-chlorophenyl)methyllazetidin-3-yl}- 3, 4-dichiorophenylsulfonamide, N-{l-[bis (4-chlo rophenyl)methyllazetidin-3-yl}- 3-cyanophenylsul fonamide, N- Ibis (4-chlorophenyl) methyl] azetidin-3-yl) 2, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- 3-trifluoromethyiphenylsulfonamide, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yllnaphth-2ylsulfonanide, N-il-[bis(4-chlorophenyl)methyllazetidin-3-yl)naphth-lylsulfonanide, [big (4-chlorophenyl)rnethyllazetidin-3-yl}- 3,4LIdifluorophenylsulfonamide, N-f1- [big (4-chiorophenyl) methyl] azetidin-3-yl)Il-methyl-lH-imidazol-4-ylsulfonamide, N- [bis (4-chiorophenyl) methyl] azeticlin- 3-yl Isulfamoyl) -2-chiorophenyl] acetamile, N-fl-Ibis (4-chlorophenyl)methyl]azetidin-3-yllpyrid- 3-ylsulfonamide, N-{l-[bis(4-chlorophenyl)methyllazetidin-3-yl)- 4-fluorophenylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yllquinol- 8-ylsulfonamide, N-{1-[bis(4-chlorophenyl)methyllazetidin- 3-yl }phenylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetiiin- 3-yll (phenylmethyl) sulfonamide, N-{l-[bis (4-chlorophenyl)methyllazetidin-3-yl}- 3, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yllpyrid- 2-ylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- (3-fluoro-5-pyrrolidin-1-ylphenyl) sulfonamide, N-{l-[bis(4-chlorophenyl)methyllazetidin-3-yll- N-methyl-4 -fluorophenylsulfonamide, N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- N-methylquinol-8-ylsul fonamide, N-fl- [bis (4-chlorophenyl)methyl]azetidin-3-yl}- N-methylphenylsulfonamide, N-fl- [bis (4-chlorophenyl)methyllazetidin-3-yl}- N-methyl (phenylmethyl) sulfonamide, N-fl- [bis C4-chlorophenyl)methyllazetidin-3-yl}- 3-sulfamoylphenylsulfonamide, 2-benzenesulfonyl-N-{l-[bis (4-chlorophenyl)methyl]azetidin-3-yl }acetamide, N-{l-[bis (4-chlorophenyl)methyllazeticiin-3-yl}- 2- (4-toluene-4-sulfonyl) acetamide, (3-chloro-4- (methylsulfonyl) thiophene-2-carboxy) 1- [bis (4-chiorophenyl) methyl] azetidin-3-yl] amide, N-Il- [bis (4-chlorophenyl)methyl]azetidin-3-yl}- 3- (2-phenylethylenesulfonyl)propionamide, N-fl- [bis (4-chlorophenyl)methyl]azetidin-3-yl}- 4- (methylsulfonyl)benzamide, N-fl- [bis (4-chlorophenyl)methyl]azetidin-3-yl}- 4- (methanesulfonyl) benzamide, (methylsulfonyl) thiophene-2-carboxy) {l-Ilbis (4-chlorophenyl)methyllazetidin-3-yllamide, (5-methylsulfonyl-3-methyl-4 -vinyithiophene- 2-carboxy) bis (4-chlorophenyl)rnethyl]azetidin- 3-yll}amide, (4-chiorophenyl) (pyridin-3-y1)methyl]azetidin-3-yll-3, (4-chiorophenyl) azetidin-3-yll-3, Ibis (4-chlorophenyl)methyllazeticlin-3-yl}- N- (6-chloropyrid-2-yl)methylsulfonamide, N-{1-Ilbis(4-chlorophenyl)methyllazetidin-3-yl}- N- (6-ethylpyrid-2-yl) methylsulfonamide, N- bis (4-chiorophenyl) methyl] azetidin-3-yl 1- N- (quinol-6-yl)methylsulfonamide, Ibis (4-chlorophenyl)methyl]azetiiin-3-yl}- N- N-{1-[bis (4-chlorophenyl)methyllazetilin-3-yl}- N- Ibis (4-chlorophenyl)methyllazetidin-3-yl}- N- (pyric-3-yl)methylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (pyrid-1-oxide-3-yl)methylsulfonamiie, N- (iR,2S, 4S) -(bicyclo hept-2-yl) Ibis- (4-chlorophenyl)methyl] azetidin-3-yl~methylsulfonamide, N-C1R,2R,4S)-(bicyclo[2.2.1]hept-2-yl)-N-{1-[bis- (4-chlorophenyl)methyl]azetidin-3-yllmethylsulfonamide, Ibis (4-chlorophenyl)methyllazetidin-3-yl}- N- Ibis (4-chlorophenyl)methyl]azeticiin-3-yl)- N- (thiazol-2-yl)methylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (3-methoxyphenyl) methylsulfonamide, Ibis (4-chlorophenyl)methyl]azetidin-3-yl}- N- (3-hydroxyphenyl) methylsulfonamide, [bis (4-chlorophenyl)methyl]azetidin-3-yl}- N- (hydroxymethyl) phenyl)methylsulfonamide, ethyl N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (methylsulfonyl) -3-arninobenzoate, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- N- (isobutylpiperid-4-yl)methylsulfonamide, N-benzyl-N-{1- [bis(4-chlorophenyl)methyllazetidin- 3-yl }amine, N-{l-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- 5-difluorobenzyl) amine, N-{1-lbis(4-chlorophenyl)methyl]azetidin-3-yl}- N- N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (pyrid-3-ylmethyl)methylsulfonamide, N-{1-[bis(4-fluorophenyl)methyllazetidin-3-yll- N- (RS) (4-chiorophenyl) (pyrid-3-yl)methyllazetidin- (4-chiorophenyl) (pyrid-3-yl)methyllazetidin- 3-yl}-N- (4-chiorophenyl) (pyrid-3-yl)methyllazetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (RS) (4-chiorophenyl) (pyrid-4-yl)methyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (4-chiorophenyl) (pyric-4-yl)methyllazetidin- 3-yll-N-(3,5-difluorophenyl)methylsulfonamide, (4-chiorophenyl) (pyrid-4-yl)methyl]azetidin- (RS) (4-chiorophenyl) azetidin-3-yl}-N- (4-chiorophenyl) azetidin-3-yl}-N- (4-chiorophenyl) azetidin-3-yll-N- (bis (4-chlorophenyl)methyl] azetidin-3-yl}-N- difluorophenyl) benzylsulfonamide, their optical isomers and their pharmaceutically acceptable salts with an inorganic or organic acid.
And even more particularly preferred are the following azetidine derivatives: 1 -[bis(4-chlorophenyl)methyl]-3-[(RS)-(3,5-difluorophenyl)(methylsulfonyl) methyl] azetidin-3-ol, 3-acetoxy-1 -[bis(4-chlorophenyl)methyl]-3-[(RS)-(3,5difluorophenyl)(methylulphonyl)methyl)methylsulfonylmethyl]azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl) methylene]azetidine, their optical isomers and their pharmaceutically acceptable salts with an inorganic or organic acid.
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 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 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 methylcellulose/0.2% polysorbate 80) in two consecutive administrations. The rats are treated from the 8th day with the vehicle, the CB1 antagonist (1-[bis(4chlorophenyl)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 solution and administered at a dose of 3 mg/kg; the CB1 antagonist is dissolved in miglyol 812N (Huls, 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.
GROUP First administration Second administration 1 miglyol 0.5% methylcellulose/ "vehicle group" 0.2%polysorbate 2 miglyol sibutramine 3 mg/kg "sibutramine group" 3 CB1 antagonist 0.5% methylcellulose/ "CB1 Antagonist group" 0.6 mg/kg 0.2% polysorbate 4 CB1 antagonist sibutramine 3 mg/kg "combination group" 0.6 mg/kg 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.
Treatment Food consumption during the 5 days of treatment (g) Vehicles 25.52 0.30 sibutramine 3 mg/kg 24.60 ±0.32* CB1 antagonist 0.6 mg/kg 24.00 ±0.24** sibutramine (3 mg/kg) 22.76 CB1 antagonist (0.6 mg/kg) *p<0.05 **p<0.01 ***p<0.0001 The results show that, in the animals receiving the sibutramine and CB1 antagonist combination, the reduction in food consumption is much greater than that of the animals treated either with sibutramine alone or with the CB1 antagonist alone.
29 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 CB1 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 (drag~es) 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 CB1 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 CB1 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.
Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
Claims (14)
1. A synergistic combination of a CB1 antagonist and of sibutramine, its hydrate or one of its pharmaceutically acceptable salts wherein the CB1 antagonist and sibutramine, its hydrate or one of its pharmaceutically acceptable salts, are administered simultaneously or sequentially.
2. The combination as claimed in claim 1, for which the CB1 antagonist is a compound of formula: R 3 R 4 'N (I) in which either R represents a chain or and /SO R 1 /SO 2 R C=CH\ or C-CH R 2 R 2 Ri represents a methyl or ethyl radical, R 2 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, -COOR s formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NR 6 R 7 -CO-NH-NR 6 R 7 -N(alk)COOR 8 cyano, -CONHR 9 -CO-NR 16 R 17 alkylsulfanyl, hydroxyalkyl, -O-alk-NR 12 R 13 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, -COOR 5 trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NR 6 R 7 -CO-NH-NR 6 cyano, -CONHR 9 alkylsulfanyl, hydroxyalkyl or alkylthioalkyl, R 3 and R 4 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-a 1k, cyano, -COOR 5 -C0NR 1 0 R 1 1 -CO-NH-NR 6 R7, alkylsulfanyl, hydroxyalkyl, -alk-NR 6 R 7 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, -COOR 5 -CO-NH-NR 6 R7, -CONRjoR 1 alk-NR 6 R 7 alkylsulfanyl, hydroxyalkyl or alkylthioalkyl, R 5 is an alkyl radical or a phenyl radical optionally substituted by one or more halogen atoms, R6 and R7,, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or else R 6 and R 7 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-NR 14 R 15 oxo, hydroxyalkyl, -alk-O-alk or -CO-NH 2 radicals, R 8 represents an alkyl radical, R 9 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 10 and R 11 which are identical or different, represent a hydrogen atom or an alkyl radical or else Rio and R1 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, R 12 and R 13 which are identical or different, represent a hydrogen atom or an alkyl or cycloalkyl radical or else R 12 and R 13 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-NR 14 R 15 radical or a saturated mono- or bicyclic heterocycle having 3 to 10 ring members and comprising a heteroatom chosen from oxygen, sulfur and nitrogen, R 14 and R 15 which are identical or different, represent a hydrogen atom or an alkyl or -COOalk radical, R 16 and R 17 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 CHR 18 radical and R 18 represents an -NHCOR 1 i or -N(R 20 )-Y-R 2 1 radical, Y is CO or S0 2 R 4 and R 3 which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR 22 R 23 -CO-NH-NR 24 R 25 alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NH 22 R 23 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-NR 2 4 R 25 -CONR 22 R 23 -alk- NR 24 R 2 5 alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R 19 represents an -alk-S0 2 -R 26 radical, an -alk-SO 2 CH=CH-R 26 radical, a Hetl radical substituted by -S0 2 -R 26 or a phenyl radical substituted by -S0 2 -R 26 or -alk-S0 2 R 26 R 20 represents a hydrogen atom or an alkyl radical, R 21 represents a phenylalkyl, Heti or Arl radical, R 22 and R 23 which are identical or different, represent a hydrogen atom or an alkyl radical or else R 22 and R 23 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, R 24 and R 25 which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or else R 24 and R 25 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 2 R 26 represents an alkyl, Arl or Hetl radical, Ari represents a phenyl, naphthyl or indenyl radical, these radicals optionally being substituted by one or more halogen, alkyl, alkoxy, cyano, -CO-alk, -COOH, -COOalk, -CONR 27 R 28 -CO-NH-NR 29 R 30 alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR 29 R 30 -NR 29 R 30 alkylthioalkyl, formyl, hydroxyl, hydroxyalkyl, Het, -O-alk-NH-cycloalkyl, OCF 3 CF 3 -NH-CO-alk, -SO 2 NH 2 -NH-COCH 3 -NH-COOalk or Het or else on 2 adjacent carbon atoms by dioxymethylene, Hetl 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 3 or CF 3 the nitrogenous heterocycles optionally being in their N- oxidized form, R 27 and R 28 which are identical or different, represent a hydrogen atom or an alkyl radical or else R 27 and R 28 form, together with the nitrogen atom to which they are attached, a saturated 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 29 and R 30 which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or else R 29 and R 30 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 2 radicals, or R represents CHR 31 and R 31 represents an -N(R 32 )R 33 -N(R 32 )-CO-R 33 or -N (R 32 -S0 2 R 34 radical, R 4 and R 3 which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, COOalk, -CONR 22 R 23 -CO-NH-NR 24 R 25 alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NRRs, 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 heteroaromatics to be unsubstituted or substituted by a halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR 24 R 25 -CONR 22 R 23 -alk-NR 24 R 25 alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl, R 32 represents a -C (R 35 (R 36 -Het 2 -Het 2 -C (R 35 (R36) -Ar 2 Ar 2 cycloalkyl or norbornyl radical, R 33 represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONRR 2 2 3 -alk-NR 22 R 23 alkoxy, Ar 2 Het 2 -CH 2 Ar 2 -CH 2 Het 2 or alkyl radical, the latter optionally substituted by one or more halogen, R 34 represents a hydroxyalkyl, -alk-COOalk, -alk-CONRR 2 2 3 -alk-NR 22 R 23 alkoxy, Ar 2 Het 2 -CH 2 Ar 2 -CH 2 Het 2 or alkyl radical, the latter optionally substituted by one or more halogen, R 35 represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONRR 2 2 3 -alk-NR 22 R 23 alkoxyalkyl, Ar 2 Het 2 -CH 2 Ar 2 -CH 2 Het 2 or alkyl radical, the latter optionally substituted by one or more halogen, R 36 represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONRR 2 2 3 -alk-NR 22 R 2 3 alkoxyalkyl or alkyl radical, the latter optionally substituted by one or more halogen, or else R 35 and R 36 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 2 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, -CONR 37 R 38 -CO-NH-R 3 9 R 4 0 alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR 3 9 R 40 -NR 3 9R 4 0, alkylthioalkyl, formyl, CF 3 OCF 3 Het, -O-alk-NH- cycloalkyl, SO 2 NH 2 hydroxyl, hydroxyalkyl, -NHCOalk or NHCOOalk or on 2 adjacent carbon atoms by dioxymethylene, Het 2 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, R 37 and R 38 which are identical or different, represent a hydrogen atom or an alkyl radical or else R 37 and R 38 form, together with the nitrogen atom to which they are attached, a saturated 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, R 39 and R 40 which are identical or different, represent a hydrogen atom or an alkyl radical or else R 39 and R 40 form, together with the nitrogen atom to which they are attached, a saturated 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, 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 is chosen from the following compounds: 1-benzhydryl-3- [(methylsulfonyl) (phenyl)- methylene]azetidine, 1-benzhydryl-3- (3-methylphenyl) (methylsulfonyl) methylene]azetidine, 1-benzhydryl-3-[(3-chlorophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[(3,5-dichlorophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[(2,5-dichlorophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[(2,3-dichiorophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[(3-fluorophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-((3,5-difluorophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[(3-bromophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[(3-iodophenyl) (methylsulfonyl)- methylene]azetidine, 1-benzhydryl-3-[ (methylsulfonyl) (3-trifluoro- methoxyphenyl)methylene]azetidine, 1-benzhydryl-3-[(methylsulfonyl) (3-trifluoro- methylphenyl)methylene]azetidine, 1-benzhydryl-3-{ 5-bis (trifluoromethyl)phenyl]- (methylsulfonyl) methylenelazetidine, 1-benzhydryl-3- 5-dibromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhyclryl-3- [(3-methoxycarbonyiphenyl) (methylsulfonyl)rnethylene] azetidine, 1-benzhydryl-3-[ (3-cyanophenyl) (methylsulfonyl)- methylene] azetidine, 1-benzhydryl-3- II(3-carbamoylphenyl) (methylsulfonyl) rethylene] azetidine, 1-benzhydryl-3-( (methylsulfonyl) (naphth-1-yl) (methyl- sulfonyl) methylene] azetidine, 1-[bis (4-chlorophenyl)methyl]-3-[ phenyl) (methylsulfonyl) methylene] azetidine, 1-[bis(4-methoxyphenyl)rnethy1]-3-[ phenyl) (methylsulfonyl) methylene] azetidine, 1-[bis(4-methylphenyl)methyl]-3-[ phenyl) (methylsulfonyl)methylene] azetidine, (RS) (3,5-difluorophenyl) (methylsulfonyl)methylene]- (4-methoxyphenyl) (phenyl)methyl) ]azetidine, (3,5-difluorophenyl) (methylsulfonyl)methylene]- (4-methoxyphenyl) (phenyl)methyl]azetidine, (3,5-difluorophenyl) (methylsulfonyl)methylenel- (4-methoxyphenyl) (phenyl)methyl]azetidine, 1- [bis(4-trifluoromethoxyphenyl)methyl]-3-[ fluorophenyl) (methylsulfonyl) methylene] azetidine, 1-[bis(4-trifluoromethylphenyl)methyl]-3-[ fluorophenyl) (methylsulfonyl)methylene] azetidine, 1-[bis(4-chlorophenyl)methyll-3-{ methyl) phenyllmethylsulfonylmethylenelazetidine, (RS) (4-chiorophenyl) (2,4-dichlorophenyl)methyl]-3-
5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (2,4-dichlorophenyl)methyl]-3- 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) 4-cichlorophenyl)methyl]-3- (methylsulfonyl)- methylene] azeticline, (4-chiorophenyl) [4- (hydroxymethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) [4- (hyciroxymethyl) phenyll methyl phenyl) (methylsulfonyl)methylene] azetidine, (4-chloropheiyl) [4- (hycroxymethyl)phenyllmethyl)-3-[(3,5-difluoro- phenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) [4- (pyrrolidylmethyl)phenyllmethyll-3-[ phenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) [4- (pyrrolidylmethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl)rnethylene] azeticline, (4-chiorophenyl) [4- (pyrrolidylmethyl)phenyllmethyll-3- phenyl) (methylsulfonyl)mrethylene] azetidine, 1-f (RS) -(4-chiorophenyl)[L4-(3, 3-dimethylpiperidin-1- ylmethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl) methylene] azeticline, (R)-(4-chlorophenyl) (3,3-dimethylpiperidin-1- ylmethyl)phenyl]methyl}-3-[ phenyl) (methylsulfonyl) methylene] azetidine, (S)-(4-chlorophenyl) (3,3-dimethylpiperidin-1- ylrethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl) methylene] azetidine, (RS)-(4-chlorophenyl) (thiomorpholin-4- ylmethyl)phenyllrnethyl}-3-[ phenyl) (methylsulfonyl) methylene] azetidine, 1-f -(4-chiorophenyl) (thiomorpholin-4- ylmethyl)phenyl]methyl}-3-[ phenyl) (methylsulfonyl) methylene] azeticline, (S)-(4-chlorophenyl) (thiomorpholin-4- ylmthyl)phenyl]methyl}-3-[ phenyl) (methylsulfonyl)methyleie] azetidine, (RS) -(4-chiorophenyl) (N-ethyl-N- cyclohexylaminomethyl)phenyllmethyl)-3-[ difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (N-ethyl-N- cyclohexylaminomethyl)phenyllmethyll-3-[ difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (N-ethyl-N- cyclohexylaminomethyl)phenyllmethyl)-3- difluorophenyl) (methylsulfonyl) methylene] azetidine, {(RS)-(4-chlorophenyl) (4-ethoxycarbonyl- piperazinyl)methyllphenyl~methyl} difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-I -(4-chiorophenyl)f{4- [(4-ethoxycarbonyl- piperazinyl)rnethyllphenyllmethyl} 1-3- difluoropheiyl) (methylsulfonyl)methylene] azeticline, -(4-chiorophenyl) [(4-ethoxycarbonyl- piperazinyl)methyllphenylimethyl} clifluoropheny1) (methylsulfonyl)methylene] azetidine, (RS) -(4-chiorophenyl) (N-cyclopropyl-N- propylaminomethyl) phenyllmethyl}-3- difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (N-cyclopropyl-.N- propylaminomethyl)phenyllmethyl)-3-[ cifluorophenyl) (rethylsulfonyl)methylene] azeticline, 1-f (SI- (4-chiorophenyl) (N-cyclopropyl-N- propylaminomethyl)phenyllmethyl)-3- difluorophenyl) (rethylsulfonyl)methylenelazetiline, (RS)-(4-chlorophenyl) (diisopropylamino- methyl)phenyllmethyl}-3-[ (methylsulfonyl) methylene] azetidine, -(4-chiorophenyl) (diisopropylaminomethyl) phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl) methylene] azeticline, (S)-(4-chlorophenyl) [4-(ciisopropylaminomethyl)- phenyllrnethyl}-3-[ 5-difluorophenyl) (methylsulfonyl)- methy2.ene] azetidine, {(RS)-(4-chlorophenyl) {4-[bis(2-methoxyethyl)- aminomethyllphenyl~methyl} (3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) {4-jjbis (2-methoxyethyl)- aminomethyllphenyllmethyll 5-difiluorophenyl) (methylsulfonyl)methylene] azeticline, (S)-(4-chlorophenyl) {4-[bis(2-methoxyethyl)- aminornethyllphenyllmethyl} 1-3-li(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS)-(4-chlorophenyl) 4[Li-c-n- propylaminomethyl)pheriyllmethyl}-3- phenyl) (methylsulfonyl)methylene] azeticline, (4-chiorophenyl) (di-n-propylaminomethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methylsulfonyl)- methylene] azetidine, (4-chiorophenyl) (ci-n-propylaminomethyl)- phenyllmethyll-3- [(3,5-clifluorophenyl) (methyl- sulfonyl) methylene] azetidine, (4-chiorophenyl) (piperidin-1-ylrnethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl)rnethylene] azetidine, (R)-(4-chlorophenyl) (piperidin-1-ylmethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, (4-chiorophenyl) (piperidin-l-ylmethyl)- phenyllmethyl)-3-[ 5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, (RS)-(4-chlorophenyl) (4-methylpiperazin-l- ylrethyl)phenyllmethyl}-3-[ (methyl sulfonyl) methylene] azetidine, (R)-(4-chlorophenyl) (4-methylpiperazin-l- ylmethyl)phenyl]methyl}-3-[ (methylsulfonyl) methylene] azetidine, (S)-(4-chlorophenyl) (4-methylpiperazin-1- ylmethyl)phenyl]methyl}-3-[ 5-clifluorophenyl) (methylsulfonyl)methylene] azetidine, (RS)-(4-chlorophenyl) (morpholin-4- ylmethyl)phenyllmethyl}-3-[ (mrethylsulfonyl) methylene] azeticline, (R)-(4-chlorophenyl) [4-(morpholin-4-ylmethyl)- phenyllmethyl}-3-[ (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (morpholin-4-ylmethyl)- phenyllmethyl}-3-[ (3,5-clifluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (diethylaminomethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl)methylene] azeticline, (4-chiorophenyl) (diethylarninomethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl) methylenel azetidine, (4-chiorophenyl) (diethylaminomethyl) phenyllmethyll-3-[ (3,5-difluorophenyl) (methyl- sulfonyl)methylene] azetidine, (RS) -(4-chiorophenyl) (piperazin-2-one-4- ylmethyJ~phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl)rnethylene] azetidine, (4-chiorophenyl) (piperazin-2-one-4-ylmethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl)methylene] azetidine, (4-chiorophenyl) (piperazin-2-one-4-ylrnethyl)- phenyllmethyl}-3-[ (3,5-clifluorophenyl) (methyl- sulfonyl)methylene] azetidine, (RS)-(4-chlorophenyl) [4-(imidazol-1-ylmethyl)- phenyllmethyll-3-[ 5-difluorophenyl) (methyl- sulfonyl)methylene] azetidine, (R)-(4-chlorophenyl) (imidazol-1-ylmethyl)- phenyllmethyl}-3- 5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, (S)-(4-chlorophenyl) [4-(imicazol-1-ylmethyl)- phenyllmethyll-3-[ (3,5-clifluorophenyl) (methyl- sulforiyl) methylene] azetidine, (4-chiorophenyl) dimethylcarbamoyl)phenyllmethyl)-3-[ cifluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) dimethylcarbamoyl)phenyllmethyl}-3- difluorophenyl) (methylsulfonyl)methylenelazetidine, (4-chiorophenyl) dimethylcarbamoyl) phenyllmethyll difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) ethylcarbarnoyl)phenyllmethyl) difluorophenyl) (methylsulfonyl)methylenelazetidine, (4-chiorophenyl) ethylcarbamoyl)phenyllmethyl}-3-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) ethyilcarbamoyl)phenyl]methyl}-3-[ difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) (4-carbamoylphenyl) (4-chlorophenyl)methyl]-3- (methylsulfonyl)niethylene]- azetidine, (4-carbamayiphenyl) (4-chlorophenyl)methyl]-3- 5-difluorophenyl) (methylsulfonyl)methylene]- azetidine, (4-carbamoylpheiyl) (4-chlorophenyl)methyl]-3- (methylsulfonyl)methylene]- azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[ phenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3-[ (3-methylsulfanyiphenyl) (methyl- sulfonyl)methylene] azetidine, 1-benzhydryl-3-[ (3-methylsulfanylmethyl)phenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-chlorophenyl)methyl] -3-f (3-cyanophenyl) (methylsulfonyl) methylene] azeticline, 1- [bis (4-chlorophenyl)methyl] -3-f (3-carbamoylphenyl) (rethylsulfonyl)methylene] azetidine, 1-[bis (4-chlorophenyl)methyl]-3-[ (3-methoxyphenyl)- (methylsulfonyl) methylene] azeticline, 1-[bis (4-chlorophenyl)methyl] -3-f (3-hydroxyphenyl)- (methylsulfonyl)methylene] azetidine, 1-[bis (4-chlorophenyljrrethyl]-3-[ (methylsulfonyl) (3- pyrrolidinyiphenyl) methylene] azetidine, 1-[bis (4-chlorophenyl)methyl]-3-[ (3-hydroxy- methyiphenyl) (methylsulforiyl)methylene] azetidine, 1-[bis (4-chlorophenyl)methyl]-3-{ (methylsulfonyl) f3- (N- piperidylcarbamoyl) phenyl] methylene }azetidine, 1-[bis (4-chlorophenyl)methyl]-3-[ (methylsulfonyl) (3- trifluoromethylsulfanylphenyl) (methylsulfonyl) methylene] azetidine, 1-fbis (4-fluorophenyl)methyl]-3-[ (methylsulfonyl)methylene] azetidine, 1-[bis (2-fluorophenyl)methyl]-3-f (methylsulfonyl)methylene] azetidine, 1-[bis(3-fluorophenyl)methyl]-3-[ (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3- [(methylsulfonyl) (phenyl)methylene]azetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3- [(methylsulfonyl) (phenyl)methylene]azetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3- [(methylsulfonyl) (phenyl)methylene]azetidine, (4-chiorophenyl) (thien-2-yl)methyl]-3-[ cifluorophenyl) (methylsulfonyl)methylene] azetidine, (R)-1-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[ cifluorophenyl) (methylsulfonyl)methylene] azetidine, (S)-l-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)methylene] azeticline, 1-benzhyciryl-3-[ (ethylsulfonyl) (phenyl)methylene]- azetidine, 1- [bis (4-chlorophenyl)methyl] (4- methylpiperazinyl)carbamoyllphenyl1 (methylsulfonyl)- methylene~azetiline, 1-[bis(4-chlorophenyl)rethyl]-3-{ dimethylcarbohydrazido) phenyl] (methylsulfonyl) methylene }azetidine, 1- [bis (thien-2-yl) methyl] 5-difluorophenyl) (methylsulfonyl)methylene] azeticline, 1-[bis (p-tolyl)methyl]-3-[ (methylsulfonyl) (phenyl)methylene] azetidine, (4-chiorophenyl) (4-hydroxymethylphenyl)methyl]-3- (methylsulfonyl)methylene]- azeticline, 1-[bis (4-chlorophenyl)methyl]-3-[ (3-methylaminophenyl)- (methylsulfonyl) methylenel azeticline, (RS)-1-[(4-chlorophenyl) (thiazol-2-yl)methyl]-3-[(3,5- difluorophenyl) (methylsulfonyl)rnethylene] azetidine, (R)-l-[(4-chlorophenyl) (thiazol-2-yl)rnethyl]-3-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3-[ difluorophenyl) (methylsulfonyl)rnethylene] azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[ (methylsulfonyl) (2- methoxycarbonylthien-5-yl)methylene] azetidine, (RS) -1-[jbis (4-chiorophenyl) methyl] -3-hydroxy-3- [(methylsulfonyl) yl) methyl] azetidine, 1-[bis (4-chlorophenyl)methyl] (2-isobutylamino- carbonylthien-5-yl) (methylsulfonyl)methylenelazetidine, 1-[bis(4-chlorophenyl)methyl]-3-[ (RS)-(3-methoxy- carbonyiphenyl) (methylsulfonyl) methyl] azeticlin-3-ol, 1-[bis(4-chlorophenyl)methyl]-3-[ (RS)-(methyl- sulfonyl) (pyridin-4-yi)methyl] azetidin-3-ol, 1-[bis(4-chlorophenyl)methyl]-3-[(Rs)- (methylsulfonyl) (pyridin-3-yl) methyl] azetidin-3-ol, 3- [bis (4-chiorophenyl) methyl] azetidin-3- yliciene} (methanesulfonyl)methyl)-N- (morpholin-4- yl) propyl) benzamile, 3- [bis (4-chiorophenyl) methyl] azetidin-3- ylidene} (methanesulfonyl)methyl)-N-(3- dimethylaminopropyl) benzamide, 3- [bis (4-chiorophenyl) methyl] azetidin-3- ylidene} (methanesulfonyl)methyl) (pyrrolidin-1- yl) ethyl) benzamide, 3-({l-Ilbis (4-chlorophenyl)methyllazetidin-3- ylidene} (methanesulfonyl)methyl) (2-dimethylamino-1- methylethyl) benzamide, 3- [bis (4-chlorophenyl) methyl] azeticlin-3- ylidene} (methanesulfonyl)methyl) (piperidin-l- yl)benzamide, 3- [bis (4-chlorophenyl) methyl] azetidin-3- ylidenel (methanesulfonyl)methyl) -N-isobutylbenzamide, 3- [bis (4-chlorophenyl) methyl] azetidin-3- yliclenel (methanesulfonyl)methyl) (imidazol-1- yl)propyl)benzamide, 3- ({l-[bis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) (2- cimethylaminoethyl) benzamide, N'-methylhydrazide of 3-({1-[bis (4-chlorophenyl)- methyllazetidin-3-ylidene} (methanesulfonyl)- methyl) benzoic acid, 3- [bis (4-chlorophenyl) methyl] azetidin-3- ylidene} (methanesulfonyl)methyl) (morpholin-4- yl) ethyl) benzamide, 3- ({l-[bis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) (l-ethylpyrrolidin- 2-ylmethyl) benzamide, 3- [bis (4-chlorophenyl) methyl] azetidin-3- ylidene} (methanesulfonyl)methyl)-N- (2,2- dimethylpropyl) benzamide, 3- (f [bis (4-chiorophenyl) methyl] azetidin-3- ylidene} (methanesulfonyl)methyl) -N- (cyclohexylmethyl) benzamide, 3- [bis (4-chiorophenyl) methyl] azetidin-3- ylidene} (methanesulfonyl)methyl) -N- Ccyclopropylmethyl) benzamide, [bis (4-chlorophenyl)methyl]azetidin-3- ylidenel (methanesulfonyl)methyl) (2- methylbutyl) ben.zamide, 3- ({1-Ibis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) (2- phenyipropyl) benzamide, 3- ({1-[bis (4-chlorophenyl)methyl]azetidin-3- ylidenel (methanesulfonyl)methyl) (tetrahydrofuran-2- ylmethyl) benzamide, 3-({1-Iibis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl)-N- (2,2- ciphenylethyl) benzamiie, 3- -[bis (4-chiorophenyl) methyl] azetidin-3- yliciene} (methanesulfonyl)methyl)-N- (2- ethylbutyl) benzamide, methyl ester of [3-({1-[bis(4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl) benzoylamino] methyl Icyclohexanecarboxylic acid, 2-amino-l-{4-113-({1-[bis(4-chlorophenyl)methyl]- azetidin-3-ylidene)}(methanesulfonyl) methyl) phenyl I- piperazin-1-yl lethanone, tert-butyl ester of (4-chlorophenyl)- methyl] azetidin-3-ylidene) (methanesulfonyl) methyl) phenyllpiperazin-1-yl}-2-oxoethyl)carbamic acid, 1-f{4- [bis (4-chiorophenyl) methyl] azetidin-3- ylidene} (methanesulfonyl)methyl)phenyllpiperazin-l-yl}- 2- (methylamino) ethanone, tert-butyl ester of chlorophenyl) methyl] azetidin-3- ylidenel (methanesulfonyl)methyl)phenyllpiperazin-1-yll- 2-oxoethyl) -N-methylcarbamic acid, N-methylamide of 4-[3-({l-[bis(4-chlorophenyl)- methyl] azetidin-3-ylidene }(methanesulfonyl) methyl) phenyllpiperazine-l-carbothioic acid, N-methylamide of ({l-[bis (4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl)phenyl] piperazine-l-carboxylic acid, methyl ester of 4-13-({1-Ibis(4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl) phenyl] piperazine-l-carboxylic acid, 1- [bis (4-chlorophenyl)methyl] azetidin-3- ylidene} (methanesulfonyl)methyl)phenyl] -4- isobutylpiperazine, l-[3-({l-[bis(4-chlorophenyl)methyl]azetiiin-3- ylidene} (methanesulfonyl)methyl) phenyl] -4- ethylpiperazine, 4-acetyl-1-113-({1-[bis (4-chlorophenyl)methyl]azetidin- 3-ylidene} (methanesulfonyl)methyl)phenyllpiperazine, l-{4-[3-({1-[bis(4-chlorophenyl)methyllazetidin-3- ylidene} (methanesulfonyl)methyl)phenyl]piperazin-1-yll- 2-dimethylaminoethanoie, 1- [bis (4-chlorophenyl)methyl] azetidin-3- ylidenel (methanesulfonyl)methyl)phenyllpiperazine, tert-butyl ester of 4-[3-({l-[bis(4-chlorophenyl)- methyl] azetidin-3-ylidene} (methanesulfonyl)methyl) phenyllpiperazine-l-carboxylic acid, 1-[bis(4-methoxycarbonylphenyl)methyl]-3-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, 3-acetoxy-l-[bis (4-methoxycarbonylphenyl)methyl]-3- 5-difluorophenyl) (methylsulfonyl)methyl] azetidine, (4-chiorophenyl) difluorophenyl) (rethanesulfonyl)methylene] azetidin-l- yl~methyl)benzyl]morpholine, (1-benzhydrylazetidin-3-ylidene) (methane- sulfonyl) methyl] phenoxylbutyl) morpholine, (l-benzhydrylazetidin-3-ylidene) (methane- sulfonyl) methyl] phenoxyipropyl) morpholine, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yllthien- 2-ylsulfonamide, N- [bis (4-chiorophenyl) methyl] azetidin-3-yl 1- 4 -methoxyphenylsulfonamiie, (4-chlorophenyl)methyllazetidin-3-yll- sulfamoyl)phenyl] acetamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yll- 4 -methyiphenylsul fonamide, N- [bis (4-chiorophenyl) methyl] azeticiin-3-yl 3, 4-dimethoxyphenylsulfonamide, N-{1-[bis(4-chlorophenyl)methyllazetidin-3-yll- 3-f luorophenylsulfonamide, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- 3, 4-dichiorophenylsulfonamide, [bis (4-chlorophenyl)methyllazetidin-3-yl}- 3-cyanophenylsulfonamiie, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- 2, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- 3-trifluoromethylphenylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl~naphth-2- ylsul fonamide, N-{1-[bis (4-chlorophenyl)methyllazeticlin-3-yllnaphth-1- ylsulfonamide, N- [bis (4 -chiorophenyl) methyl] azetidin-3-yl 3, 4-cifluorophenylsulfonamide, N-fl [bis (4-chiorophenyl) methyl] azetidin-3-yl)I- 1-methyl-lH-imidazol-4-ylsulfonamide, N- [bis (4-chlorophenyl)methyl] azetidin- 3-yl }sulfamoyl) -2-chiorophenyl] acetamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yllpyrid- 3-ylsulfonanide, N-{l-[bis (4-chlorophenyl)methyl]azeticlin-3-yl}- 4 -fluorophenylsulfonamide, N-{1-Ilbis (4-chlorophenyl)methyllazetidin-3-yllquinol-
8-ylsulfonamile, N-{l-Ilbis (4-chlorophenyl)methyl]azetidin- 3-yl lphenylsulfonamide, [bis (4-chiorophenyl) methyl] azetidin- 3-yl} (phenylmethyl) sulfonamide, N-{l-[bis (4-chlorophenyl)methyllazetidin-3-yl}- 3, 1- [bis (4-chiorophenyl) methyl] azetidin-3-yl Ipyrid- 2-ylsulfonamide, N- (1-[bis (4-chiorophenyl) methyl] azetidin-3-yl 1- sulfonamide, N-{1-ilbis (4-chlorophenyl)methyllazetidin-3-yl}- N-methyl-4 -fluorophenylsulfonamide, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yll- N-methylquinol-8-ylsulfonamide, N-f{ [bis (4-chiorophenyl) methyl] azetidin-3-yl 1- N-methylphenylsulfonamide, 1- bis (4-chlorophenyl)methyl] azetidin-3-yll- N-methyl (phenylmethyl) sulfonamide, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- 3-sulfamoylphenylsulfonamide, 2-benzenesulfonyl-N-{l-[bis(4-chlorophenyl)methyl]- azetidin-3-yll}acetamide, N-Il-[bis (4-chlorophenyl)methyl]azetiiin-3-ylJ- 2- (4-toluene-4-sulfonyl) acetamide, (3-chloro-4- (methylsulfonyl) thiophene-2-carboxy) {l-[bis (4-chlorophenyl)methyl]azetidin-3-yllamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- 3- (2-phenylethylenesulfonyl)propionamide, N-{1-[bis (4-chlorophenyl)rnethyllazetidin-3-yl}- 4- (methylsulfonyl) benzamide, N-{1-[bis(4-chlorophenyl)methyllazetidin-3-yl}- 4- (methanesulfonyl)benzamide, (methylsulfonyl) thiophene-2-carboxy) {1-[bis (4-chlorophenyl)methylllazetidin-3-yllamide, (5-methylsulfonyl-3-methyl-4-vinylthiophene- 2-carboxy) [bis (4-chlorophenyl)mnethyllazetidin- 3-yllamide, (4-chiorophenyl) (pyridin-3-yl)methyl]- azetidin-3-yl}-3, (RS) (4-chlorophenyl) azetidin-3-yl}-3, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (6-chloropyrid-2-yl)methylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (6-ethylpyrid-2-yl) methylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (quinol-6-yl)methylsulfonamide, N-f1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- N- N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (pyrid-3-yl)methylsulfonamide, N- Ibis (4-chiorophenyl) methyll azeticlin-3-yl 1- 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-yllmethylsulfonamide, N-(lR,2R,4S)-(bicyclo[2.2.1]hept-2-yl)-N-{1-[bis- (4-chlorophenyl)methyl] azetidin-3-yl~methylsulfonamide, N-f1- [bis (4-chlorophenyl)methyllazetidin-3-yll- N- 5-difluorophenyl) methylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (thiazol-2-yl) methylsulfonamide, Ibis (4-chlorophenyl)methyllazetidin-3-yl}- N- (3-methoxyphenyl) methylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yll- N- (3-hydroxyphenyl)methylsulfonamide, N-f{ [bis (4-chiorophenyl) methyl] azetidin-3-yl N- (hydroxymethyl)phenyl)methylsulfonamide, ethyl N-{1-[bis (4-chlorophenyl)rnethyl]azetidin-3-ylJ- N- (methylsulfonyl) -3-aminobenzoate, N-{l-[bis(4-chlorophenyl)methyllazetidin-3-yl}- N- (isobutylpiperid-4-yl)methylsulfonamide, N-benzyl-N-{1-[bis(4-chlorophenyl)methyllazetidin- 3-yllIamine, bis(4-chlorophenyl)methyllazetidin-3-yl}- N- 5-difluorobenzyl) amine, N- [bis (4-chiorophenyl) methyl] azetidin-3-yl)}- N- N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yll- N- (pyrid-3-ylmethyl)methylsulfonamide, N-{l-[bis (4-fluorophenyl)methyllazetilin-3-yl}- N- (4-chiorophenyl) (pyrid-3-yl)methyl]azetiiin- 3-yl}-N- (4-chiorophenyl) (pyrid-3-yl)methyllazetidin- 3-yl)-N-(3,5-difluorophenyl)methylsulfonamide, (4-chiorophenyl) (pyrid-3-yl)methyl]azetidin- 3-yl)-N- (RS) (4-chiorophenyl) (pyrid-4-yl)methyljazetidin- 3-ylI-N-(3, (4-chiorophenyl) (pyrid-4-yl)methyllazetidin- 3-yl}-N- (4-chiorophenyl) (pyrid-4-yl)methyl]azetidin- 5-difluorophenyl) methylsulfonamide, (4-chiorophenyl) azetidin-3-yl}-N- (4-chiorophenyl) azetidin-3-ylI-N- (4-chlorophenyl) azetidin-3-yl}-N- N-{1-Ilbis (4-chlorophenyl)methyllazetidin-3-yl}-N- difluorophenyl) benzylsulfonamiie, 57 their optical isomers and their pharmaceutically acceptable salts. 4. The combination as claimed in claim 2, for which the compound of formula is chosen from the following compounds: 1-[bis(4-chlorophenyl)methyl]-3-[(RS)-(3,5-difluorophenyl) (methylsulfonyl)methyl]azetidin-3-ol, 3-acetoxy-l -[bis(4-chlorophenyl)methyl]-3- 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 antagonist is SR141716, its hydrates and its pharmaceutically acceptable salts or LY320135 and its pharmaceutically acceptable salts. 6. A pharmaceutical composition comprising a CB1 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 CB1 antagonist of formula is as defined in claim 2. 8. The pharmaceutical composition as claimed in claim 7, for which the compound of formula is chosen from the following compounds: 1-benzylhydryl-3-[(methylsulfonyl)(phenyl)-methylene]azetidine, 1 -benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)-methylene]azetidine, 1-benzhydryl-3-[ (3-chiorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3-[ (3,5-dichiorophenyl) (methylsulfonyl)- methylene] azetidine, 1-benzhydryl-3-[ (2,5-dichiorophenyl) (methylsulfonyl) methylenel azetidine, 1-benzhyciryl-3-[ (2,3-dichiorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3-[ (3-fluorophenyl) (methylsulfonyl)- methylene] azetidine, 1 -benzhydryl-3-[ (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3-bromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3-[ (3-iodophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3-[ (methylsulfonyl) (3-trifluoro- methoxyphenyl) methylene] azetidine, 1-benzhydryl-3-[ (methylsulfonyl) (3-trifluoro- methylphenyl)methylene] azetidine, 1-benzhydryl-3-{[3,5-bis (trifluoromethyl)phenyl]- (methylsulfonyl) methylene }azetidine, 1-benzhydryl-3-[ (3,5-dibromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(3-methoxycarbonyiphenyl) (methylsulfonyl)methylene] azetidine, 1-benzhydryl-3-[ (3-cyanophenyl) (methylsulfonyl)- methylene] azetidine, 1-benzhydryl-3- [(3-carbamoylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3- [(methylsulfonyl) (naphth-1-yl) (methyl- sulfonyl) methylene] azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[ phenyl) (methylsulfonyl) methylene] azetidine, 1- [bis (4-methoxyphenyl) methyl] phenyl) (methylsulfonyl) methylene] azetidine, 1-[bis (4-meth~jlphenyl)methyl]-3-[ phenyl) (methylsulfonyl) methylene] azetidine, (RS) 5-difluorophenyl) (methylsulfonyl)methylene]- (4-methoxyphenyl) (phenyl)methyl) lazetidine, 5-difluorophenyl) (methylsulfonyl)methylene]- (4-methoxyphenyl) (phenyl)methyl]azetidine, (3,5-difluorophenyl) (methylsulfonyl)methylene]- (4-methoxyphenyl) (phenyl)rnethyl]azetidine, 1-[bis (4-trifluoromethoxyphenyl)methyl]-3-[ fluorophenyl) (methylsulfonyl)rnethylene] azetidine, 1-[bis (4-trifluoromethylphenyl)methyl]-3-[ fluorophenyl) (methylsulfonyl)methylene] azetidine, 1-[bis (4-chlorophenyl)methyl]-3-{ [3,5-bis (trifluoro- methyl) phenyllmethylsulfonylmethylenelazetidine, (4-chiorophenyl) (2,4-dichlorophenyl)methyl]-3- (methylsulfonyl)- methylene] azetidine, (4-chlorophenyl) (2,4-dichlorophenyl)methyl]-3- 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (2,4-dichlorophenyl)methyl]-3- 5-difluorophenyl) (methylsulfonyl) methylene] azeticline, (4-chiorophenyl) [4- (hydroxymethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) [4- (hydroxymethyl)phenyllmethyl)-3- phenyl) (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) [4- (hydroxymethyl)phenyllrnethyl}-3-[ phenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) [4- (pyrrolidylmethyl)phenyllmethyll-3-[ phenyl) (methylsulfonyl)methylene]azetidine, (4-chiorophenyl) [4- (pyrrolidylmethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl)methylene] azeticline, (4-chiorophenyl) [4- (pyrrolidylmethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (3,3-dimethylpiperidin-l- ylmethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (3,3-climethylpipericlin-1- ylmethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl) methylene] azeticline, (4-chiorophenyl) (3,3-dimethylpiperidin-1- ylmethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl)methylene] azeticline, (RS)-(4-chlorophenyl) (thiomorpholin-4- ylmethyl)phenyllmethyll-3-[ phenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (thiornorpholin-4- ylmethyl)phenyllmethyl)-3-[ phenyl) (methylsulfonyl) methylene] azetidine, (S)-(4-chlorophenyl) (thiomorpholin-4- ylmthyl)phenyllmethyll-3- phenyl) (methylsulfonyl)methylene] azetidine, (RS)-(4-chlorophenyl) (N-ethyl-N- cyclohexylaminomethyl)phenyllmethyl)-3-[ difluorophenyl) (methylsulfonyl)rnethylene] azetidine, (4-chiorophenyl) (N-ethyl-N- cyclohexylaminomethyl)phenyllmethyl}-3-[ difluorophenyl)(methylsulfonyl)methylene]azetidine, -(4-chiorophenyl) (N-ethyl-N- cyclohexylaminomethyl)phenyllmethyl}-3-[ difluorophenyl) (methylsulfonyl)mrethylene] azetidine, (4-chiorophenyl) (4-ethoxycarbonyl- piperazinyl)methyllphenyl~methyl} difluorophenyl) (methylsulfonyl) methylene] azetidine, -(4-chiorophenyl) [(4-ethoxycarbonyl- piperazinyl)methyllphenyllmethyl} 1-3-f difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (4-ethoxycarbonyl- piperazinyl)methyllphenyl~methyli 1-3-f difluorophenyl) (methylsulfonyl) methylene] azeticline, (RS) -(4-chiorophenyl) (N-cyclopropyl-N- propylaminomethyl)phenyllmethyll-3- difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (N-cyclopropyl-N- propylaminomethyl)phenyllmethyl}-3- difluorophenyl) (methylsulfonyl)metbylene] azetidine, (4-chiorophenyl) (N-cyclopropyl-N- propylaminomethyl) phenyl] methyl 1-3- cifluorophenyl) (methylsulfonyl)methylenelazetidine, (4-chiorophenyl) (diisopropylamino- methyl)phenyllmethyl}-3-[ (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (diisopropylaminomethyl)- phenyllmethyll-3- 5-difluorophenyl) (methyl- sulfonyl)mrethylene] azetidine, (4-chiorophenyl) (diisopropylaminomethyl) phenyllmethyll-3-[ 5-difluorophenyl) (rethylsulfonyl)- methylene] azetidine, (4-chiorophenyl) {4-[bis (2-methoxyethyl)- aminomethyllphenyllmethyl} 1-3- 5-clifluorophenyl) (methyl sulfonyl) methylene] azetidine, {(R)-(4-chlorophenyl) {4-[bis(2-methoxyethyl)- aminomethyllphenyllmethyl) (methylsulfonyl) methylene] azeticline, (S)-(4-chlorophenyl) {4-Ibis(2-methoxyethyl)- aminomethyl] phenyl 1methyl) 1-3- 5-clifluorophenyl) (methylsulfonyl)mrethylene] azetidine, (RS)-(4-chlorophenyl) [4-[di-n- propylaminomethyl)phenyllmethyl}-3-[ phenyl) (methylsulfonyl) methylene] azetidine, (R)-(4-chlorophenyl) (di-n-propylaminomethyl)- phenyllmethyl}-3-[ (3,5-difluorophenyl) (methylsulfonyl)- methylene] azetidine, (4-chiorophenyl) (di-n-propylaminomethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, (RS)-(4-chlorophenyl) [4-(piperidin-1-ylmethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, (4-chiorophenyl) (piperidin-1-ylmethyl) phenyllmethyll-3-[ 5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, (S)-(4-chlorophenyl) (pipericin-1-ylmethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl)methylene] azetidine, 1-f (4-chiorophenyl) [4-(4-methylpiperazin-l- ylmethyl)phenyllmethylj-3-[ (3,5-difluorophenyl) (methylsulfonyl)methylene] azetidine, (R)-(4-chlorophenyl) (4-methylpiperazin-1- ylmethyl)phenyl]methyl}-3-[ (methylsulfonyl) methylene] azetidine, 1-f (S)-(4-chlorophenyl) (4-methylpiperazin-1- ylmethyl)phenyllmethyll-3-[ (methylsulfonyl) methylene] azetidine, (RS)-(4-chlorophenyl) (morpholin-4- ylmethyl)phenyllmethyl)-3-[ (methylsulfonyl) methylene] azetidine, (R)-(4-chlorophenyl) (morpholin-4-ylmethyl)- phenyllmethyl}-3- 5-clifluorophenyl) (methylsulfonyl)mrethylene] azetidine, (S)-(4-chlorophenyl) (morpholin-4-ylmethyl)- phenyllmethyl}-3-[ (methylsulfonyl) methylene] azetidine, (RS)-(4-chlorophenyl) (diethylaminomethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, (4-chiorophenyl) (diethylaminomethyl) phenyllmethyl}-3-[ (3,5-difluorophenyl) (methyl- sulfonyl)methylene] azetidine, (4-chiorophenyl) (diethylaminomethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl)miethylene] azeticline, (RS) -(4-chiorophenyl) (piperazin-2-one-4- ylmethyl)phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, (4-chiorophenyl) (piperazin-2-one-4-ylmethyl)- phenyllrnethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl)methylene] azetidiie, (S)-(4-chlorophenyl) (piperazin-2-one-4-ylmethyl)- phenyllmethyl}-3-[ 5-ciifluorophenyl) (methyl- sulfonyl) methylene] azetidine, (RS)-(4-chlorophenyl) [4-(imidazol-1-ylmethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl)methylene] azetidine, (R)-(4-chlorophenyl) (imidazol-l-ylmethyl)- phenyllmethyll-3-[ 5-difluorophenyl) (methyl- sulfonyl)methylene] azetidine, (4-chiorophenyl) (imidazol-1-ylmethyl)- phenyllmethyl}-3-[ 5-difluorophenyl) (methyl- sulfonyl) methylene] azetidine, (4-chiorophenyl) dimethylcarbamoyl)phenyllmethyl}-3- cifluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) dimethylcarbamoyl) phenyl] methyl difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) dimethylcarbamoyl) phenyllmethyl}-3- difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) ethylcarbamoyl)phenyllmethyl) cifluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) ethylcarbamoyl)phenyllmethyll-3- difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) ethylcarbamoyl)phenyl]methyll-3-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, (RS) (4-carbamayiphenyl) (4-chlorophenyl)rnethyl]-3- 5-clifluorophenyl) (methylsulfonyl)methylene]- azetidine, (4-carbamayiphenyl) (4-chlorophenyl)methyl]-3- 5-difluorophenyl) (methylsulfonyl~methylene]- azetidine, (4-carbamayiphenyl) (4-chlorophenyl)methyl]-3- 5-difluorophenyl) (methylsulfonyl)methylene]- azetidine, 1-[bis (4-chlorophenyl)rnethyl]-3-[ phenyl) (rethylsulfonyl)methylene] azetidine, 1-benzhydryl-3- II(3-methylsulfanyiphenyl) (methyl- sulfonyl) methylenel 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-Ilbis (4-chlorophenyl)rnethyl]-3-[ (3-hydroxyphenyl)- (methylsulfonyl)methylene] azetidine, 1-[bis(4-chlorophenyl)methyl]-3-1 (methylsulfonyl) (3- pyrrolidinyiphenyl) methylene] azetidine, 1-[bis (4-chlorophenyl)methyl]-3-[ (3-hydroxy- methyiphenyl) (methylsulfonyl)methylene] azetidine, 1- [bis (4-chlorophenyl)methyl]-3-{ (methylsulfonyl) (N- piperidylcarbamoyl)phenyllmethylenelazetidine, 1-[bis(4-chlorophenyl)methyl]-3-( (methylsulfonyl) (3- trifluoromethylsulfanylphenyl) (methylsulfonyl) methylene] azetidine, 1-[bis (4-fluorophenyl)methyl]-3-[ (methylsulfonyl)methylene] azetidine, 1-[bis(2-fluorophenyl)methyl-3-[ (methylsulfonyl) methylene] azetidine, 1-[bis(3-fluorophenyl)methyl]-3-[ (methylsulfonyl) methylene] azetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3- [(methylsulfonyl) (phenyl)methylene]azetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3- [(methylsulfonyl) (phenyl)methylene]azetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3- [(methylsulfonyl) (phenyl)methylene]azetidine, (RS)-l-[(4-chlorophenyl) (thien-2-yl)methyl]-3-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (thien-2-yl)methyl]-3-[ difluorophenyl) (methylsulfonyl) methylenel azetidine, (4-chiorophenyl) (thien-2-yl)methyl]-3-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, 1-benzhydryl-3-[ (ethylsulfonyl) (phenyl)methylene]- azetidine, 1-[bis(4-chlorophenyl)methyl]-3-{ (4- rethylpiperazinyl)carbamoyllphenyl} (methylsulfonyl) methylenelIazetidine, 1-[bis(4-chlorophenyl)methyl]-3-{ dirnethylcarbohydrazido) phenyl] (methylsulfonyl) methylene }azetidine, 1-[bis(thien-2-yl)rnethyl]-3-[ (methylsulfonyl) methylene] azetidine, 1- [bis (p-tolyl)methyl] [(methylsulfonyl) (phenyl) methylene] azeticline, 1- [(4-chiorophenyl) (4-hydroxymethylphenyl)methyl] -3- [(3,5-difluorophenyl) (methylsulfonyl)methylene]- azetidine, 1-[bis (4-chlorophenyl)methyl]-3-( (3-methylaminophenyl)- (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3-[ difluorophenyl) (methylsulfonyl)methylenelazetidine, (4-chiorophenyl) (thiazol-2-yl)methyl]-3-[ 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) yl)methyl] azetidine, 1-Ilbis (4-chlorophenyl)methyl]-3-[ (2-isobutylamino- carbonylthien-5-yl) (methylsulfonyl) methylene] azeticline, 1-[bis(4-chlorophenyl)methyl]-3-[ (RS)-(3-methoxy- carbonyiphenyl) (methylsulfonyl)methyl] azetidin-3-ol, 1-[bis(4-chlorophenyl)methyl]-3-[ (RS)-(methyl- sulfonyl) (pyricin-4-yl)methyllazetidin-3-ol, 1-[bis(4-chlorophenyl)methyl]-3-f (RS)- (methylsulfonyl) Cpyridin-3-yl)methyl] azetidin-3-ol, 3- ((1-[bis (4-chiorophenyl) methyl] azetidin-3- ylidene} (methanesulfonyl)methyl) (morpholin-4- yl) propyl) benzamide, 3-({1-Ibis(4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) (3- dimethylaminopropyl) benzamide, 3- [bis (4-chiorophenyl) methyl] azetidin-3- ylidenel (methanesulfonyl)methyl) (pyrroliclin-1- yl)ethyl)benzamide, 3- [bis (4-chiorophenyl) methyl] azetidin-3- ylidene} (methanesulfonyl)methyl) (2-dimethylamino-l- methylethyl) benzamide, 3- ({1-[bis (4-chlorophenyl)methyl]azetidin-3- ylidenej (methanesulfonyl)methyl) (piperidin-1- yl) benzamide, 67 3- ({1-[bis (4-chlorophenyl)methyllazetidin-3- ylidenel (methanesulfonyl)methyl) -N-isobutylbenzamide, 3- ({1-[bis (4-chlorophenyl)methyl~azetidin-3- ylidene} (methanesulfonyl)methyl) (imidazol-1- yl)propyl)benzamide, 3- :1-[bis (4-chiorophenyl) methyl] azetidin-3- ylidene} (methanesulfonyl)methyl) (2- dimethylaminoethyl) benzamide, N'-methylhydrazide of 3- ({l-Ilbis (4-chiorophenyl) rethyllazetidin-3-ylidene} (methanesulfonyl)- methyl) benzoic acid, 3- ({1-Ibis (4-chlorophenyl)methyljazetidin-3- ylidene} (methanesulfonyl)methyl) (morpholin-4- yl) ethyl) benzamiie, 3-({1-ilbis (4-chlorophenyl)methyl]azetilin-3- ylidene} (methanesulfonyl)methyl) (1-ethylpyrrolidin- 2-ylmethyl) benzamide, 3- ({1-Ibis (4-chlorophenyl)methyl]azetidin-3- ylidene} (methanesulfonyl)methyl) (2,2- dimethylpropyl) benzamide, 3- ({1-[bis (4-chlorophenyl)methyl]azetidin-3- ylidenel (methanesulfonyl)methyl) -N- (cyclohexylmethyl) benzamide, 3- ({1-[bis (4-chlorophenyl)methyllazetilin-3- ylidenel (methanesulfonyl)rnethyl) -N- (cyclopropylmethyl) benzamide, 3- [bis (4-chlorophenyl) methyl] azetidin-3- ylidene} (methanesulfonyl)methyl) (2- methylbutyl) benzamile, 3- ({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene} (rethanesulfonyl)methyl) (2- phenylpropyl) benzamide, 3- ((1-[bis (4-chlorophenyl)methyl] azetidin-3- ylidenel (methanesulfonyl)methyl) (tetrahydrofuran-2- ylmethyl)benzamide, 3- [bis (4-chiorophenyl) methyl] azeticlin-3- ylidene} (methanesulfonyl)methyl) (2,2- diphenylethyl) benzamide, 3- [bis (4-chiorophenyl) methyl] azetidin-3- yliciene} (methanesulfonyl)methyl)-N- (2- ethylbutyl) benzamide, methyl ester of 3 -({1-[bis(4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl) benzoylaminolmethyl~cyclohexanecarboxylic acid, 2 -amino-1-{4-[3-({1-[bis(4-chlorophenyl)methyl]- azeticiin-3--ylidene} (methanesulfonyl)methyl)phenyl] piperazin-1-yl lethanone, tert-butyl ester of (4-chiorophenyl)- methyllazetidin-3-ylidene} (methanesulfonyl)methyl)- phenyllpiperazin-1-yl}-2-oxoethyl)carbamic acid, (4-chlorophenyl)methyllazetidin-3- ylidene} (methanesulfonyl)methyl)phenyllpiperazin-l-yl)- 2- (methylamino) ethanone, tert-butyl ester of chlorophenyl)methyl] azetidin-3- ylidene} (methanesulfonyl)methyl)phenyllpiperazin-1-yl}- 2-oxoethyl) -N-methylcarbamic acid, N-methylamide of (4-chiorophenyl)- methyl]azetidin-3-ylidene} (methanesulfonyl)methyl) phenyllpiperazine-1-carbothioic acid, N-methylamide of (4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl)phenyl] piperazine-1-carboxylic acid, methyl ester of 4-[3-({1-[bis(4-chlorophenyl)methyl]- azetidin-3-ylidene} (methanesulfonyl)methyl) phenyllpiperazine-1-carboxylic acid, 1- [bis (4-chlorophenyl) methyl] azetidin-3- ylidene} (methanesulfonyl)methyl)phenyl]-4- isobutylpiperazine, (4-chlorophenyl)methyl]azetidin-3- ylidenel (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- yliclene} (methanesulfonyl)methyl)phenyllpiperazin-1-yll- 2-dimethylaminoethanone, 1- [bis (4-chlorophenyl)methyl] azetidin-3- ylidene} (methanesulfonyl)methyl)phenyllpiperazine, tert-butyl ester of (4-chiorophenyl)- methyl] azeticlin-3-ylidene} (methanesulfonyl)methyl) phenyllpiperazine-1-carboxylic acid, 1- [big (4-methoxycarbonyiphenyl) methyl] difluorophenyl) (methylsulfonyl)methylenelazetidine, 3-acetoxy-l- [bis (4-methoxycarbonylphenyl)methyl] -3- (3,5-difluorophenyl) (methylsulfonyl)methyl]- azeticiine, ((4-chiorophenyl) difluorophenyl) (methanesulfonyl)methylene]azetilin-l- yl Imethyl) benzyl] morpholine, (1-benzhydrylazetidin-3-ylidene) (methane- sulfonyl)methyl]phenoxy~butyl)morpholine, (l-benzhydrylazetidin-3-ylidene) (methane- sultonyl)methyllphenoxylpropyl)morpholine, N-(1-[bis (4-chlorophenyl)methyl]azetidin-3-yllthien- 2-ylsulfonamide, N- [big (4-chiorophenyl) methyl] azetidin-3-yl I- 4 -methoxyphenylsulfonamide, N-[4-(N-{1-[bis(4-chlorophenyl)methyllazetidin-3-yl}- sulfamoyl) phenyl] acetamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- 4 -methyiphenylsulfonamide, [bis (4-chlorophenyl)methyl]azetidin-3-yl}- 3, 4-dimethoxyphenylsulfonamide, N-{l-[bis(4-chlorophenyl)methyllazetidin-3-yl}- 3-f luorophenylsulfonamile, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl1- 3, 4-dichiorophenylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- 3-cyanophenylsulfonamide, N-f1- [bis (4-chiorophenyl) methyl] azetidin-3-yl 1- 2, N-fl- Ibis (4-chlorophenyl)methyl]azetidin-3-yll- 3-trifluoromethylphenylsul fonamide, N-fl- [bis (4-chlorophenyl)methyllazetidin-3-yllnaphth-2- ylsulfonamide, N-f1- [bis (4-chiorophenyl) methyl] azetidin-3-yl Inaphth-l- ylsulfonamide, N-fl-Ibis (4-chloropheriyl)methyllazetidin-3-yl}- 3, 4-difluorophenylsulfonamide, N-fl- Ibis (4-chlorophenyl)methyllazetidin-3-yl}- 1-methyl-lH-imidazol-4-ylsulfonamide, N- (N-fl- [bis (4-chlorophenyl)methyl]azetidin- 3-yllsulfamoyl)-2-chlorophenyl]acetamide, N- Ibis (4-chiorophenyl) methyl] azetidin-3-yl Ipyrid- 3-ylsulfonamide, N-fl- Ibis (4-chlorophenyl)methyllazetidin-3-yl}- 4-fluorophenylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yllquinol- 8-ylsulfonamide, [bis (4-chiorophenyl) methyl] azeticiin- 3-yl }phenylsulfonamile, N-f{ Ibis (4-chiorophenyl) methyl] azeticlin- 3-yll}(phenylmethyl) sulfonamide, N-fl- Ibis (4-chiorophenyl) methyl] azetidin-3-yl 3, N-fl- Ibis (4-chlorophenyl) methyl] azetidin-3-yl Ipyrid- 2-ylsulfonamide, N-fl-[bis (4-chlorophenyl)methyllazetidin-3-ylI- (3-fluoro-5-pyrrolidin-1-ylphenyl) sulfonamide, N-{1-[bis(4-chlorophenyl)methyl]azetilin-3-yl}- N-methyl-4 -fluorophenylsulfonamide, N- [bis (4-chiorophenyl) methyl] azetidin-3-yl)I- N-methylquinol-8-ylsulfonamide, N-{1-[bis(4-chlorophenyl)methyllazetidin-3-yl}- N-methylphenylsulfonamide, N- [bis (4-chiorophenyl) methyl] azetidin-3-yl I- N-methyl (phenylmethyl) sulfonamide, N- [bis (4-chiorophenyl) methyl] azetidin-3-yl I- 3-sulfamoylphenylsulfonamide, 2-benzenesulfonyl-N-{ 1- [bis (4-chlorophenyl)methyl] azetidin-3-yllIacetamide, N-{l-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- 2- (4-toluene-4-sulfonyl) acetamide, (3-chloro-4- (methylsulfonyl) thiophene-2-carboxy) f1- [bis (4-chlorophenyl)methyllazetidin-3-yl]amide, N-ti- (bis (4-chlorophenyl)methyl~azetidin-3-yl}- 3- (2-phenylethylenesulfonyl) propionamide, [bis 14-chlorophenyl)methyllazetidin-3-yl}- 4- (methylsulfonyl)benzamiie, N-fl- [bis (4-chlorophenyl)methyllazetidin-3-yl}- 4- (methanesulfonyl) benzamide, (methylsulfonyl) thiophene-2-carboxy) {1-[bis (4-chlorophenyl)methyllazetidin-3-yl~amide, (5-methylsulfonyl-3-methyl-4-vinylthiophene- 2-carboxy) {1-[bis (4-chlorophenyl)methyl]azetidin- 3-yl~amide, (4-chiorophenyl) (pyridin-3-yl)methyl]- azetidin-3-yl)-3, (RS) (4-chiorophenyl) azetidin-3-yl}-3, N-fl- [bis (4-chlorophenyl)rnethyl]azetidin-3-yl)- N- (6-chloropyrid-2-yl)methylsulfonamide, N-f1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (6-ethylpyrid-2-yl)methylsulfonamide, [bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (quinol-6-yl)methylsulfonamide, N-f{ [bis (4-chiorophenyl) methyl] azetidin-3-yl I- N- N-{1-Ilbis(4-chlorophenyl)methyllazetidin-3-yl}- N- N- [bis (4-chiorophenyl) methyl] azeticiin-3-yl I- N- (pyric-3-yl)methylsulfonamide, N- [bis (4-chiorophenyl) methyl] azetidin-3-yl I- 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-yllmethylsulfonamide, N-(1R,2R,4S)-(bicyclot2.2.1]hept-2-yl)-N-{l-[bis- (4-chlorophenyl)methyl] azetidin-3-yllmethylsulfonamide, N-{1-[bis(4-chlorophenyl)methyllazetidin-3-yl)- N- N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (thiazolL-2-yl) methylsulfonamiie, N-{1-fjbis (4-chlorophenyl)methyllazetidin-3-yl}- N- (3-methoxyphenyl)methylsulfonamide, [big (4-chlorophenyl)methyl]azetidin-3-yl}- N- (3-hydroxyphenyl) methylsulfonamide, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (hydroxymethyl)phenyl)methylsulfonamide, ethyl N-{1-[bis(4-chlorophenyl)methyllazetidin-3-yl}- N- (methylsulfonyl) -3-aminobenzoate, N-il-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (isobutylpipericl-4-yl)methylsulfonamide, N-benzyl-N- [bis (4-chlorophenyl) methyl] azeticlin- 3-yljamine, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- N- 5-difluorobenzyl) amine, N-{1-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- N-{l-[bis (4-chlorophenyl)methyllazetidin-3-yl}- N- (pyrid-3-ylmethyl) methylsulfonamide, N-f{ [bis (4-fluorophenyl) methyl] azetidin-3-yl N- (4-chiorophenyl) (pyrid-3-yl)methyllazetidin- 3-yl}-N- (4-chiorophenyl) (pyrid-3-yl)methyl]azetidin- 3-yl}-N- CS) (4-chiorophenyl) (pyrid-3-yl)methyllazetidin- 3-yl}-N- 3-yll-N- (4-chlorophenyl) (pyrid-4-yl)methyl]azetidin- 3-yl}-N- (4-chiorophenyl) (pyrid-4-yl)methyl]azetidin- (RS) (4-chiorophenyl) azetidin-3-yl}-N- (4-chiorophenyl) azetidin-3-yl}-N- (4-chiorophenyl) azetidin-3-yl}-N- N-{1-[bis(4-chlorophenyl)methyllazetidin-3-yl}-N- difluorophenyl) benzylsulfonamiie, their optical isomers and their pharmaceutically acceptable salts.
9. The pharmaceutical composition as claimed in claim 7, for which the compound of formula is chosen from the following compounds: l-[bis(4-chlorophenyl)methyl]-3-[ difluorophenyl) (methylsulfonyl)methyl] azetidin-3-ol, 3-acetoxy-l-[bis (4-chlorophenyl)methyl]-3-[ difluorophenyl) (methylulphonyl) methyl)methylsulfonyl- methyl] azetidine, 1-[bis(4-chlorophenyl)methyl]-3-[ difluorophenyl) (methylsulfonyl)methylene] azetidine, their optical isomers and their pharmaceutically acceptable salts. C 10. The pharmaceutical composition as claimed in claim 6, in which the CB1 antagonist is SR141716, its hydrates and its pharmaceutically acceptable salts or Cc LY320135 and its pharmaceutically acceptable salts.
11. The pharmaceutical composition as claimed in any one of claims 6 to rc 5 for a use which is simultaneous, separate or spread out over time. C 12. The pharmaceutical composition as claimed in any one of claims 6 to 11, comprising 0.5 to 10 mg of sibutramine and 0.1 to 200 mg of the CB1 antagonist.
13. A method of treating obesity comprising administering to a subject in need of such treatment the combination as claimed in any one of claims 1 to
14. A method of treating obesity comprising administering to a subject in need of such treatment the composition as claimed in any one of claims 6 to 12. A method of reducing food consumption in a subject in need of such treatment comprising administering the combination as claimed in any one of claims 1 to
16. A method of reducing food consumption in a subject in need of such treatment comprising administering the composition as claimed in any one of claims 6 to 12.
17. A combination of a CB1 antagonist and sibutramine, its hydrate or one of its pharmaceutically acceptable salts, substantially as hereinbefore described with reference to the accompanying examples.
18. A composition of a CB1 antagonist and sibutramine, its hydrate or one of its pharmaceutically acceptable salts, substantially has hereinbefore described with reference to the accompanying examples.
19. A method substantially has hereinbefore described with reference to the accompanying examples. The use of a CB1 antagonist and sibutramine, its hydrate or one of its pharmaceutically acceptable salts, for the manufacture of a medicament for the treatment of obesity.
21. The use of a CB1 antagonist and sibutramine, its hydrate or one of its pharmaceutically acceptable salts, for the manufacture of a medicament for reducing food consumption. DATED this 2 n d day of January, 2007 AVENTIS PHARMA S.A. WATERMARK PATENT TRADE MARK ATTORNEYS KJS:RLS
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0012646A FR2814678B1 (en) | 2000-10-04 | 2000-10-04 | COMBINATION OF AN ANTAGONIST OF THE CB1 RECEPTOR AND SIBUTRAMINE, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE FOR THE TREATMENT OF OBESITY |
| FR00/12646 | 2000-10-04 | ||
| PCT/FR2001/003022 WO2002028346A2 (en) | 2000-10-04 | 2001-10-01 | Association of the cb1 receptor antagonist and sibutramin, for treating obesity |
Publications (2)
| Publication Number | Publication Date |
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| AU2001293936A1 AU2001293936A1 (en) | 2002-06-27 |
| AU2001293936B2 true AU2001293936B2 (en) | 2007-01-25 |
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|---|---|---|---|
| AU9393601A Pending AU9393601A (en) | 2000-10-04 | 2001-10-01 | Association of the cb1 receptor antagonist and a sibutramin, pharmaceutical compositions containing same and use thereof for treating obesity |
| AU2001293936A Ceased AU2001293936B2 (en) | 2000-10-04 | 2001-10-01 | Association of the CB1 receptor antagonist and sibutramin, for treating obesity |
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| AU9393601A Pending AU9393601A (en) | 2000-10-04 | 2001-10-01 | Association of the cb1 receptor antagonist and a sibutramin, pharmaceutical compositions containing same and use thereof for treating obesity |
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| EP (1) | EP1328269B2 (en) |
| JP (1) | JP4221221B2 (en) |
| KR (1) | KR20030036885A (en) |
| CN (1) | CN100409845C (en) |
| AT (1) | ATE267595T1 (en) |
| AU (2) | AU9393601A (en) |
| BG (1) | BG107739A (en) |
| BR (1) | BR0114410A (en) |
| CA (1) | CA2424934A1 (en) |
| DE (1) | DE60103556T3 (en) |
| DK (1) | DK1328269T5 (en) |
| EA (1) | EA005924B1 (en) |
| EE (1) | EE200300121A (en) |
| ES (1) | ES2217191T5 (en) |
| FR (1) | FR2814678B1 (en) |
| HR (1) | HRP20030249A2 (en) |
| HU (1) | HUP0302044A3 (en) |
| IL (1) | IL155236A0 (en) |
| MX (1) | MXPA03002845A (en) |
| NO (1) | NO20031521L (en) |
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| PL (1) | PL362833A1 (en) |
| PT (1) | PT1328269E (en) |
| SI (1) | SI1328269T2 (en) |
| SK (1) | SK4032003A3 (en) |
| TR (1) | TR200401264T4 (en) |
| WO (1) | WO2002028346A2 (en) |
| YU (1) | YU26103A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8410107B2 (en) | 2010-10-15 | 2013-04-02 | Hoffmann-La Roche Inc. | N-pyridin-3-yl or N-pyrazin-2-yl carboxamides |
| US8669254B2 (en) | 2010-12-15 | 2014-03-11 | Hoffman-La Roche Inc. | Pyridine, pyridazine, pyrimidine or pyrazine carboxamides as HDL-cholesterol raising agents |
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